DK165877B - 1,4-DIHYDRO-6-FLUORO-4-OXO-1,8-NAPHTHYRIDINE-3-CARBOXYLIC ACID DERIVATIVES AND SALTS THEREOF, ANTIBACTERIAL PREPARATIONS CONTAINING SUCH COMPOUNDS - Google Patents
1,4-DIHYDRO-6-FLUORO-4-OXO-1,8-NAPHTHYRIDINE-3-CARBOXYLIC ACID DERIVATIVES AND SALTS THEREOF, ANTIBACTERIAL PREPARATIONS CONTAINING SUCH COMPOUNDS Download PDFInfo
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
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- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Description
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DK 165877BDK 165877B
Opfindelsen angår hidtil ukendte l,4-dihydro-6-fluor- 4-oxo-l,8-naphthyridi.n-3-carboxylsyrederivater med den i krav 1 angivne formel I, der er forbindelser, der udviser antibakteriel virkning, samt præparater inde- 5 holdende sådanne forbindelser.This invention relates to novel 1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridin-3-carboxylic acid derivatives of the formula I set forth in claim 1, which are compounds which exhibit antibacterial activity, as well as compositions of the present invention. - 5 holding such compounds.
Nalidixinsyre, piromidinsyre, pipemidinsyre og lignende er hidtil i udstrakt grad blevet anvendt som syntetiske antibakterielle midler. Imidlertid udviser ingen af disse midler tilfredsstillende terapeutiske virkninger iO på infektioner forårsaget af Pseudomonas aeruginosa og over for gram-positiv bakterier, der forårsager svært behandelige sygdomme. Derfor er der udviklet forskellige pyridoncarboxylsyretype-forbindelser som f.eks. l-ethyl-6-fluor-l,4-dihydro-4-oxo-7-(l-piperazinyl)-15 3-quinolincarboxylsyre (Norfloxacin) der er beskrevet i offentliggjorte belgisk ansøgning nr. 863 429 eller l-ethyl-6-fluor-l,4-dihydro-4.oxo-7-(l-piperazinyl)- 1,8-naphthyridin-3-carboxylsyre (Emoxacin: J. Med. Chem; 1984, p 292-301, DK offentliggjort ansøgning nr. 3336/79, 20 nu fremlæggelsesskrift nr. 153 552 og lignende forbindelser. Disse forbindelser udviser glimrende anti-bak-terielle virkninger over for forskellige gram-negative bakterier herunder Ps. aeruginosa, men udviser util-fredstillende anti-bakteriel virkning over for gram-po-25 sitiv bakterier. Derfor er det særdeles ønskeligt at udvikle et syntetisk anti-bakterielt middel, der udviser et bredt anti-bakterielt spektrum, men således at midlet er effektivt ikke alene over for gramnegative bakterier, men også over for gram-positive bakterier.Nalidixic acid, pyromidic acid, pipemidic acid and the like have so far been widely used as synthetic antibacterial agents. However, none of these agents exhibit satisfactory therapeutic effects iO on infections caused by Pseudomonas aeruginosa and against gram-positive bacteria causing difficult-to-treat diseases. Therefore, various pyridone carboxylic acid type compounds such as e.g. 1-Ethyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -15-quinoline carboxylic acid (Norfloxacin) disclosed in published Belgian Application No. 863 429 or 1-ethyl-6 -Fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) - 1,8-naphthyridine-3-carboxylic acid (Emoxacin: J. Med. Chem; 1984, p 292-301, DK published application no. 3336/79, 20 presently disclosed in U.S. Patent No. 153,552 and similar compounds, which exhibit excellent anti-bacterial effects against various gram-negative bacteria, including P. aeruginosa, but exhibit unsatisfactory anti-bacterial action against gram. Therefore, it is highly desirable to develop a synthetic antibacterial agent which exhibits a broad antibacterial spectrum, but so that the agent is effective not only against gram-negative bacteria but also against gram-positive bacteria. bacteria.
30 Som et resultat af større videnskabelige undersøgelser er det således nu lykkedes at udvikle de ovennævnte 1,4-dihydro-6-fluor-4-oxo-l,8-naphthyri din-3-carboxy-derivater og salte heraf ifølge opfindelsen, der løser disse problemer ved at udvise et bredt antibakterieltThus, as a result of major scientific studies, it has now been possible to develop the aforementioned 1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxy derivatives and salts thereof according to the invention which solves these problems by exhibiting a broad antibacterial
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2 spektrum både over for gram-positive og gram-negative bakterier, specielt over for antibiotikaresistente bakterier, og som giver høje koncentrationer i blodet, dersom de administreres peroralt eller parenteralt.2 spectrum both to gram-positive and gram-negative bacteria, especially to antibiotic-resistant bacteria, and which give high concentrations in the blood if administered orally or parenterally.
5 Samtidig er forbindelserne sikre at anvende, idet de udviser ringe toxicitet.At the same time, the compounds are safe to use as they exhibit low toxicity.
Opfindelsen angår også et antibakterielt præparat af den i krav 5 angivne art.The invention also relates to an antibacterial composition of the kind set forth in claim 5.
Ved opfindelsen tilvejebringes således 1,4-dihydro-6-10 fluor-4-oxo-l,8-naphthyridin-3-carboxlsyrederivater med den almene formel: 0 ^YYYco°h R3 |2Thus, the invention provides 1,4-dihydro-6-10 fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid derivatives of the general formula: 0 YYYco ° h R 3 | 2
RR
2 hvori R betegner en arylgruppe substitueret med mindst én substituent valgt blandt et halogenatom, en alkyl-gruppe og en hydroxygruppe; og fr betegner 1-pyrrolidinyl, 15 piperidino eller 1-piperazinyl, der eventuelt er sub stitueret med mindst én substituent valgt blandt alkyl, amino, hydroxy, alkenyl og alkylaminogrupper.2 wherein R represents an aryl group substituted by at least one substituent selected from a halogen atom, an alkyl group and a hydroxy group; and fr represents 1-pyrrolidinyl, 15 piperidino or 1-piperazinyl optionally substituted with at least one substituent selected from alkyl, amino, hydroxy, alkenyl and alkylamino groups.
Opfindelsen beskrives nærmere i det følgende.The invention is described in more detail below.
Blandt eventuelt anvendte carboxylbeskyttende grupper 20 omfatter de foretrukne beskyttende grupper f.eks. de i japansk patentansøgning Kokai (offentliggjort) nr.Among any used carboxyl protecting groups 20, the preferred protecting groups include e.g. those in Japanese patent application Kokai (published) no.
80 665/84 beskrevne carboxylbeskyttende grupper, der kan fjernes på kendt måde ved behandling under milde betingelser.80 665/84 described carboxyl protecting groups which can be removed in known manner by treatment under mild conditions.
2 32 3
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Arylgruppen betegnet R substitueret med en eller flere substituenter er valgt blandt halogenatomer som f.eks. fluor, chlor, brom og lod; alkyl grupperne som fortrinsvis er lige eller forgrenede C^-C.^ alkylgrupper er 3 methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tertbutyl, pentyl, hexyl, heptyl eller octyl.The aryl group designated R substituted by one or more substituents is selected from halogen atoms such as e.g. fluorine, chlorine, bromine and solder; the alkyl groups which are preferably straight or branched C 1 -C 4 alkyl groups are 3 methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl or octyl.
22
Herudover kan R være en hydroxygruppe.In addition, R may be a hydroxy group.
R^ er som nævnt 1-pyrrolidiny1, piperidino eller 1-pi-perazinyl, der eventuelt er substitueret med en eller 10 flere substituenter valgt blandt alkylgrupper som f.eks.R 1 is, as mentioned, 1-pyrrolidinyl, piperidino or 1-piperazinyl optionally substituted with one or more substituents selected from alkyl groups such as e.g.
lige eller forgrenede C^-C^ alkylgrupper som methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl og tert-butyl; aminogruppen; hydroxylgruppen; alkenyl-grupper som f.eks. C^-C^ alkenylgrupper som vinyl eller 15 allyl; alkylaminogrupper som f.eks. C^-C^ alkylamino- grupper som methyl amino, ethyl amino, n-propylamino eller isopropylamino.straight or branched C 1 -C 4 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl; the amino group; hydroxyl group; alkenyl groups such as e.g. C ^-C ^ alkenyl groups such as vinyl or allyl; alkylamino groups such as e.g. C 1 -C 4 alkylamino groups such as methyl amino, ethyl amino, n-propylamino or isopropylamino.
Blandt forbindelserne med den almene formel I, foretræk-2 kes de, hvori R betegner en fluorsubstitueret phenyl- 20 gruppe, og R betegner en substitueret eller usubsti- tueret 1-pyrrolidinyl eller 1-piperazinylgruppe, og 2 specielt foretrukne er de, hvori R betegner en 2,4-di f luorphenylgruppe , og R'* betegner en 3-amino-l-py rro-lidinylgruppe.Among the compounds of the general formula I, 2 are preferred, wherein R represents a fluoro-substituted phenyl group and R represents a substituted or unsubstituted 1-pyrrolidinyl or 1-piperazinyl group, and 2 are particularly preferred are those in which R represents a 2,4-di-fluorophenyl group, and R 1 represents a 3-amino-1-pyrrolidinyl group.
25 Salte af de omhandlede forbindelser med formlen I omfat ter almindelig salt ved basiske grupper som f.eks. en aminogruppe og lignende og ved sure grupper som f.eks. carboxyl syregruppen. Saltene ved de basiske grupper omfatter f.eks. salt med mineralsyrer som saltsyre el-30 ler svovlsyre; salt med organiske carboxylsyrer som f.eks. oxalsyre, myresyre, trichloreddikesyre eller trifluoreddikesyre; salt med sulfonsyrer som f.eks. methansu1fonsyre, p-toluensulfonsyre eller naphthalen-Salts of the compounds of formula I include common salt at basic groups such as e.g. an amino group and the like and by acidic groups such as e.g. the carboxylic acid group. The salts of the basic groups include e.g. salt with mineral acids such as hydrochloric acid or sulfuric acid; salt with organic carboxylic acids such as e.g. oxalic, formic, trichloroacetic or trifluoroacetic; salt with sulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid or naphthalene
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4 sulfonsyre. Saltene ved de sure grupper omfatter f.eks. salte med alkalimetaller som natrium eller kalium,· salte med jordalkalimetaller som f.eks. calcium eller magnesium; ammoniumsalte; og salte med nitrogenholdige organiske 5 baser som f.eks. procain, dibenzylamin, N-benzyΙ-β-phen- ethylamin, 1-ephenamin, N,N-dibenzylethylendiamin, tri-ethylamin, trimethylamin, tributylamin, pyridin, N,N-di-methylanilin, N-methylpiperidin, N-methylmorpholin, diethylamin eller dicyclohexylamin.4 sulfonic acid. The salts of the acidic groups include e.g. salts with alkali metals such as sodium or potassium; · salts with alkaline earth metals such as calcium or magnesium; ammonium salts; and salts with nitrogen-containing organic bases, e.g. procaine, dibenzylamine, N-benzyΙ-β-phenethylamine, 1-ephenamine, N, N-dibenzylethylenediamine, triethylamine, trimethylamine, tributylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine or dicyclohexylamine.
10 Dersom forbindelsen med den almene formel I eller et salt heraf har isomere (f.eks. optiske isomere, geometriske isomere, tautomere eller lignende) omfatter opfindelsen alle disse isomere, krystalformer og hydrater heraf.If the compound of general formula I or a salt thereof has isomers (e.g., optical isomers, geometric isomers, tautomers or the like), the invention encompasses all of these isomers, crystal forms and hydrates thereof.
15 Den anti-bakterielle virkning og den akutte toxicitet er illustreret for typiske omhandlede forbindelser, og den gode antibakterielle virkning i forhold til en kendt forbindelse er ligeledes vist.The anti-bacterial action and acute toxicity are illustrated for typical compounds, and the good antibacterial effect over a known compound is also shown.
1. Antibakteriel virkning 20 Forsøgsmetode1. Antibacterial effect 20 Test method
Som beskrevet i standardmetoden fra Japan Society of Chemotherapy [CHEMOTHERAPY, 29/1), 76-79(1981)], podes en bakterieopløsning fremstillet ved dyrkning i hjerteinfusionsbouillon (fremstillet af Eiken Kagaku) ved 25 37 °C i 20 timer på en hjerteinfusionsagar indeholdende et lægemiddel, og der blev dyrket 20 timer ved 37 °C, hvorefter bakterievæksten undersøgtes for at fastslå den minimumkoncentration, ved hvilken bakterievæksten hæmmedes, som MIC (jjg/ml). Mængden af podede bakterier 30 var 10^ celler/plade (10^ celler/ml). MIC-værdierne af forsøgsforbindelserne er angivet i tabel 1As described in the standard method of the Japan Society of Chemotherapy [CHEMOTHERAPY, 29/1), 76-79 (1981)], a bacterial solution prepared by growing in cardiac infusion broth (manufactured by Eiken Kagaku) is seeded at 25 ° C for 20 hours on a cardiac infusion agar containing a drug and cultured for 20 hours at 37 ° C, after which bacterial growth was examined to determine the minimum concentration at which bacterial growth was inhibited, as MIC (µg / ml). The amount of grafted bacteria 30 was 10 ^ cells / plate (10 ^ cells / ml). The MIC values of the test compounds are given in Table 1
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5 « og sammenlignet med en kendt forbindelse i tabel 2.5 'and compared to a known compound in Table 2.
Symbolerne anvendt i tabel 1 og 2 har følgende betydninger: *1: penicillinaseproducerende bakterie 5 *2: cephalosporinaseproducerende bakterieThe symbols used in Tables 1 and 2 have the following meanings: * 1: penicillinase-producing bacterium 5 * 2: cephalosporinase-producing bacterium
*3 podemængde: 10 celler/ml* 3 graft volume: 10 cells / ml
Me: methylgruppeMe: methyl group
Et: ethylgruppe n-Pr: n-propylgruppe 10 i-Pr: isopropylgruppeEt: ethyl group n-Pr: n-propyl group 10 i-Pr: isopropyl group
Enoxacin: OEnoxacin: Oh
* W'Nv" COOH* W'Nv "COOH
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c2h5 kendt forbindelse; den kraftigst virkende fra artiklen i J. Med. Chem, 1984, p 292-301 og anvendt som en positiv kontrol til sammenligning ved sammenligningsundersøgelsen (tabel 2).c2h5 known compound; the most powerful of the article in J. Med. Chem, 1984, p 292-301 and used as a positive control for comparison in the comparison study (Table 2).
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12 2. Akut toxicitet LD,-o-v/ærd3-erne opnået ved intravenøs administrering af forsøgsforbindelser nr. 5, 6 og 12 angivet ovenfor 5 til mus (ICR-stammen, han-mus,- legemsvægt: 18 - 25 g) var 200 mg/kg eller mere.12 2. Acute Toxicity The LD, ov / ore 3s obtained by intravenous administration of test compounds Nos. 5, 6 and 12 set forth above 5 to mice (ICR strain, male mice, body weight: 18-25 g) were 200 mg / kg or more.
Fremgangsmåden til fremstilling af de omhandlede forbindelser er angivet nedenfor.The process for preparing the compounds of the invention is set out below.
De omhandlede forbindelser kan f.eks. fremstilles ved 10 følgende fremstillingsmåde:The compounds of the invention may e.g. is produced by the following method of manufacture:
O OISLAND ISLAND
p p ^Y^Y^^COORla R33 . R3b [II] [IV] eller et salt heraf i o I o rYYvCOOBla _'Υπ"13 R3a Cl 1nh-RZ r3d [III] eller et salt heraf [yl eller et salt herafp p ^ Y ^ Y ^^ COORla R33. R3b [II] [IV] or a salt thereof in o I o rYYvCOOBla _'Υπ "13 R3a Cl 1nh-RZ r3d [III] or a salt thereof [yl or a salt thereof
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ΡγΧ cooh_^ pWv cooh R3a >2 ** l2 [la] eller et salt heraf [Ib] eller et salt heraf 3 hvori R betegner en carboxybeskyttende gruppe,ΡγΧ cooh_ ^ pWv cooh R3a> 2 ** l2 [la] or a salt thereof [Ib] or a salt thereof 3 wherein R represents a carboxy protecting group,
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13 R^3 betegner det samme halogenatom som i R^; R^*3 betegner den samme substituerede eller usubstituerede cykliske 3 2 ammogruppe som i R ; og R har ovenfor anførte betydninger .13 R3 represents the same halogen atom as in R4; R 3 represents the same substituted or unsubstituted cyclic 3 2 amino group as in R; and R has the above meanings.
5 Saltene af forbindelserne med de almene formler la,The salts of the compounds of the general formulas 1a,
Ib, III, IV og V omfatter de samme salte som saltene af forbindelserne med den almene formel I.Ib, III, IV and V comprise the same salts as the salts of the compounds of general formula I.
(i)(in)
Forbindelsen med den almene formel III eller et salt 10 heraf eller forbindelsen med den almene formel V eller et salt heraf fås henholdsvis ved omsætning af forbindelsen med den almene formel II eller forbindelsen med den almene formel IV eller et salt heraf med en acetal som f.eks. N,N-diethylformamidodimethylacetal, N,N-di- 15 methylformamidodiethylacetal eller lignende og herefter 2 2 med en amin med den almene formel R -NH^ (R har samme betydning som angivet ovenfor).The compound of the general formula III or a salt thereof or the compound of the general formula V or a salt thereof is obtained, respectively, by reacting the compound of the general formula II or the compound of the general formula IV or a salt thereof with an acetal as f. eg. N, N-diethylformamidodimethylacetal, N, N-dimethylformamidodiethylacetal or the like and then 2 with an amine of the general formula R -NH 2 (R has the same meaning as set forth above).
Opløsningsmiddel der anvendes ved ovennævnte reaktioner kan være et hvilket som helt opløsningsmiddel, der er 20 inert over for reaktionerne, og omfatter, men er ikke begrænset til aromatiske carbonhydrider som f.eks. benzen, toluen eller zylen; ethere som f.eks. dioxan, tetrahydra-furan, anisol eller diethylenglycoldimethylether; halogeneret carbonhydrider som f.eks. methylenchlorid, chloro-25 form eller dichlorethan; aminer som f.eks. N,N-dimethy1- formamid eller N,N-dimethylacetamid; sulfoxider som f.eks. dimethylsulfoxid osv., og disse opløsningsmidler kan anvendes alene eller i blandinger af to eller flere. Mængden af anvendt acetal er fortrinsvis 1 mol eller 30 mere, specielt ca. 1,0 - 1,3 mol pr. mol af forbindelsen med den almene formel II eller forbindelsen med den almene formel IV eller salt heraf. Reaktionerne udføresSolvent used in the above reactions can be any solvents which are 20 inert to the reactions and include, but are not limited to, aromatic hydrocarbons such as e.g. benzene, toluene or zylene; ethers such as e.g. dioxane, tetrahydrafuran, anisole or diethylene glycol dimethyl ether; halogenated hydrocarbons such as e.g. methylene chloride, chloroform or dichloroethane; amines such as e.g. N, N-dimethylformamide or N, N-dimethylacetamide; sulfoxides such as dimethylsulfoxide, etc., and these solvents may be used alone or in mixtures of two or more. The amount of acetal used is preferably 1 mole or 30 more, especially approx. 1.0 - 1.3 moles per moles of the compound of the general formula II or the compound of the general formula IV or salt thereof. The reactions are carried out
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14 sædvanligvis ved O °C til 100 °C, fortrinsvis ved 50 °C til 80 °C og sædvanligvis i 20 minutter til 50 timer, fortrinsvis 1 til 3 timer. Aminen anvendes i en mængde på 1 mol eller mere pr. mol af forbindelsen med den 5 almene formel II eller forbindelsen med den almene formel IV eller et salt heraf. Omsætningen udføres sædvanligvis ved 0 °C til 100 °C, fortrinsvis ved 10 °C til 60 °C og sædvanligvis i 20 minutter til 30 timer, fortrinsvis i 1 til 5 timer.14 usually at 0 ° C to 100 ° C, preferably at 50 ° C to 80 ° C and usually for 20 minutes to 50 hours, preferably 1 to 3 hours. The amine is used in an amount of 1 mole or more per liter. moles of the compound of general formula II or the compound of general formula IV or a salt thereof. The reaction is usually carried out at 0 ° C to 100 ° C, preferably at 10 ° C to 60 ° C, and usually for 20 minutes to 30 hours, preferably for 1 to 5 hours.
10 Som en alternativ metode er det muligt at omsætte forbindelsen med den almene formel II eller forbindelsen med den almene formel IV eller et salt heraf med ethylor.tho-formiat eller methylorthoformiat i nærværelse af acetan- hydrid og herefter med en amin med den almene formel 2 15 R -NH2 eller et salt heraf til fremstilling af henholdsvis forbindelsen med den almene formel III eller et salt deraf eller forbindelsen med den almene formel V eller et salt deraf.As an alternative method, it is possible to react the compound of the general formula II or the compound of the general formula IV or a salt thereof with ethylortho-formate or methylorthoformate in the presence of acetane hydride and then with an amine of the general formula Or a salt thereof to prepare the compound of the general formula III or a salt thereof, respectively, or the compound of the general formula V or a salt thereof.
(ii) 20 Forbindelsen med den almene formel la eller et salt heraf eller forbindelsen med den almene formel Ib eller et salt heraf opnås henholdsvis ved at underkaste forbindelsen med den almene formel III eller et salt heraf eller forbindelsen med den almene formel V eller et 25 salt heraf for ringslutning (fortrinsvis ved opvarmning) med eller uden en base.(ii) The compound of the general formula Ia or a salt thereof or the compound of the general formula Ib or a salt thereof is obtained respectively by subjecting the compound of the general formula III or a salt thereof or the compound of the general formula V or a compound thereof. salt thereof for cyclization (preferably by heating) with or without a base.
Opløsningsmidlet der anvendes ved denne omsætning kan være et hvilket som helst opløsningsmiddel, der er inert over for reaktionen, og omfatter, men er ikke begrænset 30 til f.eks. amider som Ν,Ν-dimethylformamid eller N,N-di- methylacetamid; ethere som dioxan, anisol eller diethylen-glycoldimethylether; sulfoxider som f.eks. dimethylsulfoxidThe solvent used in this reaction may be any solvent which is inert to the reaction and includes, but is not limited to, e.g. amides such as Ν, Ν-dimethylformamide or N, N-dimethylacetamide; ethers such as dioxane, anisole or diethylene glycol dimethyl ether; sulfoxides such as dimethyl sulfoxide
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15 osv. Opløsningsmidlerne kan anvendes alene eller i blanding af to eller flere. Basen omfatter f.eks. natriumhydrogen-carbonat, kaliumcarbonat, kaliumtert-butoxid eller natrium-hydrid. Mængden af base der anvendes er fortrinsvis 5 0,5 til 5 mol pr. mol af forbindelsen med den almene formel III eller V eller et salt heraf. Omsætningen udføres sædvanligvis ved 20 °C til 160 °C, fortrinsvis ved 100 °C til 150 °C og sædvanligvis i 5 minutter til 30 timer, fortrinsvis 5 minutter til 1 time.The solvents may be used alone or in admixture of two or more. The base includes e.g. sodium bicarbonate, potassium carbonate, potassium tert-butoxide or sodium hydride. The amount of base used is preferably 5 0.5 to 5 moles per moles of the compound of general formula III or V or a salt thereof. The reaction is usually carried out at 20 ° C to 160 ° C, preferably at 100 ° C to 150 ° C and usually for 5 minutes to 30 hours, preferably 5 minutes to 1 hour.
10 (i i i )10 (i i i)
Forbindelsen med den almene formel IV eller et salt heraf, forbindelsen med den almene formel V eller et salt heraf eller forbindelsen med den almene formel Ib eller et salt heraf fås henholdsvis ved omsætning 15 af forbindelsen med den almene formel II, forbindelsen med den almene formel III eller et salt heraf eller forbindelsen med den almene formel la eller et salt heraf med en cyklisk amin med den almene formel R^-H eller et salt heraf (hvori R^*3 har ovennævnte betydning).The compound of the general formula IV or a salt thereof, the compound of the general formula V or a salt thereof or the compound of the general formula Ib or a salt thereof are obtained respectively by reaction of the compound of the general formula II, the compound of the general formula III or a salt thereof or the compound of the general formula Ia or a salt thereof with a cyclic amine of the general formula R 1 -H or a salt thereof (wherein R 3 is the above meaning).
20 Opløsningsmidlet der anvendes ved omsætningen kan være et hvilket som helst opløsningsmiddel, der er inert over for reaktionen, og omfatter men er ikke begrænset til at aromatisk carbonhydrider som benzen, toluen eller lignende; ethere som f.eks. dioxan, tetrahydrofuran, 25 anisol eller diethylenglycoldiethylether ; halogenerede carbonhydr ider som f.eks. methylenchlorid, chloroform eller dichlorethan; amider som f.eks. N,N-dimethy1form-amid eller N,N-dimethylacetamid; sulfoxider som f.eks. dimethylsulfoxid; alkoholer som methanol eller ethanol; 30 nitriler som f.eks. acetonitriler, og disse opløsnings midler kan anvendes alene eller i blandinger af to eller flere. Mængden af den cykliske amin eller saltet herafThe solvent used in the reaction may be any solvent which is inert to the reaction and includes but is not limited to aromatic hydrocarbons such as benzene, toluene or the like; ethers such as e.g. dioxane, tetrahydrofuran, anisole or diethylene glycol diethyl ether; halogenated hydrocarbons such as e.g. methylene chloride, chloroform or dichloroethane; amides such as e.g. N, N-dimethylformamide or N, N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide; alcohols such as methanol or ethanol; 30 nitriles, e.g. acetonitriles, and these solvents may be used alone or in mixtures of two or more. The amount of the cyclic amine or its salt
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16 der anvendes, er fortrinsvis et overskud, foretrukkent to til 5 mol pr. mol af forbindelsen med den almene formel II, forbindelsen med den almene formel III eller et salt heraf eller forbindelsen med den almene formel 5 la eller et salt heraf. Dersom mængden af den cykliske amin, der anvendes, er ca. 1 til 1,3 mol, er det tilstrækkeligt, at et syrebindende middel anvendes i en mængde på 1 mol pr. mol af forbindelsen med den almene formel II, forbindelsen med -den almene formel III eller 10 et salt heraf eller forbindelsen med den almene formel la og et salt heraf. Det syrebindende middel omfatter organiske eller uorganiske baser som f.eks. triethylamin, l,8-diazabicyclo[5,4,0]undec-7-en (DBU), kaliumtert-butoxid, kaliumcarbonat, natriumcarbonat eller natrium-15 hydrid.16 used is preferably an excess, preferably two to 5 moles per ml. moles of the compound of the general formula II, the compound of the general formula III or a salt thereof or the compound of the general formula 5a or a salt thereof. If the amount of cyclic amine used is approx. 1 to 1.3 moles, it is sufficient that an acid-binding agent is used in an amount of 1 mole per day. mole of the compound of the general formula II, the compound of the general formula III or a salt thereof or the compound of the general formula Ia and a salt thereof. The acid binding agent comprises organic or inorganic bases such as e.g. triethylamine, 1,8-diazabicyclo [5,4,0] undec-7-ene (DBU), potassium tert-butoxide, potassium carbonate, sodium carbonate or sodium hydride.
Salte af R^-H omfatter de samme som saltene ved den basiske gruppe af forbindelsen med den almene formel I.Salts of R 1 -H comprise the same as the salts of the basic group of the compound of general formula I.
Omsætningen udføres sædvanligvis ved 0 °C til 150 °C, 20 fortrinsvis ved 50 °C til 100 °C og sædvanligvis i 5 minutter til 30 timer, fortrisnvis 30 minutter til 3 timer.The reaction is usually carried out at 0 ° C to 150 ° C, preferably at 50 ° C to 100 ° C, and usually for 5 minutes to 30 hours, preferably 30 minutes to 3 hours.
Forbindelsen med den almene formel la, Ib, III eller 1 3 V, hvori R betegner carboxybeskyttende grupper, eller 25 et salt heraf kan omdannes til den tilsvarende frie carboxylsyre ved hydrolyse af denne i nærværelse af en almindelig syre eller alkali, der anvendes til hydrolyse, sædvanligvis ved 0 °C til 100 °C, fortrinsvis ved 20 °C til 100 °C i 5 minutter til 50 timer, for-30 trinsvis 5 minutter til 4 timer. Eventuelt kan yderli gere forbindelsen med den almene formel la, Ib, III og V eller et salt heraf omdannes til et salt eller en ester af den tilsvarende forbindelse ved at underkasteThe compound of general formula Ia, Ib, III or 13 V wherein R represents carboxy protecting groups or a salt thereof can be converted to the corresponding free carboxylic acid by hydrolysis thereof in the presence of a common acid or alkali used for hydrolysis , usually at 0 ° C to 100 ° C, preferably at 20 ° C to 100 ° C for 5 minutes to 50 hours, preferably 5 minutes to 4 hours. Optionally, further the compound of general formula Ia, Ib, III and V or a salt thereof can be converted to a salt or ester of the corresponding compound by subjecting
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17 denne for en saltdannende omsætning eller estenfice-ring, der er velkendt. Dersom forbandelsen med den almene formel la, III, IV eller V eller et salt heraf indeholder en aktiv gruppe (f.eks. en hydroxylgruppe 5 eller amingruppe) ved andre stillinger end reaktions- pladserne, er det muligt forud at beskytte den aktive gruppe ved almindelige metoder og fjerne den beskyttende gruppe efter reaktionens afslutning.17 for a salt-forming reaction or esterification known in the art. If the compound of general formula Ia, III, IV or V or a salt thereof contains an active group (e.g. a hydroxyl group 5 or amine group) at positions other than the reaction sites, it is possible to protect the active group by common methods and remove the protecting group after the end of the reaction.
De fremstillede forbindelser kan underkastes almindelig 10 isolering og rensning som f.eks. søjlechromatograf1, omkrystallisation eller ekstraktion.The compounds prepared can be subjected to ordinary insulation and purification, e.g. column chromatograph1, recrystallization or extraction.
Forbindelsen med den almene formel 1 eller et salt heraf, hvori R^ betegner et halogenatom (svarende til forbindelsen med den almene formel la), kan også anvendes som 15 et mellemprodukt til fremstilling af en forbindelse, hvori betegner en substitueret eller usubstitueret cyklisk aminogruppe (svarende til forbindelsen med den almene formel Ib).The compound of general formula 1 or a salt thereof, wherein R 1 represents a halogen atom (similar to the compound of general formula Ia), can also be used as an intermediate for the preparation of a compound which represents a substituted or unsubstituted cyclic amino group ( corresponding to the compound of general formula Ib).
Dersom den omhandlede forbindelse anvendes som lægemiddel 20 eller terapeutisk præparat, blandes det passende med bærestoffer, der anvendes indenfor almindelig farmaceutisk praksis, og omdannes til tabletter, kapsler, pulvere, sirupper, granuler, suppositorier, salver eller injektioner på sædvanlig måde. Administreringsmåden, dosis 25 og antallet af administreringer kan passende udvælges afhængigt af patientens symptomer, og præparaterne kan administreres peroralt eller parenteralt (f.eks. ved injektion, drop eller administrering i rectum) til en voksen patient i en mængde på 0,ltil 100 mg/kg/dag 30 1 en eller flere portioner.If the subject compound is used as drug 20 or therapeutic composition, it is suitably mixed with carriers used in general pharmaceutical practice and converted into tablets, capsules, powders, syrups, granules, suppositories, ointments or injections in the usual manner. The method of administration, dose 25 and the number of administrations may be suitably selected depending on the patient's symptoms, and the compositions may be administered orally or parenterally (e.g., by injection, drip or rectum administration) to an adult patient in an amount of 0.1 to 100 mg. / kg / day 30 1 or more servings.
Opfindelsen forklares nærmere nedenfor under henvisning til referenceeksempler, eksempler og præparationseksemp-The invention will be explained in more detail below with reference to reference examples, examples and preparation examples.
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1818
Symbolerne anvendt i referenceeksempler og eksemplerne har følgende betydninger:The symbols used in reference examples and examples have the following meanings:
Me: methylgruppe, Et: ethylgruppe, n-Pr: n-propylgruppe, i-Pr: isopropylgruppe, 5 Ac: acetylgruppe */ allylgruppe, /\/ : ethylengruppeMe: methyl group, Et: ethyl group, n-Pr: n-propyl group, i-Pr: isopropyl group, Ac: acetyl group * / allyl group,
Referenceeksempel 1 I 210 ml chloroform opløstes 21 g 2,6-dichlor-5-fluorniko-tinsyre, og 23,8 g thlonylchlorid og 0,1 g N,N-dimethyΙ-ΙΟ formamid tilsattes den fremstillede opløsning. Blandingen omsattes 2 timer ved 70 °C. Opløsningsmidlet og overskud af thionylchlorid afdestilleredes under reduceret tryk, og remanensen opløstes i 21 ml tetrahydrofuran. I 110 ml tetrahydrofuran opløstes 25,1 g diethylethoxymagnesium-15 malonat, og opløsningen afkøledes til -40 °C - 30 °C.·Reference Example 1 In 210 ml of chloroform was dissolved 21 g of 2,6-dichloro-5-fluoro-nicotinic acid and 23.8 g of thlonyl chloride and 0.1 g of N, N-dimethyl-ΙΟ formamide were added to the prepared solution. The mixture was reacted for 2 hours at 70 ° C. The solvent and excess thionyl chloride were distilled off under reduced pressure and the residue was dissolved in 21 ml of tetrahydrofuran. In 110 ml of tetrahydrofuran, 25.1 g of diethylethoxymagnesium malonate was dissolved and the solution cooled to -40 ° C - 30 ° C.
Til denne opløsning dryppedes en tetrahydrofuranopløsning af 2,6-dichlor-5-f luornikotinoylchlond, der var fremstillet forud ved samme temperatur i løbet af 30 minutter. Den blandede opløsning omrørtes ved denne tem-20 peratur i 1 time, og herefter hævedes opløsningens tem peratur gradvist til stuetemperatur. Opløsningsmidlet fjernedes ved afdestillation under reduceret tryk, og remanensen tilsattes 200 ml chloroform og 100 ml vand. pH indstilledes til 1 med 6 N saltsyre. Det organiske 25 lag fraskiltes, der vaskedes først med 50 ml vand, deref ter med 50 ml 5 % vandig natriumhydrogencarbonatoplésning og endelig med 50 ml mættet vandig natriumchloridopløsning, og der tørredes over vandfrit magnesiumsulfat. Opløsningsmidlet afdestilleredes under reduceret tryk, 30 og den olieagtige forbindelse tilsattes 50 ml vand og 0,15 g p-toluensulfonsyre, hvorefter den fremstillede blanding omsattes under kraftig omrøring ved 100 °C i 2 timer. Reaktionsblandingen ekstraheredes med 100 ml 19To this solution was added a tetrahydrofuran solution of 2,6-dichloro-5-fluoricotinoyl chloride, which had been prepared at the same temperature for 30 minutes. The mixed solution was stirred at this temperature for 1 hour and then the temperature of the solution was gradually raised to room temperature. The solvent was removed by distillation under reduced pressure and 200 ml of chloroform and 100 ml of water were added to the residue. The pH was adjusted to 1 with 6N hydrochloric acid. The organic layer was separated, washed first with 50 ml of water, then with 50 ml of 5% aqueous sodium hydrogen carbonate solution and finally with 50 ml of saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the oily compound was added with 50 ml of water and 0.15 g of p-toluenesulfonic acid, after which the prepared mixture was reacted with vigorous stirring at 100 ° C for 2 hours. The reaction mixture was extracted with 100 ml 19
DK 165877 BDK 165877 B
chloroform. Det organiske Jag vaskedes med 50 ml mættet vandig natrlumch1 or i dop 1øsning og tørredes over vandfrit magnesiumsu1fat, hvorefter opløsningsmidlet afdest i 1leredes under reduceret tryk. Remanensen rensedes ved hjælp af søjlechromatografi ("WAKO" SILICAGEL C-200, eluerings-5 middel: toluen), hvorved der opnåedes 23,5 g ethyl (2,6-di- chlor-5-fluornikotinoyl)-acetat, der smeltede ved 64 °C -65 °C.chloroform. The organic Jag was washed with 50 ml of saturated aqueous sodium chloride in dipping solution and dried over anhydrous magnesium sulfate, after which the solvent was evaporated off under reduced pressure. The residue was purified by column chromatography ("WAKO" SILICAGEL C-200, eluent: toluene) to give 23.5 g of ethyl (2,6-dichloro-5-fluorocininoquino) acetate melting at 64 ° C -65 ° C.
IR (KBr ) cm-1:-γ^ε = 0 1650, 1630, 1620 NMR (CDCl^) <£ værdier: 10 1,25 ( 1,29H, t, J = 7Hz) , 1,33 (1,71H, t, J=7Hz), 4.07 (1,laH, s), 4,28 (2H, q, J=7Hz), 5,82 (0,4H, s), 7,80 (IH, d, J='Hz), 12,62 (0,42H, s)IR (KBr) cm-1: -γ ^ = ε 1650, 1630, 1620 NMR (CDCl ^) δ values: 10 1.25 (1.29H, t, J = 7Hz), 1.33 (1, 71H, t, J = 7Hz), 4.07 (1, 1aH, s), 4.28 (2H, q, J = 7Hz), 5.82 (0.4H, s), 7.80 (1H, d, J = (Hz), 12.62 (0.42H, s)
Referenceeksempel 2 I 40 ml benzen opløstes 8,8 g ethyl (2,6-dichlor-5-fluor-15 nikotinoy1)acetat, og 4,5 g N,N-dimethy1formamidodimethy1- acetal tilsattes, hvorefter den fremstillede blanding omsattes 1,5 time ved 70 °C. Herefter tilsattes reaktions-blandingen 4,1 g 2,4-difluoram 1 in, og den fremstillede blanding omsattes i 4 timer ved stuetemperatur. Opløsmngs-20 midlet afdestilleredes under reduceret tryk. Remanensen rensedes ved søjlechromatografi ("WAKO" SILICAGEL C-200, elueringsmiddel: chloroform), hvorved der opnåedes 9,0 g ethy1-2-(2,6-dichlor-5-fluornikotinoy1)-3-(2,4-difluor-phenylamino)-acrylat, der smeltede ved 138 °C - 139 °C.Reference Example 2 In 40 ml of benzene, 8.8 g of ethyl (2,6-dichloro-5-fluoro-nicotinoyl) acetate was dissolved and 4.5 g of N, N-dimethylformamidodimethyl-acetal were added, and the resulting mixture was reacted with 1.5 hour at 70 ° C. Then, the reaction mixture was added 4.1 g of 2,4-difluoram 1 in and the resulting mixture was reacted for 4 hours at room temperature. The solvent was distilled off under reduced pressure. The residue was purified by column chromatography ("WAKO" SILICAGEL C-200, eluent: chloroform) to give 9.0 g of ethyl 1-2- (2,6-dichloro-5-fluoro-nicotinoyl) -3- (2,4-difluoro) phenylamino) acrylate, melting at 138 ° C - 139 ° C.
25 IR (KBr) cm"1^ c._0 169-0 (NMR ( CDC12 ) é værdier: 1.08 (3H, t, J = 7Hz) , 4,10 (2H, q, J = 7Hz), 6,77-7,40 (4H, m), 8,50 (IH, d, Jzl3Hz), 12,70 (IH, d, J=13Hz), 30IR (KBr) cm "1 ^ c.0-0-0-0.0 NMR (CDCl₂) δ values: 1.08 (3H, t, J = 7Hz), 4.10 (2H, q, J = 7Hz), 6.77 -7.40 (4H, m), 8.50 (1H, d, JHz 13Hz), 12.70 (1H, d, J = 13Hz), 30
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2020
Tabel 2 OTable 2 O
C00EtC00Et
C1^N^C1 ?H Ui- NHC1 ^ N ^ C1? H Ui- NH
R2 .Forbindelse Fysiske egenskaber i Sap. co IR(KSrl “lsR2. Compound Physical Properties of Sap. co IR (KSrl “ls
_____=__=|====____ C=Q_____ = __ = | ==== ____ C = Q
(é) 110-114 1710, 1680 _F___ fol 92-93 1710, 1680 (ofF 135-137 1720 (sh), 1690.(é) 110-114 1710, 1680 _F___ fol 92-93 1710, 1680 (orF 135-137 1720 (sh), 1690.
78-80 1690 _F F___ jfOjT 1705, 1680 (sh)78-80 1690 _F F___ jfOjT 1705, 1680 (sh)
Olieagtigoily
FIFFIF
154-155 1720 (sh), 1685 100-101 1700 (sh), 1685 _F___ (έ) 123-125 1710, 1680 _Cl___ (fortsætter)154-155 1720 (sh), 1685 100-101 1700 (sh), 1685 _F___ (έ) 123-125 1710, 1680 _Cl___ (continued)
Tabel 2 (fortsat) 21Table 2 (continued) 21
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(O) 145-146' 1705, 1680 _Br___ (o) 147-149 1685(O) 145-146 '1705, 1680 _Br___ (o) 147-149 1685
Me r'V'Me lOJ 114-116 1680 _F________Me r'V'Me lOJ 114-116 1680 _F________
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2222
Referenceeksempel 3 (1) I 55 ml chloroform opløstes 5,5 g ethyl (2,6-dichlor-5-fluornikotinoy1)acetat, 2,37 g N-methylpiperazin og 2,37 g trimethylamin, og den fremstillede opløsning 5 omsattes ved 60 °C til 65 °C i 2 timer. Reaktionsblandingen vaskedes med 30 ml vand og der tørredes over vand-frit magnesiumsulfat. Opløsningsmidlet afdestilleredes under reduceret tryk, og remanensen rensedes ved søjle-chromatografi ("WAKO" SILICAGEL C-200, elueringsmiddel: 10 chloroform), hvorved der opnåedes 5,4 g olieagtigt ethyl[2-chlor-5-fluor-6-(4-methyl-l-peperazinyl)nikotinoyl]acetat.Reference Example 3 (1) In 55 ml of chloroform, 5.5 g of ethyl (2,6-dichloro-5-fluoronicotinoyl) acetate, 2.37 g of N-methylpiperazine and 2.37 g of trimethylamine were dissolved and the resulting solution 5 was reacted at 60 ° C to 65 ° C for 2 hours. The reaction mixture was washed with 30 ml of water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by column chromatography ("WAKO" SILICAGEL C-200, eluent: 10 chloroform) to give 5.4 g of oily ethyl [2-chloro-5-fluoro-6- (4). -methyl-L-peperazinyl) nicotinoyl] acetate.
IR (rent) cm‘1:t/c_Q 1750., 1695 NMR (CDCl^) å værdier: 1,25 (3H, t, J = 7Hz), 2,32 (3H, s), 15 2,12-2,70 (4H, m), 3,55-3,96 (4H, m), 4,03 (2H, s), 4,20 (2H, q, J=7Hz), 7,78 (IH, d, J = 13Hz) På samme måde fremstilles den i tabel 3 angivne forbindelse.IR (neat) cm -1: t / c_Q 1750, 1695 NMR (CDCl3) δ values: 1.25 (3H, t, J = 7Hz), 2.32 (3H, s), 2.12- 2.70 (4H, m), 3.55-3.96 (4H, m), 4.03 (2H, s), 4.20 (2H, q, J = 7Hz), 7.78 (1H, d, J = 13Hz) Similarly, the compound listed in Table 3 is prepared.
(2) 23(2) 23
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I 22,3 ml benzen opløstes 4,5 g ethy1[2-chlor-5-fluor-6-(4-methy1-1-piperaziny1)-nikotinoy1]acetat, og 1,87 g N,N-dimehtylformamidodimethylacetat tilsattes opløsningen, 5 hvorefter blandingen omsattes 2 timer ved 70 °C. Til reaktionsblandingen sattes 1,8 g 4-methoxy-2-methylani1 in, og den fremstillede blanding omsattes 4 timer ved stuetemperatur. Herefter afdestilleredes opløsningsmidlet under reduceret tryk, og remanenser rensedes ved søjlechromato-10 grafi ("WAKO" SILICAGEL C-200, elueringsmiddel: chloroform: ethanol = 100:1 (rumfang)). Den krystallinske forbindelse vaskedes med 10 ml diethylether, hvorved der opnåedes 5,0 g ethyl-2-[2-chlor-5-fluor-6-(4-methyl-l-piperazinyl)nikotinoyl]-3-(4-methoxy-2-methylphenyl-15 amino)acrylat, der smeltede ved 141-142 °C.In 22.3 ml of benzene was dissolved 4.5 g of ethyl [2-chloro-5-fluoro-6- (4-methyl-1-piperazinyl) nicotinoyl] acetate, and 1.87 g of N, N-dimethylformamidodimethyl acetate were added to the solution. The mixture was reacted for 2 hours at 70 ° C. To the reaction mixture was added 1.8 g of 4-methoxy-2-methylanil and the resulting mixture was reacted for 4 hours at room temperature. Then, the solvent was distilled off under reduced pressure and residues were purified by column chromatography ("WAKO" SILICAGEL C-200, eluent: chloroform: ethanol = 100: 1 (volume)). The crystalline compound was washed with 10 ml of diethyl ether to give 5.0 g of ethyl 2- [2-chloro-5-fluoro-6- (4-methyl-1-piperazinyl) nicotinoyl] -3- (4-methoxyphenyl) 2-methylphenyl-15-aminoacrylate, melting at 141-142 ° C.
IR (KBr) cm-'*': 1710(sh), 1695 NMR (CDClj)^ værdier: 1,08 (3H, t, J = 7 H z ), 2,32 (3H, s), 2,40 (3H, s), 2,32-2,68 (4H, m), 3,47-3,83 (4H, m) , 3,75 (3H, s) 4,07 (2H, q, J=7Hz), 6,65-7,25 (3H, m), 7,20 (IH, d, J=13Hz), 8,48 (IH, d, J = 13Hz), 12,82 (IH, d, J=13Hz) På samme måde fremstilledes de i tabel '3 angivne forbindelser.IR (KBr) cm - ': 1710 (sh), 1695 NMR (CDClj) δ values: 1.08 (3H, t, J = 7H z), 2.32 (3H, s), 2.40 (3H, s), 2.32-2.68 (4H, m), 3.47-3.83 (4H, m), 3.75 (3H, s), 4.07 (2H, q, J = 7Hz), 6.65-7.25 (3H, m), 7.20 (1H, d, J = 13Hz), 8.48 (1H, d, J = 13Hz), 12.82 (1H, d, J = 13Hz) Similarly, the compounds listed in Table '3 were prepared.
