SI8112109A8 - Process for preparing the compounds 9-halo-7-oxo-2, 3-dihydro-7h-pyrido (1,2,3-de) (1,4) benzoxazine-6-carboxylic-acid - Google Patents

Description

A technical problem

There was a need to find a new, technologically advanced process for the preparation of novel, antibacterially effective compounds 9-halo-7-oxo-2,3-dihydro-7H-pyrido / 1,2,3-de // 1,4 / - benzoxazine -6-carboxylic acids, in good yields and with satisfactory purity.

The state of the art

The compounds of formula (I) defined below and obtained by the process of the invention are novel, and therefore a process for their preparation has not yet been described. For information, we cite the following posts:

US Patents 3 θθ3 522 and 3 984 548 describe 9-fluoro3-methyl-7-oxo-2,3-dihydro-7H-pyrido / 1,2,3-de // i, 4 / benzoxazine-6carboxylic acid, Japanese patent application (OPI) no. 138582/1979 describes 1-ethyl-6-fluoro-4-oxo-7- (4-methyl-1-piperazinyl) quinoline3-carboxylic acid and Japanese Patent Application (OPI) no. 76875/1979 describes 8- (4-methyl-1-piperazinyl) -9-fluoro-5-methyl6,7-dihydro-1-oxo-1H, 5H-benz (1j) quinolidine-2-carboxylic acid (wherein abbreviation OPI ”as used herein refers to a published, untested patent application).

Description of solution to a technical problem with implementation examples

The present invention relates to a process for the preparation of new antibacterially effective substances, i.e. 9-halo-7-oxo2,3-dihydro-7H-pyrido / 1,2,3-de [1,4] benzoxazine-6-carboxylic acid derivatives of formula (D

where X represents a halogen atom, R represents a hydrogen atom or an alkyl group of 1 to 6 carbon atoms and Z represents a monosubstituted amine group, a disubstituted amine group or a cyclic substituted amine group which may contain a further hetero atom, and the substituted amine group may be further substituted by one or more substituents selected from the group consisting of hydroxyl, alkyl of 1 to 6 carbon atoms, amino, hydroxyalkyl of 1 to 6 carbon atoms, monoalkylamines and dialkylamines of 1 to 6 carbon atoms in each alkyl moiety, and pharmaceutical acceptable salts of these derivatives. Examples of the mono-substituted amino group include monoethylamino or monomethylamino, and examples of the di-substituted amino group include diethylamino or dimethylamino. The term cyclically substituted amino group

- 5 refers to a 4- to 7-membered ring and examples include azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl and homopiperazinyl (hexahydro-1H-1,4-diazepin-1-yl). In more detail, the substituent Z is e.g. 4-methyl-1-piperazinyl,

1-piperazinyl, 1-pyrrolidinyl, 5-hydroxy-1-pyrrolidinyl, 1-piperidinyl, 4- (hydroxy-1-piperidinyl, 5-hydroxy-1-piperidinyl, 4-morpholinyl, 4- (2-hydroxyethyl) piperazinyl, 3,5-dimethyl-1-piperazinyl, 4-dimethylamino-1-piperidinyl, homopiperazinyl, 1-pyrazolidinyl, 2-methyl-1-pyrazolidinyl, N- (2-hydroxyethyl) amino, N- (2-hydroxyethyl) -K -methyl amino, hydrazyl and methylhydrazyl.

The compound of the invention may form an acid addition salt with inorganic or organic acid, such as hydrochloric sulfur or methanesulfonic acid and the like, and may form the corresponding carboxylate with sodium, potassium and the like.

Compounds of formula (I) exhibit better antibacterial efficacy against gram-negative and gram-positive bacteria as well as lower toxicity in the examples of the known compounds described above.

according to the invention to be prepared from below

The compounds will give an elucidated reaction

kJ ^er X - R and Z are as above described.

The reaction can be carried out by heating a compound of formula (II) with an amine of formula (III) at a temperature of from about 30 to 200 ° C, preferably from 70 to 150 ° C, in the presence of a suitable organic polar solvent such as dimethyl sulfoxide, 3ulpholane, . dimethylformamide, dimethylacetamide or water. It is desirable to carry out the reaction in the presence of an acid receiver, such as triethylamine, dimethylaniline, potassium carbonate and the like, at a molar ratio of 1.0 to 1.2 moles of an acid receiver per one mole of the compound of formula (II). Because the compound of formula (III) is an amine itself, it can also act as an acid acceptor. In such a case, it is desirable to use two or more moles of an amine of formula (III) against one mole of a compound of formula (II)

- 5 When using another acid receiver, such as.

triethylamine, it may be appropriate to use an amine of formula (III) in a molar ratio of 1.0 to 1.2 moles per mole of a compound of formula (II).

