SI8911674A - Spiro compounds - Google Patents

Abstract

A compound of formula I having antibacterial activity, and a pharmaceutical composition containing the compound of formula (I) wherein a represents an integer 0 or 1; b represents an integer from 2 to 5 inclusive; c represents an integer 0 or 1; and d represents even a number from 0 to 2 inclusive; Z represents -CHR1-, -NR2-, -C = NOR3-, an oxygen atom or a sulfur atom where R1 represents a hydrogen atom, an amino group, a monoalkylamino a group of 1 to 6 carbon atoms, dialkylamino a group containing 1 to 6 carbon atoms in each an alkyl, hydroxyl group, an alkoxy group of 1 to 6 carbon atoms or a hydroxyalkyl group of 1 to 6 atoms carbon; R2 represents a hydrogen atom, an alkyl group of 1 up to 6 carbon atoms, hydroxyalkyl group of 1 to 6 carbon atoms, a haloalkyl group of 1 to 6 atoms carbon, formyl group or alkylcarbonyl group z 2 to 7 carbon atoms; and R3 represents a hydrogen atom or an alkyl group of 1 to 6 carbon atoms; Q represents a partial structure of formula (II) wherein R4 represents an alkyl group of 1 to 6 carbon atoms, alkenyl a group of 2 to 6 carbon atoms, a haloalkyl group of 1 up to 6 carbon atoms, substituted or unsubstituted a 3 to 6 carbon cycloalkyl group substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, alkoxy group having 1 up to 6 carbon atoms or an alkylamino group of 1 to 6 atoms carbon; R 5 represents a hydrogen atom or an alkyl group with 1 to 6 carbon atoms; R6 represents a hydrogen atom, substituted or unsubstituted amino group, hydroxyl a group, an alkoxy group of 1 to 6 atoms carbon or halogen atom; A represents the nitrogen atom or = C-R7-, wherein R7 represents a hydrogen atom, alkyl a group of 1 to 6 carbon atoms, a halogen atom, alkoxy a group of 1 to 6 carbon atoms, a haloalkyl group of 1 up to 6 carbon atoms or a cyano group; R4 may form together with R 5 and / or R 7 substituted or unsubstituted a ring which may include an oxygen, nitrogen or sulfur atom, in which the substituent is an alkyl group of 1 to 6 atoms a carbon or haloalkyl group having 1 to 6 carbon atoms; X represents a halogen atom; Y represents a hydrogen atom, an alkyl group of 1 to 6 carbon atoms, alkoxyalkyl a group of 1 to 6 carbon atoms, a phenylalkyl group which contains from 1 to 6 carbon atoms in its alkyl moiety, respiratory group, phenyl group, acetoxymethyl group, pivaloyloxymethyl group, ethoxycarbonyloxy group, choline group, dimethylaminoethyl group, 5-indanyl group, phthalidinyl group, 5-substituted-2-oxo-1,3-dioxazol-4-ylmethyl a group or a 3-acetoxy-2-oxobutyl group, or a group thereof sol.

Description

DAIICHI PHARMACEUTICAL CO., LTD

SPIRO COMPOUND

FIELD OF THE INVENTION

The present invention relates to antibacterial spiro compounds that are important as human, veterinary and aquaculture or preservative medicines, and to antibacterial preparations containing one or more of these compounds as active ingredients.

BACKGROUND OF THE INVENTION

Various derivatives of synthetic antibacterial compounds are known. However, many of the very active derivatives are not well absorbed by oral administration.

The inventor of the present invention has worked hard to develop quinolone derivatives that have strong antibacterial activity and exhibit an effective level of oral absorption.

Summary of the Invention

The present invention relates to spiro compounds of general formula I ( ^CH o)

O>

C ~ (CH) / ^{* (2 3} \ (CH ₂ ) nq \ / Z- (CH ₂ ) _d ^Z in which a represents an integer 0 or 1, b an integer from 2 to 5 inclusive, c an integer 0 or 1 and d are an integer from 0 _in i 2 3 up to and including 2; Z represents>CHR,> NR. »NOR, oxygen atom or in 1 sulfur atom, where R is a hydrogen atom, amino group, monoalkyl amino group of 1 to 6 carbon atoms, dialkylamino group containing from 1 to 6 carbon atoms in each alkyl, hydroxyl group, alkoxy group from 1 to 6 carbon atoms or hydroxyalkyl group from 1 to 6 carbon atoms; R is a hydrogen atom, alkyl group from 1 to 6 atoms carbon, hydroxyalkyl group of 1 to 6 carbon atoms, haloalkyl group of 1 to 6 carbon atoms, formyl group or alkylcarbonyl group of 2 to 7 carbon atoms and R is a hydrogen atom or alkyl group of 1 to 6 carbon atoms; Q represents a partial structure with the formula II

wherein R represents an alkyl group of 1 to 6 carbon atoms, an alkenyl group of 2 to 6 carbon atoms, a haloalkyl group of 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl group of 3 to 6 carbon atoms, a substituted or unsubstituted aryl group, substituted or an unsubstituted heteroaryl group, an alkoxy group of 1 to 6 carbon atoms, or an alkylamino group of 1 to 6 carbon atoms; R represents a hydrogen atom or an alkyl group of 1 to 6 carbon atoms; R 4 represents a hydrogen atom, a substituted or unsubstituted amino group, a hydroxyl group, an alkoxy group of 1 to 6 carbon atoms or a halogen atom; A represents a nitrogen atom or C ^ R-R, where R is a hydrogen atom, an alkyl group of 1 to 6 carbon atoms, a halogen atom, an alkoxy group of 1 to 6 carbon atoms, a haloalkyl group of 1 to 6 carbon atoms or cyano

5 7 group; R may form together with R and / or R a substituted or unsubstituted ring which may include an oxygen, nitrogen or sulfur atom, wherein the substituent is an alkyl group of 1 to 6 carbon atoms or a haloalkyl group of 1 to 6 carbon atoms; X represents a halogen atom, preferably a fluorine atom; Y represents a hydrogen atom, an alkyl group of 1 to 6 carbon atoms, an alkoxy-4 alkyl group of 1 to 6 carbon atoms, a phenylalkyl group containing from 1 to 6 carbon atoms in its alkyl moiety, a respiratory group, a phenyl group, an acetoxymethyl group, pivaloyloxymethyl group, ethoxycarbonyloxy group, choline group, dimethylaminoethyl group, 5-indanyl group, thalidinyl group, 5-substituted-2-oxo-1,3-dioxazol-4-ylmethyl group or 3-acetoxy-2-oxobutyl group and to their salts. More specifically, the invention relates to spiro compounds of general formula I, in which a is 1, b 2, c 0 and d 1 and Z is CH (NH ₂ ), and salts thereof. The invention also relates to spiro compounds of general formula I in which a is 1, b 3, c 0 and d 1 and Z is CH (NH ₂ ), and salts thereof. The invention further relates to spiro compounds of general formula I in which a is 1, b 2, c 0 and d 2 and Z is NH, and salts thereof. More specifically, the invention relates to spiro compounds of general formula I, wherein these spiro compounds are optically pure. More specifically, the invention relates to 7- (7-amino5-azaspiro / 2,4 / heptan-5-yl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 7 - (7-amino-5-azaspiro / 2,4 / heptan-5-yl) -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 7- (7-Amino-5-azaspiro / 2,4 / heptan-5-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 7- (7-amino-5- azaspiro / 2,4 / heptan-5-yl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 7- (7-amino-5 -azaspiro / 2,4 / heptan-5-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 10- (7-amino-5- azaspiro / 2,4 / heptan-5-yl) -9-fluoro-2,3-dihydro-3- (S) -methyl-7oxo-7H-pyrido / 1,2,3-de // 1,4 / benzoxazine-6-carboxylic acid, 1-cyclopropyl-7- (4,7-diazaspiro / 2,5 / octan-7-yl) -6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 7- (7-Amino-5 azaspiro / 2,4 / heptan-5-yl) -1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7- (7-hydroxy) -aspasiro / 2 , 4 / heptan-5-yl) -8-chloro-1-cyclopropyl-6-fluoro, 4-dihydro-4-oxoquinoline-3-carboxylic acid, 7- (7-amino5-azaspiro / 2,4 / heptane- 5-yl) -1- (2-methyl-2-propyl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 7 (7-hydroxyimino-5-azaspiro) 2,4 / Heptan-5-yl) -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1-cyclopropyl-6,8-difluoro-7- (8-hydroxymethyl-6-azaspiro / 3,4 / octan-6-yl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 1-cyclopropyl-6,8-difluoro-7- (4- hydroxymethyl-2azaspiro / 4,4 / nonan-2-yl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 1-cyclopropyl-6,8-difluoro-7- (4-hydroxymethyl-2-azaspiro (4,5) decan-2-yl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 7- (8-amino-6-azaspiro / 3,4 / octan-6-yl) 1-cyclopropyl- 6,8-Difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 10- (8-amino-6-azaspiro / 3,4 / octan-6-yl) -9-fluoro-2,3 -Dihydro-3- (S) -methyl-7-oxo-7H-pyrido / 1,2,3-de [1,4] -benzoxazine-6-carboxylic acid or 7- (4-amino-2-azaspiro / 4.4 / nonan-2- yl) -1-cyclopropyl6,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid. In a further aspect, the present invention relates to an antibacterial composition comprising a compound of general formula I as the active ingredient.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention are characterized by each being a cyclic amine compound with a spiro ring and also having a quinolone derivative attached to it in a position equivalent to position 7. The term position equivalent to position 7 of the quinolone derivative means e.g. position of 7 compounds optionally substituted 4-oxyquinoline-3-carboxylic acid and compounds

4-oxo-1,8-naphthyridine-3-carboxylic acid, lego 10 7-oxopyrido / 1,2,3-de // 1,4 / benzoxazine-6-carboxylic acid or lego 8 benzo / quinolizin-2 -carboxylic acids.

The spiro ring should be in the range of 3-membered to 6-membered rings, of which 3-membered and 4-membered rings are preferred.

The ring size of the cyclic amine without the spiro ring should be in the range of 4- to 8-membered rings, of which the 5-membered and 6-membered rings are preferred. This cyclic amine is attached to a position equivalent to the position 7 of the quinolone derivative via its nitrogen atom.

This cyclic amine may further comprise one or more hetero atoms, such as oxygen, sulfur and nitrogen, of which nitrogen is preferred. This nitrogen atom may be substituted, e.g. with an alkyl group of 1 to 6 carbon atoms, a hydroxyalkyl group of 1 to 6 carbon atoms, a haloalkyl group of 1 to 6 carbon atoms, a formyl group and an alkylcarbonyl group of 2 to 7 carbon atoms.

Here are some examples for structures of a cyclic amine bearing a spirocyclic ring: 5-azaspiro / 2.4 / heptane structure, 6-azaspiro / 3.4 / octane structure, 2-azaspiro / 4.4 / nonana structure, 2-azaspiro structure / 4,5 / decane, structure 5-azaspiro / 2,5 / octane, structure 6-azaspiro / 2,5 / octane, structure 6azaspiro / 3,5 / nonana, structure 7-azaspiro / 3,5 / nonana, structure ra 7-azaspiro / 4,5 / decane, structure 8-azaspiro / 4,5 / decane, structure 2-azaspiro / 5,5 / undecane, structure 3-azaspiro / 5,5 / undecane, structure 4,7-diazaspiro / 2,5 / octane, structure 5,8-diazaspiro / 3,5 / nonane, structure 6,9-diazaspiro / 4,5 / decane, structure 7,10-diazaspiro / 5.5 / undecane, structure 7-aza-4oxaspiro / 2,5-octane, structure of 8-aza-5-oxaspiro / 3,5 / nonane, structure of 9-aza-6-oxaspiro / 4,5 / decane, structure of 7-aza-4-thiaspiro / 2,5 / octane, 8-aza-5-thiaspiro / 3,5 / nonane structure, 9-aza-6-thiaspiro / 4,5 / decane structure, 7-aza-4thiaspiro / 2,5 / octane-4-oxide structure, 8- aza-5-thiaspiro / 3,5 / nonane-5-oxide and the structure of 9-aza-6-thiaspiro / 4,5 / decane -6oxides.

If additional heteroatoms such as oxygen, sulfur or nitrogen exist in the ring of this cyclic amine, or in particular if such heteroatoms do not exist, polar substituent groups such as e.g. amino, monoalkylamino groups of 1 to 6 carbon atoms, dialkylamino groups containing 1 to 6 carbon atoms in each alkyl, aminoalkyl groups of 1 to 6 carbon atoms whose amino moiety is or is not substituted by alkyl of 1 to 6 carbon atoms or hydroxyalkyl of 1 to 6 carbon atoms, hydroxy, hydroxyalkyl groups of 1 to 6 carbon atoms, hydroxyimino and alkoxy groups of 1 to 6 carbon atoms. Amino groups are preferred.

These substituents on the cyclic amine, substituted anem. spiro, whether or not protected by suitable protecting groups. Such protecting groups can be selected from those commonly used. For example, suitable protecting groups include alkoxycarbonyl groups such as tert.-butoxycarbonyl and 2,2,2-trichloroethoxycarbonyl, aralkyloxycarbonyl groups such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl and p-nitrobenzyloxycarbonyl, acyl groups, such as acetyl, methoxyacetylacetate, acetyl, methoxyacetoacetyl formyl and benzoyl, alkyl or aralkyl groups such as tert-butyl, benzyl, p-nitrobenzyl, p-methoxybenzyl and triphenylmethyl, ether groups such as methoxymethyl, tert-butoxymethyl, tetrahydropyranyl and 2,2,2-trichloroethioxymethyl and silyl groups, such as trimethylsilyl, isopropyldimethylsilyl, tert, butyldimethylsilyl, tribenzylsilyl and tert-butyldiphenylsilyl.

If it exists on a cyclic amine substituted by a spiro ring other than a spiro ring a substituent and if the carbon atom to which the substituent is attached is an asymmetric carbon atom there is a stereoisomerism of the cyclic amine. If such a cyclic amine is used as a mixture of stereoisomers as a substituent for the position equivalent to position 7, spiro compound I may be formed as a mixture of diastereomers if there is a second asymmetric carbon atom in the spiro compound. A mixture of diastereomers is a mixture of compounds that differ in physical constants and cannot be used as a drug. In such cases, the cyclic amine must be separated into isomers before metabolism.

If spiro compound I is a racemic compound, a racemate per se can be used. However, there are cases where the optically active form is more bioavailable than the racemate. In such cases, the racemate should be optically disassembled.

For example, as regards the antimicrobial activity of both enantiomers having the structure 7-amino-5-azaspiro / 2,4 / heptane, one of them has more effective antimicrobial activity than the other. The more efficient enantiomer was found to be the 7- (S) -amino-5-azaspiro / 2,4 / heptane derivative. This fact was confirmed by X-ray crystallographic analysis of one of the isomers of 7- (7-tert-butoxycarbonylamino-5-azaspiro / 2,4 / heptan-5-yl) -8chloro-1-cyclopropyl-6-fluoro-1,4-dihydro- 4-Oxoquinoline-3-carboxylic acid to give 7- (7-amino5-azaspiro / 2,4 / heptan-5-yl) -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline isomer -3-carboxylic acids.

The cyclic amine which is substituted by a spiro ring can be synthesized as follows.

Taking 7-amino-5-azaspiro / 2,4 / heptane as an example, it is first reacted with ethyl acetoacetate with 1,2-dibromoethane in the presence of a base to form ethyl 1-acetyl-1-cyclopropanecarboxylate. Then, using bromine, the acetyl group of this compound is brominated to give ethyl 1-bromoacetyl-1-cyclopropanecarboxylate. This bromoacetyl compound was then cyclized with benzylamine to give 5-benzyl-4,7-dioxo-5-azaspiro / 2,4 / heptane. If this compound is reacted with hydroxylamine hydrochloride, the ketone in position 7 is converted to oxime to give 5-benzyl-7- (hydroxyimino) -4-oxo-5-azaspiro / 2,4 / heptane. This oxime is reduced with lithium aluminum hydride to form an aminopyrrolidine compound containing a spiro ring, i.e. 7-amino-5-benzyl5-azaspiro / 2,4 / heptane. If removed by conventional mode, such as by catalytic hydrogenolysis, the benzyl group of this compound, 7-amino-5-azaspiro / 2,4 / heptane is obtained, which is a racemic compound. Performed before this cleavage of the benzyl group after protecting the amino group, the metabolism of 2 (tert-butoxy-carbonylamino) -2-phenylacetonitrile (hereinafter referred to briefly as BOC-ON) gives 7-tert-butoxycarbonylamino-5 -azaspiro / 2,4 / heptane.

The optical isomers of 7-amino-5-azaspiro / 2,4 / heptane can be obtained as follows.

First, 7-amino-5-benzyl-5-azaspiro / 2,4 / heptane is reacted with (R) -Np-toluenesulfonylpropyl chloride to form 7 - [(R) -Np-toluenesulfonylpropyl] amino-5-benzyl-5- azaspiro / 2,4 / heptane. This compound is then reacted with benzyl chlorocarbonate to form 7 - [(R) -N-p-toluenesulfonylpropyl / amino-5-benzyloxycarbonyl-5-azaspiro / 2,4 / heptane. This product can be separated into optically active compounds by high performance liquid chromatography (hereinafter referred to briefly as HPLC). After separation, each compound is treated with 2N sodium hydroxide and the proline moiety and the benzyloxycarbonyl group are cleaved to give the corresponding optically active 7-amino-5-azaspiro / 2,4 / heptane.

It has also been found that if cyclization of ethyl 1-bromoacetyl-1-cyclopropanecarbosylate is carried out using optically active 1-phenethylamine instead of benzylamine, the following optical separation of the racemic compound is facilitated.

Another method of operation is an alternative synthesis derived from 1-acetyl-1-cyclopropanecarboxylic acid ester.

First, the 1-acetyl-1-cyclopropanecarboxylic acid ester is cleaved by acidic or basic hydrolysis or by catalytic hydrogenation. This free acid is reacted with R - (+) 1-phenylethylamine to form N- / 1- (R) -phenylethyl / -1-ethyl-1-cyclopropylcarboxamide, an amide derivative. The carbonyl portion of its acetyl group is then converted to the ketal group to give N- [1- (R) -phenylethyl] -1- (1,1-ethylenedioxyethyl) 1-cyclopropanecarboxamide. The halogenated methyl group adjacent to its ketal group is then halogenated, e.g. N- / 1- (R) -phenylethyl / 1- (1,1-ethylenedioxyethyl) -1-cyclopropanecarboxamide was converted to N- / 1- (R) -phenylethyl / -1- (2-broro-1,1-ethylenedioxyethyl) ) -1-cyclopropanecarboxamide. This halomethyl compound is cyclized in the presence of a base into 4,7-dioxo-5- / 1- (R) -phenylethyl / -5-azaspiro / 2,4 / heptane-7-ethylenacetal, which is a pyrrolidone derivative bearing a spiro cyclic ring and ketal function. Its ketal function can be cleaved by a known hydrolysis process to give 4,7-dioxo-5- / 1- (R) -phenylethyl / -5-azaspiro / 2,4 / heptane. This compound can lead to the spirocyclic amine in the above-mentioned mode of operation.

