Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—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
  • 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

Definitions

• R 2 is hydrogen; halogen; hydroxy; acyloxy; or (C 1 . 6 )alkoxy;
• R 3 is hydrogen; n is independently at each occurrence 0, 1 , or 2;
• R 1b is hydrogen; trifluoromethyl; (C ⁇ alkyl; (C 2-6 )alkenyl; (C 1-6 )alkoxycarbonyl; (C 1-
• R 7 is hydrogen; halogen; hydroxy; or (C 1-6 )alkyl;
• Z is carbon;
• this invention describes a compound of formula (I) wherein Z 1 and Z 3 are CR 1a and Z 4 is N. In some embodiments, this invention describes a compound of formula (I) wherein
• R is at each occurrence independently hydrogen; halogen; or cyano.
• this invention describes a compound of formula (I) wherein X is O.
• this invention describes a compound of formula (I) wherein X is NR 6 . In some embodiments, this invention describes a compound of formula (I) wherein
• Z 1 and Z 4 are N;
• Z 3 is CR 1a ;
• R 1 is OCH - R of Z 3 , Z 4 and Z 5 is hydrogen;
• R 1a of Z 6 is hydrogen, fluorine or cyano;
• A is CH 2 ;
• n of (CH 2 ) n is 1 ;
• R 4 is independently at each occurrence selected from the group consisting of hydrogen; hydroxy or halogen;
• X is O;
• B is CH 2 ;
• R 1 O is hydrogen; and
• U is CH 2 .
• this invention describes a compound of formula (I) wherein
• Z 1 and Z 4 are N; Z 3 is CR 1a ; R 1 is OCH o- R 1a of Z 3 , Z 4 and Z 5 is hydrogen; R 1a of Z 6 is ny ⁇ rogen, nuorine or cya ⁇ ; M IS 0H 2 ; n of (CH 2 ) n is 1 ; R 4 is independently at each occurrence selected from the group consisting of hydrogen; hydroxy or halogen; X is O; B is CH 2 ; R 10 is hydrogen; U is CH 2 ; and R 12 is: 4H-Pyrido[3,2-b][1 ,4]thiazin-3-oxo-6-yl; 8- Cyano-2,3-dihydro-benzo[1 ,4]dioxin-6-yl; 5-Cyano-2,3-dihydro-benzo[1 ,4]dioxin-7-yl; 4H- Pyrido[3,2-b][1 ,4]oxazin-3-
• this invention describes a process for the preparation of intermediates of formula (IV) useful in the preparation of compounds of formula (I), which process comprises: ⁇ a; reaciing a compouriu ui iormula (II) with a compound of formula (III) to give a useful intermediate having formula (IV):
• this invention describes a method of treating bacterial infections which comprises administering to a mammal in need thereof an effective amount of a compound of formula or any of its embodiments described herein.
• arylsulphonyl refers to a SO 2 aryl radical wherein aryl is as herein defined.
• aryl includes optionally substituted phenyl and naphthyl.
• Solvates maybe produced from crstallization from a given solvent or mixture of solvents, inorganic or organic. Solvates may also produced upon contact or exposure to solvent vapors, such as water.
• This invention includes within its scope stoichiometric and non-stoichiometric solvates including hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation.
• Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
• Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl />hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
• suspending agents for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or
• 6-Bromo-4H-pyrido[3,2-b][1 ,4]oxazin-3-one (6.0 g, 26.3 mmole) and trans-2- phenylvinylboronic acid (3.9 g, 26.3 mmole) were dissolved in 1 ,4-dioxane (150 mL) and the solution was degassed with argon.
• (Ph3P)4Pd (230 mg, 0.2 mmole) was added, followed by a solution of potassium carbonate (6.9 g, 50 mmole) in H2O (20 mL). The reaction was heated at reflux under argon overnight, then was cooled to room temperature and diluted with EtOAc (200 mL).
• 6-((E)-Styryl)-4H-pyrido[3,2-jfc>J[1 ,4]oxazin-3-one (1.2 g, 4.8 mmole) was dissolved in CH2CI2 (200 mL) and the solution was cooled to -78 0 C. Ozone was bubbled through the solution with stirring until a pale blue color appeared, then the excess ozone was removed by bubbling oxygen through the solution for 15 min. Dimethylsulfide (1.76 mL, an mm ⁇ ie; was a ⁇ e ⁇ iu me t>u ⁇ uLi ⁇ n, and the reaction was stirred at -78 0 C for 3 hr, then at room temperature overnight.
• the title compound (95 mg, 50%) was prepared as a yellow solid according to Example 16, except substituting 3-oxo-3,4-dihydro-2H-pyrido[3,2-jb][1 ,4Jthiazine-6- carbaldehyde for 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1 ,4]oxazine-6-carbaldehyde.
• the title compound (255 mg, 64%) was prepared as a mixture of diastereomers to give a light yellow solid according to Example 10, except substituting 2-[(2S)-2- (aminomethyl)-4-morpholinyl]-1 -[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethanol (310 mg, 0.758 mmol) for (1 R)-2-[(2S)-2-(aminomethyl)-4-morpholinyl]-1-[6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethanol and reacting that with 3-oxo-3,4-dihydro-2/-/-pyrido[3,2- jfc>][1 ,4]thiazine-6-carbaldehyde (166 mg, 0.855 mmol).
• the title compound (393 mg, 100%) was prepared as a colorless oil according to Example 25a, except substituting 1 ,1-dimethylethyl [(2S)-2-morpholinylmethyl]carbamate (227 mg, 1.05 mmol) for 1 ,1-dimethylethyl [ ⁇ fi ⁇ -morpholinylmethyllcarbamate and using 7-fluoro-2-(methyloxy)-8-(2-oxiranyl)-1 ,5-naphthyridine (198 mg, 0.90 mmol): LC/MS (+ve ion electrospray) m/z 437 (M+H) + .
• Certain compounds of this invention were tested in the rat infection model.
• Specific pathogen-free male Sprague-Dawley CD rats were used for all bacterial strains.
• Each therapy group consists of 5 animals. Infection was carried out by intrabronchial instillation of 100 ml bacterial suspension for H.influenzae H128, and 50 ml of bacterial suspension for S.pneumoniae 1629 via non-surgical intubation. All compounds were administered at 1 , 7, 24 and 31 hour post infection via oral gavage. In each experiment, an additional group of animals was included and served as untreated infected controls. Approximately 17 hour after the end of therapy, the animals were killed and their lungs excised and enumeration of the viable bacteria was conducted by standard methods. The lower limit of detection was 1.7 Iog10 CFU/lungs.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Communicable Diseases (AREA)
• Oncology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)

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• 2005
  • 2005-07-08 EP EP05771319A patent/EP1773831A1/en not_active Withdrawn
  • 2005-07-08 JP JP2007520525A patent/JP2008505920A/ja active Pending
  • 2005-07-08 US US11/570,441 patent/US20070254872A1/en not_active Abandoned
  • 2005-07-08 WO PCT/US2005/024221 patent/WO2006014580A1/en not_active Ceased

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