EP1957475A1 - Chromenones et leur utilisation en tant que modulateurs des recepteurs metabotropes au glutamate - Google Patents

Chromenones et leur utilisation en tant que modulateurs des recepteurs metabotropes au glutamate

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Publication number
EP1957475A1
EP1957475A1 EP06794829A EP06794829A EP1957475A1 EP 1957475 A1 EP1957475 A1 EP 1957475A1 EP 06794829 A EP06794829 A EP 06794829A EP 06794829 A EP06794829 A EP 06794829A EP 1957475 A1 EP1957475 A1 EP 1957475A1
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EP
European Patent Office
Prior art keywords
alkyl
chromen
chloro
alkylamino
tetrahydrobenzo
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP06794829A
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German (de)
English (en)
Inventor
Christopher Graham Raphael Parsons
Aigars Jirgensons
Dina Trifanova
Ivars Kalvinsh
Igors Starchenkovs
Markus Henrich
Tobias Noeske
Tanja Weil
Valerjans Kauss
Wojciech Danysz
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merz Pharma GmbH and Co KGaA
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Merz Pharma GmbH and Co KGaA
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Publication of EP1957475A1 publication Critical patent/EP1957475A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/74—Benzo[b]pyrans, hydrogenated in the carbocyclic ring

Definitions

  • the present invention is concerned with novel metabotropic gl ⁇ tamate receptor (mGluR) modulators, methods for their synthesis and the treatment and/or prevention of neurological disorders by administration of such substances.
  • mGluR metabotropic gl ⁇ tamate receptor
  • Neuronal stimuli are transmitted by the central nervous system (CNS) through the interaction of a neurotransmitter released by a neuron, which neurotransmitter has a specific effect on a neuroreceptor of another neuron.
  • CNS central nervous system
  • L-glutamic acid is considered to be the major excitatory neurotransmitter in the mammalian CNS 1 consequently playing a critical role in a large number of physiological processes.
  • Glutamate-dependent stimulus receptors are divided into two main groups. The first group comprises ligand-controlled ion channels whereas the second comprises metabotropic glutamate receptors (mGluR). Metabotropic glutamate receptors are a subfamily of G-protein- coupled receptors (GPCR). There is increasing evidence for a peripheral role of both ionotropic and metabotropic glutamate receptors outside of the CNS e.g., in chronic pain states.
  • mGluRI and mGluR ⁇ belong to Group I which couple to phospholipase C and their activation leads to intracellular calcium-ion mobilization.
  • mGluR2 and mGIuR3 belong to Group Il and mGluR4, mGluR6, mGluR7 and rnGluR ⁇ belong to Group III, which couple to adenyl cyclase with their activation causing a reduction in second messenger cAMP and as such a dampening of the neuronal activity.
  • Group I mGluR modulators have been shown to modulate the effects of the presynaptically released neurotransmitter glutamate via postsynaptic mechanisms. Moreover, as these modulators can be both positive and/or negative Group I mGluR modulators, such modulators may increase or inhibit the effects of these metabotropic receptors. Since a variety of pathophysiological processes and disease states affecting the CNS are thought to be related to abnormal glutamate neurotransmission, and Group I mGluRs are shown to be expressed in several areas of the CNS, modulators of these receptors could be therapeutically beneficial in the treatment of CNS diseases.
  • group I mGluR modulators may be administered to provide neuroprotection in acute and chronic pathological conditions such as: AIDS- related dementia, Alzheimer's disease, Creutzf eld-Jakob ' s syndrome, bovine spongiform encephalopathy (BSE) or other prion related infections, diseases involving mitochondrial dysfunction, diseases involving ⁇ -amyloid and/or tauopathy such as Down's syndrome, hepatic encephalopathy, Huntington's disease, motor neuron diseases such as amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), olivopontocerebellar atrophy, postoperative cognitive deficit (POCD), Parkinson's disease, Parkinson's dementia, mild cognitive impairment, dementia pugilistica, vascular and frontal lobe dementia, cognitive impairment, eye injuries or diseases (e.g.
  • AIDS- related dementia Alzheimer's disease, Creutzf eld-Jakob ' s syndrome, bovine spongiform encephalopathy (BSE) or other
  • hypoglycaemia hypoxia (e.g. perinatal), ischaemia (e.g. resulting from cardiac arrest, stroke, bypass operations or transplants), convulsions, epilepsy, temporal lope epilepsy, glioma and other tumours, inner ear insult (e.g. in tinnitus, sound- or drug-induced), L-Dopa-induced and tardive dyskinesias.
  • hypoxia e.g. perinatal
  • ischaemia e.g. resulting from cardiac arrest, stroke, bypass operations or transplants
  • convulsions epilepsy, temporal lope epilepsy, glioma and other tumours
  • inner ear insult e.g. in tinnitus, sound- or drug-induced
  • L-Dopa-induced and tardive dyskinesias e.g. in tinnitus, sound- or drug-induced
  • svmptomatoloqical effect on the following conditions abuse and addiction (nicotine, alcohol, opiate, cocaine, amphetamine, obesity and others), amyotrophic lateral sclerosis (ALS), anxiety and panic disorders, attention deficit hyperactivity disorder (ADHD), restless leg syndrome, hyperactivity in children, autism, convulsions, epileptic convulsions, epilepsy, temporal lobe epilepsy, dementia (e.g. in Alzheimer's disease, Korsakoff syndrome, vascular dementia, HIV infections), major depressive disorder or depression (including that resulting from Borna virus infection) and bipolar manic-depressive disorder, drug tolerance (e.g.
  • dystonia dyskinesia (e.g. L- Dopa-induced, tardive dyskinesia or in Huntington's disease), fragile-X syndrome, chorea, Huntington's chorea, irritable bowel syndrome (IBS), migraine, multiple sclerosis (MS), muscle spasms, pain (chronic and acute, e.g. inflammatory pain, neuropathic pain, allodynia, hyperalgesia, nociceptive pain), Parkinson's disease, post traumatic stress disorder, schizophrenia (positive and negative symptoms), spasticity, tinnitus, Tourette ' s syndrome, urinary incontinence , vomiting, pruritic conditions (e.g.
  • pruritis sleep disorders
  • micturition disorders neuromuscular disorder in the lower urinary tract
  • gastroesophageal reflux disease (GERD) gastroesophageal reflux disease
  • LES lower esophageal sphincter
  • functional gastrointestinal disorders dyspepsia, regurgitation, respiratory tract infection, bulimia nervosa, chronic laryngitis, asthma (e.g.