The synthesis of 4 _T 7-diazaspiro / 2.5 / octane is explained below. Cyclopropane-1,1-diamide is first reacted with bromine and base to form cyclopropane-1,1-dibromoamide and treated with alkoxide to form spiro hydantoin, namely 4,6-diazaspiro / 2,4 / heptane-5, 7-Dion. This compound is then treated with alkali to form 1-aminocyclopropanecarboxylic acid. The amino group of this compound is protected by a tert-butoxycarbonyl group to form 1- (tert-butoxycarbonylamino) -1-cyclopropanecarboxylic acid, which is then condensed with glycine ethyl ester in the presence of dicyclohexylcarbodiimide to form ethyl (1-tert-butoxycarbonyl). -1-Cyclopropylcarbonylamino) acetate. After removal of the amino protecting group, the above compound is cyclized upon heating to form a diketopiperazine compound containing a spiro ring, namely 4,7-diazaspiro / 2,5 / octane-5,8-dione. This compound is reduced with lithium aluminum hydride to form a piperazine compound containing a spiro ring, namely 4,7-diazaspiro / 2.5 / octane.

The synthesis of a cyclic amine derivative bearing a spirocyclic ring can be carried out by the method shown below. The condensation of cyclic alkyl ketone and malonic acid diester in the presence of titanium tetrachloride gives the cycloalkylidenemalonic acid diester. The metabolism of this diester of cycloalkyl of denmalonic acid and nitromethane in the presence of a base yields a Michael adduct, e.g. (1-Nitromethyl-1-cycloalkyl) malonic acid diester. Reductive cyclization of the diester (1-nitromethyl-1-cycloalkyl) malonic acid gives the pyrrolidone carboxylic acid ester bearing a spirocyclic ring, e.g. if the spirocyclic ring is a 4-membered ring, the 7-oxo-6azaspiro / 3,4 / octane-8-carboxylic acid ester is obtained. Catalytic reduction is more appropriate for this reductive cyclization. However, other chemical reduction methods are also useful. This pyrrolidone carboxylic acid ester can be converted to a cis-ring amine derivative bearing a spirocyclic ring and a tert-butoxycarbonylamino substituent by the Crutius reaction in the tert.butanol free carboxylic acid, obtained by cleavage of the ester by a known method, such as hydrolysis.

Reduction of the pyrrolidone bearing the 'spirocyclic ring and amino substituent to remove the pyrrolidine derivative with the spirocyclic ring and amino substituent after removal of the tert-butoxycarbonyl group. Reduction of a pyrrolidone carboxylic acid ester with metal hydrides such as lithium aluminum hydride to give a pyrrolidine derivative bearing a spirocyclic ring and a hydroxymethyl substituent.

Quinolone derivatives to be attached to such a cyclic amine containing a spiro ring include bi-cyclic compounds such as 1,4-dihydro-4-oxoquinoline-3-carboxylic acid, and 1,4-dihydro-4-oxo-1,8-naphthyridine -3-carboxylic acid, tricyclic compounds such as 2,3-dihydro-7-oxo-7H-pyrido / 1,2,3-de // 1,4 / benzooxazine-6-carboxylic acid, 2,3-dihydro-7 -oxo7H-pyrido / 1,2,3-de // 1,4 / benzothiazine-6-carboxylic acid, 6,7-dihydro-1,7-dioxo-1H, 5H-benzo / quinolizine-2-carboxylic acid acid and 6,7-dihydrobenzoyl-quinolysine-2-carboxylic acid, a tetracyclic compound such as 9,1-epoxymethano-5-oxo-5H-thiazolo / 3,2-a / quinoline-4-carboxylic acid. Partial structures are shown below.

etc.

COOY

R ⁵

(H)

In the case of 1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid compounds, the substituent in position 1 e.g. lower alkyl group of 1 to 6 carbon atoms such as ethyl, isopropyl and tert.-butyl, haloalkyl group of 1 to 6 carbon atoms such as 2-fluoroethyl, lower alkenyl group of 2 to 6 carbon atoms such as vinyl and isopropenyl, cycloalkyl a group of 3 to 6 carbon atoms, whether or not substituted, such as cyclopropyl, cis-2-methylcyclopropyl and 2-gem-dihalocyclopropyl, aryl or heteroaryl group, whether or not substituted, such as 4-fluorophenyl, 2,4-difluorophenyl and 2-fluoro-4-pyridyl, an alkoxy group of 1 to 6 carbon atoms such as methoxy and ethoxy, or an alkylamino group of 1 to 6 carbon atoms such as methylamino and ethylamino. Among these substituent groups are preferred ethyl, 2-fluoroethyl, vinyl, cyclopropyl, eis-2methyloylpropyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-fluoro4-pyridyl, methoxy and methylamino.

The substituent in position 2 is preferably a hydrogen atom or an alkyl group of 1 to 6 carbon atoms such as methyl, ethyl and propyl.

The preferred substituent group in position 5 is a hydrogen atom, an amino group, an unsubstituted mono-C 1-6 alkylamino or di-C 1-6 alkylamino group such as methylamino, ethylamino, isopropylamino, dimethylamino and diethylamino, hydroxyl group, halo-C_ an alkyl group, an alkoxy group such as methoxy and ethoxy or a halogen atom.

Position 6 is preferably substituted by a halogen atom, in particular fluorine or chlorine.

The position of the 8 quinoline derivatives is or is not substituted. Suitable substituents include a halogen atom, an alkyl group, an alkoxy group, a halo-C1-4 alkyl group and a cyano group. Chlorine, fluorine, methyl and methoxy are preferred.

In terms of quinolone structure, not only may be a bicyclic structure but may be a tricyclic or tetraecyclic structure, formed between position 1 and either position 8 or position 2 or between position 1 and each of positions 8 and 2 of the quinolone ring. The ring formed in such cases is preferably in the range of 4-membered to 7-membered rings and more preferably a 5 or 6-membered ring.

The ring thus formed may include nitrogen, oxygen and sulfur atoms. In addition, it can contain not only single bonds but also double bonds, and the ring can be aromatic. Further, such rings are or are not substituted by C1-6alkyl or halo-C1-6alkyl groups.

With regard to tricyclic quinolone derivatives, taking 2,3-dihydro-7-oxo-7H-pyrido / 1,2,3-de // 1,4 / benzoxazine-6-carboxylic acid as an example, position 3 may be substituted with an alkyl group of 1 to 6 carbon atoms, preferably in the S-configuration. Position 9 is preferably substituted by a halogen atom, which is preferably fluorine or chlorine. The above substitution state may also apply to other tricyclic quinolone derivatives, such as 2,3-dihydro-7-oxo-7Hpyrido / 1,2,3-de // 1,4 / benzothiazine-6-carboxylic acid, and here 6 , 7-Dihydro-1H, 5H-benzo (1 H) quinolizine-2-carboxylic acid. In the case of 3-alkyl-7-oxo-2,3-dihydro-7H-pyrido (3,2,1-yl) -1,3,4-benzoxadiazine-6-carboxylic acid, position 9 is preferably substituted by a halogen atom, which is preferably fluorine or chlorine.

Preferred quinolone derivatives to be attached to said cyclic amine containing a spiro ring are 1,4-dihydro-4-oxyquinoline-3-carboxylic acid compounds.

A cyclic amine containing a spiro ring can be introduced into such a quinolone derivative according to the procedures described in European Patents (EP) -A-167,763, EP-A-195,841, EP-A-160,578 and EP-A-2O6,283.

The procedures for the preparation of the present compounds are described below by reaction schemes.

-> compound 'I

5 6 wherein a, b, c, d, Z, A, R, R, R, Y and X are defined as a front; X 'means a halogen atom, preferably a fluorine atom.

Therefore, if a cyclic amine containing a spiro ring is reacted with a 7-haloquinolone derivative, the nitrogen atom of the pyrrolidine ring binds to the position of the 7 quinolone ring to form the desired quinolone derivative.

In the starting material of the quinolone derivative, e.g. 1-Cyclopropyl-6-fluoro-7-halo-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, the halogen atom in position 7 may be chlorine or fluorine. These starting compounds can be synthesized according to the methods described in EP-A-167,763 and EP-A-195,841. Other quinolone materials can also be synthesized by known methods.

(For example, 7-chloro-6-fluoro-1-ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, EP-A-27,752;

9,10-Difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido / 3,2,1ij / -1,4,4-benzoxadiazine-6-carboxylic acid, Japan Kokai 88-132891; 9,1-epoxymethano-7,8-difluoro-5-oxo-5H-thiazolo / 3,2-a / quinoline-4-carboxylic acid, Japan Kokai 89-117888;

7,8-Difluoro-5-oxo-5H-thiazolo / 3,2-a / quinoline-3-carboxylic acid, U.S. Pat. patent 4,550,104; 7-Halogeno-6-fluoro-1-methyl4-oxo-4H- (1,3) thiazeto / 3,2-a) quinoline-3-carboxylic acid, Japan Kokai 88-107990; 9,10-difluoro-3-methyl-2,3-dihydro-7-oxo-7H-pyrido / 1,2,3-de [1,4] benzoxazine-6-carboxylic acid, EP-A-47,005).

In the method described in EP-A-195,841, they synthesize the intermediate compound 3-chloro-2,4,5-trifluorobenzoic acid in 10 reaction steps. In contrast, the inventor of the present invention developed a process for the synthesis of the above compound in one step, based on 3-amino-2,4,5-trifluorobenzoic acid, and found that this process is also applicable to other benzoic acid derivatives.

It can further be used as starting material to be reacted with an amine containing a spiro ring, a quinolone derivative whose carboxyl group in position 3 (or position equivalent to position 3) has been esterified with a substituted boron compound. This ester may be e.g. a compound having at position 3 (or position equivalent to position 3) of the quinolone nucleus the following substituent group to form a chelate with a carbonyl group in position 4 (or position equivalent to position 4) of the quinolone ring.

Oh

II

-g-obf ₂

The upper fluorine atom may be a different halogen atom or an acetoxy group.

This dihalogenated boron compound can be readily prepared from a free carboxylic acid derivative and a suitable trihalogenated boron compound, such as the boron trifluoride-ether complex.

Thus, the carboxylic acid derivative in ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane, is suspended or dissolved, and an excess of the boron trifluoride-diethyl ether complex is added. The mixture was stirred at room temperature. The reaction can be carried out at room temperature or, if necessary, even at 100 ° C. The reaction is complete in minutes to 24 hours. As the reaction product is generally precipitated, the precipitate is collected, washed with an inert solvent such as ether and dried under reduced pressure (EP-A-206,283) ·

Derivatives in which the carboxyl moiety in position 3 (or position equivalent to position 3) is esterified are useful as synthetic intermediates or prodrugs. For example, esters. such as alkyl ester, benzyl ester, alkoxyalkyl ester, phenylalkyl ester or phenyl ester, are useful as synthetic intermediates.

The reaction for introducing a cyclic amine containing a spiro ring is generally carried out in the presence of an acid acceptor. Although the acid acceptor may be an organic base or an inorganic base, it is generally preferred to use an organic base.

Preferred organic bases include tertiary amines, including trialkylamines, such as triethylamine, tripropylamine,

N, N-diisopropylethylamine and tributylamine, aniline compounds such as N, N-dimethylaniline and N, N-diethylaniline, and heterocyclic compounds such as N-methylmorpholine, pyridine and N, N-dimethylaminopyridine.

Examples of inorganic bases include alkali metal hydroxides, carbonates, and hydrogen carbonates such as lithium, sodium, and potassium. To be precise, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate may be mentioned.

It is also possible to use a stoichiometric excess of starting material, a cyclic amine containing a spiro ring, so that it can be used both as a reactant and as an acid acceptor.

The reaction solvent can be any solvent that is inert to the reaction. Suitable solvents include acetonitrile, amides such as N, N-dimethylformamide, N-methyl-2-pyrrolidone and N, N-dimethylacetamide, aromatic hydrocarbons such as benzene, toluene and xylene, aprotic polar solvents such as dimethyl sulfoxide and sulfolane, lower alcohols , such as methanol, ethanol, propanol, butanol, amyl alcohol, isoamyl alcohol, cyclohexyl alcohol and 3-methoxybutanol, and ethers such as dioxane, dimethyl cellosolve, diethyl cellosolve and diglyme. If the solvent is soluble in water, it can be used in admixture with water. In this case, said acid acceptor is preferably an organic base.

The reaction may be carried out in a temperature range of from about 50 to about 18 ° C, preferably from about 80 to about 130 ° C.

The reaction time is 10 minutes to 48 hours and it is generally sufficient to carry out the reaction for 30 minutes to 30 hours.

If a cyclic amine containing a spiro ring is used in the metabolism after protecting its substituent group in the nucleus, subsequent removal of the protecting group from the reaction product can be carried out by a known method adapted to the particular protecting group, e.g. hydrolysis or hydrogenolysis.

If the carboxylic moiety in position 3 (or position equivalent to position 3) is not a free carboxylic group, the derivative can be converted to the free carboxylic acid according to the known technique adapted to each case. For example, If it is an ester, a conventional hydrolysis reaction may be used using alkali hydroxide in an aqueous medium. In the case of a boron compound, a method using a proton substance such as alcohol may be used.

In this case, an acid acceptor may be present in the reaction system. For example, treatment with ethanol in the presence of triethylamine may be mentioned.

The resulting spiro compound I can be purified by any or a suitable combination of recrystallization, re-precipitation, charcoal treatment, chromatography and other known methods of operation.

The following compounds are some examples of novel compounds of the present invention:

7- (7-Amino-5-azaspiro / 2,4 / heptane-5-11) -1-cyclopropyl6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

7- (7-amino-5-azaspiro / 2,4 / heptan-5-yl) -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

7- (7-amino-5-azaspiro / 2,4 / heptan-5-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

7- (7-amino-5-azaspiro / 2,4 / heptan-5-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid lina;

7- (7-amino-5-azaspiro / 2,4 / heptan-5-yl) -6,8-difluoro-1- (2-fluoroethyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

7- (7-Amino-5-azaspiro / 2,4 / heptan-5-yl) -8-chloro-6-fluoro-1- (2-fluoro-ethyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid ;

7- (7-amino-5-azaspiro / 2,4 / heptan-5-yl) -6-fluoro-1 (2-fluoroethyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

7- (7-amino-5-azaspiro / 2,4 / heptan-5-yl) -6-fluoro-1 (2-fluoroethyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3carboxyl acid;

7- (7-amino-5-azaspiro / 2,4 / heptan-5-yl) -1-ethyl-6,8difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

7- (7-Amino-5-azaspiro / 2,4 / heptan-5-yl) -8-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

7- (7-amino-5-azaspiro / 2,4 / heptan-5-yl) -1-ethyl-6fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

7- (7-amino-5-azaspiro / 2,4 / heptan-5-yl) -1-ethyl-6fluoro-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-difluoro-phenyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid ;

7- (7-amino-5-azaspiro / 2,4 / heptan-5-yl) -8-chloro-6-fluoro-1- (2,4-difluoro-phenyl) -1,4-dihydro-4-oxoquinoline- 3carboxylic acid;

7- (7-amino-5-azaspiro / 2,4 / heptan-5-yl) -6-fluoro-1 (2,4-difluoro-phenyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

7- (7-amino-5-azaspiro / 2,4 / heptan-5-yl) -6-fluoro-1 (2,4-difluoro-phenyl) -1,4-dihydro-4-oxo-1,8 -naphthyridine 3-carboxylic acid;

7- (7-amino-5-azaspiro / 2,4 / heptan-5-yl) -6,8-difluoro-vinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

7- (7-amino-5-azaspiro / 2,4 / heptan-5-yl) -8-chloro-6-fluoro-1-vinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

7- (7-amino-5-azaspiro / 2,4 / heptan-5-yl) -6-fluoro-1-vinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

7- (7-amino-5-azaspiro / 2,4 / heptan-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 / octan-7-yl) -6,8difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

8- Chloro-1-cyclopropyl-7- (4,7-diazaspiro / 2,5 / octan-7-yl) -6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

1-cyclopropyl-7- (4,7-diazaspiro-2,5 / octan-7-yl) -6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

1-cyclopropyl-7- (4,7-diazaspiro / 2,5 / octan-7-yl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid;

7- (4,7-Diazaspiro / 2.5 / octan-7-yl) -6,8-difluoro-1 (2-fluoro-ethyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid ;

8-chloro-7- (4,7-diazaspiro / 2.5 / octan-7-yl) -6-fluoro-1- (2-fluoroethyl) 1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

7- (4,7-Diazaspiro / 2.5 / octan-7-yl) -6-fluoro-1- (2fluoroethyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

7- (4,7-Diazaspiro / 2.5 / octan-7-yl) -6-fluoro-1- (2fluoroethyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid;

7- (4,7-Diazaspiro / 2.5 / octan-7-yl) -1-ethyl-6,8difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

8- Chloro-7- (4,7-diazaspiro / 2.5 / octan-7-yl) -1-ethyl6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

7- (4,7-Diazaspiro / 2.5 / octan-7-yl) -1-ethyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

7- (4,7-Diazaspiro / 2.5 / octan-7-yl) -1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid;

7- (4,7-Diazaspiro / 2,5 / octan-7-yl) -6,8-difluoro-1 (2,4-difluoro-phenyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

8- Chloro-7- (4,7-diazaspiro / 2,5 / octan-7-yl) -6-fluoro-1- (2,4-difluoro-phenyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid ;

7- (4,7-Diazaspiro / 2,5 / octan-7-yl) -6-fluoro-1- (2,4difluoro-phenyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

7- (4,7-diazaspiro / 2,5 / octan-7-yl) -6-fluoro-1- (2,4difluoro-phenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine- 3carboxylic acid;

7- (4,7-Diazaspiro / 2.5 / octan-7-yl) -6,8-difluoro-1vinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

8- Chloro-7- (4,7-diazaspiro / 2.5 / octan-7-yl) -6-fluoro-vinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

7- (4,7-Diazaspiro / 2.5 / octan-7-yl) -6-fluoro-1-vinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

7- (4,7-Diazaspiro / 2,5 / octan-7-yl) -6-fluoro-1-vinyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid;

10- (7-amino-5-azaspiro / 2,4 / heptan-5-yl) ~ 9-fluoro-3 (S) -methyl 1-2,3-dihydro-7-oxo-7H-pyricyl-1. 2,3-de (1,4) benzoxazine-6-carboxylic acid;

10- (4,7-diazaspiro / 2,5 / octan-7-yl) -9-fluoro-3- (S) methyl-2,3-dihydro-7-oxo-7H-pyrido / 1,2,3 -de // 1,4 / benzoxazine-6-carboxylic acid;

8- (7-Amino-5-azaspiro / 2,4 / heptan-5-yl) -9-fluoro-5 (S) -methyl-6,7-dihydro-1,7-dioxo-1H, 5H-benzo (ii) quinolysin-2 carboxylic acid;

8- (4,7-Diazaspiro / 2.5 / octan-7-yl) -9-fluoro-5 ~ (S) methyl-6,7-dihydro-1,7-dioxo-1H, 5H-benzo / ij / quinolysin-2carboxylic acid;

10- (7-amino-5-azaspiro / 2,4 / heptan-5-yl) -9-fluoro-3 (S) -methyl-2,3-dihydro-7-oxo-7H-pyrido / 1,2 , 3-de // 1,4 / benzothiazine-6-carboxylic acid;

10- (4,7-diazaspiro / 2,5 / octan-7-yl) -9-fluoro-3- (S) methyl-2,3-dihydro-7-oxo-7H-pyrido / 1,2. 3-de // 1,4 / benzothiazine-6-carboxylic acid;

5-amino-7- (7-amino-5-azaspiro / 2,4 / heptan-5-yl) -1cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

5-amino-7- (7-amino-5-azaspiro / 2,4 / heptan-5-yl) -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline3-carboxylic acid;

5-Amino-7- (7-amino-5-azaspiro / 2,4 / heptan-5-yl) -6,8difluoro-1- (2-fluoroethyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid ;

