JPH05331169A - Benzonaphthaylidine derivative - Google Patents

Abstract

PURPOSE:To provide a new compound having glutamic acid receptor antagonistic activity, thus useful as a preventive or medicine for neurocyte degenerative lesions induced in cerebral apoplexy, hypoglycemia, paulicardia, etc., or as a medicine for epilepsia, Huntington's chorea, or Alzheimer's disease. CONSTITUTION:The compound of formula I [X is H, alkyl, halogen, cyano, etc.; R<1> is carboxyl or a group convertible to carboxyl group in vivo; W<1> and W<2> are each H, (substituted) alkyl, (substituted) aryl, etc.], e.g. 8-chloro-2- ethoxycarbonyl-5,6-dihydro-4H-benzo[de] [1,6]-naphthyridine. The compound of the formula I can be synthesized starting from a compound of formula II (Y is Cl, Br, I, etc.; Z is alkoxycarbonyl) through a compound of formula III, etc.

Description

Detailed Description of the Invention

[0001]

The present invention relates to benzonaphthyridine derivatives. The compound of the present invention has a glutamate receptor antagonistic action, for example, a preventive or therapeutic agent for neurodegenerative disorders caused by stroke, hypoglycemia, cardiac arrest, perinatal asphyxia, etc., epilepsy, Huntington's chorea, Alzheimer's disease And the like are useful as therapeutic agents.

[0002]

BACKGROUND OF THE INVENTION Certain kynurenic acid derivatives are known to act as antagonists of glutamate receptors, especially NMDA receptor subtypes (Journal of.
Medicinal Chemistry J. Med. Chem. Vol. 33, 3
130 (1990), Vol. 34, 1243 (1991)). In addition, certain benzonaphthyridine derivatives were isolated from marine products and exhibited alpha blocker and antibacterial effects (Journal
Of Chemical Society Perkin Trans. 1 J. Chem. Soc. Perkin Trans., 173 (1
987)) is known.

[0003]

An object of the present invention is to provide a compound having a glutamate receptor antagonistic activity, which is useful as a preventive or therapeutic agent for neuronal degenerative disorders, a therapeutic agent for epilepsy, Huntington's disease, Alzheimer's disease and the like. ..

[0004]

Means for Solving the Problems It has been found that the benzonaphthyridine derivative represented by the following general formula (1) is useful as a glutamate receptor antagonist having excellent brain-localizing properties and few side effects, and to complete the present invention. I arrived.

The present invention has the general formula (1)

[Chemical 2] (In the formula, X is a hydrogen atom, an alkyl group, a halogen atom, a cyano group, a trifluoromethyl group, a nitro group, a hydroxyl group, a carboxyl group, an amino group, an alkylamino group, a dialkylamino group, an alkoxy group, an alkanoyl group, an alkoxycarbonyl. Represents a group, sulfamoyl group, alkylsulfonyl group, N-alkylsulfamoyl group, N, N-dialkylsulfamoyl group, carbamoyl group, N-alkylcarbamoyl group, N, N-dialkylcarbamoyl group or acylamino group. ¹ represents a carboxyl group or a group that can be converted into a carboxyl group in vivo.
W ¹ and W ² are independently of each other a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group,
A cycloalkylalkyl group, an aralkyl group, a substituted aralkyl group, an aryl group, a substituted aryl group, a phthalimido group, a heteroaryl group or a substituted alkyl group, or a formula —NR ⁵ CO ₂ R ³ , —NR ⁵ CONR ³ R ⁴ , —N
^{R 3 R 4, -NR 5 SO} 2 R 3, -NR 5 COR 3, -
It represents a group represented by OR ⁵ , —OCOR ⁵ , and —OCONR ³ R ⁴ . Here, R ³ , R ⁴ and R ⁵ are independently of each other a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, a cycloalkylalkyl group, an aralkyl group, a substituted aralkyl group, an aryl group, a substituted aryl group. , A heteroarylalkyl group, a substituted heteroarylalkyl group, a heteroaryl group or a substituted heteroaryl group, or R ³ and R ⁴ are bonded to each other-
NR ³ R ⁴ represents a heterocyclic group. W ¹ and W ² may combine with each other to form an unsubstituted or substituted alkylene group. ) Represents a benzonaphthyridine derivative.

In the present invention, examples of the alkyl group include a lower alkyl group, and examples of the lower alkyl group include methyl, ethyl, propyl, 2-propyl, butyl,
Examples thereof include linear or branched alkyl groups having 6 or less carbon atoms such as 2-butyl, 3-methylpropyl, 1,1-dimethylethyl, pentyl and hexyl.

Examples of the halogen atom include fluorine, chlorine, bromine and iodine.

The alkylamino group includes, for example, an amino group substituted with a lower alkyl group, and specific examples include methylamino, ethylamino, propylamino,
2-propylamino, butylamino, pentylamino,
Hexylamino and the like can be mentioned.

The dialkylamino group includes, for example, an amino group substituted with two lower alkyl groups, and specific examples thereof include dimethylamino, diethylamino, dipropylamino, di- (2-propyl) amino and dibutylamino. , Dipentylamino, dihexylamino, methylethylamino and the like.

Examples of the alkoxy group include a lower alkoxy group, and examples of the lower alkoxy group include linear or branched groups such as methoxy, ethoxy, propoxy, 2-propoxy, butoxy, 1,1-dimethylethoxy, pentoxy and hexoxy. And an alkoxy group having 6 or less carbon atoms.

Examples of the alkanoyl group include a lower alkanoyl group, and examples of the lower alkanoyl group include a linear or branched alkanoyl group having 6 or less carbon atoms such as acetyl, propanoyl, 2-propanoyl and pivaloyl.

The alkoxycarbonyl group includes, for example, a lower alkoxycarbonyl group whose alkoxy moiety is a lower alkoxy group, and specific examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 2-propoxycarbonyl and the like.

Examples of the alkylsulfonyl group include lower alkylsulfonyl groups such as methylsulfonyl, ethylsulfonyl, propylsulfonyl and 2-propylsulfonyl.

As the N-alkylsulfamoyl group,
For example, N-methylsulfamoyl, N-ethylsulfamoyl, N- (2-propyl) sulfamoyl and the like N
-Lower alkylsulfamoyl groups.

Examples of the N, N-dialkylsulfamoyl group include N, N-dimethylsulfamoyl and N, N.
-N, N-di-lower alkylsulfamoyl groups such as diethylsulfamoyl.

Examples of the N-alkylcarbamoyl group include N-lower alkylcarbamoyl groups such as N-methylcarbamoyl, N-ethylcarbamoyl and N- (2-propyl) carbamoyl.

Examples of the N, N-dialkylcarbamoyl group include N, N-dilower alkylcarbamoyl groups such as N, N-dimethylcarbamoyl and N, N-diethylcarbamoyl.

A typical example of the acyl group in the acylamino group is a lower alkanoyl group. Examples of the acylamino group include linear or branched carbon atoms having 6 or less carbon atoms such as acetamide, propionamide, butanamide and 2-butanamide. An alkanoylamino group may be mentioned.

The group X may be substituted singly on the benzene ring or two or more of the same or different, and the substitution position is preferably 7-position or 8-position, more preferably 8-position.
Rank.

The group which can be converted into a carboxyl group in the living body means a group which is decomposed by an enzyme or the like in the living body to give a free carboxyl group, and examples thereof include an alkoxycarbonyl group, a carbamoyl group and an N-alkylcarbamoyl group. Group, N, N-dialkylcarbamoyl group and the like, and more specifically, methoxycarbonyl, ethoxycarbonyl, 1,1-dimethylethoxycarbonyl, N-methylcarbamoyl, N, N-dimethylcarbamoyl and the like can be mentioned.

Examples of the cycloalkyl group include a lower cycloalkyl group, more specifically, a cycloalkyl group having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Examples of the alkenyl group include a lower alkenyl group, and more specifically, vinyl, allyl, 1
Examples include alkenyl groups having 6 or less carbon atoms such as -propenyl, 1-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl.

Examples of the alkynyl group include a lower alkynyl group, more specifically, an alkynyl group having 2 to 6 carbon atoms such as ethynyl, propargyl, 3-butynyl, 3-pentynyl and 4-pentynyl.

Examples of the cycloalkylalkyl group include lower cycloalkyl lower alkyl groups, more specifically, cycloalkylalkyl groups having 13 or less carbon atoms such as cyclopropylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylpropyl and the like. Can be mentioned.

Examples of the aralkyl group include aralkyl groups having 15 or less carbon atoms such as benzyl, phenylethyl, naphthylmethyl and naphthylpropyl.

Examples of the aryl group include aryl groups having 10 or less carbon atoms such as phenyl and naphthyl.

The heteroaryl group includes, for example, a 5- to 6-membered ring group containing 1 to 4 nitrogen atoms, a 5- to 6-membered ring containing 1 to 2 nitrogen atoms and 1 oxygen atom or 1 sulfur atom. Examples of the ring group include, more specifically, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl,
3-thienyl, 3-oxadiazolyl, 5-oxadiazolyl, 2-imidazolyl, 4-imidazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-oxazolyl, 4- Oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, tetrazolyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl and the like can be mentioned.

Examples of the substituent of the substituted alkyl group include, for example, the formulas --CO ₂ R ⁵ , --CONR ³ R ⁴ , --COR ⁵ , and --C.
^{_{N, -NR 5 CO 2 R 3}} , -NR 5 CONR 3 R 4, -
^{NR 3 R 4, -NR 5 SO} 2 R 3, -NR 5 COR 3,
^{-OR 5, -OCOR 5, -OCONR 3} R 4, -PO
^{_{(OR 5) 2, -SR 5}} , -SOR 5, a group represented by -SO ₂ R ⁵ or -SO ₃ R ^5, and phthalimide group, a heteroaryl group, and the like (wherein, R ^3, R
⁴ and R ⁵ have the same meanings as above).

Examples of the alkyl group of the substituted alkyl group for W ¹ and W ² include groups having 1 to 4 carbon atoms,
Specific examples include methyl, ethyl, propyl, 2-propyl, butyl and the like. Preferred groups include, for example, groups having 1 to 2 carbon atoms, and specifically include methyl and ethyl. A more preferable group is methyl.

Examples of the substituted alkyl group for W ¹ and W ² include, for example, the formulas —CH ₂ CONR ³ R ⁴ and —CH ₂ CO.
_{^{R 5, -CH 2 CN, -CH}} 2 NR 5 CO 2 R 3, -C
_{^{H 2 NR 5 CONR 3 R 4}} , -CH 2 NR 3 R 4, -C
_{^{H 2 NR 5 SO 2 R 3}} , -CH 2 NR 5 COR 3, -C
_{^{H 2 OR 5, -CH 2 OCOR}} 5, -CH 2 OCONR
_{^{3 R 4, -CH 2 PO (}} OR 5) 2, -CH 2 SR 5,
_{^{-CH 2 SOR 5, -CH 2 SO}} 2 R 5, -CH 2 SO
_{^{3 R 5, -CH 2 CH 2}} CONR 3 R 4, -CH 2 CH
₂ COR ⁵ , -CH ₂ CH ₂ CN, -CH ₂ CH ₂ NR
⁵ CO ₂ R ³ , -CH ₂ CH ₂ NR ⁵ CONR ³ R ⁴ ,
_{^{-CH 2 CH 2 NR 3 R 4}} , -CH 2 CH 2 NR 5 SO
_{^{2 R 3, -CH 2 CH 2}} NR 5 COR 3, -CH 2 CH
₂ OR ⁵ , -CH ₂ CH ₂ OCOR ⁵ , -CH ₂ CH _{2
^{OCONR 3 R 4, -CH 2 CH}} 2 PO (OR 5) 2,
^{_{-CH 2 CH 2 SR 5, -CH}} 2 CH 2 SOR 5, -C
H ₂ CH ₂ SO ₂ R ⁵ or -CH ₂ CH ₂ SO ₃ R ⁵
And a phthalimidomethyl group, a phthalimidoethyl group, a heteroarylalkyl group and the like (in the formula, R ³ , R ⁴ and R ⁵ have the same meanings as described above).

Examples of the heteroaryl in the heteroarylalkyl group include the same examples as described above, and examples of the alkyl group include a lower alkyl group. Specific examples of the heteroarylalkyl group include 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl,
2-thienylmethyl, 3-thienylmethyl, 3-oxadiazolylmethyl, 5-oxadiazolylmethyl, 2-
Pyridylethyl, 3-pyridylethyl, 4-pyridylethyl, 2-thienylethyl, 3-thienylethyl, 3-
Oxadiazolylethyl, 5-oxadiazolylethyl, 2-pyridylpropyl, 3-pyridylpropyl, 4
-Pyridylpropyl, 2-thienylpropyl, 3-thienylpropyl, 3-oxadiazolylpropyl, 5-oxadiazolylpropyl, 2-imidazolylmethyl, 4
-Imidazolylmethyl, 2-thiazolylmethyl, 4-thiazolylmethyl, 5-thiazolylmethyl, 3-isothiazolylmethyl, 4-isothiazolylmethyl, 5-isothiazolylmethyl, 2-oxazolylmethyl, 4-oxazolylmethyl , 5-oxazolylmethyl, 3-isoxazolylmethyl, 4-isoxazolylmethyl, 5-isoxazolylmethyl, tetrazolylmethyl, 2-furylmethyl, 3-furylmethyl, 2-pyrrolylmethyl Three
-Pyrrolylmethyl and the like.

The substituents on the aralkyl group, aryl group, heteroaryl group and heteroarylalkyl group include
For example, alkyl group, alkoxy group, halogen atom, cyano group, trifluoromethyl group, nitro group, hydroxyl group, amino group, alkylamino group, dialkylamino group, sulfamoyl group, N-alkylsulfamoyl group, N, N-
Dialkylsulfamoyl group, carboxyl group, alkoxycarbonyl group, alkylsulfonyl group, alkanoyl group, carbamoyl group, N-alkylcarbamoyl group,
Examples thereof include N, N-dialkylcarbamoyl group and acylamino group. There may be one substituent or two or more same or different substituents.

R ³ and R ⁴ are bonded to each other to form --NR ³ R ⁴
The heterocycle represented by is, for example, 1 to 3 nitrogen atoms.
A 5- to 7-membered heterocyclic ring containing 1 to 5 nitrogen atoms or a 5- to 7-membered ring containing 1 nitrogen atom and 1 oxygen atom, and specific examples thereof include pyrrolidine, piperidine, piperazine and morpholine.

The fact that W ¹ and W ² are bonded to each other to form an unsubstituted or substituted alkylene group means that the 5-position and 6-position of the general formula (1) are bonded with an unsubstituted or substituted alkylene group, and An alkylene group has, for example, 3 carbon atoms.
Alternatively, an alkylene group of 4 is exemplified, and it is shown that a 5-membered ring or a 6-membered ring is formed with carbon atoms at the 5-position and the 6-position. Examples of the substituent of the substituted lower alkylene group include those represented by the formula-
_{^{CO 2 R 5, -CONR 3 R}} 4, -COR 5, -CN,
_{^{-NR 5 CO 2 R 3, -NR}} 5 CONR 3 R 4, -NR
_{^{3 R 4, -NR 5 SO 2}} R 3, -NR 5 COR 3, -O
^{R 5, -OCOR 5, -OCONR 3} R 4, -PO (O
_{^{R 5) 2, -SR 5,}} -SOR 5, -SO 2 R 5 or -SO ₃ R ^5, a group represented by and alkyl group, a phthalimido group, a heteroaryl group, and the like (wherein, R
³ , R ⁴ and R ⁵ have the same meanings as described above.

The compound of the present invention may form a salt depending on the kind of the substituent. Examples of the salt having an acidic substituent include inorganic salts such as sodium, potassium, lithium, magnesium, aluminum and ammonia, and organic salts such as triethylamine, tripropylamine, pyridine and pyrrolidine. When it has a basic substituent, examples thereof include inorganic salts such as hydrochloric acid, sulfuric acid and hydrobromic acid, and organic salts such as acetic acid, oxalic acid, citric acid, malic acid, tartaric acid, fumaric acid and maleic acid.

The compound of the present invention can be synthesized by the following method. The compounds represented by the general formulas (6) and (7) included in the present invention can be synthesized according to the following formulas.

[Chemical 3] (The compounds represented by the general formulas (6) and (7) are the compounds included in the present invention, in which W ¹ , W ² and X have the same meanings as described above. Y represents a chlorine atom or a bromine atom. , An iodine atom, or a leaving group such as a trifluoromethanesulfonyloxy group, etc. Z represents an alkoxycarbonyl group, and typically includes, for example, a methoxycarbonyl group, an ethoxycarbonyl group, and the like.

1) The starting compound represented by the general formula (2) is known per se or can be synthesized by a method described in a literature (for example, Journal of Medicinal Chemistry, J. Med. Chem. Vol. 34, 1243 (1991)).

2) The compound represented by the general formula (3) is
It can be synthesized by the method described in the literature (Journal
Of Medicinal Chemistry J. Med. Chem. Vol.
33, 3130 (1990)). For example, a compound represented by the general formula (2) and paratoluenesulfonyl isocyanate are
Non-polar solvents such as toluene, xylene, cyclohexane,
Alternatively, to obtain a compound represented by the general formula (3) by heating in an aprotic polar solvent such as dimethylformamide, tetrahydrofuran, acetonitrile, or a mixed solvent thereof in the range of 40 ° C to 100 ° C. You can

3) A compound represented by the general formula (3) and a compound represented by the general formula (4) are mixed with toluene, xylene,
In a non-polar solvent such as cyclohexane, or an aprotic polar solvent such as dimethylformamide, tetrahydrofuran, acetonitrile, or a mixed solvent thereof,
Catalytic amount of zero valence palladium (eg tetrakistriphenylphosphine palladium etc.)
In the presence of the above, the compound represented by the general formula (5) can be obtained by reacting at room temperature to 150 ° C.

4) The raw material compound represented by the general formula (4) is an Angevante Chemie International Edition (Angew. Chem. Int. Ed. Eng., Vol. 25, 508).
(1986)).

5) If necessary, the compound represented by the general formula (5) can be hydrolyzed with an acid in a cosolvent to give the compound represented by the general formula (6). As the acid, for example, sulfuric acid, hydrochloric acid, bromic acid or the like is used. Examples of the cosolvent include THF and dioxane. Reaction temperature is 0 ℃
To room temperature range.

6) If necessary, the compound represented by the general formula (6) is hydrolyzed with an acid or alkaline water in a cosolvent to give a compound represented by the general formula (7). As the acid, for example, sulfuric acid, hydrochloric acid, bromic acid, etc., and as the alkaline water, for example, sodium hydroxide, potassium hydroxide aqueous solution, etc. are used. Examples of the cosolvent include THF, methanol, dioxane and the like. The reaction temperature may be in the range of 0 ° C. to the boiling point of the solvent.

7) The compound represented by the general formula (7) is
If necessary, the compound of the general formula (1) can be obtained by subjecting it to a reaction by an ordinary general method such as esterification or amidation.
In, a compound in which R ¹ is a group capable of being converted into a carboxyl group in vivo can be produced. In these reactions, after completion of the reaction, the product can be isolated and purified by a conventional method such as crystallization or chromatography. The compound of the present invention represented by the general formula (1) can be purified by a conventional method such as column chromatography and recrystallization. Examples of the recrystallization solvent include alcohol solvents such as methanol, ethanol and 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, aromatic solvents such as toluene, ketone solvents such as acetone and hydrocarbons such as hexane. Examples thereof include solvents and the like, or mixed solvents thereof.

The compound of the present invention has tautomers.
The compounds of the present invention include these tautomers.

The compound of the present invention may contain an asymmetric carbon atom depending on the kind of the substituent, and such compound has optical isomers and geometric isomers. The compound of the present invention includes a mixture of each of these isomers and an isolated one.
As the optical resolution method, for example, a compound represented by the general formula (7) contained in the general formula (1) in an inert solvent (for example, alcohol solvent such as methanol, ethanol, 2-propanol, ether solvent such as diethyl ether, A method of forming a salt with an ester solvent such as ethyl acetate, an aromatic solvent such as toluene, acetonitrile, etc., and an optically active amine (for example, α-phenethylamine, quinine, quinidine, cinchonidine, cinchonine, strychnine, etc.) can be used. ..

The temperature at which the salt is formed may range from room temperature to the boiling point of the solvent. In order to improve the optical purity, it is desirable to once raise the temperature to around the boiling point of the solvent. The precipitated salt can be cooled, if necessary, before collecting by filtration to improve the yield. The amount of the optically active amine used is appropriately in the range of 0.5 to 2.0 equivalents, preferably in the range of about 1 equivalent, relative to the substrate. If necessary, the crystals may be placed in an inert solvent (eg methanol, ethanol, 2
A highly pure optically active salt can also be obtained by recrystallization from an alcohol solvent such as propanol, an ether solvent such as diethyl ether, an ester solvent such as ethyl acetate, an aromatic solvent such as toluene, acetonitrile and the like.
If necessary, the obtained salt can be treated with an acid by a conventional method to obtain a free form.

The novel benzonaphthyridine derivative of the present invention can be administered orally or parenterally. That is, commonly used dosage forms such as tablets, capsules,
It can be orally administered in the form of syrup, suspension or the like, or can be administered in the form of liquid solution, emulsion, suspension or the like as an injection. It may also be administered rectally in the form of suppositories. Such a dosage form can be produced according to a general method by combining an active ingredient with a usual carrier, excipient, binder, stabilizer and the like. When used in the form of an injection, a buffering agent, a solubilizing agent, an isotonicity agent and the like can be added. The dose and frequency of administration vary depending on symptoms, age, body weight, administration form, etc., but when orally administered, it is usually 1 to 10 per day for an adult.
The range of 00 mg, preferably the range of 10 to 500 mg, can be administered once or in several divided doses. When administered as an injection, the dose may be in the range of 0.1 to 500 mg, preferably in the range of 3 to 100 mg, once or several times.

The benzonaphthyridine derivative of the present invention is used in the preparation of synaptic membrane prepared from rat brain in the form of [ ³ H] M.
It strongly inhibits K-801 binding and [ ³ H] -glycine binding. The MK-801 binding inhibition test and the glycine binding inhibition test used for this evaluation are carried out by the following methods.

[ ³ H] MK-801 binding test Crude synaptic membrane preparations were prepared from rat whole brain and then 50
50,000 x with mM Tris acetate buffer (pH 7.4)
The washing operation by centrifugation for 30 minutes is performed 3 times. The precipitate is suspended in 0.32M sucrose aqueous solution and frozen and stored at -80 ° C. For use, thaw the frozen suspension at room temperature and then
After the pretreatment with 10% of Triton X-100 at 2 ° C. for 10 minutes, the above-mentioned centrifugation and washing operation is performed twice, and the sample is subjected to a binding experiment. Membrane preparation (about 250 μg protein)
To 5 nM [ ³ H] MK-801 (29.4 Ci / mmol),
The reaction is carried out at 30 ° C. for 30 minutes. The reaction is Whatman G
Stop by suction filtration method using F / B glass filter. Radioactivity on the filter is measured by liquid scintillation method. Non-specific binding is 0.1 mM MK-
Calculated from the radioactivity in the presence of 801.

[ ³ H] Gly Binding Assay A crude synaptic membrane preparation was prepared from rat whole brain, and then this preparation was prepared using 50 mM Tris acetate buffer (pH 7.4).
The washing operation by centrifugation at 50,000 × g for 30 minutes is performed 3 times. The precipitate is suspended in 0.32M sucrose solution at -80 ℃.
Store frozen at. At the time of use, it is melted at room temperature and then pretreated with 0.08% Triton X-100 at 2 ° C. for 10 minutes. After the pretreatment, a sample prepared by performing the above-mentioned washing operation twice is used for the experiment. The [ ³ H] Gly binding test was performed using a synapse membrane preparation (about 15
0-200 μg protein) at 10 nM [ ³ H] Gly (40 C
i / mmol) at 2 ° C. for 10 minutes in the same buffer.
The reaction is stopped by a suction filtration method using Whatman GF / B glass filter. Non-specific binding is calculated from radioactivity in the presence of 1 mM Gly.

[0051]

【Example】

 Example 1

[Chemical 4] Synthesis of 8-chloro-2-ethoxycarbonyl-5,6-dihydro-4H-benzo [de] [1,6] naphthyridine

A) 8-chloro-2-ethoxycarbonyl-4-paratoluenesulfonyl-5,6-dihydro-
Synthesis of 4H-benzo [de] [1,6] naphthyridine 5,7-Dichlorokynurenic acid ethyl ester (2.19 g,
5 mmol), vinyltri-n-butyltin (1.6 mL,
5.5 mmol) and tetrakistriphenylphosphine palladium (251 mg, 0.25 mmol) were dissolved in a mixed solution of 5: 2 toluene / dimethylformamide (70 mL),
This was heated and stirred at 100 ° C. for 10 hours under a nitrogen stream.
The reaction mixture was cooled to room temperature, an aqueous solution of potassium fluoride was added thereto, the mixture was further stirred for several hours, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (2: 1 hexane / acetic acid ethyl ester) to give the title compound (1.
06 g) was obtained. (Yield 49%) ¹ H nmr (CDCl ₃ ) δ; 8.44 (s, 1H), 8.11 (d, 1 H,
J = 2 Hz), 7.76 (d, 2H, J = 9 Hz), 7.28 (d, 2 H,
J = 9 Hz), 7.24 (d, 1 H, J = 2 Hz), 4.55 (q, 2 H,
J = 7.2 Hz), 4.19 (t, 2 H, J = 6.8 Hz), 3.12 (t, 2
H, J = 6.8 Hz), 2.37 (s, 3 H), 1.49 (t, 3 H, J =
7.2 Hz).

B) 8-chloro-2-ethoxycarbonyl-5,6-dihydro-4H-benzo [de] [1,
6] Synthesis of naphthyridine 8-chloro-2-ethoxycarbonyl-4-paratoluenesulfonyl-5,6-dihydro-4H-benzo [d
e] [1,6] naphthyridine (860 mg, 2 mmol) 9
It was dissolved in 0% sulfuric acid (20 mL), and this was stirred under ice cooling for 1 hour. The reaction mixture was neutralized with aqueous sodium hydroxide solution, and the formed precipitate was collected by filtration to give the title compound (580 mg). (Yield 100%) ¹ H nmr (CDCl ₃ ) δ; 7.97 (d, 1 H, J = 2 Hz), 7.
23 (s, 1 H), 7.15 (d, 1 H, J = 2 Hz), 5.03 (bd, 1
H, J = 3.6 Hz), 4.49 (q, 2 H, J = 7.2 Hz), 3.60
(t, 2 H, J = 6.8 Hz), 3.19 (t, 2 H, J = 6.8 Hz),
1.43 (t, 3 H, J = 7.2 Hz) .mp 275 ℃ (dec.).

Example 2

[Chemical 5] 2-carboxy-8-chloro-5,6-dihydro-4H
Synthesis of -benzo [de] [1,6] naphthyridine 8-chloro-2-ethoxycarbonyl-paratoluenesulfonyl-5,6-dihydro-4H-benzo [de]
[1,6] naphthyridine (130 mg) was added to 6N hydrochloric acid (10 m
After heating and stirring in L 2) at 100 ° C. for 6 hours, the reaction mixture was concentrated to dryness to quantitatively obtain the title compound as a hydrochloride salt. ¹ H nmr (DMSO-d6) δ; 10.44 (bs, 1 H), 8.06 (d, 1
H, J = 2 Hz), 7.57 (d, 1 H, J = 2 Hz), 7.30 (s, 1
H), 3.70 (dt, 2 H, J = 2, 7.2 Hz), 3.18 (t, 2 H, J
= 7.2 Hz) .mp 222 ° C (dec.).

