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WO2008074068A1 - Dérivés de quinoline substitués utilisés comme agents non-amyloïdogéniques - Google Patents

Dérivés de quinoline substitués utilisés comme agents non-amyloïdogéniques Download PDF

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Publication number
WO2008074068A1
WO2008074068A1 PCT/AU2007/001952 AU2007001952W WO2008074068A1 WO 2008074068 A1 WO2008074068 A1 WO 2008074068A1 AU 2007001952 W AU2007001952 W AU 2007001952W WO 2008074068 A1 WO2008074068 A1 WO 2008074068A1
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optionally substituted
disease
alkyl
compound
formula
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Elisabeth Colette Louise Gautier
Kevin Jeffrey Barnham
Penelope Jane Huggins
Jack Gordon Parsons
Gaik Beng Kok
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Alterity Therapeutics Ltd
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Prana Biotechnology Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C07D239/91—Oxygen atoms with aryl or aralkyl radicals attached in position 2 or 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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

Definitions

  • the present invention relates to__heterocyclic__ compounds, processes for their preparation and their use as pharmaceutical or veterinary agents, in particular for the treatment, amelioration and/or prophylaxis of conditions caused by or associated with unbalanced metal levels and/or oxidative stress, such as neurological conditions and cellular proliferative disorders, for example Alzheimer's disease, Parkinson's disease, Huntington' s disease or brain cancer or tumours .
  • the life span is thought to be biologically fixed for each species, and the length of the human life span is uncertain, but may be up to 120 years. Since life expectancy has risen significantly in this century, the elderly are an increasing segment of our population, and their health care needs will continue to grow for decades .
  • AD nitric oxide
  • Cu plays a role in XIAP activity which modulates caspase activity which in turn controls apoptosis.
  • Apopotosis is a process of controlled cell death and dysregulation of this process has been implicated in many disease states.
  • Metalloenzymes of this type are involved in a number of important bio catalytic processes including reduction of excess oxygen species. Accordingly whenever there is either too high or too low a level of metals present in a biological system, normal processes are interrupted, typically leading to undesirable consequences. This typically occurs as many of the crucial enzymatic processes that provide protection in the biological system are suppressed or inactivated leading to undesirable consequences .
  • OS amyotrophic lateral sclerosis
  • mitochondrial/metabolic disease mitochondrial/metabolic disease
  • Friedreich's ataxia The effect of OS is not limited to any one part of the human body, with examples of the negative effects of OS being observed for almost all organs.
  • the human brain is an organ that concentrates metal ions and recent evidence suggests that a breakdown in metal homeostasis plays a critical role in a variety of age- related neurodegenerative diseases.
  • Common features of these diseases include the deposition of misfolded protein (each disease can have its own specific amyloid protein) and substantial cellular damage as a result of OS.
  • OS is the primary cause of physical damage in a wide range of disease states, including amyloidogenic neurological disorders such as AD, amylotrophic lateral sclerosis (ALS) , prion diseases - including Creutzfeldt-Jakob Disease (CJD) , transmissible spongioform encephalopathies (TSE), cataracts, mitochondrial disorders, Menke's disease, Parkinson's disease (PD) and Huntington's disease (HD).
  • AD amyloidogenic neurological disorders
  • CJD Creutzfeldt-Jakob Disease
  • TSE transmissible spongioform encephalopathies
  • cataracts mitochondrial disorders
  • Menke's disease Menke's disease
  • Parkinson's disease Parkinson's disease
  • HD Huntington's disease
  • copper metal ion deficiency has been reported as a condition associated with AD. Copper is an essential element that is required for many enzymes to function properly, particularly those enzymes that maintain a balance in antioxidant/pro-oxidant homeostasis such as superoxide dismutase and cytochrome C oxidase.
  • One consequence of copper deficiency is that the protective enzymes responsible for detoxifying reactive oxygen species (ROS) are inadequately loaded with copper and therefore do not effectively carry out normal enzyme function.
  • ROS reactive oxygen species
  • the inadequate loading of such protective enzymes leads to a general increase in OS (as is observed in AD) which will be reflected in increased protein oxidation, such as increased protein carbonyls .
  • AD ⁇ -amyloid protein
  • a hypothesis is that AD is caused by the toxic accumulation of A ⁇ amyloid, due in part to excess binding of copper and zinc, metal ions which are abundant in the regions most affected.
  • Zn 2+ and Cu 2+ ions interact with A ⁇ , aggregation of A ⁇ into fibrils and plaques occurs (Atwood et al . , 1998) ; confirmed by recent data from animals deficient in synaptic Zn 2+ (Lee et al . , 2002) .
  • the present invention provides a method for the treatment, amelioration and/or prophylaxis of conditions caused by or associated with unbalanced metal levels and/or oxidative stress, in particular conditions in which metal delivery to or from a target biological site or metal attenuation can treat, ameliorate or prevent the condition such as neurological conditions or cellular proliferative disorders including those characterised by an abnormal reaction between proteins and metals such as conditions associated with a toxic gain of function of a protein.
  • heterocyclic compounds having two fused 6-membered aromatic rings with a nitrogen atom at position 1 and a group at position 8 that provides a lone pair of electrons such as N, S, Se or P.
  • the lone pair of electrons at position 8 is believed to assist with the attenuation of metals by the compound.
  • the compounds have been prepared through the collective optimization of one or more of the following properties : (a) aqueous solubility; (b) reduced cell toxicity;
  • substituent R may further be important in enhancing plaque disaggregation. It is preferable that these substituents are planar in 3D terms . Planar substituents on the ring system allow both the free ligand and the metal attenuation component to more effectively interact with, and disaggregate, protein aggregates such as amyloid and in particular neurotic plaques .
  • ionophores can act as ionophores .
  • An ionophore is a lipid-soluble molecule that can transportions across the lipid bilayer of the cell membrane. Such small molecules bind to a particular ion, shielding its charge from the surrounding environment, and thus facilitating its crossing of the hydrophobic interior of the lipid membrane. Ionophores disrupt transmembrane ion concentration gradients, required for the proper functioning and indicate an ability to specifically target the death of cancer type cells .
  • the compounds may be used in treating cellular proliferative disorders such as cancer or tumours, in particular brain cancers or tumours .
  • R 2 is H; optionally substituted C 1-6 alkyl; optionally substituted C 2 -e alkenyl; optionally substituted C 2 -e alkynyl; optionally substituted C 3-6 cycloalkyl; optionally substituted aryl; optionally substituted heterocyclyl; OR 6 , SR 6 , COR 6 , CSR 6 , HCNOR 6 or HCNNR 6 in which R 6 is H, optionally substituted C 1-6 alkyl, optionally substituted C 2 -S alkenyl, optionally substituted C 2 - 6 alkynyl, optionally substituted Ci- S alkoxy, optionally substituted C 3-5 cycloalkyl, optionally substituted aryl or optionally substituted heterocyclyl; NR 8 R 9 , CONR 8 R 9 or SO 2 NR 8 R 9 in which R 8 and R 9 are independently selected from H, optionalIy substituted C 1 -S alkyl, optionally substituted C 2-e alkenyl, optionally
  • R 5 is selected from H and halo
  • R 7 is selected from H, halo, CO 2 R 13 , CONR 13 R 14 , optionally substituted Ci- 4 alkyl, optionally substituted C 3- gcycloalkyl, optionally substituted aryl and optionally substituted heterocyclyl;
  • R 13 and R 14 are independently selected from H, optionally substituted C 1 . 4 alkyl and optionally substituted heterocyclyl ;
  • W and X are independently selected from CH and N;
  • Y is CH, CO or CS; Z is C or N; and q is 1, 2 or 3 , salts, hydrates, solvates, derivatives, pro-drugs, tautomers and/or isomers thereof.
  • the compound of formula I as a pharmaceutical or antioxidant, preferably a neurotherapeutic or neuroprotective agent such as an antiamyloidogenic agent or an anti-cancer agent .
  • anti-cancer includes “anti-tumour” .
  • the compound of formula I is advantageously administered in the form of a pharmaceutical or veterinary composition together with a pharmaceutically or veterinarily acceptable carrier.
  • a pharmaceutical or veterinary composition comprising the compound of formula I and a pharmaceutically or veterinarily acceptable carrier.
  • a method for the treatment, amelioration and/or prophylaxis of a condition caused by or associated with unbalanced metal levels and/or oxidative stress which comprises the administration of an effective amount of the compound of formula I_ . _to a ⁇ subj ect in need thereof .
  • the compound of formula I in the manufacture of a medicament for the treatment, amelioration and/or prophylaxis of a condition caused by or associated with unbalanced metal levels and/or oxidative stress.
  • the condition caused by or associated with unbalanced metal levels and/or oxidative stress is a neurological condition or a cellular proliferative disorder.
  • the neurological condition is preferably a neurodegenerative condition, more preferably a neurodegenerative amyloidosis such as Alzheimer's disease, Parkinson's disease or Huntington's disease.
  • the cellular proliferative disorder is preferably a cancer or a tumour such as a brain cancer or tumour.
  • the present invention relates to compounds of formula I, salts, solvates, derivatives, prodrugs and/or isomers thereof .
  • X and Y in the compound of formula I are CH or X is N and Y is CO.
  • the compound of formula I has the formula
  • R 2 and R 8 are as defined above;
  • R 5 and R 7 are independently selected from H and halo
  • X is CH or N
  • Y is CH, CO or CS; and q is 1, 2 or 3 , salts, hydrates, solvates, derivatives, pro-drugs, tautomers and/or isomers thereof.
  • the compound of formula I 1 has the
  • R 2 , R 5 , R 7 , R 8 and q are as defined above.
  • a subclass of compounds of formula IA have the formula Ia
  • R 2 , R 5 , R 7 and q are as defined above,- and R 8 a is optionally substituted Ci_ 6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2 .
  • R 8 a is optionally substituted Ci_ 6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2 .
  • R 5 and R 7 are both halo, more preferably both are chloro or one is chloro and the other is iodo.
  • R 2 is preferably located at either the 2 or 3 positions or both and is selected from H; optionally substituted Ci_ 4 alkyl; optionally substituted Ci -4 alkenyl; optionally substituted C 3-5 cycloalkyl; optionally substituted 6-membered aryl optionally condensed with an optionally substituted 6 membered aryl or heteroaryl; optionally substituted saturated or unsaturated 5- or 6- membered N-containing heterocyclyl optionally condensed with an optionally substituted 6-membered aryl or heteroaryl; (CH 2 ) n R 13 in which n is as defined above and R 13 is optionally substituted Ci_ 4 alkyl, optionally substituted C 3-5 cycloalkyl, optionally substituted saturated or unsaturated 5- or 6-membered N-containing heterocyclyl or optionally substituted 6-membered aryl; NR 14 R 15 in which R 14 and R 15 are independently selected from H, optionally substituted Ci -4 alkyl, optionally substituted C 3
  • R 1 , R 2 , R 5 , R 7 and q are as defined above. Representative examples are shown below:
  • R, R 2 , R 5 , R 7 and q are as defined above. Specific examples are shown below.
  • R' , R 2 , R 5 , R 7 and q are as defined above. Representative examples are shown below.
  • R 1 , R 2 , R 5 , R 7 and q are as defined above.
  • a representative example is shown below.
  • R, R , R , R and q are as defined above.
  • the compound of formula I 1 has the formula IB
  • R 2 , R 5 , R 7 and R 8 are as defined above; and r is 1 or 2.
  • a subclass of compounds of formula IB have the formula Ib
  • R 2 , R 5 , R 7 and r are as defined above,- and R 8 b is optionally substituted Ci -6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2 _ s alkynyl, optionally substituted C 3-e cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl,
  • R 5 and R 7 are both halo, more preferably chloro .
  • R 2 is preferably located at either the 2 or 3 positions or both and is selected from H; optionally substituted C 1-4 alkyl; optionally substituted C 1-4 alkenyl; optionally substituted C 3 _ s cycloalkyl; optionally substituted 6-membered aryl optionally condensed with an optionally substituted 6 membered aryl or heteroaryl; optionally substituted saturated or unsaturated 5- or 6- membered N-containing heterocyclyl optionally condensed with an optionally substituted 6-membered aryl or heteroaryl; (CH 2 ) n R 13 in which n is as defined above and R 13 is optionally substituted Ci -4 alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted saturated or unsaturated 5- or 6-membered N-containing heterocyclyl or optionally substituted 6-membered aryl; NR 14 R 15 in which R 14 and R 15 are
  • R 21 is selected from optionally substituted C 1-6 alkyl and optionally substituted 6-membered aryl and n is as defined above, More preferably R 2 is selected from optionally substituted Ci_ 4 alkyl; optionally substituted Ci -4 alkenyl; an optionally substituted saturated or unsaturated 5- or 6-membered N-containing heterocyclyl optionally condensed with an optionally substituted 6-membered aryl or heteroaryl; (CH 2 ) ⁇ R 13 in which n is 1 to 3 and R 13 is optionally substituted C 3-6 cycloalkyl or an optionally substituted saturated or unsaturated 5- or 6-membered N- containing heterocyclyl; NR 14 R 15 in which R 14 is H and R 15 is H or optionally substituted C 1-4 alkyl or optionally substituted 6-membered aryl ; NHCOR 15 in which. R 15 is optionally substituted Ci_
  • R 8 is as defined above.
  • substituent R 2 at position 3 and R 5 generally have a limited effect, electronically or sterically, in the metal attenuating properties of the compounds of the present invention. Substitution can therefore be used to modulate other parameters such as cytotoxicity and physicochemical properties including the number of hydrogen bond donors and acceptors, lipophilicity (ClogP, ElogP and LogD) , solubility and polar surface area. Modulation of these parameters contribute to the optimisation of the pharmacokinetic profile of the compounds. It is also postulated that when substituents R 2 and R 7 in addition to modulating cytotoxicity and physicochemical properties could also affect activity if the substituent provides metal attenuating properties.
  • the compound of formula I may have the formula I ' '
  • R 2 , R 5 , R 7 , R 8 , Y and q are as defined above.
  • R 2 is located at position 2 and is selected from H, optionally substituted C ⁇ - ⁇ alkyl, optionally substituted aryl, COR 6 and CONR 8 R 9 in which R s , R 8 and R 9 are as defined above .
  • Y is CO or CS.
  • R 5 is H and R 7 is H, halo, optionally substituted aryl or optionally substituted heterocyclyl .
  • the compound of formula I may have the formula I '
  • R 2 , R 5 , R 7 , R 8 and q are as defined above.
  • R 2 is located at positions 2 or 3 and is selected from H, (CH 2 ) n NR 9 R i:L , COR S and CONR 8 R 9 in which R s , R 8 , R 9 , R 11 and n are as defined above.
  • R 7 is CO 2 R 13 , CONR 13 R 14 , C 1-4 alkyl, cyclopropyl, optionally substituted aryl or optionally substituted heterocyclyl .
  • Ci-4 alkyl refers to straight chain or branched chain hydrocarbon groups having from 1 to 6 and 1 to 4 carbon atoms, respectively. Illustrative of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl or hexyl, preferably methyl , ethyl or propyl .
  • CH 2 ) n or "(CH 2 ) ra " as used herein include both linear and branched chains.
  • C 2 _ 6 alkenyl refers to straight chain or branched chain hydrocarbon groups having at least one double bond of either E or Z stereochemistry where applicable and 2 to 6 carbon atoms. Examples include vinyl, l-propenyl, 1- and 2-butenyl and 2-methyl-2- propenyl .
  • X ⁇ C 2 . 6 alkynyl used either alone or in compound words such as "optionally substituted C 2 -s alkynyl” refers to straight chain or branched chain hydrocarbon groups having from 2 to 6 carbon atoms and having in addition one triple bond. Illustrative of such groups are ethynyl, 1-propynyl, 1- and 2-butynyl, 2- methyl-2-propynyl , 2-pentynyl, 3-pentynyl, 4-pentynyl, 2- hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl.
  • C 3-5 cycloalkyl used either alone or in compound words such as "optionally substituted C 3-6 cycloalkyl” refers to saturated carbocyclic groups having 3 to 6 carbon atoms. Illustrative of such groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, preferably cyclopropyl .
  • C 1 - G aIkOXy refers to an oxy-containing radical having C;i . - 6 alkyl as defined above. Examples include methoxy, ethoxy, propoxy, butoxy, tert-butoxy and pentoxy.
  • heterocyclyl refers to saturated or unsaturated, monocyclic or polycyclic hydrocarbon groups containing at least one heteroatom atom selected from the group consisting of nitrogen, sulphur and oxygen.
  • Suitable heterocyclyls include N-containing heterocyclic groups, such as, unsaturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl or tetrazolyl; saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, such as, pyrrolidinyl, imidazolidinyl, piperidino or piperazinyl; unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, such as indolyl, isoindo
  • unsaturated or saturated 5- or 6-membered N-containing heterocyclyl group optionally condensed with an optionally substituted 6-membered aryl used either alone or in compound words such as "optionally substituted unsaturated or saturated 5- or 6-membered N-containing heterocyclyl group optionally condensed with an optionally substituted 6-merabered aryl” refers to monocyclic or polycyclic heterocyclic groups containing at least one nitrogen atom and optionally other heteroatoms selected from sulphur and oxygen.
  • Suitable heterocyclic groups include N-containing heterocyclic groups, such as, unsaturated 5- or ⁇ -membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl or tetrazolyl; saturated 5- or 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, such as, pyrrolidinyl, imidazolidinyl, piperidino or piperazinyl; unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, such as indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl or te
  • the heterocyclyl is an unsaturated 5 or 6- membered heteromonocyclic group containing 1 to 3 nitrogen atoms such as pyrazolyl, pyridinyl or pyrimidinyl; a saturated 5 or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms such as pyrrolidinyl or piperazinyl; an unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms such as benzimidazolyl; a saturated 5 or 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms such as morpholinyl; or an unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 2 sulphur atoms and 1 to 3 oxygen atoms, such as thiazolyl .
  • aryl refers to single, polynuclear, conjugated or fused residues of aromatic hydrocarbons. Examples include phenyl, biphenyl, terphenyl, quaterphenyl , naphthyl, tetrahydronaphthyl, anthracenyl, dihydroanthracenyl, benzanthracenyl, dibenxanthracenyl and phenanthrenyl .
  • a preferred aryl is phenyl.
  • 6-membered aryl used either alone or in compound words such as "optionally substituted 6-membered aryl” denotes a 6-membered carbocyclic aromatic group.
  • aryl groups are phenyl.
  • the aryl is optionally substituted phenyl such as 4- halophenyl, more preferably 4-fluorophenyl .
  • W 6-membered heteroaryl used either alone or in compound words such as "optionally substituted 6- membered hetroaryl” denotes a 6-membered aromatic heterocycle containing one or more heteroatoms .
  • Examples include pyridyl pyrazinyl, pyrimidinyl and pyridazinyl, each of which may be optionally substituted by methyl or methoxy.
  • halo refers to fluorine, chlorine, bromine or iodine, preferably fluorine, iodine or chlorine, more preferably chlorine or iodine .
  • optionally substituted refers to a group that may or may not be further substituted with one or more groups selected from Ci_ 6 alkyl, C 3-6 cycloalkyl, C 2 _ ⁇ alkenyl, C 2-6 alkynyl, aryl, heterocycylyl, halo, _ haloCi- 6 alkyl, haloCs-scycloalkyl, haloC 2 -salkenyl, haloC 2 . 6 alkynyl, haloaryl, haloheterocycylyl, hydroxy, C ⁇ _ e alkoxy, C 2 .
  • Ci_ s alkynylamino, arylamino, heterocyclamino acyl Ci_ s alkylacyl, C 2 - 6 alkenylacyl, C 2 - 6 alkynylacyl, arylacyl, heterocycylylacyl, acylamino, acyloxy, aldehydo, C 1 . 6 alkylsulphonyl, arylsulphonyl, Ci_ 6 alkylsulphonylamino, arylsulphonylamino,
  • the optional substituent is Ci- 4 alkyl, halo C 1 . 4 alkyl, hydroxy, halo, C 1-4 alkoxy or
  • protecting group refers to an introduced functionality which renders a particular functional groups, such as a hydroxy, amino, carbonyl or carboxy group, unreactive under selected conditions and which may later be optionally removed to unmask the functional group.
  • a hydroxy protecting group is one which can temporarily render a hydroxy group unreactive.
  • a hydroxy protecting group refers to a hydroxy group which has temporarily been rendered unreactive by a hydroxy protecting group.
  • a protected phenyl group is taken to be one in which attached reactive substituents, such as OH, NH 2 , are protected by a protecting group. Suitable protecting groups are known in the art and are described in Protective Groups in Organic Synthesis, Third Edition, T.W. Greene and P. G.
  • protecting groups which may be used to protect a hydroxy group include, but are not limited to, silyl groups (eg trimethylsilyl, t-butyldimethylsj-JlyJL t __ t-butyldiphenylsilyl) , benzyl groups (eg benzyl, methoxybenzyl , nitrobenzyl) , alkyl groups (eg methyl, ethyl, n- and i-propyl, and n- , sec- and t- butyl) and acyl groups (eg acetyl and benzoyl) .
  • silyl groups eg trimethylsilyl, t-butyldimethylsj-JlyJL t __ t-butyldiphenylsilyl
  • benzyl groups eg benzyl, methoxybenzyl , nitrobenzyl
  • alkyl groups eg methyl,
  • the leaving group may be of any suitable known type , such as, for example, those leaving groups disclosed in J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure” 4 th Edition, pp 352-357, John Wiley & Sons, New York, 1992 which is incorporated herein by reference.
  • the leaving group is halogen.
  • “Chelation therapy” is a term associated clinically with the removal of bulk metals such as in Wilson's disease, ⁇ -thallesemia and haemochromatosis .
  • the breakdown in metal homeostasis in these diseases can be described as a catastrophic event much like a dam bursting leading to overwhelming flooding of the problem metal.
  • the mechanism of action of such compounds is that bulk metal is sequestered by the chelators and cleared by excretion.
  • the breakdown in metal homeostasis associated with neurological conditions of the present invention is more akin to the constant drip of a leaky tap, which if left long enough will eventually cause local damage over a long period of time .
  • the derivative is a "pharmaceutically acceptable derivative” .
  • pharmaceutically acceptable derivative is meant any pharmaceutically acceptable salt, hydrate, ester, ether, amide, active metabolite, analogue, residue or any other compound which is not biologically or otherwise undesirable and induces the desired pharmacological and/or physiological effect. ... .
  • salts of the compound of formula I are preferably pharmaceutically acceptable, but it will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the present invention, since these are useful as intermediates in the preparation of pharmaceutically acceptable salts.
  • pharmaceutically acceptable salts include salts of pharmaceutically acceptable cations such as sodium, potassium, lithium, calcium, magnesium, ammonium and aIky1ammonium; acid addition salts of pharmaceutically acceptable inorganic acids such as hydrochloric, orthophosphoric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic and hydrobromic acids; or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, trihalomethanesulphonic, toluenesulphonic ,
  • the salts may be formed by conventional means, such as by reacting the free base form of the compound with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion exchange resin.
  • solvates may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of the invention.
  • pro-drug refers to functional derivati ⁇ es_ of the compound of formula I which are readily convertible in vivo into the required compound of formula I .
  • a prodrug may be a pharmacologically inactive derivative of the active compound that requires transformation within the body in order to release the active compound, and that has improved delivery properties over the active compound.
  • the transformation in vivo may be, for example, as the result of some metabolic process, such as chemical or enzymatic hydrolysis of a carboxylic, phosphoric or sulphate ester, or reduction or oxidation of a susceptible functionality.
  • the term refers to the attachment at position 2 of an antioxidant group, in particular the 3 , 4, 5-trimethoxyphenyl moiety or derivatives thereof. Exposure to the prooxidative environment of the brain will then lead to hydroxylation of the 3 , 4 , 5-trimethoxyphenyl group to give a 2-hydroxy- 3 , 4, 5-trimethoxyphenyl substituent, the hydroxyl group of which acts to enhance the metal attenuation properties of the compound of formula I .
  • antioxidant is used herein in its broadest sense and refers to a group which has the capacity to react with a reactive oxygen species such as a hydroxyl radical in such a way as to generate a non toxic product.
  • Examples include phenols such as 3, 4, 5-trimethoxyphenyl and 3 , 5-di-t-butyl-4-hydroxyphenyl, indole amines such as melatonin and flavonoids .
  • Other examples may be found the literature (Wright, 2001; Karbownik, 2001; Gilgun-Sherki, 2001) .
  • tautomer is used herein in its broadest sense to include compounds of formula I which are capable of existing in a state of equilibrium between two isomeric forms. Such compounds may differ in the bond connecting two atoms or groups and the position of these atoms or groups in the compound.
  • the administration of the compound of the present invention may be any suitable means that results in a concentration of the compound that is effective to yield the desired therapeutic or prophylactic response.
  • the compound may be contained in any appropriate amount in any suitable carrier and is generally present in an amount of 1-95% by weight of the total weight of the composition.
  • the carrier must be "pharmaceutically acceptable" in the sense of being compatible with other ingredients of the composition and not injurious to the subject.
  • the compound of the present invention may additionally be combined with other medicaments to provide an operative combination. It is intended to include any chemically compatible combination of pharmaceutically- active agents, as long as the combination does not eliminate the activity of the compound of formula I or II. It will be appreciated that the compound of the invention and that other medicament may be administered separately, sequentially or simultaneously.
  • Other medicaments may include, for example, where the condition is a ⁇ -amyloid related condition, particularly Alzheimer's disease, an inhibitor of the acetylcholinesterase active site, for example phenserine, galantamine, or tacrine; an antioxidant, such as Vitamin E or Vitamin C; an anti-inflammatory agent such as flurobiprofen or ibuprofen optionally modified to release nitric oxide (for example NCX-2216, produced by NicOx) or an oestrogenic agent such as 17- ⁇ -oestradiol .
  • an inhibitor of the acetylcholinesterase active site for example phenserine, galantamine, or tacrine
  • an antioxidant such as Vitamin E or Vitamin C
  • an anti-inflammatory agent such as flurobiprofen or ibuprofen optionally modified to release nitric oxide (for example NCX-2216, produced by NicOx) or an oestrogenic agent such as 17- ⁇ -oestradiol .
  • other medicaments may include, for example, anti-angiogenesis agents (drugs that interfere with growth of blood vessels that feed the tumor) , immunotoxins (a toxin is attached to an antibody that hones in on tumor cells) , and differentiating agents.
  • the composition may be provided in a dosage form that is suitable for oral, parenteral (including intravenous, intramuscular, subcutaneous and intradermal) , rectal, vaginal, nasal, inhalation, topical or ocular administration routes.
  • the composition may be in form of tablets, capsules, pills, powders, granulates, suspensions, emulsions, liquids, gels including hydrogels, pastes, ointments, creams, plasters, drenches, delivery devices, suppositories, enemas, injectables, implants, sprays or aerosols.
  • the pharmaceutical compositions may be formulated according to conventional pharmaceutical practice (see , e.g., Remington: The Science and Practice of Pharmacy, (19 th ed.). A. R. Gennaro, 1995, Mack Publishing Company, Easton, PA. and Encyclopedia of
  • compositions may be formulated to release the active compound substantially immediately upon administration or at any predetermined time or time period after administration.
  • controlled release formulations include (i) formulations that create a substantially constant concentration of the active compound within the body over an extended period of time,- (ii) formulations that after a predetermined lay time create a substantially constant concentration of the active compound within the body over an extended period of time,- (iii) formulations that sustain active compound action during a predetermined time period by maintaining a relatively, constant, effective active compound level in the body with concomitant minimization of undesirable side effects associated with fluctuations in the plasma level of the active compound (sawtooth kinetic pattern) ; (iv) formulations that localise active compound action by, e.g. , special placement of a controlled release composition adjacent to or in the diseased tissue or organ; and (v) formulations that target active compound action by using carriers or chemical derivatives to deliver the active compound to a particular target cell type.
  • Administration of compounds in the form of a controlled release formulation is especially preferred in cases in which the compound has (i) a narrow therapeutic index (i.e., the difference between the plasma concentration leading to harmful side effects or toxic reactions and the plasma concentration leading to a therapeutic effect is small; in general, the therapeutic index, TI, is defined as the ratio of median lethal dose (LD 50 ) to median effective dose (ED 50 ) ) ; (ii) a narrow absorption window in the gastro-intestinal tract; or (iii) a very short biological half-like so that frequent dosing during a day is required in order to sustain the plasma level at a therapeutic level.
  • a narrow therapeutic index i.e., the difference between the plasma concentration leading to harmful side effects or toxic reactions and the plasma concentration leading to a therapeutic effect is small
  • the therapeutic index, TI is defined as the ratio of median lethal dose (LD 50 ) to median effective dose (ED 50 ) ) ; (ii) a narrow absorption window in the gastro-intestinal tract; or (i
  • controlled release is obtained by appropriate selection of various formulation parameters and ingredients, including, e.g., various types of controlled release compositions and coatings.
  • the active compound is formulated with appropriate excipients into a pharmaceutical composition, that, upon administration to the subject, releases the active compound in a controlled manner. Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, patches and liposomes.
  • Solid Dosage Forms for Oral Use Formulations for oral use include tablets containing the active compound in a mixture with non-toxic pharmaceutically acceptable excipients.
  • excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, mirocrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate or sodium phosphate) ; granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminium silicate, carboxymethylcellulose sodium, methylcellulose, hydroxypropyl
  • the tablets may be uncoated or they may be coated by known techniques, optionally to delay disintegration and absorption in the gastrointestinal tract and thereby providing a sustained action over a longer period.
  • the coating may be adapted to release the active compound in a predetermined pattern (e.g., in order to achieve a controlled release formulation) or it may be adapted not to release the active compound until after passage of the stomach (enteric coating) .
  • the coating may be a sugar coating, a film coating (e.g., based on hydroxypropyl methylcellulose, methylcellulose, methyl hydroxyethylcellulose, hydroxypropylcellulose, carboxy ⁇ iet ⁇ iylcellulose, acrylate copolymers, polyethylene glycols and/or polyvinylpyrrolidone) , or an enteric coating (e.g., based on methacrylic acid copolymer, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, shellac and/or ethylcellulose) .
  • a time delay material such as, glyceryl monostearate or glyceryl distearate may be employed.
  • the solid tablet compositions may include a coating adapted to protect the composition from unwanted chemical changes, ⁇ e.g., chemical degradation prior to the release of the active compound) .
  • the coating may be applied on the solid dosage form in a similar manner as that described in Encyclopedia of Pharmaceutical Technology, supra.
  • Formulations for oral use may also be presented as chewing tablets or as hard gelatin capsules wherein the active compound is mixed with an inert solid diluent ⁇ e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active compound is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil .
  • an inert solid diluent e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example, peanut oil, liquid paraffin or olive oil .
  • Powders and granulates may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g, a mixer, a fluid bed apparatus or a spray drying equipment .
  • Powders, dispersible powders, or granules suitable for preparation of an aqueous suspension by addition of water are convenient dosage forms for oral administration.
  • Formulation as a suspension provides the active compound in a mixture with a dispersing or wetting agent, suspending agent, and one or more preservatives.
  • Suitable dispersing or wetting agents are, for example, naturally- occurring phosphatides ⁇ e.g., lecithin or condensation products of ethylene oxide with a fatty acid, a long chain aliphatic alcohol or a partial ester derived from fatty acids) and a hexitol or a hexitol anhydride [e ⁇ g.
  • Suitable suspending agents are, for example, sodium carboxymethylcellulose, methylcellulose, sodium alginate and the like .
  • the compound may be administered parenterally by injection, infusion or implantation (intravenous, intramuscular, subcutaneous or the like) in dosage forms, formulations or via suitable delivery devices or implants containing conventional, non-toxic pharmaceutically acceptable carriers .
  • injection, infusion or implantation intravenous, intramuscular, subcutaneous or the like
  • suitable delivery devices or implants containing conventional, non-toxic pharmaceutically acceptable carriers .
  • the formulation and preparation of such compositions is well known to those skilled in the art of pharmaceutical formulation. Specific formulations can be found in Remington: The Science and Practice of Pharmacy, supra.
  • compositions for parenteral use may be presented in unit dosage forms (e.g., in single-dose ampoules) or in vials containing several doses and in which a suitable preservative may be added (see below) .
  • the composition may be in form of a solution, a suspension, an emulsion, an infusion device or a delivery device for implantation or it may be presented as a dry powder to be reconstituted with water or another suitable vehicle before use.
  • the composition may include suitable parenterally acceptable carriers.
  • the active compound may be incorporated into microspheres, microcapsules, nanoparticles, liposomes or the like for controlled release.
  • the composition may include suspending, solubilizing, stabilizing, pH-adjusting agents and/or dispersing agents.
  • the pharmaceutical compositions may be in the form suitable for sterile injection.
  • a parenterally acceptable liquid vehicle that may be employed are water, water adjusted to a suitable pH by addition of an appropriate amount of hydrochloric acid, sodium hydroxide or a suitable buffer, 1, 3-butanediol, Ringer's solution and isotonic sodium chloride solution.
  • the aqueous formulation may also contain one or more preservatives (e.g., methyl, ethyl or n-propyl p-hydroxybenzoate) .
  • a dissolution enhancing or solubilising agent can be added or the solvent may include 10- 60% w/w of propylene glycol or the like.
  • suitable dosage forms for a composition include suppositories (emulsion or suspension type) and rectal gelatin capsules (solutions or suspensions) .
  • the active compound is combined with an appropriate pharmaceutically acceptable suppository base such as cocoa butter, esterified fatty acids, glycerinated gelatin and various water-soluble or dispersible bases like polyethylene glycols and polyoxyethylene sorbitan fatty acid esters.
  • an appropriate pharmaceutically acceptable suppository base such as cocoa butter, esterified fatty acids, glycerinated gelatin and various water-soluble or dispersible bases like polyethylene glycols and polyoxyethylene sorbitan fatty acid esters.
  • Various additives, enhancers or surfactants may be incorporated.
  • compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate .
  • the active compound may be administered by any of the methods and formulations employed in the art for administration to the respiratory tract.
  • the active compound may be administered in the form of a solution or a suspension or as a dry powder .
  • Solutions and suspensions will generally be aqueous, for example prepared from water alone (for example sterile or pyrogen-free water) or water and a physiologically acceptable co-solvent (for example ethanol, propylene glycol or polyethylene glycols such as PEG 400) .
  • a physiologically acceptable co-solvent for example ethanol, propylene glycol or polyethylene glycols such as PEG 400
  • solutions or suspensions may additionally contain other excipients for example preservatives (such as benzalkonium chloride) , solubilising agents/surfactants such as polysorbates ⁇ eg. Tween 80, Span 80, benzalkonium chloride) , buffering agents, isotonicity-adjusting agents (for example sodium chloride) , absorption enhancers and viscosity enhancers.
  • Suspensions may additionally contain suspending agents (for example microcrystalline cellulose and carboxymethyl cellulose sodium) . Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray. The formulations may be provided in single or multidose form.
  • a means of dose metering is desirably provided.
  • a dropper or pipette this may be achieved by the subject administering an appropriate, predetermined volume of the solution or suspension.
  • a spray this may be achieved for example by means of a metering atomising spray pump.
  • Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the compound is provided in a pressurised pack with a suitable propellant, such as a chlorofluorocarbon (CFC) , for example dichlorodifluoromethane , trichlorofluoromethane or dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant such as a chlorofluorocarbon (CFC)
  • CFC chlorofluorocarbon
  • the aerosol may conveniently also contain a surfactant such as lecithin.
  • the dose of active compound may be controlled by provision of a metered valve.
  • the active compound may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP) .
  • a powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP) .
  • PVP polyvinylpyrrolidine
  • the powder composition may be presented in unit dose form, for example in capsules or cartridges of eg. gelatin, or blister packs from which the powder may be administered by means of an inhaler.
  • the active compound In formulations intended for administration to the respiratory tract, including intranasal formulations, the active compound will generally have a small particle size, for example of the order of 5 microns or less. Such a particle size may be obtained by means known in the art, for example by micronisation. When desired, formulations adapted to give sustained release of the active compound may be employed.
  • the active compound may be administered by oral inhalation as a free-flow powder via a "Diskhaler” (trade mark of Glaxo Wellcome pic or a meter dose aerosol inhaler.
  • a "Diskhaler” trade mark of Glaxo Wellcome pic or a meter dose aerosol inhaler.
  • compositions may also be administered topically on the skin for percutaneous absorption in dosage forms or formulations containing conventionally non-toxic pharmaceutical acceptable carriers and excipients including microspheres and liposomes.
  • the formulations include creams, ointments, lotions, liniments, gels, hydrogels, solutions, suspensions, sticks, sprays, pastes, plasters and other kinds of transdermal drug delivery systems.
  • the pharmaceutically acceptable carriers may include emulsifying agents, antioxidants, buffering agents, preservatives, humectants, penetration enhancers, chelating agents, gel forming agents, ointment bases, perfumes and skin protective agents.
  • emulsifying agents are naturally occurring gums (e.g., gum acacia or gum tragacanth) and naturally occurring phosphatides (e.g., soybean lecithin and sorbitan monooleate derivatives) .
  • antioxidants are butylated hydroxy anisole (BHA) , ascorbic acid and derivatives thereof, tocopherol and derivatives -_ thereof, butylated hydroxy anisole and cysteine.
  • preservatives are parabens, such as methyl or propyl p- hydroxybenzoate and benzalonium chloride.
  • humectants are glycerin, propylene glycol, sorbitol and urea .
  • Examples of penetration enhancers are propylene glycol, DMSO, triethanolamine, N,N-dimethylacetamide, N,N- dimethylformamide, 2-pyrrolidone and derivatives thereof, tetrahydrofurfuryl alcohol and Azone .RTM.
  • Examples of chelating agents are sodium EDTA, citric acid and phosphoric acid.
  • Examples of gel forming agents are Carbopol, cellulose derivatives, bentonite, alginates, gelatin and polyvinylpyrrolidone.
  • ointment bases are beeswax, paraffin, cetyl palmitate, vegetable oils, sorbitan esters of fatty acids (Span) , polyethylene glycols and condensation products between sorbitan esters of fatty acids and ethylene oxide (e.g., polyoxyethylene sorbitan monooleate (Tween) ) .
  • compositions described above for topical administration on the skin may also be used in connection with topical administration onto or close to the part of the body that is to be treated.
  • the compositions may be adapted for direct application or for introduction into relevant orifice(s) of the body (e.g. , rectal, urethral, vaginal or oral orifices) .
  • the composition may be applied by means of special delivery devices such as dressings or alternatively plasters, pads, sponges, strips or other forms of suitable flexible material .
  • the active compound may be in the form of a solution or suspension in a suitable sterile aqueous or non-aqueous vehicle.
  • Additives for instance buffers, preservatives including bactericidal and fungicidal agents, such as phenyl mercuric acetate or nitrate, benzalkonium chloride, or chlorohexidine and thickening agents such as hypromellose may also be included.
  • bactericidal and fungicidal agents such as phenyl mercuric acetate or nitrate, benzalkonium chloride, or chlorohexidine
  • thickening agents such as hypromellose
  • the active compounds may also be presented for use in the form of veterinary compositions, which may be prepared, for example, by methods that are conventional in the art.
  • veterinary compositions include those adapted for:
  • oral administration external application, for example drenches (e.g. aqueous or non-aqueous solutions or suspensions); tablets or boluses,- powders, granules or pellets for admixture with feed stuffs,- pastes for application to the tongue;
  • drenches e.g. aqueous or non-aqueous solutions or suspensions
  • tablets or boluses e.g. aqueous or non-aqueous solutions or suspensions
  • boluses e.g. aqueous or non-aqueous solutions or suspensions
  • - powders e.g. aqueous or non-aqueous solutions or suspensions
  • granules or pellets for admixture with feed stuffs,- pastes for application to the tongue
  • parenteral administration for example by subcutaneous, intramuscular or intravenous injection, e.g. as a sterile solution or suspension; or (when appropriate) by intramammary injection where a suspension or solution is introduced in the udder via the teat;
  • topical applications e.g. as a cream, ointment or spray applied to the skin,- or
  • the compounds of formula I may be used in the treatment, amelioration and/or prophylaxis of a condition caused by or associated with unbalanced metal levels and/or oxidative stress for example a neurological condition or a cellular proliferative disorder.
  • treatment means affecting a subject, tissue or cell to obtain a desired pharmacological and/or physiological effect and include: (a) preventing the condition from occurring in a subject that may be predisposed to the condition, but has not yet been diagnosed as having it; (b) inhibiting the condition, i.e., arresting its development; or (c) relieving or ameliorating the effects of the condition, i.e., cause regression of the effects of the condition.
  • subject refers_ to_any animal having a disease or condition which requires treatment or prophylaxis with a pharmaceutically-active agent.
  • the subject may be a mammal, preferably a human, or may be a non-human primate or non-primates such as used in animal model testing. While it is particularly contemplated that the compounds are suitable for use in medical treatment of humans, it is also applicable to veterinary treatment, including treatment of companion animals such as dogs and cats, and domestic animals such as horses, ponies, donkeys, mules, llama, alpaca, pigs, cattle and sheep, or zoo animals such as primates, felids, canids, bovids and ungulates.
  • condition caused by or associated with unbalanced metal levels refers to a condition whereby a subject has either a too high or too low total amount of metal. This term also refers to a subject with a normal total amount of metal, but the metal is not correctly or is abnormally distributed.
  • condition caused by or associated with oxidative stress refers to a condition whereby biological constituents of a subject are damaged by reactive oxygen species. It is particularly contemplated that such constituents are damaged by reactive oxygen species such as the hydroxyl radical, hydrogen peroxide and superoxide produced in Fenton's and similar reactions.
  • reactive oxygen species such as the hydroxyl radical, hydrogen peroxide and superoxide produced in Fenton's and similar reactions.
  • metals such as iron, copper, zinc chromium, vanadium and cobalt are capable of redox cycling in which a single electron may be accepted or donated by the metal, facilitating oxidative reactions.
  • the oxidative species causes modifications of amino acids (e.g. meta-tyrosine and ortho-tyrosine formation from phenylalanine) , carbohydrates and lipids (inducing peroxidation) .
  • neurodegenerative condition is used herein in its broadest sense and refers to conditions in which various cell types of the nervous s ⁇ stem_are degenerated __ and/or have been damaged as a result of neurodegenerative disorders or injuries or exposures.
  • compound of formula I can be used for the treatment of resulting conditions, in which damage to cells of the nervous system has occurred due to surgical interventions, infections, exposure to toxic agents, tumours, nutritional deficits or metabolic disorders.
  • the compound of formula I can be used for the treatment of the sequelae of neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amylotrophic lateral sclerosis, epilepsy, drug abuse or drug addiction (alcohol, cocaine, heroin, amphetamine or the like) , spinal cord disorders and/or injuries, dystrophy or degeneration of the neural retina (retinopathies) and peripheral neuropathies, such as diabetic neuropathy and/or the peripheral neuropathies induced by toxins.
  • neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amylotrophic lateral sclerosis, epilepsy, drug abuse or drug addiction (alcohol, cocaine, heroin, amphetamine or the like)
  • spinal cord disorders and/or injuries dystrophy or degeneration of the neural retina (retinopathies) and peripheral neuropathies, such as diabetic neuropathy and/or the peripheral neuropathies induced by toxins.
  • neuronal integrity refers to an abnormality in which neuronal integrity is threatened. Neuronal integrity can be threatened when neuronal cells display decreased survival or when the neurons can no longer propagate a signal.
  • Neurological conditions that can be treated with the compound of the present invention include acute intermittent porphyria; adriamycin-induced cardiomyopathy; AIDS dementia and HIV-I induced neurotoxicity; Alzheimer's disease; amylotrophic lateral sclerosis; atherosclerosis; cataract; cerebral ischaemia; cerebral palsy,- cerebral tumour; chemotherapy-induced organ damage; cisplatin- induced nephrotoxicity; coronary artery bypass surgery; Creutzfeldt-Jacob disease and its new variant associated with "mad cow” disease; dementia; diabetic neuropathy; Down's syndrome; drowning; epilepsy and post-traumatic epilepsy; fatal familial insomnia; Friedrich's ataxia; frontotemporal dementia; Gertsmann Straussler Sheinker disease,- glaucoma; glomerulopathy; haemochromatosis,- haemodialysis; haemolysis; haemolytic uraemic syndrome (Weil's disease); haemorrhagic stroke; Haller
  • the compound of the present invention may also be used to potentiate the effects of other treatments, for example to potentiate the neuroprotective effects of brain derived nerve growth factor.
  • the invention is particularly directed to conditions which induce oxidative damage of the central nervous system, including acute and chronic neurological conditions such as traumatic brain injury, spinal cord injury, cerebral ischaemia, stroke (ischaemic and haemorragic) , subharrachnoid haemorrage/cerebral vasospasm, cerebral tumour, Alzheimer's disease, Creutzfeldt-Jacob disease and its new variant associated with "mad cow” disease, Huntington's disease, Parkinson's disease, Friedrich's ataxia, cataract, dementia with Lewy body formation, multiple system atrophy, Haller Morris-Spatz disease, diffuse Lewy body disease, amylotrophic lateral sclerosis, motor neuron disease, multiple sclerosis, fatal familial insomnia, Gertsmann Straussler Sheinker disease and hereditary cerebral haemorrhage with amyoidoisis-Dutch- _, " type " .
  • acute and chronic neurological conditions such as traumatic brain injury, spinal cord injury, cerebral ischaemia, stroke (ischa
  • the invention is directed to the treatment of neurodegenerative amyloidosis .
  • the neurodegenerative amyloidosis may be any condition in which neurological damage results from the deposition of amyloid.
  • the amyloid may be formed from a variety of protein or polypeptide precursors, including but not limited to A ⁇ , synuclein, huntingtin, or prion protein.
  • the condition is preferably selected from the group consisting of sporadic or familial Alzheimer's disease, amyotrophic lateral sclerosis, motor neuron disease, cataract, Parkinson's disease, Creutzfeldt-Jacob disease and its new variant associated with "mad cow” disease, Huntington's disease, dementia with Lewy body formation, multiple system atrophy, Haller Camill-Spatz disease, and diffuse Lewy body disease.
  • the neurodegenerative amyloidosis is an A ⁇ -related condition, such as Alzheimer's disease or dementia associated with Down syndrome or one of several forms of autosomal dominant forms of familial Alzheimer's disease (reviewed in St George-Hyslop, 2000) .
  • the A ⁇ -related condition is Alzheimer's disease.
  • the compound and methods of the invention may also be suitable for use in the treatment or prevention of neurodegenerative conditions, or may be suitable for use in alleviating the symptoms of neurodegenerative conditions .
  • the compound may be able to provide at least a partial reversal of the cognitive decline experienced by patients . If administered to a subject who has been identified as having an increased risk of a predisposition to neurodegenerative conditions, or to a subject exhibiting pre-clinical manifestations of cognitive decline, such as Mild Cognitive Impairment or minimal progressive cognitive impairment, these methods and compounds may be able to prevent or delay the onset of clinical symptoms, in addition to the effect of slowing or reducing the rate of cognitive decline.
  • MCI Mild Cognitive Impairment
  • cellular proliferative disorder refers to any cellular disorder in which the cells proliferate more rapidly than normal tissue growth.
  • Cellular proliferative disorder includes but is not limited to neoplasms.
  • a neoplasm is an abnormal tissue growth, generally forming a distinct mass, that grows by cellular proliferation more rapidly than normal tissue growth.
  • Neoplasms show partial or total lack of structural organisation and functional coordination with normal tissue. These can be broadly classified into three major types.
  • neoplasms arising from epithelial structures called carcinomas, malignant neoplasms that originate from connective tissues such as muscle, cartilage, fat or bone are called sarcomas and malignant tumours affecting hematopoietic structures (structures pertaining to the formation of blood cells) including components of the immune system called leukaemias and lymphomas.
  • a tumour is the neoplastic growth of the disease cancer.
  • a "neoplasm” also referred to as a "tumour” is intended to encompass hematopoitic neoplasms as well as solid neoplasms .
  • Other cellular proliferative disorders include, but are not limited to arthritis, graft rejection, inflammatory bowel disease, proliferation induced after medical procedures, including, but not limited to, surgery, angioplasty, and the like.
  • the compounds of formula I are particularly useful for the treatment or prophylaxis of cancer including solid tumours.
  • cancer describes any array of different diseases linked by cumulative multiple genetic mutations, which result in the activation of oncogenes and/or the inactivation of tumor suppressor genes and/or linked by uncontrolled cellular proliferation. The cause and source of these mutations differs between different cancers of human body organs .
  • the invention is particularly directed to brain cancer, which includes a brain tumour.
  • a brain cancer or tumour may be a glioma or non-glioma brain tumour.
  • cancer and “tumour” may be used interchangeably herein.
  • “Cancer” may include any one of the following states: glioma, adenoma, blastoma, carcinoma, sarcoma and inclusive of any one of Medulloblastoma, Ependymoma, Astrocytoma, Optical nerve glioma, Brain stem glioma, Oligodendroglioma, Gangliogliomas, Craniopharyngioma or Pineal Region Tumours.
  • Reference to a "glioma” includes astrocytoma, glioblastoma multiforme (GBM) , anaplastic astrocytoma, mixed glioma or related brain cancers. Dosages
  • terapéuticaally effective amount means an
  • Dosage levels of the compound of formula I of the present invention are of the order of about 0.1 mg to about 20 mg per kilogram body weight, with a preferred dosage range between about 0.1 mg to about 10 mg per 0 kilogram body weight per day (from about 0.1 gms to about 3 gms per patient per day) .
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage will vary depending upon the host treated and the particular mode of administration. 5
  • a formulation intended for oral administration to humans may contain about 5 mg to 1.5g of an active compound with an appropriate and convenient amount of carrier material which may vary from about 5 to 95 percent of the total composition.
  • Dosage unit forms 0 will generally contain between from about 5 mg to 500 mg of active ingredient .
  • the compounds of the invention are administered in a divided dose schedule, such that there are at least two administrations in total in the schedule .
  • 5 Administrations are given preferably at least every two hours for up to four hours or longer,- for example the compound may be administered every hour or every half hour.
  • the divided-dose regimen comprises a second administration of the compound 0 of the invention after an interval from the first administration sufficiently long that the level of active compound in the blood has decreased to approximately from 5-30% of the maximum plasma level reached after the first administration, so as to maintain an effective content of 5 active agent in the blood.
  • one or more subsequent administrations may be given at a corresponding interval from each preceding administration, preferably when the plasma level has decreased to approximately from 10-50% of the immediately-preceding maximum.
  • N- (5 , 7-Dichloro-2-formylquinolin-8-yl) -4- methoxybenzenesulfonamide (217 mg, 0.528 mmol) was dissolved in anhydrous CH 2 Cl 2 (5 mL) treated with 2.0 M NMe 2 in MeOH (700 ⁇ L, 1.4 mmol) then NaBH 4 (60 mg, 1.59 mmol) was added and the reaction was stirred overnight at rt . TLC indicated the presence of starting material so an additional portion of 2.0 M NMe 2 (500. ⁇ L, 1.0 mmol) and NaBH 4 (20 mg, 0.529 mmol) was added to the reaction with stirring continuing for a further Ih.
  • N- (5,7-Dichloro-2-dimethylaminomethyl-quinolin-8-yl) -4- trifluoromethylsulfonamide hydrochloride -V- (5, 7-Dichloro-2-formylquinolin-8-yl) -4- trifluoromethanesulfonamide (90mg, 0.241 mmol) was suspended in 1, 2-dichlorethane (6 mL) and treated with a solution of dimethylamine hydrogen chloride (85mg, ) and DIEA (21OmM, 1.21 mmol) in 1,2-DCE (6 mL) .
  • Phenyl isothiocyanate (0.56 g, 4.20 mmol) was added drop wise to a solution of 8-aminoquinoline (0.50 g, 3.50 mmol) in acetone (3.5 mL) at room temperature. The reaction was heated at reflux in an argon atmosphere for 48 h. The reaction was concentrated under reduced pressure and purified using flash chromatography on silica (30 g) eluting with a 40% solution of ethyl acetate in hexane
  • Propyl isothiocyanate (0.73 g, 7.20 mmol) was added drop wise to a solution of 8-aminoquinoline (0.80 g, 5.50 mmol) in acetone (5.5 ttiL) at room temperature. The reaction was heated at reflux in an argon atmosphere for 48 h. Additional propyl isothiocyanate (3 mL) , was added after 24 h. The reaction was concentrated under reduced pressure and purified using flash chromatography on silica
  • a fluorometric assay was used to test the ability of a test compound to inhibit hydrogen peroxide generation by AS in the presence of copper based on dichlorofluoroscein diacetate (DCF; Molecular Probes, Eugene OR) .
  • the DCF solution (5mM) in 100% dimethyl sulphoxide (previously purged with argon for lhr at 20 0 C) was deacetylated in the presence of 0.025M NaOH for 30min and neutralised at pH 7.4 to a final concentration of ImM.
  • Horseradish peroxidase (HRP) stock solution was prepared to l ⁇ M at pH
  • the reaction solutions contained AS 1-42 at concentrations in the range of 5OnM to l ⁇ M, copper-glycine chelate (Cu-GIy) , was prepared by adding CuCl 2 to glycine in the ratio of 1:6 and added to the A ⁇ in the proportion 2Cu-GIy : IAS ) , reducing agents including dopamine (5 ⁇ M) or ascorbic acid, deacetylated DCF lOO ⁇ M, and HRP, O.l ⁇ M. l-10 ⁇ M EDTA or another chelator may also be present as a control for free copper, but was not required for the assay to function.
  • the reaction mixture was incubated at 37C for 60 min. Catalase (4000 units/ml) and H 2 O 2 (1-2.5 ⁇ M) standards in PBS pH 7.4 may be included as positive controls.
  • H 2 O 2 concentration may be established by comparing fluorescence with the H 2 O 2 standards. Inhibition of A ⁇ H 2 O 2 production was assayed by including a given concentration of test compound (s) in the test wells.
  • Cell viability is determined using the MTS assay. Culture medium is replaced with fresh neurobasal medium plus B27 supplements minus antioxidants. 1/lOth volume MTS solution (Cell Titre 36 Aqueous One, Promega Corporation) and incubated at at 37°C, 2hrs . 200 microlitre aliquots .are measured with a spectrophotometer at 560 nm.
  • LDH lactate dehydrogenase
  • Neuronal cortical cells were cultured for five days as per Assay 2. On day six the neurobasal (NB) media (Invitrogen Life Technologies) and B27 supplement
  • test compounds were individually added to the neuronal cell cultures : The test compounds were dissolved in 100% DMSO to a concentration of 2.5 mM (1OmM if excess compound was weighed out per vial - then diluted to 2.5mM) . 2.5mM stock solution was serially diluted 1 in 10 to give working solutions of 25OuM, 25uM, 2.5uM.
  • a ⁇ was initially dissolved in 2OmM NaOH to a concentration of ImM and sonicated for 5 minutes .
  • the peptide was then diluted in H 2 O and 10 X PBS to a final concentration of 20OuM A ⁇ in IX PBS.
  • the peptide was again sonicated for 5 minutes and then spun at 14000 rpm for 5 min and transferred to a fresh tube.
  • test compounds were dissolved in 100% DMSO to a concentration of 2.5 mM (1OmM if excess compound was weighed out per vial - then diluted to 2.5mM) .
  • 2.5mM stock solution was serially diluted 1 in 10 [in NB media and B27 (no antioxidants)] to give working solutions of 25OuM, 25uM, 2.5uM.
  • Test compounds were not added directly to cells, instead they were added to a 48 well ⁇ Drug Plate' as comprised below:
  • the Drug Plate was incubated at 37° C for 15 mins . 200 ul of each well was added in triplicate to the corresponding cell plate. The cell plate was incubated at
  • the assay is completed by adding MTS to the cells.
  • Neuronal cortical cells were cultured for five days as per Assay 2 in NB media and B27 supplement. On day six the test compounds were added to the neuronal cell cultures in NB media and B27 supplement minus antioxidants.
  • Test compounds were dissolved in 100% DMSO to a concentration of 2.5 mM (1OmM if excess compound was weighed out per vial - then diluted to 2.5mM) .
  • 2.5mM stock solution was serially diluted 1 in 10 to give working solutions of 25OuM, 25uM, 2.5uM.
  • Test compounds were not added directly to cells, instead they were added to a 48 well 'Drug Plate' as comprised below:
  • Well 6 576 ul NB+B27(no antioxidant) + 24 ul 25OuM test compound
  • Well 7 576 ul NB+B27(no antioxidant) + 24 ul test compound diluent**
  • Well 8 600 ul NB+B27 (no antioxidant)
  • the Drug Plate was incubated at 37°C for 15 mins . 200 ul of each well was added in triplicate to the corresponding cell plate. The cell plate was incubated at
  • Lipid Peroxidation Assay 4 Two different assays of metal-mediated lipid peroxidation can be utilized. The first assay involves measuring the oxidative activity of metallated proteins. This is determined by mixing dialyzed metallated or native protein (at designated concentrations) with 0.5 mg/mL LDL for 24 hr (37°C) . Lipid peroxidation (LPO) is measured using a lipid peroxidation assay kit (LPO 486, Oxis International Inc. Portland, OR) as per kit instructions. The level of LPO is determined by comparing absorbance (486 nm) with LDL alone (100% LPO) . The second assay is used to measure the LPO activity of native proteins in the presence of free, non-protein-bound Cu.
  • LPO lipid peroxidation assay kit
  • soluble and insoluble fractions from an extract of human brain tissue are prepared as for the amyloid solubilisation assay.
  • Metals in the two fractions are analysed by inductively-coupled plasma mass spectrometry, following appropriate pretreatment with nitric acid and/or hydrogen peroxide where necessary.
  • Ml7 human neuroblastoma cells are plated out on 6 well plates and left overnight. Enough cells are added to give approximately 70 % confluent the following day of the experiment.
  • Test compounds are added to media and mixed with equi-molar amounts of CuCl2 solution.
  • A IO ⁇ M Cu + 10 ⁇ M MPAC;
  • B IO ⁇ M Cu + 10 ⁇ M MPAC.
  • Cells are incubated in 1 ml of media/MPAC/Cu mix for 5 hours at 37°C. At the end of the incubation the media is removed with a vacuum aspirator and 1 ml of PBS added to dislodge the cells. Cells are then put into Eppendorf tubes and pelleted. The PBS is removed and the remaining cell pellets are frozen at -20 C.
  • the cell pellets are prepared as follows: Received cell pellets of similar levels in 1.5 ml microfuge tubes. Added 50 ⁇ l of concentrated Nitric Acid (Aristar, BDH) to each cell pellet and allowed them to digest over night. Heated the samples for 20 min at 90 0 C to complete the digestion. The volume of each sample was reduced to -45 ul after digestion. Added 1 ml of the 1% Nitric Acid diluent to each sample. (referred to as the "preparation solution" samples) . Measurements were made using a Varian UltraMass ICPMS instrument under operating conditions suitable for routine multi-element analysis.
  • the instrument was calibrated using Blank, 10, 50 and 100 ppb of a certified multi-element ICPMS standard solution (ICP-MS- CA12-1, Accustandard) for Fe, Cu and Zn in 1% nitric acid. Used an certified internal standard solution containing 100 ppb Yttrium (Y 89) as an internal control (ICP-MS- IS-MIXl-I, Accustandard) .
  • Transgenic mouse models are available for a number of neurological disorders, including Alzheimer's disease (Games et al., 1995; Hsiao et al . , 1996); Parkinson's disease (Masliah et al . , 2000); familial amyotrophic lateral sclerosis (ALS) (Gurney et al . , 1994); Huntington's disease (Reddy et al . , 1998); and Creutzfeld- Jakob disease (CJD) (Telling et al . , 1994) .
  • Alzheimer's disease Games et al., 1995; Hsiao et al . , 1996
  • Parkinson's disease Mosliah et al . , 2000
  • familial amyotrophic lateral sclerosis ALS
  • Huntington's disease Reddy et al . , 1998
  • Creutzfeld- Jakob disease CJD
  • Transgenic mice of the strain APP2576 (Hsiao et al 1996) are used. Eight to nine month old female mice are selected and divided into groups for treatment .
  • mice are sacrificed at intervals, and their brains examined to determine whether the treatment with test compounds decreased brain amyloid formation, and the identification of the most effective administration protocol.
  • the levels of soluble and insoluble A ⁇ in the brain and serum are determined using standard calibrated Western blots .
  • Assay 8 Cognition Assay- Mice are tested over a period of up to eight months for cognitive performance, using a Morris water maze according to standard methods. The general health and well-being of the animals is also measured every day by a blinded operator, using a five point integer scale which subjectively rates a combination of features, including motor activity, alertness and general health signs.
  • Polar surface area values were calculated using the web-based program available through "Molinspiration” , a package for calculation of molecular properties.
  • the solubility estimate was measured at both pH 2.0 and pH 6.5. This is within the pH range that can be anticipated along the proximal gastrointestinal tract in humans .
  • Theoretical Log P values are determined using the ACD Log P software .
  • the values quoted have been calculated from an untrained database and refer to the unionised species .
  • the assay is a Western blot assay which evaluates the ability of a test compound to inhibit the metal-mediated cross-linking reaction which leads to the formation of dimeric and higher order oligomers of A ⁇ .
  • the assay models the process by which a putative agent acts either to compete with A ⁇ for redox active metals or alternatively to displace such metals by binding competitively at the A ⁇ metal binding site.
  • Tricine (SigmaCat#T-5816) ; SDS (from Bio-Rad Labororatorias Cat#161-0302) ; ECL (from Amersham, Cat# RPN2106V1) ; Rabbit anti mouse-Immunoglobulin HRP (from DAKO Cat# P0260) ; 10-20% Tricine Gel 10 wells (from Invitrogen Cat# EC6625
  • Compounds to be assayed are dissolved in 100% DMSO and made up to a 5 mM stock solution. Serial dilutions of 4000 ⁇ M, 2000 ⁇ M, 1000 ⁇ M, 500 ⁇ M, 100 ⁇ M are prepared. Set up reaction in 2 ml microcentrifuge tube with the following components: Abeta 10 ⁇ M; CuCl 2 25 ⁇ M; ASC250 ⁇ M; DMSO or test compounds 1%.
  • the primary antibody for detecting dityrosine is the antidityrosine monoclonal antibody 1C3 [Kato, Y. et al (2000), Biochem. Biophys. Res. Coimun. 275, 11-5.] Oligomerisation can also be detected using generic antibodies which recognise full length Abeta and specific antibodies which are claimed only to detect soluble oligomeric forms of the peptide. (Lesne, S. et al (2006) Nature VoI 44 ⁇ ]l6 March 2006
  • Immunoreactivity is developed with secondary antibody linked to horseradish peroxidase (using a 3,39- diaminobenzidinechromagen) (Dako) and alkaline phosphatase (using 5-bromo-4-chloro 3-indoxyl phosphate and nitroblue tetrazolium chloride chromagen) (Dako) .
  • Intravenous infusion of test compound 2 mg/Kg in a suitable vehicle is administered to 2 rats and arterial blood is sampled up to 24 hours.
  • test compound 30 mg/Kg in a suitable vehicle is administered via oral gavage to 2 rats and arterial blood is sampled up to 24 hours.
  • Plasma concentrations of test compound are determined by suitable analytical method.
  • Oral administration of a test compound at 30mg/kg, as 10 a suspension in Na-Carboxymethyl Cellulose (CMC) is administered by oral gavage to four mice. Mice are sacrificed at intervals after administration in groups of 2. Blood is obtained by cardiac puncture and plasma separated by centrifugation.
  • CMC Na-Carboxymethyl Cellulose
  • the concentration of a test compound is determined by LC/MS using the triple quadrupole instrument.
  • the mobile phase consisted of an acetonitrile (ACN) /water gradient (containing 0.05% Formic acid) and the column is a Phenomenex Lunea 5 ⁇ m C8 (50 x 2mm) column.
  • the supplied acute toxicity mouse plasma samples are directly injected following a protein precipitation with ACN.
  • Emulsion carrier is used as a control for the in vitro and in vivo test compounds. All the test compounds
  • test compounds are analyzed via the MTT cell viability assay.
  • the following cell lines at least are used to determine cell viability on exposure to the test compounds : C6 - rat glioma cell line, VMDK - mouse glioma cell line, U87MG - human glioma cell line, 3T3 - Control cell line.
  • Cells are plated in 96 well plates with 100 ⁇ l of cell culture medium and be allowed to adhere over 24 hours allowing for approximately 50 % confluence. At 24 hours, the cell medium is replaced with fresh cell culture medium containing test compounds or the carrier emulsions.
  • the cells are then incubated and grown for a designated period (72 hours) after which the MTT solution are added to the wells and incubated at 37°C for 1-2 hours.
  • the absorbance of each well are then be measured with a plate reader at 570 nm.
  • the efficacy profiles are calculated relevant to the cells incubated in the absence of the test compounds over the course of the experiment .
  • CBA mice are used to receive an intracranial inoculation of the C ⁇ glioma cells. Briefly, IxIO 5 cells are inoculated into the left hemisphere via at day 5 post CS cell inoculation. The mice receive daily intraperitoneal (ip) administration of test compounds in a carrier emulsion or carrier emulsion alone as a control for 8 days until day 12. At day 14, the mice are euthanised via CO 2 inhalation and the brain rejnpved _ fox. histological processing.
  • the VMDK mouse strain is then used to screen the identical test compounds and carrier emulsions as per the C6 xenograft model in the CBA mice.
  • the VMDK mice received an inoculation of IxIO 5 SMA560 cells into the left hemisphere via standard methods.
  • the mice receive daily ip administration of test compounds in a carrier emulsion or carrier emulsion alone as a control for 12 days until day 16.
  • Identical doses of test compounds and carrier emulsions as used in the C6 xenograft model are used with the SMA560 model.
  • the mice are euthanized via CO 2 inhalation and the brain removed for histological processing.
  • a nude mouse model utilizing the U87MG human glioma cell line is used to screen compounds .
  • the nude mouse Nu/nu strain receives an inoculation of IxIO 5 U87MG cells into the left hemisphere.
  • the mice receive daily ip administration of the test compound or carrier emulsion alone as a control for 12 days until day 16.
  • the mice are euthanized via CO 2 inhalation and the brain removed for histological processing.
  • Haematoxylin and eosin stained sections are used to measure tumour dimensions in order to determine the efficacy of the test compounds on tumour growth relative to the control mice.
  • PC12 or HEK cells are transfected with 'long' and "short' CAG repeat constructs , to determine effects of a panel of test compounds on production and aggregation of htt protein, by microscopy and to determine cell survival/apoptotic indicators.
  • PC12 cells are cultured and transfected.
  • Cells cultured in Optimem media in 24-well plates are pretreated 30 minutes prior to transfection with each of the test compounds in DMSO, initially at concentrations of 0.05, 0.1, 0.5, 1, 2, 5 and 10 ⁇ M, or vehicle alone and transfected, using Lipofectamine 2000, with Q103HDexonl/GFP, Q25HDexonI or GFP alone vectors.
  • Cells are then digitally imaged (Nikon inverted fluorescence microscope with Magnafire digital imager) under phase contrast and for GFP fluorescence at -20 and 40 hours post transfection. At 48 hours they are stained with propidium iodide (PI) and Hoechst 33342 and imaged again with filters appropriate for those dyes . The percentage of cells exhibiting detectable GFP fluorescence or PI staining is determined by semi-automated counting (using NIH image) of the same field under fluorescent and phase imaging. Apoptotic nuclear fragmentation of PI negative cells is assessed by manual visual counting using overlapped Pl/Hoechst images. This, plus PI positive cells are considered to represent the total number of dead cells. At least 3 fields are counted per condition, and the experiment repeated at least 4 times after the initial concentration screen. Should a compound prove toxic or ineffective but not toxic in the initial concentration range, the range is extended accordingly.
  • PI propidium iodide
  • Test compounds showing demonstrable positive results in the above are tested for effects on: RNA and protein expression, by standard art methods of Northern and Western blotting; proteosomal degradation/inhibitor studies; polyQ construct degradation/pulse-chase experiments .
  • Statistical significance for between group comparisons are then determined by AMOVA, with differences between individual values determined by post hoc testing,-., with Dunnet's test.
  • any compound and concentration that produces a substantial (>25%) drop in percentages of Q103 expressing cells, with at most a 3-fold lesser drop in Q25 and GFP-only expression, are considered for further evaluation, including analysis of mRNA expression by Northern blotting or reverse transcription quantitative PCR, Western blotting and densitometric quantitation with anti-polyQ and antiGFP, proteasome inhibitor treatment and pulse-chase analysis.
  • Rotarod motor performance testing Beginning at 5 weeks of age, animals are tested by an experimenter blinded to genotype on a rotarod (Rotamex 4/8, Columbus instruments) . For training and establishment of baselines, animals are placed on the rod at 24 rpm and the latency to falling (to a maximum test length of 60 seconds) measured, in 4 sessions on each of 4 consecutive days. Subsequent testing is performed at intervals at rotor speeds of 15 and 44 rpm (2 trials at each speed) and continue until animals are unable to maintain balance for more than a few seconds .
  • mice are suspended by the tail for 30 s and the time of tonic spasm of the lower extremities (foot-clasping) is scored such that a 0-5 s clasping duration is given a score of 1, 5-10 s a score of 2, and greater than 10 s a score of 3.
  • Ventricular size ImageJ 1.32j (National Institutes of Health, USA) is used to measure the size of the lateral ventricles in standardized Nissl stained brain sections.
  • the 6-OHDA assay investigates if a test compound is effective at reducing 6-hydroxydopamine (6-OHDA) induced lesions and whether there is a common pathway for propagation of neuronal cell death in a mouse model of PD.
  • Mice are anaethetised and secured in a stereotaxic frame .
  • a single injection of 6-OHDA (2.5 ⁇ g, 1.5 ⁇ g/ ⁇ l) is injected slowly (0.8 ⁇ l/min) into the right SN (AP 3 mm, L 1.1 mm, DV 4.7mm with respect to bregma) this produces lesions of between 60-70% (Parish et al . , 2001) .
  • the test compound is delivered by oral gavage at a daily dosage of 5 or 30 mg/ml from the day of lesion for 14 consecutive days .
  • Rotational Behavioural monitoring The lesioned mice are placed in bowls and videotaped for one hour, then injected with 5 mg/kg amphetamine by intraperitoneal injection and videotaped for another hour. The animals rotate towards the lesioned side. The number of rotations is proportional to the loss of cells from the SN.
  • Barnham et al . (2004) Faseb J. 18 (12) 1427-1429; Kaur et al., (2003) Neuron 37(6) 899-909; Parish et al . , (2001) J. Neurosci. 21(14) 5147-5157.
  • MPTP (1-methyl 4-phenyl 1, 2, 3, 6-tetrahydropyridine) is a chemical that is related to the opioid analgesic drugs. MPTP itself does not have any opioid effect, but it may be produced accidentally during illicit manufacture of MPPP and MPTP causes Parkinsonian side-effects. This happens when MPTP is metabolized into MPP+, which kills neurons in a part of the brain called the substantia nigra. MPP+ interferes with mitochondria metabolism which leads to cell death and causes the buildup of free radicals, toxic molecules that contribute further to cell destruction.
  • MPTP has quite selective abilities to effect neuronal death in dopaminergic cells, apparently through a high- affinity uptake process in nerve terminals normally used to reuptake dopamine after it has been released into the synaptic cleft. Such effects lead to gross depletion of dopaminergic neurons which has severe implications on cortical control of complex movements .
  • mice receive five intraperitoneal injections of MPTP-HCl (23 gauge needle,
  • Control animals receive five intraperitoneal injections of
  • Animals are allowed to recover for 1 week, 2 weeks, 1 month, 12, months and 18 months. The animals are then killed and the brains removed for histological
  • Animals are treated as described above. They are treated with the test compound by oral gavage at a daily dosage of 30 mg/kg 2 days after MPTP injection until death. Test compound and analogues are be given by oral gavage at a daily dosage of 30 mg/kg. The time of killing the animals depends on the analysis of Experiment 1. However, it is one month or less.
  • mice receive five intraperitoneal injections of MPTP-HCl (23 gauge needle, 20 mg/kg of free base; Sigma, St. Louis, MO, USA) dissolved in sterile 0.9% saline at 2-h interval in 1 day. Control animals receive five intraperitoneal injections of 0.9% saline.
  • mice are assessed at prior to killing the mice for histological analysis.
  • Rotarod Motor coordination and strength are assessed using the rotarod.
  • the rotarod consists of a plastic rotating rod of 3.6 cm axial diameter partitioned by metal disks into five sections to allow the testing of multiple mice simultaneously. Mice are trained on two sessions where the rotation speed is ramped from 0-30 rpm over 5 min and one training session where rotation is a constant 16 rpm for 5min. Within two days of training, animals are formally assessed on the rotarod rotating at 16 rpm for a maximum of 3 min: the time to fall on this single test is the recorded data point .
  • Pole test This consists of a 700 mm long, 5 mm diameter, wooden rod. The rod is supported at its base and held vertical. The total walking distance for the mice is 550., mm. The time taken for the mouse to descend the pole is measured with a maximum time of 120 s. If a mouse falls, the time is scored as 120 s.
  • This fluoresence assay evaluates the ability of a test compound to inhibit the generation of hydrogen peroxide
  • H 2 O 2 H 2 O 2
  • iron in the form of FeCl 3 is allowed to react with ascorbic acid by incubating for lhr at 37°C in the presence of the fluorescing compound DCF and horseradish peroxidase.
  • H 2 O 2 generated by the system is assessed by measuring the specific fluorescence profile at the excitation and emission wavelengths of 485 and 530nm respectively, in the presence of increasing concentrations of test compound.
  • Test compounds are ranked according to their capacity to inhibit H2O2 generated by the system where lower values in Mean Fluorescence Units (mfu) reflect greater ability to inhibit H2O2 production.
  • Each compound tested demonstrates a permeability across a healthy BBB.
  • a bolus injection of each of the test compound (50 ⁇ L of a 3 mg/mL aqueous solution containing 40% propylene glycol and 10% ethanol) was administered by tail vein injection to male Swiss Outbred mice (5-7 weeks of age) .
  • mice 5-7 weeks of age
  • the whole brain was placed into preweighed polypropylene vials and stored at -20 0 C until analysis.
  • the whole brain was homogenised in 3 parts of water (on ice to reduce the potential for ex vivo brain degradation) and an aliquot of the brain homogenate and plasma was analysed for compound concentration by LCMS.
  • Standards were prepared by spiking blank brain homogenate and both samples and standards were processed by adding acetonitrile to the tissue homogenate, centrifuging and injecting an aliquot of the supernatant onto the LCMS.
  • brain homogenate was spiked with compound (in 50% acetonitrile: 50% water) to a nominal concentration of 500 ng/mL. The concentration of compound in the supernatant was then determined by LCMS and compared to the supernatant concentration when compound was added following precipitation with acetonitrile.
  • C bra i n concentration of compound in brain parenchyma (ng/g)
  • Cbrai n h o m ogenate concentration of compound in brain homogenate (ng/g)
  • Cbrain vasculature concentration of compound in__ brain vasculature (ng/g)
  • Cpias r aa concentration of compound in plasma (ng/mL)
  • Vp brain plasma volume (26 ⁇ L/g for male Swiss Outbred mice)
  • asma dt concentration of compound in plasma from time zero to 5 min post-dose (equivalent to the 5 min post-dose plasma concentration, assuming no back diffusion from brain to plasma within this time period)
  • A surface area of capillaries forming the blood-brain barrier (240 cm 2 /g brain weight for mouse) .
  • Alzheimer's disease amyloid ⁇ binds copper and zinc to generate an allosterically ordered membrane-penetrating structure containing superoxide dismutase-like subunits . J. Biol. Chem. 276, 20466-20473.

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Abstract

La présente invention concerne des composés hétérocycliques, leur méthodes de préparation et leur utilisation comme agents pharmaceutiques ou vétérinaires, en particulier pour le traitement, l'amélioration et/ou la prophylaxie d'états causés par ou associés à des taux de métal non équilibrés et/ou au stress oxydant, tels que des états neurologiques et des troubles liés à la prolifération de cellules, notamment la maladie d'Alzheimer, la maladie de Parkinson, la chorée de Huntington ou le cancer du cerveau ou des tumeurs cérébrales.
PCT/AU2007/001952 2006-12-20 2007-12-18 Dérivés de quinoline substitués utilisés comme agents non-amyloïdogéniques Ceased WO2008074068A1 (fr)

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US11628162B2 (en) 2019-03-08 2023-04-18 Incyte Corporation Methods of treating cancer with an FGFR inhibitor
US11725010B2 (en) 2019-12-02 2023-08-15 Storm Therapeutics Limited Polyheterocyclic compounds as METTL3 inhibitors
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US11820747B2 (en) 2021-11-02 2023-11-21 Flare Therapeutics Inc. PPARG inverse agonists and uses thereof
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