WO2001036426A1 - Pyridinones pour le traitement et la prevention d'infections bacteriennes - Google Patents

Pyridinones pour le traitement et la prevention d'infections bacteriennes Download PDF

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WO2001036426A1
WO2001036426A1 PCT/US2000/031879 US0031879W WO0136426A1 WO 2001036426 A1 WO2001036426 A1 WO 2001036426A1 US 0031879 W US0031879 W US 0031879W WO 0136426 A1 WO0136426 A1 WO 0136426A1
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substituted
aryl
alkynyl
alkenyl
heteroaryl
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PCT/US2000/031879
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WO2001036426B1 (fr
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Fredrik Almqvist
Hans Emtenas
Scott J. Hultgren
Jerome S. Pinkner
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Washington University
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Priority to AU19235/01A priority Critical patent/AU1923501A/en
Priority to EP00982170A priority patent/EP1233967A4/fr
Priority to US10/130,453 priority patent/US6841559B1/en
Priority to CA002390658A priority patent/CA2390658A1/fr
Publication of WO2001036426A1 publication Critical patent/WO2001036426A1/fr
Publication of WO2001036426B1 publication Critical patent/WO2001036426B1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/04—1,3-Thiazines; Hydrogenated 1,3-thiazines
    • C07D279/06—1,3-Thiazines; Hydrogenated 1,3-thiazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

