JPH08333337A - Spiro compound - Google Patents

Abstract

PURPOSE: To obtain a spiro compound from which a quinolone derivative useful as a medicine, an animal medicine, a marine medicine or a preservative, exhibiting high antimicrobial property and excellent in oral absorbability is derived. CONSTITUTION: This spiro compound is expressed by formula I [(a) is 0 or 1; (b) is an integer of 2-5; (c) is 0 or 1; (d) is an integer of 0-2; Z is a group, etc., expressed by formula II; R<1> is H, amino group, etc.; R<2> is a 1-6C hydroxyalkyl group, etc.; R<3> is a 1-6C alkyl group]. e.g. 7-amino-5- azaspiro[2,4]heptane. An alkoxycarbonyl is exemplified as a protecting group. The size of the spiro ring is preferably a 3-4-membered ring and the size of a cyclic amine ring (excluding the spiro ring) is preferably a 5-6-membered ring. The cyclic amine is bound to a position corresponding to 7 position of the quinolone derivative through nitrogen atom. The spiro ring-substituted cyclic amine is obtained by reacting ethyl acetoacetate with 1,2-dibromoethane in the presence of a base, brominating the resultant compound, cyclizing the brominated compound with benzylamine, further reacting the cyclized compound with hydroxylamine hydrochloride and reducing the resultant compound with a lithium aluminum halide.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an intermediate of an antibacterial spiro compound which is useful as a drug, a veterinary drug, a marine drug, and a preservative.

[0002]

2. Description of the Related Art Various derivatives are known to date as synthetic antibacterial compounds. However, it is known that some of those exhibiting high antibacterial activity often have poor (low) oral absorbability.

As a result of intensive studies, the present inventor has found that the quinolone derivative having a substituent derived from the compound of the present invention has a high antibacterial activity and is excellent in oral absorbability.

[0004]

The present invention is of general formula I

[0005]

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(Where a is 0 or 1 and b is 2 to 5)
To 0, c is 0 or 1, and d is an integer from 0 to 2. Z is

Here, R ¹ is a hydrogen atom, an amino group, or a carbon number of 1.
~ 6 monoalkylamino groups, each independently having 1 carbon atom
~ 6 dialkylamino group, hydroxyl group, carbon number 1-6
Represents an alkoxyl group or a hydroxyalkyl group having 1 to 6 carbon atoms,

R ² is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a hydroxyalkyl group having 1 to 6 carbon atoms, or 1 to 6 carbon atoms.
6 halogenoalkyl group, formyl group or 2 to 2 carbon atoms
Represents an alkylcarbonyl group of 7,

R ³ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. ) Concerning the spiro compound and its salt,

In the general formula I, a is 1, b is 2, c is 0, and d is 1,

In the general formula I, a is 1, b is 3, c is 0 and d is 1,

Further, in the general formula I, a is 1, b is 2, c is 0 and d is 2,

Further, 7-amino-5-azaspiro [2.4] heptane, 4,7-diazaspiro [2.5] octane, 7-hydroxy-5-azaspiro [2.4] heptane, 7-hydroxyimino-5-azaspiro [2.4] heptane , 8-hydroxymethyl
-6-Azaspiro [3.4] octane, 4-hydroxymethyl-2
-Azaspiro [4.4] nonane, 4-hydroxymethyl-2-azaspiro [4.5] decane, 8-amino-6-azaspiro [3.4]
Octane, 4-amino-2-azaspiro [4,4] nonane or
7-tertiary butoxycarbonylamino-5-azaspiro [2.
4] Regarding heptane,

The protecting group is an alkoxycarbonyl group,
An aralkyloxycarbonyl group, an acyl group, an alkyl group, an aralkyl group, an ether or a silyl group, and a salt thereof,

Further, the spiro compound and its salt in which the protecting group is an alkoxycarbonyl group, an aralkyloxycarbonyl group or an acyl group,

Further, a spiro compound in which the protecting group is a tertiary butoxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, a benzyloxycarbonyl group, a paramethoxybenzyloxycarbonyl group, a paranitrobenzyloxycarbonyl group or an acetyl group. And salts thereof, and to compounds of general formula I consisting of pure optical isomers.

The feature of the compound of the present invention is that it is a cyclic amine compound having a spiro ring. The compound having a substituent derived from this compound at the "7th position" of the quinolone derivative has excellent properties. The "7-position equivalent" of a quinolone derivative means 4-oxoquinoline-3-carboxylic acid or 4-oxo-1,8-naphthyridine-3 having various substituents.
-7-position of carboxylic acid, 7-oxopyrido [1,2,3-de]
10-position of [1,4] benzoxazine-6-carboxylic acid, benzo
[ij] means the 8-position of quinolizine-2-carboxylic acid.

The size of the spiro ring is in the range of 3 to 6 membered ring,
A 3-membered ring and a 4-membered ring are particularly preferable.

The ring size of the cyclic amine excluding the spiro ring is preferably a 4- to 8-membered ring, particularly preferably a 5-membered ring or a 6-membered ring. This cyclic amine is linked to the "7th position" of the quinolone derivative via the 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 these, a nitrogen atom is particularly preferable. The 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, and the like. May be.

Examples of the structure of the cyclic amine having a spiro ring include the following. That is, 5-azaspiro [2.4] heptane, 6-azaspiro [3.4] octane,
2-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] Nonan-5-
The structures are oxide, 9-aza-6-thiaspiro [4.5] decane-6-oxide, and the like.

When 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 when these are not present, especially, an amino group and a carbon number are present on the amine ring. 1 to 6 monoalkylamino groups, dialkylamino groups each having 1 to 6 carbon atoms independently, 1 to 6 carbon alkyl groups or 1 to 6 carbon atoms
C1-A6 aminoalkyl group having an amino group which may be substituted with a hydroxyalkyl group, hydroxyl group, C1-C6 hydroxyalkyl group, hydroxyimino group or C1-C6 alkoxy group And the like may be substituted with a polar group. Of these, amino groups are preferred.

Substituents on the ring of the spiro-substituted cyclic amine may be protected with 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 group. Aralkyloxycarbonyl groups such as oxycarbonyl group and paranitrobenzyloxycarbonyl group, acetyl group, methoxyacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, formyl group, benzoyl group and other acyl groups, Butyl group, benzyl group, paranitrobenzyl group,
Alkyl groups such as paramethoxybenzyl group, triphenylmethyl group or aralkyl groups, methoxymethyl group, tertiary butoxymethyl group, tethydropyranyl group, 2,2,2-
Examples thereof include ethers such as trichloroethoxymethyl group, silyl groups such as trimethylsilyl group, isopropyldimethylsilyl group, tertiary butyldimethylsilyl group, tribenzylsilyl group and tertiary butyldiphenylsilyl group.

When the spiro-substituted cyclic amine has a substituent other than the spiro ring, and the carbon atom to which the substituent is bonded is an asymmetric carbon, the cyclic amine has stereoisomers. Become. When such a cyclic amine is bonded as a substituent at the "7-position" in the form of a mixture of stereoisomers, the resulting quinolone derivative may be a mixture of diastereomers. A mixture of diastereomers is a mixture of compounds having different physical constants and is difficult to be applied as a medicine. In such a case, when introducing the cyclic amine, it is necessary to separate the stereoisomers and then react them.

When the quinolone derivative produced is in a racemic form, it may remain in a racemic form. However, isolation of stereoisomers to lead to optically active compounds may exhibit more advantageous biological activity than racemic forms. For example, 7-
In the case of a compound containing an amino-5-azaspiro [2.4] heptane skeleton, the steric configuration on the carbon atom to which the amino group is bonded is favored by the S-configuration isomer in terms of antibacterial activity. found. That is, 7- (7-amino-5-azaspiro
[2.4] Heptane-5-yl) -8-chloro-1-cyclopropyl
Of the two isomers of -6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, the 7- (7- Tertiary butoxycarbonylamino-5-azaspiro [2.4] heptane-5-yl) -8-
Chloro-1-cyclopropyl-6-fluoro-1,4-dihydro
X-ray crystallographic analysis of -4-oxoquinoline-3-carboxylic acid revealed that the absolute configuration at the asymmetric carbon at the base of this amino group was 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, first, 1,2-
Dibromoethane is reacted to give ethyl 1-acetyl-1-cyclopropanecarboxylate. The acetyl group of this is then brominated with bromine to give ethyl 1-bromoacetyl-1-cyclopropanecarboxylate. Then, this compound is reacted with benzylamine to close the ring, and 5-benzyl-4,7-
Convert to dioxo-5-azaspiro [2.4] heptane. When this compound is reacted with hydroxylamine hydrochloride, the ketone at the 7-position becomes an oxime and becomes 5-benzyl-7- (hydroxyimino) -4-oxo-5-azaspiro [2.4] heptane. This oxime 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. This compound becomes racemic 7-amino-5-azaspiro [2.4] heptane when the benzyl group is removed by conventional catalytic hydrogenation. In addition, if the benzyl group is removed after protecting the amino group with 2- (tertiary butoxycarbonylamino) -2-phenylacetonitrile (hereinafter abbreviated as BOC-ON), 7-tertiary butoxycarbonylamino-5
-Becomes Azaspiro [2.4] heptane.

The optically active substance of 7-amino-5-azaspiro [2.4] heptane can be obtained as follows. 7-amino
-5-Benzyl-5-azaspiro [2.4] heptane with (R) -Np-
7-[(R) -Np-toluenesulfonylprolyl] amino is reacted with acid chloride of toluenesulfonylproline.
-5-Benzyl-5- leads to azaspiro [2.4] heptane. When this product is reacted with benzyl chlorocarbonate, 7-[(R)-
Np-toluenesulfonylprolyl] amino-5-benzyloxycarbonyl-5-azaspiro [2.4] heptane is obtained. This is a high performance liquid chromatography (hereinafter referred to as HP
Each optically active substance can be separated by LC).
After isolation of the optically active compound, each was treated with 2N sodium hydroxide to remove the proline moiety and the benzyloxycarbonyl group, and the optically active compound 7-amino-5-azaspiro [2.4]
Converted to heptane.

Further, in the case of a compound in which ethyl 1-bromoacetyl-1-cyclopropanecarboxylate is reacted with an optically active 1-phenethylamine instead of benzylamine to ring-close, separation of optical isomers in a later step is easy. It turned out that it can be carried out.

That is, ethyl 1-bromoacetyl-1-cyclopropanecarboxylate was reacted with R-(+)-1-phenylethylamine to give 5- [1- (R) -phenylethyl] -4,7-dioxo. -5- Azaspiro [2.4] Heptane. This compound is reacted with hydroxylamine hydrochloride to convert the 4-position carbonyl group into an oxime. 5- [1 obtained in this way
-(R) -Phenylethyl] -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. In this compound, the 7th carbon atom is an asymmetric carbon,
Further, since it has an (R) -phenylethyl group at the 5-position, it is a mixture of two diastereomers. It was found that the separation of this mixture can be carried out by silica gel column chromatography, and the resolution of the optically active substance need not use HPLC. In addition, if various crystalline acid addition salts of this compound are synthesized, it is possible to separate even 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 obtain 7-amino-5- [ 1- (R) -Phenylethyl] -5-azaspiro
[2.4] Convert to heptane. Then, the amino group of this product is converted to a tertiary butoxycarbonylamino group with BOC-ON, and the phenylethyl group is removed by catalytic reduction to obtain the optically active 7-tertiary butoxycarbonylamino-5-azaspiro.
[2.4] Heptane is obtained.

Although an example using R-(+)-1-phenylethylamine has been described here, it can be similarly carried out with (S) -phenylethylamine. Further, it is considered that optically active 1-phenylpropylamine, 1-phenylbutylamine and the like can be used.

Further, 5- [1- (R) -phenylethyl] -4,7-dioxo-5-azaspiro [2.4] heptane can also be synthesized by the following method. That is, after hydrolyzing an ester of ethyl 1-acetyl-1-cyclopropanecarboxylic acid to form a carboxylic acid, N- [1- (R is an amide derivative with R-(+)-1-phenylethylamine. ) -Phenylethyl] -1-acetyl-1
-Cyclopropane carboxamide. This compound converts the carbonyl group of the methyl ketone moiety into a ketal to give N- [1- (R) -phenylethyl] -1- (1,1-ethylenedioxyethyl) -1-cyclopropanecarboxamide.
After this, halogenate 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 was treated under basic conditions, 4,7-dioxo-5- [1- (R) -phenylethyl] -5-azaspiro [2.4] heptane-7, a pyrrolidinedione having a spiro ring and a ketal, was obtained. -Becomes ethylene acetal. By removing the ketal under acidic conditions4,
7-dioxo-5- [1- (R) -phenylethyl] -5-azaspiro
[2.4] Converted to heptane. After this, conversion may be performed in the same manner as described above.

Next, the piperazine compound having a spiro ring will be described. For example, in the synthesis of 1,4-diazaspiro [2.5] octane, cyclopropane-1,1-diamide is first reacted with bromine and a base to give cyclopropane-1,1-dibromoamide. When it is treated with alkoxide, it is converted to spirohydantoin, ie 4,6-diazaspiro [2.4] heptane-5,7-dione. This is treated with alkali to lead to 1-aminocyclopropanecarboxylic acid. Protect the amino group of this with a tertiary butoxycarbonyl group and
(Tertiary butoxycarbonylamino) -1-cyclopropanecarboxylic acid was obtained, and then glycine ethyl ester was condensed in the presence of dicyclohexylcarbodiimide to give ethyl acetate.
Convert to (1-tertiary butoxycarbonylamino-1-cyclopropylcarbonylamino) acetate. After removal of the amino-protecting group of this product, it is ring-closed by heating, and a diketopiperazine compound having a spiro ring, that is, 4,
7-Diazaspiro [2.5] octane-5,8-dione. When this is reduced with lithium aluminum hydride, 4,
7-Diazaspiro [2.5] octane is obtained.

The cyclic amine derivative having a spiro ring can also be synthesized by the following method. Cycloalkylketone and malonic acid diester are condensed in the presence of titanium tetrachloride to give cycloalkylidene malonic acid diester. When this compound is reacted with nitromethane in the presence of a base,
(1-Nitromethyl-1-cycloalkyl) malonic acid diester is obtained. If this compound is reductively closed,
Pyrrolidonecarboxylic acid having a spiro ring, for example, 7-oxo-6-azaspiro [3.4] octane-8-carboxylic acid ester is obtained when the spiro ring is a four-membered ring. This reductive ring closure reaction is conveniently carried out by catalytic reduction in the presence of a metal catalyst, but it can also be carried out by other chemical reduction reactions.

Next, after hydrolyzing the carboxylic acid ester to convert it into a free carboxylic acid, the Curtius reaction was carried out in tertiary butanol, whereby the carboxylic acid moiety was converted to a tertiary butoxycarbonylamino group. Pyrrolidone can be obtained. After removal of the tertiary butoxycarbonyl group, reduction with a metal hydride such as lithium alnium 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 pyrrolidonecarboxylic acid is reduced with metal hydride, it can be converted into a cyclic amine having a spiro ring substituted with a hydroxymethyl group.

Examples of the quinolone derivative bonded to a cyclic amine having a spiro ring include bicyclic 1,4-dihydro-4
-Oxoquinoline-3-carboxylic acids, 1,4-dihydro-4-
Oxo-1,8-naphthyridine-3-carboxylic acids and other tricyclic 2,3-dihydro-7-oxo-7H-pyrido [1,2,3-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] quinolizine-2-carboxylic acids, 6,7-dihydrobenzo [ij] quinolizine-2-carboxylic acids, etc., and tetracyclic 9,1-epoxymethano-5H-thiazolo [3,2-a] Quinoline-3
-Carboxylic acids and the like can be mentioned. These partial structures are shown below.

[0039]

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(In the formula, R ⁴ is an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, and a carbon number of 3 which may have a substituent.
~ 6 cyclic alkyl group, aryl group which may have a substituent, heteroaryl group which may have a substituent, alkoxyl group having 1 to 6 carbon atoms or 1 to 6 carbon atoms
Means an alkylamino group of

R ⁵ represents 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,

R ⁷ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, 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 together with R ⁵ and / or R ⁷ , and the ring may contain an oxygen atom, a nitrogen atom or a sulfur atom, and further has 1 to 1 carbon atoms.
6 may be substituted with an alkyl group or a halogenoalkyl group.

X represents a halogen atom,

Y is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyalkyl group having 1 to 6 carbon atoms, or 1 to 6 carbon atoms.
Phenylalkyl group of 6 alkyl chain, dihalogenoboron group, phenyl group, acetoxymethyl group, pivaloyloxymethyl group, ethoxycarbonyloxy group, choline group, dimethylaminoethyl group, 5-indanyl group,
Phthalidinyl group, 5-substituted-2-oxo-1,3-
It means a dioxol-4-ylmethyl group or a 3-acetoxy-2-oxobutyl group. ) 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-methylcyclopropyl group,
2-gem-dihalogenocyclopropyl group, etc., substituted with cyclic alkyl groups that may have a substituent, 4-fluorophenyl group, 2,4-difluorophenyl group, 2-fluoro-4-pyridyl group, etc. Aryl groups or heteroaryl groups which may have a group, alkoxy groups such as methoxy group and ethoxy group, and alkylamino groups such as methylamino group and ethylamino group are preferable. Among these, ethyl group, 2-fluoroethyl group, vinyl group, cyclopropyl group, cis-2-methylcyclopropyl group, 4-fluorophenyl group, 2,4-difluorophenyl group, 2-fluoro-4- group
Pyridyl group, methoxy group, methylamino group and the like are preferable.

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

The 5-position substituent is a hydrogen atom or an amino group, and monoalkylamino groups having 1 to 6 carbon atoms such as methylamino group, ethylamino group, isopropylamino group, dimethylamino group and diethylamino group. Alternatively, dialkylamino groups each having 1 to 6 carbon atoms independently, hydroxyl group, halogenoalkyl groups having 1 to 6 carbon atoms, or alkoxy groups having 1 to 6 carbon atoms such as methoxy group and ethoxy group, halogen Atoms are good.

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 and a carbon number of 1 to
It may be substituted with an alkyl group having 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, a cyano group or the like. Is good.

The quinolone skeleton is not only bicyclic,
A tricyclic or tetracyclic ring structure may be formed mainly between the quinoline skeleton and between the 1-position and the 8-position or 2-position, or between the 8-position and 2-position. The size of the ring formed in these cases is preferably a 4- to 7-membered ring, and a 5- or 6-membered ring is particularly preferable. Further, the ring formed here may contain a nitrogen atom, an oxygen atom, a sulfur atom and the like.
Further, 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.

Examples of the tricyclic quinolone derivative include
2,3-dihydro-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid may have an alkyl group at the 3-position, In this case, it is preferable that the S-coordinate be substituted. The 9-position is preferably substituted with a halogen atom, particularly a fluorine atom or a chlorine atom. The situation for these substituents is 2,3-dihydro, which is another tricyclic quinolone skeleton.
-7-Oxo-7H-pyrido [1,2,3-de] [1,4] benzothiazine
-6-carboxylic acid, 6,7-dihydro-1,7-dioxo-1H, 5H-
The same applies to benzo [ij] quinolizine-2-carboxylic acid. In addition, 2,3-dihydro-7-oxo-7H-pyrido
In [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, the 9-position is preferably substituted with a halogen atom, particularly a fluorine atom or a chlorine atom.

As the quinolone derivative bonded to the cyclic amine having a spiro ring, 1,4-dihydro-4-oxoquinoline-3-carboxylic acid having various substituents described above is preferable.

Examples of the cyclic amine having a spiro ring include, for example, JP-A-61-1667, JP-A-61-205240, JP-A-60-197686 and European Patent Application Publication No.
A quinolone derivative can be introduced by the method described in 206283 (for example, 7-chloro-6-fluoro-1-ethyl-1,4-dihydro-3-carboxylic acid, European Patent 27752; 9,
10-Difluoro-3-methyl-7-oxo-2,3-dihydro-7
H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-
Carboxylic acid, JP-A-63-132891; 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).

A method for producing a quinolone derivative having a substituent derived from the compound of the present invention will be described.

[0056]

[Chemical 4] (In the formula, a , b , c , d , and Z are the same as defined above, and R ⁴ is an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, and a halogenoalkyl having 1 to 6 carbon atoms. Group, C3-6 cyclic alkyl group which may have a substituent, aryl group which may have a substituent, heteroaryl group which may have a substituent, C1-6 alkoxyl group or carbon Means an alkylamino group of the numbers 1 to 6,

R ⁵ represents 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,

R ⁷ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, 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 ring structure together with R ⁵ and / or R ⁷ , and this ring has an oxygen atom, a nitrogen atom,
It may contain a sulfur atom and may be further substituted with an alkyl group having 1 to 6 carbon atoms or a halogenoalkyl group.

X means a halogen atom,

Y is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyalkyl group having 1 to 6 carbon atoms, or 1 to 1 carbon atoms.
6 alkyl chain phenylalkyl group, dihalogenoboron group, phenyl group, acetoxymethyl group, pivaloyloxymethyl group, ethoxycarbonyloxy group, choline group, dimethylaminoethyl group, 5-indanyl group, phthalidinyl group, 5- It means a substituted-2-oxo-1,3-dioxol-4-ylmethyl group or a 3-acetoxy-2-oxobutyl group. X'represents a halogen atom. )

That is, a cyclic amine having a spiro ring and
When a 7-halogenoquinolone derivative is reacted, a quinolone derivative in which the nitrogen atom in the ring of pyrrolidine is bonded to the 7-position of quinolone is produced.

In the starting quinolone derivative, for example, 1-cyclopropyl-6-fluoro-7-halogeno-1,4-dihydro-4-oxoquinoline-3-carboxylic acid derivative, the halogen atom at the 7-position is a chlorine atom or a fluorine atom. Any of atoms may be used.
These can be synthesized by the methods described in JP-A Nos. 61-1667 and 61-205240. Also, other quinolone mother nuclei can be synthesized by a known method.

In the method described in JP-A No. 61-205240, the intermediate 3-chloro-2,4,5-trifluorobenzoic acid is synthesized by a 10-step reaction. amino-
We have developed a one-step method for synthesizing 2,4,5-trifluorobenzoic acid and found that it can be applied to other benzoic acid derivatives.

[0066]

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Further, the present inventors have found that 2,4,5-trifluoro-3-
We have also succeeded in developing a synthetic route for methyl benzoic acid, which is simple and enables large-scale synthesis. That is, the following route starting from tetrafluorophthalic acid diester. First,
For example, if dimethyl tetrafluorophthalate is dissolved in nitromethane and a base is added under cooling, 3,5,6-trifluoro
-4-Dimethyl nitromethylphthalate. The base may be either an inorganic base or an organic base. For example, the organic base may be tetramethylguanidine, 1,8-diazabicyclo [5,4,0] -7-undecene, 1,4-diazabicyclo [2,2,
2] Ultra strong bases such as octane can be mentioned. As the inorganic base, sodium amide, sodium hydride, sodium hydroxide, potassium hydroxide or the like can be used. Among these bases, it is preferable to use a super strong organic base. The reaction temperature may be in the range of -30 ° C to 50 ° C, particularly preferably 10 ° C or lower. Further, nitromethane can be used as a reaction agent and a solvent, but other solvent inert to the reaction may be used.
For example, aromatic hydrocarbons such as benzene, toluene and xylene, and ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, 1,2-dimethoxyethane and dioxane may be used.

This dimethyl 3,5,6-trifluoro-4-nitromethylphthalate was reacted with tributyltin hydride and alpha, alpha'-azobis (isobutyronitrile) to give 3,5,6-trifluoro-4. -Can be converted to dimethyl methylphthalate in one stroke. Benzene, toluene, hexane, etc. can be used as the reaction solvent, and the reaction temperature is from room temperature to 15
It may be carried out in the range of 0 ° C, preferably room temperature to 120 ° C.
Range.

This dimethyl 3,5,6-trifluoro-4-methylphthalate can also be synthesized by the following method. I.e. 3,5,
After converting the nitromethyl group of dimethyl 6-trifluoro-4-nitromethylphthalate to a dimethylamino group and further quaternizing this dimethylamino group, the quaternary salt is reduced to give the desired 4-methylphthalic acid derivative. It is a route to.
First, in the synthesis of dimethyl 4-dimethylamino-3,5,6-trifluorophthalate, dimethyl 3,5,6-trifluoro-4-nitromethylphthalate was catalytically reduced to methyl in the presence of formaldehyde. The simplest method is
Examples of the metal catalyst that can be used here include Raney nickel and palladium-carbon. The solvent is not particularly limited, but an alcohol solvent such as methanol or ethanol or water is preferable. On the other hand, the nitromethyl group may be reduced to an aminomethyl group and then dimethylated.

The quaternization of dimethyl 4-dimethylamino-3,5,6-trifluorophthalate may be carried out by reacting a dimethylaminomethyl compound with an alkyl halide. For example, the reaction of methyl iodide with the quaternary salt 2,5,6-trifluoro-3,4
-Di (methoxycarbonyl) phenylmethylene-trimethylammonium iodide is obtained. In the present specification, a trimethylammonium compound has been described as an example of the quaternary salt, but other trialkylammonium salts such as ethyl, propyl and butyl may be used. It may also be a quaternary salt composed of a plurality of alkyl groups. When the quaternary salt thus obtained is catalytically reduced in the presence of Raney nickel 3,5,
Dimethyl 6-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 an ordinary method and may be carried out under basic or acidic conditions. Depending on the type of ester, hydrogenolysis may be used. Obtained by hydrolysis 3,
When 5,6-trifluoro-4-methylphthalic acid is dissolved in water and heated at 200 ° C in a sealed tube, the carboxyl group at the para position of the methyl group is eliminated by decarboxylation, resulting in 2,4,5-trifluoro- 3-
Methylbenzoic acid is obtained. Other decarboxylation reaction conditions include polar solvents such as dimethylformamide, dimethylacetamide and dimethylsulfoxide in the presence of cuprous oxide, cupric oxide, copper (I) acetate or copper powder, and quinoline and pyridine. Examples thereof include a reaction of heating in a polar basic solvent and a reaction of heating in hydrous sulfuric acid.

The synthesis of 2,4,5-trifluoro-3-methylbenzoic acid by the above series of reactions has a short number of steps as compared with the previously known synthetic routes, is simple and is suitable for large-scale synthesis. It is an excellent route that can be applied.

A quinolone derivative in which a carboxylic acid moiety at the 3-position (or a position corresponding to the 3-position) of quinolone is a substituted boron ester may be used as a raw material for the reaction with a spiro-substituted cyclic amine. This boron ester compound has, for example, the following substituents at the 3-position (or the 3-position equivalent position) of the quinolone nucleus.

[0074]

[Chemical 6] And forms a chelate with the carbonyl group at the 4-position (or equivalent to the 4-position) of quinolone. This fluorine atom may be another halogen atom or an acetoxy group.

The dihalogeno borated product can be easily prepared from a free carboxylic acid derivative and a suitable boron trihalide compound, for example, boron trifluoride ether complex.

That is, the carboxylic acid derivative is converted into diethyl ether, diisopropyl ether, tetrahydrofuran,
It is suspended or dissolved in ethers such as dioxane, an excess amount of boron trifluoride diethyl ether complex is added, and the mixture is stirred at room temperature. The reaction temperature may be room temperature, but if necessary, 100 ° C
You may heat up to the place. 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 then dried under reduced pressure (see JP-A-62-252790).

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

The reaction for introducing the spiro-substituted cyclic amine is usually
It is carried out in the presence of a deoxidizer. As the deoxidizing agent, either an organic base or an inorganic base can be used, but in general, an organic base is preferred.

As the organic base, tertiary amines are preferable, and trialkylamines such as triethylamine, tripropylamine, N, N-diisopropylethylamine and tributylamine, N, N-dimethylaniline, N, N-diethylaniline and the like. Anilines, N-methylmorpholine, pyridine, N,
Heterocyclic compounds such as N-dimethylaminopyridine can be exemplified.

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 hydrogen carbonate,
Examples include potassium hydrogen carbonate.

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

The reaction solvent may be any one inert to the reaction, such as acetonitrile, N, N-dimethylformamide,
N-Methyl-2-pyrrolidone, N, N-amides such as dimethylacetamide, benzene, toluene, aromatic hydrocarbons such as xylene, dimethyl sulfoxide, aprotic polar solvents such as sulfolane, methanol, ethanol, propanol, Examples thereof include lower alcohols such as butanol, amyl alcohol, isoamyl alcohol, cyclohexyl alcohol and 3-methoxybutanol, and ethers such as dioxane, dimethyl cellosolve, diethyl cellosolve and diglyme. In the case of a water-soluble solvent, it may be used as a water-containing solvent. In this case, the deoxidizing agent is preferably an organic base.

The reaction temperature may be in the range of room temperature to 180 ° C, but is usually in the range of 80 to 130 ° C.

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

In the reaction of introducing a spiro-substituted cyclic amine, when the substituent on the ring of this amine is protected and reacted, the removal of the protecting group from the product can be carried out by a usual method depending on the protecting group used. Good.

When the carboxylic acid at the 3-position (or the position corresponding to the 3-position) is not a free carboxylic acid, it can be derived into a free carboxylic acid by a method according to each case. 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 a deoxidizing agent may be present at this time. For example, there is a method of treating with ethanol in the presence of triethylamine.

The produced quinolone derivative can be purified by recrystallization, reprecipitation, treatment with activated carbon, chromatography or the like, or a combination thereof.

Examples of the quinolone derivative having a substituent derived from the compound of 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] heptan-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] heptan-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] octane-7-
Yl) -6,8-difluoro-1- (2-fluoroethyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid 8-chloro-7- (4,7-diazaspiro [2.5] octane- 7-yl) -6-fluoro-1- (2-fluoroethyl) -1,4-dihydro-4
-Oxoquinoline-3-carboxylic acid 7- (4,7-diazaspiro [2.5] octane-7-yl) -6-fluoro-1- (2-fluoroethyl) -1,4-dihydro-4-oxoquinoline- 3-Carboxylic acid 7- (4,7-diazaspiro [2.5] octane-7-yl) -6-fluoro-1- (2-fluoroethyl) -1,4-dihydro-4-oxo-
1,8-naphthyridine-3-carboxylic acid

7- (4,7-diazaspiro [2.5] octane-7-
Yl) -1-ethyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 8-chloro-7- (4,7-diazaspiro [2.5] octane-7-yl)- 1-Ethyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7- (4,7-diazaspiro [2.5] octane-7-yl) -1-ethyl-6-fluoro-1 , 4-Dihydro-4-oxoquinoline-3-
Carboxylic acid 7- (4,7-diazaspiro [2.5] octane-7-yl) -1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid

7- (4,7-diazaspiro [2.5] octane-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] octane-7-yl) -6-fluoro-1- (2,4-difluorophenyl)- 1,4-Dihydro-4-oxoquinoline-3-carboxylic acid 7- (4,7-diazaspiro [2.5] octane-7-yl) -6-fluoro-1- (2,4-difluorophenyl) -1, 4-dihydro-4-oxoquinoline-3-carboxylic acid 7- (4,7-diazaspiro [2.5] octane-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] octane-7-
Yl) -6,8-Difluoro-1-vinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 8-chloro-7- (4,7-diazaspiro [2.5] octane-7-yl)- 6-Fluoro-1-vinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7- (4,7-diazaspiro [2.5] octane-7-yl) -6-fluoro-1-vinyl-1 , 4-Dihydro-4-oxoquinoline-3-
Carboxylic acid 7- (4,7-diazaspiro [2.5] octane-7-yl) -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] octane-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] octane-7-yl) -9-fluoro-5- (S) -methyl -6,7-dihydro-1,7-dioxo-1H,
5H- Benzo [ij] quinolizine-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] octane-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] Heptane-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] Heptane-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] Heptane-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] heptane-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] Heptane-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] heptane-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] octane-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] octane-7-yl) -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-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] octane-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] octane
-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] Heptane-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] octane-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] heptan-5-yl) -1-cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carvone 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] heptan-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-methyl-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] octane-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-yl) -1-ethyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxoquinoline -3-Carboxylic acid 7- (4,7-diazaspiro [2.5] octane-7-yl) -1- (2,4
-Difluorophenyl) -6-fluoro-8-methoxy-1,4-
Dihydro-4-oxoquinoline-3-carboxylic acid 7- (4,7-diazaspiro [2.5] octane-7-yl) -6-fluoro-1-vinyl-8-methoxy-1,4-dihydro-4-oxo Quinoline-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] octane-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-yl) -1-ethyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3 -Carboxylic acid 7- (4,7-diazaspiro [2.5] octane-7-yl) -6-fluoro-1- (2,4-difluorophenyl) -8-methyl-1,4-dihydro-4-oxoquinoline -3-Carboxylic acid 7- (4,7-diazaspiro [2.5] octane-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] quinolizine-2-carboxylic acid

1-Cyclopropyl-7- (5,8-diazaspiro
[3.5] Nonane-8-yl) -6,8-difluoro-1,4-dihydro
-4-oxoquinoline-3-carboxylic acid 8-chloro-1-cyclopropyl-7- (5,8-diazaspiro [3.
5] Nonane-8-yl) -6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

7- (5,8-diazaspiro [3.5] nonane-8-yl) -6,8-difluoro-1- (2-fluoroethyl) -1,4-dihydro-4-oxoquinoline-3-carvone Acid 8-chloro-7- (5,8-diazaspiro [3.5] nonan-8-yl)-
6-fluoro-1- (2-fluoroethyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid

7- (5,8-diazaspiro [3.5] nonane-8-yl) -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] nonan-8-yl)-
1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

7- (5,8-diazaspiro [3.5] nonane-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] nonane-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] quinolizine-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 -Five
-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] octane-7-yl) -6-fluoro-1,4- Dihydro-4-oxoquinoline-3-carboxylic acid

These quinolone derivatives having a spiro cyclic amine have higher lipophilicity than the corresponding quinolone derivatives having no spiro ring, and can be expected to have higher oral absorbability, and are expected to exhibit better antibacterial activity. .

The pyridonecarboxylic acid derivative may be in a free form, but may be an acid addition salt or a carboxyl group salt. Examples of the acid addition salt include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide and phosphate, or acetate, methanesulfonate and benzene. Organic acid salts such as sulfonate, toluene sulfonate, citrate, maleate, fumarate, lactate and the like can be mentioned.

Examples of the carboxyl group salt include alkali metal salts such as lithium salt, sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, ammonium salt, triethylamine salt and N salt.
-Methylglucamine salt, tris- (hydroxylmethyl) aminomethane salt and the like, which may be inorganic salts or organic salts.

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

On the other hand, the quinolone derivative in which the carboxylic acid moiety is an ester is useful as a synthetic intermediate or a prodrug. 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 which is easily cleaved in vivo to form a free form of carboxylic acid, and examples thereof include acetoxymethyl ester, pivaloyloxymethyl ester and ethoxy. Carbonyloxy ester, choline ester, dimethylaminoethyl ester, 5-indanyl ester and phthalidinyl ester, 5-substituted-2-oxo-1,3
Mention may be made of oxoalkyl esters such as -dioxol-4-ylmethyl ester and 3-acetoxy-2-oxobutyl ester.

Since the quinolone derivative having a substituent derived from 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 a preservative for foods.

When the quinolone derivative having a substituent derived from the compound of the present invention is used as a medicine for human body, the dose is 50 mg to 1 g, preferably 100 per day for an adult.
The range is from mg to 300 mg.

The dose for animals varies depending on the purpose of administration (treatment or prevention), the type and size of the animal to be treated, the type and degree of the infectious pathogen, but it is generally a daily dose. Is from 1 mg / kg to 200 kg / kg of animal weight
mg, preferably in the range of 5 mg to 100 mg.

This daily dose is administered once a day or in 2 to 4 divided doses. Also, the daily dose may exceed the above amount if necessary.

The quinolone derivatives having a substituent derived from the compound of the present invention are active against a wide range of microorganisms causing various infectious diseases, and treat, prevent, or prevent diseases caused by these pathogens. Can be reduced.

Bacteria or bacteria-like microorganisms in which the quinolone derivative having a substituent derived from the compound of the present invention is effective, Staphylococcus, Streptococcus pyogenes, Hemolytic streptococcus, Enterococcus, Streptococcus pneumoniae, Peptostreptococcus, Neisseria gonorrhoeae , Escherichia coli, Citrobacter, Shigella, Klebsiella pneumoniae, Enterobacter, Serratia, Proteus, Pseudomonas aeruginosa, Haemophilus influenzae, Acinetobacter,
Examples include Campylobacter, Trachoma chlamydia, and the like.

Diseases caused by these pathogens include folliculitis, blemishes, algae, erysipelas, cellulitis,
Lymphatic (node) inflammation, leprosy, subcutaneous abscess, sweat gland inflammation, acne conglomerate, infectious atheroma, perianal abscess, mastitis, superficial secondary infections such as trauma, burns, and surgical wounds, pharynx Inflammation, acute bronchitis, tonsillitis, chronic bronchitis, bronchiectasis, diffuse panbronchiolitis, secondary infection of chronic respiratory disease, pneumonia, pyelonephritis, cystitis, prostatitis, epididymitis, gonococcal urethra Inflammation, non-gonococcal urethritis, cholecystitis, cholangitis, shigellosis, enteritis, uterine adnexitis, intrauterine infection, bartholinitis, blepharitis, hordeolum, lacrimal cystitis, tarsal adenitis, corneal ulcer, otitis media. , Sinusitis, periodontitis, peridontitis, peritonitis, peritonitis, endocarditis, sepsis, meningitis, skin infections and the like.

Further, it is effective against various microorganisms that cause infectious diseases of animals, for example, Escherichia, Salmonella, Pasteurella, Haemophilus, Bordetella, Staphylococcus, Mycoplasma, etc.

[0143] Specific examples of disease names include colibacillosis, chicken tinea, chicken paratyphoidosis, poultry cholera, infectious coryza, staphylococcal disease, mycoplasma infection in birds, and colibacillosis, salmonellosis, pasteurellosis, in pigs. Haemophilus infection, atrophic rhinitis, exudative epidermitis, mycoplasma infection, etc., Escherichia coli disease, salmonellosis, hemorrhagic sepsis in cattle, mycoplasma infection, bovine lung disease, mastitis, etc., Escherichia coli sepsis, salmonella infection in dogs Disease, hemorrhagic septicemia,
Uterine empyema, cystitis, etc., and in cats, exudative pleurisy, cystitis, chronic rhinitis, Haemophilus infection, diarrhea of kittens, mycoplasma infection, etc. can be mentioned.

The antibacterial preparation comprising the quinolone derivative having a substituent derived from the compound of the present invention can be prepared by selecting an appropriate preparation according to the administration method and using various commonly used preparation methods. Examples of the dosage form of an antibacterial preparation containing the compound of the present invention as a main component include tablets, powders, granules, capsules, solutions, syrups, elixirs, oily or aqueous suspensions, and the like as oral preparations. .

As an injection, a stabilizer, a preservative,
A solubilizing agent may be used, and a solution that may contain these auxiliaries may be stored in a container and then freeze-dried to prepare a solid preparation, which may be prepared at the time of use. Also, one dose may be stored in a container, or multiple doses may be stored in the same container.

Examples of the external preparation include solutions, suspensions, emulsions, ointments, gels, creams, lotions and sprays.

The solid preparation includes additives which are pharmaceutically acceptable together with the active compound, and examples thereof include fillers, extenders, binders, disintegrants, dissolution promoters, wetting agents and lubricants. It is possible to select the types and the like as required and mix them to prepare a formulation.

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

The quinolone derivative having a substituent derived from the compound of the present invention may be administered to an animal directly or by mixing it in a feed, and then orally. Alternatively, after making a solution, it may be used directly or in water or in a feed. Examples of the method include the method of oral administration by addition to the above, the method of administration by injection, and the like.

Further, as a preparation for administration to animals, a powder, a fine granule, a soluble powder, a syrup, a solution, or an injection may be appropriately prepared by a technique usually used in this field. You can

Next, formulation examples will be shown.

Formulation Example 1. (Capsule): Compound 32b 100.0 mg Corn starch 23.0 mg CMC calcium 22.5 mg Hydroxypropyl dimethyl cellulose 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 to 2 g Ethyl paraoxybenzoate 0.1 g Purified water 88.9 to 98.4 g Total 100 g

Formulation Example 3. (Powder for powder mixing): Compound 55b 1 ~ 10 g Corn starch 98.5 ~ 89.5 g Light anhydrous silicic acid 0.5 g Total 100 g

[0155]

The present invention will be described in more detail with reference to the following 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 (Journal of the Japanese Society of Chemotherapy, 29 (1), 76 (1981)). Next to the table of antibacterial activity, reaction formulas for synthesizing various spiro-substituted cyclic amine derivatives, intermediate compounds for synthesizing quinolone skeleton and various spiro compounds are shown.

Example 1. 7-Amino-5-azaspiro [2.4]
Synthesis of heptane 1) Ethyl 1-acetyl-1-cyclopropanecarboxylate 2 Ethyl acetoacetate, 10.2 g of 1,2-dibromoethane 15
g, potassium carbonate 23 g, N, N-dimethylformamide (D
150 ml of MF) was mixed and stirred at room temperature for 2 days. The insoluble material was filtered off, the filtrate was evaporated to dryness under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, the pale yellow oil obtained by distilling off the solvent under reduced pressure was distilled under reduced pressure, and the title compound 2, 7.5 g as a fraction having a boiling point of 70-71 ° C / 2-3 mmHg. Got

¹ H-NMR (CDCl ₃ ) δppm: 1.30 (3 H, t, J = 7
Hz), 1.48 (4H, s), 2.49 (3H, s), 4.24 (2H, q, J = 7 H
z).

2) 5-benzyl-4,7-dioxo-5-azas
Pyro [2.4] heptane 4 Compound 2, 7 g was dissolved in 50 ml of ethanol, and bromine 8.0
g was added dropwise with stirring at room temperature. After stirring at room temperature for 2 hours,
Excess bromine and solvent were distilled off under reduced pressure, and 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 stirring with ice cooling. After returning to room temperature and stirring for 24 hours, the solvent was distilled off under reduced pressure, and the residue was washed with chloroform 2
It was dissolved in 00 ml, washed successively with 1N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure,
The residue was subjected to silica gel chromatography and eluted with 2% methanol-chloroform to give the title compound 4, 2.3 g.
Was obtained as pale yellow crystals.

¹ H-NMR (CDCl ₃ ) δppm: 1.6-1.8 (4H, m),
3.78 (2H, s), 4.68 (2H, s), 7.2-7.45 (5H, br s).

3) 5-benzyl-7- (hydroxyimino) -4-
Oxo-5-azaspiro [2.4] heptane 5 compound 4, 670 mg to hydroxylamine hydrochloride 700 mg,
Add 200 mg of triethylamine and 10 ml of ethanol,
Stir overnight at room temperature. The solvent was distilled off under reduced pressure, and 10% of the residue was
A citric acid aqueous solution was added and dissolved, followed by extraction 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. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound 5 (490 mg) as white crystals.

¹ H-NMR (CDCl ₃ ) δppm: 1.3-1.7 (4H, m),
3.80 ^* & 4.10 ^* (2H, s), 4.60 ^** & 4.70 ^** (2H, s), 7.38 (5
H, arm.) (*, **: a mixture of sin and anti)

4) 7-Amino-5-azaspiro [2.4] hepta
7 Compound 5 (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,
0.5 ml of 15% aqueous sodium hydroxide solution and 1.5 ml of water were added in this order, insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure.
-Benzyl-5-azaspiro [2.4] heptane 6, was obtained.
This was dissolved in 20 ml of ethanol without purification, 10% palladium-carbon was added, and catalytic hydrogenation was carried out under the conditions of 4.5 kg / cm ² and 50 ° C. After 6 hours, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure at a temperature below room temperature to obtain a crude product of the title compound 7.
This compound 7 was used in various reactions without purification.

5) 7-[(R) -Np-toluenesulfonylprolyl
Lu] 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 prepared separately under ice-cooled stirring (R).
-Np- Toluenesulfonylproline acid chloride (Note,
Prepared using 4 g of (R) -Np-toluenesulfonylproline and excess thionyl chloride. ) Methylene chloride 1
After 0 ml of the solution was added dropwise over 10 minutes, the temperature was returned to room temperature and the mixture was stirred for 3 hours. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate.
After evaporating the solvent under reduced pressure, the residue was subjected to flash column chromatography (silica gel 80 g), and 3.5 g of the title compound 8 as a candy-like substance was obtained from the elution part of ethyl acetate.

6) 7-[(R) -Np-toluenesulfonylprolyl
]] Amino-5-benzyloxycarbonyl-5-azaspir
[2.4] Heptane 9, an optically active substance 9a, 9b compound 8, 3.5 g, and benzyl chlorocarbonate 2.5 ml were added to dry methylene chloride 4 ml, and the mixture was stirred at room temperature for 12 hours.
After adding 4 ml of benzyl chlorocarbonate and stirring for 5 hours,
Chloroform was added, saturated aqueous sodium hydrogen carbonate solution,
It was washed successively with saturated saline. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and the residue was subjected to flash column chromatography (silica gel, 85 g) and eluted with ethyl acetate-n-hexane (2: 1 to 4: 1, v / v). Part from the title compound
9 and 3 g were obtained as a pale yellow oily substance and immediately subjected to HPLC to obtain 1.40 g and 1.45 g of optically active compounds 9a and 9b, respectively.

[0165]

7) Optically Active 7-Amino-5-azaspiro
[2.4] Heptane 7a and 7b Compound 9a (1.4 g) was dissolved in ethanol (20 ml), 2N aqueous sodium hydroxide solution (15 ml) was added, and the mixture was refluxed for 19 hr. 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 give a colorless solid as a residue. To this colorless solid, 10 ml of 50% aqueous sodium hydroxide solution was added, and the mixture was distilled under reduced pressure to obtain an aqueous solution containing compound 7a as a distillate, which was used as it was in the next reaction.

For the other compound 7b, the compound 9
It was possible to obtain from b with the same operation.

8) 7-tert-Butoxycarbonylamino-5
-Azaspiro [2.4] heptane 11 compound 6 (800 mg) was dissolved in tetrahydrofuran (30 ml), and 2- (tertiary butoxycarbonyloxyimino) -2-phenylacetonitrile (BOC-ON) (1.2 g) was added at room temperature. Reacted for hours. The solvent was evaporated under reduced pressure, chloroform was added to the residue, and the mixture was extracted with 10% aqueous citric acid solution. Adjust the pH of the citric acid extract to 10 with 1N aqueous sodium hydroxide.
After the above, extraction with chloroform was performed. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give 7-tertiary butoxycarbonylamino-5-benzyl-5-azaspiro [2.4]
Heptane 10, 900 mg was obtained. This compound 10, 870 mg
Is dissolved in 15 ml of ethanol and 10% -palladium on carbon 500
mg was added and catalytic hydrogenation was carried out under pressure (4.5 kg / cm ² ) at 40 ° C. After 2 hours, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound 11, which was used for the substitution reaction without purification.

Example 2. Optically Active 7-Amino-5-azas
Synthesis of Pyro [2.4] heptane 1) 5- [1- (R) -Phenylethyl] -4,7-dioxo-5-azas
Pyro [2.4] heptane 12 Compound 2, 35.7 g was dissolved in 200 ml of ethanol to prepare 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 and 27 g of triethylamine were simultaneously added dropwise under stirring with ice cooling for 1 hour, and then the mixture was returned to room temperature and stirred for 2 days. went. The insoluble material was filtered off, ethanol was distilled off under reduced pressure, and the residue was treated with ethyl acetate (300 m).
It was dissolved in l, washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine in that 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, chloroform to 2% methanol /
Elution with chloroform gave the title compound 12 as colorless crystals.

Melting point: 98-103 ° C. ¹ H-NMR (CDCl ₃ ) δppm: 1.62 (3H, d, J = 7.2 Hz), 1.4
-1.8 (4H, m), 3.5 (1H, d, J = 18 Hz), 3.9 (1H, d, J
= 18 Hz), 5.82 (1H, q, J = 7.2 Hz), 7.36 (5H, s).

2) 5- [1- (R) -phenylethyl] -7-hydroxy
Symino-4-oxo-5-azaspiro [2.4] heptane 13 Compound 12, 3.35 g of hydroxylamine hydrochloride 1.6
g, 2.3 g of triethylamine and 80 ml of ethanol were added, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, chloroform was added to the residue, the mixture was washed with 10% aqueous citric acid solution and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The title compound 13, by distilling off the solvent under reduced pressure,
3.5 g was obtained as colorless crystals.

Melting point: 188-194 ° C. ¹ H-NMR (CDCl ₃ ) δppm: 1.2-1.4 (2H, m), 1.53 (3H, d,
J = 7.2 Hz, & 2H, m), 3.8 (1H, d, J = 18 Hz), 4.16 (1
H, d, J = 18 Hz), 5.63 (1H, q, J = 7.2 Hz), 7.32 (5H,
s)

3) 7-amino-4-oxo-5- [1- (R) -phenyl
Ruethyl] -5-azaspiro [2.4] heptane 14a, 14b Compound 13, 3.5 g and Raney nickel 7.5 ml were added to 150 ml of methanol, and catalytic reduction was performed at room temperature for 12 hours.
After removing the catalyst by filtration, the solvent was evaporated under reduced pressure, and the residue was subjected to 100 g of silica gel column chromatography and eluted with 5% methanol / chloroform to give compound 14b.
(First eluted fraction) and Compound 14a were obtained as colorless oils (1.0 g, 0.8 g).

14b; ¹ H-NMR (CDCl ₃ ) δppm: 0.8 −
1.4 (4H, m), 1.52 (3H, d, J
= 7 Hz), 2.87 (1H, dd, J
= 10.3 Hz), 3.3-3.9 (2H,
m), 4.27 (2H, br s), 5.42
(1H, q, J = 7 Hz), 7.29 (5
H, s)

14a; ¹ H-NMR (CDCl ₃ ) δ
ppm: 0.6-1.3 (4H, m), 1.40 (2H, s), 1.53 (3H, d, J
= 7.2 Hz), 2.99 (1H, dd, J = 12.8, 7.2 Hz), 3.15-
3.45 (2H, m), 5.52 (1H, q, J = 7.2 Hz), 7.30 (5H, s)

4) 7-Amino-5- [1- (R) -phenylethyl]-
5-azaspiro [2.4] heptane 15a, 15b To 50 ml of anhydrous tetrahydrofuran was added compound 14b (1.0 g) and lithium aluminum hydride (500 mg).
Refluxed for 17 hours. After cooling, add 0.5 ml of water to the reaction mixture, 15%
0.5 ml of an aqueous sodium hydroxide solution and 1.5 ml of water were sequentially added, and the mixture was stirred at room temperature for 30 minutes. The insoluble matter was filtered, washed well with tetrahydrofuran, and the filtrate and washings were combined and dried. After the solvent was distilled off under reduced pressure, the title compound 1 was obtained as a pale yellow oily substance.
5b, 940 mg were obtained. In the same manner, compound 15a, 755 mg was obtained from compound 14a, 800 mg.

15b; ¹ H-NMR (CDCl ₃ ) δppm: 0.2-0.8 (4
H, m), 1.35 (3H, d, J = 6.6 Hz), 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 (5H, br s)

15a; ¹ H-NMR (CDCl ₃ ) δppm: 0.3-0.9 (4
H, m), 1.36 (3H, d, J = 6.7 Hz), 1.8-2.2 (2H, m),
2.2-3.2 (4H, m), 3.24 (1H, q, J = 6.7 Hz), 3.6-
3.9 (1H, m), 7.28 (5H, br s)

5) 7- (tertiary butoxycarbonylamino)-
5- [1- (R) -phenylethyl] -5-azaspiro [2.4] hepta
16a, 16b Compound 15b, 764 mg in 20 ml anhydrous tetrahydrofuran
And BOC-ON (1.3 g) 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. After washing the aqueous layer once with ethyl acetate, add 15% aqueous sodium hydroxide under cooling to make it alkaline, and then
Extraction was performed 3 times with chloroform, 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, eluted with chloroform: methanol = 20: 1, 10: 1) to obtain the title compound 16b (690 mg). This product crystallized after standing. It was washed with n-hexane. Compound 16a was obtained in a similar manner.

16b: colorless crystal Melting point: 103-105 ° C. [α] _D -15.2 ° (c = 1.475, chloroform) ¹ H-NMR (CDCl ₃ ) δppm: 0.4-0.9 (4H, m), 1.36 (3H,
d, J = 7.2 Hz), 1.44 (9H, s), 2.42 (2H, AB q, J = 10.
2 Hz), 2.79 (2H, d, J = 5.6 Hz), 3.24 (1H, q, J = 7.2
Hz), 3.6-4.0 (1H, m), 4.6-5.1 (1H, br d), 7.28 (5
(H, s) Elemental analysis: Calculated as C ₁₉ H ₂₈ N ₂ O ₂ : C 72.12, H 8.92, N 8.85 Analytical value: C 71.63, H 9.07, N 8.64

16a: colorless crystal Melting point: 94-97 ° C. [α] _D + 47.6 ° (c = 0.89, chloroform) ¹ H-NMR (CDCl ₃ ) δppm: 0.4-0.9 (4H,
m), 1.33 (3H, d, J = 6.6H
z), 1.40 (9H, s), 2.29 (1H,
d, J = 9 Hz), 2.44 (1H, d
d, J = 10.8, 3.6 Hz), 2.77.
(1H, d, J = 9 Hz), 2.88 (1
H, dd, J = 10.8, 5.3 Hz),
3.22 (1H, q, J = 6.6 Hz),
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 value: C 72.12, H 8.92, N 8.85 Analytical value: C 71.86, H 9.36, N 8.68

6) 7-tertiary butoxycarbonylamino-5
-Azaspiro [2.4] heptane 11a, 11b Compound 16b, 650 mg and 50% hydrous palladium-carbon 500 m
g was added to 30 ml of ethanol, and catalytic reduction was performed at 4.2 atm under heating. After 6 hours, the catalyst was filtered off 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 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 of the crude product was obtained.
Obtained. Compound 11a was also obtained in the same manner. Of compounds 11b and 11a
^{The 1} H-NMR spectrum was in perfect agreement.

17b; ¹ H-NMR (CDCl ₃ ) δppm: 0.4-1.0 (4
H, m), 1.42 (9H, s), 2.71 (1H, d, J = 10.2 Hz), 2.92
(1H, dd, J = 10.8, 3.6 Hz), 3.01 (1H, d, J = 10.2 H
z), 3.33 (1H, dd, J = 10.8, 5.4 Hz), 3.5-3.9 (1H,
m), 5.0-5.4 (1H, br d)

Example 3.4,7-Diazaspiro [2.5] octa
Emissions Synthesis 1) cyclopropane-1,1-dibromo-amide 18 cyclo-1,1-diamide 17, bromine 35 14.0 g
130 g of an aqueous potassium hydroxide solution suspended in 14 g of potassium hydroxide prepared from 14 g of potassium hydroxide was added dropwise under stirring at room temperature. After stirring for 1 hour, the mixture was cooled with ice water, the precipitated crystals were collected by filtration, washed with ice water, air-dried and then dried under reduced pressure at 66 ° C. for 2 hours to give the title compound 18,
28.6 g was obtained.

2) 4,6-diazaspiro [2.4] heptane-5,7
-Dione 19 Compound 18, 26 g under ice cooling with stirring, sodium 9.1 g
And sodium methoxide solution prepared from anhydrous methanol. When the cooling was stopped and the stirring was continued, the internal temperature gradually increased and suddenly increased from about 20 ° C to boiling the methanol. After heating under reflux for 10 minutes, the mixture was returned to room temperature and dried under reduced pressure. Acetone was added to the residue and filtered, the crystals were washed with acetone, the washings were added to the filtrate and concentrated under reduced pressure to give the title compound 19
The crude product of was obtained and used in the next reaction without purification.

3) 1-aminocyclopropanecarboxylic acid 2
0 and 1-tertiary butoxycarbonylaminocyclopropa
Dissolve the crude compound of carboxylic acid 21 compound 19 in 60 ml of water and add barium hydroxide.
Add 15 g, and set the external temperature in the stainless autoclave 1
The reaction was carried out at 70 ° C for 2 hours. After standing overnight, the precipitated barium carbonate was filtered off, ammonium carbonate was added to the filtrate, and the precipitated barium carbonate was filtered off. The filtrate was concentrated to obtain a crude product of amino acid compound 20. This compound 20 was subjected to tertiary butoxycarbonylation with BOC-ON without purification to give compound 21, 2.5 g.

¹ H-NMR (CDCl ₃ ) δppm: 1.85 (2H, t), 2.05
(9H, s), 2.15 (2H, t)

4) Ethyl (1-tertiary butoxycarbonyl
Amino-1-cyclopropylcarbonylamino) acetate
Compound 22 (700 mg) was dissolved in dioxane (50 ml), dicyclohexylcarbonyldiimide (800 mg) and glycine ethyl ester hydrochloride (600 mg) were added, and triethylamine (400 mg) in dioxane (10 ml) was gradually added dropwise under stirring at room temperature. Stirring was continued for another 3 hours. The solvent was evaporated under reduced pressure and the residue was subjected to silica gel column chromatography, and the title compound 22, 700 mg was eluted from the 5% methanol-chloroform eluate.
I got

5) Ethyl (1-amino-1-cyclopropyl
Carbonylamino) acetate 23 23 Compound 22, 680 mg was added with trifluoroacetic acid 10 ml and anisole 0.5 g, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure and the residue was adjusted to pH 10 by adding aqueous potassium carbonate solution.
That's it. After saturated with sodium chloride, it 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 ) δppm: 0.85 (2H, t), 1.28
(3H, t), 1.46 (2H, t, J = 4 Hz), 1.68 (2H, br-s), 4.2
1 (2H, t, J = 7 Hz), 4.40 (2H, d, J = 7 Hz)

6) 4,7-Diazaspiro [2.5] octane-5,8
-Dione 24 Compound 23, 500 mg was solidified after foaming when heated in an oil bath at 220 ° C. After continuing heating for 20 minutes, the mixture was cooled to room temperature to obtain a crude product of the title compound 24. ¹ H-NMR (DMSO-d ₆ ) δppm: 0.96 (2H, t), 1.17 (2H, t, J =
4 Hz), 3.86 (2H, J = 3 Hz), 8.0, 8.25 (1H, br-s each)

7) 4,7-Diazaspiro [2.5] octane 25 Compound 24, 350 mg was added to anhydrous tetrahydrofuran 200 ml.
The mixture was suspended in, 0.6 g of lithium aluminum hydride was added, and the mixture was heated under reflux for 14 hours. After the reaction, water under ice cooling 0.6
g, 0.6 g of a 15% aqueous sodium hydroxide solution, and 1.8 g of water were added in that order, and the precipitate was collected by filtration. The precipitate is thoroughly washed with tetrahydrofuran and ether, the washing solution is added to the filtrate, the solvent is evaporated under reduced pressure, and the residue is concentrated to obtain the title 4,7-diazaspiro [2.5] octane 25 crude product, which is further purified. It was used in the substitution reaction without any treatment.

Reference Example 1 Synthesis of Benzoic Acid Derivative 1) 3-Chloro-2,4,5-trifluoro-benzoic acid 27 Acetonitrile 150 ml was charged with anhydrous cuprous chloride 9.3 g and tertiary butyl nitrite 8.8 g. In addition, 3-amino-2,4,5-trifluoro-benzoic acid 26 (commercially available), 11
g was added and stirring was continued for 20 minutes. After cooling, 15% hydrochloric acid 500 ml
And extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography on 100 g of silica gel and eluted with chloroform to elute 8.4 g of 3-chloro-2,4,5-triethyl. Fluorobenzoic acid 27 was obtained as colorless needle crystals.

Melting point: 114-115 ° C. Elemental analysis value: theoretical value as C ₇ H ₂ ClF ₃ O ₂ C 39.93 H 0.96 measured value C 39.87 H 1.04 ¹ H-NMR (CDCl ₃ ) δppm: 7.76 (1H, ddd, J = 6.5, 8.5, 9.
9 Hz), 8.6-9.2 (1H, br s)

2) 2,4,5-Trifluoro-3-iodobenzoic acid
Acid 28 To 150 ml of acetonitrile, 10 g of cuprous iodide and 8.8 g of tert-butyl nitrite are added, and 11 g of 3-amino-2,4,5-trifluorobenzoic acid is added with stirring at 60 ° C. Stir 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 column of 100 g of silica gel and eluted with chloroform. Fractions containing the target compound were collected, the solvent was evaporated under reduced pressure, and the residue was recrystallized from n-hexane to give 8.4 g.
A colorless crystal of the title compound was obtained.

[0196] 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 ⁺ )

By using anhydrous cuprous bromide in the same manner, 3-bromo-2,4,5-trifluorobenzoic acid 29 having a melting point of 124-125 ° C. was obtained.

3) 2,4,5-Trifluorobenzoic acid 30 3-1. Direct deamination method Tertiary butyl nitrite 1.8 g of anhydrous dimethylformamide
Dissolve in 5 ml, heat and stir at 60 ° C, and wash with 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 give 1.1 g of the title compound as crystals.

3-2. Method for reduction after bromine compound 3-bromo-2,4,5-trifluorobenzoic acid 29, 5.0 g, acetic acid 30 ml, sodium acetate 2.0 g, 5% palladium-carbon
1.0 g was mixed and reduced under a hydrogen atmosphere for 4 hours. The catalyst was filtered off 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 ) δppm: 7.10 (1H, ddd,
J = 6.5, 9, 9 Hz), 7.96 (1H, ddd, J = 6.3, 8.5, 9.8
Hz), 9.2-9.6 (1H, br s)

Reference Example 2. 7- (7-amino-5-azaspiro
[2.4] Heptane-5-yl) -1-cyclopropyl-6,8-diff
Luoro-1,4-dihydro-4-oxoquinoline-3-carvone
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 (250 mg) was added to dimethylsulfoxide (5 ml), and the mixture was reacted at 100 ° C for 30 minutes. After cooling, the solvent was distilled off under reduced pressure, ethanol was added to the residue for crystallization, and the precipitated crystals were collected by filtration. The obtained crude crystals were suspended in ethanol, and 28% aqueous ammonia was added to dissolve the crude crystals.
0 mg was added and filtered. The filtrate was heated and concentrated, and the precipitated crystals were collected by filtration to obtain 170 mg of the title compound.

Melting point: 238-245 ° C Elemental analysis value: As C ₁₉ H ₁₉ F ₂ O ₃ · 1 / 2H ₂ O Theoretical value: C 59.37 H 5.24 N 10.93 Actual value: C 59.63 H 5.71 N 10.85

Reference Example 3. Optically active form of compound 31 31
Synthesis of a and 31b 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro
-4-Oxoquinoline-3-carboxylic acid (140 mg) was suspended in dimethylsulfoxide (2 ml) and triethylamine (66 m) was added.
g, and then an aqueous solution of optically active amine and compound 7a was 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 reconstituted from ethanol-28% aqueous ammonia. Crystallization gave pale yellow microcrystalline compound 31a (40.5 mg). Compound 31b and 34 mg were obtained by the same operation using compound 7b.

(+)-7- (7-Amino-5-azaspiro [2.4]
(Putan-5-yl) -1-cyclopropyl-6,8-difluoro-1,
4-Dihydro-4- oxoquinoline -3-carboxylic acid 31a Melting point: 221-235 ℃ (decomposition) [α] _D +116.2 ° (c = 0.575, concentrated ammonia water) Elemental analysis: C ₁₉ H ₁₉ F ₂ N Theoretical value as ₃ O ₃ 1 / 2H ₂ O C 59.37 H 5.24 N 10.93 Measured value C 59.31 H 5.02 N 10.93

(-)-7- (7-Amino-5-azaspiro [2.4]
(Putan-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: C ₁₉ H ₁₉ F ₂ N Theoretical value of C 59.37 H 5.24 as ₃ O ₃ 1 / 2H ₂ O
N 10.93 Found C 59.33 H 4.90.
N 10.65

Reference Example 4. 7- (7-amino-5-azaspiro
[2.4] Heptane-5-yl) -8-chloro-1-cyclopropyl-
6-Fluoro-1,4-dihydro-4-oxoquinoline-3-cal
Boronic acid 32 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 200 mg, compound 11, 150 mg, and triethylamine 70 mg in acetonitrile 5 ml In addition, 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 filtered. Wash with water, acetonitrile, ethanol, and ether in that order and dry,
(7- Tertiary butoxycarbonylamino-5-azaspiro
[2.4] Heptane-5-yl) -8-chloro-1-cyclopropyl
-6-Fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 245 mg, melting point 205-207 ° C was obtained.

To 200 mg of this carboxylic acid, 0.3 of anisole was added.
ml and trifluoroacetic acid 5 ml were added, and the mixture was stirred at room temperature for 30 minutes. After distilling off the solvent under reduced pressure, the residue was made alkaline with water and then with 1N aqueous sodium hydroxide solution, washed twice with chloroform, neutralized with 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 give the title compound 32, 105.
mg was obtained.

[0208] mp: 235 - 240 ℃ (decomposition) Elemental _{analysis: C 19 H 19 ClFN 3 O} 3 · 1 / 4H 2 O as the theoretical value: C 57.58 H 4.96 N 10.60 Found: C 57.64 H 5.33 N 10.37

Reference Example 5. 7- (7-amino-5-azaspiro
[2.4] Heptane-5-yl) -1-cyclopropyl-6-fluor
B-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 3
3 1-Cyclopropyl-6,7-difluoro-2,3-dihydro-4-
Oxoquinoline-3-carboxylic acid 250 mg, compound 11, 250
Add mg to 4 ml of dimethyl sulfoxide and add 2 at 120 ° C.
Reacted for hours. After cooling, the solvent was distilled off under reduced pressure, ethanol was added to the residue for crystallization, and the precipitated crystals were collected by filtration, and 7- (7-tertiary butoxycarbonylamino-5-azaspiro [2.4] heptane-5-yl ) -1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was obtained as a crude product.

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

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

Reference Examples 6 and 7 According to the method of Reference Example 5, 7- (7-amino-5-azaspiro
[2.4] Heptan-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

Reference Example 8. 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] be
Nazoxazine-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, 300 mg, Compound 11, 250 m
g was 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, 1 ml of triethylamine and 30 ml of 95% methanol were added to the residue, and the mixture was refluxed for 6 hours. After cooling, the solvent was distilled off under reduced pressure, ethanol was added to the residue for trituration, and the crystals were collected by filtration. The tertiary butoxycarbonyl group was removed from this crystal by an operation according to Reference Example 5 to obtain 170 mg of a crude product of the title compound.
It was dissolved in concentrated ammonia, treated with activated carbon, and recrystallized to obtain 110 mg of the title compound. Melting point: 236-237 ° C

Reference Example 9.1-Cyclopropyl-7- (4,7-dia
Zaspiro [2.5] octane-7-yl) -6-fluoro-1,4-di
Hydro-4-oxoquinoline-3-carboxylic acid 37 1-Cyclopropyl-6,7-difluoro-1,4-dihydro-4-
200 mg of oxoquinoline-3-carboxylic acid and 200 mg of a crude product of 4,7-diazaspiro [2.5] octane 25 were 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,
Chloroform: methanol: water = 15: 3: 1 (v / v) was used for elution, and the eluate was recrystallized from ethanol-concentrated ammonia to obtain the title compound 37, 160 mg.

Melting point: 243-245 ° C (decomposition) Elemental analysis value: C ₁₉ H ₂₀ N ₃ O ₃ F · 1 / 4H 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) δppm: 0.97 (2H, t, J = 6Hz), 1.12 (2
H, m), 1.36 (2H, br-t), 1.48 (2H, bt, J = 6 Hz), 7.6
4 (1H, d, J = 8 Hz), 7.92 (1H, d, J = 14 Hz), 8.52 (1
H, s)

Reference Example 10. 7- (7-acetoxy-5-azaspira
[2.4] Heptane-5-yl) -8-chloro-1-cyclopropyi
Le-6-fluoro-1,4-dihydro-4-oxoquinoline-3-
Carboxylic acid 38 7-acetoxy-5-azaspiro [2.4] heptane To a solution of 900 mg of dry acetonitrile in 10 ml of 8-chloro-1-cyclopropyl-6,7-difluoro-3-oxo-3,4-dihydroquinoline-3 -360 mg of carboxylic acid and 1 ml of triethylamine were added, and the mixture was heated under reflux for 2.5 days (after 3 hours, the above-mentioned azaspiroheptane, 400 mg was added). The reaction solution was diluted with chloroform, the organic layer was washed with 10% aqueous citric acid solution, dried and the solvent was evaporated under reduced pressure.

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

Fractions containing the desired product were collected and the solvent was evaporated under reduced pressure. A small amount of ethanol was added to the residue, which was heated for a while and left to stand. The precipitated crystals were collected by filtration and washed with diisopropyl ether to give the title compound (174 mg).

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)

Reference Example 11. 7- (7-hydroxy-5-azaspira
[2.4] Heptane-5-yl) -8-chloro-1-cyclopropyi
Le-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-3-carvone Acid 38, 174 mg
Was suspended in 8 ml of ethanol, 1.5 ml of a 1N sodium hydroxide aqueous 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 acidified with 1N hydrochloric acid and extracted with chloroform. After drying the extract, the solvent was distilled off under reduced pressure, and the residue was treated with aqueous ammonia
Recrystallization from ethanol gave 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, 3.3
5, & 3.74 (1H each), 4.09-4.13 (3H, m), 7.59 (1H,
d), 8.45 (1H, s) Elemental analysis: Calculated as C ₁₉ H ₁₈ N ₂ O ₄ ClF: C 58.10 H 4.62 N 7.13 Measured value: C 58.39 H 4.65 N 7.27

Reference Example 12. 7- (7-hydroxyimino-5-a
Zaspiro [2.4] heptane-5-yl) -8-chloro-1-cyclo
Propyl-6-fluoro-1,4-dihydro-4-oxoquinoli
-3-carboxylic acid 40 5-tertiary butoxycarbonyl-7-hydroxyimino-5-
Azaspiro [2.4] heptane 67, 678 mg with anisole
0.5 ml was added, trifluoroacetic acid 5 ml was added under ice cooling, and the mixture was stirred for 30 minutes as it was. The solvent was distilled off under reduced pressure, 100 ml of dry acetonitrile was added to the residue, and then 8-chloro-1-cyclopropyl-6,7-difluoro-4-oxo-3,4
After adding 300 mg of dihydroquinoline-3-carboxylic acid and 1 ml of triethylamine, 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 material was filtered off. 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 5
8 mg was obtained.

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: As C ₁₉ H ₁₇ N ₃ O ₄ FCl Calculated value: C 56.24 H 4.22 N 10.35 Measured value: C 56.34 H 4.34
N 10.32.

Reference Example 13. (-)-10- (7-Amino-5-azas
Pyro [2.4] heptane-5-yl) -9-fluoro-2,3-dihydride
B-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-de] [1,4] benzoxazine-
280 mg of 3-carboxylic acid BF ₂ chelate was suspended in 4 ml of anhydrous dimethyl sulfoxide, and the compound 68b, 45 was suspended at room temperature.
0 mg was added, and triethylamine 520 mg was added 45
Stir for minutes. Water was slowly added to the reaction solution while cooling with ice, and the precipitated crystals were collected by filtration. To the crystals collected by filtration, add 30 ml of 90% methanol, and add 1 ml of triethylamine in the presence of 2 ml.
The mixture was heated under reflux for 7 hours. The solvent was distilled off under reduced pressure, and the residue was recrystallized from aqueous ammonia-ethanol to give the title compound 73
to obtain mg.

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 = 5 Hz), 2.91-4.39 (8H, m), 7.28 (1H, d, J = 1
5 Hz), 8.17 (1H, s) Elemental analysis: As C ₁₉ H ₂₀ N ₃ O ₄ F ・ 1.25H ₂ O Calculated value: C 57.64 H 5.73 N 10.61 Measured value: C 57.64 H 5.21 N 10.81

Reference Example 14. (-)-7- (7-Amino-5-azaspira
[2.4] Heptane-5-yl) -1-cyclopropyl-6-full
Oro-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 1 g triethylamine
Was added to 6 ml of dimethyl sulfoxide, and the mixture was stirred at 110 ° C. for 1 hour. After the solvent was distilled off under reduced pressure, diethyl ether was added to the residue and the precipitate was collected by filtration. After adding 1N hydrochloric acid to this and washing with chloroform, the aqueous solution was made alkaline with a 1N aqueous sodium hydroxide solution and washed again with chloroform. Next, add pH 7.1 to the alkaline solution with concentrated hydrochloric acid under ice cooling.
Adjusted to. The precipitated colorless crystals were collected by filtration, washed with water, ethanol and ether and dried. Recrystallization from concentrated aqueous ammonia-ethanol gave 283 mg of the title compound as colorless fine needle crystals.

Melting point: 240-250 ° C. (decomposition) [α] _D −13.6 ° (c = 0.66, 1N NaOH) Elemental analysis: Calculated as C ₁₈ H ₁₉ H ₄ 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

Reference Example 15.7- (7-Amino-5-azaspiro
[2.4] Heptane-5-yl) -1,4-dihydro-6-fluoro-1
-(2-Methyl-2-propyl) -4-oxo-1,8-naphthyridine-3
-Suspended 200 mg of carboxylic acid 41b compound 68b in 15 ml of acetonitrile,
Add 3 ml of triethylamine, heat to reflux and add 7-chloro.
-1,4-dihydro-6-fluoro-1- (2-methyl-2-propyl)
327 mg of 4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester was added little by little. After heating under reflux for 1 hour,
The solvent was evaporated under reduced pressure, water was added to the residue, the mixture was extracted with chloroform and n-butanol, the organic layers were combined, and the solvent was evaporated 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-NMR (DMSO-d ₆ ) δ: 0.77-1.05 (4H,
m), 1.27 (3H, t, J = 7 Hz), 1.82 (9H, s), 2.86-3.36
(4H, m), 4.20 (1H, m), 4.21 (2H, q, J = 7 Hz), 7.91 (1
H, d, J = 13 Hz), 8.68 (1H, s)

[0230] The obtained white powder (510 mg) was suspended in water (2 ml), 1N aqueous sodium hydroxide solution (2 ml) was added, and the mixture was heated under reflux for 40 min. 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, it was recrystallized from ethanol to give the title compound as a white powder, 171 mg.
I got

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 =
13 Hz), 8.82 (1H, s) Elemental analysis: As C ₁₉ H ₂₃ H ₄ O ₃ F ・ 1 / 2H 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 16.2,4,5-trifluoro-3-methyl
Synthesis of benzoic acid 1) 3,5,6-trifluoro-4-nitromethylphthalic acid dime
Cyl 42 Dimethyl tetrafluorophthalate (Journal of the Chemical Society of Japan, 197
6, 200, Ishikawa, Suzuki, Tanabe), 200 g of nitromethane 400
Dissolve it in ml and cool it with ice-salt. 1,8-
171 g of diazabicyclo [5,4,0] -7-undecene was added dropwise over 30 minutes. After the dropping, the mixture was stirred at an internal temperature of 10 ° C. for another 30 minutes and poured into a mixture of 1.5 liters of 1N hydrochloric acid and 1 liter of ice.

The reaction solution was extracted with benzene, the organic layer was washed with water and 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 to give 195 g of the title compound as a yellow oil.

¹ H-NMR (CDCl ₃ ) δ: 3.88 (3H, s), 3.94 (3
H, s), 5.60 (2H, t, J = 2 Hz)

2) Dimethyl 4-dimethylaminomethyl-
Dimethyl 3,5,6-trifluorophthalate 43 compound 42, 5.0 g, Raney nickel 10 m
1, 15 ml of formalin (35%) and 70 ml of ethanol were mixed and reduced under normal pressure for 22 hours. The solvent was filtered off, the filtrate was concentrated under reduced pressure, 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 (2
H, t, J = 2 Hz), 3.96 (3H, s), 3.98 (3H, s)

3) 2,5,6-trifluoro-3,4-di (meth)
Cycarbonyl) phenylmethylene-trimethyl-ammo
5.2 g of the compound 42, which is a compound of iodide 44, was dissolved in 50 ml of ethanol, 5 ml of methyl iodide was added, and the mixture was left for 1.5 hours. The precipitated crystals were collected by filtration to give 3.6 g of the title compound as colorless crystals. Melting point: 18
6-190 ° C (decomposition)

4) 3,5,6-trifluoro-4-methylphthal
Acid Dimethyl 45 a) Compound 42, 4.6 g, tributyltin hydride 6.8
g, α, α′-azobisisobutyronitrile (300 mg) and benzene (70 ml) were mixed and heated under reflux for 4 hours. The reaction solution was concentrated under reduced pressure and the residue was applied to a column of silica gel 50 g,
Elution with benzene gave 2.45 g of the title compound as a pale yellow oil.

B) Compound 44, 17.0 g, Raney nickel
30 ml of ethanol and 350 ml of ethanol were mixed and reduced under atmospheric pressure for 25.5 hours while being heated by irradiation with a tungsten lamp. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. Water was added to the residue and 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 oily substance.

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-me
Cylphthalic acid 46 Compound 45, 2.45 g, acetic acid 10 ml, concentrated hydrochloric acid 20 ml are mixed.
The mixture was heated under reflux for 12 hours. The reaction solution was concentrated under reduced pressure, 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
Acid 47 Compound 46, 10.1 g is dissolved in 40 ml of water and the bath temperature is 2 in a sealed tube.
The reaction was carried out at 00 ° C for 4 days. The reaction solution was extracted with chloroform, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
Obtained 6.2 g of the title compound as pale yellow crystals.

Melting point: 89-90 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.29 (3 H, t, J = 2 Hz), 7.56-7.
84 (1H, m), 8.1-8.6 (1H, broad)

Reference Example 17.2,4,5-trifluoro-3-methyl
Ethyl benzoylacetate 48 2,4,5-Trifluoro-3-methylbenzoic acid 47, 9.89 g was dissolved in 200 ml of benzene, and 40 ml of thionyl chloride was added.
The mixture was heated under reflux for 14 hours. The reaction mixture was dried under reduced pressure, benzene (200 ml) was added to the residue, and the crude acid chloride obtained by drying under reduced pressure again was dissolved in 200 ml of diethyl ether.

1.26 g of magnesium, 250 ml of ethanol,
6 ml of carbon tetrachloride was mixed and stirred at room temperature for 1 hour. 50 ml of diethyl ether solution of 8.34 g of diethyl malonate
Was added dropwise over 10 minutes, and 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 above diethyl chloride solution of acid chloride was added dropwise thereto over 10 minutes, and the mixture was stirred at room temperature for 4 days. 1N Hydrochloric acid (100 ml) was added and the mixture was stirred and the ether layer was separated, washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. 50 ml of water on the residue, p
-Toluenesulfonic acid (500 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 evaporated under reduced pressure. The residue was applied to a silica gel column and eluted with benzene to obtain 6.1 g of a colorless oily substance. Partially crystallized on standing.

Reference Example 18. 2-Cyclopropylaminomethyle
-3-oxo-3- (2,4,5-trifluoro-3-methyl) -phen
Ethyl nylpropionate 49 Compound 48, 1.57 g, ethyl orthoformate 6 ml, acetic anhydride 6
ml was mixed and heated with stirring at 120 ° C. for 3 hours. The reaction solution was evaporated to dryness under reduced pressure, dissolved in 25 ml of 1,2-dichloromethane, and 400 mg of cyclopropylamine in 1,2-dichloroethane solution 1
0 ml was added and the mixture was stirred at room temperature for 14 hours. The reaction mixture was evaporated to dryness under reduced pressure to give 2 g of the title compound as colorless crystals with a melting point of 61-64 ° C.

Reference Example 1 1-Cyclopropyl-6,7-diflu
Oro-8-methyl-4-oxo-1,4-dihydroquinoline-3-
Ethyl carboxylate 50 Compound 49, 1.97 g was dissolved in 30 ml of anhydrous dioxane.
360 mg of 0% sodium hydride was added, and the mixture was stirred for 18 hours at room temperature. To the reaction mixture was added 1N hydrochloric acid (10 ml), 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 colorless crystals of the title compound. Melting point: 204-210 ° C

Reference Example 2 1-Cyclopropyl-6,7-diflu
Oro-8-methyl-4-oxo-1,4-dihydroquinoline-3-
The carboxylic acid 51 compound 50, 1.30 g, and concentrated hydrochloric acid 10 ml 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.
Washing with ethanol gave 1.12 g of the title compound. Melting point: 241-242 ° C

Reference Example 2 1-Cyclopropyl-6,7-diflu
Oro-8-methyl-4-oxo-1,4-dihydroquinoline-3-
Carboxylic acid BF ₂ - chelate 52 Compound 50, 420 mg of diethyl ether 3
Suspended in 0 ml, boron trifluoride diethyl ether complex 2
ml was added and the mixture was stirred at room temperature for 24 hours. The crystals were collected by filtration and washed with diethyl ether to obtain 487 mg of yellow crystals of the title compound. Melting point: 275-278 ° C

Reference Example 22. (-)-7- (7- Amino-5-azaspira
[2.3] Heptane-5-yl) -1-cyclopropyl-6-full
Oro-8-methyl-4-oxo-1,4-dihydroquinoline-3-
Carboxylic acid 55b Compound 52, 340 mg, 7-tertiary butoxycarbonylamino
-5-Azaspiro [2.3] heptane 11b, 330 mg, triethylamine 150 mg, and dimethylsulfoxide 5 ml were mixed and stirred at room temperature for 5 days. Chloroform 100 m
After dissolving in 1 l and washing with water, the organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure.

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

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. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated 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 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 to obtain 52 mg of colorless crystals.

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 ), 0.84-0.8
8 (1H, m), 0.90-0.97 (2H, m), 1.19-1.28 (2H, m),
2.62 (3H, s), 3.19-3.21 (1H, m), 3.29 (1H, d, J = 9
Hz), 3.36-3.39 (1H, m), 3.84 (1H, d, J = 9 Hz), 3.9
9-4.03 (1H, m), 4.05-4.08 (1H, m), 7.85 (1H, d, J
= 13.5 Hz), 8.86 (1H, s)

Reference Example 23. Optical activity 7- [7- (
Cycarbonylamino) -5-azaspiro [2.4] heptane-5-
Ill] -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 2 ml of triethylamine were dissolved in 20 ml of acetonitrile and refluxed overnight. After cooling, the solvent was concentrated under reduced pressure and the resulting precipitate was collected by filtration, washed successively with water, acetonitrile, ethanol and ether and dried under reduced pressure. 560 mg of the title compound was obtained as pale yellow crystals. 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 = 1.653, chloroform) ¹ H-NMR (CDCl ₃ ) δppm: 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: Calculated as C ₂₄ H ₂₇ N ₃ O ₅ ClF: C 58.60, H 5.53, N 8.54 Analytical value: C 58.43, H 5.59, N 8.40

56a; pale yellow crystal, melting point: 215 -216 ° C [α] _D + 131.4 ° (c = 0.77, chloroform) Elemental analysis: Calculated as C ₂₄ H ₂₇ N ₃ O ₅ ClF: C 58.60, H 5.53 , N 8.54 Analytical value: C 58.37, H 5.58, N 8.44 The NMR spectrum was in perfect agreement with 56b.

Reference Example 24. Optical activity 7- (7-amino-5-aza
Spiro [2.4] heptane-5-yl) -8-chloro-1-cyclop
Ropyl-6-fluoro-1,4-dihydro-4-oxoquinoline
-3-carboxylic acid 32a, 32b Compound 56b, 520 mg was added with 0.5 ml of anisole and 10 ml of trifluoroacetic acid under ice-cooling, then returned to room temperature and stirred for 30 minutes. After distilling off the solvent under reduced pressure, water was added to the residue,
Add 1N aqueous sodium hydroxide solution under ice cooling to adjust the pH to about 11
-12 The aqueous solution was washed twice with chloroform, and then the pH was adjusted to about 7 with concentrated hydrochloric acid and 10% aqueous citric acid solution. After extraction with chloroform three times, it was washed with water and dried.
The solvent was distilled off under reduced pressure, and the solid residue was recrystallized from ethanol-ammonia water to give the title compound 32b as pale yellow crystals.
328 mg was obtained. Similarly, the compound 32a was obtained from the compound 56a.

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) δppm: 0.6- 1.25 (8H, m),
3.08 (1H, t, J = 4.4 Hz), 3.30 (1H, d, J = 10.3 Hz),
3.41 (1H, d, J = 9.5 Hz), 3.96 (1H, d, J = 9.5 Hz),
4.11 (1H, m), 4.24 (1H, m), 7.75 (1H, d, J = 13.5 Hz),
8.55 (1H, s) Elemental analysis: Calculated as C ₁₉ H ₁₉ N ₃ O ₃ ClF ・ 1 / 2H ₂ O: 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 solution) Elemental analysis: C ₁₉ H ₁₉ N ₃ O ₃ ClF.1 Calculated as / 2H ₂ O: C 56.93, H 5.03, N 10.48 Analytical value: C 56.87, H 5.37, N 10.32 The NMR spectrum was completely in agreement with that of the compound 32b.

Reference Example 25. 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 of anhydrous diethyl ether
The suspension was suspended in 30 ml, 15 ml of boron trifluoride diethyl ether complex was added, and the mixture was stirred at room temperature for 2 hours. The precipitate was collected by filtration, washed with ether several times, and dried under reduced pressure to obtain 3.35 g of the title compound as a colorless powder.

Melting point: 245-260 ° C. (gradual decomposition) Elemental analysis value: C ₁₃ H ₇ NO ₃ Calculated as BCIF ₄ value: C 44.94 H 2.03 N 4.03 Actual value: C 45.07 H 2.21 N 4.12

Reference Example 26. (-)-7- (7-Amino-5-azaspira
[2.4] Heptane-5-yl) -8-chloro-1-cyclopropyi
Le-6-fluoro-1,4-dihydro-4-oxoquinoline-3-
Carboxylic acid 32a Compound 57, 700 mg, Compound 68b, 450 mg and triethylamine 610 mg were added to dimethylsulfoxide 7 ml and stirred at room temperature for 24 hours. Water was added to the reaction solution, and the precipitated yellow precipitate was collected by filtration and dried. 95% methanol
50 ml and triethylamine 1 ml were added and the mixture was stirred for 1 hour. The solvent was evaporated 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 saturated aqueous sodium chloride solution and dried. The solvent was evaporated under reduced pressure, and the obtained crystals were recrystallized from ammonia-ethanol to give the title compound (610 mg) as colorless crystals.

Reference Example 27. 4,7-Dioxo-5- [1- (R) -phenyl
Luethyl-5-azaspiro [2.4] heptane 12 was separately synthesized 1) 1-Acetylcyclopropane-1-carboxylic acid 58 Compound 2, 268.6 g was dissolved in 400 ml of ethanol, and 75.67 g of sodium hydroxide in 200 ml of water was dissolved. The aqueous solution was added dropwise at room temperature over 20 minutes (internal temperature was 21 to 41 ° C.), and the mixture was stirred at room temperature for 2 hours. 1,500 ml of dichloromethane in the reaction solution
And 1,500 ml of water were added, and the mixture was shaken and then separated, and the aqueous layer was washed twice with 500 ml of dichloromethane. The aqueous layer was adjusted to pH 2 with concentrated hydrochloric acid under water cooling and extracted with 1,500 ml of dichloromethane. The aqueous layer was extracted again with 500 ml of dichloromethane, the dichloromethane layers were collected, washed with 500 ml of water, and then the dichloromethane layer was dried with anhydrous sodium sulfate. Dichloromethane was distilled off under reduced pressure to obtain 232 g of the title compound as colorless and transparent.

¹ H-NMR (CDCl ₃ ) δppm: 1.6-2.0 (4H,
m), 2.21 (3H, s)

2) N- [1- (R) -phenylethyl] -1-acetyl
Ru-1-cyclopropanecarboxamide 59 Compound 58, 232.0 g was dissolved in 1,500 ml of chloroform, 250.8 ml of triethylamine was added, and the mixture was cooled to an internal temperature of -40 ° C in a dry ice-acetone bath, and 215.9 g of ethyl chloroformate was added. Dropped over 20 minutes (internal temperature -40 to -30
° C). After stirring for 40 minutes at around -30 ° C, the mixture was cooled again to -40 ° C, and 241.1 g of R-(+)-1-phenylethylamine was added dropwise over 20 minutes (internal temperature -25 ° C). Stir for 1.5 hours as it is, 1N
Hydrochloric acid was added for washing. It was washed again with 1N hydrochloric acid, washed with water and a saturated aqueous sodium hydrogen carbonate solution, and then washed with water. The chloroform layer was dried over anhydrous sodium sulfate, chloroform was distilled off under reduced pressure to give the title compound as a colorless oily substance, 489.3 g.
Obtained.

¹ H-NMR (CDCl ₃ ) δppm: 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 = 7.2Hz), 7.30 (5H, s)

3) N- [1- (R) -Phenylethyl] -1- (1,1-E
Tolylenedioxyethyl) -1-cyclopropanecarboxami
Dissolve 60 compounds 59 and 248.4 g in 800 ml of benzene, and add 230 ml of ethylene glycol and p-toluenesulfonic acid monohydrate.
10.0 g was added, and the mixture was heated under reflux for 24 hours while dehydrating. After cooling, 500 ml of water and 500 ml of benzene were added for liquid separation, followed by washing with a saturated aqueous sodium hydrogen carbonate solution and then washing with water, and the benzene layer was dried over anhydrous sodium sulfate. Benzene was distilled off under reduced pressure to obtain 227.8 g of the title compound.

¹ H-NMR (CDCl ₃ ) δppm: 0.7-0.95 & 1.0
-1.2 (each 2H, m), 1.48 (3H, s), 1.47 (3H, d, J = 7.
2 Hz), 3.98 (4H, s), 5.11 (1H, q, J = 7.2 Hz), 7.31 (5
H, s), 7.75 (1H, bs)

4) N- [1- (R) -phenylethyl] -1- (2-broth
Mo-1,1-ethylenedioxyethyl) -1-cyclopropaneca
145.4 g of bromine was added dropwise to 436 ml of ruboxamide 61 dioxane at room temperature over 30 minutes (internal temperature rose to 35 ° C). A part of the dioxane bromine complex was precipitated. After stirring for 30 minutes at the same temperature, a solution of compound 60 and 227.8 g of dichloromethane in 2,000 ml was added all at once (internal temperature dropped from 35 ° C to 25 ° C, then
Up to about 35 ° C). The mixture was stirred for 2 hours, an aqueous sodium thiosulfate solution 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 ) δppm: 0.7-1.0 & 1.0
-1.25 (2H, m each), 1.49 (3H, d, J = 7.2 Hz), 3.69 (2
H, s), 3.8-4.3 (4H, m), 5.08 (1H, q, J = 7.2 Hz),
7.30 (5H, s), 7.6 (1H, bs)

5) 4,7-Dioxo-5- [1- (R) -phenylethyl
] -5-Azaspiro [2.4] heptane-7-ethylene acetate
62 compound 61, 293.0 g of N, N-dimethylformamide 1,5
It was dissolved in 00 ml and 60% sodium hydride (43.0 g) was added in 3 portions in small portions at room temperature over 1.5 hours. Inner temperature is 28 ° C
To 35 ° C, the mixture was cooled with ice water, the reaction was continued at an internal temperature of about 30 ° C, and the reaction was performed at room temperature for 18 hours. The reaction solution was poured into ice, extracted with 3,000 ml of ethyl acetate, washed with water several times, and the ethyl acetate layer was dried over anhydrous sodium sulfate. The solvent was concentrated and treated with activated carbon, and then the solvent was distilled off under reduced pressure to obtain 203.3 g of the title compound as a black oily substance. ¹ H-NMR (CDCl ₃ ) δppm: 0.98-1.38 (4H, m), 1.50 (3H,
d, J = 7.2 Hz), 3.07 & 3.41 (each 1H, d, J = 10.2 H
z), 3.83 (4H, s), 5.61 (1H, q, J = 7.2 Hz), 7.30 (5H,
s)

6) 4,7-Dioxo-5- [1- (R) -phenylethyl
] -5-Azaspiro [2.4] heptane 12 Compound 62, 203.3 g, 1,000 ml of acetone and 1N hydrochloric acid 3
00 ml was added, and the mixture was heated under reflux for 1.5 hours. Acetone was distilled off under reduced pressure, 1,500 ml of ethyl acetate was added to the residue, washed with water, and the ethyl acetate layer was dried over anhydrous sodium sulfate. After treatment with activated carbon, ethyl acetate was distilled off under reduced pressure to obtain 160.0 g of the title compound as a crude product. The residue was subjected to silica gel column chromatography (silica gel 1.3 kg) and eluted with chloroform containing 0-10% ethyl acetate to give 65.7 g of the title compound as white crystals.

¹ H-NMR (CDCl ₃ ) δppm: 1.61 (3H, d, J =
7.2 Hz), 1.4-1.75 (4H, m), 3.48 & 3.88 (1H, d, J each
= 17.7 Hz), 5.81 (1H, q, J = 7.2 Hz), 7.34 (5H, s)

Reference Example 28.5-Tertiary butoxycarbonyl-7
-Hydroxyimino -5-azaspiro [2.4] heptane 67 1) 7,7-Ethylenedioxy-5- [1- (R) -phenylethyl]-
5-Azaspiro [2.4] heptane 63 Compound 62, 7.1 g of dry tetrahydrofuran in 150 ml of solution under ice-cooling, lithium aluminum hydride 2.5
After slowly adding g, the mixture was heated under reflux for 3.5 hours. The reaction solution was cooled, and under ice cooling, 2.5 ml of water, 2.5 ml of 15% aqueous sodium hydroxide solution, and finally 7.5 ml of water were added in that order. The insoluble material was filtered off, and the solvent of the filtrate was distilled off under reduced pressure. The residue was subjected to column chromatography (silica gel 100 g) and eluted with a mixed solvent of hexane-ethyl acetate (3: 2) to give the title compound.
Obtained 5.67 g.

¹ H-NMR (CDCl ₃ ) δppm: 0.40-0.60 (2H,
m), 0.76-0.96 (2H, m), 1.36 (3H, d, J = 7.2 Hz), 2.
40-2.88 (4H, m), 3.77 (4H, s), 7.18-7.50 (5H, m)

2) 7,7-Ethylenedioxy-5-azaspiro
[2.4] 5% Palladium-carbon (4 g) was added to a solution of heptane 64 compound 63, 3.885 g of ethanol (50 ml), and reduction was performed in a hydrogen atmosphere at 4 atm while heating with a tungsten lamp. After 3 hours, the catalyst was filtered off 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 ) δppm: 0.44-0.64 (2H,
m), 0.72-0.92 (2H, m), 3.03 & 3.05 (each 2H, s), 3.86
(4H, s)

3) 5-tertiary butoxycarbonyl-7,7-d
Tolylenedioxy-5-azaspiro [2.4] heptane 65 compound 64, 1.98 g of dry dichloromethane
To a solution of 25 ml, under ice-cooling, 1.515 g of triethylamine,
After adding 3.05 g of tert-butyl dicarbonate, the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, chloroform was added to the residue, the organic layer was washed with water and dried, and then the solvent was distilled off under reduced pressure. Column chromatography of the residue (silica gel 50
g) and mixed solvent of hexane-ethyl acetate (3: 1)
Elution with to give 3.21 g of the title compound.

4) 5-tertiary butoxycarbonyl-7-oxy
So-5-azaspiro [2.4] heptane 66 Compound 65, 3.15 g of acetone in 30 ml of solution 1N hydrochloric acid 5
ml was added, and the mixture was heated under reflux for 30 minutes. The reaction solution is concentrated under reduced pressure,
The residue was extracted with chloroform. After the chloroform layer was dried, the solvent was distilled off under reduced pressure to obtain 1.94 g of the title compound.

¹ H-NMR (CDCl ₃ ) δppm: 1.00-1.20 & 1.
30 -1.50 (each 2H, m), 4.49 (9H, s), 3.78 (2H, m), 3.95
(2H, s)

5) 5-tertiary butoxycarbonyl-7-hydrido
Roxyimino-5-azaspiro [2.4] heptane 67 Compound 66, 1.9 g of a solution of 10 ml of etal was added with 1.25 g of hydroxylamine hydrochloride and 1.8 g of triethylamine and stirred at room temperature for about 1 day (triethylamine 1
ml was added). The solvent was evaporated 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 evaporated under reduced pressure to give the title compound 1.8.
I got 6 g.

Melting point: 117-119 ° C. ¹ H-NMR (CDCl ₃ ) δppm: 0.90-1.10 & 1.14-1.34 (2H, m each), 1.45 (9H, s), 3.36
(2H, s), 4.29 (2H, s)

Example 4. 7-amino-5-azaspiro
[2.4] Heptane dihydrochloride 68b Compound 15b, 630 mg, 1N hydrochloric acid 10 ml, ethanol 20 ml
5% Palladium-carbon (800 mg) was added to the solution of (1), and reduction was performed under a hydrogen atmosphere of 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.

[0284] mp: 230 - 240 ℃ (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 Calculated as / 2H ₂ 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 ) δppm: 0.79-1.60 (4H, m), 3.08 (1H,
d, J = 12 Hz), 3.48-3.67 (3H, m), 3.93 (1H, dd, J
= 7 & 13.5 Hz)

Example 5.7 7-Tertiary butoxycarbonyl chloride
Mino-5-azaspiro [2.4] heptane 11b Compound 16b, 50% in a solution of 11.8 g ethanol 200 ml
5 g of water-containing 5% palladium-carbon was added, and catalytic reduction was performed while heating with a tungsten lamp. After 6 hours, the catalyst was removed and the solvent of the filtrate was evaporated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was extracted with 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, CHC
l ₃ )

Reference Example 29. 1) Diethylcyclobutylidene malonate 70 Tetrahydrofuran 285 ml was cooled to -30 ° C, and a solution of titanium tetrachloride 15.7 ml and carbon tetrachloride 36 ml was rapidly added dropwise thereto while stirring. Add 5 g of cyclobutane, 10.83 g of diethyl malonate and 23.1 ml of pyridine.
A solution of 50 ml of tetrahydrofuran was added dropwise over 1 hour while maintaining the internal temperature at -10 ° C or lower. After the dropping, the internal temperature is 0
Stir at 18 ° C. for 18 hours. Water and diethyl ether were added to the reaction solution, and after liquid separation, the aqueous layer was extracted twice with diethyl ether. The organic layer was washed successively with saturated aqueous sodium chloride solution, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution. The organic layer 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 oily substance.

¹ H-NMR (CDCl ₃ ) δppm: 1.29 (6H, t, J =
7.3 Hz), 1.7-2.4 (2H, m), 3.15 (4H, t, J = 7.7 H
z), 4.22 (4H, q, J = 7.3 Hz)

Diethyl cyclopentylidene malonate 71 ( ¹ H-NMR (CDCl ₃ ) δppm: 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 diethyl cyclohexylidene malonate 72 ( ¹ H-NMR (CDCl ₃ ) δppm: 1.28 (6 H,
t, J = 7.2 Hz), 1.4-1.85 (6H, br), 2.3-2.3 (4H, b
r), 4.22 (4H, q, J = 7.2 Hz)).

2) Diethyl (1-nitromethyl-1-cyclo)
(Robutyl) malonate 73 Compound 70, 15.32 g, a mixture of nitromethane 59 ml and tetramethylguanidine 4.5 ml was stirred at room temperature for 16 hours. Chloroform was added to the reaction solution, which was washed with a 10% aqueous citric acid solution, and then the organic layer was washed with a saturated aqueous sodium chloride solution.
It was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure,
19.027 g of the title compound was obtained as a yellow oil.

¹ H-NMR (CDCl ₃ ) δppm: 1.28 (6H, t, J =
7.1 Hz), 1.8-2.4 (6H, m), 4.20 (4H, q, J = 7,1 H
z), 4.82 (2H, s)

Diethyl (1-nitromethyl-1-cyclopentyl) malonate 74 ( ¹ H-NMR (C
DCl ₃ ) δppm: 1.27 (6H, t, J = 7 Hz), 1.6-2.0 (8H,
m), 3.79 (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 = 7 Hz), 1.4-1.8 (10H, M), 3.88 (1H, s), 4.20 (4H,
q, J = 7 Hz), 4.96 (2H, s)) was obtained.

3) Ethyl 7-oxo-6-azaspiro [3.
4] Dissolve Octane-8-carboxylate 76 compound 73, 19.03 g in 400 ml of ethanol,
30 ml of Raney nickel washed with water and ethanol was added and degassed, followed by catalytic reduction in a hydrogen gas atmosphere for 2 days. After the catalyst was filtered off, the solvent was distilled off under reduced pressure. Ethyl acetate and 1N hydrochloric acid were added to the residue, and the mixture was shaken and separated. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was applied to a silica gel 100 g flash column and eluted with chloroform containing 0-3% methanol to give the title compound.
2.972 g was obtained. On the other hand, the 1N hydrochloric acid layer was neutralized with sodium hydrogen carbonate and extracted with ethyl acetate. This was repeated, the organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. 1.583 g of the title compound are obtained. 4.555 in total
got g.

¹ H-NMR (CDCl ₃ ) δppm: 1.28 (3H, t, J =
7.1 Hz), 1.8-2.2 (6H, m), 3.21 (1H, s), 3.41 (1H, d
d, J = 9.7 & 1.4 Hz), 3.60 (1H, d, J = 9.7 Hz), 4.20
(2H, q, J = 7.1 Hz), 7.21 (1H, br)

In a similar manner, ethyl 3-oxo-2-azaspiro [4.4] nonane-4-carboxylate 77 ( ¹ H-NM
R (CDCl ₃ ) δppm: 1.28 (3H, t, J = 7.3 Hz), 2.6-2.8 (8
H, br), 3.07 (1H, s), 3.01 (1H, dd, J = 7.3 & 1.3 H
z), 3.45 (1H, d, J = 9.3 Hz), 4.20 (2H, q, J = 7.3 H
z), 7.30 (1H, s)) and ethyl 3-oxo-2-azaspiro [4.5] decane-4-carboxylate 78 ( ¹ H-NMR (CDCl ₃ ).
δppm: 1.29 (3H, t, J = 7.3 Hz), 1.3-1.7 (1H, br),
3.05 (1H, s), 3.17 (1H, dd, J = 9.9 & 1.4 Hz), 4.20 (2
H, q, J = 7.3 Hz), 7.30 (1H, br)) were obtained.

4) 7-oxo-6-azaspiro [3.4] octa
-8-Carboxylic acid 79 Compound 79, 1.97 g is dissolved in 20 ml of ethanol and water 2
0 ml was added, 0.8 g of sodium hydroxide was further added, and the mixture was heated under reflux for 2 hours. The organic solvent was evaporated under reduced pressure, the aqueous layer was washed with chloroform, and then the aqueous layer was neutralized with 1N hydrochloric acid under ice-cooling 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 was obtained as colorless crystals.

¹ H-NMR (CDCl ₃ ) δppm: 1.6-2.7 (6H,
m), 3.15 (1H, s), 3.40 (1H, d, J = 9.2 Hz), 3.6 (1H,
d, J = 9.2 Hz), 6.2 (1H, br)

By a method similar to the above, 3-oxo-2-azaspiro [4.4] nonane-4-carboxylate 80 ( ¹ H-NMR (CDC
l ₃ ) δppm: 1.5-2.3 (8H, m), 3.15 (1H, d, J = 9.5 H
z), 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 (10
H, m), 3.06 (1H, s), 3.11 (1H, d, J = 9.8 Hz), 3.48
(1H, d, J = 9.8 Hz), 6.47 (1H, br)) was obtained.

5) 8-Tertiary butoxycarbonylamino-7
-Oxo-6-azaspiro [3.4] octane 82 Compound 79, 1.57 g was suspended in 20 ml of benzene, 2.2 ml of diphenylphosphoryl azide and 1.55 ml of triethylamine were sequentially added with stirring, and the mixture was heated under reflux for 1.5 hours.
Here, 4.4 ml of tertiary butanol was added and the mixture was heated under reflux for 16 hours. The solvent was evaporated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution, saturated aqueous sodium chloride solution, 10% aqueous citric acid solution, and saturated aqueous sodium chloride solution. The aqueous layer was further extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was applied to a flash column of silica gel 50 g and eluted with chloroform containing 0 to 3% methanol to obtain 0.560 g of the title compound.

¹ H-NMR (CDCl ₃ ) δppm: 1.48 (9H, s), 1.5
-2.5 (6H, m), 3.27 (1H, d, J = 9.9 Hz), 3.44 (1H, d,
J = 9.9 Hz), 4.18 (1H, d, J = 7.7 Hz), 5.20 (1H, d, J
= 7.7 Hz), 7.13 (1H, brs)

In a manner similar to the above, 4-tertiary butoxycarbonylamino-3-oxo-2-azaspiro [4.4] nonane 83 ( ¹ H-NMR (CDCl ₃ ) δppm: 1.45 (9H, s), 1.2-1.8 (8
H, m), 3.13 (2H, s), 4.35 (1H, d, J = 7.9 Hz), 5.15
(1H, d, J = 7.9 Hz), 7.21 (1H, br s)) and 4-tertiary butoxycarbonylamino-3-oxo-2-azaspiro
[4.5] Decane 84 ( ¹ H-NMR (CDCl ₃ ) δppm: 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, br
s)) got.

6) 6-tertiary butoxycarbonyl-8-tertiary
Butoxycarbonylamino-6-azaspiro [3.4] octane
Tan Compound 87 Compound 82 (560 mg) was ice-cooled, 15 ml of trifluoroacetic acid was added with stirring, and the mixture was stirred at room temperature for 1.5 hr. 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 stirring, and the mixture was heated under reflux for 16 hours. Water was added to the reaction solution under ice-cooling stirring, and the insoluble material was filtered (Celite filtration). The insoluble matter was thoroughly washed with tetrahydrofuran, 1.02 g of ditertiary butyl dicarbonate was added, and the mixture was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure and the residue was applied to a flash column of silica gel 50 g, ethyl acetate: n-
Elute with a mixed solvent of hexane = 1: 10 to give the title compound 273
mg was obtained.

¹ H-NMR (CDCl ₃ ) δppm: 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)

By a method similar to the above, 2-tertiary butoxycarbonyl-4-tertiary butoxycarbonylamino-2-azaspiro [4.4] nonane 90 ( ¹ H-NMR (CDCl ₃ ) δppm: 1.45
(18H, 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
-Tertiary butoxycarbonyl-4-tertiary butoxycarbonylamino-2-azaspiro [4.5] decane 91 ( ¹ H-NMR (CDC
l ₃ ) δppm: 1.0-1.9 (28H, m), 2.9-4.1 (5H, m), 4.5
1 (1H, br d)) was obtained.

Reference Example 30.7- (8-Amino-6-azaspiro
[3.4] Octane-6-yl) -1-cyclopropyl-6,8-diff
Luoro-4-oxo-1,4-dihydroquinoline-3-carvone
Acid 94 Compound 87, 173 mg was ice-cooled, 2.7 ml of trifluoroacetic acid was added with stirring, and the mixture was stirred at room temperature for 1.5 hours.
Trifluoroacetic acid was distilled off under reduced pressure, 10 ml of acetonitrile was added to the residue, and then 1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 100 mg, Triethylamine (0.98 ml) was added and the mixture was heated under reflux for 16 hours. The reaction solution was concentrated, and diethyl ether was added to the residue. The formed crystals were collected by filtration and recrystallized from ethanol-ammonia water 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 (0.1N 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 = 15.0 Hz),
8.41 (1H, s)

By a similar method, 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 as C ₂₁ H ₂₃ F ₂ N ₃ O ₃ · 0.7H ₂ O: C 60.63 H 5.91 N 10.10 Found: 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 = 13.5 Hz), 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 Found: C 63.14 H 6.08 N 10.02 ¹ H-NMR (0.1 N 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 (1H, s)

Reference Example 31. 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]
Nzoxazine-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, a 1 ml of triethylamine was added. The mixture was heated to reflux overnight. After distilling off the solvent under reduced pressure, 95% methanol 20 ml and triethylamine were added to the residue.
1.2 ml was added and the mixture was heated to reflux for 5 hours. The solvent was distilled off under reduced pressure, and diethyl ether was added to the residue. The produced 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 as C ₂₀ H ₂₂ FN ₃ O ₃ 1 / 2H ₂ O: C 57.96 H 6.08 N 10.14 Found: 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
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 = 19.5 Hz),
8.13 (1H, s)

Reference Example 32.1 ) Tertiary butyl 7-oxo-6-azaspiro [3.4] octane
2 g of tan-8-carboxylate 99 compound 79, 2 g was dissolved in tertiary butanol with heating, 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 evaporated under reduced pressure, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution, saturated aqueous sodium chloride solution, 10% aqueous citric acid solution and saturated aqueous sodium chloride solution. Further extraction of the aqueous layer with ethyl acetate is repeated. After drying the organic layer with anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure. 75 g of the obtained oily substance on silica gel
And was eluted with chloroform containing 0 to 2% methanol to obtain 1.974 g of the title compound.

¹ H-NMR (CDCl ₃ ) δppm: 1.46 (9H, s), 1.7
-2.4 (6H, m), 3.09 (1H, s), 3.41 (1H, d, J = 10.0 H
z), 3.62 (1H, d, J = 10.0 Hz), 6.90 (1H, brs)

By a similar method, tert-butyl 3-oxo-2-azaspiro [4.4] nonane-4-carboxylate 1
00 ( ¹ H-NMR (CDCl ₃ ) δppm: 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 (19 H, br s), 2.93
(1H, s), 3.13 (1H, d, J = 11 Hz), 3.32 (1H, d, J = 11
Hz), 6.90 (1H, brs)) was obtained.

2) 6-tertiary butoxycarbonyl-8-hydride
Roxymethyl-6-azaspiro [3.4] octane 103 Compound 99, 1.94 g was ice-cooled, and ice-cooled trifluoroacetic acid 20 ml was added with stirring. Immediately after returning to room temperature and stirring for 1 hour, trifluoroacetic acid was distilled off under reduced pressure and the residue was dissolved under reduced pressure for 10 minutes and then dissolved in 100 ml of anhydrous tetrahydrofuran. Lithium aluminum hydride (3.11 g) was slowly added with stirring under ice cooling, and the mixture was heated under reflux for 18 hours. 10 ml of water was slowly added to the reaction solution while stirring with ice cooling, and the mixture was stirred at room temperature for 30 minutes. The insoluble matter is filtered off with Celite, and the insoluble matter is washed well with tetrahydrofuran. 5 of the filtrate
The mixture was concentrated to 0 ml, ditertiary butyl dicarbonate was added, and the mixture was stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure and the residue was applied to a silica gel 150 g column and eluted with a mixed solvent of n-hexane: ethyl acetate = 3: 2 to give 420 mg of the title compound.
I got

¹ H-NMR (CDCl ₃ ) δppm: 1.46 (9H,
s), 1.7-2.3 (8H, m), 3.
2-3.9 (5H, m)

By a method similar to the above, 2-tertiary 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-tertiary butoxycarbonyl-4-hydroxymethyl [4.5] decane 107 ( ¹ H-NM
R (CDCl ₃ ) δppm: 1.46 (9H, s), 1.1-1.7 (10H, m), 3.0-
3.8 (5H, m)) was obtained.

Reference Example 33.1-Cyclopropyl-6,8-diff
Luoro-7- (8-Hydroxymethyl-6-azaspiro [3.4] o
(Kutan-6-yl) -4-oxo-1,4-dihydroquinoline-3-
Carboxylic acid 108 compound 103, 120 mg was ice-cooled, and 2.7 ml of ice-cooled trifluoroacetic acid was added dropwise with stirring. 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, and 1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinolone-3-carboxylic acid 100 mg , Triethylamine 0.22
ml was added, and the mixture was heated under reflux for 18 hours. The solvent was evaporated 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. Combine the aqueous layers and add sodium hydroxide under ice-cooling to bring the pH to 13 or above. After washing the aqueous layer with chloroform, the pH was adjusted to about 7.4 with concentrated hydrochloric acid, 1N hydrochloric acid, and saturated aqueous sodium hydrogen carbonate solution.
Chloroform was added, the aqueous layer was extracted three times, the organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethanol-ammonia water, filtered while hot, and recrystallized twice to give the title compound as a yellow needle crystal.
to obtain mg.

Melting point: 273-274 ° C. Elemental analysis value: C ₂₁ H ₂₂ F ₂ N ₂ O ₄ Calculated value: C 62.37 H 5,48 N 6.93 Found value: C 63.31 H 5.39 N 6.96 ¹ H-NMR (CDCl ₃ ) δppm: 1.11-1.31 (4H, m), 1.89-
2.31 (7H, m), 3.63-3.99 (7H, m), 7.75 (1H, dd, J = 1
3.5 & 1.6 Hz), 8.62 (1H, s)

By a method similar to the 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 110 was obtained.

Compound 109: Melting point: 249-252 ° C. Elemental analysis value: Calculated as C ₂₂ H ₂₄ F ₂ N ₂ O ₄ : C 63.15 H 5.78 N 6.70 Found value: C 62.74 H 5.76 N 6.46 ¹ H-NMR ( CDCl ₃ ) δppm: 1.11-1.31 (4H, m), 1.50-
1.77 (8H, m), 2.18-2.22 (1H, m), 3.47-4.03 (7H,
m), 7.73 (1H, dd, J = 13.5 & 1.6 Hz), 8.60 (1H, s)

Compound 110: Melting point: 231-234 ° C. Elemental analysis value Calculated as C ₂₃ H ₂₆ F ₂ N ₂ O ₄ · 1 / 2H ₂ O: C 62.58 H 6.17 N 6.35 Found: C 62.92 H 6.17 N 6.25 ¹ H-NMR (CDCl ₃ ) δppm: 1.11-1.18 (2H, m), 1.24-
1.28 (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)

Example 6. 7-acetoxy-5-azaspiro
[2.4] Heptane 69 Compound 12, 1.5 g was suspended in 30 ml of tetrahydrofuran, and 500 mg of lithium aluminum hydride was added to obtain 16 parts.
Heated to reflux for hours. Under cooling, 0.5 ml of water, 0.5 ml of 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 filtered off and the filtrate was evaporated to dryness under reduced pressure to give 1.4 g of yellow oily 7-hydroxy-5- [1- (R) -phenylethyl] -5-azaspiro [2.4] heptane. This was ice-cooled 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, washed with saturated aqueous sodium hydrogen carbonate solution and water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1.6 g of yellow oily 7-acetoxy-5- [1- (R) -phenylethyl] -5-azaspiro [2.4] heptane. Dissolve this product in 20 ml of ethanol, add 1.2 g of palladium-carbon (containing 50% water), and heat with a tungsten lamp.
The catalytic reduction was carried out for 5 hours under a hydrogen atmosphere of 3.8 atm. The catalyst was filtered off and the solvent in the filtrate was evaporated under reduced pressure to give the title compound as an oil.
80 mg was obtained.

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 3
3b, melting point: 259-261 ° C

2) (-)-7- [7- (S) -amino-5-azaspiro
[2.3] Heptan-5-yl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 111b, melting point: 232 -235 ℃, [α] _D-
20.54 ° (c = 0.73, CHCl ₃ )

[0327]

[Table 1]

[0328]

[Table 2]

[0329]

[Table 3]

[0330]

[Table 4]

[0331]

[Chemical 7]

[0332]

Embedded image

[0333]

[Chemical 9]

[0334]

[Chemical 10]

[0335]

[Chemical 11]

[0336]

[Chemical 12]

[0337]

[Chemical 13]

[0338]

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─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location // A61K 31/47 A61K 31/47 31/535 31/535 31/55 ADZ 31/55 ADZ ( 31) Priority claim number Japanese Patent Application No. 1-156316 (32) Priority Day 1 (1989) June 19 (33) Priority claim country Japan (JP)

Claims (9)

[Claims] 1. The general formula I: (In the formula, a means 0 or 1, b means an integer from 2 to 5, c means 0 or 1, and d means an integer from 0 to 2. Z is Here, R ¹ is a hydrogen atom, an amino group, a monoalkylamino group having 1 to 6 carbon atoms, a dialkylamino group each having 1 to 6 carbon atoms independently, a hydroxyl group, an alkoxyl group having 1 to 6 carbon atoms, or a carbon atom. It represents a hydroxyalkyl group of the formulas 1 to 6, and the above amino group, monoalkylamino group and hydroxyl group may have a protecting group. R ² represents a hydrogen atom, 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 or an alkylcarbonyl group having 2 to 7 carbon atoms,
R ³ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. ) Spiro compounds represented by 2. In the general formula, a is 1, b is 2, c is 0, d
Is 1 and 3. In the general formula, a is 1, b is 3, c is 0, d
Is 1 and 4. In the general formula, a is 1, b is 2, c is 0, d
Is 2, 5. 7-Amino-5-azaspiro [2.4] heptane, 4,7-diazaspiro [2.5] octane, 7-hydroxy-
5-azaspiro [2.4] heptane, 7-hydroxyimino-5
-Azaspiro [2.4] heptane, 8-hydroxymethyl-6-
Azaspiro [3.4] octane, 4-hydroxymethyl-2-azaspiro [4.4] nonane, 4-hydroxymethyl-2-azaspiro [4.5] decane, 8-amino-6-azaspiro [3.4] octane, 4-amino-2- Azaspiro [4.4] Nonane or 7
-Tertiary butoxycarbonylamino-5-azaspiro [2.
4] The spiro compound and salt thereof according to claim 1, which is heptane. 6. The protecting group is an alkoxycarbonyl group, an aralkyloxycarbonyl group, an acyl group, an alkyl group, an aralkyl group, ethers or a silyl group.
Described spiro compounds and salts thereof 7. The spiro compound and the salt thereof according to claim 1, wherein the protecting group is an alkoxycarbonyl group, an aralkyloxycarbonyl group or an acyl group. 8. A protecting group is a tertiary butoxycarbonyl group,
The spiro compound and a salt thereof according to claim 1, which is a 2,2,2-trichloroethoxycarbonyl group, a benzyloxycarbonyl group, a paramethoxybenzyloxycarbonyl group, a paranitrobenzyloxycarbonyl group or an acetyl group. 9. The spiro compound and a salt thereof according to claim 1, wherein the compound represented by the general formula is a compound consisting of a pure optically active substance.