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EP0222814A1 - Use of quinolone derivatives for the treatment of mycoplasmal pneumonia in pigs - Google Patents

Use of quinolone derivatives for the treatment of mycoplasmal pneumonia in pigs

Info

Publication number
EP0222814A1
EP0222814A1 EP19860902887 EP86902887A EP0222814A1 EP 0222814 A1 EP0222814 A1 EP 0222814A1 EP 19860902887 EP19860902887 EP 19860902887 EP 86902887 A EP86902887 A EP 86902887A EP 0222814 A1 EP0222814 A1 EP 0222814A1
Authority
EP
European Patent Office
Prior art keywords
carboxylic acid
optionally substituted
oxo
dihydro
alkyl
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.)
Withdrawn
Application number
EP19860902887
Other languages
German (de)
French (fr)
Inventor
Norman Harold Rogers
Peter Charles Thomas Hannan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beecham Group PLC
Original Assignee
Beecham Group PLC
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 Beecham Group PLC filed Critical Beecham Group PLC
Publication of EP0222814A1 publication Critical patent/EP0222814A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines

Definitions

  • the present invention relates to a method of treating mycoplasmal pneumonia in pigs and to compounds for use in that method.
  • Mycoplasmal infections in animals are widespread and have been found to be very difficult to treat.
  • enzootic pneumonia in pigs is probably the most widespread and economically important pig disease in any swine-producing country in the world.
  • Mycoplasma hyopneumoniae is now well established as the principal causative agent of this disease. (Whittlestone P. (1973) Advances in Veterinary Science and Comparative Medicine 17, 1-55 and Switzer W.P. and Ross R.F. (1975) as above).
  • a method of treating pigs for the therapy and/or prophylaxis of mycoplasmal pneumonia comprises administration to a pig in need thereof, an antimycoplasmally effective amount of a quinolone derivative of formula (I)
  • Y is an optionally substituted aromatic six membered ring containing up to two nitrogen atoms
  • R 1 is C 1-4 alkyl optionally substituted by halogen, hydroxy or aryl; C 3-6 cycloalkyl; allyl or vinyl; or R 1 together with a substituent on the ring Y located at the position adjacent to the bridgehead form an optionally subtituted six membered ring containing 0,1 or 2 additional heteroatoms selected from oxygen, nitrogen and sulphur;
  • R 2 is hydrogen or R 2 together with R 1 forms an optionally substituted thiazolidinyl ring.
  • ''aryl'' includes phenyl
  • Y is an optionally substituted benzene, azine or diazine ring, preferably an optionally substituted benzene or azine ring.
  • Suitable substituents for Y include up to three members selected from C 1-4 alkyl, C 1-4 alkoxy, halogen, dioxymethylene, or an optionally substituted heterocyclic group having 5 or 6 ring atoms one or two of which may be selected from nitrogen, oxygen and sulphur.
  • Suitable substituents for the above mentioned heterocyclic groups include hydroxy, C 1-4 alkyl such as methyl, or C 1-4 alkyl substituted by amino or C 1-4 alkylamino such as ethylamino-methyl.
  • Preferred substituents for Y include fluorine, methyl, pyridinyl, 2, 5-dimethyl-pyridinyl, pyrrolidinyl,
  • substituents for that ring include oxo and C 1-4 alkyl such as methyl.
  • the ring contains one oxygen atom. It is however preferred that when this ring contains an oxygen atom and is substituted by C 1-6 alkyl at the carbon atom adjacent the nitrogen atom, that Y is not a benzene ring substituted by N-alkyl piperazinyl.
  • R 1 is ethyl, cyclopropyl or 2-fluoroethyl.
  • X is CR 2 wherein R 2 is hydrogen or together with R 1 forms a thiazolidinyl ring optionally substituted with C 1-4 alkyl such as methyl.
  • Suitable pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts, metal salts, in particular alkali metal salts such as sodium or potassium, or salts with strong organic bases for example those with lower alkylamines such as triethylamine, or with guanidine or tetramethyl-guanidine, or quaternary ammonium salts such as t-butyl ammonium salts.
  • Suitable acid addition salts of compounds of formula (I) include pharmaceutically acceptable inorganic salts such as the sulphate, nitrate, phosphate, hydrochloride and hydrobromide and pharmaceutically acceptable organic acid addition salts such as tartrate, maleate, citrate, methane-sulphonate, p-toluene-sulphonate, ⁇ -glycerophosphate, and glucose-1-phosphate.
  • pharmaceutically acceptable inorganic salts such as the sulphate, nitrate, phosphate, hydrochloride and hydrobromide
  • pharmaceutically acceptable organic acid addition salts such as tartrate, maleate, citrate, methane-sulphonate, p-toluene-sulphonate, ⁇ -glycerophosphate, and glucose-1-phosphate.
  • ester groups include those which are in-vivo hydrolysable in that they break down readily in the human or animal body to leave the parent acid or its salt.
  • An example of such an ester group is pivaloyloxymethyl.
  • esters include C 1-6 alkyl esters and amino C 3-8 alkyl esters.
  • a preferred sub group of compounds of formula (I) are compounds of formula (II)
  • X is nitrogen or CH
  • R 3 is C 1-4 alkyl or vinyl
  • R 4 is halogen such as fluorine, chlorine or bromine
  • R 5 and R 6 are each independently C 1-5 alkyl or
  • R 5 and R 6 together form a pyrrolidino, optionally substituted with hydroxy or C 1-4 alkylaminoC 1-4 alkyl; piperidino, morpholino or piperazino optionally 4-substituted by R 7 (CH 2 ) n where n is
  • R 3 is vinyl
  • R 4 is halogen
  • R 5 and R 6 together form an unsubstituted piperizino group.
  • Such compounds are described in European Published Patent Application No. 9425A.
  • a further preferred sub group of compounds of formula (I) are compounds of formula (III)
  • R 8 is hydrogen or halogen
  • R 9 is optionally substituted piperazinyl
  • R 10 is hydrogen, halogen, or C 1-4 alkoxy
  • R 11 is hydrogen
  • R 12 is C 1-4 alkyl such as methyl.
  • a further preferred sub-group of compounds of formula (I) are compounds of formula (IV)
  • R 13 is methyl, n-propyl, allyl, vinyl, 2-fluoroethyl or 2-hydroxyethyl and R 14 is piperizino; or
  • R 13 is 2-fluoroethyl and R 14 is 4-(allyl, ethyl, or 2-hydroxylethyl)piperizino, 3-or 4-hydroxypiperidino, 1-pyrollidino, morpholino or 4-dimethylaminopiperidino.
  • R 15 is C 1-4 alkyl optionally substituted with halogen or vinyl
  • R 16 and R 17 are independently selected from hydrogen or halogen; is thiazolidine or thiomorpholine; and n is 0 to 2.
  • R 18 is N or CR 22 in which R 22 is hydrogen, halogen, nitrile, carboxamide, carboxyl or an ester group;
  • R 19 is N or CH provided that R 19 i s not N when R 18 is N;
  • R 20 and R 21 are hydrogen, optionally substituted C 1-12 alkyl, optionally substituted alkenyl or optionally substituted alkynyl; or
  • R 2 O and R 21 together form an optionally substituted 3 to 7 membered ring which may contain additional heteroatoms.
  • a further sub-group of compounds of formula (I) are compounds of formula (VII)
  • R 23 is hydrogen or C 1-6 alkyl
  • R 24 is halogen
  • R 25 is mono or disubstituted amino, or optionally substituted cyclic amino.
  • R 23 is not C 1-6 alkyl when R 25 is N-alkyl substituted piperazinyl.
  • Compounds of formula (VII) we described in European Published Patent Application No. 47005 A.
  • Suitable examples of compounds of formula (I) include:
  • Compounds of formula (I) are known compounds or can be produced from known compounds by known methods.
  • the infection in which these compounds of formula (I) particularly useful is enzootic pneumonia of pigs, also known as mycoplasmal pneumonia of swine, this infection being attributable to Mycoplasma hyopneumoniae.
  • the compound of formula (I) may be administered to the animal as part of the total dietary intake. In this case the amount of compound employed may be less than 0.1% by weight of the diet.
  • the diet for animals may consist of normal foodstuffs to which the compound of formula (I) may be added or the compound of formula (I) may be included in a premix for admixture with the foodstuff.
  • a suitable method administration of the compound of formula (I) to animals is to add it to the animals' drinking water, for example at a concentration of about 5 to 500 ⁇ g/ml.
  • the compound of formula (I) is suitably administered in this way for a period of up to eight weeks depending upon the seriousness of the infection being treated.
  • the compound of formula (I) can be applied in the form of a pharmaceutical composition.
  • a composition for use in the treatment or prophylaxis of mycoplasma pneumonia in pigs which composition comprises a compound of formula (I) as hereinbefore defined and a pharmaceutically acceptable carrier.
  • composition may be formulated for administration by any suitable route, such as oral or parenteral.
  • the composition may be in the form of a dispersion or a solution of the drug in a suitable vehicle for use with an oral doser (this is a well known item of farm equipment, basically comprising a liquid reservoir, a mouthpiece adapted for insertion into animals mouths, and a pump mechanism whereby unit doses can be ejected from the reservoir through the mouthpiece).
  • a suitable vehicle for use with an oral doser this is a well known item of farm equipment, basically comprising a liquid reservoir, a mouthpiece adapted for insertion into animals mouths, and a pump mechanism whereby unit doses can be ejected from the reservoir through the mouthpiece.
  • the drug may be administered from an oral doser as an aqueous solution.
  • the vehicle will be an oil or water based cream to ensure homogeneity of the unit doses administered.
  • the invention therefore, also provides an oral doser containing a multi-dose of the drug in a veterinarily acceptable vehicle.
  • Fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred.
  • the compound, or pharmaceutically acceptable salt thereof depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • the dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use.
  • Parental suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • the dosage of the compound will depend upon the nature of the infection being treated, as well as the severity of the condition. Generally the dosage will be within the range of from 5 to 50 mg/kg per day.
  • MIC'S were determined by incorporating the compounds in Friis' medium (Friis 1975) supplemented with 1-cysteine hydrochloride (0.012% w/v) and nicotinamide - adenine dinucleotide (NAD) (0.012% w/v) and solidified with 0.65% agarose (Miles Laboratories Ltd) or in solidified SP4 medium (Tully et al 1977), and inoculating the surface of the plates with 0.001 ml of thawed aliquots of mycoplasmal cultures containing 10 6 cfu (colony forming units) per ml and incubiting them aerobically in moist conditions at 37°C for 6 days. The concentration of the compounds tested ranged from 10 ⁇ g/ml to 0.00025 ⁇ g/ml. The MIC was taken as the lowest concentration of compound to cause a 50% reduction in mycoplasmal growth.
  • a stock culture of M.hyopneumoniae strain UCD4 was maintained in Friis broth in 1 ml amounts at -70°C.
  • one vial was thawed, diluted 1:40 in Friis broth and incubated at 37°C for 72 hours.
  • 1.0 ml of neat culture was then added to 48 ml of Friis broth in 100 ml bottles. The bottles were incubated at 37°C for 2 hours.
  • a control culture containing no antibiotic was also prepared. The cultures were incubated at 37°C.
  • Results are shown graphically in the attached Figure 1 in which the number of survivors are shown (as log 10 cfu/ml) plotted against hours.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

Procédé de traitement de la pneumonie mycoplasmatique chez les porcs consistant à administrer une quantité présentant une activité antimycoplasmatique d'un dérivé de quinolone de formule (I), ou un sel ou un ester pharmaceutiquement acceptables de ce dérivé. Dans la formule Y est anneau aromatique à six membres éventuellement substitué contenant jusqu'au 2 atomes d'azote; R1 représente un alkyle comportant de 1 à 4 atomes de C substitué éventuellement par un halogène, un hydroxy ou un aryle; un cycloalkyle comportant de 3 à 6 atomes de C; allyle ou vinyle; ou alors R1 en combinaison avec un substituant sur l'anneau Y situé dans la position adjacente à la tête de pont forme un anneau à six membres substitué contenant 0, 1 ou 2 hétéroatomes supplémentaires sélectionnés parmi l'oxygène, l'azote et le soufre; R2 représente de l'hydrogène ou R2 en combinaison avec R1 forme un anneau de thiazolidinyle éventuellement substitué. Est également décrite l'utilisation du composé de formule (I) et ou d'un sel ou d'un ester pharmaceutiquement acceptables de ces composés dans la production d'un médicament pour le traitement ou la prophylaxie de la pneumonie mycoplasmatique chez les porcs.A method of treating mycoplasmatic pneumonia in pigs comprising administering an amount having antimycoplasmatic activity of a quinolone derivative of formula (I), or a pharmaceutically acceptable salt or ester of this derivative. In formula Y is an optionally substituted six-membered aromatic ring containing up to 2 nitrogen atoms; R1 represents an alkyl comprising from 1 to 4 C atoms optionally substituted by a halogen, a hydroxy or an aryl; a cycloalkyl having from 3 to 6 C atoms; allyl or vinyl; or R1 in combination with a substituent on the ring Y located in the position adjacent to the bridgehead forms a substituted six-member ring containing 0, 1 or 2 additional heteroatoms selected from oxygen, nitrogen and sulfur ; R2 represents hydrogen or R2 in combination with R1 forms an optionally substituted thiazolidinyl ring. Also described is the use of the compound of formula (I) and or a pharmaceutically acceptable salt or ester of these compounds in the production of a medicament for the treatment or prophylaxis of mycoplasmatic pneumonia in pigs.

Description

USE OF QUINOLONE DERIVATIVES FOR THE TREATMENT OF MYCOPLASMAL PNEUMONIA IN PIGS
The present invention relates to a method of treating mycoplasmal pneumonia in pigs and to compounds for use in that method.
A number of specific quinolone antibacterial agents have been found to have activity against human mycoplasma, for example M.pneumoniae (see Japanese patent application No. J.59116217A).
Mycoplasmal infections in animals are widespread and have been found to be very difficult to treat. For example, enzootic pneumonia in pigs is probably the most widespread and economically important pig disease in any swine-producing country in the world. (Switzer W.P. and Ross R.F. (1975) ''Diseases of Swine'' 4th Ed. p 749-58.) Mycoplasma hyopneumoniae is now well established as the principal causative agent of this disease. (Whittlestone P. (1973) Advances in Veterinary Science and Comparative Medicine 17, 1-55 and Switzer W.P. and Ross R.F. (1975) as above).
The applicants have found that many quinolone derivatives have surprisingly high activities against strains of Mycoplasma hyopneumoniae and furthermore are mycoplasmacidal in action.
According to the present invention there is provided a method of treating pigs for the therapy and/or prophylaxis of mycoplasmal pneumonia which method comprises administration to a pig in need thereof, an antimycoplasmally effective amount of a quinolone derivative of formula (I)
or a pharmaceutically acceptable salt or ester thereof;
wherein Y is an optionally substituted aromatic six membered ring containing up to two nitrogen atoms;
R1 is C1-4 alkyl optionally substituted by halogen, hydroxy or aryl; C3-6 cycloalkyl; allyl or vinyl; or R1 together with a substituent on the ring Y located at the position adjacent to the bridgehead form an optionally subtituted six membered ring containing 0,1 or 2 additional heteroatoms selected from oxygen, nitrogen and sulphur;
R2 is hydrogen or R2 together with R1 forms an optionally substituted thiazolidinyl ring.
Further according to the present invention there is provided the use of compound of formula (I) as hereinbefore defined in the manufacture of a medicament for the treatment or prophylaxis of mycoplasmal pneumonia in pigs.
As used herein the term ''aryl'' includes phenyl.
Suitably Y is an optionally substituted benzene, azine or diazine ring, preferably an optionally substituted benzene or azine ring. Suitable substituents for Y include up to three members selected from C1-4 alkyl, C1-4 alkoxy, halogen, dioxymethylene, or an optionally substituted heterocyclic group having 5 or 6 ring atoms one or two of which may be selected from nitrogen, oxygen and sulphur.
Suitable substituents for the above mentioned heterocyclic groups include hydroxy, C1-4 alkyl such as methyl, or C1-4 alkyl substituted by amino or C1-4 alkylamino such as ethylamino-methyl.
Preferred substituents for Y include fluorine, methyl, pyridinyl, 2, 5-dimethyl-pyridinyl, pyrrolidinyl,
3-hydroxy-pyrrolidinyl, piperazinyl,
3[(ethylamino)methyl]pyrrolidinyl, N-methyl piperazinyl and thiomorpholinyl.
When a substituent on Y forms a 5 or 6 membered ring with R1, suitable substituents for that ring include oxo and C1-4 alkyl such as methyl. Preferably the ring contains one oxygen atom. It is however preferred that when this ring contains an oxygen atom and is substituted by C1-6 alkyl at the carbon atom adjacent the nitrogen atom, that Y is not a benzene ring substituted by N-alkyl piperazinyl.
Suitably R1 is ethyl, cyclopropyl or 2-fluoroethyl.
Suitably X is CR2 wherein R2 is hydrogen or together with R1 forms a thiazolidinyl ring optionally substituted with C1-4 alkyl such as methyl.
Suitable pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts, metal salts, in particular alkali metal salts such as sodium or potassium, or salts with strong organic bases for example those with lower alkylamines such as triethylamine, or with guanidine or tetramethyl-guanidine, or quaternary ammonium salts such as t-butyl ammonium salts.
Suitable acid addition salts of compounds of formula (I) include pharmaceutically acceptable inorganic salts such as the sulphate, nitrate, phosphate, hydrochloride and hydrobromide and pharmaceutically acceptable organic acid addition salts such as tartrate, maleate, citrate, methane-sulphonate, p-toluene-sulphonate, α-glycerophosphate, and glucose-1-phosphate.
Examples of suitable pharmaceutically acceptable ester groups include those which are in-vivo hydrolysable in that they break down readily in the human or animal body to leave the parent acid or its salt. An example of such an ester group is pivaloyloxymethyl.
Further examples of pharmaceutically acceptable esters include C1-6 alkyl esters and amino C3-8 alkyl esters.
A preferred sub group of compounds of formula (I) are compounds of formula (II)
or a salt thereof wherein
X is nitrogen or CH;
R3 is C1-4 alkyl or vinyl;
R4 is halogen such as fluorine, chlorine or bromine; and
R5 and R6 are each independently C1-5 alkyl or
R5 and R6 together form a pyrrolidino, optionally substituted with hydroxy or C1-4 alkylaminoC1-4 alkyl; piperidino, morpholino or piperazino optionally 4-substituted by R7(CH2)n where n is
0-3 and R7 is hydrogen, hydroxy (if n is 2 or 3) optionally substituted phenyl, benzyl, vinyl (if n = 1 , 2 or 3 ) or lower acyl.
Suitable compounds of formula (II) are described in Belgium Patent Nos. 870,576 and 863,429, European Patent No. 9425 and Austrian Patent Application No. 8318698A.
In particular R3 is vinyl, R4 is halogen and R5 and R6 together form an unsubstituted piperizino group. Such compounds are described in European Published Patent Application No. 9425A.
A further preferred sub group of compounds of formula (I) are compounds of formula (III)
or a salt thereof
wherein
R8 is hydrogen or halogen,
R9 is optionally substituted piperazinyl,
R10 is hydrogen, halogen, or C1-4 alkoxy,
R11 is hydrogen;
R12 is C1-4 alkyl such as methyl.
Compounds of formula (III) are described in European Published Patent Application 0058392A.
A further preferred sub-group of compounds of formula (I) are compounds of formula (IV)
or a salt thereof.
Wherein R13 is methyl, n-propyl, allyl, vinyl, 2-fluoroethyl or 2-hydroxyethyl and R14 is piperizino; or
R13 is 2-fluoroethyl and R14 is 4-(allyl, ethyl, or 2-hydroxylethyl)piperizino, 3-or 4-hydroxypiperidino, 1-pyrollidino, morpholino or 4-dimethylaminopiperidino.
Suitable compounds of formula (IV) are described in Belgium Patent No. 887574. Yet a further preferred sub-group of compounds of formula ( I ) are compounds of formula (V)
or a salt or ester thereof;
wherein R15 is C1-4 alkyl optionally substituted with halogen or vinyl;
R16 and R17 are independently selected from hydrogen or halogen; is thiazolidine or thiomorpholine; and n is 0 to 2.
Suitable compounds of formula (V) are described in US Patent No. 4473568.
Yet a further preferred sub-group of compounds of formula (I) are compounds of formula (VI)
or a salt thereof wherein R18 is N or CR22 in which R22 is hydrogen, halogen, nitrile, carboxamide, carboxyl or an ester group;
R19 is N or CH provided that R19 is not N when R18 is N;
R20 and R21 are hydrogen, optionally substituted C1-12 alkyl, optionally substituted alkenyl or optionally substituted alkynyl; or
R2O and R21 together form an optionally substituted 3 to 7 membered ring which may contain additional heteroatoms.
Suitable compounds of formula (VI) we described in German Offenleggungschrift No. 3033 157.
A further sub-group of compounds of formula (I) are compounds of formula (VII)
or a salt thereof
wherein R23 is hydrogen or C1-6 alkyl;
R24 is halogen, and
R25 is mono or disubstituted amino, or optionally substituted cyclic amino.
It is preferred that R23 is not C1-6 alkyl when R25 is N-alkyl substituted piperazinyl. Compounds of formula (VII) we described in European Published Patent Application No. 47005 A.
Suitable examples of compounds of formula (I) include:
1-ethyl-6-fluoro-1,4-dihydro-7-(4-methyl-1-piperrazinyl)-4-oxoquinoline-3-carboxylic acid;
1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazinoquinoline-3-carboxylic acid;
6-chloro-1-ethyl-1,4-dihydro-4-oxo-7-piperazinoquinoline-3-carboxylic acid;
1-ethyl-6,8 difluoro-1,4-dihydro-4-oxo-7-(3-ethylaminomethyl-1-pyrrolidinyl)quinoline-3-carboxylic acid;
9-fluoro-10-(3-hydroxy-1-pyrrolidinyl)-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid;
9-fluoro-2,3-dihydro-3-methyl-7-oxo-10-(4-thiomorpholinyl)-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid;
1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazinequinoline-3-carboxylic acid;
1-ethyl-6-fluoro1l,4-dihydro-4-oxo-7-piperazino-1,8-naphthyridine-3-carboxylic acid and the sesquihydrate thereof;
1-(2-fluoroethyl)-7-(1-piperaziny1)-6,8-difluoro-4-quinolone-3-carboxylic acid; 1-ethyl-1,4-dihydro-4-oxo-7-(4-pyridyl)quinoline-3-carboxylic acid;
1-ethyl-1,4-dihydro-7-(2,6-dimethyl-4-pyridyl)-4-oxoquinoline-3-carboxylic acid;
7-fluoro-1-methyl-8-(4-methyl-1-piperazinyl)-5-oxo-5H-thiazolo[3,2-a]-quinoline-4-carboxylic acid;
7-fluoro-1-methyl-5-oxo-8-(1-piperazinyl)-5H-thiazolo [3,2-a]-quinoline-4-carboxylic acid;
9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-d,e][1,4]benzoxazine-6-carboxylic acid;
and pharmaceutically acceptable salts thereof.
Compounds of formula (I) are known compounds or can be produced from known compounds by known methods.
For example, compounds of formula (I) and the preparation thereof are described in Belgium Patent No. 870576, Belgium Patent No. 863-429, US Patent No 3,753,993, Japanese Kokai No. 53065887, German Offenlegungschift 3033157, EP 9425A, US Patent No. 4,398029, EP 47005A, US Patent No. 4,473,568 and EP 58392A.
As has been stated hitherto the infection in which these compounds of formula (I) particularly useful is enzootic pneumonia of pigs, also known as mycoplasmal pneumonia of swine, this infection being attributable to Mycoplasma hyopneumoniae. The compound of formula (I) may be administered to the animal as part of the total dietary intake. In this case the amount of compound employed may be less than 0.1% by weight of the diet. The diet for animals may consist of normal foodstuffs to which the compound of formula (I) may be added or the compound of formula (I) may be included in a premix for admixture with the foodstuff.
A suitable method administration of the compound of formula (I) to animals is to add it to the animals' drinking water, for example at a concentration of about 5 to 500μg/ml.
The compound of formula (I) is suitably administered in this way for a period of up to eight weeks depending upon the seriousness of the infection being treated.
Alternatively the compound of formula (I) can be applied in the form of a pharmaceutical composition. Further according to the present invention there is provided a composition for use in the treatment or prophylaxis of mycoplasma pneumonia in pigs which composition comprises a compound of formula (I) as hereinbefore defined and a pharmaceutically acceptable carrier.
The composition may be formulated for administration by any suitable route, such as oral or parenteral.
For oral administration the composition may be in the form of a dispersion or a solution of the drug in a suitable vehicle for use with an oral doser (this is a well known item of farm equipment, basically comprising a liquid reservoir, a mouthpiece adapted for insertion into animals mouths, and a pump mechanism whereby unit doses can be ejected from the reservoir through the mouthpiece). Conveniently the drug may be administered from an oral doser as an aqueous solution. Alternatively, the vehicle will be an oil or water based cream to ensure homogeneity of the unit doses administered.
The invention, therefore, also provides an oral doser containing a multi-dose of the drug in a veterinarily acceptable vehicle.
For parenteral administration either short-acting or long-acting formulations can be employed. Fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred. The compound, or pharmaceutically acceptable salt thereof depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum.
The dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use. Parental suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
The dosage of the compound will depend upon the nature of the infection being treated, as well as the severity of the condition. Generally the dosage will be within the range of from 5 to 50 mg/kg per day.
The following biological data illustrates the invention.
METHOD
Minimal Inhibitory Concentration (MIC)
MIC'S were determined by incorporating the compounds in Friis' medium (Friis 1975) supplemented with 1-cysteine hydrochloride (0.012% w/v) and nicotinamide - adenine dinucleotide (NAD) (0.012% w/v) and solidified with 0.65% agarose (Miles Laboratories Ltd) or in solidified SP4 medium (Tully et al 1977), and inoculating the surface of the plates with 0.001 ml of thawed aliquots of mycoplasmal cultures containing 106cfu (colony forming units) per ml and incubiting them aerobically in moist conditions at 37°C for 6 days. The concentration of the compounds tested ranged from 10μg/ml to 0.00025 μg/ml. The MIC was taken as the lowest concentration of compound to cause a 50% reduction in mycoplasmal growth.
References.
Friis M.F. (1973) Nordisk Veterinaer medicin 27,
337-339
Tully J.G., Whitcomb R.F., Clark H.F., Williamson D.L.
(1977) Science, 195, 892-894
The results obtained for compounds 1 to 14 against three strains of M.hyopneumoniae and against M.bovis by way of comparison are given in the following table.
Mycoplasmacidal Test
Method
A stock culture of M.hyopneumoniae strain UCD4 was maintained in Friis broth in 1 ml amounts at -70°C. For the test, one vial was thawed, diluted 1:40 in Friis broth and incubated at 37°C for 72 hours. 1.0 ml of neat culture was then added to 48 ml of Friis broth in 100 ml bottles. The bottles were incubated at 37°C for 2 hours. To each was then added 1.0 ml of drug solution at 50x the desired concentration (1 x agar MIC, 5 x agar MIC and 10 x agar MIC) . A control culture containing no antibiotic was also prepared. The cultures were incubated at 37°C. Immediately on addition of drug solution, and periodically thereafter, samples of culture were withdrawn for viable count determinations. These were performed by preparing serial 10-fold dilutions of the drug-containing Friis broth in drug-free Friis broth (down to 1:106) and then plating 0.02 ml amounts of the dilutions on to Friis agarose plates. Colony counts were performed after 7 days incubation at 37°C. The number of survivors was determined in this way for up to 96 hours.
Results are shown graphically in the attached Figure 1 in which the number of survivors are shown (as log10 cfu/ml) plotted against hours.

Claims

Claims
1. The use of a quinolone derivative of formula (I)
or a pharmaceutically acceptable salt or ester thereof;
wherein Y is an optionally substituted aromatic six membered ring containing up to two nitrogen atoms;
R1 is C1-4 alkyl optionally substituted by halogen, hydroxy or aryl; C3-6 cycloalkyl; allyl or vinyl; or R1 together with a substituent on the ring Y located at the position adjacent to the bridgehead form an optionally subtituted six membered ring containing 0,1 or 2 additional heteroatoms selected from oxygen, nitrogen and sulphur;
R2 is hydrogen or R2 together with R1 forms an optionally substituted thiazolidinyl ring:
for the manufacture of a medicament for the treatment or prophylaxis of mycoplasmal pneumonia in pigs.
2. The use according to claim 1 wherein Y is an optionally substituted benzene, azine or diazine ring.
3. The use according to claim 2 wherein Y has up to three substituents selected from C1-4 alkyl, C1-4 alkoxy, halogen, dioxymethylene or an optionally substituted heterocyclic group having 5 or 6 ring atoms, one or two of which may be selected from nitrogen, oxygen and sulphur.
4. The use according to any preceding claim wherein the quinolone derivative is a compound of formula (II)
or a salt thereof
wherein
X is nitrogen or CH;
R3 is C1-4 alkyl or vinyl;
R4 is halogen such as fluorine, chlorine or bromine; and
R5 and R6 are each independently C1-5 alkyl or
R5 and R6 together form a pyrrolidino, optionally substituted with hydroxy or C1-4 alkylaminoC1-4 alkyl; piperidino, morpholino or piperazino optionally 4-substituted by R7(CH2)n where n is
0-3 and R7 is hydrogen, hydroxy (if n is 2 or 3) optionally substituted phenyl, benzyl, vinyl (if n
= 1, 2 or 3 ) or lower acyl.
5. The use according to any one of claims 1 to 3 wherein the quinolone derivative is a compound of formula (III)
or a salt thereof
wherein
R8 is hydrogen or halogen,
R9 is optionally substituted piperazinyl,
R10 is hydrogen, halogen, or C1-4 alkoxy,
R11 is hydrogen;
R12 is C1-4 alkyl such as methyl.
6. The use according to any one of claims 1 to 3 wherein the quinolone derivative is a compound of formula (IV)
or a salt thereof.
Wherein R13 is methyl, n-propyl, allyl, vinyl, 2-fluoroethyl or 2-hydroxyethyl and R14 is piperizino; or R13 is 2-fluoroethyl and R14 is 4-(allyl, ethyl, or 2-hydroxylethyl)piperizino, 3-or 4-hydroxypiperidino, 1-pyrollidino, morpholino or 4-dimethylaminopiperidino.
7. The use according to any one of claims 1 to 3 wherein the quinolone derivative is a compound of formula (V)
or a salt or ester thereof;
wherein R15 is C1-4 alkyl optionally substituted with halogen or vinyl;
R16 and R17 are independently selected from hydrogen or halogen;
- is thiazolidine or thiomorpholine; and n is 0 to 2.
8. The use according to any one of claims 1 to 3 wherein the quinolone derivative is a compound of formula (VI) wherein R18 is N or CR22 in which R22 is hydrogen, halogen, nitrile, carboxamide, carboxyl or an ester group;
R19 is N or CH provided that R19 is not N when R18 is N;
R20 and R21 are hydrogen, optionally substituted C1-12 alkyl, optionally substituted alkenyl or optionally substituted alkynyl; or
R20 and R21 together form an optionally substituted 3 to 7 membered ring which may contain additional heteroatoms.
9. The use according to any one of claims 1 to 3 wherein the quinolone derivative is a compound of formula (VII)
or a salt thereof
wherein R23 is hydrogen or C1-6 alkyl;
R24 is halogen, and
R25 is mono or disubstituted amino, or optionally substituted cyclic amino.
10. The use of a quinolone derivative of formula I
or a pharmaceutically acceptable salt or ester thereof;
wherein Y is an optionally substituted aromatic six membered ring containing up to two nitrogen atoms;
R1 is C1-4 alkyl optionally substituted by halogen, hydroxy or aryl; C3-6 cycloalkyl; allyl or vinyl; or R1 together with a substituent on the ring Y located at the position adjacent to the bridgehead form an optionally subtituted six membered ring containing 0,1 or 2 additional heteroatoms selected from oxygen, nitrogen and sulphur;
R2 is hydrogen or R2 together with R1 forms an optionally substituted thiazolidinyl ring with the proviso that when Y is a benzene ring substituted by N-alkyl piperazinyl and R1 together with a substituent on Y form a six membered ring containing one oxygen atom, that this ring is not substituted by C1-6 alkyl at the carbon atom adjacent the nitrogen atom; for the manufacture of a medicament for the treatment or prophylaxis of mycoplasmal pneumonia in pigs.
11. The use according to claim 10 wherein the quinolone derivative is a compound of formula (VII)
or a salt thereof
wherein R23 is hydrogen or C1-6 alkyl
R24 is halogen and
R25 is mono or disubstituted amino or optionally substituted cyclic amino with the proviso that R23 is not C1-6 alkyl when R25 is N-alkyl substituted piperazinyl.
12. The use according to claim 1 of a compound selected from:-
1-ethyl-6-fluoro-1,4-dihydro-7-(4-methyl-1-piperrazinyl)-4-oxoquinoline-3-carboxylic acid;
1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazinoquinoline-3-carboxylic acid;
6-chloro-1-ethyl-1,4-dihydro-4-oxo-7-piperazinoquinoline-3-carboxylic acid; 1-ethyl-6,8 difluoro-1,4-dihydro-4-oxo-7-(3-ethylaminomethyl-1-pyrrolidinyl)quinoline-3-carboxylic acid;
9-fluoro-10-(3-hydroxy-1-pyrrolidinyl)-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazina-6-carboxylic acid;
9-fluoro-2,3-dihydro-3-methyl-7-oxo-10-(4-thiomorpholinyl)-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid;
1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazinequinoline-3-carboxylic acid;
1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-1,8-naphthyridine-3-carboxylic acid and the sesquihydrate thereof;
1-(2-fluoroethyl)-7-(1-piperazinyl)-6,8-difluoro-4-quinolone-3-carboxylic acid;
1-ethyl-1,4-dihydro-4-oxo-7-(4-pyridyl)quinoline-3-carboxylic acid;
1-ethyl-1,4-dihydro-7-(2,6-dimethyl-4-pyridyl)-4-oxo-quinoline-3-carboxylic acid;
7-fluoro-1-methyl-8-(4-methyl-1-piperazinyl)-5-oxo-5H-thiazolo[3,2-a]-quinoline-4-carboxylic acid;
7-fluoro-1-methyl-5-oxo-8-(1-piperazinyl)-5H-thiazolo [3,2-a]-quinoline-4-carboxylic acid;
9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-d,e][1,4]benzoxazine-6-carboxylic acid; and pharmaceutically acceptable salts thereof.
13. A method of treating pigs for the therapy and/or prophylaxis of mycoplasmal pneumonia which method comprises administration to a pig in need thereof an antimycoplasmally effective amount of a quinolone derivative of formula I
or a pharmaceutically acceptable salt or ester thereof;
wherein Y is an optionally substituted aromatic six membered ring containing up to two nitrogen atoms;
R1 is C1-4 alkyl optionally substituted by halogen, hydroxy or aryl; C3-6 cycloalkyl; allyl or vinyl; or R1 together with a substituent on the ring Y located at the position adjacent to the bridgehead form an optionally subtituted six membered ring containing 0,1 or 2 additional heteroatoms selected from oxygen, nitrogen and sulphur;
R2 is hydrogen or R2 together with R1 forms an optionally substituted thiazolidinyl ring.
14. A method of treating pigs for the therapy and/or prophylaxis of mycoplasmal pneumonia which method comprises administration to a pig in need thereof an antimycoplasmally effective amount of a quinolone derivative of formula I or a pharmaceutically acceptable salt or ester thereof;
wherein Y is an optionally substituted aromatic six membered ring containing up to two nitrogen atoms;
R1 is C1-4 alkyl optionally substituted by halogen, hydroxy or aryl; C3-6 cycloalkyl; allyl or vinyl; or R1 together with a substituent on the ring Y located at the position adjacent to the bridgehead form an optionally subtituted six membered ring containing 0,1 or 2 additional heteroatoms selected from oxygen, nitrogen and sulphur;
R2 is hydrogen or R2 together with R1 forms an optionally substituted thiazolidinyl ring, with the proviso that when Y is a benzene ring substituted by N-alkyl piperazinyl and R1 together with a substituent on Y form a six membered ring containing one oxygen atom, that this ring is not substituted by C1-6 alkyl at the carbon atom adjacent the nitrogen atom.
15. A method of treatment according to claim 13 wherein the quinolone derivative is selected from:- 1-ethyl-6-fluoro-1,4-dihydro-7-(4-methyl-1-piperrazinyl)-4-oxoquinoline-3-carboxylic acid;
1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazinoquinoline-3-carboxylic acid;
6-chloro-1-ethyl-1,4-dihydro-4-oxo-7-piperazinoquinoline-3-carboxylic acid;
1-ethyl-6,8 difluoro-1,4-dihydro-4-oxo-7-(3-ethylaminomethyl-1-pyrrolidinyl)quinoline-3-carboxylic acid;
9-fluoro-10-(3-hydroxy-1-pyrrolidinyl)-3-methyl-7-oxo-2,3-dihγdro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid;
9-fluoro-2,3-dihydro-3-methyl-7-oxo-10-(4-thiomorpholinyl)-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid;
1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazinequinoline-3-carboxylic acid;
1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-1,8-naphthyridine-3-carboxylic acid and the sesquihydrate thereof;
1-(2-fluoroethyl)-7-(1-piperazinyl)-6,8-difluoro-4-quinolone-3-carboxylic acid;
1-ethyl-1,4-dihydro-4-oxo-7-(4-pyridyl)quinoline-3-carboxylic acid;
1-ethyl-1,4-dihydro-7-(2,6-dimethyl-4-pyridyl)-4-oxo-quinoline-3-carboxylic acid; 7-fluoro-1-methyl-8-(4-methyl-1-piperazinyl)-5-oxo-5H-thiazolo[3,2-a]-quinoline-4-carboxylic acid;
7-fluoro-1-methyl-5-oxo-8-(1-piperazinyl)-5H-thiazolo [3,2-a]-quinoline-4-carboxylic acid;
9-fluoro-3-methyl-10-(4-methγl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-d,e][1,4]benzoxazine-6-carboxylic acid;
and pharmaceutically acceptable salts thereof.
EP19860902887 1985-05-14 1986-05-12 Use of quinolone derivatives for the treatment of mycoplasmal pneumonia in pigs Withdrawn EP0222814A1 (en)

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DE3705621C2 (en) * 1986-02-25 1997-01-09 Otsuka Pharma Co Ltd Heterocyclic substituted quinolonecarboxylic acid derivatives
WO2016174673A1 (en) * 2015-04-29 2016-11-03 The State Of Israel, Ministry Of Agriculture & Rural Development, Agricultural Research Organization (Aro) (Volcani Center) Anti-phytopathogenic compositions
CN117736906A (en) * 2023-11-11 2024-03-22 华东理工大学 An optimized culture medium that can increase the amount of Mycoplasma hyopneumoniae CJ strain

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US3753993A (en) * 1971-05-17 1973-08-21 Sterling Drug Inc 1,4-dihydro-4-oxo-7-pyridyl-3-quinoline-carboxylic acid derivatives
JPS53141286A (en) * 1977-05-16 1978-12-08 Kyorin Seiyaku Kk Novel substituted quinolinecarboxylic acid
GB1598915A (en) * 1977-09-20 1981-09-23 Bellon Labor Sa Roger 1,4-dihydro-quinoline-3-carboxylic acid derivatives process for their preparation and composition containing them
JPS5630964A (en) * 1979-08-22 1981-03-28 Kyorin Pharmaceut Co Ltd Novel substituted quinolinecarboxylic acid and its preparation
DE3033157A1 (en) * 1980-09-03 1982-04-01 Bayer Ag, 5090 Leverkusen 7-AMINO-1-CYCLOPROPYL-4-OXO-1,4-DIHYDRO-NAPHTHYRIDINE-3-CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THE ANTIBACTERIAL AGENTS CONTAINING THEM
SE440354B (en) * 1981-02-19 1985-07-29 Kyorin Seiyaku Kk quinolinecarboxylic
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