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WO2011031740A1 - Analogues de fluoroquinolone antibactériens - Google Patents

Analogues de fluoroquinolone antibactériens Download PDF

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Publication number
WO2011031740A1
WO2011031740A1 PCT/US2010/048104 US2010048104W WO2011031740A1 WO 2011031740 A1 WO2011031740 A1 WO 2011031740A1 US 2010048104 W US2010048104 W US 2010048104W WO 2011031740 A1 WO2011031740 A1 WO 2011031740A1
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WIPO (PCT)
Prior art keywords
compound
hydrogen
optionally substituted
alkyl
taken together
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PCT/US2010/048104
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English (en)
Inventor
Allan Scott Wagman
Heinz Ernst Moser
Glenn A. Mcenroe
James Bradley Aggen
Martin Sheringham Linsell
Adam Aaron Goldblum
Lloyd J. Simons
Thomas R. Belliotti
Christina R. Harris
Toni-Jo Poel
Michael J. Melnick
Ricky D. Gaston
John H. Griffin
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Achaogen, Inc.
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Publication of WO2011031740A1 publication Critical patent/WO2011031740A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems

Definitions

  • the present invention is directed to novel fluoroquinolone compounds, and methods for their preparation and use as therapeutic or prophylactic agents. Description of the Related Art
  • Antibiotics are chemical substances produced by various species of microorganisms (bacteria, fungi, actinomycetes) that suppress the growth of other microorganisms and may eventually destroy them.
  • antibiotics common usage often extends the term antibiotics to include synthetic antibacterial agents, such as the sulfonamides, oxazolidinones, or quinolones, that are not products of microbes.
  • the number of antibiotics that have been identified now extends into the hundreds, and many of these have been developed to the stage where they are of value in the therapy of infectious diseases.
  • Antibiotics differ markedly in physical, chemical, and pharmacological properties, antibacterial spectra, and mechanisms of action. In recent years, knowledge of molecular mechanisms of bacterial, fungal, and viral replication has greatly facilitated rational development of compounds that can interfere with the life cycles of these microorganisms.
  • Fluoroquinolone class of antibiotics are a powerful tool in combating bacterial infections. Fluoroquinolones have been used extensively to treat respiratory tract infections (including for example, bronchitis, pneumonia, tuberculosis), urinary tract infections, diarrhea, postoperative -wound infections, bone and joint infections, skin infections, inflammation of the prostate, ear infections, various sexually transmitted diseases, various infections that affect people with AIDS, and other conditions, in animals and humans. Fluoroquinolones are active against a wide spectrum of Gram-positive and Gram-negative bacteria.
  • fluoroquinolones have been found to be effective against Staphylococcus aureus, Streptococcus pneumoniae, coagulase-negative staphylococci, Streptococcus pyogenes, Staphylococcus epidermis, Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Pseudomonas aeruginosa, Proteus mirabilis, Proteus vulgaris, Providencia stuartii, Morganella morganii, Citrobacter diversus, Citrobacter freundii, Haemophilus influenzae, and Neisseria gonorrhea, and other organisms.
  • Staphylococcus aureus to both penicillin and erythromycin has made the fluoroquinolone antibiotics a viable alternative for the treatment of skin diseases and pneumoniae.
  • Fluoroquinolones were first developed in the early 1960s. The first precursor of fluoroquinolones, nalidixic acid, was approved by the FDA in 1963 for the treatment of urinary tract infections. Nalidixic acid is rapidly absorbed after oral administration and is excreted into the urine in bactericidal concentrations. Nalidixic acid, however, has several limitations that has prevented its use in other types of infections. Specifically, nalidixic acid has a narrow spectrum of activity and microorganisms easily developed resistance to the drug. The development of other fluoroquinolones by chemically altering the basic structure of nalidixic acid, however, has led to improved fluoroquinolones that are more effective against resistant bacteria and effective against a broader range of bacteria.
  • Ciprofloxacin was approved by the FDA in 1986 for the oral treatment of bacterial infections and set a benchmark especially for Gram-negative organisms. More compounds from the fluoroquinolone class were approved in the following years: levofloxacin (1993, initially approved as the racemate ofloxacin in 1985), gatifloxacin (1999), moxifloxacin (1999), and gemifloxacin (2003), to just name a few. The latter compounds were greatly improved for their potency against Gram-positive organisms including S. aureus and S. pneumoniae such that they even cover multi-drug resistant organisms (gemifloxacin for S. pneumoniae).
  • the present invention is directed to novel fluoroquinolone compounds having antibacterial activity, including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and the use of such compounds in the treatment of bacterial infections .
  • A, B and D are as follows:
  • G is hydrogen or methyl
  • Ri is optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl;
  • R 2 is hydrogen, methyl or amino
  • R 3 is hydrogen, fluorine or chlorine
  • each R 8b is, independently, hydrogen, halogen, Ci-C 6 alkyl, C 3 -C 6 cycloalkyl, Ci-C haloalkyl or C C 6 cycloalkylalkyl;
  • each Rg c is, independently, hydrogen or CrC 6 alkyl
  • each Rg d is, independently, hydrogen, Ci-C 6 alkyl optionally substituted with one or more of hydroxyl, -N(Rg a ) 2 and halogen, or C 3 -C 6 cycloalkyl optionally substituted with one or more of hydroxyl, -N(R 8a ) 2 and halogen, or R 4 and R 8 d or R 5 and R 8d , taken together with the atoms to which they are attached, form a carbocyclic or heterocyclic ring having from 3 to 6 ring atoms; and
  • each R 8e is, independently, hydrogen, hydroxyl, -N(R 8a ) 2 or Q-Q alkyl optionally substituted with one or more of hydroxyl, -N(R 8a ) 2 and halogen, or two R 8e groups, taken together with the atom to which they are attached, form a carbocyclic or heterocyclic ring having from 3 to 6 ring atoms which is optionally substituted with one or more of hydroxyl, -N(R 8a ) 2 and halogen, or R4 and R 8e or R 5 and R 8e , taken together with the atoms to which they are attached, form a carbocyclic or heterocyclic ring having from 3 to 6 ring atoms.
