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WO2008036420A2 - 9-(hétéroaryl)-isothiazolo[5,4-b]quinoléine-3,4-diones et composés apparentés en tant qu'agents anti-infectieux - Google Patents

9-(hétéroaryl)-isothiazolo[5,4-b]quinoléine-3,4-diones et composés apparentés en tant qu'agents anti-infectieux Download PDF

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Publication number
WO2008036420A2
WO2008036420A2 PCT/US2007/020611 US2007020611W WO2008036420A2 WO 2008036420 A2 WO2008036420 A2 WO 2008036420A2 US 2007020611 W US2007020611 W US 2007020611W WO 2008036420 A2 WO2008036420 A2 WO 2008036420A2
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alkyl
substituted
halogen
compound
amino
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WO2008036420A3 (fr
Inventor
Barton James Bradbury
Qiuping Wang
Jason Allan Wiles
Akihiro Hashimoto
Edlaine Lucien
Godwin Clarence Gilroy Pais
Ha Young Kim
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Achillion Pharmaceuticals Inc
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Achillion Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • 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

  • 9-(heteroaryl)-isothiazolo[5,4-b]quinoline-3,4-diones and related compounds in which the 9-position substituent is generally a substituted or un- substituted heteroaryl containing one or more nitrogen atoms, useful as antimicrobial agents.
  • Certain compounds provided herein possess potent antibacterial, antiprotozoal, or antifungal activity.
  • Particular compounds provided herein are also potent and/or selective inhibitors of prokaryotic DNA synthesis and prokaryotic reproduction.
  • the invention also provides antimicrobial compositions, including pharmaceutical compositions, containing one or more carrier, diluents, and/or excipients.
  • the invention provides pharmaceutical compositions containing a 9- (heteroaryl)-isothiazolo[5,4-b]quinoline-3,4-dione or related compound as the only active agent or containing a 9-(heteroaryl)-isothiazolo[5,4-b]quinoline-3,4-dione or related compound in combination with one or more other active agent, such as one or more other antimicrobial or antifungal agent.
  • the invention further provides methods for treating or preventing microbial infections in animals by administering an effective amount of a 9-(heteroaryl)-isothiazolo[5,4- b]quinoline-3,4-dione or related compound to an animal suffering from or susceptible to microbial infection.
  • the invention also provides methods of inhibiting microbial growth and survival by applying an effective amount of a 9-(heteroaryl)-isothiazolo[5,4-b]quinoline-3,4- dione or related compound.
  • the invention also provides novel intermediates useful for the synthesis of 9- (heteroaryl)-isothiazolo[5,4-b]quinoline-3,4-diones and related compounds.
  • the invention further provides methods of synthesis of 9-(heteroaryl)-isothiazolo[5,4-b]quinoline-3,4-diones or related compounds.
  • Antimicrobial. compounds are compounds capable of destroying or suppressing the growth or reproduction of microorganisms, such as bacteria, protozoa, mycoplasma, yeast, and fungi.
  • the mechanisms by which antimicrobial compounds act vary. However, they are generally believed to function in one or more of the following ways: by inhibiting cell wall synthesis or repair; by altering cell wall permeability; by inhibiting protein synthesis; or by inhibiting synthesis of nucleic acids.
  • beta-lactam antibacterials inhibit the essential penicillin binding proteins (PBPs) in bacteria, which are responsible for cell wall synthesis.
  • Quinolones act, at least in part, by inhibiting synthesis of DNA, thus preventing the cell from replicating.
  • Pathogenic bacteria are known to acquire resistance via several distinct mechanisms including inactivation of the antibiotic by bacterial enzymes (e.g., beta-lactamases that hydrolyze penicillin and cephalosporins); removal of the antibiotic using efflux pumps; modification of the target of the antibiotic via mutation and genetic recombination (e.g., penicillin-resistance in Neiserria gonorrhea); and acquisition of a readily transferable gene from an external source to create a resistant target (e.g., methicillin-resistance in Staphylococcus aureus).
  • bacterial enzymes e.g., beta-lactamases that hydrolyze penicillin and cephalosporins
  • removal of the antibiotic using efflux pumps e.g., modification of the target of the antibiotic via mutation and genetic recombination (e.g., penicillin-resistance in Neiserria gonorrhea); and acquisition of a readily transferable gene from an external source to create a resistant target (e.g.
  • Resistant organisms of particular note include methicillin-resistant and vancomycin- resistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumoniae, vancomycin-resistant enterococci, fluoroquinolone-resistant E. coli, cephalosporin-resistant aerobic gram-negative rods and imipenem- resistant Pseudomonas aeruginosa. These organisms are significant causes of nosocomial infections and are clearly associated with increasing morbidity and mortality. The increasing numbers of elderly and immunocompromised patients are particularly at risk for infection with these pathogens. Therefore, there is a large unmet medical need for the development of new antimicrobial agents.
  • MRSA Methicillin Resistant Staphylococcus Aureus
  • the present invention fulfills this need, and provides further related advantages.
  • the invention provides compounds of Formula I and Formula II (shown below) and includes 9-(heteroaryl)-isothiazolo[5,4-b]quinoline-3,4-diones or related compounds, which possess antimicrobial activity.
  • the invention provides compounds of Formula I and Formula II, which possess potent and/ or selective antibacterial, antiprotozoal, or antifungal activity.
  • the invention also provides compositions containing one or more compounds of Formula I or Formula II, or a salt, solvate, or prodrug, such as an acylated prodrug of such a compound, and one or more carriers, excipients, or diluents.
  • the invention further comprises methods of treating and preventing microbial infections, particularly bacterial and protozoal infections by administering an effective amount of a compound of Formula I or Formula II to a eukaryote suffering from or susceptible to a microbial infection.
  • microbial infections include bacterial infections, for example E. coli infections, Staphylococcus infections, including Methicillin Resistant Staphylococcus Aureus infections, Salmonella infections and protozoal infections, for example Chlamydia infections.
  • the invention is particularly includes methods of preventing or treating microbial infections in mammals, including humans, but also encompasses methods of preventing or treating microbial infections in other animals, including fish, birds, reptiles, and amphibians.
  • Methods of treatment include administering a compound of Formula I or Formula II as the single active agent or administering a compound of Formula I or Formula II in combination with one or more other therapeutic agent, such as an antibacterial, an antifungal, an antiviral, an interferon or other immune system modulator, an efflux-pump inhibitor, a beta- lactamase inhibitor, an anti-inflammatory, or another compound of Formula I or Formula II.
  • the invention also provides methods of inhibiting microbial growth and survival by applying an effective amount of a 9-(heteroaryl)-isothiazolo[5,4-b]quinoline-3,4-diones or related compound.
  • the invention includes, for example, methods of inhibiting microbial growth and survival on medical instruments by applying a composition containing a compound of Formula I or Formula II.
  • the invention include compounds and pharmaceutically acceptable salts of Formula I and Formula II
  • a 1 is S, O, SO, or SO 2 .
  • R 2 is hydrogen; or R 2 is C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 3 - C 7 cycloalkyl)C 0 -C4carbohydryl, (C 4 -C 7 cycloalkenyl)C 0 -C 4 carbohydryl, (aryl)C 0 -C 4 carbohydryl, or (C 2 -C 6 heterocycloalkyl)Co-C 4 carbohydryl, each of which is substituted with 0 to 5 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, C 1 -C 4 alkyl, C 1 - C 4 alkoxy, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, mono- and di-C 1 -C4alkylamino, CrQalkanoyl, C 1 - C 4 alkyl,
  • R 3 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkanoyl, mono- or di-C 1 -C ⁇ alkylcarbamate, or Q-C ⁇ alkylsulfonate; each of which is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, Q-G t alkoxy, mono- and di-C 1 -C 4 alkylamino, C 1 - C 2 haloalkyl, and Q-Qhaloalkoxy.
  • R 5 is hydrogen, halogen, hydroxy, amino, cyano, nitro, Or-NHNH 2 ; or
  • R 5 is C 1 -C 4 alkyl, C 1 -C 4 alkoxy, mono- or di-(C ! -C 4 )alkylamino, mono-, di- or tri- (C 1 -C 4 )alkylhydrazinyl, C 2 -C4alkanoyl, Q-dalkylester, C 1 -C 2 haloalkyl, or d-C 2 haloalkoxy; each of which is substituted with 0 to 3 substituents independently chosen from hydroxy, amino, halogen, oxo, C 1 -C 4 alkoxy, C 1 -C 2 haloalkyl, d-C 2 haloalkoxy, and mono- and di-(C]- C4)alkylamino.
  • R 6 is hydrogen, halogen, hydroxy, amino, cyano, C 1 -C 4 alkyl, C ! -C 4 alkoxy, mono- or di-(C 1 -C 4 )alkylamino, -SO 3 R 10 , -SO 2 R 10 , or -SO 2 NR 10 R 11 .
  • R 7 is halogen, -0(SO 2 )CF 3 , or -N 2 BF 4 .
