WO1999020627A1 - Composes antibacteriens de la classe des carbapenemes, compositions et procedes de traitement - Google Patents

Composes antibacteriens de la classe des carbapenemes, compositions et procedes de traitement Download PDF

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Publication number
WO1999020627A1
WO1999020627A1 PCT/US1998/022110 US9822110W WO9920627A1 WO 1999020627 A1 WO1999020627 A1 WO 1999020627A1 US 9822110 W US9822110 W US 9822110W WO 9920627 A1 WO9920627 A1 WO 9920627A1
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Prior art keywords
mmol
substituted
groups
ethyl
methyl
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PCT/US1998/022110
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English (en)
Inventor
Lovji D. Cama
Ronald W. Ratcliffe
Robert R. Wilkening
Kenneth J. Wildonger
Wanying Sun
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Merck & Co., Inc.
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Priority claimed from GBGB9806431.4A external-priority patent/GB9806431D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU11030/99A priority Critical patent/AU739799B2/en
Priority to CA002306565A priority patent/CA2306565A1/fr
Priority to EP98953736A priority patent/EP1027352A4/fr
Priority to JP2000516969A priority patent/JP2002509856A/ja
Publication of WO1999020627A1 publication Critical patent/WO1999020627A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
    • C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
    • C07D477/14—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates to carbapenem antibacterial agents in which the carbapenem nucleus is substituted at the 2-position with a naphthosultam linked through a CH2 group.
  • the naphthosultam is further substituted with various substituent groups including at least one cationic group -A-Q-L-B.
  • 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), and are also active against Gram negative bacteria.
  • MRSA methicillin resistant Staphylococcus aureus
  • MRSE methicillin resistant Staphylococcus epidermidis
  • MRCNS methicillin resistant coagulase negative Staphylococci
  • the antibacterial compounds of the present invention thus comprise an important contribution to therapy for treating infections caused by these difficult to control pathogens.
  • the present invention relates to a compound represented by formula I:
  • Rl represents H or methyl
  • CO2M represents a carboxylic acid, a carboxylate anion, a pharmaceutically acceptable ester group or a carboxylic acid protected by a protecting group
  • P represents hydrogen, hydroxyl, F or hydroxyl protected by a hydroxyl-protecting group
  • A-Q-L-B represents a side chain wherein:
  • X in which: b is 2 or 3; and X" is a charge balancing counterion;
  • Het is a heteroaryl group
  • Rb is NH2 or Cl-6 alkyl unsubstituted or substituted with 1-3 groups selected from halo, OH, CN and C(O)NH2;
  • Rc is independently selected from halo, ORa, SRa, OC(O)Ra, CO2Ra, CN, C(O)N(Ra) 2 and C(O)Ra, Rd is H or Cl-3 alkyl, or Rc and Rd taken together with any intervening atoms represent a 4-6 membered ring;
  • Re is H; Rc; NO2 ; N(Ra) 2 ; SO2N(R ) 2 or Ci-4 alkyl, unsubstituted or substituted with 1-3 groups selected from halo, OH and C(O)NH2; Rf Rg and Rh are independently selected from H; Cl-6 straight or branched chain alkyl, unsubstituted or substituted with 1- 3 Rc groups; C3-6 cycloalkyl, unsubstituted or substituted with 1-3 Rc groups; phenyl, unsubstituted or substituted with 1-3 R e groups and Het, unsubstituted or substituted with 1-3 Re groups, or
  • Rf and Rg taken together with the intervening N atom form a 4-6 membered ring, optionally interrupted by 1-2 of O, S, C(O) or NRh, and optionally substituted by 1-3 Rc groups; and each R independently represents H; NO2 ; N(Ra)2; SO2N(Ra)2 ; Rc or Ci-4 alkyl, unsubstituted or substituted with 1-3 groups selected from halo, OH, C(O)NH2, or
  • R together with A of the group -A-Q-L-B and any intervening atoms represent a 5-6 membered carbocyclic ring.
  • Pharmaceutical compositions and methods of treatment are also included.
  • Carboxylate anion refers to a negatively charged group -COO-.
  • alkyl refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 15 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 c , Rf and Rg, or as otherwise defined, at any available point of attachment. When the alkyl group is said to be substituted with an alkyl group, this is used interchangeably with "branched alkyl group". When a bond appears without a group attached, this signifies the presence of a methyl group. Cycloalkyl is a specie of alkyl containing from 3 to
  • 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.
  • alkynyl refers to a hydrocarbon radical straight or branched, containing from 2 to 10 carbon atoms and at least one carbon to carbon triple bond.
  • Preferred alkynyl groups include ethynyl, propynyl and butynyl.
  • Aryl refers to aromatic rings e.g., phenyl, substituted phenyl and the like, as well as rings which are fused, e.g., naphthyl, phenanthrenyl and the like.
  • An aryl group thus contains at least one ring having at least 6 atoms, with up to 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.
  • heteroaryl refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing at least one heteroatom, O, S or N, and in which 1-2 additional carbon atoms are optionally replaced by a heteroatom selected from O or S, and in which from 1-3 additional carbon atoms are optionally replaced by N, said heteroaryl group being optionally substituted as described herein. Examples include the following:
  • triazole triazole
  • pyrazole pyrazolyl
  • isoxazole isoxazole
  • isothiazole isothiazolyl pyridine (pyridinyl) pyrazine (pyrazinyl)
  • Heteroaryl includes protonated forms as well. It thus includes positively charged as well as non-charged groups. Examples include the groups shown above, having an additional H attached to a nitrogen atom.
  • the group A-Q-L-B is attached to one of the two phenyl rings shown.
  • Heteroarylium refers to heteroaryl groups bearing a quaternary or protonated atom and thus a positive charge. Examples include the following:
  • heterocycloalkyl refers to a cycloalkyl group (nonaromatic) in which one of the carbon atoms in the ring is replaced by a heteroatom selected from O, S or N, and in which up to three additional carbon atoms may be replaced by hetero atoms.
  • quaternary nitrogen and “positive charge” refer to tetravalent, positively charged atoms including, e.g., the positively charged nitrogen in a tetraalkylammonium group (e. g. tetramethylammonium), 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.
  • heteroatom means O, S or N, selected on an independent basis.
  • Halogen and "halo" refer to bromine, chlorine, fluorine and iodine.
  • Alkoxy refers to C ⁇ -C ⁇ alkyl-O-, with the alkyl group optionally substituted as described herein.
  • M is a readily removable carboxyl protecting group
  • P represents a hydroxyl which is protected by a hydroxyl-protecting group.
  • Such conventional protecting groups consist of 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.
  • 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.
  • Suitable hydroxyl protecting groups include triethylsilyl, t-butyldimethylsilyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxy carbonyl, benzyloxycarbonyl, allyloxycarbonyl, t-butyl oxy carbonyl, 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.
  • pharmaceutically acceptable ester, salt or hydrate refers to those salts, esters and hydrated forms of the compounds of the present invention which would be apparent to the pharmaceutical chemist, i.e., those which are substantially non-toxic and which may favorably affect the pharmacokinetic properties of said compounds, such as palatability, absorption, distribution, metabolism and excretion. Other factors, more practical in nature, which are also important in the selection, are cost of the raw materials, ease of crystallization, yield, stability, solubility, hygroscopicity and flowability of the resulting bulk drug. Conveniently, pharmaceutical compositions may be prepared from the active ingredients in combination with pharmaceutically acceptable carriers. Thus, the present invention is also concerned with pharmaceutical compositions and methods of treating bacterial 20627 _]_g. PCT/US98/22110
  • -CO2M which is attached to the carbapenem nucleus at position 3, this represents a carboxylic acid group (M represents H), a carboxylate anion (M represents a negative charge), a pharmaceutically acceptable ester (M represents an ester forming group) or a carboxylic acid protected by a protecting group (M represents a carboxyl protecting group).
  • the pharmaceutically acceptable salts referred to above may take the form -COOM, where M is a negative charge, which is balanced by a counterion, e.g., an alkali metal cation such as sodium or potassium.
  • 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.
  • 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- hydroxy ethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, pa
  • the pharmaceutically acceptable esters are such as would be readily apparent to a medicinal chemist, and include, for example, those described in detail in U.S. Pat. No. 4,309,438. Included within such pharmaceutically acceptable esters are those which are hydrolyzed under physiological conditions, such as pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, and others described in detail in U.S. Pat. No. 4,479,947. These are also referred to as "biolabile esters".
  • Acid addition salts of the compounds of formula I are likely protonated at physiological pH, as mentioned above.
  • Compounds such as those containing a basic N-containing moiety are capable of protonation in water at or near pH 7, so that the moiety can exist in its neutral form or as an acid addition (protonated) form.
  • X- is a charge balancing group.
  • Biolabile esters are biologically hydrolizable, and may be suitable for oral administration, due to good absorption through the stomach or intenstinal mucosa, resistance to gastric acid degradation and other factors.
  • biolabile esters include compounds in which M represents an alkoxyalkyl, alkylcarbonyl oxy alkyl, alkoxycarbonyloxyalkyl, cycloalkoxyalkyl, alkenyl oxy alkyl, aryloxyalkyl, alkoxyaryl, alkylthioalkyl, cycloalkylthioalkyl, alkenyl thioalkyl, arylthioalkyl or alkylthioaryl group. These groups can be substituted in the alkyl or aryl portions thereof with acyl or halo groups.
  • M species are examples of biolabile ester forming moieties: acetoxym ethyl, 1- acetoxyethyl, 1-acetoxy propyl, pivaloyloxymethyl, 1- isopropyloxycarbonyloxyethyl, 1-cyclohexyloxycarbonyloxyethyl, phthalidyl and (2-oxo-5-methyl-l,3-dioxolen-4-yl)methyl.
  • all compounds which have one or more cations are balanced with one or more, as necessary, of a charge balancing group X " .
  • all compounds having one or more anions are counter balanced with one or more, as necessary, charge balancing cations.
  • L or A is an alkylene interrupted or terminated by 1-3 of O, S, -S(O)-, -SO 2 -, NR a , CO 2 C(O)NR a ,...and the like.
  • X can be present or absent as necessary to maintain the appropriate charge balance. When present, these represent pharmaceutically acceptable counterions. Most anions derived from inorganic or organic acids are suitable.
  • 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.
  • the counterion indicator X represents a specie with more than one negative charge, such as malonate, tartrate or ethylenediaminetetraacetate (EDTA), or when a multivalent negatively charged counterion is present with a carbapenem which bears a net single positive charge, an appropriate number of carbapenem molecules can be found in association therewith to maintain the overall charge balance and neutrality. Numbering and nomenclature using in naming the naphthosultams are as follows:
  • the interrupting groups can be separate or together, and can terminate the C ⁇ .g alkylene group.
  • the interrupting or terminating moiety can be between the alkylene group and the naphthosultam or -Q-.
  • A can represent -O-Ci-6 alkyl- , -Cl-6 alkyl -O- , -NRa- ⁇ _g alkyl- and the like.
  • Q represents
  • interrupting or terminating moieties can be separate or together. As described above with respect to A, the moieties can be at the ends of the Ci-8 alkylene group, and between the Ci-8 alkylene moiety and Q or B.
  • ⁇ n represents a 5-10 membered mono- or bicyclic, N- containing heteroaryl group, optionally containing 1-4 additional -10-
  • heteroatoms selected from O, S and N. These include positively charged as well as neutral moieties, many of which become positively charged at neutral to acidic pH. All are included in the present invention.
  • R represents Cl-6 alkyl, it may be unsubstituted or substituted with 1-3 groups selected from halo, OH, CN and C(O)NH2.
  • R c and Rd both appear, they may be taken in combination with any intervening atoms to form a 4-6 membered ring.
  • Rf and Rg When Rf and Rg are both present, they can be taken together with the intervening atoms to form a 4-6 membered ring, which is optionally interrupted by 1-2 of O, S, C(O) and NR h .
  • the ring can be unsubstituted or substituted with 1-3 R c groups.
  • one of the R groups is taken in combination with A from the side chain A-Q-L-B, along with the intervening atoms, it represents a 5-6 membered carbocyclic ring.
  • a subset of compounds of formula I which is of interest relates to those compounds where R 1 represents methyl. Within this subset, all other variables are as originally defined.
  • Another subset of compounds of formula I that is of interest relates to those compounds where P represents hydroxyl or hydroxyl protected by a hydroxyl protecting group. Within this subset, all other variables are as originally defined.
  • Another subset of compounds of formula I that is of interest relates to compounds of formula I wherein A represents Ci-3 alkylene. Within this subset, all other variables are as originally defined.
  • Another subset of compounds of formula I that is of interest relates to compounds where L is C -5 alkylene that is interrupted or terminated by -C(O)NRd-, -C(O)NRa-Het(R e )-, -NR a - variables are as originally defined.
  • a preferred subset of compounds of formula I which is of interest relates to those compounds wherein: R 1 represents methyl;
  • CO2M represents a carboxylate anion
  • P represents hydroxyl or hydroxyl protected by a hydroxyl protecting group
  • A represents Cl-3 alkylene
  • Q represents
  • X ' in which: b is 2 or 3, and X" is a charge balancing counterion; L is Ci-5 alkylene, interrupted or terminated by
  • Q-L-B is selected from:
  • Q-L-B is selected from:
  • Q-L-B is selected from:
  • P** represents a carboxyl protecting group
  • Q* represents a group which reacts with intermediate A2 (upon activation of A2) in a manner which results in the incorporation in the final product of a member of the group defined as Q above, thus Q* may be viewed as a precursor for Q.
  • the naphthosultam side chain group used in the synthesis of the compounds of the present invention have, in some cases, been described in the chemical literature. In other cases, precursor compounds which may be readily converted to the requisite naphthosultam have been described in the literature. In cases where the requisite naphthosultam is not known in the literature it is neceessary to synthesize the naphthosultam by a newly developed synthesis.
  • One skilled in the art can adapt a previously published synthesis of an analogous naphthosultam to prepare the requisite compound in a straightforward manner without undue experimentation. Examples of naphthosultam synthesis are described herein (see below).
  • the naphthosultam side chain group 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., 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.
  • PNB p-nitrobenzyl
  • allyl allyl
  • p-methoxybenzyl trichloroethyl
  • 2- trimethylsilylethyl and the like.
  • the hydroxyl group of the ⁇ -(hydroxyethyl) side-chain is optionally protected with a hydroxyl protecting group such as trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), acetyl, allyloxycarbonyl, 2-trimethylsilylethoxy carbonyl, 2- trichloroethoxy carbonyl and the like.
  • TMS trimethylsilyl
  • TES triethylsilyl
  • TDMS tert-butyldimethylsilyl
  • TDPS tert-butyldiphenylsilyl
  • acetyl acetyl, allyloxycarbonyl, 2-trimethylsilylethoxy carbonyl, 2- trichloroethoxy carbonyl and the like.
  • the addition of the naphthosultam side chain group to the carbapenem is accomplished by treating a solution of the hydroxymethyl-carbapenem and the naphthosultam side chain group in a suitable solvent such as tetrahydrofuran (THF), ether, acetonitrile, dimethylformamide (DMF), benzene, dimethylsulfoxide (DMSO), and the like with a (premixed) suitable activating reagent such as diethyl azodicarboxylate (DEAD) / triphenylphosphine, diisopropyl azodicarboxylate (DIAD) / tributylphosphine, and the like, at a temperature between about -20 °C and 35 °C for about 5 to 90 minutes.
  • a suitable solvent such as tetrahydrofuran (THF), ether, acetonitrile, dimethylformamide (DMF), benzene, dimethylsulfoxide (DM
  • the naphthosultam and carbapenem can be mixed together with either the azodicarboxylate or the phosphine reagent in a suitable solvent and the other component of the activating reagent (the phosphine or the azodicarboxylate, respectively) can be added to that mixture.
  • the reaction is allowed to proceed at a temperature between about -20 °C and 35 °C for about 5 to 90 minutes.
  • a positively charged substituent may be introduced into the side chain by first activating the hydroxyl group by converting it to a suitable leaving group (X) such as a triflate, mesylate, tosylate, iodide, chloride, bromide, and the like, and then displacing the resulting leaving group with a compound Q*, such as a suitably substituted diazabicyclooctane or a suitably substituted N,N-dimethylpiperazine.
  • a suitable leaving group such as a triflate, mesylate, tosylate, iodide, chloride, bromide, and the like
  • the charged substituent may be incorporated in the naphthosultam side chain before addition of the naphthosultam to the carbapenem or may be introduced after deprotection of A2.
  • introduction of the charged substituent by modification of A2 before deprotection is greatly preferred.
  • activation of the hydroxyl group and displacement by Q* to produce A3 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, tributyl amine, diisopropylethylamine, and the like at a temperature between about -100°C and 0°C for about 5 to 120 minutes.
  • a suitable solvent such as dichloromethane, tetrahydrofuran, ether, benzene, and the like
  • an activating reagent such as
  • the intermediate thus obtained contains a leaving group, which may be converted to an alternative leaving group, iodide, by treating a solution of the intermediate in a suitable solvent such as acetone, methyl ethyl ketone, and the like at about -10°C to 50°C with an excess of sodium iodide or potassium iodide for about 0.25 to 24 hours.
  • a suitable solvent such as acetone, methyl ethyl ketone, and the like at about -10°C to 50°C with an excess of sodium iodide or potassium iodide for about 0.25 to 24 hours.
  • the iodide is obtained in sufficiently pure form that it may be used without further purification.
  • 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*.
  • 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.
  • the activated intermediate in one solvent, isolate the activated intermediate, and conduct the displacement reaction in a different solvent.
  • 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.
  • 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 non-nucleophilic acid such as silver trifluoromethanesulfonate, silver tetrafluoroborate and the like is then added.
  • the reaction will proceed in the absence of the silver salt, the reaction proceeds more rapidly in the presence of the silver salt.
  • 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.
  • the synthesis of the target compound is completed by removing any protecting groups which are present in the penultimate intermediate using standard techniques which are well known to those skilled in the art.
  • the deprotected final product is then purified, as necessary, using standard techniques such as ion exchange chromatography, HPLC on reverse phase silica gel, MPLC on reverse phase polystyrene gel, and the like or by recrystallization.
  • the final product may be characterized structurally by standard techniques such as NMR, IR, MS, and UV.
  • 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 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.
  • Step 1 l-(2-Acetoxy-ethyl)-naphthalene Triethylamine (691 mL, 4.96 mol) was added to an ice cold solution of l-(2-hydroxy-ethyl)-naphthalene (569 g, 3.30 mol) in dichloromethane (2.2 L). Acetyl chloride (282 mL, 3.97 mol) was added dropwise over 90 minutes. After the addition was complete, the reaction mixture was stirred for an additional 30 minutes with ice-bath cooling.
  • reaction mixture was washed sequentially with water (2 x 1 L), IN HCl (1 L, 500 mL), water (1 L), 5% aqueous NaHCO3 (500 mL), water (1 L), and brine (500 mL), then dried over magnesium sulfate, filtered, and evaporated to afford l-(2-acetoxy- ethyl)-naphthalene (723.2 g) as a yellow oil that slowly crystallized.
  • Step 2 Potassium 4-(2-acetoxy-ethyl)-naphthalene-l-sulfonate Chlorosulfonic acid (69.3 g, 590 mmol) was added dropwise over 17 minutes to a solution of l-(2-acetoxy-ethyl)- naphthalene (105.5 g, 490 mmol) in dichloromethane (200 mL). The reaction was exothermic and periodic ice-bath cooling was employed to maintain the internal temperature at 25-30°C. Approximately 10 minutes into the CLSO3H addition, voluminous evolution of HCl gas was observed. After the addition was complete, the reaction mixture was stirred at room temperature for 3 hours then cautiously added to ice (400 g).
  • the filtrate was concentrated under vacuum to afford a white suspension (355 g) which was stored in a refrigerator overnight.
  • the solid was collected by filtration, washed with cold water (100 mL), then dried under vacuum at 60 °C to afford a second crop of potassium 4-(2-acetoxy-ethyl)-naphthalene-l-sulfonate (10.67 g) as a white solid.
  • the second crop contained ca. 14% of the isomeric potassium 5-(2-acetoxy-ethyl)-l-naphthalene sulfonate as determined by IH NMR.
  • Step 3 4-(2-Acetoxy-ethyl)-naphthalene-l-sulfonyl chloride
  • Step 4 4-(2-Acetoxy-ethyl)-8-nitro-naphthalene-l-sulfonyl chloride
  • Powdered cesium carbonate (76.8 g, 236 mmol) was added to a solution of 4-(2-hydroxy-ethyl)-8-nitro-naphthalene-l- sulfonamide (30.77 g, 94.3 mmol) in anhydrous dimethylformamide (470 mL).
  • the mixture was placed under a nitrogen atmosphere, sonicated for 10 minutes, then stirred at room temperature for 20 minutes.
  • the mixture was then placed in a 100 °C oil bath and stirred vigorously. After 3.5 hours, the reaction mixture was removed from the heating bath, allowed to cool to room temperature, and left at room temperature overnight. The mixture was then filtered and the collected solid was washed with dimethylformamide.
  • Step 7 4-(2-Triethylsilanyloxy-ethyl)-1.8-naphthosultam Chlorotriethylsilane (13.57 mL, 80.86 mmol) was added dropwise over 1 minute to a vigorously stirred suspension of 4-(2- hydroxy-ethyl)-l,8-naphthosultam (17.53 g, 70.32 mmol) and imidazole (5.99 g, 87.90 mmol) in dichloromethane (351 mL). The reaction mixture was stirred under a nitrogen atmosphere at room temperature for 15 minutes, then water (350 mL) was added.
  • the organic layer was washed sequentially with 0.2 N HCl (350 mL) and water (350 mL) then dried over magnesium sulfate, filtered, and evaporated under vacuum to a dark oil (29.07 g).
  • the crude product was purified by flash column chromatography on silica gel (5 x 27 cm column, eluted with 4:1 hexanes-EtOAc followed by 3:1 hexanes- EtOAc) to afford a deep red oil (23.9 g).
  • the oil was mixed with hexanes (225 mL), sonicated to start crystallization, and stirred at room temperature.
  • Step 1 AIM f3-ri(R)-(allyloxycarbonyloxy)-ethyll-2- ⁇ l(R)-methyl-2-oxo-
  • Step 2 AIM (lS.5R.6S)-6-[(lR)-(alMoxycarbonyloxy)-ethyll-l-methyl- 2-[4-(2-triethylsilanyloxy-ethyl)-1.8-naphthosultamyl-methyl.- carbapen-2-em-3-carboxylate
  • Step 3 AIM (lS.5R.6S)-6-.(lR)-(allyloxycarbonyloxy)-ethyl.-2-.4-(2- hydroxy-propyl)-1.8-naphthosultamyl -methyl! -l-methyl-carbapen-2- em-3-carboxylate
  • Step 1 l-Bromo-2-(2-hydroxy-ethyl)-naphthalene
  • 2-(2-hydroxy-ethyl)-naphthalene 58.5 g, 0.34 mol
  • anhydrous acetonitrile 500 mL
  • N- bromo-succinimide 66.5 g, 0.37 mol
  • the resulting solution was stirred at room temperature under a nitrogen atmosphere and protected from light for 30 minutes, then heated in an oil bath at 50°C for 2 hours. After cooling to room temperature, the reaction mixture was evaporated under vacuum to a viscous oil.
  • Triethylamine (32.3 mL, 0.232 mol) was added followed by acetyl chloride (15.8 mL, 0.222 mol) dropwise over 5 minutes.
  • the reaction mixture was removed from the ice bath and stirred at room temperature for 15 minutes.
  • the reaction mixture was washed with water (300 mL), IN hydrochloric acid (200 mL) and water (250 mL), dried over magnesium sulfate, filtered, and evaporated under vacuum to afford the title compound as an oil (55.1 g).
  • Step 3 Potassium 3-(2-acetoxy-ethyl)-4-bromo-naphthalene-l- sulfonate
  • the aqueous phase was washed with methylene chloride (150 mL), briefly pumped under vacuum, then brought to pH 8 with 3M aqueous potassium hydroxide (30 mL) followed by 4M aqueous potassium carbonate (35 mL). The resulting mixture was stirred in a cold room (5°C) for 2 hours and filtered to remove the product. The recovered white solid was vacuum dried to afford the title compound (11.21 g).
  • Step 4 3-(2-Acetoxy-ethyl)-4-bromo-naphthalene-l-sulfonyl chloride Potassium 3-(2-acetoxy-ethyl)-4-bromo-naphthalene-l- sulfonate (17.75 g, 43.2 mmol) was added at room temperature to a stirred solution of N,N-dimethylformamide (0.334 mL, 4.31 mmol) in thionyl chloride (63 mL, 863 mmol). The resulting mixture was placed in an oil bath at 70°C and stirred. After 10 minutes, additional thionyl chloride (20 mL) was added to facilitate stirring.
  • Step 5 3-(2-Acetoxy-ethyl)-4-bromo-8-nitro-naphthalene-l-sulfonyl chloride
  • Step 6 3-(2-Acetoxy-ethyl)-4-bromo-8-nitro-naphthalene-l- sulfonamide
  • Step 7 4-Bromo-3-(2-hydroxy-ethyl)-8-nitro-naphthalene-l- sulfonamide Sodium methoxide in methanol (23.7 mL of a 0.5M solution, 11.8 mmol) was added to a suspension of 3-(2-acetoxy-ethyl)- 4-bromo-8-nitro-naphthalene-l-sulfonamide (4.70 g, 11.3 mmol) in methanol (33 mL). The mixture was stirred under a nitrogen atmosphere at room temperature for 90 minutes, then concentrated under vacuum to approximately half volume, diluted with ethyl acetate (200 mL), and washed with 2N hydrochloric acid.
  • the oganic solution was washed with water (100 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and left to stand at room temperature.
  • the organic solution deposited a solid which was collected by filtration, washed with ethyl acetate (2 x 15 mL), and vacuum dried to give the title comound (1.78 g). Additional poduct (1.88g) was obtained from the mother liquors after concentration under vacuum and crystallization from diethyl ether.
  • Step 8 4-Bromo-3-(2-hydroxy-ethyl)-1.8-naphthosultam A solution of 4-bromo-3-(2-hydroxy-ethyl)-8-nitro- naphthalene-1-sulfonamide (3.61 g, 9.62 mmol) in anhydrous N,N- dimethylformamide (96 mL) was treated with cesium carbonate (7.84 g, 24.1 mmol). The resulting mixture placed under a nitrogen atmospere, sonicated at room temperature for 10 minutes, stirred at room temperature for 5 minutes, and then heated in an oil bath at 100°C for 2 hours.
  • Step 10 3-(2-Triethylsilanyloxy-ethyl)-1.8-naphthosultam
  • 3-(2-hydroxy-ethyl)-l,8-naphthosultam (1.44 g, 5.78 mmol) and imdazole (0.495 g, 7.27 mmol) in anhydrous methylene chloride (39 mL), at room temperature and under a nitrogen atmosphere, was treated with chlorotriethylsilane (1.12 mL, 6.69 mmol).
  • Step 1 AIM f3-ri(R)-(allyloxycarbonyloxy)-ethyll-2- ⁇ l(R)-methyl-2-oxo-
  • Step 2 AIM (lS.5R.6S)-6-.(lR)-(allyloxycarbonyloxy)-ethyll-l-methyl- 2-[3-(2-triethylsilanyloxy-ethyl)-1.8-naphthosultamyl-methyll- carbapen-2-em-3-carboxylate
  • the solution was concentrated under vacuum to 10 mL and applied to a column (4 x 20 cm) of EM silica gel 60.
  • the column was eluted with 3:1 hexane-ethyl acetate (28 x 20 mL fractions) followed by 2:1 hexane-ethyl acetate (20 mL fractions).
  • the product containing fractions were combined and concentrated under vacuum.
  • the residue was lyophilized from benzene to give the title compound (1.894 g) as a gum.
  • Step 3 AIM (lS.5R.6S)-6-.(lR.-(allyloxycarbonyloxy)-ethyl.-2-.3-(2- hvdroxy-propyl)-1.8-naphthosultamyl-methyll-l-methyl-carbapen-2- em-3-carboxylate
  • Step 4 AIM (lS.5R.6S)-6-.(lR.-(alMoxycarbonyloxy)-ethyll-l-methyl- 2- ⁇ 3-l2-(trifluoromethanesulfonyloxy)-ethyn-1.8-naphthosultamyl- methyl.-carbapen-2-em-3-carboxylate
  • Trifluoromethanesulfonic anhydride (0.178 mL, 1.06 mmol) was added and the resulting solution was stirred in the cold for 30 minutes.
  • the solution was diluted with methylene chloride (20 mL) and water (20 mL) and shaken.
  • the organic phase was separated, washed with 0.2N hydrochloric acid (20 mL) and water (20 mL), dried over magnesium sulfate, filtered and evaporated under vacuum to give the title compound as a foam (0.531 g).
  • Step 3 Sodium 4-bromo-8-amino-naphthalene-l-sulfonate
  • Step 6 4-Hydroxymethyl-1.8-naphthosultam A solution of 4-formyl-l,8-naphthosultam (0.035 g, 0.15 mmol) in anhydrous methanol (1 mL) was cooled in an ice bath under nitrogen. Sodium borohydride (0.011 g, 0.3 mmol) was added and the solution was stirred for 30 minutes. The mixture was partitioned between methylene chloride (10 mL) and 0.2N aqueous hydrochloric acid (10 mL).
  • Step 7 4-(Triethylsilyloxy-methyl)-1.8-naphthosultam
  • a mixture of 4-hydroxymethyl-l,8-naphthosultam (2.92 g, 8.7 mmol), imidazole (0.74 g, 10.9 mmol), and triethylsilyl chloride (1.68 mL, 10.0 mmol) in dichloromethane (40 mL) was stirred at room temperature under a nitrogen atmosphere for 30 minutes. The reaction mixture was then washed with 0.1 N HCl (80 mL), water (40 mL), and brine (40 mL), then dried over MgSO4 and concentrated to a brown oil.
  • the oil was stored at 0° C for 72 hours.
  • the crude product was purified by flash chromatography on EM silica gel 60 (5 x 15 cm) eluting with 4:1 hexane-ethyl acetate (200 mL) followed by 2:1 hexane- ethyl acetate (1000 mL).
  • the product-containing fractions were combined and concentrated to give a light brown solid (2.3 g).
  • the product was further purified by recrystallization from 15:1 hexane- ethyl acetate (80 mL) to give the title compound (1.48 g) as large white needles.
  • the mother liquor was concentrated and washed with cold hexane (10 mL) to provide additional title compound (0.50 g) as smaller white needles.
  • Step 1 AIM .3-ri(R)-(allyloxycarbonyloxy)-ethyl1-2-. l(R)-methyl-2-oxo-
  • Step 2 AIM (lS.5R.6S)-6-l(lR)-(allyloxycarbonyloxy)-ethyll-l-methyl-
  • Step 3 AIM (lS.5R.6S)-6-r(lR)-(alMoxycarbonyloxy)-ethyll-2-r4-
  • Step 4 AIM (lS.5R.6S)-6-r(lR)-(alMoxycarbonyloxy)-ethyll-2-f4-
  • the reaction mixture was then partitioned between dichloromethane (250 mL) and 0.1 N aqueous HCl (200 mL), and the organic phase dried over MgSO4 then concentrated and dried under vacuum for 20 hours.
  • the resulting mesylate (1.7 g, quant.) was dissolved in acetone (60 mL) and sodium iodide (1.95 g, 13 mmol) was added. This suspension was stirred for 80 minutes at room temperature under a nitrogen atmosphere.
  • the reaction mixture was then partitioned between dichloromethane (200 mL) and water (200 mL).
  • the aqueous phase was extracted with dichloromethane (50 mL) and the combined organic phase was washed with 5% NaHSO3 (2 x 75 mL), dried over MgSO4 and then concentrated. The resulting yellow oil was lyophilized from benzene (40 mL) to afford the title compound (1.5 g, quant.) as an amorphous yellow solid.
  • n 1 , 2,3 and 4
  • Step 1 l-Azido-3-chloropropane Sodium azide (1.43 g, 22 mmol) and lithium chloride
  • Step 2 3-Azido-l(1.4-dimethyl-piperazinium)-propane trifluoromethanesulfonate.
  • the azidochloropropane from Step 1 is dissolved in acetonitrile (8 ml) and treated with 1,4-dimethylpiperazine (1.12 g, 10 mmol).
  • Sodium iodide (0.15 g, 1 mmol) is added and the reaction is stirred under nitrogen at 50° for 6 hr.
  • the solvent is removed under reduced pressure and the residue is triturated with ether, the ether solution is decanted off and the residue is taken up in acetonitrile (10 ml) and treated with silver trifluoromethane sulfonate (2.56 g, 10 mmol).
  • the precipitated silver salts are filtered through a bed of celite and washed with a little acetonitrile. The filtrate and washings are evaporated to give the crude product which is crystallized from EtOH/Et 2 O to give the product.
  • Step 1 3-Bromo-l(1.4-dimethyl-piperazinium)-butane bromide.
  • 1,3-Dibromobutane (2.15 g, 1.2 ml, 10 mmol) is dissolved in acetonitrile (2 ml).
  • DABCO (1.23 g, 11 mmol) is added.
  • the reaction mixture is heated at 65° under nitrogen for 2 hr.
  • the acetonitrile is removed under reduced pressure to give the product.
  • Step 2 3-Azido-l(1.4-dimethyl-piperazinium)-)-butane trifluoromethanesulfonate.
  • the product from Step 1 is dissolved in DMF (5 ml). Sodium azide (0.71 g, 11 mmol) and lithium chloride (0.5 g, 11 mmol) are added followed by sodium iodide (0.149 g, 1 mmol). The reaction is stirred at 50°, under nitrogen overnight. The DMF is removed under reduced pressure with an external bath temperature of 40°. The residue is taken up in acetonitrile (5 ml) and methanol (5 ml) and treated with silver triflate (2.8 g, 11 mmol). After 0.5 hr the precipitated silver salts are filtered off through a bed of celite and washed with a little methanol. The filtrate and washings are evaporated to give an oil. Trituration with ether gives the product.
  • Step 4 -(4-azidomethylphenyl)-l-(1.4-dimethyl- piperazinium)acetamide triflate
  • Step l .N-(4-aminophenethyl)-0-allyl carbamate
  • Step 2 A " -(4-(2-(Allyloxycarbonylamino)ethyl)phenyl)chloroacetamide
  • Step 1 iV-(2-aminoethyl)-0-allyl carbamate
  • Step 2 3-Nitrophenethylamine A mixture of 3-nitrophenethyl azide (0.9 g, 4.69 mmol), triphenyl phosphine (1.22 g, 4.66 mmol) and CH 2 C1 2 (80 mL) is stirred at room temperature for 3 days. Solvent is removed and the residue is taken up in EtOH (20 mL). The solution is heated to 70°C, added 2M NaOH aqueous solution (10 mL) and stirred at room temperature for 2 hrs. A 10% HCl aqueous solution (20 mL) is then added and refluxed for 2 hrs.
  • Step 4 -(2-(3-Aminophenyl)ethyl)-Q-allyl carbamate
  • Step 5 A ⁇ -((3-(2-allyloxycarbonylamino)ethyl)phenyl)chloroacetamide
  • Step 6 iV-(3-(2-Allyloxycarbonylamino)ethyl)phenyl)-l-(1.4-dimethyl- piperazinium)acetamide triflate
  • Step 1 f7?)-(-)-3-azido-2-methylpropanol
  • f.Rj-f-j-3-bromo-2-methylpropanol (1 g, 6.53 mmol
  • sodium azide (0.47 g, 7.23 mmol
  • lithium chloride (0.31 g, 7.29 mmol)
  • DMF 10 mL
  • the residue is taken up in ethyl acetate, washed with water and brine, dried over Na 2 SO 4 and concentrated to give the product (0.64 g).
  • Step 2 (S)-(-)- 3-Azido-l-(1.4-dimethyl-piperazinium)-2- methylpropane triflate f.RJ-f-J-3-azido-2-methylpropanol (0.64 g, 5.56 mmol) is dissolved in CH 2 C1 2 (40 mL). 2,6-lutidine (1.9 mL, 16.3 mmol) is added at -20°C followed by adding trifalic anhydride (1.4 mL, 8.32 mmol).
  • the mixture is kept in -20°C for 40 min, diluted with CH 2 C1 2 , washed with water, 0.1 N HCl aqueous solution, water and brine, dried over Na 2 SO 4 and concentrated to give the trifalte (1.33 g).
  • the triflate (0.7 g, 2.83 mmol) is reacted with 1,4-dimethylpiperazine (0.31 g, 2.77 mmol) in CH 3 CN for 3 hrs. The solvent is removed and the residue is dried under vacuum to give the product.
  • Step 1 AIM (lS.5R.6S)-6-.(lR)-(allyloxycarbonyloxy)-ethv ⁇ - 2-(6-.2-(4- (3-azidopropy - 1.4-dimethyl-piperazin-l-iol-ethyl-l.l-dioxo-2-H-l- thia-2-aza-acenaphthalen-2-yl-methyl)-l-methyl-carbapen-2-em-3- carboxylate bis (trifluoromethanesulfonate).
  • Step 2 (1S.5R.6S)- -2-(6-r2-(4-(3-ammoniopropyl)- 1.4-dimethyl- piperazin-l-io)-ethyl1-l -dioxo-2-H-l-thia-2-aza-aeenaphthalen-2-yl- methyl)-6-ri(R)-hydroxyethyll-l-methyl-carbapen-2-em-3-carboxylate dichloride.
  • the reaction is stirred at room temperature for 10 min. then diluted with ether (5 ml) to precipitate the product.
  • the ether solution is decanted off and the residue washed with 2x7 ml ether.
  • the combined ether solutions are centrifuged and the precipitate combined with the original precipitate is dissolved in acetonitrile/water 1/1 (2 ml).
  • This solution is applied to a column of Macro-Prep CM weak cation exchange resin (5 ml).
  • the column is eluted with 1:1 acetonitrile- water (8 ml) followed by water (10 ml).
  • the resin is eluted with 5% aqueous sodium chloride (75 ml) and collected in 5x 15 ml fractions.
  • the first four fractions containing the product are combined and treated with 5% rhodium on carbon (50 mg) and stirred under an atmosphere of hydrogen. After 1 hour the catalyst is filtered off and the filtrate is loaded onto a Rainin Microsorb C18 RP HPLC column (2x 30 cm). Gradient elution with acetonitrile/0.12M aqueous ammonium chloride gives pure product containing fractions which are combined and concentrated under vacuum. The concentrated product is applied to a column of Amberchrome CG-161 4 ml) which is eluted with water (10 ml) followed by 1:1 acetonitrile-water (10 ml). The acetonitrile-water eluate is lyophilized to give the product.
  • Step 1 above, and following the procedure of Step 2 one obtains the desired product.
  • Step 1 AIM (lS.5R.6S)-6-f(lR)-(allyloxycarbonyloxy)-ethyll-2-(3- ⁇ 2-r4- (3-azido-propyD- 1.4-dimethyl-piperazin-l-io1-ethyll-1.8- naphthosultamyl-methyl)-l-methyl-carbapen-2-em-3-carboxylate bis(trifluoromethanesulfonate)
  • Step 2 (lS.5R.6S)-2-(3-f2-.4-(3-Ammomo-propyl)- 1.4-dimethyl- piperazin-l-iol-ethyll-1.8-naphthosultamyl-methyl)-6-[(lR)-hydroxy- ethyll-l-methyl-carbapen-2-em-3-carboxylate dichloride
  • the mixture is placed under a nitrogen atmosphere, treated with N,N- diisopropylethylamine (0.074 mL, 0.423 mmol), and stirred at room temperature. After 20 minutes, the mixture is added to diethyl ether (13 mL) and centrifuged.
  • the deallylated product is dissolved in tetrahydrofuran (2 mL), water (4 mL) and ethanol (3 mL), treated with 5% rhodium on carbon (17 mg), and stirred under an atmosphere of hydrogen. After 65 minutes, the mixture is filtered and the filtrate applied to a column of Macro-Prep CM weak cation exchange resin (3 mL). The column is eluted with 1:1 acetonitrile-water (10 mL), water (12 mL), and 5% aqueous sodium chloride (40 mL).
  • Step 1 AIM (lS.5R.6S)-2-.3-(2-.4-r4-(allyloxycarbonvH-4-aza-pent-l-yll- 1.4-dimethyl-piperazin-l-io l-ethyl)-1.8-naphthosultamyl-methyl1-6- [(lR)-(allyloxycarbonyloxy)-ethyn-l-methyl-carbapen-2-em-3- carboxylate bis(trifluoromethanesulfonate)
  • the solution kept at room temperature for one hour then stored in a freezer at -10°C for 3.5 days.
  • the solvent is evaporated under vacuum.
  • the residual oil is triturated with diethyl ether, the solvent decanted, and the residue dried under vacuum to afford the title compound as an amorphous solid. It is used in the next step without further purification.
  • Step 2 (lS.5R.6S)-6-r(lR)-Hvdroxy-ethyll-l-methyl-2-(3-f2-r4-(3- methylammonio-propyl)- 1.4-dimethyl-piperazin-l-iol-ethyl,-1.8- naphthosultamyl-methyl)-carbapenem-2-em-3-carboxylate dichloride
  • the solid is dissolved in 1:1 acetonitrile-water (3 mL) and applied to a column of Macro-Prep CM weak cation exchange resin (4 mL).
  • the column is eluted with 1:1 acetonitrile-water (7 mL), water (18 mL), 5% aqueous NaCl (9 mL), and 1:1 isopropanol-10% aqueous NaCl (10 mL).
  • the product containing fractions (5% NaCl and 1:1 iPrOH-10% NaCl) wre combined and concentrated under vacuum to remove isopropanol.
  • Step 1 Allyl (lS.5R.6S)-6-.(lR)-(allyloxycarbonyloxy)-ethyll- 1-methyl- 2- ⁇ 6-(2-(4-(4-azidomethylphenyl)aminocarbonyl)methyD- 1.4-dimethyl- piperazin- l-io)-ethyl)- 1.1-dioxo- IH- l-thia-2-aza-acenaphthylen-2-yl- methyllcarbapen-2-em-3-carboxylate bis-trifluormethylsulfonate.
  • Step 2 (lS.5R.6S)-6-(l(R)-hvdroxy-ethyl)-l-methyl-2-(6-(2-(4-(4- amoniomethylphenyl)aminocarbonyl)methyl)- 1.4-dimethyl- piperazin-l-io)-ethyl)-l.l-dioxo-lH-l-thia-2-aza-acenaphthylen-2-yl- methyllcarbapen-2-em-3-carboxylate dichloride.
  • the product from Step 1 is dissolved in DMF (0.2 ml), Phenylsilane ( 30 ml) is added, followed by tetrakis(triphenylphosphine)palladium(0) (2 mg). The reaction is stirred at room temperature for 15 min. then diluted with ether (2 ml) to precipitate the product. The ether solution is decanted off and the residue washed with 2x2 ml ether. The combined ether solutions are centrifuged and the precipitate combined with the original precipitate is dissolved in acetonitrile/water 1/1 (1 ml). This solution is applied to a column of Macro-Prep CM weak cation exchange resin (1.5 ml).
  • the column is eluted with 1:1 acetonitrile-water (3 ml) followed by water (3 ml).
  • the resin is eluted with 5% aqueous sodium chloride (6 ml) and collected in 1 ml fractions.
  • the fractions containing the product are combined and treated with 5% rhodium on carbon and stirred under an atmosphere of hydrogen. After 1.5 hour more catalyst is added and the reduction continued for 1 hr.
  • the catalyst is filtered off and the filtrate is loaded onto a Rainin Microsorb C18 RP HPLC column (2x 30 cm). Gradient elution with acetonitrile/0.12M aqueous ammonium chloride gives pure product containing fractions which are combined and concentrated under vacuum.
  • the concentrated product is applied to a column of Amberchrome CG-161 1.5 ml) which is eluted with water (5 ml) followed by 1:1 acetonitrile- water (5 ml). The acetonitrile-water eluate is lyophilized to give the product.
  • Step 1 Allyl (lS.5R.6S)-2-(3-r2-(4-fr4-(2-alMoxycarbonylamino-ethyl)- phenylcarbamoyn-methyll-1.4-dimethyl-piperazin-l-io)-ethvIl-1.8- naphthosultamyl-methyl)-6-[(lR)-allyloxycarbonyloxy-ethyl1-l- methyl-carbapenem-2-em-3-carboxylate bis(trifluoromethanesulfonate)
  • Step 2 (lS.5R.6S)-2-(3-r2-(4-ff4-(2-ammonio-ethyl)-phenylcarbamovn- methyll-1.4-dimethyl-piperazin-l-io)-ethyll-1.8-naphthosultamyl- methyl.-6-.(lR)-hydroxy-ethyll-l-methyl-carbapenem-2-em-3- carboxylate dichloride
  • the product containing fractions (1:1 iPrOH-10% NaCl) are concentrated under vacuum to a hazy suspension and applied to a column of Amberchrom CG-161 resin (4 mL). The column is eluted with water (15 mL) followed by 20% isopropanol in water (6 mL). The product containing fractions (20% iPrOH) are concentrated under vacuum and lyophilized to give the title compound.

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Abstract

L'invention concerne des composés correspondant à la formule (I) ainsi que les sels pharmaceutiquement acceptables de ces composés. Le naphtosultame est substitué par divers groupes dont au moins un groupe cationique -A-Q-L-B. Les carbapénèmes de l'invention sont efficaces contre les organismes bactériens sensibles, dont le staphylocoque doré résistant à la méthicilline, le staphylocoque epidermidis résistant à la méthicilline et les staphylocoques à coagulase négative résistant à la méthicilline.
PCT/US1998/022110 1997-10-23 1998-10-19 Composes antibacteriens de la classe des carbapenemes, compositions et procedes de traitement WO1999020627A1 (fr)

Priority Applications (4)

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AU11030/99A AU739799B2 (en) 1997-10-23 1998-10-19 Carbapenem antibacterial compounds, compositions and methods of treatment
CA002306565A CA2306565A1 (fr) 1997-10-23 1998-10-19 Composes antibacteriens de la classe des carbapenemes, compositions et procedes de traitement
EP98953736A EP1027352A4 (fr) 1997-10-23 1998-10-19 Composes antibacteriens de la classe des carbapenemes, compositions et procedes de traitement
JP2000516969A JP2002509856A (ja) 1997-10-23 1998-10-19 カルバペネム系抗菌化合物、組成物および治療方法

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US9771348B2 (en) 2013-07-25 2017-09-26 Dong-A St Co., Ltd Method for preparing benzamide derivative, novel intermediate used in preparation of benzamide, and method for preparing novel intermediate

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WO1993016080A1 (fr) * 1992-02-06 1993-08-19 Yamanouchi Pharmaceutical Co., Ltd. Nouveau derive de carbapenem
US5451579A (en) * 1994-02-15 1995-09-19 Merck & Co., Inc. 1-β-methyl-carbapenem, compositions containing same and methods of use
EA001296B1 (ru) * 1996-04-24 2000-12-25 Мерк Энд Ко., Инк. Антибактериальные соединения карбапенема, содержащие их фармацевтические композиции и способы лечения
EP0977567A1 (fr) * 1996-09-13 2000-02-09 Merck & Co., Inc. Composes antibacteriens de carbapenem, compositions contenant lesdits composes et methodes de traitement

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CA2306565A1 (fr) 1999-04-29
EP1027352A4 (fr) 2001-09-19
AU739799B2 (en) 2001-10-18
EP1027352A1 (fr) 2000-08-16
JP2002509856A (ja) 2002-04-02
AU1103099A (en) 1999-05-10

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