WO2010064701A1 - キノロン化合物を含む薬剤 - Google Patents
キノロン化合物を含む薬剤 Download PDFInfo
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- WO2010064701A1 WO2010064701A1 PCT/JP2009/070383 JP2009070383W WO2010064701A1 WO 2010064701 A1 WO2010064701 A1 WO 2010064701A1 JP 2009070383 W JP2009070383 W JP 2009070383W WO 2010064701 A1 WO2010064701 A1 WO 2010064701A1
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- disease
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- lower alkyl
- quinolin
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- 239000004208 shellac Substances 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- HKZLPVFGJNLROG-UHFFFAOYSA-M silver monochloride Chemical compound [Cl-].[Ag+] HKZLPVFGJNLROG-UHFFFAOYSA-M 0.000 description 1
- 235000020374 simple syrup Nutrition 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
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- 239000007974 sodium acetate buffer Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
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- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
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- 235000012222 talc Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—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
- 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
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
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- C07D215/02—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
- 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
- C07D215/20—Oxygen atoms
- C07D215/24—Oxygen atoms attached in position 8
- C07D215/26—Alcohols; Ethers thereof
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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—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
- 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
- C07D215/36—Sulfur atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—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
- 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
- C07D215/38—Nitrogen atoms
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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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- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
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Definitions
- the present invention relates to a therapeutic and / or preventive agent for neurodegenerative diseases, diseases associated with impaired neurological function or diseases associated with decreased mitochondrial function, comprising a quinolone compound or a salt thereof as an active ingredient.
- Parkinson's disease is a neurodegenerative disease that usually develops after middle age and progresses chronically. As for the first symptom, resting tremor is seen in one side, and immobility and rigidity are added to this. This tremor, ataxia, and stiffness are called the three major signs of Parkinson's disease, all of which are caused by the selective loss of dopamine-containing neurons that project from the midbrain substantia nigra to the striatum. ing. The etiology of this disease remains unclear, but there is evidence that a disorder in the energy production system associated with mitochondrial dysfunction in the midbrain nigrostriatal dopaminergic neurons is the cause of neurodegenerative injury in this disease. It is accumulating. This mitochondrial dysfunction is considered to degenerate neurons by causing subsequent oxidative stress and calcium homeostasis failure (Non-patent Document 1).
- Parkinson's disease is roughly divided into medical treatment (pharmacotherapy) and surgical treatment (stereoscopic brain surgery).
- pharmacotherapy is an established treatment and is considered the basis of treatment.
- symptomatic therapeutic drugs are used for the purpose of compensating for the function of the midbrain nigrostriatal dopaminergic nerve that has degenerated and dropped out due to Parkinson's disease.
- L-dopa shows the most excellent therapeutic effect, and no drug exceeds this.
- a dopa decarboxylase inhibitor that suppresses peripheral metabolism is used in combination, and an expected clinical effect is obtained.
- L-DOPA therapy has a problem that several years after the start of its use, with the recurrence of motor dysfunction such as dyskinesia, the sustainability and stability of the effect are impaired, and circadian fluctuations appear.
- side effects of gastrointestinal symptoms such as nausea and vomiting due to excess dopamine
- cardiovascular symptoms such as orthostatic hypotension, arrhythmia and arrhythmia
- psychiatric symptoms such as hallucinations, delusions and confusion are problematic.
- multi-drug combination therapy using a combination of dopamine receptor agonists, dopamine metabolizing enzyme inhibitors, dopamine release promoters, central anticholinergic agents, etc. has been done.
- drug therapy must be carried out for a lifetime, and L-dopa monotherapy has problems such as a decrease in drug efficacy, side effects, and inability to suppress disease progression due to long-term administration as described above.
- Alzheimer's disease is a neurodegenerative disease in which various cognitive functions are affected progressively with a focus on memory impairment. Pathologically, it is characterized by the accumulation of two types of abnormal fibers: degeneration and loss of neurons and synapses in the hippocampus and cerebral cortex, and senile plaques and neurofibrillary tangles. The etiology of this disease has not been fully elucidated, but amyloid ⁇ protein (A ⁇ ) excised from amyloid precursor protein (APP) by various mechanisms plays an important role.
- a ⁇ amyloid ⁇ protein
- APP amyloid precursor protein
- tissue type plasminogen activator tPA
- thrombolytic therapy is rapidly spreading, it has many problems including a narrow time window of 3 hours after onset and bleeding complications. .
- free radical scavenger edaravone is used as a brain protection therapy in Japan, and it can be used in combination with tPA, but sufficient clinical effects have not been obtained.
- Patent document 1 discloses that the quinolone compound or a salt thereof disclosed in the document is effective as an anticancer agent, but it is a neurodegenerative disease, a disease associated with a disorder of neurological function or a mitochondrial function. It is not disclosed at all that it is useful as a therapeutic and / or prophylactic agent for diseases associated with a decrease.
- Patent Document 2 discloses that the quinolone compound disclosed in the document is effective for the proliferation of vascular intima, but it is a neurodegenerative disease, a disease associated with impaired neurological function, or a decrease in mitochondrial function. It is not disclosed at all that it is useful as a therapeutic and / or prophylactic agent for diseases associated therewith.
- the present invention inhibits the progressive progression of Parkinson's disease or suppresses the progression of neurological dysfunction by protecting dopamine neurons from its pathogenesis, and has an effect of improving the function while extending the period until L-dopa administration. It is an object to provide an agent for treating and / or preventing a disease.
- the present invention provides a drug useful for the treatment of a disease associated with cell death, more specifically, a drug effective for the treatment of Alzheimer's disease or the improvement of dysfunction or neurological deficits caused by a stroke.
- the task is to do.
- the present invention provides a therapeutic and / or prophylactic agent for a disease comprising the quinolone compounds shown in the following items 1 to 6 and a method for treating and / or preventing the disease.
- R 1 represents hydrogen, a lower alkyl group or a cycloC3-C8 alkyl lower alkyl group.
- R 2 represents hydrogen or a lower alkyl group.
- R 3 represents a phenyl group, a naphthyl group, a pyridyl group, a furyl group, a thienyl group, an indolyl group, a benzodioxolyl group, or a benzothienyl group.
- At least one group selected from the group consisting of the following (1) to (7) may be substituted: (1) a lower alkyl group, (2) a halogen-substituted lower alkyl group, (3) a hydroxy group, (4) a lower alkoxy group, (5) a halogen-substituted lower alkoxy group, and (6) Phenyl group (here, it may have one or more groups selected from the group consisting of a lower alkyl group and a lower alkoxy group on the phenyl group) (7) R 4 which may have one or more groups selected from the group consisting of halogen is hydrogen, lower alkyl group, halogen-substituted lower alkyl group, hydroxy group, lower alkoxy group, lower alkoxy lower alkyl group , A carbamoyl group optionally having one or two phenyl groups, cyclo C3-C8 alkyl groups or lower alkyl
- R 5 represents hydrogen, a lower alkyl group, a halogen, a lower alkoxy group, a benzoylamino or an imidazolyl group.
- R 6 represents hydrogen, halogen, a lower alkyl group, a hydroxy group or a lower alkoxy group.
- R 7 represents any one of the following groups (1) to (19).
- Neurodegenerative diseases include Parkinson's disease, Parkinson's syndrome, juvenile parkinsonism, striatal nigra degeneration, progressive supranuclear palsy, pure ataxia, Alzheimer's disease, Pick's disease, prion disease, basal ganglia degeneration Symptom, diffuse Lewy body disease, Huntington's disease, spiny erythroid chorea, benign hereditary chorea, paroxysmal choreoathetosis, essential tremor, essential myoclonus, Gilles de la Tourette syndrome, Rett syndrome, Degenerative balism, Degenerative muscular dystonia, Athetosis, Spastic torticollis, Mage syndrome, Cerebral palsy, Wilson's disease, Segawa disease, Hallelfolden spats syndrome, Axonal dystrophy, Pall palsy atrophy, Spinocerebellar degeneration, Cortical cerebellar atrophy, Holmes cerebellar atrophy, olive bridge cerebellar atrophy, hereditary olive bridge cerebellar at
- Item 3 Diseases associated with impaired neurological function include spinal cord injury, chemotherapy-induced neuropathy, diabetic neuropathy, radioactivity disorder, and multiple sclerosis, acute disseminated encephalomyelitis, transverse myelitis, progressive multiple Item 2.
