HU199481B - Process for production of piridobenzooxadiasines and medical compositions containing them - Google Patents

Description

The present invention relates to the preparation of novel tricyclic compounds. More particularly, the present invention provides a process for the preparation of novel pyrido [3,2,1-ij-1,3,4-binaxadiazine derivatives and pharmaceutical compositions containing these compounds.

The present invention relates to novel pyrido [3,2,1-ij-1,3,4-benzoxadiazine derivatives of the formula (I)

R * is hydrogen, (1-4C) alkyl, (2-7C) alkanoyloxy (1-4C) alkyl, or phenyl (1-4C) alkyl;

R ² is C 1 -C 4 alkyl optionally substituted with halogen

R ³ is hydrogen;

R ⁴ is hydrogen, C 1-4 alkyl, hydroxy (C 1-4 alkyl) or di (C 1-4 alkyl) amino (C 1-4 alkyl);

X is halogen;

R @ 4 is C1 -C4 alkyl and R @ 2 is di- (C1 -C4 alkyl) amino (C1 -C4 alkyl); obsession

R ⁵ and R ⁴ together with the adjacent nitrogen atom to which they are attached are optionally substituted on carbon by hydroxy, phenyl, C 1 -C 4 alkyl or alkoxy and / or C 1 -C 4 aminoalkyl, (C 1 -C 4) alkanoylamino - (C 1-4 alkyl), mono (C 1-4 alkyl) or di- (C 1-4 alkyl) amino (C 1-4 alkyl) -, amino- (1-4) forms a pyrrolidino, piperidino, morpholino or thiomorolino group which is mono- or di-substituted with C 1-4 alkyl) amino, benzyloxycarbonylamine, halogen, pyrrol-1-yl or N- (C 1-4 alkyl) piperazino; which may optionally exist in the form of its dioxide; or on a carbon atom optionally having 1 to 4 alkyl or phenyl groups and / or on a nitrogen atom optionally having 1 to 5 alkyl, ο οalkyl, haloalkyl, carboxyalkyl, max. Substituted with 5 C atoms of phenyl oxoalkyl, nitrophenylalkyl, hydroxyalkyl or alkenyl, (aminophenyl) alkyl, C 1-4 alkyl containing oxo and carboxyl, or sulfomethyl or a piperazino group having an oxo group at C 3; or an imidazolyl group or a homopiperazino group optionally substituted with C 1-4 alkyl or a pyrrolidino group substituted on an C atom with an N-aminobenzylamino group or a dimethylaminomethylidene amino group, and their pharmaceutically acceptable salts; ) for the preparation of hydrates or solvates of the compounds of the general formula (I).

The compounds of formula (I) are useful as active ingredients in antibacterial compositions.

The term "low carbon" as used herein, preferably denotes groups having up to 4 carbon atoms, unless otherwise stated.

^R1 is hydrogen, lower alkyl (eg. Methyl, ethyl, n-propyl or n ·-butyl), (2-7 carbon atoms), alkanoyloxy (Ci-C4) alkyl (e. acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl or 1- (pivaloyloxy) ethyl) or phenyl (lower alkyl) such as benzyl.

^R2 is optionally substituted lower alkyl by halogen, wherein the lower alkyl group 1 to 4 carbon atoms (eg. Preferably methyl, ethyl, π-propyl, isopropyl, n-butyl, etc.) And the halogen is preferably fluorine, chlorine or bromine, preferably fluorine.

In the context of R ^4, lower alkyl groups may contain from 1 to 4 carbon atoms (e.g. preferably methyl, ethyl, η-propyl, isopropyl, n-butyl, etc.). The di- (lower alkyl) amino (lower alkyl) group, e.g. dimethylaminomethyl or ethyl or diethylaminomethyl or ethyl.

^R5 R®N általános'képletben group in the (I) is preferably one consisting of 1-piperazinyl, 4-methyl-1-1-piperazinyl, 3-methyl-l-piperazinyl, 3-phenyl-l- piperazinyl ·, 3,4-dimethyl · -1-piperazinyl, 4-ethyl-1-piperazinyl, 3- (4-aminophenyl) -1-piperazinyl, 4- (n-propyl) -1-piperazinyl · 4- (2-fluoroethyl) -1-piperazinyl, 4-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-amino- benzyl) -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-ηηε1ιΊ-4-πιοΓίο1ϊηΐ1, 2,6-dimethyl-4- morpholinyl, 4-thiomorpholinyl, 1,1-dioxido-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, 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-Amino-benzylamino) -1-pyrrolidinyl, 3- (4-methyl-1-piperazinyl) -1-pyrrolidinyl, 3 - [(dimethylamino) -methylidene-amino] -1-pyrrolidinyl- , 3 - [(methylamino) methyl] -1-pyrrolidinyl, 3 - [(methylamino) methyl] -4-phenyl-β-pyrrolidinyl, 3-methyl-3 - [(methylamino) ) -methyl] -1-pyrrolidinyl ·, 3 - [(ethylamino) methyl] -1-pyrrolidinyl, 3- (acetylaminomethyl) -1-pyrrolidinyl, 3 - [(dimethylamino)

-3H-199481 Fluoro-methyl] -1-pyrrolidinyl, 3 - [(N-ethyl-N-methylamino) 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-J (ethylamino) -methyl] -1-pyrrolidinyl, 3- (aminomethyl) -4-fluoro-1-pyrrolidinyl, 3-fluoro-4 - [(methylamino) methyl] -1-pyrrolidinyl, 3- [ (ethylamino) methyl] -4-fluoro-1-pyrrolidinyl, 3- (aminomethyl) -4-methyl-β-pyrrolidinyl, 3-methyl-4 - [(methylamino) methyl] -1-pyrrolidinyl, 3 - [(ethylamino) methyl] -4-methyl-1-pyrrolidinyl, 3-hydroxy-β-pyrrolidinyl, 3-methoxy-1-pyrrolidinyl 3-chloro-1-pyrrolidinyl, , 3-fluoro-1-pyrrolidinyl, 3-hydroxy-4-methoxy-β-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, etc.

X is halogen, e.g. represents a fluorine, chlorine or bromine atom, preferably a fluorine or chlorine atom.

According to the process of the present invention, the compounds of the formula I and their pharmaceutically acceptable salts, as well as the hydrates and solvates of the compounds of the formula I and their salts, can be prepared by:

a) a compound of formula III (wherein R ¹ , R ² , R ³ , R ⁴ and X are as defined above; X 'represents a halogen atom and the amino, hydroxy and / or carboxyl groups present are optionally protected be) (IV) is reacted with an amine of formula (wherein R ⁵ and R® as hereinbefore defined) and then deprotecting when necessary; obsession

b) a compound of formula (V) (wherein R ¹ , R ² , R ⁵ , R ^B and X are as defined above and the amino, hydroxy and / or carboxyl groups present may be optionally protected); reacting a carbonyl compound of the formula (wherein R ³ and R ⁴ are as defined above) or a polymer, acetal, ketal or enol ether thereof, and if necessary, deprotecting; and then, if desired, one or more of the following transformations of a compound of formula (I) obtained by process (a) or (b):

(i) N-alkylating, alkenylating, or acylating the corresponding compound of formula (I) to form a compound of formula (I) containing the alkyl, alkenyl or acyl group as defined above in the -NR ⁵ R R heterocyclic group; or (ii) a carbon atom in the case of -NR ⁵ R® group is replaced by a mono- or di (lower szénatom4 alkyl) amino (lower) alkyl or (1) Preparation of compounds of formula containing hetero ring substituted lower alkoxy, introducing a lower alkyl group into a compound of formula (I) containing an unsubstituted amino or lower alkylamino or hydroxy substituted heterocycle; or (iii) for the preparation of a compound of formula (I) containing a 6-membered heterocyclic group containing -SO ₂ - instead of -NR ^S R ⁶ , a corresponding thiomorpholine group containing a corresponding thiomorpholine group; oxidizing a compound of formula; or (iv) removing the protecting group (s) from the corresponding compound of formula (I) containing a protected amino or carboxyl group (s) in the preparation of a compound of formula (I) having a free amino or carboxyl group; or (v) for the preparation of compounds of formula I wherein -NR ⁵ R R is a halopyrrolidino group, the corresponding hydroxy pyrrolidino compound of formula I wherein R ^{1 is} a carboxy protecting group as defined above halogen and optionally deprotecting R ¹ ; or (vi) reducing the nitro group in the corresponding nitro-substituted compound of formula (I) to produce a compound of formula (I) wherein p-aminobenzylpiperazino is substituted with -NR ⁵ R®; or for the preparation of (1) compounds of formula (VII), the 10-position substituted by a group of formula a C atom in (XIV) pyrrolidino (where R® ° and R ⁵¹ individually represent a methyl group), the corresponding amino-substituted (S reacting a compound of formula (VII) with a reactive derivative of a formamide of formula (VII) wherein R ⁵⁰ and R ⁵¹ are as defined above; or (viii) esterifying a carboxylic acid of formula (I) in the preparation of a compound of formula (I) wherein R ¹ is a carboxyl protecting group;

(ix) a group ^-NR5 R® is appropriate for the preparation of [N- (aminobenzyl) amino] Compounds containing pyrrolidino radical is a 3-

The 3-amino compound is nitrobenzylated and then reduced and / or converted to a salt, hydrate or solvate of a compound of formula I obtained by any of the above processes, or to a hydrate or solvate of a salt;

(a) Procedure

The desired compounds, as mentioned above, can be prepared by reacting a compound of formula (4) wherein R *, R ² , R ³ , R ⁴ and X are as defined above; It represents and can be protected given the present amino, hydroxy and / or carboxy groups optionally) reacting the compound (IV) with an amine of formula (wherein R ^s and R ^e are as defined above), followed if necessary by deprotection.

The compounds of formula (III) used as starting materials in process (a) are new and e.g. may be prepared as shown in Reaction Scheme A or B. In the formulas, R ² , R ³ , R ⁴ , X and X 'are as defined above; R 'represents a protecting group, e.g. benzyl, methoxybenzyl, methoxymethyl, methoxyethoxymethyl, tetrahydropyranyl, allyl, tert-butyl, tert-butyldimethylsilyl, acetyl, benzoyl, etc .; R is a protecting group, e.g. formyl, acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, tert-butoxycarbonyl, and the like. and R '' is hydrogen or ethyl.

The amino or monoalkylamino group optionally present in the starting material of formula (IV) may optionally be protected by an amino protecting group (e.g., formyl, acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl,

2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl or tertiary butoxycarbonyl).

The reaction of the compound of formula (III) with the amine of formula (IV) or a suitably protected amine is carried out in the presence or absence of a solvent, preferably at a higher temperature for the time necessary for the reaction to complete. The reaction temperature is usually ca. 30 to 200 ° C, preferably ca. 80-150 ° C.

The reaction is preferably carried out in the presence of an acid binder. For this purpose, e.g. triethylamine, pyridine, picoline, N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,4-diazabicyclo [2.2.2] octane, alkali metal. hydroxides, alkali metal carbonates, etc.). An excess of the amine of formula (IV) may also serve as an acid binder.

Suitable inert solvents (e.g. acetonitrile, alcohols, dimethylsulfoxide, dimethylformamide, dimethylacetamide, pyridine, picoline, lutidine, N, N'-dimethylpropyleneurea, etc.) may be used as the reaction medium. Mixtures of two or more solvents may be used.

After the reaction, the protecting group may be removed, if desired, by methods known per se. so e.g. the formyl group may be removed by acidic or basic hydrolysis, preferably basic treatment, while the benzyloxycarbonyl group may be removed by hydrogenolysis.

As starting material of formula (III), e.g. one of the following may be used:

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-dichloro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] benzoxadiazine-6-carboxylic acid;

9-chloro-10-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-bezoxadiazine-6-carboxylic acid;

9.10-Difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carbonyl acid ethyl ester;

9.10-Difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid benzyl ester;

9.10- difluoro-3- (2-fluoroethyl) _{-7-oxo-2,3-dihydro-15} -fH pyrido [3,2,1- ij] -1,3,4-benzoxadiazine-6-carboxylic acid;

9.10-Difluoro-2,3-dimethyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid;

9,10-difluoro-2- (hydroxymethyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6 carboxylic acid;

9.10-Difluoro-2 - [(dimethylamino) methyl] -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,425 -benzoxadiazine-6 carboxylic acid;

As an amine of formula IV, e.g. the following compounds may be used: piperazine, 4-methylpiperazine, 3-methylpiperazine,

3-phenylpperazine, 3- (4-aminophenyl) piperazine,

3- (4-nitrophenyl) piperazine, 4- (2-hydroxyethyl) piperazine, morpholine, 2-methylmorpholine, 2,6-dimethylmorpholine, thiomorpholine, 4- (aminomethyl) - piperidine, 4 - [(methylamino) methyl] piperidine, 4 - [(ethylamino) methyl] piperidine, 4-amino-piperidine, 4- (methylamino) piperidine, 4- ( ethylamino) piperidine, 4- (benzyloxycarbonylamino) piperidine, 4- (benzyloxycarbonylmethylamino) piperidine, 4- (benzyloxycarbonyl-ethylamino) -piperidine, 4-hydroxypiperidine , ₄₀ 4-methyl-piperidine, 4- (pyrrolidin-1-pyrrolyl, homopiperazine, 3- [(ethylamino) methyl] pyrrolidine, 3- [(ethylamino) methyl] pyrrolidine, 3- (acetylaminomethyl) pyrrolidine, 3-hydroxypyrrolidine, 3-methoxypyrrolidine, 3-aminopyrrolidine, 3- (benzyloxycarbonylamino) pyrrolidine, 3- (methyl ^45- amino) pyrrolidine, 3 - (benzyloxycarbonylmethyl-amino) -pyrrolidine, 3-amino-4-phenylpyrrolidine,

3-amino-3-methylpyrrolidine, 3-amino-4-methyl-pyrrolidine, 3- [(4-aminobenzyl) amino] pyrrole ₅ Q pyrrolidine, 3- (4-methyl-1-piperazinyl) pyrrolidine,

3 - [(dimethylamino) methylidene amino] pyrrolidine, 3 - [(methylamino) methyl] -4-phenylpyrrolidine, 3-methyl-3 - [(methylamino) methyl] pyrrolidine , 3- (ethylamino) -pyrrolidine, 3- ( _benzylg5 -oxycarbonyl-ethylamino) -pyrrolidine, 3 - [(dimethylamino) -methyl] -pyrrolidine, 3 - [(N-ethyl-N) -methylamino) -methyl] -pyrrolidine, 3-amino-4-methoxypyrrolidine, 3-methoxy-4- (methylamino) pyrrolidine, 3- (ethylamino) -4-methoxypyrrolidine , 3-amino-4-hydroxypyrrolidine, 3- (methyl ^60- amino) -4-hydroxypyrrolidine, 3- (ethylamino) -4-hydroxypyrrolidine, 3- (aminomethyl) -4- methylpyrrolidine, 3-methyl-4 - [(methylamino) methyl] pyrrolidine, 3 - [(ethylamino) methyl] -4-methylpyrrolidine, 3-hydroxy-4-methoxypyrrolidine, 3- (acetyl65-aminomethyl) -4-hydroxypyrrolidine, imidazole,

-5HU 199481 Β

4-methylimidazole, N, N, N'-trimethylethylenediamine and the like.

In process (b), compounds of formula (I) may be prepared by reacting a compound of formula (V) (wherein R ¹ , R ² , R ⁵ , R ⁶ and X are as defined above and the amino substituent is present). hydroxy and / or carboxyl groups may be optionally protected) with a carbonyl compound of formula VI (wherein R ³ and R ⁴ are as defined above and the amino, hydroxy and / or carboxyl groups present may be protected) or a polymer, acetal, ketal or enol ether, and if necessary, remove the protecting group present.

The compounds of formula (V) used as starting materials in process (b) are new and can be prepared by reaction of a compound of formula (H) or (Va) with an amine of formula (IV) as described in Scheme A or B.

The amino or monoalkylamino group in the carbonyl compound, polymer, acetal, ketal or enol ester of formula VI may be optionally protected, e.g. with one of the protecting groups listed for R 'in G or H.

The reaction may be carried out, if desired, in a solvent (e.g., dioxane, tetrahydrofuran, acetonitrile, chloroform, dimethylformamide, dimethylsulfoxide, N, N'-dimethylpropyleneurea, acetic acid, etc.) or a mixture of two or more of these solvents.

The reaction may be carried out, if necessary, in the presence of an acidic catalyst. As a catalyst, e.g. acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, pyridinium p-toluenesulfonate, ferric chloride, zinc chloride, chlorotrimethylsilane, Nafion Ht (perfluorinated resin sulfonic acid; Aldrich Chemical Co. Inc.), Amberlyst-15 (highly acidic macroretricular resin, Aldrich Chemical Co. Inc.) and the like. It can be used.

The reaction temperature can be varied within a relatively wide range, and is usually about 1 to about 10 minutes. We can work at 20-150 ° C.

Advantageously, about 1 mole of the compound of formula (V) may be used. 1 mol or more of the carbonyl compound of formula VI, polymer, acetal, ketal or enol ether is used.

After completion of the reaction, the protecting group which may be present on the amino or monoalkylamino group may, if desired, be removed in a manner known per se, e.g. the formyl group may be cleaved by acidic or basic hydrolysis, preferably by basic hydrolysis. The benzyloxycarbonyl group may be cleaved by hydrogenolysis.

As starting materials for the formulas (V) and (Va), for example, the following compounds may be used:

6.7-Diphioro-8-hydroxy-1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid;

6.7-Difluoro-8-hydroxy-1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid ethyl ester;

6.7-Difluoro-8-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-l, 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 - [(Benzyloxycarbonyl-ethylamino) -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-l, 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.

