FI88041B - Pyrido[3,2,1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid derivatives - Google Patents

Abstract

The invention relates to novel pyrido[3,2,1-ij]-1,3,4- benzoxadiazine-6-carboxylic acid derivatives of the formula III <IMAGE> in which R1 is hydrogen or a radical for protecting the carboxyl group, R2 is hydrogen or an alkyl which is optionally substituted by halogen, R3 and R4 are each, independent of each other, hydrogen, or an alkyl which is optionally substituted by a hydroxyl radical or by an optionally substituted amino radical, and X and X', which are identical or different, are halogens. The compounds according to the invention can be used as intermediates when preparing therapeutically active pyrido[3,2,1-ij]- 1,3,4-benzoxadiazine derivatives.

Description

1 88041

Pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid derivative 1a

Divided separated from the FI patent application 87 3940 5

The invention relates to novel pyridothS-1-yl-1H-benzooxadiazine-6-carboxylic acid derivatives of the formula 10

I!) O N

XK / wherein X 'is a halogen atom, R1 is hydrogen or a carboxy protecting radical which is lower alkyl, benzyl or lower alkanoyloxyalkyl, R2 is a lower alkyl radical which may be substituted by a fluorine atom, and R3 is hydrogen or optionally by a hydroxy radical or di (lower); alkyl) lower alkyl radical substituted by an amino radical.

The compounds of the invention are useful as intermediates in the preparation of therapeutically active pyrido [3,2,1-ij] -1,3,4-benzodiazine derivatives, especially 10-substituted-9-fluoro-7-oxo-2,3-dihydro-7H- pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid derivatives of formula 2,88041

O

F Jk. COOR1 J li y m R6-N N2

5 R5 O N

^ V

wherein R 1 is hydrogen or a carboxy protecting group which is lower alkyl, benzyl or lower alkanoyloxyalkyl; R 2 is a lower alkyl radical which may be substituted by a fluorine atom; R 3 is hydrogen or a lower alkyl radical optionally substituted by a hydroxy radical or a di (lower alkyl) amino radical; R5 is a lower alkyl radical and R6 is a di (lower alkylamino) lower alkyl radical, or R5 and Rfl together with an adjacent nitrogen atom form a piperazine ring which may be substituted in the 3-position by methyl or phenyl and / or N-substituted methyl, ethyl, acetyl or aminobenzyl; morpholino ring; 1,1-dioksiditiomorfolinorenkaan; A pyrrolidine ring substituted in the 3-position with amino, methylamino, ethylamino, aminomethyl, methylaminomethyl, ethylaminomethyl, methoxy or chlorine and in the 4-position with methyl or methoxy; an imidazole ring which may be substituted in the 4-position by methyl; or a piperidine ring which may be substituted by aminomethyl, hydroxy, amino, methylamino or methoxy; and pharmaceutically acceptable salts of the compounds of formula I, as well as hydrates or solvates or salts thereof, which are useful as active ingredients in antibacterial agents.

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

R 1 is hydrogen or a carboxy protecting radical meaning e.g. lower alkyl (e.g. methyl, ethyl, n-prop-35-yl or t-butyl); or e.g. lower alkanoyloxyalkyl (e.g. acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl and 1-pivaloyloxyethyl).

R 2 is a lower alkyl radical optionally substituted by a fluorine atom, which preferably contains 1 to 4 carbon atoms, and is especially methyl, ethyl, n-propyl, isobutyl, n-butyl or the like.

R 3 is hydrogen or a lower alkyl radical optionally substituted by a hydroxy radical or a di (lower alkyl) amino radical, which preferably contains 1 to 4 jam atoms and is in particular methyl, ethyl, n-propyl, isobutyl, n-butyl or the like. The di (lower alkyl) amino may be, for example, dimethylamino or diethylamino.

R5 is a lower alkyl radical and R6 is a di (lower alkylamino) lower alkyl radical, or R5 and R6 together with an adjacent nitrogen atom form a piperazine ring which may be substituted in the 3-position by methyl or phenyl and / or N-substituted by methyl, ethyl, acetyl or aminobenzyl; morpholino ring; 1,1-dioksiditiomorfolinorenkaan; a pyrrolidine ring substituted at the 3-position with amino, methylamino, ethylamino, aminomethyl, methylaminomethyl, ethylaminomethyl, methoxy or chloro and at the 4-position with methyl or methoxy; an imidazole ring which may be substituted in the 4-position by methyl; or a piperidine-25 ring which may be substituted by aminomethyl, hydroxy, amino, methylamino or methoxy.

Particularly preferred radicals represented by R 5 R 6 N- in formula I are 1-piperazinyl, 4-methyl-1-piperazinyl, 3-methyl-1-piperazinyl, 3-phenyl-1-piperazin-30-yl, 4-ethyl-1- piperazinyl, 4- (4-aminobenzyl) -1-piperazinyl, 4-acetyl-1-piperazinyl, morpholino, 1-dioxide-4-thiomorpholinyl, 4- (aminomethyl) -1-piperidyl, 4-hydroxy-1- piperidyl, 3-amino-1-pyrrolidinyl, 3- (methylamino) -1-pyrrolidinyl, 3- (ethylamino) -1-pyrrolidinyl, 3- (aminomethyl) -1-pyrrolidinyl, 3 - [(methyl 88041 (Amino) methyl] -1-pyrrolidinyl, 3 - [(ethylamino) methyl] -1-pyrrolidinyl, 3-methoxy-1-pyrrolidinyl, 3-chloro-1-pyrrolidinyl, 1-imidazolyl, 4-methyl-1 -imidat-solyl and the like.

Novel 10-substituted-9-fluoro-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid derivatives of the formula I, as well as their pharmaceutically acceptable salts and hydrates or solvates, and salts thereof can be prepared by reacting the above compound of formula III with an amine of general formula HN-R 5 and R 6 (IV) wherein R 5 and R 6 are as defined above. , and then, if necessary, by removing the protecting radical.

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

5 38041 a) x, XjXNO2 ..- pel — X '^ X ^ H2 H5C2OCH = C (COOC2H5b

OH OH

(A) (B)

H5C2OOC H5C2OOC

Y ^ °° = 2H5 ycOOC2H5 L OH-protecting L I IJ svclization ^ χ, 'τΤ - * «-

Ah or '(c) (o) F fvVyc °° c2h5

Χ, Λ1 »^ χ, λΛJ

IE) (F) 0 0 F ^ r ^ V ^ Sr ^ COOC2H5 F ^ i? V ^ S] / COOC2H5 „alkylation γ i deprotection ^ '1 - * 0R' A.p? - "

OR 'NHR "" K

R11 (G) (H) OH NHR2 O I 2 (Va) (Ilia) 6 88041 b)

h5c2 ° OC

., “» Insist ,, Λ, Λ, Τ OH --►

Cc; (J) / Μ- * ° R '' "> N-protection OR 'NH2” - * (E) (F)

O

xJyY PrrtrCOOC2H5.:. ° R 'NHR "* deprotection; :: OR' N-r2 L · (G) * <H): ^ ¢ ^ 1, .., .. ,, Ιιςώ '™'"

0H NHR2 n I

xVr2

R J

(Va) (IIIa) 7 38041 wherein R 2, R 3 and X 'are as defined above; R 'is a protecting radical such as benzyl, methoxybenzyl, methoxymethyl, methoxyethoxymethyl, tetrahydropyranyl, allyl, t-butyl, t-butyldimethylsilyl, acetyl, benzoyl and the like; R "is a protecting radical such as formyl, acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, t-butoxycarbonyl and the like, and R" 'is a hydrogen atom or an ethyl radical.

If the compound of formula IV contains an amino or monoalkylamino substituent, said substituent may, if desired, be protected by an amino protecting radical such as formyl, acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl-butylcarbonyloxyl, phenoxycarbonyl, phenoxycarbonyl, and the like.

The reaction between a compound of formula III and an amine of formula IV or a suitably protected amine may, if necessary, be carried out with or without a solvent, preferably at elevated temperature for a time sufficient for the reaction to proceed to completion. A suitable reaction temperature is in the range of about 30 to 200 ° C, preferably 80 to 150 ° C, to obtain a sufficiently high reaction rate.

The reaction is preferably carried out with an alkali metal hydroxy of an acid acceptor such as triethylamine, pyridine, picoline, N, N-dimethylaniline, 1,8-diazabicyclo [5.5.0] undec-7-ene, 1,4-diazabicyclo [2.2.2] octane in the presence of alkali metal carbonates and the like. Alternatively, an excess of the amine of formula IV can be used as the acid acceptor.

Suitable solvents for this reaction include non-reactive solvents such as acetonitrile, alcohols, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, pyridine, picoline, lutidine. N, N'-dimethylpropylurea 35 and the like. Mixtures of two or more solvents may also be used.

β 38041

If desired, the protecting radical can be removed after the reaction by methods known to those skilled in the art. For example, the formyl radical may be removed by acid or base hydrolysis, preferably by base hydrolysis, and the Bent-5 syloxy radical may be removed by hydrogenolysis.

Examples of intermediates of formula III are the following: 9.10-Difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6- carboxylic acid, 10 ethyl-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6- carboxylate; benzyl 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylate; 9,10-Difluoro-3- (2-fluoroethyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. acid, 9,10-Difluoro-2,3-dimethyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, 20 9,10-Difluoro-2- (hydroxymethyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid , and 9,10-difluoro-2 - [(dimethylamino) methyl] -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4- benzoxadiazine-6-carboxylic acid.

The amine of formula IV used in the above reaction is, for example, piperazine, 4-methylpiperazine-1,3-methylpiperazine, 3-phenylpiperazine, morpholine, thiomorpholine, 4- (aminomethyl) piperidine, 4-aminopiperidine, 4 - (methylamino) piperidine, 4- (benzyloxycarbonylamino) piperidine / 4- (benzyloxycarbonylmethylamino) piperidine, 4-hydroxypiperidine, 4-methoxypiperidine, 3 - [(methylamino) methyl] pyrrolidine, 3 - [(ethylamine) methyl] pyrrolidine, 3-methoxypyrrolidine, 3-aminopyrrolidine, 3- (benzyloxycarbamoyl-amino) pyrrolidine, 3- (methylamino) pyrrolidine, 3- (benzyloxycarbonylmethylamino) pyrrolidine, imidazole, 4-imidazole, 4-methidazole

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 I with an equivalent amount of the desired base or, conversely, reacting a base of formula I with an organic or inorganic acid. with. The reaction is conveniently carried out in a solvent such as water or an organic solvent (e.g. ethanol, 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 a temperature slightly above or below room temperature, for example in the range from 0 to + 50 ° C.

Examples of pharmaceutically acceptable acids that can be used in the above process include hydrogen chloride, hydrogen bromide, sulfur, phosphorus, nitrogen, ant, acetic, propionic, succinic, glycolic, lactic, malic, , wine, lemon, ascorbic, maleic, hydroxymalein, phenylacetic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, aminosalicylic , nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, gluconic, glucuronic, galacturonic, aspartic and glutamic acids; methionine, tryptophan, lysine and arginine and the like.

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 of the compounds of formula I may be prepared by reacting a compound of formula I with a metal base or amine such as alkali and alkaline earth metal hydroxide or 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-dibenzylethylenedi-5-amine, 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 hydrated forms. Hydration can be achieved automatically during the manufacturing process or can be done stepwise 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 this invention have centers of asymmetry. The pure D-isomer, the pure L-isomer, and mixtures thereof, including racemic mixtures, are also included in this invention.

The compounds of formula I, their salts, hydrates and solvates have a broad antibacterial activity against gram-positive and gram-negative organisms as well as Mycoplasma and can be used for infectious diseases. :. 30 for the treatment and prevention of diseases. The in vitro and in vivo antibacterial activities of these compounds are shown below: li 88 0 41 1. In vitro antibacterial activities of representative pyrido [3,2,1, -ij] -1,3,4-benzoxadiazine derivatives of formula I, the in vitro antibacterial activities of their salts, hydrates and solvates were studied by a standard agar dilution method [see Chemotherapy, 22 (1974), 1126]. Their minimum inhibitor concentrations (MIC; in pg / ml) are shown in Table 1 and Table 2. The compounds used herein were prepared in the corresponding examples, as mentioned below.

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Table 2

Anaerobic Antibacterial spectrum of microorganisms MIC (pg / ml) 5 _Compound of Example 5

Bacteroides fragilis ATCC 23745 0.78

Bacteroen fragilis NR 2579 3.13

Bacteroides fragilis NR 2582 0.78

Bacteroides fragilis NR 2583 0.39 10 Bacteroides fragilis NR 2584 0.78

Bacteroides distasonis NR 2578 0.78

Bacteroides thetaiotaomicron NR 2588 1.56

Bifidobacterium adolescentis ATCC 15703 0.39

Clostridium botulinum NR 2611 0.10 Clostridium perfringens NR 2612 0.39

Clostridium moniliforme ATCC 25546 0.78

Fusobacterium varium ATCC 8501 12.5

Peptococcus prevotii ATCC 9321 1.56

Peptococcus variabilis ATCC 14955 0.78 20 Peptostreptococcus anaerobius NR 2743 0.39

Propionibacterium acnes ATCC 11828 0.78

Mycoplasma

Mycoplasma hominis NR 2952 0.10: 25 _

In Vivo - Therapeutic Effect The antibacterial activities of the pyrido [3,2,1-ij] -1,3,4-benzoxadiazine derivatives prepared according to Example 5 below were studied in vivo against Escherichia coli ML4707, Pseudomonas aeruginosa 4au542 and Streptococcus. against a fatal infection caused by pneumoniae 6-001.

ICR mice weighing approximately 20 g were infected by intraperitoneal injection of 35 with the corresponding bacterial 88041 suspension. Test compounds were administered orally over 5 days. The corresponding 50% effective dose (Εϋ ^ 0 / mg / kg) to protect 50% of the animals from infection death is shown in Table 3.

5

Table 3

Antibacterial activities against in vivo systemic infection in mice (ED50, mg / kg) 10 Bacteria

Escherichia Pseudomonas Streptococcus Compound coli ML4707 aeruginosa pneumoniae _4au542_6-100_ s.c. pop. o._p.o._ 15 Example 5 0.06 0.11 13.4 10.3 3. Acute toxicity The corresponding LD50 values of the 20 compounds obtained in Examples 5, 6, 7, 13 and 14 below are greater than 2,000 mg / kg. The acute toxicity of these compounds was studied by oral administration to ICR mice.

The compounds of formula I, their salts, hydrates and solvates have a broad antimicrobial spectrum of 25 gram-positive and gram-negative bacteria and

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

·. In addition, the compounds of the formula I, their salts, hydrates and solvates 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 those of synthetic anti-35 bacterial agents, which are commercially available. 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 10, Bifidobacterium, Clostridium, Eubacterium, Peptococcus, Peptococcus, Peptococcus , Escherichia, Citrobacter, Campylobacter, Enterobacter, Klebsiella, Proteus, Pseudomonas, Serratia, Salmonella, Shigella, Vibrio, Aeromonas, Haemophilus, Neisseria, Acinetobacter, Alcali-15 genes, Bordetella, Bacteroides, Fusobacterium, Mycoplasma and others

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, hydrates and solvates are used alone or in compositions with excipients, binders, lubricants, humectants, etc., for example in the form of general pharmaceutical compositions such as tablets, granules, sugar-coated tablets, powders, capsules, gels. , in the form of dry syrup, syrup, ampoules, suspension, liquid, emulsion, ointment, paste, cream, suppositories and the like.

In addition, solubilizers, absorption accelerators, surfactants and the like, as well as other formulation additives, i.e., any pharmaceutically acceptable form, may be used.

i6 88 0 41

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 medical composition. pai noon.

A medical composition comprising a compound of formula I, a salt, hydrate or solvate 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 compound of formula I to a 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-benzoxazine derivatives) are known, for example, from EP-20 47 005. However, the compounds of formula I differ significantly from these compounds in that , that they have two adjacent nitrogen atoms in the fused ring to form pyrido [3,2,1-ij] -1,4-benzoxadiazines. As shown above, these compounds have excellent and extensive antibacterial activity against gram-positive and gram-negative bacteria as well as Mycoplasma.

The following examples illustrate the preparation of intermediates of formula III and their use.

30 Preparation of starting material

Reference Example

Preparation of diethyl N- (3,4-difluoro-2-hydroxyphenyl) aminomethylenemalonate a) A solution of 2,3-difluoro-6-nitrophenone 35 (500 mg) in methanol (7 ml) was hydrogenated with 5% Pd / C (60 mg) 17 8 SO 41 for 6 hours. The reaction mixture was filtered under a stream of nitrogen and the filtrate was evaporated to give 414 mg of crude 2-amino-5,6-difluorophenol.

b) A mixture of the amine obtained above (414 mg) and diethyl ethoxymethylmethylene malonate (618 g) was heated at 130 ° C under nitrogen for 5 minutes. The resulting solid 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 10 m / z 315 (MH +). The mother liquor was subjected to silica gel column chromatography using CHCl 3 / acetone (20: 1) as an eluent to give an additional 59 mg of crystals.

Ethyl 8-benzyloxy-6,7-difluoro-4-hydroxy-3-quinolinecarboxylate (Method 1) 15 c) To a mixture of diethyl N- (3,4-difluoro-2-hydroxyphenyl) aminomethylene 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 dichloromethane 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) aminomethylene malonate (90 mg), mp 87 ° C, MS m / z 405 (M +). .

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 successively with benzene, dichloromethane and dichloromethane / acetone (30: 1). The pure fractions were combined and the solvent 35 was removed under reduced pressure to give a crystalline residue 88,041 nös. 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 δ (M +); 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 dime-10 style formamide (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-quinolinecarboxylate; mp.

200-201 ° C? MS m / z 359 (M &lt; + &gt;); after recrystallization from 20 methanol.

Preparation of ethyl 8-benzyloxy-6,7-difluoro-1- (formylmethylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylate e) When ethyl 8-benzyloxy-6,7-difluoro A mixture of 4-hydroxy-25-oxy-3-quinolinecarboxylate (410 mg) and anhydrous potassium carbonate (315 mg) in dry dimethylformamide (10 mg) was stirred at room temperature for 3 hours, O- (2,4-dinitrophenyl) hydroxylamine ( 260 mg). 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-benzyloxy-6,7-difluoro-4-oxo-1,4-35 dihydro-3-quinolinecarboxylate.

I »88041

Analytical sample; mp. 143-144 ° C; MS m / z 374 (M &lt; + &gt;); was prepared by recrystallization from methanol.

f) 90% formic acid (0.60 ml) was added to acetic anhydride (1.51 ml) at 0 ° C. The mixture was stirred at 50 ° 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 (2.1 ml). The mixture was stirred at room temperature for 2 days. The reaction mixture was evaporated under reduced pressure 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-3-quino- liinikarboksylaattia; 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. The residue was crystallized from 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;).

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- kinoliinikarboksylaat-thia; mp. 221-225 ° C (dec.); MS m / z 326 (M &lt; + &gt;).

1) A mixture of the ester obtained above (210 mg) and 0.5 N sodium hydroxide (5.2 ml) was heated at 100 ° C for 2 hours to 5 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.

10 Analytical sample; mp. 248-250 ° C (dec.); MS m / z 270 (M &lt; + &gt;); was prepared by recrystallization from ethanol.

Example 1 9,10-Difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid 15 Meat production

In Reference Example i), 6,7-difluoro-8-hydroxy-1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (105 mg), paraformaldehyde (150 mg) and a mixture of dry dioxane (5 ml) was heated at 100 ° C for 3 hours under reduced pressure under a nitrogen atmosphere. After removal of the solvent under reduced pressure, dimethylformamide (20 ml) was added to the residue, and the mixture was stirred for 20 minutes and then filtered. The filter cake was washed with dimethylformamide and the combined filtrate was evaporated under reduced pressure. The residue was triturated with water and filtered to give 97 mg of 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-1j] -1, 3,4-Bonoxoxate azyl-6-carboxylic acid.

Analytical sample; mp. 290-292 ° C (dec.); MS m / z 30,282 (M &lt; + &gt;); was prepared by recrystallization from dimethylformamide.

21 3 3041

Example 2 9,10-Difluoro-2,3-dimethyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid Preparation 5 The 6,7-difluoro-8-hydroxy-1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (50 mg) obtained in Reference Example i) was obtained in 90% strength. a mixture of acetaldehyde (1 ml) and dioxane (5 ml) was heated at 100 ° C for 3 hours under a nitrogen atmosphere. The reaction mixture was evaporated under reduced pressure to give 52 mg of 9,10-difluoro-2,3-dimethyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3, 4-bentsoksadiat-oxazin-6-carboxylic acid; mp. 285-289 ° C; MS m / z 296 (M &lt; + &gt;).

Example 3 9,10-Difluoro-2- (hydroxymethyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadi- preparation of azine-6-carboxylic acid

6,7-Difluoro-8-hydroxy-1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (50 mg), glycolaldehyde diethyl acetal (45 μΐ) obtained in Reference Example i) and a suspension of pyridine p-toluenesulfonate (7 mg) in dry dioxane (2 mL) was heated at 110 ° C for 5 hours under a nitrogen atmosphere. After the solvent was removed under reduced pressure, the crystalline residue was washed with water and methanol to give 52 mg of 9,10-difluoro-2- (hydroxymethyl) -3-methyl-7-oxo-2,3-dihydro-7H- pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid; mp. 254-258 ° C (dec.); MS m / z 312 (M &lt; + &gt;).

Example 4 9,10-Difluoro-2 - [(dimethylamino) methyl] -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3 Preparation of 4-benzoxaziazine-6-carboxylic acid p-toluenesulfonate

In Reference Example i), 6,7-difluoro-8-hydroxy-3S-1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (50 mg), dimethylaminoacetaldehyde dimethyl a suspension of acetal (37 mg) and p-toluenesulfonic acid monohydrate (53 mg) in dry dioxane (2 ml) was heated at 110 ° C for 17 hours under a nitrogen atmosphere. After removal of the solvent under reduced pressure, the residue was recrystallized from methanol to give 61 mg of 9,10-difluoro-2-t (dimethylamino) methyl] -3-methyl-7-oxo-2,3-dihydro-7H- pyrido [3,2,1-ij] -1,3,4-bentsoksadiatsiini-6-carboxylic acid-p-toluenesulfonate; mp. 232-236 ° C (dec.); FAB-MS m / z 340 (MH &lt; + &gt;).

Example 5 (Use Example) 9-Fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1, Preparation of 3,4-benzo-oxadiazine-6-carboxylic acid 15,10-Difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] obtained in Example 1 A mixture of -1,3,4-benzoxadiazine-6-carboxylic acid (30 mg), N-methylpiperazine (47 μl) and dry pyridine (3 ml) was heated at 100-110 ° C for 9 hours under a nitrogen atmosphere. The pyridine was removed under reduced pressure and the residue was recrystallized from methanol to give 23 mg of 9-fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [ 3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid; mp. 268-269 ° C (dec.); MS m / z 362 (M &lt; + &gt;).

The following compounds were obtained in an analogous manner to Example 5 (Use Examples): 23 8 8 0 41 o

C02H

R5R6N

5 ON

X CH3

Ex. R5R6-N Melting point MS-M / z No. ° C crystallization solvent - / - ---- ---- 6 HN N- 240 ™ 245 MeOH 349 (MH +) (* 'f (dec. ) 7 HN7 ^ N-237λ / 239 MeOH / CHCl3 362 (M *) 15 CH3 "^ ^ (dec.) / - \ 8 HN N-256 ^ 259 DMF 425 (MH +) (*

Ph 2+ (dec.) 20 9 0 ^ ^ N-> 300 EtOH / CHCl 3 349 (M *) 10 ^ N-> 300 (dec.) DMF 365 (M *) 11 H 2 N 2 O 3 <v> 242 MeOH 377 (MH *) 1 * (dec.) 12 HO- (N 256 ^ 258 MeOH / CHCl 3 363 (M *) 30 _ H N 13 CH 3 N f 242 λ / 244 DMF 377 (MH +) (* (dec.) ( continued ...) 24 88041

Eg R5R6-N Melting point MS-m / z No. ° C crystallization solvent δ H N- 14 02ΗΗΝ - ^ 251a; 252 EtOH 391 (MH1) (1 - (dec.) H N - 14α AcNv4 - / 239a; 241 EtOH 405 (MH1) (110 (dec.) CH3 CH3 15 266 η; 268 EtOH 365 (MH1) CH3 (dec.) 15 16 284 a; 286 DMF 350 (MH1) HO ^ f (ha j.) CH3-r = rr ^ 17 N- 280 ^ 284 MeOH / CHCl3 / Et2 O 20 N: == - / (dec.) ) 345 (MH1) (1

FAB-MS

The following compounds were prepared from the compounds described in Examples 2, 3 and 4 in a manner analogous to that used in Example 5 (Examples of Use): 25 8 8 041 ofc ° 2li 5 R5R6N n O N_ V CH3 R3 10 Eg R5R6-N Melting point MS m / z no R 3 ° C crystallization solvent 18 HN 2 N-CH 3 240242 MeOH 362 (M *) 15 N / (dec.) 19 CH 3 Cl 2 CH 3 203 / v 2 O 6 EtOH 376 (MH +) 1 * 20 20 CH 3 N N-CH 2 OH 229 ^ 231 MeOH 393 (MH +) (* 'f (dec.) / \ 21 CH 3 N N-210 / V212 MeOH 420 (MH +) (N 1 CH 2 N (CH 3) 2 25 _

*) FAB-MS

Example 22 (Use Example) 10- [3- (Benzyloxycarbonylamino) -1-pyrrolidin-30-yl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1- Preparation of] -1,3,4-benzoxadiazine-6-carboxylic acid

The 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazin-35-n-6 obtained in Example 1 A mixture of carboxylic acid (28 mg), 3- (benzyloxycarbonyl-26,88041 amino) pyrrolidine (94 mg) and dry pyridine (3 ml) was heated at 100 ° C for 3 hours under a nitrogen atmosphere. The pyridine was removed under reduced pressure and the residue was recrystallized from methanol to give 36 mg of 10-5 [3- (benzyloxycarbonylamino) -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H- pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid; mp. 227-230 ° C; MS m / z 482 (M &lt; + &gt;).

Example 23 (Use Example) 109-Fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] - Preparation of 1,3,4-benzooxadiazine-6-carboxylic acid via the fluoroborane intermediate a) The 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido obtained in Example 1 [3, A mixture of 2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid (100 mg) and 60% aqueous fluoroboric acid (1 ml) was heated at 90 ° C for 12 hours. After cooling the reaction mixture to room temperature, the precipitate was collected by filtration, washed with methanol and dried under reduced pressure to give 110 mg of crude 9,10-difluoro-6 - {[(difluoroboryl) oxy] carbonyl} -3-methyl-2,3 dihydro-7H-pyrido [3,2, l-ij] -l, 3,4-benz-oxadiazin-7-one; FAB-MS m / z 331 (MH &lt; + &gt;).

b) To a stirred solution of the borane intermediate (33 mg) obtained above in dimethyl sulfoxide (1 ml) was added N-methylpiperazine (15 μΐ) and triethylamine (20 μΐ). After stirring at room temperature for 3 hours, the mixture was lyophilized. The residue was crystallized from methanol to give 28 mg of 6 - {[(difluoroboryl) oxy] carbonyl} -9-30 fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -2,3-dihydro-7H -pyrido [3,2,1-ij] -1,3,4-benzoxadiazin-7-one as yellow crystals; mp. 228-230 ° C (dec.); FAB-MS m / z 411 (MH &lt; + &gt;).

c) To a solution of the borane intermediate (5 mg) obtained above in 95% ethanol (1 ml) was added triethyl-27 88 0 41 amine (3 μΐ). After refluxing for 4 hours, the reaction mixture was cooled to room temperature. The separated precipitate was collected by filtration to give 9-fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-5 pyrido [3,2,1 ij] -1,3,4-bentsoksadiatsiini-6-carboxylic acid; mp. 268-269 ° C (dec.).

Example 24 9-Fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4 Preparation of benzo-10-oxadiazine-6-carboxylic acid via acetoxyborane intermediate a) 9,10-Difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] obtained in Example 1 A mixture of -1,3,4-benzoxadiazine-6-carboxylic acid (100 mg), acetic anhydride (115 ml) and triacetoxyborane (100 mg) was heated at 140 ° C for 15 minutes. The reaction mixture was evaporated under reduced pressure. The residue was triturated with acetone and filtered to give 138 mg of 6 - {[(diacetoxyboryl] oxy] carbonyl} -9,10-difluoro-3-methyl-2,3-dihydro-7H-pyrido [3,2,1- ij] -1,3,4-benzoxadiazin-7-one, FAB-MS m / z 411 (MH +).

b) To a solution of the borane intermediate (41 mg) obtained above in dimethyl sulfoxide (1 ml) was added N-methylliperazine (15 μΐ) and triethylamine (20 μΐ). After the mixture was stirred at room temperature for 2 hours, the reaction mixture was lyophilized. The residue was crystallized from methanol / ether to give 34 mg of 6 - {[(diacetoxyboryloxy) carbonyl} -9-fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -2,3-dihydro -7H-pyrido [3,2,1-ij] -1,3,4-benzoxadia-30-syn-7-one as yellow crystals, mp 156-157 ° C (dec.), FAB-MS m / z 491 (MH +).

c) The borane intermediate obtained above (5 mg) was suspended in acetone (0.1 ml) and concentrated HCl (2.5 μΐ) was added. The reaction mixture was stirred at room temperature for 35 minutes and cooled in an ice bath. The separated precipitate was collected by filtration and the precipitate was dissolved in 95% ethanol (0.1 ml). Triethylamine (2 μΐ) was added to the solution, and the mixture was refluxed for 1 hour. After cooling the solution to room temperature, the separated precipitate was collected by filtration to give 9-fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3 2, l-ij] -l, 3,4-bentsoksadiatsiini-6-carboxylic acid; mp. 268-269 ° C (dec.).

Examples 25 and 26 (Use Examples) The following compounds were obtained starting from the compound obtained in Example 1 using a method analogous to the methods of Example 5 or Example 22.

0

15 ° C

of

0 N

^ CH-j 20

Eg r5R6-N Melting point Recry- MS m / z No. ° C crystallization- ___solvent_ch30, 25 * # · ι— \ 25 N- 221-230 EtOH / 379 (MH +) H2N2 ^ (dec.) Hexane CH, 3 30 * '| - \ 26 N- 240 - 241 MeOH 363 (MH +) H2N · ^ - /

Claims (2)

1. Pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid derivatives useful as intermediates of the formula 0 F COOR1 ITT (III) which X 'is a halogen atom; R 1 is hydrogen or a carboxy group protecting radical which is a lower alkyl, benzyl or a lower alkanoyloxyalkyl; R 2 is a lower alkyl radical which may be substituted by fluorine, and R 3 is hydrogen or optionally with a hydroxy radical or a dl (lower alkyl) amino radical substituted lower alkyl radical, wherein the amino, hydroxy and / or carboxy groups present can be protected. A compound according to claim 1 which is 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4- Benzoxadiazine-6-carboxylic acid. in