Quinolone compound and pharmaceutical composition

Abstract

The present invention provides a quinolone compound represented by General Formula (1) or a salt thereof, wherein R 1 represents a hydrogen atom, etc.; R 2 represents a hydrogen atom, etc.; R 3 represents a phenyl group optionally being substituted with one or more substituents, etc.; R 4 represents a halogen atom; R 5 represents a hydrogen atom or halogen atom; R 6 represents a hydrogen atom; and R 7 represents a hydroxyl group, etc. The quinolone compound have a functional improvement effect, which suppresses progression of neurological dysfunction by inhibiting the chronic progression of Parkinson's disease or protecting dopamine neurons from the disease etiology, thereby prolonging the period before first administration begins.

1 . A quinolone compound represented by General Formula (1) 
       
         
           
           
               
               
           
         
         or a salt thereof,
 wherein R 1  represents a hydrogen atom, a lower alkyl group, a cyclo C 3-8  alkyl lower alkyl group, or a lower alkoxy lower alkyl group;
 R 2  represents a hydrogen atom, a lower alkyl group, or a halogen-substituted lower alkyl group; 
 R 3  represents a phenyl group, a furyl group, a thienyl group, or a pyridyl group, each of the groups optionally being substituted with one or more groups selected from the group consisting of the following (1) to (16) on the aromatic or heterocyclic ring represented by the above R 3 : 
 
 
         (1) lower alkyl groups, 
         (2) lower alkoxy groups, 
         (3) halogen-substituted lower alkoxy groups, 
         (4) a phenoxy group, 
         (5) lower alkylthio groups, 
         (6) a hydroxy group, 
         (7) hydroxy lower alkyl groups, 
         (8) halogen atoms, 
         (9) lower alkanoyl groups, 
         (10) lower alkoxycarbonyl groups, 
         (11) amino groups optionally substituted with one or more lower alkyl groups, 
         (12) carbamoyl groups optionally substituted with one or more lower alkyl groups, 
         (13) cyclo C 3-8  alkyl lower alkoxy groups, 
         (14) pyrrolidinyl carbonyl groups, 
         (15) morpholinyl carbonyl groups, and 
         (16) a carboxyl group;
 R 4  represents a halogen atom; 
 R 5  represents a hydrogen atom or a halogen atom; 
 R 6  represents a hydrogen atom; and 
 R 7  represents any one of groups (1) to (15) below; 
 
         (1) a hydroxy group, 
         (2) a halogen atom, 
         (3) a lower alkoxy group, 
         (4) a halogen-substituted lower alkoxy group, 
         (5) a hydroxy lower alkoxy group, 
         (6) a lower alkoxy lower alkoxy group, 
         (7) an amino group optionally substituted with one or more members selected from the group consisting of lower alkyl groups, lower alkoxy lower alkyl groups, and cyclo C 3-8  alkyl groups, 
         (8) an amino lower alkoxy group optionally substituted on the amino group with one or more members selected from the group consisting of lower alkyl groups, lower alkanoyl groups, lower alkyl sulfonyl groups, and carbamoyl groups optionally substituted with one or more lower alkyl groups, 
         (9) a cyclo C 3-8  alkyloxy group, 
         (10) a cyclo C 3-8  alkyl lower alkoxy group, 
         (11) a tetrahydrofuryl lower alkoxy group, 
         (12) a lower alkylthio group, 
         (13) a heterocyclic group selected from the group consisting of morpholinyl groups, pyrrolidinyl groups, furyl groups, thienyl groups, and benzothienyl groups, 
         (14) a phenyl lower alkoxy lower alkoxy group, and 
         (15) a pyrrolidinyl carbonyl group. 
       
     
     
         2 . A quinolone compound of General Formula (1) or a salt thereof according to  claim 1 ,
 wherein R 1  represents a hydrogen atom or a lower alkyl group;   R 2  represents a hydrogen atom or a lower alkyl group;   R 3  represents a phenyl group or a pyridyl group, each of the groups optionally being substituted with one or two groups selected from the group consisting of the following (1), (2), (6), and (8) on the aromatic or heterocyclic ring represented by the above R 3 :   (1) lower alkyl groups,   (2) lower alkoxy groups,   (6) a hydroxy group, and   (8) halogen atoms;
 R 4  represents a halogen atom; 
 R 5  represents a hydrogen atom; 
 R 6  represents a hydrogen atom; and 
 R 7  represents any one of groups (3), (4), and (7) below: 
   (3) a lower alkoxy group,   (4) a halogen-substituted lower alkoxy group, and   (7) an amino group optionally substituted with one or two lower alkyl groups.   
     
     
         3 . A quinolone compound of General Formula (1) or a salt thereof according to  claim 2  selected from the group consisting of:
 5-fluoro-3-(4-methoxyphenyl)-2-methyl-8-propoxy-1H-quinolin-4-one, 
 5-fluoro-3-(4-methoxyphenyl)-1-methyl-8-propoxy-1H-quinolin-4-one, 
 3-(2,4-dimethoxyphenyl)-5-fluoro-8-propoxy-1H-quinolin-4-one, 
 5-fluoro-8-isopropoxy-3-(4-methoxyphenyl)-1H-quinolin-4-one, 
 3-(2,4-dichlorophenyl)-5-fluoro-8-propoxy-1H-quinolin-4-one, 
 8-ethoxy-5-fluoro-3-(4-methoxyphenyl)-1H-quinolin-4-one, 
 5-fluoro-3-(4-methoxy-2-methylphenyl)-8-propoxy-1H-quinolin-4-one, 
 5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one, 
 5-fluoro-3-(2-fluoro-4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one, 
 5-fluoro-3-(4-hydroxyphenyl)-8-propoxy-1H-quinolin-4-one, 
 8-cyclopropylmethoxy-5-fluoro-3-(4-methoxyphenyl)-1H-quinolin-4-one, 
 5-fluoro-8-propoxy-3-pyridin-4-yl-1H-quinolin-4-one, 
 5-fluoro-3-(4-methoxyphenyl)-8-(N-methyl-N-propylamino)-1H-quinolin-4-one, and 
 5-fluoro-3-(4-methoxyphenyl)-8-(4,4,4-trifluorobutoxy)-1H-quinolin-4-one. 
 
     
     
         4 . A pharmaceutical composition comprising a quinolone compound of General Formula (1) or a salt thereof according to  claim 1  as an active ingredient and a pharmaceutically acceptable carrier. 
     
     
         5 . A prophylactic and/or therapeutic agent for neurodegenerative diseases, diseases induced by neurological dysfunction, or diseases induced by deterioration of mitochondrion function, comprising as an active ingredient a quinolone compound of General Formula (1) or a salt thereof according to  claim 1 . 
     
     
         6 . A prophylactic and/or therapeutic agent according to  claim 5 , wherein the neurodegenerative disease is selected from the group consisting of Parkinson's disease, Parkinson's syndrome, juvenile parkinsonism, striatonigral degeneration, progressive supranuclear palsy, pure akinesia, Alzheimer's disease, Pick's disease, prion disease, corticobasal degeneration, diffuse Lewy body disease, Huntington's disease, chorea-acanthocytosis, benign hereditary chorea, paroxysmal choreoathetosis, essential tremor, essential myoclonus, Gilles de la Tourette's syndrome, Rett's syndrome, degenerative ballism, dystonia musculorum deformance, athetosis, spasmodic torticollis, Meige syndrome, cerebral palsy, Wilson's disease, Segawa's disease, Hallervorden-Spatz syndrome, neuroaxonal dystrophy, pallidal atrophy, spino-cerebellar degeneration, cerebral cortical atrophy, Holmes-type cerebellar atrophy, olivopontocerebellar atrophy, hereditary olivopontocerebellar atrophy, Joseph disease, dentatorubropallidoluysian atrophy, Gerstmann-Straussler-Scheinker disease, Friedreich's Ataxia, Roussy-Levy syndrome, May-White syndrome, congenital cerebellar ataxia, hereditary episodic ataxia, ataxia telangiectasia, amyotrophic lateral sclerosis, progressive bulbar palsy, spinal progressive muscular atrophy, spinobulbar muscular atrophy, Werdnig-Hoffmann disease, Kugelberg-Welander disease, hereditary spastic paraparesis, syringomyelia, syringobulbia, Arnold-Chiari malformation, Stiffman syndrome, Klippel-Feil syndrome, Fazio-Londe syndrome, lower myelopathy, Dandy-Walker syndrome, spina bifida, Sjogren-Larsson syndrome, radiation myelopathy, age-related macular degeneration, and cerebral apoplexy selected from the group consisting of cerebral infarction and cerebral hemorrhage. 
     
     
         7 . A prophylactic and/or therapeutic agent according to  claim 5 , wherein the disease induced by neurological dysfunction is selected from the group consisting of spinal cord injury, chemotherapy-induced neuropathy, diabetic neuropathy, radiation damage, and demyelinating diseases selected from the group consisting of multiple sclerosis, acute disseminated encephalomyelitis, transverse myelitis, progressive multifocal leucoencephalopathy, subacute sclerosing panencephalitis, chronic inflammatory demyelinating polyneuropathy and Guillain-Barre syndrome. 
     
     
         8 . A prophylactic and/or therapeutic agent according to  claim 5 , wherein the disease induced by deterioration of mitochondrion function is selected from the group consisting of Pearson's syndrome, diabetes, deafness, malignant migraine, Leber's disease, MELAS, MERRF, MERRF/MELAS overlap syndrome, NARP, pure myopathy, mitochondrial cardiomyopathy, myopathy, dementia, gastrointestinal ataxia, acquired sideroblastic anemia, aminoglycoside-induced hearing loss, complex III deficiency due to inherited variants of cytochrome b, multiple symmetrical lipomatosis, ataxia, myoclonus, retinopathy, MNGIE, ANT1 disease, Twinkle disease, POLG disease, recurrent myoglobinuria, SANDO, ARCO, complex I deficiency, complex II deficiency, optic nerve atrophy, fatal infantile complex IV deficiency, mitochondrial DNA deficiency, mitochondrial DNA deficiency syndrome, Leigh's encephalomyelopathy, chronic-progressive-external-ophthalmoplegia syndrome (CPEO), Kearns-Sayre syndrome, encephalopathy, lactacidemia, myoglobinuria, drug-induced mitochondrial diseases, schizophrenia, major depression disorder, bipolar I disorder, bipolar II disorder, mixed episode, dysthymic disorders, atypical depression, seasonal affective disorders, postpartum depression, minor depression, recurrent brief depressive disorder, intractable depression/chronic depression, double depression and acute renal failure. 
     
     
         9 . Use of a quinolone compound of General Formula (1) or a salt thereof according to  claim 1  as a drug. 
     
     
         10 . A method for treating or preventing neurodegenerative diseases, diseases induced by neurological dysfunction, or diseases induced by deterioration of mitochondrion function, comprising administering a quinolone compound of General Formula (1) or a salt thereof according to  claim 1  to a human or an animal. 
     
     
         11 . A process for producing a quinolone compound of General Formula (1) 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and R 7  are each defined above in  claim 1 , comprising reacting a compound represented by General Formula (4) 
       
       
         
           
           
               
               
           
         
         wherein R 1 , R 4 , R 5 , R 6  and R 7  are each defined above in  claim 1 , with a compound represented by General Formula (5) 
       
       
         
           
           
               
               
           
         
         wherein R 2  and R 3  are each defined above in  claim 1 , and R 8  represents a lower alkoxy group, thereby giving an intermediate compound represented by General Formula (6) 
       
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 8  are each defined above; and 
         subjecting the resulting compound to a cyclization reaction.