Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
• • 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
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
• • 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
  • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
  • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
  • C07D513/04—Ortho-condensed systems

Definitions

• This invention relates to novel compounds, compositions containing them and their use as antibacterials.
• WO01/07433, WO01/07432, WO01/25227, WO0208224, WO0224684, PCT/GB01/05653, PCT/GB01/05661 and WO02040474 disclose quinoline and naphthyridine derivatives having antibacterial activity.
• This invention comprises compounds of the formula (I), as described hereinafter, which are useful in the treatment of bacterial infections.
• This invention is also a pharmaceutical composition comprising a compound according to formula (I) and a pharmaceutically acceptable carrier.
• This invention is also a method of treating bacterial infections in mammals, particularly in humans.
• one of Zi , Z2, Z3, Z4 and Z5 is N, one is CR ⁇ a and the remainder are CH, or one or two of Z-
• R 1 and R 1 a are independently hydrogen; hydroxy; (C-
• each R 2 is independently hydrogen, OH, NH2, substituted or unsubstituted (C-
• R3 is H, or substituted or unsubstituted (C-
• R 5 is a substituted or unsubstituted aryl group, or a substituted or unsubstituted bicyclic carbocyclic or heterocyclic ring system (A): containing up to four heteroatoms in each ring in which ring (a) is aromatic and ring (b) is aromatic or non-aromatic; X 1 is C;
• X 2 is N or CR 6 ;
• X 3 and X 5 are C;
• ⁇ 1 is a 1 to 2 atom linker group, each atom of which is independently selected from N and CR 6 ;
• Y 2 is a 2 to 6 atom linker group, each atom of Y 2 being independently selected from N, NR 8 , O, S(0)x, CO, CR 6 and CR 6 R 7 ;
• each of R 6 and R 7 is independently selected from: hydrogen; (C-j_4)alkylthio; halo; carboxy(C-
• each R 8 is independently hydrogen; trifluoromethyl; (C ⁇ .4)alkyl unsubstituted or substituted by hydroxy, (C-
• Prodrugs are considered to be any covalently bonded carriers which release the active parent drug according to formula (I) in vivo.
• the invention also provides a pharmaceutical composition, in particular for use in the treatment of bacterial infections in mammals, particularly humans, comprising a compound of formula (I), or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier.
• the invention further provides a method of treatment of bacterial infections in mammals, particularly in humans, 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 derivative thereof.
• Z5 is CH or N
• Z3 is CH or CF and Z-
• Z2 and Z4 are each CH
• is N
• Z3 is CH or CF and Z2, Z4 and Z5 are each CH.
• R 1 or R 1 a is substituted alkoxy it is preferably (C2-6) alko ⁇ y substituted by optionally N-substituted amino, guanidino or amidino, or
• R 1 and R 1 a alkoxy include methoxy, trifluoromethoxy, n-propyloxy, iso-butyloxy, aminoethyloxy, aminopropyloxy, aminobutyloxy, aminopentyloxy, guanidinopropyloxy, piperidin-4-ylmethyloxy, phthalimido pentyloxy or 2-aminocarbonylprop-2-oxy.
• R 1 and R 1 a are independently methoxy, amino(C3_5)alkyloxy, guanidino(C3_5)alkyloxy, piperidyl(C3_5)alkyloxy, nitro or halo; more preferably methoxy, amino(C3_5)alkyloxy or guanidino(C3_5)alkyloxy.
• R ⁇ is methoxy and R 1 a is H or when Z3 is CR 1 a it may be C-F.
• R 5 is substituted or unsubstituted aryl, most preferably substituted or unsubstituted phenyl.
• R 1 a is preferably hydrogen, cyano, hydroxymethyl or carboxy, most preferably hydrogen.
• Y 2 has 3-5 atoms, more preferably 4 atoms including NR 8 , O or S bonded to X 5 and NHCO bonded via N to X 3 , or O or NH bonded to X 3 .
• Ring (a) is preferably substituted and unsubstituted phenyl, pyridine, pyrrole, and imidazole.
• ring (b) is substituted and unsubstituted phenyl, pyridine, dioxane, piperidine, morpholin-3-one, thiomorpholin-3-one, oxazolidin-2-one, thiadiazole, and thiazepan-5-one.
