WO1996001260A1 - Pyridonecarboxylic acid derivative, ester thereof, salt thereof, and intermediate for synthesis of these compounds - Google Patents

Abstract

A pyridonecarboxylic acid derivative represented by general formula (I), an ester thereof, a salt thereof, and an antibacterial containing these compounds, wherein R represents optionally halogenated cycloalkyl, optionally substituted phenyl, etc.; G represents carbon, etc.; A represents C-Z or nitrogen; Z represents hydrogen, halogen, lower alkoxy, halogenated lower alkoxy, lower alkyl, halogenated lower alkyl, lower alkoxy-lower alkyl, etc.; X represents hydrogen, halogen, optionally protected amino, lower alkyl, etc.; Y represents hydrogen or halogen; R1 and R2 represent each independently hydrogen, lower alkyl, etc.; R3 represents hydrogen, halogen, lower alkoxy, lower alkoxy-lower alkyl, halogenated lower alkyl, etc.; and n represents an integer of 0 or 1. The invention also relates to a bicyclic amine compound as a direct intermediate for the pyridonecarboxylic acid derivatives.

Description

 Field damage Pyridonecarboxylic acid derivatives, their esters and salts, and synthetic intermediates thereof

 The present invention relates to a novel pyridone haponic acid derivative useful as an antibacterial agent and a novel synthetic intermediate thereof. Background art

The antibacterial pyridonecarboxylic acid derivatives, for example, _t various types have been known, in Kohyo 5-503709 discloses (W091 / 16894) represented by the following general formula (A)

Wherein R ¹ is a lower alkyl group ゃ cycloalkyl group,

R ² is “bicyclic nitrogen-containing heterocyclic group” or the like;

R ³ is a hydrogen atom or a halogen atom,

R ⁴ is a hydrogen atom or a lower alkyl group,

R ⁵ is a hydrogen atom or a halogen atom,

 A is N or CH)

A quinol izinone type compound represented by the following formula has been disclosed, but this compound is clearly different from the compound of the present invention represented by the formula (I) described later in the basic ring structure. In the above formula (A), R ₂ As an example of a “bicyclic nitrogen-containing heterocycle group” defined for the above, the above publication discloses the following formulas (a-11) to (a-3) The group represented by the formula (a-3) conceptually includes the substituent at the 7-position of the compound of the present invention. — There is no specific description of group 3).

1

 (a-l) (a-2) (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 hetero atom selected from S, 0 or N;

 A is an amino (lower alkyl) group, etc.

 Japanese Patent Application Laid-Open No. 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 ゃ a halogen atom,

Y is an optionally substituted cyclic amino group, etc. Z is a nitrogen atom, CH, etc.)

A quinolone derivative represented by the following formula (b) is described as an example of the “cyclic amino group optionally having a substituent” defined for Y. This group (when i = l) is a 2-azabicyclo [3.1.1] heptan-2-yl group, and is a substituent at the 7-position of the compound of the present invention. This is clearly different from the 3-azabicyclo [3.1.1] hepter-3-yl group.

(In the formula, i is 1 or 2, and A is a substituted or unsubstituted amino group, etc.)

 Further, as a known compound related to a bicycloamine compound of the formula (E) described below as an intermediate for producing the pyridonecarboxylic acid derivative of the present invention, for example, Japanese Unexamined Patent Publication No. 160967 (corresponding European publication number: EP317506) Is the following general formula (C)

(In the formula, R ^1- , R ² , R ³ and R ⁴ are a hydrogen atom or a phenyl group which may have a substituent, and are not simultaneously a hydrogen atom.)

Wherein the compound is different from the bicycloamine compound (I) of the present invention in that the compound does not have an optionally substituted amino group or aminomethyl group. . In addition, the compound (C) The application is a therapeutic agent for disorders of calcium metabolism, and there is no description that it is useful as an intermediate during the production of pyridonecarboxylic acid.

 In recent years, Helicobacter pylori has been considered as a causative bacterium of gastrointestinal disorders. However, the above literature describes the antibacterial activity of pyridonecarbonic acid derivatives against Helicobacter pylori. Not. A main object of the present invention is to provide a pyridonecarboxylic acid-type compound having an enhanced antibacterial activity, particularly an antibacterial activity against gram-positive bacteria, and further having an excellent antibacterial activity against Helicopacus pulp and pylori. It is. Disclosure of the invention

 According to the present invention, the following general formula (I)

[Wherein R is a lower alkyl group, a halogeno lower alkyl group, a lower alkenyl group, a halogeno lower alkenyl group, a cycloalkyl group, a halogenocycloalkyl group, a phenyl group which may have a substituent, Represents a heterocyclic group which may have a substituent,

G represents C-E or a nitrogen atom, where E is a force representing a hydrogen atom, or, together with R, forms a bridge represented by —S—CH (CH ₃ ) — Well, A represents C—Z or a nitrogen atom, where Z is a hydrogen atom, a halogen atom, a lower alkoxy group, a halogeno lower alkoxy group, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy lower alkyl group, a lower alkenyl Group, lower alkynyl group or cyano group, or together with R, represents one 0—CH ₂ —CH

(CH ₃ ) — may form a bridge represented by

 X represents a hydrogen atom, a halogen atom, an amino group which may be protected, a hydroxyl group, a lower alkyl group, a halogeno lower alkyl group or a lower alkoxy lower alkyl group;

 Y represents a hydrogen atom or a halogen atom,

Ri and R ₂ are the same or different and represent a hydrogen atom, a lower alkyl group or an amino protecting group,

R ₃ represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a lower alkoxy lower alkyl group, a halogeno lower alkyl group or a hydroxy lower alkyl group;

 n means an integer of 0 or 1)

And an ester and a salt thereof (hereinafter may be referred to as the compound (I) of the present invention).

 Further, according to the present invention, a novel compound represented by the following general formula (H) which is useful as an intermediate of the pyridonecarboxylic acid derivative represented by the above formula (I)

(Wherein, R,, 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 linear or branched alkyl having 1 to 7 carbon atoms, and examples include methyl, ethyl, propyl, isopropyl, butyl, t-butyl and pentyl. “Lower alkoxy J is a lower alkyloxy group in which the lower alkyl moiety has the above-mentioned meaning, and includes, for example, methoxy, ethoxyquin, propoxy, isopropoxy, butoxy.“ Lower alkenyl ”is a group having 2 carbon atoms. And 7 linear or branched alkenyl, for example, vinyl, aryl, 1-propenyl, isop-propenyl, and the like. “Lower alkynyl” includes, for example, ethynyl, 1-propynyl and the like. “Cycloalkyl” includes cycloalkyl having 3 to 7 carbon atoms, and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

“Halogeno lower alkyl” is a group in which at least one hydrogen atom of a lower alkyl is replaced by a halogen atom, and includes, for example, fluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl and the like. “Halogeno lower alkenyl” is a group in which at least one hydrogen atom of lower alkenyl is replaced by a halogen atom, and includes, for example, 2-fluorovinyl, 1.1-fluorovinyl, 2,2-difluorovinyl and the like. “Halogenocycloalkyl” is a group in which at least one hydrogen atom of cycloalkyl has been replaced by a halogen atom, and examples include fluorocyclopropyl, chlorocyclopropyl and the like. "Haloge The "lower alkyne" is a group in which at least one of the hydrogen atoms in the above lower alkoxy is replaced by a halogen atom, and examples thereof include fluoromethoxy, difluoromethoxy, trifluoromethoxy and the like.

 “Lower alkoxy lower alkyl” means lower alkyl substituted with lower alkyne, and includes, for example, methoxymethyl, ethoxyquinmethyl, 1-methoxyshetyl and the like, and “hydroxy lower alkyl” means It means lower alkyl substituted with xy, for example, hydroxymethyl, 111-hydroxyshethyl and the like.

 As the substituent in the “optionally substituted phenyl group j” or the “optionally substituted heterocyclic group” defined for R, a halogen atom, a lower alkyl group, Examples include a lower alkoxy group, a hydroxyl group, a nitro group, and an amino group. Examples of the heterocyclic ring in the above-mentioned “heterocyclic group optionally having substituent (s)” include, for example, pyrrole, furan, thiophene, thiazol, isothiabule, oxazole, isoxabule, pyrazonole, imidabule, pyridine, pyridazine, Hetero atoms such as pyrimidine and pyrazine include 5- or 6-membered heterocyclic groups containing N, 0 or S.

 As the “amino protective group”, any amino acid that can be easily removed without substantially affecting other structural parts by a usual deprotecting group reaction such as hydrolysis or hydrogenolysis is used. Can be adopted.

Examples of amino-protecting groups that can be easily removed by hydrolysis (labile amino-protecting groups) include ethoxycarbonyl, t-butoxycarbonyl (hereinafter sometimes abbreviated as Boc), and benzylo. Oxycarbonyl groups such as xyloxycarbonyl, p-methoxybenzyloxycarbonyl, vinyloxycarbonyl, / S- (p-toluenesulfonyl) ethoxycarbonyl; acyl groups such as formyl, acetyl, trifluoroacetyl; trimethyl Shi A silyl group such as lyl and t-butyldimethylsilyl; tetrahydrobiranyl, 0-nitrophenylsulfenyl, diphenylphosphenyl and the like.

 Examples of the amino-protecting group which is easily eliminated by hydrogenolysis (an easily hydrolyzable amino-protecting group) include an arylsulfonyl group such as p-toluenesulfonyl; benzyl, trityl, and benzyloxymethyl. A methyl group substituted by a phenyl or benzyloxy group such as: benzyloxycarbonyl, an arylmethoxycarbonyl group such as 0-methoxybenzyloxycarbonyl; / 3, β, ^ 1 And a halogenoethoxycarbonyl group such as ethoxycarbonyl.

 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. Examples of the ester that can be converted to the corresponding free rubonic acid by chemical means such as hydrolysis include lower alkyl esters such as methyl ester and ethyl ester. Esters that can be converted to the corresponding free carboxylic acid not only by chemical means but also by enzymatic means include, for example, acetomethyl ester, 1-acetoxityl ester, and vivaloyloxymethyl ester Lower alkanoyloxy lower alkyl esters, such as: 1 lower alkoxycarbonyloxy lower alkyl esters, such as 1-ethoxyquincarbonyloxyethyl ester; 2-dimethylaminoethyl ester, 2- (1-piberidinyl) In addition to aminoethyl esters such as ethyl ester, etc., 3-butyrolactonyl ester, choline ester, phthalidyl ester, (5-methyl-2-oxo-1-3-dioxol-14-yl) methyl ester and the like can be mentioned.

Particularly preferred salts of the pyridonecarboxylic acid derivative (I) of the present invention are physiologically Acceptable salts are preferred, salts with organic acids such as trifluoroacetic acid, acetic acid, lactic acid, succinic acid, methanesulfonic acid, maleic acid, malonic acid or amino acids such as gluconic acid, aspartic acid or glumic acid; Salts with inorganic acids such as hydrochloric acid and phosphoric acid; metal salts such as sodium, potassium, zinc and silver; ammonium salts; salts with organic bases such as trimethylamine, triethylamine and N-methylmorpholine. An example is given below.

Examples of the salt of the bicycloamine compound (E) of the present invention include acid addition salts with inorganic acids such as hydrochloric acid and sulfuric acid; and organic acids such as formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid and p-toluenesulfonic acid. _C The pyridonecarboxylic acid derivative (I) and the bicycloamine compound (I) of the present invention, which include an acid addition salt of the present invention, sometimes exist as a hydrate or a solvate. The compound (I) of the present invention may exist as an optically active form or a stereoisomer (cis type, trans type). These compounds are also included in the present invention. Preferred examples of the compound (I) of the present invention include compounds in which G is CH in the general formula (I). More preferably, in the above general formula (I), G is CH and R is a cycloalkyl group such as cyclopropyl, a halogenocycloalkyl group such as 2-fluorocyclopropyl, or 2,1-difluorophenyl. A phenyl group substituted with a halogen atom such as phenyl, X is a hydrogen atom, a methyl group or an amino group, Y is a fluorine atom, R, and R ₂ are the same or different, and a hydrogen atom or a methyl R ₃ is a hydrogen atom, a halogen atom such as a fluorine atom, a lower alkoxy lower alkyl group such as a methoxymethyl group or a halogenoalkyl group such as a fluoromethyl group, and A is a nitrogen atom Or C-Z, wherein Z is a hydrogen atom, a halogen atom such as a fluorine atom, a lower alkoxy group such as a methoxy group or Compounds that are a halogeno lower alkyl group such as a difluoromethoxy group are exemplified. More specific Preferred are the following compounds and their physiologically acceptable salts. Preferred examples of the bicycloamine compound (H) of the present invention include the compounds described above and the compounds corresponding to the substituent located at the 7-position of the pyridonecarboxylic acid derivatives specifically mentioned below. Can be Typical examples of the compound (I) of the present invention are as follows.

