FI93357B - 8-hydroxy-1-amino-4-oxo-1,4-dihydro-3-quinoline - Google Patents

Description

93357 8-Hydroxy ± -1-amino-4-oxo-1,4-dihydro-3-quinoline derivatives

Divided separated from the FI patent application 87 3940 5

The invention relates to novel 8-hydroxy-1-amino-4-oxo-1,4-dihydro-3-quinoline derivatives of the formula

O

10 v ^ I

F C00H

OH NHR2 wherein R1 is an imidazole or 4-methyl-1-piperazine ring and R2 is a lower alkyl radical.

The compounds of the invention are useful as intermediate compounds in the preparation of therapeutically active pyrido [3,2,1-ij] -1,3,4-benzoxadiazine derivatives, especially 10-substituted-9-fluoro-7-oxo-2,3-di- hydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid derivatives of the formula .250 pcooh R1 (I) 30 0 ^ yNv,

^ R

• · · · c e>.

• i ‘

• <C

wherein R 1 and R 2 are as defined above and their pharmaceutically acceptable salts and hydrates and solvates of the compounds of formula I or their salts.

And, which are useful as active ingredients in antibacterial agents.

The term "lower" means a carbon chain, which preferably contains up to 7 carbon atoms.

The lower alkyl radical preferably contains 1 to 4 carbon atoms and is especially methyl, ethyl, n-propyl, isopropyl, n-butyl or the like.

Novel 10-substituted-9-fluoro-7-oxo-2,3-dihydropyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid derivatives of the formula I , and pharmaceutically acceptable salts and hydrates or solvates thereof, and salts thereof can be prepared by reacting the above compound of formula V with formaldehyde or a polymer or acetal thereof.

The intermediate compound of formula V can be prepared, for example, according to the following reaction scheme a) or b).

c · V ·. · • · m 3 93357 a) reduction HgCgOCH-C (COOCgHg) ^ χ.Λγ ^ Νθ2 χ.Α ^ Λ. ^

OH OH

(A) (B) h5c2ooc cooc2h5

Ny / Δ 5 h.c2ooc cooc2h5 L · H U ΟΗ protection F il, - ** I II I] cyclomy T H X · '* OH] h (C) 0R' (D)

OH

COOC2H5 O

1 T]. . . P v ^ Ok / C00C2H5 amination ^ jj jj N-protected ^ OR *

0R 'NH

(E) NH2 (F)

O

F ^^ JL ^ COOC2H5,? TT 11 ii-i. 3. · F Jl. C00CoHc I || Il alkylomti 2 5 - * I l | l [protection I | X * ^ <V ^ N ^ -, P-repeat> 0R 'NHR "» |

OR * N-R

(G) (H) R "*! Γ1 ^ 1 amination + *; *? I deprotection p C00H ^ 0

amination ^ COOH

x '—-Tr—> LH I

I (HR) 0H NHR2 R T I,

OH NHR

(Va) (V) 4 93357

p H5C2OOCn ^ COOC2H5 OH

JT Π jj F COOC2H5 T h -> Λλν ^

OH X 'I

0H OH protection (C) (J)

OH

p ___Jl .COOC-H ,, 25 0 I 11 COOC_Hc, xSvA Fnv ^ nv / \ / 2 5 X 'jP N amination ^ jj jj 0R x' i N-protection ^ OR 'nh2 (F) 0 H C00CoHc f 25 0 LMM _ I COOC-H-.

x · and ,,,. ^. 7f yr I I alkylation ^ I || || • I - ~~ T ^ S deprotection OR 'NHR "X' ^ OR 'N-R2

(G) I

(H) R "amination + deprotection

V

o o c Fv / \ / ^ s / C00S fV ^ / V C00h. —LL JJ amination i ^ s. Where NH 1 R 2 H NHR 2 (Va) (V) 5 93357 wherein R 1 and R 2 are as defined above, X 'is hydrogen and R' is a protecting radical such as benzyl , methoxybenzyl, methoxyethoxymethyl, tetrahydropyranyl, allyl, t-butyl, t-butyldimethylsilyl, acetyl, benzoyl and the like and R "is a protecting radical such as formyl, acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, 2, 2,2-trichloroethoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, t-butoxycarbonyl and the like.

