WO2010046388A1 - (aza)-1-méthyl-1h-quinolin-2-ones substituées comme antibactériens - Google Patents

(aza)-1-méthyl-1h-quinolin-2-ones substituées comme antibactériens Download PDF

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WO2010046388A1
WO2010046388A1 PCT/EP2009/063789 EP2009063789W WO2010046388A1 WO 2010046388 A1 WO2010046388 A1 WO 2010046388A1 EP 2009063789 W EP2009063789 W EP 2009063789W WO 2010046388 A1 WO2010046388 A1 WO 2010046388A1
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methyl
amino
dihydro
fluoro
naphthyridin
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PCT/EP2009/063789
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Alan Joseph Hennessy
Graham Elgin Jones
Roger Edward Markwell
Timothy Miles
Neil David Pearson
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Glaxo Group Limited
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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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D497/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D497/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D497/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • This invention relates to novel compounds, compositions containing them and their use as antibacterials including use in the treatment of tuberculosis.
  • WO02/08224 WO02/50061, WO02/56882, WO02/96907, WO2003087098, WO2003010138, WO2003064421, WO2003064431, WO2004002992, WO2004002490, WO2004014361, WO2004041210,WO2004096982, WO2002050036, WO2004058144, WO2004087145, WO2006002047, WO2006014580, WO2006010040, WO2006017326, WO2006012396, WO2006017468, WO2006020561, WO2006081179, WO2006081264, WO2006081289, WO2006081178, WO2006081182, WO2004024712, WO2004024713, WO2004035569, WO2004087647, WO2005016916, WO2005097781, WO2006010831, WO2006021448, WO2006032466,
  • This invention provides a compound of formula (I) or a pharmaceutically acceptable salt or N-oxide thereof:
  • Z 1 and Z ⁇ are independently selected from N and CH;
  • AB is OCH 2 , CH 2 O, NR 1 1 CH 2 or CH 2 NR 1 ⁇ RI 1 is selected from H, C(j_2)alkyl; formyl; (Ci_2)alkylcarbonyl; and (C j_ 2)alkylsulphonyl;
  • Rl a is selected from hydrogen; halogen; cyano; (C j_5)alkyl; (C j_5)alkylthio; trifluoromethyl; trifluoromethoxy; carboxy ; hydroxy optionally substituted with (C ⁇ _ ( 5)alkyl or (Cj_5)alkoxy-substituted(Cj_5)alkyl; (Cj_5)alkoxy-substituted(Cj_5)alkyl; hydroxy (Cj_6)alkyl; an amino group optionally N-substituted by one or two (Cj_6)alkyl, formyl, (C j_5)alkylcarbonyl or (Cj_5)alkylsulphonyl groups; or aminocarbonyl wherein the amino group is optionally substituted by (Ci_4)alkyl; Rib is H or F; R ⁇ is hydrogen;
  • R v and R w are hydrogen, R v is absent and R ⁇ is in the 1 -position and R w is hydrogen or R v and R w together are a bond;
  • R ⁇ is hydrogen; or when R v and R w are a bond, R ⁇ is in the 2-, 3- or 4- position and when R w is hydrogen,
  • R ⁇ is in the 1-, 2-, 3- or 4-position and R ⁇ is: hydroxy optionally substituted by (Ci_g)alkyl; amino optionally mono- or disubstituted independently by (Ci_g)alkyl or (C j_5)alkylcarbonyl; fluoro; carboxy; cyano; (C ⁇ _
  • (C i_4)alkyl optionally substituted with any of the groups listed above for R ⁇ ; provided that when R ⁇ is in the 4- position it is not optionally substituted hydroxyl or amino; provided that when R ⁇ is in the 1 -position and AB is CH2NRI 1 or R ⁇ is in the 4- position, it is not optionally substituted hydroxyl or amino; and provided that when R ⁇ is in the 1 -position and AB is CH2O, it is not optionally substituted amino;
  • R 4 is UR 5 ;
  • U is selected from CO and CH2 and
  • R 5 is an optionally substituted bicyclic carbocyclic or heterocyclic ring system (B): containing up to four heteroatoms in each ring in which at least one of rings (a)and (b) is aromatic; ⁇ l is C or N when part of an aromatic ring, or CRl4 when part of a non-aromatic ring;
  • X ⁇ is N, NRl3 ? O, S(O) X , CO or CRl4 when part of an aromatic or non-aromatic ring or may in addition be CR14R15 w hen part of a non aromatic ring; ⁇ 3 and X ⁇ are independently N or C; ⁇ l is a 0 to 4 atom linker group each atom of which is independently selected from N, NR ⁇ 5 O, S(O) x , CO and CRl4 when part of an aromatic or non-aromatic ring or may additionally be CRI 4R15 w hen part of a non aromatic ring;
  • Y ⁇ is a 2 to 6 atom linker group, each atom of Y ⁇ being independently selected from N, NRl3 ? O, S(O) X , CO, CR14 when part of an aromatic or non-aromatic ring or may additionally be CRI 4R15 w hen part of a non aromatic ring; each of R ⁇ and R ⁇ is independently selected from: H; (C j_2)alkylthio; halo; carboxy(Ci_2)alkyl; (Cj_2)alkyl; (Ci_2)alkoxycarbonyl; (Ci_2)alkylcarbonyl; (C ⁇ .
  • R!4 and R ⁇ may together represent oxo; each R!3 is independently H; trifluoromethyl; (Cj_2)alkyl optionally substituted by hydroxy, (Cj_2)alkoxy, (Cj_2)alkylthio, halo or trifluoromethyl; (C2)alkenyl; (C ⁇ _ 2)alkoxycarbonyl; (Cj_2)alkylcarbonyl; (Cj_2)alkylsulphonyl; aminocarbonyl wherein the amino group is optionally mono or disubstituted by (C j_2)alkyl; each x is independently O, 1 or 2.
  • This invention also provides a method of treatment of bacterial infections in mammals, particularly in man, which method comprises the administration to a mammal in need of such treatment an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and/or N-oxide thereof.
  • the invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or N-oxide thereof, for use in the treatment of bacterial infections in mammals.
  • the invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt and/or N-oxide thereof, and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt and/or N-oxide thereof, and a pharmaceutically acceptable carrier.
  • the invention provides a compound of formula (IA), or a pharmaceutically acceptable salt and/or N-oxide thereof, which is a compound of formula
  • R 3 is in the 1-, 2-, 3- or 4-position and R 3 is: hydroxy optionally substituted by (C j_5)alkyl; amino optionally mono- or disubstituted by (C i_6)alkyl; fluoro; carboxy; cyano; or
  • (C i_4)alkyl optionally substituted with any of the groups just listed for R 3 .
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable salt and/or N-oxide thereof, which is other than a compound of formula (IA).
  • R ⁇ a is hydrogen, (C j_4)alkoxy, (C j_4)alkylthio, (C ⁇ _ 4)alkyl, cyano, carboxy, hydroxymethyl or halogen; more particularly hydrogen, cyano, or halogen.
  • RI a or Rib is other than hydrogen.
  • Rl a is halo such as chloro or fluoro or cyano and RI" is hydrogen.
  • both Rl a and RI" are hydrogen.
  • R 2 is hydrogen.
  • R 3 include hydrogen; optionally substituted hydroxy; optionally substituted amino; fluoro; (C ⁇ _ 4) alkyl; l-hydroxy-(Ci_4) alkyl; (C ⁇ _ 4) alkoxycarbonyl. More particular R 3 groups are hydrogen; 1-hydroxyalkyl e.g. CH 2 OH; optionally substituted hydroxy e.g. methoxy; optionally substituted amino; fluoro; and ethoxycarbonyl. Most particularly R 3 is hydrogen or hydroxy, and if hydroxy, more preferably substituted in the 1- or 3 -position, most preferably in the 1 -position.
  • AB is OCH 2 , CH 2 O, NHCH 2 , N(C ⁇ )CH 2 or CH 2 NH, such as OCH 2 , NHCH 2 or CH 2 NH.
  • U is CH 2 .
  • R ⁇ is an aromatic heterocyclic ring (A) having 8-11 ring atoms including 2-4 heteroatoms of which at least one is N or NR I 3 in which, in particular embodiments, Y ⁇ contains 2-3 heteroatoms, one of which is S and 1-2 are N, with one N bonded to X ⁇ .
  • the heterocyclic ring (A) has ring (a) aromatic selected from optionally substituted benzo, pyrido, pyridazino and pyrimidino and ring (b) non aromatic and Y ⁇ has 3-4 atoms including at least one heteroatom, with O, S, CH2 or NR 13 bonded to X ⁇ , where R ⁇ is other than hydrogen, and either NHCO bonded via N to X ⁇ , or O, S, CH2, or NH bonded to X ⁇ .
  • the ring (a) contains aromatic nitrogen, and more particularly ring (a) is pyridine, pyridazine or pyrimidine.
  • rings (A) include optionally substituted:
  • (b) is non aromatic l,l,3-trioxo-l,2,3,4-tetrahydrol /6-benzo[l,4] thiazin-6-yl, benzo[l,3]dioxol-5-yl, 2,3- dihydro-benzo[l ,4]dioxin-6-yl, 3-substituted-3H-benzooxazol-2-one-6-yl, 3-substituted- 3H-benzooxazole-2-thione-6-yl, 3-substituted-3H-benzothiazol-2-one-6-yl, 4H- benzo[l,4]oxazin-3-one-6-yl (3-oxo-3,4-dihydro-2H-benzo[l,4]oxazin-6-yl), 4H- benzo[l,4]thiazin-3-one-6-yl (3-oxo-3,4-dihydro-2H-benzo[l
  • R ⁇ is H if in ring (a) or in addition (Ci_4)alkyl such as methyl or isopropyl when in ring (b). More particularly, in ring (b) R ⁇ is H when NR ⁇ is bonded to X ⁇ and (Cj.z ⁇ alkyl when NR ⁇ is bonded to X ⁇ .
  • R ⁇ and R ⁇ are independently selected from hydrogen, halo, hydroxy, (C ⁇ .4) alkyl, (Cj_4)alkoxy, nitro and cyano. More particularly R ⁇ is hydrogen. More particularly each R.14 is selected from hydrogen, chloro, fluoro, hydroxy, methyl, methoxy, nitro and cyano. Still more particularly R.14 is selected from hydrogen, fluorine or nitro.
  • R.14 and R ⁇ are each H.
  • R ⁇ include:
  • alkyl includes groups having straight and branched chains, for instance, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t- butyl, pentyl and hexyl.
  • alkenyl' should be interpreted accordingly.
  • Halo or halogen includes fluoro, chloro, bromo and iodo.
  • Haloalkyl moieties include 1-3 halogen atoms.
  • Some of the compounds of this invention may be crystallised or recrystallised from solvents such as aqueous and organic solvents. In such cases solvates may be formed.
  • This invention includes within its scope stoichiometric solvates including hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation.
  • phrases such as "a compound of formula (I) or a pharmaceutically acceptable salt or N-oxide thereof are intended to encompass the compound of formula (I), an N-oxide of formula (I), a pharmaceutically acceptable salt of the compound of formula (I), a solvate of formula (I), or any pharmaceutically acceptable combination of these.
  • a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof may include a pharmaceutically acceptable salt of a compound of formula (I) that is further present as a solvate.
  • the compounds of formula (I) are intended for use in pharmaceutical compositions it will readily be understood that in particular embodiments they are provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and particularly at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions; these less pure preparations of the compounds should contain at least 1%, more suitably at least 5% and more particularly from 10 to 59% of a compound of the formula (I) or pharmaceutically acceptable salt and/or N-oxide thereof.
  • Particular compounds according to the invention include those mentioned in the examples and their pharmaceutically acceptable N-oxides, salts and solvates.
  • (I) include the acid addition or quaternary ammonium salts, for example their salts with mineral acids e.g. hydrochloric, hydrobromic, sulphuric nitric or phosphoric acids, or organic acids, e.g. acetic, fumaric, succinic, maleic, citric, benzoic, p-toluenesulphonic, methanesulphonic, naphthalenesulphonic acid or tartaric acids.
  • Compounds of formula (I) may also be prepared as the N-oxide. The invention extends to all such derivatives.
  • Certain of the compounds of formula (I) may exist in the form of optical isomers, e.g. diastereoisomers and mixtures of isomers in all ratios, e.g. racemic mixtures.
  • the invention includes all such forms, in particular the pure isomeric forms.
  • the invention includes compounds in which the configuration of the 1 ,4-substituted cyclohexyl moiety is cis or trans, in particular trans.
  • the different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.
  • Certain compounds of formula (I) may also exist in polymorphic forms and the invention includes such polymorphic forms.
  • a process for preparing compounds of formula (I), and pharmaceutically acceptable salts and/or N-oxides thereof comprises reacting a compound of formula (II) with a compound of formula (III):
  • Rl a> , R.!' and R ⁇ ' are R ⁇ a , RI " and R ⁇ as defined in formula (I) or groups convertible thereto; TJ-, 7?-, R v and R w are as defined in formula (I);
  • QI is NR2'R4' or a group convertible thereto wherein R ⁇ ' and R ⁇ ' are R ⁇ and R ⁇ as defined in formula (I) or groups convertible thereto and Q ⁇ is H or R ⁇ or Q ⁇ and Q ⁇ together form an optionally protected oxo group; and
  • X is W and Y is CONH 2 :
  • X is OH and Y and R 3 ' together form an epoxide group; in which W is a leaving group, e.g. halo, methanesulphonyloxy, trifluoromethanesulphonyloxy or imidazolyl; and thereafter optionally or as necessary converting Q 1 and Q 2 to NR 2 R 4 '; converting R l a> , R lb> , R 2 ', R 3 ' and R 4 ' to R l a , R lb , R 2 , R 3 and R 4 ; converting intermediate linker A'-B' formed by the reaction of X and Y to A-B, converting A-B to other A-B, interconverting R v , R w , R l a , R lb , R 1 1, R 2 , R 3 and/or R 4 , and/or forming a pharmaceutically acceptable salt and/or N-oxide thereof.
  • W is a leaving group
  • Process variant (i) initially produces compounds of formula (I) where A'-B' is NR 1 i-CO which may be converted to A-B NRU-CH 2 .
  • Process variant (ii) produces compounds of formula (I) wherein A-B is NR 1 1 - CH 2 . Or CH 2 -NR 1 1 .
  • Process variant (iii) produces compounds of formula (I) wherein A-B is 0-CH 2 .
  • Process variant (iv) produces compounds of formula (I) wherein one of A and B is CH 2 and the other is NR 1 1 or O.