5-Amino-7— (1-Amino-3-azabicyclo [3.1.1] Hepter-3-yl) 1-1-Cyclopropyl-1,6,8-difluoro-1,4-dihydro 4-oxoquinoline-1 3-Power Rubonic acid.

7— (1-Amino-3-azabicyclo [3.1.1] Hepter-3-yl) 1-Chloro-1-cyclopropyl-1-6-fluoro-1,4-dihydro 4-oxoquinoline-1—3-Rubon Acid.

7— (1—Amino-3-azabicyclo [3.1.1] Hep-1-yl) 1-Cyclopropyl-1-6-fluoro-1,4-dihydro-4-oxoquinoline-1-3-Rubonic acid.

7— (1-Amino-3-azabicyclo [3.1.1] Hept-1-yl) 1 1—Cyclopropyl 6-Fluoro 1,4-Dihidro 8—Methoxy 14-oxoquinoline 3--Rubonic acid.

7— (1-Amino-3-azabicyclo [3.1.1] Hepter-3-yl) 1-11 (2,4-difluorophenyl) 1-6-Fluoro 1,4 HYDRO 4-OKIFU 1,8-Naphthyridine-1-3-Rubonic acid.

1-cyclopropyl-1 6-fluoro-1,4 dihydro 8—methoxy-1 7— (1—methylamino-3-3-azabicyclo [3.1.1] heptin-1-yl) 1 4 1-oxoquinoline 1 3 —Rubonic acid.

(S) — 10— (1 Amino 3-Azabicyclo [3.1.1] Hepter 3 —yl) 19-Fluoro-2,3-dihydro-13-methyl-7-oxo-17H-pyrido [Shi 2,3-de] [Shi 4] Benzoxazine 1-force rubonic acid.

7— (1—Aminomethyl-3-azabicyclo [3.1.1] heptyl-1-yl) 1-1-cyclopropyl-1 6—fluoro-1,4 dihydro 8—methoxy-4 4-oxoquinoline 1— carboxylic acid.

5-amino-1 7- (1-amino-5-fluoro-3-azabicyclo [3.1.1] hepter-3-yl) 1-cyclopropyl-1 6,8-difluoro-1, 4—dihidraw 4 1 3-oxoquinoline 1-Rubonic acid.

7— (1-Amino 5—Fluoro-3-azabicyclo [3.1.1]) 1—8—Chloro-1-cyclopropyl-1 6—Fluoro-1,4—Dihydro-4 1 Oxoquinoline-3-carboxylic acid.

7— (1—Amino 5—Fluoro-3-azabicyclo [3.1.1]] 1-Cyclopropyl-1 6-Fluoro 1, 4 1-dihydro 1 8 —Methoxy 4 1 Oxoquinoline-3-carboxylic acid. 7— (1—Aminomethyl-3-azabicyclo [3.1.1] hepatic 3—yl) 1-cyclopropyl-1,6,8-difluoro-1,4, dihydro-1,4-oxoquinoline-1,3-dicarboxylic acid.

5-Amino-7- (1-aminomethyl-3-azabicyclo [3.1.1] hepter-3-yl) 1-cyclopropyl-1,6,8-difluoro-1,4 dihydro-4,1oxoquinoline-1,3-dicarboxylic acid. 7 — (1-Aminomethyl-3-azabicyclo [3.1.1] Hepter-3-yl) 1-8-Chloro-1-cyclopropyl-1 6-fluoro-1,4-dihydro 4-1-oxoquinoline-13-carboxylic acid.

7- (1-Aminomethyl-3-azabicyclo [3.1.1] heptyl-1-yl) 1-11 (2,4-difluorophenyl) 1 6-fluoro-1,4, dihydro-4-1,4-oxo-1,8 —Naphthyridine mono-3-rubic acid.

7- (1-Amino-5-fluoromethyl-1-3-azabicyclo [3.1.1] hepatic-3-yl) 1-cyclopropyl-1 6-fluoro-1,4-dihydro-1-8-methoxy-4-1-oxoquinoline-1 3 —Rubonic acid.

7— (1-Amino-5-fluoromethyl-3-azabicyclo [3.1.1] Hepter-3-yl) 1 1—Cyclopropyl-1-8-difluoromethoxy-6-fluoro-1,4-dihydro-1,4-oxoquinoline-3 acid. 7— (1-amino-5-methoxymethyl-3-azabicyclo (3.1 1) hepter-3-yl) 1-cyclopropyl-1-6-fluoro-1,4 dihydro _8-methoxy 4-oxoquinoline-3-caprolubone acid.

7— (1-Amino-5-methoxymethyl-3-azabicyclo [3,1.1] heptyl-3-yl) 1-cyclopropyl-18-difluoromethoxy-16-fluoro-1,4-dihydro-4-oxoquinoline-3- Power rubonic acid.

7— (1-amino-5-fluoromethyl-3-azabiziclo [3.1.1] hepter-3-yl) 1-cyclopropyl-1 6-fluoro-1,4-dihydro 8—methoxymethyl-14-oxoquinoline 3—force Rubonic acid.

7- (1-Amino-5-methoxymethyl-3-azabicyclo [3.1.1] hept-3-yl) 1-1-Cyclopropyl-1-6-fluoro-1,4-dihydro 8-Methoxymethyl-4-oxoquinoline 3--Rubonic acid.

7- (1-Ami-Fu 5-fluoromethyl-3-azabicyclo [3.1.1] hepter 3-yl) 1-1-cyclopropyl-18-ethynyl-6-fluoro-1,4, dihydro-4-oxoquinoline-3-3-hydrorubonic acid.

7- (1-amino-5-methoxymethyl-3-azabicyclo [3.1.1] heptyl-3-yl) -11-cyclopropyl-18-ethynyl-6-fluoro-1,4-dihydro-4-1-oxoquinoline-13 —Rubonic acid. 7— (1—Amino 5—Fluoromethyl-1-azabicyclo [3.1.1] Hept-1-yl) 1-Cyclopropyl-1-6-fluoro-1,4-dihydro 4 4-oxo-1 8—Tri Fluoromethylquinoline-3-hydroxycarboxylic acid.

7— (1—Amino 5—Methoxymethyl-3-azabicyclo [3.1.1] Hep-1-yl) 1-Cyclopropyl-1 6-Fluoro 4 1 Dihydro 4—Oxo 1 8—Trifluo Romethylquinoline 3-hydroxycarboxylic acid.

7— (1-Amino 5—Fluoromethyl-3-azabicyclo [3.1.1] Hept-3-I-yl) 1-1-Cyclopropyl-1-6-fluoro-1,4-dihydro 4—Oxo-8-vinylquinoline One 3-carboxylic acid.

7— (1-Amino 5—Methoxymethyl-3-azabicyclo [3.1.1] Hept-1-yl) 1 1—Cyclopropyl-1 6-Fluoro 1,4 1 Dihydro 1 4 1oxo 1 8 —Vinylquinoline-1-carboxylic acid. 7— (1-amino-5-hydroxy-3-3-azabicyclo [3.1.1] heptin-3-yl) 1-1—cyclopropyl-1-6-fluoro-1, 4—Dihydro 8—Methoxy 4—Oxoquinoline 3—Rubonic acid.

7— (1—amino-5—methoxy-3-3-azabicyclo [3.1.1]) 1-3-cyclopropyl-6-fluoro-1,4-dithiol 8-Methoxy-14-oxoquinoline-1-3-carboxylic acid. 7— (1-Amino 5-methyl-3-azabicyclo [3.1.1] Hept-3-yl) 1-1-Cyclopropyl-6-fluoro-1,4-dihydro-18-Methoxy-14-oxoquinoline One-three-rubric acid.

1-cyclopropyl-1-6-fluoro-1,8-dihydro 8- 8-methoxy-1- (1-methylamino-5-fluoromethyl-3-azabicyclo [3.1.1] hepuichi-3-yl) -14-oxoquinoline 1-Cyrurubonic acid. 1-Cyclopropyl-1-6-fluoro-4-dihydro-8-Methoxy-17- (1-Methylamino-5-Methoxymethyl-1-3-azabicyclo [3.1.1]] 3 —yl) 1 4 1-oxoquinoline 1- 3-Rubonic acid.

7— (1—Amino 3—azabicyclo [3.1.1] Hept-1-yl) 1 8—Cyanol 1-cyclopropyl-1 6-fluoro-1,4-dihydro 4- 4-oxoquinoline 1 3— carboxylic acid.

7- (1-amino-5-fluoromethyl-1-3-azabicyclo [3.1.1] hepatic-3-yl) 1 8—cyano 1-cyclopropyl 6-fluoro 1-, 4-dihydro 1 4 1-oxoquinoline-3-carboxylic acid.

7- (1-amino-5-methoxymethyl-3-azabicyclo [3.1.1] hep-1-3-yl) -1-8-cyano-1-cyclopropyl-1-6-fluoro-1,4-dihydro-4 —Oxoquinoline-3-carboxylic acid.

7— (1—Amino 1—3-azabicyclo [3.1.1] 1)-1-cyclopropyl 1-6-fluoro-1,4-dihydro-8-methyl-1 4-oxoquinoline-1 3--carboxylic acid.

1-cyclopropyl-1-6-fluoro-4-alpha--8-methoxy-1-5-methyl-7- (1-methylamino-3-azabicyclo [3.1.1] hep-1-yl) 1-4 4-oxoquinolin 1-carboxylic acid.

5—Amino 1-cyclopropyl-1-6-fluoro-1,4—dihydroxy 8—Methoxy 7— (1—Methylamino-3—azabicyclo [3.1.1] Heptuichi 3—yl) 1 4 1-oxoquino Lin-3-3-Rubonic acid.

7— (5—Chloromethyl-1 1-methylamino 3- 3-azabicyclo [3.1.1] hepter 3-yl) 1 1—Cyclopropyl-1 6-fluoro-1,4—dihydro 8—Methoxy 4—oxoquino Lin-3-3-Rubonic acid.

6—Fluoro-1-methyl-7— (1—Methylamino-0.3-azabisic mouth [3.1.1] Hepter-3-yl) 1 4 1-oxo 1 4 〔— [1,3] Thiazet [3,2— a) Quinolin-1-3-rubonic acid.

6—Fluoro-1,4-dihydro 7— (1-Methylamino 3- 3-azabicyclo [3.1.1] hepatic 3-yl) 1-4 4-oxo-1 1 — (2-phenyl) 1 8—Naphthyridine 1—3-Rubonic acid.

1-ethyl-6,8-difluoro-7- (5-fluoromethyl-1-methylamino 3--3-azabicyclo [3.1.1] heptin-3-yl) 1-1,4-dihidrone 4-oxoquinoline 1-3 —Rubonic acid. 6-Fluoro 1- (2-Fluoroethyl) 1 7- (5-Fluoromethyl 1-Methylamino-13-azabicyclo [3.1.1] Heptuichi 3-yl) 1-1,4-Jihi draw 8-Methoxy 4 Monooxoquinoline 3-carbonic acid.

6-Fluoro-7- (5-Fluoromethyl-1-1-methylamino-3-azabicyclo [3.1.1] Hepter-3-yl) 1-1,4-Dihydro-4-1-oxo-1--1-vinyl-1,8-naphthyridine 3--Rubonic acid.

6-Fluoro-7— (5-Fluoromethyl-1-methylamino) 3-azabicyclo [3.1.1] Hepter 3-yl) 1 1 1 (2-Fluorovinyl) 1 4 4-Hydro 1 4-oxo 1 8 —Naphthyridine-3-carbonic acid. The compound (I) of the present invention can be produced, for example, by the following (a) amination reaction, (b) hydrolysis reaction or (c) ring closure reaction.

(a) Amination reaction:

The compound (I) of the present invention, its ester and its salt are represented by the following general formula (1)

[Wherein, L represents a removable group, and R, G, A, X and Y represent Having the meaning described above, and the carbonyl group and the oxo group may form a boron chelate bond between these groups], an ester or a salt thereof, and a compound represented by the following general formula (I )

(Wherein, R ₂ , R ₃ and η have the above-mentioned meanings), and hydrolyzes the boron chelate moiety, if any, in the product Thus, it can be easily manufactured.

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

 This reaction is generally performed by stirring compound (E) and compound (BI) for 10 minutes to 24 hours, preferably 30 minutes to 3 hours in an inert solvent at 10 to 180 ° C, preferably 20 to 130 ° C. Can be implemented. Examples of the solvent include water, methanol, ethanol, acetonitrile, chloroform, pyridine, dimethylformamide, dimethyl sulfoxide, 1-methyl-2-pyrrolidone, and the like. These solvents may be used alone or as a mixture.

This reaction is generally carried out in the presence of an acid acceptor using compound (I) in an equivalent amount or an excess amount relative to compound (I). May be used excessively and also serve as an acid acceptor. Examples of the acid acceptor include organic bases such as 1,8-diazabicyclo [5.4.0] —7-indene (DBU), triethylamine, pyridine, quinoline, and picoline, or sodium hydroxide, Inorganic bases such as potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and the like can be mentioned. These acid acceptors can be used usually in a molar amount of 1 to 3 times the amount of the compound (E).

 The compound (ΠΠ is known or can be produced according to a known method. Both of the bicycloamine compounds (E) are novel, and their production methods will be described later.

(b) Hydrolysis reaction:

 The compound (I) of the present invention has the following formula (17)

(In the formula, U means a group convertible to a hydroxyl group by hydrolysis, and R, G, A, X, Y, R,, R ₂ , R ₃ and n have the above-mentioned meaning.)

Can also be produced by subjecting a compound represented by the formula to a hydrolysis reaction.

 Here, the group U which can be converted into a carboxyl group includes, for example, an ester, cyano, amide, amidino or a group represented by the formula C (= NH) -0-lower alkyl.

I 9 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. Examples of usable acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as acetic acid, trifluoroacetic acid, formic acid, and p-toluenesulfonic acid. 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.

 Water is usually used as the solvent, but a water-miscible organic solvent such as ethanol, ethylene glycol dimethyl ether, benzene, or dioxane is used together with water depending on the properties of compound (IV). The reaction temperature can be generally selected from the range of 0 to 150 ° C, preferably 30 to 100 ° C. This reaction can also be carried out by directly heating compound (IV) in the presence of an acid as described above, and then adding water.

(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 aryl group or a benzyl group, and R, G, A, X, Y, R,, R ₂ , R ₃ And n have the meaning described above)

Can also be produced by subjecting the compound represented by to a ring-closing reaction to remove an ester residue and a Z or amino protecting group, if necessary, and converting it to a hydrogen atom.

 As the group L ′ which can be eliminated here, the groups described above for the group L which can be eliminated are preferable, and in particular, halogen atoms such as fluorine and chlorine are preferable.

This ring closure reaction is carried out in the presence of compound (V) in the presence of a base in an amount of 1 to 3 moles per mole of compound (V), for example, potassium carbonate, sodium carbonate, sodium hydride, potassium butoxide, potassium fluoride and the like. a mixture of 30 to 150 DEG ° C with the solvent, preferably can be carried out by stirring 1-6 hours at 30 to 100 ^D C. Suitable solvents include ethanol, dioxane, tetrahydrofuran, dimethylformamide, dimethylsulfoxide and the like. -The compound (V) used as a raw material is also novel, and can be produced, for example, according to the following reaction formula 1. Reaction formula 1_

Wherein R has the same meaning as a hydrogen atom or R ₄ described above, R ₆ and R ₇ are the same or different and represent a lower alkyl group, and R, G, A, X, Y, Ri, R ₂ , R ₃ , R ₄ , L, L ′ and n have the above-mentioned meanings.] The compound (V) can be prepared by, for example, adding a compound (1) to a bicycloamine compound (IO The compound (2) is reacted to form the compound (2) .The obtained compound (2) is converted to an acid halide, and then reacted with a 3-dialkylaminoacrylic acid ester in the presence of a base to form the compound (3). It can be obtained by treating (3) with a primary amine. As another method, compound (V) is obtained by, for example, converting compound (1 ′) into an acid halide, reacting with malonate, hydrolyzing the compound, and then subjecting compound (4) to a decarboxylation reaction. The resulting compound (4) was treated in the same manner as in the synthesis of compound (2) above to give compound (5), and this compound (5) was treated with a mixture of acetic anhydride and ethyl formate. Then, it can also be obtained by reacting with primary amine. 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).

 The elimination reaction of the amino-protecting group by hydrogenolysis is advantageously carried out by treating the compound (I) of the present invention having an easily hydrolyzable amino-protecting group with hydrogen gas in a solvent in the presence of a catalyst. The compound can be converted into the compound (I) of the present invention from which the amino protecting group has been eliminated. Examples of the catalyst used in this reaction include hydrogenation catalysts such as platinum, palladium, and Raney nickel. As the solvent, for example, ethylene glycol, dioxane, dimethylformamide, ethanol, acetic acid, water and the like can be used. This reaction can be performed at 60 ° C or lower, usually at room temperature.

When the easily hydrolyzable amino protecting group is benzyl, trityl, benzyloxycarbonyl, p-toluenesulfonyl, etc., such protecting group is treated with sodium metal in liquid ammonia at a temperature of 50 50 ^ -20 ° C. Can also be desorbed. The compound (H) used as a raw material in the aforementioned method (a) is, for example, a compound represented by the following general formula (VI)

(vr)

Wherein R ₃ ′ has the same meaning as R ₃ described above or is a group convertible to R ₃ , R ₆ is an amino protecting group, and R,, R ₂ and n are as defined above. Meaningful)

Converted to hydrogen atom of the protecting group R ₅ of the compound represented in eliminated, and, R ₃ 'when is a group which can be converted into R ₃ is, R _3' and child converted into R ₃ Can be manufactured.

Here, examples of the amino-protected R ₅ include, for example, the above-mentioned easily hydrolyzable amino-protecting group and easily hydrolyzable amino-protecting group.

When R, and Z or R _{2 of} compound (VI) are amino protecting groups, it is preferable that the amino protecting group of R _{5 be different from} the amino protecting group of R and / or R _2. Preferred for later reactions. For example, when the amino protecting group of R, and Z or R _{2 is} a readily hydrolyzable amino protecting group such as a t-butoxycarbonyl group, then R ₅ is a readily hydrolyzable amino protecting group such as benzyl ditrityl. The groups are suitably chosen.

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

Examples of the “group that can be converted to R ₃ ” in R ₁ include, for example, a methanesulfonyloxy group ゃ P-toluenesulfonyloxy group, a benzyloxy group, an alkoxycarbonyl group, a carboxyl group and the like. The methanesulfonyloxy group p-toluenesulfonyloxy group can be converted to a halogen atom or a lower alkoxy group as R ₃ by a nucleophilic substitution reaction. The benzyloxy group can be converted to a hydroxyl group as R _{3 by a} hydrogenolysis reaction or a hydrolysis reaction. The alkoxycarbonyl group can be converted to various hydroxy lower alkyl groups by, for example, hydride reduction using lithium aluminum hydride or a reaction using an organometallic reagent such as methyl lithium. The carboxylic acid group can be converted to a halogen atom as R ₃ by introducing it to an acid or a rosogenide and then treating it with a Wilkinson complex {RhCl [P (C ₆ H ₅ ) ₃ ] ₃ }.

 The compound (VI) is also novel and can be produced, for example, by the methods described in Examples 1 to 9 described below or a method analogous thereto.

 The pyridonecarboxylic acid derivative (I) of the present invention and the intermediate bicycloamine compound (E) thus produced can be isolated and purified according to a conventional method. These compounds can be obtained in the form of salts, free forms or hydrates depending on the conditions of isolation and purification. These compounds are mutually converted depending on the purpose, and are converted into the desired form of the compound of the present invention. I can guide you. The stereoisomers of the compound (I) of the present invention can be separated from each other by a conventional method, for example, fractional crystallization, chromatography, and the like. For an optically active compound, a known optical resolution method is applied. Can be isolated by

 The thus-obtained compound (I) of the present invention and salts thereof are all new compounds, exhibit excellent antibacterial activity, and are valuable as antibacterial agents. The compound (I) of the present invention and salts thereof can be used not only as pharmaceuticals for humans and animals, but also as fish disease drugs, agricultural chemicals, food preservatives and the like.

The ester of the compound (I) of the present invention is a carboxy group of the compound (I) of the present invention. Although it is valuable as a raw material for synthesizing an acid derivative, when the ester itself is easily converted into the compound (I) of the present invention in vivo, it can be used as a prodrug as with the compound (I) of the present invention. In addition, it can be used as an antibacterial agent. Further, the bicycloamine compound (H) of the present invention is useful as a direct synthetic intermediate for the compound (I) of the present invention. BEST MODE FOR CARRYING OUT THE INVENTION

Next, the in vitro and in vivo antibacterial activity of the compound (I) of the present invention will be described with reference to data below. The results are shown in Tables 1 and 2. c The numbers in the table indicate the minimum inhibitory concentrations (MIC: gZml) measured according to Chemotherapy 29 (1), 76 (1981). effect against infections (ED _5;. mgZkg) shows a. The effect (ED; mg / kg) on systemic infections in mice was determined to be 5 x 10 ³ pathogenic bacteria (live bacteria) listed in Tables 1 and 2 per Std-ddy male mouse (body weight: about 20 g). The test compound was suspended in 0.4% carboxymethylcellulose and injected orally 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 determined by the probit method. Calculated.

As a reference compound, enoxacin [11-ethyl-6-fluoro-1,4-dihydro-4-oxo-17- (1-piperazinyl) -18-naphthyridine-13-potassium which is already commercially available as an excellent antibacterial agent Acid) using o Table 1: Antibacterial activity

Ten

 Fifteen

 20

twenty five Continuation of Table 1 Stock Example

 Staphylococcus Staphylococcus aureus 209 JC-1 aureus 50774

20 0.025 0.013

 [0.64]

21 0.006 ≥0.003

 [1.28]

22 0.013 0.006

 [1.25]

25 0.05 0.025

10 [1.78]

 28 0.025 0.05

29 0.05 0.05

31 0.006 0.006

Fifteen

 32 0.003; 0.003

34 0.013 0.013

35 0.006 0.006

20 36 0.013 0.013

37 0.05 0.1 Control 0.39 0.39 Compound [9.89]

twenty five Table 2: Antibacterial activity

As shown in Tables 1 and 2, the compound (I) of the present invention exhibits excellent antibacterial activity both in vitro and in animal experiments, and is particularly excellent against Gram-positive bacteria and Helicobacter pylori. Clear antibacterial activity It is. 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 a low toxicity and is useful as an antibacterial agent against mammals including humans for the 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 the age, body weight, symptoms, administration route, etc., but is generally 5 mg to 5 g once or several times a day. It is recommended that the drug be administered separately. The route of administration may be oral, parenteral or topical.

 The compound (I) of the present invention may be administered to humans or the like as it is, but is usually administered in the form of a preparation prepared together with pharmaceutically acceptable additives. Such preparations include tablets, liquids, capsules, granules, fine granules, powders, syrups, injections, ointments and the like. These preparations can be manufactured using a usual additive according to a conventional method. For example, as an additive for oral use, a carrier which is commonly used in the field of preparations such as starch, mannite, crystalline cellulose, carboxymethylcellulose Ca, water, ethanol and the like and which does not react with the compound (I) of the present invention. Or add diluent material. Examples of additives for injection include those commonly used in the field of injections, such as water, physiological saline, glucose solution, and infusion.

 The above-mentioned liquid preparations and ointments can be used in the treatment and treatment of otolaryngology and ophthalmology. Example

Next, the present invention will be described more specifically with reference to examples. Examples 1 to 9 relate to a method for producing an intermediate bicycloamine compound (I), and Examples 10 to 38 relate to a method for producing a target compound (I). Reference numeral 39 denotes an embodiment relating to production. Example 1

 1 monoamino-3-azabicyclo [3.1.1] heptane:

 [Step A]:

 After washing 1.29 g of 60% sodium hydride twice with n-hexane, the suspension was suspended in 60 ml of ether. Under ice cooling, 5.0 g of getyl malonate dissolved in 5 ml of ether was added dropwise over 10 minutes. The mixture was stirred at room temperature for 30 minutes, then cooled on ice, 5.38 g of benzylchloromethyl ether dissolved in 10 ml of ether was added over 10 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 a crude product of benzyloxymethylmalonate getyl. 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 at room temperature for 2 hours. Saturated aqueous sodium tartrate was added under ice cooling, and the mixture was stirred overnight. The insolubles were filtered off, the filtrate was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: form: ethanol = 20: 1) to give 1.96 g of 2-benzyloxymethyl-1,3-propanediol.

 I R (neat) cm— ': 3380

Ή-NMR (CDC ^ 3) 5: 2.05 (m, 1 H), 2.35 (brs, 2 H), 3.63 (d, 2 H, J = 5.5 Hz), 3.81 (dd, 4 H, J = 5.5, 5.5Hz), 4.52 (s, 2H), 7.25-7.40 (m, 5H) [Step B]:

 While cooling a mixture of 84.8 g of the compound obtained in the above step A and 360 ml of pyridine with ice-salt, 206,3 g of p-toluenesulfonyl chloride was added in three portions and added at the same temperature for 2 hours. Stirred overnight at room temperature. The reaction solution was poured into ice water and extracted with ethyl acetate. After washing with dilute hydrochloric 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) to give 2-benzyloxymethyl-1,3-bis (p-toluenesulfonyloxy). B) 162.3 g of propane was obtained.

IR (neat) cm— ¹ : 1598, 1361

Ή-NMR (CDC ₃ ) δ: 2.33 (m, 1 H), 2.44 (s, 6 H), 3.41 (d, 2 H, J = 6 Hz), 4.04 (m, 4 H), 4.34 (s, 2 H), 7.10-7.40 (m, 9 H), 7.74 (d, 4 H, J = 8Hz)

[Step. ]:

 22.8 g of 60% sodium hydride was washed twice with n-hexane, and then suspended in 350 ml of toluene. Under ice cooling, 91.lg of getyl malonate dissolved in 150 ml of toluene was added dropwise over 25 minutes. After the mixture was stirred at room temperature for 40 minutes, 119.6 g of the compound obtained in the above step B dissolved in 300 ml of toluene 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 methyl malonate were distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform: ethanol = 50: 1) to give 3-benzyloxymethylcyclobutane 1-1,1. 66.8 g of getyl monodicarboxylate was obtained.

 I R (neat) cm— ': 1726, 1263

Ή-NMR (CDC) 5: 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 = 6Hz), 4.17 (q, 2H,

J = 7 Hz), 4.21 (q, 2Η, J = 7 Hz), 4.50 (s, 2H), 7.20

— 7.40 (m, 5 H)

[Step D]:-66.8 g of the compound obtained in the above step C was dissolved in 500 ml of ethyl acetate, 6.68 g of 5% palladium carbon was added, and a theoretical amount of hydrogen was added at 30 to 40 ° C. After removing the catalyst by filtration, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent: form: ethanol = 20: 1) to give 3-hydroxymethylcyclobutane-1,1-dicarboxylate. 45.0 g was obtained.

IR (neat) cm " ¹ : 3452, 1728, 1266

 Ή-NMR (CDC ^ 3) 5: 1.25 (t, 3H, J = 7Hz), 1.27 (t, 3H, J = 7Hz), 1.70 (brs, 1H), 2.30-2.50 (m, 2H), 2.50-2.70 (m, 3 H), 3.62 (d, 2 H,

 J = 5.5 Hz), 4.20 (q, 2H, J = 7Hz), 4.23 (q, 2H,

(J = 7Hz) 48.5g of p-toluenesulfonyl chloride was added in four portions to a mixture of 45.0g of tert-hydroxymethylcyclobutane-1,1-dicarboxylate obtained in the previous section and 350ml of pyridine under ice-cooling. . After stirring at the same temperature for 5.5 hours, room temperature for 13.5 hours, and 30 to 40 ° C for 8 hours, ice water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate, water, diluted hydrochloric acid and saturated saline, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product of getyl 3-p-toluenesulfonyloxymethylcyclobutane-1,1-dicarboxylate. A mixture of the above crude product, 42.2 g of benzylamine, 32.4 g of potassium carbonate and 600 ml of dioxane was refluxed for 4.5 days. Ice water was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with saturated aqueous sodium hydrogen carbonate and then with saturated saline, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: chloroform: ethanol = 20: 1), and 3-benzylaminomethylcyclobutane-1,1-dicarboxylate 32.3 g was obtained.

IR (neat) cm " ¹ : 3324, 2813, 1727, 1263

 Ή-NMR (CDC 3) 5: 1.23 (t, 3H, J = 7Hz), 1.25 (t, 3H, J = 7Hz), 2.15-2.30 (m, 2H), 2.40-2.70

(m, 3 H), 2.67 (d, 2 H, J = 6 Hz), 3.76 (s, 2H), 4.17 (q, 2 H, J = 7 Hz), 4.21 (q, 2 H, J = 7 Hz) , 7.20-7.40 (m, 5 H) [Process E]:

 A mixture of 32.3 g of benzyl 3-ethyl 1,1-dicarboxylate, 120 ml of a 10% aqueous sodium hydroxide solution and 120 ml of tetrahydrofuran obtained in step D of the preceding section was added at room temperature for 13.5 hours, and then Stirred at 50-60 ° C for 6 hours. The mixture was concentrated under reduced pressure, added with 100 ml of water and activated carbon, and filtered. At room temperature, 54.5 ml of 20% hydrochloric acid was added to the filtrate while stirring. After cooling on ice, the crystals were collected by filtration and washed with water and ethanol to obtain 20 g of 3-benzylaminomethylcyclobutane-1,1-dicarboxylic acid.

 Melting point: 224-226. C (decomposition)

IR (KBr) cm- ¹ : 3444, 1632

Ή-NMR (DMSO- d ₆ ) ά: 2.10-2.26 (m, 2 Η), 2.30

-2.45 (m, 2Η), 2.65-2.95 (m, lH), 3.02 (d, 2Η, J = 7Hz), 4.11 (s, 2H), 7.35-7.55 (m, 5H), 9.00 (brs, 2H)

[Step F]:

The compound obtained in preceding step E 20 g of N, mixture carbonyldiimidazole 37g consisting of N- dimethylformamidine de 200ml addition, at room temperature for 13 hours, 5.5 hours at 30- 40 ^e C, 60 - 70 hand Stir 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 saturated saline, 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. 3-benzyl-2-oxo-1-3-azabicyclo [3.1.1] 15.5 g of heptonic acid rubonic acid was obtained.

 Melting point: 127-128 ° C (recrystallized from ethyl acetate)

IR (KB r) cm- ¹ : 2531, 1750, 1732

Ή-NMR (CDC £ ₃ ) δ: 1.85-2.00 (m, 2H), 2.70-

2.84 (m, 1Η), 2.84-2.97 (m, 2Η), 3.44 (d, 2Η, J = 2 Hz), 4.65 (s, 2Η), 7.20-7.45 (m, 5Η)

[Step G]:

The compound obtained in preceding step F 15.5 g, a mixture of Toryechiruamin 9.6g and t-butanol 150ml was heated to 70 ^e C, it was added dropwise Jifuweniruhosuho Riruajido 26 g. 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 purified by silica gel column chromatography (eluent: chloroform: ethanol = 50: 1) to give 3-benzyl-1-t-butoxy. 14.6 g of carbonylamino-3-azabicyclo [3.1.1] heptane-2-one was obtained.

 Melting point: 106-107 ° C (from methylene chloride-diisopropyl ether to JFRHH)

IR (KB r) cm ^-1 : 3402, 1723, 1646

^! H-NMR (CDC ₃ ) 5: 1.45 (s, 9 H), 1.70-1.83 (m, 2H), 2.56 (tt, 1 H, J = 2.5, 7 Hz), 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 the above-mentioned step G, 12 ml of 10% hydrochloric acid and 6 ml of tetrahydrofuran was heated at 50-60 for 3 hours. The mixture was concentrated under reduced pressure, a small amount of water was added to the residue, and the mixture was washed with n-hexane. The aqueous layer was made alkaline with an aqueous solution of sodium hydroxide, 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-13-azabicyclo [3.1.1] heptane-1-one.

IR (neat) cm " ¹ : 3381, 1659, 1495, 1250

, H—NMR (CDC ^ ₃ ) 5: 1.85—2.00 (m, 2 H), 1.90

(s, 2H), 2.10-2.25 (m, 2H), 2.54 (tt, 1H, J = 2.5, 7 Hz), 3.26 (d, 2H, J = 2.5Hz), 4.60 (s, 2H) ), 7.20-7.40 (m, 5 H) [Process I]:

The compound obtained in step H of the previous section 2. 30 ml of a 1.0 molar tetrahydrofuran solution of a borane-tetrahydrofuran complex was added to the mixture. After refluxing for 7 hours, the mixture was concentrated under reduced pressure. 40 ml of ethanol was added to the residue, and the mixture was refluxed for 9 hours. The mixture was concentrated under reduced pressure, ice water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and then with a saturated saline solution, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was distilled with a bulb valve distillation apparatus [Kugelrohr micro distillation apparatus (manufactured by Blichi)] to obtain 1-amino-3-benzyl-3. —Azabicyclo [3.1.1] 1.86 g of heptane was obtained.

 Boiling point: approx. 100 ° C (3 mmHg, Kugelrohr-Miku mouth distillation unit)

IR (neat) cm— ¹ : 3360, 2791, 1603

 Ή-NMR (CDC ^ s) δ 1.51 (b r s, 2H), 1.60— 1.90 (m, 4H), 2.18 (t t, 1 H, J = 3, 6 Hz), 2.65

(s, 2H), 2.69 (d, 2H, J = 3 Hz), 3.67 (s, 2H), 7.15-7.40 (m, 5 H)

[Process J]:

 1.86 g of the compound obtained in step I of the preceding paragraph was dissolved in 20 ml of ethanol, 190 mg of 5% palladium on carbon was added, and a theoretical amount of hydrogen was added. The catalyst was removed by filtration, and the solvent was distilled off under reduced pressure to obtain the desired product l.Og. Example 2

 1-t-butoxycarbonylamino-3-azabicyclo [3.1.1] heptane:

 [Process K]:

Under ice-cooling, diaminocarbonate was added to a solution of 1-amino-3-benzyl-3-azabicik obtained in step I [3.1.1] heptane l.OOg in 10 ml of dichloromethane. — A solution of 1.11 g of t-butyl in 2 ml of dichloromethane was added dropwise, and the mixture was stirred at room temperature for 18 hours. The filtrate was concentrated under reduced pressure to obtain 1.49 g of 3-benzyl-1-toxycarbonylamino-3-azabicyclo [3.1.1] heptane as a crystalline residue.

 Melting point: 86-87 ° C (recrystallized from ethyl acetate)

 I R (KB r) cn 3257, 1703

'H-NMR (CDC ₃ ) δ: 1.40 (s, 9 H), 1.90-2.25 (m, 4 H), 2.25-2.36 (m, 1 H), 2.68 (d, 2 H, J = 3.0 Hz) , 2.84 (s, 2H), 3.65 (s, 2H), 4.55 (brs, 1H), 7.18-7.38 (m, 5H)

[Process J]:

 The same treatment as in Step K of Example 1 was carried out using 1.17 g of the compound obtained in Step K of the preceding section, 120 mg of 5% palladium carbon and 20 ml of ethanol to obtain 585 mg of the desired product.

 Melting point: 151-152 V (recrystallized from ethanol-ethyl acetate)

IR (KB r) cm " ¹ : 3340, 3171, 1702, 1560, 1184

 JH-NMR (CDC s) 5: 1.42 (s, 9 H), 1.81-1.93 (m, 2H), 2.07 (brs, 1 H), 2.10-2.27 (m, 2 H), 2.27-2.38 (m, 1H), 2.94 (d, 2H, J = 2.5Hz), 3.10 (s, 2H), 4.60 (brs, 1H)

 1-Methylamino-3- 3-azabicyclo [3.1.1] Heptane: [Step L]:

10 ml of acetic anhydride was added dropwise to 20 ml of formic acid under ice cooling. 50 minutes later, Step H of Example 1 A solution of 1.99 g of 1-amino-3-benzyl-3-azabicyclo [3.1.1] heptane-2-one obtained in the above in 5 ml of methylene chloride was added, and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform: ethanol = 20: 1) to give 3-benzyl-1-monoformylamino-3-azabicyclo [3.1.1] heptane-1 2 —On 2.11 g was obtained.

 Melting point: 129-130 ° C (reconstituted from ether acetate diisopropyl ether)

IR (KB r) cm " ¹ : 3321, 1691, 1643, 1520, 1496

Ή-NMR (COC £ _s ) δ: 1.75- 1.87 (m, 2H), 2.64 (tt, 1H, J = 2.5, 7 Hz), 3.27 (d, 2H, J = 2.5Hz), 3.37- 3.51 (m, 2H), 4.61 (s, 2 H), 7.18 (brs, 1 H), 7.20-7.40 (m, 5 H), 8.28 (d, 1 H, J = 2Hz)

[Process M]:

 The same treatment as in Step I of Example 1 was carried out using 2.08 g of the compound obtained in the above step L, 30 ml of tetrahydrofuran and 43 ml of a 1.0 molar tetrahydrofuran solution of a borane-tetrahydrofuran complex to give 3-benzyl-1-methylamine 3- 1.76 g of azabicyclo [3.1.1] heptane was obtained.

 Boiling point: about 100. C (4 mmHg, Kugel lower micro distillation apparatus)

 I R (neat) cm— ': 3280, 2793, 1239, 1210

Ή-NMR (CDC £ ₃ ) δ: 1.65-1.85 (m, 4 H), 2.16- 2.27 (m, 1 H), 2.30 (s, 3 H), 2.68 (s, 2 H), 2.69 (d, 2 H, J = 3Hz), 3.67 (s, 2 H), 7.15-7.40 (m, 5 H)

[Step N]: The same treatment as in Step J of Example 1 was carried out using 1.74 g of the compound obtained in Step M of the preceding section, 170 mg of 5% palladium carbon and 20 ml of ethanol to obtain 1.0 g of the desired product. Example

 1-t-butoxycarbonylaminomethyl-3-azabicyclo [3.1.1] heptane:

 [Process S]:

 At room temperature, 4.67 g of carbonyldiimidazole was added to a mixture of 6.42 g of the compound obtained in Step F of Example 1 and 64 ml of ethyl acetate, followed by stirring. 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: form: ethanol = 20: 1) to give 3-benzyl-2-isohexyl 3-azabicyclo [3.1.1] heptane 5.77 g of 1-carboxamide was obtained.

 Melting point: 170-171 ° C (recrystallized from ethyl acetate)

 I R (KB r) cm—]: 3320, 1659, 1628, 1429

'H—NMR (CDC ₃ ) 5: 1.80— 1.90 (m, 2 H), 2.65- 2.75 (m, 1 H), 2.80-2.95 (m, 2H), 3.38 (d, 2 H, J = 2.5 Hz ), 4.64 (s, 2 H), 5.57 (brs, 1 H), 7.20-- 7.40 (m, 5 H), 8.74 (brs, 1 H)

[Process T]:

Using 6.11 g of the compound obtained in the preceding step S, 125 ml of a 1.0 molar tetrahydrofuran solution of a borane-tetrahydrofuran complex and 90 ml of tetrahydrofuran, the same treatment as in step I of Example 1 was carried out to give 1-aminomethyl-3 Benzyl 3-azabicyclo [3.1.1] heptane 4.48 g was obtained. Boiling point: about 130 ° C (3 mmHg, Kugelrohr micro distillation apparatus)

 I R (neat) cm— ': 3375, 3294, 1603, 1211, 1128

 Ή-NMR (CDC 3) o: 1.30 (brs, 2H), 1.49-1.60 (m, 2H), 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 = 3.0Hz) 3.68 (s, 2H, 7.17-7.40 (m, 5H)

[Process U]:

 Treatment with 450 mg of the compound obtained in Step T of the preceding paragraph, 468 mg of di-t-butyl dicarbonate and 7 ml of dichloromethane in the same manner as in Step K of Example 2 to give 3-benzyl-1-t-butoxycarbonyla Minomethyl-3-azabicyclo [3.1.1] 558 mg of heptane was obtained.

IR (neat) cm— ¹ : 3352, 1711

Ή-NMR (CDC 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 = 3.0Hz), 2.98 (d, 2H, J = 6.0Hz), 3.67 (s, 2H), 4.45 (brs, 1H), 7.18-7.38 (m, 5H)

[Process V]:

 The same procedures as in Step J of Example 1 were carried out, using 548 mg of the compound obtained in Step U of the preceding section, 50 mg of 5% palladium carbon and 10 ml of ethanol to obtain 343 mg of the desired product.

Melting point: 99-101 ° C (recrystallized from diisopropyl ether) Example 5

 1-Aminomethyl-1-azabicyclo [3.1.1] heptane: 1-aminomethyl-3-benzylazi-3-azabicyclo [3.1.1] heptane obtained in step T of Example 4 4.07 g, 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) [Process A]:

 Using 104.9 g of getyl fluoromalonate, 72.7 g of potassium-t-butoxide and 92.3 g of methyl ether of benzyl chloride, the reaction was carried out in getyl ether in the same manner as in Step A of Example 1 to give benzyloxyfluoromalonic acid. 116.7 g of getyl were obtained.

Boiling point: 150-153 ° C (1.5 mmHg, Kugelrohr micro distillation apparatus) 'Η- NMR (CDC ^ s) <5: 1.29 (t, 6H, J = 7Hz), 4.08 (d, 2d, J = 24Hz), 4.30 (q, 4H, J = 7Hz), 4.63 (s, 2H), 7.2-7.4 (m, 5H) A mixture consisting of 25.6g lithium borohydride and 500ml tetrahydrofuran It was stirred under. To this, a mixture of 116.7 g of the compound obtained above and 200 ml of tetrahydrofuran was added over 10 minutes. The mixture was stirred at room temperature for 20 minutes and heated under reflux overnight. 90 ml of acetone, 110 ml of cold water and 200 ml of concentrated hydrochloric acid are added little by little while cooling on ice, and the mixture is concentrated to dryness under reduced pressure. The residue is subjected to silica gel column chromatography (eluent. Nord: = 6: subjected to 1), collect the eluate, evaporated and the _c ice water to give an oil addition to, The crystals were collected by filtration to be generated, water, then washed with diisopropyl ether. The crystals were dissolved in chloroform and filtered over anhydrous sodium sulfate. The filtrate was evaporated to dryness under reduced pressure, and a mixture of diisopropyl ether and n-hexane (2: 1) was added to the crystalline residue. Filtration yielded 48.1 g of 2-benzyloxymethyl-2-fluoro-1,3-propanediol.

 Melting point: 86-87 ° C (recrystallized from ethyl ethyl diisopropyl acetate)

IR (KBr) cm- ¹ : 3360

 Ή-NMR (CDC3) 5: 2.05 (brt, 2H, J -6.5Hz),

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]:

 Compound obtained in step A of the previous section 65. lg, p-toluenesulfonyl chloride 1

Using 50 g and 325 ml of pyridine, the same treatment as in step B of Example 1 was performed.

There were obtained 109.3 g of 2-benzyloxymethyl-1,2-fluoro-1,3-bis (p-toluenesulfonyloxy) propane.

 Melting point: 97-98 ° C (Reconstituted from methylene chloride-diisopropyl ether.

IR (KBr) cm— ¹ : 1596, 1371

Ή-NMR (CDC 3) (5: 2.45 (s, 6 H), 3.58 (d, 2 Η, J = 16 Hz), 4.16 (d, 4 Η, J = 18 Hz), 4.45 (s, 2 Η), 7.15 -7.4 (m, 9Η), 7.75 (d, 4Η, J = 7.5 Hz) [Step c]:

 The same treatment as in Step C of Example 1 was carried out using 124.9 g of the compound obtained in Step B of the preceding section, 38.3 g of 60 sodium hydride, 153 g of getyl malonate and 1.3 xylene, to give 3-benzyloxy-3-fluoro. 30.8 g of octyl cyclobutane-1,1-dicarboxylate was obtained.

IR (neat) cm- ¹ : 1734, 1265

Ή-NMR (CDC ₃ ) δ: 1.21, 1.26 (both t, 3Η, J = 7 Hz), 2.8--3.0 (m, 4Η), 3.60 (d, 2Η, J = 22 Hz), 4.13, 4.23 (both q, 2Η, J-7Hz), 4.60 (s, 2Η), 7.25-7.4 (m, 5Η)

[Step D]:

 Using 30.8 g of the compound obtained in Step C of the preceding paragraph, 3.1 g of 5% palladium on carbon and 300 ml of ethyl acetate, the same treatment as in Step D of Example 1 was carried out to obtain 3-fluoro-3-hydroxy. 17.8 g of methylcyclobutane-1,1-dicarboxylate getyl were obtained.

IR (neat) cm— ¹ : 3466, 1729, 1268

'H-NMR (CDC 3) 5: 1.26.1.27 (both t, 3 H, J = 7 Hz), 1.85 (brt, 1 H, J = 6.5 Hz), 2.8-3.0 (m, 4 H), 3.75 (dd, 2H, J = 6.5, 23Hz), 4.22, 4.24 (both q, 2H, J = 7Hz) Using 17.8g of the compound obtained above, 17.8g of p-toluenesulfonyl chloride and 130ml of pyridine The same treatment as in Step D of Example 1 was carried out to obtain 20.2 £ of 3-fluoro-3-p-toluenesulfonyloxymethylcyclobutane-1,1-dicarboxylate. IR (neat) cm— ¹ : 1727, 1598, 1368

 Ή-NMR (CDC ^ 3) (5: 1.25 (t, 6 H, J = 7 Hz), 2.45 (s, 3 H), 2.7-3.0 (m, 4 H), 4.20 (d, 2 H, J = 22Hz), 4.20.4.23 (both q, 2H, J = 7Hz), 7.36.7.81 (both d, H, J = 7.5Hz) Compound obtained above 20.2g, benzylamine 16.lg, potassium carbonate 10 4 g and dioxane 120 ml were treated in the same manner as in Step D of Example 1 to obtain 14.87 g of benzyl, 3-benzylaminomethyl-3-fluorocyclobutane-1,1-dicarboxylate. .

IR (neat) cm— ¹ : 3352, 1732, 1368

 Ή-NMR (CDC ^ s) δ: 1.21.1.26 (both t, 3 H, J = 7 Hz), 2.7-3.0 (m, 4 H), 3.83 (s, 2 H), 4.14, 4.23 (both q , 2 H, J = 7 Hz), 7.2-7.4 (m, 5 H)

[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 treatment as in step E of Example 1 was carried out to give 3-benzylaminomethyl-3- —9.88 g of fluorocyclobutane-1,1-dicarboxylic acid were obtained.

 Melting point: 201-203 ° C

IR (KBr) cm— ¹ : 3416, 2828, 1632

 Ή-NMR (DMSO-de) δ: 2.6-2.9 (m, 4H), 3.46 (d, 2H, J = 23Hz), 4.12 (s, 2H), 7.35-7.55 (m, 5H)

[Step F]: The same treatment as in Step F of Example 1 was carried out using 9.59 g of the compound obtained in Step E of the preceding section, 16.6 g of carbodiimide imabourl and 100 mL of N, N-dimethylformamide to give 3-benzylbenzene. Fluoro-2-oxo-3-azabicyclo [3.1.1] heptane-1 7.42 g of monobasic rubonic acid was obtained.

 Melting point: 167-168 ° C (Reconstituted from ethyl isopropyl ether ether)

HB)

IR (KBr) cm— ¹ : 2575, 1745, 1612

 Ή-NMR (CDC 3) δ: 2.3-2.45 (m, 2H), 2.95-3.15 (m, 2H), 3.47 (d, 2H, J = 2Hz), 4.63 (s, 2H), 7.2- 7.45 (m, 5 H)

[Step G]:

 The same treatment as in Step G of Example 1 was carried out using 7.22 g of the compound obtained in Step F of the preceding section, 11.3 g of diphenylphosphoryl azide, 4.21 g of triethylamine and 72 ml of t-butanol. 6.40 g of 3-benzylamine 1 1-t-butoxycarbonylamino-5-fluoro-3-azabicyclo [3.1.1] heptan-2-one was obtained.

 Melting point: 100-101. C (diisopropyl ether-n-hexane

IR (KBr) cm— ¹ : 3405, 1719, 1660

Ή-NMR (CDC ₃ W: 1.46 (s, 9 H), 2.1-2.25 (m, 2 H), 3.34 (d, 2 H, J = 2 Hz), 3.4-3.6 (m, 2H), 4.60 (s , 2 H), 5.94 (brs, 1 H,), 7.2-7.45 (m, 5 H)

[Step H]:

6.19 g of the compound obtained in step G in the previous section, 12 ml of 10% hydrochloric acid and tetrahydrogen Using 6.2 ml of furan, treated in the same manner as in Step H of Example 1, S-amino-1-3-benzyl-5-fluoro-3-azabicyclo [3.1.1] heptane-2-one 4.17 g was obtained.

IR (neat) cm— ¹ : 3368, 1670

 'Η—band R (CDC) δ: 2.25-2.55 (m, 4 H), 3.35 (d,

2H, J = 2Hz), 4.60 (s, 2 H), 7.2-7.4 (m, 5 H)

[Process I]:

 The same treatment as in Step I of Example 1 was carried out using 4.15 g of the compound obtained in Step H of the preceding paragraph, 60 mL of a 1.0 molar tetrahydrofuran solution of a borane-tetrahydrofuran complex, and 50 mL of tetrahydrofuran to obtain 1-amino-3-benzene. 5-5-fluoro-3-azabicyclo [3.1.1] heptane 3.95 g was obtained.

^{IR (neat) cm '1:} 3366, 1604, 1227

'HNR (CDC ₃ ) δ: 1.9-2.1 (m, 2H), 2.15-2.3 (m, 2H), 2.55 (s, 2H), 2.83 (d, 2H, J = 5Hz), 3.67 ( s, 2H), 7.2-7.35 (m, 5 H)

[Process K]:

 Treatment with 3.95 g of the compound obtained in the above step I, 3.91 g of di-t-butyl dicarbonate and 25 ml of methylene chloride in the same manner as in step K of Example 2 to give 3-benzyl-11-t-butoxycarbonyl 5.14 g of aminotane 5-fluoro-3-azabicyclo [3.1.1] hebutane were obtained.

 Melting point: 108-109 ° C (recrystallized from n-hexane)

IR (KB r) cm " ¹ : 3344, 1704, 1677, 1530

'HNR (CDC ₃ ) δ: 1.40 (s, 9 H), 2.2-2.5 (m, 4H), 2.74 (s, 2H), 2.82 (d, 2H, J = 5Hz), 3.66 (s, 2H), 4.70 (brs, 1H), 7.2-7.4 (m, 5H)

[Process J]:

 The same treatment as in Step J of Example 2 was performed using 5.14 g of the compound obtained in Step K in the preceding paragraph, 0.50 g of palladium on carbon, and 70 mL of ethanol, to give 1-t-butoxycarbonylamino-1-. 3.46 g of fluoro-3-azabicyclo [3.1.1] heptane was obtained.

 Melting point: 193-195 ° C (recrystallized from ethanol-ethyl acetate)

IR (KB r) cm " ¹ : 3339, 3181, 1703, 1556

'Η— NMR (CDC ₃ ) δ: 1.43 (s, 9 H), 2.25-2.45 (m, 4 H), 2.94 (s, 2 H), 3.04 (d, 2 H, J = 4 Hz), 4.75 (brd, 1 H)

(2) A mixture consisting of 1.133 g of the compound obtained in (1) above, 10 ml of 10% hydrochloric acid and 5.0 ml of tetrahydrofuran was heated at 80 ° C. for 2 hours. The solvent was removed under reduced pressure, and ethanol was added to the residue. The generated crystals were collected by filtration, washed with ethanol and then with diisopropyl ether, and dried to obtain 992 mg of the desired product.

 Melting point: 290—295 ° C

IR (KB r) cnr ¹ : 1610, 1553, 1501

 Ή-NMR (DMSO-de) <5: 2.2-2.8 (m, 4 H), 3.3-3.5 (m, 4 H) Example 7

To 1-amino-5-fluoromethyl-3-aza-bicyclo [3.1.1] butane: [Step a]:

 0.38 g of P-toluenesulfonic acid was added at room temperature to a mixture of 27.23 g of pen-erythritol and 150 ml of 2,2-dimethoxypropane, 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 sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was concentrated under reduced pressure, extracted with chloroform, washed with saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude crystals were washed with warm hexane and then recrystallized from ethyl acetate to give 5,5-bis (hydroxymethyl) -1,2,2-dimethyl-1,3-dioxane U .20 g was obtained.

 Melting point: 123-124 ° C

1 R (KB r) cm— ¹ : 3350

 Ή-NMR (CDC ^ 3) (5: 3.75 (s, 8H), 2.40 (brs,

2 H), 1.40 (s, 6 H)

[Step b]:

 The same treatment as in step B of Example 1 was performed using 11.20 g of the compound obtained in step a of the preceding section and p-toluenesulfonyl chloride to give 2,2-dimethyl-5,5-bis (P-toluenesulfonyl). 27.40 g of 3-dioxan was obtained.

 Melting point: 148-151 ° C

IR (KBr) cm " ¹ : 3054, 1598

Ή-NMR (COC £ 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]:

67.0 g of the compound obtained in step b of the preceding paragraph and 67.2 g of getyl malonate were added. The mixture was treated in the same manner as in step C of Example 1 to obtain 2,9.8 g of 2,2-dimethyl-1,3-dioxane-5-spiro-3′-cyclobutane-11 ′, 1 ′ diethyl carboxylate.

IR (neat) cm ^-1 : 1729

 'Η— NMR (CDC s) δ: 4.22 (q, 4 H, J = 7 Hz), 3.75

(s, 4H), 2.43 (s, 4H), 1.38 (s, 6H) 1.25 (t, 6H, J = 7Hz)

[Step d]:

 A mixed solution of 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 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 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 = 1: 4) to give 3,3-bis (hydroxymethyl) cyclopropane-1,1-dicarbonate. 20.0 g of acid ethyl were obtained.

IR (neat) cm— ¹ : 3400, 1729

■ H-NMR (CDC ₃ ) δ: 4.21 (q, 4H, J = 7Hz), 3.73 (d, 4H, J = 6Hz), 2.44 (s, 4H), 2.23 (t, 2H, J = 6 Hz), 1.26 (t, 6H, J = 7Hz)

[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.Og of the compound obtained in step d of the preceding section, 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 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), and 3-t-butyldimethylmethylsiloxymethyl-3-hydroxymethylcyclopropane was purified. There was obtained 21.0 g of ethyl 1-carboxylate.

IR (neat) cm ^-1 : 3525, 1731

Ή-NMR (CDC ₃ ) 5: 4.22 (q, 4H, J = 7Hz), 3.69 (s, 2H), 3.67 (d, 2H, J = 6Hz), 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) Compounds obtained above 21. Og and chloride p —Treatment with 13.9 g of toluenesulfonyl in the same manner as in step B of Example 1 to give 3-t-butyldimethylsiloxymethyl-3 -.- toluenesulfonyloxymethylcyclopropane—26.4 g of ethyl 1,1-dicarboxylate I got

IR (neat) cm " ¹ : 1731, 1598

'H-NMR (CDC ^ ₃ ) δ: 7.72-7.33 (m, 4 Η), 4.25-4.11 (m, 4 Η), 4.03 (s, 2 Η), 3.50 (s, 2 Η), 2.44 (s,

3Η), 2.44-2.28 (m, 4Η), 1.23 (t, 6 Η, J = 7Ηζ),

0.80 (s, 9 Η), -0.02 (s, 6 Η)

[Process:

A mixture comprising 26.4 g of the compound obtained in the step e in the preceding section, 13.4 g of benzylamine, 10.4 g of potassium carbonate and 250 ml of 1,4-dioxane was refluxed for 4 days. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, silica gel column chromatography (eluent hexane: ethyl acetate = 3: 1) Then, 23.2 g of ethyl 3-, 1-dicarboxylate 3-tert-butyldimethylsiloxymethyl-3-benzylaminomethylcyclopropane was obtained.

1 R (neat) cm— ¹ : 1729, 1464

 ! H-NMR (CDC ^ s) δ: 7.33-7.20 (m, 5 Η), 4.25-4.11

(m, 4Η), 3.78 (s, 2Η), 3.56 (s, 2Η), 2.68 (s,

2 mm), 2.46-2.32 (m, 4 mm), 1.53 (brs, 1 mm), 1.28 -1.19 (m, 6 mm), 0.87 (s, 9 mm), 0.04 (s, 6 mm) [Process:

 To 300 ml of a getyl ether solution of 23.15 g of the compound obtained in the above step f was added 08 g of sodium ethoxide under ice cooling, followed by stirring 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), and 3-benzyl-5-t-butylmethyl-dimethyl xymethyl-2-oxo_3 was obtained. —Azabicyclo [3.1.1] 17.3 g of ethyl heptane-1-carboxylate was obtained.

IR (neat) cm " ¹ : 1739, 1667, 1494

'H-NMR (COC £ ₃ ) δ: 7.38-7.22 (m, 5 H), 4.59

(s, 2H), 4.27 (q, 2H, J = 7 Hz), 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 = 7Hz), 0.84 (s, 9H), -0.01 (s, 6H) [Process h]:

7.60 g of the compound obtained in step g of the preceding paragraph, 15 ml of tetrahydrofuran and A mixture consisting of 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), and 3-benzyl-5-hydroxymethyl-2-oxokifu-3-azabicyclo [3. 1.1] Heptane-one ruboonic acid 3.43 g was obtained.

 Melting point: 85-87 ° C

IR (KBr) cm " ¹ : 3476, 1736, 1652

 Ή-NMR (CDC) δ 7.39-7.23 (m, 5 H), 4.60 (s, 2 H), 4.26 (q, 2 H, J = 7 Hz), 3.56 (d, 2 H, J =

6 Hz), 3.18 (s, 2H), 2.34-2.25 (m, 2H), 2.07-1.97 (m, 2H), 1.08 (t, 1H, J = 6Hz), 1.31 (t, 3H) , J =

7 Hz)

[Step i]:

 24.2 g of the compound obtained in the step g in the preceding paragraph and 27.9 g of p-toluenesulfonyl fluoride were mixed with 200 g of molecular 4A, 77.4 g of tetrabutylamyl ammonium fluoride trihydrate 800 ml of a tetrahydrofuran solution of tetrahydrofuran And heated to reflux for 20 hours. The reaction solution was filtered through silica gel, water was added, the mixture was extracted with ethyl acetate, 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 =: 1) to give 3-benzyl-5-fluoromethyl-2-2-azabicyclo [3. 1.1] Heptane-1-ethyl carboxylate (23.2 g) was obtained.

IR (neat) cm— ': 1738, 1666 ^! H-NMR (CDC 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, 2H), 2.45-2.32 (m, 2H), 2.12-2.03 (m, 2Ή), 1.33 (t, 3H, J = 7Ήζ)

[Step j]:

 A mixture comprising a solution of 23.2 g of the compound obtained in step i in the preceding section, 240 ml of 4% sodium hydroxide and 10 ml of tetrahydrofuran was stirred at room temperature for 20 hours. To the reaction mixture was added 100 ml of 10% hydrochloric acid under ice-cooling, and the resulting crystals were collected by filtration, washed with water and dried under reduced pressure to give 3-benzyl-5-fluoromethyl-2-oxo-1-3-azabicyclo [3.1.1] 18.9 g of heptane-l-rubonic acid was obtained.

 Melting point: 141-143 ° C

IR (KBr) cm " ¹ : 1745, 1629

 Ή-NMR (CDC ^ 3) <5: 14.12 (brs, 1H), 7.44 -7.23 (m, 5H), 4.68 (s, 2H), 4.38 (d, 2H, J = 47Hz)

3.37 (s, 2H), 2.77-2.67 (m, 2H), 2.04-1.94 (m, 2H)

[Step k]:

 Using 18.9 g of the compound obtained in Step j of the preceding paragraph and 13.4 g of diphenylphosphoryl azide, the same treatment as in Step G of Example 1 was carried out to give 3-benzyl-1-amine-butoxycarbonylamine 5 —Fluoromethyl-3-azabicyclo [3.1.1] 12.8 g of hebutan-2-one was obtained.

IR (neat) cm ' ¹ : 3324, 1709, 1642

^! H-NMR (CDC ₃ ) δ: 7.39-7.21 (m, 5 H), 6.21 (brs, 1 H), 4.62 (s, 2 H), 4.41 (d, 2 H, J = 47 Hz)

3.22 (s, 2H), 3.18-3.02 (m, 2 H), 1.89-1.77 (m, 2 H) 1.45 (s, 9 H) [Process ^]:

 22.8 g of the compound obtained in the step k in the preceding paragraph was treated in the same manner as in the step H of Example 1 to give 1-amino-3-benzyl-1-5-fluoromethyl-3-azavicic mouth [3.1.1] heptane 1- 15.0 g was obtained.

IR (neat) cm— ¹ : 3390, 1666, 1586

Ή-NMR (CDC 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, 4 H), 1.18 (brs, 2 H)

[Process m]:

 Using 14.3 g of the compound obtained in the preceding step and 150 ml of a 1 molar tetrahydrofuran solution of a borane-tetraborane complex, the same treatment as in Step I of Example 1 was carried out to give 1-amino-13-benzyl-5-fluoromethyl-3. —Azabicyclo [3.1.1] 12.4 g of heptane was obtained.

IR (neat) cm— ¹ : 3370, 1603

Ή-NMR (CDC ₃ ) δ: 7.35-7.20 (m, 5Η), 4.21 (d, 2Η, J = 47Hz), 3.68 (s, 2Η), 2.66 (s, 2H), 2.62 (s, 2Η), 1.94-1,86 (m, 2Η), 1.64-1.53 (m, 2Η)

1.49 (b r s, 2 H)

[Step n]:

The same procedure as in Step J of Example 1 was carried out, using 3.51 g of the compound obtained in Step m of the preceding section and 0.35 g of 5% palladium carbon, to obtain 2.00 g of the desired product. Example 8

 1-Amino-5-methoxymethyl-3-azabicyclo [3.1.1]

 [Step 0]:

 3-benzyl-5-hydroxymethyl-2-oxo-3-azabicyclo [3.1.1] obtained in Step h of Example 7 [11.1.1] heptane-one-potency ethyl rubonate 8.60 g and methyl iodide 1.77 ml The mixture was added to a mixture consisting of 2.80 g of potassium hydroxide and 180 ml of dimethyl sulfoxide, and 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-13-azabicyclo [3.1 .1] 6.00 g of hebutane-one-force rutile acid ethyl ester was obtained.

IR (neat) cm " ¹ : 1738, 1666

 'H-NMR (CDC 3) δ: 7.38-7.22 (m, 5H), 4.59 (s, 2H), 4.26 (q, 2H, J = 6 Hz), 3.30 (s, 5H),

3.18 (s, 2H), 2.35-2.26 (m, 2 H), 2.09-2.00 (m, 2 H)

1.32 (t, 3H, J = 6Hz)

[Process P]:

 6.00 g of the compound 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-13-azabisic mouth [3.1.1] hebutane — 4.85 g of rubonic acid was obtained.

 Melting point: 127-129 ° C

IR (KB r) cm " ¹ : 1740, 1630 ^] H-NMR (CDC ₃ ) δ: 14.23 (brs, 1 H), 7.42

-7.24 (m, 5H), 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)

[Process q]:

 Using 4.85 g of the compound obtained in step p of the preceding paragraph and 4.62 g of diphenylphosphoryl azide, the same treatment as in step G of Example 1 was carried out to give 3-benzyl-11-t-butoxycarbonylamine. 4.96 g of 5-methoxymethyl-2-oxo-3-azabicyclo [3.1.1] heptane-2-one was obtained.

IR (neat) cm— ¹ : 3401, 1714, 1666

^! H-NMR (CDC ^ s) δ: 7.38-7.21 (m, 5H), 6.20 (brs, 1H), 4.60 (s, 2H), 3.42 (s, 2H), 3.29 (s, 3H) , 3.19 (s, 2H), 3.10-2.92 (m, 9 H), 1.87- 1.77 (m, 2H), 1.45 (s, 9 H)

[Step r]:

 4.90 g of the compound obtained in the step q in the preceding paragraph was treated in the same manner as in the step H of Example 1 to give 1-amino-3-benzyl-5-methoxymethyl-2-oxo-13-azabicyclo [3.1.1] heptane One 2-on 3.55 g was obtained.

IR (neat) cm ^-1 : 3389, 1665

^J H-NMR (CDC ^ s) δ: 7.38-7.23 (m, 5Η), 4.61 (s, 2Η), 3.32 (s, 2Η), 3.30 (s, 3Η), 3.18 (s, 2Η), 1.98 (s, 4Η), 1.86 (brs, 2Η)

[Step s]: 3.50 g of the compound obtained in the step r of the preceding paragraph was treated in the same manner as in the step I of Example 1 to give 1-amino-3-benzyl-5-methoxymethyl-3-azabizik mouth [3.1.1] heptane 3.30 g I got

IR (neat) cm— ¹ : 3368

 Ή-NMR (CDC 3) δ: 7.37-7.20 (m, 5 Η), 3.67

(s, 2Η), 3.32 (s, 3Η), 3.22 (s, 2Η)., 2.62 (s, 4Η), 1,92-1.83 (m, 2Η), 1.58-1.48 (m, 2Η) , 1.45 (brs, 2Η) [Process t]:

 3.20 g of the compound obtained in the step s in the preceding section was treated in the same manner as in the step J of Example 1 to obtain 2.00 g of the desired product. Example 9

 1-t-butyldimethylsiloxymethyl-5-t-butoxycarbonylaminomethyl-3-azabicyclo [3.1.1] heptane:

 [Step u]:

3-7.3-benzyl-5-t-butyldimethylsiloxymethyl-2-oxo-3-azabicyclo obtained in step g of Example 7 [3.1.1] 17.3 g of heptane ethyl acetate 17.3 g in 50 ml of ether The mixture was dissolved and added dropwise to a mixture of 3.15 g of lithium aluminum hydride and 450 ml of ether under ice-cooling, followed by stirring at room temperature for 19 hours. The reaction solution was added with 6 ml of water under ice-cooling and stirred for 1 hour. The insoluble material was filtered, and the filtrate was dried over magnesium sulfate. After concentrating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 2: 1) to give 3-benzyl-1-1-1t-dimethyldimethylsiloxymethyl-5-hydroxymethyl- 3-azabicyclo [3.1.1. 1] 10.5 g of heptane was obtained.

IR (neat) cm— ¹ : 3346

^] H-NMR (CDC ^ 3) 5: 7.37-7.18 (m, 5H), 3.69 (s, 2H), 3.42 (s, 2H), 3.36 (s, 2H), 2.68 (s, 2) H), 2.62 (s, 2 H), 1.64-1.45 (m, 4 H), 0.87 (s,

9 H), -0.01 (s, 6 H)

[Step v]:

 To a mixture of 10.5 g of the compound obtained in the above step u, 20 ml of triethylamine and 100 ml of methylene chloride was added 6.8 ml of methanesulfonyl chloride under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate =: 1), and 3-benzyl-11-tert-butyldimethylsiloxymethyl-5-methanesulfonyloxymethyl- 3-azabicyclo [3.1.1] heptane 6.0 g was obtained.

IR (neat) cm— ¹ : 1358

 Ή-NMR (CDC ^ 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, 2H), 2.61 (s, 2H), 1.70-1.56 (m,

4 H), 0.87 (s, 9 H), -0.01 (s, 6 H)

[Process w]:

A mixture of 6.00 g of the compound obtained in step v of the preceding section, 200 ml of dimethylformamide and 3.67 g of sodium azide was heated to 70 ° C. and stirred for 2 hours. After evaporating the solvent under reduced pressure, the reaction solution was poured into water and extracted with ethyl acetate. Lottery The eluate was washed with 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 = 9: 1), and 5-azidomethyl-3-benzyl-1-yl-t-butyldimethylsiloxymethyl-3- Azabicyclo [3.1.1] heptone 4.00 g was obtained.

1 R (neat) cm— ¹ : 2097

 Ή-NMR (CDC ^ 3) δ: 7.37-7.20 (m, 5 H), 3.68 (s, 2H), 3.35 (s, 2H), 3.16 (s, 2H), 2.68 (s,

2 H), 2.61 (s, 2 H), 1.66-1.54 (m, 4 H), 1.87 (s, 9 H), -0.01 (s, 6 H)

[Step x]:

 3.98 g of the compound obtained in the above step w was dissolved in 150 ml of ethanol, 0.4 g of 5% palladium on carbon was added, and a theoretical amount of hydrogen was added under ice cooling. After the catalyst was removed by filtration, the filtrate was concentrated under reduced pressure to give 3.60 g of 5-aminomethyl-3-benzyl-1-t-butyldimethylsiloxymethyl-3-azabicyclo [3.1.1] heptane. Was.

[Step y]:

 Using 3.60 g of the compound obtained in Step X of the preceding paragraph 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-l_t-butyldimethylcyclomethyl There was obtained 4.15 g of 1-t-butoxycarbonylaminoaminomethyl-3-azabicyclo [3.1.1] heptane.

IR (neat) cm— ¹ : 3368, 1708

Ή-NMR (CDC s) 5: 7.35-7.17 (m, 5 H), 4.48 (brs, 1 H), 3.68 (s, 2 H), 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) H), -0.01 (s, 6 H) [Step z]:

 Using 4.04 g of the compound obtained in step y of the preceding section and 0.40 g of 5% palladium carbon, the same treatment as in step J of Example 2 was carried out to obtain 1-t-butyldimethylsiloxymethyl-5-t-butoxycarbonyl. Aminomethyl-3-azabicyclo [3.1.1] heptane 3.24 g was obtained.

IR (neat) cm— ¹ : 3329, 1693

 'Η— NMR (CDC) <5: 4.50 (brs, 1H), 3.32 (s, 2H), 2.99 (d, 2H, J = 6 Hz), 2.88 (s, 4H), 1.65-1.57 (m , 2 H), 1.47-1.33 (m, 2 H), 1.44 (s, 9 H) 0.89 (s, 9 H), 0.02 (s, 6 H) Example 10

 7- (1-Amino-3-azabicyclo [3.1.1] Hepter-3-yl) 1-Cyclopropyl-1 6-fluoro-1,4-dihydro-8-methoxy 4-oxoquinoline-1 3-Capric acid:

1-Amino-3-azabicyclo [3.1.1] heptane obtained in Example 1 Heptane 540 mg, 1-Cyclopropyl-1,6,7-difluoro-1,4-dihydro-l- mouth 8-Methoxy-14-oxoquinoline one 3-force carboxylic monobasic BF ₂ chelate one preparative 1.5 g, 14 hours at room temperature mixed compound consisting Toryechiruamin 1.46ml and Asetonitoriru 10 ml, then stirred for 1.5 hours at 50-60 ° C. 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 the mixture was refluxed for 11 hours. Analysis 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.

 Table 3

Example 20

7— (1-amino-3-azabicyclo [3.1.1] hepter-3-yl) 1-cyclopropyl-1,6,8-difluoro-1,4—dihidro 4 1-oxoquinoline 3-butyric acid:

 154 mg of 1-amino-3-azabicyclo [3.1.1] heptane obtained in Example 1 and 1-cyclopropyl-1,6,7,8-trifluoro-1,4 dihydro-4-1, oxoquinoline-1,3-caprolubone 300 mg of the acid and 165 mg of 1,8-diazabicyclo [5.4.0] —7-indene were added to 6.0 ml of acetonitrile and heated at 110 to 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 from aqueous ammonia to obtain 2.02 mg of the desired product.

 Melting point: 235-237. C (decomposition) Examples 21 to 24

 The reaction and treatment were conducted in substantially the same manner as in Example 20 to obtain the compounds shown in Table 3 below. Table 4

Out

 An example

 No.

 R A X n Melting point (° C)

 21 CC1 H 0 242-245

 A (disassembly)

22 CF NH ₂ 0 245 1 247

 A (disassembly)

 23 N H 0 265 one 268

 F (decomposition)

 24 CH H 1 280 one 283

A (disassembly) Example 25

 7— (1-Amino-5-fluoro-3-azabicyclo [3.1.1]] 3-cyclopropyl-1-6,8-Difluoro-1,4,1-dihydro 4 4-oxoquinoline-1 3 —Capric acid:

 (1) 1-t-butoxycarbonylamino-5-fluoro 3-azabicyclo [3.1.1] obtained in Example 6 (1) heptane 423 mg, 1-cyclopropyl-1,6,7,8-trifluoro Rho 1,4—Dihidro 4-oxoquinoline-3—caprolubonic acid 400 mg, DBU 215 mg and acetonitrile 5. Treatment with Oral in the same manner as in Example 20 to give 7— (1 t-butoxycarbonyl) Amino-5-fluoro-3-azabicyclo [3.1.1] hepatic-3-yl) 1-cyclopropyl-1,6,8-difluoro-1,4, dihydro-4,1-oxoquinoline-1,3-dicarboxylic acid 440 mg was obtained. .

 (2) A mixture consisting of 440 mg of the compound obtained in the above (1), 5. Oml of 10% hydrochloric acid and 2.5 ml of tetrahydrofuran was heated at 80 ° C for 1 hour. After cooling to room temperature, the precipitated crystals were collected by filtration, washed with ethanol diisopropyl ether in that order, and dried to obtain 191 mg of the desired product.

 Melting point: 255-256 ° C (decomposition) (recrystallized from aqueous ammonia)

_T to obtain a compound shown by substantially the same reaction and treatment as in Example 20 in Table 4 below

Table 5

Out

An example

 Να

RAR ₃ n melting point (te)

26 CH H 0 300 1 303

A (disassembly)

27 N H 0 296 one 299

A (disassembly)

28 CF H 1 236 1 238

A (disassembly)

29 N H 1 226 ― 228

 (Disassembly)

30 N CH ₂ F 0 248-250

(Disassembly)

Examples 31 to 35

 The reaction and treatment were conducted in substantially the same manner as in Example 25 to obtain the compounds shown in Table 5 below <Table 6

Example 36

 7- (1-Aminomethyl-3-azabicyclo [3.1.1] Hepter-3-yl) 1-Cyclopropyl-1-6-fluoro-1,4-dihydro-8-methoxy-4-1-oxoquinoline-3-carboxylic acid:

(1) 1-t-butoxycarbonylaminomethyl-3-azabicyclo [3.1.1] heptane obtained in Example 4 700 mg, 1-cyclopropyl-16,7-difluoro-1,4-dihydro-8-methoxy (4) 1-oxoquinoline (1) 3 (1) Rubonic acid (1) BF ( ₂ ) Use l.OOg and acetonitrile (10 ml) And treated in the same manner as in Example 10 to give 7- (1-t-butoxycarbonylaminomethyl-3-azabicyclo [3.1.1] hept-3-yl) -11-cyclopropyl-16-fluoro-1, · 1.332 g of 4-dihydro-4-oxoquinoline-13-carboxylic acid was obtained.

 Melting point: 237-238. C (recrystallized from black form-ethanol)

(2) The same treatment as in Example 25 (2) was carried out using 1.255 g of the compound obtained in the above (1), 12 ml of 10% hydrochloric acid and 12 ml of tetrahydrofuran to obtain 869 mg of the desired product.

 Melting point: 219-221 ° C (decomposition) (recrystallized from aqueous ammonia) Examples 37 and 38

 Reaction and treatment were conducted in the same manner as in Example 36 to obtain the compounds shown in Table 6 below.

 Table 7

Out

 An example

 Να

ARR ₃ n melting point (.C)

37 C0CH ₂ CH (CH ₃ )-H-1 200 to 202

38 C0CH ₃ CH ₂ 0H 1 245 to 247

 A (disassembly)

Example 39: Tablet manufacturing method

250 g of the compound of Example 11 or 20 54 g corn starch

Carboxymethylcellulose C 40 g

50 g microcrystalline cellulose

Magnesium stearate 6 g

 The above components were mixed with ethanol, granulated by a conventional method, and tableted to obtain 2,000 tablets weighing 200 mg. Industrial applicability

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

Claims

Claims General formula (I)

[Wherein, R is a lower alkyl group, a halogeno lower alkyl group, a lower alkenyl group, a halogeno lower alkenyl group, a cycloalkyl group, a halogenocycloalkyl group, a phenyl group which may have a substituent, Represents a heterocyclic group which may have a substituent,

G represents C-E or a nitrogen atom, wherein E represents a hydrogen atom or, together with R, forms a bridge represented by -S—CH (CH ₃ ) —,

A represents C—Z or a nitrogen atom, where Z is a hydrogen atom, a halogen atom, a lower alkoxy group, a halogeno lower alkoxy group, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy lower alkyl group, a lower alkenyl Go, means lower alkynyl or cyano, or, together with R, forms a bridge represented by one 0—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 lower alkyl group;

 Y represents a hydrogen atom or a halogen atom,

R and R ₂ are the same or different and represent a hydrogen atom, a lower alkyl group or an amino protecting group,

R ₃ represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a lower alkoxy lower alkyl group, a halogeno lower alkyl group or a hydroxy lower alkyl group;

 n means an integer of 0 or 1)

A pyridonecarboxylic acid derivative represented by the formula:, 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. 3. The pyridonecarboxylic acid derivative, ester and salt thereof according to claim 2, wherein X is a hydrogen atom, a lower alkyl group or an amino group. 3. The pyridonecarboxylic acid derivative according to claim 2, wherein Y is a fluorine atom, its ester and its salt. 3. 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. R ₃ is a hydrogen atom, a halogen atom, a lower alkoxy lower alkyl group or 3. The pyridone carboxylic acid derivative according to claim 2, wherein is a halogeno lower alkyl group, its ester and its salt.

8. A pyridonecarboxylic acid derivative according to claim 2, wherein A is a nitrogen atom or C—Z, wherein Z is a hydrogen atom, a halogen atom, a lower alkoxy group or a halogeno lower alkoxy group. Esters and their salts.

9. R is cyclopropyl, 2-fluorocyclopropyl or 2,4 difluorophenyl, X is hydrogen, methyl or amino, Y is fluorine, R, 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, A is a nitrogen atom or C—Z, where Z The pyridonecarboxylic acid derivative according to any one of claims 2 to 8, wherein is a hydrogen atom, a fluorine atom, a chlorine atom, a methoxy group or a difluoromethoxy group, an ester thereof, and a salt thereof.

10. The following general formula (I)

[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, R ₃ represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a lower alkoxy lower alkyl group, a halogeno lower alkyl group or a hydroxy lower alkyl group, and n represents an integer of 0 or 1 ]

 And a salt thereof.

11. R 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 removed by hydrolysis, and R ₃ is a hydrogen atom, a halogen atom, a lower alkoxy lower alkyl group or a halogeno group. 11. The bicycloamine compound and an acid addition salt thereof according to claim 10, which is a lower alkyl group.

12. R and R ₂ are the same or different and each is a hydrogen atom, a methyl group or an amino-protecting t-butoxycarbonyl group or a benzyloxycarbonyl group, and R ₃ is a hydrogen atom, a fluorine atom, 12. The bicycloamine compound and an acid addition salt thereof according to claim 10 or 11, which is a methoxymethyl group or a fluoromethyl group.

13. Use of the compound (I) of claim 10 or a salt thereof as an intermediate for producing a pyridonecarboxylic acid derivative, an ester or a salt thereof according to claim 1.

14. An antibacterial agent comprising the pyridonecarboxylic acid derivative according to claim 1, an ester thereof, or a physiologically acceptable salt thereof as an active ingredient.

15. The antibacterial agent according to claim 14, which is used for controlling Helicobacter pylori.

16. The antibacterial agent _{c according} to claim 14, which is used for controlling gram-positive bacteria.

17. A pharmaceutical composition comprising the pyridonecarboxylic acid derivative according to claim 1, an ester thereof, or a physiologically acceptable salt thereof, and a pharmaceutically acceptable additive.

18. A method for treating a bacterial disease in a mammal, which comprises administering the pyridonecarboxylic acid derivative, an ester thereof, or a physiologically acceptable salt thereof according to claim 1 to the mammal. .

19. Use of a pyridonecarboxylic acid derivative, an ester thereof, or a physiologically acceptable salt thereof according to claim 1 in the treatment of a bacterial disease in a mammal.

20. Use of the pyridonecarboxylic acid derivative according to claim 1 or an ester or a physiologically acceptable salt thereof for the manufacture of a medicament.

21. (a) The following general formula

[Wherein, L represents a removable group, and R, G, A, X and Y are The carboxyl group and the oxo group may form a boron chelate bond between these groups,

 A compound represented by the formula, its ester or its salt and the following general formula

^R 1

No N- (CH ² ) _n

^R2

(Wherein, R,, R ₂ , R ₃ and n have the meaning described in claim I)

 Reacting with a bicycloamine compound represented by the formula, and if a boron chelate moiety is present in the product, hydrolyze it; or

Wherein U represents a group which can be converted to a carboxyl group by hydrolysis, and R, G, A, X, Y, Ri, R ₂ , R ₃ and n have the meanings described in claim 1 Have)

The ability to hydrolyze the compound represented by and convert the substituent U to a carboxyl group, or (C) The following general formula

[In the formula, L ′ represents a removable group, R ₄ represents a lower alkyl group, an alkyl group or a benzyl group, and R, G, A, X, Y, Ri, R ₂ , R ₃ and n has the meaning of claims 1), and subjecting the compound to a ring-closing reaction; and

 (d) if an ester residue and a Z or amino protecting group are present in the resulting compound, if necessary, remove it; and, if necessary,

(e) When free form is obtained, convert to salt, and when salt is obtained, convert to free form

 2. The method for producing a pyridone-potassium ruponic acid derivative, an ester or a salt thereof according to claim 1, characterized in that:

22. (a) The following general formula

Wherein R ₃ ′ is the same as R ₃ described in claim 1, or is a group convertible to R ₃ , R ₅ is an amino protecting group, Converting R,, R ₂ and n are converts the amino-protecting group R ₅ of the compound represented by having the meanings described claim 1, wherein the desorbed hydrogen atom, and R ₃ 'is a R ₃ If it is a possible group, convert R ₃ 'to R ₃ , and

(b) When R, and Z or R ₂ in the obtained compound are amino protecting groups, if necessary, they are removed, and if necessary,

(c) When a free form is obtained, it is converted to a salt, and when a salt is obtained, it is converted to a free form.

11. The method for producing a bicycloamine compound or a salt thereof according to claim 10, wherein: