SK282971B6 - Quinolone- and naphthyridone carboxylic acid derivatives as antibacterial agents - Google Patents

Quinolone- and naphthyridone carboxylic acid derivatives as antibacterial agents Download PDF

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SK282971B6
SK282971B6 SK3966-92A SK396692A SK282971B6 SK 282971 B6 SK282971 B6 SK 282971B6 SK 396692 A SK396692 A SK 396692A SK 282971 B6 SK282971 B6 SK 282971B6
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diazabicyclo
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oxo
carbon atoms
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Uwe Petersen
Andreas Krebs
Thomas Schenke
Thomas Philipps
Klaus Grohe
Klaus-Dieter Bremm
Rainer Endermann
Karl-Georg Metzger
Ingo Haller
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Bayer Aktiengesellschaft
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Priority claimed from DE4200414A external-priority patent/DE4200414A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P33/10—Anthelmintics

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Abstract

Disclosed are quinolone- and naphthyridone carboxylic acid derivatives of the formula (I). Their preparation method and antibacterial compositions and feed additives containing these.

Description

Oblasť technikyTechnical field

Vynález sa týka derivátov kyseliny chinolónkarboxylovej a naftyridónkarboxylovej, spôsobu ich výroby, antibakteriálnych prostriedkov a prídavkov do krmív, obsahujúcich uvedené látky a medziproduktov na výrobu týchto zlúčenín.The present invention relates to quinolone carboxylic acid and naphthyridone carboxylic acid derivatives, processes for their preparation, antibacterial agents and feed additives containing said substances and intermediates for the production of these compounds.

Doterajší stav technikyBACKGROUND OF THE INVENTION

Z EP-A-0 350 733 sú známe chinolónkarboxylové kyseliny a naftyridónkarboxylové kyseliny, ktoré sú v polohe 7 substituované bicyklickým amínovým zvyškom.EP-A-0 350 733 discloses quinolone carboxylic acids and naphthyridone carboxylic acids which are substituted at the 7-position with a bicyclic amine residue.

Podstata vynálezuSUMMARY OF THE INVENTION

Predmetom predloženého vynálezu sú deriváty kyseliny chinolónkarboxylovej a naftyridónkarboxylovej všeobecného vzorca (I)The present invention relates to quinolone carboxylic acid and naphthyridone carboxylic acid derivatives of the general formula (I)

v ktoromin which

A znamená skupinu CH, CF, CC1, C-OCH3, C-CH3 alebo N,A is CH, CF, CC1, C-OCH3, C-CH 3 or N,

X1 znamená vodíkový atóm, atóm halogénu, aminoskupinu alebo metylovú skupinu,X 1 represents a hydrogen atom, a halogen atom, an amino group or a methyl group,

R1 znamená alkylovú skupinu s 1 až 3 uhlíkovými atómami, skupinu FCH2CH2-, cyklopropylovú skupinu, fenylovú skupinu, prípadne raz až trikrát substituovanú atómom halogénu, aleboR 1 represents an alkyl group having 1 to 3 carbon atoms, an FCH 2 CH 2 - group, a cyclopropyl group, a phenyl group, optionally substituted one to three times with a halogen atom, or

R1 a A môžu znamenať spoločne mostík štruktúry C-O-CHrCH(CH3)-,R 1 and A may together represent a bridge of the structure CO-CH r CH (CH 3 ) -,

R2 znamená vodíkový atóm, alkylovú skupinu s 1 až 3 uhlíkovými atómami, prípadne substituovanú atómom halogénu alebo aminoskupinou, alebo 5-metyl-2-oxo-l,3-dioxol-4-yl-metylovú skupinu,R 2 represents hydrogen, alkyl having 1 to 3 carbon atoms, optionally substituted by halogen or amino, or a 5-methyl-2-oxo-l, 3-dioxol-4-yl-methyl,

B znamená zvyšok vzorcaB represents the remainder of the formula

x___t v ktoromx___t in which

Y znamená metylénovú skupinu aY represents a methylene group and

R4 znamená vodíkový- atóm, alkylovú skupinu s 1 až 3 uhlíkovými atómami, oxoalkylovú skupinu s 2 až 5 uhlíkovými atómami, skupiny CH2-CO-C6H5, CH2CH2CO2R', R'O2C-CH=C-CO2R',R 4 represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, an oxoalkyl group having 2 to 5 carbon atoms, CH 2 -CO-C 6 H 5 , CH 2 CH 2 CO 2 R ', R'O 2 C -CH = C-CO 2 R ',

II

-CH=CH-CO2R' alebo CH2CH2CN alebo 5-metyl-2-oxo-1,3-dioxol-4-yl-metylovú skupinu, pričom-CH = CH-CO 2 R 'or CH 2 CH 2 CN or 5-methyl-2-oxo-1,3-dioxol-4-ylmethyl, wherein:

R' znamená vodíkový atóm alebo alkylovú skupinu s 1 až uhlíkovými atómami, a ich farmaceutický použiteľné hydráty a adičné soli s kyselinami, ako i soli zodpovedajúcich kyselín s alkalickými kovmi, kovmi alkalických zemín, striebrom a guanidínom.R 1 represents a hydrogen atom or an alkyl group having 1 to carbon atoms, and the pharmaceutically usable hydrates and acid addition salts thereof, as well as the corresponding acid salts with alkali metals, alkaline earth metals, silver and guanidine.

Uvedené zlúčeniny majú vysoký antibakteriálny účinok. Ich zvláštnym znakom je silný účinok na pokojné a rezistentné kmene.Said compounds have a high antibacterial effect. Their special feature is a strong effect on calm and resistant strains.

Výhodné sú zlúčeniny všeobecného vzorca (1), v ktoromPreferred are compounds of formula (1) wherein:

A znamená skupinu CH, CF, CC1, C-OCH3 alebo N,A is CH, CF, CC1, C-OCH3 or N,

X1 znamená vodíkový atóm, atóm fluóru, chlóru alebo brómu, aminoskupinu alebo metylovú skupinu,X 1 represents a hydrogen atom, a fluorine, chlorine or bromine atom, an amino group or a methyl group,

R1 znamená etylovú skupinu, 2,4-difluórfenylovú skupinu, aleboR 1 is ethyl, 2,4-difluorophenyl, or

R1 a A môžu znamenať spoločne mostík štruktúry C-O-CH2-CH(CH3)-,R 1 and A may together represent a bridge of the structure CO-CH 2 -CH (CH 3 ) -,

R2 znamená vodíkový atóm metylovú skupinu, etylovú skupinu alebo 5-metyl-2-oxo-l,3-dioxol-4-yI-metylovú skupinu aR 2 represents hydrogen, methyl, ethyl or 5-methyl-2-oxo-l, 3-dioxol-4-yl-methyl, and

R4 znamená vodíkový atóm, alkylovú skupinu s 1 až 3 uhlíkovými atómami, skupiny CH2-CO-CH3, CH2-CO-C6H5, CH2CH2-CO-CH3, CH2CH2CO2R’, R'O2C-CH=C-CO2R', -CH=CH-CO2R' alebo CH2CH2-CN alebo | 5-metyI-2-oxo-í ,3-dioxol-4-yl-metylovú skupinu, pričomR 4 represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, 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 = C-CO 2 R', -CH = CH-CO 2 R 'or CH 2 CH 2 -CN or | A 5-methyl-2-oxo-1,3-dioxol-4-ylmethyl group wherein:

R' znamená alkylovú skupinu s 1 až 2 uhlíkovými atómami, a ich farmaceutický použiteľné hydráty a adičné soli s kyselinami, ako i soli zodpovedajúcich kyselín s alkalickými kovmi, kovmi alkalických zemín, striebrom a guanidínom.R 'represents an alkyl group having 1 to 2 carbon atoms, and the pharmaceutically usable hydrates and acid addition salts thereof, as well as the corresponding acid salts with alkali metals, alkaline earth metals, silver and guanidine.

Obzvlášť výhodný je derivát všeobecného vzorca (I), ktorým je kyselina 8-chlór-l-cyklopropyl-7-([S,S]-2,8-diazabicyk!o[4.3.0]nón-8-yl)-6-fluór-l,4-dihydro-4-oxo-3-chinolínkarboxylová a jej farmaceutický použiteľné hydráty a adičné soli s kyselinami, ako i soli zodpovedajúcich karboxylových kyselín s alkalickými kovmi, kovmi alkalických zemín, striebrom a guanidínom.Particularly preferred is a compound of formula (I) which is 8-chloro-1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6 -fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and its pharmaceutically usable hydrates and acid addition salts as well as the corresponding alkali metal, alkaline earth metal, silver and guanidine salts of the corresponding carboxylic acids.

Ďalej je výhodný derivát všeobecného vzorca (I), ktorým je kyselina l-cyklopropyl-7-([S,S]-2,8-diazabicklo[4.3.0]nón-8-yl)-6-fluór-l,4-dihydro-8-metoxy-7-oxo-3-chinolínkarboxylová.Further preferred is a compound of formula (I) which is 1-cyclopropyl-7 - ([S, S] -2,8-diazabicklo [4.3.0] non-8-yl) -6-fluoro-1,4 dihydro-8-methoxy-7-oxo-3-quinolinecarboxylic acid.

Ďalšie výhodné deriváty všeobecného vzorca (I) sú kyselina l-cyklopropyl-7-([S,S]-2,8-diazabicyklo[4.3.0]nón-8-yl)-6,8-difluór-l,4-dihydro-4-oxo-3-chinolínkarboxylová, kyselina l-cyklopropyl-7-([S,S]-2,8-diazabicyklo[4.3.0]nón-8-yl)-6-fluór-l ,4-dihydro-4-oxo-3-chinolínkarboxylová a kyselina l-cyklopropyl-7-([S,S]-2,8-diazabicyklo[4.3.0]nón-8-yl)-5,6,8-trifluór-l,4-dihydro-4-oxo-3-chinolínkarboxylová a ich soli.Other preferred derivatives of formula (I) are 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 1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro 4-oxo-3-quinolinecarboxylic acid and 1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -5,6,8-trifluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid and salts thereof.

Zlúčeniny všeobecného vzorca (I), v ktorom A znamená skupinu CH, CF, CC1, C-OCH3, C-CH3 alebo N, X1 znamená vodíkový atóm, atóm halogénu, aminoskupinu alebo metylovú skupinu,Compounds of formula (I) wherein A is CH, CF, CC 1, C-OCH 3 , C-CH 3 or N, X 1 is a hydrogen atom, a halogen atom, an amino group or a methyl group,

R1 znamená alkylovú skupinu s 1 až 3 uhlíkovými atómami, skupinu FCH2CH2-, cyklopropylovú skupinu, fenylovú skupinu, prípadne raz až trikrát substituovanú atómom halogénu, aleboR 1 represents an alkyl group having 1 to 3 carbon atoms, an FCH 2 CH 2 - group, a cyclopropyl group, a phenyl group, optionally substituted one to three times with a halogen atom, or

R1 a A môžu znamenať spoločne mostík štruktúry C-O-CH2-CH(CH3)-,R 1 and A may together represent a bridge of the structure CO-CH 2 -CH (CH 3 ) -,

R2 znamená vodíkový atóm, alkylovú skupinu s 1 až 3 uhlíkovými atómami, prípadne substituovanú atómom halogénu alebo aminoskupinou, alebo 5-metyl-2-oxo-l,3-dioxol-4-yl-metylovú skupinu,R 2 represents hydrogen, alkyl having 1 to 3 carbon atoms, optionally substituted by halogen or amino, or a 5-methyl-2-oxo-l, 3-dioxol-4-yl-methyl,

B znamená zvyšok vzorcaB represents the remainder of the formula

v ktoromin which

Y znamená metylovú skupinu aY represents a methyl group and

R4 znamená vodíkový atóm, alkylovú skupinu s 1 až 3 uhlíkovými atómami, oxoalkylovú skupinu s 2 až 5 uhlíkovými atómami, skupiny CIL-CO-CsHj, CH2CH2CO2R', RO2C-CH=C-CO2R',R 4 represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, an oxoalkyl group having 2 to 5 carbon atoms, CIL-CO-C 5 H 3 , CH 2 CH 2 CO 2 R ', RO 2 C-CH = C-CO 2 R '

-CH=CH-CO2R' alebo CH2CH2-CN alebo 5-metyl-2-oxo-1,3-dioxol-4-yl-metylovú skupinu, pričom-CH = CH-CO 2 R 'or CH 2 CH 2 CN or 5-methyl-2-oxo-1,3-dioxol-4-ylmethyl group, wherein:

R' znamená vodíkový atóm alebo alkylovú skupinu s 1 až uhlíkovými atómami, sa vyrobí tak, že sa nechá reagovať zlúčenina všeobecného vzorca (V)R 1 represents a hydrogen atom or an alkyl group having 1 to carbon atoms, is prepared by reacting a compound of formula (V)

R1 v ktorom majú A, R1, R2 a X1 uvedený význam aR 1 wherein A, R 1 , R 2 and X 1 are as defined above and a

X2 znamená atóm halogénu, obzvlášť fluóru alebo chlóru, s enantioméme čistými zlúčeninami všeobecného vzorca (VI) nX 2 represents a halogen atom, in particular fluorine or chlorine, with the enantiomerically pure compounds of the general formula (VI) n

N h h (v,>rn y v ktoromN hh (v, > rn y in which

Y znamená metylénovú skupinu aY represents a methylene group and

R4 znamená vodíkový atóm alebo alkylovú skupinu s 1 až 3 uhlíkovými atómami, prípadne za prítomnosti látok viažucich kyseliny, a reakčný produkt sa prípadne nechá reagovať ďalej so zlúčeninou všeobecného vzorca (Hla)R 4 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, optionally in the presence of acid binders, and the reaction product is optionally reacted further with a compound of formula (IIIa)

R4 - X3 (IHa), v ktorom má X3 uvedený význam aR 4 - X 3 (IIIa), wherein X 3 is as defined above and

R4 znamená oxoalkylovú skupinu s 2 až 5 uhlíkovými atómami, alebo skupiny CH2-CO-C()H5, CH2CH2CO2R’ a CH2CH2-CN, pričomR 4 represents an oxoalkyl group having 2 to 5 carbon atoms, or CH 2 -CO-C ( H ) , CH 2 CH 2 CO 2 R 'and CH 2 CH 2 -CN, wherein:

R' znamená vodíkový atóm alebo alkylovú skupinu s 1 až 3 uhlíkovými atómami, alebo s Michaelovým akceptorom, ako je dialkylester kyseliny acetylén-dikarboxylovej, alkylesterom kyseliny propiolovej alebo so zlúčeninou všeobecného vzorca (IV)R 'represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, or with a Michael acceptor, such as a dialkyl ester of acetylene dicarboxylic acid, an alkyl ester of propiolic acid or a compound of formula (IV)

CH2 = CH - R5 (IV), v ktoromCH 2 = CH-R 5 (IV) wherein

R5 znamená skupinu COCHj, CO2R' alebo CN.R 5 is COCH 3, CO 2 R 'or CN.

Keď sa napríklad použijú ako východiskové zlúčeniny kyselina 8-chlór-l-cyklopropyl-6,7-difluór-l,4-dihydro-4-oxo-3-chinolínkarboxylová a [S,S]-2,8-diazabicyklo[4.3.0]nonán, môže sa priebeh reakcie znázorniť pomocou nasledujúcej reakčnej schémy:For example, when starting from 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 may be illustrated by the following reaction scheme:

Racemické zlúčeniny, používané ako východiskové látky, sú z väčšej časti známe. Enantioméme zlúčeniny sú nové a môžu sa získať rôznymi spôsobmi:Racemic compounds used as starting materials are for the most part known. The enantiomeric compounds are novel and can be obtained in various ways:

1. Nechá sa reagovať racemická zlúčenina s enantioméme čistým pomocným činidlom, vzniknuté diastereoméry sa oddelia napríklad chromatograficky a z požadovaných diastereomérov sa chirálna pomocná skupina opäť oddelí.1. The racemic compound is reacted with an enantiomerically pure excipient, the resulting diastereomers are separated, for example, chromatographically, and the chiral auxiliary is separated again from the desired diastereomers.

2. Bicyklické amíny všeobecného vzorca (VI) sú ako enantiomérne čisté zlúčeniny nové. Môžu sa vyrobiť pomocou ďalej uvedeného postupu.2. The bicyclic amines of formula (VI) are novel as enantiomerically pure compounds. They can be produced by the following procedure.

2.1 Racemické bicyklické amíny všeobecného vzorca (a) ζχ> ω· v ktorom znamená2.1 The racemic bicyclic amines (a) ζχ> · ω which is

R4 vodíkový atóm alebo alkylovú skupinu s 1 až 3 uhlíkovými atómami, sa môžu nechať zreagovať s enantioméme čistými kyselinami, napríklad karboxylovými alebo sulfónovými kyselinami, ako je kyselina N-acctyl-L-glutámová, N-benzoyl-L-alanín, kyselina 3-brómgáfor-9-sulfónová, kyselina gáfor-3-karboxylová, kyselina cis-gáírová, kyselina gáfor-10-sulfónová, kyselina Ο,Ο'-dibenzoylvínna, kyselina D-vínna, kyselina L-vínna, kyselina mandľová, kyselina a-metoxyfenyloctová, kyselina 1-fenyletánsulfónová a kyselina α-fenyljantárová, na zmes diastereomémych solí, ktoré sa dajú frakčnou kryštalizáciou rozdeliť na diastereomérne čisté soli (pozri P. Newman, Optical Resolution Procedures for Chemical Compounds, Volume 1). Molámy pomer medzi aminom a enantioméme čistou kyselinou sa môže pohybovať v širokom rozpätí. Spracovaním tejto soli s hydroxidmi alkalických kovov alebo kovmi alkalických zemín sa dajú uvoľniť enantioméme čisté amíny.R 4, a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, can be reacted with enantiomerically pure acids such as carboxylic or sulfonic acids such as N-acetyl-L-glutamic acid, N-benzoyl-L-alanine, acid 3 -bromo-camphor-9-sulfonic acid, camphor-3-carboxylic acid, cis-camaric acid, camphor-10-sulfonic acid, Ο, Ο'-dibenzoyltartaric acid, D-tartaric acid, L-tartaric acid, mandelic acid, α- methoxyphenylacetic acid, 1-phenylethanesulfonic acid and α-phenylsuccinic acid, to a mixture of diastereomeric salts which can be separated into diastereomerically pure salts by fractional crystallization (see P. Newman, Optical Resolution Procedures for Chemical Compounds, Volume 1). The molar ratio between amine and enantiomerically pure acid can be varied within a wide range. Treatment of this salt with alkali metal or alkaline earth metal hydroxides can liberate the enantiomerically pure amines.

2.2 Podobným spôsobom, ako je opísané v odseku 2.1, sa dá uskutočňovať štiepenie racemátov bázických medzistupňov, ktoré sa vyskytujú pri výrobe racemických bicyklických amínov, pomocou uvedených enantioméme čistých kyselín. Ako príklady takýchto bázických medzistupňov je možné uviesť nasledujúce zlúčeniny (b) až (e).2.2 In a manner similar to that described in 2.1, the resolution of the racemates of the basic intermediate steps which occur in the production of racemic bicyclic amines can be carried out using the enantiomerically pure acids mentioned above. Examples of such basic intermediate steps include the following compounds (b) to (e).

oabout

V nasledujúcej reakčnej schéme je ako príklad štiepenie racemátov znázornené rozdelením 8-benzyl-cis-2,8-diazabicyklo[4.3.0]nonánu cez tartáty na enantioméry a ich prevedenie na enantioméme čisté cis-2,8-diazabicyklo[4.3.0]nonány:In the following reaction scheme, as an example, resolution of the racemates is illustrated by separating 8-benzyl-cis-2,8-diazabicyclo [4.3.0] nonane through the tartates into enantiomers and converting them into the enantiomerically pure cis-2,8-diazabicyclo [4.3.0] nonane

H HH H

HH

e.e.> 99 %e.e.> 99%

R.R-Konf gunkiflR.R-Konf gunkifl

HH

i.e.i 99i.e.i 99

S.S-KonfigurňciaS, S-Konfigurňcia

2.3 Tak racemické amíny (a), ako tiež bázické medziprodukty (bv) - (e) sa môžu chromatograficky rozdeľovať cez chirálne nosičové materiály (pozri napríklad G. Blaschke, Angew. Chem. 92 14/1980/).2.3 Both racemic amines (a) and basic intermediates (bv) - (e) can be chromatographically separated over chiral carrier materials (see, for example, G. Blaschke, Angew. Chem. 92 14 (1980)).

2.4. Tak racemické amíny (a), ako tiež bázické medziprodukty (b), (c), (e) sa môžu previesť chemickou väzbou s chirálnymi acylestermi na zmesi diastereomérov, ktoré sa dajú rozdeliť na diastereomémc čisté acylderiváty pomocou destilácie, kryštalizácie alebo chromatografie a z týchto sa dajú zmydelnením izolovať enantioméme čisté amíny. Ako príklady reagencií na väzbu s chirálnymi acylestermi je možné uviesť a metoxy-a-trifluórmetylpentacetylchlorid, metylizokyanát, D-a-fenyletylizokyanát, L-a-fenyletylizokyanát, metylester kyseliny chlórmravčej a chlorid kyseliny gáfor-10-sulfónovej.2.4 Both racemic amines (a) and basic intermediates (b), (c), (e) can be converted by chemical bonding with chiral acyl esters to diastereomeric mixtures which can be separated into diastereomerically pure acyl derivatives by distillation, crystallization or chromatography and from these enantiomerically pure amines can be isolated by saponification. Examples of reagents for binding with chiral acyl esters include methoxy-α-trifluoromethylpentacetyl chloride, methyl isocyanate, D-α-phenylethyl isocyanate, L-α-phenylethyl isocyanate, methyl chloroformate and camphor-10-sulfonic acid chloride.

