JPH0116837B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula (In the formula, R ³ is hydrogen or a lower alkyl group,
R ¹⁰ represents a monosubstituted, disubstituted or cyclically substituted amino group. These substituents may contain heteroatoms and may be substituted by hydroxy, lower alkyl, lower alkoxy, amino, lower alkylamino, hydroxy lower alkyl, oxo. X represents a halogen atom. ) 8-amino-7-oxopyrido [1,2,3-
de][1,4]benzoxazine-6-carboxylic acid derivative. Here, the lower alkyl group is methyl, ethyl, n-
Examples include propyl, i-propyl, and the like. Mono-substituted amino groups include ethylamino, hydroxyethylamino, and benzylamino; di-substituted amino groups include diethylamino, methylhydroxyethylamino, and cyclic substituted amino groups include pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, and homopiperazinyl. Examples include 5- to 7-membered ring groups. These cyclically substituted amino groups may have a hydroxy group, lower alkyl group, lower alkoxy group, amino group, lower alkylamino group, hydroxy lower alkyl group, or oxo group substituted on the ring. More detailed examples of the substituent R ¹⁰ include 1-piperazinyl, 4-methyl-1-piperazinyl, 1-pyrrolidinyl, 3-hydroxy-
1-pyrrolidinyl, 1-piperidinyl, 4-hydroxy-1-piperidinyl, 4-oxo-1-piperidinyl, 4-(2-hydroxyethyl)-1
-piperazinyl, 4-dimethylamino-1-piperidinyl, 1-morpholinyl, 1-homopiperazinyl, and the like. Chlor as a halogen atom,
Examples include fluoro. Specific examples of the salt include salts with inorganic or organic acids such as hydrochloric acid, sulfuric acid, and methanesulfonic acid, and sodium and potassium salts of carboxylic acids. Next, an example of a method for producing the compound of the present invention will be explained using a reaction formula. (In the formula, R ^{3 ,} R ¹⁰ and Room temperature to 200℃, preferably 70~
Compound () is obtained by heating at 150°C for 30 minutes to 48 hours. The compound () used as an intermediate raw material is synthesized, for example, by the route shown in the following reaction formula. That is, by reducing the compound () obtained by nitrating the compound () described in Japanese Patent Application No. 55-121540 (55.9.2), the compound () is obtained. The compound represented by the general formula () and its salt of the present invention exhibits a broad antibacterial spectrum against Gram-negative bacteria and Gram-positive bacteria including Pseudomonas amphibians,
It is expected to be used as a medicine. For example, the following table shows the results of measuring the minimum inhibitory concentration in an in vitro antibacterial test using pipemidic acid, which is used as a pharmaceutical, as a control, and shows excellent antibacterial activity. Minimum inhibitory concentration (MIC, μg/ml) Plate dilution method (heart infusion agar medium) Inoculum amount: 10 ⁶ /ml, culture conditions: 37°, 18 hours

[Table] Reference Example 5.0 g of 2,4-dichloro-3-fluoronitrobenzene and 5.8 g of powdered potassium fluoride are added to 5 ml of dimethyl sulfoxide and stirred at 140-155°C for 4.5 hours. The solvent was removed under reduced pressure and the residue was partitioned between water and chloroform. The chloroform layer was washed with water and dried, and then the chloroform was distilled off to obtain 3.8 g of 2,3,4-trifluoronitrobenzene as an oil. 20g of this and 150ml of dimethyl sulfoxide
Stir and add 10% potassium hydroxide aqueous solution dropwise at 18-20°C. The mixture was further stirred at room temperature for 2 hours, 1 portion of water was added, and the mixture was shaken with chloroform. The aqueous layer is diluted with hydrochloric acid and extracted with chloroform. The extract is washed with water, dried, and the chloroform is concentrated. The residue was purified by silica gel chromatography to obtain 5.8 g of 2,3-difluoro-6-nitrophenol as a yellow oil. Add 5.8 g of this product to 5.0 g of monochloroacetone, 8.0 g of potassium carbonate, 0.8 g of potassium iodide, and 100 ml of acetone, and reflux for 4 hours. Insoluble materials are filtered off, the solvent is distilled off, and the residue is partitioned between chloroform and water. After washing the chloroform layer with water and drying, the solvent was distilled off and the residue was treated with n-hexane to produce 2-acetonyloxy-3,4-difluoronitrobenzene as pale yellowish white crystals with a melting point of 61°C.
Obtain 5.0g. Dissolve 7.1 g of this product in 200 ml of ethanol, add 14 ml of Raney nickel, and perform atmospheric pressure catalytic reduction. After filtering off the catalyst and distilling off the solvent, the residue was decolorized through a layer of silica gel to yield 5.1 g of 7,8-difluoro-2,3-dihydro-3-methyl-4H-benzoxazine as a pale yellow oil. You can get it. A mixture of 4.8 g of this and 5.3 g of diethyl ethoxymethylenemalonate is heated at 140-145°C for 1 hour. After the raw materials disappeared, a small amount of ethanol was distilled off under reduced pressure, and 35 g of ethyl polyphosphate was added to the resulting oil.
was added, stirred for 1 hour at a bath temperature of 140 to 145℃, poured into ice water after cooling, and the precipitate was dissolved in 600 ml of chloroform (200
3) Extract. The chloroform layer was partitioned with a 5% potassium carbonate aqueous solution and then with water, and then dried with Glauber's salt to give 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrid [1,2,3
-de] [1,4] 5.1 g of white powder of benzoxazine-6-carboxylic acid ethyl ester (melting point 261
℃) is obtained. Add 4.0g of this to concentrated hydrochloric acid-acetic acid (1:4)50
ml and reflux for 3 hours in an oil bath. After cooling, the precipitated crystals are collected by filtration, thoroughly washed with water, washed with a mixture of ethanol and ether (1:4), and dried under reduced pressure to obtain 3.7 g of carboxylic acid (melting point >300°C) in the form of transparent plate-like crystals. 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3
-de] [1,4] 300 mg of benzoxazine-6-carboxylic acid is dissolved in 3 ml of concentrated sulfuric acid, and 150 mg of potassium nitrate is added while stirring while keeping the internal temperature below 5°C. After returning to room temperature and reacting for 1 hour,
Pour the reaction solution into ice water and collect the precipitate by filtration. This is washed with water and dried to obtain 340 mg of pale yellow powder. Recrystallization from a mixture of chloroform and ethanol gives 9,10-difluoro-3-methyl-8-nitro-7-oxo- as pale yellow-white needle crystals with a melting point of 262°C.
2,3-dihydro-7H-pyrido [1,2,3-
de][1,4]benzoxazine-6-carboxylic acid is obtained. Elemental analysis value C ₁₃ H ₈ F ₂ N ₂ O ₆ Calculated value C47.86, H2.47, N8.59 Analysis value C47.85, H2.54, N8.61 200 mg of the above compound and 25 mg of 5% palladium charcoal
Add to 150ml of ethanol and perform catalytic reduction. After a theoretical amount of hydrogen has been absorbed, the catalyst is filtered off by heating, and the filtrate is dried under reduced pressure to obtain 175 mg of pale yellow needle crystals. Recrystallization from a mixture of chloroform and ethanol gives 8-amino-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrid [1,2 ，
3-de][1,4]benzoxazine-6-carboxylic acid is obtained. Elemental analysis value C ₁₃ H ₁₀ F ₂ N ₂ O ₄ Calculated value C52.71, H3.40, N9.46 Analysis value C52.86, H3.49, N9.49 Example 1 8-Amino-9, 10 -difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid 70 mg and N-methylpiperazine 150 mg in dimethyl 1ml of sulfoxide plus 110
Stir at ~120°C for 2 hours. Remove the solvent under reduced pressure,
The residue is purified by silica gel column chromatography (developing solvent: chloroform-methanol = 97:3). When the eluate was recrystallized from ethanol, 8-
Amino-9-fluoro-3-methyl-10-(4-
Methyl-1-piperazinyl)-7-oxo-2,
3-dihydro-7H-pyrido [1,2,3-de]
[1,4]Benzoxazine-6-carboxylic acid 55
Get mg. Elemental analysis value C ₁₈ H ₂₁ FN ₄ O ₄ Calculated value C57.44, H5.62, N14.89 Analysis value C57.31, H5.52, N14.74 NMR: δ ^ppm _DMSO - _d6 6.94 (2H, s , NH ₂ , D ₂ O) 8.79 (1H, s, 5th-position H) Example 2 8-Amino-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H- 100 mg of pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid and 130 mg of 3-hydroxypyrrolidine are added to 2 ml of dimethyl sulfoxide and stirred at 110-115°C for 1.5 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (developing solvent: chloroform-methanol =
90:10) and recrystallized from a chloroform-ethanol mixture to give 8-amino-9-fluoro-10- as yellow microcrystals with a melting point of 293°C (decomposition).
(3-hydroxy-1-pyrrolidinyl)-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid 100mg obtain. Elemental analysis value C ₁₇ H ₁₇ FN ₃ O ₅ Calculated value C56.35, H4.73, N11.60 Analysis value C56.22, H5.02, N11.55 Example 3 8-amino-9,10-difluoro Add 50 mg of -3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid and 50 mg of pyrrolidine to 1 ml of dimethyl sulfoxide. 1 at 90-100℃
Stir for an hour. The solvent was distilled off under reduced pressure and the residue was partitioned between chloroform and water. Wash the chloroform layer with water,
After drying, chloroform was distilled off and the residue was subjected to silica gel column chromatography (developing solvent:
Purify with chloroform-methanol = 95:5). When the eluate is recrystallized from ethanol, the melting point
8-Amino- as yellow microneedles at 288℃ (decomposition)
9-Fluoro-3-methyl-10-(1-pyrrolidinyl)-7-oxo-2,3-dihydro-7H-
25 mg of pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid is obtained. Elemental analysis value C ₁₇ H ₁₇ FN ₃ O ₄ Calculated value C58.95, H4.95, N12.13 Analysis value C58.77, H5.18, N12.15 Example 4 8-amino-9,10-difluoro 50 mg of -3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid and 100 mg of N-ethylpiperazine were added to 2 ml of dimethyl sulfoxide. plus 100
Stir at ~110°C for 3 hours. Remove the solvent under reduced pressure,
The residue is purified by silica gel chromatography (developing solvent: chloroform-methanol = 95:5). When the eluate is recrystallized from ethanol, the melting point
8-Amino-10-(4-ethyl-1-piperazinyl)-9 as yellow microneedles at 282-283°C (decomposition)
-Fluoro-3-methyl-7-oxo-2,3-
Dihydro-7H-pyrido [1,2,3-de] [1,
4] Obtain 55 mg of benzoxazine-6-carboxylic acid. Elemental analysis value C ₁₉ H ₂₃ FN ₄ O ₄ Calculated value C58.46, H5.94, N14.35 Analysis value C58.26, H6.01, N14.44

Claims (1)

[Claims] 1. General formula (In the formula, R ³ is hydrogen or a lower alkyl group,
R ¹⁰ represents a monosubstituted, disubstituted or cyclically substituted amino group. These substituents may contain heteroatoms and may be substituted by hydroxy, lower alkyl, lower alkoxy, amino, lower alkylamino, hydroxy lower alkyl, oxo. X represents a halogen atom. ) and its salts. 2 8-amino-9-fluoro-3-methyl-10
-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,
3-de][1,4]benzoxazine-6-carboxylic acid or a salt thereof. 3 8-amino-9-fluoro-10-(3-hydroxy-1-pyrrolidinyl)-3-methyl-7-
Oxo-2,3-dihydro-7H-pyrido[1,
2,3-de][1,4]benzoxazine-6-
The compound according to claim 1, which is a carboxylic acid or a salt thereof.