• R 6 and R 7 are independently hydrogen; halo; carboxy(C-
• R 6 and R 7 are hydrogen, hydroxy, halo, or (C ⁇ alkyl substituted or unsubstituted by hydroxy, (C-
• R 8 is hydrogen; trifluoromethyl; (C 1 _4)alkyl unsubstituted or substituted by hydroxy, (C-
• R 8 is C-
• R 5 groups include substituted and unsubstituted: 1 ,1 ,3-trioxo-1 ,2,3,4-tetrahydro1 / 6 -benzo[1 ,4] thiazin-3-one-6-yl, benzo[1 ,3]dioxol-5-yl, 4H-benzo[1 ,4]oxazin-3-one-6-yl, 2,3-dihydro-benzo[1 ,4]dioxin-6-yl, 2-oxo-2,3-dihydro- benzooxazol-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[1 ,4]oxazin-3-one-6-yl (3-oxo-3,
• Preferred R 5 groups include 1 H-lndol-2-yl, quinolin-8-ol-2-yl, 3-Oxo-3,4-dihydro-2H- benzo[1 ,4]oxazine-6-yl, 4H-benzo[1 ,4]oxazin-3-one-6-yl, 4-Fluoro-1 H-benzoimidazol- 2-yl, 3,6-dimethyl-3H-benzooxazol-2-one, 4H-benzo[1 ,4]thiazin-3-one-6-yl, 3-Oxo-3,4- dihydro-2H-benzo[1 ,4]thiazine-6-yl, 4-Oxo-2,3,4,5-tetrahydro-benzo[b][1 ,4]thiazepine- 7-yl, 7-Chloro-3-oxo-3,4-dihydro-2H-benzo[1 ,4]thiazine-6-yl, 3-
• Preferred compounds of this invention are: 3-Oxo-3,4-dihydro-2H-benzo[1 ,4]thiazine-6-sulfonic acid ⁇ 3-[(R)-5-(6-methoxy- quinolin-4-yl)-2-oxo-oxazolidin-3-yl]-propyl ⁇ -amide;
• (C- _ Q )a ⁇ ky ⁇ when used alone or when forming part of other groups includes substituted or unsubstituted, straight or branched chain alkyl groups containing 1 to 6 carbon atoms.
• Examples of (C ⁇ _6)alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl groups.
• (C2-6) a 'kenyl means a substituted or unsubstituted alkyl group of 2 to 6 carbon atoms, wherein one carbon-carbon single bond is replaced by a carbon- carbon double bond.
• Examples of (C2-6) a l enyl include ethylene, 1-propene, 2- propene, 1-butene, 2-butene, isobutene and the several isomeric pentenes and hexenes. Both cis and trans isomers are included.
• (C3_7)cycloalkyl refers to subsituted or unsubstituted carbocyclic system of three to seven carbon atoms, which may contain up to two unsaturated carbon-carbon bonds.
• Examples of (C3_7)cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, and cycloheptyl.
• .g)alkyl, (C2- )alkenyl, (C ⁇ _ ⁇ )alkoxy and (C3_7)cycloalkyl groups includes up to three substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, carboxy, amino, amidino, sulphonamido, unsubstituted (C ⁇ _@)alkyl, unsubstituted (C-
• Halo or halogen includes fluoro, chloro, bromo and iodo.
• Haloalkyl moieties include 1-3 halogen atoms.
• heterocyclic as used herein includes optionally substituted aromatic and non-aromatic, single and fused, rings suitably containing up to four hetero-atoms in each ring selected from oxygen, nitrogen and sulphur, which rings may be unsubstituted or C-substituted by, for example, up to three groups selected from (C-
• Each heterocyclic ring suitably has from 4 to 7, preferably 5 or 6, ring atoms.
• a fused heterocyclic ring system may include carbocyclic rings and need include only one heterocyclic ring
• suitable optional substituents in such substituted amino groups include H; trifluoromethyl; (C-j_4)alkyl optionally substituted by hydroxy, (C-
• Aryl groups may be optionally substituted with up to five, preferably up to three, groups selected from (C-
• acyl includes formyl and (C-
• 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.
