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EP0544705A1 - Derives de mupirocine - Google Patents

Derives de mupirocine

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Publication number
EP0544705A1
EP0544705A1 EP91914135A EP91914135A EP0544705A1 EP 0544705 A1 EP0544705 A1 EP 0544705A1 EP 91914135 A EP91914135 A EP 91914135A EP 91914135 A EP91914135 A EP 91914135A EP 0544705 A1 EP0544705 A1 EP 0544705A1
Authority
EP
European Patent Office
Prior art keywords
ketone
normon
compound
formula
added
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Withdrawn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
EP91914135A
Other languages
German (de)
English (en)
Inventor
Peter Charles Thomas Hannan
Peter John O'hanlon
Neil David Pearson
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
Original Assignee
Beecham Group PLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB909016895A external-priority patent/GB9016895D0/en
Priority claimed from GB919105584A external-priority patent/GB9105584D0/en
Priority claimed from GB919107897A external-priority patent/GB9107897D0/en
Application filed by Beecham Group PLC filed Critical Beecham Group PLC
Publication of EP0544705A1 publication Critical patent/EP0544705A1/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Withdrawn legal-status Critical Current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
    • 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
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • 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
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • This invention relates to a novel 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.
  • Mupirocin (formerly known as pseudomonic acid) is rapidly hydrolysed in vivo to monic acid A, the compound of formula (B) :
  • the present invention provides a compound of formula (I) : OH in which R is hydrogen and R 2 is -COR 3 or
  • R 1 is -COR 3 and R is hydrogen, in which R 3 denotes a heteroaryl group, and excluding the compounds in which R 3 comprises a fur-2-yl, pyrid-2-yl or imidazol-2-yl ring.
  • the heteroaryl group includes single and fused rings, each ring suitably comprising up to four, preferably 1 or 2, heteroatoms each selected from oxygen, nitrogen and sulphur, which rings may be unsubstituted or substituted by, for example, up to three groups.
  • Each ring may have from 4 to 7, preferably 5 or 6, ring atoms.
  • a fused heteroaryl ring may include carbocyclic rings and need include only one heteroaryl ring. Suitable fused heteroaryl rings include bicyclic systems.
  • suitable rings for use in R 3 include, for example, fur-3-yl, thienyl, pyrrolyl, benzofuranyl, benzothienyl, indolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, thiatriazolyl, pyrid-3-yl, ⁇ yrid-4-yl, quinolinyl, isoquinolinyl, pyrazinyl, pyrimidinyl, pyridazinyl and triazinyl.
  • rings for use in R J include thien-2-yl, thien-3-yl, fur-3-yl, pyrrol-3-yl, thiazol-5-yl, isothiazol-5-yl, pyrazol-4-yl, pyridin-3-yl, pyridin-4-yl. pyrimidin-5-yl, and quinolin-3-yl.
  • R 3 comprises a 5- or 6- membered heteroaryl ring having a nitrogen or oxygen heteroatom
  • R is bonded to the ketone carbonyl group of -COR 3 by a ring carbon atom which is not adjacent to said ring heteroatom.
  • said ring carbon atom is located ⁇ - to the ring heteroatom.
  • an acidic hydrogen arising from the presence in the ring of an NH moiety for instance, when
  • R J is pyrazolyl, may be replaced by a substituent.
  • the substitutent (other than fluorine) is located on a ring carbon which is not ⁇ - to a ring heteroatom.
  • 'aryl' includes, unless otherwise defined, phenyl or naphthyl optionally substituted with up to five, preferably up to three substituents.
  • heterocyclyl' includes aromatic and non-aromatic single or fused rings comprising up to four hetero-atoms in the ring selected from oxygen, nitrogen and sulphur and optionally substituted with up to three substituents.
  • the heterocyclic ring comprises from 4 to 7, preferably 5 to 6, ring atoms.
  • a fused heterocyclic ring system may include carbocyclic rings and need only include one heterocyclic ring.
  • 'halogen' refers to fluorine, chlorine, bromine or iodine.
  • Substituents for groups hereinbefore defined as be ng optionally substituted, for instance alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl or heterocyclyl, include:
  • R ⁇ denotes (C ⁇ g)alkyl, (C 3 _ 7 )cycloalkyl, (C 2 _g)alkenyl, (C 3 _ 8 )cycloalkenyl, or (C2_g)alkynyl, each of which may be optionally substituted by up to three groups (which may be the same or different) chosen from the groups listed in subparagraphs (a) , (b) , (c) , (d) and (f) ; and (f) groups RPC0-, RPOCO-, R ⁇ CO-, R ⁇ OCO-, RPSO-, R p S0 2 -, R ⁇ SO-, and R ⁇ SO ? - wherein RP and R ⁇ are as defined in subparagraphs (d) and (e) respectively.
