SE440353B - QUINOLINE CARBOXYLIC ACID DERIVATIVES AND SETS FOR PREPARING THEREOF - Google Patents
QUINOLINE CARBOXYLIC ACID DERIVATIVES AND SETS FOR PREPARING THEREOFInfo
- Publication number
- SE440353B SE440353B SE8005534A SE8005534A SE440353B SE 440353 B SE440353 B SE 440353B SE 8005534 A SE8005534 A SE 8005534A SE 8005534 A SE8005534 A SE 8005534A SE 440353 B SE440353 B SE 440353B
- Authority
- SE
- Sweden
- Prior art keywords
- carboxylic acid
- dihydro
- ethyl
- oxo
- quinoline
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
- C07D215/18—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
Description
aoosszu-s 2 o Rz COOH (I) 1:3 N | R R4 1 vari R1 betecknar lägre alkyl, R2 betecknar halogen, företrädes- vis fluor eller klor, H5 betecknar piperazinyl eller N-lägre alkyl-piperazinyl, och En betecknar halogen, företrädesvis fluor, klor eller brom, lägre alkyl, företrädesvis metyl, hydraten eller de farmaceutiskt godtagbara salterna därav. aosstzu-s 2 O Rz COOH (IN) 1: 3 N | R R4 1 wherein R 1 represents lower alkyl, R 2 represents halogen, preferably fluorine or chlorine, H5 represents piperazinyl or N-lower alkyl-piperazinyl, and En represents halogen, preferably fluorine, chlorine or bromine, lower alkyl, preferably methyl, the hydrates or the pharmaceutically acceptable salts thereof.
De föredragna föreningarna i (I) såsom antibakteriella medel är följande. ifetyl-6,8-difluoro-1,U-dihydro-ü-oxo-7-(1-piperazínyl)-kino1in- -3-karboxylsyra, g 1fetyl>6,8-difluoro-1,4-dihydro-N-oxo-7-(H-metyl-1~piperazínyl)- -kínolin-3-karboxylsyra, fi8-k1oro-1-etyl-6-fluoro-1,U-dihydro-H-oxo-7-(1-piperazinyl)- "-kínolin-3-karboxylsyra, 8-k1oro-1-etyl-6-fluoro-1,ü-dihydro-U-oxo-7-(ü-metyl-1-pipera- zinyl)-kinolin-3-karboxylsyra, hydraten och de farmaceutiskt godtagbara salterna av dessa före~ ningar.The preferred compounds in (I) as antibacterial agents are following. Phetyl-6,8-difluoro-1,1-dihydro-β-oxo-7- (1-piperazinyl) -quinoline- -3-carboxylic acid, g 1-Phetyl> 6,8-difluoro-1,4-dihydro-N-oxo-7- (H-methyl-1-piperazinyl) - -quinoline-3-carboxylic acid, F8-chloro-1-ethyl-6-fluoro-1,1-dihydro-H-oxo-7- (1-piperazinyl) - "-quinoline-3-carboxylic acid, 8-chloro-1-ethyl-6-fluoro-1,1'-dihydro-U-oxo-7- (β-methyl-1-pipera- zinyl) -quinoline-3-carboxylic acid, the hydrates and the pharmaceutically acceptable salts thereof before nings.
Föreningarna enligt föreliggande uppfinning framställes med för- rfarandena A och B.The compounds of the present invention are prepared by Procedures A and B.
Z Förfarande A: Föreningen (I) framställes genom omsättning av en förening med formeln (II). aoosszal. 5 o az coon I (II) x N I al, Ri vari H1, R2 och Ru är desamma som beskrivits ovan, och X beteck- nar halogen, med en förening med formeln (III) fw - RS- N N H (III) , LJ vari R5 betecknar väte eller lägre alkylgrupp, i ett inert lös- ningsmedel såsom t.ex. vatten, alkoholer, pyridin, píkolin, N,N~dimetylformamid, dimetylsulfoxid eller liknande eller i från- varo av ett lösningsmedel vid en temperatur i intervallet från 60°C till 180°C. Det föredrages att genomföra reaktionen i när- varo av en bas såsom ett dehydrohalogenerande medel såsom alkali- hydroxid, alkalikarbonat eller aminer.Z Method A: The compound (I) is prepared by reacting a compound with formula (II). aosstzal. 5 O az coon I (II) x N IN al, Ri wherein H 1, R 2 and Ru are the same as described above, and X halogen, with a compound of formula (III) fw - RS- N N H (III) , LJ wherein R 5 represents hydrogen or lower alkyl group, in an inert solution agents such as e.g. water, alcohols, pyridine, picoline, N, N-dimethylformamide, dimethylsulfoxide or the like or in fractions being a solvent at a temperature in the range of 60 ° C to 180 ° C. It is preferred to carry out the reaction in the presence of a base such as a dehydrohalogenating agent such as alkali hydroxide, alkali carbonate or amines.
Förfarandeßz _ Föreningarna med formeln (I) erhålles genom omsättning av en förening med formeln (IV) COOH (Iv) vari H1, R2 och Ru är desamma, som nämnts ovan, med en förening med formeln (V) R6-CO-R? (V) vari R6 och R7 betecknar väte eller lägre alkyl, i närvaro av ett reducerande medel såsom t.ex. myrsyra, natrium borhydrid, katalytiskthydrerande medel eller liknande. Exempel på de lös- ningsmedel, som användes vid reaktionen, är vatten, alkoholer, 8005534s6- M a e.rer, dipolära aprotiska lösningsmedel eller liknande.Procedure _ The compounds of formula (I) are obtained by reacting a compound of the formula (IV) COOH (Iv) wherein H1, R2 and Ru are the same, as mentioned above, with a compound with the formula (V) R6-CO-R? (V) wherein R 6 and R 7 represent hydrogen or lower alkyl, in the presence of a reducing agent such as e.g. formic acid, sodium borohydride, catalytic hydrating agents or the like. Examples of the solutions Agents used in the reaction are water, alcohols, 8005534s6- M a e.rer, dipolar aprotic solvents or the like.
Följande exempel illustrerar uppfinningen.i §§empel 1 1-etyl-1,U-dihydro-U-oxo-6,7,8-trifluorokinolin-3-karboxylsyra.The following examples illustrate the invention.i §§Ample 1 1-ethyl-1,1-dihydro-U-oxo-6,7,8-trifluoroquinoline-3-carboxylic acid.
En blandning av 3-etoxikarbonyl-Ä-hydroxi-6,7,8-trifluorokinolin- (3,0 g), vattenfritt kaliumkarbonat (7,6 g), etyljodid (8,8 ml) och N,N-dimetylformamid (DMF) (100 ml) värmdes under omrörning vid 90 o/ 100°C under 10 timmar. Reaktionsblandningen indunstades till torrhet, vatten tillsattes, den erhållna fasta substansen uppsamlades, tvättades med vatten och torkades. Den fasta substan- sen upplöstes i diklorometan, filtrerades och indunstades. Till återstoden sattes 18 1-íg saltsyra (50 ml) och etanol (25 ml), och blandningen återloppskokades 2,5 timmar. Efter kylning filt- rerades fällningen av, tvättades med vatten och torkades. Den 0 fasta substansen omkristalliserades ur en blandning av DMF och etanol och gav 2,1 g 1-etyl-1,U-dihydro-U-oxo-6,7,8-trifluoro- kinolin-3-karboxylsyra som färglösa nålar med en smältpunkt av 259 ~»261°c. 0 Analys: beräknat för C12H8O3NF5 : C 53,15 H 2,97 N 5,16 funnet : C 53,30 H 2,88 N 5,2H Utgångsmateríalet, 3-etoxikarbonyl-Ä-hydroxi-6,7,8-trifluoro- kinolín erhölls med följande förfarande.A mixture of 3-ethoxycarbonyl-N-hydroxy-6,7,8-trifluoroquinoline (3.0 g), anhydrous potassium carbonate (7.6 g), ethyl iodide (8.8 ml) and N, N-dimethylformamide (DMF) (100 ml) was heated with stirring at 90 o / 100 ° C for 10 hours. The reaction mixture was evaporated to dryness, water was added, the obtained solid were collected, washed with water and dried. The solid then dissolved in dichloromethane, filtered and evaporated. To to the residue were added 18 l of hydrochloric acid (50 ml) and ethanol (25 ml), and the mixture was refluxed for 2.5 hours. After cooling felt- the precipitate was removed, washed with water and dried. The 0 the solid was recrystallized from a mixture of DMF and ethanol to give 2.1 g of 1-ethyl-1,1-dihydro-U-oxo-6,7,8-trifluoro- quinoline-3-carboxylic acid as colorless needles with a melting point of 259 ~ »261 ° c. 0 Analysis: calculated for C 12 H 8 O 3 NF 5: C 53.15 H 2.97 N 5.16 Found: C 53.30 H 2.88 N 5.2H The starting material, 3-ethoxycarbonyl-N-hydroxy-6,7,8-trifluoro- quinoline was obtained by the following procedure.
En blandning av 2,3,Hftrifluoroanilín (U,9 g) och etoximetylen- -malon-dietylester (7,2 g) uppvärmdes i 120 4»1HO°C under 1 timme.A mixture of 2,3, Trifluoroaniline (U, 9 g) and ethoxymethylene -malon-diethyl ester (7.2 g) was heated at 120 4 »1HO ° C for 1 hour.
Efter kylning försattes blandningen med difenyleter (50 ml), och blandningen återloppskokades 30 minuter. Efter kylning försattes blandningen med bensen, fällningen filtrerades, tvättades med bensen, torkades och omkristalliserades ur DMF, varvid 5,7 g 3-etoxikarbonyl-U-hydroxi~6,7,8-trifluorokinolin erhölls som färglöst pulver, smältpunkt 280 4/ 28500 (sönderfall)- Ana1ys= beräknas får c12H8o5NF5= c 53,15 H 2,97 N 5,16 funnen = c 52,83 H 2,814 N 5,10 8005531 1-ctyl-6,8-difluoro-1,U-dihydro~U-oxo-7-(piperazinyl)~ kínolin-3-karboxylsyra-hydroklorid.After cooling, the mixture was added with diphenyl ether (50 ml), and the mixture was refluxed for 30 minutes. After cooling was continued the mixture with benzene, the precipitate was filtered, washed with benzene, dried and recrystallized from DMF to give 5.7 g 3-Ethoxycarbonyl-U-hydroxy-6,7,8-trifluoroquinoline was obtained as colorless powder, melting point 280 4/28500 (decomposition) - Analysis = calculated sheep c12H8o5NF5 = c 53.15 H 2.97 N 5.16 found = c 52.83 H 2.814 N 5.10 8005531 1-ethyl-6,8-difluoro-1,1-dihydro-4-oxo-7- (piperazinyl) - quinoline-3-carboxylic acid hydrochloride.
En blandning av 1-etyl-1,U-dihydro-U-oxo-6,7,8-trifluorokinol -3-karboxylsyra (1,35 g), piperazin (2,2 g) och pyridin (10 n äterloppskokades 6 timmar. Reaktionsblandningen indunstades t torrhet. Återstoden försattes med utspädd saltsyra för juster under pH 1, och fällningen filtrerades. Den fasta substansen kristallíserades ur vatten och gav 1,U5 g 1-etyl-6,8-difluoro -díhydro-H-oxo-7-(1-piperazinyl)-kinolin-3~karboxylsyrahydrok som färglösa kristaller, smältpunkt > 30000.A mixture of 1-ethyl-1,1-dihydro-U-oxo-6,7,8-trifluoroquinol -3-carboxylic acid (1.35 g), piperazine (2.2 g) and pyridine (10 n refluxed for 6 hours. The reaction mixture was evaporated Dryness. The residue was added with dilute hydrochloric acid for adjustment below pH 1, and the precipitate was filtered. The solid was crystallized from water to give 1.5 g of 1-ethyl-6,8-difluoro -Dihydro-H-oxo-7- (1-piperazinyl) -quinoline-3-carboxylic acid hydrocarbon as colorless crystals, melting point> 30000.
Analys: beräknat för C16H17O5N3F2HCl : C 51,Ä1 H H,85 N 1 funnet 2 C 51,07 H fl,79 N 1 Exempel 3 1-etyl-6,8-dífluoro-1,4-díhydro-U-oxo-7-(H-metyl-1-piperaziny kinolin-3-karboxylsyra. 1-etyl-6,8-difluoro-1,ü-dihydro-H-oxo-7-(1-piperazinyl)-kinol -3-karboxylsyrahydroklorid (O,75 g), natriumformat (0,27 g), myrsyra (Ä ml) och 37 % formaldehydlösning (Ä ml) blandades o återloppskokades 5 timmar. Reaktíonsblandníngen indunstades.' återstoden sattes vatten (10 ml), lösningen justerades till pl genom tillsats av 10 % natriumhydroxidlösning och extraherade: diklorometan. Det organiska skiktet tvättades med vatten, torl över vattenfritt natriumsulfat och indunstades. återstoden oml stalliserades ur en blandning av DMF och etanol och gav 0,H5 g 1-etyl-6,8-difluoro-1,U-dihydro-H-oxo-7-(U-mety1~1-piperazínyl kinolin-3-karboxylsyra som färglösa kristaller med en smëltpur av 2115 ~ 2us°c.Analysis: calculated for C 16 H 17 O 5 N 3 F 2 HCl: C 51, Ä 1 H H, 85 N 1 found 2 C 51.07 H fl, 79 N 1 Example 3 1-ethyl-6,8-difluoro-1,4-dihydro-N-oxo-7- (H-methyl-1-piperazine quinoline-3-carboxylic acid. 1-Ethyl-6,8-difluoro-1,1-dihydro-H-oxo-7- (1-piperazinyl) -quinol -3-carboxylic acid hydrochloride (0.75 g), sodium formate (0.27 g), formic acid (Ä ml) and 37% formaldehyde solution (Ä ml) were mixed o refluxed for 5 hours. The reaction mixture was evaporated. the residue was added water (10 ml), the solution was adjusted to pI by adding 10% sodium hydroxide solution and extracting: dichloromethane. The organic layer was washed with water, dry over anhydrous sodium sulfate and evaporated. the remainder approx was stalled from a mixture of DMF and ethanol to give 0.5 H5 g 1-ethyl-6,8-difluoro-1,1-dihydro-H-oxo-7- (U-methyl-1-piperazinyl) quinoline-3-carboxylic acid as colorless crystals with a molten pur of 2115 ~ 2us ° c.
Analys: beräknat för C17H19O3N3F2 : C 58,11 H 5,35 N 11,95 funnet : C 57,97 H 5,48 N 12,02 8005534-6 Éxempel M 8-kloro-1'etyl-6,7-difluoro-1,U-dihydro-U~oxokinolin-3-karboxyl- syra. ” 8-kloro-6,7-difluoro-1,H-dihydro-U-oxokinolin-3-karboxylsyra- -etylester (12,0 g), vattenfritt kaliumkarbonat (29 g), etyljodid (53,6 ml), och DMF (300 ml) blandades och omrördes vid 90 ^/10000 under 12 timmar. Till blandningen sattes vattenfritt kaliumkarbonat (1H,5 g) och etyljodid (16,8 ml), och blandningen värmdes under omrörning vid 90 ^«100°C under 9,5 timmar. Blandníngen koncentre- rades till torrhet, vatten tillsattes, extraherades med dikloro- metan och indunstades. Till återstoden sattes 18 %~ig saltsyra (100 ml) och återloppskokades U timmar. Vattenlösníngen försat- tes med vatten (200 ml) och extraherades med diklorometan. Di-0 klorometanskíktet tvättades med vatten och indunstades. Ãtersto- den omkrístalliserades från en blandning av DMF och etanol och, gav 5,7 g 8-kloro-1-etyl-6,7-difluoro-1,U-dihydro-H-oxokinolin- -3-karboxylsyra som färglösa nålar, smältpunkt: 215 «-21700.Analysis: calculated for C 17 H 19 O 3 N 3 F 2: C 58.11 H 5.35 N 11.95 Found: C 57.97 H 5.48 N 12.02 8005534-6 Example M 8-chloro-1'-ethyl-6,7-difluoro-1,1-dihydro-4-oxoquinoline-3-carboxylic acid acid. ” 8-Chloro-6,7-difluoro-1,1H-dihydro-U-oxoquinoline-3-carboxylic acid -ethyl ester (12.0 g), anhydrous potassium carbonate (29 g), ethyl iodide (53.6 ml), and DMF (300 ml) was mixed and stirred at 90 ° / 10000 for 12 hours. Anhydrous potassium carbonate was added to the mixture (1H, 5 g) and ethyl iodide (16.8 ml), and the mixture was heated stirring at 90 ° C to 100 ° C for 9.5 hours. The mixture is concentrated to dryness, water was added, extracted with dichloro- methane and evaporated. To the residue was added 18% hydrochloric acid (100 ml) and refluxed for U hours. The aqueous solution with water (200 ml) and extracted with dichloromethane. Di-0 the chloromethane layer was washed with water and evaporated. Extreme it was recrystallized from a mixture of DMF and ethanol and, gave 5.7 g of 8-chloro-1-ethyl-6,7-difluoro-1,1-dihydro-H-oxoquinoline -3-carboxylic acid as colorless needles, melting point: 215 «-21700.
Analys: beräknat för C12H803N F2Cl : C 50¿11 H 2,80 N ü,87 funnet : C 50,H0 H 2,72 N U,93 Utgångsmaterialet, 8-kloro-6,7-difluoro-1,H-dihydro-U-oxokino1ín- -3-karboxylsyra-etylester erhölls med följande förfarande. 2-kloro-3,U-difluoroanilin (9,6 g) och etoximetylen-malonsyra- -dietylester (12,8 g) blandades och värmdes vid 120 ^~1}0°C under 2 timmar. Efter kylning tillsattes difenyleter (100 ml) till blandningen och återloppskokades 30 minuter. Reaktionsblandningen kyldes, och bensen (100 ml) tillsattes. Fällningen uppsamlades, tvättades med bensen och torkades. Den fasta substansen omkristal- liserades ur DMF och gav 13,3 g 8-kloro-6,7~difluoro-1,ü-dihydro- -Ä-oxokinolin-3-karboxylsyra-etylester som färglöst pulver,' smälcpunkc; 292 ~ 295l°c (sönderfall) .Analysis: calculated for C12H803N F2Cl: C50¿11 H 2.80 Nü, 87 found: C 50, H0 H 2.72 N U, 93 The starting material, 8-chloro-6,7-difluoro-1, H-dihydro-U-oxoquinoline -3-Carboxylic acid ethyl ester was obtained by the following procedure. 2-chloro-3,0-difluoroaniline (9.6 g) and ethoxymethylene malonic acid Diethyl ester (12.8 g) was mixed and heated at 120 ° C to 0 ° C below 2 hours. After cooling, diphenyl ether (100 ml) was added the mixture and refluxed for 30 minutes. The reaction mixture was cooled, and benzene (100 ml) was added. The precipitate was collected, washed with benzene and dried. The solid is recrystallized was lysed from DMF to give 13.3 g of 8-chloro-6,7-difluoro-1,10-dihydro- Α-oxoquinoline-3-carboxylic acid ethyl ester as a colorless powder, smälcpunkc; 292 ~ 295l ° C (dec.).
'Pom {;:;:31TY 8005534-4 Exempel 5 8-k1oro-1-etyl-6-fluoro-1,U-dihydro-ü-oxo-7-(1-piperaziny1)- kínolin-3-karboxylsyra-hydroklorid En blandning av 8-kloro-ljetyl-6,7-difluoro-1,H~dihydro-ä-oxo- kinolín-3-karboxylsyra (0,65 g), piperazín (1,0 g) och byrídin (5 ml) âterloppskokades 30 minuter. Reaktíonsblandningen induns- tades och surgjordes med saltsyra. Fällníngen uppsamlades och omkrístalliserades från en blandning av vatten och etanol och gav 0,60 g 8-kloro-1-etyl-6-fluoro-1,U-díhydro~U-oxo-7-(1- -píperazínyl)-kíno1in-3-karboxylsyrahydrokloríd som färglöst pulver, smältpunk: > 3oo°c. 0 Analys: beräkn. för C H O N F C1.HC1.1/4 C H OH: 16 17 3 3 2 5 C 49.33 H 4.89 N 10.46 funnet! C 49,30 H 4.59 N 10,25 Exempel § 8-kloro-1-etyl-6-fluoro-1.4-dinydro-4-oxo-7-(4-mety1-1-piper- azinyl)-kinolin-3-karboxylsyra.'Pom {;:;: 31TY 8005534-4 Example 5 8-chloro-1-ethyl-6-fluoro-1,1-dihydro-β-oxo-7- (1-piperazinyl) - quinoline-3-carboxylic acid hydrochloride A mixture of 8-chloro-ethyl-6,7-difluoro-1,1H-dihydro-α-oxo- quinoline-3-carboxylic acid (0.65 g), piperazine (1.0 g) and byridine (5 ml) was refluxed for 30 minutes. The reaction mixture is evaporated. was taken and acidified with hydrochloric acid. The precipitate was collected and was recrystallized from a mixture of water and ethanol and gave 0.60 g of 8-chloro-1-ethyl-6-fluoro-1,1-dihydro-4-oxo-7- (1- -piperazinyl) -quinoline-3-carboxylic acid hydrochloride as colorless powder, melting point:> 30 ° C. 0 Analysis: calculate. for C H O N F C1.HC1.1 / 4 C H OH: 16 17 3 3 2 5 C 49.33 H 4.89 N 10.46 found! C 49.30 H 4.59 N 10.25 Example § 8-Chloro-1-ethyl-6-fluoro-1,4-dinydro-4-oxo-7- (4-methyl-1-pipero- azinyl) -quinoline-3-carboxylic acid.
B-kloro-1-etyl-6-fluoro-1.4-díhydro-4-oxo-7-(1-píperazinyl)- -Kino1in-3-karboxylsyrahydrokloríd (O.25 g). natriunfornat (0,5 9). 87 t-iq nyrsyra (5 ml) och 37 t-ig fornaldehydlösning (5 nl) blandades och återloppskokades under 6.5 tinnar. Lös- ningen índunstades och gjordes basísk med en vattenlösning av natriunhydroxíd. Den basiska lösningen neutralíserades med ättíksyra. extraherades med díklorouetan och indunstades. Återstoden onkrístalliserades ur etanol och gav 0,21 q 8- -kloro-1-etyl-6-tluoro-1,4-dinydro-4-oxo-7-(4-netyl-1-piperaziny 1)-kinolin-3-karboxylsyra son tärglöst pulver. snältpunktz 213f“216°C.B-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) - -Cinoline-3-carboxylic acid hydrochloride (0.25 g). natriunfornat (0.5 9). 87 t -ig kidney acid (5 ml) and 37 t-g fornaldehyde solution (5 nl) was mixed and refluxed under 6.5 tins. Loose- The mixture was evaporated and basified with an aqueous solution of sodium hydroxide. The basic solution was neutralized with acetic acid. was extracted with dichloroethane and evaporated. The residue was recrystallized from ethanol to give 0.21 q 8- Chloro-1-ethyl-6-fluoro-1,4-dinydro-4-oxo-7- (4-methyl-1-piperazine 1) -quinoline-3-carboxylic acid son tar-free powder. melting point 213f 216 ° C.
Analys: beräknat för C17H1903N3Fc1.1/4 H20: C 54,84 H 5.28 N 11.29 funnet: C 54,98 H 5,20 N 11,14 pQOR QUALITY aoosszu-s Bxengel 1 g 6.5-ditlnoro-l.4-dihydro-l-netvl-4~oxo-7-(1-piperazinyl)_ -rinolin-3~karboxy1syrahvdroklorid.Analysis: Calculated for C17H19903N3Fc1.1 / 4 H2O: C 54.84 H 5.28 N 11.29 Found: C 54.98 H 5.20 N 11.14 pQOR QUALITY aosstzu-s Bxengel 1 g 6,5-dithilino-1,4-dihydro-1-methyl-4-oxo-7- (1-piperazinyl) -rinoline-3-carboxylic acid hydrochloride.
En blandning av 6.7.8-tritluoro-1.4-dihydro-l-netyl-4-oxo- -kinolin-3-karboxvlsyra (0.22 g). Pïperazin (0..37 g) och pyridin_(3 ll) återloppskokades 4 tinnar. Reaktionsblandningen indunstades till torrhet. Återstoden surgjordes genon tillsats av vari vattenhaltig ättiksyralösning. och olösligt naterial avlägsnades genol:tiltrering. Piltratet justerades till pH l ned koncentrerad saltsyra och kyldes. Den erhållna fällningen filtrerade: av och onkristalliserades från vatten och gav 6,8-difluoro-1.4-dihydro-1-nety1-4-oxo-7-(1-piperaziny13- -kinolin-3-karboxylsyrahydroklorid (0.l3 9). snältpunkt 286- -288°C (sönderfall). i Analys: C H N beräknat för C15H15F2N303 HCI: 50,08 4.48 11,53 funnet: * 49.98 4,38 11.58 Utgângsnaterialet 6,7.B-trifluoro-l.4-dihydro-1-netv1-4-oxo- kinolin-3-karboxylsyra erhölls med följande förfarande.A mixture of 6.7.8-tritluoro-1,4-dihydro-1-methyl-4-oxo- -quinoline-3-carboxylic acid (0.22 g). Piperazine (0.37 g) and pyridine (3 μl) was refluxed 4 tins. The reaction mixture evaporated to dryness. The residue was acidified by addition of which aqueous acetic acid solution. and insoluble material removed genol: tiltration. The filtrate was adjusted to pH 1 concentrated hydrochloric acid and cooled. The precipitate obtained filtered: off and recrystallized from water to give 6,8-difluoro-1,4-dihydro-1-methyl-4-oxo-7- (1-piperazinyl) -quinoline-3-carboxylic acid hydrochloride (0.13). melting point 286- -288 ° C (dec.). in Analysis: C H N calculated for C 15 H 15 F 2 N 3 O 3 HCl: 50.08 4.48 11.53 found: * 49.98 4.38 11.58 The starting material 6,7.B-trifluoro-1,4-dihydro-1-methyl-4-oxo- quinoline-3-carboxylic acid was obtained by the following procedure.
En blandning av 6.7.8-trifluoro-1.4-dihydro-4-oxokinolin-3- -karboxylsyraetylester (0.3 g). vattenfritt kaliunkarbonat (0,8 9). letyljodid (1.6 g). och N,N-dinetylfornanid-(DNF) (10 nl) värndes under omrörning vid 90-100°C under 10 tinnar.A mixture of 6.7.8-trifluoro-1,4-dihydro-4-oxoquinoline-3- -carboxylic acid ethyl ester (0.3 g). anhydrous potassium carbonate (0.89). letyl iodide (1.6 g). and N, N-dinethylformananide- (DNF) (10 nl) was protected with stirring at 90-100 ° C for 10 days.
Blandningen indunstadee till torrhet. Aterstoden behandlades med vatten. extraherades ned dikloronetan. Det organiska skik- tet tvättade: ned vatten. torkades över vattentritt natriun- sulfat och indunstades. Återstoden sattes till en blandning av 18-procentig saltsyra (5 nl) och etanol (2,5 nl), och bland- ningen återloppskokades 2.5 tinnar. sedan tillsattes vatten (5 nl) och etanol (5 nl) och kyldes, den erhållna fällningen filtrerades av och onkristalliserades från en blandning av UHF och etanol och gav-6,7.8-trifluoro-1,4-dihydro-1-nety1-4-oxo- kinolin-3-karboxylsyra (0.22 9). suältpunkt 255-z5s°c. 8005534- Exemgel 8 6.8-difluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1-n-propyl- kinolin-3-karboxylsyrahydrokloríd.The mixture is evaporated to dryness. The residue was treated with water. was extracted into dichloronethane. The organic tet washed: down water. dried over water step sodium sulfate and evaporated. The residue was added to a mixture of 18% hydrochloric acid (5 nl) and ethanol (2.5 nl), and mixed 2.5 tins were refluxed. then water was added (5 nl) and ethanol (5 nl) and cooled, the resulting precipitate was filtered off and recrystallized from a mixture of UHF and ethanol to give 6,7.8-trifluoro-1,4-dihydro-1-methyl-4-oxo- quinoline-3-carboxylic acid (0.22 9). melting point 255 ° C. 8005534- Exemgel 8 6,8-difluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -1-n-propyl- quinoline-3-carboxylic acid hydrochloride.
En blandning av 6,7,8-trifluoro-1,4-dihydro-4-oxo-1-n-propy1- kinolin-3-karboxylsyra (O.22 g), piperazin (0,34 g) och pyri- din (3 ml) återloppskokades 6 timmar. Blandningen indunstades till torrhet. justerades till pH 1 med vattenhaltig saltsyra~ lösning och kyldes. Den fasta substansen filtrerades av och omkristalliserades ur vatten och gav 6.8-difluoro-1.4-dihydro -4-oxo-7-(1-piperazinyl)-1-n-propyl-kinolin-3-karboxylsyrahyd klorid (0,l1 9). smältpunkt 279-282°C (sönderfall).A mixture of 6,7,8-trifluoro-1,4-dihydro-4-oxo-1-n-propyl- quinoline-3-carboxylic acid (0.22 g), piperazine (0.34 g) and pyridine your (3 ml) was refluxed for 6 hours. The mixture was evaporated to dryness. was adjusted to pH 1 with aqueous hydrochloric acid solution and cooled. The solid was filtered off and recrystallized from water to give 6,8-difluoro-1,4-dihydro -4-oxo-7- (1-piperazinyl) -1-n-propyl-quinoline-3-carboxylic acid hydride chloride (0.1.19). mp 279-282 ° C (dec.).
Analys: C H N beräknat för C17H19F2N303 HC1: 52,55 5,20 10,33 fflflfleß 52.46 5.16 10.68 Framställningen av utgångsmaterialet 6.7.8-trifluoro-1,4_¿1_ hydro-4-oxo-1-n-propylkinolin-3-karboxylsyra (smältpunkt 202- -205°C) skedde med samma förfarande som beskrevs för utgångs- materialet i exempel 1 med användning av n-propylbromid istä] let för metyljodid.Analysis: C H N calculated for C 17 H 19 F 2 N 3 O 3 HCl: 52.55 5.20 10.33 f flflfl es 52.46 5.16 10.68 Preparation of starting material 6.7.8-trifluoro-1,4_¿1_ hydro-4-oxo-1-n-propylquinoline-3-carboxylic acid (m.p. 202- -205 ° C) was carried out using the same procedure as described for the material of Example 1 using n-propyl bromide instead of] for methyl iodide.
Exempel 2 1-etyl-7-(4-etyl-1-piperazinyl)-6.B-difluoro-1.4-dihydro-4-ox kinolin-3-karboxylsyra.Example 2 1-ethyl-7- (4-ethyl-1-piperazinyl) -6β-difluoro-1,4-dihydro-4-ox quinoline-3-carboxylic acid.
Trietylamin (0,2 9). l-etyl-6.8-difluoro-1.4-dihydro-4-oxo-7- -(l-piperazinyl)-kinolin-3-karboxylsyrahydrokloríd (0,3 g), etyljodid (0,l9 g) och DM (5 ml) blandades. värmdes under omrörning vid 90°C under 3 timamr och lösningsmedlet avdrevs. Återstoden upplöstes i ZN natriumhydroxidlösning. Den alka- liska lösningen neutraliserades med vattenhaltig ättiksyra oc extraherades med diklorometan. Diklorometanskiktet tvättades med vatten. torkades över vattenfritt natriumsulfat och in- dunstades. återstoden omkristalliserades ur en blandning av DMF och etanol och gav 1-etyl-7-(4-etyl-1-piperazinyl)-6,8- -difluoro-1.4-díhydro-4-oxokinolin-3-karboxylsyra (0,06 g), smältpunkt 236-239°C. 8005534-6 10 Analys: a . C H N beräkn. för Cl8H2lF2N303 1/4H20 53,45 5_3¿ 11_35 fmmet* 58.38 5,14 11 31 §g2ggiggg;_; Antibakteriell aktivitet (in vitro) De antibakteriella aktiviteterna hos föreningarna enligt uppfinningen undersöktes med standardutspädningsmetoden med utstrykning på agar mot gram-positiva och gram-negativa bakterier (Chemotnerapy. 22. 1126 (1974)). Resultaten framgår av tabell 1 tillsammans med resultaten från några kända medel.Triethylamine (0.29). 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7- - (1-piperazinyl) -quinoline-3-carboxylic acid hydrochloride (0.3 g), ethyl iodide (0.9 g) and DM (5 ml) were mixed. was heated during stirring at 90 ° C for 3 hours and the solvent was evaporated. The residue was dissolved in ZN sodium hydroxide solution. The alkaline The aqueous solution was neutralized with aqueous acetic acid and was extracted with dichloromethane. The dichloromethane layer was washed with water. dried over anhydrous sodium sulfate and concentrated fumes. the residue was recrystallized from a mixture of DMF and ethanol to give 1-ethyl-7- (4-ethyl-1-piperazinyl) -6,8- -difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.06 g), mp 236-239 ° C. 8005534-6 10 Analysis: a. C H N calculate. for Cl8H21F2N3O3 1 / 4H2O 53.45 5_3¿ 11_35 fmmet * 58.38 5.14 11 31 §G2ggiggg; _; Antibacterial activity (in vitro) The antibacterial activities of the compounds according to the invention was tested by the standard dilution method with smearing on agar against gram-positive and gram-negative bacteria (Chemotherapy. 22. 1126 (1974)). The results are clear of Table 1 together with the results of some known agents.
Föreningarna enligt exemplen 2. 3, 5, 6, a-och 9 var mer aktiva än nalidixinsyra och pipemidinsyra mot gram-positiva och gram-negativa bakterier.The compounds of Examples 2. 3, 5, 6, a and 9 were more active than nalidixic acid and pipemidic acid against gram-positive and gram-negative bacteria.
Exgeriment 2 Antibakteriell aktivitet (in vivo) Den antibakteriella aktiviteten in vivo hos föreningarna enligt exemplen 2. 3 och 6 bestämdes i systeminfektioner. och resultaten framgår av tabell 2. jämfört med de från AH-715, nalidixinsyra (NA). pipemidinsyra (PPA) och miloxacin (HLX). systeminfektioner orsakades genom inokulering av hanmöss (med en vikt av 20¿2 g) intraperitonealt med följande teststammar, suspenderade i 0,5 ml hjärn-hjärt-infusion innehållande 5 % mucinz Pseudomonas aeruginosa GN11187, 3.3 x 105 celler, Ser- ratia marcescens GN7577, 2.2 x 105 celler, och Staphylococcus aureus Smith, 3.0 x 105 celler. Läkemedlen administrerades oralt till mössen två gånger om dagen, omedelbart efter och 4 timmar efter infektion, och läkemedlens terapeutiska effekt be- dömdes från överlevnadsgraden. En jämförelse av den antibakte- riella in vivo aktiviteten gjordes på basis av den medeleffek~ tiva dosen (EDSO) beräknad med probit-analys. De antibakteri- ella aktiviteterna in vivo från föreningarna enligt exemplen 2, 3 och 6 var klart mer effektiva än de från AM-715, NA, PPA och miloxacin mot systeminfektioner hos möss med varje bakte- rie. 11 0005534-6 Tabell 1 Antibakteriell aktivitet M Minsta inhiberande koncentr. (pg/ml) Förening enl.Exgeriment 2 Antibacterial activity (in vivo) The in vivo antibacterial activity of the compounds according to Examples 2. 3 and 6 were determined in systemic infections. and the results are shown in Table 2. compared to those of AH-715, nalidixic acid (NA). pipemidic acid (PPA) and miloxacin (HLX). systemic infections were caused by inoculation of male mice (with a weight of 202 g) intraperitoneally with the following test strains, suspended in 0.5 ml brain-heart infusion containing 5% mucin Pseudomonas aeruginosa GN11187, 3.3 x 105 cells, Ser- ratia marcescens GN7577, 2.2 x 105 cells, and Staphylococcus aureus Smith, 3.0 x 105 cells. The drugs were administered orally to mice twice daily, immediately after and 4 hours after infection, and the therapeutic effect of the drugs was sentenced from the survival rate. A comparison of the antibacterial riella in vivo activity was done on the basis of the mean effect ~ effective dose (EDSO) calculated by probit analysis. The antibacterial or the in vivo activities of the compounds of the examples 2, 3 and 6 were clearly more effective than those from AM-715, NA, PPA and miloxacin for systemic infections in mice with each bacterial rie. 11 0005534-6 Table 1 Antibacterial activity M Minimum inhibitory concentration. (pg / ml) Association according to
Organismer Ex.2 Ex.3 Ex.5 Ex.6 NA PE Bacillus subtilis PCI219 0-10 0.20 0.20 0.20 6.25 6.1 Staphylococcus aureus 209? 0.39' 0.39 0.78 0.78 100 25 S. aureus ATCC14775 1.56 0.78 1.56 1.56 >100' 10 Eschc-ríchia coli NIHJ 0.05 0.05 0.05 0.05 3.13 1.I E. coli ATCC10536 0.05 0.05 0.05' 0105 13.13 1.f Proteus vulgaris 3167 0.025 0.05 0.05 0.05 3.13 3.] P. vulgaris XK Dçnken 0.05 0.lO_ 0.10 0.39 3.13 6.2 kmåšiènÄ pneuååofliae 1110 5512 0.025 0.025 0.05 0.05 1.56 1.5 Pseudomønas aeruginosa V~l 0.39 1.56 1.56 6.25 100 12.Organisms Ex.2 Ex.3 Ex.5 Ex.6 NA PE Bacillus subtilis PCI219 0-10 0.20 0.20 0.20 6.25 6.1 Staphylococcus aureus 209? 0.39 '0.39 0.78 0.78 100 25 S. aureus ATCC14775 1.56 0.78 1.56 1.56> 100 '10 Eschc-ríchia coli NIHJ 0.05 0.05 0.05 0.05 3.13 1.I E. coli ATCC10536 0.05 0.05 0.05 '0105 13.13 1.f Proteus vulgaris 3167 0.025 0.05 0.05 0.05 3.13 3.] P. vulgaris XK Dçnken 0.05 0.lO_ 0.10 0.39 3.13 6.2 kmåšiènÄ pneuååo fl iae 1110 5512 0.025 0.025 0.05 0.05 1.56 1.5 Pseudomønas aeruginosa V ~ l 0.39 1.56 1.56 6.25 100 12.
P. aeruginosa IF012689 0.78 3.13 3.13 12.5 >200 25 P. aerugínosa 1IDl210 3.13 12.5 >200 50 '1>. aefuginosa 1101130 0.78 3.13 >200 25 Salmonella enteritidiç 11D604 0.20 0.39 12.5 12. shigena smmei 110969 I 0.05 0.05 1.56 1.5 Serratia àarcescens IID6.8 0.10' 0:20 '- S marcescens IID6l9 0.20 0.39 S. marcescens IID620 0.10 0.20 Yefsinia @n:ef°=011:1ca_1109s1 0.10 0.20 0.20 0.39 Acinetobacter anitratus IID876 0.78 0.20 0.39 0.39 Staphylococcus epidermidis IID866 0.78 0.78 1.56 1.56 Streptococcus pyogenes IID692 3.13 6.25 >10O >l00 S. pyogenes S-8 12.5 12.5 >100 >100 s. faecalxs 110682' 6.25 0.25 Diplococcus pneumoníae I1D552 6.25 6.25 >100 >100 Corynvbacterium pyogenes 110548 ' 3.13 6.25 4 100 NA : PPA : Na]idíxínsyra 'Pip0midinsyra 8005534-6 12 Tabell 2 Jämförande aktiviteter av föreningarna enligt exempel 2, 3 och 6, AM-715, NA, PPA och MLX man systeminfeknio- Del".P. aeruginosa IF012689 0.78 3.13 3.13 12.5> 200 25 P. aerugínosa 1IDl210 3.13 12.5> 200 50 '1>. aefuginosa 1101130 0.78 3.13> 200 25 Salmonella enteritidiç 11D604 0.20 0.39 12.5 12. shigena smmei 110969 I 0.05 0.05 1.56 1.5 Serratia àarcescens IID6.8 0.10 '0:20' - S marcescens IID6l9 0.20 0.39 S. marcescens IID620 0.10 0.20 Yefsinia @n: ef ° = 011: 1ca_1109s1 0.10 0.20 0.20 0.39 Acinetobacter anitratus IID876 0.78 0.20 0.39 0.39 Staphylococcus epidermidis IID866 0.78 0.78 1.56 1.56 Streptococcus pyogenes IID692 3.13 6.25> 10O> l00 S. pyogenes S-8 12.5 12.5> 100> 100 s faecalxs 110682 '6.25 0.25 Diplococcus pneumoniae I1D552 6.25 6.25> 100> 100 Corynvbacterium pyogenes 110548 '3.13 6.25 4 100 NA: PPA: Na] idixic acid 'Pipomidic acid 8005534-6 12 Table 2 Comparative activities of the compounds according to examples 2, 3 and 6, AM-715, NA, PPA and MLX man system infection Part".
Tabell 2 305.0 (mg/kg) P. aeruginosa S. marcescens S. aureus förening GN 11187 GN 7577 Smith ex. 2 11,2 14,5 (17,5 ex. 3 9,2 21,3 (17,5 AM-715 38,0 44,9 38,0 NA >400 )400 >4Q0 PPÅ 280 )400 183 MLX 150 78,6 98,4 AM-715 : 1-etyl-6-fluoro-1,Ä-dihydro-7-(1-píperaziny1)~U- -oxokínolín-3-karboxylsyra.Table 2 305.0 (mg / kg) P. aeruginosa S. marcescens S. aureus compound GN 11187 GN 7577 Smith ex. 2 11.2 14.5 (17.5 ex. 3 9.2 21.3 (17.5 AM-715 38.0 44.9 38.0 NA> 400) 400> 4Q0 PPÅ 280) 400 183 MLX 150 78.6 98.4 AM-715: 1-ethyl-6-fluoro-1,1-dihydro-7- (1-piperazinyl) -U- -oxoquinoline-3-carboxylic acid.
Claims (7)
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| JP10677679A JPS5630964A (en) | 1979-08-22 | 1979-08-22 | Novel substituted quinolinecarboxylic acid and its preparation |
| BE2/58706A BE884824A (en) | 1979-08-22 | 1980-08-19 | QUINOLEINE-CARBOXYLIC ACID DERIVATIVES AND PROCESS FOR THEIR PREPARATION |
| BE2059018 | 1981-02-19 |
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| US4416884A (en) * | 1978-04-12 | 1983-11-22 | Otsuka Pharmaceutical Co., Ltd. | Piperazinylbenzoheterocyclic compounds |
| JPS57176987A (en) * | 1981-04-24 | 1982-10-30 | Otsuka Pharmaceut Co Ltd | Pyrrolo(3,2,1-ij)quinoline-5-carboxylic acid derivative |
| NO156828C (en) * | 1980-11-10 | 1987-12-02 | Otsuka Pharma Co Ltd | ANALOGY PROCEDURE FOR THE PREPARATION OF ANTIBACTERYLY EFFECTIVE BENZOHETEROCYCLIC COMPOUNDS. |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL7101049A (en) * | 1970-01-28 | 1971-07-30 | ||
| BE793524A (en) * | 1971-12-30 | 1973-06-29 | Riker Laboratories Inc | BENZOQUINOLIZINE-CARBOXYLIC ACIDS AND THEIR DERIVATIVES |
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| JPS54112877A (en) | 1978-02-20 | 1979-09-04 | Sumitomo Chem Co Ltd | Preparation of 1-substituted-1,4-dihydro-4-oxo-3-pyridine carboxylic acid derivatives |
| DE2953974C2 (en) * | 1978-04-12 | 1992-06-25 | Otsuka Pharmaceutical Co., Ltd., Tokio/Tokyo, Jp | |
| AU553415B2 (en) * | 1983-09-19 | 1986-07-17 | Abbott Japan Co., Ltd. | 6-fluoro-1-4-dihydro-4-oxo-7-substituted piperazinyl- quinoline-3-carboxylic acids |
-
1979
- 1979-08-22 JP JP10677679A patent/JPS5630964A/en active Pending
-
1980
- 1980-08-04 SE SE8005534A patent/SE440353B/en not_active IP Right Cessation
- 1980-08-06 AU AU61122/80A patent/AU533141B2/en not_active Expired
- 1980-08-11 IT IT24111/80A patent/IT1132392B/en active
- 1980-08-14 CH CH614680A patent/CH645641A5/en not_active IP Right Cessation
- 1980-08-19 ES ES494352A patent/ES8104233A1/en not_active Expired
- 1980-08-19 BE BE2/58706A patent/BE884824A/en not_active IP Right Cessation
- 1980-08-21 HU HU802072A patent/HU184817B/en unknown
- 1980-08-21 FR FR8018279A patent/FR2463771A1/en active Granted
- 1980-08-21 CA CA000358778A patent/CA1159454A/en not_active Expired
- 1980-08-21 SU SU802968349A patent/SU978727A3/en active
- 1980-08-22 GB GB8027372A patent/GB2057440B/en not_active Expired
- 1980-08-22 DE DE3031767A patent/DE3031767C3/en not_active Expired - Lifetime
-
1981
- 1981-02-19 BE BE2/59018A patent/BE887574R/en not_active IP Right Cessation
- 1981-03-03 SU SU813254244A patent/SU1015827A3/en active
-
1986
- 1986-09-04 SG SG713/86A patent/SG71386G/en unknown
- 1986-12-18 HK HK984/86A patent/HK98486A/en not_active IP Right Cessation
-
1987
- 1987-12-30 MY MY155/87A patent/MY8700155A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IT1132392B (en) | 1986-07-02 |
| IT8024111A0 (en) | 1980-08-11 |
| BE884824A (en) | 1980-12-16 |
| SU1015827A3 (en) | 1983-04-30 |
| GB2057440B (en) | 1983-10-12 |
| SE8005534L (en) | 1981-02-23 |
| FR2463771B1 (en) | 1983-04-22 |
| SG71386G (en) | 1987-03-27 |
| AU6112280A (en) | 1981-02-26 |
| DE3031767A1 (en) | 1981-03-26 |
| MY8700155A (en) | 1987-12-31 |
| JPS5630964A (en) | 1981-03-28 |
| ES494352A0 (en) | 1981-04-16 |
| AU533141B2 (en) | 1983-11-03 |
| CA1159454A (en) | 1983-12-27 |
| BE887574R (en) | 1981-06-15 |
| FR2463771A1 (en) | 1981-02-27 |
| GB2057440A (en) | 1981-04-01 |
| DE3031767C2 (en) | 1994-04-14 |
| SU978727A3 (en) | 1982-11-30 |
| CH645641A5 (en) | 1984-10-15 |
| ES8104233A1 (en) | 1981-04-16 |
| HU184817B (en) | 1984-10-29 |
| HK98486A (en) | 1986-12-24 |
| DE3031767C3 (en) | 1994-04-14 |
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