[go: up one dir, main page]

US20070185153A1 - Compounds - Google Patents

Compounds Download PDF

Info

Publication number
US20070185153A1
US20070185153A1 US11/611,214 US61121406A US2007185153A1 US 20070185153 A1 US20070185153 A1 US 20070185153A1 US 61121406 A US61121406 A US 61121406A US 2007185153 A1 US2007185153 A1 US 2007185153A1
Authority
US
United States
Prior art keywords
dihydro
mmol
methyl
naphthyridin
methanol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US11/611,214
Other languages
English (en)
Inventor
Nathalie Cailleau
David Davies
Alan Hennessy
Graham Jones
Timothy Miles
Neil Pearson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Glaxo Group Ltd
Original Assignee
Glaxo Group Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Glaxo Group Ltd filed Critical Glaxo Group Ltd
Priority to US11/611,214 priority Critical patent/US20070185153A1/en
Assigned to GLAXO GROUP LIMITED reassignment GLAXO GROUP LIMITED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CAILLEAU, NATHALIE, DAVIES, DAVID THOMAS, HENNESSY, ALAN JOSEPH, JONES, GRAHAM ELGIN, MILES, TIMOTHY JAMES, PEARSON, NEIL DAVID
Publication of US20070185153A1 publication Critical patent/US20070185153A1/en
Abandoned legal-status Critical Current

Links

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
    • C07D471/12—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 three hetero rings
    • C07D471/16—Peri-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
    • 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
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • This invention relates to novel compounds, compositions containing them and their use as antibacterials.
  • 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, WO01/25227, WO02/40474, WO02/07572, WO2004024712, WO2004024713, WO2004035569, WO2004087647, WO2004089947, WO20050169
  • This invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate and/or N-oxide thereof: wherein:
  • W 1 , W 2 and W 3 are CR 4 R 8
  • W 2 and W 3 are CR 4 R 8 and W 1 represents a bond between W 3 and N;
  • X is O, CR 4 R 8 , or NR 6 ;
  • R 4 is as defined for R 1a and R 1b and the remainder and R 8 are hydrogen or one R 4 and R 8 are together oxo and the remainder are hydrogen;
  • R 6 is hydrogen or (C 1-6 )alkyl; or together with R 2 forms Y;
  • R 7 is hydrogen; halogen; hydroxy optionally substituted with (C 1-6 )alkyl; or (C 1-6 )alkyl;
  • Y is CR 4 R 8 CH 2 ; CH 2 CR 4 R 8 ; (C ⁇ O); CR 4 R 8 ; CR 4 R 8 (C ⁇ O); or (C ⁇ O)CR 4 R 8 ;
  • X 1 is C or N when part of an aromatic ring, or CR 14 when part of a non-aromatic ring;
  • X 2 is N, NR 13 , O, S(O) X , CO or CR 14 when part of an aromatic or non-aromatic ring or may in addition be CR 14 R 15 when part of a non aromatic ring;
  • X 3 and X 5 are independently N or C;
  • Y 1 is a 0 to 4 atom linker group each atom of which is independently selected from N, NR 13 , O, S(O) X , CO and CR 14 when part of an aromatic or non-aromatic ring or may additionally be CR 14 R 15 when part of a non aromatic ring;
  • Y 2 is a 2 to 6 atom linker group, each atom of Y 2 being independently selected from N, NR 13 , O, S(O) X , CO, CR 14 when part of an aromatic or non-aromatic ring or may additionally be CR 14 R 15 when part of a non aromatic ring;
  • each of R 14 and R 15 is independently selected from: H; (C 1-4 )alkylthio; halo; carboxy(C 1-4 )alkyl; (C 1-4 )alkyl; (C 1-4 )alkoxycarbonyl; (C 1-4 )alkylcarbonyl; (C 1-4 )alkoxy(C 1-4 )alkyl; hydroxy; hydroxy(C 1-4 )alkyl; (C 1-4 )alkoxy; nitro; cyano; carboxy; amino or aminocarbonyl optionally mono- or di-substituted by (C 1-4 )alkyl; or
  • R 14 and R 15 may together represent oxo
  • each R 13 is independently H; trifluoromethyl; (C 1-4 )alkyl optionally substituted by hydroxy, (C 1-6 )alkoxy, (C 1-6 )alkylthio, halo or trifluoromethyl; (C 2-4 )alkenyl; (C 1-4 )alkoxycarbonyl; (C 1-4 )alkylcarbonyl; (C 1-6 )alkylsulphonyl; aminocarbonyl wherein the amino group is optionally mono or disubstituted by (C 1-4 )alkyl;
  • each x is independently 0, 1 or 2;
  • R 9 is fluoro or hydroxy.
  • 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, solvate and/or N-oxide thereof.
  • the invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate and/or N-oxide thereof, in the manufacture of a medicament for use in the treatment of bacterial infections in mammals.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate and/or N-oxide thereof, and a pharmaceutically acceptable carrier.
  • each R 1a and R 1b is independently hydrogen, (C 1-4 )alkoxy, (C 1-4 )alkylthio, (C 1-4 )alkyl, cyano, carboxy, hydroxymethyl or halogen; more particularly hydrogen, methoxy, methyl, cyano, or halogen.
  • each R 1a and R 1b is hydrogen, methoxy, methyl, or halogen, such as chloro or fluoro.
  • halogen such as chloro or fluoro.
  • only one group R 1a or R 1b is other than hydrogen, such as R 1a chloro, fluoro or methoxy.
  • both R 1a and R 1b are other than hydrogen, more particularly halogen, such as R 1a fluoro and R 1b chloro or fluoro.
  • R 2 is hydrogen
  • R 3 include hydrogen; optionally substituted hydroxy; optionally substituted amino; halogen; (C 1-4 )alkyl; 1-hydroxy-(C 1-4 )alkyl; optionally substituted aminocarbonyl. More particular R 3 groups are hydrogen; CONH 2 ; 1-hydroxyalkyl e.g. CH 2 OH; optionally substituted hydroxy e.g. methoxy; optionally substituted amino; and halogen, in particular fluoro. Most particularly R 3 is hydrogen, hydroxy or fluoro.
  • the stereochemistry at the carbon atom to which the group R 9 is attached is S.
  • n is 1.
  • R 3 is in the 3- or 4-position.
  • A is (ia), n is 1 and R 3 is in the 3-position, and more particularly is cis to the NR 2 group.
  • A is a group (ia) in which n is 1 and R 3 is hydrogen or hydroxy.
  • X is CR 4 R 8 , R 8 is H and R 4 is H or OH and more particularly OH is trans to R 7 .
  • W 1 is a bond.
  • R 7 is H.
  • W 1 is a bond
  • X, W 2 and W 3 are each CH 2 and R 7 is H.
  • U is CH 2 .
  • R 5 is an aromatic heterocyclic ring (B) having 8-11 ring atoms including 2-4 heteroatoms of which at least one is N or NR 13 in which, in particular embodiments, Y 2 contains 2-3 heteroatoms, one of which is S and 1-2 are N, with one N bonded to X 3 .
  • the heterocyclic ring (B) has ring (a) aromatic selected from optionally substituted benzo, pyrido and pyridazino and ring (b) non aromatic and Y 2 has 3-5 atoms, more particularly 4 atoms, including at least one heteroatom, with O, S, CH 2 or NR 13 bonded to X 5 where R 13 is other than hydrogen, and either NHCO bonded via N to X 3 , or O, S, CH 2 or NH bonded to X 3 .
  • the ring (a) contains aromatic nitrogen, and more particularly ring (a) is pyridine or pyrazine.
