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WO1998011108A1 - Compositions antibacteriennes de carbapenem, preparations les contenant et methodes de traitement - Google Patents

Compositions antibacteriennes de carbapenem, preparations les contenant et methodes de traitement Download PDF

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Publication number
WO1998011108A1
WO1998011108A1 PCT/US1997/015831 US9715831W WO9811108A1 WO 1998011108 A1 WO1998011108 A1 WO 1998011108A1 US 9715831 W US9715831 W US 9715831W WO 9811108 A1 WO9811108 A1 WO 9811108A1
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groups
substituted
group
unsubstituted
straight
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PCT/US1997/015831
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English (en)
Inventor
Lovji D. Cama
Robert R. Wilkening
Ronald W. Ratcliffe
Timothy A. Blizzard
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Merck & Co., Inc.
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Priority claimed from GBGB9624277.1A external-priority patent/GB9624277D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to EP97939843A priority Critical patent/EP1021445A4/fr
Priority to JP10513746A priority patent/JP2001500862A/ja
Priority to CA002264147A priority patent/CA2264147A1/fr
Priority to AU41844/97A priority patent/AU4184497A/en
Publication of WO1998011108A1 publication Critical patent/WO1998011108A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
    • C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
    • C07D477/14—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to carbapenem antibacterial agents in which the carbapenem nucleus is substituted at the 2-position with a sulfonamide containing ring system, linked to the carbapenem through a CH 2 group.
  • the sulfonamide containing ring system is further substituted with various substituents, which can include cationic groups.
  • the carbapenems of the present invention are useful against gram positive microorganisms, especially methicillin resistant Staphylococcus aureus (MRSA), methicillin resistant Staphylococcus epidermidis (MRSE), and methicillin resistant coagulase negative Staphylococci (MRCNS).
  • MRSA methicillin resistant Staphylococcus aureus
  • MRSE methicillin resistant Staphylococcus epidermidis
  • MRCNS methicillin resistant coagulase negative Staphylococci
  • R 1 represents H or methyl
  • CO 2 M represents a carboxylic acid, a carboxylate anion, a pharmaceutically acceptable ester group or a carboxylic acid protected by a protecting group;
  • P represents hydrogen, hydroxyl, F or hydroxyl protected by a hydroxyl-protecting group
  • X 1 and X 2 represent hydrogen or X J and X 2 taken together represent a carbonyl group
  • one of AB, BC and CD represents a fused aryl, heteroaryl or heteroarylium ring, and the other variables represent R, said fused aryl, heteroaryl or heteroarylium ring being substituted with from 1 -4 R groups;
  • each R is independently selected from: -R*; -Q; hydrogen; halo; -CN; -N0 2 ; -NRaRb; -OR ⁇ -SR ⁇ ; -C(0)NRaRt>; -C(0)OR' -S(0)R c ; -S0 2 R c ; -S0 2 NR*R b ; -NR"S0 2 R b ; -C(0)R"; -OC(0)R «; -OC(0)NR a R b ; -NRaC(0)NR°R ⁇ -NR"C0 2 R h ; -OC0 2 Rh; -NR a C(0)R D ; -C 1 - 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;
  • 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' groups; or R D and R taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one to three of O, S, NR a , with R a as defined above, or -C(O)-, said ring being unsubstituted or substituted with one to four R' groups;
  • each R d independently represents halo; -CN; -N0 2 ; -NReR f ; -OR g ; -SR g ; -CONR e R'; -COOR g ; -SOR g ; -S0 2 Rs; - S0 2 NReRf; -NR e S0 2 R f ; -COR ⁇ ; -NR ⁇ CORf; -OCOR e ; -OCONR e R f ; -NReCONRfRg; -NReC0 2 R h ; -OC0 2 R h ; -C(NRe)NRfRs; .
  • R c , R f and Re represent hydrogen; -R*; -Ci - 6 straight- or branched-chain alkyl unsubstituted or substituted with one to four R' groups; or R e and R f taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one to three of O, S, -C(O)- or NR g with Rg as defined above, said ring being unsubstituted or substituted with one to four R' groups;
  • each R' independently represents halo; -CN; -NO2; phenyl; -NHS ⁇ 2R h ; -OR h , -SRh; -N(Rh) 2 ; -N+(Rh) 3 ; -C(0)N(R h ) 2 ; -S ⁇ 2N(Rh) 2 ; heteroaryl; heteroarylium; -C0 2 R h ; -C(0)Rh; -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 O, S, SO2, -C(O)-, NH and NCH3;
  • Q is selected from the group consisting of: R x R y R'
  • 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 , 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 + R k ;
  • each R m independently represents a member selected from the group consisting of: hydrogen; halo; -CN; -N0 2 ; -NR n R°; -OR”; -SR"; -CONR « R°; -COOR h ; -SOR"; -S0 2 R”; -S0 2 NR"R°; -NR"S0 2 R°; -COR”; -NR"COR « ; -OCOR”; -OCONR n R » ; -NR n C0 2 R h ; -NR n CONR°R h ; -OC0 2 R h ; -CNR"NRoRi>; -NR"CNHNR»R b ; -NR n C(NR°)R h ; -Ci-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R' groups; -C3-7 cycloalky
  • each R s independently represents hydrogen; phenyl or -C]-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"; -CONR"R v ; -COOR h ; -SOR"; -S0 2 R u ; -S0 2 NR"R v ; -NR"S0 2 R v ; -COR"; -NR"COR v ; -OCOR”; -OCONR"R v ; -NR"C0 2 R v ; -NR"CONR*R w ; -OC0 2 Rv; -Ci-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R' groups;
  • R u and R v represent hydrogen or -Cj .fi 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 W or -C(O)-, said ring being unsubstituted or substituted with one to four R j groups;
  • each R independently represents hydrogen; -Cl _6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R J 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 R n and R w taken together with any intervening atoms represent a 5-6 membered saturated ring, optionally interrupted by one or two of O, S, SO2, NH or NCH3; R x represents hydrogen or a Ci -8 straight- or branched- chain alkyl, optionally interrupted by one or two of O, S, SO, S02, NR W , N+R h R w , or -C(O)-, said chain being unsubstituted or substituted with one to four of halo, CN, N ⁇ 2, OR , SR , SORw, S02R W , NRh
  • R and R z represent hydrogen; phenyl; -Ci-6 straight or branched chain alkyl, unsubstituted or substituted with one to four R' groups, and optionally interrupted by O, S, NR , N + R h R w or -C(O)-; or R x and R y together with any intervening atoms represent a 4-8 membered saturated ring optionally interrupted by O, S, SO2, NR W , N + R h R w or -C(O)-, unsubstituted or substituted with 1 - 4 R 1 groups, and when R x and R together represent a 4-6 membered ring as defined above, R z is as defined above or R 7 represents an additional saturated 4-8 membered ring fused to the ring represented by R x and Ry taken together, optionally interrupted by O, S, NR or -C(O)-, said rings being unsubstituted or substituted with one to four R' groups.
  • 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 R d 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 three such rings being present, containing up to 14 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 (triazolyl) pyrazole (pyrazolyl) isoxazole (isoxazolyl) isothiazole (isothiazolyl) pyridine (pyridinyl) pyrazme
  • Heteroarylium refers to heteroaryl groups bearing a quaternary nitrogen atom and thus a positive charge. Examples include the following:
  • heterocycloalkyl refers to a cycloalkyl group (nonaromatic) in which one of the carbon atoms in the ring is replaced by a heteroatom selected from O, S or N, and in which up to three additional carbon atoms may be replaced by hetero atoms.
  • quaternary nitrogen and “positive charge” refer to tetravalent, positively charged nitrogen atoms including, e.g., the positively charged nitrogen in a tetraalkyl- ammonium group (e. g. tetramethyl ammonium), heteroarylium, (e.g., N-methylpyridinium), basic nitrogens which are protonated at physiological pH, and the like.
  • Cationic groups thus encompass positively charged nitrogen-containing groups, as well as basic nitrogens which are protonated at physiologic pH.
  • 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.
  • Ureido means the group -NHC(0)NH2, the hydrogens of which may be replaced with alkyl groups.
  • Guanidinyl means the group -NHC(NH)NH2, the hydrogens of which may be replaced with alkyl groups.
  • Carbamimidoyl means the group -C(NH)NH2, the hydrogens of which may be replaced with alkyl groups. When a group is termed "substituted”, unless otherwise indicated, this means that the group contains from 1 to 4 substituents thereon. With respect to R, Ra, Rb and 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 R' groups. With respect to 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 hydroxyl- protecting group.
  • Such conventional protecting groups consist of known groups which are used to protectively block the hydroxyl or carboxyl group during the synthesis procedures described herein.
  • These conventional blocking groups are readily removable, i.e., they can be removed, if desired, by procedures which will not cause cleavage or other disruption of the remaining portions of the molecule.
  • Such procedures include chemical and enzymatic hydrolysis, treatment with chemical reducing or oxidizing agents under mild conditions, treatment with a transition metal catalyst and a nucleophile and catalytic hydrogenation.
  • carboxyl protecting groups include allyl, benzhydryl, 2-naphthylmethyl, benzyl, silyl such as t-butyldimethylsilyl (TBDMS), phenacyl, p-methoxybenzyl, o-nitrobenzyl, p-methoxyphenyl, p-nitrobenzyl, 4-pyridylmethyl and t-butyl.
  • C-6 hydroxyethyl protecting groups examples include triethylsilyl, t-butyldimethylsilyl, o-nitrobenzy loxycarbonyl, p-nitrobenzyloxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, t-buty loxycarbonyl, 2,2,2-trichloroethy loxycarbonyl and the like.
  • the carbapenem compounds of the present invention are useful per se and in their pharmaceutically acceptable salt and ester forms for the treatment of bacterial infections in animal and human subjects.
  • pharmaceutically acceptable ester, salt or hydrate refers to those salts, esters and hydrated forms of the compounds of the present invention which would be apparent to the pharmaceutical chemist, i.e., those which are substantially non-toxic and which may favorably affect the pharmacokinetic properties of said compounds, such as palatability, absorption, distribution, metabolism and excretion.
  • Other factors, more practical in nature, which are also important in the selection are cost of the raw materials, ease of crystallization, yield, stability, solubility, hygroscopicity and flowability of the resulting bulk drug.
  • pharmaceutical compositions may be prepared from the active ingredients in combination with pharmaceutically acceptable carriers.
  • the present invention is also concerned with pharmaceutical compositions and methods of treating bacterial infections utilizing as an active ingredient the novel carbapenem compounds.
  • -CO2M which is attached to the carbapenem nucleus at position 3, this represents a carboxylic acid group (M represents H), a carboxylate anion (M represents a negative charge), a pharmaceutically acceptable ester (M represents an ester forming group) or a carboxylic acid protected by a protecting group (M represents a carboxyl protecting group).
  • the pharmaceutically acceptable salts referred to above may take the form -COOM, where M is a negative charge, which is balanced by a counterion, e.g., an alkali metal cation such as sodium or potassium.
  • Counterions may be calcium, magnesium, zinc, ammonium, or alkylammonium cations such as tetramethylammonium, tetrabutylammonium, choline, triethylhydroammonium, meglumine, triethanolhydroammonium, etc.
  • the pharmaceutically acceptable salts referred to above also include acid addition salts.
  • the Formula I compounds can be used in the form of salts derived from inorganic or organic acids. Included among such salts are the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesuIfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate
  • the pharmaceutically acceptable esters are such as would be readily apparent to a medicinal chemist, and include, for example, those described in detail in U.S. Pat. No. 4,309,438. Included within such pharmaceutically acceptable esters are those which are hydrolyzed under physiological conditions, such as pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, and others described in detail in U.S. Pat. No. 4,479,947. These are also referred to as "biolabile esters”. Biolabile esters are biologically hydrolizable, and may be suitable for oral administration, due to good absorption through the stomach or intenstinal mucosa, resistance to gastric acid degradation and other factors.
  • biolabile esters include compounds in which M represents an alkoxyalkyl, alkylcarbonyloxyalkyl, alkoxycarbonyloxyalkyl, cycloalkoxyalkyl, alkenyloxyalkyl, aryloxyalkyl, alkoxyaryl, alkylthioalkyl, cycloalkylthioalkyl, alkenylthioalkyl, arylthioalkyl or alkylthioaryl group. These groups can be substituted in the alkyl or aryl portions thereof with acyl or halo groups.
  • M species are examples of biolabile ester forming moieties.: acetoxymethyl, 1 -acetoxyethyl, 1 -acetoxypropyl, pivaloyloxymethyl, 1 -isopropyloxycarbonyloxyethyl, 1 -cyclohexyloxycarbonyloxyethyl, phthalidyl and (2-oxo- 5-methyl-l ,3-dioxolen-4-yl)methyl.
  • L can be present or absent as necessary to maintain the appropriate charge balance. When present, L- represents a pharmaceutically acceptable counterion. Most anions derived from inorganic or organic acids are suitable.
  • counterions are the following: acetate, adipate, aminosalicylate, anhydromethylenecitrate, ascorbate, aspartate, benzoate, benzenesulfonate, bromide, citrate, camphorate, camphorsulfonate, chloride, estolate, ethanesulfonate, fumarate, glucoheptanoate, gluconate, glutamate, lactobionate, malate, maleate, mandelate, methanesulfonate, pantothenate, pectinate, phosphate/diphosphate, polygalacturonate, propionate, salicylate, stearate, succinate, sulfate, tartrate and tosylate.
  • suitable anionic species will be apparent to the ordinarily skilled chemist.
  • L ⁇ represents a specie with more than one negative charge, such as malonate, tartrate or ethylene- diaminetetraacetate (EDTA)
  • EDTA ethylene- diaminetetraacetate
  • a subset of compounds that is of particular interest includes compounds of formula I which contain at least one positively charged moiety.
  • the ring formed by AB, BC or CD is positively charged, or at least one R contains a positive charge.
  • all other variables are as previously defined.
  • Another subset of compounds of the invention which is of interest relates to compounds where AB taken together represent an aryl, heteroaryl or heteroarylium ring, and C and D represent hydrogen atoms.
  • AB taken together represent an aryl or heteroaryl ring.
  • all other variables are as originally defined.
  • Another subset of compounds of the invention which is of interest relates to compounds where BC taken together represent an aryl, heteroaryl or heteroarylium ring, and A and D represent hydrogen atoms. In particular, BC taken together represent an aryl or heteroaryl ring. Within this subset of compounds, all other variables are as originally defined.
  • Another subset of compounds of the invention which is of interest relates to compounds where CD taken together represent an aryl, heteroaryl or heteroarylium ring, and A and B represent hydrogen atoms. In particular, CD taken together represent an aryl or heteroaryl ring. Within this subset of compounds, all other variables are as originally defined.
  • Another subset of compounds of formula I which is of interest relates to compounds of formula I wherein one R represents a group which contains a positively charged moiety, and the remaining R groups are selected from hydrogen and C ⁇ _ 6 straight or branched chain alkyl, unsubstituted or substituted with one to four R d groups. More particularly, this subset of interest includes compounds of formula I 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.
  • Another subset of compounds which is of interest is represented by formula I wherein one R group represents a -C ⁇ _ 6 straight or branched chain alkyl group, substituted with one to four R d groups, wherein one R d group represents -R* or Q. Hence, a positively charged moiety -R* or Q is attached to an alkyl group.
  • Another group of compounds of interest is represented by formula I wherein Q is selected from the group consisting of:
  • 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 by one or two of O, S, SO, S ⁇ 2, NR , N+RhRw, or -C(O)-, said chain being unsubstituted or substituted with one to four of halo, CN, N02, ORw, SR W , SOR w , S ⁇ 2R , NR Rw, N+(Rh) 2 Rw, -C(0)-R w , C(0)NRhRw, S02NR RW, C ⁇ 2R w , OC(0)Rw, OC(0)NRhRW 5 NRhC(0)Rw, or a phenyl or heteroaryl group which is in turn optionally substituted with from one to four R 1 groups or with one to two Cl -3 straight- or branched
  • 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.
  • Another subset of compounds of the invention which is of interest relates to those compounds where CO2M represents a carboxylate anion.
  • M in this instance represents a negative charge which is 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.
  • a preferred subset of compounds of formula I which is of particular interest relates to compounds represented by formula I wherein:
  • AB represents an aryl, heteroaryl or heteroarylium group, and C and D represent R groups;
  • CO2M represents a carboxylate anion; one R group which is attached to the sulfonamide containing ring system contains at least one positively charged moiety, and the remaining R groups are selected from hydrogen and straight or branched chain alkyl, unsubstituted or substituted with one to four R d groups; Rd is as originally defined; R n represents hydrogen or a Ci -6 straight or branched chain alkyl group; 0 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 Rw, or -C(O)-, said chain being unsubstituted or substituted with one to four of halo, CN, N02, ORw, SRw, SORw, S ⁇ 2R w , NRhR , N+(Rh)2RW, -C(0)-Rw, C(0)NRhRw, S ⁇ 2NRhRw, C ⁇ 2R w ,
  • 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 contains a positively charged moiety, and the other R groups are selected from hydrogen and Ci-6 straight or branched chain alkyl, unsubstituted or substituted with one to four Rd groups
  • Rd is as originally defined;
  • 0 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+RhRw ?
  • R* is selected from:
  • R x , a, b and L- are as originally defined.
  • CO2M represents a carboxylate anion
  • one R group contains a positively charged moiety, and the other R groups are selected from hydrogen and Ci- straight or branched chain alkyl, unsubstituted or substituted with one to four R d groups
  • Rd 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, S ⁇ 2, NRw, N+RhR , or -C(O)-, said chain being unsubstituted or substituted with one to four of halo, CN, N02, ORw, SRw, SORw, S ⁇ 2R w , NRhRw, N+(Rh)2Rw, -C(0)-R , C(0)NRhRw, S ⁇ 2NRhR ?
  • R w is as originally defined; R* is selected from:
  • R x , a, b and L ⁇ are as originally defined.
  • Representative examples of compounds of the invention are as follows:
  • the compounds of the present invention are prepared by reacting a suitably protected, activated 2-hydroxymethyl- carbapen-2-em-3 -carboxylate with a naphthosultam, modifying the thus-introduced side chain as desired, and then removing any protecting groups which are present to afford the desired final product.
  • the process is illustrated by the following generic scheme: SCHEME 1
  • P, R 1 , R and M are as defined with respect to the compounds of formula I.
  • P** represents a hydroxyl protecting group.
  • One of A, B, C and D, or a group which is attached to the ring represented by AB, BC or CD contains a group (e.g., OH) which can be converted into an appropriate leaving group.
  • the chain to which the leaving group is attached can be varied within wide limits to include all other values of R which form a bridge between the cyclic sulfonamide aryl platform and the quaternary group.
  • the cyclic sulfonamide platform is formed with the leaving group precursor in place, producing 4, which can be converted to the dihydro compound 5.
  • one of A, B, C and D represents a quaternary or quaternizable R group in the compounds of the invention, it can be attached from the outset.
  • one of A, B, C and D would represent a group which contains 0 or a precursor of 0-
  • Two of the other variables represent a fused ring in combination.
  • the cyclic sulfonamide is reacted with a protected carbapen-2-em-3-carboxylate having an activated hydroxymethyl group at the 2-position, via a Mitsunobu reaction between the cyclic sulfonamide and the carbapenem alcohol.
  • the carbapenem nucleus having a -CH2OH substituent at position 2 can be obtained in accordance with Schmitt, S. M. et al., J. Antibiotics 41(6): 780-787 (1988), the teachings of which are incorporated herein by reference.
  • the carboxylic acid group at C-3 of the carbapenem is generally protected as a carboxyl protecting group such as p-nitrobenzyl (PNB), allyl, p-methoxybenzyl, trichloroethyl, 2-trimethylsilylethyl, and the like.
  • hydroxyl group of the 6-(hydroxyethyI) side-chain is protected with a hydroxyl protecting group such as trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), tert- butyldiphenylsilyl (TBDPS), acetyl, allyloxycarbonyl, 2-trimethylsilylethoxy carbonyl, 2-trichloroethoxycarbonyl and the like.
  • TMS trimethylsilyl
  • TES triethylsilyl
  • TDMS tert-butyldimethylsilyl
  • TDPS tert- butyldiphenylsilyl
  • acetyl allyloxycarbonyl, 2-trimethylsilylethoxy carbonyl, 2-trichloroethoxycarbonyl and the like.
  • Addition of the cyclic sulfonamide to the carbapenem is accomplished by treating a solution of the hydroxymethyl- carbapenem and the cyclic sulfonamide in a suitable solvent such as tetrahydrofuran (THF), ether, acetonitrile, dimethylformamide (DMF), benzene, dimethylsulfoxide (DMSO), and the like with a (premixed) suitable activating reagent such as diethyl azodicarboxylate (DEAD) / triphenylphosphine, diisopropyl azodicarboxylate (DIAD) / tributylphosphine, and the like, at a temperature between about -20 °C and 35 °C for about 5 to 90 minutes.
  • a suitable solvent such as tetrahydrofuran (THF), ether, acetonitrile, dimethylformamide (DMF), benzene, dimethylsulfoxide (DMSO),
  • the side chain component and the carbapenem can be mixed together with either the azodicarboxylate or the phosphine reagent in a suitable solvent and the other component of the activating reagent (the phosphine or the azodicarboxylate, respectively) can be added to that mixture.
  • the reaction is allowed to proceed at a temperature between about -20°C and 35°C for about 5 to 90 minutes.
  • the resulting mixture is then subjected to a standard work-up procedure familiar to those skilled in the art to afford a crude 2-methyl substituted carbapenem which is purified, if necessary, by recry tall ization or by chromatography on silica gel, eluting with a suitable solvent or mixture of two or more solvents, such as hexane, ethyl acetate, ether, benzene, dichloromethane, chloroform, acetone, methanol and the like.
  • a suitable solvent or mixture of two or more solvents such as hexane, ethyl acetate, ether, benzene, dichloromethane, chloroform, acetone, methanol and the like.
  • Modification of the side chain of compounds 6 or 7 is generally necessary to introduce the charged substituent Q-
  • Q represents a group which is positively charged. Quaternization is best accomplished before removal of the protecting groups.
  • a positively charged substituent may be introduced into the side chain by first activating the hydroxyl group by converting it to a suitable leaving group such as a triflate, mesylate, tosylate, iodide, chloride, bromide, and the like, and then displacing the resulting leaving group with a quaternary compound, such as N-methyl-imidazole, N-(2-hydroxyethyl)-imidazole, N-methyl-diazabicyclooctane, l -(carbamoylmethyl)-4-aza-l - azoniabicyclo-[2.2.2.]-octane, 1 -(3-hydroxyprop- 1 -yl)-4-aza- l -azoniabicyclo-[2.2.2.]-octane, pyridine, morpholine and the like which contains a nitrogen atom that can act as a nucleophile
  • a suitable leaving group such as a triflate
  • the charged substituent may be incorporated in the side chain before addition of the sulfonamide to the carbapenem or may be introduced after deprotection.
  • introduction of the charged substituent by modification before deprotection as in Scheme 4 is greatly preferred.
  • Conversion of the hydroxyl group to a suitable leaving group is accomplished by treating the hydroxyl substituted compound in a suitable solvent such as dichloromethane, tetrahydrofuran, ether, benzene, and the like with an activating reagent, such as trifluoro- methanesulfonic anhydride, methanesulfonic anhydride, toluenesulfonic anhydride, methanesulfonyl chloride, benzenesulfonyl chloride, toluenesulfonyl chloride, and the like in the presence of a suitable base such as triethylamine, tributylamine, diisopropylethylamine, and the like at a temperature between about -100°C and 0°C for about 5 to 120 minutes.
  • a suitable solvent such as dichloromethane, tetrahydrofuran, ether, benzene, and the like
  • an activating reagent 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 at about -10°C to 50°C with an excess of sodium iodide or potassium iodide for about 0.25 to 24 hours.
  • the iodide is obtained in sufficiently pure form that it may be used without further purification.
  • the iodide if not crystalline, may be lyophilized from benzene to afford an amorphous, easily handled, solid.
  • the activated hydroxyl group or iodide is displaced by reacting the activated intermediate with reagent 0*.
  • Q* represents a group which reacts with an activated intermediate in a manner which results in the incorporation in the product of a member of the group defined as Q above. Thus, Q* may be viewed as a precursor of Q.
  • activation and displacement of the hydroxyl group may be accomplished in a single step.
  • the activating reagent is added to a solution of the hydroxyl substituted compound in the presence of a suitable base in a suitable solvent such as dichloromethane, tetrahydrofuran, ether, DMF, benzene, acetonitrile, DMSO, and the like as described in the preceding paragraphs.
  • the resulting activated intermediate is treated with 1 -3 molar equivalents of compound 0* a a temperature between about -78°C and 50°C for about 15 to 120 minutes, hi some cases, it is desirable to form the activated intermediate in one solvent, isolate the activated intermediate, and conduct the displacement reaction in a different solvent. In other cases, the displacement may be conducted without isolation of the intermediate and, in cases where Q* is also used as a base, may even be concurrent with the formation of the activated intermediate.
  • a solution of the iodide is combined with an approximately equivalent amount (0.9 - 1.05 molar equivalents) of compound O*-
  • a silver salt of a non- nucleophilic acid such as silver trifluoromethanesulfonate, silver tetrafluoroborate and the like is then added.
  • the reaction will proceed in the absence of the silver salt, the reaction proceeds more rapidly in the presence of the silver salt.
  • the silver salt assists in the removal of the displaced iodide from the reaction mixture which can improve the efficiency of subsequent steps.
  • the resulting mixture is then subjected to a standard work -up procedure familiar to those skilled in the art to afford a crude product which is purified, if necessary, by recrystallization or chromatography.
  • An alternative method for introducing a positive charge into the side chain may be applied to side chains that contain a nitrogen atom which may be quatemized by reaction with a suitable alkylating reagent, such as methyl iodide, methyl bromide, benzyl trichloroacetimidate, methyl trifluoromethanesulfonate, triethyloxonium tetrafluoroborate, and the like. Quaternization of the nitrogen atom in the side chain is effected by treating a solution of the compound with a slight excess (1.05 to 1.2 molar equivalents) of the alkylating reagent.
  • the synthesis of the target compound is completed by removing any protecting groups which are present in the penultimate intermediate using standard techniques 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. This is shown in Scheme 4.
  • the final product may be characterized structurally by standard techniques such as NMR, IR, MS, and UV. For ease of handling, the final product, if not crystalline, may be lyophilized from water to afford an amorphous, easily handled solid.
  • the compounds of the present invention are valuable antibacterial agents active against various Gram-positive and to a lesser extent Gram-negative bacteria, and accordingly find utility in human and veterinary medicine.
  • 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 compositions may utilize carriers such as conventional formulating agents, and may include sustained release properties as well as rapid delivery forms.
  • the dosage to be administered depends to a large extent upon the condition and size of the subject being treated, the route and frequency of administration, the sensitivity of the pathogen to the particular compound selected, the virulence of the infection and other factors. Such matters, however, are left to the routine discretion of the physician according to principles of treatment well known in the antibacterial arts. Another factor influencing the precise dosage regimen, apart from the nature of the infection and peculiar identity of the individual being treated, is the molecular weight of the compound.
  • compositions for human delivery per unit dosage may contain from about 0.01 % to as high as about 99% of active material, the preferred range being from about 10-60%.
  • the composition will generally contain from about 15 mg to about 2.5 g of the active ingredient; however, in general, it is preferable to employ dosage amounts in the range of from about 250 mg to 1000 mg.
  • the unit dosage will typically include the pure compound in sterile water solution or in the form of a soluble powder intended for solution, which can be adjusted to neutral pH and isotonic.
  • the invention described herein also includes a method of treating a bacterial infection in a mammal in need of such treatment comprising administering to said mammal a compound of formula I in an amount effective to treat said infection.
  • the preferred methods of administration of the Formula I antibacterial compounds include oral and parenteral, e.g., i.v. infusion, i.v. bolus and i.m. injection.
  • 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 Patent Application Nos. 79102616.4, filed July 24, 1979 (Patent No. 0 007 614); and 82107174.3, filed August 9, 1982 (Publication No. 0 072 014)] .
  • 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.
  • NAPHTHALENE- 1 -CARBOXYLIC ACID DIETHYLAMIDE To 1 -Naphthoic acid (1.72 g, 10 mmol) dissolved in methylene chloride (30 ml) and cooled to 0°C, was added dropwise, oxallyl chloride (1.75 ml, 20 mmol) followed by DMF (0.1 ml). The mixture was allowed to stir at 0°C for 0.5 hr., the ice bath was removed and stirring was continued for another 45 min. when reaction appeared to be complete. The solvent was removed under reduced pressure and the residue was treated with toluene (10 ml) and evaporated to dryness and the process was repeated to give the acid chloride.
  • Hydroxylamine-O-sulfonic acid ( 1.36 g, 12 mmol) was dissolved in water (8 ml) and cooled to 0°C.
  • NaOH 2.4 ml, 5N soln..
  • the two solutions were mixed and added to the solution of the sodium salt.
  • the ice bath was removed and the reaction mixture was stirred at room temperature for 6 hr.
  • the solvent was evaporated to remove most of the EtOH and the residue was extracted with EtOAc.
  • the organic phase was washed with water and satd. NaCl solution, dried over MgS04 and evaporated to give the crude product.
  • Example 1 3,3-dioxo-2,3-dihydro-3-thia-2-aza- cyclopenta[ ⁇ ]na ⁇ htalene-l -one from Step 3,
  • Example 1 (0.150 g, 0.64 mmol) was dissolved in EtOH (3 ml) cone.
  • HCl 0.5 ml
  • zinc dust (0.420 g, 6.4 mmol) was added in 4 equal portions over 25 min. Reaction mixture was allowed to stir for another 5 min. The reaction mixture was evaporated to dryness, the residue was taken up in EtOAc and washed with water, and satd. NaCl soln.., dried over MgS ⁇ 4 to give the product.
  • Step 3 1.1 -DIOXO- 1 ,2-DIH YDRO- 1 -THI A-2- AZA- CYCLOPENTA fllNAPHTALENE-3-ONE l -sulfamoyl-naphthalene-2-carboxylic acid diethylamide from Step 2 is taken through the procedure described in Step 3, Example 1 to give the title compound.
  • Example 3 Following the procedure of Step 5, Example 1 , the product of Step 4, Example 3 is deblocked to give the title compound.
  • Example 4 Following the procedure of Step 5, Example 1 , the product of Step 2, Example 4 is deblocked to give the title compound.
  • Example 5 1 -bromomethylnaphthalene-4-carboxylic acid diethylamide from Step 3, Example 5 was dissolved in DMF (2 ml), potassium acetate (0.196 g, 2 mmol) was added and the reaction was heated at 100°C under nitrogen for 1 hr. The reaction was cooled to room temperature and diluted with ether and washed with water 5 times followed by satd. NaCl soln.., dried over MgS04 and evaporated to give the title compound.
  • Example 5 1 -acetoxymethylnaphthalene-4-carboxylic acid diethylamide from Step 4, Example 5 was dissolved in MeOH (5 ml). A solution of NaOMe in MeOH (0.150 ml, I M) was added and the reaction allowed to stir at room temperature for 1.5 hr.. Acetic acid (0.015 ml was added and the solvent was removed under reduced pressure. The residue was taken up in EtOAc and washed with water and satd. NaCl soln., dried over MgS ⁇ 4 and evaporated to give the crude alcohol. Chromatography on silica gel plates, eluted with 50%
  • Example 1 1 - triethylsilyloxymethyl-3-sulfamoyinaphthalene-4-carboxylic acid diethylamide is converted to the title compound.
  • the triethylsilyloxy protecting group is concomitantly removed in this step.
  • the organic phase is dried over MgS04 and evaporated to give the mesylate.
  • the mesylate is dissolved in acetone (2 ml) and sodium iodide (5 eq.) is added and the mixture is stirred at room temperature for 75 min.
  • the reaction is partitioned between water and methylene chloride and the organic phase is washed with 5% aqueous NaHS03, dried over MgS ⁇ 4 and evaporated to give the title compound.
  • Example 6 is converted to the title compound by following the procedure of Step 1 1 , Example 5.

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Abstract

L'invention porte sur agents antibactériens de carbapenem dans lesquels le noyau carbapenem est substitué en position 2- par un système cyclique contenant une sulfonamide, lié au noyau carbapenem par un groupe CH2. Les composés et leurs sels pharmacocompatibles sont représentés par la formule (I) dans laquelle: R1 représente H ou méthyle; CO¿2?M représente un acide carboxylique, un anion carboxylate, un groupe ester pharmacocompatible ou un acide carboxylique protégé par un groupe protecteur; P représente H, hydroxyle, F ou hydroxyle protégé par un groupe protecteur; X?1 et X2¿ représentent H, ou X1 et X2 pris ensemble représentent un groupe carbonyle; et l'un des AB, BC et CD représente un aryle fusionné, un hétéroaryle, ou un cycle hétéroarylique, et les autres variables représentent R, lesdits aryle fusionné, hétéroaryle, ou cycle hétéroarylique étant substitués par des groupes 1-4 R. L'invention porte également sur des préparations pharmaceutiques les contenant et leurs méthodes d'utilisation.
PCT/US1997/015831 1996-09-12 1997-09-08 Compositions antibacteriennes de carbapenem, preparations les contenant et methodes de traitement WO1998011108A1 (fr)

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JP10513746A JP2001500862A (ja) 1996-09-12 1997-09-08 カルバペネム系抗菌化合物、該化合物を含む組成物および治療方法
CA002264147A CA2264147A1 (fr) 1996-09-12 1997-09-08 Compositions antibacteriennes de carbapenem, preparations les contenant et methodes de traitement
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WO1999067241A1 (fr) * 1998-06-25 1999-12-29 Merck & Co., Inc. Antibacteriens de carbapenem (heterocycliques) substitues par methyle
WO1999067240A1 (fr) * 1998-06-25 1999-12-29 Merck & Co., Inc. Antibacteriens a base de carbapenem a substitution methyle (heterocyclique)
US7378427B2 (en) 2004-06-18 2008-05-27 Wyeth Processes for preparing 6-alkyl-5-arylsulfonyl-dihydrophenanthridines
CN110156637A (zh) * 2019-06-18 2019-08-23 宁波美诺华药业股份有限公司 一种2,4-二氯-3-氰基-5-氟苯甲酸的制备方法

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US5336674A (en) * 1993-01-27 1994-08-09 Merck & Co., Inc. 2-phenanthridinyl carbaphenem antibacterial agent

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EP0463852A3 (en) * 1990-06-26 1992-08-05 Merck & Co. Inc. 2-phenanthrenyl-carbapenem antibacterial agents
IL98911A0 (en) * 1990-08-01 1992-07-15 Merck & Co Inc 2-(9-fluorenonyl)-carbapenems and pharmaceutical compositions containing them
US5374630A (en) * 1993-06-10 1994-12-20 Merck & Co., Inc. Bridged carbapenem antibacterial compounds
US5451579A (en) * 1994-02-15 1995-09-19 Merck & Co., Inc. 1-β-methyl-carbapenem, compositions containing same and methods of use
US5498777A (en) * 1994-07-20 1996-03-12 Merck & Co., Inc. 3-thioheteroaryl cephalosporin compounds, compositions and methods of use

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US5336674A (en) * 1993-01-27 1994-08-09 Merck & Co., Inc. 2-phenanthridinyl carbaphenem antibacterial agent

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999067241A1 (fr) * 1998-06-25 1999-12-29 Merck & Co., Inc. Antibacteriens de carbapenem (heterocycliques) substitues par methyle
WO1999067240A1 (fr) * 1998-06-25 1999-12-29 Merck & Co., Inc. Antibacteriens a base de carbapenem a substitution methyle (heterocyclique)
EP1089999A1 (fr) * 1998-06-25 2001-04-11 Merck & Co., Inc. Antibacteriens de carbapenem (heterocycliques) substitues par methyle
US6291448B1 (en) * 1998-06-25 2001-09-18 Merck & Co., Inc. Carbapenem antibacterial compounds, compositions containing such compounds and method of treatment
EP1089999A4 (fr) * 1998-06-25 2002-12-04 Merck & Co Inc Antibacteriens de carbapenem (heterocycliques) substitues par methyle
US7378427B2 (en) 2004-06-18 2008-05-27 Wyeth Processes for preparing 6-alkyl-5-arylsulfonyl-dihydrophenanthridines
CN110156637A (zh) * 2019-06-18 2019-08-23 宁波美诺华药业股份有限公司 一种2,4-二氯-3-氰基-5-氟苯甲酸的制备方法

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