2.5. Počas syntézy bicyklických amínov (a) sa môžu zaviesť namiesto achirálnych tiež chirálne ochranné skupiny. Týmto spôsobom dôjde k diastereomérom, ktoré sa dajú deliť. Napríklad je možné pri syntéze cis-2,8-diazabicyklo[4.3.0]nonánu nahradiť benzylový zvyšok R-konfigurovaným alebo S-konfigurovaným α-fenylovým zvyškom:2.5. During the synthesis of bicyclic amines (a), chiral protecting groups may also be introduced instead of achiral. In this way diastereomers can be separated which can be separated. For example, in the synthesis of cis-2,8-diazabicyclo [4.3.0] nonane, the benzyl radical can be replaced by an R-configured or S-configured α-phenyl residue:

2.6. Enantioméme čisté amíny všeobecného vzorca (VI) sa môžu tiež vytvoriť z enantioméme čistých predstupňov, ako je napríklad [R,R]-3,4-dihydroxypyrolidin alebo [S,S]-3,4-dihydroxypyrolidín, ktorý musí byť na dusíkovom atóme chránený ochrannou skupinou.2.6 Enantiomerically pure amines of formula (VI) may also be formed from enantiomerically pure precursors, such as [R, R] -3,4-dihydroxypyrrolidine or [S, S] -3,4-dihydroxypyrrolidine, which must be on a nitrogen atom protected by a protecting group.

Ako príklad na syntézu enantioméme čistého amínu, keď sa vychádza z enantioméme čistého l-benzyl-3,4-dihydroxypyrolidínu, je možné uviesť nasledujúcu reakčnú schému:As an example for the synthesis of the enantiomerically pure amine, starting from the enantiomerically pure 1-benzyl-3,4-dihydroxypyrrolidine, the following reaction scheme is given:

HO OH ·> HO OH ·> HO, OH HO, OH HO, 0CHjCH20H . nHO 0CHjCH 2 0H. n N N —- - Bzl Bzl 1 CO I 1 CO I 1 CO 1 WHAT R R 1 R 1 R TosO OCH.CH.OTos H ’ TosO OCH.CH.OTos H ’ r~\ O N-Bzl r ~ \ About N-Bzl O N-H s ŕ O About N-H Ltd ’ Q sh 'Q sh CO WHAT 1 1 N N R R CO WHAT H H

RR

R = napríklad skupina (CH3)3C-O a: H2, Pd/akt. uhlie b: acylácia c: NaH, BrCH2COOC2H5 alebo c: -CH2=CH-CH2Br, NaH d: LiBH4 d: O3,NaBH4 e: tosylchlorid, Net3 f: benzylamín, xylén, reflux g: hydrolýza h: H2, Pd/akt. uhlie.R =, for example, (CH 3 ) 3 CO a: H 2 , Pd / act. charcoal b: acylation c: NaH, BrCH 2 COOC 2 H 5 or c: -CH 2 = CH-CH 2 Br, NaH d: LiBH 4 d: O 3 , NaBH 4 e: tosyl chloride, Net 3 f: benzylamine, xylene , reflux g: hydrolysis h: H2, Pd / activated. coal.

Ako príklady zlúčenín všeobecného vzorca (VI) je možné uviesť nasledujúce: cis-2,8-diazabicyklo[4.3.0]nonán, cis-2-oxa-5,8-diazabicyklo[4,3.0]nonán, trans-2-oxa-5,8-diazabicyklo[4.3.0]nonán, S,S-2,8-diazabicyklo[4.3.0.]nonán, lR,6S-2-oxa-5,8-diazabicyklo[4.3.0]nonán, lS,6R-2-oxa-5,8-diazabicyklo[4.3.0]nonán, lR,6R-2-oxa-5,8-diazabicyklo[4.3.0]nonán a lS,6S-2-oxa-5,8-diazabicyklo[4.3.0]nonán.Examples of compounds of formula (VI) include: 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] nonane and 1S, 6S-2-oxa-5, 8-diazabicyclo [4.3.0] nonane.

Reakcia zlúčenín všeobecného vzorca (V) so zlúčeninami všeobecného vzorca (VI), pri ktorej sa zlúčeniny všeobecného vzorca (VI) môžu použiť tiež vo forme svojich solí, napríklad vo forme hydrochloridov, sa výhodne uskutočňuje v zrieďovacom činidle, ako je napríklad dimetylsulfoxid, Ν,Ν-dimetylformamid, N-metylpyrolidón, triamid kyseliny hexametylfosforečnej, sulfolan, acetonitril, voda alebo v alkoholoch, ako je metylalkohol, etylalkohol, n-propylalkohol, izopropylalkohol alebo v glykolmonometyléteri alebo pyridíne. Rovnako tiež je možné použiť zmesi týchto zrieďovacich činidiel.The reaction of compounds of formula (V) with compounds of formula (VI), in which the compounds of formula (VI) may also be used in the form of their salts, for example in the form of hydrochlorides, is preferably carried out in a diluent such as dimethylsulfoxide. , Ν-dimethylformamide, N-methylpyrrolidone, hexamethylphosphoric triamide, sulfolane, acetonitrile, water or in alcohols such as methanol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol or in glycol monomethyl ether or pyridine. Mixtures of these diluents may also be used.

Ako látky viažuce kyseliny sa môžu použiť všetky obvyklé anorganické a organické činidlá, viažuce kyseliny. K týmto patria výhodne hydroxidy alkalických kovov, uhličitany alkalických kovov, organické amíny a organické amidíny. Ako obzvlášť výhodné je možné jednotlivo menovať trietylamín, l,4-diazabicyklo[2.2.2.]oktán (DABCO), l,8-diazabicyklo[5.4.0]undec-7-én (DBU) alebo zvyšný amín všeobecného vzorca (VI).All conventional inorganic and organic acid binding agents can be used as acid binders. These preferably include alkali metal hydroxides, alkali metal carbonates, organic amines and organic amidines. Particularly preferred are triethylamine, 1,4-diazabicyclo [2.2.2.] Octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or the remaining amine of general formula (VI). ).

Reakčné teploty sa môžu pohybovať v širokom rozpätí, obvykle sa však pracuje pri teplote v rozpätí 20 až 200 °C, výhodne 80 až 180 °C.The reaction temperatures can be varied within a wide range, but are usually carried out at a temperature in the range of 20 to 200 ° C, preferably 80 to 180 ° C.

Reakcia sa môže uskutočňovať za normálneho tlaku, ale tiež za zvýšeného tlaku. Všeobecne sa pracuje za tlaku v rozpätí 0,1 až 10 MPa, výhodne 0,1 až 1 MPa.The reaction can be carried out at normal pressure but also at elevated pressure. In general, the process is carried out at a pressure in the range from 1 to 10 MPa, preferably from 1 to 10 MPa.

Pri uskutočňovaní uvedeného spôsobu sa používa na jeden mol zlúčeniny všeobecného vzorca (V) 1 až 15 mol, výhodne 1 až 6 mol zlúčeniny všeobecného vzorca (VI).In carrying out the process, 1 to 15 mol, preferably 1 to 6 mol, of the compound of formula (VI) is used per mole of the compound of formula (V).

Výroba adičných solí zlúčenín podľa predloženého vynálezu s kyselinami sa uskutočňuje obvyklým spôsobom, napríklad rozpustením betaínu vo vodnej kyseline a vyzrážaním soli organickým rozpúšťadlom zmiešateľným s vodou, ako je napríklad metylalkohol, etylalkohol, acetón alebo acetonitril. Môžu sa tiež zahriať ekvivalentné množstvá betaínu a kyseliny vo vode alebo v alkohole, ako je napríklad glykolmonometyléter a potom odpariť do sucha alebo vyzrážanú soľ odsať. Ako farmaceutický použiteľné soli sa rozumejú napríklad soli s kyselinou chlorovodíkovou, kyselinou sírovou, kyselinou octovou, kyselinou glykolovou, kyselinou mliečnou, kyselinou jantárovou, kyselinou citrónovou, kyselinou vínnou, kyselinou metánsulfónovou, kyselinou 4-toluénsulfónovou, kyselinou galakturónovou, kyselinou glukónovou, kyselinou embonovou, kyselinou glutámovou alebo ky selinou asparágovou.The acid addition salts of the compounds of the present invention are prepared in a conventional manner, for example by dissolving betaine in aqueous acid and precipitating the salt with a water-miscible organic solvent such as methanol, ethyl alcohol, acetone or acetonitrile. Equivalent amounts of betaine and acid in water or an alcohol such as glycol monomethyl ether may also be heated and then evaporated to dryness or the precipitated salt aspirated. Pharmaceutically useful salts are, for example, salts with hydrochloric acid, sulfuric acid, acetic acid, glycolic acid, lactic acid, succinic acid, citric acid, tartaric acid, methanesulfonic acid, 4-toluenesulfonic acid, galacturonic acid, gluconic acid, emonic acid, glutamic acid or aspartic acid.

Soli karboxylových kyselín podľa predloženého vynálezu s alkalickými kovmi alebo s kovmi alkalických zemín sa napríklad získajú rozpustením betaínu vo zvyšnom hydroxide alkalického kovu alebo kovu alkalickej zeminy, filtráciou nerozpusteného betaínu a odparením filtrátu do sucha. Farmaceutický vhodné sú soli sodné, draselné a vápenaté. Reakciou solí s alkalickými kovmi alebo kovmi alkalických zemín s vhodnou striebornou soľou, ako je napríklad dusičnan strieborný, sa získajú zodpovedajúce strieborné soli.For example, the alkali metal or alkaline earth metal salts of the carboxylic acids of the present invention are obtained by dissolving betaine in the remaining alkali metal or alkaline earth metal hydroxide, filtering the undissolved betaine and evaporating the filtrate to dryness. Pharmaceutically suitable are the sodium, potassium and calcium salts. Reaction of the alkali metal or alkaline earth metal salts with a suitable silver salt, such as silver nitrate, yields the corresponding silver salts.

Opísanými spôsobmi sa môžu okrem účinných látok, uvedených v príkladovej časti, vyrobiť napríklad tiež zlúčeniny uvedené v nasledujúcej tabuľke.In addition to the active compounds mentioned in the Examples section, the compounds described in the following table can also be prepared by the processes described.

CQOHCQOH

R3 R 3 x1 x 1 A A C2HSO2C-CH2CH,-C 2 H S O 2 C-CH 2 CH H H C-F C-F CH3O2C-CH=€H-CH 3 O 2 C-CH = € H- H H C-F C-F NC-CH2-CH2-NC-CH 2 -CH 2 - H H C-F C-F 5-Metyl-2-oxo-I,3-íiioxol-4-yl-metyl· 5-Methyl-2-oxo-3-íiioxol-4-yl-methyl · H H C-F C-F CH3-CO-CH2-CH 3 -CO-CH 2 - H H C-CI C-Cl 5-Metyl-2-oxo-l,3-dioxol-4’yl-meiyl· 5-Methyl-2-oxo-l, 3-dioxo-4'yl--methyl · H H C-CI C-Cl CHrCO-CHyCHr CH r CO-CH y CH r H H C-H C-H ch3-co-ch2-ch 3 -co-ch 2 - H H C-H C-H C2H5O2C-CHrCH2 C 2 H 5 O 2 C-CH 2 CH r H H C-H C-H CíHjOjC-CH^-COjCjHj CíHjOjC-CH -COjCjHj H H C-H C-H CH3O2C-CH=CH-CH 3 O 2 C-CH = CH- Ii Ii C-H C-H c2hso2c-ch=ch·c 2 h s o 2 c-ch = ch · F F C-F C-F CH3-CO-CH2CH2-CH 3 -CO-CH 2 CH 2 - nh2 nh 2 C-F C-F C2H3O2C-CH2CH2-C 2 H 3 O 2 C-CH 2 CH 2 - nh2 nh 2 C-F C-F ch3o2c-ch=c-co2ch3 ch 3 o 2 c-ch = c-co 2 ch 3 NH, NH, C-F C-F CýisC^CCH-C-COjCjHs CýisC ^ CCH-C-COjCjHs NH, NH, C-F C-F

R3 R 3 x1 x 1 A A C2HSO2C-CH=CH-C 2 H S O 2 C-CH = CH- NH, NH, C-F C-F ch3-co-ch2ch2-ch 3 -co-ch 2 ch 2 - H H N N c2hío2c-ch,-ch2- 2 c h s o 2 C = CH, -CH 2 - H H N N nc-ch2ch2-nc-ch 2 ch 2 - H H N N c1h3o2c-ch=c-co3c2h3 c 1 h 3 o 2 c-ch = c-co 3 c 2 h 3 H H N N CHjO2C-CH=CH-CH 2 O 2 C-CH = CH- H H N N ch3-co-ch2ch2-ch 3 -co-ch 2 ch 2 - ch3 ch 3 C-H C-H ch3-co-ch2-ch 3 -co-ch 2 - ch3 ch 3 C-H C-H c2h5o2cch2ch2-c 2 h 5 o 2 cch 2 ch 2 - CH, CH, C-H C-H c2h3o2c-ch=c-co2c2h3 c 2 h 3 o 2 c-ch = c-co 2 c 2 h 3 ch3 ch 3 C-H C-H CHjO2C-CH=C-CO2CH3 CH 2 O 2 C-CH = C-CO 2 CH 3 CH, CH, C-H C-H CjH5O2C-CH=CH-C 1 H 5 O 2 C-CH = CH- CH, CH, C-H C-H ch,o2c-ch-ch-ch, by 2 c-ch-ch- CH, CH, C-F C-F c3h5o2c-ch=c-co2c3h5 c 3 h 5 o 2 c-ch = c-co 2 c 3 h 5 CH, CH, N N

Zlúčeniny podľa predloženého vynálezu pôsobia silne antibiotický a majú pri malej toxicite široké antibakteriálne spektrum proti grampozitívnym a gramnegatívnym zárodkom, obzvlášť proti enterobakteriám, predovšetkým však proti takým, ktoré sú rezistentné proti rôznym antibiotikám, ako sú napríklad penicilíny, cefalosporíny, aminoglykozidy, sulfónamidy a tetracyklíny.The compounds of the present invention act strongly antibiotic and have a broad antibacterial spectrum at low toxicity against gram-positive and gram-negative germs, particularly enterobacteria, in particular those resistant to various antibiotics such as penicillins, cephalosporins, aminoglycosides, sulfonamides and sulfonamides.

Tieto cenné vlastnosti umožňujú ich použitie ako chemoterapeutických účinných látok v medicíne, ako i na konzervovanie anorganických a organických materiálov, obzvlášť organických materiálov všetkého druhu, napríklad polymérov, mazadiel, farieb, vlákien, kože, papiera a dreva, potravín a vody.These valuable properties allow their use as chemotherapeutic active ingredients in medicine, as well as for the preservation of inorganic and organic materials, in particular organic materials of all kinds, for example polymers, lubricants, paints, fibers, leather, paper and wood, food and water.

Zlúčeniny podľa predloženého vynálezu sú účinné proti veľmi širokému spektru mikroorganizmov. S ich pomocou je možné potláčať gramnegatívne a grampozitívne baktérie a baktériám podobné mikroorganizmy, ako i potláčať, zlepšovať a/alebo liečiť ochorenia, vyvolané týmito pôvodcami.The compounds of the present invention are active against a very wide range of microorganisms. They can be used to control gram-negative and gram-positive bacteria and bacteria-like microorganisms, as well as to control, ameliorate and / or treat diseases caused by these agents.

Zlúčeniny podľa predloženého vynálezu sa vyznačujú zosilneným účinkom na pokojové a rezistentné zárodky. Pri pokojových baktériách, teda baktériách, ktoré nemajú žiaden preukázateľný rast, pôsobia tieto zlúčeniny hlboko pod koncentráciou doposiaľ známych substancií. Toto sa týka nielen použitého množstva, ale tiež rýchlosti usmrcovania. Takéto výsledky bolo možné pozorovať pri grampozitívnych a gramnegatívnych baktériách, obzvlášť pri Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecalis a Escherichia coli.The compounds of the present invention exhibit an enhanced effect on resting and resistant germs. In resting bacteria, i.e. bacteria which have no detectable growth, these compounds act well below the concentration of the substances known so far. This applies not only to the amount used but also to the killing rate. Such results have been observed in Gram-positive and Gram-negative bacteria, particularly in Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecalis and Escherichia coli.

Obzvlášť proti baktériám, ktoré sú proti porovnateľným substanciám zaraďované ako málo citlivé, obzvlášť rezistentné kmene Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa a Enterococcus faecalis, majú zlúčeniny podľa predloženého vynálezu prekvapivé spektrum účinku.In particular, the bacteria according to the invention have a surprising spectrum of action against bacteria which are classified as being less sensitive to comparable substances, in particular resistant strains of Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Enterococcus faecalis.

Obzvlášť účinné sú zlúčeniny podľa predloženého vynálezu proti baktériám a baktériám podobným mikroorganizmom. Sú teda obzvlášť vhodné na profylaxiu a chemoterapiu lokálnych a systemických infekcií v humánnej a veterinárnej medicíne, ktoré sú vyvolávané týmito pôvodcami.The compounds of the present invention are particularly effective against bacteria and bacteria-like microorganisms. They are therefore particularly suitable for the prophylaxis and chemotherapy of local and systemic infections in human and veterinary medicine caused by these agents.

Uvedené zlúčeniny sú tiež vhodné na potláčanie protozoonos a helmintos.The compounds are also suitable for the control of protozoonoses and helminths.

Zlúčeniny podľa predloženého vynálezu sa môžu použiť v rôznych farmaceutických prípravkoch. Ako výhodné farmaceutické prípravky je možné uviesť tabletky, dražé, kapsuly, pilulky granuláty, čapíky, roztoky, suspenzie, emulzic, pasty, masti, želé, krémy, pleťové prípravky, púdre a sprej e.The compounds of the present invention can be used in various pharmaceutical compositions. Preferred pharmaceutical compositions include tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions, emulsions, pastes, ointments, jellies, creams, skin preparations, powders and sprays.

Nasledujúca tabuľka dokladá prekvapivé výhody zlúčenín podľa predloženého vynálezu v porovnaní s Ciprofloxacínom na modeli myší, infikovaných Staphylococcus aureus.The following table demonstrates the surprising advantages of the compounds of the present invention over Ciprofloxacin in a model of Staphylococcus aureus infected mice.

Tabuľka - Účinnosť pri infekcií Staphylococcus aureus pri myšiach (mg/któEfficacy in Staphylococcus aureus infections in mice (mg / któ

Substancia substance p. 0. p. 0th S. c. S. c. Ciprofoxacín ciprofoxacin 80 80 80 80 príklad 14 Example 14 10 10 2,5 2.5 príklad 16A Example 16A 5 5 5 5 príklad 18 Example 18 10 10 5 5 príklad 20 Example 20 2,5 2.5 2,5 2.5

oabout

Zlúčenina podľa vynálezu podľa príkladu 2:Example 2 compound:

ch3 ch 3

známe z EP-A-0 350 733:known from EP-A-0 350 733:

Ciprofloxacín:ciprofloxacin:

Tabuľkatable

Mikroorganizmus microorganism kmeň tribe zlúčenina compound A A B B C C Bacteroides fragilis Bacteroides fragilis ES 25 DSM2151 ES 25 DSM2151 0,25 0,25 0.25 0.25 1 0,5 1 0.5 8 4 8 4 Clostridium perfringens Clostridium perfringens 1024027 1024027 0,125 0,125 0,5 0.5 0,5 0.5 Bact. thetaiotaomicron Bact. thetaiotaomicron DSM 2079 DSM 2079 0,5 0.5 2 2 8 8

(MHK-hodnoty v pg/ml; agarový zrieďovací test v multibodovom inokulátore (Denley); Isosensites-agar)(MHK-values in pg / ml; agar dilution test in a multi-point inoculator (Denley); Isosensites-agar)

Príklady uskutočnenia vynálezuDETAILED DESCRIPTION OF THE INVENTION

Výroba predproduktovProduction of pre-products

Príklad A [S,S]-2,8-Diazabicyklo[4.3.0]nonánExample A [S, S] -2,8-Diazabicyclo [4.3.0] nonane

V H aHIn H and H

1. [S,S]-8-Benzyl-2,8-diazabicyklo[4.3.0]nonán1. [S, S] -8-Benzyl-2,8-diazabicyclo [4.3.0] nonane

Metóda IMethod I

a) Delenie diastereomémych solía) Separation of diastereomeric salts

3,0 g (20 mmol) kyseliny D(-)-vínnej sa za zahriatia na teplotu 80 °C rozpustí v 10 ml dimetylformamidu a zmieša sa s roztokom 2,16 g (10 mmol) cis-8-benzyl-2,8-diazabicyklo[4.3.0]nonánu v 3 ml dimetylformamidu. Reakčná zmes sa mieša počas 1 hodiny pri teplote 0 °C, potom sa odsaje produkt a premyje sa dietylformamidom a metoxyetanolom.D (-) - tartaric acid (3.0 g, 20 mmol) was dissolved in dimethylformamide (10 ml) with heating at 80 ° C and treated with a solution of cis-8-benzyl-2,8 (2,16 g, 10 mmol). -diazabicyclo [4.3.0] nonane in 3 ml of dimethylformamide. The reaction mixture is stirred for 1 hour at 0 ° C, then the product is filtered off with suction and washed with diethylformamide and methoxyethanol.

Výťažok: 1,93 g teplota topenia: 146-151 °C [a]D 23 =-19,3° (c = 1, H2O).Yield: 1.93 g Melting point: 146-151 ° C [α] D 23 = -19.3 ° (c = 1, H 2 O).

Jednoduchou kryštalizáciou z metoxyetanolu sa získa diastereoméme čistý [S,S]-8-benzyl-2,8-diazabicyklo[4.3.0]nonán.By simple crystallization from methoxyethanol, diastereomerically pure [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane is obtained.

[a]D 23 = - 22,7° (c = 1, H2O). teplota topenia: 148 - 154 °C.[α] D 23 = - 22.7 ° (c = 1, H 2 O). mp 148-154 ° C.

b) Uvoľnenie bázy g [S,S]-8-benzyl-2,8-diazabicyklo[4.3.0]nonánu sa rozpustí v 250 ml vody a zmieša sa s 32 g 45 % hydroxidu sodného. Vyzrážaná olejovitá kvapalina sa vyberie do 150 ml íerc-butylmetyléteru, vodná fáza sa ešte raz extrahuje 150 ml íerc-butylmctyléteru a spojené organické fázy sa po vysušení pomocou bezvodého síranu sodného zahustia. Potom sa zvyšok destiluje vo vákuu.(b) Base release g [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane is dissolved in 250 ml of water and mixed with 32 g of 45% sodium hydroxide. The precipitated oily liquid 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 dried after drying over anhydrous sodium sulphate. Then the residue is distilled under vacuum.

Výťažok: 18,5 g [S,S]-8-benzyl-2,8-diazabicyklo[4.3.0]nonánu, teplota varu: 107- 109 °C/10 Pa, [α]π 24= 17,3° (nezriedené).Yield: 18.5 g of [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane, boiling point: 107-109 ° C / 10 Pa, [α] π 24 = 17.3 ° (undiluted).

Metóda IIMethod II

75,0 g (0,5 mol) kyseliny L(+)-vínnej sa rozpustí pri teplote 80 °C v 250 ml dimetylformamidu a prikvapká saDissolve 75.0 g (0,5 mol) of L (+) - tartaric acid at 80 ° C in 250 ml of dimethylformamide and add dropwise

54,1 g (0,25 mol) cis-8-benzyl-2,8-diazabicyklo[4.3.0]nonánu ako roztoku v 75 ml dimetylformamidu. Reakčná zmes sa pomaly ochladí na teplotu 20 °C a vytvorená suspenzia kryštálov sa mieša ešte počas 1 hodiny. Vytvorené kryštály [R,R]-8-benzyl-2,8-diazabicyklo-[4.3.0]nonán-L-tartátu sa odsajú a filtrát sa zahustí na rotačnej odparke. Zvyšok sa rozpustí v 500 ml vody a spracuje sa 63 g 45 % hydroxidu sodného, ako je opísané v metóde I.54.1 g (0.25 mol) of cis-8-benzyl-2,8-diazabicyclo [4.3.0] nonane as a solution in 75 ml of dimethylformamide. The reaction mixture was slowly cooled to 20 ° C and the formed slurry of crystals was stirred for 1 hour. The formed crystals of [R, R] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane-L-tartrate are aspirated and the filtrate is concentrated on a rotary evaporator. The residue was dissolved in 500 ml of water and treated with 63 g of 45% sodium hydroxide as described in Method I.

Výťažok: 25,2 g [S,S]-8-benzyl-2,8-diazabicyklo[4.3.0]-nonánu;Yield: 25.2 g of [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] -nonane;

produkt obsahuje 3,6 % R,R-enantioméra (po derivatizácii metylesterom kyseliny chlórmravčej stanovené pomocou plynovej chromatografie).The product contains 3.6% of the R, R-enantiomer (after derivatization with methyl chloroformate as determined by gas chromatography).

Zlúčenina sa môže podľa metódy I nechať reagovať s kyselinou D-(-)-vínnou na diastereoméme čistý [S,S]-8-benzyl-2,8-diazabicyklo[4.3.0]nonán-D-tartát. Kryštalizácia tu nie je potrebná.The compound can be reacted with D - (-) - tartaric acid on diastereomeric pure [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane-D-tartate according to Method I. Crystallization is not necessary here.

Metóda IIIMethod III

K roztoku 102,9 g (0,685 mol) kyseliny L-(+)-vínnej v 343 ml dimetylformamidu sa prikvapká pri teplote v rozpätí °C až 90 °C 73,6 g (0,34 mol) cis-8-benzyl-2,8-diazabicyklo[4.3.0]nonánu ako roztoku v 111 ml dimetylformamidu. Zaočkuje sa pomocou [R,R]-8-benzyl-2,8-diazabicyklo-[4.3.0]nonán-L-tartátu a pomaly sa ochladí až na vnútornú teplotu 18 °C. Vytvorené kryštály sa odsajú, fíltrát sa zaočkuje pomocou [S,S]-8-benzyl-2,8-diazabicyklo[4.3.0]nonán-L-tartátu a zmes sa mieša až do úplného prebehnutia kryštalizácie. (Z materského roztoku sa môže po zahustení a uvoľnení báz získať podľa metódy I čistením s kyselinou D-(-)-vínnou [S,S]-8-benzyl-2,8-diazabicyklo[4.3.0]nonán-D-tartát). Potom sa kryštály odsajú, premyjú sa dimetylformamidom a izopropylalkoholom a na vzduchu sa usušia. Kryštály sa rekryštalizujú z 88 % etylalkoholu. Získa sa takto 52 g [S,S]-8-benzyl-2,8-diazabicyklo-[4.3.0]nonán-L-tartát-trihydrátu.To a solution of 102.9 g (0.685 mol) of L - (+) - tartaric acid in 343 ml of dimethylformamide, 73.6 g (0.34 mol) of cis-8-benzyl- 2,8-diazabicyclo [4.3.0] nonane as a solution in 111 ml of dimethylformamide. Inoculate with [R, R] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane-L-tartate and slowly cool to an internal temperature of 18 ° C. The formed crystals are aspirated, the filtrate is seeded with [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane-L-tartate, and the mixture is stirred until crystallization is complete. (After concentration and liberation of the bases, method D can be obtained by purification with D - (-) - tartaric acid [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane-D-tartate according to Method I ). The crystals are then filtered off with suction, washed with dimethylformamide and isopropyl alcohol and air-dried. The crystals were recrystallized from 88% ethyl alcohol. 52 g of [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane-L-tartrate trihydrate are obtained.

Teplota topenia: 201 - 204 °C, [a]D 23 = + 5,2° (c= 1, H2O).Melting point: 201-204 ° C, [α] D 23 = + 5.2 ° (c = 1, H 2 O).

Soľ sa môže spracovať, ako je opísané v metóde I (uvoľnenie bázy), na enantioméme čistý [S,S]-8-benzyl-2,8-diazabicyklo[4.3.0]nonán.The salt can be treated as described in Method I (Base Release) to enantiomerically pure [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane.

Metóda IVMethod IV

a) Delenie enantiomérov cis-8-benzyl-7,9-dioxo-2,8-diazabicyklo[4.3.0]nonánu na [lS,6R]-8-benzyl-7,9-dioxo-2,8-diazabicyklo[4.3.0]nonána) Separation of enantiomers of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane into [1S, 6R] -8-benzyl-7,9-dioxo-2,8-diazabicyclo [ 4.3.0]

Postupuje sa analogicky ako je uvedené v príklade B, (metóda Il/a), pričom sa ako chirálne pomocné činidlo použije kyselina D-(-)-vínna, alebo sa postupuje nasledujúcim spôsobom:The procedure is analogous to that described in Example B (Method II / a), using D - (-) - tartaric acid as the chiral auxiliary, or as follows:

Materský lúh a premývací lúh z [lR,6S]-8-benzyl-7,9-dioxo-2,8-diazabicyklo[4.3.0]nonán-L-tartátu (z príkladu B, metóda ΙΙ/a) sa spoločne zahustí, vyberie sa do vody a trikrát sa extrahuje toluénom. Toluénová fáza sa odstráni a vodná fáza sa zmieša s roztokom hydrogenuhličitanu sodného, ktorým sa nastaví hodnota pH na 7 až 8. Potom sa extrahuje štyrikrát metylénchloridom, spojené metylčnchloridové fázy sa vysušia pomocou bezvodého síranu horečnatého a zahustia sa.The mother liquor and the wash liquor from [1R, 6S] -8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane-L-tartrate (from Example B, method ΙΙ / a) are concentrated together It is taken up in water and extracted three times with toluene. The toluene phase is removed and the aqueous phase is mixed with sodium bicarbonate solution to adjust the pH to 7-8. Then it is extracted four times with methylene chloride, the combined methyl chloride phases are dried over anhydrous magnesium sulphate and concentrated.

Výťažok: 14,4 g (60 % teórie pôvodne vsadeného cis-8-benzyl-7,9-dioxo-2,8-diazabicyklo[4.3.0]-nonánu), [ct]D 23 = -4,5° (c = 5, etanol).Yield: 14.4 g (60% of theory of initially charged cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] -nonane), [α] D 23 = -4.5 ° ( c = 5, ethanol).

Týchto 14,4 g (59 mmol) kyseliny D(-)-vínnej sa kryštalizuje zo 120 ml etylalkoholu analogicky ako je uvedené v príklade B (metóda H/a).The 14.4 g (59 mmol) of D (-) - tartaric acid was crystallized from 120 ml of ethyl alcohol analogously to Example B (Method H / a).

Výťažok: 8,9 g (77 % teórie) [lS,6R]-8-benzyl-7,9-dioxo-2,8-diazabicyklo-[4.3.0]nonán-D-tartátu, [a]D 23 =-46,2° (c = 0,5, lnHCl).Yield: 8.9 g (77% of theory) of [1S, 6R] -8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane-D-tartrate, [α] D 23 = -46.2 ° (c = 0.5, 1n HCl).

po kryštalizácii zo zmesi etylalkoholu a glykolmonometyléteru sa dosiahne bez ďalšieho čistenia:after crystallization from a mixture of ethanol and glycol monomethyl ether, the following are obtained without further purification:

[a]D 23 = -59,3° (c = 0,5, ln HC1).[α] D 23 = -59.3 ° (c = 0.5, 1N HCl).

5,0 g (12,7 mmol) uvedeným spôsobom získaného diastereoméme čistého tartátu sa prevedie na voľný amín pomocou postupu, opísaného v príklade B, metóda Il/a. Výťažok: 3,0 g (96 % teórie) [lS,6R]-8-bcnzyi-7,9-dioxo-2,8-diazabicyklo-[4.3.0]nonánu, teplota topenia: 60-61 °C, [a]O 23 = 22,2° (c = 5, etanol).5.0 g (12.7 mmol) of the diastereomerically pure tartrate obtained above were converted to the free amine by the procedure described in Example B, Method II / a. Yield: 3.0 g (96% of theory) of [1S, 6R] -8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane, m.p. [α] D 23 = 22.2 ° (c = 5, ethanol).

Pomocou plynovej chromatografie bol po derivatizácii metylesterom kyseliny chlórmravčej zistený nadbytok enantiomérov 96,6 %.An excess of enantiomers of 96.6% were found by gas chromatography after derivatization with methyl chloroformate.

b) Redukcia [lS,6R]-8-benzyl-7,9-dioxo-2,8-diazabicykio[4.3.0]nonánu na [S,S]-8-benzyl-2,8-diazabicyklo[4.3.0]nonánb) 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] ] nonane

Postupuje sa analogicky ako v príklade B (metóda Il/b), pričom sa však ako edukt použije [lS,6R]-8-benzyl-7,9-dioxo-2,8-diazabicyklo[4.3.Ó]nonán.The procedure is analogous to Example B (Method II / b), but using [1S, 6R] -8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane as the starting material.

Surový produkt, získaný po spracovaní, sa ukázal pri derivatizácii s metylesterom kyseliny chlórmravčej ako [5.5] -8-benzyl-2,8-diazabicyklo-[4.3.0]nonán. Racemizácia nebola pri redukcii pozorovaná.The crude product obtained after work-up was shown to be [5.5] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane when derivatized with methyl chloroformate. Racemization was not observed in the reduction.

2. [S,S]-2,8-Diazabicyklo[4.3.0]nonán2. [S, S] -2,8-Diazabicyclo [4.3.0] nonane

28,4 g (0,131 mol) [S,S]-8-benzyl-2,8-diazabicklo[4.3.0Jnonánu sa v 190 ml metylalkoholu hydrogenuje za prítomnosti 5,8 g paládia na aktívnom uhlí (5 %) pri teplote 90 °C a tlaku 9 MPa počas 5 hodín. Potom sa katalyzátor odfiltruje, premyje sa metylalkoholom a filtrát sa zahustí na rotačnej odparke. Zvyšok sa bez frakcionácie destiluje. Výťažok: 15,0 g (90,5 % teórie) [S,S]-2,8-diazabicyklo[4.3.0]nonánu teplota varu: 44 - 59 °C/0,18 mbar [a]D 22 = -2,29° (neriedené).28.4 g (0.131 mol) of [S, S] -8-benzyl-2,8-diazabicklo [4.3.0] ionane are hydrogenated in 190 ml of methanol in the presence of 5.8 g of palladium on activated carbon (5%) at 90 ° C. ° C and a pressure of 9 MPa for 5 hours. The catalyst is then filtered off, washed with methanol and the filtrate is concentrated on a rotary evaporator. The residue was distilled without fractionation. Yield: 15.0 g (90.5% of theory) of [S, S] -2,8-diazabicyclo [4.3.0] nonane boiling point: 44-59 ° C / 0.18 mbar [α] D 22 = - 2.29 ° (undiluted).

ee > 99 % (zistené plynovou chromatografiou po derivatizácii Mosherovým činidlom).ee> 99% (as determined by gas chromatography after derivatization with Mosher's reagent).

Metóda VMethod

3,75 g (25 mmol) kyseliny L-(+)-vínnej sa rozpustí v 50 ml dimetylformamidu pri teplote 80 °C a prikvapká sa 10,82 g (50 mmol) cis-8-benzyl-2,8-diazabicyklo[4.3.0Jnonánu ako roztok v 15 ml dimetylformamidu. Potom sa zaočkuje [R,R]-8-benzyl-2,8-diazabicyklo[4.3.0]nonán-L-tartátom a mieša sa počas 1 hodiny pri teplote asi 72 °C, dokiaľ sa neukončí tvorba zárodočných kryštálov. Potom sa zmes pomaly ochladí na teplotu 15 °C, odsaje sa a dvakrát sa premyje vždy 13 ml dimetylformamidu. Spojené filtráty sa zahrejú na teplotu 80 °C a zmiešajú sa s ďalšími 3,75 g (25 mmol) kyseliny L-(+)-vínnej. Zahreje sa ešte na teplotu 119 °C, dokiaľ nevznikne číry roztok, a opäť sa pomaly ochladzuje na teplotu miestnosti za zaočkovania [S,S]-8-benzyi-2,8-diazabicyklo[4.3.0]nonán-L-tartátom. Vytvorené kryštály sa odsajú, postupne sa premyjú dimetylformamidom, 2-metoxyetanolom a etylalkoholom a na suchu sa usušia.3.75 g (25 mmol) of L - (+) - tartaric acid are dissolved in 50 ml of dimethylformamide at 80 ° C and 10.82 g (50 mmol) of cis-8-benzyl-2,8-diazabicyclo [dropwise] are added. 4.3.0. Jonan as a solution in 15 ml of dimethylformamide. It is then seeded with [R, R] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane-L-tartate and stirred for 1 hour at a temperature of about 72 ° C until seed formation is complete. The mixture was cooled slowly to 15 ° C, filtered off with suction and washed twice with 13 ml of dimethylformamide each time. The combined filtrates were heated to 80 ° C and treated with an additional 3.75 g (25 mmol) of L - (+) - tartaric acid. Warm to 119 ° C until a clear solution is formed and slowly cool again to room temperature while seeding with [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane-L-tartate. The crystals formed are filtered off with suction, washed successively with dimethylformamide, 2-methoxyethanol and ethyl alcohol and dried.

Výťažok: 9,59 g teplota topenia: 188 - 192 °CYield: 9.59 g, mp 188-192 ° C

Kryštály sa rekryštalizujú z 95 ml 80 % etylalkoholu, pričom sa získa 8,0 g [S,S]-8-benzyl-2,8-diazabicyklo[4.3.0]nonán-L-tartát-trihydrátu (76 % teórie), ktorý sa roztopí za vypenenia pri teplote v rozpätí 112 až 118 °C, potom znovu stuhne a opäť sa roztopí pri teplote v rozpätí 199 až 201 °C.The crystals were recrystallized from 95 ml of 80% ethyl alcohol to give 8.0 g of [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane-L-tartrate trihydrate (76% of theory), which is melted while foaming at a temperature in the range of 112 to 118 ° C, then solidifies again and melts again at a temperature in the range of 199 to 201 ° C.

[a]D 23 = 4,5° (c=l,H2O).[α] D 23 = 4.5 ° (c = 1, H 2 O).

ee: 98,0 % (zistené plynovou chromatografiou po derivatizácii metylesterom kyseliny chlórmravčej).ee: 98.0% (determined by gas chromatography after derivatization with methyl chloroformate).

Príklad B [5.5] -2-Metyl-2,8-diazabicyklo[4.3.0]nonánExample B [5.5] -2-Methyl-2,8-diazabicyclo [4.3.0] nonane

CH, IhCH, Ih

HH

1. [S,S]-8-Benzyl-2-metyl-2,8-diazabicyklo[4.3.0]nonán1. [S, S] -8-Benzyl-2-methyl-2,8-diazabicyclo [4.3.0] nonane

43,2 g (0,2 mmol) [S,S]-8-benzyl-2,8-diazabicyklo-[4.3.0]nonánu sa zmieša s 20 ml 37 % roztoku formaldehydu, 40 ml vody a 24 g ľadovej kyseliny octovej a hydrogenuje sa počas 10 hodín pri teplote 20 °C a tlaku 2,0 MPa s použitím 2 g paládia na aktívnom uhlí (5 %). Potom sa odsaje, filtrát sa zalkalizuje uhličitanom draselným a produkt sa extrahuje terc-butylmetyléterom. Po vysušení pomocou bezvodého síranu sodného sa roztok zahustí a zvyšok sa destiluje vo vákuu.43.2 g (0.2 mmol) of [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane are mixed with 20 ml of 37% formaldehyde solution, 40 ml of water and 24 g of glacial acid. acetic acid and hydrogenated for 10 hours at 20 ° C and 2.0 MPa using 2 g of palladium on charcoal (5%). It is then filtered off with suction, the filtrate is made alkaline with potassium carbonate and the product is extracted with tert-butyl methyl ether. After drying over anhydrous sodium sulfate, the solution is concentrated and the residue is distilled under vacuum.

výťažok: 14,8 g, teplota varu: 114-124 °C/0,14 mbar.yield: 14.8 g, boiling point: 114-124 ° C / 0.14 mbar.

2. [S,S]-2-Metyl-2,8-diazabicyklo[4.3.0]nonán2. [S, S] -2-Methyl-2,8-diazabicyclo [4.3.0] nonane

12,9 g (56 mmol) [S,S]-8-benzyl-2-metyl-2,8-diazabicyklo[4.3.0]nonánu sa hydrogenuje v 90 ml metylalkoholu pri teplote 90 °C a tlaku 9,0 MPa s použitím paládia na aktívnom uhlí (5 %). Potom sa zmes prefiltruje, filtrát sa zahustí na rotačnej odparke a zvyšok sa destiluje vo vákuu. Výťažok: 5,5 g enantiomérne čistého [S,S]-2-metyl-2,8-diazabicyklo[4.3.0]-nonánu (dôkaz derivatizáciou Mosherovým činidlom), teplota varu: 78 - 81 °C/14 mbar12.9 g (56 mmol) of [S, S] -8-benzyl-2-methyl-2,8-diazabicyclo [4.3.0] nonane are hydrogenated in 90 ml of methanol at 90 ° C and 9.0 MPa using palladium on activated carbon (5%). The mixture is then filtered, the filtrate is concentrated on a rotary evaporator and the residue is distilled under vacuum. Yield: 5.5 g of enantiomerically pure [S, S] -2-methyl-2,8-diazabicyclo [4.3.0] -nonane (proof by derivatization with Mosher's reagent), boiling point: 78-81 ° C / 14 mbar

Príklad C cis-7,9-Dioxo-8-([lS]-l-fenyletyl-2,8-diazabicyklo[4.3.0Jnonán oExample C cis-7,9-Dioxo-8 - ([1S] -1-phenylethyl-2,8-diazabicyclo [4.3.0] nonane)

č'lN-CH-Phč'lN-CH-Ph

CH, H OCH, H O

1. ([1 S]-1-Fenyletyl)imid kyseliny pyridín-2,3-dikarboxylovejPyridine-2,3-dicarboxylic acid ([1S] -1-phenylethyl) imide

74,5 g (0,5 mol) anhydridu kyseliny pyridin-2,3-dikarboxylovej sa pri teplote 20 °C rozpustí v 500 ml dioxánu a prikvapká sa 60,5 g (0,5 mol) S-(-)-l-fenyletylamínu, čím stúpne teplota na 33 °C. Reakčná zmes sa mieša ešte počas 1 hodiny, potom sa zahustí na rotačnej odparke a zvyšné rozpúšťadlo sa odstráni pri teplote 40 °C/0,l mbar. Získaný zvyšok sa vyberie do 245 g (2,4 mol) acetanhydridu, zmieša sa so 4,9 g (0,06 mol) bezvodého octanu sodného a mieša sa počas 1 hodiny pri teplote 100 °C. Po ochladení sa za dobrého miešania vleje do 1 litra ľadovej vody, odsaje sa, premyje sa studenou vodou a hexánom a na vzduchu sa usuší.74.5 g (0.5 mol) of pyridine-2,3-dicarboxylic acid anhydride are dissolved in 500 ml of dioxane at 20 ° C and 60.5 g (0.5 mol) of S - (-) - 1 are added dropwise. -phenylethylamine to raise the temperature to 33 ° C. The reaction mixture was stirred for 1 hour then concentrated on a rotary evaporator and the remaining solvent was removed at 40 ° C / 0.1 mbar. The residue is taken up in 245 g (2.4 mol) of acetic anhydride, mixed with 4.9 g (0.06 mol) of anhydrous sodium acetate and stirred for 1 hour at 100 ° C. After cooling, it is poured into 1 liter of ice-water with good stirring, filtered off with suction, washed with cold water and hexane and air-dried.

Surový produkt (114 g, teplota topenia: 112-114 °C) sa nechá rekryštalizovať z 285 ml metylalkoholu.The crude product (114 g, mp 112-114 ° C) was recrystallized from 285 mL of methanol.

Výťažok: 96,3 g (76 % teórie) teplota topenia: 115 -117 °C, [a]D 22 = -46,9° (c = 2, etanol).Yield: 96.3 g (76% of theory), melting point: 115 DEG -117 DEG C., [.alpha.] D @ 22 = -46.9 DEG (c = 2, ethanol).

2. cis-7,9-Dioxo-8-([ 1 Sj-1 -fenyletyl)-2,8-diazabicyklo[4.3.0]nonán2. cis-7,9-Dioxo-8 - ([1S-1-phenylethyl) -2,8-diazabicyclo [4.3.0] nonane

79,7 g (0,316 mol) ([ 1SJ-1 -fenyletyljimidu kyseliny pyridín-2,3-dikarboxylovej sa hydrogenuje v 600 ml tetrahydrofuránu pri teplote 90 °C/10 MPa s použitím 10 g paládia na aktívnom uhlí (5 %). Katalyzátor sa po ukončení prijímania vodíka odfiltruje a filtrát sa úplne zahustí. Získa sa takto 83,7 g viskózneho zvyšku.79.7 g (0.316 mol) of pyridine-2,3-dicarboxylic acid [1SJ-1-phenylethyl} amide are hydrogenated in 600 ml of tetrahydrofuran at 90 ° C / 10 MPa using 10 g of palladium on activated carbon (5%). After the hydrogen uptake is complete, the catalyst is filtered off and the filtrate is completely concentrated to give 83.7 g of a viscous residue.

Obsah: 95 % ’H-NMR (CDClj, 200 MHz): 1,4 - 1,7 (m, 3H); 1,82 a 1,83 (2d, 3H); 1,9 - 2,05 (m, 1H); 2,28 (šir. S, 1H); 2,54 - 2,86 (m, 3H); 3,77 (d, 1H); 5,39 (q, 1H); 7,24 - 7,48 ppm (m, 5H).Content: 95% H-NMR (CDCl3, 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, IH); 5.39 (q, IH); 7.24-7.48 ppm (m, 5H).

Príklad D cis-2-Oxa-5,8-diazabicyklo[4.3.0]nonánExample D cis-2-Oxa-5,8-diazabicyclo [4.3.0] nonane

HH

1. trans-l-Benzoyl-3-bróm-4-(2-hydroxyetoxy)pyrolidín1. trans-1-Benzoyl-3-bromo-4- (2-hydroxyethoxy) pyrrolidine

Rozpustí sa 95 g (0,55 mol) l-benzoyl-3-pyrolidínu v 380 g etylénglykolu a pri teplote miestnosti sa k tomuto roztoku pridá počas 2 hodín v päťgramových porciách 101 g (0,57 mol) N-brómsukcínimídu. Reakčná zmes sa potom mieša cez noc pri teplote miestnosti, vleje sa do vody, extrahuje sa metylénchloridom, vysuší sa pomocou bezvodého síranu horečnatého a výsledný roztok sa zahustí. Získaný zvyšok (188 g) sa chromatografuje na silikagéli s použitím etylesteru kyseliny octovej.95 g (0.55 mol) of 1-benzoyl-3-pyrrolidine are dissolved in 380 g of ethylene glycol and, at room temperature, 101 g (0.57 mol) of N-bromosuccinimide are added to this solution over 2 hours in portions. The reaction mixture was then stirred overnight at room temperature, poured into water, extracted with methylene chloride, dried over anhydrous magnesium sulfate and the resulting solution was concentrated. The residue (188 g) is chromatographed on silica gel using ethyl acetate.

Výťažok: 136,5 g (78 % teórie), obsah po GC: 99 %.Yield: 136.5 g (78% of theory); content after GC: 99%.

2. trans-l-Benzoyl-3-bróm-4-(2-tosyloxyetoxy)pyrolidin2. trans-1-Benzoyl-3-bromo-4- (2-tosyloxyethoxy) pyrrolidine

V 750 ml toluénu sa rozpustí 92 g (0,239 mol) trans-1-benzoyl-3-bróm-4-(2-hydroxyetoxy)pyrolidínu, 32 g (0,316 mol) trietylamínu a 1 g 4-dimetylaminopyridínu a k tomuto roztoku sa prikvapká 60 g (0,31 mol) tosylchloridu v 450 ml toluénu. Reakčná zmes sa mieša počas 2 dní pri teplote miestnosti, pridá sa voda a vodná fáza sa oddelí a extrahuje sa toluénom. Spojené toluénové roztoky sa premyjú 10 % kyselinou chlorovodíkovou, vysušia sa pomocou bezvodého síranu horečnatého a zahustia sa. Získaný zvyšok sa rozpustí v etylesteri kyseliny octovej, prefiltruje sa cez silikagél a filtrát sa zahustí. Výťažok: 125 g (91 % teórie).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 ml of this solution are added dropwise. g (0.31 mol) of tosyl chloride in 450 ml of toluene. The reaction mixture is stirred for 2 days at room temperature, water is added and the aqueous phase is separated and extracted with toluene. The combined toluene solutions were washed with 10% hydrochloric acid, dried over anhydrous magnesium sulfate and concentrated. The residue is dissolved in ethyl acetate, filtered through silica gel, and the filtrate is concentrated. Yield: 125 g (91% of theory).

Podľa chromatografie na tenkej vrstve ide o jednotnú zlúčeninu.Thin layer chromatography indicated a uniform compound.

3. cis-8-Benzoyl-5-benzyl-2-oxa-5,8-diazabicyklo[4.3.0]nonán3. cis-8-Benzoyl-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane

Zahrieva sa 124 g (0,265 mol) trans-l-benzoyl-3-bróm-4-(2-tosyloxyetoxy)pyrolidínu s 86 g (0,8 mol) benzylamínu v 1,5 1 xylénu cez noc pod spätným chladičom. Soli benzylamínu sa odsajú a filtrát sa zahustí.Heat 124 g (0.265 mol) of trans-1-benzoyl-3-bromo-4- (2-tosyloxyethoxy) pyrrolidine with 86 g (0.8 mol) of benzylamine in 1.5 l xylene overnight at reflux. The benzylamine salts are aspirated and the filtrate is concentrated.

Surový výťažok: 91,2 g.Crude yield: 91.2 g.

4. cis-5-Benzyl-2-oxa-5,8-diazabicyklo[4.3.0]nonán4. cis-5-Benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane

Zahrieva sa 91 g (0,265 mol) cis-8-benzoyl-5-benzyl-2-oxa-5,8-diazabicyklo[4.3.0]nonánu s 200 ml koncentrovanej kyseliny chlorovodíkovej a 140 ml vody cez noc pod spätným chladičom. Po ochladení sa odsaje kyselina benzoová, roztok sa zahustí na polovicu objemu, zalkalizuje sa pomocou uhličitanu draselného, extrahuje sa chloroformom, vysuš! sa pomocou uhličitanu draselného, zahustí sa a predestiluje.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 at reflux. After cooling, the benzoic acid is filtered off with suction, the solution is concentrated to half the volume, made alkaline with potassium carbonate, extracted with chloroform, dried. The reaction mixture is concentrated with the aid of potassium carbonate, concentrated and distilled.

Výťažok: 30,7 g (48,8 % teórie), teplota varu: 134 - 142 °C/0,6 mbar, obsah podľa GC: 92 %.Yield: 30.7 g (48.8% of theory), boiling point: 134-142 ° C / 0.6 mbar, GC content: 92%.

5. cis-2-Oxa-5,8-diazabicykio[4.3.0]nonán-dihydrochlorid5. cis-2-Oxa-5,8-diazabicyclo [4.3.0] nonane dihydrochloride

Hydrogenuje sa 26 g (0,11 mol, 92 %) cis-5-benzyl-2-oxa-5,8-diazabicyklo[4.3.0]nonánu v 180 ml etylalkoholu a 19 ml koncentrovanej kyseliny chlorovodíkovej s použitím 3 g paládia na aktívnom uhlí (10 % Pd) pri teplote 100 °C a tlaku vodíka 10,0 MPa. Katalyzátor sa potom odsaje, filtrát sa zahustí a vylúčené kryštály sa vysušia v exsikátore nad oxidom fosforečným.Hydrogenate 26 g (0.11 mol, 92%) of cis-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane in 180 ml of ethyl alcohol and 19 ml of concentrated hydrochloric acid using 3 g of palladium on activated carbon (10% Pd) at a temperature of 100 ° C and a hydrogen pressure of 10 bar. The catalyst is then filtered off with suction, the filtrate is concentrated and the precipitated crystals are dried in a desiccator over phosphorus pentoxide.

Výťažok: 17,1 g (77 % teórie), teplota topenia: 244 - 250 °C.Yield: 17.1 g (77% of theory), m.p. 244-250 ° C.

Príklad E Delenie enantiomérov cis-5-Benzyl-2-oxa-5,8-diazabicyklo[4.3.0]nonánuExample E Separation of enantiomers of cis-5-Benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane

150,1 g (1 mol) kyseliny D-(-)-vínnej sa vloží pri teplote v rozpätí 60 až 65 °C do 700 ml metylalkoholu a prikvapká sa 218,3 g (1 mol) cis-5-benzyl-2-oxa-5,8-dizabicyklo[4.3.0]nonánu ako roztok v 300 ml metylalkoholu. Potom sa nechá zmes pomaly ochladiť na teplotu 49 °C, kedy sa roztok zakalí, zaočkuje sa kryštálmi, získanými z predchádzajúceho pokusu, lR,6S-5-benzyl-2-oxa-5,8-diazabicyklo[4.3.0]nonán-D-tartátu a mieša sa počas 30 minút pri tejto teplote do vytvorenia zárodočných kryštálov, na čo sa pomaly ochladia až na teplotu 0 až 3 °C. Po odsatí kryš tálov sa tieto premyjú zmesou 200 ml etylalkoholu a 100 ml etylalkoholu, ochladenou na teplotu 0 °C a potom trikrát vždy 300 ml etylalkoholu. Nakoniec sa produkt usuší na vzduchu.Dissolve 150.1 g (1 mol) of D - (-) - tartaric acid at 700 to 65 ° C in 700 ml of methyl alcohol and add 218,3 g (1 mol) of cis-5-benzyl-2- oxa-5,8-disabicyclo [4.3.0] nonane as a solution in 300 ml of methanol. The mixture is then allowed to slowly cool to 49 ° C when the solution becomes cloudy, seeded with the crystals obtained from the previous experiment, 1R, 6S-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane- D-tartrate and stirred for 30 minutes at this temperature until seed formation occurred, then slowly cooled to 0-3 ° C. After suctioning off the crystals, they are washed with a mixture of 200 ml of ethanol and 100 ml of ethanol, cooled to 0 [deg.] C. and then three times with 300 ml of ethyl alcohol each time. Finally, the product is air dried.

Výťažok: 160,3 g (87 % teórie) 1 R,6S-5-benzyl-2-oxa-5,8-diazabicyklo[4.3.0]-nonán-tartátu teplota topenia: 174- 176,5 °C, ee > 97 % (po derivatizácii 1-fenyl-etylizokyanátom a vyhodnotení pomocou HPLC) [ajD 23 = +24,0° (c = 1, metanol).Yield: 160.3 g (87% of theory) of 1 R, 6S-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] non-tannate, m.p. 174-176.5 ° C, ee ≫ 97% (after derivatization with 1-phenyl-ethylisocyanate and HPLC evaluation) [ α] D 23 = + 24.0 ° (c = 1, methanol).

156,9 g prvého kryštalizátu sa rekryštalizuje z 1500 ml metylalkoholu.156.9 g of the first crystallizate are recrystallized from 1500 ml of methanol.

Výťažok: 140,0 g (89 % získané späť) teplota topenia: 176- 177 °C, [a]D 23 = +25,2° (c = 1, metanol).Yield: 140.0 g (89% recovered) melting point: 176-177 ° C, [α] D 23 = + 25.2 ° (c = 1, methanol).

Metanolický materský roztok z prvej kryštalizácie sa zahustí na rotačnej odparke. Získaný sirupovitý zvyšok (236 g) sa rozpustí v 500 ml vody a pomocou 250 ml 6 N hydroxidu sodného sa hodnota pH nastaví na 12 až 13. Tento roztok sa trikrát extrahuje vždy 350 ml toluénu, extrakt sa vysuší pomocou uhličitanu sodného a vo vákuu sa zahustí. Získa sa 113,1 g zvyšku vo forme hnedej olejovitej kvapaliny, obsahujúceho podľa skúšky plynovou chromatografiou 97 % cis-5-benzyl-2-oxa-5,8-diazabicykIo[14.3.0]nonánu, ktorý sa bez čistenia použije na výrobu lS,6R-enantiomérov.The methanolic mother liquor from the first crystallization is concentrated on a rotary evaporator. The resulting syrupy residue (236 g) is dissolved in 500 ml of water and the pH is adjusted to 12-13 with 250 ml of 6 N sodium hydroxide solution. This solution is extracted three times with 350 ml of toluene each time, dried over sodium carbonate and vacuum. concentrated. 113.1 g of residue are obtained in the form of a brown oily liquid containing 97% cis-5-benzyl-2-oxa-5,8-diazabicyclo [14.3.0] nonane which is used as gas for purification without analysis. , 6R enantiomers.

113,1 g (0,518 mol) surového obohateného lS,6R-5-benzyl-2-oxa-5,8-diazabicyklo[4.3.0]nonánu sa rozpustí v 155 ml metylalkoholu a prikvapká sa ku vriacemu roztokuDissolve 113.1 g (0.518 mol) of crude enriched 1S, 6R-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane in 155 ml of methanol and add dropwise to the boiling solution.

77,8 g (0,518 mol) kyseliny L-(+)-vínnej v 363 ml metylalkoholu. Už počas prikvapkávania sa voľne tvorí kryštálová kaša. Získaná zmes sa nechá miešať ešte 1 hodinu pri teplote 60 °C a potom sa pomaly počas 2 hodín ochladí na teplotu 0 °C. Kryštály sa potom odsajú, premyjú sa zmesou etylalkoholu a metylalkoholu (2 : 1), ochladenou na teplotu 0 °C a potom trikrát etylalkoholom, na čo sa na vzduchu usušia. Výťažok: 145,5 g (79 % teórie) lS,6R-5-benzyl-2-oxa-5,8-diazabicyklo[4.3.0]-nonán-L-tartátu, teplota topenia: 174,5 - 176,5 °C, ee > 97 % (po derivatizácii I-fenyl-etylizokyanátom a vyhodnotení pomocou HPLC) [a]D 23 = 24,0° (c = 1, metanol).77.8 g (0.518 mol) of L - (+) - tartaric acid in 363 ml of methanol. Already during the dripping, a crystal slurry forms freely. The mixture was allowed to stir for 1 hour at 60 ° C and then slowly cooled to 0 ° C over 2 hours. The crystals are then filtered off with suction, washed with a 2: 1 mixture of ethyl alcohol and methanol, cooled to 0 [deg.] C. and then three times with ethyl alcohol, then air dried. Yield: 145.5 g (79% of theory) of 1S, 6R-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] -nonane-L-tartate, melting point: 174.5-176.5 ° C, ee> 97% (after derivatization with 1-phenyl-ethylisocyanate and HPLC evaluation) [α] D 23 = 24.0 ° (c = 1, methanol).

Uvoľnenie enantioméme čistých báz:Release of enantiomerically pure bases:

144 g (0,39 mol) lS,6R-5-benzyl-2-oxa-5,8-diazabicyklo[4.3.0]nonán-tartátu sa rozpusti v 250 ml vody a pridá sa 175 ml (1,05 mol) 6 N hydroxidu sodného. Vylúčená olejovitá kvapalina sa vyberie do 500 ml toluénu, organická fáza sa oddelí a vodná fáza sa ešte trikrát extrahuje vždy 250 ml toluénu. Spojené organické fázy sa vysušia pomocou uhličitanu sodného, prefiltrujú sa a filtrát sa odparí na rotačnej odparke. Získaný zvyšok sa za vysokého vákua destiluje cez 20 cm dlhú Vigreuxovu kolónu.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 175 ml (1.05 mol) are added. 6 N sodium hydroxide. The oily liquid obtained is taken up in 500 ml of toluene, the organic phase is separated and the aqueous phase is extracted three more times with 250 ml of toluene each time. The combined organic phases were dried over sodium carbonate, filtered and the filtrate evaporated on a rotary evaporator. The residue is distilled under a high vacuum through a 20 cm Vigreux column.

Výťažok: 81,6 g (96 % teórie) lS,6R-5-benzyl-2-oxa-5,8-diazabicyklo[4.3.0]-nonánu, teplota varu: 120 - 139 °C/0,04 - 0,07 mbar, obsah: 100 % (stanovené plynovou chromatografiou), hustota: δ = 1,113 g/ml, [a]D 23 = - 60,9° (neriedené), destilačný zvyšok: 0,12 g.Yield: 81.6 g (96% of theory) of 1S, 6R-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] -nonane, b.p .: 120-139 ° C / 0.04-0 , 07 mbar, content: 100% (determined by gas chromatography), density: δ = 1,113 g / ml, [α] D 23 = - 60.9 ° (undiluted), distillation residue: 0.12 g.

Rovnakým spôsobom sa získa zo 139,2 g (0,376 mol) lR,6S-5-benzyl-2-oxa-5,8-diazabicyklo[4.3.0]nonán-tartátu 76,0 g (93 % teórie) 1R,6S-5-benzyl-2-oxa-5,8-diazabicyklo[4.3.0],In the same way 76.0 g (93% of theory) of 1R, 6S were obtained from 139.2 g (0.376 mol) of 1R, 6S-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane tartate. 5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0],

Mo23 - +61,2° (neriedené).Mo 23 - + 61.2 ° (undiluted).

Delenie enantiomérov, opísané pre cis-5-benzyl-2-oxa-5,8-diazabicyklo-[4.3.0]nonán, sa môže analogicky ušku točňovať tiež s trans-5-benzyl-2-oxa-5,8-diazabicyklo[4.3.0]nonánom na R,R- a S,S-5-benzyl-2-oxa-5,8-diazabicyklo[4.3.0]nonán.The enantiomer resolution described for cis-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane can also be analogous to the trans-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane on R, R- and S, S-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane.

Príklad FExample F

1. Terc-butylester kyseliny 3S,4S-4-alyloxy-3-hydroxypyrolidín-1 -karboxylovej1. 3S, 4S-4-Allyloxy-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester

Predloží sa 16,5 g (0,55 mol) 80 % hydridu sodného do 500 ml absolútneho dioxánu a pri teplote 60 °C sa prikvapká roztok 107,5 g (0,53 mol) íerc-butylesteru kyseliny S,S-3,4-dihydroxypyrolidín-l-karboxylovej (DE-A-3 403 194) v horúcom absolútnom dioxáne. Reakčná zmes sa mieša počas 1 hodiny pri teplote 60 °C a potom sa prikvapká 64 g (0,53 mol) alylbromidu, na čo sa mieša počas 3 hodín pri teplote 60 °C. Reakčná zmes sa zahustí a získaný zvyšok sa rozpustí v 200 ml vody a 600 ml metylalkoholu. Roztok sa trikrát extrahuje vždy 200 ml pentánu, metanol sa odstráni na rotačnej odparke, zriedi sa 200 ml vody a extrahuje sa metylénchloridom. Metylénchloridový roztok sa vysuší pomocou bezvodého síranu horečnatého, zahustí sa a získaný zvyšok sa rozpustí v íerc-butylmetyléteri (200 ml). Cez noc vykryštalizuje 9 g eduktu (44 mol). Eterový roztok sa zahustí a destiluje.16.5 g (0.55 mol) of 80% sodium hydride are introduced into 500 ml of absolute dioxane and a solution of 107.5 g (0.53 mol) of S, S-3 tert -butyl ester is added dropwise at 60 ° C, 4-dihydroxypyrrolidine-1-carboxylic acid (DE-A-3 403 194) in hot absolute dioxane. The reaction mixture was stirred for 1 hour at 60 ° C and then 64 g (0.53 mol) of allyl bromide was added dropwise, followed by stirring at 60 ° C for 3 hours. The reaction mixture is concentrated and the residue is dissolved in 200 ml of water and 600 ml of methanol. The solution is extracted three times with 200 ml of pentane each, the methanol is removed on a rotary evaporator, diluted with 200 ml of water and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous magnesium sulfate, concentrated, and the residue was dissolved in tert-butyl methyl ether (200 mL). 9 g of starting material (44 mol) crystallized overnight. The ether solution was concentrated and distilled.

Výťažok: 83 g (80 % teórie, vztiahnuté na opäť získaný edukt a dialyléter), teplota varu: 149 °C/0,7 mbar až 159 °C/0,9 mbar.Yield: 83 g (80% of theory, based on recovered starting material and dialyl ether), boiling point: 149 ° C / 0.7 mbar to 159 ° C / 0.9 mbar.

Destilát obsahuje 5 % eduktu a 4 % dialyléteru. Pentánový extrakt poskytuje 17 g zmesi 15 % požadovaného produktu a 84 % dialyléteru.The distillate contains 5% of starting material and 4% of dialyl ether. The pentane extract provides 17 g of a mixture of 15% of the desired product and 84% of dialyl ether.

[a]D 23 ~ - 10,5° (c = 1, metanol).[α] D 23 - -10.5 ° (c = 1, methanol).

2. Ferc-butylester kyseliny 3S,4S-3-hydroxy-4-(2-hydroxyetoxy)pyrolidín-l-karboxylovej2. 3S, 4S-3-Hydroxy-4- (2-hydroxyethoxy) pyrrolidine-1-carboxylic acid tert-butyl ester

Rozpustí sa 64 g (0,24 mol, 91 %) kyseliny 3S.4S-4-alyloxy-3-hydroxypyrolidín-l-karboxylovej v 250 ml metylalkoholu, roztok sa ochladí na teplotu 0 °C a zavádza sa do nej ozón, dokiaľ ďalej zaradená premývačka s roztokom jodidu draselného neindikuje výskyt ozónu a tým úplne prebehnutie reakcie. Zvyšky ozónu sa potom vytesnia prúdom dusíka a vzniknutý ozonid sa redukuje 18 g nátriumbórhydridu, ktorý sa pridáva v jednogramových porciách. Potom sa mieša ešte cez noc pri teplote miestnosti, vsádzka sa zahustí, zriedi sa vodou a zmieša sa s 20 g uhličitanu draselného, na čo sa päťkrát extrahuje vždy 100 ml metylénchloridu. Organické extrakty sa vysušia pomocou bezvodého síranu horečnatého a zahustia sa.Dissolve 64 g (0.24 mol, 91%) of 3S, 4S-4-allyloxy-3-hydroxypyrrolidine-1-carboxylic acid in 250 ml of methanol, cool the solution to 0 ° C and introduce ozone into it until a downstream washer with potassium iodide solution does not indicate the occurrence of ozone and thus the reaction is complete. The ozone residue is then displaced by a stream of nitrogen and the resulting ozonide is reduced by 18 g of sodium borohydride, which is added in one-gram portions. After stirring overnight at room temperature, the batch is concentrated, diluted with water and treated with 20 g of potassium carbonate, extracted five times with 100 ml of methylene chloride each time. The organic extracts were dried over anhydrous magnesium sulfate and concentrated.

Výťažok: 65,8 g (100 % teórie), produkt je 91 % (zistené pomocou plynovej chromatografie), [a]D 20 = -15,2° (c = 0,97, metanol).Yield: 65.8 g (100% of theory), the product is 91% (determined by gas chromatography), [.alpha.] D @ 20 = -15.2 DEG (c = 0.97, methanol).

3. 3S.4S-1 -/erc-Butoxykarbonyl-3-tosyloxy-4-(2-tosyloxyetoxy)pyrolidín3. 3S, 4S-1- tert -Butoxycarbonyl-3-tosyloxy-4- (2-tosyloxyethoxy) pyrrolidine

Predloží sa 2,7 g (10 mmol, 91 %) terc-butylesteru kyseliny 3 S,4S-3 -hydroxy-4-(2-hydroxyetoxy)pyrolidín-1 -karboxylovej v 30 ml metylénchloridu, zmieša sa so 6 ml 45 % hydroxidu sodného a 0,1 g benzyltrietylamóniumchloridu a potom sa za chladenia prikvapká roztok 2,86 g (20 mmol) tosylchloridu v 10 ml metylénchloridu. Reakčná zmes sa potom mieša ešte počas 1 hodiny pri teplote miestnosti, vleje sa do 20 ml vody, organická fáza sa oddelí a vodná fáza sa extrahuje metylénchloridom. Spojené organické fázy sa vysušia pomocou bezvodého síranu horečnatého a zahustia sa.2.7 g (10 mmol, 91%) of 3S, 4S-3-hydroxy-4- (2-hydroxyethoxy) pyrrolidine-1-carboxylic acid tert-butyl ester in 30 ml of methylene chloride are introduced, mixed with 6 ml of 45% sodium hydroxide and 0.1 g of benzyltriethylammonium chloride and then a solution of 2.86 g (20 mmol) of tosyl chloride in 10 ml of methylene chloride is added dropwise with cooling. The reaction mixture is stirred for 1 hour at room temperature, poured into 20 ml of water, the organic phase is separated and the aqueous phase is extracted with methylene chloride. The combined organic phases are dried over anhydrous magnesium sulphate and concentrated.

Výťažok: 5 g (90 % teórie), produkt je podľa chromatografie na tenkej vrstve jednotný.Yield: 5 g (90% of theory); product is uniform by thin layer chromatography.

4. Terc-Butylester kyseliny lS,6R-5-benzyl-2-oxa-5,8-diazabicyklo[4.3,0]nonán-8-karboxylovej4. 1S, 6R-5-Benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane-8-carboxylic acid tert-butyl ester

Pod spätným chladičom sa cez noc zahrieva v 1 1 xylénu 87 g (156 mmol) 3S,4S-l-teí'<?-butoxykarbonyl-3-tosyl-4-(2-tosyletoxy)pyrolidínu s 58 g (0,54 mol) benzylamínu. Potom sa reakčná zmes ochladí, odsajú sa vyzrážané soli benzylamínu a zvyšok sa zahustí.Heat 87 g (156 mmol) of 3S, 4S-1-tert-butoxycarbonyl-3-tosyl-4- (2-tosylethoxy) pyrrolidine with 58 g (0.54 mol) overnight in 1 x xylene under reflux. of benzylamine. The reaction mixture is cooled, the precipitated benzylamine salts are filtered off with suction and the residue is concentrated.

Výťažok: 43 g (58 % teórie) produkt je podľa plynovej chromatografie 67 %.Yield: 43 g (58% of theory);

5. lS,6R-5-Benzyl-5,8-diazabicyklo[4.3.0]nonán g (90 mmol) Zerc-butylesteru kyseliny lS,6R-5-benzyl-2-oxa-5,8-diazabicyklo[4.3.0]nonán-8-karboxylovej v 35 ml koncentrovanej kyseliny chlorovodíkovej a 35 ml vody sa zahrieva pod spätným chladičom až do ukončenia vývinu oxidu uhličitého. Potom sa reakčná zmes zalkalizuje pomocou uhličitanu draselného, extrahuje sa chloroformom, organický extrakt sa vysuší pomocou bezvodého síranu horečnatého, zahustí sa a dvakrát sa destiluje cez Vigreuxovu kolónu dĺžky 20 cm. Výťažok: 11,1 g (55 % teórie), teplota varu: 108 - 115 °C/0,07 mbar, [cc]d26 = -58,3° (neriedené).5. 1S, 6R-5-Benzyl-5,8-diazabicyclo [4.3.0] nonane (90 mmol) 1S, 6R-5-benzyl-2-oxa-5,8-diazabicyclo tert -butyl ester [4.3. O] nonane-8-carboxylic acid in 35 ml of concentrated hydrochloric acid and 35 ml of water are refluxed until the evolution of carbon dioxide is complete. Then, the reaction mixture is basified with potassium carbonate, extracted with chloroform, the organic extract is dried over anhydrous magnesium sulphate, concentrated and distilled twice through a 20 cm Vigreux column. Yield: 11.1 g (55% of theory), boiling point: 108-115 ° C / 0.07 mbar, [α] D 26 = -58.3 ° (undiluted).

Príklad GExample G

Kyselina 5-bróm-l-cyklopropyl-6,7,8-trifluór-l,4-dihydro-4-oxo-3-chinolínkarboxylová5-Bromo-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid

1. 2-Bróm-3,4,5,6-tetrafluór-benzoylchlorid1. 2-Bromo-3,4,5,6-tetrafluoro-benzoyl chloride

365 g (1,33 mol) kyseliny 2-bróm-3,4,5,6-tetrafluórbenzoovej (Tetrahedron 23, 4719/1967) sa vnesie do 2 1 tionylchloridu a zmes sa zahrieva počas 11 hodín pod spätným chladičom až do ukončenia vývinu plynu. Zvyšný tionylchlorid sa potom vo vákuu odtiahne a zvyšok sa destiluje.365 g (1.33 mol) of 2-bromo-3,4,5,6-tetrafluorobenzoic acid (Tetrahedron 23, 4719/1967) is added to 2 l of thionyl chloride and the mixture is refluxed for 11 hours until evolution is complete. gas. The remaining thionyl chloride is then stripped off in vacuo and the residue is distilled.

Výťažok: 330 g (85 % teórie), teplota varu: 81-85 °C/3 - 5 mbar.Yield: 330 g (85% of theory), boiling point: 81-85 ° C / 3-5 mbar.

2. Dimetylestcr kyseliny (2-bróm-3,4,5,6-tetrafluórbenzoyl)malónovej(2-Bromo-3,4,5,6-tetrafluorobenzoyl) malonic acid dimethyl ester

Predloží sa 15,9 g (0,167 mol) chloridu horečnatého do 150 ml bezvodého acetonitrilu (vysušeného pomocou zeolitu) a za chladenia sa prikvapká 26,9 g (0,167 mol) dietylesteru kyseliny malónovej. Reakčná zmes sa potom ochladí na teplotu 0 °C, prikvapká sa 46 ml (33,7 g = 0,33 mol) trietylamínu a mieša sa ešte počas 30 minút. Potom sa prikvapká 48,9 g (0,168 mol) 2-bróm-3,4,5,6-tetrafluórbenzoylchloridu, ešte 1 hodinu sa mieša pri teplote 0 °C a zmes sa cez noc nechá zahriať na teplotu miestnosti. Potom sa zmieša so 100 ml 5 N kyseliny chlorovodíkovej, extrahuje sa trikrát metylénchloridom, vysuší sa pomocou bezvodého síranu sodného a vo vákuu sa zahustí.15.9 g (0.167 mol) of magnesium chloride are introduced into 150 ml of anhydrous acetonitrile (dried with zeolite) and 26.9 g (0.167 mol) of diethyl malonic ester are added dropwise with cooling. The reaction mixture was then cooled to 0 ° C, 46 ml (33.7 g = 0.33 mol) triethylamine was added dropwise and stirred for a further 30 minutes. 48.9 g (0.168 mol) of 2-bromo-3,4,5,6-tetrafluorobenzoyl chloride are then added dropwise, stirred for 1 hour at 0 [deg.] C. and the mixture is allowed to warm to room temperature overnight. It is then treated with 100 ml of 5 N hydrochloric acid, extracted three times with methylene chloride, dried over anhydrous sodium sulfate and concentrated by evaporation in a vacuum.

Surový výťažok: 62,7 g.Crude yield: 62.7 g.

3. Etylester kyseliny (2-bróm-3,4,5,6-tetrafluórbenzoyl)octovej3. (2-Bromo-3,4,5,6-tetrafluorobenzoyl) acetic acid ethyl ester

600 g surového dietylesteru kyseliny (2-bróm-3,4,5,6-tetrafluórbcnzoyl)malónovej sa vnesie do 150 ml vody, zmieša sa s 0,6 g kyseliny 4-toluénsulfónovej a zahrieva sa pod spätným chladičom počas 6 hodín. Potom sa extrahuje metylénchloridom, extrakt sa premyje vodou, vysuší sa pomocou bezvodého síranu sodného a zahusti sa. Surový výťažok: 46 g, teplota varu (skúšobná destilácia na guľôčkovej kolóne): 150 až 160 °C/3 mbar, hmotnostné spektrum: m/e 342 (Mj, 297 (M+-OC2H5), 263 (M+-Br), 257, 255 (MT-CH2CO2C2H5), 235 (263-28).600 g of crude (2-bromo-3,4,5,6-tetrafluorobenzoyl) malonic acid diethyl ester is added to 150 ml of water, mixed with 0.6 g of 4-toluenesulfonic acid and heated at reflux for 6 hours. It is then extracted with methylene chloride, the extract is washed with water, dried over anhydrous sodium sulphate and concentrated. Crude yield: 46 g, boiling point (bead column distillation): 150-160 ° C / 3 mbar, mass spectrum: m / e 342 (M + , 297 (M + -OC 2 H 5), 263 (M + -Br) , 257, 255 (M -CH2CO T 2 C 2 H 5), 235 (263-28).

4. Etylester kyseliny 2-(2-bróm-3,4,5,6-tetrafluórbenzoyl)-3-etoxyakrylovej g surového etylesteru kyseliny (2-bróm-3,4,5,6-tetrafluórbenzoyl)octovej sa vnesie do 32,2 g (0,31 mol) anhydridu kyseliny octovej a 28,4 g (0,19 mol) trietylesteru kyseliny ortomravčej a reakčná zmes sa zahrieva počas 2 hodín pod spätným chladičom. Zvyšná reagencia sa odtiahne najprv vo vákuu a potom za vysokého vákua (teplota kúpeľa až 120 - 130 °C) a získaný surový produkt sa nechá reagovať v nasledujúcom stupni.4. The ethyl 2- (2-bromo-3,4,5,6-tetrafluorobenzoyl) -3-ethoxyacrylic acid ethyl ester of crude (2-bromo-3,4,5,6-tetrafluorobenzoyl) acetic acid is added to 32, 2 g (0.31 mol) of acetic anhydride and 28.4 g (0.19 mol) of triethyl orthoformate and the reaction mixture is heated under reflux for 2 hours. The remaining reagent is stripped off first under vacuum and then under high vacuum (bath temperature up to 120-130 ° C) and the crude product obtained is reacted in the next step.

Surový výťažok: 50,7 g.Crude yield: 50.7 g.

5. Etylester kyseliny 2-(2-bróm-3,4,5,6-tetrafluórbenzoyl)-3 -cyklopropylaminoakrylovej5. 2- (2-Bromo-3,4,5,6-tetrafluorobenzoyl) -3-cyclopropylaminoacrylic acid ethyl ester

50.7 g surového produktu zo stupňa 4. sa v 90 ml etylalkoholu zmieša po kvapkách za chladenia ľadom s 8,6 g (0,15 mol) cyklopropylamínu, zmes sa nechá ešte miešať pri teplote miestnosti a potom sa nechá stáť cez noc. Ďalej sa ešte raz dobre ochladí, kryštalizát sa odsaje, premyje sa studeným etylalkoholom a usuší sa.50.7 g of the crude product from step 4. in 90 ml of ethanol are treated dropwise with ice-cooling with 8.6 g (0.15 mol) of cyclopropylamine, the mixture is left stirring at room temperature and then left to stand overnight. It is further cooled well once again, the crystallizate is filtered off with suction, washed with cold ethyl alcohol and dried.

Výťažok: 29 g (42 % cez 4 stupne), teplota topenia: 103 - 105 °C (z etanolu).Yield: 29 g (42% over 4 steps), melting point: 103-105 ° C (from ethanol).

6. Etylester kyseliny 5-bróm-l-cyklopropyl-6,7,8-trifluór-l,4-dihydro-4-oxo-3-chinolínkarboxylovej g (68 mmol) etylesteru kyseliny 2-(2-bróm-3,4,5,6-tetrafluórbenzoyl)-3-cyklopropylaminoakryIovej sa zahrieva počas 6 hodín pod spätným chladičom v 88 ml dimetylformamidu so 6,9 g (164 mmol) fluoridu sodného. Reakčná zmes sa po ochladení vleje do vody, vypadnutá zrazenina (červená) sa odsaje, premyje sa väčším množstvom vody a vysuší sa v horúcovzdušnej obehovej sušiarni pri teplote 80 °C.6. 5-Bromo-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester g (68 mmol) of 2- (2-bromo-3,4) -ethyl ester 5,6-Tetrafluorobenzoyl) -3-cyclopropylaminoacrylic acid was heated at reflux for 6 hours in 88 ml of dimethylformamide with 6.9 g (164 mmol) of sodium fluoride. After cooling, the reaction mixture is poured into water, the precipitated precipitate (red) is filtered off with suction, washed with more water and dried in a hot-air circulation oven at 80 ° C.

Surový výťažok: 27,3 g, teplota topenia: 150 - 175 °C, teplota topenia po rekryštalizácii z glykolmonometylétcru: 187-191 °C.Crude yield: 27.3 g, melting point: 150-175 ° C, melting point after recrystallization from glycol monomethyl ether: 187-191 ° C.

7. Kyselina 5-bróm-l-cyklopropyl-6,7,8,7-trifluór-l,4-dihydro-4-oxo-3-chinolínkarboxylová7. 5-Bromo-1-cyclopropyl-6,7,8,7-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid

26.7 g (68 mmol) surového etylesteru kyseliny 5-bróm-l-cyklopropyl-6,7,8-trifluór-l,4-dihydro-4-oxo-3-chinolínkarboxylovej sa vnesie do zmesi 165 ml kyseliny octovej, 110 ml vody a 18 ml koncentrovanej kyseliny sírovej a reakčná zmes sa varí počas 2 hodín pod spätným chladičom. Ochladená reakčná zmes sa potom vleje do ľadovej vody, vypadnutá zrazenina sa odsaje, premyje sa väčším množstvom vody a vysuší sa v obehovej sušiarni pri teplote 80 °C. Výťažok: 19,7 g (80 % teórie), teplota topenia: 208 - 210 °C (rozklad), teplota topenia po kryštalizácii z glykolmonometyléteru: 212 - 214 °C (rozklad)’ ’H-NMR (DMSO): 8,73 s (IH na C-2), 4,16 m (IH, cyklopropyl), 1,2 m (4H, cyklopropyl)/ppm/, hmotnostné spektrum: m/e 361 (M+-H2O), 3,17 (M-CO2), 41 (100 %, C3H5).26.7 g (68 mmol) of crude 5-bromo-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester was added to a mixture of 165 ml of acetic acid, 110 ml of water and 18 ml of concentrated sulfuric acid, and the reaction mixture is refluxed for 2 hours. The cooled reaction mixture was then poured into ice water, the precipitated precipitate was filtered off with suction, washed with more water and dried in a circulating oven at 80 ° C. Yield: 19.7 g (80% of theory), melting point: 208-210 ° C (dec.), Melting point after crystallization from glycol monomethyl ether: 212-214 ° C (dec.) 1 H-NMR (DMSO): δ, 73 p (H on C-2), 4.16 m (H, cyclopropyl), 1.2 m (4H, cyclopropyl) / ppm / MS: m / e 361 (m + -H 2 O), 3 17 (M-CO 2 ), 41 (100%, C 3 H 5 ).

Výroba konečných zlúčenínProduction of final compounds

Príklad 1Example 1

A. Kyselina l-cyklopropyl-7-([S,S]-2,8-diazabicyklo[4.3.0]nón-8-yl)-6,8-difluór-1,4-dihydro-4-oxo-3 -chinolinkarboxylováA. 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

141,5 g (0,5 mol) kyseliny l-cyklopropyl-6,7,8-trifluór-l,4-dihydro-4-oxo-3-chinolínkarboxylovej sa zahrieva počas 1 hodiny pod spätným chladičom v zmesi 1500 ml acetonitrilu a 750 ml dimetylformamidu za prítomnosti 55 g (0,5 mol) l,4-diazabicyklo[2.2.2]oktánu sa 69,25 g (0,55 mol) (+)-[S,S]-2,8-diazabicyklo[4.3.0]nonánu (ee 99,5 %, GC141.5 g (0.5 mol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are heated under reflux in a mixture of 1500 ml of acetonitrile for 1 hour and 750 ml of dimethylformamide in the presence of 55 g (0.5 mol) of 1,4-diazabicyclo [2.2.2] octane and 69.25 g (0.55 mol) of (+) - [S, S] -2,8-diazabicyclo [4.3.0] nonane (ee 99.5%, GC

99,8 %). Suspenzia sa potom ochladí, zrazenina sa odsaje, premyje sa vodou a potom sa ešte rozmieša s 1 1 vody (pH 7). Nakoniec sa odsaje a usuší sa v obehovej sušiarni pri teplote 60 °C.99.8%). The suspension is then cooled, the precipitate is filtered off with suction, washed with water and then stirred with 1 l of water (pH 7). Finally, it is suctioned off and dried in a circulating oven at 60 ° C.

Výťažok: 163,4 g (84 % teórie), teplota topenia: 249 - 251 °C (rozklad).Yield: 163.4 g (84% of theory), melting point: 249 DEG-251 DEG C. (decomposition).

B. Hydrochlorid kyseliny (-)-cyklopropyl-7-([S,S]-2,8-diazabicyklo[4.3.0]nón-8-yI)-6,8-difluór-1,4-dihydro-4-oxo-3-chinolínkarboxylovejB. (-) - Cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6,8-difluoro-1,4-dihydro-4- acid hydrochloride oxo-3-quinolinecarboxylic acid

6,0 g (15,4 mmoí) kyseliny l-cyklopropyl-7-([S,S]-2,8-diazabicyklo[4.3.0]-nón-8-yl)-6,8-difluór-l,4-dihydro-4-oxo-3-chinolínkarboxylovej sa rozpustí v 40 ml polokoncentrovanej kyseliny chlorovodíkovej pri teplote 60 °C a roztok hydrochloridu sa odfiltruje. Filtrát sa zahustí na polovicu, ochladí sa ľadom a zmieša sa so 40 ml etylalkoholu. Žltý kryštalizát sa odsaje, premyje sa etylalkoholom a vysuší sa pri teplote 60 °C za vysokého vákua, pričom farba sa zosvetlí. Získa sa takto 5,51 g (84 % teórie) hydrochloridu, ktorý je už veľmi čistý.6.0 g (15.4 mmol) of 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 is dissolved in 40 ml of semi-concentrated hydrochloric acid at 60 ° C and the hydrochloride solution is filtered off. The filtrate is concentrated in half, cooled with ice and treated with 40 ml of ethyl alcohol. The yellow crystallizate is filtered off with suction, washed with ethyl alcohol and dried at 60 [deg.] C. under high vacuum, the color being lightened. 5.51 g (84% of theory) of hydrochloride are obtained, which is already very pure.

Na ďalšie čistenie sa uvedená zlúčenina rozpustí za tepla v 50 ml vody. Žltý roztok sa zmieša s 5 ml polokoncentrovanej kyseliny chlorovodíkovej, ochladí sa ľadom, vyzrážaný kryštalizát sa odsaje, dobre sa premyje etylalkoholom a súši sa najskôr pri teplote miestnosti a potom vo vysokom vákuu pri teplote 100 °C.For further purification, the compound is dissolved in 50 ml of water while warm. The yellow solution is mixed with 5 ml of semi-concentrated hydrochloric acid, cooled with ice, the precipitated crystallizate is filtered off with suction, washed well with ethyl alcohol and dried first at room temperature and then under high vacuum at 100 ° C.

Výťažok: 4,64 g (70 % teórie), teplota topenia: 324 - 325 °C (rozklad),Yield: 4.64 g (70% of theory), melting point: 324 DEG-325 DEG C. (decomposition),

DC (silikagél, dichlórmetán/metanol/17 % vodný amoniak = 30 : 8 : 1) jednotný produkt, Rf= 0,3, otáčavosť: [a]D 25 = -256°(c = 0,5, H2O), obsah (HPLC): 99,4 %.DC (silica gel, dichloromethane / methanol / 17% aqueous ammonia = 30: 8: 1) a single product Rf = 0.3, rotation: [a] D 25 = -256 ° (c = 0.5, H2O ), content (HPLC): 99.4%.

C20H21F2N3O3 . HCI (425,5) vypočítané C 56,4 H 5,2 N 9,9 Cl 8,3 zistené C 56,3 H 5,4 N 9,8 Cl 8,3C 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

Príklad 2Example 2

A. Kyselina 8-chlór-l-cyklopropyl-7-([S,S]-2,8-diazabicyklo [4.3.0]nón-8-yl)-6-fluór-1,4-dihydro-4-oxo-3 -chinolínkarboxylováA. 8-Chloro-1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-4-oxo -3-quinolinecarboxylic acid

Paralelne sa uskutočňujú dve vsádzky nasledujúcich veľkostí a spoločne sa spracovávajú:Two batches of the following sizes are run in parallel and processed together:

180 g (0,6 mol) kyseliny 8-chlór-l-cyklopropyl-6,7-difluór-l,4-dihydro-4-oxo-3-chinolínkarboxylovej sa v zmesi z 1,8 1 acetonitrilu a 900 ml dimetylformamidu zahrieva počas 1 hodiny pod spätným chladičom (vnútorná teplota180 g (0.6 mol) of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are heated in a mixture of 1.8 l of acetonitrile and 900 ml of dimethylformamide. for 1 hour at reflux (internal temperature

90,5 °C) za prítomnosti 99 g (0,88 mol) 1,4-diazabicyklo[2.2.2]oktánu (DABCO) s 84 g (0,67 mol) (+)-[S,S]-2,8-diazabicyklo[4.3.0]nonánu. Takto získaný žltý roztok sa ochladí a zmieša sa s očkovacími kryštálmi, získanými z 5 ml vzorky, ktorý sa zahustí a zvyšok sa rozotrie s acetonitrilom. Zmes sa mieša počas 2 hodín pri teplote asi 3 °C, vypadnutá zrazenina z obidvoch vsádzok sa ostro odsaje, premyje sa acetonitrilom a vnesie sa do 1,5 1 ľadovej vody. Suspenzia, ktorá je najprv riedka a dobre miešateľná, sa po 10 minútach premení na ťažko micšatcľnú hmotu, ktorá sa zriedi ďalšími 150 ml vody. Potom sa odsaje, premyje sa vodou a pri teplote 80 °C sa usuší v obehovej sušiarni. Výťažok: 402 g (82,7 % teórie), svetložltého produktu, teplota topenia: 193 - 196 °C (rozklad),90.5 ° C) in the presence of 99 g (0.88 mol) 1,4-diazabicyclo [2.2.2] octane (DABCO) with 84 g (0.67 mol) (+) - [S, S] -2 , 8-diazabicyclo [4.3.0] nonane. The yellow solution thus obtained is cooled and mixed with the seed crystals obtained from a 5 ml sample which is concentrated and the residue is triturated with acetonitrile. The mixture is stirred for 2 hours at a temperature of about 3 [deg.] C., the precipitated precipitate from both batches is drained vigorously, washed with acetonitrile and taken up in 1.5 l of ice-water. The slurry, which is initially thin and well miscible, is after 10 minutes turned into a difficult-to-mix mass which is diluted with an additional 150 ml of water. It is then filtered off with suction, washed with water and dried at 80 [deg.] C. in a circulating oven. Yield: 402 g (82.7% of theory), light yellow product, melting point: 193-196 DEG C. (decomposition),

Rf (silikagél; metylénchlorid/metanol/17 % vodný NH3 = = 30:8: 1) = 0,4. Rf (silica gel; methylene chloride / methanol / 17% aq NH3 = 30: 8: 1) 0.4.

B. Hydrochlorid kyseliny 8-chlór-l-cyklopropyl-7-([S,S]-2,8-diazabicyklo[4.3.0]nón-8-yl)-6-fluór-l,4-dihydro-4-oxo-3-chinolínkarboxylovejB. 8-Chloro-1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-4- oxo-3-quinolinecarboxylic acid

13,1 g (32 mmol) kyseliny 8-chlór-l-cyklopropyl-7-([S,S]-2,8-diazabicyklo[4.3.0]nón-8-yl)-6-fluór-l,4-dihydro-4-oxo-3-chinolínkarboxylovej sa suspenduje v 50 ml vody a prídavkom 50 ml polokoncentrovanej kyseliny chlorovodíkovej sa prevedie do roztoku. Tento sa prefiltruje cez sklenú fritu, vo vákuu sa zahustí a získaný zvyšok sa rozmieša s asi 300 ml absolútneho etylalkoholu. Suspenzia sa ochladí ľadom, zrazenina sa odsaje, premyje sa etylalkoholom a suší sa najprv pri teplote miestnosti a potom vo vákuu pri teplote 100 °C.13.1 g (32 mmol) of 8-chloro-1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4 of dihydro-4-oxo-3-quinolinecarboxylic acid is suspended in 50 ml of water and brought into solution by the addition of 50 ml of semi-concentrated hydrochloric acid. It is filtered through a sintered glass, concentrated in vacuo and the residue is stirred with about 300 ml of absolute ethyl alcohol. The suspension is cooled with ice, the precipitate is filtered off with suction, washed with ethyl alcohol and dried first at room temperature and then under vacuum at 100 ° C.

Výťažok: 13,4 g (93,8 % teórie), teplota topenia: 328 - 330 °C (rozklad), Rf (silikagél; metylénchlorid/metanol/17 % vodný NH3 = = 30:8: 1) = 0,4, obsah (HPLC): 99 % otáčavosť: [a]D 24 = -164,4° (c = 0,45, H2O). C20H21ClFN3O3. HCI (442,3) vypočítané C 54,3 H 5,0 N 5,0 Cl 16,0 zistené C 54,3 H 5,0 N 9,5 Cl 16,0Yield: 13.4 g (93.8% of theory), Melting point: 328-330 DEG C. (decomposition) Rf (silica gel; methylene chloride / methanol / 17% aq NH3 = 30: 8: 1) = 0 4, content (HPLC): 99% rotation: [a] D 24 = -164.4 ° (c = 0.45, H2O). C 20 H 21 ClFN 3 O 3 . HCl (442.3) calculated C 54.3 H 5.0 N 5.0 Cl 16.0 found C 54.3 H 5.0 N 9.5 Cl 16.0

C. Analogicky je možné napríklad vyrobiť tiež nasledujúce soli:C. For example, the following salts can be prepared analogously:

metánsulfonát kyseliny 8-chlór-l-cyklopropyl-7-([S,S]-diazabicyklo-[4.3.0]nón-8-yl)-6-fluór-l,4-dihydro-4-oxo-3-chinolínkarboxylovej, toluénsulfonát kyseliny 8-chlór-l-cyklopropyl-7-([S,S]-diazabicyklo- [4.3.0]nón-8-yl)-6-fluór-1,4-dihydro-4-oxo-3-chinolínkarboxylovej, sulfát kyseliny 8-chlór-l-cyklopropyl-7-([S,S]diazabicyklo[4.3.0]nón-8-yl)-6-fluór-l,4-dihydro-4-oxo-3-chinolínkarboxylovej, acetát kyseliny 8-chlór-l-cyklopropyl-7-([S,S]diazabicyklo[4.3.0]nón-8-yl)-6-fluór-l,4-dihydro-4-oxo-3-chinolínkarboxylovej, laktát kyseliny 8-chlór-l-cyklopropyl-7-([S,S]diazabicyklo[4.3.0] ηόπ-8-y l)-6-íl uór-1,4-dihydro-4-oxo-3-chinolínkarboxylovej, citrát kyseliny 8-chlór-l-cyklopropyl-7-([S,S]diazabicyklo[4.3.0]nón-8-yl)-6-fluór-l,4-dihydro-4-oxo-3-chinolínkarboxylovej a embonát kyseliny 8-chlór-l-cyklopropyl-7-([S,S]diazabicyklo[4.3.0]nón-8-yl)-6-fluór-l,4-dihydro-4-oxo-3-chinolínkarboxylovej.8-Chloro-1-cyclopropyl-7 - ([S, S] -diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid methanesulfonate 8-chloro-1-cyclopropyl-7 - ([S, S] -diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-4-oxo-3-, toluenesulfonate quinolinecarboxylic acid, 8-chloro-1-cyclopropyl-7 - ([S, S] diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid sulfate , 8-chloro-1-cyclopropyl-7 - ([S, S] diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid acetate, 8-chloro-1-cyclopropyl-7 - ([S, S] diazabicyclo [4.3.0] trans-8-yl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid lactate, 8-chloro-1-cyclopropyl-7 - ([S, S] diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid citrate and embonate 8-chloro-1-cyclopropyl-7 - ([S, S] diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.

Príklad 3Example 3

COOHCOOH

Analogicky ako je opísané v príklade 2 sa získa s kyselinou l-cyklopropyl-6,7-difluór-l,4-dihydro-4-oxo-3-chi nolínkarboxylovou.Analogously to Example 2, 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is obtained.

A. Kyselina l-cyklopropyl-7-([S,S]-diazabicyklo[4.3.0]nón-8-yl)-6-fluór-1,4- dihydro-4-oxo-3-chinolínkarboxylová, teplota topenia: 256 - 258 °C (rozklad),A. 1-Cyclopropyl-7 - ([S, S] diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, m.p. 256-258 ° C (decomposition),

B. Hydrochlorid kyseliny l-cyklopropyl-7-([S,S]-diazabicyklo[4.3.0]nón-8-yl)-6-fluór-l,4-dihydro-4-oxo-3-chinolínkarboxylovej, teplota topenia: > 320 °C (rozklad), otáčavosť: [a]D 26 = -90,6° (c = 0,48, H2O).B. 1-Cyclopropyl-7 - ([S, S] -diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride, m.p. :> 320 ° C (decomposition). Optical rotation: [a] D 26 = -90.6 ° (c = 0.48, H2O).

Príklad 4 f oExample 4 f o

A. 6 g (20 mmol) kyseliny l-cyklopropyl-5,6,7,8-tetrafluór-l,4-dihydro-4-oxo-3-chinolínkarboxylovej sa zahrieva počas 1 hodiny pod spätným chladičom v 40 ml acetonitrilu a 20 ml N-metylpyrolidónu za prítomnosti 2,2 g (20 mmol) l,4-diazabicyklo[2.2.2]oktánu s 2,7 g (21,4 mmol) (+)-[S,Sj-2,8-diazabicyklo[4.3.0]nonánu. Takto získaná suspenzia sa ochladí, zrazenina sa odsaje, premyje sa acetonitrilom a usuší sa pri teplote 100 °C mbar.A. 6 g (20 mmol) of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was heated under reflux in 40 ml of acetonitrile for 1 hour and 20 g of acetonitrile were added. 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) of (+) - [S, S] -2,8-diazabicyclo [4.3.0] nonane. The suspension thus obtained is cooled, the precipitate is filtered off with suction, washed with acetonitrile and dried at 100 DEG C. mbar.

Výťažok: 6,7 g (82,3 % teórie) kyseliny l-cyklopropyl-7-([S,S]-diazabicyklo-[4.3.0]nón-8-yl)-5,6,8-trifluór-l,4-dihydro-4-oxo-3-chinolínkarboxylovej, teplota topenia: 257 - 259 °C (rozklad; po rekryštalizácii z glykolmonometyléteru: teplota topenia: 260 - 265 °C (rozklad).Yield: 6.7 g (82.3% of theory) of 1-cyclopropyl-7 - ([S, S] -diazabicyclo [4.3.0] non-8-yl) -5,6,8-trifluoro-1 4-dihydro-4-oxo-3-quinolinecarboxylic acid, m.p. 257-259 ° C (decomposition; after recrystallization from glycol monomethyl ether: mp 260-265 ° C (decomposition)).

B. 1,5 g (3,7 mmol) produktu zo stupňa A sa vnesie do 6 ml 1 N kyseliny chlorovodíkovej, pričom po krátkom čase sa vyzráža hydrochlorid, ktorý sa odsaje, dvakrát sa premyje vždy 5 ml etylalkoholu a usuší sa pri teplote 100 °C/12 mbar. Výťažok: 1,4 g (85,7 % teórie) hydrochloridu kyseliny 1-cyklopropyl-7-([S,S]-diazabicyklo[4.3.0]nón-8-yl)-5,6,8-trifluór-l,4-dihydro-4-oxo-3-chinolínkarboxylovej, teplota topenia: > 310 °C (rozklad), otáčavosť: [a]D 26 = -272° (c = 0,5, H2O).B. 1.5 g (3.7 mmol) of the product from Step A are taken up in 6 ml of 1 N hydrochloric acid and after a short time the hydrochloride precipitates, which is filtered off with suction, washed twice with 5 ml of ethanol each time and dried at room temperature. 100 ° C / 12 mbar. Yield: 1.4 g (85.7% of theory) of 1-cyclopropyl-7 - ([S, S] -diazabicyclo [4.3.0] non-8-yl) -5,6,8-trifluoro-1 hydrochloride , 4-dihydro-4-oxo-3-quinolinecarboxylic acid, melting point:> 310 ° C (decomposition). Optical rotation: [a] D 26 = -272 ° (c = 0.5, H2O).

Príklad 5Example 5

NH2 ONH 2 O

5,2 g (13 mmol) produktu z príkladu 4A v 80 ml pyridínu sa v autokláve zmieša s 15 ml kvapalného amoniaku a počas 12 hodín sa zahrieva na teplotu 130 °C. Potom sa ochladí, autokláv sa zbaví tlaku a reakčná zmes sa zahustí. Získaný zvyšok sa spracuje acetonitrilom v ultrazvukovom kúpeli. Nerozpustená zrazenina sa odsaje, zvyšok sa za horúca rozpustí v asi 150 ml vody, roztok sa prefiltruje a vyzráža sa hydrochlorid pridaním 10 ml polokoncentrovanej kyseliny chlorovodíkovej. Zrazenina sa odsaje a usuší sa pri teplote 100 °C v horúcovzdušnej obehovej sušiarni. Takto získaný produkt sa suspenduje pri teplote v rozpätí 110 až 115 °C v 100 ml glykolmonometyléteru a prídavkom 38 ml polokoncentrovanej kyseliny chlorovodíkovej sa prevedie do roztoku. Roztok sa za horúca prefiltruje cez sklenú fritu, ochladí sa a vyzrážaný žltý kryštalizát sa odsaje, premyje sa etylalkoholom a pri teplote 120 °C/12 mbar sa usuší.5.2 g (13 mmol) of the product of Example 4A in 80 ml of pyridine are mixed with 15 ml of liquid ammonia in an autoclave and heated at 130 ° C for 12 hours. It is then cooled, the autoclave is depressurized and the reaction mixture is concentrated. The residue is treated with acetonitrile in an ultrasonic bath. The undissolved precipitate is filtered off with suction, the residue is dissolved in hot in about 150 ml of water, the solution is filtered and the hydrochloride is precipitated by adding 10 ml of semi-concentrated hydrochloric acid. The precipitate is filtered off with suction and dried at 100 ° C in a hot-air circulation drier. The product thus obtained is suspended at 110 DEG-115 DEG C. in 100 ml of glycol monomethyl ether and brought into solution by the addition of 38 ml of semi-concentrated hydrochloric acid. The solution is filtered hot through a glass frit, cooled and the precipitated yellow crystallizate is filtered off with suction, washed with ethyl alcohol and dried at 120 ° C / 12 mbar.

Výťažok: 2,5 g (44 % teórie) hydrochloridu kyseliny 5-amino-l-cyklopropyl-7-([S,S]-diazabicyklo[4.3.0]nón-8-yl)-6,8-difluór-l,4-dihydro-4-oxo-3-chinolínkarboxylovej teplota topenia: > 335 °C (rozklad, už pod teplotou 335 °C hnedé sfarbenie), otáčavosť: [a]D 28 = -280,8° (c = 0,53, H2O).Yield: 2.5 g (44% of theory) of 5-amino-1-cyclopropyl-7 - ([S, S] -diazabicyclo [4.3.0] non-8-yl) -6,8-difluoro-1 hydrochloride 4-dihydro-4-oxo-3-quinolinecarboxylate melting point:> 335 ° C (decomposition, already below 335 ° C brown color), rotation: [α] D 28 = -280.8 ° (c = 0, 53, H 2 O).

Príklad 6 oExample 6 o

1,4 g (5 mmol) kyseliny 7-chlór-l-cyklopropyl-6-fluór-l,4-dihydro-4-oxo-l,8-naftyridín-3-karboxylovej sa mieša v 15 ml acetonitrilu s 1,3 g (10,3 mmol) (+)-[S,S]-2,8-diazabicyklo[4.3.0]nonánu za zamedzenia prístupu vlhkosti počas 1 hodiny pri teplote miestnosti. Po státí cez noc sa zmes odsaje, premyje sa acetonitrilom a na vyčistenie sa chromatografuje na silikagéli (pohyblivá fáza: metylénchlorid/metanol/17 % vodný amoniak 30 : 8 : 1 ; Rf = 0,4). Získaná kyselina l-cyklopropyl-7([S,S]-diazabicyklo[4.3.0]nón-8-yl)-6-fluór-l,4-dihydro-4-oxo-l,8-naftyridín-3-karboxylová sa rozpustí v 15 ml polokoncentrovanej kyseliny chlorovodíkovej, tento roztok sa odparí a získaný zvyšok sa rozmieša s etylalkoholom. Zrazenina sa odsaje, premyje sa etylalkoholom a usuší sa pri teplote 120 °C/12 mbar. Výťažok: 960 mg (47 % teórie) hydrochloridu kyseliny 1-cyklopropyl-7-([S,S]-2,8-diazabicyklo[4.3.0]nón-8-yl)-6-fluór-l,4-dihydro-4-oxo-l,8-naftyridín-3-karboxylovej, teplota topenia: 345 - 346 °C (rozklad), [a]D 30 = + 5,4° (c = 0,5, HjO).1.4 g (5 mmol) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid are stirred in 15 ml of acetonitrile with 1.3 g (10.3 mmol) of (+) - [S, S] -2,8-diazabicyclo [4.3.0] nonane while avoiding humidity for 1 hour at room temperature. After standing overnight, the mixture was suction filtered, washed with acetonitrile and the purification was chromatographed on silica gel (eluent: methylene chloride / methanol / 17% aqueous ammonia 30: 8: 1, Rf = 0.4). The obtained 1-cyclopropyl-7 ([S, S] -diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid Dissolve in 15 ml of semi-concentrated hydrochloric acid, evaporate this solution and stir the residue with ethyl alcohol. The precipitate is filtered off with suction, washed with ethyl alcohol and dried at 120 ° C / 12 mbar. Yield: 960 mg (47% of theory) of 1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro acid hydrochloride -4-oxo-1,8-naphthyridine-3-carboxylic acid, m.p. 345-346 ° C (dec.), [Α] D 30 = + 5.4 ° (c = 0.5, H 10).

Príklad 7Example 7

1,52 g (5 mmol) etylesteru kyseliny 1-cyklopropyl-6,7,8-trifluór-l,4-dihydro-4-oxo-3-chinolínkarboxylovej sa v 30 ml acetonitrilu nechá reagovať s 550 mg (5 mmol) 1,4-diazabicyklo[2.2.2]oktánu a 760 mg (6 mmol) (+)-[S,S]-2,8-diazabicyklo[4.3.0]nonánu počas 2 hodín pri teplote 50 °C a počas 2 hodín pri teplote 60 °C. Po ochladení sa takto získaná suspenzia odsaje, zrazenina sa premyje vodou a pri teplote 90 °C sa vo vákuu usuší.1.52 g (5 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester in 30 ml of acetonitrile was treated with 550 mg (5 mmol) of 1 4-diazabicyclo [2.2.2] octane and 760 mg (6 mmol) of (+) - [S, S] -2,8-diazabicyclo [4.3.0] nonane for 2 hours at 50 ° C and 2 hours at 60 ° C. After cooling, the suspension thus obtained is filtered off with suction, the precipitate is washed with water and dried at 90 DEG C. in vacuo.

Výťažok: 0,99 g (47,5 % teórie), etylesteru kyseliny 1-cyklopropyl-7-([S,S]-2,8-diazabicyklo[4.3.0]nón-8-yl)-6,8-difluór-l,4-dihydro-4-oxo-3-chinolínkarboxylovej, teplota topenia: 194 - 195 °C (z acetonitrilu), [a]D 23 = -272° (c = 0,51, CHClj).Yield: 0.99 g (47.5% of theory), 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, m.p .: 194-195 ° C (from acetonitrile), [α] D 23 = -272 ° (c = 0.51, CHCl 3).

Príklad 8Example 8

1,4 g (5 mmol) kyseliny 9,10-difluór-2,3-dihydro-3-metyl-7-oxo-7H-pyrido [ 1,2,3-de] [ 1,4]benzoxacín-6-karboxylovej sa nechá reagovať v 15 ml acetonitrilu a 7,5 ml dimetylformamidu s 0,85 g (7,7 mmol) 1,4-diazabicyklo [2.2.2]oktánu a 0,7 g (5,6 mmol) (+)-[S,S]-2,8-diazabicyklo[4.3.0]nonánu analogicky ako je uvedené v príklade 1. Výťažok: 1,24 g (64 % teórie) kyseliny 10-([S,S]-2,8-diazabicyklo[4.3.0]nón-8-yl)-9-fluór-2,3-dihydro-3-metyl-7-oxo-7H-pyrido[l,2,3-de]-[l,4]benzoxacín-6-karboxylovej, teplota topenia: 265 - 268 °C (rozklad), [ot]D 25 = -232,2° (c = 0,58, CHClj).1.4 g (5 mmol) of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxacin-6- of carboxylic acid is reacted in 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) of (+) - [S, S] -2,8-diazabicyclo [4.3.0] nonane analogously to Example 1. Yield: 1.24 g (64% of theory) of 10 - ([S, S] -2,8) diazabicyclo [4.3.0] non-8-yl) -9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido [2,3-d] - [l, 4] m.p .: 265-268 ° C (dec.), [α] 25 D = -232.2 ° (c = 0.58, CHCl 3).

Analogicky sa získa tiež kyselina 3S-10-([S,S]-2,8-diazabicyklo [4.3.0] nón-8-yl)-9-fluór-2,3-dihydro-3 -meíyl-7-oxo-7H-pyrido[ 1,2,3-de][ 1,4]benzoxacín-6-karboxylová.Analogously, 3S-10 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -9-fluoro-2,3-dihydro-3-methyl-7-oxo acid is also obtained. -7H-pyrido [1,2,3-de] [1,4] benzoxacin-6-carboxylic acid.

Príklad 9 oExample 9 o

Ky sel ina 1 -cyklopropy 1-6,7-diflu ór-1,4-dihy dro- 8-metoxy-4-oxo-3-chinolínkarboxylová sa nechá reagovať analogicky ako je uvedené v príklade 1 a reakčný produkt sa čistí chromatograficky (silikagél, pohyblivá fáza: metylénchlorid/metanol/17 % vodný amoniak 30 : 8 : 1). Získa sa takto kyselina l-cyklopropyl-7-([S,S]-2,8-diazabicyklo[4.3.0]nón-8-yl)-6-fluór-l,4-dihydro-8-metoxy-4-oxo-3-chinolínkarboxylová.1-Cyclopropyl 1-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid is reacted in an analogous manner to that described in Example 1 and the reaction product is purified by chromatography ( silica gel, mobile phase: methylene chloride / methanol / 17% aqueous ammonia 30: 8: 1). 1-Cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-8-methoxy-4- is obtained. oxo-3-quinolinecarboxylic acid.

teplota topenia: 203 - 208 °C (rozklad), [a]D 23 =-193° (c = 0,4, CHCI,).mp: 203-208 ° C (dec.), [α] D 23 = -193 ° (c = 0.4, CHCl 3).

Príklad 10 oExample 10 o

Nechá sa reagovať analogicky ako je uvedené v príklade 1A s kyselinou l-etyl-6,7,8-trifluór-l,4-dihydro-4-oxo-3-chinolínkarboxylovou a získa sa kyselina l-etyl-7-([S,S]-2,8-diazabicyklo[4.3.0]nón-8-yl)-6,8-difluór-l,4-dihydro-4-oxo-3-chinolínkarboxylová.It is reacted analogously to Example 1A with 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid to give 1-ethyl-7 - ([S] , S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6,8-difluoro-l, 4-dihydro-4-oxo-3-quinolinecarboxylic acid.

teplota topenia: 236 - 239 °C (rozklad) (kryšt. z glykolmonometyléteru), [cc]d 23= -186,3° (c = 0,3, CHCI,).mp: 236-239 ° C (dec.) (crystallized from glycol monomethyl ether), [α] D 23 = -186.3 ° (c = 0.3, CHCl 3).

Príklad 11 oExample 11 o

rr

A. Etylester kyseliny 7-([S,S]-2,8-diazabicyklo[4.3.0]nón-8 -y 1) -1 -(2,4-difluórfeny l)-6-flu ór-1,4-dihydro-4-oxo-1,8-naftyridín-3 -karboxylovejA. 7 - ([S, S] -2,8-Diazabicyclo [4.3.0] non-8-yl) -1- (2,4-difluorophenyl) -6-fluoro-1,4 ethyl ester dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid

1,9 g (5 mmol) etylesteru kyseliny 7-chlór-l-(2,4-difluórfenyl)-6-fluór-l,4-dihydro-4-oxo-l,8-naftyridin-3-karboxylovej sa v 20 ml acetonitrilu mieša za prítomnosti 560 mg (5 mmol) l,4-diazabicyklo[2.2.2]oktánu so 680 mg (5,4 mmol) [S,S]-2,8-diazabicyklo[4.3.0]nonánu počas 3 hodín pri teplote 10 °C. Vytvorená suspenzia sa odsaje, premyje sa vodou a odsaje sa. Získa sa takto 0,35 g produktu. Zahustením materského roztoku, rozmiešaním získaného zvyšku s vodou, izoláciou nerozpustného produktu a chromatografickým čistením (silikagél, pohyblivá fáza: dichlórmetán/metanol/17 % vodný amoniak) sa izoluje ďalších 0,7 g produktu.1.9 g (5 mmol) of 7-chloro-1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester in 20 ml of acetonitrile was stirred 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 for 3 hours. hours at 10 ° C. The suspension formed is filtered off with suction, washed with water and filtered off with suction. 0.35 g of product is obtained. Concentration of the mother liquor, stirring the residue with water, isolation of the insoluble product and chromatographic purification (silica gel, eluent: dichloromethane / methanol / 17% aqueous ammonia) yielded an additional 0.7 g of product.

Celkový výťažok: 1,05 g (44 % teórie), teplota topenia: 184- 185 °C (rozklad), [a]D 23 = + 6,8° (c = 0,46, CHCI3).Total yield: 1.05 g (44% of theory), Melting point: 184- 185 ° C (dec), [a] D 23 = + 6.8 ° (c = 0.46, CHCl 3).

B. Hydrochlorid kyseliny 7-([S,S]-2,8-diazabicyklo[4.3.0]nón-8-yl)-1 -(2,4-difluórfeny l)-6-fluór-1,4-dihydro-4-oxo-1,8-naftyridín-3 -karboxylovejB. 7 - ([S, S] -2,8-Diazabicyclo [4.3.0] non-8-yl) -1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro acid hydrochloride -4-oxo-1,8-naphthyridine-3-carboxylic acid

0,8 g (1,7 mmol) produktu zo stupňa A sa zahrieva v zmesi 10 ml kyseliny octovej a 8 ml polozriedenej kyseliny chlorovodíkovej počas 4 hodín pod spätným chladičom. Reakčná zmes sa potom zahustí, zvyšok sa rozmieša s malým množstvom vody, vytvorená zrazenina sa odsaje, premyje sa ľadovým etylalkoholom a usuší sa.The product from Step A (0.8 g, 1.7 mmol) was heated under reflux in a mixture of 10 ml of acetic acid and 8 ml of semi-diluted hydrochloric acid for 4 hours. The reaction mixture is then concentrated, the residue is stirred with a small amount of water, the precipitate formed is filtered off with suction, washed with ice-cold ethanol and dried.

Výťažok: 0,67 g (83 % teórie), teplota topenia: 324 - 326 °C (rozklad), [a]D 25 = +10,8° (c = 0,37, DMF).Yield: 0.67 g (83% of theory), melting point: 324-326 DEG C. (decomposition), [.alpha.] D @ 25 = + 10.8 DEG (c = 0.37, DMF).

Príklad 12Example 12

CH, OCH, O

0,56 g (2 mmol) kyseliny l-cyklopropyl-6,7-difluór-l,4-dihydro-5-metyl-4-oxo-3-chinolínkarboxylovej sa zahrieva s 0,38 g (3 mmol) [S,S]-2,8-diazabicyklo[4.3.0jnonánu a 0,45 g (4 mmol) l,4-diazabicyklo[2.2.2]oktánu v0.56 g (2 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid was heated with 0.38 g (3 mmol) of [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 dimetylsulfoxide počas 2 hodín na teplotu 120 °C. Po ochladení sa za vysokého vákua rozpúšťadlo odstráni. Získaný zvyšok sa vyberie do acetonitrilu, pevná látka sa oddelí, premyje sa acetonitrilom a usuší sa pri teplote v rozpätí 60 až 80 °C.3.5 ml of dimethylsulfoxide for 2 hours at 120 ° C. After cooling, the solvent was removed under high vacuum. The residue is taken up in acetonitrile, the solid is collected, washed with acetonitrile and dried at 60-80 ° C.

Výťažok: 0,5 g (65 % teórie) kyseliny l-cyklopropyl-7-([S,Sj-2,8-diazabicyklo-[4.3.0]nón-8-yl)-6-fluór-l,4-dihydro-5-metyl-4-oxo-3-chinolínkarboxylovej, teplota topenia: 217 - 219 °C (rozklad), [cc]D 25 = -119° (c = 0,5, DMF).Yield: 0.5 g (65% of theory) of 1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4- dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, m.p. 217-219 ° C (dec.), [α] D 25 = -119 ° (c = 0.5, DMF).

Príklad 13Example 13

Analogicky ako je uvedené v príklade 1 sa získa s použitím [S,S]-2-metyl-2,8-diazabicyklo[4.3.0]nonánu:Analogously to Example 1, [S, S] -2-methyl-2,8-diazabicyclo [4.3.0] nonane is obtained:

A. Kyselina l-cyklopropyl-6,8-difluór-l,4-dihydro-7-([S,S]-2-metyl-2,8-diazabicyklo[4.3.0]nón-8-yl)-4-oxo-3-chinolínkarboxylová;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-quinolinecarboxylic acid;

teplota topenia: 230 - 233 °C (rozklad) (kryšt. z glykolmonometyléteru).Melting point: 230-233 ° C (decomposition) (crystallized from glycol monomethyl ether).

B. Hydrochlorid kyseliny l-cyklopropyl-6,8-difluór-l,4-dihydro-7-([S,S]-2-metyl-2,8-diazabicyklo[4.3.0]nón-8-yl)-4-oxo-3-chinolínkarboxylovej;B. 1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7 - ([S, S] -2-methyl-2,8-diazabicyclo [4.3.0] non-8-yl) hydrochloride 4-oxo-3-quinolinecarboxylic acid;

teplota topenia: 258 - 260 °C (rozklad), [a]D 25 =-216,3° (c=l,H2O).mp: 258-260 ° C (dec.), [α] D 25 = -216.3 ° (c = 1, H 2 O).

Príklad 14Example 14

1,95 g (5 mmol) produktu z príkladu 1A sa zahrieva v ml etylalkoholu počas 4 hodín pod spätným chladičom s1.95 g (5 mmol) of the product of Example 1A was heated under reflux in ml of ethyl alcohol for 4 hours.

2,1 g (30 mmol) metylvinylketónu. Reakčná zmes sa potom zahustí, zvyšok sa rozmieša s vodou, vytvorená zrazenina sa odsaje, premyje sa etylalkoholom a usuší sa pri 100 °C/12 mbar. Výťažok: 2,1 g (91,5 % teórie) kyseliny l-cyklopropyl-6,8-difluór-l,4-dihydro-4-oxo-7-([S,S]-2-[3-oxo-l-butyl]-2,8-diazabicyklo[4.3.0]nón-8-yl)-3-chinolínkarboxylovej, teplota topenia: 181 - 183 °C (rozklad) (kryšt. z glykolmonometyléteru), [a]D 24’= -120,7° (c = 0,57, CH2C12).2.1 g (30 mmol) of methyl vinyl ketone. The reaction mixture is then concentrated, the residue is stirred with water, the precipitate formed is filtered off with suction, washed with ethyl alcohol and dried at 100 ° C / 12 mbar. Yield: 2.1 g (91.5% of theory) of 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, melting point: 181-183 ° C (decomp.) (crystallized from glycol monomethyl ether), [a] D 24 ' = -120.7 ° (c = 0.57, CH 2 C1 2).

Príklad 15Example 15

1,95 g (5 mmol) produktu z príkladu 1A sa zahrieva v 30 ml dimetylformamidu počas 3 hodín na teplotu v rozpätí 50 až 80 °C s 1,0 g (10,8 mmol) chlóracetónu a 1,3 g (13 mmol) trietylamínu. Získaný roztok sa zahustí, zvyšok sa rozmieša s vodou (pH 6), nerozpustná zrazenina sa odsaje, premyje sa vodou a usuší sa pri teplote 100 °C v horúcovzdušnej obehovej sušiarni (surový výťažok: 1,3 g). Rekryštalizuje sa z glykolmonometyléteru.1.95 g (5 mmol) of the product of Example 1A was heated in 30 ml of DMF for 3 hours at 50-80 ° C with 1.0 g (10.8 mmol) of chloroacetone and 1.3 g (13 mmol). ) triethylamine. The solution obtained is concentrated, the residue is stirred with water (pH 6), the insoluble precipitate is filtered off with suction, washed with water and dried at 100 ° C in a hot-air circulating oven (crude yield: 1.3 g). Recrystallize from glycol monomethyl ether.

Výťažok: 1,12 g (50 % teórie) kyseliny l-cyklopropyl-6,8-difluór-l,4-dihydro-4-oxo-7-([S,S]-2-[2-oxopropyl]-2,8-diazabicyklo[4.3.0]nón-8-yl)-3-chinolínkarboxylovej teplota topenia: 181 -184 °C (rozklad), [a]D 23 =-72° (c = 0,55, CHC13).Yield: 1.12 g (50% of theory) of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7 - ([S, S] -2- [2-oxopropyl] -2- M.p .: 181-184 ° C (dec.), [Α] D 23 = -72 ° (c = 0.55, CHCl 3 ), 8-diazabicyclo [4.3.0] non-8-yl) -3-quinolinecarboxylic acid. .

Príklad 16Example 16

A. Nechá sa reagovať produkt z príkladu 2A a získa sa kyselina 8-chlór-1 -cyklopropyl-6-fluór-1,4-dihydro-4-oxo-7-([S,S]-2-[3-oxo-l-butyl]-2,8-diazabicyklo[4.3.0]nón-8-yl)-3-chinolínkarboxylová, teplota topenia: 107 - 109 °C, [a]D 23 = -53° (c = 0,67, CHC13), obsah: 99,2 % (HPLC).A. The product of Example 2A is reacted 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) -3-quinolinecarboxylic acid, m.p. 107-109 ° C, [α] D 23 = -53 ° (c = 0, 67, CHC1 3), content: 99.2% (HPLC).

B. Analogicky sa získa s kyselinou 8-chlór- 1-cyklopropy 1-7-cis-2,8-diazabicyklo[4.3.0]nón-8-yl)-6-fluór-l,4-dihydro-4-oxo-3-chinolínkarboxylovou rac. kyselina 8-chlór-l-cyklopropyl-6-fluór-1,4-dihydro-4-oxo-7-(cis-2-[3-oxo-1 -butyl]-2,8-diazabicyklo[4.3.0]nón-8-yl)-3-chinolínkarboxylová, teplota topenia: 124- 125 °C.B. Analogously with 8-chloro-1-cyclopropyl-7-cis-2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-4-oxo acid -3-quinolinecarboxylic rac. 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (cis-2- [3-oxo-1-butyl] -2,8-diazabicyclo [4.3.0] N-8-yl) -3-quinolinecarboxylic acid, m.p. 124-125 ° C.

Príklad 17 'Π/”“Example 17 'Π / ”“

1,95 g (4,8 mmol) produktu z príkladu 2A sa zahrieva v 30 ml glykolmonometyléteru počas 2 hodín pod spätným chladičom s 3 g (30 mmol) etylesteru kyseliny akrylovej. Reakčná zmes sa potom odparí, zvyšok sa rozmieša s vodou, získaná zrazenina sa odsaje a vysuší (surový výťažok:1.95 g (4.8 mmol) of the product of Example 2A was heated in 30 ml of glycol monomethyl ether under reflux for 2 hours with 3 g (30 mmol) of ethyl acrylate. The reaction mixture is then evaporated, the residue is stirred with water, the precipitate obtained is filtered off with suction and dried (crude yield:

1,9 g). Rekryštalizuje sa z glykolmonometyléteru. Výťažok: 1,45 g (60 % teórie) kyseliny 8-chlór-1-cyklo propyI-7-([S,S]-2-[2-etoxykarbonyletyl]-2,8-diazabicyklo[4.3.0]nón-8-yl)-6-fluór-l,4-dihydro-4-oxo-3-chinolínkarboxylovej, teplota topenia: 117 -118 °C (rozklad), [a]D 28 = -103,5° (c = 0,49, DMF), obsah: 99,6 % (HPLC).1.9 g). Recrystallize from glycol monomethyl ether. Yield: 1.45 g (60% of theory) of 8-chloro-1-cyclopropyl-7 - ([S, S] -2- [2-ethoxycarbonylethyl] -2,8-diazabicyclo [4.3.0] non- 8-yl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, m.p .: 117-118 ° C (dec.), [Α] D 28 = -103.5 ° (c = 0) , 49, DMF), content: 99.6% (HPLC).

Príklad 18Example 18

1,95 g (4,8 mmol) produktu z príkladu 2A sa zahrieva počas 5 hodín v 30 ml etylalkoholu s 0,8 g (15 mmol) akrylonitrilu pod spätným chladičom. Reakčná zmes sa potom odparí, zvyšok sa rozmieša s vodou, vysuší sa (surový výťažok 1,9 g) a rekryštalizuje sa z glykolmonometyléteru. Výťažok: 1,6 g (73 % teórie) kyseliny 8-chlór-7-([S,S]-2-[2-kyanoetyl]-2,8-diazabicyklo[4.3.0]nón-8-yl)-1 -cyklopropyl-6-fluór-l,4-dihydro-4-oxo-3-chinolínkarboxylovej, teplota topenia: 153 - 155 °C (rozklad), [a]D 27 = -98,6° (c = 0,53, DMF), obsah: 96 % (HPLC), hmotnostne spektrum: m/e 458 (M+), 250, 149 (100 %, C9H13N2), 110,49.1.95 g (4.8 mmol) of the product of Example 2A was heated under reflux for 30 hours in 30 ml of ethyl alcohol with 0.8 g (15 mmol) of acrylonitrile. The reaction mixture is then evaporated, the residue is stirred with water, dried (crude yield 1.9 g) and recrystallized from glycol monomethyl ether. Yield: 1.6 g (73% of theory) of 8-chloro-7 - ([S, S] -2- [2-cyanoethyl] -2,8-diazabicyclo [4.3.0] non-8-yl) - 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, m.p. 153-155 ° C (dec.), [Α] D 27 = -98.6 ° (c = 0, 53, DMF), content: 96% (HPLC), mass spectrum: m / e 458 (M + ), 250, 149 (100%, C 9 H 13 N 2 ), 110.49.

Príklad Example Východiskový produkt (ptíklad) Starting product (example) A A x1 x 1 Y Y Teplota topenia ľ<‘l Melting point <<‘l [a)0 (a) 0 21 21 2Λ 2Λ CC! CC! II II Cll, CLL 211-213 211-213 +6.3’ (c=0.5, CJICIj) +6.3 ’(c = 0.5, CJICIj) 22 22 22 22 Cl 1 Cl 1 CHj CH Cll, CLL 199-20! 199-20! -205’ (c=O.5. CHClj) -205 '(c = O.5. CHClj) 23 23 3A 3A Cll CLL 11 11 CH, CH, 28-1-286 28-1-286 -231° (¢=0,5, CHClj) -231 ° (¢ = 0.5, CHCl3) 24 24 5 5 CF CF ni-j2 ni-j 2 Cll, CLL 2J6-24R 2J6-24R -14* (c»0.5,CHCIj) -14 * (c »0.5, CHCl 3) 25 25 6 6 N N II II CH, CH, 219-221 219-221 •162° (c«O,25, CHClj) • 162 ° (c = 0.25, CHCl 3) 26 26 19 19 COCHj COCH II II CH, CH, -23° (c=0,25, CHClj -23 ° (c = 0.25, CHCl 3) 27 27 13C 13C CF CF F F O ABOUT 232-233 232-233 +8’ (c=0,5. CHClj) +8 ’(c = 0.5. CHClj) 29 29 IA IA CF CF 11 11 Cllj Cllj 225-227·' 225-227 · '

nekry!>ía/iz<7va«énecro!> IA / from <7VA «s

Príklad 29Example 29

COOHCOOH

Príklad 19Example 19

CH,OOCCH, OOC

COOHCOOH

1,95 g (5 mmol) produktu z príkladu 1A sa zahrieva v 60 ml etylalkoholu počas 2 hodín pod spätným chladičom s1.95 g (5 mmol) of the product of Example 1A is heated in 60 ml of ethyl alcohol for 2 hours under reflux with

1,2 g (8 mmol) dimetylesteru kyseliny acetyléndikarboxylovej. Získaná suspenzia sa zahustí, zvyšok sa rozmieša s vodou a zrazenina sa odsaje a usuší. Surový produkt (2,3 g) sa rekryštalizuje zo zmesi glykolmonometyléteru a dimetylformamidu.1.2 g (8 mmol) of acetylenedicarboxylic acid dimethyl ester. The suspension obtained is concentrated, the residue is stirred with water and the precipitate is filtered off with suction and dried. The crude product (2.3 g) was recrystallized from a mixture of glycol monomethyl ether and dimethylformamide.

Výťažok: 2 g (74 % teórie) kyseliny l-cyklopropyl-7-[2-(1,2-bis-metoxykarbonylvinyl)-l S,6S-2,8-diazabiyklo[4.3.0]nón-8-yl]-6,8-difluór-l,4-dihydro-4-oxo-3-chinolínkarboxylovej, teplota topenia: 262 - 264 °C (rozklad), [a]D 24 = +28,8° (c = 0,24, CH2C12).Yield: 2 g (74% of theory) of 1-cyclopropyl-7- [2- (1,2-bis-methoxycarbonylvinyl) -1S, 6S-2,8-diazabicyclo [4.3.0] non-8-yl] -6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, m.p .: 262-264 ° C (dec.), [Α] D 24 = + 28.8 ° (c = 0.24) , CH 2 ( C 12 ).

Analogicky ako je opísané sa nechá reagovať kyselina 8-chlór-l-cyklopropyl-7-([S,S]-2,8-diazabicyklo[4.3.0]nón-8-yl)-6-fluór-1,4-dihydro-4-oxo-3-chinolínkarboxylovej s metylesterom kyseliny propiolovej v etylalkohole alebo metylalkohole a získa sa kyselina 8-chlór-l-cyklopropyl-6-fluór-l,4-dihydro-7-[2-trans-2-metoxykarbonylvinyl)-[S,SJ-2,8-diazabicyklo[4.3.0]nón-8-yl]-4-oxo-3-chinolínkarboxylová.Analogously to that described, 8-chloro-1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4- of dihydro-4-oxo-3-quinolinecarboxylic acid with propiolic acid methyl ester in ethyl alcohol or methyl alcohol to give 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7- [2-trans-2-methoxycarbonylvinyl) - [S, SJ-2,8-diazabicyclo [4.3.0] non-8-yl] -4-oxo-3-quinolinecarboxylic acid.

teplota topenia: 220 - 222 °C (rozklad), [a]D 24 = +8,2° (c = 0,5, CHClj).mp: 220-222 ° C (dec.), [α] D 24 = + 8.2 ° (c = 0.5, CHCl 3).

Claims (12)

PATENTOVÉ NÁROKYPATENT CLAIMS L Deriváty kyseliny chinolónkarboxylovej a naftyridónkarboxylovej všeobecného vzorca (I)L Quinolone carboxylic acid and naphthyridone carboxylic acid derivatives of general formula (I) Príklad 20 oExample 20 o CHjOOCCHjOOC Analogicky ako je uvedené v príklade 9 sa nechá reagovať produkt z príkladu 2A s dimetylesterom kyseliny acetyléndikarboxylovej. V 87 % výťažku sa získa kyselina 8-chlór-l-cyklopropyl-7-[2-(l,2-bis-metoxykarbonylvinyl)-lS,6S-2,8-diazabicyklo[4.3.0]nón-8-yl)-6-fluór-l,4-dihydro-4-oxo-3-chinolínkarboxylová, teplota topenia: 210 - 212 °C (rozklad), [a]D 24 = +16,6°(c = 0,5, DMF).Analogously to Example 9, the product of Example 2A is reacted with dimethyl acetylenedicarboxylic acid ester. In 87% yield 8-chloro-1-cyclopropyl-7- [2- (1,2-bis-methoxycarbonylvinyl) -1S, 6S-2,8-diazabicyclo [4.3.0] non-8-yl) is obtained -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, melting point: 210-212 ° C (decomposition), [α] D 24 = + 16.6 ° (c = 0.5, DMF) ). Analogicky sa získajú zo zodpovedajúcich medziproduktov nasledujúce zlúčeniny:By analogy, the following compounds are obtained from the corresponding intermediates: v ktoromin which A znamená skupinu CH, CF, CC1, C-OCH3, C-CH3 alebo N,A is CH, CF, CC1, C-OCH3, C-CH 3 or N, X1 znamená vodíkový atóm, atóm halogénu, aminoskupinu alebo metylovú skupinu,X 1 represents a hydrogen atom, a halogen atom, an amino group or a methyl group, R1 znamená alkylovú skupinu s 1 až 3 uhlíkovými atómami, skupinu FCH2CH2-, cyklopropylovú skupinu, fenylovú skupinu, prípadne raz až trikrát substituovanú atómom halogénu, aleboR 1 represents an alkyl group having 1 to 3 carbon atoms, an FCH 2 CH 2 - group, a cyclopropyl group, a phenyl group, optionally substituted one to three times with a halogen atom, or R1 a A môžu znamenať spoločne mostík štruktúry C-O-CH2-CH(CH3)-,R 1 and A may together represent a bridge of the structure CO-CH 2 -CH (CH 3 ) -, R2 znamená vodíkový atóm, alkylovú skupinu s 1 až 3 uhlíkovými atómami, prípadne substituovanú atómom halogénu alebo aminoskupinou, alebo 5-metvl-2-oxo-l,3-dioxol-4-yl-metylovú skupinu,R 2 represents hydrogen, alkyl having 1 to 3 carbon atoms, optionally substituted by halogen or amino, or a 5-methyl-2-oxo-l, 3-dioxol-4-yl-methyl, B znamená zvyšok vzorca v ktoromB is a radical of the formula wherein Y znamená metylénovú skupinu aY represents a methylene group and R4 znamená vodíkový atóm, alkylovú skupinu s 1 až 3 uhlíkovými atómami, oxoalkylovú skupinu s 2 až 5 uhlíkovými atómami, skupiny CII2-CO-C6H5, CH2CII2CO2R', RO2C-CH=C-CO2R',R 4 represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, an oxoalkyl group having 2 to 5 carbon atoms, a group CII 2 -CO-C 6 H 5 , CH 2 Cl 2 2 CO 2 R ', RO 2 C-CH = C-CO 2 R ', II -CH=CH-CO2R' alebo CH2CH2-CN alebo 5-metyl-2-oxo-l,3-dioxol-4-yl-mctylovú skupinu, pričom-CH = CH-CO 2 R 'or CH 2 CH 2 -CN or 5-methyl-2-oxo-1,3-dioxol-4-ylmethyl, wherein: R' znamená vodíkový atóm alebo alkylovú skupinu s 1 až 3 uhlíkovými atómami, a ich farmaceutický použiteľné hydráty a adičné soli s kyselinami, ako i soli zodpovedajúcich kyselín s alkalickými kovmi, kovmi alkalických zemín, striebrom a guanidínom.R 'represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and their pharmaceutically usable hydrates and acid addition salts, as well as the corresponding acid salts with alkali metals, alkaline earth metals, silver and guanidine. 2. Deriváty kyseliny chinolónkarboxylovej a naftyridónkarboxylovej podľa nároku 1, všeobecného vzorca (I), v ktorom2. A compound according to claim 1, wherein the compound of formula (I): A znamená CH, CF, CC1, C-OCH3 alebo N,A is CH, CF, CC1, C-OCH3 or N, X1 znamená vodíkový atóm, atóm fluóru, chlóru alebo brómu, aminoskupinu alebo metylovú skupinu,X 1 represents a hydrogen atom, a fluorine, chlorine or bromine atom, an amino group or a methyl group, R1 znamená etylovú skupinu, 2,4-difluórfenylovú skupinu, aleboR 1 is ethyl, 2,4-difluorophenyl, or R1 a A môžu znamenať spoločne mostík štruktúry C-O-CH2-CH(CH3)-,R 1 and A may together represent a bridge of the structure CO-CH 2 -CH (CH 3 ) -, R2 znamená vodíkový atóm, metylovú skupinu, etylovú skupinu alebo 5-metyl-2-oxo-l,3-dioxol-4-yl-metylovú skupinu aR 2 represents hydrogen, methyl, ethyl or 5-methyl-2-oxo-l, 3-dioxol-4-yl-methyl, and R4 znamená vodíkový atóm, alkylovú skupinu s 1 až 3 uhlíkovými atómami, skupiny CH2-CO-CH3, CH2-CO-C6Hj, CH2CH2-CO-CH3, CH2CH2CO2R', ro2c-ch-c-co2r·, -CH=CH-CO2R' alebo CH2CH2-CN alebo | 5-metyl-2-oxo-l,3-dioxol-4-yl-metylovú skupinu, pričomR 4 represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, CH 2 -CO-CH 3 , CH 2 -CO-C 6 H 3, CH 2 CH 2 -CO-CH 3 , CH 2 CH 2 CO 2 R ', rO 2 C-CH-CO2-R ·, -CH = CH-CO2 R' or CH2 CH2 -CN, or | A 5-methyl-2-oxo-1,3-dioxol-4-ylmethyl group wherein: R' znamená alkylovú skupinu s 1 až 2 uhlíkovými atómami, a ich farmaceutický použiteľné hydráty a adičné soli s kyselinami, ako i soli zodpovedajúcich kyselín s alkalickými kovmi, kovmi alkalických zemín, striebrom a guanidínom.R 'represents an alkyl group having 1 to 2 carbon atoms, and the pharmaceutically usable hydrates and acid addition salts thereof, as well as the corresponding acid salts with alkali metals, alkaline earth metals, silver and guanidine. 3. Derivát kyseliny chinolónkarboxylovej a naftyridónkarboxylovej podľa nároku 1, všeobecného vzorca (I), ktorým je kyselina 8-chlór-l-cyklopropyl-7-([S,S]-2,8-diazabicyklo[4.3.0]nón-8-yl)-6-fluór-l,4-dihydro-4-oxo-3-chinolínkarboxylová a jej farmaceutický použiteľné hydráty a adičné soli s kyselinami, ako i soli zodpovedajúcich karboxylových kyselín s alkalickými kovmi, kovmi alkalických zemín, striebrom a guanidínom.A compound according to claim 1, which is 8-chloro-1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8). -yl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and its pharmaceutically acceptable hydrates and acid addition salts, as well as the corresponding alkali metal, alkaline earth metal, silver and guanidine salts of the corresponding carboxylic acids. 4. Derivát kyseliny chinolónkarboxylovej a naftyridónkarboxylovej podľa nároku 1, všeobecného vzorca (I), ktorým je kyselina l-cyklopropyl-7-([S,S]-2,8-diazabicyklo[4.3.0]nón-8-yl)-6-tluór-l,4-dihydro-8-metoxy-4-oxo-3-chinolínkarboxylová.A compound according to claim 1, which is 1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) - 6-fluoro-l, 4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid. 5. Deriváty kyseliny chinolónkarboxylovej a naftyridónkarboxylovej podľa nároku 1, všeobecného vzorca (I), ktorými sú kyselina l-cyklopropyl-7-([S,S]-2,8-diazabicyklo[4.3.0Jnón-8-yl)-6,8-difluór-l,4-dihydro-4-oxo-3-chinolínkarboxylová, kyselina l-cyklopropyl-7-([S,S]-2,8-diazabicyklo[4.3.0Jnón-8-yl)-6-fluór-1,4-dihydro-4-oxo-3-chinolínkarboxylová a kyselina l-cyklopropyl-7-([S,S]-2,8-diazabicyklo[4.3.0J nón-8-yl)-5,6,8-trifluór-l,4-dihydro-4-oxo-3-chinolínkarboxylová a ich soli.5. A compound according to claim 1, which is 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, 1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -5,6,8 -trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and salts thereof. 6. Spôsob výroby derivátov chinolónkarboxylových a naftyridónkarboxylových kyselín podľa nároku 1, všeobecného vzorca (I), v ktoromA process for the preparation of quinolone carboxylic acid and naphthyridone carboxylic acid derivatives according to claim 1, in which: A znamená skupinu CH, CF, CC1, C-OCH3, C-CH3 alebo N,A is CH, CF, CC1, C-OCH3, C-CH 3 or N, X1 znamená vodíkový atóm, atóm halogénu, aminoskupinu alebo metylovú skupinu,X 1 represents a hydrogen atom, a halogen atom, an amino group or a methyl group, R1 znamená alkylovú skupinu s 1 až 3 uhlíkovými atómami, skupinu FCH2CH2-, cyklopropylovú skupinu, fenylovú skupinu, prípadne raz až trikrát substituovanú atómom halogénu, aleboR 1 represents an alkyl group having 1 to 3 carbon atoms, an FCH 2 CH 2 - group, a cyclopropyl group, a phenyl group, optionally substituted one to three times with a halogen atom, or R1 a A môžu znamenať spoločne mostík štruktúry C-O-CH2-CH(CH3)-,R 1 and A may together represent a bridge of the structure CO-CH 2 -CH (CH 3 ) -, R2 znamená vodíkový atóm, alkylovú skupinu s 1 až 3 uhlíkovými atómami, prípadne substituovanú atómom halogénu alebo aminoskupinou, alebo 5-metyl-2-oxo-l,3-dioxol-4-yl-metylovú skupinu,R 2 represents hydrogen, alkyl having 1 to 3 carbon atoms, optionally substituted by halogen or amino, or a 5-methyl-2-oxo-l, 3-dioxol-4-yl-methyl, B znamená zvyšok vzorca v ktoromB is a radical of the formula wherein Y znamená metylénovú skupinu aY represents a methylene group and R4 znamená vodíkový atóm, alkylovú skupinu s 1 až 3 uhlíkovými atómami, oxoalkylovú skupinu s 2 až 5 uhlíkovými atómami, skupiny CH2-CO-C6H5, CH2CH2CO2R', RO2C-CH=C-CO2R',R 4 represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, an oxoalkyl group having 2 to 5 carbon atoms, CH 2 -CO-C 6 H 5 , CH 2 CH 2 CO 2 R ', RO 2 C-CH = C-CO 2 R ', II -CH=CH-CO2R' alebo CH2CH2-CN alebo 5-metyl-2-oxo-1,3 -dioxol-4-yl-metylovú skupinu, pričom-CH = CH-CO 2 R 'or CH 2 CH 2 -CN or 5-methyl-2-oxo-1,3-dioxol-4-ylmethyl, wherein: R' znamená vodíkový atóm alebo alkylovú skupinu s 1 až 3 uhlíkovými atómami, vyznačujúci sa tým, že sa nechá reagovať zlúčenina všeobecného vzorca (V) viR 'represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, characterized in that a compound of formula (V) vi is reacted R1 v ktorom majú A, R1, R2 a X1 uvedený význam aR 1 wherein A, R 1 , R 2 and X 1 are as defined above and a X2 znamená atóm halogénu, obzvlášť fluóru alebo chlóru, s enantioméme čistými zlúčeninami všeobecného vzorca (VI)X 2 represents a halogen atom, in particular fluorine or chlorine, with the enantiomerically pure compounds of the general formula (VI) R N*__Ύ v ktoromR N * __ Ύ in which Y znamená metylénovú skupinu aY represents a methylene group and R4 znamená vodíkový atóm alebo alkylovú skupinu s 1 ažR 4 represents a hydrogen atom or an alkyl group having from 1 to 5 carbon atoms; 3 uhlíkovými atómami, prípadne za prítomnosti látok viažucich kyseliny, a reakčný produkt sa prípadne nechá reagovať ďalej so zlúčeninou všeobecného vzorca (Hla)3 carbon atoms, optionally in the presence of acid binders, and optionally reacting the reaction product with a compound of formula (IIIa) R4 - X3 (Hla), v ktorom má X3 uvedený význam aR 4 - X 3 (H 1a), wherein X 3 is as defined above and R4 znamená oxoalkylovú skupinu s 2 až 5 uhlíkovými atómami, alebo skupiny CH2-CO-C6H5, CH2CH2CO2R' a CH2CH2-CN, pričomR 4 represents an oxoalkyl group having 2 to 5 carbon atoms, or CH 2 -CO-C 6 H 5 , CH 2 CH 2 CO 2 R 'and CH 2 CH 2 -CN, wherein: R' znamená vodíkový atóm alebo alkylovú skupinu s 1 ažR 'represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms; 3 uhlíkovými atómami, alebo s Michaelovým akceptorom, ako je díalkylester kyseliny acetyléndikarboxylovej, alkylesterom kyseliny propiolovej alebo so zlúčeninou všeobecného vzorca (IV)3 carbon atoms, or with a Michael acceptor, such as a dialkyl ester of acetylenedicarboxylic acid, an alkyl ester of propiolic acid or a compound of formula (IV) CH2 = CH - R5 (IV), v ktoromCH 2 = CH-R 5 (IV) wherein R5 znamená skupinu COCH3, CO2R' alebo CN.R 5 is COCH 3 , CO 2 R 'or CN. 7. Enantiomérne čisté zlúčeniny všeobecného vzorca (VI)7. Enantiomerically pure compounds of formula (VI) H NH N V..7 v ktoromV..7 in which Y znamená metylénovú skupinu aY represents a methylene group and R4 znamená vodíkový atóm alebo alkylovú skupinu s 1 až 3 uhlíkovými atómami, ako medziprodukty na výrobu derivátov všeobecného vzorca (I).R 4 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms as intermediates for the preparation of derivatives of the general formula (I). 8. Deriváty kyseliny chinolónkarboxylovej a naftyridónkarboxylovej podľa nároku 1 na použitie pri liečení ochorení.The quinolonecarboxylic acid and naphthyridonecarboxylic acid derivatives according to claim 1 for use in the treatment of diseases. 9. Deriváty kyseliny chinolónkarboxylovej a naftyridónkarboxylovej podľa nároku 1 na použitie pri liečení infekčných ochorení.The quinolone carboxylic acid and naphthyridone carboxylic acid derivatives according to claim 1 for use in the treatment of infectious diseases. 10. Liečivá, vyznačujúce sa tým, že ako účinnú látku obsahujú deriváty kyseliny chinolónkarboxylovej a naftyridónkarboxylovej podľa nároku 1.Medicaments, characterized in that they contain, as active ingredient, the quinolone carboxylic acid and naphthyridone carboxylic acid derivatives according to claim 1. 11. Liečivá s antibakteriálnym účinkom, vyznačujúce sa tým, že obsahujú deriváty kyseliny chinolónkarboxylovej a naftyridónkarboxylovej podľa nároku 1.Medicaments having an antibacterial action, characterized in that they contain the quinolone carboxylic acid and naphthyridone carboxylic acid derivatives according to claim 1. 12. Použitie derivátov kyseliny chinolónkarboxylovej a naftyridónkarboxylovej podľa nároku 1 pri výrobe liečiv na potláčanie infekčných ochorení.Use of quinolone carboxylic acid and naphthyridone carboxylic acid derivatives according to claim 1 in the manufacture of medicaments for controlling infectious diseases.
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