SI8910875A

SI8910875A - Optically active pyridone carboxylic acid derivatives

Info

Publication number: SI8910875A
Application number: SI8910875A
Authority: SI
Inventors: Isao Hayakawa; Yoichi Kimura
Original assignee: Daiichi Seiyaku Co
Priority date: 1988-04-27
Filing date: 1989-04-26
Publication date: 1997-06-30
Also published as: HRP930088A2; SI8910875B; HRP930088B1

Abstract

Prikazani so Ni-(1,2-cis-2-halogenociklopropil)- substituirani derivati piridon karboksilne kisline, prikazani s formulo (I) in njihove soli. Te spojine imajo močne antibakterijske učinkovitosti proti zelo raznovrstnim infekcijskim bakterijam in so koristne kot antibakterijska sredstva pri oralnem ali parenteralnem dajanju. Pripravimo jih s resnovo 7-halogeno-1-(2-cis-2-fluorociklopropil)-piridon karboksilne kisline s cikličnim aminom s formulo Rz-H, ki je lahko zaščiten z običajno zaščitno skupino, pri čemer imajo ostanki R1, X1, X2, A, X in R2 pri zahtevku 1 definirani pomen.Shown are Ni- (1,2-cis-2-halogenocyclopropyl) - substituted pyridone carboxylic acid derivatives shown of formula (I) and salts thereof. These compounds have strong antibacterial properties effectiveness against very diverse infectious bacteria and are useful as antibacterial agents in oral or parenteral administration. Prepare with 7-halogen-1- (2-cis-2-fluorocyclopropyl) -pyridone a cyclic amine carboxylic acid of formula Rz-H, which may be protected by a conventional protecting group, with residues R1, X1, X2, A, X and R2 of claim 1 defined meaning.

Description

Optično aktivni derivati piridonkarboksilne kislineOptically active pyridonecarboxylic acid derivatives

Področje izumaFIELD OF THE INVENTION

Predloženi izum se nanaša na antimikrobno spojino, koristno kot zdravilo v humani in veterinarski medicini ter ribištvu, poljedelskih kemikalijah in antiseptikih.The present invention relates to an antimicrobial compound useful as a medicament in human and veterinary medicine and in fisheries, agricultural chemicals and antiseptics.

Ozadje izumaBACKGROUND OF THE INVENTION

Derivati kinolona z ogrodjem kondenzirane piridonkarboksil ne kisline so znani kot sintetična antimikrobna sredstva in po tem, da nudijo aktivne antimikrobne spojine pri substituciji njihovega položaja 1 s ciklopropilno skupino.Quinolone derivatives with a condensed pyridonecarboxylic acid framework are known as synthetic antimicrobial agents and in that they provide active antimicrobial compounds in substitution of their position 1 with the cyclopropyl group.

Nadalje je znano, da tudi derivati 1-ciklopropil-kinolona, z uvedenim atomom fluora v položaj 2 ciklopropilne skupine v cis-konfiguraciji z delom piridonkarboksilne kisline, tudi kažejo močno antimikrobno učinkovitost, kot je prikazano v JP-A-87-12760 (izraz JP-A, kot ga tukaj uporabljamo, pomeni nepreizkušeno, objavljeno japonsko patentno prijavo). Menijo, da nimajo samo močne antimikrobne učinkovitosti, ampak tudi izboljšano varnost. Eden izmed primerov derivatov kinolona s cis-fluorociklopropilno skupino v položaju 1 je prikazan spodaj.It is further known that even 1-cyclopropyl-quinolone derivatives having introduced a fluorine atom to the 2-position of the cyclopropyl group in the cis configuration with a portion of pyridonecarboxylic acid also exhibit potent antimicrobial efficacy, as shown in JP-A-87-12760 (term JP-A, as used herein, means an untested, published Japanese patent application). They are thought to have not only strong antimicrobial efficacy but also improved safety. One example of a quinolone derivative with a cis-fluorocyclopropyl group in position 1 is shown below.

Derivati kinolona s cis-halogeno-ciklopropilno skupino, vključno cis-fluorociklopropilno skupino, v položaju 1, kot je zgoraj navedeno, imajo odlične lastnosti'‘glede antimikrobne učinkovitosti in varnosti. Pri teh spojinah, celo v primeru, ko imajo substituent brez stereo-izomerije v položaju 7 dela piridonkarboksilne kisline, nudi sam halogeno-ciklopropanski obroč 2 enantiomera, pripisana steričnemu razmerju med delom piridon karboksilne kisline in atomom halogena, z ozirom na ciklopropanski obroč, kot je pojasnjeno spodajQuinolone derivatives with the cis-halogen-cyclopropyl group, including the cis-fluorocyclopropyl group, in position 1, as indicated above, have excellent properties for antimicrobial efficacy and safety. With these compounds, even when the substituent without stereo-isomerism at the 7-position of part of the pyridonecarboxylic acid, the halogen-cyclopropane ring itself offers 2 enantiomers attributed to the steric ratio of the part of the pyridone carboxylic acid to the halogen atom with respect to the cyclopropane ring, such as is explained below

inand

kjer imajo R¹, R², A, X¹ in X² v nadaljevanju definirani pomen. Te derivate kinolona se da uporabiti kot zdravila, v kolikor so racemati. Po drugi strani, pa pri stereoizomeriji substituenta v položaju 7 dela piridon karboksilne kisline tovrstni derivati kinolona vsebujejo 4 vrste diastereomerov.wherein R ¹ , R ² , A, X ¹ and X ^{2 have the} meanings defined below. These quinolone derivatives can be used as medicaments to the extent that they are racemic. On the other hand, for the stereoisomerism of the substituent at position 7 of the pyridone carboxylic acid moiety, such quinolone derivatives contain 4 types of diastereomers.

Z zmesmi diastereomerov je težko specificirati odlične primerke ter jih dati na voljo kot zdravila.With diastereomer mixtures, it is difficult to specify excellent specimens and make them available as drugs.

Opis bistva izumaDescription of the invention

Glede na zgoraj navedeni položaj so si izumitelji izredno prizadevali, da bi dobili posamezne izomere 1-(1,2-cis2-fluorociklopropil)-substituiranih derivatov kinolona v okviru njihovih diastereomerov. Uspelo jim je dobiti vsakega izmed enantiomerov cis-2-fluorociklopropilamina kot čist izomer. Pri nadaljnjih raziskavah se jim je tudi posrečilo sintetizirati vsakega izmed enantiomerov derivata kinolona, kar je pripisati samo sterični konfiguraciji fluorociklopropanskega obroča, izhajajoč iz zgoraj opisanega amina.In view of the above situation, the inventors have made great efforts to obtain the individual isomers of 1- (1,2-cis 2-fluorocyclopropyl) -substituted quinolone derivatives within their diastereomers. They were able to obtain each of the enantiomers of cis-2-fluorocyclopropylamine as a pure isomer. In further studies, they were also fortunate to synthesize each of the enantiomers of the quinolone derivative, attributable only to the steric configuration of the fluorocyclopropane ring based on the amine described above.

Uspeh pri pridobitvi enantiomernih derivatov kinolona, koristnih kot intermediat, je omogočil sintezo optično aktivnega derivata kinolona, ki obsega eno vrsto diastereomera, s presnovo enega samega izomera amina ob uvedbi ciklične amino skupine v položaj 7. Vsak izmed teh diastereomerov se je izkazal kot antimikrobno učinkovitejši v primeri z ustreznimi derivati kinolona substituiranimi samo s ciklopropilno skupino, poleg tega pa zelo varen ob izrazito izboljšani selektivni toksičnosti. Predloženi izum smo dokončali na osnovi teh ugotovitev.The success of obtaining the enantiomeric quinolone derivatives useful as an intermediate has enabled the synthesis of an optically active quinolone derivative comprising one type of diastereomer by metabolizing a single amine isomer by introducing a cyclic amino group to position 7. Each of these diastereomers has proven to be more antimicrobially effective in the case of the corresponding quinolone derivatives substituted with the cyclopropyl group only, and very safe with markedly improved selective toxicity. The present invention was completed on the basis of these findings.

Predloženi izum se nanaša na N^-(1,2-cis-2-halogenociklopropil)-substituiran derivat piridon karboksilne kisline, prikazan s formulo (I):The present invention relates to the N, N - (1,2-cis-2-halogenocyclopropyl) -substituted pyridone carboxylic acid derivative represented by formula (I):

R¹ 0R ¹ 0

kjer R¹ predstavlja substituirano ali nesubstituirano amino skupino, hidroksilno skupino, tiolno skupino, ali atom 2 vodika; R predstavlja substituirano ali nesubstituirano ciklično amino skupino, ki lahko vsebuje najmanj en hetero atom, izbran izmed atoma dušika, kisika ali .«žvepla, v njegovem obroču; A predstavlja C-X ali atom dušika; X in X , ki sta lahko enaka ali različna vsakokrat predstavljata atom halogena, Χ^ pa predstavlja atom halogena, alkilno skupino z 1 do 6 atomi ogljika, alkoksilno skupino z 1 do 6 atomi ogljika, ciano skupino, trifluorometilno skupino ali atom vodika; s v «z 1 pridržkom, da je izključen primer, kjer je R atom vodika in 2wherein R ¹ represents a substituted or unsubstituted amino group, hydroxyl group, thiol group, or hydrogen atom 2; R represents a substituted or unsubstituted cyclic amino group which may contain at least one hetero atom selected from a nitrogen, oxygen or sulfur atom in its ring; A represents CX or a nitrogen atom; X and X, which may each be the same or different, each represent a halogen atom and Χ ^ represents a halogen atom, an alkyl group of 1 to 6 carbon atoms, an alkoxyl group of 1 to 6 carbon atoms, a cyano group, a trifluoromethyl group or a hydrogen atom; sv "with 1 reservation to exclude the case where R is a hydrogen atom and 2

R piperazinski ali 4-alkil-substituiran piperazinski ostanek, ali njegova sol.R is a piperazine or 4-alkyl-substituted piperazine residue, or a salt thereof.

Specifični predstavniki spojin, prikazanih s formulo vSpecific representatives of the compounds of formula v

(I), in njihovih soli, so tisti, kjer je R ciklična amino 2 skupina, ki je lahko substituirana; tisti, kjer je R 4- do 7-členska ciklična amino skupina, ki je lahko substituirana s hidroksilno skupino, alkilna skupina z 1 do 6 atomi ogljika, ali substituirana ali nesubstituirana amino skupina; tisti kjer je R pirolidinski, piperidinski, piperazinski, diazabicikloheptanski ali diazabiciklooktanski ostanek; tisti, kjer je R ciklična amino skupina, ki obsega en sam stereoizo2 mer; tisti, kjer je R 3-amino pirolidinilna skupina; tisti, kjer je R 7-amino-5-azaspiro/2,4/-heptan-5-ilna skupina; in tisti, kjer je X atom fluora. Bolj specifično pa spojine v skladu s predloženim izumom obsegajo 7-/3-(S)-amino-1-pirolidinil/-6-fluoro-1-(1,2-cis-2-fluorociklopropil)-4-okso-1,4dihidrokinolin-3-karboksilno, 7-/3-(S)-amino-1-pirolidinil/-8kloro-6-fluoro-1-(1,2-cis-fluorociklopropil)-4-okso-1,4dihidrokinolin-3-karboksilno, 7-/7-amino-5-azaspiro/2,4/heptan(I), and salts thereof, are those wherein R is a cyclic amino 2 group which is optionally substituted; those wherein R is a 4- to 7-membered cyclic amino group which may be substituted by a hydroxyl group, an alkyl group of 1 to 6 carbon atoms, or a substituted or unsubstituted amino group; those wherein R is a pyrrolidine, piperidine, piperazine, diazabicycloheptane or diazabicyclooctane residue; one where R is a cyclic amino group comprising a single stereoisomer; one where R is a 3-amino pyrrolidinyl group; one where R is a 7-amino-5-azaspiro / 2,4 / -heptan-5-yl group; and one where X is a fluorine atom. More specifically, the compounds of the present invention comprise 7- [3- (S) -amino-1-pyrrolidinyl] -6-fluoro-1- (1,2-cis-2-fluorocyclopropyl) -4-oxo-1, 4-Dihydroquinoline-3-carboxyl, 7- [3- (S) -amino-1-pyrrolidinyl] -8-chloro-6-fluoro-1- (1,2-cis-fluorocyclopropyl) -4-oxo-1,4-dihydroquinoline-3- carboxyl, 7- [7-amino-5-azaspiro / 2,4 / heptane

5- il/-8-kloro-6-fluoro-1-(1,2-cis-2-fluorociklopropil)-4okso-1,4-dihidrokinolin-3-karboksilno, 5-amfno-7-/3-(S)-amino1- pirolidinil/-6,8-difluoro-1-(1,2-cis-2-fluorociklopropil)4-okso-1,4-dihidrokinolin-3-karboksilno, 7-/4-(S)-amino-2-(S)metil-1-pirolidinil/-6-fluoro-1-(1,2-cis-2-fluorociklopropil)4-okso-1,4-dihidro-1,8-naftiridin-3-karboksilno, 7-/3-(R)-/1(S)-aminoetil/-1-pirolidinil/-8-kloro-6-fluoro-1-(1,2-cis2- fluorociklopropil)-4-okso-1,4-dihidrokinolin-3-karboksilno_;7-/3-amino-4-metil-1-pirolidinil/-6-fluoro-1-(1,2-cis-2fluorociklopropil)-8-metoksi-4-okso-1,4-dihidrokinolin-3karboksilno, 7-/4-(S)-amino-2-(S)-meti1-1-pirolidinil/6- fluoro-1-(1,2-cis-2-fluorociklopropil)-8-metil-4-okso1,4-dihidrokinolin-3-karboksilno, 5-amino-7-/7-amino-5azaspiro/2,4/-heptan-5-il/-6,8-difluoro-1-(1,2-cis-2fluorociklopropi1)-4-okso-1,4-dihidrokinolin-3-karboksilno kislino in njihove soli.5-yl] -8-chloro-6-fluoro-1- (1,2-cis-2-fluorocyclopropyl) -4oxo-1,4-dihydroquinoline-3-carboxylic, 5-amphno-7- / 3- (S ) -amino-1-pyrrolidinyl] -6,8-difluoro-1- (1,2-cis-2-fluorocyclopropyl) 4-oxo-1,4-dihydroquinoline-3-carboxyl, 7- / 4- (S) -amino -2- (S) methyl-1-pyrrolidinyl] -6-fluoro-1- (1,2-cis-2-fluorocyclopropyl) 4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxyl, 7- [3- (R) - [1 (S) -aminoethyl] -1-pyrrolidinyl] -8-chloro-6-fluoro-1- (1,2-cis2-fluorocyclopropyl) -4-oxo-1,4 -Dihydroquinoline-3-carboxyl _; 7- (3-amino-4-methyl-1-pyrrolidinyl) -6-fluoro-1- (1,2-cis-2fluorocyclopropyl) -8-methoxy-4-oxo-1,4-dihydroquinoline-3carboxyl, 7- [4- (S) -amino-2- (S) -methyl-1- pyrrolidinyl] -6-fluoro-1- (1,2-cis-2-fluorocyclopropyl) -8-methyl-4-oxo-1,4-dihydroquinoline -3-carboxyl, 5-amino-7- (7-amino-5azaspiro) 2,4-heptan-5-yl) -6,8-difluoro-1- (1,2-cis-2fluorocyclopropyl) -4- oxo-1,4-dihydroquinoline-3-carboxylic acid and their salts.

Podroben opis izumaDETAILED DESCRIPTION OF THE INVENTION

11

V formuli (I), kadar X predstavlja atom halogena, X in X vsakokrat prednostno predstavljata atom fluora aliIn formula (I), when X represents a halogen atom, X and X each preferably represent a fluorine atom or

1 atom klora; X pa prednostno predstavlja atom fluora. R predstavlja substituirano ali nesubstituirano amino skupino, hidroksilno skupino, tio.lno skupino ali atom vodika/ prednostno nesubstituirano amino skupino, metilamino skupino ali atom vodika.1 chlorine atom; X preferably represents a fluorine atom. R represents a substituted or unsubstituted amino group, a hydroxyl group, a thiol group or a hydrogen atom / preferably an unsubstituted amino group, a methylamino group or a hydrogen atom.

R predstavlja ciklično amino skupino, prednostno 4- doR represents a cyclic amino group, preferably 4- to

7-člensko, še bolj prednostno pa 5- do 6-člensko, ciklično amino skupino. Ciklična amino skupina lahko,, nadalje vsebuje enega ali več atomov kisika, žvepla in/ali dušika, kot v oksazolidinskem, morfolinskem, tiazolidinskem, tiomorfolinskem imidazolidinskem, pirazolidinskem in piperazinskem ostanku. Izmed teh cikličnih amino skupin sta prednostna pirolidinski in piperazinski ostanek. Ciklična amino skupina ima lahko substituente, kot polarno skupino (npr. substituirano ali nesubstituirano amino skupino, substituirano ali nesubstituira no aminoalkilno skupino, 5-substituirano 2-okso-1,3-dioksol-4il metilno skupino, hidroksilno skupino) in ravno, razvejeno ali ciklično alkilno skupino z do 6 atomi ogljika. Prednostne polarne skupine so nesubstituirana amino skupina, aminometilnaA 7-membered, and more preferably a 5- to 6-membered, cyclic amino group. The cyclic amino group may further comprise one or more oxygen, sulfur and / or nitrogen atoms, such as in the oxazolidine, morpholine, thiazolidine, thiomorpholine imidazolidine, pyrazolidine and piperazine residues. Of these cyclic amino groups, the pyrrolidine and piperazine residues are preferred. The cyclic amino group may have substituents, such as a polar group (e.g., substituted or unsubstituted amino group, substituted or unsubstituted aminoalkyl group, 5-substituted 2-oxo-1,3-dioxol-4yl methyl group, hydroxyl group) and a straight, branched or a cyclic alkyl group of up to 6 carbon atoms. Preferred polar groups are an unsubstituted amino group, aminomethyl

1-aminoetilna in hidroksilna skupina. Prednostne alkilne skupine so metilna, etilna, propilna, gem-dimetilna in gem- 7 dietilna skupina, nadalje pa te gem-alkilne skupine lahko prednostno tvorijo ciklopropanski ali ciklobutanski obroč, ki je po spiro-vezi povezan s cikličnim aminskim ogrodjem. Ciklična amino skupina nadalje vključuje biciklično amino skupino, tvorjeno s premreženjem na 4- do 7-členske ciklične amino skupine.1-aminoethyl and hydroxyl group. Preferred alkyl groups are methyl, ethyl, propyl, gem-dimethyl and gem-7 diethyl groups, and further, these gem-alkyl groups may preferably form a cyclopropane or cyclobutane ring which is spiro-linked to the cyclic amine framework. The cyclic amino group further includes a bicyclic amino group formed by crosslinking to 4- to 7-membered cyclic amino groups.

Pojasnjevalni primeri za te ciklične amino skupine, zlasti tiste, ki vsebujejo drugi aminski del, so prikazani spodaj:Explanatory examples for these cyclic amino groups, especially those containing a second amine moiety, are shown below:

d7d7

R«-N IMR⁹VR «-N IMR ⁹ V

Ν^Πΐ* ii r 6 kjer R , R , R , R , ki so lahko enaki ali različni, vsakokrat predstavljajo atom vodika ali alkilno skupino z 1 do 6 atomi ogljika; R', R in R , ki so lahko enaki ali različni, vsakokrat predstavljajo atom vodika ali alkilno skupino z 1 do 6 atomi ogljika, s pridržkom, da so izključeni primeri,R ^ Πΐ * ii r 6 where R, R, R, R, which may be the same or different, each represent a hydrogen atom or an alkyl group of 1 to 6 carbon atoms; R ', R and R, which may be the same or different, in each case represent a hydrogen atom or an alkyl group of 1 to 6 carbon atoms, with the exception that,

8 9 ko R , R in R vsakokrat predstavljajo atom vodika, m ^{7 *} 8 9 when R, R and R each represent a hydrogen atom, m ^{7 *}

9 primer, kjer R in R vsakokrat predstavljata atom vodika9 is an example where R and R each represent a hydrogen atom

- 8 Ο in R predstavlja alkilno skupino z 1 do 6 atomi ogljika;- 8 Ο and R represents an alkyl group of 1 to 6 carbon atoms;

R¹⁰ in R¹¹, ki sta lahko enaka ali različna, vsakokrat predstavljata atom vodika ali alkilno skupino z 1 do 6 atomi ogljika; R in R , ki sta lahko enaka ali različna, vsakokrat predstavljata atom vodika ali alkilno skupino z 1 do 6 atomi ogljika, ali pa sta povezana drug z drugim, da tvorita 3do 6-členski obroč, tvorjen iz metilenskih verig, zvezdica pa označuje center asimetrije.R ¹⁰ and R ¹¹ , which may be the same or different, each represent a hydrogen atom or an alkyl group of 1 to 6 carbon atoms; R and R, which may be the same or different, each represent a hydrogen atom or an alkyl group of 1 to 6 carbon atoms, or bonded together to form a 3 to 6 membered ring formed of methylene chains, with an asterisk marking the center asymmetries.

Primeri za te ciklične amino skupine so 3-aminopirolidinil,Examples of these cyclic amino groups are 3-aminopyrrolidinyl,

3-metilaminopirolidinil, 3-dimetilaminopirolidinil, 3-etilaminopirolidinil, 3-propilaminopirolidinil, 3-izopropilaminopirolidinil, 3-amino-4-metilpirolidinil, 3-amino-5-metilpirolidinil, 3-amino-4,5-dimetilpirolidinil, 3-metilamino-4-metilpirolidinil, 3-metilamino-5-metilpirolidinil, -3-raetilamino-4,5dimetilpirolidinil, 3-dimetilamino-4-metilpirolidinil,3-methylaminopyrrolidinyl, 3-dimethylaminopyrrolidinyl, 3-ethylaminopyrrolidinyl, 3-propylaminopyrrolidinyl, 3-isopropylaminopyrrolidinyl, 3-amino-4-methylpyrrolidinyl, 3-amino-5-methylpyrrolidinyl, 3-amino-4,5-dimethyl-4,5-dimethyl-4,5-dimethyl-4,5-dimethyl 4-methylpyrrolidinyl, 3-methylamino-5-methylpyrrolidinyl, -3-raethylamino-4,5-dimethylpyrrolidinyl, 3-dimethylamino-4-methylpyrrolidinyl,

3- dimetilamino-5-metilpirolidinil, 3-dimetilamino-4,5-dimetilpirolidinil, 3-metilpiperazinil, 4-metilpiperazinil, 3,4-dimetilpiperazinil, 3,5-dimetilpiperazinil, 3,4,5-trimetilpiperazinil,3- dimethylamino-5-methylpyrrolidinyl, 3-dimethylamino-4,5-dimethylpyrrolidinyl, 3-methylpiperazinyl, 4-methylpiperazinyl, 3,4-dimethylpiperazinyl, 3,5-dimethylpiperazinyl, 3,4,5-trimethylpiperazinyl,

4- etil-3,5-dimetilpiperazinil, 4-izopropil-3,5-dimetilpiperazinil, 3-aminometilpirolidinil, 3-metilaminometilpirolidinil,4-ethyl-3,5-dimethylpiperazinyl, 4-isopropyl-3,5-dimethylpiperazinyl, 3-aminomethylpyrrolidinyl, 3-methylaminomethylpyrrolidinyl,

3-(1-amino)etilpirolidinil, 3-(1-metilamino)etilpirolidinil,3- (1-amino) ethylpyrrolidinyl, 3- (1-methylamino) ethylpyrrolidinyl,

3-(1-etilamino)etilpirolidinil, 3-(1-amino)propilpirolidinil,3- (1-ethylamino) ethylpyrrolidinyl, 3- (1-amino) propylpyrrolidinyl,

3-(1-metilamino)propi1piperazinil, 3-aminopirolidinil,3- (1-methylamino) propylpiperazinyl, 3-aminopyrrolidinyl,

3-amino-4,4-dimetilpirolidinil, 7-amino-5-azaspiro/2,4/heptan5- il, 8-amino-6-azaspiro/3,4/-oktan-6-il, 3,4-diazabiciklo/3,2,1/ oktan-3-il, 9-metil-3,9-diazabiciklo/3,2,1/oktan-3-il in 9-etil-3,9-diazabiciklo/3,2,1/oktan-3-il.3-amino-4,4-dimethylpyrrolidinyl, 7-amino-5-azaspiro / 2,4 / heptan5-yl, 8-amino-6-azaspiro / 3,4-octan-6-yl, 3,4-diazabicyclo (3,2,1) octan-3-yl, 9-methyl-3,9-diazabicyclo / 3,2,1 / octan-3-yl and 9-ethyl-3,9-diazabicyclo / 3,2,1 / octan-3-yl.

Struktura ciklične amino skupine v položaju 7 ima velik vpliv na antimikrobno učinkovitost, toksičnost, oralno absorpcijo in na fizikalne lastnosti, kot je npr. vodotopnost. Tako npr. je znano, da imajo kinoloni, substituirani s 3-aminopirolidinilni skupinami, močne antimikrobne spektre proti širokemu območju mikroorganizmov, ki pokriva tako po Gramu pozitivne kot tudi po Gramu negativne bakterije. Nekateri derivati kinolona tega tipa pa so občutljivi na metabolizem ali pa kažejo majhno vodotopnost.The structure of the cyclic amino group at position 7 has a major influence on antimicrobial efficacy, toxicity, oral absorption, and physical properties, such as e.g. water solubility. So e.g. quinolones substituted with 3-aminopyrrolidinyl groups are known to have strong antimicrobial spectra against a wide range of microorganisms, covering both Gram positive and Gram negative bacteria. However, some quinolone derivatives of this type are sensitive to metabolism or exhibit low water solubility.

3-aminopirolidinilne skupine s spiro obročem na atomu ogljika, sosednjem njegovi amino skupini, nudijo derivate kinolona z izboljšano oralno absorpcijo in izboljšano in vivo stabilnostjo proti metabolizmu ob ohranitvi močne antimikrobne učinkovitosti. Spojine tega tipa so se izkazale tudi kot manjši povzročitelji krčev, kar je znan stranski efekt sintetskih antimikrobikov kinolonskega tipa.The 3-aminopyrrolidinyl groups with a spiro ring on the carbon atom adjacent to its amino group offer quinolone derivatives with improved oral absorption and improved in vivo metabolism stability while maintaining strong antimicrobial efficacy. Compounds of this type have also proven to be minor contractors of spasms, which is a known side effect of synthetic quinolone-type antimicrobials.

Nadalje dajejo 3-aminometilpirolidinilne skupine, kjer je amino skupina vezana na pirolidinilno skupino preko atoma ogljika, derivate kinolona, ki kažejo izboljšano antimikrobno učinkovitost proti bakterijam, pozitivnim po Gramu. Posebno kinoloni tega tipa, pri katerih je atom ogljika, ki veže amino s pirolidinilno skupino, substituiran z 1 ali 2 alkilnima skupinama, so se odlikovale po izboljšani oralni absorptivnosti, varnosti in vodotopnosti, v primeri z onimi brez takega ali takih substituentov.Furthermore, 3-aminomethylpyrrolidinyl groups, where the amino group is attached to the pyrrolidinyl group via a carbon atom, give quinolone derivatives exhibiting improved antimicrobial efficacy against Gram-positive bacteria. Particularly quinolones of this type, in which the carbon atom that binds the amino to the pyrrolidinyl group substituted with 1 or 2 alkyl groups, have been distinguished by their improved oral absorption, safety and water solubility, compared to those without such or such substituents.

Dodatno prednostni kot ciklične amino skupine so piperazinski ostanki kot alkilpiperazinski ostanki ter piperazinski ostanki s spiro obročem.Additionally preferred as cyclic amino groups are piperazine residues such as alkylpiperazine residues and piperazine residues with a spiro ring.

Primeri za ciklične amino skupine s substituenti, različnimi od amino skupine, so 3-hidroksipirolidinilna, 3-merkaptopirolidinilna, 3-hidroksi-4-metilpirolidinilna,Examples of cyclic amino groups with substituents other than the amino group are 3-hydroxypyrrolidinyl, 3-mercaptopyrrolidinyl, 3-hydroxy-4-methylpyrrolidinyl,

3-merkapto-4-metilpirolidinilna, morfolinska, tiomorfolinska,3-mercapto-4-methylpyrrolidinyl, morpholine, thiomorpholine,

2-metilmorfolinska, 2-metiltiomorfolinska, 2,6-dimetilmorfolinska, 2,6-dimetiltiomorfolinska, 2,2-dimetilmorfolinska in2-methylmorpholine, 2-methylthiomorpholine, 2,6-dimethylmorpholine, 2,6-dimethylthiomorpholine, 2,2-dimethylmorpholine and

2,2-dimetiltiomorfolinska skupina.2,2-dimethylthiomorpholine group.

Ciklična amino skupina je vezana na položaj 7 ogrodja piridon karboksilne kisline, prednostno na atomu dušika ciklične amino skupine. Seveda pa je lahko vezana tudi na nek drug atom.The cyclic amino group is attached to position 7 of the pyridone carboxylic acid framework, preferably at the nitrogen atom of the cyclic amino group. Of course, it can also be attached to another atom.

Stereoizomerija dela cikličnega amina v položaju 7 je pojasnjena spodaj. V primerih, kjer ima ciklični amin izomere, če ga presnovimo v obliki izomerne zmesi derivata 1-(1,2-cishalogenociklopropil)kinolona, naj bo nastali derivat kinolona zmes diastereomerov, na osnovi eteričnega razmerja z 1,2-cis2-halogenociklopropilno skupino v položaju 1. V teh primerih je torej potrebno, da se presnovi samo enega izmed izomerov izhodnega amina.The stereoisomerism of the moiety of the cyclic amine at position 7 is explained below. In cases where the cyclic amine has isomers, when metabolized in the form of an isomeric mixture of a 1- (1,2-cishalogenocyclopropyl) quinolone derivative, the quinolone derivative should be a mixture of diastereomers based on an ethereal relationship with the 1,2-cis2-halogenocyclopropyl group in position 1. In these cases, therefore, it is necessary to metabolize only one of the isomers of the starting amine.

Funkcionalno skupino ciklične amino skupine v položajuCyclic amino group functional group in position

7, kot amino, hidroksi in tiolno skupino, se da zaščititi z običajno zaščitno skupino pred substitucijo z ogrodjem kinolona. Primeri za take zaščitne skupine vključujejo alkoksi karbonilne skupine, kot so t-butoksikarbonilna in7, such as the amino, hydroxy and thiol groups, can be protected by a conventional protecting group against substitution with the quinolone framework. Examples of such protecting groups include alkoxy carbonyl groups such as t-butoxycarbonyl and

2,2,2-trikloroetoksikarbonilna skupina in podobne; aralkiloksikarbonilne skupine kot benziloksikarbonilna , p-metoksibenziloksikarbonilna, p-nitrobenziloksikarbonilna skupina in podobne; acilne skupine kot acetilna, metoksiacetilna, trifluoroacetilna, kloroacetilna, pivaloilna, formilna, benzoilna skupina in podobne; alkilne ali aralkilne skupine kot t-butilna, benzilna, p-nitrobenzilna, p-metoksibenzilna, trifenilmetilna skupina in podobne; etri kot metoksimetilna, t-butoksimetilna, 2,2,2-trikloroetoksimetilna, tetrahidrofuran2-ilna skupina in podobne; sililne skupine kot trimetilsililna, izopropildimetilsililna, t-butildimetilsililna, t-butildifenilsililna, tribenzilsililna skupina in podobne.A 2,2,2-trichloroethoxycarbonyl group and the like; aralkyloxycarbonyl groups such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl and the like; acyl groups such as acetyl, methoxyacetyl, trifluoroacetyl, chloroacetyl, pivaloyl, formyl, benzoyl groups and the like; alkyl or aralkyl groups such as t-butyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, triphenylmethyl and the like; ethers such as methoxymethyl, t-butoxymethyl, 2,2,2-trichloroethoxymethyl, tetrahydrofuran2-yl group and the like; silyl groups such as trimethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl groups and the like.

1,2-cis-2— halogenociklopropilno skupino v položaju opisujemo spodaj. Uvedba atoma halogena v ciklopropilno skupino, zlasti atoma fluora, pa povzroči zmanjšanje lipofilnosti celotne molekule. Znano je, da se zdravila raje porazdelijo v centralnem živčnem sistemu, ko se njihova lipofilnost povečuje. V tej zvezi daje uvedba 1,2-cis-2-halogenociklopropilne skupine kinolone zmanjšano toksičnostjo, ob ohranitvi odlične antiraikrobne učinkovitosti, v primeri z ustreznimi 1-ciklopropilkinoloni. Atom halogena, ki naj ga uvedemo, vključuje atome fluora in klora, pri čemer je prednosten atom fluora.The 1,2-cis-2-halogenocyclopropyl group in the position is described below. The introduction of a halogen atom into the cyclopropyl group, in particular fluorine atoms, results in a decrease in the lipophilicity of the whole molecule. Medicines are known to prefer distribution in the central nervous system as their lipophilicity increases. In this regard, the introduction of the 1,2-cis-2-halogenocyclopropyl group of quinolones is of reduced toxicity, while maintaining excellent antiraicrobial efficacy, in comparison with the corresponding 1-cyclopropylquinolones. The halogen atom to be introduced includes fluorine and chlorine atoms, the fluorine atom being preferred.

Posebno prednostno je, Particularly preferred is da sta that they are atom atom halogena halogens in del and part piridonkarboksilne kisline v pyridonecarboxylic acids v položaju position cis z cis z ozirom na with regard to ciklopro ciklopro panski obroč. Ne glede na panski ring. Whatever to, ali that, but ima there is 7-ciklična 7-cycle amino amino

skupina stereoizomere ali ne, imajo derivati kinolona s formulo (I) enantiomerne pare, pripisane cis-2-halogenociklopropilnemu delu v položaju 1, kot je pojasnjeno spodaj. Pri kateremkoli izmed teh enantiomerov smo opazili močno aktivnost in veliko varnost.group stereoisomers or not, quinolone derivatives of formula (I) are enantiomeric vapors attributed to the cis-2-halogenocyclopropyl moiety at position 1, as explained below. Strong activity and high safety were observed with any of these enantiomers.

O R’O R '

R¹ OR ¹ O

inand

HOOHOO

Derivati piridonkarboksilne kisline v skladu s predloženim izomom vključujejo vsakokratno prosto kislino, njene kislinske adicijske soli in soli njene karboksilne skupine. Kislinske adicijske soli vključujejo soli anorganskih kislin, npr. hidrokloride, sulfate, nitrate, hidrobromide, hidrojodide in fosfate; soli organskih kislin pa npr. acetate, metansulfonate, benzensulfonate, toluensulfonate, citrate, maleate, fumarate in laktate.Pyridonecarboxylic acid derivatives according to the present invention include, respectively, the free acid, its acid addition salts, and salts of its carboxylic group. Acid addition salts include salts of inorganic acids, e.g. hydrochlorides, sulfates, nitrates, hydrobromides, hydroiodides and phosphates; organic acid salts, e.g. acetates, methanesulfonates, benzenesulfonates, toluenesulfonates, citrates, maleates, fumarates and lactates.

Soli karboksilne skupine so lahko organske ali anorganske ter vključujejo soli alkalijskih kovin, npr. litijeve soli, natrijeve soli in kalijeve soli, soli zemeljskoalkalijskih kovin, npr. magnezijeve in kalcijeve soli; amonijeve soli, trietilaminske soli, N-metilglukamate in tris(hidroksimetil)aminometanske soli.Carboxyl group salts may be organic or inorganic and include alkali metal salts, e.g. lithium salts, sodium salts and potassium salts, alkaline earth metal salts, e.g. magnesium and calcium salts; ammonium salts, triethylamine salts, N-methylglucamates and tris (hydroxymethyl) aminomethane salts.

Nekatere izmed teh prostih kislin in soli lahko obstajajo kot hidrati.Some of these free acids and salts may exist as hydrates.

Zaestrenje dela karboksilne kisline derivatov piridonkarboksilne kisline s formulo (I) daje spojine, ki so koristne kot intermediati za sintezo ali pro-zdravila. Tako npr.The esterification of a carboxylic acid moiety of pyridonecarboxylic acid derivatives of formula (I) provides compounds that are useful as synthesis intermediates or pro-drugs. So e.g.

so alkilestri, benzilestri, alkoksialkilestri, fenilalkilestri in fenilestri koristni kot intermediati za sintezo. Estri, ki se v telesu zlahka razgrade, da tvorijo proste karboksilne kisline, so koristni kot pro-zdravila. Primeri takih estrov so acetoksimetilestri, pivaloiloksimetilestri, etoksikarboniloksiestri, klorovi estri, dimetilaminoetil estri, 5-indanil estri, ftalidinil estri in oksoalkil estri (npr. 5-substituirani 2-okso-1,3-dioksol-4-il-metil estri inalkyl esters, benzyl esters, alkoxyalkyl esters, phenylalkyl esters and phenyl esters are useful as synthesis intermediates. Esters that break down easily in the body to form free carboxylic acids are useful as pro-drugs. Examples of such esters are acetoxymethyl esters, pivaloyloxymethyl esters, ethoxycarbonyloxyesters, chlorine esters, dimethylaminoethyl esters, 5-indanyl esters, phthalidinyl esters and oxoalkyl esters (e.g. 5-substituted 2-oxo-1,3-dioxol-4-yl-methyl-esters

3-acetoksi-2-oksobutil estri).3-acetoxy-2-oxobutyl esters).

Postopek za sintezo derivatov piridon karboksilne kisline s formulo (I), je pojasnjen spodaj, pri čemer vzamemo 112 8 npr. spojino, kjer je A=C-H; R =H; X =X =F; in R~=Et (etilna skupina, v nadaljevanju ista)The process for the synthesis of pyridone carboxylic acid derivatives of formula (I) is explained below, taking 112 8 e.g. a compound wherein A = C-H; R = H; X = X = F; and R ~ = Et (ethyl group, hereinafter the same)

kislina al^ alkalijaacid al ^ alkali

lila, Hib odstranitev zaščitne skupine kislina ali alkalija istočasna odstranitev zaščitne skupinelila, Hib removal of the protecting group acid or alkali simultaneous removal of the protecting group

IVa, IVbIVa, IVb

2 kjer ima R enak pomen kot R , ali ciklična amino skupina, z enako strukturo kot R , le da je zaščitena.2 wherein R has the same meaning as R, or a cyclic amino group, of the same structure as R but protected.

Optično aktiven etil ester 1-(1,2-cis-2-fluorociklopropil) 6,7-difluoro-1,4-dihidro-4-oksokinolin-3-karboksilne kisline (6a) ali (6b) hidroliziramo pri kislih ali alkalnih pogojih, da dobimo prost derivat karboksilne kisline (7a) ali (7b). Prosto kislino (7a) ali (7b) presnovimo s cikličnim aminom R^-H, da dobimo želeno spojino (lila) ali (Illb). Po potrebi odstranimo zaščitno skupino iz nastale spojine ob primernih pogojih, izbranih v odvisnosti od zaščitne skupine, da dobimo želeno spojino (IVa) ali (IVb).1- (1,2-cis-2-fluorocyclopropyl) 6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (6a) or (6b) optically active ethyl ester is hydrolyzed under acidic or alkaline conditions to give the free carboxylic acid derivative (7a) or (7b). The free acid (7a) or (7b) is reacted with the cyclic amine R1-H to give the desired compound (lila) or (Illb). If necessary, the protecting group is removed from the resulting compound under suitable conditions selected depending on the protecting group to give the desired compound (IVa) or (IVb).

Reakcijo substitucije s cikličnim aminom lahko izvedemo v topilu kot dimetilsulfoksidu, piridinu, acetonitrilu in 3-metoksibutanolu, pri temperaturi od sobne temperature do 150 °C, prednostno od 40 do 120 °C, v teku 0,5 do 5 ur, običajno 0,5 do 2 uri.The cyclic amine substitution reaction can be carried out in a solvent such as dimethylsulfoxide, pyridine, acetonitrile and 3-methoxybutanol at a temperature from room temperature to 150 ° C, preferably from 40 to 120 ° C, for 0.5 to 5 hours, typically 0. 5 to 2 p.m.

Alternativno pa spojino (6a) ali (6b) presnovimo s cikličnim aminom pri enakih pogojih, kot je zgoraj navedeno, ter nastalo spojino, (Iia) ali (Ilb), kot je pripravljena, zatem hidroliziramo pri kislih ali alkalnih pogojih, ter po potrebi odstranimo zaščitno skupino, da dobimo želeno spojino (lila) ali (Illb) ali (IVa) ali (IVb).Alternatively, the compound (6a) or (6b) is reacted with the cyclic amine under the same conditions as above, and the resulting compound, (Iia) or (Ilb) as prepared, is then hydrolyzed under acidic or alkaline conditions, and optionally remove the protecting group to give the desired compound (lilac) or (Illb) or (IVa) or (IVb).

Optično aktivni ci3-2-fluorociklopropilamin lahko sintetiziramo kot sledi. 2-fluorociklopropankarboksilno kislino presnovimo z (R)-(+)- oi/ -metilbenzilaminom, da dobimo N-/1-(R)-feniletil/-1,2-cis-fluorociklopropankarboksamidOptically active ci3-2-fluorocyclopropylamine can be synthesized as follows. The 2-fluorocyclopropanecarboxylic acid is reacted with (R) - (+) - oi-methylbenzylamine to give N- / 1- (R) -phenylethyl / -1,2-cis-fluorocyclopropanecarboxamide

- 15 Reakcijo se da izvesti v tetrahldrofuranu v prisotnosti N,Nkarbonildiimidazola. Reakcijo lahko izvedemo tudi v skladu s postopkom mešanega anhidrida, pri katerem raztopimo karboksilno kislino v aprotičnem topilu ter presnovimo s halogenomravljinčnim estrom v prisotnosti baze pri nizkih temperaturah, nakar presnovimo z benzilaminom, da dobimo karboksamid. Nastali karboksamid se da ločiti na vsakega izmed izomerov po kromatografskih tehnikah.- 15 The reaction can be carried out in tetrahydrofuran in the presence of N, Ncarbonyldiimidazole. The reaction may also be carried out in accordance with a mixed anhydride process, in which the carboxylic acid is dissolved in an aprotic solvent and reacted with a halogen ester in the presence of a base at low temperatures, then reacted with benzylamine to give the carboxamide. The resulting carboxamide can be separated on each of the isomers by chromatographic techniques.

Aprotično topilo, ki naj ga uporabimo pri postopku z mešanim anhidridom, ni specifično omejeno in vključuje etre, npr. dietil eter, diizopropil eter, tetrahidrofuran, 1,4-dioksan, in 1,2-dimetoksietan; halogenirane ogljikovodike, npr. diklorometan, kloroform, 1,2-dikloroetan, in 1,1,2,2-tetra kloroetan; aromatske ogljikovodike, npr. benzen, toluen, in ksilen; in alifatske ogljikovodike, npr. pentan, heksan, heptan, in cikloheksan. Običajno uporabljamo izmed njih tetrahidrofuran ali kloroform. Vodo, ki jo vsebuje topilo, katerega naj uporabimo, običajno predhodno odstranimo.The aprotic solvent to be used in the mixed anhydride process is not specifically limited and includes ethers, e.g. diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; halogenated hydrocarbons, e.g. dichloromethane, chloroform, 1,2-dichloroethane, and 1,1,2,2-tetra chloroethane; aromatic hydrocarbons, e.g. benzene, toluene, and xylene; and aliphatic hydrocarbons, e.g. pentane, hexane, heptane, and cyclohexane. Usually tetrahydrofuran or chloroform is used. The water contained in the solvent to be used is usually pre-removed.

Atom halogena v halogenomravljinčnem estru je normalno atom klora. Halogenomravljični ester vključuje metilni, etilni, 2,2,2-trikloroetilni, fenilni, p-nitrofenilni in benzilni ester.The halogen atom in the halogen ester is normally a chlorine atom. The halogenomic ester includes methyl, ethyl, 2,2,2-trichloroethyl, phenyl, p-nitrophenyl and benzyl esters.

Baza, ki naj jo uporabimo, je lahko bodisi organska ali anorganska. Anorganska baza vključuje hidrokside, karbonate in hidrogenkarbonate alkalijskih kovin, npr. litijev hidroksid, natrijev hidroksid, kalijev hidroksid, litijev, natrijev in kalijev karbonat, natrijev hidrogenkarbonat in kalijev hidrogenkarbonat. Organska baza vključuje trialkilamine, npr. trietilamin, tripropilamin, tributilamin, N,N-diizopropil etilamin; dialkilaniline, npr. dietilanilin in dimetilanilin. ter heterociklične spojine, npr. N-metilmorfolin, piridin in N,N-dimetilaminopiridin.The base to be used can be either organic or inorganic. The inorganic base includes hydroxides, carbonates, and alkali metal hydrogen carbonates, e.g. lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium, sodium and potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate. The organic base includes trialkylamines, e.g. triethylamine, tripropylamine, tributylamine, N, N-diisopropyl ethylamine; dialkylanilines, e.g. diethylaniline and dimethylaniline. and heterocyclic compounds, e.g. N-methylmorpholine, pyridine, and N, N-dimethylaminopyridine.

Ločbo karboksamida na optične izomere lahko izvedemo po znanih tehnikah, kot s kromatografijo na koloni silikagela ob normalnem tlaku ali pod tlakom, s preparativno tankoslojno kromatografijo ter tekočinsko kromatografijo z visoko storilnostjo (HPLC). Ločbo na optične izomere se da izvesti tudi po drugih ločilnih tehnikah, ki se jih običajno uporablja, kot sta prekristalizacija in preobarjanje.Separation of carboxamide into optical isomers can be carried out by known techniques, such as by chromatography on a silica gel column under normal pressure or under pressure, preparative thin layer chromatography and high performance liquid chromatography (HPLC). Separation into optical isomers can also be carried out by other separation techniques that are commonly used, such as recrystallization and conversion.

Tako ločen, optično aktiven karboksamid se da prevesti v optično aktivno cis-2-fluorociklopropan karboksilno kislino s hidrolizo. Reakcijo se da izvesti z raztapljanjem karboksami da, npr. v koncentrirani klorovodikovi kislini, čemur sledi segrevanje. Klorovodikovo kislino se da nadomestiti z žveplovo ali solitrno kislino. Lahko uporabimo topilo kot ocetno kislino ali nižji alkohol.Such a separate, optically active carboxamide can be converted to optically active cis-2-fluorocyclopropane carboxylic acid by hydrolysis. The reaction can be carried out by dissolving the carboxamines, e.g. in concentrated hydrochloric acid, followed by heating. Hydrochloric acid can be replaced by sulfuric acid or hydrochloric acid. The solvent may be used as acetic acid or lower alcohol.

Nastalo karboksilno kislino se da takoj pretvoriti s Curtiusovo reakcijo v prisotnosti t-butanola v zaščiten cis-1-(t-butoksikarbonilamino)-2-fluoro-ciklopropan. Reakcijo se da izvesti prikladno z uporabo difenilfosforilazida, le da sinteza intermediarne azidne spojine ni omejena na to, uporabimo pa lahko splošne metode sinteze.The resulting carboxylic acid can be immediately converted by Curtius reaction in the presence of t-butanol into protected cis-1- (t-butoxycarbonylamino) -2-fluoro-cyclopropane. The reaction can be conveniently carried out using diphenylphosphorylase, except that synthesis of the intermediate azide compound is not limited thereto, and general synthesis methods can be used.

Nastali, optično aktivni derivat cis-2-fluoro-ciklopropil amina, se da uporabiti pri pripravi derivata kinolona s cis17 fluoro-ciklopropilno skupino v položaju 1, kot en sam izomer. Derivat kinolona v skladu s predloženim izumom se da tedaj dobiti z reakcijo tega izomera s cikličnim aminom, kot je opisano zgoraj.The resulting optically active cis-2-fluoro-cyclopropyl amine derivative can be used in the preparation of a quinolone derivative with the cis17 fluoro-cyclopropyl group at position 1 as a single isomer. The quinolone derivative of the present invention can then be obtained by reacting this isomer with a cyclic amine as described above.

Derivati piridon karboksilne kisline v skladu s predloženim izumom kažejo močno antimikrobno učinkovitost in se jih da zato uporabiti kot zdravila za ljudi in živali, npr. ribe, kot poljedelske kemikalije in živilske konzervanse.The pyridone carboxylic acid derivatives of the present invention exhibit potent antimicrobial efficacy and can therefore be used as medicines for humans and animals, e.g. fish, such as agricultural chemicals and food preservatives.

Doza derivatov piridonkarboksilne kisline, namenjena za uporabo kot humano zdravilo, je v območju 50 mg do 1 g, prednostno od 100 do 300 mg, dnevno za odraslega. Doza, namenjena za uporabo kot veterinarsko zdravilo, je na splošno v območju 1 do 200 mg, prednostno 5 do 100 mg, na kg telesne mase dnevno, čeprav je lahko večja ali manjša, v odvisnosti od namena dajanja (terapevtska ali preventivna uporaba itd.), vrste in velikosti živali, tipa patogenskega organizma in simptomov. Zgoraj navedeno dnevno dozo se da porazdeliti na 2 do 4 doze dnevno. Po potrebi lahko dnevna doza nekoliko odstopa od zgoraj navedenega območja.The dose of pyridonecarboxylic acid derivatives for human use is in the range of 50 mg to 1 g, preferably 100 to 300 mg, daily for an adult. The dose intended for use as a veterinary medicinal product is generally in the range of 1 to 200 mg, preferably 5 to 100 mg, per kg body weight per day, although it may be greater or less, depending on the purpose of administration (therapeutic or preventive use, etc.). ), the species and size of the animal, the type of pathogen and the symptoms. The above daily dose can be divided into 2 to 4 doses per day. If necessary, the daily dose may deviate slightly from the above range.

Derivati piridonkarboksilne kisline v smislu predloženega izuma so učinkoviti proti raznovrstnim mikroorganizmom, ki povzročajo razne infekcijske bolezni in so primerni za zdravljenje ali olajšanje in/ali preprečenje bolezni, ki jih povzročajo taki patogeni.The pyridonecarboxylic acid derivatives of the present invention are effective against a variety of microorganisms that cause various infectious diseases and are suitable for treating or alleviating and / or preventing diseases caused by such pathogens.

Pojasnjevalni primeri za bakterije ali bakterijam podobne mikroorganizme, proti katerim so derivati piridonkarbo ksilne kisline v smislu izuma učinkoviti, so Staphylo- 18 coccus sp., Streptococcus pyogenes, Streptococcus Haemolyticus, enterococci, Streptococcus pneumoniae, Peptostreptococcus sp., Neisseria gonorrhoeae, Escherichia coli, Citrobacter sp., Shigella sp., Klebsiella pneumoniae, Enterobacter sp., Serratia sp., Proteus sp., Pseudomonas aeruginosa, Haemophilus influenzae, Acinetobacter sp., Campylobacter sp., in Chlamidiae.Explanatory examples of bacteria or bacterial-like microorganisms against which pyridonecarboxylic acid derivatives of the invention are effective are Staphylo-18 coccus sp., Streptococcus pyogenes, Streptococcus Haemolyticus, enterococci, Streptococcus pneumoniae, Peptostorheriaocococaeaeococaeaeococaea Citrobacter sp., Shigella sp., Klebsiella pneumoniae, Enterobacter sp., Serratia sp., Proteus sp., Pseudomonas aeruginosa, Haemophilus influenzae, Acinetobacter sp., Campylobacter sp., And Chlamidiae.

Primeri za bolezni, ki jih povzročajo ti patogeni, vključujejo folikulitis, furunkulozo, karbunkulozo, erizipel, flegmono, limfangiitis/limfadenitis, felon (absces na prstni blazinici), subkutani absces, spiradenitis, akne konglobata, infekcijski aterom, pirianalni absces, mastadenitis, površinske sekundarne infekcije po travmi, opeklini ali kirurški travmi, faringolaringitis, akutni bronhitis, ton.zilitis, kronični bronhitis, bronhiektaze, difuzni panbronhiolitis, sekundarne infekcije kroničnih respiratornih obolenj, pnevmonijo, pielonefritis, cistitis, prostatitis, epididimitis, gonokokusni uretritis, ne-gonokokusni eritritis, holecistitis, holangiitis, bacilno dizenterijo, enteritis, adneksitis, intrauterine infekcije, bartolinitis, blefaritis, hordeolum, dakriocistitis tarzadenitis, keratohelkozo, otitis media, sinuzitis, paradentitis, perikoronitis, cirkumkoronitis, gnatitis, peritonitis, endokarditis, septikemijo, meningitis in kožne infekcije.Examples of diseases caused by these pathogens include folliculitis, furunculosis, carbunculosis, erysipelas, phlegmon, lymphangiitis / lymphadenitis, felon (abscess on the finger pad), subcutaneous abscess, spiradenitis, acne of globules, infectious atheroma, mastitis, pyrian secondary infections after trauma, burns or surgical trauma, pharyngolaryngitis, acute bronchitis, tonsilitis, chronic bronchitis, bronchiectasis, diffuse panbronchiolitis, secondary infections of chronic respiratory diseases, pneumonia, pyelonephritis, cystitis, prostatitis, epidocitis, epidocitis, epidocitis , cholecystitis, cholangiitis, bacillary dysentery, enteritis, adnexitis, intrauterine infections, bartolinitis, blepharitis, hordeolum, dacryocystitis tarzadenitis, keratohelcosis, otitis media, sinusitis, paradentitis, pericoronitis, circulitis, gnatitis, peritonitis, coronitis, peritonitis, peritonitis.

Primeri za mikroorganizme, občutljive na spojine v smislu izuma, ki povzročajo veterinarske infekcijske bolezni, vključujejo perutninske, kot so Escherichia sp., Salmonella sp., Pasteurella sp., Haemophilus sp.,Examples of microorganisms sensitive to the compounds of the invention causing veterinary infectious diseases include poultry such as Escherichia sp., Salmonella sp., Pasteurella sp., Haemophilus sp.,

Bordetella sp.,Bordetella sp.,

Staphylococcus sp., in Mycoplasma sp. specifični primeri za veterinarske bolezni, ki jih povzročajo ti mikroorganizmi, vključujejo kolibacilozo, pullorum bolezen, ptičjo paratifozo, perutninsko kolero, infekcijsko korizo, stafilokokusne infekcije in mikoplazmične bolezni; nadalje prašičje, kot so kolibaciloza, malmoneloza, pasteureloza, hemofilusna infekcija, atropični rinitis, eksudativni epidermitis in mikloplazmične bolezni. Goveji, kot so kolibaciloza, salmoneloza, hemoragič na septikemija, mikoplazmične bolezni, goveja nalezljiva plevropnevnomija in goveji mastitis; pasje, kot je koriformna sepsa, salmoneloza, hemoragična septikemija, piometra in cistitis; ter mačje, kot so hemoragični plevritis, cistitis, kronični rinitis, hemofilusna infekcija, diareja pri mladih mačkah in mikoplazmične bolezni.Staphylococcus sp., And Mycoplasma sp. specific examples of veterinary diseases caused by these micro-organisms include colibacillosis, pullorum disease, avian paratyphosis, poultry cholera, infectious maize, staphylococcal infections and mycoplasma diseases; further pigs such as colibacillosis, malmonellosis, pasteurellosis, haemophilus infection, atropic rhinitis, exudative epidermitis, and mycoplasmic diseases. Bovine, such as colibacillosis, salmonellosis, hemorrhagic on septicemia, mycoplasma diseases, bovine infectious pleuropneumonia and bovine mastitis; canines such as coriform sepsis, salmonellosis, hemorrhagic septicemia, pyometra and cystitis; and feline, such as hemorrhagic pleurisy, cystitis, chronic rhinitis, haemophilus infection, diarrhea in young cats, and mycoplasma diseases.

Spojino v smislu predloženega izuma se da formulirati v antimikrobne pripravke, v ustrezni dozirni obliki, na način dajanja, izbran po običajnih metodah priprave. Dozirna oblika za oralno dajanje vključuje tablete, praške, granule, kapsule, raztopine, sirupe, eliksire in oljne ali vodne suspenzije. Injekcije lahko vsebujejo poleg učinkovite sestavine tudi stabilizatorje, antiseptike in topilna sredstva. Raztopino, ki lahko vsebuje take dodatke, damo v posodo in nadalje lahko raztopino podvržemo liofilizaciji ali podobnemu, da pripravimo trdne pripravke, ki se jih da raztopiti pri uporabi. Posoda lahko vsebuje eno samo dozo ali več doz.The compound of the present invention can be formulated into antimicrobial preparations, in a suitable dosage form, in a route of administration selected by conventional methods of preparation. The dosage form for oral administration includes tablets, powders, granules, capsules, solutions, syrups, elixirs and oily or aqueous suspensions. Injections may contain, in addition to the effective ingredient, stabilizers, antiseptics and solvents. A solution that may contain such additives is placed in a container and further the solution may be subjected to lyophilization or the like to produce soluble, soluble preparations when used. The container may contain a single dose or several doses.

Dozirne oblike za zunanje dejanje vključujejo raztopine suspenzije, emulzije, mazila, gele, kreme, losione in razpršila.Dosage forms for external action include solutions of suspension, emulsions, ointments, gels, creams, lotions and sprays.

Pri pripravi trdnih pripravkov se da učinkovino pomešati s primerno izbranimi, farmacevtsko sprejemljivimi dodatki, kot so polnila, snovi za povečanje volumna, veziva, dezintegra torji, pospeševalci raztapljanja, omočila in maziva.In the preparation of solid preparations, the active ingredient may be admixed with suitably selected, pharmaceutically acceptable additives such as fillers, volume enhancers, binders, disintegrators, solubilizers, wetting agents and lubricants.

Tekoči pripravki, vključujejo raztopine, suspenzije in emulzije. Lahko vsebujejo dodatke, kot so stabilizatorji za suspenzijo in emulgatorji.Liquid preparations include solutions, suspensions and emulsions. They may contain additives such as suspension stabilizers and emulsifiers.

Spojino v smislu predloženega izuma lahko dajemo živalim oralno bodisi direktno ali primešano h krmi, ali pa njeno raztopino dajemo bodisi direktno ali primešano k vodi ali krmi. Spojino lahko dajemo tudi neoralno, npr. z injekcijo.The compound of the present invention can be administered to animals orally either directly or mixed with feed, or a solution thereof either directly or mixed with water or feed. The compound can also be administered orally, e.g. by injection.

Spojino v smislu izuma lahko formuliramo v pripravke za živali, kot so praški, fine granule, solubilizirani praški, sirupi, raztopine in injekcije, z običajno uporabljenimi preparativnimi metodami.The compound of the invention can be formulated into animal preparations such as powders, fine granules, solubilized powders, syrups, solutions and injections, using commonly used preparative methods.

Primeri za formulacije so navedeni v nadaljevanju, vendar samo v pojasnjevalne namene, nikakor pa ne za omejitev.Examples of formulations are given below, but for illustrative purposes only and not by way of limitation.

PRIMERI ZA FORMULACIJO ŠT. 1EXAMPLES FOR FORMULATION NO. 1

Kapsula:Capsule:

Spojina primera 8 Example 8 compound 100,0 100,0 mg mg Koruzni škrob Corn starch 23,0 23.0 mg mg Kalcijeva karboksimetil celuloza Calcium carboxymethyl cellulose 22,5 22.5 mg mg Hidroksipropilmetil celuloza Hydroxypropylmethyl cellulose 3,0 3.0 mg mg Magnezijev stearat Magnesium stearate 1,5 1.5 mg mg skupno: total: 150,0 150,0 mg mg PRIMER ZA FORMULACIJO FORMULATION EXAMPLE ŠT. 2 NO. 2 Raztopin_a:Solutions _a : Spojina primera 7 Compound of Example 7 1 1 do 10 to 10 g Mr Rücker Ocetna kislina ali natrijev hidroksid Acetic acid or sodium hydroxide 0,5 0.5 do 2 to 2 g Mr Rücker Etil p-hidroksibenzoat Ethyl p-hydroxybenzoate 0,1 0.1 g Mr Rücker Očiščena voda Purified water 88,9 88,9 do to 98,4 98.4 g Mr Rücker

skupno: 100 gtotal: 100 g

PRIMERI ZA FORMULACIJO ŽT. 3EXAMPLES FOR THE FORMULATION OF ŽT. 3

Prah za primešanje h krmi:Feed powder for mixing:

Spojina primera 6Compound of Example 6

Koruzni škrobCorn starch

Lah no brezvodna kremenična kislina do 10 g 88,5 do 98,5 gLightly anhydrous silicic acid up to 10 g 88.5 to 98.5 g

0,5 g skupno: 100 g0.5 g total: 100 g

Predloženi izum sedaj podrobneje pojasnjujemo z naslednjimi primeri in referenčnimi primeri, vendar je treba razumeti, da s tem ne mislimo omejiti predloženega izuma nanje. Referenčni primeri opisujejo sinteze optično aktivnih ogrodij iz optično aktivne cis-2-fluoro-ciklopropan karboksilne kisline.The present invention is now explained in more detail with the following examples and reference examples, but it should be understood that we do not mean to limit the present invention to them. Reference examples describe syntheses of optically active cis-2-fluoro-cyclopropane carboxylic acid frameworks.

Antimikrobno učinkovitost optično aktivnih spojin, pripravljenih v primerih, smo ovrednotili v skladu s standardno metodo, določeno v Nippon Kagakuryoho gakkai, in dobljeni rezultati so prikazani v spodnji tabeli 1, izraženi kot minimalna inhibitorska koncentracija (MIC: pg/ml).The antimicrobial efficacy of the optically active compounds prepared in the examples was evaluated according to the standard method set out in Nippon Kagakuryoho gakkai and the results obtained are shown in Table 1 below, expressed as minimum inhibitory concentration (MIC: pg / ml).

REFERENČNI PRIMER 1REFERENCE EXAMPLE 1

N-/1-(R)-feniletil/-1,2-cis-2-fluorociklopropan-karboksamid (2a, 2b);N- [1- (R) -phenylethyl] -1,2-cis-2-fluorocyclopropane-carboxamide (2a, 2b);

1-1. Karbonildiimidazolna metoda:1-1. Carbonyldiimidazole Method:

En gram cis-2-fluorociklopropankarboksilne kisline smo raztopili v 30 ml tetrahidrofurana (THF), in dodali 1,78 g N,N’-karbonildiimidazola, nakar smo zmes mešali 1 uro pri sobni temperaturi. Raztopini smo dodali 1,45 g (R) - (+) -«L-metilbenzilamina in z mešanjem nadaljevali še 2 uri. Topilo smo odstranili ob zmanjšanem tlaku in ostanek ekstrahirali s kloroformom. Ekstrakt smo zapored izprali z 10 %-no vodno raztopino citronske kisline in vodo ter sušili nad brezvodnim natrijevim sulfatom. Topilo smo odstranili ob zmanjšanem tlaku. Iz preostale viskozne oljnate snotfi smo izolirali vsakega izmed izomerov s HPLC, pri spodaj prikazanih pogojih. Vsakega izmed izomerov smo prekristalizirali iz diizopropiletra da smo dobili naslovno spojino (2a) ali (2b).One gram of cis-2-fluorocyclopropanecarboxylic acid was dissolved in 30 ml of tetrahydrofuran (THF), and 1.78 g of N, N'-carbonyldiimidazole were added, and the mixture was stirred for 1 hour at room temperature. 1.45 g (R) - (+) -? L-methylbenzylamine was added to the solution and stirred for 2 hours. The solvent was removed under reduced pressure and the residue was extracted with chloroform. The extract was washed successively with 10% aqueous citric acid and water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. Each of the isomers was isolated from the remaining viscous oily snotfi by HPLC under the conditions shown below. Each of the isomers was recrystallized from diisopropylether to give the title compound (2a) or (2b).

Pogoji pri HPLC:HPLC conditions:

KolonaColumn

Kagaku) etil acetat -THF (9:1 volumsko) 9.0 ml/minKagaku) ethyl acetate-THF (9: 1 by volume) 9.0 ml / min

TopiloSolvent

PretokFlow

Retenzijski Čas: 11 min, za spojino min. za spojino (^2b)Retention Time: 11 min, for compound min. for compound ( ^2b )

Spojina (2a):Compound (2a):

Tališče:Melting point:

108°C108 ° C

Elementna analiza za C₁₂H₁₄FNO:Elemental analysis for C ₁₂ H ₁₄ FNO:

Izrač. (%)j C 69.55; H 6.81; N 6.76Calc. (%) j C 69.55; H, 6.81; N, 6.76

Ugot.. (%): C 69.31; H 7.01; N 6.65 [a]_D; +61.96° (c=0.965, kloroform) ¹H-NMR (CDC1₃) 6 ppm:Found .. (%): C 69.31; H 7.01; N, 6.65 [a] _D ; + 61.96 ° (c = 0.965, chloroform) ¹ H-NMR (CDCl ₃ ) 6 ppm:

0.92-1.34 (2H, m), 1.50 (3H, d, J=7Hz), 1.501.96 (IH, m), 4.68 (IH, dm, J=64Hz), 5.14 (IH, m), 7.40 (5H, s)0.92-1.34 (2H, m), 1.50 (3H, d, J = 7Hz), 1.501.96 (1H, m), 4.68 (1H, dm, J = 64Hz), 5.14 (1H, m), 7.40 (5H , s)

Fizikalno-kemijske lastnosti spojine (2b):Physicochemical properties of compound (2b):

Tal.: 102°CM.p .: 102 ° C

Elementna analiza za: C₁₂H₁₄FNO:Elemental analysis for: C ₁₂ H ₁₄ FNO:

Izrač.: (%): C 69.55; H 6.81; N 6.76 Ugot.: (%): C 69.45; H 6.87; *N 6.70 [a]_D: +143.61° (c=0.830, kloroform) ¹H-NMR (CDC1₃) δ ppm:Calc .: (%): C 69.55; H, 6.81; N 6.76 Found: (%): C 69.45; H, 6.87; * N 6.70 [a] _D : + 143.61 ° (c = 0.830, chloroform) ¹ H-NMR (CDCl ₃ ) δ ppm:

0.98=1.34 (2H, m), 1.52 (3H, d, J=7Hz), 1.641.96 (IH, m), 4.58 (IH, dm, J=66Hz), 5.24 (IH, m), 7.40 (5H, m)0.98 = 1.34 (2H, m), 1.52 (3H, d, J = 7Hz), 1.641.96 (1H, m), 4.58 (1H, dm, J = 66Hz), 5.24 (1H, m), 7.40 (5H) , m)

1-2. Metoda z mešanim anhidridom1-2. The mixed anhydride method

V 50 ml tetrahidrofurana smo raztopili 4,19 g 2-fluoroci klopropankarboksilne kisline (ois-trans zmes) in 4,07 g trietilamina, nakar smo raztopino ohladili na -10 °C. Dodali smo ji raztopino 4,73 g etilkloroformata v 20 ml tetrahidrofurana in zmes mešali 10 minut. Raztopini smo nato dokapavali raztopino 4,88 g (R)-( + )-clj-metil-benzilamina v 30 ml tetrahi drofurana pri tej temperaturi, nakar smo zmes mešali 15 ur pri sobni temperaturi. Topilo smo odstranili ob zmanjšanem tlaku in ostanek ekstrahirali z benzenom. Ekstrakt smo zapored izprali z 10 %-no vodno raztopino citronske kisline,4.19 g of clopropanecarboxylic acid (ois-trans mixture) and 4.07 g of triethylamine were dissolved in 50 ml of tetrahydrofuran and then the solution was cooled to -10 ° C. A solution of 4.73 g of ethylchloroformate in 20 ml of tetrahydrofuran was added and the mixture was stirred for 10 minutes. A solution of 4.88 g of (R) - (+) -cyl-methyl-benzylamine in 30 ml of tetrahydrofuran at this temperature was then added dropwise to the solution, then the mixture was stirred at room temperature for 15 hours. The solvent was removed under reduced pressure and the residue was extracted with benzene. The extract was washed successively with 10% aqueous citric acid,

N vodno raztopino natrijevega hidroksida in vodo ter sušili nad brezvodnim natrijevim sulfatom. Topilo smo odstranili ob zmanjšanem tlaku ter nastalo, bledo rumeno, oljnato snov smo očistili s kromatografijo na koloni silikagela, ob uporabi mešanega topila benzen/etilacetat kot eluenta za vsako izmed naslovnih spojin (2a) in (2b).N aqueous sodium hydroxide solution and water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the resulting pale yellow oily material was purified by silica gel column chromatography using a benzene / ethyl acetate mixed solvent as eluent for each of the title compounds (2a) and (2b).

