WO2010093341A1 - Dérivés de c-7 isoxazolinyl quinolone/naphthyridine convenant comme agents anti-bactériens - Google Patents

Dérivés de c-7 isoxazolinyl quinolone/naphthyridine convenant comme agents anti-bactériens Download PDF

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WO2010093341A1
WO2010093341A1 PCT/US2008/071294 US2008071294W WO2010093341A1 WO 2010093341 A1 WO2010093341 A1 WO 2010093341A1 US 2008071294 W US2008071294 W US 2008071294W WO 2010093341 A1 WO2010093341 A1 WO 2010093341A1
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group
lower alkyl
amino
alkyl
compound
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PCT/US2008/071294
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English (en)
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Mark J. Macielag
Michele A. Weidner-Wells
Shu-Chen Lin
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Janssen Pharmaceutica N.V.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to C-7 isoxazolyl quinoline / naphthyhdine derivatives useful as antimicrobial compounds, pharmaceutical compositions comprising said derivatives and the use of said derivatives and pharmaceutical compositions as antimicrobial agents against pathogenic microorganisms, particularly against resistant microbes.
  • the chemical and medical literature describes compounds that are said to be antimicrobial, i.e., capable of destroying or suppressing the growth or reproduction of microorganisms, such as bacteria.
  • antibacterial agents are described in Antibiotics, Chemotherapeutics, and Antibacterial Agents for Disease Control (M. Greyson, editor, 1982), E. Gale et al., The Molecular Basis of Antibiotic Action 2d edition (1981 ), Recent Research Developments in Antimicrobial Agents & Chemotherapy (S. G. Pandalai, Editor, 2001 ), Quinolone Antimicrobial Agents (John S Wolfson, David C Hooper, Editors, 1989), and F. O'Grady, H. P. Lambert, R. G. Finch, D. Greenwood, Martin Dedicoat, "Antibiotic and Chemotherapy, 7th edn.” (1997).
  • antibacterial agents vary. However, they are generally believed to function in one or more ways: by inhibiting cell wall synthesis or repair; by altering cell wall permeability; by inhibiting protein synthesis; or by inhibiting the synthesis of nucleic acids.
  • beta-lactam antibacterial agents act through inhibiting essential penicillin binding proteins (PBPs) in bacteria, which are responsible for cell wall synthesis.
  • PBPs essential penicillin binding proteins
  • quinolones act, at least in part by inhibiting synthesis of DNA, thus preventing the cell from replicating.
  • the classes of antimicrobial agents may vary in 1 ) their relative efficacy against different types of microorganisms, 2) their susceptibility to development of microbial resistance and 3) their pharmacological characteristics such as their bioavailability and biodisthbution. Accordingly, selection of an appropriate antimicrobial agent in a given clinical situation requires analysis of many factors, including the type of organism involved, the desired method of administration, the location of the infection to be treated and other considerations.
  • Resistance can be defined as existence of organisms, within a population of a given microbial species, that are less susceptible to the action of a given antimicrobial agent. This resistance is of particular concern in environments such as hospitals and nursing homes, where relatively high rates of infection and intense use of antibacterial agents are common. See, e.g., W. Sanders, Jr. et al., "Inducible Beta-lactamases: Clinical and Epidemiologic Implications for the Use of Newer Cephalosporins", Review of Infectious Diseases, p. 830 (1988).
  • Pathogenic bacteria are known to acquire resistance via several distinct mechanisms including inactivation of the antibiotic by bacterial enzymes (e.g., ⁇ - lactamases hydrolyzing 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 Neiser ⁇ a 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., ⁇ - lactamases hydrolyzing 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 Neiser ⁇ a gonorrhea); and acquisition of a readily transferable gene from an external source to create a resistant target (e.g.
  • Patent 5017581 European Patent Publication 304087; International Patent Publication WO0136408; International Patent Publication WO02085886; Japanese Patent Publication 01090184; International Patent Publication WO9209579; International Patent Publication WO0185728; European Patent Publication 343524; Japanese Patent Publication 10130241 ; European Patent Publication 413455; International Patent Publication WO0209758; International Patent Publication WO0350107; International Patent Publication WO9415933; International Patent Publication WO9222550; Japanese Patent Publication 07300472; International Patent Publication WO0314108; International Patent Publication WO0071541 ; International Patent Publication WO0031062; and U.S. Patent 5869670.
  • US Patent 4990517 discloses quinolone and naphthyhdine antibacterial agents of the formula
  • Y is O, CH 2 , CH 2 CH 2 , or CH 2 O
  • R is hydrogen, optionally hydroxyl- substituted CrC 4 -alkyl, as well as phenyl, benzyl, CrC 4 -alkoxycarbonyl, Ci-C 4 - acyl, (5-methyl-2-oxo-1 ,3-dioxol-4-yl)methyl, or C 3 -C 8 -cycloalkyl, and the heterocyclic core is a 3-quinolone- or naphthyridone carboxylic acid derivative.
  • Japanese patent 06073056A describes antibacterial 3-quinolone-carboxylic acid and 1 ,8-naphthyridinecarboxylic acid derivatives of the formula,
  • R 1 is (un)substituted d-C ⁇ -alkyl, C 2 -C 6 -alkenyl, C 3 -C 7 -cycloalkyl, or aryl
  • R 2 is hydrogen, halogen, (un)protected OH, NH 2 , CrC ⁇ alkylamino, or di(Ci-C6- alkyl)amino
  • R 3 and R 5 are hydrogen or d-C 6 -alkyl
  • A is N or CA 1
  • a 1 is hydrogen, halogen, Ci-C 6 -alkyl, (un)substituted Ci-C 6 -alkoxy, cyano, nitro, or A 1 together with R 1 may form a ring optionally containing O, N, or S or substituted by Ci-Ce-alkyl.
  • R is selected from the group consisting of hydrogen and lower alkyl
  • Ri is selected from the group consisting of C 3 -C 6 cycloalkyl, C 4 - C ⁇ heterocycloalkyl, Ci-Csalkyl, C 2 -C 8 alkenyl, phenyl and a 5 to 6 membered heteroaryl
  • the Cs-C ⁇ cycloalkyl, C 4 -C 6 heterocycloalkyl, phenyl or 5 to 6 membered heteroaryl is optionally substituted with one to four substituents independently selected from the group consisting of halogen, lower alkyl, lower alkoxy, cyano, nitro, amino, (lower alkyl)amino and di(lower alkyl)amino;
  • A is selected from the group consisting of N and CR 5 ; wherein R 5 is selected from the group consisting of hydrogen, halogen, hydroxyl, lower alkyl, halogenated lower alkyl, lower alkoxy, halogenated lower alkoxy, Ci-C 4 alkylthio, amino, (lower alkyl)amino, di(lower alkyl)amino and cyano; alternatively, A is CR 5 , and R 5 and Ri are taken together with the atoms to
  • R2 and R3 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, (lower alkyl)amino, di(lower alkyl)amino, lower alkoxy, CrC 4 alkylthio, lower alkyl, C 2 -C 4 alkenyl and C 2 -C 4 alkynyl;
  • R 4 is selected from the group consisting of CrC 8 alkyl, -C(O)O-(lower alkyl), aryl, heteroaryl, heterocycloalkyl, -(Ci-C 4 alkyl)-C 3 -C 6 cycloalkyl, -(CrC 4 alkyl)-aryl, - (C r C 4 alkyl)-heteroaryl, and -(Ci-C 4 alkyl)-heterocycloalkyl; wherein the d-Csalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, amino, (lower alkyl)amino, di(lower alkyl)amino, aryloxy, heteroaryloxy, acyloxy, carboxy, carboxamido, acylamino, oxo, thio, and cyano; and wherein the aryl, heteroaryl or heterocycloalky
  • Illustrative of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the product prepared according to the process described herein.
  • An illustration of the invention is a pharmaceutical composition made by mixing the product prepared according to the process described herein and a pharmaceutically acceptable carrier.
  • Illustrating the invention is a process for making a pharmaceutical composition comprising mixing the product prepared according to the process described herein and a pharmaceutically acceptable carrier.
  • the compounds of this invention are effective antimicrobial agents against a broad range of pathogenic microorganisms with advantages of activity against resistant microbes.
  • the present invention is also directed to a method of treating a subject having a condition caused by or contributed to by bacterial infection, which comprises administering to said mammal a therapeutically effective amount of the compound of Formula (I).
  • the present invention is further directed to a method of preventing a subject from suffering from a condition caused by or contributed to by bacterial infection, which comprises administering to the subject a prophylactically effective dose of the pharmaceutical composition of a compound of Formula (I).
  • the present invention is further directed to the use of a compound of formula (I) for the preparation of a medicament for treating and / or preventing a condition caused by or contributed to by bacteria infection, in a subject in need thereof.
  • the present invention is directed to the use of a compound of formula (I) for the preparation of a medicament for treating and / or preventing a condition caused by or contributed to by bacteria infection associated with a drug resistant bacteria, in a subject in need thereof
  • R, R 1 , A, R 2 , R 3 and R 4 are as herein defined, and optical isomers, diastereomers, enantiomers, pharmaceutically acceptable salts, hydrates, and prodrugs thereof.
  • the compounds of formula (I) are useful as antimicrobial agents against a broad range of pathogenic microorganisms with advantages of activity against resistant microbes.
  • C x -Cy wherein x and y are numbers shall denote the number of carbon atoms present in a particular function group.
  • Ci-Csalkyl denotes any straight or branched chain alkyl as herein define of between 1 and 8 carbon atoms, inclusive.
  • C 2 -C 4 alkenyl shall denote an alkenyl group of between 2 and 4 carbon atoms inclusive.
  • alkyl shall mean a saturated, straight or branched hydrocarbon chain having 1 to 15 carbons.
  • alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl and the like.
  • lower when used with alkyl means a carbon chain composition of 1-4 carbon atoms.
  • halogenated alkyl shall mean any alkyl group as defined above substituted with one to five halogen atoms, preferably with at least one halogen atom, preferably substituted with a least one fluoro atom. Suitable examples include but are not limited to -CF 3 , -CH 2 -CF 3 , -CF 2 -CF 2 -CF 2 -CF 3 , and the like.
  • fluorinated alkyl shall mean any alkyl group as defined above substituted with one to five fluoro atoms, preferably with at least one fluoro atom. Suitable examples include but are not limited to -CF 3 , -CH 2 -CF 3 , -CF 2 -CF 2 -CF 2 -CF 3 , and the like.
  • alkene or “alkenyl” shall mean a straight or branched hydrocarbon chain having at least one carbon-carbon double bond and having 2 to 15 carbon atoms.
  • Alkyne shall mean a straight or branched hydrocarbon chain having at least one carbon-carbon triple bond and having 2 to 15 carbon atoms.
  • alkoxy shall denote an oxygen ether radical of the above described straight or branched chain alkyl groups (i.e. a group of the formula -O- alkyl). For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy, n-hexyloxy and the like. Unless otherwise noted, “lower” when used with alkoxy means an oxygen ether radical as defined above of 1 -4 carbon atoms.
  • halogenated alkoxy shall mean any alkoxy group as defined above substituted with one to five halogen atoms, preferably with at least one halogen atom, preferably substituted with a least one fluoro atom. Suitable examples include but are not limited to -OCF 3 , -OCH 2 -CF 3 , -OCF 2 -CF 2 -CF 2 -CF 3 , and the like.
  • fluorinated alkoxy shall mean any alkoxy group as defined above substituted with one to five fluoro atoms, preferably with at least one halogen atom, preferably substituted with a least one fluoro atom. Suitable examples include but are not limited to -OCF 3 , -OCH 2 -CF 3 , -OCF 2 -CF 2 -CF 2 -CF 3 , and the like.
  • alkylthio shall mean -S-alkyl . Suitable examples include but are not limited to methylthio, (-S-CH 3 ), ethyl-thio, isopropyl-thio, and the like.
  • C 3 -C 6 cycloalkyl shall mean any stable 3-6 membered monocyclic, saturated ring system. Suitable examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Further, wherein the cycloalkyl is optionally substituted, said substitution may be at any of the carbon atoms of the cycloalkyl group.
  • aryl shall refer to unsubstituted carbocylic aromatic groups such as phenyl, naphthyl, and the like.
  • heteroaryl shall denote any five or six membered monocyclic aromatic ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S; or a nine or ten membered bicyclic aromatic ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to four additional heteroatoms independently selected from the group consisting of O, N and S.
  • the heteroaryl group may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure. Unless otherwise noted, the heteroaryl group may be optionally substituted with one or more substituents as herein defined.
  • heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyhdazinyl, pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl, isoindolinyl, indazolyl, benzofuryl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyhdinyl, pteridinyl, and the like.
  • heteroaryl groups include, but are not limited to pyridyl, quinolinyl and isoquinolinyl.
  • heterocycloalkyl shall denote any five to seven membered monocyclic, saturated or partially unsaturated ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S; or a nine to ten membered saturated, partially unsaturated or partially aromatic bicyclic ring system containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to four additional heteroatoms independently selected from the group consisting of O, N and S.
  • the heterocycloalkyl group may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure. Unless otherwise noted, the heterocycloalkyl group may be optionally substituted with one or more substituents as herein defined.
  • substituted and unsubstituted heterocycloalkyl groups include, but are not limited to, pyrrolinyl, pyrrolidinyl, dioxolanyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, indolinyl, chromenyl, 3,4-methylenedioxyphenyl, 2,3- dihydrobenzofuryl, phthalimido (also known as isoindole-1 ,3-dione), isoindolinyl, and the like.
  • Preferred heterocycloalkyl groups include, but are not limited to phthalimido.
  • heteroaryloxy shall mean a group of the formula -O-heteroaryl, wherein the heteroaryl group is as defined above. Suitable examples include, but are not limited to 2-pyhdyloxy-2-pyrimidinyl-oxy- and pyridazinyl-oxy-.
  • acyl shall mean an organic radical having 2 to 6 carbon atoms
  • acyloxy shall mean a group of the formula -O-acyl, wherein the acyl group is as defined above. Suitable examples include but are not limited to acetoxy, propionoxy, and the like.
  • substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein.
  • substituents may be bound to any of the atoms of a particular group (including, but not limited to C, N or S atoms), provided that the substitution results in a stable structure and does not violate valence rules.
  • Some of the compounds of the present invention may have trans and cis isomers.
  • these isomers may be separated by conventional techniques such as preparative chromatography.
  • the compounds may be prepared as a single stereoisomer or in racemic form as a mixture of some possible stereoisomers.
  • the non-racemic forms may be obtained by either synthesis or resolution.
  • the compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation.
  • the compounds may also be resolved by covalent linkage to a chiral auxiliary, followed by chromatographic separation and/or crystallographic separation, and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using chiral chromatography.
  • the compounds according to this invention may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.
  • the enantiomer is present at an enantiomeric excess of greater than or equal to about 80%, more preferably, at an enantiomeric excess of greater than or equal to about 90%, more preferably still, at an enantiomeric excess of greater than or equal to about 95%, more preferably still, at an enantiomeric excess of greater than or equal to about 98%, most preferably, at an enantiomeric excess of greater than or equal to about 99%.
  • the diastereomer is present at a diastereomeric excess of greater than or equal to about 80%, more preferably, at a diastereomeric excess of greater than or equal to about 90%, more preferably still, at a diastereomeric excess of greater than or equal to about 95%, more preferably still, at a diastereomeric excess of greater than or equal to about 98%, most preferably, at a diastereomeric excess of greater than or equal to about 99%.
  • some of the crystalline forms for the compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention.
  • some of the compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
  • phenyld- CealkylaminocarbonylCi-C ⁇ alkyl refers to a group of the formula
  • subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. Preferably, the subject has experienced and / or exhibited at least one symptom of the disease or disorder to be treated and / or prevented.
  • terapéuticaally effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
  • prophylactically effective amount means that amount of active compound or pharmaceutical agent that prevents the development of a condition, symptoms or manifestations thereof associated with bacterial infection. Thus it elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
  • drug-resistant or “drug-resistance” refers to the characteristics of a microbe to survive in the presence of a currently available antimicrobial agent such as an antibiotic at its routine, effective concentration.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
  • reaction step(s) is performed under suitable conditions, according to known methods, to provide the desired product.
  • reagent or reagent class/type e.g. base, solvent, etc.
  • the individual reagents are independently selected for each reaction step and may be the same or different from each other.
  • the organic or inorganic base selected for the first step may be the same or different than the organic or inorganic base of the second step.
  • reaction step of the present invention may be carried out in a variety of solvents or solvent systems, said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems.
  • these isomers may be separated by conventional techniques such as preparative chromatography.
  • the compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
  • the compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-D-tartahc acid and/or (+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallization and regeneration of the free base.
  • an optically active acid such as (-)-di-p-toluoyl-D-tartahc acid and/or (+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallization and regeneration of the free base.
  • the compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
  • any of the processes for preparation of the compounds of the present invention it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.
  • the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • the present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds that are readily convertible in vivo into the required compound.
  • administering shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts.”
  • Other salts may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts.
  • alkali metal salts e.g., sodium or potassium salts
  • alkaline earth metal salts e.g., calcium or magnesium salts
  • suitable organic ligands e.g., quaternary ammonium salts.
  • representative pharmaceutically acceptable salts include the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochlohde, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laureate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, ole
  • acids and bases that may be used in the preparation of pharmaceutically acceptable salts include the following: acids including acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+)-camphohc acid, camphorsulfonic acid, (+)-(1 S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuhc acid, ethane-1 ,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid
  • Ri is selected from the group consisting of C 3-6 CyClOaIkVl, C 4-6 heterocycloalkyl, phenyl, and 6 membered heteroaryl; wherein the C 3-6 cycloalkyl, C 4-6 heterocycloalkyl, phenyl or 6 membered heteroaryl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, lower alkyl, lower alkoxy, cyano, amino, (lower alkyl)amino and di(lower alkyl)amino.
  • R 1 is selected from the group consisting of Cs-C ⁇ cycloalkyl, phenyl, and 6 membered heteroaryl; wherein the C 3 -C 6 cycloalkyl, phenyl or 6 membered heteroaryl is optionally substituted with one to three substituents independently selected from the group consisting of halogen and amino.
  • R 1 is selected from the group consisting of cyclopropyl, 2,4-difluorophenyl, 1 R-(2S- fluoro-cyclopropyl) and 2-(3,5-difluoro-6-amino-pyhdyl).
  • R 1 is selected from the group consisting of cyclopropyl, 2,4- difluorophenyl and 1 R-(2S-fluoro-cyclopropyl).
  • A is selected from the group consisting of N and CR 5 ; wherein R 5 is selected from the group consisting of hydrogen, halogen, lower alkyl, fluorinated lower alkyl, lower alkoxy and fluohnated lower alkoxy.
  • A is selected from the group consisting of N and CR 5 ; wherein R 5 is selected from the group consisting of hydrogen, halogen, lower alkoxy and fluorinated lower alkoxy.
  • A is selected from the group consisting of N and CR 5 ; wherein R 5 is selected from the group consisting of hydrogen, chloro, methoxy and difluoromethoxy.
  • A is selected from the group consisting of N and CR 5 ; wherein R 5 is selected from the group consisting of hydrogen and methoxy.
  • A is CR 5 , and R 5 and Ri are
  • A is N.
  • A is CR 5 ; wherein R 5 is selected from the group consisting of hydrogen, halogen, lower alkyl, fluorinated lower alkyl, lower alkoxy and fluohnated lower alkoxy.
  • A is CR 5 ; wherein R 5 is selected from the group consisting of hydrogen, halogen, lower alkoxy and fluorinated lower alkoxy.
  • A is CR 5 ; wherein R 5 is selected from the group consisting of hydrogen, chloro, methoxy and difluoromethoxy.
  • A is CR 5 ; wherein R 5 is selected from the group consisting of hydrogen and methoxy.
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, (lower alkyl)amino, di(lower alkyl)amino, lower alkyl and lower alkoxy.
  • R 2 is halogen.
  • R 2 is fluoro.
  • R 3 is hydrogen.
  • R 4 is selected from the group consisting of lower alkyl, -C(O)O-(lower alkyl), aryl, heteroaryl, heterocycloalkyl, - (CrC 2 alkyl)-heteroaryl and -(Ci-C 2 alkyl)-heterocycloalkyl; wherein the lower alkyl is optionally substituted with one to two substituents independently selected from the group consisting of halogen, hydroxy, amino, (lower alkyl)amino, di(lower alkyl)amino, aryloxy, heteroaryloxy, acyloxy, carboxy, oxo and cyano; wherein the aryl, heteroaryl or heterocycloalkyl, whether alone or as part of a substituent group is optionally substituted with one to two substituents independently selected from the group consisting of halogen, hydroxy, cyano, amino, (lower alkyl)amino, di(low
  • R 4 is selected from the group consisting of lower alkyl, -C(O)O-(lower alkyl), aryl, heteroaryl, heterocycloalkyl and -(Ci- C 2 alkyl)-heteroaryl; wherein the lower alkyl is optionally substituted with one to two substitutent independently selected from the group consisting of halogen, hydroxy, amino, (lower alkyl)amino, di(lower alkyl)amino, aryloxy, heteroaryloxy, acyloxy, carboxy, oxo and cyano; wherein the aryl, heteroaryl or heterocycloalkyl, whether alone or as part of a substituent group is optionally substituted with one to two substituents independently selected from the group consisting of halogen, hydroxy, cyano, amino, (lower alkyl)amino, di(lower alkyl)amino, lower alkyl, halogenated lower alky
  • R 4 is selected from the group consisting of lower alkyl, phenyl, 6 membered heteroaryl, 2-(isoindole-1 ,3-dione)-methyl-, and -C(O)O-lower alkyl; wherein the lower alkyl is optionally substituted with a substitutent selected from the group consisting of hydroxy and amino; and wherein the phenyl or 6 membered heteroaryl is optionally substituted with a substituent selected from the group consisting of halogen, lower alkoxy and fluorinated lower alkyl.
  • R 4 is selected from the group consisting of ethoxy-carbonyl-, hydroxy-methyl-, amino-methyl-, 4-chlorophenyl, 4- methoxy-phenyl, 2-(isoindole-1 ,3-dione)-methyl-, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3- (6-methoxy-pyridyl) and 3-(6-trifluoromethyl-pyridyl).
  • R 4 is selected from the group consisting of 4-chlorophenyl, 4-methoxy-phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-(6-methoxy-pyridyl) and 3-(6- trifluoromethyl-pyridyl).
  • R 4 is selected from the group consisting of 4-chlorophenyl, 4-methoxyphenyl, 2-pyridyl and 3-pyridyl.
  • the present invention is directed to compound selected from the group consisting of 7-[3-(4-chloro-phenyl)-3a,4,6,6a-tetrahydro- pyrrolo[3,4-d]isoxazol-5-yl]-1 -(2,4-difluoro-phenyl)-6-fluoro-4-oxo-1 ,4-dihydro- [1 ,8]naphthyridine-3-carboxylic acid; 1 -(2,4-difluoro-phenyl)-6-fluoro-4-oxo-7-(3- pyridin-3-yl-3a,4,6,6a-tetrahydro-pyrrolo[3,4-d]isoxazol-5-yl)-1 ,4-dihydro- [1 ,8]naphthyridine-3-carboxylic acid; 1-cyclopropyl-6-fluoro-4-oxo-7-(3-pyri
  • Additional embodiments of the present invention include those wherein the substituents selected for one or more of the variables defined herein (i.e. R, Ri, A, R2, R3, and R 4 ) are independently selected to be any individual substituent or any subset of substituents selected from the complete list as defined herein.
  • R, Ri, A, R2, R3, and R 4 are independently selected to be any individual substituent or any subset of substituents selected from the complete list as defined herein.
  • R, Ri, A, R2, R3, and R 4 are independently selected to be any individual substituent or any subset of substituents selected from the complete list as defined herein.
  • R, Ri, A, R2, R3, and R 4 are independently selected to be any individual substituent or any subset of substituents selected from the complete list as defined herein.
  • R, Ri, A, R2, R3, and R 4 are independently selected to be any individual substituent or any subset of substituents selected from the complete list as defined herein.
  • the present invention is directed to any single compound r subset of compounds selected from the representative compounds of formula ) listed in Table 3, below.
  • the present invention is directed to compounds of formula (I) whose MIC (minimal inhibitory concentration) against strain A as measured according to the procedure described in Example 84
  • the micro should be 84 is less than or equal to or equal to about 0.25 ⁇ g/mL, preferably less than or equal to or equal to about 0.12 ⁇ g/mL, more preferably less than or equal to about 0.06 ⁇ g/mL.
  • the present invention is directed to compounds of formula (I) whose MIC (minimal inhibitory concentration) against strain B as measured according to the procedure described in Example 84 is less than or equal to or equal to about 16 ⁇ g/mL, preferably less than or equal to or equal to about 8 ⁇ g/mL, more preferably less than or equal to about 4 ⁇ g/mL.
  • the present invention is directed to compounds of formula (I) whose MIC (minimal inhibitory concentration) against strain C as measured according to the procedure described in Example 84 is less than or equal to or equal to about 16 ⁇ g/mL, preferably less than or equal to or equal to about 8 ⁇ g/mL, more preferably less than or equal to about 4 ⁇ g/mL.
  • the present invention is directed to compounds of formula (I) whose MIC (minimal inhibitory concentration) against strain D as measured according to the procedure described in Example 84 is less than or equal to or equal to about 16 ⁇ g/mL, preferably less than or equal to or equal to about 8 ⁇ g/mL, more preferably less than or equal to about 4 ⁇ g/mL.
  • the present invention is directed to compounds of formula (I) whose MIC (minimal inhibitory concentration) against strain E as measured according to the procedure described in Example 84 is less than or equal to or equal to about 4 ⁇ g/mL, preferably less than or equal to or equal to about 2 ⁇ g/mL, more preferably less than or equal to about 1 ⁇ g/mL.
  • the order of synthetic steps may be varied to increase the yield of desired product.
  • the skilled artisan will also recognize the judicious choice of reactions, solvents, and temperatures are an important component in successful synthesis. While the determination of optimal conditions, etc. is routine, it will be understood that a variety of compounds can be generated in a similar fashion, using the guidance of the schemes below.
  • the starting materials used in preparing the compounds of the invention are known, made by published synthetic methods or available from commercial vendors.
  • Patent 6025370 European Patent Publication 153828, European Patent Publication 191451 , European Patent Publication 153163, European Patent Publication 230053, European Patent Publication 976749, International Patent Publication WO0118005, International Patent Publication WO9407873, U.S. Patent 4777253, European Patent Publication 421668, International Patent Publication WO0248138, European Patent Publication 230295, International Patent Publication WO9914214, U.S. Patent Publication 20020049223, International Patent Publication WO9921849, International Patent Publication WO9729102, International Patent Publication WO0334980, International Patent Publication WO0209758, International Patent Publication WO9619472, German Patent Publication DE 3142854, International Patent
  • a suitably substituted compound of formula (V), as a free base or its corresponding acid addition salt, for example its corresponding TFA salt, a known compound or compound prepared according to known methods, or compound prepared according to the processes as described in Schemes 4 and 5 herein, is reacted with a suitably substituted compound of formula (Vl), wherein L 1 is a suitably selected leaving group such as Cl, F, and the like, a known compound or compound prepared by known methods; in the presence of an organic base such as TEA, DIPEA, pyridine, and the like; in an organic solvent such as acetonitrile, DMSO, N-methylpyrrolidinone, DMF, and the like; preferably at a temperature greater than about room temperature, more preferably at a temperature in the range of from about 55 to about 100 0 C, to yield the corresponding compound of formula (Ia).
  • an organic base such as TEA, DIPEA, pyridine, and the like
  • organic solvent such as acetonitrile,
  • the compound of formula (Ia) may be further reacted with hydrazine (NH 2 NH 2 ), a known compound, in an organic solvent such as ethanol, methanol, isopropanol, and the like, preferably at a temperature greater than about room temperature, more preferably at a temperature in the range of from about 65 to about 83 0 C, to yield the corresponding compound of formula (Ib).
  • hydrazine NH 2 NH 2
  • organic solvent such as ethanol, methanol, isopropanol, and the like, preferably at a temperature greater than about room temperature, more preferably at a temperature in the range of from about 65 to about 83 0 C, to yield the corresponding compound of formula (Ib).
  • compounds of formula (Ib) may be prepared using suitably selected nitrogen protecting groups other than phthalimide, which nitrogen protecting groups may be removed according to known methods, following the reaction of compound of formula (V) with compound of formula (Vl) to yield compound of formula (Ia).
  • 1 H-pyrrole a known compound; in the presence of an organic base such as TEA, DIPEA, pyridine, and the like; in an organic solvent such as acetonitrile, DMSO, N-methylpyrrolidinone, DMF, and the like; preferably at a temperature greater than about room temperature, more preferably at a temperature in the range of from about 55 to about 100 0 C, to yield the corresponding compound of formula (VII).
  • an organic base such as TEA, DIPEA, pyridine, and the like
  • organic solvent such as acetonitrile, DMSO, N-methylpyrrolidinone, DMF, and the like
  • the compound of formula (VII) is reacted with a suitably substituted compound of formula (VIII), a known compound or compound prepared according to known methods, in the presence of an inorganic base such as NaHCO3,
  • organic solvent such as THF, diethyl ether, and the like
  • the compound of formula (IX) is reacted with a suitably substituted compound of formula (V), as a free base or its corresponding acid addition salt, for example its corresponding TFA salt, a known compound or compound prepared according to known methods, or compound prepared according to the processes as described in Schemes 4and 5 herein; in the presence of an organic base such as TEA, DIPEA, pyridine, and the like; in an organic solvent such as acetonithle, DMSO, DMF, N- methylpyrrolidinone, and the like; preferably at a temperature greater than about room temperature, more preferably at a temperature in the range of from about 55 to about 100 0 C, to yield the corresponding compound of formula (X).
  • a suitably substituted compound of formula (V) as a free base or its corresponding acid addition salt, for example its corresponding TFA salt, a known compound or compound prepared according to known methods, or compound prepared according to the processes as described in Schemes 4and 5 herein; in the presence of an organic base
  • the -CO2BF2 substituent on compound of formula (X) is then converted to its corresponding -CO 2 H substituent by reacting the compound of formula (X) with an organic base such as TEA, DIPEA, and the like, in an organic solvent such as ethanol, methanol, isopropanol, and the like, preferably at a temperature greater than about room temperature, more preferably at a temperature in the range of from about 65 to about 83 0 C, to yield the corresponding compound of formula (Ia).
  • an organic base such as TEA, DIPEA, and the like
  • an organic solvent such as ethanol, methanol, isopropanol, and the like
  • R is lower alkyl and wherein the compound of formula (VI-EST) is the corresponding alkyl ester of the compound of formula (Vl) as defined herein.
  • a compound of formula (Xl), wherein PG 1 is a suitably selected nitrogen protecting group such as BOC, Cbz, thfluoroacetyl, and the like, a known compound or compound prepared by known methods is reacted with a suitably selected compound of formula (VIII), wherein R 4 is a group such as aryl, heteroaryl and the like, a known compound or compound prepared by known methods; in the presence of an organic or inorganic base such as TEA, DIPEA, pyridine, NaHCO 3 , KHCO 3 , Na 2 CO 3 , K 2 CO 3 , and the like, in an organic solvent such as ethyl acetate, diethyl ether, and the like, at room temperature or in an organic solvent such as IPA, 2-butanol, and the like, at a temperature in the range of from about 25 to about 4O 0 C; to yield the corresponding compound of formula (V-PT), a compound or formula (V) wherein the
  • the compound of formula (V-PT) may be de-protected according to known methods, for example by reacting with a suitably selected acid such as TFA, HCI, and the like, in an organic solvent such as DCM, DCE, isopropanol, chloroform, and the like, to yield the corresponding compound of formula (V), as its corresponding acid addition salt.
  • a suitably selected acid such as TFA, HCI, and the like
  • organic solvent such as DCM, DCE, isopropanol, chloroform, and the like
  • Compounds of formula (V) wherein R 4 is -CO 2 -lower alkyl, -CH 2 -OH or - CH 2 -phthalimide may alternatively be prepared according to the process outlined in Scheme 5, below.
  • a suitably substituted compound of formula (Xl), wherein PG 1 is a suitably selected nitrogen protecting group such as BOC, Cbz, trifluoroacetyl, and the like, a known compound or compound prepared by known methods is reacted with a suitably selected compound of formula (XII), wherein X is lower alkyl, a known compound or compound prepared by known methods; in the presence of an organic or inorganic base such as TEA, DIPEA, pyridine, NaHCO 3 , KHCO 3 , Na 2 CO 3 , K 2 CO 3 , and the like, in an organic solvent such as ethyl acetate, diethyl ether, and the like, at room temperature or in an organic solvent such as IPA, 2-butanol, and the like, at a temperature in the range of form about 25 to about 4O 0 C; to yield the corresponding compound of formula (XIII) (a compound of formula (V) wherein R 4 is -CO 2 -low
  • the compound of formula (XIII) is reacted with a suitably selected reducing agent such as NaBH 4 , lithium borohydride, DIBAL, and the like, in an organic solvent such as ethanol, methanol, THF, and the like, to yield the corresponding compound of formula (XIV) (a compound of formula (V) wherein R 4 is -CH 2 -OH and wherein the nitrogen group is protected with PG 1 a suitably selected nitrogen protecting group).
  • a suitably selected reducing agent such as NaBH 4 , lithium borohydride, DIBAL, and the like
  • organic solvent such as ethanol, methanol, THF, and the like
  • the compound of formula (XIV) is reacted to convert the -OH group on the compound of formula (XIV) to a corresponding protected amine.
  • the compound of formula (XIV) is converted via a Mitsunobu reaction by combining with phthalimide, in the presence of a DIAD and PPh 3 , in an organic solvent such as THF, dioxane, and the like, to yield the corresponding compound of formula (XV).
  • the compound of formula (XV) may be further de-protected according to known methods, to yield the corresponding compound of formula (XVI).
  • the compound of formula (XIII) and / or the compound of formula (XIV) may also be de-protected according to known methods, for example by reacting with a suitably selected acid such as TFA, HCI, and the like, in an organic solvent such as DCM, DCE, isopropanol, chloroform, and the like, to yield the corresponding compounds of formula (XVII) and (XVIII) respectively, as their corresponding acid addition salts
  • the present invention further comprises pharmaceutical compositions containing one or more compounds of formula (I) with a pharmaceutically acceptable carrier.
  • Pharmaceutical compositions containing one or more of the compounds of the invention described herein as the active ingredient can be prepared by intimately mixing the compound or compounds with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral).
  • suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like;
  • suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like.
  • Solid oral preparations may also be coated with substances such as sugars or be enteric- coated so as to modulate major site of absorption.
  • the carrier will usually consist of sterile water and other ingredients may be added to increase solubility or preservation.
  • injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives.
  • compositions of this invention one or more compounds of the present invention as the active ingredient is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular.
  • a pharmaceutical carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular.
  • any of the usual pharmaceutical media may be employed.
  • suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like;
  • suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques.
  • the carrier will usually comprise sterile water, though other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included.
  • injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • the pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described above.
  • compositions herein will contain, per unit dosage unit, e.g., tablet, capsule, powder, injection, suppository, teaspoonful and the like, of from about 0.1 -5000 mg or any range therein, and may be given at a dosage of from about 0.01 -50 mg/kg/day, or any range therein, preferably from about 1.0-30 mg/kg/day, or any range therein.
  • the dosages may be varied depending upon the requirement of the patients, the severity of the condition being treated and the compound being employed. The use of either daily administration or post-periodic dosing may be employed.
  • compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
  • the composition may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection.
  • a pharmaceutical carrier e.g.
  • a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
  • preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules.
  • This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.
  • the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form yielding the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer, which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include, aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
  • the methods described in the present invention may also be carried out using a pharmaceutical composition
  • a pharmaceutical composition comprising any of the compounds as defined herein and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition may contain between about 0.01 mg and 5000 mg of the compound, or any range therein; preferably about 70 to 2000 mg of the compound, or any range therein, and may be constituted into any form suitable for the mode of administration selected.
  • Carriers include necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.
  • compositions suitable for oral administration include solid forms, such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release formulations), granules, and powders, and liquid forms, such as solutions, syrups, elixirs, emulsions, and suspensions.
  • forms useful for parenteral administration include sterile solutions, emulsions and suspensions.
  • compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those of ordinary skill in that art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture.
  • suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • the liquid forms may include suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like.
  • suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like.
  • sterile suspensions and solutions are desired.
  • Isotonic preparations which generally contain suitable preservatives, are employed when intravenous administration is desired.
  • the compound of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholine.
  • Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds of the present invention may also be coupled with soluble polymers as target able drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxy-ethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residue.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross- linked or amphipathic block copolymers of hydrogels.
  • a compound of formula (I) as the active ingredient is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration (e.g. oral or parenteral).
  • a pharmaceutical carrier may take a wide variety of forms depending of the form of preparation desired for administration (e.g. oral or parenteral).
  • Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers may be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.
  • Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever treatment with antimicrobial agents is required.
  • the daily dosage of the products may be varied over a wide range from 0.01 to 5,000 mg per adult human per day, or any range therein.
  • the compositions are preferably provided in the form of tablets containing, 0.01 , 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.01 mg/kg to about 50 mg/kg of body weight per day, or any range therein.
  • the range is from about 0.5 to about 40 mg/kg of body weight per day, or any range therein. More preferably, from about 1.0 to about 30 mg/kg of body weight per day, or any range therein.
  • the compounds may be administered on a regimen of 1 to 4 times per day.
  • Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages.
  • One skilled in the art will recognize that, both in vivo and in vitro trials using suitable, known and generally accepted cell and / or animal models are predictive of the ability of a test compound to treat or prevent a given disorder.
  • the title compound was prepared according to the method of Howe and Shelton. 2b was isolated as a white solid.
  • the title compound was prepared in an analogous manner to the 4- methoxy-3-pyhdyl case 2c using a suitably substituted oxime. 2d was isolated as an aqua solid.
  • the title compound was prepared in an analogous manner to the 4- methoxy-3-pyhdyl case 2c using a suitably substituted oxime. 2f was isolated as a cream-colored solid.
  • the title compound was prepared in an analogous manner to the A- methoxy-3-pyhdyl case 2c using a suitably substituted oxime. 2g was isolated as a white solid.
  • Examples 13-21 describe the preparation of representative cycloadducts.
  • Example 13 cis-3-(4-Chlorophenyl)-3a A6,6a-tetrahvdro-pyrrolo[3,4-d1isoxazole-
  • the title compound was prepared in an analogous manner as the 4- chlorophenyl cycloadduct 3a using chloro oxime 2b. However, two additional portions of chloro oxime and triethyl amine were used. 3b was isolated as a white solid.
  • Example 17 cis-3-(Pyridin-2-yl)-3a,4.6,6a-tetrahvdro-pyrrolo[3,4-d1isoxazole-5- carboxylic acid tert-butyl ester (3e)
  • N-Boc pyrroline (270 mg; 1.60 mmol), chloro oxime 2f (470 mg; 3.00 mmol) and sodium bicarbonate (760 mg; 9.04 mmol) in isopropanol (10 ml_) were heated at 4O 0 C overnight. An additional portion of chloro oxime and sodium bicarbonate was added and heating continued for 20 hours. After cooling, the volatiles were evaporated. The residue was dissolved in ethyl acetate (50 ml_), and washed with water (50 ml_). The organic layer was dried (MgSO 4 ), filtered and evaporated. Cycloadduct 3f was isolated as a beige powder after chromatography with 70% ethyl acetate/hexanes.
  • Example 19 cis-SaA ⁇ .ea-TetrahvdropyrrolorS ⁇ -diisoxazole-S. ⁇ -dicarboxylic acid
  • the title compound was prepared using commercially available ethyl chloro oximidoacetate (5).
  • N-Boc-pyrroline 1.0 g; 5.91 mmol
  • ethyl chloro oximidoacetate (2.55 g; 16.8 mmol)
  • sodium bicarbonate (1.77 g; 21.06 mmol) in ethyl acetate (15 ml_) were stirred for 54 hours.
  • An additional amount of chloro oxime (2.6 g; 17.28 mmol) and sodium bicarbonate (2.1 g; 25.00 mmol) was added and the reaction mixture stirred overnight. The addition of reagents was repeated again and the reaction mixture stirred for 36 hours.
  • Example 21 cis-3-(1.3-Dioxo-1.3-dihvdro-isoindol-2-ylmethyl)-3a. 4. 6 ,6a- tetrahvdro-pyrrolo[3,4-d1isoxazole-5-carboxylic acid tert-butyl ester (8).
  • Examples 22-30 describe removal of the t-butoxy-carbonyl (BOC) protecting group from the cycloadduct compounds prepared above.
  • Boc protected amine 3a 200 mg; 0.62 mmol
  • thfluoroacetic acid 0.5 ml_
  • methylene chloride 10 ml_
  • Example 28 cis ⁇ . ⁇ .G.Ga-Tetrahvdro-SaH-pyrrolofS ⁇ -diisoxazole-S-carboxylic acid ethyl ester trifluoroacetate salt (10)
  • heterocyclic nuclei were either commercially available as the carboxylic acid or the ethyl ester: 1 -cyclopropyl-1 ,4-dihydro-6,7-difluoro-8- methoxy-4-oxo-quinoline-3-carboxylic acid (52), 7-chloro-1 -cyclopropyl-6-fluoro-4- oxo-1 ,4-dihydro-naphthyhdine-3-carboxylic acid (51), 9,10-difluoro-2,3-dihydro-3- methyl-7-oxo-7H-pyrido[1 ,2,3-de]-1 ,4-benzoxazine-6-carboxylic acid (54), and 7- chloro-i ⁇ -difluorophenylJ- ⁇ -fluoro ⁇ -oxo-i ⁇ -dihydro-naphthyridine-S-carboxylic acid (50).
  • heterocyclic nuclei were prepared according to literature procedures as noted in Examples 31 -35, below: 1-cyclopropyl-1 ,4-dihydro-6,7- difluoro- ⁇ -difluoromethoxy ⁇ -oxo-quinoline-S-carboxylic acid (57), 1 -cyclopropyl- 1 ,4-dihydro-6,7-difluoro-4-oxo-quinoline-3-carboxylic acid (56), 1 -[(1 R,2S)-2- fluorocyclopropy]l-1 ,4-dihydro-6,7-difluoro-8-methoxy-4-oxo-quinoline carboxylic acid (53), 1 -(6-amino-3,5-difluoro-2-pyhdinyl)-8-chloro-6,7-difluoro-1 ,4-dihydro-4- oxo-quinoline-3-carboxylic acid (55), 1 -cyclo
  • Example 31 1 -Cvclopropyl-i ,4-dihvdro-6,7-difluoro-8-difluoromethoxy-4-oxo- quinoline-3-carboxylic acid (57)
  • Example 32 1-Cvclopropyl-i ⁇ -dihvdro-ey-difluoro ⁇ -oxo-quinoline-S-carboxylic acid (56)
  • Example 33 1 -[(1 R,2S)-2-Fluorocvclopropy]l-1 ,4-dihydro-6,7-difluoro-8-methoxy-
  • the title compound was prepared according to the method described in WO 01/072738 using the commercially available (-)-(1 R,2S)-2-fluorocyclopropylamine tosylate salt.
  • Example 34 1 -(6-amino-3,5-difluoro-2-pyridinyl)-8-chloro-6,7-difluoro-1 ,4-dihvdro-
  • N-1 substituent (monoprotected as the t-butyl amine) was prepared as described in WO97/11068.
  • the keto enol ether was prepared as described in US 4885386. Both of these intermediates were then utilized to complete the synthesis of the above compound as described in WO97/11068.
  • Example 35 1 -Cvclopropyl-i ,4-dihvdro-7-fluoro-8-nnethoxy-4-oxoquinoline-3- carboxylic acid (70)
  • Example 36 1 -Cvclopropyl-i ,4-dihvdro-6,7-difluoro-8-methoxy-4-oxo-quinoline-3- carboxylic acid difluoroborate ester (61 )
  • the title compound was prepared in a manner analogous to 1 -cyclopropyl- i ⁇ -dihydro- ⁇ J-difluoro- ⁇ -methoxy ⁇ -oxo-quinoline-S-carboxylic acid difluoroborate ester (61) but starting with 1 -cyclopropyl-1 ,4-dihydro-6,7-difluoro-8- difluoromethoxy-4-oxo-quinoline-3-carboxylic acid to yield 59 as an off-white solid.
  • Example 38 1 -[(1 R,2S)-2-Fluorocvclopropyl1-1 ,4-dihydro-6,7-difluoro-8-methoxy- 4-oxo-quinoline-3-carboxylic acid difluoroborate ester (60)
  • the title compound was prepared in a manner analogous to 1 -cyclopropyl- i ⁇ -dihydro- ⁇ J-difluoro- ⁇ -methoxy ⁇ -oxo-quinoline-S-carboxylic acid difluoroborate ester (61) but starting with 1-[(1 R,2S)-2-fluorocyclopropy]l-1 ,4- dihydro-6,7-difluoro-8-methoxy-4-oxo-quinoline carboxylic acid to yield 60 as a grey solid.
  • the title compound was prepared in an analogous manner as for difluoroborate ester 61 , but starting with S-(-)-9,10-difluoro-2,3-dihydro-3-methyl-7- oxo-7H-pyrido-[1 ,2,3-de][1 ,4]-benzoxazine-6-carboxylic acid to yield 58 as an off- white powder.
  • Example 40 1 -Cyclopropyl-i ,4-dihvdro-7-fluoro-8-methoxy-4-oxoquinoline-3- carboxylic acid difluoroborate ester (71 )
  • the title compound was prepared in an analogous manner as for difluoroborate ester 61 , but starting with 1 -cyclopropyl-1 ,4-dihydro-7-fluoro-8- methoxy-4-oxoquinoline-3-carboxylic acid (70) to yield 71 as an off-white powder.
  • Example 41 -83 describe the preparation of representative compounds of formula (I).
  • Example 41 7-[3-(4-Chloro-phenyl)-3a,4,6,6a-tetrahvdro-pyrrolo[3,4-d1isoxazol-5- yli-1 -(2,4-difluoro-phenyl)-6-fluoro-4-oxo-1 ,4-dihydro- ⁇ ,81naphthyridine-3- carboxylic acid (101 )
  • Example 42 1 -(2,4-Difluoro-phenyl)-6-fluoro-7-[3-(6-methoxy-pyridin-3-yl)- 3a , 4 , 6 , 6a-tetrahvdro-pyrrolo[3 , 4-d1isoxazol-5-yl1-4-oxo-1 , 4-dihydro- [1. ⁇ inaphthyridine-S-carboxylic acid (102)
  • Example 44 1 -(2,4-Difluoro-phenyl)-6-fluoro-4-oxo-7-(3-pyhdin-2-yl-3a,4.6,6a- tetrahvdro-pyrrolorS ⁇ -diisoxazol- ⁇ -vD-I ⁇ -dihvdro- ⁇ . ⁇ inaphthyridine-S-carboxylic
  • Example 45 1 -(2,4-Difluoro-phenyl)-6-fluoro-4-oxo-7-(3-pyhdin-3-yl-3a,4,6,6a- tetrahvdro-pyrrolofS ⁇ -diisoxazol- ⁇ -vD-I ⁇ -dihvdro-fi . ⁇ inaphthyridine-S-carboxylic acid (105)
  • Example 46 1 -(2,4-Difluoro-phenyl)-7-(3-ethoxycarbonyl-3a,4.6,6a-tetrahvdro-
  • Example 47 1 -(2,4-Difluoro-phenyl)-6-fluoro-7-(3-hvdroxymethyl-3a,4,6,6a- tetrahvdro-pyrrolo[3,4-d1isoxazol-5-yl)-4-oxo-1 ,4-dihvdro-[1 ,81naphthyridine-3- carboxvlic acid (107)
  • Example 48 1 -(2.4-Difluoro-phenyl)-7-r3-(1.3-dioxo-1.3-dihvdro-isoindol-2- ylmethyl)-3a,4,6,6a-tetrahvdro-pyrrolor3,4-d1isoxazol-5-yl1-6-fluoro-4-oxo-1 ,4- dihvdro-[1 ,81naphthyhdine-3-carboxylic acid (108)
  • Example 49 1 -Cvclopropyl-7-(2,5-dihvdro-pyrrol-1 -yl)-6-fluoro-4-oxo-1 ,4-dihvdro- H . ⁇ inaphthyridine-S-carboxylic acid (109)
  • Example 50 7-r3-(4-Chloro-phenyl)-3a.4.6.6a-tetrahvdro-pyrrolor3.4-d1isoxazol-5- v ⁇ -1 -cvclopropyl-6-fluoro-4-oxo-1 ,4-dihydro-[1 ,81naphthyridine-3-carboxylic acid
  • Example 51 i -Cvclopropyl-G-fluoro-Z-rS-fG-nnethoxypyridin-S-vD-SaAB.Ga- tetrahvdro-pyrrolorS ⁇ -cliisoxazol- ⁇ -yli ⁇ -oxo-I ⁇ -clihvdro-ri . ⁇ inaphthv ⁇ dine-S- carboxylic acid (111 )
  • Example 52 1 -Cvclopropyl-6-fluoro-4-oxo-7-r3-(6-trifluoromethyl-pyhdin-3-yl)- 3a,4.6,6a-tetrahvdro-pyrrolo[3,4-d1isoxazol-5-yl1-1 ,4-dihvdro-[1 ,81naphthyridine-3- carboxvlic acid (112)
  • Example 53 1 -Cvclopropyl-G-fluoro ⁇ -oxo-Z-O-pyridin ⁇ -yl-SaAG.Ga-tetrahvdro- pyrrolo[3,4-d1isoxazol-5-yl)-1 ,4-dihydro-[1 ,81naphthyhdine-3-carboxylic acid (113) 3
  • Example 54 1 -Cvclopropyl-G-fluoro ⁇ -oxo-Z-O-pyridin-S-yl-SaAG.Ga-tetrahvdro- pyrrolo[3,4-d1isoxazol-5-yl)-1 ,4-dihydro-[1 ,81naphthyhdine-3-carboxylic acid (114)
  • Example 55 1 -Cvclopropyl-G-fluoro ⁇ -oxo-Z-O-pyridin ⁇ -vD-SaAG.Ga-tetrahvdro- pyrrolo[3,4-d1isoxazol-5-yl)-1 ,4-dihvdro-[1. ⁇ inaphthyridine-S-carboxylic acid (115)
  • Example 56 1 -Cvclopropyl ⁇ -fS-ethoxycarbonyl-SaAG.Ga-tetrahvdro-pyrrolorS ⁇ - d1isoxazol-5-yl)-6-fluoro-4-oxo-1 ,4-dihydro-[1 ,81naphthyhdine-3-carboxylic acid
  • Example 57 1 -Cvclopropyl-G-fluoro ⁇ -fS-hvdroxymethyl-SaAB.Ga-tetrahvdro- pyrrolo[3,4-d1isoxazol-5-yl)-4-oxo-1 ,4-dihvdro-[1. ⁇ inaphthyridine-S-carboxylic acid
  • Example 58 1 -Cvclopropyl-7-r3-(1 ,3-dioxo-1 ,3-dihydro-isoindol-2-ylnnethyl)-
  • Example 59 1 -Cvclopropyl-7-(2,5-dihvdro-pyrrol-1 -yl)-6-fluoro-8-methoxy-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid (119)
  • Example 60 7-[cis-3-(4-Methoxyphenyl)-3a,4,6,6a-tetrahvdropyrrolo[3,4- diisoxazol- ⁇ -yli-i -cvclopropyl- ⁇ -nnethoxy-G-fluoro ⁇ -oxo-I ⁇ -dihvdroquinoline-S- carboxylic acid (120)
  • Example 61 7-[cis-3-(6-Trifluoromethyl-3-pyridyl)- 3a,4,6,6a-tetrahvdropyrrolo[3,4- diisoxazol- ⁇ -yli-i -cvclopropyl- ⁇ -methoxy-e-fluoro ⁇ -oxo-I ⁇ -dihvdroquinoline-S- carboxylic acid (121 )
  • Example 62 7-rcis-3-(2-py ⁇ dyl)-3a,4,6,6a-tetrahvdropyrrolor3,4-d1isoxazol-5-yl1-1 - cvclopropyl- ⁇ -methoxy-G-fluoro ⁇ -oxo-i ⁇ -dihydroquinoline-S-carboxylic acid (122)
  • Example 63 7-rcis-3-(3-Pvhdyl)-3a,4,6,6a-tetrahvdropyrrolor3,4-dlisoxazol-5-yll-1 - cvclopropyl- ⁇ -methoxy-e-fluoro ⁇ -oxo-i ,4-dihydroquinoline-3-carboxylic acid (123)
  • Example 64 7-[cis-3-(3-Ethoxycarbonyl)-3a,4,6,6a-tetrahvdropyrrolo[3,4- diisoxazol- ⁇ -yli-i -cvclopropyl- ⁇ -methoxy-e-fluoro ⁇ -oxo-I ⁇ -dihvdroquinoline-S- carboxvlic acid (124)
  • Example 65 7- [3-(1 ,3-dioxo-1 ,3-dihvdro-isoindol-2-ylmethyl)-3aA6,6a-tetrahvdro- pyrrolo[3,4-d1isoxazol-5-v ⁇ -1 -cvclopropyl- ⁇ -methoxy-e-fluoro ⁇ -oxo-i , 4- dihvdro ⁇ uinoline-3-carboxylic acid (125)
  • Example 67 7-[3-(1 ,3-dioxo-1 ,3-dihvdro-isoindol-2-ylmethyl)-3a,4,6,6a-tetrahvdro- pyrrolo[3,4-d1isoxazol-5-v ⁇ -1 -[(1 R, 2S)-2-fluorocvclopropyl1-6-fluoro-8-methoxy-4- oxo-1 ,4-dihvdro-quinoline-3-carboxylic acid (127)
  • Example 68 7-[cis-3-(4-Methoxyphenyl)-3a,4,6,6a-tetrahvdropyrrolo[3,4- diisoxazol-5-v ⁇ S-(-)-9, 10-difluoro-2,3-dihvdro-3-methyl-7-oxo-7H-pyrido- ⁇ ,2,3- dei ⁇ ⁇ I-benzoxazine-G-carboxylic acid (128)
  • Example 70 7-[cis-3-(3-pyridyl)-3a A6,6a-tetrahvdropyrrolo[3,4-d1isoxazol-5-v ⁇ S-
  • Acid 130 was isolated by reverse phase HPLC (acetonithle/water and no trifluoroacetic acid modifier) as a pale yellow powder.
  • Example 71 7-[cis-3-(ethoxycarbonyl)-3a A6,6a-tetrahvdropyrrolo[3,4-d1isoxazol- 5-yll S- M-9. l O-difluoro ⁇ .S-dihvdro-S-methyl ⁇ -oxo ⁇ H-pyrido- ⁇ ⁇ .S-deiri ⁇ l- benzoxazine-6-carboxylic acid (131 )
  • Example 73 1 -(6-Amino-3,5-difluoro-pyridin-2-yl)-8-chloro-6-fluoro-7-[3-(4- methoxy-phenyl)-3a,4.6,6a-tetrahvdro-pyrrolo[3,4-d1isoxazol-5-yl1-4-oxo-1 ,4- dihvdro-quinoline-3-carboxylic acid (133)
  • Example 75 1 -Cvclopropyl-G-fluoro-Z-rS-toyridin ⁇ -ylVSaAB.Ga-tetrahvdro- pyrrolo[3,4-d1isoxazol-5-v ⁇ -4-oxo-1 ,4-dihydro-quinoline-3-carboxylic acid (135)
  • Example 76 1 -Cvclopropyl-e-fluoro ⁇ -rS-toyridin-S-vD-SaA ⁇ .ea-tetrahvdro- pyrrolo[3,4-d1isoxazol-5-v ⁇ -4-oxo-1 ⁇ -dihydro-quinoline-S-carboxylic acid (136)
  • Example 77 1 -Cvclopropyl-8-difluoromethoxy-7-[3-(1 ,3-dioxo-1 ,3-dihvdro-isoindol-
  • Example 78 7-[cis-3-(2-pyridyl)-3a,4,6,6a-tetrahvdropyrrolo[3,4-d1isoxazol-5-v ⁇ -1 ⁇ cvclopropyl-8-nnethoxy -4-oxo-1 ,4-dihvdroquinoline-3-carboxylic acid (150)
  • Examples 79-83 describe preparation of representative compounds of formula (I) wherein the phthalimide protecting group is removed.
  • Example 79 7-(3-Aminomethyl-3a,4,6,6a-tetrahvdro-pyrrolo[3,4-d1isoxazol-5-yl)-1 ⁇ (2,4-difluoro-phenyl)-6-fluoro-4-oxo-1 ,4-dihvdro-ri ,81naphthyridine-3-carboxylic acid (200).
  • Phthalimide 108 (241 mg; 0.409mmol) and hydrazine hydrate (0.03 ml_) in ethanol (5 ml_) were heated at reflux temperature under a nitrogen atmosphere for 23 hours. After cooling, the thick reaction mixture suspension was filtered. The solid was washed with methylene chloride, water and dried to yield amine 200 as an off-white solid.
  • Example 80 7-(3-Aminomethyl-3a A6,6a-tetrahvdro-pyrrolo[3,4-d1isoxazol-5-yl)-1 - cyclopropyl-G-fluoro ⁇ -oxo-i ,4-dihydro-[1 ,81naphthyhdine-3-carboxylic acid (201 ).
  • Example 81 7- [3-Aminomethyl)-3aA6,6a-tetrahvdro-pyrrolo[3,4-d1isoxazol-5-v ⁇ - i -cvclopropyl- ⁇ -methoxy-G-fluoro ⁇ -oxo-i , 4-dihvdroquinoline-3-carboxylic acid
  • Phthalimide 125 60 mg, 0.11 mmol
  • hydrazine (0.03 ml_) in methanol (5 ml_) were heated at reflux temperature for 4 hours. The resulting mixture was concentrated and water added to the residue. No solid formed. The water was evaporated and the residue was purified by reverse phase HPLC (acetonithle/water with no TFA modifier). 202 was isolated as a yellow powder. MS 417 (M + H).
  • Example 82 7-[3-Aminomethyl)-3a,4,6,6a-tetrahvdro-pyrrolo[3,4-d1isoxazol-5-v ⁇ - 1 -[(1 R, 2S)-2-fluorocvclopropyl1-6-fluoro-8-methoxy-4-oxo-1 ,4-dihvdro-quinoline-3- carboxylic acid (203).
  • the title compound was prepared by an analogous procedure as for 202.
  • the crude material was purified by reverse phase HPLC (acetonitrile/water with no TFA modifier).
  • 203 was isolated as a yellow powder.
  • the title compound was prepared by an analogous procedure as for 202. Purification was done by reverse phase HPLC (acetonitrile/water with no TFA modifier). 204 was isolated as a yellow powder.
  • Example 84 Biological Activity
  • the compounds described in the present invention possess antibacterial activity due to their novel structure, and are useful as antibacterial agents for the treatment of bacterial infections in humans and animals.
  • Minimal inhibitory concentration (MIC) has been an indicator of in vitro antibacterial activity widely used in the art.
  • the in vitro antimicrobial activity of representative compounds of the present invention was determined by the microdilution broth method following the test method from the National Committee for Clinical Laboratory Standards (NCCLS). This method is described in the NCCLS Document M7-A4, VoM 7, No.2, "Methods for Dilution Antimicrobial Susceptibility Test for Bacteria that Grow Aerobically-Fourth Edition", which is incorporated herein by reference.
  • test organisms are prepared by adjusting the turbidity of actively growing broth cultures so that the final concentration of test organism after it is added to the wells is approximately 5 x 10 4 CFU/well.
  • the trays are incubated at 35 0 C for 16-20 hours and then read.
  • the MIC is the lowest concentration of test compound that completely inhibits growth of the test organism.
  • the amount of growth in the wells containing the test compound is compared with the amount of growth in the growth-control wells (no test compound) used in each tray.
  • representative compounds of the present invention were tested against a variety of pathogenic bacteria resulting in a range of activities depending on the organism tested.
  • Table 4 -ln vitro Antibacterial Activity (MIC in ug/mL)
  • A Staphylococcus aureus OC4172
  • strains B, C, and D are fluoroquinolone-resistant clinical isolates of Streptococcus pneumoniae that contain different constellations of amino acid substitutions in the QRDR region
  • E Streptococcus pneumoniae ATCC 49619.
  • the abbreviation "ND" indicates that the value was not determined.
  • 100 mg of compound #126 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule.

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Abstract

Dérivés de C-7 isoxazolinyl quinolone/naphthyridine convenant comme agents anti-bactériens, compositions pharmaceutiques contenant ces dérivés et utilisation de ces dérivés et compositions comme agents anti-microbiens contre des micro-organismes pathogènes, en particulier contre des microbes résistants.
PCT/US2008/071294 2009-02-10 2009-02-10 Dérivés de c-7 isoxazolinyl quinolone/naphthyridine convenant comme agents anti-bactériens WO2010093341A1 (fr)

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Cited By (8)

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CN102443015A (zh) * 2010-10-13 2012-05-09 南京明生医药技术有限公司 一种7-取代喹啉羧酸衍生物及其制备方法和在抗菌抗结核上的应用
CN104817572A (zh) * 2015-04-24 2015-08-05 河南大学 一种手性氨甲基三唑取代的三环氟喹诺酮羧酸类衍生物及其制备方法和应用
CN104910177A (zh) * 2015-04-24 2015-09-16 河南大学 一种氨甲基三唑取代的三环氟喹诺酮羧酸类衍生物及其制备方法和应用
EP3296298A1 (fr) * 2016-09-14 2018-03-21 Bayer Pharma Aktiengesellschaft 1-aryl-naphtyridin-3-ylcarboxamides substitués en position 7 et leur utilisation
WO2018050510A1 (fr) * 2016-09-14 2018-03-22 Bayer Aktiengesellschaft Amides de l'acide 1-aryl-naphthyridine-3-carboxylique substitués en position 7 et leur utilisation
US10435403B2 (en) 2015-06-09 2019-10-08 Bayer Pharma Aktiengesellschaft Positive allosteric modulators of muscarinic M2 receptor
US10519154B2 (en) 2016-07-11 2019-12-31 Bayer Pharma Aktiengesellschaft 7-substituted 1-pyridyl-naphthyridine-3-carboxylic acid amides and use thereof
EA038451B1 (ru) * 2016-12-06 2021-08-30 Байер Акциенгезельшафт 7-замещенные 1-арил-нафтиридин-3-амиды карбоновых кислот и их применение

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JPH0673056A (ja) * 1992-08-26 1994-03-15 Kaken Pharmaceut Co Ltd キノリンカルボン酸誘導体およびその塩

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US4990517A (en) * 1988-07-15 1991-02-05 Bayer Aktiengesellschaft 7-(1-pyrrolidinyl)-3-quinolone- and -naphthyridonecarboxylic acid derivatives as antibacterial agents and feed additives
JPH0673056A (ja) * 1992-08-26 1994-03-15 Kaken Pharmaceut Co Ltd キノリンカルボン酸誘導体およびその塩

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102443015A (zh) * 2010-10-13 2012-05-09 南京明生医药技术有限公司 一种7-取代喹啉羧酸衍生物及其制备方法和在抗菌抗结核上的应用
CN104817572A (zh) * 2015-04-24 2015-08-05 河南大学 一种手性氨甲基三唑取代的三环氟喹诺酮羧酸类衍生物及其制备方法和应用
CN104910177A (zh) * 2015-04-24 2015-09-16 河南大学 一种氨甲基三唑取代的三环氟喹诺酮羧酸类衍生物及其制备方法和应用
CN104817572B (zh) * 2015-04-24 2017-02-01 河南大学 一种手性氨甲基三唑取代的三环氟喹诺酮羧酸类衍生物及其制备方法和应用
CN104910177B (zh) * 2015-04-24 2017-02-22 河南大学 一种氨甲基三唑取代的三环氟喹诺酮羧酸类衍生物及其制备方法和应用
US10435403B2 (en) 2015-06-09 2019-10-08 Bayer Pharma Aktiengesellschaft Positive allosteric modulators of muscarinic M2 receptor
US10519154B2 (en) 2016-07-11 2019-12-31 Bayer Pharma Aktiengesellschaft 7-substituted 1-pyridyl-naphthyridine-3-carboxylic acid amides and use thereof
WO2018050510A1 (fr) * 2016-09-14 2018-03-22 Bayer Aktiengesellschaft Amides de l'acide 1-aryl-naphthyridine-3-carboxylique substitués en position 7 et leur utilisation
CN109689656A (zh) * 2016-09-14 2019-04-26 拜耳股份公司 7-取代的1-芳基二氮杂萘-3-羧酰胺及其用途
EP3296298A1 (fr) * 2016-09-14 2018-03-21 Bayer Pharma Aktiengesellschaft 1-aryl-naphtyridin-3-ylcarboxamides substitués en position 7 et leur utilisation
JP2019534320A (ja) * 2016-09-14 2019-11-28 バイエル アクチェンゲゼルシャフトＢａｙｅｒ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ ７−置換１−アリール−ナフチリジン−３−カルボン酸アミドおよびその使用
US10927109B2 (en) 2016-09-14 2021-02-23 Bayer Aktiengesellschaft 7-substituted 1-aryl-naphthyridine-3-carboxylic acid amides and use thereof
AU2017326297B2 (en) * 2016-09-14 2021-07-29 Bayer Aktiengesellschaft 7-substituted 1-aryl-naphthyridine-3-carboxylic acid amides and use thereof
TWI758325B (zh) * 2016-09-14 2022-03-21 德商拜耳廠股份有限公司 7-經取代之1-芳基萘啶-3-甲醯胺及其用途
CN109689656B (zh) * 2016-09-14 2022-10-04 拜耳股份公司 7-取代的1-芳基二氮杂萘-3-羧酰胺及其用途
US11472803B2 (en) 2016-09-14 2022-10-18 Bayer Aktiengesellschaft 7-substituted 1-aryl-naphthyridine-3-carboxylic acid amides and use thereof
JP7295019B2 (ja) 2016-09-14 2023-06-20 バイエル アクチェンゲゼルシャフト ７－置換１－アリール－ナフチリジン－３－カルボン酸アミドおよびその使用
EA038451B1 (ru) * 2016-12-06 2021-08-30 Байер Акциенгезельшафт 7-замещенные 1-арил-нафтиридин-3-амиды карбоновых кислот и их применение

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