AU732335B2

AU732335B2 - 3-(iodophenoxymethyl) carbapenem antibacterials

Info

Publication number: AU732335B2
Application number: AU92236/98A
Authority: AU
Inventors: Frank P. Dininno; Kevin D. Dykstra
Original assignee: Merck and Co Inc
Current assignee: Merck and Co Inc
Priority date: 1997-09-09
Filing date: 1998-09-04
Publication date: 2001-04-12
Anticipated expiration: 2018-09-04
Also published as: AU9223698A; EP1015453A4; CA2302009A1; JP2003517427A; EP1015453A1; WO1999012928A1

Description

IC WO 99/12928 PCT/US98/18578 -1- TITLE OF THE INVENTION 3- (IODOPHENOXYMETHYL) CARBAPENEM ANTIBACTERIALS BACKGROUND OF THE INVENTION The present invention relates to carbapenem antibacterial agents in which the carbapenem nucleus is substituted at the 2 -position with an iodo-substituted phenyl linked through a CH 2 group. The iodo-substituted phenyl ring is further substituted with various substituent groups including at least one cationic group.

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 (MRSA/MRCNS) which are at the same time relatively free from undesirable side effects.

SUMMARY OF THE INVENTION The compounds of the invention are represented by formula I: 3 P H HC 4 HH A-(CH 2 )n-Q

H

3 C -N _7I as well as salts and hydrates thereof, wherein: the compound contains no more than two positive charges balanced by two negative charges to provide overall charge neutrality to the compound; R' 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 hydroxylprotecting group; A represents 0, S or -CH 2 attached at position 3, 4 or N represents an integer 0-3; 15 Q is selected from the group consisting of: °o *a

(CH

2 )b Le P e -X e\ (CH)a wherein: a and b are 1, 2 or 3; L- is a pharmaceutically acceptable counterion present or absent as necessary Sto maintain the appropriate charge balance; 25 a represents 0, S or NR; X, and a represent CRt, N or N+Rs, provided that no more than one of 1, 5, L and a is N+Rs balanced by L, as defined above; each RS independently represents hydrogen; phenyl or -CI.

4 straight- or branched- chain alkyl, unsubstituted or substituted with one to four R' groups; each Rt independently represents hydrogen; halo; phenyl; -CN; -NO 2

-NRR;

R -ORu; -SRW; -CONRuRv; -COORh; -SOWR; -S02RW; -SO2NRRV; -NRSO2R; CORU; -NRCORv; -OCOR"; -OCONRu"R; -NRUC02R; -NRuCONR'RW; -OCO 2

RV;

[R:\LIBT] 13136.doc:mes WO 99/12928 PCT/US98/18578 -3- -C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R i groups; each R i independently represents halo; -CN; -NO 2 phenyl; -NHSO 2 Rh; -ORh, -SRh; -N(Rh) 2 -N+(Rh) 3 -C(O)N(Rh) 2

-SO

2 N(Rh) 2 heteroaryl; heteroarylium; -CO 2 Rh; -C(O)Rh; -OCORh; -NHCORh; guanidinyl; carbamimidoyl or ureido; each Rh independently represents hydrogen, a -C1-6 straight or branched-chain alkyl group, a -C3-C5 cycloalkyl group or phenyl, or when two Rh groups are present, said Rh groups may be taken in combination and represent a 4-6 membered saturated ring, optionally interrupted by one or two of O, S, S02, NH and

NCH

3 Ru and R v represent hydrogen or -Ci-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R i groups; or Ru and R v together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one or more of O, S, NRw or said ring being unsubstituted or substituted with one to four R i groups; each R w independently represents hydrogen; -C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups; C3-5 cycloalkyl optionally substituted with one to four Ri groups; phenyl optionally substituted with one to four

R

i groups, or heteroaryl optionally substituted with 1-4 R i 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 O, S, S02, NH or NCH3; Rx represents hydrogen or a C1-8 straight- or branchedchain alkyl, optionally interrupted by one or two of O, S, SO, SO2, NRw, N+RhRw, or said chain being unsubstituted or substituted with one to four of halo, CN, N02, ORw, SRw, SORw, WO 99/12928 PCT/US98/18578 -4- SO2R w NRhRw, N+(Rh) 2 RW, C(O)NRhRw,

SO

2 NRhRw, CO2R

W

OC(O)RW, OC(O)NRhRW, NRhC(O)Rw, NRhC(O)NRhRw, or a phenyl or heteroaryl group which is in turn optionally substituted with from one to four R i 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 Ri groups; RY and Rz represent hydrogen; phenyl; -C1-6 straight or branched chain alkyl, unsubstituted or substituted with one to four R i groups, and optionally interrupted by O, S, NRw, N+RhRw or or Rx and RY together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by O, S, S02, NR W N+RhRW or unsubstituted or substituted with 1 4 Ri groups, 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 R x and RY taken together, optionally interrupted by O, S, NR w or said rings being unsubstituted or substituted with one to four

R

i groups.

Pharmaceutical compositions and methods of treatment are also included.

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 R i as defined, at any WO 99/12928 PCT/US98/18578 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 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 phenyl, substituted phenyl and the like, as well as rings which are fused, naphthyl, phenanthrenyl and the like. An aryl group thus contains at least one ring having at least 6 atoms, with up to five such rings being present, containing up to 22 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms or suitable heteroatoms.

The preferred aryl groups are phenyl, naphthyl and phenanthrenyl.

Aryl groups may 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 gropp 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 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, thiadiazole. Examples include the following: WO 99/12928 WO 9912928PCTIUS98/'18578 -6-

NNH

-Nzz/yN~ pyrrole (pyrrolyl) imidazole (imidazolyl) thiazole (thiazolyl) oxazole (oxazolyl) furan (furyl) NH N N triazole (triazolyl) pyrazole (pyrazolyl) thiophene (thienyl) isoxazole (isoxazolyl) N

N

isothiazole (isothiazolyl) pyridine (pyridinyl) pyrazine (pyrazinyl)

N

NN

pyridazine (pyridazinyl) pyrimidine (pyrimidinyl) N N

NI)

triazine (triazinyl) Heteroarylium refers to heteroaryl groups bearing a quaternary nitrogen atom and thus a positive charge. Examples include the following: WO 99/12928 PCT/US98/18578 -7-

N

N-C CH, N N N-CH 3

N

IH

CH3

CH

3

N

CH

3

N

Ni+N CH3

NN-

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.

N-CH3 S N-CH 3

+N-CH

No 3 and N1, N-CH 3 r:N N-CH 3 The term "heterocycloalkyl" refers to a cycloalkyl group (nonaromatic) in which one of the carbon atoms in the ring is WO 99/12928 PCT/US98/18578 -8replaced 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, the positively charged nitrogen in a tetraalkylammonium group g. tetramethylammonium), heteroarylium, 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.

Guanidinyl refers to the group: H 2

NC(NH)NH-.

Carbamimidoyl refers to the group: H 2

NC(NH)-.

Ureido refers to the group: H 2

NC(O)NH-.

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 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 RE, when these variables represent substituted alkyl, the substituents available thereon are selected from the values of R i 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.

WO 99/12928 PCT/US98/18578 -9- 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 hydroxylprotecting 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-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, t-butyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl 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, 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.

WO 99/12928 PCT/US98/18578 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 -CO 2 M, which is attached to the carbapenem nucleus at position 3, this represents a carboxylic acid group (M represents 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, 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-hydroxyethanesulfonate, 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, WO 99/12928 PCT/US98/18578 11 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 intestinal 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, 1isopropyloxycarbonyloxyethyl, 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 ethylenediamine- WO 99/12928 PCT/US98/18578 12tetraacetate (EDTA), an appropriate number of carbapenem molecules can be found in association therewith to maintain the overall charge balance and neutrality.

At least one of the R groups attached to the phenyl ring contains a positively charged moiety.

A subset of compounds of the invention which is of particular interest is described with reference to formula I wherein R' represents methyl. Within this subset, all other variables are as originally defined.

Another subset of compounds of the invention which is of particular interest is described with reference to formula I wherein CO 2 M represents a carboxylic acid or a carboxylate anion.

Hence, M in this instance represents a negative charge which will be 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.

Another subset of compounds of the invention which is of particular interest is described with reference to formula I wherein P represents hydroxyl or hydroxyl protected by hydroxylprotecting group. Within this subset, all other variables are as originally defined.

Another subset of compounds of the invention which is of particular interest is described with reference to formula I wherein A represents -CH 2 Within this subset, all other variables are as originally defined.

Another subset of compounds of the invention which is of particular interest is described with reference to formula I wherein n represents 0 or 1. Within this subset, all other variables are as originally defined.

Another subset of compounds of the invention which is of particular interest is described with reference to formula I wherein Q represents WO 99/12928 PCT/US98/18578 13r cr co S I or sN a represents O, S or NRs; and p, 8, p. and o represent CRt, N or N+Rs, provided that no_more than one of 3, 8, g and o is N+Rs, balanced by L- which is a pharmaceutically acceptable counterion, and R s is as originally defined. Within this subset, all other variables are as originally defined.

Another subset of compounds of the invention which is of particular interest is described with reference to formula I wherein Q is selected from the group consisting of:

(CH

2 )b N N-Rx and NRxRYR L (CH 2 )a a and b are 2; L- is a pharmaceutically acceptable counterion; and Rx, RY and Rz are as originally defined.

Within this subset, all other variables are as originally defined.

A more preferred subset of compounds of the invention which is of interest is described with reference to formula I wherein Qis

(CH

2 )b e N eN-Rx L® (CH 2 )a Within this subset, all other variables are as originally defined.

Another subset of compounds of the invention which is of particular interest is described with reference to formula I wherein Q is WO 99/12928 PCT/US98/18578 14wherein: a represents O, S or NRs; 3, 6, k, gt and a represent CRt, N or N+Rs, provided that no_more than one of 3, 5, X, g and c is N+Rs, balanced by L",which is a pharmaceutically acceptable counterion, and all other variables are as originally defined.

