+

WO2004078119A2 - Thiopohenes substitues a activite antibacterienne - Google Patents

Thiopohenes substitues a activite antibacterienne Download PDF

Info

Publication number
WO2004078119A2
WO2004078119A2 PCT/US2004/005930 US2004005930W WO2004078119A2 WO 2004078119 A2 WO2004078119 A2 WO 2004078119A2 US 2004005930 W US2004005930 W US 2004005930W WO 2004078119 A2 WO2004078119 A2 WO 2004078119A2
Authority
WO
WIPO (PCT)
Prior art keywords
compound
diamine
alkyl
ylmethyl
propane
Prior art date
Application number
PCT/US2004/005930
Other languages
English (en)
Other versions
WO2004078119A3 (fr
Inventor
John Berge
Richard Jarvest
Catherine Simone Victoire Frydrych
Joseph Guiles
Jian Qiu
Theodore M. Tarasow
Original Assignee
Replidyne Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB0304809.7A external-priority patent/GB0304809D0/en
Application filed by Replidyne Inc. filed Critical Replidyne Inc.
Priority to AU2004218481A priority Critical patent/AU2004218481A1/en
Priority to EP04715720A priority patent/EP1603881A4/fr
Priority to JP2006508886A priority patent/JP2006519261A/ja
Priority to CA002517523A priority patent/CA2517523A1/fr
Publication of WO2004078119A2 publication Critical patent/WO2004078119A2/fr
Publication of WO2004078119A3 publication Critical patent/WO2004078119A3/fr
Priority to AU2011201854A priority patent/AU2011201854A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms 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
    • 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

Definitions

  • the present invention relates to novel substituted thiophenes that are inhibitors of bacterial methionyl t-RNA synthetase (MRS), processes for their preparation and their use in therapy as anti-bacterial agents.
  • MRS bacterial methionyl t-RNA synthetase
  • 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 GlaxoSmithKline. 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.
  • sequence of the t-RNA synthetase genes in the Gram positive organism S aureus have recently been determined (see, for instance, European Patent application no 97300317.1, SmithKline Beecham, for S aureus MRS), thereby assisting the process of identifying inhibitors.
  • sequence of t-RNA synthetase genes in other pathogenic bacteria, for instance the Gram negative organism H influenzae has also been published (R.D. Fleischmann et al., Science, 269, 496-512, 1995).
  • R 1 is selected from the group consisting of C(1 _3) alkyl, C(2-3) alkenyl, C(2-3) alkynyl;
  • R2 is a halogen, preferably Br
  • R3 is selected from the group consisting of Br, optionally fluoro-substituted C ⁇ .3) alkyl, optionally fluoro-substituted C(2-3) alkenyl, and C(2-3) alkynyl;
  • R4 is selected from the group consisting of H, and C(i_3) alkyl
  • Y is C( 1-3 ) alkyl
  • Z is selected from the group consisting of substituted or unsubstituted heteroaryl imidiazole, substituted or unsubstituted quinol ⁇ ne, substituted or unsubstituted benzimidazole, substituted or unsubstituted fused heteroaryl pyridone, substituted or unsubstituted fused aryl pyrimidone, or substituted or unsubstituted fused heteroaryl pyrimidone.
  • R! is selected from the group consisting of methyl, allyl, propene, and propyne
  • R 2 is Br
  • R3 is selected from the group consisting of Br, ethyl, cyclopropyl, difluoromethyl, trifluoromethyl, vinyl, fluorovinyl, and ethyne;
  • R 4 is H
  • Y is C 2 alkyl
  • Z is selected from the group consisting of quinoline, heteroaryl imidazole, benzimidazole, and heteroaryl pyrimidone.
  • Compounds of formula (I) are inhibitors of bacterial methionyl tRNA synthetase.
  • 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, branched, and cyclic isomers. Representative examples thereof include methyl, ethyl, rc-propyl, ⁇ -propyl, cyclopropyl, 72-butyl, sec-butyl, z ' so-butyl, t-butyl, 72-pentyl and n- hexyl.
  • fluorosubstituted alkyls may have 1 or more substitutions of F for H on the alkyl chain.
  • a representative example of an optionally fluorosubstituted alkyl is trifluoromethyl.
  • alkenyl and alkynyl include all straight chain, branched and cyclic isomers. Representative examples thereof include vinyl, ethynyl and 1- propynyl.
  • fluorosubstituted alkenyls may have 1 or more substitutions of F for H on the alkenyl chain.
  • a representative example of an optionally fluorosubstituted alkenyl is fluorovinyl.
  • Preferred substituents for alkyl and alkenyl groups include, for example, and unless otherwise defined, halogen, cyano, azido, nitro, carboxy, (C ⁇ .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,
  • aryl includes, unless otherwise defined, phenyl or naphthyl optionally substituted with up to five, preferably up to three substituents.
  • 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 ⁇ -6)alkyl, mono to perfluoro(C ⁇ -3)alkyl, (C3-7)cycloalkyl 5 (C2"6)alkenyl,
  • heteroaryl includes single or fused rings comprising up to four hetero-atoms in the ring selected from oxygen, nitrogen and sulphur.
  • 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.
  • 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.
  • 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 pha ⁇ naceutical use.
  • certain compounds of the present invention may comprise one or more chiral centres so that compounds may exist as stereoisomers, including diastereoisomers and enantiomers.
  • the present invention covers all such stereoisomers, and mixtures thereof, including racemates.
  • the present invention provides a compound of the formula (II) when Z in formula (I) is a substituted or unsubstituted heteroaryl imidazole:
  • Rl, R 2 , R 3 , R 4 and Y are defined as in Formula (I).
  • R5 is the residue of a 5 or 6-membered heteroaryl ring which is optionally substituted with from 1 to 3 substituents selected from halo, cyano, hydroxy, (C ⁇ _6)alkyl (optionally substituted by halo, hydroxy, amino, mono to perfluoro(C ⁇ _3)alkyl, carboxy or
  • heteroaryl rings formed by R ⁇ are nitrogen-containing heteroaryl rings, having 6 ring atoms and including one or two nitrogen atoms, for instance b- or c-pyrido, d- pyridimo or c-pyridazino; or sulfur-containing heteroaryl rings, having 5 ring atoms, for instance c-thieno.
  • the heteroaryl ring is unsubstituted.
  • the ring is c- pyridazino.
  • the present invention also provides compounds of the formula (III) when Z in formula (I) is a substituted or unsubstituted quinolone:
  • Rl, R2, R3, R 4 and Y are defined as in Formula (I);
  • R6 is selected from halo, cyano, hydroxy, (C 1-6 )alkyl (optionally substituted by halo, hydroxy, amino, mono to perfiuoro(C 1-3 )alkyl, carboxy or (C 1-6 )alkoxycarbonyl).
  • the present invention also provides compounds of the formula (IV) when Z in formula (I) is a substituted or unsubstituted benzimidazole:
  • Rl, R2, R3, R 4 and Y are defined as in Formula (I);
  • R 6 and m are defined as in formula (III); and salts thereof, preferably pharmaceutically acceptable salts thereof.
  • the present invention also provides compounds of the formula (V) when Z in formula (I) is a substituted or unsubstituted fused heteroaryl pyridone or fused heteroaryl pyrimidone:
  • Rl, R 2 , R3 ⁇ R 4 and Y are defined as in Formula (I);
  • W is CH and R 5 is the residue of a 5 or 6-membered heteroaryl ring, or W is N and R 5 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(C] -3 )alkyl, carboxy or (C 1-6 )alkoxycarbonyl), (C -7 )cycloalkyl, C( 1-6 )alkoxy, amino, mono- or di-(C 1- 6 )alkylamino, acylamino, carboxy, (C 1-6 )alkoxycarbonyl, carboxy(C 1-6 )alkyloxy, (C ⁇ _ 6 )alkylthio, (C 1-6 )alkylsulphinyl, (C
  • R 5 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 R 5 when the residue of an aryl ring include phenyl. Representative substituents therefore include halogen, for instance chloro or bromo. Representative examples of the moiety:
  • R 5 forms the residue of a thieno ring.
  • Preferred compounds of formula (II) include the compounds of Examples 11-21.
  • Preferred compounds of formula (III) include the compounds of Examples 1-10.
  • Preferred compounds of formula (IV) include the compounds of Examples 22-24.
  • Preferred compounds of formula (V) include the compounds of Examples 25.
  • the compounds of formula (I) may be prepared by methods described herein or by methods described in the prior art that are incorporated by reference herein below.
  • a compound of formula (I) may also be prepared by reacting a compound of formula (VI):
  • 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 (VI) may be prepared by reacting an imidazole compound of formula (VIII) with an amine compound of formula (IX).
  • R7 is a leaving group such as halo, for instance chloro, or C ⁇ _ alkylthio;
  • Suitable conditions are well known in the art and include the use of a large excess of the compound of formula (IX) 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 VII may be prepared by reacting an alkyl, alkenyl, or alkynl Boronate ester X with the appropriate substituted thiophene aldehyde XI:
  • a fluorovinyl compound of formula VII may be prepared by reacting a vinylfluorosilicon derivative XII with the appropriate substituted thiophene aldehyde XI:
  • Compounds of formula (IX) are amines and are either commercially available or may be prepared fo ⁇ n available starting materials using methods well known in the art for preparing amines, for instance by functional group interconversion Compounds of formula (II) can be prepared using methods described in U.S. Patent Application Ser No. 60/527,229, filed on December 5, 2003.
  • the compounds of this invention are active against a range of important pathogenic bacteria, including Gram positive organisms, such as Staphylococci, for instance S. aureus Oxford and coagulase negative strains of Staphylococci such as S. epidermidis; Streptococci, for instance S. pyogenes CN10 and S. pneumoniae R6; and Enterococci, for instance Ent. faecelis I.
  • Gram positive organisms such as Staphylococci, for instance S. aureus Oxford and coagulase negative strains of Staphylococci such as S. epidermidis
  • Streptococci for instance S. pyogenes CN10 and S. pneumoniae R6
  • Enterococci for instance Ent. faecelis I
  • compounds of this invention are also active against Gram negative organisms, such as Haemophilus, for instance H. influenzae Ql; Moraxella, for instance M. catarrhalis 1502; and Escherichi
  • 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.
  • 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.
  • 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 VR ⁇ 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 media, meningitis, endocarditis, skin and soft tissue infections in man, mastitis in cattle, and also respiratory infections in farm animals such as pigs and cattle.
  • 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.
  • a compound of the present invention which has a broad spectrum of anti-bacterial activity, including activity against both Gram positive and Gram negative bacteria will be of general use in the community for the empiric treatment of community acquired infections.
  • a compound of the present invention with a more limited spectrum, for instance activity against Gram positive bacteria is more likely to be used in circumstances where the causative pathogenic organism has been identified..
  • the present invention provides a pharmaceutical composition
  • 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 fo ⁇ ns, 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 100 mg/kg of body weight.
  • a daily dosage of from 1.0 to 100 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 4 7V-(4-bromo-5-(l-fluorovinyl)-3-methylthiophen-2-ylmethyl)-iV-(lH- quinolin-4-one)propane-l,3-diamine.
  • the mixture was then cooled to -78 °C and the atmosphere replaced with 1,1-difluoroethylene (excess) such that the temperature of the reaction mixture remained below -55 °C.
  • Difluoroethylene addition was stopped when the reaction temperature remained at or below -70 °C.
  • the reaction was stirred at ⁇ -70 °C until it turned a clear light yellow ( ⁇ 2 hr.) and was then allowed to warm to ambient temperature.
  • the remaining lithium wire was removed and the mixture treated with portions of Na 2 SO 4 - 10H O until no gas evolved upon addition.
  • the mixture was then dried over Na 2 SO , filtered through a silica pad and the pad rinsed with ether.
  • the combined filtrates were dried under vacuum, the resulting residue suspended/dissolved in hexanes and filtered through another silica pad. The pad was rinsed with hexanes, the filtrates combined and the solvent removed under reduced pressure to give a light yellowish liquid with some white crystalline material present.
  • the product was purified by vacuum distillation (113-117 °C at ⁇ 2 Torr) to give 44 g (59%) of the title compound as a clear colorless liquid.
  • the reaction mixture was stirred at 0 to 5 °C for 2 hr and then 2 mL of water was added. The mixture was then diluted with 5 mL IN NaOH and extracted with 25% diethyl ether/hexanes (4 x 20 mL). The combined extracts were washed with brine (1 x 5 mL), dried over Na 2 SO 4 , and the solvent removed under vacuum. The remaining residue was purified by flash silica gel chromatography (CH 2 Cl 2 /hexanes) to give a 50% yield of the title compound as a white solid.
  • Example 5 iV-(4-bromo-5-ethyl-3-metb.ylthiophen-2-ylmethyl)-N'-(lH-quinolm-4- one)propane-l,3-diamine. a) 4-Bromo-5-ethynyl-3-methylthiophene-2-carbaldehyde.
  • Example 7 /V-(4-bromo-5- difluoromethyl -3-methylthiophen-2-ylmethyl)- V f -(lH- quinolin-4-one)propane-l,3-diamine.
  • a solution of 4,5-dibromo-3- methylthiophene-2-carbaldehyde (2.84 g, 10 mmol), 1,2-dihydroxyethane (1.36 g, 22 mmol) and resin supported 4-toluenesulfonic acid in toluene (100 mL) was heated at reflux with separation of water.
  • Example 8 iV-(4-bromo-3-methyl -5- trifluoromethyl thiophen-2-ylmethyl)-7V -(1H- quinolin-4-one)propane-l,3-diamine. a) 4-Bromo-3-methyl-5-trifluoromethylthiophene-2-carbaldehyde.
  • 4,5-Dibromo-3- methylthiophene-2-carbaldehyde 250 mg, 0.88 mmol was dissolved in a mixture of DMF (10 mL) and N-methylpyrrolidine (0.5 mL) containing copper (I) iodide (200 mg, 0.96 mmol) and 2,2-difluoro-2-fluorosulfonyl acetic acid methyl ester (871 mg, 4.4 mmol). After heating at 70°C with vigorous stirring for 7 h the mixture was cooled and allowed to cool to room temperature overnight. The DMF was evaporated and the residue was partitioned between diethyl ether (30 mL) and saturated ammonium chloride solution.
  • Example 9 iV-(4-bromo-3-(l-propynyl)-5-ethyl thiophen-2-ylmethyl)-iV f -(lH-quinolin- 4-one)propane-l,3-diamine.
  • 2,3,4-Tribromo-5-ethylthiophene (1.4 g, 4.1 mmol) was dissolved in dry THF (40 mL) and cooled to -78°C under an argon atmosphere. A solution of n-butyl lithium (1.6 M in cyclohexane, 2.56 mL)was added dropwise.
  • Example 11 N-(4-Bromo-5-cyclopropyl-3-methylthiophen-2-ylmethyl)-iV , -(5H- imidazo[4,5-c]pyridazin-6-yl)propane-l,3-diamine dihydrochloride. a) [3-(5H-Imidazo[4,5-c]pyridazin-6-ylamino)propyl]carbamic acid -butyl ester.
  • Example 12 7V-(4-bromo-3-methyl -5- trifluoromethylthiophen-2-ylmethyl)-iV -(5H- imidazo[4,5-c]pyridazin-6-yl)propane-l,3-diamine dihydrochloride.
  • Using the general method for reductive amination a mixture of N-(5H-Imidazo[4,5-c]pyridazin-6-yl)propane- 1,3-diamine lib (and 8a gave the title compound as a white solid, m/z (ES+) 449 ( 100%
  • Example 13 V-(4-bromo-3-methyl-5-vinylthiophen-2-ylmethyl)- N'-(5H-imidazo[4,5- c]pyridazin-6-yl)propane-l,3-diamine dihydrochloride.
  • Using the general method for reductive amination a mixture of V-(5H-Imidazo[4,5-c]pyridazin-6-yl)propane-l,3-diamine lib and 3a gave the title compound as a white solid, m/z (ES+) 407 ( 100% M + ).
  • Example 14 V-(4-bromo-5-(l-fluorovinyl)-3-methylthiophen-2-ylmethyl)- JS'- H- imidazo[4,5-c]pyridazin-6-yl)propane-l,3-diamine dihydrochloride.
  • Using the general method for reductive amination a mixture of N-(5H-Imidazo[4,5-c]pyridazin-6-yl)propane- 1,3 -diamine lib and 4b gave the title compound as a white solid, m/z (ES+) 425 ( 100%) M+).
  • Example 15 7V-(4-bromo-5-ethynyl-3-methylthiophen-2-ylmethyl)- iV'-(5H-imidazo[4,5- c]pyridazin-6-yl)propane-l,3-diamine dihydrochloride.
  • Using the general method for reductive amination a mixture ofN-(5H-Imidazo[4,5-c]pyridazin-6-yl)propane-l,3-diamine lib and 2a gave the title compound as a white solid, m/z (ES+) 405 ( 100% M + ).
  • Example 16 JV-(4-bromo-5- difluoromethyl -3-methylthiophen-2-ylmethyl)-N -(1H- imidazo[4,5-b]pyridin-2-yl)-propane-l,3-diamine a) l,3-Dihydroimidazo[4,5-b]pyridine-2-thione To 2,3-diaminopyridine (4.36 g, 40 mmol) in pyridine (40 ml) was added carbon disulfide (3.6 ml, 60 mmol). The mixture was heated to 50°C for 6 h then concentrated to low volume by evaporation under reduced pressure and the residue triturated with tetrahydrofuran.
  • Example 17 iV-(4-bromo-5-(l-fluorovinyl)-3-methylthiophen-2-ylmethyl)-iV'-(lH- imidazo[4,5-b]pyridin-2-yl)-propane-l,3-diamine.
  • Using the general method for reductive amination a mixture ofN-(lH-imidazo[4,5-b]pyridin-2-yl)propane-l,3-diamine 16c and 4b gave the title compound as a white solid, m/z (ES+) 424 ( 100% M + ).
  • Example 18 iV-(4,5-Dibromo-3-methylthiophen-2-ylmethyl)-iV' (lH-thieno[3,4- ⁇ /]imidazol-2-yl)propane-l,3-diamine a) 3,4-Diaminothiophene.
  • Example 20 N-(4-Bromo-3-methyl -5-trifluoromethylthiophen-2-ylmethyl)-iV , -(lH- thieno[3,4- ⁇ /]imidazol-2-yl)propane-l,3-diamine.
  • Using the general method for reductive amination a mixture ofN-(lH-imidazo[4,5-b]pyridin-2-yl)propane-l,3-diamine 18d and 8a gave the title compound as a white solid, m/z (ES+) 453 ( 100% M + ).
  • Example 21 N-(4-bromo-5-(l-fluorovinyl)-3-methylthiophen-2-ylmethyl)-7V'-(lH- thieno[3,4- ⁇ / * jimidazol-2-yl)propane-l,3-diamine.
  • a mixture of 18d and 4b gave the title compound as a white solid, m/z (ES+) 429 ( 100% M+).
  • Example 22 N-(4-bromo-5-(l-fluorovinyl)-3-methylthiophen-2-ylmethyl)-iV'-(l J 6 - benzimidazole)propane-l,3-diamine.
  • 2-Chloro-l ⁇ -benzimidazole (1.53g, 10 mmol) and 1,3 diamionpropane (25 ml, 300 mmol) were heated together for 18 h at 90 C, then at 120 C for 72h. The solution was evaporated to dryness, then triturated with dichloromethane to afford a pale brown powder.
  • Example 23 ⁇ (4-bromo-5-difluoromethyl-3-methylthiophen-2-ylmethyl)-/V'-(lH- benzimidazole)propane-l,3-diamine.
  • a mixture of 2-(3-Aminopropylamino)benzimidazole 22a and 7d gave the title compound as a white solid, m/z (ES+) 429 ( 100% M+).
  • Example 24 N-(4-bromo-3-methyl-5-trifluoromethylthiophen-2-ylmethyl)-N-(lH- benzimidazole)propane-l,3-diamine.
  • a mixture of 2-(3-Aminopropylamino)benzimidazole 22a and 8a gave the title compound as a white solid, m/z (ES+) 447 ( 100% M+).
  • Example 25 iV-(4,5-Dibromo-3-methylthiophen-2-ylmethyl)-iV'-(lH-thieno [3,2- d]pyrimidin-4-one)propane-l,3-diamine
  • a) Potassium lH-thieno[3,2-d]pyrimidin-4-one-2-thiolate - 3-(3- Benzoylthioureido)-2-thiophenecarboxylic acid methyl ester 75 g; Gutschow, J. Het. Chem. 1996, 33, 355-360
  • KOH 25 g
  • ethanol ethanol
  • 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 ⁇ l reaction mix for 10 min at room temperature.
  • the reaction is terminated by the addition of 150 ⁇ l 167 mM sodium citrate, pH 2.15 containing phosphodiesterase (PDE) SPA beads (0.833 mg/ml).
  • PDE phosphodiesterase
  • E. coli MRE 600 tRNA and ATP were purchased from Boehringer-Mannheim, L- [methyl- 3 H]methionine and phosphodiesterase scintillation proximity (SPA) beads from Amersham Pharmacia Biotech and other reagents from Sigma.
  • SPA phosphodiesterase scintillation proximity
  • Examples 1 to 25 have IC50 values against S. aureus MRS in the range ⁇ 3 to 200 nM. All are highly selective with respect to the mammalian enzyme (no inliibition of rat MRS up to 1 ⁇ M).
  • Compounds of the present invention may be assayed for their ability to inhibit the enzyme methionyl tRNA synthetase (MRS), using recombinant H. influenzae MRS (R.D. Fleischmann et al., Science, 269, 496-512, 1995), as follows:
  • the reaction is started by adding 20 ⁇ l appropriately diluted pure enzyme (pre-incubated with inhibitor) to 25 ⁇ l reaction mix for 10 min at room temperature.
  • the reaction is terminated by the addition of 150 ⁇ l 167 mM sodium citrate, pH 2.15 containing phosphodiesterase (PDE) SPA beads (0.833 mg/ml).
  • PDE phosphodiesterase
  • E. coli MR ⁇ 600 tRNA and ATP were purchased from Boehringer-Mannheim, L- [methyl- 3 H]methionine and phosphodiesterase scintillation proximity (SPA) beads from Amersham Pharmacia Biotech and other reagents from Sigma.
  • SPA phosphodiesterase scintillation proximity
  • Examples 1-8, 11-15, 17, 18, 21, 22, 25 have IC50 values against H. influenzae MRS in the range ⁇ 3 to 200 nM. All are highly selective with respect to the mammalian enzyme (no inhibition of rat MRS up to 1 ⁇ M).
  • 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 catarrhalis) 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 catarrhalis
  • Examples 1-6, 8-10, 12-14, 16-22, 24, 25 had MIC's 0.06 - 0.50 ⁇ g/ml against some strains of the organisms S. aureus, S. pneumoniae, and E. faecalis. This is an unexpected improvement in potency against the major gram positive pathogens by a multiple of between 10-50 when compared to the thiophenes in the prior art.
  • Examples 7, 11, 15 and 23 had MIC's 1 - 2 ⁇ g/ml against some strains of the organisms S. aureus, S. pneumoniae, and E. faecalis.
  • Examples 4, 10-15, 18, 21, 23, 24 had MIC's 0.13 - 8 ⁇ g/ml against some strains of the organisms M. catarrhalis and H. influenzae. This is an unexpected improvement in potency against these two major gram negative pathogens by a multiple of between 10-500 when compared to the thiophenes in the prior art.

Landscapes

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

Abstract

L'invention concerne de nouveaux thiophènes substitués, inhibiteurs de la méthionyl-t-RNA synthétase(MRS) bactérienne. L'invention concerne également une méthode de préparation de ceux-ci, et leur utilisation thérapeutique comme agents antibactériens.
PCT/US2004/005930 2003-03-03 2004-02-27 Thiopohenes substitues a activite antibacterienne WO2004078119A2 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
AU2004218481A AU2004218481A1 (en) 2003-03-03 2004-02-27 Substituted thiophenes with antibacterial activity
EP04715720A EP1603881A4 (fr) 2003-03-03 2004-02-27 Thiopohenes substitues a activite antibacterienne
JP2006508886A JP2006519261A (ja) 2003-03-03 2004-02-27 抗菌活性を有する置換されたチオフェン
CA002517523A CA2517523A1 (fr) 2003-03-03 2004-02-27 Thiopohenes substitues a activite antibacterienne
AU2011201854A AU2011201854A1 (en) 2003-03-03 2011-04-21 Substituted thiophenes with antibacterial activity

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GBGB0304809.7A GB0304809D0 (en) 2003-03-03 2003-03-03 Novel compounds
GB0304809.7 2003-03-03
US52722903P 2003-12-05 2003-12-05
US60/527,229 2003-12-05

Publications (2)

Publication Number Publication Date
WO2004078119A2 true WO2004078119A2 (fr) 2004-09-16
WO2004078119A3 WO2004078119A3 (fr) 2004-12-29

Family

ID=32964063

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2004/005930 WO2004078119A2 (fr) 2003-03-03 2004-02-27 Thiopohenes substitues a activite antibacterienne

Country Status (5)

Country Link
EP (1) EP1603881A4 (fr)
JP (1) JP2006519261A (fr)
AU (2) AU2004218481A1 (fr)
CA (1) CA2517523A1 (fr)
WO (1) WO2004078119A2 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1619947A2 (fr) * 2003-05-01 2006-02-01 Replidyne, Inc. Compositions antibacteriennes et procedes associes
US7973050B2 (en) 2006-09-26 2011-07-05 Crestone, Inc. Enantiomeric compounds with antibacterial activity
US7994192B2 (en) 2006-09-26 2011-08-09 Crestone, Inc. Substituted thienopyridone compounds with antibacterial activity
US8658670B2 (en) 2006-09-26 2014-02-25 Crestone, Inc. Methods and compounds for treatment of clostridium based infection
US8697720B2 (en) 2006-09-26 2014-04-15 Crestone, Inc. Substituted phenylether-thienopyridone compounds with antibacterial activity

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000071524A1 (fr) 1999-05-19 2000-11-30 Smithkline Beecham Plc 2-nh-pyridones et pyrimidones utilisees comme inhibiteurs de mrs
WO2000071522A1 (fr) 1999-05-19 2000-11-30 Smithkline Beecham Plc Derives de benzimidazole et leur utilisation comme inhibiteurs de la methionyl-arn-t synthetase
US6320051B1 (en) 1998-04-29 2001-11-20 Smithkline Beecham Plc Quinolones used as MRS inhibitors and bactericides

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0228545D0 (en) * 2002-12-06 2003-01-15 Glaxo Group Ltd Novel compounds
AU2004258821A1 (en) * 2003-05-01 2005-02-03 Replidyne, Inc. Antibacterial methods and compositions

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6320051B1 (en) 1998-04-29 2001-11-20 Smithkline Beecham Plc Quinolones used as MRS inhibitors and bactericides
WO2000071524A1 (fr) 1999-05-19 2000-11-30 Smithkline Beecham Plc 2-nh-pyridones et pyrimidones utilisees comme inhibiteurs de mrs
WO2000071522A1 (fr) 1999-05-19 2000-11-30 Smithkline Beecham Plc Derives de benzimidazole et leur utilisation comme inhibiteurs de la methionyl-arn-t synthetase

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ANN PHARM FR, vol. 26, no. 3, 1968, pages 207 - 14
R.D. FLEISCHMANN ET AL., SCIENCE, vol. 269, 1995, pages 496 - 512

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1619947A2 (fr) * 2003-05-01 2006-02-01 Replidyne, Inc. Compositions antibacteriennes et procedes associes
EP1619947A4 (fr) * 2003-05-01 2006-05-31 Replidyne Inc Compositions antibacteriennes et procedes associes
US7973050B2 (en) 2006-09-26 2011-07-05 Crestone, Inc. Enantiomeric compounds with antibacterial activity
US7994192B2 (en) 2006-09-26 2011-08-09 Crestone, Inc. Substituted thienopyridone compounds with antibacterial activity
US8658670B2 (en) 2006-09-26 2014-02-25 Crestone, Inc. Methods and compounds for treatment of clostridium based infection
US8697720B2 (en) 2006-09-26 2014-04-15 Crestone, Inc. Substituted phenylether-thienopyridone compounds with antibacterial activity

Also Published As

Publication number Publication date
CA2517523A1 (fr) 2004-09-16
WO2004078119A3 (fr) 2004-12-29
EP1603881A4 (fr) 2010-07-07
EP1603881A2 (fr) 2005-12-14
AU2004218481A1 (en) 2004-09-16
AU2011201854A1 (en) 2011-05-19
JP2006519261A (ja) 2006-08-24

Similar Documents

Publication Publication Date Title
US10004737B2 (en) Fused imidazole and pyrazole derivatives as modulators of TNF activity
US9873703B2 (en) Imidazopyridazine derivatives as modulators of TNF activity
US20070213362A1 (en) 2-nh-heteroarylimidazoles with antibacterial activity
US20170158688A1 (en) Imidazopyridine Derivatives as Modulators of TNF Activity
US10273247B2 (en) Imidazothiazole derivatives as modulators of TNF activity
AU2007300290B2 (en) Enantiomeric compounds with antibacterial activity
CN107787319A (zh) 作为tnf活性的调节剂的吲唑衍生物
IL297879A (en) Amidopyrimidone derivatives
JP2003500397A (ja) Ｍｒｓ阻害剤としての２−ｎｈ−ピリドンおよびピリミドン
AU2011201854A1 (en) Substituted thiophenes with antibacterial activity
US20060128735A1 (en) Substituted thiophenes with antibacterial activity
US20060287360A1 (en) Novel compounds
EP4284797A1 (fr) Dérivés de pyrazoleamide

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

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

AL Designated countries for regional patents

Kind code of ref document: A2

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

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

Ref document number: 2004218481

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2006508886

Country of ref document: JP

WWE Wipo information: entry into national phase

Ref document number: 2517523

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2004218481

Country of ref document: AU

Date of ref document: 20040227

Kind code of ref document: A

WWP Wipo information: published in national office

Ref document number: 2004218481

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2004715720

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 2004715720

Country of ref document: EP

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载