TITLE OF THE INVENTION

BRIDGED BIPHENYL CARBAPENEM ANTIBACTERIAL

COMPOUNDS

BACKGROUND OF THE INVENTION

The present invention relates to antibacterial agents of the carbapenem class in which the five membered ring of the carbapenem nucleus is fused to a biphenyl group which is substituted by various cationic and neutral substituents. The fused ring compounds are described in detail below.

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:

U.S. Pat. Nos. 5,011,832 and 5,025,006 relate to carbapenems of the structure shown below which exhibit antimicrobial activity against strains of methicillin resistant staphylococci (MRS A). The carbapenems described therein possess a meta-disposed biphenyl moiety attached to the C-2 position of the carbapenem ring.

U.S. Pat. Nos. 4,374,849 and 4,374,879 issued on

February 22, 1983 to Christensen, et al., relate to compounds of the formula:

In U.S. Pat. No. 4,374,878, the R group noted above represents a hydroxy substituted ethyl group.

More recently, carbapenem antibacterial agents have been described which have a 2-substituent which is an aryl moiety optionally substituted by, e.g., aminomethyl and substituted aminomethyl. These agents are described in U.S. Patent Nos. 4,543,257 and 4,260,627 and have the formula:

Compounds of the formula:

have been disclosed in EPO 422,596 A3 published on April 17, 1991. European Publication No. 416 953 A3 published on March 13, 1991 addresses compounds of the formula:

European Publication No. 517 065 Al published on December 9, 1992 addresses compounds of the formula:

The carbapenems of the present invention are useful against gram positive microorganisms, especially methicillin resistant Staphylococcus 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 (MRSA/MRCNS) which are at the same time

safe, i.e., relatively free from undesirable side effects. And, the current agent of choice, vancomycin, a glycopeptide antibacterial, is experiencing an ever increasing amount of resistance in the MRSA/MRCNS pathogens.

SUMMARY OF THE INVENTION

The present invention addresses a compound represented by formula I:

wherein: m is an integer 0, 1, 2, 3, 4 or 5; n is an integer 0, 1, 2, 3 or 4;

X represents (a) a bond; (b) -0-; (c) -S(0) _x - with x equal to 0, 1 or 2; (d) -C(O)-; (e) -NR'- with R' representing H, Ci to C4 alkyl, acetyl or C 1-4 alkyl substituted with Rq; (f) -CH=CH-; (g) -C(0)NR'-; (h) -NR'C(O)-; (i) -CO2- (j) -OC(O)-; (k) -Sθ2NR'- or (1) -NR'S02-.

The values of m, n and X are selected such that ring B constitutes a 6 to 10 membered ring.

Y represents H, a negative charge, a pharmaceutically acceptable ester, a biolabile ester, a carboxylate protecting group or a metal cation.

Rl and R2 independently represent H, CH3-, CH3CH2-, (CH3)2CH-, HOCH2-, CH3CH(OH)-, (CH3)2C(OH)-, FCH2CH(OH)-, F2CHCH(OH)-, F3CCH(OH)-, CH3CH(F)-, CH3CF2- or (CH3)2CF-.

One of the Ra groups represents H or W, and the other represents one of the groups (a) through (d): (a)

(b)

(c) -Ap-NRlθRl lRl2(0-l); and (d)

When one of the Ra groups represents (a)

A represents -(CR3R4) _Γ -Q-(CR3R4) _S - wherein r is 0-6, s is 1-6 and Q represents: a covalent bond, -0-, -S(0)χ- with x equal to 0, 1 or 2, -NR3-, -S02NR3-, -NR3S02-, -C(0)NR3-, -NR3C(0)-, -CR3=CR4-, -C(0)-, -0C(0)- or -(O)CO-; with R3 and R4 independently representing H or Cl-4 lower alkyl, and (CR3R4) _S _ being attached to the ring nitrogen.

- ^O — ' represents a 5 or 6 membered monocyclic heterocycle or an 8-10 membered bicyclic heterocycle, bonded to A through the ring nitrogen and having a substituent group Rd optionally attached to the ring nitrogen, and having 0-3 Rc groups attached to other atoms of the heterocyclic group, said ring nitrogen being tertiary or quaternary by virtue of A, the ring bonds and optionally Rd which may be attached, said heterocyclic group being aromatic, partially aromatic or non- aromatic.

The heterocycle also contain 0-3 additional nitrogen atoms and 0-1 oxygen or sulfur atom.

Each Rc independently represents W as defined below or NRyRz, wherein Ry and Rz independently represent H, Cl to C4 alkyl or Cl to C4 alkyl substituted with Rq, or Ry and Rz are taken together to represent either a 3- to 5-membered alkylidene radical to form a ring, optionally substituted with Rq, or a 2- to 4-membered alkylidene radical interrupted by O or S(0)χ with x equal to 0, 1 or 2, to form a ring, said alkylidene being optionally substituted with Rq.

Rq is selected from hydroxy, methoxy, cyano, -C(0)NH2, -OC(0)NH2, -CHO, -OC(0)N(CH3)2, -SO2NH2, -Sθ2N(CH3)2, -SOCH3, -SO2CH3, -F, -CF3, -Sθ3Mb with Mb representing H or alkali metal, or -Cθ2Ma, where Ma is H, alkali metal, methyl or phenyl; tetrazolyl (where the point of attachment is the carbon atom of the tetrazole ring and one of the nitrogen atoms is mono-substituted by Ma as defined above).

Each Rd independently represents hydrogen, NH2, O- or Cl to C4 alkyl, optionally mono-substituted with Rq as defined above.

When one Ra group represents (b)

A' represents -(CR3R4) _m ' -Q- (CR3R4) _m ^< - with each m' independently equal to 0-6, and Q, R3 and R4 as defined above, except that when each m' is 0, Q is not a covalent bond, and -(CR3R4) _m ' attached to the phenyl ring.

a 5 or 6 membered monocyclic heterocycle or an 8-10 membered bicyclic heterocycle, said heterocycle being aromatic, partially aromatic or non-aromatic, bonded to A' through an atom other than the ring nitrogen, and optionally having 0-2 Rd substituent groups attached to the ring nitrogen, said nitrogen in the heterocycle being tertiary or quaternary by virtue of the ring bonds and the optional Rd groups which may be attached.

The heterocycle may further contain 0-1 oxygen or sulfur atom and 0-2 additional nitrogen atoms therein.

Rc and Rd are as defined above.

When one Ra group represents (c) -A _p -NRlθRl 1R12

(0-1),

A is as defined above and p is an integer 0 or 1.

RlO, Rll and when present, Rl2, are independently H, Cl-4 alkyl or Cl-4 alkyl mono-substituted with Rq; or RlO, Rl 1 and Rl2 may be taken in combination to represent a C4 to Cio alkanetriyl group, optionally substituted with up to three W groups, with W as defined below.

Where one Ra group represents (d), A', p, the N containing ring, Rc and Rd are as previously defined.

When present, each W independently represents a member selected from the group consisting of: a) trifluoromethyl group: -CF3; b) a halogen atom: -Br, -Cl, -F, or -I; c) C1-C4 alkoxy radical: -OC 1-4 alkyl, wherein the alkyl is optionally mono-substituted by Rq, where Rq is as defined above;

d) a hydroxy group: -OH; e) a carbonyloxy radical: -OC(0)Rs, where

Rs is Cl-4 alkyl or phenyl, each of which is optionally mono-substituted by Rq as defined above; f) a carbamoyloxy radical; -OC(0)N(Ry)Rz, where

Ry and Rz are independently H, Cl-4 alkyl, (optionally mono-substituted by Rq as defined above), or are taken together to represent a 3- to 5-membered alkylidene radical which forms a ring (optionally substituted with Rq as defined above), or a 2- to 4-membered alkylidene radical interrupted by -0-, -S-, -S(O)- or -S(0)2- which forms a ring, said ring being optionally mono-substituted with Rq as defined above; g) a sulfur radical: -S(0)n-R ^s , where n = 0-2, and Rs is defined above; h) a sulfamoyl group: -Sθ2N(Ry)Rz, where Ry and Rz are as defined above; i) azido: N3 j) a formamido group: -N(Rt)C(0)H, where

Rt is H or Cl-4 alkyl, said alkyl group being optionally mono-substituted with Rq as defined above; k) an alkylcarbonylamino radical: -N(Rt)C(0)Ci-4 alkyl, wherein Rt is as defined above; 1) an alkoxycarbonylamino radical:

-N(Rt)C(0)OCi-4 alkyl, where Rt is as defined above; m) a ureido group: -N(Rt)C(0)N(Ry)Rz where Rt, Ry and Rz are defined above; n) a sulfonamido group: -N(Rt)S02R ^s , where Rs and Rt are as defined above; o) a cyano group: -CN; p) a formyl or acetalized formyl radical: -C(0)H or

-CH(OCH3)2;

q) an alkylcarbonyl radical wherein the carbonyl is acetalized: -C(OCH3)2 C1-C4 alkyl, where the alkyl is optionally mono-substituted by Rq as defined above; r) a carbonyl radical: -C(0)Rs, where Rs is as defined above; s) a hydroximinomethyl radical in which the oxygen or carbon atom is optionally substituted by a C1-C4 alkyl group: -(C=NORz)Ry where Ry and Rz are as defined above, except they may not be joined together to form a ring; t) an alkoxy carbonyl radical: -C(0)OCl-4 alkyl, where the alkyl is optionally mono-substituted by Rq as defined above; u) a carbamoyl radical: -C(0)N(Ry)Rz, where Ry and Rz are as defined above; v) an N-hydroxycarbamoyl or N(Ci-C4 alkoxy )carbamoyl radical in which the nitrogen atom may be additionally substituted by a C1-C4 alkyl group: -C(0)N(ORy)Rz, where Ry and Rz are as defined above, except they may not be joined together to form a ring; w) a thiocarbamoyl group: -C(S)N(Ry)Rz where Ry and Rz are as defined above; x) carboxyl: -COOMa where Ma 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 Rq as defined above; ab) an anionic function selected from the group consisting of: phosphono [P=0(OMa)2]; alkylphosphono {P=0(OMa [0(Ci-C4 alkyl)] }; alkylphosphinyl [P=0(OMa)-(Ci-C4 alkyl)]; phosphoramido [P=0(OMa)N(Ry)Rz and P=0(OMa)NHRx]; sulfino (Sθ2Ma); sulfo (Sθ3Ma);

acylsulfonamides selected from the structures Sθ2NMaCON(Ry)RZ; and Sθ2NMaCN, where

Rx is phenyl or heteroaryl, where heteroaryl is a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, in which a carbon atom is the point of attachment, in which one of the carbon atoms has been replaced by a nitrogen atom, in which one additional carbon atom is optionally replaced by a heteroatom selected from O or S, and in which from 1 to 2 additional carbon atoms are optionally replaced by a nitrogen heteroatom, and where the phenyl and heteroaryl are optionally mono- substituted by Rq, said Rq, Ma, Ry and Rz being as defined above; ac) a C5-C7 cycloalkyl group in which one of the carbon atoms in the ring is replaced by a heteroatom selected from O, S, NH, or N(Cl-C4 alkyl) and in which one additional carbon may be replaced by the NH or N(Ci-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; ad) a C2-C4 alkenyl radical, optionally mono-substituted by one of the substituents a) to ac) above and phenyl which is optionally substituted by Rq as defined above; ae) a C2-C4 alkynyl radical, optionally mono-substituted by one of the substituents a) to ac) above; af) a C 1 -C4 alkyl radical; ag) a C1-C4 alkyl group mono-substituted by one of the substituents a) to ac) above; ah) 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 ag) above.

Novel compositions, intermediates, processes of manufacture and methods of treatment are also disclosed.

DETAILED DESCRIPTION OF THE INVENTION

The invention is described herein in detail using the terms defined below unless otherwise specified.

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, W, as defined, 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".

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 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 etenyl, propenyl, butenyl and cyclohexenyl.

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

Aryl refers to aromatic rings e.g., phenyl, substituted phenyl and the like, groups as well as rings which are fused, e.g., naphthyl, phenanthrenyl and the like. Aryl thus contain 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 likewise be substituted with Ra and W groups as defined below. Preferred substituted aryls include phenyl and naphthyl substituted with one or two preferred Ra or W groups.

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, O, S or N, in which a carbon or nitrogen atom is the point of attachment, and in which one additional carbon atom is optionally replaced by a heteroatom selected from O or S, and in which from 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms, said heteroaryl group being optionally substituted with up to four Rq groups.

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. The preferred heteroaryls are those where only nitrogen heteroatoms are present when there is more than one. Typical of these are pyrazole, tetrazole, imidazole, pyridine, pyrimidine and pyrazine and triazine.

The heteroaryl group of Rx may be optionally substituted by Rq, as defined above, and substitution can be on one of the carbon atoms or one of the heteroatoms, although in the latter case certain substitutent choices may not be appropriate.

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 O, S, NH, or N(Cl-C4 alkyl), and in which up to three additional carbon atoms may be replaced by said hetero groups.

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., tetramethyl-ammonium,

N-methylpyridinium), the positively charged nitrogen in a protonated ammonium species (e.g., trimethylhydroammonium, N-hydro- pyridinium), the positively charged nitrogen in an amine N-oxide (e.g., N-methylmo holine-N-oxide, pyridine-N-oxide), and the positively charged nitrogen in an N-amino-ammonium group (e.g., N-amino- pyridinium).

The term "heteroatom" means N, S, or O, selected on an independent basis.

Alkylene (alkylidene or alkanediyl) and arylene refer to the groups noted above with divalent points of attachment. For example, phenylene is an arylene group, attached at any of the 1, 2- 1, 3- or 1 , 4- positions. Examples of alkylene include -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CHCH3 and -CHCH2CH3.

Similarly, alkanetriyl refers to an alkane-derived group with three points of attachment. Alkanetriyl groups contain from five to fifteen carbon atoms, which may be straight, branched, cyclic or multicyclic.

Aralkyl is a specie of substituted alkyl, containing up to three aryl groups substituted on a straight, branched or cycloalkyl group. The most preferred aralkyl group is benzyl.

Halogen, or "halo" refers to bromine, chlorine, fluorine and iodine.

Alkoxy refers to C1-C4 alkyl-O-, with the alkyl group optionally substituted with the variable Rq.

Carbonyloxy refers to the radical: -OC(0)Rs, where Rs is Cl-4 alkyl or phenyl, each of which is optionally mono-substituted by Rq.

Carbamoyloxy refers to the radical: -OC(0)N(Ry)Rz, where Ry and Rz are independently H, Cl-4 alkyl, (optionally mono- substituted by Rq as defined above). Alternatively, Ry and Rz can be taken together to represent a 3- to 5-membered alkylidene radical which forms a ring (optionally substituted with Rq as defined above), or a 2- to 4-membered alkylidene radical interrupted by -0-, -S-, -S(O)- or

-S(0)2- which forms a ring, said ring being optionally mono-substituted with Rq as defined above.

The term "sulfur radical" refers to the group: -S(0)χ-Rs, where x is an integer of from O to 2, and Rs is as defined above.

The term "sulfamoyl group" refers to: -Sθ2N(Ry)Rz, where Ry and Rz are as defined above, representing H, alkyl or alkyl mono-substituted with Rq.

The term "azido" refers to the group: N3.

The term "formamido" refers to the group: -N(Rt)C(0)H, where Rt is H or Cl-4 alkyl, said alkyl group being optionally mono- substituted with Rq as defined above.

The term "alkylcarbonylamino" refers to the group: -N(Rt)C(0)Cl-4 alkyl, wherein Rt is as defined above.

The term "alkoxycarbonylamino" refers to the group: -N(Rt)C(0)OCi-4 alkyl, where Rt is as defined above.

The term "ureido" refers to the group: -N(Rt)C(0)N(Ry)Rz where Rt, Ry and Rz are defined above.

The term "sulfonamido" refers to the group: -N(Rt)Sθ2R ^s , where Rs and Rt are as defined above.

The terms "formyl" and "acetalized formyl radical" refer to the groups: -C(0)H or -CH(OCH3)2, respectively. Thus, an alkylcarbonyl radical wherein the carbonyl is acetalized is of the formula: -C(OCH3)2 C1-C4 alkyl, where the alkyl is optionally mono- substituted by Rq.

A "carbonyl radical" is represented by the formula: -C(0)Rs, where Rs is as defined above.

A "hydroximinomethyl" radical in which the oxygen or carbon atom is optionally substituted by a C1-C4 alkyl group is represented by the formula: -(C=NORz)Ry where Ry and Rz are as defined above, except they may not be joined together to form a ring.

An "alkoxycarbonyl" radical is represented by the formula: -C(0)OCl-4 alkyl, where the alkyl is optionally mono-substituted by Rq as defined above.

A "carbamoyl" radical is represented by the formula: -C(0)N(Ry)Rz, where Ry and Rz are as defined.

An N-hydroxycarbamoyl or N(Cl-C4 alkoxy)carbamoyl radical in which the nitrogen atom may be additionally substituted by a C1-C4 alkyl group is represented by the formula: -C(0)N(ORy)Rz, where Ry and Rz are as defined above, except they may not be joined together to form a ring.

A "thiocarbamoyl group" is represented by the structural formula: -C(S)N(Ry)Rz where Ry and Rz are as defined above.

A "carboxyl group" is represented by the structural formula: -COOMa where Ma is as defined above.

The term "tetrazolyl" is a heteroaryl group where the point of attachment is the carbon atom of the tetrazole ring and one of the nitrogen atoms is optionally mono-substituted by an alkali metal or a C1-C4 alkyl optionally substituted by Rq.

The term "anionic function" refers to the members of the group: phosphono [P=0(OMa)2]; alkylphosphono {P=0(OMa)-[0 (C1-C4 alkyl)] }; alkylphosphinyl [P=0(OMa)-(Cl-C4alkyl)]; phosphoramido [P=0(OMa)N(Ry)Rz and P=0(OMa)NHRx]; sulfino (Sθ2Ma); sulfo (Sθ3Ma); acylsulfonamides selected from: S02NMaCON(Ry)Rz; and Sθ2NMaCN, where R is phenyl or heteroaryl.

The carbapenems of the present invention contain a ring which has been designated "B". Ring B is fused between the carbapenem 5 membered ring and a phenyl ring. Ring B may be from 6 to 10 membered, optionally containing a heteroatom, such as when X represents NR', O or S(0)χ with x equal to an integer, 0, 1 or 2. When X represents NR', the variable group R' may be hydrogen, acetyl, acetyl substituted with Rq, or Cl to C4 alkyl, optionally substituted with Rq.

Ring B is also formed by the alkylene groups, (CH2)m and (CH2)n which may be present. In certain instances, not all values of m and n are included in combination. When X represents a direct bond, the sum of m and n is between 2 and 6. When X represents any of the

groups other than a bond, the sum of m and n is from 0 to 5. Thus, ring B constitutes a 6 to 10 membered ring.

Preferred values of m and n are such that ring B is six membered, with X preferably representing a direct bond or a heteroatom, O, S or NH.

Variables R3 and R4 independently represent H or lower alkyl.

One of the Ra groups represents a nitrogen containing group, (a) through (d) as described above. The other Ra variables represent an uncharged specie selected from H, the variables for W and NRyRz.

The values of Ra (a) through (d) shown above can be charged or uncharged. For clarity, the positive charge has not been drawn in groups (a) through (d). When the particular nitrogen containing group is drawn as having four points of attachment, such as by attachment to the A moiety, ring bonds, Rd group or groups or RlO, Rl l and Rl2, the nitrogen is considered quaternary and positively charged. When the nitrogen drawn in any of groups (a) through (d) has only three points of attachment, the nitrogen is tertiary and uncharged. Tertiary nitrogen containing groups can be quaternized by standard procedures, such as the Menshutkin reaction. Both charged and uncharged nitrogen-containing compounds are included in the invention.

When one of the Ra variables represents group (a), the spacer moiety -A- forms an alkylene chain, optionally interrupted with a heteroatom or functional group, -Q-. The length of A ranges from a methylene group to an alkyl chain of 12 carbon atoms in length, optionally also containing -Q- noted above. The -A- moiety bonds to the nitrogen containing ring through the N shown, and to the phenyl ring shown.

The heterocyclic group to which -A- bonds may be a heteroaryl group, a partially aromatic heterocycle or a non-aromatic heterocycle, with a substituent Rd optionally bonded to the ring nitrogen. When the heterocycle is aromatic, the ring nitrogen is either uncharged or positively charged by virtue of the attachment to -A-, the

ring bonds and Rd. Rd would not be required to quaternize said ring nitrogen in (a) when the ring is aromatic. Thus, the aromatic, partially aromatic and non-aromatic forms may contain neutral or positively charge nitrogen atoms.

The heterocyclic group may also optionally contain up to three additional nitrogen atoms and up to one oxygen or sulfur atom. The heterocycle can also be substituted with up to three Rc groups at any available points of attachment, either via carbon or nitrogen atoms.

When one of the Ra variables represents group (b), the spacer moiety is -A'- which represents an alkylene group, optionally interrupted with a heteroatom, Q. The ring structure is bonded to -A'- through an atom other than a ring nitrogen. The heterocycle can be aromatic, partially aromatic or non-aromatic. The ring nitrogen is optionally substituted with one or two groups Rd, as desired. When two Rd groups are present on the ring nitrogen which is shown, and the structure is non-aromatic, the nitrogen is positively charged. Also, when the ring is aromatic and one Rd is present on the ring nitrogen, the nitrogen is positively charged. Hence, the nitrogen may have up to two Rd groups present thereon, depending on the particular configuration desired.

Also, up to three Rc groups may be substituted onto the ring, at any available point of attachment.

When the variables and substituent groups are shown with bonds attached, e.g., -A-, -Rc, etc., this is to serve as a point of reference for application to the generic structure, and does not indicate that double or triple bonds are intended.

When one of the Ra variables represents group (c), the spacer moiety -A- represents an optional alkylene group, which in turn is optionally interrupted with Q, which may be a heteroatom, substituted amine, sulfonamide and the like, as described above with respect to group (a). The nitrogen bound to the -A- spacer moiety is either uncharged, such as when Rl2 is absent, or quaternary by virtue of the RlO, Rl 1 and Rl2 groups present thereon and -A- attached thereto.

These R groups may independently represent H, alkyl or substituted alkyl groups.

Alternatively, RlO, Rl 1 and Rl2 may be taken together to represent a C4 to ClO alkanetriyl group, bonded to the nitrogen. Thus, the nitrogen is quaternary.

When one of the Ra variables represents group (d), -A'- is as defined above for group (b). The thioether bridge is attached to the heterocyclic moiety through an atom in the ring other than the nitrogen atom which is shown.

The variable p is either 0 or 1, making the -A'- spacer moiety optional. There is a thioether bridge between the -A'- spacer moiety when present, and the heterocyclic group, or between the phenyl ring to which (d) is attached and the heterocyclic ring which is part of (d).

As noted above with respect to group (b), the nitrogen may be part of an aromatic ring, a partially aromatic heterocycle or a non- aromatic heterocycle and and may be unsubstituted, or substituted. The nitrogen may be quaternary with one or two Rd groups as desired.

In each instance above, one of the Ra variables represents a group selected from (a) through (d) and the other Ra group represents H, NRyRz or one of the values of W.

The bond at position one is shown as a wavy line in many instances. This indicates that the configuration of the carbon atom at position one in the carbapenem is alpha or beta, or the compound is a mixture of isomers. The preferred configuration is beta.

In the compounds of the present invention, the Ra substituent may contribute to the anti-MSRA/MRCNS activity of the overall molecule, or to the other properties of the molecule.

Some Ra substituents may be distinguishable from others chemically or with respect to the biological properties which they confer. In related compounds, it has been found that the charged compounds may afford greater water solubility and reduced potential for CNS side effects. Substituents which tend to confer improved water solubility on the overall compound have been found useful, since they

are contemplated to improve the pharmacokinetics of the compound involved. Although a substantial number and range of Ra substituents has been described herein, all of these are contemplated to be a part of the present invention in connection with the genus of formula I.

When a group is termed "substituted", unless otherwise indicated, this means that the group contains from 1 to 3 substituents Rq thereon. With respect to alkyl groups, the substituents thereon are selected from the variables specified for W. Preferred substituent groups include Cl-4 alkyl, C2-6 alkenyl, C2-6 alkynyl, hydroxy, Cl-4 alkoxy, aryl, heteroaryl, aralkyl, halo, cyano, nitro, carboxyl and the anionic function groups, as these terms are defined above.

When a functional group is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site. Suitable protecting groups for the compounds of the present invention will be recognized from the present application taking into account the level of skill in the art, and with reference to standard textbooks, such as McOmie, J. (ed) Protecting Groups in Organic Chemistry pp. 46-119 (1973).

The preferred compounds of the invention include compounds wherein Rl and R2 include H and substituted lower alkyl, respectively. Preferred substituent groups include F and hydroxy. Particularly preferred are compounds where one of Rl and R is H, and the other is 1 -hydroxyethyl. In the most prefered compounds Rl represents H, and R represents (R) CH3CH(OH)-. The designation (R) defines the absolute configuration of the stereocenter.

The preferred compounds of the invention also include compounds where the uncharged Ra variable represents H, halo, alkylthio, alkylsulfonyl or cyano.

The preferred compounds also include compounds where ring B has 6 or 7 atoms.

One preferred subgenus included in the invention relates to compounds represented by structural formula la:

wherein one Ra represents a group (a) through (d) and the other Ra represents W; W represents any of the groups recited above; Y represents H, a biolabile ester, a pharmaceutically acceptable cation or a negative charge.

Another preferred subgenus included in the invention relates to compounds represented by structural formula lb:

wherein the values of Y, Ra and W are as described above with respect to formula la.

Another preferred subgenus included in the invention relates to compounds represented by structural formula Ic:

wherein the values of Y, Ra and W are as described above with respect to formula la.

Another subgenus included in the invention relates to compounds represented by structural formula Id:

wherein the values of Y, Ra and W are as described above with respect to formula la.

Another subgenus included in the invention relates to compounds represented by structural formula Ie:

wherein the values of Y, Ra and W are as described above with respect to formula la.

Another subgenus included in the invention relates to compounds represented by structural formula If:

wherein the values of Y, Ra and W are as described above with respect to formula la.

Another subgenus included in the invention relates to compounds represented by structural formula Ig:

wherein the values of Y, Ra and W are as described above with respect to formula la.

Another subgenus included in the invention relates to compounds represented by structural formula fli:

wherein the values of Y, Ra and W are as described above with respect to formula la.

Preferred values of Ra type (a) include the following structures:

where the ring contains where the ring contains 3 carbon atoms two carbon atoms

.x: ) -A-N N

-A-N R ^c (0-2 //

N-

N-N

R ^c (0-1)

where X' = O, S, or N.

Where Rc groups are shown to have an indefinite position, they are attached to any available site of the ring. Also, in fused heterocycles, where more than one Rc group is shown, this means that substitution with up to three Rc can be present. Hence, when Rc appears twice in a two ring structure, there can be up to three such Rc groups in the rings.

Preferred values of Ra type (b) include:

R ^d

-A'- L M H ₍₀ . ₂₎ -A'* k J1 ^H (0-3) INT

R ^c

where the ring contains three carbon atoms;

-A'

X'

where X' = O or S.

For structures of type (b), where Rc and/or A' are shown to have indefinite positions, they are independently attached to any available atom of the ring.

Preferred Ra type (c) substituents include: -A _p -N(CH3)3 ⁺ , -A _p -N(CH3)(CH2CH3)2 ⁺ ,

-A _p -N(CH3)2CH2Rq ⁺ -A _p -N(CH2CH3)2CH2CH2R ⁽ 1 ⁺ ;

-A _p -Ng ^Rt

Preferred Ra type (d) values include:

The preferred compounds are zwitterionic by virtue of a positively charged nitrogen atom in group (a)-(d) and a negatively charged carboxylate group (Y represents a negative charge). The scope of Rc includes those groups suitable for attachment to ring carbon and nitrogen atoms. Persons skilled in the art will readily recognize that a wide range of organic substituents are suitably used as R . Persons skilled in the art will also recognize that some substituents, such as the -NRyRz substituents, are useful carbon substitution but not equally useful for nitrogen substitution.

Preferred Rc groups attached to ring carbon atoms are -NH2, -SCH3, -SOCH3, -CH20H, -(CH2)20H, -OCH3, -COOMb, -CH2COOMb, -CH2CH2COOMb, -CH2SOCH3, -CH2SCH3, -Sθ3Mb, -CH2S03Mb, -CH2CH2S03Mb, -Br, -Cl, -F, -I, -CH3, -CH2CH3, -CH2CONH2 and -CH2CON(Cl-C4alkyl)2 where Mb is defined above. Preferred Rc groups attached to ring nitrogen atoms are -CH2OH, -(CH2)20H, -CH2COOMb, -CH2CH2COOMb, -CH2SOCH3, -CH2SCH3, -CH2S03Mb, -CH2CH2S03Mb, -CH3, -CH2CH3, -CH2CONH2 and -CH2CON(Cl-C4alkyl)2 where Mb is defined above.

Preferred A spacer moieties include -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -OCH2CH2-, -SOCH2-, -SO2CH2-, -SCH2CH2-, -SOCH2CH2-, -SO2CH2CH2-, -NHCH2CH2-, -N(CH3)CH2CH2-, -CH2N(CH3)CH2CH2-, -CONHCH2CH2-, -SO2NHCH2CH2-, -COCH2-, -CH=CHCH2- and -CH2OCH2CH2-. Preferably, where Q is O, S, NH or N(Cl-4 alkyl), then r plus s is 2-6.

Preferred -A'- groups include the preferred groups listed for A above. Further, A' may represent -0-, -S-, -NH-, -SO2-, -SO2NH-, -CONH-, -CH=CH-, -CH2S-, -CH2NH-, -CONHCH2- or -SO2NHCH2-.

In X, when X represents S(0)χ, the preferred value of x is zero, and when X represents NR', the preferred value of R' is H.

In Ra and W, when these variables represent alkoxy substituted with Rq, the preferred Rq values are -OH, -OCH3, -CF3 and -Cθ2Ma. In -COOMa, the preferred values of Ma are H and methyl.

When Ra or W represents -OC(0)Rs, the preferred Rs values are Cl-4 alkyl and substituted Cl-4 alkyl.

When Ra or W represents -OC(0)NRyRz, the preferred Ry and Rz values are H, lower alkyl and C4-5 alkylidene.

When Ra or W represents -S(0)χ-Rs, x preferably is zero, and Rs is preferably alkyl.

When Ra or W represents -Sθ2NRyRz, Ry and Rz preferably represent H, lower alkyl or are taken together to represent a C4-5 alkylidene group.

When Ra or W represents -N(Rt)C(0)H, -N(Rt)C(0)- Cl-4 alkyl or substituted alkyl, -N(Rt)C(0)OCl-4 alkyl or substituted alkyl, -N(Rt)C(0)NRyRz or -NRtSθ2Rs, the preferred Rt groups are H and Cl-4 lower alkyl.

When Ra or W represents a C5-7 cycloalkyl group where one carbon is replaced with a heteroatom, -NH-, O, or -S(0)χ-, the preferred heteroatom is nitrogen, either -NH- or -N(Ci-4 alkyl)-.

When Ra or W represents an alkenyl group, the preferred alkenyl group is allyl, -CH2CH=CH2.

Among the more preferred Ra groups are Cl-4 alkyl mono-substituted with hydroxy, such as, hydroxymethyl; formyl; carbamoyl, such as, -CONH2; cyano; halo, such as iodo; Cl to C4 alkylthio, such as methylthio and its dioxides, such as -SO2CH3; and mono-substituted C2 to C4 alkylthio, such as hydroxyethylthio, -SCH2CH2OH.

In addition to the above, examples of the more preferred Ra and W groups include:

-OCH3 -OCH2CH20H -OCH2C02Me

-F -CF3

-Br -Cl

-OH -I

-OCONH2 -OCOCH3

-SOCH3 -SCH3

-SCH2CH2OH -SO2CH3

-SO2NH2 -SOCH2CH2OH

-NHCHO -S02N(CH3)2

-NHCO2CH3 -NHCOCH3

-CN -NHSO2CH3

-COCH3 -CHO

-CH=NOH -COCH2OH

-CH=NOCH2C02Me -CH=NOCH3

-SO2CH2CH2OH -CH=NOCMe2C02Me

-CH=NOCMe2C02Me -CO2CH2CH2OH

-CONH2 -CONHCH3

-CON(CH3)2 -CONHCH2CN

-CONHCH2CONH2 -CONHCH2C02Me

-CONHOH -CONHCH3

-tetrazolyl -C02Me

-SCF3 -P03HMe

-CONHS02Ph -CONHSO2NH2

-S03Me -SO2NHCN

-SO2NHCONH2 -CH=CHCN

-CH=CHCONH2 -CH=CHC02Me -C≡C-CONH2 -C≡C-CN -CH20H -CH2N3 -CH2C02Me and -CH2I.

Listed below are the more preferred compounds of the invention. The following numbering system applies:

wherein the representation of Ra includes attachment in either aromatic ring, at positions 1 ', 6', 7', or 8'. The most preferred compounds of the invention include the following:

Compounds where m and n represent 1; m represents 1 and n represents zero; and m represents 2 and n represents zero;

X represents a bond, -0-, -S-, -SO2-, -C(O)-, -NH-, -CH=CH- and -C(0)NH-;

Y represents a negative charge and R is selected from:

Pr = propyl Et = ethyl

The compounds of the invention can be synthesized in accordance with the following general schemes and examples.

GENERAL SYNTHESIS OF SUBSTITUTED- PHENYL-SUBSΗTUTED TETRALONES

HPNNHC

Wherein R ^a is as previously defined and X is Br, I, or OTf. PPA = polyphosphoric acid

SYNTHESIS OF SUBSΗTUTED-PHENYL- OXO-4-H-BENZOPYRAN AND THIOPYRAN

Wherein R ^a and X = O, S

SCHEME I

SYNTHESIS OF OUADRACYCLIC-CARBAPENEMS

PG = Protecting Group TMSOTF = trimethylsilyltriflate

SCHEME I

SYNTHESIS OF OUADRACYCLIC-CARBAPENEMS (CONT'D)

CHANGE Y

Wherein PG, X, R ^a , and Y are as previously defined.

SCHEME H

SYNTHESIS OF OUADRACYCLIC-CARBAPENEMS

SCHEME π

SYNTHESIS OF OUADRACYCLIC-CARBAPENEMS f CONT'D)

REMOVE PG

Wherein PG, X, W, R ^a , and Y are as previously defined.

SCHEME m

SYNTHESIS OF OUADRACYCLIC-CARBAPENEMS

1 ) SEPARATE 2) CICOC0 ₂ Y '

SCHEME m

SYNTHESIS OF OUADRACYCLIC-CARBAPENEMS (CONT'D)

Wherein and Y are as previously defined. Tf ₂ 0 = triflic anhydride

SCHEME IV

SYNTHESIS OF OUADRACYCLIC-CARBAPENEMS

1 ) SEPARATE

2) CICOC0 ₂ Y

SCHEME IV

SYNTHESIS OF OUADRACYCLIC-CARBAPENEMS (CONT'D)

Wherein PG, PG', and Y are as previously defined.

SCHEME V

SYNTHESIS OF OUADRACYCLIC-CARBAPENEMS

1) SEPARATE 2)CICOC0 ₂ Y '

SCHEME V

SYNTHESIS OF OUADRACYCLIC-CARBAPENEMS

REMOVE PG'

CHANGE Y *»

REMOVE PG

Wherein PG, PG', and Y are as previously defined.

The syntheses of compounds I are outlined in Schemes I, II, and HI, which depict strategies that progress from the most general to the more specific. Basically, the skeletal arrangement of these molecules can be assembled in three key stages. Initially, the known,

appropriately substituted acetoxyazetidinone is reacted with a cyclo- alkanonylaromatic compound in the presence of a tertiary amine base such as triethylamine, diisopropylethylamine, pyridine or the like, and a silylating agent such as trimethylsilyltrifluoromethanesulfonate, in a solvent such as dichloromethane, acetonitrile or the like, at a temperature of from -23°C to ambient temperatures, for from 1 to 24 hours, in an inert atmosphere. The reaction is such that the cycloalkanone is converted in situ to its corresponding silylenolether derivative, which in turn reacts with the activated form of the azetidinone, brought about by the the interaction of the acetoxy¬ azetidinone with a relatively small percentage of the trimethyl- silyltrifluoromethanesulfonate, to form a carbon-carbon bond from C-4 of the azetidinone to the alpha carbon of the cycloalkanone. The latter constitutes a new stereocenter in the adduct, and the ratio of the resulting diastereomers is typically almost equal. The isomers maybe separated by standard techniques and processed individually. Alternatively, the silylenolether derivative of the cycloalkanone may be produced in a separate operation and then brought into interaction with the acetoxyazetidinone derivative and an activating agent or Lewis acid such as trimethylsilyltrifluoromethanesulfonate, zinc chloride, zinc iodide, boron-trifluoride etherate, stannous chloride, tin triflate, titanium trichloride, aluminium chloride or the like, in aprotic solvents such as dichloromethane, acetonitrile, benzene, THF, hexane or the like. In this way, the stereochemical outcome of the reaction maybe altered to produce a predominance of one isomer or the other.

The second key stage is the conversion of the newly formed azetidinone to the corresponding Wittig intermediate via the "oxalimide process". This conversion is accomplished in two steps and begins with the reaction of the azetidinone and the known, appropriately protected chlorooxalylester reagent, in the presence of a suitable base such as pyridine, triethylamine or the like, in an inert solvent such a dichloromethane, toluene, or the like, from a temperature of from -23 °C to ambient temperatures, for from a few minutes to several hours. Typically the oxalimide which is rapidly formed is isolated by

conventional techniques and may be similarly purified or, more conveniently, used directly in the second step of the process. Here the oxalimide is heated with a large excess (10-20 equivalents) of an alkoxyphosphine reagent such as triethoxyphosphine, diethoxymethyl- phosphine, or the like, in an inert solvent such as benzene, toluene, xylene, or the like, at a temperature of from 50°C to 120°C for from a few minutes to several hours. The resulting alkoxyphosphorane intermediate is typically not isolated due to its hydrolytic lability, but instead can be used in situ in the final stage of the synthesis.

The last key stage involves the thermal cyclization of the alkoxyphosphorane intermediate in an inert solvent such as benzene, toluene, xylene or the like, at refluxing temperatures, in an inert atmosphere of nitrogen or helium, in the presence of a trace of hydroquinone, for from an hour to five days.

At this juncture, the remaining number of steps to complete the synthesis of the compounds I of the invention may vary. In cases where a hydroxyl group is present in the group at C-6 of the carbapenem nucleus or on the aromatic C-2 appendage, and it is covered with a protecting group (PG), the protecting group(s) maybe removed by established methods, which are discussed further below. In this instance, and in examples requiring no further chemistry at this stage, the carboxyl protecting group is analogously removed to affect the formation of I. Examples of this procedure are outlined in Schemes I and II.

On the other hand, prior to the removal of the carboxyl protecting group, additional chemistry maybe performed which allows for the introduction of functionality consistent with the scope of the invention. For example, Scheme HI depicts a chemoselective activation of a benzylic type hydroxyl group and subsequent displacement with nucleophiles, described herein, to generate penultimate intermediates to the desired I. This process is further detailed below.

Other examples of chemical transformations which can be implemented at the carbapenem stage of the synthesis provide for

certain definitions of X and Z, including, e.g., oxidation at a sulfur atom to provide either the corresponding sulfoxide or sulfone.

The starting materials for the initial stage of the foregoing sequence are either known in the art or can be readily prepared by established methods. In this regard the following references may be applicable:

5-pheny 1-1 -tetralone: K. Itoh, et al., Chem. Pharm. Bull., 32, 130(1984); 6-phenyl-l-tetralone: K. Itoh, et al, ibid.; M. S. Newman and H. V. Zahm, J. Amer. Chem. Soc, 65, 1097(1943); N. L. Allinger and E. S. Jones, /. Org. Chem., 27, 70(1962); 7-phenyl-l- tetralone: R. Buckle, et al, J. Medicinal Chem., 20, 1059(1977); M. Weizmann, et al, Chemistry and Industry, 402(1940); A. R. Katritzky and C. M. Marson, J. Chem. Soc, Perkin II, 1455(1983); 7-bromo-l- tetralone: L. F. Fieser and A. M. Seligman, J. Amer. Chem. Soc, 60, 170(1938); 6-amino-l -tetralone: N. L. Allinger and E. S. Jones, supra.

For syntheses involving the Suzuki reaction, see A. Suzuki, et al, Syn. Comm., 11, 513(1981); and related chemistry: Wiley, P.F., J. Amer. Chem. Soc, 73, 4205(1951); Flemming, W., et al, Chem. Ber., 58, 1612(1925); N. Miyaura, T. Yanagi, and A. Suzuki, Syn. Comm., 11, 513(1981); V. Snieckus, et al., J. Org. Chem., 56, 3763(1991); V. N. Kalinin, Synthesis, 413, (1992); V. Snieckus, et al, Tet. Letters, 29, 5459(1988); V. Snieckus and M. A. Siddiqui, ibid, 5463(1988).

For coupling to a known azetidinone to the side chain using Lewis acid catalysis, see, e.g., A.G.M. Barrett & P. Quayle, /. Chem. Soc. Chem. Comm. 1076(1981); Reider, P.J., et al, Tet. Let. 23, 2293 (1982); Hirai, K. et al, Heterocycles 17, 201 (1982); R. P. Attrill, A./G.M. Barrett, P. Quayle, J. Van der Westhuizen & M. J. Betts, J. Org. Chem. 49, 1679 (1984).

The synthesis, substitution and elaboration of dibenzofurans and dibenzothiophenes has been well reviewed in the literature: M.V. Sargent & P.O Stransky, Adv. Heterocycl. Chem. 35, 1-81 (1984); W.E. Parham Heterocyclyl. Comp., 2, 123 (1951); R. Livingstone in

Rodd's Chemistry of Carbon Compounds, 2d ed. Vol. IV Part A, Heterocyclic Compounds, 194-202 (1973); F.M. Dean and M.V. Sargent in Comprehensive Heterocyclic Chemistry, Vol. 4, Part 3, 599 (1979); J. Ashby & C.C. Cook, Adv. Heterocycl. Comp. 2, 164 (1951); R. Livingstone in Rodd's Chemistry of Carbon Compounds, 2d ed., Vol. IV, Part A, Heterocyclic Compounds, 300-305 (1973); S. Rajappa in Comprehensive Heterocyclic Chemistry, Vol. 4, Part 3, 741 (1979); E. Campaigne, ibid., 863 (1979).

In Scheme V, the hydroxymethyl precursor substituent may be elaborated into the desired substituent group by converting the hydroxyl into an active leaving group such as an iodide (giving -A-I), followed by reaction with a desired nitrogen containing aromatic compound. More particularly, two alternative procedures may be utilized to produce a leaving group on the moiety -A- and subsequently to replace such a leaving group with the desired substituent.

For the first procedure, the hydroxyl group of -A-OH may be converted to a methanesulfonate group by treating with methane- sulfonyl chloride (MsCl) in the presence of triethylamine. A suitable solvent, e.g., dichloromethane, is employed and the reaction is carried out at reduced temperatures. In turn, the methanesulfonate intermediate may be converted to the reactive iodide derivative by treatment with sodium iodide in a suitable solvent, e.g., acetone, at reduced or ambient temperatures. Alternatively, the hydroxyl group may be directly converted into the iodide group by common methods known to the art. For example, treatment of the hydroxyl group with methyl triphenoxy- phosphonium iodide in a suitable solvent, such as dimethylformamide, at reduced or ambient temperatures, directly provides the desired iodide. Once the iodide has been formed, the introduction of the desired substituent is accomplished simply by treating the iodide with the desired nitrogen containing compound, e.g. a heteroaromatic compound such as pyridine. The reaction will proceed in a suitable solvent, such as acetonitrile, at or about room temperature. This displacement reaction may also be facilitated by the addition of excess silver

trifluoromethanesulfonate to the reaction mixture, in which case reduced temperatures are often desirable.

In a second procedure, the hydroxyl group of -A-OH may be converted into the reactive trifluoromethanesulfonate (triflate) group (Scheme IV). However, such an activating group cannot be isolated by conventional techniques but may be formed and used in situ. Thus, treatment of the hydroxyl group with a slight excess of trifluoro- methanesulfonic (triflic) anhydride in the presence of a hindered, non- nucleophilic base such as 2,6-lutidine, 2,4,6-collidine, or 2,6-di-tert- butyl-4-methyl-pyridine in a suitable solvent, such as dichloromethane, at reduced temperatures provides for the generation of the triflate activating group. Introduction of the desired group is then accomplished by reacting the above triflate in situ with the desired nitrogen containing compound at reduced temperature.

In certain cases it is possible and desirable to use the reactive nitrogen containing compound as the base for the formation of the triflate activating group. In this case, treatment of the hydroxyl group with triflic anhydride in the presence of at least two equivalents of the reacting nitrogen compound under the conditions described above provides the desired N-containing substituent.

Where the N ring contains substitution with a substituent Rc, the most facile method of providing such a substituent is to employ as the reactant in the preparation methods described above a nitrogen containing compound which already has the desired Rc substituent in place. Such substituted compounds are readily available starting materials or may be prepared in a straightforward manner using known literature methods.

In one suggested synthesis, the hydroxyl may be converted to a reactive leaving group such as iodo, which is then reacted in a nucleophilic displacement reaction with a nitrogen containing aromatic compound which has a nucleophilic side-chain substituent such as CH2SH or CH2NH2. In this displacement reaction, it is the side-chain substituent that is the reacting nucleophile and not the aromatic ring nitrogen. Suitable substrates for this reaction include 2-(mercapto-

methyl)pyridine, 2-amino-pyridine, 2-(aminomethyl)pyridine or 4- (mercaptomethyl)-pyridine. The reaction is carried-out in an inert organic solvent, e.g., methylene chloride, at from about 0°C to room temperature in the presence of a non-nucleophilic base such as triethylamine or diisopropylethylamine.

A second suggested synthesis starting from a precursor A'- OH (e.g. hydroxymethyl) consists of oxidation of the alcohol functionally to an aldehyde followed by Wittig-type olefination with an appropriate nitrogen-containing aromatic substituted reagent. The oxidation may be conveniently accomplished by a Swern oxidation employing oxalyl chloride-dimethylsulfoxide followed by triethylamine. The reaction is conducted in methylene chloride as a solvent at from -70°C to 0°C. The Wittig reaction is carried-out by reacting the aldehyde with the desired Wittig reagent in a polar solvent such as acetonitrile or dimethylsulfoxide at about room temperature. Suitable Wittig reagents include: pyridylmethylene-triphenylphosphorane, quinolylmethylenetriphenylphosphorane and thiazolylmethylene- triphenylphosphorane. Depending on the particular Ra group desired, many other synthesis schemes may be employed, as would be apparent to an organic chemist skilled in the art.

Compounds where Ra represents type (c) may be prepared in an analogous manner to that described for type (a) substituents, except that the nitrogen containing compound employed in the displacement reaction is an aliphatic amine (i.e., NRyRz). In cases where the amino group is directly bonded to the ring nucleus (i.e., -ApNRyRz where p=0) the amine is most conveniently attached to the ring structure prior to its incorporation into the carbapenem system.

If such an amine is primary or secondary, it may require protection with a suitable amine protecting group during the steps employed to attach the ring structure to the carbapenem. Tertiary amines typically require no protection.

Compounds where Ra represents (d) may be prepared by reacting the compound A'p-S-L (Leaving Group) with an N containing ring, prior to connection to the carbapenem. In the preparation

methods described above, the carboxyl group at the 3 -position and the hydroxyl group at the 8-position of the preferred carbapenem remain blocked by protecting groups until the final product is prepared. Deblocking may be carried out in a conventional manner. For compounds prepared according to the Flow Sheets, below deprotection may be carried out first by desilylation using tetrabutylammonium fluoride and acetic acid and second by deallylation using a palladium catalyzed reaction in a solution containing potassium 2-ethylhexanoate or, alternatively, another suitable nucleophile such as pyrrolidine. Alternatively, deprotection may be conducted sequentially. Thus, the protected precusor compound is exposed initially to aqueous acidic conditions, acetic acid or dilute HCI or the like, in an organic solvent such as tetrahydrofuran at 0°C to 50°C for from a few minutes to several hours. The resulting desilylated carbapenem may be isolated by conventional techniques, but is more conveniently taken into the final deprotection process. Thus, addition of an inorganic base such as NaHC03 or KHCO3 or buffer such as sodium phosphate and 10% Pd/C followed by hydrogenation provides for the removal of the p-nitro- benzyl protecting group and the formation of the final compound of Formula I.

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, salt or hydrate," refers to those salts, esters and hydrated forms of the compounds of the present invention which would be apparent to the pharmaceutical chemist, i.e., those which are substantially non-toxic and which may 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 selection, are cost of the raw 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.

The pharmaceutically acceptable salts referred to above may take the form -COOY. The Y may be an alkali metal cation such as sodium or potassium. Other pharmaceutically acceptable cations for Y may be calcium, magnesium, zinc, ammonium, or alkylammonium cations such as tetramethylammonium, tetrabutyl-ammonium, choline, triethylhydroammonium, meglumine, triethanolhydroammonium, etc.

The pharmaceutically acceptable salts referred to above may 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, cyclopentane- propionate, 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 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. Included within such pharmaceutically acceptable esters are those which are hydrolyzed under physiological conditions, such as pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, and others described in detail in U.S. Pat. No. 4,479,947. The esters which are hydrolizable under physiological conditions are also referred to as "biolabile esters". Many biolabile esters have oral activity, protecting the drug from excessive acid degradation upon oral administration.

Some of the groups which Y represents form biolabile esters with the carboxylate to which Y is attached. Biolabile exters are biologically hydrolizable, and many are suitable for oral administration, due to good absorption through the stomach or intenstinal mucosa, resistance to gastric acid degradation and other factors. Examples of biolabile esters include compounds in which Y represents an alkoxyalkyl, cycloalkoxyalkyl, alkenyloxyalkyl, aryloxyalkyl, alkoxyaryl, alkylthioalkyl, cycloalkylthioalkyl, alkenylthioalkyl, arylthioalkyl or alkylthioaryl group. All of these groups can be substituted in the alkyl or aryl portions thereof with acyl or halo groups. The following Y species are preferred as biolabile ester forming moieties.: acetoxymethyl, 1-acetoxyethyl, 1-acetoxypropyl, pivaloyloxymethyl, 1-isopropyloxycarbonyloxyethyl, 1-cyclohexyl- oxycarbonyloxyethyl, phthalidyl and (2-oxo-5-methyl-l,3-dioxolen-4- yl)methyl.

Some of the novel carbapenem compounds of the present invention take the form COOY, where Y is a readily removable carboxyl protecting group. Such conventional groups consist of known groups which are used to protectively block the carboxyl group during the synthesis procedures described therein. These conventional 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 a transition metal catalyst and a nucleophile and catalytic hydrogenation. Examples of such ester protecting groups include benzhydryl, p-nitrobenzyl, 2- naphthylmethyl, allyl, benzyl, trichloroethyl, silyl such as trimethylsilyl or trimethylsilylethyl, phenacyl, p-methoxybenzyl, acetonyl, o- nitrobenzyl, p-methoxyphenyl, 4-pyridylmethyl, and t-butyl.

Likewise, the hydroxy group at position 8 can be protected as appropriate to facilitate the syntheses described herein.

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 compositions in concentrations ranging from about 0.01 to about 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.

Many of compounds of the present invention are biologically active against MRSA/MRCNS. This is demonstrated below using the following biological activity protocol.

In vitro antibacterial activity determined in accordance with the protocol set forth below is predictive of in vivo activity, when the compounds are administered to a mammal infected with a susceptible bacterial organism.

Minimum inhibitory concentrations for different compounds may be calculated using the procedures set forth in Lorian, V. (ed.) Antibiotics in Laboratory Medicine (3rd ed.) pages 30-35 if desired. However, by comparing disc sensitivities to a known compound, e.g., imipenem, this calculation is not required to recognize MRSA/MRCNS activity.

Assay Used to Test the Activities of Carbapenems Against Methicillin-Resistant Staphylococci: The assay is an antibiotic disc¬ diffusion assay modeled after the method described by Bauer and Kirby, et al, with the following modifications and clarifications:

Agar: This assay employs an agar depth of 2 mm instead of 4 mm.

Zone Readings: The inner, compeltely clear zone is measured.

Culture Storage: Frozen vials of strains are stored at -80°C. Working slants are prepared from frozen vials and are used for 1 month to 6 weeks. For methicillin-resistant strains the slant medium is Mueller Hinton Agar; for control strains the slant medium is Brain Heart Infusion Agar. After inoculation from frozen vials, methicillin- resistant slant cultures are incubated at 28 °C until good growth is achieved (approximately 20 hours); slants of control strains are incubated at 37°C for 16-18 hours.

Preparation of Control Inocula for Assay: Pipet 2 ml Brain Heart Infusion Broth (BHIB ) into a sterile, plastic 17 x 100 mm tube. Use a sterile cotton tipped applicator to pick up a very small amount of culture from the slant and twirl it in the BHIB to achieve a light but visible inoculum (approximately 1 x 106-107 cuf/ml). Incubate at 37°C and 220 rpm for 17-18 hours.

Preparation of Methicillin-Resistant Inocula for Assay: For methicillin-resistant strains, inoculate 0.5 ml of BHIB heavily (to achieve appromaitely 1 x 108-109 cfu/ml) from the slant culture by using a sterile cotton tipped applicator. With the applicator spread approximately 0J ml of the suspension onto the surface of a 15 x 100 mm petri plate containing 10 ml Mueller Hinton Agar. Incubate the plate at 30°C for approximately 18 hours.

Inoculum Adjustment: The 17-18 hour control Staphylococci cultures are diluted 100 x in phosphate-buffered saline (PBS).

Methicillin-resistant Staphylococci: With a cotton tipped applicator, swab enough growth off the grown plates into 1 ml BHIB to achieve a visual concentration of approximately 1 x 109 cfu/ml. Mix vigorously and dilute in PBS so that dilutions appear visually to be slightly more concentrated than the 100 x diluted control cultures. Measure % transmission (%T) at 660 nm in a Spectronic 20 or other spectrophotometer. Add measured quantities of PBS to dilutions to achieve %T @ 1 % above or below the %T measurement for the control cultures. Make sterile dilutions using the same proprotions.

Plate Incubation Following Plate Inoculation and Disc Placement: Incubate control plates for 18 hours at 37°C. Incubate methicillin-resistant Staphylococci plates for 18 hours at 30°C.

Using the tests described above, the compounds of the invention are active against MRSA, as demonstrated in the following table. Imipenem is the standard, and is assigned a relative activity level of 1. The other compounds have the activity which is indicated relative to that of imipenem.

TABLE

Compound Relative Activity

Imipenem

(MIC = 46mg/mL 1.0

Based upon the foregoing, the compounds of the present invention exhibits activity against MRSA (Strain MB #5180) which is unexpected.

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

Compositions for injection, a preferred route of delivery, may be prepared in unit dosage form in ampules, or in multidose containers. The injectable compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulating agents. Alternatively, the active ingredient may be in powder (lyophillized or non-lyophillized) form 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.

Oral compositions may take such forms as tablets, capsules, oral suspensions and oral solutions. The oral compositions may utilize conventional formulating agents, and may include sustained release properties as well as rapid delivery forms.

The dosage to be administered depends to a large extent upon the condition and size of the subject being treated, the route and frequency of administration, the sensitivity of the pathogen to the particular compound selected, the virulence of the infection and other factors. Such matters, however, are left to the routine discretion of the physician according to principles of treatment well known in the antibacterial arts. Another factor influencing the precise dosage regimen, apart from the nature of the infection and peculiar identity of the individual being treated, is the molecular weight of the compound.

The compositions for human delivery per unit dosage, whether liquid or solid, may contain from about 0.01% to as high as

about 99% of active material, the preferred range being from about 10- 60%. The composition will generally contain from about 15 mg to about 2.5 g 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 will typically include the pure compound in sterile water solution or in the form of a soluble powder intended for solution, which can be adjusted to neutral pH and isotonic.

The preferred methods of administration of the Formula I antibacterial compounds include oral and parenteral, e.g., i.v. infusion, i.v. bolus and i.m. injection.

For adults, about 5-50 mg of Formula I antibacterial compound per kg of body weight given one to four times daily is preferred. The preferred dosage is 250 mg to 1000 mg of the antibacterial given one to four times per day. More specifically, for mild infections a dose of about 250 mg two or three times daily is recommended. For moderate infections against highly susceptible gram positive organisms a dose of about 500 mg three or four is recommended. For severe, life-threatening infections against organisms at the upper limits of sensitivity to the antibiotic, a dose of about 1000- 2000 mg three to four times daily may be recommended.

For children, a dose of about 5-25 mg/kg of body weight given 2, 3, or 4 times per day is preferred; a dose of 10 mg/kg is typically recommended.

The compounds of Formula I are of the broad class known as carbapenems. Many 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, on the other hand, are less subject to such attack, and therefore 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 carbapenems are disclosed in, e.g., [European Patent Application Nos.

79102616.4, filed July 24, 1979 (Patent No. 0 007 614); and 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.

A preferred DHP inhibitor is 7-(L-2-amino-2-carboxy- ethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-hepteno ic acid or a useful salt thereof.

The invention is further described in connection with the following non-limiting examples.

PREPARATIVE EXAMPLE 1

Preparation of Tetralone Derivative

OSi(Ph) ₂ CMe ₂

The 7-bromo-l -tetralone (2.07 g, 9.21 mmole), the boronic acid derivative (5.4 g, 13.8 mmole), from example tetrakistriphenyl- phosphinepalladium (531 mg, 0.46 mmole), and 8.4 mL (16.8 mmole) of a 2.0 aqueous solution of sodium carbonate were combined and stirred in 20 mL of toluene and 10 mL of ethanol at reflux for 3 hour. The cooled mixture was partitioned between diethyl ether and water and the organic phase was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated. Purification by column chromatography on silica gel eluted with dichloromethane-pet. ether (1:1) gave 4.53 g (100%) of the product. IH NMR (CDC13) δ: 1.12 (s, 9H), 2.18 (p, J=6Hz, 2H), 2.71 (t, J=6Hz, 2H), 3.02 (t, J=6Hz, 2H), 7.32-7.76 (m, 16H), and 8.3 (d, J=2Hz, IH).

PREPARATIVE EXAMPLE 2

Preparation of Tetralone Stannane

The 7 -bromo-1 -tetralone (225 mg, 1.0 mmole), 655.2 mg (2.0 mmole) of hexamethylditin, tetrakistriphenylphosphine-palladium (57.7 mg, 0.05 mmole), and 26.2 mg (0.1 mmole) of triphenyl- phosphine were combined and stirred in 3 mL of toluene at 100°C for 1 hour. The cooled mixture was partitioned between ethyl acetate and ice-water and the organic phase was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated. Purification by plate-layer chromatography on silica gel eluted with dichloro¬ methane-pet. ether (2:1) gave 307.2 mg (99%) of the stannane. IH NMR (CDCI3) δ: 0.16-0.44 (m, 9H), 2.16 (p, J=6Hz, 2H), 2.69 (t, J=6Hz, 2H), 2.95 (t, J=6Hz, 2H), 7.22 (d, J=7.9Hz, IH), 7.6 (dd, J=1.2 and 7.9Hz, IH), and 8.16 (bs, IH).

PREPARATIVE EXAMPLE 3

Preparation of Tetralone Derivative

The 7-trimethylstannyl-l -tetralone (294J mg, 0.95 mmole), 262.8 mg (0.95 mmole) of ethyl-2-iodo-benzoate,19.8 mg (0.02 mmole) trisdibenzylideneacetonedipalladium-chloroform catalyst and 144.5 mg (0.1 mmole) of diisopropyl-ammonium hydrochloride were combined and stirred in 3 mL of N-methylpyrrolidinone at room temperature for 1.5 hour. The mixture was partitioned between diethyl ether and ice-water and the organic phase was separated, washed twice with water and then brine, dried over anhydrous sodium sulfate, filtered, and evaporated. Purification by plate-layer chromatography on silica gel eluted with dichloromethane-pet. ether (3:1) gave 214.7 mg (77%) of the coupled product.

IH NMR (CDCl 3) δ: 1.11 (t, J=7Hz, 3H), 2.18 (p, J=6Hz, 2H), 2.65 (t, J=6Hz, 2H), 3.02 (t, J=6Hz, 2H), 4.14 (q, J=7Hz, 2H), 7.29-7.54 (m, 5H), 7.87 (dd, J=1.9 and 6.7Hz, IH), and 8.0 (d, J=1.9Hz, IH). IR(CH2C12) cm-1: 1720 and 1683.

PREPARATIVE EXAMPLE 4

Preparation of Acid Tetralone Derivative

A stirred mixture of 197.6 mg (0.67 mmole) of the tetralone ester derivative and 282.1 μL (1.41 mmole) of 57V NaOH solution in 3 mL of methanol was stirred at ambient temperature for 16 hours, and then refluxed for 3 hours. The cooled mixture was concentrated in vacuo, diluted with water and extracted with ether. The separated aqueous layer was acidified with 2N HCI and extracted with ether. The extract was dried over anhydrous sodium sulfate, filtered, and evaporated to give 112 mg (63%) of the tetralone acid derivative as a colorless foam.

IH NMR (CDC13) δ: 2.2 (p, J=6Hz, 2H), 2.7 (t, J=6Hz, 2H), 3.02 (t, J=6Hz, 2H), 7.24-7.6 (m, 5H), 7.98 (m, IH), and 8.04 (m, IH).

PREPARATIVE EXAMPLE 5

Preparation of 4-t-Butyldiphenylsiloxymethylbromobenzene

Ph

CH ₂ OSiCMe ₃

Ph

To a stirred solution of 7.48 g (40 mmoles) of p-bromo- benzyl alcohol and 6.07 g (60 mmoles) of triethylamine in 70 mL of

sieve dried DMF at 0°C was added 14.3 g (52 mmoles) of neat t-butyl- diphenylsilylchloride. The ice-water bath was removed and the mixture was stirred further for 20 hours.

The mixture was partitioned between ether, ice-water, and 27V hydrochloric acid, and the organic phase was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and evaporated.

Purification by column chromatography on 200 g of EM- 60 silica gel eluting with hexanes-methylene chloride (3:1) gave 15.9 g (94%) of the title compound.

NMR (CDCL3) δ: 1.1 (S, 9H), 4.72 (S, 2H), 7.22 (D, J=8.3 HZ, 2H), 7.43 (M, 8H), 7.7 (M, 4H).

PREPARATIVE EXAMPLE 6

Preparation of 4-t-butyldiphenylsiloxymethylphenylboronic acid

Ph

Br— ~ CH ₂ OSiCMe ₃ ¹ ) ^BuLi

Ph 2) B(0-i-Pr) ₃

To a stirred solution of p-t-butylidiphenylsiloxymethyl- bromobenzene (10J g, 23.8 mmoles) in 100 mL of dry tetrahydrofuran at -78°C under nitrogen was added dropwise 9.9 mL (25.0 mmoles) of 2.5 n-butyllithium in hexane. The mixture was stirred at -78°C for 15 minutes and 4.7 g (25.0 mmoles) of triisopropylborate was added. After 5 minutes, the low temperature bath was removed, and the mixture was stirred further for 1.5 hours.

The mixture was poured onto ice-27V hydrochloric acid and ether was added. The biphasic mixture was stirred for 0.5 hour and the organic phase was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated to give 8.8 g (94.2% of crude product).

Precipitation from an ether-methylene chloride solution of the crude material with hexanes gave 7.1 g (76%) from two crops.

EXAMPLE 1

Preparation of Azetidinone 1

To a stirred mixture of 3.68 g (12.7 mmole) of azetidinone, 4.26 g (19 mmole) of 7-phenyltetralone, and 2.59 g (25.6 mmole) of triethylamine in 50 mL of sieve dried dichloromethane at 0°C was added 6.26 g (28J mmole) of trimethylsilyl triflate. The resulting mixture was stirred under an inert atmosphere of nitrogen at 0°C for four hours. The mixture was partitioned between diethyl ether, ice-water, and 27V hydrochloric acid. The organic phase was separated,

washed with brine and then saturated sodium bicarbonate and sodium chloride, dried over anhydrous sodium sulfate, filtered, and evaporated.

The residue was purified by silica gel chromatography using toluene-diethyl ether(3:l) as eluant, to give 5.5 g (95%) of the product mixture 1. By a combination of crystallization and silica gel chromatography the individual and β isomers were separated.

α-Isomer: lH NMR (CDCI3) δ: 0.08 (s, 3H), 0.1 (s, 3H), 0.9 (s, 9H), 1.3 (d, 3H),

1.94(m), 2.34(m), 2.58(m), 2.86(m), 3.08(m), 3.76 (dd, IH), 4.22 (p,

IH), 6.54 (bs, IH), 7.28-7.8 (m, 7H), and 8.22 (d, IH).

IR(CH2C12) cm-1: 3420, 1755, 1660, and 1620.

MS(m/e): 392 [M+-C(CH3)3_.

β-Isomer: lH NMR (CDCI3) δ: 0.1 (s, 6H), 0.88 (s, 9H), 1.28 (d, 3H), 1.98-2.42

(m, 2H), 2.76 (m, IH), 3.1 (m, 3H), 4.3 (p, IH), 4.48 (t, IH), 5.96 (bs,

IH), 7.3-7.8 (m, 7H), and 8.22 (d, IH).

IR(CH2C12) cm-1: 3410, 1760, 1660, and 1620.

MS(m/e): 392 [M+-C(CH3)3]. α and β isomers refer to the carbon atom attached to C-4 of the azetidinone ring.

EXAMPLE 1A

Preparation of Azetidinones

In a manner analogous to Example 1 , the following azetidinones were prepared:

¹ H NMR Shift (S\ H-4 Yields ⁽ % ⁾ g - isomer β-lsomer

PG = Si(Me) ₂ CMe ₃

EXAMPLE 2

Synthesis of Oxalimide 2

To a stirred solution of 449 mg (1 mmole) of β-isomeric azetidinone 1, from Example 1, and 316.4 mg (4 mmole) of pyridine in 4 mL of sieve dried dichloromethane at 0°C under an atmosphere of nitrogen was added 1.5 mL of a 1M stock solution of allylchlorooxalate in dichloromethane. The resulting mixture was stirred at 0°C for 0.5 hour and then partitioned between diethyl ether, ice-water, and pH 7 phosphate buffer. The organic phase was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, evaporated, and dried in vacuo to provide 568 mg of crystalline solid 2. IH NMR (CDC13) δ: 0.06 (s, 6H), 0.85 (s, 9H), 1.2 (d, J=6.3Hz, 3H), 2.04-2.3 (m, 2H), 3.1-3.3 (m, 4H), 4.3 (m, IH), 4.68 (t, J=3.4Hz, IH), 4.8 (m, 2H), 5.28-5.45 (m, 2H), 5.9-5.99 (m, IH), 7.26-7.76 (m, 7H), and 8.28 (bs, IH). IR(CH2Cl2) cm-1: 1810, 1752, 1680, and 1620.

EXAMPLE 3

Synthesis of Phosphorane 3

The oxalimide 2 (567.4 mg, 1 mmole), from Example 2, and triethylphosphite (1.68 g, 10 mmole) in 5 mL /. -xylene was stirred at 120°C under an inert atmosphere of nitrogen for 1.5 hours. The cooled mixture was rotoevaporated under high vacuum and dried further in vacuo to provide a quantitative amount of phosphorane product 3, which was used immediately without further purification.

EXAMPLE 4

Preparation of Carbapenem 4

A stirred solution of phosphorane 3 (719J mg, 1 mmole), from Example 3, with a crystal of hydroquinone in 25 mL of -xylene was kept at 140°C under an atmosphere of nitrogen for 24 hours. The cooled solution was evaporated and the residue purified by plate layer chromatography [one development pet. ether-ether (3:1)] to give 353 mg (66%) of 4 as a yellow foam. lH NMR (CDC13) δ: 0.097 (s, 6H), 0.9 (s, 9H), 1.27 (d, J=6JHz, 3H), 1.94-2.1 (m, 2H), 3.06-3.2 (m, 3H), 3.25 ( dd, J= 3.2 and 6.1Hz, IH), 4.3 (m, IH), 4.32 (dd, J= 3.2 and 7.5Hz, IH), 4.7 (m, 2H), 5.1-5.42 (m, 2H), 5.8-6.02 (m, IH), 7.16-7.6 (m, 7H), and 8.0 (d, J= 1.5Hz,lH). IR(CH2Cl2) cm-1 : 1775 and 1718. UV(dioxane) nm: 326, 269. MS(m/e): 529(M+).

EXAMPLE 4A

Preparation of Carbapenems

Using the procedures of Examples 2, 3, and 4, the following quadracyclic carbapenems were prepared:

PG = Si(Me) ₂ CMe ₃

EXAMPLE 4B

Preparation of Carbapenems

Using the procedures of Examples 2, 3, and 4, the following quadracyclic carbapenems are prepared:

m X Z Position R ^ε

EXAMPLE 5

Preparation of Carbapenem 5

To a stirred solution of 4 (98.7 mg, 0.19 mmole) in 1 mL of tetrahydrofuran at room temperature under an atmosphere of nitrogen was added sequentially neat glacial acetic acid (39.2 mg, 0.65 mmole) and 0.56 mL (0.56 mmole) of a \M solution of tetrabutyl- ammonium fluoride in THF. The mixture was stirred at ambient temperature for 24 hours.

The mixture was partitioned between ethyl acetate, ice- water, and saturated sodium bicarbonate solution and the organic phase was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated.

Purification by plate layer chromatography [one development CH2θ2-ether (3:1)] gave 45J mg (58%) of product 5. IH NMR (CDCI3) δ: 1.36 (d, J=6.2Hz, 3H), 1.94-2.2 (m, 3H), 3.08- 3.28 (m, 3H), 3.33 (dd, J= 3.2 and 6.6Hz, IH), 4.28 (m, IH), 4.36 (dd, j= 3.2 and 7.5Hz, IH), 4.7 (m, 2H), 5J-5.4 (m, 2H), 5.8-6.02 (m, IH), 7.12-7.6 (m, 7H), and 8.0 (d, J= 1.5Hz,lH).

IR(CH2Cl2) cm-1 : 3600,1775 and 1720. UV(dioxane) nm: 326, 254. MS(m/e): 415(M+).

EXAMPLE 5A

Preparation of Carbapenems

Following the procedure of Example 5, the following quadracyclic carbapenems were prepared:

¹ H NMR Shift. δ.

Yield(%) b≤ bL£

EXAMPLE 5B

Preparation of Carbapenems

Using the procedure of Example 5, the following hexacyclic carbapenems are prepared:

EXAMPLE 6

Preparation of Carbapenem derivative 6

To a stirred solution of 22.6 mg (0.05 mmole) of diol in 0.5 ml of methylene chloride at -23°C under nitrogen was added sequentially 8.8 mg (0J mmole) of N-methylimidazole and then 15 mg (0.053 mmole) of triflic anhydride. The resulting mixture was stirred further for 3 hours.

The mixture was partitioned between methylene chloride and water, and the organic phase separated, dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was dissolved in a minimum amount of methylene chloride and the product was precipitated by the addition of diethyl ether; repetition, and drying in vacuo gave 24.6 mg (86%) of 6. lH NMR (CDCl3-d6-Acetone) δ: 1.2 (d, CH3), 3.8 (s, N-CH3), and 9.1(bs).

EXAMPLE 6A

Preparation of Carbapenems

Using the procedure of Example 6, the following quadracyclic carbapenems are prepared:

m R ^£ Position R ^a

Θ bond CH ₂ -N^,NMe OTf 7' ©^ ^/ 8' bond CH ₂ -N^ _^ NMe ^uιτ f=\ ^υ OTf bond CH ₂ -N^ N(CH ₂ ) ₂ CN T

/=\ © OTf

T bond CH ₂ -N^N(CH ₂ ) ₂ OSiEt ₃

/=\ ©OTf bond CH ₂ -N^N(CH ₂ ) ₂ CONH ₂ T

EXAMPLE 6A (CONT'D)

m X _B_ Position R ^a

1 1 bond _C H ₂ -N^S ®OTf ⁷ '

EXAMPLE 6A (CONT'D)

m X _ _R Ba Position R ^a

®/—

1 zero O CH ₂ -N ^' V-NCH ₃ ⁽ 20Tf 7'

\ — / Θ

1 zero O ₇ ,

¹ zero O CH ₂ -N s ^Θ OTf ^τ

EXAMPLE 6A (CONT'D)

m _B_ Position R ^£

^{1 Zer0 S} CH _r N NMβ ® ^{0Tf T 2} © N'

10

®- 1 zero S CH ₂ -N _^ NCH ₃ © ₂ OTf T

\ — / Θ

20

1 zero S ^Θ 20Tf

1 zero S CH ₂ -N- S OTf ^{τ 2} Θ^

30

EXAMPLE 6A (CONT'D)

m X Position R ^a

^{1 Zer} ° ^S ° ² CH _r NT NMβ ^Θ ° ^{Tf T 2} © N'

1 zero S0 ₂ CH ₂ -N ^Θ OTf T

®

H ₂ N

® T\ ©rvπ

1 zero S0 ₂ CHjrlsT ) ^UTt T

1 zero S0 ₂ ^u 20Tf

1

1 I z *» ^β efrno S o S»n ⁽ 01 ₂ _ C <"*•'H■ ⁼⁼ Θ ₂ -J KI „S »"» ° ^-^OTf

² Θ^

EXAMPLE 6A (CONT'D)

m n X Rj Position R ^a

1 zero NC0 ₂ allyl ^Θ ° ^{Tf T}

1 zero NC0 ₂ allyl ©OTf T

1 zero NC0 ₂ allyl ©OTf T

1 zero NC0 ₂ allyl ^{ϋ l T} T

1 zero NC0 ₂ allyl 7'

1 zero NC0 ₂ allyl _τ

1 zero NC0 ₂ allyl CH ₂ -N^ S ^Θ OTf ^T

EXAMPLE 6A (CONT'D)

m _____ Position R ^J

1 zero CH=CH _{CH N NMe} © ₀ Tf T

© N'

1 zero CH=CH CH ₂ -N"V ^OTf _τ

1 zero CH=CH © ₂ QTf T

1 zero CH=CH CH ₂ -N _\ .S ©OTf ^τ

EXAMPLE 6A (CONT'D)

m n X R ³ Position R ^a

zero 0=CNH- ©OTf

© _/ — \

1 zero 0=CNH- CH ₂ -N"VNCH ₃ © 7'

\_ © ³ 20Tf

1 zero 0=CNH- © ₂ oτf

¹ zero 0=CNH- CH ₂ -N^S ^Θ OTf ^τ

EXAMPLE 6A (CONT'D)

m n X R ^£ Position R ^£

© ΓΛ Θ,

2 1 bond CH ₂ -N" ^ OTf T

2 1 bond ©20Tf T

2 1 bond CH^ S ©

OTf T

EXAMPLE 7

Preparation of Carbapenem Derivative 7

To a stirred solution of 24.6 mg (0.044 mmole) of salt 6 in 1.0 ml of methylene chloride at room temperature was added 6.9 mg (0.026 mmole) of triphenylphosphine, 10.1 mg (0.0088 mmole) of tetrakistriphenylphosphinepalladium(O), and 96.5 mL (0.048 mmole) of a 0.5M solution of sodium-2-ethylhexanoate. The resulting mixture was stirred under nitrogen for 0.5 hours.

The mixture was chilled in an ice-water bath and diethyl ether was added. The separated material was collected by centrifugation

and decantation of the supernatant. The crude product was washed analogously with ether and dried in vacuo to give 26.8 mg of residue. Purification by reverse phase plate layer chromatography [one development H2O-CH3CN (7:3)] gave after extraction, concentration, and lyophilization 3.3 mg (16%) of product 7. lH NMR [D2O-CD3CN (5:2)] δ: 1.5 (d, 3H), 2.1-2.4 (m, 2H), 3.28-3.6 (m, 3H), 3.8 (m, IH), 4.1 (s, N-CH3), 4.5-4.7 (m, 2H), 4.8 (s, HDO), 5.67 (s, 2H), 7.5-8.1 (m, 9H), and 9.0 (bs). UV(H2θ): λmax 303, 265 ran.

EXAMPLE 7A

Preparation of Carbapenems

Using the procedure of Example 7, the following quadracyclic carbapenems are prepared:

EXAMPLE 7A (CONT'D)

m n X R ^£ Position R ^Σ f=\ bond CH ₂ -N^NMe T ©^

10 bond CH ₂ -N^N(CH ₂ ) ₂ CN f=\ bond CH ₂ -N^ N(CH ₂ ) ₂ OH 7' f=\

15 bond CH ₂ -N _<5 ^N(CH ₂ ) ₂ CONH ₂ T

bond CH ₂ -N* NMe T © N

25 © — \ ©Cl bond CH ₂ -NΛ-NCH ₃ T \ ©

30 I= bond CHr^l^S T t ©~

EXAMPLE 7A (CONT'D)

m n x n ^a Position R ^a

zero O f=\ CH ₂ -N* _. NMe T ² © N ^'

1 zero O _{CH N}

W J

H ₂ N

25

1 zero O CH ₂ -N^S 7'

30

EXAMPLE 7A (CONT'D)

m n X R ^a Position R ^c'

zero

CH ₂ -N* NMe T ² © N'

zero CH ₂ -N* NMe © N

10 zero S _{CH N} )

® T

Θ - ®CI

1 zero S CH ₂ -N _-NCH _{3 7} .

² \___y © ⁷

20

²⁵ 1 zero CHjgPs

30

EXAMPLE 7A (CONT'D)

m n X R ^a Position R ^a

zero S0 _{2 τ}

© N

10

15

1 zero so ₂ CH ₂ -N ^ T

© -Λ ^Θ C

1 zero so ₂ CH ₂ -N _^ NCH ₃

² \ / © ³ T

20

25 1 zero S0 ₂ CH _g -N^S 7'

30

EXAMPLE 7A (CONT'D)

m n X R ^a Position R ^a

zero NH CH ₂ -N<. NMe © N

EXAMPLE 7A (CONT'D)

m n X βf Position R ^a

1 zero CH=CH CH ₂ -N^ NMe T

© N

1 zero CH=CH CH ₂ -N _. NMe T

² © N'

© — \ ©Cl

1 zero CH=CH CH ₂ -N' -NCH ₃

\_7 © ³ T

EXAMPLE 7A (CONT'D)

m n X R ^a Position R ^a

Θ_

Θ, Cl

1 zero 0=CNH- T

EXAMPLE 7A (CONT'D)

m X Position R ^£

2 1 bond f=\ T

CH ₂ -N - _. .NMe © N

10

bond r-

CH ₂ -N /> T © © \__J/ H ₂ N

25 l=\ bond CH ₂ -N _S

© ^ ^k

30