Representative examples of compounds of the invention are as follows: TABLE 1

CO

2

M

Cpd No. A-(CH 2 )n-Q N-CH 3 N I/ 1 4-

N-CH

3

N/

2 N-CH3

N

3 3- N N-

C

H3

N

4 WO 99/12928 WO 9912928PCT/US9818578 15 4-

N-CH

3

NI

4- 6

-NCH

2

CH

2

CN

H

2

N

4- 1 -C(O)NH 2 8 o OTf ,r-C(O)NH 2 9+N 3- 1 r-C(O)NH 2 o

N

WO 99/12928 PCT/US98/18578 16- 4-

/-C(O)NH

2

N+

11 Cl 4- /-C(0)NH 2

N+

12 Cl /-C(0)NH 2

N+

13 +N Cl The compounds of the present invention are prepared by reacting a suitably protected, activated 2-hydroxymethyl-carbapen-2em-3-carboxylate with an appropriately substituted phenyl ring, and then removing any protecting groups which are present to afford the desired final product. The process is illustrated by the following generic scheme: WO 99/12928 PCT/US98/18578 17- FLOW SHEET A PO H H OH H H HOH I H3c Al COP

A(CH

2 )nOSiR 3 A_ C2P A2

I

POH H R 1 Mitsunobu Reaction 0 H3

RO

2

CN=NCO

2 R N/

A(CH

2 )nOSiR 3 R'3P

O

Solvent A3 CO 2

I

POH H R1 Desilylation H P O H Bu 4 NF

A(CH

2 )nOH HOAc Solvent A4 CO 2

P

HOH H R' Activation H3 C 0- Displacement" /A(CH2)nQ Deprotection N A5 CO 2 With reference to Flow Sheet A above, P is a protecting group; R 3 represents three alkyl or aryl groups which in combination with the silyl group to which they are attached, form a hydroxyl protecting group. R 1 A, Q and n are as defined with respect to the compounds of formula I.

The substituted phenyl side chain A2 is initially reacted with a suitably protected carbapen-2-em-3-carboxylate having an activated hydroxymethyl group at the 2-position.

The carbapenem nucleus having a -CH2OH substituent at position 2 can be obtained in accordance with Schmitt, S. M. et al., WO 99/12928 PCT/US98/18578 18- 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-(hydroxyethyl) side-chain is protected with a hydroxyl protecting group such as trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), tertbutyldiphenylsilyl (TBDPS), acetyl, allyloxycarbonyl, 2-trimethylsilylethoxycarbonyl, 2-trichloroethoxycarbonyl and the like.

The addition of the quaternary side chain group to the carbapenem is accomplished by treating a solution of the hydroxymethyl-carbapenem Al and the side chain A2 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 diethylazodicarboxylate (DEAD) triphenylphosphine, diisopropyl azodicarboxylate (DIAD) tributylphosphine, and the like, at a temperature between about -20 °C and 35 "C for about 5 to minutes.

Alternatively, the side chain and carbapenem nucleus 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 side chain, carbapenem and activating reagent(s) have been mixed, the reaction is allowed to proceed at a temperature between about -20 °C and 0 C for about 5 to 90 minutes.

The resulting mixture is then subjected to a standard work-up procedure to afford a crude methyl substituted carbapenem which is purified, if necessary, by recrystallization 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.

WO 99/12928 PCT/US98/18578 19- Modification of the side chain, which is generally necessary to introduce the charged substituent, is best accomplished before removal of the protecting groups on the hydroxyethyl side chain or 3-carbapenem carboxylate. 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. This entails 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 compound, such as N-methyl-imidazole, N-(2-hydroxyethyl)-imidazole, N-methyl-diazabicyclooctane, 1-(carbamoylmethyl)-4-aza-1azoniabicyclo[2.2.2]octane, 1-(3-hydroxyprop- -yl)-4-aza-1azoniabicyclo[2.2.2]octane, pyridine, morpholine and the like which contains a nitrogen atom that can act as a nucleophile.

Alternatively, in some cases, the charged substituent may be incorporated in the side chain before addition of the side chain to the carbapenem, or may be introduced after deprotection. However, introduction of the charged before deprotection is greatly preferred.

In some cases, activation of the hydroxyl group and displacement by Q to produce A5 may be accomplished in a single step by taking advantage of the basic character of compound Q and using it as a base in the activation reaction.

The 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 trifluoromethanesulfonic anhydride, methanesulfonic anhydride, toluenesulfonic anhydride, methanesulfonyl chloride, benzenesulfonyl chloride, toluenesulfonyl chloride, and the like in the presence of a suitable base such as triethylamine, 2,6-lutidine, 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 WO 99/12928 PCT/US98/18578 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 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 Q at a temperature between about -78°C and 50'C for about 15 to 120 minutes. In 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 Q A silver salt of a nonnucleophilic 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.

WO 99/12928 PCT/US98/18578 21 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 quaternized 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. 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.

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.

WO 99/12928 PCT/US98/18578 -22- 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 ampoules, 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 (lyophilized or nonlyophilized) 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, 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.

WO 99/12928 PCT/US98/18578 23 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, 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 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 WO 99/12928 PCT/US98/18578 24the 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.

0072 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-carboxyethylthio)-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 HO N' NH HO 1 1 OTBDP H

DMF

TBDMSCI

R.T.

500 mg (4.03 mmoles) of commercially available 4hydroxybenzyl alcohol was dissolved in 5.0 ml of anhydrous DMF, placed in an N 2 atmosphere and chilled to 0°C. To the stirred DMF solution, 301 mg (4.33 mmoles) of imidazole was added followed by 604 mg (4.03 mmoles) of t-butyldimethylsilyl-chloride. The reaction was warmed to ambient temperature and stirred for 18 hrs.

WO 99/12928 PCT/US98/18578 The reaction mixture was extracted with ethyl acetate and partitioned with H20-dilute aq. sodium bicarbonate and sat.

brine. The ethyl acetate extract was dried with anhydrous sodium sulfate and concentrated in vacuo to provide a viscous oil.

The crude product was purified via flash chrom. (230- 400 mesh silica gel) and was eluted with a 4:1 mixture of hexanes: ethyl acetate to afford 908 mg of the silyl ether.

1 H NMR (CDC13) 8: 0.10 6H), 0.94 9H), 4.66 2H), 6.08 1H), 6.72 J= 7.5 Hz, 2H), 7.14 J= 8.7 Hz, 2H).

EXAMPLE 2

HO

HO 12 TIOAc OTBDMS I OTBDMS 0H 2 CI1 2

R.T.

100 mg (0.418 mmoles) of the 4-hydroxy-silyl-ether was dissolved in 2.0 ml of sieve dried dichloromethane and placed in an N 2 atmosphere. To the stirred dichloromethane solution, 109 mg (0.418 mmoles) of thallium acetate was added and the tan suspension was stirred for 5 min. at ambient temperature. 109 mg (0.813 mmoles) of iodine was then added. The purple suspension was stirred for 2hrs. and was filtered through a celite plug and was rinsed with 20 ml of ethyl acetate.

The ethyl acetate extract was partitioned with H 2 0-ice and 5% aq. sodium thiosulfate and sat. brine. The extract was dried with andydrous sodium sulfate and concentrated in vacuo to provide 108 mg of a tan solid.

The crude product was purified using plate layer chromatography with a 4:1 hexanes: ethyl acetate eluent to provide 145 mg of the iodophenol.

WO 99/12928 WO 9912928PCTJLUS98/1 8578 26 IH NMR (CDCI3)6: 0.07 6H), 0.90 9H), 4.60 2H), 5.18 (s, 1H), 6.91 J= 8.3 Hz, lH), 7.15 (dd, J= 1.9 Hz, 6.3 Hz, 1H), 7.58 J= 3.0 Hz, 1H).

EXAMPLE 3 NN H

HO

DMF

OTBDMS

'OH

TBDMSCI

Using the analogous procedure carbinol was converted to the silyl ether.of example 1, the the EXAMPLE 4

HO

OTBDMS

TIQAc

CH

2

CI

2

R.T.

.OTBDMS

Using the analogous procedure of example 2, the phenol was converted to the iodophenol.

I H NMR (CDCl3) 5: 0.06 6H), 0.91 9H), 1.68 (in, 2H), 2.55 J= 6.7 Hz, 2H), 3.58 J= 6.3 Hz, 2H), 5.22 1H), 6.88 (d, J= 8.2 Hz, 1H), 7.05 (dd, J= 2.0 Hz, 6.3 Hz, 1H), 7.48 J= 2.0 Hz, 1H).

EXAMPLE N- NH I

DMF

TBDMSCI

R.T.

OTBDMS

WO 99/12928 PCT/US98/18578 27- Using the analogous procedure of example 1, the carbinol was converted to the silyl ether.

1 H NMR (CDC13) 8: 0.12 6H), 0.96 9H), 5.72 2H), 6.70 (dd, J= 1.9 Hz, 4.7 Hz, 1H), 6.83-6.88 2H), 7.16 J= 7.7 Hz, 1H).

EXAMPLE 6

OH

12 TIOAc

CH

2

CI

2

R.T.

S OTBDMS of example 2, the phenol Using the analogous procedure was converted to the iodophenol.

1 H NMR (CDC13) 8: 0.10 6H), 0.94 9H), 4.66 2H), 5.29 (s, 1H), 6.66 (dd, J= 1.9 Hz, 4.7 Hz, 1H), 6.97 J= 2.0 Hz, 1H), 7.56 J= 7.3 Hz, 1H).

EXAMPLE 7 N~ "NH

H

DMF

TBDMSCI

R.T.

