WO1994005669A1 - Agents antibacteriens au carbapeneme-heteroaryphenyle-2-cationique - Google Patents

Agents antibacteriens au carbapeneme-heteroaryphenyle-2-cationique Download PDF

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Publication number
WO1994005669A1
WO1994005669A1 PCT/US1993/007830 US9307830W WO9405669A1 WO 1994005669 A1 WO1994005669 A1 WO 1994005669A1 US 9307830 W US9307830 W US 9307830W WO 9405669 A1 WO9405669 A1 WO 9405669A1
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ring
alkyl
group
substituted
defined above
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PCT/US1993/007830
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English (en)
Inventor
Frank Dininno
Susan M. Schmitt
Ravindra N. Guthikonda
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Merck & Co., Inc.
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Priority claimed from US07/937,618 external-priority patent/US5342933A/en
Priority claimed from US07/937,632 external-priority patent/US5292879A/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to EP93920228A priority Critical patent/EP0656900A4/fr
Priority to AU50829/93A priority patent/AU5082993A/en
Priority to JP6507242A priority patent/JPH08500835A/ja
Publication of WO1994005669A1 publication Critical patent/WO1994005669A1/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
  • antibacterial agents of the carbapenem class in which the 2-position sidechain is characterized by a heteroarylphenyl moiety, substituted by various cationic and neutral substituents, as described in more detail below.
  • antibacterial agent having a broad spectrum; it has the following formula:
  • the cationic 2-heteroarylphenyl-carbapenems of the present invention are not characterized by a broad antibacterial spectrum such as that of thienamycin or N-formimidoyl thienamycin. Rather, their spectrum of activity is largely limited to gram positive
  • microorganisms especially methicillin resistant
  • MRSA Staphylococcus aureus
  • MRSE methicillin resistant Staphylococcus epidermidis
  • MRCNS Staphylococci
  • MRSA/MRCNS agents effective against such pathogens
  • carbapenem antibacterial agents which have a 2-substituent which is an aryl moiety optionally substituted by, e.g., aminomethyl and substituted aminomethyl. These agents are described in U.S. Patent Nos. 4,543,257 and 4,260,627 and have the formula:
  • the present invention provides novel carbapenem compounds of the formula:
  • R 1 and R 2 are independently H, CH 3 -, CH 3 CH 2 -,
  • CH 3 CH(F)-, CH 3 CF 2 -, or (CH 3 ) 2 C(F)-; is a 5- or 9-membered mono- or bicyclic heteroaryl ring system wherein 1 atom is O or S, or an 8-membered bicyclic heteroaryl ring system wherein 2 atoms are O and/or S;
  • R a is each independently selected from the group consisting of hydrogen and the radicals set out below, provided that one and only one R a is selected from Type I substituents:
  • A is (CH 2 ) m -Q-(CH 2 ) n , where m is 0 to 6 and n is
  • Q is a covalent bond, O, S, SO, SO 2 , NH, -SO 2 NH-, -NHSO 2 -, -CONH-, -NHCO-, -SO 2 N(C 1 -C 4 alkyl)-, -N(C 1 -C 4 alkyl)SO 2 -, -CON(C 1 -C 4 alkyl)-, -N(C 1 -C 4 alkyl)CO-,
  • -CH CH-, -CO-, -OC(O)-, -C(O)O- or N(C 1 -C 4 alkyl) and (CH 2 ) m is attached to the phenyl aromatic moiety; is a 5- or 6-membered monocyclic heterocycle or an 8-, 9- or 10-membered bicyclic
  • heterocycle the heterocycle containing a first nitrogen in an aromatic 5- or 6-membered first ring, with attachment of the heterocycle to A by way of said first nitrogen and said first nitrogen is quaternary by virtue of the attachment and ring bonds, with the first ring containing 0 or 1 of either O or S, with the first ring containing 0 to 3 additional nitrogen atoms, with the first ring optionally fused to a 3- or 4-membered moiety to form the optional second ring, with the moiety
  • R c is R a as defined under II below, hydrogen, or
  • R y and R z are defined in II below, but independently selected from R a and from each other if more than one R c is present, and is attached to a carbon ring atom or a nitrogen heteroatom the valency of which is not satisfied by the ring bonds; is 0 or 1 ;
  • heterocycle the heterocycle containing a first nitrogen in an aromatic 5- or
  • R c is defined above;
  • R d is hydrogen, NH 2 , O- or C 1 -C 4 alkyl (where the alkyl group is optionally
  • A' is (CH 2 ) m -Q-(CH 2 ) n , where m is 0 to 6 and n is 0 to 6 and Q is defined above;
  • R y and R z are as defined under II below,
  • R y and R z may further be together a C 2 -C 4
  • alkylidene radical to form a ring (optionally mono-substituted with R q as defined below) interrupted by N(O)R e or N + (R e ) 2 (where R e is hydrogen, C 1 -C 4 alkyl, or C 1 -C 4 alkyl mono-substituted with R q as defined below), R w is hydrogen, C 1-4 alkyl, O-, NH 2 , or absent in which case the N + is neutral,
  • R w , R y and R z may further together form a C 5 -C 10 tertiary alkylidene radical which with N + forms a bicyclic ring, where the tertiary alkylidene radical is optionally
  • R q mono-substituted with R q as defined below and where the tertiary carbon of the tertiary alkylidene radical is optionally replaced with nitrogen, N + R e (where R e is defined above), or N + -O-,
  • P is 0 or 1
  • A is as defined above; whe r e