The compound of formula V is a novel compound and this compound can be prepared according to the above reaction scheme a) or b), including the final step of reacting the compound (H) or (Va) with an amino of formula HR1, wherein R1 is as defined above. .

The reaction of compounds of formula V with formaldehyde or a polymer or acetal thereof may, if desired, be carried out in a solvent such as dioxane, tetrahydrofuran, acetonitrile, chloroform, dimethylformamide, dimethylsulphoxide, N, N'-dimethylpropeacetylacetylurea. Mixtures of two or more solvents may also be used.

The reaction can be carried out, if necessary, with an acid catalyst such as acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, pyridine-p-toluenesulfonate, ferric chloride, zinc chloride, chlorodimethylsilane, chlorodimethylsilane, resin sulfonic acid; Aldrich Chemical Co., Inc.), in the presence of Amberlyst 15 (a strongly acidic, macroreticular resin; Aid-rich Chemical Co., Inc.) and the like.

The reaction temperature can vary relatively widely. la area. In general, the reaction is carried out at a temperature of 20 to 150 ° C.

In a preferred embodiment of this invention, about 1 mole or excess of formaldehyde 35 or a polymer or acetal thereof is used per mole of compound of formula V.

«. · «. · 6 93357

Examples of starting materials of formula V include 6-fluoro-8-hydroxy-7- (1-imidazolyl) -1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid and 6-fluoro-8- hydroxy-1- (methylamino) -7- (4-methyl-1-piperazinyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid.

Examples of compounds that can be reacted with a compound of formula V include formaldehyde, its polymers such as paraformaldehyde, its acetals such as dimethoxymethane and the like.

The preparation of pharmaceutically acceptable salts of the compounds of formula I or hydrates or solvates of said salts can be carried out in a manner known per se; for example by reacting a carboxylic acid of formula 1 with an equivalent amount of the desired base or vice versa, reacting a base of formula I with an organic or inorganic acid. The reaction may conveniently be carried out in a solvent such as water or an organic solvent (e.g. ethanol-20, methanol, acetone and the like). The temperature at which salt formation is performed is not critical. The salt formation is generally carried out at room temperature, but can also be carried out at temperatures slightly above and below room temperature, for example in the range 0 to + 50 ° C.

Examples of pharmaceutically acceptable acids * that may be used include hydrogen chloride, hydrogen bromide, sulfur, phosphorus, nitrogen, formic, acetic, propionic, succinic, glycolic, lactic, malic, , wine, lemon, ascorbine, maleic, hydroxymalein, phenylacetic acid, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxy-benzoic, salicylic, aminosalicylic, nicotine -, meta- ·· * nisulfonic, ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, gluconic, glucuronic, galacturonic, aspartic and glutamic acids; methionine, 35 tryptophan, lysine, arglnlinl and the like.

t · i · ··· 7 93357

Acid addition salts can be converted to the free form by treatment with a base such as metal hydroxide, ammonia and the like.

The basic salts 5 of the compounds of formula I may be prepared by reacting a compound of formula 1 with a metal base or an amine such as an alkali or alkaline earth metal hydroxide or an organic amine. Examples of the metals used as the cation include sodium, potassium, magnesium, calcium and the like. Examples of amines include diethanolamine, N, N-dibenzylethylenediamine, choline, ethylenediamine and the like.

The acid addition salts or basic salts of the compounds of formula I differ from the corresponding free form in certain physical properties, such as water solubility.

The compounds of formula I and their pharmaceutically acceptable salts may exist in unsolvated as well as solvates, including hydrate forms. Hydration can be achieved automatically during the manufacturing process or can occur in stages as a result of the hygroscopic properties of the initially anhydrous product. For the controlled preparation of the hydrate, the completely or partially anhydrous product can be placed in a humid atmosphere (e.g. at a temperature of about +10 to +40 ° C). Solvates with pharmaceutically acceptable solvents such as ethanol can be obtained, e.g., during crystallization.

