WO1999014217A1 - Composes anti-bacteriens d'aryloxymethyle carbapenem - Google Patents

Composes anti-bacteriens d'aryloxymethyle carbapenem Download PDF

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Publication number
WO1999014217A1
WO1999014217A1 PCT/US1998/019015 US9819015W WO9914217A1 WO 1999014217 A1 WO1999014217 A1 WO 1999014217A1 US 9819015 W US9819015 W US 9819015W WO 9914217 A1 WO9914217 A1 WO 9914217A1
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WIPO (PCT)
Prior art keywords
groups
substituted
carbapenem
unsubstituted
compound
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PCT/US1998/019015
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English (en)
Inventor
Frank P. Dininno
Helen Chen
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Merck & Co., Inc.
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Priority claimed from GBGB9806433.0A external-priority patent/GB9806433D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to CA002304267A priority Critical patent/CA2304267A1/fr
Priority to JP2000511766A priority patent/JP2002503638A/ja
Priority to AU97742/98A priority patent/AU9774298A/en
Priority to EP98951912A priority patent/EP1023293A4/fr
Publication of WO1999014217A1 publication Critical patent/WO1999014217A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • 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

Definitions

  • the present invention relates to carbapenem antibacterial agents in which the carbapenem nucleus is substituted at the 2-position with an aryl platform, linked through a CH2-O- group.
  • the aryl platform is further substituted with various substituent groups, typically 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).
  • MRSA methicillin resistant Staphylococcus aureus
  • MRSE methicillin resistant Staphylococcus epidermidis
  • MRCNS methicillin resistant coagulase negative Staphylococci
  • MRSA/MRCNS agents effective against such 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
  • each R group is independently selected from: hydrogen; halo; -CN; -NO2; -NRaRb; _ORc ; -SRC; -C(O)NRaRb ; -C(O)ORh; - S(O)R c ; -SO2R c ; -SO2NR Rb ; -NR a SO2R b ; -C(O)R a ; -OC(O)Ra ; - OC(O)NRaRb ; -NRaC(O)NRbRc ; -NR a CO2R h ; -OCO2R 11 ; - NR a C(O)R O ; -Ci-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R ⁇ groups; -A-(CH 2 ) n -Q and -C3-7 cycloalkyl, unsubstituted or
  • A represents O, S or -CH 2 -;
  • n an integer 0-3;
  • each R a , R D and R c independently represents hydrogen, -Ci-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R" groups, or -C3-7 cycloalkyl, unsubstituted or substituted with one to four R ⁇ groups; or R a and R D taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one or more of O, S, NR C , with R c as defined above, or -C(O)-, said ring being unsubstituted or substituted with one to four R 1 groups; or R" 3 and R c taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one to three of O, S, NR a , with R a as defined above, or -C(O)-, said ring being unsubstituted or substituted with one to four R 1 groups;
  • each R" independently represents halo; -CN; -NO2; - NReR f ; -ORg; -SRg; -CONReR* " ; -COORg; -SORg; -SO2R ; -SO2NR e R f ; -NReS02R f ; -COR ⁇ ; -NR e COR f ; -OCOR ⁇ ; -OCONR ⁇ Rf; - NR ⁇ CONRfRg; -NR e CO2R h ; -OCO2R 11 ; -C(NR e )NR f Rg; - NR e C(NH)NRfRg or -NReC(NR f )Rg;
  • R e , R* and Rg represent hydrogen; -R*; -C ⁇ -6 straight- or branched-chain alkyl unsubstituted or substituted with one to four R 1 groups; or R e and R* taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one to three of O, S, -C(O)- or NRg with Rg as defined above, said ring being unsubstituted or substituted with one to four R 1 groups;
  • each R 1 independently represents halo; -CN; -NO2; phenyl; -NHSO2R h ; -ORh, -SR h ; -N(R h )2; -N+(R h )3; -C(O)N(R h )2; - SO2N(Rh) 2 ; heteroaryl; heteroarylium; -CO2R 11 ; -C(O)R h ; -OCOR h ; - NHCORh; guanidinyl; carbamimidoyl or ureido;
  • each R 1 independently represents hydrogen, a -Ci-6 straight or branched-chain alkyl group, a -C3-C6 cycloalkyl group or phenyl, or when two R n groups are present, said B ⁇ 1 groups may be taken in combination and represent a 4-6 membered saturated ring, optionally interrupted by one or two of O, S, SO2, -C(O)-, NH and NCH3;
  • Q is selected from the group consisting of:
  • a and b are 1, 2 or 3;
  • L" is a pharmaceutically acceptable counterion;
  • ⁇ represents O, S or NR S ;
  • ⁇ , ⁇ , ⁇ , ⁇ and ⁇ represent CR*, N or N + R s , provided that no more than one of ⁇ , ⁇ , ⁇ , ⁇ and ⁇ is N + R s ;
  • each R s independently represents hydrogen; phenyl or - Ci-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R 1 groups;
  • each R ⁇ independently represents hydrogen; halo; phenyl; -CN; -NO2; -NR U R V ; -OR u ; -SRu ; -CONR u R v ; -COOR h ; - SOR U ; -SO2R u ; -SO2NR u Rv ; -NR u SO2R v ; -COR u ; -NR ⁇ COR V ; - OCOR u ; -OCONR U R V ; -NR U C02R V ; -NR u CONR v R w ; -OCO2R v ; -Ci- 6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R 1 groups;
  • R u and R v represent hydrogen or -Ci-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R 1 groups; or R u and R v together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one or more of O, S, NR W or -C(O)-, said ring being unsubstituted or substituted with one to four R 1 groups;
  • each R w independently represents hydrogen; -C ⁇ -6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R 1 groups; C3-6 cycloalkyl optionally substituted with one to four R 1 groups; phenyl optionally substituted with one to four R 1 groups, or heteroaryl optionally substituted with 1-4 R 1 groups; or Rh and R w taken together with any intervening atoms represent a 5-6 membered saturated ring, optionally interrupted by one or two of O, S, SO2, NH or NCH3;
  • R x represents hydrogen or a Ci-8 straight- or branched- chain alkyl, optionally interrupted by one or two of O, S, SO, SO2, NR W , N+R h R W , or -C(O)-, said chain being unsubstituted or substituted with one to four of halo, CN, NO2, OR w , SR W , SOR w , SO2R w , NRhRW ; N+(Rh) 2 Rw, -C(O)-RW, C(O)NR h R w , SO2NRhR ⁇ CO2R w , OC(O)R w , OC(O)NRbRw ?
  • NR h C(O)R NR h C(O)NR h R w
  • a phenyl or heteroaryl group which is in turn optionally substituted with from one to four R 1 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 1 groups;
  • RJ and R z represent hydrogen; phenyl; -Ci-6 straight or branched chain alkyl, unsubstituted or substituted with one to four R 1 groups, and optionally interrupted by O, S, NR W , N+R ⁇ R or -C(O)-;
  • R x and RY together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by O, S, SO2, NRw , N+R h R W or -C(O)-, unsubstituted or substituted with
  • R z is as defined above or R z represents an additional saturated 4-6 membered ring fused to the ring represented by R x and RJ taken together, optionally interrupted by O, S, NR W or - C(O)-, said rings being unsubstituted or substituted with one to four R 1 groups.
  • compositions and methods of treatment are also included.
  • Carboxylate anion refers to a negatively charged group -COO.
  • alkyl refers to a monovalent alkane
  • alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, cyclopentyl and cyclohexyl.
  • alkyl groups may be substituted with up to four substituent groups, selected from R ⁇ and B , as defined, at any available point of attachment.
  • substituent groups selected from R ⁇ and B , as defined, at any available point of attachment.
  • Cycloalkyl is a specie of alkyl containing from 3 to 15 carbon atoms, without alternating or resonating double bonds between carbon atoms. It may contain from 1 to 4 rings which are fused.
  • 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, in which a carbon or nitrogen atom is the point of attachment, and in which one or two additional carbon atoms is optionally replaced by a heteroatom selected from O or S, and in which from 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms, said heteroaryl group being optionally substituted as described herein. Examples of this type are pyrrole, pyridine, oxazole, thiazole and oxazine. Additional nitrogen atoms may be present together with the first nitrogen and oxygen or sulfur, giving, e.g., thiadiazole. Examples include the following:
  • triazole triazole
  • pyrazole pyrazolyl
  • isoxazole isoxazole
  • isothiazole isothiazolyl pyridine (pyridinyl) pyrazine (pyrazinyl)
  • Heteroarylium refers to heteroaryl groups bearing a quaternary nitrogen 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 nitrogen 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 C1-C alkyl-O-, with the alkyl group optionally substituted as described herein.
  • Gua idinyl 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-.
  • 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.
  • a group is “optionally interrupted"
  • this includes one or more of the interrupting moieties in combination, as well as said moieties located at either or both ends of the chain. Thus, it includes terminating the group as well.
  • 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 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.
  • 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.
  • 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.
  • 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.
  • pharmaceutical compositions may be prepared from the active ingredients in combination with pharmaceutically acceptable carriers.
  • the present invention is also concerned with pharmaceutical compositions and methods of treating bacterial infections utilizing as an active ingredient the novel carbapenem compounds.
  • -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, dodec lsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, pam
  • the pharmaceutically acceptable esters are such as would be readily apparent to a medicinal chemist, and include, for example, those described in detail in U.S. Pat. No. 4,309,438. Included within such pharmaceutically acceptable esters are those which are hydrolyzed under physiological conditions, such as pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, and others described in detail in U.S. Pat. No. 4,479,947. These are also referred to as "biolabile esters".
  • Biolabile esters are biologically hydrolizable, and may be suitable for oral administration, due to good absorption through the stomach or intestinal mucosa, resistance to gastric acid degradation and other factors.
  • biolabile esters include compounds in which M represents an alkoxyalkyl, alkylcarbonyloxyalkyl, alkoxycarbonyloxy alkyl, cycloalkoxyalkyl, alkenyloxyalkyl, aryloxyalkyl, alkoxyaryl, alkylthioalkyl, cycloalkylthioalkyl, alkenylthioalkyl, arylthioalkyl or alkylthioaryl group.
  • M species are examples of biolabile ester forming moieties.: acetoxymethyl, 1-acetoxy ethyl, 1-acetoxypropyl, pivaloyloxymethyl, 1- isopropyloxycarbonyloxyethyl, 1-cyclohexyloxycarbonyloxyethyl, phthalidyl and (2-oxo-5-methyl-l,3-dioxolen-4-yl)methyl.
  • L " can be present or absent as necessary to maintain the appropriate charge balance.
  • 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
  • L " represents a specie with more than one negative charge, such as malonate, tartrate or ethylenediaminetetraacetate (EDTA)
  • EDTA ethylenediaminetetraacetate
  • the molecule When the side chain is neutral, and the 3-carboxylate is in the form of an anion, the molecule is charge balanced by the presence of an appropriately charged group, such as L + .
  • Suitable positively charged groups include cations, such as sodium, potassium, calcium, magnesium and the like.
  • Protonated moieties are also acceptable, such as tetraalkylammonium and the like.
  • a and b are 2;
  • L is a pharmaceutically acceptable counterion; and R x , RY and R z are as originally defined. Within this subset, all other variables are as originally defined.
  • X + and X " represent appropriately charged counterions which are present to provide overall charge balance.
  • the compounds of the present invention are prepared by reacting a suitably protected, activated 2-hydroxymethyl-carbapen-2- em-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 schemes:
  • P, R, Rl, A, Q and n are as defined with respect to the compounds of formula I.
  • P** is a carboxyl covering group.
  • the side chain A2 or A5 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 hydroxymethyl 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.
  • hydroxyl group of the 6-(hydroxyethyl) side-chain is protected with a hydroxyl protecting group such as trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), acetyl, allyloxycarbonyl, 2-trimethylsilylethoxycarbonyl, 2- trichloroethoxycarbonyl and the like.
  • TMS trimethylsilyl
  • TES triethylsilyl
  • TDMS tert-butyldimethylsilyl
  • TDPS tert-butyldiphenylsilyl
  • acetyl acetyl, allyloxycarbonyl, 2-trimethylsilylethoxycarbonyl, 2- trichloroethoxycarbonyl and the like.
  • the addition of the side chain to the carbapenem is accomplished by treating a solution of the hydroxymethyl- carbapenem Al and the side chain A2 or A5 in a suitable solvent such as tetrahydrofuran (THF), ether, acetonitrile, dimethylformamide (DMF), benzene, dimethylsulfoxide (DMSO), and the like with a combination of reagents that comprise the Mitsunobu reaction (for a review see: Hughes, D.L. Organic Reactions, Paquette, L. ed., Vol. 42, John Wiley & Sons, USA, 1992.
  • a suitable solvent such as tetrahydrofuran (THF), ether, acetonitrile, dimethylformamide (DMF), benzene, dimethylsulfoxide (DMSO), and the like.
  • a tri- substituted phosphine such as triphenylphosphine, tri-n- butylphosphine, and the like, at a temperature between about -20 °C and 35 °C for about 5 to 90 minutes.
  • the naphthosultam and carbapenem can be simultaneously added to a preformed complex of the diazocarboxylate and phosphine. Once the naphthosultam, carbapenem, and activating reagent(s) have been mixed, the reaction is allowed to proceed at a temperature between about -20 °C and 35 °C for about 5 to 90 minutes.
  • the resulting mixture is then subjected to a standard work-up procedure 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.
  • a suitable solvent or mixture of two or more solvents such as hexane, ethyl acetate, ether, benzene, dichloromethane, chloroform, acetone, methanol and the like.
  • Modification of the side chain which is generally necessary to introduce the charged substituent, is best accomplished before reacting the carbapenem and the side chain, as in Flow Sheet B.
  • a positively charged substituent may be introduced into the side chain by first activating the hydroxyl group.
  • a suitable leaving group such as a triflate, mesylate, tosylate, iodide, chloride, bromide, and the like
  • Q such as N-
  • the charged substituent may be incorporated in the side chain after addition of the side chain to the carbapenem, or after deprotection. Introduction of the charged moiety Q before deprotection is greatly preferred.
  • activation of the hydroxyl group and displacement by Q to produce A8 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, tetrahydro- furan, 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, tributylamine, 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, tetrahydro- furan, 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.
  • 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.
  • 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.
  • the compounds of the invention are determined to be active against MRSA.
  • the compounds of the invention can be formulated in pharmaceutical compositions by combining the compound with a pharmaceutically acceptable carrier. Examples of such carriers are set forth below.
  • the compounds may be employed in powder or crystalline form, in liquid solution, or in suspension. They may be administered by a variety of means; those of principal interest include: topically, orally and parenterally by injection (intravenously or intramuscularly).
  • compositions for injection 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.
  • the active ingredient may be in powder (lyophilized or non-lyophilized) form for reconstitution at the time of delivery with a suitable vehicle, such as sterile water.
  • the carrier is typically comprised of sterile water, saline or another injectable liquid, e.g., peanut oil for intramuscular injections.
  • 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.
  • 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.
  • compositions for human delivery per unit dosage 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.
  • the unit dosage will typically include the pure compound in sterile water solution or in the form of a soluble powder intended for solution, which can be adjusted to neutral pH and isotonic.
  • the invention described herein also includes a method of treating a bacterial infection in a mammal in need of such treatment comprising administering to said mammal a compound of formula I in an amount effective to treat said infection.
  • the preferred methods of administration of the Formula I antibacterial compounds include oral and parenteral, e.g., i.v. infusion, i.v. bolus and i.m. injection.
  • oral and parenteral e.g., i.v. infusion, i.v. bolus and i.m. injection.
  • i.v. infusion e.g., i.v. bolus
  • i.m. injection e.g., i.v. infusion, i.v. bolus and i.m. injection.
  • 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
  • a dose of about 5-25 mg/kg of body weight given 2, 3, or 4 times per day is preferred; a dose of 10 mg/kg is typically recommended.
  • the compounds of Formula I are of the broad class known as carbapenems. Many carbapenems are susceptible to attack by a renal enzyme known as dehydropeptidase (DHP). This attack or degradation may reduce the efficacy of the carbapenem antibacterial agent. Many of the compounds of the present invention, on the other hand, are less subject to such attack, and therefore may not require the use of a DHP inhibitor. However, such use is optional and contemplated to be part of the present invention. Inhibitors of DHP and their use with carbapenems are disclosed in, e.g., [European Patent Application Nos. 79102616.4, filed July 24, 1979 (Patent No. 0 007 614); and 82107174.3, filed August 9, 1982 (Publication No. 0 072 014)].
  • DHP dehydropeptidase
  • the compounds of the present invention may, where DHP inhibition is desired or necessary, be combined or used with the appropriate DHP inhibitor as described in the aforesaid patents and published application.
  • the cited European Patent Applications define the procedure for determining DHP susceptibility of the present carbapenems and disclose suitable inhibitors, combination compositions and methods of treatment.
  • a preferred weight ratio of Formula I compound: DHP inhibitor in the combination compositions is about 1:1.
  • a preferred DHP inhibitor is 7-(L-2-amino-2-carboxy- ethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptenoic acid or a useful salt thereof.
  • Step B To a stirred solution of the product obtained from Step A
  • Step D A solution of FeSO4»7H2O (0.2258 g, 0.81 mmoles) in distilled water (3 mL) was heated to 100°C.
  • the diazonium salt from Step C was added in one portion and the resulting mixture was stirred at 100°C under N2- Gas evolution was observed for the first 5- 10 min. of the reaction. With time, the product oiled out of solution. After 30 min., the reaction was partitioned between EtOAc and ice/brine. The organic layer was collected, dried over Na2SO4, and concentrated in vacuo to give a green/brown oil (0.3317 g).
  • Step A The coupled product from Step A was reduced to its corresponding amine using the procedures described in Example 1 (Step B).
  • the amine was obtained as a green/yellow oil.
  • the acetylated product (0.0902, 0.35 mmoles) obtained from Step F was dissolved in CCI4 (0.5 mL) and placed under a N2 atmosphere. NBS (0.0817 g, 0.46 mmoles) was added followed by a crystal of AIBN. The reaction was heated to 80°C for 23 hrs. The reaction was poured into ice/brine and extracted with EtOAc. The organic layers were washed with 5% Na2S2 ⁇ 3 and brine.
  • the alkyl bromide (0.0895 g, 0.27 mmoles) from Step G was combined with KOAc (0.0541 g, 0.53 mmoles) in sieve-dried DMF (1 mL) and heated to 100°C for 1 hr. The reaction was poured into ice/H2 ⁇ and extracted with EtOAc. The organic layers were washed with additional H2O (2X) and brine, and dried over Na2SO4.
  • Step A The product from Step A was deblocked using the procedures described in Example 3 to afford the final compound as a white solid after lyophilization.
  • the crude mesylate was dissolved in acetone (2 mL) and cooled to 0°C. Nal (0.0465 g, 0.31 mmoles) was added in one portion under N2. With time the reaction became increasingly yellow. The reaction was stirred at 0°C for 1 hr and then partitioned between ice/brine and EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford the alkyl iodide as a yellow oil (0.1045 g).
  • the product (0.0696 g, 0.068 mmoles) from Step B was deblocked using the procedure described in Example 3 with the exception of sieve-dried DMF as the solvent. The reaction became increasingly cloudy over time. After 1 hr, the reaction was cooled to 0°C and the product was further precipitated with the addition of acetone. The crude material (0.0377 g) was collected as a hexanoate salt after washing with acetone and centrifugation. The compound was dissolved in a minimal amount of H2O and purified via a reverse-phase HPLC equipped with a 10 mL column of MacroPrep ion exchange resin in conjunction with a 10 mL column of Amberchrom CG 161.
  • the acetylated dibenzothiophene (0.3985, 1.55 mmoles) obtained from Example 4 (Step F) was dissolved in CCI4 (5 mL) and place under a N2 atmosphere. Recrystallized NBS (0.3051 g, 1.7 mmoles) was added followed by a crystal of AIBN. The reaction was heated to 80°C for 23 hrs. Additional NBS (0.3067 g, 1.7 mmoles) was added to the reaction and the mixture was stirred at 80°C for another 6.5 hrs. The reaction was poured into ice/brine and extracted with EtOAc. The organic layers were washed with 5% Na2S2 ⁇ 3 and brine.
  • Step B The fraction from Step B containing a mixture of the diacetate compound and the aldehyde (0.2077 g, 0.77 moles) was submitted under the same reaction conditions described in Step C.
  • the resulting mixture of aldehyde and diol was separated by plate layer chromatography with 5% EtOAc/CH2Cl2 to give 0.0895 g of clean aldehyde.
  • Step A l-Hydroxy-5-t-butyldimethylsilyloxypropyl dibenzothiophene was coupled with the bis-allyl protected carbinol using the procedure described in Example 2 to give the adduct as a yellow oil after plate layer chromatography with 3:1 CH2Cl2/hexane.
  • lH NMR (CDCI3) ⁇ : 0.09 (s, 3H), 0.94 (s, 6H), 1.29 (d, 3H),
  • the dabco quat from Step B was deallylated following the procedures described in Examples 7 (Step C) to afford the desired product as a white solid.
  • Step A A solution of carbapenem 1 (0.099 g, 0.18 mmoles) in
  • the sulfone was prepared in an analogous manner to Example 11 using 3 equivalents of MCPBA in the oxidation step (Example 11, Step A). The final compound was isolated as a white solid.
  • Step A The sulfone generated in Step A was converted to the alkyl iodide following the procedures described in Example 7 (Step A) with the exception that initial mesylation was complete after 35 min. and 5 equivalents of Nal at ambient temperature for 4.5 hrs was necessary to drive the reaction to completion.
  • the iodide was isolated in quantitative yield as a red/orange oil.
  • the dabco quaternized carbapenem was prepared by reacting the alkyl iodide isolated from Step B with the dabco acetamide triflate salt.
  • lH NMR (d6-acetone) ⁇ : 1.35 (d, 6H), 3.50 (m, IH), 3.72
  • Step B The methoxy nitrobenzene isolated from Step A was coupled with o-cresol (0.64 mL, 6.2 mmoles) using the procedures described in Example 1 (Step A) with the exception that the reaction time was 3 hrs. After purification by plate layer chromatography with 1:1 hexane/CH2Cl2, the desired adduct was obtained as a pale yellow solid.
  • Step C The adduct from Step B (1.3924 g, 5.4 mmoles) was hydrogenated under 40-46 psi of H2 in a Parr Shaker for 5 days using
  • Step D The amine from Step C was converted to its KPFQ diazonium salt using the procedures described in Example 1 (Step C). The product was isolated as a yellow solid. !H NMR (d6-acetone) ⁇ : 2.26 (s, 3H), 4.36 (s, 3H), 6.57 (d, IH), 7.25 (d, IH), 7.32 (d, IH), 7.38 (t, 2H), 7.46 (dd, IH), 8.17 (t, IH).
  • Step E A mixture of 0.438 g (0.48 mmoles) of Pd2(dba)3 in anhydrous DMSO (30 mL) was heated to 100°C under N2 and the diazonium salt from Step D (1.8489 g, 4.8 mmoles) was added in one portion, resulting in significant gas evolution. The reaction was stirred at 100°C for 40 min and then filtered through celite. The filtrate was paritioned between EtOAc and water. The organic layer was washed well with H2O (2X) followed by brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to give a black solid.
  • Step E The dibenzofuran from Step E was demethylated and acetylated using the procedures described in Example 1 (Step E) and Example 4 (Step F) respectively.
  • the desired product was obtained as a white solid over the 2 steps.
  • the diacetate was prepared after plate layer chromatography with 2:1 CH 2 Cl 2 /hexane, from the alkyl bromide of
  • Step J The diol from Step I was selectively protected at the primary position using the procedures described in Example 4 (Step J).
  • the carbapenem adduct was prepared by coupling 1- hydroxy-5-t-butyldimethylsilylmethyl dibenzofuran with bis-allyl protected carbinol in an analogous manner to Example 2 to give the desired product as a light purple oil.
  • Desilylation of the carbapenem from Step A was accomplished using the procedures described in Example 5 (Step B) to give the desired alcohol as a yellow oil.
  • Step C The alcohol from Step B was converted to its corresponding alkyl iodide following procedures presented in Example 7 (Step A).
  • Step D Utilizing the procedures presented in Example7 (Steps B and C), the alkyl iodide from Step C was displaced by dabco acetamide triflate salt and deallylated to afford the final compound. Purification of the crude product was achieved on reverse-phase HPLC by eluting the compound through a 10 mL column of Amberchrom CG 161 with a linear gradient (100% water to 40:60 CH3CN/H2O over 45 min).
  • Step A Preparation of 3-hydroxybiphenyl A stirred mixture of 660mg(3mmol) of 3-iodophenol,
  • Step A Preparation of 4'-t-butyldiphenylsilyloxymethyl-3- hydroxybiphenyl
  • step A 391mg (1 mmol) of 4- t-butyldiphenylsilyloxymethylboronic acid (prepared as exemplified in US 5,192,758) and 220 mg (1 mmol) of 3-iodophenol gave 354.3mg of the title compound.
  • Example 20 in lmL of THF at 0°C was added sequentially 19.5mL (0.34mmol) of acetic acid and 227mL (0.23mmol) of a 1.0 M solution of tetrabutylammonium fluoride in THF. The resulting mixture was stirred with the ice-water bath removed for six hours. The mixture was partitioned between ether, ice-water, and saturated NaHCO3 solution and the organic phase separated, washed with brine, dried over Na2SO4, filtered, and evaporated. Purification by plate layer chromatography using CH2Cl2-EtOAc(10:l) as eluant provided
  • carbapenem 20 prepared in Example 24 was deallylated to provide 12.5mg of carbapenem 21 after RP-PLC and lyophilization.
  • IR (nujol): 1754, 1712, 1593cm" 1 ;
  • Step A Preparation of 4-Hydroxy-9-carbomethoxy-fluorylidene
  • a stirred mixture of 401mg (2 mmol) of 4-hydroxy- fluoren-9-one and 1.37g (4.1mmol) of methyl- (triphenylphosphoranylidene)-acetate in lOmL of toluene was refluxed under an atmosphere of nitrogen for 65.5 hours.
  • the cooled reaction mixture was evaporated and the residue purified by plate layer chromatography using CH2Cl2-EtOAc (50:1) as eluant to give
  • Step A Preparation of 4-Hydroxy-9-carbomethoxymethyl-fluorene
  • the catalyst was removed by filtration through celite, washed well with EtOAc, and the filtrate evaporated and dried in vacuo to give 348.5mg of the title product.
  • Step B As previously described in Example 2, 53mg (0.208 mmol) of the fluorene derivative prepared above provided after purification by PLC eluting with CH2Cl2-EtOAc (50:1), 88mg of carbapenem 26 , as an equimixture of diastereomers, and containing a little phenolic starting material, which was used without further purification.
  • carbapenem 35 was produced after purification on macroprep and amberchrom 161 resins.
  • Step A Preparation of 4-Acetoxy-9-(2-t-butyldimethylsilyloxyethyl)- fluorene
  • Step C Preparation of 4-Acetoxy-9-E,Z-t-butyldimethylsilyloxyethenyl- fluorene A mixture of the crude product from the previous step,
  • Step D Preparation of 4-Hydroxy-9-E,Z-t- butyldimethylsilyloxyethenyl-fluorene
  • a stirred, warm solution of 1.19g (3.13 mmol) of acetate, prepared in the previous step, in 20mL EtOH was added dropwise 0.77mL (3.85 mmol) of a 5N solution of sodium hydroxide in water.
  • the resulting dark solution was stirred further for 5 minutes and then partitioned between EtOAc, ice, IN HCl, and brine.
  • the organic phase was separated, washed with brine, dried over Na2SO4, filtered, evaporated, and dried in vacuo. Purification by PLC eluted with CH2CI2 gave 890.
  • H NMR (CDCI3) 0.15 (s, 6H), 0.96 (s, 9H), 4.98 (m, 2H),
  • Step A Preparation of 2-Methoxy-6-carbomethoxy-4'-t-butyl- diphenylsilyloxymethylbiphenyl Using the procedure described in Step A of Example 18, 10. Og (34.2mmol) of methyl-2-iodo-3-methoxybenzoate (prepared as outlined by W. M. Stanley, E. McMahon, and R. Adams, J. Amer. Chem. Soc. 1933, 55, 706) was refluxed for 5 hours to give after chromatography on silica gel with CH2Cl2-hexanes (2:1) 12. Ig of the title compound.
  • Step C Preparation of 4-Methoxy-7-chloromethyl-fluoren-9-one
  • a stirred suspension of 2.0g (7.74mmol) of acid prepared in Step B in 40mL of sieve- dried CH2CI2 at 0°C was added all at once 3.55g (17.0mmol) of phosphorous pentachloride and the mixture was stirred further for 5 minutes, and then for 1 hour with the ice-water bath removed.
  • the homogenous solution was recooled to O C, and 1.55g (ll. ⁇ mmol) of AICI3 was added all at once.
  • the resulting mixture was stirred further for 0.5 hour and then partitioned between EtOAc, ice, and brine.
  • the organic phase was separated, washed with brine and saturated NaHCO3, dried over Na2SO4, filtered, evaporated, and dried in vacuo to give 2.04g of the title material as a yellow solid, which was used without further purification.
  • Step D Preparation of 4-Methoxy-7-acetoxymethyl-fluoren-9-one A mixture of 2.0g (7.7mmol) of material prepared in Step
  • Step E Preparation of 4-Methoxy-7-hydroxymethyl-fluoren-9-one
  • a stirred mixture of the acetate prepared above and 3.07mL (15.4mmol) of 5N NaOH in lOOmL of EtOH was refluxed under nitrogen for 10 minutes.
  • the cooled mixture was partitioned between EtOAc, ice-water and 2N HCl, and the organic phase was separated, washed with brine, dried over Na2SO4, filtered, evaporated, and dried in vacuo to give 2.07g of the title material as a yellow solid, which was used without further purification.
  • iH NMR (CDCI3) ⁇ : 3.96 (s, 3H), 4.68 (s, 2H), 7.01-7.77 (m,
  • Step H Preparation of 4-Hydroxy-7-hydroxymethyl-fluoren-9-one
  • a stirred mixture of 40 ⁇ .2mg (1.8mmol) of aldehyde prepared in Step G and 804.3mg (3.8mmol) of sodium triacetoxyborohydride in 27mL of anhydrous THF was refluxed under nitrogen for 1 hour.
  • the cooled mixture was partitioned between EtOAc, ice-water and saturated NaHCO3, and the organic phase was separated, washed with brine, dried over Na2SO4, filtered, evaporated, and dried in vacuo.
  • Example 38 Using the procedure of Example 38, the carbapenem 38 prepared in Example 42 in ImL acetonitrile after O. ⁇ hour was converted to 88.2mg of carbapenem 44, which contained a little of the dabco acetamide starting material and was used without further purification.
  • Example 47 Following the procedure outlined in Example 3, the carbapenem 43 prepared in Example 47 was deallylated to provide 11.4mg of 47 after purification by reverse phase chromatography (RP- PLC) using water-acetonitrile (7:3) as the eluant and lyophilization.
  • IR (nujol): 1751, 1716, 1593cm- 1 ;
  • iH NMR (D2O-CD3CN,5:2) ⁇ : 1.39 (d, J 7.4Hz, 3H), 1.45
  • Step A Preparation of 4-Acetoxy-7-formyl-fluoren-9-one To a stirred suspension of 1.53g (6.83mmol) of 4-hydroxy-
  • Step B Preparation of 4-Acetoxy-7-CE-2-carbomethoxyvinyl)-fluoren-9- one A mixture of 1.46g (5.49mmol) of aldehyde, prepared in
  • Step G Preparation of 4-Hydroxy-7-(3-t-butyldimethylsilyloxypropyl)- fluoren-9-one
  • Step I Desilylation Using the general procedure outlined in Example 21, the carbapenem prepared in the previous step provided 103.4mg of carbapenem ⁇ l.
  • iH NMR (CDCI3) ⁇ : 1.27 (d, J 7.3Hz, 3H), 1.43 (d,
  • Step A Triflate Formation Using the general procedure outlined in Step A of
  • Example 10 ⁇ 8.2mg (0.097mmol) of alcohol 51, prepared in Example 55, was converted into 70.4mg of the corresponding triflate.
  • Step B Displacement Reaction Using the general procedure outlined in Step B of
  • Example 10 the crude triflate from Step A was converted into 81.3mg of crude carbapenem 52, which was used without further purification.
  • Example 3 Following the procedure outlined in Example 3, the carbapenem ⁇ 4 prepared in Example ⁇ 8 was deallylated to provide 14mg of 55 after purification by reverse phase chromatography (RP- PLC) using water-acetonitrile (7:3) as eluant and lyophilization.
  • RP- PLC reverse phase chromatography
  • the carbapenem (268.9mg) prepared in the previous step provided 171.6mg (75%) of carbapenem 56.
  • Step A Triflate Formation Using the general procedure outlined in Step A of
  • Example 10 48.4mg (0.074mmol) of alcohol 56, prepared in Example 60, was converted into 65.6mg of the corresponding triflate.
  • Step B Displacement Reaction Using the general procedure outlined in Step B of
  • Example 10 the crude triflate from Step A was converted into 78mg of crude carbapenem 58, which was used without further purification.
  • EXAMPLE 62 PREPARATION OF CARBAPENEM ⁇ 8
  • Example 3 Following the procedure outlined in Example 3, the carbapenem 59 prepared in Example 64 was deallylated to provide 31.3mg of 60 after purification by reverse phase chromatography (RP- PLC) using water-acetonitrile (7:3) as the eluant and lyophilization.
  • RP- PLC reverse phase chromatography
  • Step A Preparation of Methyl-2,2'-dimethoxy-biphenyl-6-carboxylate Using the procedure outlined in Step A of Example 18,
  • Step B Preparation of 2,2'-dimethoxy-biphenyl-6-carboxylic acid

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Abstract

Cette invention se rapporte à des agents anti-bactériens de carbapenem représentés par la formule (I), ainsi qu'à des sels et hydrates de ces agents. Cette invention concerne également des compositions pharmaceutiques et des méthodes de traitement.
PCT/US1998/019015 1997-09-17 1998-09-14 Composes anti-bacteriens d'aryloxymethyle carbapenem WO1999014217A1 (fr)

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AU97742/98A AU9774298A (en) 1997-09-17 1998-09-14 Aryloxymethyl carbapenem antibacterials
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EP1086104A4 (fr) * 1998-06-02 2002-02-06 Merck & Co Inc Antibacteriens de carbapenem phenoxymethyle fusionnes
CN106279178A (zh) * 2016-07-18 2017-01-04 华东理工大学 耐碳青霉烯类抗生素病菌的荧光探针及合成方法与应用
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Cited By (4)

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Publication number Priority date Publication date Assignee Title
EP1086104A4 (fr) * 1998-06-02 2002-02-06 Merck & Co Inc Antibacteriens de carbapenem phenoxymethyle fusionnes
CN106279178A (zh) * 2016-07-18 2017-01-04 华东理工大学 耐碳青霉烯类抗生素病菌的荧光探针及合成方法与应用
CN106279178B (zh) * 2016-07-18 2019-01-18 华东理工大学 耐碳青霉烯类抗生素病菌的荧光探针及合成方法与应用
US11820751B2 (en) 2021-01-27 2023-11-21 Vandria Sa Urolithin derivatives and methods of use thereof

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EP1023293A4 (fr) 2002-11-20
AU9774298A (en) 1999-04-05
CA2304267A1 (fr) 1999-03-25
JP2002503638A (ja) 2002-02-05
EP1023293A1 (fr) 2000-08-02

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