CS264936B1 - 9-amino-5-fluoro-3-oxo-3H-pyrido [3,2,1-cl] phenoxazine-2-carboxylic acid - Google Patents

Abstract

The solution relates to 9-amino-5-fluoro-3-oxo-3H-pyrido[3,2,1-kl]phenoxazine-2-carboxylic acids of the general formula I where R is a fluorine atom, a piperazine or a 4-methylpiperazine residue. These previously undescribed substances exhibit antibacterial activity.

Description

The invention relates to 9-amino-5-fluoro-3-oxo-3H-pyrido[3,2,1-kl]phenoxazine-2-carboxylic acids of the general formula I

where R is a fluorine atom, a piperazine, or a 4-methylpiperazine residue.

These new, previously undescribed substances exhibit useful antibacterial activity in vitro.

Compounds of general formula I can be prepared by reducing the corresponding known 9-nitro derivatives of Czechoslovak Patent Application No. 261 338 with ferrous sulfate in an alkaline medium, preferably in aqueous ammonia, sodium hydroxide, or potassium hydroxide. Compounds of general formula I, where R is a piperazine or 4-methylpiperazine residue, can also be prepared according to the invention by reacting a compound of general formula I, where R is a fluorine atom, with an excess of piperazine or 4-methylpiperazine, either without the use of a solvent, or preferably in a pyridine solution.

or

Compounds of general formula I, where R is a fluorine atom (Ia), a piperazine residue (Ib), a 4-methylpiperazine residue (Ic), were tested in vitro for antibacterial activity.

^the activity of the substances was as follows (given in mg/l): Ia Ib Ic Streptococcus pyogenes 32 16 1 Streptococcus faecalis 32 16 8 Staphylococcus aureus 16 16 16 Pseudomonas aeruginosa 128 32 64 Escherichia coli 32 16 16 Proteus vulgaris 16 32 16

The method of preparing the substances according to the invention is simple and provides the desired products in satisfactory yields. More details result from the following examples. The examples given only illustrate the invention, and do not limit it.

Example

9-Amino-5,6-difluoro-3-oxo-3H-pyrido,2,1-cl]phenoxazine-2-carboxylic acid (Ia)

A suspension of 1.1 g of 9-nitro-5,6-difluoro-3-oxo-3H-pyrido [S,2,1-kl] phenoxazine-2-carboxylic acid (3 mmol) in a solution of 4 g of sodium hydroxide in 150 ml of water was refluxed for 0.5 hour. Then a solution of 10 g of ferrous sulfate heptahydrate in 50 ml of water was added and the mixture was refluxed for another 0.5 hour. The hot reaction mixture was filtered while hot, the solid portion was boiled twice with 200 ml of water. The combined aqueous portions were acidified with acetic acid and cooled, the insoluble portion was filtered off with suction and recrystallized from pyridine. 0.35 g of the substance (36%) was obtained, not melting at 340 ^° C. For ^c ig ^H g ^F 2 ^N 2 ^O 4 (330.3) calculated: 58.19% C, 2.44% H, 11.51% F, 8.48% N? found: 57.56% C, 2.84% H, 11.33% F, 8.00% N. IC spectrum (KBr): 1,720 cm ^-1 (COOH), 1,710 cm” ¹ (CO), 1,255 cm ^-1 (-O-), 3,260,

35 0 cm (NII^) *

CS 264 936 Bl

Example 2

9-amino-5-fluoro-6-(4-methylpiperazin-1-yl)-3-oxo-3H-pyrido ^3,2,1-klj phenoxazine-2-carboxylic acid (Ic)

By the method described in Example 1, the reduction of 5-fluoro-6-(4-methylpiperazin-1-yl)-9-nitro-3-oxo-3H-pyrido3,2,1-chlorophenoxazine-2-carboxylic acid with ferrous sulfate in 5% aqueous ammonia gave the desired compound in 40% yield with a melting point of 300-307 °C (decomposition). Mass spectrum: m/z - 410 (M ⁺ ).

Example 3

9-amino-5-fluoro-6-(4-methylpiperazin-1-yl)-3-oxo-3H-pyridoxine-3,2,1-ylphenoxazine-2-carboxylic acid (Ic)

A mixture of 0.33 g of 9-amino-5,6-difluoro-3-oxo-3H-pyrido [3,2,1-kl] phenoxazine-2-carboxylic acid Ia (1 mmol), N-methylpiperazine (0.5 g) and 20 ml of pyridine was stirred for 20 hours at 100 °C under argon. The mixture was then evaporated to dryness, the residue was boiled with 10 ml of ethanol, cooled, the insoluble fraction was filtered off with suction, washed with water and crystallized from pyridine. 0.25 g (61) of a substance with a melting point of 299 to 307 °C (decomposition) was obtained. For ^C 21 ^H 19 ^FN 4°4 (410.4) calculated: 61.46% C, 4.67% H, 4.63% F, 13.65% N; found: 61.34%

C, 4.68% H, 4.69% F, 13.89% N.

\!

Example 4

9-Amino-5'fluoro-6-(1-piperazine1)-3-oxo-3H-pyrido Qi, 2,1-clj Phenoxazine-2-carboxylic acid (Ib)

The method described in Example 3 using anhydrous piperazine gave the desired substance in 45% yield, the compound did not melt up to 340 °C. For (396.38) calculated

60.60% C, 4.32% H, 4.79% F, 14.13% N; found: 60.93% C, 4.44% H, 4.87% F, 14.33% N. Mass spectrum m/Z = 396 (M ⁺ ).

Claims (3)

SUBJECT OF THE INVENTION 1. 9-Amino-5-fluoro-3-oxo-3H-pyrido [3,2,1-cl phenoxazine-2-carboxylic acids of formula I wherein R is a fluorine atom, a piperazine or a 4-methylpiperazine residue. 2. A process for the preparation of compounds according to claim 1, wherein R is as defined above, characterized in that the corresponding 9-nitro derivatives are reduced with ferrous sulphate in an alkaline medium, preferably in aqueous ammonia, sodium hydroxide or potassium hydroxide. 3. A process for the preparation of compounds of formula I wherein R is a piperazine or 4-methylpiperazine moiety by reacting compounds of formula I wherein R is a fluorine atom with piperazine or 4-methylpiperazine.