  • R 7 is a nitrogen-linked monocyclic heterocycloalkyl group, which has 4 to 8 ring members, including 0, 1, or 2 additional ring heteroatoms independently chosen from N, O, and S, or
  • R7 is a nitrogen-linked C 1 -C 4 alkylamino substituted with a 5 or 6-membered heteroaryl group having 1 or 2 heteroatoms independently chosen from N, O, and S, or substituted with a heterocycloalkyl group, which has 4 to 8 ring members, including 1 or 2 ring heteroatoms independently chosen from N, O, and S, or
  • R7 is a nitrogen-linked heterocycloalkyl or heterocycloalkenyl group, each of which has 4 to 8 ring members, including 0, 1, or 2 additional ring heteroatoms independently chosen from N, O, and S, forming part of a bicyclic system with a 3- to 8-membered cycloalkyl or heterocycloalkyl ring in fused or spiro orientation; or
  • R7 is a nitrogen-linked 6-membered heterocycloalkyl group, having 0, 1 or 2 additional ring heteroatoms independently chosen from N, O, and S, and bridged with a methylene or ethylene bridge.
  • R 7 other than halogen, -0(SO 2 )CF 3 , and -N 2 BF 4 is substituted with 0 to 5 substituents independently chosen from (i), (ii), and (iii); wherein
  • (i) is chosen from halogen, hydroxy, amino, cyano, and nitro;
  • (ii) is chosen from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C( J aIkOXy(C 0 - C 4 alkyl), mono- and di-(C 0 -C 6 )alkylamino, Q-Qhaloalkyl, C 1 -C 2 haloalkoxy, C 3 - C 7 cycloalkyl(C 0 -C 4 carbohydryl), C 3 -C 7 cycloalkyl(Co-C 4 carbohydryl-0-), C 4 -C 7 cycloalkenyl(C 0 - C 4 carbohydryl), aryl(C 0 -C 6 carbohydryl), aryl(d-C 4 alkoxy), C 2 -C 6 heterocycloalkyl(C 0 - C 4 carbohydryl), heteroaryl(C 0 -C
  • each of (ii) and (iii) is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, oxo, -COOH, -CONH 2 , C 1 -C 4 alkyl, C 2 - C 4 alkenyl, C 2 -C 4 alkynyl, Q-Qalkoxy, C 1 -C 4 alkoxycarbonyl, C 3 -C 7 cycloalkyl(Co- C 4 carbohydryl), C 3 -C 7 cycloalkyl(C 0 -C 4 alkoxy), mono- and di-(C 1 -C 4 )alkylamino, C 1 - C 2 haloalkyl, d-C 2 haloalkoxy, C 2 -C 4 alkanoyl and phenyl.
  • substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, oxo, -COOH
  • A8 is N or CR 8 .
  • R 8 is hydrogen, halogen, hydroxy, amino, cyano, nitro, or -NHNH 2 ; or R 8 is C 1 -C 4 alkyl, C 1 -C 4 alkoxy, mono- or di-(C 1 -C 4 )alkylamino, mono-, di-, or tri- (C 1 -C 4 ) alkylhydrazinyl, C 2 -C 4 alkanoyl, C 1 -C 4 alkylester, C 1 -C 2 haloalkyl, or C 1 -C 2 haloalkoxy; each of which is substituted with 0 to 3 substituents independently chosen from hydroxy, amino, halogen, oxo, C 1 -C 4 alkoxy, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, and mono- and di-(C 1 - C 4 )alkylamino.
  • R9 is pyridine, pyrazine, pyridazine, or pyrimidine, each of which is substituted with 0 to 4 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, -COOH, -CONH 2 , C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, (C 3 -C 7 cycloalkyl)C 0 - C 4 alkyl, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkoxy, mono- and di-(C ! -C 4 )alkylamino, Q-Qhaloalkyl, C 1 - C 2 haloalkoxy, and C 2 -C 4 alkanoyl.
  • substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, -COOH, -CONH
  • the invention also provides methods of synthesizing compounds of Formula I and Formula II.
  • the compounds of Formula I and Formula II may contain one or more asymmetric elements such as stereogenic centers, stereogenic axes and the like, e.g. asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms.
  • asymmetric elements such as stereogenic centers, stereogenic axes and the like, e.g. asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms.
  • These compounds can be, for example, racemates or optically active forms.
  • these compounds with two or more asymmetric elements these compounds can additionally be mixtures of diastereomers.
  • compounds having asymmetric centers it should be understood that all of the optical isomers and mixtures thereof are encompassed.
  • compounds with carbon- carbon double bonds may occur in Z- and E-forms, with all isomeric forms of the compounds being included in the present invention.
  • the single enantiomers i.e., optically active forms can be obtained by asymmetric synthesis, synthesis from optically pure precursors, or by resolution of the racemates. Resolution of the racemates can also be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column.
  • the present invention is intended to include all isotopes of atoms occurring in the present compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium and isotopes of carbon include 11 C, 13 C, and 14 C.
  • substituted means that any one or more hydrogens on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded.
  • 2 hydrogens on the atom are replaced.
  • Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates.
  • a stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation from a reaction mixture, and subsequent formulation into an effective therapeutic agent.
  • substituents are named into the core structure. For example, it is to be understood that when (cycloalkyl)alkyl is listed as a possible substituent the point of attachment of this substituent to the core structure is in the alkyl portion.
  • alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups, having the specified number of carbon atoms.
  • C 1 - C 6 alkyl as used herein includes alkyl groups having from 1 to about 6 carbon atoms.
  • C 0 -C n alkyl is used herein in conjunction with another group, for example, (aryl)C 0 -C 4 alkyl, the indicated group, in this case aryl, is either directly bound by a single covalent bond (Co), or attached by an alkyl chain having the specified number of carbon atoms, in this case from 1 to about 4 carbon atoms.
  • alkyl examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, and sec-pentyl.
  • alkenyl indicates a hydrocarbon chain of either a straight or branched configuration having one or more carbon-carbon double bond bonds, which may occur at any stable point along the chain.
  • alkenyl groups include ethenyl and propenyl.
  • Alkynyl indicates a hydrocarbon chain of either a straight or branched configuration having one or more triple carbon-carbon bonds that may occur in any stable point along the chain, such as ethynyl and propynyl.
  • Alkoxy represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge.
  • alkoxy include, but are not limited to, methoxy, ethoxy, n- propoxy, i- propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2- pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and 3- methylpentoxy.
  • An "(alkoxy)alkyl group is an alkoxy group as defined herein attached through its oxygen atom to an alkyl bridge where the point of attachment to the substituted group is in the alkyl group.
  • the terms "mono- or di-alkylamino" or “mono- and di- alkylamino” indicate secondary or tertiary alkyl amino groups, wherein the alkyl groups are as defined above and have the indicated number of carbon atoms. The point of attachment of the alkylamino group is on the nitrogen. Examples of mono- and di-alkylamino groups include ethylamino, dimethylamino, and methyl-propyl-amino.
  • a mono- or di-(C 3 -C 6 )(C 0 - C4)alkylamino group is an alkyl amino substituent in which a first alkyl group is chosen from C 3 - C 6 alkyl and a second alkyl group is chosen from Co-G ⁇ alkyl, wherein C 0 indicates the absence of a second alkyl group, i.e. a mono-Cs-C ⁇ alkylamino.
  • the term "mono-, di-, or tri-alkylhydrazinyl” indicates from 1 to 3 independently chosen alkyl groups as defined above attached through a single-bonded nitrogen-nitrogen linkage. At least one of the alkyl groups is attached to the terminal nitrogen (the nitrogen not bound to the core structure). When the term mono- or di-alkylhydrazinyl is used only the terminal nitrogen is alkyl substituted.
  • alkylhydrazinyl groups include 2-butyl-l- hydrazinyl, 2-butyl-2-methyl-l-hydrazinyl, and 1 ,2-dimethyl-2 -propyl- 1-hydrazinyl.
  • alkylthio indicates an alkyl group as defined above attached through a sulfur linkage, i.e. a group of the formula alkyl-S-. Examples include ethylthio and pentylthio.
  • aminoalkyl indicates an alkyl group as defined above substituted with at least one amino substituent.
  • hydroxyalkyl indicates an alkyl group as defined above, substituted with at least one hydroxyl substituent. hi certain instances the alkyl group of the aminoalkyl or hydroxyalkyl group may be further substituted.
  • aryl indicates aromatic groups containing only carbon in the aromatic ring or rings. Typical aryl groups contain 1 to 3 separate, fused, or pendant rings and from 6 to about 18 ring atoms, without heteroatoms as ring members. When indicated, such aryl groups may be further substituted with carbon or non-carbon atoms or groups. Such substitution may include fusion to a 5 to 7-membered saturated cyclic group that optionally contains 1 or 2 heteroatoms independently chosen from N, O, and S, to form, for example, a 3,4- methylenedioxy-phenyl group.
  • Aryl groups include, for example, phenyl, naphthyl, including 1- naphthyl and 2-naphthyl, and bi-phenyl.
  • Carbohydryl as used herein, includes both branched and straight-chain hydrocarbon groups, which are saturated or unsaturated, having the specified number of carbon atoms.
