JP2807277B2 - Spiro compounds - Google Patents

Description

The present invention relates to an antibacterial spiro compound useful as a medicament, an animal drug, a marine medicine, and a preservative, and further relates to an antibacterial agent containing this compound as an active ingredient.

<Prior Art> Various derivatives have been known as synthetic antibacterial compounds to date. However, it is known that some of those exhibiting high antibacterial activity often have poor (low) oral absorbability.

The present inventors have enthusiastically searched for a quinolone derivative having high antibacterial activity and also having excellent oral absorbability, and completed the present invention.

<Constitution of the Invention> The present invention relates to a compound of the general formula I (Wherein a represents 0 or 1, b represents an integer from 2 to 5, c represents 0 or 1, d represents an integer from 0 to 2. Z represents CHR ¹ , NR ² , C = NOR ³ , oxygen atom,
Or a sulfur atom, wherein R ¹ is a hydrogen atom, an amino group, a monoalkylamino group having 1 to 6 carbon atoms, a dialkylamino group having 1 to 6 carbon atoms independently, a hydroxyl group,
Represents an alkoxyl group having 1 to 6 carbon atoms or a hydroxyalkyl group having 1 to 6 carbon atoms, wherein R ² is a hydrogen atom,
6 alkyl group, hydroxyalkyl group having 1 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, a formyl group or an alkylcarbonyl group having 2 to 7 carbon atoms represents, R ³
Represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
Q is the formula II (Wherein R ⁴ is an alkyl group having 1 to 6 carbon atoms, 2 to 6 carbon atoms)
An alkenyl group, a halogenoalkyl group having 1 to 6 carbon atoms,
A cyclic alkyl group having 3 to 6 carbon atoms (excluding 1,2-cis-2-halogenocyclopropyl) which may have a substituent, an aryl group which may have a substituent, and a substituent A heteroaryl group, an alkoxyl group having 1 to 6 carbon atoms or an alkylamino group having 1 to 6 carbon atoms, and R ⁵ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. R ⁶ represents a hydrogen atom, an amino group which may have a substituent, a hydroxyl group, an alkoxyl group having 1 to 6 carbon atoms or a halogen atom, and A represents a nitrogen atom or R ⁷ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms,
It means a halogen atom, an alkoxyl group having 1 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms or a cyano group. R ⁴ may form a cyclic structure with R ⁵ and / or R ⁷ , and this ring may contain an oxygen atom, a nitrogen atom, a sulfur atom, and may further have an alkyl group having 1 to 6 carbon atoms or a halogeno group. It may be substituted with an alkyl group or the like.
X represents a halogen atom; Y is a hydrogen atom;
6, an alkyl group having 6 carbon atoms, an alkoxyalkyl group having 1 to 6 carbon atoms, a phenylalkyl group having an alkyl chain having 1 to 6 carbon atoms,
Dihalogenoboron group, phenyl group, acetoxymethyl group, pivaloyloxymethyl group, ethoxycarbonyloxy group, choline group, dimethylaminoethyl group, 5-indanyl group, phthalidinyl group, 5-substituted-2-oxo-1,
It means a 3-dioxol-4-ylmethyl group or a 3-acetoxy-2-oxobutyl group. Relates spiro compounds and salts thereof represented by meaning) a partial structure represented by), also in the general formula I, a is 1, b is 2, c is 0, d is 1, Z is CH (NH ₂ And a salt thereof, wherein a is 1, b is 3, c is 0, d is 1 and Z is CH (NH ₂ ). Further, in the general formula I, a spiro compound wherein a is 1, b is 2, c is 0, d is 2 and Z is NH, and a compound of the general formula I consisting of a pure optical isomer, -(7-amino-5-azaspiro [2,4] heptane-5-yl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 7- (7-amino-5-azaspiro [2,4] heptane-5-yl) -8-chloro-
1-cyclopropyl-6-fluoro-1,4-dihydro-
4-oxoquinoline-3-carboxylic acid, 7- (7-amino-5-azaspiro [2,4] heptane-5-yl) -1
-Cyclopropyl-6-fluoro-1,4-dihydro-4
-Oxoquinoline-3-carboxylic acid, 7- (7-amino-5-azaspiro [2,4] heptane-5-yl) -6
Fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 7-
(7-Amino-5-azaspiro [2,4] heptane-5
Yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 10- (7-amino-5-azaspiro [2,4] heptane- 5-yl) -9-fluoro-2,3-dihydro-3
-(S) -methyl-7-oxo-7H-pyrido [1,2,3-d
e] [1,4] benzoxazine-6-carboxylic acid, 1-cyclopropyl-7- (4,7-diazaspiro [2,5] octan-7-yl) -6-fluoro-1,4-dihydro- 4-
Oxoquinoline-3-carboxylic acid, 7- (7-amino-
5-azaspiro [2,4] heptane-5-yl) -1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 7- (7
-Hydroxy-5-azaspiro [2,4] heptane-5
Yl) -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 7- (7-amino-5-azaspiro [2,4] heptane-5 -Yl) -1- (2-methyl-2-propyl)
-6-Fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 7- (7-hydroxyimino-5-azaspiro [2,4] heptane-5-yl)-
8-chloro-1-cyclopropyl-6-fluoro-1,4
-Dihydro-4-oxoquinoline-3-carboxylic acid, 1
-Cyclopropyl-6,8-difluoro-7- (8-hydroxymethyl-6-azaspiro [3,4] octane-6
Yl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 1-cyclopropyl-6,8-difluoro-7
-(4-hydroxymethyl-2-azaspiro [4,4] nonan-2-yl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 1-cyclopropyl-6,8-difluoro-7 -(4-hydroxymethyl-2-azaspiro [4,5] decan-2-yl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 7- (8-amino-6-
Azaspiro [3,4] octan-6-yl) -1-cyclopropyl-6,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 10- (8-amino-6
Azaspiro [3,4] octan-6-yl) -9-fluoro-2,3-dihydro-3- (S) -methyl-7-oxo-7H-pyrido [1,2,3-de] [1, 4] Benzoxazine-
6-carboxylic acid or 7- (4-amino-2-azaspiro [4,4] nonan-2-yl) -1-cyclopropyl-6,8-difluoro-4-oxo-1,4-dihydroquinoline- The present invention relates to 3-carboxylic acid, and further relates to an antibacterial agent containing the compound of the general formula I as an active ingredient.

The feature of the compound of the present invention is that it is a cyclic amine compound having a spiro ring, and that the “7-position equivalent” of the quinolone derivative is bonded thereto. The “equivalent position 7” of the quinolone derivative means the 7-position of 4-oxoquinoline-3-carboxylic acid or 4-oxo-1,8-naphthyridine-3-carboxylic acid having various substituents, or 7-position. It means the 10-position of oxopyrido [1,2,3-de] [1,4] -benzoxazine-6-carboxylic acid, the 8-position of benzo- [ij] quinolidine-2-carboxylic acid, and the like.

The size of the spiro ring is in the range of 3 to 6 membered rings, and 3 and 4 membered rings are particularly preferred.

The ring size of the cyclic amine excluding the spiro ring is 4
An 8- to 8-membered ring, particularly a 5- or 6-membered ring, is preferred. This cyclic amine is bonded to the “quinolone equivalent” via a nitrogen atom.

The cyclic amine may further have a hetero atom such as an oxygen atom, a sulfur atom or a nitrogen atom in the ring, and among them, a nitrogen atom is particularly preferable. This nitrogen atom is substituted with an alkyl group having 1 to 6 carbon atoms, a hydroxyalkyl group having 1 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, a formyl group, an alkylcarbonyl group having 2 to 7 carbon atoms, or the like. You may.

The following can be exemplified as the structure of the cyclic amine having a spiro ring. That is, 5-azaspiro [2,4] heptane, 6-azaspiro [3,4] octane,
-Azaspiro [4,4] nonane, 2-azaspiro [4,5] decane, 5-azaspiro [2,5] octane, 6-azaspiro [2,5] octane, 6-azaspiro [3,5] nonane, 7
-Azaspiro [3,5] nonane, 7-azaspiro [4,5] decane, 8-azaspiro [4,5] decane, 2-azaspiro [5,5] undecane, 3-azaspiro [5,5] undecane, 4 , 7-Diazaspiro [2,5] octane, 5,8-diazaspiro [3,5] nonane, 6,9-diazaspiro [4,5] decane, 7,10-diazaspiro- [5,5] undecane, 7- Aza-4-oxaspiro- [2,5] -octane, 8-aza-5-oxaspiro [3,5] -nonane, 9-aza-6
Oxaspiro [4,5] decane, 7-aza-4-thiaspiro [2,5] octane, 8-aza-5-thiaspiro [3,5]
Nonane, 9-aza-6-thiaspiro [4,5] decane, 7
-Aza-4-thiaspiro [2,5] octane-4-oxide, 8-aza-5-thiaspiro- [3,5] nonane-5
Oxide, 9-aza-6-thiaspiro [4,5] decane-
It is a structure such as 6-oxide.

In the case where a hetero atom such as an oxygen atom, a sulfur atom or a nitrogen atom is further present in the ring of the cyclic amine, and particularly when the hetero atom is not present, an amino group and a carbon atom having 1 to 6 carbon atoms are present on the amine ring. A monoalkylamino group, a dialkylamino group having 1 to 6 carbon atoms each independently, an amino group optionally substituted with an alkyl group having 1 to 6 carbon atoms or a hydroxyalkyl group having 1 to 6 carbon atoms. Having an aminoalkyl group having 1 to 6 carbon atoms, a hydroxyl group,
A polar group such as a 6-hydroxyalkyl group, a hydroxyimino group, or an alkoxy group having 1 to 6 carbon atoms may be substituted. Of these, amino groups are preferred.

Substituents on the ring of this spiro-substituted cyclic amine may be protected by a suitable protecting group. The protecting group may be appropriately selected from those generally used, for example, tertiary butoxycarbonyl group, alkoxycarbonyl groups such as 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyl Aralkyloxycarbonyl groups such as oxycarbonyl group and paranitrobenzyloxycarbonyl group; acyl groups such as acetyl group, methoxyacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, formyl group, and benzoyl group; Butyl group, benzyl group, paranitrobenzyl group, paramethoxybenzyl group, alkyl groups such as triphenylmethyl group or aralkyl groups, methoxymethyl group, tertiary butoxymethyl group, tetrahydropyranyl group, 2, Ethers such as a 2,2-trichloroethoxymethyl group, Examples include silyl groups such as a trimethylsilyl group, an isopropyldimethylsilyl group, a tertiary butyldimethylsilyl group, a tribenzylsilyl group, and a tertiary butyldiphenylsilyl group.

When a spiro-substituted cyclic amine has a substituent other than a spiro ring, and the carbon atom to which the substituent is bonded is an asymmetric carbon, the cyclic amine has a stereoisomer. When such a cyclic amine is bonded as a substituent at the "position equivalent to 7" as a mixture of stereoisomers, the resulting spiro compound I may be a mixture of diastereomers. A mixture of diastereomers is a mixture of compounds having different physical constants, and is difficult to apply as a medicine. In such a case, when introducing this cyclic amine, it is necessary to react after separating the stereoisomers.

When the resulting spiro compound I is racemic,
Compound I may be in a racemic form. However, isolating a stereoisomer to an optically active compound may show more advantageous biological activity than the racemic form. For example, 7
In the case of a compound containing a -amino-5-azaspiro [2,4] heptane skeleton, the S-configuration isomer is more advantageous in terms of antibacterial activity in the configuration at the carbon atom to which the amino group is bonded. It turned out to be. That is, 7- (7-amino-
5-azaspiro [2,4] heptane-5-yl) -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7- (7-tert-butoxycarbonylamino-5) which is a synthetic intermediate of the isomer having the stronger antibacterial activity
-Azaspiro [2,4] heptane-5-yl) -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid by X-ray crystallography. The absolute configuration at the asymmetric carbon at the base of the amino group was found to be the S configuration.

The cyclic amine substituted with a spiro ring can be synthesized by the following method.

For example, in the case of 7-amino-5-azaspiro [2,4] heptane, 1,2-dibromoethane is first reacted with ethyl acetoacetate in the presence of a base to obtain ethyl 1-acetyl-1-cyclopropanecarboxylate. Subsequently, the acetyl group of this product was brominated with bromine to give 1-bromoacetyl-1.
Leads to ethyl cyclopropanecarboxylate. This is then reacted with benzylamine to close the ring and convert to 5-benzyl-4,7-dioxo-5-azaspiro [2,4] heptane. When this is reacted with hydroxylamine hydrochloride, the ketone at the 7-position becomes an oxime to give 5-benzyl-7- (hydroxyimino) -4-oxo-5-azaspiro- [2,4] heptane. This oxime compound is reduced with lithium aluminum hydride to convert it into an aminopyrrolidine compound having a spiro ring, 7-amino-5-benzyl-5-azaspiro [2,4] heptane. When the benzyl group is removed by ordinary catalytic hydrogenation or the like, this compound is racemic 7-amino-5-azaspiro [2,
4] Heptane. In addition, 2- (tert-butoxycarbonylamino) -2-phenylacetonitrile (hereinafter, referred to as “2- (tert-butoxycarbonylamino) -2-phenylacetonitrile”)
After protecting the amino group with BOC-ON), the benzyl group is removed to give 7-tert-butoxycarbonylamino-.
It becomes 5-azaspiro [2,4] heptane.

An optically active form of 7-amino-5-azaspiro [2,4] heptane can be obtained as follows. 7-amino-
5-benzyl-5-azaspiro [2,4] heptane is reacted with (R) -Np-toluenesulfonylproline acid chloride to give 7-[(R) -Np-toluenesulfonylprolyl] amino Leads to -5-benzyl-5-azaspiro- [2,4] heptane. When this is reacted with benzyl chlorocarbonate, 7-[(R) -N-p-toluenesulfonylprolyl] amino-5-benzyloxycarbonyl-5-azaspiro [2,4] heptane is obtained. This can be separated into each optically active substance by high performance liquid chromatography (hereinafter abbreviated as HPLC). After isolating the optically active form, each was treated with 2N sodium hydroxide to remove the proline portion and the benzyloxycarbonyl group, and to obtain the optically active form of 7-amino-5-azaspiro [2,4].
Converted to heptane.

In addition, ethyl 1-bromoacetyl-1-cyclopropanecarboxylate has an optically active 1
-In a compound closed by reacting phenethylamine,
It has been found that separation of optical isomers can be easily carried out in a later step.

That is, R-(+)-1-phenylethylamine is reacted with ethyl 1-bromoacetyl-1-cyclopropanecarboxylate to give 5- [1- (R) -phenylethyl].
-4,7-Dioxo-5-azaspiro [2,4] heptane. This compound is reacted with hydroxylamine hydrochloride to convert the carbonyl group at the 4-position into an oxime. 5- [1- (R) -phenylethyl]-thus obtained
7-Hydroxyimino-4-oxo-5-azaspiro [2,4] heptane is catalytically reduced to convert a hydroxyimino group to an amino group, and 7-amino-4-oxo-5- [1
-(R) -phenylethyl] -5-azaspiro [2,4]
-Heptane. This compound is a mixture of two diastereomers since the carbon atom at the 7-position is an asymmetric carbon and the (R) -phenylethyl group is present at the 5-position. It was found that this mixture could be separated by silica gel column chromatography, and the resolution of the optically active substance was
HPLC need not be used. In addition, if various crystalline acid addition salts of this compound are synthesized, they can be separated by fractional recrystallization.

This 7-amino-4-oxo-5- [1- (R) -phenylethyl] -5-azaspiro [2,4] heptane is reduced with a metal hydride such as lithium aluminum hydride to give 7-amino-5- [1 -(R) -phenylethyl] -5-azaspiro [2,4] heptane. Then, the amino group is converted to a tertiary butoxycarbonylamino group by BOC-ON, and the phenylethyl group is removed by catalytic reduction, and then the optically active 7-tert-butoxycarbonylamino-5-azaspiro [2 , 4] heptane is obtained.

Here, an example using R-(+)-1-phenylethylamine has been described, but it may be similarly performed with (S) -phenylethylamine. In addition, it is considered that the method can be performed with optically active 1-phenylpropylamine, 1-phenylbutylamine, and the like.

Also, 5- [1- (R) -phenylethyl] -4,7-
Dioxo-5-azaspiro [2,4] heptane can also be synthesized by the following method. That is, after hydrolyzing the ester of ethyl 1-acetyl-1-cyclopropanecarboxylate to form a carboxylic acid, N- [1- (R ) -Phenylethyl] -1-acetyl-1-cyclopropanecarboxamide. This compound converts the carbonyl group of the methyl ketone moiety to a ketal to form N- [1- (R)
-Phenylethyl] -1- (1,1-ethylenedioxyethyl) -1-cyclopropanecarboxamide. This is followed by halogenation of the methyl group adjacent to the ketal, for example, N- [1- (R) -phenylethyl] -1- (2-
Bromo-1,1-ethylenedioxyethyl) -1-cyclopropanecarboxamide. When this halomethyl compound is treated under basic conditions, the pyrrolidinedione having a spiro ring and a ketal, 4,7-dioxo-5- [1
-(R) -phenylethyl] -5-azaspiro [2,4]
Heptane-7-ethylene acetal is obtained. This is converted to 4,7-dioxo-5- [1- (R) -phenylethyl] -5-azaspiro [2,4] heptane by removing the ketal under acidic conditions. Thereafter, the conversion may be performed in the same manner as described above.

Next, a piperazine compound having a spiro ring will be described. For example, in the synthesis of 1,4-diazaspiro [2,5] octane, first, cyclopropane-1,1-diamide is reacted with bromine and a base to obtain cyclopropane-1,1-dibromoamide. Treatment of this with alkoxide converts it to spirohydantoin, ie, 4,6-diazaspiro [2,4] heptane-5,7-dione. This is treated with alkali to give 1-aminocyclopropanecarboxylic acid. The amino group was protected with a tert-butoxycarbonyl group to give 1- (tert-butoxycarbonylamino) -1-cyclopropanecarboxylic acid, and then glycine ethyl ester was condensed in the presence of dicyclohexylcarbodiimide to give ethyl (1 Tertiary butoxycarbonylamino-1
-Cyclopropylcarbonylamino) acetate. When heated after removing the protecting group from the amino group, the ring closed and the diketopiperazine having a spiro ring,
That is, it becomes 4,7-diazaspiro [2,5] octane-5,8-dione. Reduction of this with lithium aluminum hydride gives 4,7-diazaspiro [2,5] octane.

The cyclic amine derivative having a spiro ring can also be synthesized by the following method. Condensation of the cycloalkyl ketone and the malonic diester in the presence of titanium tetrachloride gives the cycloalkylidene malonic diester. When this compound is reacted with nitromethane in the presence of chloride, (1-nitromethyl-1-cycloalkyl) malonic acid diester is obtained. When this compound is reductively closed, a pyrrolidonecarboxylic acid having a spiro ring, for example, when the spiro ring is a four-membered ring, 7-oxo-6-azaspiro [3,4] octane-8-carboxylic acid ester is obtained. Can be This reductive ring closure reaction is conveniently carried out by catalytic reduction in the presence of a metal catalyst, but can also be carried out by other chemical reduction reactions.

Next, after hydrolyzing this carboxylic acid ester to convert it to a free carboxylic acid, a Curtius reaction is carried out in tertiary butanol to obtain pyrrolidone in which the carboxylic acid moiety has been converted to a tertiary butoxycarbonylamino group. be able to. After removing this tertiary butoxycarbonyl group,
Reduction with a metal hydride such as lithium aluminum hydride gives a cyclic amine substituted with an amino group and a spiro ring, in this case pyrrolidine.

On the other hand, if the above pyrrolidone carboxylic acid is reduced with a metal hydride, it can be converted to a cyclic amine having a spiro ring substituted with a hydroxymethyl group.

Examples of the quinolone derivative to be bonded to a cyclic amine having a spiro ring include bicyclic 1,4-dihydro-4-oxoquinoline-3-carboxylic acids and 1,4-dihydro-4-carboxylic acid.
Tricyclic 2,3-dihydro-7-oxo-7H-pyrido [1,2,3] such as oxo-1,8-naphthyridine-3-carboxylic acid
-De] [1,4] benzoxazine-6-carboxylic acids,
2,3-dihydro-7-oxo-7H-pyrido [1,2,3-de]
[1,4] benzothiazine-6-carboxylic acids, 6,7-dihydro-1,7-dioxo-1H, 5H-benzo [ij] quinolidine-2-carboxylic acids, 6,7-dihydrobenzo [ij] quinolidine- 2-carboxylic acids and the like, and tetracyclic 9,1-epoxymethano-5H-thiazolo- [3,2-a] quinoline-3
-Carboxylic acids and the like. These partial structures are shown below.

Here, in the case of 1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, the 1-position is various substituents, for example, Lower alkyl groups such as ethyl group, isopropyl group and tertiary butyl group, halogenoalkyl groups such as 2-fluoroethyl group, lower alkenyl groups such as vinyl group and isopropenyl group, cyclopropyl group, cis-2 Cyclic alkyl groups which may have a substituent such as -methylcyclopropyl group and 2-gem-dihalogenocyclopropyl group (1,
Excludes 2-cis-2-halogenocyclopropyl. ), 4
-Fluorophenyl group, 2,4-difluorophenyl group,
Aryl or heteroaryl groups which may have a substituent, such as a 2-fluoro-4-pyridyl group, alkoxy groups such as a methoxy group and an ethoxy group, and alkylamino groups such as a methylamino group and an ethylamino group. Groups are good. Among them, ethyl group, 2-fluoroethyl group, vinyl group, cyclopropyl group, cis-2-methylcyclopropyl group, 4-fluorophenyl group, 2,4-difluorophenyl group, 2-fluoro-4-pyridyl Groups, methoxy groups, methylamino groups and the like are preferred.

The 2-position is preferably a hydrogen atom or an alkyl group such as a methyl group, an ethyl group or a propyl group.

Examples of the substituent at the 5-position include a hydrogen atom and an amino group, and a monoalkylamino group having 1 to 6 carbon atoms such as a methylamino group, an ethylamino group, an isopropylamino group, a dimethylamino group, and a diethylamino group. A dialkylamino group having 1 to 6 carbon atoms independently, a hydroxyl group,
A halogenoalkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms such as a methoxy group and an ethoxy group, a halogen atom and the like are preferable.

The 6-position is preferably substituted with a halogen atom, particularly a fluorine atom or a chlorine atom.

In the case of a quinoline derivative, a substituent may not be introduced at the 8-position, but a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms Or a cyano group or the like may be substituted. In this case, a chlorine atom, a fluorine atom, a methyl group or a methoxy group is particularly preferable.

The quinolone skeleton is not only bicyclic, but also mainly composed of a quinoline skeleton.
Alternatively, a tricyclic or tetracyclic cyclic structure may be formed between the 8-position and the 2-position. The size of the ring formed in these cases is preferably in the range of a 4 to 7-membered ring, and a 5- or 6-membered ring is particularly preferred. The ring formed here is a nitrogen atom,
It may contain an oxygen atom, a sulfur atom and the like. In addition, it may contain not only a single bond but also a double bond, and may be aromatized. This ring may be further substituted with an alkyl group having 1 to 6 carbon atoms or a halogenoalkyl group.

For tricyclic quinolone derivatives, for example, 2,3-dihydro-7-oxo-7H-pyrido [1,2,3-de] [1,4]-
In benzoxazine-6-carboxylic acid, the 3-position may be particularly substituted with an alkyl group, and in this case, it is preferable that the benzoxazine-6-carboxylic acid is substituted with S-coordination. The ninth position is preferably substituted with a halogen atom, particularly a fluorine atom or a chlorine atom. The status of these substituents is that of the other tricyclic quinolone skeleton 2,3-
Dihydro-7-oxo-7H-pyrido [1,2,3-de] [1,
4] benzothiazine-6-carboxylic acid, 6,7-dihydro-
1,7-dioxo-1H, 5H-benzo [ij] quinolidine-2-
The same can be said for carboxylic acids. Also, 2,3-
Dihydro-7-oxo-7H-pyrido [3,2,1-ij] -1,
In 3,4-benzoxadiazine-6-carboxylic acid, the 9-position is preferably substituted with a halogen atom, especially a fluorine atom or a chlorine atom.

Examples of the quinolone derivative to be bonded to a cyclic amine having a spiro ring include 1,4-
Dihydro-4-oxoquinoline-3-carboxylic acid is preferred.

These cyclic amines having a spiro ring include, for example, JP-A-61-1667, JP-A-61-205240, and
The quinolone derivative can be introduced by the methods described in JP-A-60-197686 and EP-A-206283 (for example, 7-chloro-6-fluoro-1-ethyl-1,4-dihydro-3-carboxylic acid, European Patent No.27752; 9,
10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido- [3,2,1-ij] -1,3,4-benzooxadiazine-6-carboxylic acid, JP 1988-1988; 9.1
-Epoxymethano-7,8-difluoro-5-oxo-5H
-Thiazolo- [3,2-a] quinoline-3-carboxylic acid,
JP-A-1-117888; 7,8-difluoro-5-oxo-5H
-Thiazolo- [3,2-a] quinoline-3-carboxylic acid,
JP-A-57-136588; 7-halogeno-6-fluoro-1-
Methyl-4-oxo-4H- [1,3] thiazeto [3,2-a]
Quinoline-3-carboxylic acid, JP-A-63-107990; 9,10
-Difluoro-3-methyl-2,3-dihydro-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-3-carboxylic acid, EP 47005).

 The production method of the compound of the present invention will be described.

(Where a , b , c , d , Z, A, R ⁴ , R ⁵ , R ⁶ , A,
Y, Z and X are as defined above, and X 'represents a halogen atom. That is, when a cyclic amine having a spiro ring is reacted with a 7-halogenoquinolone derivative, a quinolone derivative in which the nitrogen atom in the pyrrolidine ring is bonded to the 7-position of the quinolone is produced.

Starting quinolone derivative, for example, 1-cyclopropyl-
In the 6-fluoro-7-halogeno-1,4-dihydro-4-oxoquinoline-3-carboxylic acid derivative, the halogen atom at the 7-position may be either a chlorine atom or a fluorine atom. These are disclosed in JP-A-61-1667 and JP-A-61-205240.
Can be synthesized by the method described in Japanese Patent Publication No. Further, other quinolone nuclei can be synthesized by a known method.

In the method described in JP-A-61-205240, the intermediate 3-
Although chloro-2,4,5-trifluorobenzoic acid is synthesized by a 10-step reaction, the present inventor has proposed that 3-amino-2,4,
A method for synthesizing 5-trifluorobenzoic acid in one step was developed and found to be applicable to other benzoic acid derivatives.

Furthermore, the present inventor has also succeeded in developing a simple and large-scale synthesis route of 2,4,5-trifluoro-3-methylbenzoic acid. That is, the following route starting from tetrafluorophthalic acid diester. First, for example, dimethyl tetrafluorophthalate is dissolved in nitromethane, and a base is added under cooling to give 3,5,6-trifluoro-4
-Dimethyl nitromethylphthalate. The base may be any of an inorganic base and an organic base. Examples of the organic base include tetramethylguanidine, 1,8-diazabicyclo [5,4,0] -7-undecene, and 1,4-diazabicyclo [2,2, 2] Super strong bases such as octane can be mentioned. Further, as the inorganic base, sodium amide, sodium hydride, sodium hydroxide, potassium hydroxide and the like can be used. Among these bases, it is preferable to use a very strong organic base. Reaction temperature is -30 ° C to 50
The temperature may be in the range of 10 ° C, and a temperature of 10 ° C or less is particularly preferable. Nitromethane can be used as both a reactant and a solvent, but other solvents inert to the reaction may be used. For example, benzene, toluene, aromatic hydrocarbons such as xylene, diethyl ether, diisopropyl ether, tetrahydrofuran, 1,2-dimethoxyethane,
Ethers such as dioxane may be used.

This dimethyl 3,5,6-trifluoro-4nitromethylphthalate is reacted with tributyltin hydride and alpha, alpha'-azobis (isobutyronitrile).
It can be converted to dimethyl 3,5,6-trifluoro-4-methylphthalate in one step. Benzene, toluene, hexane, etc. can be used as the reaction solvent, and the reaction temperature is from room temperature to 150.
It may be carried out in the range of ℃, preferably from room temperature to 120 ℃
Range.

This dimethyl 3,5,6-trifluoro-4-methylphthalate can also be synthesized by the following method. That is, after converting the nitromethyl group of dimethyl 3,5,6-trifluoro-4-nitromethylphthalate to a dimethylamino group, and further quaternizing the dimethylamino group, reducing the quaternary salt This is a route to a 4-methylphthalic acid derivative.
First, the synthesis of dimethyl 4-dimethylamino-3,5,6-trifluorophthalate is described.
The simplest method is to methylate dimethyl 4-nitromethylphthalate catalytically in the presence of formaldehyde. The metal catalyst that can be used here is Raney nickel, palladium-carbon and the like. The solvent is not particularly limited, but is preferably an alcoholic solvent such as methanol or ethanol or water. On the other hand, a nitromethyl group may be reduced to an aminomethyl group and then dimethylated.

The quaternization of dimethyl 4-dimethylamino-3,5,6-trifluorophthalate may be achieved by reacting a dimethylaminomethyl compound with an alkyl halide. For example, the reaction of methyl iodide gives the quaternary salt 2,5,6-trifluoro-3,4-di (methoxycarbonyl) phenylmethylene-trimethylammonium iodide. In this specification, a quaternary salt has been described by taking a trimethylammonium compound as an example, but other trialkylammonium salts such as ethyl, propyl, and butyl may be used, or a quaternary salt composed of a plurality of alkyl groups may be used. . Catalytic reduction of the quaternary salt thus obtained in the presence of Raney nickel gives 3,5,6-
Dimethyl trifluoro-4-methylphthalate is obtained.

Next, the carboxyl group at the para-position of the methyl group of this compound is removed. First, the ester is hydrolyzed.
This hydrolysis may be carried out by a usual method, and may be carried out under basic or acidic conditions. Depending on the type of ester, hydrogenolysis may be used. Dissolve 3,5,6-trifluoro-4-methylphthalic acid obtained in the hydrolysis in water and in a sealed tube
When heated at 200 ° C., the carboxyl group at the para-position of the methyl group is eliminated by decarboxylation, and 2,4,5-trifluoro-3-methylbenzoic acid is obtained. Other decarboxylation reaction conditions include polar solvents such as dimethylformamide, dimethylacetamide, dimethylsulfoxide and the like in the presence of cuprous oxide, cupric oxide, copper (I) acetate or copper powder, or quinoline, pyridine and the like. Examples of the reaction include heating in a polar basic solvent and heating in aqueous sulfuric acid.

2,4,5-trifluoro-3- by the above series of reactions
The synthesis of methylbenzoic acid is an excellent route that is simpler and can be applied to large-scale synthesis, because it has a shorter number of steps than the synthesis route known so far.

A quinolone derivative in which the carboxylic acid moiety at the 3-position (or 3-position equivalent) of the quinolone is a substituted boron ester may be used as a raw material for the reaction with the spiro-substituted cyclic amine. This boron ester compound has, for example, the following substituent at the 3-position (or 3-position equivalent) of the quinolone nucleus: Which forms a chelate with the carbonyl group at the 4-position (or 4-position equivalent) of the quinolone. This fluorine atom may be another halogen atom or an acetoxy group.

This dihalogeno-boronate can be easily prepared from a free carboxylic acid derivative and a suitable boron trihalide compound, for example, a boron trifluoride etherate complex.

That is, the carboxylic acid derivative is suspended or dissolved in ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, and dioxane, and an excess amount of boron trifluoride diethyl ether complex is added, followed by stirring at room temperature. The reaction temperature may be room temperature, but may be heated to about 100 ° C. if necessary. A reaction time of 30 minutes to 24 hours is sufficient.
Since the product usually precipitates, it is collected, washed with an inert solvent such as ether, and dried under reduced pressure (see
62-252790).

When the carboxylic acid moiety at the 3-position (or 3-position equivalent) is an ester, it is useful as a synthetic intermediate or a prodrug. For example, alkyl esters, benzyl esters, alkoxyalkyl esters, phenylalkyl esters, phenyl esters, and the like are useful as synthetic intermediates.

The introduction reaction of the spiro-substituted cyclic amine is usually carried out in the presence of a deoxidizing agent. As the deoxidizing agent, any of an organic base and an inorganic base can be used, but an organic base is generally preferred.

Tertiary amines are preferred as the organic base, and trialkylamines such as triethylamine, tripropylamine, N, N-diisopropylethylamine and tributylamine, and anilines such as N, N-dimethylaniline and N, N-diethylaniline. , N-methylmorpholine, pyridine, N, N
-Heterocyclic compounds such as dimethylaminopyridine.

Examples of the inorganic base include hydroxides, carbonates, and hydrogen carbonates of alkali metals such as lithium, sodium, and potassium. Specifically, lithium hydroxide, sodium hydroxide, potassium hydroxide, anhydrous sodium carbonate,
Anhydrous potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like.

The spiro-substituted cyclic amine used in the reaction may be used in an amount equal to or more than twice the equivalent required for the reaction, and the amine itself may also serve as a deoxidizing agent.

Any reaction solvent may be used as long as it is inert to the reaction.In addition to acetonitrile, N, N-dimethylformamide, N-methyl-2-pyrrolidone, amides such as N, N-dimethylacetamide, benzene, toluene, xylene, etc. Aromatic hydrocarbons, dimethyl sulfoxide, aprotic polar solvents such as sulfolane, methanol, ethanol, propanol, butanol, amyl alcohol, isoamyl alcohol, cyclohexyl alcohol, lower alcohols such as 3-methoxybutanol, dioxane, dimethyl cellosolve, Ethers such as diethyl cellosolve and diglyme can be exemplified. In the case of a water-soluble solvent, it may be used as a water-containing solvent. In this case, an organic base is preferably used as the deoxidizing agent.

The reaction can be carried out at a temperature ranging from room temperature to 180 ° C.
The temperature may be in the range of 0 to 130 ° C.

A reaction time in the range of 10 minutes to 48 hours, usually 30 minutes to 30 hours is sufficient.

In the case of introducing a spiro-substituted cyclic amine and carrying out the reaction while protecting the substituent on the ring of the amine, removal of the protecting group from the product may be carried out by a usual method according to the protecting group used.

When the 3-position (or 3-position equivalent) carboxylic acid is not a free form, it can be derived into a free carboxylic acid by a method appropriate for each. For example, in the case of an ester, a usual hydrolysis method, that is, a method of treating in an alkali hydroxide and a water-containing solvent can be exemplified. The boron compound may be treated with a protic substance such as water or alcohol, and at this time, a deoxidizing agent may be present. For example, there is a method of treating with ethanol in the presence of triethylamine.

The generated spiro compound I can be purified by recrystallization, reprecipitation, activated carbon treatment, chromatography, or the like, or a combination thereof.

Examples of the novel spiro compound included in the present invention include the following compounds.

7- (7-amino-5-azaspiro [2,4] heptane-
5-yl) -1-cyclopropyl-6,8-difluoro-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7- (7-amino-5-azaspiro [2,4] heptane-
5-yl) -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7- (7-amino-5-azaspiro [2,4] heptane-
5-yl) -1-cyclopropyl-6-fluoro-1,4
-Dihydro-4-oxoquinoline-3-carboxylic acid 7- (7-amino-5-azaspiro [2,4] heptane-
5-yl) -1-cyclopropyl-6-fluoro-1,4
-Dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 7- (7-amino-5-azaspiro [2,4] heptane-
5-yl) -6,8-difluoro-1- (2-fluoroethyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7- (7-amino-5-azaspiro [2,4] Heptane
5-yl) -8-chloro-6-fluoro-1- (2-fluoroethyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7- (7-amino-5-azaspiro [2, 4] heptane
5-yl) -6-fluoro-1- (2-fluoroethyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7- (7-amino-5-azaspiro [2,4] heptane-
5-yl) -6-fluoro-1- (2-fluoroethyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 7- (7-amino-5-azaspiro [2 , 4] Heptane-
5-yl) -1-ethyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7- (7-amino-5-azaspiro [2,4] heptane-
5-yl) -8-chloro-1-ethyl-6-fluoro-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7- (7-amino-5-azaspiro [2,4] heptane-
5-yl) -1-ethyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7- (7-amino-5-azaspiro [2,4] heptane-
5-yl) -1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 7- (7-amino-5-azaspiro [2,4] heptane-
5-yl) -6,8-difluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxoquinoline-3
-Carboxylic acid 7- (7-amino-5-azaspiro [2,4] heptane-
5-yl) -8-chloro-6-fluoro-1- (2,4-
Difluorophenyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7- (7-amino-5-azaspiro [2,4] heptane-
5-yl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxoquinoline-3-
Carboxylic acid 7- (7-amino-5-azaspiro [2,4] heptane-
5-yl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 7- (7-amino-5-azaspiro) [2,4] Heptane-
5-yl) -6,8-difluoro-1-vinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7- (7-amino-5-azaspiro [2,4] heptane-
5-yl) -8-chloro-6-fluoro-1-vinyl-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7- (7-amino-5-azaspiro [2,4] heptane-
5-yl) -6-fluoro-1-vinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7- (7-amino-5-azaspiro [2,4] heptane-
5-yl) -6-fluoro-1-vinyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 1-cyclopropyl-7- (4,7-diazaspiro [2,5 ]
-Octane-7-yl) -6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 8-chloro-1-cyclopropyl-7- (4,7-diazaspiro [2,5 ] Octane-7-yl) -6-fluoro-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid 1-cyclopropyl-7- (4,7-diazaspiro [2,5]
-Octane-7-yl) -6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 1-cyclopropyl-7- (4,7-diazaspiro [2,5]
-Octane-7-yl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 7- (4,7-diazaspiro [2,5] octan-7-yl )
-6,8-difluoro-1- (2-fluoroethyl) -1,4
-Dihydro-4-oxoquinoline-3-carboxylic acid 8-chloro-7- (4,7-diazaspiro [2,5] octan-7-yl) -6-fluoro-1- (2-fluoroethyl) -1 7,4-Dihydro-4-oxoquinoline-3-carboxylic acid 7- (4,7-diazaspiro [2,5] octan-7-yl)
-6-fluoro-1- (2-fluoroethyl) -1,4-
7- (4,7-diazaspiro [2,5] octan-7-yl) dihydro-4-oxoquinoline-3-carboxylate
-6-fluoro-1- (2-fluoroethyl) -1,4-
7- (4,7-diazaspiro [2,5] octan-7-yl) dihydro-4-oxo-1,8-naphthyridine-3-carboxylate
-1-ethyl-6,8-difluoro-1,4-dihydro-4-
Oxoquinoline-3-carboxylic acid 8-chloro-7- (4,7-diazaspiro [2,5] octan-7-yl) -1-ethyl-6-fluoro-1,4-dihydro-4-oxoquinoline- 3-carboxylic acid 7- (4,7-diazaspiro [2,5] octan-7-yl)
-1-Ethyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7- (4,7-diazaspiro [2,5] octan-7-yl)
-1-Ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 7- (4,7-diazaspiro [2,5] octan-7-yl)
-6,8-difluoro-1- (2,4-difluorophenyl)
-1,4-Dihydro-4-oxoquinoline-3-carboxylic acid 8-chloro-7- (4,7-diazaspiro [2,5] octan-7-yl) -6-fluoro-1- (2,4 -Difluorophenyl) -1,4-dihydro-4-oxoquinoline-3
-Carboxylic acid 7- (4,7-diazaspiro [2,5] octan-7-yl)
-6-fluoro-1- (2,4-difluorophenyl)-
1,4-Dihydro-4-oxoquinoline-3-carboxylic acid 7- (4,7-diazaspiro [2,5] octan-7-yl)
-6-fluoro-1- (2,4-difluorophenyl)-
1,4-dihydro-4-oxo-1,8-naphthyridine-3-
Carboxylic acid 7- (4,7-diazaspiro [2,5] octan-7-yl)
-6,8-difluoro-1-vinyl-1,4-dihydro-4-
Oxoquinoline-3-carboxylic acid 8-chloro-7- (4,7-diazaspiro [2,5] octan-7-yl) -6-fluoro-1-vinyl-1,4-dihydro-4-oxoquinoline- 3-carboxylic acid 7- (4,7-diazaspiro [2,5] octan-7-yl)
7- (4,7-diazaspiro [2,5] octane-7-yl) -6-fluoro-1-vinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid
-6-Fluoro-1-vinyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 10- (7-amino-5-azaspiro [2,4] heptane-
5-yl) -9-fluoro-3- (S) -methyl-2,3
-Dihydro-7-oxo-7H-pyrido [1,2,3-de]
[1,4] benzoxazine-6-carboxylic acid 10- (4,7-diazaspiro [2,5] octan-7-yl)
-9-Fluoro-3- (S) -methyl-2,3-dihydro-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid 8- ( 7-amino-5-azaspiro [2,4] heptane-
5-yl) -9-fluoro-5- (S) -methyl-6,7
-Dihydro-1,7-dioxo-1H, 5H-benzo [ij] quinolizine-2-carboxylic acid 8- (4,7-diazaspiro [2,5] octan-7-yl)
-9-Fluoro-5- (S) -methyl-6,7-dihydro-1,7-dioxo-1H, 5H-benzo [ij] quinolidine-2
-Carboxylic acid 10- (7-amino-5-azaspiro [2,4] heptane-
5-yl) -9-fluoro-3- (S) -methyl-2,3
-Dihydro-7-oxo-7H-pyrido [1,2,3-de]
[1,4] benzothiazine-6-carboxylic acid 10- (4,7-diazaspiro [2,5] octan-7-yl)
-9-Fluoro-3- (S) -methyl-2,3-dihydro-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzothiazine-6-carboxylic acid 5-amino- 7- (7-amino-5-azaspiro [2,
4] Heptan-5-yl) -1-cyclopropyl-6,8-
Difluoro-1,4-dihydro-4-oxoquinoline-3
-Carboxylic acid 5-amino-7- (7-amino-5-azaspiro [2,
4] Heptane-5-yl) -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 5-amino-7- (7-amino-5 Azaspiro [2,
4] Heptan-5-yl) -6,8-difluoro-1- (2
-Fluoroethyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid 5-amino-7- (7-amino-5-azaspiro [2,
4] Heptan-5-yl) -8-chloro-6-fluoro-1- (2-fluoroethyl) -1,4-dihydro-4-
Oxoquinoline-3-carboxylic acid 5-amino-7- (7-amino-5-azaspiro [2,
4] Heptane-5-yl) -1-ethyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 5-amino-7- (7-amino-5-azaspiro [2 ,
4] Heptan-5-yl) -8-chloro-1-ethyl-
6-fluoro-1,4-dihydro-4-oxoquinoline-
3-carboxylic acid 5-amino-7- (7-amino-5-azaspiro [2,
4] Heptan-5-yl) -6,8-difluoro-1- (2,
4-difluorophenyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid 5-amino-7- (7-amino-5-azaspiro [2,
4] Heptan-5-yl) -8-chloro-6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-
4-oxoquinoline-3-carboxylic acid 5-amino-1-cyclopropyl-7- (4,7-diazaspiro [2,5] octan-7-yl) -6,8-difluoro-1,4-dihydro- 4-oxoquinoline-3-carboxylic acid 5-amino-8-chloro-1-cyclopropyl-7-
(4,7-diazaspiro [2,5] octan-7-yl) -6
-Fluoro-1,4-dihydro-4-oxoquinoline-3
-Carboxylic acid 5-amino-7- (4,7-diazaspiro [2,5] octan-7-yl) -6,8-difluoro-1- (2-fluoroethyl) -1,4-dihydro-4- Oxoquinoline-3-
Carboxylic acid 5-amino-8-chloro-7- (4,7-diazaspiro-
[2,5] Octane-7-yl) -6-fluoro-1-
(2-Fluoroethyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid 5-amino-7- (4,7-diazaspiro [2,5] octan-7-yl) -1-ethyl- 6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 5-amino-8-chloro-7- (4,7-diazaspiro-
[2,5] Octane-7-yl) -1-ethyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 5-amino-7- (4,7-diazaspiro [2, 5] Octane-7-yl) -6,8-difluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxoquinoline-
3-carboxylic acid 5-amino-8-chloro-7- (4,7-diazaspiro [2,5] -octan-7-yl) -6-fluoro-1-
(2,4-difluorophenyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid 5-amino-7- (7-amino-5-azaspiro [2,
4] Heptan-5-yl) -6,8-difluoro-1-vinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 5-amino-7- (7-amino-5-azaspiro [2 ,
4] Heptane-5-yl) -8-chloro-6-fluoro-1-vinyl-1,4-dihydro-4-oxoquinoline-
3-carboxylic acid 5-amino-7- (4,7-diazaspiro [2,5] octan-7-yl) -6,8-difluoro-1-vinyl-1,4-dihydro-4-oxoquinoline-3 -Carboxylic acid 5-amino-8-chloro-7- (4,7-diazaspiro-
[2,5] Octane-7-yl) -6-fluoro-1-vinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7- (7-amino-5-azaspiro [2,4] Heptane
5-yl) -1-cyclopropyl-6-fluoro-8-
Methoxy-1,4-dihydro-4-oxoquinoline-3-
Carboxylic acid 7- (7-amino-5-azaspiro [2,4] heptane-
5-yl) -6-fluoro-1- (2-fluoroethyl) -8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7- (7-amino-5-azaspiro [2, 4] heptane
5-yl) -1-ethyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7- (7-amino-5-azaspiro [2,4] heptane-
5-yl) -6-fluoro-1- (2,4-difluorophenyl) -8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7- (7-amino-5-azaspiro [ 2,4] heptane-
5-yl) -6-fluoro-8-methoxy-1-vinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7- (7-amino-5-azaspiro [2,4] heptane-
5-yl) -1-cyclopropyl-6-fluoro-8-
Methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7- (7-amino-5-azaspiro [2,4] heptane-
5-yl) -6-fluoro-1- (2-fluoroethyl) -8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7- (7-amino-5-azaspiro [2, 4] heptane
5-yl) -1-ethyl-6-fluoro-8-methyl-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7- (7-amino-5-azaspiro [2,4] heptane-
5-yl) -6-fluoro-1- (2,4-difluorophenyl) -8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7- (7-amino-5-azaspiro [ 2,4] heptane-
5-yl) -6-fluoro-8-methyl-1-vinyl-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid 1-cyclopropyl-7- (4,7-diazaspiro [2,5]
-Octane-7-yl) -6-fluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7- (4,7-diazaspiro [2,5] octan-7-yl)
-6-Fluoro-1- (2-fluoroethyl) -8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7- (4,7-diazaspiro [2,5] octane-7- Ill)
-1-Ethyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7- (4,7-diazaspiro [2,5] octan-7-yl)
-1- (2,4-difluorophenyl) -6-fluoro-
8-methoxy-1,4-dihydro-4-oxoquinoline-
3-carboxylic acid 7- (4,7-diazaspiro [2,5] octan-7-yl)
-6-Fluoro-1-vinyl-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 1-cyclopropyl-7- (4,7-diazaspiro [2,5]
-Octane-7-yl) -6-fluoro-8-methyl-
1,4-Dihydro-4-oxoquinoline-3-carboxylic acid 7- (4,7-diazaspiro [2,5] octan-7-yl)
-6-Fluoro-1- (2-fluoroethyl) -8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7- (4,7-diazaspiro [2,5] octane-7- Ill)
-1-Ethyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7- (4,7-diazaspiro [2,5] octan-7-yl)
-6-fluoro-1- (2,4-difluorophenyl)-
8-methyl-1,4-dihydro-4-oxoquinoline-3
-Carboxylic acid 7- (4,7-diazaspiro [2,5] octan-7-yl)
-6-Fluoro-1-vinyl-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7- (8-amino-6-azaspiro [3,4] octane-
6-yl) -1-cyclopropyl-6,8-difluoro-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7- (8-amino-6-azaspiro [3,4] octane-
6-yl) -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7- (8-amino-6-azaspiro [3,4] octane-
6-yl) -6,8-difluoro-1- (2-fluoroethyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7- (8-amino-6-azaspiro [3,4] Octane-
6-yl) -8-chloro-6-fluoro-1- (2-fluoroethyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7- (8-amino-6-azaspiro [3, 4] Octane-
6-yl) -1-ethyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7- (8-amino-6-azaspiro [3,4] octane-
6-yl) -8-chloro-1-ethyl-6-fluoro-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7- (8-amino-6-azaspiro [3,4] octane-
6-yl) -6,8-difluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxoquinoline-3
-Carboxylic acid 7- (8-amino-6-azaspiro [3,4] octane-
6-yl) -8-chloro-6-fluoro-1- (2,4-
Difluorophenyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7- (8-amino-6-azaspiro [3,4] octane-
6-yl) -6,8-difluoro-1-vinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7- (8-amino-6-azaspiro [3,4] octane-
6-yl) -8-chloro-6-fluoro-1-vinyl-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid 10- (8-amino-6-azaspiro [3,4] octane-
6-yl) -9-fluoro-3- (S) -methyl-2,3
-Dihydro-7-oxo-7H-pyrido [1,2,3-de]
[1,4] benzoxazine-6-carboxylic acid 8- (8-amino-6-azaspiro [3,4] octane-
6-yl) -9-fluoro-5- (S) -methyl-6,7
-Dihydro-1,7-dioxo-1H, 5H-benzo [ij] quinolidine-2-carboxylic acid 1-cyclopropyl-7- (5,8-diazaspiro [3,5]
-Nonan-8-yl) -6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 8-chloro-1-cyclopropyl-7- (5,8-diazaspiro [3,5 ] Nonan-8-yl) -6-fluoro-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7- (5,8-diazaspiro [3,5] nonan-8-yl)-
6,8-difluoro-1- (2-fluoroethyl) -1,4-
Dihydro-4-oxoquinoline-3-carboxylic acid 8-chloro-7- (5,8-diazaspiro [3,5] nonane-
8-yl) -6-fluoro-1- (2-fluoroethyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7- (5,8-diazaspiro [3,5] nonane-8- Il)-
6,8-difluoro-1-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 8-chloro-7- (5,8-diazaspiro [3,5] nonane-
8-yl) -1-ethyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7- (5,8-diazaspiro [3,5] nonan-8-yl)-
6,8-difluoro-1- (2,4-difluorophenyl)-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid 8-chloro-7- (5,8-diazaspiro [3,5] nonane-
8-yl) -1- (2,4-difluorophenyl) -6
Fluoro-1,4-dihydro-4-oxoquinoline-3-
Carboxylic acid 7- (5,8-diazaspiro [3,5] nonan-8-yl)-
6,8-difluoro-1-vinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 8-chloro-7- (5,8-diazaspiro [3,5] nonane-
8-yl) -1-vinyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 10- (5,8-diazaspiro [3,5] nonan-8-yl)-
9-fluoro-3- (S) -methyl-2,3-dihydro-
7-oxo-7H-pyrido [1,2,3-de] [1,4] benzothiazine-6-carboxylic acid 10- (5,8-diazaspiro [3,5] nonan-8-yl)-
9-fluoro-3- (S) -methyl-2,3-dihydro-
7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid 8- (5,8-diazaspiro [3,5] nonan-8-yl)-
9-fluoro-5- (S) -methyl-6,7-dihydro-
1,7-dioxo-1H, 5H-benzo [ij] quinolidine-2-
Carboxylic acid 7- (7-methylamino-5-azaspiro [2,4] heptane-5-yl) -8-chloro-1-cyclopropyl-
6-fluoro-1,4-dihydro-4-oxoquinoline-
3-carboxylic acid 7- (7-dimethylamino-5-azaspiro [2,4] heptane-5-yl) -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline -3-carboxylic acid 8-chloro-1-cyclopropyl-7- (4-methyl-
4,7-diazaspiro [2,5] octan-7-yl) -6
Fluoro-1,4-dihydro-4-oxoquinoline-3-
Carboxylic acids These quinolone derivatives having a spirocyclic amine have higher lipophilicity, higher oral absorbability and higher antibacterial activity than the corresponding quinolone derivatives having no spiro ring.

The pyridonecarboxylic acid derivative of the present invention may be in a free form, but may be in the form of an acid addition salt or a carboxyl group salt. Examples of acid addition salts include hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide,
Inorganic acid salts such as phosphates, or organic acid salts such as acetate, methanesulfonate, benzenesulfonate, toluenesulfonate, citrate, maleate, fumarate, lactate, etc. Can be.

Examples of the carboxyl group salt include, for example, alkali metal salts such as lithium salt, sodium salt, and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt;
Ammonium salts, triethylamine salts, N-methylglucamine salts, tris- (hydroxylmethyl) amine methane salts and the like may be any of inorganic salts and organic salts.

The free form, acid addition salt and carboxyl group salt of these pyridonecarboxylic acid derivatives may exist as hydrates.

On the other hand, quinolone derivatives in which the carboxylic acid moiety is an ester are useful as synthetic intermediates and prodrugs. For example, alkyl esters, benzyl esters, alkoxyalkyl esters, phenylalkyl esters, and phenyl esters are useful as synthetic intermediates.

Further, the ester used as a prodrug is an ester that is easily cleaved in a living body to generate a free form of a carboxylic acid, and includes, for example, acetoxymethyl ester, pivaloyloxymethyl ester, and ethoxycarbonyloxy ester. , Choline ester, dimethylaminoethyl ester, 5-indanyl ester and phthalidinyl ester, 5-substituted-2-oxo-1,3-
Oxoalkyl esters such as dioxosol-4-ylmethyl ester and 3-acetoxy-2-oxobutyl ester can be mentioned.

Since the compound of the present invention has a strong antibacterial action,
It can be used as a medicine for animals and fish, or as a pesticide and food preservative.

When the compound of the present invention is used as a medicine for the human body, the dose ranges from 50 mg to 1 g, preferably from 100 mg to 300 mg per adult per day.

The dosage for animals may vary depending on the purpose of administration (treatment or prevention), the type and size of the animal to be treated, the type and extent of the infected pathogen, but is generally used as a daily dose. 1 mg to 200 mg per kg of body weight, preferably 5 mg
To the range of 100mg.

This daily dose is administered once a day or divided into 2 to 4 times. The daily dose may exceed the above-mentioned amount if necessary.

The compounds of the present invention are active against a wide range of microorganisms that cause various infectious diseases, and can treat, prevent or reduce the diseases caused by these pathogens.

Staphylococci, S. pyogenes, hemolytic streptococci, enterococci, pneumococci, peptostreptococci, gonococci, Escherichia coli, Citrobacter, Shigella, Klebsiella , Enterobacter, Serratia, Proteus, Pseudomonas, Haemophilus influenzae, Acinetobacter,
Campylobacter, Chlamydia trachomatis and the like can be exemplified.

Diseases caused by these pathogens include folliculitis, cough, syphilis, erysipelas, cellulitis, lymphatic (node) inflammation, gourd, subcutaneous abscess, sweat glanditis, acne condensate,
Infectious nodules, perianal abscesses, mastitis, superficial secondary infections such as trauma / burns / surgical wounds, pharyngolaryngitis, acute bronchitis, tonsillitis, chronic bronchitis, bronchiectasis, diffuse generalized Bronchitis, secondary infection of chronic respiratory disease, pneumonia, pyelonephritis, cystitis, prostatitis, epididymitis, gonococcal urethritis, nongonococcal urethritis, cholecystitis, cholangitis, bacillary dysentery, enteritis, uterus Appendicitis, intrauterine infection, Bartholin's adenitis, blepharitis, stye, lacrimal sacitis, tarsal adenitis, corneal ulcer, otitis media, sinusitis, periodontitis, pericoronitis, jaw inflammation, peritonitis, heart Endometritis, sepsis,
Meningitis, skin infections and the like can be exemplified.

It is also effective against various microorganisms that cause infectious diseases in animals, for example, Escherichia, Salmonella, Pasteurella, Haemophilus, Bordetella, Staphylococcus, Mycoplasma and the like.

Illustrative disease names include avian diseases such as colibacillosis, chick dysentery, chicken paratyphoid, poultry cholera, infectious coryza,
Staphylococci, mycoplasmosis, etc., swine colisis, salmonellosis, pasteurellosis, hemophilus infection, atrophic rhinitis, exudative epidermitis, mycoplasma infection, etc., cattle coliformosis, salmonellosis, hemorrhagic sepsis, etc. Mycoplasma infection, bovine lung disease, mastitis, etc., E. coli sepsis, salmonella infection, hemorrhagic sepsis, pyometra, cystitis, etc. in dogs, and exudative pleurisy, cystitis, chronic rhinitis, hemophilus infection in cats, Kittens include diarrhea, mycoplasma infection and the like.

The antimicrobial preparation comprising the compound of the present invention can be prepared by selecting an appropriate preparation according to the administration method and using a preparation method for various preparations which are generally used. As the dosage form of the antimicrobial preparation containing the compound of the present invention as a main component, for example, tablets, powders, granules, capsules,
Solutions, syrups, elixirs, oily or aqueous suspensions, and the like can be exemplified as oral preparations.

Injectables may use stabilizers, preservatives, and solubilizing agents in the preparation.After storing the solution that may contain these adjuvants in a container, freeze-drying or the like to prepare a solid preparation at the time of use. It may be a formulation. One dose may be stored in a container, or multiple doses may be stored in the same container.

Also as external preparations solutions, suspensions, emulsions, ointments,
Examples include gels, creams, lotions, sprays and the like.

Solid preparations include pharmaceutically acceptable additives together with the active compound, such as fillers, extenders, binders, disintegrants, dissolution enhancers, wetting agents, lubricants and the like. They can be selected and mixed as needed to form a formulation.

Liquid preparations include solutions, suspensions, emulsions and the like, but may also contain suspending agents, emulsifiers and the like as additives.

The method of administering the compound of the present invention to an animal may be a method of orally administering it directly or by mixing it in a feed, or a method of orally administering a solution, and then directly or by adding it to drinking water or a feed, or injection. Can be exemplified.

As a preparation for administering the compound of the present invention to an animal,
Powders, fine granules, dissolvable powders, syrups, solutions, or injections can be appropriately prepared by techniques generally used in this field. Next, formulation examples are shown.

Formulation Example 1. (Capsule): Compound 32b 100.0 mg Cornstarch 23.0 mg CMC calcium 22.5 mg Hydroxypropyl simethylcellulose 3.0 mg Magnesium stearate 1.5 mg Total 150.0 mg Formulation Example 2. (Solution): Compound 31b 1 to 10 g acetic acid Or sodium hydroxide 0.5-2 g Ethyl paraoxybenzoate 0.1 g Purified water 88.9-98.4 g Total 100 g Formulation Example 3. (feed mixture powder): Compound 55b 1-10 g Corn starch 98.5-89.5 g Light anhydrous silicic acid 0.5 g Total 100 g Next, the present invention will be described in more detail by way of examples, but the present invention is not limited thereto. The antibacterial activity was determined according to the method specified by the Japanese Society of Chemotherapy (Japanese Society of Chemotherapy, 29 (1), 79 (1981)). Following the table of antibacterial activities, the reaction formulas for the synthesis of various spiro-substituted cyclic amine derivatives, intermediate compounds for the synthesis of quinolone skeletons and various spiro compounds are shown.

Reference Example 1. Synthesis of 7-amino-5-azaspiro [2,4] heptane 1) Ethyl 1-acetyl-1-cyclopropanecarboxylate 2 Ethyl acetoacetate, 10.4 g of 1,2-dibromoethane 15
g, potassium carbonate 23 g, N, N-dimethylformamide (DM
F) 150 ml were mixed and stirred at room temperature for 2 days. The insoluble material was removed by filtration, the filtrate was dried under reduced pressure, water was added to the residue, extracted with chloroform, and the extract was dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure, and the obtained pale yellow oil was distilled under reduced pressure to obtain 7.5 g of the title compound 2 as a fraction having a boiling point of 70 to 71 ° C./2 to 3 mmHg. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.30 (3H, t, J = 7 Hz), 1.48 (4H, s), 2.49 (3H, s), 4.
24 (2H, q, J = 7Hz) 2) 5-Benzyl-4,7-dioxo-5-azaspiro- [2,4] heptane 4 Compound 2 and 7 g are dissolved in 50 ml of ethanol, and 8.0 g of bromine is stirred at room temperature. It was dropped below. After stirring at room temperature for 2 hours, excess bromine and the solvent were distilled off under reduced pressure to give 1-bromoacetyl-1-.
Ethyl cyclopropanecarboxylate 3 was obtained. This was dissolved in 50 ml of ethanol without purification, and 12 g of benzylamine was added dropwise under ice-cooling and stirring. After returning to room temperature and stirring for 24 hours, the solvent was distilled off under reduced pressure.
, Washed with 1N hydrochloric acid and saturated saline in this order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography to give 2% methanol-
Elution with chloroform gave 2.3 g of the title compound 4, as pale yellow crystals. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.6 to 1.8 (4H, m), 3.78 (2H, s), 4.68 (2H, s) 7.2 to 7.45 (5H, brs) 3) 5-benzyl-7- ( Hydroxyimino) -4-
Oxo-5-azaspiro [2,4] heptane 5 Compound 4, 670 mg, hydroxylamine hydrochloride 700 mg,
200 mg of triethylamine and 10 ml of ethanol were added, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and the residue was dissolved by adding 10% aqueous citric acid solution and extracted with chloroform.
The chloroform extract was back-extracted with a 1N aqueous sodium hydroxide solution, and the aqueous layer was acidified with concentrated hydrochloric acid and extracted with chloroform. After the extract was dehydrated with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 490 mg of the title compound (5) as white crystals. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.3 to 1.7 (4H, m), 3.80 ^* & 4.10 ^* (2H, s) 4.60 ^** & 4.70 ^** (2H, s), 7.38 (5H, arm. 4) 7-Amino-5-azaspiro [2,4] heptane
7. Compound 490 mg was dissolved in anhydrous tetrahydrofuran (80 ml), lithium aluminum hydride (500 mg) was added, and the mixture was heated under reflux for 8 hours. After returning to room temperature, 0.5 ml of water, 15
0.5 ml of aqueous sodium hydroxide solution and 1.5 ml of water in this order,
The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give 7-amino-5.
Benzyl-5 azaspiro [2,4] heptane 6 was obtained.
This was dissolved in 20 ml of ethanol without purification, and 10% palladium-carbon was added thereto, followed by catalytic hydrogenation at 4.5 kg / cm ² and 50 ° C. After 6 hours, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure at room temperature or lower to obtain a crude product of the title compound 7. This compound 7 was used for various reactions without purification.

5) 7-[(R) -N-p-toluenesulfonylprolyl] amino-5-benzyl-5-azaspiro [2,4]
Heptane 8 Compound 6, 2.8 g, triethylamine 1.5 g, and methylene chloride 50 ml were mixed, and separately prepared under ice-cooling and stirring (R).
-Np-toluenesulfonylproline acid chloride (note, (R) -Np-toluenesulfonylproline 4 g)
And an excess of thionyl chloride. ) Was added dropwise over 10 minutes, and the mixture was returned to room temperature and stirred for 3 hours. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and saturated saline, and then dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to flash column chromatography (silica gel 80 g) to obtain 3.5 g of the title compound 8 as a candy substance from a fraction eluted with ethyl acetate.

6) 7 [(R) -Np-toluenesulfonylpropyl] amino-5-benzyloxycarbonyl-5-azaspiro [2,4] heptane 9, and optically active compounds 9a and 9b, compound 8, 3.5 g, chlorocarbonate 2.5 ml of benzyl was added to 4 ml of dry methylene chloride and stirred for 12 hours at room temperature. Further, 4 ml of benzyl chlorocarbonate was added, and the mixture was stirred for 5 hours. Then, chloroform was added, and the mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine in this order. After drying over anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure, and the residue was subjected to flash column chromatography (silica gel, 85 g) to give ethyl acetate-n.
-The title compound 9, 3 g was obtained as a pale yellow oil from the hexane (2: 1 to 4: 1, v / v) elution part, and immediately subjected to HPLC to obtain 1.40 g, 1.45 g of optically active compounds 9a and 9b, respectively. g obtained.

Column used: Nucleosyl 50-5 (20 × 250 mm) Developing solvent: Ethyl acetate Flow rate: 11 ml / min, 9a; eluted at 19.5 minutes 9b; eluted at 21 minutes 9a: [α] _D +13.6 (c 0.75, chloroform) 9b: [α] _D + 76.0 (c 0.85, chloroform) 7) Optically active 7-amino-5-azaspiro [2,4]
Heptanes 7a and 7b Compound 9a, 1.4 g, was dissolved in ethanol 20 ml, 15 ml of a 2N aqueous sodium hydroxide solution was added, and the mixture was refluxed for 19 hours. The reaction solution was acidified with concentrated hydrochloric acid, washed twice with chloroform and once with ethyl acetate, and the aqueous layer was concentrated under reduced pressure to obtain a colorless solid as a residue. 50% aqueous sodium hydroxide solution 10
The resulting mixture was distilled under reduced pressure, and an aqueous solution containing Compound 7a was obtained as a distillate, and used as it was in the next reaction.

The other compound 7b was obtained from compound 9b by the same operation.

8) 7-Tertiary butoxycarbonylamino-5-azaspiro [2,4] heptane 11 800 mg of the compound 6 was dissolved in 30 ml of tetrahydrofuran, and 2- (tert-butoxycarbonyloxyimino) -2-phenylacetonitrile was added at room temperature. (BOC-ON), 1.2g
Was added and reacted for 2 hours. The solvent was distilled off under reduced pressure, chloroform was added to the residue, and the mixture was extracted with a 10% aqueous citric acid solution. The pH of the citric acid extract was adjusted with 1N aqueous sodium hydroxide solution.
It was adjusted to 10 or more and extracted with chloroform. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 10-900 mg of 7-tert-butoxycarbonylamino-5-benzyl-5-azaspiro [2,4] heptane. This compound 10, 87
0 mg was dissolved in ethanol 15 ml, and 10% -palladium carbon 5
After adding 00 mg, the mixture was subjected to catalytic hydrogenation at 40 ° C. under pressure (4.5 kg / cm ² ). After 2 hours, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound 11, which was used for the substitution reaction without purification.

Reference Example 2. Optically active 7-amino-5-azaspiro-
Synthesis of [2,4] heptane 1) 35.7 g of 5- [1- (R) -phenylethyl] -4,7-dioxo-5-azaspiro [2,4] heptane 12 compound 2 was dissolved in 200 ml of ethanol. Bromine 40
g was added dropwise at room temperature with stirring. After stirring at room temperature for 2 hours, excess bromine and the solvent were distilled off under reduced pressure to obtain ethyl 1-bromoacetyl-1-cyclopropanecarboxylate 3.
This was dissolved in 200 ml of ethanol without purification, and 33 g of R-(+)-1-phenylethylamine was stirred under ice cooling.
And 27 g of triethylamine were simultaneously added dropwise over 1 hour, and then returned to room temperature and stirred for 2 days. After filtering off the insoluble matter, the ethanol was distilled off under reduced pressure.
It was dissolved in 300 ml, washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline in this order, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to 200 g of silica gel column chromatography, and eluted with chloroform to 2% methanol / chloroform to obtain the title compound 12 as colorless crystals.

Melting point: 98-103 ° C ¹ H-NMR (CDCl ₃ ) δ ppm: 1.62 (3H, d, J = 7.2 Hz), 1.4-
1.8 (4H, m), 3.5 (1H, d, J = 18Hz), 3.9 (1H, d, J = 18H)
z), 5.82 (1H, q, J = 7.2 Hz), 7.36 (5H, s) 2) 5- [1- (R) -phenylethyl] -7-hydroxyimino-4-oxo-5-azaspiro [2 , 4] heptane 13 compound 12, 3.35 g to hydroxylamine hydrochloride 1.6 g,
2.3 g of triethylamine and 80 ml of ethanol were added, followed by stirring at room temperature for 2 hours. The solvent was distilled off under reduced pressure, chloroform was added to the residue, and the mixture was washed with a 10% aqueous citric acid solution and saturated saline, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound 13, 3.5 g as colorless crystals.

Melting point: 188-194 ° C ¹ H-NMR (CDCl ₃ ) δ ppm: 1.2-1.4 (2H, m), 1.53 (3H, d,
J = 7.2Hz, & 2H, m), 3.8 (1H, d, J = 18Hz), 4.16 (1H, d, J
= 18 Hz), 5.63 (1H, q, J = 7.2 Hz), 7.32 (5H, s) 3) 7-amino-4-oxo-5- [1- (R) -phenylethyl] -5-azaspiro [2 , 4] Heptane 14
a, 14b Compound 13, 3.5 g and Raney nickel 7.5 ml in methanol 1
In addition to 50 ml, catalytic reduction was performed at room temperature for 12 hours. After removing the catalyst by filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to 100 g of silica gel column chromatography, and eluted with 5% methanol / chloroform. Were obtained as colorless oils, respectively, in an amount of 1.0 g and 0.8 g.

14b; ¹ H-NMR (CDCl ₃ ) δ ppm: 0.8-1.4 (4H, m), 1.52 (3
H, d, J = 7Hz), 2.87 (1H, dd, J = 10,3Hz), 3.3-3.9 (2H,
m), 4.27 (2H, br s), 5.42 (1H, q, J = 7Hz), 7.29 (5H,
s) 14a; ¹ H-NMR (CDCl ₃ ) δ ppm: 0.6-1.3 (4H, m), 1.40 (2
H, s), 1.53 (3H, d, J = 7.2 Hz), 2.99 (1H, dd, J = 12.8, 7.
2Hz), 3.15-3.45 (2H, m), 5.52 (1H, q, J = 7.2Hz), 7.3
0 (5H, s) 4) 7-amino-5- [1- (R) -phenylethylene] -5-azaspiro [2,4] heptane 15a, 15b Compound 14b, 1.0 g and lithium aluminum hydride in 50 ml of anhydrous tetrahydrofuran Add 500mg, 17
Refluxed for hours. After cooling, 0.5 ml of water, 0.5 ml of 15% aqueous sodium hydroxide solution and 1.5 ml of water were sequentially added to the reaction solution, and the mixture was further stirred at room temperature for 30 minutes. After filtering the insolubles, the residue was thoroughly washed with tetrahydrofuran, and the filtrate and the washing were combined and dried. After evaporating the solvent under reduced pressure, the title compound 15b as a pale yellow oil, 940 mg
I got Similarly, compound 14a, 800 mg to compound 15a, 7
55 mg were obtained.

15b; ¹ H-NMR (CDCl ₃ ) δ ppm: 0.2-0.8 (4H, m), 1.35 (3
H, d, J = 6.6Hz), 1.6−2.0 (2H, br m), 2.2−3.1 (4H,
m), 3.24 (1H, q, J = 6.6 Hz), 3.5-3.9 (1H, m), 7.28 (5
H, brs) 15a; ¹ H-NMR (CDCl ₃ ) δ ppm: 0.3-0.9 (4H, m), 1.36 (3
H, d, J = 6.7Hz), 1.8−2.2 (2H, m), 2.2−3.2 (4H, m),
3.24 (1H, q, J = 6.7Hz), 3.6-3.9 (1H, m), 7.28 (5H, br
s) 5) 7- (Tertiary butoxycarbonylamino) -5
[1- (R) -phenylethyl] -5-azaspiro [2,
4] Heptane 16a, 16b In 20 ml of anhydrous tetrahydrofuran, 764 mg of compound 15b and 1.3 g of BOC-ON were added, and the mixture was stirred at room temperature for 4 hours. Ethyl acetate was added to the reaction solution, washed twice with a 1N aqueous sodium hydroxide solution and once with water, and then extracted with a 10% aqueous citric acid solution. The aqueous layer was washed once with ethyl acetate, made alkaline by adding a 15% aqueous sodium hydroxide solution under cooling, extracted with chloroform three times, and the organic layer was washed with saturated saline and dried. After evaporation of the solvent, the residue was subjected to silica gel column chromatography (silica gel, 20 g, chloroform; eluted with methanol = 20: 1, 10: 1) to obtain 690 mg of the title compound 16b. This crystallized after standing.
Washed with n-hexane. Compound 16a was obtained in a similar manner.

16b: colorless crystal Melting point: 103-105 ° C [α] _D- 152 (c = 1.475, chloroform) ¹ H-NMR (CDCl ₃ ) δ ppm: 0.4-0.9 (4H, m), 1.36 (3H, d,
J = 7.2Hz), 1.44 (9H, s), 2.42 (2H, AB q, J = 10.2Hz),
2.79 (2H, d, J = 5.6Hz), 3.24 (1H, q, J = 7.2Hz), 3.6−
4.0 (1H, m), 4.6-5.1 (1H, br d), 7.28 (5H, s) Elemental analysis C ₁₉ H ₂₈ N ₂ O ₂ Calculated: C 72.12, H 8.92, N 8.85 Analytical values: C 71.63 , H 9.07, N 8.64 16a: colorless crystals Melting point: 94-97 ° C [α] _D +47.6 (c = 0.89, chloroform) ¹ H-NMR (CDCl ₃ ) δ ppm: 0.4-0.9 (4H, m), 1.33 (3H, d,
J = 6.6Hz), 1.40 (9H, s), 2.29 (1H, d, J = 9Hz), 2.44
(1H, dd, J = 10.8,3.6Hz), 2.77 (1H, d, J = 9Hz), 2.88
(1H, dd, J = 10.8,5.3Hz), 3.22 (1H, q, J = 6.6Hz), 3.6
-3.9 (1H, m), 4.7-5.2 (1H, br d), 7.27 (5H, s) Elemental analysis C ₁₉ H ₂₈ N ₂ O ₂ Calculated: C 72.12, H 8.92, N 8.85 Analysis Found: C 71.86, H 9.36, N 8.68 6) 7-tert-butoxycarbonylamino-5-azaspiro [2,4] heptane 11a, 11b Compound 16b, 650 mg, and 50% aqueous palladium-carbon 500 mg
Was added to 30 ml of ethanol and subjected to catalytic reduction under heating at 4.2 atm. Six hours later, the catalyst was removed by filtration, and the mother liquor was distilled off under reduced pressure. Ethyl acetate was added to the resulting oily residue, and the mixture was extracted twice with a 10% aqueous citric acid solution. Then, this was extracted three times with chloroform, and the chloroform layer was washed with water and dried. After evaporating the solvent, 440 mg of the title compound 11b was obtained as a crude product. Compound 11a was obtained in the same manner. The ¹ H-NMR spectra of compounds 11b and 11a were completely identical.

17b; ¹ H-NMR (CDCl ₃ ) δ ppm: 0.4-1.0 (4H, m), 1.42 (9
H, s), 2.71 (1H, d, J = 10.2Hz), 2.92 (1H, dd, J = 10.8,
3.6Hz), 3.01 (1H, d, J = 10.2Hz), 3.33 (1H, dd, J = 10.
8,5.4Hz), 3.5-3.9 (1H, m), 5.0-5.4 (1H, brd) Reference Example 3. Synthesis of 4,7-diazaspiro [2,5] octane 1) Cyclopropane-1,1- Dibromoamide 18 Cyclopropane-1,1-diamide 17, 14.0 g, Bromine 35 g
And 130 ml of an aqueous potassium hydroxide solution adjusted from 14 g of potassium hydroxide was added dropwise with stirring at room temperature. After stirring for 1 hour, the mixture was cooled with ice water, and the precipitated crystals were collected by filtration, washed with ice water, air-dried, and dried under reduced pressure at 66 ° C. for 2 hours to obtain the title compound 18, 28.6 g.

2) 4,6-Diazaspiro [2,4] heptane-5,7-dione 19 Compound 18 and 26 g were added to a sodium methoxide solution prepared from 9.1 g of metallic sodium and anhydrous methanol under ice-cooling and stirring. When the cooling was stopped and the stirring was continued, the internal temperature gradually increased, and rose at a stretch from about 20 ° C., and the methanol boiled. After heating under reflux for 10 minutes, the temperature was returned to room temperature, and the residue was dried under reduced pressure. Acetone was added to the residue and the mixture was filtered. The crystals were washed with acetone, and the washings were added to the filtrate and concentrated under reduced pressure to obtain a crude product of the title compound 19, which was used for the next reaction without purification.

3) 1-aminocyclopropanecarboxylic acid 20 and 1-
Tertiary butoxycarbonylaminocyclopropanecarboxylic acid 21 A crude product of compound 19 was dissolved in 60 ml of water, and barium hydroxide 15 was dissolved.
g was added, and the mixture was reacted at an external temperature of 170 ° C. for 2 hours in a stainless steel autoclave. After standing overnight, the precipitated barium carbonate was removed by filtration, and further, ammonium carbonate was added to the filtrate, and the precipitated barium carbonate was removed by filtration. The filtrate was concentrated to obtain a crude product of amino acid compound 20. This compound 20 can be used without purification
Tert-butoxycarbonylation using BOC-ON gave 2.5 g of compound 21. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.85 (2H, t), 2.05 (9H, s), 2.15 (2H, t) 4) Ethyl (1-tert-butoxycarbonylamino-
1-Cyclopropylcarbonylamino) acetate 22 Compound 21 (700 mg) was dissolved in dioxane (50 ml), dicyclohexylcarbonyldiimide (800 mg) and glycine ethyl ester hydrochloride (600 mg) were added, and while stirring at room temperature, triethylamine (400 mg) in dioxane (10 ml) was gradually added dropwise. ,
Stirring was continued for another 3 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain the title compound (22, 700 mg) from a 5% methanol-chloroform eluate.

5) Ethyl (1-amino-1-cyclopropylcarbonylamino) acetate 23 To 680 mg of compound 22, 10 ml of trifluoroacetic acid and 0.5 g of anisole were added, followed by stirring at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and an aqueous solution of potassium carbonate was added to the residue to adjust the pH to 10 or more. After saturated with sodium chloride, the mixture was extracted with chloroform. The chloroform layer was dehydrated with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to obtain the title compound 23 (410 mg). ¹ H-NMR (CDCl ₃ ) δ ppm: 0.85 (2H, t), 1.28 (3H, t), 1.46 (2H, t, J = 4 Hz), 1.
68 (2H, br-s), 4.21 (2H, t, J = 7Hz), 4.40 (2H, d, J =
7Hz), 6) 4,7-Diazaspiro [2,5] octane-5,8-dione 24 Compound 23, 500 mg, was heated in a 220 ° C. oil bath and solidified after foaming. After heating for 20 minutes, cool to room temperature,
A crude product of the title compound 24 was obtained. ¹ H-NMR (DMSO-d ₆ ) δ ppm: 0.96 (2H, t), 1.17 (2H, t, J = 4 Hz), 3.86 (2H, J = 3H)
z), 8.0, 8.25 (1H, br-s) 7) 4,7-Diazaspiro [2,5] octane 25 Compound 24, 350 mg were suspended in anhydrous tetrahydrofuran 200 ml, and lithium aluminum hydride 0.6 g was added.
The mixture was refluxed for 14 hours. After the reaction, 0.6 g of water, 0.6 g of a 15% aqueous sodium hydroxide solution and 1.8 g of water were sequentially added under ice cooling, and the precipitate was collected by filtration. The precipitate was sufficiently washed with tetrahydrofuran and ether, the washings were added to the filtrate, and the solvent was evaporated under reduced pressure to give a crude product of the title 4,7-diazaspiro [2,5] octane 25. Used for the displacement reaction without purification.

Reference Example 4 Synthesis of benzoic acid derivative 1) 3-chloro-2,4,5-trifluoro-benzoic acid 2
7 Add 9.3 g of anhydrous cuprous chloride and 8.8 g of tertiary butyl nitrite to 150 ml of acetonitrile, and heat and stir at 60 ° C to add 3-amino-2,4,5-trifluoro-benzoic acid 26 (commercially available). , 11g
Was added and stirring was continued for 20 minutes. After cooling, 500 ml of 15% hydrochloric acid was added, and the mixture was extracted with ethyl acetate. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was silica gel 10
The residue was subjected to 0 g of column chromatography and eluted with chloroform to obtain 8.4 g of 3-chloro-2,4,5-trifluorobenzoic acid 27 as colorless needles.

Mp: 114-115 ° C. Elemental analysis C ₇ H ₂ ClF ₃ theory as O ₂ C 39.93 H 0.96 Found ^{C 39.87 H 1.04 1 H-NMR} (CDCl 3) δppm: 7.76 (1H, ddd, J = 6.5, 8.5,9.9Hz) 8.6-9.2 (1H, brs) 2) 2,4,5-trifluoro-3-iodobenzoic acid 28 To 150 ml of acetonitrile, 10 g of cuprous iodide and 8.8 g of tertiary butyl nitrite were added. In addition, 11 g of 3-amino-2,4,5-trifluorobenzoic acid was added while heating and stirring at 60 ° C., and the mixture was stirred for 20 minutes. After cooling, 500 ml of 15% hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was applied to a 100 g column of silica gel and eluted with chloroform. The fractions containing the desired compound were collected, the solvent was distilled off under reduced pressure, and the residue was recrystallized from n-hexane to obtain 8.4 g of the title compound as colorless crystals.

Mp: 121-122 ° C. Elemental analysis _{C 7 H 2 F 3 IO 2} · 1 / 4H 2 O Calculated: C 28.26, H 0.51 analysis: C 28.19, H 0.76 MS m / z: 302 (M +) Similarly By using anhydrous cuprous bromide in the above operation, 3
-Bromo-2,4,5-trifluorobenzoic acid 29, melting point 124-
125 ° C.

3) 2,4,5-trifluorobenzoic acid 30 3-1. Direct deamination method 1.8 g of tert-butyl nitrite in anhydrous dimethylformamide
Dissolve in 5 ml and heat and stir at 60 ° C. to give 3-amino-2,4,5-
2.0 g of trifluorobenzoic acid was added, and the mixture was further stirred for 20 minutes. The reaction solution was poured into 50 ml of water and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and then dried under reduced pressure. The residue was applied to a silica gel column and eluted with chloroform to obtain 1.1 g of the title compound as crystals.

3-2. Method of post-reduction of bromo compound 3-bromo-2,4,5-trifluorobenzoic acid 29, 5.0
g, acetic acid 30 ml, sodium acetate 2.0 g, 5% palladium-
1.0 g of carbon was mixed and reduced under a hydrogen atmosphere for 4 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate, the extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 3.2 g of colorless crystals of the title compound.

30; ¹ H-NMR (CDCl ₃ ) δ ppm: 7.10 (1 H, ddd, J = 6.5,9,9H
z), 7.96 (1H, ddd, J = 6.3,8.5,9.8Hz), 9.2-9.6 (1H, b
rs) Example 1: 7- (7-Amino-5-azaspiro [2,4] heptane-5-yl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline- 3-carboxylic acid 31 7-amino-5-azaspiro [2,4] heptane 7,300
mg, 1-cyclopropyl-6,7,8-trifluoro-1,4-
Dihydro-4-oxoquinoline-3-carboxylic acid, 250m
g was added to 5 ml of dimethyl sulfoxide and reacted at 100 ° C. for 30 minutes. After cooling, the solvent was distilled off under reduced pressure, and the residue was crystallized by adding ethanol, and the precipitated crystals were collected by filtration. The obtained crude crystals were suspended in ethanol, dissolved with 28% aqueous ammonia, added with 50 mg of activated carbon, and filtered. The filtrate was concentrated by heating, and the precipitated crystals were collected by filtration to obtain 170 mg of the title compound.

Mp two hundred thirty-eight to two hundred and forty-five ° C. Elemental analysis _{C 19 H 19 F 2 O 3} · 1/2 theory as _{H 2 O C 59.37 H 5.24 N} 10.93 Found C 59.63 H 5.71 N 10.85 Example 2: optically active form of Compound 31 Synthesis of 31a, 31b 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 140 mg
Was suspended in 2 ml of dimethyl sulfoxide, 66 mg of triethylamine and then an aqueous solution of an optically active amine and compound 7a were added, and the mixture was heated at 120 ° C. for 3 hours. After evaporating the solvent under reduced pressure, the residue was purified by preparative TLC (developed in the lower layer of chloroform: methanol: water = 7: 3: 1), and the obtained crystals were re-dissolved from ethanol-28% aqueous ammonia. Crystallization gave 40.5 mg of pale yellow microcrystalline compound 31a. Compound 7
Compound 31b (34 mg) was obtained by the same operation using b.

(+)-7- (7-Amino-5-azaspiro [2,4] heptane-5-yl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3- Carboxylic acid 31a Melting point 221-235 ° C (decomposition) [α] _D +116.2 (c = 0.575, concentrated aqueous ammonia) Elemental analysis value C ₁₉ H ₁₉ F ₂ N ₃ O ₃ · 1/2 H ₂ O Theoretical value C 59.37 H 5.24 N 10.93 found C 59.31 H 5.02 N 10.93 (−)-7- (7-amino-5-azaspiro [2,4] heptane-5-yl) -1-cyclopropyl-6,8-difluoro 1,4-dihydro-4-oxoquinoline-3-carboxylic acid 31b Melting point 227-240 ° C (decomposition) [α] _D −106.3 (c 0.365, concentrated aqueous ammonia) Elemental analysis value C ₁₉ H ₁₉ F ₂ N ₃ O ₃ · 1/2 H ₂ theory as O C 59.37 H 5.24 N 10.93 Found C 59.33 H 4.90 N 10.65 example 3: 7- (7-amino-5-azaspiro [2,4] heptane-5-yl ) -8 -Chloro-1-cyclopropyl-
6-fluoro-1,4-dihydro-4-oxoquinoline-
3-carboxylic acid 32 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 200 mg, compound 11, 150 mg, and 70 mg of triethylamine
Was added to 5 ml of acetonitrile, and the mixture was heated under reflux for 24 hours. After cooling, the solvent was distilled off under reduced pressure, water was added to the residue, and the residue was collected by filtration. water,
After washing with acetonitrile, ethanol and ether in that order and drying, 7- (7-tert-butoxycarbonylamino-5
-Azaspiro [2,4] heptane-5-yl) -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 245 mg, mp 205-207 ° C. I got

0.3 ml of anisole and 5 ml of trifluoroacetic acid were added to 200 mg of the carboxylic acid, and the mixture was stirred at room temperature for 30 minutes. After evaporating the solvent under reduced pressure, the residue was made alkaline by adding water and then a 1N aqueous sodium hydroxide solution, washed twice with chloroform, neutralized with a 10% aqueous citric acid solution (pH 7.1), and extracted three times with chloroform. The extract was washed with water and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was recrystallized from ethanol-concentrated ammonia to obtain 105 mg of the title compound 32.

Melting point: 235-240 ° C (decomposition) Elemental analysis value C ₁₉ H ₁₉ ClFN ₃ O ₃ 1/4 H ₂ O Theoretical value C 57.58 H 4.96 N 10.60 Actual value C 57.64 H 5.33 N 10.37 Example 4: 7− (7-amino-5-azaspiro [2,4] heptane-5-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 33 1-cyclopropyl- 250 mg of 6,7-difluoro-2,3-dihydro-4-oxoquinoline-3-carboxylic acid, 250 mg of compound 11 were added to 4 ml of dimethyl sulfoxide, and 120 ° C.
For 2 hours. After cooling, the solvent was distilled off under reduced pressure, the residue was crystallized by adding ethanol, and the precipitated crystal was collected by filtration.
Of (7-tert-butoxycarbonylamino-5-azaspiro [2,4] heptane-5-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid A crude product was obtained.

To this compound was added 5 ml of trifluoroacetic acid, and the mixture was stirred at room temperature for 30 minutes to remove a tert-butoxycarbonyl group. The solvent was distilled off under reduced pressure, and the residue was dissolved by adding a 1N aqueous sodium hydroxide solution, washed with chloroform, and adjusted to pH 7.0 with 1N hydrochloric acid to precipitate crystals. The precipitated crystals are collected by filtration, and ethanol-
Recrystallized from concentrated aqueous ammonia to obtain 200 mg of the title compound 33.

Melting point: 249-252 ° C Elemental analysis value: C ₁₉ H ₂₀ FN ₃ O ₃ Theoretical value: C 63.85 H 5.64 N 11.76 Actual value: C 63.61 H 5.94 N 11.71 Example 5, Example 6 According to the method of Example 4, 7 -(7-amino-5-azaspiro [2,4] heptane-5-yl) -6-fluoro-
1- (2,4-difluorophenyl) -1,4-dihydro-4
-Oxoquinoline-3-carboxylic acid 34, melting point 226-228 ° C
And 7- (7-amino-5-azaspiro [2,4] heptane-5-yl) -1-cyclopropyl-6-fluoro-
1,4-dihydro-4-oxo-1,8-naphthyridine-3-
Carboxylic acid 35 was obtained.

Melting point: 256-257 ° C. Example 7: 10- (7-Amino-5-azaspiro [2,4]-
Heptan-5-yl) -9-fluoro-2,3-dihydro-3- (S) -methyl-7-oxo-7H-pyrido [1,2,
3-de]-[1,4] benzoxazine-6-carboxylic acid
36 9,10-Difluoro-2,3-dihydro-3- (S) -methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid BF ₂ -chelate, 300m
g, Compound 11 and 250 mg were added to 5 ml of dimethylacetamide, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and 1 ml of triethylamine and 30 ml of 95% methanol were added to the residue.
After cooling under reflux for 6 hours, the solvent was distilled off under reduced pressure, ethanol was added to the residue, and the mixture was triturated, and the crystals were collected by filtration.
The tertiary butoxycarbonyl group was removed from the crystals by the same procedure as in Example 4 to obtain 170 mg of a crude product of the title compound, dissolved in ethanol-concentrated ammonia, recrystallized after treatment with activated carbon, and recrystallized to give 110 mg of the title compound. I got

Melting point: 236-237 ° C. Example 8: 1-Cyclopropyl-7- (4,7-diazaspiro [2,5] octan-7-yl) -6-fluoro-1,4-dihydro-4-oxoquinoline- 3-carboxylic acid 37 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 200 mg, 4,7-
200 mg of the crude product of diazaspiro [2,5] octane 25 was added to 10 ml of dimethyl sulfoxide, 0.3 ml of triethylamine was added, and the mixture was reacted at a bath temperature of 120 ° C. for 2 hours. The solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with chloroform: methanol: water = 15: 3: 1 (v / v). The eluate was recrystallized from ethanol-concentrated ammonia This gave 160 mg of the title compound 37.

Melting point: 243 to 245 ° C (decomposition) Elemental analysis value C ₁₉ H ₂₀ N ₃ O ₃ F 1/4 H ₂ O Theoretical value C 63.03 H 5.71 N 11.61 Actual value C 62.88 H 5.99 N 11.64 ¹ H-NMR ( NaOD-DSS) δ ppm: 0.97 (2H, t, J = 6 Hz), 1.12 (2H, m), 1.36 (2H, br-
t), 1.48 (2H, bt, J = 6H), 7.64 (1H, d, J = 8Hz), 7.9
2 (1H, d, J = 14 Hz), 8.52 (1 H, s) Example 9. 7- (7-acetoxy-5-azaspiro [2,
4] Heptan-5-yl) -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 38 7-acetoxy-5-azaspiro [2,4] Heptane 900
To a solution of 10 mg of dry acetonitrile were added 360 mg of 8-chloro-1-cyclopropyl-6,7-difluoro-3-oxo-3,4-dihydroquinoline-3-carboxylic acid and 1 ml of triethylamine, and the mixture was heated under reflux for 2.5 days ( Three hours later, the above azaspiropeptane, 400 mg, was added). The reaction solution was diluted with chloroform, and the organic layer was washed with a 10% aqueous citric acid solution. After drying, the solvent was distilled off under reduced pressure.

The residue was subjected to column chromatography (silica gel, 20
g) and eluted with chloroform, 3% methanol-chloroform.

Fractions containing the desired product were collected and the solvent was distilled off under reduced pressure. A small amount of ethanol was added to the residue, and the mixture was slightly heated and allowed to stand. The precipitated crystals were collected by filtration and washed with diisopropyl ether to obtain 174 mg of the title compound.

Melting point: 179-182 ° C ¹ H-NMR (CDCl ₃ ) δ: 0.72-1.00 (4H, m), 1.00-1.40
(4H, m), 2.10 (3H, s), 7.95 (1H, d), 8.87 (1H, s) Example 10. 7- (7-Hydroxy-5-azaspiro [2,4] heptan-5-yl ) -8-Chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 39 7- (7-acetoxy-5-azaspiro [2,4] heptane-5) Yl) -8-chloro-1-cyclopropyl-
6-fluoro-1,4-dihydro-4-oxoquinoline-
38, 174 mg of 3-carboxylic acid are suspended in 8 ml of ethanol, and 1N
1.5 ml of an aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 10 minutes. The solvent was distilled off under reduced pressure, chloroform was added to the residue, and the mixture was washed with water. The aqueous layer was made acidic with 1N hydrochloric acid and extracted with chloroform. After drying the extract, the solvent was distilled off under reduced pressure, and the residue was recrystallized from aqueous ammonia-ethanol to obtain 127 mg of the title compound.

Melting point: 242-244 ° C ¹ H-NMR (1N NaOD) δ: 0.53-1.17 (8H, m), 2.98, 3.35,
& 3.74 (1H each), 4.09-4.13 (3H, m), 7.59 (1H, d),
8.45 (1 H, s) Elemental analysis: Calculated for C ₁₉ H ₁₈ N ₂ O ₄ ClF C 58.10 H 4.62 N 7.13 Found C 58.39 H 4.65 N 7.27 Example 11. 7- (7-Hydroxyimino-5-azaspiro) [2,4] Heptan-5-yl) -8-chloro-1-
Cyclopropyl-6-fluoro-1,4-dihydro-4-
Oxoquinoline-3-carboxylic acid 40 5-tert-butoxycarbonyl-7-hydroxyimino-5-azaspiro [2,4] heptane 67, 678 mg, 0.5 ml of anisole was added, and 5 ml of trifluoroacetic acid was added under ice cooling. And stirred for 30 minutes. The solvent was distilled off under reduced pressure, 100 ml of dry acetonitrile was added to the residue, and then 300 mg of 8-chloro-1-cyclopropyl-6,7-difluoro-4-oxo-3,4-dihydroquinoline-3-carboxylic acid, triethylamine After adding 1 ml, the mixture was heated under reflux for 9 hours. The solvent was distilled off under reduced pressure, methanol was added to the residue, and the insoluble matter was removed by filtration. The mother liquor was allowed to stand for 2 days, and the precipitated crystals were collected by filtration and recrystallized from aqueous ammonia-ethanol to give the title compound (58 mg).

Melting point: 239-242 ° C ¹ H-NMR (1N NaOD) δ: 0.70-1.05 (8H, m), 3.50 (2H,
s), 4.09−4.12 (1H, m), 4.29 (2H, s), 7.65 (1H, d, J =
15 Hz), 8.46 (1H, s) Elemental analysis: Calculated as C ₁₉ H ₁₇ N ₃ O ₄ FCl C 56.24 H 4.22 N 10.35 Measured value C 56.34 H 4.34 N 10.32 Example 12. (−) − 10− (7 -Amino-5-azaspiro [2,4] heptane-5-yl) -9-fluoro-2,3-
Dihydro-3- (S) -methyl-7-oxo-7H-pyrido [1,2,3-de]-[1,4] benzoxazine-3-carboxylic acid 36b (-)-9,10-difluoro- 2,3-dihydro-3-
(S) -methyl-7-oxo-7H-pyrido [1,2,3-d
e] [1,4] benzoxazine-3-carboxylic acid BF ₂ chelate 280mg was suspended in anhydrous dimethyl sulfoxide 4 ml,
At room temperature, compound 68b (450 mg) was added, and triethylamine (520 mg) was further added, followed by stirring for 45 minutes. Water was slowly added to the reaction solution while cooling on ice, and the precipitated crystals were collected by filtration. To the collected crystals was added 30 ml of 90% methanol, and triethylamine was added.
The mixture was heated under reflux in the presence of 2 ml for 17 hours. The solvent was distilled off under reduced pressure,
The residue was recrystallized from aqueous ammonia-ethanol to obtain 73 mg of the title compound.

Melting point: 217-238 ° C [α] _D -109.22 ゜ (C = 0.683, 1N NaOH) ¹ H-NMR (1N NaOD) δ: 0.38-0.68 (4H, m), 1.31 (3H,
d, J = 5Hz), 2.91-4.39 (8H, m) 7.28 (1H, d, J = 15Hz), 8.17 (1H, s) Elemental _{analysis: C 19 H 20 N 3 O} 4 F · 1 1/4 H Calculated for ₂ O C 57.64 H 5.73 N 10.61 Found C 57.64 H 5.21 N 10.81 Example 13. (−)-7- (7-Amino-5-azaspiro [2,4] heptane-5-yl) -1 -Cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid 35b 7-chloro-1-cyclopropyl-6-fluoro-4
-Oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (282.5 mg), compound 68b (200 mg) and triethylamine (1 g) were added to dimethyl sulfoxide (6 ml), and the mixture was stirred at 110 ° for 1 hour. After evaporating the solvent under reduced pressure, diethyl ether was added to the residue and the precipitate was collected by filtration. To this was added 1N hydrochloric acid, washed with chloroform, the aqueous solution was made alkaline with a 1N aqueous sodium hydroxide solution, and washed again with chloroform. . Then, the alkaline solution was concentrated to pH 7.1 with concentrated hydrochloric acid under ice-cooling.
Was adjusted. The precipitated colorless crystals were collected by filtration, washed with water, ethanol and ether and dried. Recrystallization from concentrated aqueous ammonia and ethanol gave 283 mg of the title compound as colorless fine needles.

Melting point: 240-250 ° C (decomposition) [α] _D -13.6 ゜ (C = 0.66,1N NaOH) Elemental analysis: Calculated as C ₁₈ H ₁₉ H ₃ O ₃ F 1 / 4H ₂ O C 59.58 H 5.42 N 15.44 measured value C 59.68 H 5.40 N 15.36 Example 14. 7- (7-amino-5-azaspiro [2,4]
Heptane-5-yl) -1,4-dihydro-6-fluoro-1- (2-methyl-2-propyl) -4-oxo1,8
-Naphthyridine-3-carboxylic acid 41b Compound 68b (200 mg) was suspended in acetonitrile (15 ml), triethylamine (3 ml) was added, and the mixture was heated under reflux to give 7-chloro-
1,4-dihydro-6-fluoro-1- (2-methyl-2
-Propyl) -4-oxo-1,8-naphthyridine-3-
327 mg of carboxylic acid ethyl ester were added in small portions. 1
After heating under reflux for one hour, the solvent was distilled off under reduced pressure, water was added to the residue, extracted with chloroform and n-butanol, the organic layers were combined, and the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue, and the precipitate was collected by filtration to obtain 516 mg of a white powder. ¹ H-N
_{MR (DMSO-d 6) δ} : 0.77-1.05 (4H, m), 1.27 (3H, t, J =
7Hz), 1.82 (9H, s), 2.86-3.36 (4H, m), 4.20 (1H,
m), 4.21 (2H, q, J = 7Hz), 7.91 (1H, d, J = 13Hz), 8.68
(1H, s).

510 mg of the obtained white powder was suspended in 2 ml of water, 2 ml of a 1N aqueous sodium hydroxide solution was added, and the mixture was heated under reflux for 40 minutes. 5 ml of water was added, the pH was adjusted to 7.5 with 0.25N hydrochloric acid, and the precipitated crystals were collected by filtration and washed with water. After drying, recrystallization from ethanol gave 171 mg of the title compound as a white powder.

Melting point: 243-247 ° C (decomposition) [α] _D -16.7 ゜ (C = 0.504, 1N NaOH) ¹ H-NMR (DMSO-d ₆ ) δ: 0.45-0.82 (4H, m), 1.87 (9H,
s), 2.80-3.80 (4H, m), 4.00 (1H, m), 7.98 (1H, d, J =
13Hz), 8.82 (1H, s) Elemental analysis: Calculated as C ₁₉ H ₂₀ H ₄ O ₃ F 1/2 H ₂ O Calculated value C 59.52 H 6.31 N 14.61 Measured value C 59.17 H 6.17 N 14.49 Reference example 5.2 Synthesis of 4,5-trifluoro-3-methylbenzoic acid 1) Dimethyl 3,5,6-trifluoro-4-nitromethylphthalate 42 Dimethyl tetrafluorophthalate (The Chemical Society of Japan, 19
76, 200, Ishikawa, Suzuki, Tanabe), 200 g of nitromethane 400
The mixture was dissolved in ml and cooled with ice-salt. After the dropwise addition, the mixture was further stirred at an internal temperature of 10 ° C. for 30 minutes,
The mixture was poured into a mixture of 1.5 liters of normal hydrochloric acid and 1 liter of ice.

The reaction solution was extracted with benzene, the organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was applied to a silica gel column (500 g) and eluted with benzene.
195 g of the title compound were obtained as a yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 3.88 (3H, s), 3.94 (3H, s), 5.60
(2H, t, J = 2Hz) 2) Dimethyl 4-dimethylaminomethyl-3,5,6-
Dimethyl trifluorophthalate 43 Compound 42, 5.0 g, Raney nickel 10 ml, formalin (35%) 15 ml, and ethanol 70 ml were mixed and reduced at normal pressure for 22 hours.

The solvent was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was dissolved in chloroform and washed with water. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 5.2 g of the title compound as a pale yellow oily substance. ¹ H-NMR (CDCl ₃ ) δ: 2.32 (6H, s), 3.70 (2H, t, J = 2H
z), 3.96 (3H, s), 3.98 (3H, s) 3) 2,5,6-trifluoro-3,4-di (methoxycarbonyl) phenylmethylene-trimethyl-ammonium
5.2 g of the iodide 44 compound was dissolved in 50 ml of ethanol, 5 ml of methyl iodide was added, and the mixture was allowed to stand for 1.5 hours. The precipitated crystals are collected by filtration.
3.6 g of the title compound were obtained as colorless crystals.

Melting point: 186-190 ° C (decomposition) 4) Dimethyl 3,5,6-trifluoro-4-methylphthalate 45 a) Compound 42, 4.6 g, 6.8 g of tributyltin hydride,
300 mg of α, α'-azobisisobutyronitrile and 70 ml of benzene were mixed and heated under reflux for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was applied to a 50 g column of silica gel, and eluted with benzene to obtain 2.45 g of the title compound as a pale oily substance.

b) Compound 44, 17.0 g, Raney nickel 30 ml, and ethanol 350 ml were mixed and reduced under normal pressure for 25.5 hours while irradiating and heating with a tungsten lamp.

The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. Water was added to the residue, extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 9.62 g of the title compound as a yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 2.29 (3H, t, J = 2 Hz), 3.91 (3H,
s), 3.93 (3H, s) 5) 3,5,6-trifluoro-4-methylphthalic acid 46 Compound 45, 2.45 g, 10 ml of acetic acid and 20 ml of concentrated hydrochloric acid were mixed.
Heated to reflux for an hour. The reaction solution was concentrated under reduced pressure, and the residue was extracted with diethyl ether and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 2.1 g of the title compound as colorless crystals.

Melting point: 155-160 ° C 6) 2,4,5-Trifluoro-3-methylbenzoic acid 47 Compound 46, 10.1 g was dissolved in 40 ml of water and the bath temperature was 200 ° C in a sealed tube.
The reaction solution was reacted for 4 days with chloroform, extracted with chloroform, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 6.2 g of the title compound as pale yellow crystals.

Melting point: 89-90 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.29 (3H, t, J = 2 Hz), 7.56-7.84
(1H, m), 8.1-8.6 (1H, broad) Reference Example 6. Ethyl 2,4,5-trifluoro-3-methylbenzoyl acetate 48 2,4,5-trifluoro-3-methylbenzoic acid 47, 9.89g
Was dissolved in 200 ml of benzene, and 40 ml of thionyl chloride was added.
Heated to reflux for an hour. The reaction solution was dried under reduced pressure, 200 ml of benzene was added to the residue, and the residue was again dried under reduced pressure to obtain a crude acid chloride, which was dissolved in 200 ml of diethyl ether.

Magnesium 1.26 g, ethanol 250 ml, carbon tetrachloride 6 m
and stirred at room temperature for 1 hour. Diethyl malonate
After dropwise adding 8.34 g of a diethyl ether solution (50 ml) over 10 minutes, the mixture was stirred at room temperature for 1 hour. The reaction solution was dried under reduced pressure and dissolved in 300 ml of diethyl ether. The diethyl chloride solution of the above acid chloride was added dropwise to the mixture over 10 minutes, and the mixture was stirred at room temperature for 4 days. 100 ml of 1N hydrochloric acid was added. After stirring, the ether layer was separated, washed with water, dried over anhydrous sodium sulfate, and the solvent was removed. The solvent was distilled off under reduced pressure. 50 ml of water and 50 ml of p-toluenesulfonic acid were added to the residue.
0 mg was added and the mixture was heated under reflux for 7 hours. The reaction solution was extracted with chloroform, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was applied to a silica gel column and eluted with benzene to obtain 6.1 g of a colorless oil. Partially crystallized on standing.

Reference Example 7. Ethyl 2-cyclopropylaminomethylene-3-oxo-3- (2,4,5-trifluoro-3-methyl) -phenylpropionate 49 Compound 48, 1.57 g, ethyl orthoformate 6 ml, acetic anhydride 6m
and mixed under heating at 120 ° C. for 3 hours. The reaction solution was dried under reduced pressure, dissolved in 25 ml of 1,2-dichloromethane, added with 10 ml of a 1,2-dichloromethane solution of 400 mg of cyclopropylamine, and stirred at room temperature for 14 hours. The reaction solution was evaporated to dryness under reduced pressure, melting point 61
This gave 2 g of the title compound as colorless crystals at -64 ° C.

Reference Example 8. 1-Cyclopropyl-6,7-difluoro-8
-Methyl-4-oxo-1,4-dihydroquinoline-3-
Ethyl carboxylate 50 Dissolve 1.97 g of compound 49 in 30 ml of anhydrous dioxane and 60%
360 mg of sodium hydride was added, and the mixture was stirred at room temperature for 18 hours.
The reaction solution was added with 10 ml of 1N hydrochloric acid, concentrated under reduced pressure, water was added, and the crystals were collected by filtration, washed with water, a small amount of ethanol and diethyl ether to obtain 1.35 g of the title compound as colorless crystals.

Melting point: 204-210 ° C Reference Example 9. 1-Cyclopropyl-6,7-difluoro-8
-Methyl-4-oxo-1,4-dihydroquinoline-3-
50. 1.30 g of carboxylic acid 51 compound and 10 ml of concentrated hydrochloric acid were mixed and heated under reflux for 3 hours. 50 ml of water was added to the reaction solution, and the crystals were collected by filtration and washed with water and ethanol to obtain 1.12 g of the title compound.

Melting point: 241-242 ° C. Reference Example 10. 1-Cyclopropyl-6,7-difluoro-8
-Methyl-4-oxo-1,4-dihydroquinoline-3-
Carboxylic acid BF ₂ - chelate 52 Compound 50,420mg was suspended in diethyl ether 30 ml,
Add 2 ml of boron trifluoride diethyl ether complex and add
Stir for 4 hours.

The crystals were collected by filtration and washed with diethyl ether to give 487 mg of the title compound as yellow crystals.

Melting point: 275-278 DEG C. Example 15. (-)-7- (7-Amino-5-azaspiro [2,3] heptane-5-yl) -1-cyclopropyl-6-fluoro-8-methyl-4 -Oxo-1,4-dihydroquinoline-3-carboxylic acid 55b Compound 52, 340 mg, 7-tert-butoxycarbonylamino-5-azaspiro [2,3] heptane 11b, 330 mg, triethylamine 150 mg, and dimethyl sulfoxide 5 ml are mixed. And stirred at room temperature for 5 days. The reaction solution is chloroform 100m
The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.

The residue was applied to a 30 g column of silica gel and eluted with chloroform-methanol (95: 5). The obtained 7- (7-
Tertiary butoxycarbonylamino-5-azaspiroheptane-5-yl) -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline-
3-carboxylic acid BF ₂ chelate was dissolved in 70% methanol 30 ml, was heated under reflux for 3 hours by the addition of triethylamine 1 ml.

The reaction solution was concentrated under reduced pressure, 20 ml of 10% citric acid was added to the residue, and the mixture was extracted with chloroform. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. 10 ml of trifluoroacetic acid was added to the residue, and the mixture was stirred at room temperature for 20 minutes and dried under reduced pressure. Hydrochloric acid was added to the residue, and the mixture was washed with chloroform. The aqueous layer was adjusted to pH 12 with an aqueous sodium hydroxide solution under ice cooling and washed with chloroform. The aqueous layer was adjusted to pH 7.4 with hydrochloric acid and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was recrystallized twice from aqueous ammonia-ethanol.
52 mg of colorless crystals were obtained.

Melting point 180-182 ° C [α] _D- 128.0 ゜ (c = 0.125,1N NaOH) ¹ H-NMR (CDCl ₃ ) δ: 0.61-0.63 (1H, m), 0.64-0.74
(2H, m), 0.84-0.88 (1H, m), 0.90-0.97 (2H, m), 1.1
9-1.28 (2H, m), 2.62 (3H, s), 3.19−3.21 (1H, m), 3.
29 (1H, d, J = 9Hz), 3.36-3.39 (1H, m), 3.84 (1H, d, J
= 9Hz), 3.99−4.03 (1H, m), 4.05−4.08 (1H, m), 7.85
(1H, d, J = 13.5 Hz), 8.86 (1H, s) Example 16: Optically active 7- [7- (tert-butoxycarbonylamino) -5-azaspiro [2,4] heptane-5
Yl] -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 56a, 56b 8-chloro-1-cyclopropyl-6,7-difluoro-1 , 4-Dihydro-4-oxoquinoline-3-carboxylic acid, 500 mg, compound 11b, 440 mg and triethylamine 2
ml was dissolved in 20 ml of acetonitrile and refluxed overnight. After cooling, the precipitate obtained by concentrating the solvent under reduced pressure was collected by filtration, and washed with water,
It was washed with acetonitrile, ethanol and ether in that order and dried under reduced pressure. 56 g of the title compound as pale yellow crystals
0 mg was obtained. Compound 56a was obtained from compound 11a in a similar manner.

56b; pale yellow crystal, melting point: 216-217 ° C. [α] _D- 134.7 (c = 1.655, chloroform) ¹ H-NMR (CDCl ₃ ) δ ppm: 0.4-1.6 (8H, m), 1.45 (9H,
s), 3.33 (1H, d, J = 9 Hz), 3.60 (1H, d, J = 9 Hz), 3.7-
4.5 (4H, m), 4.7-5.1 (1H, br d), 7.95 (1H, d, J = 12.9
Hz), 8.87 (1H, s ) Elemental analysis _{C 24 H 27 N 3 O 5} ClF Calculated: C 58.60, H 5.53, N 8.54 Analytical values: C 58.43, H 5.59, N 8.40 56a; pale yellow crystals, melting point : 215-216 ° C [α] _D +131.4 (c = 0.77, chloroform) Elemental analysis Calculated for C ₂₄ H ₂₇ N ₃ O ₅ ClF Calculated: C 58.60, H 5.53, N 8.54 Analytical value: C 58.37, H 5.58 , N 8.44 Incidentally, the NMR spectrum completely coincided with 56b.

Example 17: Optically active 7- (7-amino-5-azaspiro- [2,4] heptane-5-yl) -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4- Oxoquinoline-3-carboxylic acid 32a, 32b To 520 mg of compound 56b, 0.5 ml of anisole and 10 ml of trifluoroacetic acid were added under ice-cooling, and the mixture was returned to room temperature and stirred for 30 minutes. After evaporating the solvent under reduced pressure, water is added to the residue, and a 1N aqueous sodium hydroxide solution is added under ice cooling to adjust the pH to about 11-12. After washing this aqueous solution twice with chloroform, the pH was adjusted to about 7 with concentrated hydrochloric acid and a 10% aqueous citric acid solution. After extraction with chloroform three times, the extract was washed with water and dried. The solvent was distilled off under reduced pressure, and the solid residue was recrystallized from ethanol-aqueous ammonia to obtain 328 mg of the title compound 32b as pale yellow crystals. Compound 32a was obtained from compound 56a in the same manner.

Compound 32b: pale yellow crystal Melting point: 166-170 ° C. (decomposition) [α] _D- 112.6 (c = 0.43, 1N aqueous sodium hydroxide solution) ¹ H-NMR (CDCl ₃ , 500 MHz) δ ppm: 0.6-1.25 (8H, m), 3.0
8 (1H, t, J = 4.4Hz), 3.30 (1H, d, J = 10.3Hz), 3.41 (1
H, d, J = 9.5Hz), 3.96 (1H, d, J = 9.5Hz), 4.11 (1H, m),
4.24 (1H, m), 7.75 (1H, d, J = 13.5Hz), 8.55 (1H, s) Elemental analysis: C ₁₉ H ₁₉ N ₃ O ₃ ClF · 1 / 2H ₂ O Calculated value: C 56.93, H 5.03, N 10.48 Analytical value: C 57.16, H 5.44, N 10.46 Compound 32a; pale yellow crystal Melting point: 160-165 ° C (decomposition) [α] _D ＋ 110.3 (c = 0.435, 1N aqueous sodium hydroxide) Element Analysis C ₁₉ H ₁₉ N ₃ O ₃ ClF ・ 1 / 2H ₂ O Calculated: C 56.93, H 5.03, N 10.48 Analytical value: C 56.87, H 5.37, N 10.32 The NMR spectrum is completely the same as that of compound 32b. Matched.

Reference Example 11. 8-Chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-
Carboxylic acid BF ₂ -chelate 57 8-Chloro-1-cyclopropyl-6,7-difluoro-4-oxoquinoline-3-carboxylic acid 3 g is suspended in anhydrous diethyl ether 30 ml, then boron trifluoride diethyl ether complex 15 ml was added and the mixture was stirred at room temperature for 2 hours. The precipitate was collected by filtration, washed several times with ether, and dried under reduced pressure to give 3.35 g of the title compound as a colorless powder.

Melting point: 245-260 ° C (gradual decomposition) Elemental analysis value Calculated as C ₁₃ H ₇ NO ₃ BCIF ₄ C 44.94 H 2.03 N 4.03 Observed value C 45.07 H 2.21 N 4.12 Example 18. (−)-7- ( 7-Amino-5-azaspiro [2,4] heptane-5-yl) -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 32a Compound 57 , 700 mg, compound 68b, 450 mg and 610 mg of triethylamine were added to 7 ml of dimethyl sulfoxide at room temperature.
Stirred for 24 hours. Water was added to the reaction solution, and the deposited yellow precipitate was collected by filtration and dried. To this, 50 ml of 95% methanol and 1 ml of triethylamine were added and stirred for 1 hour. After evaporating the solvent under reduced pressure, 1N hydrochloric acid was added to the residue, and the mixture was washed with chloroform. The aqueous layer was made alkaline with 1N sodium hydroxide and washed again with chloroform. Next, concentrated hydrochloric acid was added dropwise to the alkaline solution under water cooling until the pH reached 7.1, and the aqueous solution was extracted three times with chloroform. The extract was washed with a saturated aqueous sodium chloride solution and dried. The solvent was distilled off under reduced pressure, and the obtained crystals were recrystallized from ammonia-ethanol to obtain 610 mg of the title compound as colorless crystals.

Reference Example 12. Separate synthesis of 4,7-dioxo-5- [1- (R) -phenylethyl-5-azaspiro [2,4] heptane 12 1) 1-Acetylcyclopropane-1-carboxylic acid 58 Compound 2 Was dissolved in 400 ml of ethanol, and an aqueous solution of sodium hydroxide (75.67 g) in water (200 ml) was added at room temperature for 20 minutes.
The mixture was added dropwise over a period of minutes (the internal temperature was 21 to 41 ° C.), and the mixture was stirred at room temperature for 2 hours. 1,500 ml of dichloromethane and 1,500 water were added to the reaction solution.
After shaking, liquid separation was performed.
And washed twice. The aqueous layer was adjusted to pH 2 with concentrated hydrochloric acid under water cooling.
Extracted with 1,500 ml of dichloromethane. The aqueous layer was extracted again with 500 ml of dichloromethane, and the dichloromethane layer was collected.
After washing with 00 ml, the dichloromethane layer was dried over anhydrous sodium sulfate. The dichloromethane was distilled off under reduced pressure to obtain 232 g of the title compound which was colorless and transparent. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.6-2.0 (4H, m), 2.21 (3H,
s) 2) N- [1- (R) -phenylethyl] -1-acetyl-1-cyclopropanecarboxamide 59 Compound 23, 232.0 g was dissolved in chloroform 1,500 ml,
Add 250.8 ml of triethylamine, cool to an internal temperature of -40 ° C in a dry ice-acetone bath, and add ethyl chloroformate.
215.9 g was added dropwise over 20 minutes (internal temperature −40 to 30 ° C.). After stirring at around -30 ° C for 40 minutes, the mixture was cooled again to -40 ° C, and R-
241.1 g of (+)-1-phenylethylamine was added dropwise over 20 minutes (internal temperature −25 ° C.). The mixture was stirred for 1.5 hours and washed with 1N hydrochloric acid. After washing again with 1N hydrochloric acid, washing with water and a saturated aqueous solution of sodium hydrogencarbonate was followed by washing with water. The chloroform layer was dried over anhydrous sodium sulfate, and chloroform was distilled off under reduced pressure to obtain 489.3 g of the title compound as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.50 (3H, d, J = 7.2 Hz), 1.4-
1.6 & 1.7-1.9 (2H, m each), 1.95 (3H, s), 5.10 (1H, q, J
= 7.2 Hz), 7.30 (5H, s) 3) N- [1- (R) -phenylethyl] -1- (1,
1-Ethylenedioxyethyl) -1-cyclopropanecarboxamide 60 Compound (59, 248.4 g) was dissolved in benzene (800 ml), ethylene glycol (230 ml), p-toluenesulfonic acid-water salt (1) were dissolved.
0.0 g was added, and the mixture was heated and refluxed for 24 hours while being dehydrated.
500 ml of water and 500 ml of benzene were added to carry out liquid separation, followed by washing with a saturated aqueous solution of sodium hydrogen carbonate and then with water, and drying the benzene layer with anhydrous sodium sulfate. The benzene is distilled off under reduced pressure,
227.8 g of the title compound were obtained. ¹ H-NMR (CDCl ₃ ) δ ppm: 0.7-0.95 & 1.0-1.2 (2H,
m), 1.48 (3H, s), 1.47 (3H, d, J = 7.2Hz), 3.98 (4H,
s), 5.11 (1H, q, J = 7.2Hz), 7.31 (5H, s), 7.75 (1H, b
s) 4) N- [1- (R) -phenylethyl] -1- (2
-Bromo-1,1-ethylenedioxyethyl) -1-cyclopropanecarboxamide 61 To 436 ml of dioxane, 145.4 g of bromine was added dropwise over 30 minutes at room temperature (the internal temperature rose to 35 degrees). Partly, a dioxane bromine complex was precipitated. The mixture was stirred at the same temperature for 30 minutes, and a solution of compound 60 and 227.8 g of dichloromethane in 2,000 ml was added all at once (the internal temperature was lowered from 35 ° C. to 25 ° C., and then raised to about 35 ° C.). The mixture was stirred for 2 hours, an aqueous solution of sodium thiosulfate was added, and after liquid separation, the organic layer was washed with water. The dichloromethane layer was dried over anhydrous sodium sulfate, and dichloromethane was distilled off under reduced pressure to obtain 326.0 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ ppm: 0.7-1.0 & 1.0-1.25 (2H,
m), 1.49 (3H, d, J = 7.2 Hz), 3.69 (2H, s), 3.8-4.3 (4
H, m), 5.08 (1H, q, J = 7.2Hz), 7.30 (5H, s), 7.6 (1H, b
s) 5) 4,7-Dioxo-5- [1- (R) -phenylethyl] -5-azaspiro [2,4] heptane-7-ethyleneacetal 62 Compound 61, 293.0 g was obtained by adding N, N-dimethylformamide 1,500
The solution was dissolved in 100 ml, and 43.0 g of 60% sodium hydride was added in three portions at room temperature in small portions over 1.5 hours. Internal temperature from 28 ℃ to 35
Since heat was generated up to about ° C, the reaction was cooled with ice water, the reaction was continued at an internal temperature of about 30 ° C, and reacted at room temperature for 18 hours. Pour the reaction mixture on ice,
The mixture was extracted with 3,000 ml of ethyl acetate and washed several times with water, and the ethyl acetate layer was dried over anhydrous sodium sulfate. After concentrating the solvent and treating with activated carbon, the solvent was distilled off under reduced pressure to obtain 203.3 g of the title compound as a black oil. ¹ H-NMR (CDCl ₃ ) δ ppm: 0.98-1.38 (4H, m), 1.50 (3H,
d, J = 7.2Hz), 3.07 & 3.41 (1H, d, J = 10.2Hz each), 3.83
(4H, s), 5.61 (1H, q, J = 7.2Hz), 7.30 (5H, s) 6) 4,7-dioxo-5- [1- (R) -phenylethyl] -5-azaspiro [2 , 4] Heptane 12 Compound 62,203.3g, acetone 1,000ml and 1N hydrochloric acid 300ml
Was added and heated under reflux for 1.5 hours. Acetone was distilled off under reduced pressure, and 1,500 ml of ethyl acetate was added to the residue. After washing with water, the ethyl acetate layer was dried over anhydrous sodium sulfate. After activated carbon treatment, the ethyl acetate was distilled off under reduced pressure to give the title compound as a crude product.
0.0 g was obtained. The residue was subjected to silica gel column chromatography (silica gel 1.3 kg), and eluted with chloroform containing 0-10% ethyl acetate to obtain 65.7 g of the title compound as white crystals. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.61 (3H, d, J = 7.2 Hz), 1.4-
1.75 (4H, m), 3.48 & 3.88 (1H, d, J = 17.7Hz each), 5.81
(1H, q, J = 7.2 Hz), 7.34 (5H, s) Reference Example 13. 5-tert-butoxycarbonyl-7-hydroxyimino-5-azaspiro [2,4] heptane 67 1) 7,7- Ethylenedioxy-5- [1- (R) -phenylethyl] -5-azaspiro [2,4] heptane 63 2.5 g of lithium aluminum hydride was slowly added to a solution of compound 62, 7.1 g of dry tetrahydrofuran in 150 ml under ice-cooling. After the addition, the mixture was heated under reflux for 3.5 hours. The reaction solution was cooled, and under ice-cooling, 2.5 ml of water and 2.5% of a 15% aqueous sodium hydroxide solution.
ml and finally 7.5 ml of water. The insoluble material was removed by filtration, and the solvent of the filtrate was distilled off under reduced pressure. The residue was eluted with a mixed solvent of hexane-ethyl acetate (3: 2) with respect to column chromatography (100 g of silica gel) to obtain 5.67 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ ppm: 0.40-0.60 (2H, m), 0.76-0.9
6 (2H, m), 1.36 (3H, d, J = 7.2Hz), 2.40−2.88 (4H,
m), 3.77 (4H, s), 7.18-7.50 (5H, m) 2) 7,7-ethylenedioxy-5-azaspiro [2, 4]
Heptane 64 4 g of 5% palladium-carbon was added to a solution of 3.885 g of compound 63 and 3.885 g of 50 ml of ethanol, and the mixture was reduced under a hydrogen atmosphere at 4 atm while heating with a tungsten lamp. Three hours later,
The catalyst was removed by filtration, and the solvent in the filtrate was distilled off under reduced pressure to obtain 2 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ ppm: 0.44-0.64 (2H, m), 0.72-0.9
2 (2H, m), 3.03 & 3.05 (2H, s each), 3.86 (4H, s) 3) 5-tert-butoxycarbonyl-7,7-ethylenedioxy-5-azaspiro [2,4] 1.515 g of triethylamine and 3.05 g of di-tert-butyl dicarbonate were added to a solution of heptane 65 compound 64 and 1.98 g of a dry dichloromethane 25 ml solution under ice-cooling, followed by stirring at room temperature for 30 minutes. The solvent was distilled off under reduced pressure and chloroform was added to the residue.
After the organic layer was washed with water and dried, the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography (silica gel 50 g).
Elution with a mixed solvent of hexane-ethyl acetate (3: 1) gave 3.21 g of the title compound.

4) 5-tert-butoxycarbonyl-7-oxo-5
-Azaspiro [2,4] heptane 66 To a solution of 3.65 g of Compound 65 and 3.15 g of acetone in 30 ml of 5N hydrochloric acid was added, and the mixture was heated under reflux for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was extracted with chloroform. After drying the chloroform layer,
The solvent was distilled off under reduced pressure to obtain 1.94 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.00-1.20 & 1.30-1.50 (each 2
H, m), 4.49 (9H, s), 3.78 (2H, m), 3.95 (2H, s) 5) 5-tert-butoxycarbonyl-7-hydroxyimino-5-azaspiro [2,4] heptane 67 1.25 g of hydroxylamine hydrochloride and 1.8 g of triethylamine were added to a solution of compound 66 and 1.9 g of ethanol in 10 ml, and the mixture was stirred at room temperature for about 1 day (1 ml of triethylamine was added on the way). The solvent was distilled off under reduced pressure, 10% aqueous citric acid solution was added to the residue, and the mixture was extracted with chloroform. The extract was washed with water and dried, and the solvent was distilled off under reduced pressure to obtain 1.86 g of the title compound.

Melting point: 117-119 ° C ¹ H-NMR (CDCl ₃ ) δ ppm: 0.90-1.10 & 1.14-1.34 (each 2
H, m), 1.45 (9H, s), 3.36 (2H, s), 4.29 (2H, s) Reference Example 14. 7-amino-5-azaspiro [2,4] heptane dihydrochloride 68b Compound 15b, 630 mg 800 ml of 5% palladium-carbon was added to a solution of 10 ml of 1N hydrochloric acid and 20 ml of ethanol, and the mixture was reduced under a hydrogen atmosphere at 4 atm while heating with a tungsten lamp. After 3.5 hours, the catalyst was removed and the solvent of the filtrate was distilled off under reduced pressure to obtain 350 mg of the title compound.

Mp: 230-240 ° C. (decomposition begins to decompose at around 190 ℃) [α] _D -41.5 ° _{(c = 1.616, H 2 O} ) Elemental analysis _{C 6 H 14 N 2 Cl 2} · 1/2 H 2 Calculated as O C 37.13 H 7.79 N 14.43 Found C 37.49 H 7.32 N 14.59 MS: m / z = 149 (M ⁺ -HCl) ¹ H-NMR (CDCl ₃ ) δ ppm: 0.79-1.60 (4H, m), 3.08 (1H,
d, J = 12Hz), 3.48-3.67 (3H, m), 3.93 (1H, dd, J = 7 &
13.5 Hz) Reference Example 15. 7-tert-butoxycarbonylamino-5
-Azaspiro [2,4] heptane 11b 11g of 50% aqueous 5% palladium-carbon was added to a solution of compound 16b and 11.8g in 200ml of ethanol, and the mixture was catalytically reduced while heating with a tungsten lamp. After 6 hours, the catalyst was removed and the solvent of the filtrate was distilled off under reduced pressure. Ethyl acetate was added to the residue, and extracted with a 10% aqueous citric acid solution. The aqueous layer was washed with ethyl acetate, made alkaline with a 15-20% aqueous sodium hydroxide solution, and extracted with chloroform. The extract was dried and the solvent was distilled off under reduced pressure to obtain 7.6 g of the title compound.

Melting point: 56-59 ° C. [α] _D −68.54 ° (c = 1.742, CHCl ₃ ) Reference Example 16.1) 285 ml of diethylcyclobutylidene malonate 70 tetrahydrofuran was cooled to −30 ° C., and stirred therein. A solution of 15.7 ml of titanium tetrachloride and 36 ml of carbon tetrachloride was quickly added dropwise. 5 g of cyclobutane and 10.83 g of diethyl malonate are added thereto, and a solution of 23.1 ml of pyridine in 50 ml of tetrahydrofuran is maintained at an internal temperature of -10 ° C or lower.
It was dropped over time. After completion of the dropwise addition, the mixture was stirred at an internal temperature of 0 ° C for 18 hours. Water and diethyl ether were added to the reaction solution, and after separation, the aqueous layer was extracted twice with diethyl ether. The organic layer was washed sequentially with a saturated aqueous sodium chloride solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated aqueous sodium chloride solution. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to obtain 17.265 g of the title compound as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.29 (6H, t, J = 7.3 Hz), 1.7-
2.4 (2H, m), 3.15 (4H, t, J = 7.7Hz), 4.22 (4H, q, J = 7.
3 Hz) Diethylcyclopentylidene malonate 71 ( ¹ H-NMR (CDCl ₃ ) δ ppm: 1.29 (6H, t, J)
= 7Hz), 1.6-2.0 (4H, m), 2.6-2.8 (4H, m), 4.24 (4
H, q, J = 7 Hz)) and diethylcyclohexylidene malonate 72 ( ¹ H-NMR (CDCl ₃ ) δ ppm: 1.28 (6 H, t, J = 7.2 H)
z), 1.4-1.85 (6H, br), 2.3-2.3 (4H, br), 4.22 (4H, br)
q, J = 7.2 Hz)).

2) Diethyl (1-nitromethyl-1-cyclobutyl) malonate 73 A mixture of compound 70, 15.32 g, nitromethane 59 ml, and tetramethylguanidine 4.5 ml was stirred at room temperature for 16 hours. After adding chloroform to the reaction solution and washing with a 10% aqueous citric acid solution, the organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 19.027 g of the title compound as a yellow oil. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.28 (6H, t, J = 7.1 Hz), 1.8-
2.4 (6H, m), 4.20 (4H, q, J = 7.1Hz), at 4,82 (2H, s) the same manner as described above, diethyl (1-nitromethyl-1-cyclopentyl) malonate 74 ⁽¹ H -NMR (CDC
_{l 3) δppm: 1.27 (6H} , t, J = 7Hz), 1.6-2.0 (8H, m), 3.7
9 (1H, s), 4.20 (4H, q, J = 7Hz), 4.71 (2H, s)) and diethyl (1-nitromethyl-1-cyclohexyl) malonate ^{75 (1 H-NMR (CDCl} 3) δppm: 1.27 (6H, t, J = 7H
z), 1.4-1.8 (10H, M), 3.88 (1H, s), 4.20 (4H, q, J = 7
Hz), 4.96 (2H, s)).

3) Ethyl 7-oxo-6-azaspiro [3,4] octane-8-carboxylate 76 Compound 73, 19.03 g, was dissolved in 400 ml of ethanol,
After degassing by adding 30 ml of Raney nickel washed with ethanol, the mixture was catalytically reduced in a hydrogen gas atmosphere for 2 days. After filtering off the catalyst, the solvent was distilled off under reduced pressure. Ethyl acetate and 1N in residue
Hydrochloric acid was added and the mixture was shaken and separated. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was applied to a flash column of 100 g of silica gel, and eluted with chloroform containing 0 to 3% of methanol to obtain 2.972 g of the title compound. On the other hand, the 1N hydrochloric acid layer was neutralized with sodium hydrogen carbonate,
Extracted with ethyl acetate. This was repeated, the organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
1.583 g of the title compound were obtained. A total of 4.555 g was obtained. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.28 (3H, t, J = 7.1 Hz), 1.8-
2.2 (6H, m), 3.21 (1H, s), 3.41 (1H, dd, J = 9.7 & 1.4H
z), 3.60 (1H, d, J = 9.7Hz), 4.20 (2H, q, J = 7.1Hz), 7.
21 (1H, br) In a similar manner, ethyl 3-oxo-2-azaspiro [4,4] nonane-4-carboxylate 77 ⁽¹ H-NMR (CD
Cl ₃ ) δ ppm: 1.28 (3H, t, J = 7.1 Hz), 2.6-2.8 (8H, b
r), 3.07 (1H, s), 3.01 (1H, dd, J = 7.3 & 1.3Hz), 3.45
(1H, d, J = 9.3Hz), 4.20 (2H, q, J = 7.3Hz), 7.30 (1H,
s)) and ethyl 3-oxo-2-azaspiro [4,5] decane-4-carboxylate ^{78 (1 H-NMR (CDCl} 3) δpp
m: 1.29 (3H, t, J = 7.3 Hz), 1.3-1.7 (1H, br), 3.05 (1
H, s), 3.17 (1H, dd, J = 9.9 & 1.4Hz), 4.20 (1H, q, J = 7.
3Hz), 7.30 (1H, br)).

4) 7-oxo-6-azaspiro [3,4] octane-
8-Carboxylic acid 79 Compound 79, 1.97 g is dissolved in ethanol 20 ml and water 20 ml
Was added, and 0.8 g of sodium hydroxide was further added, followed by heating under reflux for 2 hours. The organic solvent was distilled off under reduced pressure, and the aqueous layer was washed with chloroform and then neutralized with 1N hydrochloric acid under ice-cooling and stirring. The aqueous layer was extracted with 2-butanone, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. 1.567 g of the title compound were obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.6-2.7 (6H, m), 3.15 (1H,
s), 3.40 (1H, d, J = 9.2Hz), 3.6 (1H, d, J = 9.2Hz), 6.2
(1H, br) above and 3-oxo-2-azaspiro in the same manner [4,4] nonane-4-carboxylate 80 ⁽¹ H-NMR (CD
Cl ₃ ) δppm: 1.5-2.3 (8H, m), 3.15 (1H, d, J = 9.5Hz),
3.28 (1H, s), 3.33 (1H, d, J = 9.5Hz), 6.45 (1H, br)
And 3-oxo-2-azaspiro- [4,5] decane-4
- carboxylate ^{81 (1 H-NMR (CDCl} 3) δppm: 1.2-
2.0 (10H, m), 3.06 (1H, s), 3.11 (1H, d, J = 9.8Hz), 3.
48 (1H, d, J = 9.8 Hz), 6.47 (1H, br)).

5) 8-tert-butoxycarbonylamino-7-oxo-6-azaspiro [3,4] octane 82 Compound 79 (1.57 g) was suspended in benzene (20 ml), and stirred under stirring with diphenylphosphoryl azide (2.2 ml) and triethylamine (1.55 ml). Were added successively, and the mixture was heated under reflux for 1.5 hours. Here, 4.4 ml of tertiary butanol was added, and the mixture was further heated under reflux for 16 hours. The solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, a saturated aqueous sodium chloride solution, a 10% aqueous citric acid solution, and a saturated aqueous sodium chloride solution. The aqueous layer was further extracted with ethyl butyrate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was applied to a 50 g silica gel flash column to give
Elution with chloroform containing 3% methanol gave 0.560 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.48 (9H, s), 1.5-2.5 (6H,
m), 3.27 (1H, d, J = 9.9Hz), 3.44 (1H, d, J = 9.9Hz), 4.
18 (1H, d, J = 7.7Hz), 5.20 (1H, d, J = 7.7Hz), 7.13 (1
H, brs) In a similar manner as described above, 4-tert-butoxycarbonylamino-3-oxo-2-azaspiro [4,4] nonane 8
3 ( ¹ H-NMR (CDCl ₃ ) δ ppm: 1.45 (9H, s), 1.2-1.8 (8
H, m), 3.13 (2H, s), 4.35 (1H, d, J = 7.9Hz), 5.15 (1H,
d, J = 7.9 Hz), 7.21 (1H, brs)) and 4-tert-butoxycarbonylamino-3-oxo-2-azaspiro [4,
5] Decane 84 ( ¹ H-NMR (CDCl ₃ ) δ ppm: 1.46 (9H, s), 1.
0−1.8 (10H, m), 2.9−3.4 (2H, m), 4.15 (1H, d, J = 8.6
Hz), 4.89 (1H, d, J = 8.6 Hz), 6.71 (1H, brs)).

6) 6-tert-butoxycarbonyl-8-tert-butoxycarbonylamino-6-azaspiro [3,4] octane 87 Compound 82, 560 mg was ice-cooled, and 15 ml of trifluoroacetic acid was added with stirring. Stir at room temperature for 1.5 hours. The trifluoroacetic acid was distilled off under reduced pressure, 30 ml of tetrahydrofuran was added to the residue, 884 mg of lithium aluminum hydride was added under ice-cooling and stirring, and the mixture was heated under reflux for 16 hours. Water was added to the reaction solution under ice-cooling and stirring, and insolubles were filtered (celite filtration). After thoroughly washing the insolubles with tetrahydrofuran, 1.02 g of di-tert-butyl dicarbonate was added, and the mixture was stirred at room temperature for 16 hours. The solvent was distilled off under reduced pressure, and the residue was applied to a 50 g silica gel flash column, and ethyl acetate: n-hexane = 1: 1.
Elution with a mixed solvent of 10 gave 273 mg of the title compound. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.45 (18H, s), 1.7-2.1 (6H,
m), 3.0-3.6 (4H, m), 3.8-4.2 (1H, m), 5.1 (1H, br
d) In the same manner as above, 2-tert-butoxycarbonyl-4-tert-butoxycarbonylamino-2-azaspiro [4,4] nonane 90 ( ¹ H-NMR (CDCl ₃ ) δ ppm: 1.45 ( 1
8H, s), 1.3-1.8 (8H, m), 3.0-3.3 (3H, m), 3.4-3.7
(1H, m), 3.7-4.1 (1H, m), 4.55 (1H, br d)) and 2
- tert-butoxycarbonyl-4-tert-butoxycarbonylamino-2-azaspiro [4,5] decane 91 ⁽¹ H-N
MR (CDCl ₃ ) δ ppm: 1.0-1.9 (28H, m), 2.9-4.1 (5H,
m), 4.51 (1H, br d)).

Example 19. 7- (8-amino-6-azaspiro [3,4]
Octane-6-yl) -1-cyclopropyl-6,8-difluoro-4-oxo-1,4-dihydroquinoline-3-
The carboxylic acid 94 compound (87, 173 mg) was ice-cooled, trifluoroacetic acid (2.7 ml) was added with stirring, and the mixture was stirred at room temperature for 1.5 hours. The trifluoroacetic acid was distilled off under reduced pressure and the residue was acetonitrile 10
Then, 1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (100 mg) and triethylamine (0.98 ml) were added, and the mixture was heated under reflux for 16 hours. The reaction solution was concentrated, diethyl ether was added to the residue, and the resulting crystals were collected by filtration and recrystallized from ethanol-aqueous ammonia to obtain 125 mg of the title compound.

Melting point: 260-263 ° C Elemental analysis Calculated as C ₂₀ H ₂₁ F ₂ N ₃ O ₃ C 58.19 H 5,76 N 10.18 Found C 58.10 H 5.38 N 10.13 ¹ H-NMR (0.1 N NaOD-D ₂ O) δppm: 1.05 (2H, brs), 1.13
−1.20 (2H, m), 1.85−2.01 (6H, m), 2.15−2.22 (1H,
m), 3.25-3.95 (6H, m), 7.56 (1H, d, J = 15.0Hz), 8.41
(1H, s) 7- (4-Amino-2-azaspiro [4,4] nonan-2-yl) -1-cyclopropyl-6,8-difluoro-4-oxo-1,4 -Dihydroquinoline-3-carboxylic acid 95 and 7- (4-amino-2-azaspiro [4,5] decan-2-yl) -1-cyclopropyl-6,8-difluoro-4-oxo-1,4 -Dihydroquinoline-3-carboxylic acid 96 was obtained.

Compound 95: Melting point: 249-253 ° C Elemental analysis Calculated value for C ₂₁ H ₂₃ F ₂ N ₃ O ₃・ 0.7H ₂ O C 60.63 H 5.91 N 10.10 Observed value C 60.63 H 5.69 N 9.94 ¹ H-NMR (0.1N _{NaOD-D 2 O) δppm:} 1.00 (2H, brs), 1.11
−1.15 (2H, m), 1.4−1.7 (8H, m), 3.1−3.9 (6H, m),
7.49 (1H, d, J = 13.5Hz), 8.38 (1H, s) Compound 96: Melting point: 247-274 ° C Elemental analysis Calculated as C ₂₂ H ₂₅ F ₂ N ₃ O ₃ C 63.30 H 6.04 N 10.07 Observed ^{C 63.14 H 6.08 N 10.02 1 H} -NMR (0.1N NaOD-D 2 O) δppm: 1.00 (2H, brs), 1.10
−1.16 (2H, m), 1.20−1.63 (10H, m), 2.99−3.90 (6H,
m), 7.50 (1H, d, J = 14.5 Hz), 8.38 (1 H, s) Example 20. 10- (8-amino-6-azaspiro [3,4]
Octane-6-yl) -9-fluoro-2,3-dihydro-3- (S) methyl-7-oxo-7H-pyrido [1,2,3
-De] [1,4] benzoxazine-3-carboxylic acid 98 Compound 87 (120 mg) and trifluoroacetic acid (2 ml) were mixed and stirred at room temperature for 2 hours. Trifluoroacetic acid was distilled off under reduced pressure, and 9,10-difluoro-2,3-dihydro-3- (S) was added to the residue.
-Methyl-7-oxo-7H-pyrido- [1,2,3-de]
[1,4] benzoxazine-6-carboxylic acid BF ₂ -chelate, 85 mg, dimethyl sulfoxide 15 ml, and triethylamine 1 ml were added. The mixture was heated at reflux overnight. After evaporating the solvent under reduced pressure, 20 ml of 95% methanol and 1.2 ml of triethylamine were added to the residue, and the mixture was heated under reflux for 5 hours.
The solvent was distilled off under reduced pressure, and diethyl ether was added to the residue.
The generated crystals were collected and recrystallized from a mixed solvent of aqueous ammonia and ethanol to obtain 50 mg of the title compound.

Melting point: 229-231 ° C Elemental analysis Calculated value for C ₂₀ H ₂₂ FN ₃ O ₃ 1/2 H ₂ O C 57.96 H 6.08 N 10.14 Actual value C 57.66 H 5.84 N 10.24 ¹ H-NMR (0.1N NaOD-D ₂ O) δppm: 1.28 (3H, s), 1.60-
1.82 (5H, m), 1.95−2.04 (1H, m), 2.95−3.02 (1H,
m), 3.08-3.17 (1H, m), 3.34-3.46 (1H, m), 3.58-3.
70 (2H, m), 4.00-4.08 (1H, m), 4.18-4.24 (1H, m),
4.29-4-36 (1H, m), 7.18 (1H, d, J = 19.5Hz), 8.13
(1H, s) Reference Example 17.1) Tertiary butyl 7-oxo-6-azaspiro [3,
4] Octane-8-carboxylate 99 Compound 79 (2 g) was dissolved by heating in tert-butanol, 2.8 ml of diphenylphosphoryl azide and 1.97 ml of triethylamine were added with stirring, and the mixture was heated under reflux for 16 hours. The solvent was distilled off under reduced pressure, and the mixture was washed successively with a saturated aqueous solution of sodium hydrogen carbonate, a saturated aqueous solution of sodium chloride, a 10% aqueous solution of citric acid, and a saturated aqueous solution of sodium chloride. The aqueous layer is further extracted with ethyl acetate. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained oil was applied to a column of 75 g of silica gel and eluted with chloroform containing 0 to 2% of methanol to obtain 1.974 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.46 (9H, s), 1.7-2.4 (6H,
m), 3.09 (1H, s), 3.41 (1H, d, J = 10.0Hz), 3.62 (1H,
d, J = 10.0 Hz), 6.90 (1H, brs) In a similar manner, tertiary butyl 3-oxo-2
Azaspiro [4,4] nonane-4-carboxylate 100
( ¹ H-NMR (CDCl ₃ ) δ ppm: 1.47 (9H, s), 1.70 (8H, br
s), 2.98 (1H, s), 3.10 (1H, d, J = 9.7 Hz), 3.43 (1H, d,
J = 9.7 Hz), 7.50 (1H, brs)) and tertiary butyl 3-
Oxo-2-azaspiro [4,5] decane-4-carboxylate ^{101 (1 H-NMR (CDCl} 3) δppm: 1.45 (19H, br
s), 2.93 (1H, s), 3.13 (1H, d, J = 11 Hz), 3.32 (1H, d, J
= 11 Hz), 6.90 (1H, brs)).

2) 6-tert-butoxycarbonyl-8-hydroxymethyl-6-azaspiro [3,4] octane 103 1.94 g of compound 93 was cooled with ice, and 20 ml of ice-cooled trifluoroacetic acid was added with stirring. Immediately return to room temperature,
After stirring for 1 hour, trifluoroacetic acid was distilled off under reduced pressure, and the residue was kept under reduced pressure for more than 10 minutes.
Dissolved in 0 ml. Under ice-cooling and stirring, 3.11 g of lithium aluminum hydride was slowly added, and the mixture was heated under reflux for 18 hours. 10 ml of water was slowly added while stirring the reaction solution on ice,
The mixture was stirred at room temperature for 30 minutes. The insolubles are removed by filtration through Celite, and the insolubles are washed well with tetrahydrofuran. The filtrate was concentrated to 50 ml, di-tert-butyl dicarbonate was added, and the mixture was stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure, and the residue was 150 g of silica gel.
And eluted with a mixed solvent of n-hexane: ethyl acetate = 3: 2 to obtain 420 mg of the title compound. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.46 (9H, s), 1.7-2.3 (8H,
m), 3.2-3.9 (5H, m) In the same manner as described above, 2-tert-butoxycarbonyl-4-hydroxymethyl-2-azaspiro [4,
4] nonane ^{105 (1 H-NMR (CDCl} 3) δppm: 1.46 (9H, s),
1.61 (8H, s), 3.0-3.9 (7H, m)) and 2-tert-butoxycarbonyl-4-hydroxymethyl - [4,5] decane ^{107 (1 H-NMR (CDCl} 3) δppm: 1.46 ( 9H, s), 1.1-1.7
(10H, m), 3.0-3.8 (5H, m)).

Example 21 1-cyclopropyl-6,8-difluoro-7
-(8-Hydroxymethyl-6-azaspiro [3,4] octan-6-yl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid 108 Compound 103, 120 mg was cooled on ice and stirred. 2.7 ml of ice-cooled trifluoroacetic acid was added dropwise. The mixture was immediately returned to room temperature and stirred for 1 hour. Trifluoroacetic acid was distilled off under reduced pressure, and the residue was dissolved in 10 ml of acetonitrile.100 mg of 1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinolone-3-carboxylic acid, triethylamine
0.22 ml was added, and the mixture was heated under reflux for 18 hours. The solvent was distilled off under reduced pressure, concentrated hydrochloric acid and chloroform were added, the aqueous layer was separated, and the aqueous layer was washed twice with chloroform. The chloroform layer was extracted with a small amount of concentrated hydrochloric acid. The aqueous layers are combined, and sodium hydroxide is added under ice-cooling and stirring to adjust the pH to 13 or more. After washing the aqueous layer with chloroform, the pH was adjusted to about 7.4 with concentrated hydrochloric acid, 1N hydrochloric acid, and a saturated aqueous sodium hydrogen carbonate solution. Chloroform was added and the aqueous layer was extracted three times. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
The residue was dissolved in ethanol-aqueous ammonia, filtered while hot, and recrystallized twice to give the title compound as yellow needles.
52 mg were obtained.

Melting point: 273-274 ° C Elemental analysis: calculated as C ₂₁ H ₂₂ F ₂ N ₂ O ₄ C 62.37 H 5,48 N 6.93 found: C 63.31 H 5.39 N 6.96 ¹ H-NMR (CDCl ₃ ) δ ppm: 1.11- 1.31 (4H, m), 1.89-2.3
1 (7H, m), 3.63−3.99 (7H, m), 7.75 (1H, dd, J = 13.5 &
1.6Hz), 8.62 (1H, s) In the same manner as above, 1-cyclopropyl-6,
8-difluoro-7- (4-hydroxymethyl-2-azaspiro [4,4] nonan-2-yl) -4-oxo-1,4
-Dihydroquinoline-3-carboxylic acid 109 and 1-cyclopropyl-6,8-difluoro-7- (4-hydroxymethyl-2-azaspiro [4,5] decan-2-yl)-
4-oxo-1,4-dihydroquinoline-3-carboxylic acid 1
I got 10.

Compound 109: melting point: 249-252 ° C elemental analysis: calculated for C ₂₂ H ₂₄ F ₂ N ₂ O ₄ C 63.15 H 5.78 N 6.70 found: C 62.74 H 5.76 N 6.46 ¹ H-NMR (CDCl ₃ ) δ ppm: 1.11 −1.31 (4H, m), 1.50−1.7
7 (8H, m), 2.18−2.22 (1H, m), 3.47−4.03 (7H, m), 7.
73 (1H, dd, J = 13.5 & 1.6Hz), 8.60 (1H, s) Compound 110: mp: 231-234 ° C. Elemental analysis _{C 23 H 26 F 2 N 2} O 4 · 1 / 2H 2 O Calculated Value C 62.58 H 6.17 N 6.35 actual value C 62.92 H 6.17 N 6.25 ¹ H-NMR (CDCl ₃ ) δ ppm: 1.11-1.18 (2H, m), 1.24-1.2
8 (2H, m), 1.30-1.69 (11H, m), 3.51-4.02 (7H, m),
7.80 (1H, dd, J = 13.5 & 1.6 Hz), 8.70 (1H, s) Reference Example 18. 7-acetoxy-5-azaspiro [2,4] heptane 69 1.5 g of Compound 12 was suspended in 30 ml of tetrahydrofuran.
500 mg of lithium aluminum hydride was added, and the mixture was heated under reflux for 16 hours. Under cooling, 0.5 ml of water, 0.5 ml of a 15% aqueous sodium hydroxide solution and 1.5 ml of water were added, and the mixture was stirred at room temperature for 30 minutes. The insoluble material was removed by filtration, and the filtrate was evaporated to dryness under reduced pressure to obtain 1.4 g of 7-hydroxy-5- [1- (R) -phenylethyl] -5-azaspiro [2,4] heptane as a yellow oil. This was cooled on ice, and 5 ml of acetic anhydride and 5 ml of pyridine were added. The mixture was stirred at room temperature for 3 hours. Ethyl acetate was added to the mixture, and the mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate and water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1.6 g of 7-acetoxy-5- [1- (R) -phenylethyl] -5-azaspiro [2,4] heptane as a yellow oil. This was dissolved in 20 ml of ethanol, and palladium-
1.2 g of carbon (containing 50% water) was added, and the mixture was catalytically reduced under a hydrogen atmosphere at 3.8 atm for 5 hours while heating with a tungsten lamp. The catalyst was removed by filtration, and the solvent in the filtrate was distilled off under reduced pressure to obtain 880 mg of the title compound as an oil.

The following compounds were synthesized in addition to the above compounds. These are shown together with their physical constants. 1) (-)-7- [7- (S) -amino-5-azaspiro [2,3] -heptane-5-yl) -1-cyclopropyl-6-fluoro-1 , 4-Dihydro-4-oxoquinoline-3-carboxylic acid 33b, melting point: 259-261 ° C 2) (-)-7- [7- (S) -amino-5-azaspiro [2,3] -heptane- 5-yl) -6-fluoro-
1- (2,4-difluorophenyl) -1,4-dihydro-4
-Oxo-1,8-naphthyridine-3-carboxylic acid 111
b, melting point: 232-235 ° C., [α] _D -20.54 ° (c = 0.73, CH
Cl ₃ )

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI C07D 455/04 C07D 455/04 471/04 102 471/04 102 105 105A 105C 105E 114 114A 471/06 471/06 498/06 498 / 06 513/06 513/06 (31) Priority claim number Japanese Patent Application No. 1-156316 (32) Priority date Hei 1 (1989) June 19 (33) Priority claim country Japan (JP)

Claims (7)

(57) [Claims] 1. A compound of the general formula I (Where a is 0 or 1, b is an integer from 2 to 5, c is 0 or 1, and d is an integer from 0 to 2. Z is CHR ¹ , NR ² , C = NOR ³ , oxygen atom,
Or a sulfur atom, wherein R ¹ is a hydrogen atom, an amino group, a monoalkylamino group having 1 to 6 carbon atoms, a dialkylamino group having 1 to 6 carbon atoms independently, a hydroxyl group,
Represents an alkoxyl group having 1 to 6 carbon atoms or a hydroxyalkyl group having 1 to 6 carbon atoms, wherein R ² is a hydrogen atom,
6 alkyl group, hydroxyalkyl group having 1 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, a formyl group or an alkylcarbonyl group having 2 to 7 carbon atoms represents, R ³
Represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
Q is the formula II (Wherein R ⁴ is an alkyl group having 1 to 6 carbon atoms, 2 to 6 carbon atoms)
An alkenyl group, a halogenoalkyl group having 1 to 6 carbon atoms,
A cyclic alkyl group having 3 to 6 carbon atoms (excluding 1,2-cis-2-halogenocyclopropyl) which may have a substituent, an aryl group which may have a substituent, and a substituent A heteroaryl group, an alkoxyl group having 1 to 6 carbon atoms or an alkylamino group having 1 to 6 carbon atoms, and R ⁵ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. R ⁶ represents a hydrogen atom, an amino group which may have a substituent, a hydroxyl group, an alkoxyl group having 1 to 6 carbon atoms or a halogen atom, and A represents a nitrogen atom or R ⁷ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms,
It means a halogen atom, an alkoxyl group having 1 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms or a cyano group. R ⁴ may form a cyclic structure with R ⁵ and / or R ⁷ , and this ring may contain an oxygen atom, a nitrogen atom, a sulfur atom, and may further have an alkyl group having 1 to 6 carbon atoms or a halogeno group. It may be substituted with an alkyl group or the like.
X represents a halogen atom; Y is a hydrogen atom;
6, an alkyl group having 6 carbon atoms, an alkoxyalkyl group having 1 to 6 carbon atoms, a phenylalkyl group having an alkyl chain having 1 to 6 carbon atoms,
Dihalogenoboron group, phenyl group, acetoxymethyl group, pivaloyloxymethyl group, ethoxycarbonyloxy group, choline group, dimethylaminoethyl group, 5-indanyl group, phthalidinyl group, 5-substituted-2-oxo-1,
It means a 3-dioxol-4-ylmethyl group or a 3-acetoxy-2-oxobutyl group. A spiro compound represented by the formula: 2. A spiro compound according to claim 1, wherein a is 1, b is 2, c is 0, d is 1, and Z is CH (NH ₂ ). 3. The spiro compound according to claim 1, wherein a is 1, b is 3, c is 0, d is 1, and Z is CH (NH ₂ ). 4. The spiro compound according to claim 1, wherein a is 1, b is 2, c is 0, d is 2, and Z is NH. 5. The spiro compound according to claim 1, wherein the compound of the general formula is a compound comprising a pure optically active substance. 6. A 7- (7-amino-5-azaspiro [2,
4] Heptan-5-yl) -1-cyclopropyl-6,8-
Difluoro-1,4-dihydro-4-oxoquinoline-3
-Carboxylic acid, 7- (7-amino-5-azaspiro [2,
4] Heptan-5-yl) -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 7- (7-amino-5-azaspiro [2 , 4] Heptan-5-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 7- (7-amino-5-azaspiro [2,4] Heptane-5-yl) -6-fluoro-1
-(2,4-difluorophenyl) -1,4-dihydro-4-
Oxoquinoline-3-carboxylic acid, 7- (7-amino-
5-azaspiro [2,4] heptane-5-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 10- (7
-Amino-5-azaspiro [2,4] heptane-5-yl) -9-fluoro-2,3-dihydro-3- (S) -methyl-7-oxo-7H-pyrido [1,2,3- de] [1,4] benzoxazine-6-carboxylic acid, 1-cyclopropyl-7- (4,7-diazaspiro [2,5] octan-7-yl) -6-fluoro-1,4-dihydro- 4-oxoquinoline-3-carboxylic acid, 7- (7-amino-5-azaspiro [2,4] heptane-5-yl) -1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro -4-
Oxoquinoline-3-carboxylic acid, 7- (7-hydroxy-5-azaspiro [2,4] heptan-5-yl) -8
-Chloro-1-cyclopropyl-6-fluoro-1,4-
Dihydro-4-oxoquinoline-3-carboxylic acid, 7-
(7-Amino-5-azaspiro [2,4] heptane-5
Yl) -1- (2-methyl-2-propyl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 7- (7-hydroxyimino-5-
Azaspiro [2,4] heptane-5-yl) -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1-cyclopropyl-6,8 -Difluoro-7- (8-hydroxymethyl-6-azaspiro [3,4] octan-6-yl) -4
-Oxo-1,4-dihydroquinoline-3-carboxylic acid,
1-cyclopropyl-6,8-difluoro-7- (4-hydroxymethyl-2-azaspiro [4,4] nonane-2-
Yl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 1-cyclopropyl-6,8-difluoro-7
-(4-hydroxymethyl-2-azaspiro [4,5] decan-2-yl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 7- (8-amino-6-azaspiro [3 , 4] Octane-6-yl) -1-cyclopropyl-6,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 10- (8-amino-6-azaspiro [3, 4] Octane-6-yl) -9-fluoro-2,3-
Dihydro-3- (S) -methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid, or 7- (4-amino-2-azaspiro) [Four,
4] Nonan-2-yl) -1-cyclopropyl-6,8-difluoro-4-oxo-1,4-dihydroquinoline-3-
The spiro compound according to claim 1 which is a carboxylic acid and a salt thereof. 7. An antibacterial agent comprising the compound according to claim 1 as an active ingredient.