AU2006283359B2 - Tetrahydroquinolinones and their use as modulators of metabotropic glutamate receptors - Google Patents
Tetrahydroquinolinones and their use as modulators of metabotropic glutamate receptors Download PDFInfo
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- quinolin
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- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Description
WO 2007/023290 PCT/GB2006/003170 TETRAHYDROQUINOLINONES AND THEIR USE AS MODULATORS OF METABOTROPIC GLUTAMATE RECEPTORS FIELD OF THE INVENTION 5 [0001] 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. 10 BACKGROUND OF THE INVENTION [0002] 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. 15 [0003] 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 20 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. 25 [0004] At present, eight different members of these mGluRs are known. On the basis of structural parameters such as sequence homology, the second messenger system utilized by these receptors and their different affinity to low-molecular weight compounds, these eight receptors can be divided into three groups: mGluR1 and mGluR5 belong to group I which couple to 30 phospholipase C and their activation leads to intracellular calcium-ion mobilization. Both mGluR2 and mGluR3 belong to group 11 and mGluR4, mGluR6, mGluR7 and mGluR8 belong to group Ill, which couple to adenyl 1 WO 2007/023290 PCT/GB2006/003170 cyclase with their activation causing a reduction in second messenger cAMP and as such a dampening of the neuronal activity. [0005] Group I mGluR modulators have been shown to modulate the effects of 5 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 10 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. 15 [0006] Therefore, 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 B-amyloid and/or 20 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 25 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 (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 30 dopa-induced and tardive dyskinesias. [0007] Other indications in this context include a symptomatological effect on the following conditions: addiction (nicotine, alcohol, opiate, cocaine, 2 WO 2007/023290 PCT/GB2006/003170 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 5 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), fragile-X syndrome, Huntington's chorea, irritable bowel syndrome 10 (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 and vomiting, pruritic conditions (e.g. pruritis), sleep 15 disorders, micturition disorders, neuromuscular disorder in the lower urinary tract, gastroesophageal reflux disease (GERD), lower esophageal sphincter (LES), 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 20 related disorders. [0008] Yet further 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 25 administration of the instant compounds, for example cognitive enhancement. [0009] 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. 30 [0010]Among the Group I 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 3 particular interest. In addition to the utility of mGIuR5 modulators in preventing and/or treating the conditions and/or diseases mentioned above, mGluR5 positive modulators or agonists may be particularly useful for preventing and/or treating conditions or diseases that are associated with an insufficient stimulation or activity of 5 mGluR5 receptors. mGIuR5 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 10 neuroprotection. The discussion of the background to the invention herein is included to explain the context of the invention. This is not to be taken as an admission that any of the material referred to was published, known or part of the common general knowledge in Australia as at the priority date of any of the claims. 15 Throughout the description and claims of this specification, the word "comprise" and variations of the word, such as "comprising" and "comprises", is not intended to exclude other additives, components, integers or steps. THE PRESENT INVENTION 20 [0011] We have determined that certain ethynyl-substituted tetrahydroquinolones within the genus of compounds disclosed in our copending International Patent Application No. PCT/GB2005/000717 are Group I mGluR modulators and in particular mGluR5 modulators. Therefore, these substances may be therapeutically beneficial in the treatment of conditions which involve abnormal glutamate neurotransmission or in 25 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. 30 ASPECTS OF THE INVENTION [0012] It is one aspect of the present invention to provide novel pharmaceutical compounds which are tetrahydroquinolone Group I mGluR modulators and pharmaceutical compositions thereof. It is a further aspect of the invention to provide a novel method of treating, eliminating, alleviating, palliating, or ameliorating 35 undesirable CNS disorders which involve abnormal glutamate neurotransmission by W:jFCA818855\1M55 Specie 301107.doc A employing a compound of the invention or a pharmaceutical composition containing the same. An additional aspect of the invention is the provision of a process for producing the tetrahydroquinolone active principles. Yet additional aspects will become apparent hereinafter, and still further aspects will be apparent to one skilled in 5 the art. SUMMARY OF THE INVENTION [0013] What we therefore believe to be comprised by our invention may be summarized inter alia in the following words: 10 [0014] A compound of Formula I R2 O
R
3 R4 RS N ReR wherein R1 represents aryl or heteroaryl;
R
2 and R 3 , which may be the same or different, represent hydrogen or C 1 . 15 6 alkyl;
R
4 and R 5 , which may be the same or different, represent hydrogen or C 1 6 alkyl; it being understood that: aryl represents an unsubstituted phenyl ring or a phenyl ring that is substituted 20 with 1, 2, 3, 4 or 5 substituents, that may be the same of different, which substituents are selected from the group consisting of C 1
-
6 alkyl, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, C 1 . 6 alkoxy, which is optionally substituted W:UFO\816855\818855 Specie 301107 doc WO 2007/023290 PCT/GB2006/003170 with one or more fluorine, chlorine or bromine atoms, cycloC 3
-
12 alkyl, hydroxyl, F, CI, Br, 1, CN, nitro, di-C 1
.
6 alkylamino, N-cycloC 3 -1 2 alkyl-N-C1-6alkylamino, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 4-C 1
.
6 alkyl-piperazinyl, tetrazolyl, oxazolyl, furyl, pyrrolyl, 5 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 10 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 C 1
.
6 alkyl, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, C1.
6 alkoxy, which is optionally 15 substituted with one or more fluorine, chlorine or bromine atoms, cycloC 3
-
1 2 alkyl, hydroxyl, F, Cl, Br, I, CN, nitro, di-C 1 .alkylamino, N-cycloC 3
-
1 2 alkyl-N- C1.ealkylamino, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 4-C 1
.
6 alkyl-piperazinyl, tetrazolyl, oxazolyl, furyl, pyrrolyl, thiophenyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridinyl, 20 pyrimidyl and phenyl; and that the compounds of Formula I may not represent: 2-Phenylethynyl-7,8-dihydro-6H-quinolin-5-one 25 2-Pyridin-3-ylethynyl-7,8-dihydro-6H-quinolin-5-one 2-m-Tolylethynyl-7,8-dihydro-6H-quinolin-5-one 2-(3-Hydroxy-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one 2-(3-Methoxy-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one 2-(3-Fluoro-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one 30 2-(3-Chloro-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one 2-(3-Bromo-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one 3-(5-Oxo-5,6,7,8-tetrahydro-quinolin-2-ylethynyl)-benzonitrile 2-Thiazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one 6 WO 2007/023290 PCT/GB2006/003170 2-Oxazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one 7,7-Dimethyl-2-pyridin-3-ylethynyl-7,8-dihydro-6H-quinolin-5-one 7,7-Dimethyl-2-m-tolylethynyl-7,8-dihydro-6H-quinolin-5-one 2-(3-Hydroxy-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5 5 one 2-(3-Methoxy-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5 one 2-(3-Fluoro-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 2-(3-Chloro-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 10 2-(3-Bromo-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 3-(7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydro-quinolin-2-ylethynyl) benzonitrile 7,7-Dimethyl-2-thiazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one 7,7-Dimethyl-2-oxazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one 15 2-(2-Pheny-oxazol-5-yethynyl)-7,8-dihydro-6H-quinolin-5-one or 2-(2-Phenyl-thiazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one; and optical isomers, pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof. 20 [0015] Such a compound of Formula 1, wherein
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 25 R 4 and R 5 represent hydrogen. [0016] Such a compound of Formula I, wherein
R
2 and R 3 represent hydrogen and
R
4 and R , which may be the same or different, represent methyl, ethyl, 30 n-propyl, 2-propyl, n-butyl or tert-butyl. [0017] Such a compound of Formula 1, wherein 7 WO 2007/023290 PCT/GB2006/003170
R
2 , R 3 , R 4 and R 5 , which may be the same or different, represent hydrogen, methyl or ethyl. [0018] Such a compound of Formula I, wherein 5 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, 10 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, oxadiazolyl, pyridinyl, pyrimidyl and phenyl. 15 [0019] Such a compound of Formula I, wherein aryl represents unsubstituted phenyl or a phenyl ring that is mono- or di-substituted with the substituent(s) in the meta-position. [0020] Such a compound of Formula I, wherein the phenyl ring is di 20 substituted in the meta-position and the substituents are different. [0021] Such a compound of Formula 1, wherein the substituents are selected from F, CN, pyridinyl, tetrazolyl and unsubstituted phenyl. 25 [0022] Such a compound of Formula 1, wherein
R
1 represents heteroaryl; it being understood that: 30 heteroaryl represents pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, oxazol-5-yl, 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, 8 WO 2007/023290 PCT/GB2006/003170 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, oxadiazolyl, pyridinyl or pyrimidyl. 5 [0023] Such a compound of Formula I, wherein heteroaryl represents unsubstituted heteroaryl or an heteroaryl ring that is mono- or di-substituted with the substituent(s) in the meta-position. [0024] Such a compound of Formula 1, wherein the heteroaryl ring is di 10 substituted in the meta-position and the substituents are different. [0025] Such a compound of Formula 1, wherein the substituents are selected from F, CN, pyridinyl, tetrazolyl and unsubstituted phenyl. 15 [0026] Moreover, a method-of-treating a living animal, including a human, for a condition or a disease associated with abnormal glutamate neurotransmission or in which modulation of Group I mGluR receptors results in therapeutic benefit comprising the step of administering to the living animal, including a human, an amount of a Group I mGluR modulator selected from 20 those of Formula I R 2 O R3 R R5 N R4 wherein 25 R 1 represents aryl or heteroaryl;
R
2 and R 3 , which may be the same or different, represent hydrogen or
C
1
.
6 alkyl;
R
4 and R , which may be the same or different, represent hydrogen or
C
1
.
6 alkyl; 9 WO 2007/023290 PCT/GB2006/003170 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 5 different, which substituents are selected from the group consisting of C1.
6 alkyl, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, C1.
6 alkoxy, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, cycloC 3
-
12 alkyl, hydroxyl, F, Cl, Br, I, CN, nitro, di-CI.
6 alkylamino, N-cycloC 3
-
12 alkyl-N 10 C1.
6 alkylamino, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 4 C1.6alkyl-piperazinyl, tetrazolyl, oxazolyl, furyl, pyrrolyl, thiophenyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridinyl, pyrimidyl and phenyl; 15 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 20 consisting of C1.6alkyl, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, C1.alkoxy, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, cycloC 3
-
12 alkyl, hydroxyl, F, Cl, Br, I, CN, nitro, di-C1.
6 alkylamino, N-cycloC 3 -1 2 alkyl-N- C1.6alkylamino, azetidinyl, pyrrolidinyl, piperidinyl, 25 morpholinyl, 4-C1.6alkyl-piperazinyl, tetrazolyl, oxazolyl, furyl, pyrrolyl, thiophenyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridinyl, pyrimidyl and phenyl; and optical isomers, pharmaceutically acceptable salts, hydrates, 30 solvates, and polymorphs thereof; which is effective for alleviation of the condition or disease or for enhancing cognition. 10 WO 2007/023290 PCT/GB2006/003170 [0027] 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, 5 Alzheimer's disease, Creutzfeld-Jakob's syndrome, bovine spongiform encephalopathy (BSE) or other prion related infections, diseases involving mitochondrial dysfunction, diseases involving B-amyloid and/or tauopathy such as Down's syndrome, hepatic encephalopathy, Huntington's disease, motor neuron diseases such as amyotrophic lateral sclerosis (ALS), multiple 10 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, 15 hypoglycaemia, hypoxia (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, 20 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 25 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. inflammatory pain, neuropathic pain, allodynia, hyperalgesia, nociceptive pain), Parkinson's 30 disease, post traumatic stress disorder, schizophrenia (positive and negative symptoms), spasticity, Tourette's syndrome, urinary incontinence and vomiting, pruritic conditions (e.g. pruritis), sleep disorders, micturition disorders, neuromuscular disorder in the lower urinary tract, 11 gastroesophageal reflux disease (GERD), lower esophageal sphincter (LES), 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, agoraphobia, 5 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. 10 [0028] Such a method wherein the compound is administered in the form of a pharmaceutical composition thereof comprising the compound of Formula I in combination with one or more pharmaceutically-acceptable diluents, excipients, or carriers. 15 Further, a medicament comprising at least one of the compounds of Formula I R2 O R 3
R
5 NR wherein
R
1 represents aryl or heteroaryl; 20
R
2 and R 3 , which may be the same or different, represent hydrogen or C1. 6 alkyl;
R
4 and R , which may be the same or different, represent hydrogen or C1. 25 6 alkyl; it being understood that: aryl represents an unsubstituted phenyl ring or a phenyl ring that is substituted 30 with 1, 2, 3, 4 or 5 substituents, that may be the same of different, which substituents are selected from the group consisting of C 1 .6alkyl, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, C1. 6 alkoxy, which is optionally substituted with one or more fluorine, chlorine or W:UFO8I85516855 Spece 301107.doc 1 ) bromine atoms, cycloC 3
.
12 alkyl, hydroxyl, F, CI, Br, I, CN, nitro, di-C 1 . 6 alkylamino, N-cycIoC 3 -1 2 alkyl-N- C 1
.
6 alkylamino, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 4-C 1
.
6 alkyl-piperazinyl, tetrazolyl, oxazolyl, furyl, pyrrolyl, thiophenyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridinyl, 5 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 10 with 1, 2 or 3 substituents, that may be the same or different, which substituents are selected from the group consisting of C 1 .ealkyl, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, C1. 6 alkoxy, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, cycloC 1
-
12 alkyl, hydroxyl, F, Cl, Br, I, CN, nitro, di-C 1 . 15 ralkylamino, N-cycloC 3
.
12 alkyl-N-C 1
.
6 alkylamino, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 4-C 1 .alkyl-piperazinyl, tetrazolyl, oxazolyl, furyl, pyrrolyl, thiophenyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridinyl, pyrimidyl and phenyl; 20 and optical isomers, pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof; with the exception of the following compounds and optical isomers, pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof: 25 2-Phenylethynyl-7,8-dihydro-6H-quinolin-5-one 2-Pyridin-3-ylethynyl-7,8-dihydro-6H-quinolin-5-one 2-m-Tolylethynyl-7,8-dihydro-6H-quinolin-5-one 2-(3-Hydroxy-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one 2-(3-Methoxy-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one 30 2-(3-Fluoro-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one 2-(3-Chloro-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one 2-(3-Bromo-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one 3-(5-Oxo-5,6,7,8-tetrahydro-quinolin-2-ylethynyl)-benzonitrile 2-Thiazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one 35 2-Oxazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one 7,7-Dimethyl-2-pyridin-3-ylethynyl-7,8-dihydro-6H-quinolin-5-one 7,7-Dimethyl-2-m-tolylethynyl-7,8-dihydro-6H-quinolin-5-one WUFO\816855\86855 Specie 301107 doc 1 9' 2-(3-Hydroxy-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5- one 2-(3-Methoxy-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5- one 2-(3-Fluoro-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 2-(3-Chloro-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 5 2-(3-Bromo-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 3-(7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydro-quinolin-2-ylethynyl)-benzonitrile 7,7-Dimethyl-2-thiazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one 7,7-Dimethyl-2-oxazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one 2-(2-Phenyl-oxazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one and 10 2-(2-Phenyl-thiazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one. [0029] Further, the use of at least one compound of Formula I R2 O R 3 R N wherein 15
R
1 represents aryl or heteroaryl;
R
2 and R 3 , which may be the same or different, represent hydrogen or C 1 . 6 alkyl; 20
R
4 and R 5 , which may be the same or different, represent hydrogen or C 1 . 6 alkyl; it being understood that: 25 WJFA8185586855 Specie 301107.doc WO 2007/023290 PCT/GB2006/003170 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 5 C1.
6 alkyl, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, C 1
.
6 alkoxy, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, cycloC 3
-
12 alkyl, hydroxyl, F, Cl, Br, I, CN, nitro, di-C1.
6 alkylamino, N-cycloC 3
-
12 alkyl-N
C
1
.
6 alkylamino, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 4-C1.6 10 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 15 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 C 1
.
6 alkyl, which is optionally substituted with one or more 20 fluorine, chlorine or bromine atoms, C 1
.
6 alkoxy, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, cycloC 3 -12alkyl, hydroxyl, F, Cl, Br, I, CN, nitro, di-C 1 .ealkylamino, N-cycIoC3- 12 alkyl-N- C1.
6 alkylamino, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 4-C 1
.
6 alkyl-piperazinyl, tetrazolyl, oxazolyl, furyl, pyrrolyl, 25 thiophenyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridinyl, pyrimidyl and phenyl; and optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof; 30 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 13 WO 2007/023290 PCT/GB2006/003170 modulatory effect of Group I mGluR1 modulators and in particular of mGluR5 modulators. [0030] The compounds of Formula I used according to the present invention 5 for the manufacturing of a medicament have been found to be modulators of Group I mGIuR receptors. In particular, these compounds are modulators of mGluR5 receptors. Surprisingly it has been found that they show at least partially agonistic or positive modulatory effects on the mGluR5 receptors. 10 [0031] Consequently, one aspect of the present invention is the use of one or more compounds of formula I R2 O R 3 R R N R wherein 15
R
1 represents aryl or heteroaryl;
R
2 and R 3 , which may be the same or different, represent hydrogen or C1.
6 alkyl; 20
R
4 and R , which may be the same or different, represent hydrogen or
C
1
.
6 alkyl; it being understood that: 25 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
C
1
.
6 alkyl, which is optionally substituted with one or more fluorine, 14 WO 2007/023290 PCT/GB2006/003170 chlorine or bromine atoms, C 1
.
6 alkoxy, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, cycloC 3
-
12 alkyl, hydroxyl, F, Cl, Br, I, CN, nitro, di-C.
6 alkylamino, N-cycloC 3 -1 2 alkyl-N
C
1 .alkylamino, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 4-C1-6 5 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 10 having from I 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 C 1
.
6 alkyl, which is optionally substituted with one or more 15 fluorine, chlorine or bromine atoms, C 1
.
6 alkoxy, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, cycloC 3
-
1 2 alkyl, hydroxyl, F, Cl, Br, I, CN, nitro, di-C 1
.
6 alkylamino, N-cycloC 3
-
1 2 alkyl-N-C1.
6 alkylamino, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 4 -C1.
6 alkyl-piperazinyl, tetrazolyl, oxazolyl, furyl, pyrrolyl, 20 thiophenyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridinyl, pyrimidyl and phenyl; and optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof; 25 for the manufacturing of a medicament for the prevention and/or treatment of AIDS-related dementia, Alzheimer's disease, Creutzfeld Jakob's syndrome, bovine spongiform encephalopathy (BSE) or other prion related infections, diseases involving mitochondrial dysfunction, 30 diseases involving R-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 15 WO 2007/023290 PCT/GB2006/003170 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 5 injuries / trauma, hypoglycaemia, hypoxia (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, 10 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 15 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), fragile-X syndrome, Huntington's chorea, irritable bowel syndrome (IBS), migraine, multiple sclerosis, muscle spasms, pain 20 (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, Tourette's syndrome, urinary incontinence and vomiting, pruritic conditions (e.g. pruritis), sleep disorders, micturition disorders, 25 neuromuscular disorder in the lower urinary tract, gastroesophageal reflux disease (GERD), lower esophageal sphincter (LES), 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 30 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 16 WO 2007/023290 PCT/GB2006/003170 psychotic disorder, delirium, or for cognitive enhancement or neuroprotection. [0032] Such a medicament wherein the medicament is for the prevention 5 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. 10 [0033] Further, a pharmaceutical composition comprising, together with one or more pharmaceutically acceptable excipients or vehicles, a compound of Formula I 2 O R 15 wherein R1 represents aryl or heteroaryl; 20 R 2 and R 3 , which may be the same or different, represent hydrogen or
C
1
.
6 alkyl;
R
4 and R 5 , which may be the same or different, represent hydrogen or
C
1
.
6 alkyl; 25 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 17 WO 2007/023290 PCT/GB2006/003170 different, which substituents are selected from the group consisting of
C
1
.
6 alkyl, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, C 1
.
6 alkoxy, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, cycloC 3 -1 2 alkyl, 5 hydroxyl, F, Cl, Br, I, CN, nitro, di-C 1 .alkylamino, N-cycloC 3
-
1 2 alkyl-N C1.
6 alkylamino, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 4-C1 6 alkyl-piperazinyl, tetrazolyl, oxazolyl, furyl, pyrrolyl, thiophenyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridinyl, pyrimidyl and phenyl; 10 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 15 same or different, which substituents are selected from the group consisting of C 1
.
6 alkyl, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, C 1
.
6 alkoxy, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, cycloC3-1 2 alkyl, hydroxyl, F, Cl, Br, I, CN, nitro, di-C 1 .alkylamino, 20 N-cycloC3-1 2 alkyl-N- C 1
.
6 alkylamino, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 4-C1.
6 alkyl-piperazinyl, tetrazolyl, oxazolyl, furyl, pyrrolyl, thiophenyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridinyl, pyrimidyl and phenyl; 25 and that the compounds of Formula I may not represent: 2-Phenylethynyl-7,8-dihydro-6H-quinolin-5-one 2-Pyridin-3-ylethynyl-7,8-dihydro-6H-quinolin-5-one 2-m-Tolylethynyl-7,8-dihydro-6H-quinolin-5-one 30 2-(3-Hydroxy-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one 2-(3-Methoxy-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one 2-(3-Fluoro-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one 2-(3-Chloro-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one 18 WO 2007/023290 PCT/GB2006/003170 2-(3-Bromo-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one 3-(5-Oxo-5,6,7,8-tetrahydro-quinolin-2-ylethynyl)-benzonitrile 2-Thiazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one 2-Oxazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one 5 7,7-Dimethyl-2-pyridin-3-ylethynyl-7,8-dihydro-6H-quinolin-5-one 7,7-Dimethyl-2-m-tolylethynyl-7,8-dihydro-6H-quinolin-5-one 2-(3-Hydroxy-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5 one 2-(3-Methoxy-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5 10 one 2-(3-Fluoro-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 2-(3-Chloro-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 2-(3-Bromo-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 3-(7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydro-quinolin-2-ylethynyl) 15 benzonitrile 7,7-Dimethyl-2-thiazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one 7,7-Dimethyl-2-oxazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one 2-(2-Phenyl-oxazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one or 2-(2-Phenyl-thiazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one; 20 and optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof. [0034] Specific compounds of Formula I within the present invention include 25 but are not limited to: 6,6-Dimethyl-2-pyridin-3-ylethynyl-7,8-dihydro-6H-quinolin-5-one 2-(3-Fluoro-phenylethynyl)-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one 2-(3-Chloro-phenylethynyl)-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one 2-(3-Methoxy-phenylethynyl)-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one 30 2-(3-Hydroxy-phenylethynyl)-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one 3-(6,6-Dimethyl-5-oxo-5,6,7,8-tetrahydro-quinolin-2-yiethynyl)-benzonitrile 6,6-Dimethyl-2-thiazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one 6,6-Dimethyl-2-(3-piperidin-1 -yl-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one 19 WO 2007/023290 PCT/GB2006/003170 7,7-Dimethyl-2-(3-piperidifl-1 -yi-phenylethynyI)-7,8-dihydro-6H-quiflif-5-one 2-(3-Piperidin-1 -yI-phenylethynyl)-7,8-dihydro-6H-quinolil-5-Qfle 2-3M rhln4y-hnltyyl-,-iyr-Hqioi--n 7,-iehl2(-opoi--ipeyltyy)78dhdo6-unln5 5 one 6,-iehl2(-opoi--ipeyltyy)78dhdo6-unln5 one 6,6-Dimethyl-2-13-( I H-tetrazoI-5-yI)-phenylethynyI]-7,8-dihydro-6H-quilifl-5 one 10 7,7-Dimethyl-2-[3-( I H-tetrazol-5-yI)-phenylethynyl]-7 ,8-di hydro-6H-quinolin-5 one 2-[3-(lI H-Tetrazol-5-yI)-phenylethynyll-7 ,8-dihydro-6H-quinolin-5-one 2-[3-Fluoro-5-( I H-tetrazol-5-yl)-phenylethynyl]-6 ,6-dimethyl-7 ,8-dihyd ro-6H quinolin-5-one 15 2-[3-FI uoro-5-( I H-tetrazol-5-yI)-phenylethynyl]-7 ,7-dimethyl-7,8-dihydro-6H quinolin-5-one 2-[3-Fluoro-5-( I H-tetrazoI-5-yI)-phenylethyny]-7,8-dihydro-6H-quilil-5-oflO 2-(3-TrifluoromethyI-phenylethyny)-7,8-dihydro-6H-quilifl-5-ofle 7,7Dmty -3tilooehlpeyltyy)78dhdo6-unln5 20 one 6 ,6-Di methyI-2-(3-trifluoromethyI-phenylethyny)-7,8-dihydro-6H-quinolin-5 one 7,7-DimethyI-2-phenylethyny-7,8-dihydro-6H-quinolin-5-ofle 6,6-DimethyI-2-phenylethynyl-7,8-dihydro-6H-quinolin-5-one 25 2-(4-Methyl-thiazol-2-ylethynyl )-7 ,8-dihyd ro-6 H-quinolin-5-one 7 ,7-Dimethyl-2-(4-methyl-thiazol-2-ylethynyl)-7 ,8-dihydro-6H-quinolin-5-one 6 ,6-Di methyl-2-(4-methyl-thiazol-2- ylethynyl )-7 ,8-dihyd ro-6H-quinolin-5-one 2.-(4-Fluoro-thiazoI-2-ylethynyI)-7,8-dihydro-6H-quinoifl-5-one 2-(4-Fluoro-thiazol-2-ylethynyl)-7, 7-dimethyl-7,8-dihydro-6H-quinolin-5-one 30 2-(4-Fluoro-thiazol-2-ylethynyl)-6, 6-dimethyl-7,8-dihydro-6H-quinolin-5-one 2-(2-Phenyl-thiazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one 2-(5-Fluoro-pyridin-3-ylethynyl)-7,8-dihydro-6H-quinolin-5-one 20 WO 2007/023290 PCT/GB2006/003170 3-loo5(,-iehl5oo567,-erhdoqioi--ltyy) benzonitrile 2-4Fu r--h nlo a o--ltyn l-,-iy r-Hq ioi--n 2-4Fu r--yii--io a o--leh n l-,-iy r-H q ioi--n 5 2-(4-Fluoro-5-pyridifl-3-yI-oxazo-2-yethyfyly)-7,7dimethy-7 ,8-dihydro-6H quinolin-5-one 2-(4-Fluoro-5-pyridin-3-y-oxazoI-2-yiethyfl)-6 ,6-dimethyl-7,8-dihyd ro-6H quinolin-5-one 7,7-Dimethyl-2-pyridin-2-ylethylyl-7 ,8-dihydro-6H-quinolifl-5-ofle 10 2-Pyridin-2-yIethynyI-7,8-dihydro-6H-luilifl-5-ofle 6,6-Dimethyl-2-pyridin-2-ylethylyl-7 ,8-dihydro-6H-quinolin-5-ofle 6,6-Dimethyl-2-(4-methyl-oxazQI-2-ylethYfl)-7 ,8-dihydro-6H-quinolin-5-one 7,-ieh l2(- eh lo a o--ith n l-,-iy r-H q ioi--n 2-(4-Fluoro-5-pyridin-3-yi-1 H-i mid azol-2-ylethynyl)-7 ,8-d ihyd ro-6H-q u inol in-5 15 one 2-(4-Fluoro-5-pyridin-3-y-1 H-imidazol-2-ylethynyl)-7 ,7-dimethyl-7 ,8-dihydro 6H-quinolin-5-one 2-(4-Fluoro-5-pyridin-3-yi- I H-imidazoI-2-ylethynyI)-6,6-dimethyI-7,8-dihydro 6H-quinolin-5-one 20 6,6-Dimethyl-2-(4-pyridin-3-y-imidazoI-1 -yIethynyI)-7,8-dihydro-6H-quilifl-5 one 7,7-Dimethyl-2-(4-pyridin-3-y-imidazot-1 -ylethynyl)-7,8-dihydro-6H-qu inolin-5 one 2-(4-Pyridin-3-yI-imidazo-1 -ylethynyI)-7,8-dihydro-6H-quilifl-5-ofle 25 2-hao--ltyy-,-iy r-Hq ioi--n 2-[1 ,3,4]Thiadiazo-2-yIethyny-7,8-dihydro-6H-quilif-5-ofle 2-[1 ,3,4]Oxadiazo-2-ylethynyl-7,8-dihydro-6H-quilifl-5-ofle 2-( I H-Tetrazol-5-ylethynyl)-7 ,8-dihydro-6H-quinolin-5-ofle 6,6-Dimethyl-2-I1 ,3,4]thiadiazo-2-ylethyl-7,8-dihydro-6H-quilifl-5-ofle 30 7,7-Dimethyl-2-[1 ,3,4]thiadiazo-2-yIethyl-7,8-dihydro-6H-quilifl-5-ofle 7,7-Dimethyl-2-( I H-tetrazol-5-ylethyflyl)-7 ,8-dihydro-6H-quinoli n-S-one 6,6-Dimethyl-2-(1 H-tetrazoI-5-ylethynyI)-7,8-dihydro-6H-quinolin-5-one 6,6-Dimethyl-2-oxazol-5-ylethyflyl-7 ,8-dihydro-6H-quinolin-5-one 21 WO 2007/023290 PCT/GB2006/003170 2-Oxazol-2-ylethynyl-7,8-dihydro-6H-quinolin-5-one 6,6-Dimethyl-2-oxazol-2-yIethynyl-7,8-dihydro-6H-quinolin-5-one 7,7-Dimethyl-2-oxazol-2-yIethynyl-7,8-dihydro-6H-quinolin-5-one *6,6-Dimethyl-2-m-tolylethynyl-7,8-dihydro-6H-quinolin-5-one 5 7,7-Dimethyl-2-(2-phenyl-oxazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one 6,6-Dimethyl-2-(2-phenyl-oxazol-5-yethynyl)-7,8-dihydro-6H-quinolin-5-one 7,7-Dimethyl-2-(5-phenyl-thiazol-2-yethynyl)-7,8-dihydro-6H-quinolin-5-one 6,6-Dimethyl-2-(5-phenyl-thiazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5-one 2-(5-Fluoro-pyridin-3-ylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 10 2-(5-Fluoro-pyridin-3-ylethynyl)-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one 3-Fluoro-5-(5-oxo-5,6,7,8-tetrahydro-quinolin-2-yethynyl)-benzonitrile 3-(6,6-Dimethyl-5-oxo-5,6,7,8-tetrahydro-quinolin-2-ylethynyl)-5-fluoro benzonitrile 2-(4-Fluoro-5-phenyl-oxazol-2-yethynyl)-7,7-dimethyl-7,8-dihydro-6H 15 quinolin-5-one 2-(4-Fluoro-5-pheny-oxazol-2-yethynyl)-6,6-dimethyl-7,8-dihydro-6H quinolin-5-one 6,6-Dimethyl-2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-ylethynyl)-7,8-dihydro-6H quinolin-5-one 20 7,7-Dimethyl-2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-ylethynyl)-7,8-dihydro-6H quinolin-5-one 2-(5-Pyridin-3-yl-[1,3,4]oxadiazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5-one and optical isomers, pharmaceutically acceptable salts, hydrates, solvates, 25 and polymorphs thereof. DETAILED DESCRIPTION OF THE INVENTION [0035] For the purpose of the present invention, the carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating 30 the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix Ci.j indicates a moiety of the integer "i" to the integer "j" carbon atoms, inclusive. Thus, for example, (C 1
.
3 )alkyl refers to alkyl of one to three carbon 22 WO 2007/023290 PCT/GB2006/003170 atoms, inclusive, (i.e., methyl, ethyl, propyl, and isopropyl), straight and branched forms thereof. [0036] As used herein, the term "C 1
.
6 alkyl" comprises straight or branched 5 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; examples of these halogenated alkyl moieties include -CF 3 , -C 2
F
5 , -CBr 3 , and -CC13. The term 10 "C 1
.
6 alkoxy" comprises straight or branched chain -O-C 1
.
6 alkyl groups wherein "C 1
.
6 alkyl" is defined as given hereinbefore. Examples of "C 1
.
6 alkoxy" include methoxy, ethoxy, n-propoxy, i-propoxy. A C 1
.
6 alkoxy group optionally may be substituted by one or more fluorine, chlorine and/or bromine atoms thereby forming, for instance, -OCF 3 , -OC 2 F, -CBr 3 . The term "cycloC3-12 15 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 -12alkyl group optionally may be substituted with one or more fluorine, chlorine and/or bromine atoms. In the context of the present invention the term "di 20 C 1 .alkylamino" refers to an amino moiety in which the nitrogen atom of the amino group is substituted with two C1.ealkyl groups, that may be the same or different, as defined above. Examples of di-C 1
.
6 alkylamino groups include dimethylamino, diethylamino and N-methyl-N-isopropylamino. The term "N-cycloC3-1 2 alkyl-N-C1.6alkylamino" comprises amino groups in which the 25 nitrogen atom of the amino group is substituted by one C 1
.
6 alkyl group and one N-cycloC 3 -1 2 alkyl group. Both the C 1
.
6 alkyl group and the N-cycloC 3 -12alkyl group are defined as given hereinbefore. The term "4-C1.
6 alkyl-piperazinyl" comprises piperazinyl radicals bearing a C 1
.
6 alkyl moiety at the nitrogen atom in 4-position of the piperazine ring, said "C 1
.
6 alkyl" having the same meaning 30 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 23 WO 2007/023290 PCT/GB2006/003170 (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, 5 pyrazines, azepines. The term "halogen" represents fluorine, chlorine, bromine and iodine. [0037] The compounds of the present invention are named according to the IUPAC or CAS nomenclature system. Abbreviations which are well known to 10 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). [0038] The term "analog" or "derivative" is used herein in the conventional pharmaceutical sense, to refer to a molecule that structurally resembles a 15 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 20 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. 25 [0039] In addition, using methods known to those skilled in the art, 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 30 ability to penetrate mammalian blood-brain barriers (e.g., either higher or lower blood-brain barrier permeation rate), fewer side effects, etc. 24 WO 2007/023290 PCT/GB2006/003170 [0040] The phrase "pharmaceutically acceptable", as used in connection with 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., 5 human). Preferably, as used herein, 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. 10 [0041] Compounds 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 15 does not substantially interfere with the desired pharmacological activity. [0042] It will be appreciated by those skilled in the art that compounds of the invention having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be 20 understood that the present invention ecompasses any racemic, optically active, polymorphic, tautomeric, or stereoisomeric form, or mixture thereof, of a compound of the invention, which possesses the useful properties described herein. 25 [0043] The following Scheme I describes the preparation of compounds of Formula I of the present invention. All of the starting materials are prepared by procedures described in the scheme, by procedures well known to one of ordinary skill in organic chemistry or can be obtained commercially. All of the final compounds of the present invention are prepared by procedures 30 described in this chart or by procedures analogous thereto, which would be well known to one of ordinary skill in organic chemistry. All of the variables used in the scheme are as defined below or as in the claims. 25 WO 2007/023290 PCT/GB2006/003170 [0044] A synthetic procedure toward 2-substituted-ethynyl-7,8-dihydro-6H quinolin-5-ones with the general Formula I is given in Scheme 1. The reaction of appropriately functionalized cyclohexane-1,3-dione derivatives 1 with ammonium acetate / acetic acid in benzene gave the corresponding 3-amino 5 cyclohex-2-enone derivatives 2. Compound 2 were then reacted with alkyl propiolate and cyclization was achieved at elevated temperatures to form the quinoline-2,5-dione 3. Subsequent reaction with phosphoryl chloride gave the 2-chioro-substituted quinolin-5-one derivative 4. Substitution of the chioro substituent with appropriate acetylene derivative under palladium (0) catalysis 10 in the presence of base yielded compounds of Formula 1. Scheme I Synthesis of 2-substituted-ethynyl-7,8-dihydro-6H-quinolin-5 ones R2 0 R2 0
NH
4 0Ac
-
COOAlk
R
5 0 R 5
NH
2 1 2 R2 0 2 0 R 3
POCI
3 C R _N _ _ _ R NI
H
5 N
R
5 N Cl H 3 4 R2 0 - R- R 3 15 [0045] It will be apparent to those skilled in the art that the described synthetic procedures are merely representative in nature and that alternative synthetic processes are known to one of ordinary skill in organic chemistry. 26 WO 2007/023290 PCT/GB2006/003170 EXPERIMENTAL PART [0046] The compounds and their preparation of the present invention will be better understood in connection with the following examples, which are 5 intended as an illustration of and not a limitation upon the scope of the invention. [0047] Hereinafter, "DM F" is defined as N,N-dimethylformamide, "HCI" as hydrochloric acid, "DMSO" as dimethylsulfoxide and "TMS" as 10 tetramethylsilane. Preparation I 3-Amino-5,5-dimethylcyclohex-2-en-I -one 0
NH
2 15 [0048] The title compound was prepared according to (Baraldi, P. G.; Simoni, D.; Manfredini, S.; Synthesis 1983, (11) 902-903.) as a colorless solid in 76% yield. Preparation 2 20 7,7-Dimethyl-7,8-dihydro- 1H,6H-quinoline-2,5-dione 0 N- 0 H [0049] In analogy to (Pettit, G. R.; Fleming, W. C.; Paull, K. D. J. Org. Chem. 1968, 33 (3) 1089-1092.), 3-amino-5,5-dimethylcyclohex-2-en-1 -one was reacted with ethyl propiolate to give the title compound as a light brown solid 25 in 78.5% yield. Physical characteristics are as follows: 'H NMR (CDCl 3 , TMS) 8: 1.14, 2.42, 2.82, 6.47, and 8.04. 27 WO 2007/023290 PCT/GB2006/003170 Preparation 3 2-Chloro-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 0 N" CI 5 [0050] In analogy to (Shanazarov, A. K.; Kuzovkin, V. A.; Chistjakov, V. V.; Granik, V. G. Khim. Geterotsiki. Soedin. 1991, (1) 86-92.) 7,7-dimethyl-7,8 dihydro-1H,6H-quinoline-2,5-dione was treated with phosphoryl chloride (POC1 3 ) to give the title compound as a gray solid in 60% yield. Physical characteristics are as follows: 10 'H NMR (CDC1 3 , TMS) 5: 1.11, 2.54, 3.01, 7.30, and 8.30. Preparation 4 3-Amino-5-ethylcyclohex-2-en-1 -one 0
NH
2 15 [0051] In close analogy to (Baraldi, P. G.; Simoni, D.; Manfredini, S.; Synthesis 1983, (11) 902-903) 5-ethylcyclohexane-1,3-dione was reacted with ammonium acetate to give the title compound. Physical characteristics are as follows: 20 'H NMR (CDCl 3 , TMS) 8: 0.93 (t, 6.5 Hz, 3H); 1.42 (m, 2H); 1.88 - 2.44 (m, 5H); 4.62 (br s, 2H) and 5.23 ppm (s, I H). Preparation 5 3-Amino-6-propylcyclohex-2-en-1 -one 0 25 NH 2 28 WO 2007/023290 PCT/GB2006/003170 [0052] In close analogy to (Baraldi, P. G.; Simoni, D.; Manfredini, S.; Synthesis 1983, (11) 902-903) 4-propylcyclohexane-1,3-dione was reacted with ammonium acetate to give the title compound as a colorless solid. Physical characteristics are as follows: 5 1 H NMR (CDCl3, TMS) 8: 0.91 (t, 7 Hz, 3H); 1.25 - 1.90 (m, 5H); 1.98 - 2.18 (m, 2H); 2.35 (t, 6 Hz, 2H); 4.50 (br s, 2H) and 5.19 ppm (s, 1H). Preparation 6 3-Amino-5-isopropylcyclohex-2-en-1 -one 0
NH
2 10 [0053] In analogy to (Baraldi, P. G.; Simoni, D.; Manfredini, S.; Synthesis 1983, (11) 902-903) 5-isopropylcyclohexane-1,3-dione was reacted with ammonium acetate to give the title compound as a colorless solid. 15 Physical characteristics are as follows: 'H NMR (CDCl3, TMS) 8: 0.91 (d, 6.5 Hz); 1.48 - 1.65 (m, IH); 1.84 - 2.39 (m, 5H); 5.04 (br s, 2H) and 5.22 ppm (s, 1 H). Preparation 7 20 3-Amino-6,6-dimethycyclohex-2-en-1 -one 0
NH
2 [0054] In analogy to (Baraldi, P. G.; Simoni, D.; Manfredini, S.; Synthesis 1983, (11) 902-903) 4,4-dimethylcyclohexane-1,3-dione was reacted with 25 ammonium acetate to give the title compound as a colorless solid. Physical characteristics are as follows: Mp 153-154 -*C; 1H NMR (DMSO-D6, TMS) 8: 0.94 (s, 6H); 1.64 (t, 6.5 Hz, 2H); 2.28 (t, 6.5 Hz, 2H); 4.79 (s, I H) and 6.58 ppm (br s, 2H). 29 WO 2007/023290 PCT/GB2006/003170 Preparation 8 3-Amino-6-ethyl-6-methylcyclohex-2-en-1 -one 0
NH
2 5 [0055] In analogy to (Baraldi, P. G.; Simoni, D.; Manfredini, S.; Synthesis 1983, (11) 902-903) 4-ethyl-4-methylcyclohexane-1,3-dione was reacted with ammonium acetate to give the title compound as a colorless solid. Physical characteristics are as follows: -'H NMR (CDCI3, TMS) 5: 0.83 (t, 6.5 Hz, 3H); 1.06 (s, 3H); 1.40 - 1.80 (m, 10 3H); 1.85 - 2.00 (m, 1H); 2.35 (t, 6.5 Hz, 2H); 4.31 (br s, 2H) and 5.14 ppm (s, 1H). Mp 99-100 *C; 'H NMR (CDC1 3 , TMS) 5: 1.08, 1.73, 2.45, 2.79, 3.91, and 8.33; Anal. Found (C 17
H
2 1N 3 0) (%): C, 71.6; H, 7.5; N, 14.4 15 Preparation 9 2-Phenylethynyl-7,8-dihydro-6H-quinolin-5-one 0 N> [0056] To a solution of 2-chloro-7,8-dihydro-6H-quinolin-5-one (0.2 g, 1.1 20 mmol) and ethynylbenzene (0.17 g, 1.6 mmol) in triethylamine (7 ml) under an argon atmosphere was added tetrakis (triphenylphosphine) palladium (0.02 g, 0.062 mmol). The mixture was heated at reflux for 3 h. Then it was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel to give the title compound (0.04 g, 15%). 25 Physical characteristics are as follows: Mp 121-122 0C; "H NMR (CDCl 3 , TMS) 8: 2.20 (2H); 2.68 (2H); 3.17 (2H); 7.22-7.38 (3H); 7.46 (1H); 7.60 (2H); 8.24 (1H); MS 248 (M+1). 30 WO 2007/023290 PCT/GB2006/003170 Preparation 10 2-Pyridin-3-ylethynyl-7,8-dihydro-6H-quinolin-5-one 0 N> N 5 [0057] In analogy to the procedure described in Preparation 9, the title compound was obtained in moderate yield (120 mg, 15%, MP: 120-122.1*C). Preparation 11 10 7,7-Dimethyl-2-pyridin-3-ylethynyl-7,8-dihydro-6H-quinolin-5-one 10 0 [0058] In analogy to the procedure described in Preparation 9, the title compound was obtained in moderate yield (50 mg, 12 %, MP: 108-109.2*C). 15 Preparation 12 2-m-Tolylethynyl-7,8-dihydro-6H-quinolin-5-one 0 [0059] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. 20 31 WO 2007/023290 PCT/GB2006/003170 Preparation 13 2-(3-Hydroxy-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one 0 N OH [0060] In analogy to the procedure described in Preparation 9, the title 5 compound is obtained in moderate yield. Preparation 14 2-(3-Methoxy-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one 0 N 10 [0061] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. Preparation 15 2-(3-Fluoro-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one 0 N F 15 [0062] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. 32 WO 2007/023290 PCT/GB2006/003170 Preparation 16 2-(3-Chloro-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one 0 NI CI [0063] In analogy to the procedure described in Preparation 9, the title 5 compound is obtained in moderate yield. Preparation 17 2-(3-Bromo-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one 0 N Br [0064] In analogy to the procedure described in Preparation 9, the title 10 compound is obtained in moderate yield. Preparation 18 3-(5-Oxo-5,6,7,8-tetrahydro-quinolin-2-ylethynyl)-benzonitrile 0 NI N [0065] In analogy to the procedure described in Preparation 9, the title 15 compound is obtained in moderate yield. 33 WO 2007/023290 PCT/GB2006/003170 Preparation 19 2-Thiazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one 0 N 5 [0066] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. Preparation 20 10 2-Oxazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one 0 N [0067] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. 15 Preparation 21 2-(2-Phenyl-oxazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one 0 N O N [0068] In analogy to the procedure described in Preparation 9, the title 20 compound is obtained in moderate yield. 34 WO 2007/023290 PCT/GB2006/003170 Preparation 22 2-(2-Phenyl-thiazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one 0 "N N 5 [0069] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. Preparation 23 7,7-Dimethyl-2-m-tolylethynyl-7,8-dihydro-6H-quinolin-5-one N 10 [0070] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. Preparation 24 15 2
-(
3 -Hydroxy-phenylethynyl)-7,7-dimethyl-7,8-dihydro- 6 H-quinolin-5-one 0 H [0071] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. 35 WO 2007/023290 PCT/GB2006/003170 Preparation 25 2-(3-Methoxy-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 0 [0072] In analogy to the procedure described in Preparation 9, the title 5 compound is obtained in moderate yield. Preparation 26 2-(3-Fluoro-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one ~0 10 [0073] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. Preparation 27 2-(3-Chloro-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one N 15 [0074] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. 36 WO 2007/023290 PCT/GB2006/003170 Preparation 28 2-(3-Bromo-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 0 Br [0075] In analogy to the procedure described in Preparation 9, the title 5 compound is obtained in moderate yield. Preparation 29 3-(7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydro-quinolin-2-ylethynyl) benzonitrile 100 N 10 N [0076] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. Preparation 30 15 7,7-Dimethyl-2-thiazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one 0 Ns N [0077] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. 37 WO 2007/023290 PCT/GB2006/003170 Preparation 31 7,7-Dimethyl-2-oxazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one 0 'N N [0078] In analogy to the procedure described in Preparation 9, the title 5 compound is obtained in moderate yield. Example I 6,6-Dimethyl-2-phenylethynyl-7,8-dihydro-6H-quinolin-5-one N 10 [0079] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. Example 2 6,6-Dimethyl-2-pyridin-3-ylethynyl-7,8-dihydro-6H-quinolin-5-one -'INN 15 [0080] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. 38 WO 2007/023290 PCT/GB2006/003170 Example 3 6,6-Dimethyl-2-m-tolylethynyl-7,8-dihydro-6H-quinolin-5-one ~N [0081] In analogy to the procedure described in Preparation 9, the title 5 compound is obtained in moderate yield Example 4 2-(3-Methoxy-phenylethynyl)-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one N 10 [0082] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. Example 5 2-(3-Fluoro-phenylethynyl)-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one 15 [0083] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. 39 WO 2007/023290 PCT/GB2006/003170 Example 6 2-Thiazol-2-ylethynyl-7,8-dihydro-6H-quinolin-5-one ~0 N> 5 [0084] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. Example 7 2-(4-Methyl-thiazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5-one NN 10 [0085] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. Example 8 15 7,7-Dimethyl-2-(4-methyl-thiazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5 one 0 N [0086] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. 20 40 WO 2007/023290 PCT/GB2006/003170 Example 9 6,6-Dimethyl-2-(4-methyl-thiazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5 one 0 N 5 [0087] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. Example 10 2-(4-Fluoro-thiazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5-one 0 N~N F 10 [0088] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. 15 Example 11 2-(4-Fluoro-thiazol-2-ylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin 5-one 0 N~N F [0089] In analogy to the procedure described in Preparation 9, the title 20 compound is obtained in moderate yield. 41 WO 2007/023290 PCT/GB2006/003170 Example 12 2-(4-Fiuoro-thiazol-2-ylethynyl)-6,6-dimethyl-7,8-dihydro-6H-quinolin-5 one 0 N' N S 5 F [0090] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. Example 13 10 2-(5-Fluoro-pyridin-3-ylethynyl)-7,8-dihydro-6H-quinolin-5-one O NF N [0091] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. 15 Example 14 3-Fluoro-5-(7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydro-quinolin-2-ylethynyl) benzonitrile 0 N F N 42 WO 2007/023290 PCT/GB2006/003170 [0092] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. Example 15 5 2-(4-Fluoro-5-phenyl-oxazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5-one 0 "N 0 NN F [0093] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. 10 Example 16 2-(4-Fluoro-5-pyridin-3-yl-oxazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5 one 0 'N -N NN F [0094] In analogy to the procedure described in Preparation 9, the title 15 compound is obtained in moderate yield. Example 17 2-(4-Fluoro-5-pyridin-3-yl-oxazol-2-ylethynyl)-7,7-dimethyl-7,8-dihydro 6H-quinolin-5-one 0 NN 20 F 43 WO 2007/023290 PCT/GB2006/003170 [0095] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. Example 18 5 2-(4-Fluoro-5-pyridin-3-yl-oxazol-2-yethynyl)-7,7-dimethyl-7,8-dihydro 6H-quinolin-5-one 0 NN F [0096] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. 10 Example 19 7,7-Dimethyl-2-pyridin-2-ylethynyl-7,8-dihydro-6H-quinolin-5-one N N/ [0097] In analogy to the procedure described in Preparation 9, the title 15 compound is obtained in moderate yield. Example 20 2-Pyridin-2-ylethynyl-7,8-dihydro-6H-quinolin-5-one 0 N N/ 20 [0098] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. 44 WO 2007/023290 PCT/GB2006/003170 Example 21 2-(3-Chloro-phenylethynyl)-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one ~0 N CI 5 [0099] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. Example 22 2-(3-Hydroxy-phenylethynyl)-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one 100 N 10 OH [00100] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. Example 23 15 3-(6,6-Dimethyi-5-oxo-5,6,7,8-tetrahydro-quinolin-2-ylethynyl) benzonitrile N 45 WO 2007/023290 PCT/GB2006/003170 [00101] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. Example 24 5 6,6-Dimethyl-2-thiazol-5-yiethynyl-7,8-dihydro-6H-quinolin-5-one 0 NN N [00102] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. 10 Example 25 6,6-Dimethyl-2-(3-piperidin-1-yl-phenylethynyi)-7,8-dihydro-6H-quinolin 5-one N ND [00103] In analogy to the procedure described in Preparation 9, the title 15 compound is obtained in moderate yield. Example 26 7,7-Dimethyl-2-(3-piperidin-1 -yl-phenylethynyl)-7,8-dihydro-6H-quinolin 5-one 20 [00104] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. 46 WO 2007/023290 PCT/GB2006/003170 Example 27 2-(3-Piperidin-1 -y-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one N ND 5 [00105] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. Example 28 2-(3-Morpholin-4-yl-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one 00 "N No 10 [00106] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. Example 29 15 7,7-Dimethyl-2-(3-morpholin-4-yl-phenylethynyl)-7,8-dihydro-6H quinolin-5-one 00 [00107] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. 20 47 WO 2007/023290 PCT/GB2006/003170 Example 30 6
,
6 -Dimethyl-2-(3-morpholin-4-yl-phenylethynyl)-7,8-dihydro- 6
H
quinolin-5-one 00 5 [00108] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. Example 31 6,6-Dimethyl-2-[3-(1 H-tetrazol-5-yI)-phenylethynyl]-7,8-dihydro- 6
H
10 quinolin-5-one H IN'H.NN , N N .N [00109] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. 15 Example 32 7,7-Dimethyl-2-[3-(1 H-tetrazol-5-yl)-phenylethynyl]-7,8-dihydro- 6
H
quinolin-5-one 0H N N N ~ NN [00110] In analogy to the procedure described in Preparation 9, the title 20 compound is obtained in moderate yield. 48 WO 2007/023290 PCT/GB2006/003170 Example 33 2-[3-(1 H-Tetrazol-5-yl)-phenylethynyl]-7,8-dihydro-6H-quinolin-5-one 0 H N'N, N , N N [00111] In analogy to the procedure described in Preparation 9, the title 5 compound is obtained in moderate yield. Example 34 2-[3-Fluoro-5-(1 H-tetrazol-5-yl)-phenylethynyl]-6,6-dimethyl-7,8-dihydro 6H-quinolin-5-one 1 H, N-N N , N N 10 F [00112] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. Example 35 15 2-[3-Fluoro-5-(1 H-tetrazol-5-yl)-phenylethynyl]-7,7-dimethyl-7,8-dihydro 6H-quinolin-5-one [00113] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. 20 49 WO 2007/023290 PCT/GB2006/003170 Example 36 2-[3-Fluoro-5-(1H-tetrazol-5-yl)-phenylethynyl]-7,8-dihydro-6H-quinolin-5 one | H N'-N, 5 [00114] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. Example 37 2-(3-Trifluoromethyl-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one 10 NF F F 10 [00115] .In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. Example 38 15 7,7-Dimethyl-2-(3-trifluoromethyl-phenylethynyl)-7,8-dihydro-6H quinolin-5-one F |F F [00116] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. 20 50 WO 2007/023290 PCT/GB2006/003170 Example 39 6
,
6 -Dimethyl-2-(3-trifluoromethyl-phenylethynyl)-7,8-dihydro- 6
H
quinolin-5-one O 'N F F F 5 [00117] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. Example 40 2-(2-Phenyl-thiazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one 0 N 10 [00118] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. Example 41 15 6,6-Dimethyl-2-pyridin-2-ylethynyl-7,8-dihydro-6H-quinolin-5-one N N1/ [00119] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. 51 WO 2007/023290 PCT/GB2006/003170 Example 42 6,6-Dimethyl-2-(4-methyl-oxazol-2-ylethynyl)- 7 ,8-dihydro-6H-quinolin-5 one 0 N o 5 [00120] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. Example 43 7,7-Dimethyl-2-(4-methyl-oxazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5 10 one 0 N [00121] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. 15 Example 44 2-(4-Fluoro-5-pyridin-3-yl-1 H-imidazol-2-yiethynyl)-7,8-dihydro- 6
H
quinolin-5-one 0 H N N' Z ' N F [00122] In analogy to the procedure described in Preparation 9, the title 20 compound is obtained in moderate yield. 52 WO 2007/023290 PCT/GB2006/003170 Example 45 2-(4-Fluoro-5-pyridin-3-yl-1 H-imidazol-2-ylethynyl)-7,7-dimethyl-7,8 dihydro-6H-quinolin-5-one 0 H NN 5 F [00123] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. Example 46 10 2-(4-Fluoro-5-pyridin-3-yi-1 H-imidazol-2-yIethynyl)-6,6-dimethyl-7,8 dihydro-6H-quinolin-5-one 0 H N -N> N F [00124] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. 15 Example 47 6,6-Dimethyl-2-(4-pyridin-3-yI-imidazol-I -ylethynyl)-7,8-dihydro-6H quinolin-5-one 0 NN 20 [00125] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. 53 WO 2007/023290 PCT/GB2006/003170 Example 48 7,7-Dimethyl-2-(4-pyridin-3-yl-imidazol-1 -ylethynyl)-7,8-dihydro-6H quinolin-5-one 0 N-N N\ 5 N [00126] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. Example 49 10 2-(4-Pyridin-3-yl-imidazol-1-ylethynyl)-7,8-dihydro-6H-quinolin-5-one 0 N-N N [00127] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. 15 Example 50 2-[1,3,4]Thiadiazol-2-ylethynyl-7,8-dihydro-6H-quinolin-5-one 0 N N-N [00128] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. 20 54 WO 2007/023290 PCT/GB2006/003170 Example 51 2-[1,3,4]Oxadiazol-2-yethynyl-7,8-dihydro-6H-quinolin-5-one 0 N O -N [00129] In analogy to the procedure described in Preparation 9, the title 5 compound is obtained in moderate yield. Example 52 2-(1 H-Tetrazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one 0 H N \ N N'N' 10 [00130] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. Example 53 6,6-Dimethyl-2-[1,3,4]thiadiazol-2-ylethynyl-7,8-dihydro-6H-quinolin-5 15 one 0 N N-N [00131] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. 55 WO 2007/023290 PCT/GB2006/003170 Example 54 7,7-Dimethyl-2-[1,3,4]thiadiazol-2-ylethynyl-7,8-dihydro- 6 H-quinolin-5 one 0 N N-N 5 [00132] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. Example 55 7,7-Dimethyl-2-(1 H-tetrazol-5-yiethynyl)-7,8-dihydro-6H-quinolin-5-one 0 H N N'N 10 [00133] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. Example 56 15 6,6-Dimethyl-2-(1 H-tetrazol-5-yethynyl)-7,8-dihydro-6H-quinolin-5-one 0 NN H NN I ,,N N-N' [00134] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. 56 WO 2007/023290 PCT/GB2006/003170 Example 57 6,6-Dimethyl-2-oxazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one 0 NO N [00135] In analogy to the procedure described in Preparation 9, the title 5 compound is obtained in moderate yield. Example 58 2-Oxazol-2-ylethynyl-7,8-dihydro-6H-quinolin-5-one 0 N 0 10 [00136] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. Example 59 6,6-Dimethyl-2-oxazol-2-ylethynyl-7,8-dihydro-6H-quinolin-5-one 0 N 15 [00137] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. 57 WO 2007/023290 PCT/GB2006/003170 Example 60 7,7-Dimethyl-2-oxazol-2-ylethynyl-7,8-dihydro-6H-quinolin-5-one 0 NO [00138] In analogy to the procedure described in Preparation 9, the title 5 compound is obtained in moderate yield. Example 61 7,7-Dimethyl-2-(2-phenyl-oxazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5 one O N O N 10 [00139] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. Example 62 15 6,6-Dimethyl-2-(2-phenyl-oxazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5 one 0 NO N [00140] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. 20 58 WO 2007/023290 PCT/GB2006/003170 Example 63 7,7-Dimethyl-2-(5-phenyl-thiazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5 one 0 NN 5 [00141] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. Example 64 6,6-Dimethyl-2-(5-phenyl-thiazoi-2-ylethynyl)-7,8-dihydro-6H-quinolin-5 10 one 0 N N S [00142] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. 15 Example 65 2-(5-Fluoro-pyridin-3-ylethynyl)-6,6-dimethyl-7,8-dihydro-6H-quinolin-5 one N F N [00143] In analogy to the procedure described in Preparation 9, the title 20 compound is obtained in moderate yield. 59 WO 2007/023290 PCT/GB2006/003170 Example 66 3-Fluoro-5-(5-oxo-5,6,7,8-tetrahydro-quinolin-2-ylethynyl)-benzonitrile 0 NF N [00144] In analogy to the procedure described in Preparation 9, the title 5 compound is obtained in moderate yield. Example 67 3-(6,6-Dimethyl-5-oxo-5,6,7,8-tetrahydro-quinolin-2-yIethynyl)-5-fiuoro benzonitrile 100 10N [00145] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. Example 68 15 2-(4-Fluoro-5-phenyl-oxazol-2-ylethynyl)-7,7-dimethyl-7,8-dihydro-6H quinolin-5-one 0 N F 60 WO 2007/023290 PCT/GB2006/003170 [00146] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. Example 69 5 2-(4-Fluoro-5-phenyl-oxazol-2-ylethynyl)-6,6-dimethyl- 7 ,8-dihydro-6H quinolin-5-one 0 NNN F [00147] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. 10 Example 70 6,6-Dimethyl-2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-ylethynyl)-7,8-dihydro 6H-quinolin-5-one 0 N O N-N 15 [00148] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. Example 71 7,7-Dimethyl-2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-ylethynyl)-7,8-dihydro 20 6H-quinolin-5-one 0 N O NN N-0 N6N 61 WO 2007/023290 PCT/GB2006/003170 [00149] in analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. Example 72 5 2-(5-Pyridin-3-yl-[1,3,4]oxadiazol-2-yIethynyl)-7,8-dihydro-6H-quinolin-5 one 0 N O N-N [00150] In analogy to the procedure described in Preparation 9, the title compound is obtained in moderate yield. 10 Example 73 7,7-Dimethyl-2-phenylethynyl-7,8-dihydro-6H-quinolin-5-one N [00151] In analogy to the procedure described in Preparation 9, the title 15 compound is obtained in moderate yield. [00152] 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 20 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. Alternatively, enantiomers may be separated by chromatographic techniques using chiral stationary phases. 25 Said pure stereoisomeric forms may also be derived from the corresponding 62 WO 2007/023290 PCT/GB2006/003170 pure stereoisomeric form of appropriate starting materials, provided that the reaction occurs stereoselectively. Stereoisomeric forms of Formula I are obviously intended to be included within the scope of this invention. 5 ADDITION SALTS [00153] For therapeutic use, salts of the compounds of Formula I are those wherein the counterion is pharmaceutically acceptable. However, salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation and purification of pharmaceutically 10 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 15 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, 20 methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfonic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. Conversely, the salt form can be converted by treatment with alkali into the free base form. 25 PHARMACEUTICAL COMPOSITIONS [00154] The active ingredients of the invention, together with one or more conventional adjuvants, carriers, or diluents, 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 30 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 63 WO 2007/023290 PCT/GB2006/003170 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 5 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. 10 [00155] The term "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 15 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. METHOD OF TREATING 20 [00156] Due to their high degree of activity and their low toxicity, together presenting a most favorable therapeutic index, 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 25 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, espe cially and preferably in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parental (including intravenous and subcutaneous) 30 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 64 WO 2007/023290 PCT/GB2006/003170 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. 5 [00157] The term "therapeutically 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. 10 [00158] 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, 15 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. 20 [00159] For oral administration in the form of a tablet or capsule, 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., 25 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 30 wetting agents (e.g., sodium lauryl sulphate), coloring and flavoring agents, gelatin, sweeteners, natural and synthetic gums (such as acacia, tragacanth or alginates), buffer salts, carboxymethylcellulose, polyethyleneglycol, waxes, and the like. For oral administration in liquid form, the drug components can 65 WO 2007/023290 PCT/GB2006/003170 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 5 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. 10 [00160] 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). Liquid preparations for oral administration can take the form of, for example, solutions, syrups, emulsions or suspensions, or they can be presented as a 15 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. [00161] The active drugs can also be administered in the form of 20 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. 25 [00162] 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, 30 polyhydroxy-ethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, 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 66 WO 2007/023290 PCT/GB2006/003170 and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polyhydropyrans, polycyanoacrylates, and cross linked or amphipathic block copolymers of hydrogels. 5 [00163] For administration by inhalation, 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, trichiorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of 10 a pressurized aerosol, 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. 15 [00164] 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 20 dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The 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. Alternatively, the active ingredient can be in powder form for 25 reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. [00165] Compositions of the present invention can also be formulated for rectal administration, e.g., as suppositories or retention enemas (e.g., 30 containing conventional suppository bases such as cocoa butter or other glycerides). 67 WO 2007/023290 PCT/GB2006/003170 [001661 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 5 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. 10 [00167] As disclosed herein, 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 15 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 20 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. 25 [00168] 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 5 o (the dose lethal to 50% of the population) and the EDso (the dose therapeutically effective in 50% of the population). The dose ratio between therapeutic and toxic effects is the 30 therapeutic index and it can be expressed as the ratio ED 5 o/LD 5 0 . Compositions that exhibit large therapeutic indices are preferred. 68 WO 2007/023290 PCT/GB2006/003170 EXAMPLES OF REPRESENTATIVE PHARMACEUTICAL COMPOSITIONS [001691 With the aid of commonly used solvents, auxiliary agents and carriers, the reaction products can be processed into tablets, coated tablets, capsules, drip solutions, suppositories, injection and infusion preparations, 5 and the like and can be therapeutically applied by the oral, rectal, parenteral, and additional routes. Representative pharmaceutical compositions follow. (a) Tablets suitable for oral administration which contain the active ingredient may be prepared by conventional tabletting techniques. (b) For suppositories, any usual suppository base may be employed for 10 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. (c) For parental (including intravenous and subcutaneous) sterile solutions, the active ingredient together with conventional ingredients in usual 15 amounts are employed, such as for example sodium chloride and double distilled water q.s., according to conventional procedure, such as filtration, aseptic filling into ampoules or IV-drip bottles, and autoclaving for sterility. [00170] Other suitable pharmaceutical compositions will be immediately 20 apparent to one skilled in the art. FORMULATION EXAMPLES [00171] The following examples are again given by way of illustration only and are not to be construed as limiting. 25 EXAMPLE 1 Tablet Formulation A suitable formulation for a tablet containing 10 milligrams of active ingredient is as follows: mg 69 WO 2007/023290 PCT/GB2006/003170 Active Ingredient 10 Lactose 61 Microcrystalline Cellulose 25 Talcum 2 Magnesium stearate 1 Colloidal silicon dioxide 1 EXAMPLE 2 Tablet Formulation 5 Another suitable formulation for a tablet containing 100 mg is as follows: mg Active Ingredient 100 Polyvinylpyrrolidone, crosslinked 10 Potato starch 20 Polyvinylpyrrolidone 19 Magnesium stearate I Microcrystalline Cellulose 50 Film coated and colored. The film coating material consists of: Hypromellose 10 Microcryst. Cellulose 5 Talcum 5 Polyethylene glycol 2 70 WO 2007/023290 PCT/GB2006/003170 Color pigments 5 EXAMPLE 3 Capsule Formulation A suitable formulation for a capsule containing 50 milligrams of active 5 ingredient is as follows: mg Active Ingredient 50 Corn starch 26 Dibasic calcium phosphate 50 Talcum 2 Colloidal silicon dioxide 2 filled in a gelatin capsule. EXAMPLE 4 10 Solution for injection A suitable formulation for an injectable solution is as follows: Active Ingredient mg 10 Sodium chloride mg q.s. Water for Injection mL add 1.0 EXAMPLE 5 15 Liquid oral formulation 71 WO 2007/023290 PCT/GB2006/003170 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: mg Active Ingredient 2 Saccharose 250 Glucose 300 Sorbitol 150 Orange flavor 10 Colorant q.s. Purified water add 1000 mL 5 EXAMPLE 6 Liquid oral formulation 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: G Active Ingredient 20.00 Tragacanth 7.00 Glycerol 50.00 Saccharose 400.00 Methylparaben 0.50 Propylparaben 0.05 72 WO 2007/023290 PCT/GB2006/003170 Black currant-flavor 10.00 Soluble Red color 0.02 Purified water add 1000 mL EXAMPLE 7 Liquid oral formulation Another suitable formulation for 1 liter of a liquid mixture containing 2 5 milligrams of active ingredient in one milliliter of the mixture is as follows: G Active Ingredient 2 Saccharose 400 Bitter orange peel tincture 20 Sweet orange peel tincture 15 Purified water add 1000 mL EXAMPLE 8 Aerosol formulation 10 180 g aerosol solution contain: G Active Ingredient 10 Oleic acid 5 Ethanol 81 Purified Water 9 73 WO 2007/023290 PCT/GB2006/003170 Tetrafluoroethane 75 15 ml of the solution are filled into aluminum aerosol cans, capped with a dosing valve, purged with 3.0 bar. 5 EXAMPLE 9 TDS formulation 100 g solution contain: G Active Ingredient 10.0 Ethanol 57.5 Propyleneglycol 7.5 Dimethylsulfoxide 5.0 Hydroxyethylcellulose 0.4 Purified water 19.6 1.8 ml of the solution are placed on a fleece covered by an adhesive backing 10 foil. The system is closed by a protective liner which will be removed before use. EXAMPLE 10 Nanoparticle formulation 15 10 g of polybutylcyanoacrylate nanoparticles contain: G 74 WO 2007/023290 PCT/GB2006/003170 Active Ingredient 1.00 Poloxamer 0.10 Butylcyanoacrylate 8.75 Mannitol 0.10 Sodium chloride 0.05 Polybutylcyanoacrylate nanoparticles are prepared by emulsion polymerization in a water/0.1 N HC/ethanol mixture as polymerizsation medium. The nanoparticles in the suspension are finally lyophilized under 5 vacuum. PHARMACOLOGY - SUMMARY [00172] The active principles of the present invention, and pharmaceutical compositions thereof and method of treating therewith, are 10 characterized by unique and advantageous properties, rendering the "subject matter as a whole", as claimed herein, unobvious. The compounds and pharmaceutical compositions thereof exhibit, in standard accepted reliable test procedures, the following valuable properties and characteristics: 15 METHODS BINDING ASSAYS FOR THE CHARACTERIZATION OF MGLUR5 ANTAGONIST PROPERTIES
[
3 H]MPEP (2-methyl-6-(phenylethynyl)pyridine) binding to 20 transmembrane allosteric modulatory sites- of mGluR5 receptors in cortical membranes Preparation of rat cortical membranes: 75 WO 2007/023290 PCT/GB2006/003170 [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 5 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. Then 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 10 the presence of 50 mM Tris-HCI, pH 8.0. All centrifugation steps are carried out at 40C. After resuspension in 5 volumes of 50 mM Tris-HCI, pH 8.0 the membrane suspension is frozen rapidly at -80 0 C. [00174] On the day of assay the membranes are thawed and washed 15 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 pg/ml) is determined according to the method of Lowry (Lowry 0. H. et al., 1951. J. Biol. Chem. 193, 256-275). 20
[
3 H]MPEP Assay [00175] Incubations are started by adding ( 3 H)-MPEP (50.2 Ci/mmol, 5nM, Tocris) to vials with 125-250pg protein (total volume 0.5 ml) and various concentrations of the agents. The incubations are continued at room 25 temperature for 60 min (equilibrium was achieved under the conditions used). Non-specific binding is defined by the addition of unlabeled MPEP (10 pM). 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. Following separation and 30 rinse, 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). 76 WO 2007/023290 PCT/GB2006/003170 Characterization [00176] Specific binding is extremely high i.e. normally > 85% and essentially independent of buffer (Tris or HEPES oth 50 mM) and pH (6.8 8.9). There is a clear saturable protein dependence and the chosen protein 5 concentration used for subsequent assays (250-500 pg/ml) is within the linear portion of this dependence. Cold MPEP displaces hot ligand with an IC50 of 18.8 ± 4.1nM. The Kd of ( 3 H)-MPEP of 13.6 nM is determined by Scatchard analysis and used according to the Cheng Prussoff relationship to calculate the affinity of displacers as Kd values (IC5o of cold MPEP equates to a Ki of 10 13.7 nM). Bmax was 0.56 pm / mg protein. Compounds of the present invention exhibit specific affinity for transmembrane modulatory sites of mGLuR5 receptors in cortical/cerebellar membrane preparations. FUNCTIONAL ASSAY OF MGLUR5 RECEPTORS 15 Materials and Methods Astrocyte culture [00177] Primary astrocyte cultures were prepared from cortices of newborn rats as described by Booher and Sensenbrenner (1972). Briefly, 20 Sprague-Dawley rat pups (2 - 4 d old) were decapitated and neocortices were dissected, disintegrated with a nylon filter (poresize 80 pm) 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 (FCSi, 25 Sigma), 4 mM glutamine (Biochrom) and 50 pg/mL gentamycin (Biochrom) at 370C in a humidified atmosphere of 5% C02/95% air for 7 d with exchanging the medium at day 2. [00178] After 7 DIV, cells were shaken overnight at 250 rpm to remove 30 oligodendrocytes and microglia. The next day, astrocytes were rinsed twice with CMF-PBS, 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. 24 h after establishing the secondary culture the astrocytes were 77 WO 2007/023290 PCT/GB2006/003170 rinsed with PBS** and fed with astrocyte-defined medium (ADM) consisting of DMEM containing 1x G5-supplement (InVitrogen), 0.5 pg/mL heparan sulfate (Sigma), and 1.5 pg/ 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 5 the time of experiments astrocytes were 14-15 DIV. Immunocytochemistry [00179] Immunostaining was performed to confirm the presence of classical astrocytic markers such as GFAP as well the expression of mGluR5 10 receptors. Accumulation of [ 3 H]-Inositol Phosphates [00180] After astrocytes were cultured for 12 d ADM was removed and inositol-free DMEM (MP Biomedicals) supplemented with [aH]myo-inositol (0.5 15 pCi I well; Perkin Elmer), and the ADM chemicals was added. After 48 h the medium was replaced with 100 pL Locke's buffer (plus 20 mM Li*, pH 7.4) and incubated for 15 min at 370C before replacement with agonists / antagonists in Locke's buffer. The incubation (45 min at 37 *C) was terminated by replacing the Locke's solutions with 100 pL 0.1 M HCI (10 min on ice). The 96 20 well plates can be frozen at -20*C at this stage until further analysis. Home made resin exchange columns (AG1-X8 Biorad, 140-14444) were used to separate labeled inositol phosphates by elution with I mL of I M ammonium formate / 0.1 M formic acid into 24-well visiplates (Perkin Elmer). Scintillation liquid (UltimaFlow AF, Perkin Elmer) was added, the plate sealed and 25 vortexed before radioactivity was determined by conventional liquid scintillation counting (Microbeta,Perkin Elmer) as disintegration per minute (DPM). Calcium FLIPR studies 30 [00181] Cultured astrocytes expressed mGluR5 receptors as shown by immunostaining. The increase of intracellular calcium after stimulation with the mGluR5 agonist DHPG or L-quisqualate was measured using the fluorometric imaging plate reader (FLIPR) and the Ca-Kit (both Molecular Devices, CA). 78 WO 2007/023290 PCT/GB2006/003170 Prior to addition of agonist or antagonist the medium was aspirated and cells were loaded for 2 h at RT with 150 pL 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 5 (1.8 mM), D-glucose (15 mM), and HEPES (20 mM), pH 7.3. Subsequently, plates were transferred to FLIPR to detect calcium increase with the addition of DHPG (300 pM) 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. 10 [00182] For positive modulators, concentration-response curves for quisqualate were performed in the presence and absence of 10 pM modulator to determine the extent of potentiation / agonist potency increase. Thereafter, concentration-response curves for the positive modulator were performed in 15 the presence of a fixed concentration of quisqualate showing the biggest window for potentiation (normally 10-30 nM). Data analysis [00183] The fluorescence signal increase after addition of agonist 20 reflects the increase of intracellular calcium. Inconsistencies in the amount of cells per well were normalised by using the spatial uniformity correction of the FLIPR software. The mean of replicated temporal data (n=5) was calculated and used for graphical representation. For the evaluation of the pharmacology, the calcium changes in response to different concentrations of 25 agonist or antagonist were determined using a maximum minus minimum (MaxMin) calculation. [00184] All responses (DPM- or RFU-values) were determined as percentage of control (= maximum response at 100 nM quisqualate). 30 EC 5 o and IC5o were calculated according the logistic equation using GraFit 5.0 (Erithacus Software). 79 WO 2007/023290 PCT/GB2006/003170 Chemicals [00185] Unless otherwise stated all chemicals were purchased from Sigma. 5 References Booher and Sensenbrenner (1972) Neurobiology 2(3):97-105 Miller et al., (1993) Brain Res. 618(1):175-8 [00186] Compounds of the present invention have an EC50 range of 10 about 0.5 nM to about 100 pM. CONCLUSIONS [00187] In conclusion, from the foregoing, it is apparent that the present invention provides novel, valuable, and unpredictable applications and uses of 15 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. 20 [00188] The high order of activity of the active agent of the present invention and compositions thereof, as evidenced by the tests reported, is indicative of utility based on its valuable activity in human beings as well as in lower animals. Clinical evaluation in human beings has not been completed, 25 however. It will be clearly understood that the distribution and marketing of any compound or composition falling within the scope of the present invention for use in human beings will of course have to be predicated upon prior approval by governmental agencies, such as the U.S. Federal Food and Drug Administration, which are responsible for and authorized to pass judgment on 30 such questions. 80 WO 2007/023290 PCT/GB2006/003170 [00189] The instant ethynyl-substituted tetrahydroquinolinlone derivatives represent a novel class of Group I mGluR modulators. They are especially useful as mGIuR 5 positve modulators or agonists. In view of their potency, they will be useful therapeutics in a wide range of CNS disorders which 5 involve abnormal glutamate induced excitation. [00190] These compounds accordingly find application in the treatment of the following disorders of a living animal body, especially a human: AIDS related dementia, Alzheimer's disease, Creutzfeld-Jakob's syndrome, bovine 10 spongiform encephalopathy (BSE) or other prion related infections, diseases involving mitochondrial dysfunction, diseases involving B-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 15 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 (e.g. resulting from cardiac 20 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. [00191] These compounds also find application in the treatment of the 25 following disorders of a living animal body, especially a human: 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 30 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, 81 WO 2007/023290 PCT/GB2006/003170 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. inflammatory pain, neuropathic pain, allodynia, hyperalgesia, nociceptive pain), Parkinson's 5 disease, post traumatic stress disorder, schizophrenia (positive and negative symptoms), spasticity, tinnitus, Tourette's syndrome, urinary incontinence and vomiting, pruritic conditions (e.g. pruritis), sleep disorders, micturition disorders, neuromuscular disorder in the lower urinary tract, gastroesophageal reflux disease (GERD), lower esophageal sphincter (LES), 10 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. 15 [00192] These compounds also find application in the treatment of indications in of a living animal body, especially a human, wherein a particular condition does not necessarily exist but wherein a particular physiological parameter may be improved through administration of the instant compounds, including cognitive enhancement. 20 [00193] 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 25 pharmaceutical route, employing the selected dosage which is effective in the alleviation of the particular ailment desired to be alleviated. [00194] Use of the compounds of the present invention in the manufacture of a medicament for the treatment of a living animal for inhibition 30 of progression or alleviation of selected ailments or conditions, particularly ailments or conditions susceptible to treatment with a Group I mGluR modulator, in particular an mGluR 5 modulator, especially an mGluR 5 82 WO 2007/023290 PCT/GB2006/003170 positive modulator or agonist, 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 5 present invention in the manufacture of a medicament. [00195] Representative pharmaceutical compositions prepared by admixing the active ingredient with a suitable pharmaceutically-acceptable excipient, diluent, or carrier, include tablets, capsules, solutions for injection, 10 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. 15 [00196] The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description. 20 [00197] All patents, applications, publications, test methods, literature, and other materials cited herein are hereby incorporated by reference. 83
Claims (17)
- 2-Pyridin-3-ylethynyl-7,8-dihydro-6H-quinolin-5-one 2-m-Tolylethynyl-7,8-dihydro-6H-quinolin-5-one 2-(3-Hydroxy-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one 2-(3-Methoxy-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one 25 2-(3-Fluoro-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one 2-(3-Chloro-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one 2-(3-Bromo-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one
- 3-(5-Oxo-5,6,7,8-tetrahydro-quinolin-2-ylethynyl)-benzonitrile 2-Thiazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one 30 2-Oxazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one 7,7-Dimethyl-2-pyridin-3-ylethynyl-7,8-dihydro-6H-quinolin-5-one 7,7-Dimethyl-2-m-tolylethynyl-7,8-dihydro-6H-quinolin-5-one 85 WO 2007/023290 PCT/GB2006/003170 2-(3-Hydroxy-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5 one 2-(3-Methoxy-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5 one 5 2-(3-Fluoro-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 2-(3-Chloro-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 2-(3-Bromo-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 3-(7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydro-quinolin-2-yIethynyl) benzonitrile 10 7,7-Dimethyl-2-thiazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one 7,7-Dimethyl-2-oxazol-5-yethynyl-7,8-dihydro-6H-quinolin-5-one 2-(2-Pheny-oxazoi-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one or 2-(2-Phenyl-thiazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one; 15 and optical isomers, pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof. 2. A compound according to Claim 1, wherein R 2 and R 3 , which may be the same or different, represent methyl, ethyl, 20 n-propyl, 2-propyl, n-butyl or tert-butyl and R 4 and R represent hydrogen. 3. A compound according to Claim 1, wherein R 2 and R 3 represent hydrogen and 25 R 4 and R 5 , which may be the same or different, represent methyl, ethyl, n-propyl, 2-propyl, n-butyl or tert-butyl.
- 4. A compound according to Claim 1, wherein R 2 , R 3 , R 4 and R 5 , which may be the same or different represent 30 hydrogen, methyl or ethyl.
- 5. A compound according to any one of the preceding claims, wherein R 1 represents aryl; 86 WO 2007/023290 PCT/GB2006/003170 it being understood that: aryl represents unsubstituted phenyl or phenyl which is mono- or di 5 substituted with the same or different substituents which 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 , 0CF 3 , OC 2 F 5 , F, Cl, Br, CN, piperidinyl, morpholinyl, tetrazolyl, oxazolyl, furyl, thiophenyl, isoxazolyl, 10 thiazolyl, imidazolyl, oxadiazolyl, pyridinyl, pyrimidyl and phenyl.
- 6. A compound according to Claim 5, wherein aryl represents unsubstituted phenyl or phenyl that is mono- or di substituted bearing the substituent(s) in the meta-position. 15
- 7. A compound according to any one of Claims I to 4, wherein R' represents heteroaryl; it being understood that: 20 heteroaryl represents pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, oxazol-5-yl, 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, 25 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, oxadiazolyl, pyridinyl or pyrimidyl.
- 8. A compound according to Claim I which is selected from: 30 6,6-Dimethyl-2-pyridin-3-ylethynyl-7,8-dihydro-6H-quinolin-5-one, 2-(3-Fluoro-phenylethynyl)-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one, 2-(3-Chloro-phenylethynyl)-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one, 87 WO 2007/023290 PCT/GB2006/003170 2-(3-Methoxy-phelethyfl)-6 ,6-dimethyl-7 ,8-dihydro-6H-quinolifl-5 one, 2-(3-Hydroxy-phelethyfl)-6,6-dinmethy-7 ,8-dihydro-6H-q uinolin-5 one, 5 3-(6 ,6-Dimethyl-5-oxo-5 ,6,7 ,8-tetrahydro-quili-2-yiethyl) benzonitrile, 6,-iehl2tizl5yehnl78dhdo6-unln5oe 6,6-Dimethyl-2-(3-piperidifl-1 -y-hnltyy)78dhdo6-unln 5-one, 10 7,7-DimethyI-2-(3-piperidifl-1 -y-hnltyy)78dhdo6-unln 5-one, 2-(3-Piperidin-1 -y-hnltyy)78dhdo6-unln5oe 2-3Mrhln4y-hnltyy)78dhdo6-unln5oe 7,7-Dimethyl-2-(3-morpholifl-4-yi-phelethyfl)- 7 ,8-dihydro-6H 15 quinolin-5-one, 6,-iehl2(3mrhln4y-peyehn -,8-dihydro-6H quinolin-5-one, 6 ,6-Dimethyl-2-[3-( I H-tetrazoI-5-yl)-pheflethyflYI-7,8dihydro-6H quinolin-5-one, 20 7 ,7-Dimethyl-2-[3-(l H-tetrazol-5-yI)-phenyethynyIII-7 ,8-dihydro-6H quinolin-5-oiie, 2-[13-(1 H-erzl5y)peyehnl-78dhdo6-unln5oe 2-[3-Fluoro-5-( I H-tetrazoI-5-yI)phenyethyny]6,6dimethyI 7 ,8 dihydro-6H-quinolin-5-ofle, 25 2-[3-Fluoro-5-(1 H-tetrazol-5-y)-phenyethYnyIII- 7 ,7-dimethyl-7 ,8 dihydro-6H-quinolin-5-one, 2-[3-Fluoro-5-(1 H-erzl5y)peyehny]78dhdo6-unln 5-one, 2-(3-TrifluoromethyI-phenylethynyI)-7,8-dihyd ro-6H-quinolin-5-one, 30 7 ,7-Dimethy-2-(3-trifluoromethyI-pheflethynyI)- 7 ,8-dihyd ro-6H quinolin-5-one, 6,6Dmty--3tilurmty-hnltynl-,-iyr-H quinolin-5-one, 88 WO 2007/023290 PCT/GB2006/003170 7,7-Dimethyl-2-phenylethynyl-7,8-dihydro-6H-quinolin-5-one, 6,6-Dimethyl-2-phenylethynyl-7,8-dihydro-6H-quinolin-5-one, 2-(4-Methyl-thiazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5-one, 7,7-Dimethyl-2-(4-methyl-thiazol-2-yIethynyl)- 7 ,8-dihydro-6H-quinolin-5 5 one, 6,6-Dimethyl-2-(4-methyl-thiazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5 one, 2-(4-Fluoro-thiazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5-one, 2-(4-Fluoro-thiazol-2-ylethynyl)-7, 7-dimethyl-7,8-dihydro-6H-quinolin-5 10 one, 2-(4-Fluoro-thiazol-2-ylethynyl)-6, 6-dimethyl-7,8-dihydro-6H-quinolin-5 one, 2-(2-Phenyl-thiazol-5-yIethynyl)- 7 ,8-dihydro-6H-quinolin-5-one, 2-(5-Fluoro-pyridin-3-ylethynyl)-7,8-dihydro-6H-quinoiin-5-one, 15 3-Fluoro-5-(7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydro-quinolin-2-yIethynyl) benzonitrile, 2-(4-Fluoro-5-phenyI-oxazol-2-ylethynyl)- 7 ,8-dihydro-6H-quinolin-5 one, 2-(4-Fluoro-5-pyridin-3-yl-oxazol-2-ylethynyl)-7,8-dihydro-6H-quinolin 20 5-one, 2-(4-Fluoro-5-pyridin-3-yl-oxazol-2-ylethynyl)-7,7-dimethyl-7,8-dihydro 6H-quinolin-5-one, 2-(4-Fiuoro-5-pyridin-3-yI-oxazol-2-ylethynyl)-6,6-dimethyl-7,8-dihydro 6H-quinolin-5-one, 25 7,7-Dimethyl-2-pyridin-2-ylethynyl-7,8-dihydro-6H-quinolin-5-one, 2-Pyridin-2-yethynyl-7,8-dihydro-6H-quinolin-5-one, 6,6-Dimethyl-2-pyridin-2-yiethynyl-7,8-dihydro-6H-quinolin-5-one, 6,6-Dimethyl-2-(4-methyl-oxazol-2-yIethynyl)-7,8-dihydro-6H-quinolin-5 one, 30 7,7-Dimethyl-2-(4-methyl-oxazol-2-yIethynyl)-7,8-dihydro-6H-quinolin-5 one, 2-(4-Fluoro-5-pyridin-3-yl-1 H-imidazol-2-yethynyl)-7,8-dihydro-6H quinolin-5-one, 89 WO 2007/023290 PCT/GB2006/003170 2-(4-Fluoro-5-pyridin-3-yi-1 H-imidazol-2-ylethynyl)-7,7-dimethyl-7,8 dihydro-6H-quinolin-5-one, 2-(4-Fluoro-5-pyridin-3-yl-1 H-imidazol-2-yiethynyl)-6,6-dimethyl-7,8 dihydro-6H-quinolin-5-one, 5 6,6-Dimethyl-2-(4-pyridin-3-yl-imidazol-1 -yiethynyl)-7,8-dihydro-6H quinolin-5-one, 7,7-Dimethyl-2-(4-pyridin-3-yI-imidazol-1 -ylethynyl)-7,8-dihydro-6H quinolin-5-one, 2-(4-Pyridin-3-y-imidazol-1 -ylethynyl)-7,8-dihydro-6H-quinolin-5-one, 10 2-Thiazol-2-ylethynyl-7,8-dihydro-6H-quinolin-5-one, 2-[1,3,4]Thiadiazol-2-ylethynyl-7,8-dihydro-6H-quinolin-5-one, 2-[1,3,4]Oxadiazol-2-ylethynyl-7,8-dihydro-6H-quinolin-5-one, 2-(1 H-Tetrazol-5-ylethynyl)- 7 ,8-dihydro-6H-quinolin-5-one, 6,6-Dimethyl-2-[1,3,4]thiadiazol-2-yIethynyl-7,8-dihydro-6H-quinolin-5 15 one, 7,7-Dimethyl-2-[1,3,4]thiadiazol-2-ylethynyl-7,8-dihydro-6H-quinolin-5 one, 7,7-Dimethyl-2-(1 H-tetrazol-5-yethynyl)-7,8-dihydro-6H-quinolin-5-one, 6,6-Dimethyl-2-(1 H-tetrazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one, 20 6,6-Dimethyl-2-oxazol-5-yiethynyl-7,8-dihydro-6H-quinolin-5-one, 2-Oxazol-2-yethynyl-7,8-dihydro-6H-quinolin-5-one, 6,6-Dimethyl-2-oxazol-2-ylethynyl-7,8-dihydro-6H-quinolin-5-one, 7,7-Dimethyl-2-oxazol-2-yIethynyl-7,8-dihydro-6H-quinolin-5-one, 6,6-Dimethyl-2-m-tolyethynyl-7,8-dihydro-6H-quinolin-5-one, 25 7,7-Dimethyl-2-(2-pheny-oxazol-5-yiethynyl)-7,8-dihydro-6H-quinolin-5 one, 6,6-Dimethyl-2-(2-phenyl-oxazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5 one, 7,7-Dimethyl-2-(5-phenyi-thiazoi-2-ylethynyl)-7,8-dihydro-6H-quinolin-5 30 one, 6,6-Dimethyl-2-(5-phenyl-thiazol-2-ylethynyi)-7,8-dihydro-6H-quinolin-5 one, 90 WO 2007/023290 PCT/GB2006/003170 2-(5-Fluoro-pyridin-3-ylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5 one, 2-(5-Fluoro-pyridin-3-ylethynyl)-6,6-dimethyl-7,8-dihydro-6H-quinolin-5 one, 5 3-Fluoro-5-(5-oxo-5,6, 7 ,8-tetrahydro-quinolin-2-ylethynyl)-benzonitrile, 3-(6,6-Dimethyl-5-oxo-5,6,7,8-tetrahydro-quinolin-2-ylethynyl)-5-fluoro benzonitrile, 2-(4-Fluoro-5-phenyl-oxazol-2-ylethynyl)- 7 ,7-dimethyl-7,8-dihydro-6H quinolin-5-one, 10 2-(4-Fluoro-5-pheny-oxazol-2-ylethynyl)-6,6-dimethyl-7,8-dihydro-6H quinolin-5-one, 6,6-Dimethyl-2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-ylethynyl)-7,8-dihydro 6H-quinolin-5-one, 7,7-Dimethyl-2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-ylethynyl)-7,8-dihydro 15 6H-quinolin-5-one, 2-(5-Pyridin-3-yl-[1,3,4]oxadiazol-2-ylethynyi)-7,8-dihydro-6H-quinolin 5-one, and optical isomers, pharmaceutically acceptable salts, hydrates, 20 solvates and polymorphs thereof.
- 9. A medicament comprising at least one of the compounds of Formula I R2 O R3 RI R5 NR wherein 25 R1 represents aryl or heteroaryl; R 2 and R 3 , which may be the same or different, represent hydrogen or C 1 . 6 alkyl; 91 WO 2007/023290 PCT/GB2006/003170 R 4 and R , which may be the same or different, represent hydrogen or C1. 6 alkyl; 5 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 10 C1. 6 alkyl, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, C 1 . 6 alkoxy, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, cycloC 3 - 1 2 alkyl, hydroxyl, F, Cl, Br, I, CN, nitro, di-C 1 . 6 alkylamino, N-cycloC 3 - 1 2 alkyl-N C 1 . 6 alkylamino, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 4-C1.6 15 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 20 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 C 1 . 6 alkyl, which is optionally substituted with one or more 25 fluorine, chlorine or bromine atoms, C1. 6 alkoxy, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, cycloC 3 - 12 alkyl, hydroxyl, F, Cl, Br, I, CN, nitro, di-C 1 . 6 alkylamino, N-cycloC3-1 2 alkyl-N-CI- 6 alkylamino, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 4-C 1 . 6 alkyl-piperazinyl, tetrazolyl, oxazolyl, furyl, pyrrolyl, 30 thiophenyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridinyl, pyrimidyl and phenyl; 92 WO 2007/023290 PCT/GB2006/003170 and optical isomers, pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof; with the exception of the following compounds and optical isomers, 5 pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof: 2-Phenylethynyl-7,8-dihydro-6H-quinolin-5-one 2-Pyridin-3-ylethynyl-7,8-dihydro-6H-quinolin-5-one 2-m-Tolylethynyl-7,8-dihydro-6H-quinolin-5-one 10 2-(3-Hydroxy-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one 2-(3-Methoxy-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one 2-(3-Fluoro-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one 2-(3-Chloro-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one 2-(3-Bromo-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one 15 3-(5-Oxo-5,6,7,8-tetrahydro-quinolin-2-yethynyl)-benzonitrile 2-Thiazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one 2-Oxazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one 7,7-Dimethyl-2-pyridin-3-ylethynyl-7,8-dihydro-6H-quinolin-5-one 7,7-Dimethyl-2-m-tolylethynyl-7,8-dihydro-6H-quinolin-5-one 20 2-(3-Hydroxy-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5 one 2-(3-Methoxy-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5 one 2-(3-Fiuoro-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 25 2-(3-Chloro-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 2-(3-Bromo-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 3-(7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydro-quinolin-2-yethynyl) benzonitrile 7,7-Dimethyl-2-thiazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one 30 7,7-Dimethyl-2-oxazol-5-ylethynyl-7,8-dihydro-6H-quinoiin-5-one 2-(2-Phenyl-oxazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one and 2-(2-Phenyl-thiazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one. 93 WO 2007/023290 PCT/GB2006/003170
- 10. Use of a compound of Formula I R2 O R43 R R5 N' R wherein 5 R' represents aryl or heteroaryl; R 2 and R 3 , which may be the same or different, represent hydrogen or C 1 . 6 alkyl; 10 R 4 and R 5 , which may be the same or different, represent hydrogen or C 1 . 6 alkyl; it being understood that: 15 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 C 1 . 6 alkyl, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, C 1 . 6 alkoxy, which is optionally substituted 20 with one or more fluorine, chlorine or bromine atoms, cycloC 3 - 1 2 alkyl, hydroxyl, F, Cl, Br, I, CN, nitro, di-C 1 . 6 alkylamino, N-cycloC 3 - 12 alkyl-N C 1 . 6 alkylamino, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 4-C1.6 alkyl-piperazinyl, tetrazolyl, oxazolyl, furyl, pyrrolyl, thiophenyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridinyl, pyrimidyl and 25 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 94 WO 2007/023290 PCT/GB2006/003170 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 C 1 - 6 alkyl, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, C 1 . 6 alkoxy, which is optionally 5 substituted with one or more fluorine, chlorine or bromine atoms, cycloC 3 - 12 alkyl, hydroxyl, F, Cl, Br, I, CN, nitro, di-C 1 . 6 alkylamino, N-cycloC 3 -1 2 alkyl-N-C1. 6 alkylamino, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 4-C1.ealkyl-piperazinyl, tetrazolyl, oxazolyl, furyl, pyrrolyl, thiophenyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridinyl, 10 pyrimidyl and phenyl; and optical isomers, pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof; 15 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 mGluR5 modulators. 20 11. Use according to Claim 10, wherein the mGluR5 modulators are positive mGluR5 modulators or mGluR5 agonists.
- 12. Use of a compound of Formula I R 2 O R R5 N R*RN 25 wherein R' represents aryl or heteroaryl; R 2 and R 3 , which may be the same or different, represent hydrogen or 95 WO 2007/023290 PCT/GB2006/003170 C 1 . 6 alkyl; R 4 and R 5 , which may be the same or different, represent hydrogen or C1. 6 alkyl; 5 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 10 different, which substituents are selected from the group consisting of C1. 6 alkyl, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, C 1 . 6 alkoxy, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, cycloC 3 - 1 2 alkyl, hydroxyl, F, Cl, Br, I, CN, nitro, di-C 1 . 6 alkylamino, N-cycloC 3 - 1 2 alkyl-N 15 C 1 . 6 alkylamino, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 4 -C1. alkyl-piperazinyl, tetrazolyl, oxazolyl, furyl, pyrrolyl, thiophenyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridinyl, pyrimidyl and phenyl; 20 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 25 consisting of C1. 6 alkyl, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, C 1 . 6 alkoxy, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, cycloC3-1 2 alkyl, hydroxyl, F, Cl, Br, I, CN, nitro, di-C 1 . 6 alkylamino, N-cycloC 3 . 1 2 alkyl-N-C 1 . 6 alkylamino, azetidinyl, pyrrolidinyl, piperidinyl, 30 morpholinyl, 4-C 1 . 6 alkyl-piperazinyl, tetrazolyl, oxazolyl, furyl, pyrrolyl, thiophenyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridinyl, pyrimidyl and phenyl; 96 WO 2007/023290 PCT/GB2006/003170 and optical isomers, pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof; for the manufacturing of a medicament for the prevention and/or 5 treatment of 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 B-amyloid and/or tauopathy such as Down's syndrome, hepatic encephalopathy, Huntington's disease, motor 10 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. 15 glaucoma, retinopathy, macular degeneration), head and spinal cord injuries / trauma, hypoglycaemia, hypoxia (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 20 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 25 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), fragile-X syndrome, Huntington's chorea, irritable bowel 30 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), 97 spasticity, Tourette's syndrome, urinary incontinence and vomiting, pruritic conditions (e.g. pruritis), sleep disorders, micturition disorders, neuromuscular disorder in the lower urinary tract, gastroesophageal reflux disease (GERD), lower esophageal sphincter (LES), functional gastrointestinal disorders, 5 dyspepsia, regurgitation, respiratory tract infection, bulimia nervosa, chronic laryngitis, asthma (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 10 disorder, schizoaffective disorder, schizophreniform disorder, substance induced psychotic disorder, delirium, or for cognitive enhancement and/or neuroprotection.
- 13. Use according to Claim 12, wherein the medicament is for the prevention and/or treatment of addiction, neuropathic pain, L-dopa- induced and tardive 15 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/or neuroprotection.
- 14. A pharmaceutical composition comprising as active ingredient a compound of 20 Claim 1 together with one or more pharmaceutically acceptable excipients or vehicles.
- 15. A method-of-treating a living animal, including a human, for a condition or a disease associated with abnormal glutamate neurotransmission or in which 25 modulation of Group I mGluR receptors results in therapeutic benefit comprising the step of administering to the living animal, including a human, an amount of a Group I mGluR modulator selected from those of Formula I R2 O R 3 R R S wherein 30 R 1 represents aryl or heteroaryl; R 2 and R 3 , which may be the same or different, represent hydrogen or C1.alkyl; R 4 and R , which may be the same or different, represent hydrogen or C 1 . 6 alkyl; W JF\816855\816855 Specie 301107 doc 98 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 5 substituents are selected from the group consisting of C 1 .6alkyl, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, C 6 alkoxy, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, cycloC 3 . 12 alkyl, hydroxyl, F, Cl, Br, I, CN, nitro, di-C 1 . 6 alkylamino, N-cycloC 3 -1 2 alkyl-N-C 1 . 6 alkylamino, azetidinyl, pyrrolidinyl, 10 piperidinyl, morpholinyl, 4-C 1 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 15 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 C 1 .6alkyl, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, C1. 20 ,alkoxy, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, cycloC 3 - 12 alkyl, hydroxyl, F, Cl, Br, I, CN, nitro, di-C 6 alkylamino, N-cycloC 3 -1 2 alkyl-N-C 1 . 6 alkylamino, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 4-Ci. 6 alkyl-piperazinyl, tetrazolyl, oxazolyl, furyl, pyrrolyl, thiophenyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridinyl, 25 pyrimidyl and phenyl; and optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof; 30 which is effective for alleviation of the condition or disease or for enhancing cognition
- 16. A method according to claim 15, wherein the condition associated with abnormal glutamate neurotransmission, or wherein modulation of mGluR 35 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 W:UFO,816855X816855 Specie 301107.doc QQ involving mitochondrial dysfunction, diseases involving P-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 5 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 (e.g. resulting from cardiac arrest, stroke, bypass 10 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, 15 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 20 Huntington's disease), fragile-X syndrome, Huntington's 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, Tourette's 25 syndrome, urinary incontinence and vomiting, pruritic conditions (e.g. pruritis), sleep disorders, micturition disorders, neuromuscular disorder in the lower urinary tract, gastroesophageal reflux disease (GERD), lower esophageal sphincter (LES), functional gastrointestinal disorders, dyspepsia, regurgitation, respiratory tract infection, bulimia nervosa, chronic laryngitis, asthma (e.g. 30 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 35 psychotic disorder, delirium, or for cognitive enhancement or neuroprotection. W:UFO8168\816855 Specie 301107.docinn
- 17. A compound according to claim 1 substantially as hereinbefore described with reference to any one of the examples.
- 18. A medicament according to claim 9 substantially as hereinbefore described 5 with reference to any one of the examples.
- 19. Use according to claim 10 or claim 12 substantially as hereinbefore described with reference to any one of the examples. 10 20. A method according to claim 15 substantially as hereinbefore described with reference to any one of the examples. W:UFO\816855816855 Spece 301107 doc 1 )
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| PCT/GB2006/003170 WO2007023290A1 (en) | 2005-08-24 | 2006-08-24 | Tetrahydroquinolinones and their use as modulators of metabotropic glutamate receptors |
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| US8349852B2 (en) | 2009-01-13 | 2013-01-08 | Novartis Ag | Quinazolinone derivatives useful as vanilloid antagonists |
| US8772301B2 (en) | 2009-12-18 | 2014-07-08 | Sunovion Pharmaceuticals, Inc. | Compounds for treating disorders mediated by metabotropic glutamate receptor 5, and methods of use thereof |
| SG181715A1 (en) * | 2009-12-18 | 2012-07-30 | Janssen Pharmaceutica Nv | Bicyclic thiazoles as allosteric modulators of mglur5 receptors |
| JP5763672B2 (en) * | 2009-12-18 | 2015-08-12 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプＪａｎｓｓｅｎ Ｐｈａｒｍａｃｅｕｔｉｃａ Ｎａａｍｌｏｚｅ Ｖｅｎｎｏｏｔｓｃｈａｐ | Bicyclic thiazoles as allosteric modulators of the mGluR5 receptor |
| AR080056A1 (en) | 2010-02-01 | 2012-03-07 | Novartis Ag | CICLOHEXIL-AMIDA DERIVATIVES AS ANTAGONISTS OF CRF RECEIVERS |
| EP2531510B1 (en) | 2010-02-01 | 2014-07-23 | Novartis AG | Pyrazolo[5,1b]oxazole derivatives as crf-1 receptor antagonists |
| ES2527849T3 (en) | 2010-02-02 | 2015-01-30 | Novartis Ag | Cyclohexylamide derivatives as CRF receptor antagonists |
| WO2012052451A1 (en) | 2010-10-18 | 2012-04-26 | Merz Pharma Gmbh & Co. Kgaa | Metabotropic glutamate receptor modulators |
| WO2012139876A1 (en) | 2011-04-14 | 2012-10-18 | Merz Pharma Gmbh & Co. Kgaa | Enteric formulations of metabotropic glutamate receptor modulators |
| WO2012172093A1 (en) * | 2011-06-17 | 2012-12-20 | Merz Pharma Gmbh & Co. Kgaa | Dihydroindolizine derivate as metabotropic glutamate receptor modulators |
| WO2013050527A1 (en) | 2011-10-05 | 2013-04-11 | H. Lundbeck A/S | Quinazoline derivatives as pde10a enzyme inhibitors |
| EP2650284A1 (en) * | 2012-04-10 | 2013-10-16 | Merz Pharma GmbH & Co. KGaA | Heterocyclic derivatives as metabotropic glutamate receptor modulators |
| KR101418078B1 (en) * | 2013-01-23 | 2014-07-10 | 한국과학기술연구원 | 2-(Substituted ethynyl)quinoline derivatives as mGluR5 antagonists |
| MX2016006325A (en) | 2013-11-15 | 2016-12-02 | Wistar Inst | Ebna1 inhibitors and their method of use. |
| KR101579496B1 (en) * | 2014-07-03 | 2015-12-23 | 한국과학기술연구원 | mGluR5 Radiotracer composition |
| EP3285582B1 (en) | 2015-03-26 | 2020-11-11 | Merck Sharp & Dohme Corp. | Phosphate-substituted quinolizine derivatives useful as hiv integrase inhibitors |
| EP3294705B1 (en) | 2015-05-14 | 2021-07-21 | The Wistar Institute Of Anatomy And Biology | Ebna1 inhibitors and methods using same |
| AU2016270903B2 (en) | 2015-06-03 | 2020-04-30 | Bristol-Myers Squibb Company | 4-hydroxy-3-(heteroaryl)pyridine-2-one APJ agonists for use in the treatment of cardiovascular disorders |
| EP3459939A1 (en) * | 2017-09-26 | 2019-03-27 | Pragma Therapeutics | Novel heterocyclic compounds as modulators of mglur7 |
| TW201946919A (en) | 2018-05-17 | 2019-12-16 | 威斯塔研究所 | EBNA1 inhibitor crystalline forms, and methods of preparing and using same |
| EP4049661A4 (en) * | 2019-10-21 | 2023-11-08 | SK Biopharmaceuticals Co., Ltd. | Use of imidazopyrimidine or imidazotriazine compound for prevention, alleviation, or treatment of developmental disability |
| US20220370461A1 (en) * | 2019-10-21 | 2022-11-24 | Sk Biopharmaceuticals Co., Ltd. | Use of imidazopyrimidine or imidazotriazine compounds for prevention, alleviation, or treatment of cognitive disorders, or for improving cognitive function |
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| AU2006283359A1 (en) | 2007-03-01 |
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| CA2610873A1 (en) | 2007-03-01 |
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| EP1931635A1 (en) | 2008-06-18 |
| TWI329635B (en) | 2010-09-01 |
| WO2007023242A1 (en) | 2007-03-01 |
| IL189617A (en) | 2012-08-30 |
| WO2007023290A1 (en) | 2007-03-01 |
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