RU2105770C1 - Quinolone-and naphthiridonecarboxylic acid derivatives in admixture with isomers or individual isomers, hydrates and salts thereof, and pharmaceutical composition - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: present invention describes quinolone-and napthyridonecarboxylic acid derivatives of formula I:

wherein A is CH, CF, CCL, C-OCH₃, C-CH₃ and N′,; X¹ is hydrogen, halogen, NH₂, and CH₃; R¹ is alkyl having 1-3 carbon atoms, FCH₂CH₂-, cyclopropyl, phenyl which is mono-to trisubstituted by halogen: or A and R¹ are C-O-CH₂-CH(CH)₃ bridge; R² is hydrogen, alkyl having 1-3 carbon atoms which is substituted by hydroxy group, halogen or amino group, or 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl; 8 is residue of formulae;

wherein Y is 0 or CH₂; R³ is oxoalkyl having 2-5 carbon atoms; CH₂-CO-C₆H₅, CH₂CH₂CO₂R′,

, CH=CH-CO₂R′ or CH₂CH₂-CN wherein R′ is hydrogen or alkyl having 1-3 carbon atoms, R⁴ is hydrogen, alkyl having 1-3 carbon atoms, oxoalkyl having 2-5 carbon atoms, CH₂-CO-C₆H₅, CH₂CH₂CO₂R′, R′O₂C-CH=C-CO₂R′,

or CH₂CH₂-CN or 5-methyl-2-oxo-1,3-dioxol-4-yl methyl wherein R′ is hydrogen or alkyl having 1-3 carbon atoms, in admixture with isomers or individual isomers, hydrates and salts thereof. The present invention also describes method of preparation of drug containing said compounds. EFFECT: improved properties of the drug. 5 cl, 1 dwg, 4 tbl

Description

в которой
A CH, CF, CCl, C-OCH₃, C-CH₃, N;
X¹ водород, галоген, NH₂, CH₃;
R¹ алкил, содержащий 1 3 атома углерода, FCH₂CH₂-, циклопропил, фенил, который может быть от одного до трех раз замещен галогеном, или
A и R¹ вместе могут означать мостик структуры C-O-CH₂-CH(CH)₃,
R² водород, не замещенный или замещенный гидроксигруппой, галогеном или аминогруппой алкил, содержащий 1 3 атома углерода, или 5-метил-2-оксо-1,3-диоксол-4-ил-метил;
B остаток формул

где
Y O или CH₂;
R³ оксоалкил, содержащий 2 5 атомов углерода, CH₂-CO-C₆H₅, CH₂CH₂CO₂R', R'O₂C-CH=

-CO₂R', -CH=CH-CO₂R' или CH₂CH₂-CN, где R' означает водород или алкил, содержащий 1 3 атома углерода;
R⁴ водород, алкил, содержащий 1 3 атома углерода, оксоалкил, содержащий 2 5 атомов углерода, CH₂-CO-C₆H₅, CH₂CH₂CO₂R', R'O₂C-CH=

CH=CH-CO₂-R' или CH₂CH₂-CN или 5-метил-2-оксо-1,3-диоксол-4-ил-метил, где R' означает водород или алкил, содержащий 1 3 атома углерода,
в виде смеси изомеров или отдельных изомеров, их фармацевтически применимых гидратов и солей, например кислотно-аддитивных солей и щелочных, щелочноземельных, серебряных и гуанидиновых солей соответствующих карбоновых кислот.The invention relates to new chemical compounds with valuable properties, in particular to derivatives of quinolone and naphthyridone carboxylic acids of the general formula

wherein
A CH, CF, CCl, C-OCH ₃ , C-CH ₃ , N;
X ¹ hydrogen, halogen, NH ₂ , CH ₃ ;
R ¹ alkyl containing 1 3 carbon atoms, FCH ₂ CH ₂ -, cyclopropyl, phenyl, which may be substituted one to three times by halogen, or
A and R ¹ together can mean a bridge of structure CO-CH ₂ -CH (CH) ₃ ,
R ^{2 is} hydrogen, unsubstituted or substituted by hydroxy, halogen or amino, alkyl containing 1 to 3 carbon atoms, or 5-methyl-2-oxo-1,3-dioxol-4-yl methyl;
B the remainder of the formulas

Where
YO or CH ₂ ;
R ³ oxoalkyl containing 2 5 carbon atoms, CH ₂ -CO-C ₆ H ₅ , CH ₂ CH ₂ CO ₂ R ', R'O ₂ C-CH =

—CO ₂ R ′, —CH = CH — CO ₂ R ′, or CH ₂ CH ₂ —CN, wherein R ′ is hydrogen or alkyl containing 1 3 carbon atoms;
R ⁴ hydrogen, alkyl containing 1 3 carbon atoms, oxoalkyl containing 2 5 carbon atoms, CH ₂ -CO-C ₆ H ₅ , CH ₂ CH ₂ CO ₂ R ', R'O ₂ C-CH =

CH = CH-CO ₂ -R 'or CH ₂ CH ₂ -CN or 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl, where R' is hydrogen or alkyl containing 1 3 carbon atoms ,
in the form of a mixture of isomers or individual isomers, their pharmaceutically applicable hydrates and salts, for example acid addition salts and alkaline, alkaline earth, silver and guanidine salts of the corresponding carboxylic acids.

 New compounds have high antibacterial activity. They are especially distinguished by the fact that they are highly active against dormant and resistant microorganisms.

где
Y означает O или CH₂;
R³ CH₂-CO-CH₃, CH₂-CO-C₆H₅, CH₂CH₂-CO-CH₃, CH₂CH₂CO₂R', R'O₂C-CH=

-CO₂R', -CH=CH-CO₂R' или CH₂CH₂-CN, где R' означает алкил, содержащий 1 2 атома углерода;
R⁴ водород, алкил, содержащий 1 3 атома углерода, 5-метил-2-оксо-1,3-диоксол-4-ил-метил, CH₂-CO-CH₃, CH₂-CO-C₆H₅, CH₂CH₂CO-CH₃, CH₂CH₂CO₂R', R'O₂C-CH=

-CO₂R', -CH=CH-CO₂R' или CH₂CH₂-CN,
где
R' означает алкил, содержащий 1 2 атома углерода.Preferred are compounds of formula (I),
in which A is CH, CF, CCL, C-OCH ₃ , N;
X ¹ hydrogen, F, CL, Br, NH ₂ , CH ₃ ;
R ¹ C ₂ H ₅ , cyclopropyl or 2,4-difluorophenyl, or A and R ¹ together can mean a bridge of the structure —O — CH ₂ —CH (CH ₃ ) -;
R ² hydrogen, CH ₃ , C ₂ H ₅ , 5-methyl-2-oxo-1,3-dioxol-4-yl methyl;
B the remainder of the formulas

Where
Y is O or CH ₂ ;
R ³ CH ₂ -CO-CH ₃ , CH ₂ -CO-C ₆ H ₅ , CH ₂ CH ₂ -CO-CH ₃ , CH ₂ CH ₂ CO ₂ R ', R'O ₂ C-CH =

—CO ₂ R ′, —CH = CH — CO ₂ R ′, or CH ₂ CH ₂ —CN, wherein R ′ is alkyl containing 1 2 carbon atoms;
R ⁴ hydrogen, alkyl containing 1 3 carbon atoms, 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl, CH ₂ -CO-CH ₃ , CH ₂ -CO-C ₆ H ₅ , CH ₂ CH ₂ CO-CH ₃ , CH ₂ CH ₂ CO ₂ R ', R'O ₂ C-CH =

—CO ₂ R ′, —CH = CH — CO ₂ R ′ or CH ₂ CH ₂ —CN,
Where
R 'means alkyl containing 1 2 carbon atoms.

где
Y означает O или CH₂;
R⁴ водород, алкил, содержащий 1 3 атома углерода, 5-метил-2-оксо-1,3-диоксол-4-ил-метил, CH₂-CO-CH₃, CH₂-CO-C₆H₅, CH₂CH₂-CO-CH₃, CH₂CH₂CO₂R', R'O₂C-CH=

-CO₂R', -CH=CH-CO₂R' или CH₂CH₂-CN, где R' означает алкил, содержащий 1 2 атома углерода.Particularly preferred are compounds of formula (I),
Where
A is CH, CF, CCL, C-OCH ₃ , N;
X ¹ hydrogen, F, CL, Br, NH ₂ , CH ₃ ;
R ¹ C ₂ H ₅ , cyclopropyl or 2,4-difluorophenyl, or A and R ¹ together can mean a bridge of the structure —O — CH ₂ —CH (CH ₃ ) -,
R ² hydrogen, CH ₃ , C ₂ H ₅ ;
B the remainder of the formulas

Where
Y is O or CH ₂ ;
R ⁴ hydrogen, alkyl containing 1 3 carbon atoms, 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl, CH ₂ -CO-CH ₃ , CH ₂ -CO-C ₆ H ₅ , CH ₂ CH ₂ -CO-CH ₃ , CH ₂ CH ₂ CO ₂ R ', R'O ₂ C-CH =

—CO ₂ R ′, —CH = CH — CO ₂ R ′, or CH ₂ CH ₂ —CN, where R ′ is alkyl containing 1 2 carbon atoms.

где
R³ и Y имеют указанное выше значение,
получают тем, что соединение формулы

где
A, Y, X¹, R¹ и R² имеют указанное выше значение,
подвергают взаимодействию с соединением формулы,
R³-X³
где
R³ означает оксоалкил, содержащий 2 5 атомов углерода, CH₂-CO-C₆H₅, CH₂CH₂-CO₂R' или CH₂CH₂-CN, где R' водород или алкил, содержащий 1 3 атома углерода,
X³ галоген, в частности хлор, бром, или иод,
при необходимости, в присутствии связывающего кислоту средства. (Реакция А)
Соединения согласно формулы (I), где A, Y, X¹, R¹ и R² имеют вышеуказанное значение и B означает остаток формулы

где
Y имеет вышеуказанное значение;
R³ означает CH₂CH₂-CO-CH₃, CH₂CH₂-CO₂R', R'O₂C-CH=C-CO₂R', -CH=CH-CO₂R' или CH₂CH₂-CN, где R' означает водород или алкил, содержащий 1 3 атома углерода,
могут быть получены тем, что соединение формулы

подвергают взаимодействию с акцептором Михаэля, например, диалкиловым эфиром ацетилендикарбоновой кислоты, алкиловым эфиром пропиоловой кислоты или соединением формулы
CH₂ CH-R⁵,
в которой
R⁵ означает COCH₃, CO₂R' или CN (Реакция Б).The compounds of formula (I) in which A, X ¹ , R ¹ , R ² have the above meaning and B means the remainder of the formula

Where
R ³ and Y have the above meaning,
obtained by the fact that the compound of the formula

Where
A, Y, X ¹ , R ¹ and R ² have the above meaning,
reacted with a compound of the formula
R ³ -X ³
Where
R ³ means oxoalkyl containing 2 5 carbon atoms, CH ₂ -CO-C ₆ H ₅ , CH ₂ CH ₂ -CO ₂ R 'or CH ₂ CH ₂ -CN, where R' is hydrogen or alkyl containing 1 3 carbon atoms ,
X ³ halogen, in particular chlorine, bromine, or iodine,
optionally in the presence of an acid binding agent. (Reaction A)
The compounds according to formula (I), where A, Y, X ¹ , R ¹ and R ² have the above meaning and B means the remainder of the formula

Where
Y has the above meaning;
R ³ is CH ₂ CH ₂ —CO — CH ₃ , CH ₂ CH ₂ —CO ₂ R ′, R′O ₂ C — CH = C — CO ₂ R ′, —CH = CH — CO ₂ R ′, or CH ₂ CH ₂ —CN, where R ′ is hydrogen or alkyl containing 1 to 3 carbon atoms,
can be obtained by the fact that the compound of the formula

subjected to interaction with a Michael acceptor, for example, dialkyl ether of acetylenedicarboxylic acid, alkyl ether of propiolic acid or a compound of the formula
CH ₂ CH-R ⁵ ,
wherein
R ⁵ means COCH ₃ , CO ₂ R 'or CN (Reaction B).

в которой
A, R¹, R² и X¹ имеют вышеуказанное значение;
X² означает галоген, в частности фтор или хлор,
подвергают взаимодействию с энантиомерночистыми соединениями формулы

где
Y O или CH₂;
R⁴ водород или алкил, содержащий 1 3 атома углерода,
при необходимости в присутствии связывающего кислоту средства, и продукт реакции при желании, дальше подвергают превращению с соединением формулы
R⁴-X³,
где
X³ имеет указанное выше значение;
R⁴ означает оксоалкил, содержащий 2 5 атомов углерода, CH₂-CO-C₆H₅, CH₂CH₂CO₂R' или CH₂CH₂-CN, где R' означает водород или алкил, содержащий 1 3 атома углерода, или с акцептором Михаэля, например диалкиловым эфиром ацетилендикарбоновой кислоты, алкиловым эфиром пропиоловой кислоты или соединением формулы
CH₂ CH R⁵
где
R⁵ означает COCH₃, CO₂R' или CN (Реакция В)
Если применяют, например, в качестве исходных соединений 8-хлор-1-циклопропил-6,7-дифтор-1,4-дигидро-4-оксо-3- хинолинкарбоновую кислоту и [S,S] -2,8-диазабицикло[4.3.0]нонан, то реакция протекает по следующей схеме:

Если в качестве исходных соединений применяют, например, 6,8-дифтор-1-(2,4-дифторфенил)-1,4-дигидро-7-([1S, 6R] -2-окса-5,8-диазабицикло[4.3.0] нон-8-ил)-4-оксо-3-хинолинкарбоновую кислоту и диэтиловый эфир ацетилендикарбоновой кислоты, то реакция протекает по следующей схеме:

Применяемые в качестве исходных соединений рацемические соединения формулы (II) большей частью являются известными. Энантиомерночистые соединения формулы (II) являются новыми и могут быть получены различными путями.To obtain enantiomerically pure compounds of the formula (I), a compound of the formula

wherein
A, R ¹ , R ² and X ¹ have the above meaning;
X ² means halogen, in particular fluorine or chlorine,
react with enantiomerically pure compounds of the formula

Where
YO or CH ₂ ;
R ⁴ hydrogen or alkyl containing 1 to 3 carbon atoms,
optionally in the presence of an acid-binding agent, and the reaction product, if desired, is further converted with a compound of the formula
R ⁴ -X ³ ,
Where
X ³ has the above meaning;
R ⁴ means oxoalkyl containing 2 5 carbon atoms, CH ₂ -CO-C ₆ H ₅ , CH ₂ CH ₂ CO ₂ R 'or CH ₂ CH ₂ -CN, where R' means hydrogen or alkyl containing 1 3 carbon atoms or with a Michael acceptor, for example, acetylenedicarboxylic acid dialkyl ether, propiolic acid alkyl ester or a compound of the formula
CH ₂ CH R ⁵
Where
R ⁵ means COCH ₃ , CO ₂ R 'or CN (Reaction B)
If, for example, 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and [S, S] -2,8-diazabicyclo [ 4.3.0] nonane, the reaction proceeds according to the following scheme:

If, for example, 6.8-difluoro-1- (2,4-difluorophenyl) -1,4-dihydro-7 - ([1S, 6R] -2-oxa-5,8-diazabicyclo [ 4.3.0] non-8-yl) -4-oxo-3-quinoline carboxylic acid and diethyl ether of acetylenedicarboxylic acid, the reaction proceeds according to the following scheme:

The racemic compounds of formula (II) used as starting compounds are for the most part known. Enantiomerically pure compounds of formula (II) are new and can be obtained in various ways.

2. Бициклические амины (VI), как энантиомерночистые соединения, являются новыми. Они могут быть получены следующими способами:
2.1 Рацемические бициклические амины

где
R⁴ означает водород или алкил, содержащий 1 3 атома углерода, могут подвергаться превращению с энантиомерночистыми кислотами, например карбоновыми кислотами или сульфокислотами, как N-ацетил-L-глутаминовая кислота, N-бензоил-L-аланин, 3-бромкамфар-9-сульфокислота, камфар-3-карбоновая кислота, цис-камфарная кислота, камфар-10-сульфокисота, O,O'-дибензоил-винная кислота, D- или L-винная кислота, миндальная кислота, α-метокси-фенилуксусная кислота. 1-фенил-этансульфокислота, α-фенил-янтарная кислота, в смесь диастереомерных солей, которые разделяю. т фракционной кристаллизацией на диастереомерночистые соли (см. П.Нейман. Optical Resolution Procedures for Chemical Compounds, т. 1).1. The racemic intermediate of formula (II) is reacted with an enantiomerically pure auxiliary reagent, the resulting diastereomers are separated, for example, chromatographically, and the auxiliary chiral group is again cleaved from the obtained diastereomer. The following reaction should be given as an example:

2. Bicyclic amines (VI), as enantiomerically pure compounds, are new. They can be obtained in the following ways:
2.1 Racemic bicyclic amines

Where
R ⁴ means hydrogen or alkyl containing 1 to 3 carbon atoms, can be converted with enantiomerically pure acids, for example carboxylic acids or sulfonic acids, such as N-acetyl-L-glutamic acid, N-benzoyl-L-alanine, 3-bromocamphar-9- sulfonic acid, camphor-3-carboxylic acid, cis-camphoric acid, camphor-10-sulfonic acid, O, O'-dibenzoyl-tartaric acid, D- or L-tartaric acid, mandelic acid, α-methoxy-phenylacetic acid. 1-phenyl-ethanesulfonic acid, α-phenyl-succinic acid, in a mixture of diastereomeric salts, which I share. t by fractional crystallization into diastereomerically pure salts (see P. Neumann. Optical Resolution Procedures for Chemical Compounds, vol. 1).

 The molar ratio of amine to enantiomeric acid can vary over a wide range. By treating these salts with hydroxides of alkali and alkaline earth metals, enantiomerically pure amines are isolated.

На схеме, приведенной ниже, в качестве примера расщепления рацематов приведено разделение 8-бензил-цис-2,8-диазабицикло[4.3.0] нонана через тартраты на энантиомеры и их перевод в энантиомерночистые цис-2,8-диазабицикло[4.3.0]нонаны:
2.3 Как рацемические амины (а), так и основные промежуточные соединения (б)-(д) могут быть при необходимости после ацилирования разделены хроматографически на хиральных носителях (см. например, г. Блашке. Angew. Chem. 92, 14 [1980]).2.2 Similarly, as described in paragraph 2.1, the racemates are cleaved of the main intermediates that are formed when racemic bicyclic amines are prepared with the above enantiomerically pure acids. Examples of such basic intermediates are:

In the diagram below, as an example of racemate cleavage, the separation of 8-benzyl-cis-2,8-diazabicyclo [4.3.0] nonane through tartrates into enantiomers and their conversion to enantiomerically pure cis-2,8-diazabicyclo [4.3.0 ] nonans:
2.3 Both racemic amines (a) and the main intermediates (b) - (e) can be, if necessary, after acylation, separated chromatographically on chiral supports (see, for example, Mr. Blaschke. Angew. Chem. 92, 14 [1980] )

 2.4 Both racemic amines (a) and the main intermediates (b), (c), (e) can be converted by chemical binding to chiral acyl residues in a mixture of diastereomers, which are separated by distillation, crystallization or chromatography on diastereomeric acyl derivatives, of which enantiomerically pure amines are isolated by saponification. Examples of reagents for binding to chiral acyl residues are: α-methoxy-a-trifluoromethyl-phenylacetyl chloride, methyl isocyanate, D- or L-a-phenyl-ethyl-isocyanate, chloroformate methyl ester, camphor-10-sulfonic acid chloride.

2.6 Энантиомерночистые амины (VI) могут быть также произведены из энантиомерночистых предшественников, например, [R,R] или [S,S]-дигидроксипирролидина, который у азота должен быть защищен защитной группой.2.5. During the synthesis of bicyclic amines (a), chiral groups can also be introduced instead of achiral. Thus, diastereomers that are separated are obtained. For example, in the synthesis of cis-2,8-diazabicyclo [4.3.0] nonane, the benzyl residue can be replaced by a-phenylethyl residue with an R- or S-configuration:

2.6 Enantiomerically pure amines (VI) can also be produced from enantiomerically pure precursors, for example, [R, R] or [S, S] -dihydroxypyrrolidine, which must be protected by a protecting group on nitrogen.

R означает, например, (CH₃)₃C-O,
а: водород, палладий/активированный уголь;
б: ацилирование;
в: NaH, BrCH₂COOC₂H₅ или в: CH₂=CH-CH₂Br, NaH,
г: LiBH₄ г: O₃ NaBH₄;
д: тозилхлорид, триэтиламин;
е: бензиламин, ксилол, нагревание до образования флегмы;
ж: гидролиз;
з: водород, палладий/активированный уголь.As an example of the synthesis of enantiomeric pure amine from enantiomeric pure 1-benzyl-3,4-dihydroxy-pyrrolidine, the following scheme should be given:

R means, for example, (CH ₃ ) ₃ CO,
a: hydrogen, palladium / activated carbon;
b: acylation;
in: NaH, BrCH ₂ COOC ₂ H ₅ or in: CH ₂ = CH-CH ₂ Br, NaH,
g: LiBH ₄ g: O ₃ NaBH ₄ ;
d: tosyl chloride, triethylamine;
e: benzylamine, xylene, heating to reflux;
g: hydrolysis;
h: hydrogen, palladium / activated carbon.

As examples of compounds of formula (VI) should be mentioned:
cis-2,8-diazabicyclo [4.3.0] nonane,
cis-2-oxa-5,8-diazabicyclo [4.3.0] nonane,
trans-2-oxa-5,8-diazabicyclo [4/3/0] nonane,
S, S-2,8-diazabicyclo [4.3.0] nonane,
1R, 6S-2-oxa-5,8-diazabicyclo [4.3.0] nonane,
1S, 6R-2-oxa-5,8-diazabicyclo [4.3.0] nonane,
1R, 6R-2-oxa-5,8-diazabicyclo [4.3.0] 2 nonane,
1S, 6S-2-oxa-5,8-diazabicyclo [4.3.0] nonane.

 The interaction of (V) with (VI), in which compounds (VI) can also be used in the form of their salts, for example hydrochlorides, is preferably carried out in a diluent, for example dimethyl sulfoxide, N, N-dimethylformamide, N-methylpyrrolidone, hexamethylphosphoric triamide, sulfolane, acetonitrile, water, alcohol, for example methanol, ethanol, n-propanol, isopropanol, glycol monomethyl ether or pyridine. Mixtures of these solvents may also be used.

 As the acid binding agent, all conventional inorganic or organic acid binding agents can be used. These include, preferably, alkali metal hydroxides, alkali metal carbonates, organic amines and amidines.

 Particularly suitable are triethylamine, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] undec-7-ene or an excess of amine (VI).

The reaction temperature can vary over a wide range. Mainly operate at a temperature of 20,200 ^o C, preferably 80 180 ^o C.

 The interaction can be carried out at normal pressure, but also at elevated pressure. They generally operate at a pressure of 1,100 bar, preferably 1,110 bar.

 When implementing this method, 1 to 15 mol, preferably 1 to 6 mol, of compound (VI) is introduced per 1 mol of compound (V).

 The starting compounds of formulas (III) and (IV) are known.

 Examples include chloroacetone, 4-chloro-2-butanone, 5-chloro-2-pentanone, 1-bromo-2-butanone, chloroacetophenone, methyl acrylate, ethyl acrylate, acrylonitrile, methyl vinyl ketone, acetylenedicarboxylic acid dimethyl ether, acetylenedicarboxylic acid diethyl ether , propiolic acid methyl ester, propiolic acid ethyl ester.

 The reaction of (II) with (III) is preferably carried out in a diluent, for example dimethyl sulfoxide, N, N-dimethylformamide, N-methylpyrrolidone, hexamethylphosphoric triamide, sulfolane, acetonitrile, water, alcohol, e.g. methanol, ethanol, n-propanol, isopropanol, glycol monomethyl ether or pyridine, in the presence of an acid binding agent. Mixtures of these solvents may also be used.

 As the acid binding agent, all conventional inorganic and organic acid binding agents can be used. These preferably include alkali metal hydroxides, alkali metal carbonates, organic amines and amidines. Particularly suitable are triethylamine, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] undec-7-ene or an excess of amine (VI).

The reaction temperature can vary over a wide range. Mainly operate at a temperature of 20,200 ^o C, preferably 60 130 ^o C.

 The interaction can be carried out at normal pressure, but also at elevated pressure. They generally operate at a pressure of 1,100 bar, preferably 1,110 bar.

 When implementing this method, 1 to 15 mol, preferably 1 to 6 mol, of compound (III) is introduced per 1 mol of compound (II).

 The interaction of compounds (II) with Michael (IV) acceptors according to method B is preferably carried out in a diluent such as acetonitrile, dimethyl sulfoxide, N, N-dimethylformamide, alcohol, for example methanol, ethanol, propanol or isopropanol, or glycol monomethyl ether.

The reaction temperature can vary over a wide range. Mainly operate at temperatures of about 20 to 150 ^o C, preferably 40 to 100 ^o C.

 The interaction can be carried out at normal pressure, but also at elevated pressure. They generally operate at pressures between 1 and 100 bar, preferably between 1 and 10 bar. When carrying out the method according to the invention, 1 to 5 mol, preferably 1 to 2 mol, of compound (IV) is introduced per 1 mol of compound (II).

 The preparation of the acid addition salts of the compounds of the invention is carried out in the usual manner, for example, by dissolving betaine in aqueous acid and precipitating the salt with a water-miscible organic solvent, for example methanol, ethanol, acetone, acetonitrile. You can also heat equivalent amounts of betaine and acid in water or alcohol, for example glycol monomethyl ether, and then evaporate to dryness or filter the precipitated salt.

 Pharmaceutically acceptable salts are understood, for example, to include salts of hydrochloric acid, sulfuric acid, acetic acid, glycolic acid, lactic acid, succinic acid, citric acid, tartaric acid, methanesulfonic acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid or aspartic acid .

 Alkaline and alkaline earth acid salts according to the invention are obtained, for example, by dissolving betaine in an insufficient amount of an alkali or alkaline earth metal base, filtering insoluble betaine and evaporating the filtrate to dryness.

 Salts of sodium, potassium, or calcium are pharmaceutically acceptable. By treating the alkaline or alkaline earth salt with a suitable silver salt, for example silver nitrate, the corresponding silver salts are obtained.

 The claimed compounds of formula (I) exhibit strong antibiotic activity and, with minor toxicity, have a wide spectrum of action against gram-positive and gram-negative microbes, especially against endobacteria, especially against those that are resistant to various antibiotics, for example penicillin, cephalosporin, aminoglucosides, sulfamides, tetracycline.

 Due to these valuable properties, the compounds can be used in medicine, as well as for preserving organic and inorganic materials, especially all types of organic materials, for example polymers, lubricants, paints, fibers, leather, paper and wood, food and water. The compounds of the invention are active against a very wide range of microorganisms.

 With their help, they fight with gram-positive and gram-negative bacteria and bacterium-like microorganisms, as well as with the diseases they cause.

 The compounds of the invention exhibit strong activity against resting and resistant microorganisms. In the case of resting bacteria, i.e., in which growth is not observed, the compounds are active at concentrations much lower than the known compounds. This applies not only to the amounts administered, but also to the rate of killing. Such results were observed in gram-positive and gram-negative bacteria, in particular in Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecalis and Escherichia coli. Also in relation to bacteria, significantly less susceptible to substances taken for comparison, in particular to resistant Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Enterjcoccus faecalis, the claimed compounds show a significant increase in activity. Particularly active compounds in relation to bacteria and bacterium-like microorganisms. Therefore, they are especially suitable in medicine and veterinary medicine for the prevention and chemotherapy of local and systemic infections caused by these pathogens. The compounds are also suitable for combating protozoonosis and helminthiasis.

 The claimed compounds can be used in various formulations. Particularly preferred are tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and aerosols.

 The data given in table. 1, confirm the unexpected advantage of the claimed compounds over ciprofloxacin [1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -3-quinolinecarboxylic acid (EP 0176846 B1, class C 07 C 101/34, 1986, col. 4)] on infected Staphylicoccus aureus mice.

In the table. 2 shows the minimum concentration of inhibition (MKT) for the claimed compounds of example 2 and the known compounds of ciprofloxacin obtained by the method of serial dilution on Iso-sensitest agar (oxoid). At the same time, a number of agar plates were prepared, which, upon double dilution, contained decreasing concentrations of the active substance. Agar plates were inoculated with a Denley-type multipoint inoculator. For vaccination, Errerger cultures grown overnight were used, which were first diluted so that each inoculation point contained about 10 ⁴ colony-forming particles. The grafted agar plates were incubated at 37 ^° C and after about 20 hours the growth of microorganisms was determined. The MKT value (μg / ml) gives the lowest concentration of the active substance at which no growth was observed with the naked eye.

 The following examples illustrate the preparation of starting and intermediate products.

 Example A. [S, S] -2,8-diazabicyclo [4.3.0] nonane.

1) [S,S]-8-бензил-2,8-диазабицикло[4.3.0]нонан,
Способ I.

1) [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane,
Method I.

a) Separation of diastereomeric salts: 3.0 g (20 mmol) of D (-) - tartaric acid is dissolved in 10 ml of dimethylformamide by heating to 80 ^o C and mixed with a solution of 2.16 g (10 mmol) of cis-8-benzyl- 2,8-diazabicyclo [4.3.0] nonane in 3 ml of dimethylformamide. It is stirred for one hour at 0 ^° C., then filtered and washed with dimethylformamide and methoxyethanol.

Yield: 1.93 g; T. pl. 146 151 ^o C; [α] $\genfrac{}{}{0ex}{}{\text{23}}{\text{D}}$ = -19.3 ^o (c 1, water).

 By recrystallization once from methoxyethanol, diastereomerically pure [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane-D-tartrate is obtained.

[α] $\genfrac{}{}{0ex}{}{\text{23}}{\text{D}}$ = -22.7 ^° (c 1, water); T. pl. 148 154 ^o C.

 b) Isolation of base: 40 g of [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane-D-tartrate are dissolved in 250 ml of water and mixed with 32 g of 45% sodium alkali. The separated oil is taken up in 150 ml of tert-butyl methyl ether, the aqueous phase is extracted once more with 150 ml of tert-butyl methyl ether and the combined organic phases are concentrated after drying over sodium sulfate. Then distilled off in vacuo.

 Yield: 18.5 g of [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane.

T. bale. 107 109 ^o C / 0.1 mbar; [α] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ = 17.3 ^o (neat)
Method II 75.0 g (0.5 mol) of L (+) - tartaric acid are dissolved at 250 ^° C. in 250 ml of dimethylformamide and a solution of 54.1 g (0.25 mol) of cis-8-benzyl-2,8-diazabicyclo is added dropwise. [4.3.0] nonane in 75 ml of dimethylformamide. The mixture is slowly cooled to 20 ^° C. and the crystal suspension is stirred for one hour. The crystals ([R, R] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane-L-tartrate) are filtered off and the filtrate is concentrated in a rotary evaporator. The residue was dissolved in 500 ml of water and treated as described in method I with 63 g of 45% sodium alkali.

 Yield: 25.2 g of [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane; the product contains 3.6 R, R-enantiomers (determined by gas chromatography after obtaining the derivative with menthyl chloroformate).

 The compound can be converted with D (-) - tartaric acid into diastereomerically pure [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane-D-tartart. In this case, recrystallization is not required.

Method III To a solution of 102.9 g (0.685 mol) of L (+) - tartaric acid in 343 ml of dimethylformamide was added dropwise at 80 ^° -90 ^° C. a solution of 73.6 g (0.34 mol) of cis-8-benzyl-2,8-diazabicyclo [ 4.3.0] nonane in 111 ml of dimethylformamide. [R, R] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane-L-tartrate was added for seed and slowly cooled to an internal temperature of 18 ^° C. The crystals were filtered off. The filtrate was seeded with [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonan-L-tartrate and stirred until complete crystallization (from the mother liquor after thickening and isolation of the base, as described in method I, was obtained by treatment D (-) - tartaric acid [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane-D-tartrate). Then it is filtered off, washed with dimethylformamide and isopropanol and dried in air. The crystals are recrystallized from 88% ethanol. Obtain 52 g of the trihydrate of [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonan-L-tartrate.

T. pl. 201,204 ^° C; [α] $\genfrac{}{}{0ex}{}{\text{23}}{\text{D}}$ = + 5.2 ^o (c 1, water).

 The salt can be processed according to method I (base isolation) into enantiomerically pure [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane.

 Method IV

 a) Separation of the enantiomers of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane on [1S, 6R] -8-benzyl-7,9-dioxo-2,8-diazabicyclo [ 4.3.0] nonane. They act analogously to example B (method IIa), and D (-) - tartaric acid is used as a chiral auxiliary reagent, or they proceed as follows: the mother liquor and washing liquid containing [1R, 6S] -8-benzyl-7,9- are thickened dioxo-2,8-diazabicyclo [4.3.0] nonane-L-tartrate (from Example B, method II / a) is placed in water and extracted three times with toluene. The aqueous phase is mixed with a saturated solution of sodium hydrogencarbonate, the pH is adjusted to 7-8, and then extracted three times with methylene chloride. The combined methylene chloride phases are dried over magnesium sulfate and concentrated.

Yield: 14.4 g (60 from theory on the originally introduced racemic cis-8-benzyl-7.9-dioxo-2,8-diazabicyclo [4.3.0] nonane). [α] $\genfrac{}{}{0ex}{}{\text{23}}{\text{D}}$ = -4.5 ^o C (c 5, ethanol).

 These 14.4 g (50 mmol) crystallize with 8.6 g (57 mmol) of D (-) tartaric acid in the same manner as in Example B (method IIa).

Yield: 8.9 g (77 theory) [1S, 6R] -8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane-D-tartrate. [α] $\genfrac{}{}{0ex}{}{\text{23}}{\text{D}}$ = -46.2 ^° C (c 0.5, 1N. HCl); after recrystallization from ethanol / glycol monomethyl ether, further purification takes place: [α] $\genfrac{}{}{0ex}{}{\text{23}}{\text{D}}$ = -59.3 ^o C (c 0.5, 1N. HCl).

 5.0 g (12.7 mmol) of the diastereomeric pure tartrate thus obtained, as described in Example B, method IIa, are converted to the free amine.

Yield: 3.0 g (96 theory) [1S, 6R] -8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane; T. pl. 60 61 ^o C; [α] $\genfrac{}{}{0ex}{}{\text{23}}{\text{D}}$ = -22.2 ^° (c 5, ethanol).

After obtaining the chloroformic acid derivative with menthyl ether, an excess of the enantiomer 96.6 was determined by gas chromatography)
b) Reduction of [1S, 6R] -8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane to [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0 ] nonana. They act analogously to example B (method II b), with [1S, 6R] -8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane being taken as the starting material.

 The crude product obtained after processing turned out to be the result of the preparation of the [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane derivative with chloroformic acid methyl ethyl ester.

 Racemation during recovery was not observed.

2) [S, S] -2,8-diazabicyclo [4.3.0] nonane. 28.4 g (0.131 mol) of [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane is hydrogenated in 190 ml of methanol per 5.8 g of palladium on activated carbon (5) at 90 ^° C and 90 bar for 5 hours. The catalyst is then filtered off, washed with methanol and the filtrate is concentrated in a rotary evaporator. The residue was distilled without fractionation.

Yield: 15.0 g (90.5% of theory) [S, S] -2,8-diazabicyclo [4.3.0] nonane; T. bale. 44 59 ^o C / 0.18 mbar; [α] $\genfrac{}{}{0ex}{}{\text{22}}{\text{D}}$ = -2.29 ^o (undiluted). Isomer purity> 99 (determined by gas chromatography after preparation of a derivative with Mosher reagent)
Method V. Take 3.75 g (25 mmol) of L (+) - tartaric acid dissolved in 50 ml of dimethylformamide at 80 ^o C, and 10.82 g (50 mmol) of cis-8-benzyl-2.8- are added dropwise. diazabicyclo [4.3.0] nonane as a solution in 15 ml of dimethylformamide. [R, R] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane-L-tartrate is seeded and stirred for one hour at a temperature of about 72 ^° C. until crystalline nucleation is complete. Then it is slowly cooled to 15 ^° C., filtered off and washed twice with 13 ml of dimethylformamide. The combined filtrates are heated to 80 ^° C. and mixed with an additional 3.75 g (25 mmol) of L (+) - tartaric acid. Heated to 119 ^o C until a clear solution is formed and slowly again cooled to room temperature with the seed of [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane-L-tartrate. The crystals are filtered off, washed in turn with dimethylformamide, 2-ethoxyethanol and ethanol and dried in air.

Yield: 9.59 g; T. pl. 188 192 ^o C.

The crystals are recrystallized from 95 ml of 80% ethanol. 8.00 g of [S, S] -8-benzyl-2,8-diazobicyclo [4.3.0] nonane-L-tartrate trihydrate (76% of theory) are obtained, which melts at 112 118 ^° C with foaming, then again hardens and melts again at 199 201 ^o C.

[α] $\genfrac{}{}{0ex}{}{\text{23}}{\text{D}}$ = 4.5 ^o (c 1, water). The isomer purity is 98% (determined by gas chromatography after obtaining the derivative with chloroformic acid methyl ethyl ester).

 Example B. [R, R] -2,8-diazabicyclo [4.3.0] nonane.

1) [R,R]-8-бензил-2,8-диазабицикло[4.3.0]нонан.

1) [R, R] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane.

 Method I. Obtained according to example A, method II, crystals (49.2 g) of [R, R] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane are washed with dimethylformamide and methoxyethanol and recrystallized from 300 ml of methoxyethanol. 45.6 g of enantiomerically pure [R, R] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane-L-tartrate are obtained. The purity of the enantiomer was determined by gas chromatography after preparation of the chloroformic acid derivative with menthyl ester.

T. pl. 121 124 ^o C; [α] $\genfrac{}{}{0ex}{}{\text{23}}{\text{D}}$ = +22.3 ^o (c 1, water)
Salt (44.5 g) was transferred to the free base, as described in example A, method 1b. 20.2 g of [R, R] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane are obtained.

T. bale. 107 111 ^o C / 0.04 mbar; [α] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ = -17.5 ^o (neat)
Method II

a) Separation of the enantiomers of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane on [1R, 6S] -8-benzyl-7,9-dioxo-2,8-diazabicyclo [ 4.3.0] nonane. 24.1 g (98.8 mmol) of cis-8-benzyl-7.9-dioxo-2,8-diazabicyclo [4.3.0] nonane is heated with a mixture of 410 ml of ethanol and 25 ml of acetonitrile in a three-necked flask with stirring to boiling under reflux. In conclusion, 14.8 g (98.8 mmol) of L (+) - tartaric acid are added once. After the entire amount of tartaric acid has completely dissolved, first stop heating, but leave the flask in an oil bath. When the system cools so that the solution no longer boils, stirring is stopped. At a temperature of 50 ^° C. crystallization occurs when seed crystals are introduced. After standing overnight and cooling to room temperature, the precipitated crystals are filtered off, washed with a small amount of ethanol / petroleum ether mixture (1 1) and dried for two hours at 80 ^o C.

Yield: 9.8 g 50% of theory) [1R, 6S] -8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane-L-tartrate; [α] $\genfrac{}{}{0ex}{}{\text{23}}{\text{D}}$ = +47.7 ^° (c 0.5, 1N HCl).

Twice recrystallization from a mixture of ethanol and glycol monomethyl ether subjected to further purification: [α] $\genfrac{}{}{0ex}{}{\text{23}}{\text{D}}$ = +58.6 ^° (c 0.5, 1N HCl).

¹ H-NMR (dimethyl sulfoxide): 7.22 7.35 (2m, 2H. Aryl-H); 4.55 (s, 2H, benzyl-CH ₂ ); 4.28 (s, 2H, tartaric acid-CH); 3.91 (d, 1H, 1-CH); 2.97 (dd, 1H, 6-CH); 2.53 2.66 (m, 2H, 3-CH ₂ ); 1.78 and 1.68 (2m, 2H, 5-CH ₂ ); 1.42 and 1.28 ppm (2m, 2H, 4-CH ₂ ).

C ₁₈ H ₂₂ N ₂ O ₈ (394).

 Calculated: C 54.4; H 5.6; N, 7.1; O 32.5.

 Found: C, 54.7; H 5.8; N, 7.1; O 32.4.

3,6 г (9,1 ммоль) полученного таким путем диастереомерночистого тартрата растворяют в воде для выделения основания и смешивают с насыщенным раствором кислого углекислого натрия до установления значения pH от 7 до 8. Водный раствор экстрагируют четыре раза по 20 мл метиленхлоридом. Объединенные метиленхлоридные фазы сушат над сульфатом магния и сгущают.The complete configuration was determined using x-ray diffraction analysis:

3.6 g (9.1 mmol) of the diastereomerically pure tartrate obtained in this way are dissolved in water to isolate the base and mixed with a saturated solution of sodium hydrogencarbonate until a pH of 7 to 8. The aqueous solution is extracted four times with 20 ml of methylene chloride. The combined methylene chloride phases are dried over magnesium sulfate and concentrated.

 Yield: 2.2 g (99% of theory) [1R, 6S] -8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane.

T. pl. 60 61 ^o C; [α] $\genfrac{}{}{0ex}{}{\text{23}}{\text{D}}$ = +21.8 ^° (c 5, ethanol).

Gas chromatography gives an excess of the enantiomer 93.8 after the derivative with chloroformic acid menthyl ester is obtained
b) Reduction of [1R, 6S] -8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane to [R, R] -8-benzyl-2,8-diazabicyclo [4.3.0 ] nonana. 0.34 g (9 mmol) of lithium aluminum hydride in 18 ml of anhydrous tetrahydrofuran was placed in a heated flask in a nitrogen atmosphere and 0.73 (3 mmol) of [1R, 6S] -8-benzyl-7.9-dioxo-2.8 was added dropwise diazabicyclo [4.3.0] nonane as a solution in 3 ml of anhydrous tetrahydrofuran. Then refluxed for 16 hours. The treatment is carried out by dropping 0.34 ml of water in 10 ml of tetrahydrofuran, 0.34 ml of 10% sodium alkali, as well as 1.02 ml of water. The precipitate was filtered off, washed with tetrahydrofuran and the filtrate was concentrated. 0.7 g of crude [R, R] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane is isolated (composition by gas chromatography: 99%).

 When gas chromatographic determination of the purity of the enantiomer was not observed racemization.

2) [R, R] -2,8-diazabicyclo [4.3.0] nonane. By prescribing hydrogenated Example ₂ A 19.4 g (0.09 mol) [R, R] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane.

1) [S, S] -8-бензил-2-метил-2,8-диазабицикло[4.3.0] нонан. 43,2 г (0,2 ммоль) [S,S]-8-бензил-2,8-диазабицикло[4.3.0]нонана смешивают с 20 мл 37%-ного раствора формальдегида, 40 мл воды и 24 г уксусной кислоты и гидрируют 10 ч при 20^oC и 20 бар над 2 г палладия на активированном угле (5). Затем фильтруют, фильтрат подщелачивают карбонатом калия и продукт экстрагируют трет. -бутилметиловым эфиром. После сушки над сульфатом натрия сгущают и остаток перегоняют в вакууме. Выход: 14,8 г, Т. кип. 114 124^oC/0,14 мбар.Yield: 9.61 g (85) [R, R] -2,8-diazabicyclo [4.3.0] nonane. T. bale. 45 - 58 ^o C / 0.08 mbar; [α] $\genfrac{}{}{0ex}{}{\text{23}}{\text{D}}$ = +2.30 ^o (undiluted)
Example B. [S, S] -2-methyl-2,8-diazabicyclo [4.3.0] nonane

1) [S, S] -8-benzyl-2-methyl-2,8-diazabicyclo [4.3.0] nonane. 43.2 g (0.2 mmol) of [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane are mixed with 20 ml of a 37% formaldehyde solution, 40 ml of water and 24 g of acetic acid and hydrogenated for 10 hours at 20 ^° C. and 20 bar over 2 g of palladium on activated carbon (5). It is then filtered, the filtrate is made basic with potassium carbonate and the product is extracted with tert. butyl methyl ether. After drying over sodium sulfate, it is concentrated and the residue is distilled in vacuo. Yield: 14.8 g, T. bale. 114 124 ^o C / 0.14 mbar.

2) [S, S] -2-methyl-2,8-diazabicyclo [4.3.0] nonane. 12.9 g (56 mmol) of [S, S] -8-benzyl-2-methyl-2,8-diazabicyclo [4.3.0] nonane is hydrogenated in 90 ml of methanol at 90 ^° C. and 90 bar over 1.1 g palladium on activated carbon (5). Then it is filtered, the filtrate is evaporated in a rotary evaporator and the residue is distilled in vacuum.

Yield: 5.5 g of enantiomerically pure [S, S] -2-methyl-2,8-diazabicyclo [4.3.0] nonane (determined by preparation of a derivative with Mosher's reagent). T. bale. 78 81 ^o C / 14 mbar.

 Example G. [R, R] -2-methyl-2,8-diazabicyclo [4.3.0] nonane.

Соединение получают по описанному в примере В способу, исходя из 43,2 г (0,2 моль) [R,R]-8-бензил-2,8-диазабицикло[4.3.0]нонана.

The compound is prepared as described in Example B, starting from 43.2 g (0.2 mol) of [R, R] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane.

Yield: 4.9 g of [R, R] methyl-2,8-diazabicyclo [4.3.0] nonane; T. bale. 30 - 33 ^o C / 0.12 mbar
Example D. Cis-7,9-dioxo-8 - ([S] 1-phenyl-ethyl) -2,8-diazabicyclo [4.3.0] nonane.

1) ([S]1-фенил-этил)имид пиридин-2,3-дикарбоновой кислоты. Берут 74,5 г (0,5 моль) ангидрида пиридин-2,3-дикарбоновой кислоты, растворенного при 20^oC в 500 мл диоксана, и прикапывают 60,5 г (0,5 моль) S(-)1-фенил-этиламина, после чего повышают температуру до 33^oC. Перемешивают еще один час, затем сгущают в ротационном испарителе и удаляют оставшийся растворитель при 40^oC/0,1 мбар. Остаток поглощают в 245 г (2,4 моль) уксусного ангидрида, смешивают с 4,9 г (0,006 моль) безводного ацетата натрия и перемешивают 1 ч при 100^oC. После охлаждения при хорошем перемешивании выливают на 1 л ледяной воды, отсасывают, промывают холодной водой и сушат на воздухе. Сырой продукт (114 г, т. пл. 112 114^oC) перекристаллизовывают из 285 мл метанола.

1) ([S] 1-phenyl-ethyl) imide of pyridine-2,3-dicarboxylic acid. Take 74.5 g (0.5 mol) of pyridine-2,3-dicarboxylic acid anhydride, dissolved at 20 ^° C. in 500 ml of dioxane, and dropwise 60.5 g (0.5 mol) of S (-) 1-phenyl -ethylamine, after which the temperature is raised to 33 ^o C. Stir for another hour, then thicken in a rotary evaporator and remove the remaining solvent at 40 ^o C / 0.1 mbar. The residue is taken up in 245 g (2.4 mol) of acetic anhydride, mixed with 4.9 g (0.006 mol) of anhydrous sodium acetate and stirred for 1 h at 100 ^o C. After cooling with good stirring, it is poured into 1 liter of ice water, suctioned off, washed with cold water and air dried. The crude product (114 g, mp 112 114 ^° C.) was recrystallized from 285 ml of methanol.

Yield: 96.3 g (76%); T. pl. 115 117 ^o C; [α] $\genfrac{}{}{0ex}{}{\text{22}}{\text{D}}$ = -46.9 ^o (c 2, ethanol).

2) Cis-7,9-dioxo-8 - ([S]) 1-phenyl-ethyl) -2,8-diazabicyclo [4.3.0] nonane. 79.7 g (0.316 mol) of ([S] 1-phenyl-ethyl) -imide pyridine-2,3-dicarboxylic acid are hydrogenated in 600 ml of tetrahydrofuran at 90 ^° C./100 bar over 10 g of palladium on activated carbon. After the uptake of hydrogen, the catalyst is filtered off and the filtrate is completely concentrated. 83.7 g of a viscous residue are obtained. Content 95%
¹ H-NMR (day. Chloroform, 200 MHz): 1.4 1.7 (m, 3H); 1.82 and 1.83 (2d, 3H); 1.9 2.05 (m, 1H); 2.28 (broad s, 1H); 2.54 2.86 (m, 3H); 3.77 (d, 1H); 5.39 (q, 1H); 7.24 7.48 ppm (m, 5H).

 Example E. Cis-2-oxa-5,8-diazabicyclo [4.3.0] nonane.

1) Транс-1-бензоил-3-бром-4-(2-гидроксиэтокси)-пирролидин. Растворяют 95 г (0,55 моль) 1-бензоил-3-пирролина в 380 г этиленгликоля и добавляют при комнатной температуре 101 г (0,57 моль) N-бромсукцинимида пятиграммовыми порциями в течение 2 ч. После этого перемешивают в течение ночи при комнатной температуре, выливают на воду, экстрагируют метиленхлоридом, сушат над сульфатом магния и раствор сгущают. Остаток (188 г) хроматографируют на силикагеле с этилацетатом.

1) Trans-1-benzoyl-3-bromo-4- (2-hydroxyethoxy) -pyrrolidine. 95 g (0.55 mol) of 1-benzoyl-3-pyrroline in 380 g of ethylene glycol are dissolved and 101 g (0.57 mol) of N-bromosuccinimide are added in five-gram portions for 2 hours at room temperature. After this, it is stirred overnight at room temperature, poured onto water, extracted with methylene chloride, dried over magnesium sulfate and the solution is concentrated. The residue (188 g) was chromatographed on silica gel with ethyl acetate.

Yield: 136.5 g (78% of theory): Content by gas chromatography: 99%
2) Trans-1-benzoyl-3-bromo-4- (2-tolyloxyethoxy) pyrrolidine. 92 g (0.239 mol) of trans-1-benzoyl-3-bromo-4- (2-hydroxyethoxy) pyrrolidine, 32 g (0.316 mol) of triethylamine and 1 g of 4-dimethylaminopyridine are dissolved in 750 ml of toluene and 60 g (0, 31 mol) of tosyl chloride in 450 ml of toluene. It is stirred for two days at room temperature, water is added, the aqueous phase is separated and extracted with toluene. Toluene solutions are washed with 10% hydrochloric acid, dried over magnesium sulfate, concentrated, dissolved in ethyl acetate and filtered through silica gel. The filtrate is concentrated.

 Yield: 125 g (91% of theory). Thin layer chromatography shows a homogeneous compound.

 3) Cis-8-benzoyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane. 124 g (0.265 mol) of trans-1-benzoyl-3-bromo-4- (2-tosylethoxy) pyrrolidine are heated with 86 g (0.8 mol) of benzylamine in 1.5 L of xylene overnight under reflux. The benzylamine salt is filtered off and the filtrate is concentrated.

 Crude yield: 91.2 g.

 4) Cis-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane. 91 g (0.265 mol) of cis-8-benzoyl-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane are heated with 200 ml of concentrated hydrochloric acid and 140 ml of water overnight under reflux. After cooling, benzoic acid is filtered off, concentrated to half the volume, the solution is made alkaline with potassium carbonate, extracted with chloroform, dried over potassium carbonate, concentrated and distilled.

Yield: 30.7 g (48.8% of theory); T. bale. 134 142 ^o C / 0.6 mbar. Gas Chromatography Content 92%
5) Cis-2-oxa-5,8-diazabicyclo [4.3.0] nonane dihydrochloride. Hydrogenated 26 g (0.11 mol, 92%) of cis-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane in 180 ml of ethanol and 19 ml of concentrated hydrochloric acid with 3 g of palladium activated carbon (10% Pd) at 100 ^o C and a hydrogen pressure of 100 bar. The catalyst is filtered off, the filtrate is concentrated and the precipitated crystals are dried in a desiccator over phosphorus pentoxide.

Yield: 17.1 g (77% of theory). T. pl. 244 250 ^o C.

 Example G. Separation of the enantiomers of cis-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane.

150.1 g (1 mol) of D (-) - tartaric acid are placed at 60 65 ^° C in 700 ml of methanol and a solution of 218.3 g (1 mol) of cis-5-benzyl-2-oxa-5.8- is added dropwise. diazabicyclo [4.3.0] nonane in 300 ml of methanol. It is then allowed to slowly cool to 49 ^° C. until the solution becomes turbid, and seeded with crystals of 1R, 6S-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] non-D-tartrate obtained in the previous experiment stirred for 30 minutes at this temperature until the formation of crystal nuclei and slowly cooled to 0 3 ^o C. After filtration, washed with a mixture of 200 ml of ethanol and 100 ml of methanol cooled to 0 ^o C and then three times with 300 ml of ethanol, in conclusion, the product is dried on air.

Yield: 160 g of 1R, 6S-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane-tratrate (87% of theory). T. pl. 174.5 176.5 ^o C.

Isomer purity> 97% (after conversion with 1-phenyl ethyl isocyanate and determined by liquid chromatography under pressure). [α] $\genfrac{}{}{0ex}{}{\text{23}}{\text{D}}$ = +24.0 ^o (c 1, methanol).

 156.9 g of the first crystallizate are recrystallized from 1500 ml of methanol.

Yield: 140.0 g (90% of theory) mp. 176 177 ^o C. [α] $\genfrac{}{}{0ex}{}{\text{23}}{\text{D}}$ = +25.2 ^° (c 1, methanol).

 The methanol mother liquors of the first crystallization are evaporated in a rotary evaporator. The syrupy residue (236 g) is dissolved in 500 ml of water, using 250 ml of 6 N. sodium alkali is adjusted to pH 12 13, extracted with 350 ml of toluene three times, the extract is dried over sodium carbonate and evaporated in vacuo. The residue, 113.1 g of brown oil, which contains, according to gas chromatographic analysis, 97% cis-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane, without purification it is used to obtain 1S, 6R- enantiomers.

113.1 g (0.518 mol) of crude enriched 1S, 6R-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane is dissolved in 155 ml of methanol and 77.8 g (0.518 mol) are added dropwise to the boiling solution. ) L (+) - tartaric acid in 363 ml of methanol. Already during instillation, porridge of crystals gradually forms. Stirred for 1 hour at 60 ^o C and then slowly over two hours, cooled to 0 ^o C. The crystals are filtered and washed with chilled to 0 ^o C with a mixture (2: 1) of ethanol and methanol and finally washed with ethanol three times. Then dried in air.

Yield: 145.5 g of 1S, 6R-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane-L-tartrate (79% of theory). T. pl. 174.5 176.5 ^o C.

Isomer purity> 97% (after conversion with 1-phenyl ethyl isocyanate according to liquid chromatography under pressure) [α] $\genfrac{}{}{0ex}{}{\text{23}}{\text{D}}$ = -24.0 ^o (s 1, methanol).

Isolation of enantiomerically pure base:
144 g (0.39 mol) of 1S, 6R-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane tartrate are dissolved in 250 ml of water and treated with 175 ml (1.05 mol) of 6 n . sodium alkali. The separated oil is placed in 500 ml of toluene, the organic phase is separated and the aqueous phase is extracted three times with 250 ml of toluene. The combined organic phases are dried over sodium carbonate. Filter and evaporate in a rotary evaporator. The residue was distilled in high vacuum on a Vigreux type column (20 cm).

Yield: 81.6 g (96 theory) 1S, 6R-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane. T. bale. 120 - 139 ^o C / 0.04 0.07 mbar. Content: 100% (determined by gas chromatography). Density: δ = 1.113 g / ml. [α] $\genfrac{}{}{0ex}{}{\text{23}}{\text{D}}$ = -60.9 ^o (neat). Distillation residue: 0.12 g.

Likewise, from 139.2 g (0.376 mol) of 1R, 6S-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane tartrate 76.0 g (93 theory) 1R, 6S was obtained -5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane. [α] $\genfrac{}{}{0ex}{}{\text{23}}{\text{D}}$ = +61.2 ^o (undiluted)
The separation of enantiomers described for cis-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane is carried out similarly with trans-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane up to R, R- and S, S-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane.

 Example 3

1) 3S, 4S-4-allyloxy-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester. 16.5 g (0.55 mol) of 80% sodium hydride are placed in 500 ml of absolute dioxane and a solution of 107.5 g (0.53 mol) of tert is added dropwise at 60 ^° C. S, S-3,4-dihydroxy-pyrrolidine-1-carboxylic acid butyl ester dissolved hot in absolute dioxane. It is stirred for another hour at 60 ^° C. and then 64 g (0.53 mol) of allyl bromide are added dropwise. Finally, it was stirred for three hours at 60 ^° C. It was evaporated and the residue was dissolved in 200 ml of water and 600 ml of methanol. 200 ml of pentane are extracted three times, methanol is distilled off in a rotary evaporator, diluted with 200 ml of water and extracted with methylene chloride. The methylene chloride solution was dried over magnesium sulfate, evaporated and dissolved in tert-butyl methyl ether (200 ml). After night, 9 g of product (44 mmol) crystallizes out. The ethereal solution is concentrated and distilled.

Yield: 83 g (80 of theory, counting on the returned starting material and diallyl ether). T. bale. 149 ^o C / 0.7 mbar to 159 ^o C / 0.9 mbar.

 The distillate contains 5 starting reaction product and 4 diallyl ether.

[α] $\genfrac{}{}{0ex}{}{\text{23}}{\text{D}}$ = -10.5 ^o (c 1, methanol).

2) Tert. 3S, 3S-3-hydroxy-4- (2-hydroxyethoxy) -pyrrolidine-1-carboxylic acid butyl ester. Dissolve 64 g (0.34 mol, 91th) of 3S, 4S-4-allyloxy-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester in 250 ml of methanol, cooled to 0 ^° C and passed through a solution of ozone until until the connected washing tank with a solution of potassium iodide shows ozone and thereby the completion of the reaction. Residues of ozone are displaced by nitrogen.

Then, the resulting ozonide is reduced at 0 ^° C. with 18 g of sodium borohydride, which is added in portions of 1 g each. Finally, it is stirred overnight at room temperature, the mixture is concentrated, diluted with water, mixed with 20 g of potassium carbonate and extracted with 100 ml of methylene chloride five times. . The organic solutions are dried over magnesium sulfate and concentrated.

Yield: 65.8 g (100 of theory). The product is the 91st (gas chromatograph.). [α] $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ = -15.2 ^° (C 0.97, methanol).

 3) 3S, 4S-1-tert. Butoxycarbonyl-3-tosyloxy-4- (2-tosyloxyethoxy) -pyrrolidine. 2.7 g (10 mmol, 91th) of 3S, 4S-3-hydroxy-4- (2-hydroxyethoxy) pyrrolidine-1-carboxylic acid tert-butyl ester are added to 30 ml of methylene chloride, 6 ml of 45th are added sodium alkali and 0.1 g of benzyltriethylammonium chloride and then dropwise with cooling a solution of 2.86 g (20 mmol) of tosyl chloride in 10 ml of methylene chloride. Finally, it is stirred for another hour at room temperature, poured onto 20 ml of water, the organic phase is separated and the aqueous phase is extracted with methylene chloride. The organic phases are dried over sodium sulfate and concentrated.

Yield: 5 g (90 of theory). The product is homogeneous (thin layer chromatography)
4) 1S, 6R-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane-8-carboxylic acid tert-butyl ester. 87 g (156 mmol) of 3S, 4S-1-tert-butoxycarbonyl-3-tosyloxy-4- (2-tosyloxyethoxy) pyrrolidine are heated with 58 g (0.54 mol) of benzylamine in 1 l of xylene overnight under reflux . It is cooled, the precipitated benzylamine salt is filtered off and the residue is concentrated.

 Yield: 43 g (58 of theory). Product 67th (gas chromatographic).

 5) 1S, 6R-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane. 43 g (90 mmol) of tert are heated. 1S, 6R-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane butyl ether in 35 ml of concentrated hydrochloric acid and 35 ml of water under reflux until the carbon dioxide evolution is complete. Alkalized with potassium carbonate, extracted with chloroform, dried organic solutions over magnesium sulfate, concentrated and distilled twice on a Vigreux type column (20 ml).

Yield: 11.1 g (55 of theory). T. bale. 108 115 ^o C / 0.07 mbar, [α] $\genfrac{}{}{0ex}{}{\text{26}}{\text{D}}$ = -58.3 ^o (neat)
Example I.

 1) Tert. 3R, 4R-4-allyloxy-3-hydroxypyrrolidine -1-carboxylic acid butyl ester. The interaction occurs analogously to example 3 1) with tert. R, R-3,4-dihydroxypyrrolidine-1-carboxylic acid butyl ether.

T. bale. 145 ^o C / 0.1 mbar. [α] $\genfrac{}{}{0ex}{}{\text{23}}{\text{D}}$ = +9.5 ^o (c 1.0, methanol). The product is the 95th (gas chromatographic).

 2) Tert. 3R, 4R-3-hydroxy-4- (2-hydroxyethoxy) -pyrrolidine-1-carboxylic acid butyl ester. The interaction occurs analogously to example 3 2) with tert-butyl ether 3R, 4R-4-allyloxy-3-hydroxypyrrolidine-1-carboxylic acid.

Yield: 99 of theory (0.175 molar loading). [α] $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ = +16.5 ^o (c 0.94, methanol)
3) 3R, 4R-1-tert. Butoxycarbonyl-3-tosyloxy-4- (2-tosyloxyethoxy) -pyrrolidine. The interaction occurs analogously to example 3 3) with tert-butyl ether 3R, 4R-3-hydroxy-4- (2-hydroxyethoxy) -pyrrolidine-1-carboxylic acid.

 Yield: quantitative (0.11 molar loading).

 4) Tert. butyl ether 1R, 6S-5-benzyl-2-oxa-5,8-diazabicyclo [4.3. nonane-8-carboxylic acid. The interaction occurs analogously to example 3 4) with 3R, 4R-1-butoxycarbonyl-3-tosyloxy-4 - (2-tosyloxyethoxy) -pyrrolidine.

 Yield: 40% of theory (0.1 molar loading).

 5) 1R, 6S-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane. The interaction occurs analogously to example 3 5) with tert-butyl ether 1R, 6S-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane-8-carboxylic acid.

Yield: 63 of theory (40 μ molar loading). T. bale. 120 ^o C / 0.06 mbar. The product is the 95th (gas chromatographic). [α] $\genfrac{}{}{0ex}{}{\text{23}}{\text{D}}$ = +58.5 ^o (neat).

 Example K.

1) Dihydrochloride 1S, 6R-2-oxa-5,8-diazabicyclo [4.3.0] nonane. Hydrogenated 7.5 g (34.4 mmol) of 1S, 6R-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane in 200 ml of ethanol by adding 7 ml of concentrated hydrochloric acid with 1 g of palladium per activated carbon (10% Pd) at 100 ^o C and 100 bar. The catalyst is filtered off and washed repeatedly with water. The aqueous filtrate is concentrated, after which the residue crystallizes. The crystals are thoroughly mixed with ethanol, filtered and dried in air.

Yield: 4.6 g (66.5% of theory). T. pl. 233 235 ^o C.

2) 1S, 6R-2-oxa-5,8-diazabicyclo [4.3.0] nonane. Hydrogenate 59 g (0.27 mol) of 1S, 6R-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane in 500 ml of ethanol with 5 g of palladium on activated carbon (10% Pd) at 120 ^o C and 120 bar. The catalyst was filtered off, the filtrate was concentrated and the residue was distilled.

Yield: 32.9 g (95 of theory). T. bale. 65 ^o C / 0.03 mbar. [α] $\genfrac{}{}{0ex}{}{\text{28}}{\text{D}}$ = +8.2 ^o (undiluted).

 Purity ≥99.5% (after derivatization with Mosher reagent).

 Example L.

 1) Dihydrochloride 1R, 6S-2-oxa-5,8-diazabicyclo [4.3.0] nonane. The interaction occurs analogously to example K1 with 1R, 6S-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane.

 Yield: 77 from theory (23.8 mmolar load).

T. pl. 230 232 ^o C.

 2) 1R, 6S-2-oxa-5,8-diazabicyclo [4.3.0] nonane. The interaction occurs analogously to example K2 with 1R, 6S-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane.

Yield: 93.3% of theory (1.58 molar loading). T. bale. 63 - 65 ^o C / 0.03 mbar. [α] $\genfrac{}{}{0ex}{}{\text{23}}{\text{D}}$ = -8.4 ^o (neat)
Isomer purity: ≥99.5 (derivatization with Mosher reagent).

 1R, 6R - respectively. 1S, 6S-2-oxa-5,8-diazabicyclo [4.3.0] nonane can be obtained similarly.

 Example M. Dihydrobromide 1R, 6S-2-oxa-5,8-diazabicyclo [4.3.0] nonane.

 1) 1R. 6S- (1R-phenylethyl) -8-tosyl-2-oxa-5,8-diazabicyclo [4.3.) Nonane. 101.8 g (0.196 mol) of trans-3-bromo-1-tosyl-4- (2-tosyloxyethoxy) pyrrolidine and 72 g (0.584 mol) of R - (+) - 1-phenylethylamine in 900 ml of xylene are heated nights with reflux. Washed a cooled solution of 2 N. sodium hydroxide, dried over potassium carbonate, the desiccant is removed and the solution is concentrated. Upon cooling, crystals precipitate from the residue, which are filtered off and recrystallized from a mixture of 750 ml of washing gasoline and 200 ml of n. butanol.

 Yield: 16 g (39 of theory, optically pure material).

T. pl. 188 ^o C. [α] $\genfrac{}{}{0ex}{}{\text{28}}{\text{D}}$ = +103.7 ^o (c = 1, chloroform)
2) 1R, 6S-8-tosyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane. 13 g (33.6 mmol) of 1R, 6S-5- (1R-phenylethyl) -8-tosyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane are hydrogenated in 200 ml of ethanol over 2.5 g of palladium activated carbon (10 Pd) at 100 ^o C and 100 bar. The catalyst is filtered off, the filtrate is concentrated and recrystallized from 30 ml of toluene.

Yield: 7.5 g (79 from theory). T. pl. 160 161 ^o C. [α] $\genfrac{}{}{0ex}{}{\text{23}}{\text{D}}$ = +17.5 ^o (c 1.21, chloroform).

 3) Dihydrobromide 1R, 6S-2-oxa-5,8-diazabicyclo [4.3.0] nonane. 7 g (24.8 mmol) of 1R, 6S-8-tosyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane are dissolved in 25 ml of a 33 solution of hydrogen bromide in glacial acetic acid, 5 g of phenol are added and stirred overnight at room temperature. It is diluted with diisopropyl ether, the crystallized salt is filtered off and dried in air.

 Yield: 5.5 g.

1) 2-бром-3,4,5,6-тетрафтор-бензоилхлорид. 365 г (1,33 моль) 2-бром-3,4,5,6-тетрафторбензойной кислоты вносят в 2 л тионилхлорида и смесь нагревают 11 ч с обратным холодильником до прекращения выделения газа. Избыточный тионилхлорид отгоняют в вакууме и остаток перегоняют.Derivation with Mosher's reagent and gas chromatographic analysis show only a detectable enantiomer (isomer purity ≥99.5)
Example N. 5-bromo-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid

1) 2-bromo-3,4,5,6-tetrafluoro-benzoyl chloride. 365 g (1.33 mol) of 2-bromo-3,4,5,6-tetrafluorobenzoic acid are added to 2 L of thionyl chloride and the mixture is refluxed for 11 hours until gas evolution ceases. Excess thionyl chloride is distilled off in vacuo and the residue is distilled.

Yield: 330 g (85% of theory). T. bale. 81 85 ^o C / 3 5 mbar,
2) Diethyl ether (2-bromo-3,4,5,6-tetrafluoro-benzoyl) -malonic acid. 15.9 g (0.167 mol) of magnesium chloride are added to 150 ml of anhydrous acetonitrile (dried over zeolite) and 26.9 g (0.167 mol) of malonic acid diethyl ether are added dropwise with cooling. It is cooled to 0 ^° C., 46 ml (33.7 g of 0.33 mol) of triethylamine are added dropwise and the mixture is stirred for 30 minutes. Finally, 48.9 g (0.168 mol) of 2-bromo-3,4,5,6-tetrafluorobenzoyl chloride are added dropwise, the mixture is stirred for another hour at 0 ^° C. and the mixture is left to stand at room temperature overnight. Mix with 100 ml of 5 N. hydrochloric acid, extracted three times with methylene chloride, dried over sodium sulfate and concentrated in vacuo. Crude product: 62.7 g
3) Ethyl ester of (2-bromo-3,4,5,6-tetrafluoro-benzoyl) -acetic acid. 60 g of crude diethyl ether (2-bromo-3,4,5,6-tetrafluoro-benzoyl) -malonic acid are added to 150 ml of water, mixed with 0.6 g of toluenesulfonic acid and heated for 6 hours under reflux. It is extracted with methylene chloride, washed with water, dried over sodium sulfate and concentrated.

 Crude yield: 46 g.

T. bale. (test distillation in a ball tube): 150 160 ^o C (furnace) / 3 mbar;
Mass spectrum: m / e 342 (M ⁺ ), 279 (M ⁺ -OC ₂ H ₅ ), 263 (M ⁺ -Br), 257, 255 (M ⁺ -CH ₂ CO ₂ C ₂ H ₅ ), 235 (263-28).

4) 2- (2-Bromo-3,4,5,6-tetrafluoro-benzoyl) -3-ethoxyacrylic acid ethyl ester. Add 45 g of crude ethyl ester of (2-bromo-3,4,5,6-tetrafluoro-benzoyl) -acetic acid in 32.2 g (0.31 mol) of acetic anhydride and 28.4 g (0.19 mol) orthoformate triethyl ether and refluxed for 2 hours. The excess reagent is removed first in a vacuum, then in a deep vacuum (bath temperature 120 130 ^o C) and the crude product is fed to the next stage.

Crude yield: 50.7 g
5) 2- (2-Bromo-3,4,5,6-tetrafluoro-benzoyl) -3-cyclopropylamino-acrylic acid ethyl ester. 50.7 g of the crude product from step 4) in 90 ml of ethanol are added dropwise under ice-cooling with 8.6 g (0.15 mol) of cyclopropylamine, the mixture is stirred at room temperature, left overnight, cooled well again, the crystalline is filtered off washed with cold methanol and dried.

 Yield: 29 g (42 after four stages).

T. pl. 103 105 ^o C (from ethanol)
6) 5-Bromo-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester. 28 g (68 mmol) of 2- (2-bromo-3,4,5,6-tetrafluoro-benzoyl) -3-cyclopropylamino-acrylic acid ethyl ester is heated in 88 ml of dimethylformamide with 6.9 g (164 mmol) of sodium fluoride 6 hours with reflux. After cooling, the mixture is poured into water, the precipitate formed (red) is filtered off, washed with plenty of water and dried at 80 ^° C. in an air cabinet.

 Crude yield: 27.3 g.

T. pl. 150 170 ^o C: after recrystallization from glycol monomethyl ether, so pl. 187 191 ^o C
7) 5-Bromo-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid. 26.7 g (68 mmol) of crude ethyl 5-bromo-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are added to a mixture of 165 ml of acetic acid, 110 ml of water and 18 ml of concentrated sulfuric acid and heated for 2 hours under reflux. The cooled reaction mixture is poured into ice water, the precipitate formed is filtered off, washed with plenty of water and dried in an air cabinet at 80 ^° C.

 Yield: 19.7 (80% of theory).

T. pl. 208 210 ^o C (decomposition); after recrystallization from glycol monomethyl ether, mp 212 214 ^o C (decomposition).

¹ H-NMR (dimethyl sulfoxide: 8.73 s (1H y C-2), 4.16 m (1H, cyclopropyl), 1.2 m (4H, cyclopropyl) [h / mill]
Mass spectrum: m / e 361 (M ⁺ -H ₂ O), 317 (M-CO ₂ ), 41 (100 C ₃ H ₅ ).

 The following examples illustrate the preparation of new compounds of formula (I).

 Example 1

А. 1-Циклопропил-7-([S, S] -2,8-диазабицикло[4.3.0] нон-8-ил)- 6,8-дифтор-1,4-дигидро-4-оксо-3-хинолинкарбоновая кислота. 141,5 г (0,5 моль) 1-циклопропил-6,7,8-трифтор-1,4-дигидро-4-оксо-3- хинолинкарбоновой кислоты нагревают 1 ч с обратным холодильником в смеси из 1500 мл ацетонитрила и 750 мл диметилформамида в присутствии 55 г (0,5 моль) 1,4-диазабицикло[2.2.2]октана с 69,25 г (0,55 моль) (+)-[S,S]-2,8-диазабицикло[4.3.0]нонана (чистота изомера 99,5% газовая хроматография: 99,8%-ный). Суспензию охлаждают, осадок отфильтровывают, промывают водой и затем перемешивают еще с 1 л воды (pH 7). Отфильтровывают и сушат при 60^oC в воздушном шкафу.

A. 1-Cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) - 6,8-difluoro-1,4-dihydro-4-oxo-3- quinoline carboxylic acid. 141.5 g (0.5 mol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is heated for 1 hour under reflux in a mixture of 1500 ml of acetonitrile and 750 ml of dimethylformamide in the presence of 55 g (0.5 mol) of 1,4-diazabicyclo [2.2.2] octane with 69.25 g (0.55 mol) (+) - [S, S] -2,8-diazabicyclo [ 4.3.0] nonane (isomer purity 99.5%; gas chromatography: 99.8%). The suspension is cooled, the precipitate is filtered off, washed with water and then stirred with 1 l of water (pH 7). Filter and dry at 60 ^° C. in an air oven.

 Yield: 163.4 g (84 from theory).

T. pl. 249 251 ^o C (decomposition).

B. Hydrochloride (-) - 1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6,8-difluoro-1,4-dihydro-4 -oxo-3- quinoline carboxylic acid. 6.0 g (15.4 mmol) 1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) - 6.8-1,4-dihydro 4-oxo-3-quinolinecarboxylic acid is dissolved in 40 ml of semi-concentrated hydrochloric acid at 60 ^° C. and the hydrochloride solution is filtered. The filtrate is half-concentrated, cooled with ice and mixed with 40 ml of ethanol. The yellow crystallize is filtered off, washed with ethanol and dried at 60 ^o C in high vacuum, while the color is clarified. 5.51 g (84 of theory) of hydrochloride are obtained, which is already very pure. For further purification, dissolve it in 50 ml of water with heating. The yellow solution is mixed with 5 ml of semi-concentrated hydrochloric acid, cooled with ice, the crystallized precipitate is filtered off, washed well with ethanol and dried first at room temperature and then in high vacuum at 100 ^o C.

Yield: 4.64 g (70.8% of theory). T. pl. 324 325 ^o C (decomposed).

Thin layer chromatography (silica gel, dichloromethane / methanol / 17% aqueous ammonia 30 8 1); homogeneous, R _f 0.3. [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ = -256 ^o (c 0.5, water)
Composition: 99.4% (liquid chromatography under pressure)
C ₂₀ H ₂₁ F ₂ N ₃ O ₃ • HCL (425.5)
Calculated: C 56.4; H 5.2; N, 9.9; CL 8.3.

 Found: C, 56.3; H 5.4; N, 9.8; CL 8.3.

 Example 2

А. 8-хлор-1-циклопропил-7-([S, S]-2,8-диазабицикло[4.3.0]нон-8- ил)-6-фтор-1,4-дигидро-4-оксо-3-хинолинкарбоновая кислота. Параллельно готовят и одновременно перерабатывают 2 реакционные смеси следующего состава: 180 г (0,6 моль) 8-хлор-1-циклопропил-6,7-дифтор-1,4-дигидро-4-оксо-3- хинолинкарбоновой кислоты нагревают в смеси из 1,8 л ацетонитрила и 900 мл диметилформамида в присутствии 99 г (0,88 моль) 1,4-диазабицикло[2.2.2]октана с 84 г (0,67 моль) (+)-[S,S]-2,8-диазабицикло[4.3.0]нонана 1 ч с обратным холодильником (внутренняя температура: 90,5^oC). Желтый раствор охлаждают и смешивают с затравочными кристаллами (получены из 5 мл пробы, которую сгустили; остаток растерли с ацетонитрилом). Это перемешивают 2 ч при температуре около 3^oC, выпавший осадок из двух смесей быстро отфильтровывают, промывают ацетонитрилом и вносят в 1,5 л ледяной воды. Сначала жидкая, хорошо перемешиваемая суспензия спустя приблизительно 10 мин превращается в трудно перемешиваемую массу, которая разбавляется дополнительными 150 мл воды. Отфильтровывают, промывают водой и сушат в воздушном сушильном шкафу при 80^oC.

A. 8-chloro-1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-4-oxo- 3-quinoline carboxylic acid. In parallel, 2 reaction mixtures of the following composition are prepared and simultaneously processed: 180 g (0.6 mol) of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is heated in a mixture from 1.8 l of acetonitrile and 900 ml of dimethylformamide in the presence of 99 g (0.88 mol) of 1,4-diazabicyclo [2.2.2] octane with 84 g (0.67 mol) (+) - [S, S] - 2,8-diazabicyclo [4.3.0] nonane 1 hour under reflux (internal temperature: 90.5 ^° C). The yellow solution was cooled and mixed with seed crystals (obtained from 5 ml of a sample that was thickened; the residue was triturated with acetonitrile). This is stirred for 2 hours at a temperature of about 3 ^o C, the precipitate from the two mixtures is quickly filtered off, washed with acetonitrile and introduced into 1.5 l of ice water. First, a liquid, well-mixed suspension after about 10 minutes turns into a difficult-to-mix mass, which is diluted with additional 150 ml of water. Filtered, washed with water and dried in an air oven at 80 ^o C.

 Yield: 402 g (82.7% of theory), light yellow product.

T. pl. 193 196 ^o C (decomposition).

R _f (silica gel; methyl chloride / methanol / 17% aqueous ammonia 30 8 1) 0.4.

B. Hydrochloride 8-chloro-1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) - 6-fluoro-1,4-dihydro-4-oxo -3-quinoline carboxylic acid. 13.1 g (32 mmol) 8-chloro-1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4- dihydro-4-oxo-3-quinoline carboxylic acid is suspended in 50 ml of water and transferred to the solution by adding 50 ml of semi-concentrated hydrochloric acid. It is filtered through a glass filter, concentrated in vacuo and the residue is stirred with approximately 300 ml of absolute ethanol. The suspension is cooled with ice, the precipitate is filtered off, washed with ethanol and dried first at room temperature and then at 100 ^° C. in vacuo.

 Yield: 13.4 g (93.8 from theory).

T. pl. 328 330 ^o C (decomposition).

R _f (silica gel; methylene chloride / methanol / 17% aqueous ammonia 30 8 1) 0.4.

 Composition: 99.9% (liquid chromatography under pressure).

[α] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ = -164.4 ^o ) c 0.45, water).

C ₂₀ H ₂₁ CLFN ₃ O ₃ • HCL 9442.3).

 Calculated: C 54.3; H 5.0; N, 9.5; CL 16.0.

 Found: C, 54.3; H 5.0; N, 9.5; CL 16.0.

B. Similarly, for example, the following salts may be prepared:
8-chloro-1-cyclopropyl-7 methanesulfonate - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-4-oxo-3 -quinoline carboxylic acid.

 8-Chloro-1-cyclopropyl-7-toluenesulfonate - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-4-oxo-3 -quinoline carboxylic acid.

 Sulfate 8-chloro-1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-4-oxo-3 -quinoline carboxylic acid.

 Acetate 8-chloro-1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-4-oxo-3 -quinoline carboxylic acid.

 Lactate 8-chloro-1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-4-oxo-3 -quinoline carboxylic acid.

 8-chloro-1-cyclopropyl-7 citrate - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-4-oxo-3 -quinoline carboxylic acid.

 8-chloro-1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-4-oxo-3 embonate -quinoline carboxylic acid.

 Example 3

Аналогично примеру 1 получают с 1-циклопропил-6,7-дифтор-1,4-дигидро-4-оксо-3-хинолинкарбоновой кислотой:
А. 1-Циклопропил-7-([S,S]-2,8-диазабицикло[4.3.0]нон-8-ил)- 1,4-дигидро-4-оксо-3-хинолинкарбоновую кислоту.

Analogously to example 1 receive with 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid:
A. 1-Cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) - 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.

T. pl. 256 258 ^o C (decomposition).

 B. Hydrochloride 1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo- [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-4-oxo-3- quinoline carboxylic acid.

T. pl. > 320 ^o C (decomposed).

[α] $\genfrac{}{}{0ex}{}{\text{26}}{\text{D}}$ = -90.6 ^o (c 0.48, water).

 Example 4

А. 6 г (20 ммоль) 1-циклопропил-5,6,7,8-тетрафтор-1,4-дигидро- 4-оксо-3-хинолинкарбоновой кислоты нагревают в смеси из 40 мл ацетонитрила и 20 мл N-метилпирролидона в присутствии 2,2 г (20 ммоль) 1,4-диазабицикло[2.2.2] октана с 2,7 г (21,4 ммоль) (+)-[S,S]-2,8-диазабицикло[4.3.0]нонана один час с обратным холодильником. Полученную суспензию охлаждают, осадок отфильтровывают, промывают ацетонитрилом и сушат при 100^oC/12 мбар.

A. 6 g (20 mmol) of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are heated in a mixture of 40 ml of acetonitrile and 20 ml of N-methylpyrrolidone in the presence of 2.2 g (20 mmol) of 1,4-diazabicyclo [2.2.2] octane with 2.7 g (21.4 mmol) (+) - [S, S] -2,8-diazabicyclo [4.3.0 ] nonana one hour under reflux. The resulting suspension was cooled, the precipitate was filtered off, washed with acetonitrile and dried at 100 ^° C / 12 mbar.

 Yield: 6.7 g (82.3 theory) 1-cyclopropyl-7 - ([S, S] diazabicyclo [4.3.0] non-8-yl) -5,6,7-trifluoro-1,4 -dihydro-4-oxo-3-quinoline carboxylic acid.

T. pl. 257 259 ^o C (decomposition); after recrystallization from glycol monomethyl ether, mp 260,265 ^° C (decomposed).

B. 1.5 g (3.7 mmol) of the product from step A are added to 6 ml of 1N. of hydrochloric acid. Soon, hydrochloride precipitated, which was filtered off, washed twice with 2.5 ml of ethanol and dried at 100 ^° C / 12 mbar.

 Yield: 1.4 g (85.7% of theory) of 1-cyclopropyl-7 hydrochloride - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) - 5.6.8 , trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.

T. pl. > 310 ^o C (decomposed).

[α] $\genfrac{}{}{0ex}{}{\text{26}}{\text{D}}$ = -272 ^o (c 0.5, water).

 Example 5

5,2 г (13 ммоль) продукта из примера 4А смешивают в 80 мл пиридина в автоклаве с 15 мл жидкого аммиака и нагревают 12 ч до 130^oC. Затем охлаждают, спускают давление в автоклаве, смесь концентрируют, остаток обрабатывают ацетонитрилом в ультразвуковой бане. Нерастворившийся осадок отфильтровывают, остаток растворяют в приблизительно 150 мл воды при нагревании, раствор фильтруют и осаждают гидрохлорид 10 мл полуконцентрированной соляной кислоты, отфильтровывают и сушат при 100^oC в воздушном сушильном шкафу. Полученный продукт суспендируют в 100 мл монометилового эфира гликоля при 110 115^oC и переводят в раствор добавкой 38 мл полуконцентрированной кислоты. Раствор фильтруют в горячем виде через стеклянный фильтр, охлаждают и отфильтровывают выпавшие кристаллы, промывают этанолом и сушат при 120^oC/12 мбар.

5.2 g (13 mmol) of the product from Example 4A are mixed in an autoclave of 80 ml of pyridine with 15 ml of liquid ammonia and heated to 130 ^° C. for 12 hours. Then it is cooled, the pressure in the autoclave is lowered, the mixture is concentrated, the residue is treated with acetonitrile in an ultrasonic bath . The insoluble precipitate is filtered off, the residue is dissolved in approximately 150 ml of water with heating, the solution is filtered and the hydrochloride precipitated with 10 ml of semi-concentrated hydrochloric acid, filtered off and dried at 100 ^° C in an air oven. The resulting product was suspended in 100 ml of glycol monomethyl ether at 110-115 ^° C and transferred to the solution by the addition of 38 ml of semi-concentrated acid. The solution is filtered hot through a glass filter, the precipitated crystals are cooled and filtered off, washed with ethanol and dried at 120 ^° C / 12 mbar.

 Yield: 2.5 g (44 theory) of 5-amine-1-cyclopropyl-7 hydrochloride - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) - 6.8- difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.

T. pl. > 335 ^o C (decomposing; darkens already below 335 ^o C).

[α] $\genfrac{}{}{0ex}{}{\text{28}}{\text{D}}$ = -280.8 ^o (c 0.53, water).

1,4 г (5 ммоль) 7-хлор-1-циклопропил-6-фтор-1,4-дигидро-4- оксо-1,8-нафтиридин-3-карбоновой кислоты перемешивают в 15 мл ацетонитрила с 1,3 г (10,3 ммоль) (+)-[S,S]-2,8-диазабицикло [4.3.0]нонана в отсутствии воды 1 ч при комнатной температуре. Спустя ночь отфильтровывают, промывают ацетонитрилом и очищают путем хроматографии на силикагеле (растворитель: метиленхлорид/метанол/17% -ный водный аммиак 30 8 1; R_f 0,4). Полученную 1-циклопропил-7-([S, S] -диазабицикло[4.3.0] нон-8-ил) -6-фтор-1,4-дигидро-4-оксо-1,8-нафтиридин-3-карбоновую кислоту растворяют в 15 мл полуконцентрированной соляной кислоты, раствор упаривают и остаток размешивают с этанолом. Осадок отфильтровывают, промывают этанолом и сушат при 120^oC/12 мбар.Example 6

1.4 g (5 mmol) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid is stirred in 15 ml of acetonitrile with 1.3 g (10.3 mmol) (+) - [S, S] -2,8-diazabicyclo [4.3.0] nonane in the absence of water for 1 h at room temperature. After one night, it is filtered off, washed with acetonitrile and purified by chromatography on silica gel (solvent: methylene chloride / methanol / 17% aqueous ammonia 30 8 1; R _f 0.4). The resulting 1-cyclopropyl-7 - ([S, S] -diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic the acid is dissolved in 15 ml of semi-concentrated hydrochloric acid, the solution is evaporated and the residue is stirred with ethanol. The precipitate was filtered off, washed with ethanol and dried at 120 ^° C / 12 mbar.

 Yield: 960 mg (47 theory) of 1-cyclopropyl-7 hydrochloride - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro- 4-oxo-1,8-naphthyridine-3-carboxylic acid.

T. pl. 345 346 ^o C (decomposition).

[α] $\genfrac{}{}{0ex}{}{\text{thirty}}{\text{D}}$ = + 5.4 ^o (c 0.5, water).

 Example 7

Аналогично примеру 1 получают с (-)-[R,R]-2,8-диазабицикло[4.3.0]нонаном:
А. 1-Циклопропил-7-([R, R] -2,8-диазабицикло[4.3.0] нон-8-ил)- 6,8-дифтор-1,4-дигидро-4-оксо-3-хинолинкарбоновую кислоту.

Analogously to example 1 receive with (-) - [R, R] -2,8-diazabicyclo [4.3.0] nonane:
A. 1-Cyclopropyl-7 - ([R, R] -2,8-diazabicyclo [4.3.0] non-8-yl) - 6,8-difluoro-1,4-dihydro-4-oxo-3- quinoline carboxylic acid.

T. pl. 247 249 ^o C (decomposition).

 B. Hydrochloride 1-cyclopropyl-7 - ([R, R] -2,8-diazabicyclo [4.3.0] non-8-yl) -6,8-difluoro-1,4-dihydro-4-oxo-3 -quinoline carboxylic acid.

T. pl. 322 326 ^o C (decomposition).

Composition (liquid chromatography under pressure): 99.4
Isomer purity 98.6
[α] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ = +250 ^o (c 0.5, water).

 Example 8

Аналогично примеру 2 получают с (-)-[R,R]-2,8-диазабицикло[4.3.0]нонаном:
А. 8-Хлор-1-циклопропил-7-[R, R] -2,8-диазабицикло[4.3.0] нон-8-ил)-6-фтор-1,4-дигидро-4-оксо-хинолинкарбоновую кислоту.

Analogously to example 2 receive with (-) - [R, R] -2,8-diazabicyclo [4.3.0] nonane:
A. 8-Chloro-1-cyclopropyl-7- [R, R] -2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-4-oxo-quinolinecarboxylic acid.

T. pl. 192 195 ^o C (decomposition).

 B. 8-chloro-1-cyclopropyl-7- [R, R] -2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-4-oxo- hydrochloride 3-quinoline carboxylic acid.

T. pl. 323 324 ^o C (decomposed)
Composition (liquid chromatography under pressure): 99.9%
[α] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ = +164.5 ^o (c 0.53, water)
C ₂₀ H ₂₁ CLFN ₃ O ₃ • HCL (442.3)
Calculated: C 54.3; H 5.0; N, 9.5; CL 16.0.

 Found: C, 54.2; H 5.0; N, 9.5; CL 16.1.

 Example 9

Аналогично примеру 1 получают из 1-циклопропил-6,7-дифтор-1,4- дигидро-4-оксо-3-хинолинкарбоновой кислоты и (-)-[R,R]-2,8-диазабицикло[4.3.0]нонана:
А. 1-Циклопропил-7-([R, R] -2,8-диазабицикло[4.3.0] нон-8-ил)-6-фтор-1,4-дигидро-4-оксо-3-хинолинкарбоновую кислоту.

Analogously to example 1 is obtained from 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and (-) - [R, R] -2,8-diazabicyclo [4.3.0] nonana:
A. 1-Cyclopropyl-7 - ([R, R] -2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid .

T. pl. 254 258 ^o C (decomposition).

 B. 1-Cyclopropyl-7 - ([R, R] -2,8-diazabicyclo [4.3.0] non-8-yl) - 6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid .

T. pl. above 320 ^o C decomposition.

[α] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ = +92.5 ^o (c 0.53, water).

 Example 10

А. 1-Циклопропил-6,8-дифтор-1,4-дигидро-7-(цис-2-окса-5,8- диазабицикло[4.3.0] нон-8-ил)-4-оксо-3-хинолинкарбоновая кислота. 1,43 г (5 ммоль) 1-циклопропил-6,7,8-трифтор-1,4-дигидро-4-оксо-3- хинолинкарбоновой кислоты нагревают с обратным холодильником в течение одного часа в смеси из 15 мл ацетонитрила и 75 мл диметилформамида в присутствии 0,67 г (6 ммоль) 1,4-диазабицикло[2.2.2] октана с 0,74 г (5,4 ммоль) 93%-ного цис-2-окса-5,8-диазабицикло[4.3.0] нонана. Суспензию сгущают, остаток перемешивают с водой, осадок отфильтровывают и сушат при 80^oC в вакууме.

A. 1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7- (cis-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -4-oxo-3- quinoline carboxylic acid. 1.43 g (5 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is heated under reflux for one hour in a mixture of 15 ml of acetonitrile and 75 ml of dimethylformamide in the presence of 0.67 g (6 mmol) of 1,4-diazabicyclo [2.2.2] octane with 0.74 g (5.4 mmol) of 93% cis-2-oxa-5,8-diazabicyclo [ 4.3.0] nonana. The suspension is concentrated, the residue is stirred with water, the precipitate is filtered off and dried at 80 ^° C. in vacuo.

 Yield: 1.67 g (85.4% of theory).

T. pl. 210 212 ^o C (decomposition).

B. Hydrochloride of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (cis-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -4-oxo-3 - quinoline carboxylic acid. 1.6 g (4 mmol) of the product from step A was dissolved in 120 ml of semi-concentrated hydrochloric acid at 60 ^° C, the solution was concentrated, the residue was washed with ethanol and the precipitate was filtered off and dried at 90 ^° C in vacuo.

 Yield: 1.57 g.

T. pl. 300 303 ^o C (decomposed).

Composition by liquid chromatography under pressure: 97%
B. Analogously to example 10A, they are prepared with 1R, 6S-2-oxa-5,8-diazabicyclo [4.3.0] nonane 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (1R, 6S-2 -oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -4-oxo-3-quinolinecarboxylic acid with a melting point of 204 206 ^o C (decomposition).

D. Analogously to example 10B, 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (1R, 6S-2-oxa-5,8-diazabicyclo [4.3.0] non -8-yl) -4-oxo-3-quinolinecarboxylic acid with a melting point of 324 325 ^o C (decomposed). [α] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ = -241 ^o (s 0.59, water).

D. Analogously to example 10A receive with 1S, 6R-2-oxa-5,8-diazabicyclo [4.3.0] nonane 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (1S, 6R-2 -oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -4-oxo-3-quinolinecarboxylic acid with a melting point of 204 206 ^o C (decomposition).

[α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ = +248 ^o (c 0.57, dimethylformamide).

E. Analogously to example 10B, 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (1S, 6R-2-oxa-5,8-diazabicyclo [4.3.0] non -8-yl) -4-oxo-3-quinolinecarboxylic acid with a mp of 323 ^o C (decomposition).

[α] $\genfrac{}{}{0ex}{}{\text{26}}{\text{D}}$ = +238 ^o (s 0.5, water).

 Example 11

Аналогично примеру 10 получают с 8-хлор-1-циклопропил-6,7-дифтор-1,4-дигидро-4-оксо-3- хинолинкарбоновой кислотой:
А. 8-Хлор-1-циклопропил-6-фтор-1,4-дигидро-7-(цис-2-окса- 5,8-диазабицикло[4.3.0] нон-8-ил)-4-оксо-3-хинолинкарбоновую кислоту. Т. пл. 180 185^oC (с разложением).

Analogously to example 10 receive with 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid:
A. 8-Chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7- (cis-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -4-oxo- 3-quinoline carboxylic acid. T. pl. 180 185 ^o C (decomposed).

B. 8-Chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7- (cis-2-oxo-5,8-diazabicyclo [4.3.0] non-8-yl) -4-oxo hydrochloride -3- quinoline carboxylic acid. T. pl. 227 232 ^o C (decomposition).

C. 8-Chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7- (1R, 6S-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -4- oxo-3-quinoline carboxylic acid. T. pl. 186 188 ^o C (decomposition). [α] $\genfrac{}{}{0ex}{}{\text{26}}{\text{D}}$ = -269 ^o (c 0.5, dimethylformamide).

G. 8-Chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7- (1R, 6S-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -4 hydrochloride -oxo-3- quinoline carboxylic acid. T. pl. 278,280 ^° C (decomposed). [α] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ = -208 ^o (s 0.5, water).

D. 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7- (1S, 6R-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -4- oxo-3-quinoline carboxylic acid. T. pl. 188 190 ^o C (decomposition). [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ = +270 ^o (c 0.5, dimethylformamide).

E. 8-Chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7- (1S, 6R-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -4 hydrochloride -oxo-3-quinolinecarboxylic acid. T. pl. 292 294 ^o C (decomposition). [α] $\genfrac{}{}{0ex}{}{\text{27}}{\text{D}}$ = +193 ^o (s 0.5, water).

 Example 12

Аналогично примеру 10А получают с 1-циклопропил-6,7-дифтор-1,4-дигидро-4-оксо-3-хинолинкарбоновой кислотой:
А. 1-Циклопропил-6-фтор-1,4-дигидро-7-(цис-2-окса-5,8- диазабицикло[4.3.0]нон-8-ил)-4-оксо-3-хинолинкарбоновую кислоту. Т. пл. 246 - 249^oC (с разложением, из монометилового эфира гликоля).

Analogously to example 10A receive with 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid:
A. 1-Cyclopropyl-6-fluoro-1,4-dihydro-7- (cis-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -4-oxo-3-quinolinecarboxylic acid . T. pl. 246 - 249 ^o C (decomposed, from glycol monomethyl ether).

B. 1-Cyclopropyl-6-fluoro-1,4-dihydro-7- (1R, 6S-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -4-oxo-3- quinoline carboxylic acid. T. pl. 243 - 245 ^o C (decomposition).

B. Hydrochloride 1-cyclopropyl-6-fluoro-1,4-dihydro-7- (1R, 6S-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -4-oxo-3 -quinoline carboxylic acid. T. pl. 300 ^o C (decomposition). [α] $\genfrac{}{}{0ex}{}{\text{23}}{\text{D}}$ = -99 ^o (s 0.5, water).

 Example 13

Аналогично примеру 10А получают с 1-циклопропил-5,6,7,8- тетрафтор-1,4-дигидро-4-оксо-3-хинолинкарбоновой кислотой:
А. 1-Циклопропил-5,6,8-трифтор-1,4, -дигидро-7-(цис-2- окса-5,8-диазабицикло[4.3.0]нон-8-ил)-4-оксо-3-хинолинкарбоновую кислоту. Т. пл. 210 216^oC (с разложением).

Analogously to example 10A receive with 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid:
A. 1-Cyclopropyl-5,6,8-trifluoro-1,4, -dihydro-7- (cis-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -4-oxo -3-quinoline carboxylic acid. T. pl. 210,216 ^° C (decomposed).

B. 1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-7- (1R, 6S-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -4- oxo-3-quinoline carboxylic acid. T. pl. 234 - 237 ^o C (decomposition). [α] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ = -287 ^o (c 0.5, dimethylformamide).

C. 1-Cyclopropyl-5,6,8-trifluoro-1,4-dihydro-7- (1S, 6R-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -4- oxo-3-quinoline carboxylic acid. T. pl. 236 - 237 ^o C (decomposition). [α] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ = +282 ^o (s 0.5, dimethylformamide).

 Example 14

А. 4,1 г (10 ммоль) продукта из примера 13А смешивают в 40 мл пиридина с 5 мл жидкого аммиака и нагревают в автоклаве 10 ч до 130^oC. После охлаждения осадок отфильтровывают, промывают водой и сушат при 100^oC в воздушном сушильном шкафу. Сырой продукт (2 г) очищают перекристаллизацией из монометилового эфира гликоля (желтые кристаллы).

A. 4.1 g (10 mmol) of the product from Example 13A are mixed in 40 ml of pyridine with 5 ml of liquid ammonia and heated in an autoclave for 10 hours to 130 ^° C. After cooling, the precipitate is filtered off, washed with water and dried at 100 ^° C. in air drying cabinet. The crude product (2 g) was purified by recrystallization from glycol monomethyl ether (yellow crystals).

 Yield: 1.3 g (31 theory) 5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (cis-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -4-oxo-3-quinoline carboxylic acid.

T. pl. 233,240 ^o C (decomposed).

B. Similarly, 5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (1R, 6S-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -4-oxo-3-quinoline carboxylic acid. T. pl. 212 - 214 ^o C (decomposition). [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ = -260 ^o (with 0.5, dimethylformamide).

B. Similarly, 5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (1S, 6R-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -4-oxo-3-quinoline carboxylic acid. T. pl. 213 - 215 ^o C (decomposition). [α] $\genfrac{}{}{0ex}{}{\text{26}}{\text{D}}$ = +261 ^o (s 0.5, dimethylformamide).

Mass spectrum: m / e 406 (M ⁺ , 95%), 346, 249, 98, 41, 28 (100).

 Example 15

А. 7-(2-трет. -бутоксикарбонил-2,8-диазабицикло[4.3.0]нон-8- ил)-1-циклопропил-6,8-дифтор-1,4-дигидро-4-оксо-3- хинолинкарбоновая кислота. 7,8 г (20 ммоль) 1-циклопропил-7-(2,8-диазабицикло[4.3.0]нон-8-ил)-6,8-дифтор-1,4- дигидро-4-оксо-3-хинолинкарбоновой кислоты растворяют в смеси из 60 мл диоксана и воды (2 1) и 20 мл 1 н. натриевой щелочи и смешивают при охлаждении льдом и перемешивании с 5,24 г (24 ммоль) ди-трет.-бутилового эфира пироугольной кислоты. Перемешивают 1 ч при комнатной температуре и оставляют на ночь. Выпавший осадок отфильтровывают, промывают 250 мл воды и сушат ночь при 50^oC в воздушном сушильном шкафу.

A. 7- (2-tert.-Butoxycarbonyl-2,8-diazabicyclo [4.3.0] non-8-yl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3 - quinoline carboxylic acid. 7.8 g (20 mmol) 1-cyclopropyl-7- (2,8-diazabicyclo [4.3.0] non-8-yl) -6,8-difluoro-1,4-dihydro-4-oxo-3- quinoline carboxylic acid is dissolved in a mixture of 60 ml of dioxane and water (2 1) and 20 ml of 1 N. sodium alkali and mixed with cooling with ice and stirring with 5.24 g (24 mmol) of di-tert.-butyl ether of pyruvic acid. Stirred for 1 h at room temperature and left overnight. The precipitate formed is filtered off, washed with 250 ml of water and dried overnight at 50 ^° C. in an air oven.

 Yield: 9.34 g (95.5 from theory).

T. pl. 216,219 ^o C (decomposition).

B. 2S-methyl-1-butyl ether 7- (2-tert.-butoxycarbonyl-2,8-diazabicyclo [4.3.0] non-8-yl) -1-cyclopropyl-6,8-difluoro-1,4 dihydro-4-oxo-3-quinoline carboxylic acid. 2.15 g (4.4 mmol) of the product from step A are suspended in 60 ml of a mixture of tetrahydrofuran and water (1 1) at room temperature and 1.65 g (5 mmol) of cesium carbonate are added. Allowed to react for 20 min in an ultrasonic bath at a temperature of about 40 ^o C, about 40 ml of solvent was distilled off at 40 ^o C / 12 mbar and the remaining solution was lyophilized, and an easily soluble crude cesium salt was obtained: 3.3 g of this crude salt was dissolved in 40 ml of dimethylformamide and mixed with 1.4 g of S (+) - 1-bromo-2-methyl-butane and subjected to interaction overnight in an ultrasonic bath at 40 to 50 ^o C. the resulting suspension is concentrated, the residue is mixed with water and extracted with methylene chloride . After drying over sodium sulfate, the solution is concentrated and the residue is subjected to chromatographic purification (silica gel, solvent: methylene chloride / methanol 95 5).

 Yield: 950 mg (38% of theory).

T. pl. 72 83 ^o C (decomposed).

B. Trifluoroacetate (2S-methyl-1-butyl ether) 1-cyclopropyl-7- (2,8-diazabicyclo [4.3.0] non-8-yl) -6,8-difluoro-1,4-dihydro-4 -oxo-3-quinolinecarboxylic acid. 570 mg (1 mmol) of the product from step B was dissolved in 3 ml of trifluoroacetic acid at room temperature and the solution was concentrated at 60 ^° C / 12 mbar. The resulting viscous oil is mixed with 5 ml of diethyl ether, and a solid product precipitates. It is filtered off, washed with ether and dried at 80 ^o C in high vacuum.

 Yield: 450 mg (78 from theory).

T. pl. 214,216 ^° C (decomposed); [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ = + 2.8 ^o (s 0.5, dimethylformamide).

 Example 16

390 мг (1 ммоль) 1-циклопропил-7-(2,8-диазабицикло[4.3.0] нон-8-ил)-6,8-дифтор-1,4-дигидро-4-оксо-3-хинолинкарбоновой кислоты растворяют в растворе 40 мг гидроокиси натрия в 3 мл воды при комнатной температуре в ультразвуковой бане и раствор смешивают при охлаждении льдом с раствором 160 мг (1,1 ммоль) R(+)- -метил-бензил-изоцианата. Выпавший осадок отфильтровывают, промывают диоксаном и сушат при 100^oC в глубоком вакууме.

390 mg (1 mmol) of 1-cyclopropyl-7- (2,8-diazabicyclo [4.3.0] non-8-yl) -6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid dissolved in a solution of 40 mg of sodium hydroxide in 3 ml of water at room temperature in an ultrasonic bath, and the solution was mixed with ice cooling with a solution of 160 mg (1.1 mmol) of R (+) - methyl-benzyl-isocyanate. The precipitate formed is filtered off, washed with dioxane and dried at 100 ^° C. under high vacuum.

 Yield: 530 mg (99 theory) 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7- (2- [1R-phenyl-ethyl-amino-carbonyl] -2.8- diazabicyclo [4.3.0] non-8-yl) -3-quinoline carboxylic acid.

T. pl. 208 210 ^o C (decomposition); [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ = -23.2 ^° (c 0.5, dimethylformamide).

 The reaction product is separated chromatographically into diastereomers and the carbamoyl residue is again removed by acid hydrolysis, whereby the compounds of Examples 1 and 7 are obtained.

 Example 17

1,52 г (5 ммоль) этилового эфира 1-циклопропил-6,7,8-трифтор-1,4-дигидро-4-оксо-3-хинолинкарбоновой кислоты подвергают взаимодействию в 30 мл ацетонитрила с 550 мг (5 ммоль) 1,4-диазабицикло[2.2.2]октана и 760 мг (6 ммоль) (+)-[S,S]-2,8-диазабицикло[4.3.0]нонана 2 ч при 50^oC и 2 ч при 60^oC. После охлаждения отфильтровывают полученную суспензию, осадок промывают водой и сушат при 90^oC в вакууме.

1.52 g (5 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester is reacted in 30 ml of acetonitrile with 550 mg (5 mmol) 1 , 4-diazabicyclo [2.2.2] octane and 760 mg (6 mmol) (+) - [S, S] -2,8-diazabicyclo [4.3.0] nonane 2 hours at 50 ^o C and 2 hours at 60 ^o C. After cooling, the suspension obtained is filtered off, the precipitate is washed with water and dried at 90 ^° C. in vacuo.

 Yield: 0.99 g (47.5 theory) of ethyl 1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6.8-difluoro -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.

T. pl. 194 195 ^o C (from acetonitrile). [α] $\genfrac{}{}{0ex}{}{\text{23}}{\text{D}}$ = -188.9 ^° (c 0.51, methylene chloride).

 Example 18

1,4 г (5 ммоль) 9,10-дифтор-2,3-дигидро-3-метил-7-оксо-7Н- пиридо[1,2,3-де] [1,4]бензоксазин-6-карбоновой кислоты подвергают взаимодействию аналогично примеру 1 в смеси из 15 мл ацетонитрила и 7,5 мл диметилформамида с 0,85 г (7,7 ммоль) 1,4-диазабицикло[2.2.2] октана и 0,7 г (5,6 ммоль) (+)-[S,S]-2,8-диазабицикло[4.3.0]нонана.

1.4 g (5 mmol) of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carbon acids are reacted analogously to example 1 in a mixture of 15 ml of acetonitrile and 7.5 ml of dimethylformamide with 0.85 g (7.7 mmol) of 1,4-diazabicyclo [2.2.2] octane and 0.7 g (5.6 mmol ) (+) - [S, S] -2,8-diazabicyclo [4.3.0] nonane.

 Yield: 1.24 g (64% of theory) 10 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -9-fluoro-2,3-dihydro-3- methyl 7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid.

T. pl. 265 268 ^o C (decomposition). [α] _D = -232.2 ^° (c 0.58, methylene chloride).

 3S-10 - ([S, S] -2,8-diazabicyclo- [4.3.0] non-8-yl) -9-fluoro-2,3-dihydro-3-methyl-7-oxo- 7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid.

 Example 19

1-Циклопропил-6,7-дифтор-1,4-дигидро-8-метокси-4-оксо-3- хинолинкарбоновую кислоту подвергают взаимодействию аналогично примеру 1 и продукт превращения подвергают хроматографической очистке (силикагель, растворитель: метиленхлорид/метанол/17%-ный водный аммиак 30 8 1).

1-Cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid was reacted in the same manner as in Example 1 and the reaction product was chromatographed (silica gel, solvent: methylene chloride / methanol / 17% aqueous ammonia 30 8 1).

Get 1-cyclopropyl-7 -) [S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3 -quinoline carboxylic acid with so pl. 203 208 ^o C (decomposition).

[α] $\genfrac{}{}{0ex}{}{\text{23}}{\text{D}}$ = -193 ^o (s 0.4, methylene chloride)
Example 20

Аналогично примеру 1А подвергают превращению 1-этил-6,7,8-трифтор-1,4-дигидро-4-оксо-3-хинолинкарбоновую кислоту и получают 1-этил-7-([S,S]-2,8-диазабицикло[4.3.0] нон-8-ил)-6,8- дифтор-1,4-дигидро-4-оксо-3-хинолинкарбоновую кислоту с т. пл. 236 239^oC (с разложением, из монометилового эфира гликоля).

Analogously to example 1A, 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is converted to give 1-ethyl-7 - ([S, S] -2.8- diazabicyclo [4.3.0] non-8-yl) -6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid with a melting point of 236 239 ^o C (decomposed, from glycol monomethyl ether).

[α] $\genfrac{}{}{0ex}{}{\text{23}}{\text{D}}$ = -186? 3 ^o (c 0.3, methylene chloride).

A. Этиловый эфир 7-([S, S]-2,8-диазабицикло[4.3.0]нон-8-ил)- 1-(2,4-дифторфенил)-6-фтор-1,4-дигидро-4-оксо-1,8-нафтиридин-3- карбоновой кислоты. 1,9 г (5 ммоль) этилового эфира 7-хлор-1-(2,4-дифторфенил)-6-фтор-1,4-дигидро-4-оксо-1,6-нафтиридин- 3-карбоновой кислоты перемешивают в 20 мл ацетонитрила в присутствии 560 мг (5 ммоль) 1,4-диазабицикло[2.2.2]октана с 680 мг (5,4 ммоль) [S,S]-2,8-диазабицикло[4.3.0]нонана 3 ч при 10^oC. Суспензию отфильтровывают, промывают водой и сушат. Получают 0,35 г продукта. После сгущения маточников, размешивания остатка с водой, выделения нерастворившегося продукта и хроматографической очистки (силикагель, растворитель: дихлорметан/метанол/17%-ный водный аммиак) получают дополнительно 0,7 г продукта.Example 21

A. Ethyl ester 7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) - 1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro 4-oxo-1,8-naphthyridine-3-carboxylic acid. 1.9 g (5 mmol) of 7-chloro-1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-1,6-naphthyridine-3-carboxylic acid ethyl ester is mixed in 20 ml of acetonitrile in the presence of 560 mg (5 mmol) of 1,4-diazabicyclo [2.2.2] octane with 680 mg (5.4 mmol) of [S, S] -2,8-diazabicyclo [4.3.0] nonane 3 h at 10 ^o C. the Suspension is filtered off, washed with water and dried. 0.35 g of product is obtained. After thickening the mother liquors, stirring the residue with water, isolating the insoluble product and chromatographic purification (silica gel, solvent: dichloromethane / methanol / 17% aqueous ammonia), an additional 0.7 g of product is obtained.

 Total yield: 1.05 g (44 from theory).

T. pl. 184 185 ^o C (decomposition). [α] $\genfrac{}{}{0ex}{}{\text{23}}{\text{D}}$ = +6.8 ^o ) s 0.46, methylene chloride).

 B. Hydrochloride 7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4 -oxo-1,8-naphthyridine-3-carboxylic acid. 0.8 g (1.7 mmol) of the product from step A is heated in a mixture of 10 ml of acetic acid and 8 ml of diluted hydrochloric acid for 4 hours under reflux. The mixture is concentrated, the residue is stirred with a small amount of water, the precipitate is filtered off, washed with ice-cold ethanol and dried.

 Yield: 0.67 g (83 of theory).

T. pl. 324 326 ^o C (decomposition). [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ = +10.8 ^° (c 0.37, dimethylformamide).

 Example 22

0,56 г (2 ммоль) 1-циклопропил-6,7-дифтор-1,4-дигидро-5-метил- 4-оксо-3-хинолинкарбоновой кислоты нагревают с 0,38 г (3 ммоль) [S,S]-2,8-диазабицикло[4.3.0] нонана и 0,45 г (4 ммоль) 1,4-диазабицикло[2.2.2]октана в 3,5 млдиметилсульфоксида 2 ч до 120^oC. После охлаждения растворитель удаляют в глубоком вакууме. Остаток поглощают ацетонитрилом. Отделяют твердое вещество, промывают его ацетонитрилом и сушат при 60 80^oC.

0.56 g (2 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid is heated with 0.38 g (3 mmol) [S, S ] -2,8-diazabicyclo [4.3.0] nonane and 0.45 g (4 mmol) of 1,4-diazabicyclo [2.2.2] octane in 3.5 ml of dimethyl sulfoxide for 2 hours at 120 ^° C. After cooling, the solvent is removed in deep vacuum. The residue is taken up with acetonitrile. The solid is separated, washed with acetonitrile and dried at 60–80 ^° C.

 Yield: 0.5 g (65 theory) 1-cyclopropyl-7 - ([S, S] 02.8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro 5-methyl-4-oxo-3-quinolinecarboxylic acid.

T. pl. 217,219 ^o C (decomposed), [α] _D = -199 ^o (s 0.5, dimethylformamide).

 Example 23

А. 873 мг (3 ммоль) 1-циклопропил-6,7-дифтор-1,4-дигидро-5- метил-4-оксо-3-хинолинкарбоновой кислоты нагревают в смеси из 10 мл ацетонитрила и 5 мл диметилформамида с 1,1 г (10 ммоль) 1,4-диазабицикло[2.2.2]октана и 665 мг (3,3 ммоль) дигидрохлорида 1R,6S-окса-5,8-диазабицикло[4.3.0]нонана 2 ч с обратным холодильником, смесь упаривают, остаток перемешивают с 30 мл воды, осадок отфильтровывают и сушат при 80^oC в вакууме.

A. 873 mg (3 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid is heated in a mixture of 10 ml of acetonitrile and 5 ml of dimethylformamide with 1, 1 g (10 mmol) of 1,4-diazabicyclo [2.2.2] octane and 665 mg (3.3 mmol) of 1R, 6S-oxa-5,8-diazabicyclo [4.3.0] nonane dihydrochloride for 2 hours under reflux, the mixture was evaporated, the residue was stirred with 30 ml of water, the precipitate was filtered off and dried at 80 ^° C in vacuo.

 Yield: 400 mg (34 theory) 1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-7- (1R, 6S-2-oxa-5,8-diazabicyclo [4.3.0] non- 8-yl) - 4-oxo-3-quinoline carboxylic acid.

T. pl. 213 214 ^o C (decomposition).

B. 0.4 g of betaine from stage A is dissolved in 5 ml of semi-concentrated hydrochloric acid at room temperature, the solution is concentrated and the residue is stirred with 3 ml of ethanol. The precipitate was filtered off and dried at 80 ^° C / 12 mbar.

 Yield: 290 mg (66% of theory) of 1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-7- (1R, 6S-2-oxa-5,8-diazabicyclo hydrochloride [4.3.0] non-8-yl) -4-oxo-3-quinoline carboxylic acid.

T. pl. 305 308 ^o C (decomposition), [α] $\genfrac{}{}{0ex}{}{\text{23}}{\text{D}}$ = -79 ^o (s 0.52, water).

 Example 24

362 г (1 ммоль) 5-бром-1-циклопропил-6,7,8-трифтор-1,4-дигидро-4-оксо-3- хинолинкарбоновой кислоты нагревают в смеси из 3 мл ацетонитрила и 1,5 мл диметилформамида с 220 мг (2 ммоль) 1,4-диазабицикло[2.2.2]октана и 220 мг (1,1 ммоль) дигидрохлорида 1S,6R-2-окса-5,8-диазабицикло[4.3.0]нонана 1,5 ч с обратным холодильником.

362 g (1 mmol) of 5-bromo-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is heated in a mixture of 3 ml of acetonitrile and 1.5 ml of dimethylformamide with 220 mg (2 mmol) of 1,4-diazabicyclo [2.2.2] octane and 220 mg (1.1 mmol) of dihydrochloride 1S, 6R-2-oxa-5,8-diazabicyclo [4.3.0] nonane 1.5 hours with reflux condenser.

The suspension is cooled, the precipitate is filtered off, stirred with 30 ml of water and dried at 90 ^o C in high vacuum.

 Yield: 320 mg (68% of theory) 5-bromo-1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (1S, 6R-2-oxa-5,8-diazabicyclo [4.3.0 ] non-8-yl) -4-oxo-3-quinolinecarboxylic acid.

T. pl. 263 264 ^o C (decomposition), [α] $\genfrac{}{}{0ex}{}{\text{thirty}}{\text{D}}$ = +251 ^o (s 0.3, methylene chloride).

 Example 25

Аналогично примеру 1 получают с [S,S]-2-метил-2,8-диазабицикло[4.3.0] нонаном:
А. 1-Циклопропил-6,8-дифтор-1,4-дигидро-7-([S, S]-2-метил-2,8- диазабицикло[4.3.0]нон-8-ил)-4-оксо-3-хинолинкарбоновую кислоту.

Analogously to example 1 receive with [S, S] -2-methyl-2,8-diazabicyclo [4.3.0] nonane:
A. 1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7 - ([S, S] -2-methyl-2,8-diazabicyclo [4.3.0] non-8-yl) -4- oxo-3-quinoline carboxylic acid.

T. pl. 230,233 ^° C (decomposing, recrystallization from glycol monomethyl ether).

 B. Hydrochloride 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- ([S, S] -2-methyl-2,8-diazabicyclo [4.3.0] non-8-yl) -4 -oxo-3- quinoline carboxylic acid.

T. pl. 258 260 ^o C (with decomposition), [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ = -216.3 ^o (s 1, water).

 Example 26

Аналогично примеру 1 получают с [R,R]-2-метил-2,8-диазабицикло[4.3.0] нонаном:
А. 1-Циклопропил-6,8-дифтор-1,4-дигидро-7-([R, R]-2-метил- 2,8-диазабицикло[4.3.0]нон-8-ил)-4-оксо-3-хинолинкарбоновую кислоту.

Analogously to example 1 receive with [R, R] -2-methyl-2,8-diazabicyclo [4.3.0] nonane:
A. 1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7 - ([R, R] -2-methyl-2,8-diazabicyclo [4.3.0] non-8-yl) -4- oxo-3-quinoline carboxylic acid.

T. pl. 228 230 ^o C (decomposition, recrystallization from glycol monoethyl ether).

 B. Hydrochloride 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- 9 [R, R] -2-methyl-2,8-diazabicyclo [4.3.0] non-8-yl) -4 -oxo-3- quinoline carboxylic acid.

T. pl. 258 260 ^o C (with decomposition), [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ = +213.8 ^o (s 1, water).

 Example 27

1,95 г (5 ммоль) продукта из примера 1А нагревают в 50 мл этанола с 2,1 г (30 ммоль) метилвинилкетона 4 ч с обратным холодильником. Смесь сгущают, остаток перемешивают с водой, осадок отфильтровывают, промывают этанолом и сушат при 100^oC/12 мбар.

1.95 g (5 mmol) of the product from Example 1A is heated in 50 ml of ethanol with 2.1 g (30 mmol) of methyl vinyl ketone for 4 hours under reflux. The mixture is concentrated, the residue is stirred with water, the precipitate is filtered off, washed with ethanol and dried at 100 ^° C / 12 mbar.

 Yield: 2.1 g (91.5% of theory) 1-cyclopropyl-6.8-difluoro-1,4-dihydro-4-oxo-7 - ([S, S] -2- [3-oxo- 1-butyl] -2,8-diazabicyclo- [4.3.0] non-8-yl) -3-quinolinecarboxylic acid.

T. pl. 181 183 ^o C (decomposition, recrystallization from monomethyl glycol), [α] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ = -120.7 ^o (s 0.57, dichloromethane)
Example 28

1,95 г (5 ммоль) продукта из примера 1А нагревают в 30 мл диметилформамида с 1,0 г (10,8 ммоль) хлорацетона и 1,3 г (13 ммоль) триэтиламина 3 ч при 50 80^oC. Раствор сгущают, остаток перемешивают с водой (pH 6), нерастворившийся осадок отфильтровывают, промывают водой и сушат в воздушном сушильному шкафу при 100^oC.

1.95 g (5 mmol) of the product from Example 1A is heated in 30 ml of dimethylformamide with 1.0 g (10.8 mmol) of chloroacetone and 1.3 g (13 mmol) of triethylamine for 3 hours at 50 ^° -80 ^° C. The solution is concentrated. the residue is stirred with water (pH 6), the insoluble precipitate is filtered off, washed with water and dried in an air oven at 100 ^o C.

The yield of crude product: 1.3 g; after recrystallization from glycol monomethyl ether:
yield: 1.12 g (50% of theory) 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7 - ([S, S] -2- [2-oxopropyl] -2 , 8-diazabicyclo- [4.3.0] non-8-yl) -3-quinolinecarboxylic acid.

T. pl. 181 184 ^o C (decomposition),
[α] $\genfrac{}{}{0ex}{}{\text{23}}{\text{D}}$ -72 ^o (s 0.55, chloroform).

 Example 29

А. Аналогично примеру 27 подвергают превращению продукт из примера 2А и получают 8-хлор-1-циклопропил-6-фтор-1,4-дигидро-4- оксо-7-([S,S]-2-[3-оксо-1-бутил]-2,8-диазабицикло[4.3.0]нон-8-ил)- хинолинкарбоновую кислоту с т. пл. 107 109^oC.

A. Analogously to example 27, the product of example 2A is converted to give 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7 - ([S, S] -2- [3-oxo -1-butyl] -2,8-diazabicyclo [4.3.0] non-8-yl) -quinolinecarboxylic acid with a melting point of 107 109 ^o C.

[α] $\genfrac{}{}{0ex}{}{\text{23}}{\text{D}}$ -53 ^o (s 0.67, chloroform),
Composition: 99.2% (high pressure liquid chromatography).

B. Similarly obtained with 8-chloro-1-cyclopropyl-7- (cis-2.8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-4-oxo-3 - racemic quinoline carboxylic acid 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (cis-2- [3-oxo-1-butyl] -2,8-diazabicyclo [4.3 .0] non-8-yl) -3-quinoline carboxylic acid with a mp of 124 125 ^o C.

 Example 30

1,56 г (4 ммоль) продукта из примера 10А смешивают в 30 мл диметилформамида с 0,82 г (8,8 моль) хлорацетона и 1,05 г (10,4 ммоль) триэтиламина и нагревают 3 ч при 50 80^oC. Полученный желтый раствор сгущают при 80^oC/15 мбар, маслянистый остаток перемешивают с водой до тех пор, пока он не затвердеет. Твердый продукт отфильтровывают, промывают водой и перекристаллизовывают из монометилового эфира гликоля.

1.56 g (4 mmol) of the product from Example 10A is mixed in 30 ml of dimethylformamide with 0.82 g (8.8 mol) of chloroacetone and 1.05 g (10.4 mmol) of triethylamine and heated for 3 hours at 50 ^° C. The resulting yellow solution is concentrated at 80 ^° C / 15 mbar, the oily residue is mixed with water until it solidifies. The solid product is filtered off, washed with water and recrystallized from glycol monomethyl ether.

 Yield: 830 mg (47% of theory) 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7- (cis-5- [2-oxopropyl] -2-oxa-5.8 - diazabicyclo [4.3.0] non-8-yl) -3-quinoline carboxylic acid.

T. pl. 192 193 ^o C (decomposition).

 Example 31

1,56 г (4 ммоль) продукта из примера 10А нагревают в 50 мл этанола с 1,8 г (25,6 ммоль) метилвинилкетона 3 ч с обратным холодильником. Суспензию сгущают при 90^oC/12 мбар, остаток перемешивают с водой и перекристаллизовывают из монометилового эфира гликоля.

1.56 g (4 mmol) of the product from Example 10A is heated in 50 ml of ethanol with 1.8 g (25.6 mmol) of methyl vinyl ketone for 3 hours under reflux. The suspension is concentrated at 90 ^° C / 12 mbar, the residue is stirred with water and recrystallized from glycol monomethyl ether.

 Yield: 1.33 g (72% of theory) 1-cyclopropyl-6.8-difluoro-1,4-dihydro-4-oxo-7- (cis-5- [3-oxo-1-butyl] -2 -oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -3-quinolinecarboxylic acid.

T. pl. 188 189 ^o C (decomposition).

 Example 32

1,95 г (4,8 ммоль) продукта по примеру 2А нагревают в 30 мл монометилового эфира гликоля с 3 г (30 ммоль) этилового эфира акриловой кислоты 2 ч с обратным холодильником. Смесь упаривают, остаток перемешивают с водой, осадок отфильтровывают, сушат (выход сырого продукта: 1,9 г) и перекристаллизовывают из монометилового эфира гликоля.

1.95 g (4.8 mmol) of the product of Example 2A is heated in 30 ml of glycol monomethyl ether with 3 g (30 mmol) of ethyl acrylic acid for 2 hours under reflux. The mixture was evaporated, the residue was stirred with water, the precipitate was filtered off, dried (crude yield: 1.9 g) and recrystallized from glycol monomethyl ether.

 Yield: 1.45 g (60% of theory) 8-chloro-1-cyclopropyl-7- ([S, S] -2- [2-ethoxycarbonyl-ethyl] -2,8-diazabicyclo [4.3.0] non -8-yl) - 6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.

T. pl. 117 118 ^o C (decomposition), [α] $\genfrac{}{}{0ex}{}{\text{28}}{\text{D}}$ -103.5 ^o (s 0.49, dimethylformamide)
Composition: 99.6% (high pressure liquid chromatography).

 Example 33

1,95 г (4,8 ммоль) продукта по примеру 2А нагревают в 30 мл этанола с 0,8 г (15 ммоль) акрилнитрила 5 ч с обратным холодильником. Смесь упаривают, остаток перемешивают с водой, сушат (выход сырого продукта: 1,9 г) и перекристаллизовывают из монометилового эфира гликоля.

1.95 g (4.8 mmol) of the product of Example 2A is heated in 30 ml of ethanol with 0.8 g (15 mmol) of acrylonitrile for 5 hours under reflux. The mixture was evaporated, the residue was stirred with water, dried (crude yield: 1.9 g) and recrystallized from glycol monomethyl ether.

 Yield: 1.6 g (73% of theory) 8-chloro-7 - ([S, S] -2- [2-cyanoethyl] -2,8-diazabicyclo [4.3.0] non-8-yl) - 1-cyclopropyl-6-fluoro-1,4-dihydro-3-quinolinecarboxylic acid.

T. pl. 153 155 ^o C (decomposition),
[α] $\genfrac{}{}{0ex}{}{\text{27}}{\text{D}}$ -98.6 ^o (s 0.53, dimethylformamide)
Composition: 96% (high pressure liquid chromatography).

Mass spectrum: m / e 458 (M ⁺ ), 250, 149 (100% C ₉ H ₁₃ N ₂ ), 110.49
Example 34

1,95 г (5 ммоль) продукта по примеру 1А нагревают в 60 мл этанола с 1,2 г (8 ммоль) диметилового эфира ацетилендикарбоновой кислоты 2 ч с обратным холодильником. Суспензию сгущают, остаток перемешивают с водой, осадок отфильтровывают и сушат. Сырой продукт (2,3 г) перекристаллизовывают из смеси монометилового эфира гликоля и диметилформамида.

1.95 g (5 mmol) of the product of Example 1A is heated in 60 ml of ethanol with 1.2 g (8 mmol) of acetylenedicarboxylic acid dimethyl ether for 2 hours under reflux. The suspension is concentrated, the residue is stirred with water, the precipitate is filtered off and dried. The crude product (2.3 g) was recrystallized from a mixture of glycol monomethyl ether and dimethylformamide.

 Yield: 2 g (74% of theory) 1-cyclopropyl-7- [2- (1,2-bis-methoxycarbonyl-vinyl) -1S, 6R-2,8-diazabicyclo [4.3.0] non-8-yl ] -6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.

T. pl. 262 264 ^o C (decomposition), [α] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ +28.8 ^o (s 0.24, dichloromethane)
Example 35

Аналогично примеру 34 продукт по примеру 2А подвергают превращению с диметиловым эфиром ацетилендикарбоновой кислоты. Получают с выходом 87% 8-хлор-циклопропил-7-[2-(1,2-бис-метоксикарбонил-винил)- 1S, 6S-2,8-диазабицикло[4.3.0]нон-8-ил]-6-фтор-1,4-дигидро-4-оксо-3- хинолинкарбоновую кислоту с т. пл. 210 212^oC (с разложением), [α] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ +16,6^o (с 0,5, диметилформамид).

Analogously to example 34, the product of example 2A is subjected to conversion with acetylenedicarboxylic acid dimethyl ether. Receive with a yield of 87% 8-chloro-cyclopropyl-7- [2- (1,2-bis-methoxycarbonyl-vinyl) - 1S, 6S-2,8-diazabicyclo [4.3.0] non-8-yl] -6 -fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid with a melting point of 210 212 ^o C (decomposition), [α] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ +16.6 ^o (s 0.5, dimethylformamide).

 Example 36

780 мг (2 ммоль) 1-циклопропил-7-(цис-2,8-диазабицикло [4.3.0]нон-8-ил)-6,8-дифтор-1,4-дигидро-4-оксо-3- хинолинкарбоновой кислоты нагревают в 15 мл этанол с 500 мг (5 ммоль) этилового эфира пропиоловой кислоты в течение 1 ч с обратным холодильником. Суспензию охлаждают, осадок отфильтровывают, промывают 25 мл этанола и сушат при 0^oC в глубоком вакууме.

780 mg (2 mmol) 1-cyclopropyl-7- (cis-2,8-diazabicyclo [4.3.0] non-8-yl) -6,8-difluoro-1,4-dihydro-4-oxo-3- quinoline carboxylic acid is heated in 15 ml of ethanol with 500 mg (5 mmol) of propiolic acid ethyl ester for 1 hour under reflux. The suspension is cooled, the precipitate is filtered off, washed with 25 ml of ethanol and dried at 0 ^o C in high vacuum.

 Yield: 880 mg (90% of theory) 1-cyclopropyl-7- [2- (trans-2-ethoxycarbonyl-vinyl) -cis-2,8-diazabicyclo [4.3.0] non-8-yl] -6, 8-difluoro-4-oxo-3-quinolinecarboxylic acid.

T. pl. 244 246 ^o C
Analogously to example 36 receive are given in table. 3 and 4 of the compounds of formula (I).

 Example 48

Аналогично примеру 36 подвергают превращению 8-хлор-1-цикопропил-7-9[S, S] -2,8-диазабицикло[4.3.0] нон-8-ил)- фтор-1,4-дигидро-4-оксо-3-хинолинкарбоновую кислоту с метиловым эфиром пропиоловой кислоты в этаноле или метаноле и получают 8-хлор-1-циклопропил-6-фтор-1,4-дигидро-7-[2-(транс-2- метоксикарбонил-винил)-[S, S] -2,8-диазабицикло-[4.3.0]нон-8-ил)-4- оксо-3-хинолинкарбоновую кислоту с т. пл. 220 222^oC (с разложением), [α] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ = +8,2^o (с 0,5, хлороформ).

Analogously to example 36, 8-chloro-1-cyclopropyl-7-9 [S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -fluoro-1,4-dihydro-4-oxo is converted -3-quinoline carboxylic acid with propiolic acid methyl ester in ethanol or methanol to give 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7- [2- (trans-2-methoxycarbonyl-vinyl) - [ S, S] -2,8-diazabicyclo- [4.3.0] non-8-yl) -4-oxo-3-quinoline-carboxylic acid, m.p. 220 222 ^o C (decomposition), [α] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ = + 8.2 ^o (s 0.5, chloroform).

 Example 49

407,5 г (1 ммоль) 8-хлор-1-циклопропил-6-фтор-1,4-дигидро- 7-([1S,6R-2-окса-5,8-диазабицикло[4.3.0] нон-8-ил)-4-оксо-3- хиноликарбоновой кислоты (из примера 11Д) нагревают в 10 мл метанола с 210 мг (2,5 ммоль) метилового эфира пропиоловой кислоты 1 ч с обратным холодильником. Сгущают и перекристаллизовывают выделенный сырой продукт (450 мг) из 4 мл ацетонитрила.

407.5 g (1 mmol) 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7 - ([1S, 6R-2-oxa-5,8-diazabicyclo [4.3.0] non- 8-yl) -4-oxo-3-quinolinecarboxylic acid (from Example 11E) is heated in 10 ml of methanol with 210 mg (2.5 mmol) of propiolic acid methyl ester for 1 hour under reflux. The isolated crude product (450 mg) is thickened and recrystallized from 4 ml of acetonitrile.

 Yield: 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7- [5- (trans-2-methoxycarbonyl-vinyl) -1S, 6R-2-oxa-5,8-diazabicyclo [4.3 .0] non-8-yl) -4-oxo-3-quinolinecarboxylic acid.

T. pl. 153 156 ^o C (decomposition), [α] $\genfrac{}{}{0ex}{}{\text{28}}{\text{D}}$ = +36 ^o (s 0.5, chloroform).

 Example 50

Аналогично примеру 49 подвергают превращению соединение по примеру 13А и получают 1-циклопропил-5,6,8-трифтор-1,4- дигидро-7-[5-(транс-2-метоксикарбонил-винил)-цис-2-окса-5,8- диазабицикло[4.3.0]нон-8-ил]-4-оксо-3-хиноликарбоновую кислоту с т. пл. 169 - 170^oC (с разложением, из монометилового эфира гликоля).

Analogously to example 49, the compound of example 13A is converted to give 1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-7- [5- (trans-2-methoxycarbonyl-vinyl) -cis-2-oxa- 5.8-diazabicyclo [4.3.0] non-8-yl] -4-oxo-3-quinolinecarboxylic acid with a mp of 169 - 170 ^o C (with decomposition, from glycol monomethyl ether).

 Example 51

Аналогично примеру 49 подвергают превращению соединение по примеру 10Д и получают 1-циклопропил-6,8-дифтор-1,4-дигидро-7- [5-(транс-2-метоксикарбонил-винил)-1S, 6R-2-окса-5,8-диазабицикло [4.3.0]нон-8-ил]-4-оксо-хинолинкарбоновую кислоту с т. пл. 230 234^oC (с разложением, из монометилового эфира гликоля).

Analogously to example 49, the compound of example 10D is converted to give 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- [5- (trans-2-methoxycarbonyl-vinyl) -1S, 6R-2-oxa 5,8-diazabicyclo [4.3.0] non-8-yl] -4-oxo-quinoline carboxylic acid with a melting point of 230,234 ^° C (decomposed, from glycol monomethyl ether).

[α] $\genfrac{}{}{0ex}{}{\text{28}}{\text{D}}$ = -27 ^o (s 0.5, chloroform).

 Example 52

Аналогично примеру 49 подвергают взаимодействию соединение по примеру 24 и получают 5-бром-1-циклопропил-6,8-дифтор-1,4-дигидро-7-[5-(транс-2- метоксикарбонил-винил)-1S, 6R-2-окса-5,8-диазабицикло[4.3.0] нон-8-ил] -4-оксо-3-хинолинкарбоновую кислоту с т. пл. 158 160^oC (с разложением, из изопропанола).

Analogously to example 49, the compound of example 24 is reacted to give 5-bromo-1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- [5- (trans-2-methoxycarbonyl-vinyl) -1S, 6R- 2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl] -4-oxo-3-quinolinecarboxylic acid with a melting point of 158 160 ^o C (decomposition, from isopropanol).

[α] $\genfrac{}{}{0ex}{}{\text{28}}{\text{D}}$ = +8 ^o (s 0.27, chloroform).

 Example 53

Аналогично примеру 36 подвергают превращению соединение по примеру 17 и получают этиловый эфир 1-циклопропил-7-[2-(транс-2-этоксикарбонил-винил)-1S, 6S-2,8- диазабицикло[4.3.0] нон-8-ил] -6,8-дифтор-1,4-дигидро-4-оксо-3- хинолинкарбоновой кислоты с т.пл. 168 169^oC.

Analogously to example 36, the compound of example 17 is converted and 1-cyclopropyl-7- [2- (trans-2-ethoxycarbonyl-vinyl) -1S, 6S-2,8-diazabicyclo [4.3.0] non-8- ethyl ester is obtained sludge] -6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid; 168 169 ^o C.

 Example 54

818 мг (2 ммоль) 1-циклопропил-5,6,8-трифтор-1,4-дигидро-7- (1R,6S-2-окса-5,8-диазабицикло[4.3.0] нон-8-ил)-4-оксо-3- хинолинкарбоновой кислоты (по примеру 13Б) смешивают в 15 мл этанола с 680 г (4 ммоль) диэтилового эфира ацетилендикарбоновой кислоты и обрабатывают 1 ч при 30^oC в ультразвуковой бане. Суспензию отфильтровывают, промывают этанолом и сушат при 70^oC в глубоком вакууме.

818 mg (2 mmol) 1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-7- (1R, 6S-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl ) -4-oxo-3-quinoline carboxylic acid (according to Example 13B) is mixed in 15 ml of ethanol with 680 g (4 mmol) of ethyl acetate and treated for 1 hour at 30 ^° C. in an ultrasonic bath. The suspension is filtered off, washed with ethanol and dried at 70 ^° C. under high vacuum.

 Yield: 890 mg (77% of theory) 1-cyclopropyl-7- [5- (1,2-bis-ethoxycarbonyl-vinyl) -1R, 6S-2-oxa-5,8-diazabicyclo [4.3.0] non -8-yl) -5,6,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.

T. pl. 220 222 ^o C (decomposed, from glycol monomethyl ether), [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ = -57 ^o (c 0.5, chloroform).

 Example 55

Аналогично примеру 36 подвергают превращению 1-циклопропил- 6,8-дифтор-1,4-дигидро-7-(транс-2-окса-5,8-диазабицикло[4.3.0] нон-8-ил)-4-оксо-3-хинолинкарбоновую кислоту и получают 1-циклопропил-7-[5-(транс-2-этоксикарбонил-винил] -транс-2- окса-5,8-диазабицикло[4.3.0]нон-8-ил]-6,8-дифтор-1,4 дигидро-4-оксо-3-хинолинкарбоновую кислоту.

Analogously to example 36, 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (trans-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -4-oxo is converted -3-quinolinecarboxylic acid to give 1-cyclopropyl-7- [5- (trans-2-ethoxycarbonyl-vinyl] -trans-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl] -6 , 8-difluoro-1,4 dihydro-4-oxo-3-quinolinecarboxylic acid.

T. pl. 266 268 ^o C (decomposed, from glycol monomethyl ether).

 Example 56

Аналогично примеру 36 подвергают превращению 1-циклопропил- 6,8-дифтор-1,4-дигидро-7-(транс-2-окса-5,8-диазабицикло[4.3.0] нон-8-ил)-4-оксо-3-хинолинкарбоновую кислоту с метиловым эфиром пропиоловой кислоты и получают 1-циклопропил-7-[5-транс-2-метоксикарбонил-винил)-транс-2-окса- 5,8-диазабицико[4.3.0]нон-8-ил]-6,8-дифтор-1,4-дигидро-4-оксо-3- хинолинкарбоновую кислоту.

Analogously to example 36, 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (trans-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -4-oxo is converted -3-quinoline carboxylic acid with propiolic acid methyl ester to give 1-cyclopropyl-7- [5-trans-2-methoxycarbonyl-vinyl) -trans-2-oxa-5,8-diazabicyclo [4.3.0] non-8- yl] -6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.

T. pl. 275 277 ^o C (decomposition).

 Example 57. By known methods, tablets of the composition are prepared, mg: 500 compounds of Example 19, 55 microcrystalline cellulose, 72 wet corn starch, 30 cross-linked polyvinylpyrrolidone, 5 silicon dioxide and 5 magnesium stearate.

 Example 58. Known methods prepare an infusion solution consisting of 1.27 g of the compound of example 19, 1.45 g of lactic acid, 1.80 g of 2-M. sodium hydroxide (to establish a pH of 3.6), 1.37 mannitol and water up to 100 ml.

Claims (4)

1. Derivatives of quinolone and naphthyridone carboxylic acids of the formula

where A is CH, CF, CCl, C-OCH ₃ , N;
X ¹ hydrogen, halogen, NH ₂ , CH ₃ ;
R ¹ alkyl containing 1 3 carbon atoms, cyclopropyl, phenyl, which may be substituted one to three times by halogen, or A and R ¹ together may mean a bridge of structure C — O — CH ₂ —CH (CH ₃ ) -;
R ² hydrogen, alkyl containing 1 3 carbon atoms,
In the remainder of the formula

where Y is O or CH ₂ ;
R ³ oxoalkyl containing 2 5 carbon atoms, CH ₂ CH ₂ CO ₂ R ',

, —CH = CH — CO ₂ R ′ or CH ₂ CH ₂ —CN,
where R 'is hydrogen or alkyl containing 1 to 3 carbon atoms,
R ⁴ hydrogen, alkyl containing 1 3 carbon atoms, oxoalkyl containing 2 5 carbon atoms CH ₂ CH ₂ CO ₂ R ',

, —CH = CH — CO ₂ —R ′ or CH ₂ CH ₂ —CN,
where R 'has the above meaning,
in the form of a mixture of isomers or individual isomers, their hydrates and salts. 2. Derivatives of quinolone and naphthyridone carboxylic acids of the formula I according to claim 1, in which A CH, CF, CCl, C-OCH ₃ , N, X ¹ hydrogen, F, Cl, Br, NH ₂ , CH ₃ , R ¹ C ₂ H ₅ , cyclopropyl or 2,4-difluorophenyl, or A and R ¹ together can mean a bridge of the structure C — O — CH ₂ —CH (CH ₃ ) -, R ² hydrogen, C ₂ H ₅ , B — the remainder of the formula

where Y is O or CH ₂ ,
R ³ CH ₂ —CO — CH ₃ , CH ₂ CH ₂ —CO — CH ₃ , CH ₂ CH ₂ CO ₂ R ′,

, —CH = CH — CO ₂ R ′ or CH ₂ CH ₂ —CN, where R ′ is alkyl containing 1 2 carbon atoms,
R ⁴ hydrogen, alkyl containing 1 3 carbon atoms, CH ₂ —CO — CH ₃ , CH ₂ CH ₂ CO — CH ₃ , CH ₂ CH ₂ CO ₂ R ′,

, -CH CH-CO ₂ R 'or CH ₂ CH ₂ -CH, where R' has the above meaning,
in the form of a mixture of isomers or individual isomers, their hydrates and salts. 3. Derivatives of quinolone and naphthyridone carboxylic acids of the formula I according to claim 1, wherein A is CH, CF, CCl, C-OCH ₃ , N; X ¹ hydrogen, F, Cl, Br, NH ₂ , CH ₃ , R ¹ C ₂ H ₅ , cyclopropyl or 2,4-difluorophenyl, or A and R ¹ together can mean a bridge of the structure —O — CH ₂ —CH (CH ₃ ) -, R ₂ hydrogen, C ₂ H ₅ ; B is the remainder of the formula

where Y is O or CH ₂ ;
R ⁴ hydrogen, alkyl containing 1 3 carbon atoms, CH ₂ —CO — CH ₃ , CH ₂ CH ₂ CO —CH ₃ , CH ₂ CH ₂ CO ₂ R ′,

—CH CH CO ₂ R ′ or CH ₂ CH ₂ —CN, where R ′ is alkyl containing 1 2 carbon atoms,
in the form of a mixture of isomers or individual isomers and their hydrates and salts.  4. A pharmaceutical composition with antibacterial activity, containing an active substance based on derivatives of a heterocyclic carboxylic acid and at least one target additive, characterized in that it, as derivatives of a heterocyclic carboxylic acid, contains a compound of general formula I according to claim 1 in the form of a mixture of isomers or a single isomer or hydrate or salt in an effective amount. Priority by signs:
01/10/92. All values are A, B, X ¹ , R ¹ , R ² , R ³ , R 'R ⁴ hydrogen, CH ₂ —CO — CH ₃ , CH ₂ CH ₂ CO — CH ₃ , CH ₂ CH ₂ CO ₂ R ′, R'O ₂ C — CH = C — CO ₂ R ′, —CH = OH — CO ₂ R ′ or CH ₂ CH ₂ —CN; 01/11/93. R ⁴ alkyl containing 1 to 3 carbon atoms.

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