FI76345C - FOERFARANDE FOER FRAMSTAELLNING AV PYRIDOBENSOXAZINDERIVAT. - Google Patents

Description

7 6 3 4 5

Process for the preparation of pyridobenzoxazine derivatives

The invention relates to a new process for the preparation of 5-pyrido / T, 2,3-de7 LX, 47-benzoxazine-6-carboxylic acid derivatives of the formula I and their pharmaceutically acceptable salts,

O

XK9 8 il / 7 COOH

10 ,, - ΓνΥι '2 \ _y ο ^ λβ 1 2 3 1 15 in which the formula has a straight-chain or branched alkyl group having 1 to 6 carbon atoms, R 2 is hydrogen or a straight-chain or branched alkyl group having 1 to 6 carbon atoms carbon atom, and is halogen. These compounds have excellent antibacterial activity against gram-negative and gram-positive bacteria.

The compounds of the formula I and / or the processes for the preparation of such compounds are described in FI-Aulutus 71155 and 66612 and in DE-A-25 2804097.

The process according to the invention is characterized in that the pyrido [1,2,3-de] Z, 1,4-benzoxazine-6-carboxylic acid BF2-chelate derivative of the formula

30 ^ F2O

X1 3 I11 »35 Ta R1 2 76345 wherein X1 and have the same meaning as above and X2 is halogen is reacted with a piperazine derivative of the formula 5 / R2-N_ ^ NH (III) wherein R2 has the same meaning as above. in the presence of, if desired, the intermediate formed in the reaction of formula

_ «BF

° - f x, JL co (iv)

15 T

R ~ -N

2, wherein R 1, R 2 and X 2 are as defined above, are isolated, then treated with a proton donor, or the reaction is allowed to proceed directly without intermediates to the final product of formula I.

The present invention is based on the finding that the carboxylic acid BF2 chelate of formula II is very useful in improving the yield of compounds of formula I. If the reaction is carried out using a carboxylic acid compound or an ester thereof without BF2 chelate (cf. FI publication 71155), two different types of compounds are obtained in the substitution reaction of 30 dihalogen compounds, whereby the yield of the desired compound is considerably reduced, 3,763,445

X-, COOH

XitJ ^ _ »li * vvJ'— 'R1 0? |

x, Il C0QH> / \ JL rnnH

yyy vwN_rnrir

u, xX

(i) 1 15

In the process according to the invention, there are two different types of reactions, i. The substitution reaction of a halogen atom at the 10-position with a piperazine compound of formula (III) and the decomposition reaction of the BF2 chelate group, and the two reactions can be carried out simultaneously (sequentially) or separately. When these reactions are carried out separately, the intermediate of formula (IV) can be isolated if desired.

In a substitution reaction, the presence of an acid acceptor is necessary to remove the resulting hydrogen halide (HX2), and such acid acceptors include, for example, inorganic bases such as alkali metal or alkaline earth metal hydroxides, carbonates and bicarbonates, and organic bases such as tertiary amines, e.g. tributylamine, pyridine, etc. The piperazine compound of formula (III) used as a reactant can also act as an acid acceptor, especially when used in excess. A substantially equimolar amount of acid acceptor relative to the reactant (II) is required in the reaction, but a molar excess of acid acceptor is preferably used.

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The chelate degradation reaction requires a proton donor to form a carboxyl group (COOH). As the protonido-Norin, compounds having an active proton attached to a heteroatom such as nitrogen, oxygen or sulfur can be used, and such compounds include, for example, water, alcohols such as methanol or ethanol, thiols and appealing amines such as diethylamine. Since the piperazine compound (III) itself is a secondary amine, it can also act as a proton donor. Because there are normally small amounts of water available in the reaction, in a commercially available solvent, and because water is generally absorbed from the air during the reaction, chelate decomposition reaction can occur without the addition of a proton donor.

The cleavage of the BF2 chelate is preferably performed in the presence of an acid acceptor to remove the BF2 fragment. In the absence of an acid acceptor, the product of formula (I) is optionally obtained in the form of a boron or fluorine adduct, but the adduct can be easily converted to the free form in a conventional manner, e.g. by treatment with an organic or inorganic base. As the acid acceptors, the compounds mentioned above in connection with the substitution reaction can be used, and they are used in the reaction in equimolar amounts or more.

The reactions of the process according to the invention can be carried out without a solvent, but it is suitable to carry out the reactions in a presence of 2 to 30 times the amount of solvent relative to the reactants (II and III or IV). Examples of the solvent include non-protic, polar solvents such as dimethylformamide, dimethylacetamide, dimethylsulfoxide and the like; ketones such as acetone, ethyl methyl ketone, esters such as ethyl acetate; alcohols such as ethanol, methanol, propanol, etc., ethers such as diethyl ether or dioxane; tertiary amines such as triethyl-35 amine, and water. When the reactant or acid acceptor is a liquid, it can also be used as a solvent.

The starting materials (II) and (III) can be reacted in a molar ratio of about 1: 1, but it is preferable to use a small molar excess of the piperazine compound (III), e.g.

1.2 moles per mole of compound (II).

To prepare compounds of formula I directly from compound (II) and piperazine compound (III), the starting materials are heated at a temperature of about 50-180 ° C in the presence of an acid acceptor in a non-proton polar solvent, or heated at a temperature of about 80-10,200 ° C. in the presence of an acid acceptor in a ketone, ester, alcohol, ether, nitrile, tertiary amine or water.

To obtain intermediate (IV), the reaction between compound (II) and piperazine compound (III) is carried out at a relatively low temperature, i. either in a non-polar solvent at or below room temperature (15-35 ° C) or in a ketone such as acetone at approximately its boiling point. Thus, if necessary, the prepared compound (IV) can be precipitated by adding a suitable solvent such as water, methanol or acetone, and recovered by filtration.

Intermediate (IV) is then treated with a proton donor, preferably in the presence of an acid acceptor. Although the reaction takes place at room temperature, it can be accelerated at an elevated temperature, e.g. at the boiling point of the solvent used, and the reaction can be completed within 0.5 to 10 hours. The product is easily recovered by filtration to give a high yield.

According to a preferred embodiment of the process according to the invention, the compound of formula (I) is prepared in two steps by preparing and isolating an intermediate of formula IV which is then treated with a proton donor, whereby the product can be obtained in purer and higher yields by a single step reaction. .

6 76345

The starting materials of formula (II) can be prepared according to the following reaction scheme, BE, ° --s 0 ^ Bk 0-R1 10 (VII) (VIII) (II)

As can be seen from the reaction scheme, the starting chelate compound of formula (II) can be obtained by conjugating a 7,7-dihalo-1,4-benzoxazine compound of formula (VII) with diethyl ethoxymethylene malonate (EMME) and heating the resulting compound of formula (VIII). boron trifluoride or a complex thereof.

Pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts prepared with inorganic and organic acids such as hydrochloric acid, sulfuric acid, methanesulfonic acid and the like, and salts of the carboxylic acid with sodium, potassium and the like.

The compounds (I) prepared by the method of the invention have excellent antibacterial activity against both gram-positive and gram-negative bacteria, and are useful in the treatment of various infections, such as urinary tract infections and the like. The following table shows the in vitro antibacterial activity of the compounds of formula I (minimum inhibitory concentration, μg / ml) as determined by the dilution method in plate cultures (Mueller-Hinton Bouillon). In this experiment, 6/35 bacteria have been inoculated and incubated at 37 ° C for 18 hours.

7 76345

Table

Compound (I) and MEK (^ tq / rnl R1 = CH3 R1 = CH3 5 R2 = CH3 R2 = CH3 ν χη = f χΊ = α

Test organism 1_ _1_ E. coli NIHJ = 0.05 = 0.05

Shigella Flexneri 2, 5503 = 0.05 = 0.05

Proteus vulgaris, 3167 = 0.05 = 0.05 ^ Proteus mirabilis, 1287 0.1 0.1

Klebsiella pneumoniae, 501 0.39 0.2

Enterobacter cloacae, 12001 0.1 0.05

Serratia marcescens, 13001 0.1 0.1

Pseudomonas aeruginosa, 2061 0.78 0.78 15

Pseudomonas sepacia, IID 5132 12.5 6.25

Staphylococcus aureus, 209 P 0.39 0.2

Streptococcus pyogenes, G-36 1.56 12.5

Bacillus subtilis, ÄTCC 6633 0.1 0.1 The following examples illustrate the invention.