Example 3

[Chemical 6] 8-chloro-5-methyl-2-methoxycarbonyl-
Synthesis of 5,6-dihydro-4H-benzo [de] [1,6] naphthyridine a) 8-Chloro-5-methyl-2-methoxycarbonyl-4-paratoluenesulfonyl-5,6-dihydro-
Synthesis of 4H-benzo [de] [1,6] naphthyridine 5,7-Dichlorokynurenic acid methyl ester (2.16 g
, 5 mmol), 1-propenyltri-n-butyltin (5 mmol) and tetrakistriphenylphosphine palladium (251 mg, 0.25 mmol) were dissolved in a mixed solution of 5: 2 toluene / dimethylformamide (70 mL), This was heated and stirred at 110 ° C. for 3 hours under a nitrogen stream. The reaction mixture was cooled to room temperature, an aqueous solution of potassium fluoride was added thereto, the mixture was further stirred for several hours, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (2: 1 hexane / acetic acid ethyl ester) to give the title compound (800 m
g) was obtained. (Yield 37%) ¹ H nmr (CDCl ₃ ) δ; 8.56 (s, 1H), 8.10 (d, 1 H,
J = 2 Hz), 7.70 (d, 2H, J = 9 Hz), 7.26 (d, 2 H,
J = 9 Hz), 7.23 (d, 1 H, J = 2 Hz), 5.05 (dq, 1 H,
J = 5.4, 7.2 Hz), 4.10 (s, 3 H), 3.08 (dd, 1 H, J
= 16.2, 5.4 Hz), 2.84 (d, 1 H, J = 16.2 Hz), 2.37
(s, 3 H), 1.13 (d, 3 H, J = 7.2 Hz) .b) 8-chloro-5-methyl-2-methoxycarbonyl-5,6-dihydro-4H-benzo [de] [1, 6] Synthesis of naphthyridine The title compound was obtained in the same manner as in Example 1, b). ¹ H nmr (CDCl ₃ ) δ; 8.00 (d, 1 H, J = 2 Hz), 7.
26 (s, 1 H), 7.15 (d, 1 H, J = 2 Hz), 4.00 (s, 3
H), 3.71 − 3.85 (m, 1 H), 3.15 (dd, 1 H, J = 4.2,
16.2 Hz), 2.92 (dd, 1 H, J = 10.8, 16.2 Hz), 1.43
(d, 3 H, J = 7.2Hz) .mp 168 ℃ (dec.).

Example 4

[Chemical 7] Synthesis of 2-carboxy-8-chloro-5-methyl-5,6-dihydro-4H-benzo [de] [1,6] naphthyridine The title compound was obtained as a hydrochloride in the same manner as in Example 2. ¹ H nmr (DMSO-d6) δ; 10.44 (bs, 1 H), 8.05 (d, 1
H, J = 2 Hz), 7.55 (d, 1 H, J = 2 Hz), 7.25 (s, 1
H), 3.92 − 4.04 (m, 1 H), 3.30 (dd, 1 H, J = 5.4,
18 Hz), 2.95 (dd, 1 H, J = 9.9, 18 Hz), 1.36 (d,
3 H, J = 7.2 Hz) .mp 280 ° C (dec.).

Claims (1)

[Claims] 1. A general formula (1): (In the formula, X is a hydrogen atom, an alkyl group, a halogen atom, a cyano group, a trifluoromethyl group, a nitro group, a hydroxyl group, a carboxyl group, an amino group, an alkylamino group, a dialkylamino group, an alkoxy group, an alkanoyl group, an alkoxycarbonyl. Represents a group, sulfamoyl group, alkylsulfonyl group, N-alkylsulfamoyl group, N, N-dialkylsulfamoyl group, carbamoyl group, N-alkylcarbamoyl group, N, N-dialkylcarbamoyl group or acylamino group. ¹ represents a carboxyl group or a group that can be converted into a carboxyl group in vivo.
W ¹ and W ² are independently of each other a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group,
A cycloalkylalkyl group, an aralkyl group, a substituted aralkyl group, an aryl group, a substituted aryl group, a phthalimido group, a heteroaryl group or a substituted alkyl group, or a formula —NR ⁵ CO ₂ R ³ , —NR ⁵ CONR ³ R ⁴ , —N
^{R 3 R 4, -NR 5 SO} 2 R 3, -NR 5 COR 3, -
It represents a group represented by OR ⁵ , —OCOR ⁵ , and —OCONR ³ R ⁴ . Here, R ³ , R ⁴ and R ⁵ are independently of each other a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, a cycloalkylalkyl group, an aralkyl group, a substituted aralkyl group, an aryl group, a substituted aryl group. , A heteroarylalkyl group, a substituted heteroarylalkyl group, a heteroaryl group or a substituted heteroaryl group, or R ³ and R ⁴ are bonded to each other-
NR ³ R ⁴ represents a heterocyclic group. W ¹ and W ² may combine with each other to form an unsubstituted or substituted alkylene group. ) A benzonaphthyridine derivative represented by the formula (1) or a salt thereof.