  • C 0 -C n carbohydryl is used herein in conjunction with another group, for example, (cycloalkyl)C 0 -C4carbohydryl, the indicated group, in this case cycloalkyl, is either directly bound by a single covalent bond (C 0 ), or attached by a carbohydryl chain, such as an alkyl chain, having the specified number of carbon atoms, in this case from 1 to about 4 carbon atoms.
  • carbohydryl groups include C 1 -QaIlCyI, such as methyl, or 5-butyl, C 2 -C 6 alkynyl such as hexynyl, and C 2 -C 6 alkenyl, such as l-propenyl.
  • (aryl)alkyl aryl and alkyl are as defined above, and the point of attachment is on the alkyl group. This term encompasses, but is not limited to, benzyl, phenylethyl, and piperonyl.
  • (aryl)carbohydryl aryl and carbohydryl are as defined above and the point of attachment is on the carbohydryl group, for example a phenylpropen-1-yl group.
  • aryl and alkoxy are as defined above and the point of attachment is through the oxygen atom of the alkoxy group; if the alkoxy is a Coalkoxy the aryl is attached through an oxygen bridge.
  • Cycloalkyl indicates saturated hydrocarbon ring groups, having the specified number of carbon atoms, usually from 3 to about 8 ring carbon atoms, or from 3 to about 7 carbon atoms.
  • Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl as well as bridged or caged saturated ring groups such as norborane or adamantane.
  • Cycloalkenyl indicates an unsaturated, but not aromatic, hydrocarbon ring having at least one carbon-carbon double bond. Cycloalkenyl groups contain from 4 to about 8 carbon atoms, usually from 4 to about 7 carbon atoms. Examples include cyclohexenyl and cyclobutenyl.
  • (cycloalkyl)alkyl "(cycloalkyl)carbohydryl)," and "(cycloalkyl)alkoxy”
  • cycloalkyl, alkyl, carbohydryl, and alkoxy are as defined above, and the point of attachment is on the alkyl, carbohydryl, or alkoxy group respectively.
  • These terms include examples such as cyclopropylmethyl, cyclohexylmethyl, cyclohexylpropenyl, and cyclopentylethyoxy.
  • (cycloalkenyl)alkyl "(cycloalkenyl)carbohydryl”
  • cycloalkenyl, alkyl, and carbohydryl are as defined above, and the point of attachment is on the alkyl or carbohydryl group respectively.
  • These terms include examples such as cyclobutenylmethyl, cyclohexenylmethyl, and cyclohexylpropenyl.
  • Haloalkyl indicates both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen atoms, generally up to the maximum allowable number of halogen atoms.
  • haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, and penta-fluoroethyl.
  • Haloalkoxy indicates a haloalkyl group as defined above attached through an oxygen bridge.
  • Halo or "halogen” as used herein refers to fluoro, chloro, bromo, or iodo.
  • heteroaryl indicates a stable 5- to 7-membered monocyclic or 7- to 10- membered bicyclic heterocyclic ring which contains at least 1 aromatic ring that contains from 1 to 4, or preferably from 1 to 3, heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon.
  • the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heteroaryl group is not more than 2. It is particularly preferred that the total number of S and O atoms in the heteroaryl group is not more than 1.
  • a nitrogen atom in a heteroaryl group may optionally be quaternized.
  • heteroaryl groups may be further substituted with carbon or non-carbon atoms or groups.
  • substitution may include fusion to a 5 to 7-membered saturated cyclic group that optionally contains 1 or 2 heteroatoms independently chosen from N, O, and S, to form, for example, a [l,3]dioxolo[4,5-c]pyridyl group.
  • heteroaryl groups include, but are not limited to, pyridyl, indolyl, pyrimidinyl, pyridizinyl, pyrazinyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, benz[b]thiophenyl, isoquinolinyl, quinazolinyl, quinoxalinyl, thienyl, isoindolyl, and 5,6,7,8-tetrahydroisoquinoline.
  • heteroarylalkyl and “heteroaryl(carbohydryl),” heteroaryl, alkyl, and carbohydryl are as defined above, and the point of attachment is on the alkyl or carbohydryl group respectively.
  • heteroarylalkyl and “heteroaryl(carbohydryl),” heteroaryl, alkyl, and carbohydryl are as defined above, and the point of attachment is on the alkyl or carbohydryl group respectively.
  • heteroarylalkyl and “heteroaryl(carbohydryl),” heteroaryl, alkyl, and carbohydryl are as defined above, and the point of attachment is on the alkyl or carbohydryl group respectively.
  • pyridylmethyl thiophenylmethyl
  • pyrrolyl(l -ethyl) pyrrolyl(l -ethyl
  • heterocycloalkyl indicates a saturated cyclic group containing from 1 to about 3 heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon. Heterocycloalkyl groups have from 3 to about 8 ring atoms, and more typically have from 5 to 7 ring atoms. Examples of heterocycloalkyl groups include morpholinyl, piperazinyl, piperidinyl, and pyrrolidinyl groups. A nitrogen in a heterocycloalkyl group may optionally be quaternized.
  • heterocyclic group indicates a 4-6 membered saturated, partially unsaturated, or aromatic ring containing from 1 to about 4 heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon or a 7-10 membered bicyclic saturated, partially unsaturated, or aromatic heterocylic ring system containing at least 1 heteroatom in the two ring system chosen from N, O, and S and containing up to about 4 heteroatoms independently chosen from N, O, and S in each ring of the two ring system.
  • the heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure.
  • heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable.
  • a nitrogen atom in the heterocycle may optionally be quaternized. It is preferred that the total number of heteroatoms in a heterocyclic groups is not more than 4 and that the total number of S and O atoms in a heterocyclic group is not more than 2, more preferably not more than 1.
  • heterocyclic groups include, pyridyl, indolyl, pyrimidinyl, pyridizinyl, pyrazinyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, benz[b]thiophenyl, isoquinolinyl, quinazolinyl, quinoxalinyl, thienyl, isoindolyl, dihydroisoindolyl, 5,6,7,8-tetrahydroisoquinoline, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, and pyrrolidin
  • heterocyclic groups include, but are not limited to, phthalazinyl, oxazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzoisoxolyl, dihydro-benzodioxinyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl, isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl, beta- carbolinyl, isochromanyl, chromanonyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl, benzoxazoly
  • active agents are compounds that have pharmaceutical utility, e.g. may be used to treat a patient suffering from a disease or condition, or may be used prophylacticly to prevent the onset of a disease or condition in a patient, or that may be used to enhance the pharmaceutical activity of other compounds.
  • compositions are compositions comprising at least one active agent, such as a compound or salt of Formula I or Formula II, and at least one other substance, such as a carrier, excipient, or diluent.
  • Pharmaceutical compositions meet the U.S. FDA's GMP (good manufacturing practice) standards for human or non-human drugs.
  • Salts of the compounds of the present invention include inorganic and organic acid and base addition salts.
  • the salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
  • the appropriate base such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like
  • salts of the present compounds further include solvates of the compounds and of the compound salts.
  • “Pharmaceutically acceptable salts” includes derivatives of the disclosed compounds wherein the parent compound is modified by making non-toxic acid or base salts thereof, and further refers to pharmaceutically acceptable solvates of such compounds and such salts.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • conventional non- toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH 2 ) n -COOH where n is 0-4, and the like. Lists of additional suitable salts may be found, e.g., in Remington's Pharmaceutical Sciences, 17
  • prodrugs includes any compounds that become compounds of Formula I when administered to a mammalian subject, e.g., upon metabolic processing of the prodrug.
  • prodrugs include, but are not limited to, acetate, formate and benzoate and like derivatives of functional groups (such as alcohol or amine groups) in the compounds of Formula I and Formula II.
  • a therapeutically effective amount of a compound of this invention means an amount effective, when administered to a human or non-human patient, to provide a therapeutic benefit such as an amelioration of symptoms, e.g., an amount effective to decrease the symptoms of a microbial infection, and or an amount sufficient to reduce the symptoms of a bacterial, fungal, or protozoal infection. In certain circumstances a patient suffering from a microbial infection may not present symptoms of being infected. Thus a therapeutically effective amount of a compound is also an amount sufficient to prevent a significant increase or significantly reduce the detectable level of microorganism or antibodies against the microorganism in the patient's blood, serum, other bodily fluids, or tissues.
  • the invention also includes using compounds of Formula I and Formula II in prophylactic therapies.
  • a "therapeutically effective amount” is an amount sufficient to significantly decrease the treated animal's risk of contracting a microorganism infection.
  • a significant reduction is any detectable negative change that is statistically significant in a standard parametric test of statistical significance such as Student's T-test, where p ⁇ 0.05.
  • the numbers 1 through 9 refer specifically to positions within the tricyclic ring system whereas the letters A, B and C refer to the specific six (rings A and B) or five (ring C) membered rings as shown below.
  • Certain embodiments include compounds of Formula I and tautomers thereof of Formula II in which the variables R 2 to R 7 , A 8 , are as follows.