The reaction is normally completed within 1 to 48 hours and the product can be isolated and purified by conventional techniques such as evaporation, filtration, extraction, chromatography, recrystallization and combinations thereof. When the product is precipitated by cooling the reaction mixture, e.g. collected by filtration, and if no precipitation occurred, the reaction mixture was concentrated to dryness under reduced pressure and the residue shaken with a mixture of chloroform and water, then the product was obtained by concentrating the chloroform layer. However, where the product is colored or contains certain by-products, further purification may be carried out by chromatography on silica gel or by recrystallization.

The starting compounds of formula (II) of the process for preparing the compounds of the invention are novel compounds and can be prepared from known compound (A) [J. Amer. Chem. Soc., 81, 94-101 (1959) according to the method shown below.

In the formulas, X represents a halogen atom.

When 2,3,4-trihalonitrobenzene (A) is hydrolyzed in the presence of potassium hydroxide, triethylamine and the like, 2,3i-respiratory-6-nitrophenol (B) is produced. Compound (B) is heated with 1,2-dihalogenoethane at a temperature of from about 30 to about 150 ° C, preferably from 80 to 120 ° C, while stirring in an organic polar solvent such as ethanol, dimethylformamide, dimethylsulfoxide, in the presence of an acid receiver, such as is an inorganic base, e.g. potassium carbonate and sodium carbonate,

- 7 or an organic base, e.g. triethylamine and N, N-dimethylaniline to produce the compound of formula (C). The nitro group of compound (C) is then reduced by conventional reduction using sodium dithionite or hydrochloric acid, or by catalytic reduction with Raney nickel to produce a compound of formula (D) when the compound (D) is heated at a temperature of about 50 to 150 ° 0 in the presence of an acid receiver used in method (B) to (C), in a polar solvent such as ethanol or dimethylformamide, yields the benzoxazine derivative (E). The benzoxazine derivative (E) is heated with diethyl-ethoxymethylenemalonate at a temperature of from about 80 to 150 ° C in the presence of a solvent such as ethanol or in the absence of a solvent to produce compound (F) if a ring-coupling reaction is carried out by heating compound (F) at at a temperature of from about 120 to 150 [deg.] C. in polyphosphoric acid or its ester, a tricyclic compound (G) is prepared. The ester portion of compound (G) is hydrolyzed according to the conventional method using an acid or base to give the starting compound of formula (II) wherein the substituent R is hydrogen. Compounds (B) to (G) are also novel compounds.

In case the substituent R in formula (II) is alkyl, the starting material of formula (II) can be prepared by a slightly different procedure. The compound of formula (B) described above is heated with halomethylalkylketone, such as monochloroacetone, at a temperature of 50 to 150 ° C, in the presence of an acid receiver such as potassium carbonate or sodium carbonate, in a polar solvent such as acetone. alcohols or dimethylformamide, preferably in the presence of a catalytic amount of potassium iodide, to produce a compound of formula (H).

X (H) f ^NO 2

OCH ₂ CO-alkyl

When compound (H) is catalytically treated with Raney nickel or palladium on charcoal, the reduction of the nitro group, the dehydration ring from the resulting amino group and the oxo group, and the hydrogenation of the double bond formed simultaneously give the compound of formula (J).

Compound (J) can be converted to a starting material of formula (II) wherein the substituent R is alkyl, by the method as in the case where R is hydrogen.

Antibacterial efficacy (in vitro) of the compounds of the invention (9-fluoro-10- (4-methyl-1-piperazinyl) -3methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,5- de] [1,4] benzo-9-xazine-6-carboxylic acid (Ia), 9-fluoro-3-ethyl-7-oxo-O- (1-piperazinyl) -2,3-dihydro-7H-pyrido [1 , 2,3-de] [1,4] benzo xazine-6-carboxylic acid (Ib), 9-fluoro-10- (3-hydroxy-pyrrolidinyl) -3-methyl-7-oxo-2,3-dihydro -7H-pyrido [1,2,

3-de] [1,4] benzoxazine-6-carboxylic acid (Ic) and 9-chloro3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid (Id)) is shown in the following tables 1 and 2 in the example of pipemidic acid (8-ethyl-5,8-dihydro-5- oxo-2- (1-piperazinyl) -pyrido [2,3-d] pyrimidine-6-carboxylic acid known antibacterial drug) (abbreviated as PPA. in Table 1).

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As can be seen in Tables 1 and 2, the compound of the invention has a greater antibacterial effect on the test organisms than the known drug. In addition, the compounds of the invention exhibit very low toxicity. So e.g. is the acute toxicity (LD ^ ₀ ) of compound (Ia) 380 mgAs P ^ and mice (iv).

On the other hand, known compounds 8- (4-methyl-1-piperazinyl) -9-fluoro-5-methyl-6,7-dihydro-1-oxo-1H, 5Hbenz [ij] quinolizine-2-carboxylic acid (Japanese patent application (OPI) No 76875/1979) and 1-ethyl-6-fluoro-4-oxo-7 (4-methyl-1-piperazinyl) quinoline-3-carboxylic acid (Japanese patent application (OPI) No 138582/1979 ) exhibit relatively high toxicity [135 mg / kg and 225 mg / kg in mice (iv)], respectively. Although PPA has low toxicity [ΒΡ ^ θ = 610 to 649 mg / kg in mice (i.v.)], the antibacterial efficacy of PPA is much weaker than that of the compounds of the invention, as can be seen in the table above.

The present invention is further explained by the following examples. Unless otherwise stated, parts, percentages, ratios and the like are weighted.

- 13 EXAMPLE 1

Preparation of starting material:

g of 2,3,4-trifluoronitrobenzene was dissolved in 150 ml of dimethylsulfoxide and a solution of 10% potassium hydroxide was added to this mixture, maintaining the temperature at 18 to 20 ° C. The mixture was then stirred for 2 hours at room temperature and the reaction mixture was added 1 l of water, then shaken with chloroform. The aqueous layer was acidified with hydrochloric acid and extracted with chloroform. The extract was washed with water and dried, and the chloroform layer was concentrated. The residue was purified by silica gel column chromatography to give 5.8 g

2,3-Difluoro-6-nitrophenol as a yellow oil.

7.9 g of 2,3-difluoro-6-nitrophenol, 50 "1 g of 1,2..dibromoethane and 18.7 g of potassium carbonate are added to 80 ml of dimethylformamide and the mixture is stirred for 2.5 hours at about

Up to 100 ° C (bath temperature). The reaction mixture was concentrated to dryness in vacuo and the residue partitioned between ethyl acetate and water. The organic solvent layer was washed with water and dried and then evaporated. The residue was dissolved in benzene and purified by chromatography on a silica gel column to give 7.7 g of 2- (2-bromoethoxy) -3,4-difluoronitrobenzene as a light yellow oil.

NMR (CDCl3): cT (ppm)

3.75 (2H, t, J φ-7Ηζ, -CHpBr)

4.62 (2H, t, J = 7Hz, -OCH ₂ -)

6.92 - 7.04 and 7.65 - 7.93 (respectively 1H, m, C ^ -H and Οθ-oziroma}

1.74 g of this product is dissolved in 30 ml of methanol and a solution of 6.44 g of sodium dithionite dissolved in 15 ml of water is added to this solution. The mixture was stirred for 1 hour at room temperature. The methanol was evaporated and the residue was extracted with chloroform. After the extract was washed with water and dried, the solvent was evaporated to give 0.44 g of 2- (2-bromoxy) -3,4 difluoroaniline.

NMR (CDC1 _5): (f (ppm)

3.6? (2H, t, J = 6Hz, -CHgBr)

3.90 (2H, s, NHg)

4.42 (2H, t, J = 6Hz, -OCHg-)

6.30 - 6.90 (2H, m, C ⁵ -H and C ⁶ -H)

1.82 g of this product and 3.03 g of potassium carbonate are added to 10 ml of dime til formamide and the mixture is stirred for 1 hour at about 80 to 100 ° C (bath temperature). The reaction mixture was added to ice-cold water and extracted with ethyl acetate. After the extract was washed with water and dried, the solvent was distilled off at room temperature to give 1.21 g of 7,8-difluoro-2,3-dihydro4H- [1,4] benzoxazine from the ground. 48 to 54 ° C.

NMR (CDCl3): cT (ppm)

3.38 (2H, t, J = 5.5 Hz, -NHCHg-)

3.70 (1H, B.S., NH)

4.28 (2H, t, J = 5.5 Hz, -OCHg-)

6.17 - 6.80 (2H, m, C ⁵ -H, C ⁶ -H)

- 15 A mixture of 1.1 g of this product and 1.38 g of diethyl ethoxymethylenemalonate is stirred for 2 hours at a temperature of about 130 to 135 ° C (bath temperature).

The ethanol produced was evaporated and 20 g of ethylpolyphosphate were added to the residue. The mixture was then stirred for 1.5 hours at a temperature of about 140 to 145 ° C (bath temperature). The reaction mixture was added to ice-cold water and extracted with chloroform. The extract is completely washed with water. After drying, the solvent was evaporated and the residue was recrystallized from ethyl ethyl acetate. 1.3 g of til-9,10-difluoro-7-dxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylate are obtained as colorless needles from the ground . 265 to 266 ° C.

NMR ( 'CF ^ COOH): cT (ppm) 1.58 (3H, t, J - 7.5 Hz, -CHgCH ^) 4.76 (2H, q, J = 7.5 Hz, -CHgCH ^) 4.96 (4H, b.s., -CHg-CHg-) 8.17 (1H, q, c ⁸ -h) 9.55 (1H, s, C ⁵ -H) 1.15 g of this product is added to 12

of hydrochloric acid and acetic acid (1: 4 vol.) and the mixture was stirred at 100-110 ° C (bath temperature) for 4 hours. After cooling, the precipitated crystals were collected by filtration, washed with water, methanol and chloroform to give 0.78 g of 9.10difluoro-7-oxo-2,3-dihydro-7H-pyrido [1,2,3 “de] [1 , 4] -benzoxazine-6-carboxylic acids as colorless needles from the ground. above 300 ° C.

- 16 Analysis for C ^ H ^ FNO ^

Calcd: C 53.9 *, H 2.64, N 5.24

Found: 053.81, H 2.73, N 5.26

NMR (CF ₅ COOH): cf (ppm)

5.0 (4H, bs, -CH ₂ CH ₂ -)

8.17 (1H, q, C ⁸ -H)

9.45 (1H, s, C ⁵ -H)

EXAMPLE 2

Preparation of starting material:

5.8 g of 2,3-difluoro-6-nitrophenol, 5.0 S 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 maintained at reflux for 4 hours. After removal of the insoluble material by filtration, the solvent is evaporated and the residue partitioned between chloroform and water. The chloroform layer was washed with water and dried and the solvent was evaporated. The residue was treated with n-hexane to give 5.0 S 2-acetonyloxy-3,4difluororonitrobenzene as light yellow crystals from the ground. 61 ° C.

7.1 g of this product are dissolved in 200 ml of ethanol and 14 ml of Raney nickel is added to this mixture. The mixture is catalytically reduced at normal atmospheric pressure. After removal of the catalyst by filtration and evaporation of the solvent, the residue is dissolved in chloroform and decolourised by passage through a silica gel column to give 5.1 g of 7-8-difluoro-2,3-dihydro3-methyl-4H-benzoxazine as a light yellow oil.

- 17 A mixture of 4.8g of this product and 5.3 6 diethyl ethoxymethylene malonate is heated for 1 hour at a temperature of about 140 to 145 ° C (bath temperature). After the reaction, the ethanol product is removed by evaporation to give an oily product. 35 g of ethylpyrrolidate are added and the mixture is stirred for 1 hour at a temperature of about 140 to 145 ° C. (bath temperature). After cooling, the reaction mixture was added to ice-cold water. The precipitate was extracted with 200 ml of chloroform, this method was run 3 times and the extracts were combined and washed with 5% potassium hydroxide solution and water.

The chloroform layer was dried with sodium sulfate to give 5.1 g of ethyl-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylate as a white powder from the ground. 261 ° C.

Dissolve 4.0 g of this product in 50 ml of a mixture of concentrated hydrochloric acid and acetic acid (1: 4 vol.) And reflux this oil for 3 hours.

After cooling, the precipitated crystals were collected by filtration and washed thoroughly with water. The crystals were washed with a mixture of ethanol and ether (1/4 volume ratio) and dried in vacuo to give 3.7 g of 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2 , 3-deO [1,4] benzoxazine-6-carboxylic acids as transparent floor tiles. above 300 ° C.

EXAMPLE 3

1.0 g of 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid and 2.85 g N-methylpiperazine was added to 15 ml of dimethylsulfoxide.

The mixture was stirred at about 100 to 110 ° C (bath temperature) for 12 hours and the reaction mixture was concentrated to dryness in vacuo, then 4-0 ml of water was added to the residue. The product is then extracted with chloroform. The extract was dried and concentrated to dryness in vacuo. The residue was recrystallized from ethanol to give 550 mg of 9-fluoro-3-methyl-10- (4-methyl-1-piperazinyl) 7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] Benzoxazine-6carboxylic acids as colorless needles from the ground. 250 to 257 ° C (decomposition).

Analysis for ^C 18 ^{H 2} O ^FN A

Calcd .: 0 59.82, H 5.58, N 11.63

Found: C 59.62, H 5.59, N 11.65 EXAMPLE 4

140 mg of 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid and 404 mg of 4-hydroxypiperidine were added to 2 ml of dimethylsulfoxide. The mixture was stirred at a temperature of from about 100 to 110 [deg.] C. (bath temperature) for 5.5 hours and the reaction mixture was concentrated to dryness under vacuum. Water was added to the residue and the mixture was neutralized with dilute hydrochloric acid to give a precipitate. The precipitate was collected by filtration, washed with water and then recrystallized

- 19 from ethanol to give 66 mg of 9-fluoro-10- (4-hydroxy-1piperidinyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [ 1,4) benzoxazine-6-carboxylic acid m.p. 220 to 240 ° C (decomposition).

Analysis for ^C 18 ^H 19 ^FN 2 ° 5

Calc .: C 59.66, H 5.29, N 7.73

Found: C 59.24, H 5.26, N 7.65

EXAMPLE 5

843 mg of 9> 10-difluoro-5-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid and 646 mg of 3-hydroxypyrrolidine were added to 10 ml of dimethyl sulfoxide. The mixture was stirred at about 100 to 110 ° C (bath temperature) for 1 hour and the reaction mixture was then concentrated to dryness in vacuo. Water was added to the residue and the insoluble matter was collected by filtration.

The substance was recrystallized from a mixture of chloroform and ethanol to give 450 mg of 9-fluoro-10- (3-hydroxy-1-pyrrolidinyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2, 3-de] [1,4] benzoxazine-6-carboxylic acid m.p. 278 to 280 ° C (decomposition).

Analysis for C ^ H ^ FN ^ O ^

Calcd: 058.61, H 4.92, N 8.04

Found: 058.45, H 5.10, N 7.94

- 20 EXAMPLE 6

In the same manner as in Example $, 9-fluoro-10- (1-chloroopiperazinyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzo is produced zaxazine-6-carboxylic acid from the ground. 230 to 234 ° C (decomposition). This product is dissolved in dilute hydrochloric acid and the solution is concentrated in vacuo. Ethanol was added to the residue. The precipitated crystals were collected by filtration and washed with ethanol to give the hydrochloride 9 "fluoro-10- (1-homopiperazinyl) -3" ethyl-7 "Oxo2,3-dihydro-7H-pyridoCl, 2,3 -de] [1,4] benzoxazine-6-carboxylic acid from m.p. 285 to 290 ° C (decomposition).

Analysis for Ο ^ θΗ ^ φΡΝ ^ Ο ^ .ΗΟΐ.H ^ O. Calcd: 051.99, H 5.57, N 10.10

Found: C 51.61, H 5.25, N 10.10

EXAMPLE 7

133 mg of 9,10-difluoro-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid and 0.2 ml of methylhydrazine were added to 3 ml of dimethylformamide. The mixture was stirred at a temperature of about 100 to 110 ° C (bath temperature) for 7 ar. The reaction mixture was concentrated to dryness in vacuo and the residue was treated with water. The insoluble material was collected by filtration and recrystallized from ethanol to give 30 mg of 9-fluoro-10- (1-methylhydrazyl) -7-oxo-2,3-dihydro-7H-pyrido [1,2,3-part [1. 4] benzoxazine-6-carboxylic acids as yellow prisms from the ground. 239 to 242 ° C.

Analysis for C ^ H ^ PN ^ O ^

Calcd: 053.24, H 4.13, N 14.33

Found: 053.89, H 4.22, N 14.22

EXAMPLE 8

Preparation of starting material:

Dissolve 10.5 g (0.05 mol) of 2,4-dichloro-3-fluoronitrobenzene in 30 ml of dimethyl sulfoxide and add to the mixture 8 ml of 10% aqueous sodium hydroxide solution, and then stir the mixture for 20 hours at 60 to 70 ° C. After completion of the reaction, 200 ml of water was added and the crude starting material was removed by extraction with diethyl ether. The aqueous layer was acidified with acetic acid and extracted with diethyl ether. The ether extract was dried over sodium sulfate and the ether distilled off. The resulting residue was purified by silica gel column chromatography (100 g) using chloroform as eluent to give 3.4 g (35.5% yield) of 3-chloro-2-fluoro-6-nitrophenolas soil. 73 ° C.

A mixture of 3 g (15.7 mmol) of 3-chloro-2-fluoro-6-nitrophenol, ml of chloroacetone and 300 mg of potassium iodide in 50 ml of acetone was maintained for 6 hours under reflux and stirring. After cooling, all insoluble matter was removed by filtration, then the filtrate was concentrated and purified by silica gel column chromatography (20 g) using chloroform as eluent to give 2.5 g (54.5% yield) of 2-acetonyloxy-4- chloro-3-fluoronitrobenzene as an oil,

2.3 g (7.9 mmol) of 2-acetonyloxy-4-chloro-3-fluoronitrobenzene were dissolved in 30 ml of ethanol and catalytically reduced in the presence of 2 g of Raney nickel. After the reduction is complete

- 22 The catalyst is removed by filtration and the filtrate is concentrated. The resulting residue was purified by silica gel column chromatography (20 g) using chloroform as eluent to give

1.2 g (75.5% yield) of 7-chloro-8-fluoro-3-niethyl-2,3-dihydro-4H-1,4-benzoxazine as an oil.

Mixture of 1.11 g (5.5 mol) of 7-chloro-8-fluoro-3-methyl2,3-dihydro-4H-1,4-benzoxazine and 1.4 g (6.2 mmol) of diethyl-ethoxymethylene -Malonate is stirred for 2 hours under heating to 130 to 140 ° C (bath temperature). After confirming the disappearance of the starting benzoxazine compound by thin layer chromatography, 5 g of ethylpolyphosphate were added to the reaction mixture and allowed to react for 1 hour at 140 ° C (bath temperature). After cooling, 20 ml of water are added to the mixture and the precipitate formed is extracted with 150 ml of chloroform. The chloroform extract was dried with sodium sulfate and then the chloroform was distilled off. The residue was purified by silica gel column chromatography (20 g) using methanol-chloroform (5:95 vol.) As eluant to give

1.2 g (67.0% yield) of ethyl-9-chloro-10-fluoro-3-methyl7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1 , 4] benzoxazine-6carboxylate m.p. 263 to 264 ° C.

Analysis for C ₁₅ H ₁₃ C1FNO ₄

Calcd: 055.31, H 4.02, N 4.30

Found: 055.19 H 3.97, N 4.41

- 23 600 mg (1.8 mmol) of the benzoxazine compound obtained above are dissolved in 5 ml of concentrated hydrochloric-acetic acid (1: 4 vol.) And the solution is heated at 120 ° C for 6 hours (bath temperature). After cooling, 20 ml of water was added to the reaction solution and the precipitated crystals were collected by filtration, washed thoroughly with water, ethanol-diethyl ether (4: 1 vol.) And then with diethyl ether, then dried to give 459 mg (92.4%). yield) 9-chloro-10-fluoro-3-methyl-7-oxo-2,3 "dihydro-7H-pyrido [1,2,3-dione [1,4] benzoxazine-6-carboxylic acid from m.p. > 300 ° C as transparent tiles.

Analysis for C ^ H ^ CIFNO ^

Calcd: 052.45, H 3.05, N 4.71

Found: 052.20, H 3.13 N 4.74

EXAMPLE 9

150 mg (0.5 mmol) of 9-chloro-10 ~ fluoro-3-methyl7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid was suspended in 3 ml of dimethyl sulfoxide and 150 mg of N-methylpiperazine., added to the suspension. The mixture is then allowed to react for 6 hours at 120-130 ° C (bath temperature).

After cooling, the solvent was distilled off under reduced pressure and the residue was washed with diethyl ether to remove all insoluble matter. The resulting residue was purified by chromatography on a silica gel column (7 g) using methanol-chloroform (5:95 vol.) And then with methanol-chloroform (10:90 vol.) As eluents,

- 24 then the resulting product was recrystallized from ethanol to give 65 mg (34.4% yield) of 9-chloro-3-methyl-10 (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro -7H-pyrido [1,2,3de] [1,4] benzoxazine-6-carboxylic acid as pale yellow fine needles from the ground. 275 to 276 ° C (decomposition).

Analysis for Ο ^ θΗ ^ ΟΙΝ ^ Ο ^

Calc .: C 57.22, H 5.34, N 11.12

Found: C 57.20, H 5.11, N 11.23

EXAMPLES 10 to 32

Using analog operations as described in Examples 3 or 4 above, the following products are obtained which are crystallized from ethanol, unless otherwise described:

10. 9-Fluoro-10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid as light yellow needles from the ground. 260 to 270 ° C (dec.).

11. 9-Fluoro-10- (N-2-hydroxyethyl-N-methylamino) -7-oxo2,3-dihydro-7H-pyrido [1,2,3-de] [1,4) benzoxazine-6-carboxylic acid as light yellow needles from the ground.

262 to 265 ° C.

12. 9-Fluoro-10- (3-hydroxy-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid ( crystallize from methanol) as light yellow needles from the soil. 270 to 277 ° C (dec).

- 25 15. 9-Fluoro-10- (3-hydroxy-1-piperidinyl) -5-inethyl-7-oxo-2,5-dihydro-7H-pyrido [1,2,5 “de] [1,4 ] benzoxazine-6-carboxylic acid as light yellow needles from the ground. 267 to 275 ° C (dec.).

14. 9-Fluoro-7-oxo- _and 10- (1-piperazinyl) -2,5-dihydro-7Hpyrido [1,2,5-de] [1,4] benzoxazine-6-carboxylic acid as light yellow needles from the ground. 258 to 268 ° C (dec) (crystallized from water).

15. 9-Fluoro-5-methyl-10- (4-morpholinyl) -7-oxo-2,5-dihydro-7H-pyrido [1,2,5-de] [1,4] benzoxazine-6-carboxylic acid as colorless needles from the ground. > 500.

16. 9-Fluoro-5-methyl-7-oxo-10- (1-piperazinyl) -2,5-dihydro-7H-pyrido [1,2,5-de] [1,4] benzoxazine-6-carboxylic acid as light yellowish white crystals from the ground. 260 ° C (dec).

17. 9-Fluoro-1O- (4- (2-hydroxyethyl) piperazinyl) -5-niethyl-7-octo-2,5-dihydro-7H-pyrido [1,2,5-de] [1,4] benzoxazine -6carboxylic acid from the ground. 282 to 285 ° C (dec).

18. 9-Fluoro-5-methyl-10- (1-piperidinyl) -7-oxo-2,5-dihydro-7H-pyrido [1,2,5-de] [1,4] benzoxazine-6-carboxylic acid m.p. 268 to 275 ° C (dec.).

- 26 19. 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 from the ground. 263.5 to 264.5 ° C.

20. 9-Fluoro-3-methyl-7-oxo-10- (1-pyrrolidinyl) -2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid m.p. 268 to 269 ° C.

21. 10- (4-Dimethylamino-1-piperidinyl) -9 "fluoro-3-methyl7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxyl acid from the ground. 245 to 248 ° C (dec).

22. 10-dimethylamino-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid, m.p. 233 to 235 ° C.

23 · 9-Fluoro-3-niethyl-10- (4-methyl-1-homopiperazinyl) -7oxo-2,3-dihydro-7H-pyrido C1,2,3-de] [1,4] benzoxine zin6-carboxyl acid from the ground. 234 to 237 ° C (dec).

24. 9-Fluoro-3-methyl-10- (2-methyl-1-pyrazolidinyl) -7-oxo2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6carboxyl acid from the ground. 235 to 236 ° C.

- 27 25. 9-Fluoro-3-methyl-7-oxo-10- (1-pyrazolidinyl) -2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxyl acid from the ground. 215 to 225 ° C (dec.).

26. 9-Fluoro-10- (3-hydroxy-1-azetidinyl) -5-inethyl-7-oxo2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzocazine-6carboxyl acid from the ground. 286 to 286.5 ° C (crystallized from chloroform / ethanol).

27 · 9-Fluoro-3-methyl-7-oxo-10- (4-thiamorpholinyl) -2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid with m.p. > 300 ° C (crystallized from chloroform / ethanol).

28. 9-Fluoro-1O- (3-hydroxymethyl-1-pyrrolidinyl) -3-methyl7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxyl acid from the ground. 237 ° θ (crystallized from chloroform / ethanol).

29. 9-Fluoro-10- (2-hydroxymethyl-1-pyrrolidinyl) -3-niethyl7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxyl acid from the ground. 265 ° C (crystallized from chloroform / ethanol).

30. 9-Fluoro-10- (4-hydroxymethyl-1-piperidinyl) -3-methyl7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6carboxyl acid from the ground. 266 ° C.

- 28 31. 9-Fluoro-10- (3-hydroxymethyl-1-piperidinyl) -3-niethyl7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine- carboxylic acid from the ground. 222 ° C.

32. 1- (4-Amino-1-piperidinyl) -9-fluoro-3-methyl-7-oxo2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid (32) after the reaction of compound (II) with 4-tert-butoxycarbonyl aminopiperidine, the protected product is treated with trifluoroacetic acid to remove the tert-butoxycarbonyl group The final product contains crystalline water (3/2 ^ O) and melts at 150 to 131 ° C at and then crystallized at 170 to 180 ° C and melted again at 210 to 212 ° C).

Reference case

The compounds of the invention are effective antibacterial agents for the treatment of various infectious diseases such as urinary tract infections or infections in the mammalian respiratory organs, including humans.

The compounds are normally used by oral administration, but may also be administered by injection or topical administration, depending on the type of disease being treated.

- 29 For oral administration, the compounds may be administered at a dosage of between about 100 mg to about 1000 mg per adult daily, normally from 100 mg to 600 mg, in the form of various pharmaceutical preparations such as tablets, capsules, powders, granules, syrups and the like. , which is well known in the art. Other preparations suitable for injection or external use may also be prepared by a technique known in the art. Thus, e.g. make pharmaceutical preparations by their own known method using suitable diluents, binders, disintegrants, coating agents and the like.

An example of a preparation comprising a compound (Ia) suitable for oral administration is described below.

Capsules

Compound (Ia) 100,0 mg Corn starch 23.0 mg CMC calcium 22.5 mg Hydroxypropylmethylcellulose 5.0 mg Magnesium stearate 1.5 mg In total 150,0 mg to one

capsule v

Although the invention has been described in detail and with reference to its specific embodiments, it will be apparent to one skilled in the art that various modifications and modifications of the invention can be made without departing from its concept and scope.

-10An indication of the best known applicant for the economic exploitation of the invention

1.0 g of 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7Hpyrido / 1,2,3-de [1,4] benzoxazine-6-carboxylic acid and 2.85 g N-methylpiperazine was added to 15 ml of dimethylsulfoxide.

The mixture was stirred at about 100-110 ° C (bath temperature) for 12 hours and the reaction mixture was concentrated to dryness in vacuo, then 40 ml of water was added to the residue. The product is then extracted with chloroform. The extract was dried and concentrated to dryness in vacuo. The residue was recrystallized from ethanol to give 550 mg of 9-fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7oxo-2,3-dihydro-7H-pyrido (1,2,3-de). / 1,4 / Benzoxazine-6-carboxylic acids as colorless needles from the ground. 250 to 257 ° C (decomposition). Elemental analysis; for C gHggFN ^ O ^

Calc .: C 59.82, H 5.58, N 11.63

Found: C 59.62, H 5.59, N 11.65

Claims (2)

PATENT APPLICATION A process for the preparation of 9-halo-7-oxo-2,3-dihydro-7H pyridoi / 1,2,3-de [1,4] benzoxazine-6-carboxylic acid compound of formula (I) wherein R represents a hydrogen atom or an alkyl group of 1 to 2 carbon atoms, Z represents pyrrolidinyl, piperidinyl or piperazinyl which may be substituted by hydroxyl, methyl or ethyl, and X represents a halogen atom characterized by the metabolism of 9,10-respiratory-7 -oxo-2,3-dihydro-7H-pyrido (1,2,3-de) -4,4-benzoxazine-6-carboxylic acid or its 3-alkyl derivative of formula (II) - 32. where R and X have the above meaning, with an amine of the formula ZH, wherein Z has the above meaning, at a temperature between 90 ° C and 14O ° C and in an organic solvent, water or a mixture thereof and in the presence of an acid receiver . A process according to claim 1, characterized in that dimethylsulfoxide and dimethylformamide are used as the organic solvent.