- the therapeutic and / or prophylactic agent according to Item 1 which is a demyelinating disease selected from focal leukoencephalopathy, subacute sclerosis panencephalitis, chronic inflammatory demyelinating polyradiculoneuritis and Guillain-Barre syndrome.
- Item 4 Diseases associated with decreased mitochondrial function include Pearson's syndrome, diabetes, hearing loss, malignant migraine, Leber's disease, MELAS, MERRF, MERRF / Melas double syndrome, NARP, pure myopathy, mitochondrial cardiomyopathy, myopathy , Dementia, gastrointestinal ataxia, acquired ironblastic anemia, aminoglycoside-induced hearing loss, complex III deficiency due to cytochrome b gene mutation, symmetric polylipomatosis, ataxia, myoclonus, retinopathy, MNGIE, ANT1 Abnormalities, Twinkle abnormalities, POLG abnormalities, repetitive myoglobinuria, SANDO, ARCO, complex I deficiency, complex II deficiency, optic atrophy, complex IV deficient severe infant type, mitochondrial DNA deficiency syndrome, Lee Encephalopathy, Chronic Progressive Extraocular Muscle Paralysis Syndrome (CPEO), Keynes-Sayer Syndrome, Encephalopathy, Lacticemia, Myoglobinuria, Drug-induced Mit
- Item 6 A neurodegenerative disease, a disease associated with a disorder of nerve function, or a decrease in mitochondrial function, comprising administering a quinolone compound represented by the general formula (1) according to Item 1 or a salt thereof to a human or an animal.
- lower means 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms).
- Examples of the lower alkyl group include linear or branched alkyl groups having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms). More specifically, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-ethylpropyl, isopentyl, neopentyl, n-hexyl, 1,2 , 2-trimethylpropyl, 3,3-dimethylbutyl, 2-ethylbutyl, isohexyl, 3-methylpentyl group and the like.
- cyclo C3-C8 alkyl group examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.
- Examples of the cyclo C3-C8 alkyl lower alkyl group include the above-described lower alkyl groups having 1 to 3 (preferably 1) of the above-mentioned cyclo C3-C8 alkyl groups.
- Examples of the lower alkoxy group include linear or branched alkoxy groups having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms). More specifically, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, iso Hexyloxy, 3-methylpentyloxy groups and the like are included.
- Examples of the lower alkoxy lower alkyl group include the lower alkyl groups exemplified above having 1 to 3 (preferably 1) lower alkoxy groups exemplified above.
- halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
- halogen-substituted lower alkyl group examples include the above-described lower alkyl groups substituted with 1 to 7, more preferably 1 to 3, halogen atoms. More specifically, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, dichlorofluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl , Pentafluoroethyl, 2-fluoroethyl, 2-chloroethyl, 3,3,3-trifluoropropyl, heptafluoropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoroisopropyl, 3-chloropropyl 2-chloropropyl, 3-bromopropyl, 4,4,4-trifluorobutyl, 4,4,4,3,3-pentafluorobut
- halogen-substituted lower alkoxy group examples include the above-described lower alkoxy groups substituted with 1 to 7, preferably 1 to 3, halogen atoms. More specifically, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, bromomethoxy, dibromomethoxy, dichlorofluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, 2 -Chloroethoxy, 3,3,3-trifluoropropoxy, heptafluoropropoxy, heptafluoroisopropoxy, 3-chloropropoxy, 2-chloropropoxy, 3-bromopropoxy, 4,4,4-trifluorobutoxy, 4, 4,4,3,3-pentafluorobutoxy, 4-chlorobutoxy, 4-bromobutoxy, 2-chlorobutoxy, 5,5,5-trifluoropentoxy, 5-chlor
- Examples of the lower alkylthio group include an alkylthio group in which the alkyl portion is the lower alkyl group exemplified above.
- phenyl group which may have one or more groups selected from the group consisting of a lower alkyl group and a lower alkoxy group on the phenyl group
- examples of the phenyl group include, for example, the above-described lower alkyl group and the above-described examples.
- a phenyl group which may have 1 to 3 (preferably 1 to 2) groups selected from the lower alkoxy groups.
- Examples of the carbamoyl group optionally having one or more lower alkyl groups include carbamoyl groups optionally having 1 to 2 lower alkyl groups as exemplified above.
- the amino group may have one or two groups selected from the group consisting of a lower alkyl group, a lower alkoxy lower alkyl group and a cyclo C3-C8 alkyl group
- a lower alkyl group a lower alkoxy lower alkyl group
- a cyclo C3-C8 alkyl group an amino group optionally having 1 to 2 groups selected from the group consisting of the exemplified lower alkyl group, the exemplified lower alkoxy lower alkyl group, and the exemplified cyclo C3-C8 alkyl is mentioned.
- an amino group optionally having 1 to 2 groups selected from the group consisting of the exemplified lower alkyl group, the exemplified lower alkoxy lower alkyl group, and the exemplified cyclo C3-C8 alkyl is mentioned.
- piperazinyl group which may have one or two lower alkyl groups
- examples of the piperazinyl group which may have one or two lower alkyl groups include, for example, piperazinyl groups which may have one to two (preferably one) lower alkyl groups exemplified above. Can do.
- imidazolyl group optionally having 1 or 2 lower alkyl groups examples include imidazolyl groups optionally having 1 to 2 (preferably 1) of the lower alkyl groups exemplified above. Can do.
- Examples of the lower alkoxy lower alkyl group include the lower alkyl groups exemplified above having 1 to 3 (preferably 1) lower alkoxy groups exemplified above.
- Examples of the cyclo C3-C8 alkyloxy group include a group in which the exemplified cyclo C3-C8 alkyl group and an oxygen atom are bonded.
- the quinolone compound represented by the general formula (1) (hereinafter sometimes referred to as the compound (1)) can be produced by various methods.
- the quinolone compound represented by the following reaction formula-1 is shown. Manufactured by the above method.
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are the same as described above, and R 8 represents a lower alkoxy group.
- R 8 represents a lower alkoxy group.
- the lower alkoxy group represented by R 8 has the same definition as described above.
- the general formula (4) By reacting the compound represented by the general formula (2) and the compound represented by the general formula (3) in a solvent-free or inert solvent in the presence or absence of an acid catalyst, the general formula (4)
- the compound of the general formula (1) can be produced by obtaining an intermediate compound represented by
- the inert solvent examples include water; ether solvents such as dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether; aromatic hydrocarbon solvents such as benzene, toluene, and xylene; Examples include lower alcohol solvents such as methanol, ethanol and isopropanol; polar solvents such as N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide and acetonitrile. These inert solvents are used singly or in combination of two or more.
- ether solvents such as dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether
- aromatic hydrocarbon solvents such as benzene, toluene
- the acid catalyst known ones can be widely used, and examples thereof include acids such as toluenesulfonic acid, methanesulfonic acid, xylenesulfonic acid, sulfuric acid, glacial acetic acid, boron trifluoride and acidic ion exchangers. These acid catalysts are used singly or in combination of two or more.
- acidic ion exchangers examples include commercially available polymer cation exchangers such as Lewatit S100 and Zeo-carb 225.
- Styrene sulfonic acid polymers such as Dowex 50, Amberlite IR120 or Amberlyst 15; Polysulfonic acid condensates such as Rewacit PN or Zeocarb 215 or 315; Rewacit CNO or Duolite ( Duolite) m-phenol carboxylic acid resin such as CS100; or polyacrylic acid ester such as Permutit C, Zeocarb 226 or Amberlite IRC50, among which Also it preferred in particular to use Amberlyst 15.
- the amount of the acid catalyst used is usually in the range of 0.0001 mol to 100 mol, preferably 0.5 to 6 mol, relative to 1 mol of the compound of the general formula (2).
- the proportion of the compound of the general formula (2) and the compound of the general formula (3) used in the above reaction formula-1 is usually at least 1 mol, preferably about 1 mol to 5 mol with respect to 1 mol of the former. Good.
- This reaction can be performed under normal pressure, in an inert gas atmosphere such as nitrogen or argon, or under pressure.
- the above reaction is usually carried out at room temperature to 200 ° C., preferably room temperature to 150 ° C. During this time, water is removed azeotropically until the reaction water formation stops, and the reaction is generally completed in about 1 to 30 hours. To do.
- the step of producing the compound represented by the general formula (1) from the intermediate compound represented by the general formula (4) by a cyclization reaction can be performed by heating in a solvent such as diphenyl ether, It can also be carried out by heating the compound even in the absence of a solvent.
- the reaction is carried out at 150 to 300 ° C. for 5 minutes to 2 hours.
- the compound represented by the general formula (2) used as a starting material in the above reaction formula-1 is a known compound or can be easily produced from a known compound.
- the compound represented by the general formula (3) includes a novel compound, and the compound is produced, for example, according to the method shown in the following reaction formula-2.
- R 9 represents a lower alkoxy group.
- the lower alkoxy group represented by R 9 has the same definition as described above.
- the general formula (3 ) can be produced.
- the inert solvent examples include water; ether solvents such as dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether; aromatic hydrocarbon solvents such as benzene, toluene, and xylene; Lower alcohol solvents such as methanol, ethanol and isopropanol; ketone solvents such as acetone and methyl ethyl ketone; polar solvents such as N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide and acetonitrile be able to.
- ether solvents such as dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether
- aromatic hydrocarbon solvents such as benzene
- the inorganic base examples include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, cesium hydroxide, and lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate; hydrogen carbonate Alkali metal hydrogen carbonates such as lithium, sodium hydrogen carbonate and potassium hydrogen carbonate; Alkali metals such as sodium and potassium; Amides such as sodium amide; Alkali metal hydrides such as inorganic bases such as sodium hydride and potassium hydride Can be mentioned.
- alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, cesium hydroxide, and lithium hydroxide
- alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate
- hydrogen carbonate Alkali metal hydrogen carbonates such as lithium, sodium hydrogen carbonate and potassium hydrogen carbonate
- Alkali metals such as sodium and potassium
- Amides such as sodium amide
- Alkali metal hydrides such as inorgan
- organic bases include alkali metal lower alkoxides such as sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide; triethylamine, tripropylamine, pyridine, quinoline, piperidine , Imidazole, N-ethyldiisopropylamine, dimethylaminopyridine, trimethylamine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo [4.3.0] nonene-5 (DBN), 1,8-diazabicyclo [5. And amines such as 4.0] undecene-7 (DBU) and 1,4-diazabicyclo [2.2.2] octane (DABCO).
- alkali metal lower alkoxides such as sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium t-
- basic compounds are used singly or in combination of two or more. More preferable examples of the basic compound used in this reaction include inorganic bases such as sodium hydride and potassium hydride.
- the amount of the basic compound used is usually about 1 mol to 10 mol, preferably about 1 mol to 6 mol, per 1 mol of the compound of the general formula (5).
- the compound of the general formula (6) is usually used in an amount of at least about 1 mol, preferably about 1 to 5 mol, per 1 mol of the compound of the general formula (5).
- This reaction can be performed under normal pressure, in an inert gas atmosphere such as nitrogen or argon, or under pressure.
- the above reaction is usually performed at room temperature to 200 ° C., preferably room temperature to 150 ° C., and is generally completed in about 1 to 30 hours.
- the raw material compound used in each of the above reaction formulas may be a suitable salt, and the target compound obtained in each reaction may also form a suitable salt.
- Suitable salts thereof include suitable salts of the compound (1) exemplified below.
- Suitable salts of the compound (1) are pharmacologically acceptable salts such as alkali metal salts (for example, sodium salts and potassium salts), alkaline earth metal salts (for example, calcium salts and magnesium salts).
- Metal salts such as ammonium salts, alkali metal carbonates (for example, lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, etc.), alkali metal hydrocarbon salts (for example, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.) Salts of inorganic bases such as alkali metal hydroxides (eg, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, etc.); for example, tri (lower) alkylamines (eg, trimethylamine, triethylamine, N— Ethyldiisopropylamine), pyridine, quinoline, piperidine, imidazole, Phosphorus, dimethylaminopyridine, dimethylaniline, N- (
- solvates include hydrates.
- Each target compound obtained in each of the above reaction formulas is obtained by cooling the reaction mixture, for example, separating the crude reaction product by an isolation operation such as filtration, concentration, extraction, etc., and performing column chromatography, recrystallization, etc. It can be isolated and purified from the reaction mixture by ordinary purification procedures.
- the compound represented by the general formula (1) of the present invention naturally includes isomers such as geometric isomers, stereoisomers, and optical isomers.
- R 1 in the general formula (1) when the definition of R 1 in the general formula (1) is hydrogen, it includes a tautomer of a quinolone ring. That is, in the quinolone compound of the general formula (1), the formula (1 ′) in which R 1 represents hydrogen.
- the compound represented by the general formula (1) of the present invention naturally includes the above tautomers.
- the structural formula of the 4-quinolone compound is used for the purpose of including such tautomeric compounds and the structural formula of the starting compound for convenience.
- the present invention also provides the same isotope as the compound represented by the general formula (1) except that one or more atoms are replaced by one or more atoms having a specific atomic mass or mass number. Also includes body labeled compounds. Examples of isotopes that can be incorporated into the compounds of the present invention include hydrogen, carbon, nitrogen such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 18 F, 36 Cl, respectively. Oxygen, sulfur, fluorine, and chlorine isotopes.
- isotope-labeled compounds of the invention containing the above isotopes and / or other isotopes of other atoms, for example, compounds incorporating radioactive isotopes such as 3 H and 14 C, Useful in drug tissue distribution assays and / or matrix tissue distribution assays. Tritiated (ie 3 H) and carbon-14 (ie 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. In addition, substitution with heavier isotopes such as deuterium (ie, 2 H) provides certain therapeutic benefits resulting from improved metabolic stability, eg, increased in vivo half-life or reduced dosage requirements. Can be expected.
- the isotope-labeled compounds of the present invention are generally obtained by substituting non-isotopically labeled reagents with readily available isotope-labeled reagents by the methods disclosed in the above reaction schemes and / or examples below. Can be prepared.
- the compound of the general formula (1) and a salt thereof are used in the form of a general pharmaceutical preparation.
- the preparation is prepared by using diluents or excipients such as fillers, extenders, binders, moisturizers, disintegrants, surfactants, lubricants and the like that are usually used.
- diluents or excipients such as fillers, extenders, binders, moisturizers, disintegrants, surfactants, lubricants and the like that are usually used.
- Various forms of this pharmaceutical preparation can be selected according to the purpose of treatment. Representative examples thereof include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections ( Liquid, suspension, etc.).
- various carriers well known in the art can be widely used as carriers.
- carriers include excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, water, ethanol, propanol, simple syrup, glucose solution, starch solution, Binders such as gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, lauryl sulfate Disintegrators such as sodium, stearic acid monoglyceride, starch, lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, quaternary ammonium base, absorption promoters such as sodium lauryl sulfate, Phosphor
- a wide variety of carriers conventionally known in this field can be used.
- carriers conventionally known in this field.
- examples thereof include excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin and talc, binders such as gum arabic powder, tragacanth powder, gelatin and ethanol, and disintegrants such as laminaran and agar.
- excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin and talc
- binders such as gum arabic powder, tragacanth powder, gelatin and ethanol
- disintegrants such as laminaran and agar.
- Conventionally known carriers can be widely used when forming into a suppository form.
- examples thereof include polyethylene glycol, cocoa butter, higher alcohols, higher alcohol esters, gelatin, semi-synthetic glycerides and the like.
- Capsules are usually prepared by mixing the active ingredient compounds with the various carriers exemplified above and filling them into hard gelatin capsules, soft capsules and the like according to conventional methods.
- solutions, emulsions and suspensions are preferably sterilized and isotonic with blood, and are commonly used in this field as diluents when molded into these forms
- diluents when molded into these forms
- water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like can be used.
- a sufficient amount of sodium chloride, glucose or glycerin may be contained in the pharmaceutical preparation to prepare an isotonic solution, and a normal solubilizing agent, buffering agent, soothing agent, etc. may be added. May be. Further, if necessary, a colorant, a preservative, a flavoring agent, a sweetening agent, and other pharmaceuticals may be contained in the pharmaceutical preparation.
- the amount of the compound of the general formula (1) or a salt thereof to be contained in the pharmaceutical preparation of the present invention is not particularly limited and is appropriately selected from a wide range, but is usually about 0.1 to 70 in the pharmaceutical composition. % By weight, preferably about 0.1 to 30% by weight.
- the administration method of the pharmaceutical preparation of the present invention is not particularly limited, and it is administered by a method according to various preparation forms, patient age, sex and other conditions, the degree of disease, and the like.
- a method for example, in the case of tablets, pills, solutions, suspensions, emulsions, granules and capsules, they are administered orally.
- it is administered intravenously alone or mixed with a normal fluid such as glucose and amino acids, and further administered alone intramuscularly, intradermally, subcutaneously or intraperitoneally as necessary.
- a suppository it is administered intrarectally.
- the dosage of the pharmaceutical preparation of the present invention is appropriately selected depending on the usage, the age of the patient, sex and other conditions, the degree of disease, etc.
- the amount of the active ingredient compound is about 0.1 to 1 kg / kg body weight per day. It should be about 10 mg.
- the active ingredient compound is preferably contained in the dosage unit form in a range of about 1 to 200 mg.
- the compound of the present invention could not be obtained by conventional therapies by administering in combination with L-dopa preparations, dopamine receptor agonists, dopamine metabolizing enzyme inhibitors, dopamine release accelerators, central anticholinergic agents, etc. Effects such as dose reduction, side effect improvement, and therapeutic effect enhancement can be obtained.
- the compound of the present invention has a mitochondrial function protection improving action, a nerve cell protection and a function repair action, etc., it treats neurodegenerative diseases, diseases associated with impaired neurological function, diseases associated with decreased mitochondrial function and // Effective for prevention.
- Neurodegenerative diseases include Parkinson's disease, Parkinson's syndrome, juvenile parkinsonism, striatal nigra degeneration, progressive supranuclear paralysis, pure ataxia, Alzheimer's disease, Pick's disease, prion disease, basal ganglia Degenerative disease, diffuse Lewy body disease, Huntington's disease, spiny erythroid chorea, benign hereditary chorea, paroxysmal choreoathetosis, essential tremor, essential myoclonus, Gilles de la Tourette syndrome, Rett syndrome , Degenerative balism, deformed muscular dystonia, athetosis, spastic torticollis, mage syndrome, cerebral palsy, Wilson's disease, Segawa disease, Hallelfolden-Spatz syndrome, neuroaxonal dystrophy, pallidal atrophy, spinocerebellar degeneration , Cortical cerebellar atrophy, Holmes cerebellar atrophy, olive bridge cerebellar atrophy, hereditary olive bridge cerebellar atrophy, Joseph'
- Diseases associated with impaired neurological function include spinal cord injury, chemotherapy-induced neuropathy, diabetic neuropathy, radioactive disorders, demyelinating diseases (eg, multiple sclerosis, acute disseminated encephalomyelitis, transverse spinal cord) Inflammation, progressive multifocal leukoencephalopathy, subacute sclerosis panencephalitis, chronic inflammatory demyelinating polyradiculoneuritis, Guillain-Barre syndrome, etc.).
- demyelinating diseases eg, multiple sclerosis, acute disseminated encephalomyelitis, transverse spinal cord
- Inflammation eg, progressive multifocal leukoencephalopathy, subacute sclerosis panencephalitis, chronic inflammatory demyelinating polyradiculoneuritis, Guillain-Barre syndrome, etc.
- Diseases associated with reduced mitochondrial function include Pearson's syndrome, diabetes, hearing loss, malignant migraine, Leber's disease, MELAS, MERRF, MERRF / Melas double syndrome, NARP, pure myopathy, mitochondrial cardiomyopathy, Myopathy, dementia, gastrointestinal ataxia, acquired ironblastic anemia, aminoglycoside-induced hearing loss, complex III deficiency due to cytochrome b gene mutation, symmetric multiple lipomatosis, ataxia, myoclonus, retinopathy, MNGIE, ANT1 abnormality, Twinkle abnormality, POLG abnormality, repetitive myoglobinuria, SANDO, ARCO, complex I deficiency, complex II deficiency, optic nerve atrophy, complex IV deficiency severe infant type, mitochondrial DNA deficiency syndrome, Leigh encephalopathy, chronic progressive extraocular palsy syndrome (CPEO), Keynes-Sayer syndrome, encephalopathy, lactic acidemia, myoglobinuria, drug-induced mito Chondr
- the compound of the present invention is an ischemic heart disease and / or dysfunction associated therewith, heart failure, cardiomyopathy, aortic detachment, immunodeficiency, autoimmune disease, pancreatic insufficiency, diabetes, atheroembolic kidney disease, multiple cysts Kidney, medullary cystic disease, renal cortical necrosis, malignant nephrosclerosis, renal failure, hepatic encephalopathy, liver failure, chronic obstructive pulmonary disease, pulmonary embolism, bronchiectasis, silicosis, black lung, idiopathic pulmonary fiber It is effective for the treatment and / or prevention of diseases such as symptom, epilepsy Stevens-Johnson syndrome, toxic epidermal necrosis, muscular dystrophy, clostridial muscular necrosis and femoral condyle osteonecrosis.
- diseases such as symptom, epilepsy Stevens-Johnson syndrome, toxic epidermal necrosis, muscular dystrophy,
- the compounds of the present invention include L-dopa preparations, dopamine receptor agonists, dopamine metabolizing enzyme inhibitors, dopamine release promoters, central anticholinergic agents or cholinesterase inhibitors, glutamate N-methyl-D-aspartate receptor antagonists Or administration in combination with drugs used for thrombolytic therapy, anti-cerebral edema therapy, cerebral protection therapy, anti-thrombotic therapy and plasma dilution therapy, reduced dosage, improved side effects, Effects such as enhanced therapeutic effects can be obtained.
- Reference example 1 4-methyl-2-nitro-1-propoxybenzene 4-methyl-2-nitrophenol 4.0 g (26.1 mmol) in N, N-dimethylformamide (DMF) solution (10 ml) was charged with 5.21 g of potassium carbonate (10 ml). 37.7 mmol) and 5.80 g (34.1 mmol) of 1-iodopropane in DMF (4 ml) were added and the mixture was stirred at room temperature for 48 hours. Water was added to the reaction solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine and concentrated under reduced pressure.
- DMF N, N-dimethylformamide
- Reference example 2 5-Methyl-2-propoxyaniline 4-methyl-2-nitro-1-propoxybenzene (2.0 g, 10.2 mmol) and 5% palladium on carbon (700 mg) were added to ethanol (30 ml) and subjected to catalytic reduction at room temperature and normal pressure. The catalyst was removed by celite filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane and dried over anhydrous magnesium sulfate. The obtained dried product was concentrated under reduced pressure to obtain 1.49 g (yield 89%) of 5-methyl-2-propoxyaniline as a brown oily substance.
- Examples 2 to 109 were produced in the same manner as in Example 1 using the corresponding appropriate starting materials.
- Human neuroblastoma strain SH-SY5Y uses Dulbecco's modified Eagle's medium containing 10% fetal calf serum (DMEM, containing 50 units / ml penicillin and 50 ⁇ g / ml streptomycin as antibiotics) at 37 ° C, 5% Culturing was performed under carbon dioxide conditions.
- the cells were seeded in a 96-well (well) black plate coated with poly-D-lysine at a concentration of 3-6 ⁇ 10 4 cells / cm 2 (medium amount 100 ⁇ l / well) and cultured in the above medium for 2 days.
- the medium was replaced with the same medium in which DMEM (N2-DMEM) or 1.5 mM MPP + containing 1% N2 supplement was dissolved (100 ⁇ l / well), cultured for 39 to 48 hours, and then used for a mitochondrial redox activity measurement system.
- the test compound previously dissolved in dimethyl sulfoxide (DMSO) was diluted with N2-DMEM and added in a volume of 10 ⁇ l / well 24 hours before the activity measurement (final compound concentration 0.01-1 ⁇ g / ml).
