GB2128187A - Carbapenem antibiotics - Google Patents

Abstract

Disclosed are novel carbapenem derivatives characterized by a 2-substituent of the formula <IMAGE> in which A represents a C1-C6 straight or branched chain alkylene group; R<5> represents an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl, araliphatic, heteroaryl, heteroaraliphatic, heterocyclyl or heterocyclyl-aliphatic radical and <IMAGE> represents a nitrogen-containing aromatic heterocycle attached to the alkylene group A at a ring carbon atom and quaternized by substituent R<5>. Such derivatives are useful as potent antibacterial agents.

Description

SPECIFICATION Carbapenem antibiotics This application is based upon a continuation-in-part of U.S. Application No.425,755 filed September 28, 1982.

The present invention is directed to new carbapenem antibiotics in which the 2-substituent has the formula

in which A represents a C1-C6 straight or branched chain alkylene group; R5 represents an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl, araliphatic, heteroaryl, heteroaraliphatic, heterocyclyl or heterocyclyl-aliphatic radical; and

represents a nitrogen-containing aromatic heterocycle attached to the alkylene group A at a ring carbon atom and quaternized by substituent R5.

A number of fi-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 ss-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 ss-lactam antibiotics.

Other natural products containing the carbapenem nucleus include olivanic acid derivatives such as antibiotic MM 1 3902 of the formula

disclosed in U.S. Patent 4,113,856, antibiotic MM 17880 of the formula

disclosed in U.S. Patent 4,162,304, antibiotic MM 4550A of the formula

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

disclosed in U.S. Patent 4,264,735. In addition to the natural products, the compound desacetyl 890A,o 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 CO2R1 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 R3O3S wherein R3 is a salting ion or a methyl 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 4,267,177 discloses compounds of the formula

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

wherein R2 and R3 are H or alkyl and R4 is NH-COnR6 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 R' is H or acyl and RB is H or substituted or unsubstituted: alkyl, alkenyl, alkynyl, cycloalkyl, cyloalkylalkyl, 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 heteroaralkyl R8 substituents of the type

in which A is alkylene and

is a quaternized nitrogen-containing aromatic heterocycle attached to the alkylene group A at a ring carbon atom.

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 NR1R2 in which R is substituted or unsubstituted: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl, and R' and R2 are H or R, disclosed in U.S. Patent 4,1 94,047(4) compounds of the formula

wherein R3 is aryl, alkyl, acyl or aralkyl and R1 and R2 are independently selected from H and acyl (including acyl of the type

in which R" 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; R1 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, cycloalkylalkyl, 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, C, 6 alkoxyl, amino, C, 6 alkylamino, di(C1-6 alkyl)-amino or tri(C, 8 alkylamino) radical, an extra anion being present in the latter case; or R' 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 4-10 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, C1-10 alkyl, C2,0 alkenyl, C2,0 alkynyl, C3-10 cycloalkyl, C4,2 cycloalkylalkyl, C5-12 cycloalkylalkenyl, C3,0 cycloalkenyl, C5-12 cycloalkenylalkenyl, C4,2 cycloalkenylalkyl, C6-10 aryl, C7,6 aralkyl, 8-16 aralkenyl, C8,6 aralkynyl or monocyclic or bicyclic heteroaryl, heteroaralkyl, heterocyclyl or heterocyclyalkyl 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 heterocyclyalkyl radical contains from 1 to 6 carbon atoms; the substituent or substituents on R, R', R2 or on the ring formed by joining R' and R2 are chlorine; bromine; iodine; fluorine; azido; C1-4 alkyl; mercapto; sulpho; phosphono; cyanothio (-SCN); nitro; cyano; amino, hydrazino; amino or hydrazino having up to three C, 6 alkyl substituents; hydroxy; C1-6 alkoxy; C1-8 alkylthio; carboxyl; oxo; (C1-6 alkoxy) carbonyl; C2-10 acyloxy; carbamoyl; (C1-4 alkyl) carbamoyl or di(C, 4 alkyl) carbamoyl; R3 is a hydrogen atom, an acyl radical or a radical of the type defined for R4; R4 is a C1-10 alkyl; substituted carbonylmethyl; (C1-6 alkoxy)-(C1-6 6 alkyl), (C3B cycloalkoxy)-(C,6 alkyl); C2,2 alkanoyloxyalkyl; partially or completely halogenated C, 6 alkyl in which the halogen(s) is/are chlorine, bromine or fluorine; aminoalkyl; C2,0 alkenyl; C2,0 alkynyl; acyl; C3 14 alkoxycarbonylalkyl; C42, 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 C16 alkyl; aryl or nuclear-substituted aryl containing 6 to 10 ring carbon atoms and in which any nuclear substituent is hydroxy, C1-6 alkyl, chlorine, fluorine or bromine; aralkoxyalkyl; C2,2 alkylthioalkyl; C4,2 cycloalkylthioalkyl; (C2,0 acylthio) (C,-6 alkyl); or phenylalkenyl in which alkenyl has 2-6 carbon atoms; R5 is substituted or unsubstituted C, ,O alkyl; C2,0 alkenyl or alkynyl; ring substituted and unsubstituted cycloalkyl, cycloalkenyl, cycloalkenylalkyl, and cycloalkylalkyl having 3-6 ring carbon atoms and up to 6 carbon atoms in any chain;C6-10 aryl; aralkyl having 6-10 ring carbon atoms and 1-6 carbon atoms in the alkyl chain; monocyclic or bicyclic heteroaryl or heteroaralkyl containing 4-10 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, C1-6 alkylamino; di(C, 6 alkyl)amino or tri(C, 6 alkylamino) radical, an extra anion being present in the latter case, hydroxy, C1-6 alkoxy, C1-6 alkylthioalkyl; carboxyl; oxo, (C1-6 alkoxy)carbonyl; C2-10 acyloxy; carbamoy; (C1-4 alkyl)-carbamoyl; di(C1-4 alkyl)carbamoyl; cyanothio (-SCN) or nitro; R6 is hydrogen, hydroxy, mercapto, R, -OR, -SR or NR'R2, where R, R' 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, -0-, in which case A- is absent; A, when the compound is not in zwitterionic form, is a counter ion; M is a pharmaceutically acceptable cation; and Q is a blocking group as herein defined, are disclosed in U.K. Patent 1,604,275; and (8) compounds of the formula

wherein

attached to the amino nitrogen group of thienamycin represents a mono- or polycyclic Ncontaining heterocyclic group and R is H, substituted or unsubstituted: alkyl, aryl, alkenyl, heterocyclylalkenyl, aralkenyl, heterocyclyalkyl, aralkyl, -NR2, 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 anion. The above-mentioned quaternary amine derivative is also described in Recent Advances in the Chemistry of ~ss-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.

Carbapenem derivatives having a wide variety of 6-substituents in addition to those mentioned above have also been synthesized. Thus, for example, (1) European Patent Application 40408 discloses compounds of the formula

wherein R, is H, methyl or hydroxyl and R51 is a monovalent organic group including inter alia heterocyclicalkyl; (2) European Patent Application 8514 discloses compounds of the formula

wherein R, is an optionally substituted pyrimidinyl group and R2 is hydrogen or a group CR3R4R5 wherein R3 is hydrogen or hydroxy, R4 is hydrogen or alkyl and RB is hydrogen, alkyl, benzyl or phenyl, or RB and R4 together form a carbocyclic ring; (3) European Patent Application 38869 discloses compounds of the formula

wherein Rs, 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 -NR1R2 amino

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

oximino -SR' alkyl- and arylthio -SO2NR'R2 sulfonamido

ureido

amido -CO2 H carboxy -CO2R' 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 R1 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 C1-6 alkyl group or an optionally substituted benzyl group and R3 is a C1-6 alkyl group or an optionally substituted benzyl or phenyl group and R12 is a C1-6 alkyl, C26 alkenyl, C3 6 alkynyl wherein the triple bond is not present on the carbon adjacent to the sulfur atom, aralkyl, C, 6 alkanoyl, aralkanoyl, aryloxyalkanoyl or arylcarbonyl, any of such R12 groups being optionally substituted, as antibacterial agents.

European Patent Application 441 70 discloses carbapenem derivatives of the formula

wherein R3 is hydrogen or an organic group bonded via a carbon atom to the carbapenem ring, n is O or 1, X is a saturated or unsaturated hydrocarbon radical optionally substituted by bromo or chloro, and R4 is a C1-s alkyl, C2-C6 alkenyl, C,-C,O aralkyl or aryl group, any of such groups R4 being optionally substituted. There is no disclosure, however, of any compounds wherein the tetrazole ring is bonded to X via a quaternized nitrogen atom, i.e. a positively charged nitrogen which is not attached to a hydrogen atom.

European Patent Application 38,869 mentioned above discloses synthesis of the carbapenem derivatives via intermediates of the general formula

wherein R6 and R7 are as defined above and R2, is a readily removable carboxyl protecting group. Also disclosed as intermediates are compounds of the formula

wherein X is described as a leaving group.

At the Gordon Research Conference on Medicinal Chemistry held at New London, New Hampshire on August 2-6, 1982, a handout was distributed in which a variety of carbapenem antibiotics were disclosed. Among the compounds disclosed on page 9 of the handout is the carbapenem of the formula

which differs from the compounds of the present invention in that the quaternized heteroaromatic ring in the 2-substituent is bonded directly to the sulfur atom instead of to the carbon atom of an alkylene group.

European Patent Application 50,334 discloses carapenem derivatives of the general formula

wherein R6 and R7 are, inter alia, independently selected from the group consisting of hydrogen, alkenyl, aryl and aralkyl; A is a direct, single bond connecting the indicated S and C atoms, or A is a cyclic or acyclic connecting group selected, inter alia, from alkyl, cycloalkyl, aryl, heteroaryl or heteroalkyl; R1 and R2, which define the carbamimidoyl function are, inter alia, independently selected from hydrogen, alkyl and aryl; additionally, said carbamimidoyl is characterized by cyclic structures achieved by the joinder of the two nitrogen atoms via their substituents and by their joinder to connecting group A; additionally "carbamimidiums" are disclosed by quaternization of one of the nitrogen atoms of said carbamimidoyl.On page 1 2 of this application, there is disclosed as a possible 2-substituent the group

wherein R' is defined as hydrogen, substituted and unsubstituted: alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl and the two nitrogen atoms "participate in cyclic structures which are indicated by the dotted lines". No specific disclosure is provided of any cyclized carbamimidoyl groups containing a quaternized nitrogen atom, but page 22 does disclose a cyclized carbamimidoyl group of the formula

Based on the indicated definitions of substituent R', applicant does not believe that European Patent Application 50,334 generically discloses any of his compounds.However, since the language in the reference application is so vague as to the nature of the intended cyclic structures, applicant is making this reference of record in the present application.

While, as indicated above, the prior art has described carbapenem derivatives having a 2substituent of the general formula -S-A-Het wherein A represents an alkylene group and Het represents a heterocyclic or heteroaromatic group, there has been no disclosure of which applicants are aware teaching carbapenems wherein Het is a radical of the formula

in which R5 is an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl, araliphatic, heteroaryl, heteroaraliphatic, heterocyclyl or heterocyclylaliphatic radical and

represents a quaternized nitrogen-containing aromatic heterocycle bonded to the alkylene carbon via a ring carbon atom.As mentioned above, the carbapenem having

as the 2-substituent has been reported as well as the carbapenem having a quaternized heteroaromatic ring bonded directly to the sulfur 2-substituent.

Despite the vast number of carbapenem derivatives disclosed in the literature, there is still a need for new carbapenems 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

in which A represents a C1-C6 straight or branched chain alkylene group; R5 represents an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl, araliphatic, heteroaryl, heteroaraliphatic, heterocyclyl or heterocyclylaliphatic radical; and

represents a quaternized nitrogen-containing aromatic heterocycle bonded to the alkylene group A via a ring carbon atom.More specifically, the present invention provides carbapenem derivatives of the formula

wherein RB 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

-NR3R4

SO2NR3R4

-CO2R3 -OP(O) (OR3) (OR4) =0

-SR3

-CN -N3 -OSO3R3

-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 R1 and R8 taken together represent C2-C10 alkylidene ot C2-CtO alkylidene substituted by hydroxy;R5 is selected from the group consisting of 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 above-named R5 radicals are optionally substituted by 1-3 substituents independently selected from: C,-C6 alkyl optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl; fluoro, chloro or bromo; -OR3; -OCO2R3; -OCOR3; -OCONR3R4;

-oxo; -NR3R4; R3CONR4-; -NR3CO2R4; -NR3CONR3R4;

-SR3;

-SO3R3; -CO2 R3; -CONR3R4; -CN; or phenyl optionally substituted by 1-3 fluoro, chloro, bromo, C1-C6 alkyl, -OR3, -NR3R4, -SO3R4, -CO2R3 or -CONR3R4, wherein R3, R4 and R9 in such R5 substituents are as defined above; or R5 may be attached to

at another point on the ring so as to form a fused heterocyclic or heteroaromatic ring, which ring may contain additional, preferably up to 2, hetero atoms selected from 0, N and S; R's is 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; spirocycloalkyl having 3-6 carbon atoms; 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 abovenamed heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and 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 selected from the group consisting of: amino, mono-, di- and trialkylamino, hydroxyl, alkoxyl, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chloro, bromo, fluoro, cyano and carboxy; and wherein the alkyl moieties of the above-recited substituents have 1-6 carbon atoms; A is C,-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 ion; and

represents a substituted or unsubstituted mono-, bi- or polycyclic aromatic heterocyclic radical containing at least one nitrogen in the ring and attached to A through a ring carbon atom and having a ring nitrogen which is quaternized by group R5; 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 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 (3.3.0) hept-2-ene-2-carboxylic acid 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 SR,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 38,869 (see definition of R6). Alternatively, R8 and R' taken together may be C2-C,O alkylidene or C2-C,O alkylidene substituted, for example, by hydroxy.

The compounds of formula I may also be unsubstituted at the 1-position (R'5 = H) or substituted by substituent groups previously disclosed for other carbapenem derivatives. More specifically, R'5 may be hydrogen or any of the non-hydrogen 1-substituents disclosed for example, in Europenan Patent Application 54, 917 (see definition of R' or R2 therein) or in U.S.

Patent 4,350,631. Preferred non-hydrogen R'5 substituents include C,-C6 alkyl, most preferably methyl; phenyl; and phenyl(C,-C6)alkyl. The non-hydrogen R'5 substituent may be in either a-or ss-configuration, and it is intended that the present invention include the individual a- and fi- isomers, as well as mixtures thereof. The most preferred 1-substituted compounds are those having the ss configuration, especially those having the dimethyl substituent.

To elaborate on the definitions for R', R8 and R15: (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 groups; 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 0, 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, imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, etc.

(d) "halo" includes chloro, bromo, fluro and iodo and is preferably chloro, fluoro, 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, allyl, p-nitrobenzyl, 2-naphthylmethyl, benzyl, trichloroethyl, silyl such as trimethylsilyl, phenacyl, p-methoxybenzyl, acetonyl, o-nitrobenzyl, 4-pyridylmethyl and C1-C6 alkyl such as methyl, ethyl or t-butyl.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 addition salts may be written as

R2 = H or protecting group where X3 represents the acid anion. The counter anion X- may be selected so as to provide pharmaceutically acceptable salts for therapeutic administration but, in the case of intermediate compounds of formula I, X3 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 or R5 group or on the

radical, 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-ss-phenethylamine, N, N'-diben- zylethylenediamine, 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 R6 is hydrogen and R1 is hydrogen, CH3CH2

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

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

Another preferred embodiment comprises compounds of formula I in which R' and RB 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 1 to 6 carbon atoms. A preferred embodiment comprises those compounds in which A is -(CH2)-n in which n is 1 or 2 and a particularly preferred embodiment comprises those compounds where A is -CH2-.

The alkylene moiety "A" is attached via a ring carbon atom to an N-substituted quarternized aromatic heterocycle of the general formula

wherein the R5 substituent is preferably an optionally substituted C1-C6 alkyl, C2-C,O alkenyl, C2-C,O alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C,-C6 alkyl, phenyl, phenyl-C,-C6 alkyl, phenyl-C2-C6 alkenyl, phenyl-C2-C6 alkynyl, heteroaryl, heteroaralkyl in which the alkyl moiety has 1-6 carbon atoms, heterocyclyl or heterocyclylalkyl in which the alkyl moiety has 1-6 carbon atoms.The heteroaryl (or heteroaryl portion of heteroaralkyl) R5 substituent may be a mono-, bi- or polycyclic aromatic heterocyclic group containing 1-4 0, 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 and pyrazolyl. The heterocyclyl (or heterocyclyl portion of heterocyclylalkyl) R5 substituent may be a mono-, bi or polycyclic saturated or unsaturated non-aromatic heterocyclic group 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 and pyrrolidinyl.

The R5 substituent may be optionally substituted by 1-3 substituents independently selected from: (a) C-C6 alkyl optionally substituted by, preferably 1-3, amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl groups; (b) fluoro, chloro or bromo; (c) -OR3 (d) -OCO2R3; (e) -OCOR3; (f) -OCONR3R4;

(h) -oxo; (i) -NR3R4; (j) R3CONR4-; (k) -NR3CO2R4; (I) -NR3CONR3R4;

(n) -SR3; (o) -SOR9;

(q) -SO3R3; (r) -CO2R3; (s) -CONR3R4; (t) -CN; or (u) phenyl optionally substituted by 1-3 substituents independently selected from fluoro, chloro, bromo, Ct-C6 alkyl, -OR3, -NR3R4, -SO3R3, or -CONR3R4, wherein, relative to the above-named R5 substituents, the groups R3 and R4 are independently selected from hydrogen; alkyl, alkenyl and alkynyl, having 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 heteroaryl and heterocyclyl group or portion of a group is as defined above for R5 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 (as defined above for R5) ring; and R9 is as defined above for R3 except that it may not be hydrogen. A most preferred R5 substituent is C1-C6 alkyl, especially methyl.

In addition, the R5 substituent, together with another ring atom of the

moiety, may form a fused heterocyclic or heteroaromatic ring, which ring may contain additional, preferably 1 or 2, hetero atoms selected from 0, N and S. For example.

may be

The group

preferably represents a substituted or unsubstituted mono-, bi- or polycyclic aromatic heterocycle containing at least one nitrogen in the ring and 0-5 additional ring hetero atoms selected from 0, S and N, said heterocyclic ring being attached to A through a ring carbon atom and having a ring nitrogen atom quaternized by the group R5.

The heteroaromatic

ring may be optionally substituted at available ring carbon atoms by preferably 1-5, most preferably 1-3, substituents independently selected from the group consisting of Ct-C4 alkyl; C,-C4 alkyl substituted by, preferably 1-3, hydroxy, amino, C,-C4 alkylamino, di(C1-C4)alkylamino, C,-C4 alkoxy, carboxy, halo (hereinafter intended to mean chloro, bromo, fluoro or iodo; preferably chloro, bromo or fluoro) or sulfo; C3-C6 cycloalkyl; C3-C6 cycloalkyl(C,-C4)alkyl optionally substituted by 1-3 substituents mentioned above in connection with C,-C4 alkyl; C,-C4 alkoxy; C,-C4 alkylthio; amino; C,-C4 alkylamino; di(C,-C4)alkylamino; halo;C,-C4 alkanoylamino; C1-C4 alkanoyloxy; carboxy; sulfo;

alkyl; hydroxy; amidino; guanidino: phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halo, hydroxy, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, di(C1-C4)alkylamino, carboxy and sulfo; phenyl(C,-C4)- alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with Cr-C4 alkyl; and heteroaryl or heteroaralkyl in which the hetero atom or atoms are selected from the group consisting of 1-4 0, S or N atoms and the alkyl moiety associated with heteroaralkyl has 1-6 carbon atoms, said heteroaryl and heteroaralkyl groups being optionally substituted in the heterocyclic ring moiety by 1-3 substituents independently selected from hydroxy, amino, halo, trifluoromethyl, C,-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, di(C1-C4)alkylamino, carboxy and sulfo and in the alkyl moiety by 1-3 substituents selected from hydroxy, amino, C1-C4 alkylamino, di(C1-C4)alkylamino, C1-C4 alkoxy, carboxy, halo and sulfo.In addition, available ring nitrogen atoms (other than the quaternized nitrogen) may be substituted by 1-3 substituents independently selected from the group consisting of C1-C4 alkyl; C1-C4 alkyl substituted by, preferably 1-3, hydroxy, amino, C1-C4 alkylamino, di(C1-C4)alkylamino, C1-C4 alkoxy, carboxy, halo or sulfo groups; C3-C6 cycloalkyl:C3-C6 cycloalkyl(C 1-C4)alkyl optionally substitued by 1-3 substituents mentioned above in connection with C,-C4 alkyl; phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halo, hydroxy, trifluoromethyl, Cr-C4 alkyl, C-C4 alkoxy, C,-C4 alkylamino, di(C1 -C4)alkylamino, carboxy and sulfo; phenyl (C,-C4)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C1-C4 alkyl; and heteroaryl or heteroaralkyl in which the hetero atom or atoms are selected from the group consisting of 1-4 O, S or N atoms and the alkyl moiety associated with heteroaralkyl has 1-6 carbon atoms, said heteroaryi and heteroaralkyl groups being optionally substituted in the heterocyclic ring moiety by 1-3 substituents independently selected from hydroxy, amino, halo, trifluoromethyl, C,-C4 alkyl, C,-C4 alkoxy, C,-C4 alkylamino, di(C1-C4)alkylamino, carboxy and sulfo and in the alkyl moiety by 1-3 substituents selected from hydroxy, amino, C,-C4 alkylamino, di(C,-C4) alkylamino, C1-C4 alkoxy, carboxy, halo and sulfo. The most preferred ring carbon and nitrogen substituents are C,-C4 alkyl, especially methyl.

Within the above-described preferred embodiment, the preferred compounds are those in which A is -(CH2)-n in which n is 1 or 2, most preferably those in which A is -CH2- and wherein (a) R1 and R8 taken together represent

or (b) R8 is hydrogen and R1 represents hydrogen, CH3CH2-,

Particularly preferred are the compounds wherein R8 is hydrogen and R1 is

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

In a preferred embodiment the group

represents an aromatic 5- or 6- membered, N-containing heterocyclic ring containing 0-3 additional hetero atoms selected from 0, S or N. Such aromatic heterocycle may, where possible, be fused to another ring which may be a saturated or unsaturated carbocyclic ring, preferably a C4-C7 carbocyclic ring, an aromatic carbocyclic ring preferably a phenyl ring, a 4-7 membered heterocyclic ring (saturated or unsaturated) containing 1-3 hetero atoms selected from 0, S, N or NR1' in which R1' is hydrogen, C1-C6 alkyl optionally substituted by 1-2 substituents independently selected from -OR3, -NR3R4, -C02R3, oxo, phenyl, fluoro, chloro, bromo, -SO3R3 and -CONR3R4, or phenyl optionally substituted by 1-3 substituents independently selected from C1-C6 alkyl, -OR3, -NR3R4, fluoro, chloro, bromo, -SO3R3, -CO2R3 and -CONR3R4, wherein R3 and R4 in such R11 substituents are as defined above in connection with substituent R1, or a 5-6 membered hetero-aromatic ring containing 1-3 hetero atoms selected from 0, S, N or R11 is as defined above. The 5- or 6- membered aromatic quaternized ring or, where appropriate, the carbocyclic, heterocyclic or heteroaromatic ring fused thereto, or both such rings, may be optionally substituted on available ring atoms by, preferably up to a total of five substituents for the total ring system, the substituents mentioned above in connection with the group

Within the above-described preferred embodiment, the preferred compounds are those in which A -(CH22)n- in which n is 1 or 2, most preferably those in which A is -CH2- and wherein (a) R1 and RB taken together represent

or (b) R8 is hydrogen and R1 represents hydrogen, CH3CH2-,

Particularly preferred are the compounds wherein R8 is hydrogen and R1 is

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

Still another preferred embodiment of the present invention comprises compounds of formula I wherein

represents a radical selected from the group consisting of

wherein R6, R7 and R'O are independently selected from hydrogen; C1-C4 alkyl; C1-C4 alkyl substituted by, preferably 1-3, hydroxy, C1 -C4 alkylamino di(C1-C4 alkyl)amino, C1-C4 alkoxy, amino, sulfo, carboxy or halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo); C3-C6 cycloalkyl; C1-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);C1-C4 alkanoylamino; C1 -C4 alkanoyloxy; carboxy;

alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted by one, two or three amino, halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo), hydroxyl, trifluoromethyl, C1-C4 alkyl or C,-C4 alkoxy groups; phenyl (C1-C4)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C1-C4 alkyl; and heteroaryl and heteroaralkyl in which 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 moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms; or wherein two of R6, R7 or R10 taken together may be a fused saturated carboxyclic ring, a fused aromatic carbocyclic ring, a fused non-aromatic heterocyclic ring or a fused heteroaromatic ring, said fused rings being optionally substituted by 1 or 2 of the substituents defined above for R6, R7 and R10;

optionally substituted on a carbon atom by one to three substituents independently selected from C1 -C4 alkyl; C1 -C4 alkyl substituted by, preferably 1-3, hydroxy, C1-C4 alkylamino, sulfo, di(C1-C4 alkyl)amino, C1-C4 alkoxy, amino, carboxy or halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo); C3-C6 cycloalkyl; C,-C4 alkoxy;C,-C4 alkylthio; amino; C,-C4 alkylamino; di(C,-C4 alkyl)amino; halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo); C,-C4 alkanoylamino; C,-C4 alkanoyloxy; carboxy;

alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted by one, two or three amino, halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo), hydroxyl, trifluoromethyl, C1-C4 alkyl or C1-C4 alkoxy groups; phenyl (C1-C4)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C1-C4 alkyl; and heteroaryl or heteroaralkyl in which hetero atom or atoms in the abovenamed heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms, or optionally substituted so as to form a fused carbocyclic, heterocyclic or heteroaromatic ring optionally substituted by 1 or 2 of the substituents defined above;

optionally substituted on a carbon atom by one or two substituents independently selected from C1 -C4 alkyl; C1-C4 alkyl substituted by, preferably 1-3, hydroxy, C1-C4 alkylamino, sulfo, di(C1-C4 alkyl) amino, C1 -C4 alkoxy, amino, carboxy or halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo); C3-C6 cycloalkyl; C1-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); C1-C4 alkanoylamino; C1 -C4 alkanoyloxy; carboxy;

alkyl; hydroxy; amidino; guanidino, phenyl; phenyl substituted by one, two or three amino, halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo), hydroxyl, trifluoromethyl, C1-C4 alkyl or C1 -C4 alkoxy groups; phenyl (C,-C4)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C,-C4 alkyl; and heteroaryl or heteroaralkyl in which 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 moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms, or optionally substituted so as to form a fused carbocyclic, heterocyclic or heteroaromatic ring optionally substituted by 1 or 2 of the substituents defined above;

optionally substituted on a carbon atom by a substituent independently selected from C,-C4 alkyl; C1 -C4 alkyl substituted by, preferably 1-3, hydroxy, C,-C4 alkylamino, di(C,-C4 alkyl)amino, sulfo, C,-C4 alkoxy, amino, carboxy or halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo); C3-C6 cycloalkyl; C,-C4 alkoxy; C,-C4 alkylthio; amino;C,-C4 alkylamino; di(C,-C4 alkyl)amino; halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo); C,-C4 alkanoylamino; C,-C4 alkanoyloxy; carboxy;

alkyl; hydroxy; amidino; guanidino, phenyl; phenyl substituted by one, two or three amino, halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo), hydroxyl, trifluoromethyl, C,-C4 alkyl or C,-C4 alkoxy groups; phenyl (C,-C4)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C,-C4 alkyl; and heteroaryl or heteroaralkyl in which the hetero atom or atoms in the above-named heterocyciic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms;

wherein Xis 0, S or NR in which R is C,-C4 alkyl; C,-C4 alkyl substituted by 1-3 hydroxy, amino, C,-C4 alkylamino, di(C1-C4)-alkylamino, C,-C4 alkoxy, carboxy, halo or sulfo groups; C3-C6 cycloalkyl;C3-C6 cycloalkyl(C,-C4)alkyl optionally substituted by 1-3 substituents mentioned above in connection with C,-C4 alkyl; phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halo, hydroxy, trifluoromethyl, C,-C4 alkyl, C,-C4 alkoxy, C,-C4 alkylamino, di(C1-C4)alkylamino, carboxy and sulfo; phenyl(C,-C4)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C,-C4 alkyl; and heteroaryl and heteroaralkyl in which the hetero atom or atoms are selected from the group consisting of 1-4 0, S or N atoms and the alkyl moiety associated with heteroaralkyl has 1-6 carbon atoms, said heteroaryl and heteraral kyl groups being optionally substituted in the heterocyclic ring moiety by 1-3 substituents independently selected from hydroxy, amino, halo, trifluoromethyl, C,-C4 alkyl, C,-C4 alkoxy, C,-C4 alkylamino, di(C1-C4)alkylamino, carboxy and sulfo and in the alkyl moiety by 1-3 substituents selected from hydroxy, amino, C,-C4 alkylamino, di(C1-C4)alkylamino, C,-C4 alkoxy, carboxy, halo and sulfo; said heteroaromatic radical being optionally substituted on a carbon atom by one or more substituents independently selected from C,-C4 alkyl; C,-C4 alkyl substituted by, preferably 1-3, hydroxy, amino, C,-C4 alkylamino, di(C,-C4 alkyl)amino, Cf-C4 alkoxy, sulfo, carboxy or halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo); C3-C6 cycloalkyl; C,-C4 alkoxy;C,-C4 alkylthio; amino; C,-C4 alkylamino; di(C,-C4 alkyl)amino; halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo); C,-C4 alkanoylamino; C,-C4 alkanoyloxy; carboxy;

alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted by one, two or three amino; halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo), hydroxyl, trifluoromethyl, C,-C4 alkyl or C,-C4 alkoxy groups; phenyl (C,-C4)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C,-C4 alkyl; and heteroaryl or heteroaralkyl in which 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 moiety associated with said hetero-aralkyl moiety has 1-6 carbon atoms, or optionally substituted so as to form a fused carbocyclic, heterocyclic or heteroaromatic ring optionally substituted by 1 or 2 of the substituents defined above;

wherein Xis 0, S or NR in which R is C,-C4 alkyl; C1-C4 alkyl substituted by 1-3 hydroxy, amino, C,-C4 alkylamino, di(C1-C4)-alkylamino, C,-C4 alkoxy, carboxy, halo or sulfo groups; C3-C6 cycloalkyl;C3-C6 cycloalkyl(C,-C4)alkyl optionally substituted by 1-3 substituents mentioned above in connection with Cr-C4 alkyl; phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halo, hydroxy, trifluoromethyl, C1-C4 alkyl, C,-C4 alkoxy, C1 -C4 alkylamino, di(C1-C4)alkylamino, carboxy and sulfo; phenyl(C,-C4)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C1 -C4 alkyl; and heteroaryl and heteroaralkyl in which the hetero atom or atoms are selected from the group consisting of 1-4 0, S or N atoms and the alkyl moiety associated with heteroaralkyl has 1-6 carbon atoms, said heteroaryl and heteroaralkyl groups being optionally substituted in the heterocyclic ring moiety by 1-3 substituents independently selected from hydroxy, amino, halo, trifluoromethyl, C1 -C4 alkyl, C1 -C4 alkoxy, C1 -C4 alkylamino, di(C1-C4)alkylamino, carboxy and sulfo and in the alkyl moiety by 1-3 substituents selected from hydroxy, amino, C1-C4 alkylamino, di(C1-C4)alkylamino, C1-C4 alkoxy, carboxy, halo and sulfo; said heteroaromatic radical being optionally substituted on a carbon atom by a substituent selected from C1 -C4 alkyl; C,-C4alkyl substituted by, preferably 1-3, hydroxy, amino, C,-C4 alkylamino, di(C1-C4 alkyl)amino, C1-C4 alkoxy, sulfo, carboxy or halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo); C3-C6 cycloalkyl; C1 -C4 alkoxy; C1 -C4 alkylthio; amino; C1 -C4 alkylamino; d-(C1-C4 alkyl)amino; halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo); C1 -C4 alkanoylamino;C,-C4 alkanoyloxy; carboxy;

alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted by one, two or three amino, halo (chloro, brom, fluoro or iodo; preferably chloro, fluoro or bromo), hydroxyl, trifluoromethyl, C1-C4 alkyl or C1-C4 alkoxy groups; phenyl (C,-C4)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C,-C4 alkyl; and heteroaryl or heteroaralkyl in which 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 moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms; and

wherein R is C,-C4 alkyl;C,-C4 alkyl substituted by 1-3 hydroxy, amino, C1 -C4 alkylamino, di(C1-C4)alkylamino, C,-C4 alkoxy, carboxy, halo or sulfo groups; C3-C6 cycloalkyl; C3-C6 cycloalkyl(C,-C4)alkyl optionally substituted by 1-3 substituents mentioned above in connection with C,-C4 alkyl; phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halo, hydroxy, trifluoromethyl, C,-C4 alkyl, C,-C4 alkoxy, C,-C4 alkylamino, di(C,-C4)alkylamino, carboxy and sulfo; phenyl (C,-C4)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C,-C4 alkyl; and heteroaryl and heteroaralkyl in which the hetero atom or atoms are selected from the group consisting of 1-4 0, S or N atoms and the alkyl moiety associated with heteroaralkyl has 1-6 carbon atoms, said heteroaryl and heteroaralkyl groups being optionally substituted in the heterocyclic ring moiety by 1-3 substituents independently selected from hydroxy, amino, halo, trifluromethyl, C,-C4 alkyl, C,-C4 alkoxy, C,-C4 alkylamino, di(C,-C4)alkyamino, carboxy and sulfo and in the alkyl moiety by 1-3 substituents selected from hydroxy, amino, C,-C4 alkylamino, di(C,-C4)alkylamino C1-C4 alkoxy, carboxy, halo and sulfo. The R and R5 groups may also be taken together to form a fused heterocyclic or heteroaromatic ring.

Within the above-described preferred embodiment, the preferred compounds are those in which A is -(CH2)n- in which n is 1 or 2, most preferably those in which A is -CH2- and wherein (a) R' and R8 taken together represent

or (b) R8 is hydrogen and R' represents hydrogen, CH3CH2-,

Particularly preferred are the compounds wherein R8 is hydrogen and R' is

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

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

represents a radical of the formula

wherein R6, R7 and R10 are independently selected from the group consisting of hydrogen, C,-C4 alkyl, C,-C4 alkoxy, carboxyl and carbamoyl and R5 is as defined above, and is preferably C1 -C4 alkyl, most preferably -CH3.

Within the above-described preferred embodiment, the preferred compounds are those in which A is -(CH2)n- in which n is 1 or 2, most preferably those in which A is -CH2- and wherein (a) R1 and R8 taken together represent

or (b) R8 is hydrogen and R1 represents hydrogen, CH3CH2-,

Particularly preferred are the compounds wherein R8 is hydrogen and R1 is

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

Another preferred embodiment comprises compounds of formula I wherein

represents a radical of the formula

wherein R5 is C1 -C4 alkyl, most preferably methyl, and R6 represents hydrogen or C1-C4 alkyl;

wherein R5 is C1-C4 alkyl, most preferably methyl and R5 and R7 are hydrogen or C,-C4 alkyl;

wherein R5 is C1 -C4 alkyl, most preferably methyl and R is C,-C4 alkyl or phenyl (C,-C4)alkyl;

wherein R5 is C1-C4 alkyl, most preferably methyl and R6 is C1-C4 alkyl, most preferably methyl;;

wherein R5 is C1-C4 alkyl, most preferably methyl and R is C,-C4 alkyl, most preferably methyl; or

wherein R5 is C1-C4 alkyl, most preferably methyl.

Within the above-described embodiment, the preferred compounds are those in which A is -(CH2)n- in which n is 1 or 2, most preferably those in which A is -CH2- and wherein (a) R1 and R6 taken together represent

or (b) R8 is hydrogen and R1 represents hydrogen, CH3CH2-,

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

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

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

represents a radical of the formula

Within this above-described embodiment, the preferred compounds are those in which A is -(CH2)n- in which n is 1 or 2, most preferably those in which A is -(CH2)- and wherein (a) R' and R8 taken together represent

or (b) R8 is hydrogen and R1 represents hydrogen, CH3CH2-,

Particularly preferred are the compounds wherein R8 is hydrogen and R1 is

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

Specific preferred compounds of the present invention are those 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 ion and wherein

is

wherein the 'HNMR(D20) spctrum shows characteristic peaks at d; 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);

wherein the 'HNMR(D20) spectrum shows characteristic peaks at 8: 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);

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

represents

Within the above-described embodiment, the preferred compounds are those in which A is -(CH2)n- in which n is 1 or 2, most preferably those in which A is -CH2- and wherein (a) R1 and R6 taken together represent

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

Particularly preferred are the compounds wherein R8 is hydrogen and R1 is

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

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

wherein R', R6 and R15 are defined above and wherein R2' represents a conventional readily removable carboxyl protecting group. Compounds of formula Ill have been disclosed, for example, in European Patent Application 38,869 (compound 7) and in European Patent Application 54,917, and may be prepared by the general methods described therein.

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

L= conventional leaving group IV

A variation of the above-described process is shown in the following reaction scheme:

To elaborate on the above process, starting material Ill is reacted in an inert organic solvent such as methylene chloride, acetonitrile or dimethylformamide with about an equi-molar amount of an agent R"-L such as p-toluenesulfonic acid anhydride, p-nitrobenzene sulfonic acid anhydride, 2,4,6-triisopropylbenzenesulfonic acid anhydride, methanesulfonic acid anhydride, trifluoromethanesulfonic acid anhydride, diphenyl chlorophosphate, toluenesulfonyl chloride, pbromobenzenesulfonyl chloride, or the like, whrein L is the corresponding leaving group such as toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, diphenoxyphosphinyloxy, and other leaving groups which are established by conventional procedures and are well-known in the art. The reaction to establish the leaving group at the 2-position of intermediate Ill is advantageously carried out in the presence of a base such as diisopropylethylamine, triethylamine, 4dimethylaminopyridine, or the like, at a temperature of from about - 20" to + 40"C, most preferably at about O"C. The leaving group L of intermediate IV may also be halogen in which case such group is established by reacting intermediate Ill with a halogenating agent such as +3PCI2, +3PBr2, (00)3PBr2, oxalylchloride or the like in a solvent such as CH2Cl2, CH3CN, THF, or the like, in the presence of a base such as diisopropylethylamine, triethylamine, 4-dimethylaminopyridine, or the like. 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 II by a conventional displacement reaction.

Thus, intermediate IV may be reacted with approximately an equimolar amount of a heteroaralkyl mercaptan reagent of the formula

wherein A represents C1 -C4 straight or branched chain alkylene and

represents a mono-, bi-or polycyclic aromatic heterocyclic radical containing a quaternizable nitrogen in the ring, said ring being attached to A through a ring carbon atom, 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 is not critical, but an advantageous temperature range is from about - 40"C to 25"C. Most conveniently, the reaction is carried out with cooling, e.g. at about O"C to - 10"C.

Quaternization of the ring nitrogen in the heteroaralkyl group of intermediate II is carried out by reacting intermediate II in an inert organic solvent with at least an equivalent (up to about a 50 molar excess) of an alkylating agent of the formula R5-X' wherein R5 is as defined above and X' is a conventional leaving group such as halo (chloro, bromo or iodo most preferably iodo) or a sulfonate ester moiety such as a mesylate, tosylate or triflate. Examples of suitable non-reactive organic solvents are chloroform, methylene chloride, tetrahydrofuran, dioxane, acetone, dimethylsulfoxide and dimethylformamide. The temperature for the alkylation reaction is not critical and temperatures in the range of from about 0'C to 40"C are preferred. Most conveniently, the reaction step is carried out at room temperature.

Intermediate I' will have a counter ion X' (e.g. derived from the alkylating agent used) associated with it which at this stage or at a later stage, i.e. following the de-blocking step, may be substituted by a different counter ion, e.g. one which is more 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 d ioxane-water-ethanol, 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 50"C 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. The allyl protecting group may be removed with a catalyst comprising a mixture of a palladium compound and triphenylphosphine in a mixture of a palladium compound and triphenylphosphine in an aprotic solvent such as tetrahydrofuran, diethyl ether or methylene chloride.

Similarly, other conventional caboxyl 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 hydrolized in vivo under physiological conditions.

It will understood that where the R1, R8, R5 or R15 substituent or the heteroaromatic ring 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 de-blocked to regenerate the deisred functional group. Suitable blocking groups and procedures for introducing and removing such groups are well known to those skilled in the art.

In a variant of the above process, the carboxyl protecting group of intermediate II may be removed prior to the quaternization step. Thus, the carboxyl protecting group is removed as described above to give the corresponding free carboxylic acid and the free acid is then quaternized with alkylating agent R5-X' to give the desired quaternized product of formula I.

When the de-protected intermediate Ia is quaternized, the solvent may be water or a nonreactive organic solvent, or mixtures thereof. Examples of suitable solvents include water, organic solvents such as chloroform, methylene chloride, tetrahydrofuran, dioxane, acetone, dimethylsulfoxide and dimethylformamide and water-organic solvent mixtures such as wateracteone or water-dimethylformamide. The temperature for the quaterinization of intermediate Ia is not critical and temperatures in the range of from about - 40"C to about room temperature may be conveniently employed. Most advantageously, the reaction is carried out at about 0 C.

When deprotected intermediate Ila is obtained as a carboxylate salt, it is desirable to add a strong acid such as toluenesulfonic acid to generate the free carboxylic acid prior to quaternization. This is found to greatly facilitate the preferential quaternization of the ring nitrogen.

The above-described variant procedure is especially useful when the carboxyl protecting group is more easily removed from the unquarternized intermediate II than from quaternized intermediate 1'. For example, in preparing the product of the formula

from the intermediate of the formula

removal of the allyl protecting group prior to quaternization results in substantially improved yields of the desired end-product.

While the above-described process is suitable for preparing the compounds of the present invention, my colleague Pierre Dextraze has invented a new process which can be used to prepare compounds of formula I. This alternative process, which is disclosed and claimed in a co-pending U.S. patent application filed even data with the present continuation-in-part application, is described below and in the Examples which follow.

In the alternative process for preparation of compounds of formula I, an intermediate of the formula

wherein R1, RB and R15 are as defined above, R2' is a conventional readily removable carboxyl protecting group and L is a conventional leaving group such as toluenesulfonyloxy, p nitrobenzenesulfonyloxy, diphenoxyphosphinyloxy or halo is reacted with a thiol compound of the formula

wherein A and

are as defined above and XE is a counter anion in an inert solvent and in the presence of base to produce a carbapenem product of the formula

wherein R', RB, R2', A, R15,

and Xe are as defined above and, if desired, the carboxyl protecting group R2' is removed to give the corresponding de-blocked compound of formula I, or a pharmaceutically acceptable salt thereof.

The alternative process utilizes the intermediate of the formula

which, as mentioned before, has been disclosed, for example, in European Patent Applications 38,869 and 54,917 and which may be prepared by the general methods described therein. L represents a conventional leaving group (defined as "X" in European Patent Application 38,869) such as chloro, bromo, iodo, benzenesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, diphenoxyphosphinyloxy or di(trichloroethoxy)phosphinyloxy. The preferred leaving group is diphenoxyphosphinyloxy.

Intermediates of formula IV are generally formed in situ by reacting an intermediate of the formula

wherein R', R8, R15 and R2' are as defined above with a suitable acylating agent RO-L. The preferred intermediate IV where L is diphenoxyphosphinyloxy may be prepared by reacting keto ester Ill in an 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, 4-dimethylaminopyridine or the like at a temperature of from about - 20"C to + 40"C, most preferably at about 0 C. Intermediate IV may be isolated, if desired, but is conveniently used as the starting material for the alternative process without isolation or purification.

Carbapenem intermediate IV is reacted with a quaternary amine thiol compound of the formula

wherein

is as defined above and Xo is a counter anion. The reaction is carried out in an inert solvent such as aceton itrile, acetonitrile-dimethylformamide, tetrahydrofuran, tetrahydrofuran-H20, acetonitrile-H20 or acetone in the presence of base. The nature of the base is not critical. Suitable bases include sodium hydroxide, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1, S-diazabicyclo(4. 3.0]non-5-ene and tri(C1-C4)alkylamines such as triethylamine, tributylamine or tripropylamine.Reaction of intermediate IV and thiol VII may be carried out over a wide temperature range, e.g. - 1 5'C up to room temperature, but is preferably done at a temperature in the range of from about - 1 5'C to + 15"C, most preferably at around O"C.

The carbapenem product produced by reaction of the quaternary amine thiol VII with intermediate IV will have a counter anion associated with it (e.g. (C6H50)2PO28, CP- or the anion associated with the quaternary thiol] which may at this stage be substituted by a different counter anion, e.g. one which is more pharmaceutically acceptable, by conventional procedures.

Alternatively, the counter anion may be removed during the subsequent de-blocking step.

Where the quaternized carbapenem compound and counter anion form an insoluble product, the product may crystallize out as it is formed and be collected pure by filftration.

Following formation of the desired carbapenem product, the carboxyl protecting group R2' of Compound I' may be optionally removed 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 d ioxane-water-ethanol, tetrahydrofuran-diethyletherbuffer, 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 50"C 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. The allyl protecting group may be removed by using a catalyst comprising a mixture of a palladium compound and triphenyl phosphine in a suitable aprotic solvent such as tetrahydrofuran, methylene chloride or diethyl ether. 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.

The thiol intermediates of Formula VII may be prepared, for example, from the corresponding thiolacetate compound of the formula

wherein A is as defined above and

represents a mono-, bi- or polycyclic aromatic heterocyclic radical containing a quaternizable nitrogen in the ring, said ring being attached to A through a ring carbon atom. The thiol-acetate compound is quaternized by reacting it in an inert organic solvent such as diethyl ether, dichloromethane, methylene chloride, dioxane, benzene, xylene, toluene or mixtures thereof with a suitable alkylating agent of the formula R5-X' wherein R5 is as defined above and X' is a conventional leaving group such as halo (chloro, bromo or iodo, most preferably iodo) or a sulfonate ester moiety such as mesylate, tosylate or triflate.The temperature for the alkylation reaction is not critical, and temperatures in the range of from about 0'C to 40"C are preferred.

Prior to reaction with carbapenem intermediate IV, the quaternized thiolacetate compound is subjected to acidic or basic hydrolysis to generate quaternary thiol intermediate VII. This hydrloysis is preferably done immediately prior to coupling with IV so as to minimize decomposition of the relatively unstable quaternary thiol VII.

By proper selection of the solvents, the reaction from intermediate Ill to end product I may be carried out without isolation of the various intermediates, i.e. in a "one-pot" process. An example of such a process is illustrated below in Example 22.

As in the case of other sslactam 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 recoved 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.

It will be appreciated that certain products within the scope of formula I may be formed as optical isomers as well as epimeric mixtures thereof. It is intended that the present invention include within its scope all such optical isomers and epimeric mixtures. For example, when the 6-substituent is hydroxyethyl, such substituent may be in either the R or S configuration and the resulting isomers as well as epimeric mixtures thereof are encompassed by the present invention.

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 gramnegative 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 gram-negative bacteria.

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 pharmacetically acceptable carrier or diluent. The compounds may be administered by a variety of means; those of principal interest include; orally, topically or parenterally (e.g. 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 or four times a day.

To illustrate the potent broad-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 presently preferred carbapenem compounds of the present invention.

In Vitro Activity Samples of the carbapenem compounds prepared in Examples 1-2 after solution in water and dilution with Nutrient Broth were found to exhibit the following Minimum Inhibitory Concentrations (M.l.C.) in mcg/ml versus the indicated microorganisms as determined by overnight incubation at 37'C by tube dilution. N-Formimidoyl thienamycin is included in the following tablets as a comparison compound.

In Vitro Antibacterial Activity of Carbapenem Derivative of Example 1 MIC (mcg/ml) Organism New Compound N-Formimidoyl Thienamycin S. pneumoniae A-9585 0.25 0.004 S. pyogenes A-9604 0.06 0.001 S. aureus A-9537 0.13 0.004 S. aureus + 50% serum A-9537 0.03 0.016 S. aureus (Pen-res.) A-9606 0.06 0.008 S. aureus (Meth-res.) A15097 4 0.5 S. faecalis A20688 0.5 0.5 E. coli (10-4 dil.) A15119 0.06 0.016 E. coli (10-3) A15119 - 0.03 E. coli (10-2) A15119 - 0.06 E. coli (10-4) A20341-1 0.03 0.03 E. coli (10--3) A20341-1 - 0.03 E. coli (10-2) A20341-1 - 0.13 In vitro antibacterial activity of carbapenem derivative of Example 1-continued MIC (mcg/ml) Organism New Compound N-Formimidoyl Thienamycin K. pneumoniae A-9664 0.25 0.13 K pneumoniae A20468 0.25 0.06 P. mirabilis A-9900 0.13 0.06 P. vulgaris A21559 0.13 0.03 P. morganii A15153 0.13 0.13 P. rettgeri A22424 0.25 0.25 S. marcescens A20019 0.13 0.03 E. cloacae A-9569 0.13 0.06 E. cloacae A-9656 0.13 0.06 P. aeruginosa A-9843A 4 1 P. aeruginosa A21213 1 0.25 H. influenzae A-9833 16 16 H. influenzae A20178 32 32 H. influenzae A21518 16 32 H. influenzae A21522 8 32 B. fragilis A22862 0.03 0.016 B. fragilis A22053 0.03 0.06 B. fragilis A22696 0.25 0.13 B. fragilis A22863 0.03 1 In Vitro Antibacterial Activity of Carbapenem Derivative of Example 2 MIC (mcg/ml) Organism New Compound N-Formimidoyl Thienamycin S. pneumoniaeA-9585 0.001 0.002 S. pyogenesA-9604 0.001 0.002 S. aureusA-9537 0.004 0.004 S. aureus A-9537 0.016 0.016 + 50% serum S. aureusA-9606 0.008 0.008 (Pen-res.) S. aureusA 15097 8 4 (Meth,-res.) S. faecalisA 20688 0.25 0.5 Ecoli A 15119 0.016 0.016 Ecoli A 20341-1 0.016 0.03 K pneumoniae A9664 0.06 0.06 K. pneumoniae A20468 0.13 0.13 P. mirabilisA9900 0.03 0.06 P. vulgarisA21559 0.016 0.03 P. morganiiA15153 0.06 0.13 P. rettgeri A22424 0.13 0.13 S. marcescens A20019 0.03 0.03 E. cloacae A9659 0.13 0.06 E. cloacaeA9656 0.25 0.06 P. aeruginosa A9843A 8 1 P. aeruginosa A21213 2 0.25 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 are 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 PD50/Treatment (mg/kg) Challenge (No of Compound of N-Formimidoyl Organism organisms) Example 1 Thienamycin P. mirabilis A-9900 3.6 x 106 3.3 3*/15 P. aeruginosaA-9843a 5.5 X 104 0.3 0.5* P. aeruginosa A-20481 5.4 x 104 0.63 0.4* P. aeruginosaA-20599 1.4X 105 0.7 0.18* S. aureusA-9606 6.6 X 108 0.09 0.07* S. faecalisA-20688 2.3 X 108 3.3 2.8* E. coliA-15119 6.2X 106 0.6 2.5* K. pneumoniaeA-9964 5.1 X 106 2.5 2.2* *Historical data Treatment Schedule: Except for E. coli A15119 and K. pneumoniae A9964, mice were treated i.m. with drugs 0 and 2 hours post infection.For E. coliand K. pneumoniae the treatment schedule was 1 and 3.5 hours post-infection. 5 mice per dose 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) *LDBo Without Clinical Compound (mg/kg) Signs of Toxicity Compound of Example 1 14 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 (tlg/ml) Compound 10 20 30 45 60 90 *t1 /2 **AUC Minutes after Administration (min) (ug.h/ml) Compound of Example 1 14 10.8 6.8 2.6 0.8 < 0.6 10 6.3 N-Forminimidoyl 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 Compound of Example 1 26.1 0.5 0.1 26.7+6.7 N-Formimidoyl Thienamycin 12.1 0.1 < 0.1 12.2i3.6 Compounds were solubilized in 0.1 M phosphate buffer pH 7.

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

Additional Biological Data In Vitro Activity Samples of the carbapenem compounds indicated below (identified by example number) after solution in water and dilution with Nutrient Broth were found to exhibit the following Minimum Inhibitory Concentrations (M.l.C.) in mcg/ml versus the indicated microorganisms as determined by overnight incubation at 37'C by tube dilution. N-Formimidoyl thienamycin is included in the following tables as a comparision compound.

MIC ( g/ml) Organism Ex. 3 Ex. 4 Ex. 5 Ex. 6 Ex. 7 MK 0787* S. pneumoniae A-9585 0.002 0.002 0.004 0.004 0.004 0.002 S. pyogenes A-9604 0.002 0.001 0.004 0.004 0.004 0.002 S. faecalis A20688 0.5 0.5 0.25 0.5 0.13 0.5 S. aureus A-9537 0.016 0.008 0.004 0.03 0.008 0.004 S. aureus A-9537 90.016 0.03 0.016 0.06 0.03 0.016 + 50% serum S. aureus A-9606 0.016 0.016 0.008 0.03 0.016 0.008 (Pen-res) S. aureus A15097 4 4 8 4 2 4 (Meth-res) E. coli A15119 0.03 0.016 0.016 0.06 0.004 0.016 E. coli A20341-1 0.016 0.016 0.016 0.06 0.004 0.03 K. pneumoniae A-9664 0.06 0.03 0.03 0.13 0.016 0.06 K. pneumoniae A20468 0.06 0.03 0.06 0.25 0.016 0.13 E. Cloacae A-9659 0.13 0.03 0.08 0.25 0.016 0.06 E. cloacae A-9656 0.13 0.06 0.13 0.25 0.016 0.06 P. mirabilis A-9900 0.13 0.06 0.03 0.025 0.016 0.06 P. vulgaris A21559 0.016 0.016 0.018 0.06 0.008 0.03 M. morganii A15153 0.13 0.016 0.06 0.13 0.016 0.13 P. rettgeri A22424 0.25 0.13 0.13 0.25 0.06 0.13 S. marcescens A20019 0.016 0.03 0.06 0.13 0.008 0.03 P. aeruginosa A-9843a 2 2 4 8 1 0.25 P. aeruginosa A21213 0.5 0.13 2 1 0.25 0.25 H. influenzae A-9833 2 2 4 > 32 > 32 16 H. influenzae A21518 2 2 4 > 32 > 32 16 B. fragilis A22862 0.25 0.06 0.03 0.03 0.016 0.06 B fragilis A22696 0.5 0.5 0.25 0.25 0.25 0.13 *N-Formimidoyl Thienamycin MIC (yg/ml) Organism Ex. 8 Ex. 9 Ex. 10 Ex. 11 MK 0787* S. pneumoniae A-9585 0.002 0.001 0.001 0.002 0.002 S. pyogenes A-9604 0.002 O.Q01 0.001 0.002 0.002 S. faecalis A20688 0.5 0.13 0.25 0.5 0.25 S. aureus A-9537 0.008 0.004 0.008 0.004 0.002 S. aureus A-9537 0.03 0.008 0.06 0.016 0.016 + 50% serum S. aureus A-9606 0.03 0.008 0.008 0.016 0.008 (Pen-res) S. aureus A15097 - (Meth-res) E. coli A15119 0.016 0.008 0.016 0.016 0.016 E. coli A20341-1 0.03 0.004 0.008 0.03 0.016 K. pneumoniae A-9664 0.03 0.016 0.06 0.03 0.03 K. pneumoniae A20468 0.13 0.03 0.13 0.13 0.13 E. cloacae A-9659 0.13 0.03 0.13 0.06 0.13 E. cloacae A-9656 0.06 0.03 0.13 0.13 0.06 P. mirabilis A-9900 0.13 0.016 0.13 0.03 0.03 P. vulgaris A21559 0.03 0.008 0.016 0.03 0.016 M. morganii A15153 0.13 0.03 0.13 0.06 0.06 P. rettgeri A22424 0.13 0.06 0.13 0.13 0.13 S. marcescens A20019 0.06 0.016 0.06 0.06 0.03 P. aeruginosa A-9843A 1 2 32 0.5 1 P. aeruginosa A21213 0.25 0.13 2 0.13 0.13 *N-Formimidoyl Thienamycin MIC (ug/ml) Organism Ex. 12 Ex. 13 Ex.14 MK0787* S. pneumoniae A-9585 0.002 0.0005 0.0005 0.002 S. pyogenes A-9604 0.004 0.0005 0.0005 0.002 S. faecalis A20688 0.5 0.13 0.13 0.25 S. aureus A-9537 0.008 0.008 0.008 0.002 S. aureus A-9537 0.016 0.016 0.03 0.008 + 50% serum S. aureus A-9606 0.03 0.008 0.016 0.008 (Pen-res) S. aureus Al 5097 - - - - (Meth-res) E. coli Awl 0.016 0016 . 0.008 0.016 E. coli A20341-1 0.008 0.008 0.008 0.016 K. pneumoniae A-9664 0.03 0.03 0.03 0.03 K pneumoniae A20468 0.06 0.13 0.03 0.06 E. cloacae A-9659 0.06 0.06 0.03 0.06 E. cloacae A-9656 0.03 0.03 0.03 0.06 P. mirabilis A-9900 0.03 0.016 0.016 0.016 P. vulgaris A21559 0.016 0.008 0.016 0.016 M. morganii A15153 0.06 0.016 0.03 0.06 P. rettgeri A22424 0.13 0.25 0.06 0.13 S. marcescens A20019 0.03 0.016 0.016 0.03 P. aeruginosa A-9843A 16 32 8 1 P. aeruginosa A21213 2 2 0.5 0.13 *N-Formimidoyl Thienamycin MIC g/ml) Organism Ex. 15"A" Ex. 1S"B" Ex. 15"C" MK0787* S. pneumoniae A-9585 0.0005 0.0005 0.0005 0.002 S. pyogenes A-9604 0.0005 0.001 0.0003 0.002 S. faecalis A20688 0.13 0.5 0.5 0.25 S. aureus A-9537 0.03 0.004 0.016 0.004 S. aureus A-9537 0.03 0.016 0.06 0.008 + 50% serum S. aureus A-9606 0.004 0.008 0.03 0.008 (Pen-res) S. aureus A15097 - - - - (Meth-res) E. coli A15119 0.004 0.008 0.06 0.008 E. coli A20341-1 0.004 0.008 0.03 0.016 K. pneumoniae A-9664 0.008 0.03 0.06 0.03 K. pneumoniae A20468 0.008 0.016 0.13 0.06 E. cloacae A-9659 0.016 0.016 0.13 0.13 E. cloacae A-9656 0.016 0.03 0.13 0.13 P. mirabilis A-9900 0.008 0.03 0.06 0.06 P. vulgaris A21559 0.008 0.008 0.06 0.016 M. morganii A15153 0.03 0.06 0.25 0.13 P. rettgeri A22424 0.03 0.13 0.25 0.13 S. marcescens A20019 0.008 0.016 0.13 0.016 P. aeruginosa A-9843A 0.5 2 8 0.5 P. aeruginosa A21213 0.03 0.13 0.5 0.13 *N-Formimidoyl Thienamycin Organism Ex. 16 Ex. 1 7 MK 0787* S. pneumoniae A-9585 0.002 0.016 0.001 S. pyogenes A-9604 0.002 0.016 0.001 S. faecalis A20688 1 4 0.25 S. aureus A-9537 0.008 0.25 0.001 S. aureus A-9537 0.03 1 0.008 + 50% serum S. aureus A-9606 0.016 0.5 0.002 (Pen-res) S. aureus Al 5097 (Meth-res) E. coli A15119 0.016 0.6 0.008 E. coli A20341-1 0.016 0.6 0.008 K. pneumoniae A-9664 0.06 0.13 0.03 K. pneumoniae A20468 0.06 0.5 0.06 E. cloacae A-9659 0.06 2 0.06 E. cloacae A-9656 0.06 2 0.06 P. mirabilis A-9900 0.06 0.13 0.008 P. vulgaris A21559 0.03 0.13 0.008 M. morganii A15153 0.13 0.5 0.06 P. rettgeri A22424 0.25 2 0.06 S. marcescens A20019 0.06 0.13 0.016 P. aeruginosa A-9843A 0.25 > 63 0.5 P. aeruginosa A21213 0.13 16 0.13 *N-Formimidoyl Thienamycin Organism Ex. 18 Ex. 19 Ex. 20 My0787* S. pneumoniae A-9585 1 0.002 0.06 0.001 S. pyogenes A-9604 2 0.002 0.13 0.002 S. faecalis A20688 63 0.5 16 0.25 S. aureus A-9537 32 0.004 0.5 0.002 S. aureus A-9537 > 63 0.008 2 0.004 + 50% serum S. aureus A-9606 > 125 0.016 > 125 0.004 (Pen-res) S. aureus A15097 - - - - (Meth-res) E. coli A151 19 16 0.008 1 0.016 E. coli A20341-1 16 0.008 2 0.016 K. pneumoniae A-9664 32 0.03 4 0.03 K. pneumoniae A20468 63 0.03 4 0.06 E. cloacae A-9659 63 0.03 8 0.06 E. cloacae A-9656 125 0.03 16 0.06 P. mirabilis A-9900 32 0.03 4 0.016 P. vulgaris A21559 32 0.016 4 0.016 M. morganii A15153 32 0.06 8 0.06 P. rettgeri A22424 32 0.13 8 0.13 S. marcescens A20019 32 0.03 4 0.03 P. aeruginosa A-9843A 63 0.5 32 0.5 P. aeruginosa A21213 63 0.06 16 0.13 B-Formimidoyl Thienamycin In Vivo Activity The in vivo therapeutic efficacy of certain compounds of the present invention and Nformimidoyl thienamycin (MK 0787) after intramuscular administration to mice experimentally infected with various organisms is shown below. 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 PD50/treatment (mg/kg) Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex.

6 8 9 12 14 15("A") 15(''B'') MK0787 S. aureus A9606 - 0.21 - 0.89 0.07 - - 0.07 E. coli A15119 - 0.86 1.2 - - - - 3 K. pneumoniae A9664 - 1.8 1.8 - - - P. mirabilis A9900 - 1.4 7.1 - - - - 9 P. aeruginosa A9843A 0.4 0.19 0.19 1.8 0.45 0.39 0.89 P. aeruginosa A24081 - 0.33 0.19 - - - - 0.4 Ex. Ex. Ex.

3 4 7 MK 0787 S. aureus A9606 0.07 0.1 0.2 0.07 E. coli A15119 1 0.4 0.2 3 K. pneumoniae A9664 3 3 1 3 P. mirabilis A9900 2 4 2.4 9 P. aeruginosa A9843A 0.5 0.2 0.2 0.5 P.aeruginosa A24081 0.8 0.2 0.1 0.4 Ex.

5 MK0787 S. aureus 0.2 0.07 E. coli 4 2.2 K. pneumoniae 3 2.3 P. mirabilis 10 9 P. aeruginosa A9843A 1.6 0.5 Blood Levels in Mice After Intramuscular Administration Blood levels and the half-life of certain compounds of the present invention after intramuscular administration of 20 mg/kg in mice are shown below.

Cmax *T1/2 **AUC Compound (yg/ml) (min) ( g.h/ml) Example 1 14 10 6.3 Example 2 13.9 9 5.3 Example 3 14.5 10 6.9 Example 4 15.5 11 7.7 Example S - - - Example 6 17.7 9 8.5 Example 7 19.2 11 11.8 Example 8 18.8 11 10.5 Example 9 16.7 12 8.5 Example 10 20.1 11 9.5 Example 11 14.9 11 7.4 Example 13 14.8 11 6.4 Example 14 15.8 13 7.6 Example 15 ''A" 16.7 12 9.5 Example 15 ''B'' 15.9 10 7.4 Example 15"C" 15.1 10 7.3 MK 0787 14.6 10 6 Example 17 11 -8 3.4 Example 18 14.9 6 3.9 Example 19 27 16.7 15.1 Example 20 28.4 14 15.6 Compounds were solubilized in 0.1 M phosphate buffer, pH7.

Valves based on a single test; 4 mice per compound.

T1/2 refers to half-line in minutes " AUC refers to the area under the blood concentration-time curve The following examples illustrate but do not limit the scope of the present invention.

Example 1 Preparation of 1-Methyl-4-[2-carboxy-6a-[1 (R)-hydroxyethylj 7-oxo- 1 -azabicyclo [3. 2. O]hept-2en-3-thiomethyl]pyridinium hydroxide inner salt

A solution of 673 mg (1.86 mmol) of p-nitrobenzyl 6a-[1-(R)-hydroxyethyl]-3,7-dioxo-1- azabicyclo 3.2.0]hept-2-ene-2-carboxylate (1) in 10 ml of acetonitrile was cooled to - 10"C under a nitrogen atmosphere. A solution of 245 mg (1.90 mmol) of diisopropylethylamine in 1 ml of acetonitrile was added followed by a dropwise addition of 510 mg (1.90 mmol) of diphenyl chlorophosphate in 1 ml of acetonitrile over a period of 2 minutes.The resulting solution was stirred at -10 C for 15 minutes to provide a p-nitrobenzyl 3-(diphenyl phosphoryloxy)-6a- 1 -(R)-hydroxyethyl]-7-oxo-1 -azabicyclo-[3.2.0]hept-2-ene-2-carboxylate. To this solution was added a solution of 245 mg (1.90 mmol) of diisopropylethylamine in 0.5 ml of acetonitrile followed by a solution of 270 mg (2.16 mmol) of 4-mercaptomethylpyridine in 0.5 ml of acetonitrile. The reaction mixture was stirred at - 10 C for 60 minutes and the white precipitate which formed was collected by filtration and washed with 5 ml of ice-cold acetonitrile to give 660 mg (76% yield) of compound 2 as white crystals, m.p. 145 C.

NMR(DMSO-d6) 8: 1.20(3H, d, J = 6.0 Hz), 3.2-3.4 (3H, m), 3.7-4.1 (2H, m), 4.25 (2H, s), 5.05 (1 H, d, J = 4.0 Hz), 5.25 (1 H, d, J = 14.0 Hz), 5.48 (1 H, d, J = 14.0 Hz), 7.40 (2H, d, J = 5.5 Hz), 7.70 (2H, d, J = 8.5 Hz), 8.23 (2H, d, J = 8.5 Hz) and 8.58 (2H, d, J = 5.5 Hz).

IR (KBr) #max: 3400, 1790, 1695 and 1600 cm.

Anal. Calc'd for C22H2,N306S: 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.

To a solution of 660 mg (1.41 mmol) of intermediate 2 in 140 ml of acetone there was added 5 ml of methyl iodide. The reaction solution was stirred for 8 hours at 25 C. The solvent was evaporated in vacuo affording a slightly yellow solid which was triturated with diethyl ether to give 779 mg (90% yield) of the title compound 3 as a white amorphous solid, m.p. 130C (decomp.).

NMR (DMSO-d6) 8:1.15 (3H, d, J = 6.0 Hz), 3.2-3.4 (3H, m), 3.7-4.1 (2H, m), 4.25 (3H, s), 4.30 (2H, s), 5.25 (1 H, d, J = 14.0 Hz), 5.50 (1 H, d, J = 14.0 Hz), 7.70 (2H, d, J = 9.0 Hz), 8.10 (2H, d, J = 7.0 Hz), 8.25 (2H, d, J = 9.0 Hz) and 8.90 (2H, d, J = 7.0 Hz).

IR (KBr) ymax: 3400, 1770, 1690 and 1640cm-1.

Anal. Calc'd for C23H24N306SI H20: 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.

