SK660487A3 - PYRIDO£3,2,1-IJ|-1,3,4-BENZOXADIAZINE DERIVATIVES, METHOD FORì PRODUCING SAME, AND PHARMACEUTICAL COMPOSITIONS ON THEIR BASE - Google Patents

Description

The invention relates to pyrido [3,2,1-i] -1,3,4-benzoxadiazines of the novel derivatives, to processes for their preparation and to 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-ΟΧΟ-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid derivatives of the general formula

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)

(I)

where R ¹ . is H, lower ¹ a1ky1 buy up well, and the lower 1kanoy1oxya1ky1 or benzyl radical; R ³ represents a hydrogen atom or a lower alkyl group; which is optionally substituted with a halogen atom; R ³ and R ⁴ each independently represents a hydrogen atom, a lower alkyl group which is optionally substituted by a hydroxy group, an unsubstituted amino group or a lower alkyl (1) amino group, a lower alkylamino group or a lower cycloalkyl amine group

X represents a halogen atom;

R 5 and R 6 are each independently H 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 taken together with the nitrogen atom to to which they are attached form a 5- to 7-membered heterocyclic ring which is 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, difluoro 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 substituted amino, halogen, hydroxy and / or lower alkoxy, the 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 comprising 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 ) _n COR ⁸ wherein n is a number from 0 to 4 and R 0 is hydrogen, lower alkoxy, amino optionally substituted by lower alkyl and / or lower cycloalkyl, lower alkyl optionally substituted by carboxyl or lower alkoxycarbonyl or phenyl optionally substituted by halogen, lower alkoxy, hydroxy, nitro and / or amino;

wherein the term "lower" denotes the respective groups containing up to 7 carbon atoms and the pharmaceutically acceptable salts of the compounds of the formula I and the hydrates or solvates of the compounds of the formula I or their salts.

The invention further provides a process for the preparation of the pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivatives of the formula I as claimed in claim 1, as well as their pharmaceutically acceptable salts and hydrates or solvates of the compounds of the formula I or their salts, the compound of formula III

R * (III) wherein 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 carboxy groups present are optionally protected, reacted with an amine of formula IV

HN-R ⁵ (IV) wherein R ⁵ and are as defined above, then optionally deprotecting and optionally, the product is isolated as a salt, hydrate or solvate thereof, or a hydrate or solvate of salt thereof.

The present invention also provides a process for the preparation of the pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivatives of the formula I as claimed in claim 1, as well as their pharmaceutically acceptable salts and hydrates or solvates of the compounds of the formula

Or a salt thereof, characterized in that the compound of formula (V) is:

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

(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 invention also provides a process for the preparation of a salt 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

ABOUT

R ⁴ —b

F

I f

where

represents an anion of a pharmaceutically acceptable acid selected from the group consisting of hydrohalic acids, methanesulphonic acid and p-toluenesulphonic acid, represents a hydrogen atom or an alkali metal cation, represents 1 when R ¹ is hydrogen and Ί is 0 if R is an alkali metal cation, n _#

R 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 which is optionally substituted on the carbon atom by an amino group, which ring optionally further contains a -O- or -NR'- group, wherein R is (C 7-C alkyl) alkyl optionally substituted by a sulfo group consisting of an acid of 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 in the form of its hydrate or solvate.

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

Ί

Explanation of the meaning of the symbol R:

³ · R is H or a carboxyl protecting group, which is a lower alkyl group, a lower alkanoyloxyalkyl or benzyl, for example methyl, ethyl, n-propyl or tert-butyl, acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl and 1-pivaloyloxyethyl and benzyl. These are readily hydrolysable protecting groups in vivo.

Explanation of the meaning of the symbol R ² :

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

The above-mentioned 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 hydrogen or lower alkyl, which may be substituted by hydroxy or substituted or unsubstituted amino.

The aforementioned lower alkyl groups preferably contain 1 to 4 carbon atoms, such as, 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 methyl 8 amino, ethylamino, or a lower cycloalkylamino group such as cyclopropylamino.

K 6

Explanation of the meaning of the symbols R and R:

Each of R ⁵ and R ⁶ independently of the other is hydrogen or lower alkyl which may be substituted by hydroxy, lower alkoxy or substituted or unsubstituted amino, or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached may 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 ⁷ -CO [wherein R represents a hydrogen atom, a lower alkenyl group, a lower alkyl or aralkyl group which may be substituted, or a radical of formula II

- (CH ₂ ) _n COR ⁸ (II), (wherein n represents C to 4 a

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 a 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) 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-1H) -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 group such as 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.

A lower alkenyl radical R 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; 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-carboxyethyl; sulfone-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, halo logene 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 by a lower alkyl group such as methylamino, dimethylamino, or a lower cycloalkyl group such as cyclopropylamino.

The lower alkyl group R 0 may be substituted by carboxy or alkoxycarbonyl, for example, 2-carboxyethyl, 3-carboxy-n-propyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, 3-methoxycarbonyl-propyl and the like.

p,

The phenyl radical R 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, 4-carboxyphenyl , 4-hydroxyphenyl, 4-nitrophenyl, 4-aminophenyl and the like. Particularly preferred R ⁷ radicals are 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-oxon-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 are represented by the grouping

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-pi12 perazinyl, 4-n -propyl-1-piperazinyl, 4- (2-fluoroethyl) -1-piperazinyl, 4-allyl-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-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-pyrrolidinyl, 3-amino-4-phenyl-

1-pyrrolidinyl, 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] 13

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 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 of these compounds and these salts is characterized in that:

in which

Q p q 4

R, R; R, R 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

HN-R ⁵

Ŕ ⁶ (IV) in which

R ⁵ and R ⁶ are as defined above, with optional subsequent 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 hereinbefore defined, or with a polymer, acetal, ketal or enol ether thereof, with optional subsequent deprotection.

Some of the compounds of formula I may further be prepared by (c) reacting a compound of formula I in which R ⁷ is hydrogen with a reagent to produce a compound of formula I wherein R ⁷ is other than hydrogen. providing a group wherein R is the same as R except hydrogen, or (d) to produce a compound of formula I wherein R ⁵ and or R ⁶ are lower alkyl (or contain a di-lower alkylamino or lower alkoxy group), the compound is alkylated of formula I wherein R ⁵ and / or R ⁶ are hydrogen or contain an amino, lower alkylamino or hydroxy group, or (e) for the preparation of a compound of formula I wherein R ⁵ R ⁶ N- is a 5- to 7-membered heterocyclic ring containing a -SO- or -SO4- group, the respective compound in which said heterocyclic ring contains a -S- group is subjected to oxidation or (f) to produce the compound the compounds of formula I having a free amino, hydroxy and / or carboxy group are cleaved from the corresponding compound of formula I having a protected amino, hydroxy and / or carboxy group, or (g) halogenated to produce a compound of formula I containing a halogen atom hydroxyl group of an appropriately substituted compound of formula I, wherein R ¹ is the residue of a carboxyl protective group, and optionally is cleaved said protective radical R ^1, or (h) for the production of a compound of formula I containing an amino group, the nitro group is reduced respectively a nitro

- 16 pin substituted compounds of formula I, or (i) for producing a compound of formula I containing a group of formula

wherein 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- to 8-membered saturated N-heterocyclic ring, the amino group of the corresponding amino-substituted compound of formula I is reacted with a reactive a derivative of a formamide derivative of the general formula VII

(VII) in which

R ⁵⁰ and R ⁵¹ are as defined above, or (j) for the preparation of a compound of formula I wherein R ¹ is a carboxyl protecting group, the carboxylic acid of formula I is esterified, respectively, or (k) for the production of pharmaceutically acceptable salts, hydrates or solvates of a compound of formula (I) or hydrates or solvates of said salts, the compound of formula (I) is converted into a salt, hydrate or solvate or a hydrate or solvate of said salt.

Procedure A:

As described above, the desired compounds are prepared by reacting a compound of Formula III

COOR ¹ (III), in which

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

X 'represents 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) in which:

G r

R and R are as defined above, with optional subsequent deprotection.

In process A, the compound of formula III, used as the starting compound, is a novel compound which, for example, is according to the reaction below.

(a) or (b):

can be prepared by schemes

a)

H ₅ C ₂ OCH = C (COOC 4) ₂

gooc ₂ h ₅ cyclization —- (C) (D)

COCC.Hamination (E)

(G)

(H)

(IIIa)

COOC ^ Ij protection .--—------> CH-groups

The cyclization

HHR ^M (H) (H)

(Va)

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 with a protecting group such as formyl, acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, tert, butoxycarbonyl and Similarly.

The reaction of the compound of formula III with an amine of formula IV or with a suitably protected amine can, 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 reactant such as triethylamine, pyridine, picoline, Ν, Ν-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 reactant.

Suitable solvents for this reaction are non-reactive solvents such as acetonitrile, alcohols, dimethylsulfoxide, dimethylformamide, dimethylacetamide, piridine, picoline, lutidine, dimethyloropropyl urea and the like. It is also. a mixture of at least two solvents may be used.

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-benzoxadiazine-6-carboxylic acid, 9,10 9-chloro-10-f-dichloro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid 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-ethyl ester 9,10-Difluoro-3-methyl-7-oxo-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid benzyl ester 2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, 9,10-difluoro-3- (2-fluoroethyl) -7-oxo-2 9,10-difluoro-2,3-dimethyl-7-oxo-2,3-, 3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, 9,10-difluoro-2- (hydroxymethyl) -3-methyl-7-oxo-2,3-dihydro- 7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, 9,10-difluoro-2 - [(dimethylamino) methyl] -3-methyl-7oxo-2, 3-dihydro- -7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, 9,10-difluoro-2,2,3-trimethyl-7-oxo-2,3-dihydro-7H-pyridine [3,2,1-ij] -1,3,4-benzoxadiazine-6-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-hydroxy-piperidine, 4-methoxy-piperidine, 4- (1-pyroloyl) -piperidine, homopiperazine, 3 - [(methylamino) methyl] -pyrrolidine, 3 [(ethylamino) methyl] -pyrrolidine, 3- (acetylaminomethyl) -pyrrolidine , 3-hydroxypyrrolidine, 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-methylpyrrolidine, 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 present invention of a compound of formula V may be prepared by reaction i

OH in which

R ^{@ 1} , R ^{@ 2} , R ^{@ 5} , R ^{@ 6} and X are as defined above, wherein the aminohydroxy and / or carboxy groups present 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 novel compound and can be prepared according to the above reaction scheme a) or b), or by reacting compound (H) or (Va) with an amine of formula IV.

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

Said reaction can 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.

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 (perfluoride) acid sulfonation resin, product of Aldrich Chemical Co., Inc.), Amberlyst-15 (a strongly acidic macroreticular 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.

As an example of the starting materials of the general formula

The following compounds may be mentioned:

6,7-Difluoro-8-hydroxy-1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, 6,7-difluoro-8-hydroxy-1- (methylamino) -4oxo ethyl ester -1,4-dihydro-3-quinolinecarboxylic acid, w · 4

- 26 6,7-Difluoro-6-hydroxy-1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid benzyl ester, 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, 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 benzyl ester, 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-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- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid and the like.

Examples of compounds which 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 R ⁵ R ⁶ N- is a 5- to 7-membered heterocyclic ring containing an -NR - group, where R ⁷ is other than hydrogen, such as in group VIII (VIII),

wherein the piperazinyl radical may be substituted on an atom or carbon atoms and R ⁷ represents a lower alkenyl group, a lower alkyl or aralkyl group which may be substituted, or a group of formula II

- (CH ₂ ) _n COR ⁸ (II),

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

N-Alkylation:

Compound of Formula IX

(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, may be reacted (i) with a compound of formula X

(X) in which

Y represents a leaving group and

R ⁷⁰ is as defined above, or to obtain compounds wherein R ⁷ is a group r ⁹ co-ch ₂ -ch ₂ , (ii) with a Michael acceptor of formula XI r ⁹ -co-ch = ch ₂ (XI) v which

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 the above formula IX can be reacted with the anhydride of the formula XII

WHAT

in which

Z represents an optionally substituted alkylene chain of 2 or 3 carbon atoms, or an arylene group, n to form a compound of formula I wherein R is HOOC-Z-CO-.

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

Thus, the desired compound may be prepared by reacting a compound of formula IX with a compound of formula X. As a leaving group, for example, halogen atoms such as chlorine, bromine, iodine, acyloxy such as acetoxy, lower alkanesulfonyloxy such as methanesulfonyloxy, aryloxy such as p-toluenesulfonyloxy, optionally nitrated phenoxy, such as phenoxy, 4-nitrophenoxy or 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 defined above for 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. As a rule, the reaction is carried out at a temperature of 0 to 180 ° C, preferably 0 to 110 ° C. In illustrating 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 carboxylic 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-acetylaminophenyl chloromethyl ketone, ethyl chloroformate, 4-chloromethyl chloromethyl, methyl ester, methyl ester nitrobenzyl bromide, dimethylcarbamoyl chloride and the like.

Alternatively, the desired compound may 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 may vary 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) are 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 methyl or sulfomethyl) is usually carried out at a slightly elevated temperature, for example at about +50 to + 100 ° C.

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

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 carrying out the process according to the invention, preferably 1 mol or an excess of moles of the compounds of the formula XII is used per mole of the compound of the formula IX.

The anhydride used in the process of the present invention is, for example, succinic anhydride, glutaric anhydride, N-benzyloxycarbonylaparic acid anhydride, N-benzyloxycarbonylglutanoic anhydride, phthalic anhydride and the like.

The protecting group can, 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 ⁵ and / or R ⁶ are hydrogen or contain amino, lower alkylamino or hydroxy. This N-alkylation may be accomplished by reaction with a compound of Formula XIII.

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. The reaction can also be carried out in the same manner as the alkylation reaction of compounds of the above formula IX using compounds of formula X. O-alkylation is carried out in the same way as N-alkylation. a proton acceptor such as an alkali metal hydride such as sodium hydride is added.

Procedure E:

When a compound of formula I is to be prepared in which R ⁵ R ⁶ N- is 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, i.e. compounds containing a group - 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., acids) may be attached to the phenyl substituent.

4-methylperbenzoic, 4-methoxyperbenzoic, 3-chloroperbenzoic and monoperphthalic). Further, various inorganic oxidizing agents such as hydrogen peroxide, ozone, permanganates such as potassium or sodium permanganate, 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, in particular, the corresponding sulfoxide, i.e. the compound of formula I, in which said heterocyclic ring contains -SO- as one member, is obtained. When the amount of oxidizing agent is increased to twice the stoichiometric amount or more, the corresponding sulfone, i.e. the compound of formula I, in which said heterocyclic ring contains as one member the group -SC> 2-, is obtained. 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 can 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 nitro, benzyloxycarbonyl, benzyloxycarbonyl, benzyloxycarbonyl, benzyloxycarbonyl, benzyloxycarbonyl, benzyloxycarbonyl, benzyloxycarbonyl, benzyloxycarbonyl a pin 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 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 sulfide 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 the allyl group is removed by palladium (0) catalyzed transalkylation reaction in the presence of sodium or a 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 prepared, such as a compound in which the group R 1 -N is a group, this compound can be prepared by halogenating the corresponding compound substituted with a hydroxyl group (e.g. HO group

N).

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 are subsequently liberated again if desired, for example by hydrogenation (removal of the benzyl group).

Procedure H:

When an amine-containing compound of formula I is to be produced, such as a compound wherein R ⁵ R ⁶ N- is H _? N

it 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 are as defined above, ^{'1 1} that is a compound in which the moiety R ⁵ R ⁶ N is a radical

N-, 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 R ⁵ R ⁶ N is H

with a reactive derivative of the formamide derivative of the general formula VII

in which

R ⁵⁰ and R ⁵¹ are as defined above.

(VII),

Appropriate di- (lower alkyl) acetals, such as the corresponding dimethylacetals, can be used as the reactive derivative of the compound of formula VII. The reaction is preferably carried out in an inert solvent such as diethyl ether, dimethylformamide or dimethylsulfoxide. The reaction temperature is preferably room temperature, but this temperature may be lower or higher than room temperature, for example in the range of about 0 to 100 ° C.

Procedure J:

The preparation of esters of formula I, i.e. compounds in which R is a carboxyl protecting group, can be carried out by reacting a carboxylic acid of formula I with an appropriate halide, preferably an 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, in particular, dimethylformamide. The reaction is preferably carried out at a temperature in the range of about 0 to 40 ° C.

Procedure K:

The preparation of pharmaceutically acceptable salts of the compounds of formula I or the hydrates or solvates of these salts may be carried out by known methods; for example, the carboxylic acid of formula I is reacted with an equivalent amount of the desired base or, conversely, the free base of formula I is reacted with an organic or 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 generally takes place 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.

The 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 reacting 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.

Acid or base addition salts of the compounds of formula I differ from the corresponding free compounds of formula I 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 carried out automatically during the manufacturing process or may be progressively 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 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. Bactericidal activity. The compounds of the invention in vitro and in vivo are exemplified by the following experimental results.

1. Antibacterial activity in vitro

Antibacterial activity of pyrido [3,2,1-ij] -

1,3,4-benzoxadiazínu, produced by the process of the invention was examined on agar by standard method of serial dilutions (see Chemotherapy, 22, p. 1126 (1974)]. The minimum inhibitory concentrations of the compounds (MIC in μg.ml ^_1) are shown in Tables I and II The compounds used in these tests were made according to the procedures of the following working examples.

Table I

Antibacterial spectrum of MIC (pg.ml ^- ^)

Example compound no.

Aerobic microorganisms 5 6 7 8 9 12 13 Gram-positive bacteria Bacillus subtilis PCI 219 0.05 0.10 0.10 0,025 <0.0008 0.10 <0.0008 Staphylococcus aureus FDA 209? JC-1 0.39 0.39 0.39 0.39 0.20 0.10 0.10 Staphylococcus aureus NR 2855 0.20 3.13 1.56 0.39 0.0065 0.78 0.05 Staphylococcus aureus Smith 0.20 0.39 0.20 0.20 0.0033 0.10 0,025 Staphylococcus epidemidis IFO 12993 0.39 1.56 0.78 0.39 0.20 0.39 0.10 Staphylococcus epidermidis NR 2942 0.39 1.56 0.78 0.39 0.0065 0.39 0.05 Enterococcus faecalis NR 2943 3.13 12.5 12.5 6.25 12.5 3.13 3.13 Gram-negative bacteria Alcaligenes faecalis IFO 13111 0.39 3.13 6.25 0.78 6.25 50 3.13 Citrobacter freundii IFO 12681 0,013 0,013 0.05 0,025 0.39 0.78 0.39 Enterobacter sarogenes NR 2945 0,013 0,013 0.05 0,025 0.0065 0.20 0.20 Enterobacter cloacae NR 2945 0,025 0,025 0.10 0.05 0,013 0.78 0.39 Escherichia coli NIHJ JC-2 0,025 0,025 0.10 0.05 0.10 0.20 0.39 Escherichia coli NR 2630 0,013 0,025 0,025 0,013 <0.0008 0.10 - Klebsialla pneumoniae FDA PCI 602 0.10 0.10 0.39 0.20 3.13 3.13 0.78 Bordetalla bronchiseptica ATCC 4617 0.20 6.25 3.13 0.39 1.56 6.25 0.78 Proteus rettgeri ATCC 14505 0.20 0.10 0.78 0.39 1.56 12.5 0.78 Proteus vulgaris ATX 6898 0,013 0,013 0,025 0,025 <0.0008 0.10 0.05 Psedomonas aeroginosa A3 0.20 0.10 0.20 0.39 6.25 0.78 1.56 Pseudomonas aeruginosa NR 2950 0.78 0.78 3.13 3.13 12.5 12.5 6.25 Pseudomonas stutzeri IFO 12695 0,025 0,025 0.05 0,025 <0.0008 - 0.10 Serratia marcescens IFO 12648 0.10 0.10 0.20 0.10 0.78 3.13 0.39 Salmonella typhimurium IFO 12529 0,025 0.013. 0.05 0,025 0.0033 0.20 0.10

Table I - continued

Antibacterial Spectrum of MIC (jjg.mH)

Example 2 Compound 2

Aerobic microorganisms 15 ¹⁶ 17 18 19 21 Gram positive bacteria Bacillus subtilis OCI 219 0.05 0.20 0,013 0,013 0.05 0.05 Staphylococcus aureus FDA 209P JC-1 0.78 0.39 0.05 0.05 0.39 0.39 Staphylococcus aureus NR 2855 0.78 6.25 0.20 0.10 0.39 0.20 Staphylococcus aureus Smith 0.39 0.39 0,025 0,025 0.20 0.39 Staphylococcus epidermidis IFO 12993 0.78 1.56 0.20 0.10 0.39 0.39 Staphylococcus epidermidis NR 2942 0.78 1.56 0.10 0.10 0.39 0.39 Enterococcus faecalis NR 2943 6.25 25 1.56 1.56 6.25 3.13 Gram-negative bacteria Alcaligenas faecalis EFC 13111 3.13 50 6.25 6.25 6.25 O 78 Citrobacter freundii IFO 12681 0.05 0.10 0.20 0.10 1.56 0.78 Emterobacter aerogenes NR 2945 0.05 0.05 0.05 0.05 1.56 0.20 Enterobacter cloacae NR 2946 0.10 0.10 0.10 0.05 1.56 0.78 Escherichia coli NIHJ JC-2 0.10 0.20 0.10 0.05 1.56 0.39 Escherichia coli NR 2630 - - 0,025 0,013 0.39 0.20 Klebsialla pneumoniae FDA PCI 602 0.39 1.56 0.78 0.39 6.25 0.78 Bordetella bronchiseptica ATCC 4617 0.78 25 6.25 3.13 6.25 0.78 Proteus rettgeri ATCC 14505 0.78 1.56 1.56 0.39 3.13 0.78 Proteus vulgaris 1x19 ATCC 6898 0,025 0.10 0,025 0,025 0.39 0.05 Pseudomonas aeruginosa A3 0.78 0.39 0.39 0.78 6.25 1.56 Pseudomonas aeruginosa NR 2950 3.13 6.25 6.25 6.25 25 3.13 Pseudomonas stutzeri IFO 12695 0.05 0.05 0,025 0,025 0.39 0.20 Serratia macescens IFO 13648 0.39 0.39 0.78 0.39 3.13 0.39 Salmonella typhimurium IFO 12529 0.05 0.10 0.05 0,025 1.56 0.39

Table I - continued

Antibacterial spectrum of MIC (pg.mľ ¹ )

Example compound no.

Aerobic microorganisms 22 24 25 26 27 30 Gram positive bacteria Bacillus subtilis PCI 219 0.05 0.39 0.78 0.78 0.39 0,025 Staphylococcus aureus FDA 209P JC-1 0.20 1.56 6.25 3.13 1.56 0.05 Staphylococcus aureus NR 2855 0.39 6.25 12.5 1.56 12.5 0.39 Staphylococcus aureus Smith 0.20 1.56 1.56 3.13 1.56 0.05 Staphylococcus epidermidis, IFO 12993 0.39 3/13 6.25 3.13 6.25 0.20 Staphylococcus epidermidis NR 2942 0.20 3.13 6.25 3.13 6.25 0.20 Enterococcus faecalis NR 2943 3.13 25 100 25 50 3.13 Gram-negative bacteria ¹ Alcaligenes faecalis IFO 13111 3.13 25 50 12.5 50 1.56 Citrobacter freundii IFO 12681 0.10 1.56 0.78 0.78 0.20 0,013 Enterobacter aerogenes NR 2945 0.10 0.78 0.39 0.20 0.20 0.0033 Enterobacter cloacae NR 2946 0.10 3.13 0.78 0.78 0.78 0,013 Escherichia coli NIHJ JC-2 0.10 1.56 0.78 0.78 0.78 0,013 Escherichia coli NR 2630 0,025 0.78 0.39 0.20 - 0.0065 Klebsiella pneumoniae FDA PCI 602 0.39 6.25 3.13 3.13 3.13 0.10 Bordetella bronchiseptica AKC 4617 1.56 50 100 12.5 · 25 1.56 Proteus rettgeri AKC 14505 0.78 12.5 25 6.25 12.5 0.10 Proteus vulgaris 0X19 AKC 6898 0.0065 0.39 0.10 0.39 0.20 0.0065 Pseudcmonas aeruginosa A3 1.56 3.13 3.13 6.25 3.13 0.05 Pseudamonas aeruginosa NR 2950 6.25 25 50 50 25 0.20 Pseudomonas stutzeri IFO 12695 0.10 - 0.39 0.78 0.20 0.0033 Serratia narcesce-ns IFO 12648 0.78 6.25 3.13 1.56 3.13 0.05 Salmonella typhimurium IFO 12529 0.10 0.78 0.20 0.78 0.39 0.0065

Table I - continued

Antibacterial Spectrum MIC (pg.mľ ')

Example compound no.

Aerobic microorganisms 31 32 33 34 35 36 Gram positive bacteria Bacillus subtilis PCI 219 0.05 0.05 0.20 0.05 0.05 0,025 Staphylococcus aureus FDA 209P JC-1 0.39 0.20 0.20 0.20 0.39 0.39 Staphylococcus aureus NR 2855 0.78 0.39 1.56 1.56 1.56 0.10 Staphylococcus aureus Smith 0.20 .0,10 0.20 0.20 0.39 0.10 Staphylococcus epidermidis IPO 12993 0.39 0.39 0.78 0.78 0.78 0.20 Staphylococcus epidermidis NR 2942 0.39 0.39 0.78 0.78 0.78 0.20 Enterococcus faecalis NR 2943 6.25 3.13 6.25 6.25 3.13 Gram-negative bacteria Alcaligenes faecalis IFO 13111 3.13 1.56 50 50 25 3.13 Citrobacter freundii IFO 12681 0.05 0.10 0.20 0.20 0.20 0.20 Enterobacter aerogenes NR 2945 0,025 ’ 0,025 0.05 0.10 ' 0.10 0.05 Enterobacter cloacae NR 2946 0.05 0.10 0.20 0.20 0.39 0.10 Escherichia coli NIHJ JC-2 0.05 0.10 0.20 0.20 0.10 0.10 Escherichia coli NR 2630 0,025 0,025 0.10 0.10 0.10 0.05 Klebsiella Pneumonias FDA PCI 602 0.20 0.39 0.78 0.78 1.56 0.39 Bordetella bronchiseptica ATCC 4617 3.13 1.56 25 25 12.5 0.39 Proteus rettgeri ATCC 14505 0.39 1.56 1.56 3.13 3.13 0.78 Proteus vulgaris CX19 ATCC 6898 0,025 0,025 0.05 0,059. 0.05 0,025 Pseudomonas aeruginosa A3 0.20 0.39 0.39 0.78 1.56 0.78 Pseudomonas aeruginosa NR 2950 1.56 3.13 6.25 6.25 12.5 6.25 Pseudomonas stutzeri IFO 12695 0,025 0.10 - - - 0.10 Serratis marcescens IFO 12648 0.20 0.39 0.78 0.78 1.56 0.39 Salmonella typhimurium IFO 12529 0,025 0,025 0.10 0.10 0.10 0.10

- 46 Table I - continued

Antibacterial spectrum of HIC (pg.mľ ¹ )

Example compound no.

