EP1015453A1 - Antibacteriens du type 3-(iodophenoxymethyl) carbapenem - Google Patents

Antibacteriens du type 3-(iodophenoxymethyl) carbapenem

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Publication number
EP1015453A1
EP1015453A1 EP98944779A EP98944779A EP1015453A1 EP 1015453 A1 EP1015453 A1 EP 1015453A1 EP 98944779 A EP98944779 A EP 98944779A EP 98944779 A EP98944779 A EP 98944779A EP 1015453 A1 EP1015453 A1 EP 1015453A1
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EP
European Patent Office
Prior art keywords
groups
compound
substituted
accordance
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP98944779A
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German (de)
English (en)
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EP1015453A4 (fr
Inventor
Frank P. Dininno
Kevin D. Dykstra
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Merck and Co Inc
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Merck and Co Inc
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Priority claimed from GBGB9815806.6A external-priority patent/GB9815806D0/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP1015453A1 publication Critical patent/EP1015453A1/fr
Publication of EP1015453A4 publication Critical patent/EP1015453A4/fr
Withdrawn legal-status Critical Current

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Classifications

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

Definitions

  • the present invention relates to carbapenem antibacterial agents in which the carbapenem nucleus is substituted at the 2-position with an iodo-substituted phenyl linked through a CH2-O- group.
  • the iodo-substituted phenyl ring is further substituted with various substituent groups including at least one cationic group.
  • the carbapenems of the present invention are useful against gram positive microorganisms, especially methicillin resistant Staphylococcus aureus (MRSA), methicillin resistant Staphylococcus epidermidis (MRSE), and methicillin resistant coagulase negative
  • MRCNS Staphylococci
  • MRSA/MRCNS agents effective against such pathogens
  • 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 hydroxyl-protecting group
  • A represents O, S or -CH 2 - attached at position 3, 4 or 5;
  • n an integer 0-3;
  • Q is selected from the group consisting of:
  • a and b are 1, 2 or 3;
  • L- is a pharmaceutically acceptable counterion; ⁇ represents O, S or NR S ; ⁇ , ⁇ , ⁇ , ⁇ and ⁇ represent CR t , N or N+R s , provided that no more than one of ⁇ , ⁇ , ⁇ , ⁇ and ⁇ is N+R s balanced by L , as defined above;
  • each R s independently represents hydrogen; phenyl or
  • each R l independently represents hydrogen; halo; phenyl; -CN; -N0 2 ; -NR U R V ; -OR"; -SR"; -CONR"R v ; -COORh; -SOR”; -S0 2 R u ; -S0 2 NR"Rz -NR"S0 2 R v ; -COR”; -NR"COR v ; -OCOR u ; -OCONR ⁇ Rz -NR"C0 2 R v ; -NR"CONR v R w ; -OC0 2 R v ; -Ci-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R> groups;
  • each R> independently represents halo; -CN; -NO2; phenyl; -NHS0 2 R h ; -ORh, -SR h ; -N(Rh) 2 ; -N+(Rh) 3 ; -C(0)N(Rh) 2 ; -S ⁇ 2N(R h ) 2 ; heteroaryl; heteroarylium; -C ⁇ 2R h ; -C(0)R h ; -OCOR h ; -NHCORh; guanidinyl; carbamimidoyl or ureido;
  • each Rh independently represents hydrogen, a -Ci-6 straight or branched-chain alkyl group, a -C 3 -C5 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
  • R u and R v represent hydrogen or -Ci-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R> groups; or R u and R v together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one or more of O, S, NR W or -C(O)-, said ring being unsubstituted or substituted with one to four R> groups;
  • each R w independently represents hydrogen; -Cl-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R 1 groups; C3-.5 cycloalkyl optionally substituted with one to four R 1 groups; phenyl optionally substituted with one to four R 1 groups, or heteroaryl optionally substituted with 1-4 Ri groups; or Rh and R taken together with any intervening atoms represent a 5-6 membered saturated ring, optionally interrupted by one or two of O, S, S02, NH or NCH3;
  • R x represents hydrogen or a Cl-8 straight- or branched- chain alkyl, optionally interrupted by one or two of O, S, SO, S ⁇ 2, 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 W , SOR , S ⁇ 2R w , NRhR W , N+(Rh)2R w , -C(0)-Rw, C(0)NRhR ,
  • Ry and R z represent hydrogen; phenyl; -Ci-6 straight or branched chain alkyl, unsubstituted or substituted with one to four Ri groups, and optionally interrupted by O, S, NR W , N+R n R w or -C(O)-; or R x and R y together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by O, S, SO2, NR W , N+RhRw or -C(O)-, unsubstituted or substituted with 1 - 4 Ri groups, and when R x and RY together represent a 4-6 membered ring as defined above, R z is as defined above or R z represents an additional saturated 4-6 membered ring fused to the ring represented by R x and RY taken together, optionally interrupted by O, S, NR W or -C(O)-, said rings being unsubstituted or substituted with one to four R' groups.
  • compositions and methods of treatment are also included.
  • Carboxylate anion refers to a negatively charged group
  • 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 five such rings being present, containing up to 22 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms or suitable heteroatoms.
  • the preferred aryl groups are phenyl, naphthyl and phenanthrenyl.
  • Aryl groups may likewise be substituted as defined. Preferred substituted aryls include phenyl and naphthyl.
  • heteroaryl refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing at least one heteroatom, O, S or N, in which a carbon or nitrogen atom is the point of attachment, and in which one or two additional carbon atoms is optionally replaced by a heteroatom selected from O or S, and in which from 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms, said heteroaryl group being optionally substituted as described herein. Examples of this type are pyrrole, pyridine, oxazole, thiazole and oxazine.
  • Additional nitrogen atoms may be present together with the first nitrogen and oxygen or sulfur, giving, e.g., thiadiazole.
  • Examples include the following: pyrrole (pyrrolyl) imidazole (imidazolyl) thiazole (thiazolyl)
  • triazole triazole
  • pyrazole pyrazolyl
  • isoxazole isoxazole
  • isothiazole isothiazolyl pyridine (pyridinyl) pyrazine (pyrazinyl)
  • Heteroarylium refers to heteroaryl groups bearing a quaternary nitrogen atom and thus a positive charge. Examples include the following:
  • heterocycloalkyl refers to a cycloalkyl group (nonaromatic) in which one of the carbon atoms in the ring is replaced by a heteroatom selected from O, S or N, and in which up to three additional carbon atoms may be replaced by hetero atoms.
  • the terms “quaternary nitrogen” and “positive charge” refer to tetravalent, positively charged nitrogen atoms including, e.g., the positively charged nitrogen in a tetraalkylammonium group (e. g. tetramethylammonium), heteroarylium, (e.g., N-methyl- pyridinium), basic nitrogens which are protonated at physiological pH, and the like. Cationic groups thus encompass positively charged nitrogen-containing groups, as well as basic nitrogens which are protonated at physiologic pH.
  • heteroatom means O, S or N, selected on an independent basis.
  • Halogen and "halo" refer to bromine, chlorine, fluorine and iodine.
  • Alkoxy refers to C1-C4 alkyl-O-, with the alkyl group optionally substituted as described herein.
  • Guanidinyl refers to the group: H 2 NC(NH)NH-.
  • Carbamimidoyl refers to the group: H 2 NC(NH)-.
  • Ureido refers to the group: H 2 NC(0)NH-.
  • substituted unless otherwise indicated, this means that the group contains from 1 to 4 substituents thereon.
  • R R a , R b and R c
  • the substituents available on alkyl groups are selected from the values of R d .
  • Many of the variable groups are optionally substituted with up to four Ri groups.
  • R e , R f and RS when these variables represent substituted alkyl, the substituents available thereon are selected from the values of Ri.
  • 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 include triethylsilyl, t-butyldimethylsilyl, o-nitrobenzyl- oxycarbonyl, p-nitrobenzyloxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, t-butyloxycarbonyl, 2,2,2-trichloroethyloxy- carbonyl 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.
  • 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.
