DK173330B1 - Pyrido (3,2,1-ij) -1,3,4-benzoxadiazine derivatives, a process for their preparation, these compounds for use - Google Patents

Description

in DK 173330 B1

The present invention relates to novel pyrene; do [3,2,1-ij] -1,3,4-benzoxadiazine derivatives, a process for the preparation thereof, these compounds for use as pharmaceutically active substances, in particular for the treatment of prophylaxis of infectious diseases, use of compounds for the manufacture of medicaments for the treatment and prophylaxis of infectious diseases, pharmaceutical compositions containing them and intermediates useful in the method.

European Patent Application No. 0 047 005, Finnish Publication No. 76345, Japanese Patent Application No. 57-88182 and Japanese Patent Application No. 57-203085 disclose pyrido [1,2,3-th] [1,4] benzoxazine derivatives having antibacterial activity.

The present invention relates to pyrido [1,2,3-ij] -1,3,4-benzoxadiazine derivatives which include, inter alia. differs from the known compounds in that the compounds of the invention have a broad spectrum antibacterial effect and are therefore useful in compositions for the treatment or prophylaxis of infectious diseases.

In particular, the present invention relates to novel pyrido [3,2,1-ij] -1,3,4-benzoxadiazine derivatives according to claim 1, which are useful as active ingredients in antibacterial agents.

The various radicals of formula I, which radicals are defined above, can be described in more detail as follows; 25 references to the term "lower" shall denote a carbon chain, preferably containing up to a total of 7 carbon atoms, unless otherwise indicated.

R is as defined in claim 1.

Particularly preferred radicals represented by R in formula 30 (I) are 1-piperazinyl, 4-methyl-1-piperazinyl, 4- (4-aminobenzyl) -1-piperazinyl, 4-acetyl-1-piperazinyl, morpholino, 4 - (methoxy-1-piperidyl, 4-hydroxy-1-piperidyl, 3-amino-1-2 B1 pyrrolidinyl, 3- (aminomethyl) -1-pyrrolidinyl, 3 - [(methylamino) methyl] -1 -pyrrolidinyl, 3 - [(ethylamino) methyl] -1-pyrrolidinyl, 3-methoxy-1-pyrrolidinyl, 3-chloro-1-pyrrolidinyl, 1-imidazolyl, 4-methyl-1-imidazolyl and the like.

The novel pyrido [3,2,1-ij] -1,3,4-benzoxadiazine derivatives of formula (I) and their pharmaceutically acceptable salts and hydrates or solvates thereof and of these salts are prepared according to the present invention. The present invention by a method which is characterized by the features defined in claim 14.

Process A:

As mentioned above, the desired compounds can be obtained by a compound of the general formula

ISLAND

(out - CH where X 'is a halogen atom and carboxy groups present are optionally protected are reacted with an amine of the general formula R where R is as defined above, if necessary followed by removal of a protective radical.

In process A, the compound of formula (III) used as the starting compound is a novel compound, and this can be prepared, for example, in accordance with reaction scheme a) or b) below.

DK 3 DK 173330 B1 a) reduction H5C2OCH-C (COOC2H5) 2 χ · ^ Υ ^ νο2 - * χ, / / ^ «« 2 -L · * ->

OH OH

(A) (B) H5C2OOC. H5C2OOC.

XV ^ ti \ ^ οοο2 * 5 VCO ° C2H5 x, JULmJ OH protection ^^ J J cycling

OH H OR 'H

(C) (D)

XwVC00C2H5 x- ^ vVcooc2H5 Χ.ΛΛν ^> x, XINI _ ^ - ^ sk_ytteIse> OR 'Or · Ah2 (E) (F) * WVCOOC2H5 Χννν ° 00 (: 2Η5 alkylation deprotection TI -► Ir · i r2 --- *

OR 'NHR "w" "R

R "(G) (Η) χύτ” - · "OH nhr? O i.

A> '(Va) (Illa) 4 DK 173330 B1 b) h5c2ooc cooc h oh Χίχ Y xrry 2H5 cyclization OH protection (C) (J)

<? H O

X ^ i.COOC2H5 Xv ^ A ^ COOCjHs bonding N-phase ratio

Ar · Ar 'nh2 (E) <F) xvVyCOOC2H5 x ^ A-COOC2H5 alkylation JLm> deprotected.1 see _ xy, -> x' ^ y ^ y -> OR * NHR "Ar · lu2 Å" '(G) (H) xwVC00Rm "Y ^ cyclization ΑηΙηε? ^> Vr2 '

R4 RJ

(Va) (IIla). DK 173330 B1 where X 'is 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 protected 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 .

Thus, the invention also relates to intermediates of formula 10 III, as defined in claim 10.

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

The reaction between the compound of formula (III) and the amine of formula (IV) or the appropriately protected amine may, if desired, be carried out with or without a solvent, preferably at elevated temperature for a sufficient period of time to allow the reaction in the substantially accomplished.

The appropriate reaction temperature is in the range of approx. 30 ° C to approx. 200 ° C, preferably 80 ° C to 150 ° C, to achieve a sufficiently fast reaction rate.

The reaction is preferably carried out in the presence of an acid acceptor such as triethylamine, pyridine, picoline, N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,4-diazabicyclo [2.2. 2] octane, alkali metal hydroxides, alkali metal carbonates and the like. Alternatively, an excess of the amine of formula (IV) may be used as the acid acceptor.

Suitable solvents for this reaction are non-reactive solvents such as acetonitrile, alcohols, dimethylsulfoxide, dimethylformamide, dimethylacetamide, pyridine, picoline, lutidine, N, N'-dimethylpropylene urea and the like. Mixtures of two or more solvents may also be used.

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

The starting materials of formula (III) can be exemplified as follows: 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] - 1,3,4 -benzoxadiazin-6-carboxylic acid.

ethyl 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-yl] -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 and the like.

The amine of formula (IV) used in the above reaction is, for example, piperazine, 4-methylpiperazine, 4-hydroxypiperidine, 4-methoxypiperidine, 3 - [(methylamino) methyl] pyrrolidine, 3- [(ethylamino) ) methyl] pyrrolidine, 3-methoxypyrrolidine, 3-aminopyrrolidine, 3- (benzyloxycarbonylamino) pyrrolidine, imidazole or 4-methylimidazole.

? DK 173330 B1

Method B:

The desired compound can be obtained by reacting a compound of the general formula X R1 6 (V) R "N ^ TI 2 I OH NHR ^ ft5 wherein amino, hydroxy and / or carboxy groups 5 may be protected with formaldehyde or paraformaldehyde and if desired, followed by removal of a protective radical.

In process B, the compound of formula V as a starting compound is a novel compound and this compound can be prepared in accordance with the above reaction scheme a) or b), or by reacting a compound (H) or (Va) with an amine with formula (IV).

Thus, the invention also relates to intermediates of formula V, as defined in claim II.

The reaction may, if desired, be carried out in a solvent such as dioxane, tetrahydrofuran, acetonitrile, chloroform, dimethylformamide, dimethylsulfoxide, N, N'-dimethylpropylene urea, acetic acid and the like. Mixing of two or more solvents may also be used.

The reaction can be carried out, if necessary, in the presence of an acid catalyst such as acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, pyridinium p-toluenesulfonate, iron (III) chloride, zinc chloride, chlorotrimethylsilane, Nafion-H (perf resin sulfonic acid: Aldrich Chemical 3 DK 173330 B1

Co., Inc.), Amberlyst-15 (Highly Acid Macroretic Resin: Aldrich Chemical Co., Inc.) and the like.

The reaction temperature can be varied within a relatively wide range. Generally, the reaction is carried out at a temperature of between 20 ° C and 150 ° C.

In a preferred aspect of the method provided by the present invention, approx. 1 mole or molar excess of formaldehyde, respectively. paraformaldehyde.

The amino or monoalkylamino protecting radical may, if desired, be removed after the reaction by methods known to those skilled in the art. For example, the formyl radical can be removed by acid or base hydrolysis, preferably base hydrolysis, and the benzyloxy-carbonyl radical can be removed by hydrogenolysis.

The starting materials of formula (V) can be exemplified as follows: 6,7-difluoro-Θ-hydroxy-1- (methylamino) -4-oxo-1,4-dihydro-3-quinoline carboxylic acid, ethyl 6,7-difluoro 8-hydroxy-1- (methylamino) -4-oxo-1,4-dihydro-3-quinoline carboxylate, in benzyl-6,7-difluoro-8-hydroxy-1- (methylamino) -4-oxo 1,4-dihydro-3-quinoline carboxylate, 6-fluoro-8-hydroxy-7- (1-imidazolyl) -1- (methylamino) -4-oxo-1,4-di hydro-3-quinoline carboxylic acid, 25 ethyl 6-fluoro-8-hydroxy-7- (1-imidazolyl) -1- (methylamino) -4-oxo-1,4-dihydro-3-quinoline carboxylate, benzyl-6-fluoro-8-hydroxy-7- (1-imidazolyl) -1- (methylamino) -4-oxo-1,4-dihydro-3-quinoline carboxylate, 6-fluoro-8-hydroxy-1- (methylamino) -7- (4-methyl) -1-piperazinyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, 7- [3- [(benzyloxycarbonylethylamino) methyl] -1-pyrrolidinyl] -6-fluoro-8-hydroxy-1- ( methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid 7- [3- (benzyloxycarbonylamino) -1-pyrrolidinyl] -6-fluoro-8-hydroxy-1- (methylamino) -4-oxo-1,4-dihydr o-3-quinolinecarboxylic acid, 7- [3 - [(benzyloxycarbonylmethylamino) methyl] -4-methyl-1-pyrrolidinyl] -6-fluoro-8-hydroxy-1- (methylamino) -4-oxo- 1,4-dihydro-3-quinoline carboxylic acid, 7- [3 - [(benzyloxycarbonylamino) methyl] -4-chloro-1-pyrrolidinyl] -6-fluoro-8-hydroxy-1- (methylamino) -4-oxo -1,4-dihydro-3-quinoline carboxylic acid and the like.

Process C: When it is desired to prepare compounds of formula I wherein R represents «70 ί v N -N N- (VIII) \ _ / the desired compound may be prepared by the corresponding N-unsubstituted compound of formula I, is reacted with an acetylating agent, for example acetic anhydride as described in Example 50.

Process D: When it is desired to prepare a compound of formula I wherein R is the group = 25, these compounds can be prepared by lower alkylation of the corresponding non-alkylated compound. The O-alkylation may be carried out by reaction with a compound of the general formula ch3-y where Y is a leaving group.

For example, as leaving group Y are halogen atoms such as chlorine, bromine, iodine, acyloxy radicals such as acetoxy, lower alkanesulfonyloxy radicals such as methanesulfonyloxy, arylulfonyloxy acid radicals such as p-toluenesulfonyloxy; optionally nitrated phenoxy radicals such as phenoxy, 4-nitrophenoxy; or succinimidooxy or phthalimidooxy.

The reaction may be carried out, if desired, in a solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, N, N'-dimethylpropylene urea, dioxane, tetrahydrofuran, pyridine and the like. Mixtures of two or more solvents may also be used.

The reaction is preferably carried out in the presence of an acid acceptor such as triethylamine, pyridine, N, N-dimethylaniline, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] undec-7 ones, sodium hydride , alkali metal hydroxides, alkali metal carbonates] and the like.

The reaction temperature can be varied within a relatively wide range. Generally, the reaction is carried out at a temperature of between ca. 0 ° C to 180 ° C, preferably between 0 ° C and 110 ° C.

In carrying out the process provided in accordance with the present invention, 1 to 4 moles, preferably 1 to 2 moles of methylating agent, based on one mole of the 3-hydroxy-1-piperidyl compound, are used.

The methylating agent may be, for example, iodomethane.

A proton acceptor such as an alkali metal hydride, e.g. sodium hydride, is conveniently added.

X1 DK 173330 B1

Process F: When it is desired to prepare a compound of formula I with a free amino group, these compounds may be prepared from the corresponding compounds of formula I with this group in protected form.

Amino protecting groups are e.g. lower alkanoyl such as acetyl; benzoyl; an alkoxycarbonyl group, for example t-butoxycarbonyl or ethoxycarbonyl; a substituted alkoxycarbonyl group, e.g. trichloroethoxycarbonyl; phenoxycarbonyl; benzyloxycarbonyl; P-nitrobenzyloxycarbonyl; an aralkyl group such as trityl or benzhydryl; or a halo-alkanoyl group such as trifluoroacetyl.

The amino protecting groups can be cleaved by acid hydrolysis (e.g., the t-butoxycarbonyl or trityl group) or by basic hydrolysis (e.g., the trifluoroacetyl group). Benzyloxycarbonyl and p-nitrobenzyloxycarbonyl are removed by hydrogenolysis.

Amino-protecting groups which can be cleaved by acid hydrolysis are preferably removed by a lower alkanecarboxylic acid which can be halogenated. In particular, formic acid or trifluoroacetic acid is used. The acid hydrolysis is usually carried out at room temperature, although it can be carried out at a slightly elevated or slightly lowered temperature (e.g., a temperature in the range of from ca.

0 ° C to + 40 ° C). Protective groups which can be cleaved under basic conditions are normally hydrolyzed with dilute aqueous caustic alkali at 0 ° C to 30 ° C.

Process G: When it is desired to prepare a compound of formula I wherein R 1 is -O DK 173330 B1, this compound can be prepared by halogenating the corresponding hydroxy-substituted compound)

The halogenating agent is preferably a thionyl halide, especially thionyl chloride; or phosphorous trichloride, phosphorous oxychloride or phosphorous pentachloride. The reaction temperature is preferably between about 0 ° C and 80 ° C. Carboxy groups present are preferably protected, e.g. benzylated and then released again if desired, e.g. by hydrogenation (benzyl removal).

Process H: When it is desired to prepare a compound of formula I wherein R is

'V-Q ^ -O

For example, this compound can be prepared by reducing the nitro groups of a corresponding nitro-substituted compound of formula I. The reduction can be carried out by hydrogenation in the presence of a precious metal catalyst such as palladium on coal. The reaction is conveniently carried out in water or a lower alkanol, e.g. methanol or ethanol, if desired in admixture with other solvents soluble therein. The reaction temperature is usually between ca. 10 ° C and approx. 40 ° C, preferably at approx. room temperature.

Method K:

Preparation of the pharmaceutically acceptable salts of the compounds of formula I or the hydrates or solvates of the 25 salts can be carried out in known manner per se; for example, by reacting a carboxylic acid of formula I with an equivalent amount of the desired base or vice versa, reacting a free base of formula I with an organic or inorganic acid. The reaction: is conveniently carried out in a solvent such as water 30 or an organic solvent (e.g. ethanol, methanol, acetone and the like). The temperature at which the salt formation is carried out is not critical. Salt formation is generally carried out at room temperature, but it can be carried out at a temperature slightly higher or lower than room temperature, for example in the range of 0 ° C to + 50 ° C.

Examples of pharmaceutically acceptable acids useful in the above process are salt, bromine, sulfur, phosphorus, nitric, ant, vinegar, propion, succin, glycol, milk, apple, , wine, lemon, ascorbic, maleic, hydroxymalein, phenylacetic, benzo, 4-aminobenzo-10, anthraniline, 4-hydroxybenzo, salicyl, aminosalicyl, nicotine, methanesulfone, ethanolphone -, hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, gluconic, glucuronic, galacturonic, aspartic and glutamic acid; methionine, tryptophan, lysine, arginine and the like.

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

The base salts of the compounds of the general formula (I) can be prepared by reacting a compound of the general formula (I) with a metal base or amine such as an alkali or alkaline earth metal hydroxide, or an organic amine. Examples of the metals used as cations are sodium, potassium, magnesium, calcium and the like. Examples of amines are diethanolamine, dibenzylethylenediamine, choline, ethylenediamine and the like.

The acid addition salts or base salts of the compounds of the general formula (I) differ from the corresponding free form by certain physical properties such as solubility in water.

The compounds of general formula (I) and their pharmaceutically acceptable salts may exist in undissolved as well as 30 dissolved forms, including hydrated forms. The hydration may be carried out automatically during the manufacturing process or may occur gradually as a result of the hygroscopic properties of an initially anhydrous product. For the controlled production of a hydrate, a completely or partially anhydrous product can be exposed to a humid atmosphere (e.g. at about + 10 ° C to + 40 ° C). Solvates with pharmaceutically acceptable solvents such as ethanol can be obtained under e.g. crystallization.

Certain compounds provided by the present invention have asymmetric centers. The pure D isomer, pure L isomer as well as mixtures thereof, including racemic mixtures, are also to be considered as encompassed by the present invention.

The compounds provided by the present invention exhibit a broad antibacterial activity against Gram-positive and Gram-negative organisms and Mycoplasma and can be used as agents for the treatment and prophylaxis of infectious diseases. In vitro and in vivo antibacterial activities of the compounds of the present invention are shown as follows: 1. In vitro antibacterial activities

The in vitro antibacterial activities of the representative pyrido [3,2,1-ij] -1,3,4-benzoxadiazine derivatives according to the? The present invention was tested by the standard agar-thinning method [see: Chemotherapy, 22, 1126 (1974)]. Their minimum inhibitory concentrations (MIC, in μg / ml) are shown in Table 1 and Table 2. The compounds used here were prepared by the respective examples as mentioned below.

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Antibacterial spectrum MIC (/ zg / ml) Compound (Example No.) 5 Anaerobic microorganisms 5

Bacteroides fragilis ATCC 23745 0.78 0.20

Bacteroides fragilis NR 2579 3.13 1.56 Bacteroides fragilis NR 2582 0.78 0.39

Bacteroides fragilis NR 2583 0.39 0.10

Bacteroides fragilis NR 2584 0.78 0.78

Bacteroides distasonis NR 2578 0.78 0.78

Bacteroides thetaiotaomicron NR 2588 1.56 0.78

Bifidobacterium adolescentis ATCC 15703 0.39 0.10

Clostridium botulinum NR 2611 0.10 0.013

Clostridium perfringens NR 2612 0.39 0.10 Clostridium moniliform ATCC 25546 0.78 0.10

Fusobacterium varium ATCC 8501 12.5 peptococcus prevotii ATCC 9321 1.56 0.39 peptococcus variabilis 25 ATCC 14955 0.78 0.20 peptostreptococcus anaerobius NR 2743 0.39 0.013 propionibacterium aenes ATCC 11828 0.78 0.78 30 Mycoplasma

Mycoplasma hominis NR 2952 0.10 0.10 DK 173330 B1 2. In vivo therapeutic efficacy

The in vivo antibacterial activities of pyrido [3,2,1-ij] - 1,3,4-benzoxadiazine derivatives prepared in Example 5, Example 30 and Example 66 as mentioned below were tested against lethal infection of Escherichia coli ML4707, Pseudomonas aeruginosa 4au542 and Streptococcus pneumoniae 6-001. ICR mice weighing approx. 20 g, were infected by intraperitoneal injection of a corresponding bacterial suspension. The test compounds were administered orally or subcutaneously at the time of injection. Mortality was observed for 5 days. The respective 50% effective dose (ED50, mg / kg) which protects 50% of the animals from death caused by infection is shown in Table 3.

Table 3 21 DK 173330 B1

In vivo antibacterial activity against systemic infection in mice (ED50, mg / kg) 5 _____

Bacteria

Escherichia Pseudomonas Streptococcus

Compound coli aeruginosa pneumoniae 10 ML4707 4au542 6-001 s.c. p.o. p.o. p.o.

Example 5 0.06 0.11 13.4 10.3 Example 30 0.10 0.62 57.0 65.9

Examples 66 - 0.51 - 3. Acute toxicity

The respective LD 50 values of the compounds obtained in Examples 5, 6, 17, 18, 30 and 56 as mentioned below are more than 2000 mg / kg. The acute toxicity of these compounds was investigated by oral administration in ICR mice.

The compounds provided by the present invention exhibit a broad antimicrobial spectrum against Gram-positive, Gram-negative bacteria and Mycoplasma, especially against those resistant to various antibiotics such as penicillins, cephalosporins, aminoglycosides and tetracyclines.

22 DK 173330 B1

The compounds provided by the present invention have low toxicity and a strong and broad anti-microbial efficiency. The protective effects of the compounds of the present invention on systemic bacterial infections in mice are greater than the effects of commercially available synthetic antibacterial agents. Therefore, the compounds of the present invention can be effectively utilized in the prevention or treatment of diseases caused by gram-positive and gram-negative bacteria and bacterioid microorganisms in humans or animals.

For example, diseases caused by the microorganisms listed below or by mixtures of the microorganisms listed below can be treated and / or prevented: , Escherichia, Citrobacter, Campylobacter, Enterobacter, Klebsiella, Proteus, Pseudomonas, Serratia, Salmonella, Shigella, Vibrio, Aeromonas, 20 Haemophilus, Neisseria, Acinetobacter, Alcaligenes, Bordetel-la, Bacteroides, Fusobacterium, Mycoplasium, other

The present invention further relates to the pharmaceutical compositions containing one compound of the present invention as well as a pharmaceutical composition for the treatment and prophylaxis of infectious diseases containing a compound of the present invention.

The compounds of the present invention can be administered orally or non-orally to humans or animals by 30 different conventional methods of administration.

The compounds of the present invention are further used alone or formulated with adjuvants, liquid diluents, binders, lubricants, wetting agents, etc., for example in the form of ordinary medical preparations such as tablets, granules, sugar-coated tablets, powders, capsules, gels , dry syrup, syrup, ampoules, suspensions, liquids, emulsions, ointments, pastes, creams, suppositories and the like.

Solution delaying agents, absorption accelerating agents, surfactants and the like can be used as other additives for formulation, i.e. any form which is pharmaceutically acceptable can be used.

The compounds of the present invention may be used alone or may be a mixture of two or more different kinds of compounds and the amount of the compounds is from ca. 0.1 to 99.5%, preferably 0.5 to 95% based on the total weight of the composition.

The composition of the present invention may be formulated in a combination of the compound of the present invention or the mixture thereof with other conventional compounds which are pharmaceutically active.

A daily dose to a patient of the novel compound of the present invention may be varied depending on the individual, the animal species, their weight and the condition to be treated, but generally it is in the range of 0.5 to 500 mg. per. 1 kg weight, preferably from approx. 1 to 300 mg.

The following examples illustrate the preferred processes for preparing the compounds of the present invention.

24 DK 173330 B1

Preparation of starting materials

reference Example

Preparation of diethyl N- (3,4-difluoro-2-hydroxyphenyl) amino methylene malonate 5 (a) A solution of 2,3-difluoro-6-nitrophenol (500 mg) in methanol (7 ml) was hydrogenated over 5 % Pd / C (60 mg) for 6 hours. The reaction mixture was filtered in a nitrogen atmosphere and the filtrate was evaporated under reduced pressure to give 414 mg of crude 2-amino-5,6-difluorophenol.

(B) A mixture of the above amine (414 mg) and diethyl-ethoxymethylene malonate (618 mg) was heated at 130 ° C in a nitrogen atmosphere 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 +). An additional 59 mg of crystals were obtained after silica gel column chromatography of the mother liquor using CHCl 3 / ace tone (20: 1) as eluent.

Preparation of ethyl 8-benzyloxy-6,7-difluoro-4-hydroxy-3-quinoline carboxylate (lane 1) (c) For 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) were added benzyl bromide (30 μΐ). The mixture was stirred at room temperature for 25 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 above malonate (280 mg) in diphenyl ether (2.8 ml) was heated at 250 ° C for 30 minutes in 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 placed on a silica gel column (10 g) followed by successive elution with benzene, dichloromethane and dichloromethane / acetone (30: 1). The pure fractions were collected and the solvent removed under reduced pressure to give the crystalline residue. 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-quinoline carboxylate. An analytical sample, m.p. 200-201 ° C: MS m / z 359 (M +), was prepared by recrystallization from methanol.

Preparation of ethyl 8-benzyloxy-6,7-difluoro-4-hydroxy-3-quinoline carboxylate (lane 2)

To a stirred solution of ethyl 6,7-difluoro-4,8-dihydroxy-3-quinoline carboxylate (300 mg) in dry dimethylformamide (6 ml) was added anhydrous potassium carbonate (308 mg) and then 20 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-quinoline carboxylate, m.p. -201eC; 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-quinoline carboxylate (e) After mixing a mixture of ethyl-8-benzyloxy 6,7-difluoro-4-hydroxy-3-quinoline carboxylate (410 mg) and anhydrous potassium carbonate (315 mg) in dry dimethylformamide (10 ml) had been stirred at room temperature for 3 hours, O- (2,4-dinitroph (DK 173330 B1 nyl) hydroxylamine (260 mg) added. The mixture was stirred at room temperature for an additional 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 5 for 3 hours. The precipitate was collected by filtration and washed with cold water and then with ether to give 405 mg of ethyl 1-amino-8-benzyloxy-6,7-difluoro-4-o-o-1,4-dihydro-3-quinoline carboxylate. An analytical sample, mp 143-144 ° C; MS m / z 374 (M +) 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 above 15 amine (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 the crystalline residue which was recrystallized from ethanol to give 410 mg of ethyl 8-benzyloxy-6,7-difluoro-1- (formylamino) -4-20 oxo-1,4 dihydro-3-quinoline carboxylate, m.p. 188-190 ° C: MS m / z 402 (M +).

(g) A mixture of the above formamide (400 mg), anhydrous in potassium carbonate (275 mg) and anhydrous dimethylformamide (17 ml) was stirred at room temperature for one and a half hours. Methyl iodide 25 (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 partitioned between chloroform and water.

The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was recrystallized from ethanol to give 335 mg of ethyl 8-benzyloxy-6,7-difluoro-1- (formylmethylamino) -4-oxo-1,4-dihydro-3-quinoline carboxylate, mp 180-181 ° C: MS m / z 416 (M +).

27 DK 173330 B1

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-quinoline carboxylate (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 6,7-10 difluoro-1- (formylmethylamino) -8-hydroxy-4-oxo-1,4-dihydro-3-quinoline carboxylate. mp 221-225 ° C (dec.): MS m / z 326 (M +).

(i) A mixture of the above ester (210 mg) and 0.5N sodium hydroxide (5.2 ml) was heated at 100 ° C for 2 hours in a nitrogen atmosphere. The reaction mixture was acidified with acetic acid (0.16 ml). The precipitated 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-quinoline carboxylic acid. An analytical sample, melting point 248-250 ° C (decomposition): MS m / z 270 (M +), was prepared by recrystallization from ethanol.

EXAMPLE 1

Preparation of 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid 1 2 3 4 5 6

A mixture of 6,7-difluoro-8-hydroxy-1- (methylamino) -4-oxo-2,4-dihydro-3-quinoline carboxylic acid (105 mg) obtained in Reference 3 Example (i), paraformaldehyde (150 mg ) and dry dioxane 4 (5 ml) were heated at 100 ° C for 3 hours in a nitrogen atmosphere 5 sphere. After removing 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-ij] -1 , 3,4-benzoxadiazine-6-carboxylic acid. An analytical sample, mp 290-292 ° C (dec.): MS m / z 282 (M +) was prepared by recrystallization from dimethylformamide.

EXAMPLE 4

Preparation of 9,10-difluoro-2 - [(dimethylamino) methyl] -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4- benzoxadi az in 6-carboxylic acid p-toluenesulfonate A suspension of 6,7-difluoro-8-hydroxy-1- (methylamino) -4-oxo-1,4-dihydro-3-quinoline carboxylic acid (50 mg) (i), dimethylaminoacetaldehyde-dimethylacetal (37 mg) and p-toluenesulfonic acid monohydrate (53 mg) in dry dioxane (2 ml) were heated at 110 ° C for 17 hours in a nitrogen atmosphere. After the solvent was removed under reduced pressure, the residue was recrystallized from methanol to give 61 mg of 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 p-toluenesulfonate, mp 232-236 ° C (dec.): FAB-MS m / z 340 (MH + ).

EXAMPLE 5

Preparation 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-S-carboxylic acid 1 2 3 4 5 6

A mixture of 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-2-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid (30 mg) 3 obtained in Example 1, N-methylpiperazine (47 μΐ) and dry pyridine (3 ml) were heated at 100-110 ° C for 9 hours in a nitro 5 gene atmosphere. 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-2,3-2. B1 dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, mp 268-269 ° C (dec.): MS m / z 362 (M +).

The following compounds were obtained in an analogous manner as described in Example 5: xxir L

Example Melting Point Recrystallization ^ 5 mfz No. R + c Agent • hO- 240 ^ 245 (dec.) MeOH 349 (MH +) * 9 O-> 300 EtOH / CHCl3 349 (M +) 13 H0-Q \ - 256 ^ 258 MeOH / CHCl3 363 (M *) 17 CHJJJ3 "Ζ4Ζ <ν244 <dec ·) DMF 377 (MH +) * 18 H PVi-251 * 252 (dec.) EtOH 391 (MH +) * C2» 5 19 Η Γ \ - 239 * 241 (dec.) EtOH 405 (MH +) *

ACN ^ l-V

21 rV- 284 * 286 (dec.) DMF '350 (MH +) * H (r 22 CH3n-280 * 284 (dec.) MeOH / CHCl3 / Et2 O3 345 (MH +) * N · ** n DK 173330 B1 30 EXAMPLE 29

Preparation of 10- [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 A mixture of 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1 , 3,4-Benzoxadiazine-6-carboxylic acid (28 mg) obtained in Example 1, 3- (benzyloxycarbonylamino) pyrrolidine (94 mg) and dry pyridine (3 ml) were heated at 100 ° C for 3 hours in a nitrogen atmosphere. Pyridine was removed under reduced pressure and the residue was recrystallized from methanol to give 36 mg of 10- [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 +).

EXAMPLE 30

Preparation of 10- (3-amino-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4 -benzoxadiazine-6-carboxylic acid 10- [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 (30 mg) obtained in Example 29 was hydrogenerated over 5% Pd / C (10 mg) in dimethylformamide (2 ml) for 4.5 hours. After removal of the catalyst by filtration, the filtrate was concentrated under reduced pressure. The residue was recrystallized from methanol to give 16 mg of 10- (3-amino-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3.2.1 -1,3,4-benzoxadiazine-6-carboxylic acid, mp 230-234 ° C (dec.); MS m / z 348 (M +).

EXAMPLE 37

Preparation of 9-fluoro-10- (3-methoxy-1-pyrrolidinyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4 -benzoxadiazine-6-carboxylic acid 5 For a suspension of 9-fluoro-10- (3-hydroxy-1-pyrrolidinyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3.2 , 1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid (100 mg) obtained in Example 21 in dry dimethylformatide (10 ml) was added 60% sodium hydride in oil (30 mg) and methyl iodide (40 μΐ). ). After stirring the mixture 10 at room temperature for 2 hours, an additional 60% sodium hydride (30 mg) and methyl iodide (40 μΐ) were added and the mixture was stirred at 45 ° C for 3 hours. The solvent was then removed under reduced pressure. To the residue was added cold water (2 mL) and 0.5N sodium hydroxide (2.3 mL), and the resulting suspension was heated at 100 ° C for 2 hours. The reaction mixture was then cooled to room temperature, neutralized with acetic acid and diluted with water. The mixture was extracted with chloroform and the extract washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crystalline residue which was chromatographed on silica gel using acetone / chloroform (1: 9) as eluent.

42 mg of 9-fluoro-10- (3-methoxy-1-pyrrolidinyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido (3,2,1-yl) -1,3,4 -benzoxadiazine-6-carboxylic acid, mp 233-234 ° C; FAB-MS m / z 364 (MH +), was obtained after recrystallization from methanol.

EXAMPLE 38

Preparation of 9-fluoro-10- (4-methoxy-1-piperidyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4 -benzoxadiazine-6-carboxylic acid 9-Fluoro-10- (4-methoxy-1-piperidyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij ] -1,3,4-Benzoxadiazine-6-carboxylic acid was prepared from 9-fluoro-10- (4-hydroxy-1-piperidyl) -3- methyl-7-oxo-2,3-dihydro -7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, obtained in Example 13, analogous to Example 37, was obtained as crystals, mp 229-233 ° C (dec. ): MS m / z 377 (M +), after recrystallization of chloroform / n-hexane.

EXAMPLE 40

Preparation of 9-fluoro-3-methyl-7-oxo-10- [4- (2-oxo-n-propyl) -1-piperazinyl] -2,3-dihydro-7H-pyrido [3.2, 1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid

A mixture of 9-fluoro-3-methyl-7-oxo-10- (1-piperazinyl) -2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine -6-carboxylic acid (50 mg) obtained in Example 6, chloroacetone (17 μΐ), triethylamine (40 μΐ) and dry dimethylformamide (1 ml) were heated at 80 ° C for 3.5 hours. The volatiles were then removed under reduced pressure and the residue suspended in water. The precipitate was collected by filtration and recrystallized from a mixture of dichloromethane and methanol to give 32 mg of 9-fluoro-3-methyl-7-oxo-10- [4- (2-oxo-n-propyl) -1-piperazinyl] -2,3-dihydro-7H-pyrido [3,2,1-ij] -20 1,3,4-benzoxadiazine-6-carboxylic acid, mp 225-229 ° C

(decomposition), FAB-MS m / z 405 (MH +).

The following compounds were obtained by analogy as described in Example 40.

EXAMPLE 49 33 DK 173330 B1

Preparation of 10- [4- (3-carboxypropionyl) -1-piperazinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1 3,4-Benzoxadiazine-6-carboxylic acid 5 A mixture of 9-fluoro-3-methyl-7-oxo-10- (1-piperazinyl) -2,3-dihydro-7H-pyrido [3,2,1- ij] -1,3,4-benzoxadiazine-6-carboxylic acid (50 mg) obtained in Example 6, succinic anhydride (21.6 mg), triethylamine (40 μΐ) and dry dimethylformamide (4 ml) were heated at 80 ° C. for 2 hours. The solvent was then removed under reduced pressure and the residue suspended in water. The precipitate was collected by filtration and recrystallized from a mixture of dichloromethane and methanol to give 50 mg of 10- [4- (3-carboxypropionyl) -1-piperazinyl] 9- fluoro-3-methyl-7-oxo-2 3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-15 benzoxadiazine-6-carboxylic acid, mp 257-259 ° C (dec.): FAB-MS m / z 449 (MH + ).

EXAMPLE 50

Preparation of 10- (4-Acetyl-1-piperazinyl) -9- [11] -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1, 3,4-benzoxadiazine-6-carboxylic acid 10- (4-Acetyl-1-piperazinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3.2, 1-yl] -1,3,4-benzoxadiazine-6-carboxylic acid was prepared from 9-fluoro-3-methyl-7-oxo-10- (1-piperazinyl) -2,3-dihydro-7H-pyrido [ 3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid obtained in Example 6 and acetic anhydride analogous to Example 49, and were obtained as crystals, mp 294-296 ° C (dec.); FAB-MS m / z 391 (MH +), after recrystallization from dichloromethane / methanol.

EXAMPLE 53 "DK 173330 B1 34

Preparation of 10- [4- (4-aminobenzyl) -1-piperazinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1 3,4-Benz-zoxadiazine-6-carboxylic acid 9-Fluoro-3-methyl-10- [4- (4-nitrobenzyl) -1-piperazinyl] -7-oxo-2,3-dihydro-2-carboxylic acid 7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid (100 mg) obtained in Example 47 was hydrogenated over 5% Pd / C (10 mg) in dichloromethane / methanol (1: 1) for 2 hours. After removing the catalyst by filtration, the filtrate was concentrated to dryness under reduced pressure.

The residue was recrystallized from ethanol to give 69 mg of 10- [4- (4-aminobenzyl) -1-piperazinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3, 2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, mp 237-238 ° C (dec.); FAB-MS 15 m / z 454 (MH +).

EXAMPLE 54

Preparation of 10- [3- (aminomethyl) -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1, 3,4-Benzoxadiazine-6-carboxylic acid 1 2 3 4 5 6 7 8 9 10 11

The mixture of 10- [3- (acetylaminomethyl) -1-pyrrolidinyl] -9-2 fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1 3,4-3 benzoxadiazine-6-carboxylic acid (40 mg) obtained in Examples 19 and 4N sodium hydroxide (2.5 ml) was heated at 100 ° C for 35 hours. After cooling to room temperature, the reaction mixture was neutralized with acetic acid and the precipitated precipitate 7 was collected by filtration and recrystallized from methanol 8 to give 15 mg of 10- [3- (aminomethyl) -1-pyrrolidinyl] -9-9 fluorine -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, mp 177-180 ° C (dec. 11 split); FAB-MS m / z 363 (MH +).

EXAMPLE 55

Preparation of 6-fluoro-8-hydroxy-7- (1-imidazolyl) -1- (methylamino) -4-oxo-1,4-dihydro-3-quinoline carboxylic acid

Carbonyl diimidazole (32 mg) was added to a stirred solution 5 of 6,7-difluoro-8-hydroxy-1- (methylamino) -4-oxo-1,4-dihydro-3-quinoline carboxylic acid (50 mg) obtained in reference example ( i) in dry dimethylformamide (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 10 was suspended in water and the pH was adjusted to pH 5 with acetic acid. The precipitated precipitate was filtered and washed with methanol to give 35 mg of 6-fluoro-8-hydroxy-7- (1-imidazolyl) -1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylate. boxy acid as pale yellow powder, FAB-MS m / z 319 (MH +): 1 H-NMR (dg-DMSO) δ: 2.82 (3H, s), 7.10 (1H, d, J = 10.7 Hz ), 7.61 (1H, d), 7.75 (1H, d), 8.62 (1H, s), 8.92 (1H, s), 15.33 (1H, br, s) EXAMPLE 56

Preparation of 9-fluoro-10- (1-imidazolyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-yl] -1,3,4-benzoxadiazine-6 -carboxylic acid

A suspension of 6-fluoro-8-hydroxy-7- (1-imidazolyl) -1- (methylamino) -4-oxo-1,4-dihydro-3-quinoline carboxylic acid (15 mg) obtained in Example 55 in a mixture of 35% formalin (1 ml) and dioxane (1 ml) were heated at 100-110 ° C for one and a half hours in a nitrogen atmosphere. The solvent 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. An analytical sample, m.p.> 300 ° C; FAB-MS m / z 331 (MH +), was prepared by recrystallization from dimethylformamide and ether.

B-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 was also prepared from 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine 6-carboxylic acid and 5 imidazole in dimethyl sulfoxide analogous to Example 5.

EXAMPLE 57

Preparation of benzyl-9-fluoro-10- (3-hydroxy-1-pyrrolidinyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3 4-Benzoxadiazine-6-carboxylate A mixture of 9-fluoro-10- (3-hydroxy-1-pyrrolidinyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3, 2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid (10 mg) obtained in Example 21, anhydrous potassium carbonate (8 mg) and dimethylformamide (0.5 ml) was stirred at room temperature for one and a half hours. and then 15 benzyl bromide (10.8 mg) was added. This mixture was stirred at room temperature for 3 hours and evaporated under reduced pressure.

The residue was suspended in water and extracted with chloroform. The extract was concentrated to dryness under reduced pressure. The residue was triturated with ether to give 11 mg of benzyl-9-fluoro-10- (3-hydroxy-1-pyrrolidinyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3 , 2, 1-ij] -1,3,4-benzoxadiazine-6-carboxylate, mp 196-198 ° C (dec.): FAB-MS m / z 440 (MH +).

Example 58 Preparation of benzyl-10- (3-chloro-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] - 1,3,4-benzoxadiazine-6-carboxylate

Benzyl-9-fluoro-10- (3-hydroxy-1-pyrrolidinyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-yl] -1,3,4 -benzoxadiazine-6-carboxylate (8 mg) obtained in Example 57 was dissolved in 0.2 ml of thionyl chloride and stirred at 60 ° C for 15 minutes. The reaction mixture was diluted with water and extracted with chloroform.

The extract was concentrated under reduced pressure. The residue was chromatographed on silica gel (2 g) with chloroform to give 2.8 mg of benzyl-10- (3-chloro-1-pyrrolidinyl) -9-fluoro-3-methyl-7-ΟΧΟ-2,3-dihydro -7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylate, m.p.> 300 ° C; FAB-MS m / z 458 (MH +), 460 (MH + 2) +.

Example 59 Preparation of 10- (3-chloro-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1, 3,4-benzoxadiazine-6-carboxylic acid

Benzyl-10- (3-chloro-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4 -benzoxadiazine-6-carboxylate (2.5 mg) obtained in Example 58 was hydrogenated over 5% Pd / C (1 mg) in chloroform.

After removing the catalyst by filtration, the filtrate was concentrated to dryness under reduced pressure. The residue was recrystallized from ethanol to give 1.0 mg of 10- (3-chloro-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 269-272 ° C (dec.): FAB-MS m / z 368 (MH +), 370 (MH + 2) +.

Example 60 Preparation 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 via the fluoroborane intermediate (a) A mixture of 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] - 1,3,4-benzoxadiazine-6-carboxylic acid (100 mg) obtained in Example 1 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 [3,2,1-ij] - 1,3,4-benzoxadiazin-7-one: FAB-MS m / z 331 (MH +).

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

(c) To a solution of the above borane intermediate (5 mg) in 95% ethanol (1 ml) was added triethylamine (3 μΐ). After refluxing for 4 hours, the reaction mixture was cooled to room temperature. The precipitated 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 , 1-ij] -l, 3,4-benzoxadiazine-6-carboxylic acid. Melting point 268-269 ° C (dec.).

EXAMPLE 61

Preparation 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 via the acetoxyborane crude product (a) A mixture of 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1, 3,4-Benzoxadiazine-6-carboxylic acid (100 mg) obtained in Example 1, acetic anhydride (1 ml) and triacetoxyborane (100 mg) were heated at 140 ° C for 15 minutes. The reaction mixture was evaporated under reduced pressure.

39 DK 173330 B1

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] -i, 3,4-ben-zoxadiazin-7-one; FAB-MS m / z 411 (MH +).

5 (b) To a solution of the above borane intermediate (41 mg) in dimethyl sulfoxide (1 ml) was added N-methylpiperazine (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 by methanol / et-10 here to give 34 mg of 6 - [[(diacetoxyboryl) oxy] carbonyl] -9-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 156-157 ° C (dec.); FAB-MS m / z 491 (MH +).

(C) The above borane intermediate (5 mg) was suspended in acetone (0.1 ml) and concentrated HCl (2.5 μΐ) added. The reaction mixture was stirred at room temperature for 30 minutes and cooled in an ice bath. The precipitated precipitate was collected by filtration and the precipitate was dissolved in 95% ethanol (0.1 ml).

To the solution was added triethylamine (2 μΐ) and the mixture was refluxed for 1 hour. After cooling the solution to room temperature, the precipitated 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, 1-ij] -1, 3.4-25 benzoxadiazine-6-carboxylic acid, mp 268-269 ° C (dec.).

EXAMPLE 6 6

Preparation of α-10- (3-amino-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3 , 4-Benzoxadiazine-6-30 carboxylic acid hydrochloride pH of a solution of 10- (3-amino-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [ 3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid (20 mg) obtained in Example 30 in water (1 ml) was adjusted to 1.0 with 6N-HCl . The clear solution was then lyophilized and the residue was crystallized by water / ethanol (1: 2) to give 19 mg of 10- (3-amino-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2 3-Dihydro-7H-5-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid hydrochloride, mp 226-228 ° C (dec.).

EXAMPLE 67

Preparation of 9-fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-il] -1,3,4- benzoxadiazine-6-10 carboxylic acid hydrochloride 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 hydrochloride was obtained analogously to Example 66, mp 264-266 ° C (dec.).

EXAMPLE 68

Preparation of sodium 9-fluoro-3-methyl-10-morpholino-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-car -boxylate 9-Fluoro-3-methyl-10-morpholino-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine 6-carboxylic acid (14 mg) obtained in Example 9 was suspended in water (0.4 ml) and 1N sodium hydroxide (40 μΐ) was added with stirring. The clear solution was lyophilized and the residue was crystallized by water / ethanol (1: 4) to give 12 mg of sodium 9-25 fluoro-3-methyl-10-morpholino-7-oxo-2,3-dihydro-7H pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylate, m.p.> 300 ° C.

EXAMPLE 69

Preparation of 9-fluoro-3- (2-fluoroethyl) -10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] - 1,3,4-Benz oxadi azine 6-carboxylic acid 9-Fluoro-3- (2-fluoroethyl) -10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-2 7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid was prepared from ethyl 8-benzyloxy-6,7-difluoro-1- (formylamino) -4- oxo-1,4-dihydro-3-quinoline carboxylate obtained in Reference Example (f) according to a variety of procedures 10 in Reference Example (g, h and i) (using 1-bromo-2-fluoroethane instead of methyl iodide), Example 1 and Example 5, and were obtained as crystals, mp 220-224 ° C; MS m / z 394 (M +) after recrystallization from methanol.

Example 80 Preparation of sodium 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-carboxylate 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 20 (520 mg) was dissolved in 0.5N sodium hydroxide (2.88 ml). The clear solution was evaporated under reduced pressure to give 555 mg pale yellow powder which was recrystallized from ethanol to give 475 mg of sodium 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-carboxylate, after drying in vacuo at 80 ° C for 2 days: mp 252-254 ° C (decomposition) FAB-MS m / z 385th

The following examples illustrate pharmaceutical compositions containing a compound of the present invention: 42 DK 173330 B1

EXAMPLE A

Closely linked gelatin capsules each containing the following ingredients were prepared in a manner known per se: 9-Fluoro-3-methyl-10- (4-methyl-1-5 piperazinyl) -7-oxo-2,3-dihydro-7 pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid 200mg

Luvis char (water soluble polyvinylpyrrolidone) 20mg

Mannitol 20mg 10 Talc 15mg

Magnesium stearate 2mg 257mg

EXAMPLE B

Tablets each containing the following ingredients were prepared in a manner known per se: 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 200mg Starch 44mg

Carboxymethylcellulose calcium 30mg

Crystalline cellulose 40mg

Magnesium stearate = 6313 320mg

Claims (17)

43 DK 173330 B1 1 XXT OH NHCH 3 wherein R is as defined in claim 1; and amino, hydroxy and / or carboxy groups present may be protected, reacted with formaldehyde or paraformaldehyde, if necessary followed by removal of a protective radical, or (c) to prepare a compound of formula I wherein R represents 4-acetyl-1-piperazinyl, a compound of formula I is reacted wherein R represents the unsubstituted 1-piperazinyl residue with an agent giving the acetyl group, or (D) to prepare a compound of formula I wherein R represents 3-methoxy-1-piperidyl, a compound of formula I is methylated, or R represents the corresponding 3-hydroxy-1-piperidinyl residue, 5 (e). ) to prepare a compound of formula I with a free amino group, the amino protecting group is cleaved from a corresponding compound of formula I with a protected amino group, or (f) to produce a compound of formula I wherein R 10 represents 3-chloro-1- pyrolidinyl, a corresponding hydroxy-substituted compound of formula I is halogenated, wherein the carboxylic acid group bears a carboxy protecting radical and the carboxy protecting radical is cleaved, or (g) to produce a compound of formula I wherein R 15 represents 4- (4- aminobenzyl) -1-piperazinyl, the nitro group of a corresponding nitro-substituted compound of formula I is reduced, or (h) to prepare pharmaceutically acceptable salts, hydrates or solvates of a compound having the formula I or 20 hydrates or solvates of these salts, a compound of formula I is converted to a salt, hydrate or solvate or to a hydrate or solvate of the salt. 1. Pyrido [3,2,1-ij] -1,3,4-benzoxadiazine derivatives of the general formula q XXX ch3 wherein R represents 1-piperazinyl optionally substituted 5 at the 4-position with methyl, acetyl or 4- aminobenzyl; mother-morpholino; 1-pyrrolidino which is substituted at the 3-position by amino, aminomethyl, (methylamino) methyl, (ethylamino) methyl, methoxy or chloro; 1-imidazolyl, which may be substituted at the 4-position with methyl; or 1-piperidyl which is substituted at the 4-position by hydroxy or methoxy, as well as pharmaceutically acceptable salts thereof and hydrates or solvates of the compounds of general formula I or their salts. Compounds according to claim 1, characterized in that the group R is J 1. Compounds according to claim 1, characterized in that the group R is Compound according to claim 1, characterized in that it is 9-fluoro-3-methyl-10- (4-20 methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3, 2,1-ij] - 1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of this salt. Compound according to claim 1, characterized in that it is 9-fluoro-3-methyl-7-oxo-10- (1-piperazinyl) -2,3-dihydro-7H-pyrido [3,2,1- ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutical acceptor B1 contains salt thereof or a hydrate or solvate of this compound or of this salt. Compound according to claim 1, characterized in that it is selected from 9-fluoro-3-5 methyl-10-morpholino-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] - 1,3,4-Benzoxadiazine-6-carboxylic acid, 9-fluoro-3-methyl-10- [3 - [(methylamino) methyl] -1-pyrrolidinyl] -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, 9-fluoro-10- (3-methoxy-1-pyrrolidinyl) -3-methyl-7-oxo-2,3- dihydro-7H-10-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, 10- [3- (aminomethyl) -1-pyrrolidinyl] -9-fluoro-3-methyl 7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, 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, 9-15 fluoro-3-methyl-10- (4- methyl-1-imidazolyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, 9-fluoro-10- (4 hydroxy-1-piperidyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, (3-Chloro-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] j] -1,3,4-benzoxadiazine-6-carboxylic acid, 10- (4-acetyl-1-piperazinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3 , 2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, 9-fluoro-10- (4-methoxy-1-piperidyl) -3-methyl-7-oxo-2,3-dihydro-4-carboxylic acid 7H-pyrido [3,2, l-ij] -i, 3,4-benzoxadiazine-6-carboxylic acid. Compound according to claim 1, characterized in that it is 10- [3 - [(ethylamino) methyl] -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-1 7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of this salt. Compound according to claim 1, characterized in that it is 10- (3-amino-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3 , 2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of this salt. A compound according to claim 1, characterized in that it is 10- [4- (4-aminobenzyl) -5-piperazinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7 pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of this salt. 10. Compounds of the general formula; O F'N ^ v ^ A ^ COOH I i <III> v ch3 10 where X 'represents a halogen atom. Compounds of the general formula X ^^ J1 ^ COOR1 6 (V) R 'N X 1 2 I OH NHRZ ft5 wherein R is as defined in claim 1. Compounds according to any one of claims 1-9 for use as pharmaceutically active substances. DK 173330 B1 4 6 Compounds according to any one of claims 1-9, characterized in that they are pharmaceutically active substances for the treatment and prophylaxis of infectious diseases. A process for the preparation of the compounds according to any one of claims 1-9, characterized in that it comprises that (a) a compound of the general formula o (J) (III) x 3 wherein X 'is a halogen atom; and carboxy groups present are optionally protected, reacted with an amine of the general formula, wherein R is as defined in claim 1, if necessary followed by removal of a protective radical, or (b) a compound of the general formula O Pharmaceutical composition, characterized in that it contains a compound 25 according to any one of claims 1-9. Pharmaceutical composition for the treatment and prophylaxis of infectious diseases, characterized in that it contains a compound according to any one of claims 1-9. 48 DK 173330 B1 Use of the compounds of any one of claims 1-9 for the manufacture of medicaments for the treatment and prophylaxis of infectious diseases.