US20040229955A1 - Antibacterial agents - Google Patents

Antibacterial agents Download PDF

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Publication number
US20040229955A1
US20040229955A1 US10/754,928 US75492804A US2004229955A1 US 20040229955 A1 US20040229955 A1 US 20040229955A1 US 75492804 A US75492804 A US 75492804A US 2004229955 A1 US2004229955 A1 US 2004229955A1
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unsubstituted
alkyl
group
atoms
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US10/754,928
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English (en)
Inventor
Niels Andersen
Jason Bowman
Alice Erwin
Eric Harwood
Toni Kline
Khisimuzi Mdluli
Simon Ng
Keith Pfister
Ribhi Shawar
Allan Wagman
Asha Yabannavar
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University of Washington
Novartis Vaccines and Diagnostics Inc
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Individual
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Priority to US10/754,928 priority Critical patent/US20040229955A1/en
Application filed by Individual filed Critical Individual
Assigned to CHRION CORPORATION reassignment CHRION CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HARWOOD, ERIC
Assigned to CHIRON CORPORATION reassignment CHIRON CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SHAWAR, RIBHI
Assigned to CHIRON CORPORATION reassignment CHIRON CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MDLULI, KHISIMUZI
Assigned to CHIRON CORPORATION reassignment CHIRON CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: NG, SIMON, PFISTER, KEITH B., WAGMAN, ALLAN S., YABANNAVAR, ASHA
Assigned to CHIRON CORPORATION reassignment CHIRON CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ERWIN, ALICE
Assigned to CHIRON CORPORATION reassignment CHIRON CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KLINE, TONI
Publication of US20040229955A1 publication Critical patent/US20040229955A1/en
Assigned to UNIVERSITY OF WASHINGTON reassignment UNIVERSITY OF WASHINGTON ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BOWMAN, JASON, ANDERSON, NEILS H.
Priority to US11/187,708 priority patent/US7358359B2/en
Priority to US11/417,346 priority patent/US20070244197A1/en
Priority to US11/837,327 priority patent/US7989660B2/en
Priority to US11/894,208 priority patent/US20090247506A1/en
Priority to US11/928,122 priority patent/US8084615B2/en
Priority to US11/981,279 priority patent/US8101640B2/en
Priority to US12/563,697 priority patent/US8153843B2/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07C233/82—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/83—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of an acyclic saturated carbon skeleton
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    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07C275/16—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton being further substituted by carboxyl groups
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Definitions

  • This invention pertains generally to treating infections caused by gram-negative bacteria. More specifically, the invention described herein pertains to treating gram-negative infections by inhibiting activity of UDP-3-O-(R-3-hydroxydecanoyl)-N-acetylglucosamine deacetylase (LpxC).
  • LpxC UDP-3-O-(R-3-hydroxydecanoyl)-N-acetylglucosamine deacetylase
  • the present invention provides small molecule inhibitors of LpxC, pharmaceutical formulations containing such inhibitors, methods of treating patients with such pharmaceutical formulations, and to methods of preparing such pharmaceutical formulations and inhibitors.
  • the inhibitors can be used to treat Gram-negative infections of patients alone and in combination with other antibacterials.
  • nosocomial infections are thought to contribute to or cause more than 77,000 deaths per year and cost approximately $5 to $10 billion annually.
  • the most important resistant pathogens are methicillin-(oxacillin-)resistant Staphylococcus aureus , ⁇ -lactam-resistant and multidrug-resistant pneumococci, and vancomycin-resistant enterococci.
  • Gram-negative resistance Important causes of Gram-negative resistance include extended-spectrum ⁇ -lactamases (ESBLs) in Klebsiella pneumoniae, Escherichia coli , and Proteus mirabilis , high-level third-generation cephalosporin (Amp C) ⁇ -lactamase resistance among Enterobacter species and Citrobacter freundii , and multidrug-resistance genes observed in Pseudomonas aeruginosa, Acinetobacter , and Stenotrophomonas maltophilia . (Jones RN 2001 Chest 119 (supplement), 397S-404S: Resistance patterns among nosocomial pathogens: Trends over the past few years.)
  • the outer membrane of gram-negative bacteria contributes to this intrinsic resistance by acting as an efficient permeability barrier, because the narrow porin channels limit the penetration of hydrophilic solutes and the low fluidity of the lipopolysaccharide leaflet slows down the inward diffusion of lipophilic solutes.
  • a second mechanism contributes to the intrinsic resistance of gram-negative bacteria. Recent studies showed that multiple drug efflux pumps, sometimes with unusually broad specificity, act as this second factor to create the general intrinsic resistance of gram-negative bacteria. When their expression levels are elevated as a consequence of physiological regulation or genetic alteration, they can frequently produce impressive levels of resistance to a wide variety of antimicrobial agents. (Nikaido H 1998 Clinical Infectious Diseases 27(Suppl 1), S32-41: Antibacterial resistance caused by gram-negative multidrug efflux pumps.)
  • LpxC inhibitors In order to be useful as antibacterial agents, LpxC inhibitors would not only have to inhibit the enzymatic activity of LpxC from a variety of bacteria, but would have to defeat the intrinsic resistance mechanisms of gram- negative bacteria, as described above: they would have to penetrate the outer membrane and be relatively unsusceptible to multidrug efflux pumps.
  • Other medically important gram-negative bacteria for example Pseudomonas aeruginosa .
  • Pseudomonas aeruginosa the primary reason for their inactivity against particular, medically important gram-negative bacteria is their poor ability to inhibit P. aeruginosa LpxC; efflux by the major multidrug efflux pump or inability to penetrate the outer membrane were not the critical factors.
  • Jackrnan et al. in J.Biol.Chem. (vol. 275, no. 15, Apr. 14, 2000, pps. 11002-11009), discuss the mechanism of lipid A biosynthesis in the context of gram-negative bacteria and discloses a new class of hydroxamate-containing inhibitors of LpxC.
  • Wyckoffet al. in Trends in Microbiology (vol. 6, no. 4, April 1998, pps. 154-159), discuss the role of LpxC in lipid A biosynthesis and its role in regulation.
  • Wyckoff et al. disclose a few oxazoline hydroxamic acids that inhibit bacterial growth.
  • Wyckoff et al. also discuss the shortcomings of the available deacetylase inhibitors as bactericidal agents against Pseudomonas and that more work is needed to be done in the area.
  • U.S. Patent Publication No. 2001/0053555 (U.S. patent application Ser. No. 08/958,638) published Dec. 20, 2001, corresponding to WO 98/18754 published May 7, 1998 discloses a combinatorial library of hydroxylamine, hydroxamic acid, hydroxyurea and hydroxylsulfonamide compounds purported to be potentially useful as inhibitors of metalloproteases.
  • U.S. Pat. No. 6,281,245 a continuation in part of U.S. Ser. No. 08/958,638 claims a method of inhibiting a deformylase enzyme by administering one of the hydroxylamine compounds from the combinatorial library as disclosed in U.S. Patent Publication No.
  • the compounds are useful as antimicrobial agents that are believed to have bactericidal activity at least in part to intracellular inhibition of bacterial polypeptide deformylase.
  • the compounds are useful as antimicrobial agents useful against gram-negative and gram positive bacteria.
  • the patent publication discusses that the antibacterial activity is due, at least in part, to intracellular inhibition of bacterial polypeptide deformylase.
  • the present invention provides novel compounds, pharmaceutical formulations including the compounds, methods of inhibiting UDP-3-O-(R-3-hydroxydecanoyl)-N-acetylglucosamine deacetylase (LpxC), and methods of treating gram-negative bacterial infections.
  • LpxC UDP-3-O-(R-3-hydroxydecanoyl)-N-acetylglucosamine deacetylase
  • the present invention provides compounds of formula I:
  • L is absent or selected from the group consisting of
  • R 1L , R 2L , and R 3L are independently selected from the group consisting of
  • R 1L and R 3L together with the atoms to which they are attached can form a substituted or unsubstituted heterocyclic ring, having from 3 to 8 ring atoms, wherein 1-2 ring atoms of the heterocyclic ring system are selected from N, O and S;
  • j is an integer of 0-4;
  • k is an integer of 0-4;
  • D is absent or selected from the group consisting of
  • G is absent or selected from the group consisting of
  • Rg is H or substituted or unsubstituted C 1 -C 6 -alkyl
  • i is an interger of 0-4;
  • Y is selected from the group consisting of
  • X is selected from the group consisting of
  • X and A together with the atoms to which they are attached can form a heterocyclic ring, having from 5 to 8 ring atoms, wherein 1-2 ring atoms of the heterocyclic ring system are selected from N, O and S;
  • B is a absent or
  • R 1b and R 2b are independently selected fromr the group consisting of
  • R 1b and R 2b together with the atoms to which they are attached can form a substituted or unsubstituted heterocyclic ring, having from 5 to 8 ring atoms, wherein 1-2 ring atoms of the heterocyclic ring system are selected from N, Q and S;
  • q is an integer of 0-4;
  • R 3 is H or substituted or unsubstituted C 1 -C 6 -alkyl
  • R 3 and A together with the atoms to which they are attached can form a substituted or unsubstituted 3-10 membered cycloalkyl or a heterocyclic ring system, wherein the heterocyclic ring system may have from 3 to 10 ring atoms, with 1 to 2 rings being in the ring system and contain from 1-4 heteroatoms selected from N, O and S;
  • R 4 is H or substituted or unsubstituted C 1 -C 6 -alkyl
  • R 4 and A together with the atoms to which they are attached can form a substituted or unsubstituted heterocyclic ring, having from 3 to 8 ring atoms, wherein 1-2 ring atoms of the heterocyclic ring system are selected from N, O and S;
  • n is an integer of 0-6;
  • A is selected from the group consisting of
  • R 1a , R 2a , R 3a , R 4a , and R 5 a are independently selected from the group consisting of
  • R 4a and R 5a together with the N atom to which they are attached can form a substituted or unsubstituted heterocyclic ring, having from 5 to 8 ring atoms, wherein 1-2 ring atoms of the heterocyclic ring system are selected from N, O and S;
  • r is an integer of 0-4;
  • s is an integer of 0-4;
  • Q is absent or selected from the group consisting of
  • R 1 is selected from the group consisting of
  • R 2 is selected from the group consisting of
  • R 1 and R 2 together with the N atom to which they are attached can form a substituted or unsubstituted heterocyclic ring, having from 3 to 10 ring atoms, wherein 1-4 ring atoms of the heterocyclic ring system are selected from N, O and S,
  • R 2 and R 4 together with the N atoms to which they are attached can form a substituted or unsubstituted heterocyclic ring, having from 3 to 10 ring atoms, wherein 1-4 ring atoms of the heterocyclic ring system are selected from N, O and S;
  • R 1q , R 2q , R 3q , R 4q , and R 5q are selected from H or C 1 -C 6 alkyl
  • B is absent, or E, L, G, and B are absent, or E, L, and G are absent, or E, L, and B are absent, or E, L, D, G, and B are absent.
  • the invention provides a method of inhibiting a deacetylase enzyme in a gram-negative bacteria, thereby affecting bacterial growth, comprising administering to a patient in need of such inhibition a compound of formula I.
  • the invention provides a method of inhibiting LpxC, thereby modulating the virulence of a bacterial infection, comprising administering to a patient in need of such inhibition a compound of formula I.
  • the invention provides a method for treating a subject with a gram-negative bacterial infection comprising administering to the subject in need thereof an antibacterially effective amount of a compound of formula I with a pharmaceutically acceptable carrier.
  • the subject is a mammal and in some embodiments, a human.
  • the invention provides a method of administering an inhibitory amount of a compound of formula I to fermentative or non-fermentative gram-negative bacteria.
  • the gram-negative bacteria are selected from the group consisting of Pseudomonas aeruginosa, Stenotrophomonas maltophila, Burkholderia cepacia, Alcaligenes xylosoxidans, Acinetobacter, Enterobacteriaceae, Haemophilus , and Neisseria species.
  • the invention provides a method of administering an inhibitory amount of a compound of formula I to gram-negative bacteria, such as Enterobacteriaceae which is selected from the group consisting of organisms such as Serratia, Proteus, Klebsiella, Enterobacter, Citrobacter, Salmonella, Providencia, Morganella, Cedecea , and Edwardsiella species and Escherichia coli.
  • Enterobacteriaceae which is selected from the group consisting of organisms such as Serratia, Proteus, Klebsiella, Enterobacter, Citrobacter, Salmonella, Providencia, Morganella, Cedecea , and Edwardsiella species and Escherichia coli.
  • Another embodiment of the invention provides a pharmaceutical composition comprising an effective amount of a compound of Formula I with a pharmaceutically acceptable carrier thereof.
  • compositions according to the present invention are provided which include any of the compounds described above in combination with a pharmaceutically acceptable carrier.
  • Another embodiment of the invention provides a method of co-administering the compound of formula I with other therapeutic agents that are selected for their particular usefulness against the condition that is being treated.
  • the compound of formula I is useful in combination with other anti-bacterial agents.
  • the compound of formula I augments the sensitivity of gram-negative bacteria to existing classes of antibacterials.
  • Combinations of the presently disclosed compounds with other anti-bacterial. agents are within the scope of the invention.
  • anti-bacterial agents include, but are not limited to, erythromycin, rifampicin, Nalidixic acid, carbenicillin, bacitracin, cycloserine, fosfomycin, and vancomycin.
  • the present invention provides novel compounds, methods for inhibiting LpxC in gram-negative bacteria, and novel methods for treating bacterial infections.
  • the compounds provided herein can be formulated into pharmaceutical formulations and medicaments that are useful in the methods of the invention.
