SE501412C2 - 1,4-dihydro-4-oxonaphthyridine derivatives and salts thereof Process for the preparation thereof and antibacterial agents including these - Google Patents
1,4-dihydro-4-oxonaphthyridine derivatives and salts thereof Process for the preparation thereof and antibacterial agents including theseInfo
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- SE501412C2 SE501412C2 SE8804586A SE8804586A SE501412C2 SE 501412 C2 SE501412 C2 SE 501412C2 SE 8804586 A SE8804586 A SE 8804586A SE 8804586 A SE8804586 A SE 8804586A SE 501412 C2 SE501412 C2 SE 501412C2
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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
- 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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- 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
- 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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Abstract
Description
501 412 grampositiva bakterier. 501 412 gram-positive bacteria.
Under dessa förhållanden har sökanden, som ett resultat av vidsträckt forskning, funnit att ett nytt l,4-dihydro-4-oxo- naftyridinderivat och ett salt därav kan lösa ovannämnda problem.Under these circumstances, as a result of extensive research, the applicant has found that a novel 1,4-dihydro-4-oxonaphthyridine derivative and a salt thereof can solve the above-mentioned problems.
Ett ändamål med föreliggande uppfinning är att tillhanda- hålla ett nytt l,4-dihydro-4-oxonaftyridinderivat och ett salt därav med utmärkta egenskaper, t.ex. starka antibak- teriella aktiviteter mot grampositiva och gramnegativa bak- terier, särskilt mot antibiotikaresistenta bakterier, och som ger höga koncentrationer i blodet vid oral eller parenteral administration och uppvisar hög säkerhet.An object of the present invention is to provide a novel 1,4-dihydro-4-oxonaphthyridine derivative and a salt thereof having excellent properties, e.g. strong antibacterial activities against gram-positive and gram-negative bacteria, especially against antibiotic-resistant bacteria, and which give high concentrations in the blood during oral or parenteral administration and show high safety.
Ett annat ändamål med föreliggande uppfinning är att till- handahålla ett förfarande för framställning av ett nytt 1,4- dihydro-4-oxonaftyridinderivat och ett salt därav.Another object of the present invention is to provide a process for the preparation of a novel 1,4-dihydro-4-oxonaphthyridine derivative and a salt thereof.
Ett ytterligare ändamål med föreliggande uppfinning är att tillhandahålla ett antibakteriellt medel användbart för be- handlingen av infektioner orsakade av bakterier eller lik- nande och vilket innefattar ett nytt l,4-dihydro-4-oxo- naftyridinderivat eller ett salt därav.A further object of the present invention is to provide an antibacterial agent useful for the treatment of infections caused by bacteria or the like and which comprises a novel 1,4-dihydro-4-oxonaphthyridine derivative or a salt thereof.
Enligt föreliggande uppfinning tillhandahålles ett l,4-di- hydro-4-oxonaftyridinderivat betecknat med den allmänna for- meln: COOR (I) 501 412 3 vari R1 betecknar en väteatom eller en Cl_4-alkylgrupp, R2 betecknar en 3-fluorfenyl-, 3,4-difluorfenyl-, 2,4-difluorfe- nyl-, 2,5-difluorfenyl-, 2,6-difluorfenyl-, 4-klorfenyl-, 4- bromfenyl-, 4-metylfenyl-, 4-cyanofenyl-, 4-aminofenyl-, 4- trifluormetylfenyl-, 4-fluor-2-metylfenyl-, 4-fluor-2-hydroxi- fenyl-, 4-hydroxi-2-metylfenyl- eller 2-fluor-4-hydroxifenyl- grupp när R3 betecknar en 1-piperazinylgruppï R2 betecknar en 3-fluorfenyl-, 2,4-difluorfenyl-, 3,4-difluorfenyl-, 2,5- difluorfenyl-, 2,6-difluorfenyl-, 4-klorfenyl-, 4-bromfenyl-, 4-metylfenyl-, 4-cyanofenyl-, 4-aceytlaminofenyl-, 4-trifluor- metylfenyl-, 4-fluor-2-metylfenyl-, 4-fluor-2-metoxifenyl-, 2- fluor-4-metoxifenyl- eller 2-metyl-4-metoxifenyl-grupp när R3 betecknar en 4-acetyl-1-piperazinylgrupp; R2 betecknar en 3,4- difluorfenyl-, 4-bromfenyl-, 4-metylfenyl-, 4-metoxifenyl-, 2- metoxifenyl-, 4-fluor-2-metoxifenyl-, 2-fluor-4-metoxifenyl-, 4-metyl-2-metoxifenyl-, 4-acetylaminofenyl-, 3-metoxifenyl-, 3-fluor-4-metoxifenyl-, 3-metyl-4-metoxifenyl-, 2-metyl-4- metoxifenyl-, 3-hydroxifenyl-, 4-fluor-2-hydroxifenyl-, 3- fluor-4-hydroxifenyl-, 2-fluor-4-hydroxifenyl-, 2-hydroxi-4- metylfenyl-, 4-hydroxi-3-metylfenyl-, 4-hydroxi-2-metylfenyl- eller 4-klorfenyl-grupp när R3 betecknar en 4-metyl-l-pipera- zinylgrupp; R2 betecknar en 4-fluorfenylgrupp när R3 betecknar en 4-(N-acetyl-N-metylamino)piperidino-, 4-(N-metylamino)- piperidino-, 2,5-dimetyl-l-piperazinyl-, 4-(2-hydroxietyl)-l- piperazinyl-, 3-metylamino-l-pyrrolidinyl-, 3-(N-acetyl-N- metylamino)-l-pyrrolidinyl- eller 3-metyl-l-piperazinylgrupp; R2 betecknar en 4-metoxifenylgrupp när R3 betecknar en 3- hydroxi-l-pyrrolidinyl-, 1-pyrrolidinyl-, piperidino-, 4-etyl- l-piperazinyl-, 4-n-propyl-l-piperazinyl-, 4-isopropyl-l- piperazinyl-, 4-(2-hydroxietyl)-l-piperazinyl- eller 4-allyl- 1-piperazinylgrupp; R2 betecknar en 2,4-difluorfenylgrupp när R3 betecknar en 4-(N-acetyl-N-metylamino)piperidino-, 3-metyl- l-piperazinyl-, 3,4-dimetyl-l-piperazinyl-, 2,4-dimetyl-l- piperazinyl-, 4-allyl-l-piperazinyl-, 4-etoxikarbonyl-2-metyl- l-piperazinyl-, 3-dimetylamino-l-pyrrolidinyl-, 3-(N-acetyl-N- metylamino)-l-pyrrolidinyl, 4-(N-metylamino)piperidino-, 3- metylamino-l-pyrrolidinyl- eller 2-metyl-l-piperazinyl-grupp; R2 betecknar en 2,3,4-trifluorfenylgrupp när R3 betecknar en 501 412 4 3-amino-l-pyrrolidinyl- eller 3-acetylamino-l-pyrrolidinyl- grupp; R2 betecknar en 4-hydroxifenylgrupp när R3 betecknar en 4-etyl-l-piperazinyl-, 4-n-propyl-l-piperazinyl-, 4-isopropyl- l-piperazinyl-, 4-(2-hydroxietyl)-l-piperazinyl- eller 4- allyl-1-piperazinyl-grupp; och R2 betecknar en fenylgrupp, som kan vara substituerad med l-3 substituenter valda ur gruppen bestående av halogenatom, C1_1O-alkylgrupper, hydroxylgrupp, C1_10-alkoxigrupper, cyanogrupp, acetylaminogrupp, trifluorme- tylgrupp när R3 betecknar en halogenatom.According to the present invention there is provided a 1,4-dihydro-4-oxonaphthyridine derivative represented by the general formula: COOR (I) 501 412 3 wherein R 1 represents a hydrogen atom or a C 1-4 alkyl group, R 2 represents a 3-fluorophenyl-, 3,4-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methylphenyl, 4-cyanophenyl, 4-Aminophenyl, 4-trifluoromethylphenyl, 4-fluoro-2-methylphenyl, 4-fluoro-2-hydroxyphenyl, 4-hydroxy-2-methylphenyl or 2-fluoro-4-hydroxyphenyl group when R3 represents a 1-piperazinyl group, R2 represents a 3-fluorophenyl-, 2,4-difluorophenyl-, 3,4-difluorophenyl-, 2,5-difluorophenyl-, 2,6-difluorophenyl-, 4-chlorophenyl-, 4-bromophenyl- , 4-methylphenyl-, 4-cyanophenyl-, 4-acetylaminophenyl-, 4-trifluoromethylphenyl-, 4-fluoro-2-methylphenyl-, 4-fluoro-2-methoxyphenyl-, 2-fluoro-4-methoxyphenyl- or 2-methyl-4-methoxyphenyl group when R 3 represents a 4-acetyl-1-piperazinyl group; R 2 represents a 3,4-difluorophenyl-, 4-bromophenyl-, 4-methylphenyl-, 4-methoxyphenyl-, 2-methoxyphenyl-, 4-fluoro-2-methoxyphenyl-, 2-fluoro-4-methoxyphenyl-, 4- methyl 2-methoxyphenyl-, 4-acetylaminophenyl-, 3-methoxyphenyl-, 3-fluoro-4-methoxyphenyl-, 3-methyl-4-methoxyphenyl-, 2-methyl-4-methoxyphenyl-, 3-hydroxyphenyl-, 4 -fluoro-2-hydroxyphenyl-, 3-fluoro-4-hydroxyphenyl-, 2-fluoro-4-hydroxyphenyl-, 2-hydroxy-4-methylphenyl-, 4-hydroxy-3-methylphenyl-, 4-hydroxy-2- methylphenyl or 4-chlorophenyl group when R 3 represents a 4-methyl-1-piperazinyl group; R 2 represents a 4-fluorophenyl group when R 3 represents a 4- (N-acetyl-N-methylamino) piperidino-, 4- (N-methylamino) -piperidino-, 2,5-dimethyl-1-piperazinyl-, 4- (2 -hydroxyethyl) -1-piperazinyl-, 3-methylamino-1-pyrrolidinyl-, 3- (N-acetyl-N-methylamino) -1-pyrrolidinyl- or 3-methyl-1-piperazinyl group; R 2 represents a 4-methoxyphenyl group when R 3 represents a 3-hydroxy-1-pyrrolidinyl-, 1-pyrrolidinyl-, piperidino-, 4-ethyl-1-piperazinyl-, 4-n-propyl-1-piperazinyl-, 4-isopropyl -1-piperazinyl-, 4- (2-hydroxyethyl) -1-piperazinyl- or 4-allyl-1-piperazinyl group; R 2 represents a 2,4-difluorophenyl group when R 3 represents a 4- (N-acetyl-N-methylamino) piperidino-, 3-methyl-1-piperazinyl-, 3,4-dimethyl-1-piperazinyl-, 2,4- dimethyl-1-piperazinyl-, 4-allyl-1-piperazinyl-, 4-ethoxycarbonyl-2-methyl-1-piperazinyl-, 3-dimethylamino-1-pyrrolidinyl-, 3- (N-acetyl-N-methylamino) - 1-pyrrolidinyl, 4- (N-methylamino) piperidino, 3-methylamino-1-pyrrolidinyl or 2-methyl-1-piperazinyl group; R 2 represents a 2,3,4-trifluorophenyl group when R 3 represents a 3-amino-1-pyrrolidinyl or 3-acetylamino-1-pyrrolidinyl group; R 2 represents a 4-hydroxyphenyl group when R 3 represents a 4-ethyl-1-piperazinyl-, 4-n-propyl-1-piperazinyl-, 4-isopropyl-1-piperazinyl-, 4- (2-hydroxyethyl) -1-piperazinyl - or 4-allyl-1-piperazinyl group; and R 2 represents a phenyl group which may be substituted by 1-3 substituents selected from the group consisting of halogen atom, C 1-10 alkyl groups, hydroxyl group, C 1-10 alkoxy groups, cyano group, acetylamino group, trifluoromethyl group when R 3 represents a halogen atom.
Vidare tillhandahàlles enligt uppfinningen ett förfarande för framställning av ett l,4-dihydro-4-oxonaftyridinderivat be- tecknat med den allmänna formeln (I) eller ett salt därav jämte ett antibakteriellt medel innefattande l,4-dihydro-4- oxonaftyridinderivatet betecknat med den allmänna formeln (I) eller ett salt därav.Furthermore, according to the invention there is provided a process for the preparation of a 1,4-dihydro-4-oxonaphthyridine derivative represented by the general formula (I) or a salt thereof together with an antibacterial agent comprising the 1,4-dihydro-4-oxonaphthyridine derivative designated by the general formula (I) or a salt thereof.
