AU6133599A - Carbapenem antibacterial compositions and methods of treatment - Google Patents

Description

WO 00/12048 PCT/US99/20052 TITLE OF THE INVENTION CARBAPENEM ANTIBACTERIAL COMPOSITIONS AND METHODS OF TREATMENT 5 BACKGROUND OF THE INVENTION Within the last decade, enterococcus has become the second most common pathogen isolated in nosocomial infections. The ability of recent enterococcal isolates (i.e., Enterococcus (E.)faecium, Enterococcus (E.)faecalis) to rapidly acquire multidrug resistance to all available antimicrobials and to disseminate 10 resistance determinants through the exchange of genetic elements has resulted in a serious therapeutic dilemma. Antibiotic resistance of enterococcus is characterized according to its susceptibility to two glycopeptides - vancomycin (VANCO) and teicoplanin (TEICO) and is accordingly divided into three major classes of VANCO resistant enterococci (VRE) (phenotypes VanA, VanB, VanC and perhaps even a new 15 class). Enterococcal VanA isolates (E.faeciun and E.faecalis) are resistant to high levels of VANCO (MIC 64 tg/mL) and to TEICO (MIC >16 ptg/mL) and its plasmid transferable resistance is inducible by VANCO or TEICO, while class VanB isolates demonstrate moderate levels of resistance to VANCO (=8-64 gg/mL and retain susceptibility to TEICO (MIC <2 pg/mL). Resistance to VanB isolates is 20 induced by VANCO but is not thought to be transferable. Phenotypic class VanC VANCO resistance is found in Enterococcus (E.) gallinarun and Enterococcus (E.) casselifavus, which possess low-level resistance to VANCO (MIC 4 and 32 pg/mL) but retain susceptibility to TEICO (MIC 1 pg/mL). VanA resistant E.faecium (VREF) is intrinsically resistant to most p 25 lactam (cell-wall active) antibiotics by virtue of the relatively low affinity of their penicillin-binding proteins (PBPs), which are important enzymes in cell wall biosynthesis. p-lactam antibiotics inhibit bacterial growth through their binding of PBPs. Enterococci contain a normally low affinity PBP (PBP5) which in some recent isolates appears to be over produced and, in some cases, genetically modified. 30 Emergence of strains with resistance to most p-lactam, aminoglycoside and quinolone antibiotics when used as monotherapy have left only glycopeptides alone and in combination with aminoglycosides as the first line of defense against isolates resistant to p-lactam agents. For example, treatment of serious enterococcal infections usually includes combinations of VANCO with a number of moderately 35 active p-lactams or aminoglycosides. However, this final therapeutic option is - 1 - WO 00/12048 PCT/US99/20052 waning to the more recent isolation of enterococcal strains with high-level resistance to glycopeptides. Due to the isolation of enterococccal organisms that produce p lactamases in addition to the discovery of VRE isolates with high resistance to nearly all p-lactam antibiotics, etc. (which usually occurs following monotherapy) an 5 increased intensity in the search to discover new and innovative anti-enterococcal drugs is ever pressing. SUMMARY OF THE INVENTION The present invention relates to novel 2-(naphthosultamyl)methyl 10 carbapenem antibacterial agents or pharmaceutically acceptable salts thereof in combination with other antibiotics such as p-lactams, aminoglycosides, fluoroquinolones, related quinolones and naphthyridines, chloramphenicol, macrolides, ketolides, azalides, Synercid@, tetracyclines, glycopeptides, novobiocin , oxazolidinones and the like or a combination thereof. The 15 combination is useful against gram positive microorganisms, especially methicillin resistant Staphylococcus aureus (MRSA), methicillin resistant Staphylococcus epidermidis (MRSE), and methicillin resistant coagulase negative Staphylococci (MRCNS). The present invention also relates to novel 2 20 (naphthosultamyl)methyl-carbapenem antibacterial agents or pharmaceutically acceptable salts thereof in combination with other p-lactams, which are useful in treating and preventing enterococcal infections. The combinations have anti PBP5 activity as well as activity against the critical PBPs of sensitive isolates. The antibacterial compositions of the present invention thus comprise an 25 important contribution to therapy for treating infections caused by these difficult to control pathogens. Another aspect of the invention is concerned with the use of the novel antibiotic compositions in the treatment of bacterial infections. 30 DESCRIPTION OF THE DRAWINGS Figure 1 shows the effect of Compound A (described below), at various concentrations, alone and in combination with imipenem (20 mg/kg) in treating VanA-resistant E. faecium CL5053 using the Mouse Thigh Model. Bacterial clearance is expressed in logo reductions in CFUs. 35 -2- WO 00/12048 PCT/US99/20052 Figure 2. shows the rate of kill of VanRGentsAmps E.faecalis CL5244 by Compound A (described below), at various concentrations, alone and in combination with 12 pg/mL of gentamicin. 5 Figure 3. shows the rate of kill of VanRGentsAmps E. faecalis CL4877 by Compound A (described below), at various concentrations, alone and in combination with 1.0 ptg/mL of ciprofloxacin. Figure 4. shows the effect of Compound A (10 mg/kg) and varying 10 amounts of imipenem and meropenem as well as Compound A (10 mg/kg) in combination with varying amounts of imipenem or meropenem in treating VanA resistant E.faecium CL5053. DETAILED DESCRIPTION OF THE INVENTION 15 The present invention relates to novel 2-(naphthosultamyl)methyl carbapenem antibacterial agents (such as those disclosed in US Patent No.5,756,725, herein incorporated by reference) in combination with other p-lactams, aminoglycosides, fluoroquinolones and the like. It is known that the response to a given combination may be strain specific and is not solely related to the level of 20 sensitivity/resistance to the specific members of the combination. Thus, the combinations of the present invention are intended to be useful on all bacterial strains including those not mentioned herein. One embodiment of the invention relates to compositions comprising a pharmaceutically acceptable carrier, a 2-(naphthosultamyl)methyl-carbapenem of 25 structural formula I: HH R'

(R)

3 H H RX. N

C

H 2 -N O --(R) 3 I CO 2M O=3 or a pharmaceutically acceptable salt thereof, wherein: -3- WO 00/12048 PCT/US99/20052

