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WO1996011194A1 - Derive d'acide pyridonecarboxylique et intermediaire servant a effectuer sa synthese - Google Patents

Derive d'acide pyridonecarboxylique et intermediaire servant a effectuer sa synthese Download PDF

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Publication number
WO1996011194A1
WO1996011194A1 PCT/JP1995/002024 JP9502024W WO9611194A1 WO 1996011194 A1 WO1996011194 A1 WO 1996011194A1 JP 9502024 W JP9502024 W JP 9502024W WO 9611194 A1 WO9611194 A1 WO 9611194A1
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Prior art keywords
group
salt
ester
lower alkyl
compound
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PCT/JP1995/002024
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English (en)
Japanese (ja)
Inventor
Hidetsugu Okada
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 AU36185/95A priority Critical patent/AU3618595A/en
Priority to JP8512475A priority patent/JP2951726B2/ja
Publication of WO1996011194A1 publication Critical patent/WO1996011194A1/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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel pyridone-potassic rubonic acid derivative useful as an antibacterial agent and a novel synthetic intermediate thereof.
  • R] is a lower alkyl group or a lower cycloalkyl group
  • R 2 and R 3 are an optionally substituted aminomethyl group, etc.
  • R 4 is hydrogen, hydroxy, etc.
  • X is hydrogen or halogen, etc.
  • Y is C Q (where Q is H, F, etc.) or N,
  • Z is hydrogen or an amino group
  • m is an integer of 0 or 1
  • n is an integer of 1 or 2.
  • 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 ⁇ , N or a methylene group
  • Z is ⁇ , S or a methylene group
  • n and n are integers of 0 2 and their sum is 2 or 3; p, q, and r are integers of 0 3 and their sum is 0 3
  • A is N or C-X (where X is H, halogen, etc.)
  • R is a hydrogen atom, etc.
  • R is hydrogen, hydroxy, etc.
  • R 2 is an amino group which may be substituted
  • A is a specific pyridonecarboxylic acid residue, m is 0 or 1,
  • n and p are integers from 1 to 3.
  • a pyridonecarboxylic acid compound represented by the following formula is disclosed.
  • bicyclic amide compound examples include, for example, the following general formula (D)
  • R is a hydrogen atom, etc.
  • R 2 is an optionally protected alkylamino or amino; A is hydrogen or an amino protecting group;
  • n is an integer from 1 to 3
  • 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 or Means a heterocyclic group which may have a group,
  • 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 one 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, or means a lower alkynyl group or Shiano group, or such together with R connexion - 0-CH 2 - CH ( CH 3) - crosslinked to form 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
  • n an integer of 1 to 3
  • W represents a group represented by the formula (CH 2 ) n—N ′′ Rl ,
  • R 2 are the same or different and represent a hydrogen atom, a lower alkyl group or an amino protecting group, and n represents an integer of 0 or 1.
  • 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 having the above-mentioned structural characteristics in which a bicyclic amino group, which has not been known, is bonded to the compound represented by the formula ( c ) has an antibacterial activity, particularly against gram-positive bacteria. It has excellent antibacterial activity and is useful as an antibacterial agent.
  • the compound of the present invention will be described in more detail.
  • halogen atom examples include fluorine, chlorine, and bromine.
  • lower unless stated otherwise, means that the group to which this term is attached contains 1-7 carbon atoms.
  • Lower alkyl means linear or branched chain. Means alkyl having 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl and the like.
  • “Lower alkoxy” is a lower alkyloxy group in which the lower alkyl moiety has the above-mentioned meaning, and includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like.
  • “Lower alkenyl” means straight-chain or branched alkenyl having 2 to 7 carbon atoms, and includes, for example, vinyl, aryl, 1-propenyl, and isopropenyl.
  • “Lower alkynyl” includes, for example, Nil, 1-propynyl and the like.
  • “Cycloalkyl” includes cycloalkyl having 3 to 7 carbon atoms, and includes, for example, cyclobutyryl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • Halogeno lower alkyl is a group in which at least one hydrogen atom of lower alkyl is replaced by halogen atom, and examples include fluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl and the like.
  • Halogeno lower alkenyl is a group in which at least one hydrogen atom of a lower alkenyl is replaced by a halogen atom, and includes, for example, 2-fluorovinyl, 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.
  • the “halogeno lower alkoxy” 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, and trifluoromethoxy.
  • “Lower alkoxy lower alkyl” means lower alkyl substituted with lower alkoxy, and includes, for example, methoxymethyl, ethoxymethyl, 1-methoxyquinethyl and the like.
  • substituent in the “phenyl group optionally having substituent (s)” or the “heterocyclic group optionally having substituent (s)” defined for R a halogen atom, a lower alkyl group , Lower alkoxy groups, hydroxyl groups, nitro groups and amino groups.
  • heterocyclic group optionally having substituent (s) examples include, for example, pyrrole, furan, thiophene, thiabour, isothiazol, oxabul, isoxazol, vilabul, imidazole , Pyridine, pyridazine, pyrimidine, pyrazine and other heteroatoms include 5- or 6-membered heterocycles containing N, 0 or S Can be
  • amino protecting group can be used as long as it can be easily desorbed by a normal deprotecting group reaction such as hydrolysis or hydrogenolysis without substantially affecting other structural parts. It is.
  • amino protecting groups labile hydrolyzable amino protecting groups
  • examples of amino protecting groups which can be easily removed by hydrolysis include ethoxycarbonyl, sometimes abbreviated as B0c, and t-butoxycarbonyl, benzyloxycarbonyl, oxycarbonyl groups such as p-methoxybenzyloxycarbonyl, vinyloxycarbonyl, and mono ( ⁇ -toluenesulfonyl) ethoxycarbonyl; acyl groups such as formyl, acetyl, and trifluoroacetyl: trimethylsilyl, t-butyl Silyl groups such as dimethylsilyl; tetrahydrobiranyl, o-ditrophenylsulfenyl, diphenylphosphenyl and the like;
  • Examples of the amino-protecting group which is easily eliminated by hydrogenolysis include, for example, an arylsulfonyl group such as p-to
  • a methyl group substituted by a phenyl or benzyloxy group such as: benzyloxycarbonyl, an arylmethoxycarbonyl group such as 0-methoxybenzyloxycarbonyl;, ⁇ , / 3-trichloroethoxycarbonyl; And a halogenoethoxycarbonyl group such as doethoxycarbonyl.
  • 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, lower alkanoyloxy lower alkyl esters such as acetomethyl ester, 1-acetoxyl methyl ester, and bivaloyloxy methyl ester; lower alkoxycarbonyl such as 1-ethoxycarbonyloxy ester Lower alkyl esters: 2-dimethylaminoethyl ester, aminoethyl ester such as 2- (1-piperidinyl) ethyl ester, 3-butyrolactonyl ester, choline ester, phthalidyl ester, (5-methyl-12-) Okifu 1, 3-dioxofur 14-yl) methyl ester and the like.
  • lower alkanoyloxy lower alkyl esters such as acetomethyl ester, 1-acetoxyl methyl ester, and bivaloyloxy methyl ester
  • lower alkoxycarbonyl such
  • salt of the compound (I) of the present invention a physiologically acceptable salt is particularly preferred, and trifluorosulfonic acid, acetic acid, lactic acid, succinic acid, methanesulfonic acid, maleic acid, malonic acid, dalconic acid, and asparagine are preferred.
  • Salts with organic acids such as amino acids such as acid or glutamic acid; salts with inorganic acids such as hydrochloric acid and phosphoric acid; sodium and potassium; salts of metals such as zinc and silver; ammonium salts; trimethylamine; Salts with organic bases such as triethylamine and N-methylmorpholine are examples.
  • the salts 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, trifluoro ⁇ acid, methanesulfonate, p-toluenesulfone. Acid addition salts with organic acids such as acids.
