WO2014164526A1 - Antibiotiques à base d'oxamazine - Google Patents

Antibiotiques à base d'oxamazine Download PDF

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Publication number
WO2014164526A1
WO2014164526A1 PCT/US2014/022700 US2014022700W WO2014164526A1 WO 2014164526 A1 WO2014164526 A1 WO 2014164526A1 US 2014022700 W US2014022700 W US 2014022700W WO 2014164526 A1 WO2014164526 A1 WO 2014164526A1
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Prior art keywords
alkyl
compound
group
halide
bacteroides
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PCT/US2014/022700
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English (en)
Inventor
Tomasz Glinka
Scott Hecker
Olga Rodny
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Rempex Pharmaceuticals, Inc.
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Publication of WO2014164526A1 publication Critical patent/WO2014164526A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to the fields of chemistry and medicine. More particularly, the present invention relates to monobactam compounds that are useful for the treatment of bacterial infections, especially Gram-negative infections. The invention also relates to methods of using such compounds in the treatment of bacterial infections and to pharmaceutical compositions and pharmaceutical combinations containing such compounds.
  • Antibiotics have been effective tools in the treatment of infectious diseases during the last half-century. From the development of antibiotic therapy to the late 1980s there was almost complete control over bacterial infections in developed countries. However, in response to the pressure of antibiotic usage, multiple resistance mechanisms have become widespread and are threatening the clinical utility of antibacterial therapy.
  • the increase in antibiotic resistant strains has been particularly common in major hospitals and care centers. The consequences of the increase in resistant strains include higher morbidity and mortality, longer patient hospitalization, and an increase in treatment costs.
  • ⁇ -Lactam antibiotics have been widely used for the treatment of bacterial infections both in hospitals and in the general public.
  • ⁇ -lactam antibiotics include the penicillins, cephalosporins, cephamycins, carbacephems, oxacephems, carbapenems and monobactams.
  • Monocyclic ⁇ -lactam (monobactam) antibiotics inhibit mucopeptide synthesis in the bacterial cell wall, thereby blocking peptidoglycan crosslinking. They have a very high affinity for penicillin-binding protein-3 (PBP-3) and mild affinity for PBP-la [Antimicrobial Agents and Chemotherapy (1983), 23(1), 98-104].
  • Monobactams have strong activity against susceptible gram-negative bacteria, including Pseudomonas aeruginosa. Monobactams are known to be effective against a wide range of bacteria including Citrobacter, Enterobacter, E. coli, Haemophilus, Klebsiella, Proteus, and Serratia species (Mosby's Drug Consult 2006 [16 ed.]. Mosby, Inc.)
  • aztreonam and carumonam two such antibiotics currently in use as antibacterials, show intrinsic resistance toward class B ⁇ -lactamases [Journal of Medical Microbiology (2008), 57(8), 974-979; Journal of Chemotherapy (2011), 23(5), 263-265] (zinc containing metalloenzymes).
  • Activity against the broad spectrum of gram negative bacteria is a desirable characteristic of a modern ⁇ -lactam antibiotics and it is largely determined by the susceptibility of the ⁇ -lactam core to the enzymatic hydrolysis by a variety of bacterial ⁇ -lactamases.
  • the present invention relates to antimicrobial agents.
  • Some embodiments include compounds, compositions, pharmaceutical compositions, use and preparation thereof.
  • some embodiments relate to monocyclic ⁇ -lactam compounds.
  • One embodiment disclosed herein includes a compound having the structure of Formula I:
  • R and R are independently selected from the group consisting of H, halide, CN, Ci-3 alkyl, -X(Ci -3 alkyl), -(Ci -3 alkyl)OH, -(Ci -3 alkyl)CN and Ci -3 haloalkyl, or
  • R and R together with the atom to which they are attached form a three to four membered carbocyclic ring optionally substituted with one or more halide, or a four membered heterocyclic ring;
  • R 3 and R 4 are independently selected from the group consisting of halide, CN, C ⁇ . 3 alkyl, -X(Ci -3 alkyl), - X(Ci -3 haloalkyl), -(Ci -3 alkyl)OH, -(Ci -3 alkyl)CN and Ci -3 haloalkyl, or alternatively R 3 and R 4 together with the atom to which they are attached form a three to four membered carbocyclic ring optionally substituted with one or more halide, or a four membered heterocyclic ring;
  • R 5 and R 6 are independently selected from the group consisting of H, halide, CN, Ci.3 alkyl, -X(Ci -3 alkyl), - X(Ci -3 haloalkyl), -(Ci -3 alkyl)OH, -(Ci -3 alkyl)CN and Ci -3 haloalkyl, or alternatively R 5 and R 6 together with the atom to which they are attached form a three to four membered carbocyclic ring optionally substituted with one or more halide, or a four membered heterocyclic ring;
  • A is selected from the group consisting of C-H, C-halide, and N; and each X is independently selected from O or S.
  • some embodiments include a pharmaceutical composition comprising a therapeutically effective amount of any one of the foregoing compounds and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
  • some embodiments include any one of the foregoing compounds or compositions for the treatment of a bacterial infection.
  • some embodiments include methods for treating a bacterial infection comprising administering to a subject in need thereof, an effective amount of any one of the foregoing compounds or compositions. [0013] Some embodiments further comprise administering an additional medicament.
  • some embodiments include the use of any one of the foregoing compounds or compositions in the preparation of a medicament for the treatment of a bacterial infection.
  • the use of any one of the foregoing compounds or compositions further comprises the use of an additional medicament for treating or preventing a bacterial infection.
  • the additional medicament includes a ⁇ -lactamase inhibitor, efflux pump inhibitor, antifungal agent, an antiviral agent, an anti -inflammatory agent or an anti-allergic agent.
  • the subject is a mammal.
  • the mammal is a human.
  • the infection comprises a bacteria that includes
  • Pseudomonas aeruginosa Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia, Burkholderia cepacia group,
  • Aeromonas hydrophilia Escherichia coli, Citrobacter freundii, Salmonella typhimurium,
  • Salmonella typhi Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Francisella tularensis, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri,
  • Acinetobacter baumannii Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Acinetobacter anitratis, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis,
  • Bordetella bronchiseptica Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilus ducreyi, Pasteurella multocida,
  • Pasteurella haemolytica Branhamella catarrhalis, Helicobacter pylori, Campylobacter fetus,
  • Campylobacter jejuni Campylobacter coli, Borrelia burgdorferi, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae,
  • Neisseria meningitidis Kingella, Moraxella, Gardnerella vaginalis, Bacteroides fragilis,
  • Bacteroides distasonis Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii,
  • the infection comprises a bacteria that includes Pseudomonas aeruginosa, Pseudomonas fluorescens, Stenotrophomonas maltophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Haemophilus influenzae, Haemophilus parain
  • Some embodiments of the present invention include methods to prepare a compound of general Formula (I).
  • the present invention relates to antimicrobial agents and potentiators thereof. Some embodiments include compounds, compositions, pharmaceutical compositions, uses thereof, including methods of preparation, and methods of treatment. In particular, the present invention relates to monocyclic ⁇ -lactam compounds. Some embodiments include compounds of Formula (I):
  • R and R are independently selected from the group consisting of H, halide, CN, C 1-3 alkyl, -(C 1-3 alkyl)CN, -(C 1-3 alkyl)OH, and C 1-3 haloalkyl, or
  • R and R together with the atom to which they are attached form a three to four membered carbocyclic ring optionally substituted with one or more halide, or a four membered heterocyclic ring.
  • R and R are H.
  • R and R are independently selected from the group consisting of H, halide, CN, C 1-3 alkyl, -X(C 1-3 alkyl), -(C 1-3 alkyl)OH and haloalkyl.
  • R is H and R is selected from the group consisting of halide, CN, C 1-3 alkyl, -(C 1-3 alkyl)CN, -(C 1-3 alkyl)OH, and C 1-3 haloalkyl. In some such embodiments, R is selected from the group consisting of CN, CH 3 , CH 2 OH, CH 2 CN and CH 2 F.
  • R and R are independently selected from the group consisting of halide and C 1-3 alkyl.
  • R and R together with the atom to which they are attached form a three to four membered carbocyclic ring optionally substituted with one or more
  • R and R together with the atom to which they are attached form a ring selected from the group consisting of cyclobutyl, 3-fluoro-cyclobutyl, 2-oxetanyl, and 3-oxetanyl.
  • R 3 and R 4 are independently selected from the group consisting of halide, CN, C 1-3 alkyl, -X(C 1-3 alkyl), - X(C 1-3 haloalkyl), -(C 1-3 alkyl)OH and haloalkyl.
  • R 3 and R 4 are independently selected from the group consisting of C 1-3 alkyl and -(C 1-3 alkyl)OH. [0032] In some embodiments, R 3 and R 4 are independently selected from the group consisting F, CH 3 , CH 2 F, CHF 2 , CN, OCH 3 , SCH 3 , OCH 2 F, SCH 2 F, OCHF 2> SCHF 2> and CH 2 CN.
  • R 3 and R 4 R 3 and R 4 are independently selected from the group consisting F, CH 3 , CH 2 F, CHF 2 , CN, OCH 3 , SCH 3 , OCH 2 F, SCH 2 F, OCHF 2> SCHF 2> and CH 2 CN.
  • R 3 and R 4 together with the atom to which they are attached form a ring selected from the group consisting of cyclobutyl, 3-fluoro-cyclobutyl, 2- oxetanyl, 3-oxetanyl, and cyclopropyl.
  • R 5 and R 6 are independently selected from the group consisting of H, halide, C 1-3 alkyl, -X(C 1-3 alkyl), - X(C 1-3 haloalkyl), -(C 1-3 alkyl)OH, and C 1-3 haloalkyl, or alternatively R 5 and R 6 together with the atom to which they are attached form a three to four membered carbocyclic ring optionally substituted with one or more halide, or a four membered heterocyclic ring.
  • R 5 and R 6 are H.
  • R 5 and R 6 are independently selected from the group consisting of H, halide, CN, C 1-3 alkyl, -X(C 1-3 alkyl), - X(Ci_ 3 haloalkyl), -(Ci_ 3 alkyl)OH and haloalkyl.
  • R 5 is H and R 6 is selected from the group consisting of halide, CN, Ci -3 alkyl, -X(Ci -3 alkyl), - X(Ci -3 haloalkyl), -(Ci -3 alkyl)CN, -(Ci -3 alkyl)OH, and C 1-3 haloalkyl.
  • R 6 is selected from the group consisting of F, CH 3 , CH 2 F, CHF 2 , CN, OCH 3 , SCH 3 , OCH 2 F, SCH 2 F, OCHF 2> SCHF 2> and CH 2 CN.
  • R 5 and R 6 are independently selected from the group consisting of halide and C 1-3 alkyl.
  • R 5 and R 6 together with the atom to which they are attached form a three to four membered carbocyclic ring optionally substituted with one or more halide, or a four membered heterocyclic ring.
  • R 5 and R 6 together with the atom to which they are attached form a ring selected from the group consisting of cyclobutyl, 3-fluoro-cyclobutyl, 2-oxetanyl, 3-oxetanyl, and cyclopropyl
  • A is selected from the group consisting of C-H, C- halide, and N. In some such embodiments, A is selected from the group consisting of C-H, C- Cl, and N.
  • each X is independently selected from O or S.