R

1 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 5 group; P represents hydrogen, hydroxyl, F or hydroxyl protected by a hydroxyl-protecting group; each R is independently selected from: -R*; -Q; hydrogen; halo; CN; -NO 2 ; -NRaRb; -ORc; -SRc; -C(O)NRaRb; -C(O)ORh; -S(O)Rc; -SO 2 Rc; 10 SO 2 NRaRb; -NRaSO 2 Rb; -C(O)Ra; -OC(O)Ra; -OC(O)NRaRb; -NRaC(O)NRbRe; NRaCO 2 Rh; -OCO 2 Rh; -NRaC(O)Rb; -C 1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Rd groups; and -C3-7 cycloalkyl, unsubstituted or substituted with one to four Rd groups; each Ra, Rb and Rc independently represents hydrogen, -R*, -C 1-6 15 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Rd groups, or -C3-7 cycloalkyl, unsubstituted or substituted with one to four Rd groups; or Ra and Rb taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one or more of 0, S, NRc, with Rc as defined above, or -C(O)-, said ring being unsubstituted or substituted with one to 20 four R 1 groups; or Rb and Rc taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one to three of 0, S, NRa, with Ra as defined above, or -C(O)-, said ring being unsubstituted or substituted with one to four Ri groups; 25 each Rd independently represents halo; -CN; -N02; -NReRf; -OR8; -SRg; -CONReRf; -COORs; -SORg; -SO 2 R9; -SO 2 NReRf; NReSO 2 Rf; -CORe; -NRe CORf; -OCORe; -OCONReRf; -NReCONRfRg; NReCO 2 Rh; -OC0 2 Rh; -C(NRe)NRfRg; -NReC(NH)NRfRg; -NReC(NRf)Rg; -R* or Q; 30 Re, Rf and R9 represent hydrogen; -R*; -C 1-6 straight- or branched chain alkyl unsubstituted or substituted with one to four R1 groups; or Re and Rf taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one to three of 0, S, -C(O)- or NR8 -4- WO 00/12048 PCT/US99/20052 with Rg as defined above, said ring being unsubstituted or substituted with one to four Ri groups; each Ri independently represents halo; -CN; -N02; phenyl; -NHSO 2 Rh; -ORh, -SRh; -N(Rh) 2 ; -N+(Rh) 3 ; -C(O)N(Rh) 2 ; -SO 2 N(Rh) 2 ; 5 heteroaryl; heteroarylium; -CO 2 Rh; -C(O)Rh; -OCORh; -NHCORh; guanidinyl; carbamimidoyl or ureido; each Rh independently represents hydrogen, a -C 1-6 straight or branched-chain alkyl group, a -C3-C6 cycloalkyl group or phenyl, or when two Rh groups are present, said Rh groups may be taken in combination and represent 10 a 4-6 membered saturated ring, optionally interrupted by one or two of 0, S, S02, C(O)-, NH and NCH3; Q is selected from the group consisting of: (CH 2)b N ~ , N N , -N N-Rx and NRxRYRz \ \It L (CH 2)a wherein: 15 a and b are 1, 2 or 3; L- is a pharmaceutically acceptable counterion; ac represents 0, S or NRs; p, 6, X, jL and a represent CRt, N or N+Rs, provided that no more than one of 6, X, j and a is N+Rs; 20 R* is selected from the group consisting of: / 1 ,1 and z d'-- e Y e-9g wherein: 25 d represents 0, S or NRk; e, g, x, y and z represent CRm, N or N+Rk , provided that no more than one of e, g, x, y and z in any given structure represents N±Rk; -5- WO 00/12048 PCTIUS99/20052 Rk represents hydrogen; -C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups; or -(CH2)nQ where n = 1, 2 or 3 and Q is as previously defined; each Rnm independently represents a member selected from the group 5 consisting of: hydrogen; halo; -CN; -NO 2 ; -NRnRo; -ORn; -SRn; -CONRnRO; COORh; -SORn; -SO 2 Rn; -SO 2 NRnRO; -NRnSO 2 RO; -CORn; -NRnCORO; -OCORn; OCONRnRO; -NRnCO 2 Rh; -NRnCONRoRh; -OCO 2 Rh; -CNRnNRoRh; NRnCNHNRoRh; -NRnC(NRO)Rh; -C1 -6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups; -C3-7 cycloalkyl, 10 unsubstituted or substituted with one to four Ri groups; and -(CH2)nQ where n and Q are as defined above; Rn and RO represent hydrogen, phenyl; -C1 -6 straight- or branched chain alkyl unsubstituted or substituted with one to four R 1 groups; each Rs independently represents hydrogen; phenyl or -C 1-6 straight 15 or branched-chain alkyl, unsubstituted or substituted with one to four R' groups; each Rt independently represents hydrogen; halo; phenyl; -CN; -NO 2 ; NRuRv; -ORu; -SRu; -CONRuRv; -COORh; -SORu; -SO 2 Ru; -SO 2 NRURv; NRuSO 2 Rv; -CORu; -NRuCORv; -OCORu; -OCONRuRv; -NRuCO 2 Rv; NRuCONRvRw; -OC0 2 Rv; -C1 -6 straight- or branched-chain alkyl, unsubstituted or 20 substituted with one to four R 1 groups; Ru and Rv represent hydrogen or -C1 -6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups; or Ru and Rv together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one or more of 0, S, NRW or 25 C(O)-, said ring being unsubstituted or substituted with one to four Ri groups; each RW independently represents hydrogen; -C 1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups; C3-6 cycloalkyl optionally substituted with one to four Ri groups; phenyl optionally substituted with one to four Ri groups, or heteroaryl optionally substituted with 1-4 R' 30 groups; or Rh and Rw taken together with any intervening atoms represent a 5 6 membered saturated ring, optionally interrupted by one or two of 0, S, S02, NH or NCH3; -6- WO 00/12048 PCT/US99/20052 Rx represents hydrogen or a C1-8 straight- or branched- chain alkyl, optionally interrupted by one or two of 0, S, SO, S02, NRw, N+RhRw, or -C(O)-, said chain being unsubstituted or substituted with one to four of halo, CN, N02, ORw, SRw, SORw, S02Rw, NRhRw, N+(Rh) 2 Rw, -C(O)-Rw, C(O)NRhRw, 5 SO 2 NRhRw, CO2Rw, OC(O)Rw, OC(0)NRhRw, NRhC(O)Rw, NRhC(O)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 C1 -3 straight- or branched- chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four R 1 groups; RY and Rz represent hydrogen; phcnyl; -C1 -6 straight or branched 10 chain alkyl, unsubstituted or substituted with one to four Ri groups, and optionally interrupted by 0, S, NRw, N+RhRw or -C(O)-; or Rx and RY together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by 0, S, S02, NRw , N+RhRw or C(O)-, unsubstituted or substituted with I - 4 Ri groups, 15 and when Rx and RY together represent a 4-6 membered ring as defined above, Rz is as defined above or Rz represents an additional saturated 4-6 membered ring fused to the ring represented by RX and RY taken together, optionally interrupted by 0, S, NRW or -C(O)-, said rings being unsubstituted or substituted with one to four R 1 groups; 20 and another antibiotic including p-lactams such as carbapenems, cephalosporins (ceftriaxone), penicillins; aminoglycosides (as exemplified by gentamicin and including but not limited to amikacin, dibekacin, streptomycin, neomycin, kanamycin, spectinomycin, kasugamycin); fluoroquinolones (as exemplified by ciprofloxacin and including but not limited to trovafloxacin, sparfloxacin, gatifloxacin, grepafloxacin, 25 ofloxacin, norfloxacin, floxin, levofloxacin) and related quinolones and naphthyridines with activity against topoisomerases; chloramphenicol; as well as macrolides, ketolides, azalides (and other related polyketides), Synercid@, tetracyclines (including glycylcyclines), glycopeptides (including, but not limited to, vancomycin, teicoplainin, LY-333328), novobiocin (and coumermycin) and 30 oxazolidinones or a combination thereof. -7- WO 00/12048 PCT/US99/20052 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) 5 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 Rd and Ri, as defined, at any available point of attachment. When the alkyl group 10 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. 15 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 20 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 25 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 as defined. Preferred substituted aryls include phenyl and naphthyl. 30 The term "heteroaryl" refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing at least one heteroatom, 0, S or N, in which a carbon or nitrogen atom is the point of attachment, and in which one or two additional carbon atoms is optionally replaced by a heteroatom selected from 0 or S, and in which from -8- WO 00/12048 PCT/US99/20052 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 5 sulfur, giving, e.g., thiadiazole. Examples include the following: NH NH S N/ N/ pyrrole (pyrrolyl) imidazole (imidazolyl) thiazole (thiazolyl) N OOV oxazole (oxazolyl) furan (furyl) thiophene (thienyl) NH _NNH N/N N triazole (triazolyl) pyrazole (pyrazolyl) isoxazole (isoxazolyl) SQ isothiazole (isothiazolyl) pyridine (pyridinyl) pyrazine (pyrazinyl) N N pyridazine (pyridazinyl) pyrimidine (pyrimidinyl) N triazine (triazinyl) -9- WO 00/12048 PCT/US99/20052 Heteroarylium refers to heteroaryl groups bearing a quaternary nitrogen atom and thus a positive charge. Examples include the following: + N ..--- N -CH 3 N O" ,IQN-CH 3 IQO

N-CH

3 CH 3

OH

3 N S+N NCH3 N N

CH

3 5 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. 10

N-OH

3

N-CH

3 Nz Ny and -10- WO 00/12048 PCTIUS99/20052

-CH

3 N N CH3 The term "heterocycloalkyl" refers to a cycloalkyl group (nonaromatic) in which one of the carbon atoms in the ring is replaced by a 5 heteroatom selected from 0, 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 tetraalkylammonium group (e. g. tetramethylammonium), 10 heteroarylium, (e.g., N-methyl-pyridinium), 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 0, S or N, selected on an 15 independent basis. Halogen and "halo" refer to bromine, chlorine, fluorine and iodine. Alkoxy refers to CI-C 4 alkyl-O-, with the alkyl group optionally substituted as described herein. When a group is termed "substituted", unless otherwise indicated, 20 this means that the group contains from I to 4 substituents thereon. With respect to R, Ra, Rb and Rc, the substituents available on alkyl groups are selected from the values of Rd. Many of the variable groups are optionally substituted with up to four Ri groups. With respect to Re, Rf and Rg, when these variables represent substituted alkyl, the substituents available thereon are selected from the values of 25 Ri. 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 30 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. - 11 - WO 00/12048 PCTIUS99/20052 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 5 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 10 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 15 nitrobenzyl, 4-pyridylmethyl and t-butyl. Examples of suitable C-6 hydroxyethyl protecting groups include triethylsilyl, t-butyldimethylsilyl, o-nitrobenzyloxycarbonyl, p nitrobenzyloxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, t-butyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl and the like. 20 The carbapenems of this invention, other than the novel 2 (naphthosultamyl)methyl-carbapenem described above, includes imipenem (plus or minus cilastatin), meropenem, biapenem, panipenem, (4R, 5S, 6S)-3-[3S,5S)-5-(3 carboxyphenylcarbamoyl)pyrrolidin-3-ylthio]- 6 -(IR)-1-hydroxyethyl]-4-methyl-7 oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, an enantiomer, diastereomer or 25 pharmaceutically acceptable salt thereof. The P-lactams included in this invention include carbapenems such as imipenem (plus or minus cilastatin; with cilastatin = Primaxin@), meropenem, biapenem, panipenem, (4R, 5S, 6S)-3-[3S,5S)-5-(3 carboxyphenylcarbamoyl)pyrrolidin-3-ylthio]- 6 -(1R)-1-hydroxyethyl]-4-methyl-7 30 oxo- 1 -azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, an enantiomer, diastereomer or pharmaceutically acceptable salt thereof and the like, cephalosporins and cephamycins such as cefoperazone, cefotiam, cefpirome, cefmetazole, cafazolin, cephalexin, cefuroxime, cefaclor, cefotaxime, ceftriaxone, moxalactam, cefixime and the like and penicillins such as ampicillin, amoxicillin, piperacillin, nafcillin, oxacillin, cloxacillin - 12 - WO 00/12048 PCTIUS99/20052 and combinations of penicillins with a beta-lactamase inhibitor such as sulbactam, clavulanic acid, tazobactam, and the like. The carbapenem compositions of the present invention are useful per se and in their pharmaceutically acceptable salt and ester forms for the 5 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 10 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 15 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 20 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, 25 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. 30 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, 35 cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, - 13- WO 00/12048 PCT/US99/20052 glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, pirate, pivalate, propionate, succinate, 5 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, 10 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 intestinal 15 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 20 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-1,3-dioxolen-4-yl)methyl. 25 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, 30 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 35 will be apparent to the ordinarily skilled chemist. - 14 - WO 00/12048 PCTIUS99/20052 Likewise, when L- represents a species with more than one negative charge, such as malonate, tartrate or ethylenediamine-tetraacetate (EDTA), an appropriate number of carbapenem molecules can be found in association therewith to maintain the overall charge balance and neutrality. 5 It is preferred that least one of the R groups attached to the naphtho-sultam platform contains a positively charged moiety. Thus, it can include -R* or Q, or a moiety which in turn contains a positively charged group. Yet another embodiment of this invention is realized when the 10 compounds of structural formula I are represented by formula Ie: HO H H R1 HOO

H

3 C C Ne C 2 - N 0 or a pharmaceutically acceptable salt thereof, wherein: 15 R contains a positively charged moiety selected from the group consisting of: -R*, Q, and a C1-6 straight or branched alkyl chain substituted with one Rd group; Rd is independently selected -R* or Q; Q is selected from the group consisting of: 20 (CH 2) N Y, N I and 7 NRX L (CH 2 )a wherein L-, a and b are as originally defined, and RX represents a member selected from the group consisting of: hydrogen or a Ci. 25 8 straight- or branched- chain alkyl, optionally interrupted by one or two of 0, S, SO, S02, NRw, N+RhRw, or -C(O)-, said chain being unsubstituted or substituted with one to four of halo, CN, N02, ORw, SRW, SORW, SO 2 RW, NRhRw, - 15 - WO 00/12048 PCT/US99/20052 N+(Rh) 2 Rw, -C(O)-Rw, C(O)NRhRw, SO 2 NRhRw, CO 2 Rw, OC(O)Rw, OC(O)NRhRw, NRhC(O)Rw, NRhC(O)NRhRwv, or a phenyl or heteroaryl group which is in turn optionally substituted with from one to four R 1 groups or with one to two C 1-3 straight- or branched- chain alkyl groups, said alkyl groups being 5 unsubstituted or substituted with one to four R' groups; R* is selected from: I1 and d-- e*. 10 wherein d represents NRk; Rk represents -C1 -6 straight or branched chain alkyl; and e, g, x and y represent CRm or N+Rk, with Rk as defined above and Rm representing hydrogen. Still another embodiment of the invention is realized when the compounds of formula I are: 15 (1 S,5R,6S)-2-(5-(((carbamoylmethyl)-1,4-diazoniabicyclo[2.2.2]oct-1 -yl)methyl)(1,8 naphthosultam)methyl)-6-[1 (R)-hydroxyethyl]-1 -methylcarbapen-2-em-3-carboxylate chloride; (1S,5R,6S)-2-(5-(((3-hydroxyprop-1-yl)-1,4-diazoniabicyclo[2.2.2]oct-1 yl)methyl)(1,8-naphthosultam)methyl)-6-[I (R)-hydroxyethyl]- 1 -methylcarbapen-2 20 em-3-carboxylate chloride; (1S,5R,6S)-2-(5-((1-methylimidazol-3-ium)methyl)(1,8-naphthosultam)methyl)-6 [1(R)-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate; (1S,5R,6S)-2-(5-(((2-(1-methylimidazol-3-ium)-ethyl)(1,8-naphthosultam)methyl)-6 [1 (R)-hydroxyethyl]- I -methylcarbapen-2-em-3-carboxylate; 25 (1 S,5R,6S)-2-(4-(((carbamoylmethyl)- 1,4-diazoniabicyclo[2.2.2]oct- 1 -yl)methyl)(1,8 naphthosultam)methyl)-6-[ 1 (R)-hydroxyethyl]- 1 -methylcarbapen-2-em-3-carboxylate chloride; (I S,5R,6S)-2-(4-(2-(((carbamoylmethyl)- 1,4-diazoniabicyclo[2.2.2]oct- 1 -yl)) ethyl)(1,8-naphthosultam)methyl)-6-[ 1 (R)-hydroxyethyl] -1 -methylcarbapen-2-em-3 30 carboxylate chloride; (1S,5R,6S)-2-(4-(2-(((3-hydroxyprop-1-yl)-1,4-diazoniabicyclo[2.2.2]oct-1-yl)) ethyl)(1,8-naphthosultam)methyl)-6-[1(R)-hydroxyethyl]-I -methylcarbapen-2-em-3 carboxylate chloride; or - 16 - WO 00/12048 PCT/US99/20052 (1 S,5R,6S)-2-(4-(2-((1 -methylimidazol-3-ium))-ethyl)(1,8-naphthosultam)methyl)-6 [1 (R)-hydroxyethyl]- 1 -methylcarbapen-2-em-3-carboxylate. A preferred embodiment of the invention is realized when the compounds of formula I are: 5 (1 S,5R,6S)-2-(5-(((carbamoylmethyl)- 1,4-diazoniabicyclo[2.2.2]oct- 1 -yl)methyl)(1,8 naphthosultam)methyl)-6-[ 1 (R)-hydroxyethyl]- 1 -methylcarbapen-2-em-3-carboxylate chloride; (1 S,5R,6S)-2-(4-(((carbamoylmethyl)- 1,4-diazoniabicyclo[2.2.2]oct- 1 -yl)methyl)(1,8 naphthosultam)methyl)-6-[ 1 (R)-hydroxyethyl]- 1 -methylcarbapen-2-em-3-carboxylate 10 chloride; or (1S,5R,6S)-2-(4-(2-(((carbamoylmethyl)-1,4-diazoniabicyclo[2.2.2]oct-1-yl)) ethyl)(1,8-naphthosultam)methyl)-6-[1(R)-hydroxyethyl]-1-methylcarbapen-2-em-3 carboxylate chloride. Another preferred embodiment of the invention is realized when the 15 other antibiotic employed is selected from the group consisting of cephalosporins, penicillins, gentamicin, ciprofloxacin, imipenem, meropenem, chloramphenicol, vancomycin, or teicoplainin. In yet another aspect of this invention, the novel antibacterial compositions of this invention comprise a pharmaceuticallly acceptable carrier, a 20 therapeutically effective amount of a 2-(naphthosultamyl)methyl-carbapenem selected from (IS,5R,6S)-2-(5-(((carbamoylmethyl)-1,4-diazoniabicyclo[2.2.2]oct-1-yl)methyl)(1,8 naphthosultam)methyl)-6-[1(R)-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate chloride; 25 (lS,5R,6S)-2-(4-(((carbamoylmethyl)-1,4-diazoniabicyclo[2.2.2]oct-1-yl)methyl)(1,8 naphthosultam)methyl)-6-[I(R)-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate chloride; and (1S,5R,6S)-2-(4-(2-(((carbamoylmethyl)-1,4-diazoniabicyclo[2.2.2]oct-1-yl)) ethyl)(1,8-naphthosultam)methyl)-6-[1(R)-hydroxyethyl]-1-methylcarbapen-2-em-3 30 carboxylate chloride; and a therapeutically effective amount of another antibiotic selected from carbapenems, cephalosporins (ceftriaxone), penicillins; aminoglycosides (as exemplified by gentamicin and including but not limited to amikacin, dibekacin, streptomycin, neomycin, kanamycin, spectinomycin, kasugamycin); fluoroquinolones (as exemplified by ciprofloxacin and including but 35 not limited to trovafloxacin, sparfloxacin, gatifloxacin, grepafloxacin, ofloxacin, - 17- WO 00/12048 PCT/US99/20052 norfloxacin, floxin, levofloxacin) and related quinolones and naphthyridines with activity against topoisomerases; chloramphenicol; as well as macrolides, ketolides, azalides (and other related polyketides), Synercid@, tetracyclines (including glycylcyclines), glycopeptides (including, but not limited to, vancomycin, 5 teicoplainin, LY-333328), novobiocin (and coumermycin) and oxazolidinones or a combination thereof. An aspect of this invention is realized when the 2 (naphthosultamyl)methyl-carbapenem is (1 S,5R,6S)-2-(4-(2-(((carbamoylmethyl) 1,4-diazoniabicyclo[2.2.2]oct-1-yl))-ethyl)(1,8-naphthosultam)methyl)-6-[1(R) 10 hydroxyethyl]- I -methylcarbapen-2-em-3-carboxylate chloride; and the other antibiotic selected is from cephalosporins, penicillins, gentamicin, ciprofloxacin, imipenem, meropenem, (4R, 5S, 6S)-3-[(3S, 5S)-5-(3 carboxyphenylcarbamoyl)pyrrolidin-3-ylthio]-6-(1 R)- 1 -hydroxyethyl]-4-methyl-7 oxo- 1 -azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, chloramphenicol, 15 vancomycin, and teicoplainin. Another embodiment of this invention relates to 2 (naphthosultamyl)methyl-carbapenem antibacterial agents or ophthamologically acceptable salts thereof, described above, in combination with other carbapenems. An aspect of this invention is realized when the other carbapenem is 20 (4R, 5S, 6S)-3-[(3S, 5S)-5-(3-carboxyphenylcarbamoyl)pyrrolidin-3-ylthio]-6-(1R)-1 hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, imipenem, or meropenem from about 1 to about 100 mg/kg, preferably about 2 to about 50 mg/kg and the 2-(naphthosultamyl)methyl-carbapenem is (1S,5R,6S)-2-(4 (2-(((carbamoylmethyl)-1,4-diazoniabicyclo[2.2.2]oct-1-yl))-ethyl)(1,8 25 naphthosultam)methyl)-6-[1(R)-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate chloride, from about 0.1 to about 50 mg/kg, preferably about 0.5 to about 20 mg/kg. Another embodiment of this invention relates to from about novel 2 (naphthosultamyl)methyl-carbapenem antibacterial agents or ophthamologically acceptable salts thereof, described above, in combination with fluoroquinolones, 30 aminoglycosides, or chloramphenicol or a combination thereof. An aspect of this invention is realized when the fluoroquinolone is ciprofloxacin, from about 0.1 to about 40 mg/kg, preferably about 0.5 to about 20 mg/kg of the aminoglycoside is gentamicin from about 0.5 to about 12 mg/kg, and the 2-(naphthosultamyl)methyl-carbapenem is (1 S,5R,6S)-2-(4-(2 35 (((carbamoylmethyl)-1,4-diazoniabicyclo[2.2.2]oct-1-yl))-ethyl)(1,8 - 18- WO 00/12048 PCT/US99/20052 naphthosultam)methyl)-6-[l (R)-hydroxyethyl]- I -methylcarbapen-2-em-3-carboxylate chloride, from about 0.1 to about 50 mg/kg, preferably about o.5 to about 20 mg/kg. Still another embodiment of this invention relates to novel 2 (naphthosultamyl)methyl-carbapenem antibacterial agents or ophthamologically 5 acceptable salts thereof, described above, in combination with a imipenem or meropenem and another antibiotic selected from cephalosporins, penicillins, gentamicin, ciprofloxacin, chloramphenicol, vancomycin, or teicoplainin. The compositions of the present invention are valuable as antibacterial agents active against enterococcal infections, particularly against 10 clinical isolates of multiply resistant E.faeciun. The compositions of the present invention are also valuable as antibacterial agents active against various gram positive and gram negative bacteria. Many of compositions of the present invention are also biologically active against MRSA/MRCNS. Suitable subjects for the administration of the formulation of the 15 present invention include mammals, primates, man, and other animals. In vitro antibacterial activity is predictive of in vivo activity when the compositions are administered to a mammal infected with a susceptible bacterial organism. Using standard susceptibility tests, the compositions of the invention are determined to be active against MRSA and enterococcal infections. 20 The compounds of the invention are formulated in pharmaceutical compositions by combining the compounds 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 25 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 30 emulsions in oily or aqueous vehicles, and may contain various formulating agents. Alternatively, the active ingredient may be in powder (lyophilized or non lyophilized) 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 - 19 - WO 00/12048 PCT/US99/20052 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, 5 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. 10 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 15 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 novel antibiotic compositions of this invention for human delivery per unit dosage, whether liquid or solid, comprise from about 0.01% to as 20 high as about 99% of the 2-(naphthosultamyl)methyl-carbapenem discussed herein, the preferred range being from about 10-60% and from about 1% to about 99.99% of one or more of other antibiotics such as those discussed herein, preferably from about 40% to about 90%. The composition will generally contain from about 125 mg to about 3.0 g of the 2-(naphthosultamyl)methyl-carbapenem 25 discussed herein; however, in general, it is preferable to employ dosage amounts in the range of from about 250 mg to 1000 mg and from about 200mg to about 5 g of the other antibiotics discussed herein; preferably from about 250 mg to about 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 30 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 the claimed composition in an amount effective to treat said infection. - 20 - WO 00/12048 PCT/US99/20052 The preferred methods of administration of the claimed compositions include oral and parenteral, e.g., i.v. infusion, i.v. bolus and i.m. injection formulated so that a unit dosage comprises a therapeutically effective amount of each active component or some submultiple thereof. 5 For adults, about 5-50 mg/kg of body weight, preferably about 250 mg to about 1000 mg per person of the 2-(naphthosultamyl)methyl-carbapenem antibacterial compound and about 250 mg, to about 1000 mg per person of the other antibiotic(s) given one to four times daily is preferred. More specifically, for mild infections a dose of about 250 mg two or three times daily of the 2 10 (naphthosultamyl)methyl-carbapenem antibacterial compound and about 250 mg two or three times daily of the other antibiotic is recommended. For moderate infections against highly susceptible gram positive organisms a dose of about 500 mg each of the 2-(naphthosultamyl)methyl-carbapenem and the other antibiotics, three or four times daily is recommended. For severe, life-threatening infections 15 against organisms at the upper limits of sensitivity to the antibiotic, a dose of about 500-2000 mg each of the 2-(naphthosultamyl)methyl-carbapenem and the other antibiotics, 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. 20 The claimed compositions contain antibiotic agents which 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 25 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)]. 30 The compositions 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, 35 combination compositions and methods of treatment. It is preferred that a - 21 - WO 00/12048 PCTIUS99/20052 pharmaceutically acceptable amount of cilastatin is administered with the carbapenems. A preferred weight ratio of DHP to carbapenem: DHP inhibitor in the combination compositions is about 1:1. The amount of DHP to employed generally can be determined by the skilled artisan. US Patent 4539208, herein 5 incorporated by reference illustrates the amount of DHP that can be used with a carbapenem. A preferred DHP inhibitor is 7-(L-2-amino-2-carboxy-ethylthio)-2 (2,2-dimethylcyclopropanecarboxamide)-2-heptenoic acid or a useful salt thereof. Thus, another aspect of this invention is realized when the 2 10 (naphthosultamyl)methyl-carbapenem antibacterial agents or ophthamologically acceptable salts thereof, described above, are in combination with imipenem or meropenem containing 7-(L-2-amino-2-carboxy-ethylthio)-2-(2,2 dimethylcyclopropanecarboxamide)-2-heptenoic acid or a useful salt thereof. When imipenem contains cilastatin it is preferred that composition is Primaxin@. 15 The invention is further described in connection with the following non-limiting examples. EXAMPLE 1 The relative in-vivo protective abilities of (1S,5R,6S)-2-(4-(2 (((carbamoylmethyl)-1,4-diazoniabicyclo[2.2.2]oct-1-yl))-ethyl)(1,8 20 naphthosultam)methyl)-6-[1(R)-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate chloride (Compound A) in combination with imipenem (IPM) to influence clearance of CL5053 from local soft tissue (thigh) was measured in a cyclophosphamide-treated mouse model. Multple antibiotic treatments were administered (s.c.) over a 5 day period. Tissues were aseptically removed on day +7 and processed. 25 MATERIALS and METHODS Localized Tissue Infection Model Bacterial Culture Preparation Stock cultures of E.faecium CL5053 (obtained from Bellevue Hospital 30 in NYC) were prepared from slants or L-tubes. A shake flask containing -75 mL of trypticase soy broth (TSB) was inoculated with -mL of seed culture followed by shaking at 250 rpm for 10-12 hours at 35*C. The culture was then washed (i.e., centrifuged in a Sorvall RC-5B at 5000 rpm -15 min and bacterial cells concentrated twofold [to -109 to 1010 colony forming units (CFU/mL)] in fresh TSB containing 35 10% glycerol (or in PBS-10% glycerol) by reconstituting the pellet in -half the - 22 - WO 00/12048 PCT/US99/20052 original volume. Finally, -1 mL aliquots of the washed stock culture was stored in 70'C for later use to initiate cultures for animal infections. Prior to infection, 1 mL of the above frozen culture was thawed in cold H20, warmed to 35'C and added to -75 mL fresh TSB before incubating at 35"C for 5 -10 hours as described above. The 10 hour culture was then washed as above to remove media containing toxins, etc. released during cell growth and bacterial death. The cell pellet was then reconstituted with fresh TSB in half the original volume. 0.2 mL of the washed, concentrated culture (challenge inoculum) was injected intramuscularly (i.m.) into the right thighs of mice. Infected mice were further 10 divided into appropriate groups of 5 or 10 animals each for antibiotic treatments. Antibiotic Preparations The antibiotics of this invention were prepared in 10 mM 3-[ Morpholinolpropanesulfonic acid (MOPS) buffer, pH 7.1. For all carbapenems, the 15 above MOPS buffer also contains cilastatin, a renal dehydropeptidase-I (DHP-1) inhibitor, at a concentration which would yield a final dose of 40 mg/kg in a 0.5 mL inoculum/mouse regardless of antibiotic concentration. Antibiotic dosing (s.c. in 0.5 mL) was initiated one hour following bacterial challenge (+1 hour), followed by two treatments at four hour intervals ( +5 and +9 hours). Over the next 5 days, further 20 antibiotic treatments were administered once or twice daily (at -10 to 1 2 and at -24 hour intervals, respectively) starting at -+20 hours and continuing for a total of either 8 or 13 treatments. Two days after the last antibiotic treatment (day +7), animals were sacrificed and thigh tissues were prepared for CFU determination. 25 Animals Random outbred CD1 mice (Charles River Labs) were immunocompromised by a single injection of cyclophosphamide (Cytoxan) prepared in PBS at a final concentration of 250 mg/kg/0.5 mL/mouse -4 days prior to i.m. bacterial challenge with E. faecium CL5053. Immediately before or after bacterial 30 challenge, 0.5 mL of a 0.45 pim membrane filtered ferric iron (Fe+ 3 )/PBS solution was injected i.p. at 20 mg/kg. The source of Fe+ 3 was obtained by appropriate PBS solubilization of ferric ammonium citrate (consisting of 18.5% Fe+ 3 by weight) followed by filtering through a 0.45 im membrane just prior to its i.p. administration at the time of bacterial challenge. - 23 - WO 00/12048 PCT/US99/20052 Preparation of Tissue for Detection of Colony Forming Units (CFU) On day +7 mice were euthanized, the lower abdomen and thighs were flushed with 70% ethanol and the outer skin aseptically removed. Denuded thigh tissues were aseptically collected and placed in tubes containing 4 mL of sterile 5 PBS/10% glycerol for temporary -70"C storage or for same day processing. On the day of plating, frozen thighs were thawed in cold H20, ground with a Polytron homogenizer for 5-10 seconds each and placed on ice for further dilutions. Tenfold serial dilutions of each sample were made in tubes containing 0.9 mL of cold fresh TSB prior to plating 0.1 mL from selected dilution tubes onto Enterococcus-specific 10 m-Enterococcus agar plates. Plates were incubated at 35'C for 2 to 3 days and the number of CFU's remaining per thigh determined. Results Figure 1 show that Compound A alone effectively protects mice 15 (reducing 3.3, 2.08, -0.8 and 0.6 logs of CFU, respectively with 40, 20, 10 and 5 mg/kg). However, combinations of Compound A with a fixed amount of IPM (20 mg/kg) were significantly synergistic (e.g., .20 mg/kg of IPM increased the effective log clearance of 5 mg/kg of Compound A from 0.6 to 2.75 logs). 20 EXAMPLE 2 To evaluate the combination of Compound A with gentamicin to influence clearance of VanRGentSAmpS (where R = resistant and S=sensitive) E. faecalis CL 5244 (obtained from Washington University School of Medicine, St. Louis, MO) partial checkerboard synergy studies were performed followed by time 25 kill studies. To evaluate the combination of Compound A with ciprofloxacin to influence clearance of VanRGentSAmpS (where R = resistant and S=sensitive) E. faecalis CL 4877 (obtained from University of Maryland Hospital, University of Maryland Medical System, 22 South Green St., Baltimore, MD 21201) partial 30 checkerboard synergy studies were also performed followed by time-kill studies. - 24 - WO 00/12048 PCT/US99/20052 MATERIALS and METHODS Antibiotics Compound A stock solution was prepared in 10 mM MOPs buffer, pH 5 7.0, and its concentration confirmed using a spectrophotometric assay. Gentamicin (Sigma Chemical Co.) stock solutions were prepared in 10 mM MOPs buffer, pH 7.0 on a weight per volume basis. Bacterial Strains 10 E. faecalis, E. faecium and E. gallinarmrn strains were provided by the Merck Clinical Culture Collection. Media Organisms maintained on Brain Heart Infusion (BHI) (Difco) agar 15 slants were grown overnight in BHI broth (Difco) prior to testing. The test medium used was BHI broth. MIC Determinations MICs were determined by broth microdilution. Serial twofold 20 dilutions of each antibiotic were prepared in BHI broth and inoculated with ~106 CFU/mL. The MIC is defined as the lowest concentration of antibiotic that resulted in no visible growth after incubation at 35*C for 22 hours. Checkerboard and Time-Kill Synergy Studies 25 Serial twofold antibiotic dilutions were prepared in BHI broth and inoculated with ~106 CFU/mL. Follow-up time-kill studies were done in flasks. Compound A or Compound A in combination with gentamicin (at clinically relevant concentrations) were added to flasks containing BHI broth (50 mL/flask), inoculated with ~106 CFU/mL and incubated at 35"C with shaking at 85 rpm. Viable counts 30 were obtained at appropriate time intervals on BHI agar plates. Results Figure 2 shows that Compound A alone is effective against VanRGentSAmpS E. faecalis CL 5244. However, combinations of Compound A 35 with a fixed amount of gentamicin were significantly synergistic. - 25 - WO 00/12048 PCT/US99/20052 Figure 3 shows that Compound A alone is effective against VanRGentSAmpS E. faecalis CL 4877. However, combinations of Compound A with a fixed amount of ciprofloxacin were significantly effective. - 26 -

Claims (17)

1. 2. A composition according to claim I wherein the compounds of structural formula I are represented by formula Ie: HO H H R1 H3CN CH 2 -N R O Ie CO2- O--S 20 0 or a pharmaceutically acceptable salt thereof, wherein: R contains a positively charged moiety selected from the group consisting of: -R*, Q, and a C1-6 straight or branched alkyl chain substituted with 25 one Rd group; Rd is independently selected -R* or Q; Q is selected from the group consisting of: -31 - WO 00/12048 PCT/US99/20052 (CH 2 )b N N c and N-Rx \~ 5/ L (CH 2 )a wherein L-, a and b are as originally defined, and Rx represents a member selected from the group consisting of: hydrogen or a Ci 5 8 straight- or branched- chain alkyl, optionally interrupted by one or two of 0, S, SO, S02, NRw, N+RhRw, or -C(O)-, said chain being unsubstituted or substituted with one to four of halo, CN, N02, ORw, SRw, SORw, SO2Rw, NRhRw, N+(Rh) 2 Rw, C(O)-Rw, C(O)NRhRw, SO 2 NRhRw, CO2Rw, OC(O)Rw, OC(O)NRhRw, 10 NRhC(0)Rw, NRhC(O)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 C1-3 straight- or branched- chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four R' groups; R* is selected from: 15 esx' 11 and d-- e9. wherein d represents NRk; Rk represents -C1 -6 straight or branched chain alkyl; and e, g, x and y represent CRm or N+Rk, with Rk as defined above and Rm representing 20 hydrogen.
2. 3. A composition according to claim 1 wherein the compounds of formula I are: (1S,5R,6S)-2-(5-(((carbamoylmethyl)-1,4-diazoniabicyclo[2.2.2]oct-1-yl)methyl)(1,8 25 naphthosultam)methyl)-6-[1 (R)-hydroxyethyl]-1 -methylcarbapen-2-em-3-carboxylate chloride; (1S,5R,6S)-2-(5-(((3-hydroxyprop-1-yl)-1,4-diazoniabicyclo[2.2.2]oct- 1 yl)methyl)(1,8-naphthosultam)methyl)-6-[1 (R)-hydroxyethyl]-1-methylcarbapen-2 em-3-carboxylate chloride; - 32 - WO 00/12048 PCT/US99/20052 (1 S,5R,6S)-2-(5-(( 1 -methylimidazol-3-ium)methyl)(1,8-naphthosultam)methyl)-6 [1 (R)-hydroxyethyl] -1 -methylcarbapen-2-em-3-carboxylate; (I S,5R,6S)-2-(5-(((2-(1 -methylimidazol-3-ium)-ethyl)(1,8-naphthosultam)methyl)-6 [1 (R)-hydroxyethyl]- 1 -methylcarbapen-2-em-3-carboxylate; 5 (1 S,5R,6S)-2-(4-(((carbamoylmethyl)- 1,4-diazoniabicyclo[2.2.2]oct- 1 -yl)methyl)(1,8 naphthosultam)methyl)-6-[1 (R)-hydroxyethyl] -1 -methylcarbapen-2-em-3-carboxylate chloride; (1 S,5R,6S)-2-(4-(2-(((carbamoylmethyl)- 1,4-diazoniabicyclo[2.2.2]oct- l-yl)) ethyl)(1,8-naphthosultam)methyl)-6-[1 (R)-hydroxyethyl]- 1 -methylcarbapen-2-em-3 10 carboxylate chloride; (1S,5R,6S)-2-(4-(2-(((3-hydroxyprop-1-yI)-1,4-diazoniabicyclo[2.2.2]oct-1-yl)) ethyl)(1,8-naphthosultam)methyl)-6-[1 (R)-hydroxyethyl]- 1 -methylcarbapen-2-em-3 carboxylate chloride; or (1 S,5R,6S)-2-(4-(2-((1 -methylimidazol-3-ium))-ethyl)(1,8-naphthosultam)methyl)-6 15 [1 (R)-hydroxyethyl]- I -methylcarbapen-2-em-3-carboxylate.
3. 4. A composition according to claim 3 wherein the compounds of fonnula I are: (1 S,5R,6S)-2-(5-(((carbamoylmethyl)- 1,4-diazoniabicyclo[2.2.2]oct- 1 -yl)methyl)(1,8 20 naphthosultam)methyl)-6- [1 (R)-hydroxyethyl] -1 -methylcarbapen-2-em-3-carboxylate chloride; (1 S,5R,6S)-2-(4-(((carbamoylmethyl)- 1,4-diazoniabicyclo[2.2.2]oct- I -yl)methyl)(1,8 naphthosultam)methyl)-6-[ I (R)-hydroxyethyl]- I -methylcarbapen-2-em-3-carboxylate chloride; or 25 (1S,5R,6S)-2-(4-(2-(((carbamoylmethyl)-1,4-diazoniabicyclo[2.2.2]oct-1-yl)) ethyl)(1,8-naphthosultam)methyl)-6-[1(R)-hydroxyethyl]-1-methylcarbapen-2-em-3 carboxylate chloride.
4. 5. A composition according to claim I wherein the other 30 antibiotic is selected from the group consisting of cephalosporins, penicillins, gentamicin, ciprofloxacin, imipenem, meropenem, chloramphenicol, vancomycin, and teicoplainin. - 33 - WO 00/12048 PCT/US99/20052
5. 6. An antibiotic composition comprising a pharmaceuticallly acceptable carrier, a therapeutically effective amount of a 2-(naphthosultamyl)methyl carbapenem selected from (lS,5R,6S)-2-(5-(((carbamoylmethyl)-1,4-diazoniabicyclo[2.2.2]oct-1-yl)methyl)(1,8 5 naphthosultam)methyl)-6-[1(R)-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate chloride; (1S,5R,6S)-2-(4-(((carbamoylmethyl)-1,4-diazoniabicyclo[2.2.2]oct-1-yl)methyl)(1,8 naphthosultam)methyl)-6-[1(R)-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate chloride; and 10 (IS,5R,6S)-2-(4-(2-(((carbamoylmethyl)-1,4-diazoniabicyclo[2.2.2]oct-l-yl)) ethyl)(1,8-naphthosultam)methyl)-6-[I (R)-hydroxyethyl]- 1 -methylcarbapen-2-em-3 carboxylate chloride; and a therapeutically effective amount of another antibiotic selected from carbapenems, cephalosporins, penicillins; aminoglycosides such as gentamicin, amikacin, dibekacin, streptomycin, neomycin, kanamycin, spectinomycin, 15 kasugamycin; fluoroquinolones such as ciprofloxacin, trovafloxacin, sparfloxacin, gatifloxacin, grepafloxacin, ofloxacin, norfloxacin, floxin, levofloxacin; quinolones, naphthyridines, chloramphenicol, macrolides, ketolides, azalides, Synercid@, tetracyclines, glycylcyclines, glycopeptides such as vancomycin, teicoplainin, LY 333328; novobiocin, coumermycin, and oxazolidinones or a combination thereof. 20
6. 7. A composition according to claim 6 wherein the 2 (naphthosultamyl)methyl-carbapenem is (1S,5R,6S)-2-(4-(2-(((carbamoylmethyl)-1,4 diazoniabicyclo[2.2.2]oct-1-yl))-ethyl)(1,8-naphthosultam)methyl)-6-[1(R) hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate chloride; and the other antibiotic 25 is selected from cephalosporins, penicillins, gentamicin, ciprofloxacin, meropenem, imipenem, (4R, 5S, 6S)-3-[(3S, 5S)-5-(3-carboxyphenylcarbamoyl)pyrrolidin-3 ylthio]-6-(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2 carboxylic acid, chloramphenicol, vancomycin, and teicoplainin. 30 8. An antibacterial composition according to claim 1 wherein the other antibiotic is a carbapenem.
7. 9. A composition according to claim 8 wherein the carbapenem is imipenem, (4R, 5S, 6S)-3-[(3S, 5S)-5-(3-carboxyphenylcarbamoyl)pyrrolidin-3 35 ylthio]-6-(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2 - 34 - WO 00/12048 PCT/US99/20052 carboxylic acid, or meropenem, from about 1 to about 100 mg/kg, and the 2 (naphthosultamyl)methyl-carbapenem is (1S,5R,6S)-2-(4-(2-(((carbamoylmethyl)-1,4 diazoniabicyclo[2.2.2]oct- 1 -yl))-ethyl)(1,8-naphthosultam)methyl)-6-[1(R) hydroxyethyl]- 1 -methylcarbapen-2-em-3-carboxylate chloride, from about 0.1 to 5 about 50 mg/kg.
8. 10. A composition according to claim 9 wherein the amount of imipenem, (4R, 5S, 6S)-3-[(3S, 5S)-5-(3-carboxyphenylcarbamoyl)pyrrolidin-3 ylthio]-6-(1 R)- 1 -hydroxyethyl]-4-methyl-7-oxo- 1 -azabicyclo[3.2.0]hept-2-ene-2 10 carboxylic acid, or meropenem is about 2 to about 50 mg/kg and the amount of (1S,5R,6S)-2-(4-(2-(((carbamoylmethyl)- 1,4-diazoniabicyclo[2.2.2]oct- 1-yl)) ethyl)(1,8-naphthosultam)methyl)-6-[1 (R)-hydroxyethyl]- I -methylcarbapen-2-em-3 carboxylate chloride is about 0.5 to about 20 mg/kg. 15 11. An antibacterial composition comprising a pharmaceutically acceptable carrier, about 2 to about 50 mg/kg of imipenem, a pharmaceutically acceptable amount of cilastatin and about 0.5 to about 20 mg/kg of (1S,5R,6S)-2-(4 (2-(((carbamoylmethyl)- 1,4-diazoniabicyclo-[2.2.2]oct- I -yl))-ethyl)(1,8 naphthosultam)methyl)-6-[1 (R)-hydroxyethyl] -1 -methylcarbapen-2-em-3-carboxylate 20 chloride.
9. 12. A composition according to claim 11 wherein the imipenem and cilastatin are administered as Primaxin®. 25 13. An antibacterial composition according to claim 1 wherein the other antibiotic is a fluoroquinolone, aminoglycoside, chloramphenicol or a combination thereof.
10. 14. A composition according to claim 13 wherein the 30 fluoroquinolone is ciprofloxacin, from about 0.1 to about 40 mg/kg, the aminoglycoside is gentamicin from about 0.5 to about 12 mg/kg, and the 2 (naphthosultamyl)methyl-carbapenem is (1S,5R,6S)-2-(4-(2-(((carbamoylmethyl)-1,4 diazoniabicyclo[2.2.2]oct-1-yl))-ethyl)(1,8-naphthosultam)methyl)-6-[1(R) hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate chloride, from about 0.1 to 35 about 50 mg/kg, - 35 - WO 00/12048 PCT/US99/20052
11. 15. A composition according to claim 14 wherein the amount of ciprofloxacin is about 0.5 to about 20 mg/kg and the amount of (1S,5R,6S)-2-(4-(2 (((carbamoylmethyl)- 1,4-diazoniabicyclo[2.2.2]oct- I -yl))-ethyl)(1,8 5 naphthosultam)methyl)-6-[ 1 (R)-hydroxyethyl]- 1 -methylcarbapen-2-em-3-carboxylate chloride is about 0.5 to about 20 mg/kg.
12. 16. An antibacterial composition comprising a pharmaceutically acceptable carrier, about 0.5 to about 20 mg/kg of ciprofloxacin or about 0.5 to about 10 12 mg/kg of gentamicin and about 0.5 to about 20 mg/kg of (1S,5R,6S)-2-(4-(2 (((carbamoylmethyl)-1,4-diazoniabicyclo[2.2.2]oct-1-yl))-ethyl)(1,8 naphthosultam)methyl)-6-[1(R)-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate chloride. 15 17. A composition according to claim 1 comprising 2 (naphthosultamyl)methyl-carbapenem antibacterial agents or ophthamologically acceptable salts thereof, in combination with a imipenem, (4R, 5S, 6S)-3-[(3S, 5S)-5 (3-carboxyphenylcarbamoyl)pyrrolidin-3-ylthio]-6-(IR)-1-hydroxyethyl]-4-methyl-7 oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, or meropenem and another 20 antibiotic selected from cephalosporins, penicillins, gentamicin, ciprofloxacin, chloramphenicol, vancomycin, or teicoplainin.
13. 18. A method of treating or preventing a bacterial infection in a mammalian patient in need thereof, comprising administering to said patient an 25 effective amount of a composition of claim 1.
14. 19. A method of treating or preventing enterococcal or MRSA infections which comprises administering to a patient in need of such treatment of a unit dose of the composition of Claim 1. 30
15. 20. A method of treating or preventing enterococcal or MRSA infections which comprises administering to a patient in need of such treatment of a unit dose of the composition of Claim 6. - 36 - WO 00/12048 PCT/US99/20052
16. 21. A method of treating or preventing enterococcal or MRSA infections which comprises administeringto a patient in need of such treatment of a unit dose of the composition of Claim 11. 5 22. A method of treating or preventing enterococcal or MRSA infections which comprises administering to a patient in need of such treatment of a unit dose of the composition of Claim 14.
17. 23. A method of treating or preventing enterococcal or MRSA 10 infections which comprises administering to a patient in need of such treatment of a unit dose of the composition of Claim 16. - 37 -