CA2242713A1 - Pyrido (3,2,1-ij)-1,3,4-benzoxadiazine - Google Patents
Pyrido (3,2,1-ij)-1,3,4-benzoxadiazine Download PDFInfo
- Publication number
- CA2242713A1 CA2242713A1 CA002242713A CA2242713A CA2242713A1 CA 2242713 A1 CA2242713 A1 CA 2242713A1 CA 002242713 A CA002242713 A CA 002242713A CA 2242713 A CA2242713 A CA 2242713A CA 2242713 A1 CA2242713 A1 CA 2242713A1
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- Canada
- Prior art keywords
- compound
- formula
- methyl
- treating
- pyrido
- 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.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/06—Peri-condensed systems
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/10—Organic substances
- A23K20/116—Heterocyclic compounds
-
- 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
-
- 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
Abstract
Compounds of formula (I) wherein R is C1-6 alkyl, such as methyl or ethyl, have antibacterial activity and are therefore of use in treatment and prophylaxis of bacterial infections in humans and animals
Description
-CA 022427l3 l998-07-07 - PYRIDO (3,2,1-IJ)-1,3,4-BENZOXADIAZINE
The present invention relates to a novel compound, to processes for its production, to pharmaceutical form~ tions con-~inin~ it, and to its use in therapy, particularly in the tre~ nt of microbial in~ections.
~P-A-0 2~9 804 describes the compound of formula (A):
O O
F ~' H
~N~J O~N~
(A) (9-fluoro-3-methyl- 1 0-(4-methyl- 1 -piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido~3,2,1-ij~-1,3,4-b~n7~ 7ine-6-carboxylic acid). The compound of forrnula (A) is reported to have antibacterial activity.
The present invention provides a compound of forrnula (I~:
O O
F ~5~J~CO2R
f N~--N
~N~J O~N~
(I) wherein R is C 1-6 alkyl, such as methyl or ethyl. A particular compound of formula (I~ is 6-(ethoxycarbonyl)acetyl 9-fluoro-3-methyl-10-(~methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ij~-1,3,~b~n7.o~ ine, Compounds of formula (I) have antibacterial activity and are therefore of use inthe tre~tmPnt and prophylaxis of b~c teri~l infections in hllm~n.~ and ~nim~}.
The invention in a second aspect, further provides a process for the production of a compound of formula (I), which comprises treating a compound of formula (~):
O O
F~X
f N~--N
~N~J O~N~
(II) wherein X is a leaving group, such as imid~7ole or halide, such as chlorine, with a carbanion derivable by treating a diaL~cyl malonate with a strong base, such as sodium hydride.
The compound of formula (II) can be obtained by treating the compound of forrnula (A~ with, for example, an excess of carbonyl ~iiimi~7Ole. This reactionis typically carried out in an aprotic solvent such as chloroform at arnbient orelevated temperature, eg at reflux, under dry conditions, e.g. in an argon, atmosphere.
Generation of the carbanion is typically carried out at between-70 and 70~ C. for instance at arnbient temperature, in an aprotic solvent such as THF. A solution ~f t the compound of forrnula (II) in THF is then added and the mixture is refluxed.
After evaporation of solvent the residue is dissolved in water and the reaction - ~uenched by neutralization to pH7. The product is extracted and purified by chromatography such as HPLC.
The compound according to the invention'is suitably provided in subst~nti~11y pure forrn, for e~mple at least 50% pure, suitable at least 6û% pure, advantageously at least 75% pure, preferably at least 85% pure, more preferably at !east 9~% pure~esneGiallyatleact98% pUtP-, allpe-rGe-n-tages heingGalGU
weight/weight. An impure or less pure form of the compound according to the invention may, for example, be used in the preparation of a more pure form of the same compound.
The compound of the invention has ~ntih~r.trri~1 activity and is useful for the prophylactic and therapeutic tre~tment of bacterial infections in ~nim~1.c, especially m~mm~1~, including hl-m~nc, in particular humans and domestic~ted ~nim~1.c (including farm ~nim~l.c). The compound may be used for the tre~tment of infections caused by, among other or~ni.cmc, species of Staphylococcus, Streptococcus, Aerococcus, Enterococcus, Micrococcus, Kactob~cm~
Bifidob~rt~.ril1m, Clostridium, Eub~cteri~1m, Peptococcus, Peptostreptococcus, Propionib~terium, Citrobacter, Campylobacter, Enterobacter, ~1~.bsie11~, Proteus, Pseudomonas, Serratia, Salmonella, Shigella, Vibrio, Aeromonas, Haemophi~us, Neisseria, Acinetobacter. Alcaligenes, Bordetella, Bacteroids, Fusobacterium, Myocoplasma and other microorE~nicm.c Accordingly a third aspect of the invention provides the compound of formula (I)for use in me~ therapy, in particular for use as an antibacterial agent.
The invention further provides a method of treating a human or animal suffering from a b~ctrri~l infection by the a-lmini.stration of an effective amount of thecompound of the invention.
A particular method of the invention comprises treating or preventing bacterial infections in non-human ~nim~1c, more particularly domestir~t~l m~mm~1c and birds, such as horses. cattle, swine, sheep, companion ~nim~ including dogs and cats, and poultry including chickens. The method comprises aAmini.ctering to theanimal via the oral route an antibacterially effective amount of a compound of forrnula ~
-A further aspect of the invention provides use of a compound of formula (I) in the m~nllf~qcture of a merlir~ment for use in the tre~tmP-nt or prevention of bacterial infections in non-human ~nim~lc by ~mini.ctration via the oral route.
The invention further provides a ph~rm~e~lti~ ~l composition cornr ri.cing a compound of the formula (I~ together with a ph~rm~eutic~lly acceptable diluent or carrier.
The compound of the invention can be ~dminictered alone, but will generally be ~lmini.ctPred in ~ mixtllre with a ph~rm~elltical carrier selected with regard to the intPnded route of ~tlminictration and standard pharmaceutical pr~cti~e For example, it may be ~rlmini.ctPred orally in the form of a tablet co~t~ining suchexcipients as starch or lactose, or in a c~rsule or ovule either alone or in admixture with excipients, or in the form of an elixir or suspension cont~ining a flavouring or colouring agent. It may be iniected parenterally, for e~mrlP, intravenously, intramllcc~ rly or subcutaneously. For parenteral ~tlminictration~
it is best used in the form of a sterile solution which may contain other substances, for example, enough salt,c or glucose to make the solution isotonic.
For oral and parenteral ~rlminictr~tion, it is expected that the daily dosage level of the compound of formula (I) will be from 0.5 to ~00, preferably 1 to 300 mg/kg (in divided doses) when ~-lminictPred by either the oral or parenteral route.
No unacceptable toxicological effects are expected when the compound is a~minictered in the above mentioned dosage ranges.
The compounds and compositions according to the invention may be formulated for ~1minictration in any convenient way for use in human or veterinary medicine, by analogy with other antib~teri~l agents.
The tablets and capsules for oral ~-lminictration may be in unit dosage form, and may contain conventional excipients incl~rling, for example, binding agents, forexample, syrup, acacia, gelatin, sorbitol, tr~g~< ~nth or polyvinylpyrrollidQne fillers, for example lactose, sugar, maize~starch. calcium phosphate, sorbitol or glycine; tabletting lubricants, for example m~gnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; and pharm~ceutie~llyacceptable wetting agents, for example sodium lauryl sulrh~t~o 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 convention~l additives; in~luf~in~, for example,suspending agents, for e~cample sorbitol, methyl cellulose, gl-lcose syrup, gelatin, hydroxyet'nyl cellulose, carboxymethyl cellt~l~se. ~ minillm stearate gel or hydrogen~ted edible fats; emulsifying agents, for example lecithin, sorbitan monooleate or acacia; non-aqueous vehicles (wnich 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-hydroxy'oen7o~t~P or sorbic acid; and, if desired, conventional flavouring and colour agent~s.
Compositions according to the invention intPIlded for topical ~tTminictration may, for example, be in the form of ointments, creams, lotions, eye ointme~ts~ eye drops, ear drops, impregnated dr~P-ssing~s, and aerosols, and may contain applupliate conventional additives, including, for e~r~mplP, preservatives, solvents to assist d;ug penetration, and emollient~s in ointmPnt~c and creams. Such topical formulations may also contain compatible conve,ntion~l ca;riers, for example cream or ointment bases, and ethanol or oleyl alcohol for lotions. Such carriers may constitute from about 1% to about 98% by weight of the formulation; more usually they will constitute up to about 80% by weight of the formulation.
Compositions according to the invention may be formulated as suppositories, which may contain conventional suppository bases, for example cocoa-butter or other glycerides.
Compositions according to the invention intended for parenteral ~(lmini~strationmay conveniently be in fluid unit dosage forms, which may be prepared utiii7ing the compound and a sterile vehicle, propyleneglycol. The compound, depending on the vehicle and concentration used, may be either suspended or dissolved in the vehicle. Parenteral suspensions may be prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration. The compound may instead be sterilised by exposure to ethylene oxide before being suspended in the sterile vehicle. Advantageously, a st~ t~nt or wetting agent is included in such suspensions in order to facilitate uniform distribution of the compound.
Compositions according to the invention may also be ~riministp~ed by inhalation.By '~inh~lationll is meant intranasal and oral inh~l~tion ~ministration.
Applopliate dosage forms for such ~minictration such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques.
Preferably, the compound of formula (I) is ~lminict~red in admixture with the -animal's feedstuff or drinking water. Thus, a further aspect of the invention provides feetlstnff 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 mi~ture of abinder, such as polyvinylpyrrollidone, and a filler, such as l~t~ se, which can be extruded, granulated and mixed with or sprinkled on the ~nim~l.c' food. For addition to <1rinking water, the active is first made up as a con~entrate with aliquid carrier, such as gluconolactone.
The following example serves to illustrate the present invention.
6-(Ethoxycarbonyl)acetyl 9-fi!wro-3-me~hyl-l o-(4-methyl-l -piperazinyl)-7 2,3-dihydro-7H-pyridol3,2,1-i3]-1.3.4-benzoxn~iA~ine.
Sodium hydride (0.67g, 16.7mmol of a 60% suspension in oil) was added pOnionwise to a stirred solution of diethyl malonate (2.67g, 16.7mmol) in dry THF (SOml). The r~slllting effervescent mixture turned pale yellow after Smin and was allowed to stir at room temperature for 3h (solution A). A solution of carbonyl ~liimi(l~Qle (1.8g, 11.12mmol) and 9-fluoro-3-methyl-10-(4-methyl-l-piperazinyl)-7-oxo-2,3-dihydro-7H-pyridor3,2,1-ij]-1,3,4-~e.n7.oY~ .in~.-6-carboxylic acid (2.0g, 5.56mmol) in chloroform (SOml) was heated under reflux in an argon atmosphere for 12h. The chloroform was then evaporated in vacuo and the residue was dissolved in anhydrous THF (50ml) (solution B). Solution B
was added to solution A in one portion under an argon atmosphere and the resulting mixture was heated under reflux for a period of 16h. The volatiles were then removed by evaporation in vacuo and the residue was dissolved in water (SOml). The aqueous solution was neutralised to pH 7 by careful addition of acetic acid and the reslllting mixture was extracted with ethyl acetate ~3 x 50ml~.
The combined organic extracts were dried (MgS04) and evaporated in vacuo.
The residue was purified by normal phase HPLC using a Dynamax 300A silica column with a flow rate of l.OmVmin and 5% methanol/dichloromethane as eluant to give the title compound, retention time 20.7min, m/z (FAB~ 433 (M +
1).
O O
-F ~ COzEt N ~ O~" N ~
The present invention relates to a novel compound, to processes for its production, to pharmaceutical form~ tions con-~inin~ it, and to its use in therapy, particularly in the tre~ nt of microbial in~ections.
~P-A-0 2~9 804 describes the compound of formula (A):
O O
F ~' H
~N~J O~N~
(A) (9-fluoro-3-methyl- 1 0-(4-methyl- 1 -piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido~3,2,1-ij~-1,3,4-b~n7~ 7ine-6-carboxylic acid). The compound of forrnula (A) is reported to have antibacterial activity.
The present invention provides a compound of forrnula (I~:
O O
F ~5~J~CO2R
f N~--N
~N~J O~N~
(I) wherein R is C 1-6 alkyl, such as methyl or ethyl. A particular compound of formula (I~ is 6-(ethoxycarbonyl)acetyl 9-fluoro-3-methyl-10-(~methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ij~-1,3,~b~n7.o~ ine, Compounds of formula (I) have antibacterial activity and are therefore of use inthe tre~tmPnt and prophylaxis of b~c teri~l infections in hllm~n.~ and ~nim~}.
The invention in a second aspect, further provides a process for the production of a compound of formula (I), which comprises treating a compound of formula (~):
O O
F~X
f N~--N
~N~J O~N~
(II) wherein X is a leaving group, such as imid~7ole or halide, such as chlorine, with a carbanion derivable by treating a diaL~cyl malonate with a strong base, such as sodium hydride.
The compound of formula (II) can be obtained by treating the compound of forrnula (A~ with, for example, an excess of carbonyl ~iiimi~7Ole. This reactionis typically carried out in an aprotic solvent such as chloroform at arnbient orelevated temperature, eg at reflux, under dry conditions, e.g. in an argon, atmosphere.
Generation of the carbanion is typically carried out at between-70 and 70~ C. for instance at arnbient temperature, in an aprotic solvent such as THF. A solution ~f t the compound of forrnula (II) in THF is then added and the mixture is refluxed.
After evaporation of solvent the residue is dissolved in water and the reaction - ~uenched by neutralization to pH7. The product is extracted and purified by chromatography such as HPLC.
The compound according to the invention'is suitably provided in subst~nti~11y pure forrn, for e~mple at least 50% pure, suitable at least 6û% pure, advantageously at least 75% pure, preferably at least 85% pure, more preferably at !east 9~% pure~esneGiallyatleact98% pUtP-, allpe-rGe-n-tages heingGalGU
weight/weight. An impure or less pure form of the compound according to the invention may, for example, be used in the preparation of a more pure form of the same compound.
The compound of the invention has ~ntih~r.trri~1 activity and is useful for the prophylactic and therapeutic tre~tment of bacterial infections in ~nim~1.c, especially m~mm~1~, including hl-m~nc, in particular humans and domestic~ted ~nim~1.c (including farm ~nim~l.c). The compound may be used for the tre~tment of infections caused by, among other or~ni.cmc, species of Staphylococcus, Streptococcus, Aerococcus, Enterococcus, Micrococcus, Kactob~cm~
Bifidob~rt~.ril1m, Clostridium, Eub~cteri~1m, Peptococcus, Peptostreptococcus, Propionib~terium, Citrobacter, Campylobacter, Enterobacter, ~1~.bsie11~, Proteus, Pseudomonas, Serratia, Salmonella, Shigella, Vibrio, Aeromonas, Haemophi~us, Neisseria, Acinetobacter. Alcaligenes, Bordetella, Bacteroids, Fusobacterium, Myocoplasma and other microorE~nicm.c Accordingly a third aspect of the invention provides the compound of formula (I)for use in me~ therapy, in particular for use as an antibacterial agent.
The invention further provides a method of treating a human or animal suffering from a b~ctrri~l infection by the a-lmini.stration of an effective amount of thecompound of the invention.
A particular method of the invention comprises treating or preventing bacterial infections in non-human ~nim~1c, more particularly domestir~t~l m~mm~1c and birds, such as horses. cattle, swine, sheep, companion ~nim~ including dogs and cats, and poultry including chickens. The method comprises aAmini.ctering to theanimal via the oral route an antibacterially effective amount of a compound of forrnula ~
-A further aspect of the invention provides use of a compound of formula (I) in the m~nllf~qcture of a merlir~ment for use in the tre~tmP-nt or prevention of bacterial infections in non-human ~nim~lc by ~mini.ctration via the oral route.
The invention further provides a ph~rm~e~lti~ ~l composition cornr ri.cing a compound of the formula (I~ together with a ph~rm~eutic~lly acceptable diluent or carrier.
The compound of the invention can be ~dminictered alone, but will generally be ~lmini.ctPred in ~ mixtllre with a ph~rm~elltical carrier selected with regard to the intPnded route of ~tlminictration and standard pharmaceutical pr~cti~e For example, it may be ~rlmini.ctPred orally in the form of a tablet co~t~ining suchexcipients as starch or lactose, or in a c~rsule or ovule either alone or in admixture with excipients, or in the form of an elixir or suspension cont~ining a flavouring or colouring agent. It may be iniected parenterally, for e~mrlP, intravenously, intramllcc~ rly or subcutaneously. For parenteral ~tlminictration~
it is best used in the form of a sterile solution which may contain other substances, for example, enough salt,c or glucose to make the solution isotonic.
For oral and parenteral ~rlminictr~tion, it is expected that the daily dosage level of the compound of formula (I) will be from 0.5 to ~00, preferably 1 to 300 mg/kg (in divided doses) when ~-lminictPred by either the oral or parenteral route.
No unacceptable toxicological effects are expected when the compound is a~minictered in the above mentioned dosage ranges.
The compounds and compositions according to the invention may be formulated for ~1minictration in any convenient way for use in human or veterinary medicine, by analogy with other antib~teri~l agents.
The tablets and capsules for oral ~-lminictration may be in unit dosage form, and may contain conventional excipients incl~rling, for example, binding agents, forexample, syrup, acacia, gelatin, sorbitol, tr~g~< ~nth or polyvinylpyrrollidQne fillers, for example lactose, sugar, maize~starch. calcium phosphate, sorbitol or glycine; tabletting lubricants, for example m~gnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; and pharm~ceutie~llyacceptable wetting agents, for example sodium lauryl sulrh~t~o 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 convention~l additives; in~luf~in~, for example,suspending agents, for e~cample sorbitol, methyl cellulose, gl-lcose syrup, gelatin, hydroxyet'nyl cellulose, carboxymethyl cellt~l~se. ~ minillm stearate gel or hydrogen~ted edible fats; emulsifying agents, for example lecithin, sorbitan monooleate or acacia; non-aqueous vehicles (wnich 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-hydroxy'oen7o~t~P or sorbic acid; and, if desired, conventional flavouring and colour agent~s.
Compositions according to the invention intPIlded for topical ~tTminictration may, for example, be in the form of ointments, creams, lotions, eye ointme~ts~ eye drops, ear drops, impregnated dr~P-ssing~s, and aerosols, and may contain applupliate conventional additives, including, for e~r~mplP, preservatives, solvents to assist d;ug penetration, and emollient~s in ointmPnt~c and creams. Such topical formulations may also contain compatible conve,ntion~l ca;riers, for example cream or ointment bases, and ethanol or oleyl alcohol for lotions. Such carriers may constitute from about 1% to about 98% by weight of the formulation; more usually they will constitute up to about 80% by weight of the formulation.
Compositions according to the invention may be formulated as suppositories, which may contain conventional suppository bases, for example cocoa-butter or other glycerides.
Compositions according to the invention intended for parenteral ~(lmini~strationmay conveniently be in fluid unit dosage forms, which may be prepared utiii7ing the compound and a sterile vehicle, propyleneglycol. The compound, depending on the vehicle and concentration used, may be either suspended or dissolved in the vehicle. Parenteral suspensions may be prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration. The compound may instead be sterilised by exposure to ethylene oxide before being suspended in the sterile vehicle. Advantageously, a st~ t~nt or wetting agent is included in such suspensions in order to facilitate uniform distribution of the compound.
Compositions according to the invention may also be ~riministp~ed by inhalation.By '~inh~lationll is meant intranasal and oral inh~l~tion ~ministration.
Applopliate dosage forms for such ~minictration such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques.
Preferably, the compound of formula (I) is ~lminict~red in admixture with the -animal's feedstuff or drinking water. Thus, a further aspect of the invention provides feetlstnff 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 mi~ture of abinder, such as polyvinylpyrrollidone, and a filler, such as l~t~ se, which can be extruded, granulated and mixed with or sprinkled on the ~nim~l.c' food. For addition to <1rinking water, the active is first made up as a con~entrate with aliquid carrier, such as gluconolactone.
The following example serves to illustrate the present invention.
6-(Ethoxycarbonyl)acetyl 9-fi!wro-3-me~hyl-l o-(4-methyl-l -piperazinyl)-7 2,3-dihydro-7H-pyridol3,2,1-i3]-1.3.4-benzoxn~iA~ine.
Sodium hydride (0.67g, 16.7mmol of a 60% suspension in oil) was added pOnionwise to a stirred solution of diethyl malonate (2.67g, 16.7mmol) in dry THF (SOml). The r~slllting effervescent mixture turned pale yellow after Smin and was allowed to stir at room temperature for 3h (solution A). A solution of carbonyl ~liimi(l~Qle (1.8g, 11.12mmol) and 9-fluoro-3-methyl-10-(4-methyl-l-piperazinyl)-7-oxo-2,3-dihydro-7H-pyridor3,2,1-ij]-1,3,4-~e.n7.oY~ .in~.-6-carboxylic acid (2.0g, 5.56mmol) in chloroform (SOml) was heated under reflux in an argon atmosphere for 12h. The chloroform was then evaporated in vacuo and the residue was dissolved in anhydrous THF (50ml) (solution B). Solution B
was added to solution A in one portion under an argon atmosphere and the resulting mixture was heated under reflux for a period of 16h. The volatiles were then removed by evaporation in vacuo and the residue was dissolved in water (SOml). The aqueous solution was neutralised to pH 7 by careful addition of acetic acid and the reslllting mixture was extracted with ethyl acetate ~3 x 50ml~.
The combined organic extracts were dried (MgS04) and evaporated in vacuo.
The residue was purified by normal phase HPLC using a Dynamax 300A silica column with a flow rate of l.OmVmin and 5% methanol/dichloromethane as eluant to give the title compound, retention time 20.7min, m/z (FAB~ 433 (M +
1).
O O
-F ~ COzEt N ~ O~" N ~
Claims (11)
1. A compound of formula (I) wherein R is C1-6 alkyl.
2. Compound as claimed in claim 1 which is 6-(ethoxycarbonyl) acetyl 9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[3,2-1-ij]-1,3,4-benzoxadiazine.
3. A process for the production of a compound of formula (I), as defined in claim 1, which comprises treating a compound of formula (II) wherein X is a leaving group, with a carbanion derivable by treating a dialkyl malonate with a strong base.
4. A process as claimed in claim 3, wherein X is imidazolyl or halide.
5. Compound of claim 1 or claim 2 for use in medical therapy.
6. A method of treating a human or animal suffering from a bacterial infection comprising the administration of an effective amount of a compound of claim 1 or claim 2.
7. Method as claimed in claim 6 which comprises the administration via the oral route of an antibacterially effective amount of a compound of claim 1 or claim 2.
8. The use of a compound of claim 1 or claim 2 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.
9. A pharmaceutical composition comprising a compound of claim 1 or claim 2 together with a pharmaceutically acceptable diluent or carrier.
10. Feedstuff or drinking water for animals comprising a compound of claim 1 or claim 2.
11. Premix comprising a compound of claim 1 or claim 2 together with a veterinarily acceptable carrier.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9600886.7 | 1996-01-17 | ||
| GBGB9600886.7A GB9600886D0 (en) | 1996-01-17 | 1996-01-17 | Novel compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2242713A1 true CA2242713A1 (en) | 1997-07-24 |
Family
ID=10787122
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002242713A Abandoned CA2242713A1 (en) | 1996-01-17 | 1996-10-31 | Pyrido (3,2,1-ij)-1,3,4-benzoxadiazine |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0935602A1 (en) |
| JP (1) | JP2000501071A (en) |
| AU (1) | AU7322196A (en) |
| CA (1) | CA2242713A1 (en) |
| GB (1) | GB9600886D0 (en) |
| NZ (1) | NZ320483A (en) |
| WO (1) | WO1997026261A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2896416B1 (en) * | 2006-01-24 | 2010-08-13 | Vetoquinol | ANTI-INFECTIOUS COMPOSITION COMPRISING A PYRIDO (3,2,1-IJ) -BENZOXADIAZINE COMPOUND |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0259804B1 (en) * | 1986-09-12 | 1993-11-18 | F. Hoffmann-La Roche Ag | Pyrido[3,2,1-ij]-1,3,4-benzoxadiazine derivatives, process for their preparation, resulting pharmaceutical preparations and intermediates for use in the process |
-
1996
- 1996-01-17 GB GBGB9600886.7A patent/GB9600886D0/en active Pending
- 1996-10-31 JP JP9516887A patent/JP2000501071A/en active Pending
- 1996-10-31 CA CA002242713A patent/CA2242713A1/en not_active Abandoned
- 1996-10-31 AU AU73221/96A patent/AU7322196A/en not_active Abandoned
- 1996-10-31 EP EP96935144A patent/EP0935602A1/en not_active Withdrawn
- 1996-10-31 NZ NZ320483A patent/NZ320483A/en unknown
- 1996-10-31 WO PCT/GB1996/002674 patent/WO1997026261A1/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| AU7322196A (en) | 1997-08-11 |
| EP0935602A1 (en) | 1999-08-18 |
| WO1997026261A1 (en) | 1997-07-24 |
| GB9600886D0 (en) | 1996-03-20 |
| NZ320483A (en) | 2000-01-28 |
| JP2000501071A (en) | 2000-02-02 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |