JP2000169450A - 6-arylquinoline carboxylic acid derivatives, their addition salts and their production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a compound having an excitatory amino acid receptor, particularly an AMPA receptor antagonistic activity, comprising a 6-arylquinoline carboxylic acid derivative and an addition salt thereof as an active ingredient, and a method for producing them. The compound has a general formula (1) (Where Ar is a phenyl group optionally having one or more substituents, a naphthyl group optionally having one or more substituents, or a general formula (2) (Wherein A represents a nitrogen, oxygen or sulfur atom, and n represents 1 to 3), a 5- or 6-membered heterocyclic ring which may have one or more substituents and a condensed ring thereof. R)
Represents a nitro group, a cyano group, a trifluoromethyl group, an amino group which may be substituted, and the like, and R ¹ represents a phenyl group, an aralkyl group, a 5- or 6-membered heterocyclic ring and a condensed ring thereof (these are an aromatic ring, May have one or more substituents on the heterocyclic ring), a hydrogen atom, a lower alkyl group which may be substituted with a halogen atom, or a cyclic alkyl group, and R ² is a hydroxyl group, a lower alkoxy group, or the like. 7-arylquinoline carboxylic acid derivatives and addition salts thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a 6-arylquinoline carboxylic acid derivative effective as an excitatory amino acid receptor antagonist, particularly a selective antagonist of a non-NMDA receptor for an AMPA receptor, for the treatment of cerebral nerve cell disorders. And an addition salt thereof, a production method thereof, and a pharmaceutical composition containing these compounds.

[0002]

BACKGROUND OF THE INVENTION The excitatory amino acid glutamate is a major excitatory transmitter in the vertebrate central nervous system and is known to be the most abundant amino acid in the brain. However, it is known that when released from the nerve axon terminal beyond the physiological range, the glutamate receptor of the post-synapse is excessively excited to cause nerve cell death. this is,
It is called excitoxicity.

In recent years, glutamate-induced neuronal cell death has been deeply involved in various cranial nerve diseases such as stroke, head trauma, status epilepticus, Huntington's chorea, Parkinson's disease, amyotrophic lateral sclerosis and Alzheimer's disease. It is thought that if such excitatory neuronal cell death can be effectively prevented, there is a possibility of treatment for these intractable diseases, for which there is no cure at present.

[0004]

2. Description of the Related Art Glutamate receptors are roughly classified into ion channel receptors and G protein-coupled receptors, and this ion channel receptor is further classified into NMDA (N-
Methyl-D-aspartate) receptor, non-NMD
A receptor. In addition, the latter non-NMDA
The receptor is AMPA (α-amino-3-hydroxy-5-
It is classified into a methyl-4-isoxazolepropionic acid) receptor and a KA (kainic acid) receptor.

Research on these excitatory amino acid receptors has been advanced, and among them, AMP of non-NMDA receptor
Drugs having A receptor antagonism do not exhibit the side effects (learning / memory impairment and schizophrenia-like symptoms) of drugs having NMDA receptor antagonism (MK-801 etc.) (Neurosci. Biobehav. Rev.) ., 1992, 16, 13-24; J.Pharmaco
l.Exp.Ther., 1958, 245, 969-974 ), also can be expected to cranial nerve protective effect by administration after ischemia (Science, 1
990, 247 , 571-574) are known. In addition, compounds having a quinoxalinedione-structure AMPA receptor antagonistic activity, such as NBQX, have been reported to have drawbacks such as causing renal damage which is considered to be based on physicochemical properties (J. Cereb. Blood Flow Me
tab., 1994, 14 , 251-261), which is not a sufficient compound.

Meanwhile, as a compound having a similar structure to a quinoline carboxylic acid derivative, Dong-A Pharmaceutical Research
Laboratories reported as Korean J. Med.Chem., 5 (1), 28-37 (1995) as a compound having angiotensin II antagonistic activity.
General formula (10) described Wherein R ₁ represents an aldehyde group, an amide group, a carboxyl group or the like, and R ₂ represents a hydrogen atom.
And a compound having an anti-muscarinic activity from Istituto De Angeli SpA as a compound of the general formula (11) described in EP382687. (Wherein R represents a hydrogen atom or an alkyl group, R ₁ and R ₂ represent a hydrogen atom, a halogen, an alkyl group, an alkoxycarbonyl group, a nitro group, a cyano group, etc., R ₃ represents a hydrogen atom,
Represents an alkyl group, an aryl group, an aralkyl group, or does not have R ₃ , A represents CO, CS, or the like; Z does not have R ₃ ; Or Z is a carbon atom, and D is C when DZ is a double bond.
-R, X represents an oxygen atom, NR, etc., Y represents a substituted aminoalkyl group, a quinuclidyl group, etc.) and an anticancer effect (tyrosine kinase inhibitory effect) from BioSignal. W) as a compound having
General formula (12) described in O93 / 16064 (Wherein R ₁ represents a cyano group, a carboxyl group, an alkoxycarbonyl group, an amide group, a nitro group, an acetylamino group, etc., X represents an oxygen atom, etc., Y represents an oxygen atom, a sulfur atom, NH, ₂ and R ₄ represent a hydrogen atom, a hydroxyl group, an amino group, a trifluoromethyl group, an alkyl group, or the like;
₃ represents a hydroxyl group, an amino group, an alkylamino group, a nitroso group, a trifluoromethyl group, and the like, and R ₅ represents a hydroxyl group, an alkyl group, a halogen atom, and the like. However, these above mentioned compounds are 6,7
None has an asymmetric substituent at the position, and it is not described that it has an AMPA receptor antagonism of an excitatory amino acid receptor.

Further, as a compound having a serotonin 4 receptor antagonistic activity from Taisho Pharmaceutical, the compound represented by the general formula (13) described in WO95 / 31455 (Wherein X represents an oxygen atom, NH, m represents 0 to 6,
A represents a haloalkyl group, a hydroxyl group, an alkoxy group, a carboxyl group, a cyano group, an amide group, etc.), and a compound having a serotonin 4 receptor antagonistic action described by JP-A-8-311033. (14) (Wherein X represents O or NH, Y is 2- (diethylamino) ethyl, 8-methyl-8-azabicyclo [3,
2,1] oct-3-yl, quinuclidin-3-yl,
Which represents 1-ethylpiperidin-4-yl or the like). However, these compounds have no substituent on the benzene ring, and have a different structure from the compound of the present invention.
It is not described that it has A-antagonism.

Further, as a compound having an inhibitory effect on a pathological symptom related to hyperactivity of the excitatory amino acid pathway, a compound represented by the general formula (15) described in EP640612 from Adire et Company. (In the formula, R ₁ , R ₂ , and R ₃ represent a hydrogen atom, a halogen atom, an alkyl group, a nitro group, a cyano group, an aminosulfonyl group, and the like, and R ₄ and R ₅ represent a hydrogen atom, an alkyl group, and the like.)
A compound represented by the general formula (1) has been disclosed.
As a synthetic intermediate of 5), general formula (16) Wherein R ₁ , R ₂ and R ₃ are as described above, and a compound represented by the general formula (17): (Wherein R ₁ , R ₂ , and R ₃ are as described above). However, it is not described that these synthetic intermediates have an AMPA receptor antagonism of an excitatory amino acid receptor, and those compounds having a substituent at the 6,7-position such as the compound of the present invention are not described. It is symmetrical and has a different structure from the compound of the present invention.

Further, as a compound as a fluorescent substance of an organic light emitting device from Pioneer Electronics Co., Ltd., JP-A-3-162483.
(18) (Wherein _R 1, _{R 8} represents a hydrogen atom, an alkyl group, _{R 3}
Represents a hydrogen atom, an alkyl group, a carboxy group, a cyano group, etc., R ₄ represents a hydrogen atom, an alkyl group, an alkoxy group, etc., R ₅ represents a hydrogen atom, an amino group, etc., and R ₆ represents a hydrogen atom. , R ₇ represents a hydroxyl group, an amino group, an alkylamino group, etc.). However, it is not described that this compound is irrelevant to drugs and has an AMPA receptor antagonism of an excitatory amino acid receptor.

Also, recently, Alex A. Cordi et al. Described the conversion of the functional group at the 3-position of the 2-oxoquinoline skeleton as an excitatory amino acid antagonist by the general formula (19). (Wherein R, R ₁ , and R ₂ represent a hydrogen atom, a chlorine atom, a fluorine atom, and a nitro group, and X represents a carboxylic acid, a phosphonic acid, a boric acid, an amide, and the like).
m., 39 , 197-206 (1996). However, among these compounds, attention has been paid to a compound in which X is a phosphonic acid in the general formula (19), and a compound having an asymmetric substituent at the 6,7-position of the quinoline ring such as the compound of the present invention has been reported. Not. Also reported AMP
A antagonism and glycine antagonism are not considered to be sufficient.

[0011]

DISCLOSURE OF THE INVENTION The present invention is directed to the antagonistic action of glutamate, which is considered to be a cause of memory disorders and dementia caused by the above-mentioned diseases and selective cell death, especially non-agonism.
An object of the present invention is to provide a compound having a high affinity and selectivity for an NMDA receptor for an AMPA receptor and having a protective effect on brain neurons.

[0012]

DISCLOSURE OF THE INVENTION The present inventors have developed an excitatory amino acid receptor antagonist, particularly no
As a result of intensive studies in search of a selective antagonist of the n-NMDA receptor for the AMPA receptor, it was found that the 6-arylquinoline carboxylic acid derivative of the present invention has an excellent AMPA receptor antagonistic activity.

That is, according to the present invention, general formula (1) (Wherein Ar is a phenyl group optionally having one or more substituents, a naphthyl group optionally having one or more substituents, or a general formula (2) (Wherein A represents a nitrogen, oxygen or sulfur atom, and n represents 1 to 3), a 5- or 6-membered heterocyclic ring which may have one or more substituents and a condensed ring thereof. R)
Is a nitro group, a cyano group, a trifluoromethyl group, an amino group which may be substituted, or a compound represented by the general formula (3) (Wherein R ³ and R ⁴ are the same or different and each is a phenyl group,
An aralkyl group, a 5- or 6-membered heterocyclic ring and a condensed ring thereof (these may have one or more substituents on an aromatic ring or a heterocyclic ring), a hydrogen atom, and a lower alkyl group which may be halogen-substituted Represents a cyclic alkyl group, or forms a ring together with R ³ and R ⁴ together with a nitrogen atom (furthermore, a hetero atom is 1 or 2
And n represents 1-2), and R ¹ represents a phenyl group, an aralkyl group, a 5- or 6-membered heterocyclic ring and a condensed ring thereof (these are aromatic rings,
May have one or more substituents on the heterocyclic ring), a hydrogen atom, a lower alkyl group optionally substituted by a halogen atom,
R ² represents a hydroxyl group, a lower alkoxy group, or a general formula (4) (Wherein R ⁵ and R ⁶ are the same or different and each is a phenyl group,
An aralkyl group, a 5- or 6-membered heterocyclic ring and a condensed ring thereof (these may have one or more substituents on an aromatic ring or a heterocyclic ring), a hydrogen atom, and a lower alkyl group which may be halogen-substituted Represents a cyclic alkyl group, or forms a ring together with R ⁵ and R ⁶ together with a nitrogen atom (furthermore, a hetero atom is 1 or 2
Or one of R ⁵ and R ⁶ represents a hydrogen atom, and the other represents a hydroxyl group, a lower alkoxy group, or a phenyloxy group optionally having one or more substituents. 6 represents an aralkyloxy group which may have one or more groups or substituents) and an addition salt thereof, which have excellent AMPA receptor antagonistic activity. The invention has been completed. In the present invention the compound the general formula (1), Preferably, R is a nitro group, a trifluoromethyl group, R ¹
Is a hydrogen atom, R ² is a hydroxyl group, and Ar is a phenyl group optionally having one or more substituents, a naphthyl group optionally having one or more substituents, or a compound represented by the general formula (2) Certain compounds are mentioned.

The preferred compounds are as follows: 1,2-dihydro-7-nitro-6-phenyl-2-oxoquinoline-3-carboxylic acid 1,2-dihydro-6-phenyl-2-oxo -7-Trifluoromethylquinoline-3-carboxylic acid 1,2-dihydro-6- (3-fluorophenyl) -7
-Nitro-2-oxoquinoline-3-carboxylic acid 1,2-dihydro-6- (3-fluorophenyl) -2
-Oxo-7-trifluoromethylquinoline-3-carboxylic acid 1,2-dihydro-6- (4-fluorophenyl) -7
-Nitro-2-oxoquinoline-3-carboxylic acid 1,2-dihydro-6- (4-methylphenyl) -7-
Nitro-2-oxoquinoline-3-carboxylic acid 1,2-dihydro-6- (4-methoxyphenyl) -7
-Nitro-2-oxoquinoline-3-carboxylic acid 1,2-dihydro-7-nitro-6- (4-bromophenyl) -2-oxoquinoline-3-carboxylic acid 1,2-dihydro-7-nitro- 6- (4-nitrophenyl) -2-oxoquinoline-3-carboxylic acid 1,2-dihydro-6- (2-naphthyl) -7-nitro-2-oxoquinoline-3-carboxylic acid 1,2-dihydro -7-Nitro-6- (4-hydroxyphenyl) -2-oxoquinoline-3-carboxylic acid 6- (benzofuran-2-yl) -1,2-dihydro-
7-Nitro-2-oxoquinoline-3-carboxylic acid 6- (3-thienyl) -1,2-dihydro-7-nitro-2-oxoquinoline-3-carboxylic acid 1,2-dihydro-7-nitro- 2-oxo-6- (3
-Pyridyl) quinoline-3-carboxylic acid 2-methoxy-7-nitro-6-phenylquinoline-3
-Ethyl carboxylate Ethyl 6- (3-fluorophenyl) -2-methoxy-7-nitroquinoline-3-carboxylate Ethyl 6- (4-fluorophenyl) -2-methoxy-7-nitroquinoline-3-carboxylate Ethyl 6- (4-methylphenyl) -2-methoxy-7-nitroquinoline-3-carboxylate Ethyl 2-methoxy-6- (4-methoxyphenyl) -7-nitroquinoline-3-carboxylate 2-methoxy- Ethyl 7-nitro-6- (4-bromophenyl) quinoline-3-carboxylate Ethyl 2-methoxy-7-nitro-6- (4-nitrophenyl) quinoline-3-carboxylate 2-methoxy-6- (2 -Naphthyl) -7-nitroquinoline-3-carboxylate ethyl 6- (benzofuran-2-yl) -2-methoxy-7-
Ethyl nitroquinoline-3-carboxylate Ethyl 2-methoxy-7-nitro-6- (3-thienyl) quinoline-3-carboxylate and the like.

[0015]

In the general formula (1) of the present invention, "phenyl group optionally having one or more substituents", "naphthyl group optionally having one or more substituents" and "substituent Or 6-membered heterocyclic ring and a condensed ring thereof which may have one or more phenyl group, aralkyl group, 5- or 6-membered heterocyclic ring and a condensed ring thereof (these are aromatic ring, heterocyclic ring, May have one or more substituents) and "phenyloxy group optionally having one or more substituents" and "aralkyloxy group optionally having one or more substituents" The `` substituent '' includes a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkoxycarbonyl group, a nitro group, an amino group, a cyano group and the like, and the `` lower alkyl group '' Methyl, ethyl, n-propyl, Those having 1 to 6 carbon atoms which is linear or branched, such as so- propyl and the like, the term "cyclic alkyl group", cyclopropyl, cyclopentyl, and the like having a carbon number of 3 to 7 such as cyclohexyl.

The "halogen atom" includes fluorine, chlorine, bromine and iodine, and the "lower alkoxy group" includes linear or branched ones having 1 to 4 carbon atoms such as methoxy, ethoxy and propoxy. Examples of the "lower alkylthio group" include straight-chain or branched ones having 1 to 4 carbon atoms such as methylthio, ethylthio, and propylthio.
`` Lower alkoxycarbonyl group '' includes methoxycarbonyl, ethoxycarbonyl and the like, and `` optionally substituted amino group '' means acyl group, arylsulfonyl group such as acetyl, methanesulfonyl, phenylsulfonyl and the like. Or a lower alkyl group which may be substituted with 1 to 2 halogen atoms,
Examples include a phenyl group which may have two substituents and an amino group which may be substituted by an aralkyl group which may have 1 to 2 substituents. Here, the substituent refers to the “substituent” described above.

Further, in the description, "5- or 6-membered heterocyclic ring which may have one or more substituents and a condensed ring thereof" and "phenyl, aralkyl, 5- or 6-membered heterocyclic ring and condensed ring thereof" The term "heterocycle" in "rings (which may have one or more substituents on an aromatic ring or a heterocycle)" means a saturated or unsaturated monocyclic or polycyclic nitrogen, oxygen, sulfur, or the like. Heterocyclic group which can contain one or two atoms, such as pyrrolidyl, piperidyl, piperazyl, morpholyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidyl, pyridazyl, pyracyl and the like. "The condensed ring" means benzofuranyl, benzothienyl, indolyl, benzimidazolyl, benzoxazolidinyl, benzothiazolidinyl, quino Le, isoquinolyl, quinazolyl, quinoxalyl, cinnolyl or the like.

The phrase "forms a ring together with a nitrogen atom (and may further contain one or two hetero atoms)" means that the compound contains one or two additional saturated monocyclic nitrogen, oxygen and sulfur atoms. And a heterocyclic group which may be mentioned, for example, pyrrolidyl, piperidyl, piperazyl, morpholyl and the like. The compound of the present invention is produced, for example, by the following production method.

Among the compounds represented by the general formula (1), R ¹
Is a hydrogen atom represented by the general formula (5) (Wherein Ar, R, and R ² represent the same as described above, and R ⁷ represents a lower alkyl group or an aralkyl group which may have one or more substituents). A suitable acid in a solvent, for example, water, acetic acid, methanol, etc.
For example, it can be synthesized by reacting with hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid or the like at 25 to 120 ° C. for 0.5 to 96 hours.

The compound represented by the general formula (1) is
General formula (5) (Wherein Ar, R, R ² and R ⁷ represent the same as described above), when R ² is a lower alkoxy group, the compound is converted to an appropriate solvent, water, methanol, ethanol, etc. In a solvent of the above, a suitable alkali, for example, potassium hydroxide, sodium hydroxide or the like is reacted at 25 to 100 ° C. for 0.5 to 2 hours to form a carboxylic acid form, without solvent or a suitable solvent, for example, , Water, acetic acid, methanol or the like, using a suitable acid such as hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid or the like at 25 to 120 ° C for 0.5 to 96 ° C.
It can be synthesized by reacting for a time.

Among the compounds represented by the general formula (1), a compound in which R ¹ is a hydrogen atom is selected from a suitable solvent such as tetrahydrofuran, dioxane, N, N-dimethylformamide, N, N-dimethylacetamide. Etc.
Using a suitable base, for example, sodium hydride, sodium carbonate, potassium carbonate and the like, alkyl halide such as methyl iodide and aralkyl halide such as benzyl chloride, 4-methoxybenzyl chloride and the like, or cyclic alkyl halide For example, cyclopentyl bromide, cyclohexyl bromide, etc.
C. for 1 to 12 hours, R ¹ is a lower alkyl group,
A compound substituted with an aralkyl group (which may have one or more substituents) or a cyclic alkyl group can also be used.

The compound represented by the general formula (5) is
General formula (6) (Wherein R, R ² and R ⁷ represent the same as described above, and X represents a halogen atom) and a compound represented by the general formula (7) (Where Ar represents the same as described above) or the general formula (8) (Wherein Ar represents the same as described above, and R ¹⁰ represents a lower alkyl group) and a suitable base such as tetrahydrofuran, N, N-dimethylformamide, benzene, toluene, etc. Using sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, or the like, a suitable catalyst such as tetrakis (triphenylphosphine) palladium (Pb ⁰ )
Bis (triphenylphosphine) palladium chloride (Pb
^II ), (1,1′-bis (diphenylphosphino) ferrocene) palladium (Pb ^II ), etc.
It can be synthesized by reacting at 25 to 120 ° C for 1 to 36 hours.

Here, the compound represented by the general formula (6) is a compound represented by the general formula (9) (Wherein R, R ² and X represent the same as described above) by a known method, that is, a suitable silver catalyst in a suitable solvent such as benzene, toluene, chloroform, methylene chloride, tetrahydrofuran and the like. , For example, silver oxide,
It can be synthesized by reacting with an alkyl halide such as methyl iodide or an aralkyl halide such as 4-methoxybenzyl chloride at 25 to 120 ° C. for 2 to 24 hours using silver carbonate or the like.

Further, the compound represented by the general formula (9) is prepared by adding a borate such as tetramethyloxonium borate in a suitable solvent such as benzene, toluene, chloroform, methylene chloride, tetrahydrofuran or the like. It can also be synthesized by reacting at ５０50 ° C. for 2 to 6 hours.

The compound represented by the general formula (9) is
It can be synthesized by a known method. That is, the general formula (2)
0) in a suitable solvent, for example, an alcohol such as ethanol or methanol, tetrahydrofuran, N, N-dimethylformamide, etc., in the presence of a suitable base, for example, sodium ethoxide, potassium ter-butoxide, potassium hydroxide, etc. It can be synthesized by reacting an acid ester such as diethyl malonate. (In the formula, R and X represent the same as described above.) Among the compounds represented by the general formula (20), the compound wherein R is a nitro group can be synthesized by the method shown in the following scheme 1. That is, the general formula (21) which can be obtained or synthesized can be acetylated into a general formula (22), which can be converted into a suitable solvent, for example, nitromethane, acetic acid, sulfuric acid or the like, and a suitable nitrating agent such as concentrated nitric acid. The reaction is carried out at -10 to 80 ° C for 0.5 to 2 hours using fuming nitric acid, potassium nitrate, or the like to obtain a general formula (23). This general formula (23) is converted into a suitable solvent such as water or acetone in a suitable solvent. Oxidizing agents such as potassium permanganate, sodium periodate, etc.
The reaction is performed at 20 ° C. for 1 to 15 hours to obtain a general formula (24)
This is added to a suitable solvent, such as water, (In the formula, X represents the same as described above.) Alternatively, in a mixture of an alcohol such as ethanol or methanol and water or the like, a suitable base such as sodium hydroxide, potassium hydroxide or the like is used at 20 to 100 ° C. Alkaline hydrolysis is performed for 5 hours, or in a suitable solvent, for example, water or a mixture of water such as ethanol or methanol and water, using an appropriate acid, for example, hydrochloric acid, hydrobromic acid or the like.
Formula (25) by acid hydrolysis at 1 ° C. for 1 to 10 hours.
And Next, using a suitable reducing agent, for example, a borane complex such as a borane-tetrahydrofuran complex, a borane-dimethylsulfide complex, or a borane-pyridine complex in a suitable solvent such as ether, tetrahydrofuran, or dioxane. The reaction is carried out at 20 to 150 ° C. for 1 to 5 hours to obtain the general formula (26), which is subsequently dissolved in a suitable solvent such as chloroform, methylene chloride, tetrahydrofuran, benzene, water or the like, and a suitable oxidizing agent such as manganese dioxide or the like. And the reaction is carried out at 20 to 100 ° C. for 1 to 24 hours to obtain the general formula (20a).

Further, among the compounds represented by the general formula (20), those wherein R is a trifluoromethyl group can be synthesized by the method shown in the following scheme 2. (Where X represents the same as described above)

That is, a suitable base such as potassium ter- in a suitable solvent such as ether, tetrahydrofuran or the like for the general formula (27) which is available or can be synthesized.
Chloroform in the presence of butoxide or the like is -78 to 25 ° C.
To a general formula (28), which is reacted with an appropriate solvent such as water, acetic acid, tetrahydrofuran or a mixture thereof using an appropriate reducing agent such as titanium trichloride. After reacting at ８０80 ° C. for 10 to 30 minutes, the compound is made alkaline with a suitable alkali, for example, potassium hydroxide, sodium hydroxide, lithium hydroxide or the like, whereby the general formula (20b) can be obtained. The present invention will be described in more detail with reference to Production Examples and Examples of the compound of the present invention.

[0028]

EXAMPLES Example 1 2-Methoxy-7-nitro-6-phenylquinoline-3
-Ethyl carboxylate 6-bromo-2-methoxy-7-nitroquinoline-3-
A 2M aqueous solution of sodium carbonate (732 μl, 1.46 mmol) and tetrakis (triphenylphosphine) palladium (42.3 mg, 36.6 μm) were added to a solution of ethyl carboxylate (260 mg, 732 μmol) and phenylboric acid (134 mg, 1.10 mmol) in toluene (5 ml).
mol) were added in sequence, and the mixture was heated under reflux for 6 hours. The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off.
The obtained residue was purified by silica gel column chromatography [hexane-ethyl acetate = 4: 1] to obtain 242 mg of the title compound as a yellow powder. Yield 94
%. ¹ H-NMR (CDCl ₃ , δ): 1.44 (3H,
t, J = 7.3 Hz), 4.19 (3H, s), 4.4
5 (2H, q, J = 7.3 Hz), 7.37-7.47
(5H, m), 7.85 (1H, s), 8.31 (1
H, s), 8.60 (1H, s).

Examples 2 to 8 The compounds shown in Table 1 below were obtained in the same manner as in Example 1.

Example 2 ¹ H-NMR (CDCl ₃ , δ): 1.44 (3H,
t, J = 7.3 Hz), 4.19 (3H, s), 4.4
5 (2H, q, J = 7.3 Hz), 7.10-7.16
(3H, m), 7.39-7.45 (1H, m), 7.
84 (1H, s), 8.34 (1H, s), 8.60
(1H, s).

Example 3 ¹ H-NMR (CDCl ₃ , δ): 1.44 (3H,
t, J = 7.3 Hz), 2.42 (3H, s), 4.1
9 (3H, s), 4.44 (2H, q, J = 7.3H
z), 7.27 (4H, s), 7.83 (1H, s),
8.28 (1H, s), 8.59 (1H, s).

Example 4 ¹ H-NMR (CDCl ₃ , δ): 1.44 (3H,
t, J = 7.3 Hz), 3.86 (3H, s), 4.1
9 (3H, s), 4.44 (2H, q, J = 7.3H
z), 6.99 (2H, d, J = 8.8 Hz), 7.3
1 (2H, d, J = 8.8 Hz), 7.82 (1H,
s), 8.26 (1H, s), 8.58 (1H, s).

Example 5 ¹ H-NMR (CDCl ₃ , δ): 1.44 (3H,
t, J = 7.3 Hz), 4.19 (3H, s), 4.4
5 (2H, q, J = 7.3 Hz), 7.13-7.17
(2H, m), 7.34-7.37 (2H, m), 7.
82 (1H, s), 8.31 (1H, s), 8.59
(1H, s).

Example 6 ¹ H-NMR (CDCl ₃ , δ): 1.44 (3H,
t, J = 7.3 Hz), 4.19 (3H, s), 4.4
5 (2H, q, J = 7.3 Hz), 7.25 (2H,
d, J = 8.3 Hz), 7.59 (2H, d, J = 8.
3Hz), 7.81 (1H, s), 8.33 (1H,
s), 8.59 (1H, s).

Example 7 ¹ H-NMR (CDCl ₃ , δ): 1.44 (3H,
t, J = 7.3 Hz), 4.21 (3H, s), 4.4
6 (2H, q, J = 7.3 Hz), 7.56 (2H,
d, J = 8.8 Hz), 7.85 (1H, s), 8.3
3 (2H, d, J = 8.8 Hz), 8.46 (1H,
s), 8.62 (1H, s).

Example 8 ¹ H-NMR (CDCl ₃ , δ): 1.44 (3H,
t, J = 7.3 Hz), 4.21 (3H, s), 4.4
5 (2H, q, J = 7.3 Hz), 7.46 (1H, d
d, J = 8.8, 1.5 Hz), 7.53-7.57
(2H, m), 7.87-7.93 (4H, m), 7.
95 (1H, s), 8.37 (1H, s), 8.63
(1H, s).

Example 9 6- (benzofuran-2-yl) -2-methoxy-7-
Ethyl nitroquinoline-3-carboxylate 6-bromo-2-methoxy-7-nitroquinoline-3-
Ethyl carboxylate (150 mg, 422 μmol) and (benzofuran-2-yl) boric acid (130 mg, 633 μmol) in toluene (3 m
l) 2M aqueous sodium carbonate solution (422μl, 844μmol)
And (1,1′-bis (diphenylphosphino) ferrocene) dichloropalladium-methylene chloride (1: 1)
Complexes (17.2 mg, 21.1 μmol) were sequentially added, and the mixture was heated under reflux for 6 hours. The organic layer was separated and dried over anhydrous sodium sulfate.
The solvent was distilled off. The obtained residue was purified by silica gel column chromatography [hexane-ethyl acetate = 4: 1] to obtain 115 mg of the title compound as an orange powder. Yield 69%. ¹ H-NMR (CDCl ₃ , δ):
1.45 (3H, t, J = 7.3 Hz), 4.19 (3
H, s), 4.46 (2H, q, J = 7.3 Hz),
7.01 (1H, d, J = 1.0 Hz), 7.29 (1
H, d, J = 7.3 Hz), 7.35 (1H, td, J)
= 7.3, 1.5 Hz), 7.52 (1H, 1, J =
7.3 Hz), 7.63 (1H, d, J = 7.8H)
z), 8.22 (1H, s), 8.31 (1H, s),
8.66 (1H, s).

Example 10 Ethyl 2-methoxy-7-nitro-6- (3-thienyl) quinoline-3-carboxylate 6-bromo-2-methoxy-7-nitroquinoline-3-
Using ethyl carboxylate (150 mg, 422 μmol) and (3-thienyl) boric acid (81.0 mg, 633 μmol), 120 mg of the title compound was obtained as a tan powder in the same manner as in Example 9. 79% yield. ¹ H-NMR (CDCl ₃ , δ): 1.44 (3H,
t, J = 7.3 Hz), 4.18 (3H, s), 4.4
5 (2H, q, J = 7.3 Hz), 7.14 (1H, d
d, J = 5.4, 1.5 Hz), 7.39 (1H, d
d, J = 2.9, 1.5 Hz), 7.43 (1H, d
d, J = 5.4, 2.9 Hz), 7.90 (1H,
s), 8.24 (1H, s), 8.58 (1H, s).

Example 11 Ethyl 2-methoxy-7-nitro-6- (3-pyridyl) quinoline-3-carboxylate 6-bromo-2-methoxy-7-nitroquinoline-3-
Ethyl carboxylate (150 mg, 422 μmol) and diethyl (3
-Pyridyl) borane (93.1 mg, 633 μmol) was used to give the title compound as a yellow-white powder in the same manner as in Example 9.
9 mg were obtained. 73% yield. ¹ H-NMR (CDCl ₃ , δ): 1.44 (3H,
t, J = 7.3 Hz), 4.20 (3H, s), 4.4
5 (2H, q, J = 7.3 Hz), 7.40 (1H, d
d, J = 7.8, 4.9 Hz), 7.70 (1H, d
t, J = 7.8, 2.0 Hz), 7.85 (1H,
s), 8.43 (1H, s), 8.62 (1H, s),
8.68 (1H, d, J = 2.0 Hz), 8.69 (1
H, dd, J = 4.9, 1.5 Hz).

Example 12 1,2-Dihydro-7-nitro-2-oxo-6-phenylquinoline-3-carboxylic acid To a solution of the compound of Example 1 (242 mg, 687 μmol) in acetic acid (7 ml) was added 47% hydrobromic acid (1.4 ml), and the mixture was heated under reflux for 1 hour. Water was added to the reaction solution, and the precipitated crystals were collected by filtration, washed with water, and air-dried to obtain 209 mg of the title compound as a pale yellow powder. 95% yield. mp 256-258 ° C Anal. Calcd for C ₁₆ H ₁₀ N ₂ O ₅ · 1 / 2H ₂ O:
C, 60.19; H, 3.47; N, 8.77. Found: C, 60.25; H, 3.52; N, 8.69. HR-MS: 311.0692 (+2.4 mmu)

Examples 13 to 19 Using the compounds of Examples 2 to 8 and in the same manner as in Example 8, the compounds shown in Table 2 below were obtained.

Example 13 mp 263-265 ° C. Anal. Calcd for C ₁₆ H ₉ FN ₂ O _{5 1/5} H ₂ O:
C, 57.91; H, 2.86; N, 8.44. Found: C, 58.09; H, 2.84; N, 8.43. HR-MS: 329.0609 (+3.6 mmu)

[0043] (Example 14) mp279-281 ℃ _{(decomposition) Anal. Calcd for C 17 H} 12 N 2 O 5 · 11 / 10H
₂ O: C, 59.33; H, 4.16; N, 8.14. Found: C, 59.21; H, 3.85; N, 7.83. HR-MS: 324.0758 (+1.2 mmu)

Example 15 mp 299-301 ° C. (decomposition) Anal. Calcd for C ₁₆ H ₁₀ N ₂ O ₆ .1 / 2H ₂ O:
C, 57.32; H, 3.31; N, 8.36. Found: C, 57.21; H, 2.95; N, 8.47. HR-MS: 326.0534 (-0.4 mmu)

. [0045] (Example 16) mp258-260 ℃ Anal Calcd for C 16 H 9 FN 2 O 5 · 1 / 4H 2 O:
C, 57.75; H, 2.88; N, 8.42. Found: C, 57.91; H, 2.74; N, 8.36. HR-MS: 328.0503 (+0.8 mmu)

Example 17 mp 286-288 ° C. Anal. Calcd for C ₁₆ H ₉ BrN ₂ O ₅ · H
₂ O: C, 48.63; H, 2.47; N, 7.09. Found: C, 48.76; H, 2.30; N, 7.16. HR-MS: 387.9694 (-0.1 mmu)

(Example 18) mp> 300 ° C. Anal. Calcd for C ₁₆ H ₉ N ₃ O ₇ : C, 54.09;
2.55; N, 11.83. Found: C, 53.97; H, 2.49; N, 12.14. HR-MS: 355.0411 (-2.9 mmu)

Example 19 mp> 300 ° C. Anal. Calcd for C ₂₀ H ₁₂ N ₂ O ₅ : C, 66.67;
H, 3.36; N, 7.73. Found: C, 66.58; H, 3.47; N, 7.58. HR-MS: 361.0813 (-1.2 mmu)

Example 20 1,2-Dihydro-6- (4-methoxyphenyl) -7
-Nitro-2-oxoquinoline-3-carboxylic acid Methanol (5 ml) of the compound of Example 4 (199 mg, 520 μmol)
A 1N aqueous potassium hydroxide solution (1.04 ml, 1.04 mmol) was added to the solution, and the mixture was heated under reflux for 1 hour. After cooling, the solvent was distilled off, and the obtained residue was dissolved in water and washed with ethyl acetate. The aqueous layer was adjusted to pH 1 using concentrated hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was distilled off. After dissolving the obtained residue in acetic acid (4 ml), concentrated hydrochloric acid (1 ml) was added,
The mixture was stirred at 80 ° C. for 3 hours. After cooling, water was added, and the precipitated crystals were collected by filtration, washed with water, and air-dried to give 96.1 mg of the title compound as a tan powder. Yield 54%. mp 283-285 ° C Anal. Calcd for C ₁₇ H ₁₂ N ₂ O ₆ : C, 60.00;
H, 3.55; N, 8.23. Found: C, 60.20; H, 3.50; N, 8.15. HR-MS: 340.0701 (+0.6 mmu)

Example 21 6- (Benzofuran-2-yl) -1,2-dihydro-
7-nitro-2-oxoquinoline-3-carboxylic acid Concentrated hydrochloric acid (1 ml) was added to a solution of the compound of Example 9 (115 mg, 293 μmol) in acetic acid (5 ml), and the mixture was stirred at room temperature for 24 hours.
Water was added to the reaction solution, and the precipitated crystals were collected by filtration, washed with water and chloroform, and then air-dried to obtain 90.0 mg of the title compound as a yellow powder. Yield 87%. . mp> 300 ℃ Anal Calcd for C 18 H 10 N 2 O 6 · 1 / 4H 2 O:
C, 60.94; H, 2.98; N, 7.90. Found: C, 60.81; H, 2.94; N, 7.82. HR-FAB +: 351.0581 (-3.6 mmu)

Example 22 1,2-Dihydro-7-nitro-2-oxo-6- (3
-Thienyl) -quinoline-3-carboxylic acid To a solution of the compound of Example 10 (120 mg, 335 μmol) in acetic acid (4 ml) was added 47% hydrobromic acid (1 ml), and the mixture was stirred at room temperature for 22 hours. Water was added to the reaction solution, and the precipitated crystals were collected by filtration, washed with water and air-dried to give 9 g of the title compound as a yellow powder.
7.3 mg were obtained. 89% yield. _{. mp254-256 ℃ Anal Calcd for C 14} H 8 N 2 O 5 S · 1 / 2H 2 O:
C, 51.69; H, 2.79; N, 8.61. Found: C, 51.90; H, 2.77; N, 8.61. HR-FAB +: 371.0229 (-0.4 mmu)

Example 23 1,2-Dihydro-7-nitro-2-oxo-6- (3
-Pyridyl) quinoline-3-carboxylic acid To a solution of the compound of Example 11 (109 mg, 308 μmol) in acetic acid (4 ml) was added 47% hydrobromic acid (1 ml), and the mixture was stirred at 100 ° C. for 5 hours. After cooling, the precipitated crystals were collected by filtration, washed with water, and air-dried to obtain 85.4 mg of the title compound as a yellow powder.
Yield 71%. mp> 300 ° C HR-FAB +: 312.0626 (+0.5 mmu)

Reference Example 1 Ethyl 6-bromo-1,2-dihydro-7-nitro-2-oxoquinoline-3-carboxylate After dissolving sodium (460 mg, 20.0 mmol) in anhydrous ethanol (30 ml), diethyl malonate (4.55 ml, 30.0 mmol) was added dropwise, and the mixture was stirred at room temperature for 15 minutes. This is treated with 5-bromo-4-
The solution was added to a solution of nitroanthranildaldehyde (2.46 g, 10.0 mmol) in ethanol (30 ml), and the mixture was stirred at room temperature for 22 hours. The precipitated crystals were collected by filtration, washed with ethanol, and recrystallized from acetic acid-water to give 2.52 g of the title compound as a yellow powder.
Obtained. Yield 74%. ¹ H-NMR (DMSO-d ₆ , δ): 1.30 (3
H, t, J = 7.3 Hz), 4.30 (2H, q, J =
7.3 Hz), 7.84 (1H, s), 8.43 (1
H, s), 8.50 (1H, s), 12.46 (1H,
s).

Reference Example 2 6-Bromo-2-methoxy-7-nitroquinoline-3-
Ethyl carboxylate The compound of Reference Example 1 (2.52 g, 7.39 mmol) and silver oxide (2.06 g)
g, 8.87 mmol) in anhydrous toluene (200 ml).
Then, methyl iodide (1.38 ml, 2.22 mmol) was added thereto, and the mixture was refluxed for 1 hour. Methyl iodide (1.38 ml, 2.22 mmol) was added,
The mixture was further refluxed for 1 hour. After cooling, the mixture was filtered using Celite, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography [hexane-ethyl acetate = 2: 1] to give the title compound as a yellow-white powder (1.
77 g were obtained. Yield 68%. ¹ H-NMR (CDCl ₃ , δ): 1.43 (3H,
t, J = 7.3 Hz), 4.16 (3H, s), 4.4
5 (2H, q, J = 7.3 Hz), 8.15 (1H,
s), 8.27 (1H, s), 8.50 (1H, s).

Reference Example 3 2-bromo-4-dichloromethyl-5-nitrobenzotrifluoride Potassium tet-butoxide (35.3 g, 315 mm
ol) in tetrahydrofuran (500 ml) under stirring at −78 ° C. at 2-78 ° C. in tetrahydrofuran (50 ml) of 2-bromo-5-nitrobenzotrifluoride (25.0 g, 92.6 mmol) and chloroform (16.6 g, 139 mmol). ) The solution was slowly added dropwise. After the addition, the mixture was stirred at the same temperature for 30 minutes. A mixture of methanol (25 ml) and acetic acid (25 ml) was added to the reaction solution, the mixture was heated to room temperature, neutralized with a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 100: 0-300: 1),
21.3 g of the title compound were obtained as a yellow liquid. Yield 65%. ¹ H-NMR (DMSO-d ₆ , δ): 7.71 (1
H, s), 8.43 (1H, s), 8.52 (1H,
s).

Reference Example 4 5-Bromo-4-trifluoromethylanthranilic aldehyde Acetic acid (140) was added to a solution of the compound of Reference Example 3 (13.6 g, 38.5 mmol) in tetrahydrofuran (350 ml).
ml) and water (14 ml) were added, and a 24% aqueous solution of titanium trichloride (116 ml, 231 mmol) was slowly added dropwise at room temperature with stirring. The reaction solution was ice-cooled, adjusted to pH 12 by adding a 20% aqueous sodium hydroxide solution, ethyl acetate was added, insolubles were filtered through celite, and the residue was washed with ethyl acetate. The filtrate and the washing solution were combined, the ethyl acetate layer was separated, and the aqueous layer was extracted with ethyl acetate. The ethyl acetate layers were combined, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 40: 1-20:
1) to give 3.34 g of the title compound as a yellow powder.
Yield 32%. ¹ H-NMR (DMSO-d ₆ , δ): 7.31 (1
H, s), 7.50 (2H, s), 8.05 (1H,
s), 9.89 (1H, s).

Example 24 Ethyl 6-bromo-1,2-dihydro-2-oxo-7-trifluoromethylquinoline-3-carboxylate 1M sodium ethoxide ethanol solution (1.35m) in diethyl malonate (216mg, 1.35mmol)
1, 1.35 mmol) and stirred at room temperature for 15 minutes. This solution was treated with 5-bromo-4-trifluoromethylanthranildaldehyde (181 mg, 0.675 mm
ol) in ethanol (3 ml).
Stir for 6 hours. The precipitated crystals are collected by filtration, washed with ethanol,
It was dried under reduced pressure. The obtained crude crystals were suspended in water, and 3N hydrochloric acid was added to adjust the pH to 4. Then, the precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to give the title compound as a white powder, 144 m
g was obtained. Yield 65%. ¹ H-NMR (DMSO-d ₆ , δ): 1.31 (3
H, t, J = 6.8 Hz), 4.30 (2H, q, J =
6.8 Hz), 7.75 (1 H, s), 8.39 (1
H, s), 8.50 (1H, s), 12.38 (1H,
s).

Example 25 Ethyl 6-bromo-2-ethoxy-7-trifluoromethylquinoline-3-carboxylate Compound of Example 24 (500 mg, 1.37 mmol)
Silver (I) (635) was added to a suspension of toluene (50 ml).
mg, 2.74 mmol) and ethyl iodide (855).
mg, 5.48 mmol) and heated under reflux for 6 hours. After cooling, the reaction solution was filtered through celite, and the filtrate was concentrated.
The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 40: 1-20: 1) to obtain 402 mg of the title compound as a pale yellow powder. Yield 75%. ¹ H-NMR (DMSO-d ₆ , δ): 1.35 (3
H, t, J = 7.3 Hz), 1.40 (3H, t, J =
7.3 Hz), 4.37 (2H, q, J = 7.3H)
z), 4.54 (2H, q, J = 7.3 Hz), 8.1
7 (1H, s), 8.63 (1H, s), 8.79 (1
H, s).

Example 26 Ethyl 2-ethoxy-6-phenyl-7-trifluoromethylquinoline-3-carboxylate Compound of Example 25 (200 mg, 0.599 mmol
l) in a solution of toluene (8 ml) in phenylboric acid (10
9mg, 0.899mmol), (1,1'-bis (diphenylphosphino) ferrocene) dichloropalladium (22.0mg, 0.0300mmol) and 2M aqueous sodium carbonate solution (0.300ml, 0.599mm)
ol) and heated to reflux for 6 hours. After cooling, ethyl acetate was added to the reaction solution, washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is subjected to silica gel column chromatography (hexane: ethyl acetate = 20: 1).
To give 185 mg of the title compound as a pale yellow powder.
79% yield. ¹ H-NMR (DMSO-d ₆ , δ): 1.34 (3
H, t, J = 7.3 Hz), 1.42 (3H, t, J =
6.8 Hz), 4.36 (2H, q, J = 7.3H)
z), 4.57 (2H, q, J = 6.8 Hz), 7.4
1 (2H, m), 7.47 (3H, m), 8.09 (1
H, s), 8.18 (1H, s), 8.83 (1H,
s).

Example 27 Ethyl 2-ethoxy-6- (3-fluorophenyl) -7-trifluoromethylquinoline-3-carboxylate Compound of Example 25 (200 mg, 0.599 mmol
l) and 3-fluorophenyl boric acid (126 mg,
0.899 mmol) to give 192 mg of the title compound as a pale yellow powder in the same manner as in Example 26. Yield 7
9%. ¹ H-NMR (DMSO-d ₆ , δ): 1.34 (3
H, t, J = 7.3 Hz), 1.42 (3H, t, J =
6.8 Hz), 4.36 (2H, q, J = 7.3H)
z), 4.57 (2H, q, J = 7.3 Hz), 7.2
4-7.35 (3H, m), 7.51-7.56 (1
H, m), 8.14 (1H, s), 8.19 (1H,
s), 8.03 (1H, s).

Example 28 1,2-Dihydro-2-oxo-6-phenyl-7-trifluoromethylquinoline-3-carboxylic acid Compound of Example 26 (100 mg, 0.257 mmol
l) of acetic acid (3 ml) in 47% hydrobromic acid (0.6
ml) and stirred at room temperature for 3 hours. After standing for 2 days, the mixture was stirred at 50 ° C. for 45 minutes. The reaction solution was ice-cooled, water was added, and the precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to obtain 71.0 mg of the title compound as a pale yellow powder.
Yield 83%. HR-MS: 333.0645 (+3.2 mmu). mp: 255-257 ° C.

Example 29 1,2-Dihydro-6- (3-fluorophenyl) -2
-Oxo-7-trifluoromethylquinoline-3-carboxylic acid Compound of Example 27 (100 mg, 0.245 mmol
Using 1) and in the same manner as in Example 28, 81.0 mg of the title compound (0.8 hydrate) was obtained as a pale yellow powder. 90% yield. Anal. Calcd. for C ₁₇ H ₉ F ₄ NO
_{3 · 0.8H 2 O: C 55.84} , H 2.92, N
3.83. Found; C 55.79, H 2.66, N
4.14. HR-MS: 351.0533 (+1.4 mmu). mp: 270-272 ° C.

[Biological Activity] Binding Experiment to AMPA Receptor [ ³ H] -AMPA selectively binds to AMPA receptor on crude synaptosome membrane preparation prepared from rat cerebral cortex
(Final concentration: 5 nM), potassium thiocyanate (final concentration: 100 mM) and the test compound were added, and incubated at 0 ° C for 30 minutes. After stopping the reaction by suction filtration, the radioactivity on the filter was measured with a liquid scintillation counter. The specific binding amount of [ ³ H] -AMPA was determined by subtracting the non-specific binding amount in the presence of glutamic acid (0.1 mM) from the total binding amount. [ ³ H] -AMPA binding in the absence of the test compound was defined as 100, and the concentration (IC ₅₀ value) of the compound that reduced 50% was determined.
By converting the values into values, the binding ability of each compound to the AMPA receptor was calculated. (Eur. J. Pharmacol., 1993, 246 , 195-204)

[Results] From the above results, the 6-arylquinoxalinecarboxylic acid derivative of the present invention is a novel compound having an excellent antagonism of the excitatory amino acid receptor, particularly the non-NMDA receptor against the AMPA receptor.

The compounds of the present invention inhibit the binding of excitatory amino acids that cause neuronal cell death to AMPA receptors, and are therefore effective for the treatment of brain neuronal damage and the like caused by the above-mentioned excitatory amino acids. It can be said to be a useful compound that does not exhibit the side effects of a drug having a body antagonism.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 25/28 A61P 25/28 43/00 111 43/00 111 C07D 401/04 C07D 401/04 405/04 405/04 409/04 409/04

Claims (6)

[Claims] [Claim 1] General formula (1) (Where Ar is a phenyl group optionally having one or more substituents, a naphthyl group optionally having one or more substituents, or a general formula (2) (Wherein A represents a nitrogen, oxygen or sulfur atom, and n represents 1 to 3), a 5- or 6-membered heterocyclic ring which may have one or more substituents and a condensed ring thereof. R)
Is a nitro group, a cyano group, a trifluoromethyl group, an amino group which may be substituted, or a compound represented by the general formula (3) (Wherein R ³ and R ⁴ are the same or different and each is a phenyl group,
An aralkyl group, a 5- or 6-membered heterocyclic ring and a condensed ring thereof (these may have one or more substituents on an aromatic ring or a heterocyclic ring), a hydrogen atom, and a lower alkyl group which may be halogen-substituted Represents a cyclic alkyl group, or forms a ring together with R ³ and R ⁴ together with a nitrogen atom (furthermore, a hetero atom is 1 or 2
And n represents 1-2), and R ¹ represents a phenyl group, an aralkyl group, a 5- or 6-membered heterocyclic ring and a condensed ring thereof (these are aromatic rings,
May have one or more substituents on the heterocyclic ring), a hydrogen atom, a lower alkyl group optionally substituted by a halogen atom,
R ² represents a hydroxyl group, a lower alkoxy group, or a general formula (4) (Wherein R ⁵ and R ⁶ are the same or different and each is a phenyl group,
An aralkyl group, a 5- or 6-membered heterocyclic ring and a condensed ring thereof (these may have one or more substituents on an aromatic ring or a heterocyclic ring), a hydrogen atom, and a lower alkyl group which may be halogen-substituted Represents a cyclic alkyl group, or forms a ring together with R ⁵ and R ⁶ together with a nitrogen atom (furthermore, a hetero atom is 1 or 2
Or one of R ⁵ and R ⁶ represents a hydrogen atom, and the other represents a hydroxyl group, a lower alkoxy group, or a phenyloxy group optionally having one or more substituents. Represents an aralkyloxy group optionally having one or more groups or substituents) and an addition salt thereof. 2. The general formula (5) (Where Ar is a phenyl group optionally having one or more substituents, a naphthyl group optionally having one or more substituents, or a general formula (2) (Wherein A represents a nitrogen, oxygen or sulfur atom, and n represents 1 to 3), a 5- or 6-membered heterocyclic ring which may have one or more substituents and a condensed ring thereof. R)
Is a nitro group, a cyano group, a trifluoromethyl group, an amino group which may be substituted, or a compound represented by the general formula (3) (Wherein R ³ and R ⁴ are the same or different and each is a phenyl group,
An aralkyl group, a 5- or 6-membered heterocyclic ring and a condensed ring thereof (these may have one or more substituents on an aromatic ring or a heterocyclic ring), a hydrogen atom, and a lower alkyl group which may be halogen-substituted Represents a cyclic alkyl group, or forms a ring with R ³ and R ⁴ together with a nitrogen atom (furthermore, 1 or 2
And n represents 1 to 2), and R ² represents a hydroxyl group, a lower alkoxy group, or a general formula (4) (Wherein R ⁵ and R ⁶ are the same or different and each is a phenyl group,
An aralkyl group, a 5- or 6-membered heterocyclic ring and a condensed ring thereof (these may have one or more substituents on an aromatic ring or a heterocyclic ring), a hydrogen atom, and a lower alkyl group which may be halogen-substituted Represents a cyclic alkyl group, or forms a ring together with R ⁵ and R ⁶ together with a nitrogen atom (furthermore, a hetero atom is 1 or 2
Or one of R ⁵ and R ⁶ represents a hydrogen atom, and the other represents a hydroxyl group, a lower alkoxy group, or a phenyloxy group optionally having one or more substituents. R ⁷ represents a lower alkyl group or an aralkyl group optionally having one or more substituents). The method for producing a 6-arylquinolinecarboxylic acid derivative represented by the formula (1) wherein R ¹ is a hydrogen atom and an addition salt thereof, wherein the compound is hydrolyzed. 3. The formula (1) 2. The 7-arylquinoline carboxylic acid derivative according to claim 1, wherein R ¹ represents a hydrogen atom, wherein a lower alkyl halide, a cyclic alkyl halide, and a substituent which may be substituted with a halogen atom are provided. or a, characterized in that also the reaction of an aralkyl halide claim 1, wherein the 6-aryl quinolinecarboxylic acid derivatives (wherein R ¹
(Excluding hydrogen atoms). 4. The formula (5) (Where Ar is a phenyl group optionally having one or more substituents, a naphthyl group optionally having one or more substituents, or a general formula (2) (Wherein A represents a nitrogen, oxygen or sulfur atom, and n represents 1 to 3), a 5- or 6-membered heterocyclic ring which may have one or more substituents and a condensed ring thereof. R)
Is a nitro group, a cyano group, a trifluoromethyl group, an amino group which may be substituted, or a compound represented by the general formula (3) (Wherein R ³ and R ⁴ are the same or different and each is a phenyl group,
An aralkyl group, a 5- or 6-membered heterocyclic ring and a condensed ring thereof (these may have one or more substituents on an aromatic ring or a heterocyclic ring), a hydrogen atom, and a lower alkyl group which may be halogen-substituted Represents a cyclic alkyl group, or forms a ring together with R ³ and R ⁴ together with a nitrogen atom (furthermore, a hetero atom is 1 or 2
And n represents 1 to 2), and R ² represents a hydroxyl group, a lower alkoxy group, or a general formula (4) (Wherein R ⁵ and R ⁶ are the same or different and each is a phenyl group,
An aralkyl group, a 5- or 6-membered heterocyclic ring and a condensed ring thereof (these may have one or more substituents on an aromatic ring or a heterocyclic ring), a hydrogen atom, and a lower alkyl group which may be halogen-substituted Represents a cyclic alkyl group, or forms a ring together with R ⁵ and R ⁶ together with a nitrogen atom (furthermore, a hetero atom is 1 or 2
Or one of R ⁵ and R ⁶ represents a hydrogen atom, and the other represents a hydroxyl group, a lower alkoxy group, or a phenyloxy group optionally having one or more substituents. R ⁷ represents a lower alkyl group or an aralkyl group optionally having one or more substituents). A synthetic intermediate for producing the 6-arylquinolinecarboxylic acid derivative according to claim 1 and an addition salt thereof. 5. The general formula (6) (Wherein X represents a halogen atom, R is a nitro group, a cyano group, a trifluoromethyl group, an amino group which may be substituted, or a compound represented by the general formula (3) (Wherein R ³ and R ⁴ are the same or different and each is a phenyl group,
An aralkyl group, a 5- or 6-membered heterocyclic ring and a condensed ring thereof (these may have one or more substituents on an aromatic ring or a heterocyclic ring), a hydrogen atom, and a lower alkyl group which may be halogen-substituted Represents a cyclic alkyl group, or forms a ring together with R ³ and R ⁴ together with a nitrogen atom (furthermore, a hetero atom is 1 or 2
And n represents 1 to 2), and R ² represents a hydroxyl group, a lower alkoxy group, or a general formula (4) (Wherein R ⁵ and R ⁶ are the same or different and each is a phenyl group,
An aralkyl group, a 5- or 6-membered heterocyclic ring and a condensed ring thereof (these may have one or more substituents on an aromatic ring or a heterocyclic ring), a hydrogen atom, and a lower alkyl group which may be halogen-substituted Represents a cyclic alkyl group, or forms a ring together with R ⁵ and R ⁶ together with a nitrogen atom (furthermore, a hetero atom is 1 or 2
Or one of R ⁵ and R ⁶ represents a hydrogen atom, and the other represents a hydroxyl group, a lower alkoxy group, or a phenyloxy group optionally having one or more substituents. R ⁷ represents a lower alkyl group or an aralkyl group optionally having one or more substituents). The compound represented by the general formula (7) (Where Ar is a phenyl group optionally having one or more substituents, a naphthyl group optionally having one or more substituents, or a general formula (2) (Wherein A represents a nitrogen, oxygen or sulfur atom, and n represents 1 to 3), a 5- or 6-membered heterocyclic ring which may have one or more substituents and a condensed ring thereof. Or a compound represented by the general formula (8) (Where Ar is a phenyl group optionally having one or more substituents, a naphthyl group optionally having one or more substituents, or a general formula (2) (Wherein A represents a nitrogen, oxygen or sulfur atom, and n represents 1 to 3), a 5- or 6-membered heterocyclic ring which may have one or more substituents and a condensed ring thereof. Wherein R ¹⁰ represents a lower alkyl group). 6. The general formula (1) (Where Ar is a phenyl group optionally having one or more substituents, a naphthyl group optionally having one or more substituents, or a general formula (2) (Wherein A represents a nitrogen, oxygen or sulfur atom, and n represents 1 to 3), a 5- or 6-membered heterocyclic ring which may have one or more substituents and a condensed ring thereof. R)
Is a nitro group, a cyano group, a trifluoromethyl group, an amino group which may be substituted, or a compound represented by the general formula (3) (Wherein R ³ and R ⁴ are the same or different and each is a phenyl group,
An aralkyl group, a 5- or 6-membered heterocyclic ring and a condensed ring thereof (these may have one or more substituents on an aromatic ring or a heterocyclic ring), a hydrogen atom, and a lower alkyl group which may be halogen-substituted Represents a cyclic alkyl group, or forms a ring together with R ³ and R ⁴ together with a nitrogen atom (furthermore, a hetero atom is 1 or 2
And n represents 1-2), and R ¹ represents a phenyl group, an aralkyl group, a 5- or 6-membered heterocyclic ring and a condensed ring thereof (these are aromatic rings,
May have one or more substituents on the heterocyclic ring), a hydrogen atom, a lower alkyl group optionally substituted by a halogen atom,
R ² represents a hydroxyl group, a lower alkoxy group, or a general formula (4) (Wherein R ⁵ and R ⁶ are the same or different and each is a phenyl group,
An aralkyl group, a 5- or 6-membered heterocyclic ring and a condensed ring thereof (these may have one or more substituents on an aromatic ring or a heterocyclic ring), a hydrogen atom, and a lower alkyl group which may be halogen-substituted Represents a cyclic alkyl group, or forms a ring together with R ⁵ and R ⁶ together with a nitrogen atom (furthermore, a hetero atom is 1 or 2
Or one of R ⁵ and R ⁶ represents a hydrogen atom, and the other represents a hydroxyl group, a lower alkoxy group, or a phenyloxy group optionally having one or more substituents. Characterized by an aralkyloxy group optionally having one or more groups or substituents) and one or more addition salts thereof as an active ingredient. An excitatory amino acid receptor antagonist having body antagonism.