Example I Preparation of starting material A. 20 g of 2,3,4-trifluoronitrobenzene was dissolved in 150 ml of dimethyl sulfoxide, and to this mixture was added dropwise 10% aqueous potassium hydroxide solution while maintaining the temperature at 18-20 ° C. The mixture was then stirred for 2 hours at room temperature, and one liter of water was added to the reaction mixture, followed by shaking with chloroform. The aqueous layer was acidified with 30 hydrochloric acid and extracted with chloroform. The extract was washed with water and dried. The chloroform layer was concentrated, and the resulting residue was purified by silica gel column chromatography to give 5.8 g of 2,3-difluoro-6-nitrophenol as prisms with a melting point of 35 ° C.

8 7 6 3 4 5 B. 5.8 g of the above product, 5.0 g of monochloroacetone, 8.0 g of potassium carbonate and 0.8 g of potassium iodide were added to 100 ml of acetone, and the mixture was refluxed. for an hour. After removal of the insoluble matter by filtration, the solvent was evaporated and the residue was partitioned between chloroform and water. The chloroform layer was washed with water and dried, and then the solvent was evaporated. The residue was treated with n-hexane to give 5.0 g of 2-acetonyloxy-3,4-10 difluoronitrobenzene as needles with a melting point of 45 ° C.

C. 7.1 g of the above product was dissolved in 200 ml of ethanol, and 14 ml of Raney nickel was added to the solution. The resulting mixture was reduced under catalytic reduced pressure. After removal of the catalyst by filtration and evaporation of the solvent, the residue was dissolved in chloroform and decolorized by passing it through a silica gel column to give 5.1 g of 7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-20 benzoxazine. as prisms with a melting point of 52 ° C.

1 H-NMR (CDU 3, IS: TMS) δ (ppm): 1.16 (3H, d, -CH 2) 3.4-3.9 (3H, m,> CH-CH 2 -) 4.24 (1H , q, -NH-) 25 6.1-6.7 (2H, m, C5- and C6- = CH-) D. A mixture of 2.00 g of the above product and 2.57 g of diethylethoxymethylene malonate was heated At 120-130 ° C for 5 hours. Evaporation of the ethanol formed gave an oily residue. The resulting residue was dissolved in 10 ml of Dowtherm A (Dow Chemical

Co), and then 2.0 g of boron trifluoride tetrahydrofuran complex was added. To 10 ml of Dowtherm A preheated to 250 ° C was added dropwise the mixture obtained above over 30 minutes while maintaining the temperature at 220-240 ° C.

76345 9

The resulting mixture was allowed to react at 220-240 ° C for one hour. After cooling, 5 ml of dichloroethane was added to the reaction mixture. The resulting precipitate was collected by filtration and washed with dichloroethane and methanol-5 L to give 3.38 g of 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [2,3-d] 1,7, Benzoxazine-6-carboxylic acid BF2-chelate compound (94.2% yield) with a melting point above 300 ° C.

1 HNMR (SMSO-d 6, IS: TMS) δ δ (ppm): 1.59 (3H, d, -CH 2) 4.73 (2H, q, -CH 3) 5.35 (1H, m> CH-CH 3) ) 8.18 (1H, m, C8- = CH-) 9.68 (1H, s, C5- -CH-) Mass spectrum: M + 329

Elemental analysis for C 12 H 9 BF 3 NO 2 Calculated: C 47.45, H 2.45, N 4.26 Found: C 47.69, H 2.46, N 4.21

Example II

20 A. 10.5 g of 2,4-dichloro-3-fluoronitrobenzene was dissolved in 30 ml of dimethyl sulfoxide, and 8 ml of 40% aqueous sodium hydroxide solution was added to the solution. The resulting mixture was stirred at 60-70 ° C for 20 hours. After cooling, 200 ml of water was added to the reaction mixture, and the unreacted starting material was removed by extraction with diethyl ether. The aqueous layer was acidified with acetic acid and extracted with diethyl ether. The extract was washed with water and dried over sodium sulfate, and then the solvent was removed by distillation. The residue was purified by silica gel column chromatography using chloroform as the eluent to give 3.4 g of 3-chloro-2-fluoro-6-nitrophenol having a melting point of 73 ° C.

The product obtained above was treated as described in Example I, steps B, C and D above to give, respectively, oily 2-acetonyloxy-4-chloro-3-fluoro-76345 10 nitrobenzene (VII), 7-chloro-8-fluoro-3- methyl 2,3-dihydro-4H-1,4-benzoxazine (Vili), m.p. 68 ° C, and 9-chloro-10-fluoro-3-methyl-7-oxo-dihydro-7H -pyrido [2,3-d] 7-benzoxazine-6-carboxylic-5-acid-BF2-chelate compound (1) having a melting point above 300 ° C. In contrast to Example I, the reaction between 3-chloro-2-fluoro-6-nitrophenol and monochloroacetone in Step B was carried out at reflux for 6 hours and 7-chloro-8-fluoro-3-methyl-2,3-dihydro-4H-1,4- the reaction between benzo-10 satin and diethylethoxymethylene malonate in step D was performed by heating at 140-150 ° C for 4.5 hours.

The chelate compound (II) thus obtained had the following analytical values.

15 Elemental analysis for C - ^ ^ HgBF ^ NO ^

Calculated: C 45.20, H 2.33 N 4.05 Determined: C 44.98, H 2.29, N 4.03

Example 1

A mixture of 1.00 g of 9,10-difluoro-3-methyl-7,7-oxo-2,3-dihydro-7H-pyrido [N, N-2,3-de] -1H-benzoxazine-6- a carboxylic acid BF 2 chelate compound (a compound of formula II having methyl, compound Ha), 0.46 g of N-methylpiperazine, 0.62 g of triethylamine and 5 ml of dimethyl sulfoxide were allowed to react at room temperature for 3 hours. After the reactor, 5 ml of water was added to the reaction mixture. The resulting precipitate was collected by filtration and washed with water to give 1.23 g (98.9% yield) of 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 BF2-chelate compound (a compound of formula IV wherein R1 and R2 are methyl, compound IVa ) with a melting point of 252-255 ° C (decomposed).

Elemental analysis: Calculated: C 52.84, H 4.68, N 10.27 Found: C 52.94, H 4.67, N 10.01 76345 11 H-NMR (DMSO-d 6, IS: TMS) δ (ppm): 1.54 (3H, d, C-CH 2) 2.24 (3H, s, N-CH 3) δ 3.4 (8H, br, -1 · ) + 4.58 (2H, q, -CH 2) 5.21 (1H, m,> CH-CH 3) 7.83 (1H, d, C 8 - = CH-) δ 9.46 (1H, d, C5- = CH-)

Mass spectrum: M + 409

Example 2

A mixture of 5.00 g of compound Ha, 4.75 g of N-methylpiperazine and 25 ml of dimethylacetamide was allowed to react at room temperature for 2 hours.

After completion of the reaction, 25 ml of water was added to the mixture. The resulting precipitate was collected by filtration and washed with water to give 6.04 g (97.1% yield) of compound IV, m.p. 250-254 ° C (dec.). 20 Example 3

A mixture of 0.61 g of compound Ha, 0.58 g of N-methylpiperazine and 12 ml of acetone was refluxed for 3.5 hours. The precipitate formed after cooling was collected by filtration and washed with acetone to give 0.43 g (57.1% yield) of IVa with a melting point of 250-255 ° C (decomposed).

Example 4

A mixture of 3.00 g of compound Ha, 2.44 g of anhydrous piperazine and 15 ml of dimethylacetamide was allowed to react at room temperature for 2 hours.

After completion of the reaction, 30 ml of acetone was added to the reaction mixture. The resulting mixture was cooled to give a precipitate. The precipitate was collected by filtration and washed with acetone to give 2.97 g of 9-fluoro-3-35-methyl-10- (1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido-76345 12 rido / T- . 2,3-de7 / JT, 47-benzoxazine-6-carboxylic acid BF2-chelate (82.4% yield) with a melting point of 235 ° C (decomposed).

Elemental analysis for C 17 H 17 BrF 4 N 3 O 4: He 5 Calculated: C 51.67, H 4.34, N 10.63 Found: C 51.15, H 4.44, N 10.32 1 H-NMR (CF 3 COOH, IS: TMS ) cf (parts per million): 1.73 (3H, d, -CH 2 -) 3.7 (8H, br, -t / 1) 4.63 (2H, br, -CH 2 -) 5.1 ( 1H, m,> CH-CH3) 7.90 (1H, d, C8- = CH-) δ 9.20 (1H, s, C5- = CH-)

Example 5

As described in Example 4, but using dimethylformamide instead of dimethylacetamide as the solvent, the same compound was obtained in a yield of 96.6%.

Melting point: 230 ° C (decomposed).

Example 6

A mixture of 1.00 g of compound IVa, 0.50 g of triethylamine and 20 ml of 95% aqueous ethanol was refluxed for 6 hours. After completion of the reaction, the reaction mixture was cooled to give a precipitate. The precipitate was collected by filtration and washed with cold aqueous methanol to give 0.76 g (86% yield) of 9-fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2, 3-Dihydro-7H-pyrido [X] 2,3-de7-30 (1,4,7-benzoxazine-6-carboxylic acid (compound of formula I wherein R1 and R2 are methyl, compound Ia) The product was recrystallized from chloroform and methanol. mixture (10: 1 by volume) and dried in vacuo at 100-110 ° C for 1 hour Melting point: 254-35 256 ° C (decomposed).

13 7 6345

Elemental analysis for C 18 H 28 N 2 O 2 N 2 O 2

Calculated: C 59.82, H 5.58, N 11.63 Found: C 59.61, H 5.63, N 11.51 1 H-NMR (DMSO-d 6, IS: TMS) δ (ppm): 1.45 (3H, d, CH-CH 3) 2.22 (3H, s, N-CH 3) 3.4 (8H, br, -is / J 2 -) 4.49 (2H, q, -CH 2) ~) 4.93 (1H, m,> CH-CH 3> 7.59 (1H, d, C 8 - = CH-) 8.98 (1H, d, C 5 - = CH-)

Example 7 A mixture of 1.00 g of compound IVa, 0.50 g of triethylamine and 20 ml of methanol was refluxed for 4 hours. After completion of the reaction, the reaction mixture was cooled to give a precipitate. The precipitate was collected by filtration and washed with methanol to give 0.69 g (78% yield) of compound Ia. The product was recrystallized from dimethylformamide. Melting point: 253-255 ° C (decomposed).

Example 8

A mixture of 1.00 g of compound IVa, 0.50 g of triethylamine and 20 ml of water was refluxed for 2 hours. Water was removed by distillation in vacuo, and 20 ml of methanol was added to the residue. The insoluble matter was collected by filtration and washed with methanol to give 0.66 g (75% yield) of compound Ia. The product was dissolved in a mixture of 2 ml of concentrated aqueous ammonia and 20 ml of ethanol at room temperature, and the resulting solution was treated with activated carbon. Excess ammonia and ethanol were removed by distillation with heating to give 0.62 g of pure crystalline product with a melting point of 254-255 ° C (decomposed).

14 7 6 3 4 5

Example 9

A mixture of 1.00 g of compound IVa and 20 ml of ethanol was refluxed for 4 hours. After cooling, the precipitate formed was collected by filtration and washed with ethanol to give 0.88 g (84% yield) of compound Ia, m.p. 253-255 ° C (decomposed). Elemental analysis for C 18 H 20 FN 3 O 4. HF. For BOF Calculated: C 50.61, H 4.95, N 9.84 Determined: C 50.52, H 5.05, N 9.79 Example 10

A mixture of 1.00 g of 9-fluoro-3-methyl-10- (1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] -a, 47 -benzoxazine-6-carboxylic acid BF2 chelate, 0.62 g of triethylamine and 5 ml of dimethyl sulfoxide were heated at 120-130 ° C for 3 hours. The precipitate formed after cooling was collected by filtration and washed with methanol. The product was recrystallized from a mixture of chloroform, methanol and water to give 0.67 g of 9-fluoro-3-methyl-10- (1-20 piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [2,2 3-de7-4.7, 4.7-benzoxazine-6-carboxylic acid (72% yield) with a melting point of 258-260 ° C (decomposed).

3

Elemental analysis C ^ H ^ gFNgO ^. For H 2 O Calculated: C 54.69, H 5.40, N 11.25 25 Determined: C 54.82, H 5.06, N 11.13

Example 11

A mixture of 5.21 g of compound Ha, 4.76 g of 1M-methylpiperazine and 26 ml of dimethyl sulfoxide was heated at 110-120 ° C for 2 hours. After cooling, the resulting precipitate was collected by filtration and washed with cold ethanol to give 4.25 g (74.3% yield) of compound Ia. The product was dissolved in a mixture of aqueous ammonia and methanol (1:20 by volume) at room temperature. Excess ammonia-35 was distilled off by heating to give 7,64545 of a pure crystalline product with a melting point of 254-255 ° C (decomposed).

