JPH07252255A - 5,6,7,8-tetrahydro-2(1h-oxo-1,6-naphthyridine-3-carboxylic acid production and its salt - Google Patents

Abstract

PURPOSE:To obtain the subject compound useful as a synthetic intermediate for a medicine, especially benzodiazepine receptor such as an antianxiety agent, an antiepileptic or a therapeutic agent for sleeping disorder. CONSTITUTION:This new compound is 5,6,7,8-tetrahydro-2(2h)-oxo-1,6- naphthyridine-3-carboxyic acid of formula I [R1 is H, an acyl, a lower alkyl or R1' CH2 (R1' is a cyclo lower alkyl, a lower alkyl, etc.); R is H, a lower alkyl or benzyl; with the proviso that R1 is not methyl] or its salt such as 6-benzy1-5, 6, 7, 8-tetrahydro-2(1H)-oxo-1,6-naphthyridine-3-naphthyridine-3- carboxylic acid. The compound of formula I, for example, is obtained by reacting a compound of formula II ((n) is 1-3 integer) with a compound of formula III (Y is a halogen, etc.; Z is cyano, etc.; R is lower alkyl or benzyl) in a solvent such as methanol at 0-120 deg.C.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to pharmaceuticals, particularly 3- (1,3,4-oxadiazol-2-yl) -5,6,7,8-tetrahydro-, which is useful as a benzodiazepine receptor agonist. It relates to an intermediate for producing a 1,6-naphthyridine-2 (1H) -one derivative. More specifically, the new 5,6
7,8-Tetrahydro-2 (1H) -oxo-1,6-
It relates to a naphthyridine-3-carboxylic acid derivative or a salt thereof.

[0002]

2. Description of the Related Art Arkiv
foer Kemi 26 (41), 489-495 (1967) [Chemical Abstracts Vol. 67, 32611z (1967)]
The following formula

[0003]

[Chemical 2] Compounds represented by are described. No compound of the present invention has been reported yet.

The present invention is useful as a medicine, especially 3- (1,3,4-) having an affinity for benzodiazepine receptors.
It is intended to provide an intermediate for producing an oxadiazol-2-yl) -5,6,7,8-tetrahydro-1,6-naphthyridin-2 (1H) -one derivative. More specifically, novel 5,6,7,8-tetrahydro-2 (1H)-
It is intended to provide an oxo-1,6-naphthyridine-3-carboxylic acid derivative or a salt thereof.

[0005]

The present invention provides the following formula (I)

[0006]

[Chemical 3]

(Wherein R ₁ represents a hydrogen atom, an acyl group, a lower alkyl group or R ₁ 'CH _2- , and R ₁ ' is a cyclo lower alkyl group, a lower alkenyl group, a lower alkynyl group,
It means a benzyl group, an aryl group or an aromatic heterocyclic group, and R means a hydrogen atom, a lower alkyl group or a benzyl group. However, R ₁ is not a methyl group. ) 5,6,7,8-tetrahydro-2 (1H) -1,6-
It relates to a naphthyridine-3-carboxylic acid derivative or a salt thereof.

The compounds of the present invention are represented by the above formula (I), and preferred compounds are those of the formula (I) in which R ₁ is R ₁ 'CH _2-.
Wherein R ₁ ′ is an aryl group or an aromatic heterocyclic group, and a particularly preferred compound is a compound in which R ₁ ′ is a phenyl group or a phenyl group substituted with 1 to 2 halogen atoms.

The compound (I) of the present invention may form a salt with an acid, and examples of the salt include inorganic salts such as hydrochloride, hydrobromide, hydroiodide, sulfate and phosphate. Acid salt, acetate,
Oxalate, maleate, fumarate, malonate,
Examples thereof include organic acid salts such as lactate, malate, citrate, tartrate, benzoate, methanesulfonate, tosylate. Further, the compound (I) of the present invention in which R is a hydrogen atom in the formula (I) may form a salt with a base, and examples of the salt include alkali salts with alkali hydroxide, alkali carbonate, pyridine, Examples thereof include salts with organic bases such as triethylamine and tributylamine.

In the present specification, "lower" has 1 carbon atom.
It is synonymous with consisting of 6 linear or branched. The acyl group means a lower alkanoyl group, a benzoyl group, a naphthoyl group and the like. The "aryl group" means a phenyl group,
It means a naphthyl group or the like, and the ring may have a substituent. Preferred substituents on the ring are halogen atoms,
Examples include lower alkyl, trifluoromethyl, hydroxyl group, lower alkoxy, and nitro group. In addition, examples of the aromatic heterocyclic group include 5- to 6-membered rings containing 1 to 2 heteroatoms such as thienyl, furyl, pyridinyl and isoxazolyl, and the ring may have a substituent. "Hetero atom" means a nitrogen atom, an oxygen atom, and a sulfur atom.
Preferable substituents on the ring include halogen atom, lower alkyl, trifluoromethyl and lower alkoxy group.

The compound of the present invention can be produced by the following method.

(Production Method 1) Certain of the following compounds (6 and 7) represented by the formula (I) are Arkiv foer Kemi26 (4
1), 489-495 (1967) [Chemical Abstract No. 67
Vol. 32611z page (1967)] or by the method represented by the following reaction formula (Formula 4).

[0013]

[Chemical 4]

(In the reaction formula, Y represents a halogen atom, a lower alkoxy group or a di-lower alkylamino group, Z represents a cyano group, a lower alkoxycarbonyl group or a benzyloxycarbonyl group, and R represents a lower alkyl group or A benzyl group, n means an integer of 1 to 3, R ₁
Is the same as above. )

The compound (1) used as the starting material in the above reaction is, for example, Journal of American
Chemical Society (Journal of American Chemic
al Society) Vol. 85, p. 207 (1963). The compound (1) and the compound (2) thus produced are usually used in a solvent such as alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene and toluene, and the like, usually 0 to 120. A compound (3) is obtained by reacting at 0 ° C., and then ammonium salt such as ammonia or ammonium acetate is usually added at 0-100 ° C. in a solvent such as alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, acetonitrile and the like. Compound (4) can be obtained by reacting.

When Z is a cyano group in the compound (4), the compound (4) is usually used in the presence of a base in a solvent such as alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, and the like, usually 0 to 100. ℃
To give compound (5), and then 5 to
Compound (6) can be obtained by reacting with sodium nitrite under acidic conditions such as 10% hydrochloric acid or 5-20% sulfuric acid aqueous solution at 0-20 ° C.

When Z is a lower alkoxycarbonyl group or a benzyloxycarbonyl group in the compound (4), the compound (4) is treated with an alcohol such as methanol or ethanol, an ether such as tetrahydrofuran or dioxane, an acetonitrile or the like. Usually 50 in solvent
A compound (6) can be obtained by heating at -120 degreeC.

Next, the compound (6) is hydrolyzed by an ordinary method under acidic or alkaline conditions,
Alternatively, the compound (7) can be obtained by hydrogenolysis under a hydrogen atmosphere by a usual method.

(Production Method 2) Further, a certain compound (10) described below represented by the formula (I) can also be produced by the method represented by the following reaction formula (Formula 5).

[0020]

[Chemical 5]

(In the reaction formula, R "means a lower alkyl group, a benzyl group, a lower alkoxycarbonyl group or a benzyloxycarbonyl group, and R"'means the same group as R ₁ other than a hydrogen atom and an acyl group. However, R is the same as above.)

The substituent R "of the compound (8) and the compound (10)
The substituents R ″ ′ of can be mutually converted via the compound (9). When R ″ in the compound (8) is a lower alkyl group or a benzyl group, for example, Journal of
Organic Chemistry (Journal of Organic Che
mistry) According to the method described in Vol. 49, p. 2081 (1984), compound (9) can be obtained by treating compound (8) with 1-chloroethyl chlorocarbonate or the like.

When R "in the compound (8) is a benzyl group or a benzyloxycarbonyl group, it is usually in a solvent such as water, methanol, ethanol, acetic acid, dioxane or ethyl acetate at 25 to 80 ° C. under normal pressure or pressure. Compound (9) can be obtained by reacting with hydrogen under pressure in the presence of a catalyst such as Raney nickel or palladium-carbon.

When R "is a lower alkoxycarbonyl group or a benzyloxycarbonyl group, compound (9) can be obtained by treating with acid or base in a suitable solvent. For example, R" is tert. −
When it is a butoxycarbonyl group, dichloromethane,
Compound (9) can be obtained by treating with trifluoroacetic acid in a solvent such as chloroform at 25 to 80 ° C.

Then, the compound (9) and an alkylating agent corresponding to R ''', for example, lower alkyl, allyl, propargyl, benzyl, naphthalenemethyl, and an aromatic heterocyclic methylating agent are treated with an alkali hydroxide (for example, water). Sodium oxide,
Presence of inorganic bases such as potassium hydroxide), alkali carbonates (eg sodium carbonate, potassium carbonate), alkali bicarbonates (eg sodium bicarbonate, potassium bicarbonate) or organic bases such as pyridine, triethylamine, tributylamine Under a solvent such as acetone, methyl ethyl ketone, diethyl ketone, dimethylformamide, benzene, toluene and acetonitrile, usually 25 to 1
The compound (10) can be obtained by reacting at 00 ° C. These alkylating agents may be those usually used, and examples thereof include alkyl halides.

(Production Method 3) Also, a certain compound (14) described below represented by the formula (I) can be produced by the method represented by the following reaction formula (Formula 6).

[0027]

[Chemical 6]

(In the reaction formula, R "represents a lower alkyl group, a benzyl group or a tert-butoxycarbonyl group, X represents a halogen atom, and R"'represents a hydrogen atom and R ₁ other than an acyl group. Means the same group, and R is the same as the above.)

The compound (8) and a halogenating agent such as phosphorus halide, phosphorus oxyhalogenate, and dihalogenated phenylphosphonic acid are used in the absence of solvent or in a suitable solvent, usually 25 to
The compound (11) is reacted at 180 ° C, and then the compound (1
When R "in 1) is a lower alkyl group or a benzyl group, for example, Journal of Organic Chemistry No. 4
The compound (12) can be obtained by treating the compound (11) with 1-chloroethyl chlorocarbonate or the like according to the method described in Vol. 9, page 2081 (1984).

In the compound (11), R "is ter.
When it is a t-butoxycarbonyl group, the compound (11)
In a solvent such as dichloromethane, chloroform, etc.
Compound (12) can be obtained by treating with trifluoroacetic acid at 80 ° C.

The compound (12) obtained above and an alkylating agent corresponding to R ''', such as lower alkyl, allyl, propargyl, benzyl, naphthalenemethyl, and an aromatic heterocyclic methylating agent are treated with an alkali hydroxide ( For example, inorganic bases such as sodium hydroxide, potassium hydroxide), alkali carbonates (eg sodium carbonate, potassium carbonate), alkali bicarbonates (eg sodium bicarbonate, potassium bicarbonate), or pyridine, triethylamine, tributylamine. In the presence of organic bases such as acetone, methyl ethyl ketone, diethyl ketone, dimethylformamide, benzene, toluene, acetonitrile, etc.
Compound (13) can be obtained by reacting at -100 ° C. These alkylating agents may be those usually used, and examples thereof include alkyl halides.

Then, the compound (13) can be converted into the compound (14) by hydrolyzing the compound (13) under acidic or alkaline conditions by a conventional method.

The compound represented by the formula (I) thus produced is useful in medicine, especially as a benzodiazepine receptor agonist 3- (1, 3, 4) according to the following reaction formula (Chem. 7).
-Oxadiazol-2-yl) -5,6,7,8-tetrahydro-1,6-naphthyridin-2 (1H) -one derivative.

[0034]

[Chemical 7]

(In the reaction formula, R is a hydrogen atom, a lower alkyl group or the like, R ₂ is a lower alkyl group, a lower alkoxy group or the like, and R ₁ is the same as the above.)

That is, the compound (III) is produced from the compound (I) by reacting the compound (I) or its reactive derivative at the carboxyl group with the hydrazide represented by H ₂ NNHCOR ₂ (R ₂ is the same as the above). Is reacted under ordinary amidation reaction conditions to give compound (II), or
(I) or a reactive derivative of the carboxyl group and hydrazine are reacted under normal amidation reaction conditions,
Then, it is reacted with a reactive derivative at the carboxyl group represented by R ₂ COOH (R ₂ is the same as above) 2
Compound (II) can be obtained by stepwise reaction, and then compound (II) obtained above can be dehydrated and ring-closed in the molecule.

[0037]

EXAMPLES The compounds of the present invention will be specifically described with reference to the following Reference Examples and Examples.

