WO2000071524A1 - 2-nh-pyridones and pyrimidones as mrs inhibitors - Google Patents

2-nh-pyridones and pyrimidones as mrs inhibitors Download PDF

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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
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Prior art keywords
formula
ylamino
compound
prop
ring
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PCT/EP2000/004436
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French (fr)
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Sula Anne Armstrong
John Michael Berge
Pamela Brown
John Stephen Elder
Andrew Keith Forrest
Dieter Wolfgang Hamprecht
Richard Lewis Jarvest
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Smithkline Beecham Plc
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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/en
Publication of WO2000071524A1 publication Critical patent/WO2000071524A1/en

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    • 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.

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Abstract

Compounds of formula (I) in which: W is CH and R1 is the residue of a 5 or 6-membered heteroaryl ring, or W is N and R1 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¿1-6?)alkyl(optionally substituted by halo, hydroxy, amino, mono to perfluoro(C1-3)alkyl, carboxy or (C1-6)alkoxycarbonyl), (C3-7)cycloalkyl, C(1-6)alkoxy, amino, mono- or di-(C1-6)alkylamino, acylamino, carboxy, (C1-6)alkoxycarbonyl, carboxy(C1-6)alkyloxy, (C1-6)alkylthio, (C1-6)alkylsulphinyl, (C1-6)alkylsulphonyl, sulphamoyl, mono- and di-(C1-6)alkylsulphamoyl, carbamoyl, mono- and di-(C1-6)alkylcarbamoyl, and heterocyclyl; R?2¿ is an optionally substituted aryl or an optionally substituted heteroaryl ring; X is CH¿2? or CHR?3¿ in which R3 is C(¿1-6?)akyl or R?3¿ may be linked to the ortho position of an aryl or heteroaryl ring of R2 to form a 5 to 7 membered ring optionally including oxygen or nitrogen as a ring atom; Y is C(¿1-3?)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, are inhibitors of the bacterial enzyme S aureus methionyl t-RNA synthetase (MRS) and are of use in treating bacterial infections.

Description

2-NH-PYRIDONES AND PYRIMIDONES AS MRS INHIBITORS
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. Thus, for instance, 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. Each t-RNA synthetase represents a separate target for drug discovery. 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
We have now found a further class of compounds which are potent inhibitors of methionyl t-RNA synthetase viz 2-NH - substituted (hetero)aryl fused pyridones and pyrimidones. Accordingly, the present invention provides a compound of the formula (I):
Figure imgf000003_0001
(I) in which: 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(Cι-3)alkyl, carboxy or
(C i -6)alkoxycarbonyl), (C3-7)cycloalkyl, Cπ .g^alkoxy, amino, mono- or di-(C]-6)alkylamino, acylamino, carboxy, (Cι -g)alkoxycarbonyl, carboxy(Cι -6)alkyloxy, (Cι-g)alkylthio, (C \ -6)alkylsulphinyl, (Cι-g)alkylsulphonyl, sulphamoyl, mono- and di-(Cι-6)alkylsulphamoyl, carbamoyl, mono- and di-(C \ -g)alkylcarbamoyl, and heterocyclyl;
R2 is an optionally substituted aryl or an optionally substituted heteroaryl ring;X is CH2 or CHR^ in which R- is Cπ .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 Cπ _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. Representative examples of the moiety:
Figure imgf000004_0001
include:
W = N and Ri is the residue of an aryl ring: lH-quinazolin-4-one; W = CΗ and R^ is the residue of a heteroaryl ring: 7H-thieno[2,3-b]pyridin-4- one, 4H-thieno[3,2-b]pyridin-7-one, 4H-thieno[3,4-b]pyridin-7-one, 1H-1,8- naphthyridin-4-one ; W = N and Rl is the residue of a heteroaryl ring: lH-thieno[3,2- ]pyrimidin-4- one, lH-thieno[2,3-t ]pyrimidin-4-one, lH-thieno[3,4-- ]pyrimidin-4-one, 1H- pyrido[3,2- ]pyrimidin-4-one; lH-pyrimido[4,5-t ]pyrimidin-4-one, and 1,7- dihydropyrazolo[3,4- ]pyrimidin-4-one. Preferably, Ri forms the residue of a thieno ring.
Representative examples of R^ when aryl include phenyl and naphthyl, each of which may be optionally substituted with up to four substituents. Representative examples of such substituents include Cπ .g) alkyl, Cπ -6) alkoxy, C(l-6) alkylthio, heterocyclylCπ -6) alkoxy , halo, cyano, amino, sulphamoyl, phenylcarbonyl, aryl, and benzyloxy. Preferably, the phenyl or naphthyl is substituted by two or three lipophilic substituents such as chloro, bromo, iodo, methyl, methoxy, allyloxy, phenethyloxy, morpholinopropoxy or trifluoromethyl.
Representative examples of R^ when heteroaryl include pyrrolyl, thienyl, furanyl, pyridyl, quinolinyl, benzofuranyl, and indolyl, each of which may be optionally substituted with up to three substituents. Preferably, the heteroaryl ring is substituted by two or three lipophilic substituents such as chloro, bromo, iodo, methyl, methoxy or trifluoromethyl. Representative examples of such substituents include halo.
Preferred examples of aryl and heteroaryl groups for R^ include phenyl, thienyl and indolyl.
Representative examples of X include CΗ2 or forming, with R^, a 5 to 7-membered ring optionally containing oxygen or nitrogen fused to an aryl or heteroaryl ring.
Representative examples of 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.
Representative examples of Y include a C2 alkylene chain or a 1 ,2-cyclopentylene group.
It will be appreciated that within the compounds of formula (I) there exists a first set of pyridone compounds which W is CH: O
R1
R^ N Y N N H H H
(IA) and a second set of pyrimidone compounds in which W is N:
O
N ! 1 x !■ I R
M (IB) and in which R* , R X and Y are as hereinbefore defined.
Salts may be formed from inorganic and organic acids. Representative examples of 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.
When used herein, the term "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-(Cι_6)alkylcarbamoyl, sulpho, sulphamoyl, mono- or di-(Cι _6)alkylsulphamoyl, amino, mono- or di-(Cι _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, (Cι _6)alkylsulphinyl, (C]-.g)alkylsulphonyl, hydroxyimino, (C]_6)alkoxyimino, hydrazino, hydrazono, benzohydroximoyl, guanidino, amidino and iminoalkylamino. When used herein, the term "aryl" includes, unless otherwise defined, phenyl or naphthyl optionally substituted with up to five, preferably up to three substituents.
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, (Cj-g)alkyl, mono to perfluoro(C]-3)alkyl, (C3-7)cycloalkyl, (C2-6)alkenyl, (Cι-g)alkoxy, (C2"6)alkenoxy, arylCπ _6)alkoxy, halo(Cι-6)alkyl, hydroxy, amino, mono- or di-(Cι -6)alkylamino, acylamino, nitro, carboxy, (Cι -6)alkoxycarbonyl, (C ] -g)alkenyloxycarbonyl, (C 1 -g)alkoxycarbonyl(C 1 -6)alkyl, carboxy(C \ -6)alkyl, (C 1 -g)alkylcarbonyloxy , carboxy(C \ -g)alkyloxy , (C j -6)alkoxycarbonyl(C \ -g)alkoxy, (C \ -5)alkylthio, (C ] -6)alkylsulphinyl, (Cι-6)alkylsulphonyl, sulphamoyl, mono- and di-(Cι-6)-alkylsulphamoyl, carbamoyl, mono- and di-(Cι -6)alkylcarbamoyl, and heterocyclyl. When used herein, the term "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. Preferably 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.
When used herein, the term "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. Suitably 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.
When substituted, 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. When used herein, the terms "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:
2-[3-(3-Bromo-5-methoxy-lH-indol-7-ylmethylamino)prop-l-ylamino]-lH- quinazolin-4-one ;
2 - [3 -(3 -Bromo-5-methoxy- 1 H-indol-7-ylmethylamino)prop- 1 -ylamino]- 1 H- thieno [3 ,2-< ]pyrimidin-4-one; 2- [3 -(3 -Chloro-5 -methoxy- 1 H-indol-7-ylmethylamino)prop- 1 -ylamino]- 1 H- quinazolin-4-one;
2 - [3 -(3 -Chloro-5-methoxy- 1 H-indol-7-ylmethylamino)prop- 1 -ylamino] - 1 H- thieno[3,2--/Jpyrimidin-4-one;
2 -[3 -(3-Chloro-5-methyl-lH-indol-7-ylmethylamino)prop-l -ylamino]- 1H- thieno[3,2-< ]pyrimidin-4-one;
2-[3-(6-Chloro-8-iodochroman-4-ylamino)prop-l-ylamino]-lH-thieno[3,2-
<f]pyrimidin-4-one;
2 - [3 -(6 , 8-Dibromochroman-4-y lamino)prop- 1 -ylamino] - 1 H-thieno [3,2-
- ]pyrimidin-4-one; 2-[3-(6-Bromo-8-chloro-l,2,3,4-tetrahydroquinolin-4-ylamino)prop-l-ylamino]-
1 H-quinazolin-4-one;
2-[3-(6,8-Dibromo-l, 2, 3,4-tetrahydroquinolin-4-ylamino)prop-l -ylamino]- 1H- thieno[3,2-- ]pyrimidin-4-one;
2-[3-(6,8-Dibromo- 1,2, 3,4-tetrahydroquinolin-4-ylamino)prop-l -ylamino]- 1H- quinazolin-4-one;
2- [3 -(4,6-Dichloro- 1 H-indol-2-ylme thylamino)prop- 1 -ylamino]- 1 H-quinazolin-4- one;
2-[3-(4,6-Dichloro- 1 H-indol-2-ylmethylamino)prop- 1 -ylamino]- 1 H-thieno [3 ,2-
-/]pyrimidin-4-one; 2-{3-[3 ,5 -Dibromo-2-(3 -morpholinopropoxy)benzylamino]-prop- 1 -ylamino } - 1 H- quinazolin-4-one;
2-{3-[4,6-Dichloro-l-(2-hydroxyethyl)-lH-indol-2-ylmethylamino]prop-l- ylamino } - 1 H-thieno [3 ,2-d]pyrimidin-4-one; and
2-[3-(2-Ethoxy-5-iodo-3-methylbenzylamino)prop-l-ylamino]-lH-quinazolin-4- one. A compound of formula (I) may be prepared by reacting a compound of formula (II):
Figure imgf000009_0001
(II) in which R , W and Y are as hereinbefore defined; with either:
(a) for a compound of formula (I) in which X is CH2, an aldehyde of formula (III):
R CHO
(HI) in which R2 is as hereinbefore defined, under reductive alkylation conditions;
(b) for a compound of formula (I) in which X is CH2 substituted by π -6) alkyl or in which R2 and X are linked by a 5-7-membered ring opt. cont. oxygen or nitrogen, a ketone of formula (IV):
R R3CO
(IV) in which R2 and R are as hereinbefore defined, under reductive alkylation conditions.
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
N
R1
R N H
(V) in which Ri is as hereinbefore defined; and
R4 is a leaving group such as halo, for instance chloro, or Cπ _g) alkylthio; with an amine of the formula (VI):
R2XNHYCH2NH2
(VI) in which R2, X and Y are as hereinbefore defined; or an activated derivative thereof; under nucleophilic displacement conditions.
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):
OR6
R1
R Ν (VII) in which Ri is as hereinbefore defined; R5 is a leaving group such as halo, for instance chloro; and R° is a Cr\-6) alkyl, for instance methyl or ethyl, or an arylCn -4) alkyl group; with an amine of the formula (VI), as hereinbefore defined; or an activated derivative thereof; under nucleophilic displacement conditions; to form an intermediate which is then converted into a compound of formula (IA) by acidic hydrolysis. 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. 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 R2 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 CΝ10 and S. pneumoniae R6; Staphylococci, for instance S. aureus Oxford; Escherichia, for instance E. Coli DCO, and Enterococci, for instance Ent. faecelis I. In addition, 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, β-lactam antibiotics such as, for example, methicillin; macrolides; aminoglycosides, and lincosamides. Compounds of the present invention are therefore useful in the treatment of
MRS A, MRCΝS 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.
The compounds and 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. 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. In preparing solutions, 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. Advantageously, conventional additives including, for example, local anaesthetics, preservatives, and buffering agents can be dissolved in the vehicle. In order to enhance the stability of the solution, 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. Advantageously, 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. 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. Suitably, 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.
When the compositions according to the invention are presented in unit dosage form, each unit dose may suitably comprise from 25 to 1000 mg, preferable from 50 to 500 mg, of a compound according to the invention.
The following Examples illustrate the present invention.
General method for reductive amination To a suspension of the amine (0.2 mmol) (containing 0.5 mmol sodium acetate if the amine was present as the dihydrochloride) in methanol (2 ml) was added the aldehyde (0.2 mmol) in methanol (2 ml) and acetic acid (0.033 ml). After stirring under argon for 10 min, NaCNBH3 (24 mg, 0.4 mmol) in MeOH (1 ml) was added and the reaction stirred for 16 h. The reaction mixture was applied to a 2 g Varian Bond Elute SCX cartridge which was flushed with MeOH (8 ml). The cartridge was then eluted with 8 ml 0.2 M NH3 in MeOH, and this eluate evaporated to dryness. The residue was purified by chromatography on silica gel eluting with 2-10% (9: 1 MeOH/20 M NH3) in CH2CI2 • Product-containing fractions were combined and evaporated under reduced pressure to give the product as a white solid. To convert this into the corresponding dihydrochloride, the solid was dissolved in 1.0 M HC1 in methanol (0.4 ml) and the solution evaporated to dryness. An alternative method using polymer-supported cyanoborohydride was also used. (Polystyrylmethyl)trimethylammonium cyanoborohydride (Novobiochem) (3.64 mmol/g, 100 mg) was used in place of sodium cynoborohydride. The reaction was worked up by filtration, evaporation, followed by chromatography on silica gel as described above.
General method for alkylation of phenols To a solution of the phenol (1.2 mmol) and ethyl iodide (480 ul, 6 mmol) in dimethylformamide (2 ml) was added potassium carbonate (330 mg, 2.4 mmol). After stirring under argon at 65°C for 16 h the suspension was then diluted with diethyl ether, washed with water, dried (MgSO4) and evaporated to afford the product.
Intermediate 1 - N-(3-Aminoprop-l-yl)-3,4-dichloroben--ylamine - To 1,3- diaminopropane (42 ml) in dry THF (200 ml) at 60 °C was added dropwise a solution of 3,4-dichlorobenzylchloride (13.9 ml, 100 mmol) in 90 ml dry THF over 3 h. The mixture was kept at 60 °C for an additional 15 min and then kept at 25 °C for 3 days. The precipitate was removed by filtration and the mother liquor concentrated in vacuo. The residue was partitioned between water and t-butyl methyl ether (TBME). To the organic layer was added aq. HC1 (2 M) and the mixture was filtered. The layers were separated and NaOH was added to the aqueous layer with stirring. The resulting mixture was extracted with TBME and the organic extract was dried (Na2CO3), filtered, and the solvent evaporated to give the title compound as a slightly cloudy oil, (18.2 g, 78%). δπ (CDCI3) 1.20 (br, s, ca. 3H), 1.58-1.71 (m, 2H), 2.67 (t, J = 6.9, 2H), 2.78 (t, J = 6.8, 2H), 3.74 (s, 2H), 7.15 (dd, J = 8.2, 2.0, 1H), 7.37 (d, J = 8.2, 1H), 7.43 (d, J = 1.9, 1H); MS (ES+) 233 (MH+ 13%), 159 (100). Intermediate 2: 2-(3-Aminopropylamino)-lH-quinazolin-4-one
2-(Methylsulfanyl)-lH-quinazolin-4-one (20 g; Chern et al., Tetrahedron Asymm. 1996, 7, 1641-1648) and 1,3-diaminopropane (104 ml) were heated in a sealed vessel to 140 °C for 48 h. After cooling, a yellow crystalline solid was filtered off. The remaining reaction mixture was concentrated in vacuo, triturated with methanol, and purified by column chromatography. The crystals and the material obtained from chromatography were combined to yield the title compound: (12 g, 53%). δΗ (d6-DMSO) 1.63 (m, 2H), 2.64 (m, 2H), 3.39 (m, 2H), 5.10 (v. br., 3H), 6.87 (br, caAH), 7.06 (m, 1H), 7.21 (m, 1H), 7.52 (m, 1H), 7.87 (m, 1H). Intermediate 3: 2-(3-Aminopropylamino)-lH-thieno[3,2---]pyrimidin-4-one a) Potassium l--7-thieno[3,2-- ]pyrimidin-4-one-2-thiolate - 3-(3- Benzoylthioureido)-2-thiophenecarboxylic acid methyl ester (75 g; Gutschow, J Het. Chem. 1996, 33, 355-360) was added to a solution of KOΗ (25 g) in ethanol (1 1) and heated to reflux for 2.5 hours. A lemon coloured solid was filtered off to yield the title compound of about 85% purity which was used without further purification in the next step: (46 g). δπ (dg-DMSO) 6.87 (m, 1Η), 7.22 (m, 1Η), 10.35 (br, 1Η) plus benzoate impurity. b) 2-Methylsulfanyl-l-H-thieno[3,2-- ]pyrimidin-4-one - Potassium 1H- thieno[3,2--f|pyrimidin-4-one-2-thiolate (46 g) of about 85% purity was added to water (1 1). Methyl iodide (13 ml) was added and the mixture was stirred for 3 h. A white precipitate was filtered off and dried to yield the title compound as an off-white solid: (30 g, 82%). δΗ (d6-DMSO) 2.55 (s, 3H), 7.31 (d, J=5.2 Hz, 1H), 8.13 (d, J=5.2 Hz, 1H), 12.78 (br, 1H). c) 2-(3-Aminopropylamino)-lH-thieno[3,2-- ]pyrimidin-4-one - 2- Methylsulfanyl-lH-thieno[3,2--/]pyrimidin-4-one (20 g) was treated in the same way as described for Intermediate 2 to yield the title compound: (8.0 g, 35%). δΗ (d6-DMSO) 1.96 (m, 2H), 2.96 (m, 2H), 3.69 (m, 2H), 5.16 (br, ca. 4H under H2O peak), 7.54 (d, J=5, 1H), 8.28 (d, J=5, 1H).
Where the dihydrochloride salts of intermediates 2 or 3 were used, these were obtained quantitatively from the free amines by treatment with concentrated aqueous HC1 in methanol and evaporation.
Example 1 - 6-[3-(3,5-Dibromobenzylamino)prop-l-ylamino]-7-fir-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. The solution was stirred under argon for a further 30 min, filtered and the filtrate concentrated. The residues were partitioned between tert-butylmethylether and H2O, the organic layer separated and aqueous HC1 (1 M) added. The aqueous layer was separated, filtered and basified to pH 13 (NaOH pellets). The solution was extracted with CHCI3, dried (K2CO3), and evaporated under reduced pressure to yield the title compound as a yellow oil (6.21 g, 19 mmol): δjj (CDCI3) 1.36 (br, s, 3H + H2O), 1.65 (m, 2H), 2.67 (t, J 6.7, 2H), 2.79 (t, J 6.7, 2H), 3.74 (s, 2H), 7.42 (d, J 1.6, 2H), 7.54 (t, J 1.6, IH,); MS (ES+) 323 (100%, [M+H]+), 306 (75), 249 (100). b) 6-[3-(3,5-Dibromobenzylamino)prop-l-ylamino]-4-methoxythieno[2,3- b]pyridine - 2-Chloro-4-methoxythieno[2,3-b]pyridine (J. Chem. Res. Miniprint 1985, 2501; 275 mg, 1.38 mmol) was heated with N-(3,5-dibromobenzyl)propane- 1,3-diamine, Example la, (1.33 g, 4.14 mmol) in a Wheaton reactivial at 130°C for 40 h. The resulting oil was purified by flash chromatography on silica gel eluting with 5-10% [10:1 MeOH/conc. ΝH3(aq.)] in CH2C1 to yield the title compound as a white solid (70 mg, 0.144 mmol); δπ (CD3OD) 1.83 (m, 2H), 2.66 (t, J7.0, 2H), 3.44 (t, J6.7, 2H), 3.69 (s, 2H), 3.91 (s, 3H), 5.98 (s, IH), 6.94 (d, J5.9, IH), 7.11 (d, J 5.9, IH), 7.48 (d, J 1.7, 2H), 7.58 (t, J 1.7, IH); MS (ES+) 486 (50%, [M+H]+), 186 (100). c) 6-[3-(3,5-Dibromobenzylamino)prop-l-ylamino]-7H-thieno[2,3-b]pyridin- 4-one dihydrochloride - To the compound of Example lb (70 mg, 0.144 mmol) in 1,4-dioxane (2 ml) was added concentrated hydrochloric acid (8 ml). The mixture was refluxed at 110 °C for 32 h. The mixture was filtered and evaporated to low volume under reduced pressure to leave an off-white residue which was purified by flash chromatography on silica gel eluting with 5-10-25% [10:1 MeOH/conc. NH3(aq.)]. The isolated material was dissolved in MeOH and concentrated hydrochloric acid was added. The excess solvents were evaporated under reduced pressure to yield the title compound, isolated as the dihydrochloride salt, as a white solid (5 mg, 0.009 mmol); δy (CD3OD) 1.78 (m, 2H), 2.70 (t, J7.0, 2H), 3.30 (t, J6.6, 2H), 3.76 (s, 2H, ArCH2N), 5.39 (s, IH, HCCO), 6.85 (d, IH, J5.7, thiophene), 7.09 (d, IH, J5.7, thiophene), 7.45 (d, 2H, J 1.7, BrCCHCCH2), 7.56 (t, IH, J 1.7, BrCCHCBr); MS (ES+) 472 (100%).
Example 2 - 5-[3-(3,4-Dichlorobenzylamino)prop-l-ylamino]-4H-thieno[3,2- b]pyridin-7-one dihydrochloride a) 5-Chloro-7-methoxythieno[3,2-b]pyridine - 15-Crown-5 (1.46 ml, 7.35 mmol) was added to a solution of NaOMe (400 mg, 7.35 mmol) in THF (10 ml) and stirred for 15 minutes. 5,7-Dichlorothieno[3,2-b]pyridine (J. Chem. Res.
Miniprint 1980, 0113; lg , 4.9 mmol) was added, resulting in a deep purple suspension which was stirred under Ar for 90 minutes. The reaction mixture was partitioned between NH4CI (aq) and tert-butylmethylether, the layers separated, the organic layer washed with brine, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 4:1- 3 : 1 [hexanes/ethyl acetate] to give the title compound as an off- white solid (790 mg, 3.96 mmol); δH (CDCI3) 4.05 (s, 3H), 6.74 (s, IH), 7.44 (d, J5.4, IH), 7.70 (d, J5.4, IH); MS (ES+) 200 (75%, [M+H]+), 164 (100), 149 (63). b) 5-[3-(3,4-Dichlorobenzylamino)prop-l-ylamino]-7-methoxythieno[3,2- b]pyridine - A mixture of 5-chloro-7-methoxythieno[3,2-b]pyridine, Example 2a (0.40 g) and N-(3-aminoprop-l-yl)-3,4-dichlorobenzylamine (ca. 0.59 ml) was kept at 85 °C for 15 h and then at 125 °C for 4 h. Column chromatography (silica gel, MeOH : ΝH3 : CH2C12 10 : 1 : 100 → 30 : 3 : 200) separated residual 5- chloro-7-methoxythieno[3,2-b]pyridine (0.17 g) from material containing the title compound which was again submitted to column chromatography (silica gel, MeOH : NH3 : CH2CI2 10 : 1 : 100) to give the title compound (17 mg) as a yellow film: δ (CDCI3) 1.71 (br, s, IH, NH), 1.78-1.90 (m, 2H, CH2CH2CH2), 2.76 (t, J6.4, 2 H, CH2NHCH2), 3.47-3.55 (m, 2H, CH2N), 3.74 (s, 2H, ArCH2)- 3.95 (s, 3H, OCH3) 4.97 (br, s, 1 H, NH), 5.83 (s, 1 H, CHCO), 7.12-7.17 (m, 2H, 2Ar-H), 7.36 (d, J 8.2, 1 H, Ar-H), 7.44 (d, J 1.9, IH, ArH), 7.50 (d, J5.4, 1 H, Ar-H); m/z (ESI) 396 (MH+ 20%), 221 (100%). c) 5-[3-(3,4-Dichlorobenzylamino)prop-l-ylamino]-4H-thieno[3,2-i-']pyridin- 7-one dihydrochloride - The compound of Example 2b (17 mg) in dioxane (1 ml) and concentrated aq. HCl (5 ml) was heated at reflux for 48 h. Volatiles were evaporated in vacuo and the residue was triturated with CHCI3 and filtered to give the title compound as an off-white solid (18 mg): δjj (CD3OD) 2.08-2.25 (m, 2H, CH2CH2CH2,), 3.21-3.31 (m, 2 H, CH2NHCH2), 3.54-3.63 (m, 2H, CH2N), 4.29 (s, 2H, ArCH2), 6.27 (s, 1 H, CHCO), 7.45-7.54 (m, 2H, 2 Ar-H), 7.66 (d, J n.d., 1 H, Ar-H), 7.80 (d, Jn.d., 1 H, Ar-H), 8.10 (d, IH, Jn.d., ArH); m/z (ESI) 382 (MH+ 68%), 207 (100%).
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. The resulting oil was purified by flash chromatography on silica gel eluting with 5-10% [10:1 MeOH/conc. ΝH3(aq.)] in CH2CI2 to yield the title compound as a white solid (40 mg, 0.08 mmol); δH (CD3OD) 1.86 (m, 2H), 2.69 (t, J7.0, 2H), 3.45 (t, J6.8, 2H), 3.72 (s, 2H), 3.96 (s, 3H), 6.06 (s, IH), 7.11 (d, J5.3, IH), 7.49-7.53 (m, 2H), 7.59-7.61 (m, 2H); MS (ES+) 486 (100%, [M+H]+). b) 5- [3-(3,5-Dibromobenzylamino)prop-l -ylamino] -4H-thieno [3,2-b] p ridin- 7-one dihydrochloride - To the compound of Example 3a (40 mg, 0.08 mmol) in 1 ,4-dioxane (2 ml) was added concentrated hydrochloric acid (8 ml). The mixture was refluxed at 110 °C for 32 h. The mixture was filtered and evaporated under reduced pressure to leave an off-white residue which was purified by flash chromatography on silica gel eluting with 5-10-25% [10:1 MeOH/conc. NH3(aq.)] in CH2C-2. The isolated material was dissolved in MeOH and concentrated hydrochloric acid was added. Solvents were evaporated under reduced pressure to yield the title compound, isolated as the dihydrochloride salt, as a white solid (4 mg, 0.007 mmol); δH (CD3OD) 2.18 (m, 2H), 3.28 (m. 2H), 3.60 (t, J6.6, 2H), 4.30 (s, 2H, ArCH2N), 6.27 (s, IH, HCCO), 7.47 (d, J 5.4, IH, thiophene), 7.77 (d, J 1.4, 2H, HCCCH2), 7.90 (t, J 1.4, IH, BrCCHCBr), 8.08 (d, J 5.4, IH, thiophene); MS (ES+) 472 (100%, [M+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. The resulting material was submitted to column chromatography (silica gel, EtOAc : hexanes 2 : 1 — » 3 : 1 -» EtOAc) to give 4-chloro-2-methoxy-l,8-naphthyridine (211 mg, colourless crystals) followed by the title compound: colourless crystals (117 mg), δ (CDCI3) 4.09 (s, 3 H, OCH3), 6.83 (s, 1 H, 3-H), 7.46 (dd, J 8.3, 4.3, 1 H, 6-H), 8.50 (dd, Jn.d., IH), 9.07 (dd, Jn.d., 1 H); m/z (ESI) 217 (MNa+ 5%), 195 (MH+ 100%). b) 2-[3-(3,4-DichlorobenzyIamino)prop-l-ylamino]-4-methoxy-l,8- naphthyridine - A mixture of 2-chloro-4-methoxy-l,8-naphthyridine, Example 4a, (0.11 g) and N-(3-aminoprop-l-yl)-3,4-dichlorobenzylamine (ca. 0.17 ml) in acetonitrile (1 ml) and N,N-diisopropylethylamine (1 ml) was kept at 85 °C for 4 h, then at 25 °C for 15 h, then again at 85 °C for 24 h. Volatiles were evaporated in vacuo and the residue submitted to column chromatography (silica gel. MeOH : ΝH3 : CH2C-2 10 : 1 : 100) to give the title compound (163 mg) as a slightly yellow oil: δ (CDCI3) 1.79-1.91 (m, 3H, CH2CH2CH2 + NH), 2.77 (t, J6.3, 2 H, CH2NHCH2), 3.71 (t, J6.2, 2H, CH2N), 3.74 (s, 2H, ArCH2), 5.76 (br, t. Jn.d., 1 H, NH), 5.89 (s, 1 H, CHCO), 7.07 (dd, J 8.0, 4.5, IH, Ar-H), 7.14 (dd, Jn.d., IH, Ar-H), 7.34 (d, J 8.2, 1 H, Ar-H), 7.44 (d, J 1.9, 1 H, Ar-H), 8.22 (dd, Jn.d., IH, ArH), 8.75 (dd, Jn.d., 1 H, Ar-H); m/z (ESI) 391 (MH+ 32%), 216 (100%). c) 2-[3-(3,4-Dichlorobenzylamino)prop-l-ylamino]-lH-l,8-naphthyridin-4- one dihydrochloride - The compound of Example 4b (122 mg) in dioxane (2 ml) and concentrated aq. HCl (10 ml) was heated at reflux for 20 h. Volatiles were evaporated in vacuo and the residue was triturated with CHCI3 and filtered to give the title compound as a colourless solid (110 mg): δy (CD3OD) 2.08-2.21 (m, 2H, CH2CH2CH2,), 3.17-3.25 (m, 2 H, CH2NHCH2), 3.66-3.72 (m, 2H, CH N), 4.26 (s, 2H, ArCH2), 6.40 (s, 1 H, CHCO), 7.45-7.55 (m, 2H, 2 Ar-H), 7.62 (d, J 8.3, 1 H, Ar-H), 7.75 (d, J2.0, 1 H, Ar-H), 8.61-8.83 (m, 2H, 2ArH); m/z (ESI) 377 (MH+ 28%), 202 (100%).
Example 5 - 2-[3-(3,5-Dibromobenzylamino)prop-l-ylamino]-lH-quinazolin- 4-one
2-Methylthioquinazolin-4-one (Tetrahedron: Asymmetry 1996, 7, 1641; 100 mg, 0.52 mmol) was heated with N-(3,5-dibromobenzyl)propane-l,3-diamine,
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. ΝH3(aq)] in CH2CI2 to yield the product as an off-white solid (150 mg, 0.32 mmol); δH (CDCI3/CD3OD) 1.93 (m, 2H), 2.75 (t, J6.7, 2H), 3.59 (t, J6.5, 2H), 3.81 (s, 2H), 7.31 (m, 2H), 7.57 (s, 2H), 7.65 (m, 2H), 8.09 (m, IH); MS (ES+) 467 (100%, [M+H]+).
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. The mixture was pre-absorbed onto silica and purified by flash chromatography, eluting with 0 - 10% '10% 0.880 ammonia in methanol' in dichloromethane, to give the free base as an off-white solid. This was suspended in methanol and treated with hydrochloric acid to give the title compound as an off-white powder (0.023 g, 26%); δΗ (CD3OD) 2.2 - 2.35 (2Η, m), 3.35 (2H, t), 3.77 (2H, t), 4.35 (2H, s), 7.48 (IH, br d), 7.85 - 7.95 (3H,m), and 8.25 (IH, d); LC/MS (ES+) 471, 473, 475 (50, 100, 50%, MH+).
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. The reaction mixture was concentrated under reduced pressure, taken up in CH2Cl2:MeOH (10:1) and filtered, the filtrate evaporated under reduced pressure to give the title compound as an off-white solid (300 mg, 1.6 mmol); δH (CDCI3/CD3OD) 2.45 (s, 3H), 7.85 (s, IH); MS(APCI+) 183 (100%, [M+H]+); MS(APCI-) 181 (100%, [M-H]"). b) 6-[3-(3,5-Dibromobenzylamino)prop-l-ylamino]-l,7-dihydropyrazolo[3,4- rf]pyrimidin-4-one: 6-Methylsulfanyl-l,7-dihydropyrazolo[3,4-<f]pyrimidin-4- one, Example 7a, (100 mg, 0.55 mmol) was heated with N-(3,5- dibromobenzyl)propane-l,3-diamine, Example 5a, (350 mg,l.l mmol) in a Wheaton reactivial to 90 °C for 24 h. The reaction mixture was purified by flash chromatography over silica gel eluting with 10-25-40%) [10:1 MeOH/conc. ΝH3(aq)] in CH2CI2 to give the title compound as a white solid (20 mg, 0.04 mmol); δH (CDCI3/CD3OD) 1.80 (m, 2H), 2.66 (t, J6.7, 2H), 3.45 (t, J6.6, 2H), 3.72 (s, 2H), 7.42 (s, 2H), 7.57 (s, IH), 7.91 (s, IH); MS(ES+) 457 (100%, [M+H]+).
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 TΗF, treated with TMEDA (1.4 ml) and cooled to -78°C under an argon atmosphere. A solution of -y-butyl lithium (1.3 M in cyclohexane, 5.18 ml) was added dropwise. After stirring at -78°C for 1 h, the solution was treated with dry DMF (1.08 ml, 14 mmol) and stirred for a further 0.5 h. The cooling bath was then removed and the solution allowed to reach room temperature over 1 h. The reaction mixture was quenched with 10% aqueous NΗ4CI and the product extracted into ethyl acetate. The extracts were combined, washed with water and brine, dried (MgSO4) and evaporated. The residue was chromatographed on Kieselgel 60 eluting with 0-20% ethyl acetate in hexane. Product-containing fractions were combined and evaporated to afford the title compound (510 mg); contaminated with 35% (by weight) of the corresponding N-Boc analogue; δy (CDCI3, inter alia) 3.03 (2H, t, J =8.0 Hz, CH2), 3.76 (2H, t, J =8.1 Hz, CH2NH), 3.77 (3H, s, OMe), 6.42 (IH, br.s, NH), 6.73 (IH, d, J=0.8 Hz Ar-H), 6.90-6.92 (IH, m, Ar-H), 9.79 (IH, s, CHO). b) 5-MethoxyindoIe-7-carbaldehyde. The product from a) (80 mg; containing 0.3 mmol 5-methoxyindoline-7-carbaldehyde) was dissolved in dichloromethane (10 ml) and treated with Mnθ2 (344 mg, 4.0 mmol). The reaction mixture was stirred at room temperature for 16 h, filtered through Celite and the solvent removed in vacuo. The residue was chromatographed on Kieselgel 60 eluting with 0-20%) ethyl acetate in hexane to afford the title compound as a pale yellow solid (23 mg, 44%), δH (CDCI3) 3.91(3H, s, OMe), 6.56 (IH, dd, J= 2.2, 3.2 Hz, 3-H), 7.28 (IH, d, J=2.3 Hz, Ar-H), 7.33 (IH, t, J=2.6 Hz, 2-H), 7.46 (IH, m, Ar- H), 9.93 (IH, br.s., NH), 10.07 (IH, s, CHO). c) 3-Bromo-5-methoxyindole-7-carbaIdehyde. The product from b) (40 mg, 0.22 mmol) was dissolved in dichloromethane (5 ml), treated with N- bromosuccinimide (40 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. The residue was chromatographed on Kieselgel 60 eluting with 0-50% ethyl acetate in hexane. Product-containing fractions were combined and evaporated to afford the title compound as a pale pink solid (53 mg, 95%); δH (CDCI3) 3.94 (3H, s, OMe), 7.34 (3H, s, 2-H, 4-H, 6-H), 9.93 (IH, br.s. NH), 10.06 (IH, s, CHO). d) 2-[3-(3-Bromo-5-methoxy-lH-indol-7-ylmethylamino)prop-l-ylamino]- lH-quinazolin-4-one. The product from c) was coupled to intermediate 2 on a 0.2 mmol scale using the general method for reductive amination, with polymer-supported CNBH3 to give the title compound as a white solid (31 mg, 34%); m/z (CI+) 456 (MH+, 70%).
Example 9 - 2 -[3-(3-Bromo-5-methoxy-lH-indol-7-ylmethyIamino)prop-l- ylamino]-lH-thieno[3,2--/]pyrimidin-4-one
The product from example 8c was coupled to compound intermediate 3 on a 0.15 mmol scale using the general method for reductive amination, to give the title compound as a white solid (15 mg, 22%); m/z (CI+) 462 (MH+ 100%).
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. The residue was chromatographed on Kieselgel 60 eluting with 0- 50% ethyl acetate in hexane. Product-containing fractions were combined and evaporated to afford the title compound as a pale pink solid (115 mg, 68%); δjj (CDCI3) 3.94 (3Η, s, OMe), 7.28 (IH, d, J2.5 Hz), 7.33 (IH, d, J2.4 Hz), 7.39, (IH, d, J2.4 Hz), 9.93 (IH, br.s. NH), 10.06 (IH, s, CHO). b) 2-[3-(3-Chloro-5-methoxy-lH-indol-7-ylmethylamino)prop-l-ylamino]- lH-quinazolin-4-one. The product from a) was coupled to intermediate 2 on a 0.15 mmol scale using the general method for reductive amination, with polymer-supported CNBH3 to give the title compound as a white solid (31 mg, 50%); m/z (CI+) 412 (MH+, 80%).
Example 11 - 2 -[3-(3-Chloro-5-methoxy-lH-indol-7-ylmethylamino)prop-l- y lamino] -lH-thieno [3,2--/] py rimidin-4-one.
The product from example 10a was coupled to intermediate 3 on a 0.2 mmol scale using the general method for reductive amination, with polymer- supported cyanoborohydride, to give the title compound as a white solid (58 mg); m/z (CI+) 418 (MH+, 70%).
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. The title compound was obtained as a yellow solid (167 mg, 64%); δπ (CDCI3) 2.53(3H, s, Me), 6.56 (IH, dd, J= 2.2, 3.0 Hz, 3-H), 7.30 (IH, t, J= 3.0 Hz, 3-H), 7.47 (IH, d, J=1.0 Hz, Ar-H), 7.47 (IH, d, J= 1.0 HzAr-H), 9.98 (IH, br.s., NH), 10.10 (IH, s, CHO). b) 3-Chloro-5-methylindole-7-carbaldehyde . The product from a) (64 mg, 0.4 mmol) was converted to the title compound as described for example 10a, to give the title compound as a yellow solid (56 mg, 73%>); δfj (CDCI3) 2.55 (3H, s, Me), 7.25 (IH, t, J= 3.2 Hz, 3-H), 7.45(1H, s, Ar-H), 7.72 (IH, s, Ar-H), 9.87 (IH, br.s., NH), 10.10 (IH, s, CHO). c) 2 -[3 -(3-Chloro-5-methyl-lH-indol-7-ylmethylamino)prop-l-ylamino]-lH- thieno[3,2--/]pyrimidin-4-one dihydrochloride. The product from b was coupled to intermediate 3 on a 0.15 mmol scale using the general method for reductive amination, with polymer-supported cyanoborohydride, followed by conversion to the correspoding dihydrochloride to give the title compound as a white solid (28 mg, 47%); m/z (CI+) 402 (MH+, 70%).
Example 13 - 2-[3-(3,5-Dibromo-2-ethoxybenzylamino)prop-l-ylamino]-lH- pyrido [3,2--/Jpyrimidin-4-one dihydrochloride a) 3-(3-Benzoylthioureido)pyridine-2-carboxylic acid ethyl ester. 3-
Aminopyridine-2-carboxylic acid ethyl ester (1.3 g; Oakes et al, J. Chem. Soc. 1956, 1045) was dissolved in acetone (50 ml) and benzoyl isothiocyanate (2.2 ml) added. The solution was heated to reflux for 1 h and allowed to cool. The solution was concentrated in vacuo and a yellow precipitate was obtained on adding methanol to the resultant oil. This solid was filtered off to yield the title compound: (2.2 g, 82%). δH (d6-DMSO) 1.30 (t, J=7.0 Hz, 3H), 4.33 (q, J=7.0 Hz, 2H), 7.56 (m, 2H), 7.68 (m, 2H), 8.00 (m, 2H), 8.43 (m, IH), 8.58 (m, IH), 11.82 (br, IH), 12.96 (br, IH). b) Potassium lH-pyrido[3,2-rf]pyrimidin-4-one-2-thiolate. 3-(3-
Benzoylthioureido)pyridine-2-carboxylic acid ethyl ester (2.2 g) was treated in the same way as for Intermediate 3a to yield the crude title compound which was used directly in the next step without further purification: (1.6 g) m/z (APCI) 180 (M+H+, 95%), 440 (100%). c) 2-Methylsulfanyl-l---T-pyrido[3,2-rf]pyrimidin-4-one. Crude potassium 1H- pyrido[3,2-ύ?]pyrimidin-4-one-2-thiolate (1.6 g) was treated in the same way as for Intermediate 3b to yield the title compound: (458 mg, 36% over steps (b) and (c)), m/z (APCI) 194 (M+Η+, 100%). d) 2-(3-Aminopropylamino)-lH-pyrido[3,2-- ]pyrimidin-4-one. 2-
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-Η]", 100%). e) 2-[3-(3,5-Dibromo-2-ethoxybenzylamino)prop-l-ylamino]-lH-pyrido[3,2- ύf]pyrimidin-4-one dihydrochloride. According to the general method for reductive amination, 2-(3 -aminopropylamino)- 1 H-pyrido [3 ,2-</]pyrimidin-4-one (90 mg) was allowed to react with 3,5-dibromo-2-ethoxybenzaldehyde (126 mg) to yield the title compound as an off-white solid: (81 mg, 39%), m/z (ESI) 512 (M+Η+, 32%), 203 (100%). Example 14 - 2-[3-(3,5-DibromobenzyIamino)prop-l-ylamino]-l-flr- py rimido [4,5-rf] py rimidin-4-one
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+Η+, 100%).
Example 15 - 2-[3-(3,5-Dibromobenzylamino)prop-l-ylamino]-l/-r-thieno[2,3- Jjpyrimidin-4-one dihydrochloride a) 2-(3-Benzoylthioureido)thiophene-3-carboxylic acid methyl ester. 2-
Aminothiophene-3-carboxylic acid methyl ester (2.4 g; Gewald, Chem. Ber. 1965, 98, 3571-3577) was treated as for 13a to yield the title compound as an off-white solid: (3.6 g, 74%) m/z 319 (M+H+, 100%). b) Potassium lH-thieno[2,3-tf]pyrimidin-4-one-2-thiolate. 2-(3- Benzoylthioureido)thiophene-3-carboxylic acid methyl ester (2.9 g) was treated in the same way as for intermediate 3a to yield the crude title compound: (1.2 g), δH (d4-MeOH) 6.36 (m, IH), 6.58 (m, IH); contains 1 :1 benzoate:desired product; used crude in next step. c) 2-Methylsulfanyl-lH-thieno[2,3-rf]pyrimidin-4-one. The crude material from step b) was treated in the same way as for intermediate 3b to yield the crude title compound as an off-white solid which was used without further purification: (906 mg), m/z (APCI) 199 (M+H+, 100%). d) 2-[3-(3,5-Dibromobenzylamino)prop-l-ylamino]-lH-thieno[2,3- </]pyrimidin-4-one dihydrochloride. Example 5a (190 mg) was heated with 2- methylsulfanyl-lH-thieno[2,3-<i]pyrimidin-4-one (60 mg) for 26 h at 125 °C. The 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%). b) 2-[3-(3,5-Dichloro-2-ethoxybenzylamino)prop-l-ylamino]-lH-quinazolin- 4-one dihydrochloride According to the general method for reductive amination, 3,5-dichloro-2-ethoxybenzaldehyde (44 mg) was allowed to react with intermediate 2 (44 mg) to yield the title compound as an off-white solid: (29 mg, 29%), m/z (ESI) 421 (M+H+, 9%), 202 (100%). Example 17 - 2-[3-(3,5-Dibromo-2-ethoxybenzylamino)prop-l-ylamino]-lH- thieno[3,2-cf]pyrimidin-4-one dihydrochloride
According to the general method for reductive amination, 3,5-dibromo-2- ethoxybenzaldehyde (92 mg) was allowed to react with intermediate 3 (89 mg) to yield the title compound as an off-white solid: (58 mg, 33%), m/z (ESI) 208 ( 100%), 517 (M+H+, 25%).
Example 18 - 2-[3-(6-Chloro-8-iodochroman-4-ylamino)prop-l-ylamino]-lH- thieno[3,2-cf]pyrimidin-4-one dihydrochloride
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
(89 mg) to yield the title compound as a white solid: (9 mg, 5%), m/z (ESI) 515 (M+H+, 25%). 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). Sodium cyanoborohydride (50 mg in total) was added and the reaction mixture heated to 85°C for a total of 76 h. The reaction mixture was passed down a cation exchange cartridge and the residue purified by column chromatography. The product was converted to the corresponding dihydrochloride salt using cone. ΗC1 in methanol to yield the title compound as an off-white solid: (4 mg, 4%), m/z (ESI) 462 ([M-Η]", 100%).
Example 21 - 2-[3-(6-Ethyl-8-iodo-l,2,3,4-tetrahydroquinoIin-4- ylamino)prop-l-ylamino]-lH-quinazolin-4-one dihydrochloride
According to the procedure used for example 20, 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+Η+, 15%), 286 (100%).
Example 22 - 2-[3-(6,8-Dibromo-l,2,3,4-tetrahydroquinolin-4-ylamino)prop- 1-ylamino]- lH-thieno[3,2---]pyrimidin-4-one dihydrochloride
According to the procedure used for example 18, 6,8-dibromo-2,3-dihydro-lH- quinolin-4-one (304 mg) was allowed to react with intermediate 3 dihydrochloride (149 mg) to yield the title compound as an off-white solid: (13 mg, 4%), m/z (ESI) 514 (M+Η+ 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+Η+ 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). After stirring for 4 h at room temperature the DMF was evaporated and the residue partitioned between diethyl ether (50 ml) and water (50 ml). The organic layer was separated, washed with water, dried and evaporated to yield the title compound as a brown solid; δ (CDCI3 + D2O) 2.68 (2H, t, J = 6.4 Hz). 3.46 (2H, t, J = 6.8 Hz), 3.82 (3H, s), 6.48 (IH, d, J = 8.4 Hz), 6.85 (IH, d, J = 2 Hz), 6.97 (IH, d x d, J = 2 & 8.4 Hz); MS AP" 272Br79 (100%) MH". b) 6-Bromo-8-methoxy-2,3-dihydro-lH-quinolin-4-one 3-(2-methoxy-4- bromophenylamino)propionic acid (1 g, 3.65 mmol) was added to a mixture of phosphorus pentoxide (35 g) in 85 %> phosphoric acid (15 ml) at 100°C. After 1 h the resultant deep red mixture was poured onto ice and the aqueous solution made alkaline by cautious treatment with concentrated ammonium hydroxide. The organic material was extracted with ethyl acetate (3 x 50 ml) and the combined organic phases were washed with saturated sodium carbonate solution. The organic phase was separated, dried and evaporated to yield the title compound as a bright yellow solid; δ (CDCI3) 2.70 (2H, t, J = 6.8 Hz), 3.60 (2H, d x t, J = 2.4 & 7.1 Hz), 3.87 (3H, s), 4.92 (IH, brd. s), 6.90 (IH, d, J = 2 Hz), 7.59 (IH, d, J = 2 Hz); MS AP+ 256Br79 (100%) MH+ c) 2-[3-(6-Bromo-8-methoxy-l,2,3,4-tetrahydroquinoIin-4-ylamino)prop-l- ylamino]-li---quinazolin-4-one A mixture of 6-bromo-8-methoxy-2,3-dihydro- lH-quinolin-4-one, (85 mg, 0.33 mmol), intermediate 2 dihydrochloride (58 mg, 0.2 mmol) and sodium acetate (32.8 mg, 0.4 mmol) in 3% acetic acid in methanol (5 ml) was heated at reflux for lh, cooled, and sodium cyanoborohydride (20 mg, 0.32 mmol) added. After a further 48 h reflux the mixture was cooled and the solvent evaporated. The crude product was chromatographed over silica gel eluting with dichloromethane-methanol- ammonium hydroxide mixtures to yield the free base. Treatment with 1M methanolic hydrogen chloride gave the title compound as a cream solid; δ (CD3OD) 1.78-1.93 (2Η, m), 2.82 (2H, t, J = 6.84 Hz), 3.21-3.43 (6H, m), 3.75 (3H, s), 3.54-3.55 (IH, m), 6.76 (IH, d, J = 2 Hz). 6.92 (IH, d, J = 1.6 Hz), 7.18 (IH, J = 7.12 Hz), 7.23 (IH, d, J = 8.32 Hz), 7.59 (IH, t, J = 7.0 Hz), 7.98 (IH, d, J = 8.1 Hz); MS ES" 456Br79 (100%) [M-H]".
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. The free amine (4 g) was treated in the same way as for example 13a - 13c to yield the title compound (520 mg, 10% over 3 steps): δH (d6-DMSO) 2.49 (br, 3H), 7.60 (m, IH), 8.40 (m, IH), 12.0 (br, IH). b) 2-(3-Aminopropylamino)-lH-thieno[3,4--/]pyrimidin-4-one. 2-Methylsulf-myl-lH-thieno[3,4--/]pyrimidin-4-one (310 mg) was suspended in dioxane at 0 °C and hydrogen peroxide solution (3% w/w in Η2O, 3.5 ml) added, followed by acetic acid (5 drops) and a catalytic amount of methyl trioxorhenium. After stirring for 90 minutes at 25 °C the yellow solution was treated with Mnθ2, filtered through Celite and evaporated in vacuo. The crude product was heated with 1,3-diaminopropane (0.63 ml) for 18 h at 80 °C and purified by column chromatography to yield fractions containing the title compound which were used without further purification ( 100 mg), m/z (APCI) 225 (M+H+, 35%), 208 (100%). c) 5-Bromo-3-methylthiophene-2-carboxaldehyde 3-Methylthiophene-2- carboxaldehyde (5 g, 39.6 mmol) was dissolved in dry chloroform (100 ml) and the solution cooled to 0°C. Bromine (6.33 g, 39.6 mmol) was added dropwise then the reaction stirred at room temperature for 16 hours. The solution was diluted with chloroform, washed with 1M aqueous sodium carbonate and water. The organic solution was dried and evaporated. The residue was chromatographed on Kieselgel 60 eluting with 1 : 1 dichloromethane-hexane. Product-containing fractions were combined and evaporated to afford the title compound as a yellow solid (7.5 g, 92%); δH (CDCI3) 2.53 (3H, s, CH3), 6.96 (IH, s, Ar-H), 9.9 (IH, s, CHO). d) 4,5-Dibromo-3-methylthiophene-2-carboxaIdehyde 5-Bromo-3- methylthiophene-2-carboxaldehyde (7.5 g, 36.5 mmol) was dissolved in dry chloroform (75 ml), aluminium trichloride (12.2 g, 91.42 mmol) was added and the reaction mixture stirred for five minutes before the addition of bromine ( 5.84 g, 36.5 mmol). The reaction was stirred at room temperature for 16 hours, diluted with chloroform, and washed with aqueous sodium bicarbonate and water. The organic solution was dried and evaporated. The residue was chromatographed on Kieselgel 60 eluting with dichloromethane. Product-containing fractions were combined and evaporated to afford the title compound as a pale yellow solid (7.02 g, 70%); δH (CDCI3) 1.53 (3H, s, CH3), 9.93 (IH, s, CHO). e) 2- [3-(4,5-Dibromo-3-methylthien-2-ylmethylamino)prop-l -ylamino] -1H- thieno[3,4-rf]pyrimidin-4-one dihydrochloride. According to the general method for reductive amination, 4,5-dibromo-3-methylthiophene-2- carbaldehyde (70 mg) was allowed to react with the product of b) (50 mg) to yield the title compound as an off-white solid: (20 mg, 16%) m/z (ESI) 492 (M+Η+, 100%).
