EP0506729A1 - Composes oxazole pharmaceutiquement actifs - Google Patents

Composes oxazole pharmaceutiquement actifs

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Publication number
EP0506729A1
EP0506729A1 EP91900879A EP91900879A EP0506729A1 EP 0506729 A1 EP0506729 A1 EP 0506729A1 EP 91900879 A EP91900879 A EP 91900879A EP 91900879 A EP91900879 A EP 91900879A EP 0506729 A1 EP0506729 A1 EP 0506729A1
Authority
EP
European Patent Office
Prior art keywords
pyridyl
oxazole
normon
compound
monamide
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP91900879A
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German (de)
English (en)
Inventor
Nigel John Perryman Smithkline Beecham Broom
Peter John O'hanlon
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beecham Group PLC
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Beecham Group PLC
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Filing date
Publication date
Application filed by Beecham Group PLC filed Critical Beecham Group PLC
Publication of EP0506729A1 publication Critical patent/EP0506729A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • C07D405/14—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 three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to a class of compounds having antibacterial and antimycoplasmal activity, to processes for their preparation and to their use in human and veterinary medicine and also to intermediates for use in the preparation of such compounds.
  • group R° represents an optionally substituted 5-membered heteroaryl ring containing from 1 to 4 heteroatoms selected from oxygen, nitrogen and sulphur,
  • EP-A-0 399 645 (Beecham Group pic) (published after the priority date claimed for the present application) discloses compounds of formula (A) in which R° is a 5-furyloxazol-2-yl or a 5-isoxazolyloxazol-2-yl moiety.
  • R 1 represents a pyridyl group which is bonded via a carbon atom thereof to the oxazolyl moiety, which pyridyl group may be unsubstituted or substituted by up to five, preferably up to three, substituents which may be the same or different.
  • Suitable substituents for the pyridyl group of R 1 include, for example:
  • the divalent group Y° is bonded to two carbon atoms which are in a 1,2-relationship.
  • the divalent group Y° may be formed by the removal of a hydrogen atom from one of the substituents hereinbefore listed in sub-paragraphs (ii) to (vi) or by the linking together of two substituents hereinbefore listed in sub-paragraphs (ii) to (vi), by the removal of a hydrogen atom from each.
  • one of the pyridyl substituents is a hydroxy group located ⁇ - or ⁇ - to the pyridyl nitrogen atom, giving an ⁇ - or ⁇ -pyridone, respectively
  • one of the other pyridyl substituents may be located on the nitrogen atom.
  • groups suited to being located at the nitrogen atom of the pyridyl ring include those listed hereinbefore at sub-paragraphs (iv), (v) and (vi) and also amino optionally substituted by groups listed hereinbefore in subparagraphs (iv), (v) and (vi), in respect of substituents for the pyridyl group.
  • substituents for the pyridyl group include, for example, hydroxy, halogen, cyano, nitro, optionally substituted (C 1-6 )alkyl, aryl, heterocyclyl, (C 1-6 )alkoxy, carboxy and salts thereof, (C 1-6 )alkoxycarbonyl, acyl, amino, mono- or di-(C 1-6 )alkylamino, carbamoyl, mono- or di-(C 1-6 )alkylcarbamoyl, carbamoyloxy, mono- or di-
  • (C 1-6 )alkylcarbamoyl acylamino, (C 1-6 )alkoxycarbonylamino, (C 1-6 ) alkylthio, arylthio, (C 1-6 )alkylsulphinyl, arylsulphinyl, (C 1-6 )alkylsulphonyl, arylsulphonyl, sulphamoyl, mono- or di-(C 1-6 )alkylsulphamoyl.
  • substituents for the pyridyl group include, for instance, hydroxy; halogen, for instance fluoro, chloro and bromo; (C 1-6 )alkyl, for instance methyl; (C 1-6 )alkoxy, for instance methoxy, ethoxy; (C 1-6 )alkylthio, for instance thiomethyl; (C 1-6 )alkylsulphinyl, for instance methylsulphinyl; (C 1-6 )alkylsulphonyl, for instance methylsulphonyl; di(C 1-6 )alkylamino, for instance, dimethylamino; and di(C 1-6 )alkylcarbamoyloxy, for instance N, N diethylcarbamoyloxy.
  • 'aryl' includes, unless otherwise defined, phenyl or naphthyl optionally substituted with up to five, preferably up to three substituents.
  • the pyridyl group has a single substituent which is preferably located on a carbon atom ⁇ - or ⁇ - to the pyridyl nitrogen atom.
  • heterocyclyl includes, unless otherwise defined, 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 atoms.
  • 'halogen' refers to fluorine, chlorine, bromine and iodine.
  • Substituents for groups hereinbefore defined as being optionally substituted include:
  • Suitable substituents for an alkyl, cycloalkyl, alkenyl, cycloalkenyl or alkynyl group include, for example, halogen, cyano, azido, nitro, hydroxy, oxo, carboxy, (C 1-6 ) alkoxycarbonyl, carbamoyl, mono- or di-(C 1-6 )alkylcarbamoyl, sulpho, sulphamoyl, mono- or di-(C 1-6 )alkylsulphamoyl, amino, mono- or di-(C 1-6 )alkylamino, acylamino, ureido, (C 1-6 )alkoxycarbonylamino, 2,2,2-trichloro- ethoxycarbonylamino, aryl, heterocyclyl, (C 1-6 )alkoxy, acyloxy, 2-thenoyl, (C 1-6 )alkylthio, (C 1-6
  • Suitable substituents for an aryl group include, for example, halogen, cyano, (C 1-6 ) alkyl, phenyl, (C 1-6 )alkoxy, halo(C 1-( )alkyl, hydroxy, amino, mono- or di-(C 1-6 )alkylamino, acylamino, nitro, carboxy, (C 1-6 )alkanoyl, (C 1-6 )alkoxycarbonyl,
  • Suitable substituents for a heterocyclyl group include, for example, halogen, (C 1-6 ) alkyl, (C 1-6 ) alkoxy, halo (C 1-6 ) alkyl, hydroxy, amino, mono- or di-(C 1-6 )alkylamino, carboxy, (C 1-6 )alkoxycarbonyl, (C 1-6 )alkoxycarbonyl (C 1-6 )alkyl, aryl or oxo.
  • the pyridyl of group R 1 may be bonded to the oxazole ring via a carbon atom which is ⁇ -, ⁇ -, or ⁇ - to the pyridyl nitrogen atom.
  • the pyridyl group of R 1 is bonded to the oxazole ring by a carbon atom which is ⁇ - to the pyridyl nitrogen atom.
  • the compounds of formula (I) of the present invention are intended for use in pharmaceutical compositions, it will be understood that they are each provided in substantially pure form, for example at least 50% pure, more suitably at least 75% pure and preferably at least 95% pure (% are on a wt/wt basis). Impure preparations of the compounds of formula (I) may be used for preparing the more pure forms used in the pharmaceutical compositions. Although the purity of intermediate compounds of the present invention is less critical, it will be readily understood that the substantially pure form is preferred as for the compounds of formula (I). Preferably, whenever possible, the compounds of the present invention are obtained in crystalline form.
  • solvent of crystallisation may be present in the crystalline product.
  • This invention includes within its scope such solvates.
  • some of the compounds of this invention may be crystallised or recrystallised from solvents containing water. In such cases water of hydration may be formed.
  • This invention includes within its scope stoichiometric hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation.
  • Examples of compounds within this invention include the following:
  • the present invention provides a process for the preparation of a compound of formula (I) which process comprises cyclising a compound of formula (III):
  • R 1 is as hereinbefore defined, and Z 1 , Z 2 and Z 3 are the same or different and each is hydrogen or a hydroxyl-protecting group;
  • Compounds of formula (III) may be cyclised using a carboxylic anhydride or mixed anhydride or an acid chloride, such as trifluoroacetic anhydride or trichloroacetic anhydride or trichloroacetyl chloride, which latter is preferably used in the presence of pyridine and 4-dimethylaminopyridine.
  • a carboxylic anhydride or mixed anhydride or an acid chloride such as trifluoroacetic anhydride or trichloroacetic anhydride or trichloroacetyl chloride, which latter is preferably used in the presence of pyridine and 4-dimethylaminopyridine.
  • Trihaloacetyl groups formed during cyclisation may be removed using potassium carbonate in solvents such as water, alkanols or admixtures thereof. Appropriate deprotecting conditions for removing other acyl residues will be readily apparent to the skilled person.
  • the cyclisation of a compound of formula (III) may also be suitably effected using a chlorinating agent such as phosphorus oxychloride, phosgene, thionyl chloride or phosphorus pentachloride in the presence of a tertiary amine, such as triethylamine or pyridine.
  • a chlorinating agent such as phosphorus oxychloride, phosgene, thionyl chloride or phosphorus pentachloride
  • a tertiary amine such as triethylamine or pyridine.
  • a reaction is conveniently effected in an organic solvent, for instance dichloromethane or tetrahydrofuran, at from reduced to elevated temperature, for instance -80° to 100°C, over a period of several hours to a few days.
  • phosgene or phosphorus oxychloride is used, at a temperature of from 0° to 20°C.
  • cyclisation may be effected using triphenylphosphine and carbon tetrachloride as the chlorinating reagent, in the presence of a tertiary amine, for instance triethylamine, in an inert solvent such as acetonitrile or acetonitrile-pyridine.
  • a tertiary amine for instance triethylamine
  • an inert solvent such as acetonitrile or acetonitrile-pyridine.
  • Example of compounds within formula (III) include the following:
  • Compounds of formula (III) may be produced from monic acid A by analogy with the reaction sequence previously described in EP-A-0 087 953 (Beecham Group pic).
  • monic acid A is initially converted to an activated derivative, for instance a mixed anhydride such as that formed by reaction with iso-butylchlorformate in the presence of a suitable base such as triethylamine; followed by reaction of this intermediate with an amine hydrochloride salt of the formula (IV):
  • an activated derivative for instance a mixed anhydride such as that formed by reaction with iso-butylchlorformate in the presence of a suitable base such as triethylamine
  • R 1 is as hereinbefore defined; in the presence of a suitable base such as triethylamine.
  • the present invention also provides a process for the preparation of a compound of formula (I) which process comprises reacting a compound of formula (V): (V) in which Z 1 , Z 2 and Z 3 are the same or different and each is hydrogen or a hydroxyl-protecting group;
  • R 1 is as hereinbefore defined
  • M + is a metal cation, preferably an alkali metal cation, most preferably a lithium or sodium cation;
  • R 2 is an anion-stabilismg group which will spontaneously eliminate with a ⁇ -hydroxyl group to produce an olefin, preferably a trialkylsilyl or a dialkylphosphonate group, most preferably trimethylsilyl or diethylphosphonate;
  • reaction of a compound of formula (V) with a compound of formula (VI) may conveniently be effected in an organic solvent, such as tetrahydrofuran, diethyl ether or dimethyl sulphoxide, at from reduced to elevated temperature, such as from -80° to 100°C.
  • organic solvent such as tetrahydrofuran, diethyl ether or dimethyl sulphoxide
  • the compounds of formula (VI) may be prepared by conventional processes, by analogy with those as described in EP-A-0 123 378 (Beecham Group pic.). For instance, a compound of formula (VII):
  • W is hydrogen or halogen and R 1 is as hereinbefore defined
  • R 1 is as hereinbefore defined
  • a compound of formula (VI) in which M is lithium and R 2 is trimethylsilyl according to the methodology of W.S. Wadsworth Jr, Organic Reactions, 1977, 25, 73; and by E.J. Corey and D.L. Boger, Tet. Letters, 1978, 5; T.H. Chan,, Acc. Chem. Res. 1977, 10, 442.
  • a compound formula (VII) may be converted to a compound of formula (VI) in which M is an alkali metal and R 2 is diethylphosphonate, by anology with Hungate, J. Org. Chem., 1981, 46, 1410;
  • the present invention further provides a process for the preparation of a compound of formula (I) which process comprises treating a compound of formula (VIII):
  • Z 1 , Z 2 , and Z 3 are the same or different and each is hydrogen or a hydroxyl-protecting group, R 1 is as hereinbefore defined, and Y is a leaving group;
  • Suitable values for Y include, for instance, aryl sulphonyl, for example p-toluenesulphonyl, alkylsulphonyl, alkyl or aryl sulphinyl, quaternary ammonium, for example trialkylammonium, and dialkoxy phosphine oxide.
  • Suitable strong bases include for example 1,8-diazo- bicyclo[5.4.0]undec-7-ene (DBU) and 1,5-diazobicyclo[4.3.0]non-5-ene (DBN).
  • DBU 1,8-diazo- bicyclo[5.4.0]undec-7-ene
  • DBN 1,5-diazobicyclo[4.3.0]non-5-ene
  • the reaction is effected in a solvent such as acetonitrile, and at a temperature in the range from -20 to +80°C.
  • a solvent such as acetonitrile
  • the present invention also provides a compound of formula (VIII), as hereinbefore defined.
  • Z 1 , Z 2 , and Z 3 are the same or different and each is hydrogen or a hydroxyl-protecting group, and Y is as hereinbefore defined,
  • Suitable dehydrating conditions are similar to those hereinbefore described in respect of the cyclisation of a compound of formula (III) to give a compound of formula (I).
  • Particularly suitable conditions include the use of triphenylphosphine in combination with carbon tetrachloride or hexachloroethane, in the presence of triethylamine.
  • the present invention also provides a process for preparing a compound of formula (I) which process comprises isomerising the carbon-carbon double bond of a compound of formula (XI) :
  • Suitable isomerisation methods are described by Sonnet in Tetrahedron, 1980, 36, 557 and include photo- chemical and addition-elimination methods.
  • a compound of formula (XI) may be obtained by treating a compound of formula (V) with a compound of formula (VI), as hereinbefore described. This reaction is lacking stereoselectivity and may lead to the formation of compounds of formulae (I) and (XI), which may then be separated by conventional procedures such as chromatography.
  • the present invention also provides for the conversion of one compound of formula (I) to another compound of formula (I), which may be effected by conventional methods.
  • all or any one of the substituents of the pyridyl group of R 1 may be modified or converted. Included within this is salification and esterification of a carboxy substituent, trans- and de-esterification of an ester-containing substituent, reduction of an alkoxycarbonyl substituent and formation of the free carboxy group from a carboxylate salt.
  • Another example of such conversion is the formation of alkanesulphinyl and alkanesulphonyl compounds from the corresponding alkylthio compound of formula (I). This latter conversion may be achieved using conventional oxidising agents such as percarboxylic acids, for instance m-chloroperbenzoic acid, in a suitable solvent.
  • 'hydroxyl-protecting group' refers to any such group known in the art which may be removed without disruption of the remainder of the molecule. Suitable hydroxyl-protecting groups are described in 'Protective Groups in Organic Synthesis', T.W. Greene, Wiley-Interscience, New York 1981.
  • hydroxyl groups of monic acid A, and compounds of formulae (III), (V), (VIII), (IX) and (XI) may be protected at any stage of the above processes, using conventional methods.
  • the hydroxyl-protecting group may be removed by methods known in the art, including enzymatic methods.
  • Particularly suitable hydroxyl-protecting groups are silyl groups since these are readily removed under mild conditions.
  • Such groups are introduced using conventional silylating agents, including halosilanes and silazanes, for example those of the formulae below:
  • Me denotes methyl
  • t-Bu denotes t-butyl
  • X is halogen and each group L is independently selected from hydrogen, (C 1-6 )alkyl, (C 1-6 )alkoxy, aryl or aryl(C 1- 4 )alkyl.
  • a preferred silyating agent is trimethylsilyl chloride.
  • Particularly suitable hydroxyl-protecting groups are trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl groups. Preferred hydroxyl-protecting groups are trimethylsilyl groups because of their ease of removal.
  • glycol function of monic acid A and of the compounds of formulae (III), (V), (VIII), (IX) and (XI) may be protected by forming a cyclic derivative using a compound of formula (XII):
  • R 3 is hydrogen or (C 1-6 ) alkyl and each of R 4 , R 5 and
  • R 6 is (C 1- 6 ) alkyl.
  • Z 1 and Z 2 together are a moiety:
  • R 7 is (C 1-6 ) alkyl.
  • R 3 is hydrogen, methyl, ethyl, n- or iso-propyl; most suitably it is hydrogen.
  • the groups R 4 , R 5 and R 6 are suitably methyl, ethyl, n- or iso-propyl, or n-, iso-, sec- or t-butyl; most suitably methyl.
  • protecting groups described above may be removed by mild acid hydrolysis followed by alkaline hydrolysis, for instance, as described by J.P. Clayton, K. Luk and N.H. Rogers, in 'Chemistry of Pseudomonic Acid, Part II', J.C.S. Perkin Trans. I, 1979, 308.
  • the compounds of this invention are useful for the treatment of bacterial and mycoplasma-induced infections in animals, including humans, such as the treatment of respiratory tract infections, otitis, meningitis, skin and soft tissue infections in man, mastitis in cattle, and respiratory infections in animals such as pigs and cattle.
  • the compounds of this invention are active against both Gram negative and Gram positive organisms, including Haemophilus, for instance H.influenzae Ql; Branhamella, for instance B.Catarrhalis 1502; Streptococci, for instance S.pyogenes CN10 and S.pneumonia PU7; and Staphylococci, for instance S.aureus Oxford; and against mycoplasma.
  • compounds of this invention are active against Staphylococci organisms such as S. aureus and S. epidermis which are resistant (including multiply-resistant) to other antibacterial agents, for instance, ⁇ -lactam antibiotics such as, for example, methicillin; macrolides; aminoglycosides and lincosamides.
  • This invention also provides a pharmaceutical or veterinary composition which comprises a compound of formula (I) (hereinafter referred to as the 'drug') together with a pharmaceutically or veterinarily acceptable carrier or excipient.
  • a pharmaceutical or veterinary composition which comprises a compound of formula (I) (hereinafter referred to as the 'drug') together with a pharmaceutically or veterinarily acceptable carrier or excipient.
  • compositions may be formulated for administration by any route, and would depend on the disease being treated.
  • the compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical or sterile parenteral suspensions.
  • Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl-pyrollidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch, or acceptable wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters, glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin, hydrogenated edible fats
  • emulsifying agents for example lecithin, sorbitan monooleate, or acacia
  • non-aqueous vehicles which may include edible oils
  • almond oil fractionated coconut oil, oily esters, glycerine, propylene glyco
  • Cream or ointment formulations that may be used for the drug are conventional formulations well known in the art, for example, as described in standard text books of pharmaceutics and cosmetics, such as 'Harry's Cosmeticology' published by George Godwin, London, and the British Pharmacopoeia.
  • Suppositories will contain conventional suppository bases, e.g. cocoa-butters or other glyceride.
  • fluid unit dosage forms are prepared utilizing the drug and a sterile vehicle.
  • the drug depending on the vehicle and concentration used, can be suspended in the vehicle.
  • adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and water removed under vacuum. The dry lypophilized powder is then sealed in the vial.
  • the drug can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the drug.
  • the drug may be made up into a suspension in a suitable liquid carrier, such as water, glycerol, diluted ethanol, propylene glycol, polyethylene glycol or fixed oils.
  • the drug is formulated as a suspension in a suitable, sterile aqueous or non-aqueous vehicle.
  • Additives for instance buffers such as sodium metabisulphite or disodium edetate; preservatives including bactericidal and fungicidal agents, such as phenylmercuric acetate or nitrate, benzalkonium chloride or chlorhexidine, and thickening agents such as hypromellose may also be included.
  • compositions administered topically will, of course, depend on the size of the area being treated. For the ears and eyes each dose will typically be in the range from 10 to 100 mg of the drug.
  • Veterinary compositions for intramammary treatment of mammary disorders in animals, especially bovine mastitis will generally contain a suspension of the drug in an oily vehicle.
  • compositions may contain from 0.1% to 99% by weight, preferably from 10-60% by weight, of the drug, depending on the method of administration. Where the compositions are in unit dose form, each dosage unit will preferably contain from 50-500 mg, of the drug.
  • the dosage as employed for adult human treatment (average weight about 70 kg) will preferably range from 100 mg to 3 g per day, for instance 250 mg to 2 g of the drug per day, depending on the route and frequency of administration.
  • the drug may be administered as part of the total dietary intake of a non-human animal.
  • the amount of drug employed may be less than 1% by weight of the diet and in preferably no more than 0.5% by weight.
  • the diet for animals may consist of normal foodstuffs to which the drug may be added or the drug may be included in a premix for admixture with the foodstuff.
  • a suitable method of administration of the drug to animals is to add it to the non-human animal's drinking water. In this case a concentration of the drug in the drinking water of about 5-500 ⁇ g/ml, for example 5-200 ⁇ g/ml, is suitable.
  • the present invention provides a compound of formula (I) as hereinbefore defined for use in therapy.
  • the present invention further provides a method of treating the bacterial and/or mycoplasmal infection in human or non-human animal, 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.
  • compositions as hereinbefore described may be employed in the treatment.
  • the present invention further provides for the use of a compound of formula (I) as hereinbefore defined in the manufacture of a medicament for use in anti-bacterial and/or anti-mycoplasma therapy.
  • Chromatography was carried out using silica gel as the adsorbent.
  • Monic acid A was obtained from pseudomonic acid according to the process described in GB 1 587 058 (to Beecham Group Ltd.).
  • Trichloroacetyl chloride (9 equiv.) was added to a solution of the monamide, 4-dimethylaminopyridine (few crystals/mmol) and pyridine (20 equiv.) in dichloromethane (10ml/mmol), cooled in an ice bath. After 0.5h the solution was washed with aqueous sodium hydrogen carbonate solution and then evaporated under reduced pressure. The resulting residue evaporated under reduced pressure. The resulting residue was dissolved in methanol (5ml/mmol) and the solution cooled to 0°C before addition of potassium carbonate (3 equiv.). After 15min at 0°C brine and ethyl acetate were added and the organic layer separated.
  • the title monamide was prepared according to the general method from the amine dihydrochloride from (2b) (418mg, 2mmol) in THF:water (1:1, 10ml) and triethylamine (0.6ml, 4mmol) and isolated after column chromatography as an amorphous solid (230mg, 25%); ⁇ max (CHCl 3 ) 3600-3100, 1690, 1655, 1635cm- 1 ; ⁇ (CDCI 3 ) inter alia 0.93 (3H, d, J 7.0Hz, 17-H 3 ), 1.22 (3H, d, J 6.3Hz, 14-H 3 ), 2.21 (3H, s, 15-H 3 ), 4.82 (2H, d, J 4.5Hz, 1'-H 2 ), 5.89 (1H, s, 2-H), 7.22 (1H, bs, NH), 7.48 (1H, dd, J 4.8, 8.0Hz, 5"-H), 8.28 (1H, dd, J 1.6, 8.0
  • the title monamide was prepared according to the general method from the amine dihydrochloride from (3a) (1.56g, 7.5mmol) in THF, water (1:1), (15ml), and isolated after column chromatography as an amorphous solid (190mg).
  • the 'H n.m.r. spectrum showed that this material contained at least 20% impurities but the material was progressed through to the next sequence.
  • the title monamide was prepared according to the general method from the amine dihydrochloride from (4b) (507mg, 2.27mmol) in THF:water (1:1, 10ml) and triethylamine (0.63ml, 4.54mmol) and isolated after column chromatography as an amorphous solid (400mg, 38%); v max (CHCI 3 ) 3600-3100, 1690, 1660, 1640, 1595cm- 1 ; ⁇ max (EtOH) 231 ( ⁇ m 19,390), 270nm (5,920); ⁇ H (CDCI 3 ) inter alia 0.93 (3H, d, J 7.0Hz, 17-H 3 ), 1.22 (3H, d, J 6.2Hz, 14-H 3 ), 2.20 (3H, s, 15-H 3 ), 2.65 (3H, s, 2"-H 3 ), 4.79 (2H, d, J 4.4HZ, 1'-Hz), 5.83 (1H, s, 2-H), 6.75
  • the monamide from (4c) (337mg) was cyclised according to the general procedure to give the title oxazole as an amorphous solid (220mg, 67%); v max (CH 2 Cl 2 ) 3700-3000, 1650cm- 1 ; ⁇ max (EtOH) 224 ( ⁇ m 10,575), 302nm (24,380); ⁇ H (CDCl 3 ) inter alia 0.93 (3H, d, J 7.1Hz, 17-H 3 ); 1.21 (3H, d, J 6.3Hz,
  • the title monamide was prepared according to the general method from the amine dihydrochloride from (5b) (400mg) in THF/water (1:1, 6ml) and triethylamine (0.46ml). On work-up the aqueous residues were evaporated, digested with methanol and the solution filtered through flash silica eluting with methanol.
  • the monamide from (5c) (100mg) was cyclised according to the general procedure to give the title oxazole as an amorphous solid (60mg, 62%); v max (KBr) 3385, 1661, 1623, 1565cm- 1 ; ⁇ max (EtOH) 256 ( ⁇ m 8,220), 302nm (16,505); ⁇ H (d 4 -MeOH) inter alia 0.95 (3H, d, J 7.1Hz, 17-H 3 ), 1.20 (3H, d, J 6.4Hz, 14-H 3 ), 2.26 (3H, s, 15-H 3 ), 6.22 (1H, s, 2-H), 6.64 (1H, d, J
  • 6-Methoxynicotinic acid (3.79g, 24.8mmol) in dichloromethane (60ml) and DMF (a few drops) was treated with oxalyl chloride (2.6ml, 29.8mmol). After ca.21 ⁇ 2 hours all material was in solution; reaction mixture then added dropwise to excess diazomethane in ether. After 2 hours argon passed through the reaction mixture, then evaporated and chromatographed on silica eluting with dichloromethane/ethyl acetate mixtures. The less polar fractions afforded the title compound (430mg) and from the more polar fractions, the diazoketone was isolated (1.34g).
  • the title monamide was prepared according to the general method from the amine salt from (8c) (1.94g, 8.12mmol) in THF/water (1:1, 20ml) and triethylamine (2.26ml, 16.23mmol) and isolated after column chromatography as an amorphous solid, (2.3g, 58%); ⁇ max (EtOH) 274 ( ⁇ m 12,235), 253nm (14,780); ⁇ H (CDCl 3 ), inter alia 0.93 (3H, d, J 7.0Hz, 17-H 3 ), 1.22 (3H, d, J 6.1Hz, 14-H 3 ), 2.21 (3H, s, 15-H 3 ), 4.02 (3H, s, ArOMe), 4.75 (2H, d, J 4.4Hz, 1'-H 2 ), 5.83 (1H, s, 2-H), 6.70 (1H, t, J 4.4Hz, N-H), 6.82 (1H, d, J 8.8Hz, 3"-H), 8.14 (1
  • the monamide from (8d) (2.2g) was cyclised according to the general method to give the title oxazole (1.74g, 82%); ⁇ max (EtOH) 302 ( ⁇ m 25,880), 232nm (10,630); ⁇ C (CDCl 3 ) 12.7 (C-17), 19.6 (C-15), 20.8 (C-14), 341.7 (C-9), 39.6 (C-8), 42.8 (C-12), 42.9 (C-4), 53.7 (C-OMe), 55.6 (C-10), 61.3 (C-11), 65.5 (C-16), 68.9 (C-6), 70.4 (C-13), 71.2 (C-7), 75.3 (C-5), 111.2 (C-3"), 113.0 (C-2), 118.0 (C-5"), 121.8 (C-4), 134.5 (C-4"), 142.9 (C-6"), 147.0 (C-3), 147.6 (C-5'), 161.1 (C-2"), 163.9 (C-2').
  • the title monamide was prepared according to the general method from the amine salt from (9c) (243.5mg, lmmol) in THF/water (1:1, 6ml) and triethylamine (0.3ml, 2mmol) and isolated after chromatography as an amorphous solid (104mg, 21%); v max (KBr) 3394, 1704, 1661, 1630, 1583cm- 1 ; ⁇ H (CDCI 3 ) inter alia 0.93 (3H, d, J 6.7Hz, 17-H 3 ), 1.22 (3H, d, J 6.3Hz, 14-H 3 ), 2.20 (3H, s, 15-H 3 ), 4.78 (2H, d, J 5.4Hz, 1'-H 2 ), 5.82 (1H, s, 2-H), 6.66 (1H, t, J 4.5Hz, NH), 7.50 (1H, d, J 8.3Hz, 3"-H), 8.23 (1H, dd, J 2.2; 8.3Hz,
  • the title monaoide was prepared according to the general method from the amine salt from (10c) (520mg, 2.15mmol) in THF/water (1:1, 12ml) and triethylamine (0.6ml, 4.30mmol) and isolated after chromatography as an amorphous solid (290mg, 25%); v max (KBr) 3200, 1707, 1659, 1630, 1533, 1412cm- 1 ; ⁇ H (d 4 -MeOH) inter alia 0.95 (3H, d, J 7.0Hz, 17-H 3 ), 1.20 (3H, d, J 6.5Hz, 14-H 3 ), 2.15 (3H, s, 15-H 3 ), 4.68 (2H, s, 1'-H 2 ), 5.88 (1H, s, 2-H), 8.51 (1H, d, J 2.0Hz, 4"-H), 8.91 (1H, d, J 2.0Hz, 6"-H); m/z (FAB, Matrix 3-NOBA/N
  • the monamide from (10d) (250mg, 0.47mmol) was cyclised according to the general method to give the title oxazole (123mg, 51%); v max (KBr) 3405, 1649, 1605cm- 1 ; ⁇ max (EtOH) 314nm ) ⁇ m 22,746), 229 (11,423); ⁇ H (d 4 -MeOH) inter alia 0.95 (3H, d, J 7.1Hz, 17-H 3 ), 1.20 (3H, d, J 6.4Hz, 14-H 3 ), 2.31 (3H, s, 15-H 3 ), 6.28 (1H, s, 2-H), 7.74 (1H, s, 4'-H), 8.28 (1H, d, J 2.1Hz, 4"-H), 8.66 (1H, d, J 2.1Hz, 6"-H); ⁇ C (CDCl 3 + d 4 -MeOH) 12.3 (C-17), 19.7 (C-15), 20.4 (C-14
  • Tetramethylguanidinium azide (0.47g, 2.9mM) was added to an ice-cooled solution of 5-chloroacetyl-2-methylthiopyridine (0.41g, 2.0mM) in dichloromethane (25ml) under argon.
  • the monamide was prepared according to the general method from the amine salt (0.20g, 0.78mM) and isolatedas an amorphous solid (0.10g, 25%); v max (KBr) 3420, 1695, 1660, 1630 and 1580cm- 1 ; ⁇ max (EtOH) 223nm ( ⁇ m 19,390) and 311nm (19,050); ⁇ H (CD 3 OD) inter alia 0.96 (3H, d, J 7.0Hz,
  • the title monamide was prepared according to the general method from the amine salt from (15d) (340mgs, 1.3mmol) in THF/water (1:1, 4ml) and triethylamine (360 ⁇ l, 2.6mmol) and isolated after chromatography as a white foam (210mgs, 30% yierld); ⁇ max (EtOH) 239nm ( ⁇ m 19,700); ⁇ H (CD 3 OD) 0.95 (3H, d, J 7.0Hz, 17-H 3 ), 1.20 (3H, d, J 6.5Hz, 14-H 3 ), 2.17 (3H, s, 15-H 3 ), 4.68 (2H, s, 1'-H 2 ), 5.88 (1H, s, 2-H), 7.78 (1H, d, J 8.5Hz, 3"-H), 8.23 (1H, dd, J 8.5 and 2.5Hz, 4"-H) and 8.96 (1H, d, J 2.5Hz, 6"-H); ⁇ C (CD 3
  • the monamide from (15e) (0.2g) was cyclised according to the general method to give the title oxazole (0.07g, 40%); ⁇ max (EtOH) 313nm ( ⁇ m 25,050); ⁇ H (CD 3 OD) 0.95 (3H, d, J 7.0Hz, 17-H 3 ), 1.22 (3H, d, J 6.5Hz, 14-H 3 ), 2.31 (3H, s, 15-H 3 ), 6.28 (1H, s, 2-H), 7.66-7.71 (2H, m, 4' -H and 3" -H), 8.0 (1H, dd, J 8.5 and 2.5Hz, 4"-H) and 8.71 (1H, d, J 2.5Hz, 6"-H); ⁇ C (CD 3 OD) 12.3 (C-17), 19.9 (C-15), 20.3 (C-14), 33.0 (C-9), 41.7 (C-8), 43.8 (C-12), 44.0 (C-4), 56.9 (C-10), 61.3 (C-11
  • the monamide was prepared according to the general method from the amine salt from (16c) and isolated, after chromatography, as a white foam (0.06g, ⁇ 10%) ; ⁇ H (CDCI 3 ) inter alia 0.94 (3H, d, J 7.0Hz, 17-H 3 ), 1.23 (3H, d, J 6.5Hz, 14-H 3 ), 2.22 (3H, s, 15-H 3 ), 4.82 (2H, d, J 4.0Hz, 1'-H 2 ), 5.86 (1H, s, 2-H), 6.75 (1H, t, -NH), 7.10 (1H, dd, J 8.5 and 2.3Hz, 3"-H), 8.42 (1H, t, J 8.5Hz, 4"-H) and 8.92 (1H, s, 6"-H).
  • the monamide was prepared according to the general method from the amine salt from (17a) (0.25g, lmmol) to give, after chromatography, the title monamide (115mg, 22%); ⁇ H (CD 3 OD) 0.96 (3H, d, J 7.0Hz, 17-H 3 ), 1.21 (3H, d, J 6.5Hz, 14-H3), 1.40 (3H, t, J 7.0Hz, -CH 2 CH 3 ), 2.17 (3H, s, 15-H 3 ), 4.43 (2H, q, J 7.0Hz, -CH 2 CH 3 ), 4.68 (2H, s, 1'-H 2 ), 5.90 (1H, s, 2-H), 6.86 (1H, d, J 9.0Hz, 3"-H), 8.23 (1H, dd, J 9.0 and 2.3Hz, 4"-H) and 8.83 (1H, d, J 2.3Hz, 6"-H); m/z 506 (M + , 12%) and 150 (100).
  • the title monamide was prepared according to the general method from the amine salt from (18c) (500mgs, 1.5mmole) in THF/water (1:1, 5ml) and triethylamine (360 ⁇ l, 2.6mmol) and isolated after chromatography as a yellow foam (280mgs, 34%); ⁇ max (EtOH) 214.5nm ( ⁇ m 31,900); ⁇ H (CD 3 OD) 0.95 (3H, d, J 7.0Hz, 17-H 3 ), 1.20 (3H, d, J 6.5Hz, 14-H 3 ), 2.16 (3H, s, 15-H 3 ), 4.70 (2H, s, 1'-H 2 ), 5.88 (1H, s, 2-H), 8.52-88.58 (1H, m, 4"-H), 8.39 (1H, d, J 2.0Hz, 2"-H) and 9.10 (1H, d, J 1.5Hz, 6"-H); ⁇ C (CD 3 OD) 12.2 (C-17), 18.
  • the monamide from (18d) was cyclised according to the general method to give the title oxazole (105mgs, 50%); ⁇ max (EtOH) 317nm ( ⁇ m 20,469); ⁇ H (CD 3 OD) 0.95 (3H, d, J 7.0Hz, 17-H 3 ), 1.20 (3H, d, J 6.5Hz, 14-H 3 ), 2.32 (3H, s, 15-H 3 ), 6.29 (1H, s, 2-H), 7.75 (1H, s, 4'-H),
  • N-1-methoxy-N-1-methyl-N-(t-butoxycarbonyl)-glycinamide (0.44g, 2mmol) in dry THF (10ml) was added maintaining the temperature at -85°C. After 2 hours the cooling bath was removed and a saturated solution of ammonium chloride (20ml) was added. The mixture was extracted with ethyl acette and the organic phase washed with brine, dried (MgSO 4 ) and evaported.
  • the title monamide was prepared according to the general method from the amine salt from (19b) (190mg, 0.7mmol) in THF/water (1:1, 3ml) and triethylamine (300 ⁇ l, 2.1mmol) and isolated after chromatography as a pink foam (135mg, 38%); ⁇ H (CD 3 OD) 0.96 (3H, d, J 7.0Hz, 17-H 3 ), 1.21 (3H, d, J 6.5Hz, 14-H 3 ), 2.17 (3H, s, 15-H 3 ), 3.20 (6H, s, -N(CH 3 ) 2 ), 4.60 (2H, s, 1'- H2 ), 5.90 (1H, s, 2-H), 6.70 (1H, d, J 9.0Hz, 3"-H), 8.06 (1H, dd, J 9.0 and 2.5Hz, 4"-H) and 8.75 (1H, d, J 2.5Hz, 6"-H); m/z (FAB, thiogly
  • the monamide from (19c) was cyclised according to the general method to give the title oxazole (70mg, 55%); ⁇ max (EtOH) 330nm ( ⁇ m 23,500); ⁇ H (CD 3 OD) 0.96 (3H, d, J 7.0Hz, 17-H 3 ), 1.20 (3H, d, J 6.5Hz, 14-H 3 ), 2.29 (3H, s, 15-H 3 ), 3.12 (6H, s, -N(CH 3 ) 2 ), 6.23 (1H, s, 2-H), 6.73 (1H, d, J 9.0Hz, 3"-H), 7.30 (1H, s, 4'-H), 7.78 (1H, dd, J 9.0 and 2.5Hz, 4"-H) and 8.38 (1H, d, J 2.5Hz, 6"-H); ⁇ C (CD 3 OD) 12.3 (C-17), 19.8 (C-15), 20.4 (C-14), 33.1 (C-9) , 38.5 (-N(
  • the title monamide was prepared according to the general method from the amine salt from (20b) (250mg, 0.95mmol) in THF/water (1:1, 4ml) and triethylamine (390 ⁇ l, 2.85mmol) and an impure product isolated (270mg) which contained the title monamide; ⁇ H (CD 3 OD) inter alia 0.95 (3H, d, J 7.0Hz, 17-H 3 ), 1.20 (3H, d, J 6.5Hz, 14-H 3 ), 2.14 (3H, s, 15-H 3 ), 5.88 (1H, s, 2-H), 7.44-7.53 (1H, m, 5'-H) and 8.40-8.47 (2H, m, 4' and 6'-H).
  • the MIC values were determined after incubation for 18h at 37°C and were found to be in the range 0.25 to 32 ⁇ g/ml.

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Abstract

Des composés de formule (I), dans laquelle R1 représente un groupe pyridyle facultativement substitué, sont utiles dans les traitements anti-bactériens and anti-mycoplasmiques. On décrit également des compositions pharmaceutiques et vétérinaires contenant ces composés, ainsi que leurs procédés de préparation et les intermédiaires utilisés dans la préparation de ces composés.
EP91900879A 1989-12-21 1990-12-11 Composes oxazole pharmaceutiquement actifs Withdrawn EP0506729A1 (fr)

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GB898928839A GB8928839D0 (en) 1989-12-21 1989-12-21 Novel compounds

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US7401909B2 (en) 1994-08-24 2008-07-22 Canon Kabushiki Kaisha Ink container for ink jet printer, holder for the container, carriage for the holder and ink jet printer

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MX9100367A (es) * 1990-08-01 1992-04-01 Beecham Group Plc Derivados de heteroarilcetona y procedimiento para su preparacion
GB9207214D0 (en) * 1992-04-02 1992-05-13 Smithkline Beecham Plc Novel compounds
CA2362070A1 (fr) * 1999-02-16 2000-08-24 Masaru Mitsuda Derives d'acetylpyridine substituee et procede de preparation d'intermediaires pour agoniste du recepteur adrenergique .beta.3 optiquement actif, faisant appel a ces derives
KR20160125527A (ko) * 2012-04-17 2016-10-31 후지필름 가부시키가이샤 함질소 복소환 화합물 또는 그 염
PL3059227T3 (pl) 2013-10-16 2019-11-29 Fujifilm Corp Sól heterocyklicznego związku zawierającego azot lub jej kryształ, kompozycja farmaceutyczna i inhibitor flt3
CN107072995B (zh) 2014-08-22 2020-02-21 富士胶片株式会社 用于处置flt3突变阳性癌的医药组合物、突变型flt3抑制剂以及这些的应用
JP6412471B2 (ja) 2015-07-15 2018-10-24 富士フイルム株式会社 含窒素複素環化合物の製造方法およびその中間体

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IE55221B1 (en) * 1982-02-27 1990-07-04 Beecham Group Plc Antibacterial 1-normon-2-yl-heterocyclic compounds
GB8305316D0 (en) * 1983-02-25 1983-03-30 Beecham Group Plc Compounds
JPH0723322B2 (ja) * 1985-12-07 1995-03-15 克之 藤井 液状骨形成剤からなる注射液
JPS63125258A (ja) * 1986-11-14 1988-05-28 三菱マテリアル株式会社 骨欠損部、空隙部及び吸収部充てん材

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US7401909B2 (en) 1994-08-24 2008-07-22 Canon Kabushiki Kaisha Ink container for ink jet printer, holder for the container, carriage for the holder and ink jet printer
US7407275B2 (en) 1994-08-24 2008-08-05 Canon Kabushiki Kaisha Ink container for ink jet printer, holder for the container, carriage for the holder and ink jet printer

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IE904604A1 (en) 1991-07-03
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ZA9010216B (en) 1991-10-30
WO1991009856A1 (fr) 1991-07-11
PT96252A (pt) 1991-09-30
GB8928839D0 (en) 1990-02-28

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