  • heterocycle the heterocycle containing a first nitrogen in a first ring, with the first ring saturated or unsaturated and non-aromatic, with the first nitrogen quaternary by virtue of one or two substituents R d in addition to the ring bonds thereto, with the first nitrogen alternatively neutral by virtue of zero or one substituents R d in addition to the ring bonds thereto with attachment of the heterocycle to A' by way of a carbon atom or non-quaternary nitrogen atom of a ring, with the first ring containing in addition to carbon and the first nitrogen 0 to 1 of a member selected from the group consisting of the non-quaternary nitrogen of attachment, O, S, S(O), S(O) 2 and NR e where R e is defined above, with the first ring optionally fused to a 2-, 3- or 4-membered moiety to form the optional second ring, with the moiety
  • R d is defined above and where more than one R d is present on a nitrogen, at least one R d is hydrogen or C 1 -C 4 alkyl;
  • A' is defined above;
  • R q is defined below;
  • R q is a member selected from the group consisting of -OH, -OCH 3 , -CN, -C(O)NH 2 , -OC(O)NH 2 , CHO, -OC(O)N(CH 3 ) 2 , -SO 2 NH 2 , -SO 2 N(CH 3 ) 2 , -SOCH 3 , -SO 2 CH 3 , -F, -CF 3 , -COOM a (where M a is hydrogen, alkali metal, methyl or phenyl), tetrazolyl (where the point of attachment is the carbon atom of the tetrazole ring and one of the nitrogen atoms is mono-substituted by M a as defined above) and -SO 3 M b (where M b is hydrogen or an alkali metal);
  • R s is C 1 -C 4 alkyl or phenyl, each of which is optionally mono-substituted by R q as defined above or tri-substituted with -F; f) a carbamoyloxy radical:
  • R y and R z are independently H, C 1-4 alkyl
  • alkylidene radical to form a ring (optionally substituted with R q as defined above) or together a 2- to 4-membered alkylidene radical, interrupted by -O-, -S-, -S(O)-, -S(O) 2 - or -NR e -, to form a ring (where R e is hydrogen, C 1 -C 4 alkyl, and C 1 -C 4 alkyl mono-substituted with R q and the ring is optionally mono-substituted with Rq as defined above);
  • n 0-2, and R s is defined above;
  • R t is H or C 1 -C 4 alkyl, and the alkyl thereof is optionally mono-substituted by R q as defined above; k) a (C 1 -C 4 alkyl )carbonylamino radical: -N(R t )-C(O)C 1 -C 4 alkyl, where R t is as defined above, and the alkyl group is also optionally mono-substituted by R q as defined above;
  • R t , R y and R z are as defined above;
  • R s and R*- are as defined above; o) a cyano group: -CN;
  • oxygen or carbon atom is optionally substituted by a C 1 -C 4 alkyl group:
  • alkyl is optionally mono-substituted by R q as defined above;
  • attachment is the carbon atom of the tetrazole ring and one of the nitrogen atoms is mono-substituted by hydrogen, an alkali metal or a C 1 -C 4 alkyl optionally substituted by R q as defined above;
  • R x is phenyl or heteroaryl, where heteroaryl is a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, in which a carbon atom is the point of attachment, in which one of the carbon atoms has been replaced by a nitrogen atom, in which one additional carbon atom is optionally replaced by a heteroatom selected from O or S in the case of a 5-membered ring, and in which from 1 to 2 additional carbon atoms are optionally replaced by a nitrogen heteroatom, and where the phenyl and heteroaryl are optionally mono-substituted by R q , as defined above; M b is as defined above; and R y and R z are as defined above; ac) C 5 -C 7 cycloalkyl group in which one of the carbon atoms in the ring is
  • ah a 2-oxazolidinonyl moiety in which the point of attachment is the nitrogen atom of the oxazolidinone ring, the ring oxygen atom is optionally replaced by a heteroatom selected from -S- and NR t (where R t is as defined above) and one of the saturated carbon atoms of the oxazolidinone ring is optionally mono-substituted by one of the
  • M is selected from: i) hydrogen
  • the present invention also provides novel carbapenem intermediates of the formula:
  • R is H or CH 3 ;
  • R a is defined above, with the proviso that R q
  • P' is a removable protecting group for hydroxy
  • M is a removable protecting group for carboxy; and the Type I, R a substituent is counterbalanced with the anionic form of Z where
  • Z is methanesulfonyloxy, trifluoromethanesulfony ⁇ - oxy, fluorosulfonyloxy, p-toluenesulfonyloxy, 2,4,6-triisopropylbenzenesulfonyloxy, p-bromobenzenesulfonyloxy, p-nitrobenzenesulfonyloxy, bromo, or iodo.
  • R is H or CH 3 ;
  • P' is a removable protecting group for hydroxy
  • M is a removable protecting group for carboxy
  • R a is selected from the group consisting of H, OP',
  • X is O or S
  • the manufacture of compounds of Formula I may be carried out in a three-stage synthetic scheme followed by deprotection.
  • the objective of the first synthetic stage is to produce a base heteroarylphenyl (hereinafter HAP) compound which may be converted to be the two-position substituent of the carbapenem of Formula I.
  • the objective of the second synthetic stage is to attach the base HAP to the carbapenem.
  • the objective of the third synthetic stage is to substitute the HAP with the desired R a .
  • This third synthetic stage may either be performed after the first synthetic stage or after the second synthetic stage according to the nature of the desired R a .
  • Flow Sheet A demonstrates a suggested first stage synthesis.
  • Flow Sheets B1 and B2 demonstrate a second stage synthesis.
  • the third stage synthesis varies according to the selected R a .
  • Substituted bromophenylboronic acids A1 and substituted heteroaryldiethylboranes A5 may be prepared by conventional methods. Exposure of either of these boron compounds to aryl halides in the presence of a catalytic amount of palladium catalyst yields the desired synthons A3.
  • the second stage synthesis is to attach the base HAP to the 2-position of the carbapenem.
  • HAP M may be added to azetidin-2-one B1 in a Grignard reaction as shown in Flow Sheet B.
  • B1 is subgeneric to the more general B1*.
  • Replacing B1 by B1* (where M is as defined above under ii) produces a broader class of compounds analogous to B2, B3, and B4.)
  • the Grignard reaction requires that A3 be converted to a Grignard reagent by reaction with magnesium and 1,2-dibromoethane in THF from 20°C to 60°C and subsequently contacting A3 as a Grignard reagent with B1 in THF at from -70°C to about 20°C to produce azetidin-2-one B2.
  • A3 may be reacted with t-butyllithium, n-butyllithium, or the like in Et 2 O or THF at from -78" to -50°C followed by the addition of magnesium bromide to produce the same Grignard reagent.
  • R i of B1 is in practice pyridin-2-yl but may clearly be a variety of substituents including aromatic and heteroaromatic substituents. Further, R i might be, for example, phenyl,
  • Azetidin-2-one B2 is an intermediate that may be ring closed to a carbapenem. It is on this intermediate that R a or precursor substituent such as t-butyldimethylsilyloxy-methyl group should be modified where such modification is incompatible with the carbapenem nucleus.
  • R a or precursor substituent such as t-butyldimethylsilyloxy-methyl group
  • a convenient reaction to remove the t-butyldimethylsilyl group from a hydroxymethyl substituent of the HAP on compound B2 is to expose compound B2 to a dilute solution of sulfuric acid or hydrochloric acid in methanol at 0°C. If the t-butyldimethylsilyl group were removed from carbapenem B3 under the same conditions, a substantial portion of carbapenem would be degraded and lost.
  • carbapenem Of course it is possible to remove the t-butyldimethylsilyl group from carbapenem B3 in reduced yield by exposing B3 to tetra-n-butylammonium fluoride and acetic acid in THF.
  • Compound B2 may be ring closed to carbapenem B3 by refluxing in xylene with p-hydroquinone for about 1 to 2 hours. It is on this intermediate that final elaboration of R a from a precursor substituent, e.g. hydroxymethyl, may be accomplished. Removal of the protecting groups then provides the final
  • Flow Sheet B2 shows an alternative second stage synthesis, i.e. attachment of the base HAP such as B5 to the 2-position of the carbapenem.
  • This synthesis involves a palladium catalyzed crosscoupling reaction between a carbapenem triflate and a suitably substituted arylstannane, a process which is described in U.S. Ser. No. 650,111 filed February 4, 1991.
  • it is first necessary to modify B5 to the trimethylstannylheteroarylphenyl B6. This is accomplished by reacting B5 with t-butyllithium in THF at from -78° to -50oC followed by the addition of trimethyltin chloride.
  • B6 may be prepared by simply heating B5. with hexamethylditin in the presence of
  • a protecting group such as t-butyldimethylsilyl on a hydroxymethyl substituent may be removed by exposure to tetra-n-butylammonium fluoride in THF yielding a particular B6. If the t-butyldimethylsilyl group were removed from carbapenem B7 under the same conditions, a substantial portion of the carbapenem would be degraded and lost. Thus, modification of the precursor substituent in this instance and replacement with another precursor substituent or even an R a is best performed before attachment to the carbapenem.
  • the steps for preparing the 2-oxocarbapenam intermediate B8 are well known in the art and are explained in ample detail by D.G.
  • 2-oxocarbapenam, B8 is reacted at -78°C to -50°C with a suitable trifluoromethanesulfonyl source, such as trifluoromethanesulfonic anhydride, trifluoromethanesulfonyl chloride and the like, in the
  • triethylamine, diisopropylamine and the like in a polar aprotic solvent, such as tetrahydrofuran or methylene chloride.
  • a polar aprotic solvent such as tetrahydrofuran or methylene chloride.
  • an organic nitrogen base such as triethylamine and the like, is then added to the reaction solution followed immediately by a silylating agent, such as trimethylsilyl
  • An aprotic polar coordinating solvent such as DMF, 1-methyl-2-pyrrolidinone and the like, is optionally added.
  • a palladium compound such as tris(dibenzylidene-acetone)dipalladium-chloroform (Pd 2 (DBA) 3 •CHCl 3 ), palladium acetate and the like, optionally, a
  • phenylphosphine such as
  • a halide source such as lithium chloride, zinc chloride or ammonium chloride and the like, is added and the reaction solution is allowed to warm and is stirred at a suitable temperature, such as 0° to 50°C for from a few minutes to 48 hours.
  • the carbapenem B7 is obtained by conventional isolation/purification methodology known in the art.
  • Azetidin-2-ones B1 and B1* (Flow Sheet B1), pyridyl-thioesters, are well known compounds in the production of carbapenems. Diverse synthetic schemes useful to make B1 and B1* may be imagined by the skilled artisan. Particularly useful to the instant inventors is a synthetic scheme set out further in Flow Sheet C below in which the symbol R is as defined above. The steps for preparing intermediate B1 and B1* are analogous to the procedures described, for example, in U.S. Pat. Nos. 4,260,627 and
  • 6-fluoroalkyl compounds within the scope of the present invention is carried out in a straightforward manner using techniques well known in the art of preparing carbapenem antibacterial compounds. See, e.g., J. G. deVries et al., Heterocycles, 23(8), 1915 (1985); BE 900 718 A (Sandoz) and Japanese Patent Pub. No. 6-0163-882-A (Sanruku Ocean).
  • one of the R a substituents must be of Type I.
  • anti-MRSA/MRCNS activity results from the configuration of the overall molecule uniquely conferred by the HAP nucleus.
  • the Type I substituent provides still greater anti-MRSA/MRCNS activity to the molecule.
  • Type II R a substituents are distinguishable from Type I substituents chemically and with respect to the biological properties which they confer. In related compounds, it has been found that the Type II substituted compounds afford greater water solubility and reduced potential for CNS side effects. Substituents which tend to confer improved water solubility on the overall compound have been found useful, since they are contemplated to thereby improve the transport of the compound involved.
  • Type I substituents employed in the compounds of the present invention may have
  • R 1 is hydrogen. More preferably, R 1 is hydrogen and R 2 is (R)-CH 3 CH(OH)- or (R)-CH 3 CH(F)-. In the most preferred case, R 1 is hydrogen and R 2 is
  • R a is other than hydrogen. In the most preferred compounds, in total, up to two R a substituents are other than hydrogen.
  • Type I. a where R c is shown to have an indefinite position, it may be attached to any carbon of the ring.
  • Preferred Type I.b) substituents include
  • R q and/or A' may be attached to any carbon atom of the ring.
  • the R c substituents herein are intended to represent suitable further substituents on the Type I. a) or b) substituents for HAP. As seen above, these Type I. a) or b) substituents are monocyclic or bicyclic aromatic groups containing heteroatoms.
  • R c may be the same or different and may be selected on an independent basis from the group as defined above. While a single such
  • substitution is preferred, there is occasion to use up to two such substituents on an R a , e.g., where it is desired to enhance the effect of a particular substituent group by employing multiple
  • R c The particular choice of R c will depend upon the situation. For instance, a specific R c may lend particular stability to a nitrogen cation. At other times it may be desired to employ a substituent known to enhance antibacterial activity of the overall molecule against a particular
  • bacterium for example, while also employing a substituent known to improve some other property such as water solubility or the duration of action of the overall molecule.
  • R c herein includes two specific Types of further substituent attached to the Type I. a) or b) substituent.
  • a first Type of R c are those attached to a ring carbon and a second Type of R c are those attached to a neutral ring nitrogen.
  • R c a wide range of organic substituents are suitably used as R c .
  • R c some substituents including the -NR y R z
  • Preferred R c attached to ring carbon atoms are -NH 2 , -SCH 3 , -SOCH 3 , -CH 2 OH, -(CH 2 ) 2 OH, -OCH 3 , -COOM b , -CH 2 COOM b , -CH 2 CH 2 COOM b , -CH 2 SOCH 3 , -CH 2 SCH 3 , CN, -SO 3 M b , -CH 2 SO 3 M b , -CH 2 CH 2 SO 3 M b , -Br, -Cl, -F, -I, -CH 3 , CH 2 CH 3 , CH 2 CONH 2 and CH 2 CON(C 1 -C 4 alkyl) where M b is defined above.
  • Preferred R c attached to neutral ring nitrogen atoms are -CH 2 OH, -(CH 2 ) 2 OH, -CH 2 COOM b , -CH 2 CH 2 COOM b , -CH 2 SOCH 3 , -CH 2 SCH 3 , CN, -CH 2 SO 3 M b , -CH 2 CH 2 SO 3 M b , -CH 3 , CH 2 CH 3 , CH 2 CONH 2 and CH 2 CON(C 1 -C 4 alkyl) where M b is defined above.
  • each Type I. a) or b) substituent have no more than two R c substituents which are other than hydrogen.
  • the formula shown above for Type I. a) substituents has up to two R c substituents with the remainder of course being hydrogen.
  • the formula for the Type I. b) substituent also allows up to two R c .
  • the previously listed more specific structures should be interpreted to have no more than two R c for each monocyclic or bicyclic group.
  • any monocylic or bicyclic group have no more than a single R q substituent.
  • R d includes a single type of further substituent attached as a Type I. b) or d) substituent.
  • the R d substituents are attached to a cationic nitrogen which may or may not be aromatic.
  • Preferred R- ⁇ attached to cationic nitrogen atoms are hydrogen, -CH 3 , CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 COOM b ,
  • Type Ib when there is no R d
  • Type Ic when there is no R w
  • Type Id when there is zero to one R d , depending on Type of heterocycle
  • Whether such a Type Ib, Ic, or Id substituent will be predominately cationic or neutral in a given physical state will be governed by principles of acid-base chemistry, which are well known to those skilled in the art. For example, the particular ratio of neutral form to cationic form will depend upon the basicity of the amine and acidity of a solution. When such a
  • substituent is in a protonated quaternized state, the compound exists as a zwitterion which is internally balanced as to charge or as an ammonium salt which is externally balanced.
  • R d there is no R d on a Type lb substituent, it is understood that such a substituent is neutral (there is no positive charge on the nitrogen).
  • a compound containing such a substituent is typically produced in this form as a salt, wherein M is an alkali metal, and may exist in solution in its neutral form.
  • a compound containing a neutral Type lb substituent may be in equilibrium with, and may also be represented by a formula showing, the corresponding compound containing the quaternized protonated substituent where R d is present and is a hydrogen atom.
  • the same compound may exist with the Type lb substituent in a completely protonated quaternized form, for instance in an aqueous solution in the presence of a stoichiometric amount of a strong mineral acid. It is intended herein that both the protonated (cationic) and the unprotonated (neutral) forms of Type Ib, Ic and Id substituents of the type just described are within the scope of the present invention.
  • Suitable A spacer moieties include -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -OCH 2 CH 2 -, -SOCH 2 -, -SO 2 CH 2 -, -SCH 2 CH 2 -, -SOCH 2 CH 2 -,
  • n is 2-6.
  • the Type I. cationic substituents are generally added to HAP following attachment of HAP to the carbapenem. Conveniently, the HAP side-chain should be synthesized with a precursor substituent which may be elaborated into the desired cationic substituent. The identity of the precursor
  • substituent will vary according to the particular R a desired.
  • one such precursor substituent is -A-OH, such as hydroxymethyl.
  • the hydroxymethyl precursor substituent may be elaborated into cationic substituents of Type I. a) by converting the hydroxyl into an active leaving group such as an iodide (giving -A-I) followed by reaction with a desired nitrogen containing ⁇ aromatic compound. More particularly, two alternative
  • -A-OH may be converted to a methanesulfonate group by treating with methanesulfonyl chloride in the
  • the methanesulfonate intermediate may be converted to the reactive iodide derivative by treatment with sodium iodide in a suitable solvent, e.g., acetone, at reduced or ambient temperatures.
  • a suitable solvent e.g., acetone
  • the hydroxyl group may be directly converted into the iodide group by common methods known to the art. For example, treatment of the hydroxyl group with methyl triphenoxyphosphonium iodide in a suitable solvent, such as dimethylformamide, at reduced or ambient temperatures, directly provides the desired iodide.
  • reaction containing compound, e.g. a heteroaromatic compound such as pyridine.
  • a suitable solvent such as acetonitrile
  • This displacement reaction may also be facilitated by the addition of excess silver trifluoromethanesulfonate to the reaction mixture, in which case reduced temperatures are often desirable.
  • the hydroxyl group of -A-OH may be converted into the reactive
  • trifluoromethanesulfonate (triflate) group such an activating group cannot be isolated by conventional techniques but may be formed and used in situ.
  • treatment of the hydroxyl group with trifluoromethanesulfonic (triflic) anhydride in the presence of a hindered, non-nucleophilic base such as 2,6-lutidine, 2,4,6-collidine, or
  • the triflate activating group provides for the generation of the triflate activating group.
  • Introduction of the cationic group is then accomplished by reacting the above triflate in situ with the desired nitrogen containing compound at reduced temperature.
  • the reacting nitrogen containing compound as the base for the formation of the triflate activating group.
  • treatment of the hydroxyl group with triflic anhydride in the presence of at least two equivalents of the reacting nitrogen compound under the conditions described above provides the cationic substituent.
  • alkylsulfonyloxy substituted alkylsulfonyloxy, arylsulfonyloxy, substituted arylsulfonyloxy, fluorosulfonyloxy and halogen.
  • the common sulfonate leaving groups are:
  • methanesulfonyloxy trifluoromethanesulfonyloxy, fluorosulfonyloxy, p-toluenesulfonyloxy,
  • the Type I.b) cationic substituents are prepared by quaternization of an aromatic ring nitrogen of a neutral precursor substituent on either of the HAP rings.
  • neutral precursor substituents are -CONHCH 2 -(2-pyridyl),
  • Quaternization is accomplished by reacting the nitrogen compound in an inert organic solvent
  • an alkylating agent R d -Y where R d is given above and Y is a leaving group such as iodide, bromide, mesylate (methanesulfonate), tosylate (p-toluenesulfonate) or triflate.
  • R d is given above and Y is a leaving group such as iodide, bromide, mesylate (methanesulfonate), tosylate (p-toluenesulfonate) or triflate.
  • the aromatic ring nitrogen may be quaternized by reaction with an oxidizing agent such as 3-chloroperbenzoic acid (giving the N-oxide) or an aminating reagent such as
  • a suitable solvent e.g. dichloromethane or CH 3 CN
  • the neutral precursor substituent may be rendered cationic through
  • This may be accomplished by treatment of the neutral precursor with a suitable inorganic or organic acid, e.g. hydrochloric acid, phosphoric acid, hydrobromic acid, acetic acid or benzoic acid. Protonation may further be accomplished by a carboxylic acid function elsewhere in the molecule, including the C-3 carboxyl on the carbapenem.
  • the neutral precursor substituent may be already attached to HAP at the time of its connection to the carbapenem, or it may be elaborated from a simpler precursor after connection to the carbapenem.
  • An example of a precursor substituent for elaboration is -A'-OH such as hydroxymethyl. In one suggested synthesis, the hydroxyl may be
  • a reactive leaving group such as iodo as described above.
  • the iodide is then reacted in a nucleophilic displacement reaction with a nitrogen containing aromatic compound which has a nucleophilic side-chain substituent such as CH 2 SH or CH 2 NH 2 .
  • a nitrogen containing aromatic compound which has a nucleophilic side-chain substituent such as CH 2 SH or CH 2 NH 2 .
  • Suitable substrates for this reaction include 2-(mercaptomethyl)pyridine, 2-aminopyridine, 2-(aminomethyl)pyridine or
  • Type I.b) cationic substituent A second suggested synthesis of a Type I.b) cationic substituent starting from a precursor -A'-OH (e.g. hydroxymethyl) consists of oxidation of the alcohol functionality to an
  • the oxidation may be conveniently accomplished by a Swern oxidation employing oxalyl chloride-dimethylsulfoxide followed by triethylamine.
  • the reaction is conducted in methylene chloride as a solvent at from -70°C to 0°C.
  • the Wittig reaction is carried-out by reacting the aldehyde with the desired Wittig reagent in a polar solvent such as acetonitrile or dimethylsulfoxide at about room temperature. Suitable
  • Wittig reagents include: pyridylmethylenetriphenylphosphorane, quinolylmethylenetriphenylphosphorane, and thiazolylmethylenetriphenylphosphorane. Quaternization or protonation as described above then completes the synthesis of the Type I.b) cationic substituent. Depending on the particular R a of Type I.b) that is desired, many other synthesis schemes may be employed, as would be apparent to an organic chemist skilled in the art.
  • the Type I .d) cationic substituents are prepared by quaternization or protonation of a non-aromatic ring nitrogen of an appropriate neutral precursor substituent on HAP. Quaternization or protonation is accomplished as described above for the Type I.b) substituents.
  • the neutral precursor may already be attached to HAP at the time of its connection to the carbapenem, or the neutral precursor may be
  • the substituent may be suitably formed on HAP prior to addition to the carbapenem.
  • the substituent may be formed on B6 and reacted with B9 to form the protected
  • carbapenem B7 For example, 2-hydroxymethyl-5-(3'-trimethylstannylphenyl)thiophene, i.e. B6, may be substituted by reaction with triflic anhydride and N-methylimidazole in a suitable solvent, such as, dichloromethane under nitrogen at -78°C to room temperature to form a Type I.
  • a) substituted HAP i.e. B6.
  • This substituted HAP may be reacted with B9 employing conditions otherwise described herein and specifically using an ammonium chloride source.
  • the R a substituents can be selected based on the biological properties which they confer. In related compounds, it has been found that the neutral or anionic substituted compounds afford greater water solubility and reduced potential for CNS side
  • HAR can be represented by
  • this aryl structure may be the radical of a 5-membered furan or thiophene, of an 8-membered furofuran, thienofuran, or thienothiophene, or of a 9-membered benzofuran or benzothiophene.
  • the carbon atom at the point of attachment cannot be replaced by a heteroatom.
  • R 1 is hydrogen. More preferably, R 1 is hydrogen and R 2 is (R)-CH 3 CH(OH)- or (R)-CH 3 CH(F)-. In the most
  • R 1 is H and R 2 is (R)-CH 3 CH(OH).
  • At least one R a in the meta-position of the HAP moiety from the point of attachment to the other aromatic ring is other than hydrogen.
  • in total up to two R a substituents are other than hydrogen.
  • the hydroxymethyl group may be obtained in the R a position of the phenyl portion of HAP as shown in Flow Sheet D, in which A3 is obtained as given in Flow Sheet A.
  • Selective metallation of A3 and formylation with N,N-dimethylformamide provides synthon D1.
  • Reduction of D1 with sodium borohydride in methanol yields the preferred substituent which is protected as its silylether in the next step to give D3.
  • the latter reagent is then incorporated into Flow Sheet B1 as A3.
  • the preferred hydroxymethyl group may also be obtained in the appropriate R a positions of the heteroaryl portion of HAP.
  • the preferred formyl substitution on the HAP moiety may be obtained from the hydroxymethyl substitution of B3 or isomeric B3* described in Flow Sheet B1 by a Swern oxidation.
  • isomeric B3* is oxidized in methylene chloride at from -70°C to room temperature employing oxalyl
  • -CONH 2 may be obtained from B2 or "isomeric" B2* by oxidizing hydroxymethyl with Jones reagent to the corresponding carboxylic acid substitution as described above. This carboxylic acid is converted to -CONH 2 by sequentially contacting with
  • Substituted amides may of course be obtained by replacing ammonia with the corresponding substituted amine.
  • carboxylic acid In contrast to the carboxylic acid
  • suitable R a of Type II include:
  • Suitable hydroxyl protecting groups, P' are silyl groups such as trialkylsilyl,
  • diarylalkylsilyl and carbonate groups such as
  • alkyloxycarbonyl substituted alkyloxycarbonyl
  • t-butylmethoxyphenylsilyl t-butoxydiphenylsilyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, benzyloxycarbonyl, t-butyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl and allyloxycarbonyl.
  • Deblocking may be carried out in a
  • deprotection may be carried out in a palladium catalyzed reaction in a solution containing potassium 2-ethylhexanoate and 2-ethylhexanoic acid or, alternatively, another suitable nucleophile such as pyrrolidine.
  • deprotection is conducted for those prepared via Flow Sheet B2, deprotection is conducted
  • compound B7 is exposed initially to aqueous acidic conditions, acetic acid or dilute HCl or the like, in an organic solvent such as tetrahydrofuran at 0°C to ambient temperature for from a few minutes to several hours.
  • an organic solvent such as tetrahydrofuran
  • the overall molecule must be electronically balanced. Since a quaternary nitrogen is present in the compounds of the present invention, a balancing anion must also, in that case, be present. This is usually accomplished by allowing COOM to be COO-. However, where M is, e.g., a pharmaceutically
  • a counterion (anion) Z- must be provided, or alternatively, an anionic substituent might be utilized.
  • a counterion must also be
  • alkyl means a straight or branched chain aliphatic hydrocarbon radical.
  • quaternary nitrogen refers to a tetravalent cationic nitrogen atom including the cationic nitrogen atom in a
  • tetra-alkylammonium group e.g., tetramethylammonium, N-methylpyridinium
  • the cationic nitrogen atom in a protonated ammonium species e.g., trimethyl-hydroammonium, N-hydropyridinium
  • the cationic nitrogen atom in an amine N-oxide e.g.,
  • N-methylmorpholine-N-oxide pyridine-N-oxide
  • N-amino-ammonium group e.g., N-aminopyridinium
  • heteroatom means N, S, or O, selected on an independent basis.
  • heteroaryl has been defined herein, in relation to the R x group, to have a specific and limited meaning, being only monocyclic. It is required that the monocyclic heteroaryl have at least one nitrogen atom, and optionally at most only one additional oxygen or sulfur heteroatom may be present.
  • Heteroaryls of this type are pyrrole and pyridine (1 N); and oxazole, thiazole or oxazine (1 N + 1 O or 1 S).
  • the preferred heteroaryls are those where only nitrogen heteroatoms are present when there is more than one. Typical of these are pyrazole, imidazole, pyrimidine and pyrazine (2 N's) and triazine (3 N's).
  • the heteroaryl group of R x is always optionally mono-substituted by R q , defined above, and substitution can be on one of the carbon atoms or one of the heteroatoms, although in the latter case certain substitutent choices may not be appropriate.
  • the carbapenem compounds of the present invention are useful per se and in their
  • ester or salt refers to those salt and ester forms of the compounds of the present invention which would be apparent to the pharmaceutical
  • compositions may be prepared from the active ingredients in
  • the present invention is also concerned with pharmaceutical compositions and methods of treating bacterial infections utilizing as an active ingredient the novel carbapenem compounds of the present invention.
  • the pharmaceutically acceptable salts referred to above may take the form -COOM.
  • the M may be an alkali metal cation such as sodium or
  • M 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 may also include non-toxic 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,
  • nicotinate oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate.
  • the pharmaceutical acceptable esters of the novel carbapenem compounds of the present invention 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, Column 9, line 61 to Column 12, line 51, which is incorporated herein by reference. Included within such pharmaceutically acceptable esters are those which are hydrolyzed under physiological conditions, such as
  • novel carbapenem compounds of the present invention may take the form COOM, where M is a readily removable carboxyl protecting group.
  • M is a readily removable carboxyl protecting group.
  • Such conventional blocking groups consist of known ester groups which are used to protectively block the carboxyl group during the synthesis procedures described above. 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.
  • ester protecting groups include alkyl,
  • ester protecting groups include benzhydryl, p-nitrobenzyl, 2-naphthylmethyl, allyl, 2-chloroallyl, benzyl, t-butyl, 2,2,2-trichloroethyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, trimethylsilyl,
  • 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 antibacterials of the invention are not limited to utility as medicaments; they may be used in all manner of industry, for example: additives to animal feed, preservation of food, disinfectants, and in other industrial systems where control of bacterial growth is desired.
  • they may be employed in aqueous compositions in concentrations ranging from 0.1 to 100 parts of antibiotic per million parts of solution in order to destroy or inhibit the growth of harmful bacteria on medical and dental equipment and as bactericides in industrial applications, for example in waterbased paints and in the white water of paper mills to inhibit the growth of harmful bacteria.
  • the compounds of this invention may be used in any of a variety of pharmaceutical preparations. They may be employed in capsule, powder form, in liquid solution, or in suspension. They may be administered by a variety of means; those of
  • compositions for injection may be prepared in unit dosage form in ampules, or in multidose containers.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents.
  • the active ingredient may be in powder form for reconstitution, at the time of delivery, with a suitable vehicle, such as sterile water.
  • Topical applications may be formulated in hydrophobic or hydrophilic bases as ointments, creams, lotions, paints, or powders.
  • the dosage to be administered depends to a large extent upon the condition and size of the subject being treated as well as the route and frequency of administration, the parenteral route by injection being preferred for generalized
  • compositions for human delivery per unit dosage may contain from 0.1% to 99% of active material, the preferred range being from about 10-60%.
  • the composition will generally contain from about 15 mg to about 1500 mg of the active ingredient; however, in general, it is preferable to employ a dosage amount in the range of from about 250 mg to 1000 mg.
  • the unit dosage is usually the pure compound I in sterile water solution or in the form of a soluble powder intended for solution.
  • the preferred method of administration of the Formula I antibacterial compounds is parenteral by i.v. infusion, i.v. bolus, or i.m. injection.
  • antibacterial compounds per kg of body weight given 2, 3, or 4 times per day is preferred.
  • Preferred dosage is 250 mg to 1000 mg of the Formula I
  • antibacterial given two (b.i.d.) three (t.i.d.) or four (q.i.d.) times per day More specifically, for mild infections a dose of 250 mg t.i.d. or q.i.d. is recommended. For moderate infections against highly susceptible gram positive organisms a dose of 500 mg t.i.d. or q.i.d. is recommended. For severe, life-threatening infections against organisms at the upper limits of sensitivity to the antibiotic, a dose of 1000 mg t.i.d. or q.i.d. is recommended.
  • a dose of 5-25 mg/kg of body weight given 2, 3, or 4 times per day is preferred; a dose of 10 mg/kg t.i.d. or q.i.d. is usually
  • Antibacterial compounds of Formula I are of the broad class known as carbapenems or 1-carbadethiapenems. Naturally occuring carbapenems are susceptible to attack by a renal enzyme known as dehydropeptidase (DHP). This attack or degradation may reduce the efficacy of the carbapenem
  • the compounds of the present invention are significantly 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 carbapenem antibacterial agents are disclosed in the prior art [see European Patent Applications No.
  • 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.
  • DHP inhibition is desired or necessary
  • suitable inhibitors, combination compositions and methods of treatment they are incorporated herein by reference.
  • a preferred weight ratio of Formula I compound: DHP inhibitor in the combination compositions is about 1:1.
  • a preferred DHP inhibitor is 7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptenoic acid or a useful salt thereof.
  • the thiophene was prepared according to G. Martelli et al., J. Chem. Soc (B)., 901, (1968).
  • Aryl bromide (1 mM) was added to a stirred suspension of magnesium chips (1.25 mM) in 2mL of anhydrous tetrahydrofuran under nitrogen at R.T. 8 ⁇ L of 1,2-dibromoethane was then added. The resulting mixture was stirred 3 hours, when most of the metal was digested. The resulting dark yellow solution was used as 0.5 M solution of the aryl Grignard reagent.
  • This Grignard reagent solution was added dropwise to a stirred solution of (3S, 4R)-1-[[(allyloxy)carbonyl](triphenylphosphoranylidene) ⁇ methyl]-3-[(lR)-1-[(allyloxy)carbonyloxy]ethyl]-4-[[2'-pyridylthio)carbonyl]methyl]azetidin-2-one, ( ⁇ 0.5 mM) in 2 mL of anhydrous tetrahydrofuran at 0° under nitrogen. The reaction mixture was stirred 15 mins at 0°. Satd ammonium chloride solution (5mL) and 10 mL of ethyl acetate were added. The organic layer was separated, and washed with 2 ⁇ 5 mL of satd sodium chloride solution and dried over anhyd
  • STEP B2 GENERAL PROCEDURE FOR QUATERNIZATION:
  • the UV data are in nanometers for ⁇ max water.
  • 3-thiophenecarboxylic acid (Aldrich) was selectively brominated to 5-bromo- 3-thiophenecarboxylic acid using the method of Campaigne et al., J.A.C.S., 76, 2445 (1954).
  • hexane-soluble filtrate was re-concentrated in vacuo (2.38 g) and chromatographed on 60 g of Bakers Si gel (60-200 M Hz) packed in hexane. The material was applied to the column in 1:2 CH 2 Cl 2 /hexane and eluted with the same solvent system (300 ml) after which 10% Et 2 O in hexane was used to elute 2.
  • reaction mixture was concentrated to a small volume of yellow oil under a N 2 stream.
  • Et 2 O (30 ml) and brine (30 ml) were added, and the rection mixture was shaken in a separatory funnel. After phase

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Abstract

Carbapénèmes de formule (I) utiles en tant qu'agents antibactériens.
PCT/US1993/007830 1992-08-28 1993-08-19 Agents antibacteriens au carbapeneme-heteroaryphenyle-2-cationique WO1994005669A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP93920228A EP0656900A4 (fr) 1992-08-28 1993-08-19 Agents antibacteriens au carbapeneme-heteroaryphenyle-2-cationique.
AU50829/93A AU5082993A (en) 1992-08-28 1993-08-19 Cationic-2-heteroarylphenyl-carbapenem antibacterial agents
JP6507242A JPH08500835A (ja) 1992-08-28 1993-08-19 陽イオン性−２−ヘテロアリールフェニル−カルバペネム抗菌剤

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US07/937,618 US5342933A (en) 1992-08-28 1992-08-28 Cationic-2-heteroarylphenyl-carbapenem antibacterial agents
US937,618 1992-08-28
US937,632 1992-08-28
US07/937,632 US5292879A (en) 1992-08-28 1992-08-28 Intermediates for preparing cationic-2-heteroaryl-phenyl-carbapenem antibacterial agents

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6664278B2 (en) 1997-12-16 2003-12-16 Smithkline Beecham P.L.C. Hydrate of 5-[4-[2-(N-methyl-N-(2-pyridil)amino)ethoxy]benzyl]thiazolidine-2,4-dione maleic acid salt
US7045633B2 (en) 1997-12-16 2006-05-16 Smithkline Beecham Plc Hydrate of 5-[4-[2-(N-methyl-N-(2-pyridil)amino)ethoxy]benzyl]thiazolidine-2,4-dione maleic acid salt
US7230109B2 (en) 1997-12-16 2007-06-12 Smithkline Beecham P.L.C. 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2, 4-dione, maleic acid salt, hydrate as pharmaceutical

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU3536699A (en) 1998-04-27 1999-11-16 Ihara Chemical Industry Co. Ltd. 3-arylphenyl sulfide derivatives and insecticides and miticides

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US4543257A (en) * 1977-10-19 1985-09-24 Merck & Co., Inc. 1-Carba-2-penem-3-carboxylic acid
US4978659A (en) * 1987-02-02 1990-12-18 Merck & Co., Inc. 2-(Heteroaryliumalkyl)phenyl carbapenem antibacterial agents
US5143914A (en) * 1991-06-25 1992-09-01 Merck & Co., Inc. 2-heteroarylphenyl-carbapenem antibacterial agents

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US4543257A (en) * 1977-10-19 1985-09-24 Merck & Co., Inc. 1-Carba-2-penem-3-carboxylic acid
US4978659A (en) * 1987-02-02 1990-12-18 Merck & Co., Inc. 2-(Heteroaryliumalkyl)phenyl carbapenem antibacterial agents
US5143914A (en) * 1991-06-25 1992-09-01 Merck & Co., Inc. 2-heteroarylphenyl-carbapenem antibacterial agents

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6664278B2 (en) 1997-12-16 2003-12-16 Smithkline Beecham P.L.C. Hydrate of 5-[4-[2-(N-methyl-N-(2-pyridil)amino)ethoxy]benzyl]thiazolidine-2,4-dione maleic acid salt
US7045633B2 (en) 1997-12-16 2006-05-16 Smithkline Beecham Plc Hydrate of 5-[4-[2-(N-methyl-N-(2-pyridil)amino)ethoxy]benzyl]thiazolidine-2,4-dione maleic acid salt
US7230109B2 (en) 1997-12-16 2007-06-12 Smithkline Beecham P.L.C. 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2, 4-dione, maleic acid salt, hydrate as pharmaceutical

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CA2142708A1 (fr) 1994-03-17
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EP0656900A1 (fr) 1995-06-14
JPH08500835A (ja) 1996-01-30

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