To a solution of 779 mg (1.27 mmol) of compound 3 in tetrahydrofuran-water-diethyl ether (80 ml-80 ml-100 ml), there was added 140 mg (1.4 mmol) of potassium bicarbonate and 1 25 mg (0.7 mmol) of dibasic potassium phosphate. Then, 700 mg of 10% palladium on charcoal was added and the mixture was hydrogenated at 40 psi for 45 min on the Parr Shaker. The mixture was then filtered and the catalyst was washed with water (2 X 10 ml). The combined filtrate and washings were extracted with diethyl ether (150 ml) and then lyophilized to give a brown powder. This crude material was purified on a C18 BONDAPAK reverse phase column (30 g) (Waters Associates), eluting with water under a 8 psi pressure.Each fraction (20 ml) was screened by high pressure liquid chromatography, and fractions having an ultraviolet absorption at Amax = 300 nm were collected and lyophilized to give 1 35 mg (32% yield) of the title compound 4 as a slightly yellow solid.

NMR (D20) 8:1.25 (3H, d, J = 6.0 Hz), 2.7-3.2 (2H, m), 3.40 (1H, q, J = 9.0 and 2.5 Hz), 3.9-4.2 (2H, m), 4.40 (3H, s), 4.72 (2H, s), 8.10 (2H, d, J = 6.0 Hz).

IR (KBr) 7max: 3400, 1755, 1640 and 1590 cm.

UV Amax (H20): 296 nm ( = 7782), 258 nm ( = 6913).

Example 2

PNB = p-nitrobenzyl A suspension of 1.1 g (2.93 m moles) of diazo compound t was purged at room temperature with nitrogen for 5 minutes in 30 ml dry benzene. It was treated with 25 mg of rhodium acetate dimer and the mixture was heated to reflux for 45 minutes. The warm solution was diluted with ethyl acetate (25 ml), filtered to remove the catalyst and evaporated to dryness to give the keto compound 2 as a white solid. This was dissolved in dry acetonitrile (20 ml) and cooled to 10 C. To this solution was added, under nitrogen, diiospropylethylamine (417 mg, 3.2 m moles) followed by 810 mg (3.0 m moles) of diphenyl chlorophosphate and the reaction mixture was stirred at -- 10"C for 20 minutes.

The reaction mixture was then treated with diisopropylethylamine (420 mg, 3.2 m moles) and 2-(4-pyridyl) ethane thiol (560 mg; 4.03 m moles) in 2 ml acetonitrile [J. Org. Chem. 26: 82 (1961) Ludwig Bauer and Libero A. Gardella Jr.]. The reaction mixture was stirred at - 5"C to - 10"C for 1 hour, then diluted with methylene chloride (100 ml) and washed successively with brine - H20 (1:1), 4% H3PO4, 5% NaHCO3, H20 and brine. The organic phase was dried (MgSO4) and evaporated to give a white solid. This solid was washed with diethyl ether:hexane (1:) and dried under high vacuum to give 901 mg (63.9%) of compound 3.

IR(KBr) 1790, 1690cm-1 MR (CDCl3/DMSO) 8 1.20 (3H, d, J = 3.0 Hz, CH3), 2.8 to 3.2 (7H, m), 3.9 to 4.4 (2H, m), 5.1(1K, d), 5.4 (2H, q), 7.3 (2H, d), 8.5 (2H, q), 7.76 (2H, d), 8.3 (2H, q).

A suspension of carbapenam 3 (890 mg, 1.85 m moles) and 7 ml of iodomethane in 200 ml dry acetone and 12 ml methylene chloride was stirred at 25"C for 24 hours. The reaction mixture became a clear solution in 1 hours. The solvent was removed under reduced pressure, then the residue was washed with diethyl ether to give 920 mg (1.48 m moles) (79.8%) of 4 as a foamy solid.

IR(KBr) 1765, 1690 cm-' NMR (DMSO) 8 1.3 (3H, d, J = 3.0 Hz), 3.1 to 3.7 (7H, m), 4.1 (3H, m), 4.3 (3H, s), 5.38 (2H, q, J = 7.0 Hz), 8.1 (2H, d, J = 3.0 Hz), 8.9 (2H, d, J = 3.0 Hz), 7.6 (2H, d, J = 4.0 Hz), 8.2 (2H, d, J=4.0 Hz).

C.

The carbapenem 4 (920 mg, 1.47 m moles), dissolved in 90 ml tetrahydrofuran, 90 ml diethyl ether and 90 ml water, was treated with 265 mg (1.51 m moles) dibasic potassium phosphate, 190 mg (1.9 m moles) potassium hydrogen carbonate and 800 mg 10% palladium on carbon. It was hydrogenated at 45 psi for 1 hour. The catalyst was filtered off through CELITE and the filtrate was washed with diethyl ether (3 X 25 ml). The aqueous layer was lyophilized to give a brownish material which was then purified twice by chromatography through a 12 9*C18 column (K20) to give 55 mg of 5.

IR (KBr) 1750, 1640 cm-1.

NMR (D20) 8 1.30 (3H, d, J = 3.0 Hz), 3.0 to 3.5 (7H, m), 4.3 (3H, s), 4.0 to 4.5 (3H, m), 7.90 (2H, d) 8.70 (2H, d).

C,8BONDAPAK reverse phase column (Waters Associates)

Example 3 Preparation of 3-(N-Methylpyridine-3-yl-methanethio)-6&alpha;-[1 -(R)-hydroxyethyl]- 7-oxo- 1 -azabicyclo (3.2.0) hept-2-ene-2-carboxylate

p-Nitrobenzyl 3-(pyridine-3-yl-methane thio)- 6a-[ 1 -(R)-hydroxy ethyl]- 7-oxo- 1 -azabicyclo (3.2.0) hept-2-ene-2-carboxylate.

To a cooled (0 ) solution of 925 mg (2.66 mmole) of the keto intermediate 5 in 14 ml of acetonitrile was added a solution of 377 mg (2.9 mmole of diisopropyl ethylamine in 1 ml of acetonitrile followed by 786 mg (2.9 mmole) of diphenyl chlorophosphonate in 1 ml of acetonitrile under a nitrogen atmosphere. The resulting solution was stirred for 15 min at 0 C, and there was then added a solution of 377 mg (2.9 mmole) of 3-mercaptomethyl pyridine[prepared by the procedure described in Can. J. Chem., 56, 3068 (1 978)] in 2 ml of acetonitrile.

The reaction solution was stirred for 90 minutes at 0 . The precipitate was collected by filtration and washed with 20 ml of ethylacetate to give 950 mg (60% yield of the title product as white crystals.

NMR(DMSO-d6) 8: 1.30(3H, d, J = 6.0Hz), 3.4-4.2(5H, m) 4.25(2H, s), 5.1(1 H, d, J = 4.5Hz), 5.40(2H, ABq, J = 14.4Hz), 7.2-8.5(8H, m).

IR (KBr) ymax 3500, 1775, and 1580 cm-1. Anal Calc'd. for C22H2tJ306S1: 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.

3-(N-Methylpyridine-3-yl-methane thio)-6&alpha;-[1-(R)-hydroxymethyl]- 7-oxo- 1-azabicyclo (3.2.0) hept2-ene-2-carboxylate.

To a solution of 730 mg (1.56 mmole) of compound 19 in 120 ml of acetone was added 5 ml of methyl iodide and the reaction mixture was stirred for 18 hours at room temperature. The precipitate was collected by filtration and washed with acetone (10 ml) to give 940mg (100% yield) of the quaternized pyridine 20 as a slightly yellow powder.

NMR (DMSO-d6) 8: 1.25(3H, d, J = 5.8Hz), 3.6-4.3(5H, m), 4.20(3H, s), 4.25(2H, s) 5.25(1 H, d, J = 7.2Hz), 5.40(2K, ABq, J = 12,16Hz), and 7.6-9.2 (9H, m). lR(KBr)A max: 3300, 1765 and 1690 cm-1. Anal. Calc'd. for C23K24N3O8S111: 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 To a solution of 933 mg (1.6 mmole) of compound 20 in 90 ml of tetrahydrofuran and 90 ml of ether was added 200 mg of KHCO3 and 349 mg of K2HPO4 in 90 ml of water followed by 1.0 g of palladium on charcoal. The mixture was hydrogenated at 45 psi on the Parr shaker for 45 minutes. The mixture was filtered through a Celite pad and the catalyst was washed with water (2 X 10 ml).The combined filtrate and washing were extracted with ether (2 X 100 ml) and lypholized to give a yellow solid which was purified on a C,8 BONDAPAK (Waters Associates) reverse phase column (8 g), eluting with 5% acetonitrile in water under 8 psi pressure. Each 15 ml fraction was assayed by high pressure liquid chromatography and fractions having an ultraviolet absorption at A max 300 nm were collected and lyophilized to give 230 mg (43% yield) of the title product as slightly yellow crystals. m.p. 130 C (decomp) NMR (D2O) #: 1.25 (3H, d, J = 7.0Hz), 3.12(2H, d.d, J = 7.9Hz, 1.6Hz), 3.42 (1H, q, J = 7.2 Hz, 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) ymax: 3400, 1750 and 1580 cm-1.UVAmax (K2O): 298 nm ( = 8058). Anal. Calc'd. for C16Ht8N20- 4S,.2H20: C, 51.87; H, 5.44; N, 7.56. Found C, 51.95; H, 5.66; N,7.56.

Preparation of 3-(N-Methylpyridine-2-yl-methane thio)-6&alpha;-[1-(R)-hydroxyethyl]-7-oxo-1-azabicyclo (3.2.0) hept-2-ene-2-carboxylate

5 22 p-Nitrobenzyl-3-(pyridine-2-yl-methane thio)-6a-[1 -(R)-hydroxyethyl]- 7-oxo- 1 -azabicyclo(3. 2.0) hept-2-ene-2-carboxylate To a cooled (0 ) solution of 925 mg (2.65 mmole) of the keto intermediate 5 in 14 ml of acetonitrile was added a solution of 377 mg (2.92 mmole) of diisopropyl ethylamine in 1 ml of acetonitrile followed by 786 mg (2.90 mmole) of diphenyl chlorophosphate in 1 ml of acetonitrile under a nitrogen atmosphere.The resulting solution was stirred for 15 minutes at 0 , and there was then added a solution of 377 mg (2.92 m mole) of diisopropyl ethylamine in 1 ml of acetonitrile followed by 350 mg (3.0 mmole) of 2-mercaptomethyl pyridine [prepared by the procedure described in Can. J. Chem., 56 3068 (1978)] in 1 ml of acetonitrile. The reaction solution was stirred for 2 hours at - 10"C. The precipitate was collected by filtration and washed with 20 ml of methylene chloride to give 650 mg (54% yield) of the title product as a yellow powder. NMR(DMSO-d6) 8: 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) ymax: 3400, 1775 and 1690cm-1.

Anal. calc'd for C22H2,N306S,:4 C, 58.01; H, 4.65; N, 9.23; S, 7.04.

Found: C, 57.56, H, 4,92, N, 8.94; S, 7.03.

3-(N-Methyl pyridine-2-yl-methane thio)-6&alpha;-[ 1 -(R)-hydroxyethyl]- 7-oxo- 1 -azabicyclo (3.2.0) hept2-ene-2-carboxylate.

To a solution of 650 mg (1.39 mmole) of compound 22 in 100 ml of acetone was added 4 ml of methyl iodide. The reaction mixture was stirred for 3 days at room temperature. The precipitate was collected by filtration and washed with acetone (10 ml) to give 500 mg (60% yield) of the quaterized pyridine 23 as a slightly yellow solid.

NMR (DMSO-d6) 6: 1.26(3H, d, J = 7.0Hz) 3.9-4.2(2H, m), 4.4(3H, s), 4.78(2H,s), 5.2(1H, d, J = 3.9Hz), 5.50(2H, ABq, J = 14Hz) and 7.8-9.4 (8H, m). IR (KBr) A max: 3400,1765, and 1690 cm-1.

Anal. Calc'd for C23H24N3O6S1I1: 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.

To a solution of 1.0 9 (1.167 mmole) of compound 23 in 90 ml of tetrahydrofuran and 90 ml of ether was added 215 mg (2.15 m mole) of KHCO3 and 374 mg (2.1 mmole) of K2HPO4 in 90 ml of water followed by 1.0 9 of 10% palladium on charcoal. The mixture was hydrogenated at 45 psi on the Parr shaker for 45 minutes. The mixture was filtered through a Celite pad and the catalyst was washed with water (2 X 10 ml). The combined filtrate and washing were extracted with ether (2 X 200 ml) and lyophilized to give a yellow solid which was purified on a C,8 BONDAPAK (Waters Associates) reverse phase column (10 g), eluting with 5% acetonitrile in water under 8 psi pressure.Each 15 ml fraction was assayed by high pressure liquid chromatography and fractions having an ultraviolet absorption at Amax 300 nm were collected and lyophilized to give 390 mg (44% yield) of the title product. Recrystallisation of this material from water-acetone-ethanol produced fine needles. m.p. 194-196 C. (decomp).

NMR (D20) 8: 1.30(3H, d, J = 6.2Hz), 3.2(2H, q, J = 9.0Hz, 3.6Hz) 3.46(1H, q, J = 6.0Hz, 2.7 Hz), 4.1-4.6(3H, m), 4.60(3K, s) and 7.9-8.9(4H, m). IR (KBr) Y max: 3400, 1755, and 1590 cm - ' . UV Amax (K2O): 292 nm (E = 8092). Anal Calc'd for C16K28N204S1. 2H20: 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-2-yl-ethane thio]-6u-[l-(R)-hydroxyethyl]- 7-oxo- lazabicyclo (3.2.0) hept-2-ene-2-carboxylate

P-Nitrobenzyl-3-(pyridine-2-yl-ethane thio)-6al1 1 -(R)-hydroxyethyl]-7-oxo- 1 -azabicyclo (3.2.0) hept-2-ene-2-carboxylate.

To a cooled solution of 1.78 g (5.0mmole) of the keto intermediate 5 in 25 ml of acetonitrile was added 710 mg (5.5 mmole) of diisopropyl ethylamine in 1 ml of acetonitrile followed by 1.4 g (5.0 mmole) of diphenylchlorophosphate in 1 ml of acetonitrile under a nitrogen atmosphere. The resulting solution was stirred for 20 minutes at 0 C, and there was then added a solution of 710 mg (5.5 mmole) of diisopropyl ethylamine in 1 ml of acetonitrile followed by a solution of 850 mg (6.1 mmole) of the thiol 54 [prepared by the procedure described in J. Org.

Chem., 26, 82(1961)] in 2 ml of acetonitrile. The reaction mixture was stirred for 60 minutes at 0 C. The precipitate was collected by filtration and washed with methylene chloride (20 ml) to give 1.3 g (57%) of the title product as a yellow solid. NMR(CDC13) d: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) #max: 3400, 1780 and 1680cm-1.

3-(N-Meth yl pyridine-2-yl-ethane thio)-6-[l -(R)-hydroxyethyl]- 7-oxo- 1 -azabicyclo (3.2.0) hept-2ene-2-carboxylate.

To a suspended solution of 800 mg (1.7 mmole) of compound 53 in 50 ml of acetone was added 5 ml of methyl iodide. The reaction mixture was stirred for 48 hours at room temperature. The precipitate was collected by filtration and washed with acetonitrile (15 ml) to give 810 mg (76% yield) of the quarternized pyridine 55as a slightly yellow powder. NMR (DMSO-d6) 6: (3H, d, J = 5.6 Hz), 3.2-4.3 (9H, m), 4.20 (3H, s),-5.26 and 5.55 (1H each, ABq, J = 15 Hz) and 7.8-9.2 (8H, m). IR(KBr) ymax: 3400, 1770 and 1690 cm-1.

To a solution of 790 mg (1.27 mmole) of compound 55 in 100 ml of tetrahydrofuran and 100 ml of pH = 7.0 buffer solution followed by 1.0 9 of 10% palladium on charcoal. The mixture was hydrogenated at 40 psi on the Parr shaker for 40 minutes. The mixture was filtered through a Celite pad and the catalyst was washed with water (2 X 10 ml).

The combined filtrate and washing were extracted with ether (3 x 100 ml) and lyophilized to give a yellow powder which was purified on a C18 BONDAPAK (Waters Associates) column (30 9), eluting with 10% acetonitrile in water under 8 psi pressure.

Each 15 ml fraction was assayed by high pressure liquid chromatography and fractions having an ultraviolet absorption at Amax 300 nm were collected and lyophilized to give 65 mg (15% yield) of the title product as a yellow powder.

NMR (D20) 8:1.25(3K, d, J = 6.3Hz), 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) ymax: 3400, 1750 and 1590 cm-1. UV Amax (H2O): 300 nm (E= 8108).

Example 6 Preparation of 3-( 1 -Propylpyridine-4-yl-methane thio)-6&alpha;-[1-(R)-hydroethyl]-7-oxo-1-azabicyclo (3.2.0) hept-2-ene-2-carboxylate

P-Nitrobenzyl-3-(pyridine-4-yl-methane ethio)-6&alpha;-[1-(R)-hydroxyethyl]-7-oxo-1-azabicyclo (3.2.0)hept-2-ene-2-carboxylate.

A solution of 673 mg (1.86 m mole) of p-nitrobenzyl 6a-[-(R)-hydroxyethyl]-3,7-dioxo-1- azabicyclo [3.2.03 hept-2-ene-2-carboxylate (5) in 10 ml of acetonitrile was cooled to - 1 0'C under a nitrogen atmosphere. A solution of 245 mg (1.90 m mole) of diisopropylethylamine in 1 ml of acetonitrile was added followed by a dropwise addition of 510 mg (1.90 m mole) of diphenyl chlorophosphate in 1 ml of acetonitrile over a period of 2 minutes. The resulting solution was stirred at -10 C for 15 minutes to provide a p-nitrobenzyl 3-(diphenylphosporyloxy)-6a-[1-(R)-hydroxyethyl]-7-oxo-1-azabicyclo-(3.2.0) hept-2-ene-2-carboxylate. To this solution was added a solution of 245 mg (1.90 m mole) of diisopropylethylamine in 0.5 ml of acetonitrile followed by a solution of 270 mg (2.16 m mole) of 4-mercaptomethylpyridine in 0.5 ml of acetonitrile.The reaction mixture was stirred at -10 C for 80 minutes and the white precipitate which formed was collected by filtration and washed with 5 ml of ice-cold acetonitrile to give 660 mg (76% yield) of compound 51 as white crystals, m.p. 145'C. NMR (DMSO-d6)8: 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=14.0H), 5.48 91H, 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: 3400, 1790 and 1695 cm-1. Anal. Calc'd for C22H21N3O6S: 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.

3-(1-Allyl pyridine-4-yl-methene thio)-6&alpha;-[1-(R)-hydroxyethyl]-7-oxo-1-azabicyclo (3.2.0)-hept-2en3-2-carboxylate.

To a solution of 900 mg (2.13 m mole) of compound 51 in 150 ml of acetone was added 2 ml of allyl bromide and 380 mg of sodium iodide. The mixture was stirred for 48 hours at room temperature and the solvent was evaporated in vacuo to give a yellow solid. This material was suspended into 120 ml of acetonitrile, filtered and evaporated in vacuo to give 1.0 g (87% yield) of the title product as a yellow solid. NMR (CD3CN) #: 1.20 (3H, d, J=6.2Hz), 3.0-3.44 (4H, m), 4.0-4.4 (4H, m), 5.1-5.6 (4H, m) and 7.4-7.9(8H, m). IR (KBr)#max: 3400, 1770 and 1690 cm-1. Anal. Calc'd for C25H26N3O6S1I1: C, 48.16; H 4,21; N, 6.74; S, 5.15.

Found: C, 48.55; H, 4.48; N, 6.69; S, 5.15.

3-( 1 -Propyl pyridine-4-yl-methane thio)-6u-[l-(R)-hydroxyethyl]- 7-oxo- I-azabicyclo (3.2.0) hept-2 ene-2carboxylate.

To a solution of 1.27 g (2.15 m mole) of compound 52 in 100 ml of tetrahydrofuran and 100 ml of ether was added 100 ml of pH = 7.0 buffer solution followed by 1.0 g of 10% palladium on charcoal. The mixture was hydrogenated at 40 psi on the Parr shaker for 40 minutes. The mixture was filtered through a Celite pad and the catalyst was washed with water (2 X 10 ml). The combined filtrate and washing were extracted with ether (3 x 100 ml) and lyophillzed to give a yellow powder which was purified on a C18 BONDAPAK (Waters Associates) column (40 g), eluting with 10% acetonitrile in water under 8 psi pressure. Each 15 ml fraction was assayed by high pressure liquid chromatography and fractions having an ultaviolet absorption at Amax 300 nm were collected and lypholized to give 48 mg (6% yield) of the title product as a yellow powder. NMR(D20)8: 0.95(3H, t, J = 7.5Hz), 1.25(3H, d, 7.0Hz), 2.05(2H, sextet, J = 7.5Hz) 3.10(2H,dd, J = 10 Hz, 2.5Hz) 3.35(1K, 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) ymax: 3400, 1750, and 1590 cm-'. Anal. Calc'd for C16H22N2O4S.2H2O: C, 54.52; H, 6.10; N, 7.07.

Found: C, 54.32; H, 6.03; N, 6.99.

Example 7 Preparation of 3-(N-Methyl-3-methylpyridine-2-methane thio)-6a-[1 -(R)-hydroxyeth yl]- 7-oxo- 1 azabicyclo (3.2.0) hept-2-ene-2-carboxylate

36 37 3-Methyl-2-mercaptomethyl pyridine.

A solution of 2.45 g (17.0 mmole) of the chloro compound 36 and 1.37 g (18.0 m mole) of thiourea in 60 ml of absolute ethanol was heated at reflux for 5 hours. Evaporation of ethanol followed by addition of ether give 3.08 g (72% yield) of the isothiouronium salt which was dissolved in 10 ml of water containing 1.44 g (26 m mole) of sodium hydroxide. The solution was then heated at 100"C for 5 minutes under a nitrogen atmosphere. The reaction mixture was cooled to 5 C, adjusted to pH 6.4 by addition of acetic acid and extracted with ether (4 X 50 ml). The combined ether extracts were washed with 5% aqueous sodium bicarbonate and brine.

Evaporation of dried (MgSO4) solvent gave 1.4 g (83% Yield) of the thiol 37 as a yellow oil which was used for the next step without further purification. NMR (CDCl3)8: 2.20(3H, s), 2.5-2.7(1 H, broad s), 3.8(2H,t, J = 6.5Hz) and 6.9-8.2(3H, m).

P-Nitrobenzyl-3-[3-methyl pyridine-2-yl-methane thioj-6a-f 1 -(R)-hydroxyethylj- 7-oxo- 1 -azabicyclo (3.2.0) hept-2-ene-2-carboxylate.

To a cooled (0 C) solution of 1.74 g (5.0 mmole) of the keto intermediate 5 in 25 ml of acetonitrile was added 960 mg (5.8 m mole) of diisopropyl ethylamine in 2 ml of acetonitrile followed by 1.4 g (5.8 mmole) of diphenyl chlorophosphate in 2 ml of acetonitrile under a nitrogen atmopshere. The resulting solution was stirred for 20 minutes at 0 C, and there was then added a solution of 760 mg (5.8m mole) of diisopropyl ethylamine in 2 ml of acetonitrile followed by 810 mg of the mercaptomethyl pyridine 37 in 3 ml of acetonitrile. The reaction mixture was allowed to stir for 2 hours at 0 C. The precipitate was collected by filtration and washed with acetonitrile to give 1.56 g (66% yield) of the title product as a white solid. m.p.

145 C. NMR (DMSO-d6) 8: 1.23(3H, d, J = 6.5Hz), 2.30(3H, s), 3.1-4.3(6K, m), 4.35(2H, s), 5.20 and 4.45(1 H each, ABq,J = 15.0Hz) and 7.3-8.4(7H,m). IR(KBr) ymax: 3400, 1767 and 1695 cm-1. Anal. Calc'd for C24H26N3O9S2F: 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.

3-(N-Methyl-3-methyl pyridine-2-yl-methane thio)-6&alpha;-[1-(R)-hydrroxy ethyl]-7-oxo-1-azabicyclo (3.2.0) hept-2-ene-2-carboxylate.

To a solution of 680 mg (1.45 mmole) of compound 38 in 120 ml of methylene chloride was added 270 mg (2.33 mmole) of methyl fluorosulfonate. The reaction mixture was stirred for 3 hours at room temperature. The precipitate was collected by filtration and washed with methylene chloride (5 ml) to give 840 mg (99% yield) of the quaternized pyridine 39 as white crystals. NMR (DMSO-d6)8: 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) #max: 3400, 1750 and 1590 cm-'. Anal. Calc'd for C24H24N309S2F: 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.

To a solution of 810 mg (1.39 mmole) of compound 39 in 100 ml of tetrahydrofuran and 100 ml of ether was added 100 ml of pH = 7.0 buffer solution followed by 750 mg of 10% palladium on charcoal. The mixture was hydrogenated at 45 psi on the Parr shaker for 60 min.

in the cold room (4-6 C). The mixture was filtered through a Celite pad and the catalyst was washed with ether (2 X 10 ml). The combined filtrate and washing were extracted with ether (2 X 40 ml) and lyophilized to give a yellow solid which was purified on the C18 BONDAPAK (Waters Associates) column (20 9), eluting with 5% acetonitrile in water under 8 psi pressure.

Eash 15 ml fraction was assayed by high pressure liquid chromatography and fractions having an ultraviolet absorption at Amax 300 nm were collected and lyophilized to give 141 mg(30% yield) of the title product as a yellow solid. NMR (D20)8: 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(1K, q, J = 7.0Hz, 6.5Hz), 8.35(1K, d, J = 7.00Hz) and 8.65(1K, d, J = 6.5 Hz). IR(KBr) -'max: 3400, 1750 and 1580 cm-1. UV Amax (H2O): 296 nm (#=8014). Anal. Calc'd for C17H20N2O4S1.1/4H2O: C, 57.85; H, 5.85; N, 7.94.Found: C, 58.60; H, 5.86; N, 7.87.

Example 8 Preparation of 3-(2-Methyl-N-methylthiazole-4-yl-methane thio)-6&alpha;-[1-(R)-hydroxethyl]-7-oxo-1- azabicyclo (3.2.0) hept-ene-2-carboxylate

p-Nitrobenzyl 3-[2-methyl thiazole-4-yl-methane thio]-6u-[l -(R)-hydroxyethyl]- 7-oxo-?-azabicyclo (3.2.0) hept-2-ene-2-carboxylate.

To a cooled (0 ) solution of 1.4 g (4.0 mmole) of the keto intermediate 5 in 12 ml of acetonitrile was added 0.83 ml (4.6 mmole) of diisopropylethylamine followed by 1.16 9(4.3 mmole) of diphenylchlorophosphate in 2 ml of acetonitrile under a nitrogen atmospere. The resulting solution was stirred at 0 for 30 minutes to provide p-nitrobenzyl 3-(dipehenylphospho ryloxy)-6a-[1-(R)-hydroxyethyl]-7-oxo-1-azabicyclo (3.2.0) hept-2-ene-2-carboxylate. To this solution was added a solution of 0.83 ml (4.6 mmole) of diisopropylethylamine in 2 ml of acetonitrile followed by a solution of 0.62 g (4.2 mmole) of 2-methyl-4-mercaptomethyl thiazole [prepared by the procedure described in J. Amer. Chem Soc., 71, 3570 (1949)] in 3 ml of acetonitrile.The reaction solution was stirred for 40 minutes at 0 . The precipitate was collected and washed with ether (30 ml) to give 943 mg of the title product as a white solid.

NMR (CDCl3) 8: 1.32(3H, d, J = Hz), 2.68(3H, S), 3.20(2H, m) 3.76(1K, d, J = 5.5Hz), 4.16(2H, S), 4.20(1 H, m), 5.40(2H, q, J = 14Hz), 7.06(1 K, S), 7.68(2H, d, J = 8Hz) and 8.24(2H, d, J = 8Hz). IR(KBr) ymax: 3500, 1770, and 1700 cm-'.

3-(2-Methyl-N-methyl-thiazole-4-yl-methane thio)-6-&alpha;-[1-(R)-hydroxyethyl]-7-oxo-1-azabicyclo (3.2.0) hept-2-ene-2-carboxylate.

To a solution of 525 mg (1.1 mmole) of compound 9 in 20 ml of methylene chloride was added 0.27 ml (3.3 mmole) of methyl fluorosulfonate. The reaction mixture was stirred for 90 minutes at room temperature. The precipitate was collected by filtration and washed with methylene chloride (50 ml) to give 650 mg (100% yield) of the quaternized thiazole 10 which was used for the next step without further purification.

Thus, to a solution of compound 10 in 100 ml of tetrahydrofuran and 100 ml of ether was added 100 ml of pH = 7.0 buffer solution followed by 500 mg of 10% palladium on charcoal.

The mixture was hydrogenated at 35 psi on the Parr shaker for 45 minutes. The mixture was filtered through a Celite pad and the catalyst was washed with water (2 X 10 ml). The combined filtrate and washings were extracted with ether (2 x 100 ml) and lyopholized to give a yellow powder which was purified on a C18 BONDAPAK reverse phase column (8 9) (Water Associates), eluting with 5% acetonitrile in water under 8 psi pressure. Each 15 ml fraction was assayed by high pressure liquid chromatography and fractions having an ultraviolet absorption at Amax 300 nm were collected and lyophilized to give 145 mg (48% yield) of the title compound as a pale yellow powder.

NMR (CDCl3) 8: 1.20(3H, d, J = 7Hz), 2.92(3H, S), 3.08(1 K, d, J = 3.5Hz), 3.20 (1H, d, K = 3Hz), 3.44(1 H, dd, J = 1 Hz, J = 3.5Hz), 4.00(3H, 5), 4.20(3K, m), 4.36(2H, m) and 7.88(1K, s). IR(KBr) #max: 3400, 1750 and 1585 cm1. UV Amax (H20): 296 nm ( = 7500).

Anal. Calc'd. forC15K18N2O4S2.2K2O: 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'-Dim ethyl imidazole-2-yl-methane thio)-6&alpha;-[1-(R)-hydroxyethyl]-7-oxo-1- azabicyclo (3.2.0) hept-2-ene-2-carboxylate

2-Merceptomethyl N-methylimidazole To a solution of 10.4 g (58 m mole) of 2-chloromethyl-N-methylimidazole 31 [prepared by the procedure described in J. Amer. Chem. Soc., 71, 383 (1949)] in 200 ml of acetonitrile was added 7.1 g (60 m mole) of N-acetyl thiourea and, the reaction mixture was heated at reflux for 90 minutes. The precipitate was filtered and washed with acetonitrile (20 ml) to give the isothiouronium salt which was then dissolved into 120 ml of ethanol and heated at reflux for 18 hours under nitrogen atmosphere.The reaction mixture was cooled to room temperature, condensed in vacuo to about 60 ml of volume and the precipitate was removed by filtration.

Evaporation of the filtrate in vacuo gave 2-mercaptomethyl-N-methylimidazole 32 as a yellow oil which was used for the next step without further purification. NMR (D20) d: 3.90(3 H, s), 4.10(2H, s) and 7.25(2H, S).

p-Nitrobenzyl-3-[N-methyl imidazole-2-yl-methane thio]6&alpha;-[1-(R)-hydroxyethyl]-7-oxo-1-azabicyclo (3.2.0) hept-2-ene-2-carboxylate.

To a cooled (0 C) solution of 7.24 g (20.3 m mole) of the keto intermediate 5 in 35 ml of acetonitrile was added 2.8g (21.3 m mole) of diisopropyl ethylamine in 2 ml of acetonitrile followed by 5.5 g (20.4 m mole) of diphenyl chlorophosphate in 2 ml of acetonitrile under a nitrogen atmosphere. The resulting solution was stirred at 0 C for 15 minutes and there was then added a solution of 4.1 g (3.0 m mole) of diisopropyl ethylamine in 2 ml of acetonitrile followed by 4.6 g (31.0 m mole) of the thiol 32. The reaction mixture was allowed to stir for 60 minutes at O"C. The white precipitate was collected by filtration and washed with methylene chloride (20 ml) to give 6.6 g (71% yield) of the title product as a white solid.M.p. 142'. NMR (DMSO-d6) 8: 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 = 14.0 Hz), 7.65(2H, d, J = 6.5 Hz), 7.70(2H, s) and 8.24 (2H, d, J = 6.6Hz). IR(KBr)y max: 3450, 1770 and 1690 cm-1. Anal. Calc'd for C21H20n4O6S1.1 1/2 H2O; C, 52.18; H, 4.79; N, 11.59. Found: C, 52.22; H, 4.91; N, 12.16.

3-(N,N'-Dimethyl imidazole-2-yl-methane ethio)-6&alpha;-[1-(R)-hydroxyethyl]-7-oxo-1-azabicyclo (3.2.0) hept-2-ene-2-carboxylate.

To a suspended solution of 1.34 9 (3.0 m mole) of compound 33 in 270 ml of acetone was added 20 ml of methyl iodide. The reaction mixture was stirred for 4 days at room temperature.

The precipitate was collected by filtration and washed with acetone (20 ml) to give 1.70 9 (96% yield) of the quaternized imidazole 34 as yellow crystals. m.p. 175-177 C. NMR (DMSO-d6) o: 1.10(3H, d, H = 6.2Hz), 3.30(2H, s), 3.2-4.3(6H, m), 3.95(6H, s), 5.45(2H, ABq, J = 14Hz), 7.65(2H, d, J = 6.0Hz). IR (KBr) pmax: 3400, 1750 and 1600cm-1. Anal. Calc'd for C2,H22N406S1: C, 43.08; H ,9.60; N, 5.48. Found: C, 43.02; H, 9.02; N, 5.44.

To a solution of 1.30 9 (1.86 m mole) of compound 34 in 120 ml of tetrahydrofuran and 120 ml of ether was added 120 ml of pH = 7.0 buffer solution followed by 900 mg of 30% palladium on Celite. The mixture was hydrogenated at 40 psi on the Parr shaker for 40 minutes.

The mixture was filtered through a Celite pad and the catalyst was washed with water (2 X 15 ml). The combined filtrate and washing were extracted with ether (3 X 100 ml) and lyophilized to give a yellow amorphous powder which was purified on a C18 BONDAPAK (Waters Associates) column (30 9), eluting with 10% acetonitrile in water under 8 psi pressure.Each 20 ml fraction was assayed by high pressure liquid chromatography and fractions having an ultraviolet absorption at Amax 300 nm were collected and lypholized to give 220 mg (35% yield) of the title product as a yellow powder. NMR(D20)o: 1.12(3H, d, J = 7.0Hz), 3.08 (1H, dd, J = 13.0Hz, 6.4Hz), 3.15 (1H, dd, J = 13.0Hz, 6.4 Hz), 3.45(1H, dd, J = 3.2Hz, 4.5Hz) 3.85(6H, s,) 4.1-4.3(2K, m), 4.40 (1H, d, J = 13.5 Hz), 4.52 (1H, d, J = 13.5 Hz) and 7.40 (2H, s). IR (KBr) #max: 3500, 1750 and 1590 cm-1. UV #max (H2O): 296 nm (# = 8411).

Anal. Calc'd for C15H18N3O4S.H2O: C, 51.68; H, 5.67; N, 12.06; S, 9.50. Found: C, 49.93; H, 5.94; N, 11.46; S, 9.03.

Example 10 Preparation of 3-(2,3,4,-Trimethyl thiazole-5-yl-methane thio)-6&alpha;[1-(R)-hydroxyethyl]-7-oxo-1-aza- bicyclo (3.2.0) hept-2-ene-2-carboxylate

2,-4-Dimethyl-5-mercaptomethyl thiazole To a solution of 4.8 9 (26.0 mmole) of the chloro compound 46 [prepared by the procedure described in J. Amer. Chem. Soc., 104, 4461 (1982)] in 50 ml of absolute ethanol was added 2.4 g (30 mmole) of thiourea. The reaction mixture was heated at reflux for 18 hours. The precipitate was collected by filtration and washed with ether (20 ml) to give the isothiouronium salt which was dissolved into 22 ml of 1 N-sodium hydroxide and heated at 1 00'C for 4 minutes under a nitrogen atmosphere.The reaction mixture was then cooled to room temperature, adjusted to pH 7.0 with 1 N hydrochloric acid and extracted with ether (3 x 50 ml). The combined ether phases were washed with water, brine and dried over MgSO4.

Evaporation of dried solvent gave 780 mg (49% yield) of the thiol 47as a colorless oil which was used for the next step without further purification.

NMR (DCl3) 6: 2.05 (3H, s), 2.35 (3H, s) and 3.60 (2H, d, J = 6.5 Hz).

P-Nitrobenzyl-3-[2,4-dimethyl thiazole-5-yl-methane thio] 6aj 1 -(R)-hydroxy ethyl]-7-oxo- I-azabi- cyclo (3.2.0) hept-2-ene-2-carboxylate.

To a cooled (0 C) solution of 1.4 9 (4.0 mmole) of the keto intermediate 5 in 25 ml of acetonitrile was added 610 mg (4.7 mmole) of diisopropyl ethylamine in 1 ml of acetonitrile followed by 1.15 g (4.3 mmole) of diphenylchlorophosphate in 1 ml of acetonitrile under a nitrogen atmosphere. The resulting solution was stirred for 20 minutes at 0 C, and there was then added a solution of 610 mg (4.7 mmole) of diisopropyl ethlamine in 1 ml of acetonitrile followed by 750 mg (4.7 mmole) of the thiol 47 in 2 ml of acetonitrile. The reaction mixture was allowed to stir for 3 hours at 0 C. The precipitate was collected by filtration and washed with methylene chloride (20 ml) to give 1.14 g (61% yield) of the title product as a white solid.

NMR (DMSO-d6) 8: 1.25(3H, d, J = 6.4Hz), 2.30 (3H,s), 2.65(3H,s), 3.1-3.4(3H,m), 4.10 (1H, broad s), 4.0-4.5 (3H, m), 5.25 and 5,50 (1H each, ABq, J=4Hz), 7.68 (2H, d, J=8.5 Hz) and 8.25 (2H, d, J=8.5Hz). IR (KBr) #max: 3500, 1770 and 1690 cm-1. Anal.

Calc'd for C22H23N3I5S2: 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.

3-(2, 3, 4-Trimethyl thiazole-5-yl-methane thio)-6a-[ 1 -(R)-hydroxyethyl]- 7-oxo- 1 -azabicyclo (3.2.0) hept-2-ene-2-carboxylate.

To a solution of 1.97 9 (4.0 m mole) of compound 48 in 180 ml of methylene chloride was added a solution of 0.98 ml (13 mmole) of methyl fluorosulfonate in 2 ml of methylene chloride. The reaction mixture was stirred for 70 minutes at room temperature. The reaction mixture was poured into a solution of ether (400 ml) and n-pentane (100 ml). The precipitate was collected by filtration and washed with ether (20 ml) to give 1.6 9 (65.5% yield) of the quaternized thiazole 49 as a white amorphous powder. NMR (DMSO-d6) 8. 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, broad s), 7.60 and 8.2(1H each, d, J = 8.5Hz). IR(KBr) ymax: 3400, 1770 and 1690 cm-1. Anal. Calc'd for C23H26N3O9S3F.1/2H2O: C, 45.09; H, 4.44; N, 6.86.

Found: C.44.50; H, 4.38; N, 6.58.

To a solution of 1.0 9 (1.72 mmole) of compound 49 in 100 ml of tetrahydrofuran and 100 ml of ether was added 100 ml of pH = 7.0 buffer solution fiollowed by 1.0 9 of 10% palladium on charcoal. The mixture was hydrogenated at 40 psi on the Parr shaker for 40 minutes. The mixture was filtered through a Celite pad and the catalyst was washed with water (2 X 10 ml).

The combined filtrate and washing were extracted with ether (3 X 100 ml) and lyophilized to give a yellow powder which was purified on a C,8 BONDAPAK (Waters Associates) column (40 9), eluting with 10% acetonitrile in water under 8 psi pressure.

Each 15 ml fraction was assayed by high pressure liquid chromatography and fractions having an ultraviolet absorption at Amax 300 nm were collected and lyophilized to give 315 mg (50% yield) of the title product as a yellow solid. NMR (D20) 8:1.25 (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) ymax 3400,1750 and 1580cm-1. UV Amax: 297 nm (e = 8994). Anal. Calc'd for C15H19N3O4S.2H2O: C, 48.25; H, 6.09; N, 7.79. Found: C, 47.96; H, 5.83; N, 7.89.

Example 11 Preparation of 3-[2-(N-Methylthiazolium) methyl thio]-6&alpha;-[1.(R)-hydroxyethyl]-7-oxo-1-azabicyclo (3.2.0) hept-2-ene-2-carboxylate

2-Mercaptomethyl thiazole To a chloroform solution (30 ml) of thionyl chloride (3.81 ml, 0.052M) qas added at room temperature 3.60 9 (0.026M) of the hydroxymethyl thiazole 1 followed by heating at 50 for 2 hours. Chloroform was evaporated in vacuo leaving a brown solid which was dissolved in 30 ml of absolute ethanol. There was then added 2.04 9 (0.026M) of thiourea.

The mixture was then heated at reflux for 18 hours. The precipitate was collected by filtration, washed with ethanol and ether to give 3.4 9 (55% yield) of the isothiouronium salt 3. The isothiouronium salt 3 was dissolved in 30 ml of water and purged with N2 for 20 minutes.

There was added 1.10 9 (0.027 M) of sodium hydroxide and the mixture was heated at 100" for two minutes. The cooled (0') solution's pH was adjusted to 6.0 with acetic acid followed by ethylacetate (35ml X 2) extraction. The organic layer was dried (MgSO4) and evaporated in vacuo to give 0.759 (42% yield) of the thiol 4 as a yellow oil which was used without further purification; NMR (CDCl3) 8: 2.1(1 H, t), 4.0(2H, d, J = 10Hz), 7.27(1 H, d, J = 3.0Hz) and 8.85(1K, d, J = 3.0Hz).

p-Nitrobenzyl 3-r(2-thiazole) methyl thio]- 6&alpha;[1-(R)-hydroxyethyl]-7-oxo-1-azabicyclo (3.2.0.) hept-2-ene-2-carboxylate.

To a cooled (0 ) solution of 1.4 9 (4.0 mmole) of the keto intermediate 5 in 8 ml of acetonitrile was added 0.79 ml (4.4 mmole) of diisopropyl ethylamine followed by 1.17 g (4.4 mmole of diphenyl chlorophosphate under a nitrogen atmosphere. The resulting solution was stirred at 0" for 30 minutes to provide p-nitrobenzyl 3-(diphenyl phosphoryloxy)-6-[1-(R) hydroxyethyl]-7-oxo- 1 -azabicyclo (3.2.0) hept-2-ene-2-carboxylate. To this solution was added a solution of 0.79 ml (4.4 mmole) of diisopropyl ethylamine in 2 ml of acetonitrile followed by a solution of 0.72 g of the thiol 4 in 2 ml of acetonitrile. The reaction solution was stirred for 60 minutes at 0" and then diluted with 50 ml of ethylacetate and washed with 30 ml of water, 20 ml of 10% aqueous H3PO4 and 30 ml of brine.Evaporation of dried (MgSO4) solvent gave a crystalline solid which was triturated with ether to yield 782 mg (42% yield) of the title product 6 as a white crystalline material. m.p. 158-160"C. NMR (CDCl3) d: 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(1K, d, J =4.0Hz), 7.64(2H, d, J = 8Hz), 7.76(1 H, d, J = 4.0Hz) and 8.24(2H, d, J = 8Hz) IR(KBr) ymax: 3500, 1770 and 1700 c-1.

Anal. Calc'd. for C20H1gN306S2 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.

3-f2-(N-Methyl thiazolium) methylthioj-6a-f 1 -(R)-hydroxyethyl]- 7-oxo- 1 -azabicyclo (3.2.0) hept-2ene-2-carboxylate.

To a solution of 782 mg (1.36 mmole) of compound 6 in 55 ml of methylene chloride was added 0.5 ml of methyl fluorosulfonate and stirred for 90 minutes at room temperature. The precipitate was collected by filtration and washed with methylene chloride (30 ml) and ether (20 ml) to give 630 mg of a crude quaternized thiazole 7 which was used for next the step without further purification.

Thus, to a solution of compound 7 in 140 ml of tetrahydrofuran and 120 ml of ether was added 140 ml of pH = 7.0 buffer solution followed by 650 mg of 10% palladium on charcoal.

The mixture was hydrogenated at 30 psi on the Parr shaker for 35 minutes. The mixture was then filtered and the catalyst was washed with water (2 X 10 ml). The combined filtrate and washing were extracted with ether (2 X 150 ml) and lyophilized to give a yellow powder. The crude yellow powder was purified on C18BONDAPAK reverse phase column (7 9) (Waters Associates), eluting with 5% acetonitrile in water under 8 psi pressure. Each 15 ml fraction was assayed by high pressure liquid chromatography, and fractions having an ultraviolet absorption at Amax 300 nm were collected and lyophilized to give 23 mg (5% yield) of the title compound as a yellow amorphous solid.

NMR (D20) 8: 1.28(3H, d, J = 7.0Hz), 3.12(2H, d, J = 7.0 Hz), 3.44(1 H, dd, J = 1.OHz 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) ymax: 3400, 1740 and 1580 cm -'. uv Amax (H20) 292 nm (e= 7285).

Example 12 Preparation of 3-[1-(RS)-Methyl-N-methyl-pyridine-3-yl-methane thio] 6&alpha;-[1-(R)-hydroxyethyl]-7- oxo- 1-azabicyclo (3.2.0) hept-2-ene-2-carboxylate

P-Nitrobenzyl-3-f 1 -(R, S)methyl-pyridine-s-yl-methane thio] 6a-f 1 -(R)-hydroxyeth yl]- 7-oxo- 1 -azabicyclo (3.2.0) hept-2-ene-2-carboxylate To a cooled (0 C) solution of 1.85 g (5.3 mmole) of the keto intermediate 5 in 20 ml of acetonitrile was added 754 mg (5.8 mmole) of diisopropyl ethylamine in 1 ml of acetonitrile followed by a solution of 1.57 g (5.84 mmole) of diphenyl chlorophosphate in 2 ml of acetonitrile under a nitrogen atmosphere.The resulting solution was stirred for 15 minutes at 0 C, and there was then added a solution of 754 mg (5.8 mmole) of diisopropyl ethylamine in 1 ml of acetonitrile followed by 814 mg (5.8 mmole) of the thiol 27 in 2 ml of acetonitrile. The mixture was stirred at 0 for 3 hours, and then the reaction mixture was diluted with 200 ml of ethylacetate, and washed with ice-cold brine (200 ml), water (200 ml), aqueous bicarbonate (100 ml) and brine (100 ml. Evaporation of dried (MgSO4) solvent gave a yellow oil which was purified by silica gel column chromatography, eluting with 50% acetone-50% methylene chloride to give 1.65 9 of the title product as a yellow solid.

NMR (CDCl3) 8:1.22 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) vmax: 3400, 1765 and 1690cm-1. Anal Calc'd. for C23H23N303S,: C, 58.83; H, 4.94; N, 8.95; S, 6.83.

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

4-(1 '-mercaptoethyl)-pyridine To a solution of 25 9 of 1-(4-pyridyl)-ethanol 25 [prepared by the procedure described in J.

Chem. Soc., Perkin II, 1462(1974)] in 100 ml of chloroform was added 50 9 of thionyl chloride. He mixture was refluxed for 2 hours. Evaporation of solvents in vacuo gave the chloro compound 26 as a semi solid which was used for the next step without further purification.

Thus, to a solution of 26 in 160 ml of ethanol was added a hot solution of 14. g of thiourea in 75 ml of ethanol. The reaction mixture was heated at a reflux for 18 hours. Ethanol was evaporated and residue was dissolved in 100 ml of water and adjusted to pH 10 by addition of 2NNaOH. The mixture was stirred at room temperature for 90 minutes, adjusted to pH 6.0 by addition of 6NHCI and extracted with ether (2 x 200 ml). Evaporation of dried (MgSO4) solvent gave a yellow oil which was distilled at 5 mmHg and collected at the boiling range 60-65'C to give 11.0 9 (38% yield) of the pure thiol 27 as a colorless oil.

NMR (CDCl3) 8: 1.70(3H, d, J = 6.0Hz), 2.05(1 K, 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).

3-[1 -(RS)-methyl-N-methyl-pyridine-3-yl-methane thioj-Saj I -(R)-hydroxyethyl]- 7-oxo- 1 -azabicyclo (3.2.0) hept-2-ene-2-carboxylate To solution of 1.1 9 (2.34 mmole of compound 28 in 100 ml of acetone was added 10 ml of methyl iodide. The reaction mixture was stirred for 18 hours at room temperature. The precipitate was collected by filtration and washed with methylene chloride (10 ml) to give 1.4 9 (100% yield) of the quaternized pyridine 29 as a yellow powder.

NMR (DMSO-d6) 8:1.10 (3H, d, J = 6.5 Hz), 1.62 (3H, d, J = 7.5 Hz), 2.6-4.2 (6H, m), 4.39 (3H, s), 5.42 (2H, ABq, J = 13.6 Hz) and 7.9-9.2 (8H, m). IR(KBr) vmax: 3400, 1770 and 1190 cm-1.

Anal. Calc'd. for C24H26N306S,I,: 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.

To a solution of 1.45 9 (2.37 mmole) of compound 29 in 120 ml of tetrahydrofuran and 120 ml of ether was added 120 ml of pH = 7.0 buffer solution followed by 1.5 9 of 10% palladium on charcoal. The mixture was hydrogenated at 45 psi on the Parr shaker for 60 minutes. The mixture was filtered through a Celite pad and the catalyst was washed with water (2 X 15 ml).

The combined filtrate and washing were extracted with ether (2 X 200 ml) and lyophilized to give a yellow solid which was purified on a C,8 BONDAPAK (Waters Associates) reverse phase column (50 9), eluting with 5% acetonitrile in water under 8 psi pressure.

Each 20 ml fraction was assayed by high pressure liquid chromatography and fractions having an ultraviolet absorption at Amax 300 nm were collected and lyophilized to give 200 mg (24% yield) of the title product as a yellow amorphous solid.

NMR (D20) 8:1.32 (3H, d, J = 7.0 Hz), 1.63 (3H, d, J = 7.2 Hz). 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-'. UV Amax (H20): 296 nm ( = 7573).

Anal. Calc'd. for CC17H20N2O4S11/2H2O: 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'-benzyl imidazole-2-yl-methane thio)-6&alpha;-[1-(R)-hydroxyethyl]-7-oxo- 1 -azabicyclo (3.2.0) hept-2-ene-2-carboxylate

N-Benzyl-2-mercaptomethyl imidazole To a solution of 3.23 9 (13.0 mmole) of the chloro compound 41 [prepared by the procedure described in J. Amer. Chem. Soc., 71, 383 (1949)] in 80 ml of acetonitrile was added 1.72 9 (14.5 mmole) of N-acetylthiourea. The reaction mixture was heated at reflux for 3 hours.

The precipitate was collected by filtration and washed with acetonitrile (10 ml) to give the isothiouronium salt which was then dissolved into 80 ml of absolute ethanol and heated at reflux for 18 hours under a nitrogen atmosphere. The reaction was cooled to room temperature, condensed in vacuo to about 30 ml of volume and the precipitate was removed by filtration.

Evaporation of the filtrate in vacuo gave 3.5 9 (97% yield) of the thiol 42 as a yellow thick syrup.

NMR (CDCl3) 8: 2. 1(1H, t, J = 4.5Hz), 3.80(2H, s), 5.20(2H, s) and 6.8-7.5(7H, m).

P-Nitrobenzyl-3-[N-benzylimidazole-2-yl-methane thio] 6&alpha;-[1-(R)-hydroxyethyl]-7-oxo-1-azabicyclo (3.2.0) hept-2-ene-2-carboxylate To a cooled (0 ) solution of 3.03 g (8.5 mmole) of the keto intermediate 5 in 70 ml of acetonitrile was added 1.1 7g (9.0 mmole) of diisopropyl ethylamine in 2 ml of acetonitrile followed by 2.4 g (9.0 mmole) of diphenyl chlorophosphate in 2 ml of acetonitrile under a nitrogen atmosphere. The resulting solution was stirred for 20 minutes at O"C, and there was then added a solution of 1.17 9 (9.0 mmole) of diisopropyl ethylamine in 2 ml of acetonitrile followed by 4.8 g (15 mmole) of the thiol 42. An additional 1 .93g (15 m ml) of diisopropyl ethylamine was added and the reaction mixture was allowed to stir for 2 hours at 0 C. The precipitate was collected by filtration and washed with cold methylene chloride (20 ml) to give 2.5 g (55% yield) of the title product as a white solid. NMR (DMSO-d6) 8: 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) #max: 3400, 1775 and 1690cm-1.

3-(N Methyl-N'-benzyl imidazole-2-yl-methane thio)-6a-F 1 -(R)-hydroxyethylj- 7-oxo- 1 -azabicyclo (3.2.0) hept-2-ene-2-carboxylate.

To a solution of 1.76 9 (3.3 mmole) of compound 43 in 1.11 of methylene chloride was added 1.15 ml (13.4 mmole) of methyl fluorosulfonate. The reaction mixture was stirred for 2 hours at room teperature. The reaction was concentrated in vacuo to about 15 ml of volume.

The precipitate was collected by filtration and washed with methylene chloride (10 ml) to give 1 .58g (74% yield) of the quaternized imidazole 44 as a white solid. MMR (DMSO-d6) 6: 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=14 Hz), 5.50 (2H, s) and 7.4-8.4 (11H, m). IR (KBr) #max: 3500, 1770 and 1700 cm-1. Anal. Cald'd for C28H29N409S2F: 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.

To a solution of 1.119 (1.71 m mole) of compound 44 in 100 ml of tetrahydrofuran and 100 ml of ether was added 120 ml of pH = 7.0 buffer solution followed by 1.0 9 of 10% palladium on charcoal. The mixture was hydrogenated at 45 psi on the Parr shaker for 45 minutes. The mixture was filtered through a Celite pad and the catalyst was washed with water (2 X 10 ml).

The combined filtrate and washing were extracted with ether (2 X 70 ml) and lyophilized to give a yellow powder which was purified on a C18 BONDAPAK (Waters Associates) column (409), eluting with 10% acetonitrile in water under 8 psi pressure.

Each 15 ml fraction was assayed by high pressure liquid chromatography and fractions having an ultraviolet absorption at Amax 300nm were collected and lyophilized to give 305 mg (43%) of the title product as a slightly yellow amorphous solid. NMR (DMSO) 8: 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) # max: 340, 1760 and 1590 cm-1.

UV #max (H2O): 299 nm (# = 8807). Anal. Calc'd for C21H23H3O4S1.1 1/2 H2O: 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-methane thio)-6&alpha;-[1-(R)-hydroxyethyl]-7-oxo-1- azabicyclo (3.2.0) hept-2-ene-2-carboxylate

2-Methyl-3-mercaptomethyl pyridine The ester 12 was prepared by the procedure described in J. Org. Chem.,21 800 (1956). To a cooled (0 ) suspended solution of 2.86 g of lithium aluminum hydride in 50 ml of dry tetrahydrofuran was added dropwise a solution of 6.23 g (0.038 M) of the ester 12 in 1 5 ml of tetrahydrofuran over a 1 5 minute period. The mixture was stirred for 60 minutes at 0 , and there was then added 50 ml of ethylacetate. The precipitate was filtered, and washed with aqueous saturated ammonium chloride.The organic layer was dried over MgSO4, filtered and evaporated in vacuo affording 3.2 g (70% yield) of the hydroxymethyl pyridine 13 as a yellow oil. NMR (CDCl3) of compound 138: 2.46 (3H, S), 4.73 (2H, S), 5.1 (1H, broad), 7.2 (1H, dd.

J = 8Hz), 7.8(1 H, dd,J = 8Hz, J = 1Hz) and 8.3 (1H, dd J = 7Hz, J = 1Hz) and 8.3 (1H, dd J=7Hz, J= 1Hz).

To a cooled (0 ) solution of 4 ml of thionyl chloride in 10 ml of methlene chloride was added dropwise a solution of 3.2 g (0.026 M) of the alcohol 13 in 10 ml of methylene chloride over a 15 minute period under a nitrogen atmosphere. Cooling bath was removed and the reaction was allowed to stir for 3 hours at room temperature. All solvents were evaporated in vacuo leaving compound 14 as a brown solid which was used for the next step without purification. The crude brown solid was dissolved in 30 ml of absolute ethanol. There was then added 2.5 g (0.032 M) of thio urea and the mixture was heated at 65-70"C for 18 hours. The mixture was cooled to room temperature. The precipitate was collected by filtration and washed with ethanol (20 ml) and ether (50 ml) to yield 30 g of the isothiouronium salt.This salt was dissolved in 10 ml of water and a solution of 640 mg (0.016 M) of sodium hydroxide in 10 ml water was added under nitrogen. The reaction mixture was heated at 100" for 2 minutes and then cooled to 0 adjusted to pH = 6.0 with acetic acid and extracted with chloroform (2 X 35 ml). Evaporation of dried (MgSO4) chloroform gave 941 mg (46% yield) of the thiol 15 as a yellow oil.

NMR (COCK3) of the thiol 158:1.8(1K, t), 2.60(3H, S), 3.73(2H, d, J = 10 Hz), 7.13(1 K, dd, J = 8 Hz) 7.57(1K, dd, J = 8Hz), and 8.43(1H, dd,

P-Nitrobenzyl-3-(2-methylpyridine-3-yl-methene thio)-6&alpha;-[1-(R)-hydroxyethyl]-7-oxo-1-azabicyclo (3.2.0) hept-2-ene-2-carboxylate.

To a cooled (0 ) solution of 1.52 g (4.37 mmole) of the keto intermediate 5 in 5 ml of acetonitrile was added 0.86 ml (4.80 mmole) of diisopropyl ethylamine followed by a solution of 1.17 g (4.37 mmole) of diphenylchlorophosphate in 3 ml of acetonitrile under a nitrogen atmosphere. The resulting solution was stirred for 30 minutes at O'C to provide p-nitrobenzyl-3 (diphenylphosphoryloxy) -6a-[ 1 -( R)-hydroxy ethyl]-7-oxo- 1 -azabicyclo (3.2.0) hept-2-ene-2-carboxylate. To this solution was added a solution of 0.86 ml (4.80 ml (4.80 mmole) of diisopropyl ethyl amine in 2 ml of acetronitrile followed by a solution of 940 mg (6.76 mmole) of the thiol 15 in 2 ml of acetonitrile. The reaction mixture was stirred for 60 minutes at 0 C.The precipitate was collected by filtration and washed with ether (30 ml) to give 1.12 g (55 % yield) of the title product as a pale yellow solid. M.P. 186-188 C (decomp).

NMR (DMSO-d6) #: 1.20 (3H, d, J=7Hz), 2.60 (3H, S), 3.40 (m, 2H), 4.16 (m, 2h), 4.32 (2H, S), 6.16 (1H, d, J=5Hz), 6.44 (2H, q, J=14Hz), 7.32 (2H, m), 7.8 (2H, d, J=8Hz) 8.36 (2H, d, J=8Hz) and 8.48 (1H, dd, J=5.5Hz, 1.6Hz). IR (KBr) #max: 3500, 1770 and 1750 cm-1.

Anal. Calc'd, for C23H24N3O6S: C, 58.3; H, 4.94; N, 8.94; S, 8.83.

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

3-(2-Methyl-N-methylpyridine-3-yl-methane thio)-6&alpha;[1-(R)-hydroxyethyl]-7-oxo-1-azabicy- chlo(3.2.0) hept-2-ene-2-carboxylate To a solution of 697 mg (1.19 mmole) of compound 16 in 100 ml of methylene chloride was added dropwise at 10 C 0.5 ml (6.18 mmole) of methyl fluorosulfonate over a 10 minute period. The mixture was stirred for 2.5 hours at room temperature. The precipate was collected by filtration and washed with 30 ml of methylene chloride to give 777 mg (90%) of the quaternized pyridine 17 as a yellow solid.

NMR (CDCl3) of compound 17#: 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, 8.5H), 8.32 (2H, d, J=8Hz), 8.64 (1H, d, J=7.5Hz), and 9.08 (1H, d, J=7.5 Hz).

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

Anal. Calc'd. for C24H26FN3O9S: C, 48.91; H, 4.55; N, 7.23; S, 11.04 Found: C, 49.39; H, 3.97; N, 7.20; S, 10.98 To a solution of 1.10 g (1.88 mmole) of compound 17 in 80 ml of tetrahydrofuran and 80 ml of ether was added 80 ml of pH 7.0 buffer solution followed by 800 mg of 10% palladium on charcoal. The mixture was hydrogenated at 30 psi on the Parr shaker for 40 minutes. The mixture was filtered through a Celite pad and the catalyst was washed with water (2 X 10 ml).

The combined filtrate and washing were extracted with ether (2 X 100 ml) and lyophilized to give a yellow powder which was purified by HP-20 column chromatography, eluting with water followed by 5% acetonitrile in water. Each 15 ml fraction was assayed by high pressure liquid chromatography and fractions having an ultraviolet absorption at #max 300 nm were collected and lyophilized to give 614 mg (24% yield) of the title product as a slightly yellow powder.

NMR (C2O) #: 1.28 (d, 3H, 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) #max: 3400, 1760, and 1590 cm-1. UV #max (H2O): 298 nm (#=8391).

Anal. Calc'd for C17H20N2O3SH2O: 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)-meth ylthioj-6a-f 1 (R)-hydroxyethylj- 7-oxo- 1 azabicyclo (3.2.0) hept-2-ene-2-carboxylate

A. Preparation of isomer A

Methyltrifluoromethane sulfonate (0.58 mL, 5.1 6 mmol) was added dropwise to an icecooled, stirred, solution of 4-(methanethiolacetate)-1-methyl-1,2,3-triazole (590 mg, 3.52 mmol) in dry methylene chloride (2 mL) under nitrogen. After 0.5 h, the bath was removed and after 1 h, the solvent was removed with an aspirator. The residual oil was dissolved in a few mL of water and this solution was cooled in an icebath. A cold solution of sodium hydroxide (305 mg, 7.59 mmol) in a few mL of water was then added and the reaction was left stirring for 0.75 h.

The solution was diluted to 25 mL with water and the pH was adjusted to 7.5 by the addition of solid sodium dihydrogen phosphate monohydrate. Then, 14 mL of this solution (ca. 1.9 mmol of the triazolium thiol) was added to an ice-cooled, stirred, solution of the enol phosphate (1.0 g, 1.72 mmol) in tetrahydrofuran (THF) (10 mL). This was left stirring for 0.75 h (some crystalline material, presumably Na2HPO4 is deposited during the course of this reaction). The suspension was transferred to a pressure bottle with the aid of some THF (20 mL) and water (20 mL). Ether (30 mL) and 10% palladium on charcoal (1.0 9) were added and the mixture hydrogenated (40 P.S.I.) for 1 h. The organic phase was separated and washed with water (2 X 5 mL).The combined aqueous phases were filtered and the filtrate was concentrated under high vacuum (ca. 0.5 mm, 1.5h). The yellow solution was then chromatographed (medium pressure reverse phase column, 35 X 90 mm, H20 as eluent) to afford, after lyophilization, 395 mg of the carbapenem slightly contaminated with some inorganic material.It was purified by HPLC (10 X 300 mm Waters Microbondapack C-18 column, multiple injections, H20 as eluent) to give 310 mg (57%) of isomer A as a tan-colored powder 1HNMR (D2O) 8:1.23(3K, d, J = 6.4 Hz), 3.10 (2H, d, J = 9.1 HZ), 3.24 (1H, q, J = 2.7, 6.1Hz), 4.03-4.71 (10H, m), 8.46 (1H, s); IR (nujol) 1760 cm-1; uv (phosphate buffer, pH 7.4, M = 0.05) #max: 296 (#=7,500).

B. Preparation of isomer B and isomer C

(tentative structure) Methyltrifluoromethane sulfonate (1.60 mL, 14.0 mmol) was added dropwise to an ice-cooled solution of 4-(methanethiolacetate)-2-methyl-1,2,3-triazole (1.20 g, 7.02 mmol) in dry methylene chloride (6 mL) under nitrogen.

This was allowed to warm to room temperature and left stirring for 16 h. Additional methyltrifluoromethane sulfonate (0.40 mL, 3.56 mmol) was added and after 3 h at room temperature, the solvent was removed with an aspirator.

The residual oil was triturated with ether and the resulting gum was dissolved in water (5 mL).

This was cooled in an icebath and a solution of sodium hydroxide (844 mg, 21.1 mmol) in water (5 mL) was added. After stirring for 0.75 h, this solution was diluted to 60 mL with water and the pH adjusted to 8 by the addition of solid potassium dihydrogen phosphate. Then, 40 mL of this solution (ca. 4.7 mmol of a mixture of isomeric triazolium thiols) was added to an icecooled, stirred, solution of the enol phosphate (2.00 g, 3.45 mmol) in THF (60 mL). This mixture was left stirring in the icebath for 0.5 h after which it was transferred to a pressure bottle containing a suspension of 10% palladium on charcoal (2.00 g) and ether (60 mL). The mixture was hydrogenated (40 P.S.I.) for 1 h. The organic phase was separated and washed with water (2 X 10 mL).The combined aqueous phases were filtered and the filtrate was concentrated under high vacuum (ca. 0.5 mm, 1.5 h). The remaining solution was then chromatographed (medium pressure reverse phase column, 45 X 130 mm, H20 as eluent) to afford, after lyophilization, 595 mg of a mixture of isomeric carbapenems which were contaminated with a little inorganic material.These were separated and purified by HPLC (10 X 300 mm Waters Microbondapack C-18 column, multiple injections, H20 as eluent) to afford, in order of elution: isomer B; 153 mg (13%); 1HNMR (D20) 8:1.23 (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); IR (nujol) 1755cm-1; uv (phosphate buffer, pH = 7.4, M = 0.05) Amax: 296 nm (e= = 6,700); and isomer C; 284 mg (24%); 1HNMR (D2O) 8:1.23 (3H, d, H = 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); IR (nujol) 1750 cm-1; uv (phosphate buffer, pH 7.4, M = 0.05) Amax: 298 nm (E= 7,600).

Example 16 (5R,6S)-6-(1R-hydroxyethyl)-3-(2-methyl-1,2,3-thiadiazolium-4-ylmethylthio)-7-oxo-1-azabicyclo[3. 2. O]hept-2-ene-2-carboxylate

A. Ethyl 1,2, 3-thiadiazol-4-ylcarboxylate"

A solution of ethyl &alpha;-N-carbethoxyhydrazonoproprionate (31.2 g, 0.154 mol) in thionyl chloride (80 mL) was stirred at 23 C fo 3 h and heated at 70 C for 20 min. Thionyl chloride was evaporated and the residue was triturated in hexane (4 X 30 mL). The red solid was dissolved in dichloromethane (150 mL) and the solution was washed with saturated sodium bicarbonate solution and water. After drying over Na2SO4 the solution was concentrated until the compound crystallized. After standing at 23 C for a while, the crystals were filtered; 16.8 9, mp 86 C, 69%.The filtrate was concentrated and purified by chromatography on a silica gel column with dichloromethane as eluting solvent to give 3.17 9, mp 86 C, 13%, ir (KBr)Prnxx: 1720 (ester) cm-1;1Kmr (CDCIS) 8:1.52 (3H, t, J= 7.1 Hz, CH3CH2O), 4.57 (2H, q, J = 7.1 Hz, CH3CH2O), 9.47 (1 H, s, H of thiadiazole).

aC.D. Hurd and R.l. Mori, J. Am. Chem. Soc., 77, 5359 (195).

B. 1,2,3-thiadiazol-4-ylmethanol

To a suspension of ethyl 1,2,3-thiadiazol-4-ylcarboxylate (18.35 g, 0.116 mol) in ether (400 mL) was added portionwise lithium aluminum hydride (2.47 g, 0.065 mol) over 1 h period. The reaction mixture was stirred at 23 C for 7 h and treated with lithium aluminum hydride (2.47 g, 0.065 mL). The stirring was continued for 24 h before adding successively water (7 mL), 15% sodium hydroxide solution (7 mL) and water (21 mL). After stirring for 15 min, the ether solution was decanted and the gum was extracted with ether (5 x 100 mL). The ether extracts were combined, dried (MgSO4) and concentrated (5.4 g).The crude material was purified on silica gel column (120 9, 4 X 16 cm), with ether as eluting solvent to give 1.3 g (7%) of ethyl 1,2,3-thiadiazol-4-ylcarboxylate and 2.45 (18%) of 1,2,3-thiadiazol-4-ylmethanol; ir (film) #max: 3380 (OH) cm-1; Hmr (CDCl3)#: 2.31 (1H, s, OH), 5.22 (2H, s, CH2O), 8.50 (1H, s, H of thiadiazole).

1S.I. Rämsby, S.O. Ögren, S.B. Ross and N.E. Stjernström, Acta Pharm. Succica., 10, 285-96 (1973); C.A., 79, 1 3702W (1 973).

C. 1,2,3-thiadiazol-4-ylmethanol methanesulfonate

A solution of 1,2,3-thiadiazol-4-ylmethanol (0.75 g, 6.5 mmol) in dichloromethane (20 mL) was cooled to 5 C under a nitrogen atmosphere and treated with triethylamine (1.018 mL. 7.3 mmol) and methanesulfonyl chloride (0.565 mL, 7.3 mmol). After 15 min, the ice-bath was removed and the reaction mixture was stirred for 2 h. The solution was washed with IN hydrochloric acid solution (2 X 2 mL) and water, dried (MgSO4 + MgO) and concentrated.The residue was purified by chromatography (silica gel column 1.5 X 21 cm) with ether as eluting solvent to give 0.90 g (71 %) of 1 ,2,3-thiadiazol-4-ylmethanol methanesulfonate; ir (film)vmax: 1350 (SO2) cm-1, 1172 (SO2) cm-1; Hmr (CDCl3)8: 3.09 (3H, s, CH3), 5.75 (2H, s, CH2), 8.72 (1 H, s, H of thiadiazole); uv (CH2CI2)AmaX 251 (# 1990). Anal. calcd for C6H6N203S: 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 and 0.139 (19%) of di-(1 ,2,3-thiadiazol-4-ylmethyl)ether; ir (film)vmax: 1272, 1242, 1200, 986, 805, 728 cm -1; Hmr (CDCl3)8: 5.16 (s, 4K, CH2), 8.42 (s, 2H, H's of thiadiazole).

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

To a solution of 1 ,2,3-thiadiazol-4-ylmethanol methanesulfonate (0.90 9, 4.6 mmol) in tetrahydrofuran (9 mL) was added an aqueous solution (2 mL) of sodium thiolacetate (prepared from thiolacetic acid (0.38 mL, 5.3 mmol) and sodium bicarbonate (0.445 9, 5.3 mmol)]. The resulting mixture was stirred at 23 C for 1 h and diluted with ether (75 mL). The organic solution was washed with water (3 X 3 mL), dried (MgSO4) and concentrated. The crude mixture was purified by chromatography (silica gel column: 1.4 X 19 cm) with 50% ether in hexane as eluting solvent to give 0.60 g (75%); ir (film)vmax: 1675 (C = O) cm-1; 'Hmr (CDCl3) o: 2.37 (3H, s, CH3), 4.58 (2H, s, CH2), 8.44 (1 H, s, H of thiadiazole).Anal. calcd for C5H6N20S2: 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.

E. 4-acetylthiomethyl-2-methyl- 1,2,3-thiadiazolium trifluoro-methanesulfonate and 4acetylthiomethyl-3-methyl-1,2,3-thiadiazolium trifluormethane sulfonate

To a solution of 4-acetlythiomethyl-1 ,2,3-thiadiazole (0.60 9, 3.44 mmol) in a mixture of ether (4 mL) and dichloromethane (0.4 mL) were added a few crystals of the title compounds and trifluoromethanesulfonate (0.407 mL, 3.6 mmol) over 5 min period. The reaction mixture was stirred at 23 C under a nitrogen atmosphere for 6 h.The white solid that was a mixture of the two title compounds was filtered and washed with ether, 1.05 g, 90%; ir (KBr)vmax: 1675 (C = O) cm-1; Hmr (DMSO, d-6)8: 2.43 (3H, s, CH3COS), 3,33 (s, CH3 on N-3), 4.57 (s, CH3 on N-2), 4.66 (2H, s, CH2), 9.55 (H on thiadiazolium N-2), 9.66 ( H on thiadiazolium N-3).

Anal. calcd for C7HgN204S3F3 ; 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-mercaptome thyl-3-meth yl- 1,2, 3-thiadiazolium trifluoromethanesulfonate

A solution of a mixture of 4-acetylthiomethyl-1,2,3-thiadiazolium trifluoromethanesulfonate and 4-acetylthiomethyl-3-methyl-1 ,2,3-thiadiazolium trifluomethanesulfonate (1.05 g, 3.1 mmol) in 6N hydrochloric acid (10 mL) was heated at 65 C under a nitrogen atmosphere for 1.75 h.

The solvent was evaporated under reduced pressure leaving a yellow syrup 0.91 g. This compound was used in the next step without purification.

G. (5R, 6S) 6-( 1 R -hydroxyethyl)-3-(2-methyl- 1,2, 3-thiadiazolium-4-ylmethylthio)- 7-oxo- 1 -azabicyclo[3. 2. Ojhept-2-ene-2-carboxylate

A cold (5 C) solution of (5R,6S) paranitrobenzyl 6-(1 R-hydroxyethyl)-3-(diphenylphosphono)-7oxo-1-azabicyclo(3.2.0)-hept-2-ene-2-carboxylate (1.7 g, 2.92 mmol) in tetrahydrofuran (10 mL) was treated with a solution of a crude mixture of 4-mercaptomethyl-2-methyl-1,2,3-thiadiazo- lium trifluoromethanesulfonate and 4-mercaptomethyl-3-methyl-1,2,3-thiadiazolium trifluoromethanesulfonate (0.9 9) in a mixture of phosphate buffer (pH 7.2, 0.3M, 15 mL) and tetrahydrofuran (5 mL). The reaction mixture was stirred for 1 h and the pH was kept at 7.2 with 2N sodium hydroxide solution.The stirring was continued for one more hour before adding ether (50 mL) and 10% palladium on charcoal (1 g). The resulting mixture was hydrogenated at 23 C under 45 psi for 2 h and filtered through a Celite pad. The organic phase was separated, diluted with ether (50 mL) and phosphate buffer (pH 7.2, 0.3M, 20 mL) and hydrogenated (2 g of 10% palladium on charcoal) for 2 h under 50 psi. The aqueous phases were combined (from the first and second hydrogenolysis), washed with ether and purified by chromatography on PrePak 500-C/18 with water as eluting solvent to give 0.22 g of crude material.It was repurified by hplc with water as eluting solvent to give 0.040 g (4%) of the title compound after lyophilization, ir (KBr)vmax: 3400 (br, OH), 1745 (C = O of fi-lactam), 1580 (carboxylate) cm - 1; Hmr (D2O) #: 1.23 (3H, d, J= 6.3 Hz, CH3CHOH), 3.04, 3.05, 3.16 (2H, m, H-4), 3.38 (1H, dd, J= 2.8 Hz, J= 6.0 Hz, 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) Amax:: 224 (E4345), 262 (#4980), 296 (e6885), [&alpha;]D20 18 (c 0.18, H20); T1/2 = 9.8 h (measured at a concentration of 10-4 M in phosphate buffer pH 7.4 at 36.8 C) Example 17 Potassium 3-[5-(1-carboxylatomethyl-3-methyl-1,2,3-triazolium)-methanethio]-6&alpha;-[1-(R)-hydroxye- thyl]- 7-oxo- 1 -azabicyclo[3. 2. O]hept-2-ene-2-carboxylate

Lithium aluminum hydride (2.83 g, 70.9 mmol) was added in small portions to a stirred suspension of 1-methyl-1,2,3-triazole-4-carboxylic acid1 (9.00 g, 70.9 mmol) in dry THF (200 mL).The mixture was left stirring at room temperature for 1 5 h after which a 20% aqueous solution of sodium hydroxide (20 mL) was carefully added in ca. 1 mL aliquots. The resulting granular suspension was filtered and the solid washed with additional THF (5 X 75 mL). The combined TKF solutions were dried (MgSO4) and the solvent removed. The residual yellow oil was flash chromatographed on a silica gel column (90 x 35 mm) [100 mL portions of hexane, mixtures of ethyl acetate-hexane (1:1) and (1:3), and lastly ethyl acetate-methanol (9:1) as eluent]. This afforded 4-hydroxymethyl-1 -methyl-i ,2,3-triazoie (3.18 9, 40%) as a colourless oil: tHNMR (CDCl3) 84.07 (3H, s), 4.73 (2H, d), 7.52 (1H, s); IR (neat) 3320 cm-'.

Methanesulfonyl chloride (3.82 mL, 49.6 mmol) was added dropwise to an ice-cooled, stirred, solution of the alcohol (4.67 mL, 441.3 mmol) and triethylamine (7.47 mL, 53.7 mmol) in methylene chloride (20 mL). After 0.5 h, the solvent was removed and the residual solid was taken up in acetonitrile (30 mL). Potassium thiolacetate (7.06 9, 62.0 mmol) was then added and the suspension was left stirring at room temperature for 3 h. An additional quantity of potassium thiolacetate (3.0 g, 26.3 mmol) was added and the suspension was left stirring for a further 1 6 h. The dark-coloured suspension was then concentrated and water (10 mL) was added. This mixture was extracted with methylene chloride (5 x 40 mL). The combined extracts were dried (MgSO4) and the solvent removed.The residual oil was flash chromatographed on a silica gel column (90 X 36 mm) [hexane followed by a mixture of hexane-ethyl acetate (1:1) being used as eluent]. This afforded 4-(methanethiolacetate)-1methyl-1,2,3-triazole (5.95 9, 84%) as a faint pink coloured solid: 1HNMR (CDCl3) 2.40 (3H, s), 4.10 (3H, s), 4.20 (2H, s), 7.53 (1H, s); IR (nujol mull) 1675 cm~'.

A solution of the triazole (1.00 9, 5.85 mmol) and ethyl bromoacetate (1.48 mL, 1 3.3 mmol) in dry acetonitrile (10 mL) was heated at 60 for 90 h under nitrogen. The solvent was removed and the residual oil was triturated with ether (4 X 25 mL) to leave 1-methyl-3-(ethyl carboxyme thyl)-4-methanethiolacetate-1 ,2,3-triazolium bromide as a brownish gum which was used directly.

A cold solution of KOH (0.66 g, 12 mmol) in water (5 mL) was added to an ice-cooled, stirred, solution of the triazolium bromide in water (20 mL). After 20b min, this was diluted to 35 mL and sufficient solid potassium dihydrogen phosphate was added to bring the pH of this solution to 8.0. This was then added to a stirred, ice-cooled, solution of the enol phosphate in TKF (35 mL). After 0.5 h, this mixture was transferred to a pressure bottle containing ether (35 mL) and 10% palladium on charcoal (1.5 g). It was hydrogenated at 40 p.s.i. for 55 min. The organic phase was then separated and washed with water (2 X 5mL). The combined aqueous phases were filtered and the filtrate concentrated under high vacuum. The residual material was chromatographed on a reverse phase column (35 X 1 20 mm) with water as eluent. Lyophiliza 'C. Pederson, Acta. Chem. Scand., 1959, 13, 888 tion of the carbapenem containing fractions left 1.20 9 of green-coloured solid. This was rechromatographed on a Waters Prep. 500 HPLC (PrepPAK-S00/C18 column) with 2% acetonitrile-water as eluent. The fractions containing the carbapenem were combined and lyophilized.This material was again rechromatographed by HPLC (10 X 300 mm Waters Microbondapack C-1 8 column) with water as eluent to afford, after lyophilization, pure title compound (190 mg, 17%) as a pale yellow solid: 1KNMR (D20) 8 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:mull) 1750 cm-1; UV (phosphate buffer, pH 7.4)Amax 296 nm (e = 7,520).

Example 18 Potassium 3-[4-(1-carboxylatomethyl-3-methyl-1,2,3-triazolium)-methanethiol)-6&alpha;-[1-(R)-hydroxy- ethyl 7-oxo- 1-azabicyclo[3. 2. O]hept-2-ene-2-carboxylate

A mixture of ethyl azidoacetate (30.0 g, 0.23 mol) and propiolic acid (14.3 mL, 0.23 mol) in toluene (75 mL) was stirred at room temperature. The reaction remained mildly exothermic for 1.5 h after which it quickly became vigorously exothermic and cooling with an ice bath was necessary. After this exothermic phase had passed, the reaction was heated at reflux for 0.5 h.

After being cooled in an ice bath, the crystalline material was collected by filtration and washed with a little toluene. The crude material obtained in this manner (33.3 g, 72%) consisted of a single isomer [1HNMR (DMSO-dB) 1.20 (3H, t, J =7 Hz), 4.15 (2H, q, J = 7 Hz), 5.42 (2H, s), 8.67 (1 H, 3)], presumably 1-(ethyl carboxymethyl)-1,2,3-triazole-4-carboxylic acid by analogy with earlier works.

A solution of the carboxylic acid (5.00 9, 25.1 mmol) and triethylamine (3.68 mL, 26.4 mmol) in dry methylene chloride (50 mL) was added to an ice-cooled, stirred, solution of ethylchloroformate (2.52 mL, 26.4 mmol) in dry methylene chloride (50 mL). The purple coloured solution was left stirring for 0.5 h after which it was washed with water (10 mL), dried (MgSO4) and the solvent removed. The crude mixed anhydride was dissolved in THF (50 mL) and added slowly to an ice-cooled suspension of sodium borohydride (0.72 9, 18.9 mmol) in THF (50 mL).

After stirring for 0.5 h, additional sodium borohydride (0.30 9, 7.9 mmol) was added and the reaction was left in the ice bath for 1 h. Water (5 mL) was then added and after 10 min, this was followed by 10% aqueous HCI (3 mL). After gas evolution had ceased, solid potassium carbonate (2 9) was added with 1C. Pederson, Acta. Chem. Scand., 1959, 13, 888 stirring. The organic phase was then removed and the residual white paste was extracted with additional THF. The combined organic phases were dried (MgSO4) and the solvent removed.

Flash column chromatography on silica gel, eluting with hexane, mixtures of ethyl acetatehexane, and finally ethyl acetate afforded 1 -(ethyl carboxymethyl)-4-hydroxymethyl- 1,2, 3-triazole (2.04 g, 44%) as a crystalline solid: 1KNMR (CDCl3) 8 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).

Diisopropylazodicarboxylate (4.11 mL, 20.8 mmol) was added dropwise to an ice-cooled solution of triphenylphosphine (5.47 9, 20.8 mmol) in dry THF (100 mL) under nitrogen. After 0.5 h, an ice-cooled solution of the alcohol (1.93 9, 10.4 mmol) and thiolacetic acid (1.49 mL, 20.8 mmol) in dry TKF (50 mL) under nitrogen was added to this mixture. This was left for 2 h in the ice bath and then for an additional 1 2 h at room temperature; after which the solvent was removed. The reaction mixture was flash chromatographed on silica gel (40 9; eluting with 100 mL portions of hexane, 5%, 10%, 15%... 50% ethyl acetate-hexane).Fractions containing the thiolacetate were combined and rechromatographed on silica gel (60 9) [elution with 200 mL portions of: hexane, 5%, 10%, 15%, 20% ethyl acetate-hexane and 22.5, 25, 27.5. . .35% ethyl acetate-hexane]. This afforded 1.24 9 (49%) of 1-(ethyl carboxymethyl)-4-methanethiolacetate-1,2,3-triazole as a crystalline solid [1HNMR 8 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 mull), 1735, 1780cm-1] and an additional 1.40 9 of material contaminated with triphenylphospine oxide.

Methyl trifluoromethane sulfonate (0.51 mL, 4.53 mmol) was added dropwise to an icecooled, stirred, solution of the triazole (1.00 9, 4.1 2 mmol) in dry methylene chloride (5 mL).

The bath was removed after 0.5 h and after an additional 0.5 h, the solvent was removed with an aspirator vacuum. This left a white solid which was suspended in water (15 mL) and this stirred mixture was cooled in an icebath. A solution of KOH (0.69 g, 1 2.4 mmol) in water (5 mL) was added and the reaction was left stirring for 1 h. It was then diluted to 30 mL with water and solid potassium dihydrogen phosphate was added to bring the pH to 8.0. A portion of this solution (22 mL, ca. 3.0 mmol of the thiolcarboxylate) was added to an ice-cooled, stirred solution of the enol phosphate (1.60 9, 2.76 mmol) in THF (30 mL). After 0.5 h, the reaction was taken and put under high vacuum to remove the THF.The yellow solution was then chromatographed on a reverse phase column (35 X 120 mm) eluting with water (300 mL) followed by 100 mL portions of 5, 10, 1 5.. .30% acetonitrile-water. Lyophilization of the desired fractions afforded the p-nitrobenzyl ester as a yellow solid (930 mg). This was transferred to a pressure bottle containing ether (25 mL), TKF (25 mL), and phosphate buffer [25 mL, prepared by dissolving potassium dihydrogen phosphate (1.36 9, 0.01 mol) in water (100 mL) and adjusting the pH to 7.4 by adding 45% aqueous KOH] amd 10% palladium on charcoal (900 mg). The hydrogenation was conducted at 40 p.s.i. for 1 h after which the organic phase was separated and washed with water (2 X 5 mL). The combined aqueous phases were filtered and then concentrated under high vacuum. The residual solution was chromatographed on a reverse phase column (35 X 120 mm) eluted with water. Fractions containing the carbapenem were combined and lyophilized to afford 1.21 9 of a pale greenish solid. This was then purified by KPLC (lOX 300 mm water microbondapack C-18 column, H20 as eluent) to give pure title product, 480 mg (41%): 1HNMR (D20) 8 1.23 (3H, d, J = 6.4 Hz), 3.11 (2H, d, J = 9n Hz), 3.37 (1 H, q, J = 3.0, 6.1 Hz), 4.02 (7H, m), 5.18 (2H, s), 8.53 (1H, s): IR (nujol mull) 1750 cm-1: UV (phosphate buffer, pH 7.4)AmaX 205 nm (e= 7,810).

Example 19 3-[5-(1,4-Dimethyl-1,2,4-triazolium)methanethio]-6&alpha;-[1-(R)-hydroxyethyl]-7-oxo-1-azabicy- clo[3. 2. O]hept-2-ene-2-carboxylate

A. 1 -methyl-5-methanethiolacetate- 1,2, 4-triazole

Methanesulfonyl chloride (0.46 mL, 6.0 mmol) was added dropwise to an ice-cooled, stirred, solution of 1-methyl-5-hydroxymethyl-1,2,4-triazole* (565 mg, 5.0 mmol) and triethylamine (0.91 mL, 6.5 mmol) in methylene chloride (5 mL). After 20 min, additional triethylamine (1.05 mL, 7.5 mmol) followed by thiolacetic acid (0.53 mL, 7.5 mmol) was added and stirring was continued for 45 min. The reaction was then diluted with *R.G. Jones and C. Ainsworth, J. Amer. Chem. Soc., 1955, 77, 1938.

methylene chloride and washed with water. The aqueous phase was extracted with methylene chloride (3 X 5 mL) and the combined organic phases were dried (MgSO4) and the solvent removed. Column chromatography on silica gel afforded pure 1 -methyl-5-methanethiolacetate1,2,4-triazole (570 mg) as a yellow oil [in addition, an impure fraction (200 mg) was rechromatographed (preparative TLC, silica gel) to give a further 100 mg of pure material (total yield: 85%)]: 'HNMR (CDCl3) 2.38 (3H, s), 3.90 (3H, s), 4.25 (3H, s), 7.80(1K, s).

B. 3-[5-(1, 4-dimethyl- 1, 2, 4-triazolium)-methanethio]-6a-[1 -(R)-hydroxyethylj- 7-oxo- 1 -azabicyclo[3. 2. O]hept-2-ene-2-carboxylate

Methyl trifluoromethanesulfonate (1.20 mL, 10.7 mmol) was added dropwise to an ice-cooled solution of 1 -methyl-5-methanethiolacetate-l ,2,4-triazole (730 mg, 4.27 mmol) in methylene chloride (7 mL). The reaction mixture was slowly allowed to warm to room temperature over 3 h after which it was concentrated. The residual oil was triturated with ether to leave crude 1,4 dimethyl-5-methanethiolacetate-l ,2,4-triazolium trifluoromethanesulfonate (1.46 g) which was used directly.

A solution of sodium hyroxide (512 mg, 12.8 mmol) in water (5 mL) was added to an icecooled solution of the triazolium salt (1.45 9, 4.35 mmol) in water (5 mL). After 45 min, this was diluted to 25 mL with water and the pH was adjusted to 7.6 with solid potassium dihydrogen phosphate. This solution was then added to an ice-cooled, stirred, solution of the enol phosphate (2.00 g, 3.45 mmol) in TKF (25 mL). After 30 min, the reaction mixture was transferred to a pressure bottle containing ether (40 mL) and 10% palladium on charcoal (2.0 g). This was hydrogenated (45 p.s.i.) for 1.25 h. The reaction mixture was then diluted with (25 mL) and filtered. The organic phase was deparated and washed with water (2 X 5 mL). The combined aqueous phases were washed with ether (3 X 25 mL) and then concentrated under vacuum.Column chromatography (reverse phase, 45 x 130 mm, water as eluent), followed by lyophilization of the carbapenem-containing fractions, afforded 650 mg of crude material. This was rechromatographed to give pure title product (450 mg, 39%): 1 HNMR (D20) 8 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(1K, s); IR (nujol mull) 1755 cm-1; UV (phosphate buffer, pH 7.4) Amax 294 nm (e = 8,202); T,/2 (phosphate buffer, pH 7.4, M = 0.067, T = 37 C) 9.1 h.

Example 20 (1 'R, 5R, 6S) 3-F(1, 3-dimethyl-5-tetrazolium)-methylthio]-6-( 1 -hydroxyethyl)- 7-oxo- 1 -azabicyclo[3. 2. O]hept-2-ene-2-carboxylate

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

1 a. Methylation with diazomethane A solution of 5-carbethoxytetrazole' (9.1 7 g, 0.064 mmol) in ethyl ether2 (80 mL) was cooled and treated 1D.Moderhack, Chem, Ber., 108, 887 (1975).

2The use of a mixture of ethanol and ether gave the same ratio of isomers.

dropwise (15 min) with a solution of diazomethane (15 min) with a solution of diazomethane (3 g, 0.07lmmol) in ether (200 mL). The light yellow solution was stirred for 30 min and the excess of diazomethane was destroyed by addition of acetic acid (1 mL). Evaporation of the solvent and distillation of the residue gave a clear oil: bp 95-100 C/0.5 torr; 9.64 g, (96%).

1Kmr indicated a mixture of 1-methyl and 2-methyl isomers in a ratio 6:4. Separation of the two isomers could not be done by distillation nor hplc: ir (film) #max: 1740 cm -1 (C = O of ester); Hmr (CDCl3) 8:1.53(3K, two overlapping t, J = 7.0, CH2CH3), 4.46 and 4.53 (3H, 2S, CH3 of 1-methyl and 2-methyl tetrazoles, ration 6:4. The methyl of the 2-isomer is at lower field and is the minor product), 4.5 ppm (2H, two overlapping q, CH2CH3).

1 b. 5-Carbethoxy-2-methyltetrazole

A mixture of S-carbethoxy-2-methyltetrazole and 5-carbethoxy-l -methyltetrazoie (0.252 g, 1.61 mmol, ratio of the two isomers 1:1) in iodomethane (0.5 mL) was selaed in a glass tube and heated at 1 0O'C for 15 h and at 1 30 C for 6 h. Distillation of the reaction mixture gave the title compound as a light yellow oil: 0.139 g (55%); bp 95-100 C/0.5 torr (air bath temperature): ir (film). Ymax: 1740 cm-1 (C = O of ester); Hmr (CDCl3) 8:1.46 (3H, t, J = 7.0, CH3CH2), 4.53 (3H, s, CH3 - 2), 4.5 (2H, q, J = 7.0, CH2CH3).

2. Methylation with dimethyl sulfate A solution of 5-carbethoxytetrazole (1.42 g, 0.01 mol) in dry acetone (20 mL) was treated with anhydrous potassium carbonate (1.38 g, 0.01 mol) and dimethyl sulfate (1.26 g, 0.01 mol). The mixture was heate under reflux for 12 h. The carbonate was filtered and the solvent evaporated under reduced pressure. The residue was diluted with dichloromethane (30 mL), washed with saturated sodium bicarbonate (10 mL), brine (10 mL) and dried over anhydrous sodium sulfate. Evaporation of the solvent and distillation under vacuum gave a clear oil: 1.45 g (93%); b.p. 85-110 C/0.5 torr. 'Hmr indicated the presence of two isomers in a ratio 1:1.

B. 5-Hydroxymethyl-2-methyltetrazole

1. By reduction of the mixture of esters.

A mixture of 5-carbethoxy-l -methyltetrazole and 5-carbethoxy-1 -methyltetrazole and 5-carbethoxy-2-methyltetrazole (ratio 6:4) 7.60 9, 0.049 mol) in dry tetrahydrofuran (50 mL) was cooled to O"C and treated with lithium borohydride (1.06 9, 0.049 mmol) added in small portions over 15 min. The mixture was maintained at 1 0 C for 30 addition min and then stirred at 20"C for 4 h. The mixture was cooled to O"C and the excess hydride was carefully destroyed by addition of 6N HCI (pH of 7 after no more gas was evolved). The solvent was concentrated under vacuum and the residual oil diluted with dichloromethane (200 mL), washed with brine (10 mL) and finally dried over Na2SO4.Concentration of the solvent and distillation of the residue under vacuum gave 1.83 g (33%) of a clear oil. 1Hmr of this material indicated the product was 5-hydroxymethyl-2-methyltetrazole.

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

To a solution of S-carbethoxy-2-methyltetrazole (0.139 g, 0.89 mmol, obtained by isomerization of the mixture of esters with methyl iodide) in dry tetrahydrofuran (1 mL) at 1 0 C was added solid lithium borohydride (0.019 g, 0.87 mmol). The mixture was slowly warmed up to room temperature and stirred for 4 h. The excess borohydride was destroyed by careful addition of 6N HCI at O"C (pH 7). The solvent was evaporated and the residue dissolved in dichloromethane (25 mL) and dried over anhydrous sodium sulfate.Evaporation of the solvent gave the title compound as a clear oil: 0.092 g (91 %); bp 90-120 C/0.5 torr with decomposition; ir (film) vmax: 3350 cm-1 (broad, OK); 1Kmr (CDCl3) 8:4.4(2K, s, CH3- 2), 4.93 (2H, s, CK2 - S).

C. 5-Acetylmercaptomethyl-2-methyltetrazole

To a solution of 5-hydroxymethyl-2-methyltetrazole (1.83 g, 11.7 mmol) in dry dichloromethane (25 mL) at 0 C was added methanesulfonyl chloride (1.47 g, 1 2.9 mmol) followed by triethylamine (1.30 9, 1 2.9 mmol) added dropwise over five min. The mixture was stirred at 0 C for 1 h, and then treated with a solution of potassium thioacetate (1.60 g, 14.0 mmol) in dry N,N-dimethylformamide (10 mL). The resulting gel was stirred at 0 C for 3 h. The reaction mixture was diluted with dichloromethane (200 mL), washed with brine (20 mL) and dried over anhydrous sodium sulfate.Evaporation of the solvent under vacuum and chromatography of the resulting oil over silica gel (2 X 14 cm, eluting with dichloromethane and dichloromethaneacetone 5% gave the title compound as a clear oil: 1.31 g (65%); ir (film) vmax 1696 cm-1 (C = O of thioester); 'Hmr (CDCl3) 8: 2.43 (3H, s, SAc), 4.36 (3H, s, 2-CH3), 4.38 ppm (2H, s, 5-CH2).

D. 5-mercaptomethyl- 1,3, dimethyltetrazolium trifluoromethane-sulfonate

A solution of 5-acetylmercaptomethyl-2-methyltetrazole (0.400 g, 2.32 mmol) in dry dichloromethane (3 mL) was treated with methyltriflate (0.76 g, 4.64 mmol) and stirred at 22"C for 16 h. Evaporation of the solvent under vacuum gave a red oil. This salt was dissolved in cold oxygen-free water (5 mL) and treated with 4 M sodium hydroxide (0.8 mL, 3.2 mmol). The mixture was stirred at 0 C for 40 min, diluted with water (7 mL), and the pH was adjusted to 7.3 with saturated KH2PO4. The clear resulting solution was maintained under nitrogen and used immediately for the following step.

E. (1 'R, 5R, 6S) 3-[1, 3-dimethyl-5-tetrazolium)-methylthiol-6-( 1 -hydroxyethyl)- 7-oxo- 1 -azabicy clo(3. 2. 0)hept-2-ene-2-carboxylate

A solution of enol phosphate (0.915 g, 1.58 mmol) in tetrahydrofuran (8 mL) was cooled to 0 C and treated dropwise with the solution of 5-mercaptomethyl-1,2-dimethyltetrazolium trifluoromethanesulfonate (2.32 mmol, prepared above) over a period of 20 min. The pH of the reaction mixture was stable at 6.5 throughout the addition. After 20 additional min. the pH of the solution was adjusted to 7.0 with saturated sodium bicarbonate. The mixture was transferred to a hydrogenation bottle, diluted with THF (10 mL), ether (20 mL) and ice (20 9).The carbapenem was hydrogenated over 10% palladium on activated carbon under 45 psi while slowly increasing the temperature to 22"C for 90 min. The catalyst was filtered and washed with cold water (5 mL) and ether (20 mL). The aqueous phase was washed with ether (20 mL) and maintained under vacuum for 20 min to remove traces of organic solvent.Chromatography on PrePak 500-C/18 and elution with water gave the title compound as a white powder after lyophilization 0.266 9 (49%); [a}2D3+ 13 (c 1.04, H20); UV (H20,pH 7.4) Amax 294 nm (e7,500); ir (KBr) vmax 1755 (C = O of fi-lactam), 1600 cm-l (broad, C = O of carboxylate); 1Hmr (D20) 8:1.24 (3H, d, J = 6.4 Hz,CH3CHOH), 3.0-3.3 (2H, m, H-4), 3.42 (1 H, dd, J = 5.8, J = 2.9, H-6), 4-4.2 (2H, m, H-5 and CH3CHOH), 4.34 and 4.57 (2 X 3H, 2S, CK3 - 1 and 3 of tetrazole), 4.49 and 4.51 (2H, 2s, CH2S). The product has a half life of 10.5 hat 37 C (c of 10-4 M in pH 7.4 phosphate buffer.

Example 21 Alternate Procedure for Preparation of 3-(N-Meth yIp yridine-2-yI-methanethio)-6a-F 1 -(R)-hydroxye- thyl]- 7-oxo- 1 -azabicyclo[3. 2. 0]-hept-2-ene-2-carboxylate

In a 2 I flask equipped with a magnetic stirrer, equipped for a Vigreaux column for distillation, a heating mantle and N2, there was added 4.0 mole (432 ml) of methyl acetoacetate and 8.0 mole (464.6 g) of allyl alcohol. The reaction mixture was distilled for 12 hours at 92"C. There was added 1 36 ml (2.0 mole) of allyl alcohol and the mixture was distilled 23 hours. There was then added 1 36 ml (2.0 mole) of allyl alcohol and the mixture was distilled 1 6 hours.The reaction mixture was then distilled under vacuum and product was collected at 105-1 10'C/35 mm Hg. There was obtained 414 g o allyl acetoacetate (73% yield).

To a solution of allyl acetoacetate (226.5 9, 1.594 mole) in 3 1 acetonitrile and triethylamine (243.4 ml, 1.753 mole), there was added p-toluenesulfonyl azide (345.3 ml, 1.753 mole) over a 1 hour period while keeping the temperature at '--'20'C with a cooling bath. The reaction mixture became yellow. The reaction mixture was then stirred at room temperature under a nitrogen atmosphere for 1 8 hours. The mixture was concentrated on a rotary evaporator. The residue was dissolved in diethyl ether (2.6 1) and 1M aqueous KOH (800 ml). The organic phase was washed five times with 1 M KOH ( 500 ml) and once with brine (400 ml).After drying over MgSO4 and concentration on a rotary evaporator (temp. '30 C), there was obtained 260.2 9 (97%) of the title product.

To a stirred suspension of allyl diazoacetoacetate (203 9, 1.195 mole) in 2 1 methylene chloride and 199 ml (1.434 mole) triethylamine at 5"C, there was added 302 ml (1.315 mole) of t-butyldimethysilyl triflate over a 45 minute period. The mixture was stirred 1 hour at 5 C and then another 1 hour without cooling. The reaction mixture was washed 4 times with 500 ml K2O and then once with 500 ml brine. It was then dried over Na2SO4 and concentrated to 344 g of orange oil. This oil was used directly in the next step.

To a mixture of (1 1R, 3 R, 4 R)-3-( 1 '- tert-butyldimethyl-silyloxyethyl)-4-acetoxy-azetidin-2-one (28.7 9, 0.1 mole) and freshly fused ZnCl2 (6.8 9, 0.05 mole) in dry CH2CI2 (700 ml), there was added dropwise a solution of allyl 2-diazo-3-tert-butyldimethylsilyloxy-3-butenoate (33.84 9, 0.12 mole) in CH2CI2 (50 ml) over a 5 hour period. The mixture was stirred at room temperature for 2 hours at which time TLC (thin layer chromatography) showed a small amount of remaining starting material. An additional quantity of allyl 2-diazo-3-tert-butyldimethyl-silyloxy-3-butenoate (4.23 9, 0.015 mole) in 10 ml of CH2CI2 was added over a 1 hour period and stirring was continued at room temperature for 10 hours.The reaction was then diluted with ethyl acetate (750 ml), washed (2 X 300 ml saturated NaHCO3, 300 ml brine), dried (MgSO4) and evaporated to give 62.5 9 of dark orange oil which was dissolved in methanol (500 ml) and treated with 1 N aqueous HCI (110 ml). The resulting mixture was stirred at room temperature for 2 hours after which time there was added 10 ml N HCI followed by an additional 2 hours of stirring. The reaction mixture was concentrated to 1/2 volume and poured into a mixture of ethyl acetate (800 ml) and water (800 ml). The organic phase was separated, washed with water (800 ml) and the combined aqueous extracts washed with ethyl acetate (400 ml). The combined organic extracts were washed with brine (2 X 400 ml), dried (MgSO4) and concentrated to 32 9 of dark orange red oil.Flash chromatography afforded 9.33 9 (33% yield) of title product as a gold-yellow oil which solidified to a light yellow solid. 1H-nmr (CDCl3) 6: 6.20-5.72 (m, 2H), 5.48-5.21 (m, 2H), 4.74 (dt, J = 5.8, J' = 1.2Hz, 2H), 4.30-3.88 (m, 2H), 3.30-3.20 (m, 2K), 2.89 (dd, J = 7.3, J1 = 2.1, 1K), 2.18 (s, 1H), 1.32 (d, J = 6.2, 3K).

E.

A mixture of a-diazo ester prepared in Step D above (9.2 9, 32.7 mmole) and rhodium acetate [Rh2(OAc)4] in benzene (1 I) was refluxed for 1 hour. The solution was treated with activated charcoal and filtered through a Celite pad. The pad was washed with 100 ml of hot benzene. Concentration of the filtrate afforded 8.08 9 (97% yield) of title product as a light brown crystalline solid. 1K-nmr (CDCl3) 8: 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 = 7.1, J' = 2.0, 1H), 2.95 (dd, J = 6.9, J' = 18.9, 1K), 2.42 (dd, J = 7.6, J' = 18.8, 1K), 1.88 (s, 1K), 1.39 (d, J = 6.3, 3H).

To a solution of keto ester prepared in Step E (7.5 g, 0.03 mole) there was added at 0 C under a N2 atmosphere diisopropylamine (6.08 ml, 0.035 mole) followed by diphenylphosphoryl chloride. After 1 5 minutes, TLC showed no remaining starting material. To the reaction mixture there was added diisopropylamine (6.26 ml, 0.036 mole) and a solution of freshly distilled 2-mercaptomerhylpyridine (4.5 9, 0.036 mole) in 5 ml acetonitrile. After stirring at O"C for 2 hours, the mixture was poured into ethyl acetate (1 I), washed with water (2 x 150 ml), saturated NaHCO3 (150 ml), H20 (150 ml) and brine (200 ml). The organic phase was dried (MgSO4) and concentrated to a dark orange-yellow gum. Flash chromatography afforded the product as a golden yellow oil.The product was dissolved in diethyl ether and cooled to O"C. Filtration afforded 4.8 g (44% yield) of the purified title product as cream-colored crystals.

'H-nmr (CDCl3) 8: 8.6-8.4 (m, 1K), 7.85-7.15 (m, 3H), 6.20-5.74 (m, 1K), 5,54-5.15 (m, 2H), 4.80-4.66 (m, 2H), 4.29-4.03 (m, 1K), 4.19 (s, 2H), 3.69-2.85 (m, 1K), 2.97 (s, 1K), 1.32 (d, J = 6.2, 3H).

To a solution of the allyl ester prepared in Step F (1.79 g, 4.97 mmole), tetrakistriphenyl phosphine palladium (175 mg, 0.15 mmole) and triphenylphosphine (175 mg, 0.67 mmole) in CH2CI2 (25 ml), there was added a solution of potassium 2-ethyl-hexanoate (1.085 9, 5.96 mmole) in ethyl acetate (12 ml). After stirring at room temperature for 1 hour, TLC showed only a trace of starting material. The reaction mixture was diluted with anhydrous diethyl ether (150 ml) and the precipitate was collected by filtration, washed with ethyl acetate and then ether to give a light-brown solid. This solid was dissolved in H20 (10 ml) and purified by reversed phase chromatography to give 1.85 9 of title product as a cream-colored solid. This material was further purified by slurrying in acetone to afford 1.47 g (83%) of pure title product. 'H-nmr (D2O) : 8.45-8.36 (m, 1K), 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).

Toluenesulfonic acid (27.6 mg, 0.16 mmole) was added to a cooled (0 C) suspension of potassium 6-hydroxyethyl-2-(2-pyridylmethylthio)-carbapenem-3-carboxylate (53.8 mg, 0.15 mmole) in acetone (2 ml). The mixture was stirred at O"C for 20 minutes and then treated with methyl triflate (0.02 ml). After stirring at 0 C for 60 minutes, LA-1 resin was added followed by hexane (6 ml). The mixture was extracted with water (4 X 0.5 ml) and the combined aqueous phases purified by reversed phase HPLC to give 10 mg of the title product.

Example 22 Preparation of 3-(N-Methylpyridine-2-yl-methanethio)-6&alpha;-[1-(R)-hydroxyethyl]-7-oxo-1-azabicy- clo [3.2.0]-hept-2-ene-2-carboxylate Via "One Pot" Process

a. Preparation of enol phosphate (2)

An ice-cooled solution of ketone 1(3 g, 8.62 mmoles) in acetonitrile (30 ml) was treated with ethyl diisoproplylamine (9 mmoles, 1.04 eq, 1.57 ml) (addition time ca. 2 minutes) and chlorodiphenyl phosphate (9 mmoles, 1.04 eq, 1.87 ml) (addition time ca. 2 minutes). The reaction was stirred for 45 minutes and TLC (ethyl acetate, silica gel) showed disappearance of ketone 1.The solution was diluted with ethyl acetate (60b ml), washed with cold water (2 > : 50 ml) and brine, dried over sodium sulfate and concentrated (bath temperature below 20"C) to give a foam which was used as such.

B. Preparation of thiol (4)

An ice-cooled solution of thioacetate 3 (3.31 9, 10 mmoles) in water purged with nitrogen for 5 minutes was treated dropwise (ca. 5 minutes) with a cooled solution of sodium hydoxide (1.75 eq, 1 7.5 mmoles, 0.7 9) in water (8 ml). The mixture became yellow. After 75 minutes under nitrogen the pH was adjusted to 7.4 with saturated aqueous solution of KH2PO4. The reaction mixture was diluted with water (15 ml). This aqueous solution of thiol 4 (50 ml, 0.2 mmoles/ml) was used as such.

An ice-cooled solution of 2 (crude, prepared in A, 8.62 mmoles) in tetrahydrofuran (50 ml) was treated dropwise with the aqueous solution of thiol 4 prepared in B (5 ml of solution every 5 minutes). During the course of the reaction the pH of the reaction mixture was maintained around 6.5-7.5 (preferably 7) by adding cooled 2N sodium hydroxide solution. The reaction was followed by TLC (a) silicagel, ethyl acetate; (b) reversed phase Analtech RPSF, CH3CN- pH 7 buffer (4:6).

At the end 1.15 eq of thiol was used (50 ml of solution). The reaction was complete after 1 hour at O"C and the mixture was used as such for the hydrogenation after the pH was adjusted to 7.

D. Hydrogenation

The reaction mixture containing 5 (prepared in C) was transferred into a Parr flask with THF (10 ml), phosphate buffer (pH 7, 0.1 M) (10 ml), ether (75 ml) and Pd-C 10% (5 g) and hydrogenated at 45 psi at 3-10"C for 2 hours. Then the catalyst was filtered, washed with water (3 x 10 ml) and the pH adjusted to 6.2 carefully with cold 2N NaOH. Ether was added and the aqueous phase was separated and washed again with ether. The aqueous phase was purged of organic solvent under vacuum and then purified on Bondapak C-18 column (100 9, 4.5 x 13 cm) with cold distilled water. The light yellow fractions containing the product (checked by U.V. and TLC) were lyophilized to give 1.46 9 (50%)* of 6 as a yellow powder.

A293, = 9000, A271, = 11064 yield calculated from bycyclic ketone Example 23 Following the general procedures of Examples 1-20, the following carbapenem products are made by using the intermediate of the formula

(mixture of 3 possible isomers)

Example 24 Following the general procedures of Examples 1-20, the following carbapenem products are made using the intermediate of the formula

(mixture of 3 possible isomers)

Example 25

If in the procedure of Example 22, the keto intermediate 1 is replaced by an equimolar amount of the corresponding 1ss-methyl intermediate, there is obtained the carbapenem endproduct indicated above.

Example 26

If in the procedure of Example 22, the keto intermediate 1 is replaced by an equimolar amount of the corresponding 1 a-methyl intermediate, there is obtained the carbapenem end product indicated above.

Claims (1)

1. A compound of the formula

wherein R8 is hydrogen and R1 is selected from the group consisting of hydrogen; substituted and unsubstituted: alkykl, alkenyl and alkynyl, having from 1-10 carbon atoms; cylcloalkyl 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

-NR3R4

-CO2R3 =0

-SR

-CN -N3 -OSO3R3

-OP(O)(OR3)(0R4)

-NR CO2R4 -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 heterocyclalkyl 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-CtO alkylidene or C2-C,O alkylidene substituted by hydroxy;R5 is selected from the group consisting of substituted and unsubstituted: alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms; cycloalkyl, having 3-6 carbon atoms in the cycloalky 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, heteroalkyl, heterocyclyl and heterocyclyalkyl 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 above-named R5 radicals are optionally substituted by 1-3 substitutents independently selected from: Ct-C6 alkyl optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl; fluoro, chloro or bromo; -OR3 -OCO2R3; -OCOR3 -OCONR3R4

-oxo -NR3R4 R3CONR4 -NR3CO2R4 -NR3CONR3R4

-SR3

-SO3R3; -CO2R3; -CONR3R4 -CN; or phenyl optionally substituted by 1-3 fluoro, chloro, bromo, Ct-C6 alkyl, -OR3, -NR3R4, -SO3R3, -CO2R3 or -CONR3R4, wherein R3, R4, and R9 in such R5 substituents are as defined above; or R5 may be attached to

at another point on the ring so as to form a fused heterocyclic or heteroaromatic ring, which ring may contain additional hetero atoms selected from 0, S and N; A2 is C1 -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 ion; and

represents a substituted or unsubstituted mono, bi-or polycyclic aromatic heterocylcic radical containing at least one nitrogen in the ring, said ring being attached to A through a ring carbon atom and having a ring nitrogen which is quaternized by the group R5; or a pharmaceutically acceptable salt thereof.

A compound according to Claim 1 wherein R1 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 R1 is

5. A compound according to Claim 1 wherein R1 is

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

6. A compound according to Claim 1, 2, 3, 4 or 5 wherein A is -CH2- or -CK2CK2-.

7. A compound of the formula

wherein RB 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 cycloalkyalkyl, 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

-NR3R4

-CO2R3 =0

-SR3

-CN -N3 -OSO3R

-OP(O)(OR3)(0R4)

-NR CO2R4 -NO2 wherein, relative to the-*ove-named substituents, the groups R3 and R4 are independently selected from hydrogen < ~aíkyl alkenyl and alkynyl, having from 1-10 carbon atoms; cycloalkyl, cycloalkyalkyl and alkycYcloalkyl, 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 hetercyclylalkyl 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 RB taken together represent C2-C,O alkylidene or C2-C1O alkylidene substituted by hydroxy; R5 is selected from the group consisting of 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 heterocyclyalkyl 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 above-named R5 radicals are optionally substituted by 1-3 substituents independently selected from: Ct-C6 alkyl optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl; fluoro, chloro or bromo; -OR3 -OCO2R3; -OCOR3 -OCONR3R4

-oxo -NR3R4 R3CONR4 -NR3CO2R4 -NR3CONR3R4

-SR3

-SO3R3; -CO2R3; -CONR3R4 -CN; or phenyl optionally substituted by 1-3 fluoro, chloro, bromo, C1 -C6 alkyl, -OR3, -NR3R4, -S03R3, -CO2R3 or -CONR3R4, wherein R3, R4, and R9 in such R6 substituents are as defined above; -SO3R3, -CO2R3 or -CONR3R4, wherein R3, R4 and R9 in such R5 substituents are as defined above; or R5 may be attached to

at another point on the ring so as form a fused heterocyclic or heteroaromatic ring, which ring may contain additional hetero atoms selected from 0, S and M; A is C1 -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 ion; and

represents an aromatic mono-, bi or polycyclic N-containing heterocyclic ring containing 0-5 additional hetero atoms selected from 0, S or N, said heterocyclic ring being attached to A through a ring carbon atom and having a ring nitrogen quaternized by the group R5, and said heterocyclic ring being optionally substituted at available ring carbon atoms by 1-5 substituents independently selected from the group consisting of C1-C4 alkyl; C1-C4 alkyl substituted by 1-3 hydroxy, amino, C1-C4 alkylamino, di(C1-C4)alkylamino, C1 -C4 alkoxy, carboxy, halo or sulfo; C3-C6 cycloalkyl;C3-C6 cycloalkyl (C1-C4)alkyl optionally substituted by 1-3 substituents mentioned above in connection with C1-C4 alkyl; C1-C4 alkoxy; C1-C4 alkylthio; amino; C1-C4 alkylamino; di(C1-C4 alkanoylamino; halo; C1-C4 alkanoyloxy; carboxy; sulfo;

alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halo, hydroxy, trifluoromethyl, C1 -C4 alkyl, C1-C4 alkoxy, C1 -C4 alkylamino, di(C1-C4)alkylamino, carboxy, and sulfo; phenyl(C1-C4)alkyl in which the phenyl portion is optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion is optionally substituted by 1-3 substituents mentioned above in connection with C1 -C4 alkyl; and heteroaryl or heteroaralkyl in which the hetero atom or atoms are selected from the group consisting of 1-4 0, S or N atoms and the alkyl moiety associated with heteroaralkyl has 1-6 carbon atoms, said heteroaryl and heteroaralkyl groups being optionally substituted in the heterocyclic ring moiety by 1-3 substituents independently selected from hydroxy, amino, halo, trifluoromethyl, C1 -C4 alkyl, C1 -C4 alkoxy, C,-C4 alkylamino, di(C1-C4)-alkylamino, carboxy and sulfo and in the alkyl moiety by 1-3 substituents selected from hydroxy, amino, C1-C4 alkylamino, di(C1-C4 alkylamino, C1-C4 alkoxy, carboxy, halo and sulfo, and said heterocyclic ring being optionally substituted at available ring nitrogen atoms by 1-3 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkyl substituted by 1-3 hydroxy, amino, C,-C4 alkylamino, di (C1-C4)alkylamino, C1-C4 alkoxy, carboxy, halo or sulfo groups; C3-C6 cycloalkyl;C3-C6 cycloalkyl(C,-C4)-alkyl optionally substituted by 1-3 substituents mentioned above in connection with C1 -C4 alkyl; phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halo, hydroxy, trifluoromethyl, C,-C4 alkyl, Ct-C4 alkoxy, C,-C4 alkylamino, di(C1-C4)alkylamino, carboxy and sulfo; phenyl-(C,-C4)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C,-C4 alkyl; and heteroaryl or heteroaralkyl in which the hetero atom or atoms are selected from the group consisting or 1-4 0, S or N atoms and the alkyl moiety associated with heteroaralkyl has 1-6 carbon atoms, said heteroaryl and heteroaralkyl groups being optionally substituted in the heterocyclic ring moiety by 1-3 substituents independently selected from hydroxy, amino, halo, trifluoromethyl, C,-C4 alkyl, C,-C4 alkoxy, C,-C4 alkylamino, di(C1-C4)alkylamino, carboxy and sulfo and in the alkyl moiety by 1-3 substituents selected from hydroxy, amino, C1 -C4 alkylamino, di(C,-C4)alkylamino C-C4 alkoxy, carboxy, halo and sulfo; or a pharmaceutically acceptable salt thereof.

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

9. A compound according to Claim 7 wherein R' and RB 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 -CH2- or -CH2CH2-.

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 C,-C6 alkyl optionally substituted by amino, halo, hydroxy or carboxyl halo -OR3

-NR3R4

-CO2R3 =0

-SR3

-CN -N3 -OSO3R3

-OP (O) (OR3) (OR4)

-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 R' and R8 taken together represent C2-C,O alkylidene or C2-C,O alkylidene substituted by hydroxy;R5 is selected from the group consisting of 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 heterocyclyalkyl 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 above-named R5 radicals are optionally substituted by 1-3 substituents independently selected from: C,-C6 alkyl optionally substituted by amino, fluro, chloro, carboxyl, hydroxy or carbamoyl; fluoro, chloro or bromo; -OR3 -OCO2R3; -OCOR3; -OCONR3R4;

-oxo; -NR3R4; R3CONR4-; -NR3CO2R4; -NR3CONR3R4;

-SR3;

-SO3R3; -CO2R3; -CON R3R4; -CN; or phenyl optionally substituted by 1-3 fluoro, chloro, bromo, C,-C6 alkyl, -OR3, -NR3R4, -SO3R3, -CO2R3 or -CONR3R4, wherein R3, R4, and R9 in such R5 substituents are as defined above; or R5 may be attached to

at another point on the ring so as to form a fused heterocyclic or heteroaromatic ring, which ring may contain additional hetero atoms selected from 0, N and S; A is C,-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 ion; and

represents an aromatic 5- or 6-membered N-containing heterocyclic ring containing 0-3 additional hetero atoms selected from N, S or 0, said heterocyclic ring being optionally substituted at available ring carbon atoms by 1-5 substituents independently selected from the group consisting of C,-C4 alkyl; Cl-C4 alkyl substiituted by 1-3 hydroxy, amino, C1-C4 alkylamino, di(C1-C4)alkylamino, C,-C4 alkoxy, carboxy, halo or sulfo; C3-C6 cycloalkyl; C3-C6 cycloalkyl(C,-C4)alkyl optionally substituted by 1-3 substituents mentioned above in connection with C,-C4 alkyl; C,-C4 alkoxy; C,-C4 alkylthio; amino; Cr-C4 alkylamino; di(C,-C4)-alkylamino; halo;C1-C4 alkanoylamino; C,-C4 alkanoyloxy; carboxy; sulfo;

alkyl ; hydroxy; amidino; guanidino; phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halo, hydroxy, trifluoromethyl, C1 -C4 alkyl, C1 -C4 alkoxy, C1 -C4 alkylamino, di (C1 -C4) alkylamino, carboxy, and sulfo; phenyl (C1-C4) alkyl in which the phenyl portion is optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion is optionally substituted by 1-3 substituents mentioned above in connection with Cr-C4 alkyl; and heteroaryl or heteroaralkyl in which the hetero atom or atoms are selected from the group consisting of 1-4 0, S or N atoms and the alkyl moiety associated with heteroaralkyl has 1-6 carbon atoms, said heteroaryl and heteroaralkyl groups being optionally substituted in the heterocyclic ring moiety by 1-3 substituents independently selected from hydroxy, amino, halo, trifluoromethyl, C1-C4 alkyl, C,-C4 alkoxy, C,-C4 alkoxy, C,-C4 alkylamino, di (C1-C4)-alkylamino, carboxy and sulfo and in the alkyl moiety by 1-3 substituents selected from hydroxy, amino, C1-C4 alkylamino, di(C,-C4) alkylamino, C,-C4 alkoxy, carboxy, halo and sulfo, and said heterocyclic ring being optionally substituted at available ring nitrogen atoms by 1-3 substituents independently selected from the group consisting of C1-C4 alkyl; C1-C4 alkyl substituted by 1-3 hydroxy, amino, C,-C4 alkylamino, di (C,-C4) alkylamino, C1-C4 alkoxy, carboxy, halo or sulfo groups; C3-C6 cycloalkyl;C3-C6 cycloalkyl(C1-C4)-alkyl optionally substituted by 1-3 substituents mentioned above in connection with C,-C4 alkyl; phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halo, hydroxy, trifluoromethyl, C1 -C4 alkyl, C1-C4 alkoxy, alkylamino, di (C1-C;) alkylamino, carboxy and sulfo; phenyl-(C,-C4) alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C,-C4 alkyl; and heteroaryl or heteroaralkyl in which the hetero atom or atoms are selected from the group consisting or 1-4 0, S or N atoms and the alkyl moiety associated with heteroaralkyl has 1-6 carbon atoms, said heteroaryl and heteroaralkyl groups being optionally substituted in the heterocyclic ring moiety by 1-3 substituents independently selected from hydroxy, amino, halo, trifluoromethyl, C,-C4 alkyl, C,-C4 alkoxy, C,-C4 alkylamino, di (C,-C4) alkylamino, carboxy and sulfo and in the alkyl moiety by 1-3 substituents selected from hydroxy, amino, C,-C4 alkylamino, di (C1-C4) alkylamino, C1 -C4 alkoxy, carboxy, halo and sulfo; or a pharmaceutically acceptable salt thereof.

14. A compound according to Claim 1 3 wherein the heterocyclic ring

is optionally substituted at available ring carbon or nitrogen atoms by up to 5 substituents independently selected from (lower)alkyl.

15. A compound according to Claim 14 wherein A is -CH2-, -CH2CH2- or

16. A compound according to Claim 13, 14 or 15 wherein R1 is

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

17. 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 cycloalkyl, 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 C,-C6 alkyl optionally substituted by amino, halo, hydroxy or carboxyl halo -OR3

-NR3R4

-C02R3 =0

-SR3

-CN -N3 -OSO3R3

-OP (O) (OR3) (OR4)

-NR3CO2R4 -NO2 wherein, relative to the above-named substituents, the groups R3 and R4 are independently selected from hydrogen; alkyl, alkenyl, 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, heteraralkyl, 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 R8 taken together represent C2-C,O alkylidene or C2-C,O alkylidene substituted by hydroxy; R5 is selected from the group consisting of 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 heterocyclyalkyl 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 above-named R5 radicals are optionally substituted by 1-3 substituents independently selected from: C,-C6 alkyl optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl; fluoro, chloro or bromo; -OR3 -OCO2R3; -OCOR3; -OCONR3R4;

-oxo; -NR3R4; R3CON R4-; -NR3CO2R4; -NR3CON R3R4;

-SR3;

-SO3R3; -CO2R3; -CONR3R4; -CN; or phenyl optionally substituted by 1-3 fluoro, chloro, bromo, C,-C6 alkyl, -OR3, -NR3R4, -SO3R , -CO2R or -CONR R4, wherein R , R4, and R9 in such R5 substituents are as defined above; or R5 may be attached to

at another point on the ring so as to form a fused heterocyclic or heteroaromatic ring, which ring may contain additional hetero atoms selected from 0, N and S; A is C-C4 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 ion; and

represents a radical selected from the group consisting of

wherein RB, R7 and R10 are independently selected from hydrogen; C,-C4 alkyl; C,-C4 alkyl substituted by hydroxy, C,-C4 alkylamino, di(C1-C4 alkyl)amino, C,-C4 alkoxy, amino, sulfo, carboxy or halo; C3-C6 cycloalkyl; C,-C4 alkoxy;C,-C4 alkylthio; amino; C,-C4 alkyl-amino; di(C,-C4 alkyl)amino; halo; C,-C4 alkanoylamino; C,-C4 alkanoyloxy; carboxy;

alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted by one, two or three amino, halo, hydroxyl, trifluoromethyl, C,-C4 alkyl or C,-C4 alkoxy groups; phenyl (C,-C4)alkyl in which the phenyl portion may be optionally substituted by 1-3 substitutents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C,-C4 alkyl; and heteroaryl and heteroaralkyl in which the hetero atom or atoms in the group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms; or wherein two or R6, R7 or R10 taken together may be a fused saturated carbocyclic ring, a fused aromatic carbocyclic ring, a fused non-aromatic heterocyclic ring or a fused heteroaromatic ring, said fused rings being optionally substituted by 1 or 2 of the substituents defined above for RB, R7 and R10;

optionally substituted on a carbon atom by 1-3 substituents independently selected from C,-C4 alkyl; C,-C4 alkyl substituted by hydroxy, C,-C4 alkylamino, di(C,-C4 alkyl)amino, sulfo, C,-C4 alkoxy, amino, carboxy or halogen; C3-C6 cycloalkyl; C,-C4 alkoxy;C,-C4 alkylthio; amino; C,-C4 alkylamino; di(C,-C4 alkyl)amino; halo; C,-C4 alkanoylamino; C,-C4 alkanoyloxy; carboxy;

alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted by one, two or three amino, halo, hydroxyl, trifluoromethyl, C,-C4 alkyl or C,-C4 alkoxy groups; phenyl (C,-C4)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with Ct-C4 alkyl; and heteroaryl or heteroaralkyl in which 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 moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms, or optionally substituted so as to form a fused carbocyclic, heterocyclic or heteroaromatic ring optionally substituted by 1 or 2 of the substituents defined above;

optionally substituted on a carbon atom by one or two substituents independently selected from C,-C4 alkyl; C,-C4 alkyl substituted by hydroxy, C,-C4 alkylamino, di(C,-C4 alkyl) amino, C,-C4 alkoxy, sulfo, amino, carboxy or halogen; C3-C6 cycloalkyl; C,-C4 alkoxy; C,-C4 alkylthio; amino; C,-C4 alkylamino; di(C,-C4 alkyl)amino; halo; C,-C4 alkanoylamino; C,-C4 alkanoyloxy; carboxy;

alkyl; hydroxy, amidino, guanidino, phenyl; phenyl substituted by one, two or three amino, halo, hydroxyl, tri-fluoromethyl, C,-C4 alkyl or C,-C4 alkoxy groups; phenyl (C,-C4)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C,-C4 alkyl; and heteroaryl or heteroaralkyl in which 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 moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms, or optionally substituted so as to form a fused carbocyclic, heterocyclic or heteroaromatic ring optionally substituted by 1 or 2 of the substituents defined above;

optionally substituted on a carbon atom by a substituent independently selected from C,-C4 alkyl; C,-C4 alkyl substituted by hydroxy, amino, C,-C4 alkylamino, di(C,-C4 alkyl)amino, C,-C4 alkoxy, sulfo, carboxy or halogen; C3-C6 cycloalkyl; C1 -C4 alkoxy; Ct-C4 alkylthio; amino;C,-C4 alkylamino; di(C,-C4 alkyl)amino; halo; C1 -C4 alkanoylamino; Ct-C4 alkanoyloxy; carboxy;

alkyl; hydroxy; amidino; guanidino, phenyl; phenyl substituted by one, two or three amino, halo, hydroxyl, trifluoromethyl, C,-C4 alkyl or C,-C4 alkoxy groups; phenyl (C,-C4)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with Ct-C4 alkyl; and heteroaryl or heteroaralkyl in which the hetero atom or atoms in the above-named heterocyclic moieties are selcted from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms;

wherein X is 0, S or NR in which R is C,-C4 alkyl; Cl-C4 alkyl substituted by 1-3 hydroxy, amino, C,-C4 alkylamino, di(C1-C4)alkylamino, C,-C4 alkoxy, carboxy, halo or sulfo groups; C3-C6 cycloalkyl;C3-C6 cycloalkyl(C,-C4)alkyl optionally substituted by 1-3 substituents mentioned above in connection with C1-C4 alkyl; phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halo, hydroxy, trifluromethyl, C,-C4 alkyl, C,-C4 alkoxy, C,-C4 alkylamino, di(C1-C4)alkylamino, carboxy and sulfo; phenyl(C,-C4)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C,-C4 alkyl; and heteroaryl and heteroaralkyl in which the hetero atom or atoms are selected from the group consisting of 1-4, 0, S or N atoms and the alkyl moiety associated with heteroaralkyl has 1-6 carbon atoms, said heteroaryl and heteroaralkyl groups being optionally substituted in the heterocyclic ring moiety by 1-3 substituents independently selected from hydroxy, amino, halo, trifluoromethyl, C,-C4 alkyl, C,-C4 alkoxy, C,-C4 alkylamino, di(C1-C4)-alkylamino, carboxy and sulfo and in the alkyl moiety by 1-3 substituents selected from hydroxy, amino, C,-C4 alkylamino, di(C1-C4)alkylamino, C,-C4 alkoxy, carboxy, halo and sulfo, said radical being optionally substituted on a carbon atom by one or more substituents independently selected from C,-C4 alkyl; C,-C4 alkyl substituted by hydroxy, C,-C4 alkylamino, di(C,-C4 alkyl)amino, C,-C4 alkoxy, amino, sulfo, carboxy or halogen; C3-C6 cycloalkyl; C,-C4 alkoxy;C,-C4 alkythio; amino; C,-C4 alkylamino; di(C,-C4 alkyl)amino; halo; C,-C4 alkanoylamino; C,-C4 alkanoyloxy; carboxy;

alkyl; hydroxy; amidino; guanidino, phenyl; phenyl substituted by one, two or three amino, halo, hydroxy, trifluoromethyl, C,-C4 alkyl or C,-C4 alkoxy groups; phenyl (C,-C4)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C,-C4 alkyl; and heteroaryl or heteroaralkyl in which 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 moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms, or optionally substituted so as to form a fused carbocyclic, heterocyclic or heteroaromatic ring optionally substituted by 1 or 2 of the substituents defined above;

wherein X is 0, S or NR in which R is C,-C4 alkyl;C,-C4 alkyl substituted by 1-3 hydroxy, amino, C,-C4 alkylamino, di(C1-C4)alkylamino, C,-C4 alkoxy, carboxy, halo or sulfo groups; C3-C6 cycloalkyl; C3-C6 cycloalkyl(C,-C4)alkyl optionally substituted by 1-3 substituents mentioned above in connection with C,-C4 alkyl; phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halo, hydroxy, trifluomethyl, C,-C4 alkyl, C,-C4 alkoxy, C1-C4 alkylamino, di(C1-C4)alkylamino, carboxy and sulfo; phenyl(C,-C4)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C,-C4 alkyl; and heteroaryl and heteroaralkyl in which the hetero atom or atoms are selected from the group consisting of 1-4, 0, S or N atoms and the alkykl moiety associated with heteroaralkyl has 1-6 carbon atoms, said heteroaryl and heteroaralkyl groups being optionally substituted in the heterocyclic ring moiety by 1-3 substituents independently selected from hydroxy, amino, halo, trifluoromethyl, C,-C4 alkyl; C,-C4 alkoxy, C,-C4 alkylamino, di(C1-C4)-alkylamino, carboxy and sulfo and in the alkyl moiety by 1-3 substituents selected from hydroxy, amino, C,-C4 alkyl-amino di(C1-C4)alkylamino, C,-C4 alkoxy, carboxy, halo and sulfo, said heteroaromatic radical being optionally substituted on a carbon atom by a substituent selected from C,-C4 alkyl;; C,-C4 alkyl substituted by hydroxy, C,-C4 alkylamino, di(C,-C4 alkyl)amino, C,-C4 alkoxy, amino, sulfo, carboxy or halogen; C3-C6 cycloalkyl; C,-C4 alkoxy; Cr-C4 alkylthio; amino; C,-C4 alkylamino; di(C,-C4)alkylamino; halo; C,-C4 alkanoylamino;C1-C4 alkanoyloxy; carboxy;

alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted by one, two or three amino, halo, hydroxyl, trilfuoromethyl, C,-C4 alkyl or C,-C4 alkoxy groups; phenyl (C,-C4)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C,-C4 alkyl; and heteroaryl or heteroaralkyl in which 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 moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms; and

wherein R is C,-C4 alkyl; C,-C4 alkyl substituted by 1-3 hydroxy, amino, C,-C4 alkylamino, di(C,-C4))alkyla mino, C,-C4 alkoxy, carboxy, halo or sulfo groups; C3-C6 cycloalkyl; C3-C6 cycloalkyl(C,-C4)alkyl optionally substituted by 1-3 substituents mentioned above in connection with Cr-C4 alkyl; phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halo, hydroxy, trifluoromethyl, C,-C4 alkyl, C,-C4 alkoxy, C,-C4 alkylamino, di(C,-C4)alkylamino, carboxy and sulfo; phenyl(C,-C4)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C,-C4 alkyl; and heteroaryl and heteroaralkyl in which the hetero atom or atoms are selected from the group consisting of 1-4, 0, S or N atoms and the alkyl moiety associated with heteroaralkyl has 1-6 carbon atoms, said heteroaryl and heteroaralkyl groups being optionally substituted in the heterocyclic ring moiety by 1-3 substituents independently selected from hydroxy, amino, halo, trifluoromethyl, Ct-C4 alkyl, Ct-C4 alkoxy, C1-C4 alkylamino, di(C,-C4)al- kylamino, carboxy and sulfo and in the alkyl moiety by 1-3 substituents selected from hydroxy, amino, C,-C4 alkylamino, di(C1-C4)alkylamino, C,-C4 alkoxy, carboxy, halo and sulfo; or a pharmaceuticaly acceptable salt thereof.

18. A compound according to Claim 17 wherein

represents a radical selected from the group consisting of

wherein R5 is C1-C6 alkyl and RB, R7 and R10 are each independently hydrogen or C1 -C4 alkyl;

wherein R5 is C1-C6 alkyl and wherein available ring carbon atoms are optionally substituted by 1-3 substituents independently selected from Cr-C4 alkyl;

wherein R5 is C1 -C6 alkyl and wherein available ring carbon atoms are optionally substituted by 1 or 2 substituents independently selected from C,-C4 alkyl;

wherein R5 is C1-C6 alkyl and wherein an available ring carbon atom is optionally substituted by C,-C4 alkyl;;

wherein R5 is c1-C6 alkyl, X is O, S, NR in which R is C1-C4 alkyl and where one or more available ring carbon atoms is optionally substituted by C1-C4 alkyl;

wherein R5 is C1-C6 alkyl, X is Q, S or NR in which R is C,-C4 alkyl and wherein one or more available ring carbon atoms is optionally substituted by C1-C4 alkyl; and

wherein R5 is C1-C6 alkyl and R is Ct-C4 alkyl.