REFERENČNI PRIMER 2 (+)-cis-2-fluoroclklopropankarboksilna kislina (3a):REFERENCE EXAMPLE 2 (+) - cis-2-fluorocyclopropanecarboxylic acid (3a):

V 15 ml koncentrirane klorovodikove kisline smo raztopili 530 mg amidne spojine (2a), kot je pripravljena v referenčnem primeru 1, nakar smo raztopino segrevali 5 tfr ob mešanju pri 100 do 110 °C. Reakcijski zmesi smo dodali 20 ml vode ter zmes ekstrahirali z etilacetatom. Ekstrakt smo nato ekstrahirali z vodno raztopino natrijevega hidrogenkarbonata in ta vodni ekstrakt smo izprali z etilacetatom. Vodni ekstrakt smo uravnali na pH 5 s koncentrirano klorovodikovo kislino in ekstrahirali z etilacetatom. Ekstrakt smo sušili nad brezvodnim natrijevim sulfatom in topilo odstranili ob zamnjšanem tlaku, da smo dobili naslovno spojino (3a) kot bledo rumeno olje.530 mg of the amide compound (2a) was dissolved in 15 ml of concentrated hydrochloric acid as prepared in Reference Example 1, and then the solution was heated to 5 tfr with stirring at 100-110 ° C. 20 ml of water were added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was then extracted with aqueous sodium hydrogen carbonate solution and this aqueous extract was washed with ethyl acetate. The aqueous extract was adjusted to pH 5 with concentrated hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent removed under reduced pressure to give the title compound (3a) as a pale yellow oil.

[a]_D: -23.13° (c=1.020, kloroform) ¹ H-NMR (CDC1₃) δ ppm:[α] _D : -23.13 ° (c = 1.020, chloroform) ¹ H-NMR (CDCl ₃ ) δ ppm:

1.0-1.42 (IH, m), 1.60-2.10 (2H, m), 4.82 (IH, dm, J=65Hz), 12.0 (IH, s)1.0-1.42 (1H, m), 1.60-2.10 (2H, m), 4.82 (1H, dm, J = 65Hz), 12.0 (1H, s)

REFERENČNI PRIMER 3 (+)-cis-2-fluorociklopropankarboksilna kislina (3b)^; REFERENCE EXAMPLE 3 (+) - cis-2-fluorocyclopropanecarboxylic acid (3b) ^;

V 30 ral koncentrirane klorovodikove kisline smo raztopil 1,65 g amidne spojine (2b), kot je pripravljena v referenčnem primeru 1, nakar smo raztopino segrevali 5 ur ob mešanju pri 100 do 110 °C. pH reakcijske zmesi smo uravnali na vrednost med 8 in 9 z natrijevim hidrogenkarbonatom, nakar smo izprali s kloroformom. pH vodnega sloja smo uravnali na 4 s koncentri rano klorovodikovo kislino in ekstrahirali z etilacetatom. Ekstrakt smo sušili nad brezvodnim natrijevim sulfatom in topilo odstranili ob zmanjšanem tlaku, da smo dobili naslovno spojino (3t>) kot bledo rumeno olje.1.65 g of the amide compound (2b) was dissolved in 30 acre of concentrated hydrochloric acid as prepared in Reference Example 1, and then the solution was heated for 5 hours with stirring at 100-110 ° C. The pH of the reaction mixture was adjusted to a value between 8 and 9 with sodium hydrogen carbonate and then washed with chloroform. The pH of the aqueous layer was adjusted to 4 with hydrochloric acid concentrated and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent removed under reduced pressure to give the title compound (3t>) as a pale yellow oil.

[a]_D: +21.56° (c=1.113, kloroform) l-H-NMR (CDC1₃) δ ppm:[a] _D : + 21.56 ° (c = 1.113, chloroform) 1 H-NMR (CDCl ₃ ) δ ppm:

1.0-1.42 (IH, m), 1.56-1.98 (2H, ra,, 4.76 (IH, dni, J=66Hz), 11-32 (IH, s)1.0-1.42 (1H, m), 1.56-1.98 (2H, ra, 4.76 (1H, days, J = 66Hz), 11-32 (1H, s)

REFERENČNI PRIMER 4 (+)-cis-1-(t-butoksikarbonilamino)-2-fluorociklopropan (4a):REFERENCE EXAMPLE 4 (+) - cis-1- (t-butoxycarbonylamino) -2-fluorocyclopropane (4a):

V 5 ml t-butanola smo raztopili 200 mg karboksilne kisline (3a), kot smo jo dobili pri referenčnem primeru 2, 603 mg difenilfosforilazida in 203 rag trietilamina, nakar smo raztopino segrevali ob refluksu 4,5 ur. Po odstranitvi topila ob zmanjšanem tlaku smo preostanek ekstrahirali s kloroformom. Ekstrakt smo zapored izprali z 10 %-no vodno raztopino citronske kisline, 2 %-no vodno raztopino natrijevega hidroksida in vodo, ter sušili nad brezvodnim natrijevim sulfatom. Topilo smo odstranili ob zmanjšanem tlaku ter preostanek podvrgli kromatografiji na koloni silikagela, ob uporabi kloroforma kot eluenta, da smo dobili naslovno spojino (4a) kot brezbarvne kristale.Dissolve 200 mg of carboxylic acid (3a) in 5 ml of t-butanol as in Reference Example 2, 603 mg of diphenylphosphorylazide and 203 rag of triethylamine, and then reflux for 4.5 hours. After removal of the solvent under reduced pressure, the residue was extracted with chloroform. The extract was washed sequentially with 10% aqueous citric acid, 2% aqueous sodium hydroxide and water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was chromatographed on a silica gel column using chloroform as eluent to give the title compound (4a) as colorless crystals.

Tališče: 73°C (a]_D: +65.57° (c=0.610, kloroform) ^H-NMR (CDC1₃) 5 ppm:Melting point: 73 ° C (a] _D : + 65.57 ° (c = 0.610, chloroform) 1 H-NMR (CDCl ₃ ) 5 ppm:

0.6-1.3 (2H, m), 1.46 (9H, s), 2.48-2.74 (IH, m), 4.62 (IH, dm. J=65Hz), 4.6-5.1 (IH, široko).0.6-1.3 (2H, m), 1.46 (9H, s), 2.48-2.74 (1H, m), 4.62 (1H, dm. J = 65Hz), 4.6-5.1 (1H, broad).

REFERENČNI PRIMER 5 (-)-cis-1-(t-butoksikarbonilamino)-2-fluorociklopropan (4b):REFERENCE EXAMPLE 5 (-) - cis-1- (t-butoxycarbonylamino) -2-fluorocyclopropane (4b):

V 6 ml t-butanola smo dali 265 mg karboksilne kisline (3b), kot smo jo dobili pri referenčnem primeru 3, 800 mg difenilfosforilazida in 270 mg trietilamina. Raztopino smo pustili reagirati in jo obdelali na enak način, kot v referenčnem primeru 4, da smo dobili naslovno spojino (4b).In 6 ml of t-butanol 265 mg of carboxylic acid (3b) was obtained as in Reference Example 3, 800 mg of diphenylphosphorylazide and 270 mg of triethylamine. The solution was allowed to react and treated in the same manner as in Reference Example 4 to give the title compound (4b).

Tališče: 63°C [a]_D: -60.27 (c=0.740, kloroform)Melting point: 63 ° C [a] _D : -60.27 (c = 0.740, chloroform)

- 27a¹H-NMR (CDC1₃) δ ppm:- 27a ¹ H-NMR (CDCl ₃ ) δ ppm:

0.66-1.3 (2H, m), 1.46 (9H, s), 2.48-2.74 (IH, m), 4.58 (IH- dm, J=65Hz), 4.6-5.1 (IH, široko)0.66-1.3 (2H, m), 1.46 (9H, s), 2.48-2.74 (1H, m), 4.58 (1H- dm, J = 65Hz), 4.6-5.1 (1H, broad)

REFERENČNI PRIMER 6 (-)-etil-2-/(1,2-cis-2-fluorociklopropan-1-il)aminometilen/3-okso-3-(2,4,5-trifluorofenil)propionat (5a):REFERENCE EXAMPLE 6 (-) - Ethyl-2 - / (1,2-cis-2-fluorocyclopropan-1-yl) aminomethylene / 3-oxo-3- (2,4,5-trifluorophenyl) propionate (5a):

Etil 2,4,5-trifluorobenzoilacetat (234 mg), 2 ml etil ortoformata in 4 ml acetanhidrida smo pomešali in zmes segrevali 2 uri ob mešanju na 110 do 120 °C. Topilo smo odstranili ob zmanjšanem tlaku in ostanek raztopili v 10 ml diklorometana.Ethyl 2,4,5-trifluorobenzoyl acetate (234 mg), 2 ml of ethyl orthoformate and 4 ml of acetanhydride were mixed and the mixture heated for 2 hours with stirring at 110-120 ° C. The solvent was removed under reduced pressure and the residue dissolved in 10 ml of dichloromethane.

Spojino (4a), dobljeno pri referenčnem primeru 4 (167 mg), in 5 ml trifluoroocetne kisline smo pomešali in zmes mešali 20 minut pri sobni temperaturi, nakar smo koncentrirali do suhega ob zmanjšanem tlaku, pri čemer smo nastali amin trifluoroacetat uporabili brez čiščenja). Ostanek smo raztopili v 10 ml diklorometana in ohladili na -10 °C. Nato smo ji dokapavali raztopino 230 mg trietilamina in 10 ml diklorometana Nato smo zmesi dokapavali zgoraj pripravljeno raztopino diklorometana, čemur je sledilo mešanje čez noč pri sobni temperaturi. Topilo smo uparili do suhega ob zmanjšanem tlaku ter preostanek podvrgli kromatografiji na koloni silikagela, ob uporabi mešanega topila benzen/etilacetat (2:1 vol.). Rumeno oljnato snov smo dobili iz eluenta po odstranitvi topila. Produkt smo prekristalizirali iz diizopropil etra/n-heksana, da smo dobili naslovno spojino (5a) kot brezbarvne kristale.Compound (4a) obtained in Reference Example 4 (167 mg) and 5 ml of trifluoroacetic acid were mixed and the mixture stirred for 20 minutes at room temperature, then concentrated to dryness under reduced pressure, using the resulting amine trifluoroacetate without purification). . The residue was dissolved in 10 ml of dichloromethane and cooled to -10 ° C. A solution of 230 mg of triethylamine and 10 ml of dichloromethane was then added dropwise to the mixture. The above dichloromethane solution was added dropwise, followed by stirring overnight at room temperature. The solvent was evaporated to dryness under reduced pressure and the residue was chromatographed on a silica gel column using a benzene / ethyl acetate (2: 1 vol.) Mixed solvent. The yellow oily substance was obtained from the eluent after removal of the solvent. The product was recrystallized from diisopropyl ether / n-hexane to give the title compound (5a) as colorless crystals.

Tališče: 69-70°C (aJ_D: -10.29° (c=J.O88, kloroform)Melting point: 69-70 ° C (aJ _D : -10.29 ° (c = J.O88, chloroform)

REFERENČNI PRIMER 7 (+)-etil-2-/(1,2-cis-2-fluorociklopropan-1-il)aminometilen/-3okso-3-(2,4,5-trifluorofenil)propionat (5b) :REFERENCE EXAMPLE 7 (+) - Ethyl-2 - [(1,2-cis-2-fluorocyclopropan-1-yl) aminomethylene] -3-oxo-3- (2,4,5-trifluorophenyl) propionate (5b):

Pomešali smo etil 2,4,5-trifluorobenzoilacetat (337. mg) ml etilortofor mata in 4 ml acetanhidrida, nakar smo zmes segrevali 2 uri ob mešanju na 110 do 120 °C. Topilo smo odstranili ob zmanjšanem tlaku in preostanek raztopili v 10 ml diklorometana.Ethyl 2,4,5-trifluorobenzoyl acetate (337 mg) ml of ethylorthophore mat and 4 ml of acetanhydride were mixed, and the mixture was heated for 2 hours with stirring at 110-120 ° C. The solvent was removed under reduced pressure and the residue dissolved in 10 ml of dichloromethane.

Spojino (4b), kot smo jo dobili pri referenčnem primeru 5 (240 mg), in 5 ml trifluoroocetne kisline, smo pomešali in zmes mešali pri sobni temperaturi 1 uro, čemur je sledilo koncentriranje ob zmanjšanem tlaku (amin trifluoroacetat smo uporabili brez čiščenja). Preostanek smo raztopili v 10 ml diklorometana in raztopino ohladili na -10 °C. Raztopino 230 mg trietilamina v 10 ml diklorometana smo dodali po kapljicah ter zgoraj pripravljeno raztopino d iklorometana smo nadalje dodajali k zmesi, čemur je sledilo mešanje preko noči pri sobni temperaturi. Topilo smo odstranili ob zmanjšanem tlaku in preostanek podvrgli kromatografiji na koloni silikagela, ob uporabi mešanega topila benzena in etilacetata (2:1 vol). Rumeno oljnato snov smo dobili iz eluenta po odstranitvi topila. Prekristalizacija iz diizopropil etra/n-heksana je dala naslovno spojino (5b) kot brezbarv_ne kristale.Compound (4b) as obtained in Reference Example 5 (240 mg) and 5 ml of trifluoroacetic acid were stirred and the mixture stirred at room temperature for 1 hour, followed by concentration under reduced pressure (amine trifluoroacetate was used without purification) . The residue was dissolved in 10 ml of dichloromethane and cooled to -10 ° C. A solution of 230 mg of triethylamine in 10 ml of dichloromethane was added dropwise and the dichloromethane solution prepared above was further added to the mixture, followed by stirring overnight at room temperature. The solvent was removed under reduced pressure and the residue was chromatographed on a silica gel column using a mixed solvent of benzene and ethyl acetate (2: 1 vol). The yellow oily substance was obtained from the eluent after removal of the solvent. Recrystallization from diisopropyl ether / n-hexane gave the title compound (5b) as colorless crystals _{do not.}

II

Tališče: 69-70°C [a]_D; +12.09 (c=0.645, kloroform)Melting point: 69-70 ° C [a] _D ; +12.09 (c = 0.645, chloroform)

REFERNČNI PRIMER 8 (+)-6,7-difluoro-1-(1,2-cis-2-fluoroclklopropil)-4-okso1,4-dihidrokinolin-3-karboksilat (6a):REFERENCE EXAMPLE 8 (+) - 6,7-difluoro-1- (1,2-cis-2-fluorocyclopropyl) -4-oxo,4,4-dihydroquinoline-3-carboxylate (6a):

V 15 ml brezvodnega dioksana smo raztopili 180 mg spojine (5a), kot je dobljena pri referenčnem primeru 6, ter dodali k raztopini 200 mg 60 %-nega natrijevega hidrida, čemur je sledilo mešanje 2 uri pri sobni temperaturi. Reakcijsko zmes smo dodali k 10 %-ni vodni raztopini citronske kisline, čemur je sledilo koncentriranje ob zmanjšanem tlaku. Preostanek smo ekstrahirali s kloroformom in ekstrakt sušili nad brezvodnim natrijevim sulfatom. Topilo smo odstranili ob zmanjšanem tlaku. Preostanek smo očistili s preparativno TLC na silikagelu ob uporabi benzena/etil acetata (1:2 vol.) kot razvijalnega topila, da smo dobili naslovno spojino (6a) kot brezbarvne kristale .Dissolve 180 mg of compound (5a) in 15 ml of anhydrous dioxane as obtained in Reference Example 6 and add 200 mg of 60% sodium hydride to the solution, followed by stirring for 2 hours at room temperature. The reaction mixture was added to a 10% aqueous citric acid solution, followed by concentration under reduced pressure. The residue was extracted with chloroform and the extract was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by preparative TLC on silica gel using benzene / ethyl acetate (1: 2 vol.) As the developing solvent to give the title compound (6a) as colorless crystals.

Tališče: 231-232°C [<x)_D: +27.20° (c=0.610, kloroform) ¹H-NMR (CDC1₃) 5 ppm:Melting point: 231-232 ° C [<x] _D : + 27.20 ° (c = 0.610, chloroform) ¹ H-NMR (CDCl ₃ ) 5 ppm:

1.20 (3H, t, J=7Hz), 1.6-1.9 (2H, m), 3.28-3.56 (IH, m), 4.42 (2H, q, J=7Hz), 5.11 (IH, dm,1.20 (3H, t, J = 7Hz), 1.6-1.9 (2H, m), 3.28-3.56 (1H, m), 4.42 (2H, q, J = 7Hz), 5.11 (1H, dm.

J=63Hz), 7.60 (IH, dd, J=llHz & 7Hz), 8.28 (IH, dd, J=10Hz & 11Hz), 8.58 (IH, s)J = 63Hz), 7.60 (1H, dd, J = 11Hz & 7Hz), 8.28 (1H, dd, J = 10Hz & 11Hz), 8.58 (1H, s)

REFERENČNI PRIMER 9 (-)-etil 6,7-difluoro-1-(1,2-cis-2-fluorociklopropil)-4-okso1,4-dihidrokinolin-3-karboksilat (6b):REFERENCE EXAMPLE 9 (-) - Ethyl 6,7-difluoro-1- (1,2-cis-2-fluorocyclopropyl) -4-oxo 1,4,4-dihydroquinoline-3-carboxylate (6b):

V 15 ml brezvodnega dioksana smo raztopili 267 mg spojine (5b), kot smo jo dobili pri referenčnem primeru 7, ter ji dodali 200 mg 60 %-nega natrijevega hidrida, nakar smo zmes mešali 2 dni pri sobni temperaturi. Reakcijsko zmes smo dodali k 10 %-ni vodni raztopini citronske kisline, čemur je sledilo koncentriranje ob zmanjšanem tlaku. Preostanek smo ekstrahirali s kloroformom in sušili nad brezvodnim natrijevim sulfatom. Topilo smo odstranili ob zmanjšanem tlaku ter preostanek očistili s preparativno TLC na silikagelu, ob uporabi benzena/etilacetata (1:2 vol.).«-kot razvijalnega topila, da smo dobili naslovno spojino (6b) kot brezbarvne kristale .In 15 ml of anhydrous dioxane dissolved 267 mg of compound (5b) as obtained in Reference Example 7 and 200 mg of 60% sodium hydride was added thereto, and the mixture was stirred for 2 days at room temperature. The reaction mixture was added to a 10% aqueous citric acid solution, followed by concentration under reduced pressure. The residue was extracted with chloroform and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by preparative TLC on silica gel using benzene / ethyl acetate (1: 2 vol.). "- as a developing solvent to give the title compound (6b) as colorless crystals.

Tališče: 226-227°C [a]_D: -31.36° (c=0.610, kloroform)Melting point: 226-227 ° C [a] _D : -31.36 ° (c = 0.610, chloroform)

J-H-NMR (CDC1₃) δ ppm:1 H-NMR (CDCl ₃ ) δ ppm:

1.22 {3H, t, J=7Hz), 1.5-1.9 (2H, m), 3.26-3.52 (IH, m), 4.40 (2H, q, J=7Hz), 5.10 (IH, dm,1.22 {3H, t, J = 7Hz), 1.5-1.9 (2H, m), 3.26-3.52 (1H, m), 4.40 (2H, q, J = 7Hz), 5.10 (1H, dm.

J=63Hz), 7.58 (IH, dd, J=llHz & 7Hz), 8.26 (1Ή, dd, J=10Hz & 11Hz), 8.55 (IH, s)J = 63Hz), 7.58 (1H, dd, J = 11Hz & 7Hz), 8.26 (1Ή, dd, J = 10Hz & 11Hz), 8.55 (1H, s)

REFERENČNI PRIMER 10 (+)-6,7-difluoro-1-(1,2-cis-2-fluorociklopropil)-4-okso-1, 4dihidrokinolin-3-karboksilna kislina (7a);REFERENCE EXAMPLE 10 (+) - 6,7-Difluoro-1- (1,2-cis-2-fluorocyclopropyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (7a);

V 15 ml koncentrirane klorovodikove kisline smo raztopili 106 mg estra (6a), kot smo ga dobili v referenčnem primeruDissolve 106 mg of ester (6a) in 15 ml of concentrated hydrochloric acid as obtained in the reference example.

8, nakar smo raztopino segrevali 2 uri ob mešanju pri 100 do 110 °C. Reakcijski zmesi smo dodali 15 ml vode ter oborino zbrali s filtracijo, da smo dobili naslovno spojino (7a) kot brezbarvne kristal e.8, after which the solution was heated for 2 hours with stirring at 100-110 ° C. 15 ml of water were added to the reaction mixture and the precipitate was collected by filtration to give the title compound (7a) as a colorless crystal e.

Tališče: 265-270°C [ct]_D: +3.66° (c=0.383, ocetna kislina) ¹H-NMR (CDC1₃) δ ppm:Melting point: 265-270 ° C [ct] _D : + 3.66 ° (c = 0.383, acetic acid) ¹ H-NMR (CDCl ₃ ) δ ppm:

1.75-1.95 (2H, m), 3.58 (IH, m), 5.18 (IH, dm,1.75-1.95 (2H, m), 3.58 (1H, m), 5.18 (1H, dm,

J=64Hz), 7.82 (IH, dd, J=12Hz, & 7Hz), 8.37 (IH, dd, J=18Hz & 8Hz), 8.94 (IH, s)J = 64Hz), 7.82 (1H, dd, J = 12Hz, & 7Hz), 8.37 (1H, dd, J = 18Hz & 8Hz), 8.94 (1H, s)

REFERENČNI PRIMER 11 (-)-6,7-difluoro-1-(1,2-cis-2-fluorociklopropil)-4-okso-1,4dihidrokinolin-3-karboksilna kislina (7b):REFERENCE EXAMPLE 11 (-) - 6,7-Difluoro-1- (1,2-cis-2-fluorocyclopropyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (7b):

V 10 ml koncentrirane klorovodikove kisline smo raztopili 150 mg ekstra (6b), kot smo ga dobili v referenčnem primeruDissolve 150 mg of extra (6b) in 10 ml of concentrated hydrochloric acid as was obtained in the reference case

9, nakar smo raztopino segrevali 2 uri ob mešanju na 110 °C. Reakcijski zmesi smo dodali 20 ml vode in zmes ekstrahirali s kloroformom. Ekstrakt smo sušili nad brezvodnim natrijevim sulfatom in topilo odstranili ob zmanjšanem tlaku. Preostanek smo prekristalizirali iz etanola, da smo dobili naslovno spojino (7b) kot brezbarvne kristale.9, after which the solution was heated for 2 hours with stirring at 110 ° C. 20 ml of water were added to the reaction mixture and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent removed under reduced pressure. The residue was recrystallized from ethanol to give the title compound (7b) as colorless crystals.

Tališče: 261-264°C [<x]_D; -4.08° (c=0.343, ocetna kislina) ^H-NMR (CDC1₃) δ ppm:Melting point: 261-264 ° C [<x] _D ; -4.08 ° (c = 0.343, acetic acid) 1 H-NMR (CDCl ₃ ) δ ppm:

1.75-1.95 (2H, m), 3.58 (IH, m), 5.18 (IH, dm, J=64Hz), 7.82 (IH, dd, ,J=12Hz & 7Hz), 8.37 (IH, dd, J=12Hz δ 8 Hz), 8.94 (IH s)1.75-1.95 (2H, m), 3.58 (1H, m), 5.18 (1H, dm, J = 64Hz), 7.82 (1H, dd, J = 12Hz & 7Hz), 8.37 (1H, dd, J = 12Hz δ 8 Hz), 8.94 (1H s)

PRIMER 1EXAMPLE 1

7-/3-(S)-t-butoksikarbonilamino-1-pirolidinil/-6-fluoro1—(1,2-cis-2-fluorociklopropil)-4-okso-1, 4-dihidrokinolin-3-karboksilna kislina (8a):7- [3- (S) -t-Butoxycarbonylamino-1-pyrrolidinyl] -6-fluoro- (1,2-cis-2-fluorocyclopropyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (8a ):

mg karboksilne kisline (7a), kot smo jo dobili pri referenčnem primeru 10, 150 mg (S)-3-(t-butoksikarbonilamino)pirolidina, 200 mg trietilamina in 20 ml acetonitrila smo pomešali ter zmes segrevali 4 ure ob refluksu. Topilo smo odstranili ob zmanjšanem tlaku in preostanku dodali 10 %-no vodno raztopino citronske kisline, čemur je sledila ekstrakcija s kloroformom. Ekstrakt smo sušili nad brezvodnim natrijevim sulfatom in topilo odstranili ob zmanjšanem tlaku. Preostanek smo prekristalizirali iz etil acetata, da smo dobili naslovno spojino (8a) kot rumene kristale.mg of carboxylic acid (7a) as obtained in Reference Example 10, 150 mg (S) -3- (t-butoxycarbonylamino) pyrrolidine, 200 mg triethylamine and 20 ml acetonitrile were stirred and the mixture heated at reflux for 4 hours. The solvent was removed under reduced pressure and a 10% aqueous citric acid solution was added to the residue, followed by extraction with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent removed under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (8a) as yellow crystals.

Tališče: 236-239°C [a]_D: +1.0°(c=0.200, kloroform) ¹H-NMR (CDC1₃) δ ppmsMelting point: 236-239 ° C [a] _D : + 1.0 ° (c = 0.200, chloroform) ¹ H-NMR (CDCl ₃ ) δ ppms

1.2-1.7 (2H, m), 1.46 (9H, s), 1.7-1.9 (IH, m),1.2-1.7 (2H, m), 1.46 (9H, s), 1.7-1.9 (1H, m),

2.0-2.36 (IH, m), 3.3-4.0 (5H, m), 4.2-4.4 (IH, m), 5.06 (IH, dm, J=68Hz), 6.68 (IH, d, J=7Hz),2.0-2.36 (1H, m), 3.3-4.0 (5H, m), 4.2-4.4 (1H, m), 5.06 (1H, dm, J = 68Hz), 6.68 (1H, d, J = 7Hz).

7.84 (IH, d, J=14Hz), 8.46 (IH, s)7.84 (1H, d, J = 14Hz), 8.46 (1H, s)

PRIMER 2EXAMPLE 2

7-/3-(S)-t-butoksikarbonilamino-1-pirolidinil/-6-fluoro1-(1,2-cis-2-fluorociklopropil)-4-okso-1,4-dihidrokinolin-3-karboksilna kislina (8b):7- [3- (S) -t-butoxycarbonylamino-1-pyrrolidinyl] -6-fluoro-1- (1,2-cis-2-fluorocyclopropyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (8b ):

- 34 Karboksilno kislino, kot smo jo dobili v referenčnem primeru 11 (7b) (112 mg), 200 mg (S)-3—(t-butoksikarbonilamino)pirolidina, 220 mg trietilamina, in 15 ml acetonitrila smo pomešali ter zmes segrevali 4 ure ob refluksu. Topilo smo odstranili ob zmanjšanem tlaku ter ostanku dodali 10 %-no vodno raztopino citronske kisline, čemur je sledila ekstrakcija s kloroformom. Ekstrakt smo sušili nad brezvodnim natrijevim sulfatom in topilo odstranili ob zmanjšanem tlaku. Preostanek smo prekristalizirali iz etilacetata, da smo dobili naslovno spojino (8b) kot rumene kristale.- 34 Carboxylic acid as obtained in Reference Example 11 (7b) (112 mg), 200 mg (S) -3- (t-butoxycarbonylamino) pyrrolidine, 220 mg triethylamine, and 15 ml acetonitrile were mixed and the mixture warmed 4 hours at reflux. The solvent was removed under reduced pressure and a 10% aqueous citric acid solution was added to the residue, followed by extraction with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent removed under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (8b) as yellow crystals.

Tališče: 242-243°C (a]_D: -4.0°(c=0.448, kloroform) ¹H-NMR (CDC1₃) δ ppm:Melting point: 242-243 ° C (a) _D : -4.0 ° (c = 0.448, chloroform) ¹ H-NMR (CDCl ₃ ) δ ppm:

1.0-1.7 (2H, m), 1.40 (9H, s), 1.6-1.8 (IH, ra),1.0-1.7 (2H, m), 1.40 (9H, s), 1.6-1.8 (1H, ra),

1.9-2.1 (IH, m), 3.3-3.9 (5H, m), 4.2-4.5 (IH, ra), 5.00 (IH, dm, J=68Hz), 6.58 (IH, d, J=7Hz),1.9-2.1 (1H, m), 3.3-3.9 (5H, m), 4.2-4.5 (1H, ra), 5.00 (1H, dm, J = 68Hz), 6.58 (1H, d, J = 7Hz),

7.72 (IH, d, J=14Hz1. 8.32 (IH, s)7.72 (1H, d, J = 14Hz1. 8.32 (1H, s)

PRIMER 3EXAMPLE 3

7-/3-(S)-amino-1-pirolidinil/-6-fluoro-1-(1,2-cis-2fluorociklopropil)-4-okso-1,4-dihidrokinolin-3karboksilna kislina (9a):7- [3- (S) -amino-1-pyrrolidinyl] -6-fluoro-1- (1,2-cis-2fluorocyclopropyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (9a):

V 10 ml trifluoroocetne kisline smo raztopili 80 mg karboksilne kisline (8a), kot smo jo dobili pri primeru 1.Dissolve 80 mg of carboxylic acid (8a) in 10 ml of trifluoroacetic acid as was obtained in Example 1.

Po 20 minutah mešanja smo reakcijsko zmes uparili ob zmanjšanem tlaku do suhega. Preostanku smo dodali 5 ml vode in nadalje dodajali 1 N vodno raztopino natrijevega hidroksida, da smo raztopili preostanek. pH vodnega sloja smo uravnali na 7,5 z 1 N klorovodikovo kislino, čemur je sledila ekstrakcija s kloroformom. Ekstrakt smo sušili nad brezvodnim natrijevim sulfatom in topilo odstranili ob zmanjšanem tlaku. Prekristalizacija ostanka iz etanola je dala naslovno spojino kot brezbarvne kristale.After stirring for 20 minutes, the reaction mixture was evaporated under reduced pressure to dryness. 5 ml of water was added to the residue and further added 1 N aqueous sodium hydroxide solution to dissolve the residue. The pH of the aqueous layer was adjusted to 7.5 with 1 N hydrochloric acid, followed by extraction with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent removed under reduced pressure. Recrystallization of the residue from ethanol gave the title compound as colorless crystals.

Tališče: 248-252°C [α]_θ: -31.35° (c=0.370, IN NaOH vadna*d?assfe&pina) ¹H-NMR (CDC1₃) δ ppm:Melting point: 248-252 ° C [α] _θ : -31.35 ° (c = 0.370, IN NaOH exercise * d? Assfe & pin) ¹ H-NMR (CDC1 ₃ ) δ ppm:

1.52-1.68 (2H, m), 1.68-1.80 (IH, m), 2.05-Ϊ.15 (IH, m), 3.13-3.22 (IH, m), 3.25-3.45 (2H, m),1.52-1.68 (2H, m), 1.68-1.80 (1H, m), 2.05-Ϊ.15 (1H, m), 3.13-3.22 (1H, m), 3.25-3.45 (2H, m).

