WO2019106368A1 - Dérivés de pyrrolo[3,2-c]pyridin-4-one utilisés en tant qu'inhibiteurs de pfk utiles pour le traitement d'infections protozoaires - Google Patents

Dérivés de pyrrolo[3,2-c]pyridin-4-one utilisés en tant qu'inhibiteurs de pfk utiles pour le traitement d'infections protozoaires Download PDF

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WO2019106368A1
WO2019106368A1 PCT/GB2018/053454 GB2018053454W WO2019106368A1 WO 2019106368 A1 WO2019106368 A1 WO 2019106368A1 GB 2018053454 W GB2018053454 W GB 2018053454W WO 2019106368 A1 WO2019106368 A1 WO 2019106368A1
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methyl
pyrrolo
pyridin
dichlorophenyl
solvate
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Malcolm D. WALKINSHAW
Simon Neil Pettit
Adrian HIGHTON
Iain William MCNAE
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University of Edinburgh
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University of Edinburgh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • Compounds of formula I and their salts, hydrates and solvates have anti-protoazoal activity, and may be used to treat diseases or conditions mediated, at least in part, by a protozoal parasite infection.
  • the present application further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I and/or a pharmaceutically acceptable salt, hydrates or solvates thereof, and a pharmaceutically acceptable excipient.
  • the present application also provides a method of treating a disease or condition mediated, at least in part, by a protozoal parasite infection comprising administering to a subject in need a compound of formula I and/or a pharmaceutically acceptable salt, hydrate or solvate thereof.
  • HAT Human African Trypanosomiasis
  • HAT is caused by a parasite transmitted by tsetse flies.
  • the parasite e.g. Trypanosoma brucei, gets its energy from the breakdown of glucose obtained from the blood of the host.
  • the parasite proteins used for this process (so called glycolytic enzymes) provide the parasite with its only source of energy (ATP molecules).
  • Phosphofructokinase catalyses the formation of fructose 1 ,6-bisphosphate (F16BP) at an early step in the glycolytic pathway.
  • F16BP fructose 1 ,6-bisphosphate
  • Mammals, some protists and bacteria use ATP as the phosphodonor in an essentially irreversible reaction, while other protists, bacteria (notably anaerobic ones), and plants (one isoenzyme) use inorganic pyrophosphate (PPi).
  • PPi inorganic pyrophosphate
  • Human PFK is a homo-tetramer of 4 x 85 kDa and is regulated by a number of metabolites including fructose 2,6-bisphosphate (F26BP) and ADP as activators, and ATP and citrate as inhibitors.
  • F26BP fructose 2,6-bisphosphate
  • ADP as activators
  • ATP and citrate as inhibitors.
  • T. brucei PFK is a much smaller tetramer consisting of 4 x 55 kDa chains, each 487 amino acid residues in length. It’s only known activator is AMP and to date there are no known allosteric inhibitors. T. brucei PFK is located in peroxisome-related organelles called glycosomes which sequester the first seven enzymes in the glycolytic pathway and are a characteristic feature of this evolutionarily distinct group of organisms. T brucei PFK has been shown by RNAi to be absolutely required for parasite survival, and even partial knock down is lethal.
  • the glycolytic enzyme phosphofructokinase has been recognized as a potential therapeutic target in the fight against the bloodstream forms of Trypanosoma and other protists due to the reliance of these parasites on the metabolism of glucose as the sole mechanism for the generation of adenosine triphosphates (ATP).
  • PFK phosphofructokinase
  • ATP adenosine triphosphates
  • the present application provides potent and selective antiprotozoal compounds useful in the treatment of diseases and conditions mediated by infection by a protozoal parasite, such as trypanomiasis (e.g. HAT).
  • a protozoal parasite such as trypanomiasis (e.g. HAT).
  • the compounds disclosed herein provide alternative and/or improved compounds for the treatment of a disease or condition mediated by infection by a protozoal parasite, such as trypanomiasis (e.g. HAT).
  • a protozoal parasite such as trypanomiasis (e.g. HAT).
  • the present invention provides a compound of formula I as defined herein, and/or a salt or solvate thereof.
  • the present invention provides a pharmaceutical composition which comprises a compound of formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more pharmaceutically acceptable excipients.
  • the present invention provides a compound of formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein, for use in therapy.
  • the present invention provides a compound of formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of a disease or condition mediated by infection by a protozoal parasite.
  • the present invention provides a compound of formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of trypanosomiasis.
  • the present invention provides the use of a compound of formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treating or preventing a disease or condition mediated by infection by a protozoal parasite.
  • the present invention provides the use of a compound of formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treating or preventing trypanosomiasis.
  • the present invention provides a method for killing and/or preventing the growth of a protozoa comprising contacting the protozoa with an effective amount of a compound of formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides a method for the treatment or prevention of a protozoal infection in a subject in need thereof, comprising administering to said subject an effective amount of a compound of formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides a method for the treatment of prevention of a disease or condition mediated by infection by a protozoal parasite in an subject, comprising administering to a subject in need an effective amount of a compound of formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof.
  • Figure 1 shows plasma concentrations of Example 1 as a function of time after IV (red/circles) or oral (blue/squares) dosing.
  • FIG. 2 shows images of TbbGVR35 infected mice 23 days after infection and 24 hours post final dose Flux values (photons/sec, shown in red) range from 11750 c10 L 7 (untreated mice) down to 0.2 x 10 L 7 (Example 10 or 16 treated mice) and are proportional to the numbers of live parasites.
  • the three Melarsoprol positive controls have flux readings of 1.5 to 2.3 x 10 L 7 photons/sec.
  • the various hydrocarbon-containing moieties provided herein may be described using a prefix designating the minimum and maximum number of carbon atoms in the moiety, e.g.“(C a-b )” or“C a -C b ” or“(a-b)C”.
  • (C a-b )alkyl indicates an alkyl moiety having the integer“a” to the integer“b” number of carbon atoms, inclusive.
  • Certain moieties may also be described according to the minimum and maximum number of members with or without specific reference to a particular atom or overall structure.
  • the terms“a to b membered ring” or“having between a to b members” refer to a moiety having the integer“a” to the integer“b” number of atoms, inclusive.
  • alkyl and“alkyl group” refer to a branched or unbranched saturated hydrocarbon chain. Unless specified otherwise, alkyl groups typically contain 1-10 carbon atoms, such as 1-6 carbon atoms or 1-4 carbon atoms or 1-3 carbon atoms, and can be substituted or unsubstituted.
  • Representative examples include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n- butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, tert-butyl, isobutyl, etc.
  • alkylene and alkylene group refer to a branched or unbranched saturated hydrocarbon chain. Unless specified otherwise, alkylene groups typically contain 1-10 carbon atoms, such as 1- 6 carbon atoms or 1-3 carbon atoms, and can be substituted or unsubstituted. Representative examples include, but are not limited to, methylene (-CH2-), the ethylene isomers (-CH(CH3)- and -CH2CH2-), the propylene isomers (-CH(CH3)CH 2 -, - CH(CH 2 CH 3 )-, -C(CH 3 )3-, and -CH 2 CH 2 CH 2 -), etc.
  • alkenyl and“alkenyl group” refer to a branched or unbranched hydrocarbon chain containing at least one double bond. Unless specified otherwise, alkenyl groups typically contain 2-10 carbon atoms, such as 2-6 carbon atoms or 2-4 carbon atoms, and can be substituted or unsubstituted. Representative examples include, but are not limited to, ethenyl, 3-buten-1-yl, 2-ethenylbutyl, and 3-hexen-1-yl.
  • alkynyl and“alkynyl group” refer to a branched or unbranched hydrocarbon chain containing at least one triple bond. Unless specified otherwise, alkynyl groups typically contain 2-10 carbon atoms, such as 2-6 carbon atoms or 2-4 carbon atoms, and can be substituted or unsubstituted. Representative examples include, but are not limited to, ethynyl, 3-butyn-1-yl, propynyl, 2-butyn-1-yl, and 3-pentyn-1-yl.
  • aromatic refers to monocyclic and polycyclic ring systems containing 4n+2 pi electrons, where n is an integer.
  • Aromatic should be understood as referring to and including ring systems that contain only carbon atoms (i.e. “aryl”) as well as ring systems that contain at least one heteroatom selected from N, O or S (i.e.“heteroaromatic” or“heteroaryl”).
  • An aromatic ring system can be substituted or unsubstituted.
  • non-aromatic refers to a monocyclic or polycyclic ring system having at least one double bond that is not part of an extended conjugated pi system.
  • non-aromatic refers to and includes ring systems that contain only carbon atoms as well as ring systems that contain at least one heteroatom selected from N, O or S.
  • a non-aromatic ring system can be substituted or unsubstituted.
  • aryl and aryl group refer to phenyl and 7-15 membered bicyclic or tricyclic hydrocarbon ring systems, including bridged, spiro, and/or fused ring systems, in which at least one of the rings is aromatic.
  • Aryl groups can be substituted or unsubstituted. Unless specified otherwise, an aryl group may contain 6 ring atoms (i.e., phenyl) or a ring system containing 9 to 15 atoms, such as 9 to 11 ring atoms, or 9 or 10 ring atoms.
  • Representative examples include, but are not limited to, naphthyl, indanyl, 1 ,2,3,4-tetrahydronaphthalenyl, 6, 7,8,9- tetrahydro-5H-benzocycloheptenyl, and 6,7,8,9-tetrahydro-5H-benzocycloheptenyl.
  • an aryl group is phenyl and naphthyl, suitably phenyl.
  • arylene and“arylene group” refer to a phenylene (-CsH 4 -) or to 7 to 15 membered bicyclic or tricyclic hydrocarbon ring systems, including bridged, spiro, and/or fused ring systems, in which at least one of the rings is aromatic.
  • Arylene groups can be substituted or unsubstituted.
  • an arylene group may contain 6 (i.e., phenylene) ring atoms or be a ring system containing 9 to 15 atoms; such as 9 to 11 ring atoms; or 9 or 10 ring atoms.
  • Arylene groups can be substituted or unsubstituted.
  • alkylaryl and “alkylaryl group” refer to an alkyl group in which a hydrogen atom is replaced by an aryl group, wherein alkyl group and aryl group are as previously defined, such as, for example, benzyl (CsHsCI-h-). Alkylaryl groups can be substituted or unsubstituted.
  • Carbocyclic group and“carbocycle” refer to monocyclic and polycyclic ring systems that contain only carbon atoms in the ring(s), i.e., hydrocarbon ring systems, without regard or reference to aromaticity or degree of unsaturation.
  • carbocyclic group should be understood as referring to and including ring systems that are fully saturated (such as, for example, a cyclohexyl group), ring systems that are aromatic (such as, for example, a phenyl group), as well as ring systems having fully saturated, aromatic and/or unsaturated portions (such as, for example, cyclohexenyl, 2,3-dihydro-indenyl, and 1 ,2,3,4-tetrahydro- naphthalenyl).
  • the terms carbocyclic and carbocycle further include bridged, fused, and spirocyclic ring systems.
  • cycloalkyl and“cycloalkyl group” refer to a non-aromatic carbocyclic ring system, that may be monocyclic, bicyclic, or tricyclic, saturated or unsaturated, and may be bridged, spiro, and/or fused.
  • a cycloalkyl group may be substituted or unsubstituted. Unless specified otherwise, a cycloalkyl group typically contains from 3 to 12 ring atoms.
  • a cycloalkyl group may contain 4 to 10 ring atoms (e.g., 4 ring atoms, 5 ring atoms, 6 ring atoms, 7 ring atoms, etc.).
  • Representative examples include, but are not limited to, cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, norbornyl, norbornenyl, bicyclo[2.2.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.1]heptene, bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[3.3.2]decane.
  • alkylcycloalkyl and“alkylcycloalkyl group” refer to an alkyl group in which a hydrogen atom is replaced by a cycloalkyl group, wherein alkyl group and cycloalkyl group are as previously defined, such as, for example, cyclohexylmethyl (C 6 H 11 CH 2 -). Alkylcycloalkyl groups can be substituted or unsubstituted.
  • haloalkyl and“haloalkyl group” refer to alkyl groups in which one or more hydrogen atoms are replaced by halogen atoms.
  • Haloalkyl includes both saturated alkyl groups as well as unsaturated alkenyl and alkynyl groups.
  • Haloalkyl groups can be substituted or unsubstituted.
  • a haloalkyl group is selected from CHF 2 and CF 3 , suitably CF 3.
  • haloalkoxy and“haloalkoxy group” refer to alkoxy groups (i.e. O-alkyl groups) in which one or more hydrogen atoms are replaced by halogen atoms.
  • Haloalkoxy includes both saturated alkoxy groups as well as unsaturated alkenyl and alkynyl groups.
  • Haloalkoxy groups can be substituted or unsubstituted.
  • a haloalkyoxy group is selected from -OCFIF 2 and - OCF 3 , suitably -OCF 3 .
  • halo and halogen include fluorine, chlorine, bromine and iodine atoms and substituents.
  • heteroaryl and“heteroaryl group” refer to (a) 5 and 6 membered monocyclic aromatic rings, which contain, in addition to carbon atom(s), at least one heteroatom, such as nitrogen, oxygen or sulfur, and (b) 7 to15 membered bicyclic and tricyclic rings, which contain, in addition to carbon atom(s), at least one heteroatom, such as nitrogen, oxygen or sulfur, and in which at least one of the rings is aromatic.
  • a heteroaryl group can contain two or more heteroatoms, which may be the same or different.
  • Heteroaryl groups can be substituted or unsubstituted, and may be bridged, spiro, and/or fused.
  • a heteroaryl group may contain 5, 6, or 8 to 15 ring atoms.
  • a heteroaryl group may contain 5 to 10 ring atoms, such as 5, 6, 9, or 10 ring atoms.
  • Representative examples include, but are not limited to, 2,3-dihydrobenzofuranyl, 1 ,2- dihydroquinolinyl, 3,4-dihydroisoquinolinyl, 1 ,2,3,4-tetrahydroisoquinolinyl, 1 ,2,3,4- tetrahydroquinolinyl, benzoxazinyl, benzthiazinyl, chromanyl, furanyl, 2-furanyl, 3-furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, 2-, 3-, or 4-pyridinyl, pyrimidinyl, 2-, 4-, or 5-pyrimidinyl, pyrazolyl, pyrrolyl, 2- or 3-pyrrolyl, pyrazinyl, pyridazinyl,
  • alkylheteroaryl and“alkylheteroaryl group” refer to an alkyl group in which a hydrogen atom is replaced by a heteroaryl group, wherein alkyl group and heteroaryl group are as previously defined. Alkylheteroaryl groups can be substituted or unsubstituted. Where carbon numbers are provided, e.g. (Cn-m)alkylheteroaryl, the range refers to the whole group. Suitably, the constituent alkyl group has 1-6 carbons, suitable 1-3 carbons.
  • heterocyclic group and“heterocycle” refer to monocyclic and polycyclic ring systems that contain carbon atoms and at least one heteroatom selected from nitrogen, oxygen, sulfur or phosphorus in the ring(s), without regard or reference to aromaticity or degree of unsaturation.
  • heterocyclic group should be understood as referring to and including ring systems that are fully saturated (such as, for example, a piperidinyl group), ring systems that are aromatic (such as, for example, a pyrindinyl group), as well as ring systems having fully saturated, aromatic and/or unsaturated portions (such as, for example, 1 , 2,3,6- tetrahydropyridinyl and 6,8-dihydro-5H-[1 ,2,4]triazolo[4,3-a]pyrizinyl).
  • the terms heterocyclic and heterocycle further include bridged, fused, and spirocyclic ring systems.
  • heterocycloalkyl and “heterocycloalkyl group” refer to 3 to 15 membered monocyclic, bicyclic, and tricyclic non-aromatic ring systems, which contain, in addition to carbon atom(s), at least one heteroatom, such as nitrogen, oxygen, sulfur or phosphorus. Heterocycloalkyl groups may be fully saturated or contain unsaturated portions and may be bridged, spiro, and/or fused ring systems. In some instances a heterocycloalkyl group may contain at least two or heteroatoms, which may be the same or different. Heterocycloalkyl groups can be substituted or unsubstituted.
  • a heterocycloalkyl group may contain from 3 to 10 ring atoms or from 3 to 7 ring atoms or from 5 to 7 ring atoms, such as 5 ring atoms, 6 ring atoms, or 7 ring atoms.
  • Representative examples include, but are not limited to, tetrahydrofuranyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, indolinyl, isoindolinyl, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidyl, homopiperazinyl, thiomorpholinyl-5-oxide, thiomorpholinyl- S,S-dioxide, pyrrolidinyl, tetrahydropyranyl, piperidinyl, tetrahydrothienyl, homopiperidinyl, homothiomorpholinyl-S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyri
  • heterocycloalkylene and“heterocycloalkylene group” refer to 3 to15 membered monocyclic, bicyclic, or tricyclic non-aromatic ring systems, which contain, in addition to carbon atom(s), at least one heteroatom, such as nitrogen, oxygen, sulfur or phosphorus. Heterocycloalkylene groups may be fully saturated or contain unsaturated portions and may be bridged, spiro, and/or fused. Heterocycloalkylene groups can be substituted or unsubstituted.
  • a heterocycloalkylene group may contain from 3 to 10 ring atoms; such as from 3 to 7 ring atoms. In other instances a heterocycloalkylene group may contain from 5 to 7 ring atoms, such as 5 ring atoms, 6 ring atoms, or 7 ring atoms.
  • alkylheterocycloalkyl and“alkylheterocycloalkyl group” refer to an alkyl group in which a hydrogen atom is replaced by a heterocycloalkyl group, wherein alkyl group and heterocycloalkyl group are as previously defined, such as, for example, pyrrolidinylmethyl (C 4 H 8 NCH 2 -).
  • Alkylheteroycloalkyl groups can be substituted or unsubstituted. Where carbon numbers are provided, e.g. (Cn-m)alkylheterocycloalkyl, the range refers to the whole group.
  • the constituent alkyl group has 1-6 carbons, suitable 1-3 carbons.
  • “pharmaceutically acceptable” refers to materials that are generally chemically and/or physically compatible with other ingredients (such as, for example, with reference to a formulation), and/or is generally physiologically compatible with the recipient (such as, for example, a subject) thereof.
  • “pharmaceutical composition” refers to a composition that can be used to treat a disease, condition, or disorder in a subject, including a human.
  • pseudohalogen refers to -OCN, -SCN, -CF 3 , and -CN.
  • “stable” and“chemically stable” refer to a compound that is sufficiently robust to be isolated from a reaction mixture with a useful degree of purity.
  • the present application is directed solely to the preparation of stable compounds.
  • substituents include members which, owing to valency requirements, chemical stability, or other reasons, cannot be used to substitute a particular group, the list is intended to be read in context to include those members of the list that are suitable for substituting the particular group.
  • R 1 is a methyl group (-CH 3 )
  • subject(s) and“patient(s)” suitably refer to mammals, in particular humans.
  • “substituted” indicates that a hydrogen atom on a molecule has been replaced with a different atom or group of atoms and the atom or group of atoms replacing the hydrogen atom is a “substituent.” It should be understood that the terms“substituent”,“substituents”,“moiety”, “moieties”,“group”, or“groups” refer to substituent(s).
  • terapéutica refers to an amount a compound, composition or medicament that (a) inhibits or causes an improvement in a particular disease, condition or disorder; (b) attenuates, ameliorates or eliminates one or more symptoms of a particular disease, condition or disorder; (c) or delays the onset of one or more symptoms of a particular disease, condition or disorder described herein. It should be understood that the terms“therapeutic” and“therapeutically effective” encompass any one of the aforementioned effects (a)-(c), either alone or in combination with any of the others (a)- (c).
  • a therapeutically effective amount in, for example, a human or other mammal, can be determined experimentally in a laboratory or clinical setting, or a therapeutically effective amount may be the amount required by the guidelines of the United States Food and Drug Administration (FDA) or equivalent foreign regulatory body, for the particular disease and subject being treated. It should be appreciated that determination of proper dosage forms, dosage amounts, and routes of administration is within the level of ordinary skill in the pharmaceutical and medical arts.
  • FDA United States Food and Drug Administration
  • treating refers to and include prophylactic, ameliorative, palliative, and curative uses and results.
  • the terms“treating”, “treated”, and “treatment” refer to curative uses and results as well as uses and results that diminish or reduce the severity of a particular condition, characteristic, symptom, disorder, or disease described herein.
  • treatment can include diminishment of several symptoms of a condition or disorder or complete eradication of said condition or disorder.
  • prophylactic as used herein is not absolute but rather refers to uses and results where the administration of a compound or composition diminishes the likelihood or seriousness of a condition, symptom, or disease state, and/or delays the onset of a condition, symptom, or disease state for a period of time.
  • a“therapeutically active agent”, whether used alone or in conjunction with another term or terms, refers to any compound, i.e. a drug, that has been found to be useful in the treatment of a disease, disorder or condition and is not described by formula I. It should be understood that a therapeutically active agent may not be approved by the FDA or an equivalent foreign regulatory body.
  • A“therapeutically effective amount” means the amount of a compound that, when administered to a subject or patient for treating a disease, is sufficient to effect such treatment for the disease.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the subject or patient to be treated.
  • antiprotozoal refers to an agent capable of killing or inhibiting the growth of one or more protozoa.
  • the agent is capable of killing one or more protozoa.
  • ring A is a 5 or 6-membered heterocycloalkyl or 5 or 6-membered heteroaryl ring, each optionally substituted with one or more R a . Accordingly, ring A in combination with 5-membered ring depicted in formula I form a fused bicyclic structure.
  • a dashed line - indicates the bond of group A which attaches to the adjacent fused ring. This bond may or may not have aromatic character.
  • protozoacide refers to an agent capable of killing one or more protozoa.
  • trypanocide refers to an agent capable of killing one or more trypanosomatid.
  • ring A is a fused 5 or 6-membered heterocycloalkyl or a fused 5 or 6-membered heteroaryl ring, each optionally substituted with one or more R a ;
  • X 1 and X 2 are independently selected from C or N;
  • X 3 is selected from CH, S, NH and N; with the proviso that at least one of X 1 , X 2 and X 3 is a heteroatom; Z is selected from CH 2 , NH and O; with the proviso that when X 1 is N, Z is not NH or
  • E is selected from -NR 1 R 2 and 3-7 membered heterocycloalkyl group, optionally substituted with one or more groups selected from C 1-3 alkyl, halogen and CN;
  • R 1 and R 2 are independently selected from hydrogen, C 1-3 alkyl and C 1.3 haloalkyl wherein said C 1-3 alkyl is optionally substituted with one or more substituents selected from halogen, hydroxyl, NH 2 , NHMe, NMe 2 , O-C 1-3 alkyl, C 1-3 haloalkoxy and CN; or
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a 3 to 7- membered heterocycloalkyl ring optionally substituted by one or more R b ;
  • R 3 , R 4 , R 5 and R 6 are independently selected from hydrogen, halogen and C 1-3 alkyl; or
  • R 2 and R 3 together with the atoms to which they are attached form a 4 to 7- membered heterocycloalkyl ring optionally substituted by one or more R c ;
  • R 7 and R 9 are independently selected from hydrogen, halogen, C 1-3 alkyl, O-C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 haloalkoxy and CN;
  • R 8 is selected from halogen, C 1-3 alkyl, C 1-3 haloalkyl and CN; each R a is independently selected from hydrogen, halogen, C 1-3 alkyl, O-C 1-3 alkyl, Ci- 3 haloalkyl, C 1-3 haloalkoxy, CN, and NO 2 .
  • a compound according to paragraph 1 selected from a compound of subformula la, lb and lc, or a salt, hydrate or solvate thereof:
  • each R a is independently selected from hydrogen, halogen and C 1-3 alkyl; suitably hydrogen and C 1-3 alkyl.
  • each R a is independently selected from hydrogen, fluoro and methyl; suitably hydrogen and methyl.
  • n is selected from 1 , 2 and 3.
  • a compound according to paragraph 1 selected from a compound of subformula Ia1 , or a salt, hydrate or solvate thereof: wherein R 1 , R 2 R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are as defined in paragraph 1.
  • R 1 is selected from hydrogen and C1 -3 alkyl, wherein said C1-3 alkyl is optionally substituted with one or more substituents selected from halogen, O-C1-3 alkyl, C1 -3 haloalkoxy and CN.
  • R 1 is selected from hydrogen and C1 -3 alkyl, wherein said C1-3 alkyl is optionally substituted with one or more substituents selected from halogen and CN.
  • R 1 is selected from methyl and ethyl, wherein said groups are is optionally substituted with one or more substituents selected from halogen, O-C 1-3 alkyl, C 1-3 haloalkoxy and CN.
  • R 1 is selected from methyl and ethyl, wherein said groups are is optionally substituted with one or more substituents selected from fluoro or chloro, suitably fluoro.
  • R 2 is selected from hydrogen and C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted with one or more substituents selected from halogen, O-C 1-3 alkyl, C 1-3 haloalkoxy and CN.
  • R 2 is selected from C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted with one or more substituents selected from halogen and CN.
  • R 2 is selected from C 1.3 alkyl, wherein said C 1.3 alkyl is optionally substituted with one or more substituents selected from fluoro or chloro, suitably fluoro.
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a 5 to 6-membered heterocycloalkyl ring optionally substituted by one or more R b .
  • a compound according to paragraph 1 selected from a compound of subformula Ia1 i, or a salt, hydrate or solvate thereof:
  • R 10 and R 11 are selected from methyl and ethyl; or R 10 and R 11 together with the nitrogen atom to which they are attached form a pyrrolidine or piperidine group; and R 7 , R 8 and R 9 are as defined in paragraph 1.
  • R 7 and R 9 are independently selected from hydrogen, halogen, C1 -3 haloalkyl, 0-Ci- 3 alkyl and CN.
  • R 7 is selected from hydrogen, fluoro, chloro and bromo
  • R 8 is selected from fluoro and chloro
  • R 9 is selected from hydrogen, fluoro, chloro and bromo.
  • R 7 is selected from fluoro, chloro and bromo
  • R 8 is selected from fluoro and chloro, and R 9 is hydrogen.
  • R 7 is selected from chloro and bromo
  • R 8 is selected from fluoro and chloro
  • R 9 is hydrogen. 77.
  • a compound according to paragraph 1 or a salt, hydrate or solvate thereof, selected from:
  • a pharmaceutical composition which comprises a compound according to any one of paragraph 1 to 77, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients.
  • a method for killing and/or preventing the growth of a protozoa comprising contacting the protozoa with an effective amount of a compound according to any one of paragraphs 1 to 77, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to paragraph 78.
  • a method for the treatment or prevention of a protozoal infection in a subject in need thereof comprising administering to said subject an effective amount of a compound according to any one of paragraphs 1 to 77, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to paragraph 78.
  • a method for the treatment of prevention of a disease or condition mediated by infection by a protozoal parasite in an subject comprising administering to a subject in need an effective amount of a compound according to any one of paragraphs 1 to 77, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to paragraph 78.
  • a method for the treatment of prevention of trypanosomiasis in a subject in need thereof comprising administering to said subject a compound according to any one of paragraphs 1 to 77, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to paragraph 78.
  • the present invention may relate to any compound or particular group of compounds defined herein by way of optional, preferred or suitable features or otherwise in terms of particular embodiments, the present invention may also relate to any compound or particular group of compounds that specifically excludes said optional, preferred or suitable features or particular embodiments.
  • the present invention excludes any individual compounds not possessing the biological activity defined herein.
  • the compounds (including final products and intermediates) described herein may be isolated and used per se or may be isolated in the form of a salt, suitably pharmaceutically acceptable salts.
  • a salt suitably pharmaceutically acceptable salts.
  • industrially acceptable salts are salts that are generally suitable for manufacturing and/or processing (including purification) as well as for shipping and storage, but may not be salts that are typically administered for clinical or therapeutic use.
  • Industrially acceptable salts may be prepared on a laboratory scale, i.e. multi-gram or smaller, or on a larger scale, i.e. up to and including a kilogram or more.
  • Pharmaceutically acceptable salts are salts that are generally chemically and/or physically compatible with the other ingredients comprising a formulation, and/or are generally physiologically compatible with the recipient thereof.
  • Pharmaceutically acceptable salts may be prepared on a laboratory scale, i.e. multi-gram or smaller, or on a larger scale, i.e. up to and including a kilogram or more. It should be understood that pharmaceutically acceptable salts are not limited to salts that are typically administered or approved by the FDA or equivalent foreign regulatory body for clinical or therapeutic use in humans. A practitioner of ordinary skill will readily appreciate that some salts are both industrially acceptable as well as pharmaceutically acceptable salts. It should be understood that all such salts, including mixed salt forms, are within the scope of the application.
  • the compounds of formula I and II are isolated as pharmaceutically acceptable salts.
  • a suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric or maleic acid.
  • a suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • an alkali metal salt for example a sodium or potassium salt
  • an alkaline earth metal salt for example a calcium or magnesium salt
  • an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation
  • a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxye
  • salts of the present application can be prepared in situ during the isolation and/or purification of a compound (including intermediates), or by separately reacting the compound (or intermediate) with a suitable organic or inorganic acid or base (as appropriate) and isolating the salt thus formed.
  • the degree of ionisation in the salt may vary from completely ionised to almost non-ionised.
  • the various salts may be precipitated (with or without the addition of one or more co-solvents and/or anti-solvents) and collected by filtration or the salts may be recovered by evaporation of solvent(s).
  • Salts of the present application may also be formed via a “salt switch” or ion exchange/double displacement reaction, i.e. reaction in which one ion is replaced (wholly or in part) with another ion having the same charge.
  • salts may be prepared and/or isolated using a single method or a combination of methods.
  • Representative salts include, but are not limited to, acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate, trifluoroacetate and the like.
  • salts include alkali or alkaline earth metal cations such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, lysine, arginine, benzathine, choline, tromethamine, diolamine, glycine, meglumine, olamine and the like.
  • Certain compounds of the formula I may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms that possess antiproliferative activity.
  • N-oxides Compounds of the formula I containing an amine function may also form N-oxides.
  • a reference herein to a compound of the formula I that contains an amine function also includes the N-oxide.
  • one or more than one nitrogen atom may be oxidised to form an N-oxide.
  • Particular examples of N- oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.
  • N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g.
  • a peroxycarboxylic acid see for example Advanced Organic Chemistry, by Jerry March, 4 th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady ( Syn . Comm. 1977, 7, 509-514) in which the amine compound is reacted with m- chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.
  • mCPBA m- chloroperoxybenzoic acid
  • tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), pyrimidone/hydroxypyrimidine, imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro.
  • isomers Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.
  • Certain compounds of formula I may have one or more asymmetric centers and therefore can exist in a number of stereoisomeric configurations. Consequently, such compounds can be synthesized and/or isolated as mixtures of enantiomers and/or as individual (pure) enantiomers, and, in the case of two or more asymmetric centers, single diastereomers and/or mixtures of diastereomers. It should be understood that the present application includes all such enantiomers and diastereomers and mixtures thereof in all ratios.
  • the compounds of the present invention are described herein using structural formulas that do not specifically recite the mass numbers or the isotope ratios of the constituent atoms. As such it is intended that the present application includes compounds in which the constituent atoms are present in any ratio of isotope forms. For example, carbon atoms may be present in any ratio of 12 C, 13 C, and 14 C; hydrogen atoms may be present in any ratio of 1 H, 2 H, and 3 H; etc.
  • the constituent atoms in the compounds of the present invention are present in their naturally occurring ratios of isotope forms.
  • the compounds of formula I may be administered in the form of a pro-drug which is broken down in the human or animal body to release a compound of the invention.
  • a prodrug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the invention.
  • a pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a property-modifying group can be attached.
  • Examples of pro-drugs include in vivo cleavable ester derivatives that may be formed at a carboxy group or a hydroxy group in a compound of the formula I and in-vivo cleavable amide derivatives that may be formed at a carboxy group or an amino group in a compound of the formula I.
  • the present invention includes those compounds of the formula I as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of the formula I that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the formula I may be a synthetically-produced compound or a metabolically-produced compound.
  • a suitable pharmaceutically acceptable pro-drug of a compound of the formula I is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.
  • Various forms of pro-drug have been described, for example in the following documents a) Methods in Enzvmoloav. Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H.
  • Bundgaard Chapter 5“Design and Application of Pro-drugs”, by H. Bundgaard p. US- 191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella,“Pro-Drugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor),“Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.
  • a suitable pharmaceutically acceptable pro-drug of a compound of the formula I that possesses a carboxy group is, for example, an in vivo cleavable ester thereof.
  • An in vivo cleavable ester of a compound of the formula I containing a carboxy group is, for example, a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid.
  • Suitable pharmaceutically acceptable esters for carboxy include Ci-ealkyl esters such as methyl, ethyl and tert- butyl, Ci- 6 alkoxymethyl esters such as methoxymethyl esters, Ci- 6 alkanoyloxymethyl esters such as pivaloyloxymethyl esters, 3-phthalidyl esters, C3-8cycloalkylcarbonyloxy- Ci- 6 alkyl esters such as cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters,
  • 2-oxo-1 ,3-dioxolenylmethyl esters such as 5-methyl-2-oxo-1 ,3-dioxolen-4-ylmethyl esters and Ci- 6 alkoxycarbonyloxy- Ci- 6 alkyl esters such as methoxycarbonyloxymethyl and 1- methoxycarbonyloxyethyl esters.
  • a suitable pharmaceutically acceptable pro-drug of a compound of the formula I that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof.
  • An in vivo cleavable ester or ether of a compound of the formula I containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound.
  • Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters).
  • ester forming groups for a hydroxy group include Ci-ioalkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, Ci-ioalkoxycarbonyl groups such as ethoxycarbonyl, N,N -(Ci- 6 ) 2 carbamoyl, 2- dialkylaminoacetyl and 2-carboxyacetyl groups.
  • Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include a-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.
  • a suitable pharmaceutically acceptable pro-drug of a compound of the formula I that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a Ci- 4 alkylamine such as methylamine, a (Ci- 4 alkyl) 2 amine such as dimethylamine, /V-ethyl-/V-methylamine or diethylamine, a Ci- 4 alkoxy- C ⁇ alkylamine such as 2-methoxyethylamine, a phenyl-Ci- 4 alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.
  • an amine such as ammonia
  • a Ci- 4 alkylamine such as methylamine
  • a (Ci- 4 alkyl) 2 amine such as dimethylamine, /V-ethyl-/V-methylamine or diethylamine
  • a suitable pharmaceutically acceptable pro-drug of a compound of the formula I that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof.
  • Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with Ci-ioalkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups.
  • ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, /V-alkylaminomethyl, N,N- dialkylaminomethyl, morpholinomethyl, pi perazin-1-yl methyl and 4-(Ci- 4 alkyl)piperazin-1- ylmethyl.
  • the in vivo effects of a compound of the formula I may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the formula I. As stated hereinbefore, the in vivo effects of a compound of the formula I may also be exerted by way of metabolism of a precursor compound (a pro-drug).
  • a pharmaceutical composition which comprises a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.
  • compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).
  • oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or
  • compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
  • An effective amount of a compound of the present invention for use in therapy is an amount sufficient to treat or prevent a proliferative condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition.
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • the size of the dose for therapeutic or prophylactic purposes of a compound of the formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
  • dosages and dosing regimens may vary with the type and severity of the condition to be alleviated, and may include the administration of single or multiple doses, i.e. QD (once daily), BID (twice daily), etc., over a particular period of time (days or hours). It is to be further understood that for any particular subject or patient, specific dosage regimens may need to be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the pharmaceutical compositions. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and/or laboratory values.
  • the present application encompasses intra-patient dose-escalation as determined by the person skilled in the art.
  • Procedures and processes for determining the appropriate dosage(s) and dosing regimen(s) are well-known in the relevant art and would readily be ascertained by the skilled artisan.
  • dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the pharmaceutical compositions described herein.
  • a daily dose in the range for example, 0.1 mg/kg to 75 mg/kg body weight is received, given if required in divided doses.
  • a parenteral route is employed.
  • a dose in the range for example, 0.1 mg/kg to 30 mg/kg body weight will generally be used.
  • a dose in the range for example, 0.05 mg/kg to 25 mg/kg body weight will be used.
  • Oral administration may also be suitable, particularly in tablet form.
  • unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention.
  • the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in therapy.
  • the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use as an antiprotozoal agent.
  • the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of a protozoal infection.
  • the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of diseases mediated by infection of a protozoal parasite, suitably a trypanosomatid parasite.
  • the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of trypanosomiasis.
  • the present invention provides a method for killing and/or preventing the growth of a protozoa comprising contacting the protozoa with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.
  • the present invention provides a method for the treatment or prevention of a protozoal infection in a subject in need thereof, comprising administering to said subject an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.
  • the present invention provides a method for the treatment of prevention of a disease or condition mediated by infection by a protozoal parasite in an subject, comprising administering to a subject in need an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.
  • the present invention provides a method for the treatment of prevention of trypanosomiasis in a subject in need thereof, comprising administering to said subject a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.
  • the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, in the manufacture of an antiprotozoal agent.
  • the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, in the manufacture of medicament for treating or preventing a protozoal infection.
  • the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for treating or preventing diseases mediated by infection by a protozoal parasite, suitably a trypanosomatid parasite.
  • the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for treating or preventing trypanosomiasis.
  • the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, as a protozoacide.
  • the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, as a trypanocide.
  • the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for inhibiting phosphofructokinase in a trypanosomatid parasite.
  • the antiprotozoal agent is suitably an anti-trypanosomatid agent.
  • the antiprotozoal agent is suitably an anti-Leishmania agent or an anti-Trypanosoma agent.
  • the protozoal infection is selected from a Leishmania infection or a Trypanosoma infection.
  • the protozoal parasite is selected from a Leishmania parasite or a Trypanosoma parasite.
  • the protozoa or protist is selected from the genus Leishmania or Trypanosoma.
  • the Leishmania parasite is selected from Leishmania donovani, Leishmania infantum, Leishmania chagasi, Leishmania mexicana, Leishmania amazonensis, Leishmania venezuelensis, Leishmania tropica, Leishmania major and Leishmania aethiopica.
  • the Trypanosoma parasite is selected from the group consisting of Trypanosoma brucei, Trypanosoma congolense, Trypanosoma vivax, Trypanosoma cruzi. [00121] In one embodiment, the Trypanosoma parasite is selected from the group consisting of Trypanosoma congolense and Trypanosoma vivax.
  • the Trypanosoma parasite is selected from the group consisting of Trypanosoma brucei and Trypanosoma cruzi.
  • the Trypanosoma brucei is selected from Trypanosoma brucei brucei, Trypanosoma brucei gambiense or Trypanosoma brucei rhodesiense.
  • the disease or condition mediated by infection by a protozoal parasite is selected from leishmaniasis and trypanosomiasis.
  • the trypanosomiasis is selected from African trypanosomiasis (sleeping sickness) or South American trypanosomiasis (Chagas disease).
  • the trypanosomiasis is selected from Human African Trypanosomiasis.
  • the leishmaniasis is selected from the group consisting of visceral leishmaniasis, cutaneous leishmaniasis and mucocutaneous leishmaniasis.
  • the compounds described herein are for use in treating humans.
  • the compounds described herein are for use in treating non-human animals (e.g. livestock, such as cattle, sheep, goats and horses; and domestic pets such as cats and dogs).
  • non-human animals e.g. livestock, such as cattle, sheep, goats and horses; and domestic pets such as cats and dogs.
  • the compounds described herein are for use in treating a non-human animal (e.g. livestock, such as cattle, sheep, goats and horses; and domestic pets such as cats and dogs) and the protozoal (parasite) infection is with Trypanosoma congolense or Trypanosoma vivax.
  • a non-human animal e.g. livestock, such as cattle, sheep, goats and horses; and domestic pets such as cats and dogs
  • the protozoal (parasite) infection is with Trypanosoma congolense or Trypanosoma vivax.
  • the compounds described herein are for use in treating a human and the protozoal (parasite) infection is with Trypanosoma brucei (suitably Trypanosoma brucei gambiense or Trypanosoma brucei rhodesiense), Trypanosoma cruzi or Leishmania.
  • the subject is a human.
  • the subject in the methods of treatment described above, is a non-human animal (e.g. livestock, such as cattle, sheep, goats and horses; and domestic pets such as cats and dogs).
  • livestock such as cattle, sheep, goats and horses
  • domestic pets such as cats and dogs.
  • the subject in the methods of treatment described above, is a non-human animal (e.g. livestock, such as cattle, sheep, goats and horses; and domestic pets such as cats and dogs) and the protozoal (parasite) infection is with Trypanosoma congolense or Trypanosoma vivax.
  • livestock such as cattle, sheep, goats and horses
  • domestic pets such as cats and dogs
  • protozoal infection is with Trypanosoma congolense or Trypanosoma vivax.
  • the subject in the methods of treatment described above, is a human and the protozoal (parasite) infection is with Trypanosoma brucei (suitably Trypanosoma brucei gambiense or Trypanosoma brucei rhodesiense), Trypanosoma cruzi or Leishmania.
  • Trypanosoma brucei suitable Trypanosoma brucei gambiense or Trypanosoma brucei rhodesiense
  • Trypanosoma cruzi or Leishmania.
  • the compounds of the invention or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically/ peripherally or topically (i.e., at the site of desired action).
  • Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, sub
  • the extract was washed with brine (3x) and then dried over sodium sulfate, filtered and evaporated. It was purified on a silica column eluted with 2% methanol, 98% dichloromethane, then 3% methanol, 97% dichloromethane to give a white foam. The foam was triturated with a mixture of iso- pentane and diethyl ether to give a white solid. The solid was filtered off, washed with iso- pentane (2x) and then dried under vacuum to yield the title product as a white solid (784 mg, 63%).
  • Example 27 6-[(3-chloro-4-fluoro-phenyl)methyl]-2-(2-pyrrolidin-1-ylethyl)pyrrolo[1 ,2- a]pyrazin-1-one (589)
  • Example 30 1-[(3,4-dichlorophenyl)methyl]-5-[2-(4-fluoro-1-piperidyl)ethyl]pyrrolo[3,2- c]pyridin-4-one (602)
  • Example 32 6-[(3-bromo-4-chloro-phenyl)methyl]-2-[2-(dimethylamino)ethyl]pyrrolo[1 ,2- a]pyrazin-1-one (610)
  • the nitrogen in the alkylating agent can also be protected by a group such as t-butoxy- carbonyl or nosyl. After the alkylation the protecting group is removed to give the product.
  • Analogues where R 1 and/or R 2 is/are hydrogen can be prepared as follows.
  • Example 46 Preparation of 1-[(3,4-Dichlorophenyl)methyl]-5-[(1 R)-1-methyl-2-
  • Step 2 Preparation of 1-[(3,4-dichlorophenyl)methyl]-5-[(1 R)-2-hydroxy-1-methyl- ethyl]pyrrolo[3,2-c]pyridin-4-one (Step 2) [00223] (2R)-2-[1-[(3,4-dichlorophenyl)methyl]-4-oxo-pyrrolo[3,2-c]pyridin-5- yl]propanoic acid (0.64g, 1.76mmoles) was dissolved in dry THF (35ml) and triethylamine (0.245ml, 1.76mmoles) was added.
  • N-[2-[1-[(3,4-dichlorophenyl)methyl]-4-oxo-pyrrolo[3,2-c]pyridin-5-yl] ethyl]-N- methyl-4-nitro-benzenesulfonamide (0.048g, 0.0897mmoles) was suspended in DMF (2ml) and 4-nitrothio phenol (0.017g, 0.108mmoles) was added. Potassium carbonate (0.037g, 0.269mmoles) was added and the reaction mixture was stirred at RT for 1 hr. Very little reaction had occurred so thiophenol (0.011ml, 0.108mmoles) was added.
  • 5,6-Fused ring intermediates can be prepared as follows.
  • N-[(3,4-dichlorophenyl)methyl]-3-nitro-pyridin-4-amine (3.8g, 13mmoles) was suspended in cone hydrochloric acid (50ml) and heated to 100°C. Tin(ll)chloride dihydrate (14.7g, 65mmoles) was added portionwise. The reaction mixture was heated at 100°C for 2 hours. Allowed to cool and then filtered off the white solid. Triturated with diethyl ether to give a white solid. Added slowly to sodium bicarbonate solution with stirring and extracted with EtOAc (x2). Washed with water and dried over magnesium sulphate. Filtered and evaporated to give the product as a white solid. (1.8g, 46%)
  • Step 1 Preparation of t-Butyl 4-(t-butoxycarbonylamino)-3-oxo-butanoate (Step 1) [00336] Diisopropylamine (10.1g, 100mmoles) was dissolved in dry THF (60ml) and cooled to -70°C. Added nBuLi (2.5M in hexanes 40ml, lOOmmoles) dropwise and allowed the reaction mixture to warm to -10°C. Stirred at -10°C for 20 minutes before cooling to - 70°C and added t-butyl acetate (11.6g, lOOmmoles) in dry THF (30ml). Stirred for 2 hours at -70°C.
  • nBuLi 2.5M in hexanes 40ml, lOOmmoles
  • N-BOC glycine (5.1 g, 32mmoles) was dissolved in dry THF (30ml) and a suspension of carbodiimidazole (5.7g, 35mmoles) in THF (30ml) was added at -30°C. Allowed to warm to 0°C to give a clear solution. Stirred for 30 minutes at 0°C. Added the solution dropwise to the t-butyl acetate, LDA solution at -70°C. Stirred at 70°C for 1 hour to give a thick suspension. Poured into 4M aqueous ammonium chloride (300ml) and extracted with EtOAc (x2). Washed with brine and dried over magnesium sulphate. Filtered and evaporated to give a yellow oil. (7.9g, 90%)
  • Amino alkyl halide Intermediates can be prepared as follows.
  • N-Ethylmethylamine (5.9g, 100mmoles) was dissolved in acetonitrile (100ml) and potassium carbonate (13.8g, 100mmoles) was added with stirring.
  • 2-Chloroethanol (8.0g, 100mmoles) was added in acetonitrile (10ml) and the reaction mixture was heated at reflux for 24 hours. Allowed to cool and filtered off the solid. Evaporated to give the product as a pale yellow oil (5.2g, 50%).
  • Equipment Infors shaking incubator, Constant Systems TS cell disruptor, GE Healthcare AKTA Express Protein purification system, Centrifuge - Beckman Avanti 26 XPI
  • Reagents C41 DE3 Competent cells transformed with plasmid containing the gene of interest.
  • Protein expression was induced with 1 mM IPTG, the cells transferred to an incubator set at 18°C and shaken at 125rpm for 18 hours. The cells were harvested using xxg for 40 minutes. The cell pellets were flash frozen in liquid nitrogen and stored at -80°C until required [00362] The cell pellet was solubilised in 50 mM NaH 2 PC>4, 300 mM NaCI, 20 mM imidazole, 10% glycerol, pH 8.0 with protease inhibitors. Lysed using a constant cell disruption system and the lysate centrifuged. PFK was present in the soluble fraction.
  • the soluble fraction was loaded onto a 1 ml IMAC Hitrap HP Sepharose column. Washed with ten column volumes of wash buffer (Buffer A 50 mM NaH 2 PC>4, 300 mM NaCI, 20 mM imidazole, 10% glycerol, pH 8.0), followed by a 10 column volume wash step of 10% Buffer B, followed by a step to 100% Buffer B (50 mM NaH 2 PC>4, 300 mM NaCI, 500 mM imidazole, 10% glycerol, pH 8.0).
  • Buffer A 50 mM NaH 2 PC>4, 300 mM NaCI, 20 mM imidazole, 10% glycerol, pH 8.0
  • Buffer B 50 mM NaH 2 PC>4, 300 mM NaCI, 500 mM imidazole, 10% glycerol, pH 8.0.
  • Peak fractions were automatically selected by the optimised protocol and applied to a gel filtration column s200 26/60 pre-equilibrated in buffer (20 mM T riethanolamine-HCI (TEA), 5 mM MgCI 2 -6H 2 0, 50 mM KCI, 10% glycerol, pH 7.2). Eluted fractions were analysed by SDS PAGE, fractions containing pure PFK were pooled, aliquoted and flash frozen in liquid nitrogen.
  • buffer (20 mM T riethanolamine-HCI (TEA), 5 mM MgCI 2 -6H 2 0, 50 mM KCI, 10% glycerol, pH 7.2.
  • This assay measures the activity (and inhibition) of PFK spectrophotometrically by measuring the oxidation of NADH. This is achieved, by linking it to the reaction product Mg-ADP in the presence of an excess of the linked enzyme pyruvate kinase (PYK) and lactate dehydrogenase (LDH) upon the titration of F6P.
  • PYK pyruvate kinase
  • LDH lactate dehydrogenase
  • Equipment Molecular Devices M5 Multimode plate reader; Non-binding 96 well plates from Greiner Bio One (cat. No. 655901)
  • Reagents 2.5X Assay mix - 12 mM ATP, 5mM PEP, 1.2 mM NADH,>20U/ml PYK, >20U/ml LDH in 1x buffer; 1x Buffer: 10mM MgCI 2 , 100mM KCI, 50mM TEA, 10% glycerol, 0.005% TWEEN, 1 % DMSO, pH 7.2; 10x F6P stock (final cone. 0.6mM).
  • Protein at. approximately 60 nM final concentration is used (determined by testing each batch of protein)
  • Ligand/inhibitor stocks (10mM stock in 100% DMSO was prepared). All subsequent dilutions were made from this stock.
  • This assay was carried out using the standard ADP-GloTM Kinase Assay produced by Promega.
  • the kit measures the amount of ADP produced in a kinase reaction by first depleting any unused background ATP and sequestering the kinase reaction. A second reagent is then added to convert the remaining ADP to ATP, which is then coupled to the Luciferase reaction to produce light.
  • the assay was carried out as described by Brimacombe, K. R., et al. (2014). "Identification of ML251 , a Potent Inhibitor of T. brucei and T. cruzi Phosphofructokinase.” ACS Med Chem Lett 5(1): 12-17.
  • Equipment Molecular Devices M5 Multimode plate reader.
  • Reagents ADP-Glo kinase assay kit from Promega (Cat no V9102).
  • Ligand/inhibitor stocks (a 10mM stock in 100% DMSO was prepared). All subsequent dilutions were made from this stock. Serial dilutions were carried out by stepwise dilution (1 :3) of inhibitor compounds in 100% DMSO. A further (1 :100) dilution “gives working stocks” at a final concentration range of 80uM to 36nM in 1 % DMSO. The dilution range was determined by compound solubility, 1 :2 dilution steps were used for less soluble compounds.
  • Controls - Positive control a standard inhibitor (CTCB-000001 , ML251) was used as a positive control at a final cone of 5 mM.
  • Negative control assay buffer is used in place of ligand/inhibitor.
  • Method The protein/inhibitor mix was pre-incubated in a 96 well plate at 4°C to minimise evaporation. 10mI of ligand/inhibitor/control was added to 10mI_ TbPFK protein, sealed and incubated at 4°C for 30 minutes. The kinase reaction was started by addition of 5mI of F6P/ATP mix using a multichannel pipette. The plate was sealed and centrifuged at 2000rpm for 1 minute at 4°C. The plate was incubated at room temperature (approximately 24°C) for 30mins. ADP-Glo reagent (25mI) was added at room temperature, mixed and the plate sealed.
  • the plate was incubated at room temperature for 40 mins.
  • the kinase detection reagent 50mI was added at room temperature, mixed and the plate sealed.
  • the plate was incubated at room temperature for 40 minutes. Luminescence was recorded in end-point mode with an integration time of 750 ms.
  • Test compounds 10 mM stocks in 100% DMSO, stored at -80C
  • Control compound e.g. suramin and/or fexinidazole
  • cHMI HMI-9 medium + 10% FBS (Gibco)
  • Trypanosomes Bloodstream-form Trypanosoma brucei brucei Lister 427 (VAT 221)
  • Viability dye Alamar Blue (Invitrogen Ref. DAL1025)
  • test compounds against T. brucei brucei Lister 427 were measured using the method described by Raz et al. (197) Acta Trap 68(20 139-147.
  • a stock suspension of 5 x 10 4 trypanosomes/ml was prepared from an exponentially growing trypanosome culture by dilution with fresh medium (HMI-9 with 10% FBS).
  • Test compounds (10mM in DMSO) were diluted with media to give a stock solution (90mM). 75pL of the stock solution was added to the well plate and serial dilutions with media were carried out in order to generate the test compound concentrations.
  • 50 mI diluted trypanosome suspension per well was added to give final test compound concentrations of 45 mM, 15 mM, 5 mM, 1.67 mM, 0.56 mM, 185 hM, 61.7 hM and 20.6 hM, all in a final volume of 100 mI/well.
  • the plates were incubated for 72 h (+/- 5 h), at 37°C, with a relative humidity and under 5% CO 2.
  • 50 mI 0.2% Alamar Blue (1x diluted with DPBS) was added.
  • the plates were incubated for 4 hr at 37°C, at relative humidity and under 5% CO 2.
  • the fluorescence was measured with a plate reader (excitation wavelength ⁇ 544nm; emission wavelength ⁇ 590 nm) and the EC50 value for each compound was determined.
  • a graphic Excel program was used for data analysis.
  • the aqueous solubility assay was used to determine the limit of the concentration range that can be reliably used in the assays.
  • a turbidimetric assay was used measuring absorbance at 650nm in a SpectraMaxM5.
  • the assay included blank wells in the absence of compound, with pyrene as a positive control and aspirin as a negative control.
  • a 6pt concentration curve (normally 100, 75, 50, 25, 10 and 3mM) with final 1 % DMSO concentration was performed (triplicate wells) for all compounds.
  • the assay was performed at 25°C and the samples were shaken for 18h.
  • the assay was performed in the presence of 35mM Hepes buffer (pH 7.8) unless otherwise stated. Results were given as the highest concentration tested where the test compound remained in solution.
  • HepG2 human hepatocyte carcinoma cell line
  • EMEM media containing L-glutamine, non-essential amino acids and 10% FBS.
  • the compounds (6 point dose response curves performed of triplicates) were added to the cells (in 10mI) and incubated for a further 72h.
  • the numbers of viable cells were detected using Promega CellTitreGlo® reagent according to the manufacturer’s instructions. Essentially the number of viable cells were detected by measuring ATP using the luciferase/luciferin detection system. Luminescence was detected using a SpectraMax M5. Results were expressed as a percentage of a 'no inhibitor’ control and EC50 and/or % inhibition of the top concentration are determined. The selectivity index was calculated as the EC50 in the HepG2 assay divided by the EC50 determined in the Tbb parasite killing assay.
  • Example 1 The compound of Example 1 was administered to female CD-1 mice by IV bolus (1 mg/Kg) by tail vein injection and oral dosing (5mg/kg). Blood samples were collected from terminal cardiac puncture at 0.08 (IV only), 0.25, 0.5, 1 (PO only), 2, 4, 8 and 24 hour time points. The whole blood was centrifuged to obtain plasma. Brains were also collected following cardiac perfusion from both sets of animals at 2 hours.
  • Plasma proteins were precipitated by addition of phosphate buffered saline (1 volume) followed by 3 volumes of acetonitrile containing internal standard (verapamil). Eluent was dried under nitrogen and re-suspended in 5% acetonitrile prior to analysis. Individual brains were homogenised in PBS and diluted to 10% w/v. Aliquots of brain homogenate (0.3ml) were added to 0.9ml of acetonitrile containing internal standard. Samples were centrifuged and supernatants removed and taken through a protein precipitation plate alongside appropriate standard. Eluents were dried under nitrogen and re- suspended in 5% acetonitrile prior to analysis. Eluents were analysed by LC/MS/MS using a Phenomenex Gemini NX column (C18,30 x 2.0mm, 3 micron). Analysis of the data was carried out using PK solutions software.
  • the compound of Example 1 has high bioavailability (Figure 1) with a high brain:plasma ratio.
  • mice Female CD1 mice were used to establish the efficacy and toxicity of compounds in vivo. Oral doses up to 100mg/kg were given for each of three compounds Examples 1 , 10 and 16 without any sign of adverse effects. No liver toxicity was observed following repeated dosing at 100mg/kg. Bioavailability for Example 1 measured as the ratio of compound concentration in the plasma after i.v. delivery compared with oral delivery was 54% (Table 3). The high rate of metabolism observed in mouse liver microsomes (Table 2), was also observed in vivo and plasma levels dropped to ⁇ 1 mM in 2 hours and were completely cleared 24 hours after a dose of 50mg/kg p.o.
  • peak plasma levels were 6.8 mM, 1.8 mM and 5.0 pM for Examples 1 , 10 and 16 respectively.
  • High levels of compound were found in the brain and brain/plasma ratios for all compounds tested were between 1.5 and 2.
  • mice treated with three doses of 100mg/kg given on two consecutive days gave mean plasma levels of 9.7 mM with a mean brain: plasma ratio of 8.7 (measured 2 hours after the final dose).
  • a one day dosing regime was explored for Example 1 with 3 doses of 100mg/kg at 4 hour intervals which resulted in complete cure for 5/5 infected mice with no measurable recurrence of parasitaemia beyond 30 days after infection
  • mice received a single intraperitoneal dose of diminazene aceturate (Sigma-A!drich) at 40 mg/kg in sterile water or Meiarsoprol applied topically for 2 consecutive days served as controls for Stage 1 and Stage 2 studies respectively.
  • diminazene aceturate Sigma-A!drich
  • T. brucei GVR35-VSL2 infection was monitored primarily by in vivo bioluminescence imaging of infected mice using an IVIS Spectrum (Perkin Elmer).
  • stage 1 studies imaging of infected mice was performed before treatment on day 7 post-infection and in days following the treatment (days 8, 9 and 14). Imaging on groups of three mice was performed 12 minutes after i.p. injection of 150 mg/kg D-luciferin (Promega) in PBS.
  • stage 2 infection mice were imaged prior to treatment on day 21 and subsequently on days 22 and 23. 24 hours after the final dose, on day 23, mice were sacrificed by cervical dislocation to allow ex vivo imaging of whole brains. To this end, 100mI D-luciferin was administered onto the brain surface and imaging performed immediately.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Public Health (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés de formule I, ou des sels, des hydrates et des solvates de ceux-ci. Selon d'autres aspects, l'invention concerne des compositions pharmaceutiques comprenant les composés définis dans la description, l'utilisation des composés définis dans la description en thérapie, y compris pour le traitement d'une maladie ou d'une affection induite par une infection par un parasite protozoaire, tel que la trypanosomiase.
PCT/GB2018/053454 2017-12-01 2018-11-29 Dérivés de pyrrolo[3,2-c]pyridin-4-one utilisés en tant qu'inhibiteurs de pfk utiles pour le traitement d'infections protozoaires Ceased WO2019106368A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4267131A1 (fr) 2020-12-28 2023-11-01 Celgene Corporation Composés hétérocycliques et leur utilisation pour des maladies parasitaires

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016004297A1 (fr) * 2014-07-02 2016-01-07 Board Of Regents, The University Of Texas System Nouveaux inhibiteurs de méthionyl t-arn synthétase (tb metrs) de trypanosoma brucei pour le traitement de la trypanosomiase africaine
EP2993174A1 (fr) * 2014-09-08 2016-03-09 Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt GmbH Dérivés de pyrazolopyridine et leur utilisation en thérapie
WO2017021178A1 (fr) * 2015-07-31 2017-02-09 Universite De Nantes Nouveaux dérivés de pyrimidinone et de triazinone fusionnés, leur procédé de préparation et leurs utilisations thérapeutiques en tant qu'agents antifongiques et/ou antiparasitaires

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016004297A1 (fr) * 2014-07-02 2016-01-07 Board Of Regents, The University Of Texas System Nouveaux inhibiteurs de méthionyl t-arn synthétase (tb metrs) de trypanosoma brucei pour le traitement de la trypanosomiase africaine
EP2993174A1 (fr) * 2014-09-08 2016-03-09 Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt GmbH Dérivés de pyrazolopyridine et leur utilisation en thérapie
WO2017021178A1 (fr) * 2015-07-31 2017-02-09 Universite De Nantes Nouveaux dérivés de pyrimidinone et de triazinone fusionnés, leur procédé de préparation et leurs utilisations thérapeutiques en tant qu'agents antifongiques et/ou antiparasitaires

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KYLE R. BRIMACOMBE ET AL: "Identification of ML251, a Potent Inhibitor of T. brucei and T. cruzi Phosphofructokinase", ACS MEDICINAL CHEMISTRY LETTERS, vol. 5, no. 1, 8 November 2013 (2013-11-08), pages 12 - 17, XP055540680, ISSN: 1948-5875, DOI: 10.1021/ml400259d *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4267131A1 (fr) 2020-12-28 2023-11-01 Celgene Corporation Composés hétérocycliques et leur utilisation pour des maladies parasitaires
JP2024500989A (ja) * 2020-12-28 2024-01-10 セルジーン コーポレーション 寄生虫症のためのヘテロ環化合物およびそれらの使用
EP4267131A4 (fr) * 2020-12-28 2025-04-23 Celgene Corporation Composés hétérocycliques et leur utilisation pour des maladies parasitaires

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