FI86428C - Process for the preparation of therapeutically active 10-substituted-9-fluoro-7-oxo-2,3-dihydro-7H-pyrido- / 3,2,1-ij / -1,3,4-benzoxadiazine-6-carboxylic acid derivatives - Google Patents

Description

1 86428

Process for the preparation of therapeutically active 10-substituted-9-fluoro-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid derivatives

The invention relates to a process for the preparation of novel "tricyclic compounds", in particular pyrido (3,2,1-ij) -1,3,4-benzoxadiazine derivatives. These compounds can be used as antibacterial ingredients in pharmaceutical preparations.

Accordingly, the invention relates to a process for the preparation of novel 10-substituted-9-fluoro-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid derivatives. for the preparation of the general formula 15 0 f R6-N - 20 R5 I | (R 1 is R 3 wherein R 1 is a hydrogen atom or a carboxy protecting group which may be lower alkyl, benzyl or lower alkanoyloxyalkyl; R 2 is a lower alkyl radical optionally substituted by a fluorine atom; R 3 is a hydrogen atom or an optionally hydroxy or di (lower alkyl) amino radical) substituted lower alkyl radical, R5 is a lower alkyl radical, and R6 is a di (lower alkyl) amino-substituted lower alkyl radical, or 2 86428 R5 and R6 together with an adjacent nitrogen atom form a piperazine ring which may be C-substituted lower alkyl, oxo- and or a phenyl group and / or an N-substituted lower alkyl, lower sulfonatealkyl, nitro-5-benzyl, aminobenzyl, lower hydroxyalkyl, lower haloalkyl, lower carboxyalkyl and / or lower alkenyl group and / or a group having general formula 10 - (CH 2) n COR 8 (wherein n is 0 to 2 and R 0 is phenyl or a lower alkyl radical optionally substituted by carboxyl ai phenyl group); a morpholino ring optionally substituted with a lower alkyl group; thiomorpholino or 1,1-dioxide thiomorpholino ring; a pyrrolidine ring optionally substituted with amino, lower alkylamino, lower alkoxy, lower aminoalkyl, lower alkyl, hydroxy, halogen, benzyloxycarbonylamino-20-, lower alkylpiperazinyl, phenyl, lower alkyl, a alkylamino (lower alkyl) and / or aminobenzylamino group and / or a group of the general formula R50; N-CH = N- wherein R 50 and R 51 are each lower alkyl; an imidazole ring optionally substituted with a lower alkyl group; a piperidine ring optionally substituted with a lower aminoalkyl, hydroxy, pyrrolyl, amino, lower alkylamino and / or lower alkoxy group; or a hexahydro-1,4-diazepine ring; and pharmaceutically acceptable salts and hydrates or solvates of the compounds of formula I 35 or salts thereof, in which process 3 86428 a) a compound of general formula 0

(III) X r2 wherein R1, R2 and R3 are as defined above and X 'is a halogen atom and the amino, hydroxy and / or carboxy groups present may be protected, is reacted with an amine to: is the general formula HN - R5 (IV) R6 wherein R5 and R6 are as defined above, and then, if necessary, the protecting radical is removed; or b) a compound of general formula

O

FC00r1 25 ^ (V)

R6 — vr | OF

wherein R 1, R 2, R 5 and R 6 are as defined above and the amino, hydroxy and / or carboxy groups present may be protected, are reacted with an aldehyde of general formula R 3 - CHO (VI ) 4 86428 wherein R 3 is as defined above, or a polymer, acetal or enol ether thereof, followed by deprotection if necessary, or c) to prepare a compound of formula I wherein R 5 R 6 N- is a piperazine ring N-substituted as defined above , reacting a compound of formula I wherein R 5 R 6 N- is N-unsubstituted piperazinyl with a compound of general formula R 70 Y (X) wherein Y is a leaving group and R 70 is a group - (CH 2) n COR 8, lower alkyl, nitrobenzyl, lower hydroxyalkyl, lower haloalkyl or lower alkenyl, or (c2) with a Michael acceptor of the general formula R9-CO-CH = CH2 (XI) 20 wherein R9 is a lower alkyl radical, or (c3) formaldehyde and an ant with isic acid or alkali metal bisulphite or (c4) an aldehyde of general formula

^ CO

Z N 0 (XII) 1 - wherein Z is C 2-3 alkylene, or d) to prepare a compound of formula I wherein R 5 R 6 N - is 1,1-dioxide thiomorpholino, oxidizing the corresponding compound wherein R 5 R 6 N - is thiomorpholino; or e) for the preparation of a compound of formula I wherein R 5 R 6 N- is a pyrrolidine or piperidine ring substituted by an amino and / or hydroxy group, cleaving the protecting group (s) from the corresponding compound having a protected amino or aminomethyl group by hydrogenation of the catalyst. 5,8428 lytically benzyloxycarbonylamino or benzyloxycarbonylaminomethyl compound; or f) to prepare a compound of formula I wherein R 5 R 6 N- is a halopyrrolidine ring, halogenating the corresponding hydroxypyrrolidine compound of formula I wherein R 1 is a carboxy protecting group as defined above and, if desired, cleaving said protecting radical R 1, or g) wherein R5R6N- is an aminobenzylpiperazine ring, reducing the corresponding nitrobenzylpiperazine compound of formula I by catalytic hydrogenation, or h) preparing a compound of formula I wherein R5R6N- is a pyrrolidine ring substituted with R CH = N-R51 wherein R50 and R51 are each lower alkyl, reacting the amino group of the corresponding aminopyrrolidine compound of formula I with N, N- (di-lower alkyl) -formamide methyl acetal, or i) preparing a compound of formula I wherein R1 is a protecting radical of a carboxy group, esterified with the corresponding formula I and if desired j) for the preparation of pharmaceutically acceptable salts, hydrates or solvates of a compound of formula I or for the preparation of hydrates or solvates of said salts, converting a compound of formula I into a salt, hydrate or solvate or said salt into a hydrate or solvate.

As used herein, the term "lower" refers to a carbon chain that preferably contains up to and including 6,842,428 carbon atoms, more preferably 1 to 4 carbon atoms.

In the sense of R *, said carboxy-protecting radical, when lower alkyl, means e.g. methyl, ethyl, n-propyl or t-butyl, and when lower alkanoyloxyalkyl, e.g. acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl and 1-pivaloyloxyethyl.

In process variant a), the compound of formula III used as a starting compound is a novel compound and can be prepared, for example, according to the following reaction scheme a) or b).

ii 7 86428

Reaction scheme a)

5 Λ? ElklStyS> X '^ X.H2 H, C2 ° CH.C1C00C2H5 ^ OH OH

(A) (B)

1 ° H5C2OOC. H5C2OOC

V ^ COOC2H5 x ^>. y-cooc.Hs χ. AJAN- * -2Sl ^ 0jaUS> χ, ΧΑΝΙ cycle sound ,, »

OH H OR 'H

(C) (D) XVyVCOOC2H5 XW \ 0 ° c2H5 kv 11 Λ amination [N-protection ---> OR 'OR' nh2 20 (E) (F) 0 0 xvVVCOOC2H5 cooc2h5 X alkylation ^ deprotection ^

OR 'NHR' ^ N-R

25 (G) (H) R "30 cyclization OH NHR2 Ο Ϊ ·: V% 2 (Va) (Ilia) 8 86423

Reaction scheme b)

h5c2ooc Cooc2h5 QH

xxkX xxxVCOOC2H5 Λ I H cyclization OH protection OH -> I ->

OH

(C) (J)? H 0 Xv ^> sJ ^ Ss ^ COOC2H5 XV ^ S ^ S ^ OOC2H ^ amination N-protection ^ OR '* OR' NH2 ^ (E) (F) xYrYOOC2H5 xWyc00C2H5 alkylation deprotection ..

0R '"HR" XL 1-R2 i- (G) (H) xrrVC00R "' xnrVC00R" cyclization 0H NHR2 N2R2 R3: (Va) (IIIa) ii g 86423 wherein R2, R3, and X 'are the same as defined above; X is fluorine, R 'is a protecting radical such as benzyl, methoxybenzyl, methoxymethyl, methoxyethoxymethyl, tetrahydropyranyl, allyl, t-butyl, t-butyldimethylsilyl, acetyl, benzoyl or the like; R "is a protecting radical such as formyl, acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, t-butoxycarbonyl or 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, phenoxycarbonyl, benzyl or a t-butoxycarbonyl group or 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 sufficient time so that the reaction can proceed completely. A suitable reaction temperature is about 30 to 200 ° C, preferably 80 to 150 ° C, in order to obtain a sufficiently high reaction rate.

The reaction is preferably carried out with 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, alkali metal hydroxy- In the presence of alkali metal carbonates or the like. Alternatively, an excess of the amine of formula IV may be used as the acid acceptor.

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

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 benzyloxycarbonyl radical may be removed by hydrogenolysis.

Examples of starting materials of formula III are as follows: 9.10-Difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6 carboxylic acid, 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 ti, 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, 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, 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, 9,10-difluoro-2,2,3-trimethyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] - 1,3,4-benzoxadiazine-6-carboxylic acid and the like.

Examples of amines used in the above reaction can be found in the application examples below.

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

If a carbonyl compound of formula VI or a polymer, acetal or enol ether thereof contains an amino or monoalkylamino substituent, said substituent may, if desired, be protected by a radical as described above for R "in formulas G and H.

If desired, the reaction may be carried out in a solvent such as dioxane, tetrahydrofuran, acetonitrile, chloroform, dimethylformamide, dimethyl sulfoxide, N, N'-dimethylpropylurea, acetic acid or the like. Mixtures of two or more solvents may also be used.

The reaction can be carried out, if necessary, with an acid catalyst such as acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, pyridine p-toluenesulfonate, ferric chloride, zinc chloride, chlorotimethylsilane, chlorotrimethylsilane, -20 resin sulfonic acid; Aldrich Chemical Co., Inc.), in the presence of Amberlyst 15 (a strongly acidic, macroreticular resin; Aldrich Chemical Co., Inc.) or the like.

The reaction temperature can range from relatively wide to 25. In general, the reaction is carried out at a temperature of 20 to 150 ° C.

In a preferred embodiment of this invention, about one mole or excess of a carbonyl compound of formula VI or a polymer, acetal or enol ether per mole of a compound of formula V is used.

If desired, the amino or monoalkylamino protecting radical may be removed after the reaction by methods known to those skilled in the art. For example, the formyl radical 35 may be removed by acid or base hydrolysis, preferably i2 86 428 by base hydrolysis, and the benzyloxycarbonyl radical may be removed by hydrogenolysis.

Examples of starting materials of formula V are: 6,7-difluoro-8-hydroxy-1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, ethyl-6,7-difluoro-8 -hydroxy-1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylate, benzyl 6,7-difluoro-8-hydroxy-1- (methylamino) -4-oxo-10-iso-1,4- dihydro-3-quinolinecarboxylate, 6,7-dichloro-8-hydroxy-1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, 6-chloro-7-fluoro-8-hydroxy- 1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, 6,7-difluoro-1- [2-fluoroethyl) amino] -8-hydroxy-4-oxo-1,4-dihydro-3 -quinolinecarboxylic acid, 6-fluoro-8-hydroxy-7- (1-imidazolyl) -1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, ethyl-6-fluoro-8-hydroxy-7 - (1-imidazolyl) -1- (methyl-20-amino) -4-oxo-1,4-dihydro-3-quinolinecarboxylate, benzyl 6-fluoro-8-hydroxy-7- (1-imidazolyl) -1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylate, 6-fluoro-1 - [(2-fluoroethyl) i) amino] -8-hydroxy-7- (1-imidazolyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid 25,6-chloro-8-hydroxy-7- (1-imidazolyl) - 1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, 6-fluoro-8-hydroxy-1- (methylamino) -7- (4-methyl-1-piperazinyl) -4- oxo-1,4-dihydro-3-quinolinecarboxylic acid, 7- (3,4-dimethyl-1-piperazinyl) -6-fluoro-8-hydroxy-1- (methylamino) -4-oxo-1,4 -dihydro-3-quinolinecarboxylic acid, 7 - [(3 - [(benzyloxycarbonylethylamino) methyl] -1-35 pyrrolidinyl] -6-fluoro + 8-hydroxy-1- (methylamino) -4-oxo-1,4- dihydro-3-quinolinecarboxylic acid, 1! i3 86 428 7- [3- (Benzyloxycarbonylamino) -1-pyrrolidinyl] -6-fluoro-8-hydroxy-1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, 7- [3 - [(benzyloxycarbonylmethylamino) methyl] -4-methyl-5-pyrrolidinyl] -6-fluoro-8-hydroxy-1- (methylamino) -4-oxo-1,4-dihydro-3- Quinolinecarboxylic acid, 7- [3 - [(benzyloxycarbonylamino) methyl] -4-chloro-1-pyrrolidinyl] -6-fluoro-8-hydroxy-1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid and equivalent to -10 vat.

Examples of compounds that can be reacted with a compound of formula V include carbonyl compounds of formula VI such as formaldehyde, acetaldehyde, acetone, methyl ethyl ketone or the like; Polymers thereof such as paraformaldehyde, paracetaldehyde, trioxane or the like; their acetals such as dimethoxymethane, 1,1-dimethoxyethane, 1,3-dioxane, Gly-chaldaldehyde methyl acetal, dimethylaminoacetaldehyde methyl acetal or the like; and an enol ether thereof such as 2-methoxypropylene, 2-trimethylsilyloxypropylene or the like.

In process variant cl), the leaving group Y may be e.g. a halogen atom such as chlorine, bromine or iodine, an acyloxy radical such as acetoxy, a lower alkanesulfonyloxy radical such as methanesulfonyloxy, an arylsulfonyloxy radical such as p-toluenesulfonyloxy; optionally a nitrated phenoxy radical such as phenoxy or 4-nitrophenoxy; or succinimidooxy or phthalimidooxy.

If necessary, the reaction may be carried out in a solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, N, N'-dimethylpropylurea, dioxane, tetrahydrofuran, pyridine or the like. Mixtures of two or more solvents 35 may also be used.

i4 8 6 4 2 8

The reaction is preferably carried out with 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-ene, sodium hydride, in the presence of alkali metal hydroxides, early metal carbonates or the like.

The reaction temperature can vary over a relatively wide range. In general, the reaction is carried out at a temperature of about 0 to 180 ° C, preferably 0 to 11 ° C. In Reaction 10, 1 to 4 moles, preferably 1 to 2 moles of a compound of formula X are used based on one mole of the second starting compound.

The compound of formula X used in this invention may be iodomethane, iodoethane, bromoethane-15, 1-iodobutane, 1-bromobutane, 1-iodopropane, 2-iodipropane, 1-fluoro-2-iodoethane, 1- iodo-2-methoxyethane, N- (2-iodoethyl) acetamide, N- (2-iodoethyl) -N-methylacetamide, bromoacetic acid, allyl boride, 4-fluorobenzyl bromide, acetic anhydride, acetic anhydride, acetyl chloride, acetyl chloride propionic anhydride, propionyl chloride, benzoic anhydride, benzoyl chloride, 4 - [(trifluoroacetyl) amino] benzoic anhydride, chloroacetone, 1-chloro-2-butanone, phenylacyl chloride, 4-acetylaminophenylthioethyl, ethylmethyl) chloromethyl -nitrophenyl ketone, 4-nitrobenzyl bromide, dimethylcarbamoyl chloride or the like.

If desired, the reaction according to process variant c2) can be carried out in a solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, dioxane, tetrahydrofuran, methanol, ethanol, propanol, glycol monomethyl ether or the like. Mixtures of two or more solvents may also be used.

35 The reaction temperature can vary over a relatively wide range. In general, the reaction is carried out at a temperature of about 30 to 170 ° C, preferably 50 to 140 ° C.

15 86428

The reaction preferably uses 1 to 5 moles, more preferably 1 to 2 moles of the compound of formula XI per mole of the second starting compound.

The Michael acceptor used in the invention is e.g.

5 methyl vinyl ketone, ethyl vinyl ketone or the like.

The reaction of compounds IX with formaldehyde and formic acid or alkali metal bisulphite (process variant c3) is usually carried out at a slightly elevated temperature, e.g. at about 50-100 ° C.

The reaction according to process variant c4) can be carried out, if necessary, in a solvent such as pyridine, dimethylformamide, dioxane, tetrahydrofuran or 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, alkali metal hydroxides, alkali metal carbonates or the like.

The reaction temperature can vary over a relatively wide range. In general, the reaction is carried out at a temperature of about 0 to 120 ° C, preferably 0 to 100 ° C.

The reaction preferably uses one mole or excess mole of the compound of formula XII per mole of the second starting compound.

The anhydride used in the invention is, for example, succinic anhydride, glutaric anhydride, N-benzyloxycarbonyl aspartic anhydride, N-benzyloxycarbonylglutamic anhydride, phthalic anhydride or the like.

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 benzyloxycarbonyl radical may be removed by hydro-genolysis. The removal of the protective radical can be carried out before or after the isolation of the product.

86428 BC

The oxidation according to process variant d) is carried out by treatment with an organic or inorganic oxidant. Various compounds that readily release oxygen can be used as the oxidant, for example, organic peroxides such as monosubstituted organic peroxides (e.g., C 1-4 alkyl or alkanoyl hydroperoxides, such as t-butyl hydroperoxide), perforic acid, and peracetic acid. phenyl-substituted derivatives of hydroperoxides such as cumene hydroperoxide 10 and perbenzoic acid. The phenyl substituent may additionally have a lower group (e.g. a C 1-4 alkyl or alkoxy group), a halogen atom or a carboxy group (e.g. 4-methylperbenzoic acid, 4-methoxyperbenzoic acid, 3-chloroperbenzoic acid and monoperphthalic acid) if desired. Various inorganic oxidants can also be used as oxidants, for example hydrogen peroxide, ozone, permanganates such as potassium or sodium permanganate, hypochlorites such as sodium, potassium or ammonium hypochlorite, peroxymorosulfuric acid and peroxydisulfuric acid, 3-chloro-perehoic acid is preferred. The oxidation is preferably carried out in an inert solvent, for example an aprotic inert solvent such as tetrahydrofuran, dioxane, methylene chloride, chloroform or ethyl acetate. The oxidation is generally carried out at a temperature in the range of -20 to 50 ° C.

When an equimolar amount or a small excess relative to the starting material is used of the oxidant, a substantially corresponding sulfoxide is obtained, i.e. a compound of formula I wherein the heterocycle contains a group -SO- as a member. When the amount of oxidant 30 is added to twice the stoichiometric ratio or more, the corresponding sulfone is obtained, i. a compound of formula I wherein the heterocycle contains a group -SO 2 - as a member. It is also possible to obtain the sulfone from the corresponding sulfoxide by treating with an equimolar or larger amount of oxidant.

Il i7 B 6 4 2 8

In process variant e) the amino protecting groups are e.g. lower alkanoyl such as acetyl; benzoyl; an alkoxycarbonyl group, e.g. t-butoxycarbonyl or ethoxycarbonyl; a substituted alkoxycarbonyl group, e.g.

5 trichloroethoxycarbonyl; phenoxycarbonyl; benzyloxycarbonyl; p-nitrobenzyloxycarbonyl; an aralkyl group such as trityl or benzhydryl; or a haloalkanoyl group such as trifluoroacetyl.

Amino protecting groups can be cleaved off by acid hydrolysis (e.g., a t-butoxycarbonyl or trityl group) or by base hydrolysis (e.g., a trifluoroacetyl group). Benzyloxycarbonyl and p-nitrobenzyloxycarbonyl are removed by hydrogenolysis.

Amino protecting groups that are cleavable by acid hydrolysis are preferably removed with a lower alkanecarboxylic acid, which may be halogenated. In particular, formic acid or trifluoroacetic acid is used. Acid hydrolysis is generally performed at room temperature, although it can be performed at slightly higher or lower temperatures (e.g., in the range of about 0 to 40 ° C. Protecting groups that are cleavable under basic conditions are usually hydrolyzed with dilute aqueous Caustic base at 0-30 ° C). C.

Carboxy protecting groups include, for example, those carboxy protecting radicals discussed in R 1 above.

The removal of these protecting groups can be carried out in a manner known per se, e.g. by hydrogenation (benzyl) or by acidic or basic hydrolysis. The reaction is preferably carried out in an inert solvent at a temperature in the range of about 0 ° C to room temperature. Specific methods are also useful, e.g., removal of p-nitrobenzyl by hydrolysis in the presence of sodium sulfide at about 0 ° C (or slightly below) - at room temperature in a solvent such as dimethylformamide (aqueous solution); Removal of t-butyl-35 by reaction with trifluoroacetic acid anisole 8 6 428

In the presence of about 0 ° C to room temperature with or without another solvent such as methylene chloride; or removal of allyl by a palladium (0) catalyzed transallylation reaction in the presence of a sodium or potassium salt of 2-ethylhexanoic acid, see for example J. Org. Chem. 47 (1982) 587.

The halogenating agent used in process variant f) is preferably a thionyl halide, in particular a thionyl chloride, or a phosphonium trichloride, phosphorus oxychloride or phosphorus pentachloride. The reaction temperature is preferably about 0 to 80 ° C. The carboxy groups present are preferably protected, e.g. benzylated, and subsequently released, if desired, e.g. by hydrogenation (benzyl removal).

The reduction according to process variant g) can be carried out by hydrogenation in the presence of a noble metal catalyst such as palladium on carbon. 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 normally about 10 to 40 ° C, preferably room temperature.

In process variant h), corresponding di- (lower alkyl) acetals, such as dimethylacetal, can be used as the reactive derivative of the compound of formula VII. The reaction is preferably carried out in an inert solvent such as diethyl ether, dimethylformamide or dimethyl sulfoxide. The temperature is preferably about room temperature, but may well be below or above, e.g. about 0 to 100 ° C.

Preparation of an ester of formula I according to process variant i), i. those in which R 1 is a carboxy protecting group may be carried out by reacting a carboxylic acid of formula I with a corresponding halide, preferably iodide or bromide, containing the desired ester group. Reactions can be accelerated using a base such as alkali metal hydroxide, alkali metal carbonate or an organic amine such as triethylamine. The esterification is preferably carried out in an inert organic solvent such as dimethylacetamide, hexamethylphosphoric acid triamide, dimethylsulfoxide or especially dimethylformamide. The reaction is preferably carried out at a temperature in the range of about 0 ° C to 40 ° C.

The preparation of pharmaceutically acceptable salts of 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, a base of formula I with an organic or inorganic acid. . The reaction is conveniently carried out in a solvent such as water or an organic solvent (e.g. ethanol, methanol, acetone or the like). The temperature at which salt formation is performed is not critical. The salt formation is generally carried out at room temperature, but can also be carried out at temperatures slightly above and below room temperature, for example at 0-50 ° C.

Examples of pharmaceutically acceptable acids that can be used in the above process include hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, formic, acetic, propionic, succinic, glycolic, maize, malic -, wine, lemon, ascorbic, maleic, hydroxymalein, phenylacetic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, aminosalicylic, nicotine, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, gluconic, glucuronic, galacturonic, aspartic and glutamic acids; methionine, tryptophan, lysine, arginine and the like.

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

20 8 6 42 8

The basic salts of the compounds of formula I may be prepared by reacting a compound of formula I with a metal base such as an alkali or alkaline earth metal hydroxide, amine 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'-dibenzylethylenediamine, choline, ethylenediamine and the like.

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 occur in stages as a result of the hygroscopic properties of the initially anhydrous product. For the controlled preparation of the hydrate, the completely or partially anhydrous product can be placed in a humid atmosphere (e.g. at a temperature of about 10 to 40 ° C). Solvates with pharmaceutically acceptable solvents such as ethanol can be obtained, e.g., during crystallization. Certain compounds prepared in accordance with the 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 have a broad antibac-. 30 therapeutic effect against gram-political and gram-negative organisms as well as Mycoplasma and can be used for the treatment and prevention of infectious diseases. The in vitro and in vivo antibacterial activities of the compounds are shown below: 35 1. In vitro antibacterial activities

The in vitro antibacterial activities of the pyrido [3,2,1-ij] -1,3,4-benzoxadiazine derivatives according to the invention were examined in vitro by the standard agar dilution method, see: Chemotherapy 22 (1974) 1126. Their minimum inhibitory concentrations (MIC, in pg / l) is shown in Table 1 and Table 5 in Table 2. The compounds used herein were prepared in the corresponding examples as mentioned below.

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Anaerobic Antibacterial Spectrum MIC (pg / ml) Microorganisms Compound (From Example No.) 5 __5_30_

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 0.39 010 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 15 ATCC 15703 0.39 0.10

Clostridium botulinum NR 2611 0.10 0.013

Clostridium perfringens NR 2612 0.39 0.10

Clostridium moniliforme ATCC 25546 0.78 0.10 20 Fusobacterium varium ATCC 8501 12.5

Peptococcus prevotii ATCC 9321 1.56 0.39

Peptococcus variabilis ATCC 14955 0.78 0.20 ···. Peptostreptococcus anaerobius 25 NR 2743 0.39 0.013

Propionibacterium acnes ATCC 11828 0.78 0.78

Mycoplasma 30 _

Mycoplasma horainis NR 2952 0.10 0.10 l! 27 86 42 8 2. In vivo therapeutic effect The in vivo 5 antibacterial activity of the pyrido [3,2,1-ij] -1,3,4-bentoxadiazine derivatives prepared according to Examples 5, 30, 65 and 66 below was studied in Escherichia. coli ML4707, Pseudomonas aeruginosa 4au542 and Streptococcus pneumoniae 6-001. ICR mice weighing about 20 g were infected by intraperitoneal injection with the corresponding bacterial suspension.

10 Test compounds were administered orally over five days. The corresponding 50% effective dose (ED50, mg / kg) that protects 50% of animals from infection death is shown in Table 3.

Table 3 15 In vivo antibacterial activities against systemic infection in mice (ED50, mg / kg)

Bacteria 20 Escherichia Pseudomonas Streptococcus coli aeruginosa pneumoniae

Compound ML4707 4au542 6-001 s · c · p · O · p · o · p · O · 25 -

Example 5 0.06 0.11 13.4 10.3

Example 30 0.10 0.62 57.0 65.9

Example 65 1.12

Example 66-0.51 30-3. Acute toxicity The corresponding LD50 values of the compounds obtained in Examples 5, 6, 7, 16, 17, 18, 30, 36 and 56 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 the invention have a broad antimicrobial spectrum against gram-positive and gram-negative bacteria as well as Mycoplasma, especially those resistant to various antibiotics such as penicillins, cephalosporins, aminoglycosides, tetracyclines and the like.

In addition, the compounds of the invention have low toxicity and potent and extensive antimicrobial activity. The protective effects of the compounds on systemic bacterial infections in mice are greater than with commercially available synthetic antibacterial agents. Therefore, these compounds can be effectively used 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, Lactabacillus, Bifidobacterium, Clostridium, Eubacterium, Peptococcus, Peptostoccus , Escherichia, Citrobacter, Campylobacter, Enterobacter, Kleb-20 there, Proteus, Pseudomonas, Serratia, Salmonella, Shigella, Vibrio, Aeromonas, Haemophilus, Neisseria, Acinobacter, Alcaligenes, Bordetella, Bacteroides, Fusobacterium, Mycoplasma organisms.

The compounds according to the invention resemble a commercially available drug, ofloxacin, which is well known in structure (see FI patent 71155). However, the structural difference, two adjacent nitrogen atoms in the tricycle forming the pyrido [3,2,1-ij] -1 , Compared to the 3,4-benzoxadiazine ring of 30 nitrogen atoms in the pyrido [1,2,3-de] -1,4-benzoxadiazine ring of ofloxacin, surprisingly (see Table 1) resulted in higher antibiotic activity with the compounds of formula I having excellent antimicrobial activity. against a wide range of microorganisms.

li 29 86 428

The compounds of formula I may be administered orally or non-orally to humans or animals by a variety of conventional methods of administration.

In addition, the compounds of this invention are used alone or in compositions with excipients, liquid diluents, binders, lubricants, wetting agents, etc., for example, general pharmaceutical compositions such as tablets, granules, sugar-coated tablets, powder, capsules, gels, dry syrup. , in the form of syrup, ampoules, suspension, liquid, emulsion, ointment, paste, Kree-min, suppositories and the like. Furthermore, solubilizers, absorption accelerators, surfactants and the like, as well as other formulation additives can be used, i.e. any pharmaceutically acceptable forms.

The compounds of the invention 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 weight of the total pharmaceutical composition.

The daily dosage of a novel compound of the invention to a patient may vary depending on the individual, the species, the weight and the condition being treated, but will generally be from 0.5 to 500 mg per kilogram of body weight per day, preferably from about 1 to 300 mg.

The following examples illustrate the invention.

Preparation of starting material

Reference Example 30 Preparation of diethyl N- (3,4-difluoro-2-hydroxyphenyl) aminomethylenemalonate (a) A solution of 2,3-difluoro-6-nitrophenol (500 mg) in methanol (7 ml) was hydrogenated. 5% Pd / C (60 mg) 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.

3o 86428 (b) A mixture of the above amine (414 mg) and diethyl ethoxymethylene malonate (618 mg) was heated at 130 ° C under 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, m.p. 178-180 ° C; MS m / z 315 (M &lt; + &gt;). 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.

1 o Ethyl 8-benzyloxy-6,7-difluoro-4-hydroxy-3-quinolinecarboxylate (Method 1) __ (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), m.p. 87 ° C; MS m / z 405 (M &lt; + &gt;).

(d) A solution of the above malonate (280 mg) 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 silica gel column chromatography (10 g) eluting sequentially with benzene, dichloromethane and dichloromethane / acetone; (30: 1). The pure fractions were combined and the solvent was removed under reduced pressure to give a 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-35-4-hydroxy-3-quinolinecarboxylate. Analytical sample.

31 86428 sp. 200-201 ° C; MS m / z 359 (M +), prepared by recrystallization from methanol.

Preparation of ethyl 8-benzyloxy-6,7-difluoro-4-hydroxy-3-quinolinecarboxylate (Method 2) - To a stirred mixture of ethyl 6,7-difluoro-4,8-dihydroxy-3-quinolinecarboxylate (300 mg). to a solution of dry dimethylformamide (6 ml) was added anhydrous potassium carbonate (308 mg) and then 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-6,7-15 difluoro-4-hydroxy-3-quinolinecarboxylate; mp. 200-201 ° C; MS m / z 359 (M &lt; + &gt;), after recrystallization from methanol.

Preparation of ethyl 8-benzyloxy-6,7-difluoro-1- (formylmethylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylate (e) When ethyl 8-benzyloxy-6,7-difluoro A mixture of -4-hydroxy-3-quinolinecarboxylate (410 mg) and anhydrous ***: potassium carbonate (315 mg) in dry dimethylform-; in amide (10 mg) was stirred at room temperature for 3 hours, O- (2,4-dinitrophenyl) hydroxylamine (260 mg) was added. The mixture was stirred at room temperature for another 6.5 hours.

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

32 86428 (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 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 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- quinoline carboxylate, m.p. 188-190 ° C; MS m / z 402 (M &lt; + &gt;).

(g) A mixture of the above formamide (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, m.p. 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 (starting material of formula V) _ (h) Ethyl-8-benzyloxy-6,7 -Difluoro-1- (formyl- • methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylate 30 (330 mg) was hydrogenated over 5% Pd / C (50 mg) in chloroform (14 mL) 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 35,239 mg of ethyl 6,7-difluoro-1- (formylmethylamino) -8-hydroxy-4-oxo-1,4-dihydro-3-quinolinecarboxylate, m.p. 221-225 ° C (dec.); MS m / z 326 (M &lt; + &gt;).

Il 33 8 6 423 (i) A mixture of the above ester (210 mg) and 0.5 N sodium hydroxide (5.2 ml) was heated at 100 ° C for 2 hours under a nitrogen atmosphere. The reaction mixture was acidified with acetic acid (0.16 ml). The separated precipitate was filtered, washed with water and dried under reduced pressure to give 168 mg of 6,7-difluoro-8-hydroxy-1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid. Analytical sample, m.p. 248-250 ° C (dec.); MS m / z 270 (M +), prepared by recrystallization from ethanol.

Example 1 Preparation of 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-12] -1,3,4-benzoxadiazine-6-carboxylic acid (formula Intermediate III) _

The 6,7-difluoro-8-hydroxy-15- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (105 mg) obtained in Reference Example (i), paraformaldehyde (150 mg) and a mixture of dry dioxane (5 ml) was heated at 100 ° C for 3 hours under reduced pressure under nitrogen. 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. Residue. 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-bentsoksadiatsiini-6-carboxylic acid. Analytical sample, m.p. 290-292 ° C (dec.); MS m / z 282 (M +), prepared by recrystallization from dimethylformamide.

Example 2 9,10-Difluoro-2,3-dimethyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-b] 1,3,3,4-benzoxadiazine-6-carboxylic acid manufacture (intermediate of formula III) _

The 6,7-difluoro-8-hydroxy-1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid obtained in Reference Example (i) · 35 acid (50 mg), 90% A mixture of acetaldehyde (1 ml) and dioxane (5 ml) 34 86 423 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-i] -1,3,4-benzoxadiazine. 6-carboxylic acid, m.p. 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-b] 7,7,3,4-benzoxadiazine Preparation of -O-carboxylic acid (intermediate of formula 111) 10 6,7-Difluoro-8-hydroxy-1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid obtained in Reference Example (i) (50 mg), a suspension of glycolaldehyde diethyl acetal (45 μΐ) and pyridinium p-toluenesulfonate (7 mg) in dry dioxane (2 ml) were heated at 110 ° C for 15 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-i] -1,3,4-benzoxadiazine-6-carboxylic acid, m.p. 254-20 258 ° 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-b] 1,3,4-benzoxadiazine-6 Preparation of carboxylic acid p-toluenesulfonate 25 (intermediate of formula IIII) __

The dimethylaminoacetaldehyde dimethyl acetal (37 mg) of 6,7-difluoro-8-hydroxy-1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (50 mg) obtained in Reference Example (i) ) and a suspension of p-toluenesulfonic acid monohydrate 30 (53 mg) in dry dioxane (2 ml) was heated at 110 ° C for 17 hours under nitrogen. 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-35H-pyrido [3 , 2,1-i] -1,3,4-benzoxadiazine-6-carboxylic acid p-toluenesulfonate, m.p. 232-236 ° C (dec.); FAB-MS m / z 340 (MH &lt; + &gt;).

li 35 86423

Example 5 9-Fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1] 3,4-benzoxadiazine. Preparation of 6-carboxylic acid The 5,1,1-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4,4-benzoxadiazine-6 obtained in Example 1 a mixture of 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, m.p. 268-269 ° C (dec.); MS m / z 362 (M &lt; + &gt;).

The following compounds were obtained in an analogous manner to Example 5: 0

FyYV ° 2H

20 R5R6N «^ Y ^ N- ^ 0νχΝ * ΐΗ3

Again-

Ex. 5R6 Melting point crystallization solvent 25 m £ 2_I_fc_ solvent MS m / z 6 H0-240 * 245 (dec. MeOH 349 (MH +) * 7 ηΓ> 237 ** 239 (dec.) MeOH / CHCl3 362 (M +) 30 8 H 256 ^ 259 ^ aj.) DMF 425 (MH +) *

PH

9> 300 EtOH / CHCl 3 349 (M *) ch 3 10 (T ~ y> 300 DMF 377 (M +) 35 36 86 423

Again-

Example 56 Melting point crystallization no. ° C_ solvent_MS m / z 5 11 ¢ / -> 30 ° (dec.) DMF 365 (M +) 12 H2N \ x ^ D "238 ~ 242 (dec.) MeOH 377 (MH +) * 13 HO- (31 "256 ^ 258 MeOH / CHCl 3 363 (M +) 10 14 DO- 272 ~ 274 (dec.) EtOH 413 (MH +) * 15 270 ^ 275 H 2 O 393 (MH +) * 15 16 H Q- 243 ^ 246 MeOH / CHCl 3 362 (M +) 17 CH 2 Cl 2 242 ^ 244 (dec.) DMF 377 (MH +) * 18 rut 12K252 (dec.) EtOH 391 (MH +) * 20 c 2 H 5 N 2 O 2 19 AcNX-J-), “239 ^ 241 (dec.) EtOH 405 (MH +) * 20 266 ^ 268 (hai ·) EtOH 365 (MH +) * CHf 2 5" 21 ΓΛ- 284 ^ 286 (dec.) DMF 350 (MH +) * H 22 CH 3 TV 280-284 (dec.) MeOH / CHCl 3 / Et 2 O 345 (MH +) * 30 23 CH3! T [> - 220 ^ 222 (dec.) EtOH 391 (MH +) * ch3 · * '

* FAB-MS

i <37 86428

Example 24 9-Fluoro-3-methyl-7-oxo-10- (3-oxo-1-piperazinyl) -2,3-dihydro-7H-pyrido [3,2,1-b] 7-1 / 3, Preparation of 4-benzoxadiazine-6-carboxylic acid The 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1,3 obtained in Example 1, A mixture of 4-benzoxadiazine-6-carboxylic acid (40 mg), 2-piperazinone (31.1 mg), 1,4-diazabicyclo [2.2.2] octane (31.8 mg) and dry dimethyl sulfoxide (1 ml) was heated to 10,130. ° C for 28.5 hours under a nitrogen atmosphere. The solvent was removed under reduced pressure. The residue was purified by preparative TLC (silica gel: CHCl 3 / MeOH, 10: 1.5) and recrystallized from a mixture of dichloromethane and methanol to give 6.3 mg of 9-fluoro-3-methyl-7-oxo-15- (3 -oxo-1-piperazinyl) -2,3-dihydro-7H-pyrido [3,2,1-b] -1,3,4-benzoxadiazine-6-carboxylic acid, m.p.

> 300 ° C; FAB-MS m / z 363 (MH &lt; + &gt;).

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: 38 8 6 423

FfYYC02H

R5R6N

> X »»

Again-

Eg 5 g Melting point crystallization No. 1 RR N-R3 ° C solvent SMS m / z 2 H (Qn-CH3 240 ^ 242 (dec.) MeOH 362 (M4) 26 CH3f (] ^ N-CH3 203 ^ 206 EtOH 376 (M +) 15 27 CH3 ^ N-CH2OH 229 ^ 231 (dec.) MeOH 393 (MH4) * 1 2 3 CH3fT ~) 1-CH2N (CH3) 2 210 ^ 212 MeOH 420 (MH4) * 20 ____

* FAB-MS

Example 29 10- [3- (Benzyloxycarbonylamino) -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido-25 [3,2,1-ij] - Preparation of 1,3,4-benzoxadiazine-6-carboxylic acid__

9,10-Difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-b] 1,3,4-benzoxadiazine obtained in Example 1 -6-carboxylic acid (28 mg), 3- (benzyloxy-3-carbonylamino) pyrrolidine (94 mg) and dry pyridine. . The mixture (3 mL) was heated at 100 ° C for 3 hours under nitrogen. The pyridine was removed under reduced pressure and the residue was recrystallized from methanol to give 36 mg of 1C- [3- (benzyloxycarbonylamino) -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro -2,3-3986,428 dihydro-7H-pyrido [3,2,1-b] -1,3,4-benzoxadiazine-6-carboxylic acid, m.p. 227-230 ° C; MS m / z 482 (M &lt; + &gt;).

Example 30 10- (3-Amino-1-pyrrolidinyl) -9-fluoro-3-methyl-7-5-oxo-2,3-dihydro-7H-pyrido [3,2,1-b] -1,3,4 -Benzoxadiazine-6-carboxylic acid preparation_

The 10- [3- (benzyloxycarbonylamino) -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-b] 7-1 [ 3,4-Benzoxadiazine-6-10 carboxylic acid (30 mg) was hydrogenated over 5% Pd / C (10 mg) in dimethylformamide (2 mL) for 4.5 hours. After removing 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) -9-15 fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij]. Β-1,3,4-benzoxadiazine-6-carboxylic acid, m.p. 230-234 ° C (dec.); MS m / z 348 (M &lt; + &gt;).

The following compounds were obtained in analogy to the procedure used in Examples 29 and 30: 4o 86428 oV "rVii-Vt 0- ^ n'-CH3 5

Again-

Eg melting point crystallization no. R * * R N -_C_ solvent_MS m / z 31 286 ^ 288 (dec.) HgO 363 (MH +) * 32 ΓΛ-269 ^ 273 (dec.) MeOH 377 (MH +) * c2h5n> ^ 15 33 H2N-Qn-240 ^ 245 (dec.) MeOH 363 (MH +) * 34 CH3B-Q1-262 ^ 265 (dec.) MeOH 37; (MH +) * 20 35 C2H5il- ^ N_ 252 ^ 256 (dec.) EtOH 390 (M +)

* FAB-MS

Example 36 ... 10- (3,4-Dimethyl-1-piperazinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1- Preparation of β-1,3,4-benzoxadiazine-6-carboxylic acid

9-Fluoro-3-methyl-10- (3-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1,3, obtained in Example 7, 4-Benzoxadiazine-6-carboxylic acid 30 (60 mg), 98% formic acid (1ml) and 35% formalin. ; The mixture (1 ml) was stirred at 100-110 ° C. After heating for 2 hours, the mixture was evaporated under reduced pressure. The residue was dissolved in water, neutralized with 1 N sodium hydroxide and extracted with chloroform. The extract was washed with water and dried over anhydrous sodium sulfate. After removing solvent 4i 86 423 under reduced pressure, the crystalline residue was recrystallized from methanol to give 43 mg of 10- (3,4-dimethyl-1-piperazinyl) -9-fluoro-3-methyl-7-oxo-2,3- dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-5 6-carboxylic acid, m.p. 257-259 ° C; FAB-MS m / z 377 (MH &lt; + &gt;).

Example 37 9-Fluoro-10- (3-methoxy-1-pyrrolidinyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-b] -1,3,4 Preparation of benzoxadiazine-6-carboxylic acid The 10-fluoro-10- (3-hydroxy-1-pyrrolidinyl) -3-methyl-7-oxo-2,5-dihydro-1H-pyrido-ZS-2 obtained in Example 21 was prepared. To a suspension of 1-γ-1,3,4-benzoxadiazine-6-carboxylic acid (100 mg) in dry dimethylformamide (10 ml) was added 60% sodium hydride in oil (30 mg) and methyl 15-iodide (40 μl). After the mixture was stirred at room temperature for 2 hours, an additional 60% sodium hydride (30 mg) and methyl iodide (40 μl) were added, and the mixture was stirred at 45 μC for 3 hours. The solvent was then removed under reduced pressure. Cold water (2 ml) and 0.5 N sodium hydroxide (2.3 ml) were added to the residue, 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 was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crystalline residue, which was chromatographed on silica gel using acetone / chloroform (1: 9) as an eluent. After recrystallization from methanol, 42 mg of 9-fluoro-10- (3-methoxy-1-pyrrolidinyl) -3-methyl-7-oxo-2,3-di-30-hydro-7H-pyrido / 3.2.1 -1H-1,3,4-benzoxadiazine-6-carboxylic acid, mp 233-234 ° C; FAB-MS m / z 364 (MH &lt; + &gt;).

42 86428

Example 38 9-Fluoro-10- (4-methoxy-1-piperidyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4- Preparation of benzoxadiazine-6-carboxylic acid 5,9-fluoro-10- (4-methoxy-1-piperidyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] 7-1,3,4-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-b] -1,3,4-benzoxadiazine-10-choline-6-carboxylic acid in analogy to Example 37 and obtained as crystals, m.p. 229-233 ° C (dec.)? MS m / z 377 (M +) after recrystallization from chloroform / hexane.

Example 39 10- (1,1-Dioxide-4-thiomorpholinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-b] -1, Preparation of 3,4-benzoxadiazine-6-carboxylic acid_

9-Fluoro-3-methyl-7-oxo-10- (4-thiomorpholinyl) -2,3-dihydro-7H-pyrido [3,2,1-i} 7-1,3,4-20 obtained in Example 11 To a suspension of benzoxadiazine-6-carboxylic acid (50 mg) in dichloromethane (5 mL) was added m-chloroperbenzoic acid (70% purity, 74 mg). The mixture was stirred at room temperature for 18 hours. The solvent was then removed under reduced pressure. The residue was washed with ether, dichloromethane and a mixture of chloroform and methanol, and recrystallized from dimethylformamide to give 22 mg of 10- (1,1-dioxide-4-thiomorpholinyl) -9-fluoro-3-methyl-7-oxo-2,3 -dihydro-7H-pyrido [3,2,1-b] -1,3,4-benzoxadiazine-6-carboxylic acid, m.p. > 300 ° C; MS m / z 397 (M &lt; + &gt;).

Example 40 9-Fluoro-3-methyl-7-oxo-10- [4- (2-oxo-n-propyl) -1-piperazinyl] -2,3-dihydro-7H-pyrido [3,2,1- Preparation of 1,7,4,4-benzoxadiazine-6-carboxylic acid_

The 9-fluoro-3-methyl-7-oxo-10-35 (1-piperazinyl) -2,3-dihydro-7H-pyrido [3,2,1-b] -1,3,4- obtained in Example 6 li 43 86428 A mixture of benzoxadiazine-6-carboxylic acid (50 mg), chloroacetone (17 μΐ), triethylamine (40 μΐ) and dry dimethylformamide (1 ml) was heated at 80 ° C for 3.5 hours. The volatile components were then removed under reduced pressure and the residue was 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] -1,3,4-10 benzoxadiazine-6-carboxylic acid, m.p. 225-229 ° C (dec.), FAB-MS m / z 405 (MH &lt; + &gt;).

The following compounds were obtained in an analogous manner to Example 40.

rXÖ “!" 20 ---—

Again-

Example 70 Melting point crystallization No._2__ solvent_FAB-MS m / z 41 COCH 2 "223-2266 (dec.) DMF 467 (MH +) dec.) EtOH 391 (MH +) 44 FCH 2 CHp-257 ^ 259 (dec.) EtOH 395 (MH +) 30 cc 45 H 2 OCHCH 2 -256λ.259 (dec.) H 2 O 407 (MH +) 46 CH 2 * CHCH 2 236 ^ 238 (dec.) MeOH 389 (MH +) 47 02N-Q-CH2-27-276 (dec.) EtOH 484 (MH +) 35 44 86428

Example 48 10- [3 - [(Ethylmethylamino) methyl] -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1 Preparation of 1,2- (1,3-benzoxadiazine-6-carboxylic acid 5- [3- (Tetylmethylamino) methyl] -1-pyrrolidinyl) -4-fluoro-3-methyl-7-oxo-2,3-dihydro -7H-pyrido [3,2,1-b] 1,3,4-benzoxadiazine-6-carboxylic acid was prepared from 9-fluoro-3-methyl-10- [3- (7-methylamino) -10-methyl] -1-pyrrolidinyl] 7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4,4-benzoxadiazine-6-carboxylic acid obtained in Example 17 and ethyl iodide in analogy to Example 40 and obtained as crystals, mp. 210-225 ° C (dec.); FAB-MS m / z 405 (MH &lt; + &gt;); after recrystallization from a mixture of chloroform, methanol and n-hexane.

Example 49 10- [4- (3-Carboxypropionyl) -1-piperazinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1, Preparation of 3,4-benzoxadiazine-6-carboxylic acid The 9-fluoro-3-methyl-7-oxo-10- (1-piperazinyl) -2,3-dihydro-7H-pyrido [3,2,1- A mixture of η 7 -1,3,4-benzodiazine-6-carboxylic acid (50 mg), succinic anhydride (21.6 mg), triethylamine (40 μl) and dry dimethylformamide (4 ml) was heated at 80 ° C for 2 hours. . The solvent was then removed under reduced pressure and the ice was 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-b] -1,3,4-benzoxadiazine-: 6-carboxylic acid, m.p. 257-259 ° C (dec.); FAB-MS m / z 449 (M &lt; + &gt;).

45 86423

Example 50 10- (4-Acetyl-1-piperazinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-b] -1,4,4 Preparation of benzoxadiazine-6-carboxylic acid 5 10- (4-acetyl-1-piperazinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] 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] obtained in Example 6. -ij / -1,3,4-10 benzoxadiazine-6-carboxylic acid and acetic anhydride in analogy to Example 49 and were obtained as crystals, m.p. 294-296 ° C (dec.); FAB-MS m / z 391 (MH &lt; + &gt;); after recrystallization from dichloromethane / methanol.

Example 51 9-Fluoro-3-methyl-7-oxo-10- [4- (3-oxo-n-butyl) -1-piperazinyl] -2,3-dihydro-7H-pyrido [3,2,1- Preparation of 1-7,4-benzoxadiazine-6-carboxylic acid_

9-Fluoro-3-methyl-7-oxo-10- (1-piperazinyl) -2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-20 benzoxadiazine obtained in Example 6 A mixture of β-carboxylic acid (30 mg), methyl vinyl ketone (36 μL) and ethanol (1 mL) was refluxed for 12 hours and then cooled to room temperature. The separated precipitate was collected by filtration and crystallized from ethanol to give 28 mg of 9-fluoro-3-methyl-7-oxo-10- [4- (3-oxo-n-butyl) -1-piperazinyl] -2,3- dihydro-7H-pyrido [3,2,1-i} 7-1,3,4-benzoxadiazine-6-carboxylic acid, m.p. 187-189 ° C (dec.); FAB-MS m / z 419 (MH &lt; + &gt;).

Example 52 Disodium 9-fluoro-3-methyl-7-oxo-10- [4- (sulfonatomethyl) -1-piperazinyl] -2,3-dihydro-7H-pyrido [3,2,1] Preparation of 7- 1,3,4-benzoxadiazine-6-carboxylate_

A mixture of 35% formalin (26 mg), sodium bisulfite (32 mg) and water (0.5 mL) was heated at 75 ° C for 30 minutes and then cooled to room temperature. To this solution was added 9-fluoro-3-methyl-7-oxo-10- (1-piperazinyl) -2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4 obtained in Example 6. -benzoxadiazine-6-carboxylic acid (100 mg) and sodium hydroxide (15 mg). After the mixture was heated at 75 ° C for 1 hour, ethanol (2 ml) was added. The mixture was then cooled to room temperature.

The separated precipitate was collected by filtration and recrystallized from water / ethanol (1: 2) to give disodium 9-fluoro-3-methyl-7-oxo-10- [4- (sulfonate methyl) -1-piperazinyl]. -2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylate, m.p. 260-263 ° C (dec.); 1 H-NMR (D 2 O) δ: 2.98 (3H, S), 3.05 (4H, m), 3.39 (4H, m), 3.84 (2H, S), 5.18 (2H, S), 7.55 (1H, d, J = 13.4 Hz), 8.34 (1H, S).

15 Example 53 10- [4- (4-Aminobenzyl) -1-piperazinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-b] 7 Preparation of 11,3,4-benzoxadiazine-6-carboxylic acid_

9-Fluoro-3-methyl-10- [4- (4-20 nitrobenzyl) -1-piperazinyl] -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] 7,3 obtained in Example 47 1,4-Benzoxadiazine-6-carboxylic acid (100 mg) was hydrogenated over 5% Pd / C (10 mg) in dichloromethane / methanol (1: 1) for 2 hours. After removal of 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-η 7 -1,3,4-benzoxadiazine-6-carboxylic acid, m.p. 237-238 ° C (dec.); FAB-MS m / z 454 (MH &lt; + &gt;).

30 Example 54. . 10- [3- (aminomethyl) -1-pyrrolidinyl] -9-fluoro-3-; methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-b] -1,3,4- preparation of benzoxadiazine-6-carboxylic acid_

The 10- [3- (acetylaminomethyl) -35 1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydrol 47 86428 7H obtained in Example 19, pyrido [3,2,1,3, A mixture of 4-benzoxadiazine-6-carboxylic acid (40 mg) and 1N sodium hydroxide (2.5 ml) was heated at 100 ° C for 3 hours. After cooling to room temperature, the reaction mixture was neutralized with acetic acid, and the separated precipitate was collected by filtration and recrystallized from methanol to give 15 mg of 10- [3- (aminomethyl) -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3 -dihydro-7H-pyrido [3,2,1-b] -1,3,4-benzoxadiazine-6-carboxylic acid, m.p. 177-180 ° C (dec.); FAB-MS m / z 363 (MH &lt; + &gt;).

Example 55 Preparation of 6-fluoro-8-hydroxy-7- (1-imidazolyl) -1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (starting material of formula V) -carbonyl- imidazole (32 mg) was added to a stirred solution of 6,7-difluoro-8-hydroxy-1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid obtained in Reference Example (i). (50 mg) in dry 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 was suspended in water and the pH was adjusted to 5 with acetic acid. The separated precipitate was filtered and washed with methanol to give 35 mg of 6-fluoro-8-hydroxy-7- (1-imidazolyl) -1- (methylamino) -254-oxo-1,4-dihydro-3-quinolinecarboxylic acid as a pale yellow powder, FAB-MS m / z 319 (MH &lt; + &gt;); 1 NMR (d 6 DMSO) δ 2.82 (3H, s), 7.10 (1H, d, J = 10.7 Hz), 7.61 (1H, d), 7.75 (1H, d), 8.62 (1H, s), 8.92 (1H, s), 15.33 (1H, br.s).

Example 56 9 9-Fluoro-10- (1-imidazolyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-b] -1,3,4-benzoxadiazine. Preparation of 6-carboxylic acid_

A suspension of 6-fluoro-8-hydroxy-7- (1-imidazolyl) -1- (methylamino) -4-oxo-1,4-dihydro-3-35 quinolinecarboxylic acid (15 mg) obtained in Example 55 in 35%

48 8642G

a mixture of formalin (1 ml) and dioxane (1 ml) was heated at 100-110 ° C for 1.5 hours under 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- (1-5 imidazolyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3.2.1]. - i ΐ 7-1 / 3,4-benzoxadiazine-6-carboxylic acid as a pale red powder. Analytical sample, m.p.

> 300 ° C; FAB-MS m / z 331 (MH +), prepared by recrystallization from dimethylformamide and ether.

109-Fluoro-10- (1-imidazolyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-b] -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-i] -1,3,4-benzoxadiazine-6-carboxylic acid and imidazole In dimethyl sulfoxide analogously to Example 5.

Example 57

Benzyl 9-fluoro-10- (3-hydroxy-1-pyrrolidinyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4 - preparation of benzoxadiazine-6-carboxylate 9-Fluoro-10- (3-hydroxy-1-pyrrolidinyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2] obtained in Example 21, A mixture of 1-yl-1,3,4-benzoxadiazine-6-carboxylic acid (10 mg) anhydrous potassium carbonate (8 mg) and dimethylformamide (0.5 ml) was stirred at room temperature for 1.5 hours and then benzyl bromide (10 mg) was added. 8 mg).

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-b] 1,3,4-benzoxadiazine-6-carboxylate, m.p. 196-198 ° C (dec.); FAB-MS m / z 440 (MH &lt; + &gt;).

li 49 86423

Example 58

Benzyl-10- (3-chloro-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4,4- Preparation of benzoxadiazine-6-carboxylate The benzyl 9-fluoro-10- (3-hydroxy-1-pyrrolidinyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2] obtained in Example 57 was obtained. 1- [1-7,4,3-Benzoxadiazine-6-carboxylate (8 mg) 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-oxo-2,3-dihydro-7H -pyrido [3,2,1-ij] -15 1,3,4-benzoxadiazine-6-carboxylate, m.p. > 300 ° C; FAB-MS m / z 458 (MH &lt; + &gt;), 460 (MH &lt; + &gt; 2) +.

Example 59 10- (3-Chloro-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-b] -1,3,4 -Production of benzoxadiazine-20-rail-6-carboxylic acid_

Benzyl 10- (3-chloro-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-b] -1,3 obtained in Example 58 was obtained. The 4-benzoxadiazine-6-carboxylate (2.5 mg) was hydrogenated over 5% Pd / C (1 mg) in chloro-25 form.

After the catalyst was removed by filtration, the filtrate was concentrated to dryness under reduced pressure. The residue was recrystallized from ethanol to give 1.0 g of 10- (3-chloro-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-3H-pyrido [3.2 , 1-1 ^ 7-1,3,4-bentsoksadiatsiini-6-carboxylic acid. ·. : acid, m.p. 269-272 ° C (dec.); FAB-MS m / z 368 (MH &lt; + &gt;). 370 (MH + 2) +.

so 86 423

Example 60 9-Fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4 Preparation of benzoxadiazine-6-carboxylic acid via fluoroborane-5 intermediate (a) The 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1- A mixture of 1H-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- (7-difluoroboryl) oxy] carbonyl-3-methyl-2,3-dihydro-7H-pyrido. [3,2,1-i] -1,3,4,4-benzoxadiazin-7-one; FAB-MS m / z 331 (MH &lt; + &gt;).

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

(C) To a solution of the above borane intermediate (5 mg) in 95% ethanol (Imi) was added triethylamine (3 μL). 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-10-30 (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido. . [3,2,1-i] -1,3,4-benzoxadiazine-6-carboxylic acid, m.p. 268-269 ° C (dec.).

I: 51 86428

Example 61 9-Fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-b] -1 / 3,4 Preparation of benzoxadiazine-6-carboxylic acid via the product of acetoxyborane intermediate 5 (a) 9,10-Difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1 - A mixture of 7-1,3,4-benzoxadiazine-6-carboxylic acid (100 mg), acetic anhydride (Imi) 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] -4,9,10-difluoro-3-methyl-2,3-dihydro-7H-pyrido [3,2,1-b] -1,3 4-bentsoksadiatsin-7-one; FAB-MS 1 5 m //. 41 1 (MH +).

(b) To a solution of the above borane intermediate (41 mg) in dimethyl sulfoxide (1 mL) was added N-methylpiperazine (15 μL) and triethylamine (20 μL). 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 - ((diacetoxyboryl) oxy-7-carbonyl] -9-fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -2,3-dihydro-7H- pyrido [3,2,1-b] 7,7,4-benzoxadiazin-7-one as yellow crystals; mp. 156-157 ° C (dec.); FAB-25 MS m / z 491 (MH &lt; + &gt;).

(c) The above borane intermediate (5 mg) was suspended in acetone (0.1 ml) and added conc. HCl (2.5 μL). The reaction mixture was stirred at room temperature for 30 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) was added to the solution and the mixture was cooled for 1 hour. After cooling to room temperature, the separated precipitate was collected by filtration to give 9-fluoro-3-methyl-10- (4-methyl-1-piper-35-azinyl) -7-oxo-2,3-dihydro-7H-pyrido]. 3,2,1-1,7- [3,4-benzoxadiazine-6-carboxylic acid, m.p. 268-269 ° C (dec.).

52 86428

Example 62

Pivaloyloxymethyl-10- [3- (benzyloxycarbonylamino) -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-b] -1 Preparation of 3,4-benzoxadiazine-6 -5 carboxylic acid_

The 10 - [(3- (benzyloxycarbonylamino) -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ol] obtained in Example 29 was obtained. A mixture of 1/3, 4-benzoxadiazine-6-carboxylic acid (290 mg), pivaloyloxymethyl chloride (130 μl), anhydrous potassium carbonate (166 mg) and dry dimethylformamide (10 ml) was stirred at 45 ° C for 8 hours. The solvent was then removed under reduced pressure, the residue was dissolved in dichloromethane, the dichloromethane solution was washed with water and dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate to give 325 mg of pivaloyloxymethyl-10-3- -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-b] -1,3,4-benzoxadiazine-20-carboxylate, m.p. 185-188 DEG C. FAB-MS m / z 597 (MH &lt; + &gt;).

Example 63

Pivaloyloxymethyl-10- (3-amino-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -25 1,3, Preparation of 4-benzoxadiazine-6-carboxylate_

Pivaloyloxymethyl-10- (3-amino-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4,4- Benzoxadiazine-6-carboxylate was prepared from pivaloyloxymethyl-10- [3- (benzyloxycarbonylamino) -] 1-pyrrolidinyl-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3.2.1] -1β-1,3,4-benzoxadiazine-6-carboxylate (200 mg) obtained in Example 62, in analogy to Example 30, was obtained as a light brown powder after precipitation of a mixture of ethyl acetate and n-hexane. 1 H NMR (CDCl 3) δ: 1.22 (9H, s), 1.6-2.4 (2H, m), δ 2.99 (3H, s), 3.3-4.0 (5H, m), 4.98 (2H, s), 5.96 (2H, s), 7.64 (1H, d, J = 14.4 Hz), 8.37 (1H, s); FAB-MS m / z 463 (MH &lt; + &gt;).

53 86428

Example 64 Ethyl 10- [3- (benzyloxycarbonylamino) -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-b] [ Preparation of -1,3,4-benzoxadiazine-6-carboxylate_

The 10- [3- (benzyloxycarbonyl-10-amino) -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -7- A mixture of 1,3,4-benzoxadiazine-6-carboxylic acid (337 mg), ethyl iodide (84 μl), anhydrous potassium carbonate (193 mg) and dry dimethylformamide (12 ml) was stirred at 45 ° C for 6 hours.

The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane. The dichloromethane solution was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was then applied to a silica gel column and eluted with a mixture of chloroform and acetone (20: 1). The pure fractions were combined, concentrated to dryness under reduced pressure, and the residue was recrystallized from ethyl acetate to give 271 mg of ethyl 10- [3- (benzyloxycarbonylamino) -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro -7H-pyrido [3,2,1-b] 1,3,4-benzoxa-25-diazine-6-carboxylate, m.p. 204-207 ° C; FAB / MS m / z 511 (MH &lt; + &gt;).

Example 65

Ethyl 10- (3-amino-1-pyrrolidinyl-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-b] -1,3,4- Preparation of 30 benzoxadiazine-6-carboxylate_

The ethyl 10- [3- (benzyloxycarbonylamino) -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-1] 7 obtained in Example 64 was obtained. -1,3,4-Benzoxadiazine-6-carboxylate (200 mg) was hydrogenated over 5% Pd / C 35 (120 mg) in a mixture of chloroform (25 mL) and methanol (10 mL) 54 86428 for 23 hours. After the catalyst was removed by filtration, the filtrate was concentrated under reduced pressure. The residue was then applied to a silica gel column and eluted with a mixture of chloroform and methanol (4: 1). The pure fractions were combined and concentrated to dryness under reduced pressure. The residue was further purified by preparative TLC (silica gel; CHCl 3, MeOH, 3: 1) and recrystallized from ethanol to give 71 mg of ethyl 10- (3-amino-1-pyrrolidinyl) -9-fluoro-3-methyl- 7-oxo-2,3-dihydro-7H-pyrido-10β, 3,2,1-12H -1,3,4-benzoxadiazine-6-carboxylate, m.p. 187-192 ° C (dec.); FAB-MS m / z 377 (MH &lt; + &gt;).

Example 66 10- (3-Amino-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-b] -1,3,4- preparation of benzoxadiazine-6-carboxylic acid hydrochloride_

The 10- (3-amino-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -7-

The pH of a solution of 1,3,4-benzoxadiazine-6-carboxylic acid (20 mg) in water (1 mL) was adjusted to 1.0 6 N

With HCl. The clear solution was then lyophilized and the residue was crystallized from water / ethanol (1: 2) to give 19 mg of 10- (3-amino-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro- 7H-pyride / 3,2,1-ij [7-1,3,4-benzoxadiazine-6-carboxylic acid hydrochloride, m.p. 226-228 ° C (dec.).

Example 67 9-Fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-b] -1,3,3 , 4-benzoxadiazine-6-carboxylic acid hydrochloride-9-fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -30,7-oxo-2,3-dihydro-7H-pyrido [3,2], 1-1H-1,3,4-benzoxadiazine-6-carboxylic acid hydrochloride was obtained in analogy to Example 66, m.p. 264-266 ° C (dec.).

li 55 86428

Example 68

Preparation of sodium 9-fluoro-3-methyl-10-morpholino-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-b] 1,3,4-benzoxadiazine-6-carboxylate_5 9-Fluoro-3-methyl-10-morpholino-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-b] -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 μl) was added with stirring. The clear solution was lyophilized and the residue 10 was crystallized from water / ethanol (1: 4) to give 12 mg of sodium 9-fluoro-3-methyl-10-morpholino-7-oxo-2,3-dihydro-7H-pyrido [3], 2,1-i] -1,3,4-benzoxadiazine-6-carboxylate, m.p. > 300 ° C.

Example 69 15 9-Fluoro-3- (2-fluoroethyl) -10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] Preparation of 7-1,3,4-benzoxadiazine-6-carboxylic acid 9-fluoro-3- (2-fluoroethyl) -10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro- 7H-Pyrido [3,2,1-b] -1,3,4-20 benzoxadiazine-6-carboxylic acid was prepared from ethyl 8-benzyloxy-6,7-difluoro-1- (formylamino) -4-oxo-1, From the 4-dihydro-3-quinolinecarboxylate obtained in Reference Example (f), following the procedure of Reference Example (g, h and i) (using 1-bromo-2-fluoroethane instead of methyl iodide), Example 1 and Example 5, and as crystals, m.p. 220-224 ° C; MS m / z 394 (M +), after recrystallization from methanol.

Examples 70-77

The following compounds were obtained starting from the compound obtained in Example 1 using a method analogous to that of Example 5 or Examples 29/30.

56 86423 p

F v ^ ^ Js ^ CO 2 H

r5r6n ^ V ^ n ^

5 ON

^ ^ CH,

Again-

Eg 5D6 Melting point crystallization

No. R R N oc solvent FAB-MS m / Z

Ί 0 - 70 CK.Q-C 2 $ 2 (dec.) MeOH 432 (MH +) CH | 0

V

71 f) 221-230 (dec.) EtOH / hexane 379 (MH +)

Hi N

15 'oh H, N D- 240-245 (ha j.) EtOH / hexane 355 (MH +)

Ph '* 73 H1h »J_vN 253-255 (dec.) MeOH / eotorj 425 (MH +) 20 CH, v 74 H | NJD- 240-241 MeOH 363 (MH +) 25 75> 300 (dec.) EtOH / CHCl3 / oxane 363 (MH +) 76 -H 2 - 220-223 (dec.) EtOH 453 (MH +) ch.n \ J 1 77 211-214 (dec.) EtOH / CHCl 3 391 (MH +) 57 86428

Example 78 10- (3- (4-Aminobenzyl) amino] -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-b]} - Preparation of 1,3,4-benzoxadiazine-6-carboxylic acid 5 10- [3 - [(4-aminobenzyl) amino] -1-pyrrolidinyl] 9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3 , 2,1-iβ-1,3,4-benzoxadiazine-6-carboxylic acid was prepared in analogy to the methods described in Examples 47 and 53, starting from 10- (3-amino-1-pyrrolidinyl) -109-fluoro-3- methyl 7-oxo-2,3-dihydro-7H-pyrido [3,2,1-b] 1,3,4,3-benzoxadiazine-6-carboxylic acid obtained in Example 30; mp. 180-182 ° C (dec.), FAB-MS m / z (MH &lt; + &gt;).

Example 79 15 9-Fluoro-10- [3- (7-dimethylamino) methyleneamino] -1-pyrrolidinyl] -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-b] Preparation of -1 # 3,4-benzoxadiazine-6-carboxylic acid_

The 10- (3-amino-1-pyrrolidinyl) -209-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4- obtained in Example 30 was obtained. a suspension of benzoxadiazine-6-carboxylic acid (14 mg) and N, N-dimethylformamide dimethylacetal (6 μl) in dry DMF (0.5 ml) was stirred at room temperature for 8.5 hours. The precipitate was collected by filtration, washed with DMF and ether, and recrystallized from DMF to give 8 mg of 9-fluoro-10 [3- (7-dimethylamino) methylene] -amino] -1-pyrrolidinyl-3-methyl-7-oxo-2, 3-dihydro-7H-pyrido [3,2,1-b] -1,3,4-benzoxadiazine-6-carboxylic acid as pale yellow crystals, m.p. 218-220 ° C (dec.), FAB-MS m / z 404 (MH +).

58 86423

Example 80

Sodium 9-fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-b] -1,3 Preparation of 4-benzoxadiazine-6-carboxylate_ 5 9-Fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1- 1H-1,3,4-Benzoxadiazine-6-carboxylic acid (520 mg) was dissolved in 0.5 N sodium hydroxide (2.88 ml). The clear solution was evaporated under reduced pressure to give 555 mg of a 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 1,3-dihydro-7H-pyrido [3,2,1-b] 1,3,3,4-benzoxadiazine-6-carboxylate after drying under vacuum at 80 ° C for 2 days; mp 252-254 ° C (dec.), FAB-MS m / z 385.

Claims (13)

59 86 428 A process for the treatment of therapeutically active 10-substituted-9-fluoro-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-5 ij] -1,3,4-benzoxadiazine-6- for the preparation of carboxylic acid derivatives of the general formula 0 R5 | (I) (X \ 'X. R2 Xr3 wherein R1 is a hydrogen atom or a carboxy protecting group which may be lower alkyl, benzyl or lower alkanoyl-oxyalkyl; R 2 is a lower alkyl radical optionally substituted by a fluorine atom; R 3 is a hydrogen atom or a lower alkyl radical optionally substituted by a hydroxy or di (lower alkyl) amino radical; R5 is a lower alkyl radical; and R 6 is di (lower alkyl) amino-substituted lower alkyl. . radical; or R 5 and R 6 together with the adjacent nitrogen atom form a piperazine ring which may be C-substituted with lower alkyl, oxo and / or phenyl and / or N-substituted with lower alkyl, lower sulphonatoalkyl, nitrobenzyl, aminobenzyl -, lower hydroxyalkyl, lower haloalkyl, lower carboxyalkyl and / or lower alkenyl and / or a group of general formula 60 86423 - (CH2) nCOR8 (where n is 0 to 2 and R8 is phenyl or lower alkyl) -5 dicala optionally substituted by a carboxy or phenyl group); a morpholino ring optionally substituted with a lower alkyl group; thiomorpholino or 1,1-dioxide thiomorpholino ring; a pyrrolidine ring optionally substituted with amino, lower alkylamino-10-, lower alkoxy, lower aminoalkyl, lower alkyl, hydroxy, halogen, benzyloxycarbonylamino, lower alkylpiperazinyl, phenyl, lower alpha -alkylamino (lower alkyl) and / or aminobenzylamino and / or a group of the general formula R50, N-CH = N- R51 wherein R50 and R51 are each lower alkyl; an imidazole ring optionally substituted with a lower alkyl group; a piperidine ring optionally substituted with a lower aminoalkyl, hydroxy, pyrrolyl, amino, lower alkylamino and / or lower alkoxy group; or a hexahydro-1,4-diazepine ring; and for the preparation of pharmaceutically acceptable salts and hydrates or solvates of the compounds of the formula I or their salts, characterized in that a) a compound of the general formula O C00R1'35 r'VX "^ A \ J \ (III) \ r3» 2 not 86428 wherein R 1, R 2 and R 3 are as defined above and X 'is a halogen atom and the amino, hydroxy and / or carboxy groups present may be protected, is reacted with an amine of general formula HN to R 5 (IV) wherein R5 and R6 are as defined above, followed, if necessary, by the removal of a protecting radical, or b) a compound of general formula O C00r1 15. X y (v) i * oh L 20 wherein R 1, R 2, R 5 and R 6 are as defined above and the amino, hydroxy and / or carboxy groups present may be protected are reacted with an aldehyde of general formula R 3 to CHO (VI) wherein R 3 is as defined above, or with a polymer, acetal or enol ether thereof, and then, if necessary, deprotecting, or c) to prepare a compound of formula I wherein R 5 R 6 N- is a piperazine ring which is N- substituted as defined above, reacting a compound of formula I wherein R 5 R 6 N- is N-unsubstituted piperazinyl with a compound of general formula R 70 Y (X) 5 wherein Y is a leaving group and R 70 is a group - (CH2) nCOR8, lower alkyl, nitrobenzyl, lower hydroxyalkyl, lower haloalkyl or lower alkenyl, or (c2) with a Michael acceptor of general formula Method according to Claim 1, characterized in that one of the method variants a) to g), i) and j) is carried out. Process according to Claim 1, characterized in that 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 or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of this compound or a salt thereof. 64 8 6 42-8 Process according to Claim 1, characterized in that 9-fluoro-3-methyl-7-oxo-10- (1-piperazinyl) -2,3-dihydro-7H-pyrido [3,2,1] is prepared. -ij] -1,3,4-benzoxadiazine-6-carboxylic acid 5 or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of this compound or a salt thereof. Process according to Claim 1, characterized in that 9-fluoro-3-methyl-10- (3-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-10H-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 a salt thereof. Process according to Claim 1, characterized in that 9-fluoro-3-methyl-7-oxo-10- (3-phenyl-1-piperazinyl) -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 a salt thereof. Process according to Claim 1, characterized in that 9-fluoro-3-methyl-10-morpholino-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] is prepared. 1,3,4-Benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of this compound or a salt thereof. Process according to Claim 1, characterized in that 10- {3 - [(ethylamino) methyl] -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 a salt thereof. Process according to Claim 1, characterized in that 10- (3-amino-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2] is prepared. , 1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of this compound or a salt thereof. Process according to Claim 1, characterized in that 9-fluoro-3-methyl-10- [3- (methylamino) -1-pyrrolidinyl] -7-oxo-2,3-dihydro-7H-pyrido is prepared. [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 a salt thereof. N-CH = N-R51 wherein R50 and R51 are each lower alkyl, reacting the amino group of the corresponding aminopyrrolidine compound of formula I with N, N- (di-lower alkyl) -formamide methyl acetal, or i) to prepare a compound of formula I wherein R 1 is a carboxy protecting group, esterifying the corresponding carboxylic acid of formula I, and if desired j) converting a compound of formula I to a pharmaceutically acceptable salt, hydrate or solvate thereof or a hydrate or solvate of said salt, converting the compound of formula I to a salt, hydrate or a solvate or said salt as a hydrate or solvate. R9-CO-CH = CH2 (XI) wherein R9 is a lower alkyl radical, or (c3) formaldehyde and formic acid or alkali metal bisulphite or (c4) aldehyde of general formula <XII> wherein Z is C2-3 alkylene , or d) to prepare a compound of formula I wherein R 5 R 6 N- is 1,1-dioxide thiomorpholino, oxidizing the corresponding compound wherein R 5 R 6 N- is thiomorpholino; or e) for the preparation of a compound of formula I wherein R 5 R 6 N- is a pyrrolidine or piperidine ring substituted with an amino and / or hydroxy group, cleaving the protecting group (s) from the corresponding compound having a protected amino or aminomethyl group by hydrogenation. lytically benzyloxycarbonylamino or benzyloxycarbonylaminomethyl compound; or f) to prepare a compound of formula I wherein R 5 R 6 N- is a halopyrrolidine ring, halogenating the corresponding hydroxypyrrolidine compound of formula I wherein R 1 is a carboxy protecting group as defined above and optionally cleaving said 35 radical R 1, or 6342 ) to prepare a compound of formula I wherein R 5 R 6 N- is an aminobenzylpiperazine ring, reducing the corresponding nitrobenzylpiperazine compound of formula I by catalytic hydrogenation, or 5 h) to prepare a compound of formula I wherein R 5 R 6 N- is a pyrrolidine ring substituted with a group Process according to Claim 1, characterized in that 10- [4- (4-amino-benzyl) -1-piperazinyl] -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 a salt thereof. Process according to Claim 1, characterized in that 10- (trans-3-amino-4-methyl-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 a salt thereof. Process according to Claim 1, characterized in that 10- (trans-3-amino-4-methoxy-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H is prepared. -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 a salt thereof. 66 8 6 428