EP1032384A1 - Composes antibacteriens, compositions et procedes de traitement aux carbapenemes - Google Patents

Composes antibacteriens, compositions et procedes de traitement aux carbapenemes

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Publication number
EP1032384A1
EP1032384A1 EP98953737A EP98953737A EP1032384A1 EP 1032384 A1 EP1032384 A1 EP 1032384A1 EP 98953737 A EP98953737 A EP 98953737A EP 98953737 A EP98953737 A EP 98953737A EP 1032384 A1 EP1032384 A1 EP 1032384A1
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EP
European Patent Office
Prior art keywords
groups
substituted
straight
group
branched
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP98953737A
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German (de)
English (en)
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EP1032384A4 (fr
Inventor
Frank P. Dininno
Milton L. Hammond
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Merck and Co Inc
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Merck and Co Inc
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Priority claimed from GBGB9807362.0A external-priority patent/GB9807362D0/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP1032384A1 publication Critical patent/EP1032384A1/fr
Publication of EP1032384A4 publication Critical patent/EP1032384A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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

Definitions

  • Vancomycin a glycopeptide antibiotic
  • Staphylococcus aureus is currently the agent of choice for combating these infections which are predominantly encountered in hospital settings.
  • Vancomycin With the increased usage of Vancomycin, the emergence of resistant stains of staphylococci is inevitable, and the first confirmed report of vancomycin resistance in Staphylococcus epidermidis was disclosed at the 36th Interscience Conference on Antimicrobial Agents and
  • the present invention relates to novel tricyclic carbapenem compounds (trinems) in which the lipophilic side-chain necessary for anti-MRSA activity replaces the common simple ether based substitutents found in EPO 416,953, substituted carbon atoms found in EPO 507,313, and substituted amines found in W09523149.
  • the antibacterial compounds of the present invention thus comprise an important contribution to therapy for treating infections caused by these difficult to control pathogens.
  • MRSA/MRCNS agents effective against such pathogens
  • the present invention relates to anti-MRSA tricyclic carbapenem antibiotics containing aromatic based side-chains.
  • the side- chain imparts MRS activity previously unassociated with the trinem skeleton.
  • CO 2 M represents a carboxylic acid, a carboxylate anion counter balanced by a counterion, a pharmaceutically acceptable ester group or a carboxylic acid protected by a protecting group;
  • Rrr represents hydrogen, straight- or branched-chain alkyl, unsubstituted or substituted with one to four R' groups;
  • P represents hydrogen, hydroxyl, F or hydroxyl protected by a hydroxy 1-protecting group
  • each R is independently selected from: -R*; -Q; hydrogen; halo; -CN; -N0 2 ; -NRaRb; -OR c ; -SR C ; -C(0)NR a R b ; - C(0)OR"; -S(0)R c ; -S0 2 R c ; -S0 2 NR a Rb; -NR*S0 2 R b ; -C(0)R « ; - OC(0)R*; -OC(0)NRaRb; -NRaC(0)NRbRc; -NR ⁇ C0 2 R h ; -OC0 2 R h ; - NR a C(0)R b ; -Ci-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R d groups; and -C3-7 cycloalkyl, unsubstituted or substituted with one to four R d groups; with the
  • each R a , R b and R c independently represents hydrogen, -R*, -Ci-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R d groups, or -C3-7 cycloalkyl, unsubstituted or substituted with one to four R d groups; or R a and R b taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one or more of O, S, NR C , with R c as defined above, or -C(O)-, said ring being unsubstituted or substituted with one to four R J groups; or Rb 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 Ri groups;
  • each R d independently represents halo; -CN; -N0 2 ;
  • each R j independently represents halo; -CN; -NO2; phenyl; -NHS0 2 R h ; -OR h , -SRh; -N(Rh) 2 ; -N+(Rh) 3 ; -C(0)N(Rh) 2 ; - S ⁇ 2N(Rh) 2 ; heteroaryl; heteroarylium; -C ⁇ 2R h ; -C(0)R h ; -OCORh; - NHCOR h ; guanidinyl; carbamimidoyl or ureido;
  • each R n independently represents hydrogen, a -Ci-6 straight or branched-chain alkyl group, a -C3-C6 cycloalkyl group or phenyl, or when two R h groups are present, said R h groups may be taken in combination and represent a 4-6 membered saturated ring, optionally interrupted by one or two of 0, 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 1 , N or N+R s , provided that no more than one of ⁇ , ⁇ , ⁇ , ⁇ and ⁇ is N+R s ; R* is selected from the group consisting of:
  • d represents O, S or NR k ;
  • e, g, x, y and z represent CR m , N or N + R k , provided that no more than one of e, g, x, y and z in any given structure represents N + Rk;
  • each R m independently represents a member selected from the group consisting of: hydrogen; halo; -CN; -N0 ; -NR n R°; -OR n ; - SR n ; -CONR n R o ; -COOR"; -SOR n ; -S0 2 R"; -S0 2 NR"R°; -NR"S0 2 R°; - COR n ; -NR n COR o ; -OCOR n ; -OCONR n R°; -NR"C0 2 R h ; -NR n CONR°R h ; -OC0 2 R h ; -CNR n NR o R b ; -NR n CNHNR°R h ; -NR"C(NR°)R h ; -C ⁇ _6 straight- or branched-chain alkyl, unsubstituted or substituted with one
  • R n and R° represent hydrogen, phenyl; -Ci-6 straight- or branched-chain alkyl unsubstituted or substituted with one to four R' groups;
  • each R s independently represents hydrogen; phenyl or -Ci-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R> groups;
  • each R l independently represents hydrogen; halo; phenyl; -CN; -N0 2 ; -NR « R V ; -OR"; -SR U ; -CONR"R v ; -COOR h ; -SOR"; -S0 2 R u ; -S0 2 NR"R v ; -NR"S0 2 R v ; -COR u ; -NR"COR v ; -OCOR u ; -OCONR"R v ; -NR"C0 2 R v ; -NR u CONR v R w ; -OC0 2 R v ; -Ci-6 straight- or branched- chain alkyl, unsubstituted or substituted with one to four R' groups;
  • R u and R v represent hydrogen or -Ci-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R' groups; or R u and R v together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one or more of O, S, NR or -C(O)-, said ring being unsubstituted or substituted with one to four R> groups;
  • each R independently represents hydrogen; -Cl-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R' groups; C3-6 cycloalkyl optionally substituted with one to four R 1 groups; phenyl optionally substituted with one to four R 1 groups, or heteroaryl optionally substituted with 1-4 Ri 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, S02, NH or NCH3;
  • R x represents hydrogen or a Cl-8 straight- or branched- chain alkyl, optionally interrupted or terminated by one or two of O, S, SO, S02, NR W , N+RhR , or -C(O)-, said chain being unsubstituted or substituted with one to four of halo, CN, N02, OR w , SR W , SOR W , S02R W , NRhRW, N+(Rh) 2 R , -C(0)-RX C(0)NRhRW, S ⁇ 2NRhRW, C02R W , OC(0)Rw, OC(0)NRhRW, NRhC(0)Rw, NRhC(0)NRhR , phenyl or heteraryl, said phenyl and heteroaryl being optionally substituted with from one to four Ri groups or with one to two Cl-3 straight- or branched- chain alkyl groups, said alkyl groups being unsubstituted or substituted
  • Ry and R z represent hydrogen; phenyl; -Ci-6 straight or branched chain alkyl, unsubstituted or substituted with one to four Ri groups, and optionally interrupted by O, S, NR W , N+R h R w or -C(O)-; or R x and R y together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by 0, S, SO2,
  • compositions and methods of treatment are also included herein.
  • Carboxylate anion refers to a negatively charged group - COO-.
  • alkyl refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 10 carbon atoms unless otherwise defined. It may be straight, branched or cyclic. Preferred alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, cyclopentyl and cyclohexyl. When substituted, alkyl groups may be substituted with up to four substituent groups, selected from Rd and Ri, as defined, at any available point of attachment. When the alkyl group is said to be substituted with an alkyl group, this is used interchangeably with "branched alkyl group”.
  • Cycloalkyl is a specie of alkyl containing from 3 to 15 carbon atoms, without alternating or resonating double bonds between carbon atoms. It may contain from 1 to 4 rings which are fused.
  • 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
  • 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.
  • the terms “quaternary nitrogen” and “positive charge” refer to tetravalent, positively charged nitrogen atoms including, e.g., the positively charged nitrogen in a tetraalkylammonium group (e. g. tetramethylammonium), 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 -C4 alkyl-O-, with the alkyl group optionally substituted as described herein.
  • substituted When a group is termed "substituted”, unless otherwise indicated, this means that the group contains from 1 to 4 substituents thereon.
  • R the substituents available on alkyl groups are selected from the values of R d .
  • Many of the variable groups are optionally substituted with up to four Ri groups.
  • R e , R f and Rg when these variables represent substituted alkyl, the substituents available thereon are selected from the values of R'.
  • 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.
  • M is a readily removable carboxyl protecting group
  • P represents a hydroxyl which is protected by a hydroxy 1- 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 (TBS), phenacyl, p-methoxybenzyl, o-nitrobenzyl, p-methoxy phenyl, p-nitrobenzyl, 4-pyridylmethyl and t-butyl.
  • Suitable hydroxyl protecting groups include triethylsilyl (TES), t-butyldimethylsilyl(TBS), t-butyldiphenylsilyl (DPTB S ) , o-nitrobenzy loxy carbony 1 , p-nitrobenzyloxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, t-butyloxy carbonyl, 2,2,2-trichloroethy loxy carbonyl and the like.
  • TES triethylsilyl
  • TBS t-butyldimethylsilyl
  • DPTB S t-butyldiphenylsilyl
  • 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.
  • compositions 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.
  • salts include the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate,
  • 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 pi valoy loxy methyl, acetoxy methyl, phthalidyl, indanyl and methoxymethyl, and others described in detail in U.S. Pat. No. 4,479,947. These are also referred to as "biolabile esters".
  • Biolabile esters are biologically hydrolizable, and may be suitable for oral administration, due to good absorption through the stomach or intenstinal mucosa, resistance to gastric acid degrada- tion and other factors.
  • biolabile esters include compounds in which M represents an alkoxyalkyl, alky lcarbonyloxy alkyl, alkoxy carbony loxy alkyl, cycloalkoxy alkyl, alkeny loxy alkyl, aryloxyalkyl, alkoxyaryl, alkylthioalkyl, cycloalkylthioalkyl, alkenylthioalkyl, arylthioalkyl or alkylthioaryl group.
  • M species are examples of biolabile ester forming moieties.: acetoxy methyl, 1 -acetoxy ethyl, 1-acetoxypropyl, pivaloyloxymethyl, 1-isopropyloxycarbonyloxyethyl, 1-cyclohexy loxy carbony loxy ethyl, 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 to the
  • L- represents a specie with more than one negative charge, such as malonate, tartrate or ethylenediamine- tetraacetate (EDTA)
  • EDTA ethylenediamine- tetraacetate
  • a subset of compounds of formula la which is of interest relates to those compounds where CO2M represents a carboxylate anion.
  • M in this instance represents a negative charge which will be balanced by a positively charged group, such as in the positively charged R group.
  • a negatively charged counterion may be present which in combination with the carboxylate anion, provides overall charge neutrality.
  • Another subset of compounds of formula la which is of interest relates to compounds wherein one R represents a group which contains a positively charged moiety, and the remaining R groups are selected from hydrogen and Ci-6 straight or branched chain alkyl, unsubstituted or substituted with one to four R d groups.
  • this subset of interest includes compounds of formula la wherein one R represents a group containing a positively charged moiety and the remaining R groups are hydrogen.
  • the positively charged moiety or moieties that are contained in one or more R groups it is preferred that from 1-3 positive charges be present, and most preferably two positive charges be present, balanced by the carboxylate anion and a negatively charged counterion.
  • R group represents a -Ci-6 straight or branched chain alkyl group, substituted with one to four R d groups, wherein one R d group represents -R* or Q.
  • R d group represents -R* or Q.
  • L ⁇ > a and b are as originally defined, and R x is as originally defined, and represents a member selected from the group consisting of: hydrogen or a Cl-8 straight- or branched- chain alkyl, optionally interrupted or terminated by one or two of O, S, SO, S02, NR , N+R h R w , or - C(O)-, said chain being unsubstituted or substituted with one to four of halo, CN, N02, ORW, SRW, SORw, S ⁇ 2R w , NR ⁇ R W , N+(Rh)2R w , -C(0)-Rw, C(0)NRhRw, S ⁇ 2NRhRw, C ⁇ 2R w , OC(0)Rw, OC(0)NRhRW 5 NRhC(0)Rw, NRhC(0)NRhRw, or a phenyl or heteroaryl group which is in turn optionally substituted with from one
  • d represents NR k ;
  • R k represents -Ci-6 straight or branched chain alkyl; and
  • e, g, x and y represent CR m or N + R k , with R k as defined above and R m representing hydrogen.
  • Z represents a*;
  • CO2M represents a carboxylate anion;
  • one R group which is attached to the naphthosultam platform contains at least one positively charged moiety, and the remaining R groups are selected from hydrogen and Ci-6 straight or branched chain alkyl, unsubstituted or substituted with one to four R d groups;
  • Rd is as originally defined
  • R h represents hydrogen or a Ci-6 straight or branched chain alkyl group
  • Q is selected from the group consisting of:
  • R x represents a member selected from the group consisting of: hydrogen or a C 1-8 straight- or branched- chain alkyl, optionally interrupted or terminated by one or two of O, S, SO, S02, NR W , N+R n R w , or -C(O)-, said chain being unsubstituted or substituted with one to four of halo, CN, N02, OR W , SR W , SOR W , S ⁇ 2R w , NR h RW, N+(Rh) 2 R , -C(0)-Rw, C(0)NRhRW, S ⁇ 2NR h R , C02R W , OC(0)RW, OC(0)NRhRW ; NRhC(0)RW, NRhC(0)NRhRW, phenyl or heteroaryl, said phenyl or heteroaryl group being optionally substituted with from one to four R 1
  • d represents NR k ;
  • R k represents straight or branched chain alkyl; and
  • e, g, x and y represent CR m or N + R k , with R k as defined above and R m representing hydrogen.
  • CO2M represents a carboxylate anion
  • one R group is attached to the naphthosultam platform which contains a positively charged moiety, and the other R group is selected from hydrogen and Ci-6 straight or branched chain alkyl, unsubstituted or substituted with one to four R d groups
  • R d is as originally defined
  • Q is selected from the group consisting of:
  • R represents a member selected from the group consisting of: hydrogen or a Cl-8 straight- or branched- chain alkyl, optionally interrupted by one or two of O, S, SO, S02, NR W , N+R h R w , or - C(O)-, said chain being unsubstituted or substituted with one to four of halo, CN, N02, OR , SRW, SORW, S ⁇ 2R w , NR h R W , N+(Rh)2R , -C(0)-Rw, C(0)NRhR , S ⁇ 2NRhR , C ⁇ 2R w ,
  • R h represents hydrogen or a Ci-6 straight or branched chain alkyl group;
  • R w is as originally defined; R* is selected from:
  • d represents NR k ;
  • R k represents -Ci-6 straight or branched chain alkyl; and
  • e, g, x and y represent CR m or N + R k , with R k as defined above and R m representing hydrogen.
  • CO2M represents a carboxylate anion
  • one R group is attached to the naphthosultam platform which contains a positively charged moiety, and the other R group is selected from hydrogen, halo and Ci-6 straight or branched chain alkyl, unsubstituted or substituted with one to four R d groups
  • R d is as originally defined
  • Q is selected from the group consisting of:
  • R x represents a member selected from the group consisting of: hydrogen or a C 1-8 straight- or branched- chain alkyl, optionally interrupted by one or two of O, S, SO, S02, NR , N+R h R w , or - C(O)-, said chain being unsubstituted or substituted with one to four of halo, CN, N02, OR , SR , SOR , S ⁇ 2R w , NRhR w , N+(Rh)2R w , -C(0)-R , C(0)NR h R , S ⁇ 2NR h R w , C ⁇ 2R w , OC(0)R , OC(0)NRhRw, NRhC(0)R w , NR h C(0)NRhR , phenyl or heteroaryl, said phenyl and heteroaryl group being optionally substituted with from one to four
  • R w is as originally defined; R* is selected from:
  • CO2M represents a carboxylate anion
  • one R group is attached to the naphthosultam platform which contains a positively charged moiety, and the other R group is selected from hydrogen, halo and Ci-6 straight or branched chain alkyl, unsubstituted or substituted with one to four R d groups
  • R d is as originally defined
  • Q is selected from the group consisting of:
  • R x represents a member selected from the group consisting of: hydrogen or a Cl-8 straight- or branched- chain alkyl, optionally interrupted by one or two of O, S, SO, S02, NR , N+R h R w , or - C(O)-, said chain being unsubstituted or substituted with one to four of halo, CN, N02, OR w , SR W , SOR W , S ⁇ 2R w , NRhR W , N+(Rh)2R w , -C(0)-Rw, C(0)NRhRw, S ⁇ 2NRhR W , C ⁇ 2R w , OC(0)R , OC(0)NRhR , NRhC(0)R , NRhC(0)NRhRw, phenyl or heteroaryl, said phenyl and heteroaryl group being optionally substituted with from one to four R 1
  • R w is as originally defined; R* is selected from:
  • d represents NR k ;
  • R k represents -Ci-6 straight or branched chain alkyl; and
  • e, g, x and y represent CR m or N+R k , with R k as defined above and R m representing hydrogen.
  • the present invention relates to a compound represented by formula la wherein the R group at position 4 represents a positively charged moiety, and the R groups at position 3 and 5 represent hydrogen.
  • R contains a positively charged moiety selected from the group consisting of: -R*, Q, and a Ci-6 straight or branched alkyl chain substituted with one R d group; R d is independently selected -R* or Q;
  • Q is selected from the group consisting of:
  • R x represents a member selected from the group consisting of: hydrogen or a Cl-8 straight- or branched- chain alkyl, optionally interrupted by one or two of O, S, SO, S02, NRw, N+R h R , or -C(O)-, said chain being unsubstituted or substituted with one to four of halo, CN, N02, OR W , SR , SOR , S ⁇ 2R w , NR«R W , N+(Rh)2R w , -C(0)-R , C(0)NRhR , S ⁇ 2NRhR w , C ⁇ 2R w , OC(0)R , OC(0)NRhR , NRhC(0)R , NRhC(0)NRhR w , phenyl or heteroaryl, said phenyl and heteroaryl group being optionally substituted with from one to four Ri groups or with
  • d represents NR k ;
  • R k represents -C ⁇ 6 straight or branched chain alkyl; and
  • e, g, x and y represent CR or N+R k , with R k as defined above and R m representing hydrogen.
  • R contains a positively charged moiety selected from the group consisting of: -R*, Q, and a Cj-6 straight or branched alkyl chain substituted with one R d group;
  • R d is independently selected -R* or Q;
  • Q is selected from the group consisting of:
  • R x represents a member selected from the group consisting of: hydrogen or a Cl-8 straight- or branched- chain alkyl, optionally interrupted by one or two of O, S, SO, S02, NR , N+RhR W , or - C(O)-, said chain being unsubstituted or substituted with one to four of halo, CN, N02, OR w , SR W , SORW, S ⁇ 2R w , NRhRw, N+(Rh)2R w , -C(0)-Rw, C(0)NRhR , S ⁇ 2NRhR , C ⁇ 2R w , OC(0)R , OC(0)NRhRW, NRhC(0)Rw, NRhC(0)NRhRW, phenyl or heteroaryl, said phenyl and heteroaryl group being optionally substituted with from one to four R 1 groups or with one to
  • d represents NR k ;
  • R k represents -Ci-6 straight or branched chain alkyl; and
  • e, g, x and y represent CR m or N+R k , with R k as defined above and R m representing hydrogen.
  • R x , a, b and L ⁇ are as originally defined.
  • R represents
  • R x , a, b and L- are as originally defined.
  • CO2M represents a carboxylate anion
  • Rd is as originally defined
  • Rh represents hydrogen or a Ci-6 straight or branched chain alkyl group
  • Q is selected from the group consisting of:
  • R x represents a member selected from the group consisting of: hydrogen or a Cl-8 straight- or branched- chain alkyl, optionally interrupted by one or two of O, S, SO, S02, NR W , N+R h R w , or -C(O)-, said chain being unsubstituted or substituted with one to four of halo, CN, N02, OR , SR W , SOR W , S ⁇ 2R w , NR ⁇ R , N+(Rh)2R w , -C(0)-Rw, C(0)NRhRW, S ⁇ 2NRhRw, C ⁇ 2R w , OC(0)R , OC(0)NRhRW ; NRhC(0)R , NRhC(0)NRhRw, phenyl or heteroaryl, said phenyl and heteroaryl group being optionally substituted with from one to four R 1 groups or with
  • d represents NR k ;
  • R k represents -Ci-6 straight or branched chain alkyl; and
  • e, g, x and y represent CR m or N + R k , with R k as defined above and R m representing hydrogen.
  • Ii CO2M represents a carboxylate anion; Rd is as originally defined;
  • R ⁇ represents hydrogen or a Ci-6 straight or branched chain alkyl group
  • Q is selected from the group consisting of:
  • R x represents a member selected from the group consisting of: hydrogen or a Cl-8 straight- or branched- chain alkyl, optionally interrupted by one or two of O, S, SO, S02, NR W , N+R h R , or -C(O)-, said chain being unsubstituted or substituted with one to four of halo, CN, N02, ORX SR , SOR , S ⁇ 2R w , NR h R w , N+(Rh)2R w , -C(0)-R w , C(0)NR h R w , S ⁇ 2NR h R , C ⁇ 2R w , OC(0)RW, OC(0)NRhR , NRhC(0)R , NRhC(0)NRhR , phenyl or heteroaryl, said phenyl and heteroaryl group being optionally substituted with from one to four Ri groups
  • d represents NR k ;
  • R k represents -Ci-6 straight or branched chain alkyl; and
  • e, g, x and y represent CR m or N + R k , with R k as defined above and R m representing hydrogen.
  • CO2M represents a carboxylate anion
  • Rd is as originally defined
  • Rh represents hydrogen or a Ci-6 straight or branched chain alkyl group
  • Q is selected from the group consisting of:
  • R x represents a member selected from the group consisting of: hydrogen or a Cl-8 straight- or branched- chain alkyl, optionally interrupted by one or two of O, S, SO, S02, NR W , N+RhR w , or -C(O)-, said chain being unsubstituted or substituted with one to four of halo, CN, N02, OR w , SR W , SOR , S ⁇ 2R w , NR h R , N+(Rh)2R , -C(0)-R , C(0)NRhR , S ⁇ 2NRhR , C ⁇ 2R w , OC(0)R , OC(0)NRhRW, NRhC(0)RW, NRhC(0)NRhR , phenyl or heteroaryl, said phenyl and heteroaryl group being optionally substituted with from one to four Ri groups or with one to
  • d represents NR ;
  • R k represents -Ci-6 straight or branched chain alkyl; and
  • e, g, x and y represent CR m or N + R , with R k as defined above and R m representing hydrogen.
  • IP represents a positively charged counterion, e.g. Na + , K + , or an appropriate molar amount of a divalent cation, e.g., Ca +2 .
  • the tricyclic synthon is prepared in a similar fashion to the description found in EPO 507,313, in which the acetoxyazetidinone, wherein P is F or a suitably protected hydroxyl radical, such a ally loxy carbonyl, t-butyldimethylsilyl (TBS), t- butyldiphenylsilyl (DPTBS) or the like, is reacted with a suitably protected 2-hydroxy-cyclohexanone derivative such a trimethysilyl (TMS) or t-butyldimethylsilyl, or the like, using the conditions of Barrett, et ⁇ l. ( A. G. M. Barrett, et ⁇ l, J.
  • the configuration of the hydroxyl group is inverted prior to incorporation of the MRS active sidechain, using the Mitsunobu reaction partners with anhydrous formic acid, or the like, to produce the formate ester, or the like, of the opposite configuration as the starting alcohol.
  • Hydrolysis of the formate ester or the like provides the alcohol of the opposite configuration ready for incorporation of the MRS pharmacophore to ultimately provide the trinems of the invention in their protected form.
  • nucleophilic (NUC:) side chains naphthosultams, phenols, and mercaptobenzothiazoles
  • reagents that comprise the Mitsunobu reaction such as an azodicarboxylate like diethylazodicarboxylate (DEAD), diisopropyldiazodicarboxy late(DI AD) , and tetramethyldiazodicarboxamide (TMAD), or the like
  • a tri- substituted phosphine such as triphenylphosphine, tri-n-butylphosphine, and the like, in a suitable solvent such as tetrahydrofuran (THF), ether, acetonitrile, dimethylformamide (DM)
  • the covering groups of the resulting new trinems are then removed in accordance with the previous definitions of P.
  • P is a silyl based protecting group for the hydroxyl radical
  • the deprotections are performed sequentially: first, desilylation with TBAF HOAc or aqueous triflic acid in THF, or the like; and second, deallylation using the palladium (0) catalyzed method of Jeffrey and McCombie (JOC, 1982, 47, 587.)
  • the hydroxyl protecting is allylcarbonyl
  • the deprotections are performed simultaneously by the latter method.
  • the resulting alcohol is oxidized to the ketone via a Swern oxidation or the like, and after the removal of the azetidinone protecting group, if it was necessary, the resulting azetidinone is then processed in a fashion analogous to that outlined in Scheme 1 , ie, oxalamide and ylid formation followed by cyclization provides the fully elaborated trinems ready for the deprotection sequences.
  • the aforementioned nucleophilic partners in the Mitsunobu reaction possess functionalized substituents which allow for the introduction of the previously defined heterocycles, Q, and thereby necessitate additional chemical steps in the general synthesis plan. These steps are outlined in Scheme 3. Once the fully elaborated trinem has been synthesized, the substitutent tether from the particular side-chain class typically possesses a silyl covered hydroxyl radical which in the first step is then uncovered in the usual way as expressed above.
  • the hydroxyl group is converted to a suitable leaving group such as a triflate, mesylate, tosylate, iodide, chloride, bromide, and the like, and then displacing the resulting leaving group with a compound Q, such as N-methyl-imidazole, N-(2-hydroxyethyl)-imidazole, N- methyl-diazabicy clooctane, 1 -(carbamoylmethyl)-4-aza- l-azoniabicyclo-[2.2.2.]-octane, l-(3-hydroxyprop-l-yl)-4-aza-l- azoniabicyclo-[2.2.2.]-octane, pyridine, morpholine and the like which contain a nitrogen atom that can act as a nucleophile.
  • the charged substituent may be incorporated in the side chain before addition to the trinem or may be introduced after the final deprotections.
  • the charged substituent
  • 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, diisopropylethyl- amine, and the like at a temperature between about -100°C and 0°C for about 5 to 120 minutes, 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.
  • a suitable solvent such
  • 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
  • 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 with 1-3 molar equivalents of compound Q at a temperature between about -78°C and 50°C for about 15 to 120 minutes, in a solvent such as acetonitrile, dichloromethane, DMF, or DMSO, or the like.
  • a solvent such as acetonitrile, dichloromethane, DMF, or DMSO, or the like.
  • 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 (i.e. R sc groups) that contain a nitrogen atom which may be quaternized by reaction with a suitable alkylating reagent AR, such as methyl iodide, methyl bromide, benzyl trichloroacetimidate, methyl trifluoromethanesulfonate, triethyloxonium tetrafluoroborate, and the like. Quaternization of the nitrogen atom in the side chain is effected by treating a solution of the compound with a slight excess (1.05 to 1.2 molar equivalents) of the alkylating reagent.
  • the synthesis of the target compound is completed by removing any protecting groups which are present in the penultimate intermediate using standard techniques which are well known to those skilled in the art.
  • the deprotected final product is then purified, as necessary, using standard techniques such as ion exchange chromatography, HPLC on reverse phase silica gel, MPLC on reverse phase polystyrene gel, and the like or by recrystallization.
  • 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 ampules, or in multidose containers.
  • the injectable compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain various formulating agents.
  • the active ingredient may be in powder (lyophillized or non- lyophillized) form for reconstitution at the time of delivery with a suitable vehicle, such as sterile water.
  • 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 composions 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.
  • 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.
  • I antibacterial compounds include oral and parenteral, 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 recommended. For children, a dose of about 5-25 mg/kg of body weight given 2, 3, or 4 times per day is preferred; a dose of 10 mg/kg is typically recommended.
  • the compounds of Formula I are of the broad class known as carbapenems. Many carbapenems are susceptible to attack by a renal enzyme known as dehydropeptidase (DHP). This attack or degradation may reduce the efficacy of the carbapenem antibacterial agent. Many of the compounds of the present invention, on the other hand, are less subject to such attack, and therefore may not require the use of a DHP inhibitor. However, such use is optional and contemplated to be part of the present invention. Inhibitors of DHP and their use with carbapenems are disclosed in, e.g., [European
  • 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 2 5-(hydroxymethyl -1.8-naphthosultam A solution of 5-bromo-l,8-naphthosultam (0.5 g, 1.76 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was cooled in a dry ice / acetone bath in a three neck flask. N-butyllithium (2.75 mL of a 1.6 M solution in hexanes, 4.4 mmol) was added over 2 minutes and the suspension was stirred an additional 7 minutes.
  • Paraformaldehyde (0.317 g, 10.6 mmol), placed in the bulb of a drying tube which was attached to the flask, was heated with a heat gun while a slow stream of nitrogen was blown over the solid.
  • the generated formaldehyde was carried into the flask and the carrier gas vented through a line connected to a Firestone valve over a period of 13 minutes. After an additional 5 minutes, the mixture was removed from the bath and stirred for 10 minutes.
  • Aqueous hydrochloric acid (3 mL of a 2 N solution) was added and the clear suspension was stirred an additional 10 minutes.
  • the mixture was partitioned between ethyl acetate (50 mL) and water (50 mL).
  • Step 1 5-f2-(hydroxy)-ethyiy 8 ⁇ naphthosultam
  • N-butyllithium 3.3 mL of a 1.6 M solution in hexanes, 5.28 mmol
  • An excess of ethylene oxide was slowly bubbled into the mixture over 5 minutes.
  • Boron trifluoride etherate (0.26 mL, 2.11 mmol) was then added over 5 minutes.
  • Step 2 5-(2-(trimethylsilyloxy)-ethyl -1.8-naphthosultam A solution of 5-(2-(hydroxy)-ethyl)-l,8-naphthosultam
  • Step 1 potassium l-(methoxycarbonylmethyl)-4-naphthalene sulfonate
  • Step 2 l-(methoxycarbonylmethyl)-5-nitro-4-naphthalene sulfonic acid Potassium l-(methoxycarbonylmethyl)-4-naphthalene sulfonate (10 g, 31.4 mmol) was added portionwise over 30 minutes to 90% nitric acid, which was cooled in a methanol / ice bath to approximately -15°C. After 2 hours, the bath temperature had reached -10°C and diethyl ether (200 mL) was added to the mixture.
  • Step 3 sodium l-(methoxycarbonylmethyl)-5-amino-4-naphthalene sulfonate
  • Step 5 4-f 2-(hydroxy)-ethyl - 1.8-naphthosultam
  • tetrahydrofuran 2 mL
  • Lithium aluminum hydride (1.44 mL of a 1.0 M solution in THF, 1.44 mmol) was added over 1 minute to give a light yellow suspension.
  • water was carefully added and the mixture was partitioned between ethyl acetate (30 mL) and IN hydrochloric acid (10 mL).
  • the aqueous layer was extracted with ethyl acetate (50 mL) and the combined ethyl acetate layers were washed with saturated aqueous sodium chloride (10 mL), dried over magnesium sulfate, filtered and evaporated.
  • the residual solid (0.16g) was purified by preparative thin layer chromatography (2 x 1000 micron silica gel plates, developed/ eluted with 5% MeOH/CH 2 Cl 2 ) to give the title compound as a solid (0.127 g).
  • N,0-Bistrimethylsilylacetamide (0.31 mL, 1.25 mmol) was added to a solution of 4-(2-(hydroxy)-ethyl)-l ,8-naphthosultam (0.125 g, 0.50 mmol) in tetrahydrofuran (1 mL). After one hour the mixture was evaporated and the residue was dissolved in methylene chloride (2 mL) and filtered through silica gel (2.5 g). The silica gel was eluted with methylene chloride (50 mL), the solvent was evaporated and the residue was lyophilized from benzene (3 mL) to give the title compound as an oil (0.16 g, quant.).
  • Step 1 potassium l-bromo-4-naphthalenesulfonate
  • Step 3 sodium l-bromo-5-amino-4-naphthalenesulfonate l-Bromo-5-nitro-4-naphthalenesulfonate (1 g, 3.01 mmol) and tin chloride dihydrate (1.83 g, 8.1 mmol) were suspended in a mixture of water (10 mL) and ethanol (10 mL). The resulting mixture was heated for 3 hours in a 100 °C oil bath. The mixture was cooled to room temperature and filtered. The collected solid was suspended in water (20 mL) and the mixture was made basic with sodium carbonate then placed on a CG-161 amberchrom resin column (3 x 9 cm).
  • PREPARATIVE EXAMPLE 7 PREPARATION OF l-HYDROXY-5- T-BUTYLDIMETHYLSILYLOXYMETHYL DIBENZOTHIOPHENE
  • Step A The coupled product from Step A was reduced to its corresponding amine using the procedures described in Example 6 (Step B).
  • the amine was obtained as a green/yellow oil.
  • Step E Utilizing the procedure described in Example 6 (Step E), the product from Step D was demethylated to give the phenol as a white solid.
  • 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 F The aldehydes from Step C and Step D were combined and acetylated using the procedures described in Example 7 (Step F). The reaction was stirred at 0°C for a total of 30 min. The desired product was isolated as tan solid.
  • PREPARATIVE EXAMPLE 9 PREPARATION OF l-HYDROXY-5- T-BUTYLDIMETHYLSILYLOXYMETHYL DIBENZOFURAN
  • Step C The amine from Step C was converted to its KPF diazonium salt using the procedures described in Example 6 (Step C). The product was isolated as a yellow solid.
  • Step E The dibenzofuran from Step E was demethylated and acetylated using the procedures described in Example 6 (Step E) and Example 7 (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 CH2C12/hexane, from the alkyl bromide of Step G using the procedures described in Example 7 (Step H).
  • PREPARATIVE EXAMPLE 11 PREPARATION OF 4'-T- BUTYLDIPHENYLSILYLOXYMETHYL-3-HYDROXYBIPHENYL
  • PREPARATIVE EXAMPLE 16 PREPARATION OF 4-HYDROXY-9- E.Z-T-BUTYLDIMETHYLSILYLOXYETHENYL-FLUORENE
  • StepA Preparation of 4-Acetoxy-9-(2-t-butyldimethylsilyloxyethyl)- fluorene
  • StepB Preparation of 4- Acetoxy-9-bromo-9-(2-t- butyldimethylsilyloxyethyl)-fluorene
  • Step C Preparation of 4-Acetoxy-9-E,Z-t-butyldimethylsilyloxyethenyl- fluorene
  • Step A Preparation of 2-Methoxy-6-carbomethoxy-4'-t-butyl- diphenylsilyloxymethylbiphenyl
  • 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 0°C, and 1.55g (l l . ⁇ 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 NaHC03, dried over Na2S ⁇ 4, 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 H Preparation of 4-Hydroxy-7-hydroxymethyl-fluoren-9-one
  • a stirred mixture of 405.2mg (l . ⁇ mmol) of aldehyde prepared in Step G and 804.3mg (3.8mmol) of sodium triacetoxy borohydride in 27mL of anhydrous THF was refluxed under nitrogen for 1 hour.
  • the cooled mixture was partitioned between EtOAc, ice-water and saturated NaHC03, and the organic phase was separated, washed with brine, dried over Na2S04, filtered, evaporated, and dried in vacuo.
  • Purification by PLC with CH2Cl2-EtOAc (2: 1) yielded 303.7mg of the crystalline, title product.
  • PREPARATIVE EXAMPLE 18 PREPARATION OF 4-HYDROXY-7- (3-T-BUTYLDIMETHYLSILYLOXYPROPYLVFLUOREN-9-ONE
  • Step B Preparation of 4-Acetoxy-7-(£-2-carbomethoxyvinyl)-fluoren- 9-one
  • PREPARATIVE EXAMPLE 19 PREPARATION OF 4-HYDROXY-7- (3-T-BUTYLDIMETHYLSILYLOXYPROPYD-9- CARBOMETHOXY-FLUORYLIDENE
  • Step B Preparation of 2,2'-dimethoxy-biphenyl-6-carboxylic acid
  • reaction mixture was extracted with ethyl acetate and partitioned with H2 ⁇ -dilute aq. sodium bicarbonate and sat. brine.
  • the ethyl acetate extract was dried with anhydrous sodium sulfate and concentrated in vacuo to provide a viscous oil.
  • the crude product was purified via flash chrom. (230-400 mesh silica gel) and was eluted with a 4: 1 mixture of hexanes: ethyl acetate to afford 908 mg of the silyl ether.
  • the reaction was extracted with ethyl acetate and partitioned with H20-ice and sat. brine.
  • the ethyl acetate extract was dried with anhydrous sodium sulfate and concentrated in vacuo to dryness.
  • the crude product was purified using silica gel plate layer chromatography eluted with a 7:3 ethyl acetate: hexanes mixture to afford 120 mg of the benzyl alcohol.
  • the solid is washed similarly with ether and dried.
  • the product is purified by ion exchange chromatography on MACROPREP resin with 5% NaCl solution, followed by desalting on AMBERCHROM CG 161 resin.
  • the eluant containing the product is concentrated in vacuo and freeze-dried to give the final product.

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Abstract

L'invention concerne des agents antibactériens au carbapénème tricyclique dans lesquels le noyau de carbapénème est condensé avec un noyau carbocyclique à 6 chaînons. De plus, ce composé est substitué par divers groupes dont au moins un groupe cationique. Les composés sont représentés par la formule (I). L'invention concerne également des compositions pharmaceutiques et des procédés d'utilisation.
EP98953737A 1997-10-23 1998-10-19 Composes antibacteriens, compositions et procedes de traitement aux carbapenemes Withdrawn EP1032384A4 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US6324197P 1997-10-23 1997-10-23
US63241P 1997-10-23
GBGB9807362.0A GB9807362D0 (en) 1998-04-06 1998-04-06 Carbapenem antibacterial compounds,compositions containing such compounds and mehods of treatment
GB9807362 1998-04-06
PCT/US1998/022111 WO1999020270A1 (fr) 1997-10-23 1998-10-19 Composes antibacteriens, compositions et procedes de traitement aux carbapenemes

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EP1032384A1 true EP1032384A1 (fr) 2000-09-06
EP1032384A4 EP1032384A4 (fr) 2001-11-21

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JP5905496B2 (ja) * 2013-03-05 2016-04-20 田岡化学工業株式会社 フルオレノン誘導体の製造方法
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WO1994005666A1 (fr) * 1992-08-27 1994-03-17 Glaxo S.P.A. Derives de carbapenem condenses

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CZ285778B6 (cs) * 1989-09-08 1999-11-17 Glaxo S.P.A. Kyselina 10-(1-hydroxyethyl)-11-oxo-1-azatricyklo/7,2,0,03,8/-undec-2en-2-karboxylová a její deriváty, způsob jejich výroby, použití pro výrobu farmaceutických prostředků a farmaceutické prostředky s jejich obsahem
KR920019791A (ko) * 1991-04-05 1992-11-20 우메모또 요시마사 다환성 카르바페넴 화합물, 그의 제조방법 및 용도

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EP1032384A4 (fr) 2001-11-21
AU1103199A (en) 1999-05-10
JP2001520192A (ja) 2001-10-30
AU732995B2 (en) 2001-05-03
CA2306632A1 (fr) 1999-04-29
WO1999020270A1 (fr) 1999-04-29

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