• the compounds of formula (I) are intended for use in pharmaceutical compositions it will readily be understood that they are each provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably 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 preferably from 10 to 59% of a compound of the formula (I) or pharmaceutically acceptable derivative thereof.
• compositions of the above-mentioned compounds of formula (I) include the free base form or their 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.
• Compounds of formula (I) having a free carboxy group may also be prepared as an in vivo hydrolysable ester.
• the invention extends to all such derivatives.
• suitable pharmaceutically acceptable in vivo hydrolysable ester- forming groups include those forming esters which break down readily in the human body to leave the parent acid or its salt. Suitable groups of this type include those of part formulae (i), (ii), (iii), (iv) and (v):
• R a is hydrogen, (C-j.g) alkyl, (C3.7) cycloalkyl, methyl, or phenyl
• R D is (C-
• R a and R 13 together form a 1 ,2-phenylene group optionally substituted by one or two methoxy groups;
• R c represents (C- ⁇ g) alkylene optionally substituted with a methyl or ethyl group and R ⁇ and R e independently represent (C- ⁇ g) alkyl;
• R ⁇ represents (C-
• R9 represents hydrogen or phenyl optionally substituted by up to three groups selected from halogen, (C- ⁇ g) alkyl, or (C- ⁇ .Q) alkoxy;
• Q is oxygen or NH;
• R n is hydrogen or (C- ⁇ .Q) alkyl;
• R' is hydrogen, (C- ⁇ g) alkyl optionally substituted by halogen, (C2-6
• RJ represents hydrogen, (C- j .g) alkyl or (C- ⁇ ⁇ ) alkoxycarbonyl;
• R k represents (C- ⁇ s) alkyl, (C-j.g) alkoxy, (C- ⁇ g) alkoxy(C-
• Suitable in vivo hydrolysable ester groups include, for example, acyloxy(C-
• a further suitable pharmaceutically acceptable in vivo hydrolysable ester- forming group is that of the formula:
• R k is hydrogen, C- ⁇ alkyl or phenyl.
• R is preferably hydrogen.
• Certain of the above-mentioned 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 compound in which an A-B group CH(OH)-CH2 is in either isomeric configuration the ft-isomer is preferred.
• 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.
• DCC refers to dicyclohexylcarbodiimide
• DMAP refers to dimethylaminopyridine
• DIEA refers to diisopropylethyl amine
• EDC refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride.
• HOBt refers to 1 -hydroxybenzotriazole
• THF tetrahydrofuran
• DIEA diisopropylethylamine
• DEAD refers to diethyl azodicarboxylate
• PPh3 refers to triphenylphosphine
• DIAD diisopropyl azodicarboxylate
• DME dimethoxyethane
• DMF dimethylformamide
• NBS refers to N- bromosuccinimide
• Pd/C refers to a palladium on carbon catalyst
• PPA refers to polyphosphoric acid
• DPPA diphenylphosphoryl azide
• BOP refers to benzotriazol-1-yloxy-tris(dimethyl-amino)phosphonium hexafluorophosphate
• HF refers to hydrofluoric acid
• TEA triethylamine
• TFA trifluoroacetic acid
• Enantiomerically enriched epoxides of type (I) can be prepared prepared from 6-methoxyquinoline-4-carboxylic acid as described in the example.
• the aryl epoxide (I) (>92% ee), and a monoprotected 1 ,3-diaminopropane (II) were heated in DMF to provide the aminoalcohols (III).
• oxazolidinones (IV) Treatment with triphosgene (or a similar phosgene substitute (e.g, 1 ,1'-carbonyldiimidazole) in the presence of a weak base such as triethylamine affords oxazolidinones (IV), which are then deprotected with HCI in dioxane. Alternatively, a mixture of trifluoroacetic acid in an organic solvent may be used. The resulting amines (V) can be reacted with a tertiary amine base and appropriate sulfonyl chloride to give the sulfonamides (VI) by standard methods.
• triphosgene or a similar phosgene substitute (e.g, 1 ,1'-carbonyldiimidazole) in the presence of a weak base such as triethylamine affords oxazolidinones (IV), which are then deprotected with HCI in dioxane.
• an acid chloride is used in place of the sulfonyl chloride to prepare the corresponding amides (VII).
• the reductive amination can be carried out by well established methods. This includes complete formation of imine prior to reduction with a hydride source, and single pot procedures which reduce the imine as it is formed.
• the amines (V) can be alkylated with an alkyl halide, mesylate or tosylate by standard methods to give the amine products (VIII).
• 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.
• the antibiotic 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 antibiotics.
• the composition may be formulated for administration by any route, such as oral, topical or parenteral.
• 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 polyvinylpyrollidone; 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 50-500 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 20 mg/kg per day. No toxicological effects are indicated when a compound of formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof is administered in the above-mentioned dosage range.
• the compound of formula (I) may be the sole therapeutic agent in the compositions of the invention or a combination with other antibiotics or with a ⁇ -lactamase inhibitor may be employed.
• MIC Minimum inhibitory concentration
• Elemental analyses were performed by Quantitative Technologies Inc., Whitehouse, NJ. Melting points were obtained on a Thomas-Hoover melting point apparatus and are uncorrected. All temperatures are reported in degrees Celsius.
• E. Merck Silica Gel 60 F-254 thin layer plates were used for thin layer chromatography. Flash chromatography was carried out on E. Merck Kieselgel 60 (230-400 mesh) silica gel.
• Analytical HPLC was performed on Beckman chromatography systems. Preparative HPLC was performed using Gilson chromatography systems.
• ODS refers to an octadecylsilyl derivatized silica gel chromatographic support.
• YMC ODS-AQ® is an ODS chromatographic support and is a registered trademark of YMC Co.
• PRP-1 ® is a polymeric (styrene-divinylbenzene) chromatographic support, and is a registered trademark of Hamilton Co., Reno, Nevada.
• Celite® is a filter aid composed of acid- washed diatomaceous silica, and is a registered trademark of Manville Corp., Denver, Colorado.
• Example 1 3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-sulfonic acid ⁇ 3-[(R)-5-(6- methoxy-quinolin-4-yl)-2-oxo-oxazolidin-3-yl]-propyl ⁇ -amide
• 6-methoxyquinoline-4-carboxylic acid (10g) in dichloromethane was heated under reflux with oxalyl chloride (5ml) and dimethylformamide (2 drops) for 1 hour and evaporated to dryness.
• the absolute stereochemistry was defined to be (R) by an NMR study on the Mosher's esters derived from the product obtained by reaction with 1 -t-butylpiperazine.
• Example 2 3-Oxo-2,3,4,5-tetrahydro-benzo[b][1,4]thiazepine-7-sulfonic acid ⁇ 3- [(R)-5-(6-methoxy-quinolin-4-yl)-2-oxo-oxazolidin-3-yl]-propyl ⁇ -amide mp : 128-130°C.
• Example 4 7-Chloro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-sulfonic acid ⁇ 3- [(R)-5-(6-methoxy-quinolin-4-yl)-2-oxo-oxazolidin-3-yl]-propyl ⁇ -amide mp : 165-170°C.
• the aqueous contents were extracted (3 x 25 mL) with ethyl acetate.
• the organic layers were combined and washed (2 x 300 mL) with water and (2 x 300 L) with brine.
• the organic layer was dried over sodium sulfate, filtered and rotary-evaporated to dryness.
• the crude material was purified by flash chromatography on silica gel using 20% ethyl acetate/hexanes as the eluent to give the product 15.8 g (67%).
• Example 8 3-Oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-sulfonic acid ⁇ 3-[(R)-5-(6- methoxy-[1 ,5]naphthyridin-4-yl)-2-oxo-oxazolidin-3-yl]-propyl ⁇ -amide
• the amide compounds were prepared as above using (R)-3-(3-amino-propyl)-5-(6- methoxy-quinolin-4-yl)-oxazolidin-2-one dihydrochloride and the appropriate acid chloride in place of the sufonyl chloride.
• the amines were prepared from (R)-3-(3-amino-propyl)-5-(6-methoxy-quinolin-4-yl)- oxazolidin-2-one amine and the appropriate aldehyde using a reductive amination sequence.
• Acetic acid (30 ul, 0.475 mmol) was added to a solution of (R)-5-(6-methoxy- quinolin-4-yl)-3-(3-methylamino-propyl)-oxazolidin-2-one (150 mg, 0.475 mmol) and 1 H-indole-2-carbaldehyde [19005-93-7] (72 mg, 0.475 mmol) in methylene chloride stabilized over amylene (4.5 ml) and the mixture was stirred for 30 minutes. Sodium triacetoxyborohydride (230 mg, 1.01 mmol) was then added and stirring was maintained for 48 hours at room temperature.
• Examples 12-19 were prepared by the same method: Example 12: (R)-3- ⁇ 3-[(1 H-lndol-2-ylmethyl)-amino]-propyl ⁇ -5-(6-methoxy- quinolin-4-yl)- oxazolidin-2-one
• Example 21 3-Oxo-3,4-dihydro-2 «-benzo[1 ,4]thiazine-6-sulfonic acid ⁇ 3-[(R)-5-(6- methoxy-[1 ,5]naphthyridin-4-yl)-2-oxo-oxazolidin-3-yl]-2,2-dimethyl-propyl ⁇ - amide
• Example 23 6-( ⁇ 3-[5-(6-Methoxy-[1 ,5]naphthyridin-4-yl)-2-oxo-oxazolidin-3-yl]- propylamino ⁇ -methyl)-4H-pyrido[3,2-i_>][1,4]thiazin-3-one
• dihydrochloride salt of 3-(3-Amino-propyl)-5-(6-methoxy-[1 ,5]naphthyridin-4-yl)- oxazolidin-2-one (previous patent) (0.47 g, 1.25 mmol) in CH 2 CI 2 (14 mL) and MeOH (3.5 mL) was added triethylamine (1.0 mL, 7.2 mmol) and the mixture was stirred at room temperature until all the solid went into solution.
• Example 24 6-( ⁇ 3-[5-(6-Methoxy-[1 ,5]naphthyridin-4-yl)-2-oxo-oxazolidin-3-yl]- propylamino ⁇ -methyl)-4H-pyrido[3,2- >][1,4]oxazin-3-one
• Example 26 6-( ⁇ (S)-2-Hydroxy-3-[(R)-5-(6-methoxy-[1 ,5]naphthyridin-4-yl)-2-oxo- oxazolidin-3-yl]-propylamino ⁇ -methyl)-4H-pyrido[3,2-d][1,4]thiazin-3-one
• Example 28 6-( ⁇ (R)-2-Hydroxy-3-[(R)-5-(6-methoxy-[1 ,5]naphthyridin-4-yl)-2-oxo- oxazolidin-3-yl]-propylamino ⁇ -methyl)-4H-pyrido[3,2-_-»][1,4]thiazin-3-one
• the title compound was prepared using the same procedure as 6-( ⁇ (S)-2-Hydroxy-3- [(R)-5-(6-methoxy-[1 ,5]naphthyridin-4-yl)-2-oxo-oxazolidin-3-yl]-propylamino ⁇ -methyl)- 4H-pyrido[3,2-jb][1 ,4]thiazin-3-one (GSK-207235A) except substituting C-((S)-2,2- dimethyl-[1 ,3]dioxolan-4-yl)-methylamine for C-((R)-2,2-dimethyl-[1 ,3]dioxolan-4-yl)- methylamine.

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• 2003
  • 2003-12-03 AU AU2003294565A patent/AU2003294565A1/en not_active Abandoned
  • 2003-12-03 JP JP2004571000A patent/JP2006515862A/ja not_active Ceased
  • 2003-12-03 WO PCT/US2003/038444 patent/WO2004050036A2/en not_active Ceased
  • 2003-12-03 EP EP03787253A patent/EP1567520B1/en not_active Expired - Lifetime
  • 2003-12-03 US US10/537,034 patent/US7491714B2/en not_active Expired - Fee Related
  • 2003-12-03 DE DE60324179T patent/DE60324179D1/de not_active Expired - Lifetime
  • 2003-12-03 ES ES03787253T patent/ES2312839T3/es not_active Expired - Lifetime
  • 2003-12-03 AT AT03787253T patent/ATE411312T1/de not_active IP Right Cessation

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