5-amino-7- (7-amino-5-azaspiro / 2,4 / heptan-5-yl) -8-chloro-6-fluoro-1- (2-fluoroethyl) -1,4-dihydro-4oxyquinoline-3- carboxylic acid;

5-amino-7- (7-amino-5-azaspiro / 2,4 / heptan-5-yl) -1ethyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

5-amino-7- (7-amino-5-azaspiro / 2,4 / heptan-5-yl) -8-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

5-amino-7- (7-amino-5-azaspiro / 2,4 / heptan-5-yl) -6,8difluoro-1- (2,4-difluoro-phenyl) -1,4-dihydro-4-oxoquinoline- 3-carboxylic acid;

5-amino-7- (7-amino-5-azaspiro / 2,4 / heptan-5-yl) -8chloro-6-fluoro-1- (2,4-difluoro-phenyl) -1,4-dihydro- 4oxyquinoline-3-carboxylic acid;

5-amino-1-cyclopropyl-7- (4,7-diazaspiro / 2.5 / octan-7yl) -6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

5-amino-8-chloro-7- (4,7-diazaspiro / 2,5 / octan-7-yl) 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

5-amino-7- (4,7-diazaspiro / 2,5 / octan-7-yl) -6,8difluoro-1- (2-fluoroethyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

5-amino-8-chloro-7- (4,7-diazaspiro / 2.5 / octan-7-yl) 6-fluoro-1- (2-fluoroethyl) -1,4-dihydro-4-oxoquinoline-3carboxyl acid;

5-amino-7- (4,7-diazaspiro / 2,5 / octan-7-yl) -1-ethyl6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

5-Amino-8-chloro-7- (4,7-diazaspiro / 2.5 / octan-7-yl) 1-ethyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ;

5-amino-7- (4,7-diazaspiro / 2,5 / octan-7-yl) -6,8-difluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxoquinoline3- carboxylic acid;

5-amino-8-chloro-7- (4,7-diazaspiro / 2,5 / octan-7-yl) 6-fluoro-1- (2,4-difluoro-phenyl) -1,4-dihydro-4 -oxoquinoline3-carboxylic acid:

5-amino-7- (7-amino-5-azaspiro / 2,4 / heptan-5-yl) -6,8difluoro-1-vinyl-1,4-dihydro-4-oxoquinoline-3r-carboxylic acid;

5-amino-7- (7-amino-5-azaspiro / 2,4-heptan-5-yl) -8-chloro-6-fluoro-1-vinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

5-amino-7- (4,7-diazaspiro / 2,5 / octan-7-yl) -6,8difluoro-1-vinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

5-amino-8-chloro-7- (4,7-diazaspiro / 2,5 / octan-7-yl) 6-fluoro-1-vinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

7- (7-amino-5-azaspiro / 2,5 / heptan-5-yl) -1-cyclopropyl6-fluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic saliva;

7- (7-amino-5-azaspiro / 2,5 / heptan-5-yl) -6-fluoro-1 (2-fluoroethyl) -8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

7- (7-amino-5-azaspiro / 2,5 / heptan-5-yl) -1-ethyl-6fluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

7- (7-amino-5-azaspiro / 2,5 / heptan-5-yl) -6-fluoro-1 (2,4-difluoro-phenyl) -8-methoxy-1,4-dihydro-4-oxoquinoline3 -carboxylic acid;

7- (7-amino-5-azaspiro / 2,5 / heptan-5-yl) -6-fluoro-8methoxy-1-vinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

7- (7-amino-5-azaspiro / 2,5 / heptan-5-yl) -1-cyclopropyl6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

7- (7-amino-5-azaspiro / 2,5 / heptan-5-yl) -6-fluoro-1 (2-fluoroethyl) -8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

7- (7-amino-5-azaspiro / 2,5 / heptan-5-yl) -1-ethyl-6fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

7- (7-amino-5-azaspiro / 2,5 / heptan-5-yl) -6-fluoro-1 (2,4-difluorophenyl) -8-methyl-1,4-dihydro-4-oxoquinoline3-carboxyl acid;

7- (7-Amino-5-azaspiro / 2,5 / heptan-5-yl) -6-fluoro-8methyl-1-vinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

-cyclopropyl-7- (4,7-diazaspiro / 2,5 / octan-7-yl) -6fluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

7- (4,7-Diazaspiro / 2,5 / octan-7-yl) -6-fluoro-1- (2fluoroethyl) -8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

7- (4,7-Diazaspiro / 2.5 / octan-7-yl) -1-ethyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

7- (4,7-Diazaspiro / 2.5 / octan-7-yl) -1- (2,4-difluorophenyl) -6-fluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3carboxyl acid;

7- (4,7-Diazaspiro / 2,5 / octan-7-yl) -6-fluoro-8methoxy-1-vinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

1-cyclopropyl-7 (4,7-diazaspiro / 2,5 / octan-7-yl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

7 (4,7-Diazaspiro / 2,5 / octan-7-yl) -6-fluoro-1- (2fluoroethyl) -8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

7 (4,7-Diazaspiro / 2.5 / octan-7-yl) -1-ethyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

7 (4,7-Diazaspiro / 2.5 / octan-7-yl) -1- (2,4-difluorophenyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

7 (4,7-Diazaspiro / 2.5 / octan-7-yl) -6-fluoro-8-methyl-vinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

7- (8-Amino-6-azaspiro / 3,4 / octan-6-yl) -1-cyclopropyl6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

7- (8-amino-6-azaspiro / 3,4 / octan-6-yl) -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

7- (8-amino-6-azaspiro / 3,4 / octan-6-yl) -6,8-difluoro-1- (2-fluoroethyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

7- (8-amino-6-azaspiro / 3,4 / octan-6-yl) -8-chloro-6fluoro-1- (2-fluoroethyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

7- (8-amino-6-azaspiro / 3,4 / octan-6-yl) -1-ethyl-6,8difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

7- (8-amino-6-azaspiro / 3,4 / octan-6-yl) -8-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

7- (8-amino-6-azaspiro / 3,4 / octan-6-yl) -6,8-difluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

7- (8-Amino-6-azaspiro / 3,4 / octan-6-yl) -8-chloro-6fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxoquinoline3-carboxylic acid ;

7- (8-amino-6-azaspiro / 3,4 / octan-6-yl) -6,8-difluoro-vinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

7- (8-amino-6-azaspiro / 3,4 / octan-6-yl) -8-chloro-6fluoro-1-vinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

10- (8-amino-6-azaspiro / 3,4 / octan-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 / octan-6-yl) -9-fluoro-5 (S) -methyl-6,7-dihydro-1,7-dioxo-1H, 5H-benzo (ii) quinolysine-2-carboxylic acid;

1-cyclopropyl-7- (5,8-diazaspiro / 3,5 / nonan-8-yl) 6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

8-Chloro-1-cyclopropyl-7- (5,8-diazaspiro / 3,5 / nonan8-yl) -6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid33

7- (5,8-Diazaspiro / 3,5 / nonan-8-yl) -6,8-difluoro-1- (2fluoroethyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid

8- chloro-7- (5,8-diazaspiro / 3,5 / nonan-8-yl) -6-fluoro- (2-fluoroethyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

- (5,8-Diazaspiro / 3,5 / nonan-8-yl) -1-ethyl-6,8difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

8-chloro-7- (5,8-diazaspiro / 3,5 / nonan-8-yl) -1-ethyl6-fluoro-1,4-dihydro-4-oxoquinoline-3-carb ^with oxyl 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) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

7- (5,8-Diazaspiro / 3,5 / nonan-8-yl) -6,8-difluoro-1vinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

8- Chloro-7- (5,8-diazaspiro / 3,5 / nonan-8-yl) -6-fluoro-vinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

10- (5,8-diazaspiro / 3,5 / nonan-8-yl) -9-fluoro-3- (S) methyl-2,3-dihydro-7-oxo-7H-pyrido / 1,2,3 -de // 1,4 / - benzoxazine-6-carboxylic acid;

10- (5,8-diazaspiro / 3,5 / nonan-8-yl) -9-fluoro-3- (S) ethyl-2,3-dihydro-7-oxo-7H-pyrido / 1,2,3 -de // 1,4 / benzothiazine-6-carboxylic acid;

- 34 8- (5,8-Diazaspiro / 3,5 / nonan-8-yl) -9-fluoro-5- (S) methyl-6,7-dihydro-1,7-dioxo-1H, 5H 4 -benzo - / ij / quinolysin-2carboxylic acid;

7- (7-methylamino-5-azaspiro / 2,4 / heptan-5-yl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

7- (7-dimethylamino-5-azaspiro / 2,4 / heptan-5-yl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid; and

8- Chloro-1-cyclopropyl-7- (4-methyl 1-4,7-diazaspiro / 2,5 / octan-7-yl) -6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid .

Those quinolone derivatives having a cyclic amine moiety containing the spiro ring are more lipophilic than the corresponding spiro ring non-quinolone derivatives and are expected to be better absorbed after oral administration and exhibit antibacterial activity.

Pyridonecarboxylic acid derivatives according to the present invention can be used as free compounds, acid addition salts or salts of their carboxylic groups. Examples of such acid addition salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide and phosphate, and organic acid salts such as acetate, methanesulfonate, benzenesulfonate, toluenesulfonate, citrate, maleate, fumarate and lactate.

Examples of these salts of carboxylic groups include salts with inorganic and organic acids, e.g. alkali metal salts such as lithium salt, sodium salt, potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, ammonium salt, triethylamine salt, N-methylglucamate salt and tris (hydroxymethyl) -aminomethane salt.

These free compounds, acid addition salts and salts of the carboxyl groups of the pyridonecarboxylic acid derivatives may exist as hydrates.

On the other hand, quinolone derivatives whose carboxyl moieties are esters useful as prodrugs ”or synthetic intermediates.

Esters to be used as prodrugs are esters that are easily cleaved in the body to form free carboxylic acids. Thus, for example, suitable acetoxymethyl ester, pivaloyloxymethyl ester, ethoxycarbonyloxy ester, choline ester, dimethylaminoethyl ester, 5-indanyl ester, phthalidinyl ester, 5-substituted-2-oxo-1,3-dioxo-4-ylmethyl ester and various oxoalkyl esters such as 3- acetoxy-2-oxobutyl ester.

The compounds of the present invention have excellent antibacterial activity and can therefore be used as human and animal medicines, fish medicines, agro-chemicals and food preservatives.

The dose of the compound of the present invention as the active ingredient of the human medicament is in the range of 50 mg to 1 g per adult per day and preferably 100 to 300 mg per adult per

- 36 days. The dosage for the animal product is in the range of about 1 to 200 mg per kg body weight per day and preferably 5 to 100 mg per kg body weight per day. The daily dose should be adjusted according to such factors as the intended use (such as therapeutic or preventive), the type, size or age of the person or animal to be treated, the type of pathogenic organisms requiring treatment and the symptoms, who show up, etc.

The dose described above can be divided into 1 to 4 doses per day. It may be necessary to deviate from the amount described above in accordance with the organism-inducer or the severity of the symptoms that have manifested themselves.

The compounds of the present invention are active against a very wide range of microorganisms and it is possible to prevent, alleviate and / or cure diseases caused by such pathogenic microorganisms. Examples of susceptible bacteria or bacterial-like microorganisms include _t Staphylococcus sp., Streptococcus pyoqenes, hemolytic streptococci, enterococci, Streptococcus pneumoniae, Neisseria gonorrhoeae, Escherichia coli, Citrobacter sp., Shigella sp., Klebsiella pneumonia, Enterobacteria pneumoniae, Serberobia pneumoniae. Proteus sp., Pseudomonas aeruginosa, Haemophilus influenzae, Acinetobacter sp., Campylobacter sp. and Chlamidiae.

Among the preventable diseases, we can relieve mn r sDo iino or with compounds in accordance with 37 fusion panbronchiolitis, bronchiectasis with infection, secondary chronic respiratory infections, pharyngolaryngitis, tonsillitis, acute bronchitis, pyelonephritis, cystitis, prostatitis, epididymis gonococcal urethritis, non -ococcal urethritis, folliculitis, furuncle, furunculosis, carbuncle, erysipelas, phlegmon, lymphangiitis / lymphadenitis, felon, subcutaneous abscess, spiridenitis, ac.ne conglobata, infectious atheroma, periannectal abscess, periannectal abscess, surgical trauma, cholecystitis, cholangiitis, otitis media, sinusitis, blepharitis, chordeolum, dacryocystitis, tarsadenitis, keratochelosis, bacillary dysentery and enteritis.

Examples of susceptible microorganisms causing veterinary diseases include Escherichia sp., Salmonella sp., Pasteurella sp., Haemophysalis sp., Bordetella sp., Staphylococcus sp. and Mycoplasma sp. The following are some examples of veterinary diseases; poultry diseases include colibacillosis, chicken pox, avian paratyphosis, chicken pox, contagious infections, staphylococcal infections and mycoplasmal diseases; pig diseases include colibacillosis, salmonellosis, pasteurellosis, haemophilic infections, atrophic rhinitis, exudative epidermitis and mycoplasma diseases; bovine diseases include colibacillosis, salmonellosis, haemorrhagic septicemia, mycoplasma diseases, bovine infectious pleuropneumonia and bovine mastitis; canine diseases include coliform sepsis, salmonellosis, hemorrhagic septicemia, pyometra and cystitis; and cat diseases include hemorrhagic

- 38 pleuritis, cystitis, and chronic rhinitis, and bacterial entritis and mycoplasma diseases among muck diseases.

Pharmaceutical preparations containing one or more compounds of the present invention as the active ingredient can be prepared according to conventional preparation methods. Examples of pharmaceutical preparations for oral administration include tablets, powders, granules, capsules, solutions, syrups, elixirs and oily or aqueous suspensions.

Solid preparations may contain the active compound or compounds of the present invention together with conventional excipients such as fillers, diluents, binders, moisturizers, absorption enhancers, wetting agents, adsorbents and lubricants. Liquid preparations may include solutions, suspensions or emulsions. These may contain in their preparation in addition to the active compound or compounds conventional excipients, such as solubilizing agents, emulsifiers, stabilizers or preservatives. Solutions of the compounds (e) of the present invention, which may contain these ingredients, are placed in a container, such as ampoules or vials, and can be converted to solid state by lyophilization. When administered, dissolve the lyophilized preparation with a diluent. The container may contain either single doses or multiple doses.

Examples of topical preparations include solutions, suspensions, emulsions, ointments, gels, creams, lotions and sprays.

The compound of the present invention may also be administered to animals as oral or non-oral veterinary medicines. Such medicines can be administered in the form of a mixture of feed or water. Veterinary preparations or additives may be prepared according to conventional methods in the art, and such preparations include powders, fine grains, granules, solubilized scratches, syrups, solutions and injections.

The following are examples of formulations that are for illustrative purposes only and should not be construed as restrictive.

Formulation Example 1

Each capsule contains:

Compound 32b 100,0 mg Corn starch 23,0 mg Calcium carboxymethyl cellulose 22.5 mg Hydroxypropylmethyl cellulose 3,0 mg Magnesium stearate 1, 5 mg 150.0 mg Formulation Example 2 The solution contains: Compound 31b 1 to 10 g Acetic acid or sodium hydroxide 0.5 to 1 g Ethyl p-hydroxybenzoate 0.1 g Purified water 88.9 to 98.4 g

100,0 g

Formulation Example 3

Feed dusting powder contains:

Compound 55b Corn starch

Light quartz up to 10 g 98.5 to 89.5 g

0,5 g

100,0 g

Although the description clarifies and describes a preferred embodiment of the present invention, it is understood that it is not limited thereto.

The following examples further illustrate the present invention, but should not in any way be construed as limiting its scope.

Antibacterial activity assays were performed according to the method detailed by Japan Society of Chemotherapy (Chemotherapy 29 (1), 76 (1981). Antibacterial activity tables are followed by reaction schemes for the synthesis of various cyclic amine derivatives containing spiro ring intermediates for synthesis quinolone rings and synthesis of various spiro compounds.

REFERENCE EXAMPLE 1

Synthesis of 7-amino-5-azaspiro / 2,4 / heptane

1) Ethyl 1-acetyl-1-cyclopropanecarboxylate (compound 2)

To 10.4 g of ethyl acetoacetate were added 15 g of 1,2-dibromoethane, 23 g of calcium carbonate and 150 ml of N, N-dimethylformamide (DMF) and the mixture was stirred at room temperature for 2 days.

After insoluble filtration, the filtrate was concentrated under reduced pressure to dryness and water was added to the residue. The mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent removed under reduced pressure. The light yellow oily residue was then vacuum distilled to give 7.5 g of the title compound 2. as a fraction boiling at 70-71 ° C / 2.7 to 4.0 mbar.

¹ H-NMR (CDCl ₃ ) δ ppm:

1.30 (3H, t, J = 7 Hz), 1.48 (4H, s), 2.49 (3H, s),

4.24 (2H, q, J = 7 Hz)

2) 5-Benzyl-4,7-dioxo-5-azaspiro / 2,4 / heptane (Compound 4)

7 g of compound 2 were dissolved in 50 ml of ethanol and then 8.0 g of bromine was added dropwise while stirring at room temperature. After stirring at this temperature for 2 hours, excess bromine and solvents were removed under reduced pressure to give ethyl 1-bromoacetyl-1-cyclopropanecarboxylate (compound 3.). This product was dissolved as it was, i.e. without purification, in 50 ml of ethanol, and 12 g of benzylamine were added dropwise while stirring and cooling with ice. The mixture was then stirred at room temperature for 24 hours and then the solvent was removed under reduced pressure. The residue was dissolved in

Wash 200 ml of chloroform and the solution in succession with 1 N hydrochloric acid and saturated aqueous sodium chloride and dry over anhydrous sodium sulfate. The solvent was then removed and the residue was chromatographed on silica gel using 2% methanol-chloroform as eluent. The process gave 2.3 g of the title compound 4 as light yellow crystals. ¹ H-NMR (CDCl ₃ ) Sppm:

1.6-1.8 (4H, m), 3.78 (2H, s), 4.68 (2H, s),

7.2- 7.45 (5H, broad s).

3) 5-Benzyl-7- (hydroxyimino) -4-oxo-5-azaspiro / 2,4 / heptane (Compound 5)

To 670 mg of compound 4. 700 mg of hydroxylamine hydrochloride, 200 mg of triethylamine and 10 ml of ethanol were added. The mixture was stirred at room temperature overnight. The solvent was then removed under reduced pressure and the residue was dissolved in 10% aqueous citric acid and extracted with chloroform. The chloroform layer was extracted with 1N aqueous sodium hydroxide and the aqueous layer acidified with concentrated hydrochloric acid and extracted with chloroform. This extract was dried over anhydrous sodium sulfate and the solvent was then distilled off under reduced pressure to give 490 mg of the title compound 5_ as colorless crystals.

^X H-NMR (CDCl ₃ ) Sppm:

1.3- 1.7 (4H, m), 3.80 * & 4.10 * (2H, s),. 4,60 ** &

4.70 ** (2H, s), 7.38 (5H, arm.) (*, **: mixture of syn- and anti-isomers)

- 43 4) 7-amino-5-azaspiro / 2,4 / heptane (compound 7)

490 mg of compound 5 was dissolved in 80 ml of dry tetrahydrofuran, then 500 mg of lithium aluminum hydride was added and the mixture was refluxed for 8 hours. Then, at room temperature, 0.5 ml of water, 0.5 ml of 15% aqueous sodium hydroxide and 1.5 ml of water were added thereto and filtered off. The filtrate was concentrated under reduced pressure to give 7-amino-5-benzyl-5-azaspiro / 2,4 / heptane (compound 6). This product was dissolved as it was, i.e. without purification, catalytically hydrogenate at 4.4 bar and 50 ° C in 20 ml of ethanol and after addition of 10% palladium on charcoal. After 6 hours of digestion, the catalyst was filtered off and the filter was concentrated under reduced pressure at a temperature no higher than room temperature. The above procedure gave the title compound 7. as a crude product. This compound 7_ was used without purification in various metabolites.

5) 7 - [(R) -N-p-toluenesulfonylpropyl / amino-5-benzyl-5azaspiro / 2,4 / heptane (Compound 8)

A mixture of 2.8 g of compound 6., 1.5 g of triethylamine and 50 ml of methylene chloride was prepared and the above mixture was added dropwise over 10 minutes while cooling with ice and stirring a solution of (R) -Np-toluenesulfonylpropyl chloride (prepared from 4 g (R) -Np-toluenesulfonylprolin and excess thionyl chloride) in 10 ml of methylene chloride. The mixture was then shaken at room temperature for 3 hours. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was treated by flash column chromatography (silica gel 80 g). Ethyl acetate fraction gave 3.5 g of the title compound 8_ as a syrup.

6) 7 - / (R) -N-p-toluenesulfonylpropyl / amino-5-benzyloxycarbonyl-5-azaspiro / 2,4 / heptane (compound 9) and optical isomers (compound 9a and compound 9b)

To 4 ml of dry methylene chloride was added 3.5 g of compound 8 and 2.5 ml of benzyl chlorocarbonate and the mixture was stirred at room temperature for 12 hours. After further addition of 4 ml of benzyl chlorocarbonate, the mixture was stirred for 5 hours. Chloroform was then added to the reaction mixture. The mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride in the order mentioned and dried over anhydrous sodium sulfate. The solvent was then removed under reduced pressure and the residue was treated by flash column chromatography (silica gel 85 g). Ethyl acetate-n-hexane (2: 1-4: 1, v / v) fraction gave 3 g of the title compound 9_ as a light yellow oil. This oil was immediately treated with HPLC to give 1.40 g of compound 9a and 1.45 g of compound 9b.

Column

ethyl acetate

Eluent

Flow rate ml / min

Retention time: 9a: 19.5 min

9b: 21 min

9a: / eye / + 133.6 ° (c = 0.75, chloroform)

9b: / eye + 76.0 ° (c - 0.85, chloroform)

7) Optically active 7-amino-5-azaspiro / 2,4 / heptane (compound 7a and compound 7b)

1.4 g of compound 9a was dissolved in 20 ml of ethanol and then 15 ml of 2 N aqueous sodium hydroxide solution was added. The mixture was refluxed for 19 hours. The reaction mixture was then acidified with concentrated hydrochloric acid and washed twice with chloroform and once with ethyl acetate. The aqueous layer was then concentrated under reduced pressure to give a colorless solid residue. To this colorless substance was added 10 ml of 50% aqueous sodium hydroxide and the mixture was distilled under reduced pressure to give an aqueous solution containing compound 7a. We used this distillate as it was in the following digestion.

Another compound 7b was also obtained from compound 9b in a similar manner.

8) 7-tert-butoxycarbonylamino-5-azaspiro / 2,4 / heptane (compound 11)

800 mg of compound 6_ was dissolved in 30 ml of tetrahydrofuran, then 1.2 g of 2- (tert-butoxycarbonyloxyimino) -2-phenylacetonitrile (BOC-ON) were added at room temperature and the mixture was stirred at this temperature for 2 hours. The solvent was then removed under reduced pressure and chloroform was added to the residue. The mixture was extracted with 10% aqueous citric acid.

The citric acid extract was adjusted with 1 N aqueous sodium hydroxide to pH = 10 and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent removed under reduced pressure to give 900 mg of 7-tert-butoxycarbonylamino-5-benzyl-5-azaspiro / 2.4 / heptane (compound 10) · 870 mg of this compound 10 was obtained. dissolved in 15 ml of ethanol and catalytically hydrogenated at 40 ° C and 4.4 bar in the presence of 500 mg of 10% palladium on charcoal for 2 hours. The catalyst was then filtered off and the filtrate was concentrated under reduced pressure to give the title compound 11. This product was used without purification in the substitution reaction.

REFERENCE EXAMPLE 2

Synthesis of optically active 7-amino-5-azaspiro / 2,4 / heptane

1) 5 - [(1R) -phenylethyl] -4,7-dioxo-5-azaspiro / 2,4 / heptane (compound 12)

35.7 g of compound 2. was dissolved in 200 ml of ethanol and then 40 g of bromine was added dropwise while stirring at room temperature. The reaction mixture was stirred at room temperature for 2 hours, then excess bromine and solvent were removed under reduced pressure to give ethyl 1-bromoacetyl-1-cyclopropane-carboxylate (compound 3). This product was dissolved without purification in 200 ml of ethanol and 33 g of R - (+) 1-phenylethylamine and 27 g of triethylamine were added dropwise over 1 hour while cooling with ice and stirring. The mixture was then stirred at room temperature for 2 days. Then it was filtered off and the ethanol was removed under reduced pressure. The residue was dissolved in 300 ml of ethyl acetate and the solution was washed successively with 1 N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. The organic layer was dried over anhydrous sodium sulfate. The solvent was then removed under reduced pressure and the residue was column chromatographed on silica gel (200 g) using chloroform-2% methanol / chloroform as the eluent system. The process gave the title compound 12 as colorless crystals.

M.p .: 98-lO3 ° C ¹ H-NMR (CDCl ₃ ) δρρπίί

1., 4-1.8 (4H, -m), 1.62 (3H, d, J = 7.2 Hz),

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 - [(1R) -phenylethyl] -7-hydroxyimino-4-oxo-5azaspiro / 2,4 / heptane (Compound 13)

To 3.35 g of compound 12 was added 1.6 g of hydroxylamine hydrochloride, 2.3 g of triethylamine and 80 ml of ethanol and the mixture was stirred at room temperature for 2 hours. The solvent was then removed under reduced pressure and the residue was extracted with chloroform. The extract was washed with 10% citric acid and saturated aqueous sodium chloride. The organic layer was dried over anhydrous sodium sulfate and the solvent removed under reduced pressure. The process gave 3.5 g of the title compound 13 as colorless crystals.

Mp 188-194 ° C ¹ H NMR _r (CDC1 ₃₎ SPPM:

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 (1H, d, J = 18 Hz),

5.63 (1H, q, J = 7.2 Hz), 7.32 (5H, s)

3) 7-amino-4-oxc> -5- [(1R) -phenylethyl] -5-azaspiro / 2,4 / heptane (compound I4a and compound I4b)

To 150 ml of methanol were added 3> 5 g of compound 13 and 7.5 ml of Raney nickel. The catalytic reduction was carried out at room temperature for 12 hours. After the catalyst was filtered off, the solvent was removed under reduced pressure and the residue was column chromatographed on silica gel (100 g) using 5% methanol / chloroform as eluent. The process gave 1.0 g of compound 14b (obtained from the previously eluted fraction) and 0.8 g of compound 14a as colorless oils.

14b: ¹ H-NMR (CDCl ₃ ) Sppm:

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, broad s), 5.42 (1H, q, J = 7 Hz),

7.29 (5H, s)

14a: ¹ H-NMR (CDCl ₃ ) Sppm:

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)

- 49 4) 7-Amino-5 - / (1R) -phenylethyl / -5-azaspiro / 2,4 / heptane (compound 15a and compound 15b)

To 50 ml of dry tetrahydrofuran was added 1.0 g of 14b and 500 mg of lithium aluminum hydride and the mixture was refluxed for 17 hours. After cooling, 0.5 ml of water, 0.5 ml of 15% aqueous sodium hydroxide and 1.5 ml of water were added successively to the reaction mixture, and the mixture was stirred for 30 minutes at room temperature. The insoluble material was then removed by filtration and washed with tetrahydrofuran. The washing liquids and the filtrate were combined and dried. Finally, the solvent was removed under reduced pressure to give 940 mg of the title compound 15b as a light yellow oil. Similarly, 800 mg of compound 14a was prepared from 755 mg of compound 15a.

L: • '• H-NMR (CDCl ₃ ) Sppm:

0.2-0.8 (4H, m), 1.35 (3H, d, J = 6.6 Hz),

1.6-2.0 (2H, width m), 2.2-3.1 (4H, m),

3.24 (1H, q, J = 6.6 Hz), 3.5-3.9 (1H, m),

7.28 (5H, broad s) 1Sa: ¹ H-NMR (CDCl 3) Sppm:

0.3-0.9 (4H, 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),, 28 (5H, bs)

5) 7- (tert-butoxycarbonylamino) -5 - / (1 R) -phenylethyl] -5azaspiro / 2,4 / heptane (compound 6a and compound 1b)

764 mg of compound 15b and 1.3 g of BOC-ON were added to 20 ml of dry tetrahydrofuran. The mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate, washed twice with 1 N aqueous sodium hydroxide and once with water and extracted with 10% aqueous citric acid. After washing the aqueous layer once with ethyl acetate, it was basified with cooling with 15% aqueous sodium hydroxide during cooling and then extracted with 3 servings of chloroform. The organic layers were combined, washed with saturated aqueous sodium chloride, dried and the solvent removed. The residue was column chromatographed on silica gel (20 g) with eluent chloroform-methanol (20: 1, 10: 1). The process gave 690 mg of the title compound 16b. By product, this product crystallized. The crystals were washed with n-hexane. The title compound 16a was also prepared in a similar manner.

16b: Colorless crystals

M.p .: 103-105 ° C [a] _D -15.2 ° (c = 1.475, chloroform) ¹ H-NMR (CDCl ₃ ) Sppm:

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 = 5.6Hz), 3.24 (1H, q, J = 7.2 Hz),

3.6-4.0 (1H, m), 4.6-5.1 (1H, lat.d), 7.28 (5H, s)

Elemental analysis for

Calcd C 72.12, H Found: C 71.63, H

16a: colorless crystals ^C 19 ^H 28 ^N 2 ° 2 8,92, N 8,85

9.07, N 8.64 mp: 94-97 ° C [a] _D + 47.6 ° (c = 0 ₇ 89, chloroform) ¹ H-NMR (CDCl ₃ ) Sppm:

0.4-0.9 (4H, m), 1.33 (3H, d, J = 6.6 Hz),

1.40 (9H, s), 2.29 (1H, d, J = 9 Hz),

2.44 (1H, dd, J = 10.8, 3.6 Hz),

2.77 (1H, d, J = 9 Hz), 2.88 (1H, dd, J = 10.8,

5.3 Hz), 3.22 (1H, q, J = 6.6 Hz), 3.6-3.9 (1H, m), ^C 19 ^H 28 ^N 2 ° 2

4.7-5.2 (1H, sir.d), 7.27 (5H, s) Elemental analysis for

Calc .: C 72.12, H 8.92, N 8.85 Found · C 71.86, H 9.36, N 8.68

6) 7-bert-butoxycarbonylamino-5-azaspiro / 2,4 / heptane (compound 11a and compound Ilb, optical isomer of compound 11)

650 mg of compound 16b and 500 mg of palladium on charcoal (wetted with 50% water) were added to 30 ml of ethanol and catalytically reduced to 4.1 bar under pressure and the reaction vessel was heated with a v-tungsten lamp. The reduction reaction was performed for 6 hours. The catalyst was then filtered off and the mother liquor was condensed to dryness under reduced pressure. The resulting oily residue was diluted with ethyl acetate and extracted twice with 10% aqueous citric acid. The aqueous layer was basified with 15% aqueous sodium hydroxide and extracted with 3 portions of chloroform. The chloroform layers were combined, washed with water, dried and the solvent removed to give 440 mg of the title compound 11b as a crude product. The title compound a was also prepared in a similar manner.

T

The H-NMR spectra of compounds 11b and 1a1 were in perfect agreement.

17b: ^X H-NMR (CDCl ₃ )?

0.4-1.0 (4H, 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 Hz),

3.33 (1H, dd, J = 10.8, 5.4 Hz), 3.5-3.9 (1H, m), 5.0-5.4 (1H, broad d)

REFERENCE EXAMPLE 3

Synthesis of 4,7-diazaspiro / 2 _> 5 / octane

1) Cyclopropane-1, 1-dibromoamide (compound 18)

14.0 g of cyclopropane-1,1-diamide 17 were suspended in g of bromine and 130 ml of aqueous potassium hydroxide prepared using 14 g of potassium hydroxide was added dropwise while stirring at room temperature. After stirring for 1 hour, the reaction mixture was cooled with ice and the resulting crystals were collected by filtration, washed with ice water and air-dried. The crystals were then dried under reduced pressure at 66 ° C for 2 hours to give 28.6 g of the title compound 18.

2) 4,6-diazaspiro / 2,4 / heptane-5,7-dione (Compound 19)

To a solution of sodium methoxide prepared from 9.1 g of metallic sodium and dry methanol was added while cooling with ice and stirring 26 g of compound 18. After removing the ice bath, the mixture was further stirred and the internal temperature rose from about 5 ° C. degrees by degrees and then rose sharply to about 20 ° C to boiling point of methanol. The reaction mixture was maintained under reflux for 10 minutes and then cooled to room temperature. The reaction mixture was then concentrated under reduced pressure to dryness and acetone was added to the residue. The crystals were collected by filtration and washed with acetone. The wash liquids and the filtrate were combined and concentrated under reduced pressure. The process gave the title compound 19 as a crude product. This product was used without purification in the following metabolism.

3) 1-Aminocyclopropanecarboxylic acid 20 and 1-tert.butoxycarbonylaminocyclopropanecarboxylic acid (compound 21)

The above crude compound 19 was dissolved in 60 ml of water and then 15 g of barium hydroxide were added. The mixture was heated in a stainless steel autoclave at an outside temperature of 170 ° C for 2 hours. The reaction mixture was then allowed to stand overnight and the separated barium carbonate was filtered off. Ammonium carbonate was then added to the filtrate and the precipitated barium carbonate was filtered off. The filtrate was concentrated to give the title amino compound 20 as the crude product. This compound 20 was purified tert-butoxycarbonylated with BOC-ON without purification to give 2.5 g of the title compound 21.

¹ H-NMR (CDCl ₃ ) Sppm:

1.85 (2H, t), 2.05 (9H, s), 2.15 (2H, t)

4) Ethyl (1-tert-butoxycarbonylamino-1-cyclopropylcarbonylamino) acetate (Compound 22)

700 mg of compound 21 was dissolved in 50 ml of dioxane and then 800 mg of dicyclohexylcarbodiimide and 600 mg of glycine ethyl ester hydrochloride were added. Then, while stirring at room temperature, 10 ml of dioxane 400 mg triethylamine solution was gradually added dropwise and the mixture was stirred for another 3 hours. The solvent was then removed under reduced pressure and the residue was column chromatographed on silica gel using 5% methanol-chloroform as eluent. The process gave 700 mg of the title compound 22.

5) Ethyl (1-amino-1-cyclopropylcarbonylamino) acetate (Compound 23)

To 680 mg of compound 22 was added 10 ml of trifluoroacetic acid and 0.5 g of anisole. The mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. Aqueous potassium carbonate was added to the residue and the pH was adjusted to above 10. The mixture was saturated with sodium chloride and extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and the solvent removed under reduced pressure. The process gave 410 mg of compound 23.

1 H-NMR (CDCl ₃ ) δppm:

0.85 (2H, t), 1.28 (3H, t), 1.46 (2H, t, J = 4 Hz),

1.68 (2H, broad s), 4.21 (2H, t, J = 7 Hz),

4.40 (2H, d, J = 7 Hz)

6) 4,7-diazaspiro / 2.5 / octane-5,8-dione (Compound 24)

If 500 mg of Compound 23 was heated in an oil bath at 220 ° C, it foamed and then solidified. The heating was continued for 20 minutes, and at the end of this time the reaction system was cooled to room temperature. The process gave the title compound 24 as a crude product.

¹ H-NMR (DMSO-dg) Sppm:

0.96 (2H, t), 1.17 (2H, t, J = 4 Hz),

3.86 (2H, J = 3 Hz), 8.0, 8.25 (each 1H, broad s)

7) 4,7-diazaspiro / 2.5 / octane (compound 25)

350 mg of compound 24 was suspended in 200 ml of dry tetrahydrofuran and then 0.6 g of lithium aluminum hydride was added. The mixture was refluxed for 14 hours. This reaction mixture was then added 0.6 g of water, 0.6 g of 15% aqueous sodium hydroxide and 1.8 g of water in ice-cooling, and the resulting precipitate was removed by filtration. The precipitate was washed thoroughly with tetrahydrofuran and ether and the wash liquids and filtrate were combined. The solvent was then removed under reduced pressure to give the title compound 4,7-diazaspiro / 2.5 / octane 25 as the crude product.

This product was digested without substitution by a substitution reaction.

- 56 REFERENCE EXAMPLE 4

Synthesis of benzoic acid derivatives

1) 3-Chloro-2,4,5-trifluorobenzoic acid (Compound 27)

9.3 g of anhydrous copper (I) chloride and 8.8 g of tert.butyl nitrite were added to 150 ml of acetonitrile and 11 g of 3-amino-2,4,5-trifluorobenzoic acid were added while stirring and heating at 60 ° C. 26 (commercial product). The mixture was stirred for 20 minutes. After cooling, 500 ml of 15% hydrochloric acid were added and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was then removed under reduced pressure. Finally, the residue was column chromatographed on silica gel (100 g) using chloroform as eluent. The process yielded 8.4 g of 3-chloro-2,4,5-trifluorobenzoic acid 27 as colorless needles.

Tal .; H4-115 ° C

Elemental analysis for c ₇ h ₂ cif ₃ o Calc. : C 39.93, H 0.96 Found: C 39.87, H 1.04 H-NMR (CDC1 ₃₎ Sppm: 7.76 (1H, ddd, J = 6.5, 8.5, 8.6-9.2 (1H, ss)

2) 2,4,5-Trifluoro-3-iodo-benzoic acid (compound 28) g of copper (I) iodide and 8.8 g of tert-butyl nitrite was added 150 acre of acetonitrile and stirred at

60 g of 3-amino-2,4,5-trifluorobenzoic acid were added 11 g.

Stirring was continued for 20 minutes and after cooling, 500 ml of 15% hydrochloric acid was added. The mixture was then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was chromatographed on 100 g of silica gel eluting with chloroform. The fractions containing the title compound were collected and the solvent removed under reduced pressure. Finally, the residue was recrystallized from n-hexane to give 8.4 g of the title compound 28 as colorless crystals.

Mp: 121-122 ° C

Elemental analysis for

Calc .: C 28.26, H 0.51 Found: C 28.19, H 0.76

MS m / z: 302 (M ⁺ )

Using anhydrous copper (I) bromide in the same manner as above, 3-bromo-2,4,5trifluorobenzoic acid was synthesized (Compound 29).

Mp: 124-125 ° C

3) 2,4,5-Trifluorobenzoic acid (compound 30)

3-1 Direct Disinfection

1.8 g of tert-butyl nitrite was dissolved in 5 ml of dry dimethylformamide and 2.0 g of 3-amino-2,4,5-trifluorobenzoic acid was added while stirring at 60 ° C. The mixture was further stirred for 20 minutes. The reaction mixture was then poured into 50 ml of water and extracted with diethyl ether. The organic layer was dried over

58 anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was column chromatographed on silica gel using chloroform as eluent. The process yielded 1.1 g of crystals of the title compound 30 ·

3-2 Bromo Compound Reduction

A mixture of 5.0 g of 3-bromo-2,4,5-trifluorobenzoic acid 29, 30 ml of acetic acid, 2.0 g of sodium acetate and 1.0 g of 5% palladium on charcoal was reduced in the atmosphere hydrogen for 4 hours. The catalyst was then filtered off and the filtrate was concentrated to dryness under reduced pressure. The residue was extracted with ethyl acetate and the extract was washed with water and dried over anhydrous sodium sulfate. Finally, the solvent was removed under reduced pressure to give 3.2 g of the title compound 30 as colorless crystals.

30: ¹ H-NMR (CDCl3) Sppm:

7.10 (1H, ddd, J = 6.5, 9, 9Hz), 7.96 (1H, ddd,

J = 6.3, 8.5, 9.8 Hz), 9.2-9.6 (1H, broad s)

EXAMPLE 1

7- (7-Amino-5-azaspiro / 2,4 / heptan-5-yl) -1-cyclopropyl-6,8difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (Compound 31)

300 mg of 7-amino-5-azaspiro / 2,4 / heptane 7 and 250 mg

1-Cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was added to 5 ml of dimethyl sulfoxide.

The mixture was heated at 100 ° C for 30 minutes. After cooling, the solvent was distilled off under reduced pressure and the residue was crystallized by the addition of ethanol. The resulting crude crystals were collected by filtration, suspended in ethanol and dissolved with the addition of 28% aqueous ammonia. To this solution was added 50 mg of activated carbon and the mixture was filtered. The filtrate was concentrated by heating and the resulting crystals were collected by filtration. The process gave 170 mg of the title compound 31 ·

Tal .; 238-245 ° C

Elemental analysis for ^C 19 ^H 19 ^F 2 ^O 3 * ^isH 2 °

Calc'd c 59.37, H 5.24, N 10.93 Found. C 59.63, H 5.71, N 10.85

EXAMPLE 2

Synthesis of the optical isomer (compound 31a and compound 31b) of compound 31

140 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was suspended in 2 ml of dimethyl sulfoxide, followed by the addition of 66 mg of triethylamine and a further excess aqueous solution of the optically active amino compound. 7a. The mixture was heated at 120 ° C for 3 hours. The solvent was then removed under reduced pressure and the residue was purified by preparative TLC (developed with a chloroform-methanol-water floor layer = 7: 3 '· 1) · The resulting crystals were recrystallized from ethanol-28% aqueous ammonia to give 4 , 5 mg of compound 31a as light yellow microcrystals.

Using Compound 7b in the same manner, 34 mg of Compound 31b were also obtained.

(+) 7- (7-Amino-5-azaspiro / 2,4 / heptan-5-yl) -1-cyclopropyl6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

31a

Tal. · 221-235 ° C (decomposition) [α] ^ + 116.2 ° (c = 0.575, concentrated aqueous ammonia)

Elemental analysis for

Calcd .: C 59.37, Found. : C 59.31, ^C 19 ^H 19 ^F 2 ° 3 ' ^3HH 2 ° H 5.24, N 10.93 H 5.02', N 10.93 (-) - 7- (7-amino-5- azaspiro / 2,4 / heptan-5-yl) -1-cyclopropyl6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

31b

Tal -. : 227-240 ° C (decomposition)) [ct] _D -106.3 ° (c = 0.365, concentrated aqueous ammonia)

Elemental analysis for ^C 19 ^H 19 ^F 2 ^N 3 ° 3 ' ^JH 2 °

Calc .: C 59.37, H 5.24, N 10.93 Found: C 59.33, H 4.90, N 10.65

EXAMPLE 3

7- (7-Amino-5-azaspiro / 2,4 / heptan-5-yl) -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (Compound 32)

200 mg of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 150 mg of compound and 70 mg of triethylamine were added to 5 ml of acetonitrile and the mixture was refluxed for 24 hours. After cooling, the solvent was removed under reduced pressure and water was added to the residue. The precipitate was collected by filtration and washed successively with water, acetonitrile, ethanol and ether and dried. The process gave 245 mg of 7- (7-tert-butoxycarbonylamino-5-azaspiro / 2,4 / heptan-5-yl) -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline -3-carboxylic acids, mp 205-207 ° C.

0.3 ml of anisole and 5 ml of trifluoroacetic acid were added to 200 mg of this carboxylic acid. The mixture was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure and water was added to the residue. The mixture was basified with 1 N aqueous sodium hydroxide. The mixture was washed twice with chloroform, neutralized (pH 7.1) with 10% aqueous citric acid. The mixture was extracted with 3 servings of chloroform. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was then removed under reduced pressure and the residue was recrystallized from ethanol-concentrated aqueous ammonia. The process gave 105 mg of the title compound 32.

Melting point: 235-240 ° C (decomposition)

Elemental analysis for. C ^ gH ^ gClPN ^ O ^

Calc .; C 57.58, H 4.96, N 10.60 Found :) C 57.64, H 5.33, N 10.37

EXAMPLE 4

7- (7-Amino-5-azaspiro / 2,4 / heptan-5-yl) -1-cyclopropyl-6fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (Compound 33)

250 mg of 1-cyclopropyl-6,7-difluoro-2,3-dihydro-4-oxoquinoline-3-carboxylic acid and 250 mg of compound JJ were added to 4 ml of dimethyl sulfoxide and the mixture was heated at 120 ° C for 2 hours.

After cooling, the solvent was removed under reduced pressure and the residue was crystallized by the addition of ethanol. The crystals were collected by filtration. The process gave 7- (7-tert-butoxycarbonylamino-5-azaspiro / 2,4 / heptan-5-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid as crude product.

To this product was added 5 ml of trifluoroacetic acid and the mixture was stirred at room temperature for 30 minutes to remove the tert-butoxycarbonyl group. The solvent was then removed under reduced pressure and the residue was dissolved in 1 N aqueous sodium hydroxide. The solution was washed with chloroform and adjusted with 1 N hydrochloric acid to pH 7.0, after which crystals were removed. The crystals were collected by filtration and recrystallized from ethanol-concentrated aqueous ammonia to give 200 mg of the title compound 33 ·

Mp .: 249-252 ° C

Elemental analysis for C _ig H ₂₀ FN ₃ C> ₃

Calcd: C 63.85, H 5.64, N 11.76

Found: C 63.61, H 5.94, N 11.71

- 63 EXAMPLES 5 and 6

In the same manner as in Example 4, 7- (7-amino-5-azaspiro / 2,4 / heptan-5-yl) -6-fluoro-1- (2,4difluorophenyl) -1,4-dihydro was synthesized -4-Oxoquinoline-3-carboxylic acid (Compound 34), m.p. 226-228 ° C and 7- (7-amino-5-azaspiro / 2,4 / heptan-5-yl) -1-cyclopropyl-6- fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (Compound 35), mp 256-257 ° C.

EXAMPLE 7

10- (7-amino-5-azaspiro / 2,4 / heptan-5-yl) -9-fluoro-2,3-dihydro-3- (S) -methyl-7-oxo-7H-pyrido / 1,2, 3-de // 1,4 / benzoxazine-6-carboxylic acid (compound 36)

300 mg of 9,10-difluoro-2,3-dihydro-3- (S) methyl-7-oxo-7H-pyrido / 1,2,3-de // 1,4 / benzoxazin-6-chelate 9,10-difluoro-6- of carboxylic acid and 250 mg of compound 11 were added to 5 ml of dimethylacetamide and the mixture was stirred at room temperature for 3 hours. The solvent was then removed under reduced pressure and 1 ml of triethylamine and 30 ml of 95% methanol were added to the residue. The mixture was refluxed for 6 hours. After cooling, the solvent was removed under reduced pressure and the residue triturated with ethanol. The resulting crystals were collected by filtration and treated as described in Example 4 to remove the tert-butoxycarbonyl group. The process gave 170 mg of the title compound 36 as a crude product. This product was dissolved in ethanol-concentrated aqueous ammonia, treated with activated carbon and recrystallized to give 110 mg of the title compound 36.

M.p .: 236-237 ° C.

EXAMPLE 8

1-Cyclopropyl-7- (4,7-diazaspiro / 2,5, octan-7-yl) -6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (Compound 37)

200 mg of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 200 mg of crude 4,7-diazaspiro / 2.5 / octane 25 were added to 10 ml of dimethyl sulfoxide, then 0.3 ml of triethylamine was added. The mixture was heated on a 120 ° C bath for 2 hours. The solvent was then removed under reduced pressure and the residue was column chromatographed on silica gel eluting with chloroform-methane refraction = 15: 3: 1 (v / v). The crude product obtained from the fraction containing the desired compound was recrystallized from ethanol-concentrated aqueous ammonia to give 160 mg of the title compound 37.

Tal. at 243-245 ° C (decomposition)

Elemental analysis: for ^C 19 ^H 20 ^N 3 ° 3 ^F - * ^H 2 °

Calc .: C 63.03, H 5.71, N 11.61 Found: C 62.88, H 5.99, N 11.64 ^X H-NMR (NaOD-DSS) 6ppm:

0.97 (2H, t, J = 6 Hz), 1.12 (2H, m),

1.36 (2H, width t), 1.48 (2H, width t, J = 6 Hz),

7.64 (1H, d, J = 8 Hz), 7.92 (1H, d, J = 14 Hz),

8.52 (1H, s)

EXAMPLE 9

7- (7-Acetoxy-5-azaspiro / 2,4 / heptan-5-yl) -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (Compound 38)

360 mg of 8-chloro-1-cyclopropyl-6,7-difluoro-3-oxo3,4-dihydroquinoline-3-carboxylic acid and 1 ml of triethylamine were added to a solution of 900 mg of 7-acetoxy-5-azaspiro / 2,4 / of heptane (compound 69) in 10 ml of dry acetonitrile and the mixture refluxed for 2.5 days. (After 3 hours, 400 mg of the above azaspiro-heptane was added.) The reaction mixture was diluted with chloroform and the organic layer was washed with 10% aqueous citric acid. and dried. The solvent was then removed under reduced pressure.

The residue was column chromatographed. on silica gel (20 g) eluting with chloroform and 3% methanol-chloroform.

Fractions containing the desired compound were collected and the solvent was removed under reduced pressure. A small amount of ethanol was added to the residue and the mixture was heated and allowed to stand. The resulting crystals were collected by filtration and washed with diisopropyl ether to give 174 mg of the title compound 38.

Tal. Mp 179-182 ° C

H-NMR (CDCl ₃ ) S :,

0.72-1.00 (4H, m), 1.00-1.40 (4H, m), 2.10 (3H, s),

7.95 (1H, d), 8.87 (1H, s)

EXAMPLE 10

7- (7-hydroxy-5-azaspiro / 2,4 / heptan-5-yl) -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (Compound 39)

174 mg was suspended in 38 (7- (7-acetoxy-5-azaspiro / 2,4 / heptan-5-yl) -8chloro-1-cyclopropyl-1-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. 8 ml of ethanol then 1.5 ml of 1 N aqueous sodium hydroxide was added. The mixture was stirred at room temperature for 10 minutes. The solvent was then removed under reduced pressure and chloroform was added to the residue. The mixture was washed with water. The aqueous layer was acidified with

N hydrochloric acid and extracted with chloroform. The extract was dried and the solvent removed under reduced pressure. Finally, the residue was recrystallized from aqueous ammonia-ethanol to give 127 mg of the title compound 39.

Melting point: 242-244 ° C ¹ H-NMR (IN NaOD) S:

0.53-1.17 (8H, m), 2.98, 3.35 & 3.74 (each IH), 4,09-4,13 (3H, m), 7.59 (1H, d), 8.45 (1H, ^s ) Elemental analysis: for ^C 19 ^H 18 ^N 2 ° 4 ^ClF Calc. : C, 58.10 , H 4.62, N 7.13 Found. : C, 58.39 Λ H _of 4.65, N 7.27

EXAMPLE 11

7- (7-Hydroxyimino-5-azaspiro / 2,4 / heptan-5-yl) -8-chloro-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (Compound 40)

0.5 ml of anisole was added to 678 mg of 5-tert-butoxycarbonyl-7-hydroxyimino-5-azaspiro / 2,4 / heptane (compound 67), then 5 ml of trifluoroacetic acid was added while cooling with ice. The mixture was stirred at the same temperature for 30 minutes. The solvent was then removed under reduced pressure and 100 ml of dry acetonitrile was added to the residue. Then, 300 mg of 8-chloro-1-cyclopropyl-6,7-difluoro-4-oxo-3,4-dihydroquinoline-3-carboxylic acid and 1 ml of triethylamine were added and the mixture refluxed for 9 hours. The solvent was then removed under reduced pressure, methanol was added to the residue and filtered off. The mother liquor was left standing for 2 days and the resulting crystals were collected by filtration and recrystallized from aqueous ammonia ethanol to give 58 mg of the title compound 40.

M.p .: 239-240 ° C. ¹ H-NMR (1 N NaOD) S:

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 for C ^ gHH ^N ^O O FCl Calcd: C 56.24, H 4.22, N 10.35 Found: C 56.34, H 4.34, N 10.32

EXAMPLE 12 (-) - 10- (7-amino-5-azaspiro / 2,4 / heptan-5-yl) -9-fluoro2,3-dihydro-3- (S) -methyl-7-oxo-7H- pyrido / 1,2,3-de // 1,4, benzoxazole-3-carboxylic acid (compound 36b)

280 mg of (-) - 9,10-difluoro-2,3-dihydro-3- (S) methyl-7-oxo-7H-pyrido / 1,2,3-de (1,4) -fluoro-chelate (1,4) of benzoxazine-3-carboxylic acid was suspended in 4 ml of dry dimethyl sulfoxide, then 450 mg of compound 68b and 520 mg of triethylamine were added at room temperature. The mixture was stirred for 45 minutes. Then water was slowly added to the reaction mixture during ice-cooling and the resulting crystals were collected by filtration. 30 ml of 90% methanol and 2 ml of triethylamine were added to the crystals and the mixture was refluxed for 17 hours. The solvent was removed under reduced pressure and the residue was recrystallized from aqueous ammonia-ethanol to give 73 mg of the title compound 36b.

M.p .: 217-238 ° C.

[a] _D -109.22 ° (c = 0.683, 1 N NaOH) ¹ H-NMR (1 N 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 = 15 Hz), 8.17 (1H, ^s ) Elemental analysis for ^C 19 ^H 20 ^N 3 ° 4 ^F - ^ ^H 2 ° Calc. : C 57.64 with H 5.73, N 10.61 Found: C 57.64 with H 5.21, N 10.81

EXAMPLE 13 (-) - 7- (7-amino-5-azaspiro / 2,4 / heptan-5-yl) -1-cyclopropyl · 6-fluoro-4-oxo-1,4-dihydro-1,8- naphthyridine-3-carboxylic acid (compound 35b)

282.5 mg of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid, 200 mg of compound 68b and 1 g of triethylamine were added to 6 ml of dimethyl sulfoxide .

V O

The mixture was stirred at 110 C for 1 hour. The solvent was removed under reduced pressure and diethyl ether was added to the residue. The resulting precipitate was collected by filtration and 1 N hydrochloric acid was added. The mixture was washed with chloroform. The aqueous solution was basified with 1 N aqueous sodium hydroxide and washed again with chloroform. This alkaline solution was then adjusted with concentrated hydrochloric acid to pH 7.1 under ice-cooling, and the resulting colorless crystals were collected by filtration, washed with water, ethanol and ether and dried. The crystals were then recrystallized from concentrated aqueous ammoniaacethanol to give 283 mg of the title compound 35b as colorless fine needles.

Melting point: 24Q-250 ° C (decomposition) [a] _D -13.6 ° (c = 0.66, 1 N NaOH)

Elemental analysis for ^c i8 ^H 19 ^N 4 ° 3 ^F '^ ^H 2 °

Calc .: C 59.58, H 5.42, N 15.44 Found: C 59.68, H, 5.40, N 15.36

EXAMPLE 14

7- (7-amino-5-azaspiro / 2,4 / heptan-5-yl) -1,4-dihydro-6-fluoro-1- (2-methyl-2-propyl) -4-oxo-1,8- naphthyridine-3carboxylic acid (4lb compound)

200 mg of compound 68b was suspended in 15 ml of acetonitrile, then 3 ml of triethylamine were added and 327 mg of ethyl 7-chloro-1,4-dihydro-6-fluoro-1 (2-methyl-2-propyl) was refluxed in small portions. -4-Oxo-1,8-naphthyridine-3-carboxylate. After refluxing for 1 hour, the solvent was removed under reduced pressure and water was added to the residue. The mixture was extracted with chloroform and n-butanol. The organic layers were combined and the solvents were removed. Diethyl ether was added to the residue and the resulting precipitate was collected by filtration to give 516 mg of colorless powder. ¹ H-NMR (DMSO-d 6) 6:

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 (1H, d, J = 13 Hz),

8.68 (1H, s)

510 mg of the above colorless powder was suspended in 2 ml of water, then 2 ml of 1 N aqueous sodium hydroxide was added and the mixture was refluxed for 40 minutes. 5 ml of water were added to the reaction mixture and the pH was adjusted to 0.25 N hydrochloric acid. The resultant crystals were collected by filtration and washed with water. The crystals were dried and recrystallized from ethanol to give 171 mg of the title compound 41b as a colorless powder.

Tal .; 243-247 ° C (decomposition) [a] _D -16.7 ° (c = 0.504, 1 N NaOH) ¹ H-NMR (DMSO-dg) 5:

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 for C ^H ^H HF F. ^O Calcd · c 59.52, H 6.31, N 14.61 Found: C 59.17, H 6.17, N 14.49

REFERENCE EXAMPLE 5

Synthesis of 2,4,5-trifluoro-3-methylbenzoic acid

1) Dimethyl 3,5,6-trifluoro-4-nitromethylphthalate (Compound 42)

200 g of dimethyl tetrafluoronaphthalate were dissolved in 400 ml of nitromethane (Ishikawa, Suzuki & Tanabe: Nippon Kagaku Kaishi, 1976, 200) and the solution cooled in a bath of ice and salt. At an internal temperature of 15 to 20 ° C, 171 g of 1,8-diazabicyclo / 5,4,0 / -7-undecene were added dropwise over 30 minutes. After complete dropwise addition, the mixture was stirred at an internal temperature of 10 ° C for another 30 minutes and then the mixture was poured into a mixture of 1.5 liters of 1 N hydrochloric acid and 1 liter of ice.

The reaction mixture was extracted with benzene and the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was then removed under reduced pressure and the residue was column chromatographed on silica gel (500 g) eluting with benzene. The process yielded 195 g of the title compound 42 as a yellow oil.

¹ H-NMR (CDCl ₃ ) δ:

3.88 (3H, s), 3.94 (3H, s), 5.60 (2H, t, J = 2 Hz)

2) Dimethyl 4-dimethylaminomethyl-3,5,6-trifluorophthalate (Compound 43)

At atmospheric pressure, a mixture of 5.0 g of compound 42, 20 ml of Raney nickel, 15 ml of 35% formalin and 70 ml of ethanol was reduced for 22 hours.

The catalyst was then filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform and the solution was washed with water and dried over anhydrous sodium sulfate. The solvent was then removed under reduced pressure to give 5.2 g of the title compound 43 as a light yellow oil.