- balanced salt solution containing 10% Alamar Blue (154 mM sodium chloride, 5.6 mM potassium chloride, 2.3 mM calcium chloride, 1.0 mM magnesium chloride, 3.6 mM sodium bicarbonate, 5 mM glucose, 5 mM hepes, pH 7.2) was added at a volume of 100 ⁇ L / well, reacted in a constant temperature bath at 37 °C for 1 hour, and fluorescence intensity was detected with a fluorescence detector (Hamamatsu Photonics, excitation wavelength 530 nm, measurement wavelength 580 nm) As a result, mitochondrial redox activity was measured.
- Alamar Blue 154 mM sodium chloride, 5.6 mM potassium chloride, 2.3 mM calcium chloride, 1.0 mM magnesium chloride, 3.6 mM sodium bicarbonate, 5 mM glucose, 5 mM hepes, pH 7.2
- the relative fluorescence intensity of cells cultured in a medium containing MPP + and each test compound is shown relative to the fluorescence intensity in the wells of cells cultured in a medium containing only DMSO (final concentration 0.1%). It was. In the MPP + treated cell group, the test compound showing higher fluorescence intensity than the addition of DMSO alone was considered to have an effect of improving mitochondrial function.
- Pharmacological test 2 Measurement of dopamine neuroprotective activity using C57BL / 6 mice treated with 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP) Mice in which dopaminergic nerves were damaged by MPTP treatment [Chan P Et al., J Neurochem, 57, 348-351 (1991)], using tyrosine hydroxylase (TH) and dopamine transporter (DAT) which are marker proteins of dopamine neurons in the striatum region of the brain after compound administration. The dopamine neuroprotective action was evaluated using the dopamine content at the same site as the protein level as an index [Mori A. et al., Neurosci Res, 51, 265-274 (2005)].
- mice Male C57BL / 6 mice (10-12 weeks old, Charles River Japan Co., Ltd.) were used as test animals.
- MPTP was dissolved in physiological saline to a concentration of 4 mg / ml and subcutaneously administered to mice at a volume of 10 mg / kg.
- the test compound was suspended in 5% gum arabic / saline (w / v) to a concentration of 1 mg / ml.
- 30 minutes, 24 hours, and 48 hours after administration of MPTP to mice, each test compound or its solvent was orally administered in a volume of 10 ml / kg.
- the mice were decapitated 72 hours after MPTP administration, the brain was removed, and the left and right striatum were removed.
- the left striatum was used as a protein level analysis sample by Western blotting.
- Each tissue was treated with hepes buffered sucrose solution (0.32 M sucrose, 4 ⁇ g / ml pepstatin, 5 ⁇ g / ml aprotinin, 20 ⁇ g / ml trypsin inhibitor, 4 ⁇ g / ml leupeptin, 0.2 mM phenylmethanesulfonyl fluoride, 2 mM ethylenediamine.
- EDTA tetraacetic acid
- 2 mM ethylene glycol bis ( ⁇ aminoethyl ether) tetraacetic acid 20 mM hepes, pH 7.2
- protein quantification using the bicinchoninic acid kit for protein quantification (Pierce) It was.
- Each homogenate sample of the same protein amount dissolved in the Remley sample buffer was electrophoresed through a sodium dodecyl sulfate-polyacrylamide gel. Proteins separated by electrophoresis were electrically transferred to a polyvinylidene fluoride membrane.
- the membrane was divided into TH, DAT and housekeeping proteins (ie, sodium-potassium ATPase (Na + / K + -ATPase) ⁇ 1 subunit and actin (Na + / K + -ATPase manufactured by Upstate Biotechnology) Others were reacted with specific primary antibodies against Chemicon))). Thereafter, a horseradish peroxidase-labeled secondary antibody (Amersham) was bound to each primary antibody, and chemiluminescence derived from the enzyme activity of peroxidase was detected with an X-ray film. The protein band density on the film was analyzed with a densitometer (Biorad), and the TH value for Na + / K + -ATPase and the DAT value for actin were calculated.
- housekeeping proteins ie, sodium-potassium ATPase (Na + / K + -ATPase) ⁇ 1 subunit and actin (Na + / K + -ATPase
- the right striatum was measured immediately after excision, and used as a dopamine content analysis sample.
- Each tissue was homogenized in an 0.1 N perchloric acid solution containing isoproterenol as an internal standard substance for measurement while being cooled with ice using an ultrasonic crusher.
- the supernatant obtained after centrifuging the homogenate at 20000 g for 15 minutes at 4 ° C. was subjected to high performance liquid chromatography (manufactured by Aicom) using a reverse phase column.
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Abstract
Description
R1は、水素、低級アルキル基又はシクロC3-C8アルキル低級アルキル基を示す。
R2は、水素又は低級アルキル基を示す。
R3は、フェニル基、ナフチル基、ピリジル基、フリル基、チエニル基、インドリル基、ベンゾジオキソリル基又はベンゾチエニル基を示す。
ここで、上記R3で示される芳香環及び複素環上には、下記(1)~(7)からなる群から選ばれた少なくとも1つの基が置換していてもよい:
(1)低級アルキル基、
(2)ハロゲン置換低級アルキル基、
(3)ヒドロキシ基、
(4)低級アルコキシ基、
(5)ハロゲン置換低級アルコキシ基ならびに、
(6)フェニル基(ここで、フェニル基上に低級アルキル基及び低級アルコキシ基からなる群から選ばれた基を1個以上有していてもよい)
(7)ハロゲンからなる群から選ばれた基を1個以上有していてもよい
R4は、水素、低級アルキル基、ハロゲン置換低級アルキル基、ヒドロキシ基、低級アルコキシ基、低級アルコキシ低級アルキル基、フェニル基、シクロC3-C8アルキル基又は低級アルキル基を1個又は2個有していてもよいカルバモイル基を示す。
R5は水素、低級アルキル基、ハロゲン、低級アルコキシ基、ベンゾイルアミノ又はイミダゾリル基を示す。
R6は、水素、ハロゲン、低級アルキル基、ヒドロキシ基又は低級アルコキシ基を示す。
R7は、下記(1)~(19)のいずれかの基を示す。
(1)水素、
(2)ヒドロキシ基、
(3)低級アルキル基、
(4)低級アルコキシ基、
(5)フェノキシ基、
(6)シクロC3-C8アルキルオキシ基、
(7)ハロゲン、
(8)低級アルキルチオ基、
(9)アミノ基(ここで、アミノ基上に低級アルキル基、低級アルコキシ低級アルキル基及びシクロC3-C8アルキル基からなる群から選ばれた基を1個又は2個有していてもよい)
(10)低級アルキル基を1個又は2個有していてもよいカルバモイル基、
(11)ピロリジニル基、
(12)アゼパニル基、
(13)モルホリニル基、
(14)低級アルキル基を1個又は2個有していてもよいピペラジニル基、
(15)低級アルキル基を1個又は2個有していてもよいイミダゾリル基、
(16)フリル基、
(17)チエニル基、
(18)ベンゾチエニル基、
(19)ピロリジニルカルボニル基]
で表されるキノロン化合物又はその塩を有効成分として含有する、神経変性疾患、神経機能の障害に伴う疾患又はミトコンドリア機能の低下に伴う疾患の治療及び/又は予防剤。
[反応式-1]
一般式(3)において、R8で示される低級アルコキシ基は前記に示された定義と同じである。
[反応式-2]
一般式(6)において、R9で示される低級アルコキシ基は、前記に示された定義と同じである。
上記のような、4-キノロン化合物と4-ヒドロキシキノリン化合物との間のこの種の互変異性は技術上周知であり、両互変異性体が平衡しており相互に変換し得る状態にあることは当業者には明らかである。
4-メチル-2-ニトロ-1-プロポキシベンゼン
4-メチル-2-ニトロフェノール4.0g(26.1ミリモル)のN,N-ジメチルホルムアミド(DMF)溶液(10ml)に炭酸カリウム5.21g(37.7ミリモル)及び1-ヨードプロパン5.80g(34.1ミリモル)のDMF溶液(4ml)を加え、混合物を室温で48時間撹拌した。反応液に水を加え、得られる混合物を酢酸エチルで抽出した。有機層を飽和食塩水で2回洗浄し、減圧下に濃縮した。残渣をシリカゲルカラムクロマトグラフィー(n-ヘキサン:酢酸エチル=9:1)で精製した。精製物を減圧下に濃縮して淡黄色油状物の4-メチル-2-ニトロ-1-プロポキシベンゼン4.23g(収率83%)を得た。
1H-NMR (CDCl3) δppm : 1.05 (3H, t, J=7.4Hz), 1.80-1.86 (2H, m), 2.33 (3H, s), 4.02 (2H, t, J=6.4Hz), 6.95 (1H, d, J=8.5Hz), 7.29 (1H, d, J=8.5Hz), 7.62 (1H, s)。
5-メチル-2-プロポキシアニリン
4-メチル-2-ニトロ-1-プロポキシベンゼン2.0g(10.2ミリモル)及び5%パラジウム炭素700mgをエタノール30mlに加えて、室温常圧で接触還元した。触媒をセライト濾過して除去し、濾液を減圧下に濃縮した。残渣をジクロロメタンに溶解後、無水硫酸マグネシウムで乾燥した。得られた乾燥物を減圧下に濃縮して茶褐色油状物の5-メチル-2-プロポキシアニリン1.49g(収率89%)を得た。
1H-NMR (CDCl3 ) δppm : 1.05 (3H, t, J=7.4Hz), 1.76-1.86 (2H, m), 2.21 (3H, s), 3.73 (2H, brs), 3.91 (2H, t, J=6.5Hz), 6.49-6.50 (1H, m), 6.54 (1H, s), 6.66 (1H, d, J=8.0Hz)。
α-(ヒドロキシメチレン)-4-メトキシフェニル酢酸エチルエステル
4-メトキシフェニル酢酸エチルエステル2.0g(10.3ミリモル)のベンゼン溶液(10ml)に氷冷下、水素化ナトリウム(60%油性)467mg(11.7ミリモル)を加え、混合物を室温で5分間撹拌した。攪拌後の混合物を再び氷冷し、ぎ酸エチル1.02ml(12.6ミリモル)を加え、室温で3時間撹拌した。氷冷下、反応液に水及び酢酸エチルを加えた後、2N-塩酸6mlを加え、分液した。有機層を減圧下に濃縮し、残渣をシリカゲルカラムクロマトグラフィー(n-ヘキサン:酢酸エチル=4:1)で精製した。精製物を減圧下に濃縮して微赤褐色油状物のα-(ヒドロキシメチレン)-4-メトキシフェニル酢酸エチルエステル1.97g(収率86%)を得た。得られた目的物を窒素置換して冷凍庫に保管した。
1H-NMR (CDCl3 ) δppm : 1.28 (3H, t, J=7.1 Hz), 3.81 (3H, s), 4.28 (2H, q, J=7.1 Hz), 6.87 (2H, d, J=8.8Hz), 7.16-7.26 (3H, m), 12.02 (1H, d, J=12.5Hz)。
5-メチル-2-プロポキシアニリン1.49g(9.0ミリモル)及びα-(ヒドロキシメチレン)-4-メトキシフェニル酢酸エチルエステル2.00g(9.0ミリモル)のベンゼン溶液(50ml)に、270mgのアンバーリスト15(シグマ アルドリッチ)を加え、ディーン-スターク(Dean-Stark)トラップを用いて混合物を6時間、加熱還流下撹拌した。反応混合物を室温まで冷却し、濾過して樹脂を除去し、濾液を減圧下に濃縮した。残渣にジフェニルエーテル2.5mlを加え、混合物をマントルヒーターで加熱し、還流下50分間撹拌した。反応液を室温まで冷却後、直接シリカゲルカラムクロマトグラフィー(ジクロロメタン:メタノール=80:1→60:1)で精製した。精製物を減圧下に濃縮し、残渣を酢酸エチルから再結晶して淡黄色鱗片状晶の3-(4-メトキシフェニル)-5-メチル-8-プロポキシ-1H-キノリン-4-オン600mg(収率21%)を得た。
融点 192-193℃。
白色粉末
融点 129-131℃。
黄色粉末
融点 231-233℃。
淡褐色粉末
1H-NMR (DMSO-d6 ) δppm : 1.35 (3H, t, J=6.8Hz), 3.76 (3H, s), 4.23 (2H, q, J=6.9Hz), 6.84-6.96 (4H, m), 7.64 (2H, d, J=8.6Hz), 8.09 (1H, s), 8.11 (1H, d, J=8.8Hz), 10.33 (1H, s)。
淡黄色粉末
1H-NMR (DMSO-d6 ) δppm : 3.70 (3H, s), 3.76 (3H, s), 3.86 (3H, s), 3.93 (3H, s), 6.48 (1H, s), 6.95 (2H, d, J=8.8Hz), 7.59 (2H, d, J=8.8Hz), 8.22 (1H, s) 11.40 (1H, brs)。
淡褐色粉末
1H-NMR (DMSO-d6 ) δppm : 0.90 (3H, t, J=7.2Hz), 1.34-1.39 (2H, m), 1.55-1.59 (2H, m), 2.86 (2H, t, J=7.5Hz), 3.76 (3H, s), 6.95 (2H, d, J=8.5Hz), 7.25 (1H, t, J=7.7Hz), 7.46 (1H, d, J=6.9Hz), 7.62 (2H, d, J=8.5Hz), 7.92 (1H, s), 8.08 (1H, d, J=8.0Hz), 11.39 (1H, brs)。
白色粉末
1H-NMR (DMSO-d6 ) δppm : 0.94 (3H, t, J=7.2Hz), 1.59-1.64 (2H, m), 2.83 (2H, t, J=7.5Hz), 3.75 (3H, s), 6.93-6.95 (2H, m), 7.25 (1H, t, J=7.8Hz), 7.46 (1H, d, J=6.0Hz), 7.60-7.61 (2H, m), 7.92 (1H, s), 8.07-8.09 (1H, m), 11.40 (1H, brs)。
淡黄色粉末
1H-NMR (DMSO-d6 ) δppm : 0.96 (3H, t, J=7.2Hz), 1.59-1.66 (2H, m), 2.85 (2H, t, J=7.6Hz), 7.27 (1H, t, J=7.9Hz), 7.36 (2H, d, J=8.7Hz), 7.49 (1H, d, J=7.0Hz), 7.83 (2H, d, J=8.7Hz), 8.02 (1H, s), 8.09-8.10 (1H, m), 11.47 (1H, brs)。
白色粉末
1H-NMR (DMSO-d6 ) δppm : 0.95 (3H, t, J=7.2Hz), 1.58-1.65 (2H, m), 2.84 (2H, t, J=7.6Hz), 7.27 (1H, d, J=7.9Hz), 7.48 (1H, d, J=7.1Hz), 7.55 (2H, d, J=8.5Hz), 7.67 (2H, d, J=8.5Hz), 8.00 (1H, s), 8.08-8.09 (1H, m), 11.46 (1H, brs)。
淡褐色粉末
1H-NMR (DMSO-d6 ) δppm : 0.95 (3H, t, J=7.2Hz), 1.59-1.66 (2H, m), 2.85 (2H, t, J=7.6Hz), 3.81 (3H, s), 7.00 (2H, d, J=8.7Hz), 7.28 (1H, t, J=8.5Hz), 7.48 (1H, d, J=7.1Hz), 7.60-7.7.64 (4H, m), 7.76 (2H, d, J=8.2Hz), 8.02 (1H, s), 8.11 (1H, d, J=8.1Hz), 11.45 (1H, brs)。
白色粉末
1H-NMR (DMSO-d6 ) δppm : 1.37 (3H, t, J=6.9Hz), 3.91 (3H, s), 4.34 (2H, q, J=7.0Hz), 7.01-7.04 (2H, m), 7.54 (2H, d, J=8.4Hz), 7.69 (2H, d, J=8.4Hz), 8.20 (1H, d, J=8.8Hz), 8.24 (1H, s)。
白色粉末
1H-NMR (DMSO-d6 ) δppm : 1.38 (3H, t, J=7.0Hz), 3.91 (3H, s), 4.35 (2H, q, J=7.0Hz), 7.01-7.05 (2H, m), 7.34 (1H, t, J=7.4Hz), 7.45 (2H, t, J=7.6Hz), 7.65-7.68 (4H, m), 7.81 (2H, d, J=8.3Hz), 8.22-8.25 (2H, m)。
淡褐色粉末
融点 223-224℃。
淡黄色粉末
融点 210-211℃。
淡褐色粉末
融点 259-260℃。
淡褐色粉末
融点 231-232℃。
淡褐色アモルファス
1H-NMR (DMSO-d6 ) δppm : 1.04 (3H, t, J=7.3Hz), 1.78-1.90 (2H, m), 3.67 (3H, s), 3.84 (6H, s), 4.12 (2H, t, J=6.4Hz), 7.00 (2H, s), 7.17-7.26 (2H, m), 7.74 (1H, d, J=6.7Hz), 7.99 (1H, d, J=6.3Hz), 11.47 (1H, d, J=6.2Hz)。
淡褐色粉末
融点 250-251℃。
実施例19
淡黄色粉末
融点 214-215℃。
淡黄色粉末
融点 193-194℃。
淡灰色粉末
融点 113-114℃。
淡褐色粉末
融点 186-187℃。
淡黄色粉末
融点 174-175℃。
淡黄色粉末
融点 220-221℃。
淡黄色粉末
融点 182-183℃。
淡黄色粉末
融点 159-160℃。
緑色粉末
融点 189℃。
淡褐色粉末
融点 193℃。
淡橙色粉末
融点 230℃。
淡褐色粉末
融点 250℃。
淡黄色粉末
融点 175℃。
白色粉末
融点 224℃。
淡褐色粉末
融点 160℃。
淡黄色粉末
融点 153-154℃。
淡褐色粉末
融点 120-121℃。
淡黄色粉末
融点 161-162℃。
淡褐色粉末
融点 195-196℃。
白色粉末
融点 125℃。
白色粉末
融点 218-220℃。
白色粉末
融点 239-241℃。
淡黄色粉末
融点 253-255℃。
淡黄色粉末
融点 145-148℃。
淡黄色粉末
融点 179-180℃。
淡黄色粉末
融点 255-256℃。
淡黄色粉末
融点 117-119℃。
淡黄色粉末
融点 213-214℃。
淡黄色粉末
融点 242-244℃。
淡黄色粉末
融点 160-161℃。
淡黄色粉末
融点 169-170℃。
淡黄色粉末
融点 201-202℃。
淡黄色粉末
融点 130-133℃。
白色粉末
融点 221-223℃。
淡黄色粉末
融点 170-171℃。
淡黄色粉末
融点 200-203℃。
淡黄色粉末
融点 107-108℃。
淡黄色粉末
融点 81-84℃。
淡黄色粉末
融点 103-106℃。
淡褐色粉末
融点 104-107℃。
淡橙色粉末
融点 189-193℃。
淡褐色粉末
融点 110-115℃。
薄緑色粉末
融点 104-105℃。
淡褐色粉末
融点 106-109℃。
淡褐色粉末
融点 80-82℃。
淡褐色粉末
融点 81-83℃。
白色粉末
融点 168-170℃。
淡黄色粉末
融点 90-92℃。
淡黄色粉末
融点 196-198℃。
淡黄色粉末
融点 177-178℃。
白色粉末
融点 182-183℃。
淡黄色粉末
融点 132-135℃。
淡黄色粉末
融点 258-260℃。
白色粉末
融点 159-161℃。
淡褐色粉末
融点 260-263℃。
白色粉末
融点 265-267℃。
淡黄色粉末
融点 270-275℃(分解)。
淡黄色粉末
融点 186-188℃。
淡褐色粉末
融点 214-215℃。
白色粉末
融点 191-192℃。
白色粉末
融点 198-199℃。
淡黄色粉末
融点 156-158℃。
淡黄色粉末
融点 145-147℃。
淡黄色粉末
融点 198-200℃。
淡褐色粉末
融点 99-101℃。
黄色粉末
融点 249-250℃。
淡褐色粉末
融点 236-237℃。
淡黄色粉末
融点 185-186℃。
淡灰色粉末
融点 218-220℃。
淡褐色粉末
融点 212-214℃。
黄色粉末
融点 158-160℃。
淡褐色粉末
融点 193-195℃。
淡黄色粉末
融点 237-239℃。
白色粉末
融点 100-101℃。
黄緑色粉末
融点 213-215℃。
淡黄色粉末
融点 232-234℃。
淡橙色粉末
融点 112-113℃。
淡黄色粉末
融点 129-131℃。
白色粉末
融点 189-190℃。
白色粉末
融点 229-231℃。
白色粉末
融点 186-187℃。
橙色粉末
融点 197-199℃。
淡黄色粉末
融点 90-93℃。
白色粉末
融点 111-113℃。
白色粉末
融点 186-187℃。
白色粉末
融点 266-268℃。
淡褐色粉末
融点 254-256℃。
黄色粉末
融点 154-155℃。
黄色粉末
融点 163-165℃。
淡黄色粉末
融点 204-206℃。
淡黄色粉末
融点 189-190℃。
1-メチル-4-フェニルピリジニウム(MPP + )処置ヒト神経芽細胞腫株SH-SY5Yを用いたミトコンドリア機能改善作用の測定
MPP+処置によりミトコンドリア機能が障害されたヒト神経芽細胞腫株SH-SY5Y [Bollimuntha S.ら、J Biol Chem, 280, 2132-2140 (2005)及びShang T.ら、J Biol Chem, 280, 34644-34653 (2005)] において、化合物添加後のアラマーブルー蛍光色素を用いたミトコンドリア酸化還元活性測定値を指標 [Nakai M.ら、Exp Neurol, 179, 103-110 (2003)]に、ミトコンドリア機能改善作用を評価した。
1-メチル-4-フェニル1,2,3,6-テトラハイドロピリジン(MPTP)処置C57BL/6マウスを用いたドパミン神経保護作用の測定
MPTP処置によりドパミン作動性神経が傷害されたマウス[Chan P.ら、J Neurochem, 57, 348-351 (1991)]を用い、化合物投与後の脳線条体部位におけるドパミン神経のマーカー蛋白であるチロシン水酸化酵素(TH)並びにドパミントランスポーター(DAT)の蛋白レベルと同部位におけるドパミン含量を指標[Mori A.ら、Neurosci Res, 51, 265-274 (2005)]に、ドパミン神経保護作用を評価した。
Claims (6)
- 一般式(1)
R1は、水素、低級アルキル基又はシクロC3-C8アルキル低級アルキル基を示す。
R2は、水素又は低級アルキル基を示す。
R3は、フェニル基、ナフチル基、ピリジル基、フリル基、チエニル基、インドリル基、ベンゾジオキソリル基又はベンゾチエニル基を示す。
ここで、上記R3で示される芳香環及び複素環上には、下記(1)~(7)からなる群から選ばれた少なくとも1つの基が置換していてもよい:
(1)低級アルキル基、
(2)ハロゲン置換低級アルキル基、
(3)ヒドロキシ基、
(4)低級アルコキシ基、
(5)ハロゲン置換低級アルコキシ基ならびに、
(6)フェニル基(ここで、フェニル基上に低級アルキル基及び低級アルコキシ基からなる群から選ばれた基を1個以上有していてもよい)
(7)ハロゲンからなる群から選ばれた基を1個以上有していてもよい
R4は、水素、低級アルキル基、ハロゲン置換低級アルキル基、ヒドロキシ基、低級アルコキシ基、低級アルコキシ低級アルキル基、フェニル基、シクロC3-C8アルキル基又は低級アルキル基を1個又は2個有していてもよいカルバモイル基を示す。
R5は水素、低級アルキル基、ハロゲン、低級アルコキシ基、ベンゾイルアミノ又はイミダゾリル基を示す。
R6は、水素、ハロゲン、低級アルキル基、ヒドロキシ基又は低級アルコキシ基を示す。
R7は、下記(1)~(19)のいずれかの基を示す。
(1)水素、
(2)ヒドロキシ基、
(3)低級アルキル基、
(4)低級アルコキシ基、
(5)フェノキシ基、
(6)シクロC3-C8アルキルオキシ基、
(7)ハロゲン、
(8)低級アルキルチオ基、
(9)アミノ基(ここで、アミノ基上に低級アルキル基、低級アルコキシ低級アルキル基及びシクロC3-C8アルキル基からなる群から選ばれた基を1個又は2個有していてもよい)
(10)低級アルキル基を1個又は2個有していてもよいカルバモイル基、
(11)ピロリジニル基、
(12)アゼパニル基、
(13)モルホリニル基、
(14)低級アルキル基を1個又は2個有していてもよいピペラジニル基、
(15)低級アルキル基を1個又は2個有していてもよいイミダゾリル基、
(16)フリル基、
(17)チエニル基、
(18)ベンゾチエニル基、
(19)ピロリジニルカルボニル基]
で表されるキノロン化合物又はその塩を有効成分として含有する、神経変性疾患、神経機能の障害に伴う疾患又はミトコンドリア機能の低下に伴う疾患の治療及び/又は予防剤。 - 神経変性疾患が、パーキンソン病、パーキンソン症候群、若年性パーキンソンニズム、線条体黒質変性症、進行性核上性麻痺、純粋無動症、アルツハイマー病、ピック病、プリオン病、大脳皮質基底核変性症、びまん性レビー小体病、ハンチントン病、有棘赤血球舞踏病、良性遺伝性舞踏病、発作性舞踏アテトーゼ、本態性振戦、本態性ミオクローヌス、ジル・ド・ラ・トゥレット症候群、レット症候群、変性性バリズム、変形性筋ジストニー、アテトーゼ、痙性斜頸、メイジ症候群、脳性麻痺、ウィルソン病、瀬川病、ハレルフォルデン・スパッツ症候群、神経軸索ジストロフィー、淡蒼球萎縮症、脊髄小脳変性症、皮質性小脳萎縮症、ホームズ型小脳萎縮症、オリーブ橋小脳萎縮症、遺伝性オリーブ橋小脳萎縮症、ジョセフ病、歯状核赤核淡蒼球ルイ体萎縮症、ゲルストマン・シュトロイスラー・シャインカ症候群、フリードライヒ運動失調症、ルシー・レヴィー症候群、メイ・ホワイト症候群、先天性小脳失調症、周期性遺伝性失調症、毛細血管拡張運動失調症、筋萎縮性側索硬化症、進行性球麻痺、脊髄性進行性筋萎縮症、球脊髄性筋萎縮症、ウェルドニッヒ・ホフマン病、クーゲルベルク・ウエランダー病、遺伝性痙性対麻痺、脊髄空洞症、延髄空洞症、アーノルド・キアリー奇形、スティフマン症候群、クリッペル・ファイル症候群、ファチオーロンド病、低位脊髄症、ダンディー・ウォーカー症候群、二分脊椎、シューグレン・ラーソン症候群、放射線脊髄症、加齢黄斑変性、ならびに脳梗塞及び脳出血から選ばれる脳卒中及び/またはそれに伴う機能不全もしくは神経脱落症状からなる群から選ばれる疾患である、請求項1に記載の治療及び/又は予防剤。
- 神経機能の障害に伴う疾患が、脊髄損傷、化学療法で誘発された神経障害、糖尿病性神経障害、放射性障害、ならびに多発性硬化症、急性散在性脳脊髄炎、横断性脊髄炎、進行性多巣性白質脳症、亜急性硬化症全脳炎、慢性炎症性脱髄性多発根神経炎及びギラン・バレー症候群から選ばれる脱髄疾患である、請求項1に記載の治療及び/又は予防剤。
- ミトコンドリア機能の低下に伴う疾患が、ピアソン症候群、糖尿病、難聴、悪性片頭痛、レーバー病、メラス(MELAS)、マーフ(MERRF)、マーフ/メラス重複症候群、NARP、純粋型ミオパチー、ミトコンドリア心筋症、ミオパチー、痴呆、胃腸運動失調、後天性鉄芽球性貧血、アミノグリコシド誘発性難聴、チトクロムb遺伝子変異による複合体III欠損症、対称性多発性脂肪腫症、運動失調、ミオクローヌス、網膜症、MNGIE、ANT1異常症、トウィンクル異常症、POLG異常症、反復性ミオグロビン尿症、SANDO、ARCO、複合体I欠損症、複合体II欠損症、視神経萎縮、複合体IV欠損重症乳児型、ミトコンドリアDNA欠乏症候群、リー脳症、慢性進行性外眼筋麻痺症候群(CPEO)、キーンズ・セイヤー症候群、脳症、乳酸血症、ミオグロビン尿、薬物誘発性ミトコンドリア病、統合失調症、大うつ病性障害、双極I型障害、双極II型障害、混合状態、気分変調性障害、非定型うつ病、季節性感情障害、産後うつ病、軽症うつ病、反復性短期うつ病性障害、難治性うつ病、慢性うつ病、重複うつ病及び急性腎不全である、請求項1に記載の治療及び/又は予防剤。
- 請求項1に記載の一般式(1)で表されるキノロン化合物又はその塩を有効成分として含有する、虚血性心疾患及び/またはそれに伴う機能不全、心不全、心筋症、大動脈乖離、免疫不全症、自己免疫疾患、膵不全、糖尿病、アテローム塞栓性腎疾患、多発性嚢胞腎、髄質嚢胞性疾患、腎皮質壊死、悪性腎硬化症、腎不全、肝性脳症、肝不全、慢性閉塞性肺疾患、肺塞栓症、気管支拡張症、珪肺症、黒色肺、特発性肺線維症、スティーブンス・ジョンソン症候群、中毒性表皮壊死症、筋ジストロフィ、クロストリジウム性筋肉壊死並びに大腿骨顆部骨壊死の疾患の治療及び/または予防剤。
- 請求項1に記載の一般式(1)で表されるキノロン化合物又はその塩をヒト又は動物に投与することを含む、神経変性疾患、神経機能の障害に伴う疾患又はミトコンドリア機能の低下に伴う疾患を治療及び/又は予防する方法。
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US13/128,803 US20110251180A1 (en) | 2008-12-05 | 2009-12-04 | Pharmaceutical agent comprising quinolone compound |
JP2010541367A JP5546463B2 (ja) | 2008-12-05 | 2009-12-04 | キノロン化合物を含む薬剤 |
EP09830467.8A EP2364706B1 (en) | 2008-12-05 | 2009-12-04 | Pharmaceutical agent comprising quinolone compound |
CA2745015A CA2745015A1 (en) | 2008-12-05 | 2009-12-04 | Pharmaceutical agent comprising quinolone compound |
CN2009801486029A CN102238951A (zh) | 2008-12-05 | 2009-12-04 | 含有喹诺酮化合物的药剂 |
ES09830467.8T ES2546507T3 (es) | 2008-12-05 | 2009-12-04 | Agente farmacéutico que comprende un compuesto de quinolona |
US13/852,196 US20130217678A1 (en) | 2008-12-05 | 2013-03-28 | Pharmaceutical agent comprising quinolone compound |
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2009
- 2009-12-04 WO PCT/JP2009/070383 patent/WO2010064701A1/ja active Application Filing
- 2009-12-04 CA CA2745015A patent/CA2745015A1/en not_active Abandoned
- 2009-12-04 EP EP09830467.8A patent/EP2364706B1/en not_active Not-in-force
- 2009-12-04 ES ES09830467.8T patent/ES2546507T3/es active Active
- 2009-12-04 KR KR1020117015164A patent/KR20110096143A/ko not_active Application Discontinuation
- 2009-12-04 JP JP2010541367A patent/JP5546463B2/ja not_active Expired - Fee Related
- 2009-12-04 CN CN2009801486029A patent/CN102238951A/zh active Pending
- 2009-12-04 US US13/128,803 patent/US20110251180A1/en not_active Abandoned
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2013
- 2013-03-28 US US13/852,196 patent/US20130217678A1/en not_active Abandoned
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CA2745015A1 (en) | 2010-06-10 |
US20110251180A1 (en) | 2011-10-13 |
CN102238951A (zh) | 2011-11-09 |
EP2364706B1 (en) | 2015-07-29 |
ES2546507T3 (es) | 2015-09-24 |
EP2364706A1 (en) | 2011-09-14 |
JPWO2010064701A1 (ja) | 2012-05-10 |
EP2364706A4 (en) | 2012-08-22 |
JP5546463B2 (ja) | 2014-07-09 |
US20130217678A1 (en) | 2013-08-22 |
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