3.45-3.65 (3H, m), 5.12 (IH, dm, J=65Hz), 6.58 (IH, d, J=7Hz), 7.58 (IH, d, J=14Hz), 8.29 (IH, s)3.45-3.65 (3H, m), 5.12 (1H, dm, J = 65Hz), 6.58 (1H, d, J = 7Hz), 7.58 (1H, d, J = 14Hz), 8.29 (1H, s)

PRIMER 4EXAMPLE 4

7-/3-(S)-amino-1-pirolidinil/-6-fluoro-1-(1,2-cis-2-fluorociklopropil)-4-okso-1,4-dihidrokinolin-3-karboksilna kislina (9a):7- [3- (S) -amino-1-pyrrolidinyl] -6-fluoro-1- (1,2-cis-2-fluorocyclopropyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (9a ):

V 10 ml trifluoroocetne kisline smo dali 80 mg karboksilne kisline (8b), kot smo dobili v primeru 2. Po 20 minutah mešanja smo reakcijsko zmes uparili do suhega ob zmanjšanem tlaku.Preostanku smo dodali 5 ml vode ter nadalje dodajali 1 N vodno raztopino natrijevega hidroksida, da smo raztopili preostanek. pH vodnega sloja smo uravnali na 7,5 z 1 N klo- 36 rovodikovo kislino in temu je sledila ekstrakcija s kloroformom Ekstrakt smo sušili nad brezvodnim natrijevim sulfatom in iz njega odstranili topilo ob zmanjšanem tlaku. Prekristalizacija preostanka iz etanola je dala naslovno spojino (9b) kot brezbarvne kristale.To 10 ml of trifluoroacetic acid was added 80 mg of carboxylic acid (8b) as was obtained in Example 2. After 20 minutes of stirring, the reaction mixture was evaporated to dryness under reduced pressure. of hydroxide to dissolve the residue. The pH of the aqueous layer was adjusted to 7.5 with 1 N hydrochloric acid followed by extraction with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent removed under reduced pressure. Recrystallization of the residue from ethanol gave the title compound (9b) as colorless crystals.

Tališče: 236-240°C [a]_D: +23.72 (c=0.413, IN NaOH vodna raztopina) ^H-NMR (CDC1₃) δ ppm:Melting point: 236-240 ° C [a] _D : +23.72 (c = 0.413, IN NaOH aqueous solution) 1 H-NMR (CDCl ₃ ) δ ppm:

1.55-1.69 (2H, m), 1.69-1.77 (IH, m), 2.07-2.15 (IH, m), 3.15-3.22 (IH, m), 3.37-3.47 (2H, m),1.55-1.69 (2H, m), 1.69-1.77 (1H, m), 2.07-2.15 (1H, m), 3.15-3.22 (1H, m), 3.37-3.47 (2H, m).

3.52-3.58 (2H, m), 3.58-3.66 (IH, m), 5.13 (IH, dm, J=65Hz), 6.62 (IH, d, J⁼7Hz), 7.61 (IH, d,3.52-3.58 (2H, m), 3.58-3.66 (1H, m), 5.13 (1H, dm, J = 65Hz), 6.62 (1H, d, J ⁼ 7Hz), 7.61 (1H, d.

J=14Hz), 8.3_D LIH, s) ,J = 14Hz), 8.3_D LIH, s),

REFERENČNI PRIMER 12 ^{* 7} (-)-etil-2-//1,2-cis-2-fluoro-1-ciklopropil)amino/-metilen/3-okso-3-(3-kloro-2,4,5-trifluorofenil)propionat (lOa):REFERENCE EXAMPLE 12 ^{* 7} (-) - Ethyl-2 - // 1,2-cis-2-fluoro-1-cyclopropyl) amino] -methylene / 3-oxo-3- (3-chloro-2,4,5 -trifluorophenyl) propionate (10a):

Etil 3-kloro-2,4,5-trifluorobenzoilacetat (1,5 g), 6 ml etil ortoforfoata, ^{in 10} acetanhidrida smo pomešali in zmes segrevali na 110 do 120 °C 1,5 ure ob mešanju. Reakcijsko zmes smo koncentrirali do suhega ob zmanjšanem tlaku, nakar smo preostanek raztopili v 5 ml diklorometana.Ethyl 3-chloro-2,4,5-trifluorobenzoyl acetate (1.5 g), 6 ml ethyl orthophorophoate, ^{and 10} acetanhydride were mixed and the mixture was heated to 110-120 ° C for 1.5 hours with stirring. The reaction mixture was concentrated to dryness under reduced pressure and the residue was dissolved in 5 ml of dichloromethane.

ml trifluoroocetne kisline smo ohladili z ledom ter 480 mg (+)-cis-1-(t-butoksikarobnilamino)-2-fluorociklopropana (4a) raztopili v njej. Raztopino smo mešali pri sobni temperaturi 20 minut, čemur je sledilo uparjenje ob zmanjšanem tlaku do suhega. Preostanek smo suspendirali v 10 ml diklorometana in dodali 3 ml trietilamina ob hlajenju z ledom.ml of trifluoroacetic acid was cooled with ice and dissolved in 480 mg of (+) - cis-1- (t-butoxycarbonylamino) -2-fluorocyclopropane (4a). The solution was stirred at room temperature for 20 minutes, followed by evaporation under reduced pressure to dryness. The residue was suspended in 10 ml of dichloromethane and 3 ml of triethylamine were added while cooling with ice.

Po 20 minutah mešanja smo k temu dodali zgoraj pripravljeno raztopino diklorometana, nakar smo zmes mešali 1 uro. Reakcijsko zmes smo izprali z vodo in sušili nad brezvodnim natrijevim sulfatom. Topilo smo odstranili ob zmanjšanem tlaku. Preostanek smo podvrgli flash (bliskovito hitri) kolonski kromatografiji ob uporabi mešanega topila benzen/etilacetat (5:1 vol.) kot eluenta. Topilo smo odstranili ob zmanjšanem tlaku in preostanek sprali z diizopropiletrom, da smo dobili 620 mg naslovne spojine (10a).After stirring for 20 minutes, the dichloromethane solution prepared above was added thereto and the mixture was stirred for 1 hour. The reaction mixture was washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was subjected to flash column flash chromatography using a benzene / ethyl acetate (5: 1 vol.) Mixed solvent as eluent. The solvent was removed under reduced pressure and the residue was washed with diisopropylether to give 620 mg of the title compound (10a).

Tališče: 98-100°C (a]p: -6.66° (c=0.998, kloroform)Melting point: 98-100 ° C (a) p: -6.66 ° (c = 0.998, chloroform)

Elementna analiza za C₁₅H₁₂C1F₄NO₃:Elemental analysis for C ₁₅ H ₁₂ C1F ₄ NO ₃ :

Izrač. (%): C 49.26; H 3.31; N 3.83 Ugot. (%) :* C 49.39; H 3.22; N 3.86 ^•H-NMR (CDC1₃) 6 ppm;Calc. (%): C 49.26; H, 3.31; N 3.83 Found. (%): * C 49.39; H, 3.22; N 3.86 1 H-NMR (CDCl ₃ ) 6 ppm;

0.95, 1.08 (3H, 1:2.5, vsak t, J=7HZ), 1.0-1.5 (2H, m), 2.8-3.15 (IH, m), 4.03, 4.07 (2H,0.95, 1.08 (3H, 1: 2.5, each t, J = 7HZ), 1.0-1.5 (2H, m), 2.8-3.15 (1H, m), 4.03, 4.07 (2H,

1:2.5, vsak q, J=7Hz), 4.78 (IH, dm, J=65Hz),1: 2.5, each q, J = 7Hz), 4.78 (1H, dm, J = 65Hz),

7.13 (IH, ddd, J=5.9, 8.6, & 9.5Hz), 8.20, 8.25 (IH, 1:2.5, vsak d, J=14HZ)7.13 (1H, ddd, J = 5.9, 8.6, & 9.5Hz), 8.20, 8.25 (1H, 1: 2.5, each d, J = 14HZ)

- 38 REFERENČNI PRIMER 13 (+)-2-//1,2-cis-2-fluoro-1-ciklopropil)amino/metilen/3-okso-3-(3-kloro-2,4_>5-trifluorofenil)propionat (10b):- 38 REFERENCE EXAMPLE 13 (+) - 2 - // 1,2-cis-2-fluoro-1-cyclopropyl) amino / methylene / 3-oxo-3- (3-chloro-2,4 _> 5-trifluorophenyl) propionate (10b):

Etil 3-kloro-2,4,5-trifluorobenzoilacetat (1,5 g), 6 ml etil ortoformata, in 10 ml acet anhidrida smo pomešali ter zmes segrevali 1,5 ur ob mešanju na 110 do 120 °C. Reakcijsko zmes smo koncentrirali do suhega ob zmanjšanem tlaku in preostanek raztopili v 10 ml diklorometana. 10 ml trifluoroocet ne kisline smo ohladili z ledom ter v njej raztopili 1,12 g (-)-cis-1-(t-butoksikarbonilamino)-2-fluorociklopropana (4b), po 20 urnem mešanju pri sobni temperaturi smo zmes uparili do suhega ob zmanjšanem tlaku. Preostanek smo suspendirali v 20 ml diklorometana ter suspenziji dodali 2,0 g trietilamina ob hlajenju z ledom. K temu smo nato dodali .zgoraj pripravljeno raztopino diklorometana, Čemur je sledilo 1 urno mešanje. Reakcijsko zmes smo izprali z vodo in sušili nad brezvodnim natrijevim sulfatom. Topilo smo odstranili ob zmanjšanem tlaku. Preostanek smo podvrgli flash kolonski kromatografiji, nakar smo eluirali z mešanim topilom benzen/etilaceta (4:1 vol.). Iz eluenta smo odstranili topilo ob zmanjšanem tlaku. Preostanek smo izprali z diizopropiletrom/n-heksanom, da smo dobili 1,74 g kristalov naslovne spojine (10 b).Ethyl 3-chloro-2,4,5-trifluorobenzoyl acetate (1.5 g), 6 ml ethyl orthoformate, and 10 ml acetal anhydride were mixed and the mixture heated for 1.5 hours with stirring at 110-120 ° C. The reaction mixture was concentrated to dryness under reduced pressure and the residue dissolved in 10 ml of dichloromethane. 10 ml of trifluoroacetic acid were cooled with ice and 1.12 g (-) - cis-1- (t-butoxycarbonylamino) -2-fluorocyclopropane (4b) dissolved therein, and the mixture was evaporated to dryness after 20 hours at room temperature. at reduced pressure. The residue was suspended in 20 ml of dichloromethane and 2.0 g of triethylamine was added to the suspension while cooling with ice. To this was then added a dichloromethane solution prepared above, followed by stirring for 1 hour. The reaction mixture was washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was subjected to flash column chromatography, then eluted with a benzene / ethyl acetate mixed solvent (4: 1 vol.). The solvent was removed from the eluent under reduced pressure. The residue was washed with diisopropylether / n-hexane to give 1.74 g of the crystals of the title compound (10 b).

Tališče: 99-100°C [a]_n: +6.70° (c=0.895, kloroform)Melting point: 99-100 ° C [a] _n : + 6.70 ° (c = 0.895, chloroform)

Izrač. (%): C 49.26; H 3.31; N 3.83 Ugot. (%): C 49.41; H 3.60; N 4.06 ¹H-NMR (CDC1₃) δ ppm:Calc. (%): C 49.26; H, 3.31; N 3.83 Found. (%): C 49.41; H, 3.60; N 4.06 ¹ H-NMR (CDCl ₃ ) δ ppm:

7.13 (IH,, ddd, J=5.9, 8.6, δ 9.5Hz), 8.20, 8.25 (IH, 1:2.5, vsak d, J=14HZ)7.13 (1H, ddd, J = 5.9, 8.6, δ 9.5Hz), 8.20, 8.25 (1H, 1: 2.5, each d, J = 14HZ)

REFERENČNI PRIMER 14 (+)-etil 8-kloro-6,7-difluoro-1-(1,2-cis-2-fluoro-1-ciklopropil)-4-okso-1,4-dihidrokinolin-3-karboksilat (1 la):REFERENCE EXAMPLE 14 (+) - Ethyl 8-chloro-6,7-difluoro-1- (1,2-cis-2-fluoro-1-cyclopropyl) -4-oxo-1,4-dihydroquinoline-3-carboxylate ( 1 la):

V 7 ml brezvodnega dioksana smo raztopili 620 mg spojine (10a), kot smo jo pripravili pri referenčnem primeru 12, ter raztopini dodali 80 mg 60 %-nega natrijevega hidrida, čemur je sledilo 1 urno mešanje pri sobni temperaturi. K reakcijski zmesi smo dodali etil acetat in zmes zapored izprali z 10 %-no vodno raztopino citronske kisline in vodo. Organski sloj smo sušili nad brezvodnim natrijevim sulfatom in topilo odstranili iz njega ob zmanjšanem tlaku. Preostanek smo izprali z n-heksanom, da smo dobili 551 mg naslovne spojine (11a) kot brezbarvne kristale.620 mg of compound (10a) as prepared in Reference Example 12 was dissolved in 7 ml of anhydrous dioxane, and 80 mg of 60% sodium hydride was added to the solution, followed by stirring at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture and the mixture was washed successively with 10% aqueous citric acid solution and water. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed from it under reduced pressure. The residue was washed with n-hexane to give 551 mg of the title compound (11a) as colorless crystals.

Tališče: 18l-184°C [a]_D: +45.1° (c=1.18, kloroform)Melting point: 18l-184 ° C [a] _D : + 45.1 ° (c = 1.18, chloroform)

Elementna analiza za 'C₁₅H₁₂ClF₄NO₃:Elemental analysis for 'C ₁₅ H ₁₂ ClF ₄ NO ₃ :

Izrač. (%): C 52.12; H 3.21; N 4.05 Ugot. (%): C 52.09; H 3.33; N 4.01 ¹H-NMR (CDC1₃) δ ppm:Calc. (%): C 52.12; H, 3.21; N 4.05 Found. (%): C 52.09; H, 3.33; N 4.01 ¹ H-NMR (CDCl ₃ ) δ ppm:

1.40 (3H, t, J=7HZ), 1.4-1.9 (2H, m), 4.08 (IH, m), 4.39 (2H, q, J=7HZ), 4.90 (IH, dm, J=65Hz),1.40 (3H, t, J = 7HZ), 1.4-1.9 (2H, m), 4.08 (1H, m), 4.39 (2H, q, J = 7HZ), 4.90 (1H, dm, J = 65Hz).

8.24 (IH, dd, J=10 & 11 Hz)8.24 (1H, dd, J = 10 & 11 Hz)

REFERENČNI PRIMER 15 (-)-etil 8-kloro-6,7-difluoro-1 - (1,2-cis-2-fluoro-1-ciklopropil)4-okso-1,4-dihidrokinolin-3-karboksilat (11b):REFERENCE EXAMPLE 15 (-) - Ethyl 8-chloro-6,7-difluoro-1- (1,2-cis-2-fluoro-1-cyclopropyl) 4-oxo-1,4-dihydroquinoline-3-carboxylate (11b ):

V 10 ml brezvodnega dioksana smo suspendirali 560 mg 60 %-nega natrijevega hidrida, katerega smo bili 2-krat izprali z brezvodnim n-heksanom. Suspenzijo smo dodali k raztopini 1,70 g spojine (10b) v 20 ml brezvodnega dioksana, čemur je sledilo 2 urno mešanje pri sobni temperaturi. Topilo smo odstranili ob zmanjšanem tlaku in k preostanku dodali 0,1 N klorovodikovo kislino. Oborjene kristale smo zbrali s filtracijo izprali zapored z vodo in dietiletrom in sušili ob zmanjšanem tlaku, da smo dobili 1,44 g naslovne spojine (11b) kot brezbarvne kristale.560 mg of 60% sodium hydride was suspended in 10 ml of anhydrous dioxane, which was washed twice with anhydrous n-hexane. The suspension was added to a solution of 1.70 g of compound (10b) in 20 ml of anhydrous dioxane, followed by stirring at room temperature for 2 hours. The solvent was removed under reduced pressure and 0.1 N hydrochloric acid was added to the residue. The precipitated crystals were collected by filtration, washed successively with water and diethyl ether and dried under reduced pressure to give 1.44 g of the title compound (11b) as colorless crystals.

Tališče: 174°C [a]_D: -45.3° (c=1.05, 'kloroform)Melting point: 174 ° C [a] _D : -45.3 ° (c = 1.05, 'chloroform')

Elementna analiza za C₁₅H₁₁C1F₄NO₃:Elemental analysis for C ₁₅ H ₁₁ C1F ₄ NO ₃ :

Izrač. (%): C 52.12; H 3.21; N 4.05Calc. (%): C 52.12; H, 3.21; N, 4.05

Ugot. (%): C 51.80; H 3.45? N 4.15 ¹H-NMR (CDClj) δ ppm:Found. (%): C 51.80; H 3.45? N 4.15 ¹ H-NMR (CDCl 3) δ ppm:

8.24 (IH, dd, J=10 & 11 Hz)8.24 (1H, dd, J = 10 & 11 Hz)

IR(KBr); v_max cm^-1: 3100, 2998, 1731, 1638, 1614,IR (KBr); in _max cm ^-1 : 3100, 2998, 1731, 1638, 1614,

1470, 13171470, 1317

- 41 REFERENČNI PRIMER 16 (+)-8-kloro-6,7-difluoro-1-(1, 2-cis-2-fluoro-1-ciklopropil)4-okso-1,4-dihidrokinolin-3-karboksilna kislina (12a):- 41 REFERENCE EXAMPLE 16 (+) - 8-Chloro-6,7-difluoro-1- (1,2-cis-2-fluoro-1-cyclopropyl) 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (12a):

Pomešali smo ester (11a) (540 mg), 5 ml koncentrirane klorovodikove kisline in 5 ml ocetne kisline, nakar smo zmes segrevali 2 uri ob mešanju na 120 do 130 °C. Reakcijski zmesi smo dodali 50 ml vode in oborjene kristale zbrali s filtracijo, izprali zapored z vodo in dietiletrom in sušili ob zmanjšanem tlaku, da smo dobili 420 mg naslovne spojine (12a) kot brezbarvne kristale.The ester (11a) (540 mg), 5 ml of concentrated hydrochloric acid and 5 ml of acetic acid were mixed, then the mixture was heated for 2 hours with stirring at 120 to 130 ° C. 50 ml of water were added to the reaction mixture and the precipitated crystals were collected by filtration, washed successively with water and diethyl ether and dried under reduced pressure to give 420 mg of the title compound (12a) as colorless crystals.

Tališče: 17O-171°C [q]_D; +30.4° (c=Q.54, kloroform)Melting point: 17O-171 ° C [q] _D ; + 30.4 ° (c = Q.54, chloroform)

Elementna analiza za C₁₃H₇C1F₃NO₃: izrač. (%) : C 49.16; H 2.22? N 4.41 Ugot. (%): C 49.21; H 2.49; N 4.27 ¹H-NMR (CDC1₃) δ ppm:Elemental analysis for C ₁₃ H ₇ C1F ₃ NO ₃ : calc. (%): C 49.16; H 2.22? N 4.41 Found. (%): C 49.21; H, 2.49; N 4.27 ¹ H-NMR (CDCl ₃ ) δ ppm:

1.3-2.0 (2H, m), 4.12-4.34 (IH, m), 4.95 (IH, dm, J=63Hz), 8.27 (IH, dd, J=8 & 8Hz), 8.87,1.3-2.0 (2H, m), 4.12-4.34 (1H, m), 4.95 (1H, dm, J = 63Hz), 8.27 (1H, dd, J = 8 & 8Hz), 8.87,

8.89 (IH, vsak s, razcepljen 1:1).8.89 (1H, s each, split 1: 1).

REFERENČNI PRIMER 17 (-)-8-kloro-6,7-difluoro-1-(1,2-cis-2-fluoro-1-ciklopropil)-4 okso-1,4-dihidrokinolin-3-karboksilna kislina (12b);REFERENCE EXAMPLE 17 (-) - 8-Chloro-6,7-difluoro-1- (1,2-cis-2-fluoro-1-cyclopropyl) -4 oxo-1,4-dihydroquinoline-3-carboxylic acid (12b );

Pomešali smo ester (11b) (1,40 g) in 10 ml koncentrirane klorovodikove kisline in zmes segrevali 2,5 ure ob mešanju na 110 °C. Reakcijski zmesi smo dodali 50 ml vode, in oborjene kristale zbrali s filtracijo, izprali z vodo in dietiletrom in sušili ob zmanjšanem tlaku, da smo dobili 1,16 gEster (11b) (1.40 g) was mixed and 10 ml of concentrated hydrochloric acid was added and the mixture was heated for 2.5 hours with stirring at 110 ° C. 50 ml of water were added to the reaction mixture, and the precipitated crystals were collected by filtration, washed with water and diethyl ether and dried under reduced pressure to give 1.16 g

- 42 naslovne spojine (12 b) kot brezbarvne kristale.- 42 title compounds (12 b) as colorless crystals.

Tališče 177-182°C [a]_D: -26.8® (c=0.90, kloroform)Mp 177-182 ° C [a] _D : -26.8 (c = 0.90, chloroform)

Elementna analiza za c₁₃H₇C1F₃NO₃:Elemental analysis for c ₁₃ H ₇ C1F ₃ NO ₃ :

Izrač.: (%): C 49.16? H 2.22; N 4.41 Ugot.: (%): C 49.28; H 2.40; N-4.66 ¹H-NMR (CDC1₃) δ ppm:Calc .: (%): C 49.16? H, 2.22; N 4.41 Found: (%): C 49.28; H 2.40; N-4.66 ¹ H-NMR (CDCl ₃ ) δ ppm:

8.89 (IH, vsak s, razcepljen 1:1).8.89 (1H, s each, split 1: 1).

PRIMER 5 (+)-7-/3-( S)-amino-1-pirolidinil/-8-kloro-6-fluoro-1-(1,2cis-2-fluoro-1-ciklopropil)-4-okso-1,4-dihidrokinolin-3karboksilna kislina (13a):EXAMPLE 5 (+) - 7- [3- (S) -amino-1-pyrrolidinyl] -8-chloro-6-fluoro-1- (1,2cis-2-fluoro-1-cyclopropyl) -4-oxo- 1,4-Dihydroquinoline-3carboxylic acid (13a):

ml trifluoroocetne kisline smo ohladili z ledom ter v njej raztopili 230 mg 3-(S)-1-t-butoksikarbonil-3-(t-butoksikarbonilamino)pirolidina, čemur je sledilo mešanje 20 minut pri sobni temperaturi. Reakcijsko zmes smo uparili do suhega ob zmanjšanem tlaku ter preostanek raztopili v 15 ml acetonitrila. Raztopini smo dodali 170 mg karboksilne kisline (12a) in 400 mg trietilamina, čemur je sledilo 6,5 urno refluktiranje. Reakcijsko zmes uparili do suhega ob zmanjšanem tlaku ter preostanku dodali 1N klorovodikovo kislino. Zmes smo izprali s kloroform. pH vodnega sloja smo uravnali na 12 zml of trifluoroacetic acid was cooled with ice and dissolved in 230 mg of 3- (S) -1-t-butoxycarbonyl-3- (t-butoxycarbonylamino) pyrrolidine, followed by stirring for 20 minutes at room temperature. The reaction mixture was evaporated to dryness under reduced pressure and the residue was dissolved in 15 ml of acetonitrile. 170 mg of carboxylic acid (12a) and 400 mg of triethylamine were added to the solution, followed by 6.5 hours of reflux. The reaction mixture was evaporated to dryness under reduced pressure and 1N hydrochloric acid was added to the residue. The mixture was washed with chloroform. The pH of the aqueous layer was adjusted to 12 z

- 43 1Ν vodno raztopino natrijevega hidroksida in izprali s kloroformom. pH vodnega sloja smo ponovno uravnali na 7,6 s klorovodikovo kislino in ekstrahirali s kloroformom. Ekstrakt smo sušili nad brezvodnim natrijevim sulfatom in topilo uparili. Preostanek smo prekristalizirali iz vodnega amoniaka/ etanola, da smo dobili 138 mg naslovne spojine (13a) kot brezbarvne kristale.- 43 1Ν aqueous sodium hydroxide solution and washed with chloroform. The pH of the aqueous layer was again adjusted to 7.6 with hydrochloric acid and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was recrystallized from aqueous ammonia / ethanol to give 138 mg of the title compound (13a) as colorless crystals.

Tališče: . 214-217°C ( z razpadom) [aJ_D: +120.8° (c=0.475, 0.1N NaOH vodna raztopina)Melting point:. 214-217 ° C (decomposition) [aJ _D : + 120.8 ° (c = 0.475, 0.1N NaOH aqueous solution)

Elementna analiza za C₁₇H₁₆C1F₂N₃O₃«1/2H₂O:Elemental analysis for C ₁₇ H ₁₆ C1F ₂ N ₃ O ₃ «1 / 2H ₂ O:

Izrač. :(%)’· C 51.98; H 4.36; N 10.70 Ugot.:(%): C 52.07; H 4.71; N 10.72 ¹H-NMR (NaOD) δ ppm:Calc. : (%) '· C 51.98; H, 4.36; N 10.70 Found :(%): C 52.07; H 4.71; N 10.72 ¹ H-NMR (NaOD) δ ppm:

1.28 (IH, dm, J=27Hz), 1.69-1.78 (2H, m), 3.393.42 (IH, m), 3.51-3.61 (3H, m), 3.69-3.72 (IH, m), 4.13-4.17 (IH, m), 4.99 (IH, dm, J=70Hz),1.28 (1H, dm, J = 27Hz), 1.69-1.78 (2H, m), 3.393.42 (1H, m), 3.51-3.61 (3H, m), 3.69-3.72 (1H, m), 4.13-4.17 (1H, m), 4.99 (1H, dm, J = 70Hz),

7.72 (IH, d, J=14Hz), 8.44, 8.45 (IH, vsak s, razcepljen ,1:1)*7.72 (1H, d, J = 14Hz), 8.44, 8.45 (1H, each s, split, 1: 1) *

PRIMER 6 (-)-7-/3-(S)-amino-1-pirolidinil/-8-kloro-6-fluoro-1-(1,2-cis2-fluoro-1-ciklopropil)-4-okso-1,4-dihidrokinolin-3-karboksilna kislina (13a):EXAMPLE 6 (-) - 7- / 3- (S) -amino-1-pyrrolidinyl] -8-chloro-6-fluoro-1- (1,2-cis2-fluoro-1-cyclopropyl) -4-oxo- 1,4-Dihydroquinoline-3-carboxylic acid (13a):

ml trifluoroocetne kisline smo ohladili z ledom in v njej raztopili 230 mg 3-(S)-t-butoksikarbonil-3-(t-butoksikarbonilamino)pirolidina, čemur je sledilo 20 minutno mešanje pri sobni temperaturi. Reakcijsko zmes smo uparili do suhega ob zmanjšanem tlaku in preostanek raztopili v 15 ml acetonitri la. Raztopini smo dodali 170 mg karboksilne kisline (12b) in 400 mg trietilamina, nakar smo zmes segrevali 6,5 ur ob refluksu. Reakcijsko zmes smo uparili do suhega ob zmanjšanem tlaku. Preostanku smo dodali 1N klorovodikovo kislino ter zmes izprali s kloroformom. Vodni sloj smo uravnali na pH 12 z 1N vodno raztopino natrijevega hidroksida in vodni sloj uravnali na pH 7,6 s klorovodikovo kislino in ekstrahirali s kloroformom. Ekstrakt smo sušili nad brezvodnim natrijevim sulfatom in topilo uparili. Preostanek smo prekristalizirali iz vodnega amoniaka/etanola, da smo dobili 158 mg naslovne spojine (13b) kot brezbarvne kristale.ml of trifluoroacetic acid was cooled with ice and dissolved in 230 mg of 3- (S) -t-butoxycarbonyl-3- (t-butoxycarbonylamino) pyrrolidine, followed by stirring at room temperature for 20 minutes. The reaction mixture was evaporated to dryness under reduced pressure and the residue was dissolved in 15 ml of acetonitrile. 170 mg of carboxylic acid (12b) and 400 mg of triethylamine were added to the solution and the mixture was heated at reflux for 6.5 hours. The reaction mixture was evaporated to dryness under reduced pressure. 1N hydrochloric acid was added to the residue and the mixture was washed with chloroform. The aqueous layer was adjusted to pH 12 with 1N aqueous sodium hydroxide solution and the aqueous layer was adjusted to pH 7.6 with hydrochloric acid and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was recrystallized from aqueous ammonia / ethanol to give 158 mg of the title compound (13b) as colorless crystals.

Tališče: 247-252°C ( z razpadom) [a]_D: -94.7^e (c=0.378, 0.1N HaOH vodna raztopina)Melting point: 247-252 ° C (decomposition) [a] _D : -94.7 ^e (c = 0.378, 0.1N HaOH aqueous solution)

Elementna analiza za C₁₇H₁₆C1F₂N₃O₃*H₂O:Elemental analysis for C ₁₇ H ₁₆ C1F ₂ N ₃ O ₃ * H ₂ O:

Izrač.: (%): C 50.82; H 4.52; N 10.46 Ugot.: (%)·’ C 50.97; H 5.14; N 10.42 ¹H-NMR (NaOD) δ ppm:Calc .: (%): C 50.82; H, 4.52; N, 10.46 Found: (%) · 'C 50.97; H, 5.14; N 10.42 ¹ H-NMR (NaOD) δ ppm:

1.32 (IH, dm, J=27Hz), 1.73-1.80 (2H, m), 2.152.19 (IH, m), 3.19-3.22 (IH, m), 3.45-3.50 (IH, m), 3.58-3.62 (IH, m), 3.85-3.88 (2H, m), 4.164.20 (IH, m), 4.99 (IH, dm, J=63Hz), 7.76 (IH, d, J=14Hz), 8.54, 8.44 (IH,vsak s, razcepljen, 1:1)1.32 (1H, dm, J = 27Hz), 1.73-1.80 (2H, m), 2.152.19 (1H, m), 3.19-3.22 (1H, m), 3.45-3.50 (1H, m), 3.58-3.62 (1H, m), 3.85-3.88 (2H, m), 4.164.20 (1H, m), 4.99 (1H, dm, J = 63Hz), 7.76 (1H, d, J = 14Hz), 8.54, 8.44 ( IH, each s, split, 1: 1)

REFERENČNI PRIMER 18 (-)-eti1-2-//(1,2-cis-2-fluoro-1-ciklopropil)amino/-metilen/3-okso-3-(2,3,4,5-tetrafluoro-6-nitrofenil)-propionat (I4a):REFERENCE EXAMPLE 18 (-) - Ethyl-2 - [(1,2-cis-2-fluoro-1-cyclopropyl) amino] -methylene / 3-oxo-3- (2,3,4,5-tetrafluoro- 6-nitrophenyl) -propionate (I4a):

Pomešali smo etil 2,3,4,5-tetrafluoro-6-nitrobenzoilacetat (1,5 g), 6 ml etilortoformata in 10 ml acetanhidrida, nakar smo zmes segrevali 2 uri na 120 °C. Reakcijsko zmes smo koncentrirali do suhega in preostanek raztopili v 10 ml diklorometana.Ethyl 2,3,4,5-tetrafluoro-6-nitrobenzoyl acetate (1.5 g), 6 ml of ethylorthoformate and 10 ml of acetanhydride were mixed and the mixture was heated at 120 ° C for 2 hours. The reaction mixture was concentrated to dryness and the residue dissolved in 10 ml of dichloromethane.

ml trifluoroocetne kisline smo ohladili z ledom ter v njej raztopili 1,1 g (+)-cis-1-(t-butoksikarbonilamino)-2fluorociklopropana (4a). Raztopino smo mešali pri sobni temperaturi 2 uri, čemur je sledilo uparjenje do suhega ob zmanjšanem tlaku. Preostanek smo suspendirali v 20 ml diklorometana in mu dodali 2,0 g trietilamina ob hlajenju z ledom, čemur je sledilo 20 minutno mešanje. Nato smo k temu dodali zgoraj pripravljeno raztopino diklorometana, čemur je sledilo 30 minutno mešanje. Reakcijsko zmes smo izprali z vodo in sušili nad brezvodnim natrijevim sulfatom. Topilo smo odstranili ob zmanjšanem tlaku. Preostanek smo podvrgli ”fla h” kolonski kromatografiji ob uporabi benzena kot eluenta. Frakcije spojine (I4a) smo združili in topilo odstranili ob zmanjšanem tlaku. Preostanek smo izprali z n-heksanom, da smo dobili 1,57 g kristalov naslovne spojine (I4a).ml of trifluoroacetic acid was cooled with ice and dissolved 1.1 g (+) - cis-1- (t-butoxycarbonylamino) -2fluorocyclopropane (4a). The solution was stirred at room temperature for 2 hours, followed by evaporation to dryness under reduced pressure. The residue was suspended in 20 ml of dichloromethane and 2.0 g of triethylamine were added while cooling with ice, followed by stirring for 20 minutes. The dichloromethane solution prepared above was then added, followed by stirring for 30 minutes. The reaction mixture was washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was subjected to flash chromatography using benzene as eluent. The fractions of compound (I4a) were combined and the solvent was removed under reduced pressure. The residue was washed with n-hexane to give 1.57 g of crystals of the title compound (I4a).

Tališče: 99-100°C [a]_D: -10.3° (c=1.25, chloroform)Melting point: 99-100 ° C [a] _D : -10.3 ° (c = 1.25, chloroform)

Elementna analiza za ^C15^H11^F5^N2°5Elemental analysis for ^C 15 ^H 11 ^F 5 ^N 2 ° 5

Izrae.: (%): C 45.70; H 2.81; N 7.10 Ugot.: (%): C 45.60; H 3.01; N 7.03 ¹H-NMR (CDC1₃) δ ppm:Calc .: (%): C 45.70; H 2.81; N, 7.10 Found: (%): C 45.60; H 3.01; N 7.03 ¹ H-NMR (CDCl ₃ ) δ ppm:

1.10 (3H, t, J=7Hz), 1.2-1.55 (2E, m), 2.88-3.16 (IH, m), 4.09 (2H, q, J=7Hz), 4.45 (IH, dm,1.10 (3H, t, J = 7Hz), 1.2-1.55 (2E, m), 2.88-3.16 (1H, m), 4.09 (2H, q, J = 7Hz), 4.45 (1H, dm.