  • rings (B) include optionally substituted:
  • R 13 is H if in ring (a) or in addition (C 1-4 )alkyl such as methyl or isopropyl when in ring (b). More particularly, in ring (b) R 13 is H when NR 13 is bonded to X 3 and (C 1-4 )alkyl when NR 13 is bonded to X 5 .
  • R 14 and R 15 are independently selected from hydrogen, halo, hydroxy, (C 1-4 )alkyl, (C 1-4 )alkoxy, nitro and cyano. More particularly R 15 is hydrogen.
  • 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 15 are each H.
  • R 5 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, solvate 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, solvate 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.
  • salts of the above-mentioned compounds of formula (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 salts, solvates and/or N-oxides.
  • 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 enantiomers and diastereoisomers at the attachment points of NR 2 , R 3 and/or R 9 .
  • 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.
  • a process for preparing compounds of formula (I), and pharmaceutically acceptable salts, solvates and/or N-oxides thereof comprises reacting a compound of formula (IIA): with a compound HA-N(R 20 )R 2′ in which W is a leaving group, R 20 is UR 5 or a group convertible thereto and R 2′ is R 2 or a group convertible thereto, and A, R 1a , R 1b , R 2 , R 9 , U and R 5 are as defined in formula (I), to give a compound of formula (IIB): and and thereafter optionally or as necessary converting R 20 and R 2′ to UR 5 and R 2 , interconverting any variable groups, and/or forming a pharmaceutically acceptable salt, solvate or N-oxide thereof.
  • reaction is carried out under conventional conditions for amine coupling such as reacting together in the presence of a suitable base, such as sodium carbonate or triethylamine, in a suitable solvent such as ethanol or N,N-dimethylformamide at temperatures between ambient and 60° C.
  • a suitable base such as sodium carbonate or triethylamine
  • a suitable solvent such as ethanol or N,N-dimethylformamide
  • R 9 is OH
  • treatment with base can afford an epoxide which can react with amines to give (IIB).
  • Such reactions may proceed through this epoxide without the need for isolation.
  • the leaving group may be any conventional group such as methanesulfonyl or methylbenzenesulfonyl.
  • one of R 20 and R 2′ is an N-protecting group, such as such as t-butoxycarbonyl, benzyloxycarbonyl or 9-fluorenylmethyloxycarbonyl. 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. Wuts, Wiley-Interscience, 1999), for example conventional acid hydrolysis with, for example, trifluoracetic acid or hydrochloric acid.
  • the invention further provides compounds of formula (IIB) in which R 20 is hydrogen.
  • the free amine of formula (IIB) in which R 20 is hydrogen may be converted to NR 2 UR 5 by conventional means such as amide or sulphonamide formation with an acyl derivative R 5 COW or R 5 SO 2 W, for compounds where U is CO or SO 2 or, where U is CH 2 , by alkylation with an alkyl halide R 5 CH 2 -halide in the presence of base, acylation/reduction with an acyl derivative R 5 COW or reductive alkylation with an aldehyde R 5 CHO under conventional conditions (see for examples Smith, M. B.; March, J. M. Advanced Organic Chemistry , Wiley-Interscience).
  • the appropriate reagents containing the required R 5 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 and EP0559285.
  • R 5 contains an NH group
  • this may be protected with a suitable N-protecting group such as t-butoxycarbonyl, benzyloxycarbonyl or 9-fluorenylmethyloxycarbonyl during the coupling of the R 5 derivative with the free amine of formula (IIB).
  • the protecting group may be removed by conventional methods, such as by treatment with trifluoroacetic acid.
  • the resolution of enantiomers at the attachment position of R 9 is carried out on the compound of formula (I), (IIA) or (IIB), by any conventional method such as preparative high performance liquid chromatography.
  • the bromo-naphthyridine (1) is converted to a methylvinyl-analogue (2) under Suzuki conditions.
  • the methyl group is functionalised with NaOCl to give the chloroanalogue (3) which cyclises to give the vinyl tricyclic naphthyridone (4).
  • the vinyl tricyclic naphthyridone (4) is converted to the dihydroxylated analogue (5) using AD-mix- ⁇ and/or ⁇ , a mixture of potassium osmate, potassium ferricyanide and chiral alkaloid-derived ligand known to dihydroxylate olefins in a chiral manner, see K. B. Sharpless et al, Chem. Rev., 1994, 94, 2483.
  • Alternative chiral ligands may also be used such as hydro quinine anthraquinone-1,4-diyl diether.
  • the primary hydroxyl group is functionalised to the leaving group W of the compound of formula (IIA) conventionally, for example to the tosylate (6) with tosyl chloride/dibutyltin oxide.
  • the invention also provides compounds of formula (5).
  • Bromides such as (1) can be converted to diester (8) by copper-catalysed reaction with the sodium salt of dimethyl malonate, while triflates such as (7) can be converted directly to (8) by reaction with the sodium salt of dimethyl malonate.
  • the diesters can be converted to monoesters (9) using the conditions of Krapcho et al, J. Org. Chem., 1987, 52(9), 1880, by heating a mixture of diester with LiCl in DMSO/water at 100° C. for 24 h.
  • R 1a , R 1b , R 2 , A, R 5 and R 9 are conventional.
  • 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.
  • R 9 hydroxy may be converted to fluoro at any point in the synthesis, such as on intermediate (5), by treatment with a fluorinating agent such as (diethylamino)sulphur trifluoride.
  • a fluorinating agent such as (diethylamino)sulphur trifluoride.
  • R 1a and R 1b groups may be carried out conventionally, on compounds of formula (I) or earlier intermediates such as (5) or the free amine of formula (IIB) in which R 20 is hydrogen.
  • R 1a or R 1b methoxy is convertible to R 1a or R 1b 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 R 1a or R 1b substituted alkoxy.
  • R 1a halogen is convertible to other R 1a 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 1a fluoro may be converted to methoxy by treatment with sodium methoxide in methanol.
  • R 1b halo such as bromo may be introduced by the general method of M. A. Alonso et al, Tetrahedron 2003, 59(16), 2821 or P. Imming et al, Eur. J. Med. Chem., 2001, 36 (4), 375.
  • R 1b halo such as chloro may be introduced by treatment with N-chlorosuccinimide.
  • R 1a or R 1b halo such as bromo may be converted to cyano by treatment with copper(I) cyanide in N,N-dimethylformamide.
  • R 1a or R 1b carboxy may be obtained by conventional hydrolysis of R 1a or R 1b cyano, and the carboxy converted to hydroxymethyl by conventional reduction.
  • Compounds of formula HA-N(R 20 )R 2′ , (1) and (7) are known compounds or may be prepared analogously to known compounds, see for example WO2004/035569, WO2004/089947, WO02/08224, WO02/50061, WO02/56882, WO02/96907, WO2003087098, WO2003010138, WO2003064421, WO2003064431, WO2004002992, WO2004002490, WO2004014361, WO2004041210, WO2004096982, WO2002050036, WO2004058144, WO2004087145, WO2003082835, WO2002026723, WO06002047 and WO06014580.
  • the hydroxy-aminomethylpyrrolidines of formula (XIII) (HA-NH(R 20 ), A is (ii), X is CR 4 R 8 , W 1 is a bond, W 2 and W 3 are both CH 2 , R 4 and R 7 are H and R 8 is OH) can be prepared from doubly protected chiral intermediate (XVI), and separated by preparative HPLC.
  • the benzyloxycarbonyl protecting group is removed by hydrogenation to give (XV) and the amino function converted to a trifluoroacetamide (XIV).
  • the t-butoxycarbonyl (Boc) protecting group is removed with HCl to give the pyrrolidine hydrochloride salt (III).
  • the intermediate (XVI) may be prepared by the general method of Scheme 4:
  • aminomethylpyrrolidine of formula (XVII) (HA-NH(R 20 ), A is (ii), X is CR 4 R 8 , W 1 is a bond, W 2 and W 3 are both CH 2 , R 4 , R 7 and R 8 are all H) can be prepared from commercially available Boc-protected aminomethylpyrrolidine, and converted to the trifluoroacetamide.
  • the aminomethylmorpholine intermediate of formula (XXI) (HA-NH(R 20 ), A is (ii), X is O, W 1 , W 2 and W 3 are each CH 2 ) may be prepared from a chiral dichlorobenzyl intermediate (XXIII) (WO2003082835) (Scheme 6) by first protecting the amino function with a Boc-protecting group (XXII), removing the dichlorobenzyl group by hydrogenation to give (XXI), protecting the morpholine N-atom with a benzyloxycarbonyl group (to allow purification by chromatography) (XX), and hydrogenation to afford the required morpholine derivative (XXI).
  • 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 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.
  • compositions may be formulated for administration by any route.
  • the compositions may be in the form of tablets, capsules, powders, granules, lozenges, 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 p-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
  • 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 1.5 to 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. Some compounds of formula (I) may be active against more than one organism. This may be determined by the methods described herein.
  • DMF refers to N,N-dimethylformamide
  • TFA refers to trifluoroacetic acid
  • THF refers to tetrahydrofuran
  • Pd/C palladium on carbon catalyst
  • DCM dichloromethane
  • MP-carbonate refers to macroporous triethylammonium methylpolystyrene carbonate (Argonaut Technologies).
  • Chiralpak AD and AD-H columns comprise of silica for preparative columns (5 um particle size AD-H, 21 ⁇ 250 mm; 20 uM particle size AD, 101.6 ⁇ 250 mm) coated with Amylose tris (3,5-dimethylphenylcarbamate) (Chiral Technologies USA).
  • Chiralcel OD column comprises of silica for a preparative column (20 um particle size; 77 ⁇ 240 mm) coated with cellulose tris (3,5-dimethylphenylcarbamate). Measured retention times are dependent on the precise conditions of the chromatographic procedures. Where quoted below in the Examples they are indicative of the order of elution.
  • AD mix alpha is prepared by mixing potassium osmate (K 2 OsO 4 .2H 2 O) (0.52 g), (3a,9R,3′′′a,4′′′b,9′′′R)-9,9′-[1,4-phthalazinediylbis(oxy)]bis[6′-(methyloxy)-10,11-dihydrocinchonan] [(DHQ) 2 PHAL] (5.52 g), then adding potassium ferricyanide [K 3 Fe(CN) 6 ] (700 g) and powdered potassium carbonate (294 g). This mixture is stirred in a blender for 30 minutes. This provides approximately 1 kg of AD mix alpha, which is commercially available from Aldrich. See K.
  • AD mix beta is the corresponding mixture prepared with (9S,9′′′S)-9,9′-[1,4-phthalazinediylbis(oxy)]bis[6′-(methyloxy)-10,11-dihydrocinchonan] [(DHQD) 2 PHAL].
  • AD mix alpha/beta is referred to, this is a 1:1 mixture of the alpha and beta mix.
  • Celite® is a filter aid composed of acid-washed diatomaceous silica, and is a trademark of Manville Corp., Denver, Colo.
  • Chiralcel OD is a polysaccharide based chiral HPLC column (Chiral Technologies Inc.).
  • 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.
  • Extraction steps may if desired be carried out with ethyl acetate in place of the specified solvents.
  • DSC is conducted on a TA Instrument model Q100 Differential Scanning Calorimeter.
  • the sample is placed and weighed in a Al DSC pan.
  • the pan is sealed using the hand press supplied by the vendor.
  • the sample is ramped from 35° C. to 300° C. at 15° C./minute.
  • the sample is scanned using the following parameters:
  • 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.
  • Catalytic iodine may be used to initiate the reaction of 2-bromopropene with magnesium. Excess boric acid and derivatives thereof may be removed from the reaction mixture by filtration through Celite® before addition of pyridine.
  • the reaction was cooled down to ⁇ 10° C. and quenched with 100 ml of 10% citric acid aqueous solution (exothermic). Ethyl acetate (100 ml) was added for extraction. The organic layer was washed with 100 ml water and the aqueous layer was extracted with 100 ml ethyl acetate. The combined organic solution was concentrated to dryness to afford a dark oil and further purified by a silica column with heptane/ethyl acetate (1/0, 3/1, 2/1) as the eluent (11.8 g, ⁇ 93% yield and ⁇ 97% purity per area ratio by HPLC).
  • Zinc bromide may be substituted for zinc chloride, and the concentration of the palladium catalyst may be reduced to 0.5%.
  • the washing step may be performed with 4% citric acid aqueous solution instead of water.
  • the organic extracts may be dried by washing with brine and ethyl acetate instead of drying over magnesium sulphate.
  • the product may be taken up in n-hexane and precipitated out and the solid purified by stirring with cold acetone.
  • potassium hexacyanoferrate(III) 24.50 g
  • potassium carbonate granular, 10.25 g
  • potassium osmate(VI) dihydrate 25 mg
  • water 125 mL
  • DHQ hydroquinine anthraquinone-1,4-diyl diether
  • t-Butanol may be used in place of 2-butanol in the above reaction with (DHQ) 2 AQN and also for the extraction step in place of ethyl acetate. If necessary the product may be dissolved in warm toluene and cooled to precipitate the product as a solid.
  • Both the reaction with p-toluensulphonyl chloride and the reaction with 1,1-dimethylethyl 4-piperidinylcarbamate may be carried out in dichloromethane. Potassium carbonate may be used in place of sodium carbonate in the reaction with 1,1-dimethylethyl 4-piperidinylcarbamate. If necessary triethylamine may be added in this reaction to promote completion.
  • This reaction may alternatively be performed using c.HCl in dichloromethane as solvent.
  • the product as the hydrochloride salt may be be precipitated from acetone and used directly in stage (h) below after neutralisation using anhydrous sodium acetate.
  • the reductive alkylation reaction may also be conducted in DMF instead of DCM/methanol.
  • Molecular sieves may be included in the reaction mass.
  • the extraction may be carried out with 10% methanol in chloroform and the product may be purified by precipitation from acetone instead of chromatography on silica.
  • the title hydrochloride salt may alternatively be prepared by treatment of the free base with pyridine hydrochloride in methanol and the product precipitated out by slowly adding the solution to acetone.
  • 1,4 Dioxane 10 vol % Water (500 uL) was added to title crystalline HCl salt ( ⁇ 30 mg). The resulting slurry was, under a vortex speed of 750 rpm, held at 40° C. for 1 h then was temperature-cycled from 0-40° C. for 48 hours (ramp at ⁇ 1° C./min to 0° C., hold for 1 h, +1° C./min to 40° C., hold for 1 h). Finally the product was ramped at ⁇ 1° C./min to 23° C. and held for 1 h at a vortex speed of 500 rpm. The resulting solids and supernatant were separated by filtration at room temperature. The solid were vacuum dried under ambient laboratory conditions.
  • the cooled mixture was treated with sodium triacetoxyborohydride (169 mg, 0.8 mmol) and stirred for 16 hours.
  • the mixture was filtered through Kieselguhr, evaporated, then the residue partitioned between 20% methanol in dichloromethane and saturated aqueous sodium bicarbonate solution.
  • the aqueous phase was further extracted (twice) with 20% methanol in dichloromethane and the combined extracts were dried and evaporated.
  • the aqueous phase was extracted with ethyl acetate.
  • the organic phase was washed twice with water, dried and the solvent was removed under reduced pressure.
  • the residue was subjected to column chromatography on silica gel using a hexane and ethyl acetate gradient to provide the desired compound (63 g, 97%).
  • 1,1-dimethylethyl (1- ⁇ [(4R/S)-3-chloro-4-hydroxy-7-oxo-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-4-yl]methyl ⁇ -4-piperidinyl)carbamate (410 mg) was dissolved in dichloromethane/trifluoroacetic acid (5 ml/4 ml). After 30 minutes the mixture was evaporated. The residue was dissolved in methanol and treated with Amberlyst resin. After 1 hour the mixture was filtered and the filtrate evaporated to dryness. The crude material was chromatographed on silica eluting with 0-20% of 2M ammonia/methanol in dichloromethane affording the product (300 mg, 95%).
  • Argon was bubbled through a mixture of 4-bromo-2- ⁇ [4-(methyloxy)phenyl]methyl ⁇ -6-( ⁇ [4-(methyloxy)phenyl]methyl ⁇ oxy)-3(2H)-pyridazinone and 5-bromo-2- ⁇ [4-(methyloxy)phenyl]methyl ⁇ -6-( ⁇ [4-(methyloxy)phenyl]methyl ⁇ oxy)-3(2H)-pyridazinone (1.35 g, 3.14 mmol) in dry 1,4-dioxane (7.5 ml) for 20 minutes.
  • Butyl 3-(2- ⁇ [4-(methyloxy)phenyl]methyl ⁇ -3,6-dioxo-1,2,3,6-tetrahydro-4-pyridazinyl)propanoate (0.56 g, 1.56 mmol) was dissolved in dry THF (30 ml). The solution, under argon, was cooled to ⁇ 30° C., and treated dropwise with a 1M solution of lithium aluminium hydride in THF (1.8 ml, 1.8 mmol), allowed to warm gradually to 0° C. and stirred in an ice bath for 30 minutes. 2M hydrochloric acid was added until the pH was 3 and the mixture was partitioned between water and ethyl acetate.
  • Butyl 3-(1- ⁇ [4-(methyloxy)phenyl]methyl ⁇ -3,6-dioxo-1,2,3,6-tetrahydro-4-pyridazinyl)propanoate (0.43 g, 1.19 mmol) was dissolved in dry THF (20 ml). The solution under argon was cooled to ⁇ 30° C., treated dropwise with a 1M solution of lithium aluminium hydride in THF (1.4 ml, 1.4 mmol), allowed to warm gradually to 0° C. and stirred in an ice bath for 30 minutes. 2M Hydrochloric acid was added until the pH was 3 and the mixture was partitioned between water and ethyl acetate.
  • This material was converted to the title dihydrochloride salt (30 mg) by treating a solution of the free base (30 mg) in chloroform (1 mL) with a solution of hydrochloric acid in diethylether (1M, 1 ml) followed by dilution with diethylether ( ⁇ 5 mL), cooling to 0° C. for 5 minutes, centrifugation, decantation of the supernatant and drying the remaining white solid in vacuo.
  • This material was converted to the title dihydrochloride salt by treating a solution of the free base with a 1M solution of hydrochloric acid in diethylether.
  • reaction mixture was stirred at room temperature, under argon, for 3 hours, treated with water (100 mL) and extracted with dichloromethane (3 ⁇ 200 mL). The combined organic layers were dried over magnesium sulphate, evaporated and further dried in vacuo affording the crude product (46%), epoxide (8′-chloro-3′-fluoro-7′H-spiro[oxirane-2,4′-pyrrolo[3,2,1-de][1,5]naphthyridin]-7′-one) (10%) and unknown material (30%).
  • reaction mixture was evaporated, dissolved in water ( ⁇ 10 mL), basified by addition of solid sodium carbonate and evaporated. The residue was stirred with a 15% solution of methanol in dichloromethane (3 ⁇ 200 mL). The combined organic layers were dried over magnesium sulphate, evaporated and chromatographed eluting with a gradient of dichloromethane and 2M ammonia/methanol affording the product (215 mg, 27%).
  • This material was converted to the title dihydrochloride salt by treating a solution of the monoacetate salt with hydrochloric acid in dioxin.
  • E1 (HCl salt) net: 15 mg, >99% ee, alpha D +100.6 deg (methanol, 20 deg C., c 1.00).
  • E2 (HCl salt) net: 18 mg, >99% ee, alpha D-102.0 deg (methanol, 20 deg C., c 1.00).
  • Example number Salt form tested Structure Aldehyde/alkyl halide
  • MS* 34 hydrochloride 1,8-naphthyridine-2- carbaldehyde 461 35 dihydrochloride 2,1,3-benzothiadiazole- 5-carbaldehyde 467 36 dihydrochloride 3-isoquinoline- carbaldehyde 460 37 dihydrochloride 3-quinoline- carbaldehyde 460 38 dihydrochloride 3-(bromomethyl)- 2(1 h)-quinoxalinone 477 39 dihydrochloride 2-(chloromethyl)- 4(1 h)-quinazolinone 477 40 dihydrochloride 7-chloro-3-oxo-3,4- dihydro-2H-pyrido[3,2- b][1, 4]oxazine-6- carboxaldehyde (for a synthesis see wo2003064421, Example 15(c)) 515/ 517 41 dihydrochioride
  • Examples 58-64 were made from the specified tosylate, cyclic amine and aldehyde the general methods of Example 1(f)-(h).
  • Examples 65-68 were made from the specified amine and aldehyde by the general method of Example 1(h).
  • the oily residue was extracted with water/methanol (500 ml/1 litre). This extract was decanted from the remaining residue, treated with silica and evaporated. The silica residue was added to the top of a column, eluting with 10-30% methanol in DCM affording a pale yellow oil (2.7 g).
  • the product was purified on silica gel eluting with 10% ethyl acetate-DCM to give 3.48 g of material containing a small amount of N-(benzyloxycarbonyloxy)succinimide which was used directly in next step.
  • compounds were evaluated against a panel of Gram-negative organisms including Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Legionella pneumophila, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae and Stenotrophomonas maltophilia.
  • 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.
  • Example 66 Each of the listed Examples, as identified in the present application, were tested in at least one exemplified salt form. Unless otherwise noted, the listed Examples had a MIC ⁇ 2 ⁇ g/ml against a strain of at least one of the organisms listed above. Examples 24, 38 and 39 had an MIC ⁇ 4 ⁇ g/ml against a strain of at least one of the organisms listed above. Examples 47 and 65 had an MIC ⁇ 8 ⁇ g/ml against a strain of at least one of the organisms listed above. The MIC values for Example 66 were ⁇ 16 ⁇ g/ml against all of the strains representing the organisms listed above.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (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 Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
US11/611,214 2005-12-22 2006-12-15 Compounds Abandoned US20070185153A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US11/611,214 US20070185153A1 (en) 2005-12-22 2006-12-15 Compounds