  • a counterion e.g., an alkali metal cation such as sodium or potassium.
  • Other pharmaceutically acceptable 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.
  • salts include the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate,
  • the pharmaceutically acceptable esters are such as would be readily apparent to a medicinal chemist, and include, for example, those described in detail in U.S. Pat. No. 4,309,438. Included within such pharmaceutically acceptable esters are those which are hydrolyzed under physiological conditions, such as pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, and others described in detail in U.S. Pat. No. 4,479,947. These are also referred to as "biolabile esters".
  • Biolabile esters are biologically hydrolizable, and may be suitable for oral administration, due to good absorption through the stomach or intestinal mucosa, resistance to gastric acid degradation and other factors.
  • biolabile esters include compounds in which M represents an alkoxyalkyl, alkylcarbonyloxyalkyl, alkoxycarbonyloxyalkyl, cycloalkoxyalkyl, alkenyloxyalkyl, aryloxyalkyl, alkoxyaryl, alkylthioalkyl, cycloalkylthioalkyl, alkenylthioalkyl, arylthioalkyl or alkylthioaryl group.
  • 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 ethylenediamine- tetraacetate (EDTA)
  • EDTA ethylenediamine- tetraacetate
  • At least one of the R groups attached to the phenyl ring contains a positively charged moiety.
  • R 1 represents methyl. Within this subset, all other variables are as originally defined.
  • M in this instance represents a negative charge which will be balanced by a positively charged group, such as in the positively charged R group.
  • a positively charged R group contains more than one positive charge
  • a negatively charged counterion may be present which in combination with the carboxylate anion, provides overall charge neutrality.
  • cc represents O, S or NR S ; and ⁇ , ⁇ , ⁇ , ⁇ and ⁇ represent CR 1 , N or N+R s , provided that no_more than one of ⁇ , ⁇ , ⁇ , ⁇ and ⁇ is N+R s , balanced by L which is a pharmaceutically acceptable counterion, and R s is as originally defined. Within this subset, all other variables are as originally defined.
  • a and b are 2; L" is a pharmaceutically acceptable counterion; and R , RY and R z are as originally defined. Within this subset, all other variables are as originally defined.
  • the compounds of the present invention are prepared by reacting a suitably protected, activated 2-hydroxymethyl-carbapen-2- em-3-carboxylate with an appropriately substituted phenyl ring, and then removing any protecting groups which are present to afford the desired final product.
  • the process is illustrated by the following generic scheme: FLOW SHEET A
  • R 3 represents three alkyl or aryl groups which in combination with the silyl group to which they are attached, form a hydroxyl protecting group.
  • Rl, A, Q and n are as defined with respect to the compounds of formula I.
  • the substituted phenyl side chain A2 is initially reacted with a suitably protected carbapen-2-em-3-carboxylate having an activated hydroxymethyl group at the 2-position.
  • the carbapenem nucleus having a -CH2OH substituent at position 2 can be obtained in accordance with Schmitt, S. M. et al., J. Antibiotics 41(6): 780-787 (1988), the teachings of which are incorporated herein by reference.
  • the carboxylic acid group at C-3 of the carbapenem is generally protected as a carboxyl protecting group such as p-nitrobenzyl (PNB), allyl, p-methoxybenzyl, trichloroethyl, 2-trimethylsilylethyl and the like.
  • PNB p-nitrobenzyl
  • allyl allyl
  • p-methoxybenzyl trichloroethyl
  • 2-trimethylsilylethyl 2-trimethylsilylethyl and the like.
  • hydroxyl group of the 6- (hydroxy ethyl) side-chain is protected with a hydroxyl protecting group such as trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), tert- butyldiphenylsilyl (TBDPS), acetyl, allyloxycarbonyl, 2-trimethylsilylethoxycarbonyl, 2-trichloroethoxycarbonyl and the like.
  • TMS trimethylsilyl
  • TES triethylsilyl
  • TDMS tert-butyldimethylsilyl
  • TDPS tert- butyldiphenylsilyl
  • acetyl allyloxycarbonyl, 2-trimethylsilylethoxycarbonyl, 2-trichloroethoxycarbonyl and the like.
  • the addition of the quaternary side chain group to the carbapenem is accomplished by treating a solution of the hydroxymethyl-carbapenem AJ_ and the side chain A2 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 diethylazodicarboxylate (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), and the like
  • the side chain and carbapenem nucleus 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 to afford a crude methyl substituted carbapenem which is purified, if necessary, by recrystallization or by chromatography on silica gel, eluting with a suitable solvent or mixture of two or more solvents, such as hexane, ethyl acetate, ether, benzene, dichloromethane, chloroform, acetone, methanol and the like.
  • a suitable solvent or mixture of two or more solvents such as hexane, ethyl acetate, ether, benzene, dichloromethane, chloroform, acetone, methanol and the like.
  • Modification of the side chain which is generally necessary to introduce the charged substituent, is best accomplished before removal of the protecting groups on the hydroxyethyl side chain or 3-carbapenem carboxylate.
  • a positively charged substituent may be introduced into the side chain by first activating the hydroxyl group. This entails 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 compound, such as N-methyl-imidazole, N-(2-hydroxyethyl)-imidazole, N-methyl-diazabicyclooctane, l-(carbamoylmethyl)-4-aza-l- azoniabicyclo[2.2.2]octane, l-(3-hydroxyprop-l-yl)-4-aza-l- azoniabicyclo[2.2.2]octane, pyridine, morpholine and the like which contains a nitrogen atom that can act as a nucleophile.
  • a suitable leaving group such as a triflate, mesylate, tos
  • the charged substituent may be incorporated in the side chain before addition of the side chain to the carbapenem, or may be introduced after deprotection. However, introduction of the charged before deprotection is greatly preferred.
  • activation of the hydroxyl group and displacement by Q to produce A5 may be accomplished in a single step by taking advantage of the basic character of compound Q and using it as a base in the activation reaction.
  • the conversion of the hydroxyl group to a suitable leaving group is accomplished by treating the hydroxyl substituted compound in a suitable solvent such as dichloromethane, tetrahydrofuran, ether, benzene, and the like with an activating reagent, such as trifluoromethanesulfonic anhydride, methanesulfonic anhydride, toluenesulfonic anhydride, methanesulfonyl chloride, benzenesulfonyl chloride, toluenesulfonyl chloride, and the like in the presence of a suitable base such as triethylamine, 2,6-lutidine, diisopropylethylamine and the like at a temperature between about -100°C and 0°C for about 5 to 120 minutes.
  • a suitable solvent such as dichloromethane, tetrahydrofuran, ether, benzene, and the like
  • an activating reagent such as triflu
  • the intermediate thus obtained contains a leaving group, which may be converted to an alternative leaving group, iodide, by treating a solution of the intermediate in a suitable solvent such as acetone, methyl ethyl ketone, and the like at about -10°C to 50°C with an excess of sodium iodide or potassium iodide for about 0.25 to 24 hours.
  • a suitable solvent such as acetone, methyl ethyl ketone, and the like at about -10°C to 50°C with an excess of sodium iodide or potassium iodide for about 0.25 to 24 hours.
  • the iodide is obtained in sufficiently pure form that it may be used without further purification.
  • the iodide if not crystalline, may be lyophilized from benzene to afford an amorphous, easily handled, solid.
  • the activated hydroxyl group or iodide is displaced by reacting the activated intermediate with reagent Q.
  • activation and displacement of the hydroxyl group may be accomplished in a single step.
  • the activating reagent is added to a solution of the hydroxyl substituted compound in the presence of a suitable base in a suitable solvent such as dichloromethane, tetrahydrofuran, ether, DMF, benzene, acetonitrile, DMSO and the like as described in the preceding paragraphs.
  • the resulting activated intermediate is treated with 1-3 molar equivalents of compound Q at a temperature between about -78°C and 50°C for about 15 to 120 minutes.
  • the activated intermediate in one solvent, isolate the activated intermediate, and conduct the displacement reaction in a different solvent.
  • the displacement may be conducted without isolation of the intermediate and, in cases where Q is also used as a base, may even be concurrent with the formation of the activated intermediate.
  • a solution of the iodide is combined with an approximately equivalent amount (0.9 - 1.05 molar equivalents) of compound Q + .
  • a silver salt of a non- nucleophilic acid such as silver trifluoromethanesulfonate, silver tetrafluoroborate and the like is then added.
  • the reaction will proceed in the absence of the silver salt, the reaction proceeds more rapidly in the presence of the silver salt.
  • the silver salt assists in the removal of the displaced iodide from the reaction mixture which can improve the efficiency of subsequent steps.
  • An alternative method for introducing a positive charge into the side chain may be applied to side chains that contain a nitrogen atom which may be quaternized by reaction with a suitable alkylating reagent, such as methyl iodide, methyl bromide, benzyl trichloroacetimidate, methyl trifluoromethanesulfonate, triethyloxonium tetrafluoroborate, and the like. Quaternization of the nitrogen atom in the side chain is effected by treating a solution of the compound with a slight excess (1.05 to 1.2 molar equivalents) of the alkylating reagent.
  • the synthesis of the target compound is completed by removing any protecting groups which are present in the penultimate intermediate using standard techniques.
  • the deprotected final product is then purified, as necessary, using standard techniques such as ion exchange chromatography, HPLC on reverse phase silica gel, MPLC on reverse phase polystyrene gel, and the like or by recrystallization.
  • the final product may be characterized structurally by standard techniques such as NMR, IR, MS, and UV.
  • the final product if not crystalline, may be lyophilized from water to afford an amorphous, easily handled solid.
  • the compounds of the present invention are valuable antibacterial agents active against various Gram-positive and to a lesser extent Gram-negative bacteria, and accordingly find utility in human and veterinary medicine.
  • the compounds of the invention are determined to be active against MRSA.
  • the compounds of the invention can be formulated in pharmaceutical compositions by combining the compound with a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier examples include: topically, orally and parenterally by injection (intravenously or intramuscularly).
  • Compositions for injection, a preferred route of delivery may be prepared in unit dosage form in ampoules, or in multidose containers.
  • the injectable compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain various formulating agents.
  • the active ingredient may be in powder (lyophilized or non- lyophilized) form for reconstitution at the time of delivery with a suitable vehicle, such as sterile water.
  • 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.
  • 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.
  • Formula I antibacterial compound For adults, about 5-50 mg of Formula I antibacterial compound per kg of body weight given one to four times daily is preferred.
  • 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.
  • 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.
  • the crude product was purified via flash chrom. (230- 400 mesh silica gel) and was eluted with a 4: 1 mixture of hexanes: ethyl acetate to afford 908 mg of the silyl ether.
  • the ethyl acetate extract was partitioned with H 2 0-ice and 5% aq. sodium thiosulfate and sat. brine.
  • the extract was dried with andydrous sodium sulfate and concentrated in vacuo to provide 108 mg of a tan solid.
  • the reaction was extracted with ethyl acetate and partitioned with H 2 0-ice and sat. brine.
  • the ethyl acetate extract was dried with anhydrous sodium sulfate and concentrated in vacuo to dryness.
  • the crude product was purified using silica gel plate layer chromatography eluted with a 7:3 ethyl acetate: hexanes mixture to afford 120 mg of the benzyl alcohol.
  • reaction mixture was extracted with ethyl acetate and partitioned with H2 ⁇ - sodium bicarbonate and sat. brine.
  • the ethyl acetate extract was dried with anhydrous sodium sulfate and concentrated in vacuo to provide a viscous oil.
  • the compound was purified via flash chrom. (230-400 mesh silica gel) and eluted with a 1: 1 mixture of hexanes: ethyl acetate to afford 227 mg of the pure carbinol.
  • reaction mixture was extracted with ethyl acetate and partitioned with dilute aq. hydrochloric acid-ice, aq. sodium bicarbonate and saturated brine.
  • the ethyl acetate extract was dried with anhydrous sodium sulfate and cone, in vacuo to give 205 mg of crude mesylate.
  • the mixture was extracted with ethyl acetate and partitioned between dilute aq. sodium thiosulfate-ice, H2 ⁇ and saturated brine.
  • the ethyl acetate extract was dried with anhydrous sodium sulfate and cone, in vacuo to afford 202 mg of the alkyliodide.
  • reaction mixture was filtered through a celite pad and cone, in vacuo to a volume of ca. 1.0 ml. and was diluted with 9.0 ml of diethylether, forming a white suspension.
  • reaction mixture was filter through a celite pad and was cone, in vacuo to ca. 2.0 ml and was diluted with 8.0 ml of diethylether forming a suspension.
  • the etheral suspension was centrifuged and the resulting supernatant was discarded. The remaining off-white solid was dried in vacuo to afford 120 mg of the salt.
  • reaction was then extracted with ethyl acetate and partitioned with dilute aq. hydrochloric acid-ice, H2O and saturated brine.
  • the ethyl acetate extract was then dried with anhydrous sodium sulfate and cone, in vacuo to provide 121 mg of the alkyl triflate.
  • reaction mixture was filtered through a celite pad and cone, in vacuo to a volume of ca. 1.0 ml. and was diluted with 9.0 ml of diethylether, forming a white suspension.
  • the etheral suspension was centrifuged and the resulting supernatant was discarded. The remaining off-white solid was dried in vacuo to give 137 mg of salt.
  • reaction mixture was filtered through a celite pad and cone, in vacuo to a volume of ca. 1.0 ml. and was diluted with 9.0 ml of diethylether, forming a white suspension.
  • reaction mixture was diluted with 9.0 ml of diethylether forming an oily suspension.
  • the reaction was then diluted with 10.0 ml of diethylether forming a suspension.
  • the etheral mixture was centrifuged and the resulting supernatant was discarded.
  • the resulting deblocked carbapenem was washed twice with diethylether and dried in vacuo which gave 116 mg of an amorphous solid.
  • the dried solid was then dissolved in 5 ml of 5% aq. brine and was chromatogaphed on 2.0 mi's of MacroPrep ion exchange resin and eluted with 100 ml of 5% aq. brine.
  • the 5% aq. brine effluent containing the purified carbapenem was desalted on 15 mi's of Amberchrom CG -161 resin using an H 2 0-aq. acetonitrile gradient elution.
  • the reation was stirred for 5 min. at ambient temperature and was chilled to 0 C and stirred further for an additional 1.5 hrs.
  • the reaction mixture was then diluted with 8.0 ml of diethylether forming a white suspension.
  • the etheral mixture was centrifuged and the resulting supernatant was discarded.
  • the resulting deblocked carbapenem was washed twice with diethylether and dried in vacuo to give 11 mg of an amorphous solid.
  • 35 mg (0.0334 mmoles) of the bis-allyl protected dabco salt was dissolved in 3.0 ml of sieved dried DMF and was placed in an N2 atmosphere.
  • 7.7 mg (0.0067 mmoles) of Pd(Ph3P)4 and 5.3 mg (0.020 mmoles) of PI13P were combined and added in one portion forming a suspension.
  • 0.005 ml (0.0367 mmoles) of neat 2-ethylhexanoic acid was added followed by the addition of 0.073 ml(0.0367 mmoles) of a 0.5 M solution of sodium-2-ethylhexanoate in EtOAc.
  • the reaction was stirred for 5 min. at ambient temperature at which time a homogeneous solution was obtained.
  • the reaction was chilled to 0 C and stirred for an additional 1.5 hrs.
  • the reaction was then diluted with 10.0 ml of diethylether forming a suspension.
  • the etheral mixture was centrifuged and the resulting supernatant was discarded.
  • the resulting deblocked carbapenem was washed twice with diethylether and dried in vacuo to give 8.6 mg of the compound as the triflate salt.

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Abstract

L'invention concerne des agents antibactériens du type carbapenem, dans lesquels le noyau carbapenem est substitué en position 2 avec un phényle iodo substitué, lié par un groupe CH2-O. Les composés de l'invention sont représentés par la formule (I). L'invention porte aussi sur les sels et les hydrates desdits agents. De plus, le cycle phényle iodo est substitué par différents groupes de substituants dont au moins un groupe cationique. Des compositions pharmaceutiques et des procédés de traitement sont également décrits.
EP98944779A 1997-09-09 1998-09-04 Antibacteriens du type 3-(iodophenoxymethyl) carbapenem Withdrawn EP1015453A4 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US5822397P 1997-09-09 1997-09-09
US58223P 1997-09-09
GBGB9815806.6A GB9815806D0 (en) 1998-07-21 1998-07-21 Carbapenem antibacterial compounds compositions containing such compounds and methods of treatment
GB9815806 1998-07-21
PCT/US1998/018578 WO1999012928A1 (fr) 1997-09-09 1998-09-04 Antibacteriens du type 3-(iodophenoxymethyl) carbapenem

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EP1015453A1 true EP1015453A1 (fr) 2000-07-05
EP1015453A4 EP1015453A4 (fr) 2001-09-19

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KR101106631B1 (ko) 2003-02-13 2012-01-20 웰스태트 테러퓨틱스 코포레이션 대사 질환의 치료용 화합물
EP1765326A4 (fr) * 2004-06-10 2009-05-13 Fob Synthesis Inc Bactericides au carbapenem a activite gram-negative et procedes d'elaboration correspondants
KR20080089453A (ko) 2006-01-25 2008-10-06 웰스태트 테러퓨틱스 코포레이션 물질대사 장애의 치료용 화합물
US7820721B2 (en) 2006-01-25 2010-10-26 Wellstat Therapeutics Corporation Compounds for the treatment of metabolic disorders
EP1978948A4 (fr) 2006-02-02 2010-06-16 Wellstat Therapeutics Corp Composes pour le traitement de troubles metaboliques
WO2009122707A1 (fr) 2008-03-31 2009-10-08 興和株式会社 Dérivé de 1,3-dihydroisobenzofurane

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EP0289801A1 (fr) * 1987-04-11 1988-11-09 Lederle (Japan) Ltd. Dérivés d'acides (1R,5S,6S)-6-[(R)-1-hydroxy-éthyl]-1-méthyl-carbapénème-3-carboxyliques substitués en position 2 par un groupe thio substitué
US4978659A (en) * 1987-02-02 1990-12-18 Merck & Co., Inc. 2-(Heteroaryliumalkyl)phenyl carbapenem antibacterial agents
US5451579A (en) * 1994-02-15 1995-09-19 Merck & Co., Inc. 1-β-methyl-carbapenem, compositions containing same and methods of use

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US4978659A (en) * 1987-02-02 1990-12-18 Merck & Co., Inc. 2-(Heteroaryliumalkyl)phenyl carbapenem antibacterial agents
EP0289801A1 (fr) * 1987-04-11 1988-11-09 Lederle (Japan) Ltd. Dérivés d'acides (1R,5S,6S)-6-[(R)-1-hydroxy-éthyl]-1-méthyl-carbapénème-3-carboxyliques substitués en position 2 par un groupe thio substitué
US5451579A (en) * 1994-02-15 1995-09-19 Merck & Co., Inc. 1-β-methyl-carbapenem, compositions containing same and methods of use

Non-Patent Citations (2)

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Title
ARNOULD J C ET AL: "Synthesis and antibacterial activity of lipophilic carbapenems with anti-MRSA activity" BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,GB,OXFORD, vol. 6, no. 20, 22 October 1996 (1996-10-22), pages 2449-2454, XP004135856 ISSN: 0960-894X *
See also references of WO9912928A1 *

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EP1015453A4 (fr) 2001-09-19
JP2003517427A (ja) 2003-05-27
AU9223698A (en) 1999-03-29
AU732335B2 (en) 2001-04-12
WO1999012928A1 (fr) 1999-03-18

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