Certain compounds provided by the invention have a center of asymmetry. The pure D-isomer, the pure L-isomer, and mixtures thereof, including racemic mixtures, are also included in the invention.

... The compounds of the formula I, their salts, 1 ... hydrates and ringing agents have a broad antibacterial activity against gram-positive and gram-negative organisms as well as Mycoplasma and can be used for the treatment and prevention of infectious diseases. The in vitro and in vivo antibacterial activities of these compounds of the invention; are shown below: 1. In vitro antibacterial activities

The in vitro antibacterial activities of the representative pyrido [3,2,1-ij] -5,3,4-benzoxadiazine derivatives of the formula I, their salts, hydrates and solvates were studied by a standard agar dilution method [see Chemotherapy, 22, (1974)]. , 1126]. Their minimum inhibitor concentrations (MIC, in 10 pg / ml) are shown in Table 1 and Table 2. The compounds used herein were prepared in the corresponding examples as mentioned below.

Table 1 15

Aerobic microorganisms Compound from Example _2_2 a)

Gram-positive bacteria

Bacillus subtllis PCI 219 0.20 0.05 20 Staphylococcus aureus FDA 209P JC-1 0.39 0.39

Staphylococcus aureus NR 2855 0.78 0.20

Staphylococcus aureus Smith 0.39 0.20

Staphylococcus epidermidis IFO 12993 0.39 0.39

Staphylococcus epidermidis NR 2942 0.39 0.39 25 Enterococcus faecalis NR 2943 12.5 3.13 • <* ** 'c Alcaligenes faecalis IFO 13111 3.13 0.39

Citrobacter freundii IFO 12681 0.10 0.013

Enterobacter aerogenes NR 2945 0.10 0.013

Enterobacter cloacae NR 2946 0.05 0.025 30 Escherichia coli NIHJ JC-2 0.10 0.025 ... Escherichia coli NR 2630 0.0065 0.013 1 .. Klebsiella pneumoniae FDA PCI 602 0.39 0.10

Bordetella bronchiseptlca ATCC 4617 3.13 0.20

Proteus rettgeri ATCC 14505 1.56 0.20 35 Proteus vulgaris 0X19 ATCC 6898 0.013 0.013 ♦ • 4 9 93357

Table 1 (continued)

Pseudomonas aeruginosa A3 3.13 0.20

Pseudomonas aeruginosa NR 2950 6,25 0,78 5 Pseudomonas stutzeri IFO 12695 0,0033 0,025

Serratla marcescens IFO 12648 0.78 0.10

Salmonella typhimurium IFO 12529 0.05 0.025 10 Table 2

Antibacterial spectrum

Anaerobic microorganisms MIC (pg / ml) Compound e.g. No. 2a Bacteroides fragilis ATCC 23745 0.78

Bacteroides fragilis NR 2579 3.13

Bacteroides fragilis NR 2582 0.78

Bacteroides fragilis NR 2583 0.39

Bacteroides fragilis NR 2584 0.78 Bacteroides distasonis NR 2578 0.78

Bacteroides thetalotaomicron NR 2588 1.56

Bifidobacterium adolescentis ATCC 15703 0.39

Clostiridium botulinum NR 2611 0.10

Clostridium perfringens NR 2612 0.39 25 Clostridium monlliforme ATCC 25546 0.78 * r: '· ι Fusobacterium varium ATCC 8501 12.5

Peptococcus prevotii ATCC 9321 1.56

Peptococcus variabilis ATCC 14955 0.78

Peptostreptococcus anaerobius NR 2743 0.39 30 Propionibacterium acnes ATCC 11828 0.78 »t ·

Mycoplasma

Mycoplasma homlnls NR 2952 0.10 35 _ t · »·« 10 93357 2. In vivo therapeutic effect Pyrido [3,2,1-ij] -1,3,4-benzoxadiazine derivatives prepared according to Example 2a) below The in vivo antibacterial activities of the compounds were tested against lethal infection with Escherichia coli ML4707, Pseudomonas aeruginosa 4au542 and Streptococcus pneumoniae 6-001. ICRs weighing about 20 g were infected by intraperitoneal injection with the corresponding bacterial suspension. The test compound was administered orally over 5 days. The corresponding 50% effective dose (EDS0 / mg / kg) that protects 50% of animals from infection death is shown in Table 3.

Table 3 15

Antibacterial activities in vivo against systemic infection in mice (ED 1, mg / kg)

Bacteria 20 Escherichia Pseudomonas Streptococcus

Compound coli ML 4707 aeruginosa pneumoniae _4au5.4? _6-001_ _8tfij_P «Q« _P ifl.t_P »Q» _

Example 25 2a) 0.06 0.11 13.4 10.3 • · * et »•« o 3. Acute toxicity The corresponding LDS0 values of the compounds obtained in Examples 2 and 2a) below are more than 2,000 mg / kg.

... The acute toxicity of these compounds was studied by administering them orally to ICR mice.

The compounds of formula I, their salts, hydrates and solvates have a broad antimicrobial spectrum of 35 gram-positive and gram-negative bacteria and a il 11 93357

Against mycoplasma, which are resistant to various antibiotics such as penicillins, cephalosporins, aminoglycosides, tetracyclines and the like.

In addition, the compounds of formula I, their salts, hydrated and solvated have low toxicity and a strong and extensive antimicrobial effect. The protective effects of the compounds on systemic bacterial infections in mice are greater than with the commercially available synthetic antibacterial agents. Therefore, these compounds can be effectively utilized in the prevention or treatment of diseases caused by gram-positive and gram-negative bacteria and bacterial microorganisms in humans and animals.

For example, diseases caused by the following microorganisms or mixtures of the following microorganisms can be treated and / or prevented: Staphylococcus, Streptococcus, Aerococcus, Enterococcus, Micrococcus, Lactobacillus, Bifidobacterium, Clostridium, Eubacterium, Peptococcus, Peptostoccus, Peptostoccus , 20 Citrobacter, Campylobacter, Enterobacter, Klebsiella, Proteus, Pseudomonas, Serratia, Salmonella, Shigella, Vibrio, Aeromonas, Haemophilus, Neisseria, Acinetobacter, Alcaligenes, Bordetella, Bacteroldes, Fusobacterium, Mycoplasma and other microorganisms.

The compounds of formula I, their salts, hydrates and solvates may be administered orally or non-orally to humans or animals by a variety of conventional methods of administration.

In addition, the compounds of formula I, their salts and hydrates and solvates are used alone or ... as compositions with excipients, liquid diluents, binders, lubricants, humectants, etc., for example in general medical compositions such as tablets, granules, sugar-coated tablets. in the form of tea, powder, capsules, gels, dry syrup, syrup, ampoules, suspension, liquid, emulsion, ointments, paste, cream, suppositories and the like.

Furthermore, solubilizers, absorption accelerators, surfactants and the like, as well as other additives necessary for the formulation, i.e. any pharmaceutically acceptable forms, can be used.

The compounds of formula I, their salts, hydrates and solvates may be used alone or as a mixture of two or more different compounds, and the amount of the compounds is about 0.1 to 99.5%, preferably 0.5 to 95% based on the total the weight of the medical composition.

A medical composition which may contain a compound of formula I, a salt, hydrate or ringing agent thereof may be formulated as a combination of a compound of formula I or a mixture thereof with other conventional compounds which are pharmaceutically active.

The dosage of a novel compound of formula I per patient per day may vary depending on the individual, the species, their weight and the condition to be treated, but will generally be in the range of 0.5 to 500 mg per kg of body weight per day, preferably about 1 to 300 mg.

