JP2888987B2 - Pyridonecarboxylic acid derivatives, esters and salts thereof, and synthetic intermediates thereof - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a novel pyridonecarboxylic acid derivative useful as an antibacterial agent and a novel synthetic intermediate thereof.

BACKGROUND ART Various antibacterial pyridonecarboxylic acid derivatives are known. For example, Japanese Unexamined Patent Publication No. 5-503709 (WO91 / 16894) discloses the following general formula (A) Wherein R ¹ is a lower alkyl group or a cycloalkyl group, R ² is a `` bicyclic nitrogen-containing heterocyclic group '', R ³ is a hydrogen atom or a halogen atom, and R ⁴ is A hydrogen atom or a lower alkyl group, R ⁵ is a hydrogen atom or a halogen atom, and A is N or CH, etc.] quinolizinone type compound (quinolizinone type
compounds) are 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. Further, Otay above formula (A), defined for R ₂ "bicyclic nitrogen-containing heterocyclic group (Bicycl
In the above publication, groups represented by the following formulas (a-1) to (a-3) are listed as examples of "ic nitrogen containing heterocycle group)." Although the substituent at the 7-position of the compound of the present invention is conceptually included, the above publication does not specifically disclose the group of the formula (a-3).

Wherein v and w are CH ₂ , j and k are 1, 2 or 3, A ¹ is a carbon atom or a heteroatom selected from S, O or N, and A ² is amino ( And lower alkyl) groups.] Further, JP-A-5-255319 discloses the following general formula (B) [Wherein, R ¹ is a hydrogen atom, R ² is a lower alkyl group which may have a substituent, X is a hydrogen atom or a halogen atom, and Y has a substituent. And Z is a nitrogen atom, CH, or the like.] The quinolone derivative represented by Examples of the group include, for example, a group represented by the following formula (b), and this group (when i = 1) is a 2-azabicyclo [3.1.1] hepta-2-yl group Wherein 3-azabicyclo [3.1.
1] It is clearly different from a hepta-3-yl group.

[Wherein, i is 1 or 2, and A is a substituted or unsubstituted amino group, etc.] Further, a bicycloamine compound of the formula (II) described below as an intermediate for producing the pyridonecarboxylic acid derivative of the present invention As known compounds related to, for example, JP-A-1-160967
Publication (corresponding European publication number: EP317506) has the following general formula (C) [Wherein, 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 hydrogen atoms at the same time]. , This compound
It is different from the bicycloamine compound (II) of the present invention in that it has no amino group or aminomethyl group which may be substituted. Further, there is no description that the compound (C) is used as a therapeutic agent for disorders of calcium metabolism and is useful as an intermediate for producing pyridonecarboxylic acid.

Recently, Helicobacter pylori (Helicobact
er pylori) is thought to be a causative bacterium for gastrointestinal disorders, but the literature does not describe the antibacterial activity of pyridonecarboxylic acid derivatives against Helicobacter pylori.

A main object of the present invention is to provide a pyridonecarboxylic acid-type compound having an enhanced antibacterial activity, especially an antibacterial activity against Gram-positive bacteria, and further having an excellent antibacterial activity against Helicobacter pylori.

DISCLOSURE OF THE INVENTION According to the present invention, the following general formula (I) [Wherein, R represents 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 or a substituent which may have a substituent, G represents a CE or a nitrogen element, wherein E represents a hydrogen atom or together with R represents -S-CH
A (CH ₃ ) — may form a bridge, wherein A represents CZ or a nitrogen atom, wherein Z represents a hydrogen atom, a halogen atom, a lower alkoxy group, a halogeno lower alkoxy group, a lower alkyl group. Table with - group, halogeno-lower alkyl group, lower alkoxy-lower alkyl group, lower alkenyl group, or means a lower alkynyl group or a cyano group, or taken together with _{R, -O-CH 2 -CH (} CH 3) 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 group or a lower alkyl group; R ₁ and R ₂ are the same or different and represent a hydrogen atom, a lower alkyl group or an amino protecting group, and R ₃ is a hydrogen atom or 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, and n represents an integer of 0 or 1.] (Hereinafter, sometimes referred to as the present compound (I)), its ester and its salt.

Further, according to the present invention, a novel compound represented by the following general formula (II) useful as an intermediate of the pyridonecarboxylic acid derivative represented by the above formula (I) [Wherein, R ₁ , R ₂ , R ₃ and n have the above-mentioned meanings] and a salt thereof.

Hereinafter, the compound of the present invention will be described in more detail.

In the present specification, examples of the “halogen atom” include fluorine, chlorine, and bromine. Also,
The term "lower" means a group containing from 1 to 7 carbon atoms unless otherwise specified.

“Lower alkyl” means a straight or branched 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 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, allyl, 1-propenyl, isopropenyl 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. A “halogeno lower alkenyl” is a group in which at least one hydrogen atom of a lower alkenyl is replaced by a halogen atom, 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 is 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 lower alkoxy is replaced with a halogen atom, and examples thereof include fluoromethoxy, difluoromethoxy, and trifluoromethoxy.

"Lower alkoxy lower alkyl" means lower alkyl substituted with lower alkoxy, for example, methoxymethyl, ethoxymethyl, 1-methoxyethyl and the like, and "hydroxy lower alkyl" is substituted with hydroxy. Lower alkyl means, for example, hydroxymethyl, 1-hydroxyethyl and the like.

As the substituent in the “phenyl group optionally having substituent (s)” or “heterocyclic group optionally having substituent (s)” defined for R, a halogen atom, a lower alkyl group, a lower alkyl group, Examples include an alkoxy group, a hydroxyl group, a nitro group, and an amino group. Examples of the heterocyclic ring in the “heterocyclic group optionally having substituent (s)” include, for example, pyrrole, furan, thiophene, thiazole, isothiazole, oxazole, isoxazole, pyrazole, imidazole, pyridine, pyridazine, pyrimidine, Hetero atoms such as pyrazine include 5- or 6-membered heterocyclic groups containing N, O or S.

As the "amino protecting group", any one which can be easily removed without substantially affecting other structural parts by a normal deprotecting group reaction such as hydrolysis or hydrogenolysis is used. Can be adopted.

Examples of an amino protecting group (an easily hydrolyzable amino protecting group) which can be easily removed by hydrolysis include ethoxycarbonyl, t-butoxycarbonyl (hereinafter sometimes abbreviated as Boc), benzyloxycarbonyl, p -Methoxybenzyloxycarbonyl, vinyloxycarbonyl, β
An oxycarbonyl group such as-(p-toluenesulfonyl) ethoxycarbonyl; an acyl group such as formyl, acetyl and trifluoroacetyl; a silyl group such as trimethylsilyl and t-butyldimethylsilyl; tetrahydropyranyl, o-nitrophenylsulfenyl; Diphenylphosphenyl and the like.

Examples of an amino-protecting group (easily hydrolyzable amino-protecting group) which is easily eliminated by hydrogenolysis include, for example, p
Arylsulfonyl groups such as toluenesulfonyl; methyl groups substituted by phenyl or benzyloxy such as benzyl, trityl, benzyloxymethyl; arylmethoxycarbonyl groups such as benzyloxycarbonyl, o-methoxybenzyloxycarbonyl;
and a halogenoethoxycarbonyl group such as β, β, β-trichloroethoxycarbonyl and β-iodoethoxycarbonyl.

As the 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. Esters that can be converted to the corresponding free carboxylic acids by chemical means such as hydrolysis include 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 lower alkanoyloxy groups such as acetoxymethyl ester, 1-acetoxyethyl ester and pivaloyloxymethyl ester. Lower alkyl esters; lower alkoxycarbonyloxy lower alkyl esters such as 1-ethoxycarbonylioxyethyl ester; aminoethyl esters such as 2-dimethylaminoethyl ester and 2- (1-piperidinyl) ethyl ester;
Butyrolactonyl ester, choline ester, phthalidyl ester, (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl ester and the like.

As the salt of the pyridonecarboxylic acid derivative (I) of the present invention, a physiologically acceptable salt is particularly preferable, and trifluoroacetic acid, acetic acid, lactic acid, succinic acid, methanesulfonic acid, maleic acid, malonic acid or gluconic acid, Salts with organic acids such as amino acids such as aspartic acid or glutamic acid; Salts with inorganic acids such as hydrochloric acid and phosphoric acid; Metal salts such as sodium, potassium, zinc and silver; Ammonium salts; Trimethylamine, triethylamine, N-methylmorpholine And the like, and salts with organic bases.

Examples of the salt of the bicycloamine compound (II) 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. And acid addition salts thereof.

The pyridonecarboxylic acid derivative (I) and the bicycloamine compound (II) of the present invention sometimes exist as a hydrate or a solvate. Further, the compound (I) of the present invention may exist as an optically active substance or a stereoisomer (cis type, trans type) or the like. These compounds are also included in the present invention.

Preferred compounds among the compound (I) of the present invention include:
Compounds in which G is CH in the general formula (I) are mentioned. More preferred compounds include those represented by the aforementioned general formula (I)
Wherein G is CH, R is a cycloalkyl group such as cyclopropyl, a halogenocycloalkyl group such as 2-fluorocyclopropyl or a phenyl group substituted with a halogen atom such as 2,4-difluorophenyl, and X is A hydrogen atom, a methyl group or an amino group, Y is a fluorine atom, R ₁ and R ₂ are the same or different and are a hydrogen atom or a lower alkyl group such as a methyl group, and R ₃ is a hydrogen atom, a fluorine atom A halogen atom such as a methoxymethyl group or a halogenoalkyl group such as a fluoromethyl group, wherein A is a nitrogen atom or CZ, wherein Z is a halogen atom such as a hydrogen atom or a fluorine atom. An atom, a lower alkoxy group such as methoxy group or a halogeno lower alkyl group such as difluoromethoxy group Things. More specifically, the following compounds and their physiologically acceptable salts are preferred.

Preferred examples of the bicycloamine compound (II) of the present invention include the compounds described above and compounds corresponding to the substituent located at the 7-position of the pyridonecarboxylic acid derivatives specifically mentioned below.

Typical examples of the compound (I) of the present invention are as follows.

5-amino-7- (1-amino-3-azabicyclo [3.1.1] hepta-3-yl) -1-cyclopropyl-
6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. 7- (1-amino-3-azabicyclo [3.1.1] hepta-3-yl) -8-chloro-1-cyclopropyl-6
-Fluoro-1,4-dihydro-4-oxoquinoline-3
-Carboxylic acids. 7- (1-amino-3-azabicyclo [3.1.1] hepta-3-yl) -1-cyclopropyl-6-fluoro-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid. 7- (1-amino-3-azabicyclo [3.1.1] hepta-3-yl) -1-cyclopropyl-6-fluoro-
1,4-dihydro-8-methoxy-4-oxoquinoline-
3-carboxylic acid. 7- (1-amino-3-azabicyclo [3.1.1] hepta-3-yl) -1- (2,4-difluorophenyl)-
6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid. 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7- (1-methylamino-3-azabicyclo [3.1.1] hept-3-yl) -4-oxoquinoline-3-carboxylic acid. (S) -10- (1-Amino-3-azabicyclo [3.1.
1] Hept-3-yl) -9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido [1,2,3-de]
[1,4] benzoxazine-6-carboxylic acid. 7- (1-aminomethyl-3-azabicyclo [3.1.
1] Hept-3-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid. 5-amino-7- (1-amino-5-fluoro-3-
Azabicyclo [3.1.1] hepta-3-yl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. 7- (1-Amino-5-fluoro-3-azabicyclo [3.1.1] hepta-3-yl) -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline- 3-carboxylic acid. 7- (1-amino-5-fluoro-3-azabicyclo [3.1.1] hept-3-yl) -1-cyclopropyl-
6-Fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid. 7- (1-aminomethyl-3-azabicyclo [3.1.
1] Hept-3-yl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-
carboxylic acid. 5-amino-7- (1-aminomethyl-3-azabicyclo [3.1.1] hepta-3-yl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3 -Carboxylic acids. 7- (1-aminomethyl-3-azabicyclo [3.1.
1] Hept-3-yl) -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. 7- (1-aminomethyl-3-azabicyclo [3.1.
1] Hept-3-yl) -1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-1,8
-Naphthyridine-3-carboxylic acid. 7- (1-Amino-5-fluoromethyl-3-azabicyclo [3.1.1] hept-3-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-
4-oxoquinoline-3-carboxylic acid. 7- (1-Amino-5-fluoromethyl-3-azabicyclo [3.1.1] hepta-3-yl) -1-cyclopropyl-8-difluoromethoxy-6-fluoro-1,4-
Dihydro-4-oxoquinoline-3-carboxylic acid. 7- (1-Amino-5-methoxymethyl-3-azabicyclo [3.1.1] hept-3-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-
4-oxoquinoline-3-carboxylic acid. 7- (1-Amino-5-methoxymethyl-3-azabicyclo [3.1.1] hept-3-yl) -1-cyclopropyl-8-difluoromethoxy-6-fluoro-1,4-
Dihydro-4-oxoquinoline-3-carboxylic acid. 7- (1-Amino-5-fluoromethyl-3-azabicyclo [3.1.1] hept-3-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-
4-oxoquinoline-3-carboxylic acid. 7- (1-amino-5-methoxymethyl-3-azabicyclo [3.1.1] hept-3-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxymethyl-4-oxo Quinoline-3-carboxylic acid. 7- (1-Amino-5-fluoromethyl-3-azabicyclo [3.1.1] hepta-3-yl) -1-cyclopropyl-8-ethynyl-6-fluoro-1,4-dihydro-
4-oxoquinoline-3-carboxylic acid. 7- (1-Amino-5-methoxymethyl-3-azabicyclo [3.1.1] hepta-3-yl) -1-cyclopropyl-8-ethynyl-6-fluoro-1,4-dihydro-
4-oxoquinoline-3-carboxylic acid. 7- (1-Amino-5-fluoromethyl-3-azabicyclo [3.1.1] hept-3-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-8
-Trifluoromethylquinoline-3-carboxylic acid. 7- (1-Amino-5-methoxymethyl-3-azabicyclo [3.1.1] hept-3-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-8
-Trifluoromethylquinoline-3-carboxylic acid. 7- (1-Amino-5-fluoromethyl-3-azabicyclo [3.1.1] hept-3-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-8
-Vinylquinoline-3-carboxylic acid. 7- (1-Amino-5-methoxymethyl-3-azabicyclo [3.1.1] hept-3-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-8
-Vinylquinoline-3-carboxylic acid. 7- (1-Amino-5-hydroxy-3-azabicyclo [3.1.1] hepta-3-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-
Oxoquinoline-3-carboxylic acid. 7- (1-amino-5-methoxy-3-azabicyclo [3.1.1] hept-3-yl) -1-cyclopropyl-
6-Fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid. 7- (1-amino-5-methyl-3-azabicyclo [3.1.1] hept-3-yl) -1-cyclopropyl-
6-Fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid. 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7- (1-methylamino-5-fluoromethyl-3-azabicyclo [3.1.1] hept-3-yl) -4-oxo Quinoline-3-carboxylic acid. 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7- (1-methylamino-5-methoxymethyl-3-azabicyclo [3.1.1] hept-3-yl) -4-oxo Quinoline-3-carboxylic acid. 7- (1-amino-3-azabicyclo [3.1.1] hept-3-yl) -8-cyano-1-cyclopropyl-6
-Fluoro-1,4-dihydro-4-oxoquinoline-3
-Carboxylic acids. 7- (1-amino-5-fluoromethyl-3-azabicyclo [3.1.1] hept-3-yl) -8-cyano-1
-Cyclopropyl-6-fluoro-1,4-dihydro-4
-Oxoquinoline-3-carboxylic acid. 7- (1-Amino-5-methoxymethyl-3-azabicyclo [3.1.1] hepta-3-yl) -8-cyano-1
-Cyclopropyl-6-fluoro-1,4-dihydro-4
-Oxoquinoline-3-carboxylic acid. 7- (1-amino-3-azabicyclo [3.1.1] hepta-3-yl) -1-cyclopropyl-6-fluoro-
1,4-dihydro-8-methyl-4-oxoquinoline-3
-Carboxylic acids. 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-5-methyl-7- (1-methylamino-3-azabicyclo [3.1.1] hept-3-yl) -4
-Oxoquinoline-3-carboxylic acid. 5-amino-1-cyclopropyl-6-fluoro-1,
4-dihydro-8-methoxy-7- (1-methylamino-3-azabicyclo [3.1.1] hept-3-yl) -4
-Oxoquinoline-3-carboxylic acid. 7- (5-chloromethyl-1-methylamino-3-azabicyclo [3.1.1] hept-3-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo Quinoline-3-carboxylic acid. 6-fluoro-1-methyl-7- (1-methylamino-3-azabicyclo [3.1.1] hepta-3-yl) -4
-Oxo-4H- [1,3] thiazeto [3,2-a] quinoline-
3-carboxylic acid. 6-fluoro-1,4-dihydro-7- (1-methylamino-3-azabicyclo [3.1.1] hepta-3-yl)
-4-oxo-1- (2-thienyl) -1,8-naphthyridine-3-carboxylic acid. 1-ethyl-6,8-difluoro-7- (5-fluoromethyl-1-methylamino-3-azabicyclo [3.1.
1] Hept-3-yl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid. 6-fluoro-1- (2-fluoroethyl) -7-
(5-fluoromethyl-methylamino-3-azabicyclo [3.1.1] hepta-3-yl) -1,4-dihydro-8-
Methoxy-4-oxoquinoline-3-carboxylic acid. 6-fluoro-7- (5-fluoromethyl-1-methylamino-3-azabicyclo [3.1.1] hept-3-yl) -1,4-dihydro-4-oxo-1-vinyl-1,8-
Naphthyridine-3-carboxylic acid. 6-fluoro-7- (5-fluoromethyl-1-methylamino-3-azabicyclo [3.1.1] hept-3-yl) -1- (2-fluorovinyl) -1,4-dihydro-
4-oxo-1,8-naphthyridine-3-carboxylic acid. The compound (I) of the present invention includes, for example, (a)
It can be produced by an amination reaction, (b) hydrolysis reaction or (c) ring closure reaction.

(A) Amination reaction: The compound (I) of the present invention, its ester and its salt are represented by the following general formula (III) Wherein L represents a group capable of leaving, R, G, A, X and Y have the above-mentioned meaning, and the carboxyl group and the oxo group form a boron chelate bond between these groups. Or a compound represented by the following general formula (II): Wherein R ₁ , R ₂ , R ₃ and n have the meaning described above, and hydrolyzes the boron chelate moiety, if present, in the product Thus, it can be easily manufactured.

Examples of the removable group L in the general formula (III) include a halogen atom, a lower alkoxy group, a lower alkylthio group, a lower alkylsulfonyl group, a lower alkylsulfinyl group, a lower alkylsulfonyloxy group, and an allylsulfonyloxy group. Of these, halogen atoms such as fluorine and chlorine are preferred.

This reaction is usually performed by stirring the compound (II) and the compound (III) for 10 minutes to 24 hours, preferably 30 minutes to 30 hours in an inert solvent at 10 to 180 ° C, preferably 20 to 130 ° C. Can be implemented. Examples of the solvent include water, methanol, ethanol, acetonitrile, chloroform, pyridine, 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 an equivalent amount or a slight excess of compound (II) relative to compound (III). And may also serve as an acid acceptor. Examples of the acid acceptor include 1,8-diazabicyclo [5.4.0] -7-
Organic bases such as undecene (DBU), triethylamine, pyridine, quinoline and picoline, and inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate and potassium hydrogencarbonate can be mentioned. These acid receptors are usually compounds (I
It can be used in a molar amount of 1 to 3 times the amount of I).

Compound (III) is known or can be produced according to a known method. The bicycloamine compounds (II) are all novel, and their production methods will be described later.

(B) Hydrolysis reaction: The compound (I) of the present invention has the following formula (IV) Wherein U represents a group convertible to a carboxyl group by hydrolysis, and R, G, A, X, Y, R ₁ , R ₂ , R ₃ and n have the above-mentioned meanings. Can also be produced by subjecting a compound to a hydrolysis reaction.

Here, as the group U that can be converted to a carboxyl group,
For example, an ester, cyano, amide, amidino or formula-
And a group represented by C (= NH) -O-lower alkyl.

The hydrolysis reaction can be carried out by appropriately bringing the compound (IV) and water into contact with each other in a solvent. This reaction is usually performed in the presence of an acid or a base in the sense of accelerating the reaction. Examples of 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. Examples of the base include metal hydroxides such as sodium hydroxide and barium hydroxide, carbonates such as sodium carbonate and potassium carbonate, and sodium acetate.

As the solvent, water is usually used, but the compound (I
Depending on the properties of V), a water-miscible organic solvent such as ethanol, ethylene glycol dimethyl ether, benzene or dioxane is used together with water. The reaction temperature is usually 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.

(C) Ring Closure Reaction: The compound (I) of the present invention has the following general formula (V) [In the formula, L ′ represents a removable group, R ₄ represents a lower alkyl group, an allyl group or a benzyl group, and R, G, A, X,
Y, R ₁ , R ₂ , R ₃ and n have the same meaning as described above], subjecting the compound to a ring-closure reaction, removing an ester residue and / or an amino-protecting group, if necessary, to form a hydrogen atom It can also be produced by converting into atoms.

Here, as the group L 'which can be eliminated, the groups described above for the group L which can be eliminated, particularly halogen atoms such as fluorine and chlorine are preferable.

This ring closure reaction is carried out in the presence of a base, for example, potassium carbonate, sodium carbonate, sodium hydride, potassium t-butoxide, potassium fluoride and the like in an amount of 1 to 3 times the amount of the compound (V). 30 to a mixture of
It can be carried out by stirring at 150 ° C., preferably 30 to 100 ° C. for 1 to 6 hours. As the solvent, ethanol, dioxane, tetrahydrofuran, dimethylformamide, dimethylsulfoxide and the like are suitable.

The compound (V) used as a raw material is also novel and can be produced, for example, according to the following reaction formula 1.

Wherein R ₄ ′ 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, R ₁ , R ₂ , R ₃ , R ₄ , L, L 'and n
Has the above-mentioned meaning.] The compound (V) is obtained, for example, by reacting a compound (1) with a bicycloamine compound (II) in the presence of an acid acceptor to form a compound (2), After converting 2) into an acid halide, it is reacted with a 3-dialkylaminoacrylic acid ester in the presence of a base to form a compound (3),
Then, the compound (3) can be obtained by treating the compound with a primary amine.

Alternatively, as another method, compound (V) is converted into compound (4) by, for example, converting compound (1) into an acid halide, reacting with malonate, and then hydrolyzing, followed by decarboxylation. The compound (4) obtained 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 orthoformate, Subsequently, it can be obtained by reacting with a primary amine.

When 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).

Also, the elimination reaction of the amino protecting group by hydrogenolysis,
This can be 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, whereby the amino protecting group is eliminated. Can be converted to the compound (I) of the present invention. Examples of the catalyst used in this reaction include hydrogenation catalysts such as platinum, palladium, and Raney nickel. Further, as the solvent, for example, ethylene glycol, dioxane, dimethylformamide, ethanol, acetic acid, water and the like can be used. This reaction is 60
C. or lower, usually at room temperature.

When the readily hydrolyzable amino protecting group is benzyl, trityl, benzyloxycarbonyl, p-toluenesulfonyl, etc., such protecting group is
It can also be desorbed by treating with metallic sodium at a temperature of 50 to -20 ° C.

The compound (II) used as a raw material in the above-mentioned method (a) is, for example, a compound represented by the following general formula (VI) Wherein R ₃ ′ has the same meaning as R ₃ described above or is a group convertible to R ₃ , R ₅ is an amino-protecting group,
R ₁ , R ₂ and n have the above-mentioned meanings] wherein the protecting group R ₅ of the compound represented by the formula (1) is separated and converted to a hydrogen atom, and R ₃ ′ is a group convertible to R _3. In
It can be produced by converting R ₃ ′ to R ₃ .

Examples of the amino-protecting R _5, for example, a supra easily hydrogenolysis amino protecting group and easily hydrolyzable amino-protecting groups.

When R ₁ and / or R ₂ of the compound (VI) is an amino-protecting group, the amino-protecting group of R ₅ may have a different character from the amino-protecting group of R ₁ and / or R ₂ . Is preferred for the subsequent reaction. For example, R ₁ and / or R ₂
When the amino-protecting group is a readily hydrolyzable amino-protecting group such as a t-butoxycarbonyl group, R ₅ is suitably selected as a readily hydrolyzable amino-protecting group such as benzyl or trityl.

This elimination reaction can be carried out by subjecting compound (VI) to the above-described hydrogenolysis reaction or hydrolysis reaction.

In R ₃ ′, examples of the “group convertible to R ₃ ” include a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a benzyloxy group, an alkoxycarbonyl group, and a carboxyl group.

A methanesulfonyloxy group or a 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 is converted to R ₃ by hydrogenolysis or hydrolysis.
As a hydroxyl group. 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 methyllithium. After the carboxyl group is converted to an acid halide, the Wilkinson complex {RhCl [P
By treating with (C ₆ H ₅ ) ₃ ] ₃ ｝, it can be converted to a halogen atom as R 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 (II) thus produced can be isolated and purified according to a conventional method. Depending on the isolation and purification conditions, these compounds
It is obtained in the form of a salt, free form or hydrate, which can be mutually converted depending on the purpose and lead to the desired form of the compound of the present invention.

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, and the optically active compound can be isolated by applying a known optical resolution method. Can be released.

The thus-obtained compound (I) of the present invention and salts thereof are all novel 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 drugs 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 valuable as a raw material for synthesizing a carboxylic acid in the compound (I) of the present invention, but the ester itself is easily converted in vivo into the compound (I) of the present invention. In this case, it can be used as a prodrug as an antibacterial agent in the same manner as the compound (I) of the present invention.

Further, the bicycloamine compound (II) 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 Next, the compound (I) of the present invention is in vitro and in vivo.
The antibacterial activity of o is described below with reference to data. The results are shown in Tables 1 and 2. The numbers in the table are Ch
The minimum inhibitory concentration (MIC: μg / ml) measured according to the description of emotherapy 29 (1), 76 (1981) is shown. [] indicates the effect (ED ₅₀ ; mg / kg) on systemic infection in mice. Show.
Effect on mouse systemic infection (ED _50; mg / kg) is, Std
-A male ddy mouse (body weight: about 20 g) was infected intraperitoneally with 5 x 10 ³ pathogenic bacteria (live bacteria) listed in Tables 1 and 2 per mouse, and the test compound was suspended in 0.4% carboxymethylcellulose. The suspension was orally administered twice immediately after infection and 6 hours after infection, and calculated by the probit method from the survival rate of the mice 7 days after infection.

As a control compound, enoxacin [1-ethyl-6-fluoro-1, which is already commercially available as an excellent antibacterial agent, was used.
4-dihydro-4-oxo-7- (1-piperazinyl)
[1,8-naphthyridine-3-carboxylic acid]].

As shown in the above Tables 1 and 2, the compound (I) of the present invention exhibits excellent antibacterial activity both in vitro and in animal experiments, and in particular, has excellent antibacterial activity against Gram-positive bacteria and Helicobacter pylori. It is clear that In addition, the compound (I) of the present invention shows better antibacterial activity than the control compound (enoxacin).

In addition, the compound (I) of the present invention has low toxicity and is useful as an antibacterial agent for mammals including humans for prevention and treatment of bacterial diseases in mammals.

When the compound (I) of the present invention is used in humans as an antibacterial agent, the dosage varies depending on age, body weight, symptoms, administration route and the like, but is generally 5 mg to 5 g per day divided into one or several doses. It is recommended to administer. The administration route 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 formulations include tablets, solutions, capsules, granules, fine granules, powders,
Syrups, injections, ointments and the like can be mentioned. These preparations can be produced using ordinary additives according to a conventional method. For example, as an additive for oral use, a carrier or a diluent substance which is commonly used in the field of pharmaceuticals such as starch, mannitol, crystalline cellulose, carboxymethylcellulose-Ca, water, ethanol and does not react with the compound (I) of the present invention. Is used. Examples of additives for injection include those commonly used in the field of injections, such as water, physiological saline, glucose solutions, and infusions.

The above-mentioned liquid preparations and ointments can also be used for treatment and treatment in otolaryngology and ophthalmology.

EXAMPLES Next, the present invention will be described more specifically with reference to examples.
In Examples 1 to 9, the intermediate bicycloamine compound (I
Examples 10 to 38 relate to the production method of the target compound (I).
39 is an example relating to the preparation.

Example 1 1-Amino-3-azabicyclo [3.1.1] heptane: [Step A]: 1.29 g of 60% sodium hydride was washed twice with n-hexane and suspended in 60 ml of ether. 5 ml of ether under ice cooling
5.0 g of diethyl malonate dissolved in the solution were added dropwise over 10 minutes.
The mixture was stirred at room temperature for 30 minutes, cooled on ice,
5.38 g of benzyl chloromethyl ether dissolved in 10 ml
The mixture was added in 0 minutes, stirred at room temperature overnight, and further refluxed for 5 hours. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with saturated saline, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 9.0 g of crude diethyl benzyloxymethylmalonate.

This was dissolved in 50 ml of ether and added dropwise to a mixture of 2.85 g of lithium aluminum hydride and 300 ml of ether under ice cooling. The mixture was stirred at the same temperature for 1.5 hours and further at room temperature for 2 hours. Saturated aqueous sodium tartrate was added under ice cooling, and the mixture was stirred overnight. The insolubles were removed by filtration, the filtrate was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform: ethanol = 20: 1) to obtain 1.96 g of 2-benzyloxymethyl-1,3-propanediol.

IR (neat) cm ^-1 : 3380 ¹ H-NMR (CDCl ₃ ) δ: 2.50 (m, 1H), 2.35 (brs, 2H), 3.63
(D, 2H, J = 5.5Hz), 3.81 (dd, 4H, J = 5.5,5.5Hz), 4.52
(S, 2H), 7.25-7.40 (m, 5H) [Step B]: 84.8 g of the compound obtained by the method of the above-mentioned step A and pyridine 360
While cooling the mixture consisting of ml
206.3 g of toluenesulfonyl were added in three portions, and the mixture was stirred at the same temperature for 2 hours and at room temperature overnight. The reaction solution was poured into ice water and extracted with ethyl acetate. After washing with a dilute acid and water in that order, it was dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform: ethanol = 30: 1), and 162.3 g of 2-benzyloxymethyl-1,3-bis (p-toluenesulfonyloxy) propane was added. Obtained.

IR (neat) cm ^-1 : 1598,1361 ¹ H-NMR (CDCl ₃ ) δ: 2.33 (m, 1H), 2.44 (s, 6H), 3.41
(D, 2H, J = 6 Hz), 4.04 (m, 4H), 4.34 (s, 2H), 7.10-7.
40 (m, 9H), 7.74 (d, 4H, J = 8 Hz) [Step C]: 22.8 g of 60% sodium hydride was washed twice with n-hexane and suspended in 350 ml of toluene. Toluene 150 under ice cooling
91.1 g of diethyl malonate dissolved in ml was added dropwise over 25 minutes. After stirring this mixture at room temperature for 40 minutes, toluene 30
119.6 g of the compound obtained in the above step B dissolved in 0 ml was added, and the mixture was refluxed for 4.5 days. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with saturated saline, and dried over sodium sulfate. The solvent and unreacted diethyl malonate were distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform: ethanol = 50: 1).
66.8 g of diethyl benzyloxymethylcyclobutane-1,1-dicarboxylate was obtained.

^{IR (neat) cm -1: 1726,1263} 1 H-NMR (CDCl 3) δ: 1.23 (t, 3H, J = 7Hz) 1.25 (t, 3H, J
= 7Hz), 2.25-2.50 (m, 2H), 2.55-2.80 (m, 3H), 3.44
(D, 2H, J = 6 Hz), 4.17 (q, 2H, J = 7 Hz), 4.21 (q, 2H, J =
7 Hz), 4.50 (s, 2H), 7.20-7.40 (m, 5H) [Step D]: 66.8 g of the compound obtained in the step C in the preceding section was added to ethyl acetate 500
dissolved in 5 ml of palladium carbon and added with 6.68 g of 5% palladium carbon.
At ° C. the theoretical amount of hydrogen was added. After the catalyst was separated by filtration, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent: chloroform: ethanol = 20: 1).
45.0 g of diethyl-hydroxymethylclobutane-1,1-dicarboxylate was obtained.

IR (neat) cm ^-1 : 3452,1728,1266 ¹ H-NMR (CDCl ₃ ) δ: 1.25 (t, 3H, J = 7 Hz), 1.27 (t, 3H, J
= 7Hz), 1.70 (br s, 1H), 2.30-2.50 (m, 2H), 2.50-
2,70 (m, 3H), 3.62 (d, 2H, J = 5.5Hz), 4.20 (q, 2H, J = 7
Hz), 4.23 (q, 2H, J = 7 Hz) The 3-hydroxymethylclobutane-1, obtained in the previous section,
To a mixture of 45.0 g of diethyl 1-dicarboxylate and 350 ml of pyridine, 48.5 g of p-toluenesulfonyl chloride was added in four portions under ice cooling. 5.5 hours at the same temperature, 13.5 hours at room temperature, 30
After stirring at −40 ° C. for 8 hours, ice water was added, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate, water, diluted hydrochloric acid and saturated saline, and then dried over sodium sulfate. The solvent is distilled off under reduced pressure and 3
-P-toluenesulfonyloxymethylcyclobutane-
A combined product of diethyl 1,1-dicarboxylate was obtained.

The above product, benzylamine 42.2 g, potassium carbonate 3
A mixture of 2.4 g and 600 ml of dioxane was refluxed for 4.5 days. Ice water was added to the reaction solution, extracted with chloroform, washed with a saturated aqueous sodium hydrogen carbonate solution and then with a saturated saline solution, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent: chloroform:
Purification by ethanol = 20: 1) gave 32.3 g of diethyl 3-benzylaminomethylcyclobutane-1,1-dicarboxylate.

^{IR (neat) cm -1: 3324,2813,1727,1263} 1 H-NMR (CDCl 3) δ: 1.23 (t, 3H, J = 7Hz), 1.25 (t, 3H, J
= 7Hz), 2.15-2.30 (m, 2H), 2.40-2.70 (m, 3H), 2.67
(D, 2H, J = 6Hz), 3.76 (s, 2H), 4.17 (q, 2H, J = 7Hz),
4.21 (q, 2H, J = 7 Hz), 7.20-7.40 (m, 5H) [Step E]: 32.3 g of diethyl 3-benzylaminomethylcyclobutane-1,1-dicarboxylate obtained in Step D of the preceding section, 10 120% aqueous sodium hydroxide solution and tetrahydrofuran 1
A mixture consisting of 20 ml was added at room temperature for 13.5 hours, then 50-60
Stirred at C for 6 hours. The mixture was concentrated under reduced pressure, added with 100 ml of water and activated carbon, and filtered. At room temperature, 54.5 ml of 20% hydrochloric acid was added to the filtrate while stirring. After cooling with ice, the crystals were collected by filtration and washed with water and ethanol to obtain 20 g of 3-benzylaminomethylcyclobutane-1,1-dicarboxylic acid.

Melting point: 224-226 ° C (decomposition) IR (KBr) cm ^-1 : 3444,1632 ¹ H-NMR (DMSO-d ₆ ) δ: 2.10-2.26 (m, 2H), 2.30-2.45
(M, 2H), 2.65-2.95 (m, 1H), 3.02 (d, 2H, J = 7Hz), 4.
11 (s, 2H), 7.35-7.55 (m, 5H), 9.00 (br s, 2H) [Step F]: To a mixture comprising 20 g of the compound obtained in Step E of the preceding paragraph and 200 ml of N, N-dimethylformamide. Add carbonyldiimidazole 37 g, room temperature for 13 hours, 30-40 ℃ 5.5 hours,
Stirred at 60-70 ° C for 4 hours. The solvent was distilled off under reduced pressure, and the residue was adjusted to pH 2 by adding diluted hydrochloric acid. The mixture was extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, diisopropyl ether-n-hexane (2: 1) was added to the residue, and the precipitated crystals were collected by filtration to give 3-benzyl-2-oxo-3-azabicyclo [3.1.1] heptane-1-. 15.5 g of carboxylic acid were obtained.

Melting point: 127-128 ° C (recrystallized from ethyl acetate) IR (KBr) cm ^-1 : 2531,1750,1732 ¹ H-NMR (CDCl ₃ ) δ: 1.85-2.00 (m, 2H), 2.70-2.82
(M, 1H), 2.84-2.97 (m, 2H), 3.44 (d, 2H, J = 2Hz), 4.
65 (s, 2H), 7.20-7.45 (m, 5H) [Step G]: A mixture consisting of 15.5 g of the compound obtained in Step F of the preceding paragraph, 9.6 g of triethylamine and 150 ml of t-butanol was used for 70 minutes.
The mixture was heated to 26 ° C., and 26 g of diphenylphosphoryl azide was added dropwise. The reaction was refluxed for 15 hours. The mixture was concentrated under reduced pressure, ice water was added to the residue, and the mixture was extracted with ethyl acetate. After washing with a dilute aqueous sodium hydroxide solution and then with a saturated saline solution, the extract was dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: chloroform:
Purification with ethanol = 50: 1) gave 3-benzyl-1-t-
Butoxycarbonylamino-3-azabicyclo [3.1.
1] 14.6 g of heptane-2-one was obtained.

Melting point: 106-107 ° C (recrystallized from methylene chloride-diisopropyl ether) IR (KBr) cm ^-1 : 3402,1723,1646 ¹ H-NMR (CDCl ₃ ) δ: 1.45 (s, 9H, 1.70-1.83 (m , 2H), 2.
56 (tt, 1H, J = 2.5, 7Hz), 3.10-3.35 (m, 2H), 3.25 (d,
2H, J = 2.5Hz), 4.60 (s, 2H), 6.22 (brs, 1H), 7.20-
7.40 (m, 5H) [Step H]: A mixture of 6.07 g of the compound obtained in Step G of the preceding paragraph, 12 ml of 10% hydrochloric acid and 6 ml of tetrahydrofuran is heated to 50-60 ° C.
For 3 hours. The mixture was concentrated under reduced pressure, a small amount of water was added to the residue, and the residue was washed with n-hexane. The aqueous layer was made alkaline with an aqueous sodium hydroxide solution and extracted with chloroform. After washing with saturated saline, it was dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 4.09 g of 1-amino-3-benzyl-3-azabicyclo [3.1.1] heptan-2-one.

IR (neat) cm ^-1 : 3381,1659,1495,1250 ¹ H-NMR (CDCl ₃ ) δ: 1.85-2.00 (m, 2H), 1.90 (s, 2H),
2.10−2.25 (m, 2H), 2.54 (tt, 1H, J = 2.5,7Hz), 3.26
(D, 2H, J = 2.5 Hz), 4.60 (s, 2H), 7.20-7.40 (m, 5H) [Step I]: To a mixture comprising 2.1 g of the compound obtained in Step H of the preceding section and 25 ml of tetrahydrofuran, 30 ml of a 1.0 molar solution of borane-tetrahydrofuran complex in tetrahydrofuran was added. 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. The solvent was distilled off under reduced pressure, and the residue was distilled with a bulb-to-bulb distillation apparatus [Kugelrohr micro distillation apparatus (manufactured by Buchi)] to give 1-amino-3-benzyl-3-azabicyclo [ 3.1.1] 1.86 g of heptane was obtained.

Boiling point: about 100 ° C. (3 mmHg, Kugelrohr micro distillation ^{apparatus) IR (neat) cm -1:} 3360,2791,1603 1 H-NMR (CDCl 3) δ: 1.51 (br s, 2H), 1.60-1.90 (m ,Four
H), 2.18 (tt, 1H, J = 3.6 Hz), 2.65 (s, 2H), 2.69 (d, 2
H, J = 3 Hz), 3.67 (s, 2H), 7.15-7.40 (m, 5H) [Step J]: 1.86 g of the compound obtained in Step I of the preceding section is treated with 20 m of ethanol.
l, 190 mg of 5% palladium on carbon was added and the theoretical amount of hydrogen was added. The catalyst was removed by filtration, and the solvent was distilled off under reduced pressure.
1.0 g of the desired product was obtained.

Example 2 1-t-butoxycarbonylamino-3-azabicyclo [3.1.1] heptane: [Step K]: 1-amino-3-benzyl-3-azabicyclo [3.1. 1] To a solution of 1.00 g of heptane in 10 ml of dichloromethane was added dropwise a solution of 1.11 g of di-t-butyl dicarbonate in 2 ml of dichloromethane, and the mixture was stirred at room temperature for 18 hours.
Concentrate under reduced pressure to give 3-benzyl-1 as a crystalline residue.
1.49 g of -t-butoxycarbonylamino-3-azabicyclo [3.1.1] heptane was obtained.

Melting point: 86-87 ° C (recrystallized from ethyl acetate) IR (KBr) cm ^-1 : 3257,1703 ¹ H-NMR (CDCl ₃ ) δ: 1.40 (s, 9H), 1.90-2.25 (m, 4H),
2.25-2.36 (m, 1H), 2.68 (d, 2H, J = 3.0 Hz), 2.84 (s, 2
H), 3.65 (s, 2H), 4.55 (br s, 1H), 7.18-7.38 (m, 5
H) [Step J]: 1.17 g of the compound obtained in the above step K, 120 mg of 5% palladium on carbon and 20 ml of ethanol were treated in the same manner as in step K of Example 1 to obtain 585 mg of the desired product. .

Melting point: 151-152 ° C (recrystallized from ethanol-ethyl acetate) IR (KBr) cm ^-1 : 3340,3171,1702,1560,1184 ¹ H-NMR (CDCl ₃ ) δ: 1.42 (s, 9H), 1.81 −1.93 (m, 2H),
2.07 (br s, 1H), 2.10-2.27 (m, 2H), 2.27-2.38 (m, 1
H), 2.94 (d, 2H, J = 2.5 Hz), 3.10 (s, 2H), 4.60 (br s,
1H) Example 3 1-methylamino-3-azabicyclo [3.1.1] heptane: [Step L]: To 20 ml of formic acid, 10 ml of acetic anhydride was added dropwise under ice cooling. 50 minutes later,
1.99 g of 1-amino-3-benzyl-3-azabicyclo [3.1.1] heptan-2-one obtained in Step H of Example 1
Was added and the mixture was stirred at room temperature overnight.
After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluent: chloroform: ethanol = 20: 1), and 2.11 g of 3-benzyl-1-formylamino-3-azabicyclo [3.1.1] heptan-2-one was obtained. I got

Melting point: 129-130 ° C (recrystallized from acetic ether-diisopropyl ether) IR (KBr) cm ^-1 : 3321,1691,1643,1520,1496 ¹ H-NMR (CDCl ₃ ) δ: 1.75-1.87 (m, 2H ), 2.64 (tt, 1H, J
= 2.5,7Hz), 3.27 (d, 2H, J = 2.5Hz), 3.37-3.51 (m, 2
H), 4.61 (s, 2H), 7.18 (br s, 1H), 7.20-7.40 (m, 5
H), 8.28 (d, 1H, J = 2 Hz) [Step M]: 2.08 g of the compound obtained in Step L of the preceding paragraph, 30 ml of tetrahydrofuran and 1.0 of borane-tetrahydrofuran complex.
The same treatment as in step I of Example 1 was carried out using 43 ml of a molar tetrahydrofuran solution to obtain 1.76 g of 3-benzyl-1-methylamino-3-azabicyclo [3.1.1] heptane.

Boiling point: about 100 ° C (4 mmHg, Kugelrohr micro distillation apparatus) IR (neat) cm ^-1 : 3280,2793,1239,1210 ¹ H-NMR (CDCl ₃ ) δ: 1.65-1.85 (m, 4H), 2.16- 2.27
(M, 1H), 2.30 (s, 3H), 2.68 (s, 2H), 2.69 (d, 2H, J = 3
Hz), 3.67 (s, 2H), 7.15-7.40 (m, 5H) [Step N]: Example 1 was performed using 1.74 g of the compound obtained in Step M in the preceding section, 170 mg of 5% palladium on carbon, and 20 ml of ethanol. In the same manner as in Step J, 1.0 g of the desired product was obtained.

Example 4 1-tert-butoxycarbonylaminomethyl-3-azabicyclo [3.1.1] heptane: [Step S]: A mixture consisting of 6.42 g of the compound obtained in Step F of Example 1 and 64 ml of ethyl acetate at room temperature. Was added with 4.67 g of carbonyldiimidazole, and the mixture was stirred. After 1.5 hours, 130 ml of a saturated ammonia-ethanol solution was added, and the mixture was stirred overnight. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform: ethanol = 20: 1) to give 3-benzyl-2-oxo-3-azabicyclo [3.1.1] heptane-1-carboxamide 5.77. g was obtained.

Mp: 170-171 ° C. (recrystallized from ethyl ^{acetate) IR (KBr) cm -1:} 3320,1659,1628,1429 1 H-NMR (CDCl 3) δ: 1.80-1.90 (m, 2H), 2.65-2.75
(M, 1H), 2.80-2.95 (m, 2H), 3.38 (d, 2H, J = 2.5Hz),
4.64 (s, 2H), 5.57 (br s, 1H), 7.20-7.40 (m, 5H), 8.
74 (br s, 1H) [Step T]: A solution of 6.11 g of the compound obtained in Step S in the preceding section, a 1.0 mol solution of borane-tetrahydrofuran complex in 125 mol tetrahydrofuran 125
The mixture was treated in the same manner as in Step I of Example 1 using 90 ml of tetrahydrofuran and 4.48 g of 1-aminomethyl-3-benzyl-3-azabicyclo [3.1.1] heptane.

Boiling point: about 130 ° C (3 mmHg, Kugelrohr micro distillation apparatus) IR (neat) cm ^-1 : 3375,3294,1603,1211,1128 ¹ H-NMR (CDCl ₃ ) δ: 1.30 (brs, 2H), 1.49 −1.60 (m, 2
H), 1.60-1.76 (m, 2H), 2.25-2.35 (m, 1H), 2.51 (s,
2H), 2.68 (s, 2H), 2.79 (d, 2H, J = 3.0 Hz), 3.68 (s, 2
H), 7.17-7.40 (m, 5H) [Step U]: 450 mg of the compound obtained in the above-mentioned Step T, di-t-dicarbonate
Treated as in step K of example 2 with 468 mg of butyl and 7 ml of dichloromethane to give 3-benzyl-1-t-
558 mg of butoxycarbonylaminomethyl-3-azabicyclo [3.1.1] heptane were obtained.

IR (neat) cm ^-1 : 3352,1711 ¹ H-NMR (CDCl ₃ ) δ: 1.41 (m, 9H), 1.50-1.75 (m, 4H),
2.24−2.34 (m, 1H), 2.66 (s, 2H), 2.77 (d, 2H, J = 3.0H
z), 2.98 (d, 2H, J = 6.0 Hz), 3.67 (s, 2H), 4.45 (br s,
1H), 7.18-7.38 (m, 5H) [Step V]: The same treatment as in Step J of Example 1 was carried out using 548 mg of the compound obtained in Step U of the preceding paragraph, 50 mg of 5% palladium on carbon and 10 ml of ethanol. Thus, 343 mg of the desired product was obtained.

Melting point: 99-101 ° C (recrystallized from diisopropyl ether) Example 5 1-aminomethyl-3-azabicyclo [3.1.1] heptane: 1-aminomethyl-3- obtained in Step T of Example 4
Benzyl-3-azabicyclo [3.1.1] heptane 4.07g, 5
In the same manner as in Step J of Example 1, 2.30 g of the desired product was obtained using 410 mg of% palladium carbon and 20 ml of ethanol.

Example 6 1-amino-5-fluoro-3-azabicyclo [3.1.
1] Heptane dihydrochloride: (1) [Step A]: 104.9 g of diethyl fluoromalonate, 72.7 g of potassium tert-butoxide and benzyl chloromethyl ether 92.
Using 3 g, the reaction was carried out in diethyl ether in the same manner as in Step A of Example 1 to obtain 116.7 g of diethyl benzyloxyfluoromalonate.

Boiling point: 150-153 ° C (1.5 mmHg, Kugelrohr micro distillation apparatus) ¹ H-NMR (CDCl ₃ ) δ: 1.29 (t, 6H, J = 7 Hz), 4.08 (d, 2H, J
= 24Hz), 4.30 (q, 4H, J = 7Hz), 4.63 (s, 2H), 7.2-7.4
(M, 5H) Lithium borohydride 25.6g and tetrahydrofuran 500
The mixture consisting of ml was stirred under ice cooling. To this, a mixture consisting of 116.7 g of the compound obtained above and 200 ml of tetrahydrofuran was added over 10 minutes. Mix this mixture at room temperature for 20 minutes.
After stirring for minutes, the mixture was heated under reflux overnight. 90 ml of acetone, 110 ml of ice water and 200 ml of concentrated hydrochloric acid are added little by little while cooling on ice, concentrated to dryness under reduced pressure, and the residue is subjected to silica gel column chromatography (eluent: chloroform: ethanol =
6: 1), the eluate was collected, and the solvent was distilled off to obtain an oily substance. Ice water was added, and the resulting crystals were collected by filtration, washed with water and then with diisopropyl ether. The crystals were dissolved in chloroform, anhydrous sodium sulfate was added, and the mixture was filtered. The filtrate was dried under reduced pressure, and a mixture of diisopropyl ether and n-hexane (2: 1) was added to the crystalline residue. By filtration, 48.1 g of 2-benzyloxymethyl-2-fluoro-1,3-propanediol was obtained.

Melting point: 86-87 ° C (recrystallized from ethyl acetate-diisopropyl ether) IR (KBr) cm ^-1 : 3360 ¹ H-NMR (CDCl ₃ ) δ: 2.05 (brt, 2H, J = 6.5 Hz), 3.72
(D, 2H, J = 17Hz), 3.85 (dd, 4H, J = 6.5,18Hz), 4.58
(S, 2H), 7.25-7.45 (m, 5H) [Step B]: Step B of Example 1 using 65.1 g of the compound obtained in the above step A, 150 g of p-toluenesulfonyl chloride and 325 ml of pyridine. In the same manner as described above, 109.3 g of 2-benzyloxymethyl-2-fluoro-1,3-bis (p-toluenesulfonyloxy) propane was obtained.

Mp: 97-98 ° C. (methylene chloride - recrystallized from diisopropyl ^{ether) IR (KBr) cm -1:} 1596,1371 1 H-NMR (CDCl 3) δ: 2.45 (s, 6H), 3.58 (d, 2H, J = 16H
z), 4.16 (d, 4H, J = 18Hz), 4.45 (s, 2H), 7.15-7.4
(M, 9H), 7.75 (d, 4H, J = 7.5 Hz) [Step C]: 124.9 g of the compound obtained in the above step B, 38.3 g of 60% sodium hydride, 153 g of diethyl malonate and xylene 1.
Using 3l, treating in the same manner as in step C of Example 1,
30.8 g of diethyl benzyloxy-3-fluorocyclobutane-1,1-dicarboxylate was obtained.

IR (neat) cm ^-1 : 1734,1265 ¹ H-NMR (CDCl ₃ ) δ: 1.21, 1.26 (both t, 3H, J = 7 Hz),
2.8-3.0 (m, 4H), 3.60 (d, 2H, J = 22Hz), 4.13, 4.23 (b
oth q, 2H, J = 7 Hz), 4.60 (s, 2H), 7.25-7.4 (m, 5H) [Step D]: 30.8 g of the compound obtained in Step C of the preceding section, 3.1 g of 5% palladium on carbon and acetic acid Using 300 ml of ethyl and working up as in step D of example 1, diethyl 3-fluoro-3-hydroxymethylcyclobutane-1,1-dicarboxylate 17.
8 g were obtained.

IR (neat) cm ^-1 : 3466,1729,1268 ¹ H-NMR (CDCl ₃ ) δ: 1.26, 1.27 (both t, 3H, J = 7 Hz),
1.85 (br t, 1H, J = 6.5Hz), 2.8-3.0 (m, 4H), 3.75 (d
d, 2H, J = 6.5, 23 Hz), 4.22, 4.24 (both q, 2H, J = 7 Hz) 17.8 g of the compound obtained above, 17.8 g of p-toluenesulfonyl chloride and 130 ml of pyridine were used to prepare Example 1. By treating in the same manner as in Step D, 20.2 g of diethyl 3-fluoro-3-p-toluenesulfonyloxymethylcyclobutane-1,1-dicarboxylate was obtained.

IR (neat) cm ^-1 : 1727,1598,1368 ¹ H-NMR (CDCl ₃ ) δ: 1.25 (t, 6H, J = 7 Hz), 2.45 (s, 3
H), 2.7-3.0 (m, 4H), 4.20 (d, 2H, J = 22Hz), 4.20, 4.2
3 (both q, 2H, J = 7Hz), 7.36, 7.81 (both d, 4H, J = 7.5H
z) Treatment with 20.2 g of the compound obtained above, 16.1 g of benzylamine, 10.4 g of potassium carbonate and 120 ml of dioxane in the same manner as in Step D of Example 1 to give 3-benzylaminomethyl-3-fluorocyclobutane 14.87 g of diethyl-1,1-dicarboxylate was obtained.

IR (neat) cm ^-1 : 3352,1732,1368 ¹ H-NMR (CDCl ₃ ) δ: 1.21,1.26 (both t, 3H, J = 7Hz),
2.7-3.0 (m, 4H), 3.83 (s, 2H), 4.14, 4.23 (both q, 2
H, J = 7 Hz), 7.2-7.4 (m, 5H) [Step E]: 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 procedures as in Example 1 were carried out. The same treatment as in Step E was performed to obtain 9.88 g of 3-benzylaminomethyl-3-fluorocyclobutane-1,1-dicarboxylic acid.

Melting point: 201-203 ° C IR (KBr) cm ^-1 : 3416,2828,1632 ¹ H-NMR (DMSO- _d6 ) δ: 2.6-2.9 (m, 4H), 3.46 (d, 2H, J
= 23 Hz), 4.12 (s, 2H), 7.35-7.55 (m, 5H) [Step F]: 9.59 g of the compound obtained in Step E of the preceding paragraph, 16.6 g of carbonyldiimidazole and 100 m of N, N-dimethylformamide
Using l and treating in the same manner as in step F of Example 1,
7.42 g of benzyl-5-fluoro-2-oxo-3-azabicyclo [3.1.1] heptane-1-carboxylic acid was obtained.

Mp: 167-168 ° C. (ethyl acetate - recrystallized from diisopropyl ^{ether) IR (KBr) cm -1:} 2575,1745,1612 1 H-NMR (CDCl 3) δ: 2.3-2.45 (m, 2H), 2.95- 3.15 (m,
2H), 3.47 (d, 2H, J = 2 Hz), 4.63 (s, 2H), 7.2-7.45
(M, 5H) [Step G]: The same as Step G in Example 1 using 7.22 g of the compound obtained in Step F of the preceding paragraph, 11.3 g of diphenylphosphoryl azide, 4.21 g of triethylamine and 72 ml of t-butanol. To give 3-benzylamino-1-t-butoxycarbonylamino-5-fluoro-3-azabicyclo [3.
1.1] Heptan-2-one 6.40 g was obtained.

Melting point: 100-101 ° C (recrystallized from diisopropyl ether-n-hexane) IR (KBr) cm ^-1 : 3405,1719,1660 ¹ H-NMR (CDCl ₃ ) δ: 1.46 (s, 9H), 2.1-2.25 (M, 2H),
3.34 (d, 2H, J = 2Hz), 3.4-3.6 (m, 2H), 4.60 (s, 2H),
5.94 (br s, 1H), 7.2-7.45 (m, 5H) [Step H]: The step of Example 1 was carried out using 6.19 g of the compound obtained in the above step G, 12 ml of 10% hydrochloric acid and 6.2 ml of tetrahydrofuran. 1-amino-3-benzyl-5
-Fluoro-3-azabicyclo [3.1.1] heptane-2
4.17 g of -on were obtained.

IR (neat) cm ^-1 : 3368,1670 ¹ H-NMR (CDCl ₃ ) δ: 2.25-2.55 (m, 4H), 3.35 (d, 2H, J
= 2 Hz), 4.60 (s, 2H), 7.2-7.4 (m, 5H) [Step I]: 4.15 g of the compound obtained in Step H in the preceding section, 60 m of a 1.0 molar tetrahydrofuran solution of a borane-tetrahydrofuran complex.
l and 50 ml of tetrahydrofuran, treated analogously to step I of example 1 to give 1-amino-3-benzyl-
5-fluoro-3-azabicyclo [3.1.1] heptane 3.9
5 g were obtained.

IR (neat) cm ^-1 : 3366,1604,1227 ¹ H-NMR (CDCl ₃ ) δ: 1.9-2.1 (m, 2H), 2.15-2.3 (m, 2
H), 2.55 (s, 2H), 2.83 (d, 2H, J = 5Hz), 3.67 (s, 2H),
7.2-7.35 (m, 5H) [Step K]: 3.95 g of the compound obtained in the above step I, di-t-dicarbonate
Example 2 using 3.91 g of butyl and 25 ml of methylene chloride
And then treated in the same manner as in Step K to obtain 5.14 g of 3-benzyl-1-t-butoxycarbonylamino-5-fluoro-3-azabicyclo [3.1.1] heptane.

Melting point: 108-109 ° C (recrystallized from n-hexane) IR (KBr) cm ^-1 : 3344,1704,1677,1530 ¹ H-NMR (CDCl ₃ ) δ: 1.40 (s, 9H), 2.2-2.5 ( m, 4H), 2.
74 (s, 2H), 2.82 (d, 2H, J = 5 Hz), 3.66 (s, 2H), 4.70
(Br s, 1H), 7.2-7.4 (m, 5H) [Step J]: 5.14 g of the compound obtained in Step K of the preceding paragraph, palladium carbon
The same treatment as in Step J of Example 2 was carried out using 0.50 g and 70 ml of ethanol to obtain 3.46 g of 1-t-butoxycarbonylamino-5-fluoro-3-azabicyclo [3.1.1] heptane.

Melting point: 193-195 ° C (recrystallized from ethanol-ethyl acetate) IR (KBr) cm ^-1 : 3339,3181,1703,1556 ¹ H-NMR (CDCl ₃ ) δ: 1.43 (s, 9H), 2.25-2.45 (M, 4H),
2.94 (s, 2H), 3.04 (d, 2H, J = 4 Hz), 4.75 (br d, 1H) (2) 1.133 g of the compound obtained in the above (1), 10 m of 10% hydrochloric acid
l and a mixture of 5.0 ml of tetrahydrofuran at 80 ° C
For 2 hours. The solvent was removed under reduced pressure, and ethanol was added to the residue. The resulting crystals were collected by filtration, washed with ethanol and then with diisopropyl ether, and dried to obtain the target compound 99.
2 mg were obtained.

Mp: 290-295 ℃ IR (KBr) cm -1: 1610,1553,1501 1 H-NMR (DMSO-d 6) δ: 2.2-2.8 (m, 4H), 3.3-3.5 (m, 4
H) Example 7 1-amino-5-fluoromethyl-3-azabicyclo [3.1.1] heptane: [Step a]: A mixture of 27.23 g of pentaerythritol and 150 ml of 2,2-dimethoxypropane was added at room temperature with p- 0.38 g of toluenesulfonic acid was added and the mixture was stirred overnight. The reaction solution was concentrated under reduced pressure, 150 ml of methanol was added, and the mixture was stirred at room temperature for 2 hours. An aqueous solution of sodium hydrogen carbonate was added to the reaction solution,
After concentration under reduced pressure, the mixture was extracted with chloroform, washed with brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude crystals were washed with warm hexane and recrystallized from ethyl acetate to give 5,5-bis (hydroxymethyl) -2,2.
11.20 g of dimethyl-1,3-dioxane were obtained.

Melting point: 123-124 ° C IR (KBr) cm ^-1 : 3350 ¹ H-NMR (CDCl ₃ ) δ: 3.75 (s, 8H), 2.40 (br s, 2H), 1.4
0 (s, 6H) [Step b]: 11.20 g of the compound obtained in Step a of the preceding section and p-chloride
The same treatment as in step B of Example 1 was carried out using toluenesulfonyl to obtain 27.40 g of 2,2-dimethyl-5,5-bis (p-toluenesulfonyloxymethyl) -1,3-dioxane.

Melting point: 148-151 ° C IR (KBr) cm ^-1 : 3054,1598 ¹ H-NMR (CDCl ₃ ) δ: 7.85-7.30 (m, 8H), 4.00 (s, 2H),
3.60 (s, 2H), 2.50 (s, 6H), 1.30 (s, 6H) [Step c]: The step of Example 1 using 67.0 g of the compound obtained in step b of the preceding section and 67.2 g of diethyl malonate. By treating in the same manner as in C, 2,2-dimethyl-1,3-dioxane-5-spiro-
Diethyl 3'-cyclobutane-1 ', 1'-dicarboxylate
29.8 g were obtained.

IR (neat) cm ^-1 : 1729 ¹ H-NMR (CDCl ₃ ) δ: 4.22 (q, 4H, J = 7 Hz), 3.75 (s, 4
H), 2.43 (s, 4H), 1.38 (s, 6H), 1.25 (t, 6H, J = 7 Hz) [Step d]: 29.7 g of the compound obtained in step c of the preceding paragraph, 200 ml of dilute hydrochloric acid and 100 ml of tetrahydrofuran. The mixed solution was stirred at room temperature for 4 hours. The reaction solution was poured into an aqueous solution of sodium hydrogen carbonate, extracted with chloroform, washed with a saturated saline solution, and dried over magnesium sulfate. After distilling off the solvent under reduced pressure,
Purification by silica gel column chromatography (eluent hexane: ethyl acetate = 1: 4) gave 20.0 g of ethyl 3,3-bis (hydroxymethyl) cyclopropane-1,1-dicarboxylate.

IR (neat) cm ^-1 : 3400,1729 ¹ H-NMR (CDCl ₃ ) δ: 4.21 (q, 4H, J = 7 Hz), 3.73 (d, 4H, J
= 6Hz), 2.44 (s, 4H), 2.23 (t, 2H, J = 6Hz), 1.26 (t, 6
[Step e]: 15 ml of pyridine and 12.6 g of t-butyldimethylchlorosilane were added to 100 ml of a methylene chloride solution of 20.0 g of the compound obtained in the above step d, and the mixture was stirred at room temperature for 8 hours. The reaction solution was poured into ice water containing dilute hydrochloric acid, extracted with ethyl acetate, washed with a saturated aqueous solution of sodium carbonate and a saturated saline solution, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 3: 1) to give 3-t-butyldimethylsiloxymethyl-3-hydroxymethylcyclopropane-
21.0 g of ethyl 1,1-dicarboxylate was obtained.

IR (neat) cm ^-1 : 3525,1731 ¹ H-NMR (CDCl ₃ ) δ: 4.22 (q, 4H, J = 7 Hz), 3.69 (s, 2
H), 3.67 (d, 2H, J = 6 Hz), 2.65 (t, 1H, J = 6 Hz), 2.41
(M, 4H), 1.26 (t, 6H, J = 7Hz), 0.88 (s, 9H), 0.07 (s,
6H) Treatment with 21.0 g of the compound obtained above and 13.9 g of p-toluenesulfonyl chloride in the same manner as in Step B of Example 1 to give 3-t-butyldimethylsiloxymethyl-3
26.4 g of ethyl p-toluenesulfonyloxymethylcyclopropane-1,1-dicarboxylate was obtained.

IR (neat) cm ^-1 : 1731,1598 ¹ H-NMR (CDCl ₃ ) δ: 7.72-7.33 (m, 4H), 4.25-4.11
(M, 4H), 4.03 (s, 2H), 3.50 (s, 2H), 2.44 (s, 3H), 2.
44−2.28 (m, 4H), 1.23 (t, 6H, J = 7Hz), 0.80 (s, 9
H), -0.02 (s, 6H) [Step f]: 26.4 g of the compound obtained in Step e of the preceding paragraph, benzylamine
13.4 g, potassium carbonate 10.4 g and 1,4-dioxane 250 ml
Was refluxed for 4 days. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 3: 1) to give 3-t-butyldimethylsiloxymethyl-3-benzylaminomethylcyclopropane-1,1. -23.2 g of ethyl dicarboxylate were obtained.

^{IR (neat) cm -1: 1729,1464} 1 H-NMR (CDCl 3) δ: 7.33-7.20 (m, 5H), 4.25-4.11
(M, 4H), 3.78 (s, 2H), 3.56 (s, 2H), 2.68 (s, 2H), 2.
46−2.32 (m, 4H), 1.53 (br s, 1H), 1.28−1.19 (m, 6
H), 0.87 (s, 9H), 0.04 (s, 6H) [Step g]: 4.08 g of sodium ethoxide was added to 300 ml of a diethyl ether solution of 23.15 g of the compound obtained in the above step f under ice-cooling. The mixture was stirred at the same temperature for 1 hour. The reaction solution was poured into a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 4: 1) to give 3-benzyl-5-t-butyldimethylsiloxymethyl-2-oxo-3-azabicyclo. [3.1.1] 17.3 g of ethyl heptane-1-carboxylate was obtained.

IR (neat) cm ^-1 : 1739,1667,1494 ¹ H-NMR (CDCl ₃ ) δ: 7.38-7.22 (m, 5H), 4.59 (s, 2H),
4.27 (q, 2H, J = 7Hz), 3.48 (s, 2H), 3.13 (s, 1H), 2.30
−2.21 (m, 2H), 2.02-1.88 (m, 2H), 1.42 (t, 3H, J = 7H
z), 0.84 (s, 9H), -0.01 (s, 6H) [Step h]: A mixture of 7.60 g of the compound obtained in step g of the preceding section, 15 ml of tetrahydrofuran and 50 ml of 5% hydrochloric acid was heated to 40 ° C. And stirred for 1 hour. The reaction solution was poured into an aqueous solution of sodium hydrogen carbonate under ice-cooling, extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 1: 2) to give 3-benzyl-5-hydroxymethyl-2-oxo-3-azabicyclo [3.1.1 3.43 g of ethyl heptane-1-carboxylate was obtained.

Melting point: 85-87 ° C IR (KBr) cm ^-1 : 3476,1736,1652 ¹ H-NMR (CDCl ₃ ) δ: 7.39-7.23 (m, 5H), 4.60 (s, 2H),
4.26 (q, 2H, J = 7Hz), 3.56 (d, 2H, J = 6Hz), 3.18 (s, 2
H), 2.34-2.25 (m, 2H), 2.07-1.97 (m, 2H), 1.08 (t,
1H, J = 6 Hz), 1.31 (t, 3H, J = 7 Hz) [Step i]: 24.2 g of the compound obtained in the step g of the preceding section and 27.9 g of p-toluenesulfonyl fluoride were added to Morecala Sheep 4.
A 200 g was added to 800 ml of a tetrahydrofuran solution of tetrabutylammonium fluoride trihydrate 77.4 g, and the mixture was heated under reflux for 20 hours. The reaction solution was filtered through silica gel, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with an aqueous sodium hydrogen carbonate solution and saturated saline, and then dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent hexane: ethyl acetate = 4: 1) to give 3-benzyl-5-fluoromethyl-2-oxo-3-azabicyclo [3.1.1 23.2 g of ethyl heptane-1-carboxylate was obtained.

IR (neat) cm ^-1 : 1738,1666 ¹ H-NMR (CDCl ₃ ) δ: 7.39-7.23 (m, 5H), 4.62 (s, 2H),
4.30 (d, 2H, J = 47Hz), 4.24 (q, 2H, J = 7Hz), 3.21 (s, 2
H), 2.45-2.32 (m, 2H), 2.12-2.03 (m, 2H), 1.33 (t,
[Step j]: A mixture comprising a solution of 23.2 g of the compound obtained in step i of the preceding section, 240 ml of 4% sodium hydroxide and 10 ml of tetrahydrofuran was stirred at room temperature for 20 hours. The reaction mixture was cooled under ice
The resulting crystals were collected by filtration, washed with water and dried under reduced pressure to give 3-benzyl-5-fluoromethyl-2.
-Oxo-3-azabicyclo [3.1.1] heptane-1-
18.9 g of carboxylic acid was obtained.

Melting point: 141-143 ° C IR (KBr) cm ^-1 : 1745,1629 ¹ H-NMR (CDCl ₃ ) δ: 14.12 (brs, 1H), 7.44-7.23 (m, 5
H), 4.68 (s, 2H), 4.38 (d, 2H, J = 47Hz), 3.37 (s, 2
H), 2.77-2.67 (m, 2H), 2.04-1.94 (m, 2H) [Step k]: Example was carried out using 18.9 g of the compound obtained in step j in the preceding section and 13.4 g of diphenylphorforyl azide. Step 1 G
In the same manner as in the above, 22.8 g of 3-benzyl-1-t-butoxycarbonylamino-5-fluoromethyl-3-azabicyclo [3.1.1] heptan-2-one was obtained.

^{IR (neat) cm -1: 3324,1709,1642} 1 H-NMR (CDCl 3) δ: 7.39-7.21 (m, 5H), 6.21 (br s, 1
H), 4.62 (s, 2H), 4.41 (d, 2H, J = 47Hz), 3.22 (s, 2
H), 3.18−3.02 (m, 2H), 1.89−1.77 (m, 2H), 1.45 (s,
9H) [Step l]: 22.8 g of the compound obtained in the above step k was treated in the same manner as in step H of Example 1 to give 1-amino-3-benzyl-5.
15.0 g of -fluoromethyl-3-azabicyclo [3.1.1] heptan-2-one was obtained.

IR (neat) cm ^-1 : 3390,1666,1586 ¹ H-NMR (CDCl ₃ ) δ: 7.40-7.22 (m, 5H), 4.62 (s, 2H),
4.33 (d, 2H, J = 47Hz), 3.20 (s, 2H), 2.03 (s, 4H), 1.1
8 (brs, 2H) [Step m]: 14.3 g of the compound obtained in Step l of the preceding section and borane-
150m 1m solution of tetraborane complex in tetrahydrofuran
Using l and treating in the same manner as in Step I of Example 1,
12.4 g of amino-3-benzyl-5-fluoromethyl-3-azabicyclo [3.1.1] heptane was obtained.

^{IR (neat) cm -1: 3370,1603} 1 H-NMR (CDCl 3) δ: 7.35-7.20 (m, 5H), 4.21 (d, 2H, J
= 47Hz), 3.68 (s, 2H), 2.66 (s, 2H), 2.62 (s, 2H), 1.
94-1.86 (m, 2H), 1.64-1.53 (m, 2H), 1.49 (brs, 2
H) [Step n]: 3.51 g of the compound obtained in the above step m and 0.35 g of 5% palladium carbon were treated in the same manner as in step J of Example 1 to obtain 2.00 g of the desired product.

Example 8 1-amino-5-methoxymethyl-3-azabicyclo [3.1.1] heptane: [Step o]: 3-benzyl-5-hydroxymethyl-2-oxo- obtained in Step h of Example 7. 3-azabicyclo [3.1.
1] 8.60 g of ethyl heptane-1-carboxylate and 1.77 ml of methyl iodide were added to a mixture consisting of 2.80 g of potassium hydroxide and 180 ml of dimethyl sulfoxide, and the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into ice water, extracted with ether, and the extract was washed with saturated saline and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent hexane: ethyl acetate = 2: 1) to give 3-benzyl-5-methoxymethyl-2-oxo-3-azabicyclo [3.1.1 6.00 g of ethyl heptane-1-carboxylate was obtained.

IR (neat) cm ^-1 : 1738,1666 ¹ H-NMR (CDCl ₃ ) δ: 7.38-7.22 (m, 5H), 4.59 (s, 2H),
4.26 (q, 2H, J = 6Hz), 3.30 (s, 5H), 3,18 (s, 2H), 2.35
−2.26 (m, 2H), 2.09−2.00 (m, 2H), 1.32 (t, 3H, J = 6H
z) [Step p]: The compound 6.00 g obtained in Step o of the preceding paragraph was treated in the same manner as in Step j of Example 7, to give 3-benzyl-5-methoxymethyl-2-oxo-3-azabicyclo [3.1 .1] 4.85 g of heptane-1-carboxylic acid were obtained.

Melting point: 127-129 ° C IR (KBr) cm ^-1 : 1740,1630 ¹ H-NMR (CDCl ₃ ) δ: 14.23 (brs, 1H), 7.42-7.24 (m, 5
H), 4.65 (s, 2H), 3.37 (s, 2H), 3.35 (s, 2H), 3.31
(S, 3H), 2.71-2.61 (m, 2H), 2.02-1.92 (m, 2H) [Step q]: Performed using 4.85 g of the compound obtained in step p of the preceding section and 4.62 g of diphenylphosphoryl azide. Step G of Example 1
To give 3-benzyl-1-t-butoxycarbonylamino-5-methoxymethyl-2-oxo-3
4.96 g of azabicyclo [3.1.1] heptan-2-one were obtained.

IR (neat) cm ^-1 : 3401, 1714, 1666 ¹ H-NMR (CDCl ₃ ) δ: 7.38-7.21 (m, 5H), 6.20 (brs, 1
H), 4.60 (s, 2H), 3.42 (s, 2H), 3.29 (s, 3H), 3.19
(S, 2H), 3.10-2.92 (m, 9H), 1.87-1.77 (m, 2H), 1.4
5 (s, 9H) [Step r]: 4.90 g of the compound obtained in the step q in the preceding section was treated in the same manner as in the step H of Example 1 to give 1-amino-3-benzyl-5.
-Methoxymethyl-2-oxo-3-azabicyclo [3.
1.1] 3.55 g of heptane-2-one was obtained.

IR (neat) cm ^-1 : 3389,1665 ¹ H-NMR (CDCl ₃ ) δ: 7.38-7.23 (m, 5H), 4.61 (s, 2H),
3.32 (s, 2H), 3.30 (s, 3H), 3.18 (s, 2H), 1.98 (s, 4
H), 1.86 (br s, 2H) [Step s]: 3.50 g of the compound obtained in the above step r was treated in the same manner as in Step I of Example 1 to give 1-amino-3-benzyl-5.
3.30 g of -methoxymethyl-3-azabicyclo [3.1.1] heptane was obtained.

IR (neat) cm ^-1 : 3368 ¹ H-NMR (CDCl ₃ ) δ: 7.37-7.20 (m, 5H), 3.67 (s, 2H),
3.32 (s, 3H), 3.22 (s, 2H), 2.62 (s, 4H), 1.92-1.83
(M, 2H), 1.58-1.48 (m, 2H), 1.45 (br s, 2H) [Step t]: 3.20 g of the compound obtained in the step s in the preceding paragraph was treated in the same manner as in the step J of Example 1. Thus, 2.00 g of the desired product was obtained.

Example 9 1-t-butyldimethylsiloxymethyl-5-t-butoxycarbonylaminomethyl-3-azabicyclo [3.
1.1] Heptane: [Step u]: 3-benzyl-5-t- obtained in Step g of Example 7
Ethyl butyldimethylsiloxymethyl-2-oxo-3-azabicyclo [3.1.1] heptane-1-carboxylate 17.
3 g was dissolved in 50 ml of ether, added dropwise to a mixture of 3.15 g of lithium aluminum hydride and 450 ml of ether under ice cooling, and stirred at room temperature for 19 hours. The reaction solution was added with 6 ml of water under ice-cooling, stirred for 1 hour, filtered to remove insolubles, and dried over magnesium sulfate. After concentrating the solvent under reduced pressure,
Purification by silica gel column chromatography (eluent hexane: ethyl acetate = 2: 1) gave 3-benzyl-
10.5 g of 1-t-butyldimethylsiloxymethyl-5-hydroxymethyl-3-azabicyclo [3.1.1] heptane was obtained.

IR (neat) cm ^-1 : 3346 ¹ H-NMR (CDCl ₃ ) δ: 7.37-7.18 (m, 5H), 3.69 (s, 2H),
3.42 (s, 2H), 3.36 (s, 2H), 2.68 (s, 2H), 2.62 (s, 2
H), 1.64-1.45 (m, 4H), 0.87 (s, 9H), -0.01 (s, 6
H) [Step v]: 6.8 ml of ethanesulfonyl chloride was added to a mixture of 10.5 g of the compound obtained in step u of the preceding section, 20 ml of triethylamine and 100 ml of methylene chloride under ice-cooling, followed by stirring at the same temperature for 1 hour. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, silica gel column chromatography (eluent hexane: ethyl acetate = 4: 4)
Purification according to 1) gave 6.0 g of 3-benzyl-1-t-butyldimethylsiloxymethyl-5-methanesulfonyloxymethyl-3-azabicyclo [3.1.1] heptane.

IR (neat) cm ^-1 : 1358 ¹ H-NMR (CDCl ₃ ) δ: 7.32-7.20 (m, 5H), 4.01 (s, 2H),
3.68 (s, 2H), 3.35 (s, 2H), 2.97 (s, 3H) 2.72 (s, 2
H), 2.61 (s, 2H), 1.70-1.56 (m, 4H), 0.87 (s, 9H),
-0.01 (s, 6H) [Step w]: A mixture of 6.00 g of the compound obtained in the step v of the preceding section, 200 ml of dimethylformamide and 3.67 g of sodium azide was added to a mixture of 70%.
C. and stirred for 2 hours. After the solvent was distilled off under reduced pressure, the reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, silica gel column chromatography (eluent hexane: ethyl acetate = 9:
Purified according to 1), 5-azidomethyl-3-benzyl-
4.00 g of 1-t-butyldimethylsiloxymethyl-3-azabicyclo [3.1.1] heptane was obtained.

IR (neat) cm ^-1 : 2097 ¹ H-NMR (CDCl ₃ ) δ: 7.37-7.20 (m, 5H), 3.68 (s, 2H),
3.35 (s, 2H), 3.16 (s, 2H), 2.68 (s, 2H), 2.61 (s, 2
H), 1.66-1.54 (m, 4H), 1.87 (s, 9H), -0.01 (s, 6
H) [Step x]: 3.98 g of the compound obtained in the step w of the preceding section was added to ethanol 150
and added 0.4 g of 5% palladium carbon, and cooled with ice.
Theoretical amount of hydrogen was added. After filtering off the catalyst, the filtrate was concentrated under reduced pressure to give 5-aminomethyl-3-benzyl-1.
3.60 g of -t-butyldimethylsiloxymethyl-3-azabicyclo [3.1.1] heptane were obtained.

[Step y]: Using 3.60 g of the compound obtained in the above step x and 2.22 g of di-t-butyl dicarbonate, the same treatment as in step K of Example 2 was carried out to give 3-benzyl-1-t. 4.15 g of -butyldimethylsiloxymethyl-5-t-butoxycarbonylaminomethyl-3-azabicyclo [3.1.1] heptane were obtained.

IR (neat) cm ^-1 : 3368,1708 ¹ H-NMR (CDCl ₃ ) δ: 7.35-7.17 (m, 5H), 4.48 (brs, 1
H), 3.68 (s, 2H), 3.33 (s, 2H), 3.01 (d, 2H, J = 6Hz),
2.63 (s, 2H), 2.59 (s, 2H), 1.56-1.44 (m, 4H), 1.42
(S, 9H), 0.88 (s, 9H), -0.01 (s, 6H) [Step z]: Example 2 was performed using 4.04 g of the compound obtained in step y of the preceding section and 0.40 g of 5% palladium carbon. 1-t-butyldimethylsiloxymethyl-5
3.24 g of -t-butoxycarbonylaminomethyl-3-azabicyclo [3.1.1] heptane was obtained.

IR (neat) cm ^-1 : 3329,169 3 ¹ H-NMR (CDCl ₃ ) δ: 4.50 (br s, 1H), 3.32 (s, 2H), 2.9
9 (d, 2H, J = 6Hz), 2.88 (s, 4H), 1.65-1.57 (m, 2H),
1.47-1.33 (m, 2H), 1.44 (s, 9H), 0.89 (s, 9H), 0.02
(S, 6H) Example 10 7- (1-Amino-3-azabicyclo [3.1.1] hept-3-yl) -1-cyclopropyl-6-fluoro-
1,4-dihydro-8-methoxy-4-oxoquinoline-
3-carboxylic acid: 540 mg of 1-amino-3-azabicyclo [3.1.1] heptane obtained in Example 1, 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4- A mixture of 1.5 g of oxoquinoline-3-carboxylic acid-BF ₂ chelate, 1.46 ml of triethylamine and 10 ml of acetonitrile was stirred at room temperature for 14 hours and then at 50-60 ° C. for 1.5 hours. Ethanol was added to the residue obtained by concentration under reduced pressure to obtain crude crystals. To this, 40 ml of ethanol, 0.5 ml of water and 3 ml of triethylamine were added and stirred for 11 hours. The precipitated crystals were collected by filtration and recrystallized from aqueous acetic acid and then aqueous ammonia to give 1.13 g of the desired product.

Melting point: 228-230 ° C. (decomposition) Examples 11 to 19 Reaction and treatment were conducted in the same manner as in Example 10 to obtain the compounds shown in Table 2 below.

Example 20 7- (1-Amino-3-azabicyclo [3.1.1] hept-3-yl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid Acid: 154 mg of 1-amino-3-azabicyclo [3.1.1] heptane obtained in Example 1 and 1-cyclopropyl-6,7,8
-Trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 300 mg and 1,8-diazabicyclo [5.
4.0) -7-undecene 165 mg and acetonitrile 6.0 ml
And heated at 110-120 ° C for 2 hours. Acetonitrile was added to the residue obtained by concentration under reduced pressure to obtain crude crystals.
This was recrystallized from aqueous acetic acid and then aqueous ammonia to give 2.02
mg of the desired product was obtained.

Melting point: 235 ° -237 ° C. (decomposition) Examples 21 to 24 The reaction and treatment were carried out in substantially the same manner as in Example 20 to obtain the compounds shown in Table 3 below.

Example 25 7- (1-Amino-5-fluoro-3-azabicyclo [3.1.1] hept-3-yl) -1-cyclopropyl-
6,8-Difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid: (1) 1-t-bromocarbonylamino-5-fluoro-3- obtained in Example 6 (1) Azabicyclo (3.1.
1) Using 423 mg heptane, 400 mg 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 215 mg DBU and 5.0 ml acetonitrile, In the same manner, 7- (1-tert-butoxycarbonylamino-5-fluoro-3-azabicyclo [3.1.1] hept-3-yl) -1-cyclopropyl-6,8-difluoro-1,4 440 mg of -dihydro-4-oxoquinoline-3-carboxylic acid were obtained.

(2) 440 mg of the compound obtained in (1) above, 5.0% of 10% hydrochloric acid
l and 2.5 ml of tetrahydrofuran at 80 ° C
For 1 hour. After cooling to room temperature, the precipitated crystals were collected by filtration, washed with ethanol and diisopropyl ether in that order, and dried to obtain 191 mg of the desired product.

Melting point: 225-256 ° C (decomposition) (recrystallized from aqueous ammonia)

Examples 31 to 35 The compounds were reacted and treated in substantially the same manner as in Example 25 to obtain the compounds shown in Table 5 below.

Example 36 7- (1-Aminomethyl-3-azabicyclo [3.1.
1] Hept-3-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid: (1) 1- obtained in Example 4 t-Broxycarbonylaminomethyl-3-azabicyclo [3.1.1] heptane 700
mg, 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid -BF ₂ - as in Example 10 using chelating 1.00g and acetonitrile 10ml To 7- (1-t-butoxycarbonylaminomethyl-3-azabicyclo [3.1.
1] Hept-3-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.332 g) was obtained.

Melting point: 237-238 ° C (recrystallized from chloroform-ethanol) (2) 1.255 g of the compound obtained in the above (1), 12m of 10% hydrochloric acid
Example 25 using l and 12 ml of tetrahydrofuran
The same treatment as in (2) was performed to obtain 869 mg of the desired product.

Melting point: 219-221 ° C. (decomposition) (recrystallization from aqueous ammonia)

Example 39: Tablet Preparation Method Compound of Example 11 or 20 250 g Corn starch 54 g Carboxymethylcellulose-Ca 40 g Microcrystalline cellulose 50 g Magnesium stearate 6 g 2000 tablets were obtained.

INDUSTRIAL APPLICABILITY As described above, the compound (I) of the present invention is useful as a pharmaceutical agent for mammals including humans (for example, an antibacterial agent or a therapeutic agent for gastrointestinal diseases), and the bicycloamine compound (II)
Is useful as a direct synthetic intermediate for the compound (I) of the present invention.

────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-2-91072 (JP, A) JP-A-6-9619 (JP, A) JP-A-5-247059 (JP, A) JP-A-5-470 112554 (JP, A) JP-A-5-255319 (JP, A) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07D 221/22 C07D 471/18 CA (STN) REGISTRY (STN)

Claims (12)

(57) [Claims] 1. A compound represented by the following general formula (I) [Wherein, R represents 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 or a substituent which may have a substituent, G represents CE, wherein E represents a hydrogen atom or, together with R, represents -S-CH (CH ₃ )-. A represents CZ or a nitrogen atom, wherein Z represents 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 group. alkyl group, a lower alkenyl group, or means a lower alkynyl group or a cyano group, or taken together with _{R, -O-CH 2 -CH (} CH 3) - crosslinked to form represented by, X is water Atom, a halogen atom, an optionally protected amino group, a hydroxyl group means a lower alkyl group, a halogeno-lower alkyl group or a lower alkoxy-lower alkyl group, Y is a hydrogen atom or a halogen atom, R ₁ and R ₂ Are the same or different and represent a hydrogen atom, a lower alkyl group or an amino protecting group, and R ₃ is 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 represents an integer of 0 or 1], a pyridonecarboxylic acid derivative, an ester thereof, and a salt thereof. 2. The pyridonecarboxylic acid derivative according to claim 1, wherein G is C—H, its ester and its salt. 3. The pyridonecarboxylic acid derivative, its ester and its salt according to claim 2, wherein R is a cycloalkyl group, a halogenocycloalkyl group or a phenyl group substituted with a halogen atom. 4. The pyridonecarboxylic acid derivative according to claim 2, wherein X is a hydrogen atom, a lower alkyl group or an amino group, its ester and its salt. 5. The pyridonecarboxylic acid derivative, its ester and its salt according to claim 2, wherein Y is a fluorine atom. 6. The pyridonecarboxylic acid derivative according to claim 2, wherein R ₁ and R ₂ are the same or different and are a hydrogen atom or a lower alkyl group, an ester thereof and a salt thereof. 7. The pyridonecarboxylic acid derivative according to claim 2, wherein R ₃ is a hydrogen atom, a halogen atom, a lower alkoxy lower alkyl group or a halogeno lower alkyl group.
The ester and its salt. 8. The pyridonecarboxylic acid derivative according to claim 2, wherein A is a nitrogen atom or CZ, wherein Z is a hydrogen atom, a halogen atom, a lower alkoxy group or a halogeno lower alkoxy group. The ester and its salt. 9. R is cyclopropyl group, 2-fluorocyclopropyl group or 2,4-difluorophenyl group, X is hydrogen atom, methyl group or amino group, Y is
Is a fluorine atom, R ₁ and R ₂ are the same or different and are a hydrogen atom or a methyl group, R ₃ is a hydrogen atom, a fluorine atom, a methoxymethyl group or a fluoromethyl group, and A is a nitrogen atom Or CZ, wherein Z is a hydrogen atom, a fluorine atom, a chlorine atom, a methoxy group or a difluoromethoxy group. The pyridonecarboxylic acid derivative according to any one of claims 2 to 8, wherein , Its esters and their salts. 10. The following general formula (II) [Wherein, R ₁ and R ₂ are the same or different and represent a hydrogen atom, a lower alkyl group or an amino protecting group, and R ₃ is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a lower alkoxy group. A lower alkyl group, a halogeno lower alkyl group or a hydroxy lower alkyl group, and n represents an integer of 0 or 1.] and a salt thereof. 11. R ₁ and R ₂ are the same or different and are a hydrogen atom, a lower alkyl group or an amino protecting group which can be eliminated by hydrolysis, and R ₃ is a hydrogen atom, a halogen atom, a lower alkoxy lower alkyl group or 11. The bicycloamine compound and an acid addition salt thereof according to claim 10, which is a halogeno lower alkyl group. 12. R ₁ and R ₂ are the same or different and each is a hydrogen atom, a methyl group or an amino-protecting group, t-butoxycarbonyl group or benzyloxycarbonyl group;
12. The bicycloamine compound according to claim 10, wherein R ₃ is a hydrogen atom, a fluorine atom, a methoxymethyl group or a fluoromethyl group, and an acid addition salt thereof.