  • the invention also provides for the use of the compounds in preparing medicaments and pharmaceutical formulations, for use of the compounds in inhibiting LpxC, and for use of the compounds in treating bacterial infections in a subject.
  • LpxC is an abbreviation that stands for UDP-3-O-(R-3-hydroxydecanoyl)-N-acetylglucosamine deacetylase.
  • references to a certain element such as hydrogen or H is meant to include all isotopes of that element.
  • an R group is defined to include hydrogen or H, it also includes deuterium and tritium.
  • alkyl refers to alkyl groups that-do not contain heteroatoms.
  • the phrase includes straight chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like.
  • the phrase also includes branched chain isomers of straight chain alkyl groups, including but not limited to, the following that are provided by way of example: —CH(CH 3 ) 2 , —CH(CH 3 )(CH 2 CH 3 ), —CH(CH 2 CH 3 ) 2 , —C(CH 3 ) 3 , —C(CH 2 CH 3 ) 3 , —CH 2 CH(CH 3 ) 2 , —CH 2 CH(CH 3 )(CH 2 CH 3 ), —CH 2 CH(CH 2 CH 3 ) 2 , —CH 2 C(CH 3 ) 3 , —CH 2 C(CH 2 CH 3 ) 3 , —CH(CH 3 )CH(CH 3 )(CH 2 CH 3 ), —CH 2 CH 2 CH(CH 3 ) 2 , —CH 2 CH 2 CH(CH 3 )(CH 2 CH 3 ), —CH 2 CH 2 CH(CH 3 ) 2 , —CH 2 CH 2 CH(CH 3 ) 2
  • the phrase also includes cyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl and such rings substituted with straight and branched chain alkyl groups as defined above.
  • alkyl groups includes primary alkyl groups, secondary alkyl groups, and tertiary alkyl groups.
  • Preferred alkyl groups include straight and branched chain alkyl groups and cyclic alkyl groups having 1 to 12 carbon atoms.
  • substituted alkyl refers to an alkyl group as defined above in which one or more bonds to a carbon(s) or hydrogen(s) are replaced by a bond to non-hydrogen and non-carbon atoms such as, but not limited to, a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, and ester groups; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; a silicon atom in groups such as in trialkylsilyl groups, dialkylaryl
  • Substituted alkyl groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom is replaced by a higher-order bond (e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; nitrogen in groups such as imines, oximes, hydrazones, and nitriles.
  • Substituted alkyl groups further include alkyl groups in which one or more bonds to a carbon(s) or hydrogen(s) atoms is replaced by a bond to an aryl, heterocyclyl group, or cycloalkyl group.
  • Preferred substituted alkyl groups include, among others, alkyl groups in which one or more bonds to a carbon or hydrogen atom is/are replaced by one or more bonds to fluorine atoms.
  • Another preferred substituted alkyl group is the trifluoromethyl group and other alkyl groups that contain the trifluoromethyl group.
  • Other preferred substituted alkyl groups include those in which one or more bonds to a carbon or hydrogen atom is replaced by a bond to an oxygen atom such that the substituted alkyl group contains a hydroxyl, alkoxy, or aryloxy group.
  • Still other preferred substituted alkyl groups include alkyl groups that have an amine, or a substituted or unsubstituted alkylamine, dialkylamine, arylamine, (alkyl)(aryl)amine, diarylamine, heterocyclylamine, diheterocyclylamine, (alkyl)(heterocyclyl)amine, or (aryl)(heterocyclyl)amine group.
  • alkenyl refers to straight and branched chain and cyclic groups such as those described with respect to alkyl groups as defined above, except that at least one double bond exists between two carbon atoms. Examples include, but are not limited to vinyl, —CH ⁇ C(H)(CH 3 ), —CH ⁇ C(CH 3 ) 2 , —C(CH 3 ) ⁇ C(H) 2 , —C(CH 3 ) ⁇ C(H)(CH 3 ), —C(CH 2 CH 3 ) ⁇ CH 2 , cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others.
  • substituted alkenyl has the same meaning with respect to alkenyl groups that substituted alkyl groups had with respect to unsubstituted alkyl groups.
  • a substituted alkenyl group includes alkenyl groups in which a non-carbon or non-hydrogen atom is bonded to a carbon double bonded to another carbon and those in which one of the non-carbon or non-hydrogen atoms is bonded to a carbon not involved in a double bond to another carbon.
  • alkynyl refers to straight and branched chain groups such as those described with respect to alkyl groups as defined above, except that at least one triple bond exists between two carbon atoms. Examples include, but are not limited to —C ⁇ C(H), —C ⁇ C(CH 3 ), —C ⁇ C(CH 2 CH 3 ), —C(H 2 )C ⁇ C(H), —C(H) 2 C ⁇ C(CH 3 ), and —C(H) 2 C ⁇ C(CH 2 CH 3 ) among others.
  • substituted alkynyl has the same meaning with respect to alkynyl groups that substituted alkyl groups had with respect to unsubstituted alkyl groups.
  • a substituted alkynyl group includes alkynyl groups in which a non-carbon or non-hydrogen atom is bonded to a carbon triple bonded to another carbon and those in which a non-carbon or non-hydrogen atom is bonded to a carbon not involved in a triple bond to another carbon.
  • heterocyclyl refers to both aromatic and nonaromatic ring compounds including monocyclic, bicyclic, and polycyclic ring compounds such as, but not limited to, quinuclidinyl, containing 3 or more ring members of which one or more is a heteroatom such as, but not limited to, N, O, and S.
  • unsubstituted heterocyclyl includes condensed heterocyclic rings such as benzimidazolyl, it does not include heterocyclyl groups that have other groups such as alkyl or halo groups bonded to one of the ring members as compounds such as 2-methylbenzimidazolyl are substituted heterocyclyl groups.
  • heterocyclyl groups include, but are not limited to: unsaturated 3 to 8 membered rings containing 1 to 4 nitrogen atoms such as, but not limited to pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g. 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl etc.), tetrazolyl, (e.g.
  • saturated 3 to 8 membered rings containing 1 to 4 nitrogen atoms such as, but not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl; condensed unsaturated heterocyclic groups containing 1 to 4 nitrogen atoms such as, but not limited to, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl; unsaturated 3 to 8 membered rings containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms such as, but not limited to, oxazolyl, isoxazolyl, oxadiazolyl (e.g.
  • unsaturated 3 to 8 membered rings containing 1 to 3 sulfur atoms and 1 to 3 nitrogen atoms such as, but not limited to, thiazolyl, isothiazolyl, thiadiazolyl (e.g.
  • 1,3-benzodioxoyl, etc. unsaturated 3 to 8 membered rings containing an oxygen atom and 1 to 2 sulfur atoms such as, but not limited to, dihydrooxathiinyl; saturated 3 to 8 membered rings containing 1 to 2 oxygen atoms and 1 to 2 sulfur atoms such as 1,4-oxathiane; unsaturated condensed rings containing 1 to 2 sulfur atoms such as benzothienyl, benzodithiinyl; and unsaturated condensed heterocyclic rings containing an oxygen atom and 1 to 2 oxygen atoms such as benzoxathiinyl.
  • unsaturated 3 to 8 membered rings containing an oxygen atom and 1 to 2 sulfur atoms such as, but not limited to, dihydrooxathiinyl
  • saturated 3 to 8 membered rings containing 1 to 2 oxygen atoms and 1 to 2 sulfur atoms such as 1,4-oxathiane
  • Heterocyclyl group also include those described above in which one or more S atoms in the ring is double-bonded to one or two oxygen atoms (sulfoxides and sulfones).
  • heterocyclyl groups include tetrahydrothiophene, tetrahydrothiophene oxide, and tetrahydrothiophene 1,1-dioxide.
  • Preferred heterocyclyl groups contain 5 or 6 ring members.
  • More preferred heterocyclyl groups include morpholine, piperazine, piperidine, pyrrolidine, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, thiomorpholine, thiomorpholine in which the S atom of the thiomorpholine is bonded to one or more 0 atoms, pyrrole, homopiperazine, oxazolidin-2-one, pyrrolidin-2-one, oxazole, quinuclidine, thiazole, isoxazole, furan, and tetrahydrofuran.
  • substituted heterocyclyl refers to a heterocyclyl group as defined above in which one of the ring members is bonded to a non-hydrogen atom such as described above with respect to substituted alkyl groups and substituted aryl groups. Examples, include, but are not limited to, 2-methylbenzimidazolyl, 5-methylbenzimidazolyl, 5-chlorobenzthiazolyl, 1-methyl piperazinyl, and 2-chloropyridyl among others.
  • aryl refers to aryl groups that do not contain heteroatoms.
  • the phrase includes, but is not limited to, groups such as phenyl, biphenyl, anthracenyl, naphthenyl by way of example.
  • unsubstituted aryl includes groups containing condensed rings such as naphthalene, it does not include aryl groups that have other groups such as alkyl or halo groups bonded to one of the ring members, as aryl groups such as tolyl are considered herein to be substituted aryl groups as described below.
  • a preferred unsubstituted aryl group is phenyl.
  • Unsubstituted aryl groups may be bonded to one or more carbon atom(s), oxygen atom(s), nitrogen atom(s), and/or sulfur atom(s) in the parent compound, however.
  • substituted aryl group has the same, meaning with respect to unsubstituted aryl groups that substituted alkyl groups had with respect to unsubstituted alkyl groups.
  • a substituted aryl group also includes aryl groups in which one of the aromatic carbons is bonded to one of the non-carbon or non-hydrogen atoms described above and also includes aryl groups in which one or more aromatic carbons of the aryl group is bonded to a substituted and/or unsubstituted alkyl, alkenyl, or alkynyl group as defined herein.
  • Preferred substituents include straight and branched chain alkyl groups, —CH 3 , —C 2 H 5 , —CH 2 OH, —OH, —OCH 3 , —OC 2 H 5 , —OCF 3 , —CN, —NO 2 , —CO 2 H, —CO 2 CH 3 , —CONH 2 , —NH 2 , —F, —Cl, Br, —CF 3 , —N(CH 3 ) 2 , —NHSO 2 CH 3 , —NHCOCH 3 .
  • heteroaryl refers to a cyclic or bicyclic aromatic radical having from five to ten ring atoms in each ring of which one atom of the cyclic or bicyclic ring is selected from S, O and N; zero, one or two ring atoms are additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and naphthyridinyl, and the like.
  • substituted heteroaryl refers to a heteroaryl group as defined herein substituted by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I, OH, CN, C 1 -C 3 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy substituted with aryl, haloalkyl, thioalkoxy, amino, alkylamino, dialkylamino, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide.
  • any one substituent may be an aryl, heteroaryl, or heterocycloalkyl group.
  • Preferred substituents include straight and branched chain alkyl groups, —CH 3 , —C 2 H 5 , —CH 2 OH, —OH, —OCH 3 , —OC 2 H 5 , —OCF 3 , —CN, —NO 2 , —CO 2 H, —CO 2 CH 3 , —CONH 2 , —NH 2 , —F, —Cl, Br, —CF 3 , —N(CH 3 ) 2 , —NHSO 2 CH 3 , —NHCOCH 3 .
  • biasing refers to a group or substituent to which two aryl groups, which are not condensed to each other, are bound.
  • exemplary biaryl compounds include, for example, phenylbenzene, diphenyldiazene, 4-methylthio- 1 -phenylbenzene, phenoxybenzene, (2-phenylethynyl)benzene, diphenyl ketone, (4-phenylbuta-1,3-diynyl)benzene, phenylbenzylamine, (phenylmethoxy)benzene, and the like.
  • Preferred optionally substituted biaryl groups include: 2-(phenylamino)-N-[4-(2-phenylethynyl)phenyl]acetamide, 1,4-diphenylbenzene, N-[4-(2-phenylethynyl)phenyl]-2-[benzylamino]acetamide, 2-amino-N-[4-(2-phenylethynyl)phenyl]propanamide, 2-amino-N-[4-(2-phenylethynyl)phenyl]acetamide, 2-(cyclopropylamino)-N-[4-(2-phenylethynyl)phenyl]acetamide, 2-(ethylamino)-N-[4-(2-phenylethynyl)phenyl]acetamide, 2-[(2-methylpropyl)amino]-N-[4-(2-phenylethynyl)phenyl]acetamide,
  • heteroarylaryl refers to a biaryl group where one of the aryl groups. is a heteroaryl group.
  • exemplary heteroarylaryl groups include, for example, 2-phenylpyridine, phenylpyrrole, 3-(2-phenylethynyl)pyridine, phenylpyrazole, 5-(2-phenylethynyl)-1,3-dihydropyrimidine-2,4-dione, 4-phenyl-1,2,3-thiadiazole, 2-(2-phenylethynyl)pyrazine, 2-phenylthiophene, phenylimidazole, 3-(2-piperazinylphenyl)furan, 3-(2,4-dichlorophenyl)-4-methylpyrrole, and the like.
  • Preferred optionally substituted heteroarylaryl groups include: 5-(2-phenylethynyl)pyrimidine-2-ylamine, 1-methoxy-4-(2-thienyl)benzene, 1-methoxy-3-(2-thienyl)benzene, 5-methyl-2-phenylpyridine, 5-methyl-3-phenylisoxazole, 2-[3-(trifluoromethyl)phenyl]furan, 3-fluoro-5-(2-furyl)-2-methoxy-1-prop-2-enylbenzene, (hydroxyimino)(5-phenyl(2-thienyl))methane, 5-[(4-methylpiperazinyl)methyl]-2-phenylthiophene, 2-(4-ethylphenyl)thiophene, 4-methylthio-1-(2-thienyl)benzene, 2-(3-nitrophenyl)thiophene, (tert-butoxy)-N-[(5-phenyl(3-
  • heteroarylheteroaryl refers to a biaryl group where both of the aryl groups is a heteroaryl group.
  • exemplary heteroarylheteroaryl groups include, for example, 3-pyridylimidazole, 2-imidazolylpyrazine, and the like.
  • Preferred optionally substituted heteroarylheteroaryl groups include: 2-(4-piperazinyl-3-pyridyl)furan, diethyl(3-pyrazin-2-yl(4-pyridyl))amine, and dimethyl ⁇ 2-[2-(5-methylpyrazin-2-yl)ethynyl](4-pyridyl) ⁇ amine.
  • Optionally substituted refers to the optional replacement of hydrogen with one or more monovalent or divalent radicals.
  • Optionally substituted groups include those described herein, for each group in which a distinct definition for substitution is supplied.
  • suitable substitution groups include, for example, hydroxyl, nitro, amino, imino, cyano, halo, thio, thioamido, amidino, imidino, oxo, oxamidino, methoxamidino, imidino, guanidino, sulfonamido, carboxyl, formyl, alkyl, substituted alkyl, haloloweralkyl, loweralkoxy, haloloweralkoxy, loweralkoxyalkyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, heteroarylcarbonyl, heteroaralkylcarbonyl, alkylthio, aminoalkyl, cyanoalkyl, benzyl
  • amidino and heterocycloamidino groups include, for example, those shown below. These amidino and heterocycloamidino groups can be further substituted as will be apparent to those having skill in the organic and medicinal chemistry arts in conjunction with the disclosure herein.
  • Representative substituted alkylcarbonylamino, alkyloxycarbonylamino, aminoalkyloxycarbonylamino, and arylcarbonylamino groups include, for example, those shown below. These groups can be further substituted as will be apparent to those having skill in the organic and medicinal chemistry arts in conjunction with the disclosure herein.
  • substituted aminocarbonyl groups include, for example, those shown below. These can be further substituted by heterocyclo groups and heteroaryl groups as will be apparent to those having skill in the organic and medicinal chemistry arts in conjunction with the disclosure herein.
  • Prefered aminocarbonyl groups include: N-(2-cyanoethyl)carboxamide, N-(3-methoxypropyl)carboxamide, N-cyclopropylcarboxamide, N-(2-hydroxy-isopropyl)carboxamide, methyl 2-carbonylamino-3-hydroxypropanoate, N-(2-hydroxypropyl)carboxamide, N-(2-hydroxy-isopropyl)carboxamide, N-[2-hydroxy-1-(hydroxymethyl)ethyl]carboxamide, N-(2-carbonylaminoethyl)acetamide, N-(2-(2-pyridyl)ethyl)carboxamide, N-(2-pyridylmethyl)carboxamide, N-(oxolan
  • Representative substituted alkoxycarbonyl groups include, for example, those shown below. These alkoxycarbonyl groups can be further substituted as will be apparent to those having skill in the organic and medicinal chemistry arts in conjunction with the disclosure herein.
  • protected with respect to hydroxyl groups, amine groups, and sulfhydryl groups refers to forms of these functionalities that are protected from undesirable reaction with a protecting group known to those skilled in the art such as those set forth in Protective Groups in Organic Synthesis, Greene, T. W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999) that can be added or removed using the procedures set forth therein.
  • Examples of protected hydroxyl groups include, but are not limited to, silyl ethers such as those obtained by reaction of a hydroxyl group with a reagent such as, but not limited to, t-butyldimethyl-chlorosilane, trimethylchlorosilane, triisopropylchlorosilane, triethylchlorosilane; substituted methyl and ethyl ethers such as, but not limited to methoxymethyl ether, methythiomethyl ether, benzyloxymethyl ether, t-butoxymethyl ether, 2-methoxyethoxymethyl ether, tetrahydropyranyl ethers, 1-ethoxyethyl ether, allyl ether, benzyl ether; esters such as, but not limited to, benzoylformate, formate, acetate, trichloroacetate, and trifluoracetate.
  • a reagent such as, but not limited to
  • protected amine groups include, but are not limited to, amides such as, formamide, acetamide, trifluoroacetamide, and benzamide; imides, such as phthalimide, and dithiosuccinimide; and others.
  • protected sulfhydryl groups include, but are not limited to, thioethers such as S-benzyl thioether, and S-4-picolyl thioether; substituted S-methyl derivatives such as hemithio, dithio and aminothio acetals; and others.
  • a “pharmaceutically acceptable salt” includes a salt with an inorganic base, organic base, inorganic acid, organic acid, or basic or acidic amino acid.
  • the invention includes, for example, alkali metals such as sodium or potassium; alkaline earth metals such as calcium and magnesium or aluminum; and ammonia.
  • the invention includes, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, and triethanolamine.
  • the instant invention includes, for example, hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid.
  • the instant invention includes, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.
  • salts of basic amino acids the instant invention includes, for example, arginine, lysine and omithine.
  • Acidic amino acids include, for example, aspartic acid and glutamic acid.
  • ester refers to esters that hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
  • Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.
  • Representative examples of particular esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
  • prodrugs refers to those prodrugs of the compounds of the present invention that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
  • prodrug refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formnula, for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
  • antibacterial agent refers to agents synthesized or modified in the laboratory that have either bactericidal or bacteriostatic activity.
  • An “active” agent in this context will inhibit the growth of P. aeruginosa and other gram-negative bacteria.
  • the term “inhibiting the growth” indicates that the rate of increase in the numbers of a population of a particular bacterium is reduced. Thus, the term includes situations in which the bacterial population increases but at a reduced rate, as well as situations where the growth of th& population is stopped, as well as situations where the numbers of the bacteria in the population are reduced or the population even eliminated. If an enzyme activity assay is used to screen for inhibitors, one can make modifications in uptake/efflux, solubility, half-life, etc. to compounds in order to correlate enzyme inhibition with growth inhibition.
  • the activity of antibacterial agents is not necessarily limited to bacteria but may also encompass activity against parasites, virus, and fungi.
  • the subject invention also includes isotopically-labeled LpxC inhibitors, that are structurally identical to those disclosed above, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl, respectively.
  • Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds and of said prodrugs that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • Certain isotopically labeled compounds of the present invention, for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out known or referenced procedures and by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • the present invention provides novel compounds, pharmaceutical formulations including the compounds, methods of inhibiting UDP-3-O-(R-3-hydroxydecanoyl)-N-acetylglucosamine deacetylase (LpxC), and methods of treating gram-negative bacterial infections.
  • LpxC UDP-3-O-(R-3-hydroxydecanoyl)-N-acetylglucosamine deacetylase
  • the present invention provides compounds of formula I:
  • L is absent or selected from the group consisting of
  • R 1L , R 2L , and R 3L are independently selected from the group consisting of
  • R 1L and R 3L together with the atoms to which they are attached can form a substituted or unsubstituted heterocyclic ring, having from 3 to 8 ring atoms, wherein 1-2 ring atoms of the heterocyclic ring system are selected from N, O and S,
  • j is an integer of 0-4;
  • k is an integer of 0-4;
  • D is absent or selected from the group consisting of
  • G is absent or selected from the group consisting of
  • Rg is H or substituted or unsubstituted C 1 -C 6 -alkyl; i is an interger of 0-4;
  • Y is selected from the group consisting of
  • X is selected from the group consisting of
  • X and A together with the atoms to which they are attached can form a heterocyclic ring, having from 5 to 8 ring atoms, wherein 1-2 ring atoms of the heterocyclic ring system are selected from N, O and S;
  • B is a absent or
  • R 1b and R 2b are independently selected from the group consisting of
  • R 1b and R 2b together with the atoms to which they are attached can form a substituted or unsubstituted heterocyclic ring, having from 3 to 8 ring atoms, wherein 1-2 ring atoms of the heterocyclic: ring system are selected from N, O and S;
  • q is an integer of 0-4;
  • R 3 is H or substituted or unsubstituted C 1 -C 6 -alkyl, or R 3 and A, together with the atoms to which they are attached can form a substituted or unsubstituted 3-10 membered cycloalkyl or a heterocyclic ring system, wherein the heterocyclic ring system may have from 3 to 10 ring atoms, with 1 to 2 rings being in the ring system and contain from 1-4 heteroatoms selected from N, O and S;
  • R 4 is H or substituted or unsubstituted C 1 -C 6 -alkyl, or R 4 and A, together with the atoms to which they are attached can form a substituted or unsubstituted heterocyclic ring, having from 3 to 8 ring atoms, wherein 1-2 ring atoms of the heterocyclic ring system are selected from N, O and S;
  • n is an integer of 0-2;
  • A is selected from the group consisting of
  • R 1a , R 2a , R 3a , R 4a , and R 5a are independently selected from the group consisting of
  • R 4a and R 5a together with the N atom to which they are attached can form a substituted or unsubstituted heterocyclic ring, having from 3 to 8 ring atoms, wherein 1-2 ring atoms of the heterocyclic ring system are selected from N, O and S;
  • r is an integer of 0-4;
  • s is an integer of 0-4;
  • Q is absent or selected from the group consisting of
  • R 1 is selected from the group consisting of
  • R 2 is selected from the group consisting of
  • R 1 and R 2 together with the N atom to which they are attached can form a substituted or unsubstituted heterocyclic ring, having from 3 to 10 ring atoms, wherein 1-4 ring atoms of the heterocyclic ring system are selected from N, O and S,
  • R 1q , R 2q , R 3q , R 4q , and R 5q are selected from H or C 1 -C 6 alkyl
  • B is absent, or E, L, G, and B are absent, or E, L, and G are absent, or E, L, and B are absent, or E, L, D, G, and B are absent.
  • E is absent or selected from the group consisting of
  • L is absent or selected from the group consisting of
  • R 1L , R 2L , R 3L are independently selected from the group consisting of
  • R 1L and R 3L together with the atoms to which they are attached can form a substituted or unsubstituted heterocyclic ring, having from 5 to 8 ring atoms, wherein 1-2 ring atoms of the heterocyclic ring system are selected from N, O and S;
  • j is an integer of 0-4;
  • k is an integer of 0-4;
  • D is absent or selected from the group consisting of
  • G is absent or selected from the group consisting of
  • i is an interger of 0-4;
  • Y is selected from the group consisting of
  • X is selected from the group consisting of
  • X and A together with the atoms to which they are attached can form a heterocyclic ring, having from 5 to 8 ring atoms, wherein 1-2 ring atoms of the heterocyclic ring system are selected from N, O and S;
  • R 1b and R 2b are independently selected from the group consisting of
  • R 1b and R 2b together with the atoms to which they are attached can form a substituted or unsubstituted.heterocyclic ring, having from 5 to 8 ring atoms, wherein 1-2 ring atoms of the heterocyclic ring system are selected from N, O and S;
  • q is an integer of 0-2;
  • R 3 is H or substituted or unsubstituted C 1 -C 6 -alkyl
  • R 3 and A together with the atoms to which they are attached can form a substituted or unsubstituted 3-10 membered cycloalkyl or a heterocyclic ring system, wherein the heterocyclic ring system may have from 3 to 10 ring atoms, with 1 to 2 rings being in the ring system and contain from 1-4 heteroatoms selected from N, O and S;
  • R 4 is H or substituted or unsubstituted C 1 -C 6 -alkyl
  • R 4 and A together with the atoms to which they are attached can form a substituted or unsubstituted heterocyclic ring, having from 5 to 8 ring atoms, wherein 1-2 ring atoms of the heterocyclic ring system are selected from N, O and S;
  • A is selected from the group consisting of
  • R 1a , R 2a , R 3a , R 4a , and R 5a are independently selected from the group consisting of
  • R 4a and R 5a together with the N atom to which they are attached can form a substituted or unsubstituted heterocyclic ring, having from 5 to 8 ring atoms, wherein 1-2 ring atoms of the heterocyclic ring system are selected from N, O and S;
  • r is an integer of 0-4;
  • Q is absent or selected from the group consisting of
  • R 1 is selected from the group consisting of
  • R 2 is selected from the group consisting of
  • R 1 and R 2 together with the N atom to which they are attached can form a substituted or unsubstituted heterocyclic ring, having from 3 to 10 ring atoms, wherein 1-4 ring atoms of the heterocyclic ring system are selected from N, O and S,
  • R 1q , R 2q , and R 3q are selected from H or C 1 -C 6 alkyl
  • B is absent, or E, L, G, and B are absent, or E, L, and G are absent, or E, L, and B are absent, or E, L, D, G, and B are absent.
  • the present invention provides compounds of formula II:
  • R is selected from the group consisting of —CH 3 , —C 2 H 5 , —CH 2 OH, —OH, —OCH 3 , —OC 2 H 5 , —OCF 3 , —CN, —NO 2 , —CO 2 , —CO 2 CH 3 , —CONH 2 , —NH 2 , —F, —Cl, —Br, —CF 3 , —N(CH 3 ) 2 , —NHSO 2 CH 3 , and —NHCOCH 3 ;
  • X is selected from the group consisting of
  • the present invention provides compounds of formula III:
  • R is selected from the group consisting of —CH 3 , —C 2 H 5 , —CH 2 OH, —OH, —OCH 3 , —OC 2 H 5 , —OCF 3 , —CN, —NO 2 , —CO 2 H, —CO 2 CH 3 , —CONH 2 , —NH 2 , —F, —Cl, —Br, —CF 3 , —N(CH 3 ) 2 , —NHSO 2 CH 3 , and —NHCOCH 3 ;
  • X is selected from the groups consisting of
  • the present invention provides compounds of formula IV:
  • R is selected from the group consisting of —CH 3 , —C 2 H 5 , —CH 2 OH, —OH, —OCH 3 , —OC 2 H 5 , —OCF 3 , —CN, —NO 2 , —CO 2 H, —CO 2 CH 3 , —CONH 2 , —NH 2 , —F, —Cl, —Br, —CF 3 , —N(CH 3 ) 2 , —NHSO 2 CH 3 , and —NHCOCH 3 ;
  • X is selected from the groups consisting of
  • the present invention provides compounds of formula V:
  • R is selected from the group consisting of —CH 3 , —C 2 H 5 , —CH 2 OH, —OH, —OCH 3 , —OC 2 H 5 , —OCF 3 , —CN, —NO 2 , —CO 2 H, —CO 2 CH 3 , CONH 2 , —NH 2 , —F, —Cl, —Br, —CF 3 , —N(CH 3 ) 2 , —NHSO 2 CH 3 , and —NHCOCH 3 ;
  • X is selected from the groups consisting of
  • R 1L , R 3L are independently selected from the group consisting of
  • R 1L and R 3L together with the atoms to which they are attached can form a substituted or unsubstituted heterocyclic ring, having from 3 to 8 ring atoms, wherein 1-2 ring atoms of the heterocyclic ring system are selected from N, O and S.
  • R 1L , R 3L are independently selected from the group consisting of
  • R 1L and R 3L together with the atoms to which they are attached can form a substituted or unsubstituted heterocyclic ring, having from 3 to 8 ring atoms, wherein 1-2 ring atoms of the heterocyclic ring system are selected from N, O and S.
  • E is absent or selected from the group consisting of
  • E and R 3L together with the atoms to which they are attached can form a substituted or unsubstituted heterocyclic ring, having from 3 to 10 ring atoms, wherein 1-4 ring atoms of the heterocyclic ring system are selected from N, O and S;
  • R 1L , R 3L are independently selected from the group consisting of
  • R 1L and R 3L together with the atoms to which they are attached can form a substituted or unsubstituted heterocyclic ring, having from 3 to 8 ring atoms, wherein 1-2 ring atoms of the heterocyclic ring system are selected from N, O and S.
  • E and R 3L together with the atoms to which, they are attached can form a substituted or unsubstituted heterocyclic ring, having from 3 to 10 ring atoms, wherein 1-4 ring atoms of the heterocyclic ring system are selected from N, O and S;
  • R 1L , R 3L are independently selected from the group consisting of
  • R 1L and R 3L together with the atoms to which they are attached can form a substituted or unsubstituted heterocyclic ring, having from 3 to 8 ring atoms, wherein 1-2 ring atoms of the heterocyclic ring system are selected from N, O and S.
  • the present invention provides compounds of formula X:
  • R 1L , R 3L are independently selected from the group consisting of
  • R 1L and R 3L together with the atoms to which they are attached can form a substituted or unsubstituted-heterocyclic ring, having from 3 to 8 ring atoms, wherein 1-2 ring atoms of the heterocyclic ring system are selected from N, O and S.
  • the present invention provides compounds of formula XI:
  • the present invention provides compounds of formula XII:
  • R 1b and R 2b are independently selected from the group consisting of
  • q is an integer of 0-2;
  • the present invention provides compounds of formula XIII:
  • R 4 is selected from the group consisting of
  • A is H or —CH(CH 3 )OH—
  • R 1 is H or substituted or unsubstituted C 1-6 -alkyl
  • R 2 is selected from the group consisting of
  • R 1 and R 2 together with the N atom to which they are attached can form a substituted or unsubstituted heterocyclic ring, having from 3 to 10 ring atoms, wherein 1-2 ring atoms of the heterocyclic ring system are selected from N, O and S.
  • the present invention provides compounds of formula XIV:
  • R is selected from the group consisting of —CH 3 , —C 2 H 5 , —CH 2 OH, —OH, —OCH 3 , —OC 2 H 5 , —OCF 3 , —CN, —NO 2 , —CO 2 H, —CO 2 CH 3 , —CONH 2 , —NH 2 , —F, —Cl, —Br, —CF 3 , —N(CH 3 ) 2 , —NHSO 2 CH 3 , and —NHCOCH 3 ;
  • R 4 is selected from the group consisting of
  • the present invention provides compounds of formula XV:
  • R is selected from the group consisting of —CH 3 , —C 2 H 5 , —CH 2 OH, —OH, —OCH 3 ,—OC 2 H 5 , —OCF 3 , —CN, —NO 2 , —CO 2 H, —CO 2 CH 3 , —CONH 2 , —NH 2 , —F, —Cl, —Br, —CF 3 , —N(CH 3 ) 2 , —NHSO 2 CH 3 , and —NHCOCH 3 ;
  • the present invention provides compounds of formula XVI:
  • R is selected from the group consisting of —CH 3 , —C 2 H 5 , —CH 2 OH, —OH, —OCH 3 , —OC 2 H 5 , —OCF 3 , —CN, —NO 2 , —CO 2 H, —CO 2 CH 3 , —CONH 2 , —NH 2 , —F, —Cl, —Br, —CF 3 , —N(CH 3 ) 2 , —NHSO 2 CH 3 , and —NHCOCH 3 ;
  • R 4 is selected from the group consisting of
  • the present invention provides compounds of formula XVII:
  • R is selected from the group consisting of —CH 3 , —C 2 H 5 , —CH 2 OH, —OH, —OCH 3 , —OC 2 H 5 , —OCF 3 , —CN, —NO 2 , —CO 2 H, —CO 2 CH 3 , —CONH 2 , —NH 2 , —F, —Cl, —Br, —CF 3 , —N(CH 3 ) 2 , —NHSO 2 CH 3 , and —NHCOCH 3 ;
  • the invention provides a method of inhibiting a deacetylase enzyme in a gram-negative bacteria, thereby affecting bacterial growth, comprising administering to a patient in need of such inhibition a compound of formula I.
  • the invention provides a method of inhibiting LpxC, thereby modulating the virulence of a bacterial infection, comprising administering to a patient in need of such inhibition a compound of formula I.
  • the IC 50 value of the compound is less than or equal to 10 ⁇ M with respect to LpxC. In other such embodiments, the IC 50 value is less than or equal to 1 ⁇ M, is less than or equal to 0.1 ⁇ M, is less than or equal to 0.050 ⁇ M, is less than or equal to 0.030 ⁇ M, is less than or equal to 0.025 ⁇ M, or is less than or equal to 0.010 ⁇ M.
  • methods for treating a subject comprising administering to the subject an antibacterially effective amount of a compound of formula I, together with a pharmaceutically acceptable carrier is provided.
  • the subject is a mammal and some embodiments, a human.
  • the invention provides a method of administering an inhibitory amount of a compound of formula I to fermentative or non-fermnentative gram-negative bacteria.
  • the gram-negative bacteria are selected from the group consisting of Pseudomonas aeruginosa, Stenotrophomonas maltophila, Burkholderia cepacia, Alcaligenes xylosoxidans, Acinetobacter, Enterobacteriaceae, Haemophilus, Neisseria species.
  • the invention provides a method of administering an inhibitory amount of a compound of formula I to gram-negative bacteria, such as Enterobacteriaceae that is selected from the group consisting of organisms such as Serratia, Proteus, Klebsiella, Enterobacter, Citrobacter, Salmonella, Providencia, Morganella, Cedecea, and Edwardsiella species and Escherichia coli.
  • Enterobacteriaceae that is selected from the group consisting of organisms such as Serratia, Proteus, Klebsiella, Enterobacter, Citrobacter, Salmonella, Providencia, Morganella, Cedecea, and Edwardsiella species and Escherichia coli.
  • Another embodiment of the invention provides a pharmaceutical composition comprising an effective amount of a compound of Formula I with a pharmaceutically acceptable carrier thereof.
  • compositions according to the present invention are provided which include any of the compounds described above in combination with a pharmaceutically acceptable carrier.
  • Another embodiment of the invention provides a method of co-administering the compound of formula I with other therapeutic agents that are selected for their particular usefulness against the condition that is being treated.
  • the compound of formula I is useful in combination with other anti-bacterial agents.
  • the compound of formula I augments the sensitivity of gram-negative bacteria to existing classes of antibacterials.
  • Combinations of the presently disclosed compounds with other anti-bacterial agents are within the scope of the invention.
  • anti-bacterial agents include, but are not limited to, erythromycin, rifampicin, Nalidixic acid, carbenicillin, bacitracin, cycloserine, fosfomycin, and vancomycin.
  • a further aspect of the invention is the use of LpxC inhibitors for the treatment of an infection, particularly a bacterial infection.
  • a bacterial infection treated with the compounds of the invention can be a primary infection or a co-infection caused by a species of bacteria and one or more additional infectious agents selected from the group consisting of bacteria, virus, parasite and fungus.
  • treating refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of treating, as “treating” is defined immediately above.
  • the compounds of the invention can be used for treating conditions caused by the bacterial production of endotoxin and, in particular, by gram-negative bacteria and bacteria that use LpxC in the biosynthesis of lipopolysaccharide (LPS) or endotoxin.
  • LPS lipopolysaccharide
  • the compounds of the invention also are useful in the conditions that are caused or exacerbated by the bacterial production of lipid A and LPS or endotoxin, such as sepsis, septic shock, systemic inflammation, localized inflammation, chronic obstructive pulmonary disease (COPD) and acute exacerbations of chronic bronchitis (AECB).
  • treatment includes the administration of a compound of the invention, or a combination of compounds of the invention, optionally with a second agent wherein the second agent is a second antibacterial agent or a second non-antibacterial agent.
  • preferred second non-antibacterial agents include antiendotoxins including endotoxin receptor-binding antibodies, endotoxin-binding antibodies, antiCD14-binding protein antibodies antilipopolysaccharide-binding protein antibodies and tyrosine kinase inhibitors.
  • the compounds of the present invention may also be used with second non-antibacterial agents administered via inhalation.
  • Preferred non-antibacterial agents used in this treatment include anti-inflammatory steroids, non-steroidal anti-inflammatory agents, bronchiodilators, mucolytics, anti-asthma therapeutics and lung fluid surfactants.
  • the non-antibacterial agent may be selected from a group consisting of albuterol, salbuterol, budesonide, beclomethasone, dexamethasone, nedocromil, beclomethasone, fluticasone, flunisolide, triamcinolone, ibuprofin, rofecoxib, naproxen, celecoxib, nedocromil, ipratropium, metaproterenol, pirbuterol, salneterol, bronchiodilators, mucolytics, calfactant, beractant, poractant alfa, surfaxin and pulmozyme (also called domase alfa).
  • the compounds of the invention can be used, alone or in combination with a second antibacterial agent for the treatment of a serious or chronic respiratory tract infection including serious lung and nosocomial infections such as those caused by Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Prbteus mirabilis, Serratia marcescens, Stenotrophomonas maltophilia, Pseudomonas aeruginosa, Burkholderia cepacia, Acinetobacter calcoaceticus, Alcaligenes xylosoxidans, Flavobacterium meningosepticum, Providencia stuartii and Citrobacter freundi , community lung infections such as those caused by Haemophilus Influenzae, Legionella species, Moraxella catarrhalis, Branhamella catarrhalis, Enterobacter species, Acinetobacter species, Klebs
  • the compounds of the present invention can be used to sensitize gram-negative bacteria to the effects of a second agent.
  • antibacterial agents may be selected from the following groups:
  • Macrolides or ketolides such as erythromycin, azithromycin, clarithromycin and telithromycin;
  • Beta-lactams including penicillin, cephalosporin, and carbapenems such as carbapenem, imipenem, and meropenem;
  • Monobactams such as penicillin G, penicillin V, methicillin, oxacillin, cloxacillin, dicloxacillin, nafcillin, ampicillin, amoxicillin, carbenicillin, ticarcillin, mezlocillin, piperacillin, azlocillin, temocillin, cepalothin, cephapirin, cephradine, cephaloridine, cefazolin, cefamandole, cefuroxime, cephalexin, cefprozil, cefaclor, loracarbef, cefoxitin, cefinetazole, cefotaxime, ceftizoxime, ceftriaxone, cefoperazone, ceftazidime, cefixime, cefpodoxime, ceftibuten, cefdinir, cefpirome, cefepime, and astreonam;
  • Antibacterial sulfonanmides and antibacterial sulphanilamides including para-aminobenzoic acid, sulfadiazine, sulfisoxazole, sulfamethoxazole and sulfathalidine;
  • Aminoglycosides such as streptomycin, neomycin, kanamycin, paromycin, gentamicin, tobramycin, amikacin, netilmicin, spectinomycin, sisomicin, dibekalin and isepamicin;
  • Tetracyclines such as tetracycline, chlortetracycline, demeclocycline, minocycline, oxytetracycline, methacycline, doxycycline;
  • Rifamycins such as rifampicin (also called rifampin), rifapentine, rifabutin, bezoxazinorifamycin and rifaximin;
  • the second antibacterial agent may be administered in combination with the compounds of the present inventions wherein the second antibacterial agent is administered prior to, simultaneously, or after the compound or compounds of the present invention.
  • a compound of the invention may be formulated with a second agent into the same dosage form.
  • An example of a dosage form containing a compound of the invention and a second agent is a tablet or a capsule.
  • the compounds of the invention may be used alone or in combination with a second antibacterial agent administered via inhalation.
  • a preferred second antibacterial agent is selected from a group consisting of tobramycin, gentamicin, aztreonam, ciprofloxacin, polymyxin, colistin, colymycin, azithromycin and clarithromycin.
  • compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carrier means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • materials that can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulf
  • compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, or as an oral or nasal spray, or a liquid aerosol or dry powder formulation for inhalation.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include adjuvants such as wetting
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • the rate of drug release can be controlled.
  • biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations may also be prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.
  • compositions for rectal or vaginal administration are preferably suppositories that can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, acety
  • compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
  • compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • buffering agents include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulations, ear drops, and the like are also contemplated as being within the scope of this invention.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • compositions of the invention may also be formulated for delivery as a liquid aerosol or inhalable dry powder.
  • Liquid aerosol formulations may be nebulized predominantly into particle sizes that can be delivered to the terminal and respiratory bronchioles where bacteria reside in patients with bronchial infections, such as chronic bronchitis and pneumonia.
  • Pathogenic bacteria are commonly present throughout airways down to bronchi, bronchioli and lung parenchema, particularly in terminal and respiratory bronchioles. During exacerbation of infection, bacteria can also be present in alveoli.
  • Liquid aerosol and inhalable dry powder formulations are preferably delivered throughout the endobronchial tree to the terminal bronchioles and eventually to the parenchymal tissue.
  • Aerosolized formulations of the invention may be delivered using an aerosol forming device, such as a jet, vibrating porous plate or ultrasonic nebulizer, preferably selected to allow the formation of a aerosol particles having with a mass medium average diameter predominantly between 1 to 5 ⁇ m. Further, the formulation preferably has balanced osmolarity ionic strength and chloride concentration, and the smallest aerosolizable volume able to deliver effective dose of the compounds of the invention to the site of the infection. Additionally, the aerosolized formulation preferably does not impair negatively the functionality of the airways and does not cause undesirable side effects.
  • an aerosol forming device such as a jet, vibrating porous plate or ultrasonic nebulizer
  • Aerosolization devices suitable for administration of aerosol formulations of the invention include, for example, jet, vibrating porous plate, ultrasonic nebulizers and energized dry powder inhalers, that are able to nebulize the formulation of the invention into aerosol particle size predominantly in the size range from 1-5 pm. Predominantly in this application means that at least 70% but preferably more than 90% of all generated aerosol particles are 1 to 5 ⁇ m range.
  • a jet nebulizer works by air pressure to break a liquid solution into aerosol droplets. Vibrating porous plate nebulizers work by using a sonic vacuum produced by a rapidly vibrating porous plate to extrude a solvent droplet through a porous plate.
  • An ultrasonic nebulizer works by a piezoelectric crystal that shears a liquid into small aerosol droplets.
  • suitable devices including, for example, AeroNeb and AeroDose vibrating porous plate nebulizers (AeroGen, Inc., Sunnyvale, Calif.), Sidestream7 nebulizers (Medic-Aid Ltd., West Wales, England), Pari LC7 and Pari LC Star7 jet nebulizers (Pari Respiratory Equipment, Inc., Richmond, Va.), and Aerosonic (DeVilbiss Medizinische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffetechnik (Deutschland) GmbH, Heiden, Germany) and UltraAire7 (Omron Healthcare, Inc., Vernon Hills, Ill.) ultrasonic nebulizers.
  • Compounds of the invention may also be formulated for use as topical powders and sprays that can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound to the body.
  • dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • bacterial infections are treated or prevented in a patient such as a human or lower mammal by administering to the patient a therapeutically effective amount of a compound of the invention, in such amounts and for such time as is necessary to achieve the desired result.
  • a “therapeutically effective amount” of a compound of the invention is meant a sufficient amount of the compound to treat bacterial infections, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.
  • the total daily dose of the compounds of this invention administered to a human or other mammal in single or in divided doses can be in amounts, for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1 to 25 mg/kg body weight.
  • Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.
  • treatment regimens according to the present invention comprise administration to a patient in need of such treatment from about 10 mg to about 2000 mg of the compound(s) of this invention per day in single or multiple doses.
  • compositions for use in thepresent invention can be in the form of sterile, non-pyrogenic liquid solutions or suspensions, coated capsules, suppositories, lyophilized powders, transdermal patches or other forms known in the art.
  • a “kit” as used in the instant application includes a container for containing the pharmaceutical compositions and may also include divided containers such as a divided bottle or a divided foil packet.
  • the container can be in any conventional shape or form as known in the art that is made of a pharmaceutically acceptable material, for example a paper or cardboard box, a glass or plastic bottle or jar, a resealable bag (for example, to hold a “refill” of tablets for placement into a different container), or a blister pack with individual doses for pressing out of the pack according to a therapeutic schedule.
  • the container employed can depend on the exact dosage form involved, for example a conventional cardboard box would not generally be used to hold a liquid suspension. It is feasible that more than one container can be used together in a single package to market a single dosage form. For example, tablets may be contained in a bottle that is in turn contained within a box.
  • Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit. dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process, recesses are formed in the plastic foil. The recesses have the size and shape of individual tablets or capsules to be packed or may have the size and shape to accommodate multiple tablets and/or capsules to be packed. Next, the tablets or capsules are placed in the recesses accordingly and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil that is opposite from the direction in which the recesses were formed.
  • the tablets or capsules are individually sealed or collectively sealed, as desired, in the recesses between the plastic foil and the sheet.
  • the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
  • the written memory aid is of the type containing information and/or instructions for the physician, pharmacist or other health care provider, or subject, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen that the tablets or capsules so specified should be ingested or a card that contains the same type of information.
  • a memory aid is a calendar printed on the card e.g., as follows “First Week, Monday, Tuesday,”. . . etc . . . “Second Week, Monday, Tuesday, . . . ” etc.
  • Other variations of memory aids will be readily apparent.
  • a “daily dose” can be a single tablet or capsule or several tablets or capsules to be taken on a given day.
  • a daily dose of one or more compositions of the kit can consist of one tablet or capsule while a daily dose of another one or more compositions of the kit can consist of several tablets or capsules.
  • kits are a dispenser designed to dispense the daily doses one at a time in the order of their intended use.
  • the dispenser is equipped with a memory-aid, so as to further facilitate compliance with the regimen.
  • a memory-aid is a mechanical counter, that indicates the number of daily doses that has been dispensed.
  • a battery-powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signal that, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.
  • kits of the present invention may also include, in addition to LpxC inhibitors, one or more additional pharmaceutically active compounds.
  • the additional compound is another LpxC inhibitor or another compound useful to bacterial infections.
  • the additional compounds may be administered in the same dosage form as the LpxC inhibitor or in different dosage forms. Likewise, the additional compounds can be administered at the same time as the LpxC inhibitor or at different times.
  • compositions of the present compounds may also be used in combination with other known antibacterial agents of similar spectrum to (1) synergistically enhance treatment of severe Gram-negative infections covered by the spectrum of this compound or (2) add coverage in severe infections in which multiple organisms are suspected in which another agent of a different spectrum may be required in addition to this compound.
  • Potential agents include members of the aminoglycosides, penicillins, cephalosporins, fluoroquinolones, macrolides, glycopeptides, lipopeptides and oxazolidinones.
  • the treatment can involve administering a composition having both active agents or administration of the inventive compounds followed by or preceded by administration of an additional active antibacterial agent.
  • HPLC solvents were from Burdick and Jackson (Muskegan, Mich.), or Fisher Scientific (Pittsburg, Pa.). In some instances, purity was assessed by thin layer chromatography (TLC) using glass or plastic backed silica gel plates, such as, for example, Baker-Flex Silica Gel 1 B2-F flexible sheets. TLC results were readily detected visually under ultraviolet light, or by employing well known iodine vapor and other various staining techniques.
  • Mass spectrometric analysis was performed on one of two LCMS instruments: a Waters System. (Alliance HT HPLC and a Micromass ZQ mass spectrometer; Column: Eclipse XDB-C-18, 2.1 ⁇ 50 mm; solvent system: 5-95% (or 35-95%, or 65-95% or 95-95%) acetonitrile in water with 0.05%TFA; flow rate 0.8 mL/min; molecular weight range 500-1500; cone Voltage 20 V; column temperature 40° C.) or a Hewlett Packard System (Series 1100 HPLC; Column: Eclipse XDB-C18, 2.1 ⁇ 50 mm; solvent system: 1-95% acetonitrile in water with 0.05% TFA; flow rate 0.4 mL/min; molecular weight range 150-850; cone Voltage 50 V; column temperature 30° C). All masses are reported as those of the protonated parent ions.
  • GCMS analysis was performed on a Hewlet Packard instrument (HP6890 Series gas chromatograph with a Mass Selective Detector 5973; injector volume: 1 ⁇ L; initial column temperature: 50° C.; final column temperature: 250C; ramp time: 20 minutes; gas flow rate: 1 mL/min; column: 5% phenyl methyl siloxane, Model #HP 190915-443, dimensions: 30.0 m ⁇ 25 m ⁇ 0.25 m).
  • Nuclear magnetic resonance (NMR) analysis was performed with a Varian 300 Mhz NMR (Palo Alto, Calif.). The spectral reference was either TMS or the known chemical shift of the solvent. Some compound samples were run at elevated temperatures (e.g. 75° C.) to promote increased sample solubility.
  • Preparative separations were carried out using a Flash 40 chromatography system and KP-Sil, 60A (Biotage, Charlottesville, Va.), or by flash column chromatography using silica gel (230-400 mesh) packing material, or by HPLC using a C-18 reversed phase column.
  • Typical solvents employed for the Flash 40 Biotage system and flash column chromatography were dichloromethane, methanol, ethyl acetate, hexane, acetone, aqueous hydroxyamine and triethyl amine.
  • Typical solvents employed for the reverse phase HPLC were varying concentrations of acetonitrile and water with 0.1% trifluoroacetic acid.
  • DAP or Dap Diaminopropionate
  • DCM 4-(Dicyanomethylene)-2-methyl-6- (4-dimethylaminostyryl)-4H-pyran
  • DEAD Diethyl azodicarboxylate
  • DIEA Diisopropylethylamine
  • DME 1,2-dimethoxyethane
  • DMF N,N-Dimethylformamide
  • DMSO Dimethyl sulfoxide
  • DPPA Diphenyl phosphoryl azide
  • Et 3 N Triethylamine
  • EDC N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide
  • EDCI 1-(3-dimethylaminopropyl)3-ethylcarbodiimide
  • EtOAc Ethyl acetate EtOH: Ethanol
  • Fmoc 9-fluorenylmethoxycarbonyl
  • Gly-OH glycine HATU: O-(
  • iPrOH Isopropanol LC/MS: Liquid Chromatography/Mass Spectrometry LRMS: Low Resolution Mass Spectrometry MeOH: Methanol NaOMe: sodium methoxide nm: Nanometer NMP: N-Methylpyrrolidone PPh 3 : triphenyl phosphine RP-HPLC: Reversed-phase high-pressure liquid chromatography RT: Room temperature sat: Saturated TEA: Triethylamine TFA: Trifluoroacetic acid THF: Tetrahydrofuran Thr: Threonine TLC: Thin Layer Chromatography Trt-Br: Tert-butyl bromide
  • Example compounds Nomenclature for the Example compounds was provided using ACD Name version 5.07 software (Nov. 14, 2001) available from Advanced Chemistry Development, Inc. Some of the compounds and starting materials were named using standard IUPAC nomenclature.
  • reaction could be carried out in dry DCM.
  • a reaction using 5.44 g (14.5 mmol) of trt-allo-threonine methyl ester (2) in DCM (100 ml) with PPh 3 (3.8 g, 14.5 mmol), pure DEAD (3.4 ml, 21.8 mmol) in DCM (5 ml) and DPPA (6.3 ml, 24.0 mmol) in DCM (10 ml) were combined following the procedure above. After 3 days, the reaction did not progress further by TLC and LCMS. After the same work up, 2.97 g of the product was obtained in 51% yield.
  • Trt-Azido-Thr-OMe (3) (4.8 g, 12.0 mmol) was dissolved in a 95% TFA/DCM solution (60 ml) at rt with stirring. After 2.5 h, the reaction was complete by LCMS. The bright yellow solution was diluted with 0.5 N aq. HCl (300 ml). The aqueous layer was extracted with DCM (2 ⁇ 30 ml) and then lyophilized to dryness. The white solid was dissolved in AcCN/water (50:50) (100 ml) and again lyophilized to dryness to produce a consistent powder and remove as much of the TFA as possible. The azido-Thr′product (4), 2.26 g (97% yield, 95% pure) of a white solid, was obtained as the HCl salt.
  • the crude product was dissolved in EtOAc (100 ml) and washed with 0.2N aq. HCl (2 ⁇ 50 ml), aq. sat. NaHCO 3 (50 ml), brine (50 ml), dried (Na2SO 4 ), filtered and concentrated under reduced pressure to yield a crude brown solid.
  • the crude material was further purified by column chromatography eluting with Hexane/EtOAc (70:30) giving 245 mg (67% yield) of pure product after evaporation and drying in vacuo.
  • the pH of the reaction reached a stable 11-12 after the final portion of NaOMe was added (250 mg total). The reaction was initiated at pH 11 and proceeded quickly. After 30 min., the reaction reached 85% completion as determined by LCMS, and the reaction was placed in a ⁇ 10° C. bath. The cold mixture filtered over fine filter paper on a Büchner funnel. The white residue was washed with MeOH (15 ml). The organic fractions were collected and concentrated under reduced pressure to give crude product (750 mg).
  • the crude product (only one 150 mg portion) was dissolved in DMSO (1 ml), AcCN (100 ⁇ l) and water (100 ⁇ l ), passed through a Teflon syringe filter, and the clear filtrate was injected on a preparative HPLC.
  • the purification used a 20 ⁇ 50 mm Ultro 120 C18 column running a 22 ml/min 2% gradient (AcCN/water, 0.1% TFA) for 16 min. The purified fractions were lyophilized to dryness.
  • the product as the TFA salt was dissolved in AcCN/water (50:50) (5 ml), 1N aq. HCl (1 equivalent) and lyophilized again to give 11.5 mg of white powder as an HCl salt (23% yield).
  • reaction mixture was stirred 24 h, diluted with EtOAc (150 mL), washed with 1.0 M HCl (2 ⁇ 60 mL), saturated NaHCO 3 (2 ⁇ 60 mL), H 2 O (3 ⁇ 60 mL), dried over MgSO 4 and concentrated to give a crude white solid.
  • the resin was drained and washed with DMF (2 ⁇ 5 ml) and DCM (2 ⁇ 5 ml).] After shaking for 20 hours, the reaction was drained and washed with DMF (2 ⁇ 5 ml) and DCM (2 ⁇ 5 ml). The resin was dried and used as is in the next reaction.
  • the crude product was dissolved in DMSO (1 ml), passed through a Teflon syringe filter, and the clear filtrate was injected on a preparative HPLC.
  • the purification used a 20 ⁇ 50 mm Ultro 120 C18 column running a 22 ml/min 2% gradient (AcCN/water, 0.1% TFA) for 16 min.
  • the purified fractions were lyophilized to dryness.
  • the solid residue was lyophilized again from CH 3 CN/water (1:1) (5 ml) give 8.6 mg of pure product (4) ( ⁇ 21% yield).
  • Pd(Ph 3 ) 4 (438 mg, 0.35 mmol) was added to a vial containing biphenyl-DAP(Alloc)-Trt Resin (1) (500 mg, 0.35 mmol), Dimethyl barbituric acid (600 mg, 3.5 mmol) and PPh 3 (438 mg, 0.35 mmol) in DCM (11 ml) at rt under argon. The mixture was sparged with argon and shaken for 16 hours. The bright yellow mixture was drained and washed with DMF (8 ⁇ 10 ml) and DCM (8 ⁇ 10). The resin was dried in vacuo to give the deprotected DAP resin 2.
  • the combined TFA fractions were concentrated under reduced pressure to a reddish-brown solid.
  • the product, identified by LCMS, was purified by prep. HPLC using a 20 ⁇ 50 mm Ultro 120 C18 column running a 22 ml/min 4% gradient (AcCN/water, 0.1% TFA) for 16 min. The purified fractions were lyophilized to dryness. The solid residue was lyophilized again from CH 3 CN/water (1:1) (5 ml) give 4 mg of pure product as a white solid (3) ( ⁇ 9% yield).
  • the combined TFA fractions were concentrated under reduced pressure to a reddish-brown solid.
  • the product, identified by LCMS, was purified by prep. HPLC using a 20 ⁇ 50 mm Ultro 120 C18 column running a 22 mvmin 4% gradient (AcCN/water, 0.1% TFA) for 16 min. The purified fractions were lyophilized to dryness. The solid residue was lyophilized again from CH 3 CN/water (1:1) (5 ml) give 5 mg of pure product as a white solid (3) ( ⁇ 13% yield).
  • the reaction was cooled and diluted with water (500 ml) and hexane (100 ml). The pH was adjusted to pH 6-7. The white solid that formed was collected and washed with water (3 ⁇ 60 ml) and hexane (3 ⁇ 60 ml). The solid 3 was dried in vacuo yielding 17.3 g (approximately quantitative yield in 99% purity).
  • Triphenylphosphine (526 mg, 2.0 mmol) was added to a stirred solution of tolanyl-azido-Thr methyl ester (9) (726 mg, 2.0 mmol) at rt. After 3 days the reaction reached completion as judged by TLC (EtOAc/Hex (2:1)) and LCMS. The reaction was concentrated under reduced pressure to give an ivory colored solid. The crude amino-phosphine was dissolved in MeOH (20 ml) to give a pale yellow solution.
  • the crude product was dissolved in DMSO (8 ml) and purified by preparative HPLC (Ultro 120 C18 75 ⁇ 300 mm column) running a gradient (AcCN/water, 0.1% TFA) from 5 to 70% for 55 min. The purified fractions were pooled together and lyophilized to dryness. The product as the TFA salt was dissolved in AcCN/water (50:50) (100 ml), 1N aq. HCl (1 equivalent) and lyophilized again to give 325 mg of light yellow powder as the HCl salt (43% yield).
  • Triethylamine (3.5 mL, 20.0 mmol) was added to a stirred solution of 4-ethynylbenzoic acid 3 (910 mg, 6.22 mmol), H-Dap(Boc)-OMe hydrochloride (1.903 g, 7.47 nmnol), EDCI (1.432 g, 7.47 mmol), and HOBt (910 mg, 6.73 mmol) in DMF (50.0 mL).
  • the resin was pre-swelled by adding DCM and shaking for 30 min. The resin was drained, 20% piperdine was added in DMF, the resin was shaken 1.25 hours, and finally drained and washed in 2 ⁇ DMF and 2 ⁇ DCM. After draining comnpletely, 20% piperdine in DMF was added to attain cleavage in 1.25 hours. The resin was washed 4 ⁇ DMF, 4 ⁇ DCM and drained completely.
  • the amino acid (Fmoc-Thr tBu-OH, or Fmoc-DAP Boc-OH, 4 eq) was mixed, HATU (4 eq), DMF (60 ml) and Hunig's (8 eq) base were added and stirred for 2-3 min. The mixture was added to the resin and shaken 20-24 hours. Subsequently, the resin was drained and run with a standard wash (1 ⁇ DCM, 4 ⁇ DMF and 4 ⁇ DCM). The Fmoc was removed from the amino acid by adding 20% piperdine in DMF and shaken 1.25 hours, drained, and given the standard wash (1 ⁇ DCM, 4 ⁇ DMF and 4 ⁇ DCM).
  • the resin 1 (0.522 g, 0.365 mmol, 0.70 mmol) was swelled in DCM (5 mL) for 2 h and drained. The resin was treated with 20% piperidine in DMF (6 mL) for 1 hour, washed with DMF (4 ⁇ 6 mL) and DCM (4 ⁇ 6 mL) and drained completely.
  • the resin was drained, washed with DMF (3 ⁇ 2 mL), DCM (3 ⁇ 2 mL) and cleaved with 10% TFA/DCM (1.5 mL) for 20 min. The solution was collected and the resin was rinsed with additional 10% TFA/DCM (1.0 mL). The cleavage fractions were combined, treated with neat TFA (2.0 mL), stirred for 1 h at rt and concentrated by rotary evaporation to give a crude brown residue.
  • the resin 1 (1.330 g, 0.931 mmol, 0.70 mmol/g) was swelled in DCM (15 mL) for 2 h and drained. The resin was treated with 20% piperidine in DMF (20 mL) for 1 hour, washed with DMF (3 ⁇ 15 mL) and DCM (3 ⁇ 15 mL) and drained completely.
  • the resin was drained, washed with DMF (3 ⁇ 2 mL), DCM (3 ⁇ 2 mL) and cleaved with 10% TFA/DCM (2.0 mL) for 20 min. The solution was collected and the resin was rinsed with additional 10% TFA/DCM (1.0 mL). The cleavage fractions were combined, treated with neat TFA (3.0 mL), stirred for 1 h at rt and concentrated by rotary evaporation to give a crude brown residue.
  • the reaction was found complete by LCMS.
  • the reaction was cooled to rt and diluted with EtOAc/hexane (1:1) (300 ml).
  • the organic phase was washed with 1M HCl (2 ⁇ 50 ml), 1M NaOH (3 ⁇ 50 ml), water (2 ⁇ 50 ml), sat. brine (50 ml), dried with Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain 5.25 g of crude product as an oil.
  • the oil was treated with approximately 20 ml of a solution of 20% EtOAc/hexane that was heated to dissolve the residue.
  • Potassium hydroxide (3.700 g, 65.9 mmol) was dissolved in H 2 O (10 mL) and added to a solution of 4-(4-trimethylsilanyl-buta-1,3-diynyl)-benzoic acid methyl ester 3 (3.420 g, 13.5 mmol) in THF (26 mL) in the absence of light.
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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060154988A1 (en) * 2003-01-08 2006-07-13 University Of Washington Antibacterial agents
US20070142230A1 (en) * 2003-12-19 2007-06-21 Basf Aktiengesellschaft Benzoyl-substituted phenylalanineamides
WO2008154642A2 (fr) * 2007-06-12 2008-12-18 Achaogen, Inc. Agents antibactériens
US20100081661A1 (en) * 2006-07-24 2010-04-01 University Of Maryland, Baltimore Heme oxygenase inhibitors, screening methods for heme oxygenase inhibitors and methods of use of heme oxygenase inhibitors for antimicrobial therapy
WO2011005355A1 (fr) 2009-05-07 2011-01-13 Achaogen, Inc. Combinaisons comprenant un inhibiteur de lpxc et un antibiotique à utiliser dans le traitement d'infections induites par des bactéries à gram négatif
WO2012154204A1 (fr) 2010-11-10 2012-11-15 Achaogen, Inc. Dérivés d'acide hydroxamique et leur utilisation dans le traitement d'infections bactériennes
WO2013039947A1 (fr) 2011-09-12 2013-03-21 Achaogen, Inc. Polymorphes du n-((s)-3-amino-1-(hydroxyamino)-3-méthyl-1-oxobutan-2-yl)-4-(((1r,2r)-2-(hydroxyméthyl)cyclopropyl)buta-1,3-diynyl)benzamide
WO2014165075A1 (fr) 2013-03-12 2014-10-09 Achaogen, Inc. Agents antibactériens
US20160200682A1 (en) * 2013-08-16 2016-07-14 Duke University 2-Piperidinyl Substituted N,3-Dihydroxybutanamides
US9403758B2 (en) 2012-05-10 2016-08-02 Achaogen, Inc. Antibacterial agents
US9539305B1 (en) * 2014-03-14 2017-01-10 Fleurir Abx Llc Pristinamycin compositions, LpxC compositions, their improvements, and combinations thereof
US9738604B2 (en) 2010-09-03 2017-08-22 Duke University Ethynylbenzene derivatives
WO2017223349A1 (fr) 2016-06-23 2017-12-28 Achaogen, Inc. Agents antibactériens
US10189786B2 (en) 2013-08-16 2019-01-29 Duke University Antibacterial compounds
US10647664B2 (en) 2013-08-16 2020-05-12 Duke University Substituted hydroxamic acid compounds

Families Citing this family (127)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6777217B1 (en) 1996-03-26 2004-08-17 President And Fellows Of Harvard College Histone deacetylases, and uses related thereto
US20030129724A1 (en) 2000-03-03 2003-07-10 Grozinger Christina M. Class II human histone deacetylases, and uses related thereto
WO2004007444A2 (fr) * 2002-07-11 2004-01-22 Vicuron Pharmaceuticals, Inc. Derives de n-hydroxyamide ayant une activite anti-bacterienne
PL1651612T3 (pl) 2003-07-22 2012-09-28 Astex Therapeutics Ltd Związki 3,4-pochodne 1h-pirazolu i ich zastosowanie jako kinazy zależne od cyklin (cdk) i modulatory kinazy syntazy glikogenu-3 (gsk-3)
BRPI0415179A (pt) * 2003-10-07 2006-11-28 Renovis Inc derivados de amida como ligandos de canal de ìon e composições farmacêuticas e métodos de empregar as mesmas
US7638513B2 (en) 2004-06-02 2009-12-29 Schering Corporation Compounds for the treatment of inflammatory disorders
WO2006022442A1 (fr) * 2004-08-24 2006-03-02 Santen Pharmaceutical Co., Ltd. Nouveaux derives d’amides heterocycliques ayant une activite d’inhibition de la dihydroorotate deshydrogenase
US7776869B2 (en) 2004-10-18 2010-08-17 Amgen Inc. Heteroaryl-substituted alkyne compounds and method of use
US8404718B2 (en) 2005-01-21 2013-03-26 Astex Therapeutics Limited Combinations of pyrazole kinase inhibitors
CA2595522C (fr) 2005-01-26 2013-09-10 Allergan, Inc. Amides d'acide 3-aryl-3-hydroxy-2-amino-propionique, amides d'acide 3-heteroaryl-3-hydroxy-2-amino-propionique et composes associes presentant une activite analgesique et/ou immunostimulante
US20080300243A1 (en) * 2005-02-28 2008-12-04 Kelly Michael G Amide Derivatives as Ion-Channel Ligands and Pharmaceutical Compositions and Methods of Using the Same
US7576099B2 (en) 2005-02-28 2009-08-18 Renovis, Inc. Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same
CA2937005A1 (fr) 2005-03-22 2006-09-28 President And Fellows Of Harvard College Traitement de troubles lies a la degradation de proteines
PE20100809A1 (es) * 2005-07-11 2011-01-07 Wyeth Llc Inhibidores de glutamato de metaloproteinasas de matriz y agrecanasas
JP4961773B2 (ja) * 2005-07-29 2012-06-27 住友ベークライト株式会社 芳香族カルボン酸及びその酸ハロゲン化物
CA2634005C (fr) * 2005-12-15 2012-01-03 Vicuron Pharmaceuticals Inc. Derives de n-hydroxyamide possedant une activite antibacterienne
US8222423B2 (en) * 2006-02-14 2012-07-17 Dana-Farber Cancer Institute, Inc. Bifunctional histone deacetylase inhibitors
CA2654540C (fr) 2006-05-03 2017-01-17 President And Fellows Of Harvard College Inhibiteurs d'histone desacetylases et de tubuline desacetylases
KR20090010092A (ko) 2006-05-30 2009-01-28 아스트라제네카 아베 Ｄｇａｔ1 억제제로서의 1,3,4-옥사디아졸 유도체
DE102006033321A1 (de) * 2006-07-17 2008-01-24 Westfälische Wilhelms-Universität Münster Medizinische Verwendung von N-Phenylpropenoyl-Aminosäurederivaten und verwandten Verbindungen
US7981874B2 (en) 2006-07-20 2011-07-19 Merck Sharp & Dohme Corp. Phosphorus derivatives as histone deacetylase inhibitors
TW200821276A (en) * 2006-08-18 2008-05-16 Leo Pharma As Substituted acetylenic compounds useful for the treatment of diseases
CN101528711A (zh) 2006-08-31 2009-09-09 先灵公司 可用作抗细菌剂的乙内酰脲衍生物
AP2009004840A0 (en) * 2006-10-13 2009-04-30 Xtl Biopharmaceuticals Ltd Compounds and methods for treatment of HCV
CA2668070A1 (fr) 2006-10-30 2008-05-08 Chroma Therapeutics Ltd. Hydroxamates en tant qu'inhibiteurs de l'histone desacetylase
US8563573B2 (en) 2007-11-02 2013-10-22 Vertex Pharmaceuticals Incorporated Azaindole derivatives as CFTR modulators
WO2008105515A1 (fr) * 2007-02-28 2008-09-04 Taisho Pharmaceutical Co., Ltd. Nouveau dérivé d'acide hydroxamique
WO2008112205A1 (fr) 2007-03-09 2008-09-18 Renovis, Inc. Composés de bicyclohétéroaryle utilisés comme modulateurs de p2x7 et leurs utilisations
CN101417937B (zh) * 2007-10-23 2013-05-29 中山大学 β-醛酮类抗菌化合物及其应用
US20110015158A1 (en) 2007-12-11 2011-01-20 Viamet Pharmaceuticals, Inc. Metalloenzyme inhibitors using metal binding moieties in combination with targeting moieties
AU2008339570B2 (en) 2007-12-20 2012-04-12 Astrazeneca Ab Carbamoyl compounds as DGAT1 inhibitors 190
US20110212078A1 (en) 2008-06-25 2011-09-01 Reddy Panduranga Adulla P Synthesis and use of heterocyclic antibacterial agents
CA2731730C (fr) 2008-07-23 2017-06-13 President And Fellows Of Harvard College Inhibiteurs de desacetylase et leurs utilisations
CA2733390A1 (fr) * 2008-08-01 2010-02-04 Bioxiness Pharmaceuticals, Inc. Analogues de methionine, et procedes d'utilisation de ceux-ci
EP2315746A1 (fr) * 2008-08-04 2011-05-04 Schering Corporation Dérivés d'urée en tant qu'agents antibactériens
US8273900B2 (en) 2008-08-07 2012-09-25 Novartis Ag Organic compounds
US8372885B2 (en) * 2008-09-17 2013-02-12 Novartis Ag Organic compounds and their uses
US8722686B2 (en) 2008-09-19 2014-05-13 Pfizer Inc. Hydroxamic acid derivatives useful as antibacterial agents
EP2361242B1 (fr) 2008-10-17 2018-08-01 Oryzon Genomics, S.A. Inhibiteurs de l'oxydase et leur utilisation
EP2177502A1 (fr) * 2008-10-17 2010-04-21 Oryzon Genomics, S.A. Composants et leur utilisation
WO2010084160A1 (fr) 2009-01-21 2010-07-29 Oryzon Genomics S.A. Dérivés de phénylcyclopropylamine et leur utilisation médicale
AU2010252354B2 (en) * 2009-05-25 2016-05-19 Chiesi Farmaceutici S.P.A. A therapeutic combination comprising a pulmonary surfactant and a steroid
KR20120037939A (ko) 2009-06-19 2012-04-20 아스트라제네카 아베 Ｄｇａｔ１의 억제제로서 피라진 카르복사미드
WO2011019393A2 (fr) 2009-08-11 2011-02-17 President And Fellows Of Harvard College Inhibiteurs de hdac classe- et isoforme-spécifiques et utilisations de ceux-ci
FR2950057B1 (fr) 2009-09-17 2011-08-26 Galderma Res & Dev Nouveaux composes benzene-carboxylamides, leur procede de synthese et leur utilisation en medecine ainsi qu'en cosmetique
FR2950056B1 (fr) 2009-09-17 2011-08-26 Galderma Res & Dev Nouveaux composes benzene-carboxylamides, leur procede de synthese et leur utilisation en medecine ainsi qu'en cosmetique
US8859555B2 (en) 2009-09-25 2014-10-14 Oryzon Genomics S.A. Lysine Specific Demethylase-1 inhibitors and their use
EP2486002B1 (fr) 2009-10-09 2019-03-27 Oryzon Genomics, S.A. Acétamides d'hétéroaryl- et aryl-cyclopropylamine substitués et leur utilisation
WO2011073845A1 (fr) 2009-12-16 2011-06-23 Pfizer Inc. Dérivés d'acide hydroxamique à liaison n, utiles comme agents antibactériens
WO2011106574A2 (fr) 2010-02-24 2011-09-01 Oryzon Genomics, S.A. Inhibiteurs destinés à une utilisation antivirale
WO2011106106A2 (fr) 2010-02-24 2011-09-01 Oryzon Genomics, S.A. Inhibiteurs de lysine déméthylase pour lutter contre les maladies et troubles associés à l'hepadnaviridae
US8802868B2 (en) 2010-03-25 2014-08-12 Vertex Pharmaceuticals Incorporated Solid forms of (R)-1(2,2-difluorobenzo[D][1,3]dioxo1-5-yl)-N-(1-(2,3-dihydroxypropyl-6-fluoro-2-(1-hydroxy-2-methylpropan2-yl)-1H-Indol-5-yl)-Cyclopropanecarboxamide
CA2796726C (fr) 2010-04-19 2021-02-16 Oryzon Genomics S.A. Inhibiteurs de la demethylase-1 specifiques de la lysine, et leur utilisation
SG184958A1 (en) * 2010-04-20 2012-11-29 Taisho Pharmaceutical Co Ltd Novel hydroxamic acid derivative
CA2797118C (fr) 2010-04-22 2021-03-30 Vertex Pharmaceuticals Incorporated Procede de production de composes de cycloalkylcarboxamido-indole
RS57331B1 (sr) 2010-07-29 2018-08-31 Oryzon Genomics Sa Inhibitori demetilaze za lsd1 zasnovani na arilciklopropilaminu i njihova medicinska upotreba
US9006449B2 (en) 2010-07-29 2015-04-14 Oryzon Genomics, S.A. Cyclopropylamine derivatives useful as LSD1 inhibitors
WO2012045883A1 (fr) 2010-10-08 2012-04-12 Oryzon Genomics S.A. Inhibiteurs d'oxydases de cyclopropylamine
WO2012072713A2 (fr) 2010-11-30 2012-06-07 Oryzon Genomics, S.A. Inhibiteurs de la déméthylase spécifique de la lysine pour des maladies et troubles liés aux flaviviridés
SG191844A1 (en) 2011-01-04 2013-08-30 Novartis Ag Indole compounds or analogues thereof useful for the treatment of age-related macular degeneration (amd)
EP2712315B1 (fr) 2011-02-08 2021-11-24 Oryzon Genomics, S.A. Inhibiteurs de lysine déméthylase pour des troubles myéloprolifératifs
US8877940B2 (en) 2011-02-22 2014-11-04 Institut National De La Recherche Scientifique Antibiotic tolerance inhibitors
UA107423C2 (en) 2011-03-07 2014-12-25 Pfizer Fluoro-pyridinone derivatives useful as antibacterial agents
KR20130140164A (ko) 2011-04-08 2013-12-23 화이자 인코포레이티드 항박테리아제로서 유용한 이미다졸, 피라졸 및 트라이아졸 유도체
DK2694488T3 (en) 2011-04-08 2014-12-15 Pfizer Isoxazole derivatives useful as antibacterial SUBSTANCES
JP6006609B2 (ja) * 2011-10-19 2016-10-12 大正製薬株式会社 新規なヒドロキサム酸誘導体を含有する医薬
CN104203914B (zh) 2011-10-20 2017-07-11 奥瑞泽恩基因组学股份有限公司 作为lsd1抑制剂的(杂)芳基环丙胺化合物
US9469597B2 (en) 2011-10-20 2016-10-18 Oryzon Genomics S.A. (Hetero)aryl cyclopropylamine compounds as LSD1 inhibitors
EP2814807A4 (fr) * 2012-02-16 2015-10-07 Rqx Pharmaceuticals Inc Antibiotiques à peptide linéaire
US9388199B2 (en) 2012-06-28 2016-07-12 Novartis Ag Pyrrolidine derivatives and their use as complement pathway modulators
JP6155332B2 (ja) 2012-06-28 2017-06-28 ノバルティス アーゲー ピロリジン誘導体、および補体経路調節因子としてのその使用
ES2710491T3 (es) 2012-06-28 2019-04-25 Novartis Ag Moduladores de la vía del complemento y sus usos
CN104640855B (zh) 2012-06-28 2017-08-29 诺华股份有限公司 补体途经调节剂及其用途
JP6154897B2 (ja) 2012-06-28 2017-06-28 ノバルティス アーゲー ピロリジン誘導体、および補体経路調節因子としてのその使用
EA201590200A1 (ru) 2012-07-12 2015-08-31 Новартис Аг Модуляторы пути активации комплемента и их применение
CN103012207B (zh) * 2012-12-29 2015-05-27 吉首大学 二芳基丙酰-n-甲基氧肟酸类尿素酶抑制剂及其合成和用途
RS58930B1 (sr) 2013-03-15 2019-08-30 Fujifilm Toyama Chemical Co Ltd Novi derivati hidroksaminske kiseline ili njihova so
WO2014160649A1 (fr) * 2013-03-29 2014-10-02 Novartis Ag Dérivés d'acide hydroxamique utilisés comme inhibiteurs de lpxc pour le traitement d'infections bactériennes
GB201315335D0 (en) 2013-08-29 2013-10-09 Of Singapore Amino diacids containing peptide modifiers
KR102447581B1 (ko) 2014-04-15 2022-09-28 버텍스 파마슈티칼스 인코포레이티드 낭포성 섬유증 막전도 조절자 매개 질환 치료용 약제학적 조성물
ES2687393T3 (es) 2014-04-22 2018-10-25 Novartis Ag Derivados del ácido hidroxámico de isoxazolina como inhibidores de LpxC
US10123990B2 (en) 2014-09-12 2018-11-13 Toyama Chemical Co., Ltd. Method for using novel hydroxamic acid derivative and antibacterial substance in combination
MX2017002967A (es) 2014-09-12 2017-05-30 Toyama Chemical Co Ltd Composicion farmaceutica novedosa que contiene derivado de acido hidroxamico o sal del mismo.
CN104341475A (zh) * 2014-10-11 2015-02-11 吉首大学 利奈唑胺-腺苷型多靶点抗菌化合物及其制法和用途
CN104262433B (zh) * 2014-10-11 2016-06-15 吉首大学 噁二唑-腺苷型化合物作为TyrRS抑制剂及其制法和用途
CN104327140B (zh) * 2014-10-11 2016-06-15 吉首大学 噁唑烷酮-腺苷型多靶点抗菌化合物及其制法和用途
CN104341476A (zh) * 2014-10-11 2015-02-11 吉首大学 利奈唑胺-肌苷型多靶点抗菌化合物及其制法和用途
CN104231024B (zh) * 2014-10-11 2016-06-15 吉首大学 噁二唑-肌苷型化合物作为TyrRS抑制剂及其制法和用途
US9549916B2 (en) 2014-12-16 2017-01-24 Novartis Ag Isoxazole hydroxamic acid compounds as LpxC inhibitors
CN105777464B (zh) * 2014-12-26 2020-09-29 中国科学院上海药物研究所 异羟肟酸衍生物及其制备方法和应用
CA2986083A1 (fr) 2015-06-11 2016-12-15 Basilea Pharmaceutica International AG Inhibiteurs de la pompe a efflux et utilisations therapeutiques correspondantes
WO2017042099A1 (fr) * 2015-09-09 2017-03-16 Basilea Pharmaceutica Ag Inhibiteurs de pompes à efflux et leurs utilisations thérapeutiques
WO2017083434A1 (fr) 2015-11-09 2017-05-18 Forge Therapeutics, Inc. Composés à base de pyrone pour traiter les infections bactériennes
US10414735B2 (en) 2015-11-09 2019-09-17 Forge Therapeutics, Inc. Substituted hydroxypyrimidinones for treating bacterial infections
JP2019501896A (ja) * 2015-12-08 2019-01-24 グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッドＧｌａｘｏｓｍｉｔｈｋｌｉｎｅ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ Ｄｅｖｅｌｏｐｍｅｎｔ Ｌｉｍｉｔｅｄ 抗菌化合物としての置換ベンザジノン
US10590084B2 (en) 2016-03-09 2020-03-17 Blade Therapeutics, Inc. Cyclic keto-amide compounds as calpain modulators and methods of production and use thereof
CN109195947B (zh) * 2016-04-18 2022-03-04 维沃里翁治疗股份有限公司 安眠蛋白α和β的新型抑制剂
US11034649B2 (en) * 2016-04-25 2021-06-15 Duke University Benzoylglycine derivatives and methods of making and using same
US10071973B2 (en) 2016-06-14 2018-09-11 Novartis Ag Crystalline isoxazole hydroxamic acid compounds
MX2018016102A (es) 2016-06-21 2019-08-29 Orion Ophthalmology LLC Derivados alifaticos de prolinamida.
US10526315B2 (en) 2016-06-21 2020-01-07 Orion Ophthalmology LLC Carbocyclic prolinamide derivatives
WO2017222915A1 (fr) 2016-06-21 2017-12-28 Inception 4, Inc. Dérivés hétérocycliques de prolinamide
AU2017292646A1 (en) 2016-07-05 2019-02-07 Blade Therapeutics, Inc. Calpain modulators and therapeutic uses thereof
EP3523294A4 (fr) 2016-09-28 2021-01-13 Blade Therapeutics, Inc. Modulateurs de calpain et leurs utilisations thérapeutiques
CN110300578B (zh) * 2016-12-23 2022-12-13 英特维特国际股份有限公司 用于治疗牛或猪呼吸道疾病的化合物
US11034650B2 (en) * 2016-12-23 2021-06-15 Intervet Inc. Compounds useful for treating a Mannheimia haemolytica or Histophilus somni infection
EP3621962A4 (fr) 2017-05-10 2020-12-09 Forge Therapeutics, Inc. Composés antibactériens
US11666555B2 (en) 2017-05-17 2023-06-06 Drexel University RelA inhibitors for biofilm disruption
JOP20200001A1 (ar) 2017-07-11 2022-10-30 Vertex Pharma كاربوكسأميدات بوصفها معدلات لقنوات الصوديوم
CN111526873A (zh) 2017-07-27 2020-08-11 生物曼迪克斯有限责任公司 用于调节微生物定殖的经取代的二苯乙炔
JP7412004B2 (ja) * 2018-02-10 2024-01-12 山東亨利醫藥科技有限責任公司 抗菌剤化合物
CN113166077A (zh) * 2018-09-20 2021-07-23 福至治疗公司 抗细菌化合物
EP3873605A1 (fr) 2018-10-30 2021-09-08 Gilead Sciences, Inc. Composés pour inhibition de l'intégrine alpha4beta7
CN112969687A (zh) 2018-10-30 2021-06-15 吉利德科学公司 作为α4β7整合素抑制剂的喹啉衍生物
KR102652797B1 (ko) 2018-10-30 2024-04-02 길리애드 사이언시즈, 인코포레이티드 알파4베타7 인테그린의 억제를 위한 화합물
AU2019373244B2 (en) 2018-10-30 2022-05-26 Gilead Sciences, Inc. Imidazopyridine derivatives as alpha4beta7 integrin inhibitors
JP2022521600A (ja) * 2019-02-22 2022-04-11 シラ セラピューティック インコーポレイティッド 吸入可能な治療剤
EP4013499A1 (fr) 2019-08-14 2022-06-22 Gilead Sciences, Inc. Composés pour l'inhibition de l'intégrine alpha 4 bêta 7
CN110563611B (zh) 2019-09-19 2021-02-02 中国医学科学院医药生物技术研究所 一种异羟肟酸类衍生物及其制备方法和应用
IL293592A (en) 2019-12-06 2022-08-01 Vertex Pharma Transduced tetrahydrofurans as sodium channel modulators
CN111254091B (zh) * 2020-01-20 2022-04-19 浙江工业大学 一种嗜麦芽窄食单胞菌gyh及其在降解氯代烃类污染物中的应用
WO2021195260A1 (fr) 2020-03-25 2021-09-30 Forge Therapeutics, Inc. Inhibiteur de lpxc et procédés de fabrication
BR112022025037A2 (pt) 2020-06-10 2023-02-14 Aligos Therapeutics Inc Compostos antivirais para tratar infecções por coronavírus, picornavírus e norovírus
EP4347031A1 (fr) 2021-06-04 2024-04-10 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hétéro)aryl) tétrahydrofuran carboxamides utilisés en tant que modulateurs de canaux sodiques
IL309732A (en) 2021-07-09 2024-02-01 Aligos Therapeutics Inc Antiviral compounds
WO2023128033A1 (fr) * 2021-12-31 2023-07-06 (주)앰틱스바이오 Nouvelle composition antifongique pour inhiber la production de biofilm de champignons infectieux
CN116730870B (zh) * 2023-08-08 2023-10-13 中国医学科学院医药生物技术研究所 异羟肟酸类化合物或其可药用盐、及其用途和制备方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5925659A (en) * 1996-05-07 1999-07-20 Merck & Co., Inc. Antibacterial agents
US6228988B1 (en) * 1995-02-24 2001-05-08 British Biotech Pharmaceuticals, Ltd. Synthesis of hydroxamic acid derivatives
US6281245B1 (en) * 1996-10-28 2001-08-28 Versicor, Inc. Methods for solid-phase synthesis of hydroxylamine compounds and derivatives, and combinatorial libraries thereof
US20010053555A1 (en) * 1996-10-28 2001-12-20 Dinesh V. Patel Methods for solid-phase synthesis of hydroxylamine compounds and derivatives and combinatorial libraries thereof
US6358987B1 (en) * 1997-07-18 2002-03-19 British Biotech Pharmaceuticals Limited Metalloproteinase inhibitors

Family Cites Families (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US628988A (en) * 1898-11-21 1899-07-18 F B Fargo & Company Combined churn and butter-worker.
US2772281A (en) * 1954-12-23 1956-11-27 Merck & Co Inc Synthesis of 4-amino-3-isoxazolidone and its derivatives
CA2227237C (fr) * 1995-07-26 2005-12-13 Pfizer Inc. Derives d'acide hydroxamique n-(aroyl)glycine et composes apparentes
WO1997045402A1 (fr) * 1996-05-24 1997-12-04 Ono Pharmaceutical Co., Ltd. Derives de phenylsulfonamide
WO1998015525A1 (fr) * 1996-10-07 1998-04-16 Sumitomo Pharmaceuticals Co., Ltd. Acides hydroxamiques
AR016751A1 (es) * 1996-11-22 2001-08-01 Athena Neurosciences Inc Metodo para inhibir la liberacion del peptido beta-amiloide en una celula, composicion farmaceutica y compuestos utiles en dicho metodo
NZ503945A (en) * 1997-07-31 2002-11-26 Procter & Gamble Metalloprotease-inhibiting amide derivatives
BR9907689A (pt) 1998-02-07 2000-11-14 British Biotech Pharm Agentes antibacterianos
JP2002520333A (ja) * 1998-07-08 2002-07-09 ツシェシェ，ハラルト アミノマロン酸誘導体及びそのペプチド骨格を変性した誘導体である化合物又はそれを含む化合物
GB9901863D0 (en) 1999-01-29 1999-03-17 British Biotech Pharm Antibacterial agents
JP2002541138A (ja) * 1999-04-02 2002-12-03 デュポン ファーマシューティカルズ カンパニー マトリックスメタロプロテアーゼ、ＴＮＦ−α、およびアグレカナーゼの阻害剤としての新規アミド誘導体
JP2002541197A (ja) 1999-04-09 2002-12-03 ブリティッシュ バイオテック ファーマシューティカルズ リミテッド 抗菌剤
WO2002030873A1 (fr) * 2000-10-10 2002-04-18 Fujisawa Pharmaceutical Co., Ltd. Inhibiteur des mmp
US7323596B2 (en) * 2000-12-21 2008-01-29 De Novo Pharmaceuticals Ltd. Antimicrobial agents
GB0115195D0 (en) 2001-06-21 2001-08-15 Bae Systems Plc Split-pin drill jig
WO2003004488A1 (fr) * 2001-07-03 2003-01-16 Chiron Corporation Composes d'indazole benzimidazole utilises comme inhibiteurs de tyrosine et de serine/threonine kinase
WO2004007444A2 (fr) 2002-07-11 2004-01-22 Vicuron Pharmaceuticals, Inc. Derives de n-hydroxyamide ayant une activite anti-bacterienne
CN102267924A (zh) * 2003-01-08 2011-12-07 诺华疫苗和诊断公司 抗菌剂

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6228988B1 (en) * 1995-02-24 2001-05-08 British Biotech Pharmaceuticals, Ltd. Synthesis of hydroxamic acid derivatives
US5925659A (en) * 1996-05-07 1999-07-20 Merck & Co., Inc. Antibacterial agents
US6281245B1 (en) * 1996-10-28 2001-08-28 Versicor, Inc. Methods for solid-phase synthesis of hydroxylamine compounds and derivatives, and combinatorial libraries thereof
US20010053555A1 (en) * 1996-10-28 2001-12-20 Dinesh V. Patel Methods for solid-phase synthesis of hydroxylamine compounds and derivatives and combinatorial libraries thereof
US6358987B1 (en) * 1997-07-18 2002-03-19 British Biotech Pharmaceuticals Limited Metalloproteinase inhibitors

Cited By (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100324025A1 (en) * 2003-01-08 2010-12-23 University Of Washington Antibacterial Agents
US8084615B2 (en) 2003-01-08 2011-12-27 University Of Washington Antibacterial agents
US20110172174A1 (en) * 2003-01-08 2011-07-14 Novartis Vaccines And Diagnostics Inc. Antibacterial agents
US7358359B2 (en) 2003-01-08 2008-04-15 University Of Washington Antibacterial agents
US20080269221A1 (en) * 2003-01-08 2008-10-30 Novartis Vaccines And Diagnostics, Inc. Antibacterial agents
US20060154988A1 (en) * 2003-01-08 2006-07-13 University Of Washington Antibacterial agents
US20090163496A1 (en) * 2003-01-08 2009-06-25 University Of Washington Antibacterial agents
US8153843B2 (en) 2003-01-08 2012-04-10 University Of Washington Antibacterial agents
US20090247506A1 (en) * 2003-01-08 2009-10-01 Andersen Niels H Antibacterial agents
US8101640B2 (en) 2003-01-08 2012-01-24 Novartis Vaccines And Diagnostics, Inc. Antibacterial agents
US7989660B2 (en) 2003-01-08 2011-08-02 Novartis Vaccines And Diagnostics, Inc. Antibacterial agents
US20070244197A1 (en) * 2003-01-08 2007-10-18 University Of Washington Antibacterial agents
US20070142230A1 (en) * 2003-12-19 2007-06-21 Basf Aktiengesellschaft Benzoyl-substituted phenylalanineamides
US7687435B2 (en) * 2003-12-19 2010-03-30 Basf Aktiengesellschaft Benzoyl-substituted phenylalanineamides
US8450368B2 (en) 2006-07-24 2013-05-28 University Of Maryland, Baltimore Heme oxygenase inhibitors, screening methods for heme oxygenase inhibitors and methods of use of heme oxygenase inhibitors for antimicrobial therapy
US20100081661A1 (en) * 2006-07-24 2010-04-01 University Of Maryland, Baltimore Heme oxygenase inhibitors, screening methods for heme oxygenase inhibitors and methods of use of heme oxygenase inhibitors for antimicrobial therapy
US20100190766A1 (en) * 2007-06-12 2010-07-29 Achaogen, Inc. Antibacterial agents
US20150018331A1 (en) * 2007-06-12 2015-01-15 Achaogen, Inc. Antibacterial agents
WO2008154642A3 (fr) * 2007-06-12 2009-07-09 Achaogen Inc Agents antibactériens
WO2008154642A2 (fr) * 2007-06-12 2008-12-18 Achaogen, Inc. Agents antibactériens
US9617256B2 (en) * 2007-06-12 2017-04-11 Achaogen, Inc. Antibacterial agents
EP2662353A2 (fr) 2007-06-12 2013-11-13 Achaogen, Inc. Agents antibactériens
EP2662353A3 (fr) * 2007-06-12 2014-04-02 Achaogen, Inc. Agents antibactériens
WO2011005355A1 (fr) 2009-05-07 2011-01-13 Achaogen, Inc. Combinaisons comprenant un inhibiteur de lpxc et un antibiotique à utiliser dans le traitement d'infections induites par des bactéries à gram négatif
US9738604B2 (en) 2010-09-03 2017-08-22 Duke University Ethynylbenzene derivatives
US10597361B2 (en) 2010-09-03 2020-03-24 Duke University Ethynylbenzene derivatives
WO2012154204A1 (fr) 2010-11-10 2012-11-15 Achaogen, Inc. Dérivés d'acide hydroxamique et leur utilisation dans le traitement d'infections bactériennes
WO2013039947A1 (fr) 2011-09-12 2013-03-21 Achaogen, Inc. Polymorphes du n-((s)-3-amino-1-(hydroxyamino)-3-méthyl-1-oxobutan-2-yl)-4-(((1r,2r)-2-(hydroxyméthyl)cyclopropyl)buta-1,3-diynyl)benzamide
US9403758B2 (en) 2012-05-10 2016-08-02 Achaogen, Inc. Antibacterial agents
US9701622B2 (en) 2012-05-10 2017-07-11 Achaogen, Inc. Antibacterial agents
WO2014165075A1 (fr) 2013-03-12 2014-10-09 Achaogen, Inc. Agents antibactériens
US20160200682A1 (en) * 2013-08-16 2016-07-14 Duke University 2-Piperidinyl Substituted N,3-Dihydroxybutanamides
US9908851B2 (en) * 2013-08-16 2018-03-06 Duke University 2-piperidinyl substituted N,3-dihydroxybutanamides
US10189786B2 (en) 2013-08-16 2019-01-29 Duke University Antibacterial compounds
US10647664B2 (en) 2013-08-16 2020-05-12 Duke University Substituted hydroxamic acid compounds
US9872884B1 (en) 2014-03-14 2018-01-23 Fleurir Abx Llc Pristinamycin compositions, LPXC compositions, their improvements, and combinations thereof
US10307457B1 (en) 2014-03-14 2019-06-04 Fleurir Abx Llc Pristinamycin compositions, LpxC compositions, their improvements, and combinations thereof
US9539305B1 (en) * 2014-03-14 2017-01-10 Fleurir Abx Llc Pristinamycin compositions, LpxC compositions, their improvements, and combinations thereof
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US11951148B1 (en) 2014-03-14 2024-04-09 Fleurir Abx, Llc Pristinamycin compositions, LpxC compositions, their improvements, and combinations thereof
WO2017223349A1 (fr) 2016-06-23 2017-12-28 Achaogen, Inc. Agents antibactériens

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US7358359B2 (en) 2008-04-15
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US20060154988A1 (en) 2006-07-13
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US20070244197A1 (en) 2007-10-18
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