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
According to the general method for reductive amination, 3,4- dibromothiophene-2-carbaldehyde (54 mg, 0.2 mmol) was allowed to react with intermediate 3 (45 mg, 0.2 mmol) to yield the title compound as a white solid: (17 mg); MS ES+ 478(27%)MΗ+.
Example 28 - 2-[3-(4,6-Dichloro-lH-indol-2-ylmethylamino)prop-l-ylamino]- lH-quinazolin-4-one dihydrochloride
According to the general method for reductive amination, 4,6-dichloro-lH- indole-2-carbaldehyde (WO 99/55677; 150 mg) was allowed to react with intermediate 2 (153 mg) to yield the title compound as an off-white solid: (130 mg, 38%) m/z (ESI) 416 (M+Η+ 100%).
Example 29 - 2-[3-(4,6-Dichloro-lH-indol-2-ylmethylamino)prop-l-ylamino]- lH-thieno[3,2-έ/]pyrimidin-4-one dihydrochloride According to the general method for reductive amination, 3,4-dichloro-lH- indole-2-carbaldehyde (WO 99/55677; 150 mg) was allowed to react with intermediate 3 dihydrochloride (208 mg) to yield the title compound as a white solid: (65 mg, 19%) m/z (ESI) 422 (M+Η+, 100%).
Example 30 - 2-{3-[3,5-Dibromo-2-(3-morpholinopropoxy)benzylamino]- prop-l-ylamino}-lH-quinazolin-4-one trihydrochloride a) 3,5-Dibromo-2-(3-morpholinopropoxy)benzaldehyde
A mixture of 3,5-dibromo-2-hydroxybenzaldehyde (2.80 g), N-(3- chloropropyl)morpholine hydrochloride (2.00 g; Schliemann, W.; Buege, A.; Reppel, L. Pharmazie 1980, 35, 69-72), tetra-w-butylammonium iodide (0.74 g), potassium carbonate (1.52 g), and N.N-dimethylformamide (15 ml) were stirred at room temperature for 1 h and at 60 °C for 16 h. The mixture was then partitioned between water and ethyl acetate. The organic layer was washed (aq. ΝaHC03, brine) and concentrated to give the title compound as an orange oil in sufficient purity for the next step: (4.76 g), m/z (ESI) 406 (MH+, 32%). b) 2-{3-[3,5-Dibromo-2-(3-morpholinopropoxy)benzylamino]prop-l- ylamino}-lH-quinazolin-4-one trihydrochloride - According to the general method for reductive amination 3,5-dibromo-2-(3- morpholinopropoxy)benzaldehyde (105 mg) was allowed to react with intermediate 2 (44 mg). The product was isolated by column chromatography, treated with excess HCl in methanol, the volatiles evaporated, and the residue dissolved in water and lyophylised to give the title compound (88 mg) as a colourless solid: m/z (ESI) 610 (MH+, 76%). 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). The product was isolated by column chromatography, treated with excess ΗC1 in methanol, the volatiles evaporated, and the residue dissolved in water and lyophylised to give the title compound (74 mg) as a colourless solid: m/z (ESI) 616 (MΗ+, 57%).
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. The mixture was stirred under argon for 30 min, then methyl bromoacetate (0.19 ml, 2 mmol) added. The mixture was stirred for a further 2.5 h, then diluted with water and extracted with diethyl ether. The combined organic extracts were washed with brine, dried and evaporated to give the title compound as a beige powder (0.65 g, 98%); MS (APCI +ve) 330, 332 (30, 21%, MΗ+). b) 2-(4,6-Dichloro-2-hydroxymethyl-lH-indol-l-yl)ethanol 4,6-Dichloro-l - (methoxycarbonylmethyl)-lH-indole-2-carboxylic acid ethyl ester (0.625 g, 1.89 mmol) was dissolved in TΗF (20 ml), cooled in an ice/salt bath under argon, and treated slowly with a solution of lithium aluminium hydride (1M in TΗF, 2.27 ml, 2.27 mmol). The mixture was stirred for 2 h then quenched carefully with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried and evaporated to give the crude product as an oily solid (0.5 g, q). This material was used without further purification. c) 4,6-Dichloro-l-(2-hydroxyethyl)-lH-indole-2-carbaldehyde The crude material (max 1.89 mmol) from b) above was dissolved in dichloromethane (50 ml), manganese dioxide (1.64 g, 18.9 mmol) was added, and the mixture stirred for 3.5 h. The mixture was filtered, washing well with dichloromethane and 1 ,4- dioxane, then evaporated to give a solid. This material was dissolved in dichloromethane, pre-absorbed onto silica, then purified by flash chromatography, eluting with 0 - 20% ethyl acetate in 40 - 60 pet ether, to give the title compound as a white powder (0.203 g, 39%); MS (APCI -ve) 257, 259 (100, 66%, M-Η"). d) 2-{3-[4,6-Dichloro-l-(2-hydroxyethyl)-lH-indol-2-ylmethylamino]prop-l- ylamino}-lH-thieno[3,2-d]pyrimidin-4-one According to the general method for reductive amination the product of c) was allowed to react with intermediate 3 to give the title compound as a white powder (0.03 g, 32%); LC/MS (ES+) 466, 468 (15, 10%, MΗ+). 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. The organic layer was washed successively with a 5% aqueous solution of sodium thiosulphate, brine then dried and evaporated. The residue was chromatographed on Kieselgel 60 eluting with 0-50% toluene in hexane. Product-containing fractions were combined and evaporated to give the title compound as a white solid (330 mg, 63%); m/z (AP") 261 ([M-H]", 20%). b) 2-Ethoxy-5-iodo-3-methybenzaldehyde 2-Hydroxy-5-iodo-3- methylbenzaldehyde was alkylated on a 1.2 mmol scale using the general method for alkylation of phenols to give the title compound as a white solid (350 mg, 100%); δH (CDC13) 1.43 (3H, t, J =7.0 Hz, CH3), 2.29 (3H, s, CH3), 3.99 (2H, q, J =7.0 Hz, OCH ), 7.74 (IH, d, J =2.3 Hz, Ar-H), 7.96 (IH, d, J=2.3 Hz, Ar-H), 10.25 (IH, s, CHO). c) 2-[3-(2-Ethoxy-5-iodo-3-methylbenzyIamino)prop-l-ylamino]-lH- quinazolin-4-one 2-Ethoxy-5-iodo-3-methybenzaldehyde was coupled to intermediate 2 on a 0.2 mmol scale using the general method for reductive amination to give the title compound as a white solid (66 mg, 67%); m/z (ES+) 493 (MH+ 100%)
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. The product was purified by column chromatography eluting with 6-10% [10:1 MeOH/conc. NH3(aq.)] in CH2CI2 to yield the title compound (40 mg) as a brown oil: m/z (ESI) 419 (M+Na+, 20%). b) 5- [3-(3,4-Dichlorobenzylamino)prop-l -ylamino] -4H-thieno [3,4-b] pyridin- 7-one dihydrochloride 2-[3-(3,4-Dichlorobenzylamino)prop-l-ylamino]-4- methoxythieno[3,4-b]pyridine (40 mg) was heated in an oil bath of 120°C in dioxane (0.5 ml) and concentrated aqueous HCl (5 ml) for 16 h. Dioxane (2 ml) was added and heating continued for 7 h. The volatiles were then evaporated and the residue was triturated with chloroform, the solid collected by filtration, and further purified by column chromatography eluting with 10 - 25%) [10:1 MeOH/conc. NH3(aq.)] in CH2CI2. The oil thus obtained was treated with excess HCl in methanol, the volatiles were evaporated, and the residue was triturated with chloroform to yield, after filtration, the title compound (18 mg) as an off- white solid: m/z (ESI) 404 (M+Na+, 13%); 382 (M+H+, 20%).
Biological Data
1. Enzyme Inhibition - aminoacylation assay
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:
Reaction Mix (per 1ml )
Stock Volume (ul) Final Concentration
100mM Tris/Cl, pH 7.9 600 30 mM
250 mM KC1 75 mM
125 mM ATP 40 2.5 mM
250 mM MgC_2 80 10 mM
50 mM DTT 80 2 mM
0.5mM Met (S-35 hot and cold) 40 10 uM
Solid tRNA 4mg/ml 2mg/ml
(Mixed E. coli MRE 600)
H2O 160
10 x Inhibitor (0 - 100 uM) 5 ul per well 0 - 10 uM
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).
Reagents
Mixed E. coli MRE 600 tRNA and ATP were purchased from Boehringer- Mannheim, L- 5 S] methionine from Amersham and other reagents from Sigma.
Pure recombinant S. aureus MRS (EP application number 97300317.1, SmithKline Beecham) was obtained using standard purification procedures. The enzyme is diluted in Dilution Buffer which consists of 10 mM Tris / Cl, 2 mM DTT pH 7.9.
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).
2. Antibacterial Activity
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.
Examples 1, 3, 5, 6, 8-12, 16-25, and 27-33 had MIC's < lμg/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 μg/ml.
Examples 28 and 29 were active against H. influenzae.

Claims

Claims
1. A compound of formula (I):
Figure imgf000035_0001
(I) in which:
W is CH and RI 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, (Cl-6)alkyl (optionally substituted by halo, hydroxy, amino, mono to perfluoro(Cl-3)alkyl, carboxy or (C 1 -6)alkoxycarbonyl), (C3-7)cycloalkyl, C(l-6)alkoxy, amino, mono- or di-(Cl-6)alkylamino, acylamino, carboxy, (Cl-6)alkoxycarbonyl, carboxy(Cl-6)alkyloxy, (Cl-6)alkylthio, (Cl-6)alkylsulphinyl, (C 1 -6)alkylsulphonyl, sulphamoyl, mono- and di-(C 1 -6)alkylsulphamoyl, carbamoyl, mono- and di-(Cl-6)alkylcarbamoyl, and heterocyclyl;
R2 is an optionally substituted aryl or an optionally substituted heteroaryl ring;X is CH2 or CHR3 in which R3 is C(l-6)alkyl or R3 may be linked to the ortho position of an aryl or heteroaryl ring of R2 to form a 5 to 7 membered ring optionally including oxygen or nitrogen as a ring atom;
Y is C(l-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.
2. A compound of formula (I) as claimed in claim 1 in which R is the residue of a ring in which the heteroatom is sulphur, for instance thieno, or nitrogen, for instance pyrido and pyrazolo.
3. A compound of formula (I) as claimed in claim 1 or 2 in which R is the residue of a ring which is selected from thieno, pyrido and pyrazolo.
4. A compound of formula (I) as claimed any one of claims 1 to 3 in which X is CH2 or forms with R2 a 5-7-membered ring fused to an aryl ring or a heteroaryl ring which includes oxygen or nitrogen as a ring atom.
5. A compound of formula (I) as claimed any one of claims 1 to 4 in which
R2 when aryl is selected from phenyl and naphthyl, each of which may be optionally substituted with up to four substituents; or when heteroaryl is selected from pyrrolyl, thienyl, furanyl, pyridyl, quinolinyl, benzofuranyl, and indolyl, each of which may be optionally substituted with up to three substituents.
6. A compound of formula (I) as claimed in claim 5 in which aryl and heteroaryl groups for R2 are phenyl and indolyl, respectively.
7. A compound of formula (I) as claimed any one of claims 1 to 4 in which R2X is benzyl, chroman-4-yl, l,2,3,4-tetrahydroquinolin-4-yl, indol-2-ylmethyl, and thien-2-ylmethyl in which the aryl/heteroaryl ring may be optionally substituted.
8. A compound of formula (I) as claimed any one of claims 1 to 7 in which Y is a C2 alkylene chain.
9. A compound as claimed in any one of claims 1 to 8 of the formula (I A) or (IB):
O
R1
X
FT N Y N N H H H
(IA) and a second set of pyrimidone compounds in which W is N:
o
o
N
R1
X
R^ N Y N N H H H
(IB).
10. A compound of formula (I) as claimed in claim 1 selected from any one of the compounds named in the main title of Examples 1 to 34.
11. A compound of formula (I) as claimed in claim 10 selected from: 2-[3 -(3 -Bromo-5 -methoxy- 1 H-indol-7-ylmethylamino)prop- 1 -ylamino]- 1 H- quinazolin-4-one;
2 -[3-(3-Bromo-5-methoxy- 1 H-indol-7-ylmethylamino)prop- 1 -ylamino]- 1 H- thieno[3,2-_/]pyrimidin-4-one;
2-[3-(3-Chloro-5-methoxy-lH-indol-7-ylmethylamino)prop-l-ylamino]-lH- quinazolin-4-one ;
2 -[3-(3-Chloro-5-methoxy-lH-indol-7-ylmethylamino)prop-l-ylamino]-lH- thieno [3 ,2--f|pyrimidin-4-one; 2 -[3 -(3-Chloro-5-methyl-lH-indol-7-ylmethylamino)prop-l-ylamino]-lH- thieno [3 ,2-βf]pyrimidin-4-one;
2-[3-(6-Chloro-8-iodochroman-4-ylamino)prop-l-ylamino]-lH-thieno[3,2- t ]pyrimidin-4-one;
2-[3-(6,8-Dibromochroman-4-ylamino)prop-l-ylamino]-lH-thieno[3,2- < ]pyrimidin-4-one;
2- [3 -(6-Bromo-8-chloro- 1 ,2,3 ,4-tetrahydroquinolin-4-ylamino)prop- 1 -ylamino] -
1 H-quinazolin-4-one ;
2-[3-(6,8-Dibromo-l,2,3,4-tetrahydroquinolin-4-ylamino)prop-l -ylamino]- 1H- thieno[3,2--/]pyrimidin-4-one; 2-[3-(6,8-Dibromo-l,2,3,4-tetrahydroquinolin-4-ylamino)prop-l-ylamino]-lH- quinazolin-4-one ;
2-[3-(4,6-Dichloro-lH-indol-2-ylmethylamino)prop-l-ylamino]-lH-quinazolin-4- one;
2-[3-(4,6-Dichloro- 1 H-indol-2-ylmethylamino)prop- 1 -ylamino] - 1 H-thieno [3,2- <f]pyrimidin-4-one; 2-{3-[3,5-Dibromo-2-(3-morpholinopropoxy)benzylamino]-prop-l-ylamino}-lH- quinazolin-4-one;
2 - { 3 - [4,6-Dichloro- 1 -(2-hydroxy ethyl)- 1 H-indol-2-ylme thylamino]prop- 1 - ylamino } - 1 H- thieno [3 ,2-d]pyrimidin-4-one; and 2-[3-(2-Ethoxy-5-iodo-3-methylbenzylamino)prop-l-ylamino]-lH-quinazolin-4- one.
12. A pharmaceutical composition comprising an antibacterially effective amount of a substance or compound of formula (I) as claimed in claim 1 together with a pharmaceutically acceptable carrier or excipient.
13. A compound of formula (I) as claimed in for use in therapy.
14. A compound of formula (I) as claimed in for use in the treatment of bacterial infections.
15 Use of a compound of formula (I) as claimed in claim 1 in the manufacture of a medicament for use in the treatment of bacterial infections.
16. A process for preparing a compound of formula (I) as claimed in claim 1 which process comprises reacting a compound of formula (II):
Figure imgf000038_0001
(II) in which R , W and Y are as hereinbefore defined; with either:
(a) for a compound of formula (I) in which X is CΗ2, an aldehyde of formula (III):
R2CHO (III) in which R2 is as hereinbefore defined, under reductive alkylation conditions;
(b) for a compound of formula (I) in which X is CH2 substituted by C(l-6) alkyl or in which R2 and X are linked by a 5-7-membered ring opt.cont. oxygen or nitrogen, a ketone of formula (IV):
R2R3CO
(IV) in which R2 and R3 are as hereinbefore defined, under reductive alkylation conditions;
(c) for a compound of formula (IB), reacting a compound of formula (V):
O
. N
! R1
R N H (V) in which R is as hereinbefore defined; and
R4 is a leaving group such as halo, for instance chloro, or Cπ _g) alkylthio; with an amine of the formula (VI):
R XNHYCH2NH2
(VI) in which R2, X and Y are as hereinbefore defined; or an activated derivative thereof; under nucleophilic displacement conditions; or
(d) for a compound of formula (I A), reacting a compound of formula (VII):
OR°
R1
RD N (VII) in which R is as hereinbefore defined; R5 is a leaving group such as halo, for instance chloro; and R is a Cπ -6) alkyl, for instance methyl or ethyl, or an arylCn .4) alkyl group; with an amine of the formula (VI), as hereinbefore defined; or an activated derivative thereof; under nucleophilic displacement conditions; to form an intermediate which is then converted into a compound of formula (IA) by acidic hydrolysis.
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