JPH0714945B2 - Pyridobenzoxazines - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an antibacterial compound and a production intermediate thereof.

Prior art Ofloxacin ((±) -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: see JP-A-57-46986) is known as an excellent synthetic antibacterial agent. ing.

Problems to be Solved Ofloxacin has an asymmetric carbon at the 3-position in its structure and is obtained as a racemate ((±) specific optical rotation [α] _D 0 °) by a conventional production method.

The present inventor obtained an optically active form of this product, and the 3S form ((−) form has approximately twice the antibacterial activity of the (±) form and has less toxicity than the (+) form, and the 3R form ( (+) Body)
Has an antibacterial activity of about 1/10 to 1/100, but has the same toxicity as (±), and each optically active substance has good water solubility and can be used as an injection. The present invention has been completed by the finding of an intermediate useful for the production of this optically active substance.

Means for Solving Problems The present invention provides a compound represented by the formula IV. Compound represented by formula VI Compound represented by formula VII Compound of formula VIII And a compound of formula IX Regarding

X ₁ and X ₂ in the formula mean halogen atoms such as fluorine and chlorine, and a compound in which both are fluorine is particularly preferable. R ₁ and R ₂ each represent lower alkyl such as methyl, ethyl and propyl, with methyl being particularly preferred. R ₃ is a substituted sulfonyl group, for example, paratoluenesulfonyl, benzenesulfonyl, methanesulfonyl, an alkoxycarbonyl group, for example, tertiary butoxycarbonyl, or an aralkyloxycarbonyl group, for example, benzyloxycarbonyl, paramethoxybenzyloxycarbonyl. Meaning, a substituted sulfonyl group, especially a paratoluenesulfonyl group is preferable. R ₄ represents a lower alkyl group, and R ₅ represents a hydrogen atom or a lower alkyl group. n means an integer of 1 to 3, but 1 or 2 is usually suitable.

The compound of the present invention can be produced by the method exemplified by the reaction formula shown on the last page.

In the chemical structural formula of the reaction formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , X ₁ , X ₂ and n have the same meanings as described above, and X ₃ is hydroxyl, halogen or alkoxyl (active ester). Residue), an acid anhydride residue and the like, and a carboxyl group and its reactive derivative residue.

That is, 3-lower alkyl-7,8-dihalogeno-1,4-
When the benzoxazine derivative II and the cyclic amino acid or its reactive derivative III are condensed by an amide bond forming reaction such as an acid chloride method, an active ester method, an acid anhydride method or a DCC method, a compound IV is produced. Most commonly, acid chloride III in which X ₃ is chlorine may be reacted with compound II in an organic solvent with stirring at room temperature. The product can be isolated and purified by a general method.

In this reaction, one of the two isomers of the cyclic amino acid or its reactive derivative III, that is, the S form or the R form
The body facilitates the separation of diastereomeric mixtures of compounds of IV. That is, a derivative of S or R-proline, S or R-pipecolic acid, etc. is suitable, and the most preferable example of compound III is (S) -N.
-Benzenesulfonylproline and (S) -N-paratoluenesulfonylproline. Diastereomer
The mixture of IV can be separated by fractional crystallization or chromatography using silica gel as a carrier or a combination thereof.

The separated diastereomer V is hydrolyzed (usually under basic conditions) to give 3S-7,8-dihalogeno-3.
-Lower alkyl-1,4-benzoxazine VI which can be reacted with ethoxymethylenemalonic acid di-lower alkyl ester in a known reaction to give 3S- (7,8-
Dihalogeno-3-lower alkyl-2,3-dihydro-4H-
1,4-dibenzooxazin-4-yl) methylenemalonic acid dialkyl ester VII was reacted with polyphosphoric acid or its ester by heating to give 3S-9,10-dihalogeno-3-loweralkyl-7-oxo-2. , 3-dihydro-7
H-pyrido [1,2,3-de] [1,4] benzoxazine-6
-The carboxylic acid or its ester VIII can be obtained, and if necessary, further hydrolyzed and further reacted with N-lower alkylpiperazine to produce 10-substituted compound I.

Alternatively, compound VII or compound VIII may be heat condensed with boron trifluoride or a boron trifluoride complex to form chelate compound IX, which may be reacted with N-lower alkylpiperazine to produce 10-substituted compound I. Yes (JP-A-57
-46986, 58-29789, 58-43977, 58-725
(See Japanese Patent No. 88).

Compound I can also be produced by the method exemplified below. That is, (±) -9,10-difluoro-3-hydroxymethyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic Treating ethyl acid with 3,5-dinitrobenzoyl chloride, etc., (±) -3- (3,5-dinitrobenzoyloxy)
Leads to the methyl form. This is separated into two kinds of optically active substances by an appropriate method, for example, high performance liquid chromatography (HPLC).

The obtained optically active substance is treated with sodium hydrogen carbonate or the like,
The benzoyl moiety is selectively hydrolyzed to produce the hydroxymethyl form. This is made into a 3-iodomethyl body using an iodination reagent and reduced with n-tributylstannane or the like to produce a 3-methyl body. This product can be converted to a 3-methyl 6-carboxylic acid by hydrolysis under acidic conditions without isolation and purification. When this is reacted with N-alkylpiperazine by treatment such as heating and stirring, 10- (4
-Alkyl-1-piperazinyl) form I can be obtained.

The antibacterial activity of the optically active 3S form I and 3R form obtained as the final substance is shown in the table in comparison with ofloxacin. The test method was in accordance with the standard method specified by the Japanese Society of Chemotherapy.

Example 1: 3S-(+)-7,8-difluoro-3-methyl-
4-[(S) -N-p-toluenesulfonylprolyl]
A solution of acid chloride prepared from 61.9 g of (2,3-dihydro-4H- [1,4] benzoxazine (S) -Np-toluenesulfonylproline and thionyl chloride in dry dichloromethane (350 ml) was added to (±)- 7,8-difluoro-3-
Methyl-2,3-dihydro-4H- [1,4] benzoxazine
32.8g and 28ml pyridine dry dichloromethane (300m
l) The solution was slowly added dropwise to the solution with stirring at room temperature, and then stirred at room temperature for another 4 hours. The reaction mixture was washed successively with 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate.

Dichloromethane was distilled off and the oily residue obtained was converted to ethyl acetate 20
Dissolve in 0 ml, add 750 ml of n-hexane dropwise with stirring, and immediately crystallize (compound IV: X ₁ = X ₂ = F, R ₁ = C
H ₃ , R ₃ = p-toluenesulfonyl, (= 1) (-) form)
Is deposited. Precipitated crystals were filtered off, the filtrate was evaporated to dryness under reduced pressure, and the residue was subjected to column chromatography on silica gel (500 g).
Elution with ethyl acetate (50: 1 to 25: 1) gave an oil.
The oily substance is dissolved in 500 ml of ethanol and left standing at room temperature for one day to precipitate crystals. Diethyl ether and n-hexane were added to the crystals obtained by distilling off ethanol, and the crystals were collected by filtration and dried under reduced pressure to give 3S-(+)-7,8-difluoro-3-methyl-4-[(S). -N-p-toluenesulfonyl prolyl] -2,3-dihydro-4H-[l, 4] benzoxazine (compound _{IV: X 1 = X 2 =} F, R 1 = CH 3, R 3 = p- toluene 33.4 g of sulfonyl, (+) form of n = 1 was obtained. Melting point 107-108 ° C [α] _D + 70.7 ° (c = 0.953, chloroform) Elemental analysis value C ₂₁ H ₂₂ F ₂ N ₂ O ₄ S Calculated value C 57.79 H 5.08 N 6.42 Analytical value C 58.05 H 5.14 N 6.47 Example 2: S-(−)-7,8-difluoro-3-methyl −2,
3-Dihydro-4H- [1,4] benzoxazine 32.8 g of the (+) form obtained in Example 1 was dissolved in ethanol 1, 300 ml of 1N sodium hydroxide solution was added, and the mixture was refluxed for 3 hours. The oily residue obtained by distilling off ethanol was extracted with benzene. The extract was washed with saturated brine and dried over sodium sulfate, and benzene was distilled off. The residue was subjected to column chromatography on 200 g of silica gel and eluted with benzene to give S-(-).
-7,8-Difluoro-3-methyl-2,3-dihydro-4H-
[1,4] benzoxazine (VI: X ₁ = X ₂ = F, R ₁ = C
_{H 3), 12.7g (91.4%} ) as an oil.

[Α] _D −9.6 ° (c = 2.17, chloroform) The absolute configuration was determined to be S by X-ray analysis of this as a hydrochloride.

Example 3: S-(-)-9,10-difluoro-3-methyl-
7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de]
[1,4] Benzoxazine-6-carboxylic acid ethyl ester S-(−)-benzoxazine derivative 1 obtained in Example 2
5.8 g, diethyl ethoxymethylene malonate 24.0 g
Was added, and the mixture was stirred under reduced pressure at 130 to 140 ° C for 1 hour. After cooling
The reaction solution was dissolved in 50 ml of acetic anhydride, and 80 ml of a mixed solution of acetic anhydride-concentrated sulfuric acid (2: 1 v / v) was added dropwise thereto while stirring with ice cooling. After stirring at room temperature for 1 hour, the mixture was stirred at a bath temperature of 50 to 60 ° C for 30 minutes. After ice water was added to the reaction solution, powdery potassium carbonate was added to neutralize the solution and the mixture was extracted with chloroform. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with saturated saline, and dried with sodium sulfate. Chloroform was evaporated, diethyl ether was added to the residue, and the crystals were collected by filtration to give the title compound (VIII: X ₁
= X ₂ = F, to give a _{R 1 = CH 3, R 5} = C 2 H 5) 20.0g. Melting point 257
˜258 ° C. [α] _D −68.1 ° (c = 0.250, acetic acid) Example 4: S-(−)-9,10-difluoro-3-methyl-
7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de]
[1,4] Benzooxydine-6-carboxylic acid 19.5 g of the ester obtained in Example 3 was dissolved in 150 ml of acetic acid to obtain 400 m of concentrated hydrochloric acid.
l was added and the mixture was refluxed for 3 hours. After cooling, the precipitated crystals are collected by filtration, washed successively with water, ethanol and diethyl ether and dried,
Corresponding carboxylic acid (VIII: X ₁ = X ₂ = F, R ₁ = CH ₃ , R ₅ =
H) 16.2 g was obtained.

Melting point> 300 ° C. [α] _D −65.6 ° (c = 0.985, DMSO) Example 5: S-(−)-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 (S-ofloxacin
(−) Form 14.3 g of the carboxylic acid obtained in Example 4 was converted to diethyl ether 600
70 ml of boron trifluoride diethyl ether complex was added, and the mixture was stirred at room temperature for 5 hours. The supernatant was decanted, diethyl ether was added to the residue, and the residue was collected by filtration.
It was washed with diethyl ether and dried. Dissolve this in 100 ml of dimethyl sulfoxide, and add 14.2 m of triethylamine.
and 7.3 ml of N-methylpiperazine were added, and the mixture was stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure, diethyl ether was added to the residue, the yellow powder collected by filtration was suspended in 400 ml of 95% methanol, 25 ml of triethylamine was added, and the mixture was heated under reflux for 25 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in 500 ml of 10% hydrochloric acid, washed 3 times with chloroform, adjusted to pH 11 with 4N aqueous sodium hydroxide solution, adjusted to pH 7.3 again with 1N hydrochloric acid, and added with chloroform (2 × 3). Extracted and dried with Glauber's salt. The crystalline solid obtained by distilling off chloroform was recrystallized from ethanol-diethyl ether to obtain 12.0 g of S-(−) form of ofloxacin (I: X ₁ = F, R ₁ = R ₂ = CH ₃ ). It was

Melting point 226-230 [deg.] C. (decomposition) [[alpha]] _D- 76.9 [deg.] (C = 0.655, 0.05N NaOH) Example 6: S-(-)-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 S-(-)-9,10-difluoro-3-methyl-6-carboxylic acid 281 mg diethyl ether The mixture was suspended in 30 ml of ether, and a large excess of boron trifluoride ethyl ether complex was added with stirring at room temperature, followed by reaction for 45 minutes.

The precipitate was collected by filtration, washed with diethyl ether and dried under reduced pressure to obtain chelate IX. Decomposition point> 300 ° C Elemental analysis Calculated as C ₁₃ H ₈ BF ₄ NO ₄ C 47.46 H 2.46 N 4.26 Analytical value C 47.68 H 2.59 N 4.32 Dissolve 310 mg of this in 6 ml of dimethyl sulfoxide,
0.32 ml triethylamine and N-methylpiperazine 0.
13 ml was added, and the mixture was stirred at room temperature for 17 hours and then dried under reduced pressure. After washing the residue with diethyl ether, triethylamine
It was dissolved in 20 ml of 95% ethanol containing 0.5 ml and heated under reflux for 8 hours. The residue obtained by cooling to dryness under reduced pressure was diluted with hydrochloric acid (5
%) And the mixture was separated from chloroform, the aqueous layer was adjusted to pH 11 with 1N sodium hydroxide, and then adjusted to pH 7.4 with 1N hydrochloric acid. This was extracted with chloroform (50 × 3), dried over sodium sulfate, chloroform was distilled off, and the resulting powder was recrystallized from ethanol-diethyl ether to obtain 120 mg of the target compound I as transparent fine needle crystals.
Got

Melting point 225-227 ° C (decomposition) ▲ [α] ²⁴ _D ▼ -76.9 ° (c = 0.385,0.05N NaOH) Elemental analysis value C ₁₈ H ₂₀ FN ₃ O ₄ 1 / 2H ₂ O Calculated value: C 58.37 H 5.72 N 11.35 Analytical value: C 58.17 H 5.58 N 11.27 Example 7: Preparation of benzoyloxy derivative (±) -9,10-difluoro-3-hydroxymethyl-7
-Oxo-2,3-dihydro-7H-pyrido [1,2,3-de]
Ethyl [1,4] benzoxazine-6-carboxylate (1 g) and pyridine (500 mg) were mixed with anhydrous tetrahydrofuran (THF) 10
Suspended in 0 ml, 3,5-dinitrobenzoyl chloride 1.6 g
Was added and the mixture was refluxed at 90 ° C. After the suspension is once dissolved, a colorless precipitate is deposited. After reacting for 1.5 hours, after cooling, the precipitate was collected by filtration, washed with ethanol and ether, and dried to give colorless powder (±) -9,10-difluoro-3- (3,5-dinitrohenzoneyloxy). 1.2 g of methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid ethyl ester were obtained. Melting point 24
_{0~242 ℃ NMR (CDCl 3/5} % DMSO-d 6) δ (ppm); 1.30 (3H, t, J = 7.0Hz, -CH 2 C H 3) 4.26 (2H, q, J = 7.0Hz, _{-C H 2 CH 3) 4.4~5.4 (} 5H, m) 7.76 (1H, dd, J = 11.0Hz, 7.0Hz, C 8 - H) 8.8 (1H, s, C 5H) 9.0 (2H, d , J = 3.0 Hz, aromatic ring proton) 9.2 (1H, t, J = 3.0 Hz, aromatic ring proton) Example 8: Optical resolution 6 mg of the dinitrobenzoyloxy derivative obtained in Example 7 was purified by distillation. It was dissolved in about 0.6 ml of formamide (DMF), filtered through a Millipore filter, and then injected into the column for HPLC.

Column: Sumipax OA-4200 (2 x 25 cm) Solvent: n-hexane / 1.2-dichloroethane / ethanol =
6/3/1 Flow rate: 8 ml / min The starting elution fraction (fraction of (+) form) contains some racemic material (DM
Since it was partially hydrolyzed when it was dissolved in F), only the previous fraction was further subjected to silica gel chromatography and purified with CHCl ₃ to 10% MeOH / CHCl ₃ as an elution solvent.

By repeating the above-mentioned purification, 600 mg of the dinitrobenzoyloxy derivative was used to obtain two optically active S (-) and R compounds.
250 mg of each (+) form was obtained.

R (+) body: retention time 56-76 minutes, column temperature 22 ° C, melting point 235-240 ° C, ▲ [α] ²³ _D ▼ + 90.8 ° (c = 0.852, D
MF) S (-) form: retention time 78-98 minutes, column temperature 22 ° C, melting point 244-249 ° C, ▲ [α] ²³ _D ▼ -92.5 ° (c = 0.889, D
MF) Example 9: S-(-)-9,10-difluoro-3-hydroxymethyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] Ethyl benzoxazine-6-carboxylate S-(-) dinitrobenzoyloxy derivative 120 mg was suspended in ethanol 10 ml and saturated aqueous sodium hydrogen carbonate solution 4 ml at 50-60 ° C.
Stir for hours. After concentration, water was added to remove insoluble matter by filtration,
The crystals were washed successively with water, 95% ethanol and ether to give 68 mg of S-(-)-3-hydroxymethyl compound as colorless crystals. Melting point 235-240 ° C Elemental analysis value Calculated as C ₁₅ H ₁₃ F ₂ NO ₅ C 55.39 H 4.03 N 4.31 Analytical value C 55.44 H 4.01 N 4.49 ▲ [α] ²³ _D ▼ -125.9 ° (c = 0.918, DMF) Similarly, from R (+) dinitrobenzoyloxy form to R
(+)-3-Hydroxymethyl was obtained.

Melting point 231-234 ° C. [α] ²³ _D ▼ + 125.9 ° (c = 0.715, DMF) Example 10: S-(−)-9,10-difluoro-3-iodomethyl-7-oxo-2,3 -Dihydro-7H-pyrido [1,2,3
-De] [1,4] benzoxazine-6-carboxylate ethyl S-(-)-3-hydroxymethyl derivative 63 mg was added to anhydrous DMF12m3.
It was suspended in 1 and heated to 70-80 ° C with stirring to dissolve it, and the temperature was returned to room temperature. To the obtained solution, 340 mg of triphenylphosphite methiodide was added and stirred for 1.5 hours. After the solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, partitioned with an aqueous solution of sodium thiosulfate and then saturated saline, and then the chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled off.
Diethyl ether was added to the residue and the mixture was stirred, and the precipitated solid was collected by filtration, washed with diethyl ether, and dried under reduced pressure to obtain 78 mg of the title compound as a white powder.

Melting point 214-217 ° C. Elemental analysis value C ₁₅ H ₁₂ F ₂ INO ₄ calculated value C 41.40 H 2.78 N 3.22 Analysis value C 41.16 H 2.58 N 2.99 The R (+) form could be obtained in the same manner.

Example 11: S-(-)-9,10-difluoro-3-methyl-
7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de]
[1,4] benzoxazine-6-carboxylic acid 78 mg of the compound of Example 10 was suspended in 18 ml of absolute ethanol,
The mixture was heated and stirred at 60 to 70 ° C to dissolve it, and the temperature was returned to room temperature. To the obtained solution, 0.2 ml of n-tributylstannane was added, and the mixture was added to 50-6
The mixture was stirred at 0 ° C for 1 hour and at room temperature for 1 hour. Evaporate the solvent,
The residue was subjected to column chromatography on 8 g of silica gel and eluted with chloroform-methanol (40: 1) to obtain a crude methyl compound. This was dissolved in 2 ml of glacial acetic acid, 4 ml of agricultural hydrochloric acid was added, and the mixture was heated under reflux for 40 minutes. The reaction solution was concentrated, water was added, and the precipitated crystals were collected by filtration. The crystals were washed with water, ethanol and ether and dried under reduced pressure to give crystals (22 mg) of the title compound. Melting point> 300 ° C ▲ [α] ²³ _D ▼ -65.6 ° (c = 0.950, DMSO) Elemental analysis value Calculated value as C ₁₃ H ₉ F ₂ NO ₄ C 55.52 H 3.23 N 4.98 Analysis value C 55.79 H 3.20 N 4.91 Same And (+) body was also obtained.

▲ [α] ²³ _D ▼ + 65.6 ° (c = 0.903, DMSO) Example 12: S-(−)-9-fluoro-3-methyl-10
(4-Methyl-4-piperazinyl) -7-oxo-2,3
-Dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid S-(-)-9,10-difluoro-3-methyl-7-oxo-2,3 -Dihydro-7H-pyrido [1,2,3-de] [1,4]
21 mg of benzoxokidin-6-carboxylic acid and 30 mg of N-methylpiperazine were dissolved in 3 ml of anhydrous dimethyl sulfoxide, and the mixture was stirred at 130 to 140 ° C for 1 hour. The solvent was distilled off under reduced pressure, 2 ml of ethanol was added to the residue, and the precipitated solid was collected by filtration and washed successively with a small amount of ethanol and ether.
14 mg of the obtained powder was subjected to column chromatography on 5 g of silica gel, and chloroform-methanol-water (7: 3:
1) Elute with the lower layer solution to obtain S-(−)-9-fluoro-3-methyl-10- (4-methyl-1-piperazinyl)
-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-d
e] [1,4] benzoxokidin-6-carboxylic acid was obtained.
The mother liquor collected by filtration was collected, subjected to thin layer chromatography (silica gel, 20 × 20 cm, 0.5 mm), and developed by a lower layer solution of chloroform-methanol-water (15: 3: 1) for purification. . Both were combined to obtain 14 mg of the desired product as crystals.

Melting point 220-228 ℃ (decomposition) Elemental analysis value Calculated value as C ₁₈ H ₂₀ FN ₃ O ₄ C 59.82 H 5.58 N 11.63 Analysis value C 60.01 H 5.69 N 11.53 ▲ [α] ²⁴ _D ▼ -68.8 ° (c = 0.711) , 0.05N-NaOH) MS (m / e); 361 (M +) NMR (CDCl 3 δ (ppm): 1.63 (3H, d, C 3 -C H 3) 2.38 (3H, s, N-C H ₃ ) 2.54 to 2.60 (4H, m, 2 × C H ₂ N) 3.40 to 3.44 (4H, m, 2 × C H ₂ N) 4.35 to 4.52 (3H, m, C H and C H ₂ ) 7.76 (1H , d, aromatic C ₈ - to give H) 8.64 (1H, s, C 5 -H) in the same manner as R (+) body.

Melting point 218 to 226 ° C (decomposition) MS (m / e): 361 (M ⁺ ) ▲ [α] ²⁴ _D ▼ + 68.7 ° (c = 0.560,0.05N-NaOH) Example 13: S-(-) -10- (4-Ethyl-1-piperazinyl) -9-fluoro-3-methyl-7-oxo-2,3
-Dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid N-ethylpiperazine was used in place of N-methylpiperazine and treated as in Example 5. The title compound was obtained.
Mp 229-230 ° C. (decomposition) _[α] D -67.0 ° _{(c = 0.585, H 2 O} ) NMR (CDCl 3) δ (ppm): 1.16 (3H, t, J = 7Hz, -CH 2 CH 3) 1.63 (3H, d, J = 7Hz, CH ₃ ) 2.53 (2H, q, J = 7Hz, -C H ₂ CH ₃ ) 2.57 to 2.69 (4H, m, 2 × CH ₂ ) 3.40 to 3.53 (4H, m , 2 × CH ₂ ) 4.32-4.58 (3H, m, CH and CH ₂ ) 7.77 (1H, d, J = 12Hz, C ₈ −H) 8.67 (1H, s, C ₅ −H) Elemental analysis value C ₁₉ Calculated as H ₂₂ FN ₃ O ₄ C 60.79 H 5.91 N 11.19 Analytical value C 60.97 H 5.91 N 11.30

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Shoichi Sakano 1-16-13 Kita Kasai, Edogawa-ku, Tokyo Hideki Tsurumi Examiner, Central Research Institute of the First Pharmaceutical Sciences

Claims (2)

[Claims] 1. A general formula (In the formula, X ₁ and X ₂ each represent a halogen atom. R ₁ represents a lower alkyl group.) 2. The compound according to claim ₁ , wherein X ₁ and X ₂ are fluorine atoms and R ₁ is a methyl group.