As the carbonyl compound of formula VI to be reacted with the compounds of formula V, e.g. the following compounds may be used:

formaldehyde, acetaldehyde, acetone, methyl ethyl ketone, etc .; polymers of these compounds e.g. paraformaldehyde, paracetaldehyde, trioxane, etc .; acetals of these compounds e.g. dimethoxymethane, 1,1-dimethoxyethane, 1,3-dioxolane, glycolaldehyde dimethylacetal, dimethylaminoaceraldehyde dimethylacetal, etc .; ketals of these compounds e.g. 2,2-dimethoxypropane, etc .; enol ethers of these compounds, e.g. 2-methoxypropene, 2-trimethylsilyloxypropene and the like.

In step (i) is prepared by (I) Compounds of formula I in which the group R ⁵ R o 6-membered N-, -NR ⁷ - group

-6HU 199,481 represents Β comprising heterocikluosos ring and other ^R7 from hydrogen, i.e. az.R ⁵ R ^e N-heterocyclic ring corresponds to the general formula (VIII) (wherein the piperazinyl ring is substituted with one or more carbon atoms may also be and R ⁷⁰ is lower alkenyl, lower alkyl or phenylalkyl optionally substituted as defined above, or a compound of formula II wherein n is 0 to 4 and R @ 4 is C1 -C5 alkyl or phenyl ). These compounds are prepared by reaction of the appropriate compound of formula (I) wherein R ⁷ is hydrogen with an agent capable of introducing R ⁷⁰ . This reaction, which may be N-alkylation or N-acylation, can be carried out as follows. N-alkylation.

A compound of formula IX (wherein R ¹ , R ² , R ³ , R ⁴ and X are as defined above and may be substituted on one or more carbon atoms of the piperazinyl group and the hydroxyl and / or carboxyl groups present may be protected) (i) ) reacting a compound of Formula X (wherein Y is a leaving group and R ^{70 is} as defined above); or (ii) ^R7 is appropriate for compounds containing R ⁹ -CO-CH ₂ -CH 2, (XI) a Michael acceptor of formula when reacted (wherein R ⁹ is C 1-2 alkyl); or (iii) reacting with R ^7, where methyl or sulfomethyl is present, with formaldehyde and formic acid or an alkali metal bisulfite.

N-acylation

Reaction of a compound of Formula IX with an anhydride of Formula XII (wherein Z is preferably a C 2 or C 3 alkylene chain) provides compounds of Formula I wherein R ⁷ is HOOC-Z-CO-.

After the above reactions, the protecting group may be removed if desired.

so e.g. the desired compound can be prepared by reaction of a compound of formula IX and X. The leaving group at Y is e.g. halogen (e.g., chloro, bromo or iodo), acyloxy (e.g., actooxy), lower alkanesulfonyloxy (e.g., methanesulfonyloxy), arylsulfonyloxy (e.g., p-toluenesulfonyloxy) optionally nitrated a phenoxy group (e.g., phenoxy, 4-nitrophenoxy) or a succinimidoyloxy or phthalimidoyloxy group.

The amino group present in the compounds of formula (X) may optionally be protected, e.g. for a compound of formula (G) or (H) with a protecting group listed for R '.

If necessary, the reaction may be carried out in a solvent medium. As the reaction medium, e.g. dimethylformamide, dimethylacetamide, dimethylsulfoxide, N, N'-dimethyl-n-propylene carbamyl, dioxane, tetrahydrofuran, pyridine and the like. or a mixture of two or more of the above solvents.

The reaction is preferably carried out in the presence of an acid scavenger. For this purpose, e.g. triethylamine, pyridine, Ν, Ν-dimethylaniline, 1,4-diaza-bicyclo [2.2.2] octane, 1,8-diaza-bicyclo [5.4.0.] undec-7-ene, sodium hydride , alkali metal hydroxides, alkali metal carbonates, etc. It can be used.

The reaction can be carried out over a relatively wide temperature range. Usually approx. 0 ° C to 180 ° C, preferably ca. 0-110 ° C - can be worked. Preferably, from 1 to 4 moles, particularly preferably from 1 to 2 moles, of compound (X) may be used per mole of compound (IX).

As a compound of formula (X), e.g. methyl iodide, ethyl iodide, ethyl bromide, 1-iodobutane, 1-bromobutane, 1-iodine propane,

2-iodo-propane, 1-fluoro-2-iodoethane, 1-iodo-2-methoxyethane, bromoacetic acid, allyl bromide, acetic anhydride, acetic anhydride, acetyl chloride, propionic anhydride, propionyl chloride, benzoic anhydride, benzoyl chloride, chloroacetone, 1-chloro-2-butanone, phenacyl chloride, and the like. It can be used.

Alternatively, the desired compounds may be prepared by reacting a compound of Formula IX with a Michael acceptor of Formula XI.

The reaction may, if desired, be carried out in a solvent. As the reaction medium, e.g. dimethylformamide, dimethylacetamide, dimethylsulfoxide, dioxane, tetrahydrofuran, methanol, ethanol, propanol, glycol monomethyl ether and the like. or a mixture of two or more of the above solvents.

The reaction can be carried out over a relatively wide temperature range. Usually approx. 30-170 ° C - preferably ca. 50-140 ° C.

In the above process, it is preferable to use from 1 to 5 moles, particularly preferably from 1 to 2 moles, of compound (XI) per mole of compound (IX).

As a Michael acceptor, e.g. methyl vinyl ketone, ethyl vinyl ketone and the like. It can be used.

Reaction of a compound of formula IX with formaldehyde and formic acid or an alkali metal bisulfite provides a compound of formula I wherein R ⁷ is methyl or sulfomethyl. The reaction may generally be carried out under gentle heating (e.g., about 50-100 ° C).

-7HU 199481 Β

Alternatively, the compound of formula (IX) may be reacted with an anhydride of formula (XII).

If necessary, the reaction may be carried out in a solvent. As the reaction medium, e.g. pyridine, dimethylformamide, dioxane, tetrahydrofuran. etc or a mixture of two or more solvents.

The reaction is preferably carried out in the presence of an acid acceptor. For this purpose, e.g. triethylamine, pyridine, Ν, Ν-dimethylaniline, 1-4-diazabicyclo [2.2.2] octane, alkali metal hydroxides, alkali metal carbonates and the like. It can be used.

The reaction can be carried out over a relatively wide temperature range. Usually approx. 0-120 ° C, preferably ca. The temperature may be from 0 to 100 ° C.

Preferably, 1 mol or excess of compound of formula (XII) is used per mole of compound (IX).

In the above process, the anhydride is e.g. succinic anhydride, glutaric anhydride, etc. may be used.

The protecting group may be removed after the reaction if desired by methods known per se. so e.g. the formyl group may be cleaved by acidic or, preferably, basic hydrolysis, while the benzyloxycarbonyl group may be cleaved by hydrogenolysis.

Deprotection may be carried out before or after product isolation.

(ii) process

The process comprises the preparation of compounds of formula (I) containing a heterocycle substituted by a mono- or a di- (lower alkyl) aminoalkyl or a lower alkoxy group at the -NR ⁵ R ⁶ group. a lower alkyl group is introduced into the compound of formula (I) containing an aminoalkyl or a lower alkylaminoalkyl or a hydroxy group. Alkylation may be carried out with a compound of formula XIII (wherein R ¹⁰ is lower alkyl and Y is halogen).

The leaving group may be a leaving group of the type indicated for the compounds of formula (X). The reaction may be carried out in a manner analogous to that of the compounds of formula IX and X. The O-alkylation can be carried out as the N-alkylation. Conveniently, proton scavengers (e.g., alkali metal hydrides such as sodium hydride) may be employed.

(iii) process

In the process, compounds of general formula (I) containing a 6-membered heterocyclic group containing a -SO ₂ - group in place of R ^S R ⁶ can be prepared by oxidation of the corresponding deoxy compound of formula I containing a -S- group live.

The oxidation may be carried out using organic or inorganic oxidants. Salts capable of delivering oxygen as an oxidizing agent may be used, e.g. organic peroxides, e.g. monosubstituted organic peroxides (e.g., C ₍ - ₄ alkyl or alkanoyl hydroperoxides such as pL tertiary butyl hydroperoxide); peracetic acid, peracetic acid and phenyl substituted derivatives of hydroperoxides such as cumene hydroperoxide or perbenzoic acid. optionally substituted with a lower carbon group (i.e., C 1-4 alkyl or alkoxy), a halogen atom or a carboxyl group (e.g. 4-methylperbenzoic acid,

4-methoxy-perbenzoic acid, 3-chloro-perbenzoic acid, monoperphthalic acid, etc.). Various inorganic oxidizing agents may be used e.g. hydrogen peroxide, ozone, permanganates (e.g., sodium or potassium permanganate), hypochlorites (e.g., sodium, potassium, or ammonium hypochlorite), peroxymmonoic acid or peroxydic acid. Preferably, 3-chloroperbenzoic acid is used. The oxidation is preferably carried out in an inert solvent (e.g. an aprotic inert solvent such as tetrahydrofuran, dioxane, methylene chloride, chloroform or ethyl acetate). Usually approx. We can work at temperatures from -20 ° C to + 50 ° C.

When the oxidizing agent is used in an amount equal to or greater than twice the stoichiometric amount, the corresponding sulfone (i.e., a compound containing a heterocycle containing -SO ₂ -) is obtained.

(iv) process

The compounds of formula (I) containing the free amino or carboxyl group are prepared from the corresponding compounds of formula (I) containing one or more protected amino or carboxyl groups.

As an amino protecting group, e.g. lower alkanoyl groups (such as acetyl) or benzyloxycarbonyl may be considered.

The protecting groups on the amino group may be removed by acid hydrolysis or basic hydrolysis or hydrogenolysis (e.g., benzyloxycarbonyl).

The amino protecting groups which can be cleaved by acid hydrolysis are preferably removed using optionally halogenated lower alkanecarboxylic acids. The acid hydrolysis is preferably carried out at room temperature, but may be carried out at slightly higher or lower temperatures (i.e., about 0-40 ° C). Protective groups that can be removed in a basic medium can generally be cleaved with dilute aqueous alkali metal hydroxide at 0-30 ° C.

As a protecting group for the carboxyl group, e.g. the protecting groups listed for R ¹ may be considered.

The above protecting groups may be removed by methods known per se, e.g. hyd-8HU 199481 Β by hydrogenation (benzyl group) or by acidic or basic hydrolysis. Preferably, the reaction is carried out in an inert solvent for about 10 minutes. It can be carried out at a temperature between 0 ° C and room temperature. The tertiary butyl group was treated with trifluoroacetic acid in the presence of anisole for ca. It can be removed at a temperature between 0 ° C and room temperature in the presence or absence of an additional solvent (e.g., methylene chloride).

(v) process

Compounds of formula (I) containing a halopyrrolidino group (e.g., compounds of formula (XV) wherein R ⁵ R ^{6 is} N) include the corresponding hydroxy substituted compounds, e.g. R ⁵ R ⁶ may be prepared by halogenation of compounds having the formula (XVI) instead of N. Preferred halogenating agents are thionyl halides (especially thionyl chloride) or phosphorus trichloride, phosphorus oxychloride or phosphorus pentachloride. The reaction is preferably carried out for about 1 hour. It can be carried out at 0-80 ° C. Preferably, the carboxyl groups present are protected (e.g., by benzylation) and then re-liberated after completion of the reaction (e.g., removal of the benzyl group, by hydrogenation).

(vi) process

The compounds of formula (XVII) in place of R ⁵ R ^e N can be prepared by reduction of the corresponding nitro-substituted compounds of formula (I). The reduction may be carried out in the presence of a noble metal catalyst (e.g. palladium on carbon). The reaction is preferably carried out in the presence of water or a lower alkanol (e.g. methanol or ethanol) or a mixture thereof. The reaction is usually carried out for approx. The reaction may be carried out at 10-40 ° C, preferably at room temperature.

(vii) Procedure

Compounds of formula I wherein X ⁵⁰ and R ⁵¹ are as defined above; e.g. compounds of formula (XVIII) instead of R ⁵ R ^e N- may be prepared by reacting the corresponding compound of formula (I), e.g. reacting the amino group of a compound of formula (XIX) wherein R ⁵ R ^{6 is} N with a reactive derivative of the formamide derivative of formula VII (wherein R ⁵⁰ and R ⁵¹ are as defined above).

As a reactive derivative of a compound of formula VII, e.g. suitable di- (lower alkyl) acetals (e.g. dimethyl acetals) may be used. The reaction is preferably carried out in an inert solvent (e.g. diethyl ether, dimethylformamide or dimethylsulfoxide). Generally, temperatures of about room temperature may be employed, but lower or higher temperatures (e.g., 0-100 ° C) may be employed.

(vili) procedure

According to the process, compounds of formula (I) containing a protected carboxyl group of R ^{1 are} prepared by reacting a carboxylic acid (I) with a corresponding halide (preferably iodide or bromide) containing the desired ester group. The reaction can be accelerated by addition of a base (e.g., alkali metal hydroxides, alkali metal carbonates, or organic · amines, such as triethylamine). The esterification is preferably carried out in an inert organic solvent (e.g. dimethylacetamide, hexamethylphosphoric triamide), dimethylsulfoxide or, most preferably, dimethylformamide, etc.). Usually approx. We can work at 0-40 ° C.

Pharmaceutically acceptable salts of the compounds of formula (I) or hydrates or solvates of these compounds or salts may be prepared by methods known per se. so e.g. reacting a carboxylic acid of formula (I) with an equivalent amount of the desired base or reacting a base of formula (I) with an organic or inorganic acid. The reaction is preferably carried out in a solvent. The reaction medium may be water or organic solvents (e.g., ethanol, methanol, acetone, etc.). Temperature is not critical to the formation of salts. Usually, it is possible to work at room temperature, but it may be slightly higher or lower (e.g., 0-50 ° C).

Examples of pharmaceutically acceptable acids useful in the above process include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, citric acid, citric acid, -maleic acid, phenylacetic acid, benzoic acid, 4-aminobenzoic acid, anthranilic acid, 4-hydroxybenzoic acid, salicylic acid, amino salicylic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, p-toluenesulfonic acid, p-toluenesulfonic acid, , galacturonic acid, aspartic acid and glutamic acid; methionine, tryptophan, lysine, arginine, etc.

From the acid addition salts, the basic compounds of formula I can be liberated by treatment with a base (e.g., alkali metal hydroxide, ammonia, etc.).

The salts of the compounds of formula I with bases may be prepared by reacting a compound of formula I with a metal base or an amine (e.g. an alkali metal or alkaline earth metal hydroxide or an organic amine). The salt formation e.g. sodium, potassium, magnesium, calcium, etc., and diethanolamine, Ν, Ν'-dibenzylethylenediamine, choline, ethylenediamine, etc. It can be used.

Acid addition or base salts of the compounds of formula I with certain physical properties (e.g.

-9EN 199481 Β Authority) differ from the free compound of formula (I).

The compounds of formula (I) and their pharmaceutically acceptable salts may exist in unsolvated and solvated (or hydrated) forms. Hydration occurs automatically during the production process or may occur gradually due to the hygroscopic properties of the initially anhydrous product. In the controlled production of hydrates, the completely or partially anhydrous product is exposed to a humid atmosphere (e.g., at a temperature of about + 10 ° C to about + 40 ° C). Solvates of the compounds with pharmaceutically acceptable solvents such as ethanol, e.g. may be formed during crystallization.

Certain representative compounds of the compounds of the present invention contain asymmetric centers. The present invention is pure D-isomers. includes the preparation of pure L-isomers and mixtures thereof (including racemic mixtures).

The compounds of the present invention possess a broad range of Gram-positive and Gram-negative organisms and mycoplasmas and are therefore useful in the treatment and prevention of infectious diseases. The in vitro and in vivo antibacterial activity of the compounds of formula I is demonstrated by the following tests.

1) In vitro antibacterial activity

The in vitro antibacterial activity of some of the pyrido [3,2,1-ij] -1,3,4-benzoxadiazine derivatives of formula I is determined by the standard agar dilution method (Chemotherapy 22, 1126 (1974)). The minimum inhibitory concentration values (MIC, pg / ml) are shown in Figures I and II. is shown in Table. The compounds used are identified by the number of the preparation example.

ί

-10HU 199481 B

tendon cn 0 cn CTi cn SHE m OJ cn CO r-l OK OK * • k 0 0 0 0 0 0 tn

ch

1-1 i-l in

SHE

Oh m

i-l o

Eco

_I. spreadsheet_

Anti bacterial spectrum MIC / + 1, g / ml /

C1-I

H cn r-l

SHE

Eco

She

OJ

Eco

(SÍ ra ρ

o ra

0} tí m 1 — I cn

H

-I CM

ΟΛ

CO ίin

SHE

Eco

o o

She

Eco

vi

1 — I o

ao o

o o

tendon

OJ o

•K

ο ι — I o * o

0 60 thi. -M 0 m tendon e you • rl cl 'OJ P M the} 0 ·> 0 to • rl rM 1 0 43 H +3 ϊη ra > SHE -M vol * · Η you • rl 8 -P to S N • H • H N to 43 p 0 Ticno 0 c P rM rM Ci 60 1 r-l Ol aj ρ • rl 0 cl 0 OH rao «Ρι

σ \ THE OK 0 cn cn OK 0 0 ol OK 0 cn cn SHE cn cn OK 0 tendon OJ Vu tendon 0 tendon OJ 0 0 Kű SHE ι-1 SHE r-l rM tendon OK OK OK five k * OK 0 0 0 0 0 H tendon 0 tendon OJ 0 0 stone SHE ol SHE OJ H m 0th OK OK · » OK OK 0 0 0 0 0 r-l cn tendon OJ cn Kű stone m • k cn tendon tendon OK "-SHE • k OK 0 0 rM r-l the co 00 cn ω co CM THE c- c- cn c- t CM 0 · OK OK OK • k OK 0 0 0 0 0 STONE

0 tendon tendon OJ 0 THE THE rM SHE 0 H SHE rM • k OK «s «s 0 SHE 0 0 0 cn 0 co 0 cn cn <n r-l t r-l cn cn 1-1 OK · » «1 ·. 0 0 0 0 0 cn 0 tendon kU SHE m cn 0 0 tendon Kű SHE ol 0 0 ol SHE tendon Λ OK OK OK OK She 0 0 0 0 OJ cn cn 0 cn cn η tendon cn cn ol cn cn CM · » OK OK OK OJ OK 0 0 0 0 0 stone

cn Kű 0 co co cn tendon ol t t tendon Λ OK OK OK OK She H 0 0 0 OJ H cn cn cn Kű Kű cn H cn tendon tendon tendon · » OK OK OK OK • k 0 cn 0 H rM OJ H cn 0 0 cn σ \ cn cn OJ CM m THE H OK OK OK OK OK OK 0 0 0 0 SHE cn

ra cn «1 in to to the <n 3 0 3 in you you n 01 OOJ 0 co οχ) 0 0 to 0 0 CM 0p 0 r 0 years lake 0 O rl O -rl Ο -rl 0h OQ 0 lakes ⁰ P 0 «tí cn Ο · 0 0 0 H B O CQ 01-1 cn Ο T-i 0 r H H H H S cn H gCM Ο · Η H ra >> to > j > s «01 Íkti'J ^- o H Λ tí Λ tí X3 «(DH xl aj cn he ra A aj h The aj A ω Your A'tí CM ra 0 «5 Λ ali M ra ρ Grinding aJ H p aj • P 30 + »Vol • P 3 + »AH p ra W «Η ca ra ca ra ca aj h ca aj £ 5

-11HU 199481 B r-1

CM

CT \ i-l ra rí

Antibacterial spectrum MIC / jag / ml / ^ / ^us Compound / Example number /

C— r

KO rí in ι — I cn rí

CM cn ra cKO in tó o

E • rl μ

-Φ • P Lake ¢ 0

J3 ι

o • rl

E x>

while μ

φ «4 yrs

the

Ή taO β

o • P bfl §

ι §

SHE

oo to She to cn She to co to tendon · t * CM t (Λ CM She t t She * 1 k • k «s «s • k • k «s • k k She She She She She She She She She She tendon STONE STONE STONE STONE cn tendon tendon <n cn CM tendon tendon tn tendon cn CM CM r-1 <n «s «s ·. «s • k • k TFK «s r • k STONE r-1 rí 4-r r-l She STONE STONE cn She cn tendon tendon She tendon lf \ tendon rí cn <n cn CM CM rí SHE She She She cn rí cn SHE V? k * * • k • k «s • k ' OK • k STONE She She She She She She cn She She tendon tendon tendon She tendon She She CM to tendon STONE CM CM CM SHE rd rí She c- CM tendon SHE • k k * • k • k • k «s 4k • k • k vo She She She She She She STONE rí She She tendon She She STONE STONE She rí SHE rí CM tendon tendon Ri • k • k • k • k 1 V? rk «s She She She She She H tendon r-l She

tn cm

LA LA She She cn to to tendon CM r4 She SHE rí <n c- C- SHE • k V? • k • k «s 1 • k • k «s • k m She She She She She She She She m cn She cn cn to to to tendon rí cn CM cn <n C- t She • k «s • k k * 1 • k «s k * cn She She She She She She She She to t She CM to c ~ - She CM She rí cn rí tendon CM tendon She rí • k • k • k <k • k «s n k «s She She She She She She cn STONE CM She tendon r4

LA Ό cn to She to LA cn She rí She She 0Λ STONE kU δ OJ cn She SHE rí She r-l tendon tendon She * » • k ♦ k Λ • k «s STONE She She She She She cn rí Ri She vl vl tendon tendon m tendon to CM CM tendon tn rí She cn σ> CM t She SHE She She SHE CM cn CA She k * * «s · * • k «s «s • k She She She She She She She She She She tendon tendon tendon tendon tendon She She CM cn to CM CM SHE She <-1 Ri SHE cn 4-r t She • s «s * • k • k V? «s Μ k * kU She She She She She She cn She She cn <n tendon tendon tendon cn <n rí rí cm CM CM She ιη She rí She She SHE SHE SHE rí CM rí She »k · * ·. «s #k • k • k • k cn She She She She She She STONE She She cn cn tendon tendon cn cn cn rí rí CM CM rí She She She rd cn She SHE SHE SHE She rí CM CM She · * • k r • k • k • k • k • k • k • k She She She She She She She She She She

tendon

M · • rí • rí • rl cn STONE rí rí β τί CM '· D SHE SHE CD Φ tí co cn SHE SHE THE She b0 3 σ \ CG β Ph H CM the) the) pi • rí P u> co you Φ Φ P • P Η Ό 0) fl) p • • P pH • rí YOU CD φ β Ά Φ ιή the you Ri + » rí She IQ SHE Z Jh cm XI rí CD rí ΦΝ β Ο > ο G) OG ι — 1 X) • rita lake Φ CD O | She rí • rí ri (Q ri ιη ο QoTi r-4 you rí KO β Λ Φ •STONE •STONE Φ β CM Φ τίΚΟ 09V (£ 4 rl H A rO • CM SHE Φ She the) Ski> -3 ski cn • rl O O • ρβ'ί 3 ri you r4 Co r4 SHE β ri β b0 Ski She Φ ΦΚ0 (Q 3 KO Φ o Φ fl) CO 0 you 3 Φ She Φ CD Λ too XlCM ja the dou -Ρ U 4-> σ> She Φ o «Ρ Φ O P Ski + » She o him She Φ Φ H Ski ou Ο U Ο Η H CU Pc • rí β Ρ » the Φ prl H on it rí β o ο β Ei β Εί Ρί ο UChH w CD W o SS wV Who ftPí ΑΧ »« 4 Ρί <4

-12HU 199481 B r-l

CM cn t-l oo r — l

H

S * h £ Lake — Table I / Continued / ü

the §

β • P

Öl m

CQ • H r-l

NTF

-rl β

Φ • P £ 1 • rl

-P

OS ε

'lake

There is no μ

o ra a $ • Ö r-l 'Φ • p φ

r-l lake faithful £

bo

I o

μ • rl

S

Λ

O β

Φ

VO in rl cn r-l

CM r — l

Cn co

MO in

M0 tn o cn cn tendon H CM cn cn * «K ·» • k • k r4 m o She She tendon cn cn stone CM m r-l tn • k · * k * VO in O cn r-l CM tendon tendon co in cm cn CM lake CM O cn She • k * * k - She M0 O She She tendon cn in cm 00 tendon m CM O lake She • k · »· * · * • k She VD O She She cn in cn She cn CM o <n i-1 • k «K * k k * She MO O She She 00 cn in cn tendon lake r-10 m SHE «s • k «k k * • k She cn O She She M0 in O cn She tendon CM r-l cn r-l * » * k <K k * • k rh M0 O She She 00 m She lake tendon ι-1 CM Λ «« k * She CM 1 cn She r-l CO <n She cn tendon She 00 She CM in o lake She k * Λ * k - • k M0 CM O She She r-l v) tendon tendon cn cn cm She CM cn r-10 r-l SHE * "K" v * • k She cn o SHE She She cn m She tendon CM r-l o CM SHE • k • k ·> k * »k She cn o She She tendon tn She CO CM She r-f r-l lake o She • k • k * k • k She o o She She tendon tendon She CO CM She CM CM lake o r-l She * · * k * k ·. · * She o o She She tendon cn M0 CM r-l

cn <4 m to φ needle Φ β to β the She ο ε β Β She Ή ο τ » loyal 3 3 3 φ μ Φ to Φ η Pi Φ ΡΜ

faithfully 3 CM μ

Q ra Pm tö H β

O T- |

Β μ

Ο φ T) N 3+ »Φ 3 ra +»

CM OJ ra ö oo û CM • rl OkO

-p ocm ai Φ H μ o φ cd Pm w EH

H a • rl cn μ cm 3 in B CM • H rM ΒΛ 'á & g cq-ph aj r-l' r-l

Φ β

SHE

-13HU 199481 Β

ΝΟ cs ιη cs Φ cs η «ι Μί Ρ

tendon CN ANCESTOR She She Q She cs cs She cs rd rd CN CN rd rd * * ·> * * * SHE She She She She She d cs

US ANCESTOR WOMAN ANCESTOR co co tendon SHE rs tendon cs C- C- CN THE k * * SHE She rd She She She stranded segment

US She WOMAN She co co US She CN US 01 c- t * CN tk • k w «s • k * * She She rd She She She WOMAN

tendon

CN o

tn ε

ρ

Ρ α>

Ρ α

ο • Η

Ρ 'β • Η rf

Φ

-Ρ ϋ

φ fi • Η

-Ρ cs cs α:

§ ν * 3 cs a Q * <ο 03 r-1 Φ CS Ό rd ND CL

-P O Φ CS rd

O >>

ω

Φ>

> ·

OJ \ D

CN in

CN * 4 "

CN bO

CN

CN

She She WOMAN SHE 00 co cs CN CN US CN t c- rd «s · » «s • k * * She She rd She She She rs

O in

ιη Ο ANCESTOR ο ANCESTOR ANCESTOR US WOMAN Ο CN cs id cs cs CN tendon * * «s «s * * Ο ο ο ο ο She WOMAN rd

US ANCESTOR 00 She ANCESTOR ch She rs ί- cl cs cs US • k «s · » * She She ο She She She CN rd

rs rd

CS

US CN tn ANCESTOR US She She cs WOMAN She She cs She cl CN id US 0k *. • k ·· • * · She She She She She She cs id

ANCESTOR WOMAN WOMAN US US CS US US US CN CN * * • k * · » She rd CN rd WOMAN WOMAN rd

O in

O in

CO cs WOMAN CS cs cs c- rd tendon rd rd rd US «s * «· * * " She cs rd cs d d US CN __1

CO US WOMAN US US c- CN US US CN CN «« ·> V? • k * She WOMAN CJ rd WOMAN WOMAN She id She id YOU WOMAN US WOMAN cs CS cs US CN US rd rd «s k * * V? * She rd WOMAN rd cs CS US

CM

tendon She ANCESTOR She ANCESTOR She cs She CN cs CM CS CN rd «s "* fk * * SHE She She She She She d

• rd rd • H

-P fi = S w

ra a σ »P {—í PCI -H

O H ÖO fflft ra o

o o <

O AP o Pm I P O >> ra> - □ Λ 3 ft m (Ρ aj rf os p 3 O m ctM

03 US 03 to 3 US 2 3 CCO £ ü Ο OCN O-P o ra SHE Ο «rí Ο Ρ ο pi o e ο Pd o you o co Ο -rl σι rd rd ρ Β σι >> W > 3 n > irfCJ Λ 3 Λ 3 Λ Φ Ρ Φ & Ο "Φ ο, Ρ - Φ M Φ (4 flj · Η Ο -P 3 • ρ ο • ír Clipboard CO Φ co Φ Μ ΦΗ

ra o

□ m a P o iá OP P HCl>? RfMjf φ σι PiP CM Λ Ή -P fttó m φ b d

P

CT>

ci oi gg o

ο α Óid O rd M Φ φ O • P 0>

α φ

W <H o

Write

Ϊ4

Ό «Ρ <Ö £ 2 i>

• H • P

Φ φ

G

I o

in

CN cs cs cs rd o oa (r 0) H 3

Φ 09 bO-H Ή rd rd Φ Φ O Ο Φ

Φ freundii IPO 12681 0.10 1.56 0.78 0.78 0.20 0.013 0.05 0.10 0.20 0.20 0.20 0.20

-14HU 199481 Β cn m

Γλ r-l

Μ σι η

ι — ι cn

-ρ s α} m «« ι Ό) -ρ γ4 0 42 -Ρ Ό (> »• Ρ Η

Ο • <Η hK.

α · φ

Ο <η ρ

φ

-Μ> 5

Μ ι £ ιοί νθ

ι ο

μ

J4

Ο

Η α

ε

Ν • Η

Ö ctf

W

Η ο

ιη ο Ο ιη cn σ \ ω ιη CJ ω Ο Η ι-1 ο ρα ρα c- Ο t »k * » * * Ο Ο ο ο ο ο ο ο ο ο σ \ ο ο VP ΡΑ ιη GEAR γΜ cn γΜ Γ-ί tendon ιη Γ-1 Ο ιη * < V? V? • k • V? * Ο ο Ο Ο γΜ CM ρα ο rM

Ο ο ο ο ω ρα ιη C0 rM ΟΙ 04 γΜ Ε- rM ο t V? V? »> * • k ο ο ο ο ο ιη ΡΑ ο ο

ιη ο ο ο C0 μο ιη cn Ο OJ σι Η C- ιη Ο ΡΑ V V? • k · » * * ο ο ο ο Ο ιη γΜ ο ο

σι

ιη ιη tendon CJ σ ο CJ cn GEAR artificial CJ cn Ο Η rM Ο ΡΑ ιη tendon SHE PA V? V? ν> * · » * · • ο ο ο Ο ο γΜ rM She She ιη ιη tendon CJ m ιη CJ ο ΡΑ cn CJ She ο ο ο ο σι Η PA She CJ V V? V? ν » · » * ο ο ο ο ο ρα She She She ΓΟ ιη tendon cn ΡΑ ρα Μ3 GEAR ο rM γΜ Q ο GEAR She SHE tendon ο Ο Ο Ο r-l ιη r-l SHE She V? V? V? (k F * · * ο Ο ο ο Ο rM She She She ο C0 ca ΡΑ She PA σι σ- rM tendon σι rM V? 1 k *> • k ο ο ο ΡΑ tn CM She PA CM H

She ca CO She PA tendon cn tendon σι c- c- CM rM tendon σι PA CJ V? • k v. · » »· * SHE She She She PA CJ rM GEAR She artificial

UA ca ca cn PA SHE PA PA c- c- PA rM rM rM V? • k • k · » • She She She She PA She tendon She cn She CJ

r-l

CO PA MO co tendon cn PA P- rM tendon 0 CJ tendon PA rM • k k. V vt • k ·· She PA rM She artificial She σι She PA

ιη ι-Ι

She She She tendon σι cn MO co tendon GEAR She GEAR rM rM rM SHE PA tendon σ- SHE tendon vt v> V? vt · * ·> * She She She She She rM She She rM

tendon

cn CJ artificial • e cn • H rM SHE She • rl rM SHE SHE <! Q G) She • H SM Φ month K • H μοο aj cn cn μ t b CJ PH Ή • P TTFC << Φ S QJ you OJ • P P rM WORK 2 P P p * · • rt • H 3 ® at p, φ in β aS She 03 O Λ cm Λ r-l Gl r-l Olt- Sho > o 3 rounds you φ Ctf o I She r-l Ή r-l 03 r — l tendon ü □ o .Ω G-O Φ •MONTH RLO ai F1 CM G) -rtkO ra <· ro Em ε ö SHE φ O j μ μ pa • rl Ο O OH 3 << ' Oh k tsO μ □ Φ Omu co Bkű Φ o ^φ rx φ 3 OO <y Ο Φ She main Λ CM 42 3 -d Uh Fri p cn 3 3 p b P She o W ü a) a »H F | Ο O ο o O rM ® μ g G> Ö r ro H ro lake r-l û o Η Η E4 μ em μ X oh yeah lake <s « She WJ2 < P4 P <« «42 <C PM <! PM O «0

-15HU 199481 Β cû cn tn cn

-4cn

'al Ρ íri CÖ -Q P> »rri

SHE

kh

She j H S S Ό1 N H ta 3 SH SH She -P x ta Φ 0) P •She m RRI 'Φ ta P ' • ri r — 1 '01 -P • ri <D SH RRI Φ 23 P 3 >> bO Φ GOOD • ri P >.

rri cn

G>

cn

C-

CM's

CM tn

CM ri ·

CM t ȣ> CM

CM s§ • rl S S N • rl §

bO

IH o

tendon She cn She CM 4-r <n r4 rf <* rf "* Kű She She She tendon Kű tendon She (ri rf rf rf CM 1 r4 She r-l tendon co She CM 1 l- (ri rf rf rf Kű She She tendon 00 She CM 1 c- • ri w rf rf kU She She m She cn tendon CM r-i RRI cn SHE ·. rf rf rf cn She She She Kű tendon CM She tendon CM tendon She CM SHE rf rf rf (ri She She She She m m She tendon tendon Kű SHE CM She SHE She rf rf rf rf She She She She She cn cn CM r-l cn rf rf rf tendon She <n She CM co stone co t m c- rf rf rf She She r4 She tendon cn She cn rh CM rf · * rf She She She tendon 1 Irish\ CM co [τ- tendon Kű ο CM tendon She co SHE CM RRI c- RRI rf rf rf rf 10 She She She

She tendon tendon cn cn Kű CM CM RRI g m ra § s <ö φ Φ H to 0) vol Ρ yrs P PCD rri 'ri 0 \ o o O'ri al φ ri · (ri PCM e p B SH • rl Oku φ sin O-ri Ο Φ • P he cm P SOM ti bO • tí ts 01 Φ rri Ο t4 rH ρ tí 3P P She Φ p ra φ Φ tíra -p P Φ • dig PH Φ PH ra w SH WP H

-16HU 199481 B <n <

co • MΌ st

cn r Ί * » ΠΛ ιη (Μ Α κο ιη 04 pH ιη CM KD ιη CM r-l ιη Α 04 r-l ο ο Η ιη σι <η ο cn 00 ιη ο ΠΛ cn Μ m Ο- CM * Α THE THE THE THE Α ο ο ο ο ο ο stone

1 «Table / continued /

Aerobic Micro-Antibacterial Spectrum MIC / _z ug / ml / organism / yUg Compound / Example number / in 't

Mst cn st r-l st

O st cn cn co cn

Οπή ο

i • Η

Ό) + »cd>

Ή

Ρ

Ή

Ν

Ο ι

ιη C0 σι σι co cn tendon ο C- cn cn c- cn CM Α Α Α THE THE THE THE ο ο Ο She She She stone cn κΟ cn co cn <n cn ιη Η 0 r-l r-l THE Α Α THE THE THE Ο r-l cn She cn cn She tendon ιη 00 cn cn co cn Ο ο- m cn 0 cn tendon Α Α THE THE THE THE THE ο ο ο She She She 04 r-l ο C0 co cn σι σι tendon Η C- t cn cn cn 04 THE THE THE THE THE ο ο She She She She STONE

tendon cn cn cn cn cn tendon SHE <n cn cn <n cn CM THE THE THE THE THE THE THE She She She She She She STONE (Λ tendon tendon tendon tendon rd 04 CM CM CM tendon THE THE THE THE THE THE cn Lu STONE STONE STONE CJ SHE rd SHE

γΗ

She Kű co co stone 00 H tendon C- She- tendon r- tendon THE THE THE THE THE THE She rd She She rh She CM rd

ιη

04 σι co cn cn SHE <n e m <n cn tendon THE THE THE THE THE THE THE She She She She She She CM rd

co

She She σι She She cn cn She cn CM rd m <n tendon THE THE THE THE THE THE THE She She She She She She CM VI rd co STONE co 00 00 She r-l She She tendon She SHE SHE She She 04 She cn She SHE She She SHE She rd THE THE THE THE THE THE THE She She She She She She cn VI VI vi VJ

cn cn rd st OJ 01 oh in Φ 01 03 cn 3 3 in 3 3 3 04 H She O CO «43 She She 01 SHE ο O CM a + » O 01 O CQ 3 lakes PM o <J She O Ή Ο · Η O -rl o 3 Ο O r-l o lake ancestor ο Ό cn O * O She CQ 01 OP4 1 ancestor She & OrICTi O -rl O 01 3 'rl r-10 r-l rh r-l Β σι H S 04 O -rl r-l r4 > »Ra n> > »01 > »M > »RCM > »0St Ο H H-H Λ 3 Λ 3 43 0 43 Φ r-i 43 Φ cn CD rl P Ρ.Φ Ph Q, φ Ο.Φ ftrd 0.OCM Φ o a x> cd μ cn 0} Jh a) μ ed Ή o cd Ή -Ρ Φ com} 3 • P 30 P 3 P 3 • Ρ P.P4 + ³ 0 Lake 0 cd ffl m KI fi) CM W cd W fi} KJ ΦΗ W Φ g

-17HU 199481 Β rH

C bC 'cd ρ rH cd fi ρ' cd >> • Ρ H o • 'P

Η N.

SHE

H a

ε

'H

P

-M ra cM ta ra • H rH 'cd • rl

'H

Φ • P aj

JO • rl cd §

'3 in

ÍH o

ra cd

Ό rH '0

Pl CM <P 0) r-I. • 3> »bO ra í>

bO ra

I id bO

ÍH o

ok <

co

M · k in in <

• 3 · • 4 · m

• 4 rH • 4

SHE

-4 ^-

OK

ΙΛ

CO m

c— cn

32 OK ÜK CO stone OK WOMAN <A m c- tendon (Λ THE rh flk • k • k • k k • k k * SHE She She She rh She rh She She tendon rh σι ÜK ÜK OK She WOMAN tendon m r-l m ck m m rh THE CM rh • k «s #k • k k * • k «s ·. cn She She She She She rh Kű m Kű She She She She tendon CO UK Kű tendon rh rh CM H SHE C * - m tendon 0k • k «s • k • k «s • k «s k * r-l She She She She She SHE She rh She tendon She She She cn CO THE rh SHE CM CM rh (THE tendon c- • k • k • k • k «s • k • k • k · * CM She She She She She She CM She r-l rh stone She She She She tendon UK OK Kű tendon CM rh CM CM She m cn tendon • k • k «s • k • k • k k k «s rd She She She She She She She rh co She She She She tendon OK OK CO t rh I-1 rh rh SHE <K * m e «s «s • k • k k * «s • k • k She She She She She She She She She tendon tendon Kű tendon CM tendon tendon CM OK OK OK tendon SHE SHE SHE SHE SHE m »k • k • k «s • k • k • k r-l She She She She She She She She UK She co co OK <n m m rh t C- <K * rh rh • k «s • k • k • k «s «s She She She She She She m tendon m LA CM THE She She OK ÜK She stranded segment vo cn CNJ CM rh m CM tendon tendon rh • k • k et • k • k • k k * • k ·. stone She She. She She She F-H rh m tendon tendon CO tendon co co CM WOMAN co m CM t SHE t C-- She THE c- rh «s • k «s • k • k • k • k the. Kű She She She She She rh She m un tendon m m tendon ÜK tendon CM CM rh CM CM m CM • k · * • k * «s k * • k stone Kű <n Kű stone She tendon Kű tendon CM CM co She co She She She She m Kű tendon 24 tendon c- rh CM rh She rh tn CM She k * ·. • k k * • k 0k ·. k * • k S CM SHE She She She She rh Kű 3 rh vr • rl you ' » r-l rh -P rh CO tendon 24 rh Kű -4- -rl rl • H CD m CM ÜK Kű rh rh 'H X » rh rh CM -4 · SHE SHE CD to OK SHE Ο She bO s> She She 'H Ph íhcm • rl • P -rl Raph uh Ph to to CD CD CM -P • P + » ra H ra H -P • p Pd you tH CD ra O cd fi, ra in id you -P She m O £ 5 Λ CM xl rh cdkű rH © C- IHO bC ra ra □ -rl CD to CD Ο 1 She rh • rl rH CO rH tendon to BO-H CD rl .She you fi ra • Rho • rl O Φ TIH Φ -rkk ra Ί · you rl rH fi Ή She to o cd IH 'TO tím tH OO • p xd · * 3RL 1 Η Ö Oh, yes 'H bO t o o 0 Learn © 02 SPh ra o She <d o HH 3 to She ra id Xl CM Λ 3 Ό tí o P o § o ra p ra -P you • p o O SJ She Φ ra <í UH OO o o 'H rH cd • rl ÍH phi to tírH Rah ra Pd rh OQ o tendon EH Ü> <5h OCH W CD Η O WS wV W PiPh «X« «4 Ph <4

-18HU 199481 Β a

Ό · oo

-Φ

Η

Β

ν.

tt

WORKS IN

· Μ

«Ρ '' Χ. Cl 03 Ν 'Φ 'CO Ρ γ-1 lake JQ Ρ ^K CÖ > 1 Ρ Η Ο • Μ Η \

s a

fc p

ω ffl tn • rd rd 'Φ • rí fc

Φ

-P

Jd dS

Λ • rd • P

N <0 fc o

· Ό

Φ • d

H 'Φ

CL

-P

Φ

H

XS woe

Φ í>

etc.) a

also

Λ a o aj fc tt) © fc <í o

THE

Μ ^-

OJ dΟ • µ00

Α

C-

Α

00 THE THE THE c- H H THE • k 1 * k * Ο THE She THE She THE Α THE artificial artificial THE Α H THE THE THE • k • k - • k * ο THE She H H She THE ιη MD THE THE She Ο THE OJ THE H «s • k • k 1 «s · » ο r-l MD She She ο CO THE THE co She rd c- OJ SHE t H • k • k * - «s 0k Ο She MD SHE She She ο 00 THE She THE She rd c- OJ OJ THE OJ • k "* «s V? • k • k ο She MD She She She ο 00 THE She She rd 0 OJ 1 OJ H «s • k k * k * • k ο She VD She She Α THE 0J THE ΡΊ She She OJ Ο THE r-1 H H SHE «s • k • k • k • k • k Ο She cn She She She GEAR THE THE co Α H tendon 1 "1 0 • k k * • k I Λ • k Ri THE OJ CC She I-i ο MO vD THE 04 THE IT \ m THE • k • k n | • k ο H OJ H She H Α THE VD She Ο H THE tendon OJ • k « «s * » «s ο THE OJ 1 r4 She H Α THE THE rd OJ tendon OJ * » et k * k * THE THE SHE artificial CJ artificial CJ THE 4-r 00 Ο THE ο THE H co She ο OJ SHE c- OJ • k • k • k • k «s ο MD THE She She She VI OJ She THE THE THE « THE artificial • Η OJ ol fcOO H flj A THE bay bO C0 "4 SHE HMD lake 10 tD | x) B the dS a) Ancient td TDH lake aS a > ü a co .the lake the price H -rl A She o o o o OH the) φ «φ H fcOJ n Ed ε a s a S fc • rl Omu © aA the O · Η Ο id Ο φ • P Tooie a soy Φ rd bO d tt) • d ta dS Φ H O 'is H • P A a a a a the p fc SHE 2Λ OH φ fc φ fc φ a fc fco rd CUO FCH to Φ Φ Φ tn p Φ ro {«ι aS p »ffc PdO Pj a) ffc as Pd <0 to SH on-PH

-19HU 199481 Β

36

-20HU 199481 B

She She She co CO tendon CD tendon She She OJ She OJ OJ H co C ~ She C- OJ OJ rn ff fk ff ff ff ff ff ff ff ff She She She She She She She She She artificial She SHE

MD MO CO tendon LA cn cn σι co co K__ tendon tendon t OJ OJ co rd ro < "1 P · ff rd ff rd ff She ff MO She ff MO ff She m tendon ff She <n Ό

in oi

1 «Table / continued /

Ae r o b Micro- Antibacterial spectrum MIC Zug / ml / organism // Ug Compound / Example number /

MO in

Min co in ι-1 in o

tendon

CO MO σι cn cn cn SHE cn MO m _ » MO 1 c- tendon CO rd rd CD OJ rd tendon ΓΊ U » * ff ff ff · » · » * ff ff ff She rd She CO CO main She CO tendon rd <n CD

OJ tn co

MD co CO tendon She She σι cn <0 r J cn tendon SHE LA SHE She rd She co rd LA She rd OJ She j * · r - ff ff ff ff • k ff ff ff « ff u She She She She co rd She <n MO She ff She She

tendon co CO cn LA She She OJ CD cn CD r-l She <0 H CM H rd SHE 0 rd 0 She OJ LA SHE n Ό ff ff ff · * • k ff ff ff ff She She She She co She She She .rd She She SHE

She She LA σι co MD SHE co She 00 She OJ OJ She CO c- tendon rd c- tendon OJ * » rd ff ff ff ff ff ff · * ff ff ff She She She She She rd She She OJ She She She

ι-I

tendon LA tendon OJ She LA She tendon OJ She MO LA She tendon OJ She SHE SHE OJ CM OJ She OJ tendon SHE CM ff "* ff ff ff ff ff ff ff She She She She \ 0 She She She rd She SHE SHE

tendon

tendon She OJ She MO She SHE rd She OJ tendon OJ SHE She She She rd She MO MO She tendon CO LA tendon tendon OJ OJ rd OJ rd rd She MO CO MO

tendon OJ SHE SHE rd MO tendon tendon She She rd tendon OJ SHE ff SHE She rd She She She

cn LA co co CO OJ rj c ~ ff * She MO in i 1 She

OJ

ω 3 the} nd the} • H SHE to She SHE SHE CD She 3 SHE tendon N 3 She • H • H ε • H the co • P SHE RJ RJ rj 3 SHE • H OJ 3 to SHE □ SHE CD al CD δ C0 P 3 SHE SHE SHE She 60 β cn <O lake to She She lake • H • P 60 C0 <4 lake b a> CD 3 OJ p • -P HMO CQ cn to 3 -P • rl • H SALT 3 lakes CD in 3 3 the) 3 3 3 S " She Lake OJ lake HMD r-l 3 C ~ Oo She to SHE Q Yeah CO 3 O 1 She rd H m r-1 tendon She SHE She She She o cn 43 MO •MONTH •MONTH CD H CD HME cn Μ ^- extinguishing the SHE ε SHE GMD ^ • H Ο M · o0> Ö <O •MONTH p lake m- 3 r - 1 3 «4 Ο -H She Ή O OJ +5 OJ ö σι 3 ΦΜΟ CQ Lake 3 o CD <0 • 3 woman • 3 60 3 i-l gji-l CD OJ lake tofu 43 • d ö O Ρ o -ρ σι 3 3 3 3 3 + » h oto 3 CD <4 ö Ο O ο o OH CD She CD SHE 3 O TP Oto ca H O lake MONTH oh lake Oto ? H CQ CD Q 3 etch 3 lakes Tos "5 HB MTO fflx> <4 Lake <4 TOO lake 3 lake 3 Toh CQ M

ε • rl

Ancestor

• rl pond lake

-Ρ σι CÖ CM rHin 1-1 OJ <D r — 1 ö

OO Stó r — 1 H 3 CQ

-21HU 199481 Β

Table II

Anaerobic microorganism Antibacterial spectrum MIC / µg / ml / Test compound / example number / · 5 30th Bacteroides fragilis ATCC 23745 0.78 0.20 Bacteroides fragilis MR 2579 3.13 1.56 Bacteroides fragilis MR 2562 0.78 0.39 Bacteroides fragilis MR 2583 0.39 0.10 Bacteroides fragilis MR 2584 0.78 0.78 Bacteroides distasonis MR 2578 0.78 0.78 Bacteroides thetaiotaomicron MR 2588 1.56 0.78 Bifidobacterium adolescentis ATCC 15703 0.39 0.10 Clostridium botulinum MR 2611 0.10 0,013 Clostridium perfringens MR 2612 0.39 0.10 Clostridium moniliforme ATCC 25546 0.78 0.10 Pusobacterium varium ATCC 8501 12.5 - Peptococcus prevotii ATCC 9321 1.56 0.39 Peptococcus variabilis ATCC 14955 0.78 0.20 Peptostreptococcus anaerobius MR 2743 0.39 0,013 Propionibacterium acnes ATCC 11828 0.78 0.78 Mycoplasma Mycoplasma hominis MR 2952 0.10 0.10

2. In vivo therapeutic efficacy

In vivo antibacterial activity of the pyrido [3,2,1-ij] -1,3,4-benzoxadiazine derivatives of the formula (I) prepared according to Examples 5, 30, 65 and 66 in Escherichia coli ML4707 Pseudomonas aeruginosa 4au542 and Streptococcus pneumoniae 6-001. ICR mice weighing approximately 20 g were challenged by intraperitoneal injection of the appropriate bak22 serum suspension. The test compound is administered g0 orally or subcutaneously, at the same time as the bacterial suspension is injected. Mortality was monitored for 5 days. The ED ₅₀ (mg / kg) is the dose that protects 50% of the animals from death by infection. The results are shown in Annex III. table includes:

-22HU 199481 Β

III. • In vivo antibacterial activity against mouse systemic infection / ΕΡ ^ θ, mg / kg /

Sakiérium

Compound E. coli ΜΙ4707 Pseudomonas aeruginosa 4au542 Streptococcus pneumoniae 6-001

sc PD po po Example 5 0.06 0.11 13.4 10.3 Example 30 0.10 0.62 57.0 65.9 Example 65 - 1.12 - - Example 66 - 0.51 - -

3. Acute toxicity

Nos. 5, 6, 7, 16, 17, 18, 30, 36, and 56. Compounds of formula (I) prepared according to Examples 1 to 4 have an LD ₅₀ of more than 2000 mg / kg. Acute toxicity in ICR mice was determined by oral administration.

The compounds of the present invention exhibit antimicrobial activity against a broad range of Gram-positive, Gram-negative bacteria and mycoplasmas. The compounds are particularly effective against microorganisms resistant to various antibiotics (e.g., penicillins, cephalosporins, aminoglycosides, tetracyclines, etc.).

The novel compounds of the present invention exhibit low toxicity while having strong and broad antimicrobial activity. The compounds of formula (I) exhibit greater protective activity against systemic bacterial infections in mice than commercially available synthetic antibacterial agents. Therefore, the compounds of formula (I) can be used effectively in medicine by Gram-positive and Gram-negative bacteria and bacteroid microorganisms. for the treatment or prevention of disease caused by humans in veterinary and veterinary medicine.

With the compounds of the present invention, e.g. treating and / or preventing diseases caused by one or more of the following microorganisms: Staphylococcus, Streptococcus, Aerococcus, Enterococcus, Micrococcus, Lactobacillus, Bifidobacterium, Clostridium, Eubacterium, Peptococcus, Peptostreptococcus, , Klebsiella, Proteus, Pseudomo30, Serratia, Salmonella, Shigella, Vibrio, Aeromonas, Haemophilus, Neisseria, Acinetobacter, Alcaligenes, Bordetella, Bacteroides, Fusobacterium, Mycoplasma and other microorganisms.

The present invention also provides a process for the preparation of a pharmaceutical composition comprising one or more compounds of formula (I) or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

The pharmaceutical compositions may be administered orally or non-orally in human and veterinary medicine using conventional administration methods.

In addition to the active ingredient of the formula I, the pharmaceutical preparations contain customary auxiliaries, liquid diluents, binders, lubricants, wetting agents and the like. contain. The active ingredient50 got e.g. tablets, granules, granules, sugar coated tablets, pores, capsules, gels, dry syrups, ampoules, suspensions, liquids, emulsions, ointments, pastes, creams, suppositories, etc. or in the form of other conventional pharmaceutical compositions.

The pharmaceutical compositions may further contain dissolution delaying agents, absorption accelerating agents, surfactants, and other conventional additives.

The pharmaceutical compositions of the present invention may contain one or more of the active compounds of Formula (I) in an amount of about 1 to about 10% by weight of the composition. Preferably from 0.5 to 95 wt% in ⁶⁵ - - 0.1 to 99.5% by weight.

-23HU 199481 Β

The pharmaceutical compositions of the present invention may, if desired, contain one or more other pharmaceutically active substances in addition to the active ingredient of formula (I).

The daily dose of the compounds of formula (I) will depend on several factors (type of human or animal being treated, body weight, severity of the disease being treated, etc.) and will generally be about. 0.5 to 500 mg / kg body weight, preferably about 5 to about 500 mg / kg body weight. 1 to 300 mg / kg body weight.

The following examples further illustrate the process without limiting the invention to the examples.

Preparation of Starting Materials Reference 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 in the presence of 60 mg of 5% palladium on carbon for 6 hours. The reaction mixture was filtered under nitrogen and the filtrate was concentrated in vacuo. 414 mg of crude 2-amino-5,6-difluorophenol are obtained.

b) A mixture of 414 mg of the above amine and 618 mg of ethoxymethylenemalonic acid diethyl ester is heated under nitrogen at 130 ° C for 5 minutes. The resulting crystalline residue was triturated with ethanol and filtered. 590 mg of diethyl ester of 1+ (3,4-difluoro-2-hydroxyphenyl) aminomethylene malonic acid are obtained. 178-180 ° C, MS m / z: 315 (M ⁺ ). After chromatography on the mother liquor on a silica gel column, elution with 20: 1 chloroform-acetone gave an additional 59 mg of crystalline material.

Preparation of 8-benzyloxy-6,7-difluoro-4-hydroxy-3-quinolinecarboxylic acid ethyl ester (method 1)

c) To a mixture of 80 mg of N- (3,4-difluoro-2-hydroxyphenyl) aminomethylene malonic acid diethyl ester, 70 mg of anhydrous potassium carbonate in 1.5 ml of anhydrous dimethylformamide, bromide was added. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo, the residue was dissolved in dichloromethane and the precipitate was filtered off. The filtrate was washed with water, dried over anhydrous sodium sulfate and evaporated. The 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, m.p. z: 405 (M ⁺ ).

d) A solution of 280 mg of malonate prepared in the preceding paragraph and 2.8 ml of diphenyl ether is heated at 250 ° C for 30 minutes under a nitrogen atmosphere. The reaction mixture was cooled and the ethanol formed in the reaction mixture was removed in vacuo. The dark brown solution was applied to a silica gel column (10 g) and eluted sequentially with benzene, dichloromethane and 30: 1 dichloromethane / acetone. The pure fractions were combined and the solvent removed in vacuo. The crystalline residue was washed with a mixture of n-hexane and ethyl acetate. 90 mg of 8-benzyloxy-6,7-difluoro-4-hydroxy-3-quinolinecarboxylic acid ethyl ester are obtained. Analytical purity of the product by recrystallization from methanol melted at 200-201 ° C, MS m / z 359 (M +).

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

To a solution of 6,7-difluoro-4,8-dihydroxy-3-quinolinecarboxylic acid ethyl ester (300 mg) in anhydrous dimethylformamide (6 ml) was added 308 mg of anhydrous potassium carbonate followed by 145 μΐ of benzyl chloride. The reaction mixture was stirred at 55-66 ° C for 11 hours, then diluted with water (30 mL) and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (7 g) and eluted with 1:20 acetone / chloroform. 113 mg of 8-benzyloxy-6,7-difluoro-4-hydroxy-3-quinolinecarboxylic acid ethyl ester are obtained, m.p. 200-201 ° C, MS m / z: 359 (M ⁺ ) after recrystallization from methanol. .

Preparation of 8-benzyloxy-6,7-difluoro-1- (N-formyl-N-methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid ethyl ester

e) A mixture of 410 mg of 8-benzyloxy-6,7-difluoro-4-hydroxy-3-quinolinecarboxylic acid ethyl ester, 315 ml of anhydrous potassium carbonate and 10 ml of anhydrous dimethylformamide was stirred at room temperature for 3 hours, followed by mg of O- (2,4-dinitrophenyl) hydroxylamine are added. The reaction mixture was further stirred at room temperature

After stirring for 6.5 hours, the solvent was removed in vacuo. To the residue was added water (12 ml) and the mixture was stirred at room temperature for 3 hours. The precipitate is filtered off and washed first with cold water and then with ether. 405 mg of ethyl 1-amino-8-benzyloxy-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid are obtained, m.p. 143-144 ° C. MS m / z: 374 (M ⁺ ). An analytical sample of the product was prepared by recrystallization from methanol.

f) To 1.51 ml of acetic anhydride at 0 ° C is added 0.60 ml of 98% formic acid. The mixture was stirred at 0 ° C for 15 minutes, then at 50 ° C for 15 minutes and finally cooled to 0 ° C. To the solution is added dropwise a solution of 400 mg of the amine prepared in the preceding paragraph and 2.1 ml of 98% formic acid. The reaction mixture was stirred at room temperature for 2 days and then concentrated in vacuo. The crystalline residue is recrystallized from ethanol. 410 mg of ethyl 8-benzyloxy-6,7-difluoro-1- (formylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid are obtained, m.p. 188-190 ° C. , MS m / z: 402 (M ⁺ ).

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. Methyl iodide (0.19 mL) was added and the mixture was stirred for an additional 2.5 hours. The solvent was removed in vacuo and the residue partitioned between chloroform and water. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue was from ethanol

-24H 199481 H ⁴⁵ recrystallized. 335 mg of ethyl 8-benzyloxy-6,7-difluoro-1- (N-formyl-N-methylamino) -4-oxo-1,4-dihydro-3-quinoline carboxylic acid are obtained, m.p. >. ·. 180-181 ° C, MS m / z: 416 (M ⁺ ).

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

h) 330 mg 8-Benzyloxy-6,7-difluoro-1- (N-formyl-N-methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid ethyl ester 50 mg 5% In palladium-on-carbon catalyst, 14 ml of chloroform are hydrogenated for 4 hours. The reaction mixture was diluted with methanol (14 mL) and filtered. The filter cake was washed with 1: 1 chloroform-methanol. The combined filtrates were evaporated and the residue was recrystallized from ethanol. Ethyl ester of 6,7-difluoro-1- (N-formyl-N-methylamino) -8-hydroxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (239 mg), m.p. 221-225 ° C (dec.); MS m / z: 326 (M ⁺ ).

i) A mixture of 210 mg of the above ester and 5 (2 ml of 0.5 N sodium hydroxide solution) was heated at 100 ° C under nitrogen for 2 hours. The reaction mixture was acidified with 0.16 ml of acetic acid. The resulting precipitate was filtered off, washed with water and vacuum After drying, 168 mg of 6,7-difluoro-8-hydroxy-1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid is obtained, with an analytical purity of 248-250 by ethanol recrystallization. M.p. (dec), MS m / z 270 (M ⁺ ).

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

105 mg 6,7-difluoro-8-hydroxy-1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (compound prepared according to reference example (i)), 150 mg A mixture of paraformaldehyde and 5 ml of anhydrous dioxane was heated at 100 ° C under nitrogen for 3 hours. The solvent was removed in vacuo, and dimethylformamide (20 mL) was added to the residue and the mixture was stirred for 20 minutes. The filter cake was washed with dimethylformamide and the combined filtrates were evaporated in vacuo. The residue was triturated with water and filtered. 97 mg of the title compound are obtained. The product of analytical purity by recrystallization from dimethylformamide melts at 290-292 ° C (dec); MS m / z: 282 (M ⁺ ).

Example 2

Preparation of 9.10-Difluoro-2,3-dimethyl-7-oxp-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid mg, Reference Example 6,7-Difluoro-8-hydroxy-1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid 46 (1 ml, 90% acetaldehyde) of dioxane (100 ml) was stirred at 100 ° C under nitrogen for 3 hours. The reaction mixture was concentrated in vacuo. 52 mg of the title compound are obtained, m.p. 285-289 ° C, MS m / z: 296 (M +).

Example 3

9.10-Difluoro-2- (hydroxymethyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6 Preparation of the carboxylic acid mg, 6,7-difluoro-8-hydroxy-1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, prepared according to the reference example (i), 45 μl. A mixture of glycolaldehyde diethyl acetal and 7 mg of pyridinium p-toluenesulfonate in 2 ml of anhydrous dioxane was heated at 110 ° C for 5 hours under nitrogen. The solvent was removed in vacuo and the crystalline residue was washed with water and methanol. 52 mg of the title compound are obtained, m.p. 254-258 ° C (dec.), MS m / z: 312 (M +).

Example 4

9.10-Difluoro-2 - [(dimethylamino) methyl] -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine Preparation of -6-Carboxylic acid p-toluenesulfonate mg of 6,7-difluoro-8-hydroxy-1- (methylamino) -4-oxo-1,4-dihydro-3- prepared according to the reference example (i). A mixture of quinoline carboxylic acid, 37 mg dimethylaminoacetaldehyde dimethyl acetal, 53 mg p-toluenesulfonic acid monohydrate and 2 ml of anhydrous dioxane was heated at 110 ° C under nitrogen for 17 hours. The solvent was removed in vacuo and the residue was recrystallized from methanol. 61 mg of the title compound are obtained, m.p. 232-236 ° C (dec.); FAB-MS m / z 340 (MH +).

Target products

Example 5

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

A mixture of 2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, 47 μΐ of N-methylpiperazine and 3 ml of anhydrous pyridine was heated at 100-110 ° C under nitrogen for 9 hours. The pyridine is removed in vacuo and the residue is recrystallized from methanol. 23 mg of the title compound are obtained, m.p. 268-269 ° C (dec.), MS m / z: 362 (M ⁺ ).

In a manner analogous to that described in Example 5, the following compounds of formula XX are prepared:

-25GB 199481 Β op Recrystallization MS m / z solvent

6 / 1 / 240-245 /boml./ MeOH 349 / MH ⁺ / ^X 7 / 2 / 237-239 /boml./ MeOH / CHCl? 362 / M ⁺ / 8 / 3 / 256-259 /boml./ DMP 425 / MH ⁺ / ^X 9 / 4 / > 300 EtOH / CHCl-j 349 / M ⁺ / 10 / Five / > 300 DMP 377 / M ⁺ / 11 / 6 / > 300 / bomb / DM? 365 / M ⁺ / 12 / 7 / 238-242 /boml./ MeOH 377 / MH ⁺ / ^X 13 / 8 / 256-258 MeOH / CHCl? 363 / M ⁺ / 14 / 9 / 272-274 /boml./ EtOH 413 / MH ⁺ / ^X 15 / 10 / 270-275 h ₂ o 393 / MH ⁺ / ^X 16 / 11 / 243-246 MeOH / CHl ^ 362 / M ⁺ / 17 / 12 / 242-244 /boml./ DMP 377 / MH ⁺ / ^X 18 / 13 / 251-252 /boml./ EtOH 391 / MH + / ^X 19 / 14 / 239-241 /boml./ EtOH 405 / MH ⁺ / ^X 20 / 15 / 266-268 /boml./ EtOH 365 / MH ⁺ / ^X 21 / 16 / 284-286 /boml./ DMP 350 / MH ⁺ / ^X 22 / 17 / 280-284 /boml./ MeOH / CHCl-j / Etgü 345 / MH ⁺ / ^X 23 / 18 / 220-222 /boml./ EtOH 391 / MH ⁺ / ^X

^X F4B-MS / µ * AB = Fast Atomic Mass Spectrometry /

Example 24

9-Fluoro-3-methyl-7-oxo-10- (3-oxo-1-piperazinyl) -2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine Preparation of -6-carboxylic acid mg, 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3, prepared in Example 1, 4-benzoxadiazine-6-carboxylic acid,

A mixture of 31.1 mg of 2-piperazinone, 31.8 g of 1,4-diazabicyclo [2.2.2] octane and 1 ml of anhydrous dimethylsulfoxide was heated at 130 ° C under nitrogen for 28.5 hours. The solvent was removed in vacuo. The residue was purified by preparative thin layer chromatography (silica gel; chloroform: methanol = 10: 1.5) and recrystallized from dichloromethane / methanol. 6.3 mg of the title compound are obtained, m.p. 300 DEG C., FAB-MS m / z: 363 (MH +).

⁵⁵

From the compounds of Examples 2, 3 and 4, the following compounds of formula XXI are prepared:

-26HU 199481 Β

Example number ^K • Cross-over container tank MS m / z dosing agent

25 / 1 / CH ₃ 26 / 19 / ch ₃ 27 / 19 / -CHgOH 28 / 19 / -ch ₂ n / ch ₃ /.

240-242 / borai./MeOH 362 / M ⁺ /

203-206

229-231 /borai./

210-212

EtOH 376 / M ⁺ / MeOH 393 / MH ⁺ / ^X

MeOH 420 / MH ⁺ / ^{X Σ} PAB-MS

Example 29

10- [3- (Benzyloxycarbonylamino) -1-pyrrolidinyl] 9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-lj] -1, Preparation of 3,4-Benzoxadiazine-6-carboxylic acid 9.10-Difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1 mg prepared in Example 1. 3,4-benzoxadiazine-6-carboxylic acid, 94 mg of 3- (benzyloxycarbonyl-amino) pyrrolidine and 3 ml of pyridine nitrogénatmoszférá heated at 100 ° C for 3 h with ¹ Ban. The pyridine was evaporated in vacuo and the residue was recrystallized from methanol. 36 mg of the title compound are obtained, m.p. 227-230 ° C, MS m / z 482 (M ⁺ ).

Example 30

10- (3-Amino-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine Preparation of -6-carboxylic acid mg of 10- [3- (benzyloxycarbonylamino) -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H prepared according to Example 29. -pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid

It is hydrogenated in 2 ml of dimethylformamide in the presence of 10 mg of 5% palladium on carbon for 4.5 hours. The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was recrystallized from methanol. 16mg

230 DEG-234 DEG C. (dec.), MS m / z: 348 (M ⁺ ).

In a manner analogous to that described in Examples 29 and 30, the following compounds of formula XX are prepared:

Example row- number R ⁵ R ⁶ N- op C recrystallization solvent MS m / z 31 / 20 / 286-288 /borai./ h ₂ o 363 / MH ⁺ / ³ 32 / 21 / 269-273 /boml./ MeOH 377 / MH ⁺ / ³ 33 / 22 / 240-245 / borai./ MeOH 363 / MH ⁺ / ³ 34 / 23 / 262-265 /borai./ MeOH 377 / MH ⁺ / ² 35 / 24 / 252-256 /borai./ EtOH 390 / M ⁺ /

^X FAB-MS

Example 36

10- (3,4-Dimethyl-1-piperazinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3; Preparation of 4-benzoxadiazine-6-carboxylic acid mg of 9-fluoro-3-methyl-10- (3-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [prepared in example 7]. A mixture of 3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, 1 ml 98% formic acid and 1 ml 35% formalin is stirred at 100-110 ° C. The reaction mixture was heated for 2 hours and then concentrated in vacuo. The residue was dissolved in water, 1N sodium hydroxide 27

-27HU 199481 Β

solution and extracted with chloroform. The extract was washed with water, dried over anhydrous sodium sulfate and the solvent was evaporated in vacuo. The crystalline residue is recrystallized from methanol. Compound 43mg of the title compound, m.p .: 257- 259 ° C FAB-MS m / z: 377 (MH ^4).

Example 37

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

100 mg of 9-fluoro-10- (3-hydroxy-1-pyrrolidinyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-lj] prepared according to Example 21. To a suspension of] -1,3,4-benzoxadiazine-6-carboxylic acid and 10 ml of anhydrous dimethylformamide was added 30 mg of a 60% solution of sodium hydride in mineral oil followed by 40 μΙ of methyl iodide. After stirring at room temperature for 2 hours, an additional 30 mg of 60% sodium hydride dispersion and 40 μ 40 of methyl iodide were added. The mixture was stirred at 45 ° C for 3 hours and then concentrated in vacuo. To the residue were added 2 ml of cold water and 2.3 ml of 0.5 N sodium hydroxide solution. The 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. The mixture was extracted with chloroform, the extract was washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The crystalline residue was chromatographed on silica gel eluting with acetone-chloroform (1: 9). 42 mg of the title compound are obtained, m.p. 233-234 ° C, FAB MS m / z 364 (MH +) (after recrystallization from methanol).

Example 38

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

9-Fluoro-10- (4-hydroxy-1-piperidyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,152

-j] -1,3,4-benzoxadiazine-6-carboxylic acid was prepared in a manner analogous to that described in Example 37. The crystalline product melts at 229-233 ° C (dec.). MS: m / z 377 (M ⁺ ) (after recrystallization from chloroform / n-hexane).

Example 39

10- (1,1-dloxido-4-thiomorpholinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrrolo [3,2,1-ij] -1,3, Preparation of 4-benzoxadiazine-6-carboxylic acid 9 mg of 9-fluoro-3-methyl-10- (4-pentomorpholinyl) -7-oxo-2,3-dihydro-7H-pyrido [3.2, To a suspension of 1-µL-1,3,4-benzoxadiazine 15 -6-carboxylic acid in 5 ml of dichloromethane was added 74 µl of 70% pure m-chloroperbenzoic acid. After stirring at room temperature for 18 hours, the solvent was removed in vacuo. The residue was washed with ether, dichloromethane, then chloroform-methanol and recrystallized from dimethylformamide. 22 mg of the title compound are obtained, m.p.> 300 DEG C., MS m / z: 397 (M ⁺ ).

Example 40

9-Fluoro-3-methyl-10- (4- (2-oxo-n-propyl) -1-piperazinyl] -7-oxo-2,3-dihydro-7H-pyrido [3,2,1- ij] Preparation of 3q -1,3,4-Benzoxadiazine-6-carboxylic acid 50 mg of 9-fluoro-3-methyl-10- (1-piperazinyl) -7-oxo-2,3-dihydro prepared in Example 6. A mixture of -7H-pyrido [3,2,1-ji] 3,4, 3,4-benzoxadiazine-6-carboxylic acid, 17 μΐ of chloroacetone, 40 μΐ of triethyl35-amine and 1 ml of anhydrous dimethylformamide at 80 ° C After heating for 3.5 hours, the volatiles were removed in vacuo and the residue was suspended in water, the resulting precipitate was filtered off and recrystallized from dichloromethane / methanol to give 32 mg of the title compound, mp 225-229 ° C (dec.). FAB-MS m / z 405 (MH ⁺ ).

In a manner analogous to that described in Example 40, the following compounds of formula XXII are prepared:

Example row- number R ⁷⁰ Op. C recrystallization solvent FAB-MS m / z 41 / 25 / 223-226 /borai./ DMF 467 / MH ⁺ / 42 / 26 / 273-275 /borai./ EtOH 377 / MH ⁺ / 43 / 27 / 255-257 /boml./ EtOH 391 / MH ⁺ / 44 / 28 / 257-259 /borai./ EtOH 395 / MH ⁺ / 45 / 29 / 256-259 /borai./ h ₂ o 407 / MH ⁺ / 46 / 30 / 236-238 /borai./ MeOH 389 / MH ⁺ / 47 / 31 / 275-276 /borai./ EtOH 484 / MH ⁺ /

-28HU 199481 Β

Example 48

10- {3 - [(N-Ethyl-N-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-3-methyl-10- {3 - [(methylamino) methyl) -1-pyrrolidinyl] -7-oxo-2,3-dihydro-7H prepared according to Example 17. Pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid and ethyl iodide were prepared in a manner analogous to that described in Example 40. The crystalline product melts at 210-225 ° C (dec.); FAB-MS m / z: 405 (recrystallized from (MH ⁺ ) - chloroform / methanol / n-hexane).

Example 49

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

Preparation of 2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid 9-Fluoro-3-methyl-10- (1-piperazinyl) -7-oxo-2,3 mg prepared in Example 6. -dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, 21.6 mg of succinic anhydride, 40 μΐ triethylamine and 4 ml of anhydrous dimethylformamide at 80 ° Heat at C for 2 hours. The solvent was removed in vacuo and the residue suspended in water. The precipitated product is filtered off and recrystallized from dichloromethane / methanol. 50 mg of the title compound are obtained, m.p. 257-259 ° C (dec.); FAB-MS m / z: 449 (MH ⁺ ).

Example 50

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

9-Fluoro-3-methyl-10- (1-piperazinyl) -7-hydroxy-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3 .

Prepared by reaction of 4-benzoxadiazine-6-carboxylic acid with acetic anhydride in a manner analogous to that described in Example 49. The crystalline product melts at 294-296 ° C (dec), FAB-MS m / z: 391 (MH ⁺ ) (after recrystallization from dichloromethane / ethanol)

Example 51

9-fluoro-3-methyl-10- [4- (3-oxo-n-butyl) -l-piperazinyl] -7-oxo-2,3-dihydro-7H-pyrido [3,2-ij] Preparation of -1,3,4-benzoxadiazine-6-carboxylic acid mg of 9-fluoro-3-methyl-10- (1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido (prepared in Example 6) A mixture of [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, 36 μΐ of methyl vinyl ketone and 1 ml of ethanol was heated at reflux for 12 hours and then cooled to room temperature. The precipitate was filtered off and crystallized from ethanol. 28 mg of the title compound are obtained, m.p. 187-189 ° C (dec.); FAB-MS m / z: 419 (MH +).

Example 52

9-Fluoro-3-methyl-10- [4- (sulfomethyl) -1-piperazinyl] -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1, Preparation of 3,4-benzoxadiazine-6-carboxylic acid A mixture of mg 35% formalin, 32 mg sodium bisulfite and 0.5 ml water was heated at 30 ° C for half an hour and then cooled to room temperature. To the solution was added 100 mg of 9-fluoro-3-methyl-10- (1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1 obtained in Example 6. 3,4-Benzoxadiazine 6-carboxylic acid and 15 ml of sodium hydroxide solution are added. The reaction mixture was heated at 75 ° C for 1 hour and then 2 ml of ethanol was added. The mixture was cooled to room temperature. The precipitate was filtered off and recrystallized from water / ethanol (1: 2). M.p. 260-263 ° C (dec.). 1 H NMR (D ₂ O) δ: 2.98 (3H, S), 3.05 (4H, m), 3.39 (4H, m), 3.84 (2H, S), 5.18 ( 2H, S), 7.55 (1H, d, J = 13.4Hz), 8.34 (1H, S).

Example 53

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

100 mg of 9-fluoro-3-methyl-10- [4- (4-nitrobenzyl) -1-piperazinyl] -7-oxo-2,3-dihydro-7H-pyrido [3 , 2,1-ij] -1,3,4-carboxydiazine-6-carboxylic acid was hydrogenated in 1: 1 dichloromethane / methanol in the presence of 10 mg of 5% palladium on carbon for 2 hours. The catalyst was filtered off and the filtrate was evaporated to dryness in vacuo. The residue was recrystallized from ethanol. 69 mg of the title compound are obtained, m.p. 237-238 ° C (dec.); FAB-MS m / z: 454 (MH +).

Example 54

10- [3- (aminomethyl) -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1, Preparation of 3,4-benzoxadiazine-6-carboxylic acid mg 10- [3- (acetylaminomethyl) -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido A mixture of [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid (product of Example 19) and 2.5 ml of 1N sodium hydroxide solution at 100 ° C for 3 hours overheat. The reaction mixture was cooled to room temperature and then neutralized with acetic acid. The precipitate was filtered off and recrystallized from methanol. 15 mg of the title compound are obtained, m.p. 177-180 ° C (dec.); FAB-MS m / z 363 (MH +).

Example 55 Preparation of fluoro-8-hydroxy-7- (1-imidazolyl) -1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (intermediate) mg. diimidazole with stirring 50 mg of 6,7-difluoro-8-hydroxy-1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid prepared according to Reference Example (i) and 2 ml. dimethylformamide solution. The mixture was stirred at room temperature for 2 hours and then at 80 ° C for 5 hours. The solvent was removed in vacuo and the residue suspended in water. The pH is adjusted to 5 with acetic acid 1994811. The precipitate was filtered off and washed with methanol. 35 mg of the title compound are obtained in the form of a pale yellow powder. FAB-MS m / z: 319 (MH +); 1 H-NMR (d ₆ -DMSO) δ: 2.82 (3H, s), 7.10 (1H, d, J = 10.7 Hz), 7.61 (1H, d), 7.75 ( 1H, d), 8.62 (1H, s), 8.92 (1H, s), 15.33 (1H, broad).

Example 56

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 Preparation of mg of 6-fluoro-8-hydroxy-7- (1-imidazolyl) -1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid prepared according to Example 55. A suspension of 1 ml of a mixture of 35% formalin and 1 ml of dioxane was heated at 100-110 ° C for 1.5 hours under a nitrogen atmosphere. The solvent was removed in vacuo and the residue was washed with methanol. 15 mg of the title compound are obtained in the form of a pale pink powder. Analytical purity m.p.> 300 ° C, FAB-MS m / z 331 (MH ⁺ ).

9-Fluoro-10- (1-imidazolyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6- 9,10-Difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-ij] in a manner analogous to that described in Example 5. It can also be prepared by reacting -1,3,4-benzoxadiazine-6-carboxylic acid and imidazole in dimethyl sulfoxide.

Example 57

9-Fluoro-10- (3-hydroxy-1-pyrrolidinyl) -3-methyl-7-oxo-23-dihydro-7H-pyrrolo [3,2,1-ij] -1,3,4-benzoxadiazin-6 Preparation of the benzyl ester of carboxylic acid mg of 9-fluoro-10- (3-hydroxy-1-pyrrolidinyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3 A mixture of 2,1 l-1j] -1,3,4-benzoxadiazine-6-carboxylic acid, 8 mg of anhydrous potassium carbonate and 0.5 ml of dimethylformamide was stirred at room temperature for 1.5 hours, followed by 10.8 g of benzyl bromide is added. The reaction mixture was stirred at room temperature for 3 hours and then concentrated in vacuo. The residue was suspended in water and extracted with chloroform. The extract was evaporated to dryness in vacuo. The residue was treated with ether. 11 mg of the title compound are obtained, m.p. 196-188 ° C (dec.); FAB-MS m / z: 440 (MH +).

Example 58

10- (3-Chloro-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4 Preparation of benzoxadiazine-6-carboxylic acid benzyl ester 9 mg of 9-fluoro-10- (3-hydroxy-1-pyrrolidinyl) -3-methyl-7-oxo-2,3-dihydro-7H prepared in Example 57. Pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid benzyl ester is dissolved in 0.2 ml of thionyl chloride and the solution is stirred at 60 ° C for 15 minutes. The reaction mixture was diluted with water and extracted with chloroform. 30

The extract was concentrated in vacuo. The residue was chromatographed on silica gel (2 g) and eluted with chloroform. 2.8 g of the title compound are obtained, m.p.> 300 DEG C., FAB-MS m / z: 458 (MH +), 460 (MH + 2) +.

Example 59

10- (3-Chloro-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine Preparation of -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] prepared according to Example 58. -j] -1,3,4-Benzoxadiazine-6-carboxylic acid behzyl ester is hydrogenated in chloroform in the presence of 1 mg of 5% palladium on carbon. The catalyst was removed by filtration and the filtrate was evaporated to dryness in vacuo. The residue was recrystallized from ethanol. 1.0 mg of the title compound are obtained, m.p. 269-272 ° C (dec.); FAB-MS m / z: 368 (MH +), 370 (MH + + 2) +.

Example 60

9-Fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4- Preparation of benzoxadiazine-6-carboxylic acid via the fluoroborane intermediate

a) 100 mg, prepared according to Example 1

9,10-Difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid and 1 ml 60% Aqueous hydroboric acid was heated at 90 ° C for 12 hours. The reaction mixture was cooled to room temperature and the precipitate was filtered off, washed with methanol and dried in vacuo. 110 mg of crude 9,10-difluoro-6 - {[(difluoroborryloxy) carbonyl} -3-methyl-2,3-dihydro-7H-pyrido [3,2,1-ij] -1 3,4-Benzoxydiazin-7-one is obtained, FAB-MS m / z: 331 (MH +).

b) To a solution of 33 mg of the above borane intermediate and 1 ml of dimethyl sulfoxide are added 15 μΐ of N-methylpiperazine and 20 µl of triethylamine with stirring. The reaction mixture was stirred at room temperature for 3 hours and then lyophilized. The residue was crystallized from methanol. 28 mg of 6 - {[(difluoroborryloxy) carbonyl] -9-fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -2,3-dihydro-7H-pyrido as yellow crystals [3,2,1-ij] -1,3,4-benzoxadiazin-7-one, m.p. 228-230 ° C (dec), FAB-MS m / z 411 (MH +).

c) To a solution of 5 mg of the above borane intermediate and 1 ml of 95% ethanol is added 3µl of triethylamine. The reaction mixture was refluxed for 4 hours and then cooled to room temperature. The precipitate was filtered off. The resulting 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.

Example 61

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

-30HU 199481 Β

a) 100 mg, prepared according to Example 1

9,10-Difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,5] ij] -1,3,4-benzoxadiazine-6-carboxylic acid, 1 ml acetic anhydride and 100 ml. of triacetoxyborane (140 mg) was heated at 140 ° C for 15 minutes. The reaction mixture was concentrated in vacuo. The residue was treated with acetone and filtered. 138 mg of 6 - {[(diacetoxyboryl) oxy] carbonyl] -9,10-difluoro-3-methyl-2,3-dihydro-7H-pyrido [3,2,1-ij] -1, 3,4-Benzoxadiazin-7-one is obtained, FAB-MS m / z 411 (MH ⁺ ).

b) To a solution of 41 mg of the above borane intermediate and 1 ml of dimethylsulfoxide are added 15 μΐ of N-methylpeperazine and 20 μΐ of triethylamine. The reaction mixture was stirred at room temperature for 2 hours and then lyophilized. The residue was crystallized from methanol-ether. 34 mg of 6 - {[(diacetoxyboryl) oxy] carbonyl] -9-fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -2,3-dihydro-7H-pyrido [3,2,1] -j] -1,3,4-benzoxadiazin-7-one is obtained. 156-157 ° C (dec), FAB-MS m / z 491 (MH +).

c) 5 mg of the above borane intermediate are suspended in 0.1 ml of acetone and 2.5 μΐ of concentrated hydrochloric acid are added. The reaction mixture was stirred at room temperature for 30 minutes and then cooled in an ice bath. The precipitate was filtered off and dissolved in 0.1 ml of 95% ethanol. To the solution was added 2 μΐ triethylamine and refluxed for one hour. The solution was cooled to room temperature and the precipitate was filtered off. The received

9-Fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido (3,2,1-ij) -1,3,4-benzoxadiazine M.p. 268-269 ° C (dec.).

Example 62

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

290 mg of 10- [3- (benzyloxycarbonylamino) -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-jj] A mixture of 1,3,4-benzoxadiazine-6-carboxylic acid (Example 29 compound), 130 μΐ pivaloyloxymethyl chloride, 166 mg anhydrous potassium carbonate and 10 ml anhydrous dimethylformamide at 45 ° C for 8 hours stir. The solvent was removed in vacuo. The residue was dissolved in dichloromethane, the dichloromethane solution was washed with water and dried over anhydrous sodium sulfate. The solvent was removed and the residue was recrystallized from ethyl acetate. 325 mg of the title compound are obtained, m.p. 185-188 ° C, FAB-MS m / z: 597 (MH +).

Example 63 '

10- (3-Amino-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyran [3,2,1-lj] -1,34-benzoxadiazln- Preparation of 6-carboxylic acid plvaloyloxymethyl ester

The title compound was prepared in 200 mg of 10- [3- (benzyloxycarbonylamino) -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro Prepared from pyrido [3,2,1-ij] -1,3,4-benz58 oxadiazine-6-carboxylic acid pivaloyloxymethyl ester in a manner analogous to that described in Example 30. The product forms a pale brown powder upon contact with ethyl acetate / n-hexane. 1 H NMR (CDCl ₃ ) δ: 1.22 (9H, s), 1.6-2.4 (2H, m), 2.99 (3H, s), 3.3-4.0 (5H, m), 4.98 (2H, s), 5.96 (2H, s), 7.64 (1H, d, J = 14.4 Hz), 8.37 (1H, s); FAB-MS m / z: 463 (MH +).

Example 64

10- [3- (Benzyloxycarbonylamino) -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-jj] - Preparation of 1,3,4-benzoxadiazine-6-carboxylic acid ethyl ester 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 (Example 29 compound), 84 μΐ ethyl iodide, 193 mg anhydrous potassium A mixture of carbonate and 12 ml of anhydrous dimethylformamide was stirred at 45 DEG C. for 6 hours. The residue was applied to a silica gel column and eluted with chloroform-acetone (20: 1). FAB -MS m / z: 511 (MH +).

Example 65

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

200 mg of 10- [3- (benzyloxycarbonylamino) -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3 , 2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid ethyl ester was hydrogenated in 25 ml of chloroform and 10 ml of methanol in the presence of 120 mg of 5% palladium on carbon for 23 hours. The catalyst was filtered off and the filtrate evaporated in vacuo. The residue was applied to a silica gel column and eluted with chloroform-methanol (4: 1). The pure fractions were combined and evaporated to dryness in vacuo. The residue was purified by preparative thin layer chromatography (silica gel; chloroform: methanol = 3: 1) and recrystallization from ethanol. 71 mg of the title compound are obtained. 187-192 ° C (dec.); FAB-MS m / z: 377 (MH +).

Example 66

10- (3-Amino-1-pyrrolidinyl) -9 * fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benz Preparation of oxadiazine-6-carboxylic acid hydrochloride: mg of 10- (3-amino-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro prepared in Example 30 -7H-pyrido [3,2,1-ij] -1,3,431

-31HU 199481 Β

The solution of benzoxadiazine-6-carboxylic acid in 1 ml of water was adjusted to pH 1 with 6N hydrochloric acid. The clear solution was lyophilized and the residue was crystallized from a 1: 2 mixture of <RTI ID = 0.0> wiζ-ethanol </RTI>. 19 mg of the title hydrochloride are obtained, m.p. 226-228 ° C (dec.).

Example 67

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

The title compound was prepared in a manner analogous to that described in Example 66. 264-266 ° C (dec.).

Example 68

Preparation of sodium salt 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 mg 9-Fluoro-3-methyl-10-morpholino-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine prepared according to Example 9. 6-Carboxylic acid is suspended in 0.4 ml of water and 40 µl of 1N sodium hydroxide solution are added with stirring. The clear oil was lyophilized and the residue was crystallized from water-ethanol (1: 4). 12 mg of the title salt are obtained, m.p.

Example 69

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

8-Benzyloxy-6,7-difluoro-1- (formylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid ethyl acetate prepared according to paragraph (f) of the reference example. starting from the ester, prepared by the reaction sequence of paragraphs g, h and i of the reference example (using 1-bromo-2-fluoroethane in place of methyl iodide) and Examples 1 and 5. The crystalline title compound melts at 220-224 ° C, MS m / z: 394 (M ⁺ ) (after recrystallization from methanol).

70-77. example

From the compound prepared in Example 1, analogous to the procedure described in Examples 5 or 29 and 30, the following compounds of formula XX are prepared:

Example row- number r ⁵ r ⁵ k- op C recrystallized solvent PAB-MS m / z 70 / 32 / 262/bom/ MeOH 432 / MH ⁺ / 71 / 33 / 221-230 /boml./ EtOH / hexanes 379 / MH ⁺ / 72 / 34 / 240-245 /boml./ EtOH / hexanes 365 / MH ⁺ / 73 / 35 / 253-255 /boml./ MeOH / ether 425 / MH ⁺ / 74 / 36 / 240-241 MeOH 363 / MH ⁺ / 75 / 37 / > 300 / bomb / E t OH / CHC1.J / hexane 363 / Iffl7 76 / 36 / 220-223 /boml./ EtOH 453 / ΜΗ7 77 / 39 / 211-214 /boml./ EtOH / CHCl 391 / MH ⁺ /

Starting from the compound of Example 1, analogously to the procedure described in Examples 5 or 29 and 30, the following compounds were prepared:

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-pyridido [3.2 1,1-ij] -1,3,4-benzoxadiazine-6-carbonyl acid;

10- (3-Fluoro-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;

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; ⁰⁰ 10- [3-methoxy-4- (methylamino) -1-pyrrolidinyl] -9-fluoro-3-methyl-7 oxo-2,3-dihydro-7H-pyrido [3,2-ij] -l, 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;

-32HU 199481 Β

10- (3-Hydroxy-4-methoxy-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3 4-b ^ nzo3 (adiazin-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-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) -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-Fluoro-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;

10- [3-Hydroxy-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.

Example 78

From 10- {3 - [(4-aminobenzyl) amino] -1-pyridinyl} -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1 -j] -1,3,4-benzoxadiazine-6-carboxylic acid

The title compound was obtained in a manner analogous to that described in Examples 47 and 53, using 10- (3-amino-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid (prepared according to Example 30). 180-182 ° C (dec); FAB-MS m / z: 453 (MH +).

Example 79

9 * Fluoro-10- {3 - [(dimethylamino) methylideneamino] -1-pyrrolidinyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1 -j] -1,3,4-Benzoxadiazine-6-carboxylic acid: mg of 10- (3-amino-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2, prepared according to Example 30; 3-dihydro-7H-pyrido [3,2-ij] -l, 3,4-benz. A suspension of oxadiazine-6-carboxylic acid and 6 µl of N, N-dimethylformamide dimethylacetal in 0.5 ml of anhydrous dimethylformamide was stirred at room temperature for 8.5 hours. The precipitate was filtered off, washed with dimethylformamide and ether and recrystallized from dimethylformamide. 8 mg of the title compound are obtained in the form of pale yellow crystals, m.p. 218-220 ° C. FAB-MS m / z 404 (MH +).

Example 80

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

520 mg of 9-fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4 Benzoxadiazine-6-carboxylic acid is dissolved in 2.88 ml of 0.5 N sodium hydroxide solution. The clear solution was concentrated in vacuo. 555 mg of a pale yellow powder are obtained, which is recrystallized from ethanol. 475 mg of the title sodium salt are obtained, which are dried under vacuum at 80 ° C for 2 days. M.p. 252-254 ° C (dec.). FAB-MS m / z: 385.

Example 81

Gelatin capsules of the following compositions are prepared by known methods of pharmaceutical manufacture.

Component Quantity mg / capsule

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

Luviskol (water soluble polyvinylpyrrolidone) 20

Manni 20

Talkum 15

Magnesium stearate 2 Total weight 257 mg

Example 82

The following formulations are prepared using known methods of pharmaceutical production: Component Quantity mg / tablet

9-Fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazin-6 -Carboxylic acid 200

Starch 44

Carboxymethylcellulose calcium 30

Crystalline cellulose '40

Magnesium stearate '6 Total weight 320

PATENT CLAIMS

Claims (98)

A process for the preparation of a tricyclic compound of formula (I) wherein R ¹ is hydrogen, C 1-4 alkyl, C 2-7 alkanoyloxy (1- (C 4) alkyl or phenyl (C 1 -C 4) alkyl; R ² is C 1 -C 4 alkyl optionally substituted with halogen R ³ is hydrogen; R ⁴ is hydrogen, C 1-4 alkyl, hydroxy (C 1-4 alkyl) or di- (C 1-4 alkyl) amino (C 1-4 alkyl); X is halogen; R ⁵ is C 1-4 alkyl and R ⁶ is di- (C 1-4 alkyl) amino (C 1-4 alkyl); obsession R ⁸ and R ⁴ together with the adjacent nitrogen atom to which they are attached are optionally substituted on carbon by hydroxy, phenyl, C 1-4 alkyl or alkoxy and / or C 1-4 aminoalkyl, (C 1-4) alkanoyl; amino (C 1 -C 4 alkyl), mono- (C 1 -C 4 alkyl) or di- (C 1 -C 4 alkyl) amino (C 1 -C 4 alkyl) -, amino- (1-4) C 1-4 alkyl, amino, benzyloxycarbonylamino, halogen, pyrrol-1-yl or -C 1-4 alkyl-piperazino 33 -33H 199481 63 j 63 j single or double substitution; a pyrrolidino, piperidino, morpholino, or thiomorpholino group, optionally in the form of its dioxide, or an alkyl or phenyl group optionally having 1 to 4 carbon atoms and / or an alkyl, oxo or 1 to 5 carbon atom; alkyl, haloalkyl, carboxyalkyl, alkyl or alkenyl max. Phenyl, oxoalkyl, hydroxyalkyl, alkenyl, aminophenylalkyl, C 1-4 alkyl containing oxo and carboxyl, or sulfomethyl containing 5 C atoms substituted or peroxyamino substituted or substituted on carbon 3 by oxo; or optionally 1 - An imidazolyl group substituted with a C4 alkyl group, or a homopiperazino group, or a N-amino group (amino · benzyl) amino group or a pyridino group substituted with dimethylaminomethylidene amino) and pharmaceutically acceptable salts thereof, as well as hydrates or solvates of the compounds of formula I or salts thereof. characterized by a) a compound of formula III (wherein R ¹ , R ² , R ³ , R ⁴ and X are as defined above; X 'represents a halogen atom and the amino, hydroxy and / or carboxyl groups present are optionally protected be) is reacted with compound (IV) with an amine of formula (wherein R ⁵ and R ⁶ are as hereinbefore defined) and then deprotecting when necessary; obsession b) a compound of formula (V) (wherein R ¹ , R ² , R ⁵ , R ⁶ and X are as defined above and the amino, hydroxy and / or carboxyl groups present may be optionally protected) in one of the following: ) with a carbonyl compound of formula (wherein R ³ and R ⁴ are as defined above) or a polymer, acetal, ketal or enol ether thereof, and if necessary, deprotecting; and then, if desired, subjecting one or more of the following compounds of formula (I) to process (a) or (b): (i) N-alkylating, alkenylating or acylating the corresponding compound of formula (I) to form a compound of formula (I) containing the alkyl, alkenyl or acyl group as defined above in the -NR ⁵ R ⁸ heterocycle; or (ii) in the preparation of a compound of formula (I) containing a heterocycle substituted at one of the carbon atoms of NR ⁵ R® with a mono- or di- (lower alkylamino) lower alkyl or lower alkoxy group; introducing a lower alkyl group into the compound of formula (I) containing an aminoalkyl or (lower) alkylaminoalkyl or hydroxy group 34, or (iii) a 6-membered, ^-S ₅ R ₅ group; In the preparation of compounds of formula (I) containing a heterocyclic group containing a -SO ₂ - group, i.e. a thiomorpholine dioxide group, the corresponding thiomorpholine group containing a Oxidizing compound 10; or (iv) deprotecting the corresponding compound of formula (I) containing a protected amino or carboxyl group or a group thereof to form a compound having the free amino or carboxyl group; or (v) for the preparation of compounds of formula (I) containing a halogenopyrrolidino group at the position of -McR ⁶ , the corresponding compound of formula I having a hydroxypyrrolidino group, wherein R ^{1 is selected from} the group consisting of denotes a given carboxy protecting group - halogen and, if desired, deprotecting R ¹ ; or (vi) reducing the nitro group in the corresponding compound of formula (I) substituted by a nitro group in the preparation of a compound of formula I wherein -NR ⁵ R ⁶ is a p-aminobenzylpiperazino group; or (vii) in the preparation of compounds of formula (I) wherein the pyrrolo group is substituted at the C-position with a pyrrolo group of compounds of formula (XIV) (wherein R ⁵⁰ and R ⁵¹ are each methyl) the corresponding amino substituted (I); a) reacting a compound of formula (VII) with a reactive derivative of a formamide40 compound (VII) wherein R ³⁰ and R ⁵¹ are as defined above; or (viii) esterifying a carboxylic acid of formula (I) in the preparation of compounds of formula (I) wherein R ¹ is substituted with a carboxyl protecting group; or (ix) in the preparation of compounds having 3- [N- (aminobenzyl) amino] pyrrolidino instead of -NR ⁵ R ⁶ , a 3-amino compound is nitrobenzylated and then reduced and / or The compound of formula (I) thus obtained is converted into a salt, a hydrate or a solvate, or into a hydrazide or solvate of a salt. (Priority: 09/09/1987) Process according to Claim 1, characterized in that the process (a) or (b) is carried out, followed, if desired, by the subsequent steps (i) - (vi) ⁶⁰ and / or (viii) and / or salt formation. (Priority: September 9, 1986) 3. A process according to any one of claims 1 to 4, wherein X is fluorine 65 for the preparation of compounds of formula (I), characterized in that the appropriate starting materials are used. (Priority: September 9, 1986) 4. A process according to any one of claims 1 to 6 for the preparation of compounds of formula (I) wherein R 'is hydrogen, wherein the appropriate starting materials are used. (Priority: September 9, 1986) 5. A process according to any one of claims 1 to 6 for the preparation of compounds of formula (I) wherein R ² is methyl, wherein the appropriate starting materials are used. (Priority: September 9, 1986) Process for the preparation of compounds of formula (I) wherein R ³ is hydrogen according to any one of claims 1 to 5, characterized in that the appropriate starting materials are used. (Priority: September 9, 1986) 7. The method of claim 1, 2 or 3 to 6. A process for the preparation of a compound of formula (I) wherein R ⁴ is a hydrogen atom according to any one of claims 1 to ³ , characterized in that the appropriate starting materials are used. (Priority: September 9, 1986) 8. Articles I or 3-7. A process according to any one of claims 1 to 6 for the preparation of compounds of formula (1) 'wherein R ^{5 is a} N-substituted-4-methylpiperazino group, wherein the appropriate starting materials are used. (Priority: September 9, 1986) 9. A process according to any one of claims 1 to 6 for the preparation of compounds of formula (I) wherein R @ ⁵ R @ 3 is 3-aminopyrrolidino, wherein the appropriate starting materials are used. (Priority: September 9, 1986) The process of claim 1, 9-fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-jj] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of said compound or salts, wherein the appropriate starting materials are used. (Priority: September 9, 1986) The process according to claim 1, wherein 9-fluoro-3-methyl-10- (1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyr-time [3,2,1-ij] -1 , 3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or salts thereof, wherein the appropriate starting materials are used. (Priority: September 9, 1986) The process of claim 1, 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 or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or salts thereof, wherein the appropriate starting materials are used. (Priority: September 9, 1986) The process according to claim 1, which is 9-fluoro-3-methyl-10- (3-phenyl-1-piperazinyl) -7- [2,3-dihydro-7H-pyrido [3,2,1-i] ] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or salts thereof, wherein the appropriate starting materials are used. (Priority: September 9, 1986) The process of claim 1, wherein 9-fluoro-3-methyl-10-morpholino-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine is present. -6-carboxylic acid or pharmaceutically acceptable salts thereof, or hydrates or solvates of said compound or salts thereof, wherein the appropriate starting materials are used. (Priority: September 9, 1986) The process of claim 1, 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 or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of said compound or salts, characterized in that the appropriate starting materials are used. (Priority: September 9, 1986) The process according to claim 1, which is 9-fluoro-3-methyl-10- {3 - [(ethylamino) methyl] -1-pyrrolidinyl] -7-oxo-2,3-dihydro-7H-pyrido [3 , 2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of said compound or salts, wherein the appropriate starting materials are used. (Priority: September 9, 1986) The process of claim 1, 9-fluoro-3-methyl-10- (3-amino-1-pyrrolidinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or salts thereof, wherein the appropriate starting materials are used. (Priority: 12/09/1986) The process of claim 1, 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 or pharmaceutically acceptable salts thereof, or hydrates or solvates of said compound or salts, characterized in that the appropriate starting materials are used. (Priority: September 9, 1986) The process according to claim 1, which is 9-fluoro-3-methyl-10- [3- (ethylamino) -1-pyrrolidinyl] -7-oxo-2,3-dihydro-7H-pyrido [3,2- 1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of these compounds or salts, wherein the appropriate starting materials are used. (Priority: September 9, 1986) The process of claim 1, 9-fluoro-3-methyl-10- (3,4-dimethyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2 1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of said compound or salts thereof, -35GB 199481 Β to use the appropriate starting materials. (Priority: September 9, 1986) The process according to claim 1, which is 9-fluoro-3-methyl-10- (3-methoxy-1-pyrid-idinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i] ] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of said compound or salts, wherein the appropriate starting materials are used. (Priority: September 9, 1986) The process of claim 1, 9-fluoro-3-methyl-10- [4- (3-oxo-n-butyl) -1-piperazinyl] -7-oxo-2,3-indidro-7H-pyrido [ 3.2,1-jj -1,3, 4-Benzoxadiazine-6-carboxylic acid or pharmaceutically acceptable salts thereof, or hydrates or solvates of the compound or salts thereof, wherein the starting materials are used. (Priority: September 9, 1986) The process of claim 1, 9-fluoro-3-methyl-10- [4- (sulfomethyl) -1-piperazinyl] -7-oxo-2,3-dihydro-7H-pyrido [3,2 1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid disodium salt or hydrates or solvates of this compound, characterized in that the appropriate starting materials are used. (Priority: September 9, 1986) 24. The method of claim 1, which is 9-fluoro-3-methyl-10- [4- (4-aminobenzyl) -1-piperazinyl] -7-oxo-2,3-dihydro-7H-pyrido [3, 2.1-jj -1.3, 4-Benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of said compound or salts, wherein the appropriate starting materials are used. (Priority: September 12, 1986). 24. The process of claim 1, 9-fluoro-3-methyl-10- [4- (4-aminobenzyl) -1-piperazinyl] -7-oxo-2,3-dihydro-7H-pyrido [3, 2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or pharmaceutically acceptable salts thereof, or hydrates or solvates of said compound or salts, characterized in that the appropriate starting materials are used. (Priority: September 9, 1986) 25. The process of claim 1, which is 9-fluoro-3-methyl-10- [3- (aminomethyl) -1-pyrrolidinyl] -7-oxo-2,3-dihydro-7H-pyrido [3,2- 1-ij-1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of said compound or salts, characterized in that the appropriate starting materials are used. (Priority: September 9, 1986) The process according to claim 1, which is 9-fluoro-3-methyl-10- (1-imidazolyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1, 3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or salts thereof, wherein the appropriate starting materials are used. (Priority: September 9, 1986) 27. The process of claim 1, 9-fluoro-3-methyl-10- (4-ethyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyr time [3,2,1-i ] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of the 36 and the salts thereof, wherein the appropriate starting materials are used. 28. The process of claim 1, which is 9-fluoro-3-methyl-10- [4- (2-hydroxyethyl) -1-piperazinyl] -7-oxo-2,3-dihydro-7H-pyrido [3, 2, l-a bow-l, 3, 4-Benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of said compound or salts, wherein the appropriate starting materials are used. (Priority: September 9, 1986) 29. The process of claim 1, 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 or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or salts thereof, characterized in that the appropriate starting materials are used. (Priority: September 9, 1986) 30. The method of claim 1, from 9-fluoro-3-methyl-10- {3-methyl-4 - [(methylamino) methyl] -1-pyridinyl} -7-oxo-2,3-dihydro -7H-pyr time [3, 2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of said compound or salts, characterized in that the appropriate starting materials are used. (Priority: September 9, 1986) 31. The process of claim 1, 9-fluoro-3-methyl-10- [3- (aminomethyl) -4-methyl-1-pyrrolidinyl] -7-oxo-2,3-dihydro-7H-pyrido [ 3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of said compound or salts, characterized in that the appropriate starting materials are used. (Priority: September 9, 1986) 32. The process of claim 1, which is 9-fluoro-3-methyl-10- {3 - [(ethylamino) methyl] -4-methylpyrrolidinyl] -7-oxo-2,3-dihydro-7H-. pyrido [3, 2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or pharmaceutically acceptable salts thereof, or hydrates or solvates of said compound or salts, characterized in that the appropriate starting materials are used. (Priority: September 9, 1986) 33. The process of claim 1, which is 9-fluoro-3-methyl-10- [3- (aminomethyl) -4-chloro-1-pyrrolidinyl] -7-oxo-2,3-dihydro-7H-pyrido [ 3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of said compound or salts, characterized in that the appropriate starting materials are used. (Priority: September 9, 1986) 34. The method of claim 1, 9-fluoro-3-methyl-10- [3- (aminomethyl) -4-fluoro-1-pyrrolidinyl] -7-oxo-2,3-dihydro-7H-pyrido [ 3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or salts thereof, wherein the appropriate starting materials are used. (Priority: September 9, 1986) -36HU 199481 Β 35. The process of claim 1, which is 9-fluoro-3-methyl-10- {3-chloro-4 - [(methylamino) methyl) -1-pyrrolidinyl} -7-oxo-2,3-dihydro- 7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or pharmaceutically acceptable salts thereof, or hydrates or solvates thereof, wherein the appropriate starting materials are used. . (Priority: September 9, 1986) 36. The process of claim 1, which is 9-fluoro-3-methyl-10- (3-fluoro-4 - [(methylamino) methyl] -1-pyrrolidinyl] -7-oxo-2,3 -dihydro-7H-pyrido [3, 2,1,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or pharmaceutically acceptable salts thereof, or a salt or hydrate or solvate thereof, wherein the appropriate starting materials are used. (Priority: September 12, 1986) The process according to claim 1, which is 9-fluoro-3-methyl-10- [3-chloro-4 - [(ethylamino) methyl] -1-pyrrolidinyl] -7-oxo-2,3-dihydro- 7H-pyrido {3, 2.1-1j] -1,3,4-benzoxadiazine-6-carboxylic acid or pharmaceutically acceptable salts thereof, or hydrates or solvates of this compound or salts, characterized in that the appropriate starting materials are used. (Priority: September 9, 1986) 38. The process according to claim 1, which is 9-fluoro-3-methyl-10- {3 - [(ethylamino) methyl] -4-fluoro-pyrrolidinyl} -7-oxo-2,3-dihydro-7H-. pyrido [3, 2.1-1j] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of said compound or salts, characterized in that the appropriate starting materials are used. (Priority: September 9, 1986) 39. The process of claim 1, 9-fluoro-3-methyl-10- (3-amino-4-methoxy-1-pyrrolidinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2 1jj] -1.3, 4-Benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of said compound or salts, wherein the appropriate starting materials are used. (Priority: September 9, 1986) 40. The process of claim 1, which is 9-fluoro-3-methyl-10- [3-methyl-4- (methylamino) -1-pyrrolidinyl] -7-oxo-2,3-dihydro-7H-pyrido [ 3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of said compound or salts, characterized in that the appropriate starting materials are used. (Priority: September 9, 1986) 41. The process of claim 1, which is 9-fluoro-3-methyl-10- [3- (ethylamino) -4-methoxy-1-pyrrolidinyl) -7-oxo-2,3-dihydro-7H-pyrido [ 3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or salts thereof, wherein the appropriate starting materials are used. (Priority: September 9, 1986) 42. The process of claim 1, which is 9-fluoro-3-methyl-10-oxo- (3-hydroxy-4-methoxy-1-pyrrolidinyl) -7-oxo-2,3-dihydro-7H-pyrido [3, 2.1-jj] 70 -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of said compound or salts, wherein the appropriate starting materials are used. (Priority: September 9, 1986) 43. The process of claim 1, which is 9-fluoro-3-methyl-10- (3-amino-4-chloro-1-pyrrolidinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2 1-f] -1,3,4-benzoxadiazine-6-carboxylic acid or pharmaceutically acceptable salts thereof, or hydrates or solvates of this compound or salts, characterized in that the appropriate starting materials are used. (Priority: September 9, 1986) 44. The process of claim 1, 9-fluoc-3-methyl-10- (3-amino-4-fluoro-1-pyrrolidinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2 1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or pharmaceutically acceptable salts thereof, or a salt thereof 20 hydrates or solvates thereof, characterized in that the appropriate starting materials are used. (Priority: September 9, 1986) 45. The process of claim 1, which is 9-fluoro-3-methyl-10- [3-chloro-4- (methylamino) -1-pyrrolo [2] lidinyl] -7-oxo-2,3-dihydro [3,2 1,1'-yl] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or salts thereof, characterized in that the appropriate starting materials are used. (Priority: September 9, 1986) 46. The method of claim 1, wherein 9-fluoro-3-methyl-10- [3-fluoro-4- (methylamino) -1-pyrrolidinyl] -7-oxo-2,3-dihydro-7H-pyrido [ 3,2,135-yl] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or salts thereof, wherein the appropriate starting materials are used. (Priority: September 12, 1986) 47. The process of claim 1, which is 9-fluoro-3-methyl-10- [4- (aminomethyl) -1-piperidinyl] -7-oxo-2,3-dihydro-7H-pyrido [3,2 1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or a plate of this compound or salts thereof, characterized in that the appropriate starting materials are used. (Priority: September 9, 1986) 48. The method of claim 1, which is 9-fluoro-3-methyl-10- (4-hydroxy-1-piperidinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i ] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or salts thereof, provided that the appropriate starting materials are used. (Priority: September 9, 1986) 49. The process of claim 1, which is 9-fluoro-3-methyl-10- [4- (1-pyrrolyl) -1-piperidyl] -7-oxo-2,3-dihydro-7H-pyrido [3,2- l-ij] -1,3,4-benz "oxadiazine-6-carboxylic acid ⁶⁰ or a pharmaceutically acceptable salt or compound or salt hydrates or solvates thereof, which comprises using the corresponding starting materials. (Priority: September 9, 1986) 50. The process of claim 1, which is 9-fluoro- ^65- or-3-methyl-10- (1-homopiperazinyl) -7-oxo-2,337 -37HU 199481 Β -dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or pharmaceutically acceptable salts thereof, or hydrates or solvates of said compound or salts, characterized in that the appropriate starting materials are used . (Priority: September 9, 1986) 51. The method of claim 1, 9-fluoro-3-methyl-10- (3-hydroxy-1-pyrrolidinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-jj] -1,3,4-benzoxa diazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or salts thereof, wherein the appropriate starting materials are used. (Priority: September 9, 1986) 52. The method of claim 1, wherein 9-fluoro-3-methyl-10- [4- (n-propyl) -1-piperazinyl] -7-oxo-2,3-dihydro-7H-pyrido [3,2 1-ij-1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of said compound or salts, characterized in that the appropriate starting materials are used. (Priority: September 9, 1986) The process of claim 1, which is 9-fluoro-3-methyl-1- [4- (2-fluoroethyl) -1-piperazinyl] -7-oxo-2,3-dihydro-7H-pyrido [3, 2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof or a hydrate or a solvate of said compound or salts, characterized in that the appropriate starting materials are used. (Priority: September 9, 1986) 54. The method of claim 1, 9-fluoro-3-methyl-10- [4- (carboxymethyl) -1-piperazinyl] -7-oxo-2,3-dihydro-7H-pyrido [3,2 1jj -1) 3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or salts thereof, wherein the appropriate starting materials are used. (Priority: September 9, 1986) 55. The method of claim 1, 9-fluoro-3-methyl-10- (4-allyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij]. -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or salts thereof, wherein the appropriate starting materials are used. (Priority: September 9, 1986) 56. The method of claim 1, which is 9-fluoro-3-methyl-10- (1,1-dioxido-4-thiomorpholine) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1 -j] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof or a hydrate or solvate of the compound or salts thereof, wherein the appropriate starting materials are used. (Priority: September 9, 1986) 57. The method of claim 1, which is 9-fluoro-3-methyl-10- [4- (2-oxo-n-propyl) -1-piperazinyl] -7-oxo-2,3-dihydro-7H-pyrido [ 3,2,1-ij) benzoxadiazine-6-carboxylic acid or pharmaceutically acceptable salts thereof, or hydrates or solvates of said compound or salts, characterized in that the appropriate starting materials are used. (Priority: September 9, 1986) 58. The method of claim 1, 9-fluoro-3-methyl-10- (3-chloro-1-pyrrolidinyl) -7-oxo-2,338 -dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or pharmaceutically acceptable salts thereof, or hydrates or solvates of said compound or salts, characterized in that the appropriate starting materials are used . (Priority: September 9, 1986) 59. The method of claim 1, which is 9-fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2, 3-Dihydro-7H-pyrrolo [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of said compound or salts, wherein the appropriate starting materials are used. (Priority: September 9, 1986) 60. The method of claim 1, 9-fluoro-3-methyl-10- (4-amino-1-piperidyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij]. -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of said compound or salts, wherein the appropriate starting materials are used. (Priority: September 9, 1986) 61. The method of claim 1, 9-fluoro-3-methyl-10- [4- (methylamino) -1-piperidyl] -7-oxo-2,3-dihydro-7H-plrido [3.2 , 1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or pharmaceutically acceptable salts thereof, or hydrates or solvates of said compound or salts, characterized in that the appropriate starting materials are used. (Priority: September 9, 1986) 62. The method of claim 1, which is 9-fluoro-3-methyl-10- [4- (ethylamino) -1-piperidyl] -7-oxo-2,3-dihydro-7H-pyrido [3,2 1-ij] -1,3,4-benz. oxadiazine-6-carboxylic acid, or pharmaceutically acceptable salts thereof, or hydrates or solvates of said compound or salts, wherein the appropriate starting materials are used. (Priority: September 9, 1986) 63. The process of claim 1, which is 9-fluoro-S-methyl-10- [3 - [(N-ethyl-N-methylamino) methyl] -1-pyrrolidinyl] -7-oxo-2,3- dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of said compound or salts, characterized in that the appropriate starting materials are used. (Priority: September 9, 1986) 64. The method of claim 1, 9-fluoro-3-methyl-10- (3-amino-4-hydroxy-1-pyrrolidinyl) -7-OXO-2,3-dihydro-7H-pyrido [3,2 1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or pharmaceutically acceptable salts thereof, or hydrates or solvates of said compound or salts, characterized in that the appropriate starting materials are used. (Priority: September 9, 1986) 65. The method of claim 1, which is 9-fluoro-3-methyl-10- [3-hydroxy-4- (methylamino) -1-pyrrolidinyl] -7-oxo-2,3-dihydro-7H -pyrido [3, 2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or pharmaceutically acceptable salts thereof, or hydrates or solvates of said compound or salts, characterized in that the appropriate starting materials are used. (Priority: September 9, 1986) -38HU 199481 Β 66. The method of claim 1, 9-fluoro-3-methyl-10- (4-thiomorpholinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3 , 4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of said compound or salts, wherein the appropriate starting materials are used. (Priority: September 9, 1986) 67. The method of claim 1, 9-fluoro-3-methyl-10- (2,6-dimethyl-4-morpholinyl) -7-oxo-2,3-dihydro-7H-pyr [3,2,1 -j] -1,3,4-benzoxa diazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or salts thereof, characterized in that the appropriate starting materials are used. (Priority: 12/01/1986). 68. The method of claim 4, 9-fluoro-3-methyl-10- (3- (acetylaminomethyl) -1-pyrrolidinyl) -7; oxo-2,3-dihydro-7H-pyrido [3, 2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or salts thereof, characterized in that the appropriate starting materials are used. 69. The method of claim 1, which is 9-fluoro-3-methyl-10-] N- [2- (dimethylamino) ethyl] -N-methylamino] -7-oxo-2,3-dihydro- 7H-pyrido [3, 2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of said compound or salts, characterized in that the appropriate starting materials are used. (Priority: September 9, 1986) 70. The method of claim 1, 9-fluoro-3-methyl-10- (3-oxo-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij]. -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or salts thereof, wherein the appropriate starting materials are used. (Priority: September 9, 1986) 71. The method of claim 1, which is 9-fluoro-3-methyl-2- (hydroxymethyl) -10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [ 3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of said compound or salts, characterized in that the appropriate starting materials are used. (Priority: September 9, 1986) 72. The method of claim 1, which is 9-fluoro-3-methyl-2 - [(dimethylamino) methyl] -10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro- 7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of said compound or salts, wherein the appropriate starting materials are used. (Priority: September 9, 1986) 73. The method of claim 1, 9-fluoro-3-methyl-10- [3- (benzyloxycarbonylamino) -1-pyrrolidinyl] -7-oxo-2,3-dihydro-7H-pyrido [3, 2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or pharmaceutically acceptable salts thereof, or 74 hydrates or solvates of the compounds or salts thereof, characterized in that the appropriate starting materials are used. (Priority: September 9, 1986) The process of claim 1, which is 9-fluoro-3-methyl-10- (4-phenacyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij]. ] -l, 3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt or compound or salts hidrát10 ^j> or solvates thereof, which comprises using the corresponding starting materials. (Priority: September 9, 1986) 75. The method of 9-fluoro-3-methyl-10- according to Claim 1, [4- (4-nitro-benzyl) -l-piperazinyl phenyl _15] -7-oxo-2,3-dihydro-7H-pyrido [ 3,2,1-ij] -1, 3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of said compound or salts, characterized in that the appropriate starting materials are used. (Priority: September 9, 1986) 76. The process of claim 1, 9-fluoro-3-methyl-10- [4- (3-carboxypropionyl) -1-piperazinyl] -7-oxo-2,3-dihydro-7H-pyrido [3, 2,1-ij] 25 to ¹ · ³ · ⁴ -benzoxadiazin-6-carboxylic acid or a pharmaceutically acceptable salt or compound or salt hydrates or solvates thereof, which comprises using the corresponding starting materials. (Priority: September 9, 1986) 77. The method of claim 1, 9-fluoro-3-methyl-10- (4-acetyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij]. -1,3,4-benzoxadiazine-6-carboxylic acid or pharmaceutically acceptable salts thereof, or hydrates or solvates of said compound or salts, characterized in that the appropriate starting materials are used. (Priority: September 9, 1986) 78. The process of claim 1, which is 9-fluoro- _40- or-3-methyl-10- (4-methoxy-1-piperidyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1- ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of said compound or salts, wherein the appropriate starting materials are 45. (Priority: September 9, 1986) 79. The method of claim 1, wherein 9-fluoro-2,3-dimethyl-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7 , 2,1-ij] -1,3, 50 4-Benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof. materials. (Priority: 55 September 12, 1986) 80. The method of claim 1, which is 9-fluoro-2,3-dimethyl-3-methyl-10- (1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1- ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt or compound or salt bridge ⁶⁰ RATJEN or solvates thereof, characterized in that using the corresponding starting materials. (Priority: September 9, 1986) 81. The method of claim 1, 9-fluoro-3-methyl-10- [3- (benzyloxycarbonylamino) -65-1-pyrrolidinyl] -7-oxo-2,3-dihydro-7H ^: pyrido [39] 199481 Β [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid ethyl ester or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, wherein the appropriate starting material is materials. (Priority: September 9, 1986) 82. The method of claim 1, 9-fluoro-3-methyl-10- (3-amino-1-pyrrolidinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij]. -1,3,4-benzoxadiazine-6-carboxylic acid ethyl ester, characterized in that the appropriate starting materials are used. (Priority: September 9, 1986) 83. The method of claim 1, 9-fluoro-3-methyl-10- (3-hydroxy-1-pyrrolidinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid benzyl ester or pharmaceutically acceptable salts thereof, or hydrates or solvates of said compound or salts, wherein the appropriate starting materials are used. (Priority: September 9, 1986) 84. The method of claim k, 9-fluoro-3-methyl-10-chloro- (3-chloro-1-pyrrolidinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i ] -1,3,4-benzyl ester of zoxadiazine-6-carboxylic acid or pharmaceutically acceptable salts thereof, or hydrates or solvates of said compound or salts thereof, characterized in that the appropriate starting materials are used. (Priority: September 9, 1986) 85. The method of claim 1, which is 9-fluoro-3-methyl-10- [3- (benzyloxycarbonylamino) -1-pyrrolidinyl] -7-oxo-2,3-dihydro-7H-pyrido [3, 2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid pivaloyloxymethyl ester or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of said compound or salts, wherein the appropriate starting materials are used. (Priority: September 9, 1986) 86. The method of claim 1, 9-fluoro-3-methyl-10- (3-amino-1-pyrrolidinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij]. pivaloyloxymethyl--1,3,4-benzoxadiazine-6-carboxylate ^{or a} pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, wherein the appropriate starting materials are used. (Priority: September 9, 1986) 87. The method of claim 1, which is 9-fluoro-3-methyl-10- {3 - [(4-aminobenzyl) amino] -1-pyrrolidinyl} -7-oxo-2,3-dihydro-7H -pyrido [3, 2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or pharmaceutically acceptable salts thereof, or hydrates or solvates of said compound or salts, characterized in that the appropriate starting materials are used. (Priority: 09/09/1987) 88. The method of claim 1, which is 9-fluoro-3-methyl-10- {3 - [(dimethylamino) methylideneamino] -1-pyrrolidinyl] -7-oxo-2,3-dihydro-7H- in the preparation of pyrido [3,2,1-ij] -1,3,4-zoxa-diazine-6-carboxylic acid or pharmaceutically acceptable salts thereof, or hydrates or solvates thereof, wherein the appropriate starting materials are used. (Priority: September 9, 1987) 89. The method of claim 1, wherein 9-fluoro-3-methyl-10- [3- (4-methyl-1-piperazinyl-1-pyrrolidinyl) -7-oxo-2,3-dihydro-7H-pyrido [3 , 2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or salts thereof, wherein the appropriate starting materials are used. ) The process according to claim 90-9, 9-fluoro-3-methyl-10- (3-amino-3-methyl-1-pyrrolidinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2 1,1'-yl] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of said compound or salts, wherein the appropriate starting materials are used. (Priority: 09/09/1987) 91. The method of claim 1, which is 9-fluoro-3-methyl-10-trans-3-amino-4-methyl-1-pyrrolidinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2 1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of said compound or salts, characterized in that the appropriate starting materials are used. (Priority: 09/09/1987) 92. The method of claim 1, which is 9-fluoro-3-methyl-10- (trans-3-amino-4-phenyl-1-pyrrolidinyl) -7-oxo-2,3-dihydro-7H-pyrido [3, 2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of said compound or salts, wherein the appropriate starting materials are used. (Priority: 09/09/1987) 93. The method of claim 1, 9-fluoro-3-methyl-10-13-methyl-3 - [(methylamino) methyl] -1-pyrrolidinyl) -7-oxo-2,3-dihydro-7H-pyrido [3 2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or pharmaceutically acceptable salts thereof, or hydrates or solvates of said compound or salts, characterized in that the appropriate starting materials are used. (Priority: 09/09/1987) 94. The process of 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 or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of said compound or salts, characterized in that the appropriate starting materials are used. (Priority: 09/09/1987) 95. The method of claim 1, which is 9-fluoro-3-methyl-10- (trans-3-amino-4-methoxy-1-pyrrolidinyl) -7-oxo-2,3-dihydro-7H-pyrido [3, 2.1 µl] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or salts thereof, wherein the appropriate starting materials are used. (Priority: 09/09/1987) 96. The method of claim 1, which is 9-fluoro-3-methyl-10- (trans-3-amino-4-hydroxy-1-pyr-40H-199481H-rolidinyl) -7-oxo-2,3-dihydro-7H pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or salts thereof, wherein the appropriate starting materials are used. (Priority: September 9, 1987) 97. A process for the preparation of a pharmaceutical composition, wherein a compound of the formula (I) (wherein R ', R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and X are as defined in claim 1) Or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of a compound of formula (I) or a salt thereof, with inhaled solid or liquid carriers and / or excipients and brought into a pharmaceutically acceptable form. (Priority: 09/09/1987) 98. The method of claim 97, wherein the active ingredient is selected from the group consisting of claims 1-96. A final product as defined in any one of claims 1 to 6. (Priority: 09/09/1987)