IE58750B1 - Embonates of quinolonecarboxylic acids and of their derivatives - Google Patents

Embonates of quinolonecarboxylic acids and of their derivatives

Info

Publication number
IE58750B1
IE58750B1 IE188986A IE188986A IE58750B1 IE 58750 B1 IE58750 B1 IE 58750B1 IE 188986 A IE188986 A IE 188986A IE 188986 A IE188986 A IE 188986A IE 58750 B1 IE58750 B1 IE 58750B1
Authority
IE
Ireland
Prior art keywords
formula
methyl
represents hydrogen
embonates
derivatives
Prior art date
Application number
IE188986A
Other versions
IE861889L (en
Original Assignee
Bayer Ag
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Bayer Ag filed Critical Bayer Ag
Publication of IE861889L publication Critical patent/IE861889L/en
Publication of IE58750B1 publication Critical patent/IE58750B1/en

Links

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

Landscapes

  • 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

1. Embonates of quinolonecarboxylic acids and of their derivatives of the formula (I) see diagramm : EP0209000,P10,F1 x Yn in which n represents 1 or 2, Y represents the radical of the formula see diagramm : EP0209000,P10,F2 in which R**2 represents hydrogen, alkyl having 1 to 4 carbon atoms, B represents see diagramm : EP0209000,P10,F3 R**5 represents hydrogen, methyl or ethyl, R**6 represents hydrogen or methyl, R**7 represents hydrogen or methyl, and A represents =CH-.

Description

The present invention relates to embonates of quinolonecarboxylic acids and of their derivatives, to process for their preparation and to oral agents containing these compounds for human and veterinary medicine.
Quinolonecarboxylic acids, their derivatives and their salts are already known (compare DE-OS (German Published Specification) 3,033,157). They are distinguished by outstanding bactericidal properties. However, owing to the bitter taste which 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.
Embonic acid and its salts with certain active compounds for delayed release of active compound were known (VS-P 2,397,903, Pharmazeut. Chemie (E. Schroder et al.), Verlag G. Thieme, Stuttgart 1982, page 932). However, it was not known that they can be used to neutralize the taste of quinolonecarboxylic acids and their derivatives.
The embonates of quinolonecarboxylic acids and of their derivatives of the formula (I) have been found in which n represents 1 or 2, Y represents the radical in which R2 represents hydrogen, alkyl having 1 to 4 carbon atoms, R6 B represents R5-n nR5 represents hydrogen, methyl or ethyl, R6 represents hydrogen or methyl, R7 represents hydrogen or methyl, and A represents =CH-.
It has also been found that the embonates of quinolonecarboxylic acids and of their derivatives of the formula (I) in which n represents 1 or 2, Y represents the abovementioned radical of the formula Ila are obtained by reacting quinolonecarboxylic acids and their derivatives of the formula (Ila) with embonic acid of the formula (IV) It has been found, surprisingly, that the new compounds according to the invention have a neutral taste compared with other salts of guinolonecarboxylic acids. Thus they are outstandingly suitable for the preparation of and use in agents which can be administered orally in human medicine and veterinary medicine. They are also suitable for the preparation of medicated animal feed or of preparations which are administered in the drinking water. Furthermore in human medicine for the oral administration of these derivatives in the form of suspensions, syrups, emulsions etc. in cases where other pharmaceutical formulations, for example tablets or capsules, cannot be used.
The use of the compounds according to the invention in veterinary medicine is particularly preferred.
This was all the more surprising since it has not been possible to achieve an effect on the taste of quinolonecarboxylic acids or of their derivatives by the formation of other salts.
Particular mention may be made of embonates of the following quinolonecarboxylic acids: l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1piperazinyl or 4-methyl- or 4-ethyl-1-piperazinyl-)quinoline-3-carboxylic acid and the methyl and ethyl esters of these compounds.
The preparation of the embonates of quinolonecarboxylic 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 formulae (Ila) in a suitable solvent and, where appropriate, heating.
Quinolonecarboxylic acid and embonic acid are used for this in the ratio 1:1 or 1:2. It is preferable 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 abovementioned ratios.
It is also possible to react the salts of aminoquinolonecarboxylic acids with strong acids, such as, for example, hydrochloric acid, methanesulphonic acid or formic acid, with alkali metal or alkaline 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 as water.
The reaction is carried out at temperatures of 20-150’C. It is preferably carried out at the boiling point 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 animals.
Formulations of this type are: Oral solutions, concentrates for oral administration after dilution, emulsions and suspension for oral use.
Formulations in which the active compound is incorporated into an ointment base or into an oil-inwater or water-in-oil emulsion base; Solid formulations such as powders, premixes or concentrates, granules, pellets, tablets, boli and capsules.
Oral solutions are prepared by dissolution of the active compound in a suitable solvent and, possibly, addition of additives such as solubilizers, acids, bases, buffer substances, antioxidants and preservatives. The solutions are, where appropriate, sterilize I by filtration and dispensed into containers.
Solvents which may be mentioned are: physiologiG cally tolerated solvents such as water, alcohols, such as ethanol, butanol, benzyl alcohol, glycerol, propylene glycol and polyethylene glycols, and N-methyl-pyrrolidone and mixtures thereof.
The active compounds can also, where appropriate, be dissolved in physiologically tolerated vegetable or synthetic oils.
Solubilizers which may be mentioned are: solvents which promote the dissolution of the active compound or prevent its precipitation. Examples are polyvinylpyrrolidone, polyoxyethylated castor oil and polyoxyethylated sorbitan esters.
Examples of preservatives are benzyl alcohol, trichlorobutanol and p-hydroxybenzoic esters.
Oral solutions are used directly. Concentrates are used orally after previous dilution to the use concentration.
Emulsions which can be used orally are either of the water-in-oil type or of the oil-in-water type.
They are prepared by dissolution of the active compound in one phase and homogenization thereof with the assistance of suitable emulsifiers and, where appropriate, further auxiliaries such as pigments, substances promoting absorption, preservatives, antioxidants, sunscreen agents and substances increasing the 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 biglyceride, triglyceride mixtures with vegetable fatty acids of chain length C8_12 or other specially selected natural fatty acids, partial glyceride mixtures of saturated or unsaturated fatty acids, which possibly also contain hydroxyl groups, and mono- and diglycerides of C8. C10-fatty acids.
Fatty acid esters such as ethyl stearate, din-butyl adipate, hexyl laurate, dipropylene glycol pelargonate, esters of a branched fatty acid of medium chain length with saturated C16-C18-fatty alcohols, iso7 propyl myristate, isopropyl palmitate, caprylic/capric esters of saturated fatty alcohols of chain length C12-C18, isopropyl stearate, oleyl oleate, 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 mixtures .
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: surfactants (including emulsifiers and wetting agents) such as: 1. Non-ionic emulsifiers, for example polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, - sorbitan monostearate, ethyl alcohol, glycerol monostearate, polyoxyethyl stearate and alkylphenol polyglycol ethers, 2. Ampholytic emulsifiers such as di-Na N-lauryl-^iminodipropionate or lecithin, 3. Anionic emulsifiers such as Na lauryl sulphate, fatty alcohol ether sulphates, mono/dialkyl polyglycol 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, methylcellulose and other cellulose and starch derivatives, polyacrylates, alginates, gelatine, gum arabic, polyvinylpyrrolidone, polyvinyl alcohol, copolymers of methyl vinyl ether and maleic anhydride, polyethylene glycols and waxes; Colloidal silica or mixtures of the substances listed.
S Suspensions which can be used orally are prepared by suspension of the active compound in a liquid vehicle, where appropriate with the addition of further auxiliaries such as wetting agents, pigments, substances promoting absorption, preservatives, antioxidants and sunscreen agents .
Liquid vehicles which may be mentioned are all homogeneous solvents and solvent mixtures.
Wetting agents (dispersing agents) which may be mentioned are: Surfactants (including emulsifiers and wetting agents) such as 1. Anionic surfactants such as, for example, Na lauryl sulphate, fatty alcohol ether sulphates, mono/dialkyl polyglycol ether orthophosphate monoethanolamine salt, ligninsulphonates or dioctyl sulphosuccinate, 2. Cationic surfactants such as, for example, cetyltrimethylammonium chloride, 3. Ampholytic surfactants such as, for example, di-Na N-lauryl-^-iminodipropionate or lecithin 4. Non-ionic surfactants such as, for example, polyoxyethylated castor oil, polyoxyethylated sorbitan monoleate, sorbitan monostearate, ethyl alcohol, glycerol monostearate, polyoxyethylene stearate, alkyIphenol polyglycol ethers and Pluronic*.
Other auxiliaries which may be mentioned are those indicated above.
Semisolid formulations which can be administered orally differ from the suspensions and emulsions described above only by their higher viscosity.
To prepare solid formulations, the active compound is mixed with suitable vehicles, where appropriate with the addition of auxiliaries, and converted into the desired form.
Vehicles which may be mentioned are all physiologically tolerated solid, inert substances.
Inorganic and organic substances are used as such. Examples of inorganic substances are sodium chloride, carbonates such as calcium carbonate, bicarbonates, aluminium oxides, silicas, aluminas, precipitated or colloidal silicon dioxide, and phosphates.
Examples of organic substances are sugars, cellulose, foodstuffs and feedstuffs such as powdered milk, meat-and-bone meals, coarse and fine grain meals, and starches.
Auxiliaries are preservatives, antioxidants and pigments, which have already been listed above.
Further suitable auxiliaries are lubricants such as, for example, magnesium stearate, stearic acid, talc and bentonites, substances promoting disintegration, such as starch or crosslinked polyvinylpyrrolidone, 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 advantaqeous to use the active compounds in formulations which release the active compound in a delayed manner.
The active compounds are preferably administered 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-methionine, and salts such as lime and sodium chloride. The feed also includes supplementary, compound and mixed feedstuffs. These containing non-compound feedstuffs in a composition which ensure a balanced diet with regard to the supply of energy and proteins and the supply with 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 active compounds can be added as such, or in 0 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 include the non-compound feedstuffs or mixtures thereof.
Furthermore, they can contain other auxiliaries, such as, for example, substances which regulate the flow properties and miscibility, such as, for example, silica, bentonites and ligninsulphonates. Furthermore, it is possible to add antioxidants such as BHT, or preservatives such as sorbic acid or calcium propionate.
Concentrates for administration in the drinking water must be formulated so that a clear solution or a homogeneous suspension is produced on mixing with the drinking water.
Thus, suitable vehicles are water-soluble substances (feed 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 compounds, mineral salts, trace elements, vitamins, proteins, pigments, fats or flavourings.
The active compounds act against microorganisms which are pathogenic for humans and livestock.
These microorganisms include: 1. Spirochaetaceae (for example Treponema, Leptospira, Borrelia) 2. Spirillaceae 3. Micrococcaceae (for example Staphylococci biotype A-F, St. hyicus) 4. Streptococcaceae (for example Streptococcus uberis, Str. equi, Str. agalactiae, Str. dysgalactiae. Streptococci of Lancefield types A-N) . Pseudomonaceae ( for example Pseudomonas malei, Ps. cepacia., Ps. aeruginosa, Ps. maltophilia), Brucella such as Brucella abort, B. melitensis, B. suis, Bordetella such as Bordetella bronchiseptica, Moraxella, Acinetobacter) 6. Enterobacteriaceae (for example Salmonella of types B-E, Shigella, E. coli, Klebsiella, Proteus, Citrobacter, Edwardsiella, Haemophilus, Providencia, Yersina) 7. Vibrionaceae (for example Vibrio such as Vibrio cholerae), Pasteurella such as Pasteurella multocida, Aeromonas, Actinobacillus, Streptobacillus 8. Bacteroidaceae (for example Bacteroides, Fusobacterium), 9. Erysiphylothix, Listeria such as Listeria monocytojenes . Bacillaceae (for example Bacillus, Clostridium 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) 14. Nocardiaceae (for example Norcardia facinica, N. asteroides) . Rickettsiaceae (for example Coxiella, Rickettsia) 16. Bartonellaceae (for example Bartonella) 17. Chlamydiaceae (for example Chlamydia psittaci) 18. Mycoplasmataceae (for example Mycoplasma mycoides, M. agalactiae, M. gallisepticum).
Microorganisms pathogenic for humans and livestock can cause, as single or mixed infections, manifestations of disease in the following organ systems of the livestock: Lung and trachial cavity, digestive systems such as stomach and intestine, breast and udder, genital system such as uterus, soft tissues such as skin, muscles, nails, claws and hooves, active and passive locomotor systems such as bones, muscles, tendons and 2 joints, urogenital system 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 livestock. The livestock include: Mammals, such as, for example, cattle, horses, pigs, sheep, goats, dogs, cats, camels, fur-bearing animal a such as mink and chinchilla, and animals in zoos and laboratories, such as, for example, mice and 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, salmon, tench and eels, also ornamental fish and aquarium fish; Reptiles, such as, for example, crocodiles and snakes .
The bacterial diseases of livestock include, for example, pig dysentery; spirochaetosis pf poultry, leptospirosis of cattle, pigs, horses and dogs; Campylobacter enteritis in cattle; Campylobacter abortion in sheep and pigs; Campylobacter hepatitis of chickens; skin infections: pyoderma of dogs; otitis externa; mastitis of cattle, of sheep and of goats; streptococcal 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 cattle, horses, sheep, chickens and other species; septicaemia; Escherichia coli infection in piglets; metritis-mastitisagalactic (MMA) syndrome; Klebsiella infections; pseudotuberculosis; infectious pleuropneumonia; primary pasteurelloses; lameness of foals; necrobacillosis in cattle and domestic animals; leptospirosis; erysipelas of pigs and other species, listeriosis; anthrax; clostridioses; tetanus infections; botulism; infections with Corynebacterium pyogenes; tuberculosis of cattle, pigs, poultry and other species; paratuberculosis of ruminants; nocardiosis; Q fever; ornithosis-psittacosis; encephalo1 3 mycelitis; mycoplasmosis of cattle and other livestock, and enzootic pneumonia of pigs.
Example 1 Salt A: (n in formula (I) represents 1) A suspension of 62.1 g (0.173 mol) of 1cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (4-ethyl-lpiperazinyl)-quinoline-3-carboxylic acid and 67.3 g (0.173 mol) of embonic acid (pamoic acid, 4,4'-methylenebis-(3-hydroxy)-2-naphthoic acid, Fluka No. 45150) in 800 ml of glycol monomethyl ether is refluxed for 30 minutes. The mixture is cooled and the precipitate is filtered off with suction, washed with ethanol and dried to constant weight in vacuo at 120°C. 127.6 g (98.6% of theory) of salt A of decomposition point 232-235°C are obtained.
Example 2 Salt B: (n in formula (I) represents 2) A suspension of 71.8 g (0.2 mol) of l-cyclopropyl-6-f luoro-1 ,4-dihydro-4-oxo-7-(4-ethyl-1piperazinyl)-quinoline-3-carboxylic acid (JL) and 40 g (0.103 mol) of embonic acid (2.) in 500 ml of glycol monomethyl ether is refluxed for 1 hour. The mixture is cooled and the precipitate is filtered off with suction, washed with ethanol and dried at constant weight in vacuo at 120*C. 107.2 g (96.9% of theory) of salt B of decomposition point 226-228eC are obtained.
C61H60F2N6012 (1106) 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 l-cyclopropyl-6-fluoro1,4-dihydro-4-oxo-7-(4-ethyl-l-piperazinyl)-quinolinecarboxylic acid are prepared in analogy to the abovementioned procedures : Salts with the bases (NaOH: KOH: Ca(0H)2: Salts with the acids (HCl: HBr: HN03: CH3SO3H: CH3COOH). All these salts showed a marked bitter taste when a tasting test was carried out.
In contrast, the salts of Examples 1 and 2 showed no taste.

Claims (5)

1. Embonates of quinolonecarboxylic acids and of their derivatives of the formula (I) in which n represents Y represents 1 or 2, the radical of the formula in which
2. (Ha) R 2 represents hydrogen, alkyl having 1 to 4 carbon atoms, B represents R 5 represents hydrogen, methyl or ethyl, R e represents hydrogen or methyl, R 7 represents hydrogen or methyl, and A represents =CH-. Process for the preparation of embonates of 1 ο quinolonecarboxylic acids and of their derivatives of the formula (I) in which represents represents 1 or 2, the radical (Ila) in which R 2 represents hydrogen, alkyl having 1 to 4 carbon atoms , R 6 B represents R 5 represents hydrogen, methyl or ethyl, R 6 represents hydrogen or methyl, R 7 represents hydrogen or methyl, and A represents =CH-, characterized in that quinolonecarboxylic acids and their derivatives of the formulae (Ha) are reacted with embonic acid of the formula (IV) (IV)
3. Oral bactericidal formulations for use in the area of medicine and veterinary medicine, which contain embonates of quinolonecarboxylic acids and of their 5 derivatives of the formula (I) according to Claim 1.
4. . Formulations according to Claim 3, characterized in that they contain embonates of l-cyclopropyl-6-fluoro1,4-dihydro-4-dihydro-4-oxo-7 - (1-piperazinyl) or (1-(4ethyl-piperazinyl]) -quinoline-3-carboxylic acid. 10 5. Antibacterial medicaments, feedstuffs or drinking water, characterized in that they contain at least one formulation according to Claim 3. 6. Use of the formulations according to Claim 3 in oral administration forms and in concentrates for the 1 5 preparation thereof. 7. Process for the preparation of formulations according to Claim 3, characterized in that embonates of quinolonecarboxylic acids of the formula I according to Claim 1 are mixed with extenders and/or diluents. 20 8. An embonate of a quinolonecarboxylic acid or a derivative thereof of the formula I given and defined in Claim 1, which is any one of those specifically hereinbefore mentioned. 9. A process for the preparation of an embonate of 25 a quinolonecarboxylic acid or a derivative thereof of the formula I given and defined in Claim 1, substantially as hereinbefore described with particular reference to the accompanying Examples. 10. An embonate of a quinolonecarboxylic acid or a derivative thereof of the formula I given and defined in Claim 1 whenever prepared by a process claimed in Claim 2 or 9 .
5. 11. An oral bactericidal formulation according to Claim 3 substantially as hereinbefore described.
IE188986A 1985-07-16 1986-07-15 Embonates of quinolonecarboxylic acids and of their derivatives IE58750B1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DE19853525335 DE3525335A1 (en) 1985-07-16 1985-07-16 EMBONATES OF CHINOLON CARBONIC ACIDS AND THEIR DERIVATIVES

Publications (2)

Publication Number Publication Date
IE861889L IE861889L (en) 1987-01-16
IE58750B1 true IE58750B1 (en) 1993-11-03

Family

ID=6275883

Family Applications (1)

Application Number Title Priority Date Filing Date
IE188986A IE58750B1 (en) 1985-07-16 1986-07-15 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)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
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

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
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
CA1262350A (en) 1989-10-17
FI88389B (en) 1993-01-29
HUT42427A (en) 1987-07-28
AU6006286A (en) 1987-01-22
IL79399A0 (en) 1986-10-31

Similar Documents

Publication Publication Date Title
US5145853A (en) Bactericidal formulations for use in veterinary medicine
US5808076A (en) Orally administrable formulations of quinolone- or naphthyridonecarboxylic acids
EP1355629B1 (en) Solid phase dispersion of quinolone- or naphthyridonecarboxylic acids
IE58750B1 (en) Embonates of quinolonecarboxylic acids and of their derivatives
EP0828715B1 (en) N-oxides as antibacterial agents
IE43251B1 (en) 4-(5-nitro-2-furyl)quinaldinic acid n-oxide and its use in the treatment of bovine mastitis
JP2000501110A (en) Pyrido (3,2,1-IJ) -1,3,4-benzoxadiazine
US8674107B2 (en) Crystal of anti-bacterial compound
JPH0565512B2 (en)
JPH03218312A (en) Preventive and treating agent of microbism for animal

Legal Events

Date Code Title Description
MK9A Patent expired