Example 12

A mixture of 2.00 g of compound Ha, 0.73 g of 5 N-methylpiperazine, 1.23 g of triethylamine and 10 ml of dimethyl sulfoxide was heated at 120-130 ° C for 5 hours. The precipitate formed after cooling was collected by filtration to give 1.69 g (76.9% yield) of compound Ia. The product was recrystallized from a mixture of concentrated concentrated aqueous ammonia and ethanol (1:20 by volume). Melting point: 254-256 ° C (decomposed).

Example 13

A mixture of 0.70 g of compound Ha, 0.66 g of N-methylpiperazine and 7 ml of pyridine was refluxed for 2 hours. The reaction mixture was concentrated in vacuo, and methanol was added to the mixture. The resulting precipitate was collected by filtration and washed with methanol to give 0.60 g (78% yield of Compound Ia, m.p. 253-256 ° C (dec)).

20 Example 14

A mixture of 0.77 g of compound Ha, 0.73 g of N-methylpiperazine and 4 ml of dimethylacetamide was heated for 5 hours at 110-120 ° C. The precipitate formed after cooling was collected by filtration. The precipitate-25 nucleus was washed with ethanol to give 0.65 g (77% yield) of compound Ia. This product was recrystallized from dimethylformamide. Melting point: 254-256 ° C (decomposed).

Example 15

9-Fluoro-3-methyl-10- (1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [X, 2,3-de] -1,4-benzoxazine-6 was obtained as described in Example 14. carboxylic acid in 73.4% yield. The product was recrystallized from a mixture of chloroform, methanol and water. Melting point: 260 ° C (decomposed).

ie 7 6 3 4 5

Elemental analysis Calculated for C 54.69, H 5.40, N 11.25 Found: C 54.75, H 5.19, N 11.33

Example 16 A mixture of 0.50 g of 9-chloro-10-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [? 4, Benzoxazine-6-carboxylic acid BF 2 chelate, 0.44 g of N-methylpiperazine and 2.5 ml of dimethyl sulfoxide were heated at 110-130 ° C for 5 hours.

After cooling, methanol was added to the reaction mixture. The resulting precipitate was collected by filtration and washed with methanol to give 0.43 g of 9-chloro-3-methyl-10- (1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [1,2,3- de7ZI, C7-benzoxazine-6-carboxylic acid-15a (78% yield). The product was recrystallized from a mixture of chloroform and methanol. Melting point 280 ° C (decomposed).

Elemental analysis for C 18 H 20 ClN 3 O 4 Calculated: C 57.22, H 5.34, N 11.12 Found: C 56.78, H 5.34, N 11.07.

Claims (3)

A process for the preparation of pyridoZT, 2,3-de7- / 1,47-benzoxazine-6-carboxylic acid derivatives of the formula (I) and their pharmaceutically acceptable salts, R 1 -NV 15 in which the formula has a straight-chain or branched alkyl group having 1 to 6 carbon atoms, R 2 is hydrogen or a straight-chain or branched alkyl group having 1 to 6 carbon atoms, and is halogen, characterized in that pyrido / J »2,3-de7 / 1,4'-benzoxazine-6-carboxylic acid BF2-chelate derivative of the formula J3F O20 25 (II) '' U ,,, 30 wherein and R ^ mean above and X 2 is halogen, is reacted with a piperazine derivative of the formula 5 is 7 6345 (Rp-N NH (III)) wherein 1 * 2 is the same as above, in the presence of an acid acceptor, optionally reacting an intermediate of the formula is 10 BF 0 '' ^ Cj X1X ^ A / CO (IV, R - NN ^ N ”w IA ,, 20 wherein R1, R2 and have the same meaning as above, are isolated, then treated with a proton donor, or the reaction is allowed to proceed directly without intermediates up to the final product of formula I. 19 76345 For the preparation of pyrido / Ί., 2,3-de7-Q., 47-benzoxazine-6-carboxylic acid with a formulation I and 5 of the pharmaceutical composition of the formulation, 0 Y Λ il COO -l / ^ '(I * 10 2 \ _J TI 15. a valenic form of an alkyl group having 1-6 cholaters, R2 is a form of an alkyl group having 1 to 6 chelates and a halogen of X6 halogen , in turn, a mixture of pyrido [1,2,3-d.e7 / 1,4] benzoxazine-6-carboxylic acid-BF2-20 chelates with a formulation of 25 x2 - '' 'k / v (in 30 and R 2 are selected from the group consisting of halogen and X 2 and halogen, which are piperazined with the formula r2-nOh (III)