ESTERS OF (9-FLUORO-3-METHYL-10-(4-METHYL-1-PIPERAZINYL)-7-OXO-2,3-DIHYDRO-7H-PYRIDO[3,2,1,IJ]-1,3,4-BENZOAXADIAZINE-6-CARBOXYLIC ACID) AND THEIR USE AS ANTIBACTERIAL

Abstract: Compounds of formula (I) wherein R<1> is a pharmaceutically acceptable in vivo hydrolysable ester group, may be used to treat or prevent a bacterial infection in a non-human animal by administration via the oral route.

Description: ESTERS OF (9-FLUORO-3-METHYL-10-(4-METHYL-l-PIPERAZINYL)-7-OXO-2,3-DIHYDRO-7H- PYRIDO[3.2. I.IJJ- l.3,4-BENZOAXADlAZINE-6-CARBOXYLIC ACID) AND THEIR USE AS AN¬ TIBACTERIAL This invention relates to a method of treating or preventing bacterial infections in non-human animals, more particularly domesticated mammals and birds, such as horses, cattle, swine, sheep, companion animals including dogs and cats, and poultry including chickens. It is often convenient to administer an antibacterial compound to domesticated animals via the oral route, for example mixed with the animals' feedstuff or drinking water. It is therefore important for such compounds to be palatable to the target animal if the treatment is to be effective. EP-A-0 259 804 describes a compound of formula (A): (A) (9-fluoro-3-methyl-10-(4-methyl-1 -piperazinyl)-7-oxo-2,3-dihydro-7H- pyrido[3,2, 1 -ij]-1 ,3,4-benzadiazine-6-carboxylic acid). This compound is stated to have antibacterial activity. A disadvantage of the compound of formula (A) is that it is unpalatable and therefore difficult to administer to animals via the oral route. According to the present invention there is provided a method of treating or preventing a bacterial infection in a non-human animal, which method comprises administering to the animal via the oral route an antibacterially effective amount of a compound of formula wherein R 1 is a pharmaceutically acceptable in vivo hydrolysable ester group. Examples of suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those which break down readily in the body to leave the parent acid or its salt. Suitable ester groups of this type include those of part formulae (i), (ii), (iii) and (iv): (0 I -C0 2 CH-0 CO.FT ■ R u -C0 2 -R -N . ■ R β 0 -C0 2 -CH 2 OR ( in ) NH, wherein R a is hydrogen, C^ alkyl, C 3 7 cycloalkyl, methyl, or phenyl, R b is C,. 6 alkyl, C 1 6 alkoxy, C 3 . 7 cycloalkoxy, phenyl, benzyl, C 3 . 7 cycloalkyl, C,. 6 alkyl, C 3 . 7 cycloalkyl, 1 -amino C^ alkyl, or 1 -(C 1 6 alkyDamino C,. 6 alkyl; or R a and R b together form a 1 ,2-phenylene group optionally substituted by one or two methoxy groups; R c represents C,. 6 alkylene optionally substituted with a methyl or ethyl group and R d and R β independently represent C 1 6 alkyl; R f represents C 1 6 alkyl; R 9 represents hydrogen or phenyl optionally substituted by up to three groups selected from halogen, C,. 6 alkyl, or C,. 6 alkoxy; and Q is oxygen or NH. Examples of suitable in vivo hydrolysable ester groups include, for example, acyloxyalkyl groups such as acetoxymethyl, pivaloyloxymethyl, α-acetoxyethyl, α-pivaloyloxyethyl, 1 - (cyclohexylcarbonyloxy)prop-l -yl, and (1 -aminoethyl) carbonyloxymethyl; alkoxycarbonyloxyalkyl groups, such as ethoxycarbonyloxymethyl and α-ethoxycarbonyloxyethyl; cycloalkoxycarbonyloxyalkyl groups, such as cyclohexyloxycarbonyloxymethyl; dialkylaminoalkyl especially di- loweralkylamino alkyl groups such as dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl or diethylaminoethyl; lactone groups such as phthalidyl and dimethoxyphthalidyl; and esters linked to a second antibiotic. A further suitable pharmaceutically acceptable m vivo hydrolysable ester group is that of the formula: wherein R h is hydrogen, C 1 6 alkyl or phenyl. A particularly preferred ester group is pivaloyloxymethyl. A second aspect of the invention provides use of a compound of formula (I) in the manufacture of a medicament for use in the treatment or prevention of bacterial infections in non-human animals by administration via the oral route. Preferably, the compound of formula (I) is administered in admixture with the animal's feedstuff or drinking water. Thus, a further aspect of the invention provides feedstuff or drinking water having a compound of formula (I) mixed therewith, as well as a premix comprising a compound of formula (I) together with a veterinarily acceptable carrier. Suitable carriers include a mixture of a binder, such as polyvinylpyrroilidone, and a filler, such as lactose, which can be extruded, granulated and mixed with or sprinkled on the animals' food. For addition to drinking water, the active is first made up as a concentrate with a liquid carrier, such as gluconolactone. Compounds of the invention may also be administered orally in the form of a tablet containing such excipients as starch or lactose, or in a capsule or ovule either alone or in admixture with excipients, or in the form of an elixir or suspension containing a flavouring or colouring agent. The tablets and capsules for oral administration may be in unit dosage form, and may contain conventional excipients including, for example, binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrroilidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or giycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; and pharmaceutically acceptable wetting agents, for example sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or another suitable vehicle before use. Such liquid preparations may contain conventional additives, including, for example, suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters (for example glycerine), propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and, if desired, conventional flavouring and colour agents. The compound of formula (I) is typically provided in an amount sufficient to give from 0.5 to 500 mg/kg of animal body weight, more particularly from 1 to 300 mg/kg. Infections suitable for treatment include infections caused by organisms selected from the group consisting of Staphylococcus, Streptococcus, Aerococcus, Enterococcus, Micrococcus, Kactobacillus, Bifidobacterium, Clostridium, Eubacterium, Peptococcus, Peptostreptococcus, Propionibacterium, Citrobacter, Campylobacter, Enterobacter, Klebsiella, Proteus, Pseudomonas, Serratia, Salmonella, Shigella, Vibrio, Aeromonas, Haemophilus, Neisseria, Acinetobacter, Alcaligenes, Bordetella, Bacteroids, Fusobacterium, Myocoplasma and other microorganisms. Certain compounds of formula (I) are novel and form a further aspect of the invention. An example of such a compound is cyclohexyloxycarbonyloxymethyl 9-fluoro-3-methyl-10-(4-methyl-1 - piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[3,2, 1 -ij]-1 ,3,4- benzoxadiazine-6-carboxylate. Compounds of formula (I) can be prepared from the compound of formula (A) and its derivatives using techniques which are known in the art. For example, the compound of formula (A) or an activated derivative thereof can be treated with a compound of formula (v), (vi), (vii), (viii), (ix): R" XCH-O.CO.R" (v) -R ϋ (VI) X-R -N ■ R" XCH 2 -OR (VI I ) („,„) wherein R a to R h are as defined hereinabove and X is a leaving group such as halide, preferably chloride, or hydroxy. The reaction with the compound of formula (A) is typically carried out in a non-aqueous solvent, such as DMF, DMA, DMSO or acetone, in the presence of an acid binding agent such as an organic or inorganic base. Preferably an inorganic base, such as potassium or sodium carbonate, is used. Temperatures are typically between ambient and reflux, for example about 50°C. Alternatively, a suitable activated derivative of the compound of formula (A) can be used. Such a derivative can be prepared by treating the compound of formula (A) with dicyclohexylcarbodiimide. The invention will now be further illustrated by reference to the following examples: EXAMPLE 1 Pivaloyloxymethyl 9-fluoro-3-methyl-10-(4-methyl-1 -piperazinyl)-7- oxo-2,3-dihydro-7H-pyrido[3,2, 1 -ij]-1 ,3,4-benzoxadiazine-6- carboxylate. A solution of 9-fluoro-3-methyl-10-(4-methyl-1 -piperazinyl)-7-oxo- 2,3-dihydro-7H-pyrido[3,2, 1 -ij]-1 ,3,4-benzadiazine-6-carboxylic acid - 7/1 - ( 1 .0g, 2.78 mmol), chloromethyl pivalate (0.63g, 4.1 7 mmol) and potassium carbonate (0.77g, 5.56 mmol) in dry DMF (20ml) was stirred at 45°C under an argon atmosphere for 16h. The reaction mixture was poured into DCM (50 ml) and the organic solution was washed with water (30 ml) and then dried over sodium sulfate. The solvent was evaporated in vacuo leaving a white solid contaminated with DMF. The solid was purified by recrystallisation from ethyl acetate to give the pivaloyloxymethyl ester (0.88g, 67%) as a white, microcrystalline solid, m.p. 204-207°C, m/z (FAB) 477 (M + 1 ). (Found: C, 58.1 , H, 6.0, N, 1 1 .8%. C 23 H 29 FN 4 O 6 requires C, 58.2, H, 5.7, N, 1 1 .8%). EXAMPLE 2 Cyclohexyloxycarbonyloxymethyl 9-fluoro-3-methyl-10-(4-methyl-1 - piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[3,2, 1 -ij]-1 ,3,4- benzoxadiazine-6-carboxylate. A solution of 9-fluoro-3-methyl-1 0-(4-methyl-1 -piperazinyl)-7-oxo- 2,3-dihydro-7H-pyrido[3,2, 1 -ij]-1 ,3,4-benzadiazine-6-carboxylic acid (1 .0g, 2.78 mmol), chloromethyl cyclohexyl carbonate (0.80g, 4.1 7 mmol) and potassium carbonate (0.77g, 5.56 mmol) in dry DMF (20 ml) was stirred at 45°C under an argon atmosphere for 1 6h. The reaction mixture was poured into DCM (30ml) and the organic solution was washed with water (30ml) and then dried over sodium - 7/2 - sulfate. The solvent was evaporated in vacuo leaving a white solid which was purified by recrystallisation from ethyl acetate to give the cyclohexyloxycarbonyloxymethyl ester ( 1 .02g, 80%) as a white solid, m.p. 1 80-1 81 °C, m/z (FAB) 51 9 (M + 1 ).

Claims: CLAIMS The use of a compound of formula (I) α) wherein R 1 is a pharmaceutically acceptable in vivo hydrolysable ester group, in the manufacture of a medicament for use in the treatment or prevention of bacterial infections in non-human animals by administration via the oral route. Use as claimed in claim 1 , wherein R' is selected from the following part formulae (i), (ii), (iii) and (iv) R * 0) -CO-CH-O.CO.R 0 -C0 2 -CH.OR (III ) NH, - 9 - wherein R a is hydrogen, C, 6 alkyl, C 3 7 cycloalkyl, methyl, or phenyl, R b is C, 6 alkyl, C, 6 alkoxy, C 3 7 cycloalkoxy, phenyl, benzyl, C 3 7 cycloalkyl, C, 6 alkyl C 3 7 cycloalkyl, 1 -amino C, 6 alkyl or 1 -(C, 6 alkyl) ammo C, 6 alkyl; or R a and R b together form a 1 ,2-phenylene group optionally substituted by one or two methoxy groups; R c represents C, 6 alkylene optionally substituted with a methyl or ethyl group and R d and R β independently represent C, 6 alkyl; R' represents C, 6 alkyl; R 9 represents hydrogen or phenyl optionally substituted by up to three groups selected from halogen, C, 6 alkyl or C, 6 alkoxy; and Q is oxygen or NH. 3. Use as claimed in claim 1 , wherein R' is and wherein R h is hydrogen, C, 6 alkyl or phenyl. 4. Use as claimed in claim 1 , wherein R' is pivaloyloxymethyl. 5. Compound of formula (I) as defined in claim 1 which is cyclohexyloxycarbonyloxymethyl 9-fluoro-3-methyl-10-(4- methyl- 1 -pιperazιnyl)-7-oxo-2,3-dιhydro-7H-pyrιdo [3,2, 1 -ιj]- 1 ,3,4-benzoxadiazine-6-carboxylate. 6. The compound of claim 5 for use as a medicament. 7. Feedstuff or drinking water for animals comprising a compound of formula (I) as defined in claim 1 . - 10 - 8. Premix comprising a compound of formula (I) as defined in claim 1 together with a veteπnaπly acceptable carrier. 9. A method of treating or preventing a bacterial infection in a non-human animal which comprises administering to the animal via the oral route an antibacterially effective amount of a compound of formula (I) as defined in claim 1 .

Inventors: DORGAN RODERICK JOHN, WEBSTER RICHARD ANDREW BENTLEY, DORGAN, RODERICK, JOHN, WEBSTER, RICHARD, ANDREW, BENTLEY
Applicants: DORGAN RODERICK JOHN, PFIZER, WEBSTER RICHARD ANDREW BENTLEY, DORGAN, RODERICK, JOHN, PFIZER INC., WEBSTER, RICHARD, ANDREW, BENTLEY
Application year: 1996
Main classification: A61K31
IPC codes: A23K1, A61K31, A61P31, C07D498