  • the invention relates to novel pyridinones useful for treating infections caused by Gram-negative bacteria and to novel methods for synthesizing and using these pyridinones.
  • Pili are hair-like adhesive organelles found on a wide variety of pathogenic bacteria that are employed to adhere to and colonize host tissues by binding to receptors in the host tissues.
  • Pili are heteropolymeric surface fibers with an adhesive tip and consist of two major sub-assemblies, the pilus rod and the tip fibrillum.
  • the pilus rod is a thick rigid rod made up of repeating subunits arranged in a right handed helical cylinder whereas the tip fibrillum is a thin, flexible tip fiber extending from the distal end of the pilus rod and is composed primarily of repeating subunits arranged in an open helical configuration.
  • Periplasmic chaperones are involved in a molecular mechanism necessary for guiding biogenesis of adhesive organelles in Gram-negative bacteria.
  • periplasmic chaperones facilitate the assembly of competent complexes from subunits.
  • the periplasmic chaperones are so critical to the functioning of the pili that in the absence of an interaction with the chaperone, pilus subunits aggregate and are proteolytically degraded.
  • Pathogenic Gram-negative bacteria include organisms such as Escherichia coli, Haemophilus influenzae, Salmonella enteriditis, Salmonella typhimirium, Bordetella pertussis, Yersinia pestis, Yersinia enter ocolitica, Helicobacter pylori and Klebsiella pneumoniae.
  • the prevention or inhibition of normal pilus assembly in Gram-negative bacterium impacts the pathogenicity of the bacterium by preventing the bacterium from infecting host tissues.
  • Drugs that interfere with the assembly of pili should effectively disable pathogens responsible for a wide variety of Gram-negative infections, such as those responsible for bladder, kidney and middle ear infections as well as food poisoning, gastric ulcers, diarrhea, meningitis, and other illnesses. Drugs that interfere with the assembly of pili are known collectively as pilicides.
  • pilicides that has been developed are those with a ⁇ -lactam-like structure. These pilicides are described in patent application No. 9/252,792, entitled ⁇ - Lactam-Like Chaperone Inhibitors, invented by Scott Hultgren/Fredrik Almqvist.
  • One such method involves the oxidation of pyridinium salts to the corresponding 2-pyridinones with ferricyanide under basic conditions. Although the synthesis is straightforward, the method is limited by the availability of the corresponding pyridinium salts. Many 2-pyridinone methodologies incorporate the Michael addition, the nucleophilic addition of carbanions to ⁇ , ⁇ - unsaturated ketones, as a key step in the formation of six-membered rings. Cycloaddition procedures have also been employed to synthesize 2-pyridinones.
  • Solid phase synthesis has been employed in the preparation of certain pyridinones.
  • solid phase synthesis possesses the additional advantage of the simplicity of purifying compounds produced by it in addition to the advantages of being regioselective and functional group tolerant.
  • Solid phase synthesis is particularly useful in the making of libraries for biological testing and biological uses; solid phase synthesis is amenable to the use of automation by machines.
  • the present invention provides a novel class of pyridinones which are effective in treating or preventing Gram-negative bacterial infections. These pyridinones are highly stable and easily derivatized. Without intending to be bound by any theory, applicants believe that the compounds of the invention exert their effects by interfering with the function of chaperones required for the assembly of pili from pilus subunits in diverse Gram-negative bacteria. Such interference is particularly effective since the formation of pili is essential to bacterial pathogenicity and since the production of the pilus subunits in the absence of chaperones is known to be directly toxic.
  • the novel pyridinones of the invention comprise pyridinones having the formula:
  • Z comprises S, SO, SO 2 , O, P, PO, PO 2 , CH 2 or CR 2 ;
  • R t comprises oxo;
  • R 2 comprises (CH 2 ) n A wherein n is a natural number between 0 and 5 and A comprises hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl or substituted heteroaryl;
  • R 3 comprises (CH 2 ) m D wherein m is a natural number between 0 and 5 and D comprises hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl or substituted heteroaryl;
  • R 4 comprises CO 2 Y, B(OY) 2 , CHO, CH 2 OY, CH(CO 2 Y) 2 , PO(O
  • Pyridinones (C) and (E) of the present invention can be easily derivatized to further novel pyridinones having the formula:
  • R l5 R 2 , R 3 , R 4 and Z are as previously defined and R 5 comprises halogen, nitrile, C0 2 H, CH 2 NH 2 , cyclic CHN 4 a lactam, NO 2 , (trimethylsilyl)acetylene, G wherein G comprises alkyl, alkenyl, alkynyl, aryl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl, or (CH) 2 E wherein E comprises COR, CO 2 R, CHO, or CN and R comprises alkyl, alkenyl, alkynyl, aryl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl or substituted heteroaryl.
  • R comprises oxo
  • R 2 comprises (CH 2 ) n A wherein n is a natural number between 0 and 5 and A comprises alkyl, alkenyl, alkynyl, aryl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl or substituted heteroaryl
  • R 3 comprises (CH 2 ) m D wherein m is a natural number between 0 and 5 and D comprises hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl or substituted heteroaryl
  • R 4 comprises CO 2 Y, B(OY) 2 , CHO, CH 2 OY, CH(CO 2 Y) 2 , PO(OY) 2 wherein Y comprises hydrogen
  • R 2 comprises (CH 2 ) n A wherein n is a natural number between 0 and 5 and A comprises hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl or substituted heteroaryl;
  • R 3 comprises (CH 2 ) m D wherein m is a natural number between 0 and 5 and D comprises hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl or substituted heteroaryl;
  • R 4 comprises CO 2 Y, B(OY) 2 , CHO, CH 2 OY, CH(CO 2 Y) 2 , PO(OY) 2 wherein Y comprises hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, substituted alkyl, substituted
  • CHN 4 a lactam, NO 2 , (trimethylsilyl)acetylene, G wherein G comprises alkenyl, alkynyl, aryl, substituted alkenyl, substituted alkynyl, substituted aryl, or (CH) 2 E wherein E comprises COR, CO 2 R, CHO, or CN and R comprises alkyl, alkenyl, alkynyl, aryl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl or substituted heteroaryl.
  • the invention is also directed to novel methods of synthesizing substituted 2- pyridinones (C) and (E).
  • the first of these methods is a preparation in solution reacting a Meldrum's acid derivative (A) (a derivative of 5-acyl-2,2-dimethyl-l,3-dioxane-4,6-dione) with imines (B) or (D) in acidic conditions.
  • the second of these methods is a solid phase synthesis in which a imine bound to a resin is prepared. A Meldrum's acid derivative is reacted with the resin bound imine in acidic conditions to form the pyridinone.
  • the invention is also directed to methods of derivatizing compounds (C) and (E) to form compounds (N) and (O) and methods of reducing compounds (C) and (E) to form compounds (Z) and (AA).
  • the invention is further directed to various compounds that are useful in the preparation of the pyridinones and pyridinone derivatives. These include an imine of the formula:
  • Z comprises S, SO, SO 2 , O, P, PO, PO 2 , CH 2 , or CR 2 ;
  • R 2 comprises (CH 2 ) n A wherein n is a natural number between 0 and 5 and A comprises alkyl, alkenyl, alkynyl, aryl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl or substituted heteroaryl;
  • R 3 comprises (CH 2 ) m D wherein m is a natural number between 0 and 5: when m is between 3 and 5, D comprises alkyl, alkenyl, alkynyl, aryl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl or substituted heteroaryl; when m is 0, D comprises unsubstituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted ary
  • Z comprises S, SO, SO 2 , O, P, PO, PO 2 , CH 2 or CR 2 ;
  • R 2 comprises (CH 2 ) n A wherein n is a natural number between 0 and 5 and A comprises alkyl, alkenyl, alkynyl, aryl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl or substituted heteroaryl;
  • R 3 comprises (CH 2 ) m D wherein m is a natural number between 0 and 5: when m is between 1 and 5, D comprises alkyl, alkenyl, alkynyl, aryl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl or substituted heteroaryl; and when m is 0, D comprises unsubstituted alkyl, subsituted or unsubstituted alkenyl, substituted or unsubstituted alky
  • the present invention provides pyridinones of the formula:
  • R comprises oxo;
  • R 2 comprises (CH 2 ) n A wherein n is a natural number between 0 and 5 and A comprises hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl or substituted heteroaryl;
  • R 3 comprises (CH 2 ) m D wherein m is a natural number between 0 and 5 and D comprises hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl or substituted heteroaryl;
  • R 4 comprises CO 2 Y, B(OY) 2 , CHO, CH 2 OY, CH(CO 2 Y) 2
  • pyridinones are highly stable and can be readily derivatized in a number of ways.
  • One such method of derivatization is a further substitution on the aromatic ring of the pyridinone.
  • the present invention also provides pyridinone derivatives having the formula:
  • R hindered R 2 , R 3 , R 4 and Z are as previously defined and R 5 comprises halogen, nitrile, C0 2 H, CH 2 NH 2 , cyclic CHN 4 a lactam, NO 2 ,
  • G comprises alkyl, alkenyl, alkynyl, aryl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl, or (CH) 2 E wherein E comprises COR, CO 2 R, CHO, or CN and R comprises alkyl, alkenyl, alkynyl, aryl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl or substituted heteroaryl.
  • Pyridinone derivatives (N) and (O) are readily formed from the derivatization of pyridinones (C) and (E).
  • the active forms of the pyridinones and pyridinone derivatives of the invention are those wherein the chirality of the carbon at R 4 is as illustrated in compounds (C) and (E) of page 9. However, in (E) when R 4 is COOH and Z is S the chirality of the carbon at R 4 is S. Furthermore, in (C) when R 4 is COOH and Z is S the chirality of the carbon at R 4 is R.
  • the same stereochemistry is retained in the analogous compounds and derivatives (although the designation (R or S) of the chirality at each position may be different depending on the specific substitutions made).
  • the invention also includes racemic mixtures which include the active stereoisomer as well as mixtures of the various diastereomers.
  • salts of the pyridinones and pyridinone derivatives possessing a carboxylic acid functionality are included in the invention, especially pharmaceutically acceptable salts.
  • Salts of carboxylic acids include those derived from inorganic bases such as sodium, potassium, lithium, calcium, magnesium, zinc, aluminum, iron and similar salts. Also included are those salts derived from organic, especially nontoxic bases including primary amines such as ammonium, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion-exchange resins.
  • pyridinone refers to both pyridinones (C) and (E) and pyridinone derivatives (N) and (O), unless indicated otherwise.
  • R 4 is CO 2 H; test data indicates that those pyridinones possessing a carboxylic acid functionality are highly effective pilicides.
  • the pyridinone possesses the following substituents: Z comprises S or SO 2 ; R t comprises oxo, R 2 comprises (CH 2 ) n A wherein n is 1 and A comprises C 10 aryl; R 3 comprises (CH 2 ) m D wherein m is 1 and D comprises heteroaryl or substituted heteroaryl; and R 4 comprises CO 2 Y wherein Y comprises hydrogen.
  • the pyridinone possesses the following substituents: Z comprises S or SO 2 ; R, comprises oxo, R 2 comprises (CH 2 ) n A wherein n is 1 and A comprises C 10 aryl; R 3 comprises phenyl; and R 4 comprises CO 2 Y wherein Y comprises methyl.
  • the pyridinone possesses the following substituents: Z comprises S or SO 2 ; R, comprises oxo, R 2 comprises (CH 2 ) n A wherein n is 1 and A comprises C, 0 aryl; R 3 comprises a heteroaryl of the structure:
  • n is 0
  • Q comprises N
  • R 4 comprises CO 2 Y wherein Y comprises hydrogen.
  • Z comprises S or SO 2
  • R comprises oxo
  • R 2 comprises (CH 2 ) n A wherein n is 1 and A comprises C ]0 aryl
  • R 3 comprises a heteroaryl of the structure:
  • m is 0-4 and Q comprises O, S, SO, SO 2 , NH, NO or NR wherein R comprises alkyl, alkenyl, alkynyl, aryl, heteroaryl, acyl, or sulfonyl; and R 4 comprises CO 2 Y wherein Y comprises hydrogen.
  • the pyridinone possesses the following substituents: Z comprises S or SO 2 ; R ⁇ comprises oxo, R 2 comprises (CH 2 ) n A wherein n is 1 and A comprises C 10 aryl; R 3 comprises a heteroaryl of the structure:
  • m is 1 and Q comprises O, S, SO, SO 2 , NH, NO or NR wherein R comprises alkyl, alkenyl, alkynyl, aryl, heteroaryl, acyl, or sulfonyl; and R 4 comprises CO 2 Y wherein Y comprises hydrogen.
  • the pyridinone possesses the following substituents: Z comprises S or SO 2 ; R, comprises oxo, R 2 comprises (CH 2 ) n A wherein n is 1 and A comprises C 10 aryl; R 3 comprises a heteroaryl of the structure:
  • m is 0-4 and Q comprises O, S, SO, NH, NO or NR wherein R comprises alkyl, alkenyl, alkynyl, aryl, heteroaryl, acyl, or sulfonyl; and R 4 comprises CO 2 Y wherein Y comprises hydrogen.
  • the pyridinone possesses the following substituents: Z comprises SO 2 ; R t comprises oxo, R 2 comprises (CH 2 ) n A wherein n is 1 and A comprises C 10 aryl; R 3 comprises a heteroaryl of the structure:
  • m is 1 and Q comprises O, S, SO, SO 2 , NH, NO or NR wherein R comprises alkyl, alkenyl, alkynyl, aryl, heteroaryl, acyl, or sulfonyl; and R 4 comprises CO 2 Y wherein Y comprises hydrogen.
  • the pyridinone possesses the following substituents: Z comprises S or SO 2 ; R, comprises oxo, R 2 comprises (CH 2 ) n A wherein n is 1 and A comprises C 10 aryl; R 3 comprises a heteroaryl of the structure:
  • m is 1 and Q comprises N; and R 4 comprises CO 2 Y wherein Y comprises hydrogen.
  • the pyridinone possesses the following substituents: Z comprises SO 2 ; R, comprises oxo, R 2 comprises (CH 2 ) n A wherein n is 1 and A comprises C 10 aryl; R 3 comprises phenyl; and R 4 comprises CO 2 Y wherein Y comprises methyl.
  • the pyridinone possesses the following substituents: Z comprises S; R, comprises oxo, R 2 comprises (CH 2 ) n A wherein n is 1 and A comprises C 10 aryl; R 3 comprises (CH 2 ) m wherein m is 0; and R 4 comprises CO 2 Y wherein Y comprises methyl.
  • the pyridinone possesses the following substituents: Z comprises S; R, comprises oxo, R 2 comprises (CH 2 ) n A wherein n is 1 and A comprises C 10 aryl; R 3 comprises (CH 2 ) m wherein m is 0; and R 4 comprises CO 2 Y wherein Y comprises hydrogen.
  • the pyridinone possesses the following substituents: Z comprises S; R, comprises oxo, R 2 comprises (CH 2 ) n A wherein n is 1 and A comprises C 10 aryl; R 3 comprises phenyl; and R 4 comprises CO 2 Y wherein Y comprises methyl.
  • the pyridinone possesses the following substituents: Z comprises SO 2 ; R, comprises oxo, R 2 comprises (CH 2 ) n A wherein n is 1 and A comprises C 10 aryl; R 3 comprises phenyl; and R 4 comprises CO 2 Y wherein Y comprises hydrogen.
  • the pyridinone possesses the following substituents: Z comprises S; R x comprises oxo, R 2 comprises (CH 2 ) n A wherein n is 1 and A comprises C 10 aryl; R 3 comprises phenyl; and R 4 comprises CO 2 Y wherein Y comprises hydrogen.
  • R 5 of pyridinone derivatives (N) and (O) comprises halogen, nitrile or (CH) 2 E wherein E comprises CO 2 R and R comprises alkyl. More preferably, R 5 of pyridinone derivatives (N) and (O) comprises bromine, nitrile or (CH) 2 E wherein E comprises CO 2 R and R comprises benzyl.
  • R j comprises oxo
  • R 2 comprises (CH 2 ) n A wherein n is a natural number between 0 and 5 and A comprises alkyl, alkenyl, alkynyl, aryl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl or substituted heteroaryl
  • R 3 comprises (CH 2 ) m D wherein m is a natural number between 0 and 5 and D comprises hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl or substituted heteroaryl
  • R 4 comprises CO 2 Y, B(OY) 2 , CHO, CH 2 OY, CH(CO 2 Y) 2 , PO(OY) 2 wherein
  • the invention also provides reduced pyridinone derivative (AA) having the following formula which can be prepared by reducing pyridinone (E):
  • R_ comprises oxo
  • R 2 comprises (CH 2 ) n A wherein n is a natural number between 0 and 5 and A comprises hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl or substituted heteroaryl
  • R 3 comprises (CH 2 ) m D wherein m is a natural number between 0 and 5 and D comprises hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl or substituted heteroaryl
  • R 4 comprises CO 2 Y, B(OY) 2 , CHO, CH 2 OY, CH(CO 2 Y) 2 , PO(OY) 2 wherein
  • alkyl groups described herein are preferably lower alkyl containing from one to four carbon atoms in the principal chain and up to 6 carbon atoms. They may be substituted, straight, branched chain or cyclic and include methyl, ethyl, propyl, isopropyl, butyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • alkenyl groups described herein are preferably lower alkenyl containing from two to four carbon atoms in the principal chain and up to 6 carbon atoms. They may be substituted, straight, branched chain or cyclic and include ethenyl, propenyl, isopropenyl, butenyl, hexenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cydohexenyl and the like.
  • alkynyl groups described herein are preferably lower alkynyl containing from two to four carbon atoms in the principal chain and up to 6 carbon atoms. They may be substituted, straight, or branched chain and include ethynyl, propynyl, butynyl, hexynyl and the like.
  • the aryl moieties described herein, either alone or with various substituents contain from 6 to 15 carbon atoms and include phenyl. Substituents include alkanoxy, halogen, hydroxyl, alkyl, aryl, alkenyl, acyl, acyloxy, nitro, amino, amido, etc.
  • heteroaryl moieties described herein either alone or with various substituents, contain from 5 to 15 carbon atoms and include furans, thiophenes, indoles, furyl, pyridyl, thienyl, tryptophane and the like.
  • Substituents include alkanoxy, halogen, hydroxyl, alkyl, aryl, alkenyl, acyl, acyloxy, nitro, amino and amido.
  • the substituents of the substituted alkyl, alkenyl, alkynyl, aryl, and heteroaryl groups and moieties described herein may be hydroxy alkyl, alkenyl, alkynyl, aryl, heteroayl and or/ may contain nitrogen, oxygen, sulfur, halogens and include, for example, lower alkoxy such as methoxy, ethoxy, butoxy, halogen such as chloro or fluoro, nitro, amino, and keto.
  • natural number means a positive number including zero.
  • pilus As used herein the terms “pilus” or “pili” relate to fibrillar heteropolymeric structures protruding from the surface of the cell envelope of many tissue-adhering pathogenic bacteria, notably pathogenic Gram-negative bacteria. In the present specification the terms pilus and pili will be used interchangeably. A pilus is composed of a number of "pilus subunits" which constitute distinct functional parts of the intact pilus.
  • the term "chaperone” relates to a molecule which in living cells has the responsibility of binding to proteins in order to mature the proteins in a number of ways, such as the process of folding proteins into their native conformations, the process of assembly of pili structures, or the transport of proteins in the cell.
  • Specialized molecular chaperones are "periplasmic chaperones” which are bacterial molecular chaperones exerting their main actions in the "periplasmic space”.
  • the periplasmic space constitutes the space in between the inner and outer bacterial membrane. Periplasmic chaperones are involved in the process of correct assembly of intact pili structures.
