WO1998011108A1

WO1998011108A1 - Carbapenem antibacterial compounds, compositions containing such compounds and methods of treatment

Info

Publication number: WO1998011108A1
Application number: PCT/US1997/015831
Authority: WO
Inventors: Lovji D. Cama; Robert R. Wilkening; Ronald W. Ratcliffe; Timothy A. Blizzard
Original assignee: Merck & Co., Inc.
Priority date: 1996-09-12
Filing date: 1997-09-08
Publication date: 1998-03-19
Also published as: EP1021445A1; JP2001500862A; CA2264147A1; EP1021445A4; AU4184497A

Abstract

The present invention relates to carbapenem antibacterial agents in which the carbapenem nucleus is substituted at the 2-position with a sulfonamide containing ring system linked to the carbapenem nucleus through a CH2 group. The compounds are represented by formula (I) including pharmaceutically acceptable salts thereof, wherein: R1 represents H or methyl; CO¿2?M represents a carboxylic acid, a carboxylate anion, a pharmaceutically acceptable ester group or a carboxylic acid protected by a protecting group; P represents hydrogen, hydroxyl, F or hydroxyl protected by a hydroxyl-protecting group; X?1 and X2¿ represent hydrogen or X?1 and X2¿ taken together represent a carbonyl group; and one of AB, BC and CD represents a fused aryl, heteroaryl or heteroarylium ring, and the other variables represent R, said fused aryl, heteroaryl or heteroarylium ring being substituted with from 1-4 R groups. Pharmaceutical compositions and methods of use are also included.

Description

TFTLE OF THE INVENTION CARBAPENEM ANTIBACTERIAL COMPOUNDS, COMPOSITIONS CONTAINING SUCH COMPOUNDS AND METHODS OF TREATMENT

BACKGROUND OF THE INVENTION

The present invention relates to carbapenem antibacterial agents in which the carbapenem nucleus is substituted at the 2-position with a sulfonamide containing ring system, linked to the carbapenem through a CH₂ group. The sulfonamide containing ring system is further substituted with various substituents, which can include cationic groups.

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 for treating infections caused by these difficult to control pathogens. There is an increasing need for agents effective against such pathogens which are at the same time relatively free from undesirable side effects.

SUMMARY OF THE INVENTION The compounds of the present invention are represented by formula I:

including pharmaceutically acceptable salts thereof, wherein: R¹ represents H or methyl;

CO₂M represents a carboxylic acid, a carboxylate anion, a pharmaceutically acceptable ester group or a carboxylic acid protected by a protecting group;

P represents hydrogen, hydroxyl, F or hydroxyl protected by a hydroxyl-protecting group;

X¹ and X² represent hydrogen or X^Jand X² taken together represent a carbonyl group;

one of AB, BC and CD represents a fused aryl, heteroaryl or heteroarylium ring, and the other variables represent R, said fused aryl, heteroaryl or heteroarylium ring being substituted with from 1 -4 R groups;

each R is independently selected from: -R*; -Q; hydrogen; halo; -CN; -N0₂; -NRaRb; -OR< -SR^_; -C(0)NRaRt>; -C(0)OR' -S(0)R^c; -S0₂R^c; -S0₂NR*R^b; -NR"S0₂R^b; -C(0)R"; -OC(0)R«; -OC(0)NR^aR^b; -NRaC(0)NR°R< -NR"C0₂R^h; -OC0₂Rh; -NR^aC(0)R^D; -C₁-₆ straight- or branched-chain alkyl, unsubstituted or substituted with one to four R^d groups; and -C3-7 cycloalkyl, unsubstituted or substituted with one to four R^d groups;

each R^a, R^b and R^c independently represents hydrogen, -R*, -Ci-₆ straight- or branched-chain alkyl, unsubstituted or substituted with one to four R^d groups, or -C3.7 cycloalkyl, unsubstituted or substituted with one to four R^d groups; or R^a and R^b taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one or more of O, S, NR^C, with R^c as defined above, or -C(O)-, said ring being unsubstituted or substituted with one to four R' groups; or R^D and R taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one to three of O, S, NR^a, with R^a as defined above, or -C(O)-, said ring being unsubstituted or substituted with one to four R' groups;

each R^d independently represents halo; -CN; -N0₂; -NReR^f; -OR^g; -SR^g; -CONR^eR'; -COOR^g; -SOR^g; -S0₂Rs; - S0₂NReRf; -NR^eS0₂R^f; -COR^; -NR^ CORf; -OCOR^e; -OCONR^eR^f; -NReCONRfRg; -NReC0₂R^h; -OC0₂R^h; -C(NRe)NRfRs; . NR^eC(NH)NR«R^g; -NR^C(NR R^g; -R* or -Q;

R^c, R^f and Re represent hydrogen; -R*; -Ci -₆ straight- or branched-chain alkyl unsubstituted or substituted with one to four R' groups; or R^e and R^f taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one to three of O, S, -C(O)- or NR^g with Rg as defined above, said ring being unsubstituted or substituted with one to four R' groups;

each R' independently represents halo; -CN; -NO2; phenyl; -NHSθ2R^h; -OR^h, -SRh; -N(Rh)₂; -N+(Rh)₃; -C(0)N(R^h)₂; -Sθ2N(Rh)₂; heteroaryl; heteroarylium; -C0₂R^h; -C(0)Rh; -OCORh; -NHCOR^h; guanidinyl; carbamimidoyl or ureido;

each Rⁿ independently represents hydrogen, a -Ci-6 straight or branched-chain alkyl group, a -C3-C6 cycloalkyl group or phenyl, or when two R^h groups are present, said R^h groups may be taken in combination and represent a 4-6 membered saturated ring, optionally interrupted by one or two of O, S, SO2, -C(O)-, NH and NCH3;

Q is selected from the group consisting of: R^xR^yR'

wherein: a and b are 1 , 2 or 3;

L- is a pharmaceutically acceptable counterion; represents O, S or NR^S; β, δ, λ, μ and σ represent CR¹, N or N⁺R , provided that no more than one of β, δ, λ, μ and σ is N⁺R^s;

R* is selected from the group consisting of:

wherein: d represents O, S or NR^k; e, g, x, y and z represent CR^m, N or N⁺R^k , provided that no more than one of e, g, x, y and z in any given structure represents N⁺R^k;

R^k represents hydrogen; -Ci-6 straight- or branched- chain alkyl, unsubstituted or substituted with one to four R' groups; or -(CH₂)_nQ where n = 1 , 2 or 3 and Q is as previously defined;

each R^m independently represents a member selected from the group consisting of: hydrogen; halo; -CN; -N0₂; -NRⁿR°; -OR"; -SR"; -CONR^«R°; -COOR^h; -SOR"; -S0₂R"; -S0₂NR"R°; -NR"S0₂R°; -COR"; -NR"COR^«; -OCOR"; -OCONRⁿR^»; -NRⁿC0₂R^h; -NRⁿCONR°R^h; -OC0₂R^h; -CNR"NRoRi>; -NR"CNHNR»R^b; -NRⁿC(NR°)R^h; -Ci-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R' groups; -C3-7 cycloalkyl, unsubstituted or substituted with one to four R' groups; and -(CH )_nQ where n and Q are as defined above; Rⁿ and R° represent hydrogen, phenyl; -Ci- straight- or branched-chain alkyl unsubstituted or substituted with one to four R' groups;

each R^s independently represents hydrogen; phenyl or -C]-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R' groups;

each R^l independently represents hydrogen; halo; phenyl; -CN; -N0₂; -NR^»R^V; -OR"; -SR"; -CONR"R^v _; -COOR^h; -SOR"; -S0₂R^u; -S0₂NR"R^v; -NR"S0₂R^v; -COR"; -NR"COR^v; -OCOR"; -OCONR"R^v; -NR"C0₂R^v; -NR"CONR*R^w; -OC0₂Rv; -Ci-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R' groups;

R^u and R^v represent hydrogen or -Cj .fi straight- or branched-chain alkyl, unsubstituted or substituted with one to four R' groups; or R^u and R^v together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one or more of O, S, NR^W or -C(O)-, said ring being unsubstituted or substituted with one to four R^j groups;

each R independently represents hydrogen; -Cl _6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R^J groups; C3-6 cycloalkyl optionally substituted with one to four R¹ groups; phenyl optionally substituted with one to four R¹ groups, or heteroaryl optionally substituted with 1 -4 Ri groups; or Rⁿ and R^w taken together with any intervening atoms represent a 5-6 membered saturated ring, optionally interrupted by one or two of O, S, SO2, NH or NCH3; R^x represents hydrogen or a Ci -8 straight- or branched- chain alkyl, optionally interrupted by one or two of O, S, SO, S02, NR^W, N+R^hR^w, or -C(O)-, said chain being unsubstituted or substituted with one to four of halo, CN, Nθ2, OR , SR , SORw, S02R^W, NRhR , N+(Rh)2R , -C(0)-Rw, C(0)NRhRw, S02NRhRw, C02R^W, OC(0)RW, OC(0)NRhRw, NRhC(0)R^w, NRⁿC(0)NRhR^w, _{or a} phenyl or heteroaryl group which is in turn optionally substituted with from one to four R' groups or with one to two Cl -3 straight- or branched- chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four Ri groups;

R and R^z represent hydrogen; phenyl; -Ci-6 straight or branched chain alkyl, unsubstituted or substituted with one to four R' groups, and optionally interrupted by O, S, NR , N⁺R^hR^w or -C(O)-; or R^x and R^y together with any intervening atoms represent a 4-8 membered saturated ring optionally interrupted by O, S, SO2, NR^W , N⁺R^hR^w or -C(O)-, unsubstituted or substituted with 1 - 4 R¹ groups, and when R^x and R together represent a 4-6 membered ring as defined above, R^z is as defined above or R⁷ represents an additional saturated 4-8 membered ring fused to the ring represented by R^x and Ry taken together, optionally interrupted by O, S, NR or -C(O)-, said rings being unsubstituted or substituted with one to four R' groups.

Pharmaceutical compositions and methods of treatment are also included herein. DETAILED DESCRIPTION OF THE INVENTION

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

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

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, selected from R^d and Ri, 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 ethenyl, propenyl, butenyl and cyclohexenyl.

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.

Aryl refers to aromatic rings e.g., phenyl, substituted phenyl and the like, 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 three such rings being present, containing up to 14 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 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, O, S or N, in which a carbon or nitrogen atom is the point of attachment, and in which one or two additional carbon atoms 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 as described herein. 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. Examples include the following:

pyrrole (pyrrolyl) imidazole (imidazolyl) thiazole (thiazolyl)

C° C° 0^s oxazole (oxazolyl) furan (furyl) thiophene (thienyl)

triazole (triazolyl) pyrazole (pyrazolyl) isoxazole (isoxazolyl)

isothiazole (isothiazolyl) pyridine (pyridinyl) pyrazme

(pyrazinyl)

pyπdazine (pyndazinyl) pyrimidme (pynmidinyl)

tπazi (tπazinyl)

Heteroarylium refers to heteroaryl groups bearing a quaternary nitrogen atom and thus a positive charge. Examples include the following:

CH₃ CH₃

When a charge is shown on a particular nitrogen atom in a ring which contains one or more additional nitrogen atoms, it is understood that the charge may reside on a different nitrogen atom in the ring by virtue of charge resonance that occurs.

and

With reference to the alternative values of AB, BC and CD, the following arrangements can be considered.

(R)θ-3

When one of AB, BC and CD represents heteroaryl, at least one of /, 2, 3 and 4 is a heteroatom selected from O, S and N. When one of AB, BC and CD represents heteroarylium, one of the atoms at positions /, 2, 3 and 4 is a quaternary nitrogen atom. 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 or N, and in which up to three additional carbon atoms may be replaced by hetero atoms. The terms "quaternary nitrogen" and "positive charge" refer to tetravalent, positively charged nitrogen atoms including, e.g., the positively charged nitrogen in a tetraalkyl- ammonium group (e. g. tetramethyl ammonium), heteroarylium, (e.g., N-methylpyridinium), basic nitrogens which are protonated at physiological pH, and the like. Cationic groups thus encompass positively charged nitrogen-containing groups, as well as basic nitrogens which are protonated at physiologic pH.

The term "heteroatom" means O, S or N, selected on an independent basis. Halogen and "halo" refer to bromine, chlorine, fluorine and iodine.

Alkoxy refers to C1 -C4 alkyl-O-, with the alkyl group optionally substituted as described herein. Ureido means the group -NHC(0)NH2, the hydrogens of which may be replaced with alkyl groups.

Guanidinyl means the group -NHC(NH)NH2, the hydrogens of which may be replaced with alkyl groups.

Carbamimidoyl means the group -C(NH)NH2, the hydrogens of which may be replaced with alkyl groups. When a group is termed "substituted", unless otherwise indicated, this means that the group contains from 1 to 4 substituents thereon. With respect to R, Ra, Rb and R , the substituents available on alkyl groups are selected from the values of R^d. Many of the variable groups are optionally substituted with up to four R' groups. With respect to R^e, R^f and Rg, when these variables represent substituted alkyl, the substituents available thereon are selected from the values of R'.

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 Greene, T. W. et al. Protective Groups in Organic Synthesis Wiley, New York (1991). Examples of suitable protecting groups are contained throughout the specification.

In some of the carbapenem compounds of the present invention, M is a readily removable carboxyl protecting group, and/or P represents a hydroxyl which is protected by a hydroxyl- protecting group. Such conventional protecting groups consist of known groups which are used to protectively block the hydroxyl or carboxyl group during the synthesis procedures described herein. 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 carboxyl protecting groups include allyl, benzhydryl, 2-naphthylmethyl, benzyl, silyl such as t-butyldimethylsilyl (TBDMS), phenacyl, p-methoxybenzyl, o-nitrobenzyl, p-methoxyphenyl, p-nitrobenzyl, 4-pyridylmethyl and t-butyl.

Examples of suitable C-6 hydroxyethyl protecting groups include triethylsilyl, t-butyldimethylsilyl, o-nitrobenzy loxycarbonyl, p-nitrobenzyloxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, t-buty loxycarbonyl, 2,2,2-trichloroethy loxycarbonyl and the like.

The carbapenem compounds of the present invention are useful per se and in their pharmaceutically acceptable salt and ester forms for 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, such as 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, solubility, 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.

With respect to -CO2M, which is attached to the carbapenem nucleus at position 3, this represents a carboxylic acid group (M represents H), a carboxylate anion (M represents a negative charge), a pharmaceutically acceptable ester (M represents an ester forming group) or a carboxylic acid protected by a protecting group (M represents a carboxyl protecting group). The pharmaceutically acceptable salts referred to above may take the form -COOM, where M is a negative charge, which is balanced by a counterion, e.g., an alkali metal cation such as sodium or potassium. Other pharmaceutically acceptable counterions may be calcium, magnesium, zinc, ammonium, or alkylammonium cations such as tetramethylammonium, tetrabutylammonium, choline, triethylhydroammonium, meglumine, triethanolhydroammonium, etc.

The pharmaceutically acceptable salts referred to above also include 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-hydroxyethanesuIfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate.

The pharmaceutically acceptable esters 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. These are also referred to as "biolabile esters". Biolabile esters are biologically hydrolizable, and may be 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 M represents an alkoxyalkyl, alkylcarbonyloxyalkyl, alkoxycarbonyloxyalkyl, cycloalkoxyalkyl, alkenyloxyalkyl, aryloxyalkyl, alkoxyaryl, alkylthioalkyl, cycloalkylthioalkyl, alkenylthioalkyl, arylthioalkyl or alkylthioaryl group. These groups can be substituted in the alkyl or aryl portions thereof with acyl or halo groups. The following M species are examples of biolabile ester forming moieties.: acetoxymethyl, 1 -acetoxyethyl, 1 -acetoxypropyl, pivaloyloxymethyl, 1 -isopropyloxycarbonyloxyethyl, 1 -cyclohexyloxycarbonyloxyethyl, phthalidyl and (2-oxo- 5-methyl-l ,3-dioxolen-4-yl)methyl. L^" can be present or absent as necessary to maintain the appropriate charge balance. When present, L- represents a pharmaceutically acceptable counterion. Most anions derived from inorganic or organic acids are suitable. Representative examples of such counterions are the following: acetate, adipate, aminosalicylate, anhydromethylenecitrate, ascorbate, aspartate, benzoate, benzenesulfonate, bromide, citrate, camphorate, camphorsulfonate, chloride, estolate, ethanesulfonate, fumarate, glucoheptanoate, gluconate, glutamate, lactobionate, malate, maleate, mandelate, methanesulfonate, pantothenate, pectinate, phosphate/diphosphate, polygalacturonate, propionate, salicylate, stearate, succinate, sulfate, tartrate and tosylate. Other suitable anionic species will be apparent to the ordinarily skilled chemist.

Likewise, when L^~ represents a specie with more than one negative charge, such as malonate, tartrate or ethylene- diaminetetraacetate (EDTA), an appropriate number of carbapenem molecules can be found in association therewith to maintain the overall charge balance and neutrality.

A subset of compounds that is of particular interest includes compounds of formula I which contain at least one positively charged moiety. Thus, the ring formed by AB, BC or CD is positively charged, or at least one R contains a positive charge. Within this subset, all other variables are as previously defined. Another subset of compounds of the invention which is of interest relates to compounds where AB taken together represent an aryl, heteroaryl or heteroarylium ring, and C and D represent hydrogen atoms. In particular, AB taken together represent an aryl or heteroaryl ring. Within this subset of compounds, all other variables are as originally defined. Another subset of compounds of the invention which is of interest relates to compounds where BC taken together represent an aryl, heteroaryl or heteroarylium ring, and A and D represent hydrogen atoms. In particular, BC taken together represent an aryl or heteroaryl ring. Within this subset of compounds, all other variables are as originally defined. Another subset of compounds of the invention which is of interest relates to compounds where CD taken together represent an aryl, heteroaryl or heteroarylium ring, and A and B represent hydrogen atoms. In particular, CD taken together represent an aryl or heteroaryl ring. Within this subset of compounds, all other variables are as originally defined.

Another subset of compounds of formula I which is of interest relates to compounds of formula I wherein one R represents a group which contains a positively charged moiety, and the remaining R groups are selected from hydrogen and Cι_₆ straight or branched chain alkyl, unsubstituted or substituted with one to four R^d groups. More particularly, this subset of interest includes compounds of formula I wherein one R represents a group containing a positively charged moiety and the remaining R groups are hydrogen.

With respect to the positively charged moiety or moieties that are contained in one or more R groups, it is preferred that from 1 -3 positive charges be present, and most preferably two positive charges be present, balanced by the carboxylate anion and a negatively charged counterion.

Another subset of compounds which is of interest is represented by formula I wherein one R group represents a -Cι _₆ straight or branched chain alkyl group, substituted with one to four R^d groups, wherein one R^d group represents -R* or Q. Hence, a positively charged moiety -R* or Q is attached to an alkyl group. Another group of compounds of interest is represented by formula I wherein Q is selected from the group consisting of:

More particularly, the group of compounds which is of interest is represented by formula I wherein 0 represents:

Within this subset of compounds, L- > a and b are as originally defined, and R^x is as originally defined, and represents a member selected from the group consisting of: hydrogen or a Cl -8 straight- or branched- chain alkyl, optionally interrupted by one or two of O, S, SO, Sθ2, NR , N+RhRw, _or -C(O)-, said chain being unsubstituted or substituted with one to four of halo, CN, N02, ORw, SR^W, SOR^w, Sθ2R , NR Rw, N+(Rh)₂Rw, -C(0)-R^w, C(0)NRhRw, S02NR RW, Cθ2R^w, OC(0)Rw, OC(0)NRhRW₅ NRhC(0)Rw,

_{or a} phenyl or heteroaryl group which is in turn optionally substituted with from one to four R¹ groups or with one to two Cl -3 straight- or branched- chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four Ri groups. Another group of compounds of interest is represented by formula I wherein Q represents -N+R^xRyR^z, wherein R^x, Ry and R^z are as originally defined.

Another group of compounds of interest is represented by formula I wherein one R* group is present and is selected from:

Within this subset, d represents NR^k; R^k represents -Ci-6 straight or branched chain alkyl; and e, g, x and y represent CR^m or N⁺R^k, with R^k as defined above and R^m representing hydrogen.

Another subset of compounds of the invention which is of interest relates to those compounds where CO2M represents a carboxylate anion. Hence, M in this instance represents a negative charge which is balanced by a positively charged group, such as in the positively charged R group. Likewise, if the positively charged R group contains more than one positive charge, a negatively charged counterion may be present which in combination with the carboxylate anion, provides overall charge neutrality. A preferred subset of compounds of formula I which is of particular interest relates to compounds represented by formula I wherein:

AB represents an aryl, heteroaryl or heteroarylium group, and C and D represent R groups;

CO2M represents a carboxylate anion; one R group which is attached to the sulfonamide containing ring system contains at least one positively charged moiety, and the remaining R groups are selected from hydrogen and

straight or branched chain alkyl, unsubstituted or substituted with one to four R^d groups; Rd is as originally defined; Rⁿ represents hydrogen or a Ci -6 straight or branched chain alkyl group; 0 is selected from the group consisting of:

-^R'

wherein L- , a and b are as originally defined, and R^x represents a member selected from the group consisting of: hydrogen or a Cl -8 straight- or branched- chain alkyl, optionally interrupted by one or two of O, S, SO, S02, NR^W, N+R^hRw, _or -C(O)-, said chain being unsubstituted or substituted with one to four of halo, CN, N02, ORw, SRw, SORw, Sθ2R^w, NRhR , N+(Rh)2RW, -C(0)-Rw, C(0)NRhRw, Sθ2NRhRw, Cθ2R^w,

OC(0)RW, OC(0)NRhRW, N hc(0)RW, N C(0)NR RW_{5 or a} phenyl or heteroaryl group which is in turn optionally substituted with from one to four R¹ groups or with one to two C] -3 straight- or branched- chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four Ri groups; R* is selected from:

wherein d represents NR^k; R^k represents -Ci-₆ straight or branched chain alkyl; and e, g, x and y represent CR^m or N+R^k, with R^k as defined above and R^m representing hydrogen.

Within this subset, all other variables are as originally defined with respect to formula I.

A more preferred subset of compounds of the invention is represented by formula la:

or a pharmaceutically acceptable salt thereof, wherein: CO2M represents a carboxylate anion; one R group contains a positively charged moiety, and the other R groups are selected from hydrogen and Ci-6 straight or branched chain alkyl, unsubstituted or substituted with one to four Rd groups; Rd is as originally defined;

0 is selected from the group consisting of:

wherein L" , a and b are as originally defined, and R^x represents a member selected from the group consisting of: hydrogen or a Cl -8 straight- or branched- chain alkyl, optionally interrupted by one or two of O, S, SO, S02, NRW, N+RhRw_{? or} -C(O)-, said chain being unsubstituted or substituted with one to four of halo, CN, Nθ2, ORw, SR , SORw, Sθ2R^w, NRhRw, N+(Rh)₂R , -C(0)-R , C(0)NRhRw, Sθ2NRhR , Cθ2R , OC(0)R , OC(0)NRhRW, NRhC(0)R , NR C(0)NR R , ₀r a phenyl or heteroaryl group which is in turn optionally substituted with from one to four R¹ groups or with one to two C{ -3 straight- or branched- chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four R' groups; R^h represents hydrogen or a - straight or branched chain alkyl group; R is as originally defined;

R* is selected from:

wherein d represents NR^k; R^k represents -Ci -₆ straight or branched chain alkyl; and e, g, x and y represent CR^m or N⁺R^k, with R^k as defined above and R^m representing hydrogen. Within this subset, all other variables are as originally defined with respect to formula I.

Another more preferred subset of compounds of the invention is represented by formula la wherein: one R represents

and R^x, a, b and L- are as originally defined.

Another more preferred subset of compounds of the invention is represented by formula lb:

or a pharmaceutically acceptable salt thereof, wherein: CO2M represents a carboxylate anion; one R group contains a positively charged moiety, and the other R groups are selected from hydrogen and Ci- straight or branched chain alkyl, unsubstituted or substituted with one to four R^d groups; Rd is as originally defined;

Q is selected from the group consisting of:

wherein L- , a and b are as originally defined, and R^x represents a member selected from the group consisting of: hydrogen or a Cl -8 straight- or branched- chain alkyl, optionally interrupted by one or two of O, S, SO, Sθ2, NRw, N+RhR , _or -C(O)-, said chain being unsubstituted or substituted with one to four of halo, CN, N02, ORw, SRw, SORw, Sθ2R^w, NRhRw, N+(Rh)2Rw, -C(0)-R , C(0)NRhRw, Sθ2NRhR _? C02R^W, OC(0)R^w, OC(0)NRhRW_? NRhC(0)Rw, NRhC(0)NR^hR , or a phenyl or heteroaryl group which is in turn optionally substituted with from one to four Ri groups or with one to two Cl -3 straight- or branched- chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four R¹ groups; Rⁿ represents hydrogen or a Cj -₆ straight or branched chain alkyl group;

R^w is as originally defined; R* is selected from:

- tf and -^T?

wherein d represents NR^k; R^k represents

straight or branched chain alkyl; and e, g, x and y represent CR^m or N⁺R^k, with R as defined above and R^m representing hydrogen. Within this subset, all other variables are as originally defined with respect to formula I.

Another more preferred subset of compounds of the invention is represented by formula lb wherein: one R represents

R*

and R^x, a, b and L^~ are as originally defined. Representative examples of compounds of the invention are as follows:

TABLE

TABLE

TABLE

TABLE

wherein Q is as defined in the tables and Lr represents a pharmaceutically acceptable counterion.

The compounds of the present invention are prepared by reacting a suitably protected, activated 2-hydroxymethyl- carbapen-2-em-3 -carboxylate with a naphthosultam, modifying the thus-introduced side chain as desired, and then removing any protecting groups which are present to afford the desired final product. The process is illustrated by the following generic scheme: SCHEME 1

HOAc, Reflux

²=H SC_HEM£_2

or

SCHEME 3

1 ) activate hydroxyl group for displacement

6 or 7

2) introduce Q group by displacement one of A, B, C and D contains an R group which in turn contains -CH₂OH

or

SCHEME 4

1 ) deprotect

8 or 9

2) purify

With reference to the Schemes above, P, R 1 , R and M are as defined with respect to the compounds of formula I. P** represents a hydroxyl protecting group. One of A, B, C and D, or a group which is attached to the ring represented by AB, BC or CD contains a group (e.g., OH) which can be converted into an appropriate leaving group. Also, the chain to which the leaving group is attached can be varied within wide limits to include all other values of R which form a bridge between the cyclic sulfonamide aryl platform and the quaternary group.

The cyclic sulfonamide platform is formed with the leaving group precursor in place, producing 4, which can be converted to the dihydro compound 5. When one of A, B, C and D represents a quaternary or quaternizable R group in the compounds of the invention, it can be attached from the outset. Hence, in this instance, in Scheme I, one of A, B, C and D would represent a group which contains 0 or a precursor of 0- Two of the other variables represent a fused ring in combination.

The cyclic sulfonamide is reacted with a protected carbapen-2-em-3-carboxylate having an activated hydroxymethyl group at the 2-position, via a Mitsunobu reaction between the cyclic sulfonamide and the carbapenem alcohol.

The carbapenem nucleus having a -CH2OH substituent at position 2 can be obtained in accordance with Schmitt, S. M. et al., J. Antibiotics 41(6): 780-787 (1988), the teachings of which are incorporated herein by reference. The carboxylic acid group at C-3 of the carbapenem is generally protected as a carboxyl protecting group such as p-nitrobenzyl (PNB), allyl, p-methoxybenzyl, trichloroethyl, 2-trimethylsilylethyl, and the like. Furthermore, the hydroxyl group of the 6-(hydroxyethyI) side-chain is protected with a hydroxyl protecting group such as trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), tert- butyldiphenylsilyl (TBDPS), acetyl, allyloxycarbonyl, 2-trimethylsilylethoxy carbonyl, 2-trichloroethoxycarbonyl and the like.

Addition of the cyclic sulfonamide to the carbapenem is accomplished by treating a solution of the hydroxymethyl- carbapenem and the cyclic sulfonamide in a suitable solvent such as tetrahydrofuran (THF), ether, acetonitrile, dimethylformamide (DMF), benzene, dimethylsulfoxide (DMSO), and the like with a (premixed) suitable activating reagent such as diethyl azodicarboxylate (DEAD) / triphenylphosphine, diisopropyl azodicarboxylate (DIAD) / tributylphosphine, and the like, at a temperature between about -20 °C and 35 °C for about 5 to 90 minutes.

Alternatively, the side chain component and the carbapenem can be mixed together with either the azodicarboxylate or the phosphine reagent in a suitable solvent and the other component of the activating reagent (the phosphine or the azodicarboxylate, respectively) can be added to that mixture. Once the sulfonamide, carbapenem and activating reagent(s) have been mixed, the reaction is allowed to proceed at a temperature between about -20°C and 35°C for about 5 to 90 minutes.

The resulting mixture is then subjected to a standard work-up procedure familiar to those skilled in the art to afford a crude 2-methyl substituted carbapenem which is purified, if necessary, by recry tall ization or by chromatography on silica gel, eluting with a suitable solvent or mixture of two or more solvents, such as hexane, ethyl acetate, ether, benzene, dichloromethane, chloroform, acetone, methanol and the like.

Modification of the side chain of compounds 6 or 7 is generally necessary to introduce the charged substituent Q- This generally entails activation of a hydroxyl group to form a leaving group, LG, by conversion to a mesylate, iodide or triflate, followed by displacement with a heterocyclic or tertiary nitrogen containing species to the give a quaternary compound. Q represents a group which is positively charged. Quaternization is best accomplished before removal of the protecting groups. For compounds which contain a hydroxyl group in the side chain, a positively charged substituent may be introduced into the side chain by first activating the hydroxyl group by converting it to a suitable leaving group such as a triflate, mesylate, tosylate, iodide, chloride, bromide, and the like, and then displacing the resulting leaving group with a quaternary compound, such as N-methyl-imidazole, N-(2-hydroxyethyl)-imidazole, N-methyl-diazabicyclooctane, l -(carbamoylmethyl)-4-aza-l - azoniabicyclo-[2.2.2.]-octane, 1 -(3-hydroxyprop- 1 -yl)-4-aza- l -azoniabicyclo-[2.2.2.]-octane, pyridine, morpholine and the like which contains a nitrogen atom that can act as a nucleophile. Althernatively, in some cases, the charged substituent may be incorporated in the side chain before addition of the sulfonamide to the carbapenem or may be introduced after deprotection. However, introduction of the charged substituent by modification before deprotection as in Scheme 4 is greatly preferred.

Conversion of the hydroxyl group to a suitable leaving group is accomplished by treating the hydroxyl substituted compound in a suitable solvent such as dichloromethane, tetrahydrofuran, ether, benzene, and the like with an activating reagent, such as trifluoro- methanesulfonic anhydride, methanesulfonic anhydride, toluenesulfonic anhydride, methanesulfonyl chloride, benzenesulfonyl chloride, toluenesulfonyl chloride, and the like in the presence of a suitable base such as triethylamine, tributylamine, diisopropylethylamine, and the like at a temperature between about -100°C and 0°C for about 5 to 120 minutes. The intermediate thus obtained contains a leaving group, which may be converted to an alternative leaving group, iodide, by treating a solution of the intermediate in a suitable solvent such as acetone, methyl ethyl ketone, and the like at about -10°C to 50°C with an excess of sodium iodide or potassium iodide for about 0.25 to 24 hours.

In many cases, the iodide is obtained in sufficiently pure form that it may be used without further purification. For ease of handling, the iodide, if not crystalline, may be lyophilized from benzene to afford an amorphous, easily handled, solid.

The activated hydroxyl group or iodide is displaced by reacting the activated intermediate with reagent 0*. Q* represents a group which reacts with an activated intermediate in a manner which results in the incorporation in the product of a member of the group defined as Q above. Thus, Q* may be viewed as a precursor of Q. In some cases, activation and displacement of the hydroxyl group may be accomplished in a single step. The activating reagent is added to a solution of the hydroxyl substituted compound in the presence of a suitable base in a suitable solvent such as dichloromethane, tetrahydrofuran, ether, DMF, benzene, acetonitrile, DMSO, and the like as described in the preceding paragraphs. The resulting activated intermediate is treated with 1 -3 molar equivalents of compound 0* a a temperature between about -78°C and 50°C for about 15 to 120 minutes, hi some cases, it is desirable to form the activated intermediate in one solvent, isolate the activated intermediate, and conduct the displacement reaction in a different solvent. In other cases, the displacement may be conducted without isolation of the intermediate and, in cases where Q* is also used as a base, may even be concurrent with the formation of the activated intermediate.

In cases where the displacement reaction is best accomplished by using the iodide, a solution of the iodide is combined with an approximately equivalent amount (0.9 - 1.05 molar equivalents) of compound O*- A silver salt of a non- nucleophilic acid, such as silver trifluoromethanesulfonate, silver tetrafluoroborate and the like is then added. Although the reaction will proceed in the absence of the silver salt, the reaction proceeds more rapidly in the presence of the silver salt. In addition, the silver salt assists in the removal of the displaced iodide from the reaction mixture which can improve the efficiency of subsequent steps. The resulting mixture is then subjected to a standard work -up procedure familiar to those skilled in the art to afford a crude product which is purified, if necessary, by recrystallization or chromatography.

An alternative method for introducing a positive charge into the side chain may be applied to side chains that contain a nitrogen atom which may be quatemized by reaction with a suitable alkylating reagent, such as methyl iodide, methyl bromide, benzyl trichloroacetimidate, methyl trifluoromethanesulfonate, triethyloxonium tetrafluoroborate, and the like. Quaternization of the nitrogen atom in the side chain is effected by treating a solution of the compound with a slight excess (1.05 to 1.2 molar equivalents) of the alkylating reagent.

The synthesis of the target compound is completed by removing any protecting groups which are present in the penultimate intermediate using standard techniques which are well known to those skilled in the art. The deprotected final product is then purified, as necessary, using standard techniques such as ion exchange chromatography, HPLC on reverse phase silica gel, MPLC on reverse phase polystyrene gel, and the like or by recrystallization. This is shown in Scheme 4. The final product may be characterized structurally by standard techniques such as NMR, IR, MS, and UV. For ease of handling, the final product, if not crystalline, may be lyophilized from water to afford an amorphous, easily handled solid.

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.

Many of compounds of the present invention are biologically active against MRSA/MRCNS. In vitro antibacterial activity is predictive of in vivo activity when the compounds are administered to a mammal infected with a susceptible bacterial organism.

Using standard susceptibility tests, the compounds of the invention are determined to be active against MRSA. The compounds of the invention can be formulated in pharmaceutical compositions by combining the compound with a pharmaceutically acceptable carrier. Examples of such carriers are set forth below. The compounds 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 various 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. In injectable compositions, the carrier is typically comprised of sterile water, saline or another injectable liquid, e.g., peanut oil for intramuscular injections. Also, various buffering agents, preservatives and the like can be included.

Topical applications may be formulated in carriers such as hydrophobic or hydrophilic bases to form ointments, creams, lotions, in aqueous, oleaginous or alcoholic liquids to form paints or in dry diluents to form powders.

Oral compositions may take such forms as tablets, capsules, oral suspensions and oral solutions. The oral compositions may utilize carriers such as 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 dosage amounts 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 invention described herein also includes a method of treating a bacterial infection in a mammal in need of such treatment comprising administering to said mammal a compound of formula I in an amount effective to treat said infection.

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 times daily 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. Many of 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-heptenoic acid or a useful salt thereof.

The invention is further described in connection with the following non-limiting examples. EXAMPLE 1

SODIUM (IS. 5R. 6S) 2-(3.3-DIOXO-2.3-DlHYDRO-3-THIA-2- AZA-CYCLOPENTA 1NAPHTALENE-1 -ONE-2-Y METHYL- -f 1 (R)-HYDROXYETHYLl- 1 -METHYLCARB APENEM-2-EM-3-

CARBOXYLATE

2) Et₂NH 3) NH₂OS0₃H, NaOH

(C₆H₅)₃P, THF, 0°, 0.5 hr

[(C₆H₅)₃P]4Pd⁰, (C₆H₅)₃P

COOH OONa

STEP 1

NAPHTHALENE- 1 -CARBOXYLIC ACID DIETHYLAMIDE To 1 -Naphthoic acid (1.72 g, 10 mmol) dissolved in methylene chloride (30 ml) and cooled to 0°C, was added dropwise, oxallyl chloride (1.75 ml, 20 mmol) followed by DMF (0.1 ml). The mixture was allowed to stir at 0°C for 0.5 hr., the ice bath was removed and stirring was continued for another 45 min. when reaction appeared to be complete. The solvent was removed under reduced pressure and the residue was treated with toluene (10 ml) and evaporated to dryness and the process was repeated to give the acid chloride.

The acid chloride was dissolved in methylene chloride (30 ml), cooled to 0°C and treated with diethylamine (2.5 ml, 24 mmol) added dropwise. The mixture was stirred at 0°C for 0.5 hr. then allowed to warm to room temp. The reaction mixture was diluted with methylene chloride, and washed with water, 1 N HCl then with satd. NaCl and dried over MgSθ4. Removal of the solvent gave the crude product which was chromatographed on silica gel using 30% EtOAc/hexane as eluant to give the pure product 2.0 g. NMR (CDC13, 500 MHz) δ 1.0 and 1.4, (2t, J=7.5, CH2013); 3.12, 3.56, 3.88 (broad q, CH2CH3); 7.4 to 7.9 (m, ArH)

STEP 2 2-SULFAMOYL-N APHTHALENE- 1 -CARBOXYLIC ACID DIETHYLAMIDE

THF (16 ml) was cooled to -78°C, under nitrogen, s-butyl Lithium (4 ml, 1.3 M soln.. in cyclohexane) was added, followed by N,N,N',N'-teramethyl-ethylenediamine (0.66 ml, 4 mmol). To this was added dropwise naphthalene- 1 -carboxylic acid diethylamide (0.908 g, 4 mmol) in THF (4 ml). The solution was stirred at -78°C for 1.5 hr.. Sulfur dioxide (4 ml) was condensed into a dropping funnel under a dry-ice condenser, under nitrogen and added to the reaction mixture dropwise. The reaction mixture was allowed to stir overnight while allowing it to come to room temperature. The solvent was removed under reduced pressure and the residue was dissolved in water/EtOH 4: 1 and cooled to 0°C.

Hydroxylamine-O-sulfonic acid ( 1.36 g, 12 mmol) was dissolved in water (8 ml) and cooled to 0°C. NaOH (2.4 ml, 5N soln..) was diluted to 8 ml with water and cooled to 0°C. The two solutions were mixed and added to the solution of the sodium salt. The ice bath was removed and the reaction mixture was stirred at room temperature for 6 hr. The solvent was evaporated to remove most of the EtOH and the residue was extracted with EtOAc. The organic phase was washed with water and satd. NaCl solution, dried over MgS04 and evaporated to give the crude product.

NMR (CDCI3, 500 MHz) δl.04 and 1.43, (2t, J=7.5, CH2CΗ3); 3.1 , 3.75, (m, CΗ2CH3); 5.44, (broad s, NH); 7.6 to 8.1

(m, ArH)

STEP 3

3.3-DIOXO-2.3-DIHYDRO-3-THIA-2-AZA-

C YCLOPENTArαlN APHTALENE- 1 -ONE

2-sulfamoyl-naphthalene-l -carboxylic acid diethylamide from the above reaction was dissolved in HOAc (20 ml) and gently refluxed overnight under nitrogen. The HOAc was removed under reduced pressure. The residue was treated with toluene (10 ml) and evaporated and the procedure was repeated once again. The residue was taken up in EtOAc, washed with HCl (1 N), water and satd. NaCl soln., dried and evaporated. The residue was treated with CHCI3 to give the product (179 mg) as a crystalline solid.

NMR (CDCI3, 500 MHz) δ; 7.4 to 9.2 (m, ArH)

STEP 4 ALLYL (I S. 5R. 6S) 2-(3.3-DIOXO-2.3-DIHYDRO-3-THIA- 2-AZA-CYCLOPENTA/α 1NAPHTALENE- 1 -ONE-2-YL) METHYL-6-r 1 (RHALLYLOXYCARBONYDOX YETHYL1- 1 -METHYLCARBAPENEM-2-EM-3-CARBOXYLATE

To a solution of allyl(l S, 5R, 6S)-2-hydroxymethyl)- 6-[ l (R)-(allyloxycarbonyl)oxyethyl]-l -methylcarbapen-2-em-3- carboxylate (0.035 g, 0.1 mmol), 3,3-dioxo-2,3-dihydro-3-thia- 2-aza-cyclopenta[(2jnaphtalene-l -one (0.025 g, 0.11 mmol) and triphenylphosphine (0.032 mg, 0.12 mmol) in THF (0.5 ml), cooled to 0°C, under nitrogen, was added diethylazodicarboxylate (0.019 ml, 0.12 mmol). After 30 min. the reaction mixture was evaporated to dryness and the residue was purified by preparative T.L.C. on a lOOOμ silica gel plate using 50% EtOAc/Hexane as eluant to give the title compound (0.030 g).

NMR (CDCI3, 500 MHz) δ: 1.29 (d, J = 7.3 Hz, I-CH3); 1.46 (d, J = 7.4 Hz, CH CHO); 3.32 (dq, H-l); 3.45 (dd, H-6); 4.22 (dd, H-5); 4.58 and 4.87 (2m, 2CH2-CH=CH2); 5.12 (dq, H-8); 5.2 to 5.54 (m, -CH=CH2); 5.9 and 6.4 (2m, CH=CH2); 4.69 and 5.51 (2d, CH2N); 7.79 (t, ArH); 7.84 (t, ArH), 7.9 (d, ArH); 8.04 (d,

ArH); 8.35 (d, ArH); 9.25 (d, ArH). STEP 5

SODIUM (I S. 5R. 6S) 2-(3.3-DIOXO-2.3-DIHYDRO-3-THIA-2- AZA-CYCLOPENTAfolNAPHTALENE- 1 -ONE-2- YDMETHYL- 6-1 1 (R)-HYDROXYETHYLl- 1 -METHYLCARB APENEM-2-EM- 3-CARBOXYLATE

Allyl (IS, 5R, 6S) 2-(3,3-dioxo-2,3-dihydro-3- thia-2-aza-cyclopenta α]naphtalene- 1 -one)methyl-6-| 1 (R)- (allyloxycarbonyl)oxyethylj- 1 -methylcarbapenem-2-em-3- carboxylate (0.030 g, 0.052 mmol) was dissolved in methylene chloride (0.5 ml) and EtOAc (0.5 ml). Sodium 2-ethylhexanoate (0.009 g, 0.054 mmol), 2-ethylhexanoic acid (0.008 g, 0.055 mmol) and triphenylphosphine (0.008 g, 0.03 mmol) were added. The reaction was placed under nitrogen and treated with tetrakis(triphenylphosphine)palladium (0.012 g, 0.01 mmol). The reaction mixture was stirred at room temperature for 0.5 hr. The reaction mixture was diluted with ether (2 ml) and the precipitated solid was centrifuged and the supernatant was decanted off. The residue was treated with ether (2 ml) and the solids centrifuged down and the supernatant liquid decanted off. The residual solid was dried under vacuum to give the crude product which was purified on a lOOOμ reverse phase TLC plate developed with 25% CH3CN/O.O2M pH 7 sodium phosphate buffer. The product band was collected and eluted off the silica gel with 50% CH3CN/ water. The extract was washed twice with hexane and the aqueous phase was evaporated to about 1 ml and desalted on a 2 ml bed of-161-c resin eluting the product off the resin with 50% CH3CN/water. The eluate was freeze dried to give the title compound.

NMR (D2O, 500 MHz) δ: 1.20 (d, J = 7.3 Hz, I -CH3); 1.25 (d, J = 7.4 Hz, CH3CHO); 3.2 (dq, H-l ); 3.44 (dd, H-6); 4.16 (dd, H-5); 4.21 (dq, H-8); 4.62 and 5.28( 2d, CH2N); 7.75 (m,

ArH); 7.87 (d, ArH); 8.02 (d, ArH); 8.32 (d, ArH); 9.85 (d, ArH). EXAMPLE 2

SODIUM (IS. 5R. 6S) 2-(3.3-DIOXO-2.3-DIHYDRO-3-THIA-2-

AZA-CYCLOPENTA 1NAPHTALENE-2-YDMETHYL-6-I KR)-

HYDROXYETHYL1-1 -METHYLCARB APENEM-2-EM-3-

CARBOXYLATE

[(C₆H5)3Pl4Pd°, {C_βH₅)₃P

COOH COONa

STEP 1

3.3-DIOXO-2.3-2.3-DIHYDRO-3-THIA-2-AZA-

CYCLOPENTAfalNAPHTHALENE

3,3-dioxo-2,3-dihydro-3-thia-2-aza- cyclopenta[α]naρhtalene-l -one from Step 3, Example 1 , (0.150 g, 0.64 mmol) was dissolved in EtOH (3 ml) cone. HCl (0.5 ml ) was added and then zinc dust (0.420 g, 6.4 mmol) was added in 4 equal portions over 25 min. Reaction mixture was allowed to stir for another 5 min. The reaction mixture was evaporated to dryness, the residue was taken up in EtOAc and washed with water, and satd. NaCl soln.., dried over MgSθ4 to give the product.

NMR (CDCI3, 500 MHz) δ; 4.92 (s, NH CH7-Ar); 7.4 to 9.2 (m, ArH)

STEP 2

ALLYL ( I S. 5R. 6S) 2-(3.3-DIOXO-2.3-DIHYDRO-3- THIA-2-AZA-CYCLOPENTAfalNAPHTALENE-2-YL) METHYL-6-l 1 (RW ALLYLOXYCARBONYDOX YETHYL1- 1 -METHYLCARBAPENEM-2-EM-3-CARBOXYLATE Following the procedure of Step 4, Example 1 , but substituting the product of Step 1 , Example 2 in place of the product of Step 3, Example 1 , one obtains the title compound.

NMR (CDCI3, 500 MHz) δ: 1.30 (d, J = 7.3 Hz, I -CH3); 1.47 (d, J = 7.4 Hz, CH CHO); 3.45 (dq, H- l); 3.48 (dd, H-6); 4.26 (dd, H-5); 5.15 (dq, H-8); 5.2 to 5.54 (m, -CH=CJi2); 5.92 and 6.03 (2m, CH=CH2); 4.31 and 4.83 ( 2d, CH2N); 4.63 and 4.80 ( 2d, CH2N);7.66 to 8.06 (m, ArH). STEP 3

SODIUM (IS. 5R. 6S) 2-(3.3-DIOXO-2.3-DIHYDRO-3-THIA-2- AZA-C YCLOPENTA/fllN APHTALENE-2- YL METHYL-6-r 1 (R )- HYDROX YETH YL1- 1 -METHYLCARB APENEM-2-EM-3- CARBOXYLATE

Following the procedure of Step 5, example 1 , but substituting the product of step 2, Example 2 in place of the product of Step 4, Example 1 , one prepares the title compound.

NMR (D20, 500 MHz) δ: 1.20 (d, J = 7.3 Hz, I -CH3); 1.26 (d, J = 7.4 Hz, CH3CHO); 3.3 (dq, H-l ); 3.46 (dd, H-6); 4.22 (m, H-5 and H-8); 4.62 and 4.85 (2d. CH2N); 7.65 to 8.06 (m, ArH).

EXAMPLE 3 SODIUM (I S. 5R. 6S) 2-(l . l -DIOXO- 1.2-DIHYDRO- l -THIA-2- AZA-CYCLOPENTA 1NAPHTALENE-3-0NE-2-YDMETHYL-6- r 1 (R)-HYDROXYETHYLl- 1 -METHYLCARB APENEM-2-EM-3-

CARBOXYLATE

2) Et₂NH

3) NH₂0S0₃H, NaOH (C₆H₅)₃P, THF, 0°, 0.5 hr

[(C₆H₅)₃P]₄Pd°, (C₆H₅)₃P

,COOH COONa

STEP 1

1 -BROMO-N APHTHALENE-2-CARBOX YLIC ACID DIETHYLAMIDE l-bromo-naphthaIene-2-carboxylic acid ( 1 g, 4 mmol) was treated with oxallyl chloride followed by reaction with diethyl- amine as described in Example 1 , Step 1 to give after chromato- graphic purification on silica gel the title compound (1.19 g).

STEP 2

1 -SULFAMOYL-NAPHTHALENE-2-CARBOX YLIC ACID DIETHYLAMIDE

1 -bromo-naphthalene-2-carboxylic acid diethylamide (0.306 g, 1 mmol) was dissolved in THF (4 ml) and cooled to -78°C under nitrogen. S-butyl lithium (0.92 ml, 1.3 M) was added dropwise and the reaction mixture allowed to stir at -78°C for 1 hr. Condensed sulfur dioxide ( 1 ml) was added to the reaction mixture as described in Example 1 , Step 2 to give the lithium sulfinate which was treated with hydroxylamine-O-sulfonic acid (0.233 g, 3 mmol) and NaOH (3 mmol) as described in Example 1 , Step 2 to give the title compound.

STEP 3 1.1 -DIOXO- 1 ,2-DIH YDRO- 1 -THI A-2- AZA- CYCLOPENTA fllNAPHTALENE-3-ONE l -sulfamoyl-naphthalene-2-carboxylic acid diethylamide from Step 2 is taken through the procedure described in Step 3, Example 1 to give the title compound. NMR (ACETONE 6D, 500 MHz) δ; 7.95 (m, ArH);

8.02 (d, ArH); 8.3 l (m, ArH); 8.52 (m, ArH)

STEP 4

ALLYL ( IS. 5R. 6S) 2-f 1.1 -DIOXO- 1.2-DIH YDRO- 1 - THIA-2-AZA-CYCLOPENTA αlNAPHTALENE-3-ONE-2-

YL)METHYL-6-r 1 (R WALLYLOXYCARBONYDOXYETHYLl-

1 -METHYLCARBAPENEM-2-EM-3-CARBOXYLATE

Following the procedure of Step 4, Example 1 , Allyl

(IS, 5R, 6S)-2-hydroxymethyl)-6-[ 1 (R)-(allyloxycarbonyl)oxyethyl]- l -methylcarbapen-2-em-3-carboxylate is reacted with l ,l -dioxo-l ,2- dihydro-l -thia-2-aza-cyclopenta/α]naphtalene-3-one to give the title compound.

NMR (CDC13, 500 MHz) δ: 1.28 (d, J = 7.3 Hz, I -CH3);

1.46 (d, J = 7.4 Hz, CH CHO); 3.31 (dq, H-l ); 3.45 (dd, H-6); 4.22 (dd, H-5); 4.58 and 4.87 (2m,

5.12 (dq, H-8); 5.22 to 5.53 (m, -CH=CΗ2); 5.9 and 6.05 (2m, CH=CH2); 4.72 and 5.55

(2d, CH2N); 7.84 (m, ArH), 8.02 (d, ArH); 8.1 (d, ArH); 8.29 (d,

ArH); 8.35 (d, ArH). STEP 5

SODIUM (I S. 5R. 6S 2-( 1.1 -DIOXO- 1.2-DIHYDRO-l -TH1A-2-

AZA-CYCLOPENTA ^rfllNAPHTALENE-3-ONE-2-YL)METHYL-6-

1 1 (R)-HYDROXYETHYLl-l -METHYLCARB APENEM-2-EM-3-

CARBOXYLATE

Following the procedure of Step 5, Example 1 , the product of Step 4, Example 3 is deblocked to give the title compound.

NMR (D2θ, 500 MHz) δ: 1.1 (d, J = 7.3 Hz, 1 -CH3); 1.24 (d, J = 7.4 Hz, CΗ3CHO); 3.18 (dq, H-l ); 3.43 (dd, H-6); 4.16 (dd, H-5); 4.21 (dq, H-8); 4.64 and 5.32 ( 2d, CH2N); 7.78 (d, ArH); 7.82 (m, ArH); 8.08 (d, ArH); 8.12 (d, ArH); 8.25 (d, ArH).

EXAMPLE 4

SODIUM (IS. 5R. 6S) 2-( 1.1 -DIOXO- 1.2-DIH YDRO- l -THIA-2-

AZA-C YCLOPENTAA IN APHTALENE-2- YDMETH YL-6-1 1 (R)-

HYDROXYETHYL1-1 -METHYLCARBAPENEM-2-EM-3-

CARBOXYLATE

EAD, <C₆H₅)₃P, THF, 0°, 0.5 hi

[(CeHsbP Pd⁰, (C₆H₅)₃P

COOH COONa

STEP 1

1.1 -DIOXO- 1 ,2-DIH YDRO- 1 -THIA-2-AZA-

CYCLOPENTA lNAPHTALENE Following the procedure of Step I , Example 2, the product from Step 3, Example 3 was reduced with zinc and HCl to give the title compound.

NMR (ACETONE 6D, 500 MHz) δ; 4.67 (s, NH-CH9- Ar); 7.60 (t, ArH); 7.68 (t, ArH); 7.76 (t, ArH); 8.1 1 (d, ArH); 8.20 (d, ArH); 8.28 (d, ArH).

STEP 2

ALLYL (IS. 5R. 6S) 2-( L I -DIOXO- 1 ,2-DIHYDRO- l -THIA-2- AZA-CYCLOPENTA ^rαlNAPHTALENE-2-YL)METHYL-6-ri(R)- ( ALLYLOX YC ARBONYDOX YETH YL1- 1 -

METHYLCARB APENEM-2-EM-3-CARBOXYLATE

Following the procedure of Step 4, Example 1 , Allyl( lS, 5R, 6S)-2-hydroxymethyl)-6-[ 1 (R)-(allyloxycarbonyl)oxyethyl]- 1 - methylcarbapen-2-em-3-carboxylate is reacted with l ,l-dioxo-l ,2- dihydro-l-thia-2-aza-cyclopenta/α]naphtalene to give the title compound.

NMR (CDC13, 500 MHz) δ: 1.32 (d, J = 7.3 Hz, I -CH3); 1.46 (d, J = 7.4 Hz, CH CHO); 3.44 (dq, H-l); 3.47 (dd, H-6); 4.25 (dd, H-5); 5.15 (dq, H-8); 5.96 (m, CH=CH2); 4.30 and 4.56 ( 2d, CH9N): 4.44 and 4.81 (2d, O N); 7.18 (d, ArH); 7.66 (t, ArH); 7.75 (t, ArH); 7.98 (d, ArH); 8.08 (d, ArH); 8.42 (d, ArH).

STEP 3 SODIUM (IS. 5R. 6S 2-( 1.1 -DIOXO- 2-DIH YDRO- l -THIA-2- AZA-CYCLOPENTAfa1NAPHTALENE-3-ONE-2-YL METHYL-6- I KRVHYDROXYETHYLl-1 -METHYLCARB APENEM-2-EM-3- CARBOXYLATE

Following the procedure of Step 5, Example 1 , the product of Step 2, Example 4 is deblocked to give the title compound.

NMR (D2O, 500 MHz) δ: 1.19 (d, J = 7.3 Hz, I -CH3); 1.26 (d, J = 7.4 Hz, CH CHO); 3.29 (dq, H- l ); 3.45 (dd, H-6); 4.20 (m, H-5 and H-8); 4.23 and 4.64( 2d, CH2N); 4.48 and 4.71 (2d, CH_.2N); 7.47 (d, ArH); 7.70 (t, ArH); 7.78 (t, ArH); 8.06 (d, ArH); 8.17 (d, ArH); 8.19 (d, ArH).

EXAMPLE 5

(IS. 5R. 6S)-2-l5-(4-CARBAMOYLMETHYL-1.4-

DlAZONIABICYCLOr2.2.2IOCT- l -YL(METHYL)-

3.3-DIOXO-1.3-DIHYDRO-3-THIA-2-AZA-

CYCLOPENTAI A [NAPHTHALENE- 1 -ONE-2-YL1METHYL-

6-f( 1 RVHYDROXY-ETHYL1- 1 -METHYLCARBAPEN-

2-EM-3-CARBOXYLATE CHLORIDE

STEP 1

1 -METHYLNAPHTHALENE-4-CARBOXYLIC ACID l-bromo-4-methylnaphthalene (4.42 g, 20 mmol) was dissolved in THF (50 ml) and cooled to -78o under nitrogen. S-butyl lithium (20 ml, 1.3M in hexane) was added dropwise. The reaction mixture stirred at -78o for 1 hr. Carbon dioxide gas was bubbled into the reaction mixture for 15 min. and the reaction mixture was stirred a further 15 min. and then allowed to come to room temperature. The reaction mixture was diluted with EtOAc and extracted with NaOH soln.. (1 N). The aqueous phase was acidified and extracted with EtOAc and the EtOAc extract was washed with satd. NaCl soln., dried over MgSθ4 and evaporated to give the title compound 2.8 g.

NMR (ACETONE °D, 500 MHz) δ; 2.76 (s, CH3-Ar); 7.46 (d, ArH); 7.63 (m, ArH); 8.13 (d, ArH); 8.19 (d, ArH); 9.1 (d, ArH). STEP 2

1 -METHYLN APHTH ALENE-4-CARBOX YLIC ACID

DIETHYLAMIDE

Following the procedure of Step 1 , Example 1 , 1 -methylnaphthalene-4-carboxylic acid is converted to the title compound.

NMR (CDCI3, 200 MHz) δ 1.0 and 1.35. (2t, J=7.5, CH2CK3); 2.7 (s, CH3Ar); 3.1 , 3.52, 3.88 (broad q, CΗ2CH3); 7.2 to 8.1 (m, ArH)

STEP 3

1 -BROMOMETHYLNAPHTHALENE-4-CARBOXYLIC ACID

DIETHYLAMIDE

1 -methylnaphthalene-4-carboxylic acid diethylamide (0.241 g, 1 mmol) was dissolved CCI4 (5 ml), N-bromosuccinimide

(0.249 g, 1.4 mmol) and benzoyl peroxide (O.OlOg) were added and the mixture refluxed under nitrogen for 1.5 hr.. The reaction mixture was cooled in an ice bath and filtered to remove the insoluble succinimide. The filtrate was washed with sodium thiosulfate solution, water and satd. NaCl soln., dried over MgSθ4 and evaporated to give the title compound.

NMR (CDCI3, 500 MHz) δ 1.03 and 1.39, (2t, J=7.5,

CH9CH3): 3.13, 3.55, 3.88 (broad q, CH2CH3); 4.97 (ABq, B1CH2);

7.2 to 8.25 (m, ArH).

STEP 4

1 -ACETOXYMETHYLNAPHTHALENE-4-CARBOX YLIC ACID

DIETHYLAMIDE

1 -bromomethylnaphthalene-4-carboxylic acid diethylamide from Step 3, Example 5 was dissolved in DMF (2 ml), potassium acetate (0.196 g, 2 mmol) was added and the reaction was heated at 100°C under nitrogen for 1 hr. The reaction was cooled to room temperature and diluted with ether and washed with water 5 times followed by satd. NaCl soln.., dried over MgS04 and evaporated to give the title compound. NMR (CDCI3, 500 MHz) δ 1.03 and 1.39, (2t, .1=7.5, CH2CΗ3}; 3.12, 3.55, 3.86 (broad q, CH2CH3); 5.58 (ABq, CH2θAc); 7.2 to 8.2 (m, ArH).

STEP 5

1 -HYDROX YMETHYLN APHTH ALENE-4-CARBOXYLIC ACID DIETHYLAMIDE

1 -acetoxymethylnaphthalene-4-carboxylic acid diethylamide from Step 4, Example 5 was dissolved in MeOH (5 ml). A solution of NaOMe in MeOH (0.150 ml, I M) was added and the reaction allowed to stir at room temperature for 1.5 hr.. Acetic acid (0.015 ml was added and the solvent was removed under reduced pressure. The residue was taken up in EtOAc and washed with water and satd. NaCl soln., dried over MgSθ4 and evaporated to give the crude alcohol. Chromatography on silica gel plates, eluted with 50%

EtOAc/hexane gave the title compound (0.095 g).

NMR (CDCI3, 500 MHz) δ 0.96 and 1.39, (2t, J=7.5,

CH2CH31; 3.13, 3.55, 3.88 (broad q, Ol2^CH3); 4.77 (ABq,

BrCH2); 7.18 to 7.8(m, ArH).

STEP 6 l -TRIETHYLSILYLOXYMETHYLNAPHTHALENE-4-

CARBOXYLIC ACID DIETHYLAMIDE

A solution of 1 -hydroxymethylnaphthalene-4-carboxylic acid diethylamide in DMF is treated with triethylsilyl chloride (1.2 eq.) and imidazole (1.2 eq.). The reaction mixture is stirred overnight at room temperature, diluted with ether and washed with water 5 times, dried over Na2S04 and evaporated to give the crude product which is purified by chromatography to give the title compound. STEP 7

1 -TRIETHYLSILYLOX YMETHYL-3-

SULFAMOYLNAPHTHALENE-4-CARBOXYLIC ACID

DIETHYLAMIDE Following the procedure of Step 2, Example 1 , 1 - triethylsilyloxymethylnaphthalene-4-carboxylic acid diethylamide is converted to the title compound.

STEP 8 5-(HYDROX YMETHYLV3.3-DIOXO- 1.3-DIHYDRO-3-THIA-2-

AZA-CYCLOPENTAlalNAPHTHALENE- 1 -ONE

Following the procedure of Step 3, Example 1 , 1 - triethylsilyloxymethyl-3-sulfamoyinaphthalene-4-carboxylic acid diethylamide is converted to the title compound. The triethylsilyloxy protecting group is concomitantly removed in this step.

STEP 9

ALLYL (IS. 5R. 6S)-2-r5-HYDROXYMETHYL-3.3-DIOXO-1.3-

DIHYDRO-3-THIA-2-AZA-CYCLOPENTAIal NAPHTHALENE- 1 - ONE-2YL1METHYL-6-K1RVALLYLOXYCARBONYLOXY-

ETHYLI-1-METHYLCARBAPEN-2-EM-3-CARBOXYLATE Following the procedure of Step 4, Example

1 , 5-(hydroxymethyl)-3,3-dioxo- 1 ,3-dihydro-3-thia-2-aza- cydopenta[a]naphthalene- l-one is reacted with allyl (IS, 5R, 6S)-2-hydroxymethyl)-6-[ 1 (R)-(allyloxycarbonyl)oxyethyl]- 1 - methylcarbapen-2-em-3-carboxylate to give the title compound.

STEP 10

ALLYL (IS. 5R. 6S)-2-r5-IODOMETHYL-3.3-DIOXO- 1.3- DIHYDRO-3-THIA-2-AZA-CYCLOPENTAralNAPHTHALENE- l-ONE-2YL1METHYL-6-r(lR ALLYLOXYCARBONYLOXY-

ETHYL1-1-METHYLCARBAPEN-2-EM-3-CARBOXYLATE

To a solution of allyl (IS, 5R, 6S)-2-[5-hydroxymethyl-

3,3-dioxo-l ,3-dihydro-3-thia-2-aza-cyclopenta(a]naphthalene-l -one- 2-yl]methyl-6-[(lR)-allyloxycarbonyloxy-ethyl]-l -methylcarbapen-2- em-3 -carboxylate in dichloromethane (1.5 ml) cooled in an ice bath under nitrogen is added triethylamine (1.8 eq) followed by methane sulfonyl chloride (1.7 eq.). After 30 min. the reaction is diluted with methylene chloride and washed with 0.1 N HCl soln.. The organic phase is dried over MgS04 and evaporated to give the mesylate. the mesylate is dissolved in acetone (2 ml) and sodium iodide (5 eq.) is added and the mixture is stirred at room temperature for 75 min. The reaction is partitioned between water and methylene chloride and the organic phase is washed with 5% aqueous NaHS03, dried over MgSθ4 and evaporated to give the title compound.

STEP 1 1

( I S. 5R. 6SV2-L5-(4-CARBAMOYLMETHYL- 1.4-

DIAZONIABICYCLOr2.2.21QCT- 1 -YL(METHYL)- 3.3-DIOXO- 1.3-DIHYDRO-3-THIA-2-AZA-

CYCLOPENTAralN APHTHALENE- 1 -ONE-2YL1 METHYL-6-r( 1 RVHYDROX Y-ETHYL1- 1 - METHYLCARBAPEN-2-EM-3-CARBOXYLATE CHLORIDE To a solution of allyl (IS, 5R, 6S)-2-[5-iodomethyl- 3,3-dioxo- 1 ,3-dihydro-3-thia-2-aza-cyclopenta[a]naphthalene- 1 - one-]methyl-6-[( 1 R)-ally loxycarbonyloxy-ethy 1]- 1 -methylcarbapen- 2-em-3-carboxylate in acetonitrile is added 1 -carbamoylmethyl-4- aza-l -azoniabicyclo-[2.2.2]octane trifluoromethane sulfonate (1.2 eq.) and silver trifluoromethane sulfonate ( 1.3 eq). The reaction is stirred at room temperature for 1 hr. then filtered and the solvent is evaporated under vacuum. The residue is dissolved in DMF and the solution is cooled in an ice bath. Sodium 2-ethylhexanoate (1.1 eq.), 2-ethylhexanoic acid (1.1 eq.), triphenylphosphine (0.3 eq.) are added and the reaction is placed under nitrogen. Tetrakis (triphenylphosphine)palladium (0.3 eq) is added and the reaction is stirred for 1 hr. Diethyl ether is added to precipitate the product. The supernatant is decanted off and the solid is washed once with ether and dried under vacuum. The solid is purified by preparative HPLC, followed by desalting on Amberchrome CG-161 resin to give the title compound after freeze drying. EXAMPLE 6

COO STEP 1

5-(HYDROXYMETHYL -3.3-DIOXO- 1.3-DIHYDRO-

3-THIA-2-AZA-CYCLOPENTAralNAPHTHALENE

5-(hydroxymethyl)-3,3-dioxo-l ,3-dihydro-3-thia- 2-aza-cyclopenta[a]naphthalene-l -one from Step Example 5, is dissolved in THF and treated with 2 molar equivalents of diborane in THF solution. The reaction is heated under nitrogen for 5 hr.. The reaction mixture is treated with MeOH and evaporated to dryness and the residue is taken up in toluene and evaporated down, and the crude product is purified by chromatography on silica gel to give the title compound.

STEP 2 ALLYL (IS. 5R. 6S -2-15-HYDROXYMETHYL-3.3-DIOXO- 1.3- DIHYDRO-3-THIA-2-AZA-CYCLOPENTAIalNAPHTHALENE-2- YL1METHYL-6-K1RVALLYLOXYCARBONYLOXY-ETHYL1-1 - METHYLCARBAPEN-2-EM-3-CARBOXYLATE

Following the procedure of Step 4, Example 1 ; 5-(hydroxymethyl)-3,3-dioxo- 1 ,3-dihydro-3-thia-2-aza- cyclopentafa]naphthalene from is reacted with allyl (IS, 5R, 6S)-2-hydroxymethyl)-6-[ 1 (R)-(allyloxycarbonyl)oxyethyl]- 1 - methylcarbapen-2-em-3-carboxylate to give the title compound.

STEP 3 ALLYL (I S. 5R. 6S)-2-f5-IODOMETHYL-3.3-DIOXO-1.3-

DIHYDRO-3-THIA-2-AZA-CYCLOPENTAralNAPHTHALENE-2- YLIMETHYL-6-r(lR)-ALLYLOXYCARBONYLOXY-ETHYLl-l - METHYLCARBAPEN-2-EM-3-CARBOXYLATE

Following the procedure of Step 10, Example 5 one obtains the title compound from the product of Step 2, Example 6. STEP 4

( IS. 5R. 6S)-2-15-(4-CARBAMOYLMETHYL-1.4-

DIAZONIABICYCLOr2.2.21QCT-l -YL(METHYL)-

3.3-DIOXO- 1.3-DIHYDRO-3-THIA-2-AZA-

CYCLOPENTAIalNAPHTHALENE-2-YL1METHYL-

6-1 ( 1 R )-H YDROX Y-ETH YL1- 1 -METHYLCARB APEN-

2-EM-3-CARBOXYLATE CHLORIDE

The product of Step 3, Example 6 is converted to the title compound by following the procedure of Step 1 1 , Example 5.

Claims

WHAT IS CLAIMED IS:

1. A compound represented by formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ represents H or methyl;

each R is independently selected from: -R*; -Q; hydrogen; halo; -CN; -N0₂; -NRaRb; -ORc; -SRc; -C(0)NRaRb_; -C(0)ORh; -S(0)R^c; -S0₂R^c; -S0₂NR^«R^b; -NR«S0₂R^b; -C(0)R<>; -OC(0)R"; -OC(0)NR"Rb_; -NR«C(0)NRbRc_; -NR«C0₂Rh; -OC0₂Rh; -NR^aC(0)R^b; -Ci-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R^d groups; and -C3-7 cycloalkyl, unsubstituted or substituted with one to four R^d groups;

each R^a, R^b and R^c independently represents hydrogen,

-R*, -Ci-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R^d groups, or -C3-7 cycloalkyl, unsubstituted or substituted with one to four R^d groups; or R^a and R^b taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one or more of O, S, NR^C, with R as defined above, or -C(O)-, said ring being unsubstituted or substituted with one to four R' groups; or R^D and R taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one to three of O, S, NRa, with R^a as defined above, or -C(O)-, said ring being unsubstituted or substituted with one to four R¹ groups;

each R^d independently represents halo; -CN; -N0₂; -NR^eR^f; -ORs; -SRs; -CONR^eR^f; -COOR^β; -SORs; -S0₂Rβ; -S0₂NReRf; -NR«S0₂R^f; -COR*; -NR* CORf; -OCORe; -OCONR^Rf; -NReCONRfR^g; -NR^eC0₂R^h; -OC0₂Rh; -C(NR«)NR^fR^g; -NR^eC(NH)NR^fR^g; -NR^eC(NR^f)Rs; -R* or -Q;

R^e, R^f and Rs represent hydrogen; -R*;

straight- or branched-chain alkyl unsubstituted or substituted with one to four R' groups; or R^e and R^f taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one to three of O, S, -C(O)- or NRs with Rg as defined above, said ring being unsubstituted or substituted with one to four R' groups;

each R' independently represents halo; -CN; -NO2; phenyl; -NHSθ2R^h; -OR¹*, -SR^h; -N(R^h)₂; -N+(R^h)₃; -C(0)N(Rh)₂; -Sθ2N(Rh)2; heteroaryl; heteroarylium; -Cθ2R^h; -C(0)R^h; -OCOR^h; -NHCOR^h; guanidinyl; carbamimidoyl or ureido;

each R^h independently represents hydrogen, a -Ci-₆ straight or branched-chain alkyl group, a -C3- , cycloalkyl group or phenyl, or when two Rⁿ groups are present, said Rⁿ groups may be taken in combination and represent a 4-6 membered saturated ring, optionally interrupted by one or two of O, S, SO2, -C(O)-, NH and NCH3;

0 is selected from the group consisting of:

wherein: a and b are 1 , 2 or 3; L- is a pharmaceutically acceptable counterion; represents O, S or NR^S; β, δ, λ, μ and σ represent CR¹, N or N+R^s, provided that no more than one of β, δ, λ, μ and σ is N+R^s;

R* is selected from the group consisting of:

wherein: d represents O, S or NR^k; e, g, x, y and z represent CR^m, N or N⁺R^k , provided that no more than one of e, g, x, y and z in any given structure represents N⁺R^k; R^k represents hydrogen; -C] -6 straight- or branched- chain alkyl, unsubstituted or substituted with one to four R' groups; or -(CH₂)_nO where n = 1 , 2 or 3 and Q is as previously defined;

each R^m independently represents a member selected from the group consisting of: hydrogen; halo; -CN; -N0₂; -NRⁿR°; -OR"; -SR"; -CONR"R^»; -COOR^b; -SOR"; -S0₂R"; -S0₂NR"Ro_; -NR"S0₂R^»; -COR"; -NR"COR°; -OCOR"; -OCONR^»R^»; -NR"C0₂R^h; -NR"CONR^oR^h; -OC0₂R^h; -CNR"NR^»R^b; -NR< NHNR»Rh; -NRⁿC(NR°)R^h; -Ci-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R¹ groups; -C3-7 cycloalkyl, unsubstituted or substituted with one to four R' groups; and -(CH )_nO where n and Q are as defined above;

R" and R° represent hydrogen, phenyl; -Cj-₆ straight- or branched-chain alkyl unsubstituted or substituted with one to four R' groups;

each R^s independently represents hydrogen; phenyl or -C] -6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R' groups;

each R^l independently represents hydrogen; halo; phenyl; -CN; -N0₂; -NR"R^v; -OR"; -SR"; -CONR"Rv; -COOR^h; -SOR"; -S0₂R^u; -S0₂NR"R^v; -NR^«S0₂R^v; -COR"; -NR"COR^v; -OCOR"; -OCONR»R^v; -NR«C0₂R^v; -NR"CONRvR _; -OC0₂Rv; -Ci -6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R^j groups;

R^u and R^v represent hydrogen or -Ci-₆ straight- or branched-chain alkyl, unsubstituted or substituted with one to four R' groups; or R^u and R^v together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one or more of O, S, NR^W or -C(O)-, said ring being unsubstituted or substituted with one to four R' groups;

each R^w independently represents hydrogen; -Cl -6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R' groups; C3-6 cycloalkyl optionally substituted with one to four R¹ groups; phenyl optionally substituted with one to four R¹ groups, or heteroaryl optionally substituted with 1 -4 R^» groups; or Rⁿ and R^w taken together with any intervening atoms represent a 5-6 membered saturated ring, optionally interrupted by one or two of O, S, Sθ2, NH or NCH3;

R^x represents hydrogen or a Cl -8 straight- or branched- chain alkyl, optionally interrupted by one or two of O, S, SO, Sθ2, NRw, N+RhRw, or -C(O)-, said chain being unsubstituted or substituted with one to four of halo, CN, Nθ2, OR^w, SR , SOR , Sθ2R^w, NRhRw, N+(Rh)2R , -C(0)-Rw, C(0)NR"Rw, Sθ2NR^hR^w, Cθ2R^w, OC(0)Rw, OC(0)NR^hR , NR«C(0)RW, NR^rιC(0)NRⁿR _{? or a} phenyl or heteroaryl group which is in turn optionally substituted with from one to four R> groups or with one to two Cl -3 straight- or branched- chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four Ri groups;

Ry and R^z represent hydrogen; phenyl; -Ci-6 straight or branched chain alkyl, unsubstituted or substituted with one to four R^j groups, and optionally interrupted by O, S, NR , N+R^hR^w or -C(O)-;

or R^x and R^y together with any intervening atoms represent a 4-8 membered saturated ring optionally interrupted by O, S, SO2, NR^W , N⁺R^hR^w or -C(O)-, unsubstituted or substituted with 1 - 4 RJ groups, and when R^χ and Ry together represent a 4-6 membered ring as defined above, R^z is as defined above or R^z represents an additional saturated 4-8 membered ring fused to the ring represented by R^x and Ry taken together, optionally interrupted by O, S, NR or

-C(O)-, said rings being unsubstituted or substituted with one to four

R' groups.

2. A compound in accordance with claim 1 wherein at least one positive charge is present in the molecule.

3. A compound in accordance with claim 1 wherein one of AB, BC and CD represents an aryl or heteroaryl ring and at least one positive charge is present in the molecule.

4. A compound in accordance with claim 3 wherein AB represent aryl, heteroaryl or heteroarylium substituted with from one to four R groups, and C and D represent R groups.

5. A compound in accordance with claim 4 wherein AB represent aryl substituted with from one to four R groups.

6. A compound in accordance with claim 3 wherein

AB represent phenyl substituted with from one to four R groups.

7. A compound in accordance with claim 1 wherein BC represent aryl, heteroaryl or heteroarylium substituted with four R groups, and A and D represent R groups.

8. A compound in accordance with claim 7 wherein BC represent aryl substituted with from one to four R groups.

9. A compound in accordance with claim 8 wherein

BC represent phenyl substituted with from one to four R groups.

10. A compound in accordance with claim 1 wherein CD represent aryl, heteroaryl or heteroarylium subsituted with from one to four R groups, and A and B represent R groups.

1 1. A compound in accordance with claim 10 wherein CD repesent aryl substituted with from one to four R groups.

12. A compound in accordance with claim 1 1 wherein CD represent phenyl substituted with from one to four R groups.

13. A compound in accordance with claim 1 wherein C0 M represents a carboxylate anion.

14. A compound in accordance with claim 1 wherein one R represents a group which contains a positively charged moiety, and the remaining R groups are selected from hydrogen and Ci- straight or branched chain alkyl, unsubstituted or substituted with one to four R^d groups.

15. A compound in accordance with claim 14 wherein one R represents a group containing a positively charged moiety and the remaining R groups are hydrogen.

16. A compound in accordance with claim 1 wherein the R groups contain from 1 -3 positive charges.

17. A compound in accordance with claim 16 wherein the R groups contain two positive charges, balanced by a carboxylate anion and a negatively charged counterion.

18. A compound in accordance with claim 1 wherein one R group represents a -Cj-6 straight or branched chain alkyl group, substituted with one to four Rd groups, wherein one R^d group represents -R* or Q.

19. A compound in accordance with claim 1 wherein Q is selected from the group consisting of:

20. A compound in accordance with claim 19 wherein wherein Q represents:

L-, a and b are as originally defined, and R^x represents a member selected from the group consisting of: hydrogen or a Cl -8 straight- or branched- chain alkyl, optionally interrupted by one or two of O, S, SO, S02, NR^W, N+R^hR^w, or -C(O)-, said chain being unsubstituted or substituted with one to four of halo, CN, Nθ2, OR^w, SR^W, SOR^W, Sθ2R^w, NRhR^w, N+(R^h)2R , -C(0)-Rw, C(0)NRhR ^W, Sθ2NRhR , CO2R ^W, OC(0)R , OC(0)NRhR , NRhC(0)Rw, NRhC(0)NRhRw, or a phenyl or heteroaryl group which is in turn optionally substituted with from one to four R¹ groups or with one to two Cι_3 straight- or branched- chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four R¹ groups, and Rⁿ, Ri and R^w are as originally defined.

21. A compound in accordance with claim 1 wherein Q represents -N⁺R^xRyR^z, wherein R^x, Ry and R^z are as originally defined.

22. A compound in accordance with claim 1 wherein one R* group is present and is selected from:

d represents NR^k; R^k represents -C] -6 straight or branched chain alkyl; and e, g, x and y represent CR^m or N+R^k, with R^k as defined above and R^m representing hydrogen.

23. A compound in accordance with claim 1 wherein: CO₂M represents a carboxylate anion; one R group contains at least one positively charged moiety, and the remaining R groups are selected from hydrogen and Ci-6 straight or branched chain alkyl, unsubstituted or substituted with one to four R^d groups. R^d is as originally defined;

R^h represents hydrogen or a Cj-6 straight or branched chain alkyl group;

Q is selected from the group consisting of:

wherein L- is as originally defined; a and b represent 2, and R^x represents a member selected from the group consisting of: hydrogen or a Cl-8 straight- or branched- chain alkyl, optionally interrupted by one or two of O, S, SO, Sθ2, NR^W,

N⁺RⁿRW₅ or -C(O)-, said chain being unsubstituted or substituted with one to four of halo, CN, Nθ2, OR^W, SR , SOR^W, Sθ2R^w, NRhR , N+(Rh)2RW -C(0)-Rw, C(0)NRhRw, sθ2NRhR , C02R^W, OC(0)R^w, OC(0)NRhRw, NRhc(0)Rw, NRⁿC(0)NRⁿR^w, _{or a} phenyl or heteroaryl group which is in turn optionally substituted with from one to four R¹ groups or with one to two Cl-3 straight- or branched- chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four RJ groups;

R* is selected from:

wherein d represents NR^k; R^k represents -Ci-6 straight or branched chain alkyl; and e, g, x and y represent CR^m or N⁺R^k, with R^k as defined above and R representing hydrogen.

24. A compound represented by formula la:

or a pharmaceutically acceptable salt thereof, wherein: CO2M represents a carboxylate anion; one R group contains a positively charged moiety, and the other R groups are selected from hydrogen and Cj-6 straight or branched chain alkyl, unsubstituted or substituted with one to four R^d groups;

Rd is as originally defined; Q is selected from the group consisting of:

wherein L- , a and b are as originally defined, and R^x represents a member selected from the group consisting of: hydrogen or a Cl -8 straight- or branched- chain alkyl, optionally interrupted by one or two of O, S, SO, Sθ2, NR , N+RhRw, or -C(O)-, said chain being unsubstituted or substituted with one to four of halo, CN, N02, ORw, SRw, SOR , Sθ2R^w, NRhRw, N+(Rh)2Rw, -C(0)-R^w, C(0)NRhR^w, S02NRhR , C02R^W, OC(0)R , OC(0)NR»R , NRhC(0)R w, NRhC(0)NRhRw, or a phenyl or heteroaryl group which is in turn optionally substituted with from one to four R¹ groups or with one to two C] -3 straight- or branched- chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four Ri groups; R^h represents hydrogen or a Ci -6 straight or branched chain alkyl group;

R^w is as originally defined; R* is selected from:

wherein d represents NR^k; R^k represents -Ci-6 straight or branched chain alkyl; and e, g, x and y represent CR^m or N⁺R^k, with R^k as defined above and R^m representing hydrogen.

25. A compound in accordance with claim 24 wherein: one R represents

and R^x, a, b and L- are as originally defined.

26. A compound in accordance with claim 1 represented by formula lb:

or a pharmaceutically acceptable salt thereof, wherein: CO2M represents a carboxylate anion; one R group contains a positively charged moiety, and the other R groups are selected from hydrogen and Ci-6 straight or branched chain alkyl, unsubstituted or substituted with one to four R^d groups;

Rd is as originally defined;

0 is selected from the group consisting of:

wherein L" , a and b are as originally defined, and R^x represents a member selected from the group consisting of: hydrogen or a Cl -8 straight- or branched- chain alkyl, optionally interrupted by one or two of O, S, SO, Sθ2, NR , N+RhRw, or -C(O)-, said chain being unsubstituted or substituted with one to four of halo, CN, NO2, OR , SR , SORw, Sθ2R^w, NRhRw, N+(Rh)2R^w, -C(0)-R , C(0)NR"R , Sθ2NRhRw, Cθ2R^w, OC(0)Rw, OC^NRhRw_^ NR"C(0)RW, NRhC(0)NRhRw, _or a phenyl or heteroaryl group which is in turn optionally substituted with from one to four Ri groups or with one to two Cl -3 straight- or branched- chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four Ri groups; R^h represents hydrogen or a C]- straight or branched chain alkyl group;

R is as originally defined; R* is selected from:

wherein d represents NR^k; R^k represents -Ci-6 straight or branched chain alkyl; and e, g, x and y represent CR^m or N+R^k, with R^k as defined above and R representing hydrogen.

27. A compound in accordance with claim 1 represented by formula lb wherein: one R represents .

and R , a, b and L- are as originally defined.

28. A compound in accordance with claim represented by one of the following structures:

88-

29. A compound in accordance with claim 1 falling within one of the following tables:

TABLE

TABLE

wherein Q is as defined in the tables and L represents a pharmaceutically acceptable counterion.

30. A pharmaceutical composition comprised of a compound in accordance with claim 1 in combination with a pharmaceutically acceptable carrier.

31. A pharmaceutical composition produced by combining a compound in accordance with claim 1 with a pharmaceutically acceptable carrier.

32. A method of treating or preventing a bacterial infection in a mammalian patient in need thereof, comprising administering to said patient an effective amount of a compound of claim 1.