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WO2004069998A2 - Oxindole derivatives as antimicrobial agents - Google Patents

Oxindole derivatives as antimicrobial agents Download PDF

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Publication number
WO2004069998A2
WO2004069998A2 PCT/GB2004/000426 GB2004000426W WO2004069998A2 WO 2004069998 A2 WO2004069998 A2 WO 2004069998A2 GB 2004000426 W GB2004000426 W GB 2004000426W WO 2004069998 A2 WO2004069998 A2 WO 2004069998A2
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Prior art keywords
alkyl
hydroxy
different
same
benzylidene
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PCT/GB2004/000426
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French (fr)
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WO2004069998A3 (en
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Richard Angell
Karen Reynolds
James Lumley
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Arrow Therapeutics Limited
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Publication of WO2004069998A2 publication Critical patent/WO2004069998A2/en
Publication of WO2004069998A3 publication Critical patent/WO2004069998A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/36—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom five-membered rings
    • A01N43/38—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom five-membered rings condensed with carbocyclic 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

Definitions

  • the present invention relates to a series of oxindole derivatives which can inhibit the biosynthesis of aromatic amino acids via the sWlamate pathway.
  • the shikimate pathway is responsible for the conversion of erythrose-4- phosphate to aromatic amino acids such as tryptophan, tyrosine and phenylalanine in bacteria, algae, fungi and higher plants. Further, recent work shows evidence for the presence of enzymes of the shikimate pathway in apicomplexan parasites (Roberts et al, Nature, 393, 1998, pgs 801-805). Compounds which can inhibit the biosynthesis of amino acids via the shikimate pathway therefore have a variety of commercial applications.
  • Shikimate kinase enzymes form an essential part of the shikimate pathway. They are responsible for the selective phosphorylation of the 3-hydroxyl group of shikimic acid. Two types of shikimate kinase have been identified. Type I shikimate kinase is the product of the aroK gene. Type LI shikimate kinase is the product of the aroL gene. The binding achieved by type II shikimate kinase may be stronger than that achieved by type I shikimate kinase. Accordingly, inhibitors of type II sMkimate kinase are likely to be potent inhibitors of the shikimate pathway.
  • the present invention provides, in a first embodiment, the use of an oxindole derivative of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating or preventing infection by an organism in which the biosynthesis of aromatic amino acids is effected via the sliikimate pathway
  • Ri and R 5 are the same or different and each represent hydrogen, halogen, hydroxy, cyano, nitro, C ⁇ -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C ⁇ -C 6 alkoxy, C 2 - C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C ⁇ -C 6 alkylthio, C 2 -C 6 alkenylthio, C 2 -C alkynylthio, or -NR / R wherein R and R are the same or different and each represent hydrogen, C ⁇ -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl;
  • R 2 and R 4 are the same or different and each represent hydrogen, halogen, hydroxy, cyano, nitro, -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C ⁇ -C 6 alkoxy, C 2 - C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C ⁇ -C 6 alkylthio, C 2 -C 6 alkenylthio, C 2 -C 6 alkynylthio, C 6 -C ⁇ o aryl, C 3 -C 6 carbocyclyl, a 5- to 10- membered heterocyclic ring, a 5- to 10- membered heteroaryl ring, -NRRf, -(CI-C 6 alky ⁇ -NRR*, -(C 2 -C 6 alkenyl)- NR'R' -(C 2 -C 6 alkynyl)-NR'R' -NRCONRT -COR
  • R 3 is hydrogen, halogen, hydroxy, C ⁇ -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C ⁇ -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C ⁇ -C 6 alkylthio, C2-C 6 alkenylthio, C 2 -C 6 alkynylthio, -NRR 7 , -CO 2 H or an acid isostere, wherein R and R are the same or different and each represent hydrogen, C ⁇ -C 6 alkyl, C 2 - alkenyl or C 2 -C(5 alkynyl; each R is the same or different and represents hydroxy, halogen, cyano, nitro, Cj-C 6 alkyl, C 2 -C 6 alkenyl, C 2 - alkynyl, -C 6 alkoxy, C2-C6 alkenyloxy, C2- C
  • a C ⁇ -C 6 alkyl group or moiety is a linear or branched alkyl group or moiety containing from 1 to 6 carbon atoms, such as a C ⁇ -C alkyl group or moiety. Examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl.
  • alkyl group or moiety may be unsubsti uted or substituted at any position. Typically, it is unsubstituted or carries one, two or three substituents. Suitable substituents include halogen, for example chlorine and fluorine, amino and hydroxy. Halogen substituents are preferred.
  • a C ⁇ -C alkyl group or moiety, as used herein, is preferably an unsubstituted C ⁇ -C 6 alkyl group or moiety or a C ⁇ -C 6 haloalkyl group or moiety.
  • Preferred haloalkyl groups and moieties are perhaloalkyl groups and moieties, for example -CX 3 wherein X is a halogen atom. Particularly preferred haloalkyl groups and moieties are -CF 3 and -CCI 3 .
  • a C 2 - alkenyl group or moiety is a linear or branched alkenyl group or moiety containing from 2 to 6 carbon atoms. Linear groups and moieties are preferred. Examples of suitable alkenyl groups and moieties include C 2 - C 4 alkenyl groups and moieties such as ethenyl, propenyl and butenyl groups and moieties. Typically, an alkenyl group or moiety is saturated except for one double bond. As used herein, an alkenyl group or moiety may be unsubstituted or substituted at any position. Typically, it is unsubstituted or carries one or two substituents. Suitable substituents include halogen, for example chlorine and fluorine, amino and hydroxy.
  • a C 2 -C 6 alkynyl group or moiety is a linear or branched alkynyl group or moiety containing from 2 to 6 carbon atoms. Linear groups and moieties are preferred. Examples of suitable alkynyl groups and moieties include C 2 - C 4 alkynyl groups and moieties such as ethynyl, propynyl and butynyl groups and moieties. Typically, an alkynyl group or moiety is saturated except for one triple bond.
  • alkynyl group or moiety may be unsubstituted or substituted at any position. Typically, it is unsubstituted or carries one or two substituents. Suitable substituents include halogen, for example chlorine and fluorine, amino and hydroxy. As used herein, a C ⁇ -C ⁇ o aryl group is typically phenyl or naphthyl. Phenyl is preferred. An aryl group may be unsubstituted or substituted at any position. Typically, it is unsubstituted or carries 1, 2, 3 or 4 substituents.
  • Suitable substituents for an aryl group include Ci- , alkyl, nitro, cyano, halogen, -OR 7 -SR 7 , and -(CH 2 ) n -NRR, wherein n is from 0 to 4 and each R and R 77 are the same or different and are selected from hydrogen and C ⁇ -C 6 alkyl.
  • the substituents on an aryl group are unsubstituted or are substituted with 1 , 2 or 3 halogen substituents.
  • references to a C 6 -C ⁇ o aryl group include fused ring systems in which a said C 6 -C ⁇ o aryl group is fused to a C 3 -C 6 carbocyclyl group, a 5- to 10- membered heterocyclyl group or a 5- to 10- membered heteroaryl group.
  • Preferred such ring systems are those in which the C 6 -C ⁇ o aryl group is fused to a heterocyclyl or heteroaryl group. Examples include benzothienyl and benzofuranyl groups.
  • a 5- to 10- membered heteroaryl group is a 5- to 10- membered aromatic ring, for example a 5- or 6- membered aromatic ring, containing at least one heteroatom, for example 1, 2 or 3 heteroatoms, selected from O, S and N.
  • heteroatoms for example 1, 2 or 3 heteroatoms, selected from O, S and N.
  • Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, isothiazolyl and isoxazolyl groups.
  • Preferred heteroaryl groups are pyridyl groups.
  • a heteroaryl group may be unsubstituted or substituted at any position. Typically, it is unsubstituted or carries 1, 2 or 3 substituents. Suitable substituents for a heteroaryl group include C ⁇ -C 6 alkyl, nitro, cyano, halogen, -OR, -SR and -(CH2) n -NR 7 R 77 wherein n is from 0 to 4 and each R 7 and R 7 are the same or different and are selected from hydrogen and C ⁇ -C 6 alkyl. Typically, the substituents on a heteroaryl group are unsubstituted or are substituted with 1, 2 or 3 halogen substituents.
  • references to a 5- to 10- membered heteroaryl group include fused ring systems in which a said 5- to 10- membered heteroaryl group is fused to a C 6 -C ⁇ o aryl group, a C 3 -C 6 carbocyclyl group, a 5- to 10- membered heterocyclic group or to a further 5- to 10- membered heteroaryl group.
  • Preferred such ring systems are those in which the 5- to 10- membered heteroaryl group is fused to an aryl group, for example a phenyl group. Examples include benzothienyl groups.
  • a halogen is typically chlorine, fluorine, bromine or iodine, and is preferably chlorine, bromine or iodine.
  • a said C ⁇ -C 6 alkoxy group is typically a said C ⁇ -C 6 alkyl group attached to an oxygen atom.
  • a said C 2 - alkenyloxy group is typically a said C 2 -C 6 alkenyl group attached to an oxygen atom.
  • a said C 2 -C 6 alkynyloxy group is typically a said C 2 -C 6 alkynyl group attached to an oxygen atom.
  • a said C ⁇ -C 6 alkylthio group is typically a said C ⁇ -C 6 alkyl group attached to a thio group.
  • a said C 2 -C 6 alkenylthio group is typically a said C 2 -C 6 alkenyl group attached to a thio group.
  • a said C 2 -C 6 alkynylthio group is typically a said C 2 -C 6 alkynyl group attached to a thio group.
  • a C 3 -C 6 carbocyclyl group is a non-aromatic saturated or unsaturated hydrocarbon ring having from 3 to 6 carbon atoms.
  • a saturated C 3 -C 6 carbocyclic group i.e. a C 3 -C 6 cycloalkyl group, for example, cyclopentyl and cyclohexyl.
  • a C 3 -C 6 carbocyclic group may be unsubstituted or substituted at any position. Typically, it is unsubstituted or carries 1, 2 or 3 substituents. Suitable substituents include C ⁇ -C 6 alkyl, nitro, cyano, halogen, -OR 7 , -SR and -(CH 2 ) n -NRR 7 wherein n is from 0 to 4 and each R and R 7 are the same or different and are selected from hydrogen and C ⁇ -C 6 alkyl. Typically, the substituents on a carbocyclyl group are unsubstituted or are substituted with 1, 2 or 3 halogen atoms.
  • references to a C 3 -C 6 carbocyclyl group include fused ring systems in which a said C 3 -C 6 carbocyclyl group is fused to a C 6 -C ⁇ o aryl group, a 5- to 10- membered heterocyclyl group, a 5- to 10- membered heteroaryl group or to a further C 3 -C 6 carbocyclyl group.
  • Preferred such ring systems are those in which the C 3 -C 6 carbocyclyl group is fused to a C 6 -C ⁇ o aryl group.
  • a 5- to 10- membered heterocyclyl group is a non-aromatic, saturated or unsaturated, C 5 -C 10 carbocyclic ring in which one or more, for example 1, 2 or 3, of the carbon atoms are replaced by a heteroatom selected from N, O and S. Saturated heterocyclyl groups are preferred.
  • Examples include tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, dioxolanyl, thiazolidinyl, tetrahydropyranyl, piperidinyl, dioxanyl, piperazinyl, morpholinyl, thiomorpholinyl and thioxanyl. Piperazinyl, piperidinyl and morpholinyl are preferred.
  • a heterocyclyl group may be unsubstituted or substituted at any position. Typically, it is unsubstituted or carries 1, 2 or 3 substituents. Suitable substituents on a heterocyclyl group include C ⁇ -C 6 alkyl, nitro, cyano, halogen, -OR 7 , -SR and -(CH 2 ) n -NRR 77 wherein n is from 0 to 4 and each R and R 7 are the same or different and are selected from hydrogen and C ⁇ -C 6 alkyl.
  • references to a 5- to 10- membered heterocyclyl group include fused ring systems in which a said 5- to 10- membered heterocyclyl group is fused to a C -C ⁇ o aryl group, a C 3 -C 6 carbocyclyl group, a 5- to 10- membered heteroaryl group or to a further 5- to 10- membered heterocyclyl group.
  • Preferred such ring systems are those in which the 5- to 10- membered heterocyclyl group is fused to an aryl group, for example a phenyl group.
  • an acid isostere is a group -Z, wherein (a) H-Z has a RMM of up to 200, preferably up to 150 and (b) the moiety Z in the compound H-Z has at least one acidic proton with a pKa of less than 7, preferably less than 5, in aqueous solution.
  • Preferred acid isosteres include 5-hydroxy-pyrrole-2,4-dione-3-yl, 5- hydroxy-pyrrolidine-2,3-dione-4-yl, 3H-[l,3,4]thiadiazol-2-onyl, 3H- [l,3,4]oxadiazol-2-onyl, 2-hydroxy-[l,3,4]thiadiazol-5-yl, 2-hydroxy- [l,3,4]oxadiazol-5-yl, 3-hydroxy-lH-[l,2,4]triazol-5-yl, 3-hydroxy-isoxazolyl, 5- hydroxy-isoxazolyl, tetrazolyl, for example 2H-tetrazolyl, triazolyl, for example 2H- [l,2,3]triazolyl, 3-trifluoromethyl-4H-[l,2,4]triazolyl, ⁇ yrrolidine-2,3,5-trionyl, 5- hydroxy-[l,2,4]miadiazolyl, 5-
  • At least one, more preferably at least two, of R ⁇ , R 2 , R 4 and R 5 represent hydrogen.
  • Ri and R are the same or different and each represent hydrogen, halogen, hydroxy, Ci- , alkyl, C ⁇ -C 6 alkoxy, C ⁇ -C 6 alkylthio or -NRR 7 wherein R and R 77 are the same or different and each represent hydrogen or C ⁇ -C 6 alkyl.
  • Ri and R 5 are unsubstituted.
  • Ri and R are the same or different and each represent hydrogen, hydroxy, halogen or an unsubstituted C L -C 4 alkyl, C1-C4 haloalkyl or C ⁇ - C 4 alkoxy group.
  • Ri and R 5 are the same or different and each represents hydrogen, halogen or -OCH 3 .
  • R 2 and R 4 are the same or different and each represent hydrogen, halogen, hydroxy, C ⁇ -C 6 alkyl, C ⁇ -C 6 alkoxy, C ⁇ -C 6 alkylthio, nitro, cyano, C 6 -C ⁇ o aryl, C 3 -C 6 carbocyclyl, a 5- to 10- membered heterocyclic ring, a 5- to 10- membered heteroaryl ring, -NR 7 R 7 , -(C,-C 6 alkyl)-NRR 77 , -CO 2 R / , -COR 77 -CONRR 77 -NR-CO-NR 7 R 77 -NR-CO-R 77 , -SOR 7 , -S(O) 2 R' 7 -S(O) 2 NR'R 77 or -(Q- alkyl)-X-R 77 wherein (a) R 7 represents hydrogen or C ⁇ -C 6 alkyl and R 77 represents hydrogen, C ⁇ -C
  • a C 6 -C ⁇ o aryl group includes fused ring systems in which a C 6 -C ⁇ o aryl group is fused to a carbocyclyl, heterocyclyl or heteroaryl group.
  • the C 6 -C ⁇ o aryl moieties in the substituents R 2 and R 4 are not fused to carbocyclyl, heterocyclyl or heteroaryl groups.
  • the carbocyclyl, heterocyclyl and heteroaryl moieties in the substituents R 2 and R 4 are preferably not fused ring systems.
  • R 2 and R 4 are the same or different and each represent hydrogen, halogen, hydroxy, C ⁇ -C 6 alkyl, C ⁇ -C 6 alkoxy, C ⁇ -C 6 alkythio or -NRR wherein R 7 and R are the same or different and each represent hydrogen or C ⁇ -C 6 alkyl.
  • the substituents R 2 and R 4 are unsubstituted or are substituted by 1, 2 or 3 halogen atoms.
  • R 2 and R 4 are the same or different and each represent hydrogen, halogen or an unsubstituted C 1 -C 4 alkyl or -C alkoxy group. Most preferably, R 2 and R 4 are the same or different and each represent hydrogen, chlorine, bromine, iodine, -CH 3 , -C(CH 3 ) 3 , or -OCH 3 .
  • R 3 is hydrogen, halogen, hydroxy, C ⁇ -C 6 alkyl, C 2 -C 6 alkenyl, C 2 - C 6 alkynyl, C ⁇ -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C ⁇ -C 6 alkylthio, C 2 - C 6 alkenylthio, C 2 -C 6 alkynylthio, -NRR 77 -CO 2 H, 5-hydroxy-pyrrole-2,4-dione-3-yl, 5-hydroxy-pyrrolidine-2,3-dione-4-yl, 3H-[l,3,4]thiadiazol-2-onyl, 3H- [l,3,4]oxadiazol-2-onyl, 2-hydroxy-[l,3,4]thiadiazol-5-yl, 2-hydroxy- [l,3,4]oxadiazol-5-yl, 3-hydroxy-lH-[l,2,4]triazol-5
  • R 3 is hydrogen, halogen, hydroxy, -C 6 alkyl, C ⁇ -C 6 alkoxy, C ⁇ - C 6 alkylthio, -NRR , tetrazolyl, for example 2H-tetrazolyl, triazolyl, for example 2H- [1 ,2,3]triazolyl or -CO 2 H wherein R and R are the same or different and each represent hydrogen or C ⁇ -C 6 alkyl.
  • R 3 is hydrogen, hydroxy, -CO 2 H, 2H-tetrazolyl, 2H- [l,2,3]triazolyl, C 1 -C 4 alkoxy or -NRR 7 wherein R and R are the same or different and each represent hydrogen or C1-C 4 alkyl. More typically, R 3 is hydroxy, halogen or an unsubstituted C 1 -C 4 alkoxy or -NRR 7 group wherein R 7 and R 77 are the same or different and each represent hydrogen or an unsubstituted C 1 -C 4 alkyl group.
  • R 3 is hydroxy, halogen, for example fluorine, or an unsubstituted C 1 -C 4 alkoxy group, for example -OCH 3 .
  • each R 6 is the same or different and represents hydroxy, halogen, cyano, nitro, C ⁇ -C 6 alkyl, C ⁇ -C 6 alkoxy, C ⁇ -C 6 alkylthio, C -C ⁇ o aryl, C 3 -C 6 carbocyclyl, a 5- to 10- membered heterocyclic ring, a 5- to 10- membered heteroaryl ring, -NRR 77 -(C ⁇ -C 6 alkyl)-NR 7 R 77 , -COR 77 , -CO 2 R 7' , -CONRR 77 , -NR 7 -CO-R 77 , -NR 7 - CO-NRR 77 , -SOR 77 , -S(O) 2 R 77 , -S
  • a C 6 -C ⁇ o aryl group includes fused ring systems in which a C 6 -C ⁇ o aryl group is fused to a carbocyclyl, heterocyclyl or heteroaryl group.
  • the C 6 -C ⁇ o aryl moieties in the R 6 substituents are not fused to carbocyclyl, heterocyclyl or heteroaryl groups.
  • the carbocyclyl, heterocyclyl and heteroaryl moieties in the R substituents are preferably not fused ring systems.
  • each R 6 is the same or different and represents hydroxy, -NH 2 , halogen, cyano, nitro, C ⁇ -C 6 alkyl, C ⁇ -C 6 alkoxy, C ⁇ -C 6 alkylthio, -NRR 77 -COR 77 -CO2R 77 , -CONRR' 7 -SO 2 R or -SO 2 NR 7 R /7 wherein R 7 represents hydrogen or C ⁇ -C 6 alkyl and R 7 represents C ⁇ -C 6 alkyl.
  • each R 6 is the same or different and represents hydroxy, -NH 2 , halogen, cyano, nitro, C 1 -C4 alkyl, C 1 -C 4 alkoxy, -NR 7 R 77 , -COR 77 -CO 2 R '' or -CONRR wherein R 7 represents hydrogen or C1-C4 alkyl and R represents -C4 alkyl.
  • the alkyl moieties in the R 6 substituents are unsubstituted or are substituted with one or more, for example 1, 2 or 3, halogen atoms.
  • each R 6 is the same or different and represents halogen, for example, chlorine, bromine and iodine, nitro, cyano, C 1 -C 4 alkyl, -CO 2 -(C ⁇ -C 4 alkyl), for example -CO 2 -CH 3 or -CO-(C ⁇ -C 4 alkyl), for example -CO-CH 2 Cl.
  • R 7 is hydrogen or C ⁇ -C 6 alkyl. Typically, the substituent R 7 is unsubstituted. Preferably, R 7 is hydrogen. Preferably, n is 0 or 1.
  • Preferred compounds of the invention are compounds of formula (I), and pharmaceutically acceptable salts thereof, in which:
  • Ri and R 5 are the same or different and each represent hydrogen, halogen, hydroxy, C ⁇ -C 6 alkyl, C ⁇ -C 6 alkoxy, C ⁇ -C alkylthio or -NRR , wherein R and R are the same or different and each represent hydrogen or C ⁇ -C 6 alkyl;
  • R 2 and R 4 are the same or different and each represent hydrogen, halogen, hydroxy, C ⁇ -C 6 alkyl, C ⁇ -C 6 alkoxy, C ⁇ -C 6 alkylthio or -NRR 7 , wherein R and R are the same or different and each represent hydrogen or C ⁇ -C 6 alkyl;
  • R 3 represents hydrogen, halogen, hydroxy, C ⁇ -C 6 alkyl, C ⁇ -C alkoxy, C ⁇ -C 6 alkylthio, -NRR 77 , tetrazolyl, for example 2H-tetrazolyl, triazolyl, for example 2H- [l,2,3]triazolyl or -CO 2 H, wherein R and R are the same or different and each represent hydrogen or C ⁇ -C 6 alkyl; each R 6 is the same or different and represents hydroxy, -NH 2 , halogen, cyano, nitro, d-C ⁇ alkyl, C ⁇ -C 6 alkoxy, C ⁇ -C 6 alkylthio, -NRR 77 -COR 77 , -CO 2 R 77 -CONR'R 77 -SO 2 R ' or -SO 2 NR 7 R 7 wherein R 7 represents hydrogen or C ⁇ -C 6 alkyl and R represents C ⁇ -C 6 alkyl;
  • R is hydrogen or C ⁇ -C 6 alkyl; and n is O or l, wherein the alkyl groups and moieties in substituents Ri to R are unsubstituted or substituted by 1, 2 or 3 halo substituents.
  • Ri and R 5 are the same or different and each represent hydrogen, hydroxy, halogen or an unsubstituted C1-C 4 alkyl, C 1 -C4 haloalkyl or C1-C 4 alkoxy group;
  • R 2 and R 4 are the same or different and each represent hydrogen, halogen or an unsubstituted C1-C 4 alkyl or C 1 -C 4 alkoxy group;
  • - R3 is hydroxy, halogen, for example fluorine, or an unsubstituted C 1 -C4 alkoxy group, for example -OCH 3 ;
  • R ⁇ is halogen, for example chlorine, bromine and iodine, nitro, cyano, C ⁇ -C 4 alkyl, -CO 2 -(C ⁇ -C 4 alkyl), for example -CO 2 -CH3, or -CO-(d-C alkyl), for example -CO-CH 2 -Cl, the alkyl moieties in the substituent R being unsubstituted or substituted by 1, 2 or 3 halo substituents; n is 0 or 1 ; and
  • R 7 is hydrogen
  • Examples of these most preferred compounds include: 5-Bromo-3-(3,5-dibromo-4-hydroxy-benzylidene)-l,3-dihydro-indol-2-one 3-(3,5-Dibromo-4-hydroxy-benzylidene)-5-iodo-l,3-dil ydro-indol-2-one 5-Chloro-3-(4-hydroxy-3,5-diiodo-benzylidene)-l,3-dihydro-indol-2-one 5-Chloro-3-(3,5-dibromo-4-hydroxy-benzylidene)-l,3-dihydro-indol-2-one 7-Bromo-3-(3,5-dibromo-4-hydroxy-benzylidene)-l,3-dihydro-indol-2-one 7-Bromo-3-(3,5-dibromo-4-hydroxy-benzylidene)-l,
  • Compounds of the formula (I) may contain one or more chiral centre.