Aerobic microorganisms 37 38 39 40 41 42 Gram-positive bacteria Bacillus subtilis PCI 219 <0.0008 0.0008 0,025 0.10 3.13 0.05 Staphylococcus aureus FDA 209P JC-1 0.0016 0.39 0.39 1.56 6.25 0.39 Staphylococcus aureus NR 2855 <0.0008 0.20 0.78 0.78 6.25 0.39 Staphylococcus aureus Smith <0.0008 0.10 0.39 0.78 6.25 0.39 Staphylococcus epidemidis IFO 12993 0,025 0.39 0.39 1.56 6.25 0.39 Staphylococcus epidemidis NR 2942 <0.0008 0.39 0.39 0.78 12.5 0.39 Enterococcus faecalis NR 2943 3.13 12.5 12.5 12.5 100 6.25 Gram-negative bacteria Alcaligeneä faecalis IFO 13111 12.5 6.25 6.25 6.25 50 1.56 Citobacter freundii IFO 12681 0.78 6.25 0.78 .0,20 0.39 0.05 Enterobacter aerogenes NR 2945 0.10 3.13 0.05 0.10 0.10 0,025 Enterobacter cloacae NR 2946 0.20 6.25 0.78 0.39 0.78 0.05 Escharichia coli NIHJ JC-2 0.10 6.25 0.78 0.39 0.78 0.05 Escherichia coli NR 2630 <0.0008 0.39 0,025 0.20 0.39 0,025 Klebsiella pneumoniae FDA PCI 602 3.13 25 1.56 1.56 3.13 0.39 Bordetella bronchiseptica ATCC 4617 1.56 6.25 0.78 1.56 25 0.39 Proteus rettgeri ATCC 14505 6.25 25 3.13 3.13 3.13 0.39 Proteus vulgaris 1x19 ATCC 6898 <0.0008 3.13 0.05 0.20 1.56 0,025 Pseudomonas aeruginosa A3 6.25 25 3.13 1.56 3, i3 0.39 Pseudomonas aeruginosa NR 2950 25 50 12.5 12.5 12.5 3.13 Pseudomonas stutzeri IFO 12695 0,013 6.25 - - - 0.10 Sarratia marescens IFO 12648 0.78 12/5 1.56 1.56 3/13 0.10 Salmonella typhimurium IFO 12529 0.20 6.25 0.20 0.39 0.78 0,025

Table I - continued

Antibacterial spectrum of MIC (pg.mľ ³ )

Example compound no.

Aerobic microorganisms 43 44 45 46 48 49 Gram positive bacteria Bacillus aubtilis PCI 219 0.10 0.05 0.39 0.05 0.05 3.13 Staphylococcus aureus FDA 209P JC-1 0.78 0.78 1.56 0.78 0.39 6.25 Staphylococcus aureus NR 2855 0.78 0.39 3.13 0.39 0.39 12.5 Staphylococcus aureus Smith 0.39 0.39 0.78 0.39 0.20 6.25 Staphylococcus epidamidis IFO 12993 0.39 0.78 3.13 0.78 0.39 12.5 Staphylococcus epidermidis NR 2942 0.39 0.39 3.13 0.39 0.78 12.5 Enterococcus faecalis NR 2943 6.25 12.5 50 6.25 6.25 100 Gram-negative bacteria ilcaligenes · faecalis IFO 13111 0.78 1.56 12.5 1.56 3.13 100 Citrobacter freundii IFO 12681 0.10 0.20 0.10 0.10 0.39 0.39 Enterobacter aerogenes NR 2945 0.10 0.10 0.05 0.10 0.39 0.39 Enterobacter cloacae NR 2946 0.10 0.20 0.20 0.20 0.39 0.78 Escherichia coli NIHJ JC-2 0.10 0.20 0.20 0.10 0.39 1.56 Escherichia coli NR 2630 0.05 0.05 0.10 0.05 0.10 0.39 Klebsiella pneumoniae FDA PCI 602 0.39 0.39 0.39 0.78 1.56 1.56 Bordatella bronchiseptice ATCC 4617 0.39 0.39 12.5 0.39 6.25 50 Proteus rettgeri ATCC 14505 0.78 1.56 0.78 1.56 3.13 3.13 Proteus vulgaris ATX 6898 0.10 0.10 0.10 0.05 0.39 0.78 Pseudcmonas aeruginosa A3 0.78 0.78 0.78 1.56 3.13 3.13 Pseudcmonas aeruginosa NR 6.25 6.25 6.25 6.25 50 50 Pseudcmonas stutzeri IFO 12695 0.20 0.05 - 1.56 - Serratia marescens IFO 12648 0.20 0.39 0.78 0.39 1.56 3.13 Salmonella typhimurium IFO 12529 0.10 0.20 0.10 0.10 0.39 0.39

Table I - continued

Antibacterial spectrum of MIC (pg.ml ^-1 )

Example compound no.

Aerobic microorganisms 50 51 52 53 54 Gram positive bacteria Bacillus subtilis PCI 219 0.0065 0.10 0.20 0,025 0,025 Staphylococcus aureus FDA 209P JC-1 0.39 0.20 0.39 0.10 0,013 Staphylococcus aureus NR 2855 0.39 1.56 3.13 0.10 0.20 Staphylococcus aureus Smith 0.10 0.39 0.39 0.05 0,025 Staphylococcus epidermidis IFO 12993 0.39 0.78 1.56 0.10 0.10 Staphylococcus epidermidis NR 2942 0.20 0.78 1.56 0.10 0.10 Enterococcus faecalis NR 2943 3.13 12.5 25 1.56 1.56 Gram-negative bacteria Alcaligenes faecalis IFO 13111 12.5 3.13 12.5 3.13 6.25 Citrobacter freundii IFO 12681 3.13 0,025 0,025 0.10 0.10 Enterobacter aerogenes NR 2945 0.78 0,025 0,025 0.10 0,025 Enterobacter cloacae NR 2946 1.56 0.05 0.05 0.20 0.10 Escherichia coli NIHJ JC-2 1.56 0.10 0.05 0.20 0.10 Escherichia coli NR 2630 0.20 0,025 0,025 0.05 0,025 Klebsiella pneumoniae FDA PGI 602 6.25 0.20 0.20 0.39 0.78 Bordatella bronchiseptica ATCC 4617 3.13 1.56 6.25 0.78 3.13 Proteus rettgeri ATCC 14505 6.25 0.20 0.20 1.56 0.78 Proteus vulgaris ATX 6898 0.39 0,025 0,025 0.10 0,013 Pseudomonas aeruginosa A3 6.25 0.10 0.20 0.78 0.20 Pseudomonas aeruginosa NR 2950 25 1.56 1.56 12.5 1.56 Pseudomonas stutzeri IFO 12694 - 0.05 0.05 0.20 0,013 Serratia marcescens IFO 12648 3.13 0.10 0.20 0.78 0.39 Salmonella typhimurium IFO 12529 0.78 0,025 0,025 0.10 0,025

Table I - continued

Antibacterial Spectrum MIC

Aerobic microorganisms Example compound no. 56 59 . ⁶³ 69 Gram positive bacteria Bacillus subtilis PCI 219 0.20 0.0065 0.78 0.20 Staphylococcus aureus FDA 209P JC-1 0.39 0.39 0.78 1.56 Staphylococcus aureus NR 2855 0.78 0.10 3.13 1.56 Staphylococcus aureus Smith 0.39 0.05 0.39 0.78 Staphylococcus epidemidis IFO 12993 0.39 0.39 1.56 1.56 Staphylococcus epidemidis NR 2942 0.39 0.20 0.78 1.56 Entorococcus faecalis NR 2943 12.5 3.13 25 12.5 Gram-negative bacteria Alcaligenes faecalis IFO 13111 3.13 6.25 100 '3.13 Citrobacter freundii IFO 12681 0.10 1.56 0.78 0.10 Enterobacter aerogenes NR 2945 0.10 0.78 0.39 0.10 Enterobacter cloacae NR 2946 0.05 0.78 1.56 0.20 Escherichia coli NIHJ JC-2 0.10. 1.56 1.56 0.20 Escherichia coli NR 2630 0.0065 0.39 0.78 0.10 Klebsiella pneumoniae FDA PCI 602 0.39 3.13 6.25 0.39 Bordetalla bronchiseptice ATCC 4617 3.13 3.13 50 0.78 Proteus rettgeri ATCC 14505 1.56 3.13 6.25 0.78 Proteus vulgaris ATX 6898 0,013 0.20 0.39 0.05 Pseudomonas aeruginosa A3 3.13 3.13 3.13 0.78 Pseudomonas aeruginosa NR 2950 6.25 25 25 6.25 Pseudomonas stutzeri IFO 12695 0.0033 1.56 0.39 0.20 Serratia marcescens IFO 12648 0.78 3.13 3.13 0.20 Salmonella tyhpimurium IFO 12529 0.05 1.56 0.78 0.10

Table II ²

antibacterial spectra MIC (Úg.ml ¹ ) Example compound no. 5 30 Bacteroides fragilis ATCC 23745 0.78 0.20 Bacteroides fragilis NR 2579 3.13 1.56 Bacteroides fragilis NR 2582 0.78 0.39 Bacteroides fragilis NR 2583 0.39 0.10 Bacteroides fragilis NR 2584 0.78 0.78 Bacteroides distasonis NR 2578 0.78 0.78 Bacteroides thetaiotamicron NR 2588 1.56 0.78 Bifidobacterium adolescentis ATCC 15703 0.39 0.10 Clostridium botulinum NR 2611 0.10 0,013 Clostridium perfrigigens, NR 2612. 0,39 ' 0.10 Clostridium moniliforme ATCC 25546 0.78 0.10 Fusobacterium varium ATCC 8501 12.5 - Peptococcus prevotii ATCC 9321 1.56 0.39 Peptococcus variabilis ATCC 14955 0.78 0.20 Peptostreptococcus anaerobius NR 2743 0.39 0,013 Propionibacterium acnes ATCC 11828 0.78 0.78 Mycoplasma Mycoplasma hominis NR 2952 0.10 0.10

2. Therapeutic efficacy in vivo

The in vivo antibacterial activity of pyrido [3,2,1-ij] 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. ICR mice of 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 due to infection, is shown in Table 3.

Table 3

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

Compound. Bacteria from Example ----------—------------------------------------

Escherichia Pseudomonas Streptococcus coli aeruginosa pneumoniae ML 4707 4au542 6-100

sc after. after. after. 5 0.06 0.11 13.4 10.3 30 0.10 0.62 57.0 65.9 65 - 1.12 - - 66 - 0.51 - - 3. Acute toxicity

The respective LD ₅₀ values of the compounds prepared in Examples 5, 6, 7, 16, 17, 18, 30, 36 and 56 below 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 process 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. Accordingly, the compounds of the invention can be effectively used for the prevention or treatment of diseases caused by humans or animals by gram-positive or gram-negative bacteria and bactoricidal microorganisms.

For example, it is possible to treat and / or prevent the diseases caused by the following microorganisms or mixtures thereof: Staphylococcus, Streptococcus, Aerococcus, Enterococcus, Micrococcus, Lactobacilus, Bifidobacterium, Clostridium, Eubacterium, Peptococcus, Peptostreptia, Cept, Enterobacter, Klebsiella, 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 according to 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 uptake agents and the like, as any formulation excipients, which are 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 total 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 dosage 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 diethyl ester (a) A solution of 500 mg of 2,3-difluoro-6-nitrophenol in 7 ml of methanol is 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 the above aminophenol with 618 mg of ethoxymethylene malonic acid diethyl ester was heated at 130 ° C for 5 minutes under a nitrogen atmosphere. 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 DEG-180 DEG C .; MS m / z 315 (M &lt; ^{+ &gt;} ). 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 Add 1.5 μl of anhydrous dimethylformamide to 30 μΐ of benzyl bromide. The mixture was stirred at room temperature for 2 hours. After removal of the solvent under reduced pressure, the residue was dissolved in dichloromethane and the insoluble material was filtered off. The filtrate was washed with water, dried over anhydrous sodium sulfate and evaporated. The crystalline residue was washed with n-hexane and recrystallized from methanol to give 90 mg of N- (2-benzyloxy-3,4-difluorophenyl) aminomethylene malonic acid diethyl ester, mp 87 ° C, MS m / z 405 (M ⁺ ).

(d) A solution of 280 mg of the above 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 ethyl acid ester

8-benzyloxy-6,7-difluoro-4-hydroxy-3-quinolinecarboxylic acid. Recrystallization from methanol provided an analytical sample of "I _(" ^1: mp 200-201 C; MS m / z 359 (M ^+).

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-4-hydroxy ethyl ester Of 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 were added to the residue, and the mixture was stirred at room temperature for 3 hours. 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 0C. To this solution was added dropwise a solution of 400 mg of the above 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 the above formamide, 275 mg of anhydrous potassium carbonate and 17 ml of anhydrous dimethylformamide was stirred at room temperature for 1.5 hours. After addition of 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-1- (formylmethylamino) ethyl ester The 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, m.p. 221-225 ° C (dec.); MS m / z 326 (M &lt; ^{+ &gt;} ).

(i) A mixture of 210 mg of the above 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 was triturated with water and filtered to give 97 mg of 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3, 4-benzoxadiazine-6-carboxylic acid. Recrystallization from dimethylformamide gave an analytical sample, m.p. 290-292 ° C (dec.); MS m / z 282 (M &lt; ^{+ &gt;} ).

Example 2

Preparation 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

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 of dioxane was heated at 100 ° C for 3 hours under a nitrogen atmosphere. Then the reaction mixture was evaporated under reduced pressure to give 52 mg of 9,10-difluoro-2,3-dimethyl-7-oxo-

2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-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-ij] -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), 45 μΐ 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-ij] -1-p-toluenesulfonic acid salt , 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 acid monohydrate of p-toluenesulfonic acid in 2 ml of anhydrous dioxane was heated at 110 ° C under nitrogen for 17 hours. 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- benzoxadiazine-6-carboxylic

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-carboxylic acid, prepared in Example 1, with 47 μΐ of N-methylpiperazine and 3 ml of anhydrous pyridine are 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;} ).

Following a procedure similar to that described in Example 5, the following compounds were prepared:

Example R ⁵ R ⁶ N- Temperature no. mp

UC)

MS solvent m / z for recrystallization

6 ^H O 240 to 245 (Decomposition) 7 127 to 239 (Decomposition) 8 Q 256 to 259 H ^C 6 ^H 5 (Decomposition) Q / “Λ 0 you > 300 2 10 CH ₃ > 300 11 r ~ \ IN > 300 (Decomposition)

methylated 349 (MH ⁺ ) ⁺⁾ ch ₃ ch / I want ₃ 362 (M ⁺ ) dimethylformamide 425 (MH ⁺ ) ⁺⁾ c ₂ h ₅ I want ₃ 349 (M ⁺ ) dimethylformamide 377 (M ⁺ ) dimethylformamide 365 (M ⁺ ) ch ₃ oh 377 (MH ⁺ ) ⁺ )

Example R ⁵ R ⁶ N- Temperature no. Melting point (° C)

MS solvent m / z for recrystallization

HO

256 to 258 ch ₃ oh

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

272-274 ^C 2 ^H 5 ^OH

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

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

16 1 243 to 246 CH ₉ OH / CH 2 262 (M &lt; ^{+ &gt;)} W J J

242-244 (decomposition) dimethylformamide

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

251-252 (dec) ^C 2 ^H 5 ^OH

391 ^{(MH) +)} C ₂ H ₅ OH

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

Example R ⁵ R ⁶ temperature Solvent MS m / z no. mp on the overlay- ('C) lised

s20

266-268 (dec.) C ₂ ^h ₅ oh

284-286 (decomposition) dimethylformamide

280 to 284 (decomposition) ch ₃ oh / want ₃ / ch ₂ h ₅ oh

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

220 to 284 C ₂ H ₅ OH (decomposition)

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-ij] -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 di 64 methylsulphoxide are 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-7-acid. -oxo-10- (3-oxo-1-piperazinyl) -2,3-dihydro-7H-pyrido [3,2-b] -1,3,4-benzoxadiazine-6-carboxylic acid, m.p. 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

Ex. R ⁵ R ⁶ N- R ³ temperature solvent MS! m / z no. mp to overlay- (° C) lised 25 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 ⁺ ) ⁺⁾ 2 8 «y / y« CH ₂ N (CH ₃ ) l ₂ 210 to 212 ch ₃ oh 420 (MH ⁺ ) ⁺⁾

⁺ ) FAB-MS

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-ij] -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-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, m.p. 227-230 ° C MS m / z 482 (M ⁺ ).

Example 30

Preparation of 10- (3-amino) -1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4- benzoxadiazine-6-carboxylic acid 10- [3- (benzyloxycarbonylamino) -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] The 1,3,3-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 a and 30, the following compounds were prepared:

Example R ⁵ R ⁶ temperature Solvent MS m / z no. mp on the overlay- (° C) lised

286 to 288 (decomposition) h ₂ o 269 to 273 (decomposition) ch ₃ oh 240 to 245 (decomposition) ch ₃ oh

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

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

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

Example R ⁵ R ⁶ N- temperature solvent MS m / z no. mp on the overlay- ('C) lised ³⁴ R \ _ 262 to 265 (Decomposition) ch ₃ oh 377 (MH &lt; ^{+ &gt;} )

⁺ ) 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 -benzoxadiazín-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] -1,3,4-benzoxadiazine The 6-carboxylic acid prepared in Example 7 with 1 ml of 98% formic acid and 1 ml of 35% formalin is 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 acid. -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-ij] -1,3,4-benzoxadiazine 6-carboxylic acid

To a suspension of 100 mg of 9-fluoro-10- (3-hydroxy-

1-pyrrolidinyl) -3-methyl-7-oxo-2,3-dihydro-7 H -pyrido [3,2,1- ij] -

Of 1,3,4-benzoxadiazine-6-carboxylic acid, prepared in Example 21, in 10 ml of anhydrous dimethylformamide are 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. Recrystallization from methanol gave 42 mg of 9-fluoro-10- (3-methoxy-1-pyrrolidinyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] - 1,3,4-benzoxadiazine-6-carboxylic acid, m.p. 233-234 ° C; FAB-MS m / z 364 (MH &lt; ^{+ &gt;} ).

Example 38

Preparation of 9-fluoro-10- (4-methoxy-1-piperidyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine -6karboxylovej

69 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, gives the acid

9-Fluoro-10- (4-methoxy-1-piperidyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6 -carboxylic acid as crystals, m.p. 229-233 ° C (dec.) after recrystallization from chloroform-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 -benzoxadiazín-6-carboxylic acid

To a suspension of 50 mg of 9-fluoro-3-methyl-7-oxo-

74 mg of 10- (4-thiomorpholinyl) -2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, prepared in Example 11, is added in 5 ml of dichloromethane. 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 acid. -dihydro-7H-pyrido [3,2,1-ij] -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-propyl) -1-piperazinyl] -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-piperazinyl) -2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6 of the 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 and recrystallized from dichloromethane / methanol to give 32 mg of 9-fluoro-3-methyl-7-oxo-10- [4- (2-oxo-n-propyl) -1-piperazinyl] -2, m.p. 3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, m.p. 225-229 ° C (dec.); FAB-MS m / z 405 (MH &lt; ^{+ &gt;} ).

By a procedure similar to that described in the example

40, the following compounds are prepared:

Example R ⁷⁰ temperature Solvent MS m / z no. mp on the overlay- ('C) lised 41 ^^ - c ° -ch ₂ - 223 to 226 dimethyl-467 (MH ⁺ ) (Decomposition) formamide

- 7'1 -

Example # R ⁷⁰ Melting point (° C) Solvent for recrystallization MS: m / z 42 ch ₃ ch ₂ - 273 to 275 (Decomposition) ch ₅ oh 377 (MH ⁺ ) 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) C ₂ ^h 5 ° H 395 (MH ⁺ ) 45 hoocch ₂ - 256 to 259 (Decomposition) h ₂ ° 407 (MH ⁺ ) 46 ch ₂ = chch ₂ 236 to 238 (decomposition) ch ₃ oh 389 1 (MH ⁺ ) 4 7 0 ₂ · O ^- ® * 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-ij] -1 , 3,4benzoxadiazín-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 Of 3,4-benzoxadiazine-6-carboxylic acid prepared in Example 1 and ethyl iodide were prepared in a manner similar to that described in Example 40 to prepare 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. 210-225 ° C after recrystallization 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, 3,4benzoxadiazín-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-6 of the carboxylic acid obtained in Example 6 with 21.6 mg of succinic anhydride, 40 μΐ of triethylamine and 4 ml of dimethylformamide are heated at 80 DEG 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 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. 257-259 ° 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] -l, 3,4-benzoxadiazine-6-carboxylic

From 9-fluoro-3-methyl-7-oxo-10- (1-piperazinyl) -

The 2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid prepared in Example 6 and acetic anhydride was prepared in a manner analogous to that of Example 49. 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 crystals, m.p. 294 DEG-296 DEG 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 9-Fluoro-3-methyl-7-oxo-10- (1-piperazinyl) -2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6 The carboxylic acid prepared in Example 6 and 36 µl 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 -7 H -pyrido [3,2,1- ij] -

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-ij] -1, disodium salt 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 75 ° C for 30 minutes, then cooled to room temperature. To this was added 100 mg of 9-fluoro-3-methyl-7-oxo-10- (1-74 piperazinyl) -2,3-dihydro-7H-pyrido [3,2,1-ij] -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-oxo10 [4- (sulfonatomethyl) -1-piperazinyl] -2,3- dihydro-7H-pyrido (3,2,1-ij] -l, 3,4-benzoxadiazine-6-carboxylic acid of melting point 260 to 263'C (dec); ¹ H NMR (D ₂ O) δ: 2 98 (3H, S), 3.05 (4H, m), 3.39 (4H, m), 3.84 (2H, S), 5.18 (2H), S), 7.55 (1H) , d, J = 13.4 Hz), 8.34 (1H, s).

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 , 4benzoxadiazín-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-ij] -

The 1,3,4-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, m.p. 2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, mp 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-ij] -1,3,4-benzoxadiazine 6-carboxylic acid

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-ij] -1,3 The 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 was neutralized with acetic acid and the precipitate formed was filtered off and recrystallized from methanol to give 15 mg of 10- [3- (aminomethyl) -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo acid. -2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, m.p. 177-180 ° C (dec.); FAB-MS m / z 363 (MH &lt; ^{+ &gt;} ).

Example 55

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

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 of carbonyldiimidazole. Stirring is continued for 2 hours at room temperature and 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 (IH, d), 7.75 (1H) , d), 8.62 (IH, s), 8.92 (IH, s), 15.33 (IH, 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-benzoxadiazine-6-carboxylic acid

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, 9-fluoro-10- (1-imidazolyl)]. 2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid as a reddish 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;} ).

Prepared 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 in dimethylsulfoxide in a manner similar to that described in Example 5 also 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.

Example 57

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

10 mg of 9-fluoro-10- (3-hydroxy-1-pyrrolidinyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -

The 1,3,4-benzoxadiazine-6-carboxylic acid prepared in Example 21 and 8 mg of anhydrous potassium carbonate and 0.5 ml of dimethylformamide are stirred at room temperature for 1.5 hours, then 10.8 mg of benzyl bromide are 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-) benzyl ester.

1-pyrrolidinyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij]

1,3,4-benzoxadiazine-6-carboxylic acid, m.p. 196-198 ° C (dec.); FAB-MS m / z 440 (MH &lt; ^{+ &gt;} ).

Example 58

Preparation of 10- (3-chloro-1-pyrrolidinyl) benzyl ester -

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-benzyl ester (3-Hydroxy-1-pyrrolidinyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -

The 1,3,4-benzoxadiazine-6-carboxylic acid prepared in Example 57 is dissolved in 0.2 ml of thionyl chloride and stirred at 60 ° C for minutes. The reaction mixture was then diluted with water and extracted with chloroform.

The extract is concentrated under reduced pressure. The residue is chromatographed on 2 g of chloroform silica gel as eluent to give 2.8 mg of benzylic acid ester.

10- (3-chloro-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4- benzoxadiazine-6-carboxylic acid, m.p. &gt; 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-ij] -1,3,4-benzoxadiazine 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 [3,2] M.p. 269-172 ° 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- benzoxadiazine-6-carboxylic acid following the procedure through the fluoroborane intermediate

(a) Mixture of 100 mg of 9,10-difluoro-3-methyl-7-oxo-

The 2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid prepared in Example 1 with 1 ml of 60% aqueous fluoroboric acid is heated at a temperature of 12 hours 90 ° C. After cooling the reaction mixture to room temperature, the precipitate formed was 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-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazin-7-one; FAB-MS m / z 331 (MH &lt; ^{+ &gt;} ).

(b) To a solution of 33 mg of the above borane intermediate in 1 ml of dimethylsulphoxide is added with stirring ΐ N-methylpiperazine and 20 μΐ triethylamine. 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. 228-230 ° C (dec.); FAB-MS m / z 411 (MH &lt; ^{+ &gt;} ).

(c) 3 μΐ of triethylamine are 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 was filtered off to give 9-fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] m.p. 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-7oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid prepared in Example 1 1, with 1 ml of acetic anhydride and 100 mg of triacetoxyborane was heated at 140C 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-10,10-difluoro-3-methyl-2,3-dihydro-7H-pyrida [3,2,1- ij] -

1,3,4-benzoxadiazin-7-one; FAB-MS m / z 411 (MH &lt; ^{+ &gt;} ).

(b) 15 μ 41 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 mg 6 - [[(diacetoxyboryl) oxy) carbonyl] -9-fluoro-3-methyl-10 (4-methyl-1-piperazinyl) -2,3-dihydro -7 H -pyrido [3,2,1- ij] -

1,3.4-benzoxadiazin-7-one in the form of crystals, m.p. 156 DEG-157 DEG 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 to the suspension. 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 gave a precipitate which was filtered off to give 9-fluoro-3-methyl-10- (4-methyl-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3, m.p. M.p. 268-269 ° C (dec.).

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-benzoxadiazine-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] - The 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 was stirred at 45 ° C for 8 hours. The solvent was then removed under reduced pressure. The residue was dissolved in dichloromethane. The dichloromethane solution was washed with water and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and the residue is 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-2,5-dihydro-1H-pyrido [3,2,1-ij] -1,3-pivaloyloxymethyl ester , 4-benzoxadiazine-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-2,3-pivaloyloxymethyl ester. 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. 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 (2H, s), 7.64 (1H, d, J = 14.4 Hz), 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] -1,3,4-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- ethyl ester oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, m.p. 204 DEG-207 DEG C. & FB-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] -1,3,4-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] -1,3-ethyl ester The 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, eluent: chloroform / methanol 3: 1) and recrystallized from ethanol to give 71 mg of 10- (3-amino-1-pyrrolidinyl) -9-fluoro-ethyl ester -3-methyl-7-oxo-

2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-berizoxadiazine-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 hydrochloride -6-carboxylic acid pH of a 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-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-7-oxo acid hydrochloride -2,3-dihydro-7H-pyridine-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-ij] 1,3,4-benzoxadiazine hydrochloride 6-carboxylic acid

9-Fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] hydrochloride was prepared according to the procedure in Example 66. m.p. 264 DEG-266 DEG C. (dec.).

Example 68

Preparation 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 sodium salt mg of 9- fluoro-3-methyl-10-morpholino-7-oxo-

The 2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid prepared in Example 9 was suspended in 0.4 ml of water and added with stirring. 40 μΐ IN sodium hydroxide solution. 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-7H sodium salt. -pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, m.p. above 300 ° C.

Example 69

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

From ethyl 6-benzyloxy-6,7-difluoro-

1- (formylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, prepared in Comparative Example (f) using procedures described in Comparative Examples (g, hai) using 1-bromo-2-fluoroethane instead of methyl iodide ( Examples 1 and 5) prepare 9-fluoro-3- (2-fluoroethyl) -10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] m.p. 220-124 ° 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:

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

Solvent FAB-MS m / z for recrystallization

262 (decomposition) ch ₃ oh

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

® ₃ 0 ^J - <221 to 230 CoHp-0H / C <Hq λ · · (decomposition) «to 240 to 245 C ₂ H ₅ 0H / C ₆ H ₁₄ H.nU-Z (decomposition)

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

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

Example R ⁵ R ⁶ temperature Solvent FAB-MS m / z no. mp on the overlay- (° C) lised

¥ '

253 to 255 (decomposition)

240 to 241

CH ₃ OH / (C ₂ H ₅ ) ₂ O 425 (MH ⁺ )

_CH3 OH 363 ^(MH)

> 300 (decomposition) c ₂ h ₅ oh / want ₃ / ^C 6 ^H 14

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

220 to 223 (decomposition)

211 to 214 (dec.) C ₂ h ₅ oh

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

C ₂ H ₅ OH / CHCl ₃ 391 (MH ⁺ )

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-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-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-ij]

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

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-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 = 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 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-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-amino-4-fluoro-l-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -l, 3,4-benzoxadiazine 6-carboxylic acid 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, 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-benz oxadiazine-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-benzoxadiazine-6-carboxylic acid 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.

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] -1,3,4benzoxadiazín-6-carboxylic acid

From 10- (3-amino-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij-1,3,4-benzoxadiazine- Of 6-carboxylic acid obtained in Example 30, following a procedure similar to that described in Examples 47 and 53, 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 DEG-182 DEG 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

A suspension of 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 μΐ of Ν, Ν-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 at temperature mp 218-220 ° C (dec.); FAB-MS m / z 404 (MH &lt; ^{+ &gt;} ).

Example 80

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 acid sodium salt 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- Of 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 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

I ''

The insertable gelatin capsules, each containing the following 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-ij] -1,3,4-benzoxadiazine-

6-carboxylic acid Luvoskol (water-soluble polyvinylpyrrolidone) mannitol 200 mg 20 mg 20 mg talc 15 mg magnesium stearate 2 mg

257 mg

Example B

Tablets, each containing the following 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-ij] -1,3,4-benzoxadiazine-

6-carboxylic acid 200 mg starch 44 mg carboxymethylcellulose calcium 30 mg crystalline cellulose 40 mg magnesium stearate 6 mg 320 mg

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Claims (102)

Pyrido [3,2,1-ij] -1,3,4-benzoxadiazine derivatives of the general formula I (I) wherein R ^{@ 1} is hydrogen, lower alkyl, lower alkanoyloxyalkyl or benzyl; R ² is H or lower alkyl which is 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, 93 which is 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 substituted with 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 the formula wherein each of R ⁵⁰ and R ⁵¹ is lower alkyl or together with the nitrogen atom to which they are attached, both of these residues together form a 5- to 8-membered saturated N- a heterocycle wherein the heterocyclic ring formed from R ⁵ , R ^6, and the adjacent nitrogen atom optionally further comprises a group of the formula -NR ⁷ -, -O-, -S-, -SO-, SO- or -NR ⁷ CO-, wherein 7. R is hydrogen, lower alkenyl, lower alkyl, optionally substituted hydroxy, lower alkoxy, amino, lower alkylamino, di (lower alkyl) amino, halogen, carboxy and / or sulfo, benzyl optionally substituted - 94 amino, nitro lower alkylamino, di (lower alkyl) amino, halogen and / or lower alkoxy or a group of the formula - (CH ₂ ) _n COR ⁸ wherein n represents a number 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" denotes the respective groups containing up to 7 carbon atoms and the pharmaceutically acceptable salts of the compounds of the formula I and the hydrates or solvates of the compounds of the formula I or their salts. Pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivatives of the 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 the 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. ⁴ Pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivatives of the 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. A compound according to any one of claims 1 to 4 wherein R ³ is hydrogen and the other symbols are as defined in claims 1 to 4. 6. A compound according to any one of claims 1 to 5 wherein R &lt; ⁴ &gt; 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 the 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 CH ₃ N \ ^ N *. »And other symbols are as defined in claims 1 to 6. Pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivatives of the general formula I according to any one of claims 1 to 6, wherein the group R ⁵ R ⁶ N-represents the group of the formula n I ₀ NN \ / and 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 [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. fi 'í 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. -dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 11. A compound 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-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 12. A compound according to claim 1 which is 9-fluoro-3-methyl-7-oxo-10- (3-phenyl-). 1-piperazinyl) -2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 13. 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 compound 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 · A compound 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-ij] - 1,3,4-benzoxadiazine-6-carboxylic acid. 16. A compound according to claim 1 which is 10- (3-amino-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2. 1,3-dihydro-7H-pyrido [3,2,1-ij] -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-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 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. -oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 19. A compound according to claim 1 which is 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. 20. A compound according to claim 1 which is O-fluoro-10-O-methoxy-1-pyrrolidinyl) ¹³ -methyl-7-oxo. 2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. A compound according to claim 1 which is 9-fluoro-3-methyl-7-oxo-10- [4- (3-oxone-butyl) -1-piperazinyl] -2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. A compound according to claim 1 which is 9-fluoro-3-methyl-7oxo-10- [4- (sulfonatomethyl) -1-disodium salt. -piperazinyl] -2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 23. A compound according to claim 1 which is 10- [4- (4-aminobenzyl) -1-piperazinyl] -9-fluoro-3-methyl- [1,2,3-ij] -1,3,4-benzooxadiazine. 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- oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -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. A compound according to claim 1 which is 10- (4-ethyl-1-piperazinyl) -9-fluoro-3-methyl-7-oxo-2. 1,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 27. A compound according to claim 1 which is 9-fluoro-10 - [4- (2-hydroxyethyl) -1-piperazinyl] -3-methyl- 7-oxo-2,3-dihydro-7 H -pyrido [3,2,1- ij] - 1,3,4-benzoxadiazine-6-carboxylic acid. 28. A compound 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-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 29. A compound 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. A compound according to claim 1 which is 10- [3- (aminomethyl) -4-methyl-1-pyrrolidinyl] -9-fluoro-3. -methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1j] -1,3,4-benzoxadiazine-6-carboxylic acid. 31. A compound 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-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 32. A compound 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] -1,3,4-benzoxadiazine-6-carboxylic acid. 33. A compound according to claim 1 which is 10- [3- (aminomethyl) -4-fluoro-1-pyrrolidinyl] -9-fluoro- [3,2,1-ij] -1,3,4-benzooxadiazine. 3-Methyl-7-oxo-2,3-dihydro-7H-pyrido [3.2.1] -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-ij] -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 [3,2,1-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-fluoro [3,2,1-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. 100 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-ij) -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. A compound according to claim 1 which is 10- [3- (ethylamino) -4-methoxy-1-pyrrolidinyl] -9-fluoro- [1,3] benzooxadiazine derivative according to claim 1. 3-Methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1b] -1,3,4-benzoxadiazine-6-carboxylic acid. 41. A compound 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-ij] - 1,3,4-benzoxadiazine-6-carboxylic acid. 42. A compound according to claim 1 which is 10- (3-amino-4-chloro-1-pyrrolidinyl) -9-fluoro-3-methyl- [1,2,1-ij] -1,3,4-benzooxadiazine. 7-Oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 43. The compound of 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. A compound according to claim 1 which is 10- [3-chloro-4- (methylamino) -1-pyrrolidinyl] -9-fluoro- [3,2-ij] -1,3,4-benzooxadiazine. 3-Methyl-7-oxo-2,3-dihydro-7H-pyrido [3.2.1] -1,3,4-benzoxadiazine-6-carboxylic acid. 101 45. A compound according to claim 1 which is 9-fluoro-10- [3-fluoro-4- (methylamino) -1-pyrrolidinyl] -3- methyl-7-oxo-2,3-dihydro-7 H -pyrido [3,2,1- ij] - 1,3,4-benzoxadiazine-6-carboxylic acid. 46. The compound of claim 1 which is 10- [4- (aminomethyl) -1-piperidyl] -9-fluoro-3-methyl-7-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-1,4-benzooxadiazine derivative according to claim 1. 2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 48. A compound according to claim 1 which is 9-fluoro-3-methyl-7-oxo-10- [4- (1-pyrrolyl) -1-] -pyridine [3,2,1-ij] -1,3,4-benzooxadiazine derivative according to claim 1. piperidyl] -2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 49. The 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. A compound according to claim 1 which is 9-fluoro-10- (3-hydroxy-1-pyrrolidinyl) 3-methyl-7-oxo-pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivative according to claim 1. 2,3-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-piperazinyl). -2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 102 52. A compound according to claim 1 which is 9-fluoro-10- [4- (2-fluoroethyl) -1-piperazinyl] -3-methyl-7-pyridyl-1,2,1-ij] -1,3,4-benzooxadiazine. oxo-2,3-dihydro-7 H -pyrido [3,2,1- ij] - 1,3,4-benzoxadiazine-6-carboxylic acid. 53. A compound 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-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. * 54. A compound 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-oxo-2 55. Pyridot-3,2,1-ij] -1,3,4-benzooxadiazine derivative according to claim 1. 3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. _r 56. A compound according to claim 1 which is 9-fluoro-3-methyl-10- (1-oxide-4-thiomorpholinyl) -7-oxo-1,4-benzooxadiazine derivative according to claim 1. 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-oxonopropyl) - 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-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. - ioä - 59. A compound according to claim 1 which is 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. 60. The compound of claim 1 which is 10- (4-amino-1-piperidyl) -9-fluoro-3-methyl-7-oxo-2. 3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 61. The compound of 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) -1H-fluoro-3-methyl-7- 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-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. 64. The compound 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. A compound according to 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. 104 66. A compound according to claim 1 which is 9-fluoro-3-methyl-7-oxo-10- (4-thiomorpholinyl) -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. 67. The compound according to claim 1 which is 10- (2,6-dimethyl-4-morpholinyl) -9-fluoro-3-methyl- 7-Oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -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-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 _f 10 - ([2-dimethylamino) ethylmethylamino] - &lt; / RTI &gt; 9-Fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -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- [1,2,3-ij] -1,3,4-benzooxadiazine. 10- (4-Methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1j] -1,3,4-benzoxadiazine-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-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 105 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. 1,3-dihydro-7H-pyrido [3,2,1-ij] -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] - 7-Oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 76. A compound according to claim 1 which is 10- [4- (3-carboxypropionyl) -; 1-piperazinyl] -9-fluoro-3- methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1j] -1,3,4-benzoxadiazine-6-carboxylic acid, 77. The compound of claim 1 which is 10- (4-acetyl-1-piperazinyl) -9-fluoro-3-methyl-7-oxo-2. 1,3-dihydro-7H-pyrido [3,2,1-ij] -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. 106 80. A compound according to claim 1 which is 9-fluoro-2,3-dimethyl-7-oxo-10- (1-piperazinyl) -2,3-benzooxadiazine derivative. -dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 81. A compound according to claim 1 which is ethyl-10- [S-benzyloxycarbonylamino] -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo. -2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxydiazín-6-carboxylate. 82. A compound according to claim 1 which is ethyl-10- (3-amino-1-pyrrolidinyl) -9-fluoro-3-methyl 1-7. 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 [3,2,1] -1,3,4-benzoxadiazine-6-carboxylate. 84. A compound according to claim 1 which is benzyl-10- (3-chloro-1-pyrrolidinyl) -9-fluoro-3-methyl-7-pyrido [3,2,1-ij] -1,3,4-benzooxadiazine. oxo-2,3-dihydro-7H-pyrido [3,2,1] -1,3,4-benzoxadiazine-6-carboxylate. 85. A compound according to claim 1 which is pivaloyloxymethyl-10- [3- (benzyloxycarbonylamino) -1-pyrrolidinyl] -9-fluoro-3- methyl 7-oxo-2,3-dihydro-7H-pyrido [3,2,1] -1,3,4-benzoxadiazine-6-carboxylate. 86. The compound of claim 1 which is pivaloyloxymethyl-10- (3-amino-pyrrolidinyl) -9-fluoro-3-methyl-7- oxo-2,3-dihydro-7H-pyrido [3,2,1] -1,3,4-benzoxadiazine-6-carboxylate. 107 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] -1,3,4-benzoxadiazine-6-carboxylic acid. 88. The pyrido [3,2,1-ij] -l, 3,4-compound according to claim 1 which is 9-fluoro-10- (3 - _(([e dimetylaminojme- mesitylene) amino) -1-pyrrolidinyl 1 -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-] -pyridine [1,2,1-ij] -1,3,4-benzooxadiazine derivative according to claim 1. pyrrolidinyl] -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 90. A compound 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-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. _e 91. A compound according to claim 1 which is 10- (trans-3-amino-4-methyl-1-pyrrolidinyl) -9-fluoro. 3-Methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1l] -1,3,4-benzoxadiazine-6-carboxylic acid. 92. A 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 [3,2,1j] -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-1)]. -pyrrolidinyl] -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 108 94. The compound according to claim 1 which is 9-fluoro-3-methyl-10- (trans-3 - [(methylamino) methyl) -4 -phenyl-1-pyrrolidinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid. 95. The compound of claim 1 which is 10- (trans-3-amino-4-methoxy-1-pyrrolidinyl) -9- fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1j] -1,3,4-benzoxadiazine-6-carboxylic acid. 96. The pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivative according to claim 1 which is 10- (trans-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. 97. 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 (III) wherein R ¹ , R ² , R ³ , R ⁴ and X are as defined in claim 1 and X 'is a halogen atom, wherein the amino, hydroxy and / or carboxy groups present are optionally protected, reacted with an amine of formula IV HN-R ⁵ 109 _and wherein the meanings set forth in claim 1 then optionally remove the protecting groups and optionally isolate the product in the form of a salt, a hydrate or solvate, or a hydrate or solvate thereof. 98. A process for the preparation of the pyrido [3,2,1-ij] -1,3,4-benzooxadiazine derivatives of the formula I as claimed in claim 1 as well as their pharmaceutically acceptable salts and hydrates or solvates of the compounds of the formula I or their salts, characterized by: of the general formula R ⁶ and X that the compound of all (V) wherein R ¹ , R ² , R ⁵ , are as defined in claim 1, wherein the amino, hydroxy and / or carboxy groups present are optionally protected, reacted in a solvent at a temperature of 20 to 150 ° C with a carbonyl compound of formula VI wherein R ³ and R ⁴ are as defined in claim 1, or a polymer thereof 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 110, and optionally the product is isolated in the form of a salt, hydrate or solvate, or a hydrate or solvate thereof. 99. 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 '(Ia) wherein: A is a pharmaceutically acceptable acid anion selected from the group consisting of hydrohalic acids, methanesulfonic acid and p-toluenesulfonic acid, R ¹ is a hydrogen atom or an alkali metal cation, n is 1 when R ¹ is hydrogen and the number 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 C 1 -C 7 alkyl optionally substituted with sulfo; 111 characterized in that the acid of formula II wherein R ² , R ⁵ and R ⁶ are as defined in claim 1, is reacted with at least an equivalent amount of a pharmaceutically acceptable acid corresponding to the anion and / or base derived from an alkali metal and the resulting the salt is optionally isolated in the form of its hydrate or solvate. 100. The compound of claim 1, which is 9-fluoro-3-methyl-10 '(4-methyl-1-piperazinyl) -7-oxo-2-dibasic chloride, salt of the pyridof3,2,1-ij] -1,3,4-benzoxadiazine. 1,3-dihydro-7H-pyridof 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 which, in addition to the usual ingredients, comprises, as an active ingredient, a pyridof3,2,1-ij] -1,3,4-benzoxadiazine derivative of the Formula I, or a pharmaceutically acceptable salt or hydrate or solvate thereof. a derivative or salt according to claim 1.