  • the pyridonecarboxylic acid derivative (I) and the bicyclic amide compound (I) of the present invention sometimes exist as a hydrate or a solvate. Further, these compounds of the present invention may exist as optically active substances or stereoisomers (cis type, trans type) and the like. These compounds are also included in the present invention.
  • preferred compounds include the compounds represented by the above general formula (0, wherein G is C—H, and compounds wherein m is 3 or 1.
  • Preferred compounds are those in which R is cyclo Compound X, which is a cycloalkyl group such as propyl, a lower alkyl group such as methyl, ethyl or t-butyl, or a phenyl group substituted by a halogen atom such as 2,4-difluorophenyl, is a hydrogen atom, a halogen atom or Compounds that are amino groups;
  • Compounds in which Y is a fluorine atom Compounds in which R and R 2 in substituent W are the same or different and are a hydrogen atom or a lower alkyl group such as methyl, and the like.
  • A is a nitrogen atom or C-Z, wherein Z is a hydrogen atom or a fluorine atom.
  • Still more preferred compounds of the present invention are those represented by the above general formula (I), wherein R is a cyclopropyl group or a 2,4-difluorophenyl group, X is a hydrogen atom, a fluorine atom or an amino group, and Y is a fluorine atom.
  • R and R 2 in the substituent W are the same or different and are a hydrogen atom or a methyl group
  • 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, a methyl group, a cyano group or a trifluoromethyl group, wherein m is 3 or 1.
  • Z is a hydrogen atom, a fluorine atom
  • a chlorine atom a methoxy group, a difluoromethyoxy group, a methyl group, a cyano group or a trifluoromethyl group, wherein m is 3 or 1.
  • Representative examples of the compound (I) of the present invention excluding the compounds described in Examples described below are as follows. In the following nomenclature, the three-dimensional structure is not specified, but the compounds represented by the following chemical names include all compounds having various three-dimensional structures.
  • Benzoxazine-16-carboxylic acid Among the bicyclic amine compounds (I) of the present invention, a preferable compound is the 7-position of the pyridonecarboxylic acid derivative described above. And a compound corresponding to the substituent located at the position (1).
  • 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 group capable of leaving, R, G, A, X and Y have the above-mentioned meanings, and the carboxyl group and the oxo group in the above-mentioned formula are boron-free groups between these groups. (A bond may be formed)
  • the compound can be easily produced by reacting with a bicyclic amine compound represented by the formula below, and hydrolyzing the boron chelate moiety, if present, in the product.
  • the eliminable group L in the general formula (IE) includes, for example, a halogen atom, Lower alkoxy groups, lower alkylthio groups, lower alkylsulfonyl groups, lower alkylsulfinyl groups, lower alkylsulfonyloquine groups, arylsulfonyloxy groups, and the like, among which halogen atoms such as fluorine and chlorine are preferred. is there.
  • This reaction is generally carried out in an inert solvent at a temperature of about ⁇ ) to 180 ° C, preferably about 20 to 130 ° C, for about 10 minutes to 24 hours, with the compound (H) and the compound (II) being reacted for about 10 minutes to 24 hours. It can be preferably carried out by stirring for about 30 minutes to 3 hours.
  • Solvents that can be used include water, methanol, ethanol, acetonitrile, chloroform, pyridine, N, N-dimethylformamide, dimethylsulfoxide, 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 by using Compound (I) in an excess of Compound (I) that is not equivalent to Compound (II). And may also serve as an acid acceptor.
  • the acid acceptor include organic bases such as, for example, 8-diazabicyclo [5.4.0] -17-ndecene (DBU), triethylamine, pyridine, quinoline, picolin, or water.
  • examples include inorganic bases such as sodium oxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate.
  • the compound (I) of the present invention has the following formula (W)
  • U represents a group that can be converted to a carboxyl group by hydrolysis
  • R, G, A, X, Y, m and W have the above-mentioned meaning. It can also be manufactured by attaching.
  • 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.
  • 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 potassium carbonate; and sodium acetate.
  • Water is usually used as the solvent, but depending on the nature of compound (IV), for example, water-miscible organic solvents such as ethanol, ethylene glycol dimethyl ether, benzene, and dioxane are used together with water.
  • the reaction temperature can be generally selected from the range of about 0 to 150 ° C, preferably about 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 3 represents a lower alkyl group, an aryl group or a benzyl group
  • R, G, A, X, Y, m and W are as defined above. Meaningful
  • the group L ′ which can be eliminated is preferably a group as described above for the group L which can be eliminated, particularly a halogen atom such as fluorine or chlorine.
  • This ring closure reaction is carried out in an amount of about 1 to 3 moles of a base,
  • a mixture of compound (V) and a solvent is heated at about 30 to 150 ° C, preferably at about 30 to 100 ° C. It can be carried out by stirring for about 1 to 6 hours.
  • the solvent used in this reaction for example, ethanol, dioxane, tetrahydrofuran, N, N-dimethylformamide, dimethylsulfoxide and the like are suitable.
  • the compound (V) used as a starting material is also novel, and can be produced, for example, according to the following reaction formula 1.
  • R 3 ′ has the same meaning as a hydrogen atom or R 3 , R 4 and R 5 represent the same or different lower alkyl groups, and R, G, A, X, Y, R 3 , L, L ', m and W have the meaning described above. ]
  • Compound (V) is obtained, for example, by reacting compound (1) with compound (2) by reacting compound (1) with bicyclic amine compound (H) in the presence of an acid acceptor to obtain compound (2). After conversion to an acid halide, it is reacted with a 3-dialkylaminoacrylic acid ester in the presence of a base to form compound (3), and then obtained by treating this compound (3) with a primary amine. be able to.
  • compound (V) is converted to compound (4) by, for example, converting compound (U into an acid halide, reacting with malonate, hydrolyzing, and then performing a decarboxylation reaction.
  • the resulting compound (4) is treated in the same manner as in the synthesis of the compound (2) to give the compound (5), and the compound (5) is treated with a mixture of acetic anhydride and ethyl formate ortho, followed by
  • an ester residue can be obtained.
  • the above-described elimination reaction of the amino protecting group by hydrogenolysis is carried out in the presence of a catalyst in a solvent. It can be advantageously carried out by treating the compound (I) of the present invention having a readily hydrolyzable amino protecting group with hydrogen gas in the presence.
  • the catalyst used in this reaction include hydrogenation catalysts such as platinum, palladium, and Raney nickel.
  • the solvent for example, ethylene glycol, dioxane, N, N-dimethylformamide, ethanol, acetic acid, water and the like can be used. This reaction can be carried out at about 60 ° C or lower, usually at room temperature.
  • the readily hydrolyzable amino protecting group is benzyl, trityl, benzyloxycarbonyl, p-toluenesulfonyl, etc.
  • a protecting group is treated with metallic sodium in liquid ammonia at a temperature of about ⁇ 50 ⁇ ⁇ 20 ° C. Can also be desorbed.
  • the compound (I) of the present invention produced by any one of the above methods (a), (b) and (c) 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 for isolation and purification. These compounds are mutually converted according to the purpose, and the desired form of the compound of the present invention is obtained. Can be led to
  • stereoisomers of the compound (I) of the present invention can be separated from each other by an ordinary method, for example, fractional crystallization, chromatography, etc., and the optically active compound is applied by a known optical resolution method. 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 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 in the case of the compound (I) of the present invention. In addition, it can be used as an antibacterial agent.
  • the compound (I) used as a raw material in the aforementioned method (a) is, for example, a compound represented by the following general formula (VI)
  • R 6 is an amino protecting group
  • m and W have the above-mentioned meanings.
  • examples of the amino-protected R s include, for example, the above-mentioned easily hydrolyzable amino-protecting group and easily hydrolyzable amino-protecting group.
  • the amino protecting group of R 6 and / or those having different characteristics from the amino protecting group of R 2 be used. Preferred for later reactions.
  • the amino protecting group of R, and / or R 2 is a readily hydrolyzable amino protecting group such as a t-butoxycarbyl group
  • a readily hydrolyzable amino protecting group such as benzyl ditrityl
  • This elimination reaction can be carried out by subjecting compound (VI) to a hydrogenolysis reaction or a hydrolysis reaction as described above.
  • R and / or R 2 in W of the compound obtained by the present elimination reaction is an amino protecting group, if necessary, it is similarly degassed and converted to a hydrogen atom, and when a free product is obtained. If necessary, can be converted into a salt by a conventional method, and when the salt is obtained, it can be converted into a free form.
  • the stereoisomers of the compound (E) of the present invention thus obtained can be separated from each other by a conventional method, for example, fractional crystallization, chromatography, etc., and the optically active substance is a known optical isomer. It can be isolated by applying the resolution method.
  • the compound (VI) is also novel and can be produced, for example, by the methods described in Examples A to H described below or a method analogous thereto.
  • Table 1 shows the minimum inhibitory concentrations (MIC: / g / ml) measured according to the description in Chemotherapy 29 (1), 76 (1981), and Table 2 shows the effects on systemic infection in mice. (ED 5 ; mg / kg).
  • mice systemic infection ED 50 ; mg / kg
  • mice systemic infection 5 x 10 3 pathogenic bacteria (live bacteria) listed in Table 2 per Std-ddy male mouse (body weight: about 20 g) per mouse
  • a test compound suspended in 0.4% carboxymethylcellulose was orally administered twice a day immediately after the infection and 6 hours after the infection.
  • the survival rate of the mice 7 days after the infection was calculated by the Probit method.
  • ENX 9.89 8.41 As shown in Tables 1 and 2, the compound (I) of the present invention has excellent in vitro and in vivo antibacterial activities. In particular, 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 useful as an antibacterial agent for bacterial diseases in mammals including humans.
  • the dosage varies depending on the age, body weight, symptoms, administration route and the like, but is generally 5 mg to 5 g per day. It is recommended to administer several divided doses.
  • 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 (pharmaceutical composition) prepared with pharmaceutically acceptable additives.
  • preparations include tablets, solutions, capsules, granules ij, fine granules, powders, syrups, injections, suppositories, emollients, sprays, and eye drops.
  • oral additives include solids which are commonly used in the field of pharmaceuticals such as starch, mannite, microcrystalline cellulose, carboxymethylcellulose—Ca, water, ethanol, and do not react with the compound (I) of the present invention.
  • a liquid carrier or diluent material is used.
  • additives for injection include those commonly used in the field of injections, such as water, physiological saline, glucose solution, and infusion.
  • the above sprays and softeners can also be used in the treatment and treatment of otolaryngology and ophthalmology.
  • Working columns A to H relate to a method for producing an intermediate bicyclic amide compound (D), and Examples 1 to 35 relate to a method for producing a compound (I) of the present invention.
  • Example J is an example for a formulation.
  • ethyl 2-benzylamino-1-cyclopentene-1-carboxylate obtained in step 1 of the preceding paragraph was dissolved in 500 ml of ethanol, and 1 g of platinum dioxide was added thereto, followed by catalytic reduction at medium pressure. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: chloroform) to give cis-12-benzylamino-1-cyclopentanecarbonate. 34.0 g of acid ethyl was obtained.
  • reaction solution was separated by filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane) to give cis-1-((N-benzyl) [Ethoxycarbonylmethylamino] —92.5 g of ethyl 1-cyclopentanecarboxylate was obtained.
  • reaction solution is filtered, the filtrate is concentrated under reduced pressure, and the obtained residue is purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate 9: 1) to give cis-2-[(N-benzyl) [1 t-butoxycarbonylamino] 7.1 g of ethyl 1-cyclopropanecarboxylate is obtained.
  • Cis-2-benzylamine 1-cyclopropane power obtained in the preceding paragraph 3.7 g of ethyl ribonate was treated in substantially the same manner as in Steps 3 to 5 of Example A to give cis-12-benzyl-2-azabicyclo [ 3.1. 0] Hexane 41-year-old Obtain 1.7 g of oxime.
  • Example A obtained from (1R *, 4R *, 5R *) — 2-benzyl-4-4-t-butoxycarbonylamino-2-azabicyclo [3.1.0] hexane obtained in the preceding section To the desired (1R ', 4R *, 5'S *)-4--4-t-butoxycarbonylamine 2--2-azabicyclo [3.1.0] hexane .
  • Example F obtained from (1R *, 4R *, 5R *) — 2-benzyl-4-4-t-butoxycarbonylamino-2-azabicyclo [3.1.0] hexane obtained in the preceding section To the desired (1R ', 4R *, 5'S *)-4--4-t-butoxycarbonylamine 2--2-azabicyclo [3.1.0] hexane .
  • Example F obtained from (1R *, 4R *, 5R *) — 2-benzyl-4-4-t-butoxycarbonylamino-2-azabicyclo [3.1.0] he
  • Example 2 According to the method described in Example 1 (2), the title compound was obtained from the compound obtained in the above section (1).
  • the compound (I) of the present invention is an antibacterial agent for mammals including humans. It is useful, and the bicyclic amine compound ( ⁇ ) is useful as a direct synthetic intermediate of the compound (I) of the present invention.

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Abstract

Dérivé d'acide pyridonecarboxylique représenté par la formule générale (I), un ester et un sel de celui-ci, agent antibactérien contenant ledit dérivé et composé d'amine bicyclique servant d'intermédiaire direct pour la synthèse dudit dérivé. Dans ladite formule (I), R représente cycloalkyle, phényle éventuellement substitué; G représente entre autres carbone; A représente C-Z (Z étant hydrogène, halogéno, alcoxy inférieur etc.) ou azote; X représente hydrogène, amino; Y représente hydrogène ou halogéno; m est un entier de 1 à 3; W représente -(CH2)nN(R1)R2 (R1 et R2 étant semblables ou différents et représentant chacun hydrogène, alkyle inférieur etc. et n valant 0 ou 1).
PCT/JP1995/002024 1994-10-06 1995-10-04 Derive d'acide pyridonecarboxylique et intermediaire servant a effectuer sa synthese WO1996011194A1 (fr)

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AU36185/95A AU3618595A (en) 1994-10-06 1995-10-04 Pyridonecarboxylic acid derivative and intermediate for the synthesis of the same
JP8512475A JP2951726B2 (ja) 1994-10-06 1995-10-04 ピリドンカルボン酸誘導体およびその合成中間体

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0924213A4 (fr) * 1996-09-27 2002-10-23 Daiichi Seiyaku Co Derives de pyridobenzoxazine
US7723524B2 (en) 2003-09-29 2010-05-25 Daiichi Pharmaceutical Co., Ltd. 8-cyanoquinolonecarboxylic acid derivative

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0256479A (ja) * 1988-05-23 1990-02-26 Shionogi & Co Ltd ピリドンカルボン酸系抗菌剤
JPH03218312A (ja) * 1989-11-21 1991-09-25 Shionogi & Co Ltd 動物用細菌感染症予防、治療剤
JPH06239857A (ja) * 1992-12-25 1994-08-30 Dai Ichi Seiyaku Co Ltd 二環性環状アミン誘導体

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0256479A (ja) * 1988-05-23 1990-02-26 Shionogi & Co Ltd ピリドンカルボン酸系抗菌剤
JPH03218312A (ja) * 1989-11-21 1991-09-25 Shionogi & Co Ltd 動物用細菌感染症予防、治療剤
JPH06239857A (ja) * 1992-12-25 1994-08-30 Dai Ichi Seiyaku Co Ltd 二環性環状アミン誘導体

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0924213A4 (fr) * 1996-09-27 2002-10-23 Daiichi Seiyaku Co Derives de pyridobenzoxazine
US7723524B2 (en) 2003-09-29 2010-05-25 Daiichi Pharmaceutical Co., Ltd. 8-cyanoquinolonecarboxylic acid derivative

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