SK278990B6 - Pyrido£3,2,1-ij|-1,3,4-benzoxadiazine derivatives, method for producing same, and pharmaceutical compositions on their base - Google Patents

Abstract

This patent describes pyrido[3,2,1-ij]-1,3,4- -benzoaxadiazine derivatives with a general formula (I), where the individual symbols are explained in the patent description together with pharmaceutical compositions based on these derivatives. The above mentioned derivatives are anti-bacterial effective.

Description

The invention relates to pyrido [3,2,1-ij] -1,3,4-benzoxadiazine derivatives, processes for their preparation and pharmaceutical compositions based thereon.

BACKGROUND OF THE INVENTION

The closest prior art to the claimed subject matter of the invention is EP 0 047 005 (Seiyaku Co. Ltd.). Disclosed herein are 9-halo-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid derivatives of the general formula:

ABOUT

wherein X is a halogen atom, R is a hydrogen atom or an alkyl group, and Z is a substituted amino group, and pharmaceutically acceptable salts thereof that exhibit antibacterial activity.

The compounds of the invention differ from these compounds in that they are benzoxadiazepines which contain, in addition to the nitrogen atom of the quinolone ring, a second nitrogen atom.

SUMMARY OF THE INVENTION

The present invention provides pyrido [3,2,1-ij] -1,3,4-benzoxadiazine derivatives of formula (I):

where

R ^{@ 1} is hydrogen, lower alkyl, lower alkanoyloxyalkyl or benzyl;

R ² is H or lower alkyl optionally substituted by halogen;

R ³ and R ⁴ are each independently hydrogen, lower alkyl optionally substituted by hydroxy, unsubstituted amino, or di (lower alkyl amino, lower alkylamino or lower cycloalkylamino);

X represents a halogen atom;

R ⁵ and R ⁶ are each independently hydrogen or lower alkyl optionally substituted by hydroxy, lower alkoxy, unsubstituted amino, or di (lower alkyl amino, lower alkylamino or lower cycloalkylamino) or R ⁵ and R ⁶ together with the nitrogen atom, to which they are attached form a five to seven membered heterocyclic ring optionally substituted by one or more substituents attached to an atom or carbon atoms selected from hydroxy, lower alkoxy, amino, lower alkylamino, lower cycloalkylamino, di (lower alkyljamino, lower alkanoylamino) , benzyloxycarbonylamino, halogen, lower alkyl, amino-lower alkyl, lower alkylamino-lower alkyl, lower cycloalkylamino lower alkyl, di (lower alkyl) amino-lower alkyl, lower alkanoylamino-lower alkyl, hydroxy-lower alkyl, phenyl, optionally substituted amino, halogen, hydroxy and / or lower alkoxy, heterocyclic ring, benzylamino, optionally substituted by nitro, amino, halogen, hydroxy and / or lower alkoxy, and a group of formula,

wherein each of R ⁵⁰ and R ⁵¹ represents lower alkyl or, together with the nitrogen atom to which they are attached, both radicals together form a five- to eight-membered saturated N-heterocycle, the heterocyclic ring formed from R ⁵ , R ⁶ and the adjacent the nitrogen atom optionally further comprises a group of the formula -NR ⁷ -, -O-, -S-, -SO-, SO- or -NR ⁷ CO-, wherein

R ⁷ is hydrogen, lower alkenyl, lower alkyl, optionally substituted hydroxy, lower alkoxy, amino, lower alkylamino, di (lower alkyl) amino, halogen, carboxy and / or sulfo, benzyl which is optionally substituted amino, nitro lower alkylamino, di ( lower alkyl, amino, halogen and / or lower alkoxy or a group of formula,

- (CH ₂ ) "COR ⁸ wherein n is an integer from 0 to 4 and R ⁸ represents a hydrogen atom, a lower alkoxy group, an amino group optionally substituted by lower alkyl and / or lower cycloalkyl, a lower alkyl group optionally substituted by carboxyl or lower alkoxycarbonyl or phenyl optionally substituted by halogen, lower alkoxy, hydroxy, nitro and / or amino;

wherein the term "lower" refers to the respective groups containing up to 7 carbon atoms and pharmaceutically acceptable salts of the compounds of formula (I) and hydrates or solvates of the compounds of formula (1) or salts thereof.

The present invention further provides a process for the preparation of the pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivatives of formula (I) according to claim 1, as well as their pharmaceutically acceptable salts and hydrates or solvates of the compounds of formula (I) or a salt thereof, characterized in that the compound of formula (ΠΙ),

wherein R ¹ , R ² , R ³ , R ⁴ and X are as defined above and X ¹ represents a halogen atom, wherein the amino, hydroxy and / or carboxy groups present are optionally protected, reacted with an amine of formula (IV),

(IV) wherein R ⁵ and R ⁶ are as defined, then optionally deprotecting and optionally isolating the product in the form of a salt, hydrate or solvate, or a hydrate or solvate thereof.

The present invention also provides a process for the preparation of the pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivatives of formula (I) according to claim 1, as well as their pharmaceutically acceptable salts and hydrates or solvates of the compounds of formula (I) or a salt thereof, characterized in that the compound of formula (V):

wherein R ¹ , R ² , R ⁵ , R ⁶ and X are as defined above, wherein the amino, hydroxy and / or carboxy groups present are optionally protected, reacted in a solvent at 20 to 150 ° C with the carbonyl compound of formula (VI) .

wherein R ³ and R ⁴ are as defined above, or a polymer such as paraformaldehyde, trioxane or paraacetaldehyd; acetal such as dimethoxymethane, 1,1-dimethoxyethane, 1,3-dioxolane, glycol aldehyde dimethylacetal or dimethylaminoacetaldehyde dimethylacetal with a ketal such as 2,2-dimethoxypropane; or an enol ether such as 2-methoxypropene or 2-trimethylsilyloxypropene; then optionally protecting groups are cleaved and optionally the product isolated in the form of a salt, hydrate or solvate, or a hydrate or solvate of the salt.

The present invention further provides a process for the preparation of a salt of the pyrido [3,2,1-1] -1,3,4-benzoxadiazine derivatives of the general formula (I) according to claim 1, wherein the salts have a structure corresponding to the general formula (Ia).

where

A is a pharmaceutically acceptable acid anion selected from the group consisting of hydrohalic acids, methanesulfonic acid and p-toluenesulfonic acid,

R ¹ represents a hydrogen atom or an alkali metal cation, n represents 1 when R ¹ is hydrogen and 0 when R ¹ is an alkali metal cation,

R ² is C 1 -C 7 alkyl;

R ⁵ and R ^{6 taken} together, together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocyclic ring optionally substituted on the carbon atom with an optionally further amino group -O- or -NR ⁷ -, wherein R ⁷ is an alkyl group having 1 to 7 carbon atoms optionally substituted by a sulfo group, characterized in that the acid is of the formula (II),

wherein R ² , R ⁵ and R ⁶ are as defined above, reacted with at least an equivalent amount of a pharmaceutically acceptable acid corresponding to the anion and / or alkali metal base and the resulting salt optionally isolated as a hydrate or solvate thereof.

Finally, the present invention also provides a pharmaceutical composition comprising, in addition to the usual ingredients, a defined pyrido [3,2,1-ij] -1,3,4-benzoxadiazine derivative of the formula (I) or a pharmaceutical thereof as an active ingredient a suitable salt or hydrate or solvate thereof.

Explanation of the meaning of the symbol R ¹ :

R ¹ represents a hydrogen atom or a carboxyl protecting group which is lower alkyl, lower alkanoyloxyalkyl or benzyl, for example methyl, ethyl, n-propyl and tert-butyl, acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl and 1-pivaloyloxyethyl and benzyl. These are readily hydrolyzable protecting groups in vivo.

Explanation of the meaning of the symbol R ² :

R ² is H or lower alkyl, optionally substituted with halogen.

Said lower alkyl group preferably contains 1 to 4 carbon atoms, such as in particular methyl, ethyl, n-propyl, isopropyl, n-butyl and the like, and the halogen atom is a fluorine, chlorine or bromine atom, preferably fluorine.

Explanation of the symbols R ³ and R ⁴ :

R ³ and R ⁴ are each independently of the other hydrogen or lower alkyl, which may be substituted by hydroxy or substituted or unsubstituted amino.

Said lower alkyl groups preferably contain 1 to 4 carbon atoms, in particular methyl, ethyl, n-propyl, isopropyl, n-butyl and the like. The substituted amino groups may be a di-lower alkylamino group such as dimethylamino diethylamino or a lower alkylamino group such as methylamino, ethylamino, or a lower cycloalkylamino group such as cyclopropylamino.

Explanation of the symbols R ⁵ and R ⁶ :

Each R ^s and R ⁶ independently of the other a hydrogen atom or a lower alkyl group which may be substituted by hydroxy, lower alkoxy or substituted or unsubstituted amino, or the symbols R ⁵ and R ⁶ together with the nitrogen atom to which they are attached, to form a five- to seven-membered heterocyclic ring which may be substituted with at least one substituent on the atom or carbon atoms and which may further contain an -NR ⁷ -, -O-, -S-, -SO-, -SO ₂ - or -NR group ⁷ -CO- [wherein R ⁷ represents a hydrogen atom, a lower alkenyl group, a lower alkyl or aralkyl group which may be substituted or a radical of formula (II),

SK 278990 Β6

(CH ₂ ) _r COR ⁸ (II), (wherein n is C to 4 and

R ⁸ represents a hydrogen atom, a lower alkoxy group, or an amino group, a lower alkyl group or an aryl group which may be substituted).

The above groups and residues will be explained in more detail below:

Said lower alkyl group preferably contains 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl and the like. The lower alkoxy group preferably contains 1 to 4 carbon atoms such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and the like. The substituted amino group may be a di-lower alkylamino group such as dimethylamino, diethylamino or ethylmethylamino or a lower alkylamino group such as methylamino, ethylamino, n-propylamino, isopropylamino or lower cycloalkylamino group such as cyclopropylamino and the like.

The 5- to 7-membered heterocyclic ring formed by R ⁵ and R ⁶ may be piperazinyl, morpholinyl, thiomorpholinyl, piperidyl, homopiperazinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolyl, triazolyl and the like. Examples of substituents attached to the carbon atom (s) of the heterocyclic ring are hydroxy, lower alkoxy such as methoxy, ethoxy, n-propoxy, amino, lower alkylamino such as methylamino, ethylamino, n-propylamino, isopropylamino, lower cycloalkylamino, cyclopropylamino, di-lower alkylamino such as dimethylamino, diethylamino, ethylmethylamino, lower alkanoylamino such as acetylamino, benzylamino optionally substituted with nitro, amino, halogen, hydroxy and / or lower alkoxy such as (4-aminobenzyl) , a group of the general formula:

wherein each of R ⁵⁰ and R ⁵¹ represents a lower alkyl group, or both together with the nitrogen atom to which they are attached, represents a 5-8 membered saturated N-heterocyclic ring such as (dimethylamino) methyleneamino, (hexahydro-1); H-azepin-1-yl) methyleneamininobenzyloxycarbonylamino; halogen such as fluorine, chlorine, bromine; a lower alkyl group such as methyl, ethyl, n-propyl, isopropyl; an amino-lower alkyl group; a lower alkylamino-lower alkyl group; a lower cycloalkylamino-lower alkyl group; a di-lower alkylamino-lower alkyl group; a lower alkanoylamino lower alkyl group, examples of which are aminomethyl, (methylamino) methyl, (ethylamino) methyl, (n-propylamino) methyl, (isopropylamino) methyl, (cyclopropylamino) methyl, (dimethylamino) methyl, (diethylamino) methyl, (ethylmethylamino) methyl, acetylaminomethyl, 2-aminoethyl, 2- (methylamino) ethyl, 2- (ethylalmethylamino) ethyl; hydroxy- (lower alkyl) such as hydroxymethyl, 2-hydroxyethyl; phenyl optionally substituted with amino, halogen, hydroxy and / or lower alkoxy such as 4-aminophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-hydroxyphenyl, 4-methoxyphenyl; a heterocyclic ring such as a pyrrolyl 4-methyl-1-piperazinyl ring and the like.

The lower alkenyl radical R ⁷ is, for example, allyl, 3-methyl-2-butenyl, 2-butenyl, 1-methyl-2-propenyl, 3-butenyl and the like.

A substituted alkyl radical R ⁷ is hydroxy- (lower alkyl) such as 2-hydroxyethyl, 3-hydroxybutyl; lower alkoxy-lower alkyl such as 2-methoxyethyl, 2-ethoxyethyl; amino-lower alkyl such as 2-aminoethyl, 3-aminobutyl; lower alkylamino-lower alkyl such as 2- (methylamino) ethyl, 2- (ethylamino) ethyl, 3- (methylaminobutyl, 3- (ethylaminobutyl; di-lower alkylamino-lower alkyl such as 2- (dimethylamino) ethyl), 2 - (diethylamino) ethyl, 3- (dimethylamino) butyl, 3- (diethylamino) butyl, halo-lower alkyl such as 2-fluoroethyl, 3-fluoro-n-butyl, carboxy-lower alkyl such as carboxymethyl, 2- sulfonyl-lower alkyl such as sulfomethyl, 2-sulfoethyl and the like.

The benzyl radical R ⁷ may be substituted by at least one substituent selected from the group consisting of amino, nitro, lower alkylamino, di (lower alkyl) amino, halogen and / or lower alkoxy such as 4-aminobenzyl, 4-nitrobenzyl, 4- ( dimethylamino) benzyl, 4-fluorobenzyl, 4-chlorobenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl and the like.

The amino group R ⁸ may be substituted with a lower alkyl group such as methylamino, dimethylamino or a lower cycloalkyl group such as cyclopropylamino.

The lower alkyl group R ⁸ may be substituted by carboxy or alkoxycarbonyl, for example 2-carboxyethyl, 3-carboxy-n-propyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, 3-methoxycarbonyl-n-propyl and the like.

The phenyl radical R ⁸ may be substituted by at least one substituent selected from halogen, lower alkoxy, hydroxy, nitro and / or amino, for example 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, -carboxyphenyl, 4-hydroxyphenyl, 4-nitrophenyl, 4-aminophenyl and the like. Particularly preferred residues of significance

R ⁷ is hydrogen methyl, ethyl, n-propyl, isopropyl, 2-hydroxyethyl, 2-methoxyethyl, 2-aminoethyl, 3-amino-n-butyl,

2- (methylamino) ethyl, 2- (ethylamino) ethyl, 2-fluoroethyl, carboxymethyl, sulfomethyl, allyl, 4-aminobenzyl, 4-fluorobenzyl, formyl, acetyl, propionyl, benzoyl, 4-aminobenzoyl, 2-oxo-n- propyl, 2-oxo-n-butyl, 3-oxo-n-butyl,

3-oxo-n-pentyl, 3-carboxypropionyl, 3-ethoxycarbonylpropionyl, 4-carboxy-n-butyryl, phenacyl, 4'-aminophenacyl, ethoxycarbonyl, methoxycarbonyl, carbamoyl and the like.

Particularly preferred residues represented by R ⁵ R ⁶ N- in formula (I) are 1-piperazinyl, 4-methyl-1-piperazinyl, 3-methyl-1-piperazinyl, 3-phenyl-1-piperazinyl, 3,4 -dimethyl-1-piperazinyl, 4-ethyl-1-piperazinyl, 3- (4-aminophenyl) -1-piperazinyl, 4-n-propyl-1-piperazinyl, 4- (2-fluoroethyl) -1-piperazinyl, 4 -alyl-1-piperazinyl, 4- (2-oxo-n-propyl) -1-piperazinyl, 4- (carboxymethyl) -1-piperazinyl, 4- (3-oxo-n-butyl) -1-piperazinyl, 4 - (sulfomethyl) -1-piperazinyl, 4- (4-aminobenzyl) -1-piperazinyl, 4- (2-hydroxyethyl) -1-piperazinyl, 3-oxo-1-piperazinyl, 4-phenacyl-1-piperazinyl, 4 - (3-carboxypropionyl) -1-piperazinyl, 4-acetyl-1-piperazinyl, 4- (4-nitrobenzyl) -1-piperazinyl, morpholino, 2-methyl-4-morpholinyl, 2,6-dimethyl-4-morpholinyl 4-thiomorpholinyl, 1-oxide-4-thiomorpholinyl, 1,1-dioxide-4-thiomorpholinyl, 4 (aminomethyl) -1-piperidyl, 4 - [(methylamino) methyl] -1-piperidyl, 4-methoxy-1 -piperidyl, 4-hydroxy-1-piperidyl, 4- (1-pyrrolyl) -1-piperidyl, 4-amino-1-piperidyl, 4- (methylamino) -1-piperidyl, 4- (ethylamino) -1,4

-piperidyl, 1-homopiperazinyl, 4-methyl-1-homopiperazinyl, 3-amino-1-pyrrolidinyl, 3- (methylamino) -1-pyrrolidinyl), 3- (ethylamino) -1-pyrrolidinyl, 3- (benzyloxycarbonylamino) - 1-pyrrolidinyl, 3- (aminomethyl) -1-pyrrolidines 1,3-amino-4-phenyl-1-pyrrolidines 1,3-amino-3-methyl-1-pyrrolidinyl, 3-amino-4-methyl-1 -pyrrolidinyl, 3- (4-aminobenzylamino) -1-pyrrolidinyl, 3- (4-methyl-1-piperazinyl) -1-pyrrolidinyl, 3 - [(dimethylamino) methyleneamino] -1-pyrrolidinyl, 3 - [(methylamino) methyl] -1-pyrrolidinyl, 3 - [(methylamino) methyl-4-phenyl-1-pyrrolidinyl, 3-methyl-3 - [(methylamino) methyl] -1-pyrrolidinyl, 3 - [(ethylamino) methyl] - 1-pyrrolidinyl, 3- (acetylaminomethyl) -1-pyrrolidinyl, 3 - [(dimethylamino) methyl] -1-pyrrolidinyl, 3 - [(ethylmethylamino) methyl] -1-pyrrolidinyl, 3-amino-4-methoxy-1- pyrrolidinyl, 3-methoxy-4- (methylamino) -1-pyrrolidinyl, 3- (ethylamino) -4-methoxy-1-pyrrolidinyl, 3-amino-4-chloro-1-pyrrolidinyl, 3-chloro-4- (methylamino) -1-pyrrolidinyl, 3-chloro-4- (ethylamino) -1-pyrrolidinyl, 3-amino-4-fluoro-1-pyrrolidinyl, 3-fluoro-4- (methylamino) -1-pyrrolidinyl, 3- (ethylamino) -4-fluoro-1-pyrrolidinyl, 3- (aminomethyl) -4-chloro-1-pyrrolidinyl, 3-chloro-4 - [(methylamino) methyl] -1-pyrrolidinyl 3-chloro-4 - [(ethylamino) methyl] -1-pyrrolidinyl, 3- (aminomethyl) -4-fluoro-1-pyrrolidinyl, 3-fluoro-4 - [(methylamino) methyl] -1-pyrrolidinyl, 3 - [(ethylamino) methyl] -4-fluoro-1-pyrrolidinyl, 3- (aminomethyl) -4-methyl-1-pyrrolidinyl, 3-methyl-4 - [(methylamino) methyl] -1-pyrrolidinyl, 3 - [( ethylamino) methyl] -4-methyl-1-pyrrolidinyl, 3-hydroxy-1-pyrrolidinyl,

3-methoxy-1-pyrrolidinyl, 3-chloro-1-pyrrolidinyl, 3-fluoro-1-pyrrolidinyl, 3-hydroxy-4-methoxy-1-pyrrolidinyl, 1-imidazolyl, 4-methyl-1-imidazolyl, 3- amino-4-hydroxy-1-pyrrolidinyl, 3- (methylamino) -4-hydroxy-1-pyrrolidinyl, 3- (ethylamino) -4-hydroxy-1-pyrrolidinyl, 3- (dimethylamino) -4-hydroxy-1- pyrrolidinyl, [2- (dimethylamino) ethyl] methylamino and the like.

Explanation of the meaning of the symbol X:

X represents a halogen atom such as fluorine, chlorine or bromine, preferably fluorine or chlorine.

The process according to the invention for the preparation of the novel pyrido [3,2,1-ij] -1,3,4-benzoxadiazine derivatives of the general formula (I) and their pharmaceutically acceptable salts and hydrates or solvates thereof and characterized by:

(a) reacting a compound of formula (πη,

in which

R ¹ , R ² ; R ^3, R ⁴ and X are as defined above, and

X 'is halogen, wherein the amino, hydroxy and / or carboxy groups present may be protected, with an amine of formula (IV), optionally followed by deprotection, or (b) reacting a compound of formula (V),

in which

R ¹ , R ² ; R ⁵ , R ⁶ and X are as defined above, wherein the amino, hydroxy and / or carboxy groups present may be protected with a carbonyl compound of formula (VI),

(VI>

in which

R ³ and R ⁴ are as defined herein, or with a polymer, acetal, ketal or enol ether thereof, with optional subsequent deprotection.

Further, some of the compounds of formula (I) may be prepared by (c) leaving a compound of formula (I) in which R ⁷ is produced to produce a compound of formula (I) wherein R ⁷ is other than hydrogen. is hydrogen, react with a reagent providing a group wherein R ⁷⁰ has the same meaning as R ⁷ except hydrogen, or (d) to produce a compound of formula (I) wherein R ⁵ and or R ⁶ are lower alkyl (or contain di (lower alkylamino or lower alkoxy), alkylates a compound of formula (I) wherein R ⁵ and / or R ⁶ are hydrogen or contain an amino, lower alkylamino or hydroxy group, or (e) to produce a compound of formula (I), in wherein R ⁵ R ⁶ N- is a 5- to 7-membered heterocyclic ring containing a -SO- or -SO ₂ - group, the compound in which said heterocyclic ring contains a -S- group is oxidized or (f) ) for the preparation of a compound of formula (I) having a free amino, hydroxy and / or carboxy group, the protecting group (s) is cleaved from the corresponding compound of formula (I) having a protected amino, hydroxy and / or carboxy group; A halogen-containing compound of formula (I) is halogenated with an appropriately hydroxyl-substituted compound of formula (I) in which R ¹ is a carboxyl protecting group and optionally cleaves said protective residue R ¹ , or (h) to produce a compound of formula (I). I) containing an amino group, reducing the nitro group of the correspondingly nitro substituted compound of formula (I), or (i) to produce a compound of formula (I) containing a group of formula,

HN-R ⁵

in which

R ⁵ and R ⁶ are as defined in which each of R ⁵⁰ and R ⁵¹ represents a lower alkyl group or together with the nitrogen atom to which they are attached a 5-8 membered saturated N-heterocyclic ring, the amino group is left respectively with an amino group substituted compound of formula (I) with a reactive derivative of the formamide derivative of formula (VII), r ⁵⁰ \

N, N-CHO (VII) & lt _; 51 >

R ⁵⁰ and R ⁵¹ are as hereinbefore defined, or (j) for the preparation of a compound of formula (I) in which R ¹ represents a carboxyl protecting group, the carboxylic acid of formula (I) is esterified, respectively, or salts, hydrates or solvates of a compound of formula (I) or hydrates or solvates of said salts are converted to a salt, hydrate or solvate or a hydrate or solvate of said salt.

Procedure A:

As mentioned, the desired compounds are prepared by reacting a compound of formula (III),

(III>

in which

R ¹ , R ² , R ³ , R ⁴ and X are as defined above and X 'is a halogen atom, wherein the amino, hydroxy and / or carboxyl group present may be protected with an amine of formula (IV),

HN-R ⁵ (IV) wherein

R ⁵ and R ⁶ are as defined herein, with the eventual subsequent deprotection.

In process A, the compound of formula (III) is used as the starting compound, a novel compound which can be prepared, for example, according to reaction scheme a) or b):

I II avinácia

-

<B |

in these general formulas

R ^2, R ^3, R ^4, X and X 'are as defined above,

R 1 represents a protecting group such as benzyl, methoxybenzyl, methoxymethyl, methoxyethoxymethyl, tetrahydropyranyl, allyl, tert-butyl, tert-butyldimethylsilyl, acetyl, benzoxyl and the like.

R is a protecting group such as formyl, acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, tert-butoxycarbonyl and the like. and

R represents a hydrogen atom or an ethyl group.

When a compound of formula (I) contains an amino or monoalkylamino group, this group may, if desired, be protected by a protecting group such as formyl, acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, tert, butoxycarbonyl and the like.

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

The reaction is preferably carried out in the presence of an acid-reactive substance such as triethylamine, pyridine, picoline, Ν, dim-dimethylaniline, 1,8-diazabicyclo [5.4.0] undec-7-an, 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-reactive substance.

Suitable solvents for this reaction are non-reactive solvents such as acetonitrile, alcohols, dimethylsulfoxide, dimethylformamide, dimethylacetamide, piridine, picoline, lutidine, dimethylaminourea dimers and the like. It is also possible to use a mixture of at least two solvents.

The protecting group may, if desired, be removed after the reaction by known methods. For example, the formyl residue can be removed by acidic or basic hydrolysis, preferably basic hydrolysis, and the benzyloxycarbonyl radical can be removed by hydrogenolysis.

Examples of starting materials of formula (III) include: 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1 3,4,10-benzoxadiazine-6-carboxylic acid, 9,10-dichloro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4 -benzoxadiazine-6-carboxylic acid, 9-chloro-10-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine 6-carboxylic acid, 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4-benzoxadiazine-6- ethyl ester 9,10-Difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4-benzoxadiazine-6-carboxylic acid benzyl ester 9,10-Difluoro-3- (2-fluoroethyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4-benzoxadiazine-6-carboxylic 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, l-ij] -1,3,4-benzoxadiazine-6-carboxylate 9,10-Difluoro-2 - [(dimethylamino) methyl] -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-oxoic acid -benzoxadiazine-6-carboxylic acid, 9,10-difluoro-2,2,3-trimethyl-7-oxo-2,3-dihydro-7H-pyridine [3,2,1-i] -1,3,4 -benzoxadiazine-δ-carboxylic acid and the like.

The amine of formula (IV) used in the reaction is, for example, piperazine, 4-methylpiperazine, 3-methylpiperazine, 3-phenylpiperazine, 3- (4-aminophenyl) -piperazine, 3- (4-nitrophenyl) -piperazine, 4- ( 2-hydroxyethyl) -piperazine, morpholine, 2-methylmorpholine, 2,6-dimethylmorpholine, thiomorpholine, 4- (amino-methyl) -piperidine, 4 - [(methylamino) methyl] -piperidine, 4 - [(ethylamino) methyl] -piperidine, 4-aminopiperidine, 4- (methylamino) -piperidine, 4- (ethylamino) -piperidine, 4- (benzyloxycarbonylamino) -piperidine, 4- (benzyloxycarbonylmethylamino) -piperidine, 4- (benzyloxycarbonylethylamino) -piperidine, 4-hydroxypiperidine 4-methoxypiperidine, 4- (1-pyroloyl) -piperidine, homopiperazine, 3 - [(methylamino) methyl] -pyrrolidine, 3 - [(ethylamino) methyl] -pyrrolidine, 3- (acetylaminomethyl) -pyrrolidine, 3-hydroxypyro lidine, 3-methoxy-pyrrolidine, 3-aminopyrrolidine, 3- (benzyloxycarbonylamino) -pyrrolidine, 3- (methylamino) -pyrrolidine, 3- (benzyloxycarbonylmethylamino) -pyrrolidine, 3-amino-4-phenylpyrrolidine, 3-amino-3-methylpyrrolidine, 3-amino-4-methyl ylpyrrolidine, 3- (4-aminobenzylamino) -pyrrolidine, 3- (4-methyl-1-piperazinyl) -pyrrolidine, 3 - [(dimethylamino) methyleneamino-pyrrolidine, 3 - [(methylamino) methyl] -4-phenylpyrrolidine, 3 -methyl-3 - [(methylamino) methyl] -pyrrolidine, 3- (ethylamino) -pyrrolidine, 3- (benzyloxycarbonylethylamino) -pyrrolidine, 3 - [(dimethylamino) methyl] -pyrrolidine, 3 - [(ethylmethylamino) methylpyrrolidine, 3 -azido-4-methoxy-pyrrolidine, 3-amino-4-methoxy-pyrrolidine, 3-methoxy-4- (methylamino) -pyrrolidine, 3- (ethylamino) -4-methoxy-pyrrolidine, 3-azido-4-hydroxypyrrolidine, 3-amino-4 -hydroxypyrrolidine, 3- (methylamino) -4-hydroxypyrrolidine, 3- (ethylamino) -4-hydroxypyrrolidine, 3- (aminomethyl) -4-methylpyrrolidine, 3-methyl-4 - [(methylamino) methyl] -pyrrolidine, 3- [(ethylamino) methyl] -4-methylpyrrolidine, 3-hydroxy-4-methoxy-pyrrolidine, 3- (acetylaminomethyl) -4-hydroxypyrrolidine, imidazole, 4-methylimidazole, Ν, Ν, Ν'-trimethylethylenediamine and the like.

Procedure B:

A compound of the invention may be prepared by reacting a compound of formula (V),

in which

R ¹ , R ² , R ⁵ , R ⁶ and X are as defined above, wherein the present aminohydroxy and / or carboxy groups may be protected with a carbonyl compound of formula (VI),

in which

R ³ and R ⁴ are as defined herein, wherein the amino groups present may be protected, or with a polymer, acetal, ketal or enol ether thereof, with optional subsequent deprotection.

In process B, the compound of formula (V) used as the starting compound is a new compound and can be prepared according to reaction scheme a) or b), or by reacting compound (H) or (Va) with an amine of formula (IV).

When a carbonyl compound of formula (VI) or a polymer, acetal, ketal or enol ether thereof contains an amino or a monoalkylamino group as a substituent, this substituent may optionally be protected as described in the meaning of R in formulas (G) and (H).

Said reaction may optionally be carried out in a solvent such as dioxane, tetrahydrofuran, acetonitrile, chloroform, dimethylformamide, dimethylsulfoxide, dimethylpropylurea, acetic acid and the like. It is also possible to use a mixture of at least two solvents.

SK 278990 Β6

Said reaction may optionally be carried out 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 (perfluorin-H). acid sulfonation resin, product of Aldrich Chemical Co., Inc.), Amberlyst-15 (a strongly acidic macroretic acid resin, product of 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 20 to 150 ° C.

In a preferred embodiment of the process of the invention, about 1 mol or molar excess of the carbonyl compound of formula (VI) or its polymer, acetal, ketal or enol ether is used per mole of compound of formula (V).

The amino or monoalkylamino protecting group may optionally be removed by known methods after the reaction. For example, the formyl group may be removed by acid hydrolysis or basic hydrolysis, preferably by basic hydrolysis, and the benzyloxycarbonyl group may be removed by hydrogenolysis.

Examples of starting compounds of formula (V) include: 6,7-difluoro-8-hydroxy-1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, ethyl ester 6 6,7-Difluoro-6-hydroxy-1- (methylamino) -4-oxo, 7-difluoro-8-hydroxy-1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, benzyl ester -1,4-dihydro-3-quinolinecarboxylic acid, 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 ester 6-fluoro-8-hydroxy-7- (1-imidazolyl) -1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, 6-fluoro-8-hydroxy-7- (benzyl) ester 1-imidazolyl) -1-methylamino) -4-oxo-1,4-dihydro-3-quinol 6-fluoro-1 - [(2-fluoroethyl) amino] -8-hydroxy-7- (1-imidazolyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid), 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 1-1-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-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- dihydro-3-quinolinecarboxylic acid 7- [3 - [(benzyloxycarbonylmethylamino) methyl) -4-methyl-1-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- (methylamide) ino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid and the like.

Examples of compounds that can be reacted with a compound of formula (V) are carbonyl compounds of formula (VI), such as formaldehyde, acetaldehyde, acetone, methyl ethyl ketone and the like, polymers thereof such as paraformaldehyde, paracetaldehyde, trioxane and the like. , their acetals such as dimethoxymethane, 1,1-dimethoxyethane, 1,3-dioxolane, glycol aldehyde dimethylacetal, dimethylaminoacetaldehyde dimethylacetal and the like, their ketals such as 2,2-dimethoxypropane and the like and their enol ethers such as 2-methoxypropane, 2-trimethylsilyloxypropane and the like.

Procedure C:

When compounds of formula (I) are to be prepared in which the group R'R ^N N- represents a 5- to 7-membered heterocyclic ring containing the group -NR ⁷ -, wherein R ⁷ has a meaning other than hydrogen, such as in group (VIII) , __y- (wine) in which the piperazinyl radical can be substituted on a carbon or carbon atoms and R ⁷ is a lower alkenyl group, a lower alkyl or aralkyl group which may be substituted or a group of formula (II),

- (CH ₂ ) "COR ^S (II) (where n is 0 to 4 and R ⁸ is hydrogen, lower alkoxy or amino, lower alkyl or aryl which may be substituted), the desired compound may be prepared by reacting a compound of the general formula of formula (I), wherein R ⁷ is hydrogen, with a reagent providing a group R ⁷⁰ . This reaction, i.e. N-alkylation (or N-acylation), can be carried out, for example, as follows:

N-Alkylation:

Compound of formula (IX),

in which

R ¹ , R ² , R ³ , R ⁴ and X are as defined above, wherein the piperazinyl moiety may be substituted on an atom or carbon atoms and the amino, hydroxy and / or carboxy groups present may be protected, reacted with (i) with the compound of formula (X),

R ⁷⁰ -Y (X) wherein

Y is a leaving group and R ⁷⁰ is as defined above, or to provide compounds wherein R ⁷ is R ⁹ CO-CH ₂ -CH ₂ , (ii) with a Michael acceptor of formula (xi),

R < CO-CH = CH, (XI) wherein

R ⁹ is lower alkyl or lower alkoxy, or to give compounds wherein R ⁷ is methyl or sulfomethyl, (iii) with formaldehyde and formic acid or alkali metal bisulfite.

N-acylation:

The compound of formula (IX) may be reacted with an anhydride of formula (XII),

FROM \

Z, c (XIII \ / ^x what in which

Z is an optionally substituted C 2 or C 3 alkylene chain or an arylene group to form a compound of formula (I) wherein R ⁷ is HOOC-Z-CO-.

All of these reactions are followed, if necessary, by cleavage of a possible protecting group.

Thus, the desired compound can be prepared by reacting a compound of formula (IX) with a compound of formula (X). Cleavable groups include, for example, halogen atoms, such as chlorine, bromine, iodine, acyloxy, such as acetoxy, lower alkanesulfonyloxy, such as methanesulfonyloxy, arylsulfonyloxy, such as p-toluenesulfonyloxy, nitro, phenoxy, nitro, phenoxy, p-toluenesulfonyloxy, succinimidoxy or phthalimidooxy.

When a compound of formula (X) contains an amine or monoalkylamine substituent, this substituent may optionally be protected by a group as indicated by R in formulas (G) and (H).

Said reaction may optionally be carried out in a solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, dimethyl-n-propylurea, dioxyn, tetrahydrofuran, pyridine and the like. It is also possible to use a mixture of at least two solvents.

Said 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-an, alkali metal hydroxides, alkali metal carbonates, sodium hydride and the like.

The reaction temperature may vary within relatively wide limits. Generally, this reaction is carried out at a temperature of 0 to 180 ° C, preferably 0 to 110 ° C. In demonstrating the process of the invention, 1 to 4 moles, preferably 1 to 2 moles, of a compound of formula (X) are used per mole of the compound of formula (IX).

The compound of formula (X) used in the process of the invention may be iodomethane, iodoethane, bromoethane, 1-iodobutane, 1-bromobutane, 1-iodopropane, 2-iodopropane, 1-fluoro-2-iodoethane, 1-iodo-2- methoxyethane, N- (2-iodoethyl) acetamide, N- (2-iodoethyl) N-methylacetamide, bromoacetic acid, allyl bromide, 4-fluorobenzyl bromide, mixed acetic and formic anhydride, acetic anhydride, acetyl chloride, propionic anhydride, propionyl chloride, benzoic anhydride benzyl chloride, 4 - [(trifluoroacetyl) amino] benzoic anhydride, chloroacetone, 1-chloro-2-butanone, phenacyl chloride, 4-acetyl aminophenyl chloromethyl ketone, chloroformic acid ethyl ester, chloroformic acid methyl ester, chloromethyl-4-nitrophenylbenzamethylbenzamide, 4-nitrophenylbenzonamide, Similarly.

Alternatively, the desired compound can be prepared by reacting a compound of formula (IX) with a Michael acceptor of formula (XI).

This reaction may optionally be carried out in a solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, dioxane, tetrahydrofuran, methanol, ethanol, propanol, glycol monomethyl ether and the like. It is also possible to use a mixture of at least two solvents.

The reaction temperature can be varied within a relatively wide range. Generally, the reaction is carried out at a temperature of about 30 to about 170 ° C, preferably between 50 to 140 ° C. In carrying out the process according to the invention, preferably 1 to 5 mol, in particular up to 2 mol, of the compound of the formula (XI) is used per mole of the compound of the formula (IX).

The Michael acceptor used in the process of the invention is, for example, methyl vinyl ketone, ethyl vinyl ketone and the like.

The reaction of compounds of formula (IX) with formaldehyde and formic acid or alkali metal bisulfite (to give compounds of formula (I) in which R ⁷ is a methyl or sulfomethyl group) is usually carried out at a slightly elevated temperature, for example at about +50 to + + Mp 100 ° C.

In addition, the desired compound can be prepared by reacting a compound of formula (IX) with an anhydride of formula (Π).

This reaction may optionally be carried out in a solvent such as pyridine, dimethylformamide, dioxane, tetrahydrofuran and the like. It is also possible to use a mixture of at least two solvents.

The reaction is preferably carried out in the presence of an acid acceptor such as triethylamine, pyridine, N, N-dimethylaniline, 1,4-disabicyclo [2.2.2] octane, 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 in the range of about 0 to 120 ° C, preferably between 0 and 100 ° C.

In demonstrating this process of the invention, preferably 1 mole or excess moles of the compounds of formula (XII) is used per mole of the compound of formula (IX).

The anhydride used in the process of the invention is, for example, succinic anhydride, glutaric anhydride, N-benzyloxycarbonylaparapyric anhydride, N-benzyloxycarbonylglutanic anhydride, phthalic anhydride and the like.

The protecting group may, if desired, be removed by known methods after the reaction has been carried out. For example, the formyl group may be removed by acidic or basic hydrolysis, and preferably by basic hydrolysis; the benzyloxycarbonyl group can be removed by hydrogenolysis.

Deprotection can be performed either before or after the reaction product has been installed.

Procedure D:

When the preparation of the compounds of formula (I), wherein R ⁵ and / or R ⁶ is lower alkyl (or the di-lower alkylamino or lower alkoxy), these compounds may be prepared by alkylation of the corresponding non-alkylated compound, namely the compound of formula (I) wherein R 1 and / or R ⁶ are hydrogen or contain amino, lower alkylamino or hydroxy. This alkylation can be carried out by reaction with a compound of formula (ΧΙΠ),

R ¹⁰ -Y (XIII) wherein

R ¹⁰ represents a lower alkyl group and

Y is a leaving group.

This leaving group is of the same type as that used in the compounds of formula (X). Also, the reaction can be carried out in the same manner as the alkylation reaction of compounds of formula (IX) using compounds of formula (X). O-alkylation is carried out in the same way as Nalkylation, but conveniently a proton acceptor, such as an alkali metal hydride, for example sodium hydride, is added.

Procedure E:

When a compound of formula (I) is to be prepared in which the group R 1 '1' - represents a 5- to 7-membered heterocyclic ring containing a -SO- or -SO ₂ - group, these compounds can be prepared by oxidation of the corresponding desoxy compounds of formula (I), -S- containing compounds in the heterocyclic ring.

The oxidation is carried out using an organic or inorganic oxidizing agent. Various compounds that readily provide oxygen, such as organic peroxides, such as monosubstituted organic peroxides (e.g., C 1 -C 4 alkyl or alkanoyl hydroperoxides, such as tert-butyl hydroperoxide), permetic acid and peracetic acid, as well as phenyl substituted derivatives of these hydroperoxides such as cumane hydroperoxide and perbenzoic acid. Optionally, another lower group (e.g., C 1-4 alkyl or alkoxy), halogen, or carboxyl (e.g., 4-methylperbenzoic acid, 4-methoxyperbenzoic acid, 3-chloroperbenzoic acid, and monoperphthalic acid) may be attached to the phenyl substituent. Furthermore, various inorganic oxidizing agents such as hydrogen peroxide, ozone, permanganates such as potassium or sodium permanganate, a hypochlorite such as sodium, potassium or ammonium hypochlorite, peroxymonosulfuric acid and peroxydisulfuric acid can be used as oxidizing agents. The use of 3-chloroperbenzoic 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 of -20 to + 50 ° C.

When the oxidizing agent is used in an equimolar amount or in a slight excess relative to the starting compound, mainly the corresponding sulfoxide, i.e. the compound of formula (I), in which said heterocyclic ring contains as -SO- as one member, is obtained. When the amount of the oxidizing agent is increased to twice the stoichiometric amount or more, to give the corresponding sulfone, i.e. a compound of formula (1), wherein said heterocyclic ring contains one member of such a group -SO ₂ -. This sulfone can also be prepared from the corresponding sulfoxide by treatment with an equimolar or greater amount of oxidizing agent.

Procedure F:

When a compound of formula (I) containing free aminohydroxy and / or carboxy is to be prepared, these compounds may be prepared from the corresponding compounds of formula (I) containing at least one amino, hydroxy and carboxy group in protected form.

Amino protecting groups are, for example, lower alkanoyl such as acetyl, benzoyl, alkoxycarbonyl such as tert-butoxycarbonyl or ethoxycarbonyl, substituted alkoxycarbonyl such as trichloroethoxycarbonyl, phenoxycarbonyl, arbenzoyloxy, benzyloxy such as a trityl or benzhydryl group or a haloalkanoyl group such as a trifluoroacetyl group.

The amino protecting groups may be cleaved by acid hydrolysis (e.g., tert-butoxycarbonyl or trityl) or by basic hydrolysis (e.g., trifluoroacetyl). The benzyloxycarbonyl and p-nitrobenzyloxycarbonyl groups are removed by hydrogenolysis.

The amino protecting groups which are cleavable by acid hydrolysis are preferably removed using a lower alkanecarboxylic acid which can be halogenated. In particular, formic acid or trifluoroacetic acid is used. The acid hydrolysis is generally carried out at room temperature, although it can also be carried out at a slightly higher or lower temperature (for example at a temperature of about 0 to + 40 ° C). Protective groups which are cleavable under basic conditions are usually removed by hydrolysis with dilute aqueous alkaline liquor at 0 to 30 ° C.

The protective groups of the carboxyl groups, for example protecting groups of the carboxyl groups in paragraph the Illustrative meanings of R ^1st

Removal of these protecting groups may be carried out by known methods, for example by hydrogenation (benzyl group) or by acidic or basic hydrolysis. The reaction is preferably carried out in an inert solvent at a temperature of from 0 ° C to room temperature. Special methods are also preferred, for example, the p-nitrobenzyl group is removed by hydrolysis in the presence of sodium simia at a temperature of about 0 ° C or lower to room temperature in a solvent such as dimethylformamide (aqueous); tert, the butyl group is removed by treatment with trifluoroacetic acid in the presence of anisole at a temperature of about 0 ° C to room temperature, optionally in the presence of another solvent such as methylene chloride or allyl is removed by a palladium (O) catalyzed transalkylation reaction in the presence of sodium or potassium salt of 2-ethylhexanoic acid (see, for example, J. Org. Chem., 1982, 47, 587).

Procedure G:

When a compound of formula (I) containing a halogen atom is to be produced, such as a compound in which R ⁵ R ⁶ N- is the group "O", this compound can be prepared by halogenating the corresponding hydroxyl-substituted compound (e.g. R ⁵ , R ^S Means a group

The halogenating agent is preferably a thionyl halide, in particular thionyl chloride or phosphorus trichloride, phosphorus oxychloride or phosphorus trichloride. The reaction temperature is preferably in the range of about 0 to 80 ° C. The carboxyl groups present are preferably protected, for example benzylated, and subsequently, if desired, released again, for example by hydrogenation (removal of the benzyl group).

Procedure H:

When an amine-containing compound of formula (I) is to be prepared, such as a compound wherein R ⁵ R ⁶ N- is

this compound can be produced by reducing the nitro groups of the corresponding nitro substituted compound of formula (I). The reduction can be carried out by hydrogenation in the presence of a noble metal catalyst, for example palladium-containing activated carbon. The reaction is conveniently carried out in water or a lower alkanol, for example methanol or ethanol, optionally with admixture of other solvent-soluble solvents in the reaction mixture. The reaction temperature is usually in the range of about 10 to about 40 ° C; room temperature is preferred.

Procedure I:

When a compound of formula (I) containing a group of formula is to be produced

in which

R ⁵⁰ and R ⁵¹ have the same meaning as that in which R ⁵ R ⁶ N- is

N-group, this compound can be prepared by reacting the amino group of the corresponding compound of formula (I) substituted with an amino group (e.g., wherein the group R ⁵ R ^{6 is} not a group

with a reactive derivative of the formamide derivative of the general formula (VII),

(VII) in which

R ⁵⁰ and R ⁵¹ are as defined above.

As a reactive derivative of the compound of formula (VII), the corresponding di- (lower alkyl acetals) such as the corresponding dimethylacetals may be used The reaction is preferably carried out in an inert solvent such as diethyl ether, dimethylformamide or dimethylsulfoxide. be lower or higher than room temperature, for example in the range of from about 100 ° C.

Procedure J:

The preparation of esters of formula (I), i.e. compounds in which ^R1 is a carboxyl protecting group, can be carried out by reacting a carboxylic acid of formula (I) with a corresponding halide, preferably iodide or bromide containing the desired ester group. The reaction may be accelerated with a base such as an alkali metal hydroxide, an 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 triamide, dimethylsulfoxide or especially dimethylformamide. The reaction is preferably carried out at a temperature in the range of about 0 to 40 ° C.

Procedure K:

The preparation of the pharmaceutically acceptable salts of the compounds of formula (I) or the hydrates or solvates of these salts can be carried out by known methods: for example, reacting the carboxylic acid of formula (I) with an equivalent amount of the desired base or vice versa. or an inorganic acid. The reaction is conveniently carried out in a solvent such as water or an organic solvent, for example ethanol, methanol, acetone and the like.

The temperature at which the salt preparation is carried out is not a determining factor. The salt formation is generally carried out at room temperature, but can also be carried out at a temperature slightly higher or lower than room temperature, for example at 0 to +50 ° C.

Examples of therapeutically acceptable acids that can be used to form salts of the compounds are hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleinic acids. , phenylacetic benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, aminosalicylic, nicotine, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, gluconic, glucuronic, galacturonic, aspartic and glutamate; methionine, tryptophan, lysine, arginine and the like.

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

Salts of compounds of formula (I) with bases can be prepared by reaction of a compound of formula (I) with a metal hydroxide or amine, such as an alkali metal or alkaline earth metal hydroxide, or an organic amine. Examples of 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 or base addition salts of the compounds of formula (I) differ from the corresponding free compounds of formula (1) by certain physical properties, such as water solubility.

The compounds of formula (I) and their pharmaceutically acceptable salts may exist in unsolvated as well as solvated forms, including hydrated forms. The hydration may be performed automatically during the manufacturing process or may occur gradually due to the hygroscopicity of the initially anhydrous product. For the controlled preparation of the hydrate, the wholly or partially anhydrous product may be exposed to 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, for example, during crystallization.

Some of the compounds produced by the process of the invention have asymmetric centers. Included within the scope of the invention are the pure D isomer, the pure L isomer, as well as mixtures thereof including racemic mixtures.

The compounds of the invention exhibit broad antibacterial activity against gram-positive and gram-negative organisms and mycoplasmas and can be used as agents for the treatment and prophylaxis of contagious diseases. The bactericidal activity of the compounds of the invention in vitro and in vivo is exemplified by the above experimental results.

1. Antibacterial activity in vitro

The antibacterial activity of the pyrido [3,2,1-i] 1,3,4-benzoxadiazine derivatives produced by the method of the invention has been investigated by the standard stepwise agar method (see Chemotherapy, 22, 1126 (1974)). the inhibitory concentrations of these compounds (MIC, in gg.m ^-1 ) are shown in Tables I and II The compounds used in these assays were made according to the procedures of the Examples.

Table I - continued

AntibdkteriaLne ípaktwi KIC)

Example no.

Aerobic likraorganlziy 22 2 <15 26 12 30 Craipciltiv bacteria ladUua «hrili. Kl 219 0.45 0,1) 1.70 1.71 4.3 » 1,115 StaphylaenEevi ittei Ri 2012 X-1 0.10 1,5i s, 25 1.11 1,5i 0.05 Stapkylccocna atnui ® 1955 1.35 (B 12.5 1,9i 11.5 4.19 SUptyloMccm aunci Saitk 1.20 13 « 1,5i 3.13 l Si 4.05 SUpbybccccu ipUenidh, IM 12511 1/1 ' J, 13 4.15 3, B and B 0.10 SUpbylococcM epideraidii n 1942 4.20 ), With I, I! 3.13 EXAMPLE B 0.20 btacoeMcui faaealii n Bil 1.11 25 100 25 50 1.11 Grurjgatlwe Baktlcia ilcalLpoti fatealis ΠΟ 13111 1.11 25 51 U-9 M l.SÍ CitioMctar tnoadii IM 12 (91 1.11 1.9 ' 0.71 C, X 0.20 0,011 latembactar aerogetti R 2145 0.11 4.70 4.31 0.20 4,21 0.0033 totanbactar claeae Π 3544 0.10 1.13 0.11 Oji 0.79 0,013 Tseberiekia csli KU X-2 0J0 1.5 ' 0 » 4.10 0.11 0,033 CKcrickia coli B HM »,« 5 9.79 t, 3) 9.20 0.00 ' (ltbilella pucmin TOk Kl (01 0.19 (.1! J, U 1.11 1.13 0.10 SotdtCtlU bnockiicptíw Hcc 4411 1,5i 51 110 B, 5 25 1.56 Read rICt 14545 0.79 12.5 25 4,2í 11.9 0.11 Fnltai vnlyarii 0119 UCC (BI 0.0045 0.15 1.10 1.19 0.20 9 DM5 Fitodaacaai aingiuaa Λ3 1.54 3, U 1.13 «, 15 3.11 1.05 hnfeMus atn ^ iteaa R 25 « 4.2 ' 25 50 » 25 00:20 Hhúokui «tetzari IM 11 (15 1.10 4.39 0.71 1.20 0.0013 Senitla Mraxa 2N 12 (40 0.70 4.25 3.13 1.5 ' 3,1) 1.19 Salaooalla lyftiaarita ΣΗ 12515 0.14 1.71 1.10 4.1 tons 0.31 1.00 (5

Table I - continued

Antibacterial ipeltna MIC Ι ^, ιΓ ¹ )

Table I

Antibacterial tpciire MIC Igg.

kecoteí aikroorgaauay 5 ( T s ll 11 Crupotltírna baktirie ladllu icbtília Kl H! 1.05 0.10 0.10 4,025 <0.0000 0.10 <0.0101 Stapiylococcu umu fO * 11 »? L-X 4, B 0.35 0.35 0.31 0,1í 0.10 4.10 ttipkyloeocm · ucaui n 1155 «, 21 3, B 1.5 ( 0.35 0.00 (5 0.70 0.05 SUpkylocececi uceaa Saitk 0.21 4.31 0.20 0.20 4.0011 0.10 4,015 Stapkylacomi tpUeoúdii IM 111J1 9.35 1,5i 0.11 0.35 0.20 0, B 0.10 SUpkylococni tpideaUit n 2511 4, M 1 » 0.71 0.35 4.00 (5 0.35 0.15 tacccccceae Utcal n 1HJ ], II n, p 12.1 0.15 11.5 3.13 3, B Ciuueqttint bacteria Uuiipwi bralu iro um í, 31 3.13 (, 25 0.70 i, 25 M 3, II Citwhactet iraodli IM 1111] 0,017 0,011 0.05 0,025 0, B 0 » 0,3) litirabaetir irrocaota n H45 0,017 0,013 0.05 0,025 0.00 (5 0.20 1.11 Zatarobutac clMGaa M15U 0,015 0,025 0.10 4.05 0,413 0.70 1.3 » lickKICK call HU JC-2 0,015 1,021 0.10 0.05 0.10 0.20 1.39 tactaickh coli M 2 (10 0.D1J 1,025 0,015 0,013 <0,0001 0.10 XlateialU poaaaoaaa KM KI íll 0.10 0.10 0,1í 0.20 1.13 3.11 4.7 ' Lodatalla bmehuptla kKC 4 (17 0.20 i, 21 J, 13 0.35 1. » », 25 1.10 Frátra nttpei «and MMS 0,2í í, M 0.71 0.37 1 » 12.5 í, M third Tslyuia «15 * KC (151 0,413 0,013 0,015 0,021 <0,0001 0.10 1.05 liadaoau urogibcH il 4 » 0.10 0.20 D, B s, 25 0.1 ( 1,5i hHdtaoui uragiam K 15 « 0.70 i /! 3, U J, U 12.1 12.5 (.15 Pindaoaai ititmi m 11 (51 0,025 0,021 0.05 0,015 <0.1001 o ii dance Bunicanc IM 12449 1.10 0.10 0.20 0.10 0.11 3, ll 0.11 SalMUlla typkiuwiua m 11515 0,025 0.11! {0! 0,015 0.0031 0.20 4.10

Example 2

Aerobic ikrooqaaitay Jr 32 31 at when her Graffiti-related bacteria Sacllluj aubtilú Kl 219 1.05 9.05 1.20 0.05 00:05 9,425 Stapkylceocciu wrwi Πΐί 209? L-X 0.39 1.20 0.20 0.20 0.39 0.39 Stapäylccmu urtai To Itii 0.79 4.2? 1 » 2.14 J.5 ( 0.10 Suphylococaii urn Saitb 0.10 .4,10 4.20 0.21 about," 0.10 Staphylccsccinamide IN 12991 4.39 0.39 4.7 tons 0.79 0.71 0.20 Staphyl Kccai and amdli n 2H1 »,» 0.39 0.71 0,7í 1.71 the ip Zntexocecou fatealii D 2943 12.5 s, 19 1.11 4.25 4.25 3.13 CruM ^ atĹau bacteria UealigtMa íaenlii Π0 13111 .mu.l 1.5 ' 50 50 15 3 U Citrotatar fnoadii IM 12 (01 0.05 4.10 0.21 0.20 0.20 0.21 btirohctar atrogacti Kl 2945 0,425 9,025 0.05 0.19 0.10 0.05 latinbactar cLoaeaa n 214i 0.05 0.10 4.20 9.24 0.3 » 0.14 bchacichia ccli HU X-2 0.05 0.10 4.20 0.24 0.11 0.14 Itdtedehia eeli n 2110 0,025 4,025 0,1) 0.10 4.1 ' 00:05 IlabiialU pctwiai KK Ki (02 0.20 0.39 0.79 0.71 1,5i 0.35 Iczdatallí brmckiiaptin KCC 4 (17 1.0 I ' 25 when 32.5 9.39 Tzctaci «ttgiri 1KC 14505 0.19 1,5i 1.5i 3/11 3,1J 0.71 Xrotiii wlguii CX191KC (919 0,025 0,025 0.05 0,059 0.05 0,025 4,21 0.71 1, with ( 0.11 fttcdaiaeu aanfiacta n MO 2.9i 3.23 3,3i «, 25 11.9 i, 25 FaacdaoMt itctzari (M 12 (15 0,425 0.10 4.11 Sarratit uKtictu IM 12 (49 0.20 0.39 9.70 0.1 s 1,5i 0 » SalsiMuU typhiMriu 170 12519 0,025 0,025 1.11 0.10 0.10 0.14

Table I - continued

Table I - continued

XnLlbikUriielae (Mttjui χκ

AMibakLwiílre ifxklrua HtC (^ .a) ' ¹ )

IlireuM and Example no.

Mrcboí eÍkroorgibiay 15 11 17 10 15 21 GtupoiitITT bacteria Uci.Uu nbtilb (Cl 211 0 » 0.20 O.ílJ 0,013 4.45 »Q1 Stapkylacecaa aurai FU 2115 X-! l) l (,)! 0.05 0.05 0.31 0.31 SUpfylococre car B 2155 OJI 15 0.2 ' 0.14 ( 'J1 , m SUpbylocxcu Btni (aitb 4.15 0.35 0,025 1,071 1.24 0.31 Stipbylocal apldeaiiii IM 12511 1.71 1,5i 0.21 0.1 ' 0,5) 4,3) SUpbylococcea epUateldii n 2111 4.10 1.54 J » 1.14 0,1) 0.35 lataraoccu tuollí R 11 (1 4.15 25 1,5i 1,5i 4.25 3,1J OunagatlvM baktícle Mcalijaau hacalLí DC 11111 1.13 5 t s, 25 1.25 s, C 4.11 Citnbactu t r «udli. ifO 12 (11 4.45 t is 4.24 1. » 1,5i 4,7) Mantactv aerepM K 2H5 0.05 4.05 0.05 0.05 l Si 1,2) OtunUeia cImoc IX 294i 0.10 4.11 I 1C 0.15 l II ¢, 71 hetetidLi «11 X-l 0.10 0.20 0.10 1.05 1,5i 0.35 licbulcUa coli IIN 1,425 1,413 0.3 » 1.20 IlebaUUa fMaaaiu HU K! (41 1.3 » L, W 1.10 0,3í (.25 4.10 MctilU hnacbilcptici UCC (117 0.71 25 «<25 3.11 1.25 4.10 OnI's Rettyer MC ((545 i.n (.5 * 1 » EXAMPLE B 1. U 0.71 Frokra ralyuii «Β UCC II! · Ml! 1.10 0.01) 1,015 0 » 4.05 haadaeua tangÍMta U 0.11 o.n 1. » 1,1) EXAMPLE 15 1,5i tindcaaau unyiaua n 1551 1,1) (U 4.15 4.15 15 3.11 hcidwMi ittturi IK 11 (11 4.5 1.05 0,515 4,015 0, M 0.10 Sanatia aacucw in 0.39 0.15 0.71 1 » 3.12 o, w talaoaaUa typhieatlta IM 11525 1.11 0.10 0.15 1,111 1.54 1. »

Example compound no.

krihré iicroorgrnÍ2af 31 39 39 40 41 42 Crupodtívae bacteria Baciilu lubtills Kl 219 <0.0001 a.oocj 0,015 0.10 1.13 0.05 SUpbylococns atirem MA 209? JC-l 0,041 0 » 0.39 1.54 s, 25 OJ ' SUpbyloccccui aarm n 1055 <D.N09 D 20 4? 0 0.10 i, $ 2 0.3 ' StiplfMeoeeta ivre »SKitk <A, DMT EXAMPLE LI s, » 4.78 (H 0, H Suphyloccccui apidaaidij IFO 12993 0,015 0.39 1.19 1,5i and H 0.3 ' SUphylococci tpidetiidii R 2142 <0.0001 4.39 0.39 0.70 H.5 0.31 tatazoncciM iaacalia U 2913 3, B 12.5 12.5 12.5 10) 4.25 Craneyatirx bacteria UealigtMt žaeealia IM 13111 12.5 (.25 «.25 (.25 5) 1 ' Citobactir freuodii IM 12 (91 0.71 (, 25 4.19 .0,20 4.19 0.05 IntircbutK aerogeíei n 2145 0.10 1.13 9.05 1.10 0.10 0,015 latuetutir ds® n 2Hi 0.20 4.25 IJ! 1.19 0.11 0.95 coli thietaride O13J JC-2 0.10 s, 25 4.10 I » 0.11 0.05 liAiridia ccli n 2110 <0.0009 4.39 0,025 (.20 o, I ' 0,025 Ilabliilla púmiÚM F0A ΚΙ M2 3.13 25 1,5i 1.5 ' 3.13 0.39 UCC 1017 1,5i 4.25 0.70 J.H. 25 0.3 ' Plowed rettgad MCC 14545 (.25 25 1.13 1.13 3.13 0.11 ? rrtaus wlgaria 0X19 JffCC I9K <0,0X0 1.13 0.03 4.10 1.5 ' 0,025 iMcdooui unqiaon 13 4.25 25 3.13 1.5 ' 343 0.31 btudenu unpiaoM Dl 2951 25 50 12.5 U 5 12.5 3.13 htudcMUi ituttid 173 12 (95 0,011 4.15 - 0.10 Sarutia unictu Π012 (49 0.70 11.5 1.5 ' 1.5 ' 1.11 0.10 Salioulla typkiairim 170 12521 0.10 15 0.20 0.31 0.19 0,015

Table I - continued

Table II

Mitektani.ta iprttru. MC

taraW likiMtyuiiaf 41 '4 Crupaltin · Bact <: ia tuned * · ebtUia ΚΣ 11 * • 4 ' Rqj ^ loeoeai aut ** MA 3ΜΓ JC ·! o, n «, 11 RqbflKaceu car B 1155 s, n Ο, Μ mcm * children 1.1 » 0.1 » ft ^ lacscca * apUuaUh W124 * 1 «)» ί, Μ ftigttylccscca app * Hi> 1’U », 31 0.11 Imi u rim * Lm 1M1 1.31 IL * Ctwwptin · tektlňa UdlifaMi .lualil IN Bili 0.7 tons 1.51 CttnbacUr landii m IWI «4« • 40 BMHbtftK MNfHU B 1 * 45 0 '. » 1.1! KtnUetu eleo R 31 « 14 « 4, N bAuitUa alt IIH K-1 04 « «« bBaricUa «11 B II» »H 4.4! DBiklla M Kt (U 0.31 0) 1 ktUUU btwrtiuftif ICC 411 ’ »J! 0,1i Mu ntt * il aa 1 (545 IN" 1.51 hatMi nlfuil «H« t (Hl o, i> (U hataau urifiMuU i.n i, 'i Itakeeu wnfiM · n 1.11 1.11 1M ^ taau rtrtitfl W 1111 $ »M tarntii, inter alia, VO 12141 1 » tjftaati * VO 111 » * 41 00:20

I titanium drink * t.

C «41

Antibacterial Spectrum »MIC (kig.al ´ ^) 5 30 Bacteroides fragilie ATCC 23745 0,7B 0.20 Bacteroides fragille FR 2579 3.13 1.56 Bacteroidea fragilie FR 2582 0.78 0.39 Bacteroides fragilis NR 2583 C, 39 0.10 Bacteroides fragilis NR 2584 0.78 0,7B Bacteroides dlstascnis MR2S78 0.78 0.78 Bacteroides thetalotankin HR 2588 1.56 0.78 Bifidobaeteri · adolescentis ATCC 15703 0.39 0.10 ClosCrldiUD botulinum NR 2611 0.10 D, 013 Clostridium perfringens NR 2612 0.39 0.10 Clostridiun Bonillforne ATCC 25546 0.78 0.10 Fusobacteriun varlun ATCC 8501 12.5 - Beptococcus prevotii ATCC 9321 1.56 0.39 Peptccoccua variabllis ATCC 14955 0.78 0.20 Peptcstreptococcus anaerobius NR 2743 0.39 0,013 PropionibacteriUB acnea ATCC 11828 0.78 0.78 Mycoplasaa Mycoplasaa hoainis NR 2952 0.10 0.10

TABLE I - CONTINUATION OF COTHICALLY APPLICATION OF ItC (n-I ¹ ) TarotMorroJuiup llitaiii t frftlidu t.

! 5 Si 51 52 5 «

GrwpotllívM biktiri *

Buľlu nAtilíi KI 11 ´ 0.034!

SUpbyloaeai n: ni fM fly K-1 0,3>

Supkylonni hihi R lt15i, 3 '

SUpkjloarai eiw Slitk!, Ll

SUj * yl &quot; p &quot; W H &apos; 1C, 35

SUfkyloaecu (pUanilii B 1 * 421.10 btuccocc * · (honored B 1 * 413.1!

CrungiibM biktéúi

ΗμΗ, μμ tuaUi ΠΌ U1111,5

CitrfecUr (bored QO 1) 013,13 btuotacUt utqnit n J45 <, 1t of total R 294 (l, M cell * or IIU JC-11,14 tactenellt coli B MJO (, M

Kňbililla ptnmiu TO KI (Clí, 15 lorítttili brwúiitptiu Ltt (? 3,1 3,13

Protw nttyiri ua 14505JJ5 fretMi valfiru «11 Ktt U1I0,3’

FinduMii uRfiMM U1,15 fittdoMu unfitou n 25 M25 ludacMi ititiKi iro 12 (11

SimtU urcuau (TO 1Μ1Ι>, 13

SilMulli lypiluri · UO 1252? 0.11

0.10 • 4 » •, «25 «$ 02 1.1 ' 0.11 0.15 0,011 1.5 ' 3.11 1.10 0.3 ' 1.11 4, J1 $ 0.0 0.0 » 0.1 » 1.54 0.1 » 440 J, 11 1,5i 0.10 0.10 11.5 25 1,5i t, F 3.13 11.5 1.13 0J5 0,025 0,025 t 10 0.10 0,125 $ 1.02 0.10 0,025 0, (5 0.05 1.20 0.10 0.1 ' D, K 1.20 0.10 1,025 $ 0.42 Press 0, (25 1.2! 0.2! 0,3) 0.70 l 5T s, 25 0.11 3, B «, 20 «, 10 1 ' 0.10 0.01! 0125 4.10 4013 «, 10 0.10 s, TI 0.20 1.5 » 1.5 ' 11.5 l, 5 < 0.05 0.05 0.20 0,013 «, 10 0.2 ' OJI o, i> 0,025 0,025 0.10 0,015

2. Therapeutic efficacy in vivo

The in vivo antibacterial activity of pyrido [3,2,1-i] -1,3,4-benzoxadiazine derivatives, prepared according to the procedures of Examples 5, 30, 65 and 66 below, was tested against lethal infection by Escherichia coli ML 4707, Pseudomonas aeruginosa 4au542; and Streptococcus pneumoniae 6-001. 1CR mice weighing approximately 20 g are infected by intraperitoneal injection of the appropriate bacterial suspension. Test compounds are administered orally or subcutaneously when infected. Mortality is monitored for 5 days. The corresponding 50% effective dose (ED ₅₀ , mg.kg ^-1 ), which protects 50% of the test animals from death caused by infection, is shown in Table 3.

Table 3

Table I - continued

Antibacterial MIC (wq.sľ ^]

Antibacterial efficacy in vivo against systemic infection in mice (ED ₅₀ , mg.kg ^-1 ) ktrobftd ikroorganižay

Sbitttuni and Example no.

5I 5 ‘13 i)

GrupMÍtívw Bacteria

Bicillut mbtilU? CI 219 4.20 0.0065 Stíphylocoec * wxitw 2C9T JC-1 «, 19 0.31 SUpbylocoecu * aonot 0 2855 0.78 0.10 Staplylomecno ajnos Siltb 9.19 0.05 Stoptylococcii «pldenidij IFO 11991 0.19 0.39 Stiphylococcus pidtoidio R 2941 0.19 0.20 latorococCT * tucalis Dt 2941 U 5 3.11 Gram-positive bacteria lligigmi ImcíLíí IN 13111 3.11 1.25 Citrobtóer «modii-lFO 11981 0.19 1.56 Snttrebut »i« rogtui D 2985 0.10 9.78 tateccbactir cImcm 0 29 « 0.05 9.18 E. coli IIU JC-2 0.10 1.56 EscbetkbU coli R 2630 0.0 «5 0.19 Iltbiiallo paeaaonla * ΚΛ KI (01 C, 39 3.11 Bcxdatalla broachlseptie * MCC 4 (17 3.13 3.13 Mainly MCC 145C5 1.56 3.13 lines ·· wl ^ ari »0119 ÍSCC 6911 8,013 0.20 Psetdsweii aera ^ ibOM U 3.13 3.11 NM &apos; atngiaoia R 1550 6.25 25 ŕieudoBma * itutrari IFU 12695 9.0013 1,5i Stcratia untsctoi IO 12648 0.19 3.11 SalaouUa tyhpiBitLu IM 12529 0.95 1.56

0.78

9.78 i, i0, H i, s <

0.78

100

0,7í

0.31

1,5i

1,5i

0.7 '

6.25

LH

0 »

3.13

0.39

3.1) ¢, 10

1.55

0.11), 5

I, 55

II, 5], 1J

0.10

0.10

0.20

0.20

0.10

0.35

0.7!

