Classifications

• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/42—Oxazoles
• • 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
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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.
• R* represents a 2-nitro-furan-5-yl group which may be further substituted by up to two, preferably one, additional substituents and Zj_, Z2 and Z3 which may be the same or different is each hydrogen or a hydroxyl protecting group.
• Rl may be represented by the sub-formula:
• R a and ⁇ include, for example (C ⁇ _6)alkyl and halogen.
• Rl is 5- nitro-furan-2-yl.
• 'halogen' refers to fluorine, chlorine, bromine and iodine.
• the compounds of formula (la) 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 (la) 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 (la). 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 5-(5-nitrofuran-
• Compounds of formula (I) can be prepared by analogy with the methods described in EP-A-0 399 645 and WO-A-91/09586 (Beecham Group).
• the present invention provides a process for preparing a compound of formula (I) which process comprises cyclising a compound of formula (III): am in which ⁇ _ -, Z]_, Z2 and Z3 are as hereinbefore defined, to form a compound of formula (I) and thereafter, and if necessary, removing any hydroxyl- protecting groups.
• 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-dimethylamino- pyridine.
• 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-dimethylamino- pyridine.
• Trihaloacetyl groups formed during cyclisation may be removed using potassium carbonate in solvents such as water, alkanols or admixtures thereof.
• hydroxyl groups of the 1- normon-2-yl radical maybe protected, prior to cyclising with a carboxylic anhydride, and deprotected by conventional methods such as described below.
• 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.
• 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): RlCOCH 2 NH 3 +Cl" (IV) wherein Rl is as hereinbefore defined; in the presence of a suitable base such as triethylamine.
• 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
• 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):
• R is as hereinbefore defined; M+ is a metal cation, preferably an alkali metal cation, most preferably a lithium or sodium cation; and R2 is an anion-stabilising 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; and, thereafter and if necessary, removing any hydroxyl-protecting groups.
• M+ is a metal cation, preferably an alkali metal cation, most preferably a lithium or sodium cation
• R2 is an anion-stabilising 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; and, thereafter and if necessary, removing any hydroxyl-
• 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
• this compound When this compound is produced with hydroxyl protecting groups already in place it may be used directly or even in situ in the above reaction or it may be optionally deprotected and/or isolated.
• the compounds of formula (VI) may be prepared by conventional processes, by analogy with those as described in EP-A-0 123 378 (Beecham
• (VII) wherein W is hydrogen or halogen and R ⁇ is as hereinbefore defined may be converted into a compound of formula (VI) in which M is lithium and 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, Tetrahedron, 1978, 5; T.H. Chan,, Ace 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 ⁇ is diethylphosphonate, by anology with the method of B.H. Lipshutz and K.W. Hungate, J. Org.
• the present invention further provides a process for the preparation of a compound of formula (I) which process comprises treating a compound of formula (V ⁇ i):
• 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 l,5-diazobicyclo[4.3.0]non-5-ene (DBN).
• DBU 1,8- diazo-bicyclo[5.4.0]undec-7-ene
• DBN l,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.
• 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):
• a compound of formula (XI) in which R Z , Z 2 and Z3 are as hereinbefore defined; by methods known for the isomerisation of a carbon-carbon double bond. 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.
• '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.
• the 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, includin halosilanes and silazanes, for example those of the following formulae :
• L 3 SiY; L 2 SiY 2 ; L 3 SiNL 2 ; L 3 SiNHSiL 3 ; L 3 SiNHCOL; L 3 SiO-C(L) NSiL 3 ; L 3 SiNHCONHSiL 3 ; LNHCONHSiL 3 ; tBuMe 2 Si-O-SO 2 -CF 3 ;
• each group L is independently selected from hydrogen, (Ci"6)alkyl, (C ⁇ -g)alkoxy, aryl or aryl(C ⁇ -4)alkyl.
• a preferred silyating agent is trimethylsilyl chloride.
• Particularly suitable hydroxyl-protecting groups are trimethylsilyl, triethylsilyl and t-butyldimethylsilyl 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, methyl, ethyl, n- or iso-propyl; most suitably it is hydrogen.
• the groups R 4 , ⁇ and R*> are suitably methyl, ethyl, 7i- or iso-propyl, or n-, iso-, sec- or t-butyl; most suitably methyl.
• the hydroxyl groups of a compound of formula (I) may also be protected prior to conversion to a further compound of formula (I) as described above.
• the protecting groups described above may be removed by mild acid hydrolysis followed by alkaline hydrolysis, for instance, as described by Clayton et al, J.C.S. Perkin Trans. 1, 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.
• the 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, for instance, tablets, capsules, powders, granules, suppositories, lozenges and liquid or gel preparations, including oral, topical and 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.
• 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.
• 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.
• compositions for intramammary treatment of mammary disorders in animals will generally contain a suspension of the drug in an oily vehicle.
• the 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.
• 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.
• 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 (la) as hereinbefore defined for use in therapy.
• the present invention further provides a method of treating bacterial and/or mycoplasmal 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 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.
• the compounds of this invention are active against both Gram negative and Gram positive organisms, including Haemophilus, for instance H.influenzae Ql; Branhamella,fo ⁇ instance B.catarrhalis 1502; Streptococci, for instance S.pyogenes CN10 and S.pneumoniae PU7; Staphylococci, for instance S.aureus Oxford; and Legionella, for instance L. pneumophila.
• compounds of this invention are active against Staphylococci organisms such as S. aureus and coagulase negative strains of Staphylocci such as iS.
• epidermidis which are resistant (including multiply-resistant) to other anti-bacterial agents, for instance, ⁇ -lactam antibiotics such as, for example, methicillin; macrolides; aminoglycosides, and lincosamides ie compounds of the present invention are useful in the treatment of MRSA, MRCNS and MRSE. Furthermore, compounds of the present invention are useful in the treatment of Staphylococci organisms which are resistant to mupirocin.
• 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. Accordingly in a further aspect, 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 (la).
• Example 1 5-(5-Nitrofuran-2-yl)-2-(l-normon-2-yl)oxazole a) 5-(5-Nitrofuran-2-yl)-2-(6,7,13-0-*ris-trimethylsilyl-l-normon-2- yl) oxazole - TVis-trimethylsilyl tosylmethylmonamide (60.0g, 82.4mmol) (EP-A-O 399 645; Example 12(c), Beecham Group pic) was dissolved in acetonitrile (175ml).
• the black viscous oil was purified by vacuum flash chromatography on silica (1kg), eluting with 0-14% ethyl acetate in hexane, to give the title compound as an orange oily foam (43.0g, 75%); ⁇ ⁇ n (CDC1 3 ) inter alia 0.91 (3H, d, J 7.1Hz, I7-H3), 1.20 (3H, d, J 6.3Hz, 14-H 3 ), 2.32 (3H, s, I5-H3), 6.28 (1H, s, 2-H), 6.74 (1H, d, J 3.9Hz, 3"-H), 7.42 (1H, d, 3.9Hz, 4"-H), and 7.62 (1H, s, 4'-H); mlz 694 ( ⁇ f+,1%), 605 (1), 117 (100), and 73 (90).
• Human foetal lung fibroblast (MRC-5) cells were prepared by growing to 80% confluency in 6-well plates, removing the medium and then washing the monolayers twice with Dulbecco's PBS). These cells were then inoculated and after 16 hours, the medium was removed and the inoculated monolayers washed twice to remove any adherent, non-intracellular, organisms.
• MRC-5 cells Human foetal lung fibroblast (MRC-5) cells were prepared by growing to 80% confluency in 6-well plates, removing the medium and then washing the monolayers twice with Dulbecco's PBS). These cells were then inoculated and after 16 hours, the medium was removed and the inoculated monolayers washed twice to remove any adherent, non-intracellular, organisms.
• Test compound prepared to the required concentrations in TCM, was added to the cells.
• the compound of Example 1 was tested at 0.5, 2 and

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• 1992
  • 1992-04-02 GB GB929207214A patent/GB9207214D0/en active Pending
• 1993
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