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2424
Tabsi 3 OTab 3 O
NHNH
I, . R2I,. R2
Forbindelse Fysiske egenskaber - ; Ί ir{*) R R Smeltepunkt cm-1: ν~π _ (°C)__c~° Αγ *2 [OJ 1735, Y Olieagtig 1700 F ·Compound Physical Properties -; Ί ir {*) R R Melting point cm-1: ν ~ π _ (° C) __ c ~ ° Αγ * 2 [OJ 1735, Y Oily 1700 F ·
Note: *1: KBr *2: BentNote: * 1: KBr * 2: Bent
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2 52 5
Eksempel 1 (mellemprodukt) I 90 ml N,N-dimethylformamid opløstes 9,0 g ethy1-2-(2,6-di-chlor-5-fluornikotinoyl)-3-(2,4-difluorphenylamino)acrylat, 3,6 g natriumhydrogencarbonat tilsattes opløsningen, 5 hvorefter blandingen omsattes 20 minutter ved 120 °C.Example 1 (Intermediate) In 90 ml of N, N-dimethylformamide were dissolved 9.0 g of ethyl 2- (2,6-dichloro-5-fluoronicotinoyl) -3- (2,4-difluorophenylamino) acrylate, 3.6 g of sodium bicarbonate was added to the solution, and the mixture was reacted for 20 minutes at 120 ° C.
Herefter afdestilleredes opløsningsmidlet ved reduceret tryk, og remanensen opløstes i 50 ml chlorform. Den fremstillede opløsning vaskedes først med 30 ml vand og derefter med mættet vandig natriumchloridopløsning, 10 hvorefter der tørredes over vandfrit magnesiumsulfat.The solvent was then distilled off at reduced pressure and the residue dissolved in 50 ml of chlorine form. The solution prepared was washed first with 30 ml of water and then with saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate.
Opløsningsmidlet afdestilleredes under reduceret tryk, og den krystallinske forbindelse vaskedes med 30 ml diethylether, hvorved der fremstilledes 7,0 g ethyl-7-chlor-6-fluor-l-(2,4-difluorphenyl)-l,4-dihydro-4-oxo-l,8-15 naphthyridin-3-carboxylat med smeltepunktet 220 °C - 222 °c.The solvent was distilled off under reduced pressure and the crystalline compound was washed with 30 ml of diethyl ether to give 7.0 g of ethyl 7-chloro-6-fluoro-1- (2,4-difluorophenyl) 1,4-dihydro-4 -oxo-1,8-15 naphthyridine-3-carboxylate, mp 220 ° C - 222 ° C.
IR (KBr) cm_1:^c = 0 1730, 1690 NMR (CDCl^) £ værdier: 1,36(3H, t, J = 7Hz), 43Q(2H, q, J=7Hz), 6,80-7,60(3H, m), 8,27(1H, d, J=7Hz), 20 8,42(IH, s) På samme måde fremstilledes de i tabel 4 angivne forbindelser, der er værdifulde mellemprodukter ved fremstillingen af forbindelserne med formlen I.IR (KBr) cm_1:: c c = 0 1730, 1690 NMR (CDCl ^) δ values: 1.36 (3H, t, J = 7Hz), 43Q (2H, q, J = 7Hz), 6.80-7 , 60 (3H, m), 8.27 (1H, d, J = 7Hz), 20.42 (1H, s) Similarly, the compounds listed in Table 4, which are valuable intermediates in the preparation of the compounds with formula I.
Tabel 4 26Table 4 26
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:χύ~· I 2 ir: χύ ~ · I 2 ir
Forbindelse Fysiske eqenskaber I I 77 7T IR(KBr) •p2 Smeltepunkt (°C) cm : VC=0 ώ 1730, I 231-232 ‘ 1705Compound Physical Properties I I 77 7T IR (KBr) • p2 Melting point (° C) cm: VC = 0 ώ 1730, I 231-232 '1705
FF
(o^ 239-241 1685 A/ 1735, .(o ^ 239-241 1685 A / 1735 ,.
lOj 205-208 1685 244-246 1720, I F 1680lOj 205-208 1685 244-246 1720, I F 1680
FF
(fortsætter)(continues)
Tabel 4 (fortsat) 27Table 4 (continued) 27
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Å-F 1730, jOj 207-209,5 1690 T-l rÅ-F 1730, jOj 207-209.5 1690 T-l r
F I FF I F
VY 1735 (sh), (OJ 210-214 1705 'of γΎ· 207-208 1730, * 1680VY 1735 (sh), (OJ 210-214 1705 'or γΎ · 207-208 1730, * 1680
FF
fol 173°' V 181-186 1685 C1 fol i73°^ V 204"205 1685fol 173 ° V 181-186 1685 C1 fol i73 ° V 204 "205 1685
Br Φ1735, 216-218 1695Br Φ1735, 216-218 1695
MeMe
Xwe OJ 1735, Y 199-202 1685Xwe OJ 1735, Y 199-202 1685
FF
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2828
Eksempel 2 (mellemprodukt) (1) I 35 ml chloroform opløstes 3,5 g ethyl-7-chlor-6-fluor-l-(2,4-difluorphenyl)-l,4-dihydro-4-oxo-l,8-naphthyridin-3-carboxylat, og 1,5 g N-acetylpiperazin og 1,6 g triethyl-5 amin tilsattes derefter opløsningen, hvorefter hele blandingen omsattes 1 time ved 60 °C. Dernæst afdestillere-des opløsningsmidlet under reduceret tryk, og remanensen rensedes ved søjlechromatografi ("WAKO SILICAGEl C-200, elueringsmiddel: chloroform: ethanol = 30 ml (rumfang)), 10 hvorved der opnåedes 3,5 g ethyl-7-(4-acetyl-l-piperazi-nyl)-6-fluor-l-(2,4-difluorphenyl)-l,4-dihydro-4-oxo-l,8-naphthyridin-3-carboxylat, der smeltede ved 207 °C - 209 °C.Example 2 (Intermediate) (1) In 35 ml of chloroform were dissolved 3.5 g of ethyl 7-chloro-6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1.8 Naphthyridine-3-carboxylate, and 1.5 g of N-acetylpiperazine and 1.6 g of triethylamine were then added to the solution, and the whole mixture was reacted at 60 ° C for 1 hour. Next, the solvent was distilled off under reduced pressure and the residue was purified by column chromatography ("WAKO SILICAGE1 C-200, eluent: chloroform: ethanol = 30 ml (volume)) to give 3.5 g of ethyl 7- (4- acetyl-1-piperazinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, melting at 207 ° C. 209 ° C.
IR (KBr) cm-1: oc_Q 1730, 1695 NMR (CDClj) £ værdier: 15 1,38(4H, t, J=7Hz), 2,05(3H, s), 3,53(8H, bs), 4,30(2H, q, J=7Hz), 6,80-7,75(3H, m), 8,00(1H, d, J = 13Hz), 8,30( IH? s) På samme måde fremstilledes de i tabel 5 angivne forbindelser, der er værdifulde mellemprodukter ved fremst.il-20 lingen af forbindelserne med formlen I.IR (KBr) cm -1: oc_Q 1730, 1695 NMR (CDCl3) δ values: 1.38 (4H, t, J = 7Hz), 2.05 (3H, s), 3.53 (8H, bs) , 4.30 (2H, q, J = 7Hz), 6.80-7.75 (3H, m), 8.00 (1H, d, J = 13Hz), 8.30 (1H? S) In this way, the compounds listed in Table 5 which are valuable intermediates in the preparation of the compounds of formula I. were prepared.
Tabel 5 29Table 5 29
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F YY^/C00Et R ! R2F YY ^ / C00Et R! R2
Forbindelse Fysiske egenskaber 1 1 Smeltepunkt Π« R R (°C) cm-1: vc-0 /“N 1730, (OJ *\J- . 217-218 1695 F__Compound Physical Properties 1 1 Melting point R R R R (° C) cm-1: vc-0 / “N 1730, (OJ * \ J-. 217-218 1695 F__
Me /—\ 1730,Me / - \ 1730,
" HN^ n- 144-146 169Q"HN ^ n- 144-146 169Q
MeMe
.. N)—S.. N) —S
HN N- 143 1730 ______HN N- 143 1730 ______
MeMe
Va 1725, BN N- 198-202 1690 __\e___ A /~\ 1730, 1<U MS\_yN- 193-lg4 1700 F · 'Va 1725, BN N- 198-202 1690 __ \ e___ A / ~ \ 1730, 1 <U MS \ _yN- 193-lg4 1700 F · '
Tabel 5 (fortsat) 30Table 5 (continued) 30
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j J __ ér ™.j J __ er ™.
| N—1 1685| N-1 1685
FF
Me >—\ 1730 t 153-154 ,1700 _/ Me ΓΛ 1730, 153~155 1695 / \ 1730 (sh),Me> - \ 1730 t 153-154, 1700 _ / Me ΓΛ 1730, 153 ~ 155 1695 / \ 1730 (sh),
" 166-168 16QQ"166-168 16QQ
I /-Λ 1725, [OJ 207 1695I / -Λ 1725, [OJ 207 1695
Cl fol A“\ ' ' 1730' I^J MeN^JJ- 208 1690Cl fol A “\ '' 1730 'I ^ J MeN ^ JJ- 208 1690
Br (ΟΙ /Ά 1730' IUJ 167-169 1695Br (ΟΙ / Ά 1730 'IUJ 167-169 1695
MeMe
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31 (2) I 25 ml 6 N saltsyre opløstes 2,5 g ethyl-7-(4-acetyl-l-piperazinyl)-6-fluor-l-(2,4-difluorphenyl)-l,4-dihydro- 4-oxo-l,8-naphthyridin-3-carboxylat, og den fremstillede opløsning opvarmedes 2 timer med tilbagesvaling. Herefter 5 afkøledes reaktionsblandingen til stuetemperatur, og blandingen pH indstilledes til 12 med 1 N vandig natriumhydroxidopløsning og herefter til 6,5 med eddikesyre.(2) In 25 ml of 6N hydrochloric acid was dissolved 2.5 g of ethyl 7- (4-acetyl-1-piperazinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4 -oxo-1,8-naphthyridine-3-carboxylate, and the resulting solution was heated at reflux for 2 hours. Then, the reaction mixture was cooled to room temperature and the pH was adjusted to 12 with 1N aqueous sodium hydroxide solution and then to 6.5 with acetic acid.
De aflejrede krystaller frafiltreredes, der vaskedes med 30 ml vand og tørredes, hvorved der opnåedes 1,8 10 g 6-fluor-l-(2,4-difluorphenyl)-l,4-dihydro-4-oxo-7- (1-piperazinyl)- l,8-naphthyridin-3-carboxylsyre.The deposited crystals were filtered off, washed with 30 ml of water and dried to give 1.8 g of 6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-7- (1 (piperazinyl) - 1,8-naphthyridine-3-carboxylic acid.
NMR (TFA-d^)^ værdier: 3,30-4,50(8H, m), 7,00-7,85(3H, m), 8,33(IH, d, J = 13Hz ), 9,21(1H, s) 15 På samme måde fremstilledes de i tabel 6 angivne forbindelser.NMR (TFA-d 6) δ values: 3.30-4.50 (8H, m), 7.00-7.85 (3H, m), 8.33 (1H, d, J = 13Hz), 9 , 21 (1H, s) 15 Similarly, the compounds listed in Table 6 were prepared.
Tabel 6 32Table 6 32
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;χ)Τ“; Χ) Τ "
R . IR. IN
R2R2
Forbindelser Fysiske egenskaber 2 . 3 Smeltepunkt IR(KBr) R R —Compounds Physical Properties 2. 3 Melting point IR (KBr) R R -
____[°C]_ cm : vc=Q____ [° C] _ cm: vc = Q
MeHN O >280 1720 (sh) IMeHN O> 280 1720 (sh) I
FF
" \- 279-280 1725 (sh) (θΧ^ " 234-236 1720"\ - 279-280 1725 (sh) (θΧ ^" 234-236 1720
rVFRVF
lOJ " 222-224 1725 \Ap " >280 1720lOJ "222-224 1725 \ Ap"> 280 1720
FF
(fortsætter)(continues)
Tabel 6 (fortsat) 33Table 6 (continued) 33
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'ίο/'Ίο /
MeNHH^yi- 254-258 1725MeNHH ^ yi- 254-258 1725
FF
j—\ JO) HN^ ^J- 205-207 1730j— \ JO) HN ^^ J- 205-207 1730
FF
fyVf |OJ " 225-227 1725 ~é> S/ · " >280 1725fyVf | OJ "225-227 1725 ~ é> S / ·"> 280 1725
Cl (o) " 273-277 1720Cl (o) "273-277 1720
Br ” 245-246 1725Br ”245-246 1725
MeMe
Tabel 6 (fortsat) 34Table 6 (continued) 34
DK 165877 BDK 165877 B
(OJ HN 230-232 1730(OJ HN 230-232 1730
FF
- - *— - ' ^ - — — I- - - -- - * - - '^ - - - I- - - -
Note: * N-metoden anvendes i stedet for KBr-metoden.Note: * The N method is used instead of the KBr method.
Eksempel 3 (1) I 5 ml chloroform opløstes 0,50 g ethyl-7-chlor-6-fluor-l-(2,4-difluorphenyl)-l,4-dihydro-4-oxo-l,8-naphthyridin-3-carboxylat, og til den fremstillede opløsning sattes 0,20 g 3-acetylaminopyrrolidin og 0,15 g triethylamin, hvorefter hele blandingen omsattes 1 time ved 60 °C.Example 3 (1) In 5 ml of chloroform was dissolved 0.50 g of ethyl 7-chloro-6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine. 3-carboxylate, and to the solution prepared were added 0.20 g of 3-acetylaminopyrrolidine and 0.15 g of triethylamine, then the whole mixture was reacted for 1 hour at 60 ° C.
Dernsst afdestilleredes opløsningsmidlet under reduceret tryk, og remanensen rensedes ved søjlechromatografi ("WAK0" SLILIGAGEL C-200, elueringsmiddel: chloroform: ethanol = 30 : 1 (rumfang)), hvorved der opnåedes 0,5 g ethyl-7-(3-acetylamino-l-pyrrolidinyl)-6-fluor-l-(2,4-difluorphenyl)-l,4-dihydro-4-oxo-l,8-naphthyridin-3-car-boxylat, der havde smeltepunkt ved 233 °C - 235 °C.Next, the solvent was distilled off under reduced pressure and the residue was purified by column chromatography ("WAK0" SLILIGAGEL C-200, eluent: chloroform: ethanol = 30: 1 (vol)) to obtain 0.5 g of ethyl 7- (3-acetylamino) -1-pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, melting at 233 ° C - 235 ° C.
DK 165877 BDK 165877 B
35 IR (KBr) cm-1: ^C_Q 1725, 1700 NMR (CDClj) tf værdier: 1,32(4H, t, J=7Hz), 1,77-2,27(m) 2,08 (s)>(5H)’ 5 3,12-3,74(4H, m), 4,02-4,74(m) 4,29(q, j = 7Hz ; (3H) ’ 6,75-7,60(4H, m), 7,93(1H, d, J=8Hz), 8,24(IH, s) På samme måde fremstilledes de i tabel 7 angivne forbind-10 eiser.IR (KBr) cm -1: C C_Q 1725, 1700 NMR (CDClj) δ values: 1.32 (4H, t, J = 7Hz), 1.77-2.27 (m) 2.08 (s) > (5H) δ 3.12-3.74 (4H, m), 4.02-4.74 (m) 4.29 (q, j = 7Hz; (3H) '6.75-7.60 (4H, m), 7.93 (1H, d, J = 8Hz), 8.24 (1H, s). Similarly, the compounds listed in Table 7 were prepared.
DK 165877 BDK 165877 B
3636
Tabel 7 R2Table 7 R2
Forbindelser Fysiske egenskaber_ 9 3 . Smeltepunkt IR(KBr) R R ion „ -1. „ I C] cm : vc=0 (o) H°V\ 1730' ^ [_/- 231-233 17Q0Compounds Physical Properties_ 9 3. Melting point IR (KBr) R R ion "In C] cm: vc = 0 (o) H ° V \ 1730" ^ [_ / - 231-233 17Q0
FF
(2) I *2,5 ml 6 N saltsyre opløses 0,25 g ethyl-7-(3-acetyl-amino-1-pyrrolidinyl)-6-fluor-l-(2,4-di fluorphenyl)-l,4-di-hydro-4-oxo-l,8-naphthyridin-3-carboxylat, og opløsningen opvarmes 2 timer med tilbagesvaling. Herefter afkøledes s reaktionsblandingen til stuetemperatur, og blandingens pH indstilledes til 12 med 1 N vandig natriumhydroxidopløsning og herefter til 6,5 med eddikesyre. De aflejrede krystaller frafiltreredes, der vaskedes med 2 liter vand og tørredes, hvorefter der opnåedes 0,18 g 7-(3-ami-13 no-1-pyrrolidiny1)-6-fluor-l-(2,4-difluorphenyl)-l,4-dihy- dr0-4-oxo-1,8-naphthyridin-3-carboxylsyre.(2) Dissolve 0.25 g of ethyl 7- (3-acetylamino-1-pyrrolidinyl) -6-fluoro-1- (2,4-di-fluorophenyl) -1 in 2.5 ml of 6N hydrochloric acid. 4-di-hydro-4-oxo-1,8-naphthyridine-3-carboxylate, and the solution is heated at reflux for 2 hours. The reaction mixture was then cooled to room temperature and the pH of the mixture was adjusted to 12 with 1 N aqueous sodium hydroxide solution and then to 6.5 with acetic acid. The deposited crystals were filtered off, washed with 2 liters of water and dried to give 0.18 g of 7- (3-ami-13-no-1-pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl) 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid.
NMR (TFA-d^) <5 værdier: 2,25-2,85(2H, m), 3,37-4,69(5H, m), 6,93-7,81(3H, m·, 8,22(1H, d, JrllHz), 15 9,16(IH, s) På samme måde fremstilledes de i tabel 8 angivne forbindelser .NMR (TFA-d 6) <5 values: 2.25-2.85 (2H, m), 3.37-4.69 (5H, m), 6.93-7.81 (3H, m ·, 8.22 (1H, d, Jr11Hz), 9.16 (1H, s) Similarly, the compounds listed in Table 8 were prepared.
DK 165877 BDK 165877 B
3737
Tabel 8 OTable 8 O
F COOHF COOH
VrYvry
hH
RR
Forbindelse Fysiske egenskaberCompound Physical Properties
Smeltepunkt IR (KBr) R R -1 v (°C) cm : C=0 fnl π^ν-χ _V 260-263 1720Melting point IR (KBr) R R -1 v (° C) cm: C = 0 fnl π + ν-χ V 260-263 1720
FF
MeHNMehn
. " N- 259-261 1720 (sh) A/ ' 10J " 275-278 1720 (sh). "N- 259-261 1720 (sh) A / '10J" 275-278 1720 (sh)
FF
rVF H2N>-\ 101 N- 278-280 1720· I F ^rVF H2N> - \ 101 N- 278-280 1720 · I F ^
FF
Eksempel 4Example 4
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38 (1) I 15 ml 6 N saltsyre opslæmmedes 0,50 g ethyl-7-chlor- 6-fluor-l-(2, 4-difluorphenyl)-l,4-dihydro-4-oxo-l,8-naph-thyridin-3-carboxylat, og suspensionen opvarmedes 3 timer 5 med tilbagesvaling. Herefter' fortyndedes reaktionsblandingen med 50 ml vand, og den ekstraheredes med tre 50 ml portioner chloroform. Ekstrakterne blev slået sammen og vasket med 100 ml mættet vandig natriumchlo- ridopløsning og tørret over vandfrit magnesiumsulfat.38 (1) In 15 ml of 6N hydrochloric acid was slurried 0.50 g of ethyl 7-chloro-6-fluoro-1- (2,4-difluorophenyl) 1,4-dihydro-4-oxo-1,8-naph thyridine-3-carboxylate and the suspension was heated at reflux for 3 hours. Then, the reaction mixture was diluted with 50 ml of water and extracted with three 50 ml portions of chloroform. The extracts were combined and washed with 100 ml of saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate.
X0 Opløsningsmidlet afdesti lieredes under reduceret tryk, og den krystallinske masse vaskedes med 15 ml diethyl- ether, hvorved det opnåedes 0,40 g 7-chlor-6-fluor-1- (2,4-difluorphenyl)-l,4-dihydro-4-oxo-l,8-naphthyri- din-3-carboxylsyre, der smeltede ved 244 °C - 248 °C.The solvent was distilled off under reduced pressure and the crystalline mass was washed with 15 ml of diethyl ether to give 0.40 g of 7-chloro-6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro -4-oxo-1,8-naphthyridine-3-carboxylic acid melting at 244 ° C - 248 ° C.
15 IR (KBr) cnT1:^ C=0 1720 NMR (dg-DMS0)^ værdier 7,26-8,56 (3H, m), 8,86 (IH, d, J=7Hz), 9,18 (IH, s) (2) I 3 ml dimethylsulfoxid opslæmmedes 0,30 g 7-chlor-6-20 fluor-l-(2,4-difluorphenyl)-l,4-dihydro-4-oxo-l,8-naph- thyridin-3-carboxylsyre, og til suspensionen sattes herefter 0,25 g N-methylpiperazin, hvorefter suspensionen omsattes 30 minutter ved 60 °C. Dernæst afdestilleredes opløsningsmidlet under reduceret tryk, og remanensen 25 tilsattes 30 ml vand. Blandingens pH indstilledes til 12 med 10 % vandig natriumhydroxidopløsning, herefter indstilledes til 7 med eddikesyre. Den aflejrede krystallinske masse frafiltreredes og vaskedes med 5 ml vand, hvorved der opnåedes 0,24 g 6-fluor-l-(2,4-difluorphenyl)-30 1,4-dihydro-7-(4-methyl-l-piperazinyl)-4-oxo-l,8-naph- thyridin-3-carboxylsyre, der smeltede ved 208 °C - 209 °C.IR (KBr) cnT1: C C = 0 1720 NMR (dg-DMSO) δ values 7.26-8.56 (3H, m), 8.86 (1H, d, J = 7Hz), 9.18 ( 1H, s) (2) In 3 ml of dimethyl sulfoxide, 0.30 g of 7-chloro-6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naph was suspended. - thyridine-3-carboxylic acid, and then 0.25 g of N-methylpiperazine was added to the suspension, and the suspension was reacted for 30 minutes at 60 ° C. Next, the solvent was distilled off under reduced pressure and the residue 25 was added with 30 ml of water. The pH of the mixture was adjusted to 12 with 10% aqueous sodium hydroxide solution, then adjusted to 7 with acetic acid. The deposited crystalline mass was filtered off and washed with 5 ml of water to give 0.24 g of 6-fluoro-1- (2,4-difluorophenyl)-1,4-dihydro-7- (4-methyl-1-piperazinyl) ) -4-oxo-1,8-naphthyridine-3-carboxylic acid melting at 208 ° C - 209 ° C.
DK 165877 BDK 165877 B
39 IR (KBr) cm"1: C = 0 1730 NMR (TFA-d^)^ værdier: 3,30 (3H, s), 3,45-5,25 (8H,m), 7,12-8,10 (3H, m), 8,49 (IH, d, 3=13Hz), 5 9,38 (IH, s)39 IR (KBr) cm "1: C = 0 1730 NMR (TFA-d ^) δ values: 3.30 (3H, s), 3.45-5.25 (8H, m), 7.12-8 , 10 (3H, m), 8.49 (1H, d, 3 = 13Hz), δ 9.38 (1H, s)
Eksempel 5 I 50 ml N,N-dimethylformamid opløstes 5,0 g ethyl-2-[2-chlor-5-fluor-6-(4-methyl-l-piperazinyl)nikotinoyl]-3-(4-methoxy-2-methylphenylamlno)-acrylat, herefter satin tes 1,03 g natriumhydrogencarbonat til opløsningen, og blandingen omsattes 3 timer ved 120 °C. Opløsningsmidlet afdestilleredes herefter under reduceret tryk, og remanensen opløstes i 50 ml chloroform. Den fremstillede opløsning vaskedes først med 30 ml vand og derefter 1 Tj med 30 ml mættet vandig natriumchloridopløsning, hvorefter der tørredes over vandfrit magnesiumsulfat. Opløsningsmidlet afdestilleredes under reduceret tryk, og den krystallinske masse vaskedes med 30 ml diethylether, hvorved der opnåedes 2,38 g ethyl-6-fluor-l,4-dihydro-l-2Π (4-methoxy-2-methylphenyl)-7-(4-methyl-l-piperazinyl)-4-oxo-1,8-naphthyridin-3-carboxylat, der smeltede ved 144 °C - 145 °C.Example 5 In 50 ml of N, N-dimethylformamide were dissolved 5.0 g of ethyl 2- [2-chloro-5-fluoro-6- (4-methyl-1-piperazinyl) nicotinoyl] -3- (4-methoxy-2 -methylphenylamino) acrylate, then 1.03 g of sodium bicarbonate is added to the solution and the mixture is reacted at 120 ° C for 3 hours. The solvent was then distilled off under reduced pressure and the residue dissolved in 50 ml of chloroform. The prepared solution was washed first with 30 ml of water and then 1 Tj with 30 ml of saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the crystalline mass was washed with 30 ml of diethyl ether to give 2.38 g of ethyl-6-fluoro-1,4-dihydro-1,2-(4-methoxy-2-methylphenyl) -7 (4-methyl-1-piperazinyl) -4-oxo-1,8-naphthyridine-3-carboxylate, melting at 144 ° C - 145 ° C.
-1 V-1 V
IR (KBr) cm : C=0 1730, 1690 NMR (CDClj) 6 værdier: 25 1,33 (3H, J=7Hz), 1,95 (3H, s), 2,20 (3H, s, 2,05-2,62 (4H, m), 3,32-3,63 (4H, m), 3,82 (3H, s), 4,32 (2H, q, J=7Hz), 6,60-7,15 (3H, m), 8,02 (IH, d, J=13Hz), 8,23 (IH, s) 30 På samme måde fremstilledes de i tabel 9 angivne forbindelser.IR (KBr) cm: C = 0 1730, 1690 NMR (CDCl 3) δ values: 1.33 (3H, J = 7Hz), 1.95 (3H, s), 2.20 (3H, s, 2, 05-2.62 (4H, m), 3.32-3.63 (4H, m), 3.82 (3H, s), 4.32 (2H, q, J = 7Hz), 6.60- 7.15 (3H, m), 8.02 (1H, d, J = 13Hz), 8.23 (1H, s). Similarly, the compounds listed in Table 9 were prepared.
DK 165877BDK 165877B
AOAO
Tabel 9 OTable 9 O
F li COOEtF li COOEt
YxVYxV
R IR I
i2i2
Forbindelse Fysiske egenskaberCompound Physical Properties
Smeltepunkt IR (KBr) R · r3 -1 v (°C) cm : VC=0 (rtf' f~\ 1735,Melting point IR (KBr) R 3 R 3 -1 v (° C) cm: VC = 0 (rtf
MeN N- 168-171 ^ ' N-/ 1720ME N- 168-171 ^ 'N- / 1720
FF
- 41- 41
Eksenpel 6Example 6
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I 5 ni 47 % hydrogenbrornidsyre opløstes 2,0 g ethyl-5- fluor-l,4-dihydro-I-(4-methoxy-2-methylphenyl)-7-(4-me- thyl-l-piperazinyl)-4-oxo-l,8-naphthyridin-3-carboxylat,Dissolve 2.0 g of ethyl 5-fluoro-1,4-dihydro-1- (4-methoxy-2-methylphenyl) -7- (4-methyl-1-piperazinyl) -4 oxo-l, 8-naphthyridine-3-carboxylate,
3 og den fremstillede opløsning omsattes 2 timer ved 120 °C3 and the resulting solution was reacted for 2 hours at 120 ° C
til 125 °C. Herefter indstilledes reaktionsblandingens pH til 13 med 10 % vandig natriumhydroxidopløsning og herefter til 6,5 med eddikesyre. De aflejrede krystaller frafiltreredes, og der vaskedes med 10 ml vand, hvorved 10 der opnåedes 1,8 g 6-fluor-I,4-dihydro-l-(4-hydroxy-2-me- thylphenyl)-7-(4-methyl-l-piperazinyl)-4-oxo-l,8-naphthy-ridin-3-carboxylsyre med et smeltepunkt >280 °C.to 125 ° C. The pH of the reaction mixture was then adjusted to 13 with 10% aqueous sodium hydroxide solution and then to 6.5 with acetic acid. The deposited crystals were filtered off and washed with 10 ml of water to give 1.8 g of 6-fluoro-1,4-dihydro-1- (4-hydroxy-2-methylphenyl) -7- (4- methyl-1-piperazinyl) -4-oxo-1,8-naphthyridine-3-carboxylic acid having a melting point> 280 ° C.
IR (KBr) cm"1: ^0=0 1725, 1700 (sh) NRM (TFA-d^) £> værdier: 15 2,08 (3H, s), 2,12 (3H, s), 2,88-5,12 (8H, n), 6,93-7,62 (3H, m), 9,25 (IH, s), 9,43 (IH, d, 3=13Hz) På samme nåde fremstilledes de i tabel 10 angivne forbindelser.IR (KBr) cm "1: 0 0 = 0 1725, 1700 (sh) NRM (TFA-d ^) δ> values: 2.08 (3H, s), 2.12 (3H, s), 2, 88-5.12 (8H, n), 6.93-7.62 (3H, m), 9.25 (1H, s), 9.43 (1H, d, 3 = 13Hz) compounds listed in Table 10.
' 42'42
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Tabel 10 OTable 10 O
F II COOHF II COOH
γνγ r3/^n^n^ _Forbindelse___Fysiske egenskaber______ 2 3 IR (KBr) K R Smeltepunkt Ί ,(°c) cm : vc=0 fo| Γ\ 1725, ( N- · 143-146 i \_/ 1710γνγ r3 / ^ n ^ n ^ _ Compound___ Physical Properties______ 2 3 IR (KBr) K R Melting point Ί, (° c) cm: vc = 0 fo | 17 \ 1725, (N- · 143-146 i \ _ / 1710
OH L/XUOH L / XU
" ffi/ N- >280 1710 / \ " MeN_N- >280 1710"ffi / N-> 280 1710 / \" MeN_N-> 280 1710
EtN ^S- · >280 1730 \_/ A~\ " n-PrN^_N- >280 1725 " i-PrN N- >280 1715 /—\ 1720, " HO^-N N- 200-205 N-/ 1705 .EtN ^ S->> 280 1730 \ _ / A ~ \ "n-PrN ^ _N-> 280 1725" i-PrN N-> 280 1715 / - \ 1720, "HO ^ -N N- 200-205 N- / 1705.
" /VN_N- >280 1725 (fortsættes)"/ VN_N-> 280 1725 (continued)
IDK 165877 BIDK 165877 B
Tabel 10 (fortsat) 43 _;_I--—__j ____________i_-......... i 1 Me/Λ- 245‘250 1725' (0] N / (dekomp.) 1700 (sh)Table 10 (continued) 43 _; _ I --—__ j ____________ i _-......... i 1 Me / Λ- 245'250 1725 '(0] N / (decomp.) 1700 (sh)
OHOH
A/oh 1725' (of " >2S0 · 1690 [Oj^ HN N- 220-224 T N—f 1710A / oh 1725 '(or 2S0 · 1690 [Oj HN N- 220-224 T N-f 1710
FF
/—\ 1730, " MeN N- >280 ,,./ - \ 1730, „MeN N-> 280 ,,.
\ f 1710 (sh) (O^ " >280 1730\ f 1710 (sh) (O ^ "> 280 1730
OHOH
/ \ " HN^_N- >255 1725 /—\ lOJ MeN^_N- 251-252 1720/ \ "HN ^ _N-> 255 1725 / - \ lOJ MeN ^ _N- 251-252 1720
OHOH
1725 (sh) ' >28° 17001725 (sh) '> 28 ° 1700
Me fo] 1730' ^Me " 228-230 1700 (sh)Me fo] 1730 "^ Me" 228-230 1700 (sh)
OHOH
(fortsættes)(to be continued)
Tabel (fortsat) 44Table (continued) 44
DK 165877 BDK 165877 B
I Ms -- HN V 275 1720 OH _I Ms - HN V 275 1720 OH _
Eksempel 7 I 10 ml 47?ί hydrogenbromidsyre opløstes 0,40 g ethyl-6-fluor-l,4-dihydro-l-(4-methoxyphenyl)-7-(l-pyrrolidinyl)- 4-oxo-l,8-naphthyridin-5-carboxylat, og opløsningen 5 omsattes 2 timer ved 120 - 125 °C. Reaktionsblandingens pH indstilledes til 15 med 10?ό vandig natriumhydroxid-opløsning og herefter til 6,5 med eddikesyre. De aflej- rede krystaller frafiltreredes og vaskedes med 4 ml •vand, hvorved der opnåede 0,50 g 6-fluor-l,4-dihydro-10 l-(4-hydroxyphenyl)-7-(l-pyrrolidinyl)-4-oxo-l,8-naphthy- ridin-5-carboxylsyre, der smeltede ved 265 - 265 °C.Example 7 In 10 ml of 47 µl of hydrobromic acid was dissolved 0.40 g of ethyl 6-fluoro-1,4-dihydro-1- (4-methoxyphenyl) -7- (1-pyrrolidinyl) -4-oxo-1,8 naphthyridine-5-carboxylate and the solution 5 was reacted for 2 hours at 120 - 125 ° C. The pH of the reaction mixture was adjusted to 15 with 10? Aqueous sodium hydroxide solution and then to 6.5 with acetic acid. The deposited crystals were filtered off and washed with 4 ml of water to give 0.50 g of 6-fluoro-1,4-dihydro-10- (4-hydroxyphenyl) -7- (1-pyrrolidinyl) -4- oxo-1,8-naphthyridine-5-carboxylic acid melting at 265-265 ° C.
IR (KBr) cm“1:'Oc = 0 1725, 1705 NMR (TFA-d^)£ værdier 1,54 - 2,40 (4H, m), 5,14 - 4,14 (4H, 15 m), 6,95 - 7,69· (4H, m), 8,09 (IH, d, J=12 Hz), 9,14 (IH, s).IR (KBr) cm “1: O 0 = 0 1725, 1705 NMR (TFA-d ^) δ values 1.54 - 2.40 (4H, m), 5.14 - 4.14 (4H, 15 m) , 6.95 - 7.69 · (4H, m), 8.09 (1H, d, J = 12 Hz), 9.14 (1H, s).
På samme måde fremstilles følgende forbindelse: 6-Fluor-l,4-dihydro-l-(4-hydroxyphenyl)-7-(5-hydroxy- l-pyrrolidinyl)-4-oxo-l,8-naphthyridin-5-carboxylsyreSimilarly, the following compound is prepared: 6-Fluoro-1,4-dihydro-1- (4-hydroxyphenyl) -7- (5-hydroxy-1-pyrrolidinyl) -4-oxo-1,8-naphthyridine-5-carboxylic acid
20 Smp. : 180 - 185 °CM.p. : 180 - 185 ° C
IR (KBr) cm-1: 'i C = 0 1725, 1705.IR (KBr) cm -1: C = 0 1725, 1705.
Eksempel .8 45Example .8 45
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Til 0,1 g ethyl-7-(4-acetyl-l-piperazinyl)-6-fluor-l-(4-fluorpheny1)-1,4-dihydro-4-oxo-l,8-naphthyridin-3-carboxylat sattes 2 ml 1 N vandig natriumhydroxidopløs-5 ning og 2 ml ethanol, og den fremstillede opløsning omsattes i 10 minutter ved 40 - 50 °C. Herefter tilsattes reaktionsblandingen eddikesyre for at indstille pH til 6,5. Blandingen ekstraheredes med to 5 ml portioner chloroform. De forenede chloroformekstrakter vaskedes 10 først med 5 ml vand og derefter med 5 ml mættet vandig natriumchloridopløsning, og der tørredes over vandfrit magnesiumsulfat. Opløsningsmidlet afdestilleredes under reduceret tryk, og den krystallinske masse vaskedes med to ml diethylether, hvorved der opnåedes 0,08 g 15 7-(4-acetyl-l-piperazinyl)-6-fluor-l-(4-fluorphenyl)- 1,4-dihydro-4-oxo-l,8-naphthyridin-3-carboxylsyre, der smeltede ,>280 °C.To 0.1 g of ethyl 7- (4-acetyl-1-piperazinyl) -6-fluoro-1- (4-fluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate 2 ml of 1N aqueous sodium hydroxide solution and 2 ml of ethanol were added and the solution prepared was reacted for 10 minutes at 40 - 50 ° C. Then, the reaction mixture was added acetic acid to adjust the pH to 6.5. The mixture was extracted with two 5 ml portions of chloroform. The combined chloroform extracts were washed first with 5 ml of water and then with 5 ml of saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the crystalline mass was washed with two ml of diethyl ether to give 0.08 g of 7- (4-acetyl-1-piperazinyl) -6-fluoro-1- (4-fluorophenyl) -1 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid melted> 280 ° C.
IR (KBr) cm"1:^ C=0 1730 NMR (dg-DMSQ)ζværdier 20 2,05 ( 3H, s), 3,57 (8H, bs), 7,13 - 7,80 (4H, m), 8,13 (IH, d, 0=13 Hz), 8,70 (IH, s).IR (KBr) cm "1: C C = 0 1730 NMR (dg-DMSQ) 20 values 20 2.05 (3H, s), 3.57 (8H, bs), 7.13 - 7.80 (4H, m ), 8.13 (1H, d, 0 = 13 Hz), 8.70 (1H, s).
På samme måde fremstilledes forbindelserne i tabel 11.Similarly, the compounds of Table 11 were prepared.
Tabel IITable II
4646
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00
F v I! COOHF v I! COOH
' bYXj i* _Forbindelse__Fysiske egenskaber_ 2 2 Smeltepunkt IR (KBr) (°C) cm"1: VC=0 tP) · Me/~V 282-290 Z \_( 1700 (sh) Γ'bYXj in * Compound__ Physical Properties_ 2 2 Melting point IR (KBr) (° C) cm) 1: VC = 0 tP) · Me / ~ V 282-290 Z \ _ (1700 (sh) Γ)
Me " V~\ HN N- 268-270 1725Me "V ~ \ HN N- 268-270 1725
Me / \ ” HN N- 283-285 1720 )-1Me / \ ”HN N- 283-285 1720) -1
MeMe
MeMe
) V) V
" HN N- 267-270 1730"HN N- 267-270 1730
N-CN-C
Me 1 1 (fortsættes)Me 1 1 (continued)
Tabel H (fortsat) 47Table H (continued) 47
DK 165877 BDK 165877 B
MeN ^51- >280 1720 P N / .....Λ/ : lOJ " 208-209 1730MeN ^ 51-> 280 1720 P N / ..... Λ /: lOJ „208-209 1730
FF
Me V~\ " HN_N- >280 1720Me V ~ \ "HN_N-> 280 1720
Me " MeN_^N- 210-211 1735Me "MeN_ ^ N- 210-211 1735
MeMe
/—C/ -C
" MeN_^N- 225-226 1720 /—\ " #\/\_219-220 1730 (O) MeN ^N- 283-284 1730, N ' 1700 (sh) (fortsættes)"MeN_ ^ N- 225-226 1720 / - \" # \ / \ _ 219-220 1730 (O) MeN ^ N- 283-284 1730, N '1700 (sh) (continued)
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Tabel 11 (fortsat) 48 ^ _ _ _ _rt 1730 , fol MeN N- 277-280 \_/ 1700 (sh)Table 11 (continued) 48 ^ _ _ _ _rt 1730, fol MeN N- 277-280 \ _ / 1700 (sh)
Br - _____ (o) « 271-274 1725Br - _____ (o) «271-274 1725
Me __________Me __________
Eksempel 9Example 9
Til 0,10 g ethyl-6-fluor-l-(4-fluorphenyl)-l,4-dihydro- 7-(3-hydroxy-l-pyrrolidinyl)-4-oxo-l,8-naphthyridin- 3-carboxylat sattes 2 ml 1 N vandig natriumhydroxid-5 opløsning og 2 ml ethanol, og blandingen omsattes 10 minutter ved 40 - 50 °C. Herefter tilsattes reaktions-blandingen eddikesyre for at indstille til pH 1,5. Blandingen ekstraheredes herefter med to 5 ml portioner chloroform. De forenede ekstrakter vaskedes herefter 1(1 først med 5 ml vand og derefter med 5 ml mættet vandig natriumchloridopløsning, hvorefter der tørredes over vandfrit magnesiumsulfat. Opløsningsmidlet afdestille-redes under reduceret tryk, og den krystallinske masse vaskedes med 2 ml diethylether, hvorved der opnåedes 15 0,08 g 6-fluor-l-(4-fluorphenyl)-l,4-dihydro-7-(3-hydroxy- 1-pyrrolidiny1)-4-oxo-1,8-naphthyridin-3-carboxylsyre, der smeltede >280 °C.To 0.10 g of ethyl 6-fluoro-1- (4-fluorophenyl) 1,4-dihydro-7- (3-hydroxy-1-pyrrolidinyl) -4-oxo-1,8-naphthyridine-3-carboxylate 2 ml of 1 N aqueous sodium hydroxide solution and 2 ml of ethanol were added and the mixture was reacted for 10 minutes at 40 - 50 ° C. Then, the reaction mixture was added acetic acid to adjust to pH 1.5. The mixture was then extracted with two 5 ml portions of chloroform. The combined extracts were then washed 1 (1 first with 5 ml of water and then with 5 ml of saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the crystalline mass was washed with 2 ml of diethyl ether to give 0.08 g of 6-fluoro-1- (4-fluorophenyl) -1,4-dihydro-7- (3-hydroxy-1-pyrrolidinyl) -4-oxo-1,8-naphthyridine-3-carboxylic acid melted> 280 ° C.
IR (KBr) cm"1: ^0 = 0 1730 NMR (d^-DMSO)^værdier 49IR (KBr) cm "1: 0 0 = 0 1730 NMR (d ^-DMSO) 49 values 49
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1,92 - 2,52 (2H, m), 3,22 - 5,00 (5H, m), 6,97 - 7,60 UH, m), 8,01 (IH, d, J = ll Hz), 9,00 (IH, s).1.92 - 2.52 (2H, m), 3.22 - 5.00 (5H, m), 6.97 - 7.60 UH, m), 8.01 (1H, d, J = 11 Hz ), 9.00 (1H, s).
På samme måde fremstilledes de i tabel 12 angiv/ne for-5 bindeiser.Similarly, the compounds mentioned in Table 12 were prepared.
Tabel .12 'vyV'” i’.Table .12 'vyV' ”i '.
Forbindelse Fysiske egenskaberCompound Physical Properties
Smeltepunkt IR (KBr) R RJ · Ί (°C) cm 1i VC=0Melting point IR (KBr) R RJ · Ί (° C) cm -1 in VC = 0
Å Me0NÅ Me0N
J _N- .264-265 1725 LSJ " 227 1725J _N- .264-265 1725 LSJ „227 1725
FF
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5050
Eksempel 1QExample 1Q
I 2,5 ml koncentreret saltsyre opløstes 0,25 g 6-fluor- 1,4-dihydro-l-(4-hydroxy-2-methylphenyl)-4-oxo-7-(1-pi-perazinyl)-1,8-naphthyridin-3-carboxylsyre, og herefter 5 tilsattes den fremstillede opløsning 20 ml ethanol, hvorefter blandingen omrørtes 15 minutter ved stuetemperatur. De udfældede krystaller frafiltreredes og vaskedes i med 5 ml ethanol, hvorved der opnåedes 0,2 g af saltsyresaltet af 6-fluor-1,4-dihydro-l-(4-hydroxy-2-methyl-10 phenyl)-4-oxo-7-(l-piperazinyl)-l,8-naphthyridin-3-carb- oxylsyre, der smeltede } 280 °C.In 2.5 ml of concentrated hydrochloric acid was dissolved 0.25 g of 6-fluoro-1,4-dihydro-1- (4-hydroxy-2-methylphenyl) -4-oxo-7- (1-piperazinyl) -1 8-naphthyridine-3-carboxylic acid, and then 5 of the resulting solution was added 20 ml of ethanol and the mixture was stirred for 15 minutes at room temperature. The precipitated crystals were filtered off and washed with 5 ml of ethanol to give 0.2 g of the hydrochloric acid salt of 6-fluoro-1,4-dihydro-1- (4-hydroxy-2-methyl-10-phenyl) -4-oxo -7- (1-piperazinyl) -1,8-naphthyridine-3-carboxylic acid melting} 280 ° C.
IR (KBr) cm"1:>?C = 0 1725 (sh), 1705.IR (KBr) cm "1: C C = 0 1725 (sh), 1705.
Pa samme made fremstilledes de i tabel 13 angivne forbindelser .Similarly, the compounds listed in Table 13 were prepared.
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5151
Tabel 13 OTable 13 O
F I COOHF I COOH
Saltsyresy-Saltsyresy-
resaltet af IIthe salt of II
i2i2
Forbindelse Fysiske egenskaberCompound Physical Properties
Smeltepunkt IR (KBr) IT R -1 Λ, (°C) cm : VC=0 fol / \Melting point IR (KBr) IT R -1 Λ, (° C) cm: VC = 0
MeN N- 283 1730 F N / (ΟΙ ΉΝ N- 275-278 1720 T^F V_/ F_.....MeN N- 283 1730 F N / (ΟΙ ΉΝ N- 275-278 1720 T ^ F V_ / F _.....
(r^ 249-252 ^ " (dekomp.) 1730(r ^ 249-252 ^ "(decomp.) 1730
FF
(C)) " >280 1710(C)) "> 280 1710
OHOH
" MeN N- 280-282 1730 p r~\ i72o (sh), |OJ HN N- 279-283 T N-f 1705"Me N- 280-282 1730 p r ~ \ i72o (sh), | OJ HN N- 279-283 T N-f 1705
OHOH
(fortsættes)(to be continued)
Tabel 13 (fortsat) 52Table 13 (continued) 52
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1* /—\ 1720 (sh), \r^\ MeN N- 266-269 V_y 17001 * / - \ 1720 (sh), \ r ^ \ MeN N- 266-269 V_y 1700
OHOH
I Me " 282 1730In Me "282 1730
OHOH
Eksempel 11 I 20 ml koncentreret saltsyre opløstes 2,0 g 7-(3-amino-l-pyrrolidiny1)-6-fluor-l-(2, 4-difluorphenyl)-1,4-dihydro- 4-oxo-l,8-naphthyridin-3-carboxylsyre, og herefter til-5 sattes opløsningen 200 ml ethanol ved stuetemperatur, og der omrørtes i 15 minutter. De aflejrede krystaller fra filtreredes, og der vaskedes med 40 ml ethanol, hvorved der opnåedes 1,4 g af saltsyresaltet af 7-(3-ami-no-l-pyrrolidinyl)-6-fluor-l-(2,4-difluorphenyl)-l,4-ig dihydro-4-oxo-l,8-naphthyridin-3-carboxylsyre, der smeltede ved 247 - 250 °C (dekomp.).Example 11 In 20 ml of concentrated hydrochloric acid was dissolved 2.0 g of 7- (3-amino-1-pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid, and then the solution was added 200 ml of ethanol at room temperature and stirred for 15 minutes. The precipitated crystals were filtered off and washed with 40 ml of ethanol to give 1.4 g of the hydrochloric acid salt of 7- (3-amino-1-pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl) ) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid melting at 247-250 ° C (decomp.).
IR (KBr) cm'1:^ C=0 1730.IR (KBr) cm -1: C = 0 1730.
Eksempel J.2 (1) I 2,5 ml chloroform opløstes 0,5 g ethyl-2-(2,6-di-15 chlor-5-fluornicotinoyl)-3-(2,4-difluorphenylamino)acry-lat, 0,143 g N-methylpiperazin og 0,145 g triethylamin, og den fremstillede opløsning opvarmedes 3 1/2 time med tilbagesvaling. Herefter vaskedes reaktionsblandingen først med 3 ml vand og derefter med 3 ml mættet vandigExample J.2 (1) In 2.5 ml of chloroform was dissolved 0.5 g of ethyl 2- (2,6-dichloro-5-fluoronicotinoyl) -3- (2,4-difluorophenylamino) acrylate, 0.143 g of N-methylpiperazine and 0.145 g of triethylamine, and the resulting solution were heated at reflux for 3 1/2 hours. Then the reaction mixture was washed first with 3 ml of water and then with 3 ml of saturated aqueous
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53 natriumchloridopløsning, og der tørredes over vandfrit magnesiumsulfat. Opløsningsmidlet afdampedes under reduceret tryk, og remanensen rensedes ved søjlechromatogra-fi ("WAKO" silicagel C-200, elueringsmiddel: chloro-5 formrethanol = 50:1 (rumfang)), hvorved der opnåedes 0,294 g af det olieagtige ethyl-2-[2-chlor-5-fluor-6-(4-methyl-l-piperazinyl)nicotinoyl]-3-(2,4-difluorphenyl-amino)acrylat.53 sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue purified by column chromatography ("WAKO" silica gel C-200, eluent: chloroformformethanol = 50: 1 (vol)) to give 0.294 g of the oily ethyl 2- [ 2-chloro-5-fluoro-6- (4-methyl-l-piperazinyl) nicotinoyl] -3- (2,4-difluorophenyl-amino) acrylate.
IR (rent) cm"1: ^C=0 1735, 1700 10 NMR (CDC1j)&værdier 1,13 (3H, t, J=7 Hz), 2,36 (3H, s), 2,55 (4H, t, J=5 Hz), 3,70 (4H, t, J=5 Hz), 4,15 (2H, q, J = 7 Hz), 6,77 - 7,90 (4H, m), 8,51 (IH, d, J=13 Hz), 12,50 (IH, d, J=13 Hz).IR (neat) cm "1: C C = 0 1735, 1700 NMR (CDCl1) & values 1.13 (3H, t, J = 7 Hz), 2.36 (3H, s), 2.55 (4H, t, J = 5 Hz), 3.70 (4H, t, J = 5 Hz), 4.15 (2H, q, J = 7 Hz), 6.77 - 7.90 (4H, m), 8 , 51 (1H, d, J = 13 Hz), 12.50 (1H, d, J = 13 Hz).
15 (2) Ved at behandle 0,2 g ethyl-2-[2-chlor-5-fluor-6- (4-methyl-l-piperazinyl)nicotinoyl]-3-(2,4-difluorphenyl-amino)acrylat som beskrevet i eksempel 6 og 9 opnåedes 0,12 g 6-fluor-1-(2,4-difluorphenyl)-1,4-dihydro-7-(4-methyl-l-piperazinyl)-4-oxo-l,8-naphthyridin-3-carboxyl-20 syre, der smeltede ved 208 - 209 °C.(2) By treating 0.2 g of ethyl 2- [2-chloro-5-fluoro-6- (4-methyl-1-piperazinyl) nicotinoyl] -3- (2,4-difluorophenylamino) acrylate As described in Examples 6 and 9, 0.12 g of 6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo-1 was obtained. 8-naphthyridine-3-carboxylic acid, melting at 208-209 ° C.
Eksempel 13Example 13
Til 0,3 g ethyl-7-(4-ethoxycarbonyl-2-methyl-l-pipera-zinyl)-6-fluor-l-(2,4-difluorphenyl)-l,4-dihydro-4-oxo- 1,8-naphthyridin-3-carboxylat sattes 5 ml 1 N vandig 25 natriumhydroxidopløsning og 5 ml ethanol, og blandingen omsattes 2 timer ved 90 °C. Herefter tilsattes reaktions-blandingen eddikesyre for at indstille til pH 6,5. De aflejrede krystaller fra filtreredes, der vaskedes med vand og tørredes, hvorved der opnåedes 0,2 g 6-fluor-30 l-(2,4-difluorphenyl)-l,4-dihydro-7-(2-methyl-l-pipera- zinyl)-4-oxo-l,8-naphthyridin-3-carboxylsyre, der smeltede ved 230 - 239 °C.To 0.3 g of ethyl 7- (4-ethoxycarbonyl-2-methyl-1-piperazinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1 8-Naphthyridine-3-carboxylate was added 5 ml of 1 N aqueous sodium hydroxide solution and 5 ml of ethanol, and the mixture was reacted at 90 ° C for 2 hours. Then, the reaction mixture was added acetic acid to adjust to pH 6.5. The deposited crystals were filtered off, washed with water and dried to give 0.2 g of 6-fluoro-30- (2,4-difluorophenyl) -1,4-dihydro-7- (2-methyl-1- piperazinyl) -4-oxo-1,8-naphthyridine-3-carboxylic acid, melting at 230 - 239 ° C.
5454
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IR (KBr) cm'1: \>C = 0 1730 NMR (TFA-d^) £ værdier 1,50 (3H, s), 3,20 - 5,15 (7H, m), 7,00 - 7,90 (3H, m), 8,35 (1H, d, J=13 Hz), 9,20 5 (1H, s).IR (KBr) cm -1: C = 0 1730 NMR (TFA-d 6) δ values 1.50 (3H, s), 3.20 - 5.15 (7H, m), 7.00 - 7 , 90 (3H, m), 8.35 (1H, d, J = 13 Hz), 9.20 (1H, s).
Eksempel 14 I 20 ml ethanol opslæmmedes 1,0 g af dihydrochlorid -saltet af 3-aminopyrrolidin, og 2,06 g triethylamin tilsattes den fremstillede suspension til dannelse af 10 en opløsning. Herefter tilsattes opløsningen 2,0 g ethyl- 7-chlor-6-fluor-1-(2,4-difluorphenyl)-l,4-dihydro-4-oxo- 1,8-naphthyridin-3-carboxylat i løbet af 15 minutter ved 30 °C, og den fremkomne blanding omsattes 3 timer ved denne temperatur. Efter omsætningen tilsattes reak-15 tionsblandingen 30 ml vand, og de udfældede krystaller frafiltreredes og vaskedes med 4 ml vand. Den krystallinske masse opslæmmedes i 13 ml 6 N saltsyre, og den fremstillede suspension opvarmedes 2 timer med tilbagesvaling. Derefter afkøledes reaktionsblandingen, og de 20 udfældede krystaller frafiltreredes og vaskedes med to 2 ml portioner vand, hvorved der opnåedes 1,97 g af saltsyresaltet af 7-(3-amino-l-pyrrolidinyl)-6-fluor-1-(2,4-difluorphenyl)-l,4-dihydro-4-oxo-l,8-naphthyridin- 3-carboxylsyre.Example 14 In 20 ml of ethanol, 1.0 g of the dihydrochloride salt of 3-aminopyrrolidine was slurried and 2.06 g of triethylamine was added to the resulting suspension to form a solution. Then, 2.0 g of ethyl 7-chloro-6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate solution was added over 15 minutes. minutes at 30 ° C and the resulting mixture was reacted for 3 hours at this temperature. After the reaction, the reaction mixture was added 30 ml of water and the precipitated crystals were filtered off and washed with 4 ml of water. The crystalline mass was slurried in 13 ml of 6N hydrochloric acid and the resulting suspension was heated at reflux for 2 hours. Then, the reaction mixture was cooled and the 20 precipitated crystals were filtered off and washed with two 2 ml portions of water to give 1.97 g of the hydrochloric acid salt of 7- (3-amino-1-pyrrolidinyl) -6-fluoro-1- (2 4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid.
25 IR (KBr) cm"1: ^0=0 1730 Eksempel 15 I 75 ml ethanol og 75 ml vand opslæmmedes 10,0 g 7-(3-amino-l-pyrrolidinyl)-6-fluor-l-(2,4-difluorphenyl)-1,4-dihydro-4-oxo-l,8-naphthyridin-3-carboxylsyre. Til sus-30 pensionen sattes 5,2 g p-toluensulfonsyremonohydrat ved 40 °C, og blandingen omrørtes ved denne temperaturExample 15 In 75 ml of ethanol and 75 ml of water, 10.0 g of 7- (3-amino-1-pyrrolidinyl) -6-fluoro-1- (2, 4-Difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid To the suspension was added 5.2 g of p-toluenesulfonic acid monohydrate at 40 ° C and the mixture was stirred at this temperature.
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5 5 i 30 minutter. Herefter afkøledes reaktionsblandingen til 15 °C, og de udfældede krystaller frafiltreredes og vaskedes med et blandet opløsningsmiddel af 5 ml ethanol og 5 ml vand, hvorved der opnåedes 12,8 g p-5 toluensulfonsyremonohydratsalt af 7-(3-amino-l-pyrro-lidinyl)-6fluor-l-(2,4-difluorphenyl)-l,4-dihydro-4-oxo-1,8-naphthyridin-3-carboxylsyre, der smeltede ved 258 - 260 °C.5 5 for 30 minutes. Then the reaction mixture was cooled to 15 ° C and the precipitated crystals were filtered off and washed with a mixed solvent of 5 ml of ethanol and 5 ml of water to give 12.8 g of p-5 toluenesulfonic acid monohydrate salt of 7- (3-amino-1-pyrro -lidinyl) -6fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, melting at 258-260 ° C.
IR (KBr) cm'1:'^C = 0 1735 10 NMR (DMSO-dg)^værdier 1,82 - 2,42 (m)1 ($h) 3,12 - 4,30 2,27 (s) J ’ (5H, m) 6,92 - 8,17 (8H, m), 8,79 (IH, s).IR (KBr) cm -1: 1 C = 0 1735 NMR (DMSO-d 6) δ values 1.82 - 2.42 (m) δ ($ h) 3.12 - 4.30 2.27 (s) ) J '(5H, m) 6.92 - 8.17 (8H, m), 8.79 (1H, s).
På samme måde fremstilledes følgende forbindelse: 15 Oxalsyresaltet af 7-(3-amino-l-pyrrolidiny1)-6-fluor- l-(2,4-difluorphenyl)-l,4-dihydro-4-oxo-l,8-naphthyri-din-3-carboxylsyre, der smeltede ved 250 - 253 °C.Similarly, the following compound was prepared: The oxalic acid salt of 7- (3-amino-1-pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1-8 naphthyri-din-3-carboxylic acid, melting at 250 - 253 ° C.
Smp.: 250 - 253 °C IR (KBr) cm"1:'? C = 0 1730.Mp: 250 - 253 ° C IR (KBr) cm -1: C = 0 1730.
20 Eksempel 16Example 16
Til en opløsning af 1,6 g methansulfonsyre og 25 ml eddikesyre sattes 5,^00 g 7-( 3-amino-l-pyrrolidinyl )-6-f luor-l-(2,4-difluorphenyl)-l,4-dihydro-4-oxo-l,8-napthyridin-3-carboxylsyre, hvorefter den fremstillede suspension 25 omrørtes ved stuetemperatur til dannelse af en opløs ning. Opløsningen tilsattes 100 ml ethanol i løbet af 30 minutter ved 40 - 45 °C. Herefter afkøledes reaktionsblandingen til stuetemperatur, og der omrørtes i 30 minutter. De udfældede krystaller frafiltreredes og 30 vaskedes med tre 20 ml portioner ethanol, hvorved der 56To a solution of 1.6 g of methanesulfonic acid and 25 ml of acetic acid was added 5.00 g of 7- (3-amino-1-pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dioxide. dihydro-4-oxo-1,8-napthyridine-3-carboxylic acid, after which the prepared suspension was stirred at room temperature to form a solution. To the solution was added 100 ml of ethanol over 30 minutes at 40 - 45 ° C. The reaction mixture was then cooled to room temperature and stirred for 30 minutes. The precipitated crystals were filtered off and washed with three 20 ml portions of ethanol to give 56
DK 165877BDK 165877B
opnåedes 3,12 g-methansulfonsyresalt af 7-(3-amino-l-pyr-rolidinyl)-6-fluor-l-(2,4-difluorphenyl)-l,4-dihydro-4-oxo-1,8-naphthyridin-3-carboxylsyre, der smeltede >300 °C.3.12 g of methanesulfonic acid salt of 7- (3-amino-1-pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8- naphthyridine-3-carboxylic acid melting> 300 ° C.
5 IR (KBr) cm-1: °C=0 1735.IR (KBr) cm -1: ° C = 0.1735.
På samme måde fremstilledes følgende forbindelse:Similarly, the following compound was prepared:
Svolvsyresaltet af 7-(3-amino-l-pyrrolidinyl)-6-fluor-l-(2,4-difluorphenyl)-l,4-dihydro-4-oxo-1,8-naphthyridin- 3-carboxylsyre, der smeltede ved 220 - 230 °C.The sulfuric acid salt of 7- (3-amino-1-pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid melting at 220 - 230 ° C.
10 IR (KBr) cm"1: ^C=0 1735.IR (KBr) cm -1: C = 0 1735.
Præparationseksempel 1 50 g 6-fluor-l-(2,4-difluorphenyl-l,4-dihydro-4-oxo- 7-(l-piperazinyl)-l,8-naphthyridin-3-carboxylsyre blandedes med 49 g krystallinsk cellulose, 50 g majsstivelse 15 og 1 g magnesiumstearat, og blandingen blev slået til 1000 flade tabletter.Preparative Example 1 50 g of 6-fluoro-1- (2,4-difluorophenyl-1,4-dihydro-4-oxo-7- (1-piperazinyl) -1,8-naphthyridine-3-carboxylic acid were mixed with 49 g of crystalline cellulose , 50 g corn starch 15 and 1 g magnesium stearate, and the mixture was beaten into 1000 flat tablets.
Prsparationseksempel 2 100 g 6-fluor-l-(2,4-difluorphenyl)-l,4-dihydro-4-oxo-7-(l-piperazinyl)-l,8-naphthyridin-3-carboxylsyre blev 20 blandet med 50 g majsstivelse, og der fyldtes i 1000 ti kapsler.Preparation Example 2 100 g of 6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-7- (1-piperazinyl) -1,8-naphthyridine-3-carboxylic acid were mixed with 50 g of corn starch and filled with 1000 ten capsules.
Præparationseksempel 3 50 g 7-(3-amino-l-pyrrolidinyl)-l-(2,4-difluorphenyl)-6-f luor-1,4-dihydro-4-oxo-l,8-naphthyridin-3-carboxylsyre 25 blev blandet med 49 g krystallinsk cellulose, 50 g majsstivelse og 1 g magnesiumstearat, og blandingen blevPreparative Example 3 50 g of 7- (3-amino-1-pyrrolidinyl) -1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 25 were mixed with 49 g of crystalline cellulose, 50 g of corn starch and 1 g of magnesium stearate, and the mixture was
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57 slået til 1000 flade tabletter.57 turned to 1000 flat tablets.
Præparationseksempel 4 '100 g 7-(3-amino-l-pyrrolidinyl)-l-(2,4-difluorphenyl)- 6-fluor-l,4-dihydro-4-oxo-l,8-naphthyridin-3-carboxyl-5 syre blandedes med 50 g majsstivelse og 1000 kapsler blev fyldt med blandingen.Preparative Example 4 '100 g of 7- (3-amino-1-pyrrolidinyl) -1- (2,4-difluorophenyl) - 6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxyl -5 acid was mixed with 50 g of corn starch and 1000 capsules were filled with the mixture.
Claims (5)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8496384 | 1984-04-26 | ||
| JP59084963A JPS60228479A (en) | 1984-04-26 | 1984-04-26 | 1,4-dihydro-4-oxonaphthyridine derivative and salt thereof |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| DK185685D0 DK185685D0 (en) | 1985-04-25 |
| DK185685A DK185685A (en) | 1985-10-27 |
| DK165877B true DK165877B (en) | 1993-02-01 |
| DK165877C DK165877C (en) | 1993-06-21 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK185685A DK165877C (en) | 1984-04-26 | 1985-04-25 | 1,4-DIHYDRO-6-FLUORO-4-OXO-1,8-NAPHTHYRIDINE-3-CARBOXYLIC ACID DERIVATIVES AND SALTS THEREOF, ANTIBACTERIAL PREPARATIONS CONTAINING SUCH COMPOUNDS |
Country Status (30)
| Country | Link |
|---|---|
| JP (1) | JPS60228479A (en) |
| KR (1) | KR870001693B1 (en) |
| AR (1) | AR241911A1 (en) |
| AT (2) | AT389698B (en) |
| AU (2) | AU565087B2 (en) |
| BE (1) | BE902279A (en) |
| CH (1) | CH673458A5 (en) |
| CS (1) | CS250684B2 (en) |
| DD (1) | DD238795A5 (en) |
| DE (2) | DE3514076A1 (en) |
| DK (1) | DK165877C (en) |
| EG (1) | EG17339A (en) |
| ES (2) | ES8700256A1 (en) |
| FI (1) | FI80453C (en) |
| FR (2) | FR2563521B1 (en) |
| GB (2) | GB2158825B (en) |
| HU (2) | HU197571B (en) |
| ID (1) | ID21142A (en) |
| IL (1) | IL75021A (en) |
| IT (1) | IT1209953B (en) |
| LU (1) | LU85871A1 (en) |
| NL (2) | NL187314C (en) |
| NO (1) | NO162238C (en) |
| NZ (1) | NZ211895A (en) |
| PH (3) | PH22801A (en) |
| PL (1) | PL147392B1 (en) |
| PT (1) | PT80349B (en) |
| RO (2) | RO95509B (en) |
| SE (2) | SE463102B (en) |
| ZA (1) | ZA853102B (en) |
Families Citing this family (28)
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| JPS6172753A (en) * | 1984-09-18 | 1986-04-14 | Dainippon Pharmaceut Co Ltd | Pyridyl ketone derivative |
| AU576657B2 (en) * | 1985-01-23 | 1988-09-01 | Toyama Chemical Co. Ltd. | Naphthyridine and pyridine derivatives |
| AT392789B (en) * | 1985-01-23 | 1991-06-10 | Toyama Chemical Co Ltd | METHOD FOR PRODUCING 1-SUBSTITUTED ARYL-1,4-DIHYDRO-4-OXONAPHTHYRIDINE DERIVATIVES |
| DE3525108A1 (en) * | 1985-06-07 | 1986-12-11 | Bayer Ag, 5090 Leverkusen | ANTIBACTERIAL EFFECT OF CHINOLON CARBON ACID ESTERS |
| EP0207420B1 (en) * | 1985-06-26 | 1992-05-06 | Daiichi Pharmaceutical Co., Ltd. | Pyridonecarboxylic acid derivatives |
| US4962112A (en) * | 1987-08-04 | 1990-10-09 | Abbott Laboratories | 7-(2-methyl-4-aminopyrrolidinyl)naphthryidine and quinoline compounds |
| IE62600B1 (en) * | 1987-08-04 | 1995-02-22 | Abbott Lab | Naphtyridine antianaerobic compounds |
| US4859776A (en) * | 1988-03-11 | 1989-08-22 | Abbott Laboratories | (S)-7-(3-aminopyrrolidin-1-yl)-1-(ortho, para-difluorophenyl)-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid and method for its preparation |
| JP2844079B2 (en) * | 1988-05-23 | 1999-01-06 | 塩野義製薬株式会社 | Pyridonecarboxylic acid antibacterial agent |
| DE3934082A1 (en) * | 1989-10-12 | 1991-04-18 | Bayer Ag | CHINOLON CARBONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS AN ANTIVIRAL AGENT |
| WO1992012155A1 (en) * | 1991-01-14 | 1992-07-23 | Hanmi Pharmaceutical Co., Ltd. | Novel quinolone compounds and processes for preparation thereof |
| FR2692577B1 (en) * | 1992-05-26 | 1996-02-02 | Bouchara Sa | NOVEL FLUORINATED QUINOLONES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME. |
| KR940014395A (en) * | 1992-12-09 | 1994-07-18 | 강박광 | Novel quinolone derivatives and preparation methods thereof |
| KR0148277B1 (en) * | 1993-01-18 | 1998-11-02 | 채영복 | Novel fluoroquinolone derivatives and process for the preparation thereof |
| WO1994025464A1 (en) * | 1993-04-24 | 1994-11-10 | Korea Research Institute Of Chemical Technology | Novel quinolone carboxylic acid derivatives and process for preparing the same |
| KR950018003A (en) * | 1993-12-09 | 1995-07-22 | 스미스클라인 비참 피엘씨 | Novel quinolone derivatives and methods for their preparation |
| WO1996012704A1 (en) * | 1994-10-20 | 1996-05-02 | Wakunaga Seiyaku Kabushiki Kaisha | Novel pyridonecarboxylate derivative or salt thereof and antibacterial containing the same as active ingredient |
| EP0897919B1 (en) | 1996-04-19 | 2004-06-16 | Wakunaga Pharmaceutical Co., Ltd. | Novel pyridonecarboxylic acid derivatives or salts thereof and antibacterial agents containing the same as the active ingredient |
| KR20000052892A (en) * | 1996-10-30 | 2000-08-25 | 빌프리더 하이더 | Method of producing naphthyridine compounds and novel intermediate products |
| DE19713506A1 (en) | 1997-04-01 | 1998-10-08 | Bayer Ag | Process for the preparation of 2,6-dichloro-5-fluoronicotinonitrile and the chemical compound 3-cyano-2-hydroxy-5-fluoropyrid-6-one monosodium salt and its tautomers |
| AU3192700A (en) | 1999-03-17 | 2000-10-04 | Daiichi Pharmaceutical Co., Ltd. | Medicinal compositions |
| DE19926400A1 (en) | 1999-06-10 | 2000-12-14 | Bayer Ag | Improved process for the preparation of 2,6-dichloro-5-fluoro-nicotinic acid and coarse and particularly pure 2,6-dichloro-5-fluoro-nicotinic acid |
| JP3477466B2 (en) | 1999-09-02 | 2003-12-10 | 湧永製薬株式会社 | Quinolinecarboxylic acid derivatives or salts thereof |
| EP1313708A1 (en) * | 2000-08-29 | 2003-05-28 | Chiron Corporation | Quinoline antibacterial compounds and methods of use thereof |
| KR100981351B1 (en) * | 2003-10-29 | 2010-09-10 | 주식회사 엘지생명과학 | Process for preparing 7-chloro-1-cyclopropyl-6- fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid |
| CN101792443A (en) * | 2010-03-09 | 2010-08-04 | 北京欧凯纳斯科技有限公司 | Fluoro-carbostyril derivative as well as preparation method and application thereof |
| JOP20190045A1 (en) | 2016-09-14 | 2019-03-14 | Bayer Ag | 7-substituted 1-aryl-naphthyridine-3-carboxylic acid amides and use thereof |
| CN114369092A (en) * | 2021-12-20 | 2022-04-19 | 赤峰万泽药业股份有限公司 | Tosufloxacin tosylate and preparation method thereof |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2125310A1 (en) * | 1971-05-21 | 1972-11-30 | Sterling Drug Inc , New York, NY (V St A) | 1-alkyl-1,4-dihydro-4-oxo-1,8-naphtyridine 3-carboxylic acids antibac |
| AR223983A1 (en) * | 1978-08-25 | 1981-10-15 | Dainippon Pharmaceutical Co | A PROCEDURE FOR PREPARING 6-HALOGEN-4-OXO-7- (1-PIPERAZINYL) -1,8-NAFTIRIDIN-3-CARBOXYLIC ACID DERIVATIVES |
| DE3033157A1 (en) * | 1980-09-03 | 1982-04-01 | Bayer Ag, 5090 Leverkusen | 7-AMINO-1-CYCLOPROPYL-4-OXO-1,4-DIHYDRO-NAPHTHYRIDINE-3-CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THE ANTIBACTERIAL AGENTS CONTAINING THEM |
| US4382937A (en) * | 1981-02-27 | 1983-05-10 | Dainippon Pharmaceutical Co., Ltd. | Naphthyridine derivatives and their use as anti-bacterials |
| IE55898B1 (en) * | 1982-09-09 | 1991-02-14 | Warner Lambert Co | Antibacterial agents |
| IL74064A (en) * | 1984-01-26 | 1988-09-30 | Abbott Lab | 1,7-disubstituted-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid derivatives and antibacterial compositions containing them |
| NZ210847A (en) * | 1984-01-26 | 1988-02-29 | Abbott Lab | Naphthyridine and pyridopyrimidine derivatives and pharmaceutical compositions |
| AU576657B2 (en) * | 1985-01-23 | 1988-09-01 | Toyama Chemical Co. Ltd. | Naphthyridine and pyridine derivatives |
| DE3525108A1 (en) * | 1985-06-07 | 1986-12-11 | Bayer Ag, 5090 Leverkusen | ANTIBACTERIAL EFFECT OF CHINOLON CARBON ACID ESTERS |
-
1984
- 1984-04-26 JP JP59084963A patent/JPS60228479A/en active Granted
-
1985
- 1985-04-18 DE DE19853514076 patent/DE3514076A1/en active Granted
- 1985-04-18 DE DE3546658A patent/DE3546658C2/de not_active Expired - Lifetime
- 1985-04-23 GB GB08510297A patent/GB2158825B/en not_active Expired
- 1985-04-23 PH PH32174A patent/PH22801A/en unknown
- 1985-04-23 NL NLAANVRAGE8501172,A patent/NL187314C/en not_active IP Right Cessation
- 1985-04-24 RO RO126286A patent/RO95509B/en unknown
- 1985-04-24 RO RO118517A patent/RO91871B/en unknown
- 1985-04-24 PT PT80349A patent/PT80349B/en unknown
- 1985-04-24 NZ NZ211895A patent/NZ211895A/en unknown
- 1985-04-24 NO NO851643A patent/NO162238C/en not_active IP Right Cessation
- 1985-04-24 AU AU41650/85A patent/AU565087B2/en not_active Expired
- 1985-04-24 IL IL7502185A patent/IL75021A/en not_active IP Right Cessation
- 1985-04-24 AT AT0122485A patent/AT389698B/en not_active IP Right Cessation
- 1985-04-24 DD DD85275518A patent/DD238795A5/en unknown
- 1985-04-24 EG EG261/85A patent/EG17339A/en active
- 1985-04-25 DK DK185685A patent/DK165877C/en not_active IP Right Cessation
- 1985-04-25 AR AR85300190A patent/AR241911A1/en active
- 1985-04-25 BE BE0/214909A patent/BE902279A/en not_active IP Right Cessation
- 1985-04-25 SE SE8502017A patent/SE463102B/en not_active IP Right Cessation
- 1985-04-25 ID IDP980525A patent/ID21142A/en unknown
- 1985-04-25 FI FI851637A patent/FI80453C/en not_active IP Right Cessation
- 1985-04-25 HU HU873675A patent/HU197571B/en unknown
- 1985-04-25 ES ES542584A patent/ES8700256A1/en not_active Expired
- 1985-04-25 KR KR1019850002822A patent/KR870001693B1/en not_active IP Right Cessation
- 1985-04-25 ZA ZA853102A patent/ZA853102B/en unknown
- 1985-04-25 CS CS853035A patent/CS250684B2/en not_active IP Right Cessation
- 1985-04-25 FR FR858506327A patent/FR2563521B1/en not_active Expired
- 1985-04-25 HU HU851599A patent/HU194226B/en unknown
- 1985-04-25 CH CH1798/85A patent/CH673458A5/de not_active IP Right Cessation
- 1985-04-26 IT IT8548002A patent/IT1209953B/en active
- 1985-04-26 PL PL1985253108A patent/PL147392B1/en unknown
- 1985-04-26 LU LU85871A patent/LU85871A1/en unknown
-
1986
- 1986-01-31 ES ES551538A patent/ES8706673A1/en not_active Expired
-
1987
- 1987-07-17 GB GB8716897A patent/GB2191776B/en not_active Expired - Lifetime
- 1987-10-20 PH PH35960A patent/PH25228A/en unknown
- 1987-10-20 PH PH35958A patent/PH25046A/en unknown
- 1987-11-25 AU AU81804/87A patent/AU612993B2/en not_active Expired
-
1988
- 1988-06-30 FR FR888808836A patent/FR2614620B1/en not_active Expired - Lifetime
- 1988-10-31 AT AT0267888A patent/AT390258B/en not_active IP Right Cessation
- 1988-12-20 SE SE8804586A patent/SE501412C2/en not_active IP Right Cessation
-
1991
- 1991-04-15 NL NL9100648A patent/NL9100648A/en not_active Application Discontinuation
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| PUP | Patent expired |