  • R 2 is hydrogen, or R 2 is d-C 6 alkyl, C 2 -C 6 alkenyl, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, (aryl)C 0 -C 4 alkyl, or (C 2 -C 6 heterocycloalkyl)C 0 -C 2 alkyl, each of which is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, -COOH, -CONH 2 , C 1 -C 4 alkyl, Q ⁇ alkoxy, d-C 2 haloalkyl, d-C 2 haloalkoxy, and mono- and di-(C ! - C 4 )alkylamino, and C 2 -C 4 alkanoyl.
  • R 3 is hydrogen, Q-Cealkyl, or C 2 -C 6 alkanoyl.
  • R 5 is hydrogen, halogen, hydroxy, amino, Q-Qalkyl, C 1 -C 2 alkoxy, mono- or di- (C 1 -GOalkylamino, or mono- or di-(C 1 -C4)alkylhydrazinyl.
  • R 6 is hydrogen, halogen, hydroxy, amino, cyano, d-Gjalkyl, C ! -C 4 alkoxy, mono- or di-(C 1 -C 4 )alkylamino.
  • R 7 is a nitrogen-linked heterocycloalkyl group, which has 4 to
  • R 7 is a nitrogen-linked C 1 -C4alkylamino substituted with a 5- or 6-membered heteroaryl group having 1 or 2 heteroatoms independently chosen from N, O, and S, or substituted with a heterocycloalkyl group, which has 4 to 8 ring members, including 1 or 2 ring heteroatoms independently chosen from N, O, and S, or
  • R7 is a nitrogen-linked heterocycloalkyl or heterocycloalkenyl group, each of which has 4 to 8 ring members, including 0, 1, or 2 additional ring heteroatoms independently chosen from N, O, and S, forming part of a bicyclic system with a 3- to 8-membered cycloalkyl or heterocycloalkyl ring in fused or spiro orientation; or
  • R7 is a nitrogen-linked 6-membered heterocycloalkyl group, 0, 1 or 2 additional ring heteroatoms independently chosen from N, O, and S, and bridged with a methylene or ethylene bridge.
  • R 7 is substituted with 0 or 1 or more substituents independently chosen from (a) and 0 or 1 substituents chosen from (b); wherein (a) is chosen from halogen, hydroxy, amino, nitro, d-C 4 alkyl, d-C ⁇ alkoxy, C 1 -C 2 haloalkyl, and d-C 2 haloalkoxy, and (b) is oxo, amino, cyano, hydroxyC 1 -C4alkyl, aminoQ ⁇ alkyl, C!-C 6 alkylthio, C 2 -C 6 alkanoyl, (mono- or di-C 1 -C4alkyl)aminoC 0 -C4alkyl, (C3-C 7 cycloalkyl)C 0 -C4alkyl, (C 3 -C 7 cycloalkyl)aminoC 0 - C 4 alkyl, (C 3 -C 7 cycl
  • Each of (b) other than oxo and cyano is substituted with 0 to 2 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, oxo, -COOH, -CONH 2 , Q- C4alkyl, C 2 -C4alkenyl, C 2 -C4alkynyl, C 1 -C4alkoxy, mono- and di-(C 1 -C4)alkylamino, C 1 - C 2 haloalkyl, and C 1 -C 2 haloalkoxy.
  • A8 is N or CR 8 ; wherein R 8 is hydrogen, halogen, hydroxy, amino, cyano, nitro, or -NHNH 2 ; or R 8 is C 1 -C 6 alkyl, d-C ⁇ alkoxy, (C 3 -C 7 cycloalkyl)C 0 -C 2 alkyl substituted with 0 or 1 or more halogen substituents, (C 3 -C 7 cycloalkyl)C 0 -C 2 alkoxy substituted with 0 or 1 or more halogen substituents, mono- or di-(C 1 -C4)alkylamino, mono-, di-, or Ui-(C 1 ⁇ ) alkylhydrazinyl, C 2 -C 4 alkanoyl, Cj-C 2 haloalkyl, or d-C 2 haloalkoxy.
  • R9 is pyridine, pyrazine, pyridazine, or pyrimidine, each of which is substituted with 0 to 4 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, - COOH, -CONH 2 , C 1 -C 4 EIlCyI, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, d-C 4 alkoxy, (C 3 -C 7 cycloalkyl)C 0 - C 4 alkyl, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkoxy, mono- and di-(C 1 -C 4 )alkylamino, C 1 -C 2 HaIOaIlCyI, C 1 - C 2 haloalkoxy, and C 2 -C 4 alkanoyl.
  • substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, -
  • the invention also includes compounds of Formula I and Formula II in which the variables (e.g. A 1 , R 2 , R 3 , R A , etc.) are independently defined as described below.
  • the A 1 variable e.g. A 1 , R 2 , R 3 , R A , etc.
  • a 1 is S; e.g. compounds and salts of Formula III and Formula IV are included herein.
  • Ai is SO; e.g. compounds and salts of Formula V and VI are included herein:
  • a 1 is SO 2 ; e.g. compounds and salts of Formula VII and VIII are included herein.
  • a 1 is O; e.g. compounds and salts of Formula IX and X are included herein.
  • the R2 variable (compounds and salts of Formula I):
  • R 2 is hydrogen, C 1 -C 6 alkyl or (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl.
  • R 2 is hydrogen.
  • the R 3 variable (compounds and salts of Formula II):
  • R 3 is hydrogen, C 1 -QaHCyI, or C 2 -C 6 alkanoyl.
  • R 3 is hydrogen.
  • R 5 is hydrogen, halogen, amino, Q-Qalkyl, C 1 -C ⁇ alkoxy, mono- or di-(d- C 4 )alkylamino, or mono- or di-(C 1 -C 4 )alkylhydrazinyl.
  • R 5 is hydrogen.
  • R 6 is hydrogen, halogen, or amino.
  • R 6 is fluoro or hydrogen.
  • R 7 is halogen, -0(SO 2 )CF 3 , or -N 2 BF 4 .
  • R 7 is C 3 -C 7 cycloalkyl, phenyl, pyrid-3-yl, pyrid-4-yl, pyrimidin-5-yl, furan-3-yl, quinolin-3-yl, quinolin-5-yl, quinolin-6-yl, isoindol-5-yl, tetrahydroisoquinolin-5-yl, tetrahydroisoquinolin-6-yl, tetrahydroisoquinolin-7-yl, tetrahydroisoquinolin-8-yl, or indol-5-yl.
  • R 7 is substituted with O or 1 or more substituents independently chosen from halogen, hydroxy, Q-G t alkyl, C 1 -C ⁇ aIkOXy, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy, Each of which R 7 is also substituted with O or 1 amino, cyano, C 1 -C 2 hydroxyalkoxy, mono- and di-C 1 - C 4 alkylamino, C 2 -C 4 alkanoyl, (C 3 -C 7 cycloalkyl)C 0 C 2 alkyl, (heterocycloalkyl(C 0 -C 2 alkyl, or aryl.
  • R 7 is a nitrogen-linked heterocycloalkyl group, which has 4 to 8 ring members, including 0, 1 or 2 additional ring heteroatoms independently chosen from N, O, and S which heterocycloalkyl, which R 7 is substituted with 0 or 1 or more substituents independently chosen from (a) and 0 or 1 substituents chosen from (b);
  • R 7 is a pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, or azepanyl group substituted with substituted with 0 to 2 substituents independently chosen from or more of (a) and 0 or 1 substituents (b).
  • R 7 is a pyrrolidinyl group, which is substituted with 0 to 2 substituents independently chosen from one or more of (a) and 0 or 1 substituents (b).
  • R 7 is pyrrolidinyl group optionally substituted with 1 methyl or halogen substituent and substituted with one group (b) wherein (b) is oxo, amino, cyano, hydroxyQ- C 4 alkyl, aminoC 1 -C 4 alkyl, C 2 -C 4 alkanoyl, (mono- or di-C 1 -C 4 alkyl)aminoCo-C 4 alkyl, (C 3 - C 7 cycloalkyl)Co-C 2 alkyl substituted with amino, (C 3 -C 7 cycloalkylamino)C 0 -C 4 alkyl, or (C 3 - C 7 cycloalkyl)(C 1 -C 4 alkyl)aminoCo-C 4 alkyl.
  • R 7 is a pyrrolidinyl group substituted with a (5-membered heteroaryl)C 0 - C 4 alkyl, which is substituted with 0 to 2 independently chosen from 0 to 2 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, oxo, -COOH, -CONH 2 , C 1 - C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, mono- and di-(C 1 -C 4 alkyl)amino, C 1 - C 2 haloalkyl, and C 1 -C 2 haloalkoxy.
  • a (5-membered heteroaryl)C 0 - C 4 alkyl which is substituted with 0 to 2 independently chosen from 0 to 2 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, oxo, -COOH,
  • R 7 is a pyrrolidinyl group substituted with a (5-membered heteroaryl)Co- C 4 alkyl and the 5-membered heteroaryl is an imidazolyl, thiazolyl, furanyl, oxazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, or oxadiazolyl, each of which R 7 is substituted with 0 to 2 independently chosen from 0 to 2 substituents independently chosen from halogen, hydroxy, amino, cyano, nitro, oxo, -COOH, -CONH 2 , d-C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 - C 4 alkoxy, mono- and di-(C 1 -C 4 alkyl)amino, C 1 -C 2 haloalkyl, and C 1 -C 2
  • R 7 is a pyrrolidinyl group substituted with a (5-membered heteroaryl)C 0 - C 4 alkyl wherein the 5-membered heteroaryl is a thiazolyl methyl group substituted with amino or an oxazolyl methyl group substituted with amino.
  • R 7 is a group of formula
  • R15 is (a) or (b); R 16 is O, 1, or more substituents independently chosen from chloro, fluoro, methyl, or methoxy; and R 17 is hydrogen, chloro, fluoro, amino, methyl, ethyl, methoxy, C 1 -C 6 alkyl substituted with amino or hydroxy, or mono- or di-(Co-C4)alkylamino
  • Ri 5 is oxo, cyano, hydroxyC 1 -C 4 alkyl, aminoC 1 -C 4 alkyl, acetyl, (mono- or di-C 1 -C 2 alkylamino)C 1 -C 4 alkyl, cyclopropyl substituted with amino, or (C 3 - C 7 cycloalkylamino)Co-C 4 alkyl; and R 16 is 0 or 1 substituent chosen from hydroxy, amino, chloro, and methyl.
  • R 7 is a group of the formula
  • R 7 is a nitrogen-linked Cj-C 4 alkylamino substituted with a 5 or 6- membered heteroaryl group having 1 or 2 heteroatoms independently chosen from N, O, and S, or substituted with a heterocycloalkyl group, which has 4 to 8 ring members, including 1 or 2 ring heteroatoms independently chosen from N, O, and S.
  • R 7 is substituted with 0 or 1 or more substituents independently chosen from (a) and 0 or 1 substituents chosen from (b).
  • R 7 is C 1 -C 2 alkylamino substituted with pyridyl, piperazinyl, piperidinyl, or morpholinyl, each of which is substituted with 0, 1, or 2 substituents independently chosen from halogen, methyl, and methoxy.
  • R 7 is a nitrogen-linked heterocycloalkyl or heterocycloalkenyl group, each of which has 4 to 8 ring members, including 0, 1, or 2 additional ring heteroatoms independently chosen from N, O, and S, forming part of a bicyclic system with a 3- to 8-membered cycloalkyl or heterocycloalkyl ring in fused or spiro orientation, Each of which R 7 is substituted with 0 or 1 or more substituents independently chosen from (a) and 0 or 1 substituents chosen from (b), where (a) and (b) carry the definitions set forth above.
  • R 7 is a piperidinyl, piperazinyl, or pyrrolidinyl group, which is part of a bicyclic system having a spiro attached C 3 -C 4 cycloalkyl, dioxolanyl, or azetidinyl group, which bicyclic system is substituted with 0, 1, or 2 substituents independently chosen from halogen, hydroxy, amino, oxo, cyano, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy.
  • R 7 is a group of formula:
  • a 8 is nitrogen.
  • a 8 is CR 8 , and R 8 is hydrogen, halogen, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, C 1 - C 2 haloalkyl, or C 1 -C 2 haloalkoxy.
  • a 8 is CR 8 , and R 8 is hydrogen, halogen, or d-C 2 alkoxy.
  • a 8 is CR 8 and R 8 is methoxy.
  • the R 9 Variable
  • R 9 is pyridine, pyrazine, pyridazine, or pyrimidine, each of which is substituted with 1 to 4 substituents independently chosen from halogen, amino, C 1 -C 4 alkyl, and mono- and di-(C 1 -C4)alkylamino.
  • R 9 is pyridine which is substituted with 1 to 4 substituents independently chosen from halogen, amino, Cj ⁇ alkyl, and mono- and di-(C 1 -C 4 )alkylamino;
  • R. 9 is pyridine, which is substituted with 1 to 4 substituents independently chosen from halogen, amino, Q ⁇ alkyl, and mono- and di-(C 1 -C4)alkylamino.
  • R.9 is pyridine group of the formula
  • R 20 is hydrogen or C 1 .C-jalkyl; and R 21 and R 22 are independently chosen halogen substituents.
  • R 20 is hydrogen, and R 2 i and R 22 are both fluoro.
  • the invention includes compounds and salts of Formula I in which condition (2) is met for variables R 2 , R 5 , and R ⁇ , condition (10) is met for the R 7 variable, condition (3) is met for A 8 and condition (4) is met for R 9 .
  • the invention includes compounds and salts in which:
  • R 2 and R 5 are hydrogen
  • R 6 is fluoro or hydrogen
  • R 7 is a pyrrolidinyl group, which is substituted with 0 to 2 substituents independently chosen from one or more of (a) and 0 or 1 substituent (b);
  • a 8 is CR 8 , and R « is hydrogen, halogen, Q-Qalkyl, d-C 2 alkoxy, C ⁇ -C 2 haloalkyl, or Cj- C 2 haloalkoxy;
  • R 9 is pyridine group of the formula
  • R 20 21 wherein R 20 is hydrogen or C 1- C 4 alkyl; and R 21 and R 22 are independently chosen halogen substituents. In some embodiments R 20 is hydrogen, and R 2 i and R 22 are both fluoro.
  • the invention includes compounds of Formulas XI and XII shown below:
  • R 6 is hydrogen or halogen
  • R 8 is hydrogen, halogen, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, trifluoromethyl, or trifluoromethoxy.
  • R 8 is hydrogen, halogen, C]-C 2 alkyl, or C!-C 2 alkoxy or R 8 is methoxy.
  • Certain compounds of Formula I and Formula II possess potent antibacterial, antifungal, and/or anti-protozoal activity.
  • Particular compounds of the invention exhibit Minimum Inhibitory Concentrations (MIC) of 64 ⁇ g/ ml or less against Staphyloccocus aureus and/ or Escherichia coli in a standard assay for determining the MIC of a compound against these bacteria, such as the assay provided in Example 5 below.
  • Preferred compounds of the Formula I and II exhibit MIC values of 10 ⁇ g/ ml or less against Staphyloccocus aureus and/ or Escherichia coli. More preferred compound of the Formula I and II exhibit MIC values of 4 ⁇ g/ ml or less, or even more preferably 1 ⁇ g/ ml or less, against Staphyloccocus aureus and/ or Escherichia coli.
  • Certain compounds of Formula I and Formula II are selective antimicrobial agents; having the ability to kill or inhibit the growth or reproduction of microbial organisms, while having little or no effect on the cells of fish, amphibians, reptiles, birds, or mammals.
  • the selectivity of compounds of Formula I and Formula II may be assessed by determining the CC 50 (the concentration at which 50% of the cells are killed) for cultured cells of a higher animal, such as a fish, reptiles, amphibian, bird, or mammal.
  • Certain compounds of the invention exhibit a CC 50 of greater that 100 micromolar for mammalian cells.
  • Certain compounds of the invention exhibit a CC 50 of greater than 100 micromolar for cultured human hepatocytes, and also exhibit MIC values of 64 ⁇ g/ ml or less, preferably 10 ⁇ g/ ml or less, or more preferably 4 ⁇ g/ ml or less, or still more preferably 1 ⁇ g/ ml or less against Staphylococcus aureus and/ or Escherichia coli.
  • the invention also includes novel intermediates useful for the synthesis of antimicrobial compounds of Formula I and Formula II.
  • Compounds in which R 7 is a substituent, XR A , attached via a carbon-carbon are formed by coupling reactions occur between (XR A )-M and R-Y in the presence of catalyst Q, where M is Li, Mg, B, Al, Si, Zn, Cu, Zr, or Sn; where Y is I, Br, Cl, -0(SO 2 )CF 3 , or -N 2 BF 4 ; and where Q is Fe, Ni, Cu, Pd, or Rh.
  • M is Boron, di-substituted with OH, OG, or G, where G is an optionally substituted straight, branched or cyclic alkyl group, or other suitable group; Y is Br, and where Q is Pd.
  • G is an optionally substituted straight, branched or cyclic alkyl group, or other suitable group; Y is Br, and where Q is Pd.
  • a general review of this chemistry can be found in Tamao, K and Miyaura, N. Topics in Current Chemistry 219: 1-9 (2002).
  • a review of the use of coupling reagents in which M is Boron with a listing of potential boronates, palladium catalysts, and reaction conditions can be found in Miyaura, N. Topics in Current Chemistry 219: 11-59 (2002).
  • the invention includes synthetic intermediates of Formula XIII and XIV
  • the invention also includes synthetic intermediates of Formula XIII and XIV, above, in which Y is fluoro. Such compounds are useful for synthesis of compounds of Formula I and Formula II in which R 7 is a substituent bound via a nitrogen-carbon bond.
  • the invention provides anti-microbial compositions, including anti-bacterial compositions, comprising a compound or salt thereof of Formula I or Formula II, together with a carrier, diluent, and/or excipient.
  • the invention provides pharmaceutical compositions comprising a compound or salt thereof of Formula I or Formula II.
  • compositions comprising a compound or pharmaceutically acceptable salt of Formula I or Formula II, together with one or more pharmaceutically acceptable carrier, excipients, adjuvant, diluent, or other ingredient.
  • the pharmaceutical composition may be formulated as any pharmaceutically useful form, e.g., as an aerosol, a cream, a gel, a pill, a capsule, a tablet, a syrup, a transdermal patch, or an ophthalmic solution.
  • compositions and formulations comprising a compound or pharmaceutically acceptable salt of Formula I, together with one or more pharmaceutically acceptable carriers, excipients, adjuvant, diluent, or other ingredients.
  • Compounds and salts of the invention may be administered orally, topically, parenterally, by inhalation or spray, sublingually, transdermally, via buccal administration, rectally, as an ophthalmic solution, or by other means, in dosage unit formulations.
  • Compounds and salts of Formula I may be prepared and administered as orally administrable liquid formulations, suspensions, emulsions, dispersible powders, solid oral dosage forms such as tablets or capsules, injectable and parenteral formulations, suppositories, topical formulations, sublingual, buccal, or nasal dosage forms.
  • the invention also includes methods for making pharmaceutical compositions comprising a compound or salt of Formula I.
  • Excipients must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the animal being treated.
  • An excipient can be inert or it can possess pharmaceutical benefits.
  • the amount of excipient employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound.
  • Carriers and excipients are selected with respect to the intended form of administration, i.e. oral tablets, capsules (either solid-filled, semi-solid filled or liquid filled), powders for constitution, oral gels, elixirs, dispersible granules, syrups, suspensions, and the like, and consistent with conventional pharmaceutical practices.
  • a compound or salt of Formula I may be combined with any oral non-toxic pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms) and the like.
  • suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated I in the mixture
  • compositions comprising pharmaceutical formulations in a unit dosage form, hi such form, the preparation is subdivided into i suitably sized unit doses containing appropriate quantities of the active components, e.g., an effective amount to achieve the desired purpose.
  • binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes.
  • lubricants useful in pharmaceutical dosage forms include boric acid, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • disintegrants include starch, methylcellulose, guar gum and the like. Sweetening and flavoring agents and preservatives may also be included where appropriate. Disintegrants, diluents, lubricants, binders and the like, are discussed in more detail below.
  • compositions of the present invention may be formulated in sustained release form to provide the rate controlled release of I any one or more of the components or active ingredients to optimize the therapeutic effects, i.e. HCV inhibitory activity and the like.
  • Suitable dosage forms for sustained release include layered tablets containing layers of varying disintegration rates or controlled release polymeric matrices: impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.
  • Amount of compound or salt of Formula I in a unit dose may be generally varied or adjusted from about 1.0 milligram to about 1,000 milligrams, from about 1.0 to about 950 milligrams, from about 1.0 to about 500 milligrams, or from about 1 to about 250 milligrams, according to the particular application and the potency of the compound.
  • the actual dosage employed may be varied depending upon the patient's age, sex, weight and severity of the condition being treated.
  • the invention includes solid dosages forms such as tablets and capsules.
  • a compound or salt of Formula I comprises about 5 percent to about 95 percent by weight of the solid dosage form.
  • a capsule is a dosage form administered in a special container or enclosure containing an active agent.
  • the active agent may be present in solid, liquid, gel, or powder form, or any other pharmaceutically acceptable form.
  • a capsule shell may be made of methyl cellulose, polyvinyl alcohols, or denatured gelatins or starch or other material. Hard shell capsules are typically made of blends of relatively high gel strength bone and pork skin gelatins.
  • the capsule itself may contain small amounts of dyes, opaquing agents, plasticizers and preservatives.
  • Conventional methods for preparing tablets are known. Such methods include dry methods such as direct compression and compression of granulation produced by compaction, or wet methods or other special procedures. Conventional methods for preparing other solid dosage forms, for example, capsules, suppositories and the like are also well known.
  • solid form preparations that are intended to be converted shortly before use to liquid form preparations for either oral or parenteral administration.
  • liquid forms include solutions, suspensions and emulsions.
  • Liquid form preparations include solutions, suspensions, and emulsions.
  • liquid pharmaceutical preparations include water or water-propylene glycol solutions for parenteral injections and sweetened solutions for oral dosage forms, suspensions, and emulsions.
  • Liquid form preparations may also include solutions for intranasal administration.
  • Aerosol preparations suitable for inhalation include solutions and: solids in powder form, which may be in combination with a pharmaceutically acceptable carrier such as inert, compressed gas, e.g. nitrogen.
  • Suppository formulations may contain a low melting wax such as a mixture of fatty acid glycerides such as cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein by stirring or similar mixing. The molten homogeneous mixture is then poured into convenient sized: molds, allowed to cool and thereby solidify.
  • a low melting wax such as a mixture of fatty acid glycerides such as cocoa butter
  • the compounds of the invention may also be deliverable transdermally.
  • the transdermal compositions may take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are
  • An oral gel is a formulation in which the active agent dispersed or solubilized in a hydrophillic semi-solid matrix.
  • An oral gel may be administered as a complete dosage form or may be contained in a capsule.
  • Diluents often comprise a major portion of the composition or dosage form. Suitable diluents include sugars such as lactose, sucrose, mannitol and sorbitol; starches derived from wheat, corn, rice and potato; and celluloses such as microcrystalline cellulose.
  • the amount of diluent in the composition may be, for example, about 10 to about 90% by weight of the total composition, about 25 to about 75%, about 30 to about 60% by weight, or about 12 to about 60%.
  • Disintegrants are materials added to a pharmaceutical composition to help it break apart (disintegrate) and release the active agent.
  • Suitable disintegrants include starches; including "cold water soluble" modified starches such as sodium carboxymethyl starch; natural and synthetic gums such as locust I bean, karaya, guar, tragacanth and agar; cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose; microcrystalline celluloses and cross-linked microcrystalline celluloses such as sodium croscarmellose; alginates such as alginic acid and sodium alginate; clays such as bentonites; and effervescent mixtures.
  • the amount of disintegrant in the composition can range, for example, from about 2 to about 15% by weight of the composition or from about 4 to about 10% by weight.
  • Binders are substances that bind or "glue" powders together and make them cohesive by forming granules, thus serving as the "adhesive" in the formulation. Binders add cohesive strength already available in the diluent or bulking agent. Suitable binders include sugars such as sucrose; starches derived from wheat, corn rice and potato; natural gums such as acacia, gelatin and tragacanth; derivatives of seaweed such as alginic acid, sodium alginate and ammonium calcium alginate; cellulosic materials such as; methylcellulose and sodium carboxymethylcellulose and hydroxypropylmethylcellulose; polyvinylpyrrolidone; and inorganics such as magnesium aluminum silicate.
  • the amount of binder in the composition can range, for example, from about 2 to about 20% by weight of the composition, or from about 3 to about 10% by weight, even more preferably from about 3 to about 6% by weight.
  • Lubricants are substances added to a pharmaceutical formulation to enable the tablet, granules, etc. after it has been compressed, to release from the; mold or die by reducing friction or wear.
  • Suitable lubricants include metallic stearates such as magnesium stearate, calcium stearate or potassium stearate; stearic acid; high melting point waxes; and water soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols and di-leucine.
  • Lubricants are usually added at the very last step before compression, since they must be present on the surfaces of the granules and in between them and the parts of the tablet press.
  • the amount of lubricant in the composition can range, for example, from about 0.2 to about 5% by weight of the composition, from about 0.5 to about 2%, or from about 0.3 to about 1.5% by weight.
  • Glidents are materials that prevent caking and improve the flow characteristics of granulations, so that flow is smooth and uniform.
  • Suitable glidents include silicon dioxide and talc.
  • the amount of glident in the composition can range, for example, from about 0.1% to about 5% by weight of the total composition or from about 0.5 to about 2% by weight.
  • Coloring agents provide coloration to the composition or dosage form.
  • excipients can include food grade dyes and food grade dyes adsorbed onto a suitable adsorbent such as clay or aluminum oxide.
  • the amount of the coloring agent can vary, for example from about 0.1 to about 5% by weight of the composition or from about 0.1 to about 1%.
  • the invention includes packaged pharmaceutical formulations.
  • packaged formulations include a pharmaceutical composition containing one or more compounds or salts of Formula I or Formula II in a container and instructions for using the composition to treat an animal (typically a human patient) suffering from a microorganism infection) or prevent a microorganism infection in an animal.
  • the instructions may also be instructions for using the composition to treat a patient suffering from a bacterial infection, such as a S. aureus infection.
  • compositions can be administered alone or as mixtures, and the compositions may further include additional drugs or excipients as appropriate for the indication.
  • the invention includes methods of preventing and treating microorganism infections, particularly bacterial and protozoal infections, by administering an effective amount of one or more compounds of Formula I or Formula II to an animal at risk for a microorganism infection or suffering from a microorganism infection.
  • the animal may be a fish, amphibian, reptile or bird, but is preferably a mammal. Methods of treating and preventing microorganism infections in livestock animals, companion animals, and human patients are particularly preferred.
  • the compounds disclosed herein are useful for preventing and treating bacterial infections in animals. Furthermore compounds of the invention may be used to treat a variety of conditions not attributed to bacterial infections. These include diseases and disorders caused fungal infections, mycoplasma infections, protozoal infections, or other conditions involving infectious organisms.
  • an effective amount of a compound of Formula I or Formula II may be an amount sufficient to reduce the symptoms of the microorganism infection.
  • an effective amount of a Compound of Formula I may be an amount sufficient to significantly reduce the amount of microorganism or antibodies against the detectable in a patient's tissues or bodily fluids.
  • Methods of treatment also include inhibiting microorganism replication in vivo, in an animal at risk for a microorganism infection or suffering from such an infection, by administering a sufficient concentration of a compound of Formula I and Formula II to inhibit bacterial survival in vitro.
  • a sufficient concentration of a compound administered to the patient is meant the concentration of the compound available in the animal's system to prevent or combat the infection.
  • concentration by be ascertained experimentally, for example by assaying blood concentration of the compound, or theoretically, by calculating bioavailability.
  • the amount of a compound sufficient to inhibit bacterial survival in vitro may be determined with a conventional assay for bacterial survival such as the Minimum Inhibitory Concentration (MIC) Assay disclosed in Example 5, which follows.
  • MIC Minimum Inhibitory Concentration
  • the invention also includes using compounds of Formula I and Formula II in prophylactic therapies.
  • an effective amount of a compound of the invention is an amount sufficient to significantly decrease the treated animal's risk of contracting a microorganism infection.
  • Compounds of the invention are particularly useful for treating and preventing infectious disorders. These include for example: ocular infections such as conjunctivitis; urinary tract and genital infections, such as complicated urinary tract infections, acute urinary tract and genital infections, such as pyelonephritis, cervical gonococcal infections, cystitis, urethral chlamydial infections, cervical chlamydial infections, urethral gonococcal infections, and prostatitis, respiratory infections, such as lower respiratory tract infections, acute sinusitis, acute exacerbations of chronic bronchitis, community-acquired pneumonia, and nosocomial pneumonia, skin infections, such as skin-structure infections, impetigo, folliculitis, boils, scalded skin syndrome, and cellulites, and other infections such as bone infections, joint infections, infectious diarrhea, typhoid fever, intra-abdominal infections, gynecologic infections, including toxic shock syndrome, pelvic infections,
  • the disclosed compounds are useful for treating infections caused by the following microorganisms:
  • Aerobic Gram-positive Microorganisms Including but not limited to Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus (including methicillin S. aureus), Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptococcus pneumoniae, Streptococcus pyogenes , Staphylococcus haemolyticus, and Staphylococcus hominis;
  • Aerobic Gram-negative Microorganisms Including but not limited to Campylobacter jejuni, Citrobacter diversus, Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Morganella morganii, Neisseria gonorrhoeae, Proteus mirabilis, Proteus vulgaris, Providencia rettgeri, Providencia stuartii, Pseudomonas aeruginosa, Stenotrophomonas maltophila, Salmonella typhi, Serratia marcescens, Shigella boydii.
  • Shigella dysenteriae Shigella flexneri, Shigella sonnei.
  • Acinetobacter Iwoffi Aeromonas hydrophila, Edwardsiella tarda, Enter obacter aerogenes, Klebsiella oxytoca, Legionella pneumophila, Pasteurella multocida, Salmonella enteritidis, Vibrio cholerae, Vibrio par ahaemolyticus, Vibrio vulnificus, Yersinia enterocolitica and H. Pylori.
  • Non-bacterial microorganisms Mycoplasma, Legionella and Chlamydia.
  • Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day).
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
  • Frequency of dosage may also vary depending on the compound used and the particular disease treated. However, for treatment of most infectious disorders, a dosage regimen of 4 times daily or less is preferred and a dosage regimen of 1 or 2 times daily is particularly preferred.
  • the compounds of the invention may also be useful in combination with other pharmaceutically active agents such as antibacterial agents, antiviral agents, antifungal agents, antiinflammatories, interferon, efflux-pump inhibitors, and beta-lactamase inhibitors.
  • Antibiotic agents include any molecule that tends to prevent, inhibit or destroy life and as such, includes anti-bacterial agents, anti-fungicides, anti-viral agents, and anti-parasitic agents.
  • compositions of the invention include single dosage forms containing of a compound of Formula I and/or Formula II and one or more other active agent, dosage forms containing more than one compound of Formula I and/ or Formula II, and separate administration of a compound of Formula I and/or Formula II with another active agent.
  • active agents which are useful in combinations of the invention, may be isolated from an organism that produces the agent or synthesized by methods known to those of ordinary skill in the art of medicinal chemistry or purchased from a commercial source.
  • Anti-bacterial antibiotic agents include, but are not limited to, penicillins, cephalosporins, carbacephems, cephamycins, carbapenems, monobactams, aminoglycosides, glycopeptides, quinolones, tetracyclines, macrolides, and fluoroquinolones (see Table below).
  • antibiotic agents include, but are not limited to, Penicillin G (CAS Registry No.: 61- 33-6); Methicillin (CAS Registry No.: 61-32-5); Nafcillin (CAS Registry No.: 147-52-4); Oxacillin (CAS Registry No.: 66- 79-5); Cloxacillin (CAS Registry No.: 61-72-3); Dicloxacillin (CAS Registry No.: 3116-76-5); Ampicillin (CAS Registry No.: 69-53-4); Amoxicillin (CAS Registry No.: 26787-78-0); Ticarcillin (CAS Registry No.
  • Anti-fungals agents include but are not limited to Amphotericin B, Candicidin, Dermostatin, Filipin, Fungichromin, Hachimycin, Hamycin, Lucensomycin, Mepartricin, Natamycin, Nystatin, Pecilocin, Perimycin, Azaserine, Griseofulvin, Oligomycins, Neomycin, Pyrrolnitrin, Siccanin, Tubercidin, Viridin, Butenafine, Naftifme, Terbinafine, Bifonazole, Butoconazole, Chlordantoin, Chlormidazole, Cloconazole, Clotrimazole, Econazole, Enilconazole, Fenticonazole, Flutrimazole, Isoconazole, Ketoconazole, Lanoconazole, Miconazole, Omoconazole, Oxiconazole, Sertaconazole, Sulconazole, Tioconazole, Tolciclate, To
  • Antiviral agents include, but are not limited to, Acyclovir, Cidofovir, Cytarabine, Dideoxyadenosine, Didanosine, Edoxudine, Famciclovir, Floxuridine, Ganciclovir, Idoxuridine, Inosine Pranobex, Lamivudine, MADU, Penciclovir, Sorivudine, Stavudine, Trifluridine, Valacyclovir, Vidarabine, Zalcitabine, Zidovudine, Acemannan, Acetylleucine, Amantadine, Amidinomycin, Delavirdine, Foscarnet, Indinavir, Interferon- ⁇ , Interferon- ⁇ , Interferon- ⁇ , Kethoxal, Lysozyme, Methisazone, Moroxydine, Nevirapine, Podophyllotoxin, Ribavirin, Rimantadine, Ritonavir, Saquinavir
  • Antiinflammatory agents include, but are not limited to, Enfenamic Acid, Etofenamate, FIufenamic Acid, Isonixin, Meclofenamic Acid, Mefenamic Acid, Niflumic Acid, Talniflumate, Terofenamate, Tolfenamic Acid, Aceclofenac, Acemetacin, Alclofenac, Amfenac, Amtolmetin Guacil, Bromfenac, Bufexamac, Cinmetacin, Clopirac, Diclofenac, Etodolac, Felbinac, Fenclozic Acid, Fentiazac, Glucametacin, Ibufenac, Indomethacin, Isofezolac, Isoxepac, Lonazolac, Metiazinic Acid, Mofezolac, Oxametacine, Pirazolac, Proglumetacin, Sulindac, Tiaramide, Tolmetin, Tropesin, Zomepir
  • Beta lactamase inhibitors include, but are not limited to Clavulanic acid, Sulbactam, Sultamacillin, and Tazobactam.
  • Compounds of the invention may also be combined with one or more efflux pump inhibitor, such as a quinazolinone efflux pump inhibitors, d-ornithine-d-homophenylalanine-3- aminoquinoline, Phe-Arg-b-naphthylamide, propafenone, a phenothiazine or thioxanthene efflux pump inhibitor, l-aza-9-oxafluorenes, N-[4-[2-(3,4-dihydro-6,7-dimethoxy-2(lH)- isoquinolinyl)ethyl]phenyl]-9, 10-dihydro-5-methoxy-9-oxo-4-Acridinecarboxamide, reserpine, Milbemycin, Cinchonine, Verapamil, L-phenylalanyl-N-2-naphthalenyl-L-Argininamide (and analogs), 5'-methoxyhydnoc
  • the compounds of the invention are prepared according to methods well-known to those skilled in the art of organic chemical synthesis.
  • the starting materials used in preparing the compounds of the invention are known, made by known methods, or are commercially available.
  • one optical isomer including a diastereomer and enantiomer, or a stereoisomer
  • a racemic mixture is discussed herein, it is clearly contemplated to include both optical isomers, including diastereomers and enantiomers, or one stereoisomer substantially free of the other.
  • the chemical shifts for 1 H and 13 C are reported in parts per million ( ⁇ ) relative to external tetramethylsilane and are referenced to signals of residual protons in the deuterated solvent.
