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WO1999010351A1 - Derives d'acide pyridonecarboxylique et intermediaires aux fins de leur preparation - Google Patents

Derives d'acide pyridonecarboxylique et intermediaires aux fins de leur preparation Download PDF

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Publication number
WO1999010351A1
WO1999010351A1 PCT/JP1997/002918 JP9702918W WO9910351A1 WO 1999010351 A1 WO1999010351 A1 WO 1999010351A1 JP 9702918 W JP9702918 W JP 9702918W WO 9910351 A1 WO9910351 A1 WO 9910351A1
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Prior art keywords
group
compound
hydrogen atom
lower alkyl
amino
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PCT/JP1997/002918
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English (en)
Japanese (ja)
Inventor
Nobuhiko Horiuchi
Takenori Yonezawa
Katsumi Chiba
Hiroaki Yoshida
Original Assignee
Dainippon Pharmaceutical Co., Ltd.
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Publication date
Application filed by Dainippon Pharmaceutical Co., Ltd. filed Critical Dainippon Pharmaceutical Co., Ltd.
Priority to AU39523/97A priority Critical patent/AU3952397A/en
Priority to PCT/JP1997/002918 priority patent/WO1999010351A1/fr
Publication of WO1999010351A1 publication Critical patent/WO1999010351A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel pyridonecarboxylic acid derivative useful as an antibacterial agent and a novel synthetic intermediate thereof.
  • Landscape technology a novel pyridonecarboxylic acid derivative useful as an antibacterial agent and a novel synthetic intermediate thereof.
  • X, and X 2 are halogen atoms
  • Ri is an amino group which may have a substituent
  • R 3 and R 4 are a hydrogen atom, an alkyl group, etc.
  • Y is 0, N or a methylene group, etc.
  • Z is 0, S or a methylene group, etc.
  • m and n are integers from 0 to 2 and their sum is 2 or 3;
  • p, q and r are integers from 0 to 3 and their sum is 0 to 3 and
  • A is N Or C—X (where X is a hydrogen atom, halogen, etc.), and R is a hydrogen atom, etc.
  • the bicyclic amino group which is a substituent at the 7-position in the compound of the general formula (A) is composed of a first ring containing a nitrogen atom and a second ring containing an oxygen atom and the like.
  • the substituent on the ring is different from the compound of the present invention represented by the formula (I) described later.
  • Japanese Patent Application Laid-Open No. 6-192262 (corresponding European Patent Application Publication No .: EP—A-5899318) has the following general formula (B). Where:
  • Xj is halogen or nitro
  • ⁇ 2 is hydrogen, amino, etc.
  • R 1 is alkyl, cycloalkyl, etc.
  • R 2 is hydrogen or the like
  • A is N or C one R 5, wherein R 5 is hydrogen, halo,
  • Z is a group represented by the following formula
  • R 4 is hydrogen, methyl, etc.
  • the bicyclic amino group (Z) which is a substituent at the 7-position of this compound is a condensation of a first ring containing a nitrogen atom and a second ring containing an oxygen atom.
  • the format differs from the compounds of the invention. Disclosure of the invention
  • R represents a lower alkyl group, a lower alkenyl group or a lower cycloalkyl group (these groups may be optionally substituted by a halogen atom) or a phenyl group (this group may be An amino group optionally substituted with a lower alkyl group and a Z or halogen atom).
  • X represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group or an amino group which may be protected
  • Y represents a hydrogen atom or a halogen atom
  • A represents a nitrogen atom or a group represented by C-Z, wherein Z represents a hydrogen atom, a halogen atom or a cyano group, or a lower alkoxy group, a lower alkyl group, a lower alkylthio group, a lower alkenyl group.