Isoquinolines with a fused oxamethylene ring (i.e. forming pyrido [1,2,3-de] -1,4'-c'benzoxate derivatives) are known, for example, from EP-A-47 005. The compounds of the formula I differ significantly from these. however, in that they have two adjacent nitrogen atoms in the fused ring to form pyrido [3,2,1-ij] -, .. 1,4-benzoxadiazines. These compounds, as shown above, have excellent and extensive active bacterial activity against gram-positive and gram-negative bacteria as well as Mycoplasma.

35 «. · Fc · «il 13 93357

The following examples illustrate the preparation of intermediates of formula V and their use in the preparation of the corresponding final products of formula I. Preparation of starting material 5 Reference example

Preparation of diethyl N- (3,4-difluoro-2-hydroxyphenyl) aminomethylenemalonate a) A solution of 2,3-difluoro-6-nitrophenol (500 mg) in methanol (7 ml) was hydrated with 5% Pd. / C for 10 (60 mg) for 6 hours. The reaction mixture was filtered under a stream of nitrogen and the filtrate was evaporated to give 414 g of crude 2-amino-5,6-difluorophenol.

b) A mixture of the amine obtained above (414 mg) and diethylethoxymethylene malonate (618 mg) was heated at 130 ° C under nitrogen for 5 minutes. The resulting crystalline residue was triturated with ethanol and filtered to give 590 mg of diethyl N- (3,4-difluoro-2-hydroxyphenyl) aminomethylene malonate; mp. 178-180 ° C; MS m / z 315 (M &lt; + &gt;). Additional chromatography of the mother liquor on silica gel column-20 using CHCl 3 / acetone (20: 1) as eluent gave 59 mg of crystals.

Ethyl 8-benzyloxy-6,7-difluoro-4-hydroxy-3-quinolinecarboxylate (Method 1) c) To a mixture of diethyl N- (3,4-difluoro-2-hydroxyphenyl) aminomethyl malonate (80 mg) and anhydrous potassium carbonate (70 mg) in dry dimethylformamide (1.5 ml), benzyl bromide (30 μΐ) was added. The mixture was stirred at room temperature for 2 hours. After removal of the solvent under reduced pressure, the residue was dissolved in dichloro-30 methane and the precipitate was filtered off. The filtrate was washed with water, dried over anhydrous sodium sulfate and evaporated. The crystalline residue was washed with n-hexane and recrystallized from methanol to give diethyl N- (2-benzyloxy-3,4-difluorophenyl) aminomethyl malonate (90 mg); mp. 87 ° C; MS m / z 405 (M &lt; + &gt;).

14 93357 d) A solution of the malonate (280 mg) obtained above in diphenyl ether (2.8 ml) was heated at 250 ° C for 30 minutes under a nitrogen atmosphere. After cooling the reaction mixture, the ethanol formed in the reaction medium was removed under reduced pressure. The dark brown solution was subjected to column silica gel chromatography (10 g) eluting sequentially with benzene, dichloromethane and dichloromethane / acetone (30: 1). The pure fractions were combined and the solvent removed under reduced pressure to give crystalline ice. The residue was washed with a mixture of n-hexane and ethyl acetate to give 90 mg of ethyl 8-benzyloxy-6,7-difluoro-4-hydroxy-3-quinolinecarboxylate. Analytical sample; mp. 200-201 ° C; MS m / z 359 (M &lt; + &gt;); was prepared by recrystallization from methanol.

Preparation of ethyl 8-benzyloxy-6,7-difluoro-4-hydroxy-3-quinolinecarboxylate (Method 2)

To a stirred solution of ethyl 6,7-difluoro-4,8-dihydroxy-3-quinolinecarboxylate (300 mg) in dry dimethylformamide (6 mL) was added anhydrous potassium carbonate (308 mg) followed by benzyl chloride (145 μΐ). .

The mixture was stirred at 55-65 ° C for 11 hours. The reaction mixture was diluted with water (30 ml) and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel (7 g) using acetone / chloroform (1:20) as eluent to give 113 mg of ethyl 8-benzyloxy-6,7-difluoro-4-hydroxy-3-chlorolinecarboxylate; mp. 200-201 ° C; MS m / z 359 (M +), after recrystallization from methanol.

Preparation of ethyl 8-benzyloxy-6,7-difluoro-1- (formylmethylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylate e) When ethyl 8-benzyloxy-6, A mixture of 7-difluoro-4-hydroxy-3-quinolinecarboxylate (410 mg) and anhydrous potassium carbonate (315 mg) in dry dimethylformamide

WU

After 93357 dls (10 mg) was stirred at room temperature for 3 hours, O- (2,4-dinitrophenyl) hydroxyl lamp (260 mg) was added. The mixture was stirred at room temperature for another 6.5 hours. After removing the solvent under reduced pressure, water (12 ml) was added to the residue, and the mixture was stirred at room temperature for 3 hours. The precipitate was collected by filtration and washed with cold water and then ether to give 405 mg of ethyl 1-amino-8-benzyloxy-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate. Analytical sample; mp. 143-144 ° C; MS m / z 374 (M &lt; + &gt;); was prepared by recrystallization from methanol.

f) 98% formic acid (0.60 ml) was added to acetic anhydride (1.51 ml) at 0 ° C. The mixture was stirred at 0 ° C for 15 minutes, at 50 ° C for 15 minutes and then cooled to 0 ° C. To this solution was added dropwise a solution of the amine obtained above (400 mg) in 98% formic acid to give a crystalline residue which was recrystallized from ethanol to give 410 mg of ethyl 8-benzyloxy-6,7-difluoro-1- (formylamino). -4-oxo-1,4-dihydro-20-3-quinolinecarboxylate; mp. 188-190 ° C; MS m / z 402 (M &lt; + &gt;).

g) A mixture of the formamide obtained above (400 mg), anhydrous potassium carbonate (275 mg) and anhydrous dimethylformamide (17 ml) was stirred at room temperature for 1.5 hours. Methyl iodide (0.19 ml) was added to the mixture and stirring was continued for 2.5 hours. The solvent was removed under reduced pressure, and the residue was partitioned between chloroform and water. The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. Residue ki-30 was taken up in ethanol to give 335 mg of ethyl 8-benzyloxy-6,7-difluoro-1- (formylmethylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylate; mp. 180-181 ° C; MS m / z 416 (M &lt; + &gt;).

35 16 93357 Preparation of 6,7-difluoro-8-hydroxy-1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid h) Ethyl 8-benzyloxy-6,7-difluoro-1- ( formylmethylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylate (330 mg) was hydrogenated over 5% Pd / C (50 mg) in chloroform (14 mL) for 4 hours. The reaction mixture was diluted with methanol (14 mL) and filtered. The filter cake was washed with chloroform / methanol (1: 1). The combined filtrate was evaporated and the residue was recrystallized from ethanol to give 239 mg of ethyl 6,7-difluoro-1- (formylmethylamino) -8-hydroxy-4-oxo-1,4-dihydro-3-quinolinecarboxylate; mp. 221-225 ° C (dec.); MS m / z 326 (MH &lt; + &gt;).

i) A mixture of the above ester (210 mg) and 0.5 N sodium hydroxide (5.2 ml) was heated at 100 ° C for 2 hours under a nitrogen atmosphere. The reaction mixture was acidified with acetic acid (0.16 ml). The separated precipitate was filtered, washed with water and dried under reduced pressure to give 168 mg of 6,7-difluoro-8-hydroxy-1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid. Analytical sample 20; mp. 248-250 ° C (dec.); MS m / z 270 (MH &lt; + &gt;); was prepared by recrystallization from ethanol.

Example 1 Preparation of 6-fluoro-8-hydroxy-7- (1-imidazolyl) -1- (methyl- * amino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid * 1 Carbonyldiimidazole (32 mg) was added to a stirred solution of 6,7-difluoro-8-hydroxy-1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid obtained in Reference Example i) (50 mg). in dry di-30 methylformamide (2 mL). Stirring was continued at room temperature for 2 hours and then at 80 ° C for 5 hours. The solvent was removed under reduced pressure and the residue was suspended in water and the pH was adjusted to 5 with acetic acid. The separated precipitate was filtered and washed with methanol to give 35 mg of 6-fluoro-8-hydroxy-7- (1-imidazolyl) -1- (methylamino) -

II

& l V

17,9357 4-oxo-1,4-dihydro-3-quinolinecarboxylic acid as a pale yellow powder; FAB-MS m / z 319 (MH &lt; + &gt;); 1 NMR (d 6 DMSO) δ: 2.82 (3H, s), 7.10 (1H, d, J = 10.7 Hz), 7.61 (1H, d), 7.75 (1H, d), δ .62 (1H, s), 8.92 (1H, s) and 15.33 (1H, 5 br.s).

Example 2 (Use Example) 9-Fluoro-10- (1-imidazolyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4- Preparation of benzoxadiazine-6-carboxylic acid 10 The 6-fluoro-8-hydroxy-7- (1-imidazolyl) -1- (methylamino) -4-oxo-1,4-dihydro-3-quinoline obtained in Example 1 was prepared. a suspension of nicarboxylic acid (15 mg) in a mixture of 35% formalin (1 ml) and dioxane (1 ml) was heated at 100-110 ° C for 1.5 hours under a nitrogen atmosphere. The solvent 15 was removed under reduced pressure, and the crystalline residue was washed with methanol to give 15 mg of 9-fluoro-10- (1-imidazolyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3, 2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid as a pink powder. Analytical sample; mp. > 300 ° C; FAB-MS 20 m / z 331 (MH &lt; + &gt;); was prepared by recrystallization from dime-style formamide and ether.

In an analogous manner, the following starting compound of formula V is converted to the corresponding product of formula I. The use of compounds of formula V is described in more detail in the parent application of this application, FI patent application 87 3940.

2a) 6-fluoro-8-hydroxy-1- (methylamino) -7- (4-methyl-1-piperazinyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid; the hydrochloride was obtained as yellow crystals, FAB-MS m / z 30,350 (MH +) -HCl. This crude crystalline material was used directly without further purification 9-fluoro-3-methyl-10- (4-methyl) -1-piperazinyl-7-oxo-2,3-dihydro-H-pyrido [3,2, 1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid cyclization agent; pale yellow crystals, m.p. 268 35-269 ° C (dec.); MS m / z 362 (MH &lt; + &gt;).

* t. V

Claims (3)

18 93357 1. 8-Hydroxy-1-amino-4-oxo-1,4-dihydro-3-quinoline derivatives of the formula 5 0 F C00H (V) 10 '1p OH NHR wherein R1 is imidazole or 4 -methyl-1-piperazine ring and R 2 is a lower alkyl radical. 2. A compound according to claim 1, which is 6-fluoro-8-hydroxy-7- (1-imidazolyl) -1- (methylamino) -4-oxo-1,4-dihydro-3- quinoline-20 carboxylic acid. Compound according to Claim 1, characterized in that it is 6-fluoro-8-hydroxy-7- (1-imidazolyl) -1- (methylamino) -4-oxo-1,4-dihydro-3- kino-liinikarboksyylihappo. A compound according to claim 1, characterized in that it is 6-fluoro-8-hydroxy-1- (methylamino) -7- (4-methyl-1-piperazinyl) -4-oxo-1 , 4-dihydro-ro-3-quinolinecarboxylic acid. 9 · · C il 19 93357 1. 8-hydroxy-1-amino-4-oxo-1,4-dihydro-3-quinoline derivative with the formula 5 OF COOH T if (v) 10 μl N ^ OH NHR2 15. R1 is selected from the group consisting of imidazole and 4-methyl-1-piperazinyl and R2 and alkyl. 3. A compound according to claim 1, which is 6-fluoro-8-hydroxy-1- (methylamino) -7- (4-methyl-1-piperazinyl) -4-oxo-1,4 dihydro-3-quinolinecarboxylic acid. • ·· c <C (• I