DD203719A5 - PROCESS FOR PREPARING NEW ANTIBACTERIAL PYRIDO (1,2,3-DE) (1,4) BENZOXAZINE-5-CARBOXYLIC ACID DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the preparation of pyrido & 1,2,3-de! & 1,4! Benzoxazine-5-carboxylic acid derivatives of the general formula (I) in which R & ind1! a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, R & ind2! a hydrogen atom or a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms and X & ind1! represent a halogen atom, and their pharmaceutically acceptable salts. In the process according to the invention, a pyrido & 1,2,3-de! & 1,4! Benzoxazine-6-carboxylic acid BF & ind 2! -Chelate compound is reacted with a piperazine compound either directly or via isolation of an intermediate compound to give a compound of the general formula (I) around. The compounds prepared by the process according to the invention are valuable antibacterial agents.

Description

M 23 188

Field of application of the invention

The compounds prepared by the process according to the invention are antibacterial agents against both Gram-positive and Gram-negative bacteria. They can be used to combat various infections, in particular Hamsysteminfektionen.

Characteristic of the known technical solutions

There are already a number of antibacterial compounds known. However, these agents usually only work against very specific types of bacteria.

Object of the invention

The antibacterial compounds which can be prepared by the process according to the invention enrich the range of known active substances. New drugs with antibacterial effects are being provided for the treatment of various infections.

Explanation of the essence of the invention

The present invention provides a process for the preparation of novel and antibacterial pyrido- [1,2,3-de] [i, 4] benzoxazine-5-carboxylic acid derivatives of the general formula ϊ:

-2FEB 1983 * 066315

M 23 188 2 /

where ' _o

R 1 is a straight-chain or branched alkyl group having 1 to 6 carbon atoms,

Rp represents a hydrogen atom or a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms and

X ^ represent a halogen atom,

and their pharmaceutically acceptable salts, which have excellent antibacterial activity against Gram-negative and Gram-positive bacteria.

The reaction scheme of the process according to the invention is as follows:

15.

(II)

, -NNH

-N N

COOH

-'2FEB 1983 * 066315

M 23 188 3 '£

Here, R ₁ , R ₂ and X _{1 have} the meanings given above and X ₂ represents a halogen atom.

In the method according to the invention is in particular

[1,2,3-cLe] [i, 4] benzoxazine-6-carboxylic acid BF ₂ chelate compound of the general formula (II). a piperazine compound of general formula (III) 'to a compound of general formula (I).

In the process according to the invention, two types of reactions take place, ie a substitution of the halogen atom (X ₂ ) in the 10-position by a piperazine compound of the general formula (III) and a decomposition of the BF ₂ -chelate unit. These two reactions can be carried out simultaneously, successively or separately. If these reactions are carried out separately from one another, it is possible, if desired, to isolate an intermediate compound of the general formula (IV).

The substitution reaction must be carried out in the presence of an acid acceptor in the reaction system to remove the resulting hydrogen halide (HX ₂ ). Examples of such acid acceptors are inorganic bases, such as alkali metal or alkaline earth metal hydroxides, carbonates or bicarbonates, or organic bases, such as tertiary amines, for example triethylamine, tributylamine, pyridine, etc. The piperazine compound of the general formula (III ) may also serve as an acid acceptor, especially when used in excess. A substantially equimolar amount of the acid acceptor, based on the reactant of the general formula (II), is necessary for the reaction. Preferably

³ , the acid acceptor is present in molar excess.

- ¹ ZFEB 1983 * 066315

M 23 188 4 Z

For the formation of a carboxyl group (COOH), a proton donor is required for the decomposition of the chelate. As the proton donor, one may employ compounds containing a heteroatom, e.g. a nitrogen, oxygen or sulfur atom to which an active proton is attached. Examples of such compounds are water, alcohols, such as methanol or ethanol, thiols and secondary amines, such as diethylamine. Since the piperazine compound of the general formula (III) per se is a secondary amine, it can also be used as a proton donor. However, since a small amount of water is normally present in the commercial solvents used for the reaction or is generally absorbed in the reaction from the air, the decomposition reaction of the chelate can be carried out without addition of the proton donor.