  • Process variant (v) produces compounds of formula (I) wherein A-B is OCH 2 .
  • Process variant (vi) initially produces compounds of formula (I) where A'-B' is NHCO which may be converted to A-B NR 1 1 -CH 2 .
  • Process variant (vii) produces compounds of formula (I) wherein A-B is OCH 2 and R 3 is OH in the 1 -position.
  • the reaction is a standard amide formation reaction involving e.g.: 1. Activation of a carboxylic acid (e.g. to an acid chloride, mixed anhydride, active ester or other species), and treatment with an amine (Ogliaruso, M. A.; Wolfe, J.F. in The Chemistry of Functional Groups (Ed. Patai, S.) Suppl. B: The Chemistry of Acid Derivatives, Pt. 1 (John Wiley and Sons, 1979), pp 442-8; Beckwith, A.L.J, in The Chemistry of Functional Groups (Ed. Patai, S.) Suppl. B: The Chemistry of Amides (Ed.
  • the acid and amine are preferably reacted in the presence of an activating agent such as l-(dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDC) or 1-hydroxybenzotriazole (HOBT) or O-(7- azabenzotriazol-l-yl)- ⁇ /, ⁇ /,N',N'-tetramethyluronium hexafluorophosphate (HATU); or 2.
  • EDC l-(dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride
  • HOBT 1-hydroxybenzotriazole
  • O-(7- azabenzotriazol-l-yl)- ⁇ /, ⁇ /,N',N'-tetramethyluronium hexafluorophosphate (HATU) or 2.
  • reaction is a standard reductive alkylation using, e.g., sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride (Gribble, G. W. in Encyclopedia of Reagents for Organic Synthesis (Ed. Paquette, L. A.) (John Wiley and Sons, 1995), p 4649).
  • sodium borohydride sodium cyanoborohydride
  • sodium triacetoxyborohydride sodium triacetoxyborohydride
  • a base for example sodium hydride
  • a methyl cyclohexane-derived alkylating agent such as a cyclohexylmethyl methanesulphonate.
  • the latter may be prepared from a hydroxymethyl cyclohexane (prepared from the corresponding acid by reduction with eg.
  • the process variant (iv) is a standard alkylation reaction well known to those skilled in the art, for example where an alcohol or amine is treated with an alkyl halide in the presence of a base (for example see March, J; Advanced Organic Chemistry, Edition 3 (John Wiley and Sons, 1985), p364-366 and p342-343).
  • the process is preferably carried out in a polar solvent such as N,N-dimethylformamide or 1,4-dioxane.
  • the leaving group W is halogen, methanesulphonyloxy, ethanesulphonyloxy or trifluoromethanesulphonyloxy and the reaction is a standard amine formation reaction such as direct alkylation described in (Malpass, J. R., in Comprehensive Organic Chemistry, Vol. 2 (Ed. Sutherland, I. O.), p 4 ff.) or aromatic nucleophilic displacement reactions (see references cited in Comprehensive Organic Chemistry, Vol. 6, p 946-947 (reaction index); Smith, D. M. in Comprehensive Organic Chemistry, Vol. 4 (Ed. Sammes, P. G.) p 20 ff).
  • This transformation may also be catalysed by a transition metal such as palladium (for examples see Surry, David S.; Buchwald, Stephen L. Angewandte Chemie, International Edition (2008), 47(34), 6338-6361).
  • a transition metal such as palladium
  • X and Y contains OH
  • this is preferably converted to an OM group where M is an alkali metal by treatment of an alcohol with a base.
  • the base is preferably inorganic such as NaH, K2CO3, lithium diisopropylamide or sodium, or metal alkoxide such as sodium methoxide.
  • the leaving group W is a halogen, methanesulphonyloxy, ethanesulphonyloxy or trifluoromethanesulphonyloxy.
  • the reaction may be carried out as described in Chapman et.al., J. Chem Soc, (1956),1563, Gilligan et. al, J. Med.
  • the leaving group W is preferably chloro, bromo or trifluoromethylsulphonyl and the reaction is the palladium catalysed process known as the "Buchwald" reaction (J. Yin and S. L. Buchwald, Org.Lett., 2000, 2, 1101).
  • This utilizes a suitable palladium catalyst/ligand combination, for example tris(dibenzylideneacetone)dipalladium(0) and 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (xantphos), and a base, for example caesium carbonate.
  • process variant (vii) is the standard epoxide opening of the epoxide (III) with the anion OM where M is an alkali metal, formed by treatment of the alcohol
  • the base is preferably inorganic such as NaH, lithium diisopropylamide or sodium, or, metal alkoxide such as sodium methoxide.
  • An amide group A' -B' may be reduced to the corresponding amine using a reducing agent such as lithium aluminium hydride.
  • a reducing agent such as lithium aluminium hydride.
  • An example of a group Ql convertible to NR ⁇ R4 is NR2'R4' or halogen. Halogen may be displaced by an amine HNR2'R4' by a conventional displacement reaction.
  • R ⁇ ' and R ⁇ ' are novel and as such form part of the invention.
  • one of R ⁇ ' and R ⁇ ' is an N-protecting group, such as such as t- butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl or trifluoroacetyl. This may be removed by several methods well known to those skilled in the art (for examples see "Protective Groups in Organic Synthesis, T.W. Greene and P.G.M.
  • R ⁇ COW or reductive alkylation with an aldehyde R ⁇ CHO under conventional conditions (see for examples Smith, M.B.; March, J. M. Advanced Organic Chemistry, Wiley- Interscience).
  • Suitable conditions include a borohydride reducing agent such as sodium cyanoborohydride (in methanol/chloro form/acetic acid). If the amine (III) is a hydrochloride salt then sodium acetate may be added to buffer the reaction.
  • Sodium triacetoxyborohydride is an alternative reducing agent.
  • the appropriate reagents containing the required R ⁇ group are known compounds or may be prepared analogously to known compounds, see for example WO02/08224, WO02/50061, WO02/56882, WO02/96907, WO2003087098, WO2003010138, WO2003064421, WO2003064431, WO2004002992, WO2004002490, WO2004014361, WO2004041210,WO2004096982, WO2002050036, WO2004058144, WO2004087145, WO06002047, WO06014580, WO06010040, WO06017326, WO06012396, WO06017468, WO06020561, WO2004/035569, WO2004/089947, WO2003082835, WO06002047, WO06014580, WO06010040, WO06017326, WO06012396, WO06017468
  • Interconversions of A-B, R v , R w , R l a , R lb , R 2 , R 3 and/or R 4 are conventional.
  • RI a halo may be introduced by conventional halogenation reactions eg chlorination with chlorosuccinimide in acetic acid to introduce a chloro group at R ⁇ a .
  • suitable conventional hydroxy protecting groups which may be removed without disrupting the remainder of the molecule include acyl and alkylsilyl groups. N-protecting groups are removed by conventional methods.
  • RI a methoxy is convertible to RI a hydroxy by treatment with lithium and diphenylphosphine (general method described in Ireland et al, J. Amer. Chem. Soc, 1973, 7829) or HBr. Alkylation of the hydroxy group with a suitable alkyl derivative bearing a leaving group such as halide, yields RI a substituted alkoxy.
  • RI a halogen is convertible to other Rl a by conventional means, for example to hydroxy, alkylthiol (via thiol) and amino using metal catalysed coupling reactions, for example using copper as reviewed in Synlett (2003), 15, 2428-2439 and Angewandte Chemie, International Edition, 2003, 42(44), 5400-5449.
  • R l a> and R lb> are preferably R l a and R lb .
  • R 3 ' is R 3 or more preferably hydrogen or hydroxy. Conversions of R 3 ' to R 3 and interconversions of R 3 are carried out conventionally, for example as described in WO2004002992 or WO03087098.
  • RI 1 hydrogen is convertible to other RI 1 by conventional means.
  • RI 1 alkyl may be introduced by alkylation with the appropriate alkyl iodide and sodium hydride.
  • 2-Chloro-6-alkoxy-4-nitropyridine (XIIa) is ethoxyvinylated using 1- (ethoxyvinyl)tributylstannane in the presence of dichlorobis(diphenylphosphine) palladium(2).
  • the resulting vinyl ether (XIIb) is fluorinated with a fluorinating agent such as l-chloromethyl-4-fluoro-l,4-diazoniumbicyclo[2.2.2]octane bis (tetrafluoroborate) Selectfluor® and the resulting fluoroketone (XIII) is treated with dimethylformamide diethylacetal to give dimethylamino vinyl ketone (XIV). This is then hydrogenated to reduce the nitro group and cyclised by treatment with hydrochloric acid to give the 3-fluoro-4-hydroxynaphthyridine (IVd).
  • 2,4-pyridinediol 1 is mono-nitrated with, for example nitric acid and converted to the corresponding 2,4-dichloro-3-nitropyridine 3 using standard conditions with a chlorinating agent such as phosphorus oxychloride.
  • a chlorinating agent such as phosphorus oxychloride.
  • Di-substitution by a nucleophilic fluoride source such as potassium fluoride followed by mono-substitution by an alkoxide anion such as benzoxide or p-methoxylbenzoxide delivers the ether 5.
  • a protected glycine is introduced under thermal conditions followed by selective reduction of the nitro group with a suitable reducing agent such as zinc in acetic acid,to give the amine 7.
  • Standard N-methylation with eg methyl iodide followed by acid-mediated cyclisation/deprotection delivers 8-hydroxy- 1 -methyl-3 ,4-dihydropyrido [2 ,3 -b]pyrazin- 2(lH)-one 9.
  • the final step is oxidation using a mild oxidant such as activated manganese dioxide to deliver 8-hydroxy-l-methylpyrido[2,3-b]pyrazin-2(lH)-one 10.
  • Nitro compound 12 is treated with ammonium carbonate and triethylamine to give 13 which is then acylated and cyclised to give 15. Ring reduction and alkylation gives 17, which is treated under palladium catalysed conditions to give 18 (for a similar reaction see Anderson, Kevin W.; Ikawa, Takashi; Tundel, Rachel E.; Buchwald, Stephen L.. Journal of the American Chemical Society (2006), 128(33), 10694-10695.).
  • 4-Vinyl derivatives may be prepared by conventional procedures from a corresponding 4-halogeno derivative of formula (II) by e.g. a Heck synthesis as described in e.g. Organic Reactions, 1982, 27, 345.
  • 4-vinyl derivatives may be prepared from the 4-bromo derivative of formula (II) by conventional procedures such as a Suzuki reaction via trivinylcyclotriboroxane (J.Org. Chem. 2002, 67, 4968-4971), see also WO2008006648.
  • 4-Vinyl derivatives may be converted to 4-hydroxymethyl compounds of formula (II) by ozonolysis with sodium borohydride to decompose the ozonide.
  • 4-Carboxaldehyde and 4-hydroxymethyl derivatives of compounds of formula (II) may be prepared by reduction of 4-carboxy derivatives which may themselves be prepared by conventional procedures for preparation of carboxy heteroaromatics well known to those skilled in the art, for example by carbonylation of the corresponding 4- bromo or 4-trifluoromethanesulphonyloxy derivative using a palladium catalyst.
  • These 4-carboxy derivatives may be activated by conventional means, e.g. by conversion to an acyl halide or anhydride.
  • 4-Carboxy derivatives such as esters may be reduced to the 4-carboxaldehyde and 4-hydroxymethyl derivatives with for example lithium aluminium hydride or sodium borohydride. Reaction of the 4-hydroxymethyl derivative with mesyl chloride and triethylamine would give the mesylate derivative, while halogenation with phosphorus oxychloride or triphenylphosphine/carbon tetrachloride would give the halomethyl derivative.
  • the 4-carboxaldehyde may be obtained from from the acid or 4-alkenyl derivative by standard procedures well known to those skilled in the art.
  • 4-Aminomethyl derivatives of formula (II) may be prepared from a 4-CH ⁇ W derivative by displacement with sodium azide to give 4-CH2N3 followed by conventional reduction of the azide, or by displacement of the leaving group W with sodium or potassium succinimide followed by cleavage with eg hydrazine or methylhydrazine to give the amine (Gabriel synthesis).
  • antibacterial compounds according to the invention may be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other antibacterials.
  • compositions of the invention may be formulated for administration by any route and include those in a form adapted for oral, topical or parenteral use and may be used for the treatment of bacterial infection in mammals including humans.
  • the compositions may be in the form of tablets, capsules, powders, granules, lozenges, suppositories, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
  • topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
  • the formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
  • suitable conventional carriers such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
  • Such carriers may be present as from about 1% up to about 98% of the formulation. More usually they will form up to about 80% of the formulation.
  • Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • 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,
  • Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride.
  • fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • the dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • compositions may contain from 0.1% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit will preferably contain from 50-1000 mg of the active ingredient.
  • the dosage as employed for adult human treatment will preferably range from 100 to 3000 mg per day, for instance 1500 mg per day depending on the route and frequency of administration. Such a dosage corresponds to about 1.5 to about 50 mg/kg per day. Suitably the dosage is from 5 to 30 mg/kg per day.
  • the compound of formula (I) may be the sole therapeutic agent in the compositions of the invention or a combination with other antibacterials. If the other antibacterial is a ⁇ -lactam then a ⁇ -lactamase inhibitor may also be employed.
  • Compounds of formula (I) may be used in the treatment of bacterial infections caused by a wide range of organisms including both Gram-negative and Gram-positive organisms, such as upper and/or lower respiratory tract infections, skin and soft tissue infections and/or urinary tract infections.
  • Compounds of formula (I) may be also used in the treatment of tuberculosis caused by Mycobacterium tuberculosis. Some compounds of formula (I) may be active against more than one organism. This may be determined by the methods described herein.
  • MS mass spectrum
  • ES Electrospray mass spectroscopy
  • TFA trifluoroacetic acid
  • THF tetrahydrofuran
  • Pd/C palladium on carbon catalyst
  • DCM dichloromethane
  • MeOH refers to methanol
  • Et 2 O refers to diethyl ether
  • EtOAc refers to ethyl acetate
  • DIAD diisopropyl azodicarboxylate
  • PPI1 3 refers to triphenyl phosphine
  • PPI1 3 O refers to triphenyl phosphine oxide
  • Pd refers to tetrakis(triphenylphosphine)palladium(0).
  • HATU refers to O- (y-Azabenzotriazol-l-y ⁇ -N ⁇ N ⁇ N ⁇ tetramethyluronium hexafluorophosphate.
  • Mass spectra were obtained using electrospray (ES) ionization techniques. All temperatures are reported in degrees Celsius.
  • MP-carbonate refers to macroporous triethylammonium methylpolystyrene carbonate (Argonaut Technologies).
  • Amberlyst (A-21) refers to a weakly basic ion- exchange resin.
  • Celite refers to an inert, insoluble filtration aid, (also known as diatomaceous earth or Kieselguhr).
  • the SCX (Strong Cation eXchange) column has benzene sulphonic acid covalently attached to a silica support and as such strongly retains high pKa (ie basic) organic molecules such as amines, which can be subsequently liberated with excess ammonia in an appropriate solvent.
  • pKa ie basic organic molecules
  • references to preparations carried out in a similar manner to, or by the general method of, other preparations may encompass variations in routine parameters such as time, temperature, workup conditions, minor changes in reagent amounts etc.
  • Reactions involving metal hydrides including lithium hydride, lithium aluminium hydride, di-isobutylaluminium hydride, sodium hydride, sodium borohydride and sodium triacetoxyborohydride are carried out under argon or other inert gas.
  • Example 1 6- ⁇ (trans-4- ⁇ r(3-Fluoro-5-methyl-6-oxo-5.,6-dihvdro- 1 ,5-naphthyridin-4- yl)oxylmethyl ⁇ cvclohexyl)aminolmethyl ⁇ -2H-pyrido[3. l 2-61[l. l 41thiazin-3(4H)-one hydrochloride
  • Example 3 7-Fluoro-l -methyl-8- ⁇ (Urans-4- ⁇ ( ⁇ 1 ,31 oxathiolo [5,4-cl pyridin-6- ylmethyl)aminolcyclohexyl ⁇ methyr)oxyl-l,5-naphthyridin-2(lH)-one hydrochloride
  • the title compound was prepared from 8- ⁇ [(trans -A- aminocyclohexyl)methyl]oxy ⁇ -7-fluoro- 1 -methyl- 1 ,5-naphthyridin-2( lH)-one hydrochloride (for a preparation see Example l(j)) (60mg) and [l,3]oxathiolo[5,4- c]pyridine-6-carbaldehyde (39mg) (for a synthesis see WO2004058144, Example 61) by the general method of Example l(k).
  • Example 5 8- ⁇ (itmns-4- [(2,3-Dihydro [ 1 ,41 dioxino [2,3-cl pyridin-7- ylmethyl)aminolcvclohexyl ⁇ methyl)oxyl-7-fluoro-l-methyl-l,5-naphthyridin-2(lH)- one hydrochloride
  • Example l(j) The title compound was prepared from %- ⁇ [(trans-4- aminocyclohexyl)methyl]oxy ⁇ -7-fluoro- 1 -methyl- 1 ,5-naphthyridin-2( lH)-one hydrochloride (for a preparation see Example l(j)) (60mg) and 2,3- dihydro[l,4]dioxino[2,3-c]pyridine-7-carboxaldehyde (for a synthesis see WO2004058144 Example 2(c) or WO2003087098 Example 19(d)) (38.5mg), by the general method of Example l(k). The crude product, after work-up, was chromatographed on a reverse-phase ⁇ PLC system with mass-directed collection
  • Example 6 3- ⁇ ⁇ (trans-4- ⁇ r(3-Fluoro-5-methyl-6-oxo-5.,6-dihvdro- 1 ,5-naphthyridin-4- vDoxylmethyllcvclohexyDaminolmethyll-SH-pyridazinorS ⁇ - ⁇ iri ⁇ lthiazin- ⁇ fTH)- one hydrochloride
  • the title compound was prepared from 8- ⁇ [(trans-4- aminocyclohexyl)methyl]oxy ⁇ -7-fluoro- 1 -methyl- 1 ,5-naphthyridin-2( lH)-one hydrochloride (for a preparation see Example l(j)) (80 mg) and 6-oxo-6,7-dihydro-5 ⁇ - pyridazino[3,4-b][l,4]thiazine-3-carbaldehyde (for a synthesis see WO2004058144, Example 58) (50% pure; 91 mg) by the general method of Example l(k) (elution with 0- 20% methanol-DCM in the silica gel chromatography) to give a yellow solid (31 mg), after conversion to a hydrochloride salt.
  • Example 7 7-Chloro-6- ⁇ ⁇ (trans-4- ⁇ r(3-Fluoro-5-methyl-6-oxo-5,6-dihvdro- 1 ,5- naphthyridin ⁇ -vDoxylmethyllcvclohexyDaminolmethyll-lH-pyridorS.,!- b] [l,41oxazin-3(4H)-one hydrochloride
  • the title compound was prepared from %- ⁇ [(trans-4- aminocyclohexyl)methyl]oxy ⁇ -7-fluoro- 1 -methyl- 1 ,5-naphthyridin-2( lH)-one hydrochloride (for a preparation see Example l(j)) (65 mg) and 7-chloro-3-oxo-3,4- dihydro-2H-pyrido[3,2- ⁇ ][l,4]oxazine-6-carboxaldehyde (35 mg) (for a synthesis see WO2003064421, Example 15(c)) by the general method of Example l(k) to give a yellow solid (29 mg), after conversion to the hydrochloride salt.
  • Example 8 6- ⁇ (trans-4- ⁇ [(3-Fluoro-5-methyl-6-oxo-5,6-dihydro- 1 ,5-naphthyridin-4- yl)oxylmethyl ⁇ cyclohexyl)aminolmethyl ⁇ -2H-pyrido[3,2-l>Ul,41oxazin-3(4H)-one hydrochloride
  • the title compound was prepared from %- ⁇ [(trans-4- aminocyclohexyl)methyl]oxy ⁇ -7-fluoro- 1 -methyl- 1 ,5-naphthyridin-2( lH)-one hydrochloride (for a preparation see Example l(j)) (65 mg) and 3-oxo-3,4-dihydro-2H- pyrido[3,2- ⁇ ][l,4]oxazine-6-carboxaldehyde (29 mg) (for asynthesis see WO2004058144, Example 1(1)) by the general method of Example l(k) to give a yellow solid (56 mg), after conversion to the hydrochloride salt.
  • the title compound was prepared from 8- ⁇ [(trans -A- aminocyclohexyl)methyl]oxy ⁇ -7-fluoro- 1 -methyl- 1 ,5-naphthyridin-2( lH)-one hydrochloride (for a preparation see Example l(j)) (80 mg) and 2-oxo-2,3-dihydro-lH- pyrido[2,3- ⁇ ][l,4]thiazine-7-carboxaldehyde (for a synthesis see WO2004058144, Example 48(e)) by the general method of Example l(k) to give a yellow solid (46 mg) after conversion to the HCl salt.
  • Example 10 3- ⁇ ⁇ (trans-4- ⁇ r(3-Fluoro-5-methyl-6-oxo-5.,6-dihvdr()- 1 ,5-naphthyridin- 4-yl)aminolmethyl ⁇ cvclohexyl)aminolmethyl ⁇ -5H-pyridazino[3. l 4-61 [l. l 41thiazin- 6(7H)-one dihydrochloride
  • the title compound was prepared from crude 10-fluoro-2,2-dimethyl-2,3-dihydro- lH,5H-[l,4,2]diazasilino[6,5,4-(ie]-l,5-naphthyridin-5-one and caesium fluoride (7.0 g) by the general method of Example l(f) (heated at 110 0 C for 24 hours). The crude product was chromatographed on silica gel (methanol-DCM) to give a solid (0.78 g). LC/MS (+ve ion electrospray): m/z 194 [MH + ].
  • the title compound was prepared from 1,1-dimethylethyl (trans -4- ⁇ [(3 -fluoro-5 - methyl-6-oxo-5,6-dihydro-l,5-naphthyridin-4-yl)amino]methyl ⁇ cyclohexyl)carbamate (0.8 g) with ⁇ Cl-l,4-dioxane by the general method of Example l(j), followed by treatment with MP-carbonate resin (2.8-3.5 mmol/g) (3.0 g) in DCM-methanol (1 : 1) (50 ml) for 5 hours at room temperature, to give the oily free base.
  • the title compound was prepared from %- ⁇ [(trans-4- aminocyclohexyl)methyl] amino ⁇ -7-fluoro- 1 -methyl- 1 ,5 -naphthyridin-2( lH)-one (62 mg; 95% purity) and 6-oxo-6,7-dihydro-5 ⁇ -pyridazino[3,4-b][l,4]thiazine-3-carboxaldehyde (for a synthesis see WO2004058144, Example 58)) (50% pure; 76 mg) by the general method of Example l(k) to give a yellow solid (26 mg) after conversion to the dihydrochloride salt.
  • Example 11 8-[( ⁇ r ⁇ »s-4-[(3.,4-Dihv(iro-2H-pyrano[2,3-clpyri(iin-6- ylmethvDaminolcvclohexyllmethvDoxyl-T-fluoro-l-methyl-l ⁇ -naphthyridin-KlH)- one hydrochloride
  • Example l(j) The title compound was prepared from 8- ⁇ [(trans -A- aminocyclohexyl)methyl]oxy ⁇ -7-fluoro- 1 -methyl- 1 ,5-naphthyridin-2( lH)-one hydrochloride (for a preparation see Example l(j)) (65 mg) and 3,4-dihydro-2H- pyrano[2,3-c]pyridine-6-carbaldehyde (for a synthesis see WO2004058144, Example 126(e)), by the general method of Example l(k).
  • Example 12 7-Fluoro-l-methyl-8- ⁇ r(trans-4- ⁇ r(7-oxo-l,5,6,7-tetrahydro-l.,8- naphthyridin-2-yl)methyll amino ⁇ cyclohexyDmethyll oxy ⁇ - 1 ,5-naphthyridin-2(lH)- one hydrochloride
  • the title compound was prepared from %- ⁇ [(trans-4- aminocyclohexyl)methyl]oxy ⁇ -7-fluoro- 1 -methyl- 1 ,5-naphthyridin-2( lH)-one hydrochloride (for a preparation see Example l(j)) (80 mg) and 7-oxo-5,6,7,8-tetrahydro- l,8-naphthyridine-2-carboxaldehyde (42 mg) (for a synthesis see WO2003087098, Example 307(f)) by the general method of Example l(k).
  • Example 13 7-Fluoro-l-methyl-8-[( ⁇ r ⁇ «y-4-[([l,31oxathiolo[5.,4-clpyridin-6- ylmethyl)aminolcyclohexyl ⁇ methyl)aminol-l,5-naphthyridin-2(lH)-one dihydrochloride
  • the title compound was prepared from %- ⁇ [(trans-4- aminocyclohexyl)methyl] amino ⁇ -7-fluoro- 1 -methyl- 1 ,5 -naphthyridin-2( lH)-one (for a preparation see Example 10(e)) (65 mg; 90% purity) and [l,3]oxathiolo[5,4-c]pyridine-6- carbaldehyde (for a synthesis see WO2004058144, Example 61) (32.5 mg) by the general method of Example l(k) (omitting the sodium acetate) to give a pale yellow solid (71 mg) after conversion to the title dihydrochloride salt).
  • Example 2(c) or WO2003087098 Example 19(d)) (15mg), by the general method of Example l(k) (initial stirring time Ih, then 5h after addition of borohydride).
  • the crude product was chromato graphed on silica gel, eluting with 0-20% methanol/dichloromethane to give the free base of the title compound (23mg, 54%).
  • Example 15 8- ⁇ (Urans-4- r(2,3-Dihydro ⁇ 1 ,41 dioxino f2,3-cl pyridin-7- ylmethyl)aminolcvclohexyl ⁇ methyl)aminol-7-fluoro-l-methyl-l,5-naphthyridin- 2(lH)-one dihydrochloride
  • Example 10(e) The title compound was prepared from 8- ⁇ [(trans -A- aminocyclohexyl)methyl] amino ⁇ -7-fluoro- 1 -methyl- 1 ,5 -naphthyridin-2( lH)-one (for a preparation see Example 10(e)) (65 mg; 90% purity) and 2,3-dihydro[l,4]dioxino[2,3- c]pyridine-7-carboxaldehyde (for a synthesis see WO2004058144 Example 2(c) or WO2003087098 Example 19(d)) (32 mg) by the general method of Example l(k)
  • Example 17 8- ⁇ (Urans-4- r(6J-Dihvdro [ 1 ,41 dioxino [2,3-cl pyridazin-3- ylmethyl)aminolcyclohexyl ⁇ methyl)oxyl-7-fluoro-l-methyl-l,5-naphthyridin-2(lH)- one hydrochloride
  • Example 18 A 2- U(trans-4- ⁇ r(3-Fluoro-5-methyl-6-oxo-5,6-dihvdro- 1 ,5- naphthyridin ⁇ -yDoxylmethyllcyclohexyDaminolmethyll-lH-pyrimidorS ⁇ - b] [l,41oxazin-7(6H)-one hydrochloride
  • trans-4-( ⁇ [(1,1 -Dimethylethyl)oxy] carbonyl ⁇ amino)cyclohexanecarboxylic acid To a stirred solution of trans-4-aminocyclohexanecarboxylic acid (1 g, 6.98 mmol) in tert-BuOH (10 niL) and NaOH (0.307 g, 7.68 mmol) in H 2 O (10 niL) was added di-tert-butyldicarbonate (1.7 rnL) at 0 C. The reaction mixture was stirred at room temperature overnight. To the reaction mixture hexane (50 mL) was added and the pH was adjusted to pH ⁇ 6 with 6N HCl.
  • the isolated yield of 8- ⁇ [(trans -4-aminocyclohexyl)methyl]oxy ⁇ -7-fluoro- 1- methyl-l,5-naphthyridin-2(lH)-one can be improved by and using unpurified 1,1- dimethylethyl (trans -4- ⁇ [(3 -fluoro-5-methyl-6-oxo-5,6-dihydro- 1,5 -naphthyridin-4- yl)oxy]methyl ⁇ cyclohexyl)carbamate material in the deprotection step.
  • Trifluoroacetic acid (5 mL, 64.9 mmol) was added to a solution of 1,1- dimethylethyl (trans-4- ⁇ [(7-fluoro- 1 -methyl-2-oxo- 1 ,2-dihydro-8- quinolinyl)oxy]methyl ⁇ cyclohexyl)carbamate (0.7g) in DCM (10 mL) and the mixture stirred at rt for Ih. The mixture was evaporated and the residue partitioned between water (20 mL) and DCM (20 mL). The aqueous was then washed with more DCM (30 mL), then CHCI 3 (30 ml) to remove PI1 3 PO from previous reaction.
  • the reaction mixture was stirred at rt for 0.5 h and then sodium triacetoxyboro hydride (239 mg, 1.128 mmol) was added. The suspension was stirred at rt for 3 h then additional sodium triacetoxyborohydride (239 mg, 1.128 mmol) was added and the suspension was stirred at rt overnight. Additional sodium triacetoxyborohydride (398 mg, 1.880 mmol) was added and the suspension was stirred at rt for a further 1.5 h. Saturated aq. NaHCO 3 (5OmL) was added to the reaction and the aqueous layer was extracted with 20%MeOH/DCM (3 x 5OmL).
  • the reaction mixture was stirred for 16 hours at rt.
  • the reaction mixture was concentrated under vacuum and washed with NaHCO 3 solution (30 ml), extracted in DCM (3 x 30 ml).
  • the combined organic layer was dried over Na 2 SO 4 , filtered and concentrated under vacuum to give crude compound.
  • the crude compound was purified by flash column chromatography with silica gel and eluted with 2-3% MeOH: CHCI 3 to obtain the free base of the title compound as white solid (75 mg).
  • Examples 27-30 were made using 8-(4-Amino-cyclohexyloxymethyl)-7-fluoro- l-methyl-lH-[l,5]naphthyridin-2-one (for a preparation see Example 26(g)) according to the general procedure of Example 26(h)
  • Example 31 6-1 [(4- ⁇ ydroxy-4- ⁇ r(5-methyl-6-oxo-5.,6-dihydro-l ,5-naphthyridin-4- yl)aminolmethyl ⁇ cyclohexyl)aminolmethyl ⁇ -2H-pyrido[3.,2-bl [l. l 41oxazin-3(4H)-one hydrochloride
  • Examples 32-36 were made using 8- ⁇ [(4-amino-l- hydroxycyclohexyl)methyl] amino ⁇ - 1 -methyl- 1 ,5 -naphthyridin-2( lH)-one (for a preparation see Example 31(e)) according to the general procedure of Example 31(f)
  • Examples 38-39 were made using %- ⁇ [(trans-4- aminocyclohexyl)methyl] amino ⁇ -7-fluoro- 1 -methyl- 1 ,5 -naphthyridin-2( lH)-one (for a preparation see Example 10(e)) according to the general procedure of Example 37.
  • Examples 40-50 were made according to the procedure of Example 18A(e) from 8- ⁇ [(trans -4-aminocyclohexyl)methyl]oxy ⁇ -7-fluoro- 1 -methyl- 1 ,5-naphthyridin-2( IH)- one (for a preparation see Example 18 A (d))
  • Example 51 6- ⁇ [ ⁇ r ⁇ «s-4- ⁇ [(3-Fluoro-5-methyl-6-oxo-5.,6-(iihv(iro-1,5-naphthyri(iin- 4-yl)methyllamino ⁇ cvclohexyl)aminolmethyl ⁇ -2H-pyrido[3 ,2-b] [1 ,4]oxazin-3(4H)- one hydrochloride
  • Example 52 7-Chloro-6- ⁇ [(fm «s-4- ⁇ r(3-fluoro-5-methyl-6-oxo-5,6-dihvdro-l,5- naphthyridin-4-yl)methyllamino ⁇ cvclohexyl)aminolmethyl ⁇ -2H-pyrido[3.,2- b] [l,41oxazin-3(4H)-one hydrochloride
  • the reaction mixture was diluted with CHCl 3 (30 mL) and washed with aq .NaHCO 3 solution (2 x 5 mL). The organic layer was washed with brine; dried over Na 2 SO 4 and concentrated.
  • the crude product was purified by silica gel (100-200) column chromatography by using 0-5% of MeOH in DCM as an eluent to yield the free base of the title compound (100 mg, 62%) as a cream color solid.
  • the reaction mixture was diluted with DCM (10 mL) and washed with aq.NaHCO 3 solution (5 mL). The aqueous layer was extracted with DCM (25 mL). The combined organic layers were washed with brine; dried over Na 2 SO 4 and concentrated.
  • the crude product was purified by silica gel (100-200) column chromatography by using 0-8% of MeOH in CHCl 3 as an eluent to yield the free base of the title compound (20 mg, 32%) as a yellow solid.
  • the reaction mixture was diluted with DCM (30 mL) and washed with sat. NaHCO 3 solution (10 mL). The organic layer was dried over Na 2 SO 4 and concentrated.
  • the crude compound was purified by silica gel (100-200 mesh) column chromatography by using 1-10% methanol in DCM as an eluent to afford the free base of the title compound (67 mg, 25.8%) as yellow solid.
  • Examples 58-62 were made from 8-(4-amino-cyclohexylmethoxy)-l-methyl- lH-pyrido[2,3-b]pyrazin-2-one (for a preparation see Example 57(m)) according to the general procedure of Example 57(n).
  • the title compound was prepared from ethyl 8-(bromomethyl)-l,4- dioxaspiro[4.5]decane-8-carboxylate (commercial) and 7-fluoro-8-hydroxy-l-methyl-l,5- naphthyridin-2(lH)-one (for a preparation see Example l(f)) using a standard alkylation reaction with caesium carbonate in DMF.
  • reaction mixture was heated at 100 0 C for 16 hours.
  • the solvents were distilled off and the reaction mixture was diluted with water (50ml) and stirred for 1 hour, filtered and washed with ethyl acetate (15ml) followed by diethyl ether (40 ml) to obtain the title compound as an off white solid (450mg, 82%).
  • the cake was slurried in water and stirred for 30 min at rt.
  • the solid was collected by filtration, and washed with water and dried under vacuum to give the product (1.54 g, 55%).
  • NCLS National Committee for Clinical Laboratory Standards
  • the minimum inhibitory concentration (MIC) was determined as the lowest concentration of compound that inhibited visible growth. A mirror reader was used to assist in determining the MIC endpoint. Compounds were evaluated against Gram-positive organisms, selected from
  • Enterococcus faecalis and Enter ococcus faecium were evaluated against Gram-negative organisms selected from Haemophilus influenzae, Moraxella catarrhalis, Acinetobacter baumanii, Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Legionella pneumophila, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae and Stenotrophomonas maltophilia.
  • the L. pneumophila isolates were tested using a modified CLSI procedure for broth microdilution. For this assay, compounds were tested in serial doubling dilutions over a concentration range of 0.03 to 32 mcg/mL. An inoculum of each test isolate was prepared in buffered yeast broth and adjusted to a density equivalent to a 0.5 McFarland standard. After inoculation, the microtitre plates were incubated at 37°C for 72 hours.
  • Example 63 which had a MIC ⁇ 8 ⁇ g/ml against a strain of at least one of the organisms listed above.
  • Example 63 which had a MIC ⁇ 8 ⁇ g/ml against a strain of at least one of the organisms listed above.
  • Example 63 which had a MIC ⁇ 8 ⁇ g/ml against a strain of at least one of the organisms listed above.
  • At least one strain of every organism listed above at least one Example had a MIC ⁇ 2 ⁇ g/ml.
  • the measurement of the minimum inhibitory concentration (MIC) for each tested compound was performed in 96 wells flat-bottom, polystyrene microtiter plates. Ten two- fold drug dilutions in neat DMSO starting at 400 ⁇ M were performed. Five ⁇ l of these drug solutions were added to 95 ⁇ l of Middlebrook 7H9 medium. (Lines A-H, rows 1-10 of the plate layout). Isoniazid was used as a positive control, 8 two-fold dilution of Isoniazid starting at 160 ⁇ gml ' ⁇ was prepared and 5 ⁇ l of this control curve was added to 95 ⁇ l of Middlebrook 7H9 (Difco catalogue Ref. 271310) + ADC medium (Becton Dickinson Catalogue Ref. 211887). (Row 11, lines A-H). Five ⁇ l of neat DMSO were added to row 12 (growth and Blank controls).
  • the inoculum was standardised to approximately 1x10 ' cfu/ml and diluted 1 in 100 in Middlebrook 7H9+ADC medium and 0.025% Tween 80 (Sigma P4780), to produce the final inoculum of H37Rv strain (ATCC25618).
  • One hundred ⁇ l of this inoculum was added to the entire plate but G-12 and H-12 wells (Blank controls). All plates were placed in a sealed box to prevent drying out of the peripheral wells and they were incubated at 37 0 C without shaking for six days.
  • a resazurin solution was prepared by dissolving one tablet of resazurin (Resazurin Tablets for Milk Testing; Ref 330884Y VWR International Ltd) in 30 ml sterile PBS (phosphate buffered saline). 25 ⁇ l of this solution was added to each well. Fluorescence was measured (Spectramax M5 Molecular Devices, Excitation 530nm, Emission 590nm) after 48 hours to determine the MIC value. Examples 1, 3, 5, 7-9, 14, 15, 18A, 18B, 25-40, 44-46, 49-54 and 59-63 were tested in the Mycobacterium tuberculosis H37Rv inhibition assay.
  • Examples 9, 27, 37, 38, 44 and 45 showed an MIC value of 1.1 ⁇ g/ml or lower.
  • Examples 1, 7, 8, 18A, 18B, 25, 26, 28, 29, 39, 46, 49 and 50 showed an MIC value of 0.2 ⁇ g/ml or lower.
  • Examples 3, 5, 30-36, 40, 51-54, 59-63 showed an MIC value of 3.0 ⁇ g/ml or lower.
  • Examples 14 and 15 gave MIC values higher than 3.0 ⁇ g/ml.

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Abstract

La présente invention concerne des composés bicycliques contenant de l’azote et leur utilisation comme antibactériens.
PCT/EP2009/063789 2008-10-23 2009-10-21 (aza)-1-méthyl-1h-quinolin-2-ones substituées comme antibactériens WO2010046388A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013021363A1 (fr) 2011-08-11 2013-02-14 Actelion Pharmaceuticals Ltd Dérivés de quinazoline-2,4-dione
WO2014022752A1 (fr) 2012-08-03 2014-02-06 Amgen Inc. Macrocycles en tant qu'inhibiteurs de pim
WO2017029602A3 (fr) * 2015-08-16 2017-04-13 Glaxosmithkline Intellectual Property Development Limited Composés à utiliser dans des applications antibactériennes
WO2024050370A1 (fr) * 2022-08-30 2024-03-07 1Cbio, Inc. Composés hétérocycliques et leurs procédés d'utilisation

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AR096135A1 (es) 2013-05-02 2015-12-09 Actelion Pharmaceuticals Ltd Derivados de la quinolona
AR101704A1 (es) 2014-08-28 2017-01-04 Otsuka Pharma Co Ltd Compuestos heterocíclicos fusionados

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WO2003087098A1 (fr) * 2001-05-25 2003-10-23 Smithkline Beecham P.L.C. Heterocycles bicycliques contenant de l'azote et utilises comme produits antibacteriens
WO2004002992A1 (fr) * 2002-06-26 2004-01-08 Glaxo Group Limited Composés
WO2004035569A2 (fr) * 2002-10-10 2004-04-29 Morphochem Aktiengesellschaft für kombinatorische Chemie Nouveaux composes antibacteriens
WO2008006648A1 (fr) * 2006-06-09 2008-01-17 Glaxo Group Limited 1-méthyl-1h-quinolin-2-ones et 1-méthyl-1h-1,5-naphthyridin-2-ones substitués, en tant qu'antibactériens

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WO2003087098A1 (fr) * 2001-05-25 2003-10-23 Smithkline Beecham P.L.C. Heterocycles bicycliques contenant de l'azote et utilises comme produits antibacteriens
WO2004002992A1 (fr) * 2002-06-26 2004-01-08 Glaxo Group Limited Composés
WO2004035569A2 (fr) * 2002-10-10 2004-04-29 Morphochem Aktiengesellschaft für kombinatorische Chemie Nouveaux composes antibacteriens
WO2008006648A1 (fr) * 2006-06-09 2008-01-17 Glaxo Group Limited 1-méthyl-1h-quinolin-2-ones et 1-méthyl-1h-1,5-naphthyridin-2-ones substitués, en tant qu'antibactériens

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013021363A1 (fr) 2011-08-11 2013-02-14 Actelion Pharmaceuticals Ltd Dérivés de quinazoline-2,4-dione
US8916573B2 (en) 2011-08-11 2014-12-23 Actelion Pharmaceuticals Ltd. Quinazoline-2,4-dione derivatives
WO2014022752A1 (fr) 2012-08-03 2014-02-06 Amgen Inc. Macrocycles en tant qu'inhibiteurs de pim
AU2016307969B2 (en) * 2015-08-16 2019-02-14 Glaxosmithkline Intellectual Property Development Limited Antibacterial agents comprising a pyrazino[2,3-b][1,4]oxazin-3-one or a related ring system
CN108137616A (zh) * 2015-08-16 2018-06-08 葛兰素史克知识产权开发有限公司 包含吡嗪并[2,3-b][1,4]噁嗪-3-酮或相关环系的抗菌剂
JP2018523675A (ja) * 2015-08-16 2018-08-23 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 ピラジノ［２，３−ｂ］［１，４］オキサジン−３−オン又は関連する環系を含む抗菌剤
WO2017029602A3 (fr) * 2015-08-16 2017-04-13 Glaxosmithkline Intellectual Property Development Limited Composés à utiliser dans des applications antibactériennes
US10364254B2 (en) 2015-08-16 2019-07-30 Glaxosmithkline Intellectual Property Development Limited Compounds for use in antibacterial applications
AU2016307969C1 (en) * 2015-08-16 2019-09-05 Glaxosmithkline Intellectual Property Development Limited Antibacterial agents comprising a pyrazino[2,3-b][1,4]oxazin-3-one or a related ring system
EA033314B1 (ru) * 2015-08-16 2019-09-30 Глаксосмитклайн Интеллекчуал Проперти Дивелопмент Лимитед АНТИБАКТЕРИАЛЬНЫЕ АГЕНТЫ, СОДЕРЖАЩИЕ ПИРАЗИНО[2,3-b][1,4]ОКСАЗИН-3-ОН ИЛИ РОДСТВЕННУЮ КОЛЬЦЕВУЮ СИСТЕМУ
AU2019200226B2 (en) * 2015-08-16 2020-01-23 Glaxosmithkline Intellectual Property Development Limited Antibacterial agents comprising a pyrazino[2,3-b][1,4]oxazin-3-one or a related ring system
US10683307B2 (en) 2015-08-16 2020-06-16 Glaxosmithkline Intellectual Property Development Limited Compounds for use in antibacterial applications
CN108137616B (zh) * 2015-08-16 2020-06-26 葛兰素史克知识产权开发有限公司 包含吡嗪并[2,3-b][1,4]噁嗪-3-酮或相关环系的抗菌剂
WO2024050370A1 (fr) * 2022-08-30 2024-03-07 1Cbio, Inc. Composés hétérocycliques et leurs procédés d'utilisation

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