  • Suitable substituents for an alkyl, cycloalkyl, alkenyl or alkynyl group include for example, halogen, cyano, azido, nitro, carboxy, (C 1 _g)alkoxycarbonyl, carbamoyl, mono- or di- (C ⁇ _g)alkylcarbamoyl, sulpho, sulphamoyl, mono- or di-(C- j ⁇ g)alkylsulphamoyl, amino, mono- or di- (C- ⁇ _g)alkylamino, acylamino, ureido, (C ⁇ _g)alkoxycarbonylamino,
  • Suitable substituents for an aryl group include, for example, halogen, cyano, (C ⁇ g)alkyl, phenyl, (C ⁇ _g)alkoxy, halo(C ⁇ . )alkyl, hydroxy, amino, mono- or di- (C-L_g)alkylamino, acylamino, nitro, carboxy,
  • (C ⁇ _g)alkylsulphinyl (C ⁇ .g)alkylsulphonyl, sulphamoyl, mono- or di- (C ⁇ _g)alkylsulphamoyl, carbamoyl, and mono- or di- (C ⁇ _g) alkylcarbamoyl.
  • Suitable substituents for a heteroaryl group include, for example, halogen, (C ⁇ _ )alkyl, (C ⁇ .g)cycloalkyl, (C ⁇ _g)alkoxy, halo( ⁇ g)alkyl, hydroxy, amino, mono- or di-(C ⁇ _g)alkylamino, carboxy, (C ⁇ _g)alkoxycarbonyl, (C ⁇ _g)alkoxycarbonyl(C ⁇ _g)alkyl, aryl, oxo, non-aromatic heterocyclyl, (C 1 _g)alkylthio, (C- ⁇ g)alkylsulphinyl, or (C ⁇ _g)alkylsulphonyl.
  • Suitable substituents for a heterocyclyl group include, for example, halogen, (C- j ⁇ g) alkyl, (C- ⁇ g)alkoxy, halo(C ⁇ .g)alkyl, hydroxy, amino, mono- or di- (C 1 _g)alkylamino, carboxy, (C ⁇ g) alkoxycarbonyl, ( -L.-.g)alkoxycarbonyl (C- ⁇ .g)alkyl, aryl or oxo.
  • a compound of formula (I) of this invention incorporates a tri-substituted carbon-carbon double bond and may therefore exist as a E- (natural) or Z- (or iso) diastereoisomer. It is to be understood that both diastereoisomers of the compound of formula (I) are included within the scope of this invention, as well as mixtures of the two diastereoisomers. If general it is found that greater activity is associated with the E-isomer of a particular compound of formula (I) and it is therefore preferable to employ this isomer.
  • the present invention provides compounds of formulae (la) (the E-isomer) and (lb) (the Z-isomer) :
  • 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:
  • Compounds of the present invention may be prepared by methods known for the preparation of ⁇ , ⁇ -unsaturated ketones. Some of these processes will be more appropriate than others.
  • compounds of formula (I) may be prepared by a process which comprises treating the acid of formula (III) : in which Z 1 , Z 2 and Z 3 are the same or different and each is hydrogen or a hydroxyl-protecting group, or an activated derivative thereof, with an organometallic reagent; and thereafter, and if necessary, removing any hydroxyl-protecting groups.
  • Suitable organometallic reagents include:
  • the reaction with the organometallic reagent may be conveniently carried out in an ethereal or hydrocarbon solvent, the choice of which is dependent upon the specific requirements of the organometallic reagent.
  • the Grignard reagent is generated and used in diethyl ether or tetrahydrofuran.
  • the reaction is generally carried out in an inert atmosphere such as argon or nitrogen and at ambient temperature or below.
  • the period for which the reaction is allowed to proceed depends upon the particular starting materials employed.
  • the course of the reaction may be followed by conventional methods such as thin layer chromatography and the reaction may be terminated when an optimum quantity of product is present in the reaction mixture.
  • Suitable activated derivatives of the acid of formula (III) include thio-esters of formula (IV) :
  • N represents a 5- or 6-membered heterocyclic ring which may contain in addition to the nitrogen atom, one or two further heteroatoms selected from oxygen, nitrogen and sulphur and which may be substituted or fused to a benzene ring which may itself be substituted.
  • Preferred thio-esters are of formula (IVa) :
  • a compound of formula (IVa) may be prepared by treating of a compound of formula (III) with 2,2'-dipyridyl disulphide in the presence of triphenylphosphine, by analogy with the method described by E.J. Corey and D.A Clark in Tetrahedron Letters, 1979, 31, 2875.
  • Z 1 , Z 2 , and Z 3 are as hereinbefore defined, and R 5 and R° are the same or different and each denotes an aryl group, for instance phenyl, or a (C 1 _g)alkoxy group, for instance ethoxy.
  • a compound of formula (V) may be obtained by treating a compound of formula (III) with for instance a suitable derivative of the formula R 3 0COCl using the method described by Crimmin M.J. et al.. J.C.S. Perkin I, 1989, 2047.
  • a compound of formula (VI) may be obtained by treating a compound of formula (III) with CLPOR 5 R° using the method described by Baxter A.J.G. et al., Tetrahedron Letters, 1980, 2i, 5071.
  • Z 1 , Z 2 , and Z 3 are as hereinbefore defined and R 9 and R 1 , together with the nitrogen atom to which they are bonded, form an imidazolyl or triazolyl ring.
  • a preferred compound of formula (VII) is the N-methoxy- N-methylamide (i.e. R and R° is each methyl) as described in PCT/GB90/01932 (Beecham Group) .
  • N-methoxy-N-methylamide with an organolithium or a Grignard reagent to form a ketone is described by Nahm and Weinreb in Tetrahedron Letters, 1981, 3815.
  • a preferred amide of formula (VIII) is the imidazol-1-yl derivative.
  • the reaction of an ⁇ , ⁇ -unsaturated acid or its imidazolyl derivative with a Grignard reagent is described in Chem. Ber., 1965, .95.1284.
  • Amides of formulae (VII) and (VIII) may suitably be obtained from monic acid or isomonic acid by treatment thereof with iso-butyl chloroformate in tetrahydrofuran, in the presence of triethylamine, at a temperature of from -5 to 20°C, for about 30 min, to form an intermediate mixed anhydride (monic/isomonic acid isobutyl carbonic anhydride) .
  • This intermediate may then be reacted with an amine HN(OR 7')RR° in dichloromethane at about 20°C for about 2h or an amine HNR ⁇ R- ⁇ .HCl in the presence of triethylamine and p-dimethylaminopyridine, in THF, at about 20°C, to form the compound of formula (VII) in which Z 1 ,Z 2 and Z 3 is each hydrogen (with R 3 ,R 7 ,R 8 , R 9 and R 10 as hereinbefore defined) .
  • the hydroxyl groups thereof may be protected by treatment with a suitable hydroxyl protecting agent such as chlorotrimethylsilane, in a solvent such as THF in the presence of triethylamine and 4-dimethylamino pyridine as a catalyst.
  • a suitable hydroxyl protecting agent such as chlorotrimethylsilane
  • an amide of formula (VII) or (VIII) is treated with an organolithium reagent of formula R 3 Li as hereinbefore defined.
  • a compound of formula (I) is prepared by a process which comprises treating a compound of formula (VII) as hereinbefore defined, with an organolithium reagent of formula R 3 Li as hereinbefore defined.
  • Suitable organometallic reagents may be prepared according to conventional procedures.
  • Suitable organomanganous reagents of the formula R MnCl may be conveniently prepared by addition of an organolithium reagent R J L ⁇ to a solution of manganous chloride and lithium chloride in dry THF, or a suspension of anhydrous manganous chloride in dry THF. An excess of R 3 MnCl is preferably employed. Alternatively, a Grignard reagent may be used in place of the organolithium reagent, to generate the 3 organomanganous reagent R ⁇ MnCl.
  • organomanganous reagents which may be used instead of R 3 MnCl include:
  • the above organomanganous reagents may be prepared in. situ when required.
  • Organocerium reagents may be generated in situ by treating an organolithium compound of the formula R 3 Li, in which R 3 is as hereinbefore defined, with cerium (III) halide, by analogy with the procedure described by Imamoto e_t al; J.Chem. Soc Chem. Commun, 1982, 1042.
  • R 3 , Z 1 , Z 2 and Z 3 are as hereinbefore defined, with an oxidising agent which converts allylic alcohols into ⁇ , ⁇ -unsaturated ketones, and thereafter, and if necessary, removing any hydroxyl-protecting groups.
  • Suitable such oxidising agents include activated manganese dioxide, pyridinium dichromate and pyridinium chlorochromate.
  • the oxidation reaction is carried out in a non-polar organic solvent such as, for example, benzene or toluene.
  • the invention further provides compounds of formula (IX) as hereinbefore defined.
  • An allylic alcohol of formula (IX) may be prepared by treatment of the corresponding aldehyde of formula (X) :
  • An aldehyde of formula (X) may be treated with a Grignard reagent of formula R 3 MgX or, more preferably, with an organoceriu reagent R 3 Li-CeX3, as hereinbefore defined.
  • An aldehyde of formula (X) may be prepared by treatment of a amide of formula (VII) , as hereinbefore defined, with a suitable reducing agent such as diisobutyl-aluminium hydride, and thereafter, and if necessary, removing any hydroxyl-protecting group. It is found that in practice, such treatment of the E-isomer of an amide of formula (VII) in which R 7 and R 8 is each methyl leads to a mixture of the E- and Z-isomers of the aldehyde of formula (X) . These isomers may be readily separated by conventional chromatography, thereby affording a convenient source of starting material for the subsequent preparation of Z-isomer compounds of formula (I) . Other suitable methods of preparation of an aldehyde of formula (X) are described in EP-A-0 029 665 (Beecham Group) .
  • a compound of formula (I) may also be prepared by treating a ketone of formula (XI) :
  • '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 include those described in 'Protective Groups in Organic Synthesis', T.W. Greene, Wiley-Interscience, New York 1981.
  • the hydroxyl groups of the compounds of formulae (III) to (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, of the formulae below:
  • Me denotes methyl and fc Bu denotes t-butyl
  • Y is halogen and each group L is independently selected from hydrogen, (C ⁇ _g)alkyl, (C 1 _g)alkoxy, aryl or aryl(C 1 _ 4 )alkyl.
  • a preferred silyating agent is trimethylsilyl chloride.
  • Particularly suitable protecting groups are trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl groups. Preferred protecting groups are trimethylsilyl groups because of their ease of removal. -23-
  • glycol function of the compounds of formulae (III) to (XI) may be protected by forming a cyclic derivative using a compound of formula (XIII) :
  • R 1 i 1 X is hydrogen or (C ⁇ g)alkyl and each of R1.?, R1 J " and R 14 is (C ⁇ )alkyl.
  • R 1 i 1 X is hydrogen or (C ⁇ g)alkyl and each of R1.?, R1 J " and R 14 is (C ⁇ )alkyl.
  • Z 1 and Z 2 together are a moiety:
  • R 1 ⁇ is (C 1 _g)alkyl.
  • R 11 is hydrogen, methyl, ethyl, n- or iso-propyl; most suitably it is hydrogen.
  • the groups R 12 , R 13 and R 14 are suitably methyl, ethyl, n- or iso-propyl, or n-, iso-, sec- or t-butyl; most suitably methyl.
  • hydroxyl 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.
  • 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 polyvinylpyrollidone; 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 such as 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 such as glycer
  • 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' 7th Ed., ed Wilkinson J.B. and Moore R.J., George Goodwin, London, 1982, 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.
  • 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 treating an adult human 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 to non-human animals as part of the total dietary intake.
  • 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 a non-human animal 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 compounds of this invention are useful for the treatment of bacterial and mycoplasma-induced infections in non-human and human animals, such as the treatment of respiratory tract infections, otitis, meningitis, skin and soft tissue infections in human animals, mastitis in cattle, and respiratory infections in non-human animals such as pigs and cattle.
  • the present invention provides a method for treating the human or non-human animal which method comprises administering an 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 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.pyoqenes 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 anti ⁇ bacterial agents, for instance, ⁇ -lactam antibiotics such as, for example, methicillin; macrolides; aminoglycosides and lincosamides.
  • the compounds of this invention are also active against mycoplasma-induced infections, in particular infections caused by Mycoplasma fermentans, which has been implicated as a co-factor in the pathogenesis of AIDS.
  • the present invention provides a method of treating humans infected with M. fermentans, in particular humans also infected with HIV, which method comprises treating humans in need of such therapy with an anti-mycoplasmal effective amount of a compound of formula (I) .
  • the present invention provides a compound of formula (I) for use in the manufacture of a medicament for antibacterial and/or antimycoplasmal therapy in human and non-human animals.
  • N,0_-Dimethyl hydroxylamine hydrochloride (1.95g, 20mmol) was dissolved in dichloromethane and aqueous sodium hydroxide (20ml:10ml, 2.5M). The aqueous layer was re-extracted with dichloromethane (10ml) and the combined organic layers washed with saturated brine (5ml) . The organic layer was dried (MgS0 4 ) and added to monic acid isobutyl carbonic anhydride (lOmmol) After stirring at 20°C for Ih the reaction mixture was dilv 2d with dichloromethane and washed with saturated aqueous scxum hydrogen carbonate and brine. The combined aqueous solutions were extracted with ethyl acetate, and the combined organic solutions dried (MgSO ⁇ ) and concentrated to give the amide, (3.0g) .
  • Di-isobutylaluminium hydride (1.0M in hexane) (20.00ml, 20.00mmol) was added dropwise to a solution of N- methoxy-N-methyl-6,7,13-0-tris (trimethylsilyl)monamide (ll.OOg, 18.24mmol) in THF (150ml) cooled to -78°C whilst maintaining the temperature below -70°C. After 3h at -70°C, methanol (20ml) and saturated sodium sulphate solution (20ml) were added. The precipitated solids were removed by filtration, the filtrate dried (MgS0 4 ) and evaporated to dryness under reduced pressure.
  • n-Butyllithium (1.6M in hexane) (1.88ml, 3.0mmol) was added dropwise to a solution of 1-methyltriazole (0.25g, 3.0mmol) in THF (10ml) maintaining the temperature below -60°C. 35 After lh at -65°C cerium trichloride (0.74g, 3.0mmol) was added. After a further lh at -65°C N-methoxy-N-methyl-6,7,13-O-tris(trimethylsilyl)monamide (0.60g, lmmol) in THF (5ml) was added dropwise maintaining the temperature below -60°C.
  • n.-Butyllithium (1.6M in hexane) (1.09ml, 1.74mmol) was added dropwise to 5-bromo-2-methoxypyrimidine (0.33g, 1.74mmol) in THF (10ml) maintaining the temperature below -85°C.
  • lh at -85°C cerium trichloride (0.43g, 1.74mmol) was added.
  • 6,7,13-O-tris (trimethylsilyl)monaldehyde (0.63g, 1.16mmol) in THF (5ml) was added dropwise maintaining the temperature below -85°C.
  • n-Butyllithium (1.6M in hexane) (1.09ml, 1.74mmol) was added dropwise to 5-bromo-2-dimethylaminopyrimidine in THF (10ml) whilst maintaining the temperature below -85°C. After lh at -90°C cerium trichloride (0.43g, 1.74mmol) was added. After a further lh at -90°C
  • n-Butyllithium (1.6M in hexane) (3.27ml, 5.22mmol) was added dropwise to 5-bromo-2-methylthiopyridine (1.06g, 5.22mmol) in THF (45ml) at -85°C.
  • lh at -85°C cerium trichloride (1.29g, 5.22mmol) was added and after a further lh at -85°C 6,7, 13-O-tris (trimethylsilyl)monaldehyde (1.89g, 3.47mmol) in THF (7ml) was added dropwise whilst maintaining the temperature below -85°C.
  • m-Chloroperoxybenzoic acid (85%) (0.050g, 0.242mmol) was 35 added to the ketone of example 9 (0.10g, 0.22mmol) in dichloromethane (3ml) and saturated sodium hydrogen solution (2ml) . After 2h at room temperature water (10ml) was added and the solution extracted with ethyl acetate.
  • Triethylamine (2.94g, 4.06ml, 29.2mmol) and triethylsilyl trifluoromethanesulphonate (5.76g, 4.93ml, 1.83mmol) were added sequentially to 2-acet"- " '-4,5dibromofuran (3.93g,
  • N-Methylpiperazine 0.5g, 5.68mmol
  • 5-bromo-2- chloropyrimidine l.OOg, 5.17mmol
  • methanol 25ml
  • n-Butyllithium (1.6M in hexane) (1.09ml, 1.74mmol) was added 5 dropwise to 5-bromo-2-(l-methylpiperazin-4-yl)pyrimidine (0.44g, 1.74mmol) in THF (20ml) at -85°C. After lh at -85°C, cerium trichloride (0.43g, 1.74mmol) was added and the solution kept at -85°C for a further lh. 6,7,13-tris(trimethylsilyl)monaldehyde (0.63g,
  • n-Butyllithium (1.6M in hexane) (1.05ml, 1.68mmol) was added 30 dropwise to the above quinoline in THF (20ml) whilst maintaining the temperature below -85°C. After lh at -85°C cerium (III) chloride (0.40g, 1.65mmol) was added and after a further lh at -85°C acetic acid (0.10ml) then water (20ml) were added. Extraction with ethyl acetate, drying 35 (Na,S0 4 ) and evaporation to dryness under reduced pressure gave the crude alcohols.
  • n-Butyl lithium (1.6M in hexane) (1.00ml, 1.60mmol) was 30 added dropwise to diisolpropylamine (0.18g, 1.78mmol) in THF (4ml) whilst maintaining the temperature at 020°C. After 10 mins at -20°C, 2-methoxythiophene (0.17g, 1.50mmol) was added dropwise whilst maintaining the temperature below -65°C. After 15 mins at -70°C, cerous chloride (0.37 C C, 351.50mmol) was added whilst maintaining the temperature below -65°C.
  • N-methoxy- N-methyl-6,7, 13-O-tris-(trimethylsilyl)monamide (0.60g, l.OOmmol) in THF (5ml) was added dropwise whilst maintaining the temperature below -65°C.
  • acetic acid (0.14g) was added followed by water (20ml) .
  • Tetrabutylammonium hydroxide (1.0M in methanol) (5.00ml, 5.0mmol) and iodomethane (0.739, 5.0mmol) were add dropwise to 2-mercaptothiazole (0.59g, 5.0mmol) in THF (5ml) at room temperature. After 1.5h and evaporation to dryness under reduced pressure, the reaction mixture was triturated with hexane and diethyl ether (1:1), taking the solid up in dichlormethane.
  • N-methyl-6,7,13-O-tris (trimethylsilyl)monamide (0.6g, l.OOmmol) in THF (5ml) was added dropwise whilst maintaining the temperature below -65°C. After 1.5h at -70°C, acetic acid (0.14g) was added followed by water (20ml) . Extraction with diethyl ether, drying (MgSo 4 ) , evaporation to dryness under reduced pressure and purification by flash chromatography using ethyl acetate in hexane (0-25%) as eluent gave the trimethylsilyl protected title compound (0.48g, 72%) as a white foam.
  • n-Butyllithium (1.6M in hexane) (3.47ml, 5.53mmol) was added dropwise to 5-bromo-2-( ⁇ iperidin-l-yl)pyrimidine (1.34g, 5.53mmol) in THF (80ml) maintaining the temperature below -85°C.
  • lh at -85°C cerium trichloride (1.36g, 5.53mmol) was added.
  • N-methoxy-N-methyl- 6,7,13-O-tris (trimethylsilyl)monamide (3.60g, 6.00mmol) in THF (20ml) was added dropwise whilst maintaining the temperature below -85°C.
  • Example 29 As for Example lib using the above ketone (0.99g) giving the title compound (0.51g, 74%) as a pale yellow foam; (all ⁇ spectroscopic data were identical to those of Example lib) .
  • Example 29 As for Example lib using the above ketone (0.99g) giving the title compound (0.51g, 74%) as a pale yellow foam; (all ⁇ spectroscopic data were identical to those of Example lib) .
  • n-Butyllithium (1.6M in hexane) (6.25ml, lO.OOmmol) was added dropwise to 5-bromo-2-dimethylaminopyrimidine (2.01g, lO.OOmmol) in THF (80ml) at -85°C.
  • lh at -85°C cerium trichloride (2.47g, lO.OOmmol) was added.
  • N-methoxy-N-methyl-6,7,13-O-tris (trimethylsilyl)monamide (3.00g, 4.97mmol) in THF (20ml) was added dropwise at -85°C.
  • N-methoxy-N-methyl-6,17,13-O-tris(trimethylsilyl)monamide (1.80g, 3.00mmol) in THF (10ml) was added dropwise at -75°C. After 3h at -75°C acetic acid (0.36ml) then water (60ml) were added. Extraction with ethyl acetate, drying (MgS0 4 ),
  • n-Butyllithium (1.6M in hexane) (5.00ml, ⁇ .OOmmol) was added dropwise to 2-bromothiophene (1.22g, 7.50mmol) in THF (20ml) whilst maintaining the temperature below -65°C.
  • N-methoxy-N-methyl-6,7,13-0- tris(trimethylsilyl) onamide (3.00g, 5.00mmol) in THF (25ml) was added dropwise maintaining the temperature below -65°C. 5
  • acetic acid (0.70g) was added followed by water (100ml) .
  • n-Butyllithium (1.6M in hexane) (3.75ml, 6.00mmol) was added dropwise to 2,5 dibromopyridine (1.42g, 6.0mmol) in THF (16ml) whilst maintaining the temperature below -85°C. After 10 mins. at -90°C N-methoxy-N-methyl-6,7,13-0- tris (trimethylsilyl) onamide (1.82g, 3.00mmol) in THF (20ml) was added dropwise maintaining the temperature below -85°C. 5 After 30 mins. allowing the temperature to increase to -70°C, acetic acid (0.56g) was added, followed by water (60ml).
  • N-methoxy-N-methyl-6,7,13-0- tris(trimethylsilyl)monamide (0.60g, l.OOmmol) in THF (3ml) was added dropwise maintaining the temperature below -65°C. After 45 mins. at -70°C acetic acid (0.14g) was added followed by water (20ml) .
  • the Examples were tested for antibacterial activity against a range of bacterial strains important in human infections (H. influenzae Ql; 13. catarrhalis 1502; Strep. pyoqenes CN 10; Strep, pneumoniae PU7 and Steph. aureus Oxford) in a conventional microbiological assay, using serial dilutions in nutrient agar with 5% chocolate horse blood. The MICs were determined after incubation for 18h at 37° values in the range 0.06 to 32 ⁇ g ml A were observed.

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Abstract

L'invention décrit des dérivés cétoniques C-1 hétéroaryle d'acides moniques et isomoniques, leur utilisation dans des thérapies anti-bactériennes et anti-mycoplasmiques ainsi que leurs procédés de préparation.
EP91914135A 1990-08-01 1991-07-30 Derives de mupirocine Withdrawn EP0544705A1 (fr)

Applications Claiming Priority (6)

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GB909016895A GB9016895D0 (en) 1990-08-01 1990-08-01 Novel compounds
GB9016895 1990-08-01
GB919105584A GB9105584D0 (en) 1991-03-16 1991-03-16 Novel compounds
GB9105584 1991-03-16
GB9107897 1991-04-13
GB919107897A GB9107897D0 (en) 1991-04-13 1991-04-13 Novel compounds

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CA (1) CA2088505A1 (fr)
IE (1) IE912684A1 (fr)
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GB9201391D0 (en) * 1992-01-22 1992-03-11 Smithkline Beecham Plc Method of treatment
JPH07503244A (ja) * 1992-01-24 1995-04-06 スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー 抗菌性１−ノルモン−２−イルチアゾリルケトン類
EP0580465A1 (fr) * 1992-06-25 1994-01-26 Sanofi Nouvelle utilisation thérapeutique d'hétérocyclyl-pipérazines comme 5-HT3 agonistes et nouveaux dérivés
JPH0665203A (ja) * 1992-06-25 1994-03-08 Elf Sanofi ピペラジンのヘテロ環誘導体
GB9215854D0 (en) * 1992-07-25 1992-09-09 Smithkline Beecham Plc Novel compounds
GB9320561D0 (en) * 1993-10-06 1993-11-24 Zeneca Ltd Heterocyclic compounds
WO1997005126A1 (fr) * 1995-07-29 1997-02-13 Smithkline Beecham Plc Mupirocinsulfamates a activite antibacterienne

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GB1587058A (en) * 1976-06-15 1981-03-25 Beecham Group Ltd Oxiranylmethyltetrahydropyran derivatives
DE3066424D1 (en) * 1979-11-10 1984-03-08 Beecham Group Plc Antibacterial derivatives of monic acid, processes for their preparation and compositions containing them
GB8928839D0 (en) * 1989-12-21 1990-02-28 Beecham Group Plc Novel compounds

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KR930701431A (ko) 1993-06-11
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NZ239191A (en) 1994-04-27
MX9100367A (es) 1992-04-01
WO1992002518A1 (fr) 1992-02-20
AU651988B2 (en) 1994-08-11
IE912684A1 (en) 1992-02-12
PT98511A (pt) 1992-06-30

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