CA1222249A - Bactericidal agents based on quinolonecarboxylic acids - Google Patents
Bactericidal agents based on quinolonecarboxylic acidsInfo
- Publication number
- CA1222249A CA1222249A CA000449254A CA449254A CA1222249A CA 1222249 A CA1222249 A CA 1222249A CA 000449254 A CA000449254 A CA 000449254A CA 449254 A CA449254 A CA 449254A CA 1222249 A CA1222249 A CA 1222249A
- Authority
- CA
- Canada
- Prior art keywords
- carbon atoms
- amino
- oxo
- cyclopropyl
- dihydro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- 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
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- 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
- C07D401/12—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 linked by a chain containing hetero atoms as chain links
Abstract
ABSTRACT
Bactericidal agents based on quinolonecarboxylic acids The invention relates to the bactericidal use of new 1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid derivatives of the formula (I)
Bactericidal agents based on quinolonecarboxylic acids The invention relates to the bactericidal use of new 1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid derivatives of the formula (I)
Description
~22Z249 The invention relates to the bactericidal use of new 1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid derivatives.
Certain l-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecar-boxylic acids, such as, for example, l-cyclopropyl-6-fluoro-1,4~
dihydro-4-oxo-7-~1-piperazinyl)-3-quinolinecarboxylic acid, are already known (compare European Patent Specification 49,355).
Only their use in the drugs sector is known, and nothing is known of a microbicidal action in the plant protection sector~
It has furthermore been disclosed that certain quinolone-carboxylic acid derivatives, such as, for example, 7-chloro-1-ethyl-6-fluoro~1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, have a bactericidal action in the plant protection sector (compare European Patent Application 0,203). However, the activity is not always satisfactory when low concentrations are used.
It has been found that the l-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid derivatives of the formula (I) R -N N ~ COOH (I) R4~ ~ R5 in which Rl represents a CO-R6, CN, SO2-R or S-R radical, R6 represents hydrogen, or represents straight--chain or branched alkyl which has 1 to 5 carbon atoms and is optionally mono-, di- or tri-substituted by amino, chlorine, alkoxycarbonyl -;
.
l~ZZZ49 with 1 to 4 carbon atoms in the alkyl part, carboxyl, alkoxy with 1 to 4 carbon atoms, hydroxy or trifluoromethylthio, or represents phenyl which is optionally mono-, di-, tri-, tetra- or penta-substituted by identical or diEferent substituents from the group comprising halogen, hydroxyl, methoxy, amino, nitro and carboxyl, or represents benzyl which is optionally substituted by amino in the methylene radical, or represents alkoxy or alkylthio which has 1 to 5 carbon atoms and is optionally substituted by fluorine, chlorine, pyrazol-l-yl, 1,2,3-triazol-1-yl or N-oxido-2-, -3-L0 or -4-pyridyl, or represents benzyloxy or amino, or represents alkylamino which has 1 to 5 carbon atoms and is optionally sub-stituted by alkoxycarbonyl with 1 to 3 carbon atoms in the alkyl part, benzyloxycarbonyl, carboxyl or halogen, or represents phenylamino, R7 represents straight-chain or branched alkyl which has 1 to 4 carbon atoms and is optionally substituted by 1 to 3 substituents from the group comprising fluorine, chlorine and amino, or represents phenyl or methylphenyl, R8 represents methoxycarbonyl, trichloromethyl or di-chlorofluoromethyl, R2, R3, R4 and R5 represent hydrogen, methyl or ethyl and X represents hydrogen, fluorine, chlorine or nitro, and acid addition, alkali metal and alkaline earth metal salts, heavy metal salts and hydrates thereof, have a bactericidal action in the plant protection sector.
Surprisingly, the l-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid derivatives of the formula (I) have a better bactericidal action than 7--chloro-1,4-dihydro-1-ethyl-6-fluoro-4-oxo-3-quinolinecarboxylic acid, which is a comparable compound known from the prior art and is very closely related chemically and from the point of view of its action. The new use of the active compounds thus represents an enrichment of the art.
Particularly preferred compounds of the formula (I~ are those in which R represents COR6, CN, So2R7 or S-R , R6 represents hydrogen, or represents straight-chain or branched alkyl which has 1 to 4 carbon atoms and is optionally substituted by 1 or 2 '; J
- 4 - ~LZZZ249 substituents from the ~roup comprising amino, alkoxycarbonyl ~ith 1 to 3 carbon atoms in the alkyl part, carboxyl~ alkoxy ~ith 1 to 3 carbon atoms and trifluoromethylthio, or represents S phenyl wh;ch is optionally substituted by 1 to 5 substituents from the group comprising chlorine, hydroxyl, amino and carboxyl, or represents benzyL ~hich is opt;onally substituted by amino in the methylene radical, or represents alkoxy uhiçh has 1 to 4 c3rbon atoms and is optionally substituted by pyrazol-1-yl, 1,2,3 triazol-1-yl or N-oxido-2-~ -3- or -4-pyridyl, or represents alkylthio ~;th 1 or 2 carbon atoms, benzyloxy or amino~ or represents alkylamino which has 1 to 5 carbon atoms and is optionally substituted by alkoxycarbonyl with 1 to 3 carbon atoms in the alkyl part, chlorine or carboxyl, R7 represents straight-chain or branched alkyl w;th 1 to 3 carbon atoms, dichlorofluoromethyl, chlorobutyl, phenyl or methylphenyl, R8 represents methoxycarbonyl, trichloromethyl or dichlorofluoromethyl, R2 represents hydrogen, methyl or ethyl, R3 represents hydrogen, R4 represents hydrogen or methyl~
RS represents hydrogen and X r~presents hydrogen, fluorine, chlorine or nitro~
Specific compounds of the formula (I) to be used according to the invention which may be mentioned are:
30 7-C4-(2-carboxy-3,4,5,6-tetrachlorobenzoyl)-1-p;peraz-inyl~-1-cyclopropy l-6-f luoro-1 ,4-dihydro-4-oxo-3-qu;no-linecarboxylic acid9 7-~4-~3-methoxycarbonyl-propionyl-1-piperazinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 7-~4-(trifluoromethylthio-35 açetyl)-1-piperazinyl]-1-cyc(opropyl-6-fluoro-1,4-di-hydro-4-oxo-3-quinolinecarboxylic acid, 7-C4-prop;onyl-Le A 22 110 - Forei n countries 9 . , _
Certain l-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecar-boxylic acids, such as, for example, l-cyclopropyl-6-fluoro-1,4~
dihydro-4-oxo-7-~1-piperazinyl)-3-quinolinecarboxylic acid, are already known (compare European Patent Specification 49,355).
Only their use in the drugs sector is known, and nothing is known of a microbicidal action in the plant protection sector~
It has furthermore been disclosed that certain quinolone-carboxylic acid derivatives, such as, for example, 7-chloro-1-ethyl-6-fluoro~1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, have a bactericidal action in the plant protection sector (compare European Patent Application 0,203). However, the activity is not always satisfactory when low concentrations are used.
It has been found that the l-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid derivatives of the formula (I) R -N N ~ COOH (I) R4~ ~ R5 in which Rl represents a CO-R6, CN, SO2-R or S-R radical, R6 represents hydrogen, or represents straight--chain or branched alkyl which has 1 to 5 carbon atoms and is optionally mono-, di- or tri-substituted by amino, chlorine, alkoxycarbonyl -;
.
l~ZZZ49 with 1 to 4 carbon atoms in the alkyl part, carboxyl, alkoxy with 1 to 4 carbon atoms, hydroxy or trifluoromethylthio, or represents phenyl which is optionally mono-, di-, tri-, tetra- or penta-substituted by identical or diEferent substituents from the group comprising halogen, hydroxyl, methoxy, amino, nitro and carboxyl, or represents benzyl which is optionally substituted by amino in the methylene radical, or represents alkoxy or alkylthio which has 1 to 5 carbon atoms and is optionally substituted by fluorine, chlorine, pyrazol-l-yl, 1,2,3-triazol-1-yl or N-oxido-2-, -3-L0 or -4-pyridyl, or represents benzyloxy or amino, or represents alkylamino which has 1 to 5 carbon atoms and is optionally sub-stituted by alkoxycarbonyl with 1 to 3 carbon atoms in the alkyl part, benzyloxycarbonyl, carboxyl or halogen, or represents phenylamino, R7 represents straight-chain or branched alkyl which has 1 to 4 carbon atoms and is optionally substituted by 1 to 3 substituents from the group comprising fluorine, chlorine and amino, or represents phenyl or methylphenyl, R8 represents methoxycarbonyl, trichloromethyl or di-chlorofluoromethyl, R2, R3, R4 and R5 represent hydrogen, methyl or ethyl and X represents hydrogen, fluorine, chlorine or nitro, and acid addition, alkali metal and alkaline earth metal salts, heavy metal salts and hydrates thereof, have a bactericidal action in the plant protection sector.
Surprisingly, the l-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid derivatives of the formula (I) have a better bactericidal action than 7--chloro-1,4-dihydro-1-ethyl-6-fluoro-4-oxo-3-quinolinecarboxylic acid, which is a comparable compound known from the prior art and is very closely related chemically and from the point of view of its action. The new use of the active compounds thus represents an enrichment of the art.
Particularly preferred compounds of the formula (I~ are those in which R represents COR6, CN, So2R7 or S-R , R6 represents hydrogen, or represents straight-chain or branched alkyl which has 1 to 4 carbon atoms and is optionally substituted by 1 or 2 '; J
- 4 - ~LZZZ249 substituents from the ~roup comprising amino, alkoxycarbonyl ~ith 1 to 3 carbon atoms in the alkyl part, carboxyl~ alkoxy ~ith 1 to 3 carbon atoms and trifluoromethylthio, or represents S phenyl wh;ch is optionally substituted by 1 to 5 substituents from the group comprising chlorine, hydroxyl, amino and carboxyl, or represents benzyL ~hich is opt;onally substituted by amino in the methylene radical, or represents alkoxy uhiçh has 1 to 4 c3rbon atoms and is optionally substituted by pyrazol-1-yl, 1,2,3 triazol-1-yl or N-oxido-2-~ -3- or -4-pyridyl, or represents alkylthio ~;th 1 or 2 carbon atoms, benzyloxy or amino~ or represents alkylamino which has 1 to 5 carbon atoms and is optionally substituted by alkoxycarbonyl with 1 to 3 carbon atoms in the alkyl part, chlorine or carboxyl, R7 represents straight-chain or branched alkyl w;th 1 to 3 carbon atoms, dichlorofluoromethyl, chlorobutyl, phenyl or methylphenyl, R8 represents methoxycarbonyl, trichloromethyl or dichlorofluoromethyl, R2 represents hydrogen, methyl or ethyl, R3 represents hydrogen, R4 represents hydrogen or methyl~
RS represents hydrogen and X r~presents hydrogen, fluorine, chlorine or nitro~
Specific compounds of the formula (I) to be used according to the invention which may be mentioned are:
30 7-C4-(2-carboxy-3,4,5,6-tetrachlorobenzoyl)-1-p;peraz-inyl~-1-cyclopropy l-6-f luoro-1 ,4-dihydro-4-oxo-3-qu;no-linecarboxylic acid9 7-~4-~3-methoxycarbonyl-propionyl-1-piperazinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 7-~4-(trifluoromethylthio-35 açetyl)-1-piperazinyl]-1-cyc(opropyl-6-fluoro-1,4-di-hydro-4-oxo-3-quinolinecarboxylic acid, 7-C4-prop;onyl-Le A 22 110 - Forei n countries 9 . , _
2;Z~
1-piperazinyl~ cyclopropyl-6-fluoro-1,4-dihydro-4-oxo
1-piperazinyl~ cyclopropyl-6-fluoro-1,4-dihydro-4-oxo
3-quinolinecarboxylic acid, 7-C4-butyryl-1-p;perazinyl]-1-cyclopropyl-6~luoro-1~4-dihydro~4-oxo-3-quinolinecar-boxylic acid~ 7-C4-~4-ch~orobutyryl)-1-piperazinyl~-1-5 cyclopropyL-b-fluoro-1,4-dihydro-4-oxo-3-quinolinecar-boxyl;c ac;d, 7~4-(3-methyl-butyryl)-1-p;perazinyl~-1-cyclopropyl-6-fluoro-1,4-d;hydro-4-oxo-3-quinolinecar-boxylic acid~ 7-~4-(3-methoxypropionyl)-1-piperazinyl~-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid, 7-~4-benzoyl-1-piperazinyl~-1-cyclo-propyl-6-fluoro-1~4-dihydro-4-oxo-3-quinolinecarboxylic acid, 7-[4-(4-nitrobenzoyl)-1-piperazinyl~-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxy~ic acid, 7-t4-t4-aminobenzoyl)-1-piperazinyl~-1-cyclopropyl-6-f~uoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid~ 7-~4-t3-carboxypropionyl)-1-piperazinyl]-1-cyclopropyl-6-fluoro-1,4-d;hydro-4-oxo-3-qu;nolinecarboxylic acid, 7-~4-(4-carboxybutyryl)-1-piperazinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 7-~4-(2-carboxybenzoyl~ piperazinyl~1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 7-~4-(2-carboxy-3,4,5,6-tetrachlorobenzoyl)-1-piperazinyl]-1-cyclopropyl-6-f~uoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid, 7-~4-(3-methoxycarbonyl-propionyl)-1-piperazinyl~-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 7-C4-(hydroxyacetyl)-1-piperaz-inyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4~oxo-3-quino-linecarboxyl;c acid, 7-C4-(aminoacetyl~-1-piperazinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid, 7-C4-(2-aminopropionyl)-1-piperazinyl~-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid, 7-C4-(2-amino-3-methyl-butyryl)-1-piperazinyl~ cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid~ 7-C4-(2-amino-4-methyl-pentan-oyl)-1-p;perazinyl~-1-cyclopropyl-6-fluoro-1,4-dihydro-
4-oxo-3 quinolinecarboxylic acid, 7-C4-(2-hydroxy-4-amino-Le A 22_110 -_Forei~n countr es butyryl~ piperazinyl~-1-cyclopropyl-6-fluoro-1~4-di-hydro-4-oxo-3-quinol;necarboxylic acid, 7-C4-methoxy-carbonyl-1-piperazinyl~ cyclopropyl-6-fluoro-1,4-di-hydro-4-oxo-3-quinolinecarboxylic acid, 7-C4-ethoxy-carbonyC-1-piperaz;nyl~-1-cyclopropyl-6-fluoro-1,4-di-hydro-4-oxo-3-qwinolinecarboxy~ic acid, 7-t4-n-bu~oxy-carbonyl-1-piperazinyl]-1-cyclopropyl-6-fluoro-1,4-di-hydro-4-oxo-3-quinolinecarboxylic acidO 7-t4-tert.-butoxycarbonyl-1-piperazinyl]-1-cyclopropyl-6-~luoro-1,4-d;hydro-4-oxo-3-quinolinecarboxylic acid, 7-~4-C2-(1-pyrazolyl) ~thoxycarbonyl~-1-piperazinyl}-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 7-~4-~2-(1,2,3-triazol-1-yl)-ethoxycarbonyl~-1-piperaz-inyl~-1-cyclopropyl~6-fluoro-1,4-dihydro-4-oxo-3-quino-linecarboxylic acid, 7-C4-(~-chloroethoxycarbonyl)-1-piperazinyl~-1-cycLopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic ac;d, 7-~4-t(N-oxido-3-pyridyl)-methoxycarbonyl~-1-piperazinyl}-1-cyclopropyl-6-fluoro-1~-dihydro-4-oxo-3-quinolinecarboxylic acid, 7-C4-car-bamoyl-1-piperazinyl]-1-cyclopropyl-6-fluoro-1,4-d,hydro-4-oxo-3-quinolinecarboxylic acid, 7-C4-methylcarbamoyl-1-piperazinyl~-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 7-C4-hexylcarbamoyl-1-piperaz-inyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quino-linecarboxylic acid, 7-C4-phenylcarbamoyl-1-piperazinyl~-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid, 7-4-C(3-m~thoxycarbonylpropyl)-carbam-oyl]-1-piperazinyl}-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 7-~4-C(5-methoxycarbon-ylpentyl)-carbamoyl]-1-piperazinyl}~1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 7-~4-t(3-carboxypropyl)-carbamoyl~-1-piperazinyl~ cyclo-propyl-6~fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 7- 4 t(5-carboxypentyl)-carbamoyl~-1-piperazinyl~-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-qu;noline-carboxylic acid, 7~ (2-propoxycarbonyl)-carbamoyl~
Le A 22 110 - Foreian countries 7 ~2~2249 p;peraz;nyl}-1-cyclopropyl 6-fluoro-1~4~dihydro-~-oxo-3-quinol;necarboxyl;c ac;d, 7-~4-~(2-carboxyethyl~-carbam-oyl~ p;peraz;nyl~-1-cyclopropyl-6-fluoro~1,4~dihydro~
4-oxo-3-quinolinecarboxylic acid, 7-t4-dimethy~carbamoyl-1-piperazinyL~-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxyLic acid, 7-4-~(4-chlorobutyl~-carbam-oyl~-1-piperazinyl~-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo 3-quinolinecarbsxylic acid, 7-~4-cyano-1-piperazin-yl~-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid, 7-~4-tr;chloromethanesulphenyL-1-piperaz-inyl3-1- cyclo~ropyl-6-fluoro-1,4-dihydro-4-oxo-3-quino-linecarboxylic acid, 7-~4-methoxycarbonylsulphenyl-1-piperaz;nyl]-1-cyclopropyL-6-f~uoro-1,4-dihydro-4-oxo-3 quinolinecarboxyl;c acid, 7-~4-methanesulphonyl-1-piperazinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 7-C4-dichlorofluoromethane-sulphonyl-1-piperazinyl~~1~cyclopropyl-6-fluoro-1,4-di-hydro-4-oxo-3-quinolinecarboxylic acid, 7-t4-n-propane-sulphonyl-1-piperaz;nyl~-1-cyclopropyl-6-fluoro-1,4-di-hydro-4-oxo 3-quinolinecarboxylic acid, 7-~4-(4-chloro-butanesulphonyl)-1 piperazinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 7-C4-perfluorobutanesulphonyl-1-piperazinyl]-1-cyclo-propyl-6-fluoro-1,4-dihydro 4-oxo-3-quinolinecarboxylic acid, 7-t4-acetyl-3-methyl-1-piperazinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3 quinol;necarboxylic acid, 7-~3-methyl-4-prop;onyl-1-p;perazinyl]-1-cyclopropyl-6 fluoro-1,4-d;hydro-4-oxo-3-quinol;necarboxylic acid, 7-~3-methyl-4-methylcarbamoyl-1-piperaz;nyl~-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxyl;c acid, 7-~2,5-dimethyl-4-formyl-1-p;perazinyl]-1-cyclopropyl-~-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 7-~2,5-dimethyl-4-butyryl-1-piperazinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 7-~3,5-dimethyl-4-acetyl-1-piperazinyl3-1~cyclopropyl-6-fluoro-1,4-d hydro-4-oxo-3-quinol;necarboxylic acid, 7-L A 22 11û Fore; n countries e 9 ~L222Z~9 [3,5-dimethyl-4-carbamoyl-1-piperazinyl]-1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid, 6-(4-butyryl-1-piperazinyl)-l-cyclopropyl-1,4-dihydro-6-nitro-4-oxo-3-quinoline-carboxylic acid, 7-(4-butyryl-1-piperazinyl)-6-chloro-~-cyclopropyl 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 7-(4-butyryl-1-piperazinyl)-l-cyclopropyl-1,4-dihydro-4-oxo-3-quinolincarboxylic acid, 7-[4-(2-aminopropionyl)-3-methyl-1-piperazinyl]-1-cyclo-propyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 7-(4-butyryl-3,5-dimethyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.
If appropriate, the compounds of the formula (I) which can be used according to the invention can be converted into a salt with an organic or inorganic acid. Examples of suitable acids for salt formation are hydrogen halide acids, such as hydrochloric acid, hydrobromic acid and hydriodic acid, and sulphuric acid, acetic acid, citric acid, ascorbic acid, methane-sulphonic acid and benzenesulphonic acid. Suitable alkali metal salts and alkaline earth metal salts are, preferably, the sodium, potassium, calcium and magnesium salts, and suitable heavy metal salts are, preferably, the copper, zinc and manganese salts.
The active compounds to be used according to the invention are not yet known. However, they are the subject of an earlier patent application which has been filed by the Applicant Company and has not yet been published ~Canadian Patent Application No. 448,124] and are obtained by a process in which f ~ZZ~:~9 - 8a -a) a compound of the formula ~II) R2 ~ COOH (II) H~
\~
~"
_ 9 ~ Z249 in ~hich X, R2~ R3, R4 and R5 have the abovementioned meanings, ;s reacted ~;th a compound of the formula (III)~
R1_y (III) in wh;ch R1 has the abovement;oned meaning and Y represents a leaving group, such as halogen, preferably chlorine, fluorine or brom;ne, or methoxy, ethoxy, phenoxy, 4-nitrophenoxy or 2O3,5-trichlorophenoxy~ or 3 lkoxycarbonyloxy, or in which b) compounds of the formula (I~) -o ~COOEI
H~_<`J ~ ( I I ) R~ R~
in which R2, R3, R4, R5 and X have the abovementioned meaning, are reacted with isocyanates of the formula (IV) R'-NC0 (IV) in ~hich R' denotes optionally substituted alkyl or phenyl, to give the compounds of the formula (Ia) according to the invention Le A 22 110 - Fore; n countr;es 1 o ~2~ 2~9 ~-NH-CO~ f~
~4 in ~hich R', R2, R3~ R40 ~5 and X have the above-mentioned meaning, or in which c) compounds of the formula (II) ~ X ~ OOH
~' 1 ' ~ R~
in which R2, R3, R4, R5 and X have the abovementioned meaning, are reacted with anhydrides of the formula (V) ~CO~ (V) ~CO
;n ~hich A denotes an opt;onally substituted alkylene chain with Z or 3 carbon atoms or an arylene radical, to give the compounds of the formula (Ib) according to the invention ~ ~COO~
~OGG-A-CO_~ ~ ' ~ (Ib) R ~ R
~herein Le A 22 110 ~ Foreign countr;es :~2~24~
R2O R3~ R4, R5, X and A have the above-ment;oned meaning.
The compounds of the formula (II) used as start-ing compounds can be prepared by reacting compounds of the formula (VI~
o X~ fOOH (VI) Cl with piperazine or piperazine derivatives of the formula (VII) R~ R~
R4~ P~ (VII) This reaction is carried out in a diluent, such as, for example, dimethylsulphoxide, hexamethylphosphoric acid triamide, sulpholane, water, an alcohol or pyridine, at temperatures of 20 - 200C, preferably at 80 - 180C.
In carrying out the process, 1 - 15 moles of the compound 15 (VII), preferably 1 - 6 moles of the compound (VII), is employed per mole of carboxylic acid (VI). If equivalent amounts of the carboxylic acid (VI) and the piperazine derivative (VII) are used, the reaction is carried out in the presence of an acid-binding agent, for example triethylamine, 1,4-diaza-bicyclo-~2.2.2]-octane or 1,8-diaza-bicyclo[5.4.0~undec-7-ene.
The 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of the formula V~a (VI;
X ~ F) used as the intermediate can be prepared in accordance with the following equation:
Le A 27 110 ~ Forei~n countries :~;Z22249 F~COCl ~ 2 5 ~1 1 ~COOCl ~S
(1) (2 , COC)C2 ~ F l::-C~2 COOC
F~ --COOC~ ~5 Cl ~ Cl ( 3 ) O
0 11 .
C1~ --C-COOC,1~, F~ --C-CO~C2~ -(;) (6) . ~ .
(7) According to this equation, diethyl malonate (2) ;s acylated in the presence of a magnesium alcoholate ~ith 2,4-dichloro-5-fluoro-benzoyl chloride (1) CGerman Patent Application No. 3 142 856.8~ to give the acylmalonate (3) tOrganikum, 3rd edition 1964, page 438~.
Part;al hydrolysis and decarboxylation of (3) in an aqueous medium ~;th catalytic amounts of p~toluene-Le A 2Z 110 - Foreign countries 122;2~49 sulphonic acid gives a good yield of the ethy~ aroyl-acetate (4), which ;s converted into ethyl 2-(2,4-di-chloro-5-fluoro-benzoyl3-3-e~hoxy-acrylate (S) with o-formic acid triethyl estertacetic anhydride. The reac-tion of (5) with cyclopropylamine in a solvent, such as,for example, methylene chlor;de, alcohol, chloroform, cyclohe%ane or toluene~ leads to the desired intermediate (6) in a slightly exothermic reaction.
The cyclisation reaction (6) ~ ~(7~ is carried out in a temperature range from about 60 to 280C, preferably 80 to 180C.
Dioxane, d;methylsulphoxide, N-methyl pyrrolidone, sulpholane, hexamethylphosphoric acid triam;de and, preferably, N,N-dim~thyLformamide can be used as the diluent.
Possible acid-binders for this reaction stage are potassium tert.-butanolate, butyl-lithium, lithium-phenyl, phenyl-magnesium bromide, sod;um methylate, sodium hydride and, particularly preferably, potassium carbonate or sodium carbonate. It may be advantageous to use an excess of 10 mole X of base.
~ The ester hydrolysis of (7) under basic or acid conditions which takes place in the last step leads to 7-chloro-1-cyclopropyl-6-fluoro-1,4 dihydro-4-oxo-3-quinolinecarboxylic acid VIa.
The 2,4-dichloro~S-fluoro-benzoyl chloride ~1) used as the start;ng material for this synthesis route and the corresponding carboxylic acid, and the 3-fluoro-4,6-dichlorotoluene (10~ required for the preparation of (1) are prepared in accordance with the following equa-tion, starting from 2,4-dichloro-5-methyl-aniline (8~:
Le A 22 110 - Forei n countries 9_ .
1 4 _ P222249 c~3 C ~ 1 ~a'~O 2 ' ~ 3 ~
~Y2 ~ (Cr3) 3 Cl (3 CCl (10) (11 ) COCl COOR Cl ~
Cl ~ ~ ~ r Cl ~12) (1) According to this equation, 2,4-dichloro-5-methyl-anil;ne (8) is diazot;sed w;th the aid of NaN02 and the diazon;um salt thereby formed is converted ;nto the tri-azene (9) with dimethylamine.
The triazene (9) is dissolved in aqueous anhydrous HF. The triazene thereby splits ;nto 2,4-dichloro-5-methyl-diazonium fluor;de and dimethylamine. This solu-tion is split, ~ithout intermediate isolation, under the influence of heat at 130 - 140C into 3~fluoro-4,6-di-chlorotoluene (10~, N? being split off. Yield: 77.7%
of theory.
Le A 22 110 - Foreign countries :~Z2Z;249 The 3-fluoro-4,6~dichlorotoluene (10) ;s chlorina-ted in a temperature range of 110 - 160C under irrad;a-tion w;th UV l;ght to give 2,4 dichloro-S-fluoro-1~tri-chloromethylbenzene (11).
Hydrolysis of (11) ~ith 95X strength sulphuric acid leads to 2,4-dichloro 5-fluoro-benzoic acid t12), ~hich ;s converted into the carboxylic acid chloride (1) (boiling point 121/20 mbar; n20 1.5722) ~ith ~hionyl chloride.
The following quinolonecarboxylic acids used as intermediates are prepared in an analogous manner.
7-Chloro-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid (Vlb) (melting point 308C) from 2,4-dichlorobenzoyl chloride (J. Chem. Soc. 83, 1213 (1903~));
o ,~,COOH
Cl~ (VIb) i 6,7-Dichloro-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid (VIc) (melting point 265C) from 2,4,5-trichlorobenzoyl chloride tLiebigs Ann. Chem. 152, 238 (1896)];
o Cl ~ 00~
~ (VIc) Cl 7-Chloro-1-cyclopropyl-1,4-dihydro 6-nitro-4-oxo-3-quino-linecarboxylic acid (VId) ~melting point 265 - 275C
decomposition~ from 2,4-dichloro-5-nitro-benzoyl chloride (Liebigs Ann~ Chem. 677, 8 (1964)).
Le A 22 110 - Forei~n countries ~2Z2~
- 16 ~
a ~,~3,C O 01~ ( V I d ) The compounds of the formula (III) ~hich can be used as starting substances are already known.
The ;socyanates ~IV) ~hich can be used as start-;ng compounds are also kno~n, as are the anhydr;des (V).
The reaction of (II) with ~III) (method a) is preferably carried out in a diluent, such as dimethyl-sulphox;de, N,N-d;methyLformam;de, tetrahydrofuran, sulpholane, dioxane~ pyridine or ~ater or in m;xtures of these diluents, at temperatures of 0C - 140C, preferably 1 0C -- 1 1 [)1 r The reaction can be çarried out under normal pressure, but also under increased pressure. In general, it is carried out under pressures between about 1 and about 100 bar, preferably between 1 and 10 bar.
All the customary inorganic and organic ac;d-bind;ng agents can be used as the ac;d-b;nders. These ;nclude, preferably, the alkaL; metal hydroxides and alkal; metal carbonates, pyr;d;ne and tert;ary am;nes, such as tr;ethylam;ne and 1,4-d;azab;cycloC2.2.2]octaneO
In carry;ng out process var;ant a), 1 to 4 moles, preferably 1 to 1.5 moLes, of the compound (III) ar~
employed per mole of the compound ~II).
The reaction of (II) w;th (IV) (method b) is preferably carr;ed out ;n a d;luent, such as, for example, d;oxane, dimethylsulphoxide, N,N-dimethyLform-amide or dilute sodium hydroxide solution, or in mixtures of these diluents.
The reaction temperatures can be varied ~ithin a substantial range~ In general, the reaction is carried out between about 0C and about 100C, preferably between Le A 22 110 - Forei~n_countr;es _ 5C and 50C.
The reaction can be carried out under normal pressure, but also under increased pressure. In general, it is carried out under pressures between about 1 and about 100 bar, preferabLy between 1 and 10 bar.
In carrying out process var;ant b), 1 - 5 moles~
preferably 1 - 2 moles, of the compound ~IV) are employed per mole of the compound (II).
The react;on of (II) with tV~ tmethod c) is carried out in a diluent, such as, for example, N,N-dimethylformamide, dioxane, tetrahydrofuran, pyridine or water, or in mixtures of these diluent~. The reaction temperatures can be varied within a substantial range.
In general, the reaction is carried out between about q 15 and about 14ûC, preferably between 10 and 100C. --The reaction can be carried out under normal pressure, but also under increased pressure. In general, ;t is carried out under pressures bet~een about 1 bar and about 100 bar, preferably between 1 and 10 bar.
All the customary inorganic and organic acid bind;ng agents can be used as the acid-binder. These include, preferably, the alkali metal hydroxides and alkali metal carbonates, pyridine and tertiary amines~
such as tr;ethylamine and 1,4-diazabicyclo~2.2.2]octane.
In carrying out process variant c), 1 to 3 moles, preferably 1 to 1.3 moles, of the compound (V) are employed per moLe of the compound (II).
The active compounds to be used according to the invention exhibit a powerful microbicidal action and can be employed in practice for combating undesired micro-organisms. The active compounds are suitable for use as plant protection agents.
Bacter;cidal agents are used in plant protection for combating Pseudomonadaceae, Rhizobiaceae, Entero-bacteriaceae, Corynebacteriaceae and Streptomycetaceae.
The active compounds to be used according to ~heLe A 22 110 - Foreign countries ~Z2;~4~
;nvention also exh;bit a qood fung;cidal action, for example aga;nst Pyricular;a oryzae on rice.
The good tolerat;on9 by plants, of the active compounds, at the concentrations required for combating plant diseases, permits treatment of above-ground parts of plants, of vegetative propagat;on stock and seeds~ and of the soil.
The active compounds can be converted to the cus-tomary formulations~ such as solutions, emulsions, sus-pensions, powders, foams, pastes, granules, aerosols,very fine capsules ;n polymeric substances and in coating compos;tions for seed, and ULY formulations.
These formulations are produced ;n known manner, for example by mixing the active compounds with exten-ders, that is, liquid solvents, liquefied gases under:pressure, and/or solid carriers, optionally ~ith the use of surface-active agents, that is, emulsifying agents and/or dispersing agents, and/or foam-forming agents.
In the case of the use of water as an extender, organic solvents can, for example, also be used as auxiliary sol-vents. As liquid solvents, there are suitable in the main: aromatics, such as xylene, toluene or alkyl naphthalenes~ chlorinated aromatiçs or chlorinated ali-phatic hydrocarbons, such as chlorobenzenes, chloro-ethylenes or methylene chloride, aliphatic hydrocarbons,such as cyclohexane or paraffins, for example mineral o;l fractions, alcohols, such as butanol or glycol as ~ell as their ethers and esters, ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone or cyclohexanone, strongly polar solvents, such as dimethylformamide and dimethylsulphoxide, as well as water. By liquefied gaseous extenders or carriers arP meant liquids which are gaseous at normal temperature and under normal pressure, for example aerosol propellants, such as halogenated ~5 hydrocarbons as well as butane, propane, nitrogen and carbon dioxide. As solid carriers there are suitable:
Le A 22 110 - Forei n countries 12~2Z~49 for example ground natural m;nerals, such as kaolins, clays~ talc~ cha~k, quartz, attapulgite, montmoriLlonite or d;atomaceous earth, and ground synthetic m;nerals, such as highly-dispersed silicic acid, alumina and sili-cates. As solid carriers for granules there are suitable:for example crushed and fractionated natural rocks such as calcite, marble~ pumice~ sepiolite and dolomite, as ~ell as synthEtic granules of inorganic and organ;c meals, and granules of organic material such as sawdust~
coconut shells, maize cobs and tobacco staLks. As emul-s;fying and/or foam-forming agents there are suitable:
for example non-ionic and anionic emulsifiers, such as polyoxyethylene-fatty acid esters, polyoxyethylene-fatty alcohol ethers, for example alkylaryl po~yglycol ether~s, alkyl sulphonates, alkyl sulphates, aryl sulphonates -as well as album;n hydrolysation products. As dispersing agents there are suitable: for example lignin-sulphite waste liquors and methylcellulose.
Adhesives such as carboxymethylcellulose ande natural and synthetic polymers in the form of powd~rs, granules or latices, such as gum arabic, polyvinyl alco-hol and polyvinyl acetate, and natural phospholipids, such as cephalins and lecithins, and synthetic phospholipids, can be used in the formulations. Further additives can be m;neral and vegetable oils.
It is possible to use colorants such as inorganic pigments, for example iron oxide, titan;um oxide and Prussian Blue, and organic dyestuffs, such as alizar;n dyestuffs, azo dyestuffs and metal phthalocyanine dye-stuffs, and trace nutrients such as salts of iron, man-ganese, boron, copper, cobalt, molybdenum and zinc.
The formulations in general contain bet~een 0~1 and 95 per cent by ~eight of active compound, preferably between 0.5 and 90%.
The active compounds according to the invention can be present in the formulations as a mixture ~ith Le A 22 110 - Foreign countries ~;~2;~ 49 - ZO
other known active compounds, such as fungicides, insect-cides, acaric;des and herbic;des, and in mixtures with fertil;sers and growth regulators.
The active compounds can be used as such or in the form of their formulations or the use forms prepared therefrom, such as ready-to-use solutions, emulsifiable concentrates, emuls;onsO foams, suspensions, ~ettable po~ders, pastes, soluble powders, dusts and granules~
They are used in the customary manner, for example by water;ng, spray;ng, atomising, scattering, dusting, foaming, coating and the like. It is fur~hermore pos-sible to apply the active compounds by the ultra~low volume process or to inject the formulation of active compound or the act;ve compound ;tself ;nto the soil.
The seed of plants can also be treated.
~n the treatment of parts of plants, the active compound concentrations in the use forms can be varied with;n a substantial range. They are, in general, bet~een 1 and 0.0001X by weight, preferably bet~een 0.5 and 0.001~.
In the treatmer,t of seed, amounts of active com-pound of 0.001 to 50 9 per kilogram of seed~ preferably 0.01 to 10 9, are generally required.
For the treatment of soil, active compound con-centrations of 0.00001 to 0.1X by ~eight, preferably 25 0.0001 to 0.02X, are required at the place of action.
Preparat;on Examples I Startin~ compounds ~.~
o F~5 O O H
~J ~
A mixture of 19.7 9 of 7-chloro-1-cyclopropyl-6-fluoro-1,4-d;hydro-4-oxo-3-qu;nolinecarboxylic acid, 30.1 9 of anhydrous piperazine and 100 ml of dimethyl-sulphoxide is heated at 135 - 140C for 2 hours~ The Le A 22 110 - Forei n countries 9 __ 2;~4~
solvent is d;stilled off under a fine vacuum and the res;due is suspended in H20~ filtered off w;th suct;on and washed w;th water. For further purification~ the mo;st crude product is boiled up ~;th 100 ml of uater, f;ltered off with suction at room temperature~ ~ashed w;th H20 and dr;ed to constant weight over CaCl2 at 100C in a vacuum drying cabinet. 19.6 9 of 1-cyclo-propyl 6-fluoro-1f4-dihydro-4-oxo-7-(1-pipera2inyl)-3 quinolinecarboxylic ac;d of decomposit;on po;nt 255 -257C are obtained.
The 7-chloro~1-cyclopropyl-6-fluoro-1,4-d;hydro-4-oxo-3-quinolinecarboxyl;c ac;d VIa used as the s~arting material ;s prepared as follows:
24.3 9 of magnes;um f;l;ngs are suspended in 50 ml of anhydrous ethanol. 5 ml of carbon tetrachlot;de are added and, when the react;on has started, a mixture of 160 9 of diethyl malonate, 100 ml of absolute ethanol and 4~0 ml of anhydrous ether is added drspw;se, where-upon v;gorous reflux ;s to be observed. When the reaction has subs;ded, the mixture ;s heated at the boiLing point for a further 2 hours and cooled to -5C to ~1ûC with dry ;ce/acetone, and a solut;on of 227.5 9 of 2,4-d;-chloro-5-fluoro-benzoyl chloride (1) in 1ûO ml of abso-lute ether is slowly added drop~;se at th;s temperature.
The mixture is stirred at 0C to -5C for 1 hour and ;s allowed to come to room temperature overnight, and a mixture of 400 ml of ice-water and 25 ml of concentrated sulphuric acid ;s allo~ed to run ;n, wh;le cool;ng with ice. The phases are separated and subsequently extracted twice ~ith ether. The comb;ned ether solutions are ~ashed ~ith saturated NaCl solution and dried with Na2S04 and the solvent is stripped off in vacuo. 349.5 9 of diethyl 2,4-dichloro-5-fluoro benzoylmalonate ~3) are obtained as the crude product.
0.15 9 of p-toluenesulphonic acid ;s added to an emuls;on of 34.9 9 of crude d;ethyl 2,4-d;chloro-5-fluoro-Le A ?2 110 ~ Foreign countries ~.~ZZ;~4g benzoylmaLonate C3) in S0 ml of ~ater. The mixture is heated at the bo;l;ng point for 3 hours, while stirring thoroughLy, the cooled emulsion is extracted several t;mes with methylene chloride, the comb;ned CH2Cl2 solutions are ~ashed once ~ith saturated NaCl solution and dried with Na2S04 and the solvent is distilled off in vacuo. Fractionation of the residue in vacuo gives 21.8 g of ethyl 2,4-dichloro-5-fluoro-benzoyl-acetate (4) of boiling point 127 - 142C/0.09 mbar.
A mixture of 21.1 9 of ethyl Z,4 dichloro-5-fluoro-benzoyl-acetate (4), 16.65 9 of ethyl o-formate and 18 55 9 of acetic anhydride is heated at 150C for 2 hours. The volatile constituents are then distilled off under a waterpump vacuum and, finally, under a fine vacuum, at a bath temperature of 120C. 25~2 9 of crude ethyl 2-t2,4-dichloro-5-benzoyl)-3-ethoxy-acrylate
Le A 22 110 - Foreian countries 7 ~2~2249 p;peraz;nyl}-1-cyclopropyl 6-fluoro-1~4~dihydro-~-oxo-3-quinol;necarboxyl;c ac;d, 7-~4-~(2-carboxyethyl~-carbam-oyl~ p;peraz;nyl~-1-cyclopropyl-6-fluoro~1,4~dihydro~
4-oxo-3-quinolinecarboxylic acid, 7-t4-dimethy~carbamoyl-1-piperazinyL~-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxyLic acid, 7-4-~(4-chlorobutyl~-carbam-oyl~-1-piperazinyl~-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo 3-quinolinecarbsxylic acid, 7-~4-cyano-1-piperazin-yl~-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid, 7-~4-tr;chloromethanesulphenyL-1-piperaz-inyl3-1- cyclo~ropyl-6-fluoro-1,4-dihydro-4-oxo-3-quino-linecarboxylic acid, 7-~4-methoxycarbonylsulphenyl-1-piperaz;nyl]-1-cyclopropyL-6-f~uoro-1,4-dihydro-4-oxo-3 quinolinecarboxyl;c acid, 7-~4-methanesulphonyl-1-piperazinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 7-C4-dichlorofluoromethane-sulphonyl-1-piperazinyl~~1~cyclopropyl-6-fluoro-1,4-di-hydro-4-oxo-3-quinolinecarboxylic acid, 7-t4-n-propane-sulphonyl-1-piperaz;nyl~-1-cyclopropyl-6-fluoro-1,4-di-hydro-4-oxo 3-quinolinecarboxylic acid, 7-~4-(4-chloro-butanesulphonyl)-1 piperazinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 7-C4-perfluorobutanesulphonyl-1-piperazinyl]-1-cyclo-propyl-6-fluoro-1,4-dihydro 4-oxo-3-quinolinecarboxylic acid, 7-t4-acetyl-3-methyl-1-piperazinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3 quinol;necarboxylic acid, 7-~3-methyl-4-prop;onyl-1-p;perazinyl]-1-cyclopropyl-6 fluoro-1,4-d;hydro-4-oxo-3-quinol;necarboxylic acid, 7-~3-methyl-4-methylcarbamoyl-1-piperaz;nyl~-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxyl;c acid, 7-~2,5-dimethyl-4-formyl-1-p;perazinyl]-1-cyclopropyl-~-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 7-~2,5-dimethyl-4-butyryl-1-piperazinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 7-~3,5-dimethyl-4-acetyl-1-piperazinyl3-1~cyclopropyl-6-fluoro-1,4-d hydro-4-oxo-3-quinol;necarboxylic acid, 7-L A 22 11û Fore; n countries e 9 ~L222Z~9 [3,5-dimethyl-4-carbamoyl-1-piperazinyl]-1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid, 6-(4-butyryl-1-piperazinyl)-l-cyclopropyl-1,4-dihydro-6-nitro-4-oxo-3-quinoline-carboxylic acid, 7-(4-butyryl-1-piperazinyl)-6-chloro-~-cyclopropyl 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 7-(4-butyryl-1-piperazinyl)-l-cyclopropyl-1,4-dihydro-4-oxo-3-quinolincarboxylic acid, 7-[4-(2-aminopropionyl)-3-methyl-1-piperazinyl]-1-cyclo-propyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 7-(4-butyryl-3,5-dimethyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.
If appropriate, the compounds of the formula (I) which can be used according to the invention can be converted into a salt with an organic or inorganic acid. Examples of suitable acids for salt formation are hydrogen halide acids, such as hydrochloric acid, hydrobromic acid and hydriodic acid, and sulphuric acid, acetic acid, citric acid, ascorbic acid, methane-sulphonic acid and benzenesulphonic acid. Suitable alkali metal salts and alkaline earth metal salts are, preferably, the sodium, potassium, calcium and magnesium salts, and suitable heavy metal salts are, preferably, the copper, zinc and manganese salts.
The active compounds to be used according to the invention are not yet known. However, they are the subject of an earlier patent application which has been filed by the Applicant Company and has not yet been published ~Canadian Patent Application No. 448,124] and are obtained by a process in which f ~ZZ~:~9 - 8a -a) a compound of the formula ~II) R2 ~ COOH (II) H~
\~
~"
_ 9 ~ Z249 in ~hich X, R2~ R3, R4 and R5 have the abovementioned meanings, ;s reacted ~;th a compound of the formula (III)~
R1_y (III) in wh;ch R1 has the abovement;oned meaning and Y represents a leaving group, such as halogen, preferably chlorine, fluorine or brom;ne, or methoxy, ethoxy, phenoxy, 4-nitrophenoxy or 2O3,5-trichlorophenoxy~ or 3 lkoxycarbonyloxy, or in which b) compounds of the formula (I~) -o ~COOEI
H~_<`J ~ ( I I ) R~ R~
in which R2, R3, R4, R5 and X have the abovementioned meaning, are reacted with isocyanates of the formula (IV) R'-NC0 (IV) in ~hich R' denotes optionally substituted alkyl or phenyl, to give the compounds of the formula (Ia) according to the invention Le A 22 110 - Fore; n countr;es 1 o ~2~ 2~9 ~-NH-CO~ f~
~4 in ~hich R', R2, R3~ R40 ~5 and X have the above-mentioned meaning, or in which c) compounds of the formula (II) ~ X ~ OOH
~' 1 ' ~ R~
in which R2, R3, R4, R5 and X have the abovementioned meaning, are reacted with anhydrides of the formula (V) ~CO~ (V) ~CO
;n ~hich A denotes an opt;onally substituted alkylene chain with Z or 3 carbon atoms or an arylene radical, to give the compounds of the formula (Ib) according to the invention ~ ~COO~
~OGG-A-CO_~ ~ ' ~ (Ib) R ~ R
~herein Le A 22 110 ~ Foreign countr;es :~2~24~
R2O R3~ R4, R5, X and A have the above-ment;oned meaning.
The compounds of the formula (II) used as start-ing compounds can be prepared by reacting compounds of the formula (VI~
o X~ fOOH (VI) Cl with piperazine or piperazine derivatives of the formula (VII) R~ R~
R4~ P~ (VII) This reaction is carried out in a diluent, such as, for example, dimethylsulphoxide, hexamethylphosphoric acid triamide, sulpholane, water, an alcohol or pyridine, at temperatures of 20 - 200C, preferably at 80 - 180C.
In carrying out the process, 1 - 15 moles of the compound 15 (VII), preferably 1 - 6 moles of the compound (VII), is employed per mole of carboxylic acid (VI). If equivalent amounts of the carboxylic acid (VI) and the piperazine derivative (VII) are used, the reaction is carried out in the presence of an acid-binding agent, for example triethylamine, 1,4-diaza-bicyclo-~2.2.2]-octane or 1,8-diaza-bicyclo[5.4.0~undec-7-ene.
The 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of the formula V~a (VI;
X ~ F) used as the intermediate can be prepared in accordance with the following equation:
Le A 27 110 ~ Forei~n countries :~;Z22249 F~COCl ~ 2 5 ~1 1 ~COOCl ~S
(1) (2 , COC)C2 ~ F l::-C~2 COOC
F~ --COOC~ ~5 Cl ~ Cl ( 3 ) O
0 11 .
C1~ --C-COOC,1~, F~ --C-CO~C2~ -(;) (6) . ~ .
(7) According to this equation, diethyl malonate (2) ;s acylated in the presence of a magnesium alcoholate ~ith 2,4-dichloro-5-fluoro-benzoyl chloride (1) CGerman Patent Application No. 3 142 856.8~ to give the acylmalonate (3) tOrganikum, 3rd edition 1964, page 438~.
Part;al hydrolysis and decarboxylation of (3) in an aqueous medium ~;th catalytic amounts of p~toluene-Le A 2Z 110 - Foreign countries 122;2~49 sulphonic acid gives a good yield of the ethy~ aroyl-acetate (4), which ;s converted into ethyl 2-(2,4-di-chloro-5-fluoro-benzoyl3-3-e~hoxy-acrylate (S) with o-formic acid triethyl estertacetic anhydride. The reac-tion of (5) with cyclopropylamine in a solvent, such as,for example, methylene chlor;de, alcohol, chloroform, cyclohe%ane or toluene~ leads to the desired intermediate (6) in a slightly exothermic reaction.
The cyclisation reaction (6) ~ ~(7~ is carried out in a temperature range from about 60 to 280C, preferably 80 to 180C.
Dioxane, d;methylsulphoxide, N-methyl pyrrolidone, sulpholane, hexamethylphosphoric acid triam;de and, preferably, N,N-dim~thyLformamide can be used as the diluent.
Possible acid-binders for this reaction stage are potassium tert.-butanolate, butyl-lithium, lithium-phenyl, phenyl-magnesium bromide, sod;um methylate, sodium hydride and, particularly preferably, potassium carbonate or sodium carbonate. It may be advantageous to use an excess of 10 mole X of base.
~ The ester hydrolysis of (7) under basic or acid conditions which takes place in the last step leads to 7-chloro-1-cyclopropyl-6-fluoro-1,4 dihydro-4-oxo-3-quinolinecarboxylic acid VIa.
The 2,4-dichloro~S-fluoro-benzoyl chloride ~1) used as the start;ng material for this synthesis route and the corresponding carboxylic acid, and the 3-fluoro-4,6-dichlorotoluene (10~ required for the preparation of (1) are prepared in accordance with the following equa-tion, starting from 2,4-dichloro-5-methyl-aniline (8~:
Le A 22 110 - Forei n countries 9_ .
1 4 _ P222249 c~3 C ~ 1 ~a'~O 2 ' ~ 3 ~
~Y2 ~ (Cr3) 3 Cl (3 CCl (10) (11 ) COCl COOR Cl ~
Cl ~ ~ ~ r Cl ~12) (1) According to this equation, 2,4-dichloro-5-methyl-anil;ne (8) is diazot;sed w;th the aid of NaN02 and the diazon;um salt thereby formed is converted ;nto the tri-azene (9) with dimethylamine.
The triazene (9) is dissolved in aqueous anhydrous HF. The triazene thereby splits ;nto 2,4-dichloro-5-methyl-diazonium fluor;de and dimethylamine. This solu-tion is split, ~ithout intermediate isolation, under the influence of heat at 130 - 140C into 3~fluoro-4,6-di-chlorotoluene (10~, N? being split off. Yield: 77.7%
of theory.
Le A 22 110 - Foreign countries :~Z2Z;249 The 3-fluoro-4,6~dichlorotoluene (10) ;s chlorina-ted in a temperature range of 110 - 160C under irrad;a-tion w;th UV l;ght to give 2,4 dichloro-S-fluoro-1~tri-chloromethylbenzene (11).
Hydrolysis of (11) ~ith 95X strength sulphuric acid leads to 2,4-dichloro 5-fluoro-benzoic acid t12), ~hich ;s converted into the carboxylic acid chloride (1) (boiling point 121/20 mbar; n20 1.5722) ~ith ~hionyl chloride.
The following quinolonecarboxylic acids used as intermediates are prepared in an analogous manner.
7-Chloro-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid (Vlb) (melting point 308C) from 2,4-dichlorobenzoyl chloride (J. Chem. Soc. 83, 1213 (1903~));
o ,~,COOH
Cl~ (VIb) i 6,7-Dichloro-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid (VIc) (melting point 265C) from 2,4,5-trichlorobenzoyl chloride tLiebigs Ann. Chem. 152, 238 (1896)];
o Cl ~ 00~
~ (VIc) Cl 7-Chloro-1-cyclopropyl-1,4-dihydro 6-nitro-4-oxo-3-quino-linecarboxylic acid (VId) ~melting point 265 - 275C
decomposition~ from 2,4-dichloro-5-nitro-benzoyl chloride (Liebigs Ann~ Chem. 677, 8 (1964)).
Le A 22 110 - Forei~n countries ~2Z2~
- 16 ~
a ~,~3,C O 01~ ( V I d ) The compounds of the formula (III) ~hich can be used as starting substances are already known.
The ;socyanates ~IV) ~hich can be used as start-;ng compounds are also kno~n, as are the anhydr;des (V).
The reaction of (II) with ~III) (method a) is preferably carried out in a diluent, such as dimethyl-sulphox;de, N,N-d;methyLformam;de, tetrahydrofuran, sulpholane, dioxane~ pyridine or ~ater or in m;xtures of these diluents, at temperatures of 0C - 140C, preferably 1 0C -- 1 1 [)1 r The reaction can be çarried out under normal pressure, but also under increased pressure. In general, it is carried out under pressures between about 1 and about 100 bar, preferably between 1 and 10 bar.
All the customary inorganic and organic ac;d-bind;ng agents can be used as the ac;d-b;nders. These ;nclude, preferably, the alkaL; metal hydroxides and alkal; metal carbonates, pyr;d;ne and tert;ary am;nes, such as tr;ethylam;ne and 1,4-d;azab;cycloC2.2.2]octaneO
In carry;ng out process var;ant a), 1 to 4 moles, preferably 1 to 1.5 moLes, of the compound (III) ar~
employed per mole of the compound ~II).
The reaction of (II) w;th (IV) (method b) is preferably carr;ed out ;n a d;luent, such as, for example, d;oxane, dimethylsulphoxide, N,N-dimethyLform-amide or dilute sodium hydroxide solution, or in mixtures of these diluents.
The reaction temperatures can be varied ~ithin a substantial range~ In general, the reaction is carried out between about 0C and about 100C, preferably between Le A 22 110 - Forei~n_countr;es _ 5C and 50C.
The reaction can be carried out under normal pressure, but also under increased pressure. In general, it is carried out under pressures between about 1 and about 100 bar, preferabLy between 1 and 10 bar.
In carrying out process var;ant b), 1 - 5 moles~
preferably 1 - 2 moles, of the compound ~IV) are employed per mole of the compound (II).
The react;on of (II) with tV~ tmethod c) is carried out in a diluent, such as, for example, N,N-dimethylformamide, dioxane, tetrahydrofuran, pyridine or water, or in mixtures of these diluent~. The reaction temperatures can be varied within a substantial range.
In general, the reaction is carried out between about q 15 and about 14ûC, preferably between 10 and 100C. --The reaction can be carried out under normal pressure, but also under increased pressure. In general, ;t is carried out under pressures bet~een about 1 bar and about 100 bar, preferably between 1 and 10 bar.
All the customary inorganic and organic acid bind;ng agents can be used as the acid-binder. These include, preferably, the alkali metal hydroxides and alkali metal carbonates, pyridine and tertiary amines~
such as tr;ethylamine and 1,4-diazabicyclo~2.2.2]octane.
In carrying out process variant c), 1 to 3 moles, preferably 1 to 1.3 moles, of the compound (V) are employed per moLe of the compound (II).
The active compounds to be used according to the invention exhibit a powerful microbicidal action and can be employed in practice for combating undesired micro-organisms. The active compounds are suitable for use as plant protection agents.
Bacter;cidal agents are used in plant protection for combating Pseudomonadaceae, Rhizobiaceae, Entero-bacteriaceae, Corynebacteriaceae and Streptomycetaceae.
The active compounds to be used according to ~heLe A 22 110 - Foreign countries ~Z2;~4~
;nvention also exh;bit a qood fung;cidal action, for example aga;nst Pyricular;a oryzae on rice.
The good tolerat;on9 by plants, of the active compounds, at the concentrations required for combating plant diseases, permits treatment of above-ground parts of plants, of vegetative propagat;on stock and seeds~ and of the soil.
The active compounds can be converted to the cus-tomary formulations~ such as solutions, emulsions, sus-pensions, powders, foams, pastes, granules, aerosols,very fine capsules ;n polymeric substances and in coating compos;tions for seed, and ULY formulations.
These formulations are produced ;n known manner, for example by mixing the active compounds with exten-ders, that is, liquid solvents, liquefied gases under:pressure, and/or solid carriers, optionally ~ith the use of surface-active agents, that is, emulsifying agents and/or dispersing agents, and/or foam-forming agents.
In the case of the use of water as an extender, organic solvents can, for example, also be used as auxiliary sol-vents. As liquid solvents, there are suitable in the main: aromatics, such as xylene, toluene or alkyl naphthalenes~ chlorinated aromatiçs or chlorinated ali-phatic hydrocarbons, such as chlorobenzenes, chloro-ethylenes or methylene chloride, aliphatic hydrocarbons,such as cyclohexane or paraffins, for example mineral o;l fractions, alcohols, such as butanol or glycol as ~ell as their ethers and esters, ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone or cyclohexanone, strongly polar solvents, such as dimethylformamide and dimethylsulphoxide, as well as water. By liquefied gaseous extenders or carriers arP meant liquids which are gaseous at normal temperature and under normal pressure, for example aerosol propellants, such as halogenated ~5 hydrocarbons as well as butane, propane, nitrogen and carbon dioxide. As solid carriers there are suitable:
Le A 22 110 - Forei n countries 12~2Z~49 for example ground natural m;nerals, such as kaolins, clays~ talc~ cha~k, quartz, attapulgite, montmoriLlonite or d;atomaceous earth, and ground synthetic m;nerals, such as highly-dispersed silicic acid, alumina and sili-cates. As solid carriers for granules there are suitable:for example crushed and fractionated natural rocks such as calcite, marble~ pumice~ sepiolite and dolomite, as ~ell as synthEtic granules of inorganic and organ;c meals, and granules of organic material such as sawdust~
coconut shells, maize cobs and tobacco staLks. As emul-s;fying and/or foam-forming agents there are suitable:
for example non-ionic and anionic emulsifiers, such as polyoxyethylene-fatty acid esters, polyoxyethylene-fatty alcohol ethers, for example alkylaryl po~yglycol ether~s, alkyl sulphonates, alkyl sulphates, aryl sulphonates -as well as album;n hydrolysation products. As dispersing agents there are suitable: for example lignin-sulphite waste liquors and methylcellulose.
Adhesives such as carboxymethylcellulose ande natural and synthetic polymers in the form of powd~rs, granules or latices, such as gum arabic, polyvinyl alco-hol and polyvinyl acetate, and natural phospholipids, such as cephalins and lecithins, and synthetic phospholipids, can be used in the formulations. Further additives can be m;neral and vegetable oils.
It is possible to use colorants such as inorganic pigments, for example iron oxide, titan;um oxide and Prussian Blue, and organic dyestuffs, such as alizar;n dyestuffs, azo dyestuffs and metal phthalocyanine dye-stuffs, and trace nutrients such as salts of iron, man-ganese, boron, copper, cobalt, molybdenum and zinc.
The formulations in general contain bet~een 0~1 and 95 per cent by ~eight of active compound, preferably between 0.5 and 90%.
The active compounds according to the invention can be present in the formulations as a mixture ~ith Le A 22 110 - Foreign countries ~;~2;~ 49 - ZO
other known active compounds, such as fungicides, insect-cides, acaric;des and herbic;des, and in mixtures with fertil;sers and growth regulators.
The active compounds can be used as such or in the form of their formulations or the use forms prepared therefrom, such as ready-to-use solutions, emulsifiable concentrates, emuls;onsO foams, suspensions, ~ettable po~ders, pastes, soluble powders, dusts and granules~
They are used in the customary manner, for example by water;ng, spray;ng, atomising, scattering, dusting, foaming, coating and the like. It is fur~hermore pos-sible to apply the active compounds by the ultra~low volume process or to inject the formulation of active compound or the act;ve compound ;tself ;nto the soil.
The seed of plants can also be treated.
~n the treatment of parts of plants, the active compound concentrations in the use forms can be varied with;n a substantial range. They are, in general, bet~een 1 and 0.0001X by weight, preferably bet~een 0.5 and 0.001~.
In the treatmer,t of seed, amounts of active com-pound of 0.001 to 50 9 per kilogram of seed~ preferably 0.01 to 10 9, are generally required.
For the treatment of soil, active compound con-centrations of 0.00001 to 0.1X by ~eight, preferably 25 0.0001 to 0.02X, are required at the place of action.
Preparat;on Examples I Startin~ compounds ~.~
o F~5 O O H
~J ~
A mixture of 19.7 9 of 7-chloro-1-cyclopropyl-6-fluoro-1,4-d;hydro-4-oxo-3-qu;nolinecarboxylic acid, 30.1 9 of anhydrous piperazine and 100 ml of dimethyl-sulphoxide is heated at 135 - 140C for 2 hours~ The Le A 22 110 - Forei n countries 9 __ 2;~4~
solvent is d;stilled off under a fine vacuum and the res;due is suspended in H20~ filtered off w;th suct;on and washed w;th water. For further purification~ the mo;st crude product is boiled up ~;th 100 ml of uater, f;ltered off with suction at room temperature~ ~ashed w;th H20 and dr;ed to constant weight over CaCl2 at 100C in a vacuum drying cabinet. 19.6 9 of 1-cyclo-propyl 6-fluoro-1f4-dihydro-4-oxo-7-(1-pipera2inyl)-3 quinolinecarboxylic ac;d of decomposit;on po;nt 255 -257C are obtained.
The 7-chloro~1-cyclopropyl-6-fluoro-1,4-d;hydro-4-oxo-3-quinolinecarboxyl;c ac;d VIa used as the s~arting material ;s prepared as follows:
24.3 9 of magnes;um f;l;ngs are suspended in 50 ml of anhydrous ethanol. 5 ml of carbon tetrachlot;de are added and, when the react;on has started, a mixture of 160 9 of diethyl malonate, 100 ml of absolute ethanol and 4~0 ml of anhydrous ether is added drspw;se, where-upon v;gorous reflux ;s to be observed. When the reaction has subs;ded, the mixture ;s heated at the boiLing point for a further 2 hours and cooled to -5C to ~1ûC with dry ;ce/acetone, and a solut;on of 227.5 9 of 2,4-d;-chloro-5-fluoro-benzoyl chloride (1) in 1ûO ml of abso-lute ether is slowly added drop~;se at th;s temperature.
The mixture is stirred at 0C to -5C for 1 hour and ;s allowed to come to room temperature overnight, and a mixture of 400 ml of ice-water and 25 ml of concentrated sulphuric acid ;s allo~ed to run ;n, wh;le cool;ng with ice. The phases are separated and subsequently extracted twice ~ith ether. The comb;ned ether solutions are ~ashed ~ith saturated NaCl solution and dried with Na2S04 and the solvent is stripped off in vacuo. 349.5 9 of diethyl 2,4-dichloro-5-fluoro benzoylmalonate ~3) are obtained as the crude product.
0.15 9 of p-toluenesulphonic acid ;s added to an emuls;on of 34.9 9 of crude d;ethyl 2,4-d;chloro-5-fluoro-Le A ?2 110 ~ Foreign countries ~.~ZZ;~4g benzoylmaLonate C3) in S0 ml of ~ater. The mixture is heated at the bo;l;ng point for 3 hours, while stirring thoroughLy, the cooled emulsion is extracted several t;mes with methylene chloride, the comb;ned CH2Cl2 solutions are ~ashed once ~ith saturated NaCl solution and dried with Na2S04 and the solvent is distilled off in vacuo. Fractionation of the residue in vacuo gives 21.8 g of ethyl 2,4-dichloro-5-fluoro-benzoyl-acetate (4) of boiling point 127 - 142C/0.09 mbar.
A mixture of 21.1 9 of ethyl Z,4 dichloro-5-fluoro-benzoyl-acetate (4), 16.65 9 of ethyl o-formate and 18 55 9 of acetic anhydride is heated at 150C for 2 hours. The volatile constituents are then distilled off under a waterpump vacuum and, finally, under a fine vacuum, at a bath temperature of 120C. 25~2 9 of crude ethyl 2-t2,4-dichloro-5-benzoyl)-3-ethoxy-acrylate
(5) remain. The product is sufficiently pure for the further reactions.
4.3 9 of cyclopropylamine are added dropwise to a solution of 2~,.9 9 of ethyl 2-(2~4-dichloro-5-fluoro-benzoyl)-3-ethoxy-acrylate (5) in 80 ml of ethanol, while cooling with ice and stirring. When the exothermic reac-tion has subsided, st;rring is continued at room tempera-ture for a further hour, the solvent ;s stripped off in vacuo and the residue is recrystallised from cyclohexane/
petroleum ether. 22.9 9 of ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-cyclopropylamino-acrylate (6) of melting point 8~ - 90C are obtained.
3.44 9 of 80 per cent pure sodium hydride are added in portions to a solution of 31.9 9 of ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-cyclopropylamino-acrylate (6~ in 100 ml of anhydrous dioxane, while cool-ing with ice and stirring. The mixture is then stirred at room temperature for 30 minutes and under reflux for 2 hours and the dioxane is stripped off in vacuo. The residue (40.3 9) is suspended in 150 ml of water, 6.65 9 Le A 22 110 - Fore;gn countries ~ 2Z2~9 ~ 23 -of alkali metal hydroxide are added and the mixture is refluxed for 1 D5 hours. The ~arm solution is filtered and the residue is rinsed with HzO. The filtrate is then acidified to pH 1 - 2 with half-concentrated hydro-chloric acid, while cooling with ice, and the precipitateis f;ltered off ~ith suction, washed with ~ater and dried at 100C in vacuo. 27.7 9 of 7-chloro-1-cyclopropyl-
4.3 9 of cyclopropylamine are added dropwise to a solution of 2~,.9 9 of ethyl 2-(2~4-dichloro-5-fluoro-benzoyl)-3-ethoxy-acrylate (5) in 80 ml of ethanol, while cooling with ice and stirring. When the exothermic reac-tion has subsided, st;rring is continued at room tempera-ture for a further hour, the solvent ;s stripped off in vacuo and the residue is recrystallised from cyclohexane/
petroleum ether. 22.9 9 of ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-cyclopropylamino-acrylate (6) of melting point 8~ - 90C are obtained.
3.44 9 of 80 per cent pure sodium hydride are added in portions to a solution of 31.9 9 of ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-cyclopropylamino-acrylate (6~ in 100 ml of anhydrous dioxane, while cool-ing with ice and stirring. The mixture is then stirred at room temperature for 30 minutes and under reflux for 2 hours and the dioxane is stripped off in vacuo. The residue (40.3 9) is suspended in 150 ml of water, 6.65 9 Le A 22 110 - Fore;gn countries ~ 2Z2~9 ~ 23 -of alkali metal hydroxide are added and the mixture is refluxed for 1 D5 hours. The ~arm solution is filtered and the residue is rinsed with HzO. The filtrate is then acidified to pH 1 - 2 with half-concentrated hydro-chloric acid, while cooling with ice, and the precipitateis f;ltered off ~ith suction, washed with ~ater and dried at 100C in vacuo. 27.7 9 of 7-chloro-1-cyclopropyl-
6-fluoro-1,4-d;hydro-4-oxo 3-qu;nol;necarboxylic acid VIa of melting point 234 - 237C are obtained in this manner.
Example B
r~ 0~
C~ ~ X 1/2 H20 A mixture of Z.8 9 (0.01 mole) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-qu;noline-carboxylic ac;d and 5.1 9 (0.051 mole) of 2-methyl-piperaz;ne in 6 ml of dimethylsulphoxide ;s heated at140C for 2 hours. The solvent ;s then d;st;lled off under a high vacuum, 6 ml of hot water are added to the residue and the mixture is kept at 95C for 1 hour.
It is cooled with ice and the precipitate ~hich has separated out is washed with a little water and dissolved in a mixture of 0.8 ml of acetic acid and 10 ml of water at 90 - 100C. The filtrate is brought to pH 8 ~ith potassium hydroxide solution (0.75 9 of KOH in 0.7 ml of water), and the precipitate which has separated out is recrystallised from methanol~ 1.8 9 (52X of theory) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(3 methyl-1-piperazinyl)-3-quinolinecarboxylic ac;d sem;hydrate of decomposit;on po;nt 23û - 232C are obtained.
Le A Z2 110 - Forei n countries ~L~ZZZ49 ~
~ OOH
A mixture of 9.3 9 ~0.03 mole) of 7-chloro-1-cyclopropyl-1,4 dihydro-6-n;tro-4-oxo-3-quinolinecarbo~y-lic acid and 12.9 9 tO.15 mole) of piperazine in 60 ml ofd;methylsulphoxide is warmed to 120C in the course of 15 minutes. After a short time, a precipitate separates out of the hot solutionO The mixture is concentrated under a high vacuum~ the residue is stirred with 30 m~ of water and the mixture is heated again at 95C for 30 minutes. The m;xture ;s brought to pH 8 ~ith 2 N hydro-chloric acid and the precipitate is filtered off ~ith suction and washed with ~ater and methanol. 5.8 9 t54X
of theory~ of 1 cyclopropyl-1,4-dihydro-6-nitro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid of decomposi-tion point 296 - 298C are isolated.
Example D
o ~ COO~I
6,7-Dichloro-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is reacted analogously to Example C to give 1-cyclopropyl-o-chloro-1,4-dihydro-4-oxo-7-t1-piperazinyl)-3-quinolinecarboxylic acid of decomposition point ~95 - 298C.
Le A 22 110 - Fore~n countries z~9 Exam~le E
O
COO~
Example B
r~ 0~
C~ ~ X 1/2 H20 A mixture of Z.8 9 (0.01 mole) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-qu;noline-carboxylic ac;d and 5.1 9 (0.051 mole) of 2-methyl-piperaz;ne in 6 ml of dimethylsulphoxide ;s heated at140C for 2 hours. The solvent ;s then d;st;lled off under a high vacuum, 6 ml of hot water are added to the residue and the mixture is kept at 95C for 1 hour.
It is cooled with ice and the precipitate ~hich has separated out is washed with a little water and dissolved in a mixture of 0.8 ml of acetic acid and 10 ml of water at 90 - 100C. The filtrate is brought to pH 8 ~ith potassium hydroxide solution (0.75 9 of KOH in 0.7 ml of water), and the precipitate which has separated out is recrystallised from methanol~ 1.8 9 (52X of theory) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(3 methyl-1-piperazinyl)-3-quinolinecarboxylic ac;d sem;hydrate of decomposit;on po;nt 23û - 232C are obtained.
Le A Z2 110 - Forei n countries ~L~ZZZ49 ~
~ OOH
A mixture of 9.3 9 ~0.03 mole) of 7-chloro-1-cyclopropyl-1,4 dihydro-6-n;tro-4-oxo-3-quinolinecarbo~y-lic acid and 12.9 9 tO.15 mole) of piperazine in 60 ml ofd;methylsulphoxide is warmed to 120C in the course of 15 minutes. After a short time, a precipitate separates out of the hot solutionO The mixture is concentrated under a high vacuum~ the residue is stirred with 30 m~ of water and the mixture is heated again at 95C for 30 minutes. The m;xture ;s brought to pH 8 ~ith 2 N hydro-chloric acid and the precipitate is filtered off ~ith suction and washed with ~ater and methanol. 5.8 9 t54X
of theory~ of 1 cyclopropyl-1,4-dihydro-6-nitro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid of decomposi-tion point 296 - 298C are isolated.
Example D
o ~ COO~I
6,7-Dichloro-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is reacted analogously to Example C to give 1-cyclopropyl-o-chloro-1,4-dihydro-4-oxo-7-t1-piperazinyl)-3-quinolinecarboxylic acid of decomposition point ~95 - 298C.
Le A 22 110 - Fore~n countries z~9 Exam~le E
O
COO~
7 Chloro-1 cyclopropyl-1,4-d;hydro-4-oxo-3-quinolinecarboxylic acid is reacted ~ith piperazine analogously to Example C to give 1-cyclopropyl-1,4-di-hydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid of decomposition point 298 - 3ûOC.
II End products Example 1 o F~,~,~ OOEI
C~ CO~
~ 3.3 9 (0.01 mole) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid is dissolved in a mixture of 20 ml of dioxane and a solution of 0.4 9 of sodium hydroxide in 5 ml of water.
A solution of 0.9 9 (0.011 mole) of acetyl chloride in 5 ml of dioxane and a solut;on of 0.4 9 (0.01 mole) of sodium hydroxide in 5 ml of water are simultaneously added dropwise to this solution, while coolin~ with ice, the pH vaLue being kept > 8. The mixture is subse-quently stirred at room temperature for 2 hours, 30 ml of~ater are added to the suspension, the mixture is acidi-fied ~ith 2 N hydrochloric acid and the precipitate is filtered off ~ith suction and recrystallised from glycol monomethyl ether. 2 9 ~54% of theory) of 7-(4-acetyl-1-piperazinyL)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of decomposition point 267 -Le A 22 110 - Foreign countries 12ZZ;~49 270C are isolated.
The following compounds are obtained according to Example 1: ~
OOH
Melting point 2 CH3-cH2-co 267 (c;ecomm~s,t-,cn) 3 CH3 CH2 2 282 (decorl~osition) 4 / CH-CH2-CO 286 (decompositio~n) CF -S-CH2-cO 252 (decomposition) 6 ~ CO- 324 (decomposition) 7 CH3o-co-c~l2-cH2-co 205
II End products Example 1 o F~,~,~ OOEI
C~ CO~
~ 3.3 9 (0.01 mole) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid is dissolved in a mixture of 20 ml of dioxane and a solution of 0.4 9 of sodium hydroxide in 5 ml of water.
A solution of 0.9 9 (0.011 mole) of acetyl chloride in 5 ml of dioxane and a solut;on of 0.4 9 (0.01 mole) of sodium hydroxide in 5 ml of water are simultaneously added dropwise to this solution, while coolin~ with ice, the pH vaLue being kept > 8. The mixture is subse-quently stirred at room temperature for 2 hours, 30 ml of~ater are added to the suspension, the mixture is acidi-fied ~ith 2 N hydrochloric acid and the precipitate is filtered off ~ith suction and recrystallised from glycol monomethyl ether. 2 9 ~54% of theory) of 7-(4-acetyl-1-piperazinyL)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of decomposition point 267 -Le A 22 110 - Foreign countries 12ZZ;~49 270C are isolated.
The following compounds are obtained according to Example 1: ~
OOH
Melting point 2 CH3-cH2-co 267 (c;ecomm~s,t-,cn) 3 CH3 CH2 2 282 (decorl~osition) 4 / CH-CH2-CO 286 (decompositio~n) CF -S-CH2-cO 252 (decomposition) 6 ~ CO- 324 (decomposition) 7 CH3o-co-c~l2-cH2-co 205
8 CN 276 (decomposition)
9 CH30-C0 210 (decomposition) C2H5C 315( decomposition) 11 n-C4HgOC0 24i 12 ~ -CH2-0-C0- 230 12a C H -S-C0- 322Idecomposition) 13 CH3-SO2- 305(decomposition) 14 n-C3H7 S2 268 (decomposition) FCl2 2 278( decomposition) 16 C13 172(decomposition) 17 FC12 188 ~decomposition) 18 CH30-C0-S- 204 (decomposition) Le A 22 110 - Foreicln countries ~2;;~ZZ'~9 2~ -Example 20 ,~COO~
~-C~
The procedure followed is as in Example 1, us;ng formic acid/acetic acid anhydride~ and 1-cyclopropyl-6 fluoro-7~4-formyl-1 piperazinyl)-1,4-dihydro-4-oxo-3 quinolinecarboxylic acid of decomposition point 278 -281C is obta;ned.
Example 21 O
COO~ ' 300C-C~-CE~-C0- ~ ~
3.3 9 ~0.01 mole) of 1-cyclopropyl-6-fluoro-1,4-- dihydro-4-oxo-7~ piperazinyl)-3-quinolinecarboxylic acid are dissolved in a solut;on of 0.4 9 of sod;um hydroxide in 20 ml of water, and a solution of 1 9 of succinic anhydride in 10 ml of dioxane and 0.4 9 of sodium hydroxide in 10 ml of water are simultaneously added at room temperature. The mixture is subsequently stirred at room temperature for 2 hours and is acidified with 2 N hydrochloric acid, and the precipitate ~hich has separated out is filtered off with suction and washed with water and methanoL. 3.4 9 ~79% of theory) of 7-~4-(3-carboxypropionyl)-1-piperazinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinol;necarboxylic acid of decomposition point 284 - 286C are obtained.
The following compounds are obtained according to Example Z1:
L A 2Z 110 - Forei n countries e ~ -~Z2;Za'49 o F ,~, C OQ~
,~
a-~ ~
Example ~ Melting point / o C /
22 Hooc-c~2-c~2-cH2-co- 273 23 C ~ C0- 2O3 (decomposit-on) Cl ~ COO~
Example 24 -~f s 1/2 E~,O
C~ C 0- ~
3 9 of N-(tert.-butoxycarbonyl)-glycine 4-nitro-phenyl ester are added to 3.3 9 (0.01 mole) of 1-cyclo-propyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid in 50 ml of pyridine and the mixture is stirred at room temperature for 4 hours. The solution is concentrated, 30 ml of water are added and the pH is adjusted to 5 with 2 N hydrochloric acid. The precipitate which has separated out is filtered off with suction, washed with water and methanoL and dried. 2.7 9 (55X of theory) of 7-[4-(tert.-butoxyrarbonylamino-acetyl)-1-piperazinyl]-1-cyclopropyl-6-fluoro-1~4-di-hydro-4-oxo-3-quinolinecarboxylic acid of decomposition ~;~2Z249 point 236 - 238C are obtained. 10 ml of concentrated hydrochlor;c ac;d are added to a suspens;on of 2.2 ~
tO.0045 mole~ of this intermediate in 100 ml of methanol and the mixture is Left to stand at room temperature for S 3 hours. The methanol and excess hydrogen chloride are then stripped off in vacuo, the aqueous solution ;s adjusted to pH 8 with d;lute sodium hydroxide soLution and the prec;p;tate ;s filtered off ~ith suction and ~lashed w;th methanol. 1~4 9 (78X of theory) of 7- [4-(amino-1Q acetyl~-l-piperazinyl~-l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-qu;nol;necarboxylic acid sem;hydrate of deçomposition point 245 - 248C are obta;ned.
The follo~ing compounds are prepared analogously to Example 24:
~00~ .
Decomposition point xample / C7 ~ CH-CO- 297 ~H2 X HCl x H2O
26 3 , 240 CH ~ L
CH / ~H2 x HCl 28 H ~-CH -CH2-CO- 274 x HCl L A 22 110 - Fore; n countr;es e 9 9~2:~22~
-- ~o --Example Z9 F~,C 00 (C~)a~-O~C0~ ~ ~
6 9 of di-tert.-butyl pyrocarbonate are added to a solution sf 8.25 9 (0.025 mole) of 1 cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline-carboxylic acid in 75 ml of dioxane/water (2:1~ and 25 ml of 1 N sod;um hydroxide solution, ~hile cooling ~ith ice, and the m;xture is then stirred at room temperature for 30 m;nutes. It ;s concentrated down to one-third of t~e volume, covered ~ith a layer of 50 ml of ethyl acetatè
and acidified to pH 3 ~ith dilute potassium bisulphate solution~ The precipitate ~h;ch has separated out is filtered off ~ith suction, washed with water ar,d methanol and dried under a h;gh vacuum. 10 9 (92% of theory) of ~-(4-tert.-butoxycarbonyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of decomposition point 249 - 252C are obtained.
Example_30 o F~,~ ~COO~I
C~ C~ CO-~
A m;xture of 3.3 9 (0.01 mole) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline-carboxyLic acid and 2~8 9 (0.01 mole) of 4-nitrophenyl 2-(1-pyrazolyl)-ethyl carbonate in 40 ml of pyr;dine is stirred at room temperature for 1 day. It is then dilu-ted w;th 30 ml of ~ater and acidified with 2 N hydro-chloric acid, and the precipitate is filtered off ~ith Le A 22 110 - Forei n countries _ . ~
;2Z~'~
suct;on and recrystallised from glycol monomethyl ether.
2.8 9 (60% of theory) of 1-cyclopropyl-6-fluoro-1,4-d;
hydro-4-oxo-7-~-4-CZ~(1-pyrazolyl)-ethoxycarbonyl~
piperazinyl~3-quinolinecarboxylic acid of melting point S 205 - 208C are obtained.
The 4-nitrophenyl 2-(1-pyrazolyl)-ethyl carbonate used as the starting substance is obtained by the follo~-ing route: 4.6 9 of 1-t2-hydroxyethyl)-pyrazole are stirred ;n 80 ml of acetonitrile ~ith 4 9 of 4-nitro-phenyl chlorocarbonate at room temperature for 12 hours,the solution is concentrated, ~he resulting oil ;s taken up in methylene chloride and the mixture is washed ~ith water. It is dried w;th sodium sulphate and concentrated and the crude carbonate is obtained as a viscous oil.~
The following compounds are obtained analogou-sly to Example 30:
o ~,COO~
~-O-CO- ~
Example R Melting point 31 ~ -C~2C~- 226 32 ~ C3~- 230 (decomposition) 33 o ~- ~ CE,- ~3 tdecomposition) Le A 22 110 - Foreign countries ~,2zz24~
Example 34 o ~ COOEI
C~ V~ C~a~1~ C0 r ~J
6.6 g (0.~2 mole) of 1-cyclopropyl-6-fluoro 1,4-dihydro-4-oxo-7~ piperazinyl)-3-quinolinecarbo~yLic acid are d;ssolved in a solution of 0.4 9 of sodium hydroxide in 40 ml of ~ater, and a solution of 3.2 9 (0.022 mole) of methyl 4-isocyanato-butyrate in 12 ml of dioxane is added, ~hile cooling with ice. The mixture is then subsequently stirred at room temperature for Z~
hours and brought to pH 5 with 2 N hydrochloric acid,-and the precipitate is filtered off ~ith suction and re~
crystallised from methanol. 6 9 (63X of theory) o~ 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-{4-~3-methoxy~
carbc~nylpropyl)-carbamoyl]-1-piperazinyl~-3-qu;noline-carboxyl;c ac;d of melting point 198 - 200C are obtained.
The following compounds are obtained accsrding to Example 34:
F ~ ~ C00 B ~
Example R Melting point (C) CH3o-cotcH2)s-NH-co- 178 36 C H 0-C0-(CH2)2-NH-Co- 180 (decomposition) 37 CH3-NH-C0- 280 (decomposition) Le A 22 110 - Foreign countries ~;~ZZ;~49~
Example 38 o ~IOOC- (CE~ 0-~
2C37 9 of the compound of Example 34 are heated at 150 - 160C in a mixture of 10 ml of glacial acetic acid, 6.5 mL of water and 1 ml of concentrated sulphur;c acid for 1.5 hours. When the mixture has cooled to room temperature, ;t is poured onto 50 ml of ic~-waterO and - the precipitate is filtered off ~i~h suction and re-crystallised from glycol monomethyl ether. 1.2 9 (52X' of theory) of 7-~4-C~3-carboxy-propyl)-carbamoyl]-1-pipera~inyl~ cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic ac;d of decomposition point 245 -248C are obta;ned.
The following compounds are obtained in a manner correspond;ng to that in Example 38, by hydrolysis of - the products from Examples 35 and 36:
o F~l, C O OEI
~IO~)C- (C~ ) ~ C O~
Example n Meltin~ point ~C~
39 5 224 ~decomposition) 2 209 (decomposition~
Le A 22 110 Foreign countries ~, _ 1~2Z9~g ~ 34 -Example 41 C~
-n-C~H7--1-Cyclopropyl~1,4-dihydro 6-nitro-4-oxo-7~
piperaz;nyl)-3-quinolinecarboxyl;c acid and butyryl 5 chloride are reacted according to Example 1 ~o give 7-~4-butyryl-1-piperazinyl)-1-cyclopropyl-1,4-dihydro-6-nitro-4-oxo-3-quinolinecarboxyl;c acid of decomposition point 223 ~ 226Co Example_42 C l~ , C O OH
~,, ~, ~I-C, ~ -CO-~ ~
6-Chloro-1-cyclopropyl-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3 quinolinecarboxylic acid and bu~yryl chloride are reacted according to Example 1 to giYe 7-~4-butyryl-1-piperazinyl)-6-chloro-1-cyclopropyl-1,4-di-hydro-4-oxo-3-quinolinecarboxyLic acid of decomposition point 280 -283C.
Example 43 o Q-C~7--cO- ~ COOH
1-Cyclopropyl-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-qu;nolinecarboxylic acid and butyryl chloride are reacted according to Example 1 to give 7-(4-butyryl-1-Le A 22 110 - Foreisn countries ~2;~ 9 piperazinyl)-1-cyclopropyl 1,4-dihydro~4-oxo-3-quinoline-carboxyl;c ac;d of decomposit;on point 252 - ~55C~
Example 44 F ~ ~ OOH
~~Cg ~ ~C~
C~, 1 Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-methyl-1-piperazinyl)-3-qu;nol;necarboxyl;c acid and butyryl chlor;de are reacted according to Example 1 to give 7-(4-butyryl-3-methyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-194-dihydro-4-oxo-3-quinolinecarboxylic acid'of
~-C~
The procedure followed is as in Example 1, us;ng formic acid/acetic acid anhydride~ and 1-cyclopropyl-6 fluoro-7~4-formyl-1 piperazinyl)-1,4-dihydro-4-oxo-3 quinolinecarboxylic acid of decomposition point 278 -281C is obta;ned.
Example 21 O
COO~ ' 300C-C~-CE~-C0- ~ ~
3.3 9 ~0.01 mole) of 1-cyclopropyl-6-fluoro-1,4-- dihydro-4-oxo-7~ piperazinyl)-3-quinolinecarboxylic acid are dissolved in a solut;on of 0.4 9 of sod;um hydroxide in 20 ml of water, and a solution of 1 9 of succinic anhydride in 10 ml of dioxane and 0.4 9 of sodium hydroxide in 10 ml of water are simultaneously added at room temperature. The mixture is subsequently stirred at room temperature for 2 hours and is acidified with 2 N hydrochloric acid, and the precipitate ~hich has separated out is filtered off with suction and washed with water and methanoL. 3.4 9 ~79% of theory) of 7-~4-(3-carboxypropionyl)-1-piperazinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinol;necarboxylic acid of decomposition point 284 - 286C are obtained.
The following compounds are obtained according to Example Z1:
L A 2Z 110 - Forei n countries e ~ -~Z2;Za'49 o F ,~, C OQ~
,~
a-~ ~
Example ~ Melting point / o C /
22 Hooc-c~2-c~2-cH2-co- 273 23 C ~ C0- 2O3 (decomposit-on) Cl ~ COO~
Example 24 -~f s 1/2 E~,O
C~ C 0- ~
3 9 of N-(tert.-butoxycarbonyl)-glycine 4-nitro-phenyl ester are added to 3.3 9 (0.01 mole) of 1-cyclo-propyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid in 50 ml of pyridine and the mixture is stirred at room temperature for 4 hours. The solution is concentrated, 30 ml of water are added and the pH is adjusted to 5 with 2 N hydrochloric acid. The precipitate which has separated out is filtered off with suction, washed with water and methanoL and dried. 2.7 9 (55X of theory) of 7-[4-(tert.-butoxyrarbonylamino-acetyl)-1-piperazinyl]-1-cyclopropyl-6-fluoro-1~4-di-hydro-4-oxo-3-quinolinecarboxylic acid of decomposition ~;~2Z249 point 236 - 238C are obtained. 10 ml of concentrated hydrochlor;c ac;d are added to a suspens;on of 2.2 ~
tO.0045 mole~ of this intermediate in 100 ml of methanol and the mixture is Left to stand at room temperature for S 3 hours. The methanol and excess hydrogen chloride are then stripped off in vacuo, the aqueous solution ;s adjusted to pH 8 with d;lute sodium hydroxide soLution and the prec;p;tate ;s filtered off ~ith suction and ~lashed w;th methanol. 1~4 9 (78X of theory) of 7- [4-(amino-1Q acetyl~-l-piperazinyl~-l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-qu;nol;necarboxylic acid sem;hydrate of deçomposition point 245 - 248C are obta;ned.
The follo~ing compounds are prepared analogously to Example 24:
~00~ .
Decomposition point xample / C7 ~ CH-CO- 297 ~H2 X HCl x H2O
26 3 , 240 CH ~ L
CH / ~H2 x HCl 28 H ~-CH -CH2-CO- 274 x HCl L A 22 110 - Fore; n countr;es e 9 9~2:~22~
-- ~o --Example Z9 F~,C 00 (C~)a~-O~C0~ ~ ~
6 9 of di-tert.-butyl pyrocarbonate are added to a solution sf 8.25 9 (0.025 mole) of 1 cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline-carboxylic acid in 75 ml of dioxane/water (2:1~ and 25 ml of 1 N sod;um hydroxide solution, ~hile cooling ~ith ice, and the m;xture is then stirred at room temperature for 30 m;nutes. It ;s concentrated down to one-third of t~e volume, covered ~ith a layer of 50 ml of ethyl acetatè
and acidified to pH 3 ~ith dilute potassium bisulphate solution~ The precipitate ~h;ch has separated out is filtered off ~ith suction, washed with water ar,d methanol and dried under a h;gh vacuum. 10 9 (92% of theory) of ~-(4-tert.-butoxycarbonyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of decomposition point 249 - 252C are obtained.
Example_30 o F~,~ ~COO~I
C~ C~ CO-~
A m;xture of 3.3 9 (0.01 mole) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline-carboxyLic acid and 2~8 9 (0.01 mole) of 4-nitrophenyl 2-(1-pyrazolyl)-ethyl carbonate in 40 ml of pyr;dine is stirred at room temperature for 1 day. It is then dilu-ted w;th 30 ml of ~ater and acidified with 2 N hydro-chloric acid, and the precipitate is filtered off ~ith Le A 22 110 - Forei n countries _ . ~
;2Z~'~
suct;on and recrystallised from glycol monomethyl ether.
2.8 9 (60% of theory) of 1-cyclopropyl-6-fluoro-1,4-d;
hydro-4-oxo-7-~-4-CZ~(1-pyrazolyl)-ethoxycarbonyl~
piperazinyl~3-quinolinecarboxylic acid of melting point S 205 - 208C are obtained.
The 4-nitrophenyl 2-(1-pyrazolyl)-ethyl carbonate used as the starting substance is obtained by the follo~-ing route: 4.6 9 of 1-t2-hydroxyethyl)-pyrazole are stirred ;n 80 ml of acetonitrile ~ith 4 9 of 4-nitro-phenyl chlorocarbonate at room temperature for 12 hours,the solution is concentrated, ~he resulting oil ;s taken up in methylene chloride and the mixture is washed ~ith water. It is dried w;th sodium sulphate and concentrated and the crude carbonate is obtained as a viscous oil.~
The following compounds are obtained analogou-sly to Example 30:
o ~,COO~
~-O-CO- ~
Example R Melting point 31 ~ -C~2C~- 226 32 ~ C3~- 230 (decomposition) 33 o ~- ~ CE,- ~3 tdecomposition) Le A 22 110 - Foreign countries ~,2zz24~
Example 34 o ~ COOEI
C~ V~ C~a~1~ C0 r ~J
6.6 g (0.~2 mole) of 1-cyclopropyl-6-fluoro 1,4-dihydro-4-oxo-7~ piperazinyl)-3-quinolinecarbo~yLic acid are d;ssolved in a solution of 0.4 9 of sodium hydroxide in 40 ml of ~ater, and a solution of 3.2 9 (0.022 mole) of methyl 4-isocyanato-butyrate in 12 ml of dioxane is added, ~hile cooling with ice. The mixture is then subsequently stirred at room temperature for Z~
hours and brought to pH 5 with 2 N hydrochloric acid,-and the precipitate is filtered off ~ith suction and re~
crystallised from methanol. 6 9 (63X of theory) o~ 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-{4-~3-methoxy~
carbc~nylpropyl)-carbamoyl]-1-piperazinyl~-3-qu;noline-carboxyl;c ac;d of melting point 198 - 200C are obtained.
The following compounds are obtained accsrding to Example 34:
F ~ ~ C00 B ~
Example R Melting point (C) CH3o-cotcH2)s-NH-co- 178 36 C H 0-C0-(CH2)2-NH-Co- 180 (decomposition) 37 CH3-NH-C0- 280 (decomposition) Le A 22 110 - Foreign countries ~;~ZZ;~49~
Example 38 o ~IOOC- (CE~ 0-~
2C37 9 of the compound of Example 34 are heated at 150 - 160C in a mixture of 10 ml of glacial acetic acid, 6.5 mL of water and 1 ml of concentrated sulphur;c acid for 1.5 hours. When the mixture has cooled to room temperature, ;t is poured onto 50 ml of ic~-waterO and - the precipitate is filtered off ~i~h suction and re-crystallised from glycol monomethyl ether. 1.2 9 (52X' of theory) of 7-~4-C~3-carboxy-propyl)-carbamoyl]-1-pipera~inyl~ cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic ac;d of decomposition point 245 -248C are obta;ned.
The following compounds are obtained in a manner correspond;ng to that in Example 38, by hydrolysis of - the products from Examples 35 and 36:
o F~l, C O OEI
~IO~)C- (C~ ) ~ C O~
Example n Meltin~ point ~C~
39 5 224 ~decomposition) 2 209 (decomposition~
Le A 22 110 Foreign countries ~, _ 1~2Z9~g ~ 34 -Example 41 C~
-n-C~H7--1-Cyclopropyl~1,4-dihydro 6-nitro-4-oxo-7~
piperaz;nyl)-3-quinolinecarboxyl;c acid and butyryl 5 chloride are reacted according to Example 1 ~o give 7-~4-butyryl-1-piperazinyl)-1-cyclopropyl-1,4-dihydro-6-nitro-4-oxo-3-quinolinecarboxyl;c acid of decomposition point 223 ~ 226Co Example_42 C l~ , C O OH
~,, ~, ~I-C, ~ -CO-~ ~
6-Chloro-1-cyclopropyl-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3 quinolinecarboxylic acid and bu~yryl chloride are reacted according to Example 1 to giYe 7-~4-butyryl-1-piperazinyl)-6-chloro-1-cyclopropyl-1,4-di-hydro-4-oxo-3-quinolinecarboxyLic acid of decomposition point 280 -283C.
Example 43 o Q-C~7--cO- ~ COOH
1-Cyclopropyl-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-qu;nolinecarboxylic acid and butyryl chloride are reacted according to Example 1 to give 7-(4-butyryl-1-Le A 22 110 - Foreisn countries ~2;~ 9 piperazinyl)-1-cyclopropyl 1,4-dihydro~4-oxo-3-quinoline-carboxyl;c ac;d of decomposit;on point 252 - ~55C~
Example 44 F ~ ~ OOH
~~Cg ~ ~C~
C~, 1 Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-methyl-1-piperazinyl)-3-qu;nol;necarboxyl;c acid and butyryl chlor;de are reacted according to Example 1 to give 7-(4-butyryl-3-methyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-194-dihydro-4-oxo-3-quinolinecarboxylic acid'of
10 decomposition point 226 - 228C.
Use Examples The following compound ;s employed as the com-parison substance ;n the examples which follow:
Fl~:OOH
C
Le A 22 11G - Foreign countr_es 'l.Z~Z;~4'~
Example ~
Xanthomonas oryzae testlbacteriosis/rice/systemic Solvent: 48~5 parts by weight of dimethylformamide Emulsifier: 1.5 parts by weight of alky~aryl polyglycol ether To produce 3 suitable preparation of active compound, 1 part by we;ght of active compound is mixed with the stated amounts of solvent and emulsifier, and the concentrate is dil~ted with water to the 1~ desired concentration.
To test for systemic properties, standard soil in which young plants have been gro~n is ~atered ~ith 100 ml of the preparation of active compound.
3 days after the treatment, the plants are inoculated, with an aqueous suspension of Xanthomonas oryzae by pr;cking. Thereafter, the plants remain ;n a greenhouse at 24 to 26C and 70 to 80~ relat;ve atmospheric humidity for 14 days until they are evaluated.
In this test, a clearly superior activity com-pared with the prior art is shown, for example~
by the compounds according to the following preparation examples:
Le A 22110 - foreign countries ~Z2~4'9 T a b l e Xanthomon3s oryzae test / bacteriosis / rice / systemic Active compounds Amount Disease applied infestation in mg in X of the of untreated active control compound systemic per2 100 cm F~ CGCH
ClJ~ 1 0 6 0 (known) FCl. 2C-S-N~ COOH 1 û 40 ~N~ cH2 ~ -- ~ ~
~{E'~-CH~.C~2{X~ 10 40 ~ FOOH
Le A 22 110 - Foreign co~ntries ~%z2~9 Example II
Agar pLate test Nutrient medium used 15 parts by weight of agar agar 10 parts by ~eight of sucrose 8 parts by weight of casein hydrolysate ~ parts by weight of yeast extract 2 parts by we;ght of dipotass;um hydrogen phosphate 0.3 part by we;ght of magnesium phosphate are dissolved ;n 1,030 mL of distilled water and the sol-ution is kept in an autoclave at 121C for 15 minutes.
Solvent: 10 parts by weight of dimethylformamide Ratio of the amounts of solvent to nutr;ent med;um:
0.2: 99.8~
To produce a su;table preparation of active com-pound, 1 part by weight of active compound is mixed with the stated amount of solvent.
The concentrate is thoroughly mixed, in the stated proportion, with the liquid nutrient med;um and the mix-ture is then poured into Petri dishes.
When the nutrient medium has cooled and solid;-fied~ the plates are ;noculated with the following micro-organisms and are incubated at about 28C:
Evaluat;on is carr;ed out after 2 days, the inh;-bition of growth be;ng used as a measure of the action of the preparat;ons.
In this test, a clear superiority compared with the prior art is shown by the compounds according to the following preparation examples:
Le A 22 110 - Forei n countries ~2;Z;Z;~49 J
o ,.
o ut .
o) 11 c o~
E asuauV5~ U el~
:~ c U~n~ eq~3u~0 o o su~l ~e ~ 3uln-'' " U~nl.~a~eqo~
~ ~ s c ~
o L E O O O
Q
C Cl Q a ~ C
~ O
Le A 2Z 110 - Foreign countries .
~2~
,_ -o v~
cn c o~
E
asuau~ u ~ N ~
c o uml~a~c[au,~10 Cli L
~ O
V O O
3 c . sua~ aum O 11 ~ r~
~ ~ u~ a~ o~5~
~ o o _ E ~ O O O
O L- E ~--C ~1 .~ C
_ O
~: O
.
~ ~ ~ Z
er Cl:
Le A 22 110 ~2Z;~Z49 ~o c ~ o~
v ~ E
3~u~ asuat~ F~Fu O C
c ~ nl~a~eqau~o~
..
o o o O " ~ su~l~e3~ n~ ~ r~ ~
L ~-- ~
~5 _ ~ umFxa~ qo~k o .
E :11 O L E O O o ~ ~ Q _ _ .
~:~
Cl:
C
_~ C~
~ ~
_ QJ E ~z O t~
~ ~ I I
Q ~ O _~- C.) X
~_ L ~ O C,) Z:
~) ~S: ~ ~ C ,_ Le A 22 110 _
Use Examples The following compound ;s employed as the com-parison substance ;n the examples which follow:
Fl~:OOH
C
Le A 22 11G - Foreign countr_es 'l.Z~Z;~4'~
Example ~
Xanthomonas oryzae testlbacteriosis/rice/systemic Solvent: 48~5 parts by weight of dimethylformamide Emulsifier: 1.5 parts by weight of alky~aryl polyglycol ether To produce 3 suitable preparation of active compound, 1 part by we;ght of active compound is mixed with the stated amounts of solvent and emulsifier, and the concentrate is dil~ted with water to the 1~ desired concentration.
To test for systemic properties, standard soil in which young plants have been gro~n is ~atered ~ith 100 ml of the preparation of active compound.
3 days after the treatment, the plants are inoculated, with an aqueous suspension of Xanthomonas oryzae by pr;cking. Thereafter, the plants remain ;n a greenhouse at 24 to 26C and 70 to 80~ relat;ve atmospheric humidity for 14 days until they are evaluated.
In this test, a clearly superior activity com-pared with the prior art is shown, for example~
by the compounds according to the following preparation examples:
Le A 22110 - foreign countries ~Z2~4'9 T a b l e Xanthomon3s oryzae test / bacteriosis / rice / systemic Active compounds Amount Disease applied infestation in mg in X of the of untreated active control compound systemic per2 100 cm F~ CGCH
ClJ~ 1 0 6 0 (known) FCl. 2C-S-N~ COOH 1 û 40 ~N~ cH2 ~ -- ~ ~
~{E'~-CH~.C~2{X~ 10 40 ~ FOOH
Le A 22 110 - Foreign co~ntries ~%z2~9 Example II
Agar pLate test Nutrient medium used 15 parts by weight of agar agar 10 parts by ~eight of sucrose 8 parts by weight of casein hydrolysate ~ parts by weight of yeast extract 2 parts by we;ght of dipotass;um hydrogen phosphate 0.3 part by we;ght of magnesium phosphate are dissolved ;n 1,030 mL of distilled water and the sol-ution is kept in an autoclave at 121C for 15 minutes.
Solvent: 10 parts by weight of dimethylformamide Ratio of the amounts of solvent to nutr;ent med;um:
0.2: 99.8~
To produce a su;table preparation of active com-pound, 1 part by weight of active compound is mixed with the stated amount of solvent.
The concentrate is thoroughly mixed, in the stated proportion, with the liquid nutrient med;um and the mix-ture is then poured into Petri dishes.
When the nutrient medium has cooled and solid;-fied~ the plates are ;noculated with the following micro-organisms and are incubated at about 28C:
Evaluat;on is carr;ed out after 2 days, the inh;-bition of growth be;ng used as a measure of the action of the preparat;ons.
In this test, a clear superiority compared with the prior art is shown by the compounds according to the following preparation examples:
Le A 22 110 - Forei n countries ~2;Z;Z;~49 J
o ,.
o ut .
o) 11 c o~
E asuauV5~ U el~
:~ c U~n~ eq~3u~0 o o su~l ~e ~ 3uln-'' " U~nl.~a~eqo~
~ ~ s c ~
o L E O O O
Q
C Cl Q a ~ C
~ O
Le A 2Z 110 - Foreign countries .
~2~
,_ -o v~
cn c o~
E
asuau~ u ~ N ~
c o uml~a~c[au,~10 Cli L
~ O
V O O
3 c . sua~ aum O 11 ~ r~
~ ~ u~ a~ o~5~
~ o o _ E ~ O O O
O L- E ~--C ~1 .~ C
_ O
~: O
.
~ ~ ~ Z
er Cl:
Le A 22 110 ~2Z;~Z49 ~o c ~ o~
v ~ E
3~u~ asuat~ F~Fu O C
c ~ nl~a~eqau~o~
..
o o o O " ~ su~l~e3~ n~ ~ r~ ~
L ~-- ~
~5 _ ~ umFxa~ qo~k o .
E :11 O L E O O o ~ ~ Q _ _ .
~:~
Cl:
C
_~ C~
~ ~
_ QJ E ~z O t~
~ ~ I I
Q ~ O _~- C.) X
~_ L ~ O C,) Z:
~) ~S: ~ ~ C ,_ Le A 22 110 _
Claims (28)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A method of combating plant-pathogenic bacteria, com-prising applying to the bacteria or to a habitat thereof a bactericidally effective amount of a 1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid derivative of the formula (I) in which R1 represents a CO-R6, CN, SO2-R7 or S-R8 radical, wherein R6 represents hydrogen, or represents straight-chain or branched alkyl which has 1 to 5 carbon atoms and is optionally mono-, di-or tri-substituted by amino, chlorine, alkoxycarbonyl with 1 to 4 carbon atoms in the alkyl part, carboxyl, alkoxy with 1 to 4 carbon atoms, hydroxy or trifluoromethylthio, or represents phenyl which is optionally mono-, di-, tri-, tetra- or penta-substituted by fluorine, chlorine, hydroxyl, methoxy, amino, nitro or carboxyl, or represents benzyl which is optionally substituted by amino in the methylene radical, or represents alkoxy or alkylthio which has 1 to 5 carbon atoms and is optionally substituted by fluorine, chlorine, pyrazol-1-yl, 1,2,3-triazol-1-yl or N-oxido-2-, -3- or -4-pyridyl, or represents benzyloxy or amino, or represents alkyl-amino which has 1 to 5 carbon atoms and is optionally substituted by alkoxycarbonyl with 1 to 3 carbon atoms in the alkyl part, benzyloxycarbonyl, carboxyl or halogen, or represents phenylamino, R7 represents straight-chain or branched alkyl which has 1 to 4 carbon atoms and is optionally mono-, di- or tri-substituted by fluorine, chlorine or amino, or represents phenyl or methylphenyl, R8 represents methoxycarbonyl, trichloromethyl or dichlorofluoro-methyl, R2, R3, R4 and R5 denotes hydrogen, methyl or ethyl and X denotes hydrogen, fluorine, chlorine or nitro, or a non-phyto-toxic acid addition, alkali metal or alkaline earth metal salt, heavy metal salt or hydrate thereof.
2. A method according to claim 1, in which R6 represents hydrogen, or represents alkyl which has 1 to 4 carbon atoms and is optionally mono- or di-substituted by amino, alkoxycarbonyl with 1 to 3 carbon atoms in the alkyl part, carboxyl, alkoxy with 1 to 3 carbon atoms or trifluoromethylthio, or represents phenyl which is optionally mono-, di-, tri-, tetra- or penta-substituted by chlorine, hydroxyl, amino or carboxyl, or represents benzyl which is optionally substituted by amino in the methylene radical, or represents alkoxy which has 1 to 4 carbon atoms and is optionally substituted by pyrazol-1-yl, 1,2,3-triazol-1-yl or N-oxide-2-, -3- or -4-pyridyl, or represents alkylthio with 1 or 2 carbon atoms, benzyloxy or amino, or represents alkylamino which has 1 to 5 carbon atoms and is optionally substituted by alkoxycarbonyl with 1 to 3 carbon atoms in the alkyl part, chlorine, or carboxyl, R7 represents straight-chain or branched alkyl with 1 to 3 carbon atoms, dichlorofluoromethyl, chlorobutyl, phenyl or methylphenyl, R8 represents methoxycarbonyl, trichloro-methyl or dichlorofluoromethyl, R2 represents hydrogen, methyl or ethyl, R3 represents hydrogen, R4 represents hydrogen or methyl, and R5 represents hydrogen.
3. A method according to claim 1, wherein the derivative of formula (I) is 7-(4-acetyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of the formula
4. A method according to claim 1, wherein the derivative of formula (I) is 7-[4-(4-carboxybutyryl)-1-piperazinyl]-1-cyclo-propyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of the formula
5. A method according to claim 1, wherein the derivative of formula (I) is 7-[4-(aminoacetyl)-1-piperazinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of the formula
6. A method according to claim 1, wherein the derivative of formula (I) is 7-(4-butyryl-1-piperazinyl)-1-cyclopropyl-1,4-dihydro-6-nitro-4-oxo-3-quinolinecarboxylic acid of the formula
7. A method according to claim 1, 2 or 3, wherein the derivative of formula (I) is applied to a plant, seed or site where a plant is to be grown.
8. A method according to claim 1, 2 or 3, wherein the derivative of formula (I) is applied in the form of an acid addi-tion, alkali metal or alkaline earth metal salt, heavy metal salt or hydrate thereof.
9. A method according to claim 1, wherein the derivative of formula (I) is applied in the form of a composition containing said derivative as active ingredient in admixture with a suitable carrier or diluent.
10. A method according to claim 9, wherein the derivative is applied to plant parts and the active ingredient concentration in said composition is between 0.0001 and 1% by weight.
11. A method according to claim 10, wherein the active ingredient concentration in said composition is between 0.001 and 0.5% by weight.
12. A method according to claim 1, 9 or 11, wherein the derivative of formula (I) is applied to seed in an amount of 0.001 to 50 g per kg of seed.
13. A method according to claim 1, 9 or 11, wherein the derivative of formula (I) is applied to seed in an amount of 0.01 to 10 g per kg of seed.
14. A method according to claim 1, 9 or 11, wherein the derivative of formula (I) is applied to soil in an amount to give a soil concentration of 0.00001 to 0.1 % by weight at the place of action.
15. A method according to claim 1, 9 or 11, wherein the derivative of formula (I) is applied to soil in an amount to give a soil concentration of 0.0001 to 0.02 % by weight at the place of action.
16. A heavy metal salt of a 1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid derivative of the formula in which R1 represents a CO-R6, CN, SO2-R7 or S-R radical, wherein R5 represents hydrogen, or represents straight-chain or branched alkyl which has 1 to 5 carbon atoms and is optionally mono-, di- or tri-substituted by amino, chlorine, alkoxycarbonyl with 1 to 4 carbon atoms in the alkyl part, carboxyl, alkoxy with 1 to 4 carbon atoms, hydroxy or trifluoromethylthio, or represents phenyl which is optionally mono-, di-, tri-, tetra- or penta-substituted by fluorine, chlorine, hydroxyl, methoxy, amino, nitro or carboxyl, or represents benzyl which is optionally substituted by amino in the methylene radical, or represents alkoxy or alkyl-thio which has 1 to 5 carbon atoms and is optionally substituted by fluorine, chlorine, pyrazol-1-yl, 1,2,3-triazol-1-yl or N-oxido-2-, -3- or -4-pyridyl, or represents benzyloxy or amino, or represents alkylamino which has 1 to 5 carbon atoms and is optionally substituted by alkoxycarbonyl with 1 to 3 carbon atoms in the alkyl part, benzyloxycarbonyl, carboxyl or halogen, or represents phenylamino, R7 represents straight-chain or branched alkyl which has 1 to 4 carbon atoms and is optionally mono-, di-or tri-substituted by fluorine, chlorine or amino, or represents phenyl or methylphenyl, R8 represents methoxycarbonyl, trichloro-methyl or dichlorofluoromethyl, R2, R3, R4 and R5 denotes hydro-gen, methyl or ethyl and X denotes hydrogen, fluorine, chlorine or nitro.
17. A heavy metal salt of a 1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid derivative according to claim 16, wherein R6 represents hydrogen, or represents straight-chain or branched alkyl which has 1 to 5 carbon atoms and is optionally mono-, di- or tri-substituted by amino, chlorine, alkoxycarbonyl with 1 to 4 carbon atoms in the alkyl part, carboxyl, alkoxy with 1 to 4 carbon atoms, hydroxy or trifluoromethylthio, or represents phenyl which is optionally mono-, di-, tri-, tetra-or penta-substituted by fluorine, chlorine, hydroxyl, methoxy, amino, nitro or carboxyl, or represents benzyl which is optionally substituted by amino in the methylene radical, or represents alkoxy or alkylthio which has 1 to 5 carbon atoms and is optionally substituted by fluorine, chlorine, pyrazol-1-yl, 1,2,3-triazol-1-yl or N-oxido 2-, -3- or -4-pyridyl, or represents benzyloxy or amino, or represents alkylamino which has 1 to 5 carbon atoms and is optionally substituted by alkoxycarbonyl with 1 to 3 carbon atoms in the alkyl part, benzyloxycarbonyl, carboxyl or halogen, or represents phenylamino, R7 represents straight-chain or branch-ed alkyl which has 1 to 4 carbon atoms and is optionally mono-, di- or tri-substituted by fluorine, chlorine or amino, or repre-sents phenyl or methylphenyl, R8 represents methoxycarbonyl, trichloromethyl or dichlorofluoromethyl, R2, R3, R4 and R5 denotes hydrogen, methyl or ethyl and X denotes hydrogen, fluorine, chlorine or nitro.
18. A heavy metal salt of a 1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid derivative according to claim 17, in which R6 represents hydrogen, or represents alkyl which has 1 to 4 carbon atoms and is optionally mono- or di-substituted by amino, alkoxycarbonyl with 1 to 3 carbon atoms in the alkyl part, car-boxyl, alkoxy with 1 to 3 carbon atoms or trifluoromethylthio, or represents phenyl which is optionally mono-, di-, tri-, tetra-or penta-substituted by chlorine, hydroxyl, amino or carboxyl, or represents benzyl which is optionally substituted by amino, or represents alkoxy which has 1 to 4 carbon atoms and is option-ally substituted by pyrazol-1-yl, 1,2,3-triazol-1-yl or N-oxido-2-, -3- or -4 pyridylmethyl, or represents alkylthio with 1 or 2 carbon atoms, benzyloxy or amino, or represents alkylamino which has 1 to 5 carbon atoms and is optionally sub-stituted by alkoxycarbonyl with 1 to 3 carbon atoms in the alkyl part or carboxyl, R7 represents straight-chain or branched alkyl with 1 to 3 carbon atoms, dichlorofluoromethyl, chlorobutyl, phenyl or methylphenyl, R8 represents methoxycarbonyl, trichloro-methyl or dichlorofluoromethyl, R2 represents hydrogen, methyl or ethyl, R3 represents hydrogen, R4 represents hydrogen or methyl, and R represents hydrogen.
19. A heavy metal salt of a quinolinecarboxylic acid according to claim 16, in which the heavy metal is copper, zinc or manganese.
20. A composition for combatting plant-pathogenic bacteria comprising, as an active ingredient, a compound according to claim 16 in admixture with a suitable diluent or carrier.
21. A composition according to claim 20 wherein the active ingredient concentration in the composition is between 0.0001 and 1% by weight.
22. A composition according to claim 20 wherein the active ingredient concentration in the composition is between 0.001 and 5% by weight.
23. A composition according to claim 20 or 22 wherein the active ingredient is a compound according to claim 17.
24. A composition according to claim 20 or 22 wherein the active ingredient is a compound according to claim 18.
25. A composition according to claim 20 or 22 wherein the active ingredient is a compound according to claim 19.
26. A composition according to claim 20 or 22 wherein the active ingredient is a non-phytotoxic heavy metal salt of 7-(4-ace-tyl-l-piperazinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-qui-nolinecarboxylic acid.
27. A composition according to claim 20 or 22 wherein the active ingredient is a non-phytotoxic heavy metal salt of 7-[4-(4-carboxybutyryl)-1-piperazinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.
28. A composition according to claim 20 or 22 wherein the active ingredient is a non-phytotoxic heavy metal salt of 7-[4-(aminoacetyl)-1-piperazinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3308909.4 | 1983-03-12 | ||
| DE19833308909 DE3308909A1 (en) | 1983-03-12 | 1983-03-12 | BACTERICIDALS BASED ON CHINOLONIC CARBONIC ACID |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1222249A true CA1222249A (en) | 1987-05-26 |
Family
ID=6193319
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000449254A Expired CA1222249A (en) | 1983-03-12 | 1984-03-09 | Bactericidal agents based on quinolonecarboxylic acids |
Country Status (12)
| Country | Link |
|---|---|
| EP (1) | EP0121727B1 (en) |
| JP (1) | JPS59170069A (en) |
| AT (1) | ATE22387T1 (en) |
| AU (1) | AU569494B2 (en) |
| BR (1) | BR8401084A (en) |
| CA (1) | CA1222249A (en) |
| DE (2) | DE3308909A1 (en) |
| DK (1) | DK148384A (en) |
| GR (1) | GR81891B (en) |
| HU (1) | HU194024B (en) |
| IL (1) | IL71200A (en) |
| ZA (1) | ZA841764B (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL80114A0 (en) * | 1985-09-24 | 1986-12-31 | Hoffmann La Roche | Quinoline derivatives,their manufacture and pharmaceutical compositions containing them |
| DE3542002A1 (en) * | 1985-11-28 | 1987-06-04 | Bayer Ag | 1-CYCLOPROPYL-6-FLUOR-1,4-DIHYDRO-4-OXO-7- (1-PIPERAZINYL) -3-QUINOLINE CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THEIR ANTIBACTERIAL AGENTS CONTAINING THEM |
| US4788320A (en) * | 1986-01-20 | 1988-11-29 | Kyorin Pharmaceutical Co., Ltd. | Benzoylacetic acid ester derivatives and process for their preparations |
| DE3705621C2 (en) * | 1986-02-25 | 1997-01-09 | Otsuka Pharma Co Ltd | Heterocyclic substituted quinolonecarboxylic acid derivatives |
| SI8712447A8 (en) | 1987-12-31 | 1995-12-31 | Krka Tovarna Zdravil | Process for preparing 1-substituted 6-fluoro-4-oxo-7-(1-piperazinyl) -1,4-dihydroquinoline-3-carboxylic acid and new intermediate used in this process |
| US5328908A (en) * | 1988-10-24 | 1994-07-12 | Procter & Gamble Pharmaceuticals, Inc. | Antimicrobial quinolone thioureas |
| SI9200377A (en) | 1992-12-11 | 1994-06-30 | Krka | Process for the preparation of 1-substituted 6-fluoro-4-oxo-7-(1-piperazinyl)-1,4-dihydroquinoline-3-carboxilic acid, novel intermediate used in this process and process for its preparation |
| CA2114981A1 (en) * | 1993-02-09 | 1994-08-10 | Kazumi Ogata | Quinolonecarboxylic acid derivatives |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS604820B2 (en) * | 1979-02-26 | 1985-02-06 | 大塚製薬株式会社 | Quinoline carboxylic acid derivative |
| 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 |
| DE3306771A1 (en) * | 1983-02-25 | 1984-08-30 | Bayer Ag, 5090 Leverkusen | CHINOLONIC CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THE ANTIBACTERIAL AGENTS CONTAINING THEM |
-
1983
- 1983-03-12 DE DE19833308909 patent/DE3308909A1/en not_active Withdrawn
-
1984
- 1984-02-29 DE DE8484102122T patent/DE3460791D1/en not_active Expired
- 1984-02-29 EP EP84102122A patent/EP0121727B1/en not_active Expired
- 1984-02-29 AT AT84102122T patent/ATE22387T1/en not_active IP Right Cessation
- 1984-02-29 DK DK148384A patent/DK148384A/en not_active Application Discontinuation
- 1984-03-08 JP JP59043032A patent/JPS59170069A/en active Pending
- 1984-03-09 CA CA000449254A patent/CA1222249A/en not_active Expired
- 1984-03-09 ZA ZA841764A patent/ZA841764B/en unknown
- 1984-03-09 IL IL71200A patent/IL71200A/en not_active IP Right Cessation
- 1984-03-09 BR BR8401084A patent/BR8401084A/en unknown
- 1984-03-09 HU HU84969A patent/HU194024B/en not_active IP Right Cessation
- 1984-03-12 GR GR74068A patent/GR81891B/el unknown
- 1984-03-12 AU AU25516/84A patent/AU569494B2/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| ATE22387T1 (en) | 1986-10-15 |
| DE3308909A1 (en) | 1984-09-13 |
| IL71200A0 (en) | 1984-06-29 |
| EP0121727B1 (en) | 1986-09-24 |
| AU2551684A (en) | 1984-09-13 |
| IL71200A (en) | 1988-03-31 |
| EP0121727A1 (en) | 1984-10-17 |
| BR8401084A (en) | 1984-10-16 |
| DK148384A (en) | 1984-09-13 |
| HU194024B (en) | 1988-01-28 |
| HUT34665A (en) | 1985-04-28 |
| AU569494B2 (en) | 1988-02-04 |
| ZA841764B (en) | 1984-10-31 |
| DE3460791D1 (en) | 1986-10-30 |
| GR81891B (en) | 1984-12-12 |
| JPS59170069A (en) | 1984-09-26 |
| DK148384D0 (en) | 1984-02-29 |
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