J=63Hz), 8.29 (IH, d, J=14Hz)J = 63Hz), 8.29 (1H, d, J = 14Hz)

IR(KBr): v_max cnr¹: 3454 1734, 1626, 1566, 1521,IR (KBr): in _ma x cnr ¹ : 3454 1734, 1626, 1566, 1521,

14821482

REFERENČNI PRIMER 19 (+)-eti1-2-//(1,2-cis-2-fluoro-1-ciklopropil)amino/-metilen/3-okso-3-(2,3,4,5-tetrafluoro-6-nltrofeni1)propionat (14b):REFERENCE EXAMPLE 19 (+) - Ethyl-2 - [(1,2-cis-2-fluoro-1-cyclopropyl) amino] -methylene / 3-oxo-3- (2,3,4,5-tetrafluoro- 6-nitrophenyl) propionate (14b):

Pomešali smo etil 2,3,4,5-tetrafluoro-6-nitrobenzoilacetat (1,5 g), 6 ml etil ortofor mata in 10 ml acetanhidrida, nakar smo zmes segrevali 1 uro ob mešanju na 110 do 120 °C. Reakcijsko zmes smo koncentrirali do suhega in preostanek raztopili v 10 ml diklorometana.Ethyl 2,3,4,5-tetrafluoro-6-nitrobenzoyl acetate (1.5 g), 6 ml of ethyl orthophore mat and 10 ml of acetanhydride were mixed and the mixture was heated for 1 hour with stirring at 110-120 ° C. The reaction mixture was concentrated to dryness and the residue dissolved in 10 ml of dichloromethane.

ml trifluoroocetne kisline smo hladili z ledom in v njej raztopili 1,10 g (-)-cis-1-(t-butoksikarbonilamino)-2-fluorociklopropana (4b), čemur je sledilo 20 minutno mešanje pri sobni temperaturi. Reakcijsko zmes smo uparili do suhega ob zmanjšanem tlaku in preostanek suspendirali v 20 ml diklorometana. Suspenziji smo dodali 1,8 g trietilamina ob hlajenju z ledom, čemur je sledilo 20 minutno mešanje. Zmesi smo dodali zgoraj pripravljeno raztopino diklorometana, čemur je sledilo 2 urno mešanje. Reakcijsko zmes smo izprali z vodo in sušili nad brezvodnim natrijevim sulfatom. Topilo smo uparili ob zmanjšanem tlaku in preostanek podvrgli flash” kolonski kromatografiji ob uporabi benzena kot eluenta. Frakcije produkta (I4b) smo združili in topilo odstranili ob zmanjšanem tlaku. Preostanek smo izprali z n-heksanom, da smo dobili 1,50 g kristalov naslovne spojine (I4b).ml of trifluoroacetic acid was cooled with ice and 1.10 g (-) - cis-1- (t-butoxycarbonylamino) -2-fluorocyclopropane (4b) was dissolved in it, followed by stirring at room temperature for 20 minutes. The reaction mixture was evaporated to dryness under reduced pressure and the residue was suspended in 20 ml of dichloromethane. 1.8 g of triethylamine were added to the suspension under ice-cooling, followed by stirring for 20 minutes. The dichloromethane solution prepared above was added to the mixture, followed by stirring for 2 hours. The reaction mixture was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was subjected to flash column chromatography using benzene as eluent. Product fractions (I4b) were combined and the solvent was removed under reduced pressure. The residue was washed with n-hexane to give 1.50 g of crystals of the title compound (I4b).

- 47 Tališče: 98-100°C- 47 Melting point: 98-100 ° C

-10.1« (c=2.09, kloroform)-10.1 "(c = 2.09, chloroform)

Elementna analiza za ^ci5^HiiF₅N₂ ^O5 IzraČ.: (%)s C 45.70; H 2.81; N 7.10Elemental analysis for ^c i5 ^H iiF ₅ N ₂ ^O 5 Calc: (%) with C 45.70; H 2.81; N, 7.10

Ugot.: (%)·. c 45.77; H 3.38; N 7.18 ¹H-NMR (CDC1₃) δ ppm:Found: (%) ·. c 45.77; H, 3.38; N 7.18 ¹ H-NMR (CDCl ₃ ) δ ppm:

1.10 (3H, t, J=7Hz), 1.2-1.5 (2H, m), 2.88-3.12 (IH, m), 4.09 (2H, q, J=7Hz), 4.45 (IH, dm,1.10 (3H, t, J = 7Hz), 1.2-1.5 (2H, m), 2.88-3.12 (1H, m), 4.09 (2H, q, J = 7Hz), 4.45 (1H, dm.

J=63Hz), 8.30 (IH, d, J=14Hz)J = 63Hz), 8.30 (1H, d, J = 14Hz)

IR(KBr): v_max cm-i; 3454 1695, 1638, 1554, 1515IR (KBr): in _max cm-1; 3454 1695, 1638, 1554, 1515

REFERENČNI PRIMER 20 (+)-etil 6,7,8-trifluoro-1-(1,2-cis-2-fluoro-1-oiklopropil)-5nitro-4-okso-1,4-dihidrokinolin-3-karboksilat (15a):REFERENCE EXAMPLE 20 (+) - ethyl 6,7,8-trifluoro-1- (1,2-cis-2-fluoro-1-ocyclopropyl) -5nitro-4-oxo-1,4-dihydroquinoline-3-carboxylate ( 15a):

V 20 ml brezvodnega dioksana smo suspendirali 580 mg 60 %-nega natrijevega hidrida, katerega smo bi.li 2-krat izprali z n-heksanom. Suspenzijo smo dodali k raztopini 1,90 g spojine (I4a) v 20 ml brezvodnega dioksana. Zmes smo mešali 1 uro pri sobni temperaturi in topilo odstranili iz reakcijske zmesi ob zmanjšanem tlaku. Preostanku smo dodali 0,1N klorovodikovo kislino. Tako tvorjene kristale smo zbrali s filtracijo zapored izprali z vodo in dietiletrom in sušili ob zmanjšanem tlaku, da smo dobili 1,65 g naslovne spojine (15a) kot brezbarvne kristale.580 mg of 60% sodium hydride was suspended in 20 ml of anhydrous dioxane, which was washed twice with n-hexane. The suspension was added to a solution of 1.90 g of compound (I4a) in 20 ml of anhydrous dioxane. The mixture was stirred for 1 hour at room temperature and the solvent was removed from the reaction mixture under reduced pressure. 0.1N hydrochloric acid was added to the residue. The crystals thus formed were collected by filtration, washed successively with water and diethyl ether and dried under reduced pressure to give 1.65 g of the title compound (15a) as colorless crystals.

Tališče: I72-176«C !<?]„: +10.7° (c=1.12, kloroform,Melting point: I72-176 "C! <?]": + 10.7 ° (c = 1.12, chloroform,

Elementna analiza za i ^cis^hio^F4^N2°5 Izrač.: (%): c 48.14; H 2.69; N 7.49 Ugot.: (%): C 48.29; H 2.78; N 7.20 ^-NMR (CDC1₃) δ ppm:Elemental analysis for i ^c is ^h io ^F 4 ^N 2 ° 5 Calc: (%): c 48.14; H 2.69; N, 7.49 Found: (%): C 48.29; H, 2.78; N 7.20 N-NMR (CDCl ₃ ) δ ppm:

1.36 (3H, t, J=7Hz), 1.4-1.92 (2H, m), 3.80-4.08 (IH, m), 4.34 (2H, q, J=7Hz),.4.99 (IH, dm,1.36 (3H, t, J = 7Hz), 1.4-1.92 (2H, m), 3.80-4.08 (1H, m), 4.34 (2H, q, J = 7Hz), 4.99 (1H, dm.

J=63Hz), 8.55 (IH, s)J = 63Hz), 8.55 (1H, s)

IR(KBr): Vmax cm^_l: 3454 1734, 1626, 1566, 1521 1482IR (KBr): Vmax cm ^@ -1: 3454 1734, 1626, 1566, 1521 1482

REFERENČNI PRIMER 21 (-)-etil 6,7,8-trifluoro-1-(1,2-cis-2-fluoro-1-ciklopropil)-5 nitro-4-okso-1,4-dihidrokinolin-3-karboksilat (15b):REFERENCE EXAMPLE 21 (-) - Ethyl 6,7,8-trifluoro-1- (1,2-cis-2-fluoro-1-cyclopropyl) -5 nitro-4-oxo-1,4-dihydroquinoline-3-carboxylate (15b):

V 10 ml brezvodnega dioksana smo suspendirali 440 mg 60 %-nega natrijevega hidrida, katerega smo bili 2-krat izprali z n-heksanom. Suspenzijo smo dodali k raztopini 1,45 g spojine (I4b) v 20 ml brezvodnega dioksana, čemur je sledilo 30 minutno mešanje pri sobni temperaturi. Topilo smo odstrani li iz reakcijske zmesi ob zmanjšanem tlaku··. Preostanku smo dodali 0,1N klorovodikove kisline in tvorjene kristale zbrali s filtracijo, zapored izprali z vodo in dietiletrom in sušili ob zmanjšanem tlaku, da smo dobili 1, 18 g naslovne spojine (15b) kot brezbarvne kristale.In 10 ml of anhydrous dioxane was suspended 440 mg of 60% sodium hydride, which was washed twice with n-hexane. The suspension was added to a solution of 1.45 g of compound (I4b) in 20 ml of anhydrous dioxane, followed by stirring at room temperature for 30 minutes. The solvent was removed from the reaction mixture under reduced pressure. 0.1N hydrochloric acid was added to the residue and the crystals formed were collected by filtration, washed sequentially with water and diethyl ether and dried under reduced pressure to give 1, 18 g of the title compound (15b) as colorless crystals.

Tališče: 17l-175°C [a]_Ds -11.1· (c=0.27, kloroform)Melting point: 17l-175 ° C [a] _D with -11.1 · (c = 0.27, chloroform)

Elementna analiza za ^<-ΐ5^Ηιο^Ρ4^Ν2θ5 Izrač.: (%)_:C 48.14; H 2.69; N 7.49 Ugot.: _(%). c 48.44; H 3.17; N-7.48 ¹H-NMR (CDC1₃) 6 ppm:Elemental analysis for ^< -ΐ5 ^Η ιο ^Ρ 4 ^Ν 2θ5 Calcd: (%) _: C 48.14; H 2.69; N 7.49 Found: _(% ). c 48.44; H 3.17; N-7.48 ¹ H-NMR (CDCl ₃ ) 6 ppm:

1.36 (3H, t, J=7Hz), 1.4-1.92 (2H, m), 3.74-4.02 (IH, m), 4.36 (2H, g, J=7Hz), 4.94 (IH, dm,1.36 (3H, t, J = 7Hz), 1.4-1.92 (2H, m), 3.74-4.02 (1H, m), 4.36 (2H, g, J = 7Hz), 4.94 (1H, dm.

J=62Hz), 8.54 (IH, s)J = 62 Hz), 8.54 (1H, s)

IR(KBr): v_raax cm-1: 1731, 1626, 1566, 1485, 1323,IR (KBr): in _raax cm-1: 1731, 1626, 1566, 1485, 1323,

12751275

REFERENČNI PRIMER 22 (+)-etil 5-amino-6,7,8-trifluoro-1-(1,2-cis-2-fluoro-1-ciklopropil)-4-okso-1,4-dihidrokinolin-3-karboksilna kislina (l6a):REFERENCE EXAMPLE 22 (+) - Ethyl 5-amino-6,7,8-trifluoro-1- (1,2-cis-2-fluoro-1-cyclopropyl) -4-oxo-1,4-dihydroquinoline-3- carboxylic acid (l6a):

Pomešali smo nitro spojino (15a) (1,60 g) 6 ml Raneyevega niklja in 200 ml etanola, nakar smo zmes stresali 2,5 ure v atmosferi vodika, katalizator smo odstranili s filtracijo/ skozi Celite ter filtrat koncentrirali ob zmanjšanem tlaku. Preostanek smo podvrgli kromatografiji na koloni silikagela ob uporabi kloroforma kot eluenta. Frakcije produkta (16a) smo združili in iz njega odstranili topilo ob zmanjšanem tlaku. Preostanek smo prekristalizirali iz etanola, da smo dobili 770 mg naslovne spojine (l6a) kot bledorumene kristale.The nitro compound (15a) (1.60 g) was mixed with 6 ml of Raney nickel and 200 ml of ethanol, after which the mixture was shaken for 2.5 hours under a hydrogen atmosphere, the catalyst was removed by filtration / Celite and the filtrate was concentrated under reduced pressure. The residue was chromatographed on a silica gel column using chloroform as eluent. The product fractions (16a) were combined and the solvent removed under reduced pressure. The residue was recrystallized from ethanol to give 770 mg of the title compound (16a) as pale yellow crystals.

Tališče: 190-191^eC [a]o: +26.0° (c=0.76, kloroform)Melting point: 190-191 ^e C [a] o: + 26.0 ° (c = 0.76, chloroform)

Elementna analiza za ^ci5^Hi2^F4^N2°3Elemental analysis for ^c i5 ^H i2 ^F 4 ^N 2 ° 3

Izrač. (%): C 52.33; H 3.51; N 8.14 Ugot.:’(%): C 52.13; H 3.95; N 3.13 ¹H-NMR (CDC1₃) δ ppm:Calc. (%): C 52.33; H 3.51; N, 8.14. Found :'(%): C 52.13; H, 3.95; N 3.13 ¹ H-NMR (CDCl ₃ ) δ ppm:

1.39 (3H, t, J=7Hz), 1.4-1.8 (2H, m), 3.60-3.88 (IH, m), 4.38 (2H, q, J=7Hz), 4.87 (IH, dm,1.39 (3H, t, J = 7Hz), 1.4-1.8 (2H, m), 3.60-3.88 (1H, m), 4.38 (2H, q, J = 7Hz), 4.87 (1H, dm.

J=63Hz), 6.8-7.1 (2H, m), 8.37 (IH, s)J = 63Hz, 6.8-7.1 (2H, m), 8.37 (1H, s)

IR(KBr): v_max cm-1: 3436, 1683, 1653, 1557, 1461,IR (KBr): in _m ax cm-1: 3436, 1683, 1653, 1557, 1461,

12841284

- 50 --- ---- - :- 50 --- ---- -:

REFERENČNI PRIMER 23 (-)-etil-5-araino-6,7,8-tri f luoro-1 -(1 ,'2-cis-2-fluoro-1ciklopropil)-4-okso-1,4-dihidrokinolin-3-karboksilat (16b)REFERENCE EXAMPLE 23 (-) - Ethyl-5-aryano-6,7,8-trifluoro-1- (1,1 '2-cis-2-fluoro-1-cyclopropyl) -4-oxo-1,4-dihydroquinoline- 3-carboxylate (16b)

Nitro spojino (15b) (1,60 g), 3 ral Raneyevega niklja in 120 ml etanola zmešamo in zmes stresamo 4,5 ure v vodikovi atmosferi. Katalizator odstranimo pri filtriranju skozi Celit in filtrat koncentriramo pod zmanjšanim tlakom. Preostanek kromatografiramo na koloni silikagela s kloroformom kot eluentom. Frakcije s produktom (16b) združimo in topilo odstranimo pod zmanjšanim tlakom. Preostanek prekristaliziramo iz etanola, da dobimo 620 mg naslovne spojine (16b) kot bledo-rumene kristale.The nitro compound (15b) (1.60 g), 3 acre of Raney nickel and 120 ml of ethanol were mixed and the mixture was shaken for 4.5 hours under hydrogen atmosphere. The catalyst was removed by filtration through Celite and the filtrate was concentrated under reduced pressure. The residue is chromatographed on a silica gel column with chloroform as eluent. Combine the fractions with product (16b) and remove the solvent under reduced pressure. The residue was recrystallized from ethanol to give 620 mg of the title compound (16b) as pale yellow crystals.

'faiisee: 191-193°C (<x]_D: -25.9° (c=0.65, chloroform)'faiisee: 191-193 ° C (<x] _D : -25.9 ° (c = 0.65, chloroform)

Elementna analiza za ^₁₅H₁₂ ^F4^N2°3Elemental analysis for ^ ₁₅ H ₁₂ ^F 4 ^N 2 ° 3

Izrac.; (%): C 52.33; H 3.51; N 8.14 Ugot.: (%): C 52.16; H 3.54; N 8.08 ^H-NMR (CDC1₃) δ ppm:Izrac .; (%): C 52.33; H 3.51; N, 8.14. Found: (%): C 52.16; H, 3.54; N, 8.08. 1 H-NMR (CDCl ₃ ) δ ppm:

J=63Hz), 6.8-7.1 (2H, m), 8.38 (IH, s)J = 63Hz, 6.8-7.1 (2H, m), 8.38 (1H, s)

IR(KBr): v_max cm-1; 3436, 1683, 1653, 1593, 1464,IR (KBr): in _max cm-1; 3436, 1683, 1653, 1593, 1464,

12841284

REFERENČNI PRIMER 24REFERENCE EXAMPLE 24

5-amino-6,7,8-trifluoro-1-(1,2-cis-2-fluoro-1-ciklopropil )-4-okso-1 ,4-dihidrokinolin-3-karboksilna kislina (17a)5-Amino-6,7,8-trifluoro-1- (1,2-cis-2-fluoro-1-cyclopropyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (17a)

Ester (l6a) (750 mg) in 10 ml koncentrirane klorovodikove kisline zmešamo in zmes segrevamo pri 100°C 2 uri med mešanjem. Reakcijski zmesi dodamo 20 ml vode in oborjene kristale zberemo s filtriranjem, da dobimo 610 mg naslovne spojine (17a) v obliki brezbarvnih kristalov.The ester (1-6a) (750 mg) and 10 ml of concentrated hydrochloric acid were stirred and the mixture was heated at 100 ° C for 2 hours while stirring. 20 ml of water was added to the reaction mixture and the precipitated crystals were collected by filtration to give 610 mg of the title compound (17a) as colorless crystals.

Tališče: 297-300°CMelting point: 297-300 ° C

Elementna analiza za C^HgF^N^P^Izfac.:(%): C 49.38; H 2.55? N 8.86 Ugot.: (%): C 49.43; H 2.91; N. 8.84 ¹H-NMR (DMSO-d₆) δ ppm:Elemental analysis for C ^HgF ^N NP P Iz Izfac .: (%): C 49.38; H 2.55? N, 8.86 Found: (%): C 49.43; H, 2.91; N. 8.84 ¹ H-NMR (DMSO-d ₆ ) δ ppm:

1.4-2.1 (2H, m), 3.9-4.2 (IH, m), 5.08 (IH, dm,1.4-2.1 (2H, m), 3.9-4.2 (1H, m), 5.08 (1H, dm,

J=65Hz), 7.72 (IH, s), 8.62 (IH, s)J = 65Hz), 7.72 (1H, s), 8.62 (1H, s)

IR(KBr): v_max cm-1: 3448, 3334, 1725, 1656, 1596,IR (KBr): in _max cm-1: 3448, 3334, 1725, 1656, 1596,

1566, 15181566, 1518

REFERENČNI PRIMER 25REFERENCE EXAMPLE 25

5-amino-6,7,8-trifluoro-1-( 1,2-cis-2-fluoro-1-ciklopropil)4-okso-1,4-dihidrokinolin-3-karboksilna kislina (17b)5-Amino-6,7,8-trifluoro-1- (1,2-cis-2-fluoro-1-cyclopropyl) 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (17b)

Ester (16b) (588 mg) in 10 ml koncentrirane klorovodikove kisline zmešamo in zmes segrevamo pri 100 doThe ester (16b) (588 mg) and 10 ml of concentrated hydrochloric acid were mixed and the mixture was heated to 100 to

110°C 2 uri med mešanjem. Reakcijski zmesi dodamo 20 ml vode in oborjene kristale zberemo s filtriranjem, da dobimo 514 mg naslovne spojine (17b) v obliki brezbarvnih kristalov.110 ° C for 2 hours while stirring. 20 ml of water was added to the reaction mixture and the precipitated crystals were collected by filtration to give 514 mg of the title compound (17b) as colorless crystals.

Tališče: 295-300°CMelting point: 295-300 ° C

Elementna analiza za ^ci3^H8^F4^N2°3Elemental analysis for ^c i3 ^H 8 ^F 4 ^N 2 ° 3

Izrač.:(%)·* C 49.38; H 2.55? N 8.86Calc .: (%) · * C 49.38; H 2.55? N, 8.86

Ugot.:(%): C 49.41? H 2.81; N 8.88Found :(%): C 49.41? H 2.81; N, 8.88

- 52.-.7/ ./ /. /-...¹H-NMR (CDC1₃) δ ppm:- 52 .-. 7 / ./ /. ¹ H-NMR (CDCl ₃ ) δ ppm:

J=65Hz), 7.72 (IH, s), 8.62 (IH, s)J = 65Hz), 7.72 (1H, s), 8.62 (1H, s)

IR: v_max cm-i: 3448, 3334, 1725, 1656, 1596,IR: in _max cm: 3448, 3334, 1725, 1656, 1596,

1566, 15181566, 1518

PRIMER 7 (_)-5-amino-7-/3-(S)-amino-1-pirolidinil/-6,8-difluoro1 —(1,2-cis-2-fluoro-1-ciklopropil)-4-okso-1,4-dihidrokinolin-3-karboksilna kislina (I8a) ml trifluorocetne kisline ohladimo v ledu in v njej raztopimo 230 mg 3-(S)-1-t-butoksikarbonil-3-(t-butoksikarbonilamino)pirolidina, nakar mešamo pri sobni temepraturi nadaljnjih 30 minut. Reakcijsko zmes uparimo do suhega pod zmanjšanim tlakom in preostanek raztopimo v 25 ml acetonitrila. Raztopini dodamo 160 mg karboksilne kisline (17a) in 400 mg trietilamina in zmes segrevamo pri refluksu 12 ur. Reakcijsko zmes uparimo do suhega pod zmanjšanim tlakom in ostanku dodamo 1 N klorovodikovo kislino. Po spiranju zmesi s kloroformom, uravnamo pH vodnega sloja na 12 z 1 N vodno raztopino natrijevega hidroksida, nakar ga speremo s kloroformom. Nato uravnamo pH vodnega sloja na 7,6 s klorovodikovo kislino in ga esktrahiramo s kloroformom. Ekstrakt posušimo preko brezvodnega natrijevega sulfata in topilo odstranimo pod zmanjšanim tlakom. Preostanek prekristaliziramo iz vodnega amoniaka/ etanola, da dobimo 128 mg naslovne spojine (18a) v obliki brezbarvnih kristalov.EXAMPLE 7 (S) -5-Amino-7- [3- (S) -amino-1-pyrrolidinyl] -6,8-difluoro-1- (1,2-cis-2-fluoro-1-cyclopropyl) -4- oxo-1,4-dihydroquinoline-3-carboxylic acid (I8a) ml of trifluoroacetic acid is cooled in ice and dissolved in it 230 mg of 3- (S) -1-t-butoxycarbonyl-3- (t-butoxycarbonylamino) pyrrolidine and then stirred at room temperature for a further 30 minutes. The reaction mixture was evaporated to dryness under reduced pressure and the residue was dissolved in 25 ml of acetonitrile. To the solution was added 160 mg of carboxylic acid (17a) and 400 mg of triethylamine and the mixture was heated at reflux for 12 hours. The reaction mixture was evaporated to dryness under reduced pressure and 1 N hydrochloric acid was added to the residue. After washing the mixture with chloroform, the pH of the aqueous layer was adjusted to 12 with 1 N aqueous sodium hydroxide and then washed with chloroform. The pH of the aqueous layer was then adjusted to 7.6 with hydrochloric acid and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent removed under reduced pressure. The residue was recrystallized from aqueous ammonia / ethanol to give 128 mg of the title compound (18a) as colorless crystals.

Tališče: 224-230°C faL·: -4.72° (c=0.888, 0.1N NaOH vodna raztopina ^{1 J} D t *Melting point: 224-230 ° C faL ·: -4.72 ° (c = 0.888, 0.1N NaOH aqueous solution ^{1 J} D t *

Elementna analiza za C^H^FgN^Og 'Izrač. :(%): C 53.40; H 4.48; N 14.65 Ugot.:(%): C 53.28; H 4.08; N 14.54 ¹H-NMR (NaOD)) δ ppm:Elemental analysis for C ^ H ^ FgN ^ Og 'Calc. : (%): C 53.40; H, 4.48; N 14.65 Found :(%): C 53.28; H, 4.08; N 14.54 ¹ H-NMR (NaOD)) δ ppm:

1.47-1.58 (IH, m), , 1.67-1.78 (2H, m), 2.072.11 (IH, m),· 3.28-3.44 (IH, m), 3.48-3.52(lH, m), 3.60-3.66 (IH, m), 3.71-3.78 (2H, m), 4.92 (IH, dm, J=72Hz), 8.18 (IH, s)1.47-1.58 (1H, m),, 1.67-1.78 (2H, m), 2.072.11 (1H, m), · 3.28-3.44 (1H, m), 3.48-3.52 (1H, m), 3.60-3.66 (1H, m), 3.71-3.78 (2H, m), 4.92 (1H, dm, J = 72Hz), 8.18 (1H, s)

IR: v_roax cm-l: 3400, 1728, 1635, 1605, 1518,IR: in _roa x cm-l: 3400, 1728, 1635, 1605, 1518,

1433, 1350, 13081433, 1350, 1308

PRIMER 8 (+)-5-amino-7-/3-(S)-amino-1-pirolidinil/-6,8-difluoro-1(1,2-cis-2-fluoro-1-ciklopropil)-4-okso-1,4-dihidrokinolin3-karboksilna kislina (I8b) ml trifluorocetne kisline ohladimo v ledu in v njej raztopimo 230 mg 3-(S)—1-t-butoksikarbonil-3-(t-butoksikarbonilamino)pirolidina, nakar mešamo pri sobni temperaturi še 30 minut. Reakcijsko zmes uparimo do suhega pod zmanjšanim tlakom in preostanek raztopimo v 25 ml acetonitrila. Raztopini dodamo 160 mg karboksilne kisline (17b) in 400 mg trietilamina in zmes segrevamo pod refluksom 12 ur. Reakcijsko zmes uparimo do suhega pod zmanjšanim tlakom in preostanku dodamo 1 N klorovodikovo kislino. Po spiranju zmesi s kloroformom, uravnamo pH vodnega sloja na 12 z 1 N vodno raztopino natrijevega hidroksida, nakar ga speremo s kloroformom. Nato uravnamo pH vodnega sloja na 7,6 s klorovodikovo kislino, in ga ekstrahiramo s kloroformom. Ekstrakt posušimo preko brezvodnega natrijevega sulfata in topilo odstranimo pod zmanjšanim tlakom. Preostanek prekristaliziramo iz vodnega amoniaka/etanola, da dobimo 68 mg naslovne spojine (I8b) v obliki brezbarvnih kristalov.EXAMPLE 8 (+) - 5-amino-7- / 3- (S) -amino-1-pyrrolidinyl) -6,8-difluoro-1 (1,2-cis-2-fluoro-1-cyclopropyl) -4 -oxo-1,4-dihydroquinoline-3-carboxylic acid (I8b) ml of trifluoroacetic acid is cooled in ice and dissolved in it 230 mg of 3- (S) -1-t-butoxycarbonyl-3- (t-butoxycarbonylamino) pyrrolidine, then stirred at room temperature for another 30 minutes. The reaction mixture was evaporated to dryness under reduced pressure and the residue was dissolved in 25 ml of acetonitrile. To the solution was added 160 mg of carboxylic acid (17b) and 400 mg of triethylamine and the mixture was refluxed for 12 hours. The reaction mixture was evaporated to dryness under reduced pressure and 1 N hydrochloric acid was added to the residue. After washing the mixture with chloroform, the pH of the aqueous layer was adjusted to 12 with 1 N aqueous sodium hydroxide and then washed with chloroform. The pH of the aqueous layer was then adjusted to 7.6 with hydrochloric acid, and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent removed under reduced pressure. The residue was recrystallized from aqueous ammonia / ethanol to give 68 mg of the title compound (I8b) as colorless crystals.

Tališče: 214-217°C [a)_D: +31.3° (c=0.268, 0.1N NaOH vodna raztopina Elementna analiza za C₁₇H₁₇F₃N₄O₃·1/2Η₂Ο:Melting point: 214-217 ° C [a) _D : + 31.3 ° (c = 0.268, 0.1N NaOH aqueous solution Elemental analysis for C ₁₇ H ₁₇ F ₃ N ₄ O ₃ · 1 / 2Η ₂ Ο:

Izrač.:(%): C 52.18; H 4.64; N 14.32 Ugot.:(%): C 52.22; H 4.93; N 14.23 ¹H-NMR (NaOD) δ ppm:Calc .: (%): C 52.18; H 4.64; N, 14.32; Found :(%): C 52.22; H, 4.93; N 14.23 ¹ H-NMR (NaOD) δ ppm:

1.48-1.58 (IH, m), , 1.66-1.79 (2H, m), 2.062.12 (IH, m), 3.29-3.32 (IH, ra), 3.48-3.52(lH, m), 3.60-3.64 (IH, m), 3.70-3.78 (2H, ra), 4.92 (IH, dm, J=72Hz), 8.19 (IH, s)1.48-1.58 (1H, m),, 1.66-1.79 (2H, m), 2.062.12 (1H, m), 3.29-3.32 (1H, ra), 3.48-3.52 (1H, m), 3.60-3.64 ( 1H, m), 3.70-3.78 (2H, ra), 4.92 (1H, dm, J = 72Hz), 8.19 (1H, s)

IR: v_max cm-1: 3490, 1716, 1635, 1521, 1437,IR: in _max cm-1: 3490, 1716, 1635, 1521, 1437,

1356, 13051356, 1305

REFERENČNI PRIMER 26REFERENCE EXAMPLE 26

Sinteza optično aktivnega 7-amlno-5-azaspiro-/2,4/-heptana ¹) 5-/(1R)-feniletil /-4,7-diok3o-5-azaspiro/2,4/-heptan (19)Synthesis of optically active 7-amino-5-azaspiro- (2,4) -heptane ¹ ) 5 - / (1R) -phenylethyl) -4,7-dioxo-5-azaspiro / 2,4 / -heptane (19)

K 10,4 g etil acetoaeetata dodamo 15 g 1,2-dibromoetana, 23 g kalijevega karbonata in 150 ml N,N-dimetilformamida (DMF) in zmes mešamo pri sobni temperaturi 2 dni.To 10.4 g of ethyl acetoacetate was added 15 g of 1,2-dibromoethane, 23 g of potassium carbonate and 150 ml of N, N-dimethylformamide (DMF) and the mixture was stirred at room temperature for 2 days.

Kakršno koli netopno snov odstranimo s filtriranjem in filtrat uparimo do suhega pod zmanjšanim tlakom. Preostanku dodamo vodo in zmes ekstrahiramo s kloroformom. Kloroformov ekstrakt posušimo preko brezvodnega natrijevega sulfata in topilo odstranimo pod zmanjšanim tlakom. Nastalo bledo rumeno oljnato substanco destiliramo pri zmanjšanem tlaku, da dobimo 7,5 g etil 1-acetil-1-ciklopropankarboksilata z vreliščem od 70 do 71°C/2 do 3 mmHg. (T-3-3-9 mbara).Any insoluble matter is removed by filtration and the filtrate is evaporated to dryness under reduced pressure. Water was added to the residue and the mixture was extracted with chloroform. The chloroform extract was dried over anhydrous sodium sulfate and the solvent removed under reduced pressure. The resulting pale yellow oily substance was distilled off under reduced pressure to give 7.5 g of ethyl 1-acetyl-1-cyclopropanecarboxylate at a boiling point of 70 to 71 ° C / 2 to 3 mmHg. (T-3-3-9 mbar).

¹H-NMR (CDCI3) δ ppm: ¹ H-NMR (CDCl 3) δ ppm:

1.30 (3H, t, J=7Hz), 1.48 (4H, s), 2.49 (3H, s), 4.24 (2H, q, J=7Hz)1.30 (3H, t, J = 7Hz), 1.48 (4H, s), 2.49 (3H, s), 4.24 (2H, q, J = 7Hz)

35,7 g zgoraj dobljene spojine raztopimo v 200 ml etanola in raztopini dodamo pri sobni temperaturi med mešanjem po kapljicah 40 g broma. Zatem mešamo pri sobni temepraturi še 2 uri in nato odstranimo prebitek broma in topilo pri zmanjšanem tlaku, da dobimo etil 1-bromoacetil-1-ciklopropankarboksilat, katerega nato brez nadaljnjega’ čiščenja raztopimo v 200 ml etanola. K raztopini istočasno dodajamo po kapljicah med mešanjem in hlajenju z ledom 33 g R-(+)-1-feniletilamina in 27 g trietilamina v časovnem razdobju 1 ure. Po končanem dodajanju pustimo da reakcijska temperatura doseže sobno temperaturo in nadaljujemo mešanje pri sobni temperaturi 2 dni. Kakršnokoli netopno snov odstranimo s filtriranjem_?etanol pa odstranimo iz filtrata pri zmanjšanem tlaku. Preostanek raztopimo v 300 ml etilacetata in raztopino zaporedoma speremo z 1 N klorovodikovo kislino, nasičeno vodno raztopino natrijevega hidrogenkarbonata in nasičeno vodno raztopino natrijevega klorida^ v tem vrstnem redu. Organski sloj posušimo preko brezvodnega natrijevega sulfataDissolve 35.7 g of the above compound in 200 ml of ethanol and add 40 g of bromine dropwise at room temperature while stirring. The mixture was then stirred at room temperature for 2 hours and then the excess bromine and solvent removed under reduced pressure to give ethyl 1-bromoacetyl-1-cyclopropanecarboxylate, which was then dissolved in 200 ml of ethanol without further purification. 33 g of R - (+) - 1-phenylethylamine and 27 g of triethylamine are added dropwise to the solution simultaneously while stirring and cooling with ice over a period of 1 hour. After the addition is complete, allow the reaction temperature to reach room temperature and continue stirring at room temperature for 2 days. Any insoluble matter removed by filtration _? ethanol was removed from the filtrate under reduced pressure. The residue was dissolved in 300 ml of ethyl acetate and the solution was washed successively with 1 N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride ^ in that order. The organic layer was dried over anhydrous sodium sulfate

- 56 --in odstranimo pri zmanjšanem tlaku. Preostanek kromatografiramo na 200 g koloni silikagela, katero spiramo z 0 do 2 %-nim metanolnim kloroformom, da dobimo naslovno spojino (19) v obliki brezbarvnih kristalov.- 56 - and removed under reduced pressure. The residue is chromatographed on a 200 g silica gel column, which is washed with 0 to 2% methanol chloroform to give the title compound (19) as colorless crystals.

Tališče: 98-103°C ^H-NMR (CDCI3) δ ppm:Melting point: 98-103 ° C. @ 1 H-NMR (CDCI3) δ ppm:

1.62 (3H, d, J=7.2Hz), 3.5 (IH, d, J=18Hz), 3.9 (IH, d, J=18Hz), 5.82 (IH, q, J=7.2Hz), 7.36 (5H, s)1.62 (3H, d, J = 7.2Hz), 3.5 (1H, d, J = 18Hz), 3.9 (1H, d, J = 18Hz), 5.82 (1H, q, J = 7.2Hz), 7.36 (5H. s)

2) 5-/(1R)-feniletil/-7-hidrok3imino-4-okso-5-azaspiro/2,4/heptan (20)2) 5 - [(1R) -phenylethyl] -7-hydroxyimino-4-oxo-5-azaspiro / 2,4 / heptane (20)

K 3,35 g spojine (19) dodamo 1,6 g hidroksilaminhidroklorida 2,3 g trietilamina in 80 ml etanola in zmes mešamo pri sobni temepraturi 2 uri. Topijo odstranimo pri zmanjšanem tlaku in dodamo preostanku kloroform. Zmes speremo zaporedoma z 10 %-no vodno raztopino citronske kisline in nasičeno vodno raztopino natrijevega klorida. Organski slojTo 3.35 g of compound (19) was added 1.6 g of hydroxylamine hydrochloride 2.3 g of triethylamine and 80 ml of ethanol and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and chloroform was added to the residue. The mixture was washed successively with 10% citric acid aqueous solution and saturated aqueous sodium chloride solution. Organic layer

posušimo preko brezvodnega dried over anhydrous natrijevega sodium sulfata. sulfate. Topilo Solvent odstranimo pod zmanjšanim tlakom tako, removed under reduced pressure so that da dobimo to get 3,5 g 3,5 g naslovne spojine (20) v obliki the title compounds (20) in the form brezbarvnih colorless kristalov. of crystals. Tališče: 188-194°C Melting point: 188-194 ° C ¹H-NMR (CDCI3) δ ppm: ¹ H-NMR (CDCl 3) δ ppm: 1.2-1.4 (2H, m), 1.53 1.2-1.4 (2H, m), 1.53 (3H, d, J=7 (3H, d, J = 7 .2Hz & 2H, .2Hz & 2H, m), m),

3.8 (IH, d, J=18Hz), 4.16 (lH_r d, J=18Hz), 5.63 (IH, q, J=7.2Hz), 7.32 (5H, s)3.8 (1H, d, J = 18Hz), 4.16 (1H _r d, J = 18Hz), 5.63 (1H, q, J = 7.2Hz), 7.32 (5H, s)

- -5-7 ·3) 7-amino-4-okso-5-/(1R)-feniletil/-5-azaspiro/2,4/-heptan (21a, 21b)- -5-7 · 3) 7-amino-4-oxo-5 - [(1R) -phenylethyl] -5-azaspiro / 2,4 / -heptane (21a, 21b)

K 150 ml metanola dodamo 3,5 g spojine (20) in 7,5 ml Raneyevega niklja in vršimo katalitsko redukcijo pri sobni temperaturi 12 ur. Po odstranitvi katalizatorja s filtriranjem odstranimo topilo iz filtrata pri zmanjšanem tlaku. Preostanek kromatografiramo na 100 g koloni silikagela, katero spiramo z zmesnim topilom 5 % metanola ,v kloroformu, pri čemer dobimo 1,0 g naslovne spojine (21b) iz zgodnjih frakcij in 0,8 g naslovne spojisne (21a) iz kasnejših frakcij, vsako kot brezbarvno oljnato substanco.3.5 g of compound (20) and 7.5 ml of Raney nickel were added to 150 ml of methanol and the catalytic reduction was carried out at room temperature for 12 hours. After removal of the catalyst by filtration, the solvent is removed from the filtrate under reduced pressure. The residue was chromatographed on 100 g of a silica gel column, which was washed with a mixed solvent of 5% methanol in chloroform to give 1.0 g of the title compound (21b) from the early fractions and 0.8 g of the title compound (21a) from the subsequent fractions, each as a colorless oily substance.

Spojina (21b):Compound (21b):

^H-NMR (CDC1₃) « ppm:1 H-NMR (CDCl ₃ )? Ppm:

0.8-1.4 (4H, m), 1.52 (3H, d, J=7Hz), 2.87 (IH, dd, J=10, & 3Hz), 3.3-3.9 (2H, m)', 4.27 (2H, airok s), 5.42 (IH, q, J=7Hz), 7.29 (5H, s)0.8-1.4 (4H, m), 1.52 (3H, d, J = 7Hz), 2.87 (1H, dd, J = 10, & 3Hz), 3.3-3.9 (2H, m) ', 4.27 (2H, airo ), 5.42 (1H, q, J = 7Hz), 7.29 (5H, s)

Spojina (21a):Compound (21a):

¹H-NMH (CDCI3) δ ppm: ¹ H-NMH (CDCl 3) δ ppm:

0.6-1.3 (4H, m), 1.40 (2H, s),- 1.53 (3H, d,0.6-1.3 (4H, m), 1.40 (2H, s), - 1.53 (3H, d,

J=7.2Hz), 2.99 (IH, dd, J=12.8, & 7.2Hz),J = 7.2Hz), 2.99 (1H, dd, J = 12.8, & 7.2Hz),

3.15-3.45 (2H, m), 5.52 (IH, q, J=7.2Hz), 7-30 (5H, s)3.15-3.45 (2H, m), 5.52 (1H, q, J = 7.2Hz), 7-30 (5H, s)

4) 7-amino-5-/(1R)-feniletil/-5-azaspiro/2,4/heptan (22a, 22b)4) 7-amino-5 - [(1R) -phenylethyl] -5-azaspiro / 2,4 / heptane (22a, 22b)

K 50 ml brezvodnega tetrahidrofurana dodamo 1,0 g spojine (21b) in 500 mg litijevega aluminijevega hidrida in zmes refluktiramo 17 ur. Po ohladitvi reakcijskih zmesiTo 50 ml of anhydrous tetrahydrofuran was added 1.0 g of compound (21b) and 500 mg of lithium aluminum hydride and the mixture was refluxed for 17 hours. After cooling the reaction mixtures

- 58 zaporedoma dodamo 0,5 ml vode, 0,5 ml 15 %-ne vodne raztopine natrijevega hidroksida in 1,5 ml vode v tem vrstnem redu, nakar dobro mešamo pri sobni temperaturi še 30 minut. Kakršnokoli netopno snov odstranimo s filtriranjem in dobro speremo s tetrahidrofuranom. Filtrat in izpirke združimo in posušimo. Topilo odstranimo pri zmanjšanem tlaku, da dobimo 940 mg naslovne spojine (22b) kot bledo rumeno oljnato substanco. Na enak način smo dobili 755 mg naslovne spojine (22a) iz 800 mg spojine (21a).- 58 ml of water, 0.5 ml of 15% aqueous sodium hydroxide solution and 1.5 ml of water in this order are added consecutively, then stirred well at room temperature for another 30 minutes. Any insoluble matter is removed by filtration and washed well with tetrahydrofuran. The filtrate and washings are combined and dried. The solvent was removed under reduced pressure to give 940 mg of the title compound (22b) as a pale yellow oily substance. In the same manner, 755 mg of the title compound (22a) was obtained from 800 mg of the compound (21a).

Spojina (21b):Compound (21b):

¹H-NMR (CDCI3) δ ppm: ¹ H-NMR (CDCl 3) δ ppm:

0.2-0.8 (4H, m), 1.35(3H, d,- J=6.6Hz), 1.6-2.0 (2H, uirok m), 2.2-3.1 (4H, m), 3.24 (IH, q,0.2-0.8 (4H, m), 1.35 (3H, d, - J = 6.6Hz), 1.6-2.0 (2H, width m), 2.2-3.1 (4H, m), 3.24 (1H, q.

J=6.6Hz), 3.5-3.9 (IH, m), 7.28 (5H, širok s)J = 6.6Hz), 3.5-3.9 (1H, m), 7.28 (5H, broad s)

Spojina (22a):Compound (22a):

¹H-NMR (CDCI3) δ ppm: ¹ H-NMR (CDCl 3) δ ppm:

0.3-0.9 (4H, m), 1.36 (3H, d, J=6.7Hz), 1.8-2.2 (2H, m), 2.2-3.2 (4H, m), 3.24 (IH, q, J=6.7Hz), 3.6-3.9 (IH, m), 7.28 (5H, široke)0.3-0.9 (4H, m), 1.36 (3H, d, J = 6.7Hz), 1.8-2.2 (2H, m), 2.2-3.2 (4H, m), 3.24 (1H, q, J = 6.7Hz) , 3.6-3.9 (1H, m), 7.28 (5H, broad)

5) 7-( t-butoksikarbonilamlno)-5-/1R)-feniletil/-5-azaspiro/2,4/heptan (23a, 23b)5) 7- (t-Butoxycarbonylamino) -5- (1R) -phenylethyl / -5-azaspiro / 2,4 / heptane (23a, 23b)

K 20 ml brezvodnega tetrahidrofurana dodamo 764 mg spojine (22b) in 1,3 g Boc-ON /Boc-ON; 2-(t-butoksikarbonil oksiimino /-2-fenilacetonitrilaTo 20 ml of anhydrous tetrahydrofuran was added 764 mg of compound (22b) and 1.3 g of Boc-ON / Boc-ON; 2- (t-Butoxycarbonyl oxyimino / -2-phenylacetonitrile

CN (CH₃)₃COCOON=CN (CH ₃ ) ₃ COCOON =

rr

5‘9‘ in zmes mešamo pri sobni temperaturi 4 ure. Reakcijski zmesi dodamo etil acetat in jo speremo dvakrat z 1 N vodno raztopino natrijevega hidroksida in nato enkrat z vodo, čemu sledi ekstrakcija z 10 %-no vodno raztopino citronske kisline. Vodne ekstrakte speremo enkrat z etilacetatom in vodnemu sloju med hlajenjem dodamo 15 %-no vodno raztopino natrijevega hidroksida, da ga naalkalimo. Zmes ekstrahiramo trikrat s kloroformom in nato organski sloj speremo z nasičeno vodno raztopino natrijevega klorida in ga nato posušimo. Topilo odstranimo pri zmanjšanem tlaku in preostanek kromatografiramo na koloni silikagela (silikagel: 20 g; elucijsko sredstvo: kloroform:metanol = 20:1, 10:1), da dobimo 690 mg naslovne spojine (23b). To spojino pustimo, da kristalizira in jo speremo n-heksanom. Naslovno spojino (23a) dobimo na enak način.5′9 ′ and the mixture was stirred at room temperature for 4 hours. Ethyl acetate was added to the reaction mixture and washed twice with 1 N aqueous sodium hydroxide solution and then once with water, followed by extraction with 10% aqueous citric acid. The aqueous extracts were washed once with ethyl acetate and a 15% aqueous solution of sodium hydroxide was added to the aqueous layer during cooling to make it alkaline. The mixture was extracted three times with chloroform and then the organic layer was washed with saturated aqueous sodium chloride solution and then dried. The solvent was removed under reduced pressure and the residue was chromatographed on a silica gel column (silica gel: 20 g; eluent: chloroform: methanol = 20: 1, 10: 1) to give 690 mg of the title compound (23b). This compound was allowed to crystallize and washed with n-hexanes. The title compound (23a) is obtained in the same manner.

Spojina (23b) (brezbarvni kristali):Compound (23b) (Colorless Crystals):

Tališče: 1Q3-1O5°C [a]_D: -15.2® (c=1.475, kloroform) ¹H-NMR (CDC1₃) 6 ppm:Melting point: 1Q3-1O5 ° C [a] _D : -15.2® (c = 1.475, chloroform) ¹ H-NMR (CDCl ₃ ) 6 ppm:

0.4-0.9 (4H, m), 1.36 (3H, d, J=7.2Hz), 1.44 (9H, s), 2.42 (2H, AB q, J=10.2 Hz), 2.79 (2H, d, J=5.6 Hz), 3.24 (IH, q, J=7.2Hz), 3.6-4.0 (IH, m), 4.6-5.1 (IH, šir. d), 7.28 (5H, s)0.4-0.9 (4H, m), 1.36 (3H, d, J = 7.2Hz), 1.44 (9H, s), 2.42 (2H, AB q, J = 10.2 Hz), 2.79 (2H, d, J = 5.6 Hz), 3.24 (1H, q, J = 7.2Hz), 3.6-4.0 (1H, m), 4.6-5.1 (1H, lat d), 7.28 (5H, s)

Elementna analiza za C₁₉H₂₈N₂O₂:Elemental analysis for C ₁₉ H ₂₈ N ₂ O ₂ :

Izrač. X%): C 72.12; H 8.92; N 8.85 Ugot.O): C 71.63; H 9.07; N 8.64Calc. X%): C 72.12; H, 8.92; N, 8.85; Found: O): C, 71.63; H, 9.07; N, 8.64

Spojina (23a) (brezbarvni kristali):Compound (23a) (Colorless Crystals):

Tališče: 94-97°C [a]_D: +47.6° (c=0’.89, kloroform) ¹H-NMR (CDC1₃) δ ppm:Melting point: 94-97 ° C [a] _D : + 47.6 ° (c = 0'.89, chloroform) ¹ H-NMR (CDCl ₃ ) δ ppm:

0.4-0.9 (4H, m), 1.33 (3H, d, J=6.6Hz), 1.40 (9H, s), 2.29 (IH, d, J=9Hz), -2.44 (IH, dd, J=10.8 & 3.6Hz), 2.77 (IH, d, J=9Hz), 2.88 (IH, dd, J=10.8 & 5.3Hz), 3.22 (IH, q, J=6.6Hz), 3.63.9 (IH, m), 4.7-5.2 (IH,sir. d), 7.27 (5H, s)0.4-0.9 (4H, m), 1.33 (3H, d, J = 6.6Hz), 1.40 (9H, s), 2.29 (1H, d, J = 9Hz), -2.44 (1H, dd, J = 10.8 & 3.6Hz), 2.77 (1H, d, J = 9Hz), 2.88 (1H, dd, J = 10.8 & 5.3Hz), 3.22 (1H, q, J = 6.6Hz), 3.63.9 (1H, m). 4.7-5.2 (1H, broad d), 7.27 (5H, s)

Elementna analiza za C_igH₂₈N₂O₂:Elemental analysis for C _ig H ₂₈ N ₂ O ₂ :

Izrač.:(%): C 72.12; H 8.92; N 8.85 8got.:(%): C 71.86; H 9.36; N 8.68Calc .: (%): C 72.12; H, 8.92; N, 8.85; H, 9.36; N, 8.68

6) 7-t-butoksikarbonilamino-5-azaspiro/2,4/heptan (24a, 24b)6) 7-t-Butoxycarbonylamino-5-azaspiro / 2,4 / heptane (24a, 24b)

K 30 ml etanola dodamo 650 mg spojine (23b) in 500 mg 50 %-nega hidrogeniranega paladija na oglju in vršimo katalitsko redukcijo pri segrevanju in tlaku 4,2 bara. Po 6 urah katalizator odfiltriramo in odstranimo topilo pri zmanjšanem tlaku. Oljnatemu preostanku dodamo etilacetat in ga dvakrat ekstrahiramo z 10 %-no vodno raztopino citronske kisline. Vodni ekstrakt naalkalimo s 15 %-no vodno raztopino natrijevega hidroksida in trikrat ekstrahiramo s kloroformom. Klorofornni sloj speremo z vodo in posušimo. Topilo odstranimo pri zmanjšanem tlaku, da dobimo 440 mg naslovne spojine (24b) kot surovi produkt. Naslovno spojino (24a) dobimo na enak način kot zgoraj. NMR spektra spojine (24b) in (24a) se popolnoma ujemata drug z drugim.650 mg of compound (23b) and 500 mg of 50% hydrogenated palladium on charcoal were added to 30 ml of ethanol and catalytic reduction was obtained at 4.2 bar heating and pressure. After 6 hours, the catalyst was filtered off and the solvent removed under reduced pressure. Ethyl acetate was added to the oily residue and extracted twice with 10% aqueous citric acid. The aqueous extract was basified with 15% aqueous sodium hydroxide solution and extracted three times with chloroform. The chlorophyll layer was washed with water and dried. The solvent was removed under reduced pressure to give 440 mg of the title compound (24b) as a crude product. The title compound (24a) is obtained in the same manner as above. The NMR spectra of compounds (24b) and (24a) are in perfect agreement with each other.

Spojina (24) ¹H-NMR (CDC1₃) δ ppm:Compound (24) ¹ H-NMR (CDCl ₃ ) δ ppm:

0.4-1.0 (4H, m), 1,42 (9H, s), 2.71 (IH, d.0.4-1.0 (4H, m), 1.42 (9H, s), 2.71 (1H, d.

J=10.2Hz), 2.92 (IH, dd, J=10.8 & 3.6 Hz), 3.01 (IH, d, J=10.2Hz), 3.33 (IH, dd, J=10.8 & 5.4 Hz), 3.5-3.9 (IH, m), 5.0-5.4 (IH, sir. d)J = 10.2Hz), 2.92 (1H, dd, J = 10.8 & 3.6 Hz), 3.01 (1H, d, J = 10.2Hz), 3.33 (1H, dd, J = 10.8 & 5.4 Hz), 3.5-3.9 ( 1H, m), 5.0-5.4 (1H, sir d)

PRIMER 9EXAMPLE 9

7-(7-t-butoksikarbonilamino-5-azaspiro/2,4/heptan-5-il)-8kloro-6-fluoro-1 - (1,2-cis-2-fluoro-1-ciklopropil)-1,4dihidro-4-oksokinolin-3-karboksilna kislina (25 bb)7- (7-t-butoxycarbonylamino-5-azaspiro / 2,4 / heptan-5-yl) -8chloro-6-fluoro-1- (1,2-cis-2-fluoro-1-cyclopropyl) -1. 4-Dihydro-4-oxoquinoline-3-carboxylic acid (25 bb)

V 0,6 ml acetonitrila raztopimo 160 mg 8-kloro-6,7difluoro-1-(1,2-cis-2-fluoro-1-ciklopropil)-1,4-dihidro-4oksokinolin-3-karboksilne kisline (12b), 150 mg amina spojine (24b), in 0,5 ml trietilamina, in raztopino segrevamo pri refluksu 5 ur. Po ohladitvi oborjene brezbarvne kristale zberemo s filtracijo. Topilo matičnice odstranimo pri zmanjšanem tlaku in preostanek čistimo s preparativno tankoplastno kromatografijo na silikagelu (TLC) z uporabo kloroform-metanola kot topila za razvijanje (5:1 volumsko). Očiščeni produkt in zgoraj dobljene kristale združimo, da dobimo 255 mg naslovne spojine (25bb).Dissolve 160 mg of 8-chloro-6,7-difluoro-1- (1,2-cis-2-fluoro-1-cyclopropyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid in 0.6 ml of acetonitrile (12b) , 150 mg of the amine of compound (24b), and 0.5 ml of triethylamine, and the solution heated at reflux for 5 hours. After cooling, the precipitated colorless crystals were collected by filtration. The mother liquor was removed under reduced pressure and the residue was purified by preparative thin layer chromatography on silica gel (TLC) using chloroform-methanol as the developing solvent (5: 1 by volume). The purified product and the crystals obtained above were combined to give 255 mg of the title compound (25bb).

Tališče: 213-218°C ¹H-NMR (CDC1₃) 6 ppm:Melting point: 213-218 ° C. ¹ H-NMR (CDCl ₃ ) 6 ppm:

0.6-1.0 (6H, m), 1,45 (9H,,s)_r 7.99 (12^ č,0.6-1.0 (6H, m), 1.45 (9H, s) _r 7.99 (12H,

J=13.1Hz), 8.74, 8.78 (vsak 0.5H, s)J = 13.1Hz), 8.74, 8.78 (each 0.5H, s)

PRIMER 10 (-)-7-(7-amino-5-azaspiro/2,4/heptan-5-il)-8-kloro-6-fluoro1 —(1,2-cis-2-fluoro-1- ciklopropil )-1,4-dihidro-4-oksokinolin3-karboksilna kislina (26bb)EXAMPLE 10 (-) - 7- (7-amino-5-azaspiro / 2,4 / heptan-5-yl) -8-chloro-6-fluoro- (1,2-cis-2-fluoro-1-cyclopropyl ) -1,4-Dihydro-4-oxoquinoline3-carboxylic acid (26bb)

K 255 mg Boc-spojine (25bb) dobljene v primeru 9 dodamo med hlajenjem z ledom 0,5 ml anizola in 10 ml trifluor- -62- ocetne kisline. Po segrevanju do sobne temperature zmes mešamo nadaljnjih 30 minut. Topilo odstranimo pri zmanjšanem tlaku in preostanku dodamo 1 N vodno raztopino natrijevega hidroksida, da uravnamo pH od 11 do 12. Alkalno vodno raztopino speremo dvakrat s kloroformom. Vodnemu sloju uravnamo pH na približno 7 s koncentrirano klorovodikovo kislino in 10 %-no vodno raztopino citronske kisline in ekstrahiramo trikrat s kloroformom. Ekstrakt speremo z vodo in posušimo preko brezvodnega natrijevega sulfata. Topilo odstranimo pri zmanjšanem tlaku in preostalo trdno snov prekristaliziramo iz etanol^/koncentriranega vodnega amoniaka,da dobimo 142 mg naslovne spojine (26bb) v obliki brezbarvnih kristalov.To the 255 mg of Boc compound (25bb) obtained in Example 9, 0.5 ml of anisole and 10 ml of trifluoro-62-acetic acid were added during ice-cooling. After warming to room temperature, the mixture was stirred for a further 30 minutes. The solvent was removed under reduced pressure and the residue was added with 1 N aqueous sodium hydroxide solution to adjust the pH from 11 to 12. The alkaline aqueous solution was washed twice with chloroform. The aqueous layer was adjusted to about 7 with concentrated hydrochloric acid and 10% aqueous citric acid and extracted three times with chloroform. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the remaining solid was recrystallized from ethanol / concentrated aqueous ammonia to give 142 mg of the title compound (26bb) as colorless crystals.

Tališče 127-14O°C (z razpadom) [a]„: -199.2® (c=0.24, IN NaOH)Melting point 127-14O ° C (decomposition) [a] ': -199.2® (c = 0.24, IN NaOH)

Elementna analiza za C₁₉H₁₈N₃O₃F₂C1’1/4H₂O: rzrac. : (%) i C 55.08; H 4.50; N 10.14 Ugot.': (%): C 54.86; H 4.80; -N 10.03Elemental analysis for C ₁₉ H ₁₈ N ₃ O ₃ F ₂ C1'1 / 4H ₂ O: rzrac. : (%) and C 55.08; H, 4.50; N, 10.14 Found:: (%): C 54.86; H 4.80; -N 10.03

PRIMER 11EXAMPLE 11

Sinteza spojine (26ab)Compound Synthesis (26ab)

Spojino (26ab) dobimo iz spojine (12a) in spojine (24b) na enak način, kot je opisano v primerih 9 in 10. Tališče: 123-128°C (z razpadom) [a]_D: +21.5° (c=0.195, IN NaOH)Compound (26ab) is obtained from compound (12a) and compound (24b) in the same manner as described in Examples 9 and 10. Melting point: 123-128 ° C (decomposition) [a] _D : + 21.5 ° (c = 0.195, IN NaOH)

Elementna analiza za C₁₉H₁₈N₃O₃F₂C1-1/2H₂O:Elemental analysis for C ₁₉ H ₁₈ N ₃ O ₃ F ₂ C1-1 / 2H ₂ O:

Izrač’..: (%): C 54.49; H 4.57; N 10.03 trgat.: (%): C 54.33; H 4.73; N 9.81Calc'd.: (%): C 54.49; H, 4.57; N, 10.03 Ht .: (%): C 54.33; H, 4.73; N, 9.81

PRIMER 12EXAMPLE 12

Sinteza spojine (26a)Synthesis of compound (26a)

Spojino (26a) sintetiziramo in spojine (12b) in spojine (24a) na enak način kot je opisano v primerih 9 inThe compound (26a) was synthesized and the compounds (12b) and the compounds (24a) in the same manner as described in examples 9 and

10.10.

Tališče: 121-127°C (z razpadom) [q]_Di -21,1° (c=0.275, IN NaOH)Melting point: 121-127 ° C (decomposition) [q] _D i -21,1 ° (c = 0.275, IN NaOH)

Elementarna analiza za C₁₉H₁₈N₃O₃F₂C1’1/2H₂O:Elemental analysis for C ₁₉ H ₁₈ N ₃ O ₃ F ₂ C1'1 / 2H ₂ O:

izrač.: (%): C 54.49; H 4.57; N 10.03 Ugot.:(%): C 54.77; H 4.43; N 9.86Calc .: (%): C 54.49; H, 4.57; N 10.03 Found :(%): C 54.77; H, 4.43; N, 9.86

PRIMER 13EXAMPLE 13

Sinteza spojine 26aa)Synthesis of compound 26aa)

Spojino (26aa) sintetiziramo iz spojine (12a) in spojine (24a) na enak način kot v primerih 9 in 10.The compound (26aa) was synthesized from compound (12a) and compound (24a) in the same manner as in Examples 9 and 10.

Tališče: 126-145°C (z razpadom) [a]_D: +186.6° (c=0.228, IN NaOH)Melting point: 126-145 ° C (decomposition) [a] _D : + 186.6 ° (c = 0.228, IN NaOH)

Elementna analiza za C_igH₁₈N₃O₃F₂Cl*3/4H₂O:Elemental analysis for C _ig H ₁₈ N ₃ O ₃ F ₂ Cl * 3 / 4H ₂ O:

Izrač.:(%): C 53.91; H 4.64; N 9.93 Ugot.:(%)j £ 53.80,γ H 4.47; N 9.82Calc .: (%): C 53.91; H 4.64; N 9.93 Found :(%)j £ 53.80, γ H 4.47; N, 9.82

REFERENČNI PRIMER 27 (-)-etil-8-kloro-7-fluoro-1-(1,2-cis-2-fluoro-1-ciklopropil)4-okso-l,4-dihidro-l,8-naftiridin-3-karboksilat (29a)REFERENCE EXAMPLE 27 (-) - Ethyl-8-chloro-7-fluoro-1- (1,2-cis-2-fluoro-1-cyclopropyl) 4-oxo-1,4-dihydro-1,8-naphthyridine- 3-carboxylate (29a)

Zmes 1 g etil 2,6-dikloro-5-fluoro-nikotinoilacetata (27), 3 ml etil ortoformata in 6 ml acetanhidrida med mešanjem segrevamo pri 120°C 1 uro. Reakcijsko zmes tparimo do suhega pri zmanjšanem tlaku in preostanek raztopimo v 10 ml diklorometana.A mixture of 1 g of ethyl 2,6-dichloro-5-fluoro-nicotinoyl acetate (27), 3 ml of ethyl orthoformate and 6 ml of acetanhydride was heated at 120 ° C for 1 hour with stirring. The reaction mixture was evaporated to dryness under reduced pressure and the residue was dissolved in 10 ml of dichloromethane.

ml trifluorocetne kisline ohladimo z ledom in v njej raztopimo 750 mg (+)-cis-1-(t-butoksi-karbonilamino)2-fluoroclklopropana (4a). Raztopino mešamo pri sobni temperaturi 20 minut, nakar jo odparimo do suhega pri zmanjšanem tlaku. Preostanek suspendiramo v 20 ml diklorometana in med hlajenjem z ledom dodamo 2,0 g trietilamina. K suspenziji nato dodamo zgoraj pripravljeno raztopino diklorometana in mešamo pri sobni temperaturi 30 minut.ml of trifluoroacetic acid was cooled with ice and dissolved 750 mg of (+) - cis-1- (t-butoxycarbonylamino) 2-fluorocyclopropane (4a). The solution was stirred at room temperature for 20 minutes and then evaporated to dryness under reduced pressure. The residue was suspended in 20 ml of dichloromethane and 2.0 g of triethylamine were added while cooling with ice. The suspension of dichloromethane prepared above was then added to the suspension and stirred at room temperature for 30 minutes.

Reakcijsko zmes speremo z vodo in posušimo preko brezvodnega natrijevega sulfata. Topilo odstranimo pri zmanjšanem tlaku. Preostanek kolonsko kromatografiramo na 50 g silikagela z uporabo kloroforma kot eluenta, da dobimo 1,29 g etil 2-(2,6-dikloro-5-fluoronikotinoil)-3-(1,2-cis-2fluoro-1-ciklopropil)akrilata (28a) kot brezbarvno olje.The reaction mixture was washed with water and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure. The residue was column chromatographed on 50 g of silica gel using chloroform as eluent to give 1.29 g of ethyl 2- (2,6-dichloro-5-fluoronicotinoyl) -3- (1,2-cis-2fluoro-1-cyclopropyl) acrylate (28a) as a colorless oil.

¹H-NMR (CDC1₃) δ ppms' ¹ H-NMR (CDCl ₃ ) δ ppms'

1.06 (3H, t, J=7Hz), 1.1-1.6 (2H, m), 2.86-3.18 (IH, m), 4.05 (2H, q, J=7Hz), 4,78 (IH, dm,1.06 (3H, t, J = 7Hz), 1.1-1.6 (2H, m), 2.86-3.18 (1H, m), 4.05 (2H, q, J = 7Hz), 4.78 (1H, dm.

J=63Hz), 7.36 (IH, d, J=7Hz), 8.31 (IH, d, J=14 Hz)J = 63Hz), 7.36 (1H, d, J = 7Hz), 8.31 (1H, d, J = 14 Hz)

V 25 ml brezvodnega dioksana raztopimo 1,29 g spojine (28a) in raztopini dodamo 300 mg 60 %-nega natrijevega hidrida ter mešamo 1 uro. Reakcijsko zmes koncentriramo pri zmanjšanem tlaku in preostanku dodamo 0,1 N klorovodikovo kislino. Izpadle kristale zberemo s filtracijo in zaporedoma speremo z vodo in dietiletrom, da dobimo 860 mg naslovne spojine (29a) kot brezbarvne kristale.Dissolve 1.29 g of compound (28a) in 25 ml of anhydrous dioxane and add 300 mg of 60% sodium hydride to the solution and stir for 1 hour. The reaction mixture was concentrated under reduced pressure and 0.1 N hydrochloric acid was added to the residue. The precipitated crystals were collected by filtration and washed sequentially with water and diethyl ether to give 860 mg of the title compound (29a) as colorless crystals.

- 65 Tališče: 184-185^eC [α]η: -1.26° (c=0.793, chloroform) ' Elementna analiza za - ₁F₂ ^W2°3- 65 Melting point: 184-185 ^e C [α] η: -1.26 ° (c = 0.793, chloroform) 'Elemental analysis for - ₁ F ₂ ^W 2 ° 3

Izrač.:(%): C 51.16; H 3.37; N 8.52 Ugot.:(%): C 51.12; H 3.26; N 8.52 ¹H-NMR (CDC1₃) 6 ppm:Calc .: (%): C 51.16; H, 3.37; N, 8.52. Found :(%): C 51.12; H, 3.26; N, 8.52. ¹ H-NMR (CDCl ₃ ) 6 ppm:

1.41 (3H, t, J=7Hz), 1.4-1.84 (2H, m), 3.50 (IH, m), 4.40 (2H, q, J=7Hz), 5.02 (IH, dm, J=65Hz),1.41 (3H, t, J = 7Hz), 1.4-1.84 (2H, m), 3.50 (1H, m), 4.40 (2H, q, J = 7Hz), 5.02 (1H, dm, J = 65Hz).

8.43 (IH, d, J=7$z), 8.66 (IH, s)8.43 (1H, d, J = 7 $ z), 8.66 (1H, s)

REFERENČNI PRIMER 28 (+)-etil 8-kloro-7-fluoro-1-(1,2-cis-2-fluoro-1-ciklopropil)4-okso-l,4-dihidro-1, 8-naftt,iridin-3-karboksilat (29b)REFERENCE EXAMPLE 28 (+) - Ethyl 8-chloro-7-fluoro-1- (1,2-cis-2-fluoro-1-cyclopropyl) 4-oxo-1,4-dihydro-1,8-naphthyl, iridine -3-carboxylate (29b)

Zmes 1,0 g etil 2,6-dikloro-5-fluoronikotinoilacetata (27), 3 ml etil ortoformata in 6 ml^.acetanhidrida med mešanjem segrevamo pri 120°C 1,5 ure. Reakcijsko zmes odparimo do suhega pri zmanjšanem tlaku in preostanek raztopimo v 10 ml diklorometana.A mixture of 1.0 g of ethyl 2,6-dichloro-5-fluoronicotinoyl acetate (27), 3 ml of ethyl orthoformate and 6 ml of ethyl acetate is heated at 120 ° C for 1.5 hours under stirring. The reaction mixture was evaporated to dryness under reduced pressure and the residue was dissolved in 10 ml of dichloromethane.

ml trifluoroocetne kisline ohladimo z ledom in v njej raztopimo 750 mg (-)-cis-1-(t-butoksi-karbonilamino)2-fluorociklopropana (4b). Raztopino mešamo pri sobni temperaturi 20 minut in odparimo do suhega pri zmanjšanem tlaku. Preostanek suspendiramo v 30 ml diklorometana in med hlajenjem z ledom dodamo 2,0 g trietilamina. K suspenziji nato dodamo zgoraj pripravljeno raztopino diklorometana in zmes mešamo pri sobni temperaturi 30 minut.ml of trifluoroacetic acid was cooled with ice and dissolved 750 mg of (-) - cis-1- (t-butoxycarbonylamino) 2-fluorocyclopropane (4b). The solution was stirred at room temperature for 20 minutes and evaporated to dryness under reduced pressure. The residue was suspended in 30 ml of dichloromethane and 2.0 g of triethylamine were added while cooling with ice. The dichloromethane solution prepared above was then added to the suspension and the mixture was stirred at room temperature for 30 minutes.

Reakcijsko zmes speremo z vodo in posušimo preko brezvodnega natrijevega sulfata. Topilo odparimo in preostanek čistimo s kolonsko kromatografijo na 50 g silikagela z uporabo kloroforma kot eluenta, da dobimo 1,29 g etil 2-(2,6dikloro-5-fluoronikotinoil)-3-(1,2-cis-2-fluoro-1-ciklopropil) akrilata (28b) kot brezbarvno olje.The reaction mixture was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by column chromatography on 50 g of silica gel using chloroform as eluent to give 1.29 g of ethyl 2- (2,6-dichloro-5-fluoronicotinoyl) -3- (1,2-cis-2-fluoro- 1-cyclopropyl) acrylate (28b) as a colorless oil.

Spojino (28b) (1,29 g) reagiramo na enak način kot spojino (28a), da dobimo 936 mg naslovne spojine (29b) kot brezbarvne kristale.Compound (28b) (1.29 g) was reacted in the same way as compound (28a) to give 936 mg of the title compound (29b) as colorless crystals.

Tališče: 183-185^eC [aId: +1.12° (c=1.07, kloroform) 'Elemejitna analiza· za ^ΐ4^ιι^Ρ2^2θ3Melting point: 183-185 ^e C [aId: + 1.12 ° (c = 1.07, chloroform) 'Elemental analysis · for ^ ΐ4 ^ ιι ^Ρ 2 ^ 2θ3

Izrač.: (%): C 51.16; H 3.37; N 8.52 Ugot»*: (%): C 51.39; H 3.24; N 8.49Calc .: (%): C 51.16; H, 3.37; N, 8.52. Found: *: (%): C 51.39; H, 3.24; N, 8.49

REFERENČNI PRIMER 29 (-)-8-kloro-7-fluoro-1-(1,2-cis-2-fluoro-1-Čiklopropil)-4okso-1,4-dihidro-1,8-naft.tiridin-3-karboksilna kislin a ( 30a)REFERENCE EXAMPLE 29 (-) - 8-Chloro-7-fluoro-1- (1,2-cis-2-fluoro-1-cyclopropyl) -4oxo-1,4-dihydro-1,8-naphthyridin-3 -carboxylic acid a (30a)

Zmes 800 mg spojine (29a) in 15 ml koncentrirane klorovodikove kisline med mešanjem segrevamo pri 100°C 1,5 ure. Reakcijski zmesi dodamo vodo in izpadle kristale zberemo s filtracijo, da dobimo 610 mg naslovne spojine (30a) v obliki brezbarvnih kristalov.A mixture of 800 mg of compound (29a) and 15 ml of concentrated hydrochloric acid was stirred at 100 ° C for 1.5 hours under stirring. Water was added to the reaction mixture and the precipitated crystals were collected by filtration to give 610 mg of the title compound (30a) as colorless crystals.

Tališče: 215-219°C /<A/_d: -20,65° (c = 0,910, kloroform)Melting point: 215-219 ° C / <A / _d : -20.65 ° (c = 0.910, chloroform)

REFERENČNI PRIMER 30 (+)-8-kloro-7-fluoro-1-(1,2-cis-2-fluoro-1-ciklopropil)-4okso-1,4-dihidro-1,8-naftfr iridin-3-karboksiln' a kislina (30b)REFERENCE EXAMPLE 30 (+) - 8-chloro-7-fluoro-1- (1,2-cis-2-fluoro-1-cyclopropyl) -4oxo-1,4-dihydro-1,8-naphthyridin-3- carboxylic acid (30b)

Zmes 870 mg spojine (29b) in 20 ml koncentrirane klorovodikove kisline med mešanjem segrevamo pri 100°C 2 uri. Reakcijski zmesi dodamo vodo in izpadle kristale zberemo s filtracijo, da dobimo 715 mg naslovne spojine (30b) v obliki brezbarvnih kristalov.A mixture of 870 mg of compound (29b) and 20 ml of concentrated hydrochloric acid was heated at 100 ° C for 2 hours while stirring. Water was added to the reaction mixture and the precipitated crystals were collected by filtration to give 715 mg of the title compound (30b) as colorless crystals.

Tališče 218-22O°C /<^£/_d: +22,34° (c = 0,555, kloroform)Melting point 218-22O ° C / <^ £ / _d : + 22,34 ° (c = 0.555, chloroform)

PRIMER 14EXAMPLE 14

7-/4-(S)-amino-2-(S)-metil-1-pirolidinil/-6-fluoro-1-(1,2cis-2-fluoro-1-ciklopropil)-4-okso-1,4-dihidro-1,8-nafttiridin7- [4- (S) -amino-2- (S) -methyl-1-pyrrolidinyl] -6-fluoro-1- (1,2cis-2-fluoro-1-cyclopropyl) -4-oxo-1, 4-Dihydro-1,8-naphthyridine

3- karboksilna kislina (31a)3- Carboxylic acid (31a)

V 15 ml trifluorocetne kisline raztopimo 3θθ mgDissolve 3θθ mg in 15 ml of trifluoroacetic acid

4- (S)-araino-1-t-butoksikarbonil-2-(S)-metilpirolidina (32) (prim. Terry Ronson, et al., J. Med. Chem., Vol. 31, s 1598 (1988), in raztopino mešamo pri sobni temperaturi 20 minut, nakar jo uparimo do suhega pri zmanjšanem tlaku. Preostanek raztopimo v 20 ml acetonitrila, raztopini dodamo 150 mg spojine (30a) in 2 ml trietilamina in refluktiramo 30 minut. Reakcijsko zmes uparimo do suhega pri zmanjšanem tlaku in preostanku dodamo klorovodikovo kislino. Zmes speremo s kloroformom. Z natrijevim hidroksidom uravnamo pH vodnega sloja na 13 in speremo s kloroformom. Nato uravnamo pH vodnega sloja na 7,5 in ekstrahiramo s kloroformom. Organski sloj posušimo preko brezvodnega natrijevega sulfata in topilo odstranimo pod zmanjšanim tlakom. Preostanek prekristaliziramo iz vodnega amoniaka/etanola, da dobimo 150 mg naslovne spojine (31a) kot brezbarvne kristale.4- (S) -araino-1-t-butoxycarbonyl-2- (S) -methylpyrrolidine (32) (cf. Terry Ronson, et al., J. Med. Chem., Vol. 31, p. 1598 (1988) , and the solution was stirred at room temperature for 20 minutes and then evaporated to dryness under reduced pressure. Hydrochloric acid was added to the pressure and the mixture was washed with chloroform, sodium hydroxide was adjusted to pH 13 and washed with chloroform, then the pH was adjusted to 7.5 and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed. The residue was recrystallized from aqueous ammonia / ethanol to give 150 mg of the title compound (31a) as colorless crystals.

Tališče 255-258°C /<<7_d: -14,52° (c=O,4l3, 0,1 N NaOH)255-258 ° C / << 7 _d : -14.52 ° (c = O, 4l3, 0.1 N NaOH)

Elementna analiza za C₁₇H₁₈F₂N₄O₃*1/4H₂O:Elemental analysis for C ₁₇ H ₁₈ F ₂ N ₄ O ₃ * 1 / 4H ₂ O:

IzraČ.-i (%)^: C 55.36; H 5.06; N 15.19Calc'd (%) ^: C 55.36; H, 5.06; N, 15.19

Ugot.:(%): C 55.09; H 5.40; N.15.04Found :(%): C 55.09; H 5.40; N.15.04

PRIMER 15 (-)-7-/3-(R)-/1-(S)-aminoetil/-1-pirolidinil/-8-kloro-6fluoro-1-(1,2-cis-2-fluorociklopropil)-4-okso-1,4-dihidrokinolin-3-karboksllna kislina (34b)EXAMPLE 15 (-) - 7- / 3- (R) - [1- (S) -aminoethyl] -1-pyrrolidinyl] -8-chloro-6-fluoro-1- (1,2-cis-2-fluorocyclopropyl) - 4-Oxo-1,4-dihydroquinoline-3-carboxylic acid (34b)

Zmes 159 mg (-)-8-kloro-6,7-difluoro-1-(1,2-cis-2fluoro—1-ciklopropil)-4-okso-1,4-dihidrokinolin-3-karboksilne kisline (12b), 160 mg 3-(R)-/1-(S)-t-butoksikarbonilaminoetil/. pirolidina (prim. JP—A—61 —31 1992), 400 mg trietilamina in 20 ml acetonitrila segrevamo pri refluksu 12 ur. Reakcijsko zmes koncentriramo pri zmanjšanem tlaku in preostanek raztopimo v kloroformu. Organsko raztopino zaporedoma speremo z 10 %-no vodno raztopino citronske kisline in vodo in posušimo preko brezvodnega natrijevega sulfata. Topilo odparimo in preostanek prekristaliziramo iz etilacetata/izopropiletra, da dobimo 220 mg (-)-7-/3-(R)-/1-(S)-t-butoksikarbonilaminoetil/ 1-pirolidinil/-8-kloro-6-fluoro-1-(1,2-cis-2-fluoro-1-ciklopropil)-4-okso-1,4-dihidrokinolin-3-karboksilne kisline (33b).A mixture of 159 mg of (-) - 8-chloro-6,7-difluoro-1- (1,2-cis-2fluoro-1-cyclopropyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (12b) , 160 mg 3- (R) - (1- (S) -t-butoxycarbonylaminoethyl). of pyrrolidine (cf. JP-A-61-31 1992), 400 mg of triethylamine and 20 ml of acetonitrile were heated at reflux for 12 hours. The reaction mixture was concentrated under reduced pressure and the residue dissolved in chloroform. The organic solution was washed successively with 10% aqueous citric acid and water and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was recrystallized from ethyl acetate / isopropyl ether to give 220 mg of (-) - 7- / 3- (R) - / 1- (S) -t-butoxycarbonylaminoethyl (1-pyrrolidinyl) -8-chloro-6-fluoro -1- (1,2-cis-2-fluoro-1-cyclopropyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (33b).

Tališče 189-193°C /pC/_D: -205° (c=O,985, kloroform)Mp 189-193 ° C / pC / _D : -205 ° (c = O, 985, chloroform)

Elementna analiza za ^C24^H28C1F₂ ^N3°5Elemental analysis for ^C 24 ^H 28 ^C 1 F ₂ ^N 3 ° 5

Izrač.: (%) s C 56.31; H 5.51; N 8.21 Ugot.: (%): C 56.16; H 5.48; N-8.21Calc .: (%) s C 56.31; H, 5.51; N 8.21 Found: (%): C 56.16; H, 5.48; N-8.21

- 69 V 10 ml trifluorocetne kisline raztopimo 200 mg spojine (33 b) in raztopino mešamo 30 minut. Reakcijsko zmes odparimo do suhega pri zmanjšanem tlaku in preostanek raztopimo v 1 N vodni raztopini natrijevega hidroksida in speremo s kloroformom. S klorovodikovo kislino uravnamo pH vodnega sloja na 7,4 in ekstrahiramo s kloroformom. Organski sloj posušimo preko brezvodnega natrijevega sulfata in topilo odparimo. Preostanek prekristaliziramo iz vodnega amoniak^/ etanola, da dobimo 140 mg naslovne spojine (34b) kot brezbarvne kristale.- 69 Dissolve 200 mg of compound (33 b) in 10 ml of trifluoroacetic acid and stir for 30 minutes. The reaction mixture was evaporated to dryness under reduced pressure and the residue was dissolved in 1 N aqueous sodium hydroxide solution and washed with chloroform. Hydrochloric acid was adjusted to pH 7.4 and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was recrystallized from aqueous ammonia / ethanol to give 140 mg of the title compound (34b) as colorless crystals.

Tališče: . 204-207°C (oJd: “160.0° (c=0.605, 0.1N NaOH)Melting point:. 204-207 ° C (oJd: 160.0 ° (c = 0.605, 0.1N NaOH)

Elementna analiza za ^ci9^H2o^clF2^N3°3*^H2^0jIzrač.: (%): C 53.09; H 5.38; N 9.?7 Ugot.:(%): C 53.20; H 5.17; N 9.66Elemental analysis for ^C i9 ^H 2o ^CLF 2 ^N 3 O 3 * ^H 2 ^0J Calcd .: (%): C, 53.09; H, 5.38; N 9.?7 Found :(%): C 53.20; H, 5.17; N, 9.66

REFERENČNI PRIMER 31REFERENCE EXAMPLE 31

Etil-2-(3-acetoksi-2,4,5-trifluorobenzoil)-3-(1,2-cis-2fluoro-ΐ-ciklopropil)akrilat (36b)Ethyl 2- (3-acetoxy-2,4,5-trifluorobenzoyl) -3- (1,2-cis-2fluoro-N-cyclopropyl) acrylate (36b)

Zmes 1,0 g etil 3-acetoksi-2,4,5-trifluorobenzoilacetata (35) (prim. JP-A-87-175485), 6 ml etil ortoformata in 6 ml acetanhidrida med mešanjem segrevamo pri 120°C 3 ure. Reakcijsko zmes odparimo do suhega pri zmanjšanem tlaku in preostanek raztopimo v 10 ml diklorometana. .A mixture of 1.0 g of ethyl 3-acetoxy-2,4,5-trifluorobenzoyl acetate (35) (cf. JP-A-87-175485), 6 ml of ethyl orthoformate and 6 ml of acetanhydride was heated at 120 ° C for 3 hours under stirring. The reaction mixture was evaporated to dryness under reduced pressure and the residue was dissolved in 10 ml of dichloromethane. .

V 5 ml trifluorocetne kisline raztopimo 467 mg (-)-cis-1-t-butoksikarbonilamino-2-fluorociklopropana (4b), in raztopino mešamo 20 minut, nakar jo odparimo do suhega pri zmanjšanem tlaku. Preostanek suspendiramo v 20 ml diklorometana in po kapljicah, med hlajenjem z ledom dodamo 5 ml raztopine diklorometana, ki vsebuje 500 mg trietilamina, nakar raztopino mešamo nadaljnjih 10 minut. K tej raztopini dodamo zgoraj pripravljeno raztopino diklorometana in zmes mešamo pri sobni temperaturi 16 ur. Reakcijsko zmes speremo zaporedoma z 10 %-no vodno raztopino citronske kisline in vodo. Organski sloj posušimo preko brezvodnega natrijevega sulfata in odparimo pri zmanjšanem tlaku, da dobimo 1,25 g naslovne spojine (36b).Dissolve 467 mg of (-) - cis-1-t-butoxycarbonylamino-2-fluorocyclopropane (4b) in 5 ml of trifluoroacetic acid and stir the solution for 20 minutes then evaporate to dryness under reduced pressure. The residue was suspended in 20 ml of dichloromethane and added dropwise while cooling with ice 5 ml of dichloromethane containing 500 mg of triethylamine were added and the solution was stirred for a further 10 minutes. The dichloromethane solution prepared above was added to this solution and the mixture was stirred at room temperature for 16 hours. The reaction mixture was washed successively with 10% aqueous citric acid and water. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 1.25 g of the title compound (36b).

REFERENČNI PRIMER 32 (-)-etil 6,7,-difluoro-1-(1,2-cis-2-fluoro-1-oiklopropil)-8metoksi-4-okso-1,4-dihidrokinolin-3-karboksilat (37b)REFERENCE EXAMPLE 32 (-) - Ethyl 6,7, -difluoro-1- (1,2-cis-2-fluoro-1-cyclopropyl) -8methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (37b )

V 40 ml dioksana raztopimo 1,25 g spojine (36b) in 440 mg kalijevega karbonata, nato dodamo 10 ml vode in mešamo pri sobni temperaturi 19 ur. Reakcijsko zmes nevtraliziramo s klorovodikovo kislino, koncentriramo pri zmanjšanem tlaku in ekstrahiramo s kloroformom. Ekstrakt posušimo preko brezvodnega natrijevega sulfata in topilo odstranimo pri zmanjšanem tlaku. Preostanek raztopimo v 40 ml brezvodnega dioksana, dodamo 300 mg 60 %-nega natrijevega hidrida in 1 ml etiljodida in mešamo pri sobni temperaturi 24 ur. Reakcijsko zmes koncentriramo pri zmanjšanem tlaku in preostanek ekstrahiramo s kloroformom, speremo z vodo in posušimo preko brezvodnega natrijevega sulfata. Topilo odparimo. Preostanek prekristaliziramo in izopropiletra, da dobimo 235 mg naslovne spojine (37b) kot brezbarvne kristale.Dissolve 1.25 g of compound (36b) and 440 mg of potassium carbonate in 40 ml of dioxane, then add 10 ml of water and stir at room temperature for 19 hours. The reaction mixture was neutralized with hydrochloric acid, concentrated under reduced pressure and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. Dissolve the residue in 40 ml of anhydrous dioxane, add 300 mg of 60% sodium hydride and 1 ml of ethyl iodide and stir at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure and the residue was extracted with chloroform, washed with water and dried over anhydrous sodium sulfate. Evaporate the solvent. The residue was recrystallized and isopropyl ether to give 235 mg of the title compound (37b) as colorless crystals.

Tališče: 163-64®C [α]ο: -22.9® (c=0.490, kloroform) ¹H-NMR (CDC1₃) δ ppm:Melting point: 163-64®C [α] ο: -22.9® (c = 0.490, chloroform) ¹ H-NMR (CDC1 ₃ ) δ ppm:

1.40 (3H, t, J=7Hz), 1.3-1.8 (2H, m), 3.7-4.0 (IH, m), 4.10 (3H, d, J=2Hz), '4.38 (2H, g,1.40 (3H, t, J = 7Hz), 1.3-1.8 (2H, m), 3.7-4.0 (1H, m), 4.10 (3H, d, J = 2Hz), '4.38 (2H, g.

J=7Hz), 4.85 (IH, dm, J=63Hz), 8.02 (IH, dd,J = 7Hz), 4.85 (1H, dm, J = 63Hz), 8.02 (1H, dd,

J=9Hz, & 8.5Hz), 8.55 (IH, s)J = 9Hz, & 8.5Hz), 8.55 (1H, s)

Elementna analiza za ^ci6^Hi4^P3^NO4Elemental analysis for ^c i6 ^H i4 ^P 3 ^NO 4

Izrač.:(%):C 56.31; H 4.13; N 4.10 Ugot.:(%)? C 56.62; H 4.18; N 4.11Calc .: (%): C 56.31; H, 4.13; N 4.10 Found :(%)? C 56.62; H, 4.18; N, 4.11

REFERENČNI PRIMER 33-1 (+)-cis-4-araino-1-benzil-3-metil-2-oksopirolidin (45)REFERENCE EXAMPLE 33-1 (+) - cis-4-aryano-1-benzyl-3-methyl-2-oxopyrrolidine (45)

Zmes 5,13 g etil 1-benzil-3-metil-2-okso-3-pirolidinkarboksilata (42, prim. JP-A-62-4284), 40 ml 50 %-nega etanola in 2 g natrijevega hidroksida mešamo pri sobni temperaturi 42 ur. K tej reakcijski zmesi dodamo 100 ml vode in zmes speremo s kloroformom. Vodni sloj nevtraliziramo s klorovodikovo kislino in ekstrahirmo z etilacetatora. Ekstrakt posušimo preko brezvodnega natrijevega sulfata. Topilo odparimo, da dobimo 3,40 g (+)-1-benzil-2-okso-3-pirolidin karboksilne kisline (43) v obliki brezbarvnih kristalov.A mixture of 5.13 g of ethyl 1-benzyl-3-methyl-2-oxo-3-pyrrolidinecarboxylate (42, cf. JP-A-62-4284), 40 ml of 50% ethanol and 2 g of sodium hydroxide was stirred at room temperature. 42 hours. To this reaction mixture was added 100 ml of water and the mixture was washed with chloroform. The aqueous layer was neutralized with hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated to give 3.40 g of (+) - 1-benzyl-2-oxo-3-pyrrolidine carboxylic acid (43) as colorless crystals.

Spojino (43) (3,40 g), 4,45 g difenilfosforilazida 1,9 g trietilamina in 50 ml t-butilalkohola zmešamo in zmes segrevamo pri refluksu 12 ur. Reakcijsko zmes koncentriramo pri zmanjšanem tlaku in preostanek raztopimo v kloroformu. Raztopimo speremo zaporedoma z 10 %-no vodno raztopinoCompound (43) (3.40 g), 4.45 g diphenylphosphorylazide 1.9 g triethylamine and 50 ml t-butyl alcohol were stirred and the mixture was heated at reflux for 12 hours. The reaction mixture was concentrated under reduced pressure and the residue dissolved in chloroform. The solution is washed successively with 10% aqueous solution

ΊΖ ·citronske kisline, 2 %-no vodno raztopino natrijevega hidroksida in vodo, ter posušimo preko brezvodnega natrijevega sulfat?. Topilo odparimo in preostanek čistimo s kolonsko kromatografijo na silikagelu, z uporabo kloroform-metanola (97,5:2,5 volumsko) kot eluenta, da dobimo 1,76 g (+-cis-1benzi1-4-t-butoksikarbonilamino-3-metil-4-oksopirolidina (44) kot brezbarvno olje.Cit · Citric acid, 2% aqueous sodium hydroxide solution and water, and dried over anhydrous sodium sulfate ?. The solvent was evaporated and the residue was purified by silica gel column chromatography using chloroform-methanol (97.5: 2.5 by volume) as eluant to give 1.76 g (+ -cis-1benzyl-4- t -butoxycarbonylamino-3- methyl-4-oxopyrrolidine (44) as a colorless oil.

1,76 g spojine (44) raztopimo v 15 ml trifluorocetne kisline. Po 1 uri raztopino koncentriramo pri zmanjšanem tlaku. Preostanku dodamo 100 ml vode in zmes speremo z benzenom. Z natrijevim hidroksidom uravnamo pH vodnega sloja na 12 in ekstrahiramo s kloroformom. Organski sloj posušimo preko brezvodnega natrijevega sulfata in topilo odparimo, da dobimo naslovno spojino (45) kot brezbarvno..olje.1.76 g of compound (44) are dissolved in 15 ml of trifluoroacetic acid. After 1 hour the solution was concentrated under reduced pressure. To the residue was added 100 ml of water and the mixture was washed with benzene. The pH of the aqueous layer was adjusted to 12 with sodium hydroxide and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated to give the title compound (45) as a colorless oil.

^H-NMR (CDC1₃) 6 ppm:1 H-NMR (CDCl ₃ ) δ ppm:

1.25 (3H, d, J=7Hz), 1.44 (2H, s), 2.16 (IH, dt,1.25 (3H, d, J = 7Hz), 1.44 (2H, s), 2.16 (1H, dt,

J=7Hz), 2.83 (IH, dd, J=6.7Hz, & 8Hz), 3.14 (IH, •m), 3.38 (IH, dd, J=6.7Hz, & 8Hz), 4.48 (2H, s),J = 7Hz), 2.83 (1H, dd, J = 6.7Hz, & 8Hz), 3.14 (1H, • m), 3.38 (1H, dd, J = 6.7Hz, & 8Hz), 4.48 (2H, s).

7.28 (5H, s)7.28 (5H, s)

REFERENČNI PRIMER 33-2 >REFERENCE EXAMPLE 33-2>

Optična ločitev cis-4-amino-1-benzil-3-metil-2-oksopirolidina (45)Optical separation of cis-4-amino-1-benzyl-3-methyl-2-oxopyrrolidine (45)

V 40 ml diklorometana raztopimo 4,17 g spojine (45) in 3,3 ml piridina in raztopini po kapljicah dodamo raztopino 7,7 g (S)-N-p-toluensulfonilprolil klorida v 50 ml diklorometana in mešamo 4 ure.Dissolve 4.17 g of compound (45) and 3.3 ml of pyridine in 40 ml of dichloromethane and add a solution of 7.7 g (S) -N-p-toluenesulfonylpropyl chloride in 50 ml of dichloromethane dropwise and stir for 4 hours.

- 73 Reakcijsko zmes speremo zaporedoma z 1 N klorovodikovo kislino, nasičeno vodno raztopino natrijevega hidrogen karbonata in vodo ter posušimo preko brezvodnega natrijevega sulfata. Topilo odparimo pri zmanjšanem tlaku in preostanek kromatografiramo na koloni silikagela, pri čemer uporabimo etil acetat kot eluent za izolacijo izomerov. Vsakega od izomerov prekristaliziramo iz etilacetata, da dobimo 3,3 g in 3,6 g cis-1-benzil-3-metil-4-/(S)-N-p-toluensulfonilprolilamino/-2-oksopirolidina (46a) oz. (46b).- 73 The reaction mixture was washed successively with 1 N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was chromatographed on a silica gel column using ethyl acetate as the eluent to isolate the isomers. Each of the isomers was recrystallized from ethyl acetate to give 3.3 g and 3.6 g of cis-1-benzyl-3-methyl-4 - / (S) -N-p-toluenesulfonylprolylamino / -2-oxopyrrolidine (46a) or. (46b).

Spojina (46a);Compound (46a);

Rf ( silikagel tlC; etil acetat : 0.69 Tališče; 162°C [a]_D; -87.3® (c=0.735, kloroform)Rf (silica gel tlC; ethyl acetate: 0.69 Melting point; 162 ° C [a] _D ; -87.3® (c = 0.735, chloroform)

Spojina (46b);Compound (46b);

Rf (silikagel TLC; etil acetat): 0,61 Tališče: 175-177°CRf (silica gel TLC; ethyl acetate): 0.61 Melting point: 175-177 ° C

-148,6° (c=O,665, kloroform)-148.6 ° (c = O, 665, chloroform)

REFERENČNI PRIMER 33-3 (+)-cis-1-benzil-3-t-butoksikarbonilamino-4-metil-pirolidin (47a)REFERENCE EXAMPLE 33-3 (+) - cis-1-benzyl-3-t-butoxycarbonylamino-4-methyl-pyrrolidine (47a)

Zmes 3,23 g spojine (46a) in 50 ml koncentrirane klorovodikove kisline segrevamo pri refluksu 5 ur, nakar jo koncentriramo pri zmanjšanem tlaku. Preostanku dodamo 1 N vodno raztopino natrijevega hidroksida in raztopino ekstrahiramo s kloroformom. Organski sloj posušimo preko brezvodnega natrijevega sulfata in topilo odparimo, da dobimo 1,48 g spojine (45a) kot brezbarvno olje.A mixture of 3.23 g of compound (46a) and 50 ml of concentrated hydrochloric acid was refluxed for 5 hours, then concentrated under reduced pressure. To the residue was added 1 N aqueous sodium hydroxide solution and the solution was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated to give 1.48 g of compound (45a) as a colorless oil.

- 74 Produkt raztopimo v 10 ml tetrahidrofurana in raztopino po kapljicah dodajamo suspenziji 2,0 g litijevega aluminijevega hidrida v 50 ml tetrahidrofurana. Zmes segrevamo pri refluksu 24 ur. Nato dodamo k zmesi po kapljicah med hlajenjem z ledom 10 ml vode in po mešanju 30 minut kakršnokoli netopno snov odstranimo s filtracijo. Filtratu dodamo 1,92 g Boc-ON in mešamo nadaljnjih 24 ur. Reakcijsko zmes koncentriramo pri zmanjšanem tlaku in preostanek ektrahiramo s kloroformom. Ekstrakt zaporedoma speremo s 5 %-no vodno raztopino natrijevega hidroksida in vodo ter posušimo preko brezvodnega natrijevega sulfata. Topilo nato odparimo.- 74 The product is dissolved in 10 ml of tetrahydrofuran and a solution of dropwise 2.0 g of lithium aluminum hydride in 50 ml of tetrahydrofuran is added dropwise. The mixture was heated at reflux for 24 hours. Then 10 ml of water are added dropwise to the mixture during ice-cooling and after stirring for 30 minutes any insoluble matter is removed by filtration. 1.92 g of Boc-ON was added to the filtrate and stirred for a further 24 hours. The reaction mixture was concentrated under reduced pressure and the residue was extracted with chloroform. The extract was washed successively with 5% aqueous sodium hydroxide solution and water and dried over anhydrous sodium sulfate. The solvent was then evaporated.

Preostanek čistimo s kolonsko kromatografijo na silikagelu, pri čemer uporabimo kloroform-metanol (1:0 do 9:1 volumsko) kot eluent, da dobimo 1,7$ g kristalov. K produktu dodamo n-heksan in zmes mešamo, pri čemer izpade dl spojina. Kristale zberemo s filtracijo in filtrat koncentrira mo. Ta postopek dvakrat ponovimo. Pri tem dobimo 100 mg dl spojine iz filtrne pogače, in 1,61 g naslovne optično aktivne spojine (47a) iz matičnice.The residue was purified by silica gel column chromatography using chloroform-methanol (1: 0 to 9: 1 by volume) as eluant to give 1.7 g of crystals. N-Hexane was added to the product and the mixture was stirred to yield dl compound. The crystals were collected by filtration and the filtrate was concentrated. We repeat this process twice. This gives 100 mg dl of the compound from the filter cake and 1.61 g of the title optically active compound (47a) from the mother liquor.

Tališče; 48-52°C [a]o: +27.2° (c=2.33, kloroform) ^XH-NMR (CDC1₃) δ ppm:Melting point; 48-52 ° C [a] o: + 27.2 ° (c = 2.33, chloroform) ^X H-NMR (CDCl ₃ ) δ ppm:

1.07 (3H, d, J=7Hz), 1.43 (9H, s), 1.78-2.02 (2H, m), 2.62 (2H, d, J=5Hz), 2.84-3.10 (IH, m), 3.55 (2H, s), 3.5-3.8 (IH, m), 4.8-5.2 (IH, širok), 7.23 (5H, s)1.07 (3H, d, J = 7Hz), 1.43 (9H, s), 1.78-2.02 (2H, m), 2.62 (2H, d, J = 5Hz), 2.84-3.10 (1H, m), 3.55 (2H , s), 3.5-3.8 (1H, m), 4.8-5.2 (1H, broad), 7.23 (5H, s)

REFERENČNI PRIMER 33-4 (-)-cis-1-benzil-3-t-butoksikarbonilamino-4-metil-pirolidin (47b)REFERENCE EXAMPLE 33-4 (-) - Cis-1-benzyl-3-t-butoxycarbonylamino-4-methyl-pyrrolidine (47b)

Na enak način, kot za sintezo spojine (47a), toda izhajajoč iz 3,52 g spojine (46b) dobimo 1,72 g naslovne spojine (47b).In the same way as for the synthesis of compound (47a), but starting from 3.52 g of compound (46b), 1.72 g of the title compound (47b) is obtained.

Tališče: 57-6l°C /dl/_D: -31,21°.Melting point: 57-6l ° C / dl / _D : -31.21 °.

REFERENČNI PRIMER 33-5 cl3-3-t-butoksikarbonilamino-4-metilpirolidin (39a), (39b)REFERENCE EXAMPLE 33-5 cl3-3-t-butoxycarbonylamino-4-methylpyrrolidine (39a), (39b)

Spojino (47a) (1,61 g), 1,5 g 5 % paladija na oglju in 80 ml etanola mešamo in vršimo katalitsko redukcijo 5 ur med obsevanjem zmesi z infrardečo lučjo v vodikovi atmosferi pri pritisku 4 bare. Po končani peakciji katalizator odstranimo s filtracijo in filtrat koncentriramo, da dobimo 1,09 g surovega produkta kot brezbarvno olje. Produkt, ki se strdi pri stanju kot karbonat, smo uporabili brez nadaljnjega čiščenja.Compound (47a) (1.61 g), 1.5 g of 5% palladium on charcoal and 80 ml of ethanol were stirred and catalytically reduced for 5 hours while irradiating the mixture with an infrared light in a hydrogen atmosphere at a pressure of 4 bar. After the reaction was complete, the catalyst was removed by filtration and the filtrate was concentrated to give 1.09 g of crude product as a colorless oil. The product, which solidified as carbonate, was used without further purification.

Na enak način kot za sintezo spojine (39a) dobimo 1,1 g spojine (39b) iz 1,70g spojine (47b), kot brezbarvno olje.In the same way as for the synthesis of compound (39a), 1.1 g of compound (39b) is obtained from 1.70g of compound (47b) as a colorless oil.

REFERENČNI PRIMER 34REFERENCE EXAMPLE 34

Etil 2-(2,4,5-trifluoro-3-metilbenzoil)-3-(1,2-cis-2-fluoro1-ciklopropil)akrilat (50b)Ethyl 2- (2,4,5-trifluoro-3-methylbenzoyl) -3- (1,2-cis-2-fluoro-cyclopropyl) acrylate (50b)

Zmes 710 mg etil 2,4,5-trifluoro-3-metilbenzoilacetata (pripravljenega iz 2,4,5-trifluoro-3—«metilbenzojske kisline (48), 'prim.jP-A-62-215572), 6 ml etil ortoformata in 6 ml acetanhidrida med mešanjem segrevamo pri 120°C 2 uri. Reakcijsko zmes odparimo do suhega pri zmanjšanem tlaku In preostanek raztopimo v 10 ml diklorometana.Mixture of 710 mg ethyl 2,4,5-trifluoro-3-methylbenzoyl acetate (prepared from 2,4,5-trifluoro-3- methylbenzoic acid (48), cf. p-A-62-215572), 6 ml ethyl of the orthoformate and 6 ml of acetanhydride were heated at 120 ° C for 2 hours while stirring. The reaction mixture was evaporated to dryness under reduced pressure and the residue was dissolved in 10 ml of dichloromethane.

V 5 ml trifluorocetne kisline raztopimo 580 mg (-)-cis-1-t-butoksikarbonilamino-2-fluorociklopropana (4b), raztopino mešamo 30 minut, nakar jo odparimo do suhega pri zmanjšanem tlaku. Preostanek suspendiramo v 20 ml diklorometana in dodamo med hlajenjem z ledom 700 mg trietilamina. Raztopino mešamo 10 minut, nakar dodamo zgoraj pripravljeno raztopino diklorometana in pustimo stati preko noči. Reakcijsko zmes speremo z vodo in posušimo preko brezvodnega natrijevega sulfata. Topilo odparimo in preostanek kristaliziramo iz n-heksana, da dobimo 787 mg naslovne spojine (50b) kot bledo rumene kristale.Dissolve 580 mg of (-) - cis-1-t-butoxycarbonylamino-2-fluorocyclopropane (4b) in 5 ml of trifluoroacetic acid, stir the solution for 30 minutes and then evaporate to dryness under reduced pressure. The residue was suspended in 20 ml of dichloromethane and 700 mg of triethylamine was added while cooling with ice. The solution was stirred for 10 minutes, then the above dichloromethane solution was added and allowed to stand overnight. The reaction mixture was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was crystallized from n-hexane to give 787 mg of the title compound (50b) as pale yellow crystals.

REFERENČNI PRIMER 35 (-)-etil 6,7-difluoro-1-(1,2-cis-2-fluoro-1-ciklo-propil)-8metil-4-okso-l,4-dihidroklnolin-3-karboksilat (51b)REFERENCE EXAMPLE 35 (-) - Ethyl 6,7-difluoro-1- (1,2-cis-2-fluoro-1-cyclopropyl) -8methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate ( 51b)

V 20 ml brezvodnega dioksana raztopimo 600 mg spojine (50b) in raztopini dodamo suspenzijo 100 mg 60 %-nega natrijevega hidrida, spranega z n-heksanom, v majhni množini brezvodnega dioksana. Raztopino mešamo pri sobni temperaturi 1 uro, nakar dodamo 10 ml 10 %-ne vodne raztopine citronske kisline in koncentriramo pri zmanjšanem tlaku. Izpadle kristale zberemo s filtracijo, zaporedoma speremo z vodo, majhno množino etanola in dietil etra, pri čemer dobimo 480 mg naslovne spojine (51b) kot brezbarvne kristale.Dissolve 600 mg of compound (50b) in 20 ml of anhydrous dioxane and add a suspension of 100 mg of 60% sodium hydride washed with n-hexane in a small amount of anhydrous dioxane. The solution was stirred at room temperature for 1 hour, then 10 ml of a 10% aqueous citric acid solution was added and concentrated under reduced pressure. The precipitated crystals were collected by filtration, washed successively with water, a small amount of ethanol and diethyl ether to give 480 mg of the title compound (51b) as colorless crystals.

Tališče: 230-231°C (α]ηϊ -80.0° (c=0.350, .kloroform) ¹H-NMR (CDC1₃) 6 ppm:Melting point: 230-231 ° C (α] ηϊ -80.0 ° (c = 0.350, chloroform) ¹ H-NMR (CDCl ₃ ) 6 ppm:

1.40 (3H, t, J=7Hz), 1.1-1.7 (2H, m), 2.71 (3H, d, J=3.3Hz), 3.77-3.98 (IH, m), 4.38 (2H, q,1.40 (3H, t, J = 7Hz), 1.1-1.7 (2H, m), 2.71 (3H, d, J = 3.3Hz), 3.77-3.98 (1H, m), 4.38 (2H, q.

J=7Hz), 4.85 (2H, dm, J=64Hz), 8.12 (IH, dd,J = 7Hz), 4.85 (2H, dm, J = 64Hz), 8.12 (1H, dd,

J=10Hz), 8.54 (IH, d, J=3Hz)J = 10Hz), 8.54 (1H, d, J = 3Hz)

REFERENČNI PRIMER 36 (-)-6,7-difluoro-1-(1,2-cis-2-fluoro-1-ciklopropil)-8-metil4-okso-1,4-dihldrokinolin-3-karboksilri^ kislina (52b)REFERENCE EXAMPLE 36 (-) - 6,7-Difluoro-1- (1,2-cis-2-fluoro-1-cyclopropyl) -8-methyl4-oxo-1,4-dihydroquinoline-3-carboxylic acid (52b )

Zmes 480 mg estra spojine (51 b) in 10 ml koncentrirane klorovodikove kisline segrevamo med mešanjem pri 120°C 75 minut. Zmes ohladimo in izpadle kristale zberemo s filtracijo in speremo z vodo in etanolom, pri čemer dobimo 380 mg naslovne spojine (52b) kot brezbarvne kristale.A mixture of 480 mg of ester of compound (51 b) and 10 ml of concentrated hydrochloric acid was heated under stirring at 120 ° C for 75 minutes. The mixture was cooled and the precipitated crystals were collected by filtration and washed with water and ethanol to give 380 mg of the title compound (52b) as colorless crystals.

Tališče: 204°C [<x]ds “60.0° (c=0.100, kloroform) ¹H-NMR (CDC1₃) δ ppm:Melting point: 204 ° C [<x] ds 60.0 ° (c = 0.100, chloroform) ¹ H-NMR (CDCl ₃ ) δ ppm:

1.3-1.9 (2H, m), 2.80 (3H, d, J=5.8Hz), 4.1-4.4 (IH, m,, 4.15 (IH, dm, J=64Hz), 8.17 (IH, dd, J=16Hz), 8.82 (IH, d, J=4Hz), 14.2 (IH, s)1.3-1.9 (2H, m), 2.80 (3H, d, J = 5.8Hz), 4.1-4.4 (1H, m,, 4.15 (1H, dm, J = 64Hz), 8.17 (1H, dd, J = 16Hz) ), 8.82 (1H, d, J = 4Hz), 14.2 (1H, s)

PRIMER 16EXAMPLE 16

Hidroklorid (-)-6-/3-(R)-(1-(S)-aminoetil)-1-pirolidinil/-6fluoro-1-(1,2-cis-2-fluoro-1-ciklopropil)-8-metil-4-okso-1,4dihidrokinolin-3-karboksilne kisline (54b)(-) - 6- / 3- (R) - (1- (S) -aminoethyl) -1-pyrrolidinyl] -6-fluoro-1- (1,2-cis-2-fluoro-1-cyclopropyl) -8 hydrochloride -methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (54b)

Zmes 198 mg spojine (52b), 350 mg 3-(R)-/1-(S)-tbutoksikarbonilaminoetil/pirolidina, 5 ml dimetil sulfoksidaMixture of 198 mg of compound (52b), 350 mg of 3- (R) - / 1- (S) -butoxycarbonylaminoethyl / pyrrolidine, 5 ml of dimethyl sulfoxide

- 78 in 1,5 g trietilamina med mešanjem segrevamo pri 110 do 120°C 5 ur. Reakcijsko zmes uparimo do suhega pri zmanjšanem tlaku. Preostanek raztopimo v kloroformu in raztopino speremo z 10 %-no vodno raztopino citronske kisline in vodo, ter posušimo preko brezvodnega natrijevega sulfata. Topilo odparimo. Preostanek kromatografiramo na preparativni plošči za tankoslojno kromatografijo (TLC), katero razvijemo z zmesnim topilom kloroform/metanol (95:5 volumsko), pri čemer dobimo 110 mg 7-/3-(R)-/1-(S)-t-butoksikarbonilaminoetil/pirolidinil/-6,7difluoro-8-metil-4-dihidrokinolin-3-karboksilne kisline (53b) Rot bledo rumen prašek.- 78 and 1.5 g of triethylamine are stirred at 110-120 ° C for 5 hours while stirring. The reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in chloroform and the solution was washed with 10% aqueous citric acid solution and water, and dried over anhydrous sodium sulfate. Evaporate the solvent. The residue is chromatographed on a thin-layer chromatography (TLC) preparative plate, which is developed with a chloroform / methanol (95: 5 vol.) Mixed solvent, yielding 110 mg 7- / 3- (R) - / 1- (S) -t- butoxycarbonylaminoethyl / pyrrolidinyl) -6,7difluoro-8-methyl-4-dihydroquinoline-3-carboxylic acid (53b) Rot a pale yellow powder.

(CDC1₃) δ ppm:(CDC1 ₃ ) δ ppm:

1.24 (3H, d, J=7Hz), 1.45 (9H, s), 1.2-1.9 (2^H' m), 2.52 (3H, s), 1.9-2.7 (3H, m).> 3.2-4.2 (6^fl' m), 4.73 (IH, d, J=8Hz), 4.98 (IH, dm, J=65H^) r 7.77 (IH, d, J=13Hz), 8.70 (IH, d, J=3.5H%)1.24 (3H, d, J = 7Hz), 1.45 (9H, s), 1.2-1.9 ( ^2H 'm), 2.52 (3H, s), 1.9-2.7 (3H, m).> 3.2-4.2 (6 ^fl 'm), 4.73 (1H, d, J = 8Hz), 4.98 (1H, dm, J = 65H ^) r 7.77 (1H, d, J = 13Hz), 8.70 (1H, d, J = 3.5H%) )

K 110 mg spojine (53b) dodamo 5 mi koncentrirane HCl in mešamo pri sobni temperaturi 10 minut, nakar jo uparimo do suhega pri zmanjšanem tlaku. Preostanek prekristaliziramo iz etanola-dietiletra, pri čemer dobimo 62 mg naslovne spojine (54b) kot rumene kristale.To 110 mg of compound (53b) was added 5 m of concentrated HCl and stirred at room temperature for 10 minutes, then evaporated to dryness under reduced pressure. The residue was recrystallized from ethanol-diethyl ether to give 62 mg of the title compound (54b) as yellow crystals.

Tališče: 149-153°C /Λχ/θ: -34,4° (¢=0,168, 1N HCl)Melting point: 149-153 ° C / Λχ / θ: -34.4 ° (¢ = 0.168, 1N HCl)

PRIMER 17EXAMPLE 17

5-amino-7-(7-amino-5-azaspiro/2,4/heptan-5-il)-6,8-difluoro1- (1,2-cis-2-fluoro-1-ciklopropil)-4-okso-1,4-dihidrokinolin3-karboksilna kislina (56b)5-amino-7- (7-amino-5-azaspiro / 2,4 / heptan-5-yl) -6,8-difluoro-1- (1,2-cis-2-fluoro-1-cyclopropyl) -4- oxo-1,4-dihydroquinoline3-carboxylic acid (56b)

Zmes 100 mg (-)-5-amino-6,7,8-trifluoro-1-(1,2-cis2- fluoro-1-ciklopropil)-4-okso-1,4-dihidrokinolin-3-karboksilne kisline (17b), 100 mg 7-t-butoksikarbonilamino-5-azaspiro/2,4/heptana (24b), 300 mg trietilamina in 20 ml acetonitrila segrevamo pri refluksu 23 ur.A mixture of 100 mg (-) - 5-amino-6,7,8-trifluoro-1- (1,2-cis2-fluoro-1-cyclopropyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid ( 17b), 100 mg of 7-t-butoxycarbonylamino-5-azaspiro / 2,4 / heptane (24b), 300 mg of triethylamine and 20 ml of acetonitrile were heated at reflux for 23 hours.

Reakcijsko zmes uparimo do suhega pri zmanjšanem tlaku in preostanek raztopimo v 100 ml kloroforma. Raztopino speremo zaporedoma z 10 %-no vodno raztopino citronske kisline in vodo. Organski sloj posušimo preko brezvodnega natrijevega sulfata in topilo odparimo. Preostanek prekristaliziramo iz acetonitrila, pri čemer dobimo 120 mg 5-amino-77-t-butoksikarbonilamino-5-azaspiro/2,4/heptan-5-il/-6,8difluoro-1-(1,2-cis-2-fluoro-1-ciklopropil)-4-okso-1,4-dihidro kinolin-3-karboksilne kisli (55bb) kot rumene iglicam podobne kristale.The reaction mixture was evaporated to dryness under reduced pressure and the residue was dissolved in 100 ml of chloroform. The solution is washed successively with 10% aqueous citric acid and water. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was recrystallized from acetonitrile to give 120 mg of 5-amino-77-t-butoxycarbonylamino-5-azaspiro / 2,4 (heptan-5-yl) -6,8-difluoro-1- (1,2-cis-2- fluoro-1-cyclopropyl) -4-oxo-1,4-dihydro quinoline-3-carboxylic acid (55bb) as yellow needle-like crystals.

Tališče: 25O-253°C ¹H-NMR (CDC1₃) δ ppm:Melting point: 25O-253 ° C. ¹ H-NMR (CDCl ₃ ) δ ppm:

0.6-0.8 (2H, m), 0.8-1.0 (2H, m), 1.45 (9H, S),0.6-0.8 (2H, m), 0.8-1.0 (2H, m), 1.45 (9H, S),

1.3-1.8 (2H, m), 3.2-3.4 (IH, m), 3.6-3.9 (3H, m), 3.9-4.3 (2H, m), 4.85 (IH, dm, J=63Hz), 4.75.0 (IH, širok) 8.51 (IH, s)1.3-1.8 (2H, m), 3.2-3.4 (1H, m), 3.6-3.9 (3H, m), 3.9-4.3 (2H, m), 4.85 (1H, dm, J = 63Hz), 4.75.0 (1H, broad) 8.51 (1H, s)

V 5 ml trifluorocetne kisline raztopimo 120 mg spojine (55bb) in raztopino mešamo 30 minut, nakar jo uparimoDissolve 120 mg of compound (55bb) in 5 ml of trifluoroacetic acid and stir the solution for 30 minutes, then evaporate

- 80 do suhega pri zmanjšanem tlaku. Preostanek raztopimo v klorovodikovi kislini in raztopino speremo s kloroformom. Nato uravnamo pH vodnega sloja na 7,4 in ekstrahiramo s kloroformom. Ekstrakt posušimo preko brezvodnega natrijevega sulfata in topilo odparimo pri zmanjšanem tlaku. Preostanek prekristaliziramo iz vodnega amoniaka/etanola, pri čemer dobimo 65 mg naslovne spojine (56bb) kot rumene kristale.- 80 to dry under reduced pressure. The residue was dissolved in hydrochloric acid and the solution was washed with chloroform. The pH of the aqueous layer was then adjusted to 7.4 and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was recrystallized from aqueous ammonia / ethanol to give 65 mg of the title compound (56bb) as yellow crystals.

Tališče: 213-217°C /i/W_D: -96,7° (c=0,120, DMF).Melting point: 213-217 ° C / i / W _D : -96.7 ° (c = 0.120, DMF).

PRIMER 18EXAMPLE 18

7-/4-(S)-amino-2-(S)-metil-1-pirolidinil/-6-fluoro-1-(1,2cis-2-fluoro-1-ciklopropil)-4-okso-1,4-dihidro-1,8-naftiridin7- [4- (S) -amino-2- (S) -methyl-1-pyrrolidinyl] -6-fluoro-1- (1,2cis-2-fluoro-1-cyclopropyl) -4-oxo-1, 4-Dihydro-1,8-naphthyridine

3- karboksilna kislina (31b)3- Carboxylic acid (31b)

V 15 ml trifluorocetne kisline.. raztopimo 300 mgDissolve 300 mg in 15 ml of trifluoroacetic acid

4- (S)-amino-1-t-butoksikarbonil-2-(S)-metilpirolidina (32), raztopimo mešamo pri sobni temperaturi 20 minut, nakar jo uparimo do suhega pri zmanjšanem tlaku. Preostanek raztopimo v 20 ml brezvodnega acetonitrila in raztopini dodamo 150 mg spojine (30b) in 2 ml trietilamina, nakar jo refluktiramo 15 minut. Reakcijsko zmes uparimo do suhega pri zmanjšanem tlaku in preostanku dodamo 1 N klorovodikovo kislino; zmes speremo s kloroformom. Vodni sloj naalkalimo z 1 N vodno raztopino natrijevega hidroksida in speremo s kloroformom. Nato uravnamo pH vodnega sloja na 7 in ekstrahiramo s kloroformom. Organski sloj posušimo in topilo odparimo. Preostanek prekristaliziramo iz vodnega amonik^/etanola, pri čemer dobimo 130 ng naslovne spojine (31b).4- (S) -amino-1-t-butoxycarbonyl-2- (S) -methylpyrrolidine (32) was dissolved at room temperature for 20 minutes and then evaporated to dryness under reduced pressure. The residue was dissolved in 20 ml of anhydrous acetonitrile and 150 mg of compound (30b) and 2 ml of triethylamine were added to the solution and then refluxed for 15 minutes. The reaction mixture was evaporated to dryness under reduced pressure and 1 N hydrochloric acid was added to the residue; the mixture was washed with chloroform. The aqueous layer was basified with 1 N aqueous sodium hydroxide solution and washed with chloroform. The pH of the aqueous layer was then adjusted to 7 and extracted with chloroform. The organic layer was dried and the solvent was evaporated. The residue was recrystallized from aqueous ammonia / ethanol to give 130 ng of the title compound (31b).

Tališče: 247-255°C ( z razpadom) [a]_D: +120° (c=0.950, IN NaOH)Melting point: 247-255 ° C (decomposition) [a] _D : + 120 ° (c = 0.950, IN NaOH)

Elementna 'analiza za c₁₇ ·1/4Η₂ΟElemental 'analysis for c ₁₇ · 1 / 4Η ₂ Ο

Izrač.:(%): C 55.36? H 5.06? N 15.19 Ugot.:(%)_: C 55>$0; H 5.25; N 14.97Calc .: (%): C 55.36? H 5.06? N 15.19 Found _:( %) _: C 55> $ 0; H, 5.25; N, 14.97

PRIMER 19EXAMPLE 19

5-amino-6,8-difluoro-1-(1,2-cis-2-fluoro-1-ciklopropil)-7piperazinil-4-okso-kinolin-3-karboksilna kislina (57b)5-Amino-6,8-difluoro-1- (1,2-cis-2-fluoro-1-cyclopropyl) -7-piperazinyl-4-oxo-quinoline-3-carboxylic acid (57b)

Zmes 75 mg spojine (17b) in 45 mg brezvodnega piperazina v 5ml acetonitrila segrevamo pri refluksu 2 uri.A mixture of 75 mg of compound (17b) and 45 mg of anhydrous piperazine in 5 ml of acetonitrile was heated at reflux for 2 hours.

Reakcijo zmes uparimo pri zmanjšanem tlaku in preostanek prekristaliziramo iz etanola, pri čemer dobimo 72 mg naslovne spojine (57b) kot rumene kristale .The reaction mixture was evaporated under reduced pressure and the residue was recrystallized from ethanol to give 72 mg of the title compound (57b) as yellow crystals.

Tališče: 23O-239°C /cA-/_D: +8,00° (c=0,225, 1 N NaOH)Melting point: 23O-239 ° C / cA- / _D : + 8.00 ° (c = 0.225, 1 N NaOH)

REFERENČNI PRIMER 37REFERENCE EXAMPLE 37

6,7-difluoro-1-(1,2-cis-2-fluoro-1-ciklopropil)-8-metoksi-4okso-1,4-dihidrokinolin-3-karboksilna kislina »BF2“kelat (38b)6,7-Difluoro-1- (1,2-cis-2-fluoro-1-cyclopropyl) -8-methoxy-4oxo-1,4-dihydroquinoline-3-carboxylic acid "BF2" chelate (38b)

Zmes 230 mg estrske spojine (37b) in 5 ml 42 % fluoroborove kisline med mešanjem segrevamo pri 110°C 2 uri. Ohladimo, izpadle kristale zberemo s filtracijo in speremo z vodo, pri čemer dobimo 210 mg brezbarvnih kristalov naslovne spojine.A mixture of 230 mg of ester compound (37b) and 5 ml of 42% fluoroboronic acid was heated at 110 ° C for 2 hours while stirring. Cooled, the precipitated crystals were collected by filtration and washed with water to give 210 mg of colorless crystals of the title compound.

Tališče: 261-271°C.Melting point: 261-271 ° C.

Pri reakciji cis-3-t-butoksikarbonilamino-4-metilpirolidina (39a) in kelata spojine (38b), dobimo 7-(cis-3amino-4-metilpirolidinil)-6-fluoro-8-metoksi-4-okso-1,4-dihidro kinolin-3-karboksilno kislino (40ba). Nadalje pri reakciji aminske spojine (24) in kelatne spojine (38b), dobimo 7.(7-amino5-azaspiro/2,4/heptan-5-il )-6-fluoro-8-metoksi-4-okso-1,4dihidrokinolin-3-karboksilno kislino (4lbb).Reaction of cis-3-t-butoxycarbonylamino-4-methylpyrrolidine (39a) and chelate of compound (38b) yields 7- (cis-3amino-4-methylpyrrolidinyl) -6-fluoro-8-methoxy-4-oxo-1. 4-Dihydro quinoline-3-carboxylic acid (40ba). Further, by reaction of amine compound (24) and chelate compound (38b), 7. (7-amino5-azaspiro / 2,4 / heptan-5-yl) -6-fluoro-8-methoxy-4-oxo-1 is obtained. 4dihydroquinoline-3-carboxylic acid (4lbb).

Shema postopka je prikazana na priloženi sliki.The process diagram is shown in the attached figure.

Čeprav smo izum podrobno opisali z ozirom na njegove specifične izvedbe, pa bo strokovnjaku jasno razvidno, da je možno na njem izvesti razne spremembe in modifikacije, ne da bi se oddaljili od njegove zamisli in obsega.Although the invention has been described in detail with respect to its specific embodiments, it will be apparent to one skilled in the art that various modifications and modifications can be made to it without departing from its concept and scope.

3.3.

Tabela. Antimikrobna aktivnostTable. Antimicrobial activity

Γ3 CO CO CM Γ3 CO., LTD CO., LTD CM < 0.1 <0.1 ro > ro> 0.10 0.10 0.39 0.39 o **-4 o o ** - 4 o ro > ro> 0.20 0.20 0.39 0.39 O Oh X* X * ^“4 ^ “4 «—« «-« v—4 v — 4 T^4 T ^ 4 •—4 • —4 CM CM -Q -Q • • CO CO., LTD O Oh o o O Oh ca ca. o o O Oh ca ca. O Oh CM CM v v v v v v v v v v V V v v ca ca. ^4 ^ 4 »~4 »~ 4 «*—4 «* —4 ^4 ^ 4 ^“4 ^ “4 •4 • 4 Λ Λ • • CO CO., LTD O Oh O Oh O Oh O Oh O Oh C9 C9 ca ca. ca ca. r—« r— « v v v v v v v v v v v v v v ca ca. w™4 w ™ 4 »^4 »^ 4 4 4 ^4 ^ 4 +Ή + Ή ^4 ^ 4 ^4 ^ 4 CM CM CO CO., LTD 09 09 O Oh o o O Oh O Oh O Oh «O «Oh O Oh C9 C9 T—4 T-4 v v v v v v v v V V V V v v o o +*“4 + * “4 4 4 ^“4 ^ “4 τΗ τΗ *-4 * -4 *“4 * “4 «-4 «-4 CM CM ^9 ^ 9 CO CO., LTD C9 C9 C9 C9 O Oh o o θ θ O Oh ca ca. o o ^4 ^ 4 v v V V V V v v V V v v v v o o »“4 "" 4 w—4 w - 4 ^4 ^ 4 v—l v — l ^4 ^ 4 ^4 ^ 4 ^4 ^ 4 CM CM co co co co C9 C9 O Oh O Oh O Oh O Oh O Oh ca ca. O Oh v v v v V V v v v v v v v v ca ca. C9 C9 03 03 03 03 ^4 ^ 4 »H »H +-4 + -4 »•4 »• 4 ^4 ^ 4 ^4 ^ 4 CO CO., LTD e— e— ja yes 03 03 O Oh O Oh O Oh O Oh O Oh O Oh ca ca. ca ca. v v v v v v v v o o o o 03 03 o o o o 03 03 t— t— ,—4 , —4 »—4 »—4 cm cm CO CO., LTD ^4 ^ 4 ^4 ^ 4 co co tn tn co co 03 03 O Oh O Oh o o O Oh O Oh o o o o »4 »4 V V co co co co ’’*»· '' * »· ca ca. 03 03 3 3 o o ·—4 · —4 o o •“4 • “4 W W o o CM CM o o Ή Ή ^4 ^ 4 o o r·—4 r · —4 rH rH tn tn O Oh 'i? 'i? O Oh r—4 r — 4 CM CM CM CM cn cn o o o o co co CO CO., LTD CO CO., LTD tn tn t- t- a a co co * * cu cu «c «C Ui Ui o o tO tO • • • • • • •-o • -o C C co co co co 03 03 ui ui • • 03 03 Ul Ul Ul Ul o o •*4 • * 4 Ul Ul *—« * - « ω ω O Oh o o o o CM CM Ό Ό ••4 •• 4 SC SC ·—'4 · —'4 Ul Ul c c c c ••4 •• 4 •—4 • —4 CQ CQ u in 03 03 *«4 * «4 •«4 • «4 • • ε ε CO CO., LTD •r^ ¹ • r ^ ¹ • • co co O Oh bo will to that ui ui U U o o «H «H • • »O "Oh U U SJ SJ o o =3 = 3 03 03 03 03 P P ••4 •• 4 -H -H co co L- L- u in 03 03 Ό Ό CO CO., LTD m m ·—t · —T 3 3 e e 03 03 03 03 U U ••4 •• 4 M-4 M-4 4-5 4-5 o o > > co co <0 <0 3 3 O. O. o o • • «0 «0 03 03 • • ra ra • • u in • • • • U U 37 37 ♦ ♦ U U 03 03 to that ui ui « « • • 4-J 4-J LU LU cu cu tn tn cu cu C- C- cn cn to that tn tn

Daiichi Seiyaku Co., Ltd. . ./'.OptAČTlp Aktivni derivati ...Daiichi Seiyaku Co., Ltd. . ./'.OptAČTlp Active derivatives ...

REAKCIJSKA SHEMAREACTION SCHEME

PhPh

F COOH XcH3F COOH XcH3

8a,8b8a, 8b

9a,9a,

- 1Daiichi Seiyaku Co., Ltd. »Optično .aktivni derivati ...”- 1Daiichi Seiyaku Co., Ltd. "Optical .active derivatives ..."

ClCl

10a,10b10a, 10b

Ha. IlbHa. Ilb

12a,12b12a, 12b

13a,13b13a, 13b

NO2 oNO2 o

17a,17b 18a.18b17a, 17b 18a.18b

Daiichi Seiyaku Co., Ltd. .. . Optično.aktivni derivati ...Daiichi Seiyaku Co., Ltd. ... Optical.active derivatives ...

2020

22a,22b22a, 22b

NHBocNHBoc

23a,23b23a, 23b

NN

HH

24a,24b24a, 24b

Daiichi Seiyaku Co., Ltd. Optično aktivni derivati ...Daiichi Seiyaku Co., Ltd. Optically active derivatives ...

CtCt

AAi sN FAAi sN F

28a,26b28a, 26b

30a,30b30a, 30b

H2N'H2N '

31a, 31b31a, 31b

33b33b

34b34b

Daiichi Seiyaku Co., Ltd. .Optično aktivni derivati ...Daiichi Seiyaku Co., Ltd. .Optically active derivatives ...

Me COOB ^PhMe COOB ^ Ph

Me COOHMe COOH

Me -NHBocMe -NHBoc

Me NH2 °-Q ^PhMe NH 2 ° -Q ^ Ph

TsTs

46a,46b46a, 46b

Me NH2Me NH2

45a,45b45a, 45b

Me NHBocMe NHBoc

HH

47a,47b47a, 47b

39a,39b39a, 39b

Daiichi Seiyaku Co., Ltd.- ' <'-(TptieflQak'£ivni derivati ...Daiichi Seiyaku Co., Ltd.- '<' - (TptieflQak 'Derivatives ...

Claims

PATENTNI ZAHTEVKIPATENT APPLICATIONS

1. Postopek za pripravo N^-(1,2-cis-2-halogenociklopropil)subst. deri vata piridonkarboksilne kisline, prikazane z naslednjo formuloA process for the preparation of N, N - (1,2-cis-2-halogenocyclopropyl) subst. pyridonecarboxylic acid derivatives represented by the following formula

R¹ 0 kjer R predstavlja substituirano ali nesubstituirano amino skupino, hidroksilno skupino, tiolno skupino, ali atom vodika; R predstavlja substituirano ali nesubstituirano ciklično amino skupino, ki lahko vsebuje najmanj en hetero atom, izbran izmed atoma dušika, kisika ali žvepla, v njegovem 3 - 1 2 obroču; A predstavlja C-X ali atom dušika; X in X', ki sta lahko enaka ali različna vsakokrat predstavljata atom halogena,R ¹ 0 wherein R represents a substituted or unsubstituted amino group, a hydroxyl group, a thiol group, or a hydrogen atom; R represents a substituted or unsubstituted cyclic amino group which may contain at least one hetero atom selected from a nitrogen, oxygen or sulfur atom in its 3 - 1 2 ring; A represents CX or a nitrogen atom; X and X ', which may be the same or different at each time, represent a halogen atom

OOh

X^J pa predstavlja atom halogena, alkilno skupino z 1 do 6 atomi ogljika, alkoksilno skupino z 1 do 6 atomi ogljika, ciano skupino, trifluorometilno skupino ali atom vodika; s 1 pridržkom, da je izključen primer, kjer je R atom vodika in 2X ^J represents a halogen atom, an alkyl group of 1 to 6 carbon atoms, an alkoxyl group of 1 to 6 carbon atoms, a cyano group, a trifluoromethyl group or a hydrogen atom; with the proviso that the case where R is a hydrogen atom and 2 is excluded

R piperazinški ali 4-alkil-substituiran piperazinski ostanek, ali njegova sol.R is a piperazine or 4-alkyl-substituted piperazine residue, or a salt thereof.

označen s tem, da presnovimo 7-halogeno-1-(1,2-cis-2fluorociklopropiOpiridon karboksilno kislino z naslednjo formulocharacterized in that 7-halogeno-1- (1,2-cis-2fluorocyclopropyopyridone carboxylic acid is reacted with the following formula

R¹ 0 x’ γΛγΛ^εοοΗ x v2R ¹ 0 x 'γΛγΛ ^ εοοΗ x v2

VV

112 kjer imajo R , X , X in A zgoraj definirani pomen, X pa predstavlja atom halogena,112 wherein R, X, X and A have the meanings defined above and X represents a halogen atom,

2 _v v s ciklično aminsko spojino s formulo R -H, ki je lahko zaščite2 na z običajno zaščitno skupino, pri čemer ima R zgoraj navedeni pomen.2 _{to a} cyclic amine compound of formula R -H which may be protected2 to a conventional protecting group, wherein R is as defined above.

2. Postopek po zahtevku 1, označen s tem, da je R 4-do 7-členska ciklična amino skupina, ki je lahko substituirana z eno ali več hidroksilnih skupin, alkilnih skupin zA process according to claim 1, characterized in that R is a 4- to 7-membered cyclic amino group which may be substituted by one or more hydroxyl groups, alkyl groups with

1 do 6 atomi ogljika ali substituiranih ali nesubstituiranih amino skupin.1 to 6 carbon atoms or substituted or unsubstituted amino groups.

3. Postopek po zahtevku 1 ali 2, označen s tem, da je v 2 v ogrodje ciklične amino skupino R elan, izbran iz skupine, ki jo tvorijo pirolidin, piperidin, diazabicikloheptan in diazabiciklooktan,Process according to claim 1 or 2, characterized in that v 2 into the framework of the cyclic amino group R is a elan selected from the group consisting of pyrrolidine, piperidine, diazabicycloheptane and diazabicyclooctane,

4. Postopek po zahtevku 1 ali 2, kjer je R ciklična amino skupina, ki obsega en sam stereoizomer.The process of claim 1 or 2, wherein R is a cyclic amino group comprising a single stereoisomer.

5. Postopek po zahtevku 4, kjer je R 3-amino pirolidinilna skupina.The process of claim 4, wherein R is a 3-amino pyrrolidinyl group.

6. Postopek po zahtevku 4, označen s tem, da je R 7-ami no-5-azaspiro/2.4/heptan-5-ilna skupina.A process according to claim 4, wherein R is a 7-amino-5-azaspiro / 2.4 / heptan-5-yl group.

„ 2„2

7. Postopek po zahtevku 1, označen s tem, da je X atom fluora.A process according to claim 1, wherein X is a fluorine atom.