.OTBDMS

Using the analogous procedure of example 1, the carbinol was converted to the silyl ether.

1 H NMR (CDC13) 5: 0.08 6H), 0.88 9H), 2.76 J= 7.2 Hz, 2H), 3.78 J= 7.2 Hz, 2H), 6.65-6.69 2H), 6.76 J= 7.4 Hz, 1H), 7.12 J= 6.5 Hz, 1H).

WO 99/12928 PCT/US98/18578 28- EXAMPLE 8 HO ^OTBDMS 12 HO OTBDMS TIOAc 0 CH 2

CI

2

R.T.

1 H NMR (CDC13) 6: 0.10 6H), 0.88 9H), 2.72 J= 7.0 Hz, 2H), 3.77 J= 6.9 Hz, 2H), 5.49 1H), 6.53 (dd, J= 2.0 Hz, 6.1Hz, 1H), 6.89 J= 2.0 Hz, 1H), 7.52 J= 8.0 Hz, 1H).

EXAMPLE 9 OMe OH 48% HBr I HOAc 2COMe 1200C CO 2

H

500 mg (1.712 mmoles) of the methyl ester (Stanley, W., McMahan, Adams, R. JACS, 1933, 55, 706) was dissolved in 2.9 ml of 48% HBr and 1.49 ml of acetic acid and was placed in an

N

2 atmosphere. The reaction was stirred for 4 hrs. at 120 0 C. The cooled reaction mixture was basified to pH 10.0 with 2 ml of 5N aq.

sodium hydroxide and partitioned with ethyl acetate-H 2 0 and ice.

The aq. layer was saved and acidified to pH 2.5 with 2.0 N aq.

hydrochloric acid, forming a white solid that precipitated from solution. The solid was collected in a sintered glass funnel, washed with 10 ml of deionized H 2 0 and dried in vacuo to provide 286 mg of benzoic acid.

1 H NMR (d 6 -Me 2 CO) 6: 7.06 1H), 7.29 J= 8.0 Hz, 1H), 7.51 (dd, J= 1.5 Hz, 5.9 Hz, 1H).

WO 99/12928 PCT/US98/18578 -29- EXAMPLE OH OH 1 IC BH 3

.THF

THF

OH

CO

2 H R.T.

286 mg (1.08 mmoles) of benzoic acid was dissolved in ml of anhydrous THF and was placed in an N 2 atmosphere. To the stirred THF solution, 2.16 ml of borane-THF complex was added dropwise over 20 min. and the reaction was stirred for 2 hrs. at ambient temperature. 10 ml of methanol was then added to the THF solution slowly over 1 hr.

The reaction was extracted with ethyl acetate and partitioned with

H

2 0-ice and sat. brine. The ethyl acetate extract was dried with anhydrous sodium sulfate and concentrated in vacuo to dryness.

The crude product was purified using silica gel plate layer chromatography eluted with a 7:3 ethyl acetate: hexanes mixture to afford 120 mg of the benzyl alcohol.

EXAMPLE 11 OH OH N NH 1 OH DMF OTBDMS

TBDMSCI

R.T.

1 H NMR (CDC13) 6: 0.10 6H), 0.95 9H), 4.70 2H), 4.94 (s, 1H), 6.68 (dd, J= 2.3 Hz, 5.5 Hz, 1H), 6.83 1H), 7.16 J= 7.8 Hz, 1H).

WO 99/12928 PCT/US98/18578 EXAMPLE 12 02CO SO H

OH

N H SI

OTBDMS

I

0 2 C H H

OTBDMS

DIAD

N

OO

Ph 3

P

THF 0 00C 301 mg (0.824 mmoles) of bis-allyl protected carbinol, 261 mg (0.687 mmoles) of the iodophenol (Finch, Pegg, A.; Evans, B. Tetrahedron Lett., 1993, 34, 8353) and 67 mg (0.824 mmoles) triphenylphosphine were combined and was placed in an N2 atmosphere. The mixture was dissolved with 2.0 ml of anhydrous THF and chilled to OOC. To the stirred THF solution, 0.162 ml of diisopropylazodicarboxylate (0.824 mmoles) was added. The reaction was stirred for 20 min. and evaporated.

The product was purified by plate layer chromatography with a 4:1 hexanes: ethyl acetate eluent to afford 389 mg of the silyl ether.

WO 99/12928 PCT/US98/18578 -31- 1 H NMR (CDC13) 8: 0.1 6H), 0.9 1.27 J= 7.3 Hz, 3H), 1.45 J= 6.5 Hz, 3H), 2.68-2.73 J= 6.6 Hz, 2H), 3.44 (dd, J= 3 Hz, 5 Hz, 1H), 3.62 1H), 3.72-3.78 J= 4.1 Hz, 2H), 4.18 (dd, J= 3 Hz, 7 Hz, 1H), 4.61-4.83 5H), 5.11-5.26 1H), 5.3-5.54 5H), 5.89-6.02 2H), 6.71 J= 8.3 Hz, 1H), 7.12 (dd, J= 2.1 Hz, 1.9 Hz, 1H), 7.63 J= 1.9 Hz, 1H) EXAMPLE 13 2CO H H

OTBDMS

TBAF

O0 HOAc O THF O

R.T.

~\/O2C

OH

389 mg (0.536 mmoles) of the silyl ether was dissolved with 4.0 ml of anhydrous THF, chilled to 0 0 C and placed in a N2 atmosphere. To the stirred THF solution, 0.121 ml (2.140 mmoles) of glacial acetic acid was added immediately followed by 1.287 ml (1.069 mmoles) of a 1.0 M THF solution of tetra-butylammonium fluoride. The cooling bath was removed and the reaction was stirred for 6 hrs at ambient temperature.

The reaction mixture was extracted with ethyl acetate and partitioned with H20-sodium bicarbonate and sat. brine. The WO 99/12928 PCT/US98/18578 -32ethyl acetate extract was dried with anhydrous sodium sulfate and concentrated in vacuo to provide a viscous oil.

The compound was purified via flash chrom. (230-400 mesh silica gel) and eluted with a 1:1 mixture of hexanes: ethyl acetate to afford 227 mg of the pure carbinol.

1H NMR (CDC13) 1.27 J= 7.3 Hz, 3H), 1.45 J= 6.5 Hz, 3H), 2.74-2.78 J= 6.6 Hz, 2H), 3.44 (dd, J= 3 Hz, 5 Hz, 1H), 3.62 1H), 3.78-3.83 J= 6.5 Hz, 2H), 4.18 (dd, J= 3 Hz, 7 Hz, 1H), 4.61-4.83 5H), 5.11-5.26 1H), 5.3-5.54 5H), 5.89-6.02 2H), 6.73 J= 8.5 Hz, 1H), 7.12 (dd, J= 2.1 Hz, 6.2 Hz, 1H), 7.65 J= 1.9 Hz, 1H) EXAMPLE 14 2CO H H

OH

2 C

O

H -H 1. TEA

DCM

O

OC

0 2. MsCI 2

C

O H H j OMs

N!

0 0 0 227 mg (0.370 mmoles) of carbinol was dissolved in ml of sieve dried dichloromethane and was chilled to OOC and was placed under an N2 atmosphere. To the dichloromethane solution, 0.098 ml (0.704 mmoles) of triethylamine was added and the WO 99/12928 PCT/US98/18578 -33reaction was stirred for 5 min. 0.046 ml (0.592 mmoles) of neat mesylchloride was added and the reaction was stirred for 1 hr.

The reaction mixture was extracted with ethyl acetate and partitioned with dilute aq. hydrochloric acid-ice, aq. sodium bicarbonate and saturated brine. The ethyl acetate extract was dried with anhydrous sodium sulfate and conc. in vacuo to give 205 mg of crude mesylate.

1 H NMR (CDC13) 8: 1.29 J= 7.3 Hz, 3H), 1.48 J= 6.5 Hz, 3H), 2.89-2.94 J= 6.6 Hz, 2H), 2.95 3H), 3.44 (dd, J= 3 Hz, Hz, 1H), 3.62 1H), 4.35-4.39 J= 6.5 Hz, 2H), 4.18 (dd, J= 3 Hz, 7 Hz, 1H), 4.61-4.83 5H), 5.11-5.26 1H), 5.3-5.54 (m, 5.89-6.02 2H), 6.73 J= 8.5 Hz, 1H), 7.14 (dd, J= 2.1 Hz, 5.9 Hz, 1H), 7.67 J= 1.9 Hz, 1H) EXAMPLE 0 2 C H H OMs Nal 0 Me 2

CO

O

R.T.

0 02CO 0

^O

205 mg (0.296 mmoles) of the crude mesylate was dissolved in 2.0 ml of acetone and was placed in an N2 atmosphere.

WO 99/12928 PCT/US98/18578 34- To the acetone solution, 222 mg (1.481 mmoles) of sodium iodide was added and the reaction was stirred for 42 hrs. at ambient temperature.

The mixture was extracted with ethyl acetate and partitioned between dilute aq. sodium thiosulfate-ice, H20 and saturated brine. The ethyl acetate extract was dried with anhydrous sodium sulfate and conc. in vacuo to afford 202 mg of the alkyliodide.

1 H NMR (CDC13) 5: 1.25 J= 7.3 Hz, 3H), 1.43 J= 6.5 Hz, 3H), 3.03-3.07 J= 6.9 Hz, 2H), 3.44 (dd, J= 3 Hz, 5 Hz, 1H), 3.62 1H), 3.25-3.29 J= 7.8 Hz, 2H), 4.18 (dd, J= 3 Hz, 7 Hz, 1H), 4.61-4.83 5H), 5.11-5.26 1H), 5.3-5.54 5H), 5.89-6.02 2H), 6.73 J= 8.5 Hz, 1H), 7.07 (dd, J= 2.0 Hz, 6.1 Hz, 1H), 7.58 J= 1.9 Hz, 1H) EXAMPLE 16 o 02CO H N NMe No 0 MeCN 0 AgOTf O OTf 02CO D NMe S? WO 99/12928 PCT/US98/18578 50 mg (0.069 mmoles) of the alkyliodide was dissolved with 1.0 ml of sieve dried acetonitrile and was placed in an N2 atmosphere. To the stirred acetonitile solution, 0.011 ml (0.138 mmoles) of neat N-methylimidazole was added, immediately followed by the addition of 0.069 ml (0.0691 mmoles) of a 1.0 M solution of AgOTf in acetonitrile. Upon addition of the AgOTf solution, a yellow solid formed. The reaction was stirred for 24 hrs.

at ambient temperature and for 2 hrs. at 50 0

C.

The reaction mixture was filtered through a celite pad and conc. in vacuo to a volume of ca. 1.0 ml. and was diluted with 9.0 ml of diethylether, forming a white suspension.

The etheral suspension was centrifuged and the resulting supernatant was discarded. The remaining white solid was dried in vacuo to give 32 mg of the imidazolium salt.

EXAMPLE 17 I OTf 0 2 C O H O O\ CONH 2 0 MeCN 0/ AgOTf

\R.T.

2 OTf WO 99/12928 PCT/US98/18578 36- 157 mg (0.216 mmoles) of the alkyliodide was combined with 69 mg (0.216 mmoles) of the dabco acetamide triflate salt and ml of sieve dried acetonitrile in an N2 atmosphere. To the acetonitrile solution, 0.216 ml (0.216 mmoles) a 1.0 M solution of AgOTf in acetonitrile was added. Upon the addition of the AgOTf solution, a yellow ppt. formed. The reaction was stirred for 24 hrs.

at R.T.

The reaction mixture was filter through a celite pad and was conc. in vacuo to ca. 2.0 ml and was diluted with 8.0 ml of diethylether forming a suspension.

The etheral suspension was centrifuged and the resulting supernatant was discarded. The remaining off-white solid was dried in vacuo to afford 120 mg of the salt.

EXAMPLE 18 02CO H H

OH

N

/HO

0

O

0I

OTBDMS

<2O^ IH H DIAD

N

Ph 3

P

THF

0C WO 99/12928 PCT/US98/18578 37- Using the analogous procedure of example 12, the bisallyl protected carbinol was converted to the silyl ether.

1 H NMR (CDC13) 8: 0.048 6H), 0.90 1.28 J= 6.2 Hz, 3H), 1.45 J= 6.3 Hz, 3H), 1.75 2H), 2.56 J= 8.9 Hz, 2H), 3.44 (dd, J= 2.9 Hz, 6 Hz, 1H), 3.60 3H), 4.19 (dd, J= 3.0 Hz, Hz, 1H), 4.60 2H), 4.63-4.87 3H), 5.11 1H), 5.26- 5.54 5H), 5.89-6.02 2H), 6.71 J= 8.4 Hz, 1H), 7.07 (dd, J= 2.2 Hz, 6.2 Hz, 1H), 7.60 J= 2.1Hz, 1H) EXAMPLE 19

IDMS

TBAF

HOAc

THF

R.T.

Using the analogous procedure of example 13, the silyl ether was converted to the carbinol.

WO 99/12928 PCT/US98/18578 -38- 1 H NMR (CDC13) 1.27 J= 7.4 Hz, 3H), 1.45 J= 6.3 Hz, 3H), 1.81 2H), 2.59 J= 8.9 Hz, 2H), 3.44 (dd, J= 3.0 Hz, 4.9 Hz, 1H), 3.57 3H), 4.19 (dd, J= 3.1 Hz, 6.9 Hz, 1H), 4.61 (m, 2H), 4.68-4.87 3H), 5.11 1H), 5.26-5.54 5H), 5.89-6.02 2H), 6.72 J= 8.4 Hz, 1H), 7.09 (dd, J= 2.0 Hz, 6.3 Hz, 1H), 7.62 J= 2.0 Hz, 1H) EXAMPLE 02CO 0 00 o 0' e 2,6-lutidine

DCM

TfPO -200C OTf 131 mg (0.209 mmoles) of the carbinol was dissolved in 1 ml of sieve dried dichloromethane and chilled to -20°C and was placed in an N2 atmosphere. To the stirred solution, 0.026 ml (0.220 mmoles) of 2,6-lutidine was added and the reaction was WO 99/12928 PCT/US98/18578 39stirred for 5 min. 0.038 ml (0.231 mmoles) of triflic anhydride was then added and the reaction was stirred for an additional 20 min.

The reaction was then extracted with ethyl acetate and partitioned with dilute aq. hydrochloric acid-ice, H20 and saturated brine. The ethyl acetate extract was then dried with anhydrous sodium sulfate and conc. in vacuo to provide 121 mg of the alkyl triflate.

EXAMPLE 21 0 2 C O

H

02CO (OTf N N

CONH

2 MeCN AgOTf

R.T.

2 OTf 121 mg (0.160 mmoles) of the triflate was combined with the dabco acetamide triflate salt and dissolved in 2.0 ml of acetonitrile and was placed in an N2 atmosphere. The reaction was stirred for 1 hr. at ambient temperature.

The reaction mixture was filtered through a celite pad and conc. in vacuo to a volume of ca. 1.0 ml. and was diluted with ml of diethylether, forming a white suspension.

WO 99/12928 PCT/US98/18578 The etheral suspension was centrifuged and the resulting supernatant was discarded. The remaining off-white solid was dried in vacuo to give 137 mg of salt.

EXAMPLE 22 ~~02C 1 NMe MeCN AgOTf

R.T.

7f OTf 37 mg (0.0781 mmoles) of the alkyl triflate was combined with 0.0053 ml (0.0664 mmoles) of N-methylimidazole and dissolved in 2.0 ml of acetonitrile and was placed in an N2 atmosphere. The reaction was stirred for 1 hr. at ambient temperature.

The etheral suspension was centrifuged and the resulting supernatant discarded. The remaining off-white solid was dried in vacuo to give 62 mg of the imidazolium salt.

WO 99/12928 WO 9912928PCTIUS98/1 8578 41 EXAMPLE 23 0 2

CI

+H H 'J

.OTBDMS

DIAD

Ph 3

P

THF

OOC

Using the analogous procedure of example 12, the bisallyl protected carbinol was converted to the silyl ether.

1 H NMR (CDC13) 8: 0.092 6H), 0.93 1.27 J= 7.5 Hz, 3H), 1.45 J= 6.3 Hz, 3H), 3.44 (dd, J= 2.9 Hz, 5 Hz, I1H), 3.56 (in, 1H), 4.19 (dd, J= 3 Hz, 7 Hz, 1H), 4.61-4.64 (in, 4H), 4.69-4.87 (in, 3H), 5.11 (in, 1H), 5.26-5.56 (in, 1H), 5.87-6.02 (mn, 2H), 6.76 J= 7.4 Hz, 1H), 7.21 (dd, J= 2.0 Hz, 6.4, 1H), 7.73 J= 2.1 Hz, 1H).

WO 99/12928 WO 99/ 2928PCTIUS98/1 8578 -42- EXAMPLE 24

TBAF

HOAc

THF

R.T.

Using the analogous procedure of example 13, the silyl ether was converted to the benzyl alcohol.

1 H NMR (CDCl3) 8: 1.27 1= 7.4 Hz, 3H), 1.45 1= 6.4 Hz, 3H), 3.41 (dd, J= 3.1 Hz, 5 Hz, 1H), 3.55 (in, 1H), 4.17 (dd, J= 3 Hz, 7 Hz, 1H), 4.56 J= 5.4 Hz, 2H), 4.59-4.62 (in, 2H), 4.67-4.84 (in, 3H), 5.09 (mn, 1H), 5.24-5.54 (mn, 5H), 5.58-6.0 (in, 2H), 6.72(d, J=8.4 Hz, lH), 7.24 (dd, J= 2.2 Hz, 6.2, 1H), 7.77 J= 2.1 Hz, 1H).

WO 99/12928 WO 9912928PCT/US98/1 8578 -43- EXAMPLE 1. TEA

DCM

2. MsCI 02CO Using the analogous procedure of example 14, the benzyl alcohol was converted to the mesylate.

1 H NMR (CDCl3) 8: 1.27 J= 7.4 Hz, 3H), 1.45 J= 6.4 Hz, 3H), 2.96 3H), 3.45 (dd, J= 3.0 Hz, 5 Hz, 1H), 4.20 (in, 1H), 4.61 (in, 2H), 4.63-4.85 (mn, 3H), 5.13 2H), 5.26-5.59 (in, 5H), 5.89- (in, 2H), 6.82 J=8.4 Hz, 1H), 7.34 (dd, J= 2.2 Hz, 7.2, 1H), 7.85 J= 2.1 Hz, I1H).

WO 99/12928 WO 9912928PCTIUS98/1 8578 -44- EXAMPLE 26 0 2 c( Nal Me 2

CO

R.T.

0200 00

N

0 Using the analogous procedure of example 15, the mesylate was converted to the benzyl iodide.

1 H NMR (CDCl3) 6: 1.26 J= 7.4 Hz, 3H), 1.45 J= 6.4 Hz, 3H), 3.45 (dd, J= 3.2 Hz, 4.9 Hz, 1H), 3.59 (in, 1H), 4.20 (dd, J= 3.9 Hz, 7.1 Hz,1H), 4.38 2H), 4.61-4.68 (in, 2H), 4.68-4.87 (in, 3H), 5.11l(m, I1H), 5.26-5.55 (in, 5H), 5.87-6.02 (mn, 2H), 6.71 Hz, 1H), 7.29 (dd, J= 2.3 Hz, 6.2, 1H), 7.79 J= 2.2 Hz, 1H).