  • the chemical structures depicted herein are intended to embrace all stereoisomers of the compounds shown, including racemic and non-racemic mixtures and pure enantiomers and/or diastereoisomers.
  • Preferred compounds of the invention which contain a chiral centre are optically active isomers.
  • preferred compounds of formula (I) containing one chiral centre include an R enantimomer in substantially pure form, an S enantiomer in substantially pure form, and enantiomeric mixtures which contain an excess of the R enantiomer or an excess of the S enantiomer.
  • Further preferred compounds of the invention are pure E geometric isomers, pure Z geometric isomers, and mixtures of E and Z isomers which contain an excess of either the E or the Z isomer.
  • a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base.
  • Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p-toluenesulphonic acid.
  • Pharmaceutical acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases such as alkyl amines, aralkyl amines or heterocyclic amines.
  • Ri and R 5 are the same or different and each represent hydrogen, halogen, hydroxy, cyano, nitro, C ⁇ -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C ⁇ -C 6 alkoxy, C 2 - C 6 alkenyloxy, C 2 -C 6 alkynyloxy, Ci- alkylthio, C 2 -d alkenylthio, C 2 -C 6 alkynylthio, or -NRR 77 wherein R and R 77 are the same or different and each represent hydrogen, C ⁇ -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl; - R 2 and R 4 are the same or different and each represent hydrogen, halogen, hydroxy, cyano, nitro, C ⁇ -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C ⁇ -C 6 alk
  • R 7 is hydrogen, Ci- alkyl, C 2 -C alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 carbocyclyl or C 6 -C ⁇ o aryl, provided that:
  • R 2 and R 3 are not simultaneously -OCH 3 ;
  • each R 6 is other than chlorine, fluorine, -CF 3 O, ethyl, i-propoxy,
  • n, Ri, R 2 , R 3 , R4, R 5 and R 7 in the formula (lb) are the same as those set out above for the corresponding substituents in the formula (I).
  • each R ⁇ in the formula (lb) is the same or different and represents hydroxy, -NH 2 , halogen, cyano, nitro, Ci- alkyl, Ci-d alkoxy, C ⁇ -C alkylthio,
  • R 7 represents C ⁇ -C 6 alkyl.
  • each R 6 in the formula (lb) is the same or different and represents hydroxy, -NH 2 , halogen, cyano, nitro, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, -NRR 77 -COR', -CO 2 R' or -CONRR 7 wherein R represents hydrogen or C 1 -C 4 alkyl and Represents
  • alkyl, alkenyl and alkynyl moieties in substituent R 6 in the formula (lb) are unsubstituted or are substituted with one or more, for example 1, 2 or 3, halogen atoms.
  • each Re in the formula (lb) is the same or different and represents halogen, for example, chlorine, bromine and iodine, nitro, cyano, C 1 -C 4 alkyl, -CO 2 -(d-C 4 alkyl), for example -CO 2 -CH 3 or -CO-(C ⁇ -C 4 alkyl), for example -CO-CH 2 -CI.
  • halogen for example, chlorine, bromine and iodine, nitro, cyano, C 1 -C 4 alkyl, -CO 2 -(d-C 4 alkyl), for example -CO 2 -CH 3 or -CO-(C ⁇ -C 4 alkyl), for example -CO-CH 2 -CI.
  • Preferred compounds of the formula (lb) are those in which:
  • Ri and R 5 are the same or different and each represent hydrogen, hydroxy, halogen or an unsubstituted C 1 -C 4 alkyl, C1-C 4 haloalkyl or C 1 -C 4 alkoxy group;
  • R 2 and R 4 are the same or different and each represent hydrogen, halogen or an unsubstituted C 1 -C 4 alkyl or C 1 -C4 alkoxy group;
  • R 3 is hydroxy, halogen, for example fluorine, or an unsubstituted C 1 -C 4 alkoxy group, for example -OCH 3 ;
  • - R 6 is halogen, for example chlorine, bromine and iodine, nitro, cyano, C 1 -C 4 alkyl, -CO 2 -(d-C 4 alkyl), for example -CO 2 -CH 3 or -CO-(C ⁇ -C 4 alkyl), for example -CO-CH 2 -CI, the alkyl moieties in the substituent Rg being unsubstituted or substituted by 1 , 2 or 3 halo substituents; n is 0 or 1 ; and - R 7 is hydrogen, provided that:
  • R 3 is -OCH , either R 2 is halogen or Ri and R are both C 1 -C 4 alkoxy;
  • R 2 and R 4 are not simultaneously -OCH 3 ; and (4) either (a) neither R 2 nor R 4 is halogen when R 3 is hydroxy or (b) (i) n is 1 , (ii) R 6 is other than chlorine, fluorine and ethyl, (iii) when R 6 is iodine, nitro or cyano R 2 and R 4 are iodine, (iv) when Re is bromine either R is at the 7- position of the indole moiety and R 2 and R 4 are bromine or iodine or one of R ⁇ and R is bromine, (v) when R 6 is -CO 2 Me it is at the 7- position of the indole moiety and (vi) when R 6 is -CO- (C 1 -C 4 alkyl) it is not at the 5- position of the indole moiety.
  • Examples of these preferred compounds of formula (lb) include: 7-Bromo-3-(3,5-dibromo-4-hydroxy-benzylidene)-l,3-dihydro-indol-2-one 7-Bromo-3-(4-hydroxy-3,5-diiodo-benzylidene)-l,3-dil ⁇ ydro-indol-2-one 3-(4-Hydroxy-3,5-diiodo-benzylidene)-2-oxo-2,3-dihydro-lH-indole-5-carbonitrile 3-(3,5-Dibromo-4-hydroxy-benzylidene)-2-oxo-2,3-dihydro-lH-indole-7-carboxylic acid methyl ester 3-(4-Hydroxy-3,5-diiodo-benzylidene)-2-oxo-2,3-dihydro-lH-indo
  • R 2 and R 3 are not simultaneously alkoxy groups.
  • R 2 and R 4 are both C ⁇ -C 6 alkyl groups.
  • the phenyl ring substituted by Ri to R 5 is 3,5-dihalo-4-hydroxyphenyl, for example 3,5-dibromo-4- hydroxyphenyl and 3,5-diiodo-4-hydroxyphenyl, 3,5-di-(d-d alkyl)-4- hydroxyphenyl, for example 3,5-di-(t-butyl)-4-hydroxyphenyl and 3,5-dimethyl-4- hydroxyphenyl, 4-hydroxy-5-halophenyl, for example 4-hydroxy-5-bromophenyl, 4- methoxy-5-halophenyl, for example 4-methoxy-5-bromophenyl, 2,4,6- trimethoxyphenyl, 4-halophenyl, for example 4-fluorophenyl, 4-hydroxyphenyl or 2,3-dihalo-4-hydroxy-5-methoxyphenyl for example 2,3-dibromo-4-hydroxy-5- methoxyphenyl, provided when
  • R 3 is not an alkoxy, alkenyloxy or alkynyloxy group.
  • R 2 nor R 4 is halogen or nitro when R 3 is hydroxy.
  • R 2 nor R 4 is halogen, hydroxy, cyano, nitro, -CONR 7 R 77 , -S(O) 2 NRR' J -NRR 77 , Ci-d alkoxy, C 2 -C 6 alkenyloxy or C 2 -d alkynyloxy when R 3 is hydroxy or -NH- S(O) 2 CF 3 or (b) Ri and R 5 are not simultaneously hydrogen.
  • the compounds of formula (I) may be prepared by reacting an oxindole of formula (II) with an aldehyde of formula (III) as follows.
  • the reaction takes place in the presence of a base, such as piperidine, in a solvent such as ethanol.
  • a base such as piperidine
  • a solvent such as ethanol.
  • the reaction may be conducted under non- extreme temperatures, typically in the range of 0 to 120°C.
  • the compounds of formula (I) may be prepared by reacting an oxindole of formula (II) with an aldehyde of formula (III) in the presence of catalytic quantity of acid, such as pTS A.
  • the reaction may also be carried out in the presence of strong acid, for example in a catalytic quantity of 2N HCI, preferably under non- extreme temperatures, typically in the range of 0 to 120°C.
  • R is other than hydrogen
  • introduction of alkyl, alkenyl, alkynyl or cycloalkyl groups at the R 7 position can be effected by combining a compound in which R is hydrogen with a base such as potassium carbonate, sodium hydride, sodium carbonate, sodium hydroxide, potassium hydroxide, potassium t-butoxide or butyl lithium.
  • the amount of base is typically 0.5 to 1 mols, based on 1 mol of reactant compound in which R 7 is hydrogen.
  • the reaction can be effected in a suitable solvent such as acetone, chloroform, methylene chloride, dimethylformamide, ethanol, butanol, isopropanol, dimethylsulfoxide or a mixture of two or more of the foregoing solvents.
  • a suitable solvent such as acetone, chloroform, methylene chloride, dimethylformamide, ethanol, butanol, isopropanol, dimethylsulfoxide or a mixture of two or more of the foregoing solvents.
  • an appropriate halide or sulphate can be added.
  • the reaction can be stirred for a period of time from two to about 72 hours, at a temperature between 0°C to 100°C. Additional reagents, such as phase transfer catalysts, can be added if required.
  • Compounds of formula (LI) and (El) are commercially available or can be prepared by analogy with known techniques.
  • the compounds of formula (I) are found to be inhibitors of type II shikimate kinase enzymes. Typically, therefore, the said medicament is for use in the inhibition of a type IL sliikimate kinase enzyme.
  • Preferred compounds of the invention have an IC 5 o value against a type II shikimate kinase enzyme of 10 ⁇ M or less, preferably 5 ⁇ M or less, more preferably 1 ⁇ M or less.
  • the present invention also provides a method for treating a patient suffering from or susceptible to infection by an organism in which the biosynthesis of aromatic amino acids is effected via the shikimate pathway, which method comprises administering to said patient an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the organisms in which the biosynthesis of aromatic amino acids is effected via the shiLkimate pathway can easily be identified by those of skill in the art. Such organisms can be identified, for example, by (a) determining whether in vitro growth is inhibited by well characterised inhibitors of the shikimate pathway, such as glyphosphate, and (b) determining whether such inhibition is reversed by addition of ?-aminobenzoate. A positive determination in each of steps (a) and (b) indicates that the organism in question is one in which biosynthesis of aromatic amino acids is effected via the shikimate pathway.
  • the shikimic acid pathway is essential for the synthesis of aromatic amino acids in fungi and bacteria. Accordingly, the compounds of the invention are effective in treating or preventing bacterial or fungal infection. Said organism is typically a bacterium or fungus, therefore. The compounds of the invention are particularly effective against bacteria.
  • the present invention provides the use of the compounds of the invention in the manufacture of a medicament for use in treating or preventing a bacterial infection.
  • a method of treating a patient suffering from or susceptible to a bacterial infection comprises the administration thereto of a compound of the invention.
  • the infection is an infection by a Staphylococcus, Enterococcus, Corynebacterium, Listeria, Neisseria, Propionibacterium or Moraxella bacterium.
  • it is an infection by a strain of Staphylococcus aureus, in particular methicillin-resistant Staphylococcus aureus, Enterococcus faecium, in particular vancomycin-resistant or vancomycin-sensitive Enerococcus faecium, Enterococcus faecalis, Corynebacterium minutissimum, Corynebacterium auris, Corynebacterium urealyticum, Listeria monocytogenes NCTC 10357, Listeria monocytogenes NCTC 11007, Listeria monocytogenes, Neisseria meningitides, Neisseria flava, Neisseria elongata, Propionibacterium Sp ox Moraxella catarrhalis.
  • Staphylococcus aureus in particular methicillin-resistant Staphylococcus aureus, Enterococcus faecium, in particular vancomycin-resistant or vancomycin-sensitive Enerococc
  • said organism in which the biosynthesis of aromatic amino acids is effected via the shikimate pathway is not methicillin-resistant Staphylococcus aureus. More typically, in this embodiment of the invention said organism is not a strain of Staphylococcus aureus, in particular methicillin-resistant Staphylococcus aureus, Enterococcus faecium, in particular vancomycin-resistant or vancomycin-sensitive Enterococcus faecium, Enterococcus faecalis, Corynebacterium minutissimum, Coiynebacteriam auris, Corynebacterium urealyticum, Listeria monocytogenes NCTC 10357, Listeria monocytogenes NCTC 11007, Listeria monocytogenes, Neisseria meningitides, Neisseria flava, Neisseria elongata, Propionibacterium Sp or Moraxella catarrhalis.
  • said organism is not a Staphylococcus, Enterococcus, Coiynebacterium, Listeria, Neisseria, Propionibacterim or Moraxella bacterium. More preferably, in the embodiment of the invention, said organism is not a bacterium.
  • the compounds of the invention can also be used generally to prevent bacterial growth.
  • they may be added to solutions, such as solutions for contact lenses, to prevent bacterial growth. They may also be used in antibiotic coatings on surgical instruments and in products such as medicated soaps.
  • the present invention also provides the non-therapeutic use of a compound of the invention in inhibiting bacterial growth.
  • a contact lens solution or a medicated soap comprising a compound of the invention.
  • the present invention provides a surgical instrument having thereon an antibiotic coating comprising a compound of the invention.
  • the shikimic acid pathway is also implicated in the metabolism of parasites. For example, it is implicated in the metabolism of apicomplexan parasites.
  • the compounds of the invention are effective in the treatment or prevention of infection by a parasite in which the biosynthesis of aromatic amino acids is effected via the shikimate pathway.
  • said parasites can be identified, for example, by (a) determining whether in vitro growth is inhibited by well characterised inhibitors of the shikimate pathway, such as glyphosphate, and (b) determining whether such inhibition is reversed by addition ofp-aminobenzoate.
  • the compounds of the invention are active against Toxoplasma gondii, Ciyptosporidium parvum and Plasmodium falciparum. Plasmodium falciparum is known to cause malaria.
  • the said patient is typically suffering from or susceptible to, and the said medicament is typically for use in the treatment or prevention of, infection by an apicomplexan parasite.
  • the said patient is typically suffering from or susceptible to, and the said medicament is typically for use in the treatment or prevention of, malaria.
  • the compounds of the invention may be administered in a variety of dosage forms.
  • they can be administered orally, for example as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules.
  • the compounds of the invention may also be administered parenterally, whether subcutaneously, intravenously, intramuscularly, intrasternally, transdermally or by infusion techniques.
  • the compounds may also be administered as suppositories.
  • the present invention also provides a compound of formula (lb), as defined above, or a pharmaceutically acceptable salt thereof, for use in a method of treating the human or animal body. It further provides a pharmaceutical composition containing a compound of formula (lb), as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
  • a compound of the invention is typically formulated for administration with a pharmaceutically acceptable carrier or diluent.
  • solid oral forms may contain, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents; e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g.
  • Such pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tableting, sugar coating, or film coating processes.
  • Liquid dispersions for oral administration may be syrups, emulsions and suspensions.
  • the syrups may contain as carriers, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol.
  • Suspensions and emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol.
  • the suspension or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.
  • Solutions for injection or infusion may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions.
  • a therapeutically effective amount of a compound of the invention is administered to a patient.
  • a typical dose is from about 0.001 to 50 mg per kg of body weight, according to the activity of the specific compound, the age, weight and conditions of the subject to be treated, the type and severity of the disease and the frequency and route of administration.
  • daily dosage levels are from 5 mg to 2 g.
  • the shikimic acid pathway is also essential in higher plants, algae and fungi.
  • the compounds of the invention are therefore effective in controlling higher plants, algae and fungi. They can be used as selective herbicides and fungicides, for example.
  • the present invention provides the use of a compound of formula (I), or an agriculturally acceptable salt thereof, as a herbicide or a fungicide.
  • a method of controlling weeds or fungi at a locus which method comprises treating the locus with a compound of formula (I) or an agriculturally acceptable salt thereof.
  • the locus comprises agricultural or horticultural plants or a medium in which such plants grow.
  • a preferred method of controlling fungi is a method of treating a plant for, or protecting a plant against, fungal attack, which method comprises applying to the plant a compound of formula (I) or an agriculturally acceptable salt thereof. Smuts and rusts on a plant can, for example, be treated by this method.
  • the active compound is applied to the leaves.
  • the number of applications and the rate of application depend on the intensity of the fungal attack.
  • an active compound can also be applied to a plant through the roots via the soil (systemic action) by impregnating the locus of the plant with a liquid composition comprising the active compound, or by applying the compound in solid form to the soil, e.g. in granular form (soil application).
  • the active compound may also be applied to seeds (coating) by impregnating the seeds either with a liquid formulation containing the active compound, or coating them with a solid formulation. In special cases, further types of application are also possible, for example, selective treatment of the plant stems or buds.
  • Suitable agriculturally acceptable salts include those salts mentioned above as examples of pharmaceutically acceptable salts.
  • the said herbicidal or fungicidal composition may be prepared by mixing a compound of formula (I), or an agriculturally acceptable salt thereof, with an agriculturally acceptable carrier or diluent.
  • Suitable such compositions include wettable powders, granules, water-dispersible granules, emulsion concentrates, suspension concentrates, and powders suitable for dusting plants.
  • the fungicidal or herbicidal compositions may comprise further agricultural chemicals, for example further fungicides and herbicides or insecticides, miticides, plant growth regulators, fertilizers and soil conditioners.
  • the herbicidal or fungicidal composition preferably comprises a further fungicide or herbicide. This leads not only to a reduction in dose and manpower, but also to broadening of the herbicidal or fungicidal spectrum. This broadening is attributable to cooperative activities.
  • Suitable agriculturally acceptable carriers and diluents include solid or liquid carriers and diluents.
  • solid carriers or diluents examples include clays such as kaolinites, montmorillonites, illites and polygroskites, more specifically pyrophyllite, attapulgite, sepiolite, kaolinite, bentonite, vermiculite, mica and talc.
  • Other inorganic substances such as gypsum, calcium carbonate, dolomite, diatomaceous earth, magnesium lime, phosphorus lime, zeolite, silicic anhydride and synthetic calcium silicate may also be used.
  • Suitable organic carriers and diluents include soybean flour, tobacco flour, walnut flour, wheat flour, wood flour, starch and crystalline cellulose.
  • Further synthetic or natural polymers such as coumarone resin, petroleum resin, alkyd resin, polyvinyl chloride, polyalkylene glycol, ketone resin, ester gum, copal gum and dammar gum are suitable, as are waxes such as carnauba wax and bee wax.
  • liquid carriers and diluents include paraffin or naphthene hydrocarbons such as kerosene, mineral oil, spindle oil and white oil, aromatic hydrocarbons such as xylene, ethylbenzene, cumene and methylnaph- thalene, chlorinated hydrocarbons such as trichloroethylene, monochlorobenzene and o-chloro toluene, ethers such as dioxane and tetrahydrofuran, ketones such as acetone, methyl ethyl ketone, diisobutyl ketone, cyclohexanone, acetophenone and isophorone, esters such as ethyl acetate, amyl acetate, ethylene glycol acetate, diethylene glycol acetate, dibutyl maleate and diethyl succinate, alcohols such as methanol, n-hexanol, ethylene glycol, diol
  • the herbicidal and fungicidal compositions comprise a surfactant and/or another auxiliary agent suitable for various purposes such as emulsification, dispersion, humidification, spreading, dilution, combination destruction control, stabilization of active ingredients, improvement of flowability, prevention of corrosion and prevention of freezing.
  • the herbicidal and fungicidal compositions of the invention comprise at least one surfactant.
  • the present invention also provides a herbicidal or fungicidal composition comprising: an oxindole of formula (I) or an agriculturally acceptable salt thereof; at least one surfactant; and an agriculturally acceptable carrier or diluent.
  • Suitable surfactants include nonionic, anionic, cationic and amphoteric surfactants. Nonionic and anionic surfactants are preferred. Suitable anionic surfactants can be both water-soluble soaps and water- soluble synthetic surface-active compounds.
  • Suitable soaps are the alkali metal salts, alkaline earth metal salts or unsubstituted or substituted ammonium salts of higher fatty acids (chains of 10 to 22 carbon atoms), for example the sodium or potassium salts of oleic or stearic acid, or of natural fatty acid mixtures which can be obtained for example from coconut oil or tallow oil.
  • the fatty acid methyltaurin salts may also be used.
  • fatty sulfonates especially fatty sulfonates, fatty sulfates, sulfonated benzimidazole derivatives or alkylarylsulfonates.
  • the fatty sulfonates or sulfates are usually in the form of alkali metal salts, alkaline earth metal salts or unsubstituted or substituted ammonium salts and have a C 8 to C 22 alkyl radical which also includes the alkyl moiety of alkyl radicals, for example, the sodium or calcium salt of lignonsulfonic acid, of dodecylsulfate or of a mixture of fatty alcohol sulfates obtained from natural fatty acids.
  • These compounds also comprise the salts of sulfuric acid esters and sulfonic acids of fatty alcohol/ethylene oxide adducts.
  • the sulfonated benzimidazole derivatives preferably contain 2 sulfonic acid groups and one fatty acid radical containing 8 to 22 carbon atoms.
  • alkylarylsulfonates are the sodium, calcium or triethanolamine salts of dodecylbenzenesulfonic acid, dibutylnapthalenesulfonic acid, or of a naphthalenesulfomc acid/formaldehyde condensation product.
  • corresponding phosphates e.g. salts of the phosphoric acid ester of an adduct of p- nonylphenol with 4 to 14 moles of ethylene oxide.
  • Non-ionic surfactants are preferably polyglycol ether derivatives of aliphatic or cycloaliphatic alcohols, or saturated or unsaturated fatty acids and alkylphenols, said derivatives containing 3 to 30 glycol ether groups and 8 to 20 carbon atoms in the (aliphatic) hydrocarbon moiety and 6 to 18 carbon atoms in the alkyl moiety of the alkylphenols.
  • non-ionic surfactants are the water-soluble adducts of polyethylene oxide with polypropylene glycol, ethylenediamine propylene glycol and alkylpolypropylene glycol containing 1 to 10 carbon atoms in the alkyl chain, which adducts contain 20 to 250 ethylene glycol ether groups and 10 to 100 propylene glycol ether groups. These compounds usually contain 1 to 5 ethylene glycol units per propylene glycol unit.
  • non-ionic surfactants are nonylphenolpolyethoxyethanols, castor oil polyglycol ethers, polypropylene /polyethylene oxide adducts, tributylphenoxypolyethoxyethanol, polyethylene glycol and octylphenoxyethoxy ethanol.
  • Fatty acid esters of polyoxyethylene sorbitan and polyoxyethylene sorbitan trioleate are also suitable non-ionic surfactants.
  • Cationic surfactants are preferably quaternary ammonium salts which have, as N- substituents, at least one Cs-C 22 alkyl radical and, as further substituents, lower unsubstituted or halogenated alkyl, benzyl or lower hydroxyalkyl radicals.
  • the salts are preferably in the form of halides, mefhylsulfates or ethylsulfates, e.g. ste-uyltrimethylammonium chloride or benzyldi(2-chloroethyl)ethylammomium bromide.
  • the said auxiliary agent includes casein, gelatin, albumin, glue, sodium alginate, carboxymethylcellulose, methylcellulose, hydroyethylcellulose and polyvinyl alcohol.
  • the content of active compound in the herbicidal and fungicidal composition of the invention may vary widely depending on the form of formulation.
  • the amount of active compound is 0.1 to 99%, preferably 1 to 80% by weight of the composition.
  • wettable powders typically contain 25 to 90% by weight of active compound.
  • Granules typically contain 1 to 35% by weight of active compound, which may be mixed with the solid carrier or diluent uniformly, or mixed to or absorbed on the surface of the solid carrier or diluent uniformly. It is preferred that the diameter of the granules is from 0.2 to 1.5mm.
  • Emulsion concentrates typically contain 5 to 30% by weight of active compound, and in additional 5 to 20% by weight of an emulsifier. Suspension concentrates typically contain 5 to 50% by weight of active compound, and in addition 3 to 10% by weight of a dispersion wetting agent.
