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WO1986006630A1 - 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

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Publication number
WO1986006630A1
WO1986006630A1 PCT/GB1986/000258 GB8600258W WO8606630A1 WO 1986006630 A1 WO1986006630 A1 WO 1986006630A1 GB 8600258 W GB8600258 W GB 8600258W WO 8606630 A1 WO8606630 A1 WO 8606630A1
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WO
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Patent type
Prior art keywords
substituted
optionally
formula
acid
ring
Prior art date
Application number
PCT/GB1986/000258
Other languages
French (fr)
Inventor
Norman Harold Rogers
Peter Charles Thomas Hannan
Original Assignee
Beecham Group P.L.C.
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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47Quinolines; Isoquinolines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/535Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines

Abstract

A method of treating mycoplasmal pneumonia in pigs comprising administration of 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 from an optionally substituted 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. The use of compounds of formula (I) or a pharmaceutically acceptable salt or ester thereof in the manufacture of a medicament for the treatment or prophylaxis of mycoplasmal pneumonia in pigs is also included.

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.
PCT/GB1986/000258 1985-05-14 1986-05-12 Use of quinolone derivatives for the treatment of mycoplasmal pneumonia in pigs WO1986006630A1 (en)

Priority Applications (2)

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GB8512143A GB8512143D0 (en) 1985-05-14 1985-05-14 Method of treatment
GB8512143 1985-05-14

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WO1986006630A1 true true WO1986006630A1 (en) 1986-11-20

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PCT/GB1986/000258 WO1986006630A1 (en) 1985-05-14 1986-05-12 Use of quinolone derivatives for the treatment of mycoplasmal pneumonia in pigs

Country Status (3)

Country Link
EP (1) EP0222814A1 (en)
GB (1) GB8512143D0 (en)
WO (1) WO1986006630A1 (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4855292A (en) * 1986-02-25 1989-08-08 Otsuka Pharmaceutical Company, Limited 1-cyclopropyl-6-fluoro-8-alkyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid derivatives
US4874764A (en) * 1986-02-25 1989-10-17 Otsuka Pharmaceutical Company, Limited Benzoheterocyclic compounds
US4880806A (en) * 1986-02-25 1989-11-14 Otsuka Pharmaceutical Company, Limited 1-Cyclopropyl-6-fluoro-7-piperazinyl-1,4-Dihydro-4-oxo-quinoline-3-carboxylic acid derivatives
US4935420A (en) * 1986-02-25 1990-06-19 Otsuka Pharmaceutical Company, Ltd. Benzoheterocyclic compounds

Also Published As

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GB8512143D0 (en) 1985-06-19 grant

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