  • a pharmaceutical composition comprising a compound having structure (I) or (II), or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
  • the present invention provides a method of treating a bacterial infection in a mammal, comprising administering to the mammal an effective amount of a compound having structure (I) or (II), or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof.
  • Amino refers to the -NH 2 radical.
  • Niro refers to the -N0 2 radical.
  • Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, which is saturated or unsaturated (i.e., contains one or more double and/or triple bonds), having from one to twelve carbon atoms (C)-Ci 2 alkyl), preferably one to eight carbon atoms (Ci-C 8 alkyl) or one to six carbon atoms (Cj-C 6 alkyl), and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (wo-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (/-butyl), 3-methylhexyl, 2-methylhexyl, ethenyl, prop-l-enyl, but-l-enyl, pent-l-enyl, penta-l,4-dieny
  • alkyl group may be optionally substituted.
  • "Alkylene” or “alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, which is saturated or unsaturated (i.e., contains one or more double and/or triple bonds), and having from one to twelve carbon atoms, e.g., methylene, ethylene, propylene, n-butylene, ethenylene, propenylene, «-butenylene, propynylene, «-butynylene, and the like.
  • the alkylene chain is attached to the rest of the molecule through a single or double bond and to the radical group through a single or double bond.
  • the points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene chain may be optionally substituted.
  • Alkoxy refers to a radical of the formula -OR a where R a is an alkyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted.
  • Alkylamino refers to a radical of the formula -NHR a or -NR a R a where each R a is, independently, an alkyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkylamino group may be optionally substituted.
  • Thioalkyl refers to a radical of the formula -SR a where R a is an alkyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, a thioalkyl group may be optionally substituted.
  • Aryl refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring.
  • the aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems.
  • Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, s-indacene, 5-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
  • Aralkyl refers to a radical of the formula -Rb-Rc where R b is an alkylene chain as defined above and Rc is one or more aryl radicals as defined above, for example, benzyl, diphenylmethyl and the like. Unless stated otherwise specifically in the specification, an aralkyl group may be optionally substituted.
  • Cycloalkyl or “carbocyclic ring” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having from three to fifteen carbon atoms, preferably having from three to ten carbon atoms, and which is saturated or unsaturated and attached to the rest of the molecule by a single bond.
  • Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkyl group may be optionally substituted.
  • Cycloalkylalkyl refers to a radical of the formula -RbRd where 3 ⁇ 4 is an alkylene chain as defined above and R g is a cycloalkyl radical as defined above.
  • C C 6 cycloalkylalkyl refers to a radical wherein the alkylene chain has from one to six carbon atoms. Unless stated otherwise specifically in the specification, a cycloalkylalkyl group may be optionally substituted.
  • fused refers to any ring structure described herein which is fused to an existing ring structure in the compounds of the invention.
  • the fused ring is a heterocyclyl ring or a heteroaryl ring
  • any carbon atom on the existing ring structure which becomes part of the fused heterocyclyl ring or the fused heteroaryl ring may be replaced with a nitrogen atom.
  • Halo or halogen refers to bromo, chloro, fluoro or iodo.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group may be optionally substituted.
  • Heterocyclyl or “heterocyclic ring” refers to a stable 3- to 18-membered non-aromatic ring radical which consists of two to twelve carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
  • the heterocyclyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclyl radical may be partially or fully saturated.
  • heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thio
  • N-heterocyclyl refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. Unless stated otherwise specifically in the specification, a N-heterocyclyl group may be optionally substituted.
  • Heterocyclylalkyl refers to a radical of the formula -RbRe where 3 ⁇ 4 is an alkylene chain as defined above and Re is a heterocyclyl radical as defined above, and if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be attached to the alkyl radical at the nitrogen atom. Unless stated otherwise specifically in the specification, a heterocyclylalkyl group may be optionally substituted.
  • Heteroaryl refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring.
  • the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[3 ⁇ 4][l,4]dioxepinyl, 1 ,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothioph
  • N-heteroaryl refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. Unless stated otherwise specifically in the specification, an N-heteroaryl group may be optionally substituted.
  • Heteroarylalkyl refers to a radical of the formula -Rt,R f where 3 ⁇ 4 is an alkylene chain as defined above and R f is a heteroaryl radical as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkyl group may be optionally substituted.
  • substituted means any of the above groups (i.e., alkyl, alkylene, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atoms such as, but not limited to: a halogen atom such as F, CI, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, and ester groups; a sulfur atom in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such
  • Substituted also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles.
  • a higher-order bond e.g., a double- or triple-bond
  • nitrogen in groups such as imines, oximes, hydrazones, and nitriles.
  • R g and R h are the same or different and independently hydrogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl.
  • Substituted further means any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl group.
  • each of the foregoing substituents may also be optionally substituted with one or more of the above substituents.
  • Prodrug is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound of the invention.
  • prodrug refers to a metabolic precursor of a compound of the invention that is pharmaceutically acceptable.
  • a prodrug may be inactive when administered to a subject in need thereof, but is converted in vivo to an active compound of the invention.
  • Prodrugs are typically rapidly transformed in vivo to yield the parent compound of the invention, for example, by hydrolysis in blood.
  • the prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)).
  • prodrugs are provided in Higuchi, T., et al., A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, Ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
  • prodrug is also meant to include any covalently bonded carriers, which release the active compound of the invention in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of a compound of the invention may be prepared by modifying functional groups present in the compound of the invention in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound of the invention.
  • Prodrugs include compounds of the invention wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the compound of the invention is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively.
  • Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol or amide derivatives of amine functional groups in the compounds of the invention and the like.
  • the invention disclosed herein is also meant to encompass all pharmaceutically acceptable compounds of structures (I) and (II) being isotopically- labelled by having one or more atoms replaced by an atom having a different atomic mass or mass number.
  • isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, n C, 13 C, 14 C, ,3 N, 15 N, 15 0, 17 0, 18 0, 31 P, 32 P, 35 S, 18 F, 36 C1, 123 I, and 125 I, respectively.
  • radiolabelled compounds could be useful to help determine or measure the effectiveness of the compounds, by characterizing, for example, the site or mode of action, or binding affinity to pharmacologically important site of action.
  • Certain isotopically-labelled compounds of structures (I) and (II), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon- 14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • substitution with heavier isotopes such as deuterium, i.e. H may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Isotopically-labeled compounds of structures (I) and (II) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples set forth below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
  • the invention disclosed herein is also meant to encompass the in vivo metabolic products of the disclosed compounds. Such products may result from, for example, the oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the invention includes compounds produced by a process comprising administering a compound of this invention to a mammal for a period of time sufficient to yield a metabolic product thereof. Such products are typically identified by administering a radiolabelled compound of the invention in a detectable dose to an animal, such as rat, mouse, guinea pig, monkey, or to human, allowing sufficient time for metabolism to occur, and isolating its conversion products from the urine, blood or other biological samples.
  • an animal such as rat, mouse, guinea pig, monkey, or to human
  • Solid compound and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • “Mammal” includes humans and both domestic animals such as laboratory animals and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife and the like.
  • Optional or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
  • optionally substituted aryl means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
  • “Pharmaceutically acceptable carrier, diluent or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
  • “Pharmaceutically acceptable salt” includes both acid and base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- 1 ,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesul
  • “Pharmaceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like.
  • basic ion exchange resins such as
  • Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. Often crystallizations produce a solvate of the compound of the invention.
  • the term "solvate" refers to an aggregate that comprises one or more molecules of a compound of the invention with one or more molecules of solvent.
  • the solvent may be water, in which case the solvate may be a hydrate.
  • the solvent may be an organic solvent.
  • the compounds of the present invention may exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms.
  • the compound of the invention may be true solvates, while in other cases, the compound of the invention may merely retain adventitious water or be a mixture of water plus some adventitious solvent.
  • a “pharmaceutical composition” refers to a formulation of a compound of the invention and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g., humans.
  • a medium includes all pharmaceutically acceptable carriers, diluents or excipients therefor.
  • Effective amount refers to that amount of a compound of the invention which, when administered to a mammal, preferably a human, is sufficient to effect treatment, as defined below, of a bacterial infection in the mammal, preferably a human.
  • the amount of a compound of the invention which constitutes a “therapeutically effective amount” will vary depending on the compound, the condition and its severity, the manner of administration, and the age of the mammal to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.
  • Treating covers the treatment of the disease or condition of interest in a mammal, preferably a human, having the disease or condition of interest, and includes:
  • disease and “condition” may be used interchangeably or may be different in that the particular malady or condition may not have a known causative agent (so that etiology has not yet been worked out) and it is therefore not yet recognized as a disease but only as an undesirable condition or syndrome, wherein a more or less specific set of symptoms have been identified by clinicians.
  • the compounds of the invention, or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (/?)- or (S)- or, as (D)- or (L)- for amino acids.
  • the present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms.
  • Optically active (+) and (-), (i?)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization.
  • a “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable.
  • the present invention contemplates various stereoisomers and mixtures thereof and includes “enantiomers”, which refers to two stereoisomers whose molecules are nonsuperimposeable mirror images of one another.
  • a “tautomer” refers to a proton shift from one atom of a molecule to another atom of the same molecule. The present invention includes tautomers of any said compounds.
  • Bacterial infection refers to the establishment of a sufficient population of a pathogenic bacteria in a patient to have a deleterious effect on the health and well-being of the patient and/or to give rise to discernable symptoms associated with the particular bacteria.
  • Fluoroquinolone antibiotic resistant bacterium or “fluoroquinolone- resistant bacterium” refers to bacterium against which at least one of the following known fluoroquinolone antibiotics, namely, ciprofloxacin, levofloxacin, moxifloxacin and gemifloxacin, has a minimum inhibitory concentration (MIC) greater than or equal to 4 ⁇ g/mL.
  • MIC minimum inhibitory concentration
  • compounds having antibacterial activity are provided, the compounds having one of the following structures (I) or (II):
  • A, B and D are as follows:
  • G is hydrogen or methyl
  • Ri is optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl;
  • R 2 is hydrogen, methyl or amino
  • R 3 is hydrogen, fluorine or chlorine
  • each Rg b is, independently, hydrogen, halogen, Ci-C 6 alkyl, C 3 -C 6 cycloalkyl, C ! -C 6 haloalkyl or Q-Q cycloalkylalkyl;
  • each R 8c is, independently, hydrogen or Cj-C 6 alkyl
  • each R 8d is, independently, hydrogen, Cj-C 6 alkyl optionally substituted with one or more of hydroxyl, -N(R 8a )2 and halogen, or C 3 -C 6 cycloalkyl optionally substituted with one or more of hydroxyl, -N(R 8a )2 and halogen, or R4 and R 8 d or R 5 and R 8d , taken together with the atoms to which they are attached, form a carbocyclic or heterocyclic ring having from 3 to 6 ring atoms; and
  • each R 8e is, independently, hydrogen, hydroxyl, -N(R 8a ) 2 or Q-Q alkyl optionally substituted with one or more of hydroxyl, -N(Rg a ) 2 and halogen, or two R 8e groups, taken together with the atom to which they are attached, form a carbocyclic or heterocyclic ring having from 3 to 6 ring atoms which is optionally substituted with one or more of hydroxyl, -N(Rg a ) 2 and halogen, or R4 and R 8e or R5 and R 8e , taken together with the atoms to which they are attached, form a carbocyclic or heterocyclic ring having from 3 to 6 ring atoms.
  • each R 8 may be hydrogen.
  • A is -CH 2 -.
  • R 8a and R 8b may be hydrogen, Ci-C 6 alkyl or C ! -C 6 cycloalkyl.
  • B is -CH 2 -.
  • A may be
  • -C(R 8b ) 2 - and D may be -C(R 8b ) 2 - or -0-.
  • R 8b may be hydrogen, Q-C 6 alkyl or Q-Q cycloalkyl.
  • B is -0-.
  • A may be -C(R 8b ) 2 - and D may be -C(R 8b ) 2 -.
  • R 8b may be hydrogen, Cj-C 6 alkyl or C ⁇ - C 6 cycloalkyl.
  • B is -S-.
  • A may be -C(R 8b ) 2 - and D may be -C(R 8b ) 2 -.
  • R 8b may be hydrogen, C ⁇ -C alkyl or Ci- Ce cycloalkyl.
  • D is -CH 2 -.
  • A-B taken
  • R 8a and R 8b may be hydrogen, C C 6 alkyl or Cj-C 6 cycloalkyl.
  • D is -0-.
  • A-B taken
  • R 8a and R 8b may be hydrogen, Ci-C 6 alkyl or C C 6 cycloalkyl.
  • D is -N(R 8a )-.
  • R 8a may be hydrogen or methyl.
  • R 8a and R 8b may be hydrogen, Cj-C 6 alkyl or Ci-C 6 cycloalkyl.
  • A may be -C(Rg b ) 2 -.
  • R 8 may be hydrogen, Ci-C 6 alkyl or Ci-C6 cycloalkyl.
  • W is -C(R 8e ) 2 - and the compound has the following structure (I- A):
  • each R 8e may be hydrogen.
  • W is -N(R 8d )- and the compound has the following structure (I-B):
  • R 8d may be hydrogen
  • one of each ⁇ and R 5 taken together, and the compound has one of the following structures (I-B-1) or (I-B-2):
  • R4, R 5 , Re and R 7 are, independently, hydrogen, amino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkylamino or -N(R 8a ) 2 . In further embodiments, R4, R , Re and R 7 may each be hydrogen.
  • R4, R 5 and 3 ⁇ 4 may each be hydrogen, one R 7 may be hydrogen, and one R 7 may be amino, substituted alkyl, substituted cycloalkyl, alkylamino, or -N(R 8a ) 2 , wherein substituted alkyl is -(C!-C 6 alkyl)N(R 8a ) 2 and substituted cycloalkyl is -(C 3 -C 6 cycloalkyl)N(R 8a ) 2 .
  • each R 8a may be hydrogen and one R 7 may be -NH 2 , -CH 2 NH 2 , -CH(CH 3 )NH 2 , -C(CH 3 ) 2 NH 2 , or 1-amino-cycloprop-l-yl.
  • R4, Re and R 7 may each be hydrogen, one R 5 may be hydrogen and one R5 may be amino, substituted alkyl, substituted cycloalkyl, alkylamino, or -N(R 8a ) 2 , wherein substituted alkyl is -(Cj- C 6 alkyl)N(R 8a ) 2 and substituted cycloalkyl is -(C 3 -C 6 cycloalkyl)N(R 8a )2.
  • each R 8a may be hydrogen and one R 5 may be -NH 2j -C3 ⁇ 4NH 2 , -CH(CH 3 )NH 2 , -C(CH 3 ) 2 NH 2 , or 1-amino-cycloprop-l-yl.
  • one of each R 4 and R 5 taken together with the atom to which they are attached, form a carbocyclic or heterocyclic ring having from 3 to 6 ring atoms.
  • one of each 3 ⁇ 4 and R 7 taken together with the atom to which they are attached, form a carbocyclic or heterocyclic ring having from 3 to 6 ring atoms.
  • R ⁇ is optionally substituted alkyl.
  • Ri may be Cj-C 6 alkyl.
  • R] is optionally substituted cycloalkyl.
  • Rj may be cyclopropyl.
  • R 2 is hydrogen
  • R 3 is fluorine
  • R 3 is hydrogen
  • E is -CH 2 -.
  • E is -CH(CH 3 )- or -C(CH 3 ) 2 -.
  • G is hydrogen
  • any embodiment of the compounds of structures (I) and (II), as set forth above, and any specific substituent set forth herein for a A, B, D, E, G, W, R], R 2 , R 3 , R 4 , R 5 , R and R 7 group in the compounds of structures (I) and (II), as set forth above, may be independently combined with other embodiments and/or substituents of compounds of structures (I) and (II) to form embodiments of the inventions not specifically set forth above.
  • any specific combination set forth herein for the A, B and D groups in the compounds of structures (I) and (II) is specific with respect to the position of such groups.
  • the terminology "A-B-D, taken together, are -CH 2 N(R 8a )S0 2 -" indicates that A is -CH 2 -, B is -N(R 8a )- and D is -S0 2 -.
  • combinations of substituents and/or variables of the depicted formulae are permissible only if such contributions result in stable compounds.
  • the above embodiments of the compounds of structures (I) and (II) it is understood that:
  • compositions of the present invention comprise a compound of structure (I) or (II) and a pharmaceutically acceptable carrier, diluent or excipient.
  • the compound of structure (I) or (II) is present in the composition in an amount which is effective to treat a particular disease or condition of interest - that is, in an amount sufficient to treat a bacterial infection, and preferably with acceptable toxicity to the patient.
  • the antibacterial activity of compounds of structure (I) and (II) can be determined by one skilled in the art, for example, as described in the Examples below. Appropriate concentrations and dosages can be readily determined by one skilled in the art.
  • the compounds of the present invention possess antibacterial activity against a wide spectrum of gram positive and gram negative bacteria, as well as enterobacteria and anaerobes.
  • Representative susceptible organisms generally include those Gram-positive and Gram-negative, aerobic and anaerobic organisms whose growth can be inhibited by the compounds of the invention, such as species of Staphylococcus, Enterococcus, Streptococcus, Sarcina, Escherichia, Enter obacter, Klebsiella, Pseudomonas, Burkholderia, Acinetobacter, Aeromonas, Proteus, Campylobacter, Pasteurella, Citrobacter, Legionella, Neisseria, Bordetella, Baccillus, Bacteroides, Moraxella, Morganella, Edwardsiella, Peptococcus, Clostridium, Providencia, Salmonella, Stenotrophomonas, Shigella, Serratia, Haemophilus, Vibrio and Yers
  • the compounds possess antibacterial activity against the following bacteria: Enterococcus faecium, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus saprophyticus, Streptococcus agalactiae, Streptococcus (Group C/F), Streptococcus (Group G), Viridans group streptococci, Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter Iwoffii, Aeromonas hydrophila, Bordetella pertussis, Burkholderia cepacia, Campylobacter jejuni, Citrobacter diversus, Citrobacter freundii, Enterobaeter aerogenes, Enterobacter agglomerans, Enterobacter sakazaki, Edwardsiella tarda, Haemophilus influenzae, Haemophilus para
  • the compounds of the present invention have MIC ⁇ 2 ⁇ , for each of (i) one or more Gram-negative bacteria selected from the group consisting of Acinetobacter anitratus, Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter Iwoffii, Aeromonas hydrophila, Bordetella pertussis, Burkholderia cepacia, Campylobacter jejuni, Citrobacter diversus, Citrobacter freundii, Enterobaeter aerogenes, Enterobacter agglomerans, Enterobacter cloacae, Enterobacter sakazaki, Escherichia coli, Edwardsiella tarda, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Legionella pneumophila, Moraxella catarrhalis, Morganella morganii, Neisseria gon
  • the compounds of the present invention have MIC ⁇ 2 ⁇ g/mL for each of (i) one or more Gram-negative bacteria selected from the group consisting of Acinetobacter baumannii, Acinetobacter calcoaceticus, Burkholderia cepacia, Citrobacter freundii, Enterobaeter aerogenes, Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia stuartii, Pseudomonas aeruginosa, Salmonella enteritidis, Serratia liquefaciens, Serratia marcescens, Shigella dysenteriae, Shigella flexneri and Yersinia enterocolitica, and (ii) one or more Gram-positive bacteria selected from the group consisting of Acinetobacter
  • the compounds of the present invention possess antibacterial activity against bacterial species resistant to conventional fluoroquinolone antibiotics, such as fluoroquinolone resistant Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, Streptococcus pneumoniae, Klebsiella pneumoniae, Morganella morganii, Proteus mirabilis, Enterobaeter aerogenes, Enterobacter cloacae, Providencia stuartii or Serratia marcescens bacterium.
  • fluoroquinolone resistant Acinetobacter baumannii Pseudomonas aeruginosa
  • Escherichia coli Staphylococcus aureus
  • Streptococcus pneumoniae Klebsiella pneumoniae
  • Morganella morganii Proteus mirabilis
  • Enterobaeter aerogenes Enterobacter cloacae
  • fluoroquinolone resistant Acinetobacter baumannii Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus or Streptococcus pneumoniae bacterium.
  • compositions of the invention can be prepared by combining a compound of the invention with an appropriate pharmaceutically acceptable carrier, diluent or excipient, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols.
  • compositions of the invention are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient.
  • Compositions that will be administered to a subject or patient take the form of one or more dosage units, where for example, a tablet may be a single dosage unit, and a container of a compound of the invention in aerosol form may hold a plurality of dosage units.
  • composition to be administered will, in any event, contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for treatment of a disease or condition of interest in accordance with the teachings of this invention.
  • a pharmaceutical composition of the invention may be in the form of a solid or liquid.
  • the carrier(s) are particulate, so that the compositions are, for example, in tablet or powder form.
  • the carrier(s) may be liquid, with the compositions being, for example, an oral syrup, injectable liquid or an aerosol, which is useful in, for example, inhalatory administration.
  • the pharmaceutical composition When intended for oral administration, the pharmaceutical composition is preferably in either solid or liquid form, where semi-solid, semi-liquid, suspension and gel forms are included within the forms considered herein as either solid or liquid.
  • the pharmaceutical composition may be formulated into a powder, granule, compressed tablet, pill, capsule, chewing gum, wafer or the like form.
  • a solid composition will typically contain one or more inert diluents or edible carriers.
  • binders such as carboxymethylcellulose, ethyl cellulose, microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, Primogel, corn starch and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; a flavoring agent such as peppermint, methyl salicylate or orange flavoring; and a coloring agent.
  • excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, Primogel, corn starch and the like
  • lubricants such as magnesium stearate or Sterotex
  • glidants such as colloidal silicon dioxide
  • sweetening agents such as sucrose or saccharin
  • a flavoring agent such as peppermint, methyl sal
  • the pharmaceutical composition when in the form of a capsule, for example, a gelatin capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or oil.
  • a liquid carrier such as polyethylene glycol or oil.
  • the pharmaceutical composition may be in the form of a liquid, for example, an elixir, syrup, solution, emulsion or suspension.
  • the liquid may be for oral administration or for delivery by injection, as two examples.
  • preferred composition contain, in addition to the present compounds, one or more of a sweetening agent, preservatives, dye/colorant and flavor enhancer.
  • a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer and isotonic agent may be included.
  • the liquid pharmaceutical compositions of the invention may include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer's solution, isotonic sodium chloride, fixed oils such as synthetic mono or diglycerides which may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • Physiological saline is a preferred adjuvant.
  • a liquid pharmaceutical composition of the invention intended for either parenteral or oral administration should contain an amount of a compound of the invention such that a suitable dosage will be obtained.
  • the pharmaceutical composition of the invention may be intended for topical administration, in which case the carrier may suitably comprise a solution, emulsion, ointment or gel base.
  • the base for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, bee wax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers.
  • Thickening agents may be present in a pharmaceutical composition for topical administration.
  • the composition may include a transdermal patch or iontophoresis device.
  • the pharmaceutical composition of the invention may be intended for rectal administration, in the form, for example, of a suppository, which will melt in the rectum and release the drug.
  • the composition for rectal administration may contain an oleaginous base as a suitable nonirritating excipient.
  • bases include, without limitation, lanolin, cocoa butter and polyethylene glycol.
  • the pharmaceutical composition of the invention may include various materials, which modify the physical form of a solid or liquid dosage unit.
  • the composition may include materials that form a coating shell around the active ingredients.
  • the materials that form the coating shell are typically inert, and may be selected from, for example, sugar, shellac, and other enteric coating agents.
  • the active ingredients may be encased in a gelatin capsule.
  • the pharmaceutical composition of the invention in solid or liquid form may include an agent that binds to the compound of the invention and thereby assists in the delivery of the compound.
  • Suitable agents that may act in this capacity include a monoclonal or polyclonal antibody, a protein or a liposome.
  • the pharmaceutical composition of the invention may consist of dosage units that can be administered as an aerosol.
  • aerosol is used to denote a variety of systems ranging from those of colloidal nature to systems consisting of pressurized packages. Delivery may be by a liquefied or compressed gas or by a suitable pump system that dispenses the active ingredients. Aerosols of compounds of the invention may be delivered in single phase, bi-phasic, or tri-phasic systems in order to deliver the active ingredient(s). Delivery of the aerosol includes the necessary container, activators, valves, subcontainers, and the like, which together may form a kit. One skilled in the art, without undue experimentation may determine preferred aerosols.
  • compositions of the invention may be prepared by methodology well known in the pharmaceutical art.
  • a pharmaceutical composition intended to be administered by injection can be prepared by combining a compound of the invention with sterile, distilled water so as to form a solution.
  • a surfactant may be added to facilitate the formation of a homogeneous solution or suspension.
  • Surfactants are compounds that non-covalently interact with the compound of the invention so as to facilitate dissolution or homogeneous suspension of the compound in the aqueous delivery system.
  • the compounds of the invention are administered in a therapeutically effective amount, which will vary depending upon a variety of factors including the activity of the specific compound employed; the metabolic stability and length of action of the compound; the age, body weight, general health, sex, and diet of the patient; the mode and time of administration; the rate of excretion; the drug combination; the severity of the particular disorder or condition; and the subject undergoing therapy.
  • Compounds of the invention, or pharmaceutically acceptable derivatives thereof, may also be administered simultaneously with, prior to, or after administration of one or more other therapeutic agents.
  • Such combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound of the invention and one or more additional active agents, as well as administration of the compound of the invention and each active agent in its own separate pharmaceutical dosage formulation.
  • a compound of the invention and the other active agent can be administered to the patient together in a single oral dosage composition such as a tablet or capsule, or each agent administered in separate oral dosage formulations.
  • the compounds of the invention and one or more additional active agents can be administered at essentially the same time, i.e., concurrently, or at separately staggered times, i.e., sequentially; combination therapy is understood to include all these regimens.
  • starting components may be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, etc. or synthesized according to sources known to those skilled in the art (see, for example, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition (Wiley, December 2000)) or prepared as described in this invention.
  • Suitable protecting groups for hydroxy include, for example, trialkylsilyl or diarylalkylsilyl (for example, triethylsilyl (TES), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBS), t-butyldiphenylsilyl (TBDPS) or trimethylsilyl (TMS)), fert-butoxycarbonyl (Boc), allyloxycarbonyl (Alloc), carboxybenzyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), trichloroethoxycarbonyl (Troc), trityl (Trt), benzyl, methoxybenzyl, dimethoxybenzyl, chlorobenz
  • Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like.
  • Suitable protecting groups for mercapto include -C(0)-R" (where R" is alkyl, aryl or arylalkyl), -methoxybenzyl, trityl and the like.
  • Suitable protecting groups for carboxylic acid include alkyl, aryl or arylalkyl esters. Protecting groups may be added or removed in accordance with standard techniques, which are known to one skilled in the art and as described herein. The use of protecting groups is described in detail in Green, T.W. and P.G.M.
  • the protecting group may also be a polymer resin such as a Wang resin, Rink resin or a 2-chlorotrityl-chloride resin.
  • Ethyl- 1 -cyclopropyl-6,7-difluoro-8-hydroxy-4-oxo- 1 ,4- dihydroquinoline-3-carboxylate (1) (309 mg, 1 mmol) and 1 -benzyl-4-/er/-butyl-2-(2- hydroxyethyl)piperazine-l,4-dicarboxylate (2) (364 mg, 1 mmol) were combined in THF (5 mL) with stirring at RT.
  • 4-(diphenylphosphino)pyridine (263 mg, 1 mmol) was added and followed by 4 equal portions of diisopropyl azodicarboxylate (193 ⁇ , 1.0 mmol) added in THF (4 mL) delivered over 20 minutes.
  • the crude reaction was diluted with ethanol (-10 mL) and then stirred for 5 minutes before filtering through a short plug of Celite 545 to remove the precipitated salts.
  • the filtrate was concentrated in vacuo and then subjected to regular phase silica gel chromatography on a 40 g silica gel cartridge, eluting with 0 to 30% ethyl acetate in DCM to afford the purified product (3).
  • the reaction was then partially evacuated and back filled with hydrogen x3, sparged with 3-1L balloons filled with hydrogen, and then maintained under an atmosphere of hydrogen with a hydrogen filled balloon and checked after 30-45 minutes for completion. The reaction was checked at this time, showing no progress. More hydrogen was added (by sparging) and continued under an atmosphere of hydrogen for several hours with no change.
  • the reaction mixture was filtered through a short plug of Celite 545 and then rinsed with 20 mL of ethanol. The filtrate (in a 100 mL flask) was sparged with nitrogen for 3 minutes and then placed under an atmophere of nitrogen and 10% palladium on carbon (85 mg) was added.
  • the reaction vessel was then partially evacuated and back-filled with hydrogen (x3) and then kept under an atmosphere of hydrogen with a balloon.
  • the reaction was checked after 2-3 hrs and found to be complete, with no apparent over-reduction.
  • the reaction was filtered through a short plug of Celite 545 and then the filtrate was concentrated in vacuo.
  • Silica gel chromatography using 0 to 35% ethyl acetate in CH 2 C1 2 afforded purified product (4).
  • the resulting solution was sparged with nitrogen for 2 minutes and then capped and heated at 55 °C overnight (-10 hr) with stirring. After this period of time, the reaction was checked by HPLC for completion. HPLC shows complete consumption of the starting material.
  • the reaction mixture was concentrated in vacuo and then subjected to silica gel chromatography (40 g silica gel column), eluting with 0, 2.5, 5, 7.5 and 10% methanol in chloroform (-300 mL each). The fractions containing product were combined to afford the cyclized product.
  • the crude cylized product was put in a 40-mL scintillation vial, at room temperature and under an atmosphere of nitrogen, was dissolved in methylene chloride (25 mL) and trifluoroacetic acid (1.12 mL, 14.6 mmol) was added in one portion. The reaction was stirred overnight (-10 hr) at ambient temperature and then checked by HPLC. After this period of time, the reaction was determined to be complete based on HPLC and the solvent was removed with a stream of nitrogen.
  • N-diisopropylethylamine (0.357 mL, 2.05 mmol) and tetrakis(triphenylphosphine)palladium(0) (120 mg, 0.10 mmol) were added with continued sparging ( ⁇ 3 min) and then finally copper(I) iodide (39 mg, 0.20 mmol) was added and the resultant clear, yellow-colored reaction mixture was heated at 60 °C for 8-9 hr and then checked by HPLC/LCMS and TLC. Analysis after this period of time shows complete consumption of the starting triflate and formation of the desired coupled product, based on MS.
  • the crude reaction was diluted with ethanol (-10 mL) and then stirred for 5 minutes before filtering through a short plug of Celite 545 to remove the precipitated salts.
  • the filtrate was concentrated in vacuo and then subjected to regular phase silica gel chromatography on a 40 g silica gel cartridge, eluting with 0 to 30% ethyl acetate in DCM to afford the purified product (3).
  • the resulting solution was sparged with nitrogen for 2 minutes and then capped and heated at 55 °C overnight (-10 hr) with stirring. After this period of time, the reaction was checked by HPLC for completion. HPLC shows complete consumption of the starting material.
  • the reaction mixture was concentrated in vacuo and then subjected to silica gel chromatography (40 g silica gel column), eluting with 0, 2.5, 5, 7.5 and 10% methanol in chloroform (-300 mL each). The fractions containing product were combined to afford the cyclized product (5).
  • the reaction was diluted with EtOAc (50 ml) and washed with water (5 ml), IN citrate (5 ml), water (5 ml) and brine (5 ml). The organic phase was dried over Na 2 S0 4 , filtered and evaporated under reduced pressure. The residue was immediately dissolved in DCM (10 ml) and TFA (0.5 ml) at RT with stirring. The reaction was complete by LCMS after 10 min. The reaction was evaporated under reduced pressure and taken up in THF (10 ml). Excess of NN-diisopropylethylamine (0.5 ml) was added to the reaction beyond the point where the mixture was basic as judged by pH paper.
  • the reaction mixture was heated to 60 °C for 10 min at which time the annulation to the monoketopiperazine was complete by LCMS.
  • the solvent was removed under reduced pressure and the residue purifed by silica gel chromatography (20 g silica gel column), eluting with 0, 5, and 10% methanol in chloroform (-50 mL each). The fractions containing product were combined to afford the cyclized product (6).
  • Analytical HPLC was performed using an Agilent 1100 HPLC with one of the following methods:
  • Method A Agilent Scalar CI 8 150' x 4.6 mm 5 micron column; 1.5 mL/min; solvent A— water (0.1% TFA); solvent B— acetonitrile (0.07% TFA, gradient: 10 min 95%A to 95%B; 5 min hold; then recycle; UV detection @ 214, 250 and 280 nm.
  • Method B Agilent XDB CI 8 50 x 4.6 mm/1.8 micron column; 1.5 mL/min; solvent A— water (0.1% TFA), solvent B— acetonitrile (0.07% TFA); gradient: 5 min 95% A to 95% B then 1 min hold, 1 min 95% B to 95% A then 30 sec hold; UV detection @ 210, 254, and 280 nm.
  • solvent A is 0.07% TFA in acetonitrile
  • solvent B is 0.10% TFA in water
  • rate is 20 mL/min
  • 30 minute run 5%> to 70% A over 14 minute ramp
  • 3 minute ramp from 80% to 100% A; hold 100% A for 3 minutes; ramp down from 100% to 5% A over 5 minutes; hold 10 minutes then recycle.
  • the reaction was concentrated to remove the excess TFA and quenched with 10% ammonium hydroxide.
  • the mixture was extracted with methylene chloride (3x 100 mL).
  • the diol amine was water soluble.
  • the organic layer was dried with sodium sulfate, filtered and concentrated in vacuo.
  • the residue was dissolved in acetonitrile and ethanol.
  • Acetic acid, ethyl trifluoroacetate (2 niL, 20 mmol) and N,N- diisopropylethylamine (1 niL, 6 mmol) were added and the reaction was allowed to stand for 3 days. The reaction was checked after this time period and was determined to be complete.
  • the reaction was concentrated and dissolved once more in methylene chloride (20 mL), 10-Camphorsulfonic acid (2 g) was added, and the reaction was allowed to stir overnight. After this period of time, the reaction was complete by based on LC/MS analysis.
  • the reaction was diluted with methylene chloride (100 mL) and washed with water (3 x 100 mL). The organic layer was then dried with sodium sulfate, filtered and concentrated in vacuo.
  • the crude material was purified by silica gel chromatography on 40g of silica gel using 50-80% ethyl acetate in hexanes as the eluant to afford 205 mg (27%) of the desired product (4) as an off-white solid.
  • the reaction was stirred at room temperature for 2 hours. After this period of time, the reaction was 50% complete based on HPLC analysis. The reaction was heated to 40°C for an additional 2 hours and was found to be complete based on HPLC analysis after this time period. 10% Acetic acid ( ⁇ 8 drops) was added until the pH was ⁇ 7, and the reaction was concentrated to remove the acetonitrile. The mixture was purified by preparative HPLC (Method E). The pure fractions were combined and concentrated to remove the acetonitrile and the resultant solution was lyophilized to yield 35 mg of the TFA salt of (5) (87%) as an off white solid.
  • the reaction mixture was cooled, diluted with 50 mL ethyl acetate and washed with two 50 mL portions of H 2 0 and 50 mL brine.
  • the organic phase was dried over Na 2 S0 4 , filtered and concentrated.
  • the material was purified by flash chromatography (40 g flash silica gel; 2-6% MeOH/CH 2 Cl 2 ) to yield the title compound (3) as a solid.
  • the reaction mixture was diluted with 15 mL CH 2 C1 2 and 1 mL MeOH and washed with 20 mL sat NaHC0 3 solution.
  • the aqueous phase was back extracted with 10 mL CH 2 C1 2 and the combined organic extracts were washed with 10 mL portions of H 2 0 and brine and dried over Na 2 S0 4 .
  • the solution was filtered and concentrated to a residue which was purified by flash chromatography (30 g flash silica gel, 3-10% EtOH/CH 2 Cl 2 ) to yield the title compound (4) as a solid.
  • the aqueous phase was washed with 5 mL CH 2 Cl 2 and the combined organic phase was dried over Na 2 S0 4 .
  • the solution was filtered and concentrated under reduced pressure.
  • the material was purified by flash chromatography (25 g flash silica gel, 2-6% EtOH/CH 2 Cl 2 ) to yield the title compound (5) as a solid.
  • the solid was filtered and washed with a water (1ml) followed by diethyl ether (4 ml) to produce a solid.
  • the material was treated with 0.1 M of trifluoroacetic acid in water (1.08 mL) and 1 mL H 2 0 and the solution was lyophilized to yield the title compound (6) as a solid.
  • MIC Minimum inhibitory concentrations
  • CLSI Clinical and Laboratory Standards Institute
  • Quality control ranges utilizing E. coli ATCC 25922, P. aeruginosa ATCC 27853 and S. aureus ATCC 29213, and interpretive criteria for comparator agents were as published in CLSI M100-S17 [2007].
  • serial two-fold dilutions of the test compounds were prepared at 2X concentration in Mueller Hinton Broth.
  • the compound dilutions were mixed in 96-well assay plates in a 1:1 ratio with bacterial inoculum.
  • the inoculum was prepared by suspension of a colony from an agar plate that was prepared the previous day.

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Abstract

La présente invention concerne des composés présentant une activité antibactérienne, représentés par les structures (I) et (II) suivantes, ainsi que certains de leurs stéréoisomères, de leurs sels pharmaceutiquement admis, et de leurs promédicaments. Dans ces structures, les A, B, D, E, G, W, R1, R2, R3, R4, R5, R6 et R7 sont tels que définis dans la description. L'invention concerne également, d'une part des procédés associés à l'élaboration et à l'utilisation de tels composés, et d'autre part des compositions pharmaceutiques comprenant de tels composés.
PCT/US2010/048104 2009-09-09 2010-09-08 Analogues de fluoroquinolone antibactériens WO2011031740A1 (fr)

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US9388185B2 (en) 2012-08-10 2016-07-12 Incyte Holdings Corporation Substituted pyrrolo[2,3-b]pyrazines as FGFR inhibitors
US9533954B2 (en) 2010-12-22 2017-01-03 Incyte Corporation Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3
US9533984B2 (en) 2013-04-19 2017-01-03 Incyte Holdings Corporation Bicyclic heterocycles as FGFR inhibitors
US9580423B2 (en) 2015-02-20 2017-02-28 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US9611267B2 (en) 2012-06-13 2017-04-04 Incyte Holdings Corporation Substituted tricyclic compounds as FGFR inhibitors
US9708318B2 (en) 2015-02-20 2017-07-18 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US9890156B2 (en) 2015-02-20 2018-02-13 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
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WO2023098752A1 (fr) * 2021-11-30 2023-06-08 广州白云山医药集团股份有限公司白云山制药总厂 Nouveau composé de quinolone non fluorée et son application
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US12122767B2 (en) 2019-10-01 2024-10-22 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US12303573B2 (en) 2018-11-23 2025-05-20 Bayer Aktiengesellschaft Formulation of contrast media and process of preparation thereof

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