WO 99/12928 PCT/US98/18578 EXAMPLE 27 ^02CO H H O

H

°0 H 2 N N 0 MeCN

SR.T.

0

H

0 H O ©/N 0 NH 2 N I 00 0 mg (0.0353 mmoles) of the benzyl iodide was dissolved with 1.0 ml of sieve dried acetonitrile and was placed in an N2 atmosphere. To the stirred acetonitrile solution, 6.6 mg (0.0707 mmoles) of 2-aminopyridine was added and the reaction was stirred for 18 hrs. at ambient temperature.

The reaction mixture was diluted with 9.0 ml of diethylether forming an oily suspension.

The etheral suspension was centrifuged and the resulting supernatant was discarded. The remaining oil was dried in vacuo to give 32 mg of the pyridinium salt.

WO 99/12928 PCT/US98/18578 -46- EXAMPLE 28 0 MeCN 0'

R.T.

0 S\,I N CN

O

HoH 0 N O mg (0.042 mmoles) of the benzyl iodide was dissolved with 2.0 ml of sieve dried acetonitrile and was placed in an N2 atmosphere. To the stirred acetonitrile solution, 0.007 ml (0.085 mmoles) of neat N-cyanoethylimidazole was added to the reaction and was stirred for 18 hrs. at ambient temperature. The reaction mixture was conc. in vacuo to ca. 1.0 ml and was diluted with 9.0 ml of diethylether forming an oily precipitate.

The etheral mixture was centrifuged and the resulting supernatant discarded. The remaining oil was dried in vacuo to give 26 mg of the imidazolium salt.

WO 99/12928 PCT/US98/18578 -47- EXAMPLE 29 /--C0 2

NH

2

GN

02C 0 SH 2 OTf 0 N/ Pd(Ph 3

P)

4 0 Ph 3

P

O Sodium-2-ethylhexanoate 0 2-ethylhexanoic acid

DMF

0OC /-C0 2

NH

2 H H O CI

N

O

O0 0 137 mg (0.127 mmoles) of the bis-allyl protected dabco salt was dissolved in 3.0 ml of sieved dried DMF and placed in an N2 atmosphere. To the stirred DMF solution, 29 mg (0.025 mmoles) of Pd(Ph3P)4 and 20 mg (0.076 mmoles) of Ph3P were combined and added in one portion forming a suspension. 0.020 ml (0.140 mmoles) of neat 2-ethylhexanoic acid was added followed by the addition of 0.283 ml (0.140 mmoles) of a 0.5 M solution of sodium- 2-ethylhexanoate in ethyl acetate.

The reaction was stirred for 5 min. at ambient temperature, at which time a homogeneous solution was obtained.

The reaction was chilled to 0°C and stirred for an additional 1.5 hrs.

The reaction was then diluted with 10.0 ml of diethylether forming a suspension. The etheral mixture was WO 99/12928 PCT/US98/18578 -48centrifuged and the resulting supernatant was discarded. The resulting deblocked carbapenem was washed twice with diethylether and dried in vacuo which gave 116 mg of an amorphous solid.

The dried solid was then dissolved in 5 ml of 5% aq.

brine and was chromatogaphed on 2.0 ml's of MacroPrep ion exchange resin and eluted with 100 ml of 5% aq. brine. The 5% aq.

brine effluent containing the purified carbapenem was desalted on ml's of Amberchrom CG -161 resin using an H 2 0-aq. acetonitrile gradient elution.

The resulting aq. fractions which contained the purified carbapenem were combined and lyophilized to give 33 mg of the desired carbapenem as a white lyophilizate.

1 H NMR (D20) 8:1.49 J= 6.9 Hz, 3H), 1.53 J= 6.5 Hz, 3H), 2.33 2H), 2.89 2H), 3.67 2H) 3.79-3.83 2H), 4.23 (bs, 6H), 4.39 (dd, J= 3 Hz, 7 Hz, 1H), 4.49 (bs, 6H) 4.63 1 H), 5.01 J= 13.7 Hz, 1H), 5.85 J= 9.2 Hz, 1H), 7.27 J= 8.5 Hz, 1H), 7.56 (dd, J= 2.0 Hz, 6.4 Hz, 1H), 8.02 J= 2.1 Hz, 1H) WO 99/12928 PCT/US98/18578 -49- EXAMPLE I

CN

2OgC O H H 0 N Pd(Ph 3

P)

4 O Ph 3

P

0 Sodium-2-ethylhexanoate 2-ethylhexanoic acid DCM/ EtOAc R.T. 0C I

CN

HO (D H H 0

HO

0 0 26 mg (0.0314 mmoles) of the bis-allyl protected imidazolium salt was dissolved with 1.0 ml of a 1:1 mixture of dichloromethane and ethyl acetate and was placed in an N2 atmosphere. To the stirred solution, 7.3 mg (0.0063 mmoles) of Pd(Ph3P)4 and 5 mg (0.019 mmoles) of Ph3P were combined and added in one portion forming a suspension. 0.0048 ml (0.0345 mmoles) of neat 2-ethylhexanoic acid was added followed the addition of 0.069 ml (0.0345 mmoles) of a 0.5 M solution of sodium-2-ethylhexanoate in ethyl acetate.

The reation was stirred for 5 min. at ambient temperature and was chilled to 0°C and stirred further for an additional 1.5 hrs.

The reaction mixture was then diluted with 8.0 ml of diethylether forming a white suspension. The etheral mixture was centrifuged and the resulting supernatant was discarded. The resulting deblocked WO 99/12928 PCT/US98/18578 carbapenem was washed twice with diethylether and dried in vacuo to give 11 mg of an amorphous solid.

The crude product was purified with reverse phase plate layer chromatography in a 4:1 mixture of H20: acetonitrile to afford 6.7 mg of desired carbapenem as a white lyophilizate.

1 H NMR (D20) 8: 1.52 J= 7.4 Hz, 3H), 1.56 J= 6.2 Hz, 3H), 3.43 J= 2.5 Hz, 2H), 3.68 2H), 4.42-4.45 (dd, J= 3 Hz, 7.3 Hz, 1H), 4.49 1H), 4.82 J= 4.1 Hz, 2H), 5.11 J= 7.7 Hz, 1H), 5.63 2H), 5.92 J= 5.9 Hz, 1H), 7.40 J= 5.4 Hz, 1H), 7.78 J= 9.5 Hz, 1H), 7.85 J= 1.8 Hz, 1H), 7.93 1.8 Hz, 1H), 8.21 J= 2.1 Hz, 1H).

EXAMPLE 31 I NMe O2CO (D H

H

0 Pd(Ph 3

P)

4 O Ph 3

P

0 0 Sodium-2-ethylhexanoate 2-ethylhexanoic acid DCM/ EtOAc 0OO NMe HO N HH

N--

O

Using the analogous procedure from example 30, the bis-allyl protected imidazolim salt was deblocked to give the desired carbapenem.

WO 99/12928 WO 9912928PCTIUS98/I 8578 51 IH NMR (D20) 8:1.54 J= 6.7 Hz, 3H), 1.57 J= 5.4 Hz, 3H), 3.69 (in, 2H), 4.18 3 4.43 J= 3 Hz, 10. 1 Hz, I1H), 4.5 (in, 1H), 5.12 J= 13.1 Hz, 1H), 5.58 2H), 5.93 J=13.9 Hz, 2H), 7.39 (dd, J= 4.9 Hz, 2.2 HZ, 1H), 7.40 J= 5.4 Hz, 1H), 7.59-7.79 (in, 3H), 8.21 I1H).

EXAMPLE 32 0 2

C'

N NMe N1 OTf Pd(Ph 3

P)

4 Ph 3

P

Sodium-2-ethylhexanoate 2-ethyihexanoic acid DCM/ EtOAc R.T. 0 0

C

Using the analogous procedure of example 30, the imidazolium product was obtained.

I H NMR (D20) 8: 1.38 (dd, J= 6.1 Hz, 3H), 1.43 (dd, 1= 6.1 Hz, 3H), 2.34 (in, 2H), 2.78 (in, 2H), 3.57 (in, 2H), 3.99 3H), 4.29- 4.37(dd, J= 2.8 Hz, 7.1 Hz, 1H), 4.40 (in, 2H), 4.93 J=14.1, Hz, 1H), 5.39 J= 14.1 Hz, 1H), 7.12 J= 4.4 Hz, 1H), 7.37 J= WO 99/12928 WO 9912928PCTIUS98/1 8578 52 58.0 Hz, lH), 7.55 III), 7.58(s, lH), 7.58(s, 1H), 7.80(s, lH), 8.74(s, 1H) EXAMPLE 33 02C0(

N

0

NH

2 N! Pd (Ph 3

P)

4 0 Ph 3

P

0 Sodium-2-ethylhexanoate 2-ethyihexanoic acid DOM! EtOAc 0 00 HO SN 00 00 00 0 Using the analogous procedure of example 30, the bisallyl protected pyridinium salt was deblocked to give the desired carbapenem.

I H NMR (1320) 6:1.54 J= 6.1 Hz, 3H), 1.57 J= 5.4 Hz, 3H), 3.69 (in, 211), 4.43 J= 3 Hz, 10. 1 Hz, I1H), 4.5 (mn, I1H), 5.12 (d, J= 13.1 Hz, 1H), 5.58 2H), 5.93 J=13.9 Hz, 2H1), 7.27 J= 8.7 Hz, 3.2 Hz, 1 7.40 J= 8. 1, Hz, 1 7.61 J= 8.7 Hz, 1H), 7.98 J= 2.3 Hz, 1H), 8.15 11H), 8.20 (in, 2H).

WO 99/12928 PCT/US98/18578 -53 EXAMPLE 34 -C 0 2

NH

2 N (O H H 0 -0 O 2 OTf N Pd(Ph 3

P)

4 O Ph 3

P

O Sodium-2-ethylhexanoate 2-ethylhexanoic acid

DMF

0°C 0 2

NH

2 HO N (D H H 0 OTf

N

0 0 0

O

mg (0.0334 mmoles) of the bis-allyl protected dabco salt was dissolved in 3.0 ml of sieved dried DMF and was placed in an N2 atmosphere. To the stirred DMF solution, 7.7 mg (0.0067 mmoles) of Pd(Ph3P)4 and 5.3 mg (0.020 mmoles) of Ph3P were combined and added in one portion forming a suspension. 0.005 ml (0.0367 mmoles) of neat 2-ethylhexanoic acid was added followed by the addition of 0.073 ml(0.0367 mmoles) of a 0.5 M solution of sodium-2-ethylhexanoate in EtOAc.

The reaction was stirred for 5 min. at ambient temperature at which time a homogeneous solution was obtained.

The reaction was chilled to 0°C and stirred for an additional 1.5 hrs.

The reaction was then diluted with 10.0 ml of diethylether forming a suspension. The etheral mixture was centrifuged and the resulting supematant was discarded. The resulting deblocked carbapenem was washed twice with diethylether WO 99/12928 WO 99/ 2928PCTIUS98/1 8578 54 and dried in vacuo to give 8.6 mg of the compound as the triflate salt.

IH NMR (D20) 8: 1.51-1.54 (in, 6H), 3.68-3.71 (in, 2H), 4.23 (s, 6H), 4.43 (mn, 8H), 4.62 2H), 4.95 2H), 5.15 J= 13.7 Hs, 1H), 5.93 J=13.7 Hz, 1H), 7.46 J=8.7 Hz, IH), 7.84 1=8.7 Hz, 1H), 8.30 1H).

EXAMPLE H~C HN 0 0 Ph 3

P

Sodium-2-ethylhexanoate 2-ethyihexanoic acid

DMF

O

0

C

HO Cf C 2

NH

2 H H 0

(D

Using the analogous procedure of example 29, the bisallyl protected dabco salt was deblocked to give the desired carbapenem.

1 H NMR (D20) 8: 1.49 J= 6.9 Hz, 3 1. 53 J= 6.5 Hz, 3 H), 3.37 (in, 2H) 3.66 (mn, 2H), 4.03 (mn, 2H), 4.31 (bs, 6H), 4.40 J= Hz, 2H) 4.73 (in, 8H), 5.04 J= 13.9 Hz, 1H), 5.85 J= 13.0 Hz, 1H), 7.30 (dd, J= 8.1 Hz, 3.2 Hz, 1H), 7.63 J= 8.5 Hz, 1H), 8.10 1H) WO 99/12928 WO 9912928PCTIUS98/1 8578 55 EXAMPLE 36 H OH 00 0 HO OTBDMS DIAD Ph 3

P

THF

000

OTBDMS

02C0

N!

0 0 Using the analogous procedure of example 12, the hisallyl protected carbinol was converted to the silyl ether.

I H NMR (CDCl3) 6: 0.09 6H), 0.93 1.22 J= 8.3 Hz, 3H), 1.44(d, J= 6.3 Hz, 3H), 3.44 (in, 2H), 4.12 (dd, J= 3 Hz, 7 Hz, 1H), 4.62 (dd, J=9.2 Hz, 1.3 Hz, 2H), 4.70-4.87 (in, 5H), 5.10 (in, 1H), 5.25-5.5 (in, 5H), 5.68-6.0 (mn, 2H), 6.74 (dd, J= 8.2 Hz, 2.1 Hz, 1H), 6.89 (mn, 1H), 7.23 J=7.9 Hz, 1H) WO 99/12928 WO 9912928PCTIUS98/1 8578 56 EXAMPLE 37

TBAF

HOAc

THF

000 02C0

HH

N!

0 0 0 Using the analogous procedure of example 13, the silyl ether was converted to the benzyl alcohol.

I H NMR (CDC13) 8: 1.22 J= 8.3 Hz, 3H), 1.44(d, J= 6.3 Hz, 3H), 3.44 (in, 2H), 4.15 (dd, J= 3 Hz, 7 Hz, 1H), 4.59 (dd, J=7.0 Hz, Hz, 2H), 4.64 (bs, 2H), 4.68-4.80 (in, 3H), 5.08 (in, 1H), 5.23 (in, 5H), 5.83 (in, 211), 6.81 (dd, 1= 1.4 Hz, 8 Hz, 1H), 6.93 (in, 1H), 7.23 J=9 Hz, 1H).

WO 99/12928 WO 99/ 2928PCT/US98/1 8578 57 EXAMPLE 38 0, 1. TEA

DOM

0 0

C

2. MSCI Using the analogous procedure of example 14, the benzyl alcohol was converted to the benzylic mesylate.

I H NMR (CDC13) 8: 1.22 J= 7.4 Hz, 3H), 1.44 J= 4.4 Hz, 3H), 2.94 3H), 3.42 (in, 2H), 4.16 (dd, J= 3.1 Hz, 6.9 Hz, 1H), 4.60 (mn, 2H), 4.62 (mn, 3H1), 5.10 (in, 1H), 5.19 2H), 5.25 (in, 5.85-6.02 (mn, 2H), 6.89 (mn, 2H), 6.90 (in, 7.28 J= 7.9 Hz, 1 H) WO 99/12928 WO 9912928PCT/US98/1 8578 58 EXAMPLE 39 1 OMS 0 Nal N! Me 2

CO

R.T.

0 00 0 0 Using the analogous procedure of example 15, the benzylic mesylate was converted to benzyl iodide.

1 H NMR (CDCI3) 8: 1.24 J= 5.7 Hz, 3H), 1.44 J= 6.3 Hz, 3H), 3.42 (in, 2H), 4.16(dd, J= 3.0 Hz, 9.8 Hz, 1H), 4.39 2H) 4.60 (mn, 2H), 4.71 (in, 3H), 5.10 (mn, 1H), 5.25 (in, 5H), 5.85-6.02 (in, 2H), 6.75 (dd, J= 2.5 Hz, 5.5 Hz, 1H), 6.90 (mn, 1H), 7.16 J= 8.9 Hz, I1H) WO 99/12928 PCT/US98/18578 -59- EXAMPLE I OH 02 C H H N"NMe O 0 MeCN

R.T.

4/NMe 0 11 N I.D0

M

N e 2O 0 H H OTf

N'

0 46 mg (0.0619 mmoles) of benzyl alcohol was dissolved in 1 ml of sieve dried dichloromethane and was placed in an N 2 atmosphere. The stirred solution, was chilled to -40 0 C and 0.012 ml (0.1299 mmoles) of N-methylimidazole was added. The solution was stirred for 5 min. and 0.0136 ml (0.0136 mmoles) of a 1.0 M solution of AgOTf in acetonitrile was added.

The reaction mixture was diluted with 9.0 ml of diethylether, forming a white suspension.

The etheral suspension was centrifuged and the resulting supernatant was discarded. The remaining off-white solid was dried in vacuo to give 24 mg of the imidazolium salt.

WO 99/12928 WO 9912928PCT/US98/1 8578 60 EXAMPLE 41 (DoTf Pd(Ph 3

P)

4 Ph 3

P

Sodi u m-2-ethylhexanoate 2-ethyihexanoic acid 0CM! EtOAc R.T. 000-OO Using the analogous procedure of example 30, the bisallyl protected imidazolium salt was deblocked to provide the desired carbapenem.

1 H NMR (D20) 6:1.41 J= 7.3 Hz, 3H), 1.50 J= 6.4 Hz, 3H), 3.43 (in, IlH), 3.60 (in, 1H), 4.16 3H), 4.28 J= 9.6 Hz, lH), 4.45 (in, 1H), 5.03 J= 14.0 Hz, 1H), 5.60 2H), 5.78 J= 13.9 Hz, lH), 7.26 1H), 7.31 (mn, 2H), 7.76-7.71 (mn, 2H).

WO 99/12928 WO 9912928PCTIUS98/1 8578 61 EXAMPLE 42 (DOTf (DG CONH 2 MeCN AgOTf

R.T.

S0, 2 DOTf Using the analogous procedure of example 17, the benzyl iodide was converted to the triflate salt.

WO 99/12928 WO 9912928PCTIUS98/1 8578 62 EXAMPLE 43 G® /T CONH 2 020 H 00 N/2 OTf Pd(Ph 3

P)

4 o Ph 3

P

0 Sodium-2-ethylhexanoate 0 2-ethyihexanoic acid

DMF

0 CONH 2

HO

H H 0 0 00 Using the analogous procedure of example 29, the bisallyl protected dabco salt was deblocked to give the desired carbapenem.

I H NMR (D20) 8: 1.41 d, J=7.4 Hz, 3H), 1.46 J=6.4Hz, 3H), 3.46 (in, 1H), 3.64 (m 1H), 4.19 (bs, 6H), 4.29 J=4.0 Hz, 1H), 4.43 (bs, 8H), 4.57 (in, 1H), 4.96 2H), 5.07 J= 14.0 Hz, 1 H), 5.80 J= 13.9 Hz, 1 7.39-7.47 (in, 2H), 7.75 J=7.6 Hz, 1H).

WO 99/12928 WO 99/ 2928PCTIUS98/1 8578 63 EXAMPLE 44

OH

HOOTBOMS

DIAD

Ph 3

P

THF

00C 02C0 H 0 0 Using the analogous procedure of example 12, the bisallyl protected carbinol was converted to the silyl ether.

1 H NMR (CDCl 3 8: 0.094 6H), 0.929 9H), 1.27 J=7.2 Hz, 3H), 1.46 J=6.3 Hz, 3H), 3.43 (dd, J=3.0 Hz, 5.0 Hz, 1H), 3.60 (in, 1H), 4.20 (dd, J=3.1 Hz, 6.0 Hz, 1H), 4.63 (dd, J=1.2 Hz, 4.6 Hz, 2H), 4.64-4.867 (in, 5H), 5.11 (in, 1H), 5.26-5.56 (mn, 5H), 5.91 (in, 2H), 6.70 (dd, J=1.8 Hz, 6.2 Hz, 1H), 6.84 (bs, 1H), 7.68 Hz, I1H).

WO 99/12928 WO 9912928PCTIUS98/1 8578 64 EXAMPLE

TBAF

HOAc

THE

R.T.

Using the analogous procedure of example 13, the silyl converted to the desired carbinol. ether was 1 H NMR (CDCl 3 8: 1.28 J=7.4 Hz, 3H), 1.46 J=6.3 Hz, 3H), 3.45 (dd, J=3.0 Hz, 5.0 Hz, 1H), 3.65 (in, 1H), 4.22 (dd, J=3.0 Hz, 6.9 Hz, 1H), 4.63 (in, 4H), 4.71-4.87 (mn, 3H), 5.11 (in, 1H), 5.26- 5.56 (in, 5H), 5.87 (mn, 2H), 6.73 (dd, J=1.8 Hz, 6.1 Hz, 1H), 6.87 (d, J= 1.87 Hz, 1H), 7.73 J=8.0 Hz, 1H).

WO 99/12928 WO 9912928PCTIUS98/1 8578 65 EXAMPLE 46 1. TEA

DCM

000 2. MsCI Using the analogous procedure of example 14, the benzyl alcohol was converted to the benzylic mesylate.

1 H NMR (CDCI,) 8: 1.29 J=7.2 Hz, 3H), 1.47 J=6.3 Hz, 3H), 2.98 3H), 3.45 (dd, J= 2.8 Hz, 4.9 Hz, 1H), 3.59 (in, 1H), 4.20 (dd, J=3.2 Hz, 6.9 Hz, 1H), 4.62 (mn, 2H), 4.71-4.78 (mn, 3H), 5.11 (in, 1H), 5.26-5.60 (mn, 5H), 5.89-6.03 (in, 2H), 6.78 (dd, J=1.4 Hz, 6.7 Hz, 1H), 6.87 J= 1.6 Hz, 1H), 7.79 J= 7.8 Hz, 1H).

WO 99/12928 WO 9912928PCT/US98/1 8578 66 EXAMPLE 47 Nal Me 2

CO

R.T.

Using the analogous procedure of example 15, the benzylic mesylate was converted to the benzyl iodide.

1 H NMR (CDC1 3 8: 1.27 J=7.3 Hz, 3H), 1.46 J=6.3 Hz, 3H), 3.45 (dd, J= 3.0 Hz, 5.0 Hz, 1H), 3.59 (in, 1H), 4.20 (dd, J=3.0 Hz, Hz, 1H), 4.36 J= 1.8 Hz, 2H), 4.61-4.65 (in, 2H), 4.71-4.89 (in, 3H), 5.18 (mn, I1H), 5.26-5.57 (in, 5H), 5.87-6.04( in, 2H), 6.75 (dd, J=2.0 Hz, 6.0 Hz, 1H), 6.83 J= 1.6 Hz, 1H), 7.66 J= Hz, 1H).

WO 99/12928 PCT/US98/18578 -67- EXAMPLE 48 N NMe MeCN

R.T.

Using the analogous procedure of example 16, the benzyl iodide was converted to the imidazolium salt.

WO 99/12928 WO 9912928PCT[US98/1 8578 68 EXAMPLE 49 (DOTf p-\~CONH 2 MeCN AgOTf

R.T.

(D

2 OTt Using the analogous procedure of example 17, the benzyl iodide was converted to the triflate salt.

WO 99/12928 WO 99/ 2928PCT/US98/1 8578 69 EXAMPLE 02C0 H H 0 I Pd(Ph 3

P)

4 N Ph 3

P

0 Sodium-2-ethylhexanoate 00 2-ethylhexanoic acid DCM/ EtOAc R.T. OOC

HO

N!

0

N

Using the analogous procedure of example 30, the hisallyl protected imidazolim salt was deblocked to provide the desired carbapenem.

1 H NMR (D 2 0) 8: 1.46 J=7.1 Hz, 3H), 1.50 J= 6.0 Hz, 3H), 3.54 (in, 1H), 3.63 (in, 1H), 4.17 3H), 4.27 dd, J=3.0, 7.1 Hz 1 4.46 (in, 1H), 5.12 1= 14.2 Hz, lH), 5.59 J=3.4 Hz, 2H), 5.90 J=14.2 Hz, lH), 7.13 J=9.8 Hz, 1H), 7.28 lH), 7.69 J=3.0 Hz, lH), 8.17 J=8.0 Hz, 1H), 9.03 lH).

WO 99/12928 WO 9912928PCTIUS98/1 8578 EXAMPLE 51 0 _0 2 OTf eCONH2 Pd(Ph 3

P)

4 Ph 3

P

Sodium -2-ethylhexanoate 2-ethyihexanoic acid

DMF

O

0

C

OCI

Using the analogous procedure of example 29, the bisallyl protectedl dabco salt was deblocked to provide the desired carbapenem.

IH NMR (D 2 0) 8: 1.50 (in, 6H), 3.51 (in, 1H), 3.65 (in, 1H), 4.21 (mn, 6H), 4.33 (dd, 1= 2.8 Hz, 7.3 Hz, 1H), 4.45(mi, 9 4.97 (s, 2H), 5.22 J= 14.0 Hz, 1H), 5.98 J= 13.8 Hz, 1H), 7.23 J= Hz, 1H), 7.46 1H), 8.31 J=8.0 Hz, 1H).

WO 99/12928 WO 9912928PCT/US98/1 8578 71 EXAMPLE 52 H OH

N!

0 0 0 HO

NOTBDMS

r DIAD Ph 3

P

THE

00c Using the analogous procedure of example 12, the bisallyl protected carbinol was converted to the silyl ether.

IH NMR (CDC1 3 8: 0.088 6H), 0.869 9H), 1.27 J=7.4 Hz, 3H4), 1.46 J=6.3 Hz, 3H), 2.73 J=6.8 Hz, 2H), 3.43 (dd, Hz, 7.0 Hz, 1H), 3.74 (in, 1H), 3.77 J=5.7 Hz, 2.0 4.21 (dd, Hz, 7.1 Hz, 1H), 4.62 (mn, 1H), 4.64 (mn, 1H), 5.11 (mn, 1H), 5.26-5.56 (in, 5H), 5.89 (mn, 2H), 6.60 (dd, J=1.8 Hz, 6.2 Hz, 1H), 6.67 J= 1.8 Hz, 1H), 7.63 J=8.0 Hz, 1H).

WO 99/12928 WO 9912928PCTIUS98/1 8578 72 EXAMPLE 53 02CI

TBAF

HOAc

THE

R.T.

OH

I H NMR (CDCl 3 8: 1.29 J=7.4 Hz, 3H), 1.48 J=6.3 Hz, 3H), 2.83 J=6.8 Hz, 2H), 3.43 (dd, J=3.O Hz, 7.0 Hz, 1H), 3.74 (in, 1H), 3.85 J=5.7 Hz, 2.0 4.21 (dd, J=3.0 Hz, 7.1 Hz, 1H), 4.62 (in, 1H), 4.64 (mn, 1H), 5.11 (in, 1H), 5.26-5.56 (in, 5H), 5.91 (mn, 2H), 6.63 (dd, J=1.8 Hz, 6.2 Hz, 1H), 6.67 J= 1.8 Hz, 1H), 7.65 J=8.0 Hz, 1H).

WO 99/12928 WO 9912928PCTIUS98/1 8578 73 EXAMPLE 54 02C( 2,6-lutidine

DCM

Tf 2

O

-200C 020 H H

N!

0 0 0 Using the analogous procedure of example 20, the carbinol was converted to the alkyl triflate.

WO 99/12928 WO 9912928PCTIUS98/1 8578 74 EXAMPLE W' N M e MeCN

R.T.

G)OTf Using the analogous procedure of example 22, the alkyl triflate was converted to the imidazolium salt.

WO 99/12928 WO 9912928PCT/US98/1 8578 75 EXAMPLE 56 (DOTf GCNH2 MeON

R.T.

0, e 2 OTf

\-CNH

2 Using the analogous procedure of example 2 1, the alkyl triflate was converted to the triflate salt.

WO 99/12928 WO 9912928PCTJUS98/1 8578 76 EXAMPLE 57 Ne Pd(Ph 3

P),

Ph 3

P

Sod iu m-2-ethylhexanoate 2-ethyihexanoic acid DOM! EtOAc R.T. f- OOC Using the analogous procedure of example 30, the bisallyl protected imidazolium salt was deblocked to provide the desired carbapenem.

I H NMR (13 2 0) 5: 1.37 J=7.6 Hz, 3H), 1.41 J= 5.8 Hz, 3H), 3.29 J= 6.6 Hz, 1H), 3.45 (in, 1H), 3.58 (mn, 1H), 3.97 3H), 4.23 d, J=10.0, Hz, 1 4.37 (mn, 1H), 4.59 J= 6.1 Hz, 2H),4.90 J= 14.0 Hz, 1H), 5.74 J=14.9 Hz, 1H), 6.97 1H1), 7.51 (s, 1H), 7.54 LH), 7.93 J= 6.4 Hz, 1H), 8.84 1H).

WO 99/12928 WO 9912928PCTIUS98/1 8578 77 EXAMPLE 58 Pd(Ph 3

P)

4 Ph 3

P

Sodi um-2-ethylhexanoate 2-ethyihexanoic acid

DMF

R.T. 0 0

C

0 2 OTf CON H 2 Using the analogous procedure of example 29, the bisallyl protected dabco salt was deblocked to provide the desired carbapenem.

III NMR 8: 1.49 J= 7.3 Hz, 6H), 3.37 (in, 3H), 3.66 (in, 1H), 4.00-4.08 (mn, 1H), 4.23-4.38 (in, 6H), 4.4 (in, 1H), 4.45( m, 9 4.53 (in, 9H), 5.14 J= 14.0 Hz, 1H), 5.98 1= 14.2 Hz, 1H), 7.05 J= 8.0 Hz, 1H), 7.31 1H), 8.10 J= 7.8 Hz, IH).

Claims

1. A compound represented by formula I: P .R H H3CN/ CH 2 0. .CO 2 M as well as salts and hydrates thereof, wherein the compound contains no more that two positive charges balanced by two negative charges to provide overall charge neutrality to the compound and; R 1 represents H or methyl; C0 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 hydroxyl- protecting group; 0@O B00 0 00 0 0 S 0@ see** oe lose **so* Get& A represents 0, S or -CH 2 attached at position 3, 4 or n represents an integer 0-3; Q is selected from the group consisting of: Na L 84 N /N/C (CH2)b N- NN- R x iR (CH 2 )a and N RxRYRz wherein: aandb are 1,2or3; [R:\LIBT] I 3345.doc:mes L- is a pharmaceutically acceptable counterion present or absent as necessary to maintain the appropriate charge balance; a represents O, S or NRs p, 6, X, jp and c represent CRt, N or N+Rs, provided that no more that one of P, 6, X, and a is N+R balanced by L, as defined above; each RS independently represents hydrogen; phenyl or -C 1 -6 straight- 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; -S02Ru; -SO 2 NRRV; -NRUSO2RV; -CORU; -NRuCORV; -OCORu; -OCONRuRV; -NRUCO 2 RV; -NRuCONRvR"; -OCO 2 R; -C1- 6 straight- or branched- chain alkyl, unsubstituted or substituted with one to four R' groups; each R' independently represents halo; -CN; -NO 2 phenyl; -NHSO 2 Rh; -ORh; -SRh; -N(R) 2 -N(Rh) 3 -C(O)N(Rh) 2 -SO 2 N(Rh)2; heteroaryl; heteroarylium; -CO 2 Rh; -C(O)Rh; -OCORh; -NHCORh; guanidinyl; carbamimidoyl or ureido; 20 each Rh independently represents hydrogen, a -C1- 6 straight- or branched- chain alkyl group, a -C 3 -Cs cycloalkyl group or phenyl, or when two Rh groups are present, said Rh groups may be taken in combination and represent a 4-6 membered saturated ring, optionally interrupted by one or two of O, S, SO 2 NH and NCH 3 25 Ru and Rv represent hydrogen or -C 1 -6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R' groups; or Ru and R' together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one or more of O, S, NR' or said ring being unsubstituted or substituted with one to four R' groups; [R:\LIBT] 13345.doc:mes each Rw independently represents hydrogen; -C1- 6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R' groups; C3- 5 cycloalkyl optionally substituted with one to four R' groups; phenyl optionally substituted with one to four R' groups, or heteroaryl optionally substituted with 1-4 R' 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 O, S, SO 2 NH or NCH 3 Rx represents hydrogen or a CI-8 straight- or branched-chain alkyl, optionally interrupted by one or two of O, S, SO, S02, NR, N+RhR, or said chain being unsubstituted or substituted with one to four of halo, CN, NO 2 ORw, SR", SOR", SO 2 Rw, NRhR, N (Rh) 2 RW, C(O)NRhR W SO 2 NhR w CO 2 R, OC(O)R w OC(O)NRhR w NRhC(O)Rw, NRhC(O)NRhRW, or a phenyl or heteroaryl group which is in turn optionally substituted with from one to four R' groups or with one to two Ci-3 straight- or branched- chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four R' groups; SR Y and Rz represent hydrogen; phenyl; -C 1 -6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R' groups, and optionally interrupted by O, S, NR", N+RhR' or or R x and R y together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by O, S, SO 2 NRw, N+RhR or unsubstituted or substituted with 1-4 R' groups, and when R x and R y together represent a 4-6 membered ring as defined above, 25 Rz is as defined above or Rz represents an additional saturated 4-6 membered ring fused to the ring represented by Rx and R Y taken together, optionally interrupted by O, S, NRw or said rings being unsubstituted or substituted with one to four R' groups. [R:\LIBT] 13345.doc:mes 81

2. A compound in accordance with claim 1 wherein R I represents methyl.

3. A compound in accordance with claim 1 wherein jo C0 2 M represents a carboxylic acid or a carboxylate anion.

4. A compound in accordance with claim 1 wherein P represents'hydroxyl or hydroxyl protected by hydroxyl-protecting group. A compound in accordance with claim I wherein A represents -CH 2

6. A compound in accordance with claim 1 wherein 20 n represents 0orl.

7. A compound in accordance with claim 1 wherein Q represents 61, or wheivin: ax represents 0, S or W tt and (Y represent CR!, N -or tat nomoret1Iaone f~&I~as 'i 30hih s pharmaceutically acceptable counteflon, originally defined.- NWk. provided balanced by L_ and RW is as

8. A compound in acwcrdance with claim 1 wherein Q is selected from the group consisting of: (CH 2 )b "R and. &N..BXYR7 N N L(CH 2 )a -82- a and b are 2; L- is a pharmaceutically acceptable counterion; and Rx, RY and Rz are as originally defined.

9. A compound in accordance with claim 8 wherein Q is (CH2)b I NA N- Rx Le (CH 2 )a :i 10. A compound in accordance with claim 1 wherein S Qis wherein: 8, Ix and a represent CRt, N or N+Rs, provided that no more than one of. 8, X, jI and o is N+Rs, balanced by L,which is a pharmaceutically acceptable counterion, and 25 all other variables are as originally defined.

11. A compound in accordance with claim 1 falling within the following table: WO 99/12928 WO 9912928PCTIUS98/1 8578 83 TABLE 1 C0 2 M C pd No. IA-(CH 2 4- 2 SN-CH3 3+ 3- SN-CH3 4 +N WO 99/12928 WO 9912928PCTIUS98/1 8578 84 4- N-CH 3 4- 6 N-CH 2 CH 2 CN H 2 N 7 N 4- NH 2 8 o OTf f-C()NH 2 9 o Cl- WO 99/12928 WO 99/ 2928PCTIUS98I1 8578 3- ()H N +ND 4- ,r-C(O)NH 2 Cl- 4- p C(O)NH 2 N 12 C Cl- 86 /-C(O)NH 2 N-i+ 13 N Cl-

12. A compound falling within table 2: TABLE 2 -QTBDMS .12 I WO 99/12928 PCT/US98/1 8578 87 88 J. 19 .1 I; I WO 99/12928 WO 9912928PCTIUS98/1 8578 89 (D(Dx .4 I. WO 99/12928 WO 9912928PCT/US98/1 8578 90 I NH 2 I NJ-\c WO 99/12928 WO 99/ 2928PCTIUS98/1 8578 91 I -NNCN HO HI- 300 0 00 HO W 310 0 0 0 HO I N-U ,H 32 0 00 WO 99/12928 WO 9912928PCTIUS98/1 8578 92 NH 2 0 ,'-00 2 NH 2 I%@ HO (D N C 0 2 NH 2 H Hj N 0~J N 0 0 0 00 36 0 N' 0 0o WO 99/12928 WO 9912928PCTIUS98/I 8578 93 I. i. t d. WO 99/12928 WO 9912928PCT/US98/1 8578 94 T E) //NMe e OTf t (o 4N Me 0 1- 2GX WO 99/12928 WO 99/ 2928PCTIUS98/I 8578 95 D T_ CONH 2 -N N- Gx 1* .1. WO 99/12928 WO 9912928PCTJUS98/1 8578 96 (Dx G) N e WO 99/12928 WO 9912928PCT/US981 18578 97 HO 0 (Ox 51 0 0 ~CONH 2 0 no H HI 52 0 0 OTBDMS 0 H H 4 0 N 0 Ot WO 99/12928 WO 9912928PCTIUS98/1 8578 98 Y -1NMe CONH 2 HO 57 0 (D HO 58 1 00 \-CONH 2 99 wherein X- represents a counterion.

13. A process of preparing a 3-(iodophenoxymethyl) carbapenem antibacterial compound, the process being substantially as hereinbefore described with reference to Flow Sheet A of the Examples.

14. A compound prepared by the process in accordance with claim 13. A pharmaceutical composition which is comprised of a compound in accordance with any one of claims 1 to 12 or 14 or a pharmaceutically acceptable salt or hydrate thereof, in combination with a pharmaceutically acceptable carrier.

16. A composition in accordance with claim 15 wherein the compound is in accordance with claim 1.

17. A pharmaceutical composition which is made by combining a compound in accordance with claim 1 or a pharmaceutically acceptable salt or hydrate thereof, with a pharmaceutically acceptable carrier.

18. A pharmaceutical composition in accordance with claim 15 further comprised S 15 of a compound which inhibits dehydropeptidase.

19. A pharmaceutical composition in accordance with claim 17 further comprised f a compound which inhibits dehydropeptidase. o a

20. A method of treating or preventing a bacterial infection in a mammalian patient, the method comprising administering to said patient an anti-infective amount of a compound in accordance with any one of claims 1 to 12 or 14 or of a pharmaceutical composition in accordance with any one of claims 15 to 19.

21. A compound in accordance with any one of claims 1 to 12 or 14 or a pharmaceutical composition in accordance with any one of claims 15 to 19 when used in treating or preventing a bacterial infection in a mammalian animal.

22. Use of a compound in accordance with any one of claims 1 to 12 or 14 in the manufacture of a medicament for treating a bacterial infection in a mammalian animal. Dated 30 January, 2001 Merck Co., Inc. Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON (I:\DayLib\LibF] 11461.doc:rns