Example 1 : 6-benzyl-5,6,7,8-tetrahydro-2 (1
H) -Oxo-1,6-naphthyridine-3-carboxylate ethyl:

(1) 1-benzyl-4-piperidone 19
A solution of g (0.1 mol) and 10.7 g (0.15 mol) of pyrrolidine in 200 ml of toluene was added while distilling off water.
Heated to reflux for hours. After the reaction solution was concentrated to dryness under reduced pressure, 200 ml of anhydrous toluene was added to the residue. Then, 17 g of ethyl ethoxymethylene cyanoacetate under stirring with ice cooling
A solution of (0.1 mol) in 50 ml of anhydrous toluene was slowly added dropwise. After returning to room temperature and stirring overnight, 13 ml of concentrated hydrochloric acid was added dropwise under ice cooling. The obtained hydrochloride was collected by filtration and washed with ethyl acetate and isopropyl ether in this order. This hydrochloride was dissolved in 300 ml of ethanol, and saturated with ammonia gas blown therein under ice cooling. After returning to room temperature and standing overnight, the solution was concentrated to dryness under reduced pressure. Isopropanol was added to the residue, and the precipitated crystals were collected by filtration and dried to obtain 10 g of crude crystals.

The above crude crystals were dissolved in 100 ml of ethanol, and a 10% aqueous sodium hydroxide solution was added dropwise while stirring with ice cooling. After returning to room temperature and stirring for 30 minutes, water 10 was added under ice cooling.
0 ml was added. The precipitated crystals were collected by filtration, washed with water, and recrystallized from isopropanol to give colorless solid 2-amino-6-benzyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate ethyl ester. 5 g (yield 27.
3%) was obtained. Melting point 141-143 [deg.] C.

(2) To a solution of 10 g (32 mmol) of the above ester in 100 ml of 10% sulfuric acid aqueous solution, an aqueous solution of 4.5 g (65 mmol) of sodium nitrite in 20 ml of water was slowly added dropwise while stirring with ice cooling. After completion of dropping, the mixture was stirred for 2 hours as it was. The mixture was made alkaline with a 20% aqueous sodium hydroxide solution under stirring with ice cooling, and extracted with chloroform. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.
The obtained crystals were recrystallized from isopropanol to obtain 6.8 g (yield 68%) of a colorless solid. Melting point 168-170
° C.

Example 2 : 6-benzyl-5,6,7,8-tetrahydro-2 (1
H) -oxo-1,6-naphthyridine-3-carboxylic acid hydrochloride:

(A) Ethyl 6-benzyl-5,6,7,8-tetrahydro-2 (1H) -oxo-1,6-naphthyridine-3-carboxylate 6.8 g (22 mmol) and a 20% hydrochloric acid aqueous solution. The 70 ml solution was heated to reflux for 3 hours.
After cooling, the precipitated crystals were collected by filtration and washed with water. Recrystallization from methanol-water yielded 7.0 g of the desired product as a colorless solid (yield 99.2).
%) Was obtained. Melting point 260-263 [deg.] C.

(B) 1-benzyl-4-piperidone 10
0 g (0.53 mol) and 70 ml of pyrrolidine (0.795
A solution of 1.5 mol of toluene in 1.5 mol) was heated under reflux for 5 hours while distilling off water. The reaction solution was concentrated to dryness under reduced pressure, and 1 L of dioxane was added to the residue. Then, 126 g of diethyl ethoxymethylenemalonate (0.
(58 mol) was added and the mixture was heated under reflux for 6 hours. Return to room temperature,
82 g (1.06 mol) of ammonium acetate was added,
The mixture was heated and stirred at ℃ for 1 hour. The reaction solution was concentrated to dryness under reduced pressure. The resulting 6-benzyl-5,6,7,8-tetrahydro-2 (1H) -oxo-1,6-naphthyridine-
20% without isolation and purification of ethyl 3-carboxylate
600 ml of an aqueous hydrochloric acid solution was added, and the mixture was heated under reflux for 3 hours. After cooling, the precipitated crystals were collected by filtration and washed with water. Recrystallization from methanol-water gave 105 g of the desired product as a colorless solid (yield 61.9%).
Got Melting point 260-263 [deg.] C.

Example 3 : 5,6,7,8-Tetrahydro-2 (1H) -oxo-
Ethyl 1,6-naphthyridine-3-carboxylic acid acetate:

6-benzyl-5,6,7,8-tetrahydro-2 (1H) -oxo-1,6-naphthyridine-3
-To a solution of 8 g of ethyl carboxylate and 360 ml of glacial acetic acid was added 200 mg of 10% palladium-carbon as a catalyst, and catalytic hydrogen reduction was carried out at room temperature in a hydrogen atmosphere. After absorbing the theoretical amount of hydrogen gas, the catalyst was filtered off and the filtrate was concentrated to dryness under reduced pressure. Ethanol was added to the residue, the crystals were collected by filtration, and then recrystallized from ethanol-water to obtain 6.8 g of a colorless solid (yield 94%). Melting point 125-130 [deg.] C.

Example 4 : Ethyl 6- (3-fluorobenzyl) -5,6,7,8-tetrahydro-2 (1H) -oxo-1,6-naphthyridine-3-carboxylate:

5,6,7,8-Tetrahydro-2 (1
H) -Oxo-1,6-naphthyridine-3-carboxylic acid ethyl acetate 2.0 g (7.1 mmol), 3-bromide
A suspension of 1.7 g (9 mmol) of fluorobenzyl and 2.0 g (24 mmol) of sodium bicarbonate in 100 ml of methyl ethyl ketone was heated under reflux for 16 hours. The insoluble material was filtered off, and the filtrate was concentrated to dryness under reduced pressure. The residue was subjected to medium pressure column chromatography using Diaion CHP-20P and eluted with a concentration gradient of acetonitrile / water.
Purified. Recrystallized from ethanol, colorless solid 1.91
g (yield 81.4%) was obtained. Melting point 276-280 [deg.] C.

Example 5 : 6- (2-Fluorobenzyl) -5,6,7,8-tetrahydro-2 (1H) -oxo-1,6-naphthyridine-3-carboxylic acid hydrochloride:

(1) To 1 ml of phenylphosphonic acid dichloride at room temperature was added 6-benzyl-5,6,7,8-tetrahydro-2.
After adding 1.0 g (3.2 mmol) of ethyl (1H) -oxo-1,6-naphthyridine-3-carboxylate, 1
The mixture was stirred at 50 ° C for 1 hour. After cooling, diisopropyl ether was added and the crystals were collected by filtration. The crystals were suspended in chloroform, and 28% aqueous ammonia was added little by little under ice-cooling stirring to make the mixture alkaline. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained oily substance was subjected to silica gel column chromatography, and eluted and purified with chloroform-methanol (200: 1) to give 6-benzyl-2-chloro-5,6,7,8-tetrahydro-1,6-. 0.7 g (yield 66.1%) of ethyl naphthyridine-3-carboxylate was obtained as a colorless oil.

(2) To a solution of 20.0 g (60 mmol) of the above ester in 200 ml of methylene chloride, 10.4 g (72 mmol) of chlorocarbonic acid (1-chloroethyl) was added dropwise at room temperature and stirred for 20 hours. Next, the reaction solution was concentrated to dryness under reduced pressure, 200 ml of methanol was added to the residue, and the mixture was heated and stirred at 40 ° C. for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, diisopropyl ether was added to the residue, and the crystals were collected by filtration. Recrystallization from ethanol gave colorless solid 2-chloro-5,6,7,8-tetrahydro-1,6-
Naphthyridine-3-carboxylate ethyl hydrochloride 21.2
g (yield 85.8%) was obtained. Melting point 153-156 [deg.] C.

(3) 5.0 g (18 mmol) of the above hydrochloride and 4.0 g (40 mmol) of triethylamine
2-Fluorobenzyl bromide 3.1 in a solution of 50 ml MF.
g (21 mmol) was added, and the mixture was heated with stirring at 60 ° C. for 15 hours. The reaction solution was concentrated to dryness under reduced pressure. The residue was dissolved in chloroform and washed with 10% aqueous potassium carbonate solution and water in this order. After drying the organic layer with anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure. The obtained oily substance was subjected to silica gel column chromatography, and eluted and purified with chloroform-methanol (100: 1) to give 2-chloro-6-.
Ethyl (2-fluorobenzyl) -5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate (4.6 g, yield 73.3%) was obtained as a colorless oil.

(4) A solution of 4.6 g (13 mmol) of the above ester and 80 ml of 20% aqueous hydrochloric acid was heated under reflux for 24 hours. After cooling with ice, the precipitated crystals were collected by filtration and washed with water. Recrystallization from ethanol gave 3.4 g (yield 77.2%) of the desired product as a colorless solid. Melting point 273-276 [deg.] C.

Example 5 using the corresponding starting compounds
Reaction and treatment were carried out in the same manner as (3) and (4) to obtain the compounds of Examples 6 to 52 listed in Tables 1 to 3.

[0055]

[Table 1]

[0056]

[Table 2]

[0057]

[Table 3]

Reference Example 1 : 6-benzyl-3- (5-methoxy-1,3,4-oxadiazol-2-yl) -5,6,7,8-tetrahydro-1,6-naphthyridine-2 Production of (1H) -one:

(1) 3.0 g (9.4 mmol) of 6-benzyl-5,6,7,8-tetrahydro-2 (1H) -oxo-1,6-naphthyridine-3-carboxylic acid / hydrochloride. 2.3 g of N, N'-carbonyldiimidazole
(14 mmol) N, N-dimethylformamide (D
A solution of 50 ml of MF) was heated and stirred at 70 ° C. for 3 hours. Next, 1.0 g (11 mmol) of methyl carbazate was added to this solution, and the mixture was heated with stirring at the same temperature for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, and isopropanol and triethylamine were added to the residue. The precipitated crystals were collected by filtration and recrystallized from methanol to give N'-methoxycarbonyl-6-benzyl-5,6,7,8-tetrahydro- as a colorless solid.
2.4 g (71.6% yield) of 2 (1H) -oxo-1,6-naphthyridine-3-carbohydrazide was obtained. Melting point 240-242 [deg.] C.

(2) 2.0 g (5.6 mmol) of the above compound, 3.0 g (11 mmol) of triphenylphosphine and 2.0 g (20 mmol) of triethylamine.
In 50 ml of anhydrous tetrahydrofuran (THF),
2.2 g of diisopropyl azodicarboxylate with stirring under ice cooling
A solution of (11 mmol) in 10 ml of anhydrous THF was added dropwise. After stirring at room temperature for 1 hour, a small amount of water was added and the mixture was concentrated to dryness under reduced pressure. Isopropanol was added to the residue, and the precipitated crystals were collected by filtration and recrystallized from acetonitrile to obtain 0.8 g of a colorless solid (yield 43%). Melting point 176-178
° C. (Yield 44.8%) was obtained. Melting point 221-223
° C.

Pharmacology : The compound of Reference Example 1 has a marked affinity for the benzodiazepine receptor and an excellent antagonism against pentylenetetrazole-induced clonic convulsion in mice. It is useful as a receptor agonist, for example, an anxiolytic drug, an antiepileptic drug, or a therapeutic drug for sleep disorders.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Kiyoshi Furukawa 2-12-12, Onomizumei, Shiga-cho, Shiga-gun, Shiga Prefecture (72) Inventor Makoto Oka 17-26 Takada-cho, Ibaraki-shi, Osaka

Claims (3)

[Claims] 1. The following formula: (In the formula, R ₁ represents a hydrogen atom, an acyl group, a lower alkyl group or R ₁ 'CH _2- , and R ₁ ' is a cyclo lower alkyl group, a lower alkenyl group, a lower alkynyl group, a benzyl group, an aryl group or It means an aromatic heterocyclic group, and R means a hydrogen atom, a lower alkyl group or a benzyl group.
However, R ₁ is not a methyl group. ), 5, 6,
A 7,8-tetrahydro-2 (1H) -1,6-naphthyridine-3-carboxylic acid derivative or a salt thereof. 2. The compound according to claim 1, wherein R ₁ is R ₁ ′ CH ₂ —, and R ₁ ′ is a phenyl group or a phenyl group substituted with 1 to 2 halogen atoms, or a salt thereof. 3. 6-Benzyl-5,6,7,8-tetrahydro-2 (1H) -oxo-1,6-naphthyridine-
3-carboxylic acid, 6- (2-chlorobenzyl) -5,
6,7,8-tetrahydro-2 (1H) -oxo-1,
6-naphthyridine-3-carboxylic acid, 6- (4-chlorobenzyl) -5,6,7,8-tetrahydro-2 (1
H) -oxo-1,6-naphthyridine-3-carboxylic acid, 6- (2-bromobenzyl) -5,6,7,8-tetrahydro-2 (1H) -oxo-1,6-naphthyridine-3- Carboxylic acid, 6- (2-chloro-5-fluorobenzyl) -5,6,7,8-tetrahydro-2 (1
H) -oxo-1,6-naphthyridine-3-carboxylic acid, and 6- (2-bromo-5-fluorobenzyl)
Any one compound selected from -5,6,7,8-tetrahydro-2 (1H) -oxo-1,6-naphthyridine-3-carboxylic acid or a salt thereof.