  • the chemical shifts for 19 F are reported in parts per million (S) relative to external fluorotrichloromethane.
  • Assignment of NMR data is based on two-dimensional correlation experiments ( 1 H- 1 H COSY, 1 H- 13 C HMQC, 1 H- 13 C HMBC, and 1 H- 1 H NOESY) and the usual principles of NMR spectroscopy (the magnitudes of coupling constants and chemical shifts).
  • Analytical HPLC is performed using a YMC Pack Pro Cl 8 50 x 4.6 mm 5 ⁇ m column with an isocratic elution of 0.24 min at 90:10 H 2 OiCH 3 CN containing 0.1% TFA followed by a 4-min linear gradient elution from 90:10 to 10:90 at a flow rate of 2.5 mL/min with UV detection at 254 nm.
  • 2,4,5-trifluorobenzoyl chloride (2) is prepared from 2,4,5-trifluorobenzoic acid as described previously. [Reuman, M.; et. al, J. Med. Chem. (1995) 38, 2531-2540]. Thionyl chloride (8 ml) is added to a solid 2,4,5-trifluoro-3-methoxy-benzoic acid (154 mg, 0.75 mmole ). The reaction mixture is refluxed for 4 hours. It is distilled to remove excess thionyl chloride and further dried under vacuum at rt for the further reaction. Step 2. 3-Oxo-3 -(2, 4, 5-t ⁇ fluoro-phenyl)-propionic acid ethyl ester (B).
  • the mixture is warmed to - 5 0 C for about two minutes until there is no further disappearance of pink color (to be sure the amount of BuLi is adequate to form the dianion), cooled to -75 0 C, and added slowly to a solution of 2,4,5-trifluorobenzoyl chloride (0.75 mmole) in THF (2-3mL).
  • the resulting reaction mixture is warmed up to room temperature, diluted with ethyl acetate (5OmL), acidified with IN HCl with stirring.
  • the organics were washed with 5% NaHCO 3 (30mLx2), brine (50mLx2), dried over Na 2 SO 4 , and concentrated.
  • Step 6 9-6(but-3-allylamino)-3, 5-difluoropyridin-2-yl)-6, 7-difluoroisothiazolo[5 ,4-b] quinoline- 3,4-(2H,9H)-dione (F).
  • Step 7 9-(6-(allylamino)-3,5-difluoropy ⁇ din-2-yl)-6-fluoro-7-(3-hydroxyazetidin-l- yl)isothiazolo[5,4-b]quinoline-3,4-(2H,9H)-dione ⁇ G).
  • Step 8 9-(6-amino-3,5-difluoropyridin-2-yl)-6-fluoro-7-(3-hydroxyazetidin-l-yl)isothiazolo[5,4- b]quinoline-3,4-(2H,9H)-dione (Compound 1).
  • Rh(Ph 3 P) 3 Cl (5%, 0.0014 mmole)is added to a solution of G (13mg) in CH 3 CN (3 ml) and water (0.5mL). The reaction mixture is heated to 50 0 C until completion. The catalyst is filtered off and the filtrate concentrated to give 6mg (50%) of Compound 1.
  • EXAMPLE 4. ADDITIONAL 9-(HETEROARYL)-ISOTHIAZOLO[5,4-B]QUINOLINE-3,4(2H,9H)-DIONES [0193] The following compounds are prepared by the method illustrated in Example 3. Certain compounds of this Example exhibit an EC50 of less than 1 micromolar in the assay described in Example 5.
  • the antimicrobial activity of the compounds of the invention may be evaluated by a number of methods, including the following visual minimum inhibitory concentration (MIC) assay. This assay determines the minimum concentration of compound required to inhibit growth of a bacterial strain.
  • MIC visual minimum inhibitory concentration
  • test organism ⁇ 1 x 10 6 cfu/mL
  • the final test concentrations ranges from 0.125-128 ⁇ g/mL.
  • Inoculated plates are incubated in ambient air at 37°C for 18 to 24 hours.
  • the organisms selected for testing included laboratory strains S. aureus ATCC 29213 and E. coli ATCC 25922 (strains purchased from American Type Culture Collection, Manassas, VA)m , S. aureus FQR700699, and Paeruginosa 27853.
  • the minimum inhibitory concentration (MIC) is determined as the lowest concentration of compound that inhibited visible growth of the test organism.
  • Optimal cell density is first determined by plating cells in a 96-well plate standard sterile tissue culture plates in 100 ⁇ l media, 10%FBS at six cell densities from 500 cells/ well to 15,000 cells/ well. A cell free well containing only media is used as a control. Cells are incubated at 37 oC in a 5% CO 2 incubator for 24 hours. 10% culture volume (lOul) of Alamar Blue (Biosource, DALl 100, 10OmL) is then added. Cells are incubated at 37 oC in a 5% CO2 incubator and read in a Victor V plate reader, 544nm excitation, 590nm emission, at 3, 4, and 24 hours after the addition of Alamar Blue. The cell number vs.
  • Cells are plated at optimal cell density in a standard sterile tissue culture 96 well plate, and incubated at 37 0 C O/N in a 5% CO 2 incubator. 12 to 48 hours post-plating media is removed. The cells are washed 1 or 2 times with IX PBS and replaced with fresh media containing the test compound in 1% DMSO. 24 to 72 hours after addition of compound, the media is removed, and the cells washed 1 to 2 times with IX PBS. Fresh media containing 1/10 volume of Alamar Blue is then added. Plates are incubated 4 hours at 37 oC in a 5% CO2 incubator and read in a Victor V plate reader, 544 nm excitation, 590 nm emission.
  • Compounds are diluted to 20 micromolar in 1% DMSO and media and screened in duplicate to obtain single concentration cytotoxicity data. Eight concentration points from 0.78 micromolar to 100 micromolar, run in duplicate, are used to determine cyctotoxicity CC50 values. Cells with 1% DMSO and media are used as a negative control, compounds having a known CC50 against a particular cell type are used as positive controls.
  • Preferred compounds disclosed in Example 1 and 2 exhibit CC50 values greater than 10 uM against each of the cell lines listed below.
  • Other cell types that may be used include but are not limited to Balb/3TC, CEM-SS, HeLa, Hep2, HepG2, HT-29, MRC-5, SK-N-SH, U- 87 MG, 293T, and Huh-7. More preferred are compounds with a CC50 value greater than 50 uM. Most preferred are compounds with a CC50 value greater than 100 uM. Should the most preferred compounds have CC50 greater than 10 micromolar.

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Abstract

L'invention concerne des composés et des sels représentés par la Formule (I) et la Formule (II) et possédant une activité anti-microbienne. L'invention concerne également de nouveaux intermédiaires synthétiques utiles dans la fabrication de composés représentés par la Formule (I) et par la Formule (II). Les variables R2, R3, R5, R6, R7, A8 et R9 sont définies présentement. Certains composés représentés par la Formule (I) et par la Formule (II) décrites présentement sont des inhibiteurs puissants et/ou sélectifs de la synthèse de l'ADN bactérien et de la réplication bactérienne. L'invention concerne également des compositions anti-microbiennes comprenant des compositions pharmaceutiques contenant un ou plusieurs composés représentés par la Formule (I) ou par la Formule (II) et un ou plusieurs supports, excipients ou diluants. De telles compositions peuvent contenir un composé représenté par la Formule (I) ou par la Formule (II) en tant qu'unique agent actif ou peuvent contenir une combinaison d'un composé représenté par la Formule (I) ou par la Formule (II), et un ou plusieurs autres agents actifs. L'invention concerne également des procédés pour traiter des infections microbiennes chez les animaux.
PCT/US2007/020611 2006-09-21 2007-09-21 9-(hétéroaryl)-isothiazolo[5,4-b]quinoléine-3,4-diones et composés apparentés en tant qu'agents anti-infectieux Ceased WO2008036420A2 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011031745A1 (fr) 2009-09-09 2011-03-17 Achaogen, Inc. Analogues de fluoroquinolone antibactériens
WO2017098430A1 (fr) 2015-12-10 2017-06-15 Novartis Ag Nouveau procédé et composés intermédiaires

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US4767762A (en) * 1985-12-23 1988-08-30 Abbott Laboratories Tricyclic quinoline and naphthyride antibacterials
BRPI0413528A (pt) * 2003-08-12 2006-10-10 Achillion Pharmaceuticals Inc isotiazol quinolonas e compostos afins como agentes antiinfecciosos
US7199128B2 (en) * 2005-02-02 2007-04-03 Achillion Pharmaceuticals, Inc. 8-N-substituted-2H-isothiazolo[5,4-b]quinolizine-3,4-diones and related compounds as antiinfective agents
KR20070107123A (ko) * 2005-02-16 2007-11-06 아칠리온 파르마세우티칼스 인코포레이티드 항-감염제들로서의 새로운 이소티아졸로퀴놀론들 및 관련화합물들

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011031745A1 (fr) 2009-09-09 2011-03-17 Achaogen, Inc. Analogues de fluoroquinolone antibactériens
WO2017098430A1 (fr) 2015-12-10 2017-06-15 Novartis Ag Nouveau procédé et composés intermédiaires

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