Tetrahydroquinolinones and their use as modulators of metabotropic glutamate receptors

Abstract

The invention relates to ethynyl-substituted tetrahydroquinolinone derivatives as well as their pharmaceutically acceptable salts. The invention further relates to a process for the preparation of such compounds. The compounds of the invention are group I mGluR modulators and are therefore useful for the control and prevention of acute and/or chronic neurological disorders.

1 . A method for treating a condition selected from AIDS-related dementia; Creutzfeld-Jakob's syndrome; bovine spongiform encephalopathy (BSE) or other prion related infections; diseases involving mitochondrial dysfunction; diseases involving β-amyloid and/or tauopathy including Down's syndrome; hepatic encephalopathy; motor neuron diseases including 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, including glaucoma, retinopathy, and macular degeneration; hypoglycaemia; hypoxia, including perinatal hypoxia; ischaemia, including ischaemia resulting from cardiac arrest, stroke, bypass operations or transplants; glioma; melanoma; carcinoma; inner ear insult, including in sound or drug-induced tinnitus; tardive dyskinesia; panic disorders; attention deficit hyperactivity disorder (ADHD); restless leg syndrome; hyperactivity in children; autism; convulsions; dementia, including in Alzheimer's disease, Korsakoff syndrome, vascular dementia, and HIV infections; bipolar manic-depressive disorder; movement disorders; dystonia; fragile-X syndrome; Huntington's chorea; irritable bowel syndrome (IBS); muscle spasms; post traumatic stress disorder; spasticity; Tourette's syndrome; urinary incontinence and vomiting; pruritic conditions, including pruritis; sleep disorders; micturition disorders; neuromuscular disorder in the lower urinary tract; lower esophageal sphincter (LES) disease; functional gastrointestinal disorders; dyspepsia; regurgitation; respiratory tract infection; bulimia nervosa; chronic laryngitis; asthma, including reflux-related asthma; lung disease; eating disorders; obesity and obesity-related disorders; agoraphobia; obsessive-compulsive disorder; panic disorder; social phobia; substance-induced anxiety disorder; delusional disorder; schizoaffective disorder; schizophreniform disorder; substance-induced psychotic disorder; and delirium, in a subject in need thereof, comprising administering a therapeutically effective amount of a compound selected from those of Formula I: 
       
         
           
           
               
               
           
         
       
       wherein
 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 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 with 1, 2, 3, 4 or 5 substituents, that may be the same or different, which substituents are selected from 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 3-12 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-C 1-6 alkyl-piperazinyl, tetrazolyl, oxazolyl, furyl, thiophenyl, pyrrolyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridinyl, pyrimidyl, and phenyl; 
 heteroaryl represents a (hetero)aromatic 5-, 6- or 7-membered ring having from 1 to 4 heteroatoms, said heteroatoms being independently selected from oxygen, nitrogen and sulfur, wherein said ring is unsubstituted or substituted with 1, 2 or 3 substituents, that may be the same or different, which substituents are selected from 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 3-12 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-C 1-6 alkyl-piperazinyl, tetrazolyl, oxazolyl, furyl, thiophenyl, pyrrolyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridinyl, pyrimidyl, and phenyl; 
 and optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof. 
 
     
     
         2 . The method of  claim 1 , wherein
 R 2  and R 3 , which may be the same or different, represent methyl, ethyl, n-propyl, 2-propyl, n-butyl, tert-butyl and   R 4  and R 5  represent hydrogen.   
     
     
         3 . The method of  claim 1 , wherein
 R 2  and R 3  represent hydrogen and   R 4  and R 5 , which may be the same or different, represent methyl, ethyl, n-propyl, 2-propyl, n-butyl, tert-butyl.   
     
     
         4 . The method of  claim 1 , wherein
 R 2 , R 3 , R 4  and R 5 , which may be the same or different represent hydrogen, methyl or ethyl.   
     
     
         5 . The method of  claim 1 , wherein
 R 1  represents aryl;   it being understood that:   aryl represents unsubstituted phenyl or phenyl which is mono- or di-substituted with the same or different substituents which are selected from methyl, ethyl, n-propyl, 2-propyl, n-butyl, tert-butyl, hydroxyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, CF 3 , CH 2 F, CH 2 F, C 2 F 5 , OCF 3 , OC 2 F 5 , F, Cl, Br, CN, piperidinyl, morpholinyl, tetrazolyl, oxazolyl, furyl, thiophenyl, pyrrolyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridinyl, pyrimidyl, and phenyl.   
     
     
         6 . The method of  claim 5 , wherein
 aryl represents unsubstituted phenyl or phenyl that is mono- or di-substituted bearing substituent(s) in the meta-position.   
     
     
         7 . The method of  claim 1 , wherein
 R 1  represents heteroaryl;   it being understood that:   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, 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, and/or pyrimidyl.   
     
     
         8 . The method of  claim 1 , wherein the compound of Formula I is selected from: 
       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, 
       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, 
       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-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, 
       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, 
       2-(2-Phenyl-thiazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one, 
       2-Pyridin-2-ylethynyl-7,8-dihydro-6H-quinolin-5-one, 
       7,7-Dimethyl-2-pyridin-2-ylethynyl-7,8-dihydro-6H-quinolin-5-one, 
       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, 
       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-ylethynyl)-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, 
       7,7-Dimethyl-2-(3-piperidin-1-yl-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one, 
       2-(3-Piperidin-1-yl-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one, 
       2-(3-Morpholin-4-yl-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one, 
       7,7-Dimethyl-2-(3-morpholin-4-yl-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one, 
       6,6-Dimethyl-2-(3-morpholin-4-yl-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one, 
       6,6-Dimethyl-2-[3-(1H-tetrazol-5-yl)-phenylethynyl]-7,8-dihydro-6H-quinolin-5-one, 
       7,7-Dimethyl-2-[3-(1H-tetrazol-5-yl)-phenylethynyl]-7,8-dihydro-6H-quinolin-5-one, 
       2-[3-(1H-Tetrazol-5-yl)-phenylethynyl]-7,8-dihydro-6H-quinolin-5-one, 
       2-[3-Fluoro-5-(1H-tetrazol-5-yl)-phenylethynyl]-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one, 
       2-[3-Fluoro-5-(1H-tetrazol-5-yl)-phenylethynyl]-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one, 
       2-[3-Fluoro-5-(1H-tetrazol-5-yl)-phenylethynyl]-7,8-dihydro-6H-quinolin-5-one, 
       2-(3-Trifluoromethyl-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one, 
       7,7-Dimethyl-2-(3-trifluoromethyl-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one, 
       6,6-Dimethyl-2-(3-trifluoromethyl-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one, 
       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-ylethynyl)-7,8-dihydro-6H-quinolin-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-one, 
       2-(4-Fluoro-thiazol-2-ylethynyl)-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one, 
       2-(2-Phenyl-oxazol-5-ylethynyl)-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, 
       3-Fluoro-5-(7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydro-quinolin-2-ylethynyl)-benzonitrile, 
       2-(4-Fluoro-5-phenyl-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-5-one, 
       2-(4-Fluoro-5-pyridin-3-yl-oxazol-2-ylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one, 
       2-(4-Fluoro-5-pyridin-3-yl-oxazol-2-ylethynyl)-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one, 
       6,6-Dimethyl-2-pyridin-2-ylethynyl-7,8-dihydro-6H-quinolin-5-one, 
       6,6-Dimethyl-2-(4-methyl-oxazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5-one, 
       7,7-Dimethyl-2-(4-methyl-oxazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5-one, 
       2-(4-Fluoro-5-pyridin-3-yl-1H-imidazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5-one, 
       2-(4-Fluoro-5-pyridin-3-yl-1H-imidazol-2-ylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one, 
       2-(4-Fluoro-5-pyridin-3-yl-1H-imidazol-2-ylethynyl)-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one, 
       6,6-Dimethyl-2-(4-pyridin-3-yl-imidazol-1-ylethynyl)-7,8-dihydro-6H-quinolin-5-one, 
       7,7-Dimethyl-2-(4-pyridin-3-yl-imidazol-1-ylethynyl)-7,8-dihydro-6H-quinolin-5-one, 
       2-(4-Pyridin-3-yl-imidazol-1-ylethynyl)-7,8-dihydro-6H-quinolin-5-one, 
       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-(1H-Tetrazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one, 
       6,6-Dimethyl-2-[1,3,4]thiadiazol-2-ylethynyl-7,8-dihydro-6H-quinolin-5-one, 
       7,7-Dimethyl-2-[1,3,4]thiadiazol-2-ylethynyl-7,8-dihydro-6H-quinolin-5-one, 
       7,7-Dimethyl-2-(1H-tetrazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one, 
       6,6-Dimethyl-2-(1H-tetrazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one, 
       6,6-Dimethyl-2-oxazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one, 
       2-Oxazol-2-ylethynyl-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-ylethynyl-7,8-dihydro-6H-quinolin-5-one, 
       6,6-Dimethyl-2-m-tolylethynyl-7,8-dihydro-6H-quinolin-5-one, 
       7,7-Dimethyl-2-(2-phenyl-oxazol-5-ylethynyl)-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-phenyl-thiazol-2-ylethynyl)-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, 
       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-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, 
       2-(4-Fluoro-5-phenyl-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-6H-quinolin-5-one, and 
       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, and polymorphs thereof. 
 
     
     
         9 . The method of  claim 1 , wherein the condition is selected from: ALS, fragile-X syndrome, Parkinson's disease, and cognitive impairment. 
     
     
         10 . The method of  claim 1 , wherein the compound of Formula I is administered as a pharmaceutical composition comprising the compound of Formula I together with one or more pharmaceutically acceptable excipients or vehicles. 
     
     
         11 . A method for providing cognitive enhancement and/or neuroprotection in a subject in need thereof, comprising administering a therapeutically effective amount of a compound selected from those of Formula I: 
       
         
           
           
               
               
           
         
       
       wherein
 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 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 with 1, 2, 3, 4 or 5 substituents, that may be the same or different, which substituents are selected from 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 3-12 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-C 1-6 alkyl-piperazinyl, tetrazolyl, oxazolyl, furyl, thiophenyl, pyrrolyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridinyl, pyrimidyl, and phenyl; 
 heteroaryl represents a (hetero)aromatic 5-, 6- or 7-membered ring having from 1 to 4 heteroatoms, said heteroatoms being independently selected from oxygen, nitrogen and sulfur, wherein said ring is unsubstituted or substituted with 1, 2 or 3 substituents, that may be the same or different, which substituents are selected from 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 3-12 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-C 1-6 alkyl-piperazinyl, tetrazolyl, oxazolyl, furyl, thiophenyl, pyrrolyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridinyl, pyrimidyl, and phenyl; 
 and optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.