19. A compound according to Claim 18 wherein R1 is hydrogen, CH3CH2-,

20. A compound according to Claim 18 wherein R and R8 taken together represent

21. A compound according to Claim 18 wherein R' is

22. A compound according to Claim 18 wherein R1 is

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

23. A compound according to Claim 17, 18, 19, 20, 21 or 22 wherein A is -CH2 or -CH2CH2-.

24. A compound of the formula

wherein R8 is hydrogen and R2 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 C,-C6 alkyl optionally substituted by amino, halo, hydroxy or carboxyl halo -OR3

-NR3R4

-CO2R3 =0

-SR3

-CN -N3 -OS03R3

-OP (O) (OR3) (OR4)

-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 R' and R8 taken together represent C2-C,O alkylidene or C2-C,O alkylidene substituted by hydroxy; R5 is selected from the group consisting of 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 heterocyclyalkyl 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 above-named R5 radicals are optionally substituted by 1-3 substituents independently selected from: C,-C6 alkyl optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl; fluoro, chloro or bromo; -OR3 -OCO2R3; -OCOR3; -OCONR3R4;

-oxo; -NR3R4; R3CONR4-; -NR3CO2R4; -NR3CONR3R4;

-SR3;

-SO3R3; -CO2R3; -CONR3R4; -CN; or phenyl optionally substituted by 1-3 fluoro, chloro, bromo, C,-C6 alkyl, -OR3, -NR3R4, -SO3R3, -CO2R3 or -CONR3R4, wherein R3, R4, and R9 in such R5 substituents are as defined above; or R5 may be attached to

at another point on the ring so as to form a fused heterocyclic or heteroaromatic ring, which ring may contain additional hetero atoms selected from 0, N and S; A is C,-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 ion; and

represents a radical selected from the group consisting of

wherein Re, R7 and R'O are independently selected from hydrogen; C1 -C4 alkyl; C1 -C4 alkyl substituted by hydroxy, Ct-C4 alkylamino, di(C1-C4 alkyl)amino, C,-C4alkoxy, amino, sulfo, carboxy or halo; C3-C6 cycloalkyl; C1 -C4 alkoxy; C1-C4 alkylthio; amino; C1 -C4 alkylamino; di(C1-C4 alkyl)amino; halo;C1-C4 alkanoylamino; C1 -C4 alkanoyloxy; carboxy;

alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted by one, two or three amino, halo, hydroxyl, trifluoromethyl, C1 -C4 alkyl or C1 -C4 alkoxy groups; phenyl (C1-C4)alkyl in which the phenyl portion may be optionally substituted by 1-3 substitutents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C1 -C4 alkyl; and heteroaryl and heteroaralkyl in which the hetero atom or atoms in the group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms; or wherein two of R6, R7 or R10 taken together may be a fused saturated carbocyclic ring, a fused aromatic carbocyclic ring, a fused non-aromatic heterocyclic ring or a fused heteroaromatic ring, said fused rings being optionally substituted by 1 or 2 of the substituents defined above for RB, R7 and R'O; or a pharmaceutically acceptable salt thereof.

25. A compound according to Claim 24 wherein R1 is hydrogen, CH3CH2-,

26. A compound according to Claim 24 wherein R' and R8 taken represent

27. A compound according to Claim 24 wherein R1 is

28. A compound according to Claim 24 wherein R' is

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

29. A compound according to Claim 24, 25, 26, 27 or 28 wherein A is -CH2- or -CH2CH2-

30. A compound of the formula

wherein R8 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 consisiting 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 C,-C6 alkyl optionally substituted by amino, halo, hydroxy or carboxyl halo -OR3

-NR3R4

-C02R3 =0

-SR3

-CN -N3 -OSO3R3

-OP (O) (OR3) (OR4)

-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 RB taken together represent C2-C10 alkylidene or C2-C10 alkylidene substituted by hydroxy; R5 is selected from the group consisting of 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, heterocycly and heterocyclyalkyl 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 above-named R5 radicals are optionally substituted by 1-3 substituents independently selected from: C1-C6 alkyl optionally substituted by amino, fluoro, chloro, carboyl, hydroxy or carbamoyl; fluoro, chloro or bromo; -OR3 -OCO2R3; -OCOR3; -OCONR3R4;

-oxo; -NR3R4; R3CONR4-; -NR3CO2R4; -NR3CONR3R4;

-SR3;

-SO3R3; -CO2R3; -CONR3Rw -CN; or phenyl optionally substited by 1-3 fluoro, chloro, bromo, C,-C6 alkyl, -OR3, -NR3R4, -S03R3, -CO2R3 or -CONR3R4, wherein R3, R4, and R9 in such RB substituents are as defined above; or R5 may be attached to

at another point on the ring so as to form a fused heterocyclic or heteroaromatic ring, which ring may contain additional hetero atoms selected from 0, N and S; A2 is C1-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 ion; and

represents a radical of the formula

optionally substituted on a carbon atom by 1-3 substituents independently selected from C1-C4 alkyl; C1 -C4 alkyl substituted by hydroxy, C,-C4 alkylamino, di(C1-C4 alkyl)amino, sulfo, C1-C4 alkoxy, amino, carboxy or halogen; C3-C6 cycloalkyl; C1 -C4 alkoxy; C1-C4 alkylthio; amino; Ct-C4 alkylamino; di(C1-C4 alkyl)amino; halo;C1-C4 alkanoylamino; C1 -C4 alkanoyloxy; carboxy;

alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted by one, two or three amino, halo, hydroxyl, trifluoromethyl, C,-C4 alkyl or Ct-C4 alkoxy groups; phenyl (C,-C4)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C,-C4 alkyl; and heteroaryl or heteroaralkyl in which 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 moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms, or optionally substituted so as to form a fused carboxyxlic, heterocyclic or heteroaromatic ring optionally substituted by 1 or 2 of the substituents defined above; or a pharmaceutically acceptable salt thereof.

31. A compound according to Claim 30 wherein

32. A compound according to Claim 30 wherein

33. A compound accordng to Claim 30 wherein

34. A compound according to Claim 30, 31, 32 or 33 wherein R1 is hydrogen, CH3CH2-,

35. A compound according to Claim 30, 31, 32 or 33 wherein R1 and RB taken together represent

36. A compound according to Claim 30, 31, 32 or 33 wherein R1 is

37. A compound according to Claim 30, 31, 32 or 33 wherein R' is

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

38. A compound according to Claim 30, 31, 32 or 33 wherein A is -CH2- or -CH2CH2-, R' is

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

39. A compound of the formula

wherein R8 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; cycloalkyi 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 heterocyclyalkyl 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

-NR3R4

-CO2R =0

-SR3

-CN -N3 -OSO3R3

-OP (O) (OR3) (OR4)

-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, cycloalkyalkyl 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 heterocyclyalkyl 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; R5 is selected from the group consisting of 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 heterocycyalkyl 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 above-named R5 radicals are optionally substituted by 1-3 substituents independently selected from: C1 -C6 alkyl optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl; fluoro, chloro or bromo; -OR3 -OCO2R3; -OCOR3; -OCONR3R4;

-oxo; -NR3R4; R3CONR4-; -NR3CO2R4; -NR3CONR3R4;

-SR3;

-SO3R3; -CO2R3; -CON R3R4; -CN; or phenyl optionally substituted by 1-3 fluoro, chloro, bromo, C1 -C6 alkyl, -OR3, -NR3R4, -SO3R3, -CO2R3 or -CONR3R3, wherein 3, R4, and R9 in such R5 substituents are as defined above; or R5 may be attached to

at another point on the ring so as to form a fused heterocyclic or heteroaromatic ring, which ring may contain additional hetero atoms selected from 0, N and S; A is C1-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 ion; and

represents a radical of the formula

optionally substituted on a carbon atom by 1-3 substituents independently selected from C1-C4 alkyl;C1-C4 alkyl substituted by hydroxy, C1 -C4 alkylamino, di(C1-C4 alkyl)amino, sulfo, C,-C4 alkoxy, amino, carboxy or halogen; C3-C6 cycloalkyl; C1-C4 alkoxy; C,-C4 alkylthio; amino; C1-C4 alkylamino; di(C1-C4 alkyl)amino; halo; C1-C4 alkanoylamino;C1-C4 alkanoyloxy; carboxy;

alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted .by one, two or three amino, halo, hydroxyl, trifluoromethyl, Cl-C4 alkyl or C,-C4 alkoxy groups; phenyl (C,-C4)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C1-C4 alkyl; and heteroaryl or heteroaralkyl in which 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 moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms, or optionally substituted so as to form a fused carbocyclic, heterocyclic or heteroaromatic ring optionally substituted by 1 or 2 of the substituents defined above; or a pharmaceutically acceptable salt thereof.

40. A compound according to Claim 39 wherein R1 is hydrogen, CH3CH2-,

41. A compound according to Claim 39 wherein R1 and R8 taken together represent

42. A compound according to Claim 39 wherein R2 is

43. A compound according to Claim 39 wherein R' is

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

44. A compound according to Claim 39, 40, 41, 42 or 43 wherein A is -CH2- or -CH2CH2--

45. A compound of the formula

wherein RB 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 heterocyclylalkly 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

-NR3R4

-CO2R3 =0

-SR3

-CN N3 -OS03R3

-OP (O) (OR3) (OR4)

-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 R8 taken together represent C2-CtO alkylidene or C2-C,O alkylidene substituted by hydroxy;R5 is selected from the group consisting of 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 heterocyclyalkyl 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 above-named R5 radicals are optionally substituted by 1-3 substituents independently selected from: C,-C6 alkyl optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl; fluoro, chloro or bromo; -OR3 -OCO2R3; -OCOR3; -OCON R3R4;

-oxo; -NR3R4; R3CONR4-; -NR3CO2R4; -NR3CONR3R4;

-SR3;

-SO3R3; -CO2R3; -CONR3R4; -CN; or phenyl optionally substituted by 1-3 fluoro, chloro, bromo, C,-C6 alkyl, -OR3, -NR3R4, -S03R3, -CO2R3 or -CONR3R4, wherein R3, R4, and R9 in such R5 substituents are as defined above; or R5 may be attached to

at another point on the ring so as to form a fused heterocyclic or heteroaromatic ring, which ring may contain additional hetero atoms selected from 0, N and S; A is C,-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 ion; and

represents a radical of the formula

optionally substituted on a carbon atom by a substituent independently selected from C1 -C4 alkyl; C,-C4 alkyl substituted by hydroxy, amino, C,-C4 alkylamino, di(C,-C4) alkylamino, sulfo, C1-C4 alkoxy, carboxy or halogen; C3-C6 cycloalkyl; C,-C4 alkoxy; C1-C4 alkylthio; amino;C,-C4 alkylamino; di(C1-C4)alkylamino; halo; C1-C4 alkanoylamino; C1-C4 alkanoyloxy; carboxy;

alkyl, hydroxy; amidino; guanidino, phenyl; phenyl substituted by one, two or three amino, halo, hydroxyl, trifluoromethyl, C1 -C4 alkyl or C1-C4 alkoxy groups; phenyl (C1-C4)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C1-C4 alkyl; and heteroaryl or heteroaralkyl in which 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 moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms; or a pharmceuticaly acceptable salt thereof.

46. A compound accordng to Claim 45 wheren R1 is hydrogen, CH3CH2-,

47. A compound according to Claim 45 wherein R1 and RB taken together represent

48. A compound according to Claim 45 wherein R1 is

49. A compound according to Claim 45 wherein R1 is

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

50. A compound according to Claim 45, 46, 47, 48 or 49 wherein A is -CH2- or -CH2CH2-

51. 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 whrein 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 radical are independently selected from the group consisting of C1-C6 alkyl optionally substituted by amino, halo, hydroxy or carboxyl halo -OR3

-NR3R4

-CO2R3 =0

-SR3

-CN -N3 -OS03R3

-OP (O) (OR3) (OR4)

-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 nitrogen to which at least one is attached may form a 5-or 6membered nitrogen-containing heterocyclic ring;R9 is as defined for R3 except that it may not be hydrogen; or wherein R1 and RB taken together represent C2-C1O alkylidene or C2-C,O alkylidene substituted by hydroxy; R5 is selected from the group consisting of 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 heterocyclyalkyl wherein the hetero atom or atoms in the abovenamed 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 above-named R5 radicals are optionally substituted by 1-3 substituents independently selected from: C1-C6 alkyl optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl; fluoro, chloro or bromo; -OR3 -OCO2R3; -OCOR3; -OCON R3R4;

-oxo; -N R3R4; R3CONR4-; -N R3C02R4; -NR3CONR3R4;

-SR3;

-SO3R3; -CO2R3; -CON R3R4; -CN; or phenyl optionally substituted by 1-3 fluoro, chloro, bromo, C,-C6 alkyl, -OR3, -NR3R4, -SO3R3, -CO2R3 or -CONR3R4, wherein R3, R4, and R9 in such RB substituents are as defined above; or Rs may be attached to

at another point on the ring so as to form a fused heterocyclic or heteroaromatic ring, which ring may contain additional hetero atoms selected from 0, N and S; A is C1-C8-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 ion; and

represents a radical of the formula

wherein X is 0, S or NR in which R is C1-C4 alkyl; Cr-C4 alkyl substituted by 1-3 hydroxy, amino, C,-C4 alkylamino, di(C1-C4)alkylamino, C,-C4 alkoxy, carboxy, halo or sulfo groups; C3-C6 cycloalkyl;C3-C6 cycloalkyl(C,-C4)alkyl optionally substituted by 1-3 substituents mentioned above in connection with C1 -C4 alkyl; phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halo, hydroxy, trifluoromethyl, C,-C4 alkyl, C1 -C4 alkoxy, C-C4 alkylamino, di(C1-C4)alkylamino, carboxy and sulfo; phenyl(C,-C4)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C,-C4 alkyl; and heteroaryl and heteroaralkyl in which the hetero atom or atoms are selected from the group consisting of 1-4, 0, S or N atoms and the alkyl moiety associated with heteroaralkyl has 1-6 carbon atoms, said heteroaryl and heteroaralkyl groups being optionally substituted in the heterocyclic ring moiety by 1-3 substituents independently selected from hydroxy, amino, halo, trifluoromethyl, C,-C4 alkyl, C,-C4 alkoxy, C,-C4 alkylamino, di(C1-C4)-alkylamino, carboxy and sulfo and in the alkyl moiety by 1-3 substituents selected from hydroxy, amino, C,-C4 alkylamino, di(C1-C4)alkylamino, C,-C4 alkoxy, carboxy, halo and sulfo, said heteroaromatic radical being optionally substituted on a carbon atom by one or more substituents independently selected from C,-C4 alkyl; C,-C4 alkyl substituted by hydroxy, C,-C4 alkylamino, di(C1-C4)alkylamino, C,-C4 alkoxy, amino, sulfo, carboxy or halogen; C3-C8 cycloalkyl; C,-C4 alkoxy, C,-C4 alkylthio; amino; C,-C4 alkylamino, di(C-C4)alkylamino; halo; C,-C4 alkanoylamino;C,-C4 alkanoyloxy; carboxy;

alkyl, hydroxy; amidino; guanidino, phenyl; phenyl substituted by one, two or three amino, halo, hydroxyl, trifluoromethyl, C,-C4 alkyl or C1 -C4 alkoxy groups; phenyl (C,-C4)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C,-C4 alkyl; and heteroaryl or heteroaralkyl in which 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 moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms, or optionally substituted so as to form a fused carboxyxlic, heterocyclic or heterocaromatic ring optionally substituted by 1 or 2 of the substituents defined above; or a pharmaceutically acceptable salt thereof.

52. A compound according to Claim 51 wherein R' is hydrogen, CH3CH2-,

53. A compound according to Claim 51 wherein R1 and RB taken together represent

54. A compound according to Claim 51 wherein R1 is

55. A compound according to Claim 51 wherein R' is

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

56. A compound of Claim 51, 52, 53, 54 or 55 wherein A is -CH2- or -CH2CH2-.

57. A compound of the formula

wherein RB 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

-NR3R4

-CO2R3 =0

-SR3

-CN -N3 -OSO3R3

-OP (O) (OR3) (OR4)

-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 heterq 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 RB taken together represent C2-C,O alkylidene or C2-C,O alkylidene substituted by hydroxy; R5 is selected from the group consisting of 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 heterocyclyalkyl 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 above-named R5 radicals are optionally substituted by 1-3 substituents independently selected from: C1-C6 alkyl optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl; fluoro, chloro or bromo; -OR3 -OCO2R3; -OCOR3; -OCON R3R4;

-oxo; -NR3R4; R3CONR4-; -N R3CO2R4; -NR3CONR3R4;

-SR3;

-SO3R3; -CO2R3; -CON R3R4; -CN; or phenyl optionally substituted by 1-3 fluoro, chloro, bromo, C,-C6 alkyl, -OR3, -NR3R4, -SO3R3, -CO2R3 or -CONR3R4, wherein R3, R4, and R9 in such R5 substituent are as defined above; or R5 may be attached to

at another point on the ring so as to form a fused heterocyclic or heteroaromatic ring, which ring may contain additional hetero atoms selected from 0, N and S; A is C1 -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 ion; and

represents a radical of the formula

wherein X isO, S or NR in which R is C1-C4 alkyl; C1-C4 alkyl substituted by 1-3 hydroxy, amino, C1-C4 alkylamino, di(C1-C4)alkylamino, C1-C4 alkoxy, carboxy, halo or sulfo groups; C3-C6 cycloalkyl;C3-C6 cycloalkyl(C1-C4)alkyl optionally substituted by 1-3 substituents mentioned above in connection with C1-C4 alkyl; phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halo, hydroxy, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, C,-C4 alkylamino, di(C1-C4)alkylamino, carboxy and sulfo; phenyl(C,-C4)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C1-C4 alkyl; and heteroaryl and heteroaralkyl in which the hetero atom or atoms are selected from the group consisting of 1-4, O, S or N atoms and the alkyl moiety associated with heteroaralkyl has 1-6 carbon atoms, said heteroaryl and heteroaral kyl groups being optionally substituted in the heterocyclic ring moiety by 1-3 substitutents independently selected from hydroxy, amino, halo, trifluoromethyl, C,-C4 alkyl, C,-C4 alkoxy, C,-C4 alkylamino, di(C1-C4)alkylamino, carboxy and sulfo and in the alkyl moiety by 1-3 substituents selected from hydroxy, amino, C,-C4 alkylamino, di(C1-C4)alkylamino, C,-C4 alkoxy, carboxy, halo and sulfo, said heteroaromatic radical being optionally substituted on a carbon atom by a substituent selected from C1-C4 alkyl;; C1 -C4 alkyl substituted by hydroxy, C1-C4 alkylamino, di(C1-C4)alkylamino, C1-C4 alkoxy, amino, sulfo, carboxy or halogen; C3-C6 cycloalkyl; C1-C4 alkoxy, C1 -C4 alkylthio; amino; C,-C4 alkylamino; di(C,-C4)alkylamino; halo; C,-C4 alkanoylamino; C,-C4 alkanoyloxy; carboxy;

alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted by one, two or three amino, halo, hydroxyl, trifluoromethyl, C,-C4 alkyl or C,-C4 alkyl or C,-C4 alkoxy groups; phenyl (C,-C4)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C1-C4 alkyl; and heteroaryl or heteroaralkyl in which 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 moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms; or a pharmaceutically acceptable salt thereof.

58. A compound according to Claim 57 wherein R1 is hydrogen, CH3CH2-,

59. A compound according to Claim 57 wherein R1 and R8 taken together represent

60. A compound according to Claim 57 wherein R1 is

61. A compound according to Claim 57 wherein R1 is

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

62. A compound according to Claim 57, 58, 59, 60 or 61 wherein A is -CH2- or -CH2CH2-

63. A compound of the formula

wherein RB 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 heterocycly lalkyl 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 C,-Css alkyl optionally substituted by amino, halo, hydroxy or carboxyl halo -OR3

-NR3R4

-CO2R3 =0

-SR3

-CN -N3 -OSO3R3

-OP (O) (OR3) (OR4)

-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 R' and RB taken together represent C2-C10 alkylidene or C2-C10 alkylidene substituted by hydroxy; R5 is selected from the group consisting of 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 heterocyclyalkyl 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 above-named R5 radicals are optionally substituted by 1-3 substituenmts independently selected from: C1 -C6 alkyl optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl; fluoro, chloro or bromo; -OR3 -OCO2R3; -OCOR3; -OCONR3R4;

-oxo; -NR3R4; R3CON R4-; -N R3CO2R4; -NR3CONR3R4;

-SR3;

-SO3R3; -CO2R3; -CON R3R4; -CN; or phenyl optionally substituted by 1-3 fluoro, chloro, bromo, C1-C6 alkyl, -OR3, -NR3R4, -SO3R3, -CO2R3 or -CONR3R4, wherein R3, R4, and R9 in such R5 substituents are as defined above; or R5 may be attached to

at another point on the ring so as to form a fused heterocyclic or heteroaromatic ring, which ring may contain additional hetero atoms selected from 0, N and S; A is C1-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 ion; and

represents a radical of the formula

wherein R is C1 -C4 alkyl; Ct-C4 alkyl substituted by 1-3 hydroxy, amino, Ct-C4 alkylamino, di(C1-C4)alkylamino, C,-C4 alkoxy, carboxy, halo or sulfo groups; C3-C6 cycloalkyl;C3-C6 cycloalkyl(C1-C4)alkyl optionally substituted by 1-3 substituents mentioned above in connection with C1-C4 alkyl; phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halo, hydroxy, trifluoromethyl, C1-C4 alkyl, C1 -C4 alkoxy, C1-C4 alkylamino, di(C1-C4)alkylamino, carboxy and sulfo; phenyl (C1 -C4) alkyl in which the phenyl portion may be optionally substituted by 1-3 substitutents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C1 -C4 alkyl; and heteroaryl and heteroaralkyl in which the hetero atom or atoms are selected from the group consisting of 1-4, 0, S or N atoms and the alkyl moiety associated with heteroaralkyl has 1-6 carbon atoms, said heteroaryl and heteroaralkyl groups being optionally substituted in the heterocyclic ring moiety by 1-3 substituents independently selected from hydroxy, amino, halo, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, C1 -C4 alkylamino, di (C1-C4)alkylamino, carboxy and sulfo and in the alkyl moiety by 1-3 substituents selected from hydroxy, amino, C1-C4 alkylamino, di(C1-C4)alkylamino, Ct-C4 alkoxy, carboxy, halo and sulfo; or a pharmaceutically acceptable salt thereof.

64. A compound acording to Claim 63 wherein R1 is hydrogen, CH3CH2-,

65. A compound according to Claim 63 wherein R1 and R8 taken together represent

66. A compound according to Claim 63 wherein R1 is

67. A compound according to Claim 63 wherein R1 is

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

68. A compound according to Claim 63, 64, 65, 66 or 67 wherein A is -CH2-, -CH2CH2-.

69. A compound of the formula

wherein RB 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

-NR3R4

-C02R3 =0

-SR3

-CN -N3 -OSO3R3

-OP (O) (OR3) (OR4)

-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 RB taken together represent C2-C10 alkylidene or C2-C10 alkylidene substituted by hydroxy; R5 is selected from the group consisting of 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 heterocyclyalkyl 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 above-named R5 radicals are optionally substituted by 1-3 substituents independently selected from: C1 -C6 alkyl optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl; fluoro, chloro or bromo; -OR3 -OCO2R3; -OCOR3; -OCONR3R4;

-oxo; -NR3R4; R3CONR4-; -NR3CO2R4; -NR3CONR3R4;

-SR3;

-SO3R3; -CO2R3; -CON R3R4; -CN; or phenyl optionally substituted by 1-3 fluoro, chloro, bromo, C1-C6 alkyl, -OR3, -NR3R4, -SO3R3, -CO2R3 or -CONR3R4, wherein R3, R4, and R9 in such R5 substituents are as defined above; A is C1-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 ion; and

represents a radical of the formula

wherein RB, R7 and R10 are independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, carboxy and carbamoyl; or a pharmaceutically acceptable salt thereof.

70. A compound according to Claim 69 wherein R1 is hydrogen, CH3CK2-,

71. A compound according to Claim 69 wherein R1 and R8 taken together represent

72. A compound according to Claim 69 wherein R1 is

73. A compound according to Claim 69 wherein R1 is

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

74. A compound according to Claim 69, 70, 71, 72 or 73 wherein A is -CH2- or -CK2CK2-.

75. A compound having the formula

wherein A is C1-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 ion; and

represents a radical of the formula

wherein R5 is C1-C4 alkyl and R6 represents hydrogen or C1 -C4 alkyl;

wherein R5 is C1-C4 alkyl and R6 and R7 are hydrogen or C1-C4 alkyl;

wherein R5 is C1-C4 alkyl and R is C1-C4 alkyl or phenyl-(C1-C4) alkyl

wherein R5 is C1-C4 alkyl and R6 is C1-C4 alkyl;

wherein R5 is C1-C4 alkyl and R is C,-C4 alkyl; or

wherein R5 is C1-C4 alkyl; or a pharmaceutically acceptable salt thereof.

76. A compound having the formula

wherein A is C1-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 ion; and

represents a radical of the formula

or a pharmaceutically acceptable salt thereof.

77. A compound having 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 ion and wherein

wherein the 1HNMR (D2O) spectrum shows characteristics peaks at 8:1.23 (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,

wherein the 1HNMR (D20) spectrum shows characteristic peaks at 8:1.23 (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,

or a pharmaceutically acceptable salt thereof.

78. 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 ion; or a pharmaceutically acceptable salt thereof.

82. The compound according to Claim 81 wherein R2 is p-nitrobenzyl.

83. The compound according to Claim 81 wherein R2 is anionic charge.

84. 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 ion; or a pharmaceutically acceptable salt thereof.

85. The compound according to Claim 84 wherein R2 is p-nitrobenzyl.

86. The compound according to Claim 84 wherein R2 is an anionic charge.

87. 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 ion; or a pharmaceutically acceptable salt thereof.

88. The compound according to Claim 87 wherein R2 is p-nitrobenzyl.

89. The compound according to Claim 87 wherein R2 is an anionic charge.

90. 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 ion; or a pharmaceutically acceptable salt thereof.

91. The compound according to Claim 90 wherein R2 is p-nitrobenzyl.

92. The compound according to Claim 90 wherein R2 is an anionic charge.

93. 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 ion; or a pharmaceutically acceptable salt thereof.

94. The compound according to Claim 93 wherein R2 is p-nitrobenzyl.

95. The compound according to Claim 93 wherein R2 is an anionic charge.

96. 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 ion; or a pharmaceutically acceptable salt thereof.

97. The compound according to Claim 96 wherein R2 is p-nitrobenzyl.

98. The compound according to Claim 93 wherein R2 is an anionic charge.

99. 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 ion; or a pharmaceutically acceptable salt thereof.

100. The compound according to Claim 99 wherein R2 is p-nitrobenzyl.

101. The compound according to Claim 99 wherein R2 is an anionic charge.

102. 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 ion; or a pharmaceutically acceptable salt thereof.

103. The compound according to Claim 102 wherein R2 is p-nitrobenzyl.

104. The compound according to Claim 102 wherein R2 is an anionic charge.

105. 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 ion; or a pharmaceutically acceptable salt thereof.

106. The compound according to Claim 105 wherein R2 is p-nitrobenzyl.

107. The compound according to Claim 105 wherein R2 is an anionic charge.

108. 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 ion; or a pharmaceutically acceptable salt thereof.

109. The compound according to Claim 108 wherein R2 is p-nitrobenzyl.

110. The compound according to Claim 108 wherein R2 is an anionic charge.

111. 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 ion; or a pharmaceutically acceptable salt thereof.

11 2. The compound according to Claim 111 wherein R2 is p-nitrobenzyl.

11 3. The compound according to Claim 111 wherein R2 is an anionic charge.

114. 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 ion; or a pharmaceutically acceptable salt thereof.

11 5. The compound according to Claim 11 4 wherein R2 is p-nitrobenzyl.

116. The compound according to Claim 114 wherein R2 is an anionic charge.

11 7. 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 ion; or a pharmaceutically acceptable salt thereof.

11 8. The compound according to Claim 11 7 wherein R2 is p-nitrobenzyl.

11 9. The compound according to Claim 11 7 wherein R2 is an anionic charge.

1 20. 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 proteting group, there is also present a counter ion; or a pharmaceutically acceptable salt thereof.

121. The compound according to Claim 120 wherein R2 is p-nitrobenzyl.

1 22. The compound according to Claim 1 20 wherein R2 is an anionic charge.

123. 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 ion; or a pharmaceutically acceptable salt thereof.

124. The compound according to Claim 1 23 wherein R2 is p-nitrobenzyl.

1 25. The compound according to Claim 1 23 wherein R2 is an anionic charge.

126. 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 ion; or a pharmaceutically acceptable salt thereof.

1 27. The compound according to Claim 1 26 wherein R2 is p-nitrobenzyl.

128. The compound according to Claim 1 26 wherein R2 is an anionic charge.

129. 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 ion; or a pharmaceutically acceptable salt thereof.

1 30. The compound according to Claim 129 wherein R2 is p-nitrobenzyl.

1 31. The compound according to Claim 1 29 wherein R2 is an anionic charge.

1 32. 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 ion; or a pharmaceutically acceptable salt thereof.

1 33. The compound according to Claim 1 32 wherein R2 is p-nitrobenzyl.

1 34. The compound according to Claim 132 wherein R2 is an anionic charge.

135. 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 ion; or a pharmaceutically acceptable salt thereof.

136. The compound according to Claim 135 wherein R2 is p-nitrobenzyl.

137. The compound according to Claim 135 wherein R2 is an anionic charge.

138. A compound of the formula

wherein the 1KNMR (D20) spectrum shows characteristic peaks at S: 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, 6.0Hz), 4.07-4.68 (10H, m), 8.19 (1H, s), or a pharmaceutically acceptable salt or ester thereof.

139. The compound according to Claim 138 wherein the carboxyl group is protected as a pnitrobenzyl ester.

140. A compound of the formula

wherein the 'HNMR (D20) spectrum shows characteristic peaks at 5:1.23 (3H, d, J = 6.4 Hz), 3.15 (2H, q, J = 3.7, 9.0 Hz), 3.37(1K, q, J = 2.6, 6.0Hz), 3.95-4.65 (10H, m), 8.62(1K, s), or a pharmaceutically acceptable salt or ester thereof.

141. The compound according to Claim 140 wherein the carboxyl group is protected as a pnitrobenzyl ester.

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

wherein RB 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 C -C6 alkyl optionally substituted by amino, halo, hydroxy or carboxyl halo -OR3

-NR3R4

-CO2R =0

-SR3

-CN -N3 -OSO3R3

-OP(O)(OR3)(0R4)

-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 heterocyclyalkyl 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 RB taken together represent C2-C10 alkylidene or C2-C10 alkylidene substituted by hydroxy; R5 is selected from the group consisting of substituted and unsubstituted: alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms;cycloalkyl and cycloalkyalkyl, 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 heterocyclyalkyl 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 above-named R5 radicals are optionally substituted by 1-3 substituents independently selected from: C1-C6 alkyl optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl; fluoro, chloro or bromo; -OR3 -OCO2R3; -OCOR3 -OCONR3R4

-oxo -NR3R4 R3CONR4 -NR3CO2R4 -NR3CONR3R4

-SR3

-SO3R3; -CO2R3; -CONR3R4 -CN; or phenyl optionally substituted by 1-3 fluoro, chloro, bromo, C1-C6 alkyl, -OR3, -NR3R4, -S03R3, -CO2R3 or -CONR3R4, wherein R3, R4, and R9 in such R5 substitutents are as defined above;or R5 may be attached to

at another point on the ring so as to form a fused heterocyclic or heteroaromatic ring, which ring may contain additional hetero atoms selected from 0, S and N; R'5 is 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; spirocycloalkyl having 3-6 carbon atoms; 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 abovenamed heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and 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 selected from the group consisting of: amino, mono-, di- and trialkylamino, hydroxyl, alkoxyl, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chloro, bromo, fluoro, cyano and carboxy; and wherein the alkyl moieties of the above-recited substituents have 1-6 carbon atoms; A is C1 -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 ion; and

represents a substituted or unsubstituted mono-, bi- or polycyclic aromatic heterocyclic radical containing at least one nitrogen in the ring, said ring being attached to A through a ring carbon atom and having a ring nitrogen which is quaternized by the group R5; or a pharmaceutically acceptable salt thereof, which process comprises the steps of (1) reacting an intermediate of the formula

wherein R1, RB and RIB are as defined above and R2' is a conventional readily removable carboxyl protecting group in an inert organic solvent with a reagent capable of introducing a conventional leaving group L at the 2-position of intermediate Ill to give an intermediate of the formula

wherein R1, R8, R15, L and R2' are as defined above and L is a conventional leaving group;; (2) reacting intermediate IV in an inert organic solvent and in the presence of base with a mercaptan reagent of the formula

wherein A is as defined above and

represents a mono-, bi- or polycyclic aromatic heterocyclic radical containing a quaternizable nitrogen in the ring, said ring being attached to A through a ring carbon atom, to give an intermediate of the formula

wherein R1, R8, R15, A, R21 and

Re as defined above;; (3) reacting intermediate II in an inert organic solvent with an alkylating agent of the formula R5-X' wherein R5 is as defined above and X' is a conventional leaving group so as to quaternize with the R5 group a ring nitrogen of substituent

on intermediate II and form a compound of the formula

"'hOrCin R1, R8, PIB, R2@ A,

and X' are as defined above; and, if desired, replacing counter ion X/ by a different counter ion and, if desired, removing the carboxyl protecting group R2' to give the desired de-blocked compound of formula I, or a pharmaceutically acceptable salt thereof.

143. A process according to Claim 142 wherein the quaternization step is carried out after removal of the carboxyl protecting group R2'.

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

wherein RB 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 substitutent 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

-NR3R4

-CO2R3 =0

-SR3

-CN -N3 -OS03R3

-OP(O)(OR3)(0R4)

-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, hereoaralkyl, 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 RB taken together represent C2-C10 alkylidene or C2-C10 alkylidene substituted by hydroxy;R5 is selected from the group consisting of substituted and unsubstituted: alkyl, alkenyl and alkyl, 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 heterocyclyalkyl 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 above-named R5 radicals are optionally substituted by 1-3 substituents independently selected from:C,-C6 alkyl optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl; fluoro, chloro or bromo; -OR3 -OCO2R -OCOR3 -OCONR3R4

-oxo -NR R4 R3CON R4- -NR3CO2R4 -NR3CONR3R4

-SR3

-SO3R3 -CO2R -CONR3R4 -CN; or phenyl optionally substituted by 1-3 fluoro, chloro, bromo, C1-C8 alkyl, -OR3, -NR3R4, -S03R3, -C02R3, -C02R3 or -CONR3R4, wherein R3, R4, and R9 in such R5 substituents are as defined above; or R5 may be attached to

at another point on the ring so as to form a fused heterocyclic or heteroaromatic ring, which ring may contain additional hetero atoms selected from 0, S and N; R'5 is 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; spirocycloalkyl having 3-6 carbon atoms; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclyalkyl wherein the hetero atom or atoms in the abovenamed heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and 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 selected from the group consisting of: amino, mono-, di- and trialkylamino, hydroxyl, alkoxyl, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chloro, bromo, fluoro, cyano and carboxy; and wherein the alkyl moieties of the above-recited substituents have 1-6 carbon atoms; A is C1-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 ion; and

represents a substituted or unsubstituted mono-, bi- or polycyclic aromatic heterocyclic radical containing at least one nitrogen in the ring, said ring being attached to A through a ring carbon atom and having a ring nitrogen which is quaternized by the group R5; or a pharmaceutically acceptable salt thereof, which process comprises reacting an intermediate of the formula

wherein R', R8, Rl5, A and R2' are as defined above and

represents a mono-, bi- or polycyclic aromatic heterocyclic radical containing a quaternizable nirogen in the ring, said ring being attached to A through a ring carbon atom, in an inert organic solvent witn an alkylating agent of the formula R5-X' wherein R5 is as defined above and Xss is a conventional leaving group so as to quaternize with the R5 group a ring nitrogen of substituent

on intermediate il and form a compound of the formula

wherein R1, RB, RIB, R21, A,

and X' are as defined above; and, if desired, replacing counter ion X' by a different counter ion and, if desired, removing the carboxyl protecting group R2' to give the desired de-blocked compound of formula I, or a pharmaceutically acceptable salt thereof.

145. The process according to Claim 1 44 wherein the quaternization is carried out after removal of the carboxyl protecting group R2'.

146. 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

-NR3R4

=O

-SR3

-CN -N3 -OSO4R3

-OP(O)(OR )(OR4)

-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, cycloalkyalkyl and alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; phenyl; aralkyl, aralkenyl and aralkynly 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 hetrocyclic 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 RB taken together represent C2-C10 alkylidene or C2-C10 alkylidene substituted by hydroxy; R5 is selected from the group consisting of substituted and unsubsitituted: 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 heterocyclyalkyl 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 above-named R5 radicals are optionally substituted by 1-3 substituents independently selected from: C1-C6 alkyl optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl; fluoro, chloro or bromo; -OR3 -OCO2R3; -OCOR3 -OCONR3R4

-oxo -NR3R4 R3CONR4 -NR3CO2R4 -NR3CONR3R4

-SR3

-SO3R3; -CO2R3; -CONR3R4 -CN; or phenyl optionally substituted by 1-3 fluoro, chloro, bromo, C1-C6 alkyl, -OR3, -NR3R4, -SO3R3, -CO2R3 or -CONR3R4, wherein R3, R4, and R9 in such R5 substituents are as defined above;or R5 may be attached to

at another point on the ring so as to form a fused heterocyclic or heteroaromatic ring, which ring may contain additional hetero atoms selected from 0, S and N; R15 is 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; spirocycloalkyl having 3-6 carbon atoms; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclyalkyl wherein the hetero atom or atoms in the abovenamed heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and 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 selected from the group consisting of: amino, mono-, di- and trialkylamino, hydroxyl, alkoxyl, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chloro, bromo, fluoro, cyano and carboxy; and wherein the alkyl moieties of the above-recited substituents have 1-6 carbon atoms; A is C1-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 ion; and

represents a substituted or unsubstituted mono-, bi- or polycyclic aromatic heterocyclic radical containing at least one nitrogen in the ring, said ring being attached to A through a ring carbon atom and having a ring nitrogen which is quaternized by the group R5; or a pharmaceutically acceptable salt thereof.

147. A compound of the formula

wherein RB 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 C,-C6 alkyl optionally substituted by amino, halo, hydroxy or carboxyl halo -OR3

-NR3R4

-C02R3 =0

-SR3

-CN -N3 -OSO3R3

-OP(O)(OR3)(0R4)

-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 R' and RB taken together represent C2-C10 alkylidene or C2-C10 alkylidene substituted by hydroxy;R5 is selected from the group consisting of 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 heterocyclyalkyl 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 above-named R5 radicals are optionally substituted by 1-3 substituents independently selected from; C1 -Ce alkyl optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl; fluoro, chloro or bromo; -OR3 -OCO2R3; -OCOR3 -OCONR3R4

-oxo -NR3R4 R3CONR4 -NR3CO2R4 -NR3CONR3R4

-SR3

-SO3R -CO2R -CONR3R4 -CN; or phenyl optionally substituted by 1-3 fluoro, chloro, bromo, C1-C6 alkyl, -OR3, -NR3R4, -SO3R3, -CO2R3 or -CONR3R4, wherein R3, R4, and R9 in such R5 substituents are as defined above; or R5 may be attached to

at another point on the ring so as to form a fused heterocyclic or heteromatic ring, which ring may contain additional hetero atoms selected from 0, S and N; RIB is selected from the group consisting of 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; spirocycloalkyl having 3-6 carbon atoms; 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 and 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 selected from the group consisting of: amino, mono-, di- and trialkylamino, hydroxyl, alkoxyl, mecapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chloro, bromo, fluoro, cyano and carboxy; and wherein the alkyl moieties of the above-recited substituents have 1-6 carbon atoms; A is C1-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 ion; and

represents a substituted or unsubstituted mono-, bi- or polycyclic aromatic heterocyclic radical containing at least one nitrogen in the ring, said ring being attached to A through a ring carbon atom and having a ring nitrogen which is quaternized by the group R5; or a pharmaceutically acceptable salt thereof.

148. A compound according to Claim 147 wherein R' is

and R16 is methyl. 149. A compound according to Claim 147 wherein R1 is

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

1 50. A compound according to Claim 147, 148, or 149 wherein A is -CH2- or -CH2CH2-.

151. A compound of the formula

wherein RB 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 cycloalkyalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; phenyl, aralkyl, and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; heteroaryl, heteroaralkyl, hereocyclyl 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, hyrdoxy or carboxyl halo -OR3

-NR3R4

-C02R3 =0

-SR3

-CN -N3 -OSO3R

-OP(O)(OR3)(0R4)

-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 R9 taken together represent C2-C10 alkylidene or C2-C10 alkylidene substituted by hydroxy;R5 is selected rom the group consisting of 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 moities; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclyalkyl 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 above-named R5 radicals are optionally substituted by 1-3 substituents independently selected from: C,-C6 alkyl optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl; fluoro, chloro or bromo; -OR3 -OCO2R3; -OCOR3 -OCONR3R4

-oxo -NR3R4 R3CONR4- -NR3CO2R4 -NR3CONR3R4

-SR3

-SO3R3; -CO2R3; -CONR3R4 -CN; or phenyl optionally substituted by 1-3 fluoro, chloro, bromo, C,-C6 alkyl, -OR3, -NR3R4, -SO3R3, -CO2R3 or -CONR3R4, wherein R3, R4, and R9 in such R5 substituents are as defined above; -SO3R3, -CO2R3 or -CONR3R4, wherein R3, R4 and R9 in such R5 substituents are as defined above; or R5 may be attached to

at another point on the ring so as form a fused heterocyclic or heteroaromatic ring, which ring may contain additional hetero atoms selected from 0, S, and N; R16 is selected from the group consisting of 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; spirocycloalkyl having 3-6 carbon atoms; 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 and 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 selected from the group consisting of: amino, mono-, di- and trialkylamino, hydroxyl, alkoxyl, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chloro, bromo, fluoro, cyano and carboxy; and wherein the alkyl moieties of the above-recited substituents have 1-6 carbon atoms; A is C,-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 ion; and

represents an aromatic mono-, bi- or polycyclic N-containing heterocyclic ring containing 0-5 additional hetero atoms selected from 0, S or N, said heterocyclic ring being attached to A through a ring carbon atom and having a ring nitrogen quaternized by the group R5, and said heterocyclic ring being optionally substituted at available ring carbon atoms by 1-5 substituents independently selected from the group consisting of C,-C4 alkyl;C1-C4 alkyl substituted by 1-3 hydroxy, amino, C,-C4 alkylamino, di (C,-C4) alkylamino, C,-Ci alkoxy, carboxy, halo or sulfo; C3-C6 cycloalkyl; C3CB cycloalkyl (C,-C4) alkyl optionally substituted by 1-3 substituents mentioned above in connection with C1-C4 alkyl; C1-C4 alkoxy; C1 -C4 alkylthio; amino; C1 -C4 alkylamino; di (C1-C4) alkylamino; halo; C1-C4 alkanoylamino;C1-C4 alkanoyloxy; carboxy; sulfo;

alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halo, hydroxy, trifluoromethyl, C1 -C4 alkyl, C1-C4 alkoxy, Cl-C4 alkylamino, di (C1 -C4) alkylamino, carboxy, and sulfo; phenyl (C1 -C4) alkyl in which the phenyl portion is optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion is optionally substituted by 1-3 substituents mentioned above in connection with C1 -C4 alkyl; and heteroaryl or heteroaralkyl in which the hetero atom or atoms are selected from the group consisting of 1-4 0, S or N atoms and the alkyl moiety associated with heteroaralkyl has 1-6 carbon atoms, said heteroaryl and heteroaralkyl groups being optionally substituted in the heterocyclic ring moiety by 1-3 substituents independently selected from hydroxy, amino, halo, trifluoromethyl, C1 -C4 alkyl, C,-C4 alkoxy, C,-C4 alkylamino, di (C1-C4)-alkylamino, carboxy and sulfo and in the alkyl moiety by 1-3 substituents selected from hydroxy, amino, C1 -C4 alkylamino, di (C1 -C4) alkylamino, C1 -C4 alkoxy, carboxy, halo and sulfo, and said heterocyclic ring being optionally substituted at available ring nitrogen atoms by 1-3 substituents independently selected from the group consisting of C1 -C4 alkyl; C,-C4 alkyl substituted by 1-3 hydroxy, amino, C1-C4 alkylamino, di (C1-C4) alkylamino, C1-C4 alkoxy, carboxy, halo or sulfo groups; C3-CB cycloalkyl; C3-C6 cycloalkyl (C1-C4)-alkyl optionally substituted by 1-3 substituents mentioned above in connection with C1 -C4 alkyl; phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halo, hydroxy, trifluoromethyl, C1 -C4 alkyl, C1 -C4 alkoxy, C1-C4 alkylamino, di (C1 -C4) alkylamino, carboxy and sulfo; phenyl-(C1-C4) alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C1-C4 alkyl; and heteroaryl or heteroaralkyl in which the hetero atom or atoms are selected from the group consisting or 1-4 0, S or N atoms and the alkyl moiety associated with heteroaralkyl has 1-6 carbon atoms, said heteroaryl and heteroaralkyl groups being optionally substituted in the heterocyclic ring moiety by 1-3 substituents independently selected from hydroxy, amino, halo, trifluoromethyl, C,-C4 alkyl, C,-C4 alkoxy, C,-C4 alkylamino, di (C1 -C4) alkylamino, carboxy and sulfo and in the alkyl moiety by 1-3 substituents selected from hydroxy, amino, C1 -C4 alkylamino, di (C1-C4) alkylamino, C1 -C4 alkoxy, carboxy, halo and sulfo; or a pharmaceutically acceptable salt thereof.

152. A compound according to Claim 151 wherein R1 is

and RIB is methyl.

153. A compound according to Claim 151 wherein R1 is

R16 is methyl and the absolute configuration is 5R, 6S, 8R.

154. A compound according to Claim 151, 152, or 153 wherein A is -CH2- or -CH2CH2-.

1 55. A compound of the formula

wherein RB 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

-NR3R4

-CO2R3 =0

-SR3

-CN -N3 -OSO3R3

-OP (O) (OR3) (OR4)

-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 aiyl 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 RB taken together represent C2-C10 alkylidene or C2-C10 alkylidene substituted by hydroxy;R5 is selected from the group consisting of 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 heterocyclyalkyl 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 above-named R5 radicals are optionally substituted by 1-3 substituents independently selected from: C1-C6 alkyl optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl; fluoro, chloro or bromo; -OR3 -OCO2R3; -OCOR3; -OCONR3R4;

oxo; -NR3R4; R3CON R4-; N R3C02R4; -N R3CON R3R4;

-SR3;

-SO3R3; -CO2R3; -CON R3R4; -CN; or phenyl optionally substituted by 1-3 fluoro, chloro, bromo, C1-Có alkyl, -OR3, -NR3R4, -SO3R3, -CO2R3 or -CONR3R4, wherein R3, R4, and R9 in such R5 substituents are as defined above; or R5 may be attached to

at another point on the ring so as to to form a fused heterocyclic or heteroaromatic ring, which ring may contain additional hetero atoms selected from 0, N and S; R16 is selected from the group consisting of 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; spirocycloalkyl having 3-6 carbon atoms; 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 and 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 selected from the group consisiting of: amino, mono-, di- and trialkylamino, hydroxyl, alkoxyl, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chloro, bromo, fluoro, cyano and carboxy; and wherein the alkyl moieties of the above-recited substituents have 1-6 carbon atoms; A is C1-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 ion; and

represents an aromatic 5- or 6-membered N-containing heterocyclic ring containing 0-3 additional hetero atoms selected from N, S or 0, said heterocyclic ring being optionally substituted at available ring carbon atoms by 1-5 substituents independently selected from the group consisting of C1 -C4 alkyl; C1 -C4 alkyl substituted by 1-3 hydroxy, amino, C1-C4 alkylamino, di (C1-C4) alkylamino, C1-C4 alkoxy, carboxy, halo or sulfo; C3-C6 cycloalkyl; C3-C6 cycloalkyl (C1 -C4) alkyl optionally substituted by 1-3 substituents mentioned above in connection with C,-C4 alkyl; C1 -C4 alkoxy; C1-C4 alkylthio; amino;C1-C4 alkylamino; di (C1 -C4)- alkylamino; halo; C1 -C4 alkanoylamino; C1-C4 alkanoyloxy; carboxy; sulfo;

alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halo, hydroxy, trifluoromethyl, C1-C4 alkyl, C1 -C4 alkoxy, C1 -C4 alkylamino, di (C1-C4) alkylamino, carboxy, and sulfo; phenyl (C1-C4) alkyl in which the phenyl portion is optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion is optionally substituted by 1-3 substituents mentioned above in connection with C1 -C4 alkyl; and heteroaryl or heteroaralkyl in which the hetero atom or atoms are selected from the group consisting of 1-4 0, S or N atoms and the alkyl moiety associated with heteroaralkyl has 1-6 carbon atoms, said heteroaryl and heteroaralkyl groups being optionally substituted in the heterocyclic ring moiety by 1-3 substituents independently selected from hydroxy, amino, halo, trifluoromethyl, C1-C4 alkyl, C1 -C4 alkoxy, C1 -C4 alkylamino, di (C1-C4)-alkylamino, carboxy and sulfo and in the alkyl moiety by 1-3 substituents selected from hydroxy, amino, C1-C4 alkylamino, di (C1-C4) alkylamino, C1-C4 alkoxy, carboxy, halo and sulfo, and said heterocyclic ring being optionally substituted at available ring nitrogen atoms by 1-3 substituents independently selected from the group consisting of C1-C4 alkyl;; C1 -C4 alkyl substituted by 1-3 hydroxy, amino, C1-C4 alkylamino, di (C1-C4) alkylamino, C1-C4 alkoxy, carboxy, halo or sulfo groups; C3-C6 cycloalkyl; C3-C6 cycloalkyl (C1 -C4) alkyl optionally substituted by 1-3 substituents mentioned above in connection with C1 -C4 alkyl; phenyl; substituted by 1-3 substituents independently selected from amino, halo, hydroxy, trifluoromethyl, C1-C4 alkyl, C1 -C4 alkoxy, C1-C4 alkylamino, di (C1-C4)alkylamino, carboxy and sulfo; phenyl(C1-C4)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C1-C4 alkyl; and heteroaryl or heteroaralkyl in which the hetero atom or atoms are selected from the group consisting or 1-4 0, S or N atoms and the alkyl moiety associated with heteroaralkyl has 1-6 carbon atoms, said heteroaryl and heteroaralkyl groups being optionally substituted in the heterocyclic ring moiety by 1-3 substituents independently selected from hydroxy, amino, halo, trifluoromethyl, C1 -C4 alkyl, C1-C4 alkoxy, C1 -C4 alkylamino, di (C1-C4) alkylamino, carboxy and sulfo and in the alkyl moiety by 1-3 substituents selected from hydroxy, amino, C1 -C4 alkylamino, di (C1 -C4) alkylamino, C1 -C4 alkoxy, carboxy, halo and sulfo; or a pharmaceutically acceptable salt thereof.

1 56. A compound according to Claim 1 55 wherein the heterocyclic ring

is optionally substituted at available ring carbon or nitrogen atoms by up to 5 substituents independently selected from (lower) alkyl.

157. A compound according to Claim 1 56 wherein A is -CH2-, -CH2CH2- or

1 58. A compound according to Claim 155, 1 56 or 1 57 wherein R1 is

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

159. A compound of the formula

wherein RB 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 heterocyclalkyl 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

-NR3R4

-CO2R3 =0

-SR3

-CN -N3 -OSO3R3

-OP(O)(OR3)(0R4)

-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 R8 taken together represent C2-C10 alkylidene or C2-C10 alkylidene substituted by hydroxy; R5 is selected from the group consisting of 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 heterocyclalkyl 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 above-named R5 radicals are optionally substituted by 1-3 substituents independently selected from: C1-C6 alkyl optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl; fluoro, chloro or bromo; -OR3 -OCO2R3; -OCOR3 -OCONR3R4

-oxo -NR3R4 R3CON R4 -NR3CO2R4 -NR3CONR3R3

-SR3

-SO3R3; -CO2R3; -CONR3R4 -CN; or phenyl optionally substituted by 1-3 fluoro, chloro, bromo, C1-C6 alkyl, -OR3, -NR3R4, -SO3R3, -CO2R3 or -CONR3R4, wherein R3, R4, and R9 in such R5 substituents are as defined above; or R5 may be attached to

at another point on the ring so as to form a fused heterocyclic or heteroaromatic ring, which ring may contain additional hetero atoms selected from 0, N and S; RIB is selected from the group consisting of 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; spirocycloalkyl having 3-6 carbon atoms; phenyl; aralkyl, aralkenyi 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 and 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 selected from the group consisting of: amino, mono-, di- and trialkylamino. hydroxyl, alkoxyl, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chloro, bromo, fluoro, cyano and carboxy; and wherein the alkyl moieties of the above-recited substituents have 1-6 carbon atoms; A is C1-C6 straight or branched chain alkylene; R2 is hydrogen, an anionic charge or a conventional readily removable carboxy protecting group, providing that when R2 is hydrogen or a protecting group, there is also present a counter ion; and

represents a radical selected from the group consisting of

wherein R6, R7 and R'O are independently selected from hydrogen; C1 -C4 alkyl; C1-C4 alkyl substituted by hydroxy, Ct-C4 alkylamino, di(C1-C4 alkyl)amino, C1-C4 alkoxy, amino, sulfo, carboxy or halo;C3-C6 cycloalkyl; C1 -C4 alkoxy; C1 -C4 alkylthio; amino; C1 -C4 alkylamino; di(C1-C4 alkyl)amino; halo; C1 -C4 alkanoylamino; C1-C4 alkanoyloxy; carboxy;

alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted by one, two or three amino, halo, hydroxyl, trifluoromethyl, C1-C4 alkyl or C1 -C4 alkoxy groups; phenyl (C1-C4)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C1 -C4 alkyl; and heteroaryl and heteroaralkyl in which the hetero atom or atoms in the group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms; or wherein two of R6, R7 or R10 taken together may be a fused saturated carbocyclic ring, a fused aromatic carbocyclic ring, a fused non-aromatic heterocyclic ring or a fused heteroaromatic ring, said fused rings being optionally substituted by 1 or 2 of the substituents defined above for R6, R7 and R10;

optionally substituted on a carbon atom by 1-3 substituents independently selected from C1-C4 alkyl; C1 -C4 alkyl substituted by hydroxy, C1-C4 alkylamino, di(C1-C4 alkyl)amino, sulfo, C1 -C4 alkoxy, amino, carboxy or halogen; C3-C6 cycloalkyl;; C1 -C4 alkoxy; C1 -C4 alkylthio; amino; C1-C4 alkylamino; di(C1-C4 alkyl)amino; halo; C1 -C4 alkanoylamino; C,-C4 alkanoyloxy; carboxy;

alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted xy one, two or three amino, halo, hydroxyl, trifluoromethyl, C1-C4 alkyl or C1 -C4 alkoxy groups; phenyl (C1-C4)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C1-C4 alkyl; and heteroaryl or heteroaralkyl in which 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 moiety associated with said hteroaralkyl moiety has 1-6 carbon atoms, or optionally substituted so as to form a fused carbocyclic, heterocyclic or heteraromatic ring optionally substituted by 1 or 2 of the substituents defined above;

optionally substituted on a carbon atom by one or two substituents independently selected from C1-C4 alkyl; C1-C4 alkyl substituted by hydroxy, C1-C4 alkylamino, di(C1-C4 alkyl)amino, C1 -C4 alkoxy, sulfo, amino, carboxy or halogen; C3-C6 cycloalkyl; C1-C4 alkoxy; C1-C4 alkylthio; amino; C1 -C4 alkylamino; di(C1-C4 alkyl)amino; halo; C1-C4 alkylamino;C1-C4 alkanoyloxy; carboxy;

alkyl; hydroxy, amidino; guanidino, phenyl; phenyl substituted by one, two or three amino, halo, hydroxyl, trifluoromethyl, C1-C4 alkyl or C1 -C4 alkoxy groups; phenyl (C1-C4)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C1 -C4 alkyl; and heteroaryl or heteroaralkyl in which 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 moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms, or optionally substituted so as to form a fursed carbocyclic, heterocyclic or heteroaromatic ring optionally substituted by 1 or 2 of the substituents defined above;

optionally substituted on a carbon atom by a substituent independently selected from C1-C4 alkyl; C1 -C4 alkyl substituted by hydroxy, amino, C1 -C4 alkylamino, di(C1-C4 alkyl)amino, C1 -C4 alkoxy, sulfo, carboxy or halogen; C3-C6 cycloalkyl; C1 -C4 alkoxy; C1 -C4 alkylthio; amino;C,-C4 alkylamino; di(C1-C4 alkyl)amino; halo; C1 -C4 alkanoylamino; C1-C4 alkanoyloxy; carboxy;

alkyl; hydroxy; amidino; guanidino, phenyl; phenyl substituted by one, two or three amino, halo, hydroxyl, trifluoromethyl, C1-C4 alkyl or C1 -C4 alkoxy groups; phenyl (C1-C4)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned abive in connection with C1-C4 alkyl; and heteroaryl or heteroaralkyl in which 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 moiety associated wth said heteroaralkyl moiety has 1-6 carbon atoms;

wherein X is 0, S or NR in which R is C1-C4 alkyl; C1 -C4 alkyl substituted by 1-3 hydroxy, amino, C1 -C4 alkylamino, di(C1-C4)alkylamino, C1 -C4 alkoxy, carboxy, halo or sulfo groups; C3-C6 cycloalkyl; C3-C6 cycloalkyl(C1-C4)alkyl optionally substituted by 1-3 substituents mentioned above in connection with C1-C4 alkyl; phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halo, hydroxy, trifluoromethyl, C1 -C4 alkyl, C1 -C4 alkoxy, C1-C4 alkylamino, di(C1-C4)alkylamino, carboxy and sulfo; phenyl(C1-C4)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C1 -C4 alkyl; and heteroaryl and heteroaralkyl in which the hetero atom or atoms are selected from the group consisting of 1-4, 0, S or N atoms and the alkyl moiety associated with heteroaralkyl has 1-6 carbon atoms, said heteroaryl and heteroaralkyl groups being optionally substituted in the heterocyclic ring moiety by 1-3 substituents independently selected from hydroxy, amino, halo, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, di(C1-C4)alkylO substituents selected from hydroxy, amIno, C1-C4 alkylamino, di(C1-C4)alkylamino, C1 -C4 alkoxy, carboxy, halo and sulfo, said radical being optionally substituted on a carbon atom by one or more substituents independently selected from Ct-C4 alkyl;; C1 -C4 alkyl substituted by hydroxy, C1 -C4 alkylamino, di(C1-C4 alkyl)amino, C1 -C4 alkoxy, amino, sulfo, carboxy or halogen, C3-C6 cycloalkyl; C1-C4 alkoxy; C1 -C4 alkylthio; amino; C1 -C4 alkylamino; di(C1-C4 alkyl)amino; halo; C1 -C4 alkanoylamino; C1 -C4 alkanoyloxy; carboxy;

alkyl; hydroxy; amidino; guanidino, phenyl; phenyl substituted by one, two or three amino, halo, hydroxyl, trifluoromethyl, C1 -C4 alkyl or C1-C4 alkoxy groups; phenyl (C1-C4)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C1-C4 alkyl; and heteroaryl or heteroaralkyl in which 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 moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms, or optionally substituted so as to form a fused carbocyclic, heterocyclic or heteroaromatic ring optionally substituted by 1 or 2 of the substituents defined above;

wherein X isO, S or NR in which R is C1-C4 alkyl;C1-C4 alkyl substituted by 1-3 hydroxy, amino, C1-C4 alkylamino, di(C1-C4)alkylamino, C1 -C4 alkoxy, carboxy, halo or sulfo groups; C3-C6 cycloalkyl; C3-C6 cycloalkyl(C1-C4)alkyl optionally substituted by 1-3 substituents mentioned above in connection with C1 -C4 alkyl; phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halo, hydroxy, trifluoromethyl, C1 -C4 alkyl, C1 -C4 alkoxy, C1 -C4 alkylamino, di(C1-C4)alkylamino, carboxy and sulfo; phenyl(C1-C4)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C1 -C4 alkyl; and heteroaryl and heteroaralkyl in which the hetero atom or atoms are selected from the group consisting of 1-4, 0 S or N atoms and the alkyl moiety associated with heteroaralkyl has 1-6 carbon atoms, said heteroaryl and heteroaryl and heteroaralkyl groups being optionally substituted in the heterocyclic ring moiety by 1-3 substituents independently selected from hydroxy, amino, halo, trifluoromethyl, C1 -C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, di(C1-C4)alkylamino, carboxy and sulfo and the alkyl moiety by 1-3 substituents selected from hydroxy, amino, C1-C4 alkylamino, di(C1-C4)alkylamino, C1-C4 alkoxy, carboxy, halo and sulfo, said heteroaromatic radical being optionally substituted on a carbon atom by a substituent selected from C1-C4 alkyl; C1-C4 alkyl substituted by hydroxy, C1 -C4 alkylamino, di(C,-C4 alkyl)amino, C,-C4 alkoxy, amino, sulfo, carboxy or halogen; C3-C6 cycloalkyl; C1-C4 alkoxy; C1 -C4 alkylthio; amino;C1-C4 alkylamino; di(C1-C4)alkylamino; halo; C1 -C4 alkanoylamino; C1 -C4 alkanoyloxy; carboxy;

alkyl; hydroxy; amidino; guanidino; phenyl; phenyl substituted by one, two or three amino, halo, hydroxyl, trilfuoromethyl, C1-C4 alkyl or C1-C4 alkoxy groups; phenyl (C1-C4)alkoxy in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C,-C4 alkyl; and heteroaryl or heteroaralkyl in which 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 moiety associated with said heteroalkyl moiety has 1-6 carbon atoms; and

wherein R is C1-C4 alkyl; C1-C4 alkyl substituted by 1-3 hydroxy, amino, C1-C4 alkylamino, di(C1-C4)alkylamino, C1-C4 alkoxy, carboxy, halo or sulfo groups; C3-C6 cycloalkyl; C3-C6 cycloalkyl(C1-C4)alkyl optionally substituted by 1-3 substituents mentioned above in connection with C,-C4 alkyl; phenyl; phenyl substituted by 1-3 substituents independently selected from amino, halo, hydroxy, trifluoromethyl, C1 -C4 alkyl, C1 -C4 alkoxy, C1 -C4 alkylamino, di(C1-C4)alkylamino, carboxy and sulfo; phenyl(C1-C4)alkyl in which the phenyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with phenyl and the alkyl portion may be optionally substituted by 1-3 substituents mentioned above in connection with C1 -C4 alkyl; and heteroaryl and heteroaralkyl in which the hetero atom or atoms are selected from the group consisting of 1-4, 0, S or N atoms and the alkyl moiety associated with heteroaralkyl has 1-6 carbon atoms, said heteroaryl and heteroaralkyl groups being optionally substituted in the heterocyclic ring moiety by 1-3 substituents independently selected from hydroxy, amino, halo, trifluoromethyl, C1-C4 alkyl, C1 -C4 alkoxy, C1 -C4 alkylamino, di(C1-C4)alkylamino, carboxy and sulfo and in the alkyl moiety by 1-3 substituents selected from hydroxy, amino, C1-C4 alkylamino, di(C1-C4)alkylamino, C1 -C4 alkoxy, carboxy, halo and sulfo; or a pharmaceutically acceptable salt thereof.

1 60. A compound according to Claim 1 59 wherein

represents a radical selected from the group consisting of

wherein R5 is C1-C6 alkyl and R6, R7 and R10 are each independently hydrogen or C1-C4 alkyl;

wherein R5 is C1-C6 alkyl and wherein available ring carbon atoms are optionally substituted by 1-3 substituents independently selected from C1-C4 alkyl;

wherein R5 is C1-C6 alkyl and wherein available ring carbon atoms are optionally substituted by 1 or 2 substituents independently selected from C1-C4 alkyl;

wherein R5 is C1-C6 alkyl and wherein an available ring carbon atom is optionally substituted by C1-C4 alkyl;;

wherein R5 is C1-C6 alkyl, X is 0, S or NR in which R is C1-C4 alkyl and wherein one or more available ring carbon atoms is optionally substituted by C1-C4 alkyl;

wherein R5 is C1-C6 alkyl, X is 0, S or NR in which R is C1-C4 alkyl and wherein one or more available ring carbon atoms is optionally substituted by C1-C4 alkyl; and

wherein R5 is C1-C6 alkyl and R is C1-C4 alkyl.

1 61. A compound according to Claim 160 wherein R1 is

and RIB is methyl.

162. A compound according to Claim 160 wherein R1 is

R16 is methyl and the absolute configuration is 5R, 6S, 8R.

163. A compound according to Claim 159, 160, 161 or 162 wherein A is -CH2 or -CK2CH2-.

164. A compound having the formula

wherein A is C1-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 ion; and

represents a radical of the formula

wherein R5 is C1-C4 alkyl and R6 represents hydrogen or C1-C4 alkyl;

wherein R5 is C1-C4 alkyl and Rs and R7 are hydrogen or C1-C4 alkyl;

wherein R5 is C1-C4 alkyl and R is C1-C4 alkyl or phenyl(C1-C4)alkyl;

wherein R5 is C1-C4 alkyl and R6 is C1-C4 alkyl;

wherein R5 is C1-C4 alkyl and R is C1-C4 alkyl; or

wherein R5 is C1-C4 alkyl; or a pharmaceutically acceptable salt thereof.

165. A compound having the formula

wherein A is C1-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 ion; and

represents a radical of the formula

or a pharmaceutically acceptable salt thereof.

166. 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 ion; or a pharmaceutically acceptable salt thereof.

1 67. 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 ion; or a pharmaceutically acceptable salt thereof.

168. 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 ion; or a pharmaceutically acceptable salt thereof.

1 69. 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 ion; or a pharmaceutically acceptable salt thereof.

1 70. 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 ion; or a pharmaceutically acceptable salt thereof.

1 71. 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 ion; or a pharmaceutically acceptable salt thereof.

1 72. 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 ion; or a pharmaceutically acceptable salt thereof.

1 73. 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 ion; or a pharmaceutically acceptable salt thereof.

1 74. 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 ion; or a pharmaceutically acceptable salt thereof.

1 75. 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 ion; or a pharmaceutically acceptable salt thereof.

176. 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 ion; or a pharmaceutically acceptable salt thereof.

177. 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 ion; or a pharmaceutically acceptable salt thereof.

178. 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 ion; or a pharmaceutically acceptable salt thereof.

179. 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 ion; or a pharmaceutically acceptable salt thereof.

180. 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 ion; or a pharmaceutically acceptable salt thereof.

1 81. 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 ion; or a pharmaceutically acceptable salt thereof.

1 82. 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 ion; or a pharmaceutically acceptable salt thereof.

183. 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 ion; or a pharmaceutically acceptable salt thereof.

1 84. 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 ion; or a pharmaceutically acceptable salt thereof.

1 85. 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 ion; or a pharmaceutically acceptable salt thereof.

186. 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 ion; or a pharmaceutically acceptable salt thereof.

1 87. 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 ion; or a pharmaceutically acceptable salt thereof.

1 88. A process for the preparation of a carbapenam derivative substantially as indicated any of the foregoing Examples.

189. A carbapenem derivative prepared by a process as claimed in any of claims 142 to 145 or claim 188.

1 90. A pharmaceutical composition comprising at least one carbapenem derivative as claimed in any of claims 1 to 141 and 146 to 187, or claim 189, together with a pharmaceutically acceptable carrier or diluent.