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WO1996001260A1 - Derive d'acide pyridone-carboxylique, l'un de ses esters, l'un de ses sels, et produit intermediaire pour la synthese de ces composes - Google Patents

Derive d'acide pyridone-carboxylique, l'un de ses esters, l'un de ses sels, et produit intermediaire pour la synthese de ces composes Download PDF

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Publication number
WO1996001260A1
WO1996001260A1 PCT/JP1995/001293 JP9501293W WO9601260A1 WO 1996001260 A1 WO1996001260 A1 WO 1996001260A1 JP 9501293 W JP9501293 W JP 9501293W WO 9601260 A1 WO9601260 A1 WO 9601260A1
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Prior art keywords
group
lower alkyl
salt
alkyl group
compound
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PCT/JP1995/001293
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English (en)
Japanese (ja)
Inventor
Masahiro Fujita
Katsumi Chiba
Yukio Tominaga
Akira Minami
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Dainippon Pharmaceutical Co., Ltd.
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Application filed by Dainippon Pharmaceutical Co., Ltd. filed Critical Dainippon Pharmaceutical Co., Ltd.
Priority to AU28065/95A priority Critical patent/AU2806595A/en
Priority to JP8503777A priority patent/JP2888987B2/ja
Publication of WO1996001260A1 publication Critical patent/WO1996001260A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom

Definitions

  • the present invention relates to a novel pyridone haponic acid derivative useful as an antibacterial agent and a novel synthetic intermediate thereof.
  • antibacterial pyridonecarboxylic acid derivatives for example, t various types have been known, in Kohyo 5-503709 discloses (W091 / 16894) represented by the following general formula (A)
  • R 1 is a lower alkyl group ⁇ cycloalkyl group
  • R 2 is “bicyclic nitrogen-containing heterocyclic group” or the like
  • R 3 is a hydrogen atom or a halogen atom
  • R 4 is a hydrogen atom or a lower alkyl group
  • R 5 is a hydrogen atom or a halogen atom
  • A is N or CH
  • a quinol izinone type compound represented by the following formula has been disclosed, but this compound is clearly different from the compound of the present invention represented by the formula (I) described later in the basic ring structure.
  • R 2 As an example of a “bicyclic nitrogen-containing heterocycle group” defined for the above, the above publication discloses the following formulas (a-11) to (a-3) The group represented by the formula (a-3) conceptually includes the substituent at the 7-position of the compound of the present invention. — There is no specific description of group 3).
  • V and W are CH 2 .
  • j and k are 1, 2 or 3
  • a 1 is a carbon atom or a hetero atom selected from S, 0 or N;
  • A is an amino (lower alkyl) group, etc.
  • R 1 is a hydrogen atom
  • R 2 is a lower alkyl group which may have a substituent
  • X is a hydrogen atom ⁇ a halogen atom
  • Y is an optionally substituted cyclic amino group, etc.
  • Z is a nitrogen atom, CH, etc.
  • a quinolone derivative represented by the following formula (b) is described as an example of the “cyclic amino group optionally having a substituent” defined for Y.
  • i 1 or 2
  • A is a substituted or unsubstituted amino group, etc.
  • R 1- , R 2 , R 3 and R 4 are a hydrogen atom or a phenyl group which may have a substituent, and are not simultaneously a hydrogen atom.
  • the compound is different from the bicycloamine compound (I) of the present invention in that the compound does not have an optionally substituted amino group or aminomethyl group.
  • the compound (C) The application is a therapeutic agent for disorders of calcium metabolism, and there is no description that it is useful as an intermediate during the production of pyridonecarboxylic acid.
  • a main object of the present invention is to provide a pyridonecarboxylic acid-type compound having an enhanced antibacterial activity, particularly an antibacterial activity against gram-positive bacteria, and further having an excellent antibacterial activity against Helicopacus pulp and pylori. It is. Disclosure of the invention
  • R is a lower alkyl group, a halogeno lower alkyl group, a lower alkenyl group, a halogeno lower alkenyl group, a cycloalkyl group, a halogenocycloalkyl group, a phenyl group which may have a substituent, Represents a heterocyclic group which may have a substituent,
  • G represents C-E or a nitrogen atom, where E is a force representing a hydrogen atom, or, together with R, forms a bridge represented by —S—CH (CH 3 ) —
  • A represents C—Z or a nitrogen atom, where Z is a hydrogen atom, a halogen atom, a lower alkoxy group, a halogeno lower alkoxy group, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy lower alkyl group, a lower alkenyl Group, lower alkynyl group or cyano group, or together with R, represents one 0—CH 2 —CH
  • (CH 3 ) — may form a bridge represented by
  • X represents a hydrogen atom, a halogen atom, an amino group which may be protected, a hydroxyl group, a lower alkyl group, a halogeno lower alkyl group or a lower alkoxy lower alkyl group;
  • Y represents a hydrogen atom or a halogen atom
  • Ri and R 2 are the same or different and represent a hydrogen atom, a lower alkyl group or an amino protecting group,
  • R 3 represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a lower alkoxy lower alkyl group, a halogeno lower alkyl group or a hydroxy lower alkyl group;
  • n an integer of 0 or 1)
  • halogen atom examples include fluorine, chlorine, and bromine.
  • lower means a group containing from 1 to 7 carbon atoms, unless otherwise specified.
  • “Lower alkyl” means a linear or branched alkyl having 1 to 7 carbon atoms, and examples include methyl, ethyl, propyl, isopropyl, butyl, t-butyl and pentyl.
  • “Lower alkoxy J is a lower alkyloxy group in which the lower alkyl moiety has the above-mentioned meaning, and includes, for example, methoxy, ethoxyquin, propoxy, isopropoxy, butoxy.
  • Lower alkenyl is a group having 2 carbon atoms. And 7 linear or branched alkenyl, for example, vinyl, aryl, 1-propenyl, isop-propenyl, and the like.
  • “Lower alkynyl” includes, for example, ethynyl, 1-propynyl and the like. “Cycloalkyl” includes cycloalkyl having 3 to 7 carbon atoms, and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • Halogeno lower alkyl is a group in which at least one hydrogen atom of a lower alkyl is replaced by a halogen atom, and includes, for example, fluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl and the like.
  • Halogeno lower alkenyl is a group in which at least one hydrogen atom of lower alkenyl is replaced by a halogen atom, and includes, for example, 2-fluorovinyl, 1.1-fluorovinyl, 2,2-difluorovinyl and the like.
  • Halogenocycloalkyl is a group in which at least one hydrogen atom of cycloalkyl has been replaced by a halogen atom, and examples include fluorocyclopropyl, chlorocyclopropyl and the like.
  • “Haloge The "lower alkyne” is a group in which at least one of the hydrogen atoms in the above lower alkoxy is replaced by a halogen atom, and examples thereof include fluoromethoxy, difluoromethoxy, trifluoromethoxy and the like.
  • “Lower alkoxy lower alkyl” means lower alkyl substituted with lower alkyne, and includes, for example, methoxymethyl, ethoxyquinmethyl, 1-methoxyshetyl and the like, and “hydroxy lower alkyl” means It means lower alkyl substituted with xy, for example, hydroxymethyl, 111-hydroxyshethyl and the like.
  • substituent in the “optionally substituted phenyl group j” or the “optionally substituted heterocyclic group” defined for R a halogen atom, a lower alkyl group
  • substituents in the “optionally substituted phenyl group j” or the “optionally substituted heterocyclic group” defined for R include a lower alkoxy group, a hydroxyl group, a nitro group, and an amino group.
  • heterocyclic group optionally having substituent (s) examples include, for example, pyrrole, furan, thiophene, thiazol, isothiabule, oxazole, isoxabule, pyrazonole, imidabule, pyridine, pyridazine, Hetero atoms such as pyrimidine and pyrazine include 5- or 6-membered heterocyclic groups containing N, 0 or S.
  • amino protective group any amino acid that can be easily removed without substantially affecting other structural parts by a usual deprotecting group reaction such as hydrolysis or hydrogenolysis is used. Can be adopted.
  • amino-protecting groups examples include ethoxycarbonyl, t-butoxycarbonyl (hereinafter sometimes abbreviated as Boc), and benzylo.
  • Oxycarbonyl groups such as xyloxycarbonyl, p-methoxybenzyloxycarbonyl, vinyloxycarbonyl, / S- (p-toluenesulfonyl) ethoxycarbonyl; acyl groups such as formyl, acetyl, trifluoroacetyl; trimethyl Shi A silyl group such as lyl and t-butyldimethylsilyl; tetrahydrobiranyl, 0-nitrophenylsulfenyl, diphenylphosphenyl and the like.
  • amino-protecting group which is easily eliminated by hydrogenolysis (an easily hydrolyzable amino-protecting group)
  • an arylsulfonyl group such as p-toluenesulfonyl; benzyl, trityl, and benzyloxymethyl.
  • a methyl group substituted by a phenyl or benzyloxy group such as: benzyloxycarbonyl, an arylmethoxycarbonyl group such as 0-methoxybenzyloxycarbonyl; / 3, ⁇ , ⁇ 1 And a halogenoethoxycarbonyl group such as ethoxycarbonyl.
  • ester of the compound (I) of the present invention those which can be converted to the compound (I) of the present invention by elimination by chemical means or enzymatic means are suitable.
  • ester that can be converted to the corresponding free rubonic acid by chemical means such as hydrolysis include lower alkyl esters such as methyl ester and ethyl ester.
  • 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, and vivaloyloxymethyl ester
  • Lower alkanoyloxy lower alkyl esters such as: 1 lower alkoxycarbonyloxy lower alkyl esters, such as 1-ethoxyquincarbonyloxyethyl ester; 2-dimethylaminoethyl ester, 2- (1-piberidinyl)
  • aminoethyl esters such as ethyl ester, etc., 3-butyrolactonyl ester, choline ester, phthalidyl ester, (5-methyl-2-oxo-1-3-dioxol-14-yl) methyl ester and the like can be mentioned.
  • Particularly preferred salts of the pyridonecarboxylic acid derivative (I) of the present invention are physiologically Acceptable salts are preferred, salts with organic acids such as trifluoroacetic acid, acetic acid, lactic acid, succinic acid, methanesulfonic acid, maleic acid, malonic acid or amino acids such as gluconic acid, aspartic acid or glumic acid; Salts with inorganic acids such as hydrochloric acid and phosphoric acid; metal salts such as sodium, potassium, zinc and silver; ammonium salts; salts with organic bases such as trimethylamine, triethylamine and N-methylmorpholine. An example is given below.
  • Examples of the salt of the bicycloamine compound (E) of the present invention include acid addition salts with inorganic acids such as hydrochloric acid and sulfuric acid; and organic acids such as formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid and p-toluenesulfonic acid.
  • C The pyridonecarboxylic acid derivative (I) and the bicycloamine compound (I) of the present invention, which include an acid addition salt of the present invention, sometimes exist as a hydrate or a solvate.
  • the compound (I) of the present invention may exist as an optically active form or a stereoisomer (cis type, trans type). These compounds are also included in the present invention.
  • Preferred examples of the compound (I) of the present invention include compounds in which G is CH in the general formula (I). More preferably, in the above general formula (I), G is CH and R is a cycloalkyl group such as cyclopropyl, a halogenocycloalkyl group such as 2-fluorocyclopropyl, or 2,1-difluorophenyl.
  • Preferred examples of the bicycloamine compound (H) of the present invention include the compounds described above and the compounds corresponding to the substituent located at the 7-position of the pyridonecarboxylic acid derivatives specifically mentioned below.
  • Can be Typical examples of the compound (I) of the present invention are as follows.
  • 5-Amino-7 (1-Amino-3-azabicyclo [3.1.1] Hepter-3-yl) 1-1-Cyclopropyl-1,6,8-difluoro-1,4-dihydro 4-oxoquinoline-1 3-Power Rubonic acid.
  • 6-Fluoro-7- (5-Fluoromethyl-1-1-methylamino-3-azabicyclo [3.1.1] Hepter-3-yl) 1-1,4-Dihydro-4-1-oxo-1--1-vinyl-1,8-naphthyridine 3--Rubonic acid.
  • 6-Fluoro-7 (5-Fluoromethyl-1-methylamino) 3-azabicyclo [3.1.1] Hepter 3-yl) 1 1 1 (2-Fluorovinyl) 1 4 4-Hydro 1 4-oxo 1 8 —Naphthyridine-3-carbonic acid.
  • the compound (I) of the present invention can be produced, for example, by the following (a) amination reaction, (b) hydrolysis reaction or (c) ring closure reaction.
  • L represents a removable group
  • R, G, A, X and Y represent Having the meaning described above, and the carbonyl group and the oxo group may form a boron chelate bond between these groups
  • an ester or a salt thereof and a compound represented by the following general formula (I )
  • Examples of the removable group L in the general formula (II) 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 arylsulfonyloxy group and the like.
  • halogen atoms such as fluorine and chlorine are preferred.
  • This reaction is generally performed by stirring compound (E) and compound (BI) for 10 minutes to 24 hours, preferably 30 minutes to 3 hours in an inert solvent at 10 to 180 ° C, preferably 20 to 130 ° C.
  • an inert solvent at 10 to 180 ° C, preferably 20 to 130 ° C.
  • the solvent include water, methanol, ethanol, acetonitrile, chloroform, pyridine, dimethylformamide, dimethyl sulfoxide, 1-methyl-2-pyrrolidone, and the like. These solvents may be used alone or as a mixture.
  • This reaction is generally carried out in the presence of an acid acceptor using compound (I) in an equivalent amount or an excess amount relative to compound (I). May be used excessively and also serve as an acid acceptor.
  • the acid acceptor include organic bases such as 1,8-diazabicyclo [5.4.0] —7-indene (DBU), triethylamine, pyridine, quinoline, and picoline, or sodium hydroxide, Inorganic bases such as potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and the like can be mentioned.
  • DBU 1,8-diazabicyclo [5.4.0] —7-indene
  • DBU 1,8-diazabicyclo [5.4.0] —7-indene
  • Inorganic bases such as potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and the like can be mentioned.
  • These acid acceptors can be used usually in a molar amount of 1 to 3 times the amount of
  • the compound ( ⁇ is known or can be produced according to a known method. Both of the bicycloamine compounds (E) are novel, and their production methods will be described later.
  • the compound (I) of the present invention has the following formula (17)
  • the hydrolysis reaction can be carried out by appropriately contacting compound (IV) with water in a solvent. This reaction is usually performed in the presence of an acid or a base in the sense of accelerating the reaction.
  • usable acids 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 potassium carbonate; and sodium acetate.
  • Water is usually used as the solvent, but a water-miscible organic solvent such as ethanol, ethylene glycol dimethyl ether, benzene, or dioxane is used together with water depending on the properties of compound (IV).
  • the reaction temperature can be generally selected from the range of 0 to 150 ° C, preferably 30 to 100 ° C. This reaction can also be carried out by directly heating compound (IV) in the presence of an acid as described above, and then adding water.
  • the compound (I) of the present invention has the following general formula (V)
  • L ′ represents a removable group
  • R 4 represents a lower alkyl group, an aryl group or a benzyl group
  • R, G, A, X, Y, R,, R 2 , R 3 And n have the meaning described above
  • the groups described above for the group L which can be eliminated are preferable, and in particular, halogen atoms such as fluorine and chlorine are preferable.
  • This ring closure reaction is carried out in the presence of compound (V) in the presence of a base in an amount of 1 to 3 moles per mole of compound (V), for example, potassium carbonate, sodium carbonate, sodium hydride, potassium butoxide, potassium fluoride and the like.
  • a mixture of 30 to 150 DEG ° C with the solvent preferably can be carried out by stirring 1-6 hours at 30 to 100 D C.
  • Suitable solvents include ethanol, dioxane, tetrahydrofuran, dimethylformamide, dimethylsulfoxide and the like.
  • the compound (V) used as a raw material is also novel, and can be produced, for example, according to the following reaction formula 1. Reaction formula 1_
  • R has the same meaning as a hydrogen atom or R 4 described above, R 6 and R 7 are the same or different and represent a lower alkyl group, and R, G, A, X, Y, Ri, R 2 , R 3 , R 4 , L, L ′ and n have the above-mentioned meanings.
  • the compound (V) can be prepared by, for example, adding a compound (1) to a bicycloamine compound (IO The compound (2) is reacted to form the compound (2) . The obtained compound (2) is converted to an acid halide, and then reacted with a 3-dialkylaminoacrylic acid ester in the presence of a base to form the compound (3). It can be obtained by treating (3) with a primary amine.
  • compound (V) is obtained by, for example, converting compound (1 ′) into an acid halide, reacting with malonate, hydrolyzing the compound, and then subjecting compound (4) to a decarboxylation reaction.
  • the resulting compound (4) was treated in the same manner as in the synthesis of compound (2) above to give compound (5), and this compound (5) was treated with a mixture of acetic anhydride and ethyl formate. Then, it can also be obtained by reacting with primary amine.
  • the compound (I) of the present invention produced by any of the above methods (a), (b) and (c) has an amino-protecting group, it may be subjected to a hydrolysis reaction or a hydrogenolysis reaction, if desired. This leads to the compound (I) of the present invention in which the amino protecting group has been converted to a hydrogen atom.
  • the elimination reaction of the amino protecting group by hydrolysis can be carried out in the same manner as in the method described in the above method (b).
  • 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 a solvent in the presence of a catalyst.
  • the compound can be converted into the compound (I) of the present invention from which the amino protecting group has been eliminated.
  • the catalyst used in this reaction include hydrogenation catalysts such as platinum, palladium, and Raney nickel.
  • the solvent for example, ethylene glycol, dioxane, dimethylformamide, ethanol, acetic acid, water and the like can be used. This reaction can be performed at 60 ° C or lower, usually at room temperature.
  • the compound (H) used as a raw material in the aforementioned method (a) is, for example, a compound represented by the following general formula (VI)
  • R 3 ′ has the same meaning as R 3 described above or is a group convertible to R 3 , R 6 is an amino protecting group, and R,, R 2 and n are as defined above. Meaningful
  • examples of the amino-protected R 5 include, for example, the above-mentioned easily hydrolyzable amino-protecting group and easily hydrolyzable amino-protecting group.
  • R, and Z or R 2 of compound (VI) are amino protecting groups
  • the amino protecting group of R 5 be different from the amino protecting group of R and / or R 2. Preferred for later reactions.
  • R 5 is a readily hydrolyzable amino protecting group such as a t-butoxycarbonyl group
  • R 5 is a readily hydrolyzable amino protecting group such as benzyl ditrityl.
  • the groups are suitably chosen.
  • This elimination reaction can be carried out by subjecting compound (VI) to a hydrogenolysis reaction or a hydrolysis reaction as described above.
  • Examples of the “group that can be converted to R 3 ” in R 1 include, for example, a methanesulfonyloxy group ⁇ P-toluenesulfonyloxy group, a benzyloxy group, an alkoxycarbonyl group, a carboxyl group and the like.
  • the methanesulfonyloxy group p-toluenesulfonyloxy group can be converted to a halogen atom or a lower alkoxy group as R 3 by a nucleophilic substitution reaction.
  • the benzyloxy group can be converted to a hydroxyl group as R 3 by a hydrogenolysis reaction or a hydrolysis reaction.
  • the alkoxycarbonyl group can be converted to various hydroxy lower alkyl groups by, for example, hydride reduction using lithium aluminum hydride or a reaction using an organometallic reagent such as methyl lithium.
  • the carboxylic acid group can be converted to a halogen atom as R 3 by introducing it to an acid or a rosogenide and then treating it with a Wilkinson complex ⁇ RhCl [P (C 6 H 5 ) 3 ] 3 ⁇ .
  • the compound (VI) is also novel and can be produced, for example, by the methods described in Examples 1 to 9 described below or a method analogous thereto.
  • the pyridonecarboxylic acid derivative (I) of the present invention and the intermediate bicycloamine compound (E) thus produced 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. These compounds are mutually converted depending on the purpose, and are converted into the desired form of the compound of the present invention. I can guide you.
  • the stereoisomers of the compound (I) of the present invention can be separated from each other by a conventional method, for example, fractional crystallization, chromatography, and the like. For an optically active compound, a known optical resolution method is applied. Can be isolated by
  • the thus-obtained compound (I) of the present invention and salts thereof are all new compounds, exhibit excellent antibacterial activity, and are valuable as antibacterial agents.
  • the compound (I) of the present invention and salts thereof can be used not only as pharmaceuticals for humans and animals, but also as fish disease drugs, agricultural chemicals, food preservatives and the like.
  • the ester of the compound (I) of the present invention is a carboxy group of the compound (I) of the present invention. Although it is valuable as a raw material for synthesizing an acid derivative, when the ester itself is easily converted into the compound (I) of the present invention in vivo, it can be used as a prodrug as with the compound (I) of the present invention. In addition, it can be used as an antibacterial agent. Further, the bicycloamine compound (H) of the present invention is useful as a direct synthetic intermediate for the compound (I) of the present invention. BEST MODE FOR CARRYING OUT THE INVENTION
  • the compound (I) of the present invention exhibits excellent antibacterial activity both in vitro and in animal experiments, and is particularly excellent against Gram-positive bacteria and Helicobacter pylori. Clear antibacterial activity It is.
  • the compound (I) of the present invention shows better antibacterial activity than the control compound (enoxacin).
  • the compound (I) of the present invention has a low toxicity and is useful as an antibacterial agent against mammals including humans for the prevention and treatment of bacterial diseases in mammals.
  • the dosage varies depending on the age, body weight, symptoms, administration route, etc., but is generally 5 mg to 5 g once or several times a day. It is recommended that the drug be administered separately.
  • the route of administration may be oral, parenteral or topical.
  • 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 prepared together with pharmaceutically acceptable additives.
  • Such preparations include tablets, liquids, capsules, granules, fine granules, powders, syrups, injections, ointments and the like.
  • These preparations can be manufactured using a usual additive according to a conventional method.
  • a carrier which is commonly used in the field of preparations such as starch, mannite, crystalline cellulose, carboxymethylcellulose Ca, water, ethanol and the like and which does not react with the compound (I) of the present invention.
  • additives for injection include those commonly used in the field of injections, such as water, physiological saline, glucose solution, and infusion.
  • liquid preparations and ointments can be used in the treatment and treatment of otolaryngology and ophthalmology.
  • Examples 1 to 9 relate to a method for producing an intermediate bicycloamine compound (I), and Examples 10 to 38 relate to a method for producing a target compound (I).
  • Reference numeral 39 denotes an embodiment relating to production.
  • Example 1
  • the solvent was distilled off under reduced pressure to obtain a crude product of getyl 3-p-toluenesulfonyloxymethylcyclobutane-1,1-dicarboxylate.
  • a mixture of the above crude product, 42.2 g of benzylamine, 32.4 g of potassium carbonate and 600 ml of dioxane was refluxed for 4.5 days. Ice water was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with saturated aqueous sodium hydrogen carbonate and then with saturated saline, and dried over sodium sulfate.
  • a mixture of 32.3 g of benzyl 3-ethyl 1,1-dicarboxylate, 120 ml of a 10% aqueous sodium hydroxide solution and 120 ml of tetrahydrofuran obtained in step D of the preceding section was added at room temperature for 13.5 hours, and then Stirred at 50-60 ° C for 6 hours.
  • the mixture was concentrated under reduced pressure, added with 100 ml of water and activated carbon, and filtered.
  • 54.5 ml of 20% hydrochloric acid was added to the filtrate while stirring. After cooling on ice, the crystals were collected by filtration and washed with water and ethanol to obtain 20 g of 3-benzylaminomethylcyclobutane-1,1-dicarboxylic acid.
  • step H of the previous section 2 The compound obtained in step H of the previous section 2.
  • 30 ml of a 1.0 molar tetrahydrofuran solution of a borane-tetrahydrofuran complex was added to the mixture. After refluxing for 7 hours, the mixture was concentrated under reduced pressure.
  • 40 ml of ethanol was added to the residue, and the mixture was refluxed for 9 hours.
  • the mixture was concentrated under reduced pressure, ice water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and then with a saturated saline solution, and then dried over sodium sulfate.
  • Boiling point approx. 100 ° C (3 mmHg, Kugelrohr-Miku mouth distillation unit)
  • Step K of Example 1 The same treatment as in Step K of Example 1 was carried out using 1.17 g of the compound obtained in Step K of the preceding section, 120 mg of 5% palladium carbon and 20 ml of ethanol to obtain 585 mg of the desired product.
  • Step I of Example 1 The same treatment as in Step I of Example 1 was carried out using 2.08 g of the compound obtained in the above step L, 30 ml of tetrahydrofuran and 43 ml of a 1.0 molar tetrahydrofuran solution of a borane-tetrahydrofuran complex to give 3-benzyl-1-methylamine 3- 1.76 g of azabicyclo [3.1.1] heptane was obtained.
  • Boiling point about 100. C (4 mmHg, Kugel lower micro distillation apparatus)
  • Step N The same treatment as in Step J of Example 1 was carried out using 1.74 g of the compound obtained in Step M of the preceding section, 170 mg of 5% palladium carbon and 20 ml of ethanol to obtain 1.0 g of the desired product.
  • Step J of Example 1 The same procedures as in Step J of Example 1 were carried out, using 548 mg of the compound obtained in Step U of the preceding section, 50 mg of 5% palladium carbon and 10 ml of ethanol to obtain 343 mg of the desired product.
  • Step C of Example 1 The same treatment as in Step C of Example 1 was carried out using 124.9 g of the compound obtained in Step B of the preceding section, 38.3 g of 60 sodium hydride, 153 g of getyl malonate and 1.3 xylene, to give 3-benzyloxy-3-fluoro. 30.8 g of octyl cyclobutane-1,1-dicarboxylate was obtained.
  • Step C of the preceding paragraph 3.1 g of 5% palladium on carbon and 300 ml of ethyl acetate, the same treatment as in Step D of Example 1 was carried out to obtain 3-fluoro-3-hydroxy. 17.8 g of methylcyclobutane-1,1-dicarboxylate getyl were obtained.
  • step D Using 14.8 g of the compound obtained in the above step D, 53 ml of a 10% aqueous sodium hydroxide solution and 53 ml of tetrahydrofuran, the same treatment as in step E of Example 1 was carried out to give 3-benzylaminomethyl-3- —9.88 g of fluorocyclobutane-1,1-dicarboxylic acid were obtained.
  • Step F The same treatment as in Step F of Example 1 was carried out using 9.59 g of the compound obtained in Step E of the preceding section, 16.6 g of carbodiimide imabourl and 100 mL of N, N-dimethylformamide to give 3-benzylbenzene. Fluoro-2-oxo-3-azabicyclo [3.1.1] heptane-1 7.42 g of monobasic rubonic acid was obtained.
  • Step G of Example 1 The same treatment as in Step G of Example 1 was carried out using 7.22 g of the compound obtained in Step F of the preceding section, 11.3 g of diphenylphosphoryl azide, 4.21 g of triethylamine and 72 ml of t-butanol. 6.40 g of 3-benzylamine 1 1-t-butoxycarbonylamino-5-fluoro-3-azabicyclo [3.1.1] heptan-2-one was obtained.
  • Step I of Example 1 The same treatment as in Step I of Example 1 was carried out using 4.15 g of the compound obtained in Step H of the preceding paragraph, 60 mL of a 1.0 molar tetrahydrofuran solution of a borane-tetrahydrofuran complex, and 50 mL of tetrahydrofuran to obtain 1-amino-3-benzene. 5-5-fluoro-3-azabicyclo [3.1.1] heptane 3.95 g was obtained.
  • Step J of Example 2 The same treatment as in Step J of Example 2 was performed using 5.14 g of the compound obtained in Step K in the preceding paragraph, 0.50 g of palladium on carbon, and 70 mL of ethanol, to give 1-t-butoxycarbonylamino-1-. 3.46 g of fluoro-3-azabicyclo [3.1.1] heptane was obtained.
  • step B of Example 1 The same treatment as in step B of Example 1 was performed using 11.20 g of the compound obtained in step a of the preceding section and p-toluenesulfonyl chloride to give 2,2-dimethyl-5,5-bis (P-toluenesulfonyl). 27.40 g of 3-dioxan was obtained.
  • a mixture comprising 26.4 g of the compound obtained in the step e in the preceding section, 13.4 g of benzylamine, 10.4 g of potassium carbonate and 250 ml of 1,4-dioxane was refluxed for 4 days.
  • the reaction solution was poured into ice water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate.
  • Example 8 The same procedure as in Step J of Example 1 was carried out, using 3.51 g of the compound obtained in Step m of the preceding section and 0.35 g of 5% palladium carbon, to obtain 2.00 g of the desired product.
  • Example 8 The same procedure as in Step J of Example 1 was carried out, using 3.51 g of the compound obtained in Step m of the preceding section and 0.35 g of 5% palladium carbon, to obtain 2.00 g of the desired product.
  • Example 8 The same procedure as in Step J of Example 1 was carried out, using 3.51 g of the compound obtained in Step m of the preceding section and 0.35 g of 5% palladium carbon, to obtain 2.00 g of the desired product.
  • Example 8 The same procedure as in Step J of Example 1 was carried out, using 3.51 g of the compound obtained in Step m of the preceding section and 0.35 g of 5% palladium carbon, to obtain 2.00 g of the desired product.
  • Example 8 The same procedure as in Step J of Example 1 was carried
  • step G of Example 1 Using 4.85 g of the compound obtained in step p of the preceding paragraph and 4.62 g of diphenylphosphoryl azide, the same treatment as in step G of Example 1 was carried out to give 3-benzyl-11-t-butoxycarbonylamine. 4.96 g of 5-methoxymethyl-2-oxo-3-azabicyclo [3.1.1] heptane-2-one was obtained.
  • step J of Example 2 Using 4.04 g of the compound obtained in step y of the preceding section and 0.40 g of 5% palladium carbon, the same treatment as in step J of Example 2 was carried out to obtain 1-t-butyldimethylsiloxymethyl-5-t-butoxycarbonyl. Aminomethyl-3-azabicyclo [3.1.1] heptane 3.24 g was obtained.
  • Example 6 (1) 1-t-butoxycarbonylamino-5-fluoro 3-azabicyclo [3.1.1] obtained in Example 6 (1) heptane 423 mg, 1-cyclopropyl-1,6,7,8-trifluoro Rho 1,4—Dihidro 4-oxoquinoline-3—caprolubonic acid 400 mg, DBU 215 mg and acetonitrile 5.
  • Example 25 (2) The same treatment as in Example 25 (2) was carried out using 1.255 g of the compound obtained in the above (1), 12 ml of 10% hydrochloric acid and 12 ml of tetrahydrofuran to obtain 869 mg of the desired product.
  • the compound (I) of the present invention is useful as a pharmaceutical for mammals including humans (for example, an antibacterial agent or a therapeutic agent for gastrointestinal diseases), and the bicycloamine compound (H) is useful as the compound (I) of the present invention.
  • the compound (I) of the present invention Is useful as a direct synthetic intermediate.

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Abstract

La présente invention concerne un dérivé d'acide pyridone-carboxylique représenté par la formule générale (I), l'un de ses esters, l'un de ses sels et un antibactérien à base de ces composés. Dans cette formule générale (I), R représente notamment un cycloalkyle éventuellement halogéné ou un phényle éventuellement substitué, G représente notamment un carbone, A représente C-Z ou l'azote, Z représente notamment l'hydrogène, un alcoxy inférieur, un alcoxy inférieur halogéné, un alkyle inférieur, un alkyle inférieur halogéné ou un alkyle inférieur d'un alcoxy inférieur, X représente notamment un hydrogène, un halogène, un amino éventuellement protégé ou un alkyle inférieur, Y représente un hydrogène ou un halogène, R1 et R2 représentent chacun indépendamment notamment un hydrogène ou un alkyle inférieur, R3 représente notamment un hydrogène, un halogène, un alcoxy inférieur, un alkyle inférieur d'alcoxy inférieur ou un alkyle inférieur halogéné, et n est un entier valant 0 ou 1. L'invention concerne également un composé aminé bicyclique servant d'intermédiaire direct pour l'obtention des dérivés d'acide pyridone-carboxylique.
PCT/JP1995/001293 1994-07-01 1995-06-29 Derive d'acide pyridone-carboxylique, l'un de ses esters, l'un de ses sels, et produit intermediaire pour la synthese de ces composes WO1996001260A1 (fr)

Priority Applications (2)

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AU28065/95A AU2806595A (en) 1994-07-01 1995-06-29 Pyridonecarboxylic acid derivative, ester thereof, salt thereof, and intermediate for synthesis of these compounds
JP8503777A JP2888987B2 (ja) 1994-07-01 1995-06-29 ピリドンカルボン酸誘導体、そのエステルおよびその塩ならびにこれらの合成中間体

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1650186A1 (fr) * 2004-10-22 2006-04-26 Bioprojet Nouveaux derivés d'acides dicarboxyliques
CN108864043A (zh) * 2018-09-18 2018-11-23 中国医学科学院生物医学工程研究所 一种新型喹诺酮化合物的制备方法和用途

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05112554A (ja) * 1992-02-19 1993-05-07 Chugai Pharmaceut Co Ltd 新規なキノロンカルボン酸誘導体
JPH05247059A (ja) * 1992-03-06 1993-09-24 Hokuriku Seiyaku Co Ltd チアゼトキノリン−３−カルボン酸誘導体
JPH05255319A (ja) * 1992-03-10 1993-10-05 Wakunaga Pharmaceut Co Ltd 新規キノロン誘導体又はその塩、並びに該化合物を含有する抗菌剤
JPH069619A (ja) * 1992-04-28 1994-01-18 Chugai Pharmaceut Co Ltd キノロンカルボン酸誘導体の製造方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05112554A (ja) * 1992-02-19 1993-05-07 Chugai Pharmaceut Co Ltd 新規なキノロンカルボン酸誘導体
JPH05247059A (ja) * 1992-03-06 1993-09-24 Hokuriku Seiyaku Co Ltd チアゼトキノリン−３−カルボン酸誘導体
JPH05255319A (ja) * 1992-03-10 1993-10-05 Wakunaga Pharmaceut Co Ltd 新規キノロン誘導体又はその塩、並びに該化合物を含有する抗菌剤
JPH069619A (ja) * 1992-04-28 1994-01-18 Chugai Pharmaceut Co Ltd キノロンカルボン酸誘導体の製造方法

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1650186A1 (fr) * 2004-10-22 2006-04-26 Bioprojet Nouveaux derivés d'acides dicarboxyliques
CN108864043A (zh) * 2018-09-18 2018-11-23 中国医学科学院生物医学工程研究所 一种新型喹诺酮化合物的制备方法和用途

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