  • the use of the term “chaperone” designates a molecular, periplasmic chaperone unless otherwise indicated.
  • treatment includes both prophylaxis and therapy.
  • the Meldrum's acid derivative is only presented in enol form. It is recognized, however, that the Meldrum's acid derivative exists as a tautomer.
  • the Meldrum's acid derivative may exist primarily in the enol form, primarily in the keto form, or in a mixture of both enol and keto forms depending on the solvent. All forms and mixtures thereof are intended to be included in the term "Meldrum's acid derivative" as used herein.
  • the term “acidic work-up” includes but is not limited to quenching with acid, such as acetic acid, washing the resulting mixture with water, and centrifugation to remove the precipitated product.
  • the present invention further provides two novel methods of synthesizing ring fused substituted 2-pyridinones. Synthesis may be done in solution and involves reacting a Meldrum's acid derivative and an imine in acidic conditions. Alternatively, a solid phase synthesis of the pyridinones is accomplished by preparing an imine bound to a solid substrate and adding a Meldrum's acid derivative in acidic conditions.
  • the pyridinones of the present invention can be synthesized by the following general reactions:
  • Z comprises S, SO, SO 2 , O, P, PO, PO 2 CH 2 , or CR 2 ;
  • R comprises oxo;
  • R 2 comprises (CH 2 ) n A wherein n is a natural number between 0 and 5 and A comprises hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl or substituted heteroaryl;
  • R 3 comprises (CH 2 ) m D wherein m is a natural number between 0 and 5 and D comprises hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl or substituted heteroaryl;
  • R 4 comprises CO 2 Y, B(OY) 2 , CHO, CH 2 OY, CH(CO 2 Y) 2 , PO(OY)
  • Meldrum's acid derivative (A) is reacted in solution with imine (B) to form pyridinone (C).
  • Z comprises S or SO 2 , n is 1, A comprises aryl, m is 0, D comprises aryl, R 4 comprises C0 2 Y wherein Y comprises hydrogen or alkyl. More preferably, Z comprises S, R comprises oxo, n is 1, A comprises napthyl, m is 0, D comprises phenyl, R 4 comprises CO 2 Y wherein Y comprises hydrogen.
  • the invention also includes embodiments where Y comprises alkyl, alkenyl, alkynyl, aryl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl or substituted heteroaryl.
  • the process also comprises the further step of hydrolysis of the pyridinone.
  • the hydrolysis can be accomplished in basic conditions through the use of a base such as NaOH or KOH, and is usually followed by acidic work-up with an acid such as acetic acid or another suitable acid.
  • Meldrum's acid derivative (A) is reacted in solution with imine (D) to form pyridinone (E).
  • Z comprises S or SO 2 , n is 1 , A comprises aryl, m is 0, D comprises aryl, R 4 comprises C0 2 Y wherein Y comprises hydrogen or alkyl. More preferably, Z comprises S, R, comprises oxo, n is 1, A comprises napthyl, m is 0, D comprises phenyl, R 4 comprises CO 2 Y wherein Y comprises hydrogen.
  • the invention also includes embodiments where Y comprises alkyl, alkenyl, alkynyl, aryl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl or substituted heteroaryl.
  • the process also comprises the further step of hydrolysis of the pyridinone. This hydrolysis can be accomplished in basic conditions through the use of a base such as NaOH or KOH, and is usually followed by acidic work-up with an acid such as acetic acid or another suitable acid.
  • Reaction Scheme I illustrates the general reaction to form a pyridinone of type (C).
  • the Meldrum's acid derivative of formula (F) is reacted with the thiazoline of formula (G) to obtain the illustrative pyridinone of the invention, compound (H).
  • the Meldrum's acid derivative (F) of Reaction Schemes I and II is obtained by condensing an appropriate carboxylic acid with a Meldrum's acid as shown in Reaction Scheme III. 1) oxalyl ic chloride, benzene DMF (catalytic amount)
  • Reaction Scheme III The thiazoline derivative of Reaction Scheme I is prepared as shown in Reaction Scheme IV.
  • the Meldrum's acid derivative (F) used in Reaction Schemes I and II was prepared as set forth in Reaction Scheme III.
  • the Meldrum's acid derivative used in Reaction Schemes I and II was prepared using conditions similar to those for other Meldrum's acid derivatives described in Yamamoto, Y. etal. Chem Pharm Bull (1987) 35: 1860- 1870, which is herein incorporated by reference.
  • the conditions set forth on page 1868 are most exemplary.
  • the thiazoline derivative (G) used in Reaction Scheme I was prepared as set forth in Reaction Scheme IV. This preparation is based on one described in Meyers, A.I.; Witten, C.E.; Heterocycles, 1976, 4:1687-1692, which is herein incorporated by reference.
  • the hydrochloride salt of L-methyl cysteinate (L) was reacted with ethyl benzylimidate hydrochloride (K) using the conditions set forth on page 1688 of the Meyers reference. Specifically, L-methyl cysteinate (L) was dissolved in dichloromethane and treated with ethyl benzylimidate hydrochloride (K) in the presence of triethylamine.
  • the thiazoline derivative (I) used in Reaction Scheme II is prepared as set forth in Reaction Scheme V. This preparation is based on one described in Meyers, A.I.; Witten, C.E.; Heterocycles, 1976, 4:1687-1692, which is herein incorporated by reference.
  • the hydrochloride salt of L-methyl homocysteinate (L) is reacted with ethyl benzylimidate hydrochloride (K) using the conditions set forth on page 1688 of the Meyers reference. Specifically, L-methyl cysteinate (L) is dissolved in dichloromethane and treated with ethyl benzylimidate hydrochloride (K) in the presence of triethylamine.
  • the solid phase synthesis of pyridinones involves generally a process for the synthesis of ring fused 2-pyridinones on a solid support wherein an imine bound to a solid substrate is prepared and a Meldrum's acid derivative is added in acidic conditions.
  • the process for the synthesis of ring fused 2-pyridinones on a solid support comprises the steps of: (a) coupling a protected amino acid to a solid support via an acid stable linker, (b) removing the protecting groups, (c) adding an iminoether to form an imine, and (d) adding a Meldrum's acid derivative in acidic conditions.
  • the solid support can be a resin such as a polystyrene resin or a functionalized polystyrene resin, such as a carboxypolystyrene resin, a tentagel S-bromide resin, or a PAM resin.
  • a resin such as a polystyrene resin or a functionalized polystyrene resin, such as a carboxypolystyrene resin, a tentagel S-bromide resin, or a PAM resin.
  • the solid support is an acid stable resin. More preferably the solid support is an acid stable HMBA-AM resin.
  • the amino acid can be homocysteine or cysteine or could be prepared from serine or homoserine.
  • the amino acid is cysteine.
  • the amino acid can be protected by various protecting groups for amino acids.
  • the amino acid protecting group is an acid labile protecting group.
  • Protecting groups for the amino group of the amino acid include but are not limited to t-butoxycarbonyl group (Boc), 2-(4-biphenylyl)propyl(2)oxycarbonyl
  • the preferred protecting group for the amino group is t-butoxycarbonyl group (Boc).
  • Protecting groups for the thiol group of the amino acid include but are not limited to tert-butyl ('Bu), acetamidomethyl (Acm), and triphenylmethyl(trityl) (Trt).
  • the prefened protecting group for the thiol group is triphenylmethyl(trityl) (Trt).
  • the protected amino acid is Boc-Cys(Trt)-OH.
  • amino acid and the iminoether are reacted in acidic conditions, but once formed the ring fused 2-pyridinone is cleaved from the solid support by the addition of an appropriate base, such as NaOH or CeCO 3 .
  • the iminoether of the solid phase synthesis has the following formula:
  • R 3 comprises (CH 2 ) m D wherein m is a natural number between 0 and 5 and D comprises hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl or substituted heteroaryl.
  • the Meldrum's acid derivative of the solid phase synthesis has the following formula:
  • R 2 comprises (CH 2 ) n A wherein n is a natural number between 0 and 5 and A comprises hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl or substituted heteroaryl.
  • the imine bound to a solid substrate has the following formula:
  • Z comprises S, SO, SO 2 , 0, P, PO, PO 2 , CH 2 , or CR 2
  • R 2 comprises (CH 2 ) n A wherein n is a natural number between 0 and 5 and A comprises hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl or substituted heteroaryl
  • R 3 comprises (CH 2 ) m D wherein m is a natural number between 0 and 5 and D comprises hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl or substituted heteroaryl.
  • the ring fused 2-pyridinones formed by the solid phase synthesis have the following formula:
  • R comprises oxo
  • R 2 comprises (CH 2 ) n A wherein n is a natural number between 0 and 5 and A comprises hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl or substituted heteroaryl
  • R 3 comprises (CH 2 ) m D wherein m is a natural number between 0 and 5 and D comprises hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl or substituted heteroaryl
  • R 4 comprises CO 2 H.
  • n 0, A comprises alkyl, m is 0 and D comprises aryl. More preferably, n is 0, A comprises methyl, m is 0 and D comprises phenyl.
  • the pyridinones are made by the following steps: 1) Attachment of Boc-Cys(Trt)-OH to acid stable HMBA-AM resin to give A
  • Boc-Cys(Trt)-OH was attached to acid stable HMBA-AM resin by combining Boc-Cys(Trt)-
  • the acid labile protecting groups were removed by adding a mixture of TFA, thioanisol, and ethanedithiol followed by agitation.
  • TEA and phenyliminoether were added, followed by additional TEA.
  • the resin was then alternately rinsed with DMF and dichloromethane. This was followed by the addition of more phenyliminoether and TEA to yield the resin bound thiazoline.
  • the desired pyridinone G was cleaved from the resin by the addition of NaOH and THF, followed by rinsing of the resin and acidification and purification of the filtrate.
  • the present invention is also directed to intermediates useful in the synthesis of the pyridinones and pyridinone derivatives of the invention.
  • An imine of the formula below is provided:
  • Z comprises S, SO, SO 2 , 0, P, PO, PO 2 , CH 2 , or CR 2 ;
  • R 2 comprises (CH 2 ) n A wherein n is a natural number between 0 and 5 and A comprises alkyl, alkenyl, alkynyl, aryl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl or substituted heteroaryl;
  • R 3 comprises (CH 2 ) m D wherein m is a natural number between 0 and 5 and when m is between 3 and 5, D comprises alkyl, alkenyl, alkynyl, aryl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl or substituted heteroaryl and when m is 0, D comprises unsubstituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted aryl
  • Z comprises S, SO, SO 2 , 0, P, PO, PO 2 , CH 2 , or CR 2 ;
  • R 2 comprises (CH 2 ) n A wherein n is a natural number between 0 and 5 and A comprises alkyl, alkenyl, alkynyl, aryl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl or substituted heteroaryl;
  • R 3 (CH 2 ) m D wherein m is a natural number between 0 and 5 and when m is between 1 and 5, D comprises alkyl, alkenyl, alkynyl, aryl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl or substituted heteroaryl and when m is 0, D comprises unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl,
  • thiazoline of the formula is provided:
  • pyridinone derivatives (N) and (O) can be prepared from pyridinones (C) and (E). Also preparable from pyridinones (C) and (E) are reduced pyridinone derivatives (Z) and (AA).
  • One of the embodiments of the present invention includes the halogenation of the pyridinone at the position designated as R 5 by reacting pyridinone (C) or (E) with a halogenating agent to form a halogen substituted pyridinone derivative. Such a reaction is illustrated with pyridinone (C) in Reaction Scheme VI. A similar result in Reaction Scheme VI can be obtained for pyridinone (E).
  • Z comprises S, SO, SO 2 , 0, P, PO, PO 2 CH 2 or CR 2 ;
  • R 2 comprises (CH 2 ) n A wherein n is a natural number between 0 and 5 and A comprises hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl or substituted heteroaryl;
  • R 3 comprises (CH 2 ) m D wherein m is a natural number between 0 and 5 and D comprises hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl or substituted heteroaryl;
  • R 4 comprises CO 2 Y, B(OY) 2 , CHO, CH 2 OY, CH(CO 2 Y) 2 , PO(OY) 2 wherein Y comprises hydrogen, alkyl,
  • Possible halogens include chlorine, fluorine, iodine, and bromine.
  • the halogen comprises bromine or iodine.
  • Prefened halogenating agents include bromine and iodine monochloride.
  • the iodination of pyridinone (C) at the position designated as R 5 occurs by reacting pyridinone (C) with iodine monochloride by using a catalytic amount of ferrocenium tetrakis(3,5-bis(trifluoromethyl)phenyl)borate in the coexistence of DDQ or ZnO.
  • This iodination reaction is illustrated by a procedure described by Mukaiyama, T., Kitigawa, H., Matsuo, J.
  • a bromine substituted pyridinone derivative (P) can be further derivatized via an organometallic coupling to possess a conjugated ester, a conjugated ketone, a conjugated aldehyde, or a conjugated nitrile.
  • a similar result in Reaction Scheme VII can be obtained for the corresponding derivative of pyridinone (E).
  • E comprises COR, CO 2 R, CHO, or CN and R comprises alkyl, alkenyl, alkynyl, aryl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl or substituted heteroaryl.
  • E comprises C0 2 R wherein R comprises aryl. More preferably, E comprises C0 2 R wherein R comprises benzyl.
  • the organometallic coupling of (CH) 2 E to pyridinone derivative (P) is accomplished by heating Pd(PPh 3 ) 2 Cl 2 (CH) 2 E, pyridinone derivative (P) and triethylamine to reflux
  • a pyridinone derivative (P) can be reacted with a cyanating agent to yield nitrile substituted pyridinone derivative (R).
  • R nitrile substituted pyridinone derivative
  • a similar result in Reaction Scheme VIII can be obtained for the corresponding derivative of pyridinone (E).
  • Reaction Scheme VIII wherein Z, R 2 , R 3 , and R 4 are as defined in Reaction Scheme VI.
  • Exemplary cyanating agents include but are not limited to CuCN and (Zn) 2 CN.
  • Pyridinone derivative (P) can be refluxed with CuCN in DMF for 16 hours.
  • FeCl 3 in HCI is then added to the mixture to produce pyridinone (R) after extraction and purification.
  • Nitrile substituted pyridinone derivative (R) can be hydrolyzed to form pyridinone derivative (S) possessing a carboxylic acid functionality as shown in Reaction Scheme IX.
  • a similar result in Reaction Scheme IX can be obtained for the conesponding derivative of pyridinone (E).
  • Reaction Scheme IX wherein Z, R 2 , R 3 , and R 4 are as defined in Reaction Scheme VI, however, of those pyridinone derivatives of (R) wherein R 4 is CO 2 Y and Y is substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, or heteroaryl, R 4 of (S) may be CO 2 Y wherein Y is hydrogen.
  • the hydrolysis is accomplished using potassium hydroxide in ethanol solvent.
  • pyridinone derivative (S) is illustrated by a procedure described by Reidlinger, G.H., Hans, J., Synthesis 1991, 835-838, in their article describing the use of cyanonitropropenides as synthons for the preparation of nitropyridines, the entirety of which is hereby incorporated by reference.
  • the authors specifically describe the preparation of 6- amino-5-nitro-2-oxo-l,2-dihydropyridin-3-carboxylic acid from 6-amino-2-methoxy-5- nitropyridin-3-methylester by dissolving 6-amino-2-methoxy-5-nitropyridin-3-methylester in a solution of potassium hydroxide in water and ethanol and heating for 1.5 hours at 70 degrees Celcius. After that, the solution was cooled, acidified with 10% HCI to pH 2, solidified, crystallized, and isolated by suction to form 6-amino-5-nitro-2-oxo-l,2- dihydropyridin-3-carboxylic acid.
  • Pyridinone derivative (S) can be reduced to form pyridinone derivative (T) as shown in Reaction Scheme X.
  • a similar result in Reaction Scheme X can be obtained for the conesponding derivative of pyridinone (E).
  • Reaction Scheme X wherein Z, R 2 , R 3 , and R 4 are as defined in Reaction Scheme VI.
  • the reduction of the nitrile substituted pyridinone derivative (S) is accomplished by combining PtO 2 and the nitrile substituted pyridinone in dry ethanol and adding CHC1 3 . The combined reaction mixture is agitated under hydrogen pressure at room temperature for about 24 hours.
  • the preparation of pyridinone derivative (T) is illustrated by a procedure described by Clive D.L. J., Hisaindee, S., J. Org. Chem. 2000, 65: 4923-4929 in their synthesis of racemic brevioxime and related model compounds, the entirety of which is hereby incorporated by reference.
  • Pyridinone derivative (T) can be further functionalized to form pyridinone derivative (U) possessing a tetrasol at R 5 as shown in Reaction Scheme XI.
  • a similar result in Reaction Scheme XI can be obtained for the corresponding derivative of pyridinone (E).
  • Reaction Scheme XI wherein Z, R 2 , R 3 , and R 4 are as defined in Reaction Scheme VI.
  • the further transformation is accomplished by reacting the nitrile substituted pyridinone derivative with trimethylsilylazide and dibutyltin oxide in an organic solvent and heating the reaction mixture for 24-72 hours. Suitable organic solvents include toluene.
  • pyridinone derivative (U) in Reaction Scheme XI is illustrated by a procedure described by Wittenberger, S.J., and Dormer B.G. J. Org. Chem. 1993, 58:4139-4141, the entirety of which is hereby incorporated by reference.
  • dibutyltin oxide was added to a solution of the nitrile and trimethylsilylazide dissolved in toluene.
  • the resulting mixture was heated for 24-72 hours until the nitrile was consumed by the reaction.
  • the reaction mixture was concentrated, extracted and filtered to yield the 5-substituted tetrazole.
  • Pyridinone derivative (P) can also be derivatized to pyridinone derivative (V) via organometallic coupling as shown in Reaction Scheme XII.
  • a similar result in Reaction Scheme XII can be obtained for the conesponding derivative of pyridinone (E).
  • Reaction Scheme XII wherein Z, R 2 , R 3 , and R 4 are as defined in Reaction Scheme VI, G is aryl, alkyl, alkenyl, or alkynyl, and X is I, Br, or Cl.
  • organozinc halide reagents include organozinc iodide and organozinc bromide.
  • G, the organic component of the organozinc reagent include but are not limited to the following compounds:
  • the organometallic coupling is accomplished by reacting the halogenated pyridinone derivative with an organozink halide and Pd(PPh 3 ) 4 in an organic solvent such as THF.
  • an organic solvent such as THF.
  • the preparation of pyridinone derivative (V) in Reaction Scheme XII is illustrated by the reaction of organozinc compounds with aryl and vinyl halides described by Zhu L., Wehmeyer, R., andRieke,R.J. Or . Chem. 1991, 56:1445-1453, the entirety of which is hereby incorporated by reference.
  • Pyridinone derivative (P) can also be derivatized to form pyridinone derivative (W) by the organometallic coupling of (trimethylsilyl)acetylene as shown in Reaction Scheme XIII.
  • a similar result in Reaction Scheme XIII can be obtained for the conesponding derivative of pyridinone (E).
  • Reagents for the organometallic coupling include PdCl 2 (PPh 3 ) 2 and Cul or other suitable organometallic reagents.
  • the organometallic coupling is accomplished by combining the halogenated pyridinone derivative with (trimethylsilyl)acetylene and triphenylphosphine, PdCl 2 (PPh 3 ) 2 and Cul and then heating at 120 degrees Celcius for 72 hours.
  • the preparation of pyridinone derivative (W) is illustrated by a procedure described by Padwa A., Sheehan S.M., and Straub C.S.,J Org.
  • Pyridinone derivative (P) can also be derivatized to form lactam substituted pyridinone derivative (X) by organometallic coupling as shown in Reaction Scheme XIV.
  • a similar result in Reaction Scheme XIV can be obtained for the conesponding derivative of pyridinone (E).
  • Reagents for the organometallic coupling include palladium compounds or other appropriate organometallic reagents.
  • Preferred reagents for the organometallic coupling include palladium acetate(II).
  • the organometallic coupling is accomplished by heating the halogenated pyridinone derivative with palladium acetate(II), l,r-bis(diphenylphosphino)-ferrocene, sodium tert- butoxide, and a lactam in an organic solvent such as toluene under an inert atmosphere for around 48 hours.
  • pyridinone derivative (X) is illustrated by a procedure described by Shakespeare W., Tetrahedron Letters 1999, 40: 2035-2038 for the palladium- catalyzed coupling of lactams with bromobenzenes, the entirety of which is hereby incorporated by reference.
  • the author describes the preparation of 1 -phenyl-pyrrolidin-2-one by combining palladium acetate(II), l,l'-bis(diphenylphosphino)-fenocene (DPPF), sodium tert-butoxide, a lactam, and a bromobenzene in toluene and heating in a sealed tube for 48 hours. After filtration and concentration, flash chromatography yielded the desired 1 -phenyl- pyrrolidin-2-one.
  • nitrating agents include but are not limited to nitric acid in a suitable solvent, such as acetic acid or acetic anhydride.
  • Prefened nitrating agents include nitric acid dissolved in acetic anhydride.
  • the preparation of pyridinone derivative (Y) is accomplished by reacting pyridinone (C) with nitric acid and acetic anhydride.
  • the preparation of pyridinone derivative (Y) is illustrated by a procedure described by Barker A., and Barker C, J. Org. Chem.
  • Reaction Scheme XVI wherein Z comprises S, SO, SO 2 , O, P, PO, PO 2 CH 2 or CR 2 ; R, comprises oxo; R 2 comprises (CH 2 ) n A wherein n is a natural number between 0 and 5 and A comprises hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl or substituted heteroaryl; R 3 comprises (CH 2 ) m D wherein m is a natural number between 0 and 5 and D comprises hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl or substituted heteroaryl; and R 4 comprises CO 2 Y, B(OY) 2 , CHO, CH 2 OY, CH(CO 2 Y) 2 , PO(OY)
  • the reduction is accomplished by adding a catalytic amount of PtO 2 to a solution of the pyridinone in acetic acid and stirring under a hydrogen atmosphere of 90 psi for 2 hours. Reduction of aromatic moieties in the R 2 , R 3 and R 5 substituents is expected to result from the reduction procedure.
  • the preparation of pyridinone derivative (Z) is illustrated by a procedure described by Padwa A., Sheehan S.M., and Straub C.S., J. Org. Chem. 1999, 64: 8648-8659 for an isomunchnone-based method for the synthesis of highly substituted 2(1H)- pyridones, the entirety of which is hereby incorporated by reference.
  • the authors describe the preparation of 5-oxoindolizidine from 2,3-dihydro-5(lH)-indolizinone.
  • the specific preparation procedure employed by the authors involved the addition of a catalytic amount of PtO 2 to a solution of 2,3-dihydro-5(lH)-indolizinone in acetic acid.
  • the reaction mixture was stined under a hydrogen atmosphere of 90 degrees psi for 2 hours.
  • the organic layer was washed with brine, dried over Na j SO,, and concentrated under reduced pressure.
  • the crude residue was subjected to flash silica gel chromatography to yield 5-oxoindolizidine.
  • Pyridinone derivatives (P) and (Y) are preparable from pyridinone (C) according to Reaction Scheme VI and Reaction Scheme XV, respectively. Furthermore, pyridinone derivatives (Q), (R), (V), (W) or (X) can be prepared from pyridinone derivative (P) according to the reaction schemes described above. Thus, any of pyridinone derivatives (Q), (R), (V), (W) or (X) can be prepared from an imine and a Meldrum's acid derivative via either the synthesis in solution or the solid phase synthesis of pyridinone (C) and derivatization of pyridinone (C) to pyridinone derivative (P).
  • any of pyridinone derivatives (S), (T), and (U) can be prepared from pyridinone derivative (P) via the further derivatization of pyridinone derivative (R). Therefore, each of pyridinone derivatives (S), (T), and (U) are also preparable from an imine and a Meldrum's acid derivative via either the synthesis in solution or the solid phase synthesis of pyridinone (C) and derivatization of pyridinone (C) to pyridinone derivative (P). Similar results in the above reaction schemes can be obtained for pyridinone (E) and the corresponding derivatives of pyridinone (E).
  • compositions Containing the Pyridinones and Methods of Use Containing the Pyridinones and Methods of Use
  • the present invention further provides antibacterial compositions, including pharmaceutical compositions containing these compounds, and methods to inhibit or prevent bacterial growth using the compounds of the invention as well as antibodies specific for them.
  • the compounds of the invention are effective in inhibiting a variety of Gram-negative bacteria. They can be employed in disinfectant compositions and as preservatives for a wide variety of materials that possess nutrients for bacterial organisms such as foodstuffs, cosmetics, and medicaments.
  • the compounds in the invention are supplied either as a single compound, in a mixture with several other compounds of the invention or in a mixture with additional antimicrobial agents.
  • the compounds of the invention can be formulated as pharmaceutical or veterinary compositions.
  • the compounds are formulated in ways consistent with the mode of administration, the subject to be treated, and the type of treatment desired, for example prevention, prophylaxis, therapy. A summary of these techniques is provided in Remington's Pharmaceutical Sciences, latest edition, Mack Publishing Co., Easton, PA.
  • the compounds of the invention may be used alone or in combination with antibiotics such as erythromycin, tetracycline, and macrolides such as azithromycin and cephalosporins.
  • antibiotics such as erythromycin, tetracycline, and macrolides such as azithromycin and cephalosporins.
  • particular formulations of the compounds will vary formulated depending on the method by which they are to be administered to the affected areas.
  • Formulations may be prepared in a manner suitable for systemic administration or topical or local administration.
  • Systemic formulations include those designed for injection (e.g. intramuscular, intravenous or subcutaneous injection) or may be prepared for transdermal, transmucosal or oral administration.
  • the formulation will generally include a diluent as well as, in some instances, adjuvants, buffers, preservatives and the like.
  • the compounds can be administered also in liposomal compositions or as microemulsions.
  • formulations can be prepared in conventional forms as liquid solutions or suspensions or as solid forms suitable for solution or suspension in liquid prior to injection or as emulsions.
  • Suitable excipients include water, saline, dextrose, glycerol and the like.
  • compositions may also contain amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents such as sodium acetate and sorbitan monolaurate.
  • nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents such as sodium acetate and sorbitan monolaurate.
  • Suitable dosage forms for oral use include tablets, dispersable powders, granules, capsules, suspensions, syrups, and elixers.
  • Inert diluents and carriers for tablets include, for example, calcium carbonate, sodium carbonate, lactose and talc. Tablets may also contain granulating and disintegrating agents such as starch and alginic acid, binding agents such as starch, gelatin and acacia, and lubricating agents such as magnesium stearate, stearic acid and talc.
  • Tablets may be uncoated or may be coated by unknown techniques; e.g., to delay disintegration and absorption.
  • Inert diluents and carriers which may be used in capsules include, for example, calcium carbonate, calcium phosphate and kaolin.
  • Suspensions, syrups and elixers may contain conventional excipients, for example, methyl cellulose, tragacanth, sodium alginate; wetting agents, such as lecithin and polyoxyethylene stearate; and preservatives, e.g. ethyl-p-hydroxybenzoate.
  • the invention also includes a pharmaceutical composition containing the pyridinone, its derivatives or the salts thereof and one or more pharmacologically acceptable, inert or physiologically active diluents or adjuvants.
  • an effective amount of the compounds of the invention is that amount sufficient to inhibit pilus assembly in Gram-negative bacteria and thus to prevent or treat infection by such Gram-negative bacteria.
  • This effective amount is typically a dosage of 0.1-100 mg/kg.
  • dosage levels vary considerably depending on the nature of the infection, the condition of the patient and the frequency and method of administration.
  • an effective amount is considered to be that amount which inhibits pilus formation in Gram-negative bacteria and thus prevents bacterial colonization in that environment or surface. This amount will vary depending on the nature of the environment or surface.
  • Antibodies to the compounds of the invention may also be produced using standard immunological techniques for production of polyclonal antisera and, if desired, saving the antibody-producing cells of the immunized host for sources of monoclonal antibody production. Techniques for producing antibodies to any substance of interest are well known.
  • the immunogenicity of the substance may be enhanced by coupling the hap ten to a carrier.
  • Carriers useful for this purpose include substances which do not themselves elicit an immune response in the subject mammal. Common carriers used include keyhole limpet hemocyanin (KLH) diptheria taxoid, serum albumin, and the viral coat protein of rotavirus, VP6. Coupling the hapten to the carrier is effected by standard techniques such as contacting the carrier with the peptide in the presence of a dehydrating agent such as dicyclohexylcarbodiimide or through the use of linkers.
  • KLH keyhole limpet hemocyanin
  • VP6 viral coat protein of rotavirus
  • the compounds of the invention in immunogenic form are then injected into a suitable mammalian host and antibody titers in the serum are monitored.
  • Polyclonal antisera may be harvested when titers are sufficiently high.
  • antibody-producing cells of the host such as spleen cells or peripheral blood lymphocytes may be harvested and immortalized.
  • the immortalized cells are then cloned as individual colonies and screened for the production of the desired monoclonal antibodies.
  • the genes encoding monoclonal antibodies secreted by selected hybridomas or other cells may be recovered, manipulated if desired, for example, to provide multiple epitope specificity or to encode a single-chain form and may be engineered for expression in alternative host cells.
  • the present invention includes antibodies specifically immunoreactive with the pyridinones and pyridinone derivatives of the present invention. Such antibodies can be used in immunoassays for the qualitative and quantitative detection of varying types of analytes of interest, such as antigens or hormones.
  • Antichaperone binding activity can be measured by any number of direct methods such as monitoring spectral changes in the compound and/or chaperone, or determining the extent of compound binding to immobilized chaperone or vice versa, or by indirect methods such as competition assays to determine the extent to which these compounds inhibit chaperone binding to target pilus subunits and/or derivative (Soto, et al., Embo J.. (1998) 17:6155; Karlsson et al., Bioorg Med Chem.
  • a Reconstitution Assay was performed to obtain the percentages of inhibition found in the table below.
  • various amounts of inhibitor were added to the chaperone and FimH and they were allowed to competitively inhibit, and the resulting material was run on a cation exchange column.
  • the resulting peak areas were compared to that of a control to determine the percentages of inhibition. This is accomplished by taking a chaperone adhesin complex such as a FimC -FimH complex and separating it by incubating it in 3 molar urea. It is then put over a cation exchange column to isolate FimH. The isolated
  • FimH is then mixed with free FimC and run over an ion exchange column to produce a peak conesponding to the concentration of the resulting reconstituted FimC-FimH complex.
  • the same procedure is followed in the presence of the subject compound being tested and the reduction of resulting peak area is conelated to the percentage of inhibition.
  • the Reconstitution Assay is applicable to any chaperone adhesin complex or chaperone pilin complex.
  • the subject compound (inhibitor tested as identified below) was mixed with chaperone at room temperature for 15 minutes.
  • the concentration of FimH used was 1 mg/ml of FimH in MES buffer.
  • the concentration of FimC used was 12 mg/ml of FimC in MES buffer.
  • FimC and FimH were in a 1 to 1 molar ratio in this assay.
  • the various inhibitor to FimC ratios and inhibitor to PapD ratios employed in the assay are shown in the table below. It is recognized that varying the above concentrations and conditions may result in different percent inhibition values.
  • PapD and FimC were investigated using a direct binding assay on BIACORE 3000.
  • PapD 50 g/ML in lOmM NaAc pH 5.5
  • FimC 50 g/mL in lOmM NaAc pH 5.5
  • Immobilization levels 4000-10 000 RU were obtained.
  • Unmodified dextrane in one of the flow cells was used as reference surface.
  • the pyridinone was diluted from 10 mM DMSO stock solution to a final concentration of 30 ⁇ M in running buffer (6.7 mM phosphate buffer (9.6 g Na 2 HPO 4 «2H 2 0, 1.7 G KH 2 PO 4 , 4.1 g NaCl, lOOmL H 2 O), 3.4mM EDTA, 0.01%TWEEN, 5%DMSO, pH 7.4) so that the concentrations of DMSO and buffer substances were carefully matched.
  • the compounds were injected (flow rate was 30 L/min at 25 °C) and the binding of the compounds to the immobilized chaperone proteins was observed on real time.
  • the surface was regenerated by injection of 10 mM glycin ⁇ Cl, pH 2.0 and then washed with a 1 : 1 mixture of DMSO and water.
  • the pyridinone was injected (flow rate was 30 L/min at 25 °C) at a concentration of 30 ⁇ M in triplicate.
  • PapD 50 ⁇ g/ML in lOmM NaAc pH 5.5
  • FimC 50 ⁇ g/mL in lOmM NaAc pH 5.5
  • Immobilization levels 4000-10 000 RU were obtained.
  • Unmodified dextrane in one of the flow cells was used as reference surface.
  • the pyridinone was diluted from 10 mM DMSO stock solution to a final concentration of 30 ⁇ M in running buffer (6.7 mM phosphate buffer (9.6 g N- ⁇ HPO ⁇ HA 1.7 G KH 2 PO 4 , 4.1 g NaCl, lOOmL H 2 O), 3.4mM EDTA, 0.01%TWEEN, 5%DMSO, pH 7.4) so that the concentrations of DMSO and buffer substances were carefully matched.
  • the compounds were injected (flow rate was 30 ⁇ L/min at 25 °C) and the binding of the compounds to the immobilized chaperone proteins was observed on real time.
  • the surface was regenerated by injection of 10 mM glycin » HCl, pH 2.0 and then washed with a 1 : 1 mixture of DMSO and water.
  • PapD and FimC were investigated using a direct binding assay on BIACORE 3000.
  • PapD 50 ⁇ g/ML in lOmM NaAc pH 5.5
  • FimC 50 ⁇ g/mL in lOmM NaAc pH 5.5
  • Immobilization levels 4000-10 000 RU were obtained.
  • Unmodified dextrane in one of the flow cells was used as reference surface.
  • the pyridinone was diluted from 10 mM DMSO stock solution to a final concentration of 30 ⁇ M in running buffer (6.7 mM phosphate buffer (9.6 g Na 2 HPO 4 « 2H 2 0, 1.7 G KH 2 PO 4 , 4.1 g NaCl, lOOmL H 2 O), 3.4mM EDTA, 0.01%TWEEN, 5%DMSO, pH 7.4) so that the concentrations of DMSO and buffer substances were carefully matched.
  • the compounds were injected (flow rate was 30 ⁇ L/min at 25 °C) and the binding of the compounds to the immobilized chaperone proteins was observed on real time.
  • the surface was regenerated by injection of 10 mM glycin » HCl, pH 2.0 and then washed with a 1 :1 mixture of DMSO and water.
  • PapD 50 ⁇ g/ML in lOmM NaAc pH 5.5
  • FimC 50 ⁇ g/mL in lOmM NaAc pH 5.5
  • Immobilization levels 4000-10 000 RU were obtained.
  • Unmodified dextrane in one of the flow cells was used as reference surface.
  • the pyridinone was diluted from 10 mM DMSO stock solution to a final concentration of 30 ⁇ M in running buffer (6.7 mM phosphate buffer (9.6 g N- ⁇ HPO ⁇ H , 1.7 G KH 2 PO 4 , 4.1 g NaCl, lOOmL H 2 O), 3.4mM EDTA, 0.01%TWEEN, 5%DMSO, pH 7.4) so that the concentrations of DMSO and buffer substances were carefully matched.
  • the compounds were injected (flow rate was 30 ⁇ L/min at 25 °C) and the binding of the compounds to the immobilized chaperone proteins was observed on real time.
  • the surface was regenerated by injection of 10 mM glycin » HCl, pH 2.0 and then washed with a 1 : 1 mixture of DMSO and water.
  • HMBA-AM resin 5031 mg, capacity 1.16 mmol g, 0.58 mmol was allowed to swell in
  • CH 2 C1 2 (4 ml) was added to each RV containing swelled resin-bound cysteine TFA salt, TEA (40 ⁇ l) was added dropwise, and the mixture was agitated for 30min.
  • the CH 2 C1 2 and TEA were washed out, and phenyliminoether D (150 mg, 1.00 mmol) was added, followed by 4 ml CH 2 C1 2 and TEA (20 ⁇ l) and the mixture was agitated overnight.
  • the resin was washed three times with CH 2 C1 2 , three times with DMF and three additional times with CH 2 C1 2 .
  • the resin was swelled for 20min, and another 85 mg iminoether D and 20 ⁇ l TEA was added, followed by agitation for 5.5h and washing of the resin, which was used without further purification.
  • the desired pyridinone G was cleaved from the swelled resin by addition of 3 ml 1M NaOH and 1 ml THF to each RV, followed by agitation for lh.
  • the resin was filtrated and the filtrate was collected in a vial. The cleavage procedure was repeated twice.
  • the combined product collections were made acidic with amberlite IR- 120(H), which was filtered off and washed with methanol.
  • the filtrate was concentrated and the residue lyophilized to yield 40 mg (47% overall) of G as a bright yellow solid.
  • the spectroscopic data were identical to the conesponding 2-pyridinone prepared in solution.
  • Organozink iodide (2.16 mmol, in about 10 mL of THF) is transferred via a canula to a THF solution of 5 mol % Pd(PPh 3 ) 4 (0.127 g, 0.11 mmol) and brominated 2-pyridinone (X g, 2.19 mmol) at room temperature under an argone atmosphere. The solution is then stirred for 3 h. The mixture is thereafter worked up by pouring it into a saturated NH 4 C1 aqueous solution (20 mL) and extracting with diethyl ether. The combined organic layers are dried over CaCl 2 . The organic extracts are filtered and concentrated under reduced pressure. The crude residue is subjected to flash silica gel chromatography to give the desired R 5 substituted 2-pyridinone.
  • 2-pyrrolidinone (151 ⁇ L, 2.0 mmol), brominated 2-pyridinone (X g, 3.0 mmol), 1,1 '- bis(diphenylphosphino)-fenocene (66 mg, 0.12 mmol), palladium (II) acetate (22 mg, 0.10 mmol) and sodium tert-butoxide (0.29 g, 3.0 mmol) in 10 mL of toluene under N 2 are heated in a sealed tube at 120 °C for 48 hr. The mixture is cooled to room temperature, filtered through Celite, and the filtrate concentrated onto silica gel. Flash chromatography then gives the lactam substituted 2-pyridinone.
  • a 2-pyridinone (1 g) is added during 10 min. to a stined mixture of nitric acid (95 %, 10 mL) and acetic anhydride (2.4 mL) at -12 °C. After 2 more minutes the solution is poured into ice- water, and the solid is removed, washed until acid-free and dried to give the desired nitrated 2-pyridinone.

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  • Pyridine Compounds (AREA)

Abstract

L'invention porte sur des nouveaux pyridinones et leurs dérivés, efficaces dans le traitement ou la prévention d'infections bactériennes à Gram négatif, lesdits pyridinones étant stables et faciles à dérivatiser, et sur les procédés au moyen desquels les dérivatisations sont assurées. Deux méthodes stéréosélectives et tolérantes des groupes fonctionnels, pour la synthèse des nouveaux pyridinones sont également décrites. Une des méthodes synthétiques consiste à faire réagir une imine et un dérivé d'acide de Meldrum en solution. L'autre méthode synthétique consiste également en une synthèse en phase solide desdits pyridinones, dans laquelle une imine est préparée liée à un support solide, et un dérivé d'acide de Meldrum est mis en réaction avec l'imine. Des nouveaux intermédiaires utiles dans les méthodes de synthèse en phase solide ou en solution des pyridinones sont décrits.
PCT/US2000/031879 1999-11-19 2000-11-20 Pyridinones pour le traitement et la prevention d'infections bacteriennes WO2001036426A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU19235/01A AU1923501A (en) 1999-11-19 2000-11-20 Pyridinones to treat and prevent bacterial infections
EP00982170A EP1233967A4 (fr) 1999-11-19 2000-11-20 Pyridinones pour le traitement et la prevention d'infections bacteriennes
US10/130,453 US6841559B1 (en) 1999-11-19 2000-11-20 Pyridinones to treat and prevent bacterial infections
CA002390658A CA2390658A1 (fr) 1999-11-19 2000-11-20 Pyridinones pour le traitement et la prevention d'infections bacteriennes

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US60/166,621 1999-11-19

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7262211B2 (en) 2001-12-04 2007-08-28 Dendreon Corporation Aromatic heterocyclic non-covalent inhibitors of urokinase and blood vessel formation
JP2008500270A (ja) * 2003-10-15 2008-01-10 イーエムテーエム ゲーエムベーハー 異なるタイプの細胞に機能的に影響を及ぼし、免疫性疾患、炎症性疾患、神経疾患、およびその他の疾患を治療するための新規なジペプチジルペプチダーゼｉｖ阻害剤
WO2009134203A1 (fr) 2008-04-30 2009-11-05 Fredrik Almqvist Nouveaux composés peptidomimétiques
US7659364B2 (en) * 2001-11-15 2010-02-09 Cis Bio International N-methyl-homocysteines and their use as well as process for their production
WO2011076687A1 (fr) 2009-12-22 2011-06-30 Bayer Schering Pharma Aktiengesellschaft Dérivés de pyridinone et compositions pharmaceutiques associées
WO2016075296A1 (fr) * 2014-11-13 2016-05-19 Quretech Bio Ab Dérivés de 2,3-dihydro-thiazolo [3,2-a] pyridin-5-one, leurs intermédiaires et leur utilisation comme agents antibactériens
CN113975274A (zh) * 2016-04-08 2022-01-28 快尔生物技术公司 环稠和的噻唑啉2-吡啶酮、其制备方法及其在治疗和/或预防结核中的用途

Citations (1)

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US4594431A (en) * 1983-08-01 1986-06-10 Eli Lilly Company Octahydroindolizinepropanoic acids and related compounds as enzyme inhibitors

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
DD84850A (fr) *

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Title
CHEMICAL ABSTRACTS, vol. 78, no. 12, 26 March 1973, Columbus, Ohio, US; abstract no. 72121Y, OLTHOFF ET AL.: "Thiazolo (3,2-a) pyridones" page 474; column 2; XP002939289 *
See also references of EP1233967A4 *
TODD ET AL.: "The synthesis of analogs of penicillin", vol. 75, 20 April 1953 (1953-04-20), pages 1895 - 1900, XP002939290 *

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7659364B2 (en) * 2001-11-15 2010-02-09 Cis Bio International N-methyl-homocysteines and their use as well as process for their production
US7262211B2 (en) 2001-12-04 2007-08-28 Dendreon Corporation Aromatic heterocyclic non-covalent inhibitors of urokinase and blood vessel formation
JP2008500270A (ja) * 2003-10-15 2008-01-10 イーエムテーエム ゲーエムベーハー 異なるタイプの細胞に機能的に影響を及ぼし、免疫性疾患、炎症性疾患、神経疾患、およびその他の疾患を治療するための新規なジペプチジルペプチダーゼｉｖ阻害剤
JP2011519372A (ja) * 2008-04-30 2011-07-07 フレードリク・アルムクヴィスト 新規ペプチド摸倣化合物
CN102066385A (zh) * 2008-04-30 2011-05-18 弗雷德里克·阿尔姆奎斯特 新的拟肽化合物
WO2009134203A1 (fr) 2008-04-30 2009-11-05 Fredrik Almqvist Nouveaux composés peptidomimétiques
US8598195B2 (en) 2008-04-30 2013-12-03 Fredrik Almqvist Peptidomimetic compounds
WO2011076687A1 (fr) 2009-12-22 2011-06-30 Bayer Schering Pharma Aktiengesellschaft Dérivés de pyridinone et compositions pharmaceutiques associées
WO2016075296A1 (fr) * 2014-11-13 2016-05-19 Quretech Bio Ab Dérivés de 2,3-dihydro-thiazolo [3,2-a] pyridin-5-one, leurs intermédiaires et leur utilisation comme agents antibactériens
CN107074878A (zh) * 2014-11-13 2017-08-18 快尔生物技术公司 2,3‑二氢‑噻唑并[3,2‑a]吡啶‑5‑酮衍生物、其中间体及其作为抗细菌剂的用途
US10294244B2 (en) 2014-11-13 2019-05-21 Quretech Bio Ab 2,3-dihydro-thiazolo[3,2-A]pyridin-5-one derivatives, intermediates thereof, and their use as antibacterial agents
AU2015345042B2 (en) * 2014-11-13 2019-10-17 Quretech Bio Ab 2,3-dihydro-thiazolo[3,2-a]pyridin-5-one derivatives, intermediates thereof, and their use as antibacerial agents
CN107074878B (zh) * 2014-11-13 2019-12-24 快尔生物技术公司 2,3-二氢-噻唑并[3,2-a]吡啶-5-酮衍生物、其中间体及其作为抗细菌剂的用途
CN113975274A (zh) * 2016-04-08 2022-01-28 快尔生物技术公司 环稠和的噻唑啉2-吡啶酮、其制备方法及其在治疗和/或预防结核中的用途
CN113975274B (zh) * 2016-04-08 2024-04-09 快尔生物技术公司 环稠和的噻唑啉2-吡啶酮、其制备方法及其在治疗和/或预防结核中的用途

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AU1923501A (en) 2001-05-30
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EP1233967A1 (fr) 2002-08-28
WO2001036426B1 (fr) 2001-12-06

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