KR830000314B1 - Preparation of furonaphthyridine compound - Google Patents

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Description

Preparation of furonaphthyridine compound

The present invention relates to a method for preparing 2,3,5,8-tetrahydrofuro and 5,8-dihydrofuro [3,2-b] -1; 8 naphthyridine compound of the following general formula (1) will be.

In the above general formula

R ¹ is an alkyl group having 1 to 6 carbon atoms

M is a hydrogen atom, an alkali metal, or an alkaline earth metal.

The compound of the present invention is excellent in antimicrobial activity to Gram-positive bacteria as well as to Gram-negative bacteria, and its efficacy is similar to that of the compound of the present invention. -1,3 -dioxolo [4,5 -g] Quinoline is more potent than carboxylic acid 7. The object of the present invention is to develop a new antimicrobial agent with very low toxicity.

The antimicrobial agent of the present invention exhibits a strong effect on Gram-positive bacteria as well as Gram-negative bacteria, and particularly shows a good effect on Pseudomonas aeruginosa.

Dotted line indicated in furan ring in general formula (1)

은In other words,

silver

Single bond or two hydrogen atoms. Therefore, the compound of the present invention represented by general formula (I) is 5,8-dihydrofuro [3,2-b] -1,8-naphthyridine of general formula (Ia) and 2 of general formula (Ib). , 3,5,8-tetrahydrofuro [3,2-b] -1,8-naphthyridine and the like.

In the above general formula

R ¹ and M are as described above.

In the antibacterial agent of the present invention, the antibacterial activity of the compound of the general formula (Ia) is superior to that of the general formula (Ib).

The process of preparing the antimicrobial compound of the present invention is shown in the following scheme.

In the above general formula

R ¹ , R ² and R ³ each represent a straight or branched chain alkyl group having 1 to 6 carbon atoms (e.g. methyl, ethyl, n-furophyll, isoprofil or n-butyl), X is a halogen atom (e.g. For example, chlorine, fluorine, or oxo atom, A is an alkoxy group having 1 to 6 carbon atoms (e.g., each of the alkalyl groups in the ethoxy group or the dialkylamino group, the dialkyl group, and the amino group may be selected from dimethylamino group or diethylamino group). To carbon atoms of 6 to 6, and M represents a hydrogen atom, an alkali or alkaline earth metal atom (for example, sodium, potassium, calium or magnesium atom, or double sodium atom predominates).

In the reaction process, 2-alkoxy-2-methylpyridine of general formula (II) is nitrified to form 3-alkoxy-2-methyl-5-nitropyridine of general formula (III), which is reduced to general formula (IV). ) To 3-alkoxy-2-methyl-S-aminogrouppyridine. The nitration reaction can be achieved with fuming nitric acid under acidic sulfuric acid at a temperature of 0 ° to 30 ° C.) and the reduction reaction is carried out with a catalyst such as palladium black or Raney-Nickel in solvents such as methanol and ethanol.

The compound of the general formula (IV) and the alkoxymethylene mannonic acid ester or the dialkylamino methylene mannonic acid ester compound of the general formula (V) may be optionally added in the presence of alcohols such as methanol and ethanol or chloroform (preferably alcohol). Heated to ° 150 ° C. to form 2-alkoxy-2-methyl-S- (2,2-dialkoxy carbonylethenyl) aminopyridine of formula (VI), which has a high boiling point of 200 ° to 300 ° C. 6-alkoxy-7-methyl-4-hydroxy-1,8-naphthyridine-3-carboxylic acid of the general formula by heating to 200 ° to 260 ° C in a nonpolar solvent such as dimethyl ether or biphenyl To produce an ester.

Alkylating the compound of general formula (VIII) and 1,4-dihydro-1-alkyl-4-oxo-8-alkoxy-7-methyl-1,8-naphthyridine-2-carboxy which is general formula (VIII) Make a acid ester. The alkylation reaction is a common method of heating a compound of general formula with an alkyl halide such as ethyl iodide in the presence of a hydrogen halide acceptor such as potassium carbonate, sodium carbonate, and tertiary amine (triethylamine). Alkylation with dialkyl sulfuric acid. Compound 1,4-dihydro-1-alkyl-4-oxo-6-hydroxy-7-form, which is a general formula, is subjected to two reaction processes of oxidation and reduction or reduction and oxidation. To yield mill-1,8-naphthyridine-2-carboxylic acid ester.

In the reaction, 7-methyl group is oxidized with an oxidizing agent such as selenium dioxide to form formyl group at 7-site, and 6-alkoxy group is hydrolyzed with Lewis acid such as aluminum halide and boron bromide to form hydroxykey at 6-site. The above oxidation reaction is carried out in the presence or absence of a solvent, preferably by heating a compound of formula (VII) with a solvent such as sulfolane, dimethyl sulfone and the like. The hydrolysis reaction is also carried out in dichloromethane or carbon disulfide (preferably dichloromethane) at room temperature.

The compound of formula (VII) is subjected to a general ring closure reaction to give 5,8-dihydro-5-alkyl-8-oxofuro [3,2-b] -1,8-naphthyridine- of formula (X). Make 2,7-dicarboxylic acid.

(J. Heterocyclic Chem, 15 29 (1978)). That is, the compound of formula (III) is heated together with bromomalonic acid ester in a solvent such as dimethylformamide, methylethyl ketone, dichloroethane (preferably dichloromethane) to which a halogenated hydrogen acceptor such as triethylamine or potassium carbonate is added. It is treated with acid such as sulfuric acid or alkali such as potassium carbonate (preferably 20% by volume of sulfuric acid) and hydrolyzed decarbonated and dehydrated to produce compound of general formula. .

The compound of formula (VII) was reacted countercurrently in a solvent such as dimethylacetamide, dimethylformamide, quinoline (preferably a combination of copper oxide and dimethylacetamide) to which copper powder, cuprous oxide and cupric oxide were added. To 5,8-dihydro-5-alkyl-8-oxofuro [3,2-b] -1,8-naphthyridine-7carboxylic acid.

On the other hand, formula (Ⅸ) compound trimethyl sulfoxide Sony Titanium iodide to Id _{[((CH 3) 3 S} = O) + I -] and the with the method of treatment in dimethyl sulfoxide at room temperature with stirring under a stream of nitrogen [see Holt's method in Tetrahedronle, 683 (1966)], 5-alkyl-hydroxy-8-oso-2,3,5,8-tetrahydrofuro [3,2-b] -1 The 8-napriridine-7-carboxylic acid ester is prepared and heated to a dot to dehydrate the furango and hydrolyze the ester moiety with an acid to give a compound of formula (Ia).

Compound (XI) is treated with a halogenated reactant portion such as thionyl chloride in a non-polar solvent such as chloroform to produce a 2-halogen compound of general formula (XIII), and the compound (XIII) is again converted into palladium black or Raney-Ninkel. Catalytic reduction followed by heat hydrolysis with an acid such as hydrochloric acid, sulfuric acid, or an alkali such as sodium hydroxide to give the 2,3,5,8-tetrahydro compound of formula (1b), i.e. 5-alkyl-8-oxo-2, Prepare 3,5,8-tetra hydrofuro [3,2-b] -1,8-naphthyridine-7-carboxylic acid. The compound of formula (1a) may be catalyzed by the same method described above to form (1b).

3-halogenated compound (XII) is treated with 1,8-diazabicyclo [5,4,0] -7-undecane or triethylamine hydrogen halide acceptor to dehydrate and dehalogen and heated with acid such as hydrochloric acid, sulfuric acid Hydrolysis can be made to the compound.

The compounds of the present invention have very good toxicity while having good antibacterial effect. Thus the compounds of the present invention are very useful antimicrobial agents. The antimicrobial efficacy (in vitro) and acute toxicity (LD ₅₀ ) of the compounds of the present invention are shown in the following table in comparison with oxolinic acid.

Compounds (1a) and (1b) may be made of alkali or alkaline earth metal salts in the usual manner.

* Determined by the Japan Chemotherapeutic Society standard method: In other words, 10 ⁶ / ml bacteria were inoculated by dilution of plate culture (heart infusion agar culture) and incubated at 37 ° C for 18 hours.

The invention will be explained in more detail in the following examples. Unless otherwise indicated, all parts mean% and ratio means weight ratio.

Example 1

Stir in a solution of 70 g of 2-ethoxy-2-methylpyridine (R ² = C ₂ H ₅ compound) dissolved in 280 ml of sulfuric acid while cooling on ice, and keep the internal temperature between 0 and 3 ° C. A mixed solution of fuming nitric acid and 50 ml of concentrated sulfuric acid is added. After 30 minutes of stirring at the same temperature, the reaction mixture is poured into ice water and extracted with chloroform. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated to give 85 2-ethoxy-2-methyl-6-nitropyridine (compound R ² = C ² H ⁵ ) having a melting point of 90 to 92 ° C.

Elemental Analysis: C ₈ H ₁₀ N ₂ O ₃

Calculated Value: C 52.74%, H 5.53%, N 15.38%

Found: 52.53%, 5.47% 15.21%

18.2 g of the nitro compound obtained above are suspended in 300 ml of ethanol and reduced on 2 g of 5% palladium block under atmospheric pressure. After the reaction, the catalyst is filtered off and the solvent is evaporated in vacuo. The residue is crystallized in benzene to give 13.8 g of 2-ethoxy-2-methyl-S-aminopyridine (compound with R ² = C ₂ H ₅ ) having a melting point of 98 to 99 ° C.

Elemental Analysis: C ₈ H ₁₂ N ₂ O

Calculated Value: C 63.13%, H 7.95%, N 18.41%

Found: 63.38%, 8.04% 18.27%

Dissolve 10.6 g of amino compound and 15.9 g of diethyl ethoxymethylmalonate (Compound V with A = C ₂ H ₅ O and R ³ = C ₂ H ₅ ) obtained in 30 ml of ethanol and reflux it for 1 hour Cool. The crystals were precipitated by addition of isopropyl ether and recrystallized from ethanol by filtration to 19.0 g of 2-ethoxy-2-methyl-S- (2,2-diethoxycarbonyl having a melting point of 137 to 138 ° C. Ethenyl) aminopyridine (Compound VI with R ² = R ³ = C ₂ H ₅ ) is obtained.

Elemental analysis: C ₁₆ H ₂₂ N ₂ O ₅

Calculated Value: C 59.61%, H 6.88%, N 8.69%

Found: 59.92%, 6.71% 8.63%

16.1 g of Compound VI obtained above is added to 160 ml of boiling Dow Dumb (manufactured by Dow Chemical Company) and refluxed for 1 hour. After cooling, the precipitated crystals were collected by filtration to obtain 11.8 g of crude crystals, which were recrystallized from dimethylformamide to obtain ethyl-6-ethoxy-4-hydroxy-7-1,8- with a melting point of 279 to 282 ° C (decomposition). Methylnaphthyridine-3-carboxylate (Compound VIII with R ² = R ² = C ₂ H ₅ ) is obtained.

Elemental Analysis: C ₁₄ H ₁₆ N ₂ O ₄

Calculated Value: C 60.86%, H 5.84%, N 10.14%

Found: 60.67%, 5.98% 9.97%

11.0 g of the stomach obtained in 110 ml of dimethylformamide was added dropwise with compound VII and 6.6 g of potassium carbonate mixture for 10 minutes at a temperature of 90 to 100 ° C. for 7.5 g of ethyl iodine.

The resulting mixture is stirred for another 1 hour at the same temperature. The solubles are filtered off and the filtrate is concentrated under reduced pressure. Water and chloroform were added to the residue, and the separated chloroform layer was washed with water and concentrated to dryness with anhydrous sodium sulfide to obtain 10.5 g of crude crystals. Ethyl 1,4-dihydro-S-ethoxy-1-ethyl-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylate having a melting point of 163 to 164 ° recrystallized from ethanol (R ¹ = Compound vIII is obtained, wherein R ² = R ³ = C ₂ H ₅ .

Elemental Analysis: C ₁₆ H ₂₀ N ₂ O ₄

Calculated Value: C 63.14%, H 6.62%, N 9.21%

Found: 62.93%, 6.59% 9.36%

20.2 g of Compound VII obtained above are dissolved by heating at 175 to 185 ° C. under nitrogen vapor so as to dissolve and 10 g of selenium oxide is added several times. Under nitrogen steam, the mixture is reacted under the same conditions for 20 minutes. After cooling, chloroform is added to the reaction mixture, insoluble materials are removed by filtration, and the filtrate is concentrated in vacuo. The obtained residue was recrystallized from ethanol to form 13.2 g of ethyl 1,4-dihydro-S-ethoxy-1-ethyl-7-formyl-4-oxo-1,8-naphthyridine- having a melting point of 169 to 170 ° C. Obtain 2-carboxylate.

Elemental analysis: C ₁₆ H ₁₈ N ₂ O ₅

Calculated Value: C 60.37%, H 5.70%, N 8.80%

Found: 60.58%, 5.44% 8.91%

3.95 g of the compound obtained above was added to a solution in which 20.5 g of aluminum bromide was dissolved in 450 ml of the carbon sulfide while cooling with ice, and then refluxed for 1 hour.

500 ml of water is added to the reaction solution and stirred. Chloroform is added to the solution for extraction. The separated chloroform layer is washed with water, dried over anhydrous sodium sulfate and evaporated in vacuo. The remaining residue was recrystallized from ethanol to 3.12 g of ethyl 1,4-dihydro-1-ethyl-7-formyl-3-hydroxy-4-oxo-1,8-naphthyridine having a melting point of 243 ° to 245 ° C. Obtain a compound of (IX) with 3-carboxylate (R ¹ = R ³ = C ₂ H ₅ ).

Elemental Analysis: C ₁₄ H ₁₄ N ₂ O ₅

Calculated Value: C 57.93%, H 4.86%, N 9.65%

Found: 58.04%, 4.82% 9.57%

6.0 g of the above compound, 5.6 g of diethyl bromalonate and 4.5 g of potassium carbonate were added to 300 ml of methyl ethyl ketone and refluxed for 9 hours. The resulting insoluble matter is filtered off and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel.

The solvent was removed and eluted with chloroform to give 6.1 g of triethyl 5-ethyl-S-hydroxy-8-oxo-2,3,5,8-tetrahydrofuro [3,2- with a melting point of 193 ° C. b] -1,8-naphthyridine-2,2,7-tricarboxylate.

Elemental analysis: C ₂₁ H ₂₄ N ₂ O ₉

Calculated Value: C 56.24%, H 5.39%, N 6.25%

Found: 55.80%, 5.32% 6.21%

1.2 g of the above compound and 0.48 g of potassium carbonate are added to 4 ml of mole and 14 ml of ethanol mixture. The solution was refluxed for 30 minutes, 5 ml of 2N caustic soda solution was added, and then reacted for 30 minutes.

The reaction mixture is treated with hydrochloric acid, and the precipitated crystals are collected by filtration. 0.52 g of 5,8-dihydro-S-ethyl-3-oxofuro [3,2-b] -1,8-naphthyridine-2,7-dicarboxylic acid having a melting point of 300 ° C. or higher after recrystallization from dimethylformamide ( X compound having R ¹ C ₂ H ₅ ).

Elemental Analysis: C ₁₄ H ₁₀ N ₂ O ₆

Calculated Value: C 55.63%, H 3.34%, N 9.27%

Found: 55.91%, 3.42% 9.35%

A mixture of 525 mg equipowder and 20 ml quinoline is heated to 160 ° C. and 1.9 g (X) is added while passing through a stream of nitrogen. The internal temperature of this mixture is raised to 195 ° C. and stirring is continued for 15 minutes.

After cooling, the mixture is added to a vessel containing 200 ml of chloroform and the insoluble substance is filtered off. Wash the filtrate with 5% hydrochloric acid five times to remove quinoline. The chloroform layer is washed with water, dried over anhydrous sodium sulfate, and the solvent is evaporated in vacuo.

The residue is treated with column chromatography of silica gel. Elution with a mixture of methanol and chloroform removes the solvent and then crude crystals are obtained. This crude crystal was recrystallized from dimethylformamide to give 1.1 g of 5,8-dihydro-S-ethyl-3-oxofuro [3,2-b] -1,8-naphthyridine-7 having a melting point of 260 ° C. or higher. -Carboxylic acid (compound of (1a) with R ¹ = C ₂ H ₅ ) is obtained.

Elemental Analysis: C ₁₅ H ₁₀ N ₂ O ₄

Calculated Value: C 60.46%, H 4.26%, N 10.88%

Found: 60.79%, 3.90% 10.85

Example 2

1.59 g of trimethylsulfonium iodide was stirred at room temperature under nitrogen and under vigorous stirring at 342 mg of 50% sodium hydride and 12 mg of ethyl 1,4-dihydro-1-ethyl-7-formyl-6-hydro 20 ml of anhydrous methyl sulfoxide solution dissolved in oxy-4-oxo-1,8-naphthyridine-3-carboxylate (compound of XI with R ¹ = R ³ = C ₂ H ₅ ) was added and stirred at room temperature for 1 hour. do.

The reaction mixture is poured into iced water and extracted with chloroform. The extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated in vacuo to give 1.2 g of 5-ethyl-S-hydroxy-8-oxo-2,3,5,8-tetrahydrofuro [3,2-b]- 1,8-naphthyridine-7-carboxylate (compound of XI with R ¹ = R ³ = C ₂ H ₅ ) is obtained.

35 mg of the compound obtained above was dissolved in 2 ml of dimethyl sulfoxide, heated to 180 ° to 190 ° C. for 20 hours, and dehydrated to obtain ethyl 5,8-dihydro-5-ethyl-8-oxofuro [3,2-b] -1. , 8-naphthyridine-7-carboxylate was produced. The above compound is heated in a 10% caustic soda solution to give a comparable carboxylic acid (compound of Ia with R ¹ = C ₂ H ₅ ).

Example 3

280 mg of ethyl 5-ethyl-3-hydroxy-8-oxo-2,3,5,8-tetrahydrofuro [3,2-b] -1,8-naphthyridine-7- obtained in Example 2 To a solution of carboxylate (XI) having R ¹ = R ³ = C ₂ H ₅ is dissolved in 5 ml of anhydrous chloroform, 100 mg of thionyl chloride is added dropwise at 10 DEG C. After stirring for 40 minutes, the reaction mixture is poured into Neutralize with sodium bicarbonate The chloroform layer is separated, dehydrated on anhydrous sodium sulfate, and the solution is evaporated in jinsong.

300 mg of impure ethyl 2-chloro-5-ethyl-8-oxo-2,3,5,8-tetrahydrofuro [3,2-b] -1,8-naphthyridine-7-carboxylate obtained above Compound (XI) with R ¹ = R ³ = C ₂ H ₅ ) is dissolved in 30 ml of methanol and reduced at atmospheric pressure with 5% palladium black (200 mg). After the reaction, the catalyst was filtered off and the solvent was distilled off under reduced pressure to obtain 240 mg of impure 5-ethyl-8-oxo-2,3,5,8-tetrahydrofuro [3,2-b] -1,8-naphthyridine -7-carboxylate is obtained.

To the obtained product, 5 ml of 10% sodium hydroxide solution was added and heated to 100 ° C. for 1 hour. After cooling, the solution was acidified with hydrochloric acid, and the precipitated crystals were collected by filtration and recrystallized from chloroform to give 5-ethyl-8-oxo-2,3,5,8-tetrahydrofuro [3,2-b] -1, 8-naphthyridine-7-carboxylic acid (compound with R ¹ = C ₂ H ₅ ) is obtained. Melting Point 292 ℃

Elemental Analysis: C ₁₃ H ₁₂ N ₂ O ₄

Calculated Value: C 59.99%, H 4.65%, N 10.77%

Found: 59.77%, 4.72% 10.59%

Example 4

100 mg of 5,8-dihydro-5-ethyl-8-oxofuro [3,2-b] -1,8-naphthyridine-7-carboxylic acid, described above, compound Ia wherein R ¹ = C ₂ H ₅ ) Is dissolved in 50 ml of methanol and reduced on a 5% palladium black (100 mg) in a hydrogen stream at 4 atmospheres of initial pressure.

When treated as above, 5-ethyl-8-oxo-2,3,5,8-tetrahydrofuro [3,2-b] -1,8-naphthyridine-7-carboxylic acid as in Example 3 (R Compound Ib) is obtained wherein ¹ = C ₂ H ₅ .

Example 5

30.4 g of ethyl 1,4-dihydro-S-ethoxy-1-ethyl-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylate (R ¹ = R ² = R ³ = C A mixture of ₂ H ₅ phosphorus compound iii) and 100 ml of sulfonic acid is stirred at 140-145 ° C. and 22 g of selenium dioxide is added in a limit. The mixture is allowed to react for 5 hours under the same conditions, then cooled and chloroform is added. Insoluble matters are removed by filtration. The filtrate is continuously washed with 3% sodium carbonate solution and water, then dehydrated and evaporated over sodium sulfate. Isopropanol was added to the residue, and the precipitated crystals were collected by filtration. 22.0 g of ethyl 1,4-dihydro-S-ethoxy-1-ethyl-7-formyl-4-oxo-1,8-naphthyridine-3- Obtain a carboxylate. (Melting point: 169 to 170 ° C)

53 g of aluminum chloride powder is added to 500 ml of dichloromethane and stirred at room temperature for 1 hour. 25.0 g of ethyl 1,4-dihydro-6-ethoxy-1-ethyl-7-formyl-4-oxo-1,8-naphthyridine-3-carboxylate was dissolved in 200 ml of dichloromethane in this mixture. The solution is slowly added dropwise. After stirring for 3 hours at room temperature, ice water is added to separate the two layers. The aqueous layer was extracted with chloroform, the chloroform extract and the organic layer were collected, washed with water and evaporated to dryness in vacuo. Then, 21.8 g of ethyl 1,4-dihydro-1-ethyl-7-formyl-S- hardhydroxy-4-oxo-1 , 8-naphthyridine-3-carboxylate (formula (IX) of R ¹ = R ³ = C ₂ H ₅ ) is obtained.

Example 6

3.2 g of ethyl 3-chloro-5-ethyl-8-oxo-2,3,5,8-tetrahydrofuro [3,2-b] -1,8-naphthyridine- dissolved in 50 ml of dimethylformamide. Into a 7-carboxylate (Compound XII where R ¹ = R ³ = C ₂ H ₅ , X = Cl) solution, slowly dropwise 3.2 g of 1,8-diazabicyclo [5,4,0] -7-undecine The mixture is stirred at 40-45 ° C. for 1 hour. After removal of the solvent the residue is dissolved in dilute hydrochloric acid and extracted with chloroform. The separated chloroform layer was washed with water, dried and evaporated in vacuo to give 2.3 g of ethyl 5,8-dihydro-5-ethyl-8-oxofuro [3,2-b] -1,8-naphthyridine-7- Obtain a carboxylate.

Elemental Analysis: C ₁₅ H ₁₄ N ₂ O ₄

Calculated Value: C 62.93%, H 4.93%, N 9.79%

Found: 62.75, 5.06, 9.67

To 30 ml of 1 N hydrochloric acid solution containing 90% acetic acid was added 2.86 g of the compound obtained above and refluxed for 2 hours. After cooling, the precipitated crystals were collected by filtration to collect 1.85 g of 5,8-dihydro-5-ethyl-8-oxofuro [3,2-b] -1,8-naphthyridine-7 having a melting point of 305 to 3707 ° C. -Carboxylic acid (a compound having R ¹ = C ₂ H ₅ ) is obtained. (decomposition)

NMR spectrum (CF ₃ COOH): r (ppm)

1.85 (3H, tM CH ₂ CH ₃ ), 5.30 (1H, q, CH ₂ CH ₃ ), 7.45 (1H, dd, C ₃ -H), 8.65 (1H, d, C ₂ -H),

9.15 (1H, d, C ₉ -H), 9.70 (1H, s, C ₆ -H)

IR spectrum (KBr): cm ^-1 (in absorbance order)

1715, 1480, 1390, 1600, 1420, 1620, 1440, 800, 1350, 1270

To the solution obtained by suspending 25.8 g of the compound obtained above in 250 ml of water, slowly dropwise stirring about 100 ml of 1N aqueous sodium hydroxide solution was added dropwise. The mixture is filtered to remove insoluble matters. Ethanol is gradually added to the filtrate to precipitate the sodium salt. After cooling, the precipitated crystals were collected by filtration and 26.7 g of sodium 5,8-dihydro-5-ethyl-8-oxofuro- [3,2-b] -1,8-naphthyridine having a melting point of 300 ° C. or higher. Obtain -7-carboxylate monohydrate.

Elemental _{analysis: C 13 H 9 N 2 O} 4 N a · H 2 O

Calculated Value: C 52.35, H 3.72, N 9.40

Found: 52.18, 3.84 9.27

Example 7

5.0 g of triethyl 5-ethyl-3-hydroxy-8-oxo-2,3,5,8-tetrahydrofuro [3,2-b] -1,8-naphthyridine-2,2,7- Tricarboxylate is added to 80 ml of 20% sulfuric acid and stirred at 100 ° C. for 2 hours. After cooling, the reaction solution is poured into ice water. The precipitated crystals were collected by filtration, recrystallized from dimethylformamide, and 2.61 g of 5,8-dihydro-5-ethyl-8-oxofuro [3,2-b] -1,8-naphth having a melting point of 300 ° C. or higher. Ridine-2,7-dicarboxylic acid (Compound X where R ¹ = C ₂ H ₅ ) is obtained.

The mixture of 10.0 g of the compound obtained as described above and a solution containing 120 mg of first copper oxide in 300 ml of dimethylacetamide was refluxed for 3 hours, and the hot reaction solution was filtered to remove insoluble matters. The filtrate is concentrated and the precipitated crystals are collected by filtration. The crude crystals are dissolved in acetic acid and treated with activated charcoal and filtered. The filtrate is concentrated until crystals precipitate and then left to cool. The precipitated crystals were collected by filtration, washed with ethyr and dried to obtain 5.7 g of 5,8-dihydro-5-ethyl-8-oxofuro [3,2-b] -1,8-naphthyridine-7-carboxylic acid. (R ¹ is C ₂ H ₅ in the formula (Ia) compound) to obtain a.

Example 8

270 g of 5,8-dihydro-5-ethyl-8-oxofuro [3,2-b] -1,8-naphthyridine-2,7-carboxylic acid in 4 l of dimethylacetamide (R ¹ is C ₂ H _The mixture containing ₅ phosphorus compound X) and 3.24 g of primary oxidation lamp is heated at reflux for 2.5 hours. The reaction solution is concentrated to dryness and the residue is washed with chloroform to obtain 203 g of the initial product. The chloroform solution layer is concentrated to dryness to afford 12 g of the second product.

The crude product obtained as above is collected and made into a powder. The powder is dissolved in chloroform and heated at reflux. After filtration to remove impurities, the filtrate is decolorized by treatment with 21.5 g of activated carbon. The resulting solution is added to a silica gel column (500 g) and eluted with 2 l of chloroform. The melt is concentrated in vacuo to a volume of about 900 ml. The precipitated crystals were collected by filtration, washed with 800 ml of chloroform and dried to give 126.4 g of 5,8-dihydro-5-ethyl-8-oxofuro [3,2-b] -1,8-naphthyridine-7- A carboxylic acid (structure (Ia) compound wherein R ¹ is C ₂ H ₅ ) is obtained.

Example 9

9.5 g of 5, 8-dihydro-5-ethyl-8-oxofuro [3, 2-b] -1, 8-naphthyridine-2,7-dicarboxylic acid (R ¹ is C ₂ H ₅ Compound (X)) 0.8 g equipotent powder and 250 ml of diethylphthalate mixed medicine is heated at 250 to 260 ° for 25 minutes. After cooling, the reaction mixture is partitioned between chloroform and aqueous potassium carbonate solution. The separated aqueous layer is acidified with hydrochloric acid and extracted with chloroform. The extract layer is treated with activated carbon and concentrated to dryness. Precipitated crystals were added by ethanol to collect 4.2 g of 5,8-dihydro-5-ethyl-8-oxofuro [3,2-b] -1,8-naphthyridine-7-carboxylic acid (R ¹ A compound of formula (Ia) that is C ₂ H ₅ .

The compound of the present invention can be administered orally in an adult dose of about 250-3000 mg per day, but may be administered in three divided doses per day. These compounds may be administered in conventional formulations such as tablets, calcels, powders or syrups, which are binders, such as hydroxymethyfurophyllulose, carboxymethylcellulose, polyoxyethylene stearate, as known in the art. Surface active agents such as [MYS-40], and excipients (carriers) such as starch, lactose, and glucose.

Typical pharmaceutical formulations are shown below and in addition to the compounds of the present invention can also be prepared in other dosage forms well known in the art for administration.

The above formulation can be administered orally by filling in a hard gelatin capsule.

Since the description of the present invention has been described in detail with specific embodiments, it will be apparent to those skilled in the art that various applications and modifications may be made without departing from the spirit and scope of the present invention.

Claims (1)

The compound of formula (IX) is then heated with bromomalonic acid ester and acid or alkali treated to give 5,8-dihydro-5-alkyl-8-oxofuro [3,2-b of formula (X). ] -1,8-naphthyridine-2,7-dicarboxylic acid followed by decarboxylaion to 5,8-dihydrofuro [3,2-b] -1,8-naphti of formula (Ia) Method for preparing a ridine derivative.

In the above general formula R ₁ is an alkyl group having 1 to 6 carbon atoms. R ₃ represents an alkyl group having 1 to 6 carbon atoms.