  • Group or lower alkynyl group (these groups may be optionally substituted with halogen atoms) or together with R are represented by — 0— CH 2 —CH (CH 3 ) — Crosslinks,
  • R and R 2 are the same or different and each represent a hydrogen atom, a lower alkyl group or an amino protecting group
  • R 3 represents a hydrogen atom or a lower alkyl group
  • R 4 , R 5 , R 6 , RT, R 8 and R 9 are the same or different and each represent a hydrogen atom, a halogen atom or a lower alkyl group;
  • n 0 or 1
  • n and p are the same or different and are each 0 or 1; and a novel pyridonecarboxylic acid derivative represented by the following formula (hereinafter sometimes referred to as compound (I) of the present invention), its ester and its salt are provided.
  • the structural feature of the compound (I) of the present invention is represented by the following general formula at the 7-position or a position equivalent to the 7-position of a specific pyridonecarboxylic acid.
  • the compound (I) of the present invention which has a structural characteristic as described above, having a bicyclic amino group, which has not been known, is represented by And is useful as an antibacterial agent is there.
  • halogen atom examples include fluorine, chlorine, and bromine.
  • “Lower alkyl” means a straight or branched chain. It means alkyl having 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl and the like.
  • “Lower alkoxy” is a lower alkyloxy group in which the lower alkyl moiety has the above meaning, and examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like.
  • “Lower alkenyl” refers to straight or branched alkenyl having 2 to 7 carbon atoms, and includes, for example, vinyl, aryl, 1-propenyl, and isopropyl.
  • “Lower alkynyl” includes, for example, ethynyl, 1-propynyl and the like.
  • “Lower cycloalkyl” includes cycloalkyl having 3 to 7 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • “Lower alkylthio” includes, for example, methylthio, ethylthio and the like.
  • the lower alkyl, lower alkenyl and lower cycloalkyl groups defined for R may be optionally substituted by one or more halogen atoms.
  • halogen atoms include fluoromethyl, difluoro-pi-methyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2,2-difluoroethyl, 2-fluorovinyl, 1-fluorovinyl, 2 , 2-difluorovinyl, 2-fluorocyclopropyl, 2-chlorocyclopropyl and the like.
  • a lower alkoxy group, a lower alkyl group, a lower alkylthio group, The lower alkenyl group and lower alkynyl group may be optionally substituted with one or more halogen atoms.
  • Examples of the above-mentioned groups substituted by a halogen atom include, in addition to the examples of the lower alkyl group and the lower alkenyl group substituted by a halogen atom described above for R, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2 —Flouroet pheasant, 2,
  • Examples include 2-difluoroethoxy, 2,2,2-trifluoroethoxy, difluoromethylthio, trifluoromethylthio, fluorethynyl, and trifluoropropynyl.
  • phenyl group (this group may be optionally substituted with an amino group optionally substituted with a lower alkyl group and Z or a halogen atom)
  • examples of "phenyl group (this group may be optionally substituted with an amino group optionally substituted with a lower alkyl group and Z or a halogen atom)" include 2,4-difluorophenyl, 3-— Examples thereof include amino-4,6-difluorophenyl, 4-chloro-2-fluorophenyl, 2-chloro-4-fluorophenyl, 3-amino-4-fluorophenyl, and 4,6-difluoro-3-methylaminophenyl.
  • Protecting groups in "amino protecting groups” or “optionally protected amino groups” include those which substantially affect other structural moieties by ordinary deprotecting reactions such as hydrolysis or hydrogenolysis. Any material that can be easily desorbed without giving can be used.
  • amino-protecting groups labile hydrolyzable amino-protecting groups
  • B0c ethyne carbonyl
  • tert-butoxydicarbonyl ethyne carbonyl
  • benzyl Oxycarbonyl groups such as oxycarbonyl, p-methoxybenzyloxycarbonyl, vinyloxycarbonyl, / 3— (p-toluenesulfonyl) ethoxycarbonyl
  • acyls such as formyl, acetyl, trifluoroacetyl Groups
  • silyl groups such as trimethylsilyl and tert-butyldimethylsilyl
  • tetrahydrobilanyl 0-ditrophenylsulfenyl, diphenylphosphenyl and the like. I can do it.
  • amino protecting group which is easily eliminated by hydrogenolysis examples include, for example, an aryl sulfonyl group such as p-toluenesulfonyl; benzyl, trityl, benzyloxymethyl A methyl group substituted by a phenyl or benzyloxy group such as benzyloxycarbonyl or an aryl carbonyl group such as o-methoxybenzyloquincarbonyl; S, ⁇ , 3-trichloroethoxycarbonyl; And a halogenoethoxycarbonyl group such as ethoxycarbonyl.
  • an aryl sulfonyl group such as p-toluenesulfonyl
  • benzyl, trityl benzyloxymethyl A methyl group substituted by a phenyl or benzyloxy group such as benzyloxycarbonyl or an aryl carbonyl group such as o-me
  • ester of the compound (I) of the present invention those which can be converted into the compound (I) of the present invention by being eliminated in vivo or in vitro by chemical means or enzymatic means are suitable.
  • Esters that can be converted to the corresponding free carboxylic acids by chemical means such as hydrolysis include, for example, lower alkyl esters such as methyl esters and ethyl esters.
  • Esters that can be converted to the corresponding free carboxylic acid not only by chemical means but also by enzymatic means include, for example, acetomethyl ester, 1-acetoxityl ester, pivaloyloxymethyl ester
  • Lower alkenylcarbonyl lower alkyl esters such as 1-ethoxycarbonyloxyshethyl ester
  • lower alkoxycarbonyloxy lower alkyl esters such as 1-ethoxycarbonyloxyshethyl ester
  • aminoethyl esters such as 2-dimethylaminoethyl ester and 2- (1-piperidinyl) ethyl ester
  • a physiologically acceptable salt is particularly preferred, for example, trifluoroacetic acid, acetic acid, lactic acid, succinic acid, methanesulfone Salts with organic acids such as acids, maleic acid, malonic acid, gluconic acid, aspartic acid or glumic acid; salts with inorganic acids such as hydrochloric acid, phosphoric acid; sodium, potassium, zinc, silver Salts with metals such as trimethylamine, triethylamine, N-methylmorpholine and the like.
  • Examples of the salt of the bicyclic amine compound (H) of the present invention include acid addition salts with inorganic acids such as hydrochloric acid and sulfuric acid; formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, P-toluenesulfonic acid and the like. Acid addition salts with organic acids are mentioned.
  • the pyridonecarboxylic acid derivative (I) and the bicyclic amide compound (I) of the present invention sometimes exist as a hydrate or a solvate. These compounds of the present invention may exist in the form of an optically active substance, a stereoisomer (cis type, trans type) or a mixture thereof. All of these compounds are included in the present invention.
  • preferred compounds include those in which n is 1 in the aforementioned general formula (I).
  • more preferred compounds are those represented by the general formula (I):
  • R is cyclopropyl, 2-fluorocyclopropyl and the like, and a lower cycloalkyl group optionally substituted with halogen, or 2,4-difluorophenyl, 3-amino-1,4,6- Compounds such as difluorophenyl, which is a phenyl group substituted by a halogen atom and Z or an amino group,
  • A is a nitrogen atom or C-Z, wherein Z is a hydrogen atom; a halogen atom such as a fluorine atom or a chlorine atom; a cyano group; methoxy, difluoro A lower alkoxy group optionally substituted with a halogen atom such as methoxy, ethoxy, 2-fluoroethoxy, etc .; a lower alkyl group such as methyl; a lower alkylthio group such as methylthio; a lower alkenyl group such as vinyl; A compound that is a lower alkynyl group,
  • Still more preferred compounds of the present invention are those represented by the formula (I), wherein R is cyclopropyl group, 2-fluorocyclopropyl group, 2,4-difluorophenyl group or 3-amino-4,6- A difluorophenyl group, X is a hydrogen atom, a methyl group, a hydroxyl group or an amino group, Y is a fluorine atom, A is a nitrogen atom or C-Z, where Z is a hydrogen atom, a fluorine atom, A chlorine atom, a methoxy group, a difluoromethyoxy group, an ethoxy group, a 2-fluoroethoxy group, a methyl group, a methylthio group, a vinyl group, an ethynyl group or a cyano group, and R 2 is the same or different and a hydrogen atom Or a methyl group, R 3 is a hydrogen atom, R 4 , R 5 , R 6
  • the compound (I) of the present invention can be produced, for example, by an amination reaction or a ring closure reaction.
  • an amination reaction which is a typical production method, will be described.
  • the compound (I) of the present invention, its ester and its salt are represented by the following general formula (IE)
  • L represents a group capable of leaving
  • R, X, Y and A have the above-mentioned meanings
  • the carboxyl group and oxo group in the above formula represent a boron chelate bond between these groups.
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , m , n and p have the above-mentioned meanings
  • the compound can be easily produced by reacting with a bicyclic amide compound represented by the formula below, and hydrolyzing the boron chelate moiety, if present, in the product.
  • Examples of the removable group L in the general formula (dish) include a halogen atom, a lower alkoxy group, a lower alkylthio group, a lower alkylsulfonyl group, a lower alkylsulfinyl group, a lower alkylsulfonyloxy group, an aryl Examples thereof include a sulfonyloxy group.
  • a halogen atom such as fluorine-chlorine is preferable.
  • reaction between compound (H) and compound (m) is usually carried out in an inert solvent at about ⁇ ⁇
  • the inert solvent that can be used in this case include water, methanol, ethanol, acetonitril, chloroform, pyridine, N, N-dimethylformamide, dimethyl sulfoxide, and 1-methyl-2. —Pyrrolidone and the like. These solvents may be used alone or as a mixture.
  • compound (E) is generally used in the presence of an acid acceptor in an equivalent amount or an excess amount relative to compound (LI), but compound (H) is used in excess. And may also serve as an acid acceptor.
  • the acid acceptor include organic bases such as 1,8-diazabicyclo [5.4.0] -17-indene (DBU), triethylamine, pyridine, quinoline and picolin, or water.
  • organic bases such as 1,8-diazabicyclo [5.4.0] -17-indene (DBU), triethylamine, pyridine, quinoline and picolin, or water.
  • inorganic bases such as sodium oxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate.
  • Compound (E) is known or can be produced according to a known method.
  • the bicyclic amine compounds (I) are all novel, and their production methods will be described later.
  • the hydrolysis reaction can be carried out by bringing the compound of the present invention (I) having an ester of the compound of the present invention (I) and / or an easily hydrolyzable amino protecting group into contact with water in a suitable solvent. It can.
  • This reaction is usually performed in the presence of an acid or a base in the sense of accelerating the reaction.
  • the acid that can be used include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as acetic acid, trifluoroacetic acid, formic acid, and p-toluenesulfonic acid.
  • the base include metal hydroxides such as sodium hydroxide and barium hydroxide; carbonates such as sodium carbonate and carbonated lime; and sodium acetate.
  • Water is usually used as the solvent, but a water-miscible organic solvent such as ethanol, ethylene glycol dimethyl ether, or dioxane is used together with water depending on the properties of the compound.
  • the reaction temperature can be generally selected from the range of about 0 to 150 ° C, preferably about 30 to 100. This reaction can also be carried out by directly heating the compound in the presence of an acid as described above, and then adding water.
  • the elimination reaction of the amino-protecting group by hydrogenolysis is advantageously carried out by treating the compound (I) of the present invention having an easily hydrolyzable amino-protecting group with hydrogen gas in the presence of a catalyst in a solvent.
  • a catalyst in a solvent.
  • the catalyst include hydrogenation catalysts such as platinum, palladium, and Raney nickel.
  • the solvent for example, ethylene glycol, Xane, N, N-dimethylformamide, ethanol, acetic acid, water, etc. can be used. This reaction can be carried out at about 60 ° C or less, usually at room temperature.
  • the readily hydrolyzable amino protecting group is benzyl, trityl, benzyloxycarbonyl, p-toluenesulfonyl, etc.
  • a protecting group should be treated with sodium metal in liquid ammonia at a temperature of about 150 to 20 ° C. Can also be desorbed.
  • the compound (I) of the present invention produced by the above amination reaction can be isolated and purified according to a conventional method. These compounds can be obtained in the form of salts, free forms or hydrates depending on the conditions of isolation and purification. It can lead to invention compounds.
  • stereoisomers of the compound (I) of the present invention can be separated from each other by a conventional method, for example, fractional crystallization, chromatography, etc., and the optically active compound is obtained by applying a known optical resolution method. It can be isolated.
  • the thus-obtained compound (I) of the present invention and salts thereof are both novel compounds, exhibit excellent antibacterial activity, and are valuable as antibacterial agents.
  • the compound (I) of the present invention and a salt thereof can be used as a human or non-human animal drug, or as a pesticide, food preservative, or the like.
  • the ester of the compound (I) of the present invention is valuable as a raw material for synthesizing the compound (I) of the present invention.
  • Is also useful as a prodrug, and can be used as an antibacterial agent, like the compound (I) of the present invention.
  • the compound (mutual) used as a raw material in the aforementioned amination reaction method is for example, the following general formula (IV)
  • R is an amino protecting group
  • R 2 , R 3 , R 4 , R 5 , R 6 , Ri, R 8 , R 9 , m, ⁇ and ⁇ have the above-mentioned meanings.
  • Protecting group R can be produced by desorbing and converting to a hydrogen atom.
  • amino protecting group examples thereof include the above-mentioned easily hydrolyzable amino protecting group and easily hydrolyzable amino protecting group.
  • amino protecting group for R, and Z or R 2 is a readily hydrolyzable amino protecting group such as a tert-butoxycarbonyl group, R,.
  • a readily hydrolyzable amino protecting group such as benzyltrityl is preferably selected.
  • Amino protecting group. Can be carried out by subjecting compound (IV) to a hydrogenolysis reaction or a hydrolysis reaction as described above.
  • Compound (IV) is also novel, and can be produced by the method shown in the following reaction schemes 1 to 9 or a method analogous thereto.
  • R H represents an alcohol protecting group such as, for example, t er t-butyldimethylsilyl, acetyl, tetrahydrobilanyl,
  • 2 is lower alkylsulfonyl group, halogeno lower alkylsulfo Nil group or arylsulfonyl group,
  • R! 3 represents a hydrogen atom or a lower alkyl group
  • R represents an amino protecting group
  • R 2 ′ and R 3 ′ each represent a lower alkyl group
  • X 2 and X 3 each represent a halogen atom, q represents an integer of 1 to 3,
  • Compound 3 is obtained by sulfonylation of the terminal alcohol moiety of compound 3 to compound 4, elimination of the alcohol protecting group RH to form compound 5, and ring closure.
  • compound 7 can also be obtained by removing the alcohol protecting group R !! of compound 3 to give compound 6, and reacting it with a sulfonylation reagent in the presence of a base.
  • compound 9 is obtained.
  • the target compound 12 included in the compound (IV) can be obtained by protecting the amino group of the compound 11. Further, by alkylating compound 12 or reducing the amino protecting group to form a lower alkyl group R 2 ′, By introducing the protecting group R, the target compound 13 included in the compound (I?) Can be obtained.
  • the target compound 26 included in the compound (I?) Can be obtained from the compound 23 in exactly the same manner as in the reaction scheme 2.
  • the target compound 29 included in the compound (IV) can be obtained from the compound 21 in exactly the same manner as in the reaction scheme 2.
  • Oxidation of compound 7 obtained in reaction scheme 1 gives compound 33, and reaction with a lower alkyl metal reagent gives compound 34.
  • Compound 35 can be obtained by reducing compound 34, and then the target compound 36 included in compound (IV) can be obtained by Ritsuyuichi reaction.
  • the alcohol protecting group R H of compound 38 is eliminated to give compound 39, and the compound is closed by ring closure to give compound 40.
  • Compound 41 is obtained by halogenating compound 40. Thereafter, the target compound 44 included in the compound (IV) can be obtained from the compound 41 in exactly the same manner as in the reaction scheme 2.
  • Table 1 shows the minimum inhibitory concentration (MIC: g Zml) measured according to the description of Chemotherapy ⁇ (1), 76 (1981), and Table 2 shows the effect on mouse systemic infection (ED 5 ;; mg / kg).
  • the effect on mouse systemic infection (ED 5 ; mg / kg) was determined by intravenous injection of 5 x 10 8 Staphylococcus aureus 50774 strains (live bacteria) per Std-ddy male mouse (body weight: about 20 g).
  • the test compound was dissolved in an equivalent amount of sodium hydroxide solution, and the test compound was diluted with physiological saline and administered orally twice immediately after infection and 6 hours after infection.Mice 14 days after infection was calculated by the probit method from the survival rate.
  • enoxacin [1—ethyl-6-fluoro-1,4—dihydro-14-oxo-17- (1-piperazinyl) 1-1,8—naphthyridine-13, which is already marketed as an excellent antibacterial agent, was used.
  • Rubonic acid abbreviated as ENX).
  • test compounds in Tables 1 and 2 below are specified by the numbers in the Examples described later.
  • the compound (I) of the present invention has excellent in vitro antibacterial activity and in vivo effect.
  • the antibacterial activity of the compound (I) of the present invention against Gram-positive bacteria is much stronger than that of ENX (enoxacin).
  • the compound (I) of the present invention is preferably used as an antibacterial agent for the treatment of bacterial diseases in humans or animals other than humans. Can be.
  • the dosage varies depending on age, body weight, symptoms, administration route and the like, but is generally daily. It is recommended that 5 mg to 5 g be administered in one or several divided doses.
  • the route of administration may be oral, parenteral or topical, but oral administration is recommended.
  • the compound (I) of the present invention may be administered to humans or the like as it is, but is usually administered in the form of a preparation (pharmaceutical composition) prepared with pharmaceutically acceptable additives. .
  • Such preparations include tablets, solutions, capsules, granules, fine granules, powders, syrups, injections, suppositories, ointments, sprays, eye drops and the like.
  • compositions can be produced using ordinary additives according to a conventional method.
  • a solid that is commonly used in the field of pharmaceuticals such as starch, mannite, microcrystalline cellulose, carboxymethylcellulose—Ca, water, ethanol, and does not react with the compound (I) of the present invention
  • a liquid carrier or diluent material is used as an additive for oral use.
  • Additives for injection include those commonly used in the field of injections, such as water, physiological saline, glucose solutions, and infusions.
  • Examples A to M relate to a method for producing an intermediate bicyclic amine compound (H), and Examples 1 to 60 relate to a method for producing a compound (I) of the present invention.
  • Example N is an example relating to a formulation.
  • D-tartaric acid was used as a raw material and was prepared according to the description of Org. Chem. 60, 103-108 (1995) (3R *, 4S *, 5R *) — 1 1-benzyl-3,4-bis ( tert over butyldimethylsilyl O carboxymethyl) - 5- (2-arsenate Dorokishechi Le) - 2-pyrrolidinone 125.5g of 60% aqueous acetic acid 1200ml addition, after c concentration under reduced pressure was refluxed overnight, the residue concentrated aqueous ammonia 300ml and methanol 500ml Was added and stirred at room temperature overnight.
  • D-tartaric acid was used as a raw material and prepared according to the description of J. Org. Chem. 60, 103-108 (1995) (3R *, 4S *, 5R *) — 5-aryl-1 —benzyl-3,4 —Bis (tert-butyldimethylsilyloxy) —2-pyrrolidinone lOOg was added to 670 tnl of tetrahydrofuran, and after ice cooling, 87. lm 1 of a 1.0 mol-tetrahydrofuran solution of a borane-tetrofuran complex was added.
  • D-tartaric acid was used as a raw material and was prepared according to the description of J. Org. Chem. 60, 103-108 (1995) (3R *, 4S *, 5R *) — 5-aryl-1 1-benzyl —
  • a mixture of 3,4-bis (tert-butyldimethylsilyloxy) —150 g of 2-pyrrolidinone, 500 ml of ethanol and 20 ml of concentrated hydrochloric acid was heated to 50 ° C. and stirred for 2 days.
  • the reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was washed with n-hexane and extracted with chloroform. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.
  • Step 2 6.5 g of the compound obtained in Step 1 of the preceding paragraph was treated in the same manner as in Step 4 of Example A to give (1R *, 5S *, 8S *) — 8-azido 6-benzyl-13-methyl-17 —Oxo-1 2-Oxa-1-6-azabiziclo [3.3.0] Octane 5.6 g was obtained. Melting point: 70-73 ° C
  • step 2 of the preceding paragraph was added to 200 ml of tetrahydrofuran, and after cooling with ice, 104 ml of a 1.0 mol solution of borane-tetrahydrofuran complex in tetrahydrofuran was added. After 30 minutes, the mixture was heated and refluxed. The reaction was cooled to room temperature and excess reagent was treated with ethanol. After concentration under reduced pressure, 500 ml of ethanol was added to the residue, and the mixture was refluxed. After concentration under reduced pressure, 10% aqueous hydrochloric acid was added to the residue, and the product was extracted into the aqueous layer and washed with ethyl acetate.
  • the compound (I) of the present invention is useful as an antibacterial agent for humans or animals other than humans, and the bicyclic amine compound (H) is useful for the compound (I) of the present invention.

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Abstract

L'invention a trait à des dérivés d'acide pyridonecarboxylique de la formule générale (I), à leurs sels et à leurs esters, à des médicaments les contenant ainsi qu'à des composés bicycliques amine, intermédiaires directs de ces dérivés d'acide pyridonecarboxylique. Dans la formule générale (I), R représente un cycloalkyle éventuellement halogéné ou analogue, X représente un hydrogène, un alkyle de faible poids moléculaire, un hydroxy ou un amino, Y représente un hydrogène ou un halogéno, A représente un azote ou un groupe de C-Z (où Z représente un alcoxy de faible poids moléculaire éventuellement halogéné ou analogue), R1 et R2 représentent, chacun de manière indépendante un hydrogène ou analogue, R3 représente un hydrogène ou un alkyle de faible poids moléculaire, R4, R5, R6, R7, R8 et R9 représentent, chacun de manière indépendante, un hydrogène ou un halogéno ou un alkyle de faible poids moléculaire, m vaut 0 ou 1 et n et p valent, chacun de manière indépendante 0 ou 1.
PCT/JP1997/002918 1997-08-22 1997-08-22 Derives d'acide pyridonecarboxylique et intermediaires aux fins de leur preparation WO1999010351A1 (fr)

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AU39523/97A AU3952397A (en) 1997-08-22 1997-08-22 Pyridonecarboxylic acid derivatives and intermediates for the preparation thereof
PCT/JP1997/002918 WO1999010351A1 (fr) 1997-08-22 1997-08-22 Derives d'acide pyridonecarboxylique et intermediaires aux fins de leur preparation

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007501819A (ja) * 2003-08-13 2007-02-01 バイエル・ヘルスケア・アクチェンゲゼルシャフト キノロン抗生物質の新規使用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0352889A (ja) * 1989-07-19 1991-03-07 Taisho Pharmaceut Co Ltd ピロリジン化合物
WO1997031919A1 (fr) * 1996-02-27 1997-09-04 Dainippon Pharmaceutical Co., Ltd. Derives d'acide pyridonecarboxylique et leur intermediaires de synthese

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0352889A (ja) * 1989-07-19 1991-03-07 Taisho Pharmaceut Co Ltd ピロリジン化合物
WO1997031919A1 (fr) * 1996-02-27 1997-09-04 Dainippon Pharmaceutical Co., Ltd. Derives d'acide pyridonecarboxylique et leur intermediaires de synthese

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007501819A (ja) * 2003-08-13 2007-02-01 バイエル・ヘルスケア・アクチェンゲゼルシャフト キノロン抗生物質の新規使用

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