CS264936B1 - 9-amino-5-fluor-3-oxo-3h-pyrido/3,2,1-yl/phenoxazin-2-carboxylic acids - Google Patents

Abstract

The solution relates to 9-amino-5-fluoro-3- -oxo-3H-pyrido [3,2,1-cl] phenoxazine-2- carboxylic acids of formula I wherein R is fluorine, piperazine, or 4-methylpiperazine residue. These have not yet unlabeled substances show antibacterial properties activity.

Description

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

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

These novel, yet undescribed substances exhibit useful antibacterial activity in vitro.

The compounds of formula (I) may be prepared by reduction of the corresponding 9-nitro derivative (s) known per se. AO No. 261 338 with ferrous sulfate in an alkaline medium, preferably an aqueous ammonia, sodium hydroxide or potassium hydroxide medium. The compounds of formula I wherein R is piperazine or 4-methylpiperazine may also be prepared according to the invention by reacting a compound of formula I wherein R is fluorine with an excess of piperazine or 4-methylpiperazine, either without solvent or preferably in pyridine solution.

or

Compounds of formula I wherein R is fluoro (Ia), piperazine residue (Ib), 4-methylpiperazine residue (Ic) were tested in vitro for antibacterial activity.

The activity of the substances was as follows (given in mg / l): Ia [0057] 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 process for preparing the compounds of the invention is simple and provides the desired products in satisfactory yields. Further details are given in the following examples. The examples given are merely illustrative and not limiting.

He did

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

A suspension of 1.1 g of 9-nitro-5,6-difluoro-3-oxo-3H-pyrido [2,1-a] 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 hours. A solution of 10 g of ferrous sulfate heptahydrate in 50 ml of water was then poured in and the mixture was refluxed for a further 0.5 hours. The hot reaction mixture was filtered while hot, the solid was boiled twice with 200 ml of water. The combined aqueous fractions were acidified with acetic acid and cooled, the insoluble material was filtered off with suction and recrystallized from pyridine. There was obtained 0.35 g of (36%) does not melt up to 340 ° C for ^{C Q} 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 spectra.-n (KBr): 1,720 cm ^-1 (COOH), 1,710 cm ^-1 ( CO), 1,255 cm ^-1 (-O-), 3,260,

0 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-k] phenoxazine-2-carboxylic acid (Ic)

By the method described in Example 1, reduction of 5-fluoro-6- (4-methylpiperazin-1-yl) -9-nitro-3-oxo-3H-pyridine-3,2,1-cleno-phenoxazine-2-carboxylic acid by ferrous sulfate in medium 5 m.p. 300 DEG-307 DEG C. (decomposition). Mass spectrum: m / z - 410 (M ⁺ ).

Example 3

9-Amino-5-fluoro-6- (4-methylpiperazin-1-yl) -3-oxo-3H-pyridine-3,2,1-kilo phenoxazine-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 were stirred for 20 hours at 100 ° C under an argon atmosphere. The mixture was then evaporated to dryness, the residue was boiled with 10 ml of ethanol, cooled, the insoluble material was filtered off with suction, washed with water and crystallized from pyridine. There was obtained 0.25 g (61), m.p. 299-307 ° C (dec.). For ^C 21 ^H 19 ^FN 4 ° 4 (410.4) calculated: C 61.46, H 4.67, % N, 13.65% Found: 61.34%

C, 4.68; H, 4.69; N, 13.89.

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Example 4

9-amino-5-fluoro-6- (1-piperazinyl) -3-oxo-3H-pyrido Q1,1,1-phenoxazine-2-carboxylic acid (Ib)

Following the procedure described in Example 3 using anhydrous piperazine, the title compound was obtained in 45% yield, the compound melting to 340 ° C. For (396.38) calculated

% C, 60.60;% H, 4.32;% F, 4.79;% N, 14.13; Found: C 60.93, H 4.44, F 4.87, N 14.33%. 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.