GB2301820A - 2-(dibenzofuranyl)-and 2-(dibenzothienyl)-carbapenems,compositions containing such compounds and methods of use - Google Patents

Abstract

Carbapenem compounds of the formula: are disclosed. R is H or CH 3 ; R 1 and R 2 are independently H, CH 3 -, CH 3 CH 2 ,-(CH 3 ) 2 CH-, HOCH 2 -, CH 3 CH(OH)-, (CH 3 ) 2 C(OH)-, FCH 2 CH(OH)-, F 2 CHCH(OH)-, F 3 CCH(OH)-, CH 3 CH(F)-, CH 3 CF 2 -, or(CH 3 ) 2 C(F)-; X represents O, S, S(O) or S(O) 2 ; A represents a group selected from: a) b) and c) and ```m plus n, plus any R c groups present on A, equals an integer of from 0 to 4. Also included in the invention are pharmaceutical compositions and methods of use.

Description

TITLE OF THE INVENTION 2-(DIBENZOFURANYL)- AND 2-(DIBENZOTHIENYL) CARBAPENEMS, COMPOSrflONS CONTAINING SUCH COMPOUNDS AND METHODS OF USE BACKGROUND OF THE INVENTION The present invention relates to antibacterial agents of the carbapenem class, in which the 2-position sidechain contains a dibenzofuranyl or dibenzothienyl moiety, which is substituted by various cationic and neutral substituents.

Thienamycin was an early carbapenem antibacterial agent having a broad spectrum; it has the following formula:

Later, N-formimidoyl thienamycin was discovered; it has the formula:

More recently, U. S. Patent No. 5,025,008 issued on June 18, 1991, addressing compounds of the formula:

wherein Z represents (A) or (B):

In these compounds, Ra and Rb are uncharged.

U. S. Patent No. 5,240,920 issued on August 31, 1993 addresses similar such compounds, with charged side chains. However, the charged moiety is not attached directly to the multi-ring platform (A) or (B). The present invention differs in this respect.

The carbapenems of the present invention are, in particular, potent antibiotics against methicillin resistant Staphvlococcus aureus (MRSA), methicillin resistant Staphylococcus epidermidis (MRSE), and methicillin resistant coagulase negative Staphylococci (MRCNS). The antibacterial compounds of the present invention thus comprise an important contribution to therapy of these difficult to control pathogens.

Moreover, there is an increasing need for agents effective against such pathogens which are at the same time safe, i.e., free from undesirable toxic side effects. The current agent of choice, vancomycin, a glycopeptide antibacterial, is known to exhibit a somewhat undesirable level of toxicity.

SUMMARY OF THE INVENTION The present invention provides novel carbapenem compounds of the formula:

wherein: RisHorCH3; R1 and R2 are independently H, CH3-, CH3CH2,-(CH3)2CH-, HOCH2-, CH3CH(OH)-, (CH3)2C(OH)-, FCH2CH(OH)-, F2CHCH(OH)-, F3CCH(OH)-, CH3CH(F)-, CH3CF2-, or (CH3)2C(F)-; X represents 0, S, S(O) or S(O)2; A represents a group selected from: a)

wherein Rw', Rx', RY' and Rz' independently represent a member selected from the group consisting of:H, C1-4 4 alkyl and CiA alkyl substituted with 13 Rq groups; or Ry' and Rzl are taken together and represent a C3-5 alkylidene group, optionally substituted with 1-3 Rq groups; or Rx' and Rz' are taken together and represent a C2-4 saturated or unsaturated alkylidene group, optionally substituted with 1-3 Rq groups; b)

Rc is as defined below; Rd represents a member selected from the group consisting of: hydrogen, NH2 or C1-4 alkyl, said alkyl group being unsubstituted or substituted with 1-3 Rq groups; c)

m plus n, plus any RC groups present on A, equals an integer of from 0 to 4, such that 04 Rc groups are present and are independently selected from the group set forth below; a) a trifluoromethyl group: -CF3; b) a halogen atom: -Br, -Cl, -F, or -I; c) C1-C4 alkoxy radical: -OC1-4 alkyl, wherein the alkyl is optionally substituted by 1-3 Rq groups, where Rq is a member selected from the group consisting of -OH, -OCH3, -CN, -C(O)NH2,-OC(O)NH2, CHO, -S02NH2, -SOCH3, -S02CH3, -F, -CF3, -CO2CH3, -C(O)CH3, -C(O)NHCH3, -C(O)N(CH3)2 and -COOMb (where Mb is hydrogen or an alkali metal); d) a hydroxy group: -OH; e) a carbonyloxy radical: -O(C=O)Rs, where Rs is Cl -4 alkyl or phenyl, each of which is optionally substituted by 13 Rq groups, as defined above; f) a carbamoyloxy radical: O(C=O)N(Ry')Rz', wherein RY and Rz' are as previously defined; g) a sulfur radical: -S(O)n-Rs wherein n = 0-2, and Rs is defined above; h) a sulfamoyl group: SO2N(Ry')Rz' wherein Ry' and Rz' are as defined above; i) azido: N3; j) a formamido group: -N(Rt)(C=O)H, wherein Rt is H or C14 alkyl, optionally substituted with 1-3 Rq groups as defined above; k) a (C1-C4 alkyl)carbonylamino radical: -N(Rt)(C=O)C1-4 alkyl, wherein Rt is as defined above; 1) a (C1-C4 alkoxy)carbonylamino radical: -N(Rt)(C=O)OC1-4 alkyl, wherein Rt is as defined above; m) a ureido group: -N(Rt)(C=O)N(Ry)Rz wherein Rt, Ry' and Rz' are as defined above; n) a sulfonamido group: -N(Rt)SO2Rs, wherein Rs and Rt are as defined above; o) a cyano group: -CN; p) a formyl or acetalized formyl radical: -(C=O)H or -CH(OCH3)2; q) a (C1-C4 alkyl)carbonyl radical wherein the carbonyl is acetalized: -C(OCH3)2C 1 -4 alkyl, where the alkyl is optionally substituted with 1-3 Rq groups as defined above; r) a carbonyl radical: -(C=O)Rs, wherein Rs is as defined above; s) a hydroximinomethyl radical in which the oxygen or carbon atom is optionally substituted: -(C=NORx')Ry' wherein Ry and Rx are as defined above, t) a (C1-C4 alkoxy)carbonyl radical: -(C=O)OC1-4 alkyl, wherein the alkyl is optionally substituted by 1-3 Rq groups as defined above; u) a carbamoyl radical: -(C=O)N(Ry')Rz' wherein Ray and Rz' are as defined above; v) an N-hydroxycarbamoyl or N(C1-C4 alkoxy) carbamoyl radical in which the nitrogen atom may be additionally substituted by a C1-C4 alkyl group: -(C=O)-N(ORy1)Rz' wherein Ry' and Rz are as defined above; w) a thiocarbamoyl group: -(C=S)N(Ry')Rz' wherein Ray and Rz' are as defined above; x) carboxyl: -COOMb, wherein Mb is as defined above; y) thiocyanate: -SCN; z) trifluoromethylthio: -SCF3; aa) tetrazolyl, where the point of attachment is the carbon atom of the tetrazole ring and one of the nitrogen atoms is mono-substituted by hydrogen, an alkali metal or a C1-C4 alkyl optionally substituted by 1-3 Rq groups as defined above; ab) a C5-C7 cycloalkyl group in which one of the carbon atoms in the ring is replaced by a heteroatom selected from 0, S, NH, or N(C1-C4 alkyl) and in which one additional carbon may be replaced by NH or N(C1 -C4 alkyl), and in which at least one carbon atom adjacent to each nitrogen heteroatom has both of its attached hydrogen atoms replaced by one oxygen thus forming a carbonyl moiety and there are one or two carbonyl moieties present in the ring; ac) a C2-C4 alkenyl radical, optionally substituted by one to three of the substituents a) to ac) above and phenyl which is optionally substituted by 1-3 Rq groups as defined above; ad) a C2-C4 alkynyl radical, optionally substituted by one to three of the substituents a) to ac) above; ae) a C1-4 alkyl radical; af) a C 1-4 alkyl substituted by one to three of the substituents a) - ac) above; ag) a 2-oxazolidinonyl moiety in which the point of attachment is the nitrogen atom of the oxazolidinone ring, the ring oxygen atom is optionally replaced by a heteroatom selected from S and NRt (where Rt is as defined above) and one of the saturated carbon atoms of the oxazolidinone ring is optionally mono-substituted by one of the substrtuents a) lo 4 above; M is selected from: i) hydrogen; ii) a pharmaceutically acceptable esterifying group or removable carboxyl protecting group; iii) an alkali metal or other pharmaceutically acceptable cation; and iv) a negative charge which is balanced by a positively charged group.

Also included in the invention are pharmaceutical compositions and methods of use.

DETAILED DESCRIPTION OF THE INVENTION The invention is described herein in detail using the terms defined below unless otherwise specified.

Carboxylic acid refers to -COOH.

Carboxylate anion refers to a negatively charged group -COO-.

An N-hydroxycarbamoyl or N(C1 4 alkoxy)carbamoyl radical in which the nitrogen atom may be additionally substituted by a CiA alkyl group is: -C(O)N(ORY')Rz', wherein RY' and Rz' are as defined, except they may not be joined together to form a ring.

The term "alkyl" refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 10 carbon atoms unless otherwise defined. It may be straight, branched or cyclic. Preferred alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, cyclopentyl and cyclohexyl. When substituted, alkyl groups may be substituted with up to four substituent groups, at any available point of attachment. When the alkyl group is said to be substituted with an alkyl group, this is used interchangeably with "branched alkyl group".

The arm "alkoxy" wafers to a CIA alkoxy radical: -OC1-4 alkyl, wherein the alkyl is optionally substituted by 1-3 groups selected from Rq. Rq is a member selected from the group consisting of -OH, -OCH3, -CN, -C(O)NH2,-OC(O)NH2, CHO, -S02NH2, -50CH3, -S02CH3, -F, -CF3, -C02CH3, -C(O)CH3, -C(O)NHCH3, -C(O)N(CH3)2 and -COOMb (where Mb is hydrogen or an alkali metal). The preferred alkoxy group is methoxy.

The term "alkali metal" refers to alkali metal species which may be positively charged, such as, for example, Na, K, Ca, Mg and the like.

A hydroximinomethyl radical in which the oxygen or carbon atom is optionally substituted by a ClA alkyl group is the group: C=N(ORZ)RYT wherein Rz' and RY' are as previously defined, except they may not be joined together to form a ring.

The term "oxime" and "hydroxyimino" can be used interchangeably to refer to the group: =N-OH. When the oxime is substituted on the hydroxyl portion thereof, this is represented by the structure: =N-ORZ'.

Cycloalkyl is a specie of alkyl containing from 3 to 15 carbon atoms, without alternating or resonating double bonds between carbon atoms. It may contain from 1 to 4 rings which are fused. The preferred cycloalkyl groups are cyclopentyl and cyclohexyl.

The term "alkenyl" refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond. Preferred alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl.

Cycloalkenyl is a subset of alkenyl, containing from 5 to 10 carbon atoms, in one or two fused rings, with at least one carbon to carbon double bond.

The term "alkynyl" refers to a hydrocarbon radical straight or branched, containing from 2 to 10 carbon atoms and at least one carbon to carbon triple bond. Preferred alkynyl groups include ethynyl, propynyl and butynyl.

Aiyl reiem to aromatic Tings t.g., phenyl, subsiituted phenyl and the like, groups as well as rings which are fused, e.g., naphthyl, phenanthrenyl and the like. An aryl group thus contains at least one ring having at least 6 atoms, with up to five such rings being present, containing up to 22 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms or suitable heteroatoms. The preferred aryl groups are phenyl, naphthyl and phenanthrenyl. Aryl groups may be substituted as defined.

Preferred substituted aryls include phenyl and naphthyl.

The term "heteroaryl" refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing at least one heteroatom, 0, S or N, in which a carbon or nitrogen atom is the point of attachment, and in which one or two additional carbon atoms are optionally replaced by a heteroatom selected from 0 or S, and in which from 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms, said heteroaryl group being optionally substituted as described herein.

Heteroaryl thus includes aromatic and partially aromatic groups which contain one or more heteroatoms. Examples of this type are pyrrole, pyridine, oxazole, thiazole and oxazine. Additional nitrogen atoms may be present together with the first nitrogen and oxygen or sulfur, giving, e.g., thiadiazole. Preferred heteroaryl groups are thiazolyl, imidazolyl, pyridyl and pyrrolyl.

Heteroarylium groups are those heteroaryls which contain one or more quatemary nitrogen atoms.

The term "heterocycloalkyl" refers to a cycloalkyl group (nonaromatic) in which one of the carbon atoms in the ring is replaced by a heteroatom selected from 0, S or N, and in which up to three additional carbon atoms may be replaced by said heteroatoms. Preferred heterocycloalkyl groups include piperidinyl, pyrrolidinyl and tetrahydrofuranyl. The N atoms of said heterocycloalkyl groups may be tertiary or quaternary.

The term "quaternary nitrogen" refers to a tetravalent positively charged nitrogen atom including, e.g., the positively charged nitrogen in a tetraalkylammonium group (e.g.. tetramethylammonium, N-methylpyridinium), the positively charged nitrogen in protonated ammonium species (e.g. trimethylhydroammonium, N-hydropyridinium), the positively charged nitrogen in amine Noxides (e.g.N-methylmorpholine-N-oxide, pyridine-N-oxide), and the positively charged nitrogen in an N-amino-ammonium group (e.g.. N-aminopyridinium).

In the compounds of the present invention, the structure:

includes compounds wherein the carbapenem is attached to the multiring platform at position 2 or 3:

Also, it is noted that the variable group A is drawn attached to the center ring; this means that A is attached to one of the benzene rings at any available point of attachment:

means

The overall molecule has from 0 to 4 Rc groups attached at available points of attachment. As such, m and n represent integers, such that m plus n, plus any RC groups present on A, equal an integer of from 0 to 4. Each Rc is independently selected from the list of substituent groups provided herein.

A preferred embodiment of the invention includes compounds of the formula:

wherein the variable groups R, R1, R2, M, A, X, n and RC are as previously defined. Since m is absent, the sum of n plus any RC variables appearing on A represents an integer in the range of from 0 to 4.

Another preferred embodiment of the invention includes compounds represented by the formula:

wherein all variable groups are as previously defined.

More preferably, in compounds of formula Ia and Ib, X represents 0 or S; R1 represents H and R2 represents CH3CH(OH)-.

The preferred value of A is type (a). Examples of A type (a) include the following:

Preferred species falling within the invention described herein include the following: Table 1

Cmpd Rr

1 \0o/ H2N 0N+H 2 H3CN 0N+H H 3 (CH3)2NANH 4 HN A NH Cmpd Rr

5 C\N0 NH w N 6 44o4J mi N H3CuNANoCH3 v\N fizz HN NH 9 3 CH3 Cmpd Rr

N 10 0 11 o CH3 Table 2

Cmpd Rr

H2N NH Cmpd Rr

N 2 11 N0 H3CHNANH H N 3 11 N0 (CH3)2NANH N 4 t HN ANH mi N 5 N H3C Nmi\0N+H N 6 N H3 NNOCH3 mi' Cmpd Rr

N 7 N0 H3CO,CH3 N 8 vo4J HN NH 9 X Q0' CH3 9 OH3 N 10 93 Cmpd R'

N 11 N CH3 Preferred Rc groups include:: -OCH3 -CH2I -OCH2CH2OH -SO2NHCONH2 -F -CF3 -Br -Cl -OH -I -OCONH2 -OCOCH3 -SOCH3 -SCH3 -SCH2CH2OH -SO2CH3 -SO2NH2 -SOCH2CH20H -NHCHO -SO2N(CH3)2 -NHCO2CH3 -NHCOCH3 -CN -NHSO2CH3 -COCH3 -CHO -CH=NOH -COCH20H -C=C-CONH2 -CH=NOCH3 -SO2CH2CH2OH -CH2N3 -CH=NOCMe2CO2Me -C02CH2CH20H -CONH2 -CONHCH3 -CON(CH3)2 -CONHCH2CN -CONHCH2CONH2 -C=C-CN -CONHOH -CONHCH3 -tetrazol y 1 -CH=CHCN -SCF3 -CH2OH -CH=CHCONH2 and -CONHS02NH2 The synthesis of compounds of formula I may be carried out in a three-stage scheme, followed by a final step which allows for the removal of any protecting groups.The objective of the first synthetic stage is to produce a base dibenzofuranyl- or dibenzothienylcompound which may be converted to the two-position substituent of the carbapenem of Formula I. The objective of a second synthetic stage is to attach the base dibenzofuranyl- or dibenzothienyl- compound to the carbapenem. Finally, the objective of a third synthetic stage is to introduce the desired A, Re and Rd. This third synthetic stage may be performed at any point according to the nature of the various A, Re and Rd groups present on the molecule Flow sheets A-F demonstrate suggested first stage syntheses. Flow Sheet G demonstrates a suggested second stage synthesis in which the products of Flow Sheets A-F may be utilized.

The third synthesis varies according to the selected A, Re and Rd.

Flow sheet A demonstrates a suggested first stage synthesis for a dibenzofuranyl- or dibenzothienyW compound substituted with a Type a) cationic substituent. Referring to Flow Sheet A, l-forrnyl- 3-bromodibenzofuran is converted to the oxime Al by reaction with hydroxylamine hydrochloride in ethanol-pyridine. Dehydration of Al to the nitrile A2 is accomplished by treatment of Al with triethylamine and trifluoromethanesulfonic anhydride in dichloromethane/tetrahydrofuran at reduced temperature. Compound A2 is then reacted with hexa methyl ditin, tetrakis(triphenylphosphine)-palladium(0) and triphenylphosphine in toluene at about 11 OOC to produce the trimethylstannane A3.Compound A3 is reacted with the methylchloroaluminum amide A4 in a suitable inert solvent such as toluene, at a suitable temperature such as from about 20OC to 1 lOOC for from about 1 hour to 48 hours to provide the amidinium chloride A5 after hydrolytic work-up by exposure to methanol and silica gel. A variety of methylchloroaluminum amide reagents A4 may be prepared according to the known literature [eg. R. S. Garigipati, Tetrahedron Lett*, 31, 1969 (1990); J. I.

Levin, E. Turos and S. M. Weinreb, Synth. Comm., 12, 989 (1982)].

FLOW SHEET A

B H2NQH-HCI B pyridine, EtOH 00 tort 0 CHO HC > NOH Al Et3N, Tt2O | CH2C12, THF -70" Me3Sn Br M\ Pd(PPh3)4 PPh3, toluene, A 64J CN 8 82 | CH3AI(CI)NRYRZ A4 toluene, 90" Me3Sn 9 RY RZ NH2 4 Flow sheet B demonstrates a suggested first stage synthesis for a dibenzofuranyl- or dibenzothienyl- compound substituted with a cyclic Type a) cationic substituent.Referring to Flow Sheet B, compound A2 is reacted with an excess of a diamino compound B 1 in the presence of a catalytic amount of carbon disulfide at a suitable temperature such as from about 20OC to 11 00C for from about 1 hour to 48 hours to provide the amidine B2 after evaporation of the excess B 1. Alternatively, a suitable solvent such as toluene may be employed.

A variety of diamino compounds of type B 1 are commercially available and may be prepared by standard methods well-known in the art.

Compound B2 is then reacted with hexamethylditin, tetrakis (triphenylphosphine)palladium(0) and triphenylphosphine in toluene at about 1 100C to produce the trimethylstannane . The N-substitution of B3 to produce the cationic amidinium substituent is accomplished by reacting B3 with an alkylating or protonating agent Rz'-Y' to produce B4. The reaction is carried-out in a suitable inert solvent such as dichloromethane or tetrahydrofuran at a temperature from -80 C to 600C. Y' is a leaving group such as iodide, bromide, methanesulfonate or trifluoromethanesulfonate and Rz' is as defined above.

In addition to lhe procedures illutted in Flow Sheets A and B, many other methods of preparing amidines may be employed.

[eg. "The Chemistry of Amidines and Imidates," Ed. S. Patai, Interscience, New York, 1991; G. Tennant, in "Comprehensive Organic Chemistry", D. Barton and W. D. Ollis, Ed., Pergamon Press, 1979, Vol. II p. 385; P. A. S. Smith, in "The Chemistry of Open Chain Nitrogen Compound", Vol. I, W. A. Benjamin, Inc., 1965, Chapter 4; "Organic Functional Group Preparations", Vol. m, Ed. S. R. Sandler and W. Karo, Academic Press, New York, 1972, Chapter 6, Amidines].

FLOW SHEET B

Flow Sheet C illustrates the synthesis of starting materials for Flow Sheets D and F. Referring to Flow Sheet C, 1 ,3-dibromodibenzofuran is lithiated by reaction with n-butyllithium in tetrahydrofuran at reduced temperature and the resulting anion is reacted with acetaldehyde to provide after hydrolysis and conventional isolation compound C1. Oxidation of C1 with Jones reagent (Cr03, H20, H2S04) in acetone in a conventional manner yields the ketone C2.

Conversion of C2 to the corresponding oxime is accomplished by reaction with hydroxylamine hydrochloride in pyridine. Beckmann rearrangement of C3 by reaction with phosphorous pentachloride in benzene gives the acetamide derivative C4. Basic hydrolysis of the acetamide of C4 with potassium hydroxide in ethanol with heating provides the amine C5.

FLOW SHEET C

Br Br 1) THF, -75" 2) 2) acetaldehyde, THF Br -750 to H3C OH HC' C1 Jones reagent acetone Br H2NOH*HCI Br H2NOHHCI pyiidine H3C NOH H3C 0 Za C3 o C2 PCI,benzene Br Br h KOH,EtOH,A 0 HN H2N 0CH3 Flow sheet D demonstrates a suggested first stage synthesis for a dibenzofuranyl- or dibenzothienyl- compound substituted with a type b) cationic substituent.

The suggested first synthesis can generally be outlined as a condensation between an amine and an isothiocyanate to form a thiourea, followed by cyclization to produce an imidazole. 1-amino-3- bromodibenzofuran CS is converted to the isothiocyanate D1 by reaction with CSC12. This reaction may be carried out in a two-phase medium of water and dichloromethane, at 0 to 50C with calcium carbonate. The resultant compound D1 is reacted with an appropriate acetal to form thiourea D2. This is a simple condensation reaction which may be effected by heating the reactants under reflux conditions using inert solvents, e.g., ethanol, toluene or DMF at 80"C. A dimethylacetal is shown, although clearly, a diethylacetal could also be used.The thiourea D2 is subjected to a cyclization reaction to form the imidazole D3 bearing a sulfhydryl substituent. The cyclization reaction may be carried out by treatment of D2 with acid, preferably by refluxing the intermediates with aqueous hydrochloric acid in ethanol.

The sulfhydryl substituent of D3 is sub-sequently removed to produce imidazole D4. This removal might be by catalytic reduction (i.e.

desulfurization), preferably utilizing Raney nickel or by oxidation with dilute nitric acid at 800 to 900C. Intermediate D5 may be obtained by reaction of D4 with hexamethylditin in the presence of a palladium(0) catalyst, such as tetrakis(triphenylphosphine)-palladium(0) in an inert solvent such as toluene at from 250C to 110"C for from 0.25-24 hours to provide the stannane.

Substitution of the N-imidazolium compound D6 may be accomplished by reacting imidazole D5 with an alkylating agent Rd Y'. Moiety Rd is described above and stable to the conditions of the reaction or is a substituent described above and appropriately protected, or is stable to the conditions of the reaction or is a substituent described above and appropriately protected, or is stable precursor substituent to a substituent described above. The reaction is generally carried out in an inert organic solvent (e.g. CH2Cl2) at a temperature from -80 C to room temperature. Y' is a leaving group, such as iodide, bromide, mesylate (methanesulfonate), tosylate (P-toluenesulfonate) or O-triflate (trifluoromethanesuifonate).

Alternatively, N-substitution may be obtained by reaction with an amidinating agent, such as o-(2,4,6-triisopropylbenzenesulfonyl) hydroxylamine, giving the N-amino derivative, in a suitable solvent (e.g. CH2C12 or CH3CN) at about room temperature.

In a preferred variation of Flow Sheet D, starting material D4 may be alkylated with RdY' and the resulting imidazolium compound may be reacted with hexamethylditin, tetrakis (triphenylphosphine)-palladium (0) and triphenylphosphine in toluene at about 1 1 0 C to produce the trimethylstannane D6.

The acetal for reaction with thiourea is depicted as unsubstituted. Any substituent groups defined above must, of course, be stable to the reactions to follow or may be in protected form, or a stable precursor. Suitable groups include C1-C4 alkyl, such as methyl, which might also serve as a precursor substituent, or protected hydroxymethyl.

Flow Sheet D

Br Me3Sn t Me3SnSnMe3, Pd(PPh3)4 X \ PPh3, toluene, A o C,a I Pfi Me3Sn X CH2CI2 . JO Rd

Flow sheet E demonstrates an alternative first stage synthesis for a 9-oxo- or 9,9-dioxo-dibenzothienyl compound substituted with a Type b) cationic substituent. 1,3-dibromo-9,9dioxodibenzothiphene is reacted with 1-trimethylsilylimidazole and tetra-n-butylammonium fluoride in a suitable solvent such as tetrahydrofuran, acetonitrile or 1 -methyl-2-pyrrolidinone at from about 200C to the reflux temperature of the selected solvent for from 1 to 72 hours to produce, After conventional isolation and separation, the imidazole compound E2 along with its isomer El. Other sources of imidazole anion such as sodium l-imidazolide or lithium l-imidazolide may also be employed. Compound E2 is then reacted with hexamethylditin, tetrakis-(triphenylphosphine)palladium(0) and triphenylphosphine in toluene at about 1 100C to produce the trimethylstannane E3. The N-substitution of E3 to produce the cationic imidazolium substituent is accomplished by reacting E3 with an alkylating agent Rd.Y' to produce E4. The reaction is carried-out in a suitable inert solvent such as dichloromethane or tetrahydrofuran at a temperature from -80 C to 60 C. Y' is a leaving group such as iodide, bromide, methanesulfonate or trifluoromethanesulfonate and Rd is as defined above.

FLOW SHEET E

Flow sheet F demonstrates a suggested first stage synthesis for a dibenzofuranyl- or dibenzothienyl- compound substituted with a Type c) cationic substituent. This synthesis can generally be described as a Zincke exchange reaction. In this reaction, a Zincke reagent of formula Z1 is employed to produce intermediate F2. The Zincke reagent may be prepared by reacting 1 -chloro-2,4-dinitrobenzene with a pyridine compound of the formula Z2. Of course certain Re are compatible with this reaction and others may require the use of a protecting group or a suitable precursor substituent. Suitable substituted pyridines Z2 and their manufacture are well known to persons skilled in the art.Referring to Flow Sheet F, starting material C5 is reacted with hexamethylditin, tetrakis(triphenylphosphine)-palladium(0) and triphenylphosphine in toluene at about 1 100C to produce the trimethylstannane F1. The reaction of F1 with the Zincke reagent Z1 is generally carried out in the presence of a suitable base, such as triethylamine or sodium methoxide, in an appropriate organic solvent such as methanol of dioxane, at a temperature ranging from about 200C to 1200C and for a time of from about 30 minutes to 24 hours.The Zincke reaction is well known in the art and is further described in Zincke et al., Anna len, 333, 296 (1904); Lettre', Annalen, 579, 123 (1953); Keijzer, et al., Heterocycles, 16, 87 (1981).

In a preferred variation of Flow Sheet F, starting material C5 may be reacted with Z1 in the Zincke reaction and the resulting pyridinium compound may be reacted with hexamethylditin, tetrakis (triphenylphosphine)-palladium(0) and triphenylphosphine in toluene at about 1 lOOC to produce the trimethylstannane F2.

FLOW SHEET F

Br Me3SnSnMe3 Me3Sn Pd(PPh3)4 X \ PPh3, PhCH3, A H2N H2N C5 F1 Me3Sn NO2 RC M\ (i-Pr)2EtN 02N Cle CH3OH 02N Rc NO+ 0 dioxane Cl ) RC RCS F2 Rc Rc y RC 02N CI + NRc RC 72 The object compounds of Flow Sheets A, B, D, E and F form the nucleus of the 2-position substitution of the carbapenem compounds taught herein. As such they may be Re substituted.

However, it is immediately clear to persons skilled in the art that certain Re groups listed above, if substituted on intermediates, would not survive or permit synthesis. Thus, where a certain Re is desired, and is incompatible with the synthesis scheme, then a compatible precursor substituent might be employed.

The identity of the precursor substituent employed is not crucial so long as it does not interfere with the synthesis, and so long as it is convertible to the more desireable substituent.

The second stage is to attach the base platform to the 2-position of the carbapenem. This involves a palladium catalyzed cross-coupling reaction between a carbapenem triflate and a suitably substituted arylstannane. Referring to Flow Sheet G, the 2-oxocarbapenam is reacted with a suitable trifluoromethanesulfonyl source, such as trifluoromethanesulfonic anhydride, in the presence of an organic nitrogen base, such as triethylamine, diisopropylamine, diisopropylethylamine and the like, in a polar aprotic solvent, such as tetrahydrofuran or methylene chloride. Optionally, an organic nitrogen base, such as triethylamine and the like, is then added to the reaction solution, followed immediately by a silylating agent, such as trialkylsilyl trifluoromethanesulfonate to provide intermediate G2.An aprotic polar coordinating solvent, such as DMF, l-methyl-2-pyrrolidinone and the like, is optionally added. This is followed by the addition of a palladium compound, such as tris(dibenzylideneacetone)dipalladium- chloroform, palladium acetate and the like, and the stannane G3, which represents the products of the other flow sheets, AS, B4, D6, E4 and F2. A protic solvent such as methanol may also optionally be employed in cases where the stannane is poorly soluble in the medium.

A halide source, such as lithium chloride, zinc chloride or tetraalkylammonium chloride and the like, is added and the reaction solution is allowed to warm and is stirred at a suitable temperature, such as 0 to 50"C for from a few minutes to 48 hours. The carbapenem G4 is obtained by conventional isolation'purification methodology.

Generally speaking, the mild conditions of the synthesis shown in Flow Sheet G allow for a range of functional groups to be present. However, in certain cases it is advantageous for the substituent(s) of the stannane to be introduced in a protected or precursor form. Final elaboration from a precursor substitutent, e.g. hydroxymethyl or hydroxypropyl, might be accomplished on carbapenem intermediate G4. Removal of hydroxyl and carboxyl protecting groups then provides the final compound of Formula I. Such final elaboration and deprotection is described in further detail below.

It is clear that in each instance where a charged compound is shown or discussed, there is by necessity a counterion.

Thus, the preferred intermediates described above, as well as the active compounds, have a counterion to the charged moiety A. The identity of the counterion will, initially at least, depend on the leaving group employed in the substitution of the A group. Herein, for example, Y might be the residue of iodide, mesylate, tosylate, etc. Of course, the counterion is easily replaced with various counterions which have no connection to the counterion formation. For example, chloride is not a highly reactive leaving group, but as Cl - it can readily serve as a suitable replacement counterion.

The steps for preparing the 2-oxocarbapenam intermediate G1 are well known in the art and are explained in ample detail by D.G.

Melillo et al., Tetrahedron Letters, 1980, 21, 2783, T. Salzmann et al., J. Am. Chem. Soc., 1980, 102, 6161, and L.M. Fuentes, I. Shinkai, and T.N. Salzmann, J. Am. Chem. Soc., 1986. 108, 4675. The syntheses are also disclosed in U.S. Pat. No. 4,269,772, U.S. Pat. No. 4,350,631, U.S.

Pat. No. 4,383,946 and U.S. Pat. No. 4,414,155 all assigned to Merck and Company, Inc.

FLOW SHEET G

HO R TMSO R 1) t 1) EtN(i-Pr)2, Tt2O C 2:CH2C12, -700 0 2) EtN(i-Pr)2 EtN(i-Pr), CO2PNB 2) EtN(i-Pr)2 0 G1 G2 CO2PNB Me3Sn Pd2(DBA)3oCHCI3 Pd2(DBA),CHCS + \ (CH3CH2)4N A Y Hz G3 if CH2C12 TMSO R 1) HCI,THF H20,00 H x 2) NaHOD3, Haze 10% Pd(C A C02PNB PNB = p-nitrobenzyl 0 002e A TMS = trimethylsilyl = Tf = trifluoromethanesulfonyl The above Flow Sheets illustrate a particular isomeric attachment of the cationic substituent, A, to the dibenzofuran or dibenzothiophene. The various other possible isomeric attachments of the cationic substituent can be analogously obtained by starting with the corresponding isomeric starting material in the Flow Sheets. For example, the isomeric bromo-formyl-dibenzofuran or dibenzothiophene starting materials for Flow Sheet A may be obtained by conventional means from the corresponding bromodibenzofuran or bromodibenzothiophene carboxylic acids, which are known in the art (cf U.S. patent No. 5,240,920, issued August 31, 1993). The same bromodibenzofuran or bromodibenzothiophene carboxylic acids may also be used to produce the isomeric CS starting materials for Flow Sheets D and F by conventional means.

In the preparation methods described herein, the carboxyl group at the 3-position and the hydroxyl group at the 8-position of the carbapenem typically remain blocked until the final product is prepared.

These blocking groups are readily removable, i.e., they can be removed, if desired, by procedures which will not cause cleavage or other disruption of the remaining portions of the molecule. Such procedures include chemical and enzymatic hydrolysis, treatment with chemical reducing or oxidizing agents under mild conditions, treatment with fluoride ion, treatment with a transition metal catalyst and a nucleophile, and catalytic hydrogenation.

Examples of suitable hydroxyl protecting groups are: t-butylmethoxyphenylsilyl, t-butoxydiphenylsilyl, trimethylsilyl, triethylsilyl, o-nitrobenzyloxycarbony1, p-nitrobenzyloxycarbonyl, benzyloxycarbonyl, t-butyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl and allyloxycarbonyl. Preferred hydroxyl protecting groups are trimethylsilyl and triethylsilyl.

Examples of suitable carboxyl protecting groups are: benzhydryl, o-nitrobenzyl, p-nitrobenzyl, 2-naphthylmethyl, allyl, 2chloroallyl, benzyl, 2,2,2-trichloroethyl, trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, 2-(trimethylsilyl)ethyl, phenacyl, p-methoxybenzyl, acetonyl, p-methoxyphenyl, 4-pyridylmethyl and t-butyl. A preferred carboxyl protecting group is p-nitrobenzyl.

Many other suitable hydroxyl and carboxyl protecting groups are known in the art. See, e.g., T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc., 1981 (Chapters 2 and 5).

Removal of the protecting groups of G3 wherein P is trimethylsilyl and M is p-nitrobenzyl is accomplished by exposing G3 to aqueous acidic conditions, such as dilute hydrochloric acid, in an organic solvent such as tetrahydrofuran at from 0 C to 30"C for a few minutes to several hours. The resulting desilylated carbapenem may be isolated by conventional techniques, but is more conveniently taken directly into the final deprotection process.Thus, the reaction mixture is neutralized by addition of an inorganic base such as sodium bicarbonate or sodium hydroxide and optionally a pH 6.5 to pH 7.0 aqueous buffer such as 4-morpholinepropanesulfonic acid/NaOH (MOPS) or NaH2P04/Na2HPO4. The reaction mixture is then hydrogenated at or slightly above atmospheric pressure over a heterogeneous catalyst such as rhodium on carbon, rhodium on alumina, palladium on carbon or the like at from O"C to 30"C for from 30 minutes to 6 hours to remove the p-nitrobenzyl ester protecting group.

The formulas depicting Type (a), (b) and (c) substituents show positively charged states for those substituents. It is understood that certain of those substituents, which are cationic by virtue of having a protonating hydrogen atom attached to the nitrogen, may also exist or be produced under certain conditions as neutral substituents by virtue of the absence of such a hydrogen atom Whether such a substituent will be predominately cationic or neutral in a given physical state will be governed by principles of acid-base chemistry, which are well known to those skilled in the art. For example, the particular ratio of neutral form to cationic form will depend upon the basicity of the amine and the acidity of the solution.When such a substituent is in a protonated quatemized state, the compound exists as a zwitterion which is internally balanced as to charge or as an ammonium salt which is extemally balanced. A compound containing such a substituent is typically produced as a salt, e.g., wherein M is an alkali metal, and may exist in solution in its neutral form. However, depending upon conditions, a compound containing a neutral substituent may be in equilibrium with, and may also be represented by a formula showing, the corresponding compound containing the quaternized protonated substituent. Furthermore the same compound may exist in a completely protonated quaternized form, for instance in an aqueous solution in the presence of a stoichiometric amount of a strong mineral acid.It is intended herein that both the protonated (cationic) and the unprotonated (neutral) forms are within the scope of the present invention.

The overall molecule must be electronically balanced.

Since a quatemary nitrogen is typically present in the compounds of the present invention, a balancing anion must also, in that case, be present.

This is usually accomplished by allowing COOM to be COO-.

However, when M is, e.g., a pharmaceutically acceptable ester, a counterion (anion) is provided.

The carbapenem compounds of the present invention are useful per se and in their pharmaceutically acceptable salt and ester forms in the treatment of bacterial infections in animal and human subjects. The term "pharmaceutically acceptable ester or salt" refers to those salt and ester forms of the compounds of the present invention which would be apparent to the pharmaceutical chemist, i.e., those which are non-toxic and which would favorably affect the pharmacokinetic properties of said compounds, their palatability, absorption, distribution, metabolism and excretion. Other factors, more practical in nature, which are also important in the silection, are cost of the aw materials, ease of crystallization, yield, stability, hygroscopicity, and flowability of the resulting bulk drug. Conveniently, pharmaceutical compositions may be prepared from the active ingredients in combination with pharmaceutically acceptable carriers. Thus, the present invention is also concerned with pharmaceutical compositions and methods of treating bacterial infections utilizing as an active ingredient the novel carbapenem compounds of the present invention.

The pharmaceutically acceptable salts referred to above may take the form -COOM, where M represents an alkali metal cation such as sodium or potassium. Other pharmaceutically acceptable cations for M may be calcium, magnesium, zinc, ammonium, or alkylammonium cations such as tetramethylammonium, tetrabutylammonium, choline, triethylhydroammonium, meglumine, triethanolhydro ammonium, etc.

The pharmaceutically acceptable salts referred to above also include non-toxic acid addition salts. Thus, the Formula I compounds can be used in the form of salts derived from inorganic or organic acids. Included among such salts are the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalare, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate.

The pharmaceutically acceptable esters of the novel carbapenem compounds of the present invention are such as would be readily apparent to a medicinal chemist, and include, for example, those described in detail in U.S. Pat. No. 4,309,438, Column 9, line 61 to Column 12, line 51. Included within such pharmaceutically acceptable esters are those which are hydrolyzed under physiological conditions, such as pivaloyloxymeihyl, acetovmethyl, phlhalidyl, indanyl lmd methoxymethyl, and those described in detail in U.S. Pat. No.

4,479,947.

The compounds of the present invention are valuable antibacterial agents active against various Gram-positive and to a lesser extent Gram-negative bacteria and accordingly find utility in human and veterinary medicine. The antibacterials of the invention are not limited to utility as medicaments; they may be used in all manner of industry, for example: additives to animal feed, preservation of food, disinfectants, and in other industrial systems where control of bacterial growth is desired.For example, they may be employed in aqueous compositions in concentrations ranging from 0.1 to 100 parts of antibiotic per million parts of solution in order to destroy or inhibit the growth of harmful bacteria on medical and dental equipment and as bactericides in industrial applications, for example in water-based paints and in the white water of paper mills to inhibit the growth of harmful bacteria.

The compounds of this invention may be used in any of a variety of pharmaceutical preparations. They may be employed in capsule, powder form, in liquid solution, or in suspension. They may be administered by a variety of means; those of principal interest include: topically, orally or parenterally by injection (intravenously or intramuscularly).

Compositions for injection, the preferred route of delivery, may be prepared in unit dosage form in ampules, or in multidose containers. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain various formulating agents. Alternatively, the active ingredient may be in powder from for reconstitution, at the time of delivery, with a suitable vehicle, such as sterile water. Topical applications may be formulated in hydrophobic or hydrophilic bases as ointments, creams, lotions, paints, or powders.

The dosage to be administered depends to a large extent upon the condition and size of the subject being treated as well as the route and frequency of administration, the parenteral route by injection being preferred for generalized infections. Such matters, however, are left to the routine discretion of the therapist according to principles of treatment well known in the antibacterial art.

The compositions for human delivery per unit dosage, whether liquid or solid, may contain from about 0.1% to about 99% active material, the preferred range being about 10-60%. The composition will generally contain from about 100 mg to about 1500 mg of the active ingredient; however, in general, it is preferable to employ a dosage amount in the range of from about 250 mg to 1000 mg. In parenteral administration, the unit dosage is usually the compound in sterile water for injection or in the form of a soluble powder intended for dissolution.

The preferred method of administration of the Formula I antibacterial compounds is parenteral by i.v. infusion, i.v. bolus or i.m.

injection.

For adults, about 5-50 mg of Formula I antibacterial compounds per kg of body weight given 2, 3, or 4 times per day is preferred. The preferred dosage is about 250 mg to 1000 mg of the compound given one (qd), two (b.i.d.), three (t.i.d.) or four (q.i.d.) times per day. More specifically, for mild infections a dose of 250 mg b.i.d. to q.i.d. is recommended. For moderate infections against highly susceptible gram positive organisms a dose of 500 mg b.i.d. to q.i.d. is recommended. For severe, life-threatening infections against organisms at the upper limits of sensitivity to the antibiotic, a dose of 1000 mg t.i.d. or q.i.d. is recommended.

For children, a dose of 5-25 mg/kg of body weight given 2,3, or 4 times per day is preferred; a dose of 10 mg/kg t.i.d. or q.i.d.

is usually recommended.

Antibacterial compounds of Formula I are of the broad class known as carbapenems. Naturally occuring carbapenems are susceptible to attack by a renal enzyme known as dehydropeptidase (DHP). This attack or degradation may reduce the efficacy of the carbapenem antibacterial agent. The compounds of the present invention having a 1-methyl substituent, and most preferably a lss- methyl group, are significantly less subject to such attack, and there fore may not require the use of a DHP inhibitor. However, such use is optional and contemplated to be part of the present invention.

Inhibitors of DHP and their use with carbapenem antibacterial agents are disclosed in European Patent Applications No. 79102616.4, filed July 24, 1979 (Patent No. 0 007 614); and No. 82107174.3, filed August 9, 1982 (Publication No. 0 072 014)].

The compounds of the present invention may, where DHP inhibition is desired or necessary, be combined or used with the appropriate DHP inhibitor as described in the aforesaid patents and published application. The cited European Patent Applications define the procedure for determining DHP susceptibility of the present carbapenems and disclose suitable inhibitors, combination compositions and methods of treatment. A preferred weight ratio of Formula I compound: DHP inhibitor in the combination compositions is about 1:1. The preferred DHP inhibitor is 7-(L-2-amino-2-carboxyethylthio) 2-(2,2-dimethylcyclopropanecarbox-amide)-2-heptenoic acid or a useful salt thereof.

EXAMPLE 1

Br H2NOH*HCI Br p$iOn)HtOoI O0to rt CHO NOH 3-bromo- 1 -oximo-dibenzofuran (1) 3-bromo- 1 -formyl-dibenzofuran (2.77 g) was dissolved in ethanol (50 ml) and pyridine (50 ml) and cooled to 0 C. Hydroxylamine hydrochloride was added as a solid and the solution was allowed to stir for 10 minutes before the bath was removed. The solution was stirred for 50 minutes at room temperature, after which time it was diluted with ethyl acetate, washed with sat'd NH4C1, water, and sat'd NaCI. The organic layer was dried over Na2S04, filtered, and evaporated under reduced presure to give 2.94 g of the title compound.

1H NMR (400 MHz , CDC13) 6 7.38 (t, J= 7.5 Hz, 1H), 7.51 (t, J= 8.4 Hz, 1H), 7.63 (d J= 8.3 Hz, 1H), 7.83 (s, 1H), 7.91 (d, J= 8.1 Hz, 1H), 7.95-8.05 (bs, 1H), 8.06 (s,1H), 8.55 (s,1H) EXAMPLE 2

3-bromo-1-cyano-dibenzofuran (2) Oxime 1 (2.94 g) was dissolved in ThF (50 ml) and CH2Cl2 (100 ml) and cooled to -70 C at which time a precipitate formed. Triethylamine (3.1 ml) and additional ThF (30 ml) were added and the cloudy mixture was allowed to stir for 15 minutes before triflic anhydride (1.87 ml) was added. After 15 minutes of stirring, the reaction was quenched with sat'd NH4CI, diluted with ethyl acetate and washed with sat'd NH4Cl, sat'd NaHCO3, water and sat'd NaCI.

The organic layer was dried over Na2SO4, filtered, and evaporated under reduced presure. Silica gel chromatography (CH2Cl2/hexane) yielded 1.74 g of the title compound.

1H NMR (400 MHz, CDCl3) # 7.43 (t, J= 7.7Hz, 1H), 7.58 (t, J= 8.5 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.81 (s, 1H), 7.93 (d, J=8.0 Hz, 1H), 8.27 (s, 1H) EXAMPLE 3

BMe3Sn Me3SnSnMe3, Pd(PPh3)4 > 3 I M PPh3, toluene, A ON0 ON 3 1-cyano-3-trimethylstannyl-dibenzofuran (3) 3-bromo- 1 -cyano-diberizofuran (0.926 g) was suspended in toluene (35 ml). Pd(PPh3)4 (0.196 g), and PPh3 (45 mg) were added and heating was begun. As the suspension was being heated to 1150 C, the solid went into solution, and hexamethylditin (1.225 g) was added.

After 3 hours, the solution was cooled, diluted with ethyl ether, washed with 1/2 sat'd NaHC03, water and sat'd NaCI. The organic layer was dried over Na2SO4, filtered, and evaporated under reduced presure.

Silica gel chromatography (ethyl acetate/hexane) gave 718 mg of the title compound.

1H NMR (400 MHz , CDC13) 6 0.39 (s, 1H), 7.40 (t, J= 7.5 Hz, 1H), 7.53 (t, J= 8.4 Hz, 1H), 7.65 (d, J= 8.4 Hz), 7.76 (s, 1H), 7.98 (d, J= 7.6 Hz, 1H), 8.23 (s, 1H) EXAMPLE 4

Me3Sn Me3Sn 3A1(CI)NHCH3 I C toluene, 90 0 900 H NH2 4 1 -(1 .methylamidinium-2-yl)-3-trimethylstannyl-dibenzofuranyl chloride (O Stannane 3 (176 mg) was dissolved in toluene (3.5 ml), and freshly prepared aluminum reagent (1.47 ml of 0.67 M solution) was added. The solution was heated to 900 C and monitored by TLC for conversion to baseline material.After 70 hr, a second portion of reagent (1.47 ml) was added. Following another 24 hr of heating, the reaction mixture was poured into a slurry of silica gel in chloroform.

The resulting slurry was stirred for 5 minutes and filtered using methanol to remove compound 4 from the silica gel. The solution was evaporated under reduced pressure to give a white solid which was dissolved in CH2C12 and filtered to remove any residual silica gel.

Chromatography (methanol/ethyl acetate/methylene chloride) gave 135.4 mg of the title compound.

1H NMR (400 MHz , CD30D) 8 0.42 (s, 9H), 3.22 (s, 3H), 4.8-5.0 (bs, 4H), 7.46 (t, J= 7.5 Hz, 1H), 7.57 (t, J= 8.3 Hz, 1H), 7.70 (d, J= 8.3 Hz, 1H), 7.86 (s, 1H), 8.17 (d, J= 7.9 Hz), 8.49 (s, 1H) EXAMPLE 5

1) EtN(i-Pr)2, Tf2O CH2CI2, -70" 2) EtN(i-Pr)2 TMSOTf, -70"

3) Compound 4 Pd2(DBA)3#CHCl3 (CH3CH2)4NCI CH2CI2, MeOH

(5R,6S)-2-[(1-(1-methylamidinium-2-yl))-3-dibenzofuranyl]-6-[1R (trimethyls ilyloxy)ethyl] -carbapen-2-em-3 -(4-nitrobenzyl)carboxylate chloride (5) A stirring solution of ADC-13 (202 mg) in CH2C12 (2.9 ml) was cooled to -70 , and isopropylethylamine (116 ,ul) was added during the cooling.Once the solution was allowed to cool completely, triflic anhydride (102 pl) was added. TLC showed clean conversion to the enol triflate; therefore, a second portion of isopropylethylamine (111 1) was added followed by TMSOTf (112 1). The resulting TMS protected enol triflate was added to a solution of l-methylamido-3trimethylstannyldibenzofuran (158 mg) in CH2C12 (1.5 ml) and methanol (0.5 ml). The palladium catalyst (12 mg) and tetraethylammonium chloride (70 mg) were added as solids, and the resulting wine red solution was stirred for 4 hours. The solution was diluted with ethyl acetate and washed with water. Drying over Na2S04 was followed by filtration and evaporation under reduced pressure. The residue was dissolved in CH2C12 and ethyl ether was added to give a precipitate. The mixture was centrifuged and the supematant was removed. The precipation was repeated and 226.6 mg of the title compound were obtained.

1H NMR (400 MHz , CDCl3) 0.12 (s, 9H), 1.26 (d, J= 6.2 Hz), 3.30 (s, 3H), 3.30-3.55 (m, 3H), 4.20-4.31 (m, 1H), 4.33-4.40 (m, 1H), 5.13 (d, J= 13.8 Hz, 2H), 5.26 (d, J= 14.1 Hz, 2H), 7.38 (t, J= 7.6 Hz, 1H), 7.42 (d, J= 8.7 Hz, 2H), 7.52 (t, J= 8.4 Hz, 1H), 7.59 (d, J= 8.4 Hz, 1H), 7.80 (d, J= 7.7 Hz, 1H), 7.95 (d, J= 8.7 Hz, 2H), 8.07 (s, 1H), 8.16 (s, 1H) 8.30-8.50 (bs, 2H), 8.80-8.95 (bs, 1H) EXAMPLE 6

(5R,6s)-2-[(1-(1-methylamidinium-2-yl))-3-dibenzofuranyl]-6-(1Rhydroxyethyl)-carbapen-2-em-3-carboxylate (6) Carbapenem 5 was dissolved in ThF (1.2 ml) and water (0.6 ml) and cooled to 0 C. HCI (40 1 of a 1 N solution) was added and the solution was stirred for 25 minutes. Neutralization with NaHCO3 (0.24 ml) was followed by addition of 10% Pd/C (32 mg).

The mixture was purged with hydrogen and stirred under balloon pressure for 1.5 hours at which time the starting material appeared to be gone by RP-TLC. The catalyst was removed by filtration washing with 2:1 water/acetonitrile, and the resulting solution was lyophilzed.

The crude lyophilizate was purified on reverse phase preparatory plates using acetonitrile/water as the mobile phase. After extraction from the reverse phase silica gel with acetonitrile/water, the solution was washed with hexane, filtered, evaporated under reduced pressure to remove the acetonitrile, and lyophilized to give 37.5 mg of the title compound.

1H NMR (400 MHz 2:1 D20/CD3CN) 6 1.62 (d, 6.4 Hz, 3H), 3.49 (s, 3H), 3.40-3.55 (m, 1H), 3.78-3.90 (m, 2H), 4.50-4.60 (m, 1H), 4.604.70 (m, 1H), 7.83 (t, J= 8.0 Hz, 1H), 7.96 (t, J= 8.4 Hz, 1H), 8.04 (d, J= 8.4 Hz, 1H), 8.11 (s, 1H), 8.48 (d, J= 7.7 Hz, 1H) EXAMPLE 7

3-bromo-1-(4,5-dihydro-imidazo-2-yl)-dibenzofuran (7) Ethylenediamine (7.4 ml) and catalytic carbondisulfide (33 p1) were added to 3-bromo-l -cyano-dibenzofuran (752 mg), and the mixture was heated to 110 C. The yellow solution eventually became green and a precipitate formed. After 2 hours of heating, it was cooled and evaporated under reduced pressure. The resulting residue was dissolved in CH2C12 and washed with water.Drying over Na2SO4, filtration, evaporation under reduced pressure, and silica gel chromatography (methanoVethyl acetate/ammonium hydroxide) gave 800 mg of the title compound.

1H NMR (400 MHz , CDC13) 8 3.80-4.10 (bs, 4H), 5.95-6.10 (bs, 1H), 7.38 (t, J= 7.5 Hz, 1H), 7.51 (t, J= 8.3 Hz, 1H), 7.60 (d, J= 8.3 Hz, 1H), 7.91 (d, J= 7.6 Hz, 1H), 8.10 (s, 1H), 8.31 (s, 1H) EXAMPLE 8

Me3Sn Me3SnSnMe3, Pd(PPh3)4 X PPh3, ,r" HNss toluene, A N Z 1-(4,5-dihydro-imidazo-2-yl)-3-trimethylstannyl-dibenzofuran (8) 3-bromo-1-(4,5-dihydro-imidazo-2-yl)-dibenzofuran was stannalyted as in example 3 to give the title compound.

1H NMR (400 MHz , CDCl3)# 0.37 (s, 9H), 3.91 (s, 4H), 7.38 (t, J= 7.5 Hz, 1H), 7.48 (t, J= 8.4 Hz, 1H), 7.60 (d, J= 8.3 Hz), 7.98 (d, J= 7.4 Hz, 1H), 8.13 (s, 1H), 8.34 (s, 1H) EXAMPLE 9

Me3Sn Me3Sn < HCI/dioxane X '0' CH2C12, 00 C HNt s HN+ & BR< I/ I/ C'v 8 9 1 -(4,5-dihydro-imidazolium-2-yl)-3-trimethylstannyl-dibenzofuranyl chloride (9) After dissolving 1-(4 ,5-dihydro-imidazo-2-yl)-3 -trimethyl- stannyl-dibenzofuran (35 mg) in CH2C12 (1 ml), it was cooled to OOC.

HCI (20 l of 4.0 M solution in dioxane) was added to give a precipitate. The reaction mixture was evaporated under reduced pressure to give 39 mg of the title compound.

1H NMR (400 MHz , d6-acetone) 6 0.42 (s, 9H), 4.17 (s, 4H), 7.48 (t, 6.9 Hz, 1H), 7.60 (t, J= 7.2 Hz, 1H), 7.71 (d, J= 8.3 Hz, 1H), 8.24 (d, J= 7.0 Hz, 1H), 8.47 (s, 1H) EXAMPLE 10

Br 1 ) n-BuLi, Br O ft% 2) n-BuLl, THF, THF + 2) acetaldehyde, THF \/ Br -750 to rt 0 H3C OH OH 3-bromo-1-(1-hydroxyethyl)-dibenzofuran (10) 1,3-dibromo-dibenzofuran (9.04 g) was dissolved in THF (250 ml) and cooled to -70" C. A 2.5 M solution of n-butyllithium in hexanes (12.2 ml) was added. After stirring for 30 minutes, a solution of acetaldehyde (1.705 ml) in THF (25 ml) was added, and the bath was removed.The solution was allowed to warm to room temperature, and a saturated NH4CI solution and ethyl acetate were added. After removal of the aqueous layer, the organic layer was washed with sat'd NH4Cl, water, and sat'd NaCl, dried over NaSO4, filtered and evaporated under reduced pressure to give the 8.4 g of the title compound.

1H NMR (400 MHz , CDC13) 6 1.64 (d, J= 6.5 Hz, 3H), 5.35-5.45 (m, 1H), 7.33 (t, J= 7.0 Hz, 1H), 7.46 (t, J= 8.4 Hz, 1H), 7.55 (d, J= 8.1 Hz, 1H), 7.61 (s, 1H), 7.84 (d, J= 7.7 Hz, 1H), 7.89 (s, 1H) EXAMPLE 11

Br Br I Jonesreagent ) X > acetone < g > H3C OH H3C 1Q 1 -acetyl-3-bromo-dibenzofuran (11) 3-bromo-1-(1 -hydroxyethyl)-dibenzofuran (8.4 g) was dissolved in acetone (275 ml) and cooled to 0 C. Dropwise addition of Jones reagent (9.7 ml of a 4N[O] solution) resulted in the formation of a precipitate. The suspension was allowed to warm to room temperature and was diluted with ethyl acetate. It was washed with water and sat'd NaCI and dried over NaSO4, filtered and evaporated under reduced pressure to give the crude product. Purification using silica gel chromatography gave 5.89 g of the title compound.

1H NMR (400 MHz , CDCl3) 8 2.92 (s, 3H), 7.38 (t, J= 7.6 Hz, 1H), 7.54 (t, J= 7.2 Hz, 1H), 7.64 (d, J= 8.4 Hz), 7.93 (d, J=8.4 Hz), 8.12 (s, 1H), 8.22 (s, 1H) EXAMPLE 12

Br Step A Br I \ H2 NOH.HC I pyridine H3O 0li H3C NOH 0 11 rp B Step B PCI5, benzene

3-bromo-1-aminoacetyl-dibenzofuran (12) Step A: l-acetyl-3-bromo-dibenzofuran (5.89 g) and hydroxylamine hydrochloride (1.63 g) were dissolved in pyridine and allowed to stir at room temperature for 7.5 hours.The mixture was diluted with ethyl acetate, washed with sat'd NH4Cl and dried over Na2SO4.

Filtration and evaporation afforded 5.97 g of the oxime.

Step B: The oxime (4.84 g) was dissolved in benzene (375 ml) and placed in a 0 C water bath. PCl5 (4.97 g) was added as a solid in 5 portions over 30 minutes. Following the addition, the ice bath was removed and the suspension was allowed to stir 3 hours at room temperature. Dilution with ethyl acetate was followed by washing with sat'd NaHCO3, water and sat'd NaCl, and drying over Na2S04.

Filtration, evaporation under reduced pressure, and silica gel chromatography gave 2.93 g of the title compound.

1H NMR (400 MHz , CDCl3) # 2.31 (s, 1H), 7.36 (t, J= 8.0 Hz, 1H), 7.48 (t, 3=8.4 Hz, 1H), 7.55 (d, J=8.1 Hz, 1H), 7.62-7.75 (bs, 1H), 7.77 (s, 1H), 7.87 (d, J= 7.6 Hz, 1H), 8.54 (s, 1H) EXAMPLE 13

1-amino-3-bromodibenzofuran (13) The carboxamide (3.5 g) and KOH (8.4 g) were suspended in ethanol (95 ml) and heated to 90 C to give a clear solution until a precipitate came out after 3 hours of heating. After 5.5 hours, the pH was adjusted to 6-7 and ethyl acetate was added. The solution was washed with sat'd NH4Cl, water and sat'd NaCI, dried over Na2S04, filtered and evaporated under reduced pressure.Silica gel chromatography gave 2.09 g of the title compound.

EXAMPLE 14

3-bromo-1-(N-thiocyano)-dibenzofuran (14) 1 -amino-3-bromo-dibenzofuran (998 mg) in CH2Cl2 (17 ml) was added to a 0 C stirring biphasic mixture of CSCl2 (334 l), CaCO3 (572 mg), H20 (19 ml), and CH2C12 (3 ml). After 3 hours, the mixture was filtered using CH2C12 to rinse the filter. The organic layer was washed with sat'd NH4Cl and sat'd NaCl. Drying over Na2S04, filtration, and evaporation under reduced pressure gave 1.11 g of the title compound.

1H NMR (400 MHz, CDCl3) #7.38 (t, J= 8.0 Hz, 1H), 7.53 (t, J=8.2 Hz, 1H), 7.63 (d, J= 8.3 Hz), 7.89 (d, J= 7.5 Hz, 1H), 7.94 (s, 1H) EXAMPLE 15

Step A Br Br > :/13 I OCH3L EtOH, A N S NH 8N C /NH 10% HCI JOCH3 StepS H3CO OCH3 EtOH, A Br 20% Step X I Step I A 15 3-bromo-1 -(imidazo-l -yl)-dibenzofuran (o) Step A:: 3-bromo-l -(N-thioeyano)-dibenzofuran (1.11 g) was suspended in ethanol (40 ml) and heated to 100 C to give a clear solution, the amine (396 l) was added, and the solution was stirred for 45 minutes. It was cooled and evaporated under reduced pressure to give the crude product which was used in the next step without purification.

Step B: Crude Product from step A was suspended in ethanol (5 ml) and heated to 1 150C. During the heating, a 10% HCI solution in water (35 ml) was added. After 1 hour, an additional 2 ml of ethanol were added, and the suspension was allowed to stir overnight at 120 C.

The reaction mixture was cooled and the product was filtered off to give 1.17 g which was used directly in the next step.

Step C: A 20% solution of HNO3 (10 ml) was added to the product of step B resulting in gas evolution. The mixture was heated to 100 C for 20 minutes to give a solution. The solution was made strongly basic, and the product was extracted with CH2Cl2 and washed with water and sat'd NaCl. Drying over Na2SO4, filtration, and evaporation under reduced pressure gave 980 mg of the crude product which was chromatographed through silica gel to give 605 mg of the title compound.

1H NMR (400 MHz, CDCl3) # 7.25-7.35 (bs, 1H), 7.44 (t, J= 7.4 Hz, 1H), 7.50-7.65 (m, 4H), 7.95 (d, 7.4 Hz), 8.04 (s, 1H), 8.25 (bs, 1H) EXAMPLE 16

Br Me3SnSnMe3, Me3SnSnMe3, Pd(PPh3) (N 15 PPh3, toluene, A 16 1-(imidazo-1-yl)-3-trimethylstannyl-dibenzofuran (16) 3-bromo-1-(imidazo-1-yl)-dibenzofuran was stannylated as in example 3 to give the title compound.

1H NMR (400 MHz , CDCl3) 5 0.39 (s, 9H), 7.30 (s, 1H), 7.39 (t, J= 8.0 Hz, 1H), 7.48-7.52 (m, 2H), 7.57-7.60 (m, 2H), 7.95-8.05 (m, 2H), 8.20 (s, 1H) EXAMPLE 17

1 -(3 -methylimidazolium- 1 -yl)-3-trimethylstannyl-dibenzofuranyl trifluoromethanesulfonate (17) 1-(1-imidazoyl)-3-trimethylstannyl-dibenzofuran (127 mg) was dissolved in CH2Cl2 {3.2 ml). Dropwise addition of methyl triflate (40 l) resulted in the formation of a precipitate. The suspension was stirred for 10 minutes and evaporated under reduced pressure to give 179 mg of the title compound.

1H NMR (400 MHz , CDCl3) # 0.43 (s, 9H), 4.26 (s, 3H), 7.44 (t, J= 7.6 Hz, 1H), 7.52-7.56 (m, 2H), 7.62 (d, J= 8.3 Hz, 1H), 7.86 (s, 1H), 7.96 (m, 1H), 8.03 (d, J= 7.0 Hz, 1H), 8.17 (s, 1H), 9.86 (s, 1H) EXAMPLE 18

Br Me3Sn MeSnSnMe3, Pd(PPh3)4 PPh3, toluene, A H2N H2N 13 18 1 -amino-3-trimethylstannyl-dibenzofuran (18) 1-amino-3-bromo-dibenzofuran was stannylated as in example 3 to give the title compound.

1H NMR (400 MHz , CDCl3) # 0.32 (s, 1H), 4.01 (bs, 2H), 6.90 (s, 1H), 7.31 (t, J= 7.4 Hz, 1H), 7.42 (t, J=8.3 Hz, 1H), 7.46 (s, 1H), 7.54 (d, J= 8.3 Hz, 1H), 7.93 (d, J= 7.7 Hz, 1H) EXAMPLE 19

Me3Sn o2 Me3Sn I \ > 3 O-edSOdN X H2N (i-Pr)2EtN 18 CH3OH i7)I 9 1-(N-pyridinium)-3-trimethylstannyl-dibenzofuranyl chloride (19) Stannane 18 (108 mg) and the pyridinium salt (88 mg) were dissolved in dioxane (2.8 ml) and methanol (0.7 ml) to give a deep orange colored solution. Treatment with diisopropylethylamine (54 p1) was followed by heating at 430C for 19 hours.The reaction was evaporated under reduced pressure, dissolved in minimum methylene chloride. Addition of ethyl ether resulted in the formation of an oil.

The mixture was centrifuged and the supematant was removed from the oil which had settled to the bottom of the centrifuge tube. The oil was recovered to give 165 mg of the title compound which was used without further purification.

1H NMR (400 MHz , acetone-d6) 6 0.45 (s, 9H), 7.51 (t, J= 7.8 Hz, 1H), 7.62 (t, J= 7.2 Hz, 1H), 8.29 (d, J= 7.6 Hz, 1H), 8.36 (s, 1H), 8.63-8.68 (m, 3H), 9.06-9.08 (m, 1H), 9.85 (d, J= 5.0 Hz) EXAMPLE 20

1 ,3-dibromo-9,9-dioxodibenzothiophene (m) To a stirred mixture of 1 ,3-dibromodibenzothiophene (3.415 g, 9.984 mmol) in 100 mL of dichloromethane at room temperature was added 4.66 g of 85% mchloroperbenzoic acid (-2.3 eq). After 18 h, an additional 1 g of m-chloroperbenzoic acid was added. After 45 h, the solution was washed with 5% Na2SO4, 1N NaOH, H20 and brine.Drying over Na2SO4 and evaporation gave 3.83 g of product as a white solid which was used without purification in the next reaction.

EXAMPLE 21

3-bromo-1-(imidazo-1-yl)-9,9-dioxodibenzothiophene (21) To a stirred mixture of dibromide 20 (163 mug, 0.436 mmol) in THF was added trimethylsilyl imidazole (0.096 ml, 1.5 equiv.) followed by a solution of 1 .0M tetra-n-butylammonium fluoride in THF (0.57 ml, 1.3 equiv.) and the mixture was heated to reflux temperature. After 16h, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic solution was washed with water (3x) and brine, dried over Na2SO4 and evaporated in vacuo to give 152.6 mg of white solid. Chromatography on silica gel (5:30:65 MeOH/EtOAc/CHC13) gave 21.6 mg of compound 21 as a solid along with 53.4 mg of recovered 20 and 40.4 mg of 22.

For compound 21: 1H NMR (400 MHz , CDC13) 7.31 (bs, 1H), 7.59 (d, J= 1.5 Hz, 1H), 7.60-7.65 (m, 2H), 7.72 (dt, J= 7.7, 1.1 Hz, 1H), 7.80-7.85 (m, 2H), 7.96 (d, J= 1.5 Hz, 1H), 8.13 (bs, 1H).

EXAMPLE 22

1-(imidazo-1-yl)-3-trimethylstannyl-9,9-dioxodibenzothiophene (23) To a stirred mixture of compound 21 (81.3 mg, 0.225 mmol), tetrakis(triphenylphosphine)palladium(0) (13 mg, 0.05 equiv.) and triphenylphosphine (6 mg, 0.1 equiv.) in toluene was added a 1 .0M solution of hexamethylditin in toluene (0.25 ml, 1.1 equiv.).

The reaction mixture was heated at reflux for 21 hours, and was then cooled to room temperature and diluted with ethyl acetate. The organic solution was washed with water and brine, dried over Na2S04 and evaporated in vacuo to give 114 mg of an oil. Chromatography on silica gel (5:30:65 MeOH/EtOAc/CHC13) gave 60.5 mg of compound 23 as a solid.

1H NMR (400 MHz , CDC13) 0.43 (s, 9H), 7.28 (bs, 1H), 7.47 (s, 1H), 7.56 (t, J= 7.5 Hz, 1H), 7.60 (bs, 1H), 7.67 (t, J=7.6 Hz, 1H), 7.81 (d, J= 7.7 Hz, 1H), 7.89 (d, J= 7.7 Hz, 1H), 7.91, (s, 1H), 8.03 (bs, 1H).

EXAMPLE 23

1 -(3 -methylimidazolium-l -yl)-3 -trimethylstannyl-9 ,9- dioxodibenzothiophene trifluoromethanesulfonate (24) To a stirred mixture of compound 23 (86.4 mg, 0.194 mmol) in dichloromethane was added methyl trifluoromethanesulfonate (0.024 ml, 1.1 equiv.). After 1 hour the reaction mixture was evaporated to dryness in vacuo to give 115 mg of compound 24 as a solid.

1H NMR (400 MHz , d6-acetone) 5 0.55 (s, 9H), 4.23 (s, 3H), 7.76 (dt, J= 7.6, 1.1 Hz, 1H), 7.85 (dt, J= 7.6, 1.2 Hz, 1H), 7.96 (d, J= 7.7 Hz, 1H), 8.03 (t, J= 1.3 Hz, 1H), 8.08 (d, j= 2.1 Hz, 1H), 8.22 (dd, J= 7.7, 0.8 Hz, 1H), 8.38 (t, J= 1.9 Hz, 1H), 8.57 (d, J= 2.2 Hz, 1H), 9.81 (s, 1H).

Employing the procedures described herein, additional compounds of the present invention were prepared. These are described in Table I which additionally includes characterizing data.

Table I

UV (NH2OH extinguishable) Example R' us #max

24 9 299 H2N tH N 25 1 297 nm t0 332 nm (C H3)2N tH N 26 < 302 nm N o 348 nm NH ANH w 27 1 299 nm 27 < 3 331 nm 331 nm 3 sNA NH w' 28 11N 298 nm N 327 nm H3CN N'CH3 UV (NH2OH extinguishable) Example Rr #max

29 \ 0; ;0 298 328 nm 3 N No 3 30 II 299 nm II 333 NH V 31 < 293 nm 318 no 6 Ne h /I 32 303 nm 0 33 \ < 301 nm N, 00 345 nm N N < 3 CH3

Claims (9)

WHAT IS CLAIMED IS:

1. A carbapenem compound of the formula:

wherein: R is H or CH3; R1 and R2 are independently H, CH3-, CH3CH2,-(CH3)2CH-, HOCH2-, CH3CH(OH)-, (CH3)2C(OH)-, FCH2CH(OH)-, F2CHCH(OH)-, F3CCH(OH)-, CH3CH(F)-, CH3CF2-, or (CH3)2C(F)-; X represents 0, S, S(O) or S(O)2; A represents a group selected from: a)

wherein Rw', Rx', RY' and Rz' independently represent a member selected from the group consisting of:H, C1-4 alkyl and C1-4 alkyl substituted with 13 Rq groups; or RY' and RZ are taken together and represent a C3-5 alkylidene group, optionally substituted with 1-3 Rq groups; or Rx' and RZ are taken together and represent a C2-4 saturated or unsaturated alkylidene group, optionally substituted with 1-3 Rq groups; b)

Re is as defined below; Rd represents a member selected from the group consisting of: hydrogen, NH2 or CiA alkyl, said alkyl group being unsubstituted or substituted with 1-3 Rq groups; c)

m plus n, plus any Rc groups present on A, equals an integer of from 0 to 4, such that 0-4 Rc groups are present and are independently selected from the group set forth below; a) -CF3; b) a halogen atom selected from the group consisting of: -Br, -Cl, -F, and -I; c) C1-C4 alkoxy radical: -OCi -4 alkyl, wherein the alkyl is optionally substituted by 1-3 Rq groups, wherein Rq is a member selected from the group consisting of -OH, -OCH3, -CN, -C(O)NH2,-OC(O)NH2, CHO, -S02NH2, -SOCH3, -SO2CH3, -F, -CF3, -CO2CH3, -C(O)CH3, -C(O)NHCH3, -C(O)N(CH3)2 and -COOMb (wherein Mb is hydrogen or an alkali metal selected from the group consisting of Na, K, Mg and Ca); d) -OH; e) -O(C=O)Rs, wherein Rs is Ci -4 alkyl or phenyl, each of which is optionally substituted by 1-3 Rq groups, as defined above; f) -O(C=O)N(Ry')Rz', wherein RY' and Rzl are as previously defined; g) -S(O)n-Rs wherein n = 0-2, and Rs is defined above; h) SO2N(Ry')Rz' wherein Ry' and Rz' are as defined above; i) N3; j) -N(Rt)(C=O)H, wherein Rt is H or Cl -4 alkyl, optionally substituted with 1-3 Rq groups as defined above; k) -N(Rt)(C=O)Cl 4 alkyl, wherein Rt is as defined above; 1) -N(Rt)(C=O)OC1-4 alkyl, wherein Rt is as defined above; m) -N(Rt)(C=O)N(Ry')Rz' wherein Rt, Ry' and Rz' are as defined above; n) a sulfonamido group: -N(Rt)S02Rs, wherein Rs and Rt are as defined above; o) -CN; p) -(C=O)H or -CH(OCH3)2; q) -C(OCH3)2C1 -4 alkyl, wherein the alkyl is optionally substituted with 1-3 Rq groups as defined above; r) -(C=O)Rs, wherein Rs is as defined above; s) (C=NORx ')Ry' wherein Ry' and Rx are as defined above, t) -(C=O)OC1-4 alkyl, wherein the alkyl is optionally substituted by 1-3 Rq groups as defined above; u) -(C=O)N(Ry')Rz' wherein Ry' and Rz' are as defined above; v) -(C=O)-N(ORy')Rz' wherein Ry' and R' are as defined above; w) -(C=s)N(Ry')Rz' wherein Ry' and Rz' are as defined above; x) -COOMb, wherein Mb is as defined above; y) -SCN; z) -SCF3; aa) tetrazolyl, where the point of attachment is the carbon atom of the tetrazole ring and one of the nitrogen atoms is mono-substituted by hydrogen, an alkali metal or a C1-C4 alkyl optionally substituted by 1-3 Rq groups as defined above; ab) a C5-C7 cycloalkyl group in which one of the carbon atoms in the ring is replaced by a heteroatom selected from 0, S, NH, or N(C1 -C4 alkyl) and in which one additional carbon may be replaced by NH or N(C1-C4 alkyl), and in which at least one carbon atom adjacent to each nitrogen heteroatom has both of its attached hydrogen atoms replaced by one oxygen thus forming a carbonyl moiety and there are one or two carbonyl moieties present in the ring; ac) a C2-C4 alkenyl radical, optionally substituted by one to three of the substituents a) to ac) above and phenyl which is optionally substituted by 1-3 Rq groups as defined above; ad) a C2-C4 alkynyl radical, optionally substituted by one to three of the substituents a) to ac) above; ae) a C1-4 alkyl radical; af) a C1 -4 all substituted by one to three of the substituents a) - ac) above; ag) a 2-oxazolidinonyl moiety in which the point of attachment is the nitrogen atom of the oxazolidinone ring, the ring oxygen atom is optionally replaced by a heteroatom selected from S and NRt (where Rt is as defined above) and one of the saturated carbon atoms of the oxazolidinone ring is optionally mono-substituted by one of the substituents a) to af) above; and M is selected from: i) hydrogen; ii) a pharmaceutically acceptable esterifying group or removable carboxyl protecting group; iii) an alkali metal or other pharmaceutically acceptable cation; and iv) a negative charge which is balanced by a positively charged group.

2. A compound in accordance with claim 1 of the formula:

wherein R, R1, R2, M, A, X, n and Re are as previously defined.

3. A compound in accordance with claim 1 represented by the formula:

wherein R, R1, R2, M, A, X and Re are as previously defined.

4. A compound in accordance with claim 1 wherein A represents type (a).

5. A compound in accordance with claim 4 wherein A is selected from the group consisting of:

6. A carbapenem compound in accordance with Table 1 or Table 2: Table 1

Cmpd Rr

1 m3 H2NANH Cmpd Rr

2 \0o/ H 3 (CH3)2N NH HN)%NH HN \0 ml 5 5 \X3 N NH 6 \00/0 H3ONN N ml

7 H3O N OH3 N N/ Cmpd Rr

8 HN < NH 9 v C?e CH3 1 0 904 11 11 I oo CH3 Table 2

Cmpd R'

1 II H2N+NH 2 H3OHN 0N+H H 'NH (CH3)2NANH 4 < 4 HN/6 ml Cmpd Rr

o/0 HSC. NH H3ON NH 6 H3ON CH3 7 H3CuNANi)oCH3 \=J MN{N+HOI) 8 II 9 N\(3 CH3 Cmpd R'

.

N 11 \W3 -N 0 N (3 CH3

7. A carbapenem compound in accordance with claim 1 wherein from one to three Rc groups are present which are selected from the group consisting of: -OCH3 -CH2I -OCH2CH2OH -SO2NHCONH2 -F -CF3 -Br -Cl -OH -I -OCONH2 -OCOCH3 -SOCH3 -SCH3 -SCH2CH20H -S02CH3 -S 02NH2 -SOCH2CH2OH -NHCHO -SO2N(CH3)2 -NHC02CH3 -NHCOCH3 -CN -NHSO2CH3 -COCH3 -CHO -CH=NOH -COCH2OH -C=C-CONH2 -CH=NOCH3 -S02CH2CH20H -CH2N3 -CH=NOCMe2C02Me -C02CH2CH20H -CONH2 -CONHCH3 -CON(CH3)2 -CONHCH2CN -CONHCH2CONH2 -C#C-CN -CONHOH -CONHCH3 -tetrazolyl -CH=CHCN -SCF3 -CH2OH -CH=CHCONH2 and -CONHSO2NH2 8. A pharmaceutical composition comprised of a compound in accordance with claim 1 in combination with a pharmaceutically acceptable carrier.

9. A method of treating a bacterial infection in a mammalian patient in need of such treatment, comprising administering to said patient an antibacterially effective amount of a compound in accordance with claim 1.