Föreliggande uppfinning förklaras nedan i detalj.The present invention is explained in detail below.
I föreningen betecknad med den allmänna formeln (I) eller ett salt därav inkluderar den karboxylskyddande gruppen för R1 t.ex. esterbildande grupper, vilka kan avlägsnas med kataly- tisk reduk- tion, kemisk reduktion eller andra behandlingar under milda betingelser; esterbildande grupper, vilka lätt kan avlägsnas i en levande kropp: organiska silylhaltiga grupper, organiska fosforhaltiga grupper och organiska tennhaltiga grupper, som lätt kan avlägsnas genom behandling med vatten eller en alkohol samt andra olika välkända esterbildande grupper.In the compound represented by the general formula (I) or a salt thereof, the carboxyl protecting group for R 1 includes e.g. ester-forming groups, which can be removed by catalytic reduction, chemical reduction or other treatments under mild conditions; ester-forming groups, which can be easily removed in a living body: organic silyl-containing groups, organic phosphorus-containing groups and organic tin-containing groups, which can be easily removed by treatment with water or an alcohol, and other various well-known ester-forming groups.
Bland dessa karboxylskyddande grupper inkluderar de föredragna skyddande grupperna, t.ex. karboxylskyddande grupper beskrivna i den japanska utlagda (Kokai) patentansökan nr. 80 665/84.Among these carboxyl protecting groups, the preferred protecting groups include, e.g. carboxyl protecting groups described in Japanese Laid-Open (Kokai) Patent Application No. 80 665/84.
Arylgruppen för R2 inkluderar exempelvis fenyl. Arylgruppen kan vara substituerad med en eller fler substituentr valda bland halogenatomer, exempelvis fluor, klor och brom; alkyl- grupper, t.ex. Cl-C10-alkylgrupper med rak eller grenad kedja, 501 412 5 såsom metyl, etyl, n-propyl, isopropyl, n-butyl, isobutyl, sek-butyl, tert-butyl, pentyl, hexyl, heptyl, oktyl och lik- nande; hydroxylgrupper; alkoxigrupper, t.ex. C1-C1O-alkoxi- grupper med rak eller grenad kedja, såsom metoxi, etoxi, n- propoxi, isopropoxi, n-butoxi, isobutoxi, sek-butoxi, tert- butoxi, pentyloxi, hexyloxi, heptyloxi, oktyloxi och liknande: cyanogrupp; aminogrupp; acetylamino och trifluormetyl.The aryl group for R 2 includes, for example, phenyl. The aryl group may be substituted with one or more substituents selected from halogen atoms, for example fluorine, chlorine and bromine; alkyl groups, e.g. C1-C10 straight or branched chain alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl and the like ; hydroxyl groups; alkoxy groups, e.g. C 1 -C 10 straight or branched chain alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy and the like: cyano group; amino group; acetylamino and trifluoromethyl.
Dessutom inkludrar halogenatomen för R3 exempelvis fluor, klor och brom. Den cykliska aminogruppen för R3 har åtminstone en kväveatom och inkluderar 5- eller 6-ledade cykliska aminogrup- per, såsom 1-pyrrolidinyl, piperidino och 1-piperazinyl. De nämnda cykliska aminogrupperna kan vara substituerade med en eller fler substituenter utvalda bland alkylgrupper, t.ex. C1- C4-alkylgrupper med rak eller grenad kedja, såsom metyl, etyl, n-propyl och isopropyl; amino; 2-hydroxietyl; hydroxyl, allyl, acetyl, metylamino, dimetylamino, acetylamino, etoxikarbonyl och N-acetyl-N-metylamino.In addition, the halogen atom for R 3 includes, for example, fluorine, chlorine and bromine. The cyclic amino group for R 3 has at least one nitrogen atom and includes 5- or 6-membered cyclic amino groups such as 1-pyrrolidinyl, piperidino and 1-piperazinyl. The said cyclic amino groups may be substituted by one or more substituents selected from alkyl groups, e.g. C 1 -C 4 straight or branched chain alkyl groups such as methyl, ethyl, n-propyl and isopropyl; amino; 2-hydroxyethyl; hydroxyl, allyl, acetyl, methylamino, dimethylamino, acetylamino, ethoxycarbonyl and N-acetyl-N-methylamino.
Bland föreningarna betecknade med den allmänna formeln (I) föredrages de vari R2 betecknar en fluorsubstituerad fenyl- grupp och R3 betecknar en substituerad eller osubstituerad 1- pyrrolidinyl- eller 1-piperazinylgrupp.Among the compounds represented by the general formula (I), those in which R 2 represents a fluoro-substituted phenyl group and R 3 represents a substituted or unsubstituted 1-pyrrolidinyl or 1-piperazinyl group are preferred.
Saltet av föreningen betecknad med den allmänna formeln (I) inkluderar sedvanliga salter vid basiska grupper såsom en aminogrupp och liknande och vid sura grupper, såsom en kar- boxylgrupp och liknande. Salterna vid den basiska gruppen in- kluderar t.ex. salter med mineralsyror, såsom saltsyra, sva- velsyra och liknande; salter med organiska karboxylsyror, såsom oxalsyra, myrsyra, triklorättiksyra, trifluorättiksyra och liknande; salter med sulfonsyror, såsom metansulfonsyra, p-toluensulfonsyra, naftalensulfonsyra och liknande. Salterna vid de sura grupperna inkluderar exempelvis salter med alkali- metaller, såsom natrium, kalium och liknande; salter med alka- liska jordartsmetaller, såsom kalcium, magnesium och liknande; ammoniumsalter och salter med kvävehaltiga organiska baser, såsom prokain, dibensylamin, N-bensyl-B-fenetylamin, 1- 501 412 6 efenamin, N,N-dibensyletylendiamin, trietylamin, trimetylamin, tributylamin, pyridin, N,N-dimetylanilin, N-metylpiperidin, N- metylmorfolin, dietylamin, dicyklohexylamin och liknande.The salt of the compound represented by the general formula (I) includes customary salts at basic groups such as an amino group and the like and at acidic groups such as a carboxyl group and the like. The salts in the basic group include e.g. salts with mineral acids such as hydrochloric acid, sulfuric acid and the like; salts with organic carboxylic acids such as oxalic acid, formic acid, trichloroacetic acid, trifluoroacetic acid and the like; salts with sulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid and the like. The salts of the acidic groups include, for example, salts with alkali metals such as sodium, potassium and the like; salts with alkaline earth metals, such as calcium, magnesium and the like; ammonium salts and salts with nitrogen-containing organic bases, such as procaine, dibenzylamine, N-benzyl-β-phenethylamine, phenamine, N, N-dibenzylethylenediamine, triethylamine, trimethylamine, tributylamine, pyridine, N, N-dimethylaniline methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine and the like.
Om föreningen betecknad med den allmänna formeln (I) och ett salt därav har isomerer (t.ex. optiska isomerer, geometriska isomerer, tautomerer och liknande) inkluderar föreliggande uppfinning samtliga dessa isomerer, kristallformer och hydra- ter därav.If the compound represented by the general formula (I) and a salt thereof has isomers (eg optical isomers, geometric isomers, tautomers and the like), the present invention includes all of these isomers, crystal forms and hydrates thereof.
Antibakteriella aktiviteter och akuta toxiciteter illustre- ras med hänvisning till vanliga föreningar enligt före- liggande uppfinning. l. Antibakteriell aktivitet Testmetod Enligt standardmetoden från Japan Society of Chemotherapy /CHEMOTHERAPY, 29(l), 76-79(l98l)/, inokulerades en bak- terielösning erhållen genom odling av Heart Infusion-buljong (framställd av Eiken Kagaku) vid 37°C i 20 timmar på "Heart Infusion“-agar innehållande ett läkemedel och odlad vid 37°C i 20 timmar, varefter bakteriernas tillväxt observerades i syfte att bestämma den minimala koncentration vid vilken bakterietillväxten inhiberades som MIC (pg/ml). Mängden inokulerad bakteria var 104 celler/platta (106 celler/ml).Antibacterial activities and acute toxicities are illustrated with reference to common compounds of the present invention. Antibacterial activity Test method According to the standard method of the Japan Society of Chemotherapy / CHEMOTHERAPY, 29 (l), 76-79 (l98l) /, a bacterial solution obtained by culturing Heart Infusion broth (manufactured by Eiken Kagaku) was inoculated at 37 °. C for 20 hours on "Heart Infusion" agar containing a drug and cultured at 37 ° C for 20 hours, after which the growth of the bacteria was observed in order to determine the minimum concentration at which the bacterial growth was inhibited as MIC (pg / ml). was 104 cells / plate (106 cells / ml).
MIC-värdena för följande testföreningar visas i tabell 1.The MIC values for the following test compounds are shown in Table 1.
De i tabell 1 använda symbolerna har följande betydelser: *l: penicillinas-producerande bakterier, *2: cefalosporinas-producerande bakterier, *3: inokuleringsstorlek: 108 celler/ml, Me: metylgrupp, Et: etylgrupp, n-Pr: n-propylgrupp, i-Pr: isopropylgrupp 501 412 mm.A mH.m wß.o mn.o mm.o N«m~mzU mmocflmøumn .mm m~.m m.~H mm.A æß.o m~.m mvwmomfi mmocflmsumm .mm æß.o ~.o N.o ~.c ~.o und mflumuuflcm .Mod mH.m mH.m wm.fl mm.o mm.o mwøw mmocflmfluwm .mm 2.3 2.3 2.3 2.3 2.3 Nåæåzo 38 .m 2.3 2.3 2.3 2.3 2.3 STE. 38 .m 2.3 ...2.3 2.3 ...2.3 2.3 2:2 33 .u ~.o ~.o mm.o ~.o H.o Haßmfium mnwunm .um Wo Wo 3.... 9.2.2 H5 2203 mfiëeäuomw .ä ~.o ~.o ~.o ~.o H.o mmo~ . wfluwuxmm m w m N a Hc mcfiswnmm åUzäå ..z\|WZ@..= |z]zm umJzm àfiJzwz m -_~ rak KL ,|\ Fk m z z mm |®V|oæ |@xom än lßwlom x mooo /m m: .m f... N o H Hflmnmfi 501 412 3.0 Sá 21,. wm.a mmIH m.~fl mïm io H6 ~¿ Wo wmïfi æÜo m~.w mÜm mo.ow mo.ow .Üo mo.o.v. 3.3 2.3 10 2.8 mo.ow mo.ow mm.o mo.ow N.o Üo N.o m.o ~.o ~.o 2.0 wïo N.o ~.o N.o N.o n w ß m |a1Jz nu |zwJz~mu IQ/ JO/ f _ N ,L _ N . zmwZ zmmš mun m0 mun m0 |A1%V|m nßïívlm |ß@®Tm |¿@@v|øm m .m ^.wu»o«V H Hfimnma 501 412 2. Akut toxicitet LD50-värden erhållna genom att intravenöst administrera testföreningarna nr. 5 och 6 nämnda ovan till möss (ICE- stam, hankön, kroppsvikt: 18 - 24 g) var 200 mg/kg eller högre.The symbols used in Table 1 have the following meanings: * 1: penicillinase-producing bacteria, * 2: cephalosporinase-producing bacteria, * 3: inoculation size: 108 cells / ml, Me: methyl group, Et: ethyl group, n-Pr: n- propyl group, i-Pr: isopropyl group 501 412 mm. mmoc fl msumm .mm æß.o ~ .o No ~ .c ~ .o und m fl umuu fl cm .Mod mH.m mH.m wm. fl mm.o mm.o mwøw mmoc fl m fl uwm .mm 2.3 2.3 2.3 2.3 2.3 Nåæåzo 38 .m 2.3 2.3 2.3 2.3 2.3 STE. 38 .m 2.3 ... 2.3 2.3 ... 2.3 2.3 2: 2 33 .u ~ .o ~ .o mm.o ~ .o Ho Haßm fi um mnwunm .um Wo Wo 3 .... 9.2.2 H5 2203 m fi ëeäuomw .ä ~ .o ~ .o ~ .o ~ .o Ho mmo ~. w fl uwuxmm mwm N a Hc mc fi swnmm åUzäå ..z \ | WZ @ .. = | z] zm umJzm à fi Jzwz m -_ ~ rak KL, | \ Fk mzz mm | ®V | oæ | @xom än lßwlom x mooo / mm: .m f ... N o H H fl mnm fi 501 412 3.0 Sá 21 ,. wm.a mmIH m. ~ fl mïm io H6 ~ ¿Wo wmï fi æÜo m ~ .w mÜm mo.ow mo.ow .Üo mo.o.v. 3.3 2.3 10 2.8 mo.ow mo.ow mm.o mo.ow No Üo No mo ~ .o ~ .o 2.0 wïo No ~ .o No No nw ß m | a1Jz nu | zwJz ~ mu IQ / JO / f _ N, L _ N. zmwZ zmmš mun m0 mun m0 | A1% V | m nßïívlm | ß @ ®Tm | ¿@@ v | øm m .m ^ .wu »o« VH H fi mnma 501 412 2. Acute toxicity LD50 values obtained by intravenous administration test compounds no. 5 and 6 mentioned above in mice (ICE strain, male, body weight: 18 - 24 g) were 200 mg / kg or higher.
Förfarandet för framställning av föreningen enligt före- liggande uppfinning förklaras nedan.The process for preparing the compound of the present invention is explained below.
Föreningen enligt föreliggande uppfinning kan exempelvis framställas enligt följande framställningssätt: 0 o F_:I:>:[:l\\,/coonla F_:::ø:[:%\\/,cooR1a ----e» N cl N Cl R3a R3b [II] [IV] eller ett salt därav LO lo F coonla F coonla _.í__>.The compound of the present invention can be prepared, for example, according to the following preparation methods: 0: F_: I:>: [: l \\, / coonla F _ ::: ø: [:% \\ /, cooR1a ---- e »N cl N Cl R3a R3b [II] [IV] or a salt thereof LO lo F coonla F coonla _.í __>.
N Cl 2 N cl nu-R2 R3a NH-R R3 [III] eller ett salt därav [V] eller ett salt därav l 10 CQQRI coonl F N N o N N a | ab 2 R2 R l F RB IL [Ia] eller ett salt därav [Ib] eller ett salt därav 501 412 10 vari Rla betecknar samma karboxiskyddande grupp som i Rl; R3a betecknar samma halogenatom som i R3; R representerar samma substituerade eller osubstituerade cykliska aminogrupp som i R3 och Rl och R2 har ovan angiven betydelse.N Cl 2 N cl nu-R2 R3a NH-R R3 [III] or a salt thereof [V] or a salt thereof 1 CQQRI coonl F N N o N N a | ab 2 R2 R 1 F RB IL [Ia] or a salt thereof [Ib] or a salt thereof wherein R1a represents the same carboxy-protecting group as in R1; R3a represents the same halogen atom as in R3; R represents the same substituted or unsubstituted cyclic amino group as in R 3 and R 1 and R 2 have the meaning given above.
Salterna av föreningarna betecknade med de allmänna form- lerna (Ia), (Ib), (III), (IV) och (V) inkluderar samma sal- ter som de av föreningarna betecknade med den allmänna for- meln (I). (i) Föreningen betecknad med den allmänna formeln (III) eller ett salt därav eller föreningen betecknad med den allmänna formeln (V) eller ett salt därav erhålles genom att man om- sätter föreningen betecknad med den allmänna formeln (II) resp. föreningen betecknad med den allmänna formeln (IV) eller ett salt därav med en acetal, såsom N,N-dietylform- amidodimetylacetal, N,N,dimetylformamidodietylacetal eller liknande och därefter med en amin betecknad med den allmänna formeln R2-NH2 (R2 har ovan angiven betydelse).The salts of the compounds represented by the general formulas (Ia), (Ib), (III), (IV) and (V) include the same salts as those of the compounds denoted by the general formula (I). (i) The compound represented by the general formula (III) or a salt thereof or the compound represented by the general formula (V) or a salt thereof is obtained by reacting the compound represented by the general formula (II) resp. the compound represented by the general formula (IV) or a salt thereof with an acetal such as N, N-diethylformamide dimethylacetal, N, N, dimethylformamidodiethyl acetal or the like and then with an amine represented by the general formula R2-NH2 (R2 has above specified meaning).
Det lösningsmedel, som skall användas i ovanstående reak- tioner, kan vara vilket som helst lösningsmedel inert till reaktionerna och inkluderar, utan att begränsas därtill, aromatiska kolväten såsom bensen, toluen, xylen och lik- nande; etrar såsom dioxan, tetrahydrofuran, anisol, di- etylenglykoldimetyleter och liknande; halogenerade kol- väten såsom metylenklorid, kloroform, dikloretan och lik- nande; aminer såsom N,N-dimetylformamid, N,N-dimetylacet- amid och liknande; sulfoxider såsom dimetylsulfoxid och liknande, etc. och dessa lösningsmedel kan användas enbart eller i blandning av två eller fler. Den använda acetal- mängden är företrädesvis l mol eller mer, särskilt cirka 1,0 - 1,3 mol, per mol förening betecknad med den allmänna formeln (II) eller föreningen betecknad med den allmänna formeln (IV) eller salt därav. Reaktionerna genomföres van- ligen vid o° till 1oo°c, företrädesvis via so° till ao°c och vanligen under 20 minuter till 50 timmar, företrädesvis 501 412 ll l till 3 timmar. Därjämte användes aminen i en mängd av l mol eller mer per mol förening betecknad med den allmänna formeln (II) eller föreningen betecknad med den allmänna formeln (IV) eller salt därav. Reaktionen genomföres vanli- gen vid 0° till l00OC, företrädesvis l0o till 60°C och van- ligen i 20 minuter till 30 timmar, företrädesvis l till 5 timmar.The solvent to be used in the above reactions may be any solvent inert to the reactions and includes, but is not limited to, aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol dimethyl ether and the like; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and the like; amines such as N, N-dimethylformamide, N, N-dimethylacetamide and the like; sulfoxides such as dimethyl sulfoxide and the like, etc. and these solvents may be used alone or in a mixture of two or more. The amount of acetal used is preferably 1 mole or more, especially about 1.0 - 1.3 moles, per mole of compound represented by the general formula (II) or the compound represented by the general formula (IV) or salt thereof. The reactions are usually carried out at 0 ° to 100 ° C, preferably via 50 ° to 100 ° C and usually for 20 minutes to 50 hours, preferably 501,412 μl to 3 hours. In addition, the amine is used in an amount of 1 mole or more per mole of compound represented by the general formula (II) or the compound represented by the general formula (IV) or salt thereof. The reaction is usually carried out at 0 ° to 100 ° C, preferably 10 ° to 60 ° C and usually for 20 minutes to 30 hours, preferably 1 to 5 hours.
Som en alternativ metod är det möjligt att omsätta förenin- gen betecknad med den allmänna formeln (II) eller föreningen betecknad med den allmänna formeln (IV) eller ett salt där- av med etylortoformiat eller metylortoformiat i närvaro av ättiksyraanhydrid, och därefter med en amin betecknad med den allmänna formeln R2-NH2 eller ett salt därav för att erhålla föreningen betecknad med den allmänna formeln (III) eller ett salt därav resp. föreningen betecknad med den all- männa formeln (V) eller ett salt därav. (ii) Föreningen betecknad med den allmänna formeln (Ia) eller ett salt därav eller föreningen betecknad med den allmänna formeln (Ib) eller ett salt därav erhålles genom att man låter föreningen betecknad med den allmänna formeln (III) eller ett salt därav resp. föreningen betecknad med . den allmänna formeln (V) eller ett salt därav genomgå ring- slutningsreaktion (företrädesvis under upphettning) i när- varo eller frånvaro av en bas.As an alternative method, it is possible to react the compound represented by the general formula (II) or the compound represented by the general formula (IV) or a salt thereof with ethyl orthoformate or methyl orthoformate in the presence of acetic anhydride, and then with an amine represented by the general formula R 2 -NH 2 or a salt thereof to obtain the compound represented by the general formula (III) or a salt thereof resp. the compound denoted by the general formula (V) or a salt thereof. (ii) The compound represented by the general formula (Ia) or a salt thereof or the compound represented by the general formula (Ib) or a salt thereof is obtained by allowing the compound represented by the general formula (III) or a salt thereof resp. the association designated by. the general formula (V) or a salt thereof undergoes cyclization reaction (preferably under heating) in the presence or absence of a base.
Lösningsmedlet, som skall användas i denna reaktion, kan vara vilket som helst lösningsmedel inert till reaktionen och inkluderar, men begränsas inte till, exempelvis amider såsom N,N-dimetylformamid, N,N-dimetylacetamid och lik- nande; etrar såsom dioxan, anisol, dietylenglykoldimetyl- eter och liknande; sulfoxider, såsom dimetylsulfoxid och liknande, etc. Dessa lösningsmedel kan användas enbart eller i blandning av två eller fler. Basen inkluderar exempelvis natriumvätekarbonat, kaliumkarbonat, kalium-tert-butoxid, natriumhydrid och liknande. Den basmängd, som skall användas, 501 412 12 är företrädesvis 0,5 till 5 mol per mol förening beteck- nad med den allmänna formeln (III) eller (V) eller ett salt därav. Reaktionen genomföres vanligen vid 200 till l60OC, företrädesvis vid 1000 till l50°C, och vanligen under 5 minu- ter till 30 timmar, företrädesvis 5 minuter till l timme. (iii) Föreningen betecknad med den allmänna formeln (IV) eller ett salt därav, föreningen betecknad med den allmänna formeln (V) eller ett salt därav eller föreningen betecknad med den allmänna formeln (Ib) eller ett salt därav erhålles resp. genom att man omsätter föreningen betecknad med den allmänna formeln (II), föreningen betecknad med den allmänna formeln (III) eller ett salt därav eller föreningen beteck- nad med den allmänna formeln (Ia) eller ett salt därav med en cyklisk amin betecknad med den allmänna formeln R3b-H eller ett salt därav (vari R3b har ovan angiven betydelse).The solvent to be used in this reaction may be any solvent inert to the reaction and includes, but is not limited to, for example, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and the like; ethers such as dioxane, anisole, diethylene glycol dimethyl ether and the like; sulfoxides, such as dimethyl sulfoxide and the like, etc. These solvents may be used alone or in a mixture of two or more. The base includes, for example, sodium bicarbonate, potassium carbonate, potassium tert-butoxide, sodium hydride and the like. The amount of base to be used is preferably 0.5 to 5 moles per mole of compound represented by the general formula (III) or (V) or a salt thereof. The reaction is usually carried out at 200 DEG to 160 DEG C., preferably at 1000 DEG to 150 DEG C., and usually for 5 minutes to 30 hours, preferably 5 minutes to 1 hour. (iii) The compound represented by the general formula (IV) or a salt thereof, the compound represented by the general formula (V) or a salt thereof or the compound represented by the general formula (Ib) or a salt thereof are obtained resp. by reacting the compound represented by the general formula (II), the compound represented by the general formula (III) or a salt thereof or the compound represented by the general formula (Ia) or a salt thereof having a cyclic amine designated by the the general formula R3b-H or a salt thereof (wherein R3b has the meaning given above).
Lösningsmedlet, som skall användas i reaktionen, kan utgöras av vilket som helst lösningsmedel inert till reaktionen och inkluderar, men begränsas inte till, aromatiska kolväten, såsom bensen, toluen, xylen och liknande; etrar, såsom di- oxan,_tetrahydrofuran, anisol, dietylenglykoldietyleter och liknande; halogenerade kolväten, såsom metylenklorid, kloro- form, dikloretan och liknande; amider, såsom N,N-dimetyl- formamid, N,N-dimetylacetamid och liknande; sulfoxider, så- som dimetylsulfoxid och liknande; alkoholer, såsom metanol, etanol och liknande; nitriler, såsom acetonitril och lik- nande, etc. och dessa lösningsmedel kan användas enbart eller i blandning av tvâ eller fler. Mängden cyklisk amin eller ett salt därav, som skall användas, är företrädesvis ett överskott, mer föredraget 2 till 5 mol per mol förening betecknad med den allmänna formeln (II), föreningen beteck- nad med den allmänna formeln (III) eller ett salt därav eller föreningen betecknad med den allmänna formeln Ia) eller ett salt därav. Om den använda mängden cyklisk amin är cirka l till l,3 mol är det tillräckligt att ett syrabindande medel användes i en mängd av l mol per mol förening betecknad 501 412 13 med den allmänna formeln (II), föreningen betecknad med den allmänna formeln (III) eller ett salt därav eller föreningen betecknad med den allmänna formeln (Ia) eller ett salt därav.The solvent to be used in the reaction may be any solvent inert to the reaction and includes, but is not limited to, aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and the like; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and the like; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and the like; sulfoxides, such as dimethyl sulfoxide and the like; alcohols such as methanol, ethanol and the like; nitriles, such as acetonitrile and the like, etc. and these solvents may be used alone or in a mixture of two or more. The amount of cyclic amine or a salt thereof to be used is preferably an excess, more preferably 2 to 5 moles per mole of compound represented by the general formula (II), the compound represented by the general formula (III) or a salt thereof or the compound represented by the general formula Ia) or a salt thereof. If the amount of cyclic amine used is about 1 to 1.3 moles, it is sufficient that an acid-binding agent is used in an amount of 1 mole per mole of compound designated 501 412 13 of the general formula (II), the compound designated of the general formula ( III) or a salt thereof or the compound represented by the general formula (Ia) or a salt thereof.
Det syrabindande medlet inkluderar organiska eller oorga- niska baser, såsom trietylamin, 1,8-diazabicyklo/5,4,0/undek- 7-en (DBU), kalium-tert-butoxid, kaliumkarbonat, natrium- karbonat, natriumhydrid och liknande.The acid-binding agent includes organic or inorganic bases such as triethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), potassium tert-butoxide, potassium carbonate, sodium carbonate, sodium hydride and the like. .
Saltet av R3b-H inkluderar samma som salterna vid den ba- siska gruppen i föreningen betecknad med den allmänna for- meln (I).The salt of R3b-H includes the same as the salts of the basic group of the compound represented by the general formula (I).
Reaktionen genomföres vanligen vid 00 till l50°C, före- trädeevis via so° till 1oo°c, och vanligen i 5 minuter till 30 timmar, företrädesvis 30 minuter till 3 timmar.The reaction is usually carried out at 0 DEG to 150 DEG C., preferably via 50 DEG to 100 DEG C., and usually for 5 minutes to 30 hours, preferably 30 minutes to 3 hours.
Föreningen betecknad med den allmänna formeln (Ia), (Ib),(111) eller (V), vari Rl eller Rla betecknar en karboxylskyddande grupp, eller ett salt därav kan, om så önskas, omvandlas till mot- svarande fria karboxylsyra genom att man hydrolyserar den- samma i närvaro av en sedvanlig syra eller alkali, vilken användes för hydrolys, vanligen vid 00 till IOOOC, före- trädesvis vid 200 till l00°C i 5 minuter till 50 timmar, företrädesvis 5 minuter till 4 timmar. Vidare kan föreningen betecknad med den allmänna formeln (Ia), (Ib), (III) eller (V) eller ett salt därav, om så önskas, omvandlas till ett salt eller en ester av motsvarande förening genom att man utsätter densamma för saltbildande reaktion eller förestring känd per se. Om föreningen betecknad med den allmänna for- meln (Ia), (III), (IV) eller (V) eller ett salt därav upp- visar en aktiv grupp (t.ex. hydroxylgrupp, aminogrupp eller liknande) vid andra lägen än reaktionsställena är det möj- ligt att dessförinnan skydda den aktiva gruppen enligt kon- ventionell metod och avlägsna den skyddande gruppen efter avslutad reaktion.The compound represented by the general formula (Ia), (Ib), (111) or (V), wherein R 1 or R 1a represents a carboxyl protecting group, or a salt thereof can, if desired, be converted into the corresponding free carboxylic acid by it is hydrolyzed in the presence of a customary acid or alkali, which is used for hydrolysis, usually at 00 to 100 ° C, preferably at 200 to 100 ° C for 5 minutes to 50 hours, preferably 5 minutes to 4 hours. Furthermore, the compound represented by the general formula (Ia), (Ib), (III) or (V) or a salt thereof, if desired, may be converted into a salt or an ester of the corresponding compound by subjecting it to a salt-forming reaction. or esterification known per se. If the compound represented by the general formula (Ia), (III), (IV) or (V) or a salt thereof shows an active group (eg hydroxyl group, amino group or the like) at positions other than the reaction sites it is possible to protect the active group beforehand according to a conventional method and remove the protecting group after the reaction has ended.
Den så erhållna föreningen kan genomgå sedvanliga isolerings- 501 412 14 och reningssteg, såsom kolonnkromatografi, omkristallisa- tion, extraktion och liknande.The compound thus obtained can undergo conventional isolation and purification steps, such as column chromatography, recrystallization, extraction and the like.
Föreningen betecknad med den allmänna formeln (I) eller ett salt därav, vari R3 betecknar en halogenatom (motsvarande föreningen betecknad med den allmänna formeln (Ia)), är också användbar som mellanprodukt för att erhålla en före- ning, vari R3 betecknar en substituerad eller osubstituerad cyklisk aminogrupp (motsvarande föreningen betecknad med den allmänna formeln (Ib)).The compound represented by the general formula (I) or a salt thereof, wherein R 3 represents a halogen atom (corresponding to the compound represented by the general formula (Ia)), is also useful as an intermediate to obtain a compound, wherein R 3 represents a substituted or unsubstituted cyclic amino group (corresponding to the compound represented by the general formula (Ib)).
När föreningen enligt föreliggande uppfinning användes som läkemedel eller medicin kombineras den lämpligt med bärare använda i konventionella farmacevtiska beredningar och be- redes till tabletter, kapslar, pulver, siraper, granuler, suppositorier, salvor, injektioner och liknande på sed- vanligt sätt. Administrationssätt, doser och antalet ad- ministrationer kan lämpligt varieras beroende på patientens symtom och den administreras vanligen oæalteller parente- ralt (t.ex. som injektion, dropp, administration till rektum) till en vuxen i en mängd av 0,1 till 100 mg/kg/dag i en till flera portioner.When the compound of the present invention is used as a medicine or medicine, it is suitably combined with carriers used in conventional pharmaceutical preparations and prepared into tablets, capsules, powders, syrups, granules, suppositories, ointments, injections and the like in the usual manner. Methods of administration, doses and number of administrations may be suitably varied depending upon the patient's symptoms and it is usually administered orally or parenterally (eg as injection, drip, administration to the rectum) to an adult in an amount of 0.1 to 100 mg / kg / day in one to several portions.
Föreliggande uppfinning förklaras nedan med hänvisning till referensexempel, exempel och beredningsexempel.The present invention is explained below with reference to Reference Examples, Examples and Preparation Examples.
Symboler använda i referensexempel och exempel har följande betydelser: Me: metylgrupp, Et: etylgrupp, n-Pr: n-propylgrupp, i-Pr: isopropylgrupp, Ac: acetylgrupp, ¿9~V/ : allylgrupp, /^\,, : etylengrupp.Symbols used in reference examples and examples have the following meanings: Me: methyl group, Et: ethyl group, n-Pr: n-propyl group, i-Pr: isopropyl group, Ac: acetyl group, ¿9 ~ V /: allyl group, / ethylene group.
Referensexempel l I 210 ml kloroform löstes 21 g 2,6-diklor-5-fluornikotinsyra 501 412 15 och 23,8 g tionylklorid och 0,1 g N,N-dimetylformamid sattes till den resulterande lösningen. Resulterande blandning omsattes vid 70OC i 2 timmar. Lösningsmedlet och överskott på tionylklorid avlägsnades med destillation under reducerat tryck och den så erhållna återstoden löstes i 21 ml tetra- hydrofuran. I ll0 ml tetrahydrofuran löstes 25,1 g dietyl- etoximagnesiummalonat och lösningen kyldes till -400 till -30oC. In i denna lösning droppades en tetrahydrofuranlös- ning av 2,6-diklor-5-fluornikotinoylklorid, som tidigare beretts vid samma temperatur över 30 minuter. Denna blandade lösning omrördes vid samma temperatur i 1 timme, varefter lösningens temperatur gradvis ökades till rumstemperatur.Reference Example 1 In 210 ml of chloroform, 21 g of 2,6-dichloro-5-fluoronicotinic acid were dissolved and 23.8 g of thionyl chloride and 0.1 g of N, N-dimethylformamide were added to the resulting solution. The resulting mixture was reacted at 70 DEG C. for 2 hours. The solvent and excess thionyl chloride were removed by distillation under reduced pressure, and the residue thus obtained was dissolved in 21 ml of tetrahydrofuran. In 110 ml of tetrahydrofuran was dissolved 25.1 g of diethyl ethoxymagnesium malonate and the solution was cooled to -400 to -30 ° C. A tetrahydrofuran solution of 2,6-dichloro-5-fluoronicotinoyl chloride, previously prepared at the same temperature over 30 minutes, was dropped into this solution. This mixed solution was stirred at the same temperature for 1 hour, after which the temperature of the solution was gradually increased to room temperature.
Lösningsmedlet avlägsnades med destillation under reducerat tryck och till den så erhållna återstoden sattes 200 ml kloroform och 100 ml vatten. pH justerades till l med 6 N saltsyra. Det organiska skiktet frânskildes, tvättades i följd med 50 ml vatten, 50 ml 5%-ig vattenhaltig natrium- vätekarbonatlösning och 50 ml av en mättad vattenhaltig natriumkloridlösning samt torkades över vattenfritt magne- siumsulfat. Lösningsmedlet avlägsnades med destillation under reducerat tryck och till den erhållna oljiga produkten sattes 50 ml vatten och 0,15 g p-toluensulfonsyra, varefter den resulterande blandningen fick reagera under kraftig om- rörning vid l00°C i 2 timmar. Reaktionsblandningen extra- herades med 100 ml kloroform. Det organiska skiktet tvät- tades med 50 ml mättad vattenhaltig natriumkloridlösning och torkades över vattenfritt magnesiumsulfat, varefter lös- ningsmedlet avlägsnades med destillation under reducerat tryck. Erhâllen återstod renades med kolonnkromatografi (WAKO SILICA GEL C-200, elueringsmedelz toluen) för att er- hålla 23,5 g etyl-(2,6-diklor-5-fluornikotinoyl)-acetat med smältpunkt 64 - 6s°c.The solvent was removed by distillation under reduced pressure, and to the residue thus obtained were added 200 ml of chloroform and 100 ml of water. The pH was adjusted to 1 with 6 N hydrochloric acid. The organic layer was separated, washed successively with 50 ml of water, 50 ml of 5% aqueous sodium bicarbonate solution and 50 ml of a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the resulting oily product was added 50 ml of water and 0.15 g of p-toluenesulfonic acid, after which the resulting mixture was allowed to react with vigorous stirring at 100 ° C for 2 hours. The reaction mixture was extracted with 100 ml of chloroform. The organic layer was washed with 50 ml of saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure. The obtained residue was purified by column chromatography (WAKO SILICA GEL C-200, eluent toluene) to obtain 23.5 g of ethyl (2,6-dichloro-5-fluoronicotinoyl) acetate, m.p. 64-6 ° C.
IR (xsr) cm'1= øczo 1650. 1630, 1620 NMR (CDC13) rf-värden: 1,25 (l,29H, t, J=7Hz), 1,33 (1,7lH, t, J=7Hz), 4,07 (l,l4H, S), 4,28 (2H, q, J=7Hz), 5,82 ¶0,43H, s), 501 412 16 7,80 (lH, d, J=7Hz), 12,62 (0,43H, S).IR (xsr) cm -1 = δ 1650. 1630, 1620 NMR (CDCl 3) rf values: 1.25 (1.29H, t, J = 7Hz), 1.33 (1.7lH, t, J = 7Hz ), 4.07 (1,14H, S), 4.28 (2H, q, J = 7Hz), 5.82 ¶0.43H, s), 501 412 16 7.80 (1H, d, J = 7Hz), 12.62 (0.43H, S).
Referensexempel 2 I 40 ml bensen löstes 8,8 g etyl-(2,6-diklor-5-fluornikoti- noyl)acetat och 4,5 g N,N-dimetylformamidodimetylacetal till- sattes, varefter den resulterande blandningen fick reagera vid 70°C i 1,5 timmar. Därefter sattes 4,1 g 2,4-difluor- anilin till reakticnsblandningen och den resulterande bland- ningen fick reagera vid rumstemperatur i 4 timmar. Lösnings- medlet avlägsnades med destillation under reducerat tryck.Reference Example 2 In 40 ml of benzene was dissolved 8.8 g of ethyl (2,6-dichloro-5-fluoronicotinoyl) acetate and 4.5 g of N, N-dimethylformamidodimethylacetal were added, after which the resulting mixture was allowed to react at 70 ° C for 1.5 hours. Then 4.1 g of 2,4-difluoroaniline were added to the reaction mixture and the resulting mixture was allowed to react at room temperature for 4 hours. The solvent was removed by distillation under reduced pressure.
Den erhållna återstoden renades med kolonnkromatografi (WACO SILICA GEL C-200, elueringsmedel: kloroform) för att erhålla 9,0 g etyl-2-(2,6-diklør-5-fluornikotinoyl)-3-(2,4- difluorfenylamino)-akrylat med smältpunkt 138 - l39°C.The obtained residue was purified by column chromatography (WACO SILICA GEL C-200, eluent: chloroform) to obtain 9.0 g of ethyl 2- (2,6-dichloro-5-fluoronicotinoyl) -3- (2,4-difluorophenylamino) acrylate, m.p. 138 DEG-139 DEG.
IR (xßr) cm'l= 0C=O 1690 NMR (CDCI3) 3 -värden: 1,08 (3H, t, J=7Hz), 4,10 (2H, q, J=7Hz), 6,77-7,40 (4H, m), 8,50 (ln, d, J=13Hz). 12,70 (lH, d, J=l3Hz) På liknande sätt erhölls föreningarna visade i tabell 2. 501 412 17 Tabell 2 O F COOEt CH N Cl cl *H R2 Förening Fysikaliska egenskaper R2 smält- IR(KBr) cm'1= punkt (°C) vc=o Cí] 87-es 1690 © 110-114 1710, 1680 F 92-93 1710, 1680 F F 135-137 1720(sh), 1690.- [::L\ 78-80 1690 F F F C) Oljig 1705, 1s8o(sn) F F F 154-155 1720(sh), 1685 KY ' _ F 100-101 1700(Sh), 1685 F ä) I 123-125 1710, 1680 Cl 501 412 '19 Tabell 2 (fOrtS.) [:] 145-146 1705, 1680 Br fšj 147-149 1685 e 'k oljig 1695 OMe [å]-OMG 119-121 1700 'k Oljig 1700 cm (:] 183-186 1685, 1670 NHAC [:] 136-138 1705, 1680 CF3 Me ' [:]/ 114-116 1680 F one 137.5-139 1725(sh), 1680 F KÄJIF 92-95 1705 Me OMe 125-126 17oo(sh), 1660 Me [::I'Me 91-92 1705, 1690 Anm: Den rena metoden (neat method) användes i stället för KBr-metoden. 19 Referensexempel 3 501 412 (1) I 55 ml kloroform löstes 5,5 g etyl-(2,6-diklor-5- fluornikotinoyl)acetat, 2,37 g N-metylpiperazin och 2,37 g trietylamin och den resulterande lösningen fick reagera vid 600 till 6500 i 2 timmar. Reaktionsblandningen tvättades med 30 ml vatten och torkades över vattenfritt magnesiumsulfat.IR (xßr) cm -1 = OC = O 1690 NMR (CDCl 3) δ values: 1.08 (3H, t, J = 7Hz), 4.10 (2H, q, J = 7Hz), 6.77- 7.40 (4H, m), 8.50 (1n, d, J = 13Hz). 12.70 (1H, d, J = 13Hz) In a similar manner the compounds shown in Table 2 were obtained. 501 412 17 Table 2 OF COOEt CH N Cl cl * H R2 Compound Physical properties R2 melt-IR (KBr) cm -1 = point (° C) vc = o Cí] 87-es 1690 © 110-114 1710, 1680 F 92-93 1710, 1680 FF 135-137 1720 (sh), 1690.- [:: L \ 78-80 1690 FFFC ) Oily 1705, 1s8o (sn) FFF 154-155 1720 (sh), 1685 KY '_ F 100-101 1700 (Sh), 1685 F ä) I 123-125 1710, 1680 Cl 501 412 '19 Table 2 (fOrtS .) [:] 145-146 1705, 1680 Br fšj 147-149 1685 e 'k oljig 1695 OMe [å] -OMG 119-121 1700' k Oljig 1700 cm (:] 183-186 1685, 1670 NHAC [:] 136-138 1705, 1680 CF3 Me '[:] / 114-116 1680 F one 137.5-139 1725 (sh), 1680 F KÄJIF 92-95 1705 Me OMe 125-126 17oo (sh), 1660 Me [:: I 91-92 1705, 1690 Note: The neat method was used instead of the KBr method 19 Reference Example 3 501 412 (1) In 55 ml of chloroform was dissolved 5.5 g of ethyl (2,6-dichloro). -5-fluoronicotinoyl) acetate, 2.37 g of N-methylpiperazine and 2.37 g of triethylamine and the resulting solution was r eagera at 600 to 6500 for 2 hours. The reaction mixture was washed with 30 ml of water and dried over anhydrous magnesium sulfate.
Lösningsmedlet avlägsnades med destillation under reducerat tryck och den erhållna återstoden renades med kolonnkroma- tografi (WAKO SILICA GEL C-200, elueringsmedel: kloroform) för att erhålla 5,4 g oljigt etyl-/2-klor-5-fluor-6-(4- metyl-l-piperazinyl)nikotinoyl/acetat. l IR (rent) cm' = 1750, 1695 Vc=o NMR (cDc13) 6 -värden: 1,25 (3H, t, J=7Hz), 2,32 (3H, s), 2,12-2,70 (4H, m), 3,55-3,96 (4H, m), 4,03 (zu, s), 4,20 (2H, q, J=7Hz). 7,78 (lH, d, J=l3Hz).The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography (WAKO SILICA GEL C-200, eluent: chloroform) to obtain 5.4 g of oily ethyl / 2-chloro-5-fluoro-6- ( 4-methyl-1-piperazinyl) nicotinoyl / acetate. 1 IR (pure) cm -1 = 1750, 1695 Vc = 0 NMR (cDc13) 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 (zu, s), 4.20 (2H, q, J = 7Hz). 7.78 (1H, d, J = 13 Hz).
På liknande sätt erhölls föreningen visad i tabell 3. 501 412 70 Tabell 3 O COOEt F N l R3 Förening Fysikaliska egenskaper R3 smält- IR (xßr) cm'1= punkt( C) vC=o T ACN N- 67-71 1730 \_J (2) I 22,5 ml bensen löstes 4,5 g etyl-/2-k1or-5-fluor-6- (4-metyl-l-piperazinyl)nikotinoyl/acetat och 1,87 g N,N - dimetylformamido-dimetylacetal sattes till den resulterande lösningen, varefter den resulterande blandningen fick rea- gera vid 70°C i 2 timmar. Till reaktionsblandningen sattes 1,8 g 4-metoxi-2-metylanilin och den resulterande bland- ningen fick reagera vid rumstemperatur i 4 timmar. Därefter avlägsnades lösningsmedlet med destillation under reducerat tryck och den sålunda erhållna återstoden renades med kolonnkromatografi /WAKO SILICA GEL C-200, elueringsmedel: kloroformzetanol = l00:l (räknat på volymen)/. Den erhållna kristallina substansen tvättades med 10 ml dietyleter för att ge 5,0 g etyl-2-/2-klor-5-fluor-6-(4-metyl-l-piperazi- nyl)nikotinoyl/-3-(4-metoxi-2-metylfenylamino)akrylat med smäitpunkt 141 - 142°c. 501 412 21 IR (Ksr) cm_l= vC=O 1710 (sh), 1695 NMR (CDC13) 6 -värden; 1,08 (3H, t, J=7Hz), 2,32 (3H, s), 2,40 (3H, s), 2,23-2,68 (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 (lH, d, J=l3H2), 12,82 (lH, d, J=l3Hz).In a similar manner the compound shown in Table 3 was obtained. 501 412 70 Table 3 COOEt FN 1 R3 Compound Physical properties R3 melt- IR (xßr) cm -1 = point (C) vC = o T ACN N- 67-71 1730 (2) In 22.5 ml of benzene was dissolved 4.5 g of ethyl β-chloro-5-fluoro-6- (4-methyl-1-piperazinyl) nicotinoyl / acetate and 1.87 g of N, N-dimethylformamido -dimethylacetal was added to the resulting solution, after which the resulting mixture was allowed to react at 70 ° C for 2 hours. To the reaction mixture was added 1.8 g of 4-methoxy-2-methylaniline, and the resulting mixture was allowed to react at room temperature for 4 hours. Then the solvent was removed by distillation under reduced pressure and the residue thus obtained was purified by column chromatography / WAKO SILICA GEL C-200, eluent: chloroform-ethanol = 100: 1 (by volume) /. The resulting crystalline substance 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- methoxy-2-methylphenylamino) acrylate, m.p. 141 DEG-142 DEG. 501 412 IR (Ksr) cm -1 = vC = O 1710 (sh), 1695 NMR (CDCl 3) δ values; 1.08 (3H, t, J = 7Hz), 2.32 (3H, s), 2.40 (3H, s), 2.23-2.68 (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 = 13H2), 12.82 (1H, d, J = 13Hz).
På liknande sätt erhölls föreningarna visade i tabell 4. 501 412 22 Tabell 4 O F r ool-:c H RB N 1 | bIIH R2 Förening Fysikaliska egenskaper R2 R3 Smältpunkt IRÉÉ) (°C) cm : vczo _ *2 [i:] Meš §L_ oljig 1720 (sh), 1715 *2 F.In a similar manner the compounds shown in Table 4 were obtained. 501 412 22 Table 4 O F r ool-: c H RB N 1 | bIIH R2 Compound Physical properties R2 R3 Melting point IRÉÉ) (° C) cm: vczo _ * 2 [i:] Meš §L_ oily 1720 (sh), 1715 * 2 F.
II 1700 F *2 ßí:]\ " Oljig 1695 OMe | *I [::fi 1685. " l 1-l | 6 64 leva NHAC *2 I 1720 (Sh), F Qljig 1715 OMe 4'12 23 Tabell 4 (forts.) *1 MeN N- 132-136 1705 (sh)' e L/ less ome /Me *2 / \ _.II 1700 F * 2 ßí:] \ "Oljig 1695 OMe | * I [:: fi 1685." l 1-l | 6 64 leva NHAC * 2 I 1720 (Sh), F Qljig 1715 OMe 4'12 23 Table 4 (cont.) * 1 MeN N- 132-136 1705 (sh) 'e L / less ome / Me * 2 / \ _.
ACN N- 01319 1720 (sh)' \__/ 17oo one Anm: *l: KBr *2: rent 501 412 24 Exempel l I 90 ml N,N-dimetylformamid löstes 9,0 g etyl-2-(2,6-di- klor-5-fluornikotinoyl)-3-(2,4-difluorfenylamino)akrylat, 3,6 g natriumvätekarbonat sattes till den resulterande lös- ningen, varefter den resulterande blandningen fick reagera vid l20°C i 20 minuter. Därefter avlägsnades lösningsmedlet med destillation under reducerat tryck och den erhållna återstoden löstes i 50 ml kloroform. Den resulterande lös- ningen tvättades i följd med 30 ml vatten och 30 ml mättad vattenhaltig natriumkloridlösning för att därefter torkas över vattenfritt magnesiumsulfat. Lösningsmedlet avlägsna- des med destillation under reducerat tryck och den erhållna kristallina substansen tvättades med 30 ml dietyleter för att ge 7,0 g etyl-7-klor-6-fluor-l-(2,4-difluorfenyl)-l,4- dihydro-4-oxo-l,8-naftyridin-3-karboxylat med smältpunkt 220 - 222°c.ACN N-01319 1720 (sh) '\ __ / 17oo one Note: * 1: KBr * 2: pure 501 412 24 Example 1 In 90 ml of N, N-dimethylformamide was dissolved 9.0 g of ethyl 2- (2.6 -dichloro-5-fluoronicotinoyl) -3- (2,4-difluorophenylamino) acrylate, 3.6 g of sodium bicarbonate were added to the resulting solution, after which the resulting mixture was allowed to react at 120 ° C for 20 minutes. Then, the solvent was removed by distillation under reduced pressure, and the obtained residue was dissolved in 50 ml of chloroform. The resulting solution was washed successively with 30 ml of water and 30 ml of saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting crystalline substance 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-naphthyridine-3-carboxylate, m.p. 220 DEG-222 DEG.
IR (Kßr) cm"l QC=O 1730, 1s9o NMR (CDCl3) Ö -värden: 1,36 (3H, t, J=7Hz), 4,30 (2H, q, J=7Hz), 6,80-7,60 (3H, m), 8,27 (lH, d, J=7Hz), 8,42 (lH, s).IR (Kßr) cm -1 QC = O 1730, 1009 NMR (CDCl 3) δ values: 1.36 (3H, t, J = 7Hz), 4.30 (2H, q, J = 7Hz), 6.80 -7.60 (3H, m), 8.27 (1H, d, J = 7Hz), 8.42 (1H, s).
På liknande sätt erhölls föreningarna visade i tabell 5. 412 25 Tabell 5 O F I COOEt cl *f R2 Förening Fysikaliska egenskaper R2 Smältpunkt IRíïBr¿ (9C) Cm : C=O 1730, .222-224 1685 1730, F 231-232 1705 [;ï]\ 239-241 1635 F 1735, 205-208 1685 @ 244-246 1720' F 1680 F 501 412 26 Tabell 5 (forts.) 1 F 173o, F F F 1735 (Sh)| 210-214 1705 1730, 1680 207-208 1730, l C) F C B ß? M f? O 1730, r 1735, 216'2l8 1695 e 1735, 196'l98 less Me 27 Tabell 5 (forts.) 5()1 OMG 1730, l56'l60 1690 [::J 1730. 231-236 1685 CN [::] 270-273 l73°' 1690 NHAc 1730, 199-201 1680 CF3 Me 1735, 199-202 1685 F me 1730, 208-211 1695 F ' F 1740, 142-144 1695 OMe 4-12 501 412 28 Tabell 5 (forts.) OMe l730, 163-165 1695 Me e 1735, OMG Exempel 2 (1) I 35 ml kloroform löstes 3,5 g etyl-7-klor-6-fluor-l- (2¿4-difluorfenyl)-l,4-dihydro-4-oxo-1,8-naftyridin-3- karboxylat och 1,5 g N-acetylpiperazin och 1,6 g trietyl- amin sattes därefter till den resulterande lösningen, var- efter den resulterande blandningen fick reagera vid 60°C i 1 timme. Därefter avlägsnades lösningsmedlet med destilla- tion under reducerat tryck och den erhållna återstoden rena- des med kolonnkromatografi /WAKO SILICA GEL C-200, eluerings- medel: kloroformzetanol = 30:l (räknat på volymenfl för att ge 3,5 g etyl-7-(4-acetyl-l-piperazinyl)-6-fluor-l-(2,4- difluorfenyl)-1,4-dihydro-4-oxo-1,8-naftyridin-3-karboxylat med en smältpunkt av 207 - 209OC.In a similar manner the compounds shown in Table 5 were obtained. 412 Table 5 OFI COOEt cl * f R2 Compound Physical properties R2 Melting point IR1BR¿ (9C) Cm: C = O 1730, .222-224 1685 1730, F 231-232 1705 [ ; ï] \ 239-241 1635 F 1735, 205-208 1685 @ 244-246 1720 'F 1680 F 501 412 26 Table 5 (cont.) 1 F 173o, FFF 1735 (Sh) | 210-214 1705 1730, 1680 207-208 1730, l C) F C B ß? M f? O 1730, r 1735, 216'2l8 1695 e 1735, 196'l98 less Me 27 Table 5 (cont.) 5 () 1 OMG 1730, l56'l60 1690 [:: J 1730. 231-236 1685 CN [:: ] 270-273 l73 ° '1690 NHAc 1730, 199-201 1680 CF3 Me 1735, 199-202 1685 F me 1730, 208-211 1695 F' F 1740, 142-144 1695 OMe 4-12 501 412 28 Table 5 ( cont.) OMe 1730, 163-165 1695 Me e 1735, OMG Example 2 (1) In 35 ml of chloroform was 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 resulting solution, after which the resulting mixture was allowed to react at 60 ° C for 1 hour. Then the solvent was removed by distillation under reduced pressure and the obtained residue was purified by column chromatography / WAKO SILICA GEL C-200, eluent: chloroform-ethanol = 30: 1 (calculated on the volume fl 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, m.p. 209OC.
IR (xsr) cm'l Jczo 1730, 1695 NMR (CDCl3) 5 -värden: 1,38 (3n, t, J=7Hz>, 2,05 (3H, S), 3,53 (an, bs), 4,30 (za, q, J=7Hz). 6,80-7,75 (3n, m), 8,00 (ln, d, J=13Hz), 8,30 (ln, s). 501 412 29 På liknande sätt erhölls föreningarna visade i tabell 6.IR (xsr) cm -1 Jczo 1730, 1695 NMR (CDCl 3) δ values: 1.38 (3n, t, J = 7Hz>, 2.05 (3H, S), 3.53 (an, bs), 4.30 (za, q, J = 7Hz), 6.80-7.75 (3n, m), 8.00 (ln, d, J = 13Hz), 8.30 (ln, s), 501 412 In a similar manner, the compounds shown in Table 6 were obtained.
Tabell 6 O I I R3/ N R2 Föreninq Fysikaliska egenskaper 2 3 smältpunkt INKBI) R R -l (°C) cm : vC=o AC |_/-\ 1730, MeN\ N- 155-156 1690 M šfi 1730, " HN N- - 144 146 1690 Me §"“\ 1 1725, " HN - - N 98 202 1690 Me no~n N- 220-222 1730' “-1 1695 F AcN N- 211-213 1735 F .1 501 412 30 Tabell 6 (forts.) F 1725, " 206 1690 __ 1730 F F 1725, u AC - F TC 1725, Me N- 186°187 1690 (sn)_ F M ?'“\ 1 20, H N- 155-157 7 \__/ 1685 F Ma)__\ 1730, u MGN N” f-(Me 1730, I! MeU- ,_¶ 1730 (sh). .. ¿7\,N N- 166-168 . , 1690 31 Tabell 6 (forts.) 501 412 íme 1730, ~ Etozcq N- 202-204 1690 1725 (sh) ' * 30-231 I AcN¥_JN- 2 1695 1720 (sh), 1680, " 193-194 1675 1725, [:?J new y- 207 1695 cl 1730, Acfi “- 254 1690 _ , N c1 1730, Kà:] Meg N- 208 1690 Br 1730, " Acá¥_)g- 246-247 1690 1730, s MeN' h- 167-169 1695 Me 501 412 32 Tabell 6 (forts.) 1730, 1730, OMG 1695 1735, “ Etátïïfl- l80-181 ,_ 1730 I n-Prm N- 171-172.5 1685 OMe /-\ 1730, H i_prN¥_jN- 208.5-210 1690 /-\ 1730, “ HO/\/N N- 200-202 1690 /-\ 1725, n , ¿ø»/N\_JN- 162-l63 1690 501 412 33 Tabell 6 (forts.) one /-\ 1725, MeN N- 136-138 1685 /-\ l730_ [:;] Acq¥_Jy- 270-272 1690' CN 1730, " 245-249 1695 NHÅC 1730, Acá:::N- 249-252 1695 *CF3 Me " 263-264 1730 F OMQ f-\ 1730 f Meq¥_jN- 166-169 1685 F " ACN - 222.5-223.5 1730' V ,\._/ 1690 _ F _ /-\ 1730, [:ç]// Me§ N- 165-168 1685 one 1730, " Acš N- 215-219 1695 501 412 34 Tabell 6 (forts.) one f-1 1725 I Me Me N 2 1730, N' 156 1590 F Me | 1725, ,, A _ _ F M N 82 1730, ' 165 1690 F MeN I 1730, F ACHN 1725 \ï::y- 241-244 1700 F P [:;] \ y- 153-155 1735 OMe HO 1730, 4 _ 185-187 1690 501 412 b.) LH (2) I 25 ml 6 N saltsyra löstes 2,5 g etyl-7-(4-acetyl-l- piperazinyl)-u-fluor-l-(2,;adifluorfenyl)-l,4-dihydro-4- oxo-l,8-naftyridin-3-karboxylat och den resulterande lös- ningen upphettades under återflöde i 2 timmar. Därefter kyldes reaktionsblandningen till rumstemperatur och dess pH justerades till 12 med l N vattenhaltig natriumhydroxid- lösning och därefter till 6,5 med ättiksyra. Så fällda kristaller uppsamlades genom filtrering, tvättades med 30 ml vatten för att sedan torkas i syfte att ge 1,8 g 6-fluor- l-(2,4-difluorfenyl)-l,4-dihydro-4-oxo-7-(l-piperazinyl)- l,8-naftyridin-3-karboxylsyra.Table 6 OII R3 / N R2 Compound Physical properties 2 3 melting point INKBI) RR -1 (° C) cm: vC = o AC | _ / - \ 1730, MeN \ N- 155-156 1690 M š fi 1730, "HN N - - 144 146 1690 Me § "“ \ 1 1725, "HN - - N 98 202 1690 Me no ~ n N- 220-222 1730 '“ -1 1695 F AcN N- 211-213 1735 F .1 501 412 30 Table 6 (cont.) F 1725, "206 1690 __ 1730 FF 1725, u AC - F TC 1725, Me N- 186 ° 187 1690 (sn) _ FM? '“ \ 1 20, H N- 155-157 7 \ __ / 1685 F Ma) __ \ 1730, u MGN N ”f- (Me 1730, I! MeU-, _¶ 1730 (sh). .. ¿7 \, N N- 166-168., 1690 31 Table 6 (cont.) 501 412 íme 1730, ~ Etozcq N- 202-204 1690 1725 (sh) '* 30-231 I AcN ¥ _JN- 2 1695 1720 (sh), 1680, "193-194 1675 1725, [: ? J new y- 207 1695 cl 1730, Ac fi “- 254 1690 _, N c1 1730, Kà:] Meg N- 208 1690 Br 1730," Acá ¥ _) g- 246-247 1690 1730, s MeN 'h- 167-169 1695 Me 501 412 32 Table 6 (cont.) 1730, 1730, OMG 1695 1735, “Etátïï fl- l80-181, _ 1730 I n-Prm N- 171-172.5 1685 OMe / - \ 1730, H i_prN ¥ _jN- 208.5-210 1690 / - \ 1730, “HO / \ / N N- 200-202 1690 / - \ 1725, n, ¿ø» / N \ _JN- 162-l63 1690 501 412 33 Table 6 (cont.) One / - \ 1725, MeN N- 136-138 1685 / - \ l730_ [:;] Acq ¥ _Jy- 270-272 1690 'CN 1730, " 245-249 1695 NHÅC 1730, Acá ::: N- 249-252 1695 * CF3 Me "263-264 1730 F OMQ f- \ 1730 f Meq ¥ _jN- 166-169 1685 F" ACN - 222.5-223.5 1730 'V , \ ._ / 1690 _ F _ / - \ 1730, [: ç] // Me§ N- 165-168 1685 one 1730, "Acš N- 215-219 1695 501 412 34 Table 6 (cont.) One f -1 1725 I Me Me N 2 1730, N '156 1590 F Me | 1725, ,, A _ _ FMN 82 1730, '165 1690 F MeN I 1730, F ACHN 1725 \ ï :: y- 241-244 1700 FP [:;] \ y- 153-155 1735 OMe HO 1730, 4 _ 185-187 1690 501 412 b.) LH (2) In 25 ml of 6 N hydrochloric acid was dissolved 2.5 g of ethyl 7- (4-acetyl-1-piperazinyl) -u-fluoro-1- (2,; adifluorophenyl) 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate and the resulting solution was heated under reflux for 2 hours. Then the reaction mixture was cooled to room temperature and its pH was adjusted to 12 with 1 N aqueous sodium hydroxide solution and then to 6.5 with acetic acid. Thus precipitated crystals were collected by filtration, washed with 30 ml of water and then 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-dl) 8 -värden: 3,30-4,50 (BH, m), 7,00-7,85 (3H, m), 8,33 (lH, d, J=l3Hz), 9,21 (lH, s).NMR (TFA-dl) δ values: 3.30-4.50 (BH, m), 7.00-7.85 (3H, m), 8.33 (1H, d, J = 13Hz), δ , 21 (1H, s).
På liknande sätt erhölls föreningarna visade i tabell 7. 501 412 36 Tabell 7 O F coofl R2 Förening Fysikaliska egenskaper R2 R3 Smältpunkt IRí§Br) (oc) Cm 2 VC=O MeHN-Ox- >2ao 1720 (sn) " 234-236 1720 F " >280 1720 501 412 37 Tabell 7 (forts.) F MeNH-CN- 254-258 1725 I F F HN N- 205-207 1730 F F F " 225-227 1725 [::] " >2ao 1725 c1 Kj:] " 273-277 1720 [:çJ " 245-246 1725 § me 1 2 [:ç] " >2so 1725 § CN ' i [å:] 1730, 5 >28° 1710 NHZ å 501 412 38 Tabell 7 (forts.) 1725, Me '- 232-236 1710' N\_JN 1690 NHAC | K::] HN N- >2s0 1725 CF3 e " 230-232 1730 F HZN \ i- 260-263 1720 F MeHN " N- 259-261 1720 (sn) F " 275-278 1720 (sn) F P azn 4 N- 276-200 1720 F P AnnL: * Nujolmetoden användes istället för KBr-metoden 501 412 39 Exempel 3 I 50 ml N,N-dimetylformamid löstes 5,0 g etyl-2-/2-klor-5- fluor-6-(4-metyl-l-piperazinyl)nikotinoyl/-3-(4-metoxi-2- metylfenylamino)akrylat varefter 1,03 g natriumvätekarbonat sattes till den resulterande lösningen och den resulterande blandningen fick reagera vid l20°C i 3 timmar. Därefter av- lägsnades lösningsmedlet med destillation under reducerat tryck och den så erhållna återstoden löstes i 50 ml kloro- form. Den resulterande lösningen tvättades i följd med 30 ml vatten och 30 ml mättad vattenhaltig natriumkloridlösning för att därefter torkas över vattenfritt magnesiumsulfat.In a similar manner the compounds shown in Table 7 were obtained. 501 412 36 Table 7 OF coo fl R2 Compound Physical properties R2 R3 Melting point IRi§Br) (oc) Cm 2 VC = O MeHN-Ox-> 2ao 1720 (sn) 1720 F "> 280 1720 501 412 37 Table 7 (cont.) F MeNH-CN- 254-258 1725 IFF HN N- 205-207 1730 FFF" 225-227 1725 [::] "> 2ao 1725 c1 Kj:] "273-277 1720 [: çJ" 245-246 1725 § me 1 2 [: ç] "> 2so 1725 § CN 'i [å:] 1730, 5> 28 ° 1710 NHZ å 501 412 38 Table 7 (cont. ) 1725, Me '- 232-236 1710' N \ _JN 1690 NHAC | K ::] HN N-> 2s0 1725 CF3 e "230-232 1730 F HZN \ i- 260-263 1720 F MeHN" N- 259- 261 1720 (sn) F "275-278 1720 (sn) FP azn 4 N- 276-200 1720 FP AnnL: * The Nujol method was used instead of the KBr method 501 412 39 Example 3 In 50 ml of N, N-dimethylformamide was dissolved 5, 0 g of ethyl 2- [2-chloro-5-fluoro-6- (4-methyl-1-piperazinyl) nicotinoyl] -3- (4-methoxy-2-methylphenylamino) acrylate and 1.03 g of sodium bicarbonate were added thereto. the resulting solution and the resulting mixture were allowed to react 120 ° C for 3 hours. Then the solvent was removed by distillation under reduced pressure and the residue thus obtained was dissolved in 50 ml of chloroform. The resulting solution was washed successively with 30 ml of water and 30 ml of saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate.
Lösningsmedlet avlägsnades med destillation under reducerat tryck och den erhållna kristallina substansen tvättades med 30 ml dietyleter för att ge 2,38 g etyl-6-fluor-l,4-dihydro- l-(4-metoxi-2-metylfenyl)-7-(4-metyl-1-piperazinyl)-4-oxo- l,8-naftyridin-3-karboxylat med smältpunkt 144 - l45°C.The solvent was removed by distillation under reduced pressure, and the resulting crystalline substance was washed with 30 ml of diethyl ether to give 2.38 g of ethyl 6-fluoro-1,4-dihydro-1- (4-methoxy-2-methylphenyl) -7- (4-methyl-1-piperazinyl) -4-oxo-1,8-naphthyridine-3-carboxylate, m.p. 144 DEG-145 DEG.
IR (KBr) cm-1: 0 C=O NMR (CDCI3) 5 -värden 1,33 (3H, t, 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), 6,60-7J5 (3H, m), 8,02 (lH, d, J=l3Hz), 8,23 (lH, s). 1730, 1690 På liknande sätt erhölls föreningarna visade i tabell 8. 501 412 40 Tabell 8 O F COOEt R3 N T R2 Förening íysikaliska egenskaper 2 3 Smält- IR (KBr) R R punkt _l (°C) cm : VC=O OMe 1695 1730, " 174-175 1725, " amorf NHAC 1690 7 1725, “ 186-189 F _ - 1690 OMe 1730, " 166-168 Me 1695 OMe Me /-“\ 1725, AcN N- 169-172 \__/ 1690 OMe 501 412 41 Exempel 4 I 5 ml 47% bromvätesyra löstes 2,0 g etyl-6-fluor-l,4- dihydro-l-(4-metoxi-2-metylfenyl)-7-(4-metyl-l-piperazinyl)- 4-oxo-l,8-naftyridin-3-karboxylat och den resulterande lös- ningen fick reagera vid 12o° till 125°c 1 2 timmer. Reak- tionsblandningens pH justerades till 13 med 10% vatten- haltig natriumhydroxidlösning, därefter till 6,5 med ättik- syra. Så fällda kristaller uppsamlades med filtrering och tvättades med 10 ml vatten för att ge 1,8 g 6-fluor-l,4- dihydro-l-(4-hydroxi-2-metylfenyl)-7-(4-metyl-l-piperazi- nyl)-4-oxo-l,8-naftyridin-3-karboxylsyra med smältpunkt >2so°c.IR (KBr) cm-1: 0 C = 0 NMR (CDCl 3) δ values 1.33 (3H, t, 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, 60-7J5 (3H, m), 8.02 (1H, d, J = 13Hz), 8.23 (1H, s). 1730, 1690 In a similar manner the compounds shown in Table 8 were obtained. 501 412 40 Table 8 OF COOEt R3 NT R2 Compound Physical Properties 2 3 Melt IR (KBr) RR point _1 (° C) cm: VC = O OMe 1695 1730, "174-175 1725," amorphous NHAC 1690 7 1725, "186-189 F _ - 1690 OMe 1730," 166-168 Me 1695 OMe Me / - “\ 1725, AcN N- 169-172 \ __ / 1690 OMe 501 Example 4 In 5 ml of 47% hydrobromic acid was dissolved 2.0 g of ethyl 6-fluoro-1,4-dihydro-1- (4-methoxy-2-methylphenyl) -7- (4-methyl-1-piperazinyl) 4-oxo-1,8-naphthyridine-3-carboxylate and the resulting solution was reacted at 120 ° to 125 ° C for 2 hours, the pH of the reaction mixture was adjusted to 13 with 10% aqueous sodium hydroxide solution, then to 6.5 with acetic acid So precipitated crystals were collected by filtration 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 with melting point> 250 ° C.
IR (xßr) em'1= JC=0 1725, 1700 (sh) NMR (TFA-dl) 6 -värden: 2,08 (3H, S), 3,12 (3H, S), 2,88-5,12 (8H, m), 6,93-7,62 (3H, m), 9,25 (1H, s). 9,43 (ln, d, J=13Hz).IR (xßr) em '1 = JC = 0 1725, 1700 (sh) NMR (TFA-dl) δ values: 2.08 (3H, S), 3.12 (3H, S), 2.88-5 12 (8H, m), 6.93-7.62 (3H, m), 9.25 (1H, s). 9.43 (ln, d, J = 13Hz).
På liknande sätt erhölls föreningarna visade i tabell 9. 501 412 42 Tabell 9 O F COOH R3 N N I R2 Förening Fysikaliska egenskaper IR (KB R2 R3 Smältpunkt r) (°c) cnfl: “c=o EtN N- >280 1730 \_/ _QH " n-PrN N- >280 1725 \__/ " i-PrN N- >280 1715 \__/ /““\ 1720, " HO-\«N N- 200-205 \-/ nos " A,-N N- >280 1725 \__/ 4'l2 OH 5(J1 Tabell (forts.) f-w _ - MeN N_ 245 \ / ö er- d:1:1ng) 1700 (Sh) on OH /-\ 1725, HN N- 220-224 \_/ 1710 F " men N >2a0 1730' \ , 1710 (sn) [::l\ ' " >2s0 1730 F on F men N- 251-252 1720 \__/ on OH 1725 (sh), II > 280 1700 Me [::l\ u 1730, Me 220-230 1700 (sh) on Me /*"\ HN N- 275 1720 \__/ 501 412 44 Exempel 5 Till 0,1 g etyl-7-(4-acetyl-l-piperazinyl)-6-fluor-l-(4- fluorfenyl)-l,4-dihydro-4-oxo-l,8-naftyridin-3-karboxylat sattes 2 ml l N vattenhaltig natriumhydroxidlösning och 2 ml etanol och den resulterande lösningen fick reagera vid 400 till SOOC i l0 minuter. Därefter sattes ättiksyra till reak- tionsblandningen för att justera dess pH till 6,5. Sedan extraherades blandningen med två 5 ml portioner kloroform.In a similar manner the compounds shown in Table 9 were obtained. 501 412 42 Table 9 OF COOH R3 NNI R2 Compound Physical properties IR (KB R2 R3 Melting point r) (° c) cnfl: “c = o EtN N-> 280 1730 _QH "n-PrN N-> 280 1725 \ __ /" i-PrN N-> 280 1715 \ __ / / ““ \ 1720, "HO - \« N N- 200-205 \ - / nos "A, - N N-> 280 1725 \ __ / 4'l2 OH 5 (J1 Table (cont.) Fw _ - MeN N_ 245 \ / ö er- d: 1: 1ng) 1700 (Sh) on OH / - \ 1725, HN N- 220-224 \ _ / 1710 F "men N> 2a0 1730 '\, 1710 (sn) [:: l \'"> 2s0 1730 F on F men N- 251-252 1720 \ __ / on OH 1725 ( sh), II> 280 1700 Me [:: l \ u 1730, Me 220-230 1700 (sh) on Me / * "\ HN N- 275 1720 \ __ / 501 412 44 Example 5 Till 0.1 g ethyl- 7- (4-Acetyl-1-piperazinyl) -6-fluoro-1- (4-fluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate was added 2 ml of 1 N aqueous sodium hydroxide solution and 2 ml of ethanol and the resulting solution was allowed to react at 400 to 50 ° C for 10 minutes, then acetic acid was added to the reaction mixture to adjust its pH to 6.5. The mixture was diluted with two 5 ml portions of chloroform.
De kombinerade extrakten tvättades i följd med 5 ml vatten och 5 ml mättad vattenhaltig natriumkloridlösning och torka- des därefter över vattenfritt magnesiumsulfat. Lösnings- medlet avlägsnades med destillation under reducerat tryck och den så erhållna kristallina substansen tvättades med 2 ml dietyleter för att ge 0,08 g 7-(4-acetyl-l-piperazi- nyl)-6-fluor-l-(4-fluorfenyl)-l,4-dihydro-4-oxo-l,8- naftyridin-3-karboxylsyra med smältpunkt;>280°C.The combined extracts were washed successively with 5 ml of water and 5 ml of saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the crystalline substance thus obtained was washed with 2 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, m.p.> 280 ° C.
IR (mar) crrfl; uc=o 1730 NMR (d6-DMSO) 5 -värden: 2,05 (3H, s), 3,57 (8H, bs), 7,l3-7,80 (4H, m), 8,13 (lH, d, J=l3HZ), 8,70 (lH, s), På liknande sätt erhölls föreningarna visade i tabell 10.IR (mar) crrfl; uc = δ 1730 NMR (d 6 -DMSO) δ values: 2.05 (3H, s), 3.57 (8H, bs), 7.13-7.80 (4H, m), 8.13 (1H , d, J = 13Hz), 8.70 (1H, s). Similarly, the compounds shown in Table 10 were obtained.
Tabell 10 501 412 Förening Fysikaliska egenskaper 2 3 Smält- IR (KBr) R R punkt _1 v (°C) cm : C= Me [:] HN N- 267-270 1730 F < Me HO/\/N N- 138-139 1690 \__/ F F MeN N- >28O 1720 LJ F F Me ' HN N- >28O 1720 \__/ F Me " MeN N- 210-211 1735 \__/ Me " MeN N- 225-226 1720 \_/ " N N- 219-220 1730 C 501 412 46 Tabell 10 (forts.) men N- 283-284 173°' 1700 h cl (S ) men N- 277-zso 1730' \__/ 1700 (sh) Br K:j " 271-274 1725 Me K:] " 250-252 1725 OMe Exempel 6 Till 0,10 g etyl-6-fluor-l-(4-fluorfenyl)-l,4-dihydro-7-(3- hydroxi-l-pyrrolidinyl)-4-oxo-1,Sfnaftyridin-3-karboxylat sattes 2 ml l N vattenhaltig natriumhydroxidlösning och 2 ml etanol och den resulterande blandningen fick reagera vid 400 till 50°C i 10 minuter. Därefter sattes ättiksyra till reaktionsblandningen för att justera dess pH till 6,5. Sedan extraherades blandningen med två 5 ml portioner kloroform.Table 10 501 412 Compound Physical Properties 2 3 Melt IR (KBr) RR point _1 v (° C) cm: C = Me [:] HN N- 267-270 1730 F <Me HO / \ / N N- 138- 139 1690 \ __ / FF MeN N-> 28O 1720 LJ FF Me 'HN N-> 28O 1720 \ __ / F Me "MeN N- 210-211 1735 \ __ / Me" MeN N- 225-226 1720 \ _ / "N N- 219-220 1730 C 501 412 46 Table 10 (cont.) Men N- 283-284 173 ° '1700 h cl (S) men N- 277-zso 1730' \ __ / 1700 (sh) Br K 271-274 1725 Me K:] 250-252 1725 OMe Example 6 To 0.10 g of ethyl 6-fluoro-1- (4-fluorophenyl) -1,4-dihydro-7- (3-hydroxy -1-pyrrolidinyl) -4-oxo-1,1-Snaphthyridine-3-carboxylate 2 ml of 1 N aqueous sodium hydroxide solution and 2 ml of ethanol were added and the resulting mixture was allowed to react at 400 to 50 ° C for 10 minutes, then acetic acid was added to the reaction mixture for to adjust its pH to 6.5, then the mixture was extracted with two 5 ml portions of chloroform.
De kombinerade extrakten tvättades i följd med 5 ml vatten och 5 ml mättad vattenhaltig natriumkloridlösning och torka- des därefter över vattenfritt magnesiumsulfat. Lösningsmed- let avlägsnades med destillation under reducerat tryck och den så erhållna kristallina substansen tvättades med 2 ml dietyleter för att ge 0,08 g 6-fluor-l-(4-fluorfenyl)-l,4- 501 412 47 dihydro-7-(3-hydroxi-l-pyrrolidinyl)-4-oxo-l,8-naftyridin-3- xarboxylsyra med smältpunkt >-28OOC.The combined extracts were washed successively with 5 ml of water and 5 ml of saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the crystalline substance thus obtained was washed with 2 ml of diethyl ether to give 0.08 g of 6-fluoro-1- (4-fluorophenyl) -1,4-501 412 47 dihydro-7- (3-hydroxy-1-pyrrolidinyl) -4-oxo-1,8-naphthyridine-3-xarboxylic acid, m.p.
IR (KBr) cm* »Czo 1730 NMR (d6-DMSO) 5 -värden: 1,92-2,52 (2H, m), 3,22-5,00 (5Hf m)r 6,97-7,60 (4H, m), 8,01 (lH, Ö, J=llHZ)| 9,00 (lH, s).IR (KBr) cm -1 C 20 1730 NMR (d 6 -DMSO) δ values: 1.92-2.52 (2H, m), 3.22-5.00 (5Hf m) δ 6.97-7, 60 (4H, m), 8.01 (1H, Ö, J = 11HZ) | 9.00 (1H, s).
På liknande sätt erhölls föreningarna visade i tabell ll.In a similar manner, the compounds shown in Table II were obtained.
Tabell ll O F COOH R3 N N I R2 Förening Fysikaliska egenskaper R2 R3 Smältpunkt IR (xßr) (°C) cm-1: vC=0 [:] Me2N F I N- 264-265 1725 F " 227 1725 F 501 412 48 Exempel 7 I 2,5 ml koncentrerad saltsyra löstes 0,25 g 6-fluor-l,4- dihydro-l-(4-hydroxi-2-metylfenyl)-4-oxo-7-(l-piperazinyl)- 1,8-naftyridin-3-karboxylsyra varefter den resulterande lös- ningen försattes med 20 ml etanol, och den resulterande blandningen omrördes vid rumstemperatur i 15 minuter där- efter. De så fällda kristallerna uppsamlades med filtrering och tvättades med 5 ml etanol för att ge 0,2 g av saltsyra- saltet av 6-fluor-l,4-dihydro-l-(4-hydroxi-2-metylfenyl)- 4-oxo-7-(l-piperazinyl)-l,8-naftyridin-3-karboxylsyra med smältpunkt >-2800C.Table 11 OF COOH R3 NNI R2 Compound Physical properties R2 R3 Melting point IR (xßr) (° C) cm-1: vC = 0 [:] Me2N FI N- 264-265 1725 F "227 1725 F 501 412 48 Example 7 I 2.5 ml of concentrated hydrochloric acid were dissolved in 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, after which the resulting solution was added with 20 ml of ethanol, and the resulting mixture was stirred at room temperature for 15 minutes thereafter, The crystals thus precipitated were collected by filtration 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-methylphenyl) -4-oxo-7- (1-piperazinyl) -1,8-naphthyridine-3-carboxylic acid, m.p. > -2800C.
IR mer) cm'l= u 1725 (sn), 1705.IR mer) cm -1 = u 1725 (sn), 1705.
C=O På liknande sätt erhölls föreningarna visade i tabelll2 . 501 412 49 Tabell 12 O F COOH Saltsyrasalt 3 aV R N I? R2 Förening Fysikaliska egenskaper R2 R3 Smältpunkt IR (KBI) (°C) cm_l: vC=O HN N- 275-278 1720 F \_J F F 249-252 (sönder- 1730 F delning) G ' - 30 [:] M N N 280 282 17 \__/ 6 OH F / \ 1720 (sh), HN N- 279-283 \-/ 1705 OH F /_“\ l720 (sh), MeN N- 266-269 L-f 1700 OH Me Ü " 282 1730 OH 1 501 412 50 Exempel 8 Till 0,3 g etyl-7-(4-etoxikarbonyl-2-metyl-l-piperazinyl)- 6-fluor-l-(2,4-difluorfenyl)-l,4-dihydro-4-oxo-l,8-nafty- ridin-3-karboxylat sattes 5 ml l N vattenhaltig natrium- hydroxidlösning och 5 ml etanol och den resulterande bland- ningen fick reagera vid 90°C i 2 timmar. Sedan försattes reaktionsblandningen med ättiksyra för att justera dess pH till 6,5. De så fällda kristallerna uppsamlades med filtre- ring, tvättades med vatten och torkades därefter för att ge 0,2 g 6-fluor-l-(2,4-difluorfenyl)-l,4-dihydro-7-(2-metyl-l- piperazinyl)-4-oxo-l,8-naftyridin-3-karboxylsyra med smält; punkt 230 - 239°c.C = 0 In a similar manner, the compounds shown in Table 12 were obtained. 501 412 49 Table 12 O F COOH Hydrochloric acid salt 3 aV R N I? R2 Compound Physical properties R2 R3 Melting point IR (KBI) (° C) cm -1: vC = O HN N- 275-278 1720 F \ _J FF 249-252 (decomposition 1730 F partition) G '- 30 [:] MNN 280 282 17 \ __ / 6 OH F / \ 1720 (sh), HN N- 279-283 \ - / 1705 OH F / _ “\ l720 (sh), MeN N- 266-269 Lf 1700 OH Me Ü" 282 1730 OH 1 501 412 50 Example 8 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 to 5 ml of 1 N aqueous sodium hydroxide solution and 5 ml of ethanol, and the resulting mixture was allowed to react at 90 ° C for 2 hours, then the reaction mixture was added with acetic acid to to adjust its pH to 6.5 The crystals thus precipitated were collected by filtration, washed with water and then dried to give 0.2 g of 6-fluoro-1- (2,4-difluorophenyl) -1,4- dihydro-7- (2-methyl-1-piperazinyl) -4-oxo-1,8-naphthyridine-3-carboxylic acid, m.p. 230 DEG-239 DEG.
IR (rar) cm'l uC=O 1730 NMR (TFA-dl) 5-värden: 1,50 (3H, S), 3,20-5,15 (7H, N), 7,00-7,90 (3H, m), 8,35 (lH, d, J=l3HZ): 9,20 (lH, s).IR (rar) cm -1 uC = O 1730 NMR (TFA-dl) δ values: 1.50 (3H, S), 3.20-5.15 (7H, N), 7.00-7.90 (3H, m), 8.35 (1H, d, J = 13Hz): 9.20 (1H, s).
Beredningsexempel l Med 50 g 6-fluor-l-(2,4rdifluorfenyl)-l,4-dihydro-4-oxo- 7-(l-piperazinyl)-l,8-naftyridin-3-karboxylsyra blandades 49 g kristallin cellulosa, 50 g majsstärkelse och l g magne- siumstearat och blandningen komprimerades till l000 tabletter av platt typ.Preparation Example 1 With 50 g of 6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-7- (1-piperazinyl) -1,8-naphthyridine-3-carboxylic acid was mixed 49 g of crystalline cellulose, 50 g of corn starch and 1 g of magnesium stearate and the mixture were compressed into 1000 flat type tablets.
Beredningsexempel 2 Med 100 g 6-fluor-l-(2,4-difluorfenyl)-l,4-dihydro-4- oxo-7-(l-piperazinyl)-l,8-naftyridin-3-karboxylsyra blanda- des 50 g majsstärkelse och 1000 kapslar fylldes med den resulterande blandningen för att erhålla kapslar.Preparation Example 2 With 100 g of 6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-7- (1-piperazinyl) -1,8-naphthyridine-3-carboxylic acid was mixed 50 g of corn starch and 1000 capsules were filled with the resulting mixture to obtain capsules.
Claims (8)
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| JP59084963A JPS60228479A (en) | 1984-04-26 | 1984-04-26 | 1,4-dihydro-4-oxonaphthyridine derivative and salt thereof |
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| SE8804586D0 SE8804586D0 (en) | 1988-12-20 |
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| SE8502017A SE463102B (en) | 1984-04-26 | 1985-04-25 | 1,4-DIHYDRO-4-OXONAFTYRIDINE DERIVATIVES AND SALTS THEREOF, PROCEDURES FOR THE PREPARATION OF THESE ANTIBACTERIAL AGENTS INCLUDING THESE |
| SE8804586A SE501412C2 (en) | 1984-04-26 | 1988-12-20 | 1,4-dihydro-4-oxonaphthyridine derivatives and salts thereof Process for the preparation thereof and antibacterial agents including these |
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| JP (1) | JPS60228479A (en) |
| KR (1) | KR870001693B1 (en) |
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| AT (2) | AT389698B (en) |
| AU (2) | AU565087B2 (en) |
| BE (1) | BE902279A (en) |
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| CS (1) | CS250684B2 (en) |
| DD (1) | DD238795A5 (en) |
| DE (2) | DE3546658C2 (en) |
| DK (1) | DK165877C (en) |
| EG (1) | EG17339A (en) |
| ES (2) | ES8700256A1 (en) |
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| GB (2) | GB2158825B (en) |
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| JPS6172753A (en) * | 1984-09-18 | 1986-04-14 | Dainippon Pharmaceut Co Ltd | Pyridyl ketone derivative |
| AT392789B (en) * | 1985-01-23 | 1991-06-10 | Toyama Chemical Co Ltd | METHOD FOR PRODUCING 1-SUBSTITUTED ARYL-1,4-DIHYDRO-4-OXONAPHTHYRIDINE DERIVATIVES |
| 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 |
| 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 |
| CA2100242A1 (en) * | 1991-01-14 | 1992-07-15 | Soon K. Moon | 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 |
| AU4272793A (en) * | 1993-04-24 | 1994-11-21 | 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 |
| DE69531305T2 (en) * | 1994-10-20 | 2004-05-13 | Wakunaga Seiyaku K.K. | PYRIDONE CARBOXYLATE DERIVATIVES OR SALTS THEREOF AND ANTIBACTERIAL COMPOSITIONS CONTAINING THEM AS AN ACTIVE COMPONENT |
| 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 |
| EP0935600A1 (en) * | 1996-10-30 | 1999-08-18 | Bayer Ag | Method or 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 |
| CN1343128B (en) | 1999-03-17 | 2010-04-21 | 第一制药株式会社 | Medicinal compositions |
| US6441182B1 (en) | 1999-06-10 | 2002-08-27 | Bayer Aktiengesellschaft | Method for the production of 2,6-dichloro-5-fluoro-nicotinic acid and coarse and particularly pure 2,6-dichloro-5-fluoro-nicotinic acid |
| WO2001017991A1 (en) | 1999-09-02 | 2001-03-15 | Wakunaga Pharmaceutical Co., Ltd. | Quinolinecarboxylic acid derivative or its salt |
| 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 |
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| 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 |
| NZ210847A (en) * | 1984-01-26 | 1988-02-29 | Abbott Lab | Naphthyridine and pyridopyrimidine derivatives and pharmaceutical compositions |
| 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 |
| 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 |
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- 1985-04-26 IT IT8548002A patent/IT1209953B/en active
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1986
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1987
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