[go: up one dir, main page]

WO2000071524A1 - 2-nh-pyridones et pyrimidones utilisees comme inhibiteurs de mrs - Google Patents

2-nh-pyridones et pyrimidones utilisees comme inhibiteurs de mrs Download PDF

Info

Publication number
WO2000071524A1
WO2000071524A1 PCT/EP2000/004436 EP0004436W WO0071524A1 WO 2000071524 A1 WO2000071524 A1 WO 2000071524A1 EP 0004436 W EP0004436 W EP 0004436W WO 0071524 A1 WO0071524 A1 WO 0071524A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
ylamino
compound
prop
ring
Prior art date
Application number
PCT/EP2000/004436
Other languages
English (en)
Inventor
Sula Anne Armstrong
John Michael Berge
Pamela Brown
John Stephen Elder
Andrew Keith Forrest
Dieter Wolfgang Hamprecht
Richard Lewis Jarvest
Original Assignee
Smithkline Beecham Plc
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
Priority claimed from GBGB9911596.6A external-priority patent/GB9911596D0/en
Priority claimed from GBGB9911595.8A external-priority patent/GB9911595D0/en
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to AU52133/00A priority Critical patent/AU5213300A/en
Priority to JP2000619781A priority patent/JP2003500397A/ja
Publication of WO2000071524A1 publication Critical patent/WO2000071524A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C07D239/90—Oxygen atoms with acyclic radicals attached in position 2 or 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel 2-NH-pyridones and pyrimidones which are inhibitors of methionyl t-RNA synthetase (MRS), processes for their preparation and their use in therapy as anti-bacterial agents.
  • t-RNA synthetases are involved in protein biosynthesis so that inhibition thereof may be expected to lead to a cessation of cell growth.
  • the compound mupirocin produced by the organism Pseudomonas fluorescens, is an anti-bacterial agent and is used as the active ingredient in the product Bactroban, marketed by SmithKline Beecham. Mupirocin has been shown to be an inhibitor of the isoleucyl t-RNA synthetase.
  • t-RNA synthetase inhibitors which are selective for bacterial cells over mammalian cells are of considerable therapeutic interest as they have the potential to be used as anti-bacterial agents.
  • the sequence of the t-RNA synthetase genes in organisms such as S aureus have recently been determined, see for instance European Patent application no 97300317.1 (SmithKline Beecham, S aureus MRS), thereby assisting the process of identifying inhibitors.
  • WO 99/ and WO 00/21949 (SmithKline Beecham, published after the priority date of the present application) describe a class of 2-(NH- or O- substituted) quinolones which are potent inhibitors of methionyl t-RNA synthetase
  • W is CH and R ⁇ is the residue of a 5 or 6-membered heteroaryl ring, or W is N and Ri is the residue of an 5 or 6-membered heteroaryl ring or an aryl ring, which heteroaryl or aryl ring is optionally substituted with from 1 to 3 substituents selected from halo, cyano, hydroxy, (C ⁇ -g)alkyl (optionally substituted by halo, hydroxy, amino, mono to perfluoro(C ⁇ -3)alkyl, carboxy or
  • R2 is an optionally substituted aryl or an optionally substituted heteroaryl ring
  • X is CH2 or CHR ⁇ in which R- is C ⁇ .g)alkyl or R- may be linked to the ortho position of an aryl or heteroaryl ring of R ⁇ to form a 5 to 7 membered ring optionally including oxygen or nitrogen as a ring atom
  • Y is C ⁇ _3)alkylene or C(4_6)cycloalkylene; including tautomeric forms of the pyrimidone ring (when W is N); and salts thereof, preferably pharmaceutically acceptable salts thereof.
  • Compounds of formula (I) are inhibitors of S aureus methionyl tRNA synthetase.
  • Representative examples of R* when the residue of a heteroaryl ring include rings in which the heteroatom is sulphur, for instance thieno, or nitrogen, for instance pyrido, pyrimido and pyrazolo.
  • Representative examples of Rl when the residue of an aryl ring include phenyl.
  • Representative substituents therefor include halogen, for instance chloro or bromo.
  • R ⁇ when aryl include phenyl and naphthyl, each of which may be optionally substituted with up to four substituents.
  • substituents include C ⁇ .g) alkyl, C ⁇ -6) alkoxy, C(l-6) alkylthio, heterocyclylC ⁇ -6) alkoxy , halo, cyano, amino, sulphamoyl, phenylcarbonyl, aryl, and benzyloxy.
  • the phenyl or naphthyl is substituted by two or three lipophilic substituents such as chloro, bromo, iodo, methyl, methoxy, allyloxy, phenethyloxy, morpholinopropoxy or trifluoromethyl.
  • R ⁇ when heteroaryl include pyrrolyl, thienyl, furanyl, pyridyl, quinolinyl, benzofuranyl, and indolyl, each of which may be optionally substituted with up to three substituents.
  • the heteroaryl ring is substituted by two or three lipophilic substituents such as chloro, bromo, iodo, methyl, methoxy or trifluoromethyl.
  • substituents include halo.
  • aryl and heteroaryl groups for R ⁇ include phenyl, thienyl and indolyl.
  • X include C ⁇ 2 or forming, with R ⁇ , a 5 to 7-membered ring optionally containing oxygen or nitrogen fused to an aryl or heteroaryl ring.
  • R ⁇ X include benzyl, chroman-4-yl, 1,2,3,4- tetrahydroquinolin-4-yl, indol-2-ylmethyl, indol-7-ylmethyl, and thien-2-ylmethyl in which the aryl/heteroaryl ring may be optionally substituted.
  • Y include a C2 alkylene chain or a 1 ,2-cyclopentylene group.
  • Salts may be formed from inorganic and organic acids.
  • suitable inorganic and organic acids from which pharmaceutically acceptable salts of compounds of formula (I) may be formed include maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, hydrochloric, hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric and nitric acids.
  • alkyl and similar terms such as “alkoxy” includes all straight chain and branched isomers. Representative examples thereof include methyl, ethyl, «-propyl, wo-propyl, w-butyl, -.eobutyl, iso-butyl, t-butyl, ---pentyl and /--hexyl.
  • Preferred substituents for an alkyl group include, for example, and unless otherwise defined, halogen, cyano, azido, nitro, carboxy, (Ci _g)alkoxycarbonyl, carbamoyl, mono- or di-(C ⁇ _6)alkylcarbamoyl, sulpho, sulphamoyl, mono- or di-(C ⁇ _6)alkylsulphamoyl, amino, mono- or di-(C ⁇ _6)alkylamino, acylamino, ureido, (C].6)alkoxycarbonylamino, 2,2,2-trichloroethoxycarbonylamino, aryl, heterocyclyl, hydroxy, (Ci _g)alkoxy, acyloxy, oxo, acyl, 2-thienoyl, (C]_6)alkylthio, (C ⁇ _6)alkylsulphinyl, (C]-.g)alkyl
  • an aryl group When substituted, an aryl group may have up to three substituents.
  • Preferred substituents for an aryl group include, for example, and unless otherwise defined, halogen, cyano, (C j -g)alkyl, mono to perfluoro(C]-3)alkyl, (C3-7)cycloalkyl, (C2-6)alkenyl, (C ⁇ -g)alkoxy, (C2"6)alkenoxy, arylC ⁇ _6)alkoxy, halo(C ⁇ -6)alkyl, hydroxy, amino, mono- or di-(C ⁇ -6)alkylamino, acylamino, nitro, carboxy, (C ⁇ -6)alkoxycarbonyl, (C ] -g)alkenyloxycarbonyl, (C 1 -g)alkoxycarbonyl(C 1 -6)alkyl, carboxy(C ⁇ -6)alkyl, (C 1 -g)alky
  • heteroaryl includes single or fused rings comprising up to four hetero-atoms in the ring selected from oxygen, nitrogen and sulphur and optionally substituted with up to three substituents.
  • the heteroaryl ring comprises from 4 to 7, preferably 5 to 6, ring atoms.
  • a fused heteroaryl ring system may include carbocyclic rings and need only include one heterocyclic ring.
  • heterocyclyl includes aromatic and non-aromatic single or fused rings comprising up to four hetero-atoms in the ring selected from oxygen, nitrogen and sulphur and optionally substituted with up to three substituents.
  • the heterocyclic ring comprises from 4 to 7, preferably 5 to 6, ring atoms.
  • a fused heterocyclic ring system may include carbocyclic rings and need only include one heterocyclic ring.
  • a heteroaryl or a heterocyclyl group may have up to three substituents. Preferred such substituents include those previously mentioned for an aryl group as well as oxo.
  • substituents include those previously mentioned for an aryl group as well as oxo.
  • halogen and “halo” include fluorine, chlorine, bromine and iodine and fluoro, chloro, bromo and iodo, respectively.
  • the compounds according to the invention are suitably provided in substantially pure form, for example at least 50% pure, suitably at least 60% pure, advantageously at least 75% pure, preferably at least 85% pure, more preferably at least 95% pure, especially at least 98% pure, all percentages being calculated as weight/weight.
  • An impure or less pure form of a compound according to the invention may, for example, be used in the preparation of a more pure form of the same compound or of a related compound (for example a corresponding derivative) suitable for pharmaceutical use.
  • Preferred compounds of formula (I) include:
  • a compound of formula (I) may be prepared by reacting a compound of formula (II):
  • Suitable reductive alkylating conditions are well known in the art and include for instance, the use of sodium triacetoxyborohydride in a solvent system such as DMF/acetic acid or sodium cyanoborohydride in methanol/acetic acid.
  • Reductive alkylation with an aldehyde is typically carried out at room temperature for a period of 1 - 16 h.
  • Reductive alkylation with a ketone is typically carried out in refluxing methanol for a period of 16 - 40 h.
  • a compound of formula (IB) may be prepared by reacting a compound of formula (V): O
  • R4 is a leaving group such as halo, for instance chloro, or C ⁇ _g) alkylthio; with an amine of the formula (VI):
  • Suitable conditions are well known in the art and include the use of a large excess of the compound of formula (VI) to drive the reaction to completion and heating at a temperature of 60 - 130 °C. Addition of a base may be advantageous in some cases, eg a tertiary base such as N,N-di(cyclohexyl)ethylamine.
  • a compound of formula (IA) may also be prepared by reacting a compound of formula (VII):
  • Suitable conditions are well known in the art and include the use of a large excess of the compound of formula (VI) to drive the reaction to completion and heating at a temperature of 60 - 130 °C.
  • a base may be advantageous in some cases, eg a tertiary base such as N,N-di(cyclohexyl)ethylamine.
  • Acid hydrolysis may be carried out with refluxing concentrated hydrochloric acid where R° is methyl or with trifluoroacetic acid at room temperature where R° is 4-methoxybenzyl.
  • a compound of formula (II) may be prepared by reacting a compound of formula (VII) with a compound of formula (VI) in which R 2 is hydrogen.
  • the compounds of this invention are active against both Gram negative and Gram positive organisms, including Haemophilus, for instance H influenzae Ql; Moraxella, for instance M. catarrhalis 1502; Streptococci, for instance S. pyogenes C ⁇ 10 and S. pneumoniae R6; Staphylococci, for instance S. aureus Oxford; Escherichia, for instance E. Coli DCO, and Enterococci, for instance Ent. faecelis I.
  • compounds of this invention are active against
  • Staphylococci organisms such as S. aureus and coagulase negative strains of Staphylocci such as S. epidermidis which are resistant (including multiply- resistant) to other anti-bacterial agents, for instance, ⁇ -lactam antibiotics such as, for example, methicillin; macrolides; aminoglycosides, and lincosamides.
  • ⁇ -lactam antibiotics such as, for example, methicillin; macrolides; aminoglycosides, and lincosamides.
  • MRS A MRC ⁇ S and MRSE.
  • Compounds of the present invention are also active against strains of E. faecalis including vancomycin resistant strains and therefore of use in treating infections associated with VRE organisms. Furthermore, compounds of the present invention are useful in the treatment of Staphylococci organisms which are resistant to mupirocin.
  • Bacterial infections which may be treated include respiratory tract infections, otitis, meningitis, endocarditis, skin and soft tissue infections in man, mastitis in cattle, and respiratory infections in animals such as pigs and cattle. Accordingly, in a further aspect, the present invention provides a method of treating bacterial infection in human or non-human animals, which method comprises administering a therapeutically effective amount of a compound of formula (I) as hereinbefore defined, to a human or non-human animal in need of such therapy.
  • the present invention provides a pharmaceutical composition comprising a compound of formula (I) together with a pharmaceutically acceptable carrier or excipient.
  • the present invention also provides a method of treating bacterial infections in animals, especially in humans and in domesticated mammals, which comprises administering a compound of formula (I), or a composition according to the invention, to a patient in need thereof.
  • the invention further provides the use of a compound of formula (I) in the preparation of a medicament composition for use in the treatment of bacterial infections.
  • the compounds and compositions 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.
  • compositions according to the invention may be formulated for administration by any route, for example oral, topical or parenteral.
  • the compositions may, for example, be made up in the form of tablets, capsules, powders, granules, lozenges, creams, syrups, or liquid preparations, for example solutions or suspensions, which may be formulated for oral use or in sterile form for parenteral administration by injection or infusion.
  • Tablets and capsules for oral administration may be in unit dosage form, and may contain conventional excipients including, for example, binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrollidone; 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; and pharmaceutically acceptable wetting agents, for example 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 another suitable vehicle before use.
  • Such liquid preparations may contain conventional additives, including, for example, 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 (for example glycerine), propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and, if desired, conventional flavouring and colour 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
  • compositions according to the invention intended for topical administration may, for example, be in the form of ointments, creams, lotions, eye ointments, eye drops, ear drops, impregnated dressings, and aerosols, and may contain appropriate conventional additives, including, for example, preservatives, solvents to assist drug penetration, and emollients in ointments and creams.
  • Such topical formulations may also contain compatible conventional carriers, for example cream or ointment bases, and ethanol or oleyl alcohol for lotions. Such carriers may constitute from about 1% to about 98% by weight of the formulation; more usually they will constitute up to about 80% by weight of the formulation.
  • Compositions according to the invention may be formulated as suppositories, which may contain conventional suppository bases, for example cocoa-butter or other glycerides.
  • compositions according to the invention intended for parenteral administration may conveniently be in fluid unit dosage forms, which may be prepared utilizing the compound and a sterile vehicle, water being preferred.
  • the compound depending on the vehicle and concentration used, may be either suspended or dissolved in the vehicle.
  • the compound may be dissolved in water for injection and filter-sterilised before being filled into a suitable vial or ampoule, which is then sealed.
  • conventional additives including, for example, local anaesthetics, preservatives, and buffering agents can be dissolved in the vehicle.
  • the composition may be frozen after being filled into the vial, and the water removed under vacuum; the resulting dry lyophilized powder may then be sealed in the vial and a accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use.
  • Parenteral suspensions may be prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration.
  • the compound may instead be sterilised by exposure to ethylene oxide before being suspended in the sterile vehicle.
  • a surfactant or wetting agent is included in such suspensions in order to facilitate uniform distribution of the compound.
  • a compound or composition according to the invention may suitably be administered to the patient in an antibacterially effective amount.
  • a composition according to the invention may suitably contain from 0.1% by weight, preferably from 10 to 60% by weight, of a compound according to the invention (based on the total weight of the composition), depending on the method of administration.
  • the compounds according to the invention may suitably be administered to the patient at a daily dosage of from 1.0 to 50 mg/kg of body weight.
  • a daily dosage of from 1.0 to 50 mg/kg of body weight For an adult human (of approximately 70 kg body weight), from 50 to 3000 mg, for example about 1500 mg, of a compound according to the invention may be administered daily.
  • the dosage for adult humans is from 5 to 20 mg/kg per day. Higher or lower dosages may, however, be used in accordance with normal clinical practice.
  • each unit dose may suitably comprise from 25 to 1000 mg, preferable from 50 to 500 mg, of a compound according to the invention.
  • Example 1 6-[3-(3,5-Dibromobenzylamino)prop-l-ylamino]-7-fi r -thieno[2,3- b]pyridin-4-one dihydrochloride a) 7V-(3,5-Dibromoben__yl)propane-l,3-diamine - 3,5-Dibromobenzyl bromide (9.96 g, 30.2 mmol) was dissolved in THF (70 ml) and added dropwise over 90 minutes to a solution of propane- 1,3-diamine (12.6 ml, 151 mmol) in THF (50 ml) at 60°C.
  • Example 3 5-[3-(3,5-Dibromobenzylamino)prop-l-ylamino]-4H-thieno[3,2- b]pyridin-7-one dihydrochloride a) 5- [3-(3,5-Dibromobenzylamino)prop-l-y lamino] -7-methoxy thieno [3,2- bjpyridine - 5-Chloro-7-methoxythieno[3,2-b]pyridine, Example 2a, (345 mg, 1.73 mmol) was heated N-(3,5-dibromobenzyl)propane-l,3-diamine, Example la, (1.67 g, 5.19 mmol) in a Wheaton reactivial at 130 °C for 40 h.
  • Example 4 2-[3-(3,4-DichIorobenzylamino)prop-l-ylamino]-l_-- -l,8- naphthyridin-4-one dihydrochloride a) 2-Chloro-4-methoxy-l,8-naphthyridine - To 2,4-dichloro-l,8-naphthyridine (Berichte 1927, 60, 407; 0.43 g) was added NaOMe in MeOH (1 M, 4.3 ml) and the mixture was heated at reflux for 30 min. EtOAc (ca. 5 ml) was added and then removed in vacuo and this procedure was repeated.
  • Example la (334 mg, 1 mmol) in a Wheaton reactivial at 85 °C for 24 h. The residue was purified by flash chromatography on silica gel eluting with 5-10-20% [10:1 MeOH/conc.
  • Example 6 2-[3-(3,5-Dibromobenzylamino)prop-l-ylamino]-lH-thieno[3,2- - ]pyrimidin-4-one dihydrochloride : N-(3,5-Dibromobenzyl)propane-l,3- diamine, Example 5a, (0.105 g, 0.33 mmol) and 2-ethylsulfanyl-l H-thieno [3,2- -/]pyrimidin-4-one (J Med. Chem., 1995, 38, 2763; 0.035 g, 0.165 mmol) were reacted together at 125°C for 24 h.
  • Example 7 6-[3-(3,5-Dibromobenzylamino)prop-l-ylamino]-l,7- dihydropyrazolo[3,4--/]pyrimidin-4-one a) 6-Methylsulfanyl-l,7-dihydropyrazolo[3,4--/]pyrimidin-4-one: 4-Hydroxy- 6-mercaptopyrazolo[3,4--/]pyrimidine (500 mg, 2.97 mmol) was added to a solution of potassium bicarbonate (300 mg, 3.0 mmol) and methyl iodide (0.2 ml, 3.0 mmol) in EtOH (15 ml) and stirred under Ar for 16 h.
  • potassium bicarbonate 300 mg, 3.0 mmol
  • methyl iodide 0.2 ml, 3.0 mmol
  • Example 8 2-[3-(3-Bromo-5-methoxy-lH-indol-7-ylmethylamino)prop-l- ylamino]-lH-quinazolin-4-one a) 5-Methoxyindoline-7-carbaldehyde. l-(tert-Butoxycarbonyl)-5- methoxyindoline (Heterocycles, 1992, 34, 1031; 1.75 g, 7.0 mmol) was dissolved in dry T ⁇ F, treated with TMEDA (1.4 ml) and cooled to -78°C under an argon atmosphere.
  • Example 10 2-[3-(3-Chloro-5-methoxy-lH-indol-7-ylmethylamino)prop-l- ylamino]-lH-quinazolin-4-one a) 3-Chloro-5-methoxyindole-7- carbaldehyde.
  • the product from example 8b (140 mg, 0.80 mmol) was dissolved in dichloromethane (10 ml), treated with N-chlorosuccinimide (105 mg), and the mixture stirred at room temperature for 16 h. The solution was then diluted with dichloromethane, washed with water and brine, dried (MgSO4) and evaporated.
  • Example 11 2 -[3-(3-Chloro-5-methoxy-lH-indol-7-ylmethylamino)prop-l- y lamino] -lH-thieno [3,2--/] py rimidin-4-one.
  • Example 12 2 -[3 -(3-Chloro-5-methyl-lH-indoI-7-ylmethylamino)prop-l- ylamino]-l--_T-thieno[3,2-rf]pyrimidin-4-one dihydrochloride a) 5-Methylindole-7-carbaldehyde. 1 -(tert-Butoxycarbonyl)-5-methylindoline (J. Org Chem, 1999, 64, 3595; 2.9g 12.5 mmol) was converted to the 7-aldehyde as described for example 8a. A portion of this product (1.5 mmol) was converted to the corresponding indole as described for example 8b.
  • Methylsulfanyl-lH-pyrido[3,2- ]pyrimidin-4-one (450 mg) was treated in the same way as for Intermediate 2 to yield the title compound: (100 mg, 19%>) m/z (ESI) 218 ([M- ⁇ ]", 100%).
  • Example 5 (334 mg) was heated with 2-methylsulfanyl-lH-pyrimido[4,5- d]pyrimidin-4-one (100 mg) for 18 h at 85 °C. The reaction mixture was purified by column chromatography to yield the title compound as a pale yellow solid: (10 mg, 4%), m/z (ESI) 469 (M+ ⁇ +, 100%).
  • reaction mixture was purified by column chromatography and the product converted to the corresponding dihydrochloride salt using cone. HCl in methanol to yield the title compound as an off-white solid: (50 mg, 31%), m/z (ESI) 473 (M+H+, 100%).
  • Example 16 2-[3-(3,5-Dichloro-2-ethoxybenzylamino)prop-l-ylamino]-l_--- r - quinazolin-4-one dihydrochloride a) 3,5-Dichloro-2-ethoxybenzaldehyde 3,5-Dichloro-2-hydroxybenzaldehyde was alkylated on a 5.2 mmol scale using the general method for alkylation of phenols to give the title compound as a yellow solid (1.14 g, 99%); m/z (ES + ) 219 (MH+, 70%).
  • 6-Chloro-8-iodochroman-4-one 300 mg and intermediate 3 (289 mg) were dissolved in 3% v/v acetic acid in methanol (10 ml) and sodium methoxide (104 mg) added.
  • Sodium cyanoborohydride 122 mg was added and the reaction mixture heated for 24 h at 80 °C. The mixture was evaporated in vacuo and the residue purified by column chromatography. The product was converted to the corresponding dihydrochloride salt using cone. HCl in methanol to yield the title compound as an off-white solid: (20 mg, 4%), m/z (ESI) 517 (M+H+, 100%).
  • Example 19 2- [3-(6,8-Dibromochroman-4-ylamino)prop-l -ylamino] -1H- thieno[3,2--/]pyrimidin-4-one dihydrochloride - According to the procedure used for example SA6, 6,8-dibromochroman-4-one (ref WO 00/, SmithKine Beecham) (92 mg) was allowed to react with intermediate 3 dihydrochloride
  • Example 20 2-[3-(6-Bromo-8-chloro-l,2,3,4-tetrahydroquinolin-4- ylamino)prop-l-ylamino]-lH-quinazolin-4-one dihydrochloride 6-Bromo-8-chloro-2,3-dihydro-lH-quinolin-4-one (ref WO 00/, SmithKine Beecham) (40 mg) and intermediate 2 dihydrochloride (45 mg) were dissolved in 3% v/v acetic acid in methanol (5 ml).
  • 6-ethyl-8-iodo-2,3-dihydro-lH- quinolin-4-one (ref WO 00/, SmithKine Beecham) (60 mg) was allowed to react with intermediate 2 dihydrochloride (58 mg) to yield the title compound as an off-white solid: (10 mg, 8%), m/z (ESI) 504 (M+ ⁇ +, 15%), 286 (100%).
  • Example 23 2-[3-(6,8-Dibromo-l,2,3,4-tetrahydroquinolin-4-ylamino)prop- l-ylamino]-lH-quinazolin-4-one dihydrochloride According to the procedure used for example 20, 6,8-dibromo-2,3-dihydro-lH- quinolin-4-one (52 mg) was allowed to react with intermediate 2 dihydrochloride (58 mg) to yield the title compound as an off-white solid: (1 mg, 1%), m/z (ESI) 508 (M+ ⁇ + 100%).
  • Example 24 2-[3-(6-Bromo-8-methoxy-l,2,3,4-tetrahydroquinolin-4- ylamino)prop-l-ylamino]-lH-quinazolin-4-one a) 3-(2-Methoxy-4-bromophenylamino)propionic acid 3-(2- Methoxyphenylamino)propionic acid (J. Chem. Soc, Perkin I, 1972, 932; J. Med. Chem., 1965, 8, 566; 1.95 g, 10 mmol) dissolved in dry DMF (20 ml) at 0°C was treated with recrystallised N-bromosuccimide (1.78 g, 10 mmol).
  • Example 25 2-[3-(4,5-Dibromo-3-methylthien-2-ylmethylamino)prop-l- ylamino]-lH-thieno[3,4-( Jpyrimidin-4-one dihydrochloride a) 2-Methylsulfanyl-lH-thieno[3,4-- ]pyrimidin-4-one. 4-Aminothiophene-3- carboxylic acid methyl ester was liberated from the hydrochloride salt by passing down a column of alumina eluting with 10% methanol in dichloromethane.
  • Example 26 2-[3-(4,5-Dibromothien-2-ylmethylamino)prop-l-ylamino]-lH- quinazolin-4-one dihydrochloride According to the general method for reductive amination, 4,5-dibromothien-2- carbaldehyde (54 mg, 0.2 mmol) was allowed to react with intermediate 2 (43mg, 0.2mmol) to yield the title compound as a white solid: (29mg, 26%). MS (ES + ) 471/473/475 (12/24/13%) MH + , 253/255/257 (50/100/50%).
  • Example 27 2-[3-(4,5-Dibromothien-2-ylmethylamino)prop-l-ylamino]-lH- thieno[3,2-d]pyrimidin-4-one dihydrochloride
  • Example 31 2- ⁇ 3-[3,5-Dibromo-2-(3-morpholinopropoxy)benzylamino]- prop-l-ylamino ⁇ -lH-thieno[3,2-- ]pyrimidin-4-one trihydrochloride According to the general method for reductive amination example 30a (105 mg) was allowed to react with intermediate 3 (45 mg).
  • Example 32 2- ⁇ 3-[4,6-Dichloro-l-(2-hydroxyethyl)-lH-indol-2- ylmethylamino]prop-l-ylamino ⁇ -lH-thieno[3,2-d]pyrimidin-4-one a) 4,6-Dichloro-l-(methoxycarbonylmethyl)-lH-indole-2-carboxylic acid ethyl ester 4,6-Dichloro-lH-indole-2-carboxylic acid ethyl ester (0.516 g, 2 mmol) was disolved in DMF (5 ml) and then potassium carbonate (0.276 g, 2 mmol) was added.
  • Example 33 2-[3-(2-Ethoxy-5-iodo-3-methylbenzylamino)prop-l-ylamino]- lH-quinazolin-4-one a) 2-Hydroxy-5-iodo-3-methylbenzaldehyde 2-Hydroxy-3 -methylbenzaldehyde (272 mg, 2.0 mmol) was dissolved in dimethylformamide (10 ml), treated with sodium iodide (360 mg, 2.4 mmol) then chloramine T (546 mg, 2.4 mmol). After stirring at room temperature for 4 h, the suspension was treated with water, acidified with IN HCl and the mixture extracted with ethyl acetate.
  • Example 34 5-[3-(3,4-Dichlorobenzylamino)prop-l-ylamino]-4H-thieno[3,4- b]pyridin-7-one dihydrochloride a) 2-[3-(3,4-Dichlorobenzylamino)prop-l-ylamino]-4-methoxythieno[3,4- b]pyridine 2-Chloro-4-methoxythieno[3,4-b]pyridine (0.13 g; Barker et al, J. Chem. Res. Miniprint 1989, 7, 1501-1523) and intermediate 1 (0.4 ml) were heated with stirring at 120 °C for 16 h.
  • Compounds of the present invention may be assayed for their ability to inhibit the enzyme methionyl tRNA synthetase (MRS), using recombinant S. aureus MRS, as follows:
  • the reaction is started by adding 20 ul appropriately diluted pure enzyme (pre- incubated with inhibitor) to 25 ul reaction mix for 10 min at room temperature.
  • the reaction is terminated by the addition of 100 ul 5% trichloroacetic acid, 10% glycerol.
  • the TCA precipitate is harvested onto dry Unifilter GFC plates using a Packard Filtermate Cell Harvester. The filters are washed with 4 x 200ul of 50% industrial methylated spirit, before drying. 30 ul of Microscint 20 is added to each well and plates are counted on a TopCount. (Packard 96 well counter).
  • E. coli MRE 600 tRNA and ATP were purchased from Boehringer- Mannheim, L- 5 S] methionine from Amersham and other reagents from Sigma.
  • Results Examples 1 to 34 have IC50 values against S. aureus MRS in the range ⁇ 3 to 800 nM. All are highly selective with respect to the mammalian enzyme (no inhibition of rat MRS up to 1 uM).
  • Compounds of the present invention were assayed for antibacterial activity against a range of pathogenic organisms (strains of S aureus, S pneumoniae, E faecalis, H influenzae and M catarrhal 'is) in a standard MIC assay modified by the inclusion of cyclodextrin, to assist with solubility.
  • pathogenic organisms strains of S aureus, S pneumoniae, E faecalis, H influenzae and M catarrhal 'is
  • Examples 1, 3, 5, 6, 8-12, 16-25, and 27-33 had MIC's ⁇ l ⁇ g/ml against some strains of the organisms S. aureus, S. pneumoniae, and E. faecalis; and MIC's against M. Catarrhalis, in the range 2 - >64 ⁇ g/ml.
  • Examples 28 and 29 were active against H. influenzae.

Landscapes

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

Abstract

L'invention concerne des composés, lesquels correspondent à la formule (I) dans laquelle: W est CH et R1 est le résidu d'un noyau hétéroaryle à 5 ou 6 éléments, ou W est N et R1 est le résidu d'un noyau hétéroaryle à 5 ou 6 éléments ou d'un anneau aryle, ledit noyau hétéroaryle ou aryle étant éventuellement substitué avec 1 à 3 substituants choisis parmi halo, cyano, hydroxy, (C1-6) alkyle éventuellement substitué par halo, hydroxy, amino, mono à perfluoro(C1-3)alkyle, carboxy ou (C1-6)alkoxycarbonyle), (C3-7)cycloalkyle, C(1-6)alkoxy, amino, mono- ou di-(C1-6)alkylamino, acylamino, carboxy, (C1-6)alkoxycarbonyle, carboxy(C1-6)alkyloxy, (C1-6)alkylthio, (C1-6)alkylsulphinyle, (C1-6)alkylsulphonyle, sulphamoyle, mono- et di-(C1-6)alkylsulphamoyle, carbamoyle, mono- et di-(C1-6)alkylcarbamoyle, et hétérocyclyle; R2 est un aryle éventuellement substitué ou un noyau hétéroaryle éventuellement substitué; X est CH¿2? ou CHR?3¿ dans lesquels R3 est C(¿1-6?)akyle ou R?3¿ peut être lié à la position ortho d'un aryle ou d'un noyau hétéroaryle de R2 pour former un noyau à 5 à 7 éléments comprenant éventuellement de l'oxygène ou de l'azote comme atome du noyau; Y est C(¿1-3?)alkylène ou C(4-6)cycloalkylène. Cette invention concerne également des formes tautomeriques du noyau pyrimidone (lorsque W est N), leurs sels, de préférence leurs sels pharmaceutiquement acceptables. Ces composés constituent des inhibiteurs de l'enzyme bactérienne S aureus méthionyl-ARNt synthétase (S aureus methionyl t-RNA synthetase / MRS) et sont utiles dans le traitement d'infections bactériennes.
PCT/EP2000/004436 1999-05-19 2000-05-16 2-nh-pyridones et pyrimidones utilisees comme inhibiteurs de mrs WO2000071524A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU52133/00A AU5213300A (en) 1999-05-19 2000-05-16 2-nh-pyridones and pyrimidones as mrs inhibitors
JP2000619781A JP2003500397A (ja) 1999-05-19 2000-05-16 Ｍｒｓ阻害剤としての２−ｎｈ−ピリドンおよびピリミドン

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GBGB9911596.6A GB9911596D0 (en) 1999-05-19 1999-05-19 Novel compounds
GB9911595.8 1999-05-19
GB9911596.6 1999-05-19
GBGB9911595.8A GB9911595D0 (en) 1999-05-19 1999-05-19 Novel compounds

Publications (1)

Publication Number Publication Date
WO2000071524A1 true WO2000071524A1 (fr) 2000-11-30

Family

ID=26315562

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2000/004436 WO2000071524A1 (fr) 1999-05-19 2000-05-16 2-nh-pyridones et pyrimidones utilisees comme inhibiteurs de mrs

Country Status (3)

Country Link
JP (1) JP2003500397A (fr)
AU (1) AU5213300A (fr)
WO (1) WO2000071524A1 (fr)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6677352B1 (en) 2001-09-26 2004-01-13 Yamin Wang 1,6-naphthyridine derivatives and their use to treat diabetes and related disorders
WO2004078119A2 (fr) 2003-03-03 2004-09-16 Replidyne Inc. Thiopohenes substitues a activite antibacterienne
EP1619947A2 (fr) * 2003-05-01 2006-02-01 Replidyne, Inc. Compositions antibacteriennes et procedes associes
US7030137B2 (en) 2003-03-03 2006-04-18 Replidyne, Inc. Substituted thiophenes with antibacterial activity
US7973050B2 (en) * 2006-09-26 2011-07-05 Crestone, Inc. Enantiomeric compounds with antibacterial activity
US7994192B2 (en) * 2006-09-26 2011-08-09 Crestone, Inc. Substituted thienopyridone compounds with antibacterial activity
DE102011009961A1 (de) 2011-02-01 2012-08-02 Merck Patent Gmbh 7-Azaindolderivate
US8658670B2 (en) 2006-09-26 2014-02-25 Crestone, Inc. Methods and compounds for treatment of clostridium based infection
US8697720B2 (en) * 2006-09-26 2014-04-15 Crestone, Inc. Substituted phenylether-thienopyridone compounds with antibacterial activity
US9181276B2 (en) 2007-06-08 2015-11-10 Senomyx, Inc. Modulation of chemosensory receptors and ligands associated therewith
US9371317B2 (en) 2013-02-19 2016-06-21 Senomyx, Inc. Sweet flavor modifier
US9382196B2 (en) 2008-07-31 2016-07-05 Senomyx, Inc. Processes and intermediates for making sweet taste enhancers
US9420814B2 (en) 2012-08-06 2016-08-23 Senomyx, Inc. Sweet flavor modifier
US9603848B2 (en) 2007-06-08 2017-03-28 Senomyx, Inc. Modulation of chemosensory receptors and ligands associated therewith
US11945813B2 (en) 2018-08-07 2024-04-02 Firmenich Incorporated 5-substituted 4-amino-1H-benzo[c][1,2,6]thiadiazine 2,2-dioxides and formulations and uses thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5827857A (en) * 1996-01-16 1998-10-27 Bayer Aktiengesellschaft Pyrido-fused thienyl- and furanyl-oxazolidinones
WO1999055677A1 (fr) * 1998-04-29 1999-11-04 Smithkline Beecham Plc Quinolones utilisees comme inhibiteurs de mrs et bactericides
WO2000021949A1 (fr) * 1998-10-12 2000-04-20 Smithkline Beecham Plc Quinolones tenant lieu d'inhibiteurs d'arnt synthetase et d'agents antibacteriens

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5827857A (en) * 1996-01-16 1998-10-27 Bayer Aktiengesellschaft Pyrido-fused thienyl- and furanyl-oxazolidinones
WO1999055677A1 (fr) * 1998-04-29 1999-11-04 Smithkline Beecham Plc Quinolones utilisees comme inhibiteurs de mrs et bactericides
WO2000021949A1 (fr) * 1998-10-12 2000-04-20 Smithkline Beecham Plc Quinolones tenant lieu d'inhibiteurs d'arnt synthetase et d'agents antibacteriens

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6964971B2 (en) 2001-09-26 2005-11-15 Bayer Pharmaceuticals Corporation 1,6-naphthyridine derivatives and their use to treat diabetes and related disorders
US7109196B2 (en) 2001-09-26 2006-09-19 Bayer Pharmaceuticals Corporation 1,8 Naphthyridine derivatives and their use to treat diabetes and related disorders
US6677352B1 (en) 2001-09-26 2004-01-13 Yamin Wang 1,6-naphthyridine derivatives and their use to treat diabetes and related disorders
WO2004078119A2 (fr) 2003-03-03 2004-09-16 Replidyne Inc. Thiopohenes substitues a activite antibacterienne
WO2004078119A3 (fr) * 2003-03-03 2004-12-29 Replidyne Inc Thiopohenes substitues a activite antibacterienne
US7030137B2 (en) 2003-03-03 2006-04-18 Replidyne, Inc. Substituted thiophenes with antibacterial activity
EP1619947A2 (fr) * 2003-05-01 2006-02-01 Replidyne, Inc. Compositions antibacteriennes et procedes associes
EP1619947A4 (fr) * 2003-05-01 2006-05-31 Replidyne Inc Compositions antibacteriennes et procedes associes
US8658670B2 (en) 2006-09-26 2014-02-25 Crestone, Inc. Methods and compounds for treatment of clostridium based infection
US7973050B2 (en) * 2006-09-26 2011-07-05 Crestone, Inc. Enantiomeric compounds with antibacterial activity
US7994192B2 (en) * 2006-09-26 2011-08-09 Crestone, Inc. Substituted thienopyridone compounds with antibacterial activity
US8697720B2 (en) * 2006-09-26 2014-04-15 Crestone, Inc. Substituted phenylether-thienopyridone compounds with antibacterial activity
US9603848B2 (en) 2007-06-08 2017-03-28 Senomyx, Inc. Modulation of chemosensory receptors and ligands associated therewith
US9181276B2 (en) 2007-06-08 2015-11-10 Senomyx, Inc. Modulation of chemosensory receptors and ligands associated therewith
US9732052B2 (en) 2008-07-31 2017-08-15 Senomyx, Inc. Processes and intermediates for making sweet taste enhancers
US10570105B2 (en) 2008-07-31 2020-02-25 Firmenich Incorporated Processes and intermediates for making sweet taste enhancers
US10308621B2 (en) 2008-07-31 2019-06-04 Senomyx, Inc. Processes and intermediates for making sweet taste enhancers
US9382196B2 (en) 2008-07-31 2016-07-05 Senomyx, Inc. Processes and intermediates for making sweet taste enhancers
US10087154B2 (en) 2008-07-31 2018-10-02 Senomyx, Inc. Processes and intermediates for making sweet taste enhancers
DE102011009961A1 (de) 2011-02-01 2012-08-02 Merck Patent Gmbh 7-Azaindolderivate
EP3133074A2 (fr) 2011-02-01 2017-02-22 Merck Patent GmbH Derives 7-azaindole
WO2012104007A2 (fr) 2011-02-01 2012-08-09 Merck Patent Gmbh Dérivés de 7-azaindole
EP2746281A2 (fr) 2011-02-01 2014-06-25 Merck Patent GmbH Dérivés de 7-azaindole
US9687015B2 (en) 2012-08-06 2017-06-27 Senomyx, Inc. Sweet flavor modifier
US9745293B2 (en) 2012-08-06 2017-08-29 Senomyx, Inc. Sweet flavor modifier
US9420814B2 (en) 2012-08-06 2016-08-23 Senomyx, Inc. Sweet flavor modifier
US9695162B2 (en) 2013-02-19 2017-07-04 Senomyx, Inc. Sweet flavor modifier
US9475803B2 (en) 2013-02-19 2016-10-25 Senomyx, Inc. Sweet flavor modifier
US9371317B2 (en) 2013-02-19 2016-06-21 Senomyx, Inc. Sweet flavor modifier
US11945813B2 (en) 2018-08-07 2024-04-02 Firmenich Incorporated 5-substituted 4-amino-1H-benzo[c][1,2,6]thiadiazine 2,2-dioxides and formulations and uses thereof

Also Published As

Publication number Publication date
AU5213300A (en) 2000-12-12
JP2003500397A (ja) 2003-01-07

Similar Documents

Publication Publication Date Title
KR100691546B1 (ko) Ｌｈ 작용약으로서 유용한 비시클릭 헤테로방향족 화합물
US8022223B2 (en) 2-aminopyridine analogs as glucokinase activators
CA2943815C (fr) Inhibiteurs de indole mcl-1 substitues
WO2000071524A1 (fr) 2-nh-pyridones et pyrimidones utilisees comme inhibiteurs de mrs
IL142959A (en) Nitrogen containing heterobicycles and pharmaceutical compositions comprising same
JP2002517396A (ja) 細胞接着阻害抗炎症性化合物
JPS6333382A (ja) 新規ヘトラゼピンおよびその製法
MX2014000621A (es) Inhibidores triciclicos de cinasas utiles para el tratamiento de enfermedades proliferativas.
NZ552751A (en) Thienopyrimidines useful as aurora kinase inhibitors
WO2000071522A1 (fr) Derives de benzimidazole et leur utilisation comme inhibiteurs de la methionyl-arn-t synthetase
AU2007300290B2 (en) Enantiomeric compounds with antibacterial activity
US20070213362A1 (en) 2-nh-heteroarylimidazoles with antibacterial activity
AU2011201854A1 (en) Substituted thiophenes with antibacterial activity
WO2000021949A1 (fr) Quinolones tenant lieu d'inhibiteurs d'arnt synthetase et d'agents antibacteriens
US20060128735A1 (en) Substituted thiophenes with antibacterial activity
US6858616B2 (en) Nitrogen containing heterobicycles as factor Xa inhibitors
US20060287360A1 (en) Novel compounds

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
ENP Entry into the national phase

Ref country code: JP

Ref document number: 2000 619781

Kind code of ref document: A

Format of ref document f/p: F

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase