JPS6139312B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the formula Pyrido [1,2,3-de] [1,
4] Concerning benzoxazine derivatives and salts thereof. 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. Compounds having a structure similar to the compound of the present invention include those described in JP-A-50-108298, JP-A-51-127099, and JP-A-55-76875. The compounds of the present invention also exhibit extremely excellent activity. An example of the method for producing the compound of the present invention will be explained using a reaction formula. That is, the compound [] is mixed with N-methylpiperazine in a polar solvent such as dimethylsulfoxide, sulfolane, dimethylformamide, dimethylacetamide, or water at room temperature to 200°C, preferably at 70°C.
Compound [] is obtained by heating at ~150°C for 1 to 48 hours. The compounds of the present invention and their salts exhibit strong antibacterial activity against Gram-negative bacteria and Gram-positive bacteria, including Pseudomonas aeruginosa, and can be expected to be used as pharmaceuticals. For example, the minimum inhibitory concentration was measured in an in vitro antibacterial test using pipemidic acid, which is used as a pharmaceutical, as a control, and the results show excellent antibacterial activity as shown in the table below. Minimum inhibitory concentration (MIC, μg/ml) Plate dilution method (heart infusion agar medium) Inoculum amount 10 ⁶ /ml Culture conditions 37℃, 18 hours

【table】

[Table] Next, reference examples and examples are described. 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, dried, and the chloroform was distilled off to obtain 3.8 g of 2,3,4-trifluoronitrobenzene as an oily substance.
get. 20g of this and 150ml of dimethyl sulfoxide
Mix with 10% potassium hydroxide aqueous solution at 18-20℃
Drop 50ml. Stir further at room temperature for 2 hours, then add 1 liter of water.
Add chloroform and shake. 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 is 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. The chloroform layer is washed with water, dried, and then the solvent is distilled off and the residue is treated with n-hexane to obtain 5.0 g of 2-acetonyloxy-3,4-difluoronitrobenzene as pale yellow-white crystals. 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 give 7,8'-difluoro-2,3-dihydro-3-methyl-4H-
5.1 g of [1,4]benzoxazine can be obtained as a pale yellow oil. 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.
and stir for 1 hour at a bath temperature of 140-145°C. After cooling, pour into ice water and dissolve the precipitate in chloroform 600ml (200ml).
×3) Extract. After partitioning the chloroform layer with a 5% aqueous potassium carbonate solution and then water, it was dried with Glauber's salt,
9,10-difluoro-3-methyl-7-oxo-
2,3-dihydro-7H-pyrido [1,2,3-
5.1 g of white powder of de][1,4]benzoxazine-6-carboxylic acid ethyl ester was obtained. melting point
261℃. 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 were collected by filtration, thoroughly washed with water, washed with a mixture of ethanol and ether (1:4), and dried under reduced pressure to obtain transparent plate-like crystals of 9,10-difluoro-3-methyl-7-oxo-2. ,3-dihydro-7H-pyrido [1,2,
3.7 g of 3-de][1,4]benzoxazine-6-carboxylic acid is obtained. Melting point >300℃. NMR (CF ₃ COOH) δppm: 1.88 (3H, d, C _{3 -} CH ₃ ) 4.72 (2H, bsC ₂ - H ₂ ) 4.8 - 5.1 (1H, m, C _{3 -} H) 7.9 - 8.2 (1H, q , C ₈ -H) 9.42 (1H, s, C ₅ -H) Example 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3
-de] [1,4] 1.0 g of benzoxazine-6-carboxylic acid and 2.85 g of N-methylpiperazine were added to 15 ml of dimethyl sulfoxide, and the mixture was heated at 100 to 110°C.
Stir for 12 hours. The reaction mixture was dried under reduced pressure, 40 ml of water was added to the residue, and the mixture was extracted with chloroform. After drying the extract, it was dried under reduced pressure and the residue was recrystallized from ethanol to give 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 550
Get mg. Elemental analysis value C ₁₈ H ₂₀ FN ₃ O ₄ Calculated value C59.82, H5.58, N11.63 Analysis value C59.62, H5.59, N11.65 ¹ H-NMR (CDCl ₃ ) δppm: 1.63 ( 3H, d, J = 7Hz, C ₃ - C H ₃ ) 2.38 (3H, s, N - C H ₃ ) 2.54 - 2.60 (4H, m,

【formula】 3.40~3.44 (4H, m,

[Formula] 4.35-4.51 (3H, m, _C3 - H and _C2 - _H2 ) 7.75 (1H, d, J=12Hz, _C8 - H ) 8.64 (1H, s, _C5 - H ).

Claims (1)

[Claims] 1 9-fluoro-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-
7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid and its salts.