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US75314905P 2005-12-22 2005-12-22
US86687706P 2006-11-22 2006-11-22
US11/611,214 US20070185153A1 (en) 2005-12-22 2006-12-15 Compounds

Publications (1)

Publication Number Publication Date
US20070185153A1 true US20070185153A1 (en) 2007-08-09

Family

ID=37763790

Family Applications (2)

Application Number Title Priority Date Filing Date
US11/611,214 Abandoned US20070185153A1 (en) 2005-12-22 2006-12-15 Compounds
US12/158,397 Expired - Fee Related US7732460B2 (en) 2005-12-22 2006-12-15 Heterocyclic compounds, their preparation and their use as antibacterials

Family Applications After (1)

Application Number Title Priority Date Filing Date
US12/158,397 Expired - Fee Related US7732460B2 (en) 2005-12-22 2006-12-15 Heterocyclic compounds, their preparation and their use as antibacterials

Country Status (10)

Country Link
US (2) US20070185153A1 (zh)
EP (1) EP1963324B1 (zh)
JP (1) JP2009520779A (zh)
AR (1) AR058587A1 (zh)
AT (1) ATE465163T1 (zh)
DE (1) DE602006013878D1 (zh)
ES (1) ES2344523T3 (zh)
PE (1) PE20071064A1 (zh)
TW (1) TW200801001A (zh)
WO (1) WO2007071936A1 (zh)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080221110A1 (en) * 2005-10-21 2008-09-11 Nathalie Cailleau Compounds
US20100137282A1 (en) * 2007-04-20 2010-06-03 David Evan Davies Tricyclic nitrogen containing compounds as antibacterial agents

Families Citing this family (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE481406T1 (de) 2006-04-06 2010-10-15 Glaxo Group Ltd Pyrrolochinoxalinonderivate als antibakterielle mittel
GB0608263D0 (en) * 2006-04-26 2006-06-07 Glaxo Group Ltd Compounds
GB0613208D0 (en) * 2006-07-03 2006-08-09 Glaxo Group Ltd Compounds
GB0705672D0 (en) * 2007-03-23 2007-05-02 Glaxo Group Ltd Compounds
CL2008001002A1 (es) 2007-04-11 2008-10-17 Actelion Pharmaceuticals Ltd Compuestos derivados de oxazolidinona; composicion farmaceutica que comprende a dichos compuestos; y su uso para preparar un medicamento para tratar una infeccion bacteriana.
GB0707706D0 (en) * 2007-04-20 2007-05-30 Glaxo Group Ltd Compounds
EP2005995A1 (en) * 2007-06-22 2008-12-24 Glaxo Group Limited Heterocyclic compounds for the treatment of tuberculosis
PL2221309T3 (pl) * 2007-11-26 2013-12-31 Toyama Chemical Co Ltd Monohydrat pochodnej naftyrydyny i sposób jego wytwarzania
EP2080761A1 (en) 2008-01-18 2009-07-22 Glaxo Group Limited Compounds
WO2009104147A2 (en) * 2008-02-20 2009-08-27 Actelion Pharmaceuticals Ltd Azatricyclic antibiotic compounds
WO2009104159A1 (en) 2008-02-22 2009-08-27 Actelion Pharmaceuticals Ltd Oxazolidinone derivatives
WO2009125809A1 (ja) * 2008-04-11 2009-10-15 第一三共株式会社 ピペリジン誘導体
WO2009125808A1 (ja) * 2008-04-11 2009-10-15 第一三共株式会社 アミノシクロヘキシル誘導体
CN102007128A (zh) 2008-04-15 2011-04-06 埃科特莱茵药品有限公司 三环抗生素
WO2009141399A1 (en) * 2008-05-23 2009-11-26 Glaxo Group Limited Tricyclic nitrogen containing compounds and their use as antibacterials
BRPI0912995A2 (pt) * 2008-05-23 2015-10-13 Glaxo Group Ltd compostos tricíclicos contendo nitrogênio e sua utilização como agentes antibacterianos
CN104151316B (zh) * 2008-10-07 2016-06-15 埃科特莱茵药品有限公司 三环噁唑烷酮抗生素化合物
US20110275661A1 (en) 2008-10-17 2011-11-10 Glaxo Group Limited Tricyclic nitrogen compounds used as antibacterials
MX2011005905A (es) 2008-12-12 2011-06-20 Actelion Pharmaceuticals Ltd Derivados de 5-amino-2-(1-hidroxi-etil)-tetrahidropirano.
US8318940B2 (en) 2009-01-15 2012-11-27 Glaxo Group Limited Naphthyridin-2 (1 H)-one compounds useful as antibacterials
AR087875A1 (es) 2011-09-16 2014-04-23 Actelion Pharmaceuticals Ltd Proceso para la elaboracion de derivados de piridazina como intermediarios de sintesis de antibioticos
CA2854266A1 (en) 2011-11-30 2013-06-06 Actelion Pharmaceuticals Ltd 3,7-disubstituted octahydro-2h-pyrido[4,3-e][1,3]oxazin-2-one antibiotics
CN106659717B (zh) 2014-08-22 2019-09-06 葛兰素史密斯克莱知识产权发展有限公司 用于治疗淋病奈瑟球菌感染的三环含氮化合物

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9622386D0 (en) 1996-10-28 1997-01-08 Sandoz Ltd Organic compounds
GB0101577D0 (en) * 2001-01-22 2001-03-07 Smithkline Beecham Plc Compounds
GB0112836D0 (en) * 2001-05-25 2001-07-18 Smithkline Beecham Plc Medicaments
WO2003064431A2 (en) 2002-01-29 2003-08-07 Glaxo Group Limited Aminopiperidine compounds, process for their preparation, and pharmaceutical compositions containing them
PA8577501A1 (es) 2002-07-25 2004-02-07 Warner Lambert Co Inhibidores de quinasas
JP2007522093A (ja) 2003-09-22 2007-08-09 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ ７−アミノアルキリデニル−複素環式キノロンおよびナフチリドン
US7732612B2 (en) 2004-09-09 2010-06-08 Janssen Pharmaceutica, N.V. 7-amino alkylidenyl-heterocyclic quinolones and naphthyridones
CA2626641A1 (en) * 2005-10-21 2007-07-19 Glaxo Group Limited Compounds
ATE481406T1 (de) 2006-04-06 2010-10-15 Glaxo Group Ltd Pyrrolochinoxalinonderivate als antibakterielle mittel
GB0608263D0 (en) 2006-04-26 2006-06-07 Glaxo Group Ltd Compounds
GB0613208D0 (en) 2006-07-03 2006-08-09 Glaxo Group Ltd Compounds

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080221110A1 (en) * 2005-10-21 2008-09-11 Nathalie Cailleau Compounds
US20080280892A1 (en) * 2005-10-21 2008-11-13 Nathalie Cailleau Compounds
US20100137282A1 (en) * 2007-04-20 2010-06-03 David Evan Davies Tricyclic nitrogen containing compounds as antibacterial agents
US8389524B2 (en) 2007-04-20 2013-03-05 Glaxo Group Limited Tricyclic nitrogen containing compounds as antibacterial agents

Also Published As

Publication number Publication date
AR058587A1 (es) 2008-02-13
ATE465163T1 (de) 2010-05-15
ES2344523T3 (es) 2010-08-30
TW200801001A (en) 2008-01-01
JP2009520779A (ja) 2009-05-28
EP1963324A1 (en) 2008-09-03
US7732460B2 (en) 2010-06-08
PE20071064A1 (es) 2007-12-16
DE602006013878D1 (de) 2010-06-02
EP1963324B1 (en) 2010-04-21
WO2007071936A1 (en) 2007-06-28
US20090036433A1 (en) 2009-02-05

Similar Documents

Publication Publication Date Title
US11229646B2 (en) Method for treating gonorrhea with (2R)-2-({4-[(3,4-dihydro-2H-pyrano[2,3-C]pyridin-6-ylmethyl)amino]-1-piperidinyl}methyl)-1,2-dihydro-3H,8H-2A,5,8A-triazaacenaphthylene-3,8-dione
US7732460B2 (en) Heterocyclic compounds, their preparation and their use as antibacterials
US8389524B2 (en) Tricyclic nitrogen containing compounds as antibacterial agents
US7732461B2 (en) Tryclic nitrogen containing compounds and their use as antibacterials
US7709483B2 (en) Pyrrolo-quinoxalinone derivatives as antibacterials
US20100004230A1 (en) Azatricyclic compounds and their use
US20080280892A1 (en) Compounds
US20100256124A1 (en) Substituted 1-Methyl-1H-Quinolin-2-Ones And 1-Methyl-1H-1,5-Naphthyridin-2-Ones As Antibacterials
US20100048544A1 (en) Pyrrolo (3, 2, 1-ij) quinoline-4-one-derivatives for treating tuberculosis
US20100056502A1 (en) Compounds
US20100087424A1 (en) Tricyclic nitrogen containing heterocycles as antibacterial agents
US20100184751A1 (en) Heterocyclic compounds for the treatment of tuberculosis
HK1138000B (zh) 作为抗菌剂的三环含氮化合物

Legal Events

Date Code Title Description
AS Assignment

Owner name: GLAXO GROUP LIMITED, UNITED KINGDOM

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:CAILLEAU, NATHALIE;DAVIES, DAVID THOMAS;HENNESSY, ALAN JOSEPH;AND OTHERS;REEL/FRAME:019611/0646;SIGNING DATES FROM 20070501 TO 20070504

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION