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WO1993006118A1 - Composes antibacteriens et antimycoplasmiques apparentes a la mupirocine - Google Patents

Composes antibacteriens et antimycoplasmiques apparentes a la mupirocine Download PDF

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Publication number
WO1993006118A1
WO1993006118A1 PCT/GB1992/001760 GB9201760W WO9306118A1 WO 1993006118 A1 WO1993006118 A1 WO 1993006118A1 GB 9201760 W GB9201760 W GB 9201760W WO 9306118 A1 WO9306118 A1 WO 9306118A1
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Prior art keywords
epoxy
hydroxy
tetrahydropyran
methylhexyl
title compound
Prior art date
Application number
PCT/GB1992/001760
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English (en)
Inventor
Nigel John Perryman Broom
Peter John O'hanlon
John Stephen Elder
Original Assignee
Smithkline Beecham 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 GB919120491A external-priority patent/GB9120491D0/en
Priority claimed from GB929201507A external-priority patent/GB9201507D0/en
Priority claimed from GB929219053A external-priority patent/GB9219053D0/en
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to JP5505935A priority Critical patent/JPH06510781A/ja
Priority to EP92919853A priority patent/EP0605524A1/fr
Publication of WO1993006118A1 publication Critical patent/WO1993006118A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • 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
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/01—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing oxygen

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 (IA), (IB) or (IC):
  • R° denotes a substituted or unsubstituted hydrocarbyl or heterocyclyl group. More specifically R° denotes the term (A) n - (B) m ; wherein n and m are integers having a value of 0 or 1; A is a (C 1 -6 ) alkyl, (C 2-6 ) alkenyl, or (C 2-6 ) alkynyl group; B is a (C 3-7 ) cycloalkyl, (C 4-7 ) cycloalkenyl, aryl, heterocyclyl or heteroaryl group. Both A and B may be optionally substituted as herein below defined.
  • B is a substituted or unsubstituted (C 4-7 ) cycloalkenyl, aryl, heterocyclyl or heteroaryl group.
  • B is preferably an aryl or heteroaryl moiety. More specifically, B is a cyclohexenyl, phenyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyrazolyl, oxazolyl, or thiazolyl group.
  • A is a (C 1-6 )alkyl moiety.
  • A is preferably a substituted or unsubstituted butyl group.
  • A is a (C 2-6 )alkenyl, (C 2-6 )alkynyl group.
  • B is a substituted or unsubstituted aryl or heteroaryl group, such as a furanyl or phenyl. More preferably A is an ethenyl or acetylenyl (ethynyl) group.
  • B is a substituted or un-substituted aryl or heteroaryl group.
  • (un)substituted refers to both the substituted and unsubstituted derviative.
  • B is a (un)substituted phenyl, (un)substituted pyrimidinyl, (un)substituted thiazolyl, (un)substituted oxazolyl, or (un)substituted pyridyl. More preferably B is an
  • a or B may be optionally substituted
  • Suitable X groups for A, when n is 1, include, cyano, amino,
  • substituents (X 1 ), for B when m is 1, include, for example, (C 1-6 )alkyl, (po-y)halo(C 1-6 )alkyl, cyano, (un)substituted heterocyclyl, amino, (C 1-6 )alkanoylamino, mono- or di-(C 1-6 )alkylamino, substituted mono- or di-(C 1-6 )alkylamino, [also referred to as -NR 2 R 3 ], hydroxy, (C 1-6 )alkoxy, substituted (C 1-6 )alkoxy [also referred to as -O-R 1 ], (C 1-6 )alkenoxy, hydroxy substituted (C 1-6 )alkoxy, (un)substituted heterocyclylthio, arylthio, arylsulphinyl, arylsulphonyl, (C 1-6 )alkylthio,
  • R 1 group may be a (C 2-6 ) alkenyl, (C 1-6 ) alkoxy alkyl, (poly)hydroxy
  • (C 1-6 ) alkyl (poly)halo(C 1-6 ) alkyl, substituted or unsubstituted heteroaryl (C 1-6 ) alkyl, substituted mono- or di- amino (C 1-6 ) alkyl, substituted or unsubstituted heterocyclyl (C 1-6 ) alkyl, or N-(C 1-6 alkyl)- N- heteroaryl-(C 1-6 )alkyl.
  • (poly) refers to the optional substitution of more than one, such as (poly)haloalkyl would allow for more than one halogen, independently on the alkyl moiety, i.e., -CF 3 .
  • the R 1 group is a C 2-3 alkenyl, hydroxy C 1-6 alkyl,
  • the heteroaryl is a pyridyl, or furanyl moiety.
  • the heterocyclyl is a piperidine group.
  • R 1 is ethenyl, 2-ethanol, 3-propanol, -CH 2 -O-CH 3 ,
  • R 2 and R 3 moieties are independently a (C 1-6 ) alkyl group or one of R 2 or R 3 may be a hydroxy (C 1-6 ) alkyl group.
  • R 2 and R 3 are (C 1-6 ) alkyl, more preferably methyl; or one of R 2 R 3 is methyl and the other 2-ethanol.
  • the X 1 substitutents are selected from hydroxy, substituted and unsubstituted (C 1-6 )alkoxy, (C 1-6 )alkyl, oxy(C 1-6 )alkyl, cyano, chloro, fluoro, bromo, nitro, hydroxy(C 1-6 )alkyl, (C 1-6 )alkylthio,
  • X 1 is methoxy, C(O)CH 3 , methyl, cyano, chloro, fluoro, bromo, -CH(OCH 2 CH 3 )2, nitro, -CH(O), N(CH 3 ) 2 , SCH 3 , S(O)CH 3 , S(O) 2 CH 3 , -CH 2 OH, piperidine, O-CF 3 , hydroxy, ethenyloxy, 2- hydroxyethoxy, N-(2-hydroxyethyl)-N-methylamino, 3-hydroxypropyloxy, azidoethoxy, N-methyl-N-pyridylaminoethoxy, piperidinylethoxy, pyridylmethyloxy, nitrofuranyl methyloxy, or furanylmethyloxy.
  • the optional substituents for said groups are independently substituted up to five times, preferably up to three times, from the same group listed herein under the X 1 term.
  • (unsubstituted carbamoyl would allow the nitrogen atom to be mono- or di-substituted with a (C 1-6 )alkyl moiety;
  • the (un)substitued heterocyclic would allow, for example, a piperidine ring to be substituted by a (C 1-6 )alkyl, or hydroxy moiety;
  • an (un)substituted heteroaryl would allow for a furanyl ring to be substituted by a nitro group.
  • Preferred substituent groups (X 1 ) when B is an aryl group include, for example, halogen, cyano, (C 1-6 )alkyl, hydroxy(C 1-6 )-alkyl, oxo(C 1-6 )alkyl, gem di(C 1-6 )alkoxy(C 1-6 )alkyl, (C 1-6 )alkoxy, (C2-g)alkenoxy,
  • (C 1-6 )-alkylsulphonyl sulphamoyl, mono- or di-(C 1-6 )alkylsulphamoyI, carbamoyl, mono- or di-(C 1-6 )alkylcarbamoyl and heterocyclyl.
  • Preferred substituents (X 1 ) when B is a heteroaryl group include, for example, halogen, (C 1-6 )alkyl, (C 1-6 )cycloalkyl, (C 1-6 )alkoxy,
  • Preferred substituent (X 1 ) when B is a heterocyclyl group include, for example, halogen, (C 1-6 )alkyl, hydroxy(C 1-6 )alkyl, (C 1-6 )alkoxy, hydroxy(C 1-6 )alkoxy, halo(C 1-6 )alkyl, hydroxy, amino, mono- or
  • a substituent group preferably in the (B) m term, has an acidic hydrogen arising from the presence in a heteroaryl ring of an NH moiety, for instance, when R° is pyrazolyl, the hydrogen may be replaced by a (X or X 1 ) substituent as hereinbefore defined.
  • the substitutent is a (C 1-6 ) alkyl group.
  • alkyl group or moiety referred to herein may be a straight or branched hydrocarbon chain, and may contain, for example, up to 12 carbon atoms, suitably up to 6 carbon atoms.
  • the alkyl chain may be unsubstituted or substituted.
  • the alkyl group or moiety may be an unsubstituted or substituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, isobutyl or tert-butyl group.
  • suitable optional substituents for any such alkyl group or moiety include the above-listed substituents for the (A) n term.
  • the term 'aryl' includes, unless otherwise defined, phenyl or naphthyl.
  • the term 'heterocyclyl' and 'heterocyclic' includes non-aromatic single or fused rings comprising up to four heteroatoms in each ring selected from oxygen, nitrogen and sulphur.
  • the heterocyclic ring comprises from 4 to 7, preferably from 5 to 6 ring atoms.
  • a fused heterocyclic ring system may include aromatic carbocyclic and heteroaryl rings.
  • the heterocyclic group is piperidinyl.
  • heteroaryl' includes aromatic hetrocyclic containing rings and ring systems as is commonly defined in the art, such as by Katritzky et al., Handbook of Heterocyclic Chemistry, Pergamon Press, Oxford, England (1985).
  • a heteroaromatic structure is based on the 6 ⁇ -electron system. These structure are related to and formally derived from benzene by successive replacement of one or two annular CH groups by trivalent or divalent heteroatom groups respectively. The overall patttern of filled bonding molecular orbitals is retained.
  • heteroaryl ring has 5 to 6 ring atoms in each ring.
  • Prefered heteroaryl groups herein include, pyridyl, pyrim idinyl, furanyl, thienyl, thiazolyl, isoxazolyl, oxazolyl and pyrazolyl.
  • hydrocarbyl may include groups having up to 18 carbon atoms, suitably up to 10 carbon atoms, conveniently up to 6 carbon atoms. Suitable groups include those listed under the (A) n term and the (B) m term groups which do not contain a heteroatom, i.e.
  • cycloalkyl cycloalkenyl and aryl.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • the halogen is fluoro, chloro or bromo.
  • mupirocin i.e. [2S, 3R, 4R, 5S] about the tetrahydropyran ring and [2S, 3S, 4S, 5S] in the 5-(2,3-epoxy-5-hydroxy-4-methylhexyl) sidechain ofthe tetrahydropyran ring.
  • the compounds of the present invention may exist in the forms shown in formulae (IA), (IB) or (IC), the three forms being in equilibrium.
  • 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 ofthe compounds of formula (I) may be used for preparing the more pure forms used in the
  • 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 the scope of this invention include the following:
  • Compounds of the present invention may be prepared by methods known for the preparation of ⁇ -diketones. Some of these processes will be more appropriate than others.
  • compounds of formula (I) may be prepared by a process which
  • Z 1 , Z 2 and Z 3 are the same or different and each is hydrogen or a hydroxyl-protecting group, and R° is as hereinbefore defined; with an oxidising agent which converts a ⁇ -hydroxyketone into a
  • oxidising agents include, for example, activated manganese
  • the oxidation reaction is effected in a organic solvent such as, for example, dioxan, acetonitrile, tetrahydrofuran, ether, carbon
  • a compound of formula (III) may be obtained by treating a ketone compound of formula (V):
  • Z 1 , Z 2 and Z 3 are as hereinbefore defined, with a suitable enolising agent such as, for example, lithium diisopropylamide.
  • the compound of formula (III) may be generated in situ, prior to the treatment thereof with a compound of formula (IV).
  • the present invention provides a second process for preparing a compound of formula (I) as hereinbefore defined, which process comprises treating a compound of formula (VI):
  • Suitable reagents for effecting such a conversion include ozone and osmium tetroxide, each of which forms an intermediate which may then be converted to the compound of formula (I).
  • Alternative reagents useful in the conversion herein may be found in Harrison et al, Compendium of Organic Synthetic Methods, Wiley-Interscience (1971).
  • Ozonolysis may be effected under conditions conventionally used for such a reaction.
  • the reaction may be effected at a low temperature, for instance about -70°, in the presence of a suitable solvent such as dichloromethane.
  • the intermediate ozonide thus formed may be conveniently decomposed by an agent conventionally used for such a task, of which triphenyl phosphine is especially preferred.
  • the compound of formula (VI) may be treated with osmium tetroxide, according to the procedure described by V. Van Rheenen, R.C. Kelly and D.Y. Cha, Tetrahedron Lett, 1976, 1973.
  • osmium tetroxide a catalytic quantity of osmium tetroxide is employed, in the presence of a
  • tertiaryamine oxide catalyst such N-methylmorpholine N-oxide
  • a solvent such as aqueous tetrahydrofuran
  • an oxidising agent such as sodium periodate
  • a further aspect of the invention also provides a compound of formula (VI) as hereinbefore defined.
  • compounds of formula (VI) may be prepared by a process which comprises treating the acid of formula (VII) or an activated derivative thereof:
  • Suitable organometallic reagents include:
  • an organocerium reagent R°Li-CeX 3 in which R° is as defined with respect to formula (I) and X represents chlorine, bromine or iodine.
  • reaction with the organometallic reagent may be conveniently carried out in an ethereal or hydrocarbon solvent, the choice of which is
  • 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 ofthe 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 ofthe acid of formula (VII) include
  • 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 (Vllla):
  • Z 1 , Z 2 , and Z 3 are as hereinbefore defined, and R 2 and R 3 are the same or different and each denotes an aryl group, for instance phenyl, or a (C 1-6 )alkoxy group, for instance ethoxy.
  • R 4 and R 5 are the same or different, and each is (C 1 -6 )alkyl, preferably methyl, or the substituents R 4 and R 5 form a (C 2-7 )alkylene chain and; amides of the formula (XII):
  • Z 1 , Z 2 , and Z 3 are as hereinbefore defined and R 6 and R 7 , together with the nitrogen atom to which they are bonded, form an imidazolyl or triazolyl ring.
  • organomanganous reagent of formula R°MnCl, as hereinbefore defined.
  • organolithium reagent of formula R°Li as hereinbefore defined:
  • Suitable organometallic reagents may be prepared according to
  • Suitable organomanganous reagents of the formula R°MnCl may be conveniently prepared by addition of an organolithium reagent R°Li 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°MnCl is preferably employed. Alternatively, a Grignard reagent may be used in place ofthe organolithium reagent, to generate the
  • organomanganous reagent R°MnCl organomanganous reagent
  • organomanganous reagents which may be used instead of R°MnCl include:
  • Organocerium reagents may be generated in situ by treatment of an organolithium compound ofthe formula R°Li, in which R° is as
  • cerium (III) halide by analogy with the procedure described by Imamoto el al; J.Chem. Soc. , Chem. Commun, 1982, 1042.
  • the activated derivatives of compounds of formula (VI) may be prepared from the compounds of formula (VI) by standard methodology.
  • Compounds of formula (VII) may be obtained by treating the protected methylester of monic acid with a base such as lithium diisopropylamide, as described by Crimmin et at, J. Chem. Soc. Perkin Trans 1. 1985, 549, followed by ester hydrolysis.
  • a base such as lithium diisopropylamide
  • a compound of formula (VI) may be prepared by treating a compound of formula (XI) in which R 4 and R 5 each is methyl with an organometallic reagent which is preferably an organolithium reagent of the formula R°Li.
  • Z 1 , Z 2 , Z 3 , R 4 and R 5 are as hereinbefore defined, with a strong non-nucleophilic base such as, for example, lithium diisopropylamide, followed by quenching with a mild proton source such as ammonium chloride.
  • a strong non-nucleophilic base such as, for example, lithium diisopropylamide
  • Compounds of formula (XIII) may be prepared from monic acid by initial conversion thereof to an activated derivative, for instance a mixed anhydride such as that formed with iso-butylchloroformate, followed by subsequent treatment with an amine HN(OR 4 )R 5 in which R 4 and R 5 are as hereinbefore defined, or a salt thereof; under standard conditions, for instance, with dichloromethane as the reaction solvent, at about 0°C for 2h; and thereafter and if required, introducing any hydroxyl-protecting groups that may be subsequently required.
  • an activated derivative for instance a mixed anhydride such as that formed with iso-butylchloroformate
  • the present invention provides a third process for preparing a compound of formula (I) which process comprises treating a compound of formula (XlV):
  • a further aspect ofthe invention provides a compound of formula (XEV) as hereinbefore defined.
  • Compounds of formula (XIV) may be prepared from the corresponding acids of formula (XVI):
  • Compounds of formula (XVI) may be prepared from compounds of formula (V), as hereinbefore defined, and in which the hydroxyl groups are protected, preferably as a silylether, by initial conversion thereof to the enol form followed by ozonoloysis and subsequent decomposition of the intermediate ozonide using, for instance, dimethyl sulphide.
  • Compounds of formula (I) may be obtained from other compounds of formula (I) by suitable manipulation ofthe substituents present in the group R° according to conventional methodology.
  • an alkylthio substituent may be converted to an alkyl sulphinyl or an alkylsulphonyl substitutent by treatment thereof with a conventional oxidising agent such as m-chloroperbenzoic acid.
  • the term 'hydroxyl-protecting group' refers to any such group known in the art which may be removed without disruption of the remainder ofthe 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 (II), (III), (V) to (XIV) and (XVI) 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, ofthe formulae below: LgSiO-C-NSiLj
  • a preferred silyating agent is trimethylsilyl chloride.
  • Particularly suitable protecting groups are trimethylsilyl, triethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl groups. Preferred protecting groups are trimethylsilyl groups because of their ease of removal.
  • the glycol function ofthe compounds of formulae (II), (III), (V) to (XIV) and (XVI) may be protected by forming a cyclic derivative using a compound of formula (XVII):
  • R 8 is hydrogen or (C 1-6 )alkyl and each of R 9 , R 10 and R 11 is (C 1-6 )alkyl.
  • Z 1 and Z 2 together are a moiety:
  • R 8 is as hereinbefore defined and R 12 is (C 1-6 )alkyl.
  • R 8 is hydrogen, methyl, ethyl, n- or iso-propyl; most suitably it is hydrogen.
  • the groups R 9 , R 10 and R 11 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
  • the compounds of this invention are useful in therapy, in particular 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 compounds of this invention are active against both Gram negative and Gram positive organisms, including Haemophilus. for instance
  • Streptococci for instance S,pyogrenes CN10 and S.pneumonia PU7; and Staphylococci. for instance S.aureus Oxford, Legrionella. for instance L. pneumophila: and against mycoplasma.
  • compounds of the present 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 macrolides; aminoglycosides; lincosamides; and ⁇ -lactams, such as, for example methicillin.
  • the compoimds of this invention are also active against
  • 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 (II).
  • 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, for instance, by topical, parenteral or oral administration 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, 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
  • preservatives for example methyl or propyl p-hydroxybenzoate or
  • 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 Longman, and the British Pharmacopoeia.
  • Suppositories will contain conventional suppository bases, e.g.
  • cocoa-butters or other glyceride 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 may 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
  • 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 ofthe drug.
  • compositions for intramammary treatment of mammary disorders in animals, especially bovine mastitis will generally contain a suspension ofthe drug in an oily vehicle.
  • the compositions may contain from 0.1% to 99% by weight, preferably from 10-60% by weight, ofthe drug.depending on the method of
  • each dosage unit will preferably contain from 50-500 mg ofthe drug.
  • the dosage as employed for adult human treatment 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 ofthe 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 adimxture 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 present invention further provides a method for treating the human or non-human animal which method comprises administering a compound of formula (I) as hereinbefore defined, to a human or non-human animal in need of such therapy.
  • compositions as hereinbefore described may be employed in the treatment.
  • the present invention also provides a compound of formula (I) as hereinbefore defined for use in therapy.
  • the present invention also provides a compound of formula (I) as hereinbefore defined for use in the manufacture of a medicament for anti-bacterial therapy or mycoplasma-induced infections.
  • a compound of formula (I) as hereinbefore defined for use in the manufacture of a medicament for anti-bacterial therapy or mycoplasma-induced infections.
  • N,O -dim ethyl hydroxylamine hydrochloride (1.95grams (hereinafter g.), 20milimoles (hereinafter mmoles)) was dissolved in
  • dichloromethane/aqueous sodium hydroxide (20milliters (hereinafter ml: 10ml, 2.5Molar (hereinafter M)).
  • ml 10ml, 2.5Molar (hereinafter M)
  • M 10ml, 2.5Molar
  • the aqueous layer was re- extracted with dichloromethane (10ml) and the combined organic layers washed with saturated brine (5ml).
  • the organic layer was dried (MgS04) and added to monic acid isobutyl carbonic anhydride (10mmol)*.
  • the reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium hydrogen chloride and brine.
  • the combined aqueous solutions were extracted with ethyl acetate, and the combined organic solutions dried (MgSO 4 ) and concentrated to give the amide, 3.0g.
  • furan-3-carboxaldehyde (0.28ml, 3.2mmol) was reacted to give the title compound (1.3g, 75%); ⁇ H (CDCI 3 ) inier alia 0.90 (3H, d, J 7.1Hz, 17-H 3 ), 1.20 (3H, d, J 6.3Hz, 14-H 3 ), 4.07-4.18 (1H, m, 5-H), 5.05-5.18 (1H, m, 1-H), 6.38-6.42 (1H, m, 4'-H), 7.35-7.44 (2H, m, 2',5'-H 2 ).
  • ⁇ H (CDCI 3 /CD 3 OD) inter alia 0.93 (3H, d, J 7.0Hz, 17-H 3 ), 1.21 (3H, d, J 6.3Hz, 14-H 3 ), 3.19 (6H, s, N(CH 3 ) 2 ), 6.13 (1H, s, 2- H), 6.53 (1H, d, J 9.1Hz, 3'-H), 7.94 (1H, dd, J 2.3 and 9.1Hz, 4'-H), and 8.71 (1H, d, J 2.3Hz, 6'-H); ⁇ C (CDCI 3 /CD 3 OD) 12.6 (C-17), 20.6 (C-14), 31.7 (C-9), 38.1 (N(CH 3 ) 2 ), 39.6 (C-8), 41.8 (C-4), 42.7 (C-12), 55.7 (C-10), 61.2 (C-11), 65.6 (C-16), 68.9 (C-6), 70.2 (C-7), 71.1 (C-13), 74.0 (C-5), 95.6 (C-2
  • 2-Chloropyridine-5-carboxylic acid (1.576g, 10mmol) was dissolved in dry THF (100ml), cooled in an ice-bath, then triethylamine (1.5ml, llmmol) added, followed by iso-butylchloroformate (1.3ml, 10mmol). The mixture was stirred for 3/4h, then N,O-dimethylhydroxylamine (ex hydrochloride salt, 15mmol) in dichloromethane (70ml) was added. After stirring for 13/4h, the mixture was diluted with dichloromethane, washed with water, aqueous sodium hydrogen carbonate, and brine, dried and
  • N-methoxy, N-methyl-2- bromopyridine-5-carboxamide (1.60g, 6.53mmol) was reacted to give the title compound (1.042g, 86%); m.p.103.5-104°C (chloroform/hexane); found C, 38.72; H, 2.09; N, 7.53; Br, 42.62%.
  • C 6 H4BrNO requires C, 38.74; H, 2.17; N, 7.53; Br.
  • Ethyl 2-mercaptoimidazole-4(5)-carboxylate (10.0g, 58mmol) was dissolved in dry DMF (200ml), and sodium hydride (80% in oil, 3.5g, 116mmol) added slowly with cooling. The mixture was stirred for 1h under argon, cooled in an ice bath, and methyl iodide (14.4ml, 232mmol) added. The reaction was then stirred overnight, diluted with water (200ml) and extracted with ethyl acetate (6 x 100ml). The combined organic extracts were washed with brine, dried and evaporated.
  • Ethyl 2-(3-triethylsilyloxyprop-1-oxy)pyridine-5-carboxylate (1.53g, 4.5mmol) was dissolved in dry THF (50ml) under argon, then diisobutylaluminium hydride (1.0M, 5ml, 5mmol) was added slowly. After stirring for 1 ⁇ 2 h, more diisobutylaluminium hydride (5ml) was added, and stirring continued for a further 1h. Methanol (11ml) and saturated sodium sulphate (14ml) were added, and the mixture stirred for l5minutes.
  • 2-Methoxythiazole (contained 25% 2-bromothiazole, 0.50g, 4.3mmol) was dissolved in THF (20ml), cooled to -70%, and treated dropwise with n- butyllithium (1.5M, 3.2ml, 4.8mmol). The mixture was stirred for 75 minutes, then N,N-dimethylformamide (1.16ml, l5mmol) added. Stirred for a further 11 ⁇ 2 h, then quenched with saturated ammonium chloride and ether. The phases were separated, the organic washed with water, dried and reduced to a small volume.
  • diethylazodicarboxylate (1.26ml, 8mmol). After 1 ⁇ 4 hour ice bath removed. After 1 hour reaction mixture evaporated, added ethyl acetate and 5N hydrochloric acid. Acid phase separated, covered with ethyl acetate and basified with saturated sodium hydrogen carbonate. Organic phase separated, dried and evaporated.
  • Furfurylalcohol (0.86ml, 10mmol) was added dropwise to a cold (5°C) mixture of sodium hydride (80%, 300mg, 10mmol) in DMF (40ml). After 1 hour p-fluoro-benzaldehyde (1.07ml, 10mmol) was added. After 3 hours reaction mixture poured into water and extracted with ethyl acetate.
  • MacFarland's barium sulphate opacity standard 0.5 The suspension is further diluted 1:100 in TCM to yield a final inoculum of 4.83 x 106 cfu/ml.
  • Human foetal lung fibroblast (MRC-5) cells are grown to 80% confluency in 6-well plates. The medium is removed and the monolayers washed twice with Dulbecco's PBS and the inoculum added.
  • Dosing Sixteen hours after infection (time Oh), the medium is removed and the inoculated monolayers washed twice to remove any adherent, non-intracellular, organisms. The compounds are prepared to the required concentrations (0.5, 2 and 8 ⁇ g/ml) in TCM, and added to the cells. Erythromycin at 0.5 and 2 ⁇ g/m is used as a control.
  • Stability tests The stability ofthe compounds in TCM is also examined over a 72h period. Solutions of 2 ⁇ g/ml of each ofthe compounds to prepared in TCM and incubated at 37°C or 4°C and aliquots are removed at intervals. The compounds of formula (I) are assayed against Bacillus subtilis ATCC 6633 and erythromycin lactobinate against Sarcina lutea NCTC 8340, using standards prepared in TCM.

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Abstract

L'invention se rapporte à une nouvelle catégorie de composés dérivés de la mupirocine, répondant à la formule (I) et présentant une modification du fragment C-1 à C-3. Les composés de β-dicétone de la formule (I) peuvent être utilisés comme agents antibactériens et antimycoplasmiques. Les composés de cette invention sont représentés par la formule (I) où R0 représente un groupe hétérocyclique ou hydrocarbyle.
PCT/GB1992/001760 1991-09-26 1992-09-24 Composes antibacteriens et antimycoplasmiques apparentes a la mupirocine WO1993006118A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP5505935A JPH06510781A (ja) 1991-09-26 1992-09-24 ムピロシン関連の抗菌性、抗マイコプラスマ性化合物
EP92919853A EP0605524A1 (fr) 1991-09-26 1992-09-24 Composes antibacteriens et antimycoplasmiques apparentes a la mupirocine

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
GB919120491A GB9120491D0 (en) 1991-09-26 1991-09-26 Novel compounds
GB9120491.7 1991-09-26
GB929201507A GB9201507D0 (en) 1992-01-24 1992-01-24 Novel compounds
GB9201507.2 1992-01-24
GB929219053A GB9219053D0 (en) 1992-09-09 1992-09-09 Novel compounds
GB9219053.7 1992-09-09

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WO1993006118A1 true WO1993006118A1 (fr) 1993-04-01

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AU (1) AU2594092A (fr)
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WO (1) WO1993006118A1 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2282536A (en) * 1993-10-06 1995-04-12 Zeneca Ltd Herbicidal compositions
US6291514B1 (en) 1998-02-09 2001-09-18 3-Dimensional Pharmaceuticals, Inc. Heteroaryl amidines, methylamidines and guanidines, preparation thereof, and use thereof as protease inhibitors
US6534037B1 (en) 1998-01-21 2003-03-18 Neorx Corporation Non-steroidal compounds for steroid receptors and uses relating thereto
US7045519B2 (en) 1998-06-19 2006-05-16 Chiron Corporation Inhibitors of glycogen synthase kinase 3
US7196089B2 (en) 2003-01-29 2007-03-27 Asterand Uk Limited EP4 receptor antagonists
US7417068B2 (en) 2003-10-16 2008-08-26 Asterand Uk Limited EP4 receptor antagonists
US7649098B2 (en) 2006-02-24 2010-01-19 Lexicon Pharmaceuticals, Inc. Imidazole-based compounds, compositions comprising them and methods of their use
US7825150B2 (en) 2007-09-06 2010-11-02 Lexicon Pharmaceuticals, Inc. Compositions and methods for treating immunological and inflammatory diseases and disorders
WO2017038650A1 (fr) * 2015-08-28 2017-03-09 積水メディカル株式会社 Composé benzyle

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0090603A2 (fr) * 1982-03-25 1983-10-05 Beecham Group Plc Composés bactériostatiques

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0090603A2 (fr) * 1982-03-25 1983-10-05 Beecham Group Plc Composés bactériostatiques

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF MEDICINAL CHEMISTRY, Vol. 32, No. 1, January 1989, Washington, US., KLEIN L.L. et al., "Synthesis and Activity of Nonhydrolyzable Pseudomonic Acid Analogs", pages 151-160. *
JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1, No. 1, January 1985, Letchworth, GB., CRIMMIN M.J. et al., "The Chemistry of Pseudomonic Acid. Part 8. Electrophilic Substitutions at C-2 and C-15 of the Pseudomonic Acid Nucleus by Means of Lithium Dienolates", pages 549-555. *

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2282536A (en) * 1993-10-06 1995-04-12 Zeneca Ltd Herbicidal compositions
US6534037B1 (en) 1998-01-21 2003-03-18 Neorx Corporation Non-steroidal compounds for steroid receptors and uses relating thereto
US6291514B1 (en) 1998-02-09 2001-09-18 3-Dimensional Pharmaceuticals, Inc. Heteroaryl amidines, methylamidines and guanidines, preparation thereof, and use thereof as protease inhibitors
US6403633B2 (en) 1998-02-09 2002-06-11 3-Dimensional Pharmaceuticals, Inc. Heteroaryl amidines, methylamidines and guanidines, and use thereof as protease inhibitors
US6562840B1 (en) 1998-02-09 2003-05-13 3-Dimensional Pharmaceuticals, Inc. Heteroaryl amidines, methylamidines and guanidines, and the use thereof as protease inhibitors
US7425557B2 (en) 1998-06-19 2008-09-16 Novartis Vaccines And Diagnostics, Inc. Inhibitors of glycogen synthase kinase 3
US7045519B2 (en) 1998-06-19 2006-05-16 Chiron Corporation Inhibitors of glycogen synthase kinase 3
US7528157B2 (en) 2003-01-29 2009-05-05 Asterand Uk Limited EP4 receptor antagonists
US7858644B2 (en) 2003-01-29 2010-12-28 Asterand Uk Limited EP4 receptor antagonists
US7507754B2 (en) 2003-01-29 2009-03-24 Asterand Uk Limited EP4 receptor antagonists
US7196089B2 (en) 2003-01-29 2007-03-27 Asterand Uk Limited EP4 receptor antagonists
US7569602B2 (en) 2003-10-16 2009-08-04 Asterand Uk Limited Furan derivatives as EP4 receptor antagonists
US7417068B2 (en) 2003-10-16 2008-08-26 Asterand Uk Limited EP4 receptor antagonists
US7649098B2 (en) 2006-02-24 2010-01-19 Lexicon Pharmaceuticals, Inc. Imidazole-based compounds, compositions comprising them and methods of their use
US8093267B2 (en) 2006-02-24 2012-01-10 Lexicon Pharmaceuticals, Inc. Methods of treating rheumatoid arthritis
US7825150B2 (en) 2007-09-06 2010-11-02 Lexicon Pharmaceuticals, Inc. Compositions and methods for treating immunological and inflammatory diseases and disorders
WO2017038650A1 (fr) * 2015-08-28 2017-03-09 積水メディカル株式会社 Composé benzyle
JP2018002700A (ja) * 2015-08-28 2018-01-11 積水メディカル株式会社 ベンジル化合物
CN108026116A (zh) * 2015-08-28 2018-05-11 积水医疗株式会社 苄基化合物
US10822357B2 (en) 2015-08-28 2020-11-03 Sekisui Medical Co., Ltd. Benzyl compound
US11591351B2 (en) 2015-08-28 2023-02-28 Sekisui Medical Co., Ltd. Benzyl compound

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JPH06510781A (ja) 1994-12-01
MX9205457A (es) 1993-03-01
AU2594092A (en) 1993-04-27
PT100902A (pt) 1993-11-30
EP0605524A1 (fr) 1994-07-13

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