¹ H-NMR (CDCl ₃ ) δ:

2.32 (6H, s), 3.70 (2H, t, J = 2 Hz), 3.96 (3H, s),

3.98 (3H, s)

3) 2,5,6-Trifluoro-3,4-di (methoxycarbonyl) phenylmethylpentimethylammonium iodide (compound 44)

5.2 g of compound 42 was dissolved in 50 ml of ethanol, then 5 ml of methyl iodide was added and the mixture was allowed to stand for 1.5 hours. The resulting crystals were collected by filtration. The process gave 3.6 g of colorless crystals of the title compound 44.

Mp: 186-19 ° C (dec.).

4) Dimethyl 3,5,6-trifluoro-4-methylphthalate (compound 45)

a) A mixture of 4.6 g of compound 42, 6.8 g of tributyl tin hydride, 300 mg oi, <% '- azobisisobutyronitrile and 70 ml of ben was refluxed for 4 hours. The reaction mixture was then finally triturated under reduced pressure and the residue was chromatographed on silica gel (50 g) eluting with benzene. The process yielded 2.45 g of the title compound 45 as a light yellow oil.

b) A mixture of 17.0 g of compound 44. »30 ml of Raney nickel and 350 ml of ethanol were reduced at atmospheric pressure by irradiation with a Tungsten lamp for 25.5 hours.

The catalyst was then filtered off and the filtrate was concentrated under reduced pressure. Water was added to the residue and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was then removed under reduced pressure to give 9.62 g of the title compound 45 as a yellow oil.

¹ H-NMR (CDCl ₃ ) 6:

2.29 (3H, t, J = 2 Hz), 3.91 (3H, s), 3.93 (3H, s)

5) 3,5,6-Trifluoro-4-methylphthalic acid (Compound 46)

A mixture of 2.45 g of compound 45, 10 ml of acetic acid and 20 ml of concentrated hydrochloric acid was refluxed for 12 hours. The reaction mixture was then concentrated under reduced pressure and the residue was extracted with diethyl ether. The extract was dried over anhydrous sodium sulfate. The solvent was then removed under reduced pressure to give 2.1 g of the title compound 46 as colorless crystals.

M.p .: 155-16 ° C

6) 2,4,5-Trifluoro-3-methylbenzoic acid (Compound 47)

10.1 g of compound 46 was dissolved in 40 ml of water and the mixture was heated in a sealed tube at 200 ° C for 4 days. The reaction mixture was then extracted with chloroform and the extract was dried over anhydrous sodium sulfate. Finally, the solvent was removed under reduced pressure to give 6.2 g of the title compound 47 as light yellow crystals.

Mp: 89-90 ° C. ¹ H-NMR (CDCl ₃ ) S:

2.29 (3H, t, J = 2 Hz), 7.56-7.84 (1Η, m),

8.1-8.6 (1H, broad)

REFERENCE EXAMPLE 6

Ethyl 2,4,5-trifluoro-3-methylbenzoyl acetate (compound 48)

9.89 g of 2,4,5-trifluoro-3-methylbenzoic acid 47 were dissolved in 200 ml of benzene, then 40 ml of thionyl chloride was added and the mixture was refluxed for 14 hours. The reaction mixture was then concentrated to dryness under reduced pressure and 200 ml of benzene was added to the residue. The mixture was concentrated again to dryness under reduced pressure and the crude acid chloride obtained was dissolved in 200 ml of diethyl ether.

A mixture of 1.26 g of magnesium, 250 ml of ethanol and 6 ml of carbon tetrachloride was stirred at room temperature for 1 hour and 50 ml of diethyl ether solutions® were added dropwise thereafter. 8.34 g of diethyl malonate. The mixture was then stirred at room temperature for 1 hour. The reaction mixture was then concentrated to dryness under reduced pressure and the residue dissolved in 300 ml of diethyl ether. To this solution was added dropwise over 10 minutes the diethyl ether solution of acid chloride prepared above, and the mixture was stirred at room temperature for 4 days. Then, 100 ml of 1 N hydrochloric acid were added and the ether layer was removed after stirring, washed with water and dried over anhydrous sodium sulfate. The solvent was then removed under reduced pressure. 500 ml of water and 500 mg of p-toluenesulfonic acid were added to the residue and the mixture was refluxed for 7 hours. The reaction mixture was extracted with chloroform, the organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was column chromatographed on silica gel using benzene as eluent. The process gave 6.1 g of the title compound 48 as a colorless oil. Leaving it standing, the oil partially crystallized.

REFERENCE EXAMPLE 7

Ethyl 2-cyclopropylaminomethylene-3-oxo-3- (2,4 _; 5-trifluoro-3-methyl) phenylpropionate (Compound 49)

A mixture of 1.57 g of compound 48, 6 ml of ethyl orthoformate and 6 ml of acetic anhydride was heated at 120 ° C with stirring for one hour. The reaction mixture was then concentrated to dryness under reduced pressure. The residue was dissolved in 25 ml of 1,2-dichloro methane, then 10 ml of solution prepared by dissolving 400 mg of cyclopropylamine in 1,2-dichloromethane were added. The mixture was stirred at room temperature for 14 hours. The reaction mixture was then concentrated to dryness under reduced pressure to give 2 g of the title compound 49 as colorless crystals, which melted at 61 to 64 ° C.

REFERENCE EXAMPLE 8

Ethyl 1-cyclopropyl-6,7-difluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (Compound 50)

1.97 g of compound 49 were dissolved in 30 ml of dry dioxide ·, then 360 mg of 60% sodium hydride was added and the mixture was stirred at room temperature for 18 hours. After the addition of 10 ml of 1 N hydrochloric acid, the reaction mixture was concentrated under reduced pressure and water was added to the residue. The resultant crystals were only collected by filtration and washed with water and small amounts of ethanol and diethyl ether. The process gave 1.35 g of the title compound 50 as colorless crystals.

REFERENCE EXAMPLE 9

1-Cyclopropyl-6,7-difluoro-8-methyl-4-oxo -1,4-dihydroquinoline-3-carboxylic acid (Compound 51)

A mixture of 1.30 g of compound 50 and 10 ml of concentrated hydrochloric acid was refluxed for 3 hours, after which time 50 ml of water were added to the reaction mixture. The resulting crystals were collected by filtration and washed with water and ethanol to give 1.12 g of the title compound 51.

M.p .: 241-242 ° C

REFERENCE EXAMPLE 10

1-Cyclopropyl-6,7-difluoro-8-methyl-4-oxo-1,4-bicarboxylic acid chelate: --- dihydroquinoline-3-carboxylic acid (Compound 52)

420 mg of compound 50 was suspended in 30 ml of diethyl ether, then 2 ml of boron trifluoridadiethyl ether complex was added and the mixture was stirred at room temperature for 24 hours.

The resulting crystals were collected by filtration and washed with diethyl ether. The process gave 487 mg of the title compound 52 as yellow crystals.

Tal. 275-278 ° C.

EXAMPLE 15 (-) - 7- (7-amino-5-azaspiro / 2,3 / heptan-5-yl) -1-cyclopropyl6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3- carboxylic acid (compound 55b)

A mixture of 340 mg of compound 5_2, 330 mg of 7-tert-butoxycarbonylamino-5-azaspiro / 2,3 / heptane (compound 11b), 150 mg of triethylamine and 5 ml of dimethyl sulfoxide was stirred at room temperature for 5 days. The reaction mixture was then dissolved in 100 ml of chloroform and the solution was washed with water. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure.

The residue was column chromatographed on silica gel (30 g) eluting with chloroform-methanol (95: 5). The resulting 7- (7-tert-butoxycarbonylamino-578 azaspiroheptan-5-yl) -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid BF2 ~ chelate was dissolved in 30 ml of 70% methanol, then 1 ml of triethylamine was added and the mixture refluxed for 3 hours.

The reaction mixture was then concentrated under reduced pressure and 20 ml of 10% citric acid was added to the residue. The mixture was extracted with chloroform and the organic layer was dried over anhydrous sodium sulfate. The solvent was then removed under reduced pressure. To the residue was added 10 ml of trifluoroacetic acid and the mixture was stirred at room temperature for 20 minutes and then concentrated to dryness under reduced pressure.

Hydrochloric acid was added to the residue and the mixture was washed with chloroform. After cooling with ice, the aqueous layer was adjusted with aqueous sodium hydroxide to pH 12 and washed with chloroform. The aqueous layer was adjusted to pH 7.4 and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and the solvent removed. The residue was recrystallized twice from aqueous ammonia-ethanol to give 52 mg of the title compound 55b as colorless crystals.

M.p .: 180-182 ° C

[<X] _D -128.0 ° (C = o, 125, 1 N NaOH) ¹ H-NMR (CDCl ₃ ) S: 0.61-0.63 (IH, m), 0,64-0,74 (2H, m), 0,84-0,88 (IH, m), 0,90-0,97 (2H, m), 1,19-1,28 (2H, m), 2.62 (3H, ^S ) z 3,19-3,21 3.29 (1H, d, J = 9 Hz), 3.36 -3.39 (1H, m),

3.84 (IH, d, J = 9 Hz), 3.99 -4.03 (1H, m), 4,05- -4.08 (1H, m), 7.85 (IH, d, J = 13.5 Hz), 8.86 (IH, ^s )

EXAMPLE 16

Optically active 7- / 7- (tert-butoxycarbonylamino) -5azaspiro / 2, H / heptane-6-ylZ-S-chloro-1-cyclopropyl-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (compound 56a and compound 56b)

500 mg of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 440 mg of compound 11b and 2 ml of triethylamine were dissolved in 20 ml of acetonitrile and the solution was refluxed overnight. . After cooling, the solvent was removed under reduced pressure and the resulting precipitate was collected by filtration, washed successively with water, acetonitrile, ethanol and ether and dried under reduced pressure. The process gave 560 mg of the title compound 56b as light yellow crystals. Using compound 11a in the same manner, the title compound 56a was synthesized.

56b; light yellow crystals, m.p. 216-217 ° C [ct] _D -134.7 ° (c = 1.653, chloroform) ¹ H-NMR (CDCl ₃ ) δρρπι:

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, broad _{d) f} 7.95 (1H, d, J = 12.9 Hz), 8.87 (1H, s)

Elemental analysis for C _n .H _nn N _o 0 „ClF with 4 z / J □

Calcd: c 58.60, H 5.53, N 8.54

Found:; c 58.43, H 5.59, N 8.40 56a: light yellow crystals, m.p. 215-216 ° C [a] _D + 131.4 ° (c = 0.77, chloroform)

Elemental analysis for C ₂₄ H ₂₇ N ₃ O ₅ C1F

Calcd: C 58.60, H 5.53, N 8.54

Found .; C, 58.37; H, 5.58; N, 8.44

The NMR spectra of compound 56a were in perfect agreement with that of compound 56b.

EXAMPLE 17

7- (7-Amino-5-azaspiro / 2,4 / heptan-5-yl) 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid optically active (Compound 32a and the compound

32b)

0.5 ml of anisole and 10 ml of trifluoroacetic acid were added under ice-cooling to 520 mg of compound 56b. The mixture was then stirred at room temperature for 30 minutes. The solvent was then removed under reduced pressure and water was added to the residue.

The mixture was adjusted to pH about 11-12 with 1 N aqueous sodium hydroxide while cooling with ice. This aqueous solution was washed twice with chloroform and adjusted to about pH 7 with concentrated hydrochloric acid and 10% citric acid. This solution was extracted 3 times with chloroform and the extract was washed with water and dried. The solvent was then removed under reduced pressure and the solid was recrystallized from ethanol-aqueous ammonia to give 328 mg of the title compound 32b as light yellow crystals. Similarly, from compound 56a, compound 32a was prepared.

Compound 32b; light yellow crystals Melting point: 166-170 ° C (decomposition) [<x] _D -112.6 ° (c = 0.43, 1 N aqueous NaOH) 1 H-NMR (CDCl ₃ , 500 MHz) Sppm:

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: C18H4N4O4ClF4H3O3 Izra ... c 56.93, H 5.03, N 10.48

Found: C 57.16, H 5.44, N 10.46 compound. 32a: light yellow crystals

M.p .: 160-165 ° C (decomposition) [α] _β + 110.3 ° (c = 0.435, 1 N aqueous NaOH)

Elemental analysis for ^c i9 ^H i9 ^N 3 ° 3 ^ClF · ^ ^Η 2 °

Calc .; c 56.93, H 5.03, N 10.48 Found: C 56.87, H 5.37, N 10.32

The NMR spectra of compound 32a were in perfect agreement with that of compound 32b.

REFERENCE EXAMPLE 11

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

Tal. ·. 245-260 ° C (decomposition)

Elemental analysis for

Calc .: C 44.94, Found: C 45.07, c ₁₃ h ₇ no ₃ bcif ₄ H 2.03, N 4.03 H 2.21, N 4.12

EXAMPLE 18 (-) - 7- (7-amino-5-azaspiro / 2,4 / heptan-5-yl) -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxyl acid (compound 32a)

A mixture of 700 mg of compound 57, 450 mg of 7-amino-5-azaspiro / 2,4 / heptane dihydrochloride J, compound 68b), 610 mg of triethylamine and 7 ml of dimethyl sulfoxide was stirred at room temperature for 24 hours. Water was added to the mixture and the yellow precipitate was collected by filtration and dried. 50 ml of 95% methanol and 1 ml of triethylamine were added to the precipitate. The mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and 1 N hydrochloric acid was added to the residue. The mixture was washed with chloroform and the aqueous layer basified with 1 N aqueous sodium hydroxide. The aqueous layer was washed again with chloroform. The pH of the alkaline aqueous solution was adjusted to pH 7.1 with cooling with concentrated hydrochloric acid. The aqueous solution was extracted three times with chloroform. The extract was washed with saturated aqueous sodium chloride and dried. The solvent was removed under reduced pressure. The residue was recrystallized from concentrated ammonia, water and ethanol to give 610 mg of the title compound 32a as a colorless cryst.

REFERENCE EXAMPLE 12

Alternative synthesis of 4,7-dioxo-5- / 1- (R) -phenylethyl / -5-azaspiro / 2,4 / heptane 12

1) 1-Acetylcyclopropane-1-carboxylic acid (Compound 58)

To a solution of 268.6 g of compound 2 in 400 ml of ethanol was added dropwise at room temperature for 20 minutes an aqueous solution of 75.67 g of sodium hydroxide in 200 ml of water. The mixture was stirred at room temperature for 2 hours. 1500 ml of dichloromethane and 500 ml of water were added to the mixture. The mixture was shaken and then the aqueous layer was separated. The aqueous layer was washed with two 500 ml portions of dichloromethane. The aqueous layer was adjusted to pH 2 with concentrated hydrochloric acid while cooling and the mixture was extracted with 1500 ml of dichloromethane. The aqueous layer was extracted with 500 ml of dichloromethane and the extracts were combined. The combined organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was distilled under reduced pressure to give 232 g of the title compound 58 as a colorless oil.

¹ H-NMR (CDCl ₃ ) δppm:

1.6-2.0 (4H, m), 2.21 (3H, s)

2) N- / 1- (R) -phenylethyl / -1-acetyl-1-cyclopropanecarboxamide (compound 59)

A solution of 232 g of compound 58, 1500 ml of chloroform and 250.8 ml of triethylamine was cooled in a dry ice-acetone bath to an internal temperature of -40 ° C. 215.9 g of ethyl chloroformate were added dropwise over 20 minutes.

The mixture was stirred while cooling, maintaining the internal temperature at about -30 ° C for 40 minutes. The mixture was cooled to an internal temperature of -40 ° C and 241.1 g of R - (+) 1-phenylethylamine were added to the mixture. The mixture was stirred for 1.5 hours. The mixture was washed with 1 N hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and water. The chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 489.3 g of the title compound 59 as a colorless oil.

¹ H-NMR (CDCl ₃ ) δppm:

1.50 (3H, d, J = 7.2 Hz), 1.4-1.6 & 1.7-1.9 (2H each, m), 1.95 (3H, s), 5.10 (1H, q, J = 7.2 Hz),

7.30 (5H, s)

3) N- / 1- (R) -phenylethyl / -1- (1,1-ethylenedioxyethyl) 1-cyclopropanecarboxamide (compound 60)

A mixture of 248.4 g of compound 59, 800 ml of benzene, 230 ml of ethylene glycol and 10.0 g of p-toluenesulfonic acid monohydrate was refluxed for 24 hours. The water formed during the reaction was removed. After cooling, 500 ml of water and 500 ml of benzene were added to the mixture. The mixture was then shaken. The organic layer was separated and washed with saturated aqueous sodium bicarbonate solution and water. The organic layer was dried over anhydrous sodium sulfate and the solvent removed under reduced pressure to give 227.8 g of the title compound 60.

1 H-NMR (CDCl ₃ ) Sppm:

0.7-0.95 & 1.0-1.2 (2H each, m), 1.48 (3H, s),

1.47 (3H, d, J = 7.2 Hz), 3.98 (4H, S) r 5.11 (IH, q, J - 7.2 Hz), 7.31 (5H, S), 7.75 (IH, width .s)

4) N- / 1- (R) -phenylethyl / -1- (2-bromo-1,1-ethylenedioxyethyl) -1-cyclopropane-carboxamide (compound 61)

145.4 g of bromine was added dropwise to 436 ml of dioxane at room temperature for 30 minutes. The mixture was stirred at room temperature for 30 minutes and a solution of 227.8 g of compound 60 in 2000 ml of dichloromethane was added to the mixture. The mixture was stirred at room temperature for 2 hours. The mixture was washed with aqueous sodium thiosulphate solution and water. The organic layer was dried over anhydrous sodium sulfate and the solvent removed under reduced pressure to give 326.0 g of the title compound 61.

- 86 ¹ H-NMR (CDCl ₃ ) Sppm:

0.7-1.0 & 1.0-1.25 (2H each, m),

1.49 (3H, d, J = 7.2 Hz), 3.69 (2H, s),

3.8-4.3 (4H, m), 5.08 (1H, q, J = 7.2 Hz),

7.30 (5H, s), 7.6 (1H, broad _S )

5) 4,7-dioxo-5- / 1- (R) -phenylethyl-5-azaspiro / 2,4 / heptane-7-ethylene acetal (compound 62) g of 60% sodium hydride was added at room temperature in run for 1.5 hours in three portions to a solution of 293 g of compound 61 in 1500 ml of N, N-dimethylformamide. While the sodium hydride was added, the mixture was cooled to maintain the internal temperature at about 30 ° C. The mixture was stirred at room temperature for 18 hours. The mixture was poured into ice and extracted with ethyl acetate. The organic layer was separated and washed with water. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 203.3 g of the title compound 62 as a dark oil.

1 H-NMR (CDCl ₃ ) Sppm:

0.98-1.38 (4H, m), 1.50 (3H, d, J = 7.2 Hz),

3.07 & 3.41 (1H each _, d, J = 10.2 Hz),

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 (Compound 12)

A mixture of 203.3 g of compound 62, 300 ml of 1 N hydrochloric acid and 1000 ml of acetone was refluxed for 1.5 hours. The solvent was then removed under reduced pressure and the residue was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The extract was decolourised with activated charcoal and the solvent removed under reduced pressure. The residue was purified by silica gel column chromatography (1300 g) eluting with chloroform containing 0-10% ethyl acetate to give 65.7 g of the title compound 12 as a colorless crystal.

1 H-NMR (CDCl ₃ ) δ ppm:

1.61 (3H, d, J = 7.2 Hz), 1.4-1.75 (4H, m),

3.48 & 3.88 (1H each, j = 17.7 Hz),

5.81 (1H, q, J = 7.2 Hz), 7.34 (5H, s)

REFERENCE EXAMPLE 13

Synthesis of 5-tert-butoxycarbonyl-7-hydroxyimino-5azaspiro / 2,4 / heptane (compound 67)

1) 7,7-Ethylenedioxy-5- / 1- (R) -phenylethylZ-5-azaspiro / 2,4 / heptane (Compound 63)

2.5 g of lithium aluminum hydride were added to a solution of 7.1 g of compound 62 in 150 ml of anhydrous tetrahydrofuran and the mixture refluxed for 3.5 hours. The mixture was cooled with ice and 2.5 ml of water, 2.5 ml of 15% aqueous sodium hydroxide solution and 7.5 ml of water respectively were added to the mixture.

The insoluble material was removed by filtration and the solvent was removed from the filtrate. The residue was purified by silica gel column chromatography (100 g) eluting with a mixture of n-hexane and ethyl acetate (3: 2) to give 5.67 g of the title compound 63 · ¹ H-NMR (CDC1 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, ra),

3.77 (4H, s), 7.18-7.50 (5H, m) '

2) 7,7-Ethylenedioxy-5-azaspiro / 2,4 / heptane (Compound 64)

A mixture of 3.89 g of compound 63, 50 ml of ethanol and 4 g of 5% palladium on charcoal was shaken under a hydrogen atmosphere of 3.9 bar. During the reduction reaction, the reaction vessel was heated from the outside with a tungsten lamp. The reduction reaction was continued for 3 hours. The catalyst was removed by filtration. The solvent was removed from the filtrate under reduced pressure to give 2 g of the title compound 64.

¹ H-NMR (CDCl ₃ ) δ ppm:

0.44-0.64 (2H, ra), 0.72-0.92 (2H, m),

3.03 & 3.05 (2H each, s), 3.86 (4H, s)

3) 5-tert-butoxycarbonyl-7,7-ethylenedioxy-5-azaspiro / 2,4 / heptane (Compound 65)

1.515 g of triethylamine and 3.05 g of di-tert-butyl dicarbonate were added to an ice-cooled solution of 1.98 g of compound

64 in 25 ml of anhydrous dichloromethane. The mixture was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure. The residue was extracted with chloroform and the extract was washed with water. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (50 g) eluting with a mixture of nhexane and ethyl acetate (3 *. 1) to give 3.21 g of the title compound 65.

4) 5-tert-butoxycarbonyl-7-oxo-5-azaspiro / 2,4 / heptane (Compound 66)

A mixture of 3.15 g of compound 65, 30 ml of acetone and 5 ml of 1 N hydrochloric acid was refluxed for 30 minutes. The solvent was removed under reduced pressure. The residue was extracted with chloroform and the extract was dried. The solvent was removed under reduced pressure to give 1.94 g of the title compound

66.

¹ H-NMR. (CDCl ₃ ) Sppm:

1.00-1.20 & 1.30-1.50 (2H each, m), 4.49 (9H, s),

3.78 (2H, m), 3.95 (2H, s)

5) 5-tert-butoxycarbonyl-7-hydroxyimino-5-azaspiro / 2,4 / heptane (Compound 67)

1.25 g of hydroxylamine hydrochloride and 1.8 g of triethylamine were added to a solution of 1.9 g of compound 66. The mixture was stirred at room temperature for 1 day. The solvent was removed under reduced pressure and a 10% aqueous citric acid solution was added to the residue. The mixture was extracted with chloroform and the extract was washed with water. The extract was dried and the solvent removed under reduced pressure to give 1.86 g of the title compound

67.

M.p .: 117-119 ° C. ¹ H-NMR (CDCl ₃ ) δppm:

0.90-1.10 & 1.14-1.34 (2H each, m), 1.45 (9H, s),

3.36 (2H, s), 4.29 (2H, s)

REFERENCE EXAMPLE 14

7-amino-5-azaspiro / 2,4 / heptane dihydrochloride (compound 68b)

A mixture of 630 mg of compound 15b, 10 ml of 1 N hydrochloric acid, 20 ml of ethanol and 800 mg of 5% palladium on charcoal was shaken under a nitrogen atmosphere of 3.9 bar. During the reduction reaction, the reaction vessel was heated from the outside with a tungsten lamp. The reduction reaction was continued for 3.5 hours. The catalyst was removed by filtration and the solvent removed to give 350 mg of the title compound 68b.

[a] _D -41.5 ° (c = 1.616, H ₂ O)

Mp .: 230-240 (dec., Decomposition began at ca.

190 ° C)

Elemental analysis for CgH ^ NjClj · ^ HjO

Calcd: 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 (D ₂ O) δ ppm:

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)

REFERENCE EXAMPLE 15

7-tert-butoxycarbonylamino-5-azaspiro / 2,4 / heptane (compound 11b)

A mixture of 11.8 g of compound 16b, 200 ml of ethanol and 11 g of 5% palladium on charcoal was shaken under a hydrogen atmosphere of 3.9 bar. During the reduction reaction, the reaction vessel was heated with a tungsten lamp. The reduction reaction was performed for 6 hours. The catalyst was removed by filtration and the solvent was removed from the filtrate under reduced pressure. The residue was dissolved in ethyl acetate and the solution was extracted with 10% aqueous citric acid. The aqueous layer was washed with ethyl acetate. The aqueous layer was basified with aqueous sodium hydroxide solution and extracted with chloroform. The extract was dried and the solvent removed under reduced pressure to give 7.6 g of the title compound 11b.

M.p .: 56-59 ° C [a] _D -68.54 ° (c = 1.742, CHC1 ₃ )

REFERENCE EXAMPLE 16

1) Diethyl cyclobutylidene malonate (Compound 70)

A solution of 15.68 ml of titanium tetrachloride in 35.7 ml of carbon tetrachloride was quickly added dropwise to 285 ml of tetrahydrofuran, which was cooled to -30 ° C. 5 g of cyclobutanone and 10.83 g of diethyl malonate were added to the mixture. A solution of 23.1 ml of pyridine in 50 ml of tetrahydrofuran was then added dropwise over 1 hour, maintaining the temperature of the reaction mixture below -10 ° C. The mixture was stirred for 18 hours, maintaining the temperature of the mixture at 0 ° C. Water was added to the mixture and the mixture was extracted with diethyl ether. The ether layer was separated and the aqueous layer was extracted with diethyl ether. The combined organic layers were washed with saturated aqueous sodium chloride solution, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 17.265 g of the title compound 70 as a colorless oil.

¹ H-NMR (CDCl ₃ ) Sppm:

1.29 (6H, 6, J = 7.3 Hz), 1.7-2.4 (2H, m),

3.15 (4H, t, J = _7? 7 Hz), 4.22 (4H, q, J = 7.3 Hz)

A similar procedure gave diethyl cyclopentylidene malonate {compound 7 1) (1 H-NMR (CDCl ₃ ) Sppm:

1.29 (6H, t, J = 7 Hz), 1.6-2.0 (4H, m), 2.6-2.8 (4H, m),

4.24 (4H, q, J = 7 Hz)) and diethyl cyclohexylidene malonate '(compound 72) (1 H-NMR (CDCl ₃ ) Sppm: 1.28 (6H, t.

J = 7.2 Hz), 1.4-1.85 (6H, broad), 2.3-2.6 (4H, broad>), 4.22 (4H, q, J = 7.2 Hz) )).

2) Diethyl (1-nitromethyl-1-cyclobutyl) malonate (compound 73)

A mixture of 15.32 g of compound 70, 59 ml of nitromethane and

4.5 ml of tetramethylguanidine was stirred at room temperature for hours. A 10% citric acid aqueous solution was added to the mixture and the mixture was shaken. The organic layer was separated and washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 19.03 g of the title compound 73 as a yellow oil.

¹ H-NMR (CDCl ₃ ) Sppm:

1.28 (6H, t, J = 7.1 Hz), 1.8-2.4 (6H, m),

3.80 (1H, s), 4.20 (4H, q, J = 7.1 Hz), 4.82 (2H, s)

Diethyl (1-nitr or methyl-1-cyclopentyl) malonate (compound 74) ( ¹ H-NMR (CDCl ₃ )) Sppm: 1.27 (6H, t, J = 7 Hz), 1.6 -2.0 (8H, m),

3.79 (1H, s), 4.20 (4H, q, J = 7 Hz), 4.71 (2H, s)) _and diethyl (1-nitromethyl-1-cyclohexyl) malonate (compound 75) ( ¹ H-NMR (CDCl ₃ ) Sppm: 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 ) b

3) Ethyl 7-oxo-6-azaspiro / 3,4 / octane-8-carboxylate (compound 76) ml of Raney nickel, washed with water and ethanol, was added to a solution of 19.03 g of compound 73 in 400 ml of ethanol. The catalytic reduction was carried out for 2 days. The catalyst was removed by filtration and the solvent removed under reduced pressure. Ethyl acetate and 1 N hydrochloric acid were added to the residue and the mixture was shaken. The organic layer was dried over anhydrous sodium sulfate and the solvent removed under reduced pressure. The residue was purified by silica gel column chromatography (100 g) eluting with

- 9.4 chloroform containing 0-3% methanol to give 2.97 g of the title compound 76. The hydrochloric acid layer was neutralized with sodium bicarbonate and the mixture extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent removed under reduced pressure to give 1.58 g of the title compound 76. Finally, a total of 4.56 g of the title compound 76 was obtained.

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, dd, 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, sir)

A similar procedure yielded ethyl 3-oxo-2azaspiro / 4.4 / nonane-4-carboxylate (compound 77) ( ¹ H-NMR (CDCl ₃ ) 6ppm: 1.28 (3H, t, J = 7.3 Hz ), 2.6-2.8 (8H, broad),

3.07 (1H, s), 3.01 (1H, dd, J = 9.3 & 1.3 Hz), 3.45 (1H, d, J = 9.3 Hz), 4.20 (2H , q, J = 7.3 Hz), 7.30 (IH, cheese. ")) and ethyl 3-oxo-2-azaspiro / 4,5 / decan-4-karbosilat (.spojina 78) ⁽¹ H- NMR (CDCl ₃ ) Sppm: 1.29 (3H, t, J =

7.3 Hz), 1.3-1.7 (10H, broad), 3.05 (1H, s), 3.17 (1H, dd, J = 9.9 & 1.4 Hz), 4, 20 (2H, q, J = 7.3 Hz), 7.30 (1H, sir)),

4) 7-Oxo-6-azaspiro / 3,4 / octane-8-carboxylic acid (compound 79) ml of water and 0.8 g of sodium hydroxide were added to a solution of 1.97 g of compound 76 in 20 ml of ethanol. The mixture was refluxed for 2 hours. The ethanol was removed under reduced pressure and the aqueous layer was washed with chloroform. The aqueous layer was neutralized by cooling with ice with 1 N hydrochloric acid. The aqueous layer was extracted with 2-butanone and the extract was dried over anhydrous magnesium sulfate. The solvent was removed to give 1.57 g of the title compound 79 as colorless crystals of ¹ H-NMR (CDCl ₃ ) 8 ppm:

1.6-2.7 (6H, m), 3.15 (1H, s),

3.40 (1H, d, J = 9.2 Hz), 3.60 (1H, d, J = 9.2 Hz),

6.2 (1H, broad ^

A similar procedure gave 3-oxo-2-azaspiro / 4,4 / nonan-4-carboxylic acid (Compound 80) (H-NMR (CDCl ₃ ) 6ppm: 1.5-2.3 (8H, m). 3.15 (1H, d, J = 9.5 Hz),

3.28 (1H, s), 3.33 (1H, d, J = 9.5 Hz), 6.45 (1H, broad>) and 3-oxo-2-azaspiro / 4.5 / decane-4 -carboxylic acid (Compound 81) (1 H-NMR (CDCl ₃ ) 5 ppm: 1.2-2.0 (10H, m),

3.06 (1H, s), 3.11 (1H, d, J = 9.8 Hz), 3.48 (1H, d,

J = 9.8 Hz), 6.47 (1H, broad)),

5) 8-tert-butoxycarbonylamino-7-oxo-6-azaspiro / 3,4 / octane (Compound 82)

2.2 ml of diphenyl phosphorylase and 1.55 ml of triethylamine were added while stirring to a suspension of 1.57 g of compound 79 in 20 ml of benzene. The mixture was refluxed for 1.5 hours. Then 4.4 ml of tert-butanol were added to the mixture and the mixture was refluxed for 16 hours. The solvent was removed under reduced pressure. The residue was extracted with ethyl acetate and the extract was washed with saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution, 10% aqueous citric acid solution and saturated aqueous sodium chloride solution. The wash liquids were extracted with ethyl acetate and the combined extracts were dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (50 g) eluting with chloroform containing 0-3% methanol to give 0.56 g of the title compound 82.

H-NMR (CDC1 ₃₎ Sppm: • 1.48 (9H, S) r 1, 5-2.5 (6H, m), 3.27 (IH, d, J = 9.9 Hz), 3,44 (1H, d, J = 9.9 Hz) 4,18 (IH, d, J = 7.7 Hz), 5.20 (IH, d, J = 7.7 Hz) 7.13 (IH, lat. s)

In a similar procedure was obtained 4-tert-butoxycarbonylamino-3-oxo-2-azaspiro / 4,4 / nonane (compound 83) ^(X 'H-NMR (CDC1 ₃₎ SPPM: 1.45 (9H, s), 1.2-1.8 (8H, m),

3.13 (2H, s), 4.35 (1H, d, J = 7.9 Hz), 5.15 (1H, d;

J = 7.9 Hz), 7.21 (1H, broad s)) and 4-tert-butoxycarbonyl-1 amino-3-oxo-2-azaspiro / 4.5 / decane (compound 84) (H- NMR (CDCl ₃ ) Sppm: 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, broad s)).

- 97 6) 6-tert-butoxycarbonyl-8-ter c. -butoxycarbonylamino-6azaspiro / 3,4 / octane (compound 87) ml of trifluoroacetic acid was added while stirring to 560 mg of ice-cooled compound 82. The mixture was then stirred at room temperature for 1.5 hours. The trifluoroacetic acid was removed under reduced pressure and the residue dissolved in 30 ml of anhydrous tetrahydrofuran. The solution was cooled with ice and 884 mg of lithium aluminum hydride was added to the mixture. The mixture was refluxed for 16 hours. The mixture was cooled with ice and water was added while stirring. The insoluble material was removed by filtration and washed with tetrahydrofuran. The filtrate and washings were combined and 1.02 g of di-tert-butyl dicarbonate were added. The mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (50 g) eluting with a mixture of ethyl acetate and n-hexane (1:10) to give 273 mg of the title compound 87.

¹ H-NMR (CDCl ₃ ) δρριη:

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, lat d)

A similar process gave 2-tert-butoxycarbonyl 1-4-tert-butoxycarbonylamino-2-azaspiro / 4,4 / nonane (compound 90) ( ¹ H-NMR (CDCl ₃ ) Sppm: 1.45 (18H, s ), 1.3-1.8 (8K, m), 3.0-3.3 (3H, m), 3.4-3.7 (1H, m),

3) 7-4,1 (1H, m), 4,55 (1H, broad d) j and 2-tert-butoxycarbonyl-4-tert-butoxycarbonylamino-2-azaspiro / 4,5 / decane ( Compound 93) ( ¹ H-NMR (CDCl 3) Sppm: 1.0-1.9 (28H, m), 2.9-4.1 (5H, m), 4.51 (1H, broad d)) .

- 98 EXAMPLE 19

7- (8-Amino-6-azaspiro / 3,4 / octan-6-yl) -1-cyclopropyl6,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Compound 94)

2.7 ml of trifluoroacetic acid were added while stirring to 173 mg of ice-cooled compound 87 · Trifluoroacetic acid was removed under reduced pressure. The residue was dissolved in 10 ml of acetonitrile and 100 mg of 1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and 0.98 ml of triethylamine were added to the solution. The mixture was refluxed for 16 hours. The solvent was removed under reduced pressure. Diethyl ether was added to the residue. A precipitate formed during cooling. The precipitate was collected by filtration and recrystallized from ethanol and ammonia water to give 125 mg of the title compound 94.

M.p .: 260-263 ° C

Elemental analysis for C 20 ^H 21 ^N 3 ° 3 ^F 2 Calc .: C 58.19, H 5.76, N 10.18

Found: C 58.10, H 5., 38, N 10.13 ¹ H-NMR (0.1 N NaOD-D ₂ O) 8 ppm:

1.05 (2H, bs), 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 Hz),

8.41 (1H, s)

By a similar procedure, 7- (4-amino-2azaspiro / 4,4 / nonan-2-yl) -1-cyclopropyl-6,8-difluoro-499 oxo-N, 4- dihydroquinoline-3-carboxylic acid was obtained (compound 95) and 7- (H-amino-2-azaspiro / 4,5 / decan-2-yl) -1-cyclopropyl "

6,8-Difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Compound 96).

7- (4-amino-2-α-aspiro / 4,4 / nonan-2-yl) -1-cyclopropyl-6,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 95: m.p. : 249-253 ° C

Elemental analysis for ^c 2i ^H 23 ^N 3 ° 3 ^F 2 * ⁰ .7H ₂ O Calc .: C 60.63, H 5.91, N 10.10 Found: C 60.63, H 5.69, N 9.94 ¹ H-NMR (0.1 N Na0D-D ₂ 0) δρρπι:

1.00 (2H, Width s), 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)

7- (4-Amino-2-azaspiro / 4,5 / decan-2-yl) -1-cyclopropyl-6,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 96 Mp. : 247-274 ° C

Elemental analysis for ^C 22 ^H 25 ^N 3 ° 3 ^F 2 Calc .: C 63.30, H 6.04, N 10.07 Found: C 63.14, H 6.08, N 10.02 ^L H- NMR (0.1 N NaOD-D ₂ O) δ ppm:

1.00 (2H, Width s), 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)

- 100 EXAMPLE 20

10- (8-amino-6-azaspiro / 3,4 / octan-6-yl) -9-fluoro-2,3-dihydro-3- (S) -methyl-7-oxo-7H-pyrido / 1,2, 3-de // 1,4 / ~ benzoxazine-6-carboxylic acid (compound 98)

A mixture of 120 mg of compound 87 in 2 ml of trifluoroacetic acid was stirred at room temperature for 2 hours and then the trifluoroacetic acid was removed under reduced pressure. To the residue was added 85 mg of 9,10-difluoro-2,3-dihydro-3- (S) -methyl 7-oxo-7H-pyrido / 1,2,3-de // 1,4 / benzoxazine BF ^ -kelate -6-carboxylic acid, 15 ml of dimethyl sulfoxide and 1 ml of triethylamine. The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. 20 ml of 95% methanol and 1.2 ml of triethylamine were added to the mixture and the mixture was refluxed for 5 hours. The solvent was removed under reduced pressure and diethyl ether was added to the residue. The resulting crystalline product was collected by filtration and recrystallized from ammonia water and eta nol to give 50 mg of the title compound 98.

Tal- .; 229-231 ° C

Elemental analysis for ^C 20 ^H 22 ^N 3 ° 4 ^F ' ^3sH 2 ^O Calc. C 57.96, H 6.08, N 10.14

Found: C 57.66, H 5.84, N 10.24 ¹ H-NMR (0.1 N NaOD-D ₂ O) δρρπι:

1.28 (3H, s), 1.60-1.82 (5H, m), 1.95-2.04 (1H, m), 2.95-3.02 (1H, m), 3. 08-3.17 (1H, m),

3.34-3.46 (1H, m), 3.58-3.70 (2H, m),

4.00-4.08 (1H, m), 4.18-4.24 (1H, m),

4.29-4.36 (1H, m), 7.18 (1H, d, J = 19.5 Hz),

8.13 (1H, s)

1

REFERENCE EXAMPLE 17

1) Tert-butyl 7-oxo-6-azaspiro / 3,4 / octane-8-carboxylate (compound 99) g of compound 79 was dissolved in 30 ml of tert-butanol during stirring. 2.8 ml of diphenyl phosphorylazide and 1.97 ml of triethylamine were added to the solution and the mixture was refluxed for 16 hours. The solvent was removed under reduced pressure. The residue was extracted with ethyl acetate and the extract was washed with saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution, 10% citric acid aqueous solution and saturated aqueous sodium chloride solution. The wash liquids were extracted with ethyl acetate and the extracts were washed in the same manner. The organic layer was dried over anhydrous sodium sulfate and the solvent removed under reduced pressure. The residue was purified by silica gel column chromatography (75 g) eluting with chloroform containing 0 to 2% methanol to give 1.97 g of the title compound 99.

¹ H-NMR (CDCl ₃ ) Sppm:

1.46 (9H, s), 1.7-2.4 (6H, m), 3.09 (1H, s),

3.41 (1H, d, J = 10 Hz), 3.62 (1H, d, J = 10 Hz),

6.90 (1H, broad)

A similar process gave tert-butyl 3-oxo-2-azaspiro / 4,4 / nonane-4-carboxylate (compound 100) (H-NMR (CDCl ₃ ) Sppm: 1.47 (9H, s), 1.70 (8H, broad _S ), 2.98 (1H, s), 3.10 (1H, d, J = 9.7 Hz), 3.43 (1H, d, J = 9.7 Hz),

7.50 (1H, broad s) in-tert-butyl 3-oxo-2-azaspiro / 4,5 / 102 decane-4-carboxylate (compound 101) ( ¹ H-NMR (CDCl 2)) Sppm:

1.45 (19H, broad s), 2.93 (1H, s), 3.13 (1H, d, J = 11Hz),

3.32 (1H, d, J = 11 Hz), 6.90 (1H, bs)

2) 6-tert-butoxycarbonyl-8-hydroxymethyl-6-azaspiro / 3,4 / octane (compound 103) ml of ice-cooled trifluoroacetic acid was added to 1.94 g of ice-cooled compound while stirring. 22 · The mixture was stirred at room temperature for 1 hour and the trifluoroacetic acid was removed under reduced pressure. The residue was dissolved in 100 ml of anhydrous tetrahydrofuran and the solution was cooled in an ice bath. 3.11 g of lithium aluminum hydride were slowly added to the solution and the mixture was refluxed for 18 hours. The mixture was cooled with ice and 10 ml of water was slowly added to the solution. The mixture was stirred at room temperature for 30 minutes. The insoluble material was removed by filtration and washed with tetrahydrofuran. The combined filtrate and washings were condensed under reduced pressure to a volume of about 50 ml. Diethyl tert-butyl dicarbonate was added to the solution and the mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (150 g) eluting with a mixture of nhexane and ethyl acetate (3: 2) to give 420 mg of the title compound 103.

¹ H-NMR (CDCl ₃ ) δppm:

1.46 (9H, s), 1.7-2.3 (8H, m), 3.2-3.9 (5H, m)

103 In a similar procedure, 2-tert-butoxycarbonyl-4-hydroxymethyl-2-azaspiro / 4,4 / nonane (Compound 105) ( ¹ H-NMR (CDCl ₃ <5ppm: 1.46 (9H, s)) was obtained , 1.61 (8H, s), 3.0-3.9 (7H, m)) and 2-tert-butoxycarbonyl-4-hydroxymethyl-2-azaspiro / 4.5 / decane (Compound 107) ( ¹ H-NMR (CDCl ₃ )? 5 ppm: 1.46 (9H, s), 1.1-1.7 (10H, m), 3.0-3.8 (5H, m)).

EXAMPLE 21

1-Cyclopropyl-6,8-difluoro-7- (8-hydroxymethyl-6-azaspiro / 3,4 / octan-6-yl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Compound 108)

2.7 ml of ice-cooled trifluoroacetic acid was added dropwise while stirring to 120 mg of ice-cooled compound 103. The mixture was stirred at room temperature for 1 hour. Trifluoroacetic acid was removed under reduced pressure. The residue was dissolved in 10 ml of acetonitrile and 100 mg of 1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and 0.22 ml of triethylamine were added to the solution. The mixture was refluxed for 18 hours. The solvent was removed under reduced pressure and concentrated hydrochloric acid and chloroform were added to the residue. The mixture was shaken and the aqueous layer separated. The aqueous layer was washed with chloroform and the chloroform washes were extracted with a small amount of concentrated hydrochloric acid. The combined aqueous layers were cooled with ice and the pH was adjusted with sodium hydroxide to above 13-

104 washed with chloroform. The aqueous layer was then adjusted to pH 7.4 with concentrated hydrochloric acid and saturated sodium bicarbonate solution. The aqueous layer was extracted with chloroform and the extract was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was recrystallized from ethanol and ammonia water to give 52 mg of the title compound 108 as yellow needles. Tal. _; 273-274 ° C

Elemental analysis for ^c 2i ^H 22 ^N 2 ° 4 ^F 2 Calc.: C 62.37, H 5.48, N 6.93 Found: C 62.31, H 5.39, N 6.96 H-NMR (CDCl ₃ ) Sppm: 1.11-1.31 (4H, m), 1.89-2.31 (7H, m), 3.63-3.99 (7H, m), 8.62 (1H, s) 7.75 (1H, dd, J = 13.5

In a similar procedure, 1-cyclopropyl-6,8-difluoro-7- (4-hydroxymethyl-2-azaspiro / 4,4 / nonan-2-yl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid was obtained ( compound 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 (compound 110).

1-Cyclopropyl-6,8-difluoro-7- (4-hydroxymethyl-2-azaspiro / 4,4 / nonan-2-yl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Compound 109) :

M.p .: 249-252 ° C

105 -

Elemental an aliza for. C 22 ^H 24 ^N 2 ° 4 ^F 2 Calculated ·: C 63.15, H 5 , 78, N 6.70 Found: C 62.74, H 5 76, N 6.46 H-NMR (CDCl3) 5 ppm: 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

1-Cyclopropyl-6,8-difluoro-7- (4-hydroxymethyl-2-azaspiro / 4,5 / decan-2-yl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Compound 110) :

M.p .: 231-234 ° C

Elemental analysis for

Calculated ·: C 62.58 , H 6.17, N 6, 35 Found. : C 62.92 , H 6.17, N 6, 25 H-NMR (CDC1 ₃₎ δ ppm: 1,13-1,18 (2H, i m), 1,24-; L, 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

REFERENCE EXAMPLE 18

Synthesis of 7-acetoxy-5-azaspiro / 2,4 / heptane (Compound 69)

A suspension of 1.5 g of compound 12 and 500 mg of lithium aluminum hydride in 30 ml of tetrahydrofuran was refluxed for 16 hours. 0.5 ml of water, 0.5 ml of 15% aqueous sodium hydroxide and 1.5 ml of water in this order were added to the mixture and the mixture was stirred at room temperature for 30 minutes. The insoluble material was removed by filtration and the filtrate was concentrated to

106 dry to give 1.4 g of 7-hydroxy-5- / 1- (R) -phenylethyl / -5azaspiro / 2,4 / heptane as a pale yellow oil. 5 ml of acetic anhydride and 5 ml of pyridine were added to 1.4 g of 7-hydroxy-5- / 1- (R) -phenylethyl / -5-azaspiro / 2,4 / heptane, which was cooled in an ice bath. The mixture was stirred at room temperature for 3 hours. Ethyl acetate was added thereto, and the solution was washed with saturated aqueous sodium bicarbonate and water, then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 1.6 g of 7-acetoxy-5- / 1- (R) -phenylethyl / -5-azaspiro / 2,4 / heptane as a yellow oil. A mixture of 1.6 g of 7-acetoxy-5- / 1- (R) -phenylethyl / -5-azaspiro / 2.4 / heptane and 1.2 g of palladium on charcoal (moistened with 50% water) in 20 ml of ethanol was obtained. shook under hydrogen pressure 3.7 bar for 5 hours. During the reduction reaction, the reaction vessel was heated with a tungsten lamp. The catalyst was removed by filtration and the solvent removed under reduced pressure to give 880 mg of the title compound 69 as an oil.

In addition to the above compounds, the following compounds were synthesized. Physical data of the relevant compounds are also provided.

1: (-) - 7- / 7- (S) -amino-5-azaspiro / 2,3 / heptan-5-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxyl acid 33b, melting point: 259-26l ° 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-carboxylate 111b, melting point: 232-235 ° C, / 0C / _D -20.54 ° (c = 0.73, CHC1).

107

Table: Antibacterial activity (MIC, pg / ml)

108

Table: Antibacterial activity (-MIC, pg / ml)

109

CH3COCH2COOEt

CH3COCCOOEt

A

BrCHžCOCCOOEt

A '3

0 <n>

with, NaOH oO

CH2Ph

GH2Ph

5-0 <AnHCO ^ N ²

CH2Ph

O / NH2

CH2Ph

I 6

T • <3 zNHBOC v

CH2Ph

A / NH2

Oh

H

NHBOC <3 / NHCO- ^ hp φ, ΗΟΟ ^

C00CH2Ph

CH3C0CC00Et

A

COOCH2Ph

9a, 9b <3 _ *? NH2

H

7a, 7b

BrCH2C0CC00Et

A

3.

<A ^ 0H

Ua.Ub

Ο ^ ιψ '

T O J »u /

110 p \ XONH2

IX ^ CONH2

CONHBr

CONHBr

NH2

COOH>

r \ NHBOC

COOH r \ .NHSOC lX ^ CONHCH2COOEt rx ^ ^NH2

Ι ^ ΟΟΝΗεΗ2θΟΟΕί

COOMe

Fv / J \ .COOMe

F

COOMe COOMe

COOMe F ^^ COOMe

F- ^ J ^ F F- ^ J ^ F

CH2NO2 43 CH2NMe ₂

COOMe

49

112 ch ₂ (cooei) ₂ = o = ((CH ₂ ) _n

EtOOC / - ··.

> = / (CH ₂ ) _n

EtOOC ····· '

70 (n = 1) 71 (n = 2) 72 (n = 3)

Etooc ch ₂ no _{2 £ tooc} ί (ČH _{2) n}

- ~

73 (n = 1) ^H 76 (n = 1)

74 (n = 2) 77 (n = 2)

75 (n = 3) 78 (n = 3)

(n = 3) 92 (n = 3) 93 (n = 3)

HOOC I (CH ₂ ) _n

H

101 (n = 3)

HO (CH ₂ ) _n

HO (CH ₂ )

102 (n = 1) 104 (n = 2) 106 (n = 3) 'N

Boc

103 (n = 1)

1O5 (n = 2)

107 (n = 3)

113

Ο

νη ₂

114

OH

115

35b

-j «* -

COOH b

116

54b

55b

117

While the invention has been described in detail and with reference to its specific embodiments, it will be apparent to one skilled in the art that various modifications and modifications can be made therein without departing from its spirit and scope.

Claims (7)

PATENT APPLICATIONS A spiro compound of formula I (CH (CH 2'c C- ( ^CH ) / ^{2 a} \ N-Q - ( ^CH 2> dv which a represents an integer 0 or 1; b represents an integer from 2 to 5 inclusive; c represents an integer 0 or 1; and d represents an integer from 0 to 2 inclusive; 12 3 Z represents> CHR,> NR,)> C = NOR, an oxygen atom or a sulfur atom, where R represents a hydrogen atom, an amino group, a monoalkylamino group of 1 to 6 carbon atoms, a dialkylamino group containing 1 to 6 carbon atoms in any alkyl, hydroxyl group, alkoxy group of 1 to 6 carbon atoms or hydroxyalkyl group of 1 to 6 carbon atoms; R represents a hydrogen atom, an alkyl group of 1 to 6 carbon atoms, a hydroxyalkyl group of 1 to 6 carbon atoms, a haloalkyl group of 1 to 6 carbon atoms, a formyl group or an alkyl • 5 carbonyl group of 2 to 7 carbon atoms; and R represents a hydrogen atom or an alkyl group of 1 to 6 carbon atoms; Q represents a partial structure of formula II: wherein R1 represents an alkyl group of 1 to 6 carbon atoms, an alkenyl group of 2 to 6 carbon atoms, a haloalkyl group of 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl group of 3 to 6 carbon atoms, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, an alkoxy group of 1 to 6 carbon atoms or an alkylamino group having 1 to 6 carbon atoms; R represents a hydrogen atom or an alkyl group of 1 to 6 carbon atoms; R ° represents a hydrogen atom, a substituted or unsubstituted amino group, a hydroxyl group, an alkoxy group of 1 to 6 carbon atoms or a halogen atom; A represents a nitrogen atom 7 7 or ^ C-R, where R represents a hydrogen atom, an alkyl group of 1 to 6 carbon atoms, a halogen atom, an alkoxy group of 1 to 6 carbon atoms, a haloalkyl group of 1 to 6 carbon atoms 4 5 7 or a cyano group; R may form together with R and / or R a substituted or unsubstituted ring, which may include an oxygen, nitrogen or sulfur atom in which the substituent is an alkyl group of 1 to 6 carbon atoms or a haloalkyl group of 1 to 6 carbon atoms; X represents a halogen atom; Y represents a hydrogen atom, an alkyl group of 1 to 6 carbon atoms, an alkoxyalkyl group of 1 to 6 carbon atoms, a phenylalkyl group, 1 to 20 containing, in its alkyl moiety, 1 to 6 carbon atoms, a respiratory group, a phenyl group, an acetoxymethyl group, a pivaloyloxymethyl group, an ethoxycarbonyloxy group, a choline group, a dimethylaminoethyl group, a 5-indanyl group, a phthalidinyl group, a 5-substituted-2-oxo group -1,3-dioxazol-4-ylmethyl group or 3-acetoxy-2-oxobutyl group, and salts thereof. 2. Spiro compound s formula I PO claim 1, wherein is a 1, b is 2, c is 0 and d is 1 in Z represents Χ ^ ΗζΝί ^), but hers sol. 3. Spiro compounds s formula I by claim 1, wherein is a 1, b is 3, c is 0 and d is 1 in Z represents ^ CHCNH ^), but hers sol. • 4. Spiro compound s formula I by claim 1, wherein is a 1, b is 2, c is 0 and d is 2 and Z represents> NH, but its salt • 5. Spiro compound s formula I by to a claim wherein this is spiro compound optically pure. A spiro compound of formula I according to claim 1, wherein said spiro compound is selected from the group consisting of 7- (7-amino-5-azaspiro / 2,4 / heptan-5-yl) -1-cyclopropyl-6 , 8-Difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 7- (7-amino-5-azaspiro / 2,4 / heptan-5-yl) -8-chloro-1-cyclopropyl6- fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 7- (7-amino-5-azaspiro / 2,4 / heptan-5-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 7- (7- amino-5-azaspiro / 2,4 / heptan-5-yl) -6-fluoro-1- (2,4-difluoro121 phenyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 7- ( 7 amino-5-azaspiro/2,4/heptan-5-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid, 1Q_ (7-Amino-5-azaspiro / 2,4 / heptan-5-yl) - 9-Fluoro-2,3-dihydro-3- (S) -methyl-7-oxo-7H-pyrido / 1,2,3-de [1,4] benzoxazine-6-carboxylic acid, 1-cyclopropyl- 7- (4,7diazaspiro / 2,5 / octan-7-yl) -6-fluoro-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-hydroxy5-azaspiro / 2,4 / heptan-5-yl) ) -8-chloro-1-cyclopropyl-6fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 7- (7-amino-5-azaspiro / 2,4 / heptan-5-yl) -1 - (2-methyl-2propyl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3carboxylic acid, 7- (7-hydroxyimino-5-azaspiro / 2,4 / heptane-5 -yl) -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1-cyclopropyl-6,8-difluoro-7 (8-hydroxymethyl-6-azaspiro (3,4) octan-6-yl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 1-cyclopropyl-6,8difluoro-7- (4-hydroxymethyl-2-azaspiro / 4.4 / nonan- 2-yl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 1-cyclopropyl-, 6,8-difluoro-7- (4-hydroxymethyl-2-azaspiro / 4,5 / deca n-2-yl) 4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 7- (8-amino-6-azaspiro / 3,4 / octan-6-yl) -1-cyclopropyl-6,8difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 122 10- (8-amino-6-azaspiro / 3,4 / octan-6-yl) -9-fluoro-2,3-dihydro3- (S) -methyl-7-oxo-7H-pyrido / 1,2, 3-de // 1,4 / benzoxazine-6carboxylic acid, 7- (4-amino-2-azaspiro / 4,4 / nonan-2-yl) -1-cyclopropyl-6,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and their salts. 7. A process for the preparation of a spiro compound of formula I (CH) N-Q I \ / 2- (CH ₂ ) 'in which a represents an integer 0 or 1; b represents an integer from 2 to 5 inclusive; c represents an integer 0 or 1; and d represents an integer from 0 to 2 inclusive; 12 3 Z represents> CHR,> NR, / C = NOR, an oxygen atom or an atom j sulfur wherein R represents a hydrogen atom, an amino group, a monoalkylamino group of 1 to 6 carbon atoms, a dialkylamino group containing 1 to 6 carbon atoms in each alkyl, a hydroxyl group, an alkoxy group with 1 to 6 carbon atoms or a hydroxyalkyl group with 1 up to 6 carbon atoms; R represents a hydrogen atom, an alkyl group of 1 to 6 carbon atoms, a hydroxyalkyl group of 1 to 6 carbon atoms, a haloalkyl group of 1 to 6 carbon atoms, a formyl group or an alkylcarbonyl group of 2 to 7 carbon atoms; and R represents a hydrogen atom or an alkyl group of 1 to 6 carbon atoms; Q represents a partial structure of formula II: 123 in which R represents an alkyl group of 1 to 6 carbon atoms, an alkenyl group of 2 to 6 carbon atoms, a haloalkyl group of 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl group of 3 to 6 carbon atoms, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, an alkoxy group of 1 to 6 carbon atoms or an alkylamino group of 1 to 6 carbon atoms; R represents a hydrogen atom or an alkyl group of 1 to 6 carbon atoms; R 4 represents a hydrogen atom, a substituted or unsubstituted amino group, a hydroxyl group, an alkoxy group of 1 to 6 carbon atoms or a halogen atom; A represents a nitrogen atom 7 7 or ^ C-R, where R represents a hydrogen atom, an alkyl group of 1 to 6 carbon atoms, a halogen atom, an alkoxy group of 1 to 6 carbon atoms, a haloalkyl group of 1 to 6 carbon atoms 4 5 7 or a cyano group; R may form together with R and / or R a substituted or unsubstituted ring, which may include an oxygen, nitrogen or sulfur atom in which the substituent is an alkyl group of 1 to 6 carbon atoms or a haloalkyl group of 1 to 6 carbon atoms; X represents a halogen atom; Y represents a hydrogen atom, an alkyl group of 1 to 6 carbon atoms, an alkoxyalkyl group of 1 to 6 carbon atoms, a phenylalkyl group. 124 P-1674/89 containing in its alkyl moiety 1 to 6 carbon atoms, a respiratory group, a phenyl group, an acetoxymethyl group, a pivaloyloxymethyl group, an ethoxycarbonyloxy group, a choline group, a dimethylaminoethyl group, a 5-indanyl group, a phthalidinyl group, a 5-substituted- 2-Oxo-1,3-dioxazol-4-ylmethyl group or 3-acetoxy-2-oxobutyl group, and salts thereof, characterized in that the cyclic amine bearing a spiro _c ii ring is formed by the following formula