  • the compounds of the invention may be applied in effective amounts to various places to be protected, for example farm-lands such as paddy fields and upland, or non-crop lands.
  • herbicides When used as herbicides they may be applied prior to germination of weeds or to weeds of various stages from after germination to growth period.
  • the dose When the compounds of the invention are used as herbicides, the dose is generally, as amount of active ingredients, on the order of 0.1 to 10,000 g/ha, preferably 1 to 5,000 g/ha, more preferably from 50 to 3,000 g/ha.
  • the dose may be varied depending on the kind of objective weeds, their growth stages, places of application and weather.
  • the compounds of the invention When the compounds of the invention are used as fungicides, the dose is typically from 50g to 5kg of active ingredient per hectare, preferably from lOOg to 2kg per hectare, more preferably from 200g to 500g per hectare.
  • the shikimic acid pathway is also essential for the synthesis of aromatic amino acids in algae. Accordingly, the compounds of the present invention are effective in controlling algae.
  • the present invention therefore provides the use of a compound of formula (I), or a salt thereof, in controlling algae.
  • the invention provides a method of treating algae in a fish tank or pond, which method comprises applying to the fish tank or pond a compound of formula (I) or a salt thereof.
  • This material was prepared as described for Example 1 except that 7-bromo- oxindole was used.
  • the title compound was a yellow solid (0.1 lOg, 50%)
  • This material was prepared as described for Example 1 except that 7-bromo- oxindole was used.
  • the title compound was a yellow solid (0.132g, 50%)
  • This material was prepared as described for Example 1 except that 7-bromo- oxindole (0.47mmol) and 3,5-methyl-4-hydroxybenzaldehyde (0.47mmol) were used.
  • the title compound was a yellow solid (131mg, 81%)
  • Example 22 7-Bromo-3-(2,4,6-tiimethoxy-benzylidene)-l,3-dihydro-indol-2-one This material was prepared as described for Example 1 except that 7-bromo- oxindole (0.47mmol) and 2,4,6-trimethoxybenzaldehyde (0.47mmol) were used. The title compound was a yellow solid (136mg, 74%)
  • This material was prepared as described for Example 1 except that 6-cyano- oxindole (0.47mmo ⁇ ) and 2,4,6-trimethoxybenzaldehyde (0.47mmol) were used.
  • the title compound was a yellow/orange solid (37mg, 23%)
  • This material was prepared as described for Example 1 except that 7-cyano- oxindole (0.47mmol) and 3-bromo-4-methoxybenzaldehyde (0.47mmol) were used.
  • the title compound was a yellow/orange solid (39mg, 23%)
  • This material was prepared as described for Example 1 except that 7-cyano- oxindole (0.47mmol) and 3,5-diiodo-4-hydroxybenzaldehyde (0.47mmol) were used.
  • the title compound was a yellow/orange solid (11 Omg, 46%)
  • the adenosine diphosphate produced acted as a cofactor for pyruvate kinase in the production of pyruvic acid, which was then converted to lactic acid with lactate dehydrogenase.
  • lactate dehydrogenase As this latter reaction is accompanied by a reduction in NADH levels, which can be monitored in a UN spectrophotometer at 340 nm Molecular Devices Spectramax plus microtitre plate reader), shikimate kinase activity is effectively coupled to a UN readout system.
  • Compounds were tested at 10 mM for their ability to increase the absorbance (over control levels) at 340 nm, representing reduced conversion of ⁇ ADH to NAD and therefore reduced ADP production and reduced shikimate kinase activity.
  • Reagents for 1 plate screen were prepared as follows: A buffer of 500 mM triethanolamine (TEA) buffer (10X) plus cations was prepared, and made up to a final volume of 1 litre (92.5g TEA, 37g KCl, 12.3g MgSO 4 & 1 litre distilled H 2 O (measured in a measuring cylinder) were mixed in a 1000ml Duran bottle). The pH of this buffer was adjusted to pH7.0 with 1M KOH and then made up to a final volume of 1 litre. The buffer was stored at +4°C, equilibrated to 25°C before use. A stock of lOOmM shikimic acid was prepared from 348mg shikimic acid.
  • TEA triethanolamine
  • the pH of this solution was adjusted to pH 7.0 using 1M KOH, made up to a final volume of 15ml and aliquoted into 500 ⁇ l volumes and stored at -20°C.
  • a stock of lOmM PEP was prepared from 380mg PEP.
  • the pH of this solution was adjusted to pH 7.0 using 1M KOH made up to a final volume of 20ml using dH 2 O and aliquoted into 500 ⁇ l volumes and stored at -20°C.
  • a stock of 20mM NADH was prepared from 113.4mg NADH made up to a final volume of 8 ml using dH 2 O, aliquoted into 500 ⁇ l volumes and stored at -20°C.
  • a stock of 8ml 500mM ATP was prepared from 2.2g ATP and 8ml dH 2 O, aliquoted into 500 ⁇ l volumes and stored at -20°C.
  • Enzyme mixtures A and B were made up immediately before use as follows:
  • A 18.7ml of 50mM TEA buffer (plus cations), 72 ⁇ l of lOOmM shikimic acid, 78 ⁇ l of 500mM ATP, 377 ⁇ l of 20mM NADH, 714 ⁇ l of lOOmM PEP, 54U of pyruvate kinase and 54U of lactate dehydrogenase; B: 15 ml 500mM TEA buffer (plus cations) and 75LT shikimate kinase.
  • test compounds were added to the remaining wells at 20 ⁇ l (maximum of
  • MIC determinations were performed using broth microdilution methodology in accordance with guidelines set out by the National Committee for Clinical Laboratory Standards (NCCLS) in the following publications: M7-A5 Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically - Fifth Edition; Approved Standard (2000); and Ml 1-A5 Methods for antimicrobial susceptibility testing of anaerobic bacteria - Fifth Edition; Approved Standard (2001).
  • Bacterial strains were selected from 5 methicillin-resistant strains of Staphylococcus aureus (MRSA), 2 vancomycin-resistant (NRE) strains of Enterococcus faecium, 2 vancomycin-susceptible strains of E.
  • MRSA Staphylococcus aureus
  • NRE vancomycin-resistant
  • Escherichia coli ATCC 25922 and Staphylococcus aureus ATCC 29213 were used as control organisms.
  • Yeast autolysate growth supplement (Oxoid; SR0105B)
  • the culture medium was prepared in accordance with the manufacturer's instructions. After autoclaving and cooling to 48 ⁇ 2°C, Columbia Agar was supplemented with 5% v/v defibrinated horse blood before pouring into sterile petri dishes. 'Lab M' Mueller Hinton JJ broth (supplied by International Diagnostics Group) had been adjusted with respect to calcium and magnesium content and therefore required no further cation adjustment.
  • Chocolate Blood Agar was based on Columbia Blood Agar, for which the initial stages of preparation were described above. Immediately after addition of 5% v/v blood to the molten agar, the bottle contents was gently mixed and placed in a waterbath operating at 80 ⁇ 2°C. The bottle contents were mixed at intervals during heating, until the agar has attained a uniform chocolate brown colour. Chocolate Columbia Blood Agar (CCBA) was returned to a 48 + 2°C waterbath until cooled to this temperature, then poured into sterile 90 mm petri dishes.
  • CCBA Cold Columbia Blood Agar
  • Neisseria Test Medium Neisseria Test Medium was prepared from Mueller Hinton Broth. After autoclaving and cooling to 48°C or below, one vial of Yeast Autolysate Growth Supplement was added per 500 ml of medium. Finally, 5% v/v lysed blood was be added to the medium.
  • Solution A Primary stock solution 5260
  • Solution B 100 ⁇ l Solution A + 100 ⁇ l DMSO 2630
  • Microtitre plates bearing a pattern of 12 x 8 wells were used. Plates with round or conical well bases, and with a nominal well volume of 200 ⁇ l, were selected. In each experimental run, all test compounds were screened against an appropriate set of test organisms. This allowed the relative activity of each test compound to be accurately determined without the influence of inoculum variability. The latter might have been significant if a given test organism was screened against each compound on different days.
  • Bacterial strains were subcultured from frozen stocks on to Columbia Blood Agar (Enterococcus, Neisseria, Coiynebacterium, Moraxella and Listeria strains), Fastidious Anaerobe Agar (Propionibacterium spp) or Nutrient Agar (all other strains) and were incubated under appropriate aerobic conditions at 37 ⁇ 1°C until discrete colonies were visible:
  • Columbia Blood Agar Enterococcus, Neisseria, Coiynebacterium, Moraxella and Listeria strains
  • Fastidious Anaerobe Agar Propionibacterium spp
  • Nutrient Agar all other strains
  • Each plate culture was used to produce a standardized bacterial suspension, from which inocula for MIC plates were prepared. At least five well-isolated colonies was sampled from the plate using a sterile swab, and this material was suspended in a sterile 5-10 ml aliquot of the appropriate broth until turbidity equivalent to a 0.5 McFarland standard was attained. Comparison with the McFarland standard was made against a white card bearing contrasting black lines. Standardized bacterial suspensions contained approximately 1 x 10 s cfu per ml.
  • Neisseria Test Medium - Neisseria spp
  • Each adjusted suspension was diluted by transferring 0.1 ml of the standardised bacterial suspension to 20 ml of the broth. This provided the NCCLS recommended inoculum density of approximately 5 x 10 3 cfu per ml when microtitre plates were prepared.
  • MIC values for control strains were set up with the first and last MIC runs and treated in the same way as other test strains. MIC values for control organisms did not differ by more than 2 doubling dilutions between the beginning and end of the study.
  • MIC results were summarized in a tabular format showing the MIC 9 o and geometric mean MIC values for each genus.
  • the MIC o is the minimum concentration of test compound inhibitory to 90%> of the test strains in a particular group.
  • Geometric mean is the most appropriate mean for application to data on a logarithmic scale (MIC data are on a log 2 scale). It is calculated as follows:
  • Compounds of the invention were screened in two stages. First, they were screened at concentrations 30 and lOO ⁇ M. If the compounds inhibited growth at 30 ⁇ M they were advanced to a second assay (National Committee for Clinical Laboratory Standards protocol) where they were screened at concentrations of 50, 25, 12, 6, 3, 1.5, 0.8 and 0.4 ⁇ M.
  • the concentrations of compounds were made up in Eppendorf tubes using DMSO as the diluent, taking into consideration that only 2.5 ⁇ l of each compound solution would be added to lOO ⁇ l of broth.
  • Eppendorf tubes containing the diluted compounds were vortexed and 2.5 ⁇ l were pipetted into labelled wells of 96 round bottom well microtitre plates. Each plate included two growth control wells (2.5 ⁇ l DMSO and lOO ⁇ l Mueller Hinton (MH) broth) and two negative (uninoculated) wells (lOO ⁇ l MH broth) for sterilization assessment of the MH broth.
  • Positive controls also included compounds of known MIC (Arrow compound A358, MIC of 3-5 ⁇ M) and ampicillin as a known antibiotic (MIC of 0.1 ⁇ M).
  • Inoculum was prepared by making a saline suspension of the isolated colonies of identical morphological type selected from the 18-24h agar plate. The top of each colony was touched with a plastic loop and growth transferred to a vial containing an NaCI solution to yield a suspension to match the 0.5 McFarland turbidity standard which was then diluted 1:10 in saline. LTsing fresh pipettes each time 5 ⁇ l of the S. aureus suspension was pipetted and mixed into each test well and growth control wells. Purity plates were streaked out from the diluted culture onto CLED and Columbia blood agar plates and incubated overnight at 37°C.
  • microtitre plates were placed into incubation boxes at 37°C for 16-20h. Damp tissue paper was also placed in the box to produce a humid environment and to prevent evaporation.

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Abstract

Use of an oxindole derivative of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating or preventing infection by an organism in which the biosynthesis of aromatic amino acids is effected via the shikimate pathway.

Description

ANTIMICROBIAL COMPOUNDS
The present invention relates to a series of oxindole derivatives which can inhibit the biosynthesis of aromatic amino acids via the sWlamate pathway. The shikimate pathway is responsible for the conversion of erythrose-4- phosphate to aromatic amino acids such as tryptophan, tyrosine and phenylalanine in bacteria, algae, fungi and higher plants. Further, recent work shows evidence for the presence of enzymes of the shikimate pathway in apicomplexan parasites (Roberts et al, Nature, 393, 1998, pgs 801-805). Compounds which can inhibit the biosynthesis of amino acids via the shikimate pathway therefore have a variety of commercial applications.
Shikimate kinase enzymes form an essential part of the shikimate pathway. They are responsible for the selective phosphorylation of the 3-hydroxyl group of shikimic acid. Two types of shikimate kinase have been identified. Type I shikimate kinase is the product of the aroK gene. Type LI shikimate kinase is the product of the aroL gene. The binding achieved by type II shikimate kinase may be stronger than that achieved by type I shikimate kinase. Accordingly, inhibitors of type II sMkimate kinase are likely to be potent inhibitors of the shikimate pathway.
It has now surprisingly been found that particular oxindole derivatives of the general formula (I) set out below act as inhibitors of type II shikimate kinase.
Accordingly, the present invention provides, in a first embodiment, the use of an oxindole derivative of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating or preventing infection by an organism in which the biosynthesis of aromatic amino acids is effected via the sliikimate pathway
Figure imgf000002_0001
wherein:
Ri and R5 are the same or different and each represent hydrogen, halogen, hydroxy, cyano, nitro, Cι-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cι-C6 alkoxy, C2- C6 alkenyloxy, C2-C6 alkynyloxy, Cι-C6 alkylthio, C2-C6 alkenylthio, C2-C alkynylthio, or -NR/R wherein R and R are the same or different and each represent hydrogen, Cι-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl;
R2 and R4 are the same or different and each represent hydrogen, halogen, hydroxy, cyano, nitro, -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cι-C6 alkoxy, C2- C6 alkenyloxy, C2-C6 alkynyloxy, Cι-C6 alkylthio, C2-C6 alkenylthio, C2-C6 alkynylthio, C6-Cιo aryl, C3-C6 carbocyclyl, a 5- to 10- membered heterocyclic ring, a 5- to 10- membered heteroaryl ring, -NRRf, -(CI-C6 alky^-NRR*, -(C2-C6 alkenyl)- NR'R' -(C2-C6 alkynyl)-NR'R' -NRCONRT -CORX, -COSR', -CONRT^, -NR7-CO- R , -SOR7, -S(0)2R -S(O)2NR/R/or -L-H-R , wherein (a) R and R'are the same or different and each represent hydrogen, Cι-C alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-Cιo aryl, C3-C6 carbocyclyl, a 5- to 10- membered heterocyclic ring, a 5- to 10- membered heteroaryl ring or -L-X-R , (b) each L is the same or different and represents a divalent C]-C6 alkyl, C2-C alkenyl or C2-C6 alkynyl group, (c) each X is the same or different and represents -O-, -S-, -SO-, -SO2-, -NH- or a direct bond and (d) each R is the same or different and represents Cι-C6 alkyl, C6-Cιo aryl, C3-C carbocyclyl, a 5- to 10- membered heterocyclic ring or a 5- to 10- membered heteroaryl ring;
R3 is hydrogen, halogen, hydroxy, Cι-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cι-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, Cι-C6 alkylthio, C2-C6 alkenylthio, C2-C6 alkynylthio, -NRR7, -CO2H or an acid isostere, wherein R and R are the same or different and each represent hydrogen, Cι-C6 alkyl, C2- alkenyl or C2-C(5 alkynyl; each R is the same or different and represents hydroxy, halogen, cyano, nitro, Cj-C6 alkyl, C2-C6 alkenyl, C2- alkynyl, -C6 alkoxy, C2-C6 alkenyloxy, C2- C6 alkynyloxy, Cι-C6 alkylthio, C2-C6 alkenylthio, C2-C6 alkynylthio, C6-Cιo aryl, C3-C6 carbocyclyl, a 5- to 10- membered heterocyclic ring, a 5- to 10- membered heteroaryl ring, -N t , -(Cι-C6 alkyO-NKR , -(C2-Cό alkenyl)-NRR' -(C2-C6 alkynyD-NRR7', -COR7', -CO2R7 -CONRX , -NR'-CO-R77, -NR'-CO-NR' '', -SOR'' -S(O)2R/, -S(O)2NR/R or -L-X-R , wherein (a) R and R are the same or different and each represent hydrogen, Cι-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-Cι0 aryl, C3- C6 carbocyclyl, a 5- to 10- membered heterocyclic ring, a 5- to 10- membered heteroaryl ring or -L-X-R , (b) each L is the same or different and represents a divalent Cι-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl group, (c) each X is the same or different and represents -O-, -S-, -SO-, -SO2-, -NH- or a direct bond and (d) each R/ is the same or different and represents Cι-C6 alkyl, C6-Cιo aryl, C3-C6 carbocyclyl, a 5- to 10- membered heterocyclic ring or a 5- to 10- membered heteroaryl ring; n is 0, 1, 2 or 3; and - R7 is hydrogen, Cι-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 carbocyclyl or C6-Cιo aryl.
As used herein, a Cι-C6 alkyl group or moiety is a linear or branched alkyl group or moiety containing from 1 to 6 carbon atoms, such as a Cι-C alkyl group or moiety. Examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl.
An alkyl group or moiety may be unsubsti uted or substituted at any position. Typically, it is unsubstituted or carries one, two or three substituents. Suitable substituents include halogen, for example chlorine and fluorine, amino and hydroxy. Halogen substituents are preferred. Thus, a Cι-C alkyl group or moiety, as used herein, is preferably an unsubstituted Cι-C6 alkyl group or moiety or a Cι-C6 haloalkyl group or moiety. Preferred haloalkyl groups and moieties are perhaloalkyl groups and moieties, for example -CX3 wherein X is a halogen atom. Particularly preferred haloalkyl groups and moieties are -CF3 and -CCI3.
As used herein, a C2- alkenyl group or moiety is a linear or branched alkenyl group or moiety containing from 2 to 6 carbon atoms. Linear groups and moieties are preferred. Examples of suitable alkenyl groups and moieties include C2- C4 alkenyl groups and moieties such as ethenyl, propenyl and butenyl groups and moieties. Typically, an alkenyl group or moiety is saturated except for one double bond. As used herein, an alkenyl group or moiety may be unsubstituted or substituted at any position. Typically, it is unsubstituted or carries one or two substituents. Suitable substituents include halogen, for example chlorine and fluorine, amino and hydroxy.
As used herein, a C2-C6 alkynyl group or moiety is a linear or branched alkynyl group or moiety containing from 2 to 6 carbon atoms. Linear groups and moieties are preferred. Examples of suitable alkynyl groups and moieties include C2- C4 alkynyl groups and moieties such as ethynyl, propynyl and butynyl groups and moieties. Typically, an alkynyl group or moiety is saturated except for one triple bond.
An alkynyl group or moiety may be unsubstituted or substituted at any position. Typically, it is unsubstituted or carries one or two substituents. Suitable substituents include halogen, for example chlorine and fluorine, amino and hydroxy. As used herein, a Cό-Cιo aryl group is typically phenyl or naphthyl. Phenyl is preferred. An aryl group may be unsubstituted or substituted at any position. Typically, it is unsubstituted or carries 1, 2, 3 or 4 substituents. Suitable substituents for an aryl group include Ci- , alkyl, nitro, cyano, halogen, -OR7 -SR7, and -(CH2)n-NRR, wherein n is from 0 to 4 and each R and R77 are the same or different and are selected from hydrogen and Cι-C6 alkyl. Typically, the substituents on an aryl group are unsubstituted or are substituted with 1 , 2 or 3 halogen substituents. As used herein, references to a C6-Cιo aryl group include fused ring systems in which a said C6-Cιo aryl group is fused to a C3-C6 carbocyclyl group, a 5- to 10- membered heterocyclyl group or a 5- to 10- membered heteroaryl group. Preferred such ring systems are those in which the C6-Cιo aryl group is fused to a heterocyclyl or heteroaryl group. Examples include benzothienyl and benzofuranyl groups. As used herein, a 5- to 10- membered heteroaryl group is a 5- to 10- membered aromatic ring, for example a 5- or 6- membered aromatic ring, containing at least one heteroatom, for example 1, 2 or 3 heteroatoms, selected from O, S and N. Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, isothiazolyl and isoxazolyl groups. Preferred heteroaryl groups are pyridyl groups. A heteroaryl group may be unsubstituted or substituted at any position. Typically, it is unsubstituted or carries 1, 2 or 3 substituents. Suitable substituents for a heteroaryl group include Cι-C6 alkyl, nitro, cyano, halogen, -OR, -SR and -(CH2)n-NR7R77 wherein n is from 0 to 4 and each R7and R7are the same or different and are selected from hydrogen and Cι-C6 alkyl. Typically, the substituents on a heteroaryl group are unsubstituted or are substituted with 1, 2 or 3 halogen substituents.
As used herein, references to a 5- to 10- membered heteroaryl group include fused ring systems in which a said 5- to 10- membered heteroaryl group is fused to a C6-Cιo aryl group, a C3-C6 carbocyclyl group, a 5- to 10- membered heterocyclic group or to a further 5- to 10- membered heteroaryl group. Preferred such ring systems are those in which the 5- to 10- membered heteroaryl group is fused to an aryl group, for example a phenyl group. Examples include benzothienyl groups. As used herein, a halogen is typically chlorine, fluorine, bromine or iodine, and is preferably chlorine, bromine or iodine.
As used herein, a said Cι-C6 alkoxy group is typically a said Cι-C6 alkyl group attached to an oxygen atom. A said C2- alkenyloxy group is typically a said C2-C6 alkenyl group attached to an oxygen atom. A said C2-C6 alkynyloxy group is typically a said C2-C6 alkynyl group attached to an oxygen atom. A said Cι-C6 alkylthio group is typically a said Cι-C6 alkyl group attached to a thio group. A said C2-C6 alkenylthio group is typically a said C2-C6 alkenyl group attached to a thio group. A said C2-C6 alkynylthio group is typically a said C2-C6 alkynyl group attached to a thio group.
As used herein, a C3-C6 carbocyclyl group is a non-aromatic saturated or unsaturated hydrocarbon ring having from 3 to 6 carbon atoms. Preferably it is a saturated C3-C6 carbocyclic group, i.e. a C3-C6 cycloalkyl group, for example, cyclopentyl and cyclohexyl.
A C3-C6 carbocyclic group may be unsubstituted or substituted at any position. Typically, it is unsubstituted or carries 1, 2 or 3 substituents. Suitable substituents include Cι-C6 alkyl, nitro, cyano, halogen, -OR7, -SR and -(CH2)n-NRR7 wherein n is from 0 to 4 and each R and R7 are the same or different and are selected from hydrogen and Cι-C6 alkyl. Typically, the substituents on a carbocyclyl group are unsubstituted or are substituted with 1, 2 or 3 halogen atoms.
As used herein, references to a C3-C6 carbocyclyl group include fused ring systems in which a said C3-C6 carbocyclyl group is fused to a C6-Cιo aryl group, a 5- to 10- membered heterocyclyl group, a 5- to 10- membered heteroaryl group or to a further C3-C6 carbocyclyl group. Preferred such ring systems are those in which the C3-C6 carbocyclyl group is fused to a C6-Cιo aryl group.
As used herein, a 5- to 10- membered heterocyclyl group is a non-aromatic, saturated or unsaturated, C5-C10 carbocyclic ring in which one or more, for example 1, 2 or 3, of the carbon atoms are replaced by a heteroatom selected from N, O and S. Saturated heterocyclyl groups are preferred. Examples include tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, dioxolanyl, thiazolidinyl, tetrahydropyranyl, piperidinyl, dioxanyl, piperazinyl, morpholinyl, thiomorpholinyl and thioxanyl. Piperazinyl, piperidinyl and morpholinyl are preferred.
A heterocyclyl group may be unsubstituted or substituted at any position. Typically, it is unsubstituted or carries 1, 2 or 3 substituents. Suitable substituents on a heterocyclyl group include Cι-C6 alkyl, nitro, cyano, halogen, -OR7, -SR and -(CH2)n-NRR77 wherein n is from 0 to 4 and each R and R7 are the same or different and are selected from hydrogen and Cι-C6 alkyl.
As used herein, references to a 5- to 10- membered heterocyclyl group include fused ring systems in which a said 5- to 10- membered heterocyclyl group is fused to a C -Cιo aryl group, a C3-C6 carbocyclyl group, a 5- to 10- membered heteroaryl group or to a further 5- to 10- membered heterocyclyl group. Preferred such ring systems are those in which the 5- to 10- membered heterocyclyl group is fused to an aryl group, for example a phenyl group.
As used herein, an acid isostere is a group -Z, wherein (a) H-Z has a RMM of up to 200, preferably up to 150 and (b) the moiety Z in the compound H-Z has at least one acidic proton with a pKa of less than 7, preferably less than 5, in aqueous solution. Preferred acid isosteres include 5-hydroxy-pyrrole-2,4-dione-3-yl, 5- hydroxy-pyrrolidine-2,3-dione-4-yl, 3H-[l,3,4]thiadiazol-2-onyl, 3H- [l,3,4]oxadiazol-2-onyl, 2-hydroxy-[l,3,4]thiadiazol-5-yl, 2-hydroxy- [l,3,4]oxadiazol-5-yl, 3-hydroxy-lH-[l,2,4]triazol-5-yl, 3-hydroxy-isoxazolyl, 5- hydroxy-isoxazolyl, tetrazolyl, for example 2H-tetrazolyl, triazolyl, for example 2H- [l,2,3]triazolyl, 3-trifluoromethyl-4H-[l,2,4]triazolyl, ρyrrolidine-2,3,5-trionyl, 5- hydroxy-[l,2,4]miadiazolyl, 5-hydroxy-[l,2,4]oxadiazolyl, 2,4-dioxo- tetrahydrofuranyl, l,3,4-triaza-2-onyl, l,2,4-oxadiazal-5-onyl, benzothiazolone-S,S- dioxidyl, benzothiazolone-l,l-dioxidyl, -NH-S(O)2-CF3 and -CONH-S(O)2-CH3 groups.
The symbol "^ww" indicates that the double bond between the benzyl moiety and the indol-2-one moiety may be in either the E or the Z configuration. For the avoidance of doubt, the chemical structures depicted herein are intended to embrace all geometrical isomers of the compounds shown, including mixtures thereof.
Preferably, at least one, more preferably at least two, of R\, R2, R4 and R5 represent hydrogen.
Typically, Ri and R are the same or different and each represent hydrogen, halogen, hydroxy, Ci- , alkyl, Cι-C6 alkoxy, Cι-C6 alkylthio or -NRR7 wherein R and R77are the same or different and each represent hydrogen or Cι-C6 alkyl. Preferably, Ri and R5 are unsubstituted.
More preferably, Ri and R are the same or different and each represent hydrogen, hydroxy, halogen or an unsubstituted C L-C4 alkyl, C1-C4 haloalkyl or C\- C4 alkoxy group.
Most preferably, Ri and R5 are the same or different and each represents hydrogen, halogen or -OCH3.
Typically, R2 and R4 are the same or different and each represent hydrogen, halogen, hydroxy, Cι-C6 alkyl, Cι-C6 alkoxy, Cι-C6 alkylthio, nitro, cyano, C6-Cιo aryl, C3-C6 carbocyclyl, a 5- to 10- membered heterocyclic ring, a 5- to 10- membered heteroaryl ring, -NR7R7, -(C,-C6 alkyl)-NRR77, -CO2R/, -COR77 -CONRR77 -NR-CO-NR7R77 -NR-CO-R77, -SOR7, -S(O)2R'7 -S(O)2NR'R77 or -(Q- alkyl)-X-R77 wherein (a) R7 represents hydrogen or Cι-C6 alkyl and R77 represents hydrogen, Cι-C6 alkyl, C6-Cιo aryl, C3-C6 carbocyclyl, a 5- to 10- membered heterocyclic ring, a 5- to 10- membered heteroaryl ring or -(Cι-C6 alkyl)-X-R7, (b) each X is the same or different and represents -O-, -NH- or a direct bond and (c) each R77' is the same or different and represents C6-Cιo aryl, C3- carbocyclyl, a 5- to 10- membered heterocyclic ring or a 5- to 10- membered heteroaryl ring.
As explained above, as used herein a C6-Cιo aryl group includes fused ring systems in which a C6-Cιo aryl group is fused to a carbocyclyl, heterocyclyl or heteroaryl group. Preferably, however, the C6-Cιo aryl moieties in the substituents R2 and R4 are not fused to carbocyclyl, heterocyclyl or heteroaryl groups. Further, the carbocyclyl, heterocyclyl and heteroaryl moieties in the substituents R2 and R4 are preferably not fused ring systems.
More typically, R2 and R4 are the same or different and each represent hydrogen, halogen, hydroxy, Cι-C6 alkyl, Cι-C6 alkoxy, Cι-C6 alkythio or -NRR wherein R7and R are the same or different and each represent hydrogen or Cι-C6 alkyl. Typically, the substituents R2 and R4 are unsubstituted or are substituted by 1, 2 or 3 halogen atoms.
Preferably, R2 and R4 are the same or different and each represent hydrogen, halogen or an unsubstituted C1-C4 alkyl or -C alkoxy group. Most preferably, R2 and R4 are the same or different and each represent hydrogen, chlorine, bromine, iodine, -CH3, -C(CH3)3, or -OCH3.
Typically, R3 is hydrogen, halogen, hydroxy, Cι-C6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl, Cι-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, Cι-C6 alkylthio, C2- C6 alkenylthio, C2-C6 alkynylthio, -NRR77 -CO2H, 5-hydroxy-pyrrole-2,4-dione-3-yl, 5-hydroxy-pyrrolidine-2,3-dione-4-yl, 3H-[l,3,4]thiadiazol-2-onyl, 3H- [l,3,4]oxadiazol-2-onyl, 2-hydroxy-[l,3,4]thiadiazol-5-yl, 2-hydroxy- [l,3,4]oxadiazol-5-yl, 3-hydroxy-lH-[l,2,4]triazol-5-yl, 3-hydroxy-isoxazolyl, 5- hydroxy-isoxazolyl, tetrazolyl, for example 2H-tetrazolyl, triazolyl, for example 2H- [l,2,3]triazolyl, 3-trifluoromethyl-4H-[l,2,4]triazolyl, pyrrolidine-2,3,5-trionyl, 5- hydroxy-[l,2,4]thiadiazolyl, 5-hydroxy-[l,2,4]oxadiazolyl, 2,4-dioxo- tetrahydrofuranyl, l,3,4-triaza-2-onyl, l,2,4-oxadiazal-5-onyl, benzothiazolone-S,S- dioxidyl, benzothiazolone-l,l-dioxidyl, -NH-S(O)2.CF3 or -CONH-S(O)2-CH3, wherein R and R77 are the same or different and each represent hydrogen, Cι-C alkyl, C2-C6 alkenyl or C2-C6 alkynyl.
Preferably, R3 is hydrogen, halogen, hydroxy, -C6 alkyl, Cι-C6 alkoxy, C\- C6 alkylthio, -NRR , tetrazolyl, for example 2H-tetrazolyl, triazolyl, for example 2H- [1 ,2,3]triazolyl or -CO2H wherein R and R are the same or different and each represent hydrogen or Cι-C6 alkyl.
More preferably, R3 is hydrogen, hydroxy, -CO2H, 2H-tetrazolyl, 2H- [l,2,3]triazolyl, C1-C4 alkoxy or -NRR7wherein R and R are the same or different and each represent hydrogen or C1-C4 alkyl. More typically, R3 is hydroxy, halogen or an unsubstituted C 1-C4 alkoxy or -NRR7 group wherein R7 and R77 are the same or different and each represent hydrogen or an unsubstituted C1-C4 alkyl group. Most preferably, R3 is hydroxy, halogen, for example fluorine, or an unsubstituted C1-C4 alkoxy group, for example -OCH3. Typically, each R6 is the same or different and represents hydroxy, halogen, cyano, nitro, Cι-C6 alkyl, Cι-C6 alkoxy, Cι-C6 alkylthio, C -Cιo aryl, C3-C6 carbocyclyl, a 5- to 10- membered heterocyclic ring, a 5- to 10- membered heteroaryl ring, -NRR77 -(Cι-C6 alkyl)-NR7R77, -COR77, -CO2R7', -CONRR77, -NR7-CO-R77, -NR7- CO-NRR77, -SOR77, -S(O)2R77, -S(O)2NRR77or -(d-C6 alkyl)-X-R , wherem (a) R7 represents hydrogen or Cι-C6 alkyl and R represents hydrogen, Cι-C6 alkyl, C6-Cιo aryl, C3-C6 carbocyclyl, a 5- to 10- membered heterocyclic ring, a 5- to 10- membered heteroaryl ring or -(Cι-C6 alkyl)-X-R7, (b) each X is the same or different and represents -O-, -NH- or a direct bond and (c) each R7 is the same or different and represents Cι-C6 alkyl, C6-Cιo aryl, C3-C6 carbocyclyl, a 5- to 10- membered heterocyclic ring or a 5- to 10- membered heteroaryl ring.
As explained above, as used herein a C6-Cιo aryl group includes fused ring systems in which a C6-Cιo aryl group is fused to a carbocyclyl, heterocyclyl or heteroaryl group. Preferably, however, the C6-Cιo aryl moieties in the R6 substituents are not fused to carbocyclyl, heterocyclyl or heteroaryl groups. Further, the carbocyclyl, heterocyclyl and heteroaryl moieties in the R substituents are preferably not fused ring systems.
Typically, each R6 is the same or different and represents hydroxy, -NH2, halogen, cyano, nitro, Cι-C6 alkyl, Cι-C6 alkoxy, Cι-C6 alkylthio, -NRR77 -COR77 -CO2R77, -CONRR'7 -SO2R or -SO2NR7R/7 wherein R7 represents hydrogen or Cι-C6 alkyl and R7 represents Cι-C6 alkyl.
Preferably, each R6 is the same or different and represents hydroxy, -NH2, halogen, cyano, nitro, C1-C4 alkyl, C1-C4 alkoxy, -NR7R77, -COR77 -CO2R''or -CONRR wherein R7 represents hydrogen or C1-C4 alkyl and R represents -C4 alkyl.
Typically, the alkyl moieties in the R6 substituents are unsubstituted or are substituted with one or more, for example 1, 2 or 3, halogen atoms. Most preferably, each R6 is the same or different and represents halogen, for example, chlorine, bromine and iodine, nitro, cyano, C1-C4 alkyl, -CO2-(Cι-C4 alkyl), for example -CO2-CH3 or -CO-(Cι-C4 alkyl), for example -CO-CH2Cl.
Typically, R7 is hydrogen or Cι-C6 alkyl. Typically, the substituent R7 is unsubstituted. Preferably, R7 is hydrogen. Preferably, n is 0 or 1.
Preferred compounds of the invention are compounds of formula (I), and pharmaceutically acceptable salts thereof, in which:
Ri and R5 are the same or different and each represent hydrogen, halogen, hydroxy, Cι-C6 alkyl, Cι-C6 alkoxy, Cι-C alkylthio or -NRR , wherein R and R are the same or different and each represent hydrogen or Cι-C6 alkyl;
R2 and R4 are the same or different and each represent hydrogen, halogen, hydroxy, Cι-C6 alkyl, Cι-C6 alkoxy, Cι-C6 alkylthio or -NRR7, wherein R and R are the same or different and each represent hydrogen or Cι-C6 alkyl;
R3 represents hydrogen, halogen, hydroxy, Cι-C6 alkyl, Cι-C alkoxy, Cι-C6 alkylthio, -NRR77, tetrazolyl, for example 2H-tetrazolyl, triazolyl, for example 2H- [l,2,3]triazolyl or -CO2H, wherein R and R are the same or different and each represent hydrogen or Cι-C6 alkyl; each R6 is the same or different and represents hydroxy, -NH2, halogen, cyano, nitro, d-Cό alkyl, Cι-C6 alkoxy, Cι-C6 alkylthio, -NRR77 -COR77, -CO2R77 -CONR'R77 -SO2R' or -SO2NR7R7 wherein R7 represents hydrogen or Cι-C6 alkyl and R represents Cι-C6 alkyl;
R is hydrogen or Cι-C6 alkyl; and n is O or l, wherein the alkyl groups and moieties in substituents Ri to R are unsubstituted or substituted by 1, 2 or 3 halo substituents.
Further preferred compounds of the invention are compounds of formula (I), and pharmaceutically acceptable salts thereof, in which: Ri and R5 are the same or different and each represent hydrogen, hydroxy, halogen or an unsubstituted C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 alkoxy group;
R2 and R4 are the same or different and each represent hydrogen, halogen or an unsubstituted C1-C4 alkyl or C1-C4 alkoxy group; - R3 is hydroxy, halogen, for example fluorine, or an unsubstituted C1-C4 alkoxy group, for example -OCH3;
Rδ is halogen, for example chlorine, bromine and iodine, nitro, cyano, Cι-C4 alkyl, -CO2-(Cι-C4 alkyl), for example -CO2-CH3, or -CO-(d-C alkyl), for example -CO-CH2-Cl, the alkyl moieties in the substituent R being unsubstituted or substituted by 1, 2 or 3 halo substituents; n is 0 or 1 ; and
R7 is hydrogen,
Examples of these most preferred compounds include: 5-Bromo-3-(3,5-dibromo-4-hydroxy-benzylidene)-l,3-dihydro-indol-2-one 3-(3,5-Dibromo-4-hydroxy-benzylidene)-5-iodo-l,3-dil ydro-indol-2-one 5-Chloro-3-(4-hydroxy-3,5-diiodo-benzylidene)-l,3-dihydro-indol-2-one 5-Chloro-3-(3,5-dibromo-4-hydroxy-benzylidene)-l,3-dihydro-indol-2-one 7-Bromo-3-(3,5-dibromo-4-hydroxy-benzylidene)-l,3-dihydro-indol-2-one 7-Bromo-3-(4-hydroxy-3,5-diiodo-benzylidene)-l,3-dihydro-indol-2-one 3-(4-Hydroxy-3,5-diiodo-benzylidene)-2-oxo-2,3-dihydro-lH-mdole-5-carbonitrile 3-(3,5-Dibromo-4-hydroxy-benzylidene)-2-oxo-2,3-dihydro-lH-indole-7-carboxylic acid methyl ester
3-(4-Hydroxy-3,5-diiodo-benzylidene)-2-oxo-2,3-dihydro-lH-indole-7-carboxylic acid methyl ester 3-(3,5-Di-tert-butyl-4-hydroxy-benzylidene)-2-oxo-2,3-dihydro-lH-indole-5- carbonitrile
5-Chloro-3-(4-hydroxy-3,5-dimethyl-benzylidene)-l,3-dihydro-indol-2-one 5-Bromo-3-(4-hydroxy-3,5-dimethyl-benzylidene)-l,3-dihydro-indol-2-one 3-(3-Bromo-4-methoxy-benzylidene)-5-nitro-l,3-dihydro-indole-2-one 5-Bromo-3-(3,5-di-tert-butyl-4-hydroxy-benzylidene)-l,3-dihydro-indol-2-one 6-Bromo-3-(3,5-di-tert-butyl-4-hydroxy-benzylidene)-l,3-dihydro-indol-2-one 3-(3,5-Di-tert-butyl-4-hydroxy-berιzylidene)-l,3-dihydro-indol-2-one 5-Chloro-3-(3,5-di-tert-butyl-4-hydroxy-benzylidene)-l,3-dihydro-indol-2-one 5-Iodo-3-(2,4,6-trimethoxy-benzylidene)-l,3-dihydro-indol-2-one 7-Bromo-3-(3,5-di-tert-butyl-4-hydroxy-benzylidene)-l,3-dihydro-indol-2-one 7-Bromo-3-(4-hydroxy-3,5-dimethyl-benzylidene -l,3-dihydro-indol-2-one 3-(4-Hydroxy-3,5-dimethyl-benzylidene)-2-oxo-2,3-dihydro-lH-indole-7-carboxylic acid methyl ester
7-Bromo-3-(2,4,6-trimethoxy-benzylidene)-l,3-dihydro-indol-2-one 5-CUoro-3-(2,4,6-trimethoxy-benzylidene)-l,3-dihydro-indol-2-one 5-Bromo-3-(4-fluoro-benzylidene)- 1 ,3-dihydro-indol-2-one 3-(4-Hydroxy-3,5-dimethyl-benzylidene)-2-oxo-2,3-dihydro-lH-indole-5- carbonitrile
3- 4-Hydroxy-3,5-diiodo-benzylidene)-2-oxo-2,3-dmydro-lH-mdole-6-carbonitrile 3-(3-Bromo-4-methoxy-benzylidene)-2-oxo-2,3-dihydro-lH-indole-6-carbonitrile 2-Oxo-3-(2,4,6-trimethoxy-benzylidene)-2,3-dihydiO-lH-indole-6-carbonitrile 3-(3-Bromo-4-methoxy-ber-2^1idene)-2-oxo-2,3-dmydro-lH-indole-7-carbonitrile 5-Bromo-3-(4-hydiOxy-benzylidene)-l,3-dihydro-indol-2-one 5-Bromo-3-(4-hydroxy-3,5-diiodo-benzylidene)-l,3-dihydro-indol-2-one 6-Bromo-3-(3,5-dibromo-4-hydroxy-benzylidene)-l,3-dihydro-indol-2-one 5-Bromo-3-(2,3-dibromo-4-hydroxy-5-methoxy-benzylidene)-l,3-dihydro-indol-2- one
3-(4-Hydroxy-3,5-diiodo-benzylidene)-5-iodo-l,3-dihydro-indol-2-one 3-(4-Hydroxy-3,5-diiodo-benzylidene)-5-nitro-l,3-dihydro-indol-2-one 3-(4-Hydroxy-3,5-diiodo-benzylidene)-2-oxo-2,3-dihydro-lH-mdole-7-carbonitrile 5-(2-Chloro-acetyl)-3-(3,5-dibromo-4-hydroxy-benzylidene)-l,3-dihydro-indol-2- one and pharmaceutically acceptable salts thereof.
Compounds of the formula (I) may contain one or more chiral centre. For the avoidance of doubt, the chemical structures depicted herein are intended to embrace all stereoisomers of the compounds shown, including racemic and non-racemic mixtures and pure enantiomers and/or diastereoisomers.
Preferred compounds of the invention which contain a chiral centre are optically active isomers. Thus, for example, preferred compounds of formula (I) containing one chiral centre include an R enantimomer in substantially pure form, an S enantiomer in substantially pure form, and enantiomeric mixtures which contain an excess of the R enantiomer or an excess of the S enantiomer.
Further preferred compounds of the invention are pure E geometric isomers, pure Z geometric isomers, and mixtures of E and Z isomers which contain an excess of either the E or the Z isomer.
For the avoidance of doubt, the compounds of the formula (I) can, if desired, be used in the form of solvates. Further, for the avoidance of doubt, the formula (I) set out above is intended to embrace all tautomeric forms of the depicted compounds. As used herein, a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p-toluenesulphonic acid. Pharmaceutical acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases such as alkyl amines, aralkyl amines or heterocyclic amines.
Also provided is a compound of formula (lb) or a pharmaceutically acceptable salt thereof
Figure imgf000014_0001
wherein:
Ri and R5 are the same or different and each represent hydrogen, halogen, hydroxy, cyano, nitro, Cι-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cι-C6 alkoxy, C2- C6 alkenyloxy, C2-C6 alkynyloxy, Ci- alkylthio, C2-d alkenylthio, C2-C6 alkynylthio, or -NRR77 wherein R and R77are the same or different and each represent hydrogen, Cι-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; - R2 and R4 are the same or different and each represent hydrogen, halogen, hydroxy, cyano, nitro, Cι-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cι-C6 alkoxy, C2- C6 alkenyloxy, C2-C6 alkynyloxy, Cι-C6 alkyltliio, C2-C6 alkenylthio, C2-C6 alkynylthio, C -Cιo aryl, C3-C6 carbocyclyl, a 5- to 10- membered heterocyclic ring, a 5- to 10- membered heteroaryl ring, -NRR77 -(Cι-C6 alkyty-NKk77, -(C2-C6 alkenyl)- NRR77, -(C2-C6 alkynyl)-NRR77, -NR7-CONRR77 -COR77, -CO2R77 -CONRR77, -NR7-CO- R77, -SOR7 -S(O)2R77 -S(O)2NRR7or -L-X-R77, wherein (a) R7and R^are the same or different and each represent hydrogen, Cι-C alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6- C10 aryl, d-C6 carbocyclyl, a 5- to 10- membered heterocyclic ring, a 5- to 10- membered heteroaryl ring or -L-X-R , (b) each L is the same or different and represents a divalent Cι-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl group, (c) each X is the same or different and represents -O-, -S-, -SO-, -SO2-, -NH- or a direct bond and (d) each R is the same or different and represents Cι-C6 alkyl, C6-Cιo aryl, d-d carbocyclyl, a 5- to 10- membered heterocyclic ring or a 5- to 10- membered heteroaryl ring; - R3 is hydrogen, halogen, hydroxy, Ci-d alkyl, C2-C6 alkenyl, C2-C6 alkynyl,
Cι-C6 alkoxy, C2-C6 alkenyloxy, C2-d alkynyloxy, Cι-C6 alkylthio, C2-d alkenylthio, C2-C6 alkynylthio, -NRR77 -CO2H, 5-hydroxy-pyrrole-2,4-dione-3-yl, 5- hydroxy-pyrrolidine-2,3-dione-4-yl, 3H-[1 ,3,4]thiadiazol-2-onyl5 3H- [l,3,4]oxadiazol-2-onyl, 2-hydroxy-[l,3,4]thiadiazol-5-yl, 2-hydroxy- [l,3,4]oxadiazol-5-yl, 3-hydroxy-lH-[l,2,4]triazol-5-yl, 3-hydroxy-isoxazolyl, 5- hydroxy-isoxazolyl, tetrazolyl, for example 2H-tetrazolyl, triazolyl, for example 2H- [l,2,3]triazolyl, 3-trifluoromethyl-4H-[l,2,4]triazolyl, pyrrolidine-2,3,5-trionyl, 5- hydroxy-[l,2,4]thiadiazolyl, 5-hydroxy-[l,2,4]oxadiazolyl, 2,4-dioxo- tetrahydrofuranyl, l,3,4-triaza-2-onyl, l,2,4-oxadiazal-5-onyl, benzothiazolone-S,S- dioxidyl, benzothiazolone-l,l-dioxidyl, -NH-S(O)2-CF3 or -CO-NH-S(O)2-CH3, wherein R and R7 are the same or different and each represent hydrogen, Ci- alkyl, C2-C6 alkenyl or C2-C6 alkynyl; each R6 is the same or different and represents hydroxy, halogen, cyano, nitro, Cι-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cι-C6 alkoxy, C2-C6 alkenyloxy, C2- C6 alkynyloxy, d-d alkylthio, C2-C6 alkenylthio, C2-C6 alkynyltl io, -NR7R77, -COR77 -CO2R77 -CONR7R77, -NR-CO-NR77, -SOR77 -S(O)2R77 wherein R and R77 are the same or different and each represent hydrogen, Ci- alkyl, C -C6 alkenyl or C2-C6 alkynyl; n is 0, 1, 2 or 3; and
R7 is hydrogen, Ci- alkyl, C2-C alkenyl, C2-C6 alkynyl, C3-C6 carbocyclyl or C6-Cιo aryl, provided that:
(1) when R3 is -OCH3j either R2 is halogen or Ri and R are both Ci-d alkoxy;
(2) when n is 0, R2 and R4 are not simultaneously hydrogen;
(3) R2 and R3 are not simultaneously -OCH3; and
(4) either (a) neither R2 nor R4 is halogen or nitro when R2 is hydroxy or (b) (i) n is 1, 2 or 3, (ii) each R6 is other than chlorine, fluorine, -CF3O, ethyl, i-propoxy,
-CH2NH2, -N(CH3) , -NH2, -CONH2, -CO2H, -S(O)2CH3, -CONH2 and -CONH-
CH -CH2-OH, (iii) when an Re moiety is iodine, nitro or cyano, R2 and R4 are iodine,
(iv) when an R6 moiety is bromine, either the R6 moiety is at the 7- position of the indole moiety and R2 and R4 are bromine or iodine or one of R\ and R is bromine, (v) when an R6 moiety is -CO2Me it is at the 7- position of the indole moiety, and
(vi) when an R moiety is -COR7 is not at the 5- position of the indole moiety.
Preferred definitions for n, Ri, R2, R3, R4, R5 and R7 in the formula (lb) are the same as those set out above for the corresponding substituents in the formula (I). Typically, each Rδ in the formula (lb) is the same or different and represents hydroxy, -NH2, halogen, cyano, nitro, Ci- alkyl, Ci-d alkoxy, Cι-C alkylthio,
-NRR77 -COR77, -CO2R , -CONRR7' or -SO2R77 wherein R7 represents hydrogen or d-
C6 alkyl and R7represents Cι-C6 alkyl.
Preferably, each R6 in the formula (lb) is the same or different and represents hydroxy, -NH2, halogen, cyano, nitro, C1-C4 alkyl, C1-C4 alkoxy, -NRR77 -COR', -CO2R' or -CONRR7 wherein R represents hydrogen or C1-C4 alkyl and Represents
C1-C4 alkyl. Typically, the alkyl, alkenyl and alkynyl moieties in substituent R6 in the formula (lb) are unsubstituted or are substituted with one or more, for example 1, 2 or 3, halogen atoms.
Most preferably, each Re in the formula (lb) is the same or different and represents halogen, for example, chlorine, bromine and iodine, nitro, cyano, C1-C4 alkyl, -CO2-(d-C4 alkyl), for example -CO2-CH3 or -CO-(Cι-C4 alkyl), for example -CO-CH2-CI.
Preferred compounds of the formula (lb) are those in which:
Ri and R5 are the same or different and each represent hydrogen, hydroxy, halogen or an unsubstituted C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 alkoxy group;
R2 and R4 are the same or different and each represent hydrogen, halogen or an unsubstituted C1-C4 alkyl or C1-C4 alkoxy group;
R3 is hydroxy, halogen, for example fluorine, or an unsubstituted C1-C4 alkoxy group, for example -OCH3; - R6 is halogen, for example chlorine, bromine and iodine, nitro, cyano, C1-C4 alkyl, -CO2-(d-C4 alkyl), for example -CO2-CH3 or -CO-(Cι-C4 alkyl), for example -CO-CH2-CI, the alkyl moieties in the substituent Rg being unsubstituted or substituted by 1 , 2 or 3 halo substituents; n is 0 or 1 ; and - R7 is hydrogen, provided that:
(1) when R3 is -OCH , either R2 is halogen or Ri and R are both C1-C4 alkoxy;
(2) when n is 0, R2 and R4 are not simultaneously hydrogen;
(3) R2 and R4 are not simultaneously -OCH3; and (4) either (a) neither R2 nor R4 is halogen when R3 is hydroxy or (b) (i) n is 1 , (ii) R6 is other than chlorine, fluorine and ethyl, (iii) when R6 is iodine, nitro or cyano R2 and R4 are iodine, (iv) when Re is bromine either R is at the 7- position of the indole moiety and R2 and R4 are bromine or iodine or one of R\ and R is bromine, (v) when R6 is -CO2Me it is at the 7- position of the indole moiety and (vi) when R6 is -CO- (C1-C4 alkyl) it is not at the 5- position of the indole moiety.
Examples of these preferred compounds of formula (lb) include: 7-Bromo-3-(3,5-dibromo-4-hydroxy-benzylidene)-l,3-dihydro-indol-2-one 7-Bromo-3-(4-hydroxy-3,5-diiodo-benzylidene)-l,3-dilιydro-indol-2-one 3-(4-Hydroxy-3,5-diiodo-benzylidene)-2-oxo-2,3-dihydro-lH-indole-5-carbonitrile 3-(3,5-Dibromo-4-hydroxy-benzylidene)-2-oxo-2,3-dihydro-lH-indole-7-carboxylic acid methyl ester 3-(4-Hydroxy-3,5-diiodo-benzylidene)-2-oxo-2,3-dihydro-lH-indole-7-carboxylic acid methyl ester
3-(3,5-Di-tert-butyl-4-hydroxy-benzylidene)-2-oxo-2,3-dihydro-lH-indole-5- carbonitrile 5-Chloro-3-(4-hydroxy-3,5-dimethyl-benzylidene)-l,3-dihydro-indol-2-one 5-Bromo-3-(4-hydroxy-3,5-dimethyl-benzylidene)-l,3-dihydro-indol-2-one 3-(3-Bromo-4-methoxy-benzylidene)-5-nitro-l,3-dihydro-indole-2-one 5-Bromo-3-(3,5-di-tert-butyl-4-hydroxy-benzylidene)-l,3-dihydro-indol-2-one 6-Bromo-3-(3,5-di-tert-butyl-4-hydroxy-benzylidene)-l,3-dihydro-indol-2-one 3-(3,5-Di-tert-butyl-4-hydiOxy-benzylidene)-l,3-dihydro-indol-2-one 5-Chloro-3-(3,5-di-tert-butyl-4-hydroxy-benzylidene)-l,3-dihydro-indol-2-one 5-Iodo-3-(2,4,6-trimethoxy-benzylidene)-l,3-dihydro-indol-2-one 7-Bromo-3-(3,5-di-tert-butyl-4-hydroxy-benzylidene)-l,3-dihydro-indol-2-one 7-Bromo-3-(4-hydroxy-3,5-dimethyl-benzylidene)-l,3-dihydro-indol-2-one 3-(4-Hydroxy-3,5-dimethyl-benzylidene)-2-oxo-2,3-dihydro-lH-indole-7-carboxylic acid methyl ester
7-Bromo-3-(2,4,6-trimethoxy-benzylidene)-l,3-dihydro-indol-2-one 5-Chloro-3-(2,4,6-trimethoxy-benzylidene)-l,3-dihydiO-indol-2-one 5-Bromo-3-(4-fluoro-benzylidene)-l,3-dihydro-indol-2-one 3-(4-Hydroxy-3,5-dimethyl-benzylidene)-2-oxo-2,3-dihydro-lH-indole-5- cai'bonitrile
3-(4-Hyαroxy-3,5-diiodo-benzylidene)-2-oxo-2,3-dihydro-lH-indole-6-carbonitrile 3-(3-Bromo-4-methoxy-benzylidene)-2-oxo-2,3-dihydro-lH-indole-6-carbonitrile 2-Oxo-3-(2,4,6-trimethoxy-benzylidene)-2,3-dihy<-ιro-lH-indole-6-carbonitrile 3-(3-Bromo-4-methoxy-benzylidene)-2-oxo-2,3-dihydro-lH-indole-7-carbonitrile 5-Bromo-3-(4-hydroxy-benzylidene)-l ,3-dihydro-indol-2-one
5-Bromo-3-(2,3-dibromo-4-hydroxy-5-methoxy-benzylidene)-l,3-dihydro-indol-2- one 3-(4-Hydroxy-3,5-diiodo-benzylidene)-5-iodo-l,3-dihydro-indol-2-one 3-(4-Hydroxy-3,5-diiodo-benzylidene)-5-nitro-l,3-dihydro-indol-2-one 3-(4-Hydroxy-3,5-diiodo-ben2ylidene)-2-oxo-2,3-dmydro-lH-indole-7-carbonitrile
Preferably, in the compounds of formula (lb), R2 and R3 are not simultaneously alkoxy groups.
Preferably, in the compounds of formula (lb), when n is 0, R2 and R4 are both Cι-C6 alkyl groups.
More preferably, in the compounds of formula (lb), the phenyl ring substituted by Ri to R5 is 3,5-dihalo-4-hydroxyphenyl, for example 3,5-dibromo-4- hydroxyphenyl and 3,5-diiodo-4-hydroxyphenyl, 3,5-di-(d-d alkyl)-4- hydroxyphenyl, for example 3,5-di-(t-butyl)-4-hydroxyphenyl and 3,5-dimethyl-4- hydroxyphenyl, 4-hydroxy-5-halophenyl, for example 4-hydroxy-5-bromophenyl, 4- methoxy-5-halophenyl, for example 4-methoxy-5-bromophenyl, 2,4,6- trimethoxyphenyl, 4-halophenyl, for example 4-fluorophenyl, 4-hydroxyphenyl or 2,3-dihalo-4-hydroxy-5-methoxyphenyl for example 2,3-dibromo-4-hydroxy-5- methoxyphenyl, provided when the phenyl ring is substituted by Ri to R5 is a 4- fluorophenyl moiety n is 1 and R-5 is halogen.
Typically, in the compounds of formula (lb), R3 is not an alkoxy, alkenyloxy or alkynyloxy group. In a further preferred embodiment of the invention, in the compounds of formula (lb) neither R2 nor R4 is halogen or nitro when R3 is hydroxy.
Further preferred compounds of formula (lb) are those in which either (a) neither R2 nor R4 is halogen, hydroxy, cyano, nitro, -CONR7R77, -S(O)2NRR'J -NRR77, Ci-d alkoxy, C2-C6 alkenyloxy or C2-d alkynyloxy when R3 is hydroxy or -NH- S(O)2CF3 or (b) Ri and R5 are not simultaneously hydrogen.
The compounds of formula (I) may be prepared by reacting an oxindole of formula (II) with an aldehyde of formula (III) as follows.
Figure imgf000020_0001
(ID (IV)
Typically, the reaction takes place in the presence of a base, such as piperidine, in a solvent such as ethanol. The reaction may be conducted under non- extreme temperatures, typically in the range of 0 to 120°C.
Alternatively, the compounds of formula (I) may be prepared by reacting an oxindole of formula (II) with an aldehyde of formula (III) in the presence of catalytic quantity of acid, such as pTS A. The reaction may also be carried out in the presence of strong acid, for example in a catalytic quantity of 2N HCI, preferably under non- extreme temperatures, typically in the range of 0 to 120°C.
Compounds of formulae (I) and (II), wherein R is other than hydrogen can be prepared from compounds in which R is hydrogen, using reaction conditions well known to one skilled in the art. For example, introduction of alkyl, alkenyl, alkynyl or cycloalkyl groups at the R7 position can be effected by combining a compound in which R is hydrogen with a base such as potassium carbonate, sodium hydride, sodium carbonate, sodium hydroxide, potassium hydroxide, potassium t-butoxide or butyl lithium. The amount of base is typically 0.5 to 1 mols, based on 1 mol of reactant compound in which R7 is hydrogen. The reaction can be effected in a suitable solvent such as acetone, chloroform, methylene chloride, dimethylformamide, ethanol, butanol, isopropanol, dimethylsulfoxide or a mixture of two or more of the foregoing solvents. To this mixture, an appropriate halide or sulphate can be added. The reaction can be stirred for a period of time from two to about 72 hours, at a temperature between 0°C to 100°C. Additional reagents, such as phase transfer catalysts, can be added if required. Compounds of formula (LI) and (El) are commercially available or can be prepared by analogy with known techniques.
The compounds of formula (I) are found to be inhibitors of type II shikimate kinase enzymes. Typically, therefore, the said medicament is for use in the inhibition of a type IL sliikimate kinase enzyme. Preferred compounds of the invention have an IC5o value against a type II shikimate kinase enzyme of 10 μM or less, preferably 5 μM or less, more preferably 1 μM or less.
The present invention also provides a method for treating a patient suffering from or susceptible to infection by an organism in which the biosynthesis of aromatic amino acids is effected via the shikimate pathway, which method comprises administering to said patient an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
The organisms in which the biosynthesis of aromatic amino acids is effected via the shiLkimate pathway can easily be identified by those of skill in the art. Such organisms can be identified, for example, by (a) determining whether in vitro growth is inhibited by well characterised inhibitors of the shikimate pathway, such as glyphosphate, and (b) determining whether such inhibition is reversed by addition of ?-aminobenzoate. A positive determination in each of steps (a) and (b) indicates that the organism in question is one in which biosynthesis of aromatic amino acids is effected via the shikimate pathway.
The shikimic acid pathway is essential for the synthesis of aromatic amino acids in fungi and bacteria. Accordingly, the compounds of the invention are effective in treating or preventing bacterial or fungal infection. Said organism is typically a bacterium or fungus, therefore. The compounds of the invention are particularly effective against bacteria.
Indeed they are found to be so active against bacteria that they may be inhibiting bacterial growth not only by inhibiting the shikimate pathway, but also by an additional mechanism. Thus, in a preferred embodiment, the present invention provides the use of the compounds of the invention in the manufacture of a medicament for use in treating or preventing a bacterial infection. Also provided is a method of treating a patient suffering from or susceptible to a bacterial infection, which method comprises the administration thereto of a compound of the invention. Typically, the infection is an infection by a Staphylococcus, Enterococcus, Corynebacterium, Listeria, Neisseria, Propionibacterium or Moraxella bacterium. More preferably, it is an infection by a strain of Staphylococcus aureus, in particular methicillin-resistant Staphylococcus aureus, Enterococcus faecium, in particular vancomycin-resistant or vancomycin-sensitive Enerococcus faecium, Enterococcus faecalis, Corynebacterium minutissimum, Corynebacterium auris, Corynebacterium urealyticum, Listeria monocytogenes NCTC 10357, Listeria monocytogenes NCTC 11007, Listeria monocytogenes, Neisseria meningitides, Neisseria flava, Neisseria elongata, Propionibacterium Sp ox Moraxella catarrhalis. In a further embodiment of the invention, said organism in which the biosynthesis of aromatic amino acids is effected via the shikimate pathway is not methicillin-resistant Staphylococcus aureus. More typically, in this embodiment of the invention said organism is not a strain of Staphylococcus aureus, in particular methicillin-resistant Staphylococcus aureus, Enterococcus faecium, in particular vancomycin-resistant or vancomycin-sensitive Enterococcus faecium, Enterococcus faecalis, Corynebacterium minutissimum, Coiynebacteriam auris, Corynebacterium urealyticum, Listeria monocytogenes NCTC 10357, Listeria monocytogenes NCTC 11007, Listeria monocytogenes, Neisseria meningitides, Neisseria flava, Neisseria elongata, Propionibacterium Sp or Moraxella catarrhalis. Preferably, in this embodiment of the invention, said organism is not a Staphylococcus, Enterococcus, Coiynebacterium, Listeria, Neisseria, Propionibacterim or Moraxella bacterium. More preferably, in the embodiment of the invention, said organism is not a bacterium.
The compounds of the invention can also be used generally to prevent bacterial growth. For example, they may be added to solutions, such as solutions for contact lenses, to prevent bacterial growth. They may also be used in antibiotic coatings on surgical instruments and in products such as medicated soaps. Accordingly, the present invention also provides the non-therapeutic use of a compound of the invention in inhibiting bacterial growth. Also provided is a contact lens solution or a medicated soap comprising a compound of the invention. Further, the present invention provides a surgical instrument having thereon an antibiotic coating comprising a compound of the invention. The shikimic acid pathway is also implicated in the metabolism of parasites. For example, it is implicated in the metabolism of apicomplexan parasites. Accordingly, the compounds of the invention are effective in the treatment or prevention of infection by a parasite in which the biosynthesis of aromatic amino acids is effected via the shikimate pathway. As indicated above, said parasites can be identified, for example, by (a) determining whether in vitro growth is inhibited by well characterised inhibitors of the shikimate pathway, such as glyphosphate, and (b) determining whether such inhibition is reversed by addition ofp-aminobenzoate.
In particular, the compounds of the invention are active against Toxoplasma gondii, Ciyptosporidium parvum and Plasmodium falciparum. Plasmodium falciparum is known to cause malaria. Thus, the said patient is typically suffering from or susceptible to, and the said medicament is typically for use in the treatment or prevention of, infection by an apicomplexan parasite. In particular, the said patient is typically suffering from or susceptible to, and the said medicament is typically for use in the treatment or prevention of, malaria.
When used for treating the above disorders, the compounds of the invention may be administered in a variety of dosage forms. Thus, they can be administered orally, for example as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules. The compounds of the invention may also be administered parenterally, whether subcutaneously, intravenously, intramuscularly, intrasternally, transdermally or by infusion techniques. The compounds may also be administered as suppositories.
The present invention also provides a compound of formula (lb), as defined above, or a pharmaceutically acceptable salt thereof, for use in a method of treating the human or animal body. It further provides a pharmaceutical composition containing a compound of formula (lb), as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
A compound of the invention is typically formulated for administration with a pharmaceutically acceptable carrier or diluent. For example, solid oral forms may contain, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents; e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g. starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, such as lecithin, polysorbates, laurylsulphates; and, in general, non toxic and pharmacologically inactive substances used in pharmaceutical formulations. Such pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tableting, sugar coating, or film coating processes.
Liquid dispersions for oral administration may be syrups, emulsions and suspensions. The syrups may contain as carriers, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol.
Suspensions and emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol. The suspension or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.
Solutions for injection or infusion may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions. A therapeutically effective amount of a compound of the invention is administered to a patient. A typical dose is from about 0.001 to 50 mg per kg of body weight, according to the activity of the specific compound, the age, weight and conditions of the subject to be treated, the type and severity of the disease and the frequency and route of administration. Preferably, daily dosage levels are from 5 mg to 2 g.
The shikimic acid pathway is also essential in higher plants, algae and fungi. The compounds of the invention are therefore effective in controlling higher plants, algae and fungi. They can be used as selective herbicides and fungicides, for example. Accordingly, the present invention provides the use of a compound of formula (I), or an agriculturally acceptable salt thereof, as a herbicide or a fungicide. Also provided is a method of controlling weeds or fungi at a locus, which method comprises treating the locus with a compound of formula (I) or an agriculturally acceptable salt thereof.
Typically the locus comprises agricultural or horticultural plants or a medium in which such plants grow. A preferred method of controlling fungi is a method of treating a plant for, or protecting a plant against, fungal attack, which method comprises applying to the plant a compound of formula (I) or an agriculturally acceptable salt thereof. Smuts and rusts on a plant can, for example, be treated by this method.
Typically, the active compound is applied to the leaves. The number of applications and the rate of application depend on the intensity of the fungal attack. However, an active compound can also be applied to a plant through the roots via the soil (systemic action) by impregnating the locus of the plant with a liquid composition comprising the active compound, or by applying the compound in solid form to the soil, e.g. in granular form (soil application). The active compound may also be applied to seeds (coating) by impregnating the seeds either with a liquid formulation containing the active compound, or coating them with a solid formulation. In special cases, further types of application are also possible, for example, selective treatment of the plant stems or buds.
Suitable agriculturally acceptable salts include those salts mentioned above as examples of pharmaceutically acceptable salts.
The said herbicidal or fungicidal composition may be prepared by mixing a compound of formula (I), or an agriculturally acceptable salt thereof, with an agriculturally acceptable carrier or diluent. Suitable such compositions include wettable powders, granules, water-dispersible granules, emulsion concentrates, suspension concentrates, and powders suitable for dusting plants. The fungicidal or herbicidal compositions may comprise further agricultural chemicals, for example further fungicides and herbicides or insecticides, miticides, plant growth regulators, fertilizers and soil conditioners.
The herbicidal or fungicidal composition preferably comprises a further fungicide or herbicide. This leads not only to a reduction in dose and manpower, but also to broadening of the herbicidal or fungicidal spectrum. This broadening is attributable to cooperative activities. Suitable agriculturally acceptable carriers and diluents include solid or liquid carriers and diluents.
Examples of the solid carriers or diluents include clays such as kaolinites, montmorillonites, illites and polygroskites, more specifically pyrophyllite, attapulgite, sepiolite, kaolinite, bentonite, vermiculite, mica and talc. Other inorganic substances such as gypsum, calcium carbonate, dolomite, diatomaceous earth, magnesium lime, phosphorus lime, zeolite, silicic anhydride and synthetic calcium silicate may also be used. Suitable organic carriers and diluents include soybean flour, tobacco flour, walnut flour, wheat flour, wood flour, starch and crystalline cellulose. Further synthetic or natural polymers such as coumarone resin, petroleum resin, alkyd resin, polyvinyl chloride, polyalkylene glycol, ketone resin, ester gum, copal gum and dammar gum are suitable, as are waxes such as carnauba wax and bee wax.
Examples of suitable liquid carriers and diluents include paraffin or naphthene hydrocarbons such as kerosene, mineral oil, spindle oil and white oil, aromatic hydrocarbons such as xylene, ethylbenzene, cumene and methylnaph- thalene, chlorinated hydrocarbons such as trichloroethylene, monochlorobenzene and o-chloro toluene, ethers such as dioxane and tetrahydrofuran, ketones such as acetone, methyl ethyl ketone, diisobutyl ketone, cyclohexanone, acetophenone and isophorone, esters such as ethyl acetate, amyl acetate, ethylene glycol acetate, diethylene glycol acetate, dibutyl maleate and diethyl succinate, alcohols such as methanol, n-hexanol, ethylene glycol, diethylene glycol, cyclohexanol and benzyl alcohol, ether alcohols such as ethylene glycol ethyl ether and diethylene glycol butyl ether and polar solvents such as dimethylformamide, dimethyl sulfoxide and water. Typically the herbicidal and fungicidal compositions comprise a surfactant and/or another auxiliary agent suitable for various purposes such as emulsification, dispersion, humidification, spreading, dilution, combination destruction control, stabilization of active ingredients, improvement of flowability, prevention of corrosion and prevention of freezing. Preferably, the herbicidal and fungicidal compositions of the invention comprise at least one surfactant. The present invention also provides a herbicidal or fungicidal composition comprising: an oxindole of formula (I) or an agriculturally acceptable salt thereof; at least one surfactant; and an agriculturally acceptable carrier or diluent.
Suitable surfactants include nonionic, anionic, cationic and amphoteric surfactants. Nonionic and anionic surfactants are preferred. Suitable anionic surfactants can be both water-soluble soaps and water- soluble synthetic surface-active compounds.
Suitable soaps are the alkali metal salts, alkaline earth metal salts or unsubstituted or substituted ammonium salts of higher fatty acids (chains of 10 to 22 carbon atoms), for example the sodium or potassium salts of oleic or stearic acid, or of natural fatty acid mixtures which can be obtained for example from coconut oil or tallow oil. The fatty acid methyltaurin salts may also be used.
More frequently, however, so-called synthetic surfactants are used, especially fatty sulfonates, fatty sulfates, sulfonated benzimidazole derivatives or alkylarylsulfonates. The fatty sulfonates or sulfates are usually in the form of alkali metal salts, alkaline earth metal salts or unsubstituted or substituted ammonium salts and have a C8 to C22 alkyl radical which also includes the alkyl moiety of alkyl radicals, for example, the sodium or calcium salt of lignonsulfonic acid, of dodecylsulfate or of a mixture of fatty alcohol sulfates obtained from natural fatty acids. These compounds also comprise the salts of sulfuric acid esters and sulfonic acids of fatty alcohol/ethylene oxide adducts. The sulfonated benzimidazole derivatives preferably contain 2 sulfonic acid groups and one fatty acid radical containing 8 to 22 carbon atoms. Examples of alkylarylsulfonates are the sodium, calcium or triethanolamine salts of dodecylbenzenesulfonic acid, dibutylnapthalenesulfonic acid, or of a naphthalenesulfomc acid/formaldehyde condensation product. Also suitable are corresponding phosphates, e.g. salts of the phosphoric acid ester of an adduct of p- nonylphenol with 4 to 14 moles of ethylene oxide.
Non-ionic surfactants are preferably polyglycol ether derivatives of aliphatic or cycloaliphatic alcohols, or saturated or unsaturated fatty acids and alkylphenols, said derivatives containing 3 to 30 glycol ether groups and 8 to 20 carbon atoms in the (aliphatic) hydrocarbon moiety and 6 to 18 carbon atoms in the alkyl moiety of the alkylphenols. Further suitable non-ionic surfactants are the water-soluble adducts of polyethylene oxide with polypropylene glycol, ethylenediamine propylene glycol and alkylpolypropylene glycol containing 1 to 10 carbon atoms in the alkyl chain, which adducts contain 20 to 250 ethylene glycol ether groups and 10 to 100 propylene glycol ether groups. These compounds usually contain 1 to 5 ethylene glycol units per propylene glycol unit. Representative examples of non-ionic surfactants are nonylphenolpolyethoxyethanols, castor oil polyglycol ethers, polypropylene /polyethylene oxide adducts, tributylphenoxypolyethoxyethanol, polyethylene glycol and octylphenoxyethoxy ethanol. Fatty acid esters of polyoxyethylene sorbitan and polyoxyethylene sorbitan trioleate are also suitable non-ionic surfactants.
Cationic surfactants are preferably quaternary ammonium salts which have, as N- substituents, at least one Cs-C22 alkyl radical and, as further substituents, lower unsubstituted or halogenated alkyl, benzyl or lower hydroxyalkyl radicals. The salts are preferably in the form of halides, mefhylsulfates or ethylsulfates, e.g. ste-uyltrimethylammonium chloride or benzyldi(2-chloroethyl)ethylammomium bromide.
The surfactants customarily employed in the art of formulation are described, for example, in "McCutcheon's Detergents and Emulsifϊers Annual", MC Publishing Corp. Ringwood, New Jersey, 1979, and Sisely and Wood, "Encyclopaedia of Surface Active Agents", Chemical Publishing Co., Inc. New York, 1980.
The said auxiliary agent includes casein, gelatin, albumin, glue, sodium alginate, carboxymethylcellulose, methylcellulose, hydroyethylcellulose and polyvinyl alcohol.
The above-described carriers or diluents and various auxiliary agents may be used alone or in combination.
The content of active compound in the herbicidal and fungicidal composition of the invention may vary widely depending on the form of formulation. Typically, the amount of active compound is 0.1 to 99%, preferably 1 to 80% by weight of the composition. More specifically, wettable powders typically contain 25 to 90% by weight of active compound. Granules typically contain 1 to 35% by weight of active compound, which may be mixed with the solid carrier or diluent uniformly, or mixed to or absorbed on the surface of the solid carrier or diluent uniformly. It is preferred that the diameter of the granules is from 0.2 to 1.5mm. Emulsion concentrates typically contain 5 to 30% by weight of active compound, and in additional 5 to 20% by weight of an emulsifier. Suspension concentrates typically contain 5 to 50% by weight of active compound, and in addition 3 to 10% by weight of a dispersion wetting agent.
The compounds of the invention may be applied in effective amounts to various places to be protected, for example farm-lands such as paddy fields and upland, or non-crop lands. When used as herbicides they may be applied prior to germination of weeds or to weeds of various stages from after germination to growth period. When the compounds of the invention are used as herbicides, the dose is generally, as amount of active ingredients, on the order of 0.1 to 10,000 g/ha, preferably 1 to 5,000 g/ha, more preferably from 50 to 3,000 g/ha. The dose may be varied depending on the kind of objective weeds, their growth stages, places of application and weather. When the compounds of the invention are used as fungicides, the dose is typically from 50g to 5kg of active ingredient per hectare, preferably from lOOg to 2kg per hectare, more preferably from 200g to 500g per hectare.
The shikimic acid pathway is also essential for the synthesis of aromatic amino acids in algae. Accordingly, the compounds of the present invention are effective in controlling algae. The present invention therefore provides the use of a compound of formula (I), or a salt thereof, in controlling algae. In particular, the invention provides a method of treating algae in a fish tank or pond, which method comprises applying to the fish tank or pond a compound of formula (I) or a salt thereof.
The following Examples illustrate the invention. They do not, however, limit the invention in any way. In this regard, it is important to understand that the particular assays used in the Examples are designed only to provide an indication of activity in inhibiting shikimate kinase. Other assays are available to determine the activity of given compounds as shikimate kinase inhibitors, and a negative result in any one particular assay is not determinative. Examples
In this section, all temperatures are in °C. Flash column chromatography was carried out using Merck 9385 silica. Solid phase extraction (SPE) chromatography was carried out using Jones Chromatography (Si) cartridges under 15mmHg vacuum with stepped gradient elution. Thin layer chromatography (TLC) was carried out on plastic plates.
LC-MS CONDITIONS Samples were run on a MicroMass ZMD, using electrospray with simultaneous positive - negative ion detection.
Column : YMC-PACK FL-ODS AQ, 50 x 4.6mm I.D S-5μm.
Gradient : 95:5 to 5:95 v/v H2O/CH3CN + 0.05% Formic Acid over 4.0 min, hold 3 min, return to 95:5 v/v H2O/CH3CN + 0.05 % Formic Acid over 0.2 min and hold at 95 :5 v/v H2O/CH3CN + 0.05%> Formic Acid over 3 min.
Detection : PDA 250 - 340 nm.
Flow rate : 1.5 ml/min
Example 1
5-Bromo-3-(3,5-dibromo-4-hydroxy-benzylidene)-l,3-dihydro-indol-2-one
A mixture of 5-bromo-oxindole (O.lg, 0.47mmol) and 3,5-dibromo-4- hydroxybenzaldehyde (0.132g, 0.47mmol) in ethanol (1ml) and piperidine (lOul) was heated at gentle reflux overnight (lShrs). The cooled reaction mixture was concentrated in vacuo before washing the resultant solid with 2N HCI (5ml) and diethyl ether (5ml). The product, collected by filtration and dried by suction filtration overnight, was isolated as a mixture of isomers, the solid being yellow in colour (0.174g, 7S%).
1H NMR (d6 DMSO, δ) 10.8(1H, 2s), 8.75(2H, s), 7.90(1H, s), 7.85, 7.60(1H, 2d), 7.80, 7.50(lH,2s), 7.40(1H, 2dd), 6.80 (IH, 2d). LC MS RT=5.90, 6.43 Found [M+H]+ = 475
Example 2
3-(3,5-Dibromo-4-hydroxy-benzylidene)-5-iodo-l,3-dihydro-indol-2-one
This material was prepared as described for Example 1 except that 5-iodo- oxindole was used. The title compound was a yellow solid (0.120g, 50%)
LC/MS RT= 5.81, 6.33 min Found ES- = 520 NMR (δ, d6DMSO) 10.70 (IH, 2s), 8.80, 7.90 (IH, 2s), 8.00, 7.80 (IH, 2d), 7.85, 7.75 (IH, 2s), 7.55 (IH, 2dd), 6.75 (IH, 2d)
Example 3
5-Chloro-3-(4-hydroxy-3,5-diiodo-benzylidene)-l,3-dihydro-indol-2-one
This material was prepared as described for Example 1 except that 5-chloro- oxindole and 3,5-diiodo-4-hydroxybenzaldehyde were used. The title compound was a yellow solid (0.183g, 74%)
LC/MS RT= 5.88 min Found ES+ =524
1H NMR (d6 DMSO, δ) 10.70(1H, 2s), 9.00(1H, s), 8.10 (2H, s), 7.60(1H, s), 7.70, 7.55(1H, 2d), 7.30, 7.20(1H, 2dd), 6.90, 6.80(1H, 2d)
Example 4 5-Chloro-3-(3,5-dibromo-4-hydroxy-benzylidene)-l,3-dihydro-indol-2-one
This material was prepared as described for Example 1 except that 5-chloro- oxindole was used. The title compound was a yellow solid (0.142g, 70%)
LC/MS RT= 5.83, 6.35 min Found ES+ = 430
1H NMR (do DMSO, δ) 10.80 (IH, 2s), 8.80 (2H, s), 7.90(1H, s), 7.80, 7.50(1H, 2s), 7.70, 7.40(1H, 2d), 7.25 (IH, 2dd), 6.85 (IH, 2d) Example 5 7-Bromo-3-(3,5-dibromo-4-hydroxy-berLzylidene)-l,3-dihydro-indol-2-one
This material was prepared as described for Example 1 except that 7-bromo- oxindole was used. The title compound was a yellow solid (0.1 lOg, 50%)
LC/MS RT= 5.84, 6.30 min Found ES+ = 475 1H 1H NNMMRR ((dd66 DDMMSSOO,, δδ)) 1100..6600,, 1100..5500 ((IIHH,, 22ss)),, 8.80 (2H, s), 8.40 (IH, bs), 7.80, 7.50 (IH, s), 7.70, 7.55 (IH, 2dd), 7.35, 7.20 (IH, 2d), 6.85 (IH, 2t)
Example 6 7-Bromo-3-(4-hydroxy-3,5-diiodo-benzylidene)-l,3-dihydro-indol-2-one
This material was prepared as described for Example 1 except that 7-bromo- oxindole was used. The title compound was a yellow solid (0.132g, 50%)
LC/MS RT=6.13, 6.55 min Found ES+ = 569
1H NMR (d6 DMSO, δ) 10.50, 10.65 (IH, 2s), 8.95 (2H, s), 8.30 (IH, bs), 7.60, 7.50 (IH, 2s), 7.45, 7.40 (IH, 2s), 7.30, 7.20 (IH, 2d), 6.85 (IH, 2t)
Example 7 3-(4-Hydroxy-3,5-diiodo-ber-2ylidene)-2-oxo-2,3-dihydro-lH-mdole-5-carbonitrile
This material was prepared as described for Example 1 except that 5-cyano- oxindole (0.47mmol) and 3,5-diiodo-4-hydroxybenzaldehyde (0.47mmol) were used. The title compound was a yellow solid (16mg, 6%)
LC/MS RT=5.36 min Found ES+ = 515 Example 8
3-(3,5-Dibromo-4-hydroxy-benzylidene)-2-oxo-2,3-dil ydro-lH-indole-7-carboxylic acid methyl ester
This material was prepared as described for Example 1 except that methyl oxindole-7-carboxylate (0.47mmol) and 3,5-dibromo-4-hydroxybenzaldehyde (0.47mmol) were used. The title compound was a yellow solid (98mg, 46%)
LC/MS RT= 5.75, 6.15min Found ES+ = 452 IH NMR (d6 DMSO, δ) 10.10, 10.00 (IH, 2brs), 8.90 (2H, brs), 7.85 (IH, 2d), 7.65 (2H, m), 7.10 (IH, t), 3.90 (3H, s)
Example 9
3-(4-Hydroxy-3,5-diiodo-benzylidene)-2-oxo-2,3-dihydro-lH-indole-7-carboxylic acid methyl ester
This material was prepared as described for Example 1 except that methyl oxindole-7-carboxylate (0.47mmol) and 3,5-diiodo-4-hydroxybenzaldehyde (0.47mmol) were used. The title compound was a yellow solid (22mg, 8%)
LC/MS RT= 6.1 lmin Found ES+ = 548
Example 10
3-(3,5-Di-tert-butyl-4-hydroxy-benzylidene)-2-oxo-2,3-dihydro-lH-indole-5- carbonitrile
This material was prepared as described for Example 1 except that methyl oxindole-7-carboxylate (0.47mmol) and 3,5-diiodo-4-hydroxybenzaldehyde (0.47mmol) were used. The title compound was a yellow solid (22mg, 8%)
LC/MS RT=6.44 min Found ES+ = 548 Example 11 5-Chloro-3-(4-hydroxy-3,5-dimethyl-benzylidene)-l,3-dihydro-indol-2-one
This material was prepared as described for Example 1 except that 5-chloro- oxindole (0.47mmol) and 3,5-dimethyl-4-hydroxybenzaldehyde (0.47mmol) were used. The title compound was a yellow solid (117mg, 84%)
LC/MS RT= 5.42min Found ES+ = 300
IH NMR (d6 DMSO, δ) 10.65 (IH, 2brs), 8.20 (IH, s), 7.75, 7.65, 7.50 (2H, d , 2app s), 7.40 (IH, s), 7.25 (IH, 2dd), 6.85 (IH, 2d), 2.20 (6H, 2s)
Example 12 5-Bromo-3-(4-hydroxy-3,5-dimethyl-benzylidene)-l,3-dihydro-indol-2-one
This material was prepared as described for Example 1 except that 5-bromo- oxindole (0.47mmol) and 3, 5 -dimethyl -4-hydroxybenzaldehyde (0.47mmol) were used. The title compound was a yellow solid (21mg, 13%)
LC/MS RT=5.51, 5.93 min Found ES+ = 345
Example 13 3-(3-Bromo-4-methoxy-benzylidene)-5-nitro-l,3-dihydro-indole-2-one
This material was prepared as described for Example 1 except that 5-nitro- oxindole (0.47mmol) and 3-bromo-4-methoxybenzaldehyde (0.47mmol) were used. The title compound was a yellow solid (108mg, 60%>)
LC/MS RT= 5.64 and 6.01min Found ES+ =373 IH NMR (d6 DMSO, δ) 11.19 (brs, IH), 9.04 (d, IH), 8.66 (d, IH), 8.45 (2d, IH), 8.33 - S.07 (m, IH), 7.86 - 7.77 (m, IH), 7.301 (t, IH), 7.04 (2d, IH), 3.96 (s, 3H) Example 14 5-BiOmo-3-(3,5-di-tert-butyl-4-hydroxy-benzylidene)-l,3-dihydro-indol-2-one
This material was prepared as described for Example 1 except that 5-bromo- oxindole (0.47mmol) and 3,5-di-tert-butyl-4-hydroxybenzaldehyde (0.47mmol) were used. The title compound was a yellow solid (103mg, 51%)
LC/MS RT=7.07 min Found ES+ = 429
IH NMR (d6 DMSO, D δ) 10.65, 10.45 (IH, 2s), 8.45 (IH, s), 7.95, 7.80, 7.65 (3H, d, app 2s), 7.30 (IH, 2dd), 6.80 (IH, 2d), 1.40 (18H, s)
Example 15 6-Bromo-3-(3,5-di-tert-butyl-4-hydroxy-benzylidene)-l,3-dihydro-indol-2-one
This material was prepared as described for Example 1 except that 6-bromo- oxindole (0.47mmol) and 3,5-di-tert-butyl-4-hydroxybenzaldehyde (0.47mmol) were used. The title compound was a yellow solid (27mg, 13%)
LC/MS RT= 7.14, 7.22min Found ES+ = 429 1H NMR (d6 DMSO, δ)
Example 16 3-(3,5-Di-tert-butyl-4-hydroxy-benzylidene)-l,3-dihydro-indol-2-one
This material was prepared as described for Example 1 except that oxindole
(0.47mmol) and 3,5-di-tert-butyl-4-hydroxybenzaldehyde (0.47nιmol) were used. The title compound was a yellow solid (13mg, 8%)
LC/MS RT=6.61, 6.71 min Found ES+ = 350 Η NMR (d6 DMSO, δ) Example 17 5-Chloro-3-(3,5-di-tert-butyl-4-hydroxy-benzylidene)-l,3-dihydro-indol-2-one
This material was prepared as described for Example 1 except that 5-chloro- oxindole (0.47mmol) and 3,5-di-tert-butyl-4-hydroxybenzaldehyde (0.47mmol) were used. The title compound was a yellow solid (84mg, 47%)
LC/MS RT=7.00 min Found ES+ = 384 IH NMR (d6 DMSO, δ). 10.70, 10.60 (IH, 2bs), 8.50 (IH, s), 7.85, 7.80 (IH, 2s), 7.70, 7.65 (IH, 2s), 7.55 (IH, s), 7.20 (IH, 2dd), 6.85 (IH, 2d), 1.40(1SH, s)
Example 18 5-Iodo-3-(2,4,6-trimethoxy-benzylidene)-l,3-dihydro-indol-2-one
This material was prepared as described for Example 1 except that 5-iodo- oxindole (0.47mmol) and 2,4,6-trimethoxybenzaldehyde (0.47mmol) were used. The title compound was a yellow solid (16Smg, 82%)
LC/MS RT= 5.8 and 5.97min Found ES+ = 438
IH NMR (d6 DMSO, δ). 10.56 (brs, IH), 7.50-7.46 (m, 2H), 7.06 (d, IH), 6.6S (d,
IH), 6.40 (s, 2H), 3.89 (s, 3H), 3.79 (s, 6H)
Example 19
7-Bromo-3-(3,5-di-tert-butyl-4-hydroxy-benzylidene)-l,3-dihydro-indol-2-one
This material was prepared as described for Example 1 except that 7-bromo- oxindole (0.47mmol) and 3,5-di-tert-butyl-4-hydroxybenzaldehyde (0.47mmol) were used. The title compound was a yellow solid (42mg, 21%)
LC/MS RT= 7.14 and 7.20min Found ES+ = 429 1H NMR (d6 DMSO, δ)
Example 20 7-BiOmo-3-(4-hydroxy-3,5-dimethyl-benzylidene)-l,3-dihydro-indol-2-one
This material was prepared as described for Example 1 except that 7-bromo- oxindole (0.47mmol) and 3,5-methyl-4-hydroxybenzaldehyde (0.47mmol) were used. The title compound was a yellow solid (131mg, 81%)
LC/MS RT= 5.48, 5.89min Found ES+ = 345
IH NMR (d6 DMSO, δ) 10.80 (IH, brs), 8.20 (IH, s), 7.65
(2H, m), 7.35 (2H, m), 6.90 (IH, 2t), 2.20 (6H, s)
Example 21
3-(4-Hydroxy-3,5-dimethyl-benzylidene)-2-oxo-2,3-dihydro-lH-indole-7-carboxylic acid methyl ester
This material was prepared as described for Example 1 except that methyl oxindole-7-carboxylate (0.47mmol) and 3,5-methyl-4-hydroxybenzaldehyde (0.47mmol) were used. The title compound was a yellow solid (126mg, S4%)
LC/MS RT= 5.53, 5.90min Found ES+ = 324
1' lIHH NNMMRR ((dd66 DDMMSSOO,, δδ)) 1100..4400,, 1100..2255 ((IIHH,, 221brs), 8.20 (qlH, s), 8.00 (IH, t), 7.75
(2H, m), 7.40 (IH, s), 7.05 (IH, 2t), 4.00 (3H, s), 2.25 (6H, s)
Example 22 7-Bromo-3-(2,4,6-tiimethoxy-benzylidene)-l,3-dihydro-indol-2-one This material was prepared as described for Example 1 except that 7-bromo- oxindole (0.47mmol) and 2,4,6-trimethoxybenzaldehyde (0.47mmol) were used. The title compound was a yellow solid (136mg, 74%)
LC/MS RT= 5.79, 5.89min Found ES+ = 391
IH NMR (d6 DMSO, δ). 10.70 (IH, brs), 7.50 (IH, s), 7.30 (IH, m), 6.80 (2H, m),
6.35 (2H, s), 3.85 (3H, s), 3.75 (6H, s)
Example 23
5-Cl loro-3-(2,4,6-trimethoxy-benzylidene)-l,3-dihydro-indol-2-one
This material was prepared as described for Example 1 except that 5-chloro- oxindole (0.47mmol) and 2,4,6-trimethoxybenzaldehyde (0.47mmol) were used. The title compound was a yellow solid (112mg, 70%)
LC/MS RT= 5.61, 5.76min Found ES+ = 346
IH NMR (d6 DMSO, δ). 10.50 (IH, brs), 7.50 (IH, s), 7.25 (IH, dd), 6.85 (IH, d), 6.75 (IH, d), 6.40 (IH, s), 4.00 (3H, s), 3.80 (6H, s)
Example 24
5-Bromo-3-(4-fluoro-benzylidene)- 1 ,3-dihydro-indol-2-one
This material was prepared as described for Example 1 except that 5-bromo- oxindole (0.47mmol) and 4-fluorobenzaldehyde (0.47mmol) were used. The title compound was a yellow/orange solid (1 lOmg, 74%)
LC-MS: RT 5.82, 6.11 ES+ 320
IH NMR (d6 DMSO, δ). 10.70 (IH, brs), 7.70 (2H, m), 7.60 (IH, s), 7.45 (IH, s), 7.35 (3H, m), 6.80 (IH, d) Example 25
3-(4-Hydroxy-3,5-dimethyl-benzylidene)-2-oxo-2,3-dihydro-lH-indole-5- carbonitrile
This material was prepared as described for Example 1 except that 5- cyanooxindole (0.47mmol) and 3,5-dimethyl-4-hydroxybenzaldehyde (0.47mmol) were used. The title compound was a yellow/orange solid (22mg, 16%)
LC-MS: RT 4.69, 5.06 ES+ 291
IH NMR (d6 DMSO, δ). 10.90 (IH, 2brs), 8.10 (2H, 2s), 7.80 (IH, 2s), 7.45 (IH, 2dd), 7.50, 7.30 (2H, 2s), 6.85 (IH, 2d), 2.10 (6H, 2s)
Example 26 3-(4-Hydroxy-3,5-diiodo-benzylidene)-2-oxo-2,3-dihydro-lH-indole-6-carbonitrile
This material was prepared as described for Example 1 except that 6-cyano- oxindole (0.47mmol) and 3,5-diiodo-4-hydroxybenzaldehyde (0.47mmol) were used. The title compound was a yellow/orange solid (33mg, 14%)
LC-MS: RT 5.45, 5.87 ES" 513
Example 27
3-(3-Bromo-4-methoxy-benzylidene)-2-oxo-2,3-dihydro-lH-indole-6-carbonitrile
This material was prepared as described for Example 1 except that 6-cyano- oxindole (0.47mmol) and 3-bromo-4-methoxybenzaldehyde (0.47mmol) were used. The title compound was a yellow/orange solid (43mg, 26%) LC-MS: RT 5.55, 5.84 ES" 353
IH NMR (d6 DMSO, δ).11.00 (IH, 2brs), 9.00 (IH, d), 8.35 (IH, dd), 8.00 (2H, s), 7.90, 7.65 (IH, 2d), 7.40, 7.20 (2H, m), 3.90 (3H, s)
Example 28 2-Oxo-3-(2,4,6-trimethoxy-benzylidene)-2,3-dihydro-lH-indole-6-carbonitrile
This material was prepared as described for Example 1 except that 6-cyano- oxindole (0.47mmoι) and 2,4,6-trimethoxybenzaldehyde (0.47mmol) were used. The title compound was a yellow/orange solid (37mg, 23%)
LC-MS: RT 5.13 ES+ 337
IH NMR (d6 DMSO, δ). 10.80 (IH, brs), 7.63 (IH, s), 7.31 (IH, d), 7.16 (IH, s), 6.93 (IH, d), 6.85 (2H, s), 3.89 (3H, s), 3.77 (6H, s)
Example 29
3-(3-Bromo-4-methoxy-benzylidene)-2-oxo-2,3-dihydro-lH-indole-7-carbonitrile
This material was prepared as described for Example 1 except that 7-cyano- oxindole (0.47mmol) and 3-bromo-4-methoxybenzaldehyde (0.47mmol) were used. The title compound was a yellow/orange solid (39mg, 23%)
LC-MS: RT 5.13 ES" 353
IH NMR (d6 DMSO, δ).11.60 (IH, brs), 9.10 (IH, d), 8.50 (IH, dd), 8.10, 7.80 (IH, 2s), 8.05 (IH, d), 7.65 (IH, t), 7.35 (IH, d), 7.20, 7.10 (IH, 2t), 4.10 (3H, s)
Example 30
5-Bromo-3-(4-hydroxy-benzylidene)-l,3-dihydro-indol-2-one This material was prepared as described for Example 1 except that 5-bromo- oxindole (0.47mmol) and 4-hydroxybenzaldehyde (0.47mmol) were used. The title compound was a yellow/orange solid (57mg, 38%)
LC-MS: RT 4.82, 5.16 ES+ 316
IH NMR (d6 DMSO, δ). 10.50, 10.10 (2H, 2brs), 8.20 (2H, 2s), 7.80 (IH, d), 7.65 (IH, s), 7.10 (IH, 2dd), 6.65 (2H, m), 6.50 (2H, d)
Example 31
5-Bromo-3-(4-hydroxy-3,5-diiodo-benzylidene)-l,3-dihydro-indol-2-one
This material was prepared as described for Example 1 except that 5-bromo- oxindole (0.47mmol) and 3,5-diiodo-4-hydroxybenzaldehyde (0.47mmol) were used. The title compound was a yellow/orange solid (36mg, 13%)
LC-MS: RT 5.97, 6.45 ES" 567
IH NMR (d6 DMSO, δ). 10.80 (IH, s), 9.00 (2H,s), 8.20 (IH, s), 7.90, 7.75 (IH, 2d), 7.80, 7.50 (IH, 2s), 7.40, 7.30 (IH, 2dd), 6.90, 6.80 (IH, 2d)
Example 32 6-Bromo-3-(3,5-dibromo-4-hydroxy-benzylidene)-l,3-dihydro-indol-2-one
This material was prepared as described for Example 1 except that 6-bromo- oxindole (0.47mmol) and 3,5-dibromo-4-hydroxybenzaldehyde (0.47mmol) were used. The title compound was a yellow/orange solid (24mg, 11%)
LC-MS: RT 5.82, 6.24 ES+ 475
IH NMR (d6 DMSO, δ). 10.40 (IH, 2s), 8.70 (IH, s), 8.20, 7.50 (IH, 2s), 7.70 (IH, s), 7.50, 7.40 (IH, 2d), 7.40 (IH, s), 7.10 (IH, 2dd), 6.90 (IH, d) Example 33
5-Bromo-3-(2,3-dibromo-4-hydroxy-5-methoxy-benzylidene)-l,3-dihydro-indol-2- one
This material was prepared as described for Example 1 except that 5-bromo- oxindole (0.47mmol) and 2,3-dibrom-4-hydroxy-5-methoxybenzaldehyde (0.47mmol) were used. The title compound was a yellow/orange solid (160mg, 68%)
LC-MS: RT 5.67, 6.30 ES" 502
IH NMR (do DMSO, δ). 10.80, 10.63 (IH, 2brs), 8.41, 7.79 (IH, 2s), 7.89, 7.59 (IH, 2s), 7.55, 7.31, 7.41 (2H, s&m), 6.82 (IH, 2d), 3.82 (3H, s)
Example 34 3-(4-Hydroxy-3,5-diiodo-benzylidene)-5-iodo-l,3-dihydro-indol-2-one
This material was prepared as described for Example 1 except that 5-iodo- oxindole (0.47mmol) and 3,5-diiodo-4-hydroxybenzaldehyde (0.47mmol) were used. The title compound was a yellow/orange solid (250mg, 87%)
LC-MS: RT 5.79, 6.24 ES" 614
IH NMR (d6 DMSO, δ). 10.38, 10.26 (IH, 2brs), 8.80 (IH, s), 8.16 (IH, brs), 7.89 (IH, s), 7.74 (IH, d), 7.36-7.15 (2H, m), 6.47 (IH, 2d)
Example 35
3-(4-Hydroxy-3,5-diiodo-benzylidene)-5-nitro-l,3-dihydro-indol-2-one This material was prepared as described for Example 1 except that 5-nitro- oxindole (0.47mmol) and 3,5-diiodo-4-hydroxybenzaldehyde (0.47mmol) were used. The title compound was a yellow/orange solid (190mg, 76%)
LC-MS: RT 5.52, 6.04 ES" 533
IH NMR (d6 DMSO, δ). 1 1.60 (IH, s), 9.30 (IH, s), 8.90, 8.70 (IH, 2d), 8.40 (2H, m), 7.25 (IH, 2d)
Example 36
3-(4-Hydroxy-3,5-diiodo-benzylidene)-2-oxo-2,3-dihydro-lH-indole-7-carbonitrile
This material was prepared as described for Example 1 except that 7-cyano- oxindole (0.47mmol) and 3,5-diiodo-4-hydroxybenzaldehyde (0.47mmol) were used. The title compound was a yellow/orange solid (11 Omg, 46%)
LC-MS: RT 5.35, 5.68 ES" 513
IH NMR (d6 DMSO, δ). 11.10 (IH, brs), 8.93 (2H, brs), 7.72 (IH, d), 7.45 (lH, s), 7.26 (IH, d), 6.95 (IH, t)
Example 37
5-(2-Chloro-acetyl)-3-(3,5-dibromo-4-hydroxy-benzylidene)-l,3-dil ydro-indol-2- one
This material was prepared as described for Example 1 except that 5-(2- Chloro-acetyl)-oxindole (0.47mmol) and 3,5-dibromo-4-hydroxybenzaldehyde (0.47mmol) were used. The title compound was a yellow/orange solid (199mg, 90%)
LC-MS: RT 5.10, 5.43 ES" 470 IH NMR (d6 DMSO, δ). 11.30 (IH, 2s), 10.90 (IH, brs) 9.00 (IH, s), 8.60 (IH, 2s), 8.20 (2H, m), 7.70, 7.30 (IH, 2d), 7.15 (IH, 2d), 5.30, 5.20 (2H, 2s)
Example 38 Shikimate Kinase Low Throughput Assay Protocol
Inhibition of shikimate kinase (purified from E. Coli) was measured in 96- well plates at multiple concentrations of compound in order to plot dose-response curves and calculate IC5o values for the compounds of interest. Briefly, a three-enzyme linked assay employing sl ikimate kinase, pyruvate kinase and lactate dehydrogenase was constructed. In the presence of this enzyme mixture the substrate, shikimic acid, is converted into shikimate phosphate with a concomittant production of adenosine diphosphate from adenosine triphosphate. The adenosine diphosphate produced acted as a cofactor for pyruvate kinase in the production of pyruvic acid, which was then converted to lactic acid with lactate dehydrogenase. As this latter reaction is accompanied by a reduction in NADH levels, which can be monitored in a UN spectrophotometer at 340 nm Molecular Devices Spectramax plus microtitre plate reader), shikimate kinase activity is effectively coupled to a UN readout system. Compounds were tested at 10 mM for their ability to increase the absorbance (over control levels) at 340 nm, representing reduced conversion of ΝADH to NAD and therefore reduced ADP production and reduced shikimate kinase activity.
Reagents for 1 plate screen were prepared as follows: A buffer of 500 mM triethanolamine (TEA) buffer (10X) plus cations was prepared, and made up to a final volume of 1 litre (92.5g TEA, 37g KCl, 12.3g MgSO4 & 1 litre distilled H2O (measured in a measuring cylinder) were mixed in a 1000ml Duran bottle). The pH of this buffer was adjusted to pH7.0 with 1M KOH and then made up to a final volume of 1 litre. The buffer was stored at +4°C, equilibrated to 25°C before use. A stock of lOOmM shikimic acid was prepared from 348mg shikimic acid.
The pH of this solution was adjusted to pH 7.0 using 1M KOH, made up to a final volume of 15ml and aliquoted into 500μl volumes and stored at -20°C. A stock of lOmM PEP was prepared from 380mg PEP. The pH of this solution was adjusted to pH 7.0 using 1M KOH made up to a final volume of 20ml using dH2O and aliquoted into 500μl volumes and stored at -20°C.
A stock of 20mM NADH was prepared from 113.4mg NADH made up to a final volume of 8 ml using dH2O, aliquoted into 500μl volumes and stored at -20°C. A stock of 8ml 500mM ATP was prepared from 2.2g ATP and 8ml dH2O, aliquoted into 500μl volumes and stored at -20°C.
Enzyme mixtures A and B were made up immediately before use as follows:
A: 18.7ml of 50mM TEA buffer (plus cations), 72μl of lOOmM shikimic acid, 78μl of 500mM ATP, 377μl of 20mM NADH, 714μl of lOOmM PEP, 54U of pyruvate kinase and 54U of lactate dehydrogenase; B: 15 ml 500mM TEA buffer (plus cations) and 75LT shikimate kinase.
Two wells each were used for positive control (+ 20μl 10%o DMSO) and negative control (+ 80μl TEA buffer instead of slύkimate kinase), respectively. The test compounds were added to the remaining wells at 20μl (maximum of
10% DMSO), followed b 80μl of enzyme mix B (=0.4U/well). Plates were read in the plate reader at 340nm to detect any compound absorbance. Then lOOμl of enzyme mix A were added per well to give final concentrations per well of O.lSmM shikimic acid, 0.975mM ATP, 0.2mM NADH, l.SmM PEP, 0.27U pyruvate kinase, 0.27LI lactate dehydrogenase and 0.4U shikimate kinase. Plates were incubated for lOmin at 25°C, re-read at 340nm and absorbencies calculated. The results are set out in the Table below.
Figure imgf000045_0001
Figure imgf000045_0002
Figure imgf000046_0001
Figure imgf000046_0002
Example 39
Determination of Minimum Inhibitory Concentration (MIC) against bacterial pathogens
MIC determinations were performed using broth microdilution methodology in accordance with guidelines set out by the National Committee for Clinical Laboratory Standards (NCCLS) in the following publications: M7-A5 Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically - Fifth Edition; Approved Standard (2000); and Ml 1-A5 Methods for antimicrobial susceptibility testing of anaerobic bacteria - Fifth Edition; Approved Standard (2001). Bacterial strains were selected from 5 methicillin-resistant strains of Staphylococcus aureus (MRSA), 2 vancomycin-resistant (NRE) strains of Enterococcus faecium, 2 vancomycin-susceptible strains of E. faecium, 1 strain ofE. faecalis, 2 strains of Coiynebacterium minutissimum , 1 strain of C. auris, 1 strain of C. urealyticum, 1 strain of Listeria monocytogenes ΝCTC 10357, one strain of L. monocytogenes ΝCTC 11007, two strains of environmental isolates ofZ. monocytogenes, 2 strains of Neisseria meningitides, 1 strain of N. flava, 1 strain of N. elongata, 4 Propionibacterium sp., and 4 strains of Moraxella catarrhalis, all of which are clinical isolates unless otherwise indicated.. Escherichia coli ATCC 25922 and Staphylococcus aureus ATCC 29213 were used as control organisms.
Culture media, media supplements and other reagents) (Abbreviations used subsequently are shown in the right-hand column)
Fastidious Anaerobe Agar (LabM; LAB 90) - FAA
Nutrient Agar (Lab M; LAB 8) - NA
Columbia Agar (Lab M; LAB 1) - COL
Mueller Hinton Broth II (Lab M; LAB 114) - MHB
Dimethyl sulfoxide (Sigma-Aldrich; D8779) - DMSO
Horse blood, defibrinated (Southern Group Laboratory; 9011)
Horse blood, lysed (Southern Group Laboratory; 9016)
Yeast autolysate growth supplement (Oxoid; SR0105B)
Yeast Extract (Oxoid; L21)
Maximum Recovery Diluent (DWS; G50011) - MRD
The culture medium was prepared in accordance with the manufacturer's instructions. After autoclaving and cooling to 48±2°C, Columbia Agar was supplemented with 5% v/v defibrinated horse blood before pouring into sterile petri dishes. 'Lab M' Mueller Hinton JJ broth (supplied by International Diagnostics Group) had been adjusted with respect to calcium and magnesium content and therefore required no further cation adjustment.
Chocolate Blood A -garar
Chocolate Blood Agar was based on Columbia Blood Agar, for which the initial stages of preparation were described above. Immediately after addition of 5% v/v blood to the molten agar, the bottle contents was gently mixed and placed in a waterbath operating at 80 ± 2°C. The bottle contents were mixed at intervals during heating, until the agar has attained a uniform chocolate brown colour. Chocolate Columbia Blood Agar (CCBA) was returned to a 48 + 2°C waterbath until cooled to this temperature, then poured into sterile 90 mm petri dishes.
Neisseria Test Medium Neisseria Test Medium was prepared from Mueller Hinton Broth. After autoclaving and cooling to 48°C or below, one vial of Yeast Autolysate Growth Supplement was added per 500 ml of medium. Finally, 5% v/v lysed blood was be added to the medium.
Procedure: preparation of test compound stock solution
For each compound, 0.0263 g was accurately weighed and transferred to a 5 ml volumetric flask. The compound was dissolved by addition of DMSO, and the solution was mixed. Finally, the flask was made up to volume with DMSO. Final test compound concentration in each stock solution was 5260 μg/ml. This primary stock solution was designated 'Solution A' and was stored frozen in suitable aliquots at a nominal temperature of -80 °C. The volume of primary stock solution prepared was scaled down if only a limited quantity of solid compound was available.
Procedure: preparation of test plates (broth dilution method) For each test compound, primary stock solution (Solution 'A') was diluted in DMSO to produce a series of dilutions required for the MIC test. Working dilutions 'B' to 'N' were prepared in accordance with the following scheme:
Nominal
Solution Method of Preparation Concentration
(μg/ml)
Solution A Primary stock solution 5260
Solution B 100 μl Solution A + 100 μl DMSO 2630
Solution C 100 μl Solution B + 100 μl DMSO 1315
Solution D 100 μl Solution C + 100 μl DMSO 658
Solution E 100 μl Solution D + 100 μl DMSO 329
Solution F 100 μl Solution E + 100 μl DMSO 164
Solution G 100 μl Solution F + 100 μl DMSO 82.0
Solution H 100 μl Solution G +100 μl DMSO 41.0
Solution I 100 μl Solution H +100 μl DMSO 20.5
Solution J 100 μl Solution I + 100 μl DMSO 10.3
Solution K 100 ml Solution J + 100 μl DMSO 5.13
Solution L 100 ml Solution K + 100 μl DMSO 2.56
Solution M 100 ml Solution L + 100 μl DMSO 1.28
Solution N 100 ml Solution M +100 μl DMSO 0.64
Microtitre plates bearing a pattern of 12 x 8 wells were used. Plates with round or conical well bases, and with a nominal well volume of 200 μl, were selected. In each experimental run, all test compounds were screened against an appropriate set of test organisms. This allowed the relative activity of each test compound to be accurately determined without the influence of inoculum variability. The latter might have been significant if a given test organism was screened against each compound on different days.
Using the scheme described above, the first eight dilutions for a given compound (Solutions A to H) was dispensed in 5 μl aliquots into successive wells of the first column in a microtitre plate. When these 8 wells had been used, remaining dilutions (Solutions I to N) were dispensed into successive wells of the first column in a second microtitre plate. The process described above was repeated for each of the test compounds, using successive columns in the microtitre plates. Thus, each pair of microtitre plates accommodated three sets of dilutions for each compound. To the first empty well at the base of each column, 5 μl of DMSO (free from test compound) was added. To the remaining empty well, 5 μl of DMSO and 200 μl of Mueller Hinton broth was added.
Procedure: preparation of bacterial inocula
Bacterial strains were subcultured from frozen stocks on to Columbia Blood Agar (Enterococcus, Neisseria, Coiynebacterium, Moraxella and Listeria strains), Fastidious Anaerobe Agar (Propionibacterium spp) or Nutrient Agar (all other strains) and were incubated under appropriate aerobic conditions at 37±1°C until discrete colonies were visible:
• Propionibacterium - anaerobic, 2-5 days
• Neisseria - air + 5% CO2, 1-3 days
• All other strains - aerobic, 24-48 hours
Each plate culture was used to produce a standardized bacterial suspension, from which inocula for MIC plates were prepared. At least five well-isolated colonies was sampled from the plate using a sterile swab, and this material was suspended in a sterile 5-10 ml aliquot of the appropriate broth until turbidity equivalent to a 0.5 McFarland standard was attained. Comparison with the McFarland standard was made against a white card bearing contrasting black lines. Standardized bacterial suspensions contained approximately 1 x 10s cfu per ml.
Broths to be used:
Mueller Hinton Broth - Staphylococcus spp. Enterococcus spp.
Corynebacterium spp. Mueller Hinton Broth + 5% v/v - Listeria spp lysed horse blood
Neisseria Test Medium - Neisseria spp
Wilkins-Chalgren Anaerobe Broth - Propionibacterium spp
Each adjusted suspension was diluted by transferring 0.1 ml of the standardised bacterial suspension to 20 ml of the broth. This provided the NCCLS recommended inoculum density of approximately 5 x 103 cfu per ml when microtitre plates were prepared.
Procedure: inoculation of MIC test plates
Prepared microtitre plates were inoculated with standardized bacterial suspensions such that the concentration of test compound in each well was diluted. For each test and control strain, the diluted suspension was dispensed in 0.2 ml aliquots into each well in a vertical column, producing a final range of test compound dilutions from 128 μg/ml to 0.016 μg/ml, plus a positive control (growth control) containing no test compound. At the end of each column, the second well containing broth alone was left uninoculated.
Procedure: incubation of test plates Inoculated plates were incubated at 37±1°C for 24±1 h under the appropriate incubation conditions. The exact incubation period was recorded.
Procedure: plate reading and interpretation of results
Plates were placed on a dark non-reflecting surface for reading. The MIC was recorded as the lowest concentration of test compound that completely inhibited growth, as detected by the unaided eye. For a test to be considered valid, acceptable growth (at least a 2 mm cell 'button' or definite turbidity) must have occurred in the positive control well. Raw data in the form of growth/no growth (+/-) of each inoculum at each concentration of test compound was recorded in tabular form. For certain test strains, acceptable growth may not have occurred after 24 h. Where this was the case, plates was re-incubated for a further 24 ± 1 h and read again. If acceptable growth did not occur after extended incubation, or if there was no growth at low test compound concentrations but growth at higher concentrations, culture purity was checked and the test repeated
Test reproducibility was monitored on the basis of MIC values for control strains. These strains was set up with the first and last MIC runs and treated in the same way as other test strains. MIC values for control organisms did not differ by more than 2 doubling dilutions between the beginning and end of the study.
MIC results were summarized in a tabular format showing the MIC9o and geometric mean MIC values for each genus. The MIC o is the minimum concentration of test compound inhibitory to 90%> of the test strains in a particular group. Geometric mean is the most appropriate mean for application to data on a logarithmic scale (MIC data are on a log2 scale). It is calculated as follows:
∑logy Geometric Mean antilog
where n Number of strains in genus y\ - y, MIC values for each of the strains 1 to n
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Example 40
S. aureus Minimum Inhibitory Concentration (MIC) determination
An isolated colony of S. aureus (Smith strain) was streaked aseptically onto Mueller Hinton nutrient agar 18-24h before the assay.
Compounds of the invention were screened in two stages. First, they were screened at concentrations 30 and lOOμM. If the compounds inhibited growth at 30 μM they were advanced to a second assay (National Committee for Clinical Laboratory Standards protocol) where they were screened at concentrations of 50, 25, 12, 6, 3, 1.5, 0.8 and 0.4μM.
The concentrations of compounds were made up in Eppendorf tubes using DMSO as the diluent, taking into consideration that only 2.5 μl of each compound solution would be added to lOOμl of broth. Eppendorf tubes containing the diluted compounds were vortexed and 2.5μl were pipetted into labelled wells of 96 round bottom well microtitre plates. Each plate included two growth control wells (2.5μl DMSO and lOOμl Mueller Hinton (MH) broth) and two negative (uninoculated) wells (lOOμl MH broth) for sterilization assessment of the MH broth. Positive controls also included compounds of known MIC (Arrow compound A358, MIC of 3-5μM) and ampicillin as a known antibiotic (MIC of 0.1 μM). Using fresh tips each time, lOOμl of MH broth were pipetted into each well. Assays were performed in duplicate plus a compound control. Inoculum was prepared by making a saline suspension of the isolated colonies of identical morphological type selected from the 18-24h agar plate. The top of each colony was touched with a plastic loop and growth transferred to a vial containing an NaCI solution to yield a suspension to match the 0.5 McFarland turbidity standard which was then diluted 1:10 in saline. LTsing fresh pipettes each time 5μl of the S. aureus suspension was pipetted and mixed into each test well and growth control wells. Purity plates were streaked out from the diluted culture onto CLED and Columbia blood agar plates and incubated overnight at 37°C.
The microtitre plates were placed into incubation boxes at 37°C for 16-20h. Damp tissue paper was also placed in the box to produce a humid environment and to prevent evaporation.
After the prescribed incubation period purity plates were checked to make sure there was no contamination and broth-only and growth control wells were checked for visible growth. Plates were examined for growth, the MIC being read as the lowest concentration of the tested compound which allowed no visible growth of S. aureus.
Figure imgf000055_0001

Claims

1. Use of an oxindole derivative of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating or preventing infection by an organism in which the biosynthesis of aromatic amino acids is effected via the sl ikimate pathway,
Figure imgf000056_0001
wherein:
Ri and R5 are the same or different and each represent hydrogen, halogen, hydroxy, cyano, nitro, Ci- alkyl, C2-C6 alkenyl, C2-d alkynyl, Cι-C6 alkoxy, C2- C6 alkenyloxy, C2-d alkynyloxy, Cι-C alkylthio, C2-C alkenylthio, C -C6 alkynylthio, or -NRR/ wherein R and R are the same or different and each represent hydrogen, Ci-d alkyl, C2-C6 alkenyl or C2-C6 alkynyl;
R2 and R4 are the same or different and each represent hydrogen, halogen, hydroxy, cyano, nitro, Ci- alkyl, C2-C6 alkenyl, d-C alkynyl, Cι-C6 alkoxy, C2- d alkenyloxy, d-d alkynyloxy, Cι-C alkylthio, d-C6 alkenylthio, C2-C6 alkynylthio, C6-Cιo aryl, d-d carbocyclyl, a 5- to 10- membered heterocyclic ring, a 5- to 10- membered heteroaryl ring, -NRt , -(CrC6 alky -MR-t , -(C2-C6 alkenyl)- NR'R7, -(d-d alkynyl)-NRE , -NR'CONR' ", -COR , -røR'7, -CONRF , - R -CO- R.' -SOR , -S(O)2R/, -S(O)2NR/R'or -L-H-R , wherein (a) R and R^are the same or different and each represent hydrogen, Cι-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, d-Cio aryl, C3-C6 carbocyclyl, a 5- to 10- membered heterocyclic ring, a 5- to 10- membered heteroaryl ring or -L-X-R , (b) each L is the same or different and represents a divalent Ci-d alkyl, C2-C6 alkenyl or C2-d alkynyl group, (c) each X is the same or different and represents -O-, -S-, -SO-, -SO2-, -NH- or a direct bond and (d) each R is the same or different and represents Cι-C6 alkyl, C6-Cι0 aryl, C3-d carbocyclyl, a 5- to 10- membered heterocyclic ring or a 5- to 10- membered heteroaryl ring;
R3 is hydrogen, halogen, hydroxy, Ci-d alkyl, C2-C6 alkenyl, C2-d alkynyl, d-d alkoxy, C2-d alkenyloxy, Cι- (, alkynyloxy, Cι-C6 alkylthio, C2-C6 alkenylthio, C2-C6 alkynylthio, -NRR , -CO2H or an acid isostere, wherein R7 and R' are the same or different and each represent hydrogen, Ci-d alkyl, C2-d alkenyl or C2-C6 alkynyl; each ζ is the same or different and represents hydroxy, halogen, cyano, nitro, Ci-d alkyl, C2-C6 alkenyl, C2-d alkynyl, Cι-C6 alkoxy, d-d alkenyloxy, C2- C6 alkynyloxy, Cι-C6 alkylthio, C -C6 alkenylthio, C2-C6 alkynylthio, d-Cio aryl, d-d carbocyclyl, a 5- to 10- membered heterocyclic ring, a 5- to 10- membered heteroaryl ring, -NRR77, -(Cι-C6 alkyl)-NR7R77 -(C2-C6 alkenyl)-NRR77 -(C2-d alkynyl)-NR7R77, -COR", -CO2R77, -CONR/R/, -NR7-CO-R77 -NR7-CO-NR7R77, -SOR77 -S(O)2R77, -S(O)2NR/R//or -L-X-R7", wherein (a) R and R7 are the same or different and each represent hydrogen, Cι-C6 alkyl, C2-d alkenyl, C2-C6 alkynyl, C6-Cιo aryl, C3- C6 carbocyclyl, a 5- to 10- membered heterocyclic ring, a 5- to 10- membered heteroaryl ring or -L-X-R7', (b) each L is the same or different and represents a divalent d-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl group, (c) each Xis the same or different and represents -O-, -S-, -SO-, -SO2-, -NH- or a direct bond and (d) each R is the same or different and represents Cι-C6 alkyl, C6-Cιo aryl, C3-d carbocyclyl, a 5- to 10- membered heterocyclic ring or a 5- to 10- membered heteroaryl ring; n is 0, 1, 2 or 3; and
R7 is hydrogen, Cj-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 carbocyclyl or C6-Cιo aryl.
2. Use according to claim 1 , wherein at least one of Ri, R2, R4 and R5 represent hydrogen.
3. Use according to claim 1 or 2, wherein Rj and R are the same or different and each represent hydrogen, halogen, hydroxy, Cι-C6 alkyl, Cι-C6 alkoxy, Cι-C6 alkylthio or -NRR77 wherein R and R7are the same or different and each represent hydrogen or Cι-C6 alkyl.
4. Use according to claim 3, wherein R\ and R5 are the same or different and each represent hydrogen, hydroxy, halogen, or an unsubstituted C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 alkoxy group.
5. Use according to any one of the preceding claims, wherein R2 and R4 are the same or different and each represent hydrogen, halogen, hydroxy, Ci- alkyl, Cι-C6 alkoxy, Cι-C6 alkylthio, nitro, cyano, C6-Cιo aryl, d-C6 carbocyclyl, a 5- to 10- membered heterocyclic ring, a 5- to 10- membered heteroaryl ring, -NRR , -(Cι-C alkyl)-NR7R7', -CO2R77 -COR77, -CONR7R77, -NR7-CO-NRR77, -NR7-CO-R , -SOR77, -S(O)2R , -S(O)2NR7R7 or -(C 1 -C6 alkyl)-X-R , wherein (a) R7 represents hydrogen or Cι-C6 alkyl and R77 represents hydrogen, Cι-C6 alkyl, C6-Cιo aryl, C3-C6 carbocyclyl, a 5- to 10- membered heterocyclic ring, a 5- to 10- membered heteroaryl ring or -(Cj- d alkyl)-X-R , (b) each X is the same or different and represents -O-, -NH- or a direct bond and (c) each R is the same or different and represents C6-Cιo aryl, C3-C6 carbocyclyl, a 5- to 10- membered heterocyclic ring or a 5- to 10- membered heteroaryl ring.
6 Use according to any one of the preceding claims, wherein R2 and R4 are the same or different and each represent hydrogen, halogen, hydroxy, Cι-C6 alkyl, Ci-d alkoxy, Cι-C6 alkythio or -NRR7 wherein R and R'' are the same or different and each represent hydrogen or Ci-d alkyl.
7. Use according to claim 6, wherein R2 and R4 are the same or different and each represent hydrogen, halogen or an unsubstituted C1-C4 alkyl or C1-C4 alkoxy group.
8. Use according to any one of the preceding claims, wherein R3 is hydrogen, halogen, hydroxy, Cι-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, d-d alkoxy, C2-C6 alkenyloxy, C2-d alkynyloxy, Ci-d alkylthio, C2-C6 alkenylthio, C2-C6 alkynylthio, -NRR77, -CO H, 5-hydroxy-pyrrole-2,4-dione-3-yl, 5-hydroxy-pyrrolidine-2,3-dione- 4-yl, 3H-[l,3,4]thiadiazol-2-onyl, 3H-[l,3,4]oxadiazol-2-onyl, 2-hydroxy-
[l,3,4]tlιiadiazol-5-yl, 2-hydroxy-[l,3,4]oxadiazol-5-yl, 3-hydroxy-lH-[l,2,4]triazol- 5-yl, 3-hydroxy-isoxazolyl, 5-hydroxy-isoxazolyl, tetrazolyl, for example 2H- tetrazolyl, triazolyl, for example 2H-[l,2,3]triazolyl, 3-trifluoromethyl-4H- [l,2,4]triazolyl, pyrrolidine-2,3,5-trionyl, 5-hydroxy-[l,2,4]thiadiazolyl, 5-hydroxy- [l,2,4]oxadiazolyl, 2,4-dioxo-tetrahydrofuranyl, l,3,4-triaza-2-onyl, 1 ,2,4-oxadiazal- 5-onyl, benzothiazolone-S,S-dioxidyl, -NH-S(O)2-CF3 or -CONH-S(O)2-CH3, wherein R and R77 are the same or different and each represent hydrogen, Ci-d alkyl, C2-C6 alkenyl or C2-C6 alkynyl.
9. Use according to claim 8, wherein R3 is hydrogen, halogen, hydroxy, Ci-d alkyl, Ci- alkoxy, Cι-C6 alkylthio, -NRR , tetrazolyl, triazolyl or -CO2H, wherein R and R are the same or different and each represent hydrogen or Ci-d alkyl.
10. Use according to claim 9, wherein R3 is hydrogen, hydroxy, -CO2H, 2H- tetrazolyl, 2H-[l,2,3]triazolyl, C1-C4 alkoxy, C1-C4 alkylthio or -NR7R77 wherein R7 and R are the same or different and each represent hydrogen or C1-C4 alkyl.
11. LTse according to any one of the preceding claims, wherein each R6 is the same or different and represents hydroxy, halogen, cyano, nitro, Ci-d alkyl, Cι-C6 alkoxy, Cι-C6 alkylthio, d-Cio aryl, d-C6 carbocyclyl, a 5- to 10- membered heterocyclic ring, a 5- to 10- membered heteroaryl ring, -NRR, -(Cι-C6 alkyl)- NRR77, -COR77 -CO2R77 -CONRR77 -NR7-CO-R77, -NR7-CO-NR7R7 -SOR77 -S(O)2R77 -S(O)2NRR7 or -(Ci-d alkyl)-X-R , wherein (a) R represents hydrogen or Ci-d alkyl and R77 represents hydrogen, Ci-d alkyl, d-Cio aryl, C3-C6 carbocyclyl, a 5- to 10- membered heterocyclic ring, a 5- to 10- membered heteroaryl ring or -(Cι-C6 alkyl)-X-R , (b) each X is the same or different and represents -O-, -NH- or a direct bond and (c) each R" is the same or different and represents Cι-C6 alkyl, C -Cιo aryl, d-d carbocyclyl, a 5- to 10- membered heterocyclic ring or a 5- to 10- membered heteroaryl ring.
12. Use according to claim 11, wherein each R6 is the same or different and represents hydroxy, -NH2, halogen, cyano, nitro, Cι-C6 alkyl, Cι-C6 alkoxy, Cι-C6 alkyi io, -NRR77, -COR77', -CO2R77, -CONRR77, -SO2R77 or -S O2NRR7' wherein R7 represents hydrogen or Ci-d alkyl and R represents Cι-C6 alkyl.
13. Use according to claim 12, wherein each R6 is the same or different and represents hydroxy, -NH2, halogen, cyano, nitro, C1-C4 alkyl, C1-C4 alkoxy, -NRR77, -COR7', -CO2R77or -CONR7R7 wherein R represents hydrogen or C1-C4 alkyl and R77 represents C1-C4 alkyl.
14. Use according to any one of the preceding claims wherein R is hydrogen or d-d alkyl.
15. Use according to any one of the preceding claims, wherein:
Ri and R5 are the same or different and each represent hydrogen, hydroxy, halogen, or an unsubstituted Cι-C alkyl, Cι-C haloalkyl or C1-C4 alkoxy group; - R2 and R4 are the same or different and each represent hydrogen, halogen or an unsubstituted C1-C4 alkyl or C1-C4 alkoxy group;
R3 is hydroxy, halogen or an unsubstituted C1-C4 alkoxy group;
R is halogen, nitro, cyano, C1-C4 alkyl, -CO2-(Cι-d alkyl) or -CO-(Cι-C4 alkyl), the alkyl moieties in the substituent R^ being unsubstituted or substituted by 1, 2 or 3 halo substituents; n is 0 or 1 ; and
R7 is hydrogen.
16. Use according to any one of the preceding claims, wherein said organism is a bacterium or fungus.
17. Use according to claim 16, wherein said organism is other than a Staphloccocus, Enterococcus, Coiynebacterium, Listeria, Neisseria, Propionibacterium or Moraxella bacterium.
18. Use according to claim 17, wherein said organism is not a bacterium.
19. Use according to any one of claims 1 to 15, wherein said organism is an apicomplexan parasite.
20. Use according to claim 19, wherein the medicament is for use in the treatment or prevention of malaria.
21. Use of an oxindole derivative of formula (I), as defined in any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in treating or preventing an infection by a Staphloccocus, Enterococcus, Coiynebacterium, Listeria, Neisseria, Propionibacterium or Moraxella bacterium.
22. A herbicidal or fungicidal composition, comprising: - an oxindole derivative of formula (I), as defined in any one of claims 1 to 15, or an agriculturally acceptable salt thereof; at least one surfactant; and an agriculturally acceptable carrier or diluent.
23. Use of an oxindole derivative of formula (I), as defined in any one of claims 1 to 15, or an agriculturally acceptable salt thereof, as a herbicide or a fungicide.
24. A method of controlling weeds or fungi at a locus, which method comprises administering thereto an oxindole derivative of formula (I), as defined in any one of claims 1 to 15, or an agriculturally acceptable salt thereof, or a composition according to claim 22.
25. A method according to claim 24, wherein the locus comprises agricultural or horticultural plants or a medium in which such plants grow.
26. Use of an oxindole derivative of formula (I) as defined in any one of claims 1 to 15, or a salt thereof, in controlling algae.
27. A method of treating algae in a fish tank or pond, which method comprises applying to the fish tank or pond an oxindole derivative of formula (I), as defined in any one of claims 1 to 15, or a salt thereof.
2S. Non-therapeutic use of an oxindole derivative of formula (I), as defined in any one of claims 1 to 15, or a salt thereof, in inhibiting bacterial growth.
29. An oxindole derivative of formula (lb), or a pharmaceutically acceptable salt thereof,
Figure imgf000062_0001
wherein:
Ri and R5 are the same or different and each represent hydrogen, halogen, hydroxy, cyano, nitro, Cι-C6 alkyl, C2-C6 alkenyl, C2-C alkynyl, Cι-C6 alkoxy, C2- C6 alkenyloxy, C2-d alkynyloxy, Crd alkylthio, C2-d alkenylthio, C2-C6 alkynylthio, or -NRR wherein R and R are the same or different and each represent hydrogen, Cι-C6 alkyl, C2-C6 alkenyl or C2-C alkynyl;
R2 and R4 are the same or different and each represent hydrogen, halogen. hydroxy, cyano, nitro, C.-d alkyl, C2-C6 alkenyl, C2-d alkynyl, Ci-Ce alkoxy, C2- d alkenyloxy, C2-C6 alkynyloxy, Cι-C6 alkylthio, C2-C6 alkenylthio, C2-C6 alkynylthio, C6-Cιo aryl, C3-C6 carbocyclyl, a 5- to 10- membered heterocyclic ring, a 5- to 10- membered heteroaryl ring, -NRR7', -(Cι-C6 alkyl)-NRR77 -(C2-C6 alkenyl)- NRR77, -(C2-d alkynyl)-NRR77 -NR-CONR7R77, -COR77 -CO2R77, -CONRR77 -NR-CO- R77, -SOR7", -S(O)2R77 -S(O)2NR7R77 or -L-X-R , wherein (a) R7 and R77 are the same or different and each represent hydrogen, Cι-C6 alkyl, C2-d alkenyl, C2-C6 alkynyl, C6- Cio aryl, C3-C6 carbocyclyl, a- 5- to 10- membered heterocyclic ring, a 5- to 10- membered heteroaryl ring or -L-X-R /, (b) each L is the same or different and represents a divalent Ci-d alkyl, C2-C6 alkenyl or C2-d alkynyl group, (c) each X is the same or different and represents -O-, -S-, -SO-, -SO2-, -NH- or a direct bond and (d) each R is the same or different and represents Cι:C6 alkyl, -Cio aryl, C3-C6 carbocyclyl, a 5- to 10- membered heterocyclic ring or a 5- to 10- membered heteroaryl ring; - R3 is hydrogen, halogen, hydroxy, C]-C6 alkyl, C2-C6 alkenyl, C -C alkynyl,
Cι-C6 alkoxy, C2-d alkenyloxy, C2-C6 alkynyloxy, Cι-C6 alkylthio, C2-C6 alkenylthio, C2-d alkynylthio, -NRR7, -CO2H, 5-hydroxy-pyrrole-2,4-dione-3-yl, 5- hydroxy-pyrrolidine-2,3-dione-4-yl, 3H-[1 ,3,4]thiadiazol-2-onyl, 3H- [l,3,4]oxadiazol-2-onyl, 2-hydroxy-[l,3,4]thiadiazol-5-yl, 2-hydroxy- [l,3,4]oxadiazol-5-yl, 3-hydroxy-lH-[l,2,4]triazol-5-yl, 3-hydroxy-isoxazolyl, 5- hydroxy-isoxazolyl, tetrazolyl, for example 2H-tetrazolyl, triazolyl, for example 2H- [l,2,3]triazolyl, 3-trifluoromethyl-4H-[l,2,4]triazolyl, pyrrolidine-2,3,5-trionyl, 5- hydroxy-[l,2,4]thiadiazolyl, 5-hydroxy-[l,2,4]oxadiazolyl, 2,4-dioxo- tefrahydrofuranyl, l,3,4-triaza-2-onyl, l,2,4-oxadiazal-5-onyl, benzothiazolone-S,S- dioxidyl, -NH-S(O)2-CF3 or -CO-NH-S(O)2-CH3, wherein R7 and R77 are the same or different and each represent hydrogen, Cι-C6 alkyl, C -C6 alkenyl or C2-C6 alkynyl; each R6 is the same or different and represents hydroxy, halogen, cyano, nitro, Ci-d alkyl, C2-C6 alkenyl, C2-d alkynyl, Cι-C6 alkoxy, d-d alkenyloxy, C2- C6 alkynyloxy, Ci-Ce alkylthio, C2-C6 alkenylthio, C2-C6 alkynylthio, -NRR77, -COR7', -CO2R7', -CONR'R7', -NR7-CO-NR77, -SOR7, -S(O)2R77 wherein R7 and R7' are the same or different and each represent hydrogen, Cι-C6 alkyl, C -d alkenyl or C2-d alkynyl; n is 0, 1, 2 or 3; and
R7 is hydrogen, Ci- alkyl, C2-C6 alkenyl, C2-d alkynyl, C3-d carbocyclyl or Ce-Cio aryl, provided that: (1) when R3 is -OCH3, either R2 is halogen or Rj and R5 are both Ci-d alkoxy;
(2) when n is 0, R2 and R4 are not simultaneously hydrogen;
(3) R2 and R3 are not simultaneously -OCH3; and
(4) either (a) neither R2 nor R4 is halogen or nitro when R2 is hydroxy or (b) (i) n is 1 , 2 or 3, (ii) each R6 is other than chlorine, fluorine, -CF3O, ethyl, i-propoxy, -CH2NH2, -N(CH3)2, -NH2, -CONH2, -CO2H, -S(O)2CH3, -CONH2 and -CONH-
CH2-CH2-OH, (iii) when an Re moiety is iodine, nitro or cyano, R and R4 are iodine, (iv) when an Re moiety is bromine, either the R6 moiety is at the 7- position of the indole moiety and R2 and R4 are bromine or iodine or one of Rj and R5 is bromine, (v) when an R6 moiety is -CO2Me it is at the 7- position of the indole moiety, and (vi) when an R6 moiety is -COR77 is not at the 5- position of the indole moiety.
30. A compound according to claim 29, wherein Ri, R2, R3, R4, R5 and R7 are as defined in any one of claims 2 to 11 and 13 to 15.
,
31. A compound according to claim 29 or 30, wherein each e in the formula (lb) is the same or different and represents hydroxy, -NH2, halogen, cyano, nitro, d-C6 alkyl, Ci-Ce alkoxy, C,-C6 alkylthio, -NRR77 -COR77 -CO2R77, -CONR7R7 or -SO2R' wherein R represents hydrogen or Cι-C6 alkyl and R7 represents Cι-C6 alkyl
32. A compound according to claim 29, wherein:
Ri and R5 are the same or different and each represent hydrogen, hydroxy, halogen or an unsubstituted C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 alkoxy group;
R and 4 are the same or different and each represent hydrogen, halogen or an unsubstituted C1-C4 alkyl or Ci- alkoxy group; - R3 is hydroxy, halogen or an unsubstituted C1-C4 alkoxy group; Re is halogen, nitro, cyano, Cpd alkyl, -CO -(d-C4 alkyl) or -CO-(Cι-C4 alkyl), the alkyl moieties in the substituent Re being unsubstituted or substituted by 1,
2 or 3 halo substituents; n is 0 or 1 ; and - R is hydrogen, provided that:
(1) when R3 is -OCH3, either R2 is halogen or Ri and R5 are both C1-C4 alkoxy;
(2) when n is 0, R2 and R4 are not simultaneously hydrogen;
(3) R2 and R4 are not simulatenously -OCH3; and (4) either (a) neither R2 nor R4 is halogen when R3 is hydroxy or (b) (i) n is 1, (ii) R6 is other than chlorine, fluorine and ethyl, (iii) when Re is iodine, fluorine or cyano R2 and R4 are iodine, (iv) when R6 is bromine either R6 is at the 7- position of the indole moiety and R2 and R4 are bromine or iodine or one of Ri and R5 is bromine, (v) when R6 is -CO2Me it is at the 7- position of the indole moiety and (vi) when R6 is -CO-(Cι-C4 alkyl) it is not at the 5- position of the indole moiety.
33. A compound according to claim 29 which is:
7-Bromo-3-(3,5-dibromo-4-hydroxy-benzylidene)-l,3-dihydro-indol-2-one
7-Bromo-3-(4-hydroxy-3,5-diiodo-benzylidene)-l,3-dihydro-indol-2-one 3-(4-Hydroxy-3,5-diiodo-benzylidene)-2-oxo-2,3-dmydro-lH-mdole-5-carbonitrile
3-(3,5-Dibromo-4-hydroxy-benzylidene)-2-oxo-2,3-dihydro-lH-indole-7-carboxylic acid methyl ester
3-(4-Hydroxy-3,5-diiodo-benzylidene)-2-oxo-2,3-dihydro-lH-indole-7-carboxylic acid methyl ester 3-(3,5-Di-tert-butyl-4-hydroxy-benzylidene)-2-oxo-2,3-dihydro-lH-indole-5- carbonitrile
5-Chloro-3-(4-hydroxy-3,5-dimethyl-benzylidene)-l,3-dihydro-indol-2-one
5-Bromo-3-(4-hydroxy-3,5-dimethyl-benzylidene)-l,3-dihydro-indol-2-one
3 -(3 -Bromo-4-methoxy-benzylidene)-5-nitro- 1 ,3 -dihydro-indole-2-one 5-Bromo-3-(3,5-di-tert-butyl-4-hydroxy-benzylidene)-l,3-dihydro-indol-2-one 6-BiOmo-3-(3,5-di-tert-butyl-4-hydroxy-benzylidene)-l,3-dihydro-indol-2-one 3-(3,5-Di-tert-butyl-4-hydroxy-benzylidene)-l,3-dilιydro-indol-2-one 5-Chloro-3-(3,5-di-tert-butyl-4-hydroxy-benzylidene)-l,3-dihydro-indol-2-one 5-Iodo-3-(2,4,6-trimethoxy-benzylidene)-l,3-dihydro-indol-2-one 7-Bromo-3-(3 ,5-di-tert-butyl-4-hydroxy-benzylidene)- 1 ,3 -dihydro-indol-2-one 7-Bromo-3-(4-hydroxy-3,5-dimethyl-benzylidene)-l,3-dihydro-indol-2-one 3-(4-Hydxoxy-3,5-dimethyl-benzylidene)-2-oxo-2,3-dihydro-lH-indole-7-carboxylic acid methyl ester
7-Bromo-3-(2,4,6-trimethoxy-benzylidene)-l,3-dihydro-indol-2-one 5-Chloro-3-(2,4,6-trimethoxy-benzylidene)-l,3-dihydro-indol-2-one 5-Bromo-3-(4-fluoro-benzylidene)-l,3-dihydro-indol-2-one 3-(4-Hydroxy-3,5-dimethyl-benzylidene)-2-oxo-2,3-dihydro-lH-indole-5- carbonitrile
3-(4-Hydxoxy-3,5-diiodo-benzylidene)-2-oxo-2,3-dihydro-lH-indole-6-carbonitrile 3-(3-Bromo-4-methoxy-benzylidene)-2-oxo-2,3-dihydro-lH-indole-6-carbonitrile 2-Oxo-3-(2,4,6-trimethoxy-berizylidene)-2,3-dihydro-lH-indole-6-carborιitrile 3-(3-Bromo-4-methoxy-benzylidene)-2-oxo-2,3-dihydro-lH-indole-7-carbonitrile 5-Bromo-3-(4-hydroxy-benzylidene)-l,3-dihydro-indol-2-one 5-Bromo-3-(2,3-dibromo-4-hydroxy-5-methoxy-benzylidene)-l,3-dihydro-indol-2- one 3-(4-Hydroxy-3,5-diiodo-benzylidene)-5-iodo-l,3-dihydro-indol-2-one 3-(4-Hydroxy-3,5-diiodo-benzylidene)-5-nitro-l,3-dihydro-indol-2-one
3-(4-Hydroxy-3,5-diiodo-berιzylidene)-2-oxo-2,3-dihydro-lH-indole-7-carbonitrile or a pharmaceutically acceptable salt thereof.
34. A compound according to any one of claims 29 to 33 wherein R2 and R3 are not simultaneously alkoxy groups.
35. A compound according to any one of claims 29 to 34, wherein, when n is 0, R2 and R4 are both Ci-d alkyl groups.
36. A compound according to any one of claims 29 to 35, wherein the phenyl ring substituted by Ri to R5 is 3,5-dihalo-4-hydroxyphenyl, 3,5-di-(Cι-d alkyl)-4- hydroxyphenyl, 4-hydroxy-5-halophenyl, 4-mefhoxy-5-halophenyl, 2,4,6- trimethoxyphenyl, 4-halophenyl, 4-hydroxyphenyl or 2,3-dihalo-4-hydroxy-5- methoxyphenyl provided when the phenyl ring is substituted by Ri to R5 is a 4- fluorophenyl moiety n is 1 and Re is halogen.
37. A compound according to any one of claims 29 to 36, wherein R3 is not an alkoxy, alkenyloxy or alkynyloxy group.
38. A compound according to any one of claims 29 to 37, wherein either (a) neither R2 nor R4 is halogen, hydroxy, cyano, nitro, -CONR'R7', -S(O)2NRR77 -NRR77, Ci-C6 alkoxy, C2-C6 alkenyloxy or C2-C6 alkynyloxy when R3 is hydroxy or -NH- S(O)2-CF3 or (b) Ri and R5 are not simultaneously hydrogen.
39. An oxindole derivative as defined in any one of claims 29 to 38, or a pharmaceutically acceptable salt thereof, for use in the treatment of the human or animal body.
40. A pharmaceutical composition comprising an oxindole derivative as defined in any one of claims 29 to 39, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
41. A herbicidal or fungicidal composition comprising an oxindole derivative of the formula (lb), as defined in any one of claims 29 to 39, or an agriculturally acceptable salt thereof, and an agriculturally acceptable carrier or diluent.
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KR20200145116A (en) * 2019-06-20 2020-12-30 영남대학교 산학협력단 Novel oxindole derivatives and anti-bacterial composition comprising the same as an active ingredient

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WO2006095195A1 (en) * 2005-03-11 2006-09-14 University Of Strathclyde Antimicrobial compounds
US7972610B2 (en) 2005-03-11 2011-07-05 University Of Strathclyde Antimicrobial compounds
CN110204538A (en) * 2019-06-04 2019-09-06 烟台大学 Aryl thiazole-tryptamines class marine red tide algae algicide and its preparation method and application
CN110204538B (en) * 2019-06-04 2022-02-08 烟台大学 Aryl thiazole-tryptamine ocean red tide algae algicide and preparation method and application thereof
KR20200145116A (en) * 2019-06-20 2020-12-30 영남대학교 산학협력단 Novel oxindole derivatives and anti-bacterial composition comprising the same as an active ingredient
KR102214988B1 (en) 2019-06-20 2021-02-10 영남대학교 산학협력단 Novel oxindole derivatives and anti-bacterial composition comprising the same as an active ingredient

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