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Definitions

• the present invention is concerned with novel metabotropic glutamate receptor (mGluR) modulators, methods for their synthesis and the treatment and/or prevention of neurological disorders by administration of such substances.
• mGluR metabotropic glutamate 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, 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 mGluR3 belong to group Il and mGluR4, mGluR ⁇ , mGluR7 and mGluR ⁇ 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, 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), olivoponto-cerebellar atrophy, post-operative cognitive deficit (POCD), Parkinson's disease, Parkinson's dementia, mild cognitive impairment, dementia pugilisitca, vascular and frontal lobe dementia, cognitive impairment, eye injuries or diseases (e.g.
• AIDS- related dementia Alzheimer's disease, Creutzfeld-Jakob ' s syndrome, bovine spongiform encephalopathy (BSE) or other
• 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
• svmptomatological effect on the following conditions 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 and hyperactive 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.
• 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. reflux-related asthma), lung disease, eating disorders, obesity and obesity- related disorders.
• asthma e.g. reflux-related asthma
• lung disease eating disorders
• obesity and obesity- related disorders e.g. reflux-related asthma
• 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.
• mGluR ⁇ modulators those which exhibit a modulatory effect on mGluR5 receptors and thus may affect conditions or diseases associated with the function of those mGluR5 receptors are of particular interest.
• mGluR ⁇ positive modulators or agonists may be particularly useful for preventing ahd/or treating conditions or diseases that are associated with an insufficient stimulation or activity of rnGluR ⁇ receptors.
• mGluR5 modulators and especially mGluR5 positive modulators or agonists may be particularly useful for preventing and/or treating addiction, neuropathic pain, L-dopa-induced and tardive dyskinesias, ALS, fragile-X syndrome, Parkinson's disease, anxiety disorders, epilepsy, positive and/or negative symptoms of schizophrenia, cognitive impairment, or for cognitive enhancement and neuroprotection.
• An additional object of the invention is the provision of a process for producing the tetrahydroquinolone active principles.
• R 1 represents aryl or heteroaryl
• R 2 and R 3 which may be the same or different, represent hydrogen or Ci- ⁇ alkyl
• R 4 and R 5 which may be the same or different, represent hydrogen or Ci- 6 alkyl
• aryl represents an unsubstituted phenyl ring or a phenyl ring that is substituted with 1 , 2, 3, 4 or 5 substituents, that may be the same of different, which substituents are selected from the group consisting of Ci-6alkyl, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, C-i- ⁇ alkoxy, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, cycloC 3 .i2alkyl, hydroxyl, F, Cl, Br, I, CN, nitro, di-C-
• heteroaryl represents a (hetero)aromatic 5-, 6- or 7-membered ring having from 1 to 4 heteroatoms said heteroatoms being independently selected from oxygen, nitrogen and sulfur, wherein said ring is unsubstituted or substituted with 1 , 2 or 3 substituents, that may be the same or different, which substituents are selected from the group consisting of Ci-ealkyl, 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, cycloC 3 -i 2 alkyl, hydroxyl, F, Cl, Br, I, CN, nitro, di-Ci-6alkylamino, N-cycloC 3 -i 2 alkyl-N- Ci- ⁇ alkylamino, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 4-C-i- 6 al
• R 2 and R 3 which may be the same or different, represent methyl, ethyl, n-propyl, 2-propyl, n-butyl or tert-butyl and R 4 and R 5 represent hydrogen.
• R 4 and R 5 which may be the same or different, represent methyl, ethyl, n-propyl, 2-propyl, n-butyl or tert-butyl.
• Such a compound of Formula I wherein R 2 , R 3 , R 4 and R 5 , which may be the same or different, represent hydrogen, methyl or ethyl.
• R 1 represents aryl; it being understood that: aryl represents unsubstituted phenyl or phenyl that is mono- or di- substituted with the same or different substituents that are selected from the group consisting of methyl, ethyl, n-propyl, 2-propyl, n-butyl, tert-butyl, hydroxyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, CF 3 , CH 2 F, CH 2 F, C 2 F 5 , OCF 3 , OC 2 F 5 , F, Cl, Br 1 CN, piperidinyl, morpholinyl, tetrazolyl, oxazolyl, furyl, thiophenyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridinyl
• wherein aryl represents unsubstituted phenyl or a phenyl ring that is mono- or di-substituted with the substituent(s) in the meta-position.
• Such a compound of Formula I 1 wherein the substituents are selected from F, CN, pyridinyl, tetrazolyl and unsubstituted phenyl.
• heteroaryl represents pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, oxazol-5-yI, thiazol-5-yl, wherein each of these rings may be unsubstituted or mono or di-substituted with phenyl, methyl, ethyl, n-propyl, 2-propyl, n-butyl, tert-butyl, hydroxyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, CF 3 , CH 2 F, CH 2 F, C 2 F 5 , OCF 3 , OC 2 F 5 , F, Cl, Br, CN, piperidinyl, morpholinyl, tetrazolyl, oxazolyl, furyl, thiophenyl, isoxazolyl, thiazolyl, imidazolyl, oxadia
• Such a compound of Formula I wherein the substituents are selected from F, CN, pyridinyl, tetrazolyl and unsubstituted phenyl.
• R 1 represents aryl or heteroaryl
• R 2 and R 3 which may be the same or different, represent hydrogen or
• R 4 and R 5 which may be the same or different, represent hydrogen or
• Ci -6 alkyl it being understood that:
• aryl represents an unsubstituted phenyl ring or a phenyl ring that is substituted with 1 , 2, 3, 4 or 5 substituents, that may be the same of different, which substituents are selected from the group consisting of
• Ci- 6 alkyl which is optionally substituted with one or more fluorine, chlorine or bromine atoms, Ci- ⁇ alkoxy, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, cycloC 3 -i 2 alkyl, hydroxyl, F, Cl, Br, I, CN, nitro, di-Ci- 6 alkylamino, N-cycloC 3 - 12 alkyl-N- Ci -6 alkylamino, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 4-
• heteroaryl represents a (hetero)aromatic 5-, 6- or 7-membered ring having from 1 to 4 heteroatoms said heteroatoms being independently selected from oxygen, nitrogen and sulfur, wherein said ring is unsubstituted or substituted with 1 , 2 or 3 substituents, that may be the same or different, which substituents are selected from the group consisting of Ci- ⁇ alkyl, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, C-i- ⁇ alkoxy, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, cycloC 3- i 2 alkyl, hydroxyl, F 1 Cl, Br, I, CN, nitro, di-Ci- ⁇ alkylamino, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 4-Ci -6 alkyl-piperazinyl, tetrazolyl, oxazolyl,
• Such a 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), olivoponto-cerebellar atrophy, post-operative cognitive deficit (POCD), Parkinson's disease, Parkinson's dementia, mild cognitive impairment, dementia pugilisitca, 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 glioma and other tumours
• inner ear insult e.g. in tinnitus, sound or drug-induced
• L- dopa-induced and tardive dyskinesias addiction (nicotine, alcohol, opiate, cocaine, amphetamine, obesity and others), anxiety and panic disorders, attention deficit hyperactivity disorder (ADHD), restless leg syndrome and hyperactive children, autism, convulsions / epilepsy, dementia (e.g.
• 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. L-Dopa-induced, tardive dyskinesia or in Huntington's disease), fragile-X syndrome, Huntington's chorea, irritable bowel syndrome (IBS), migraine, multiple sclerosis, muscle spasms, pain (chronic and acute, e.g.
• reflux-related asthma lung disease, eating disorders, obesity and 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 or neuroprotection.
• R 1 represents aryl or heteroaryl
• R 2 and R 3 which may be the same or different, represent hydrogen or Ci- 6 alkyl
• R 4 and R 5 which may be the same or different, represent hydrogen or Ci -6 alkyl
• aryl represents an unsubstituted phenyl ring or a phenyl ring that is substituted with 1 , 2, 3, 4 or 5 substituents, that may be the same of different, which substituents are selected from the group consisting of d- ⁇ alkyl, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, C-i- ⁇ alkoxy, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, cycloC 3 -i 2 alkyl, hydroxyl, F, Cl, Br, I, CN, nitro, di-Ci- 6 alkylamino, N-cycloC 3 --i2alkyl-N- Ci- ⁇ alkylamino, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 4-Ci -6 alkyl-piperazinyl, tetrazolyl, oxazolyl,
• heteroaryl represents a (hetero)aromatic 5-, 6- or 7-membered ring having from 1 to 4 heteroatoms said heteroatoms being independently selected from oxygen, nitrogen and sulfur, wherein said ring is unsubstituted or substituted with 1 , 2 or 3 substituents, that may be the same or different, which substituents are selected from the group consisting of Ci_ 6 alkyl, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, Ci- ⁇ alkoxy, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, cycloC 3 -i 2 alkyl, hydroxyl, F, Cl, Br, I, CN, nitro, di-Ci- 6 alkylamino, N-cycloCs- ⁇ alkyl-N- Ci- ⁇ alkylamino, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 4-Ci- 6 alkyl
• a medicament for the manufacturing of a medicament for the prevention and/or treatment of a condition or disease in an animal including a human being which condition or disease is affected or facilitated by the modulatory effect of Group I mGluRI modulators and in particular of mGluR ⁇ modulators.
• the compounds of Formula I used according to the present invention for the manufacturing of a medicament have been found to be modulators of Group I mGluR receptors.
• these compounds are modulators of mGluR ⁇ receptors.
• one aspect of the present invention is the use of one or more compounds of formula I
• R 1 represents aryl or heteroaryl
• R 2 and R 3 which may be the same or different, represent hydrogen or Ci -6 alkyl
• R 4 and R 5 which may be the same or different, represent hydrogen or Cujalkyl
• aryl represents an unsubstituted phenyl ring or a phenyl ring that is substituted with 1 , 2, 3, 4 or 5 substituents, that may be the same of different, which substituents are selected from the group consisting of 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, cycloC 3 -i2alkyl, hydroxyl, F, Cl, Br, I 1 CN, nitro, di-Ci- 6 alkylamino, N-cycloC 3 -i2alkyl-N- Ci -6 alkylamino, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 4-Ci- 6 alkyl-piperazinyl, tetrazolyl, oxazolyl, furyl, pyrrolyl, thiophenyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridinyl, pyrimidyl and phenyl;
• heteroaryl represents a (hetero)aromatic 5-, 6- or 7-membered ring having from 1 to 4 heteroatoms said heteroatoms being independently selected from oxygen, nitrogen and sulfur, wherein said ring is unsubstituted or substituted with 1, 2 or 3 substituents, that may be the same or different, which substituents are selected from the group consisting of Ci_ 6 alkyl, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, Ci- ⁇ alkoxy, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, cycloC 3 -i 2 alkyl, hydroxyl, F, Cl, Br, I 1 CN, nitro, di-Ci.
• 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), olivoponto-cerebellar atrophy, post-operative cognitive deficit (POCD), Parkinson's disease, Parkinson's dementia, mild cognitive impairment, dementia pugilisitca, vascular and frontal lobe dementia, cognitive impairment, eye injuries or diseases (e.g. glaucoma, retinopathy, macular degeneration), head and spinal cord injuries / trauma, hypoglycaemia, hypoxia (e.g. perinatal), ischaemia
• ALS amyotrophic lateral sclerosis
• MS multiple sclerosis
• POCD post-
• convulsions e.g. resulting from cardiac arrest, stroke, bypass operations or transplants
• convulsions glioma and other tumours
• inner ear insult e.g. in tinnitus, sound or drug-induced
• L-dopa-induced and tardive dyskinesias addiction (nicotine, alcohol, opiate, cocaine, amphetamine, obesity and others), anxiety and panic disorders, attention deficit hyperactivity disorder (ADHD), restless leg syndrome and hyperactive 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.
• Parkinson's disease e.g. adrene-associated bowel syndrome
• IBS irritable bowel syndrome
• 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 e.g., Tourette ' s syndrome
• urinary incontinence and vomiting 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, 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 or neuroprotection.
• Such a medicament wherein the medicament is for the prevention and/or treatment of addiction, neuropathic pain, L-dopa-induced and tardive dyskinesias, ALS, fragile-X syndrome, Parkinson's disease, anxiety disorders, epilepsy, positive and/or negative symptoms of schizophrenia, cognitive impairment, or for cognitive enhancement and neuroprotection.
• composition comprising, together with one or more pharmaceutically acceptable excipients or vehicles, a compound of Formula I
• R 1 represents aryl or heteroaryl
• R 2 and R 3 which may be the same or different, represent hydrogen or Ci. 6 alkyl
• R 4 and R 5 which may be the same or different, represent hydrogen or Ci- 6 alkyl
• aryl represents an unsubstituted phenyl ring or a phenyl ring that is substituted with 1 , 2, 3, 4 or 5 substituents, that may be the same of different, which substituents are selected from the group consisting of Ci- ⁇ alky ⁇ , which is optionally substituted with one or more fluorine, chlorine or bromine atoms, Ci- ⁇ alkoxy, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, cycloC 3 -i 2 alkyl, hydroxyl, F, Cl 1 Br, I 1 CN, nitro, di-Ci- 6 alkylamino, N-cycloC 3 -i2alkyl-N-
• Ci- ⁇ alkylamino azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 4-Ci_ ealkyl-piperazinyl, tetrazolyl, oxazolyl, furyl, pyrrolyl, thiophenyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridinyl, pyrimidyl and phenyl;
• heteroaryl represents a (hetero)aromatic 5-, 6- or 7-membered ring having from 1 to 4 heteroatoms said heteroatoms being independently selected from oxygen, nitrogen and sulfur, wherein said ring is unsubstituted or substituted with 1 , 2 or 3 substituents, that may be the same or different, which substituents are selected from the group consisting of Ci- ⁇ alkyl, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, Ci- ⁇ alkoxy, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, cycloC 3 -i 2 alkyl, hydroxyl, F, Cl, Br, I, CN, nitro, di-Ci- 6 alkylamino, N-cycloCa- ⁇ alkyl-N- Ci- 6 alkylamino, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 4-Ci- 6 alkyl
• 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 Q-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.
• these alkyl groups may optionally be substituted by one or more fluorine, chlorine and/or bromine atoms; examples of these halogenated alkyl moieties include -CF 3 , -C 2 F5, -CBr3, and -CCI 3 .
• Ci- ⁇ alkoxy comprises straight or branched chain -O-Ci- ⁇ alkyl groups wherein "Ci- ⁇ alkyl” is defined as given hereinbefore.
• Examples of “Ci_ 6 alkoxy” include methoxy, ethoxy, n-propoxy, i-propoxy.
• a C-i- ⁇ alkoxy group optionally may be substituted by one or more fluorine, chlorine and/or bromine atoms thereby forming, for instance, -OCF 3 , -OC 2 Fs, -CBr 3 .
• cycloC3-i2 alkyl 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 Ci- ⁇ alkyl groups, that may be the same or different, as defined above.
• di-C-i- ⁇ alkylamino groups include dimethylamino, diethylamino and N-methyl-N-isopropylamino.
• N-cycloC3-i 2 alkyl-N-Ci- 6 alkylamino comprises amino groups in which the nitrogen atom of the amino group is substituted by one C-
• 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.
• the term "(hetero)aromatic 5-, 6- or 7-membered ring” refers to heterocyclic rings having up to 4 oxygen, nitrogen and/or sulfur atoms in the ring that comprises 5, 6 or 7 carbon and hetero atoms, said heterocyclic ring being an aromatic ring system.
• Examples of such (hetero)aromatic 5-, 6- or 7-membered rings 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.
• analog or “derivative” is used herein in the conventional pharmaceutical sense, to refer to a molecule that structurally resembles a reference molecule (such as 7,8-dihydro-6H-quinolin-5-one), but has been modified in a targeted and controlled manner to replace one or more specific substituents of the referent 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 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.
• pharmaceutically acceptable 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).
• the term "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.
• DMF N,N-dimethylformamide
• HCI hydrochloric acid
• DMSO dimethylsulfoxide
• TMS tetramethylsilane
• 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 stereoisomers form of appropriate starting materials, provided that the reaction occurs stereoselective ⁇ .
• Stereoisomer ' ⁇ 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, more broadly, 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, or 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, preferably concurrently, simultaneously, or together with one or more pharmaceutically-acceptable excipients, carriers, or diluents, especially and preferably 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, preferably 10-500 milligrams daily, and especially 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 a
• binding agents e.g., pregelatinized maize
• 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.
• the tablets can be coated by methods well known in the art.
• the 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 polyvinylpyrrolidone, 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 (i.m.), 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).
• the 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 and/or may contain different dosage levels to facilitate dosage titration.
• 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 50 ZLD 50 .
• 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:
• 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:
• EXAMPLE 5 Liquid oral formulation 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:
• Another suitable formulation for 1 liter of a liquid mixture containing 20 milligrams of active ingredient in one milliliter of the mixture is as follows:
• Aerosol formulation 18O g aerosol solution contain:
• TDS formulation lution contain:
• Nanoparticle formulation 10 g of polybutylcyanoacrylate nanoparticles contain: Active Ingredient 1.00
• 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.
• rat cortical membranes [00173] Male Sprague-Dawley rats (200-250 g) are decapitated and their brains are removed rapidly. The cortex is dissected and homogenized in 20 volumes of ice-cold 0.32 M sucrose using a glass-Teflon homogenizer. The homogenate is centrifuged at 1000xg for 10 min. The pellet is discarded and the supernatant centrifuged at 20,000xg for 20 min. The resulting pellet is re- suspended in 20 volumes of distilled water and centrifuged for 20 min at 8000xg.
• the supernatant and the buffy coat are centrifuged at 48,000xg for 20 min in the presence of 50 mM Tris-HCI, pH 8.0.
• 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°C. After resuspension in 5 volumes of 50 mM Tris-HCI, pH 8.0 the membrane suspension is frozen rapidly at -80°C.
• 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 was achieved under the conditions used). Non-specific binding is defined by the addition of unlabeled MPEP (10 ⁇ M). Incubations are terminated using a Millipore 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). Characterization
• astrocyte cultures were prepared from cortices of newborn rats as described by Booher and Sensenbrenner (1972). Briefly, Sprague-Dawley rat pups (2 - 4 d old) were decapitated and neocortices were dissected, disintegrated with a nylon filter (poresize 80 ⁇ m) and carefully triturated.
• the cell suspension was 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 (FCSj, Sigma), 4 mM glutamine (Biochrom) and 50 ⁇ g/mL gentamycin (Biochrom) at 37 0 C in a humidified atmosphere of 5% CO 2 /95% air for 7 d with exchanging the medium at day 2.
• DMEM Dulbecco's Modified Eagle's Medium
• FCSj heat inactivated fetal calf serum
• Biochrom fetal calf serum
• Biochrom 50 ⁇ g/mL gentamycin
• 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 was exchanged and the cells incubated for another 2-3 d, so that at the time of experiments astrocytes were 14-15 DIV.
• the 96 well plates can be frozen at -2O 0 C at this stage until further analysis.
• Home made resin exchange columns AG1-X8 Biorad, 140-14444
• Scintillation liquid UltimaFlow AF, Perkin Elmer
• the medium Prior to addition of agonist or antagonist the medium was aspirated and cells were loaded for 2 h at RT with 150 ⁇ l_ of loading buffer consisting of Ca- sensitive dye (MD # R8033) reconstituted in sodium chloride (123 nriM), potassium chloride (5.4 nriM), magnesium chloride (0.8 ⁇ TIM), calcium chloride (1.8 mM), D-glucose (15 nriM), and HEPES (20 mM), pH 7.3. Subsequently, plates were 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 were tested, these compounds were pre-incubated for 10 min at RT before addition of the respective agonist.
• Ca- sensitive dye MD # R8033
• concentration-response curves for quisqualate were 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 were performed in the presence of a fixed concentration of quisqualate showing the biggest window for potentiation (normally 10-30 nM).
• the fluorescence signal increase after addition of agonist reflects the increase of intracellular calcium. Inconsistencies in the amount of cells per well were normalised by using the spatial uniformity correction of the
• Compounds of the present invention have an EC50 range of about 0.5 nM to about 100 ⁇ M.
• the present invention provides novel, valuable, and unpredictable applications and uses of the compounds of the present invention, which compounds comprise the active principle according to the present invention, as well as novel pharmaceutical compositions thereof and methods of preparation thereof and of treating therewith, all possessed of the foregoing more specifically- enumerated characteristics and advantages.
• 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 pugilisitca, vascular and frontal lobe dementia, cognitive impairment, eye injuries or diseases (e.g.
• ALS amyotrophic lateral sclerosis
• MS multiple sclerosis
• POCD post-operative cognitive deficit
• Parkinson's disease Parkinson's dementia
• mild cognitive impairment dementia pugilisitca
• 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
• 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. reflux-related asthma), lung disease, eating disorders, obesity and obesity-related disorders.
• 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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