  • lung disease eating disorders, obesity, obesity-related disorders, binge eating disorders, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, anxiety disorder, posttraumatic stress disorder, social phobia, substance-induced anxiety disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder and delirium.
  • indications for Group I mGluR modulators include those indications wherein a particular condition does not necessarily exist but wherein a particular physiological parameter may be improved through administration of the instant compounds, for example cognitive enhancement.
  • Positive modulators may be particularly useful in the treatment of positive and negative symptoms in schizophrenia and cognitive deficits in various forms of dementia and mild cognitive impairment.
  • chromenones are Group I mGluR modulators. Therefore, these substances may be therapeutically beneficial in the treatment of conditions which involve abnormal glutamate neurotransmission or in which modulation of Group I mGluR receptors results in therapeutic benefit. These substances are preferably administered in the form of a pharmaceutical composition, wherein they are present together with one or more pharmaceutically acceptable diluents, carriers, or excipients.
  • An additional object of the invention is the provision of a process for producing the chromenone active principles.
  • R 2 represents hydrogen, d- ⁇ alkyl, aryl, heteroaryl, arylCi -6 alkyl, heteroarylC-i- ⁇ alkyl, cyano, nitro, halogen, hydroxy or C 2 - 6 alkoxy;
  • R 1 and R 2 together represent -W 1 -X 1 -Y 1 -Z 1 -, wherein
  • W 1 represents a single bond, oxygen, sulfur, -NR 7 - or -CR 8 R 9 -, and
  • X 1 , Y 1 and Z 1 each independently represents oxygen, sulfur, -NR 7 - or
  • R 4 represents hydrogen, halogen, nitro, amino, hydroxy, -OR 12 , -SO3CF3, Ci-ealkyl, cycloC 3 .i 2 alkyl, cycloCs- ⁇ alkyl-Ci-ealkyl, C 2-6 alkenyl, C ⁇ alkynyl, aryl, biaryl, arylC-i_ 6 alkyl, arylC 2 - 6 alkenyl, arylC 2 - 6 alkynyl, heteroaryl, heteroarylCi- ⁇ alkyl, heteroarylC 2 - 6 alkenyl, heteroarylthio, 2,3-dihydro-1 H-indenyl, Ci -6 alkoxyCi.
  • R 6 represents hydrogen, C h alky!, aryl, heteroaryl, halogen, hydroxy or Ci -6 alkoxy
  • R 7 represents hydrogen, C 1-6 alkyl, aryl, heteroaryl, arylCi -6 alkyl, Ci -6 alkoxy, halogen, hydroxy, cyano, nitro, hydroxyCi -6 alkyl, cycloC3-i2 alkoxy, Ci- ⁇ alkylamino, di-C-i- ⁇ alkylamino, cycloCa- ⁇ alkylamino, cycloCa- ⁇ alkyl-Ci-ealkylamino, di-Ci-ealkylaminoCi- ⁇ alkyl, arylamino, arylCi.
  • R 8 and R 9 each independently represent hydrogen, Ci. 6 alkyl, aryl, heteroaryl, arylC 1-6 alkyl, Ci -6 alkoxy, halogen, hydroxy, cyano, nitro, amino or cycloC-s- ⁇ alkyl;
  • R 10 represents hydrogen, C f - ⁇ alkyl, cycloCs- ⁇ alkyl (e.g. adamantyl), aryl, heteroaryl or carboxyCi -6 alkyl;
  • R 11 represents hydrogen, Ci -6 alkyl, cycloC 3 -i 2 alkyl (e.g. adamantyl), aryl, heteroaryl, carboxyCi- 6 alkyl or Ci- ⁇ alkylcarbonyl;
  • R 13 represents amino, pyrrolidino or piperidino
  • R 1 and R 2 represent -W 1 -X 1 -Y 1 -Z 1 - and W 1 does not represent a single bond
  • R 3 and R 4 , R 4 and R 5 or R 5 and R 6 together with the carbon atoms to which they are attached may form a 5-6 membered ring which may be saturated or unsaturated, wherein the ring may optionally have 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, and wherein the ring may be optionally substituted by one or more (e.g.
  • substituents selected from hydrogen, Ci -6 alkyl, cycloC 3- i 2 alkyl, aryl, heteroaryl, arylCi- 6 alkyl, carboxyC-t-6 alkyl, alkylcarbonyl, arylcarbonyl, oxo, thioxo, Ci -6 alkoxy, Ci-e alkylthio, arylCi. 6 alkylthio, arylCi.
  • Ci- 6 alkyl denotes straight or branched chain groups which may be unsubstituted or substituted by one or more (e.g. 1 , 2, 3, 4 or more) fluorine, chlorine and/or bromine atoms;
  • Ci-ealkoxy denotes straight or branched chain groups which may be unsubstituted or substituted by one or more (e.g. 1 , 2, 3, 4 or more) fluorine, chlorine and/or bromine atoms;
  • cycloC 3- i 2 alkyl denotes monocyclic, bicyclic or tricyclic groups which may be unsubstituted or substituted by one or more (e.g.
  • aryl denotes phenyl or naphthyl or phenyl substituted by one or more (e.g. 1 , 2, 3, 4 or more) substituents, which may be the same or different, selected from Ci -6 alkyl, C 2-6 alkenyl, d- ⁇ alkoxy, cycloC 3 -i 2 alkyl, hydroxy, halogen, cyano, nitro, Ci -6 alkoxycarbonyl, amino, Ci- 6 alkylamino, di-Ci- 6 alkylamino, N-cycloC 3 _i 2 alkyl-N- Ci- ⁇ alkylamino, azetidinyl, pyrrolyl, piperidinyl, morpholinyl, 4-Ci -6 alkylpiperazinyl, tetrazolyl, oxazolyl, fury!, thiophenyl
  • substituents which may be the same or different, selected from Ci -6 alkyl, C ⁇ alkoxy, cycloC 3-12 alkyl, hydroxy, halogen, cyano, nitro, C 1-6 alkoxycarbonyl, amino, Ci- ⁇ alkylamino, di-Ci- ⁇ alkylamino, N- cycloCa-iaalkyl-N-Ci-ealkylamino, azetidinyl, pyrrolyl, piperazinyl, morpholinyl, 4-Ci-6alkylpiperazinyl, tetrazolyl, oxazolyl, furyl, thiophenyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridinyl, pyrimidyl and phenyl;
  • W 1 represents a single bond or -CR 8 R 9 -
  • X 1 , Y 1 , and Z 1 each independently represent -CR 8 R 9 -
  • R 8 and R 9 are each independently selected from hydrogen, C 1-6 alkyl, aryl and heteroaryl.
  • Such a compound of Formula I wherein R 12 represents Ci -6 alkyl optionally substituted by one or more substituents selected from hydroxy, di-Ci -6 alkylamino, morpholino, halogen, cycloC 3- i 2 alkyl, arylamino and -C( O)R 13 (e.g. as in CF 3 or CHF 2 ); cycloC 3- i 2 alkyl; Ci -6 alkoxycycloC 3-12 alkyl or heteroaryl.
  • Such a compound of Formula I wherein R 4 represents bromo, methoxy, iso- propoxy, -C( O)N(R 11 ) 2 , /sopropylsulfanyl, difluoromethoxy, dimethylamino or diethylamino.
  • composition comprising as active ingredient a compound of the invention as hereinbefore defined, together with one or more pharmaceutically acceptable excipients or vehicles.
  • a method for treating or preventing a condition or disease associated with abnormal glutamate neurotransmission or a method for modulating Group I mGluR receptors to achieve therapeutic benefit, or a method for enhancing cognition comprising administering to a living animal, including a human, a therapeutically effective amount of a compound of the invention as hereinbefore defined but not subject to the foregoing proviso to Formula I.
  • Such a use or method wherein the condition associated with abnormal glutamate neurotransmission, or wherein modulation of mGluR receptors results in therapeutic benefit is selected from: AIDS-related dementia, Alzheimer's disease, Creutzfeld-Jakob ' s syndrome, bovine spongiform encephalopathy (BSE) or other prion related infections, diseases involving mitochondrial dysfunction, diseases involving ⁇ -amyloid and/or tauopathy such as Down's syndrome, hepatic encephalopathy, Huntington's disease, motor neuron diseases such as amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), olivopontocerebellar atrophy, post-operative cognitive deficit (POCD), Parkinson's disease, Parkinson's dementia, mild cognitive impairment, dementia pugilistica, vascular and frontal lobe dementia, cognitive impairment, eye injuries or diseases (e.g.
  • hypoglycaemia e.g. perinatal
  • ischaemia e.g. resulting from cardiac arrest, stroke, bypass operations or transplants
  • convulsions e.g. resulting from cardiac arrest, stroke, bypass operations or transplants
  • convulsions e.g. resulting from cardiac arrest, stroke, bypass operations or transplants
  • epileptic convulsions e.g. adenosarcoma
  • epilepsy e.g. perinatal
  • temporal lobe epilepsy e.g. glioma and other tumours
  • inner ear insult e.g.
  • dyskinesia in tinnitus, sound- or drug-induced
  • L-Dopa- induced and tardive dyskinesias abuse and addiction (nicotine, alcohol, opiate, cocaine, amphetamine, obesity and others), anxiety and panic disorders, attention deficit hyperactivity disorder (ADHD), restless leg syndrome, hyperactivity in children, autism, convulsions / epilepsy, dementia (e.g. in Alzheimer's disease, Korsakoff syndrome, vascular dementia, HIV infections), major depressive disorder or depression (including that resulting from Borna virus infection) and bipolar manic- depressive disorder, drug tolerance (e.g. to opioids), movement disorders, dystonia, dyskinesia (e.g.
  • L-Dopa-induced, tardive dyskinesia or in Huntington's disease L-Dopa-induced, tardive dyskinesia or in Huntington's disease
  • fragile-X syndrome Huntington's chorea
  • chorea chorea
  • irritable bowel syndrome IBS
  • migraine multiple sclerosis
  • muscle spasms pain (chronic and acute, e.g. inflammatory pain, neuropathic pain, allodynia, hyperalgesia, nociceptive pain), Parkinson's disease, post traumatic stress disorder, schizophrenia (positive and negative symptoms), spasticity, tinnitus, Tourette ' s syndrome, urinary incontinence, vomiting, pruritic conditions (e.g.
  • pruritis sleep disorders
  • micturition disorders neuromuscular disorder in the lower urinary tract
  • gastroesophageal reflux disease (GERD) gastroesophageal reflux disease
  • LES lower esophageal sphincter
  • functional gastrointestinal disorders dyspepsia, regurgitation, respiratory tract infection, bulimia nervosa, chronic laryngitis, asthma (e.g.
  • lung disease eating disorders, obesity and obesity-related disorders, binge eating disorders, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, anxiety disorder, posttraumatic stress disorder, social phobia, substance-induced anxiety disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder, delirium, or for cognitive enhancement and/or neuroprotection.
  • Such a use or method wherein the condition associated with abnormal glutamate neurotransmission, or wherein modulation of mGluR receptors results in therapeutic benefit is selected from: addiction, neuropathic pain,
  • Parkinson's disease anxiety disorders, epilepsy, positive and/or negative symptoms of schizophrenia, cognitive impairment, or for cognitive enhancement and/or neuroprotection.
  • Such a use or method wherein the condition associated with abnormal glutamate neurotransmission, or wherein modulation of mGluR receptors results in therapeutic benefit is selected from: neuropathic pain, diabetic neuropathic pain (DNP), cancer pain, pain related to rheumathic arthritis, inflammatory pain, L-Dopa-induced and tardive dyskinesias, Parkinson's disease, anxiety disorders, Huntington's chorea and/or epilepsy.
  • DNP diabetic neuropathic pain
  • cancer pain pain related to rheumathic arthritis
  • inflammatory pain L-Dopa-induced and tardive dyskinesias
  • Parkinson's disease anxiety disorders
  • Huntington's chorea and/or epilepsy is selected from: neuropathic pain, diabetic neuropathic pain (DNP), cancer pain, pain related to rheumathic arthritis, inflammatory pain, L-Dopa-induced and tardive dyskinesias, Parkinson's disease, anxiety disorders, Huntington's chorea
  • Such a use or method wherein the compound of Formula I is selected from: 3-(adamantane-1-carbonyl)-7-methoxychromen-2-one, 3-(adamantane-1-carbonyl)-7-dimethylaminochromen-2-one, 3-(adamantane-1-carbonyl)-7-diethylaminochromen-2-one, 3-(adamantane-1-carbonyl)-7-bromochromen-2-one,
  • the carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix C ⁇ j indicates a moiety of the integer "i" to the integer "j" carbon atoms, inclusive.
  • Ci- 3 alkyl refers to alkyl of one to three carbon atoms, inclusive, (i.e., methyl, ethyl, propyl, and isopropyl), straight and branched forms thereof.
  • Ci- 6 alkyl comprises straight or branched chain alkyl groups having 1 , 2, 3, 4, 5 or 6 carbon atoms. Said alkyl groups may be unsubstituted and include, e.g., methyl, ethyl, n-propyl, 2-propyl, n-butyl, tert- butyl. Further, these alkyl groups may optionally be substituted by one or more fluorine, chlorine and/or bromine atoms.
  • halogenated alkyl moieties include -CF 3 , -C 2 F 5 , -CBr 3 , and -CCI 3 ; thus, for example, groups such as R 2 , R 4 , R 5 and R 7 -R 11 may represent e.g. trifluoromethyl.
  • the term "Ci- ⁇ alkoxy" comprises straight or branched chain -O-C-i- ⁇ alkyl groups wherein "Ci -6 alkyl” is defined as given hereinbefore. Examples of "Ci -6 alkoxy” include methoxy, ethoxy, n-propoxy, i-propoxy.
  • a Ci -6 alkoxy group optionally may be substituted by one or more fluorine, chlorine and/or bromine atoms thereby forming, for instance, -OCF 3 and -OC2F5.
  • the term "cycloC 3- i 2 alkyr represents monocyclic, bicyclic or tricyclic alkyl groups having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl and adamantyl.
  • a cycloC 3 -i 2 alkyl group optionally may be substituted with one or more fluorine, chlorine and/or bromine atoms.
  • di-Ci -6 alkylamino refers to an amino moiety in which the nitrogen atom of the amino group is substituted with two C- ⁇ - 6 alkyl groups, which may be the same or different, as defined above.
  • . 6 alkylamino groups include dimethylamino, diethylamino and N-methyl- N-isopropylamino.
  • N-cycloC 3 -i 2 alkyl-N-Ci- 6 alkylamino comprises amino groups in which the nitrogen atom of the amino group is substituted by one C h alky! group and one N-cycloC 3- i 2 alkyl group.
  • Both the d- ⁇ alkyl group and the N-cycloC 3- i 2 alkyl group are defined as given hereinbefore.
  • the term "4-Ci- 6 alkyl-piperazinyl” comprises piperazinyl radicals bearing a Ci. 6 alkyl moiety at the nitrogen atom in 4-position of the piperazine ring, said "Ci -6 alkyl” having the same meaning as given hereinbefore.
  • aryl represents phenyl or naphthyl or phenyl substituted by one or more substituents, which may be the same or different, selected from Ci -6 alkyl, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, C 2-6 alkenyl, Ci -6 alkoxy, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, cycloC 3 --
  • heteroaryl represents an aromatic 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, or a bicyclic group comprising a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, wherein the heteroaryl group may be optionally substitued by one or more substituents, which may be the same or different, selected from Ci -6 alkyl, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, Ci -6 alkoxy, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, cycloCs- ⁇ alkyl, hydroxy, halogen, cyano, nitro, Ci- 6 alkoxycarbonyl, amino, Ci -6 alkylamino, di-Ci- 6 alkylamino
  • heteroaryl groups include unsubstituted or appropriately substituted pyrroles, oxazoles, thiophens, furans, isoxazoles, imidazoles, oxazoles, oxadiazoles, thiazoles, imidazolines, pyrazoles, oxazolidines, isoxazolidines, thiazolidines, pyridines, pyridazines, pyrimidines, pyrazines, azepines.
  • halogen represents fluorine, chlorine, bromine and iodine.
  • the compounds of the present invention are named according to the IUPAC or CAS nomenclature system. Abbreviations which are well known to one of ordinary skill in the art may be used (e.g. "Ph” for phenyl, “Me” for methyl, “Et” for ethyl, “h” for hour or hours, and “rt” for room temperature).
  • analog or “derivative” is used herein in the conventional pharmaceutical sense, to refer to a molecule that structurally resembles a reference molecule, but has been modified in a targeted and controlled manner to replace one or more specific substituents of the reference molecule with an alternate substituent, thereby generating a molecule which is structurally similar to the reference molecule.
  • Synthesis and screening of analogs e.g., using structural and/or biochemical analysis, to identify slightly modified versions of a known compound which may have improved or biased traits (such as higher potency and/or selectivity at a specific targeted receptor type, greater ability to penetrate mammalian blood-brain barriers, fewer side effects, etc.) is a drug design approach that is well known in pharmaceutical chemistry.
  • analogs and derivatives of the compounds of the invention can be created which have improved therapeutic efficacy in controlling neurological conditions including dementia, i.e., higher potency and/or selectivity at a specific targeted receptor type, either greater or lower ability to penetrate mammalian blood- brain barriers (e.g., either higher or lower blood-brain barrier permeation rate), fewer side effects, etc.
  • dementia i.e., higher potency and/or selectivity at a specific targeted receptor type, either greater or lower ability to penetrate mammalian blood- brain barriers (e.g., either higher or lower blood-brain barrier permeation rate), fewer side effects, etc.
  • compositions of the invention refers to molecular entities and other ingredients of such compositions that are physiologically tolerable and do not typically produce untoward reactions when administered to a mammal (e.g., human).
  • pharmaceutically acceptable means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals, and more particularly in humans.
  • compositions of the present invention may be in the form of pharmaceutically acceptable salts.
  • “Pharmaceutically acceptable salts” refers to those salts which possess the biological effectiveness and properties of the parent compound and which are not biologically or otherwise undesirable. The nature of the salt or isomer is not critical, provided that it is non-toxic and does not substantially interfere with the desired pharmacological activity.
  • Chromenone 3A may be prepared by Pechmann condensation of a resorcinol 1 with a substituted ⁇ -ketoester 2 according to Scheme 1.
  • Compound 4 may be prepared by Pechmann condensation of a mono O- alkylated resorcinol 5 with a substituted ⁇ -ketqester 2 or, alternatively, by O- alkylation, arylation or acylation of chromenone 3A.
  • Compound 6 may be prepared from compound 3B via reaction with an amine derivative (e.g., morpholine) and formaldehyde under acidic conditions (Scheme 2). Alkylation of compound 6 at oxygen with an alkyl bromide (e.g. /sopropyl bromide) yields chromenone derivative 7.
  • an amine derivative e.g., morpholine
  • formaldehyde under acidic conditions
  • Nitration of compound 3B yields nitrochromenone 8 (Scheme 3). Alkylation of nitro derivative 8 at oxygen yields compound 9. Reduction of the nitro group of 9 provides aniline 10.
  • the amino group of 10 may be mono- or bis- alkylated, acylated, sulfonylated, and/or carbamoylated to yield compound 11.
  • the nitro group in compound 8 may be reduced to yield aniline 12 with a free hydroxy group, the amino group of which may be mono- or bis- acylated, sulfonylated, and/or carbamoylated in the presence of potassium carbonate to yield compound 11.
  • R a H
  • iPr Nitration of compound 3C yields nitro chromenone 13 (Scheme 4).
  • Alkylation of nitro derivative 13 at oxygen yields compound 14, the nitro group of which may be reduced to provide aniline 15.
  • the amino group of aniline 15 may be mono- or bis-alkylated, acylated, sulfonylated, and/or carbamoylated to yield compound 16.
  • the nitro group of compound 13 may be reduced to yield aniline 17 with a free hydroxy group, the amino group of which may be mono- or bis- acylated, sulfonylated, and/or carbamoylated to yield compound 16.
  • Trifluorosulfonic acid ester 18 may be prepared from chromenone derivative 3A according to Scheme 5.
  • Triflate 18 may be used to prepare stannyl derivative 19 which may be utilized in a palladium catalyzed coupling reaction with an aryl halide to prepare compound 20, or compound 19 may be coupled with an acyl chloride to prepare compound 21.
  • Scheme 5
  • Amino phenol 17 may be condensed with a carboxylic acid to prepare oxazole 28 (Scheme 8). Condensation of amino phenol 17 with an ⁇ -keto carboxylic acid ester yields compound 29. Treatment of amino phenol 17 with carbonyldiimidazole provides oxazolidinone 30 which may be alkylated at nitrogen to give compound 31. Treatment of amino phenol 17 with thiocarbonyldiimidazole provides oxazolidinethione 32 which may be
  • R 14 represents hydrogen, Ci -6 alkyl, cycloC 3 -i 2 alkyl, aryl, heteroaryl, carboxyCi- 6 alkyl, arylC- ⁇ _ 6 alkyl, alkylcarbonyl or CF 3
  • R 15 represents hydrogen, d- ⁇ alkyl, cycloC- 3 -i 2 alkyl, aryl, heteroaryl, arylCi ⁇ alkyl, carboxyC-i- ⁇ alkyl, alkylcarbonyl, CF 3
  • Amino phenol 12 may be condensed with a carboxylic acid to prepare oxazole 35 (Scheme 9). Condensation of amino phenol 12 with an ⁇ -keto carboxylic acid ester yields compound 36. Treatment of amino phenol 12 with carbonyldiimidazole provides oxazolidinone 37 which may be alkylated at nitrogen to provide compound 38. Treatment of amino phenol 12 with thiocarbonyldiimidazole provides oxazolidinethione 39 which may be alkylated at sulfur to provide compound 40. Replacement of sulfur with an amine in oxazolidinethione 39 yields compound 41 (wherein R 14 and R 15 are as previously defined).
  • Trifluorosulfonic acid ester 42 may be prepared from chromenone derivative 3D (Scheme 10). Triflate 42 may be used to prepare stannyl derivative 43 which may be utilized for palladium catalyzed coupling with an aryl halide to prepare compound 44, or compound 43 may be coupled with an acyl chloride to prepare compound 45.
  • Nitration of compound 3E yields nitrochromenone 46 (Scheme 11).
  • Alkylation of nitro derivative 46 at oxygen yields compound 47, the nitro group of which may be reduced to yield aniline 48.
  • the amino group in aniline 48 may be mono- or bis- alkylated, acylated, sulfonylated, and/or carbamoylated to yield compound 49.
  • the nitro group in compound 46 may be reduced to give aniline 50 with a free hydroxy group, the amino group of which may be mono- or bis- acylated, sulfonylated, and/or carbamoylated to give compound 49.
  • Amino phenol 50 may be condensed with a carboxylic acid to prepare oxazole 51 (Scheme 12). Condensation of amino phenol 50 with an ⁇ -keto carboxylic acid ester yields compound 52. Treatment of amino phenol 50 with carbonyldiimidazole provides oxazolidinone 53 which may be alkylated at nitrogen to give compound 54. Treatment of amino phenol 50 with thiocarbonyldiimidazole provides oxazolidinethione 55 which may be alkylated at sulfur to yield compound 56. Replacement of sulfur with an amine in thione 55 yields compound 57 (wherein R 14 and R 15 are as previously defined).
  • 3-Acylchromenone derivative 60 may be prepared by piperidine catalysed condensation of 2-acylphenol 58 with ⁇ -ketoester 59 (Scheme 13).
  • DMF N.N-dimethylformamide
  • HCI hydrochloric acid
  • DMSO dimethylsulfoxide
  • TMS tetramethylsilane
  • Trifluoromethanesulfonic acid 2-chloro-6-oxo-7,8,9,10-tetrahydro-6H- benzo[c]chromen-3-yl ester
  • Pure stereoisomeric forms of the compounds and the intermediates of this invention may be obtained by the application of art-known procedures.
  • Diastereomers may be separated by physical separation methods such as selective crystallization and chromatographic techniques, e.g. liquid chromatography using chiral stationary phases.
  • Enantiomers may be separated from each other by selective crystallization of their diastereomeric salts with optically active acids.
  • enantiomers may be separated by chromatographic techniques using chiral stationary phases.
  • Said pure stereoisomeric forms may also be derived from the corresponding pure stereoisomeric form of appropriate starting materials, provided that the reaction occurs stereoselective ⁇ .
  • Stereoisomeric forms of Formula I are obviously intended to be included within the scope of this invention.
  • salts of the compounds of Formula I are those wherein the counterion is pharmaceutically acceptable.
  • salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation and purification of pharmaceutically acceptable compounds. All salts whether pharmaceutically acceptable or not are included within the ambit of the present invention.
  • the pharmaceutically acceptable salts as mentioned above are meant to comprise the therapeutically active non-toxic salt forms which the compounds of Formula I are able to form. The latter can conveniently be obtained by treating the base form with such appropriate acids as inorganic acids, e.g.
  • hydrohalic acids such as hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids such as acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, 2-hydroxy-1 ,2,3- propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4- methylbenzenesulfonic, cyclohexanesulfonic, 2-hydroxybenzoic, 4-amino- 2-hydroxybenzoic and the like acids.
  • the salt form can be converted by treatment with alkali into the free base form.
  • the active ingredients of the invention may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as coated or uncoated tablets or filled capsules, or liquids, such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use; in the form of suppositories or capsules for rectal administration or in the form of sterile injectable solutions for parenteral (including intravenous or subcutaneous) use.
  • Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional or new ingredients in conventional or special proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
  • Tablets containing one (1 ) to one hundred (100) milligrams of active ingredient or zero point five (0.5) to five hundred (500) milligrams per tablet, are accordingly suitable representative unit dosage forms.
  • carrier applied to pharmaceutical compositions of the invention refers to a diluent, excipient, or vehicle with which an active compound is administered.
  • Such pharmaceutical carriers can be sterile liquids, such as water, saline solutions, aqueous dextrose solutions, aqueous glycerol solutions, and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences” by E.W. Martin, 18 th Edition.
  • the active principles of the invention may be administered to a subject, e.g., a living animal (including a human) body, in need thereof, for the treatment, alleviation, modulation, amelioration, palliation, or elimination of an indication or condition which is susceptible thereto, or representatively of an indication or condition set forth elsewhere in this application, optionally concurrently, simultaneously, or together with one or more pharmaceutically-acceptable excipients, carriers, or diluents, and optionally in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parental (including intravenous and subcutaneous) or in some cases even topical route, in an effective amount.
  • Suitable dosage ranges are 1-1000 milligrams daily, 10-500 milligrams daily, and 50-500 milligrams daily, depending as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and the preference and experience of the physician or veterinarian in charge.
  • terapéuticaally effective applied to dose or amount refers to that quantity of a compound or pharmaceutical composition that is sufficient to result in a desired activity upon administration to a living animal body in need thereof.
  • the active agents of the present invention may be administered orally, topically, parenterally, or mucosally (e.g., buccally, by inhalation, or rectally) in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers. It is usually desirable to use the oral route.
  • the active agents may be administered orally in the form of a capsule, a tablet, or the like (see Remington: The Science and Practice of Pharmacy, 20 th Edition (2000), Philadelphia, PA).
  • the orally administered medicaments may be administered in the form of a time-controlled release vehicle, including diffusion-controlled systems, osmotic devices, dissolution- controlled matrices, and erodible/degradable matrices.
  • the active drug component can be combined with a non-toxic, pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, sucrose, glucose, mannitol, sorbitol and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or silica, steric acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate, and the like); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate), coloring and flavoring agents, gelatin, sweeteners, natural and synthetic gums (such as acacia, traga, traga, traga, g
  • the drug components can be combined with non-toxic, pharmaceutically acceptable inert carriers (e.g., ethanol, glycerol, water), suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e.g., lecithin or acacia), non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils), preservatives (e.g., methyl or propyl-p- hydroxybenzoates or sorbic acid), and the like.
  • Stabilizing agents such as antioxidants (BHA, BHT, propyl gallate, sodium ascorbate, citric acid) can also be added to stabilize the dosage forms.
  • compositions of the invention can be also introduced in microspheres or microcapsules, e.g., fabricated from polyglycolic acid/lactic acid (PGLA).
  • PGLA polyglycolic acid/lactic acid
  • Liquid preparations for oral administration can take the form of, for example, solutions, syrups, emulsions or suspensions, or they can be presented as a dry product for reconstitution with water or other suitable vehicle before use. Preparations for oral administration can be suitably formulated to give controlled or postponed release of the active compound.
  • the active drugs can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines, as is well known.
  • Drugs of the invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • Active drugs may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinyl-pyrrolidone, pyran copolymer, polyhydroxy-propyl methacrylamide-phenol, polyhydroxy- ethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
  • active drug may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polyhydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
  • biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polyhydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
  • the therapeutics according to the present invention can be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • the dosage unit can be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the formulations of the invention can be delivered parenterally, i.e., by intravenous (i.v.), intracerebroventricular (i.c.v.), subcutaneous (s.c), intraperitoneal (i.p.), intramuscular (Lm.), subdermal (s.d.), or intradermal (i.d.) administration, by direct injection, via, for example, bolus injection or continuous infusion.
  • Formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • compositions can take such forms as excipients, suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient can be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • Compositions of the present invention can also be formulated for rectal administration, e.g., as suppositories or retention enemas (e.g., containing conventional suppository bases such as cocoa butter or other glycerides).
  • compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient, optionally at various dosage levels to act as a titration pack.
  • the pack may, for example, comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • Compositions of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • the dose of the components in the compositions of the present invention is determined to ensure that the dose administered continuously or intermittently will not exceed an amount determined after consideration of the results in test animals and the individual conditions of a patient.
  • a specific dose naturally varies depending on the dosage procedure, the conditions of a patient or a subject animal such as age, body weight, sex, sensitivity, feed, dosage period, drugs used in combination, seriousness of the disease.
  • the appropriate dose and dosage times under certain conditions can be determined by the test based on the above- described indices but may be refined and ultimately decided according to the judgment of the practitioner and each patient's circumstances (age, general condition, severity of symptoms, sex, etc.) according to standard clinical techniques.
  • Toxicity and therapeutic efficacy of the compositions of the invention can be determined by standard pharmaceutical procedures in experimental animals, e.g., by determining the LD 5O (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between therapeutic and toxic effects is the therapeutic index and it can be expressed as the ratio ED 5 o/LD 5O .
  • Compositions that exhibit large therapeutic indices are preferred.
  • reaction products can be processed into tablets, coated tablets, capsules, drip solutions, suppositories, injection and infusion preparations, and the like and can be therapeutically applied by the oral, rectal, parenteral, and additional routes.
  • Representative pharmaceutical compositions follow.
  • Tablets suitable for oral administration which contain the active ingredient may be prepared by conventional tabletting techniques.
  • any usual suppository base may be employed for incorporation thereinto by usual procedure of the active ingredient, such as a polyethyleneglycol which is a solid at normal room temperature but which melts at or about body temperature.
  • a suitable formulation for a tablet containing 10 milligrams of active ingredient is as follows:
  • Tablet Formulation Another suitable formulation for a tablet containing 100 mg is as follows:
  • the film coating material consists of:
  • Capsule Formulation A suitable formulation for a capsule containing 50 milligrams of active ingredient is as follows:
  • a suitable formulation for an injectable solution is as follows:
  • a suitable formulation for 1 liter of a an oral solution containing 2 milligrams of active ingredient in one milliliter of the mixture is as follows:
  • Aerosol formulation 18O g aerosol solution contain:
  • Purified water 19.6 1.8 ml of the solution are placed on a fleece covered by an adhesive backing foil.
  • the system is closed by a protective liner which will be removed before use.
  • Nanoparticle formulation 10 g of polybutylcyanoacrylate nanoparticles contain:
  • Polybutylcyanoacrylate nanoparticles are prepared by emulsion polymerization in a water/0.1 N HCI/ethanol mixture as polymerizsation medium. The nanoparticles in the suspension are finally lyophilized under vacuum.
  • the pellet is then re-suspended and centrifuged two to three more times at 48,000xg for 20 min in the presence of 50 mM Tris-HCI, pH 8.0. All centrifugation steps are carried out at 4 0 C. After resuspension in 5 volumes of 50 mM Tris-HCI, pH 8.0 the membrane suspension is frozen rapidly at -80 0 C.
  • the membranes On the day of assay the membranes are thawed and washed four times by resuspension in 50 mM Tris-HCI, pH 8.0 and centrifugation at 48,000xg for 20 min. and finally re-suspended in 50 mM Tris-HCI, pH 7.4.
  • the amount of protein in the final membrane preparation (250-500 ⁇ g/mL) is determined according to the method of Lowry (Lowry O. H. et al., 1951. J. Biol. Chem. 193, 256-275).
  • Incubations are started by adding ( 3 H)-MPEP (50.2 Ci/mmol, 5nM, Tocris) to vials with 125-250 ⁇ g protein (total volume 0.5 ml) and various concentrations of the agents. The incubations are continued at room temperature for 60 min (equilibrium is achieved under the conditions used). Non-specific binding is defined by the addition of unlabeled MPEP (10 ⁇ M). Incubations are terminated using a Miliipore filter system. The samples are rinsed twice with 4 mL of ice cold assay buffer over glass fibre filters (Schleicher & Schuell) under a constant vacuum.
  • the filters are placed into scintillation liquid (5 mL Ultima Gold) and radioactivity retained on the filters is determined with a conventional liquid scintillation counter (Hewlett Packard, Liquid Scintillation Analyser).
  • astrocyte cultures are prepared from cortices of newborn rats as described by Booher and Sensenbrenner (1972). Briefly, Sprague-Dawley rat pups (2 - 4 d old) are decapitated and neocortices are dissected, disintegrated with a nylon filter (poresize 80 ⁇ m) and carefully triturated.
  • the cell suspension is plated on poly-D-lysine precoated flasks (Costar) and cultivated in Dulbecco's Modified Eagle's Medium (DMEM, InVitrogen) supplemented with 10% heat inactivated fetal calf serum (FCSi, Sigma), 4 mM glutamine (Biochrom) and 50 ⁇ g/mL gentamycin (Biochrom) at 37°C in a humidified atmosphere of 5% CO 2 /95% air for 7 d with exchanging the medium at day 2. After 7 DIV, cells are shaken overnight at 250 rpm to remove oligodendrocytes and microglia.
  • DMEM Dulbecco's Modified Eagle's Medium
  • FCSi heat inactivated fetal calf serum
  • Biochrom heat inactivated fetal calf serum
  • Biochrom gentamycin
  • astrocytes are rinsed twice with CMF-PBS 1 trypsinized and subplated on poly-D-lysine precoated 96-well plates (Becton Dickinson #6516 or #6640) at a density of 40,000 - 45,000 cells/well.
  • astrocyte-defined medium consisting of DMEM containing 1x G5-supplement (InVitrogen), 0.5 ⁇ g/mL heparan sulfate (Sigma), and 1.5 ⁇ g/ mL fibronectin (Sigma) (Miller et al., 1993). 3 d later the medium is exchanged and the cells incubated for another 2-3 d, so that at the time of experiments astrocytes are 14-15 DIV.
  • lmmunocytochemistry lmmunostaining is performed to confirm the presence of classical astrocytic markers such as GFAP as well the expression of mGluR ⁇ receptors.
  • the 96 well plates can be frozen at -20 0 C at this stage until further analysis.
  • Home made resin exchange columns AG1-X8 Biorad, 140-14444 are used to separate labeled inositol phosphates by elution with 1 mL of 1 M ammonium formate / 0.1 M formic acid into 24-well visiplates (Perkin Elmer).
  • Scintillation liquid (UltimaFlow AF, Perkin Elmer) is added, the plate sealed and vortexed before radioactivity is determined by conventional liquid scintillation counting (Microbeta, Perkin Elmer) as disintegration per minute (DPM).
  • the medium Prior to addition of agonist or antagonist the medium is aspirated and cells are loaded for 2 h at RT with 150 ⁇ L of loading buffer consisting of Ca-sensitive dye (MD # R8033) reconstituted in sodium chloride (123 mM), potassium chloride (5.4 mM), magnesium chloride (0.8 mM), calcium chloride (1.8 mM), D-glucose (15 mM), and HEPES (20 mM), pH 7.3.
  • loading buffer consisting of Ca-sensitive dye (MD # R8033) reconstituted in sodium chloride (123 mM), potassium chloride (5.4 mM), magnesium chloride (0.8 mM), calcium chloride (1.8 mM), D-glucose (15 mM), and HEPES (20 mM), pH 7.3.
  • plates are transferred to FLIPR to detect calcium increase with the addition of DHPG (300 ⁇ M) or L-quisqualate (100 nM) measured as relative fluorescence units (RFU). If antagonists are tested, these compounds are
  • concentration-response curves for quisqualate are performed in the presence and absence of 10 ⁇ M modulator to determine the extent of potentiation / agonist potency increase. Thereafter, concentration-response curves for the positive modulator are performed in the presence of a fixed concentration of quisqualate showing the biggest window for potentiation (normally 10-30 nM).
  • MaxMin maximum minus minimum
  • Cerebellar cortici are obtained from P8 postnatal Sprague Dawley rats, mechanically disrupted into small pieces with forceps and then transferred to Ca 2+ and Mg 2+ free Hank's buffered salt solution (HBSS-CMF) on ice. After three washes in HBSS-CMF, the tissue pieces are incubated at 37 0 C for 8 minutes in the presence of 0.25% trypsin / 0.05% DNase. The enzymatic reaction is stopped with 0.016% DNAase / 0.1 % ovomucoid before centrifugation at 800 rpm for 5 minutes.
  • HBSS-CMF Ca 2+ and Mg 2+ free Hank's buffered salt solution
  • the supernatant is replaced twice with NaHCO 3 /HEPES-buffered basal Eagle medium (BME) plus 20 mM KCI.
  • BME basal Eagle medium
  • Cells are mechanically dissociated in 2 ml of BME by trituration through three Pasteur pipettes of successively decreasing tip diameter and then filtered through a 48 ⁇ M gauge filter. Cells are plated at a density of 150,000 cells in 50 ⁇ l in each well of poly-L-Lysin pre-coated 96 well plates (Falcon).
  • the cells are nourished with BEM supplemented with 10% foetal calf serum, 2 mM glutamine (Biochrom), 20 mM KCI and gentamycin (Biochrom) and incubated at 36 0 C with 5% CO 2 at 95% humidity. After 24 h, cytosine- ⁇ -D- arabinofuranoside (AraC, 10 ⁇ M) is added to the medium.
  • IP3 assay with [ 3 H]myoinositol After 6 DIV the culture medium is replaced completely with inositol free DMEM (ICN) containing [ ⁇ ]myo-inositol (Perkin Elmer) at a final concentration of 0.5 ⁇ Ci / 100 ⁇ l / well and incubated for a further 48 hours.
  • the culture medium in each well is replaced with 100 ⁇ l_ Locke ' s buffer (containing in (mM) NaCI (156), KCI (5.6), NaHCO 3 (3.6), MgCI 2 (1.0), CaCI 2 (1.3), Glucose (5.6), HEPES (10)) with additional (20 mM Li + , pH 7.4) and incubated for 15 min at 37°C.
  • Locke's buffer is replaced with agonists / antagonists / putative mGluRI ligands in Locke's buffer and incubated for 45 min. These solutions are then replaced by 100 ⁇ L 0.1 M HCI in each well and incubated for a further 10 mins on ice. The 96 well plates can be frozen at - 20 0 C at this stage until further analysis.
  • Home made resin exchange columns (AG1-X8 Biorad, 140-14444) are used to separate labeled inositol phosphates. On the day of assay, columns are washed with 1 ml of 0.1 M formic acid followed by 1 ml of distilled water.
  • each assay well is then added to one column and washed with 1 ml distilled water followed by 1 ml of 5 mM sodium tetraborate / 60 mM sodium formate.
  • the retained radioactive inositol phosphates are then eluted with 2 * 1 ml of 1 M ammonium formate / 0.1 M formic acid into 24-well visiplates.
  • Scintillation liquid (UltimaFlow AF, Perkin Elmer) is added, the plate sealed and vortexed before radioactivity is determined by conventional liquid scintillation counting (Microbeta, Perkin Elmer) as disintegration per minute (DPM).
  • Compounds of the present invention have a potency (EC 50 or IC 50 , respectively) range of about 0.5 nM to about 100 ⁇ M.
  • the instant chromenone derivatives represent a novel class of Group I mGluR modulators. In view of their potency, they will be useful therapeutics in a wide range of CNS disorders which involve abnormal glutamate induced excitation.
  • AIDS-related dementia Alzheimer's disease, Creutzfeld-Jakob ' s syndrome, bovine spongiform encephalopathy (BSE) or other prion related infections, diseases involving mitochondrial dysfunction, diseases involving ⁇ -amyloid and/or tauopathy such as Down's syndrome, hepatic encephalopathy, Huntington's disease, motor neuron diseases such as amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), olivopontocerebellar atrophy, post- operative cognitive deficit (POCD), Parkinson's disease, Parkinson's dementia, mild cognitive impairment, dementia pugilistica, vascular and frontal lobe dementia, cognitive impairment, eye injuries or diseases (e.g.
  • hypoglycaemia e.g. perinatal
  • ischaemia e.g. resulting from cardiac arrest, stroke, bypass operations or transplants
  • convulsions e.g. in tinnitus, sound- or drug-induced
  • L-Dopa-induced and tardive dyskinesias e.g. in tinnitus, sound- or drug-induced
  • ALS amyotrophic lateral sclerosis
  • ADHD attention deficit hyperactivity disorder
  • restless leg syndrome hyperactivity in children
  • autism convulsions / epilepsy
  • dementia e.g. in Alzheimer's disease, Korsakoff syndrome, vascular dementia, HIV infections
  • major depressive disorder or depression including that resulting from Borna virus infection
  • bipolar manic-depressive disorder drug tolerance (e.g. to opioids), movement disorders, dystonia, dyskinesia (e.g.
  • pruritis sleep disorders
  • micturition disorders neuromuscular disorder in the lower urinary tract
  • gastroesophageal reflux disease (GERD) gastroesophageal reflux disease
  • LES lower esophageal sphincter
  • functional gastrointestinal disorders dyspepsia, regurgitation, respiratory tract infection, bulimia nervosa, chronic laryngitis, asthma (e.g.
  • lung disease eating disorders, obesity, obesity- related disorders, agoraphobia, generalized anxiety disorder, obsessive- compulsive disorder, panic disorder, posttraumatic stress disorder, social phobia, substance-induced anxiety disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder, delirium, or for cognitive enhancement and/or neuroprotection.
  • the method-of-treating a living animal body with a compound of the invention, for the inhibition of progression or alleviation of the selected ailment therein, is as previously stated by any normally-accepted pharmaceutical route, employing the selected dosage which is effective in the alleviation of the particular ailment desired to be alleviated.
  • Use of the compounds of the present invention in the manufacture of a medicament for the treatment of a living animal for inhibition of progression or alleviation of selected ailments or conditions, particularly ailments or conditions susceptible to treatment with a Group I mGluR modulator is carried out in the usual manner comprising the step of admixing an effective amount of a compound of the invention with a pharmaceutically-acceptable diluent, excipient, or carrier, and the method-of-treating, pharmaceutical compositions, and use of a compound of the present invention in the manufacture of a medicament.
  • compositions prepared by admixing the active ingredient with a suitable pharmaceutically-acceptable excipient, diluent, or carrier include tablets, capsules, solutions for injection, liquid oral formulations, aerosol formulations, TDS formulations, and nanoparticle formulations, thus to produce medicaments for oral, injectable, or dermal use, also in accord with the foregoing.

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Abstract

L’invention concerne des dérivés chroménone ainsi que leurs sels pharmaceutiquement acceptables. L’invention concerne également un procédé de préparation de ces composés. Les composés de l’invention sont des modulateurs des mGluR du Groupe I ; ils sont par conséquent utiles dans le cadre de la régulation et de la prévention des troubles neurologiques aigus et/ou chroniques.
EP06794829A 2005-10-21 2006-10-19 Chromenones et leur utilisation en tant que modulateurs des recepteurs metabotropes au glutamate Withdrawn EP1957475A1 (fr)

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IL190740A0 (en) 2009-09-22

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