The decomposition of the BFp chelate is preferably carried out in the presence of an acid acceptor to remove the BF.sub.fr fragment. When no acid acceptor is used, the compound of general formula (I) can be obtained in the form of a boron and fluoro adduct, but this adduct is easily removed by ordinary means, i. by treatment with an organic or inorganic base, in the free form can convert. As acid acceptor it is also possible to use those compounds which have already been described above for the substitution reaction and in this reaction in equimolar or .alpha

be used in larger quantities

 30

The process according to the invention can be carried out without a solvent. However, the solvent is expediently present in 2 to 30-fold excess, based on the reactant (based on II and III or IV). As solvent one can call for example:

aprotic, polar solvents, such as DimethyIfmr

-lFEai933 * 066315

M 23 188

243

amide, dimethy! acetamide, dimethyl sulfoxide and the like; Ketones, such as acetone, ethyl methyl ketone; Esters, such as ethyl acetate; Alcohols, such as ethanol, methanol, propanol and the like, ethers, such as diethyl ether or dioxane; tertiary amines, such as triethylamine; and water. If one uses a liquid reactant or liquid acid acceptor, then one can also use this as a solvent.

The reaction conditions are chosen according to the desired purpose.

The starting compounds of general formulas (II) and (III) are reacted in a molar ratio of about 1: 1. Preferably, however, the piperazine compound of the general formula (III) is used in a slight molar excess, for example 1.2 mol / mol of the compound of the general formula (II).

If the desired compound of the general formula (I) is obtained directly from the compound of the general formula (II) and the piperazine compound of the general formula (III), then the starting compounds are heated to about 50.degree. In an aprotic polar solvent in the presence of an acid acceptor about 180 ⁰ C. by working in ketones, esters, alcohols, ethers, Nitri len, tertiary amines, or water in the presence of an acid acceptor, then heated to about 80 to about 200 ° C.

To obtain the intermediate of the general formula (IV), the reaction between the compound of the general formula (II) and the piperazine compound of the general formula (III) is carried out at a relatively low temperature, either in an aphotic polar solvent at room temperature (15 to 35 ° C) or lower or in a ketone, such as acetone, at its boiling point. The so-called

^{M 2} ^ iss 6 24 3 11 6 ö compound of the general formula (IV) can, if necessary, by addition of a suitable solvent, for example, water, methanol or acetone, precipitate and filter off

 5

The intermediate compound of general formula (IV) is then treated with a proton donor, preferably in the presence of an acid acceptor. Although this reaction takes place at room temperature, it can be accelerated by elevated temperature, e.g. by working at the boiling temperature of the solvent used. The reaction is then completed within a period of 0.5 to 10 hours. It is possible to filter off the product obtained in high yield without difficulty.

In a preferred embodiment of the process according to the invention, the compound of the general formula (II) is prepared in two stages. For this purpose, the intermediate compound of general formula (IV) is prepared, isolated and then reacted with a proton donor, the product is then obtained in higher yield and purity than in the single-stage procedure.

The pharmaceutically acceptable salts of the compounds of general formula (I) are, for example, acid addition salts with inorganic or organic acids, e.g. Hydrochloric acid, sulfuric acid, methanesulfonic acid and the like, and also carboxylic acid salts with sodium, potassium and the like

The compounds of the general formula (I) prepared by the process according to the invention have excellent antibacterial activities against both gram-positive and gram-negative bacteria and can be used for the control of various infections, in particular urinary system infections and the like

• -2FEB 1933 * 066315

M 23 188 7

31 1

become. The in vitro antibacterial activity (minimum inhibitory concentration: / μg / ml) of the compounds prepared by the method according to the invention is shown in the table below. These results were obtained by the dilution method on plate cultures (Mueller-Hinton broth). In this test, 10 / ml bacteria were inoculated and incubated at 37 ^° C. for 18 hours.

Compound of general formula (i) and minimum inhibitory concentration (/ μg / ml)

R, · = CH-7

Test organism X ^ = F X ^ = Cl

A. coli NIHJ,. < _{0 05 <0 05}

  · '

Shigella .flexneri 2a. 5503 <0.05. '< ₀ . 05

^Proteus vulgaris , 3167 <_{0; 0} 5 <o 05

Proteus mirabilis . 1287 ol ο 1

ella pneumoniae , 501. 0.39 ο 2

Enterobacter cloacae , 12001 ol. ^ 12:05

Serratia marcescens , 130 & 1 ο 1. ο 1

Pseudomonas aeruginosa , 2061 0 _; 78. 78

Pseudomonas sepacia , HD 5132 12.5 6 25

Staphylococcus aureus , 209 P 0 ^ 9 ο 2

Streptococcus pyogenes , G-36 .1.56 '12 5

Bacillus subtilis . ATCC 6633 01 0 1

The starting compound of general formula (II) used in the process of the present invention can be prepared according to the following reaction scheme. 35

M 23 188

CfCOOEt).

BF,

(VIII)

4 3 116

(II)

As shown in this reaction scheme, the starting chelate compound of the general formula (II) can be obtained by reacting a 7,8-dihalo-1,4-benzoxazine compound of the general formula (VII) with diethylethoxymethylenemalonate (EMME). and the resulting compound of formula (VIII) is heated with boron trifluoride or a complex thereof.

Preparation of Starting Compounds Example 1

A. Dissolve 20 g of 2,3,4-trifluoronitrobenzene in 150 ml of dimethyl sulfoxide and added dropwise to this mixture, a 10% aqueous potassium hydroxide solution, keeping the temperature between 18 and 20 ° C. Then the mixture is stirred for 2 h at room temperature. Then 1 1 of water is added to the reaction mixture and shaken with chloroform. The aqueous layer is acidified with hydrochloric acid, extracted with chloroform, the extract is washed with water, dried, the chloroform layer is concentrated and the residue obtained is purified by column chromatography on silica gel, giving 5.8 g of 2,3-difluoro-6-nitrophenol ( Prisms), mp 62 ⁰ C.

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 are added to 100 ml of acetone, the mixture is heated for 4 h at reflux, filtered from the insoluble constituents, the evaporated

-9TFR

M 23 188 9 24 3 116 0

Solvent and the residue is partitioned between chloroform and water. The chloroform layer is washed with water, dried and then evaporated the solvent. The residue is treated with η-hexane to give 5> 0 g of 2-acetonyloxy-3,4-difluoronitrobenzene (needles), mp 45 ⁰ C ₅ receives.

C. 7.1 g of the above product are dissolved in 200 ml of ethanol, 14 ml of Raney nickel are added to the solution, the resulting mixture is reduced under atmospheric pressure, the catalyst is catalytically filtered off, the solvent is evaporated off, the residue is dissolved in chloroform and zum is decolorized Silica gel column run. This gives 5.1 g of 7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine (prisms), mp. 52 ° C.

H-NMR (CDCl _3, IS: TMS) S (ppm):

1.16 (3H, d, _-CH3), 3.4-3.9 (3H, M, ^ CH-CH ₂ -), 4.24 (1H, q, -NH-), creates 6.1 6.7 (2H, M, C ⁵ - and C ⁶ - = CH-)

 20

D. A mixture of 2.00 g of the above product and 2.57 g Diäthyläthoxymethylenmalonat 5 h at 120 to 13G ⁰ C, evaporates the resulting ethanol and receives an oily residue. Dissolve the obtained

· ,. , 25 residue in 10 ml Dowtherm A (a product of Dow Chemical Co.) and then 2.0 g of a boron trifluoride-tetrahydrofuran complex is added. The mixture thus obtained is added to 10 ml of Dowtherm A (preheated to 250 ° C.) over a period of 30 minutes, keeping the temperature at 220 to 240 ° C. Maintaining the resulting "mixture for 1 hour at 220 to 240 ⁰ C, then after cooling is 5 ml dichloroethane to the reaction mixture, the precipitate formed filtered off and washed with dichloroethane and methanol wherein one 3.38 g of 9,10-difluoro ~ 3 -methyl-7-oxo-2,3-dihydro-7H-pyrido [i, 2,3-de] [i, 4] benzoxazine-6-carboxylic acid-BF ₂ chelate compound, mp. 300 ⁰ C, receives (94.2 ^ yield).

-'i FEB19 d 3 * U (j 6 315

M 23 188 10 9 / "5 1 1 C O

* · Η ο ι Sy y

1 H-NMR (DMSO-d6, IS: TMS) 6 (ppm):

1.59 (3H, D, -CH ₃ ), 4.73 (2H, Q, -CH ₂ -),

5.35 (1H, m, ^ CH-CH _3), 8.18 (1H, m, C ⁸ - = CH ~),

9.68 (1H, S, C ⁵ - -CH-)

5 mass spectrum: M 329 elemental analysis: for C ₁₃ HgBF ^ NO ^

Calculated: C 47.45% H 2.45% N 4.26%; Found: 47.69 2.46 4.21.

B-egg game 2 '·

A. Dissolve 10.5 g of 2,4-dichloro-3-fluoronitrobenzene in 30 ml of dimethyl sulfoxide, add 8 ml of a 40% aqueous sodium hydroxide solution, the resulting mixture is stirred for 20 h at 60 to 70 ° C, cooled, gives 200 ml of water to the reaction mixture, the unreacted starting material is removed by extraction with diethyl ether, the aqueous layer is acidified with acetic acid and extracted with diethyl ether. The extract is washed with water, dried over sodium sulphate, the solvent is then distilled off and the residue is purified by column chromatography on silica gel using chloroform as the eluent, giving 3 »4 g of 3-chloro-2-fluoro-6-nitrophenol, m.p. 73 ° C.

This product is treated similarly as in Example 1, Steps B, C and D, to give oily 2-acetonyl-oxy-4-chloro-3-fluoro-nitrobenzene (VII), 7-chloro-8-fluoro-3- methyl-2,3-dihydro-4H-1,4-benzoxazine (VIII), m.p. 6O ⁰ C, and 9-chloro-10-fluoro-3-methyl-7-oxo-2,3-dihydro-7H- pyrido [i, 2,3-de] [i, 4] benzoxazine-6-carboxylic acid BF 2 ~ chelate compound (II), mp. Over 300 ⁰ C, but with the reaction of 3-chloro-2 -fluoro-6-nitrophenol and monochloroacetone in step B for 6 h at reflux and for the reaction of 7-chloro-8-fluoro-3-methyl-2,3-dihydro-4H-1, 4-benzoxazine and Diäthyläthoxymethylenmalonat in step D. Heated to 14O to 150 ⁰ C for 4.5 h.

-2FEB19ä3 * 0'663l5

M 23 188 11 J

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

Elemental analysis: for C ^ ₃ HgBClF ₃ NO, calculated: C 45 _; 20% H 2.33% N 4.05% Found: 44.98 2.29 4.03.

Preparation Examples example 1

A mixture of 1.00 g of a 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [i, 2,3-de] [i, 4] benzoxazine-ö is left -carboxylic acid-BFp-chelate compound (II: wherein R ^ is methyl; this compound will be referred to as "Ha" hereinafter), 0.46 g of N-methylpiperazine, 0.62 g of triethylamine and 5 ml of dimethyl thyulfide react at room temperature for 3 h, then add 5 mL of water to the reaction mixture, filter the formed precipitate, and wash 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 [i, 2,3-de] [i] jbenzoxazine-δ-carboxylic acid BFp chelate compound (IV: where R ^ and R 2 is methyl; this compound will be referred to as "IVa" hereinafter), mp 252 to 255 ° C (dec.)

Elementary Analysis: for C ^ gH.gBF calculated N ₃ O: C 52.84% H 4.68% N 10.27% found: 52.94 4.67 10.01

H-NMR (DMSO-dg, IS: TMS) S (ppm):

1.54 (3H, D, C-CH ₅ ), 2.24 (3H, S, N-CH ₃ ), 3.4 (6H, br., -Ifj-), 4.5 & (2H, Q, -CH ₂ -), '5,21 (1H, M, ^ CH-CH ₃ ), 7,83 (1H, D, C ⁸ - = CH-),

9.46 (1H, D, C ⁵ = CH-) mass spectrum: M 409.

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μ 23188 12 243116 O

Example 2 _c

A mixture of 5.00 g of compound Ha, 4.57 g of N-methylpiperazine and 25 ml of dimethylacetamide is allowed to react at room temperature for 2 h, 25 ml of water are added to the reaction mixture after completion of the reaction, the precipitate formed is filtered off and washed with water. to obtain 6.04 g (97.1% yield) of compound IVa, m.p. 250 to 254 ° C (dec.).

Example 5

A mixture of 0.61 g of compound Ha, 0.58 g of N-methylpiperazine and 12 ml of acetone is refluxed for 3.5 hours, the reaction mixture is cooled, the precipitate formed is filtered off and washed with acetone, giving 0.43 g (57.1% yield) Compound IVa, mp. 250-255 ° C (dec.).

Example 4

A mixture of 3.00 g of compound Ha, 2.44 g

-20 anhydrous piperazine and 15 ml of dimethylacetamide for 2 h at room temperature, 30 ml of acetone is added to the reaction mixture, the resulting mixture is cooled to give a precipitate, and the precipitate is filtered off. It is washed with acetone to give 2.97 g of 9-fluoro-3-methyl-10- (1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [i, 2,3-de] [ i, 4] benzoxazine-6-carboxylic acid BF ₂ -chelate compound (82.4% yield), mp. 235 ° C (dec.)

 Elemental analysis: for C.yH ^ yBF, N, 0 »

Calculated: C 51.67% H 4.34% N 10.63% Found: 51.15 4.44 10.32

H-NMR (CF ₃ COOH, IS: TMS) £ (ppm):

1.73 (3H, D, -CH ₃ ), 3.7 (8H, br., -IVF), 4.63 (2H, br., -CH ₂ -), 5.1 (1H, M, ^ CH-CH _3), 7.90 (1H, D, C ⁸ - = CH-), 9.20 (1H, S, C ⁵ - = CH-).

M 23 188 13 J

Example 5 _c -

The procedure is as described in Example 4, but using dimethylformamide as the solvent instead of dimethylacetamide. This gives the same compound in 96 oily yield, mp. 230 ⁰ C (dec.) ·

Example 6

It boils a mixture of 1.00 g of compound IVa, 0.50 g of triethylamine and 20 ml of 95% aqueous ethanol solution for 6 h at reflux, cooled after the reaction, the reaction mixture to obtain a precipitate, the precipitate filtered off 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 [ 1,2,3-de] [i, 4] benzoxazine-6-carboxylic acid (I: wherein R 1 and R p are methyl, this compound is hereinafter referred to as "Ia"), the product is crystallized from a mixture of chloroform and methanol (volume ratio 10: 1) and dried for 5 h in vacuo at 100 to 11O ⁰ C, mp 254-256 ° C (dec.).

Element ar analysis: for C. qH ^ FN ^ O;

Calculated: C 59.82% H 5.58% N 11.63%

found: 59.61 5.63 11.51 25

H-NMR (DMSO-d ⁶ , IS: TMS) 6 (ppm):

1.45 (3H, d, CH-CH _3), 2.22 (3H, S, N-CH _3), 3.4 (8H, br., -Ίί ~ ^ Ν-), 4.49 (2Η , Q, -CH ₂ ), 4.93 (1Η, M, CHCH-CH ₃ ), 7.59 (1Η, D, C ⁸ - = CH-), 8.98 (1Η, D, C ⁵ - = CH-).

Example 7

It boils a mixture of 1.00 g of compound IVa, 0.50 g of triethylamine and 20 ml of methanol for 4 h at reflux, the reaction mixture is cooled after completion of the reaction, wherein

- ZFERi983 * ObG315

M 23 188 14

43116

forms a precipitate, the precipitate is filtered off and washed with methanol to give 0.69 g (78% yield) of Compound Ia. The product is recrystallised from dimethylformamide, mp. 253-255 ° C (dec.).

Example 8

A mixture of 1.00 g of compound IVa, 0.50 g of triethylamine and 20 ml of water is refluxed for 2 h, the water is distilled off in vacuo, 20 ml of methanol are added to the residue, the insoluble constituents are filtered off and washed with methanol, to obtain 0.66 g (75% yield) of Compound Ia. The product is dissolved in a mixture of 2 ml of concentrated aqueous ammonia and 20 ml of ethanol at room temperature, then the resulting solution is treated with charcoal and excess ammonia and ethanol are distilled off by heating to give 0.62 g of a pure, crystalline product. mp. 254-255 ⁰ C (dec.) are obtained.

20 Example 9

A mixture of 1.00 g of compound IVa and 20 ml of ethanol is refluxed for 4 hours, cooled, the precipitate formed is filtered off and washed with ethanol to give 0.88 g (84% yield) of compound Ia, mp 253 to 255 ° C

25 (Zers.), Receives.

Elementary Analysis: for C ₁₈ H ₂₀ FN ₅ O ^ .HF.BOF calculated: C 50.61% H 4.95% N 9.84% found: 50.52 5.05 9.79.

30 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] [1, 4 Jbenzoxazin-ö-carboxylic acid-BFp-chelate compound, 0.62 g of triethylamine and 5 ml of dimethyl sulfoxide for 3 h at 120 to 130 ⁰ C, cooled, the precipitate formed is filtered off and washed with methanol. The pro-

M 23 188 15

431

from a mixture of chloroform, methanol and water to give 0.67 g of 9-fluoro-3-methyl-10- (i-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [i, 2,3-de] [i, 4] benzoxazine-6-carboxylic acid (yield 72%), mp. 258-260 ⁰ C.

5 (Zers.), Receives.

Elemental analysis: for C ,, H ₁₈ FN, 0 ^ .3 / 2H ₂ 0 Calculated: C 54.69% H 5.40% N 11.25% found ': 54,82 5,06 11,13

10 example 11

A mixture of 5.21 g of compound Ha, 4.76 g of N-methylpiperazine and 26 ml of dimethyl sulfoxide is heated to 110 to 120 ° C. for 2 hours, cooled, the precipitate formed is filtered off and washed with cold ethanol to give 4.25 g (74.3% yield) Compound Ia. The product is dissolved at room temperature in a mixture of concentrated aqueous ammonia and methanol (volume ratio 1:20) and excess ammonia is distilled off by heating to give a pure, crystalline product, mp 254-255 ⁰ C (dec.). , receives.

Example 12

A mixture of 2.00 g of compound Ha, 0.73 g of N-methylpiperazine, 1.23 g of triethylamine and 10 ml of dimethyl sulfoxide is heated to 120 to 130 ^° C. for 5 h, the precipitate formed is filtered off, and 1.69 is obtained g (76.9% yield) Compound Ia. The product is recrystallized from a mixture of concentrated aqueous ammonia and ethanol (1:20 by volume), mp 254-256 ° C

30 (Zers.).

Example 13

A mixture of 0.70 g of compound Ha, 0.66 g of N-methylpiperazine and 7 ml of pyridine is refluxed for 2 hours, the reaction mixture is concentrated in vacuo and the residue is combined with methanol. The formed precipitate becomes

-J CPP.

M 23 188 16 ^ H

filtered off and washed with methanol, where <0.60 g (78% yield) of compound Ia, mp. 253 to 256 ⁰ C (dec.) Obtained.

Example 14

A mixture of 0.77 g of compound Ha, 0.73 g of N-methylpiperazine and 4 ml of dimethylacetamide is heated to 110 to 120 ^° C. for 5 hours, cooled, the precipitate formed is filtered off and washed with ethanol to give 0.65 g (77% yield) Compound Ia. This product is recrystallised from dimethylformamide, m.p. 254-256 ° C (dec.).

Example 15

The procedure is as described in Example 14 and obtained 9-fluoro-3-methyl-1O- (1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [i, 2,3-de] [i , 4] benzoxazine-6-carboxylic acid in a yield of 73.4%. The product is recrystallized from a mixture of chloroform, methanol and water, mp.

260 ° C (decomp.).

Elemental analysis: for C ₁ -H ₁

Calculated: C 54.69% H 5.40% N 11.25% Found: 54.74 5.19 11.33.

Example 16

A mixture of 0.50 g of 9-chloro-10-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [i, 2,3-de] [i, 4] benzoxazine is heated. δ-carboxylic acid BFp-chelate compound, 0.44 g of N-methylpiperazine and 2.5 ml of dimethylsulfoxide at 110 to 130 ⁰ C for 5 h, cooled, methanol is added to the reaction mixture, the precipitate formed is filtered off and washed with methanol 0.43 g of 9-chloro-3-methyl-10- (i-piperazinyl) -7-0x0-2,3-dihydro-7H-pyrido [i, 2,3-de] [i, 4] benzoxazine 6-carboxylic acid (78% yield). The product was crystallized from a mixture of chloroform and methanol in order, mp. 280 ⁰ C (dec.).

M 23 188

1 elemental analysis: for C-gHpQClN ^ O.

Calculated: C 57.22% H 5.34% N 11.12%

found

56.78

5.34

11.07.

Claims (2)

M 23 188
invention claim 1. Process for the preparation of pyrido [i, 2,3-de] - [1,4] benzoxazine-6-carboxylic acid derivatives of the general formula (i) COOH (D wherein R _{1 is} a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, R _{2 is} a hydrogen atom or a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, and X _{1 is} a halogen atom
represent and their pharmaceutically acceptable salts, characterized in that a pyrido [i, 2,3-de] [i, 4] benzoxazine-6-carboxylic acid BF2-chelate compound of the general formula (II). ·· (II) in which X ₁ and R _{1 have} the abovementioned definition and X _{2 represents} a halogen atom, with a piperazine compound of the general formula (III) M 23 188 R ₂ - N NH wherein R _{2 has} the meaning given above, to a compound of general formula (IV) 10 15 20 25 30 R ₂ -N wherein R ₁ , R ₂ and X _{1 have} the meanings given above, converts and the BF ₂ ~ chelate unit of the compound
general formula (IV) to obtain a compound of general formula (i). 2. The method according to item 1, characterized in that one isolates the intermediate compound of general formula (IV). 35