  • R and R are independently selected from the group consisting of H, -CH 3 , CN, -CH 2 OH, -CH 2 F, -CHF 2 and F. 1 2
  • R are linked to form a ring which selected from the group consisting of:
  • R 3 and R 4 are independently selected from the group consisting of -CH 3 , CN, -CH 2 OH, -CH 2 F, -CHF 2 , -OCH 3 , SCH 3 , -OCH 2 F, -SCH 2 F, -OCHF 2 , - SCHF 2 , and F.
  • R 3 and R 4 are linked to form a ring which selected from the group consisting of:
  • R 5 and R 6 are independently selected from the group consisting of H, -CH 3 , CN, -CH 2 OH, -CH 2 F, -CHF 2 , -OCH 3 , SCH 3 , -OCH 2 F, -SCH 2 F, -OCHF 2 , -SCHF 2 , and F.
  • R 5 and R 6 are linked to form a ring which selected from the group consisting of:
  • the compounds disclosed herein may exist as individual enantiomers and diastereomers or as mixtures of such isomers, including racemates. Separation of the individual isomers or selective synthesis of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art. Unless otherwise indicated, all such isomers and mixtures thereof are included in the scope of the compounds disclosed herein. Furthermore, compounds disclosed herein may exist in one or more crystalline or amorphous forms. Unless otherwise indicated, all such forms are included in the scope of the compounds disclosed herein including any polymorphic forms. In addition, some of the compounds disclosed herein may form solvates with water (i.e., hydrates) or common organic solvents. Unless otherwise indicated, such solvates are included in the scope of the compounds disclosed herein.
  • Isotopes may be present in the compounds described. Each chemical element as represented in a compound structure may include any isotope of said element.
  • a hydrogen atom may be explicitly disclosed or understood to be present in the compound.
  • the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen- 1 (protium) and hydrogen-2 (deuterium).
  • reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.
  • Solvate refers to the compound formed by the interaction of a solvent and a compound described herein or salt thereof. Suitable solvates are pharmaceutically acceptable solvates including hydrates.
  • pharmaceutically acceptable salt refers to salts that retain the biological effectiveness and properties of a compound and, which are not biologically or otherwise undesirable for use in a pharmaceutical.
  • the compounds disclosed herein are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, as described in WO 87/05297, Johnston et al., published September 11, 1987 (incorporated by reference herein in its entirety).
  • C a to C b or "C a- b” in which "a” and “b” are integers refer to the number of carbon atoms in the specified group. That is, the group can contain from “a” to "b", inclusive, carbon atoms.
  • a “Ci to C 4 alkyl” or “Ci -4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH 3 -, CH 3 CH 2 -, CH 3 CH 2 CH 2 -, (CH 3 ) 2 CH-, CH 3 CH 2 CH 2 CH 2 -, CH 3 CH 2 CH(CH 3 )- and (CH 3 ) 3 C-.
  • alkyl means a branched, or straight chain chemical group containing only carbon and hydrogen, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso- butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, sec-pentyl and neo-pentyl.
  • alkyl groups will comprise 1 to 9 carbon atoms, preferably 1 to 6, more preferably 1 to 4, and most preferably 1 to 3 carbon atoms.
  • Carbocyclyl means a cyclic ring system containing only carbon atoms in the ring system backbone, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl. Carbocyclyls may include multiple fused rings. Carbocyclyls may have any degree of saturation provided that at least one ring in the ring system is not aromatic. Typically, carbocyclyl groups will comprise 3 to 10 carbon atoms, preferably 3 to 4.
  • halo is a chloro, bromo, fluoro or iodo atom radical. Chloro, bromo and fluoro are preferred halides. Most preferred halide is fluorine.
  • haloalkyl means a hydrocarbon substituent, which is a linear or branched alkyl, alkenyl or alkynyl substituted with chloro, bromo, fluoro or iodo atom(s). Most preferred of these are fluoroalkyls, wherein one or more of the hydrogen atoms have been substituted by fluoro. Preferred haloalkyls are of 1 to about 3 carbons in length, more preferred haloalkyls are 1 to about 2 carbons, and most preferred are 1 carbon in length.
  • haloalkylene means a diradical variant of haloalkyl, such diradicals may act as spacers between radicals, other atoms, or between the parent ring and another functional group.
  • carbocyclyl means a non-aromatic cyclic ring or ring system containing only carbon atoms in the ring system backbone. When the carbocyclyl is a ring system, two or more rings may be joined together in a fused, bridged or spiro-connected fashion. Carbocyclyls may have any degree of saturation provided that at least one ring in a ring system is not aromatic.
  • carbocyclyls include cycloalkyls, cycloalkenyls, and cycloalkynyls.
  • the carbocyclyl group may have 3 to 20 carbon atoms, although the present definition also covers the occurrence of the term "carbocyclyl" where no numerical range is designated.
  • the carbocyclyl group may also be a medium size carbocyclyl having 3 to 10 carbon atoms.
  • the carbocyclyl group could also be a carbocyclyl having 3 to 6 carbon atoms.
  • the carbocyclyl group may be designated as "C 3- 6 carbocyclyl" or similar designations.
  • carbocyclyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydro-indene, bicycle[2.2.2]octanyl, adamantyl, and spiro[4.4]nonanyl.
  • heterocyclyl means a cyclic ring system comprising at least one heteroatom in the ring system backbone.
  • Heterocyclyls may include multiple fused rings. Heterocyclyls may have any degree of saturation provided that at least one ring in the ring system is not aromatic.
  • More preferred heterocycles are of 4-7 members. Most preferred heterocycles are 4 membered. In six membered monocyclic heterocycles, the heteroatom(s) are selected from one up to three of O, N or S, and wherein when the heterocycle is five membered, preferably it has one or two heteroatoms selected from O, N, or S.
  • heterocyclyl examples include azirinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, 1,4,2-dithiazolyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[l,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihydropyridinyl, 1,3- dioxanyl, 1 ,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyranyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyridinyl,
  • R2 are defined as selected from the group consisting of hydrogen and alkyl, or R 1 and R2 are defined as selected from the group consisting of hydrogen and alkyl, or R 1 and R2 are defined as selected from the group consisting of hydrogen and alkyl, or R 1 and R2 are defined as selected from the group consisting of hydrogen and alkyl, or R 1 and R2 are defined as selected from the group consisting of hydrogen and alkyl, or R 1 and R2 are defined as selected from the group consisting of hydrogen and alkyl, or R 1 and
  • R 1 and R can be selected from hydrogen or alkyl, or alternatively, the substructure has structure:
  • ring A is a heterocycle ring containing the depicted nitrogen.
  • agent includes any substance, molecule, element, compound, entity, or a combination thereof. It includes, but is not limited to, e.g., protein, polypeptide, peptide or mimetic, small organic molecule, polysaccharide, polynucleotide, and the like. It can be a natural product, a synthetic compound, or a chemical compound, or a combination of two or more substances. Unless otherwise specified, the terms “agent”, “substance”, and “compound” are used interchangeably herein.
  • administering refers to a method of giving a dosage of a compound or pharmaceutical composition to a vertebrate or invertebrate, including a mammal, a bird, a fish, or an amphibian, where the method is, e.g., orally, subcutaneously, intravenously, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, ontologically, neuro-otologically, intraocularly, subconjuctivally, via anterior eye chamber injection, intravitreally, intraperitoneally, intrathecally, intracystically, intrapleurally, via wound irrigation, intrabuccally, intra- abdominally, intra-articularly, intra-aurally, intrabronchially, intracapsularly, intrameningeally, via inhalation, via endotracheal or endobronchial instillation, via direct instillation into pulmonary cavities,
  • a "diagnostic” as used herein is a compound, method, system, or device that assists in the identification and characterization of a health or disease state.
  • the diagnostic can be used in standard assays as is known in the art.
  • the term "mammal” is used in its usual biological sense. Thus, it specifically includes humans, cattle, horses, dogs, and cats, but also includes many other species.
  • microbial infection refers to the invasion of the host organism, whether the organism is a vertebrate, invertebrate, fish, plant, bird, or mammal, by pathogenic microbes. This includes the excessive growth of microbes that are normally present in or on the body of a mammal or other organism. More generally, a microbial infection can be any situation in which the presence of a microbial population(s) is damaging to a host mammal.
  • a mammal is "suffering" from a microbial infection when excessive numbers of a microbial population are present in or on a mammal's body, or when the effects of the presence of a microbial population(s) is damaging the cells or other tissue of a mammal.
  • this description applies to a bacterial infection.
  • the compounds of preferred embodiments are also useful in treating microbial growth or contamination of cell cultures or other media, or inanimate surfaces or objects, and nothing herein should limit the preferred embodiments only to treatment of higher organisms, except when explicitly so specified in the claims.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” includes any and all solvents, co-solvents, complexing agents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like which are not biologically or otherwise undesirable.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” includes any and all solvents, co-solvents, complexing agents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like which are not biologically or otherwise undesirable.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions. In addition, various adjuvants such as are commonly used in the art may be included.
  • Subject as used herein, means a human or a non-human mammal, e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non -human primate or a bird, e.g., a chicken, as well as any other vertebrate or invertebrate.
  • a non-human mammal e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non -human primate or a bird, e.g., a chicken, as well as any other vertebrate or invertebrate.
  • Some embodiments include use of a therapeutically effective amount or a pharmaceutically effective amount of a compound disclosed herein.
  • a “therapeutically effective amount” or “pharmaceutically effective amount” of a compound as provided herein is one which is sufficient to achieve the desired effect and may vary according to the nature and severity of the disease condition, and the potency of the compound.
  • “Therapeutically effective amount” is also intended to include one or more of the compounds of Formula (I) in combination with one or more other agents that are effective to treat a microbial infection and/or conditions.
  • the combination of compounds is preferably a synergistic combination.
  • Synergy occurs when the effect of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent.
  • a synergistic effect is most clearly demonstrated at sub-optimal concentrations of the compounds. It will be appreciated that different concentrations may be employed for prophylaxis than for treatment of an active disease. This amount can further depend upon the patient's height, weight, sex, age and medical history.
  • a therapeutic effect relieves, to some extent, one or more of the symptoms of the disease, and includes curing a disease. "Curing” means that the symptoms of active disease are eliminated. However, certain long-term or permanent effects of the disease may exist even after a cure is obtained (such as extensive tissue damage).
  • Treatment refers to administering a compound or pharmaceutical composition to a subject for prophylactic and/or therapeutic purposes.
  • therapeutic treatment refers to administering treatment to a patient already suffering from a disease thus causing a therapeutically beneficial effect, such as ameliorating existing symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, postponing or preventing the further development of a disorder and/or reducing the severity of symptoms that will or are expected to develop.
  • prophylactic treatment refers to treating a subject who does not yet exhibit symptoms of a disease or condition, but who is susceptible to, or otherwise at risk of, a particular disease or condition, whereby the treatment reduces the likelihood that the patient will develop the disease or condition.
  • compositions comprising: (a) a safe and therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
  • Administration of the compounds disclosed herein or the pharmaceutically acceptable salts thereof can be via any of the accepted modes of administration for agents that serve similar utilities including, but not limited to, orally, subcutaneously, intravenously, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, ontologically, neuro-otologically, intraocularly, subconjuctivally, via anterior eye chamber injection, intravitreally, intraperitoneally, intrathecally, intracystically, intrapleurally, via wound irrigation, intrabuccally, intra-abdominally, intra-articularly, intra- aurally, intrabronchially, intracapsularly, intrameningeally, via inhalation, via endotracheal or endobronchial instillation, via direct instillation into pulmonary cavities, intraspinally, intrasynovially, intrathoracically, via thoracostomy irrigation, epidurally, intratympanically
  • compositions may include solid, semi-solid, liquid, solutions, colloidal, liposomes, emulsions, suspensions, complexes, coacervates and aerosols.
  • Dosage forms such as, e.g., tablets, capsules, powders, liquids, suspensions, suppositories, aerosols, implants, controlled release or the like.
  • the compounds may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, milling, grinding, supercritical fluid processing, coacervation, complex coacervation, encapsulation, emulsification, complexation, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.
  • the compounds can also be administered in sustained or controlled release dosage forms, including depot injections, osmotic pumps, pills (tablets and or capsules), transdermal (including electrotransport) patches, implants and the like, for prolonged and/or timed, pulsed administration at a predetermined rate.
  • the compounds can be administered either alone or more typically in combination with a conventional pharmaceutical carrier, excipient or the like.
  • a conventional pharmaceutical carrier excipient or the like.
  • excipient is used herein to describe any ingredient other than the compound(s) provided herein.
  • Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-a-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,
  • Cyclodextrins such as ⁇ -, ⁇ , and ⁇ -cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-b-cyclodextrins, or other solubilized derivatives can also be advantageously used to enhance delivery of compounds described herein.
  • Dosage forms or compositions containing a compound as described herein in the range of 0.005% to 100% with the balance made up from non-toxic carrier may be prepared.
  • compositions may contain 0.001%-100% active ingredient, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%, Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 22 nd Edition (Pharmaceutical Press, London, UK. 2012).
  • the compositions will take the form of a unit dosage form such as a pill or tablet and thus the composition may contain, along with the active ingredient, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like.
  • a diluent such as lactose, sucrose, dicalcium phosphate, or the like
  • a lubricant such as magnesium stearate or the like
  • a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like.
  • a powder, marume, solution or suspension ⁇ e.g., in propylene carbonate, vegetable oils, PEG's, poloxamer 124 or triglycerides
  • a capsule gelatin or cellulose base capsule
  • Unit dosage forms in which the two active ingredients are physically separated are also contemplated; e.g., capsules with granules (or tablets in a capsule) of each drug; two-layer tablets; two-compartment gel caps, etc. Enteric coated or delayed release oral dosage forms are also contemplated.
  • Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc. an active compound as defined above and optional pharmaceutical adjuvants in a carrier ⁇ e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like) to form a solution, colloid, liposome, emulsion, complexes, coacervate or suspension.
  • a carrier e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like
  • the pharmaceutical composition can also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, co-solvents, solubilizing agents, pH buffering agents and the like ⁇ e.g., sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, and the like).
  • nontoxic auxiliary substances such as wetting agents, emulsifying agents, co-solvents, solubilizing agents, pH buffering agents and the like ⁇ e.g., sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, and the like).
  • the unit dosage of compounds of Formula (I) is 0.25 mg/Kg to 120 mg/Kg in humans. [0079] In some embodiments, the unit dosage of compounds of Formula (I) is 0.50 mg/Kg to 70 mg/Kg in humans.
  • the unit dosage of compounds of Formula (I) is 1.0 mg/Kg to 50 mg/Kg in humans.
  • the unit dosage of compounds of Formula (I) is 1.50 mg/Kg to 10 mg/Kg in humans.
  • compositions are provided in unit dosage forms suitable for single administration of a precise dose.
  • compositions are provided in unit dosage forms suitable for twice a day administration of a precise dose.
  • compositions are provided in unit dosage forms suitable for three times a day administration of a precise dose.
  • Injectables can be prepared in conventional forms, either as liquid solutions, colloid, liposomes, complexes, coacervate or suspensions, as emulsions, or in solid forms suitable for reconstitution in liquid prior to injection.
  • Suitable excipients may be included to achieve the desired pH, including but not limited to NaOH, sodium carbonate, sodium acetate, HC1, and citric acid.
  • the pH of the final composition ranges from 2 to 8, or preferably from 4 to 7.
  • Antioxidant excipients may include sodium bisulfite, acetone sodium bisulfite, sodium formaldehyde, sulfoxylate, thiourea, and EDTA.
  • excipients found in the final intravenous composition may include sodium or potassium phosphates, citric acid, tartaric acid, gelatin, and carbohydrates such as dextrose, mannitol, and dextran. Further acceptable excipients are described in Powell, et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 238-311 and Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Sci and Tech 2011, 65 287-332, both of which are incorporated herein by reference in their entirety.
  • Antimicrobial agents may also be included to achieve a bacteriostatic or fungistatic solution, including but not limited to phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol.
  • compositions for intravenous administration may be provided to caregivers in the form of one more solids that are reconstituted with a suitable diluent such as sterile water, saline or dextrose in water shortly prior to administration.
  • a suitable diluent such as sterile water, saline or dextrose in water shortly prior to administration.
  • the compositions are provided in solution ready to administer parenterally.
  • the compositions are provided in a solution that is further diluted prior to administration.
  • the combination may be provided to caregivers as a mixture, or the caregivers may mix the two agents prior to administration, or the two agents may be administered separately.
  • the composition will comprise 0.1-10% of the active agent in solution.
  • the composition will comprise 0.1-5% of the active agent in solution.
  • the composition will comprise 0.1-4% of the active agent in solution.
  • the composition will comprise 0.15-3% of the active agent in solution.
  • the composition will comprise 0.2-2% of the active agent in solution.
  • compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of 1-96 hours.
  • compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of 1-72 hours.
  • compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of 1-48 hours.
  • compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of 1-24 hours.
  • compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of 1-12 hours.
  • compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of 1-6 hours.
  • compositions can be administered by:
  • compositions can be administered by
  • compositions can be administered by:
  • compositions can be administered by:
  • compositions can be administered by intravenous infusion to humans at doses of 50 mg/m 2 to 200 mg/m 2 .
  • compositions can be administered by:
  • compositions can be administered by:
  • concentrations and dosage values may also vary depending on the specific compound and the severity of the condition to be alleviated. It is to be further understood that for any particular patient, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions.
  • compositions can be administered to the respiratory tract (including nasal and pulmonary) e.g., through a nebulizer, metered-dose inhalers, atomizer, mister, aerosol, dry powder inhaler, insufflator, liquid instillation or other suitable device or technique.
  • aerosols intended for delivery to the nasal mucosa are provided for inhalation through the nose.
  • inhaled particle sizes of about 5 to about 100 microns are useful, with particle sizes of about 10 to about
  • inhaled particle size is desired to maximize impaction on the nasal mucosa and to minimize or prevent pulmonary deposition of the administered formulation.
  • aerosols intended for delivery to the lung are provided for inhalation through the nose or the mouth.
  • inhaled aerodynamic particle sizes of about less than 10 ⁇ are useful, with an aerodynamic particle size of about 1 to about 10 microns being preferred.
  • Inhaled particles may be defined as liquid droplets containing dissolved drug, liquid droplets containing suspended drug particles (in cases where the drug is insoluble in the suspending medium), dry particles of pure drug substance, drug substance incorporated with excipients, liposomes, emulsions, colloidal systems, coacervates, aggregates of drug nanoparticles, or dry particles of a diluent which contain embedded drug nanoparticles.
  • compounds of Formula (I) disclosed herein intended for respiratory delivery can be administered as aqueous formulations, as non-aqueous solutions or suspensions, as suspensions or solutions in halogenated hydrocarbon propellants with or without alcohol, as a colloidal system, as emulsions, coacervates or as dry powders.
  • Aqueous formulations may be aerosolized by liquid nebulizers employing either hydraulic or ultrasonic atomization or by modified micropump systems (like the soft mist inhalers, the Aerodose ® or the AERx ® systems).
  • Propellant-based systems may use suitable pressurized metered-dose inhalers (pMDIs).
  • Dry powders may use dry powder inhaler devices (DPIs), which are capable of dispersing the drug substance effectively. A desired particle size and distribution may be obtained by choosing an appropriate device.
  • compositions of Formula (I) disclosed herein can be administered to the ear by various methods.
  • a round window catheter e.g., U.S. Pat. Nos. 6,440,102 and 6,648,873 can be used.
  • formulations can be incorporated into a wick for use between the outer and middle ear (e.g., U.S. Pat. No. 6,120,484) or absorbed to collagen sponge or other solid support (e.g., U.S. Pat. No. 4,164,559).
  • formulations of the invention can be incorporated into a gel formulation (e.g., U.S. Pat. Nos. 4,474,752 and 6,911,211).
  • compounds of Formula (I) disclosed herein intended for delivery to the ear can be administered via an implanted pump and delivery system through a needle directly into the middle or inner ear (cochlea) or through a cochlear implant stylet electrode channel or alternative prepared drug delivery channel such as but not limited to a needle through temporal bone into the cochlea.
  • Other options include delivery via a pump through a thin film coated onto a multichannel electrode or electrode with a specially imbedded drug delivery channel (pathways) carved into the thin film for this purpose.
  • the acidic or basic solid gacyclidine can be delivered from the reservoir of an external or internal implanted pumping system.
  • Formulations of the invention also can be administered to the ear by intratympanic injection into the middle ear, inner ear, or cochlea (e.g., U.S. Pat. No. 6,377,849 and Ser. No. 11/337,815).
  • Intratympanic injection of therapeutic agents is the technique of injecting a therapeutic agent behind the tympanic membrane into the middle and/or inner ear.
  • the formulations described herein are administered directly onto the round window membrane via transtympanic injection.
  • the ion channel modulating agent auris-acceptable formulations described herein are administered onto the round window membrane via a non-transtympanic approach to the inner ear.
  • the formulation described herein is administered onto the round window membrane via a surgical approach to the round window membrane comprising modification of the crista fenestrae cochleae.
  • the compounds of Formula (I) are formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG (like PEG ointments), and the like.
  • Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable non- irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt or erode/dissolve in the rectum and release the drug.
  • suitable non- irritating excipient include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter is first melted.
  • a liquid composition which is formulated for topical ophthalmic use, is formulated such that it can be administered topically to the eye.
  • the comfort should be maximized as much as possible, although sometimes formulation considerations (e.g. drug stability) may necessitate less than optimal comfort.
  • the liquid should be formulated such that the liquid is tolerable to the patient for topical ophthalmic use.
  • an ophthalmically acceptable liquid should either be packaged for single use, or contain a preservative to prevent contamination over multiple uses.
  • solutions or medicaments are often prepared using a physiological saline solution as a major vehicle.
  • Ophthalmic solutions should preferably be maintained at a comfortable pH with an appropriate buffer system.
  • the formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and surfactants.
  • Preservatives that may be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric, acetate and phenylmercuric nitrate.
  • a useful surfactant is, for example, Tween 80.
  • various useful vehicles may be used in the ophthalmic preparations disclosed herein. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purified water.
  • Tonicity adjusters may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjuster.
  • buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed.
  • an ophthalmically acceptable antioxidant includes, but is not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.
  • excipient components which may be included in the ophthalmic preparations, are chelating agents.
  • a useful chelating agent is edetate disodium, although other chelating agents may also be used in place or in conjunction with it.
  • Topical formulations may generally be comprised of a pharmaceutical carrier, co-solvent, emulsifier, penetration enhancer, preservative system, and emollient.
  • Solid compositions can be provided in various different types of dosage forms, depending on the physicochemical properties of the drug, the desired dissolution rate, cost considerations, and other criteria.
  • the solid composition is a single unit. This implies that one unit dose of the drug is comprised in a single, physically shaped solid form or article. In other words, the solid composition is coherent, which is in contrast to a multiple unit dosage form, in which the units are incoherent.
  • Examples of single units which may be used as dosage forms for the solid composition include tablets, such as compressed tablets, film-like units, foil-like units, wafers, lyophilized matrix units, and the like.
  • the solid composition is a highly porous lyophilized form.
  • Such lyophilizates, sometimes also called wafers or lyophilized tablets, are particularly useful for their rapid disintegration, which also enables the rapid dissolution of the active compound.
  • the solid composition may also be formed as a multiple unit dosage form as defined above.
  • multiple units are powders, granules, microparticles, pellets, mini-tablets, beads, lyophilized powders, and the like.
  • the solid composition is a lyophilized powder.
  • Such a dispersed lyophilized system comprises a multitude of powder particles, and due to the lyophilization process used in the formation of the powder, each particle has an irregular, porous microstructure through which the powder is capable of absorbing water very rapidly, resulting in quick dissolution.
  • Effervescent compositions are also contemplated to aid the quick dispersion and absorption of the compound.
  • Another type of multiparticulate system which is also capable of achieving rapid drug dissolution is that of powders, granules, or pellets from water-soluble excipients which are coated with the drug, so that the drug is located at the outer surface of the individual particles.
  • the water-soluble low molecular weight excipient is useful for preparing the cores of such coated particles, which can be subsequently coated with a coating composition comprising the drug and, preferably, one or more additional excipients, such as a binder, a pore former, a saccharide, a sugar alcohol, a film-forming polymer, a plasticizer, or other excipients used in pharmaceutical coating compositions.
  • Some embodiments of the present invention include methods of treating bacterial infections with the compounds and compositions comprising compounds described herein. Some methods include administering a compound, composition, pharmaceutical composition described herein to a subject in need thereof.
  • a subject can be an animal, e.g., a mammal, a human.
  • the bacterial infection comprises a bacteria described herein.
  • methods of treating a bacterial infection include methods for preventing bacterial infection in a subject at risk thereof.
  • the subject is a human.
  • Further embodiments include administering a combination of compounds to a subject in need thereof.
  • a combination can include a compound, composition, pharmaceutical composition described herein with an additional medicament.
  • Some embodiments include co-administering a compound, composition, and/or pharmaceutical composition described herein, with an additional medicament.
  • co-administration it is meant that the two or more agents may be found in the patient's bloodstream at the same time, regardless of when or how they are actually administered.
  • the agents are administered simultaneously.
  • administration in combination is accomplished by combining the agents in a single dosage form.
  • the agents are administered sequentially.
  • the agents are administered through the same route, such as orally.
  • the agents are administered through different routes, such as one being administered orally and another being administered i.v.
  • Examples of additional medicaments include an antibacterial agent, antifungal agent, an antiviral agent, an anti-inflammatory agent and an anti-allergic agent.
  • Some embodiments include a combination of the compounds, compositions and/or pharmaceutical compositions described herein with an additional agent, wherein the additional agent comprises a ⁇ -lactamase inhibitor.
  • additional agent comprises a ⁇ -lactamase inhibitor.
  • ⁇ -lactamase inhibitors include clavulanic acid, tazobactam, sulbactam, RPX-7009, NXL104, MK-7655, BAL-29880, SYN-2190, BLI-489, AM-112, and ME1071.
  • the ⁇ - lactamase inhibitor is a class A, B, C, or D ⁇ -lactamase inhibitor.
  • An example of a class B ⁇ - lactamase inhibitor includes ME1071 [Antimicrob. Agents Chemother. (2010), 54(9), 3625- 3629].
  • Some embodiments include co -administering the compound, composition or pharmaceutical composition described herein with one or more additional agents.
  • the compounds and compositions comprising monocyclic ⁇ -lactam derivatives described herein can be used to treat bacterial infections.
  • Bacterial infections that can be treated with the compounds, compositions and methods described herein can comprise a wide spectrum of bacteria.
  • Examples of bacterial infections include Pseudomonas aeruginosa,
  • Pseudomonas fluorescens Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia, Burkholderia cepacia, Aeromonas hydrophilia,
  • Escherichia coli Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei,
  • Enterobacter cloacae Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca,
  • the peak multiplicities are denoted as follows, s, singlet; d, doublet; t, triplet; q, quartet; ABq, AB quartet; quin, quintet; sex, sextet; sep, septet; non, nonet; dd, doublet of doublets; d/ABq, doublet of AB quartet; dt, doublet of triplets; td, triplet of doublets; dq, doublet of quartets; m, multiplet.
  • CDCI 3 deuterated chloroform
  • PCI 5 phosphorus pentachloride
  • optically pure starting materials or chiral catalysts may be employed in stereoselective synthetic sequences leading to single stereoisomers [Tetrahedron (1983), 39(12), 2085-2092; Tetrahedron (1988), 44(17), 5277-5292; Journal of the American Oil Chemists ' Society (1997), 74(11), 1345-1360; Tetrahedron: Asymmetry (2001), 12(3), 481-486; The Journal of Organic Chemistry (2002), 68(1), 177-179].
  • P 1 -P 7 denotes typical protecting groups compatible with requisite chemistry and L denotes typical leaving groups.
  • Pi - P 7 may also denote hydrogen.
  • Scheme 1 describes a method for preparation of the ⁇ -lactam core intermediates X and XI by either starting with bis N-protected glycine ester (II) [Tetrahedron (1988), 44(12), 3685-3692] which is first reacted with ketone (III) followed by bis deprotection of the amine and then monoprotection to give ⁇ -hydroxyacid (VI).
  • ⁇ -hydroxyacid (VI) can also be synthesized starting with the mono N-protected glycine ester (II) [Tetrahedron Letters (1986), 27(25), 2789-2792; Sundeen, J. E. (1987, July).
  • Scheme 2 describes a method for preparation of the ⁇ -lactam core intermediates X and XI which starts with the alkylation [Hoppe-Seyler 's Zeitschrift fuer Physio strige Chemie (1961), 327, 41-48] of a copper(II)glycinate derivative (XII) with ketone (III) to yield a ⁇ -hydroxyacid (IV).
  • ⁇ -hydroxyacid (VI) is N-protected before then being coupled with a protected hydroxylamine (VII) followed by either cyclization by the Mitsunobu reaction or 2-picoline (or pyridine)-SC>3 complex to give the protected ⁇ -lactam (XIII).
  • XIII can be first N-deprotected to give intermediate XIV or further O-deprotected to give intermediate XV. All three racemic ⁇ -lactams can be optically resolved by known procedures [Slusarchyk, William A.; Koster, William H., [3S(Z)]-2-[[[l-(2-amino-4-thiazolyl)-2-[[2,2-dimethyl-4-oxo-l- (sulfooxy)-3-azetidinyl] amino] -2-oxoethylidene] -amino] oxy] acetic acid and intermediate, US Patent 4,638,061, Jan. 20, 1987.; The Journal of Peptide Research (1998), 52(2), 143-15].
  • Scheme 3 describes a method [Tetrahedron Letters (1986), 27(25), 2789- 2792; Sundeen, J. E. (1987, July). Preparation of monosulfactams as antibiotics. Eur. Pat. Appl. EP0229012, Squibb and Sons, Inc., USA; Sundeen, J. E. (1987, July). O-Sulfated spiro ⁇ -lactam hydroxamic acids.
  • Scheme 5 describes a method [European Journal of Medicinal Chemistry (1981), 16(4), 307-316] for preparation of monobactam derivatives (XXXII) from the protected carboxymethoxyimmoacetic acid intermediate XXVIII.
  • XXVIII can be synthesized by coupling hydroxyimino derivative (XXII or XXIII) with the protected acetic acid derivative (XXIV) followed any necessary deprotection or by direct coupling of the aminoxyacetic acid derivative (XXVII) with glycolic acid derivative (XXVI).
  • XXVIII can then be coupled with O-protected ⁇ -lactam derivative (X) or with unprotected ⁇ -lactam derivative (XI) to ultimately give monobactam derivative (XXX).
  • the free hydroxy of XXX is then coupled with protected a- haloacetic acid derivative (XXI) to yield fully protected monobactam derivative (XXXI) which can be deprotected to give the desired final monobactam derivatives (XXXII).
  • Scheme 6 describes an alternative method for preparation of monobactam derivatives (XXXII) by coupling 3-amino-P-lactam (XIX) with the protected carboxymethoxyiminoacetic acid intermediate XXVIII to give fully protected monobactam derivative (XXXI) which can be deprotected to give the desired final monobactam derivatives (XXXII).
  • ethylideneaminooxy)acetate (93 mg, 0.121 mmol) in ethylene chloride (2 mL) was added a mixture of ethylene chloride/TFA (4 mL) while cooling in an ice bath. The reaction was warmed to room temperature and stirred until no partial deprotection products can be observed by LCMS. Reaction mixture was concentrated under vacuum before diisopropyl ether was added. The precipitate was filtered yielding the crude product. The crude material was dissolved in water (1 mL) and filtered.
  • Potency and spectrum of compound 1 was determined using the panel of isogenic engineered strains, each containing a plasmid carrying a cloned gene expressing a ⁇ - lactamase enzyme.
  • the strain that contained the empty vector was included to evaluate the impact of individual ⁇ -lactamases on microbiological activity of compound 1 vs comparator antibiotics.
  • the host strain was wild-type strain of Escherichia coli, ECM5497.
  • the vector plasmid was pUCP24.
  • Microbiological activity is defined as Minimal inhibitory concentration (MIC), or the lowest concentration of antibiotics, at which the visible growth of the organism is completely inhibited. MIC was assessed using broth microdilution method as recommended by the NCCLS (National Committee for Clinical Laboratory Standards.
  • Microtiter plates are incubated during 20 h at 35°C and are read using a microtiterplate reader (Molecular Devices) at 650 nm as well as visual observation using a microtiter plate reading mirror.
  • the MIC is defined as the lowest concentration of antibiotics at which the visible growth of the organism is completely inhibited. Results are presented in Tables 2 and 3.
  • Table 2 contains MICs of compound 1 and comparator antibiotics for each test strain and Table 3 contains MIC ratios vs vector only control (strain ECM6704).
  • ⁇ - Lactamases present in the test panel belonged to all four currently described classes of enzymes, A, B, C and D. These ⁇ -lactamases also represent the major groups of the most relevant enzymes.

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Abstract

L'invention concerne des composés de monobactames du type oxamazine et leur utilisation en tant qu'antibiotiques résistant à la dégradation par les bêta-lactamases. L'invention concerne également des compositions pharmaceutiques contenant les composés et des procédés de synthèse.
PCT/US2014/022700 2013-03-13 2014-03-10 Antibiotiques à base d'oxamazine WO2014164526A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017180794A1 (fr) * 2016-04-13 2017-10-19 Skyline Antiinfectives, Inc. Acides hydroxamiques de bêta-lactame o-sulfatés deutérés et bêta-lactames n-sulfatés deutérés
US10047077B2 (en) 2016-04-13 2018-08-14 Skyline Antiinfectives, Inc. Deuterated O-sulfated beta-lactam hydroxamic acids and deuterated N-sulfated beta-lactams
US10093666B2 (en) 2016-04-13 2018-10-09 Arixa Pharmaceuticals, Inc. Deuterated O-sulfated beta lactam hydroxamic acids and deuterated N-sulfated beta lactams

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