OJI

0.05

0.79

5.25

0.20

0.20

0.10

Example compound no. bacterium Escherichia coli ML 4707 Pseudomonas aeruginosa 4au54 2 Streptococcus pneumoniae 6-100 S.C. after. after. P. D. 5 0.06 0.11 13.4 10.3 30 0.10 0.62 57.0 66.9 65 - 1.12 - - 66 - 0.51 - -

3. Acute toxicity

The corresponding LD _{S ()} values of the compounds prepared in Examples 5, 6, 7, 16, 17, 18, 30, 36 and 56 are greater than 2000 mg.kg ^-1 . The acute toxicity of these compounds is determined after oral administration to ICR mice.

The compounds produced by the method of the invention exhibit a broad antimicrobial spectrum against Gram-positive, Gram-negative bacteria and mycoplasmas, particularly 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 robust and broad antimicrobial activity. The protective effects of the compounds of the invention against systemic bacterial infections in mice are greater than those of commercially available synthetic antibacterial agents. Therefore, the compounds of the invention can be effectively used for the prevention or treatment of diseases caused to humans or animals by Gram-positive or Gram-negative bacteria and bactoricidal microorganisms.

For example, it is possible to treat and / or prevent diseases caused by the following microorganisms or mixtures thereof: Staphylococcus, Streptococcus, Aerococcus, Enterococcus, Micrococcus, Lactobacilus, Bifidobacterium, Clostridium, Eubacterium, Peptococcus, Glycerobacteria, Glycerobacteria, Glyphobia, Proteus, Pseudomonas, Serratia, Salmonella, Vibrio, Aeromonas, Haemophilus, Neisseria, Acinetobacter, Alcaligenes, Bocteroides, Fusobacterium, Mycoplasma and other microorganisms.

The invention further relates to pharmaceutical compositions comprising at least one compound produced by the process of the invention.

The compounds of the invention may be administered to humans or animals orally or non-orally by various conventional methods of administration.

The compounds of the invention are used either as such or formulated with excipients, liquid diluents, binders, lubricants, humectants and the like, for example in the form of conventional medicaments such as tablets, granules, sugar-containing tablets, powders, capsules, gels, anhydrous. syrups, syrups, ampoules, suspensions, liquids, emulsions, ointments, pastes, creams, suppositories and the like.

It is also possible to use dissolution retarding agents, surfactant absorption enhancers, and the like, as any formulation excipient, which is any formulation which is pharmaceutically acceptable.

The compounds of the invention may be used alone or mixtures of at least two different representatives of these compounds may be used, the amount of which is about 0.1 to 99.5%, preferably 0.5 to 95%, by weight of the composition. the amount of the entire drug.

The medicament composition of the invention may be formulated as a combination of a compound of the invention or a mixture thereof with other suitable compounds that are pharmaceutically active.

The daily dose of a novel compound of the invention to a patient may vary depending on the individual, the species of animal, their weight and the type of disease, but is generally in the range of 0.5 to 500 mg per kg body weight, preferably about 1 to 300 mg.

The preparation of the compounds according to the invention is illustrated by the following examples.

Preparation of starting materials

Comparative example

Preparation of N- (3,4-difluoro-2-hydroxyphenyl) aminomethylene malonic acid dictyl ester (a) A solution of 500 mg of 2,3-difluoro-6-nitrophenol in 7 ml of methanol was hydrogenated for 6 hours using 60 mg of activated carbon containing 5% palladium. The reaction mixture was then filtered under 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 414 mg of said aminophenol with 618 mg of ethoxymethylene malonic acid diethyl ester was heated at 130 ° C under a nitrogen atmosphere for 5 minutes. The crystalline residue obtained is triturated with ethanol and filtered to give 590 mg of N- (3,4-difluoro-2-hydroxyphenyl) aminomethylene malonic acid diethyl ester, m.p. 178-180 ° C; MS m / z 315 (M ⁺ ). An additional 59 mg of these crystals were obtained by chromatography of the mother liquor on a silica gel column using chloroform / acetone (20: 1) as eluent.

Preparation of 8-Benzyloxy-6,7-difluoro-4-hydroxy-3-quinolinecarboxylic acid ethyl ester (Procedure 1) (c) To a mixture of 80 mg of N- (3,4-difluoro-2-hydroxyphenyl) aminomethylenemalonic acid diethyl ester with 70 mg of anhydrous potassium carbonate 1.5 ml of anhydrous dimethylformamide are added with 30 μΐ of benzyl bromide, the mixture is stirred at room temperature for 2 hours, after removal of the solvent under reduced pressure, the residue is dissolved in dichloromethane and the insolubles are filtered off, washed with water, dried over anhydrous sodium sulphate. The crystalline residue was washed with n-hexane and recrystallized from methanol to give 90 mg of diethyl N- (2-benzyloxy-3,4-difluorophenyl) aminomethylene malonic acid, m.p. 87 ° C, MS m / z 405 (M ⁺ ) .

(d) A solution of 280 mg of said malonate in 2.8 ml of diphenyl ether was heated at 250 ° C for 30 minutes under a nitrogen atmosphere. After cooling the reaction mixture, ethanol formed was removed from the reaction medium under reduced pressure. The dark brown solution is applied to a column of 10 g of silica gel, followed by successive elution with benzene, dichloromethane and a mixture of dichloromethane and acetone (30: 1). The pure fractions were combined and the solvent was removed under reduced pressure to give a crystalline residue. This was washed with a mixture of n-hexane and ethyl acetate to give 90 mg of 8-benzyloxy-6,7-difluoro-4-hydroxy-3-quinolinecarboxylic acid ethyl ester. Recrystallization from methanol gave an analytical sample, mp 200-201 ° C; MS m / z 359 (M &^lt; + & gt ^; ).

Preparation of 8-Benzyloxy-6,7-difluoro-4-hydroxy-3-quinolinecarboxylic acid ethyl ester (Method 2)

To a solution of 300 mg of 6,7-difluoro-4,8-dihydroxy-3-quinolinecarboxylic acid ethyl ester in 6 ml of anhydrous dimethylformamide is added, with stirring, 308 mg of anhydrous potassium carbonate and then 145 μΐ of benzyl chloride. The mixture was then stirred at 55-65 ° C for 11 hours. The reaction mixture was then diluted with 30 mL of water and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is chromatographed on 7 g of silica gel, eluting with acetone / chloroform (1:20), to give 113 mg of 8-benzyloxy-6,7-difluoro-4-hydroxy-3-quinolinecarboxylic acid ethyl ester, m.p. up to 201 ° C; MS m / z 359 (M ⁺ ), after recrystallization from methanol.

Preparation of 8-Benzyloxy-6,7-difluoro-1- (formylmethylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid ethyl ester (e) A mixture of 410 mg of 8-benzyloxy-6,7-difluoro- Of 4-hydroxy-3-quinolinecarboxylic acid with 315 mg of anhydrous potassium carbonate in 10 ml of anhydrous dimethylformamide is stirred at room temperature for 1 hour, then 260 mg of O- (2,4-dinitrophenyl) -hydroxylamine are added. The mixture was then stirred at room temperature for an additional 6.5 hours. After removal of the solvent under reduced pressure, 12 ml of water was added to the residue and the mixture was stirred at room temperature for 1 hour. The precipitate formed is filtered off and washed first with cold water and then with ether to give 405 mg of 1-amino-8-benzyloxy-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid ethyl ester. Recrystallization from methanol gave an analytical sample, mp 143-144 ° C; MS m / z 374 (M &lt; ^{+ &gt;} ).

(f) To 1.51 mL of acetic anhydride was added 0.60 mL of 98% formic acid 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 is added dropwise a solution of 400 mg of said amine in 2.1 ml of 98% formic acid. The mixture was stirred at room temperature for 2 days. The reaction mixture is then evaporated under reduced pressure to give a crystalline residue which is recrystallized from ethanol; 410 mg of 8-benzyloxy-6,7-difluoro-1- (formylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid ethyl ester of melting point 188-190 ° C are obtained; MS m / z 402 (M &lt; ^{+ &gt;} ).

(g) A mixture of 400 mg of said formamide, 275 mg of anhydrous potassium carbonate and 17 ml of anhydrous dimethylformamide was stirred at room temperature for 1.5 hours. After adding 0.19 ml of methyl iodide to the mixture, stirring was continued for 2.6 hours. The solvent was then removed under reduced pressure and the residue was partitioned between chloroform and water. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was recrystallized from ethanol to give 335 mg of 8-benzyloxy-6,7-difluoro-1- (formylmethylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid ethyl ester, 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 (h) 330 mg of 8-benzyloxy-6,7-difluoro-ethyl ester

The 1- (formylmethylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid was hydrogenated for 4 hours using 50 mg of activated carbon containing 5% palladium catalyst in 14 ml of chloroform. The reaction mixture was then diluted with 14 mL of methanol and filtered. The filter cake was washed with a 1: 1 mixture of chloroform and methanol. The combined filtrates were evaporated and the residue was recrystallized from ethanol to give 239 mg of 6,7-difluoro-1- (formylmethylamino) -8-hydroxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid ethyl ester, m.p. Mp 221-225 ° C (dec.); MS m / z 326 (M &lt; ^{+ &gt;} ).

(i) A mixture of 210 mg of said ester with 5.2 ml of 0.5 N sodium hydroxide solution was heated at 100 ° C for 2 hours under a nitrogen atmosphere. The reaction mixture is then acidified with 0.16 ml of acetic acid. The precipitate formed is filtered off, 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. Recrystallization from ethanol gave an analytical sample, m.p. 248-250 ° C (dec.); MS m / z 270 (M &lt; ^{+ &gt;} ).

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

A mixture of 105 mg of 6,7-difluoro-8-hydroxy-1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid prepared in Comparative Example (i) with 150 mg of paraformaldehyde and 5 ml of anhydrous of dioxane was heated at 100 ° C for 3 hours under a nitrogen atmosphere. After removal of the solvent under reduced pressure, 20 ml of dimethylformamide was added to the residue, and the mixture was stirred for 20 minutes, then filtered. The filter cake was washed with dimethylformamide and the combined filtrates were evaporated under reduced pressure. The residue is 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-benzoxazine-6-carboxylic-diazine. Recrystallization from dimethylformamide gave an analytical sample, m.p. 290-292 ° C (dec.); MS m / z 282 (M ^4).

Example 2

Preparation 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

A mixture of 50 mg of 6,7-difluoro-8-hydroxy-1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, prepared in Comparative Example (i), 1 ml of 90% acetaldehyde and 5 ml The mixture was evaporated under reduced pressure to give 52 mg of 9,10-difluoro-2,3-dimethyl-7-oxo-2,3-dihydro- 7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, m.p. 285-289 ° C; MS m / z 296 (M &lt; + &gt;).

Example 3

Preparation of 9,10-Difluoro-2- (hydroxymethyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4-benzoxadiazine-6 carboxylate

A suspension of 50 mg of 6,7-difluoro-8-hydroxy-1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid prepared in Comparative Example (i), 45 µl of glycol aldehyde diethyl acetal and 7 mg of pyridinium- of p-toluenesulfonate in 2 ml of anhydrous dioxane was heated at 110 ° C for 5 hours under a nitrogen atmosphere. After removal of the solvent under reduced pressure, the crystalline residue was washed with water and methanol to give 52 mg of 9,10-difluoro-2- (hydroxymethyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [ 3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, m.p. 254-258 ° C (dec.); MS m / z 312 (M &lt; ^{+ &gt;} ).

Example 4 Preparation of 9,10-Difluoro-2 - [(dimethylamino) methyl] -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] - p-toluenesulfonic acid salt 1,3,4-benzoxadiazine-6-carboxylic acid

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

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 -benzoxadiazín-6-carboxylic acid

A mixture of 30 mg of 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6 acid

of the carboxylic acid, prepared in Example 1, with 47 μΐ of N-methylpiperazine and 3 ml of anhydrous pyridine is heated at 100 to 110 ° C for 9 hours under a nitrogen atmosphere. The pyridine is then removed under reduced pressure and the residue is 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 (MH &lt; ^{+ &gt;} ).

In a similar manner to that described in Example 5, the following compounds were prepared:

Example R ⁵ R ⁶ N- Temperature no. melting ('C)

Solvent MS m / z for recrystallization

T * 3 20 266 to 269 (Decomposition)

c ₂ h ₅ oh

21 about- 284 to 286 dimethyl (Decomposition) formamide

C

280-284 CH ₃ OH / CHC1 _3/345 ^{(MH) +)} (dec) CHjHgOH

Example R ⁵ R ⁶ N-No. Melting point CC) Solvent for recrystallization MS m / z 6 ABOUT 240 to 245 (decomposition) methylated 349 7 HN B. 3 127 to 239 (decomposition) CHjCH / CflCl-j 362 | M ⁺ ) 8 I '? ^c 6 ^h 5 256 to 259 (decomposition) dimethyl formamide 425 (*) * ¹ 9 about > 300 C ₂ H ₅ CH / CHCl ₃ 349 (M) 10 CH ₃ > 300 dimethylformamide 377 (M ⁺ ) 11 about- > 300 (Decomposition) dinetyl- fornanld 365 (H ⁺ > 12 238 to 242 ch ₃ oh 377 * W'l ' 13 _B ° —o 256 to 258 ch ₃ oh 363 (MH ⁺ ) ⁺⁾ 14 0-0 272 to 274 c ₂ h ₅ oh 413 ¹⁵ 270 to 275 h ₂ o 393 (MH ⁺ ) ⁺¹ 16 HLCS W 243 to 246 ch ₃ oh / chi ₃ 262 (M ⁺ ) 17 242 to 244 (decomposition) dimethyl formamide 377 (MH ⁺ ) ⁺⁾

251-252 (decomposition) c ₂ h ₅ ° h

391 (MH ⁺ ) &lt; ^{+ & gt;} ) FAB-MS

Example 24

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

A mixture of 40 mg of 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxydiazine-6-carboxylic acid prepared in Example 1 and 31.1 mg of 2-piperazinene, 31.8 mg of 1,4-diazabicyclo [2.2.2] octane and 1 ml of anhydrous dimethylsulfoxide were heated at 130 ° C for 28.5 hours under a nitrogen atmosphere. The solvent is then removed under reduced pressure. The residue was purified by preparative thin layer chromatography (silica gel; eluent - CHCl ₃ / CH ₃ OH 10: 1.5) and recrystallized from dichloromethane-methanol to give 6.3 mg of 9-fluoro-3-methyl acid. -7-oxo-10- (3-oxo-1-piperazinyl) -2,3-dihydro-7H-pyrido [3,2,1-ij-1,3,4-benzoxadiazine-6-carboxylic acid, m.p. above 300 ° C; FAB / MS m / z (MH &lt; ^{+ &gt;} ).

The following compounds were prepared from the compounds described in Examples 2, 3 and 4 in a manner analogous to that of Example 5:

239 to 241 (decomposition)

C ₂ H ₅ OH

405 (ΜΗ · ·) ⁺⁾

Ex. R ⁵ R ⁶ N- r ³ temperature solvent MS n / z No. mp on the overlay- ('C) lised ²⁵ y * ^ch 3 240 to 242 ch ₃ oh 362 (M ⁺ ) 26 CH ₃ 203 to 206 c ₂ h ₅ oh 376 (M ⁺ ) 27 CH ₂ OH 229 to 231 ch ₃ oh 393 (MH ⁺ ) &lt; ⁺ &gt; ^{2 6} “Λ y * ch ₂ n (ch ₃ ) ₂ 210 to 212 ch ₃ oh 420 (MH ⁺ ) ⁺

⁺ ) FAB-MS

SK 278990 Β6

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 28 mg of 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4-benzoxadiazine-6-carboxylic acid, prepared in Example 1, with 94 mg of 3- (benzyloxycarbonylamino) -pyrrolidine and 3 ml of anhydrous pyridine was heated at 100 ° C for 3 hours under a nitrogen atmosphere, then 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-i] -1,3,4- 227 DEG -230 DEG 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-i] -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 1'-1,3,4-benzoxadiazine-6-carboxylic acid, prepared in Example 29, was hydrogenated using 10 mg of activated carbon containing 5% palladium catalyst in 2 mL of dimethylformamide for 4.5 hours. After filtering off the catalyst, the filtrate is 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-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, m.p. 230-234 ° C (dec.); MS m / z 348; (M ⁺ ).

In a manner similar to that described in Examples 29 and 30, the following compounds were prepared:

about

Example R ⁵ R ⁶ N- Temperature

no. mp

CC)

Solvent MS m / z for recrystallization

- J>

³³ v-CX

286 to 268 H ₂ O (decomposition)

269 to 273 CH 3 OH (decomposition)

240-245 CH-jOH (decomposition)

363 (MH &lt; ^{+ &gt;} )

262-265 (dec.) ^{@ +} FAB MS

Example 36

Preparation 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-6-carboxylic acid

A mixture of 60 mg of 9-fluoro-3-methyl-10- (3-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij]

1,3-benzoxadiazine-6-carboxylic acid prepared in Example 7 with 1 ml of 98% formic acid and 1 ml of 35% formalin 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 solution and extracted with chloroform. The extract was washed with water and dried over anhydrous sodium sulfate. After removal of the solvent 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-6-carboxylic acid, m.p. 257-259 ° C; FAB-MS m / z 377 (MH &lt; ^{+ &gt;} ).

Example 37

Preparation of 9-fluoro-10- (3-methoxy-1-pyrrolidinyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4 -benzoxadiazín-6-carboxylic acid

To a suspension of 100 mg of 9-fluoro-10- (3-hydroxy-1-pyrrolidinyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1, Of 3,4-benzoxadiazine-6-carboxylic acid, prepared in Example 21, in 10 ml of anhydrous dimethylformamide is added 30 mg of an oil solution of 60% sodium hydride and 40 μΐ of methyl iodide. The mixture is stirred at room temperature for 2 hours, then 30 mg of a 60% oil solution of sodium hydride and 40 μΐ of methyl iodide are added and the resulting mixture is stirred for a further 3 hours at 45 ° C. The solvent is then distilled off under reduced pressure. 2 ml of cold water and 2.3 ml of 0.5N sodium hydroxide solution were added to the residue, and the resulting suspension was heated at 100 ° C for 2 hours. The reaction mixture was cooled to room temperature, neutralized with acetic acid and diluted with water, then extracted with chloroform. 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 a 1: 9 mixture of acetone and chloroform as eluent. After recrystallization from methanol, 42 mg of 9-fluoro-10- (3-methoxy-1-pyrrolidinyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] was obtained. 1, 3,4-benzoxadiazine-6-carboxylic acid, m.p. 233-234 ° C; FAB-MS m / z 364 (MH +).

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 -benzoxadiazín-6-carboxylic acid

Following a procedure similar to that described in Example 37, starting 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 prepared in Example 13 affords 9-fluoro-10- (4-methoxy-1-piperidyl) -3-methyl-7-oxo-2, 3-Dihydro-7H-pyrido [3,2,1-i] -1,3,4-benzoxadiazine-6-carboxylic acid in the form of crystals, m.p. 229 DEG-233 DEG C. (dec.) After recrystallization from a mixture of chloroform and n. n-hexane; MS m / z 377 (M &^lt; + ^&gt; ).

Example 39

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

To a suspension of 50 mg of 9-fluoro-3-methyl-7-oxo-10- (4-thiomorpholinyl) -2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4- of benzoxadiazine-6-carboxylic acid, prepared in Example 11, in 5 ml of dichloromethane was added 74 mg of m-chloroperbenzoic acid with a purity of 70%. The mixture was stirred at room temperature for 18 hours, then the solvent was 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-i] -1,3,4-benzoxadiazine-6-carboxylic acid, m.p. &gt; 300 ° C; MS m / z 397 (M &lt; ^{+ &gt;} ).

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] -l, 3,4-benzoxadiazine-6-carboxylic acid

50 mg of 9-fluoro-3-methyl-7-oxo-10- (1-piperazinyl) -2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine Of the 6-carboxylic acid prepared in Example 6 with 17 μΐ of chloroacetone, 40 μΐ of triethylamine and 1 ml of anhydrous dimethylformamide are heated at 80 ° C for 3.5 hours. The volatiles were then removed under reduced pressure and the residue suspended in water. The resulting precipitate was filtered off and recrystallized from dichloromethane / methanol to give 32 mg of 9-fluoro-3-methyl-7-oxo-10- [4- (2-oxo-n-propyl) -1-piperazinyl 1] -2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4-benzoxadiazine-6-carboxylic acid, m.p. 225-229 ° C (dec.); FAB-MS m / z 405 (MH &lt; ^{+ &gt;} ).

Following a procedure similar to that described in Example 40, the following compounds were prepared:

about

Example R ⁷⁰ Temperature Solvent for recrystallization MS m / z no. mp CC) 41 C0-Ca ₂ - 223 to 226 (decomposition) dimethylformamide 467 (HH ⁺ ) 42 CH ₃ CH ₂ - 273 to 275 (decomposition) ch ₅ oh 377 (HB ⁺ ) 43 CH ₃ CH ₂ CH ₂ - 255 to 257 (decomposition) c ₂ H ₅ OH 391 (MH ⁺ ) 44 FCH ₂ CH ₂ - 257 to 259 (decomposition) CjHgOH 395 (MH +) 45 HOOCCH ₂ - 256 to 259 (decomposition) ^h 2 ° 407 (MH ⁺ ) 46 CH ₂ -CHCH ₂ - 236-238 (decomposition) ch ₃ oh 389 (MH ⁺ ) 47 ^{275 to 276} (decomposition) ^c 2 ^h 5 ^oh 484 (MH ⁺ )

Example 48

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

From 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 prepared in Example 17 and ethyl iodide were prepared in a manner similar to that described in Example 40 to give 10- [3 - [(ethylmethylamino) 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 as crystals, m.p. 210 up to 225 ° C after recrystallization from a mixture of chloroform with methanol and n-hexane; FAB-MS m / z 405 (MH &lt; ^{+ &gt;} ).

Example 49

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

50 mg of 9-fluoro-3-methyl-7-oxo-10- (1-piperazin-1) -2,3-dihydro-7H-pyrido [3,2,1-i] -1,3 mixture The 4-benzoxadiazine-6-carboxylic acid obtained in Example 6 with 21.6 mg of succinic anhydride, 40 μΐ of triethylamine and 4 ml of dimethylformamide was heated at 80 ° C for 2 hours. Then the solvent is distilled off under reduced pressure and the residue is suspended in water. The resulting precipitate was filtered off and recrystallized from dichloromethane-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-benzoxadiazine-6-carboxylic acid, m.p. 257 DEG-259 DEG C. (dec.); FAB-MS m / z 449 (MH &lt; ^{+ &gt;} ).

Example 50

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

From 9-fluoro-3-methyl-7-oxo-10- (1-piperazinyl) -2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4-benzoxadiazine-6 of the carboxylic acid prepared in Example 6 and 10- (4-acetyl-1-piperazinyl) -9-fluoro-3-methyl-7-oxo-2,3- dihydro-7H-pyrido [3,2,1-ij] -1,4-benzoxadiazine-6-carboxylic acid as crystals, m.p. 294-296 ° C (dec.) after recrystallization from dichloromethane-methanol; FAB-MS m / z 391 (MH &lt; ^{+ &gt;} ).

Example 51

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

30 mg of 9-fluoro-3-methyl-7-oxo-10- (1-piperazinyl) -2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4-benzoxadiazine The 6-carboxylic acid, prepared in Example 6 and 36 μΐ of methyl vinyl ketone and 1 ml of ethanol are heated at reflux for 12 hours, then cooled to room temperature. The precipitate formed is filtered off and recrystallized 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] -1,3,4-benzoxadiazine-6-carboxylic acid, m.p. 187-189 ° C (dec.); FAB-MS m / z 419 (MH &lt; ^{+ &gt;} ) ·

Example 52

Preparation of 9-fluoro-3-methyl-7-oxo-10- [4- (sulfonatomethyl) -1-piperazinyl] -2,3-dihydro-7H-pyrido [3,2,1-i] acid disodium salt - 1,3,4-benzoxadiazine-6-carboxylic acid A mixture of 26 mg of 35% formalin with 32 mg of sodium bisulfite and 0.5 ml of water was heated at 0 ° C for 30 minutes, then cooled to room temperature. To this solution was added 100 mg of 9-fluoro-3-methyl-7-oxo-10- (1-piperazinyl) -2,3-dihydro-7H-pyrido [3,2,1-i] -1, 3,4-benzoxadiazine-6-carboxylic acid prepared in Example 6 and 15 mg of sodium hydroxide. The mixture is then heated at 75 ° C for 1 hour, then 2 ml of ethanol are added. The mixture was then cooled to room temperature. The precipitate formed is filtered off and recrystallized from water / ethanol (1: 2) to give 9-fluoro-3-methyl-7-oxo-10 [4- (sulfonatomethyl) -1-piperazinyl] -2, disodium salt. 3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, m.p. 260 DEG-263 DEG C. (dec.); 1 H NMR (D ₂ O) δ: 2.98 (3H, S), 3.05 (411, 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).

Example 53

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-benzoxadiazine-6-carboxylic acid

100 mg of 9-fluoro-3-methyl-10- [4- (4-nitrobenzyl) -1-piperazinyl] -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1, The 3,4-benzoxadiazine-6-carboxylic acid prepared in Example 47 was hydrogenated for 2 hours in a 1: 1 mixture of dichloromethane and methanol using 10 mg of activated carbon containing 5% palladium catalyst. After filtering off the catalyst, the filtrate is evaporated 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, m.p. 237-238 ° C (dec.); FAB-MS m / z 454 (MH &lt; ^{+ &gt;} ).

Example 54

Preparation of 10- [3- (aminomethyl) -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1, 3,4-benzoxadiazine-6-karboxylovcj

A mixture of 40 mg of 10- [3- (acetylaminomethyl) -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1 The 3,4-benzoxadiazine-6-carboxylic acid prepared in Example 19 with 2.5 ml of 1 N sodium hydroxide solution was heated at 100 ° C for 3 hours. After cooling to room temperature, the reaction mixture is neutralized with acetic acid and the precipitate formed is filtered off 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-i] -1,3,4-benzoxadiazine-6-carboxylic acid, m.p. 177-180 ° C (dec.); FAB-MS m / z 363 (MH ^4).

Example 55

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

To a solution of 50 mg of 6,7-difluoro-8-hydroxy-1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid prepared in Comparative Example i in 2 ml of anhydrous dimethylformamide was added with stirring 32 mg carbonyldiimidazole. Stirring was continued for 2 hours at room temperature, then for 5 hours at 80 ° C. The solvent was then removed under reduced pressure and the residue suspended in water, then adjusted to pH 5 by addition of acetic acid. The precipitate formed was filtered off and washed with methanol to give 35 mg of 6-fluoro-8-hydroxy-7- ( 1-imidazolyl) -1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid as a yellowish powder; FAB-MS m / z 319 (MH ⁺ ): 1 H-NMR (d ₆ -dimethylsulfoxide) δ: 2.82 (3H, S), 7.10 (1H, d, J = 10.7Hz) 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-ij] -1,3,4-benzoxadiazol-6 carboxylate

A suspension of 15 mg of 6-fluoro-8-hydroxy-7- (1-imidazolyl) -1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, prepared in Example 55, in a mixture of 1 ml of 35 % formalin with 1 ml of dioxane is heated at 100 to 110 ° C under a nitrogen atmosphere for 1.5 hours. Then 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 pinkish powder. Recrystallization from dimethylformamide and ether gave an analytical sample with a melting point above 300 ° C; FAB-MS m / s 331 (MH &lt; ^{+ &gt;} ).

From 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-5-carboxylic acid and imidazole, 9-fluoro-10- (1-imidazolyl) -3-methyl-7-oxo-2,3'-dihydro-7H-pyrido [3,2,1-ij] was prepared by dimethylsulfoxide in a manner similar to that described in Example 5. -l, 3,4-benzoxadiazine-6-carboxylic acid.

Example 57

Preparation of 9-Fluoro-10- (3-hydroxy-1-pyrrolidinyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1,3, benzyl ester 4-benzoxadiazine-6-carboxylic acid

A mixture of 10 mg of 9-fluoro-10- (3-hydroxy-1-pyrrolidinyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3 The 4-benzoxadiazine-6-carboxylic acid prepared in Example 21 and 8 mg of anhydrous potassium carbonate and 0.5 ml of dimethylformamide were stirred at room temperature for 1.5 hours, then 10.8 mg of benzyl bromide was added. The resulting mixture was stirred at room temperature for 3 hours and then evaporated under reduced pressure.

The residue was suspended in water and the resulting suspension was extracted with chloroform. The extract was evaporated to dryness under reduced pressure. The evaporation residue was triturated with ether to give 11 mg of 9-fluoro-10- (3-hydroxy-1-pyrrolidinyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3] benzyl ester M.p. 196-198 ° C (dec.): FAB-MS m / z 440 (MH ⁺ ).

Example 58

Preparation of 10- (3-Chloro-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3-benzyl ester 4-benzoxadiazine-6-carboxylic acid 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, prepared in Example 57, was dissolved in 0.2 ml thionyl chloride and the solution was stirred at 60 ° C for 15 minutes. The reaction mixture was then diluted with water and extracted with chloroform.

The extract is concentrated under reduced pressure. The residue was chromatographed on 2 g of chloroform silica gel to give 2.8 mg of 10- (3-chloro-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3- benzyl ester. dihydro-7H-pyrido [3,2- ij] -l, 3,4-benzoxadiazine-6

-carboxylic acid having a melting point above 300 ° C; FAB-MS m / z 458 (MH &lt; ^{+ &gt;} ), 460 (MH &lt; + &gt;) ⁺ .

Example 59

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

2.5 mg of 10- (3-chloro-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1-benzyl ester The 3,4-benzoxadiazine-6-carboxylic acid prepared in Example 58 was hydrogenated in chloroform using 1 mg of activated carbon containing 5% palladium catalyst.

After filtering off the catalyst, the filtrate is evaporated 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, m.p. 2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, m.p. 269-272 ° C (dec.); FAB-MS m / z 368 (MH &lt; ^{+ &gt;} ), 370 (MH &lt; + &gt;) ⁺ .

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 of the benzoxadiazine-6-carboxylic acid by the procedure via the fluoroborane intermediate

(a) A mixture of 100 mg of 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4-benzoxadiazole-6-carboxylic acid prepared in Example 1 with 1 ml of 60% aqueous fluoroboric acid was heated at 90 ° C for 12 hours. After cooling the reaction mixture to room temperature, the precipitate formed is filtered off, 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-7 H -pyrido [3,2- ij] -l, 3,4-benzoxadiazine-7-one; FAB-MS m / z 331 (MH +).

(b) 15 μΐ of N-methylpiperazine and 20 μΐ of triethylamine are added with stirring to a solution of 33 mg of the above borane intermediate in 1 ml of dimethyl sulphoxide. The mixture was then stirred at room temperature for 3 hours, then lyophilized. The residue was crystallized from methanol to give 28 mg of 6 - [[(difluoroboryl) -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, m.p. 228 DEG-230 DEG C. (dec.); FAB-MS m / z 411 (MH &lt; ^{+ &gt;} ).

(c) 3 μΐ of triethylamine is added to a solution of the above borane intermediate (5 mg) in 1 ml of 95% ethanol. The mixture was heated at reflux for 4 hours, then cooled to room temperature. The precipitate formed is filtered off 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-benzoxadiazine-6-carboxylic acid, m.p. Mp 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 a process via the acetoxyborane intermediate

a) A mixture of 100 mg of 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazol-6-carboxylic acid prepared in Example 1 with 1 ml of acetic anhydride and 100 mg of triacetoxyborane was heated at 140 ° C for 15 minutes. The reaction mixture was then evaporated under reduced pressure. The residue was triturated with acetone and filtered to give 138 mg of 6 - [[(diacetoxyboryl) oxy] carbonyl] -9,10-difluoro-3-methyl-2,3-dihydro-7H-pyrida [3,2, 1-yl] -1,3,4-benzoxadiazin-7-one; FAB-MS m / z 411 (MH &lt; ^{+ &gt;} ).

(b) 15 μΐ of N-methylpiperazine and 20 μΐ of triethylamine are added to a solution of 41 mg of the above borane intermediate in 1 ml of dimethyl sulphoxide. The mixture was stirred at room temperature for 2 hours, then lyophilized. The residue was crystallized from methanol / ether 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-i] -1,3,4-benzoxadiazin-7-one in the form of crystals, m.p. 156-157 ° C (dec.); FAB-MS m / z 491 (MH &lt; ^{+ &gt;} ).

(c) 5 mg of the above borane intermediate is suspended in 0.1 ml of acetone and 2.5 μΐ of concentrated hydrochloric acid is added. The reaction mixture was then stirred at room temperature for 30 minutes, then cooled in an ice bath. The precipitate formed is filtered off and dissolved in 0.1 ml of 95% ethanol. To this solution was added 2 μΐ of triethylamine and the mixture was heated under reflux for 1 hour. Cooling the solution to room temperature precipitates and is filtered to give 9-fluoro-3-methyl-10- (4-methyl-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3]. M.p. 268 DEG-269 DEG C. (with decomposition).

Example 62

Preparation of 10- [3- (Benzyloxycarbonylamino) -1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1-pivaloyloxymethyl ester, 3,4-benzoxadiaζίη-6-carboxylic acid

A mixture of 290 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 prepared in Example 29 with 130 μΐ of pivaloyloxymethyl chloride, 166 mg of anhydrous potassium carbonate and 10 ml of anhydrous dimethylformamide are 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- (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, m.p. 185-188 ° C; FAB-MS m / z 597 (MH &lt; ^{+ &gt;} ).

Example 63

Preparation of 10- (3-Amino-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,3-pivaloyloxymethyl ester 4-benzoxadia7.ín-6-carboxylic acid

From 200 mg of 10- [3-benzyloxycarbonylamino) -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1-pivaloyloxymethyl ester The 3,4-benzoxadiazine-6-carboxylic acid prepared in Example 62 was prepared in a manner similar to that described in Example 30 to give 10- (3-amino-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo pivaloyloxymethyl ester. -2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiamine-6-carboxylic acid as a light brown powder after precipitation from a mixture of ethyl acetate and n-hexane. 1 H NMR (CDCl ₃ ) δ: 1.22 (9H,

s), 1.6-2.4 (2H, m) 2.99 (3H, s), 3.3-4.0 (5H, m), 4.98 (2H, S), 5.96 (s) 2H, s), 7.64 (1H, d, J = 14.4Hz), 8.37 (1H, s); FAB-MS m / z 463 (MH &lt; ^{+ &gt;} )

Example 64

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

A mixture of 337 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, prepared in Example 29, with 84 μΐ of ethyl iodide, 193 mg of anhydrous potassium carbonate and 12 ml of anhydrous dimethylformamide are stirred at 45 ° C for 6 hours. The solvent was then 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 loaded onto a silica gel column and eluted with chloroform / acetone (20: 1). The pure fractions were combined, evaporated to dryness under reduced pressure, and the residue was recrystallized from ethyl acetate to give 271 mg of 10- [3- (benzyloxycarbonylamino) -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo ethyl ester -2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4-benzoxadiazine-6-carboxylic acid, m.p. 204-207 ° C, FAB-MS m / z 511 (MH ⁺⁾ ).

Example 65

Preparation of 10- (3-amino-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3, ethyl ester, 4-Benzoxadiazine-6-carboxylic acid

200 mg of 10- [3- (benzyloxycarbonylamino) -1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1-ethyl ester The 3,4-benzoxadiazine-6-carboxylic acid prepared in Example 64 was hydrogenated in a mixture of 25 ml of chloroform with 10 ml of methanol for 23 hours using 120 mg of activated carbon containing 5% palladium catalyst. After filtering off the catalyst, the filtrate is concentrated under reduced pressure. The residue was applied to a silica gel column and eluted with a 4: 1 mixture of chloroform and methanol. The pure fractions were combined and evaporated to dryness under reduced pressure. The residue was further purified by preparative thin layer chromatography (silica gel, 3: 1 chloroform-methanol) and recrystallized from ethanol to give 71 mg 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, m.p. 187-192 ° C (dec.) ; FAB-MS m / z 377 (MH &lt; ^{+ &gt;} ).

Example 66

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 pH solution of 20 mg 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, prepared in Example 30, in 1 ml of water was adjusted to 1.0 by addition of 6N hydrochloric acid. The resulting 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- hydrochloride. 7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, m.p. 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-i] -1,3, 4-benzoxadiazine-6-carboxylic acid

Following the procedure of Example 66, 9-fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1- mp] -1,3,4-benzoxadiazine-6-carboxylic acid, m.p. 264-266 ° C (dec.).

Example 68

Preparation of 9-fluoro-3-methyl-10-morpholino-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4-benzoxadiazine-6-carboxylic acid sodium salt mg of 9-fluoro-3-methyl-10-morpholino-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, prepared in Example 9, is suspended in 0.4 ml of water and 40 μΐ of 1N sodium hydroxide solution is added with stirring. The clear solution was lyophilized and the residue was crystallized from water / ethanol (1: 4) to give 12 mg of 9-fluoro-3-methyl-10-morpholino-7-oxo-2,3-dihydro- 7II-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, m.p. &gt; 300 ° C.

Example 69

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

From 6-benzyloxy-6,7-difluoro-1- (formylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid ethyl ester, prepared in Comparative Example (f), following the procedures described in Comparative Examples (g, hai) ) using 1-bromo-2-fluoroethane instead of methyl iodide (Examples 1 and 5) to prepare 9-fluoro-3- (2-fluoroethyl) -10- (4-methyl-1-piperazinyl) -7-oxo-2, 3-Dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid as crystals, m.p. 220-224 ° C after recrystallization from methanol MS m / z 394 (M ⁺ ).

Examples 70 to 77

The following compounds were prepared from the compound prepared in Example 1 by a procedure similar to that described in Example 5 or Examples 29/30:

about

Example R ⁵ R ^e N- temperature Solvent FAB-MS m / z e. mp on the overlay- < 'C) pressing

432 (MH &lt; ⁺ &gt;)

262 (decomposition)

_and

240 to 245 (decomposition)

CjHgOH / C

365 KH ⁺

SK 278990 Β6

Example R ⁵ R ⁶ temperature Solvent FAB-MS m / z no. mp to overlay- CC) lised

253 to 255 (decomposition)

CH ₃ OH / (C ₂ H ₅ ) ₂ O 425 (MH ⁺ )

> 300 (decomposition)

C ₂ H OH / CHC1 _3/363 (MH ^{+) C} 6 »14

453 (MH +)

211 to 214 (decomposition) c ₂ h ₅ ok / i want ₃

392 (KH ⁺ )

The following compounds were also prepared from the compound obtained in Example 1 in a manner similar to that described in Example 5 or Examples 29/30: 10- [3- (aminomethyl) -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 10- [3 - [(ethylamino)] methyl] -4-methyl-l-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7 H -pyrido [3,2- ij] -l, 3,4-benzoxadiazine 6-carboxylic acid 10- [3- (aminomethyl) -4-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 10- [3- (aminomethyl) -4-fluoro-1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2, 3-Dihydro-7H-pyrido [3,2,1-i] -1,3,4-benzoxadiazine-6-carboxylic acid 10- [3-chloro-4 - [(methylamino) methyl] -1-pyrrolidinyl 9-Fluoro-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4-benzoxadiazine-6-carboxylic acid -10- [3-Fluoro-4 - [(methylamino) methyl] -1-pyrrolidinyl] -3-methyl-7-oxo-2,3-dih Ydro-7H-pyrido [3,2,1-i] -1,3,4-benzoxadiazine-6-carboxylic acid 10- [3-chloro-4 - [(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 10- [3 - [( ethylamino) methyl] -4-fluoro-l-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2, l-ij] -1,3,4 9-Fluoro-10- [3-methoxy-4- (methylamino) -1-pyrrolidinyl] -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [9-fluoro-10-benzoxad] -benzoxad [ 3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid 10- [3- (ethylamino) -4-methoxy-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- (3-hydroxy-4-methoxy-1) -pyrrolidinyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid 10- (3-amino) 4-chloro-l-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7 H -pyrido [3,2- ij] -l, 3,4-benzoxadiazine-6 -carboxylic acid 10- (3-amino-4-fluoro-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2 3-dihydro-7H-pyrido [3,2,1-i] -1,3,4-benzoxadiazine-6-carboxylic acid 10- [3-chloro-4- (methylamino) -1-pyrrolidinyl] -1- 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 - [3-fluoro-4-methylamino) -1-pyrrolidinyl] -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine 6-carboxylic acid, 9-fluoro-3-methyl-10- (1-oxide-4-thiomorpholinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1 3,4-benzoxadiazol-6-carboxylic acid, 9-fluoro-10- [3-hydroxy-4- (methylamino) -1-pyrrolidinyl] -3-methyl-7-oxo-2,3-dihydro-7H- pyrido [3,2, l-ij] -1,3,4-benzoxadiazine-6-carboxylic acid.

Example 78

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

From 10- (3-amino-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1,3, 4-Benzoxadiazine-6-carboxylic acid obtained in Example 30 was prepared in a manner analogous to that described in Examples 47 and 53 to prepare 10- [3 - [(4-aminobenzyl) 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, m.p. 180-182 ° C (dec.); FAB-MS m / z 453 (MH &lt; ^{+ &gt;} ).

Example 79

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

Suspension 14 mg of 10- (3-amino-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3 The 4-benzoxadiazine-6-carboxylic acid obtained in Example 30 and 6 .mu.m of N, N-dimethylformamide dimethyl acetal in 0.5 ml of anhydrous dimethylformamide are stirred for 8.5 hours at room temperature. The precipitate formed is filtered off, washed with dimethylformamide and ether and recrystallized from dimethylformamide to give 8 mg of 9-fluoro-10- [3 - [[(dimethylamino) methylene] amino] -1-pyrrolidinyl] -3-methyl-7- oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid as pale yellow crystals, m.p. 218-220 ° C (dec.); FAB-MS m / z 404 (MH &lt; ^{+ &gt;} ).

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-carboxylic acid

520 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 is dissolved in 2.88 ml of 0.5 N sodium hydroxide solution. The resulting 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 9-fluoro-3 sodium salt after drying at 80 ° C for 2 days under reduced pressure. - 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. Mp 252-254 ° C (dec.); FAB-MS m / z 385.

The following are examples of pharmaceutical compositions comprising a compound produced by the process of the invention:

Example A

Insertable gelatine capsules, each containing the above ingredients, are prepared by a conventional process:

9-fluoro-3-methyl-1-10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4 -benzoxadiazín-6-carboxylic

Luvoskol (water-soluble polyvinylpyrrolidone) mannitol talc magnesium stearate

200 mg mg mg mg mg

257 mg

Example B

Tablets, each containing the above ingredients, are made by the usual process:

9-fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4-benzoxadiazine- 6-carboxylic acid 200 mg starch 44mg carboxymethylcellulose calcium 30mg crystalline cellulose 40mg magnesium stearate6 mg

Claims (101)

1. Pyrido [3,2,1-ij] -1,3,4-benzoxadiazine derivatives of general formula (I): R ^{@ 1} is hydrogen, lower alkyl, lower alkanoyloxyalkyl or benzyl; R ² is H or lower alkyl optionally substituted by halogen; R ³ and R ⁴ are each independently hydrogen, lower alkyl optionally substituted by hydroxy, unsubstituted amino, or di (lower alkyl amino, lower alkylamino or lower cycloalkylamino); X represents a halogen atom; R ⁵ and R ⁶ are each independently hydrogen or lower alkyl optionally substituted by hydroxy, lower alkoxy, unsubstituted amino, or di (lower alkyl amino, lower alkylamino or lower cycloalkylamino) or R ⁵ and R ⁶ together with the nitrogen atom, to which they are attached form a 5- to 7-membered heterocyclic ring optionally substituted with one or more substituents attached to an atom or carbon atoms selected from the group consisting of hydroxy, lower alkoxy, amino, lower alkylamino, lower cycloalkylamino, di (lower alkyl) amino , lower alkanoylamino, benzyloxycarbonylamino, halogen, lower alkyl, amino-lower alkyl, lower alkylamino-lower alkyl, lower cycloalkylamino-lower alkyl, di (lower alkyl-amino-lower alkyl, lower alkanoylamino-lower alkyl, hydroxy-lower alkyl, phenyl, optionally substituent amino, halogen, hydroxy and / or lower alkoxy, heterocyclic ring, benzylamino, optionally substituted by nitro, amino, halogen, hydroxy and / or lower alkoxy, and a group of formula, R ⁵⁰ wherein each of R ⁵⁰ and R ⁵¹ represents lower alkyl or, together with the nitrogen atom to which they are attached, both residues together form a five- to eight-membered saturated N-heterocycle, the heterocyclic ring formed from R ⁵ , R ⁶ and the adjacent nitrogen atom optionally further comprises a group of formula -NR ⁷ -, -O-, -S-, -SO-, SO- or -NR ⁷ CO-, wherein R ⁷ is hydrogen, lower alkenyl, lower alkyl, optionally substituted hydroxy, lower alkoxy, amino, lower alkylamino, di (lower alkyl) amino, halogen, carboxy and / or sulfo, benzyl which is optionally substituted amino, nitro lower alkylamino, di ( lower alkyl, amino, halogen and / or lower alkoxy or a group of formula, - (CH ₂ ) "COR ⁸ wherein n is an integer from 0 to 4 and R ⁸ represents a hydrogen atom, a lower alkoxy group, an amino group optionally substituted by lower alkyl and / or lower cycloalkyl, a lower alkyl group optionally substituted by carboxyl or lower alkoxycarbonyl or phenyl optionally substituted by halogen, lower alkoxy, hydroxy, nitro and / or amino; wherein the term "lower" refers to the respective groups containing up to 7 carbon atoms and the pharmaceutically acceptable salts of the compounds of formula (I) and the hydrates or solvates of the compounds of formula (I) or salts thereof. Pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivatives of general formula (I) according to claim 1, wherein X represents fluorine and the other symbols have the meaning given in claim 1. Pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivatives of general formula (I) according to claim 1 or 2, wherein R ¹ represents hydrogen and the other symbols have the meaning given in claim 1 or 2. Pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivatives of general formula (I) according to any one of claims 1 to 3, wherein R ² is methyl and the other symbols are as defined in claims 1 to 3 . Pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivatives of the general formula (1) according to any one of claims 1 to 4, wherein R ³ represents hydrogen and the other symbols are as defined in claims 1 to 4 . Pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivatives of the general formula (I) according to any one of claims 1 to 5, wherein R ⁴ is hydrogen and the other symbols are as defined in claims 1 to 5 . Pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivatives of general formula (I) according to any one of claims 1 to 6, wherein the group R ⁵ R ⁶ N- represents a group of the formula εΗ, ιΧ ³ V_ and / or the other symbols have the meaning given in claims 1 to 6. Pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivatives of general formula (I) according to any one of claims 1 to 6, wherein the group R ⁵ R ⁶ N-represents the group of formula h ₂ for the other symbols are as defined in claims 1 to 6. 9. A compound according to claim 1 which is 9-fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo. -2,3-dihydro-7H-pyrido [3,2- ij] - -1,3,4-benzoxadiazine-6-carboxylic acid. 10. A compound according to claim 1 which is 9-fluoro-3-methyl-7-oxo-10- (1-piperazinyl) -2,3-pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivative according to claim 1. -dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 11. The pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivative according to claim 1 which is 9-fluoro-3-methyl-10- (3-methyl- -1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4-benzoxadiazine-6-carboxylic acid. 12. The pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivative according to claim 1 which is 9-fluoro-3-methyl-7-oxo-10- (3-phenyl-1-piperazinyl) - 2,3-dihydro-7 H -pyrido [3,2- ij] - -1,3,4-benzoxadiazine-6-carboxylic acid. A compound according to claim 1 which is 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. A pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivative according to claim 1 which is 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. The pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivative according to claim 1 which is 10- [3 - [(ethylamino) methyl) -1-pyrrolidinyl) -9-fluoro-3-methyl -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4-benzoxadiazine-6-carboxylic acid. 16. The pyrido (3,2,1-ij) -1,3,4-benzooxadiazine derivative according to claim 1 which is 10- (3-amino-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo- 2,3-dihydro-7H-pyrido [3,2,1-i] - -1,3,4-benzoxadiazine-6-carboxylic acid. 17. A compound according to claim 1 which is 9-fluoro-3-methyl-10- [3- (methylamino) -1-pyrrolidinyl] -7. oxo-2,3-dihydro-7 H -pyrido [3,2- ij] -l, 3,4-benzoxadiazine-6-karboxylovákyselina. A compound according to claim 1 which is 10- (3- (ethylamino) -1-pyrrolidinyl) -9-fluoro-3-methyl-7-pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivative. -oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4-benzoxadiazine-6-carboxylic acid. A compound according to claim 1 which is 10- (3,4-Dimethyl-1-piperazinyl) -9-fluoro-3-methyl-7-pyridyl [3,2,1-ij] -1,3,4-benzooxadiazine. -oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4-benzoxadiazine-6-carboxylic acid. 20. A compound according to claim 1 which is 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. 21. The pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivative according to claim 1 which is 9-fluoro-3-methyl-7-oxo-10- [4- (3-oxo-n-) - butyl) -1-piperazinyl] -2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4-benzoxadiazine-6-carboxylic acid. A compound according to claim 1 which is the disodium salt of 9-fluoro-3-methyl-7-oxo-10- [4- (sulfonatomethyl) - 1-piperazinyl] -2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 23. The pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivative according to claim 1 which is 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. 24. A compound according to claim 1 which is 10- [3- (Aminomethyl) -1-pyrrolidinyl] -9-fluoro-3-methyl-7-pyrido [3,2,1-ij] -1,3,4-benzooxadiazine. -oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4-benzoxadiazine-6-carboxylic acid. 25. A compound according to claim 1 which is 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. 26. The pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivative according to claim 1 which is 10- (4-ethyl-1-piperazinyl) -9-fluoro-3-methyl-7-oxo- 2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 27. The pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivative according to claim 1 which is 9-fluoro-10- [4- (2-hydroxyethyl) -1-piperazinyl] -3-methyl -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 28. A pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivative according to claim 1 which is 9-fluoro-3-methyl-10- (4-methyl-1-imidazolyl) -7-oxo- 2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4-benzoxadiazine-6-carboxylic acid. 29. The pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivative according to claim 1 which is 9-fluoro-3-methyl-10- (3-methyl-4 - [(methylamino) methyl] - 1-pyrrolidinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 30. The pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivative according to claim 1 which is 10- [3- (aminomethyl) -4-methyl- 1-Pyridinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine- 6-carboxylic acid. 31. A pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivative according to claim 1 which is 10- (3 - [(ethylamino) methyl] -4-methyl-1-pyrrolidinyl) -9-fluoro-3 methyl-7-oxo-2,3-dihydro -7H-pyrido [3,2,1-i] -1,3,4-benzoxadiazine-6-carboxylic acid. 32. The pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivative according to claim 1 which is 10- [3- (aminomethyl) -4-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. 33. The pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivative according to claim 1 which is 10- [3- (aminomethyl) -4-fluoro-1-pyrrolidinyl] -9-fluoro-3- methyl 7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 34. A compound according to claim 1 which is 10- [3-chloro-4 - [(methylamino) methyl] -1-pyrrolidinyl) -9- Fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4-benzoxadiazine-6-carboxylic acid. 35. A compound according to claim 1 which is 9-fluoro-10- (3-fluoro-4 - [(methylamino) methyl] -1-pyrrolidinyl or pyrido [3,2-ij] -1,3,4-benzooxadiazine. 3-Methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 36. The compound of claim 1 which is 10- (3-chloro-4 - [(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. 37. A compound according to claim 1 which is 10- (3 - [(ethylamino) methyl] -4-fluoro-1-pyrrolidinyl) -9- (pyrido [3,2,1-ij] -1,3,4-benzooxadiazine). fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 38. A compound according to claim 1 which is 10- (3-amino-4-methoxy-1-pyrrolidinyl) -9-fluoro-3-methyl. -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4-benzoxadiazine-6-carboxylic acid. 39. A compound according to claim 1 which is 9-fluoro-10- [3-methoxy-4- (methylamino) -1-pyrrolidinyl] -3 methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 40. The pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivative according to claim 1 which is 10- [3- (ethylamino) -4-methoxy-1-pyrrolidinyl] -9-fluoro-3- methyl 7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 41. The pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivative according to claim 1 which is 9-fluoro-10- (3-hydroxy-4-methoxy-1-pyrrolidinyl) -3-methyl- 7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4-benzoxadiazine-6-carboxylic acid. A compound according to claim 1 which is 10- (3-amino-4-chloro-1-pyrrolidinyl) -9-fluoro-3-methyl, pyrido [3,2,1-ij] -1,3,4-benzooxadiazine. -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4-benzoxadiazine-6-carboxylic acid. 43. The pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivative according to claim 1 which is 10- (3-amino-4-fluoro-1-pyrrolidinyl) -9-fluoro-3-methyl- 7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 44. The pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivative according to claim 1 which is 10- [3-chloro-4- (methylamino) -1-pyrrolidinyl] -9-fluoro-3- methyl 7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 45. The compound of claim 1 which is 9-fluoro-10- [3-fluoro-4- (methylamino) -1-pyrrolidinyl] -3. methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 46. A compound according to claim 1 which is 10- [4- (aminomethyl) -1-piperidyl] -9-fluoro-3-methyl-7-pyrido [3,2,1-ij] -1,3,4-benzooxadiazine. -oxo-2,3-dihydro-7H-pyrido (3,2,1-ij) -1,3,4-benzoxadiazine-6-carboxylic acid. 47. A compound according to claim 1 which is 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. 48. The pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivative according to claim 1 which is 9-fluoro-3-methyl-7-oxo-10- [4- (1-pyrrolyl) -1]. -piperidyl] -2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4-benzoxadiazine-6-carboxylic acid. 49. A compound according to claim 1 which is 9-fluoro-10- (1-homopiperazinyl) -3-methyl-7-oxo-2,3. -dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 50. The pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivative according to claim 1 which is 9-fluoro-10- (3-hydroxy-1-pyrrolidinyl) -3-methyl-7-oxo-2. 1,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 51. A compound according to claim 1 which is 9-fluoro-3-methyl-7-oxo-10- (4-n-propyl-1-). piperazinyl) -2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 52. The pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivative according to claim 1 which is 9-fluoro-10- [4- (2-fluoroethyl) -1-piperazinyl] -3-methyl- 7-Oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4-benzoxadiazine-6-carboxylic acid. 53. The pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivative according to claim 1 which is 10- [4- (carboxymethyl) -1-piperazinyl] -9-fluoro-3-methyl-7- oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4-benzoxadiazine-6-carboxylic acid. 54. The pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivative according to claim 1 which is 10- (4-allyl-1-piperazinyl) -9-fluoro-3-methyl-7-oxo- 2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 55. A compound according to claim 1 which is 10- (1,1-dioxide-4-thiomorpholinyl) -9-fluoro-3-methyl-7-pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivative according to claim 1. -oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 56. The pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivative according to claim 1 which is 9-fluoro-3-methyl-10- (1-oxide-4-thiomorpholinyl) -7-oxo- 2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 57. A compound according to claim 1 which is 9-fluoro-3-methyl-7-oxo-10- [4- (2-oxo-n) -pyridine [3,2,1-ij] -1,3,4-benzooxadiazine derivative according to claim 1. -propyl) -1-piperazinyl] -2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 58. The compound of claim 1 which is 10- (3-chloro-1-pyrrolidinyl) -9-fluoro-3-methyl-7- oxo-2,3-dihydro-7H-pyrido [3,2,1-i] - -1,3,4-benzoxadiazine-6-carboxylic acid. 59. A compound according to claim 1 which is 9-fluoro-3- (2-fluoroethyl) -10- (4-methyl-1-piperazinyl). 7-oxo-2,3-dihydro-7 H -pyrido [3,2- ij] -l, 3,4-benzoxadiazine-6-karboxylovákyselina. 60. The pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivative according to claim 1 which is 10- (4-amino-1-piperidyl) -9-fluoro-3-methyl-7-oxo- 2,3-dihydro-7H-pyrido [3,2,1-i] - -1,3,4-benzoxadiazine-6-carboxylic acid. 61. A compound according to claim 1 which is 9-fluoro-3-methyl-10- [4- (methylamino) -1-piperidyl] -7. -oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 62. A compound according to claim 1 which is 10- [4- (ethylamino) -1-piperidyl) -9-fluoro-3-methyl-7-pyridyl [3,2,1-ij] -1,3,4-benzooxadiazine. -oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 63. A compound according to claim 1 which is 10- [3 - [(ethylmethylamino) methyl] -1-pyrrolidinyl] -9-fluoro-3- (pyrido [3,2,1-ij] -1,3,4-benzooxadiazine). methyl 7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4-benzoxadiazine-6-carboxylic acid. 64. The pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivative according to claim 1 which is 10- (3-amino-4-hydroxy-1-pyrrolidinyl) -9-fluoro-3-methyl- 7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 65. The compound of claim 1 which is 9-fluoro-10- [3-hydroxy-4- (methylamino) -1-pyrrolidinyl] -3. methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. SK 278990 Β6 66. A compound according to claim 1 which is 9-fluoro-3-methyl-7-oxo-10- (4-thiomorpholinyl) -2, 3-Dihydro-7H-pyrido [3,2,1-i] -1,3,4-benzoxadiazine-6-carboxylic acid. 67. A compound according to claim 1 which is 10- (2,6-dimethyl-4-morpholinyl) -9-fluoro-3-methyl-7-pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivative. -oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4-benzoxadiazine-6-carboxylic acid. 68. A compound according to claim 1 which is 10- [3- (acetylaminomethyl) -1-pyrrolidinyl] -9-fluoro-3-methyl-7-pyrido [3,2,1-ij] -1,3,4-benzooxadiazine. -oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 69. A compound according to claim 1 which is 10 - ([2-dimethylamino) ethylmethylamino] -9-fluoro-3-methyl-7-oxo-69-pyrido [3,2,1-ij] -1,3,4-benzooxadiazine 2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4-benzoxadiazine-6-carboxylic acid. 70. A compound according to claim 1 which is 9-fluoro-3-methyl-7-oxo-10- (3-oxo-1-piperazinyl). -2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 71. The compound according to claim 1 which is 9-fluoro-2- (hydroxymethyl) -3-methyl-10- (4-methyl-1- piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadazine-6-carboxylic acid. 72. A compound according to claim 1 which is 2 - [(dimethylamino) methyl] -9-fluoro-3-methyl-10- (4-methyl). -1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4-benzoxadiazine-6-carboxylic acid. 73. A compound according to claim 1 which is 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. 74. The compound of claim 1 which is 9-fluoro-3-methyl-7-oxo-10- (4-phenacyl-1-piperazinyl). -2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4-benzoxadiazine-6-carboxylic acid. 75. A compound according to claim 1 which is 9-fluoro-3-methyl-10- [4- (4-nitrobenzyl) -1-piperazinyl] -pyrido [3,2,1-ij] -1,3,4-benzooxadiazine]. -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4-benzoxadiazine-6-carboxylic acid. 76. The compound of Claim 1 which is 10- [4- (3-carboxypropionyl) -1-piperazinyl] -9-fluoro-3-methyl. -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4-benzoxadiazine-6-carboxylic acid. ΊΊ. 10. A compound according to claim 1 which is 10- (4-acetyl-1-piperazinyl) -9-fluoro-3-methyl-7-oxo-2-pyrido [3,2,1-ij] -1,3,4-benzooxadiazine. 1,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4-benzoxadiazine-6-carboxylic acid. 78. A compound according to claim 1 which is 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. 79. A compound according to claim 1 which is 9-fluoro-2,3-dimethyl-10- (4-methyl-1-piperazinyl) -7. -oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 80. A compound according to claim 1 which is 9-fluoro-2,3-dimethyl-7-oxo-10- (1-piperazinyl) -2. 1,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 81. The compound of claim 1 which is ethyl-10- [3- (benzyloxycarbonylamino) -1-pyrrolidinyl] -9-fluoro-3-methyl. 7-oxo-2,3-dihydro-7 H -pyrido [3,2- ij] -l, 3,4-benzoxydiazín-6-carboxylate. 82. A compound according to claim 1 which is ethyl 10- (3-amino-1-pyrrolidinyl) -9-fluoro-3-methyl-7-pyrido [3,2,1-ij] -1,3,4-benzooxadiazine. oxo-2,3-dihydro-7H-pyrido [3,2,1] -1,3,4-benzoxadiazine-6-carboxylate. 83. A compound according to claim 1 which is benzyl-9-fluoro-10- (3-hydroxy-1-pyrrolidinyl) -3-methyl-7-pyridyl [3,2,1-ij] -1,3,4-benzooxadiazine. oxo-2,3-dihydro-7H-pyrido [3,2, l] -l, 3,4-benzoxadiazine-6-carboxylate. 84. A compound according to claim 1 which is benzyl-10- (3-chloro-1-pyrrolidinyl) -9-fluoro-3-methyl-7. oxo-2,3-dihydro-7H-pyrido [3,2,1] -1,3,4-benzoxadiazine-6-carboxylate. 85. The compound of claim 1 which is pivaloyloxymethyl-10- [3- (benzyloxycarbonylamino) -1-pyrrolidinyl] -9-fluoro-3-methyl. 7-oxo-2,3-dihydro-7H-pyrido [3,2, l] -l, 3,4-benzoxadiazine-6-carboxylate. 86. The compound of claim 1 which is pivaloyloxymethyl-10- (3-amino-1-pyrrolidinyl) -9-fluoro-3-methyl-7. oxo-2,3-dihydro-7H-pyrido [3,2,1] -1,3,4-benzoxadiazine-6-carboxylate. 87. A compound according to claim 1 which is 10- [3 - [(4-aminobenzyl) 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. 88. A compound according to claim 1 which is 9-fluoro-10- (3 - (([dimethylamino] methylene) amino) -1-pyrrolidinyl). 3-Methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 89. A compound according to claim 1 which is 9-fluoro-3-methyl-10- [3- (4-methyl-1-piperazinyl) - 1-pyrrolidinyl] -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4-benzoxadiazine-6-carboxylic acid. The pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivative according to claim 1 which is 10- (3-amino-3-methyl-1-pyrrolidinyl) -9-fluoro-3- methyl 7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4-benzoxadiazine-6-carboxylic acid. 91. A compound according to claim 1 which is 10- (trans-3-amino-4-methyl-1-pyrrolidinyl) -9-fluoro-3, pyrido [3,2,1-ij] -1,3,4-benzooxadiazine. -methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4-benzoxadiazine-6-carboxylic acid. 92. The compound according to claim 1 which is 10- (trans-3-amino-4-phenyl-1-pyrrolidinyl) -9-fluoro-3. -methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 93. A compound according to claim 1 which is 9-fluoro-3-methyl-10- (3-methyl-3 - [(methylamino) methyl-) -pyridine [3,2,1-ij] -1,3,4-benzooxadiazine. 1-pyrrolidinyl] -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 94. The compound according to claim 1 which is 9-fluoro-3-methyl-10- (trans-3 - [(methylamino) methyl) -4] -pyrido [3,2,1-ij] -1,3,4-benzooxadiazinium derivative. -phenyl-1-pyrrolidinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] -1,3,4-benzoxadiazine-6-carboxylic acid. 95. The pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivative according to claim 1 which is 10- (trans-3-amino-4-methoxy-). -1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 96. A compound according to claim 1 which is 10- (trans-3-amino-4-hydroxy-1-pyrrolidinyl) -9-fluoro-3-pyridyl [3,2,1-ij] -1,3,4-benzooxadiazine. -methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. A process for the preparation of the pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivatives of the general formula (I) according to claim 1, as well as their pharmaceutically acceptable salts and hydrates or solvates of the compounds of the general formula (I) or their a salt, characterized in that the compound of formula (III) wherein R ¹ , R ² , R ³ , R ⁴ and X are as defined in claim 1 and X 'represents a halogen atom, wherein amino, hydroxy and / or present carboxy groups are optionally protected, reacted with an amine of formula (IV), HN-R ⁵ I. (IV) R ⁶ wherein R ⁵ and R ⁶ are as defined in claim 1, then optionally deprotecting and optionally isolating the product in the form of a salt, hydrate or solvate, or a hydrate or solvate thereof. A process for the preparation of the pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivatives of the general formula (I) according to claim 1, as well as their pharmaceutically acceptable salts and hydrates or solvates of the compounds of the general formula (I) or their a salt, characterized in that the compound of formula (V) wherein R ¹ , R ² , R ⁵ , R ⁶ and X are as defined in claim 1, wherein the amino, hydroxy and / or carboxy groups present are optionally protected, reacted in a solvent at 20 to 150 ° C with a carbonyl compound of formula (VI), and optionally the product is isolated in the form of a salt, a hydrate or solvate, or a hydrate or solvate thereof. A process for producing salts of the pyrido [3,2,1-ij] -1,3,4-benzoxadiazine derivatives of the general formula (I) according to claim 1, wherein the salts have a structure corresponding to the general formula (Ia), o where A is a pharmaceutically acceptable acid anion selected from the group consisting of hydrohalic acids, methanesulfonic acid and p-toluenesulfonic acid, R ¹ represents a hydrogen atom or an alkali metal cation, n represents 1 when R ¹ is hydrogen and 0 when R ¹ is an alkali metal cation, R ² is C 1 -C 7 alkyl; R ⁵ and R ^{6 taken} together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring optionally substituted on the carbon atom with an optionally further amino group -O- or -NR ⁷ -, wherein: R ⁷ is C 1 -C 7 alkyl optionally substituted with a sulfo group, characterized in that the acid of formula (II), wherein R ² , R ⁵ and R ⁶ are as defined in claim 1, reacted with at least an equivalent amount of a pharmaceutically acceptable acid corresponding to the anion and / or alkali metal base and the resulting salt optionally isolated in the form of its hydrate or solvate. 100. The salt of the pyrido [3,2,1-ij] -1,3,4-benzoxadiazine derivative according to claim 1 which is 9-fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7 hydrochloride. oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 101. The salt of the pyrido [3,2,1-ij] -1,3,4-benzoxadiazine derivative according to claim 1 which is the sodium salt 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. 102. A pharmaceutical composition comprising, in addition to the usual ingredients, the pyrido [3,2,1-ij] -1,3,4-benzoxadiazine derivative of formula (I) or a pharmaceutically acceptable salt or hydrate or solvate thereof as an active ingredient. the derivative or salt of claim 1. wherein R ³ and R ⁴ are as defined in Claim 1, or a polymer such as paraformaldehyde or trioxane; acetal such as dimethoxymethane, 1,1-dimethoxyethane, 1,3-dioxolane, glycol aldehyde dimethylacetal or dimethylaminoacetaldehyde dimethylacetal with a ketal such as 2,2-dimethoxypropane; or an enol ether such as 2-methoxypropene or 2-trimethylsilyloxypropene; then optionally protecting groups are cleaved