+

WO2007017267A2 - Nouveaux composes - Google Patents

Nouveaux composes Download PDF

Info

Publication number
WO2007017267A2
WO2007017267A2 PCT/EP2006/007878 EP2006007878W WO2007017267A2 WO 2007017267 A2 WO2007017267 A2 WO 2007017267A2 EP 2006007878 W EP2006007878 W EP 2006007878W WO 2007017267 A2 WO2007017267 A2 WO 2007017267A2
Authority
WO
WIPO (PCT)
Prior art keywords
optionally substituted
alkyl
hydrogen
compound
heterocyclyl
Prior art date
Application number
PCT/EP2006/007878
Other languages
English (en)
Other versions
WO2007017267A3 (fr
Inventor
Andrew Keith Forrest
Richard Lewis Jarvest
Robert John Sheppard
Original Assignee
Glaxo Group Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Publication of WO2007017267A2 publication Critical patent/WO2007017267A2/fr
Publication of WO2007017267A3 publication Critical patent/WO2007017267A3/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/27—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by saturated carbon chains
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
    • C07C215/50—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/18—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides
    • C07C235/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/16—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound oxygen atoms bound to the same carbon atom of an acyclic carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/14—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to novel N-benzyl-N-[(1 ,2-substituted)-ethyl]amines which are inhibitors of bacterial phenylalanyl t-RNA synthetase (FRS), 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 antibacterial 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 antibacterial agents.
  • the sequence of the t-RNA synthetase genes in organisms such as S aureus have recently been determined, see for instance US Patent no 5 756 329 (FRS alpha and beta sub-units), thereby assisting the process of identifying inhibitors.
  • E coli FRS has been well described (see for instance Santi et al, Biochemistry, 1971 , 10, 4804-4812). Santi et al have also described a class of inhibitors of E coli FRS which are ⁇ /-benzyl- ⁇ /-(1-methyl-2-phenylethyl)amines.
  • ⁇ /-benzyl- ⁇ /-(1 ,2-disubstituted-ethyl)amines include ⁇ /-benzyl- ⁇ /-[2- cyclohexyl-1-(cyclohexylmethyl)ethyl]amine (Edgerton et al, J Am Pharm Assoc, 48, 1959, 320-3), prepared as a potential side chain for use in a penicillin G derivative and ⁇ /-benzyl- ⁇ /-[1-methyl-2-(4-phenylcyclohexyl)ethyl]amine (De Ivleglio et al, Farmaco, Ed Sci, 1980, 35, 191-202) which was investigated for analgesic, anorexigenic and anti- reserpine activity.
  • the present invention provides a compound of the formula (I):
  • R1 is hydrogen, trifluoromethyl or C(-
  • R2 is hydrogen or C(-
  • R 3 is hydrogen or a substituent OR 4 in which R 4 is hydrogen, C( ⁇
  • alkyl, alkenyl, cycloalkyl, cycloalkenyl or heterocyclyl is optionally substituted by one or two substituents selected from hydroxy, C(-
  • Compounds of formula (I) are inhibitors of bacterial phenylalanyl tRNA synthetase, including S aureus phenylalanyl tRNA synthetase.
  • mixtures of the R and S compounds for instance a racemic mixture, will have activity as inhibitors of S aureus phenylalanyl tRNA synthetase, by virtue of the presence of the compound with the S configuration and accordingly fall within the scope of the present invention.
  • R ⁇ include hydrogen and trifluoromethyl.
  • R 2 include hydrogen and methyl.
  • R ⁇ is a substituent OR** in which R ⁇ is hydrogen, C(3_6)alkyl, C(2- 6)alkenyl, C(3_7)cycloalkyl, C(3_7)cycloalkenyl or heterocyclyl, in which alkyl, alkenyl, cycloalkyl, cycloalkenyl or heterocyclyl is optionally by one or two substituents selected from hydroxy, C(-
  • R ⁇ include hydrogen and OR ⁇ in which R ⁇ is hydrogen, methyl, allyl, methallyl, cyclopentyl, cyclohexenyl, heterocyclyl comprising one or two oxygen atoms for instance tetrahydrofuranyl, or an alkyl group, for instance methyl, ethyl, propyl or butyl optionally substituted by one or two substituents selected from nitrile, hydroxy, carboxy, optionally substituted phenyl for instance phenyl and
  • a representative example of a disubstituted group OR ⁇ is 2,3-dihydroxypropoxy.
  • OR"* when R ⁇ is a substituted alkyl group include those in which the substituent is -CONR 5 R 6 and in which R 5 is hydrogen, methyl or ethyl and R 6 is hydrogen or C(i_2)alkyl optionally substituted by hydroxy,- CONHMe, or tetrahydrofuran-2-yl.
  • 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, n-propyl, /so-propyl, n-butyl, sec-butyl, /so-butyl, f-butyl, n-pentyl and n- hexyl.
  • Preferred substituents for an alkyl group include, for example, and unless otherwise defined, halogen, cyano, azido, nitro, carboxy, (C ⁇
  • cycloalkyl and cycloalkenyl include, unless otherwise defined, carbocyclic rings having from three to seven ring carbon atoms.
  • the cycloalkyl and cycloalkenyl rings comprise five or six ring carbon atoms.
  • 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-
  • 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 or 6, ring atoms.
  • a fused heteroaryl ring system may include carbocyclic rings and need only include one heterocyclic ring.
  • heterocyclyl includes 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.
  • '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 the compounds of Examples 6, 21 , 24, 28, 30 and 31.
  • a compound of formula (I) may be prepared by a process which comprises reacting an aldehyde compound of formula (II):
  • RI and R ⁇ are as hereinbefore defined; or a salt thereof under reductive alkylation conditions.
  • Reductive alkylation conditions include, for instance, adding the aldehyde of formula (II) to a stirred solution of the amine of formula
  • borohydride reducing agent for instance, sodium cyanoborohydride or sodium triacetoxyborohydride, or, more preferably, a resin supported reagent such as (polystyrylmethyl)-trimethylammonium cyanoborohydride.
  • Aldehydes of formula (II) and amines of formula (III) are available from commercial sources or may be readily prepared therefrom by adapting well known synthetic transformations. It will be appreciated that the above reductive alkylation may be performed in the reverse orientation by coupling a cyclohexylpropanone with a benzylamine derivative.
  • the compounds of this invention are active against both Gram positive and Gram negative organisms, including Haemophilus, for instance H. influenzae Q1 ; Moraxella, for instance M. catarrhalis 1502; Streptococci, for instance S. pyogenes CN 10 and S. pneumoniae R1629 and N 1387; Staphylococci, for instance S.
  • 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, D-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, D-lactam antibiotics such as, for example, methicillin; macrolides; aminoglycosides, and lincosamides.
  • D-lactam antibiotics such as, for example, methicillin; macrolides; aminoglycosides, and lincosamides.
  • Compounds of the present invention are therefore useful in the
  • Bacterial infections which may be treated include respiratory tract infections, otitis media, meningitis, endocarditis, skin and soft tissue infections and urinary tract 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 27 The compound of Example 27 (0.15 g, 0.5 mmol) was dissolved in 1 ,2-dichlorobenzene (5 ml) and tributyltin azide (0.82 g, 2.5 mmol) was added. After stirring at 125°C for 1 h, the reaction mixture was chromatographed on Kieselgel 60 eluting with 0-5% methanol ammonia (9:1 ) in dichloromethane to yield the title compound (0.124 g); m/z (ES + ) 344 (MH + , 100%).
  • Compounds of the present invention may be assayed for their ability to inhibit the enzyme phenylalanyl tRNA synthetase (FRS), using recombinant S. aureus FRS, as follows:
  • the beads are allowed to settle for at least 45 minutes or spun for 5 min at 2500rpm, using a MISTRAL 3000E centrifuge before counting on the TopCount (Packard) or Microbeta Trilux (Wallac). The least squares fitting was performed using GRAFIT (4).
  • Examples 1 , 5-21 , 26, 30 and 31 were tested in an E. coli lysate FRS assay; compounds 1 , 6-8, 10-13, 15-17, 20, 21 and 30 had IC50 values ⁇ 20 nM.
  • 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 catarrhalis) in a standard MIC assay modified by the inclusion of cyclodextrin, to assist with solubility.
  • Examples 1 , 6-13, 17, 18 and 21-31 had MIC values ⁇ 16 ⁇ g/ml against some strains of the organisms S. pneumoniae, H. influenzae and/or M. catarrhalis.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne des composés représentés par la formule (I) qui sont des inhibiteurs de la synthétase ARN-t phénylalanyle bactérienne et qui sont utiles dans le traitement des infections bactériennes. Formule (I)
PCT/EP2006/007878 2005-08-08 2006-08-04 Nouveaux composes WO2007017267A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0516270.6 2005-08-08
GBGB0516270.6A GB0516270D0 (en) 2005-08-08 2005-08-08 Novel compounds

Publications (2)

Publication Number Publication Date
WO2007017267A2 true WO2007017267A2 (fr) 2007-02-15
WO2007017267A3 WO2007017267A3 (fr) 2007-04-26

Family

ID=34984260

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2006/007878 WO2007017267A2 (fr) 2005-08-08 2006-08-04 Nouveaux composes

Country Status (2)

Country Link
GB (1) GB0516270D0 (fr)
WO (1) WO2007017267A2 (fr)

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012014109A1 (fr) 2010-07-30 2012-02-02 Ranbaxy Laboratories Limited Sulfamides hétérocycliques servant d'inhibiteurs de synthétase d'arn de transfert, destinés à être utilisés en tant qu'agents antibactériens
US8952171B2 (en) 2013-03-15 2015-02-10 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US9012450B2 (en) 2011-12-28 2015-04-21 Global Blood Therapeutics, Inc. Substituted heteroaryl aldehyde compounds and methods for their use in increasing tissue oxygenation
US9018210B2 (en) 2011-12-28 2015-04-28 Global Blood Therapeutics, Inc. Substituted benzaldehyde compounds and methods for their use in increasing tissue oxygenation
US9422279B2 (en) 2013-03-15 2016-08-23 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US9458139B2 (en) 2013-03-15 2016-10-04 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US9604999B2 (en) 2013-03-15 2017-03-28 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US9802900B2 (en) 2013-03-15 2017-10-31 Global Blood Therapeutics, Inc. Bicyclic heteroaryl compounds and uses thereof for the modulation of hemoglobin
US9957250B2 (en) 2013-03-15 2018-05-01 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US9981939B2 (en) 2013-03-15 2018-05-29 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10004725B2 (en) 2015-03-30 2018-06-26 Global Blood Therapeutics, Inc. Methods of treatment
US10077249B2 (en) 2016-05-12 2018-09-18 Global Blood Therapeutics, Inc. Process for synthesizing 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde
US10100043B2 (en) 2013-03-15 2018-10-16 Global Blood Therapeutics, Inc. Substituted aldehyde compounds and methods for their use in increasing tissue oxygenation
US10137118B2 (en) 2014-02-07 2018-11-27 Global Blood Therapeutics, Inc. Crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US10266551B2 (en) 2013-03-15 2019-04-23 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10450269B1 (en) 2013-11-18 2019-10-22 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10493035B2 (en) 2016-10-12 2019-12-03 Global Blood Therapeutics, Inc. Tablets comprising 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US11014884B2 (en) 2018-10-01 2021-05-25 Global Blood Therapeutics, Inc. Modulators of hemoglobin
US11020382B2 (en) 2015-12-04 2021-06-01 Global Blood Therapeutics, Inc. Dosing regimens for 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US11053195B2 (en) 2013-03-15 2021-07-06 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US11236109B2 (en) 2013-03-15 2022-02-01 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US11261201B2 (en) * 2018-01-12 2022-03-01 President And Fellows Of Harvard College TRNA synthetase inhibitors

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040006061A1 (en) * 2001-10-04 2004-01-08 Wolfgang Haap Alkoxybenzylamine
WO2006073547A1 (fr) * 2005-01-06 2006-07-13 Mallinckrodt Inc. Procede pour preparer des amines benzylees
WO2006117762A2 (fr) * 2005-05-03 2006-11-09 Ranbaxy Laboratories Limited Agents antimicrobiens

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040006061A1 (en) * 2001-10-04 2004-01-08 Wolfgang Haap Alkoxybenzylamine
WO2006073547A1 (fr) * 2005-01-06 2006-07-13 Mallinckrodt Inc. Procede pour preparer des amines benzylees
WO2006117762A2 (fr) * 2005-05-03 2006-11-09 Ranbaxy Laboratories Limited Agents antimicrobiens

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE BEILSTEIN [Online] Beilstein Institut zur Förderung der Chemischen Wissenschaften,Frankfurt am Main, DE; XP002421450 Database accession no. BRN:6720418 *
DATABASE CA [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; DE MEGLIO, P. ET AL: "New phenylcyclohexyl- and cyclohexylphenyl-substituted amines. Synthesis and pharmacological activity" XP002421449 retrieved from STN Database accession no. 1980:426010 cited in the application & FARMACO, EDIZIONE SCIENTIFICA , 35(3), 191-202 CODEN: FRPSAX; ISSN: 0430-0920, 1980, *
DATABASE CA [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; EDGERTON, WM. H. ET AL: "Substituted .alpha.-benzylphenethylamines" XP002421448 retrieved from STN Database accession no. 1959:121650 cited in the application & JOURNAL OF THE AMERICAN PHARMACEUTICAL ASSOCIATION, SCIENTIFIC EDITION , 48, 320-3 CODEN: JAPMA8; ISSN: 0095-9553, 1959, *

Cited By (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012014109A1 (fr) 2010-07-30 2012-02-02 Ranbaxy Laboratories Limited Sulfamides hétérocycliques servant d'inhibiteurs de synthétase d'arn de transfert, destinés à être utilisés en tant qu'agents antibactériens
US10822326B2 (en) 2011-12-28 2020-11-03 Global Blood Therapeutics, Inc. Substituted heteroaryl aldehyde compounds and methods for their use in increasing tissue oxygenation
US9012450B2 (en) 2011-12-28 2015-04-21 Global Blood Therapeutics, Inc. Substituted heteroaryl aldehyde compounds and methods for their use in increasing tissue oxygenation
US9018210B2 (en) 2011-12-28 2015-04-28 Global Blood Therapeutics, Inc. Substituted benzaldehyde compounds and methods for their use in increasing tissue oxygenation
US10806733B2 (en) 2011-12-28 2020-10-20 Global Blood Therapeutics, Inc. Substituted benzaldehyde compounds and methods for their use in increasing tissue oxygenation
US10377741B2 (en) 2011-12-28 2019-08-13 Global Blood Therapeutics, Inc. Substituted heteroaryl aldehyde compounds and methods for their use in increasing tissue oxygenation
US10034879B2 (en) 2011-12-28 2018-07-31 Global Blood Therapeutics, Inc. Substituted benzaldehyde compounds and methods for their use in increasing tissue oxygenation
US9957250B2 (en) 2013-03-15 2018-05-01 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10829470B2 (en) 2013-03-15 2020-11-10 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US9776960B2 (en) 2013-03-15 2017-10-03 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US9981939B2 (en) 2013-03-15 2018-05-29 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US11530191B2 (en) 2013-03-15 2022-12-20 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10017491B2 (en) 2013-03-15 2018-07-10 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US9604999B2 (en) 2013-03-15 2017-03-28 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US11236109B2 (en) 2013-03-15 2022-02-01 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10100040B2 (en) 2013-03-15 2018-10-16 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10100043B2 (en) 2013-03-15 2018-10-16 Global Blood Therapeutics, Inc. Substituted aldehyde compounds and methods for their use in increasing tissue oxygenation
US11053195B2 (en) 2013-03-15 2021-07-06 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10266551B2 (en) 2013-03-15 2019-04-23 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10315991B2 (en) 2013-03-15 2019-06-11 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US9458139B2 (en) 2013-03-15 2016-10-04 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10435393B2 (en) 2013-03-15 2019-10-08 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10858317B2 (en) 2013-03-15 2020-12-08 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US9802900B2 (en) 2013-03-15 2017-10-31 Global Blood Therapeutics, Inc. Bicyclic heteroaryl compounds and uses thereof for the modulation of hemoglobin
US8952171B2 (en) 2013-03-15 2015-02-10 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US9422279B2 (en) 2013-03-15 2016-08-23 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10450269B1 (en) 2013-11-18 2019-10-22 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US11452720B2 (en) 2014-02-07 2022-09-27 Global Blood Therapeutics, Inc. Crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US10722502B2 (en) 2014-02-07 2020-07-28 Global Blood Therapeutics, Inc. Crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US10137118B2 (en) 2014-02-07 2018-11-27 Global Blood Therapeutics, Inc. Crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US10695330B2 (en) 2015-03-30 2020-06-30 Global Blood Therapeutics, Inc. Methods of treatment
US10004725B2 (en) 2015-03-30 2018-06-26 Global Blood Therapeutics, Inc. Methods of treatment
US11944612B2 (en) 2015-12-04 2024-04-02 Global Blood Therapeutics, Inc. Dosing regimens for 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US11020382B2 (en) 2015-12-04 2021-06-01 Global Blood Therapeutics, Inc. Dosing regimens for 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US10577345B2 (en) 2016-05-12 2020-03-03 Global Blood Therapeutics, Inc. Process for synthesizing 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde
US10077249B2 (en) 2016-05-12 2018-09-18 Global Blood Therapeutics, Inc. Process for synthesizing 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde
US10493035B2 (en) 2016-10-12 2019-12-03 Global Blood Therapeutics, Inc. Tablets comprising 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US11261201B2 (en) * 2018-01-12 2022-03-01 President And Fellows Of Harvard College TRNA synthetase inhibitors
US11014884B2 (en) 2018-10-01 2021-05-25 Global Blood Therapeutics, Inc. Modulators of hemoglobin

Also Published As

Publication number Publication date
GB0516270D0 (en) 2005-09-14
WO2007017267A3 (fr) 2007-04-26

Similar Documents

Publication Publication Date Title
WO2007017267A2 (fr) Nouveaux composes
US6320051B1 (en) Quinolones used as MRS inhibitors and bactericides
TWI444378B (zh) 具有β－分泌酶抑制作用之含硫雜環衍生物及其用途
US9403804B2 (en) Inhibitors of c-fms kinase
US6495551B1 (en) Substituted phenyloxazolidinones and their use as antibiotics
US8404731B2 (en) Substituted imidazole derivatives, compositions, and methods of use as PTPase inhibitors
US20120196897A1 (en) New compounds
JP2002503655A (ja) 抗菌剤として有用な置換アミノフェニルイソオキサゾリン誘導体
JP2000505063A (ja) アテローム性動脈硬化症の治療のためのアゼチジノン化合物
EP2091536B1 (fr) Composés énantiomères à activité antibactérienne
WO2000071522A1 (fr) Derives de benzimidazole et leur utilisation comme inhibiteurs de la methionyl-arn-t synthetase
US20070213362A1 (en) 2-nh-heteroarylimidazoles with antibacterial activity
EP0352581A2 (fr) Dérivés d'éthylènediamine monoamide
EP2094714B1 (fr) Composés thiénopyridone substitués à activité antibactérienne
WO2008039641A2 (fr) Composés phényléther-thiénopyridone substitués à activité antibactérienne
US7994192B2 (en) Substituted thienopyridone compounds with antibacterial activity
US7160907B2 (en) Pleuromutilin derivatives
WO2000021949A1 (fr) Quinolones tenant lieu d'inhibiteurs d'arnt synthetase et d'agents antibacteriens
US8697720B2 (en) Substituted phenylether-thienopyridone compounds with antibacterial activity
US7442793B2 (en) Peptide deformylase inhibitors
US7973050B2 (en) Enantiomeric compounds with antibacterial activity
US20070259965A1 (en) Acyclic 1,3-Diamine And Uses Therefor
US20060287360A1 (en) Novel compounds
CA2517523A1 (fr) Thiopohenes substitues a activite antibacterienne
EP0338824A2 (fr) Esters de dérivés d'acide 6-bêta-(alpha-oxyimino)-acylamino-pénicillanique

Legal Events

Date Code Title Description
NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 06763020

Country of ref document: EP

Kind code of ref document: A2

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