WO2000073287A1 - Derives isoxazoline carboxylate de mutiline et leur utilisation comme antibacteriens - Google Patents

Derives isoxazoline carboxylate de mutiline et leur utilisation comme antibacteriens Download PDF

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WO2000073287A1
WO2000073287A1 PCT/EP2000/004232 EP0004232W WO0073287A1 WO 2000073287 A1 WO2000073287 A1 WO 2000073287A1 EP 0004232 W EP0004232 W EP 0004232W WO 0073287 A1 WO0073287 A1 WO 0073287A1
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compound
formula
group
oct
aza
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PCT/EP2000/004232
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English (en)
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David Kenneth Dean
Steven Howard
Antoinette Naylor
Andrew Kenneth Takle
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Smithkline Beecham Plc
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Priority to AU49199/00A priority Critical patent/AU4919900A/en
Publication of WO2000073287A1 publication Critical patent/WO2000073287A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member

Definitions

  • the present invention relates to novel compounds, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medical therapy, particularly antibacterial therapy
  • Pleuromutilm the compound of formula (A), is a naturally occurring antibiotic which has anti- mycoplasmal activity and modest antibacterial activity Mutilm and other compounds with a free OH at C-14 are inactive. The impact of further modification at C-14 on the activity of pleuromutilm has been investigated (H. Egger and H Remshagen, J Antibiotics, 1976,_29, 923).
  • WO 97/25309 (SmithKline Beecham) desc ⁇ bes further modification of the acyloxy group, disclosing 14-O-carbamoyl derivatives of mutilm or 19,20-d ⁇ hydromut ⁇ lm, in which the N- atom of the carbamoyl group is unsubstituted, mono- or di-substituted.
  • WO 98/05659 discloses 14-O-carbamoyl de ⁇ vatives of mutilin or 19,20-d ⁇ hydromut ⁇ lm, m which the N-atom of the carbamoyl group is acylated by a group which includes an azabicychc moiety.
  • WO 99/21855 (SmithKline Beecham) describes further de ⁇ vatives of mutilin or 19,20- 0 dihydromutilm, in which the glycohc ester moiety at position 14 is modified.
  • the present invention is based on the unexpected discovery that novel mutilin derivatives having an isoxazoline carboxylate substituent at the 14-position also have potent antimicrobial activity.
  • R! is an optionally substituted aryl group, or an optionally substituted nitrogen containing heterocycle
  • R2 is vinyl or ethyl
  • R 3 is H, OH or F; and R 4 is H, or R 3 is H and R 4 is F.
  • R* when an aryl group include phenyl.
  • R ⁇ is aryl
  • a preferred number of substituents is up to three, more preferred is one.
  • Representative substituents include (Cj. ⁇ alkoxy, for example methoxy.
  • R* is a nitrogen containing heterocycle.
  • nitrogen containing heterocycle refers to a saturated or partially saturated non-aromatic mono- or bicyclic group linked via a ring carbon atom.
  • the group may comprise one to three nitrogen atoms, preferably one or two, more preferably one nitrogen atom.
  • the group is monocyclic it can contain between 4 and 8 ring atoms, and when bicyclic it can contain between 5 and 10 ring atoms in each ring.
  • the aza-bicyclic ring system may, for example, be represented by the formulae (X) or (Y):
  • each of a, b, c, d and e which may be the same or different, is for a, b and c an integer from 1 to 4, and for d and e 0 or an integer from 1 to 3, such that any one ring has between 5 and 10 ring atoms.
  • the nitrogen containing heterocycle can be optionally substituted on carbon by up to 3 substituents.
  • Suitable substituents include alkyl, alkyloxy, alkenyl and alkenyloxy, each of which may be carried by either a bridgehead or a non-bridgehead carbon atom.
  • the or each nitrogen atom may be substituted by oxygen, to form an N-oxide, or by mono- or d-(C ⁇ _6)alkyl, in which case it will be appreciated that a quaternary cation can be formed.
  • Representative nitrogen substituents include (Ci _g) alkyl, preferably methyl.
  • the counter ion may be a halide ion such as chloride or bromide, preferably chloride.
  • the ring system additionally may contain one or more double bonds.
  • nitrogen containing heterocycles include optionally substituted azabicyclo- octyl and piperidinyl.
  • Preferred nitrogen containing heterocyclic moieties include optionally substituted l-aza-bicyclo[2.2.2]oct-4-yl, piperidin-4-yl and 8-aza-bicyclo[3.2.1]oct-3-yl.
  • the linking ring carbon in an azabicyclic system may be a bridgehead atom or a non-bridgehead atom.
  • aryl refers to, unless otherwise defined, phenyl or naphthyl optionally substituted with up to five, preferably up to three substituents.
  • Suitable substituents for an aryl group include, for example, and unless otherwise defined, halogen, (C ⁇ _g)alkyl, aryl, aryl(C ⁇ _6)alkyl, (C ⁇ alkoxy, (C ⁇ _6)alkoxy(C ⁇ _6)alkyl, halo(C ⁇ _g)alkyl, aryl(C ⁇ _g)alkoxy, hydroxy, nitro, cyano, azido, amino, mono- and di-N-
  • two adjacent ring carbon atoms may be linked by a (C3.. 5)alkylene chain, to form a car
  • alkyl and alkenyl refer to (individually or as part of alkoxy or alkenyloxy) straight and branched groups containing up to six carbon atoms and are optionally substituted by one or more groups selected from the group consisting of aryl, heteroaryl, heterocyclyl, (C 1 _6)alkoxy, (C ⁇ _6)alkylth ⁇ o, aryl(C ⁇ _5)alkoxy, aryl(C ⁇ _6)alkylth ⁇ o, ammo, mono- or d ⁇ -(C 1 _6)alkylammo, cycloalkyl, cycloalkenyl, carboxy and esters thereof, amide, ureido, guamdmo, (C ⁇ _6)alkylguan ⁇ d ⁇ no, amidmo, (C 6)alkylam ⁇ d ⁇ no, (C1 _g)acyloxy, azido, hydroxy, and halogen.
  • cycloalkyl and cycloalkenyl refer to groups having from three to eight ⁇ ng carbon atoms and are optionally substituted as described heremabove for alkyl and alkenyl groups.
  • heterocyclyl and “heterocychc” refer to, unless otherwise defined, non-aromatic, single and fused, rings suitably containing up to four heteroatoms in each ⁇ ng, each of which is selected from oxygen, nitrogen and sulphur, which rings, may be unsubstituted or substituted by, for example, up to three substituents.
  • Each heterocychc ring preferably has from 4 to 7, preferably 5 or 6, ring atoms.
  • a fused heterocychc ⁇ ng system may include carbocychc ⁇ ngs and need include only one heterocychc ⁇ ng.
  • a substituent for a heterocyclyl group is selected from oxo, and the group hereinbefore defined as suitable aryl substituents.
  • heteroaryl suitably includes, unless otherwise defined, a mono- or bicyclic heteroaromatic ⁇ ng system comp ⁇ smg up to four, preferably 1 or 2, heteroatoms each selected from oxygen, nitrogen and sulphur. Each ⁇ ng may have from 4 to 7, preferably 5 or 6, ring atoms.
  • a bicyclic heteroaromatic ring system may include a carbocychc ⁇ ng.
  • a substituent for a heteroaromatic ring system is selected from the group hereinbefore defined as suitable aryl substituents
  • the present invention includes the individual diastereoisomers and mixtures thereof
  • the 2-hydroxy-subst ⁇ tuted compounds of formula (IA) are of the (2S) configuration
  • the 2-F- substituted compounds of formula (IA) may of (2S) configuration or (2R) configuration, or be provided as mixtures thereof
  • the (2S) configuration is however preferred.
  • the stereochemistry at the 5-pos ⁇ t ⁇ on m the isoxazoline ring may be either of R configuration or S configuration, or a mixture thereof
  • Preferred compounds of the invention include-
  • the compounds of this invention may be in crystalline or non-crystallme form, and, if crystalline, may optionally be hydrated or solvated.
  • This invention includes withm its scope stoichiomet ⁇ c hydrates as well as compounds containing va ⁇ able amounts of water.
  • the compounds according to the invention are suitably provided in substantially pure form, for example at least 50% pure, suitable at least 60% pure, advantageously at least 75% pure, preferably at least 85% pure, more preferably at least 95% pure, especially at least 98% pure, all percentages being calculated as weight/weight.
  • Compounds of the invention that contain a basic group such as an amino substituent may be in the form of a free base or an acid addition salt.
  • Compounds having an acidic group such as a carboxy substituent may be in the form of a pharmaceutically acceptable salt.
  • Compounds of the invention having both a basic and an acidic centre may be in the form of zwitterions, acid addition salt of the basic centre or alkali metal salts (of the carboxy group). Pharmaceutically acceptable salts are preferred.
  • Acid-addition salts include those described by Berge, Bighley, and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19.
  • Suitable salts include the hydrochloride, maleate, and methanesulphonate; particularly the hydrochloride.
  • salts include those described by Berge, Bighley, and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19.
  • Suitable salts include alkali metal salts such as the sodium and potassium salts.
  • Compounds of the present invention may be readily prepared from a pleuromutilin or a 19,20- dihydro-pleuromutilin derivative by adapting procedures well known in the art for forming an isoxazoline group. Suitable procedures are reviewed, for example, by W. Curruthers in Cycloaddition Reactions in Organic Synthesis, Tetrahedron Organic Chemistry Series, vol. 8; J.E. Baldwin and P.D. Magnus, eds., (Pergamon Press).
  • the present invention provides a process for preparing a compound of formula (IA) or (IB) which comprises reacting a compound of formula (IIA) or (IIB):
  • HA (IIB) in which: P is hydrogen or a removable hydroxy-protecting group; R3A an( j R4A are R3 anc j R4 as d e fl ne d for formulae (IA) and (IB) or a group convertible to R 3 and R 4 respectively; and R2 is as hereinbefore defined;
  • RIA is R! as defined for formulae (IA) and (IB) or a group convertible to R*; and X is chloro or bromo, or a group convertible to chloro or bromo; in a 1,3-dipolar cycloaddition reaction and thereafter, and if so needed; converting P to hydrogen, and if necessary converting an R- ⁇ -A . or R4A grou o an R 3 or R 4 group.
  • an organic solvent such as N,N-dimethylformamide, dichloromethane or 1,4-dioxane (preferably NN-dimethylformamide or a mixture of dichloromethane and 1,4- dioxane), at a temperature of-20°C to 60°C (preferably -10°C to 25°C), and in the presence of a tertiary organic base such as triethylamine, di-isopropyl ethylamine or ⁇ - methylmorpholine (preferably triethylamine).
  • organic solvent such as N,N-dimethylformamide, dichloromethane or 1,4-dioxane (preferably NN-dimethylformamide or a mixture of dichloromethane and 1,4- dioxane)
  • a tertiary organic base such as triethylamine, di-isopropyl ethylamine or ⁇ - methylmorpholine (preferably triethylamine).
  • this ring forming process generally produces a mixture of R and S isomers at the 5 position of the isoxazoline ring. These may be separated by conventional techniques such as chromatography or fractional crystallisation.
  • P is a hydroxyl protecting group such as an acyl group, for example so that -OP is trifluoroacetoxy or dichloroacetoxy.
  • R 3 - ⁇ is also preferably acyloxy, for example acetyl or dichloroacetyl. Hydroxyl groups at positions 11 and
  • the protecting acyl groups may be removed to restore the hydroxyl groups, for instance by hydrolysis e.g. using NaOH in either MeOH or tetrahydrofuran water solution.
  • Suitable hydroxy, carboxy and amino protecting groups are those well known in the art and which may be removed under conventional conditions and without disrupting the remainder of the molecule.
  • a comprehensive discussion of the ways in which hydroxy, carboxy and amino groups may be protected and methods for cleaving the resulting protected derivatives is given in for example Protective Groups in Organic Chemistry, T.W. Greene and P.G.M. Wuts, (Wiley-Interscience, New York, 2nd edition, 1991).
  • Particularly suitable hydroxy protecting groups include, for example, triorganosilyl groups such as, for instance, trialkylsilyl and also organocarbonyl and organooxycarbonyl groups such as, for instance, acetyl, allyloxycarbonyl and 4-methoxybenzyloxycarbonyl.
  • Particularly suitable carboxy protecting groups include alkyl and aryl esters, for instance methyl, ethyl and phenyl.
  • Particularly suitable amino protecting groups include alkoxycarbonyl and 4-methoxybenzyloxycarbonyl.
  • R ⁇ A is typically hydrogen, fluoro or protected hydroxyl, such as acyloxy.
  • protecting acyl groups may be removed to restore the hydroxyl groups by hydrolysis e.g. using NaOH in MeOH.
  • a compound of formula (IA) may also be prepared from an epi-matilin starting material. Accordingly, in a further aspect, the present invention provides a process for preparing a compound of formula (IA) in which R 3 and R 4 are both hydrogen which comprises reacting an epi -mutilin compound of formula (IIC):
  • the acid treatment indicated above converts the ep. -mutilin configuration of formula (IIC) to the usual mutilin nucleus of formula (IIA). Typically this conversion is carried out by treatment with cone. HC1 or Lukas reagent (cone. HC1 saturated with ZnCl2) in dioxane.
  • R , R R 3 or R 4 group may be interconvert to another R , R R 3 or R 4 group. This typically arises when one compound of formula (IA/B) is used as the immediate precursor of another compound of formula (IA/B) or when it is easier to introduce a more complex or reactive substituent at the end of a synthetic sequence.
  • a substituent group in R* can be converted into another substituent group using one of the general methods for functional group transformation described in the literature (e.g. a carboxylic ester can be hydrolysed to a carboxylic acid with base; an acid can be converted into an amide; a tert-butoxy-carbonyl-amino group can be converted into an amine by treatment with trifluoroacetic acid; an amino group can be alkylated or acylated), provided that the method chosen is compatible with other functional groups in the molecule (e.g. the ketone at C-3 in the pleuromutilm nucleus, the isoxazoline or the acrylate groups).
  • a carboxylic ester can be hydrolysed to a carboxylic acid with base
  • an acid can be converted into an amide
  • a tert-butoxy-carbonyl-amino group can be converted into an amine by treatment with trifluoroacetic acid
  • an amino group can be alkylated or acylated
  • R ⁇ A is typically the R ⁇ group vinyl, and this may be converted to the alternative R ⁇ ethyl group by hydrogenating the vinyl group to form an ethyl group, typically by hydrogenation over a palladium catalyst (e.g. 10% palladium-on-carbon) in a solvent such as ethyl acetate, ethanol, dioxane, or tetrahydrofuran.
  • a palladium catalyst e.g. 10% palladium-on-carbon
  • a solvent such as ethyl acetate, ethanol, dioxane, or tetrahydrofuran.
  • R2A to R2 may not be feasible after the formation of the acrylate group, the isoxazoline ring or compounds of formula (IVB), thus such modifications should be carried out prior to these synthetic modifications.
  • Compounds of formula (IIA) m which R->A is fluoro may be obtained by reacting 2-d ⁇ azo- mutilm with a source of hydrogen fluoride.
  • the hydrogen fluo ⁇ de source is an amme complex of hydrogen fluoride such as hydrogen fluo ⁇ de-py ⁇ dine.
  • the reaction may be carried out in an anhydrous solvent (e g diethyl ether, tetrahydrofuran, 1 ,2-d ⁇ methoxyethane), at a temperature of - 15°C to 25°C. This reaction produces (2S)-2-fluoro derivatives.
  • (2R)-2- Fluoro-mutilm de ⁇ vatives may be prepared by treating the (2S)- ⁇ somer with a base (e g sodium hydroxide or potassium hydroxide ethanol). This will usually produce a mixture of (2S) and (2R)- ⁇ somers that may be separated using conventional techniques such as chromatography and crystallisation.
  • a base e g sodium hydroxide or potassium hydroxide ethanol
  • the resulting aldoxime may be reacted with a suitable halogenatmg agent such as N-bromosuccimmide, N-chlorosuccmimide or chlo ⁇ ne in a solvent such as N,N-d ⁇ methylformam ⁇ de, py ⁇ dme or carbon tetrachlo ⁇ de to give an ⁇ -haloaldoxime of formula (III).
  • a suitable halogenatmg agent such as N-bromosuccimmide, N-chlorosuccmimide or chlo ⁇ ne
  • a solvent such as N,N-d ⁇ methylformam ⁇ de, py ⁇ dme or carbon tetrachlo ⁇ de
  • Suitable aldehydes may be readily prepared by adapting procedures well known in the art and are desc ⁇ bed in, for instance, Comprehensive Functional Group Transformations, Vol 3, A.R. Kat ⁇ tzky, O. Meth-Kohn and C.W Rees eds. (Elsevier Science Ltd., Oxford, 1995).
  • the present invention provides for the in situ generation of compounds of formula (III) which comprises reacting an aldoxime with a halogenatmg agent such as N- bromosuccimmide in a solvent such as N,N-d ⁇ methylformam ⁇ de at 0°C to 25°C.
  • the compound of formula (IIA) or (IIB) may then be introduced to the reaction mixture containing the ⁇ -haloaldoxime of formula (III) at a temperature of-10°C in the presence of an organic base such as tnethylamme.
  • the compounds of the present invention may contain a chiral centre, and therefore the above processes may produce a mixture of diastereoisomers.
  • a single diastereoisomer may be prepared by separating such a mixture of diastereoisomers by conventional techniques such as chromatography or fractional crystallisation
  • the compounds of this invention may be m crystalline or non-crystallme form, and, if crystalline, may optionally be hydrated or solvated.
  • solvent of crystallisation may be present in the crystalline product
  • some of the compounds of this invention may be crystallised or recrystalhsed from solvents containing water. In such cases water of hydration may be present in the crystalline product Crystallisation procedures will usually produce stoichiomet ⁇ c hydrates. Compounds containing variable amounts of water may be produced by processes such as lyophihsation.
  • the compounds according to the invention are suitably provided m substantially pure form, for example at least 50% pure, suitable at least 60% pure, advantageously at least 75% pure, preferably at least 85% pure, more preferably at least 95% pure, especially at least 98% pure, all percentages being calculated as weight/weight.
  • An impure or less pure form of a compound according to the invention may, for example, be used in the preparation of a more pure form of the same compound or of a related compound (for example a corresponding de ⁇ vative) suitable for pharmaceutical use.
  • the present invention also includes pharmaceutically acceptable salts and de ⁇ vatives of the compounds of the invention.
  • Salt formation may be possible when one of the substituents car ⁇ es an acidic or basic group.
  • Salts may be prepared by salt exchange in conventional manner.
  • Acid-addition salts may be pharmaceutically acceptable or non-pharmaceutically acceptable In the latter case, such salts may be useful for isolation and purification of the compound of the invention, or intermediates thereto, and will subsequently be converted into a pharmaceutically acceptable salt or the free base
  • the compounds of the present invention and their pharmaceutically acceptable salts or de ⁇ vatives have antimicrobial properties and are therefore of use in therapy, m particular for treating microbial infections in animals, especially mammals, including humans, in particular humans and domesticated animals (including farm animals)
  • the compounds may be used for the treatment of infections caused by, for example, Gram-positive and Gram-negative bacteria and mycoplasmas, including, for example, Staphylococcus aureus.
  • Staphylococcus epidermidis Enter ococcus faecalis, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus pneumoniae, Haemoph ⁇ us sp , Neissena sp , Legwnella sp , Chlamydia sp , Moraxella catarrhahs, Mycoplasma pneumoniae, and Mycoplasma gallisepticum
  • the present invention also provides a method of treating microbial infections in animals, especially in humans and m domesticated mammals, which comprises administering a compound of the invention or a pharmaceutically acceptable salt or de ⁇ vative or solvate thereof, or a composition according to the invention, to a patient in need thereof
  • the invention further provides the use of a compound of the invention or a pharmaceutically acceptable salt or de ⁇ vative or solvate thereof in the preparation of a medicament for use in the treatment of microbial infections
  • Compounds of the present invention may be used to treat sk and soft tissue infections and acne, by topical application Accordingly, m a further aspect the present invention provides the use of a compound of the invention or a pharmaceutically acceptable salt or de ⁇ vative or solvate thereof in the preparation of a medicament adapted for topical administration for use in the treatment of skm and soft tissue infections and also in the treatment of acne in humans.
  • the present invention provides for the use of a compound of the invention or a pharmaceutically acceptable salt or derivative or solvate thereof in the manufacture of a medicament adapted for administration to the nasal cavity, for reducing or eliminating the nasal carnage of pathogenic organisms
  • the medicament is adapted for focussed delivery to the nasopharynx, m particular the anterior nasopharynx
  • the present invention provides for the use of a compound of the invention or a pharmaceutically acceptable salt or denvative or solvate thereof in the manufacture of a medicament adapted for administration to the nasal cavity, for prophylaxis of recurrent acute bacterial sinusitis or recurrent otitis media
  • the present invention provides for the use of a compound of the invention or a pharmaceutically acceptable salt or denvative or solvate thereof in the manufacture of a medicament, for treating of chronic sinusitis
  • the compounds according to the invention may suitably be administered to the patient at a daily dosage of from 1.0 to 50 mg/kg of body weight.
  • a daily dosage of from 1.0 to 50 mg/kg of body weight For an adult human (of approximately 70 kg body weight), from 50 to 3000 mg, for example about 1500 mg, of a compound according to the invention may be administered daily
  • the dosage for adult humans is from 5 to 20 mg/kg per day Higher or lower dosages may, however, be used m accordance with normal clinical practice.
  • drug substance is administered on a daily basis, for a small number of days, for instance from 2 to 10, suitably 3 to 8, more suitably about 5 days, the administration then being repeated after an interval, for instance, on a monthly basis over a period of months, for instance up to six months.
  • the drug substance may be administered on a continuing, daily basis, over a prolonged period, for instance several months.
  • drug substance is administered once or twice a day
  • drug substance is administered du ⁇ ng the winter months when bacterial infections such as recurrent otitis media and recurrent sinusitis tend to be more prevalent.
  • the drug substance may be administered at a dosage of from 0.05 to l.OOmg, typically about 0.1 to 0.2mg, in each nostril, once or twice a day.
  • compositions according to the invention may be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other antibiotics.
  • the present invention provides a pharmaceutical composition compnsmg a compound of the invention or a pharmaceutically acceptable salt or de ⁇ vative or solvate thereof together with a pharmaceutically acceptable earner or excipient.
  • compositions according to the invention may be formulated for administration by any route, for example oral, topical or parenteral.
  • the compositions may, for example, be made up in the form of tablets, capsules, powders, granules, lozenges, creams, syrups, sprays or liquid preparations, for example solutions or suspensions, which may be formulated for oral use or in sterile form for parenteral administration by injection or infusion.
  • Tablets and capsules for oral administration may be in unit dosage form, and may contain conventional excipients including, for example, binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, or polyvmylpyrrohdone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tablettmg lub ⁇ cants, for example magnesium stearate, talc, polyethylene glycol or silica; dismtegrants, for example potato starch; and pharmaceutically acceptable wetting agents, for example sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or another suitable vehicle before use.
  • Such liquid preparations may contain conventional additives, including, for example, suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters (for example glycerine), propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl /- -hydroxybenzoate or sorbic acid; and, if desired, conventional flavouring and colour agents.
  • suspending agents for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats
  • emulsifying agents for example lecithin, sorbitan monoo
  • compositions according to the invention intended for topical administration may, for example, be in the form of ointments, creams, lotions, eye ointments, eye drops, ear drops, nose drops, nasal sprays, impregnated dressings, and aerosols, and may contain appropriate conventional additives, including, for example, preservatives, solvents to assist drug penetration, and emollients in ointments and creams.
  • Such topical formulations may also contain compatible conventional carriers, for example cream or ointment bases, ethanol or oleyl alcohol for lotions and aqueous bases for sprays.
  • Such carriers may constitute from about 1% to about 98% by weight of the formulation; more usually they will constitute up to about 80% by weight of the formulation.
  • compositions according to the invention intended for topical administration may also contain a steroidal anti-inflammatory agent; for example, betamethasone.
  • a steroidal anti-inflammatory agent for example, betamethasone.
  • compositions according to the invention may be formulated as suppositories, which may contain conventional suppository bases, for example cocoa-butter or other glycerides.
  • compositions according to the invention intended for parenteral administration may conveniently be in fluid unit dosage forms, which may be prepared utilizing the compound and a sterile vehicle, water being preferred.
  • the compound depending on the vehicle and concentration used, may be either suspended or dissolved in the vehicle.
  • the compound may be dissolved in water for injection and filter-sterilised before being filled into a suitable vial or ampoule, which is then sealed.
  • conventional additives including, for example, local anaesthetics, preservatives, and buffering agents can be dissolved in the vehicle.
  • the composition may be frozen after being filled into the vial, and the water removed under vacuum; the resulting dry lyophilised powder may then be sealed in the vial and a accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use.
  • Parenteral suspensions may be prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration.
  • the compound may instead be sterilised by exposure to ethylene oxide before being suspended in the sterile vehicle.
  • a surfactant or wetting agent is included in such suspensions in order to facilitate uniform distribution of the compound.
  • a compound or composition according to the invention is suitably administered to the patient in an antimicrobially effective amount.
  • a composition according to the invention may suitably contain from 0.001% by weight, preferably (for other than spray compositions) from 10 to 60% by weight, of a compound according to the invention (based on the total weight of the composition), depending on the method of administration.
  • each unit dose may suitably comprise from 25 to 1000 mg, preferable from 50 to 500 mg, of a compound according to the invention.
  • compositions of the present invention include those adapted for intranasal administration, in particular, those that will reach into the nasopharynx. Such compositions are preferably adapted for focussed delivery to, and residence within, the nasopharynx.
  • the term 'focussed delivery' is used to mean that the composition is delivered to the nasopharynx, rather than remaining within the nares.
  • the term 'residence' within the nasopharynx is used to mean that the composition, once delivered to the nasopharynx, remains within the nasopharynx over a course of several hours, rather than being washed away more or less immediately.
  • Preferred compositions include spray compositions and creams.
  • Representative spray compositions include aqueous compositions, as well as oily compositions that contain amphiphilic agents so that the composition increases in viscosity when in contact with moisture. Creams may also be used, especially creams having a rheology that allows the cream to spread readily in the nasopharynx.
  • Preferred aqueous spray compositions include, in addition to water, further excipients including a tonicity modifier such as a salt, for instance sodium chloride; preservative, such as benzalkomum salt, a surfactant such as a non-ionic surfactant, for instance a polysorbate; and buffer, such as sodium dihydrogen phosphate; present m low levels, typically less than 1%.
  • a tonicity modifier such as a salt, for instance sodium chloride
  • preservative such as benzalkomum salt
  • a surfactant such as a non-ionic surfactant, for instance a polysorbate
  • buffer such as sodium dihydrogen phosphate
  • Representative oily spray and cream compositions are descnbed m WO 98/14189 (SmithKline Beecham).
  • Representative aqueous sprays are described m International Application no PCT/GB98/03211 (SmithKline Beecham).
  • the drug substance is present in compositions for nasal delivery in between 0.001 and 5%, preferably 0.005 and 3%, by weight of the composition. Suitable amounts include 0.5% and 1% by weight of the composition (for oily compositions and creams) and from 0.01 to 0.2% (aqueous compositions).
  • Spray compositions according to the present invention may be delivered to the nasal cavity by spray devices well known m the art for nasal sprays, for instance an air lift pump.
  • Preferred devices include those that are metered to provide a unit volume of composition, preferably about lOO ⁇ l, and optionally adapted for nasal administration by addition of a modified nozzle
  • Step 2 (32?) 3-Deoxo-ll-deoxy-19,20-dihydro-3-methoxy-ll-oxo-4-ep/-mutilin-14- acrylate -
  • the product from Step 1 (9.75g, 0.029 mole) in dry dichloromethane (100 ml) was cooled to 0°C under argon.
  • Step 3 (3- )-3-Deoxo-ll-deoxy-19,20-dihydro-3-methoxy-ll-oxo-4-ep -mutilin-14- [(5-R5)-3-phenyl-4,5-dihydroisoxazole-5-carboxylate -
  • the product of Step 2 (200 mg, 0.51 mmol) was dissolved in dioxane (5 ml) and dichloromethane (5 ml).
  • Step 4 19,20-DihydromutiIin-14-[(5-R,-S)-(3-phenyI-4,5-dihydroisoxazole-5-carboxylate] -
  • Step 3 The product of Step 3 (27 mg, 0.05 mmol) was dissolved in dioxane (1 ml) and treated with a saturated solution of zinc chloride in cone. HC1 (1 ml). The reaction mixture was stirred at room temperature for 1.5 hours and then diluted with ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate. The organic phase was washed with brine, dried (MgSO4) and concentrated in vacuo.
  • Example 2 19,20-Dihydromutilin-14-[(5_R,-S -3-(4-methoxyphenyl)-4,5-dihydroisoxazoIe- 5-carboxylate] Step 1. 19,20-Dihydromutilin-14-acrylate -
  • the product of Example 1, Step 2 (313 mg, 0.80 mmol) was dissolved in dioxane (4 ml) and treated with concentrated hydrochloric acid (3 ml). The reaction mixture was stirred at room temperature for 4 hours and then diluted with ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate. The organic phase was washed with brine, dried (MgSO4) and concentrated in vacuo.
  • Step 2 19,20-Dihydromutilin-14-[(5_R,-y)-3-(4-metl ⁇ oxypl ⁇ enyI)-4,5-dihydroisox--zole-5- carboxylate] -
  • the product of Step 1 (90 mg, 0.24 mmol) was dissolved in dioxane (4 ml) and dichloromethane (4 ml).
  • the mixture was diluted with dichloromethane, washed with saturated aqueous sodium hydrogen carbonate solution, dried (MgSO4) and concentrated in vacuo.
  • the product was purified by chromatography on silica gel eluting with 5% ethyl acetate in dichloromethane.
  • Step 2 (3_R)-3-Deoxo-l l-deoxy-19,20-dihydro-3-methoxy-l l-oxo-4-e »-mutilin-14- [(5_R-S)-3 ⁇ (l---za-bicyclo [2.2.2] oct-4-yl)-4,5-dihydroisoxazole-5-carboxylate] -
  • a suspension of the product of Step 1 (190mg, lmmol) m N-N-dimethylformamide (10ml) was stirred at room temperature under an atmosphere of argon.
  • N-Bromosuccmimide (196mg, 1. lmmol) was added portion-wise and the mixture was stirred at room temperature for 90 minutes.
  • Step 3 19,20-Dihydromutilin-14-[(5 J R,-S)-3-(l-aza-bicycIo[2.2.2]oct-4-yl)-4,5- dihydroisoxazole-5-carboxylate] -
  • a solution of the product of Step 2 (250mg, 0.46mmol) in dioxane (3ml) and concentrated hydrochlo ⁇ c acid (3ml) was stirred at room temperature under an atmosphere of argon for 4 hours. The solution was diluted with ethyl acetate and water. The aqueous layer was separated and solid potassium carbonate was added to adjust the pH of the solution to pH 10.
  • Example 4 and 5 19,20-Dihydromutilin-14-[(5_R)-3-(l-aza-bicyclo[2.2.2]oct-4-yl)-4,5- dihydroisoxazole-5-carboxylate] and 19,20-dihydromutilin-14-[(5S)-3-(l-aza- bicyclo [2.2.2] oct-4-yl)-4,5-dihydroisoxazole-5-carboxylate].
  • Example 3 The product from Example 3 (50mg) was purified by HPLC using a Hypersil BDS Hypercarb column (100 x 3 mm, 7mm), eluting with acetonitrile : ethanol : 37% aqueous ammonia (800:200: 1) at a flow rate of 10 ml /minute. Other parameters were as follows: detection wavelength, 210 nm; injection volume; 0.1ml. The material was purified in several chromatography runs and gave samples of the title compounds (5mg and 7.5mg respectively); MS (electrospray) m/z 529 (MH + ). The later compound was found to contain 10% of former.
  • Example 6 Mutilin-14-[(5-R,-S)-3-(l-aza-bicyclo[2.2.2]oct-4-yl)-4,5-dihydroisoxazole-5- carboxylate].
  • Step 1 Mutilin 11-trifluoroacetate - Mutilin (960 mg) in dry tetrahydrofuran (12 ml) was treated with pyridine (0.3 ml) and the solution was cooled to 0°C. Trifluoroacetic anhydride (0.48 ml) was added dropwise over 3 minutes to the stirred solution. The solution was kept at
  • Step 3 Mutilin-14-[(5-R,-S)-3-(l-aza-bicyclo[2.2.2]oct-4-yl)-4,5-dihydroisoxazole-5- carboxylate]-l 1-trifluoroacetate -
  • the product of Example 3, Step 1 (950mg, 4.2 mmol) was suspended in N,N-dimethylformamide (70 ml) and cooled to 0 °C under an argon atmosphere. N-bromosuccinimide (826 mg, 4.6 mmol) was then added portionwise over 20 minutes. The yellow suspension was allowed to warm to room temperature and then stirred for a further 90 minutes.
  • Step 2 The reaction was then cooled to -10°C and mutilin- 14-acrylate-l 1-trifluoroacetate (1.98 g, 4.2 mmol) (Step 2) was added followed by the dropwise addition of triethylamine (1.17 ml, 8.4 mmol) over a 20 minute period.
  • the reaction was stirred for 1 hour at -10 °C and for a further 2 hours at room temperature after which the solvent was removed in vacuo.
  • the residue was partitioned between saturated potassium carbonate and chloroform.
  • the aqueous layer was then extracted with a further 2 portions of chloroform and the combined organic fraction dried (sodium sulphate), filtered and evaporated in vacuo.
  • Step 4 Mutilin-14-[(5 ⁇ ,5)-3-(l-aza-bicyclo [2.2.2]oct-4-yl)-4,5-dihydroisoxazole-5- carboxylate] -
  • a solution of the product from Step 1 in tefrahydrofuran/water (5:1) was treated with 0.5M aqueous sodium hydroxide (5.78 ml) and allowed to stand for 1 hour. The mixture was then partitioned between chloroform and saturated aqueous potassium carbonate. The aqueous layer was separated and further extracted with 2 portions of chloroform. The combined organic fraction was dried (sodium sulphate), filtered and concentrated.
  • Step 1 l-Methyl-piperidin-4-carbaldehyde oxime - 1 -Methyl piperidin-4-carbaldehyde ⁇ K. Prokai-Tatrai, J. Organomet. Chem., 1986, 315, 231 ⁇ (880mg, 7mmol) was dissolved in methanol (20 ml) and stirred with hydroxylamine hydrochloride (480mg) for 16 hours. The solvent was removed and the residue partitioned between saturated aqueous potassium carbonate and chloroform. The aqueous layer was separated and extracted with a further 2 portions of chloroform.
  • Step 2 Mutilin-14-[(5R,_S)-3-(l-methyl-piperidin-4-yl)-4,5-dihydroisoxazole-5- carboxylate] -
  • the product from Step 1 (623mg, 4.42 mmol) was treated with 1 M hydrogen chloride in diethyl ether and then evaporated to dryness.
  • the product was then dissolved in dimethylformamide (60 ml), and treated successively with N-bromosuccinimide (865 mg, 4.86 mmol), mutilin- 14-acrylate-l 1-trifluoroacetate (2.28 g, 4.86 mmole) and triethylamine (1.23 ml, 8.84 mmol) according to the procedure in Example 6, Step 3.
  • Example 10 Mutilin-14-[(5R,_S)-3-(ex ⁇ .-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-4,5- dihydroisoxazole-5-carboxylate] .
  • Step 3 The product from Step 1 (1.44 g, 0.00306 mole) was treated successively with 1M hydrochlo ⁇ c acid in diethyl ether, N- bromosuccmimide, mutilm- 14-acrylate- 11 -t ⁇ fluoroacetate and triethylamine according to the procedure in Example 6, Step 3.
  • the product was purified by silica gel chromatography eluting with chloroform : methanol : 35% aqueous ammonia (93.4 : 6 : 0.6) to give the title compound (1.18 g, 60%) as a foam; MS (+ve ion electrospray) m/z 637 [M+H] + .

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Abstract

cette invention concerne des dérivés de pleuromutiline représentés par les formules (IA) et (IB). Ces dérivés ont une activité antimicrobienne efficace et conviennent pour une thérapie de lutte contre l'infection.
PCT/EP2000/004232 1999-06-01 2000-05-09 Derives isoxazoline carboxylate de mutiline et leur utilisation comme antibacteriens WO2000073287A1 (fr)

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AU49199/00A AU4919900A (en) 1999-06-01 2000-05-09 Isoxazoline carboxylate derivatives of mutiline and their use as antibacterials

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002012199A1 (fr) * 2000-08-03 2002-02-14 Smithkline Beecham P.L.C. Esters de mutiline heterocycliques et leur utilisation en tant qu'agents antibacteriens
WO2008143343A1 (fr) 2007-05-24 2008-11-27 Kyorin Pharmaceutical Co., Ltd. Dérivé de la mutiline ayant une structure d'acide carboxylique à noyau aromatique hétérocyclique en substituant à la position 14
US7556948B2 (en) 2002-08-09 2009-07-07 Glaxo Group Limited Method for producing crystallized pleuromutilins

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2157828A1 (fr) * 1971-10-05 1973-06-08 Sandoz Sa
EP0013768A1 (fr) * 1979-01-12 1980-08-06 Sandoz Ag Pleuromutilines, leur préparation et des compositions pharmaceutiques les contenant
WO1997025309A1 (fr) * 1996-01-03 1997-07-17 Smithkline Beecham Plc Derives carbamoyloxy de mutiline et leur utilisation en tant qu'agents antibacteriens
WO1999021855A1 (fr) * 1997-10-29 1999-05-06 Smithkline Beecham P.L.C. Derives de pleuromutiline utilises comme agents antimicrobiens

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2157828A1 (fr) * 1971-10-05 1973-06-08 Sandoz Sa
EP0013768A1 (fr) * 1979-01-12 1980-08-06 Sandoz Ag Pleuromutilines, leur préparation et des compositions pharmaceutiques les contenant
WO1997025309A1 (fr) * 1996-01-03 1997-07-17 Smithkline Beecham Plc Derives carbamoyloxy de mutiline et leur utilisation en tant qu'agents antibacteriens
WO1999021855A1 (fr) * 1997-10-29 1999-05-06 Smithkline Beecham P.L.C. Derives de pleuromutiline utilises comme agents antimicrobiens

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
EGGER H ET AL: "NEW PLEUROMUTILIN DERIVATIVES WITH ENHANCED ANTIMICROBIAL ACTIVITY.II. STRUCTURE-ACTIVITY CORRELATIONS", JOURNAL OF ANTIBIOTICS,JP,JAPAN ANTIBIOTICS RESEARCH ASSOCIATION. TOKYO, vol. 29, no. 9, 1 September 1976 (1976-09-01), pages 923 - 927, XP002028938, ISSN: 0021-8820 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002012199A1 (fr) * 2000-08-03 2002-02-14 Smithkline Beecham P.L.C. Esters de mutiline heterocycliques et leur utilisation en tant qu'agents antibacteriens
JP2004505953A (ja) * 2000-08-03 2004-02-26 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 ヘテロ環ムチリンエステル及び抗細菌剤としてのその使用
US6878704B2 (en) 2000-08-03 2005-04-12 Smithkline Beecham P.L.C. Heterocyclic mutilin esters and their use as antibacterials
US7556948B2 (en) 2002-08-09 2009-07-07 Glaxo Group Limited Method for producing crystallized pleuromutilins
WO2008143343A1 (fr) 2007-05-24 2008-11-27 Kyorin Pharmaceutical Co., Ltd. Dérivé de la mutiline ayant une structure d'acide carboxylique à noyau aromatique hétérocyclique en substituant à la position 14

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