CA1262350A - Embonates of quinolonecarboxylic acids and of their derivatives - Google Patents
Embonates of quinolonecarboxylic acids and of their derivativesInfo
- Publication number
- CA1262350A CA1262350A CA000513667A CA513667A CA1262350A CA 1262350 A CA1262350 A CA 1262350A CA 000513667 A CA000513667 A CA 000513667A CA 513667 A CA513667 A CA 513667A CA 1262350 A CA1262350 A CA 1262350A
- Authority
- CA
- Canada
- Prior art keywords
- methyl
- represents hydrogen
- piperazinyl
- cyclopropyl
- ethyl
- 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
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
- C07C65/105—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups polycyclic
- C07C65/11—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups polycyclic with carboxyl groups on a condensed ring system containing two rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
- C07C65/105—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups polycyclic
- C07C65/15—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups polycyclic with carboxyl groups on a condensed ring system containing more than two rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/06—Peri-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Quinoline Compounds (AREA)
- Fodder In General (AREA)
- Medicinal Preparation (AREA)
Abstract
Embonates of Quinolonecarboxylic Acids and of Their Derivatives ABSTRACT
To eliminate the bad taste of quinolonecarboxylic acids when used to combat bacteria in human and veterinary medicine, the acids are administered in the form of their novel salts with embonic acid
To eliminate the bad taste of quinolonecarboxylic acids when used to combat bacteria in human and veterinary medicine, the acids are administered in the form of their novel salts with embonic acid
Description
~6~,~15~
The present invent;on relates to embonates of quinolonecarboxylic acids and of their derivatives, to process for their preparation and to oral agents con~
taining these compounds for human and veterinary medicine.
Quinolonecarboxylic ac;dsy their derivatives and their salts are already known (compare DE-OS tGer-man Published Specif;cation) 3,033,157). They are distinguished by outstanding bactericidal properties.
However, o~ing to the bitter taste ~hich some of them have, there are limits to their oral use in the form of solutions, suspensions or admixtures to feed or in drinking water. For example, it is not possible for these active compounds to be directly administered orally to livestock with a highly developed sense of taste, such as, for example~ pigs.
The embonates of quinolonecarboxylic acids and of their derivatives of the formula tI) have been found ~ COOH
The present invent;on relates to embonates of quinolonecarboxylic acids and of their derivatives, to process for their preparation and to oral agents con~
taining these compounds for human and veterinary medicine.
Quinolonecarboxylic ac;dsy their derivatives and their salts are already known (compare DE-OS tGer-man Published Specif;cation) 3,033,157). They are distinguished by outstanding bactericidal properties.
However, o~ing to the bitter taste ~hich some of them have, there are limits to their oral use in the form of solutions, suspensions or admixtures to feed or in drinking water. For example, it is not possible for these active compounds to be directly administered orally to livestock with a highly developed sense of taste, such as, for example~ pigs.
The embonates of quinolonecarboxylic acids and of their derivatives of the formula tI) have been found ~ COOH
2~ C~2 x Y~
~C OOH
in ~hich n represents 1 or 2, Y represents radicals of the formulae (II~ or (III) CO~"2 ~II) B A
Le A 23 943 .3~9 o F~C^~
B ~ N~
! ~ ~
~ R
in which A represents nitrogen or =C-R4, R4 represents hydrogen, fluorine, chlorine~ n;tro or methyl, representS ~5-N N ~ and B also R ~
represents R when R1 does not ~ N-denote cyclopropyl, and R represents hydrogen, a branched or unbranched alkyl group ~hich has 1 to 4 carbon atoms and can optionally be substituted by a hydroxyl or methoxy group, R6 represents hydrogen, methyl or phenyl, R7 represents hydrogen or methyl, R~ represents amino, alkyl- or dialkylamino having 1 or 2 carbon atoms in the alkyl group, aminomethyl, alkyl- or dialkylam;nomethyl having 1 or 2 carbon atoms in the alkyl group, R represen~s an alkyl radical having 1 to 3 carbon atoms9 cyclopropyl, 2-fluoroethyl, vinyl, methoxy~ 4-fluoro-phenyl or methylamino, R2 represents hydrogen, alkyl having 1 to 6 carbon atoms, and cyclohexyl~
benzyl~ Z-oxopropyl, phenacyl and Le A 23 943 ,35~?
ethoxycarbonylmethyL, R represents hydrogen, methyl or ethyl, Z represents oxygen, nitrogen which is substituted by methyl or phenyl, and =CH2-.
It has also been found that the embonates of quinolonecarboxyLic acids and of their derivatives of the formula (I) ~COOH
Yn (I) ~OH
COOH
in which n represents 1 or 2, Y represents radicals of the formulae (Il) or (111) 0 ~_' COOR2 ( 11 ) B A N
R
o ~'COOR2 ~ I 11 ) ZJ~R 3 in ~hich A represents nitrogen or =C-R4~
R4 represents hydrogen, fluorine, chlorine, nitro or methyl, ~ repreSents -N N- , and ~ also R
~8 represents ~ ~hen R1 does not Le A 23 943 ,3~
denote cyclopropyl~ and R5 represents hydrogen, a branched or unbranched alkyl group which has 1 to 4 carbon atoms and can optionally be substituted by a hydroxyl or methoxy group, R6 represents hydrogen, methyl or phenyl, R7 represents hydrogen or methyl, R8 represents am;no, alkyl- or d;alkylamino hav;ng 1 or 2 carbon atoms in the alkyl group, aminomethylO
alkyl~ or dialkylaminomethyl having 1 or 2 carbon atoms in the alkyl group, R1 represents an alkyl radical having 1 to 3 carbon atoms, cycLopropyl, 2-fluoroethyl, vinyl, methoxy, 4-fluoro-phenyl or methylamino, R2 represents hydrogen, alkyl having 1 to 6 carbon atoms, and cyclohexyl, benzyl, 2-oxopropyl~ phenacyl and ethoxycarbonylmethyl, R3 represents hydrogen, methyl or ethyl~
Z represents oxygen, nitrogen which is subst;tuted by methyl or phenyl, and are obta;ned by reaction of quinolonecarboxylic acids and of their derivatives of the formulae (II) or tllI) w;th embon;c acid of the formula (IV) OH
i ~I
r ~j, I
~C~
Le A 23 943 ~2~i~13~
It has been found, surprisingly, that the new compounds according to the invention have a neutral taste compared with other sal~s of quinolonecarboxylic acids. Thus they are outstandingly suitable for the preparation and use in agents which can be aclminis-tered orally in human medicine and veterinary medi-cineu They are also suitable for the preparation of medicated animal feed or of preparations ~hich are administered in the drinking ~ater. Furthermore in human medicine for the oral administration of these derivatives in the form of suspensions, syrups, emul-sions etcO in cases where other pharmaceutical formul-ations~ for example tablets or capsules, cannot be used~
The use of the compounds according to the ;nvention in veterinary medicine is part;cularly pre-ferred.
This ~as all the more surpr;s;ng since ;t has not been possible to ach;eve an effect on the taste of qu;nolonecarboxylic acids or of the;r derivatives by the formation of other salts.
The invention preferably relates to embonates of quinolonecarboxylic acids and of their derivatives of the formula (lla) ~OR~
a B~A~N~
Le A 23 943 ` ~2~.35~3 in which 8 represents R~-N N- or ~ N-when R1 does not denote cyclopropyl in the latter case, and A, R2, R5, R6, R7 and R8 have the above-mentioned meaning.
The invention particularly preferably relates to embonates of quinolonecarboxylic acids and of their derivatives of the formula (Ila) ~COOR ~ 1 1 a ) E~ A N
in which R2 represents hydrogen, alkyl having 1 to 4 carbon atoms, and benzyl, 2-oxopropyL, phen-acyl and ethoxycarbonylmethyl, R~
B represents R5-N N-R represents hydrogen, methyl or ethyl, R6 represents hydrogen or methyl, R7 represents hydrogen or methyl, and A has the abovementioned meaning.
Particular mention may be made of embonates of the following quinolonecarboxylic acids and of their derivatives:
1-cyclopropyl-6-fluoro-1,4-dihydro--4-oxo-7-~ (1-pipe~razinyl or 4-methyl- or 4~ethyl-1-piperazinyl-)-l 25 quinol~ine-3-carboxylic acid, 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-methyl-1-piperazinyl)-quinoline-3-Le A 23 943 ,3~i~
carboxylic acid, 1~ethyl-6-fluoro-1,4-dihydro-4-oxo-7~ piperazinyl)-quinoline-3-carboxylic acid, 1-ethyl-6-fluoro-1,~-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3~carboxylic acid, 9-fluoro-3-methyl-10-(4-methyL-1-piperazinyl)-7-oxo-2,3-dihydro-7,4-pyridot1,2,4-de]1,4-benzoxazine-6-carboxylic acid and the methyl and ethyl esters of these compounds.
The preparation of the embonates of qu;nolone-carboxylic acids and of their derivatives of the formula (I~ is preferably carried out by addition of embonic acid to quinolonecarboxylic acids and their derivatives of the formuLa (II~ or (III) in a suitable solvent and, ~here appropriate, heating.
Quinolonecarboxylic acid and embonic acid are used for this in the ratio ~:1 or 1:2. It is prefer-able to use for this an excess of embonic acid of 1-10%, preferably 1-5%, relative to the amount of embonic acid necessary for the abo~ementioned ratios.
It is also possible to react the salts of am;noqu;nolonecarboxylic acids with strong acids, such as, for example, hydrochloric acid, methane-sulphonic acid or formic acid, with alkali metal or alkal;ne earth metal salts of embonic acid.
Solvents suitable for the reaction which may be mentioned are inert organic solvents such as alcohols, for example methanol or ethanol, ethers such as diethyl ether or diisopropyl ether, glycol ethers such as glycol monomethyl ether, hydrocarbons such as petroleum ether, toluene, benzene and xylene, as well 3û as water.
The reaction is carried out at temperatures of 2û-150C. It is pre~erably carried out at the boiling psint of the solvent. It is also possible to carry out the reaction at room temperature~
The active compounds are preferably used in the form of oral formulations suitable for humans and Le A 23 943 35~
animals. Formulations of this type are:
Oral solutions, concentrates for oral adminis-tration after dilution, emulsions and suspensions ~or oral suspension.
Formulations in which the active compound is incorporated into an ointment base or into an oil-in-water or water-in-oil emulsion base; solid formulations such as powder, premixes or concentrates, granules, pellets, tablets, boli and capsules.
~ral solutions are prepared by dissolution of the active compound in a suitable solvent and, pos-sibly, addition of additives such as solubilizers, acids, bases, buffer substances, antioxidants and pre-servatives. The solutions are, ~here appropriate, sterilized by filtration and dispensed into containers.
Solvents ~hich may be mentioned are: physi-logically tolerated solvents such as water, alcohols, such as ethanol, butanol, benzyl acohol, glycerol, propylene glycol and polyethylene glycols, and N-methyl-pyrrolidone and mixtures thereof.
The active compounds can also, where appropri-ate, be dissolved in physiologically tolerated vege-table or synthetic oils.
Solubilizers which may be mentioned are:
solvents uhich promote the dissolution of the active compound or prevent its precipitation. Examples are polyvinylpyrrolidone, polyoxyethylated castor oil and polyoxyethylated sorbitan esters.
Examples o~ preservatives are benzyl alcohol, trichlorobutanol and p-hydroxybenzoic esters.
Oral solutions are used directly. Concen-trates are used oralLy after previous ~ilution to the use concentration.
Emulsions which can be used orally are either of the ~ater-in-oil type or of the oil-in-wzter type.
They are prepared by dissolution of the active Le A 23 943 5~1i compound in one phase and homogenization thereof with the assistance of suitable emulsifiers and, ~here appropriate, further auxiliaries such as pigments, substances promoein9 absorption, preservatives, anti-oxidants, sunscreen agents and substances increasingthe viscosity.
The following may be mentioned as hydrophobic phase (oils): paraffin oils, silicone oils, natural vegetable oils such as sesame oil, almond oil and castor oil, synthetic triglycerides such as caprylic/
capric acid bigylceride, triglyceride mixtures with vegetable ~atty acids of chain length Cg_12 or other specially selected natural fatty acids, partial gly-ceride mixtures of saturated or unsaturated fatty acids, which possibly also contain hydroxyl groups, and mono- and diglycerides of Cg_C10-fatty acids.
Fatty acid esters such as ethyl stearate, di-n-butyryl adipate, hexyl laurate, dipropylene glycol pelargonate, esters of a branched fatty acid of medium chain length with saturated C16-C1g-fatty alcohols, isopropyl myristate, isopropyl palmitate, caprylic/
capric esters of saturated fatty alcohols of chain length C12-C1g, isopropyl stearate, oleyl ol~ate, decyl oleate, ethyl oleate, ethyl lactate, wax-like fatty acid esters such as artificial duck preen gland fat~ dibutyl phthalate, diisopropyl adipate, ester mixtures related to the latter, etc.
Fatty alcohols such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol and oleyl alcohol.
Fatty acids such as, for example, oleic acid and its mi~tures~
The following may be mentioned as hydrophilic phase: water, alcohols such as, for example, propylene glycol, glycerol, sorbitol and their mixtures.
Emulsifiers which may be mentioned are:
Le A 23 943 ~2~,35~
surfactants (including emulsifiers and wetting agents) such as:
1. Hon-ionic emulsifiers, for example polyoxyethylated castor oil, polyoxyethylated sorbitan monoleate, sorbitan monostearate~ ethyl alcohol, glycerol monostearate9 polyoxyethyl stearate and alkylphenol polyglycol ethers, 2. Ampholytic emulsifiers such as di-Na N-lauryl-~-iminocdipropionate or lecithin,
~C OOH
in ~hich n represents 1 or 2, Y represents radicals of the formulae (II~ or (III) CO~"2 ~II) B A
Le A 23 943 .3~9 o F~C^~
B ~ N~
! ~ ~
~ R
in which A represents nitrogen or =C-R4, R4 represents hydrogen, fluorine, chlorine~ n;tro or methyl, representS ~5-N N ~ and B also R ~
represents R when R1 does not ~ N-denote cyclopropyl, and R represents hydrogen, a branched or unbranched alkyl group ~hich has 1 to 4 carbon atoms and can optionally be substituted by a hydroxyl or methoxy group, R6 represents hydrogen, methyl or phenyl, R7 represents hydrogen or methyl, R~ represents amino, alkyl- or dialkylamino having 1 or 2 carbon atoms in the alkyl group, aminomethyl, alkyl- or dialkylam;nomethyl having 1 or 2 carbon atoms in the alkyl group, R represen~s an alkyl radical having 1 to 3 carbon atoms9 cyclopropyl, 2-fluoroethyl, vinyl, methoxy~ 4-fluoro-phenyl or methylamino, R2 represents hydrogen, alkyl having 1 to 6 carbon atoms, and cyclohexyl~
benzyl~ Z-oxopropyl, phenacyl and Le A 23 943 ,35~?
ethoxycarbonylmethyL, R represents hydrogen, methyl or ethyl, Z represents oxygen, nitrogen which is substituted by methyl or phenyl, and =CH2-.
It has also been found that the embonates of quinolonecarboxyLic acids and of their derivatives of the formula (I) ~COOH
Yn (I) ~OH
COOH
in which n represents 1 or 2, Y represents radicals of the formulae (Il) or (111) 0 ~_' COOR2 ( 11 ) B A N
R
o ~'COOR2 ~ I 11 ) ZJ~R 3 in ~hich A represents nitrogen or =C-R4~
R4 represents hydrogen, fluorine, chlorine, nitro or methyl, ~ repreSents -N N- , and ~ also R
~8 represents ~ ~hen R1 does not Le A 23 943 ,3~
denote cyclopropyl~ and R5 represents hydrogen, a branched or unbranched alkyl group which has 1 to 4 carbon atoms and can optionally be substituted by a hydroxyl or methoxy group, R6 represents hydrogen, methyl or phenyl, R7 represents hydrogen or methyl, R8 represents am;no, alkyl- or d;alkylamino hav;ng 1 or 2 carbon atoms in the alkyl group, aminomethylO
alkyl~ or dialkylaminomethyl having 1 or 2 carbon atoms in the alkyl group, R1 represents an alkyl radical having 1 to 3 carbon atoms, cycLopropyl, 2-fluoroethyl, vinyl, methoxy, 4-fluoro-phenyl or methylamino, R2 represents hydrogen, alkyl having 1 to 6 carbon atoms, and cyclohexyl, benzyl, 2-oxopropyl~ phenacyl and ethoxycarbonylmethyl, R3 represents hydrogen, methyl or ethyl~
Z represents oxygen, nitrogen which is subst;tuted by methyl or phenyl, and are obta;ned by reaction of quinolonecarboxylic acids and of their derivatives of the formulae (II) or tllI) w;th embon;c acid of the formula (IV) OH
i ~I
r ~j, I
~C~
Le A 23 943 ~2~i~13~
It has been found, surprisingly, that the new compounds according to the invention have a neutral taste compared with other sal~s of quinolonecarboxylic acids. Thus they are outstandingly suitable for the preparation and use in agents which can be aclminis-tered orally in human medicine and veterinary medi-cineu They are also suitable for the preparation of medicated animal feed or of preparations ~hich are administered in the drinking ~ater. Furthermore in human medicine for the oral administration of these derivatives in the form of suspensions, syrups, emul-sions etcO in cases where other pharmaceutical formul-ations~ for example tablets or capsules, cannot be used~
The use of the compounds according to the ;nvention in veterinary medicine is part;cularly pre-ferred.
This ~as all the more surpr;s;ng since ;t has not been possible to ach;eve an effect on the taste of qu;nolonecarboxylic acids or of the;r derivatives by the formation of other salts.
The invention preferably relates to embonates of quinolonecarboxylic acids and of their derivatives of the formula (lla) ~OR~
a B~A~N~
Le A 23 943 ` ~2~.35~3 in which 8 represents R~-N N- or ~ N-when R1 does not denote cyclopropyl in the latter case, and A, R2, R5, R6, R7 and R8 have the above-mentioned meaning.
The invention particularly preferably relates to embonates of quinolonecarboxylic acids and of their derivatives of the formula (Ila) ~COOR ~ 1 1 a ) E~ A N
in which R2 represents hydrogen, alkyl having 1 to 4 carbon atoms, and benzyl, 2-oxopropyL, phen-acyl and ethoxycarbonylmethyl, R~
B represents R5-N N-R represents hydrogen, methyl or ethyl, R6 represents hydrogen or methyl, R7 represents hydrogen or methyl, and A has the abovementioned meaning.
Particular mention may be made of embonates of the following quinolonecarboxylic acids and of their derivatives:
1-cyclopropyl-6-fluoro-1,4-dihydro--4-oxo-7-~ (1-pipe~razinyl or 4-methyl- or 4~ethyl-1-piperazinyl-)-l 25 quinol~ine-3-carboxylic acid, 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-methyl-1-piperazinyl)-quinoline-3-Le A 23 943 ,3~i~
carboxylic acid, 1~ethyl-6-fluoro-1,4-dihydro-4-oxo-7~ piperazinyl)-quinoline-3-carboxylic acid, 1-ethyl-6-fluoro-1,~-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3~carboxylic acid, 9-fluoro-3-methyl-10-(4-methyL-1-piperazinyl)-7-oxo-2,3-dihydro-7,4-pyridot1,2,4-de]1,4-benzoxazine-6-carboxylic acid and the methyl and ethyl esters of these compounds.
The preparation of the embonates of qu;nolone-carboxylic acids and of their derivatives of the formula (I~ is preferably carried out by addition of embonic acid to quinolonecarboxylic acids and their derivatives of the formuLa (II~ or (III) in a suitable solvent and, ~here appropriate, heating.
Quinolonecarboxylic acid and embonic acid are used for this in the ratio ~:1 or 1:2. It is prefer-able to use for this an excess of embonic acid of 1-10%, preferably 1-5%, relative to the amount of embonic acid necessary for the abo~ementioned ratios.
It is also possible to react the salts of am;noqu;nolonecarboxylic acids with strong acids, such as, for example, hydrochloric acid, methane-sulphonic acid or formic acid, with alkali metal or alkal;ne earth metal salts of embonic acid.
Solvents suitable for the reaction which may be mentioned are inert organic solvents such as alcohols, for example methanol or ethanol, ethers such as diethyl ether or diisopropyl ether, glycol ethers such as glycol monomethyl ether, hydrocarbons such as petroleum ether, toluene, benzene and xylene, as well 3û as water.
The reaction is carried out at temperatures of 2û-150C. It is pre~erably carried out at the boiling psint of the solvent. It is also possible to carry out the reaction at room temperature~
The active compounds are preferably used in the form of oral formulations suitable for humans and Le A 23 943 35~
animals. Formulations of this type are:
Oral solutions, concentrates for oral adminis-tration after dilution, emulsions and suspensions ~or oral suspension.
Formulations in which the active compound is incorporated into an ointment base or into an oil-in-water or water-in-oil emulsion base; solid formulations such as powder, premixes or concentrates, granules, pellets, tablets, boli and capsules.
~ral solutions are prepared by dissolution of the active compound in a suitable solvent and, pos-sibly, addition of additives such as solubilizers, acids, bases, buffer substances, antioxidants and pre-servatives. The solutions are, ~here appropriate, sterilized by filtration and dispensed into containers.
Solvents ~hich may be mentioned are: physi-logically tolerated solvents such as water, alcohols, such as ethanol, butanol, benzyl acohol, glycerol, propylene glycol and polyethylene glycols, and N-methyl-pyrrolidone and mixtures thereof.
The active compounds can also, where appropri-ate, be dissolved in physiologically tolerated vege-table or synthetic oils.
Solubilizers which may be mentioned are:
solvents uhich promote the dissolution of the active compound or prevent its precipitation. Examples are polyvinylpyrrolidone, polyoxyethylated castor oil and polyoxyethylated sorbitan esters.
Examples o~ preservatives are benzyl alcohol, trichlorobutanol and p-hydroxybenzoic esters.
Oral solutions are used directly. Concen-trates are used oralLy after previous ~ilution to the use concentration.
Emulsions which can be used orally are either of the ~ater-in-oil type or of the oil-in-wzter type.
They are prepared by dissolution of the active Le A 23 943 5~1i compound in one phase and homogenization thereof with the assistance of suitable emulsifiers and, ~here appropriate, further auxiliaries such as pigments, substances promoein9 absorption, preservatives, anti-oxidants, sunscreen agents and substances increasingthe viscosity.
The following may be mentioned as hydrophobic phase (oils): paraffin oils, silicone oils, natural vegetable oils such as sesame oil, almond oil and castor oil, synthetic triglycerides such as caprylic/
capric acid bigylceride, triglyceride mixtures with vegetable ~atty acids of chain length Cg_12 or other specially selected natural fatty acids, partial gly-ceride mixtures of saturated or unsaturated fatty acids, which possibly also contain hydroxyl groups, and mono- and diglycerides of Cg_C10-fatty acids.
Fatty acid esters such as ethyl stearate, di-n-butyryl adipate, hexyl laurate, dipropylene glycol pelargonate, esters of a branched fatty acid of medium chain length with saturated C16-C1g-fatty alcohols, isopropyl myristate, isopropyl palmitate, caprylic/
capric esters of saturated fatty alcohols of chain length C12-C1g, isopropyl stearate, oleyl ol~ate, decyl oleate, ethyl oleate, ethyl lactate, wax-like fatty acid esters such as artificial duck preen gland fat~ dibutyl phthalate, diisopropyl adipate, ester mixtures related to the latter, etc.
Fatty alcohols such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol and oleyl alcohol.
Fatty acids such as, for example, oleic acid and its mi~tures~
The following may be mentioned as hydrophilic phase: water, alcohols such as, for example, propylene glycol, glycerol, sorbitol and their mixtures.
Emulsifiers which may be mentioned are:
Le A 23 943 ~2~,35~
surfactants (including emulsifiers and wetting agents) such as:
1. Hon-ionic emulsifiers, for example polyoxyethylated castor oil, polyoxyethylated sorbitan monoleate, sorbitan monostearate~ ethyl alcohol, glycerol monostearate9 polyoxyethyl stearate and alkylphenol polyglycol ethers, 2. Ampholytic emulsifiers such as di-Na N-lauryl-~-iminocdipropionate or lecithin,
3. Anionic emulsifiers such as La lauryl sulphate, fatty alcohol ether sulphates, mono/dialkyl poly-glycol ether orthophosphate monoethanolamine salt,
4~ Cationic emulsifiers such as cetyltrimethylammonium chloride Further auxiliaries which are suitable are:
substances which increase the viscosity and stabilize the emulsion, such as carboxymethylcelluLose, methyl-cellulose and other celluluse and starch derivatives, polyacrylates, alginates, gelatine, gum arabic, poly-vinylpyrrolidone, polyvinyl alcohol, copolymers of methyl vinyl ether and maleic anhydride, polyethylene glycols and waxes.
Colloidal silica or mixtures of the substances listed.
Suspensions which can be used orally are pre-pared by suspension of the active compound in a liquid vehicle, where appropriate with the addition of ~ur-ther auxiliaries such as wetting agents, pigments, substances promoting absorption, preservatives, anti-oxidants and sunscreen agents.
Liquid vehicles which may be mentioned are all homogeneous solvents and solvent mixtures.
~etting agents (dispersing agents) which may be mentioned are:
Surfactants (including emulsifiers and ~etting agents) such as Le A 23 943 1. Anionic surfactants such as, for example, Na lauryl sulphate, fatty alcohol ether sulPhates, mono/dialkyl polyglycol ether orthophosphate mono-ethanolamine salt, lignin sulphonates or dioctyl S sulphosuccinate, 2. Cationic surfactants such as, for example, cetyl trimethylammonium chloride, 3. Ampholytic surfactants such as, for example, di-Na N~lauryl-~-iminodipropionate or lecithin 4. Non-ionic surfactants such 35, for example, poly-oxyethylated castor oil, polyoxyethylated sorbitan monoleate, sorbitan monostearate, ethyl alcohol, glycerol monostearate, polyoxyethylene stearate, alkylphenol polyglycol ethers and Pluronic~.
Other auxiliaries which may be mentioned are those indicated above.
Semisolid formulations which can be adminis-tered orally differ from the suspensions and emulsions described above only by their higher viscosity.
2~ To prepare solid formulations, the active com-pound is mixed with suitable vehicles, where appropri-ate with the addition of auxiliaries, and converted into the desired form.
Vehicles which may be mentioned are all physi-ologically tolerated solid, inert substances. Allsuch serve inorganic and organic substances. Examples of inorganic substances are sodium chloride~ carbon-ates such as calcium carbonate, bicarbonates~ alumin-ium oxides, silicas, aluminas, precipitated or colloidal silicon dioxide, and phosphates.
Examples of organic substances are sugars, cellulose, foodstuffs and feedstuffs such as po~dered milk, meat-and-bone meals, coarse and fine grain meals, and starches.
Auxiliaries are preservatives, antioxidants and pigments, which have already been listed above.
Ie A 23 943 ,3~7 Further suitable auxiliaries are lubricants such as, for example, magnesium stearate, stearic acid~ talc and bentonites, substances promoting dis-integration, such as starch or crosslinked polyvinyl-pyrrolidone, binders such as, for example, starch,gelatine or linear polyvinylpyrrolidone, and dry binders such as microcrystalline cellulose.
The active compounds can also be encapsulated in the form of their abovementioned solid or liquid formulations. It may also be advantageous to use the active compounds in formulations ~hich release the active compound in a delayed manner.
The active compounds are preferably adminis-tered together with the feed and/or the drinking water.
The feed includes non-compound feedstuffs of vegetable origin such as hay, roots, grain and grain byproducts, non-compound feedstuffs of animal origin such as meat, fats, milk products, bonemeal and fish products, also the non-compound feedstuffs such as vitamins, proteins, amino acids, for example DL-methircines, and salts such as lime and sodium chlor-ide. The feed also includes supplementary, compound and mixed feedstuffs. These contain non-compound ~5 feedstuffs in a composition which ensures a balanced d;et w;th regard to the supply of energy and proteins and the supply ~ith vitamins, mineral salts and trace elements.
The concentration of the active compounds in the feed is normally about 0.01-500 ppm, preferably 0.1-50 ppm.
The ~ctive compounds can be added as such, or in the form of premixes or feed concentrates, to the feed.
Premixes and feed concentrates are mixtures of the active compound with a suitable vehicle. Vehicles Le A 23 943 ,, .
include the non-compound feedstuffs or mixtures thereof.
Furthermore, they can contain other auxili-aries such as, for example, substances which regulate the flow o~ properties and miscibility, such as, for example, s;lica, bentonites and l;gninsulphonates.
Furthermore, it is possible to add antioxidants such as BHT, or preservatives such as sorbic acid or cal-cium propionate.
Concentrates for administration in the drink-ing water must be formulated so that a clear solution or a homogeneous suspension is produced on mixing with the drinking ~ater.
Thus, suitable vehicles are water-soluble substances (~eed additives) such as sugars or salts (for example citrates, phosphates, sodium chloride and Na carbonate).
They can likewise contain antioxidants and preservatives.
The active compounds can be present in the formulations alone or mixed with other active com-pounds, mineral salts, trace elements, vitamins, pro-teins, pigments, fats or flavourings.
The active compounds act against micro-organisms which are pathogenic for humans and live-stock.
These microorganisms ;nclude:
1. Spirochaetaceae (for example Treponema, Leptospira, Porrelia) 2. Spirillaceae 3. Micrococcaceae (for example Staphylococc; Piotype A-Fo St. hyicus) 4. Streptococcaceae (for example Streptococcus uberis, Str. equi, Str. agalactiae~ Str. dysgaLactiae, Streptococci of Lancefield types A-N)
substances which increase the viscosity and stabilize the emulsion, such as carboxymethylcelluLose, methyl-cellulose and other celluluse and starch derivatives, polyacrylates, alginates, gelatine, gum arabic, poly-vinylpyrrolidone, polyvinyl alcohol, copolymers of methyl vinyl ether and maleic anhydride, polyethylene glycols and waxes.
Colloidal silica or mixtures of the substances listed.
Suspensions which can be used orally are pre-pared by suspension of the active compound in a liquid vehicle, where appropriate with the addition of ~ur-ther auxiliaries such as wetting agents, pigments, substances promoting absorption, preservatives, anti-oxidants and sunscreen agents.
Liquid vehicles which may be mentioned are all homogeneous solvents and solvent mixtures.
~etting agents (dispersing agents) which may be mentioned are:
Surfactants (including emulsifiers and ~etting agents) such as Le A 23 943 1. Anionic surfactants such as, for example, Na lauryl sulphate, fatty alcohol ether sulPhates, mono/dialkyl polyglycol ether orthophosphate mono-ethanolamine salt, lignin sulphonates or dioctyl S sulphosuccinate, 2. Cationic surfactants such as, for example, cetyl trimethylammonium chloride, 3. Ampholytic surfactants such as, for example, di-Na N~lauryl-~-iminodipropionate or lecithin 4. Non-ionic surfactants such 35, for example, poly-oxyethylated castor oil, polyoxyethylated sorbitan monoleate, sorbitan monostearate, ethyl alcohol, glycerol monostearate, polyoxyethylene stearate, alkylphenol polyglycol ethers and Pluronic~.
Other auxiliaries which may be mentioned are those indicated above.
Semisolid formulations which can be adminis-tered orally differ from the suspensions and emulsions described above only by their higher viscosity.
2~ To prepare solid formulations, the active com-pound is mixed with suitable vehicles, where appropri-ate with the addition of auxiliaries, and converted into the desired form.
Vehicles which may be mentioned are all physi-ologically tolerated solid, inert substances. Allsuch serve inorganic and organic substances. Examples of inorganic substances are sodium chloride~ carbon-ates such as calcium carbonate, bicarbonates~ alumin-ium oxides, silicas, aluminas, precipitated or colloidal silicon dioxide, and phosphates.
Examples of organic substances are sugars, cellulose, foodstuffs and feedstuffs such as po~dered milk, meat-and-bone meals, coarse and fine grain meals, and starches.
Auxiliaries are preservatives, antioxidants and pigments, which have already been listed above.
Ie A 23 943 ,3~7 Further suitable auxiliaries are lubricants such as, for example, magnesium stearate, stearic acid~ talc and bentonites, substances promoting dis-integration, such as starch or crosslinked polyvinyl-pyrrolidone, binders such as, for example, starch,gelatine or linear polyvinylpyrrolidone, and dry binders such as microcrystalline cellulose.
The active compounds can also be encapsulated in the form of their abovementioned solid or liquid formulations. It may also be advantageous to use the active compounds in formulations ~hich release the active compound in a delayed manner.
The active compounds are preferably adminis-tered together with the feed and/or the drinking water.
The feed includes non-compound feedstuffs of vegetable origin such as hay, roots, grain and grain byproducts, non-compound feedstuffs of animal origin such as meat, fats, milk products, bonemeal and fish products, also the non-compound feedstuffs such as vitamins, proteins, amino acids, for example DL-methircines, and salts such as lime and sodium chlor-ide. The feed also includes supplementary, compound and mixed feedstuffs. These contain non-compound ~5 feedstuffs in a composition which ensures a balanced d;et w;th regard to the supply of energy and proteins and the supply ~ith vitamins, mineral salts and trace elements.
The concentration of the active compounds in the feed is normally about 0.01-500 ppm, preferably 0.1-50 ppm.
The ~ctive compounds can be added as such, or in the form of premixes or feed concentrates, to the feed.
Premixes and feed concentrates are mixtures of the active compound with a suitable vehicle. Vehicles Le A 23 943 ,, .
include the non-compound feedstuffs or mixtures thereof.
Furthermore, they can contain other auxili-aries such as, for example, substances which regulate the flow o~ properties and miscibility, such as, for example, s;lica, bentonites and l;gninsulphonates.
Furthermore, it is possible to add antioxidants such as BHT, or preservatives such as sorbic acid or cal-cium propionate.
Concentrates for administration in the drink-ing water must be formulated so that a clear solution or a homogeneous suspension is produced on mixing with the drinking ~ater.
Thus, suitable vehicles are water-soluble substances (~eed additives) such as sugars or salts (for example citrates, phosphates, sodium chloride and Na carbonate).
They can likewise contain antioxidants and preservatives.
The active compounds can be present in the formulations alone or mixed with other active com-pounds, mineral salts, trace elements, vitamins, pro-teins, pigments, fats or flavourings.
The active compounds act against micro-organisms which are pathogenic for humans and live-stock.
These microorganisms ;nclude:
1. Spirochaetaceae (for example Treponema, Leptospira, Porrelia) 2. Spirillaceae 3. Micrococcaceae (for example Staphylococc; Piotype A-Fo St. hyicus) 4. Streptococcaceae (for example Streptococcus uberis, Str. equi, Str. agalactiae~ Str. dysgaLactiae, Streptococci of Lancefield types A-N)
5. Pseudomonaceae (for example Pseudomonas malei~ Ps.
Le A 23 943 2~i~23~
cepacia., ~s. aeruginosa, Ps. maltophilia), 8ruceLLa such as erucella abort, B. melitensis, B.
suis, Bordetella such as Bordetella bronchiseptica, Moraxella, Acinetobacter)
Le A 23 943 2~i~23~
cepacia., ~s. aeruginosa, Ps. maltophilia), 8ruceLLa such as erucella abort, B. melitensis, B.
suis, Bordetella such as Bordetella bronchiseptica, Moraxella, Acinetobacter)
6. Enterobacteriaceae (for example Salmonella o~ ~ypes B-E, Shigella, E. coli, Klebsiella~ Proteus, Citro-bacter, Edwardsiella, Uaemophilus, Providencia, Yersina)
7. Vibrionaceae (for example Yibrio such as V;brio cholerae), Pasteurella such as Pasteurella multo-cida~ Aeromonas, Actinobacillus, Streptobacillus
8. Bacteoi~aceae (for example Bacteroides, Fusobac-terium),
9. Erysiphylothix, Listeria such as Listeria monocyto-jenes
10.Bacillaceae (for exampLe BaciLlus, Clostridiumof types A-D, such as Clostridium perfringens), Lactobacillaceae and anaerobic Cocci such as for exampLe Peptostreptococci and Peptococci
11.Coryneform bacteria (for example Corynebacterium pyogenes)
12.Mycobacteriaceae (for example Mycobacterium bovis, M. avium, M. tuberculosis)
13.Actinomyceae (for example Actinomyces bovis, A.
israelii)
israelii)
14.Nocardiaceae (for example Norcardia facinica, N.
asteroides)
asteroides)
15.Rickettsiaceae tfor example Coxiella, Rickettsia)
16.Bartonellaceae (for exampLe aartoneLla)
17.Chlamycliaceae (for example Chlamydia psittaci)
18.Mycoplasmataceae (for example Mycoplasma mycoides, M. agalactiae, M~ gallisepticum~.
Microorganisms pathogenic for humans and live-stock can cause, as singLe or mixed infections, mani-festations of disease in the following organ systems of the livestock:
Le A 23 943 ~ 2~
Lung and trachial cavity, digestive systems such as stomach and intestine, breast and udder, genital systems such as uterus, soft tissues such as skin, muscles~ naiLs, claws and hooves, active and passive locomotor systems such as bones, muscles, tendons and joints, urogenital systems such as kidneys, urethra and ureter, nervous system, auditory apparatus and eyes.
As already mentioned, the active compounds are used to combat bacterial diseases of humans and live-stock. The livestock include:
Mammals, such as, for example, cattle, horses, pigs, sheep, goats, dogs, cats, camels, fur-bearing animals such as mink and chinchilla, and animals in zoos and laboratories, such as, for example, mice ancl rats;
Birds, such as, for example, geese, chickens, turkeys, ducks, pigeons, zoo birds, and laboratory birds such as, for example, parrots and budgerigars;
Fish, such as, for example, carp, trout, sal-mon, tench and eels, also ornamental fish and aquarium fish;
Reptiles, such as, for e~ample, crocodiles and snakes.
The bacterial diseases of livestock include, for example, pig dysentery; spirochaetosis of poultry, leptospirosis of cattle, pigs, horses and dogs; Cam-pylobacter enteritis in cattle; Campylobacter abortion in sheep and pigs; Campylc,bacter hepatitis of chickens;
skin infections: pyoderma of dogs; otitis externa;
mastitis of cattle, of sheep and of goats; strepto-coccal mastitis; streptococcal infections of horses, in pigs and other species; pneumococcal infections of calves and other species; glanders; conjunctivitis;
enteritis; pneumonia; brucellosis of cattle, sheep and pigs; rhinitis atrophicans of pigs; salmonellosis of Le A 23 ~43 cattle, horses, sheep, chickens and other species;
septicaemia; Escherichia coli infection in piglets;
metritis-mastitis-agalactic (MMA) syndrome; Klebsiella infestions; pseudotuberculosis; infectivus pleuro-pneumonia; primary pasteurelloses; lameness of foals;
necrobacillosis in cattle and domestic animals; lep-tospirosis; erysipelas of pigs and other species, listeriosis; anthrax; clostridioses; tetanus infec-tions; botulism; infections with Coynebacteria pyo-genes; tuberculosis of cattle, pigs, poultry and otherspecies; paratuberculosis of ruminants; nocardiosis;
Q fever; ornithosis-psittacosis; encephalomyclitis;
mycoplasmosis of cattle and other livestock, and enzotic pneumonia of pigs.
Example 1 __ Salt A:
, (n in Formula (I) represents 1) A suspension of 62.1 g (0.173 mol) of 1-cyclopropyL-6-fluoro-1,4-dihydro-4-oxo-7-(4-ethyl-1-piperazinyl)quinoline-3-carboxylic acid and 67.3 g (0.173 mol) of embonic acid (pamoic acid, 4,4'-methylene-bis-(3-hydroxy)-2~naptho;c acid, Fluka No.
45150) in 800 ml of glycol monomethyl ether is re-fluxed for 30 minutes. The mixture is cooled and the precipitate is filtered off with suct;on, uashed with ethanol and dried to constant ~eight in vacuo at 120C.
127.6 9 (~8.6% of theory) of salt A of decomposition po;nt 232-235C are obtained~
Example 2 Salt ~:
(n in Formula (I) represents 2) A suspension of 7108 9 (0.2 mol) of 1-cyclo-propyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-ethyl-1-piper-azinyl)quinoline-3-c3rboxylic acid (1) and 40 9 ~0.103 mol) of embonic acid (2~ in 5ûO Ql of glycol monomethyl ether is refluxed for one hour. The mixture is cooled Le A 23 943 .3~
- 17 ~
and the precipitate is ~iltered off with suct;on, washed with ethanol and dried at constant weight in vacuo at 120C. 107.2 9 (96.9X of theory) of salt B
of decomposition point 226-228C are obtained.
S C61H60F2N6o12 tl106) Calculated: C 66.16 H 5.42 N 7.59 F 3.43 Found: 66.0 5.6 7.5 3.4 The following salts of 1-cyclopropyl-6-fluoro-1~4-dihydro-4-oxo-7-(4-ethyl-1-piperazinyl)-quinoline-carboxylic acid are prepared in analogy to the above-mentioned procedures:
Salts with the bases (NaOH: KOH: Ca(OH)2:
Salts with the acids (HCl: H~r: HN03: CH3S03H:
CH3COOH). All these salts showed a marked bitter taste ~hen a tasting test was carried out.
In contrast, the salts of Examples 1 and 2 showed nc taste.
Le A 23 943 .
Microorganisms pathogenic for humans and live-stock can cause, as singLe or mixed infections, mani-festations of disease in the following organ systems of the livestock:
Le A 23 943 ~ 2~
Lung and trachial cavity, digestive systems such as stomach and intestine, breast and udder, genital systems such as uterus, soft tissues such as skin, muscles~ naiLs, claws and hooves, active and passive locomotor systems such as bones, muscles, tendons and joints, urogenital systems such as kidneys, urethra and ureter, nervous system, auditory apparatus and eyes.
As already mentioned, the active compounds are used to combat bacterial diseases of humans and live-stock. The livestock include:
Mammals, such as, for example, cattle, horses, pigs, sheep, goats, dogs, cats, camels, fur-bearing animals such as mink and chinchilla, and animals in zoos and laboratories, such as, for example, mice ancl rats;
Birds, such as, for example, geese, chickens, turkeys, ducks, pigeons, zoo birds, and laboratory birds such as, for example, parrots and budgerigars;
Fish, such as, for example, carp, trout, sal-mon, tench and eels, also ornamental fish and aquarium fish;
Reptiles, such as, for e~ample, crocodiles and snakes.
The bacterial diseases of livestock include, for example, pig dysentery; spirochaetosis of poultry, leptospirosis of cattle, pigs, horses and dogs; Cam-pylobacter enteritis in cattle; Campylobacter abortion in sheep and pigs; Campylc,bacter hepatitis of chickens;
skin infections: pyoderma of dogs; otitis externa;
mastitis of cattle, of sheep and of goats; strepto-coccal mastitis; streptococcal infections of horses, in pigs and other species; pneumococcal infections of calves and other species; glanders; conjunctivitis;
enteritis; pneumonia; brucellosis of cattle, sheep and pigs; rhinitis atrophicans of pigs; salmonellosis of Le A 23 ~43 cattle, horses, sheep, chickens and other species;
septicaemia; Escherichia coli infection in piglets;
metritis-mastitis-agalactic (MMA) syndrome; Klebsiella infestions; pseudotuberculosis; infectivus pleuro-pneumonia; primary pasteurelloses; lameness of foals;
necrobacillosis in cattle and domestic animals; lep-tospirosis; erysipelas of pigs and other species, listeriosis; anthrax; clostridioses; tetanus infec-tions; botulism; infections with Coynebacteria pyo-genes; tuberculosis of cattle, pigs, poultry and otherspecies; paratuberculosis of ruminants; nocardiosis;
Q fever; ornithosis-psittacosis; encephalomyclitis;
mycoplasmosis of cattle and other livestock, and enzotic pneumonia of pigs.
Example 1 __ Salt A:
, (n in Formula (I) represents 1) A suspension of 62.1 g (0.173 mol) of 1-cyclopropyL-6-fluoro-1,4-dihydro-4-oxo-7-(4-ethyl-1-piperazinyl)quinoline-3-carboxylic acid and 67.3 g (0.173 mol) of embonic acid (pamoic acid, 4,4'-methylene-bis-(3-hydroxy)-2~naptho;c acid, Fluka No.
45150) in 800 ml of glycol monomethyl ether is re-fluxed for 30 minutes. The mixture is cooled and the precipitate is filtered off with suct;on, uashed with ethanol and dried to constant ~eight in vacuo at 120C.
127.6 9 (~8.6% of theory) of salt A of decomposition po;nt 232-235C are obtained~
Example 2 Salt ~:
(n in Formula (I) represents 2) A suspension of 7108 9 (0.2 mol) of 1-cyclo-propyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-ethyl-1-piper-azinyl)quinoline-3-c3rboxylic acid (1) and 40 9 ~0.103 mol) of embonic acid (2~ in 5ûO Ql of glycol monomethyl ether is refluxed for one hour. The mixture is cooled Le A 23 943 .3~
- 17 ~
and the precipitate is ~iltered off with suct;on, washed with ethanol and dried at constant weight in vacuo at 120C. 107.2 9 (96.9X of theory) of salt B
of decomposition point 226-228C are obtained.
S C61H60F2N6o12 tl106) Calculated: C 66.16 H 5.42 N 7.59 F 3.43 Found: 66.0 5.6 7.5 3.4 The following salts of 1-cyclopropyl-6-fluoro-1~4-dihydro-4-oxo-7-(4-ethyl-1-piperazinyl)-quinoline-carboxylic acid are prepared in analogy to the above-mentioned procedures:
Salts with the bases (NaOH: KOH: Ca(OH)2:
Salts with the acids (HCl: H~r: HN03: CH3S03H:
CH3COOH). All these salts showed a marked bitter taste ~hen a tasting test was carried out.
In contrast, the salts of Examples 1 and 2 showed nc taste.
Le A 23 943 .
Claims (16)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing an embonate of a quinolonecar-boxylic acid of the formula (I) (I) or a derivative thereof, in which n represents 1 or 2, Y represents a radical of the formulae (II) or (III) (II) (III) in which A represents nitrogen or =C-R4, R4 represents hydrogen, fluorine, chlorine, nitro or methyl, B represents , and B also represents when R1 does not denote cyclopropyl, and R5 represents hydrogen, a branched or unbranched alkyl group which has 1 to 4 carbon atoms and can optionally be substitut-ed by a hydroxyl or methoxy group, R6 represents hydrogen, methyl or phenyl, R7 represents hydrogen or methyl, R8 represents amino, alkyl- or dialkylamino having 1 or 2 carbon atoms in the alkyl group, aminomethyl, alkyl- or dialkyl-aminomethyl having 1 or 2 carbon atoms in the alkyl group, R1 represents an alkyl radical having 1 to 3 carbon atoms, cyclopropyl, 2-fluoroethyl, vinyl, methoxy, 4-fluorophenyl or methylamino, R2 represents hydrogen, alkyl having 1 to 6 carbon atoms, and cyclohexyl, benzyl, 2-oxopropyl, phenacyl and ethoxycarbonyl-methyl, R3 represents hydrogen, methyl or ethyl, Z represents oxygen, nitrogen which is substituted by methyl or phenyl, and =CH2, which process comprises (a) reacting a quinolonecarboxylic acid of the formula (II) or (III), or a derivative thereof, with embonic acid of the for-mula (IV) (IV) or (b) a salt of an aminoquinolonecarboxylic acid with a strong acid is reacted with an alkali metal or alkaline earth metal salt of embonic acid.
2. A process for preparing an embonate of a quinolonecar-boxylic acid of formula (I) as defined in claim 1, or a derivative thereof, which process comprises reacting a quinolonecarboxylic acid of formulae (II) or (III), as defined in claim 1, or a derivative thereof, with embonic acid of formula (IV) as defined in claim 1.
3. The process of claim 2 wherein R1 is cyclopropyl.
4. The process of claim 2 wherein R2 represents hydrogen, alkyl having 1 to 4 carbon atoms, and benzyl, 2-oxopropyl, phenacyl, B represents R5 represents hydrogen, methyl or ethyl, R6 represents hydrogen or methyl, and R7 represents hydrogen or methyl.
5. The process of claim 2 wherein R1 is cyclopropyl, R2 is hydrogen, B is 1-piperazinyl, A represents =C-R4 and R4 is hydro-gen.
6. The process of claim 2 wherein R1 is cyclopropyl, R2 is hydrogen, B is 4-ethyl-1-piperazinyl, A represents =C-R4 and R
is hydrogen.
is hydrogen.
7. A process for preparing an embonate of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1-quinoline-3-carboxylic acid which comprises reacting embonic acid with 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1-quinoline-3-carboxylic acid.
8. An embonate of 1-cyclopropyl-6-fluoro-1,4 dihydro-4-oxo-7-(1-piperazinyl)-1-quinoline-3-carboxylic acid.
9. A process for preparing an embonate of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo 7-(1-[4-ethyl-piperazinyl])-quinolone-3-carboxylic acid which comprises reacting embonic acid with 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-[4-ethyl-piperazinyl]) quinolone-3-carboxylic acid.
10. An embonate of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-[4-ethyl-piperazinyl])-quinolone-3-carboxylic acid.
11. An embonate of a quinolonecarboxylic acid of the formula (I) (I) or a derivative thereof, in which n represents 1 or 2, Y represents a radical of the formulae (II) or (III) (II) (III) in which A represents nitrogen or =C-R4, R4 represents hydrogen, fluorine, chlorine, nitro or methyl, B represents and B also represents when R1 does not denote cyclopropyl, and R5 represents hydrogen, a branched or unbranched alkyl group which has 1 to 4 carbon atoms and can optionally be sub-stituted by a hydroxyl or methoxy group, R6 represents hydrogen, methyl or phenyl, R7 represents hydrogen or methyl, R8 represents amino, alkyl- or dialkylamino having 1 or 2 carbon atoms in the alkyl group, aminomethyl, alkyl- or dialkyl-aminomethyl having 1 or 2 carbon atoms in the alkyl group, R1 represents an alkyl radical having 1 to 3 carbon atoms, cyclopropyl, 2-fluoroethyl, vinyl, methoxy, 4-fluorophenyl or methylamino, R2 represents hydrogen, alkyl having 1 to 6 carbon atoms, and cyclohexyl, benzyl, 2-oxopropyl, phenacyl and ethoxy-carbonylmethyl, R3 represents hydrogen, methyl or ethyl, Z represents oxygen, nitrogen which is substituted by methyl or phenyl, and =CH2.
12. An embonate of claim 11, wherein Y represents the formula:
(IIa) (in which B represents , and the other symbols are as defined in claim 1).
(IIa) (in which B represents , and the other symbols are as defined in claim 1).
13. An embonate of claim 12, in which:
R2 represents hydrogen, C1-4 alkyl, benzyl, 2-oxopropyl, phenacyl or ethoxycarbonylmethyl;
R5 represents hydrogen, methyl or ethyl;
R6 represents hydrogen or methyl; and R7 represents hydrogen or methyl.
R2 represents hydrogen, C1-4 alkyl, benzyl, 2-oxopropyl, phenacyl or ethoxycarbonylmethyl;
R5 represents hydrogen, methyl or ethyl;
R6 represents hydrogen or methyl; and R7 represents hydrogen or methyl.
14. An embonate of claim 11, which is selected from the group consisting of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl or 4-methyl- or 4-ethyl-1-piperazinyl-)-quinoline-3-carboxylic acid, 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-methyl-1-piperazinyl)-quinoline-3-carboxylic acid, 1-ethyl-6-fluoro-1,4-di-hydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid, 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naph-thyridine-3-carboxylic acid, 9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7,4-pyrido[1,2,4-de]1,4-benz-oxazine-6-carboxylic acid and the methyl and ethyl esters of these compounds.
15. A pharmaceutical formulation for oral administration, which comprises a bactericidal effective amount of the embonate as defined in claim 11, 12 or 13 in admixture with a pharmaceutically acceptable vehicle.
16. An animal feed or preparation to be added in an animal drinking water which contains a bactericidal effective amount of the embonate as defined in claim 11, 12 or 13 in admixture with animal feed stuff or a vehicle for the preparation.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3525335.5 | 1985-07-16 | ||
| DE19853525335 DE3525335A1 (en) | 1985-07-16 | 1985-07-16 | EMBONATES OF CHINOLON CARBONIC ACIDS AND THEIR DERIVATIVES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1262350A true CA1262350A (en) | 1989-10-17 |
Family
ID=6275883
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000513667A Expired CA1262350A (en) | 1985-07-16 | 1986-07-14 | Embonates of quinolonecarboxylic acids and of their derivatives |
Country Status (20)
| Country | Link |
|---|---|
| EP (1) | EP0209000B1 (en) |
| JP (1) | JPH0772177B2 (en) |
| KR (1) | KR940002823B1 (en) |
| AR (1) | AR242570A1 (en) |
| AT (1) | ATE55600T1 (en) |
| AU (1) | AU582255B2 (en) |
| BR (1) | BR8603333A (en) |
| CA (1) | CA1262350A (en) |
| CS (1) | CS255878B2 (en) |
| DE (2) | DE3525335A1 (en) |
| DK (1) | DK168042B1 (en) |
| ES (1) | ES2000678A6 (en) |
| FI (1) | FI88389C (en) |
| GR (1) | GR861823B (en) |
| HU (1) | HU194151B (en) |
| IE (1) | IE58750B1 (en) |
| IL (1) | IL79399A (en) |
| NZ (1) | NZ216815A (en) |
| PL (1) | PL149651B1 (en) |
| ZA (1) | ZA865256B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3705621C2 (en) * | 1986-02-25 | 1997-01-09 | Otsuka Pharma Co Ltd | Heterocyclic substituted quinolonecarboxylic acid derivatives |
| DE19633480A1 (en) * | 1996-08-20 | 1998-02-26 | Bayer Ag | Orally administrable formulations of quinolone and naphthyridonecarboxylic acids |
| KR101173696B1 (en) * | 2003-02-10 | 2012-08-13 | 바이엘 파마 악티엔게젤샤프트 | Treatment of bacterial diseases of the respiratory organs by locally applying fluoroquinolones |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2397903A (en) * | 1944-09-19 | 1946-04-02 | Vick Chemical Company | Methylene-bis-2 hydroxy-3 naphthoates |
| US2641610A (en) * | 1950-10-27 | 1953-06-09 | May & Baker Ltd | Quaternary ammonium salts |
| JPS5762259A (en) * | 1980-09-05 | 1982-04-15 | Kyorin Pharmaceut Co Ltd | Preparation of substituted quinolinecarboxylic acid derivative |
| US4382937A (en) * | 1981-02-27 | 1983-05-10 | Dainippon Pharmaceutical Co., Ltd. | Naphthyridine derivatives and their use as anti-bacterials |
| HU188181B (en) * | 1981-06-11 | 1986-03-28 | Warner-Lambert Co,Us | Process for producing salts of naphtiridine and quinoline compounds of antimicrobial activity |
| DE3525108A1 (en) * | 1985-06-07 | 1986-12-11 | Bayer Ag, 5090 Leverkusen | ANTIBACTERIAL EFFECT OF CHINOLON CARBON ACID ESTERS |
-
1985
- 1985-07-16 DE DE19853525335 patent/DE3525335A1/en not_active Withdrawn
-
1986
- 1986-07-02 EP EP86109036A patent/EP0209000B1/en not_active Expired - Lifetime
- 1986-07-02 AT AT86109036T patent/ATE55600T1/en not_active IP Right Cessation
- 1986-07-02 DE DE8686109036T patent/DE3673476D1/en not_active Expired - Lifetime
- 1986-07-11 AU AU60062/86A patent/AU582255B2/en not_active Expired
- 1986-07-11 NZ NZ216815A patent/NZ216815A/en unknown
- 1986-07-11 JP JP61162170A patent/JPH0772177B2/en not_active Expired - Lifetime
- 1986-07-14 CS CS865351A patent/CS255878B2/en not_active IP Right Cessation
- 1986-07-14 FI FI862942A patent/FI88389C/en not_active IP Right Cessation
- 1986-07-14 CA CA000513667A patent/CA1262350A/en not_active Expired
- 1986-07-14 GR GR861823A patent/GR861823B/en unknown
- 1986-07-14 IL IL79399A patent/IL79399A/en not_active IP Right Cessation
- 1986-07-15 IE IE188986A patent/IE58750B1/en not_active IP Right Cessation
- 1986-07-15 ZA ZA865256A patent/ZA865256B/en unknown
- 1986-07-15 DK DK335386A patent/DK168042B1/en not_active IP Right Cessation
- 1986-07-15 PL PL1986260626A patent/PL149651B1/en unknown
- 1986-07-15 BR BR8603333A patent/BR8603333A/en unknown
- 1986-07-15 KR KR1019860005709A patent/KR940002823B1/en not_active IP Right Cessation
- 1986-07-15 HU HU862915A patent/HU194151B/en unknown
- 1986-07-16 AR AR86304525A patent/AR242570A1/en active
- 1986-07-16 ES ES8600335A patent/ES2000678A6/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| FI862942A0 (en) | 1986-07-14 |
| GR861823B (en) | 1986-11-11 |
| DK335386A (en) | 1987-01-17 |
| DE3525335A1 (en) | 1987-01-22 |
| AR242570A1 (en) | 1993-04-30 |
| HU194151B (en) | 1988-01-28 |
| DK168042B1 (en) | 1994-01-24 |
| KR940002823B1 (en) | 1994-04-04 |
| JPS6219569A (en) | 1987-01-28 |
| IE861889L (en) | 1987-01-16 |
| IE58750B1 (en) | 1993-11-03 |
| IL79399A (en) | 1990-08-31 |
| BR8603333A (en) | 1987-02-24 |
| FI862942A (en) | 1987-01-17 |
| EP0209000A3 (en) | 1988-05-25 |
| ATE55600T1 (en) | 1990-09-15 |
| PL149651B1 (en) | 1990-03-31 |
| JPH0772177B2 (en) | 1995-08-02 |
| PL260626A1 (en) | 1987-06-15 |
| CS255878B2 (en) | 1988-03-15 |
| DE3673476D1 (en) | 1990-09-20 |
| FI88389C (en) | 1993-05-10 |
| ES2000678A6 (en) | 1988-03-16 |
| NZ216815A (en) | 1988-10-28 |
| DK335386D0 (en) | 1986-07-15 |
| ZA865256B (en) | 1987-03-25 |
| CS535186A2 (en) | 1987-07-16 |
| EP0209000B1 (en) | 1990-08-16 |
| KR870001210A (en) | 1987-03-12 |
| EP0209000A2 (en) | 1987-01-21 |
| AU582255B2 (en) | 1989-03-16 |
| FI88389B (en) | 1993-01-29 |
| HUT42427A (en) | 1987-07-28 |
| AU6006286A (en) | 1987-01-22 |
| IL79399A0 (en) | 1986-10-31 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |