HRP930082A2 - Spiro compound - Google Patents

Description

Field of invention

The presented invention relates to antibacterial spiro compounds, which are known as human medicines, veterinary medicines and medicines for use in fish farming or as preservatives, 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. Also, many of the highly active derivatives are not well absorbed when administered orally.

The inventor of the present invention has worked hard to develop conolone derivatives that have strong antibacterial activity and show an effective degree of oral absorption.

The essence of the invention

The presented invention relates to spiro compounds of the general formula I

[image]

where a denotes an integer 0 or 1, b an integer from 2 to 5 inclusive, c an integer 0 or 1 and d an integer from 0 to 2 inclusive; Z stands for >CHR1, >NR2, >C=NOR3, an oxygen atom or a sulfur atom, where R1 is a hydrogen atom, an amino group, a monoalkylamino group with 1 to 6 carbon atoms, a dialkylamino group containing in each alkyl 1 to 6 carbon atoms, hydroxyl group, 1 to 6 carbon atom alkoxy group or 1 to 6 carbon atom hydroxyalkyl group; R2 is a hydrogen atom, an alkyl group with 1 to 6 carbon atoms, a hydroxyalkyl group with 1 to 6 carbon atoms, a haloalkyl group with 1 to 6 carbon atoms, a formyl group or an alkylcarbonyl group with 2 to 7 carbon atoms and R3 is a hydrogen atom or alkyl a group with 1 to 6 carbon atoms; Q represents part of the structure of formula II

[image]

where R4 denotes an alkyl group with 1 to 6 carbon atoms, an alkenyl group with 2 to 6 carbon atoms, a haloalkyl group with 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl group with 3 to 6 carbon atoms, a substituted or unsubstituted aryl group, a substituted or an unsubstituted heteroaryl group, an 1 to 6 carbon alkoxy group or a 1 to 6 carbon alkylamino group; R5 denotes a hydrogen atom or an alkyl group with 1 to 6 carbon atoms; R6 denotes a hydrogen atom, a substituted or unsubstituted amino group, a hydroxyl group, an alkoxy group with 1 to 6 carbon atoms or a halogen atom; A represents a nitrogen atom or >C-R7, where R7 is a hydrogen atom, an alkyl group with 1 to 6 carbon atoms, a halogen atom, an alkoxy group with 1 to 6 carbon atoms or a cyano group; R4 and/or R7 a substituted or unsubstituted ring, which may include an oxygen, nitrogen or sulfur atom, where the substituent is an alkyl group with 1 to 6 carbon atoms or a haloalkyl group with 1 to 6 carbon atoms; X denotes a halogen atom, preferably a fluorine atom; Y denotes a hydrogen atom, an alkyl group with 1 to 6 carbon atoms, an alkoxyalkyl group with 1 to 6 carbon atoms, a phenylalkyl group, which contains in its alkyl part 1 to 6 carbon atoms, a dihaloboron group, a phenyl group, an acetoxymethyl group, a pivaloyloxymethyl group, ethoxycarbonyloxy group, choline group, dimethylaminoethyl group, 5-indanyl group, phthalidinyl group, 5-substituted-2oxo-1,3-dioxazol-4-ylmethyl group or 3-acetoxy-2-oxobutyl group and their salts. In more detail, the invention may refer to spiro compounds of the general formula I, in which a denotes 1, b 2, c 0 and d 1 and Z denotes CH(NH2) and to their salts. The invention relates to spiro compounds of the general formula I, in which a denotes 1, b3, c 0 and d 1 and Z denotes CH (NH2) and to their salts. The invention further relates to spiro compounds of the general formula I, in which a denotes 1, b 2, c 0 and d 2 and Z denotes NH and to their salts. In more detail, the invention relates to spiro compounds of the general formula I, where these spiro compounds are optically pure. In more detail, the invention relates to 7-(7-amino-5-azaspiro[2,4]heptan-5-yl)-1-cyclopropyl-6fluoro-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-7-oxo-7H-pyrido[1, 2,3-de]-[1,4]benzoxazine-6-carboxylic acid, 1-cyclopropyl-7-(4,7-diazaspiro [2,5]octan-7-yl)-6-fluoro-1,4 -dihydro-4-oxoconoline-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-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-(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-2-azaspiro[4,4]nonan-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 1-cyclopropyl-6,8-difluoro- 7-(4-hydroxymethyl-2-azaspiro[4,5]decan-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 7-(8-amino-6-azaspiro[3, 4]octan-6-yl)-1-cyclopropyl-6,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 10-(8-amino-6-azaspiro[3,4]octane -6-yl)-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6- carboxylic acid or 7-(4-amino-2-azaspiro[4,4]nonan-2-yl)-1-cyclopropyl-6,8,difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid. In a further aspect, the presented invention relates to an antibacterial preparation containing a compound of the general formula I as an active agent.

Detailed description of the invention

For the compounds in terms of the presented invention, it is significant that each of them is a cyclic amine compound with a spiro ring and that a quinolone derivative is attached to it through its "position, equivalent position". The term "position equivalent to the 7-position" of the conolone derivative means, for example, the 7-position of the compound in the given example of the substituted 4-oxyquinoline-3-carboxylic acid and the 4-oxo-1,8-naphthyridine-3-carboxylic acid compound, the 10-7-oxo position -pyrido[1,2,3-de] [1,4]benzoxazine-6-carboxylic acid or position 8 of benzo[i,j]quinolizine-2-carboxylic acid.

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

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

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

The following are some examples of the structures of a cyclic amine bearing a spirocyclic ring: the structure of 5-azaspiro[2,4]heptane, the structure of 6-azaspiro[3,4]octane, the structure of 2-azaspiro[4,4]nonane, the structure of 2-azaspiro [4,5] decane, structure of 5-azaspiro[2,5]octane, structure of 6-azaspiro[2,5]octane, structure of 6-azaspiro[3,5]nonane, structure of 7-azaspiro[3,5]nonane , structure of 7-azaspiro[4,5]decane, structure of 8-azaspiro[4,5]decane, structure of 2-azaspiro[5,5]undecane, structure of 3-azaspiro[5,5]undecane, structure of 4,7- diazaspiro[2,5]octane, structure of 5,8-diazaspiro[3,5]nonane, structure of 6,9-diazaspiro[4,5]decane, structure of 7,10-diazaspiro[5,5]undecane, structure of 7- aza-4-oxaspiro [2,5]octane, structure 8-aza-5-oxaspiro]3,5]nonane, structure 9-aza-6-oxaspiro[4,5]decane, structure 7-aza-4-thiaspiro [2,5]octane, structure of 8-aza-5-thiaspiro[3,5]nonane, structure of 9-aza-6-thiaspiro[4,5]decane, structure of 7-aza-4-thiaspiro[2,5] octane-4-oxide, structure of 8-aza-5-thiaspiro[3,5]nonane-5-oxide and structure of 9-aza-6-thiaspiro o[4,5]decane-6-oxide.

If an additional heteroatom remains in the ring of that cyclic amine, such as oxygen, sulfur or nitrogen, or especially if this heteroatom does not remain, polar substituent groups, such as amino, monoalkylamino groups with 1 to 6 carbon atoms, dialkylamino groups can remain on the amine ring containing 1 to 6 carbon atoms in each alkyl, aminoalkyl group with 1 to 6 carbon atoms, the amino part of which is or is not substituted with alkyl with 1 to 6 carbon atoms or hydroxyalkyl with 1 to 6 carbon atoms, hydroxy, hydroxyalkyl groups with 1 up to 6 carbon atoms, hydroxyimino and alkoxy groups with 1 to 6 carbon atoms. Amino groups are advantageous.

These substituents on the spiro-substituted cyclic amine may or may not be protected with exemplary protecting groups. We can choose such protected groups from those that are usually used. For example exemplary 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, methoxyacetyl, trifluoroacetyl, chloroacetyl, pivaloyl, formyl and benzoyl, alkyl or aralkyl groups such as tert.-butyl, benzyl, p-nitrobenzyl and triphenylmethyl, ether groups such as methoxymethyl, tert.-butoxymethyl, tetrahydropyranyl and 2,2,2-trichloroethoxymethyl and silyl groups such as trimethylsilyl, isopropyldimethylsilyl, tert.-butyldimethylsilyl, tribenzylsilyl and tert.-butyldiphenylsilyl.

If the substituent remains on the cyclic amine, substituted with a spiro ring, except for the spiro ring, and if the carbon atom to which the substituent is attached is an asymmetric carbon atom, the stereoisometry of the cyclic amino remains. If we use such a cyclic amine as a mixture of stereoisomers as a substituent for the "position, equivalent to position 7", a spiro compound AND a mixture of diastereomers can be formed if the second asymmetric carbon atom remains in the spiro compound. A mixture of diastereomers is a mixture of compounds that differ in physical constants and cannot be used as medicine. In such examples, it is necessary to separate the cyclic amine into isomers before partitioning.

If the obtained spiro compound is a racemic compound, we can use the racemate as such. Of course, there are examples where the optically active form is used biologically as a racemate. In such cases, it is necessary to resolve the racemate optically.

For example, when observing the antimicrobial activity of both enantiomers, which have the structure of 7-amino-5-azaspiro[2,4] heptane, one of them has a more effective activity than the other. We found that the more effective enantiomer is the 7-(S)-amino-5 derivative

-azaspiro[2,4]heptane. We confirmed this activity with X-ray crystallographic analysis of one of the isomers 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.

Cyclic amine, which is substituted with a spiro ring, can be synthesized in the following way.

If we take 7-amino-5-azaspiro[2,4]heptane as an example, we first decompose ethyl acetoacetate with 1,2-dibromoethane in the presence of a base to form ethyl 1-acetyl-1-cyclopropane carboxylate. Then, with the use of bromine, we brominate the acetyl group of that compound to form ethyl 1-bromoacetyl-1-cyclopropanecarboxylate. This bromoacetyl compound is then cyclized with benzylamine to form 5-benzyl-4,7-dioxo-5-azaspiro[2,4]heptane. If we block this compound with hydroxylamine hydrochloride, the ketone in position 7 turns into an oxime and we get 5-benzyl-7-(hydroxyimino)-4-oxo-5-azaspiro[2,4] heptane. We reduce this oxime with lithium aluminum hydride to form an aminopyrrolidine compound containing a spiro ring, i.e. 7-amino-5-benzyl-5-azaspiro[2,4]heptane. If we separate the benzyl group of that compound using a known method, such as with catalytic hydrolysis, we get 7-amino-5-azaspiro[2,4]heptane, which is a racemic compound. If we carry out before this removal of the benzyl group, then, having protected the amino group, we divide 2-(tert.-butoxy-carbonylamino)-2-phenylacetonitrile (abbreviated below as BOC-ON), we get 7-tert.-butoxy-carbonylamino -5-azaspiro[2,4]heptane.

Optical isomers of 7-amino-5-azaspiro[2,4]heptane can be obtained in the following way.

First, we partition 7-amino-5-benzyl-5-azaspiro[2,4]heptane with (R)-N-p-toluenesulfonylpropyl chloride, to form 7-[(R)-N-p-toluenesulfonylpropyl]amino-5-benzyl- 5-azaspiro[2,4]heptane. This compound is then partitioned 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 with high-pressure liquid chromatography (abbreviated HPLC below). After separation, we treat each compound with 2N sodium hydroxide, to cleave the proline part and the benzyloxycarbonyl group, to form the corresponding optically active 7-amino-5-azaspiro[2,4]heptane. We also found that if we carry out the cyclization of ethyl 1-bromoacetyl-1-cyclopropanecarboxylate using optically active 1-phenethylamine instead of benzylamine, the subsequent optical separation of the racemic compound is facilitated.

The following method is an alternative synthesis derived from 1-acetyl-1-cyclopropanecarboxylic acid esters. First, we cleave the ester of 1-acetyl-1-cyclopropanecarboxylic acid ester with acid or base hydrolysis or with catalytic hydrogenation. We divide this simple acid with R-(+)-1-phenylethylamine to form N-[1-(R)-phenylethyl]-1-acetyl-1-cyclopropanecarboxamide, an amide derivative. Then we convert the carbonyl part of its acetyl group into a ketal group, where we get N-[1-(R)-phenylethyl]-1-(1,1-ethylenedioxyethyl)-1-cyclopropane-carboxamide. Then we halogenate the methyl group, which lies next to its ketyl group, for example N-[1-(R)-phenylethyl]-1-(1,1- ethylenedioxyethyl)-1-cyclopropanecarboxamide, turn it into N-[1-(R)- phenylethyl]-1-(2-bromo-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-ethylene acetal, which is a derivative of pyrrolidone, bearing a spiro cyclic ring and ketal function. Its ketal function can be cleaved with a known hydrolysis procedure to form 4,7-dioxo-5-[1-(R)-phenylethyl]-5-azaspiro[2,4]heptane. This compound can be converted to a spirocyclic amine according to the appropriate mode of operation. The synthesis of 4,7-diazaspiro[2,5]octane is indicated below. Cyclopropane-1,1-diamide is first partitioned with bromine and a base to form cyclopropane-1,1-dibromoamide, and treated with an alkoxide to form spiro hydantoin, especially 4,6-diazaspiro[2,4]heptane-5, 7-dione. This compound is then treated with alkali to form 1-aminocyclopropanecarboxylic acid.

We protect the amino group of that compound with 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.-butoxycarbonylamino- 1-Cyclopropylcarbonylamino)-acetate. After removing the protective group for amino, we cyclize the above group with heating, so that the diketopiperazine compound, which contains a spiro ring, especially 4,7-diazaspiro[2,5]octane-5,8-dione, disappears. This compound is reduced with lithium aluminum hydride to form a piperazine compound containing a spiro ring, especially 4,7-diazaspiro [2,5]octane.

The synthesis of a derivative of a cyclic amine, which carries a spirocyclic ring, can be performed according to the procedure shown below. Condensation of a cyclic alkyl ketone and a malonic acid diester in the presence of titanium tetrachloride gives a cycloalkylidenmalonic acid diester. Rearrangement of this cycloalkylidenemalolic acid diester with nitromethane in the presence of a base gives a Michael adduct, eg (1-nitromethyl-1-cycloalkyl)-malonic acid diester. Reductive cyclization of (1-nitromethyl-1-cycloalkyl)malonic acid diester gives pyrrolidone carboxylic acid ester, which carries a spirocyclic ring, e.g. if the spirocyclic ring is a 4-membered ring, we get 7-oxo-6-azaspiro[3,4] octane-8-carboxylic acids. Catalytic reduction is more favorable for this reductive cyclization. Other chemical reduction procedures can also be used. There, we can convert the pyrrolidone carboxylic acid ester into a derivative of a cyclic amine, which carries a spirocyclic ring and a tert.-butoxycarbonylamino substituent with a Crutius reaction in tert.-butanol of a simple carboxylic acid, which is obtained by grafting the ester using a known process, such as hydrolysis or hydrogenolysis. The reduction of pyrrolidone, which carries a spirocyclic ring and an amino substituent, yields a pyrrolidone derivative with a spirocyclic ring and an amino substituent after the separation of the tert.-butoxycarbonyl group. Reduction of the pyrrolidone carboxylic acid ester with a metal hydride, such as lithium aluminum hydride, gives a pyrrolidone derivative bearing a spirocyclic ring and a hydroxymethyl substituent. Quinolone derivatives, which may be attached to such a cyclic amine containing a spiro ring, include bicyclic compounds such as 1,4-dihydro-4-oxaquinoline-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]benzooxazin-6-carboxylic acid, 2,3- dihydro-7-oxo-7H-pyrido[1,2,3-de][1,4]benzothiazine-6-carboxylic acid, 6,7-dihydro-1,7-dioxo-1H,5H-benzo[ij] quinolysine-2-carboxylic acid 6,7-dihydrobenzo[ij]quinolysine-2-carboxylic acid, tetracyclic compound as 9,1-epoxymethane-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylic acid . The working structures are shown below.

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If we are talking about the compounds 1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, a possible substituent in position 1 is, for example, lower an alkyl group with 1 to 6 carbon atoms, such as ethyl, isopropyl and tert-butyl, a haloalkyl group with 1 to 6 carbon atoms, such as 2-fluoroethyl, a lower alkenyl group with 2 to 6 carbon atoms, such as vinyl and isopropenyl, a cycloalkyl group with 3 to 6 carbon atoms, which may or may not be substituted, such as cyclopropyl, cis-2-methylcyclopropyl and 2-gem-dihalocyclopropyl, an aryl or heteroaryl group, which may or may not be substituted, such as 4-fluorophenyl, 2,4-difluorophenyl and 2-Fluoro-4-pyridyl, an alkoxy group with 1 to 6 carbon atoms, such as methylamino and ethylamino. Among these substituent groups, ethyl, 2-fluoroethyl, vinyl, cyclopropyl, cis-2-methyloylpropyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-fluoro-4-pyridyl, methoxy and methylamino are preferred.

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

A favorable substituent group in position 5 is a hydrogen atom, an amino group, an unsubstituted mono-C1-6-alkylamino or di-C1-6-alkylamino group, such as methylamino, ethylamino, isopropylamino, dimethylamino and diethylamino, a hydroxyl group, a halo-C1-6alkylamino group, C1-6aloxy group, as well as methoxy and ethoxy or a halogen atom.

Position 6 is advantageously substituted with a halogen atom, especially fluorine or chlorine.

Position 8 of the quinoline derivative is or is not substituted. Preferred substituents include a halogen atom, a C 1-6 -alkyl group, a C 1-6 -aloxy group, a halo-C 1-6 -alkyl group and a cyano group. Chlorine, fluorine, methyl and methoxy are favorable.

As for the quinolone structure, it can be not only a bicyclic structure, but it can be a tricyclic or tetracyclic structure, formed at position 1 and especially at position 8 or position 2 or at position 1 and each of positions 8 and 2 of the quinolone ring. The ring formed in such examples is preferably in the range of 4-membered to 7-membered rings and more preferably a 5- or 6-membered ring.

The resulting ring can include nitrogen, oxygen and sulfur atoms. In addition, they may contain not only single bonds, but also double bonds, and the ring may be aromatic. Further, such rings may or may not be substituted with C 1-6 -alkyl or halo-C 1-6 -alkyl groups.

As for tricyclic quinolone derivatives, where we take as an example 2,3-dihydro-7-oxo-7H-pyrido[1,2,3-de] [1,4]benzoxazine-6-carboxylic acid, position 3 can be substituted with an alkyl group of 1 to 6 carbon atoms, which is preferably in the S-configuration. Position 9 is preferably substituted with a halogen atom, which is preferably fluorine or chlorine. The above condition regarding substitution may also apply to other tricyclic quinolone derivatives, such as 2,3-dihydro-7-oxo-7H-pyrido[1,2,3-de][1,4]benzothiazine-6-carboxylic acid and also for 6,7-dihydro-1H,5H-benzo[ij]quinolizine-2-carboxylic acids. In the example of 3-alkyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid, position 9 is advantageously substituted with a halogen atom, which is preferably fluorine or chlorine.

Favorable quinolone derivatives, which may be attached to the mentioned cyclic amine, which contains a spiro ring, are compounds of 1,4-dihydro-4-oxyquinoline-3-carboxylic acid.

A cyclic amine containing a spiro ring can be introduced into this quinolone derivative according to the procedures described in European patents (EP)-A-167,763, EP-A-195,841, EP-A-11160,587 and EP-A-206,283.

The preparation procedures of the corresponding compounds are described below with reaction schemes.

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compound I

where a, b, c, d, Z, A, R4, R5, R6, Y and X are the same as above; X' denotes a halogen atom, preferably fluorine. If we then divide the cyclic amine, which contains a spiro ring, with a 7-haloquinolone derivative, the nitrogen atom of the pyrrolidine ring is attached to position 7 of the quinolone ring, and the desired quinolone derivative is formed.

In the starting material of the quinolone derivative, for example 1-cyclopropyl-6-fluoro-7-halo-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, the halogen atom in position 7 can be chlorine or fluorine. These starting compounds can be synthesized according to the procedures described in EP-A-167,763 and EP-A-195,841. We can also synthesize other quinolone materials by known procedures.

(For example, 7-chloro-6-fluoro-1-ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, EP-A27,752; 9,10-difluoro-3 -methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid, Japan Kokai 88-132891; 9,1-epoxymethane -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, US Patent 4,550,104;7-halo-6-fluoro-1-methyl-4-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 process described in EP-A-195,841, we synthesize the intermediate compound 3-chloro-2,4,5-trifluorobenzoic acid in 10 reaction steps. In contrast, the inventor of the presented invention developed a procedure for the synthesis of the above compound in one step, starting from 3-amino-2,4,5-trifluorobenzoic acid, and established that this procedure is also applicable to other benzoic acid derivatives.

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Furthermore, we can use as a starting material, which should be partitioned with an amine, which contains a spiro ring, a quinolone derivative, in which the carboxyl group in position 3 (or a position equivalent to position 3) was esterified with a substituted boron compound. This ester can be, for example, a compound that has the following substituent group in position 3) of the quinolone core, to form a chelate with the carbonyl group in position 4 (or a position equivalent to position 4) of the quinolone ring.

[image]

The upper fluorine atom can also be another halogen atom or an acetoxy group.

This dihalogenated boron compound can be especially prepared from a simple carboxylic acid derivative from a primary trihalogenated boron compound, as a boron trifluoride-ether complex.

Thus, we suspend or dissolve the carboxylic acid derivative in an ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane, and add the rest of the boron trifluoride-diethyl ether complex. Mix the mixture at room temperature. The reaction can be carried out at room temperature, and if necessary, also with heating up to 100°C. The reaction was carried out in 30 minutes to 24 hours. When the reaction product is mostly 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 part in position 3 (or a position equivalent to position 3) was esterified, were used as synthetic intermediates or "prodrugs". For example, esters, such as alkyl ester, benzyl ester, alkoxyalkyl ester, phenylalkyl or phenyl ester, have been used as synthetic intermediates.

The reaction for the introduction of a cyclic amine, which contains a spiro ring, is generally carried out in the presence of an acid acceptor. If the acid acceptor is an organic base or an inorganic base, it is generally advantageous 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-diethylaniline, and heterocyclic compounds such as N,methylmorpholine, pyridine, and N,N-dimethylaminopyridine.

Examples of inorganic bases include hydroxides, carbonates and hydrogencarbonates of alkali metals such as lithium, sodium and potassium. As we have established, we can use lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate or potassium hydrogencarbonate.

It is also necessary to use a stoichiometric amount of the starting material, a cyclic amine, which contains a spiro ring, so that it can be used as a reactant as an acid acceptor.

The reaction solvent can be any solvent, which is inert to the reaction. Favorable solvents include acetonitrile, amides, 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. In this example, the appropriate acid acceptor is preferably an organic base.

The reaction can be carried out in a temperature range from about 50 to about 180°C, preferably from about 80 to about 130°C.

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

If we use a cyclic amine, which contains a spiro ring, in the partition after protection of its substituent group in the core, we can perform the subsequent separation of the protecting group from the reaction product with known procedures, adapted to the selected protecting group, for example, hydrolysis or hydrogenolysis.

If the carboxyl part in position 3 (or a position equivalent to position 3) is not a simple carboxyl group, we can convert the derivative into a simple carboxylic acid according to a known technique, adapted to any example. For example, if it is an ester, we can use the usual hydrolysis reaction using an alkali hydroxide in an aqueous medium. In the example of a boron compound, we can use a procedure that uses a protonic substance, such as an alcohol. In this example, an acid acceptor may be present in the reaction system. For example, we can choose to treat with ethanol in the presence of triethylamine.

The resulting spiro compound I can be purified by any or a suitable combination of recrystallization, reprecipitation, treatment with activated carbon, chromatography and other known methods.

The following compounds represent some examples of new compounds that belong to the presented invention:

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

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

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

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

7-(7-amino-5-azaspiro[2,4]heptan-5-yl)-6,8-difluoro-1-(2-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-oxoquinolin- 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- 3-carboxylic acid;

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

7-(7-amino-5-azaspiro[2,4]heptan-5-yl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ;

7-(7-amino-5-azaspiro[2,4]heptan-5-yl)-6,8-difluoro-1-(2,4-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-3-carboxylic acid;

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

7-(7-amino-5-azaspiro[2,4]heptan-5-yl)-8-chloro-6-fluoro-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)-6,8-difluoro-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-fluoro-ethyl)-1,4-dihydro-4-oxoquinolin-3- carboxylic acid;

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

7-(4,7-diazaspiro[2,5]octan-7-yl)-6-fluoro-1-(2-fluoro-ethyl)-1,4-dihydro-4-oxo-1,8-naphthyridin- 3-carboxylic acid;

7-(4,7-diazaspiro[2,5]octan-7-yl)-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

8-chloro-7-(4,7-diazaspiro[2,5]octan-7-yl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

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

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

7-(4,7-diazaspiro[2,5]octan-7-yl)-6,8-difluoro-1-(2,4-difluoro-phenyl)-1,4-dihydro-4-oxoquinolin-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-(2,4-difluoro-phenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ;

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

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

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

7-(4,7-diazaspiro[2,5]octan-7-yl)-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-2,3-dihydro-7-oxo-7H-pyrido[1, 2,3-de][1,4]benzoxazine-6-carboxylic acid;

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

8-(7-amino-5-azaspiro[2,4]heptan-5-yl)-9-fluoro-5-(S)-methyl-6,7-dihydro-1,7-dioxo-1H,5H- benzo[ij]quinolisine-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]quinolysine-2-carboxylic 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]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]benzothiazine-6-carboxylic acid;

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

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

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

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

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

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

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

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

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

5-amino-8-chloro-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)-6,8-difluoro-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- 3-carboxylic acid;

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

5-amino-8-chloro-7-(4,7-diazaspiro[2,5]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-oxoquinoline- 3-carboxylic acid;

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

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

5-amino-7-(7-amino-5-azaspiro[2,4]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)-6,8-difluoro-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-cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

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

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

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

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

7-(7-amino-5-azaspiro[2,5]heptan-5-yl)-1-cyclopropyl-6-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-oxoquinolin-3- carboxylic acid;

7-(7-amino-5-azaspiro[2,5]heptan-5-yl)-1-ethyl-6-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-oxoquinolin-3- carboxylic acid;

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

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

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

7-(4,7-diazaspiro[2,5]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-difluoro-phenyl)-6-fluoro-8-methoxy-1,4-dihydro-4-oxoquinolin- 3-carboxylic acid;

7-(4,7-diazaspiro[2,5]octan-7-yl)-6-fluoro-8-methoxy-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-(2-fluoroethyl)-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-difluoro-phenyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinolin- 3-carboxylic acid;

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

7-(8-amino-6-azaspiro[3,4]octan-6-yl)-1-cyclopropyl-6,8-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-6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxoquinolin-3- carboxylic acid;

7-(8-amino-6-azaspiro[3,4]octan-6-yl)-1-ethyl-6,8-difluoro-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-oxoquinolin-3- carboxylic acid;

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

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

7-(8-amino-6-azaspiro[3,4]octan-6-yl)-8-chloro-6-fluoro-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[ij]quinolisine-2-carboxylic acid;

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

8-chloro-1-cyclopropyl-7-(5,8-diazaspiro[3,5]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

7-(5,8-diazaspiro[3,5]nonan-8-yl)-6,8-difluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

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

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

8-chloro-7-(5,8-diazaspiro[3,5]nonan-8-yl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

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

8-chloro-7-(5,8-diazaspiro[3,5]nonan-8-yl)-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-1-vinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

8-chloro-7-(5,8-diazaspiro[3,5]nonan-8-yl)-6-fluoro-1-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)-methyl-2,3-dihydro-7-oxo-7H-pyrido[1,2, 3-de][1,4]benzoxazine-6-carboxylic acid;

8-(5,8-diazaspiro[3,5]nonan-8-yl)-9-fluoro-5-(S)-methyl-6,7-dihydro-1,7-dioxo-1H,5H-benzo[ ij]quinolysine-2-carboxylic 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-4,7-diazaspiro[2,5]octan-7-yl)-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ;

These quinolone derivatives, which have a cyclic amine part, containing a spiro ring, are more lipophilic than the corresponding quinolone derivatives that do not have a spiro ring, and we state that as such they are better absorbed when taken orally and show antibacterial activity.

Derivatives of pyridonecarboxylic acid according to the mentioned invention can be used as simple compounds, acid addition salts or salts of their carboxyl groups. Examples of such acid salts include salts of inorganic acids, such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, and phosphate, and salts of organic acids, such as acetate, methanesulfonate, benzenesulfonate, toluenesulfonate, citrate, maleate, fumarate, and lactate.

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

These simple compounds, acid addition salts and salts of carboxyl groups of pyridonecarboxylic acid derivatives can exist as hydrates.

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

Esters that should be used as "prodrugs" are esters that are easily broken down in the body to form simple 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-imethyl ester and various oxoalkyl esters , as 3-acetoxy-2-oxobutyl esters.

The compounds of the present invention have strong antibacterial activity and can therefore be used as medicines for humans and animals, medicines for fish, agricultural chemicals and food preservatives.

The dose of the compound of the present invention as an active ingredient of a medicine for use in humans is in the range of 50 mg to 1 g per day in an adult and is preferably 100 to 300 mg per day in an adult. The dose for the drug for use in animals is in the range of about 1 to 200 mg per kg of body weight per day and is preferably 5 to 100 mg per kg of body weight per day. The daily dose should be adjusted according to such factors as the purpose (such as therapeutic or preventive), the type, weight or age of the person or animal to be treated, the type of pathogenic organisms for which treatment is required and the symptoms that are displayed, etc.

The dose described above can be divided into 1 to 4 meals a day. If necessary, we can change the above dose amount according to the causative organism or the actual symptoms that are shown.

The compounds according to the presented invention are active against a very wide spectrum of microorganisms and it is possible to prevent, alleviate and/or cure diseases caused by such pathogenic microorganisms. Examples of such bacteria or bacteria-friendly microorganisms include Staphylococcus sp., Streptococcus pyogenes, hemolytic streptococci, enterococci, Streptococcus pneumoniae, Neisseria gonorrhoeae, Escherichia coli, Citrobacter sp, Shigella sp., Klebisiella pneumoniae, Enterobacter sp., Serratia sp., Proteus sp. ., Pseudomonas aeruginosa, Haemophilus influenzae, Acinetobacter sp., Campylobacter sp., and Chlamidiae.

Examples of diseases that can be prevented, alleviated and/or cured with the compound or compounds according to the present invention include pneumonia, chronic bronchitis, fusible panbronchiolitis, bronchiectasis with infection, secondary infections of chronic respiratory diseases, pharyngolaryngitis, tonsillitis, acute bronchitis, pyelonephritis, cystitis, prostatitis, epidemicitis, gonococcal urethritis, nongonococcal urethritis, folliculitis, furuncle, furunculosis, carbuncle, erysipelas, phlegmon, lymphangitis/lymphadenitis, felon, subcutaneous abscess, spiradenitis, acne conglobata, infectious atheroma, perianal abscess, mastadenitis, superficial secondary infections in trauma, cholecystis, cholangitis, otitis media, sinusitis, blepharitis, hordeolum, dekryocystitis, tarzadenitis, keratohelcosis, bacillary dysentery and enteritis.

Examples of susceptible organisms that cause disease in animals include Escherichia sp., Salmonella sp., Haemophysalis sp., Bordetella sp., Staphylococcus sp. and Mycoplasma sp. The following are some examples of diseases in animals; poultry diseases include colibacillosis, fowl plague, avian paratyphoid, fowl cholera, whooping cough, staphylococcal infections and mycoplasmal diseases; pig diseases include colibacillosis, salmonellosis, pasteurellosis, hemophilic infections, atrophic rhinitis, exudative epidemics and mycoplasmal diseases; cattle diseases include colibacillosis, salmonellosis, hemorrhagic septicemia, mycoplasmal diseases, non-contagious bovine pleuropneumonia and bovine mastitis; dog diseases include coliform sepsis, salmonellosis, hemorrhagic septicemia, pyometra and cystitis; and feline diseases include hemorrhagic pleurisy, cystitis and chronic rhinitis; cat diseases include bacterial enteritis and mycoplasmal diseases.

Pharmaceutical preparations, which contain one or more compounds in terms of the presented invention as active ingredients, can be prepared in accordance with usual preparation procedures. Examples of pharmaceutical compositions for oral administration include tablets, powders, granules, capsules, solutions, syrups, elixirs, and oily or aqueous suspensions.

The solid preparations may contain the active compound or compound of the present invention together with the usual excipients, such as fillers, diluents, binders, wetting agents, absorption improvers, emollients, absorbents and lubricants. Liquid preparations may include solutions, suspensions or emulsions. In addition to the active compound, the preparations may also contain the usual auxiliary substances, such as solubilizers, emulsifiers, stabilizers or preservatives. Solutions of the compounds in terms of the presented invention containing these ingredients are placed in suitable packaging, such as ampoules or vials, and after that the solution is converted into a solid state by lyophilization. When administering, dissolve the lyophilized preparation with a solvent. The packaging can contain any single dose or multiple doses.

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

The compounds of the present invention can be administered to animals as oral or non-oral veterinary drugs. We give such medicines in the form of a mixture with food or water. Preparations for veterinary medicine or supplements can be prepared in accordance with the usual procedures in the field and such preparations include powders, granules, granules, solubilized powders, syrups, solutions and injections.

The following are examples of wording, which clarify some of the possible ways of implementation and should not be taken as limiting in any way.

Example of formulation 1

Each capsule contains:

Compound 32b 100.0 mg

Corn starch 23.0 mg

Calcium carboxymethyl cellulose 22.5 mg

Hydroxypropylmethyl 3.0 mg

Magnesium stearate 1.5 mg

150.0 mg

Example of formulation 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

Distilled water 88.9 to 98.4 g

100.0 g

Example of formulation 3

The powder for mixing with food contains:

Compound 55b 1 to 10 g

Corn starch 98.5 to 89.5g

Silicon dioxide 0.5 g

100.0 g

In fact, the description clarifies and describes an advantageous embodiment of that invention, and it is understood that it is not limited thereto.

The following examples further illustrate the presented invention, and should not be considered as limiting its scope.

Antibacterial activity experiments were performed according to the procedure detailed in the Japan Society of Chemotherapy (Chemotherapy 29(1), 76 (1981)). The tables of antibacterial activity are followed by reaction schemes for the synthesis of various derivatives of cyclic amines, which contain a spiro ring, intermediate compounds for the synthesis of rings and the 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)

15 g of 1,2-dibromoethane, 23 g of calcium carbonate and 150 ml of N,N-dimethylformamide (DMF) were added to 10.4 g of ethyl acetoacetate and the mixture was stirred at room temperature for 2 days. After separating the insoluble part by filtration, the filtrate was concentrated to dryness under reduced pressure and water was added to the residue. The mixture was extracted with chloroform. We dried the extract over anhydrous sodium sulfate and separated the solvent under reduced pressure. The light yellow oily residue was then distilled in vacuo to give 7.5 g of the title compound 2 as a fraction, boiling at 70-71°C/2.7 to 4.0 mbar.

1H-NMR (CDCl3) 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)

We dissolved 7 g of compound 2 in 50 ml of ethanol and then added 8.8 g of bromine dropwise with stirring at room temperature. After 2 hours of stirring at that temperature, the excess bromine and solvent were separated under reduced pressure to obtain ethyl 1-bromoacetyl-1-cyclopropanecarboxylate (compound 3). We dissolved this product as it was, i.e. without cleaning, in 50 ml of ethanol and added 12 g of benzylamine dropwise while mixing and cooling with ice. The mixture was then stirred at room temperature for 24 hours, then the solvent was removed under reduced pressure. The residue was dissolved in 200 mg of chloroform and the solution was washed with 1 N hydrochloric acid and saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was then removed and the residue was chromatographed on silica gel using 2% methanol-chloroform as eluent. The procedure afforded 2.3 g of the title compound 4 as light yellow crystals.

1H-NMR (CDCl3) δ ppm: 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-(hydroxyamino)-4oxo-5-azaspiro[2,4]heptane (compound 5)

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

1H-NMR (CDCl3) δ ppm: 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)

4) 7-amino-5-azaspiro[2,4]heptane (compound 7)

We dissolved 490 mg of compound 5 in 80 ml of dry tetrahydrofuran, added 500 mg of lithium aluminum hydride and refluxed the mixture for 8 hours. Then, at room temperature, we added 0.5 ml of water, 0.5 ml of 15% aqueous sodium hydroxide and 1.5 ml of water in the above order and filtered off the insoluble part. The filtrate was concentrated under reduced pressure to obtain 7-amino-5-benzyl-5-azaspiro[2,4]heptane (compound 6). We dissolved this product as it was, i.e. without cleaning, in 20 ml of ethanol and, after adding 10% palladium on charcoal, catalytically hydrogenated it at 4.4 bar and 50°C. After 6 hours of reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure at a temperature that was not higher than room temperature. The above procedure afforded the title compound 7 as a crude product. We used this compound 7 without purification in different reactions.

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

We prepared a mixture of 2.8 g of compound 6, 1.5 g of triethylamine and 50 ml of methylene chloride and added dropwise to the above mixture during 10 minutes while cooling with ice and mixing (R)-N-p-toluenesulfonylpropyl (prepared from 4 g of (R)-N-p- toluenesulfonylproline and excess amounts of thionyl chloride) in 10 ml of methylene chloride. The mixture was then stirred at room temperature for 3 hours. The reaction mixture was washed with saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was separated under reduced pressure and the residue was processed by light chromatography on an 80 g silica gel column. From the ethyl acetate fraction, we obtained 3.5 g of the title compound 8 as a syrup.

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

3.5 g of compound 8 and 2.5 ml of benzyl chlorocarbonate were added to 4 ml of dry methylene chloride 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. Then we added chloroform to the reaction mixture. The mixture was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride in the appropriate order and dried over anhydrous sodium sulfate. The solvent was then separated under reduced pressure and the residue was processed by light chromatography on an 85 g silica gel column. From the ethyl acetate-n-hexane (2:1-4:1, v/v) fraction, we obtained 3 g of the title compound 9 as a light yellow oil. We processed this oil with HPLC to obtain 1.4 g of compound 9a and 1.45 g of compound 9b.

Column: Nucleosil® 50-5 (20 x 250 mm)

Eluent: ethyl acetate

Flow: 11 ml/min

Dwelling time: 9a: 19.5 min

9b: 21 min

9a: [α]D + 133.6° (c=0.75, chloroform)

9b: [α]D+ 76.0° (c=0.85, chloroform)

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

We dissolved 1.4 g of compound 9a in 20 ml of ethanol, then added 15 ml of 2 N aqueous sodium hydroxide solution. We refluxed the mixture 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 obtain a colorless solid residue. We added 10 ml of 50% aqueous sodium hydroxide to this colorless substance and distilled the mixture under reduced pressure to obtain an aqueous solution containing compound 7a. We used that distillate as it was in the next reaction.

The second compound 7b was also obtained from compound 9b in a convenient way.

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) was added at room temperature and the mixture was stirred at that temperature for 2 hours. The solvent was then removed under reduced pressure and chloroform was added to the residue. We extracted the mixture with 10% aqueous lemon caustic soda. 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 was removed under reduced pressure to obtain 900 mg of 7-tert.-butoxycarbonylamino-5-benzyl-5-azaspiro[2,4]heptane (compound 10). 870 mg of compound 10 was 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 obtain 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-azasipro[2,4]heptane (compound 12)

We dissolved 35.7 g of compound 2 in 200 ml of ethanol and then added 40 g of bromine dropwise while stirring at room temperature. The reaction mixture was stirred at room temperature for 2 hours, after which the excess bromine and solvent were separated under reduced pressure to obtain ethyl 1-bromoacetyl-1-cyclopropane carboxylate (compound 3). We dissolved this product without cleaning in 200 ml of ethanol and, while cooling with ice and stirring, simultaneously added 33 g of R-(+)-1-phenylethylamine and 27 g of triethylamine in drops over the course of 1 hour. Then we stirred the mixture for 2 days at room temperature. Then we filtered off the insoluble part and separated the ethanol under reduced pressure. The residue was dissolved in 230 ml of ethyl acetate and the solution was washed sequentially with 1 N hydrochloric acid, saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride. We dried the organic compound over anhydrous sodium sulfate. The solvent was then left under reduced pressure and the residue was chromatographed on a silica gel column (200 g) using chloroform-2% methanol/chloroform as an eluent system. The procedure gives the title compound 12 as colorless crystals.

Melting point 98-103°C

1H-NMR (CDCl3) δ ppm: 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)

5-[(1R)-phenylethyl]-7-hydroxyamino-4-oxo-5-azasipro[2,4]heptane (compound 13)

1.6 g of hydroxylamine hydrochloride, 2.3 g of triethylamine and 80 ml of ethanol were added to 3.35 g of compound 12 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. We dried the organic compound over anhydrous sodium sulfate and separated the solvent under reduced pressure. The procedure gives 3.5 g of the title compound 13 as colorless crystals.

Melting point 188-194°C

1H-NMR (CDCl3) δ ppm: 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-oxo-5-[(1R)-phenylethyl]-5-azasipro[2,4]heptane (compound 14a and compound 14b)

3.5 g of compound 13 and 7.5 ml of Reney's nickel were added to 150 ml of ethanol. Cataline reduction was performed at room temperature for 12 hours. After filtering the catalyst, the solvent was separated under reduced pressure and the residue was chromatographed on a silica gel column (100 g) using 5% methanol/chloroform as eluent. The procedure gives 1.0 g of compound 14b (obtained from the previously eluted fraction) and 0.8 g of compound 14a as a colorless oil.

14b: 1H-NMR (CDCl3) δ ppm: 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, width s), 5.42 (1H, q, J=7 Hz), 7.29 (5H, s)

14a: 1H-NMR (CDCl3) δ ppm: 0.6-1.3 (4H, m), 1.40 (2H, s), 1.53 (3H, d, J=7.2 Hz), 2.99 (1H, dd, J=12.8, 7.2 Hz), 3.15-3.45 (2H, m), 5.52 (1H, q, J=7.2 Hz), 7.30 (5H, s)

4) 7-amino-5-[(1R)-phenylethyl]-5-azasipro[2,4]heptane (compound 15a and compound 15b)

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

15b: 1H-NMR (CDCl3) δ ppm: 0.2-0.8 (4H, m), 1.35 (3H, d, J=6.6 Hz), 1.6-2.0 (2H, lat. m), 2.2-3.1 (4H, m ), 3.24 (1H, q, J=6.6 Hz), 3.5-3.9 (1H, m), 7.28 (5H, width s)

15a: 1H-NMR (CDCl3) δ ppm: 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=6.7Hz), 3.6-3.9 (1H, m), 7.28 (5H, width s)

5) 7- (tert.-butoxycarbonylamino-5-[(1R)-phenylethyl]-5-azaspiro[2,4]heptane (compound 16a and compound 16b)

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. Then, when the aqueous layer was washed once with ethyl acetate, it was alkylated with 15% aqueous sodium hydroxide while cooling and then extracted with 3 portions of chloroform. The organic layers were combined, washed with saturated aqueous sodium chloride, dried and the solvent separated. The residue was chromatographed on a silica gel column (20 g) with chloroform-methanol (20:1, 10:1) as eluent. The procedure yields 690 mg of the title compound 16b. According to the condition, this product crystallized. The crystals were washed with n-hexane. We then prepared the title compound 16a in a suitable manner.

16b: colorless crystals

Melting point: 103-105°C

[α]D -15.2° (c=1,475, chloroform)

1H-NMR (CDCl3) δ ppm: 0.4-0.9 (4H, m), 1.36 (3H, d, J=7.2 Hz), 1.44 (9H, s), 2.42 (2H, AB q, J=10.2 Hz), 2.79 (2H, d, J=5.6 Hz), 3.24 (1H, q, J=7.2 Hz), 3.6-4.0 (1H, m), 4.6-5.1 (1H, wid.d), 7.28 (5H, s)

Elemental analysis: C19H28N2O2

Calculated: C 72.12 H 8.92 N 8.85

Found: C 71.63 H 9.07 N 8.64

16a: colorless crystals

Melting point: 94-97°C

[α]D +47.6° (c=0.89, chloroform)

1H-NMR (CDCl3) δ ppm: 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), 2.88 (1H, dd, J=10.8, 5.3 Hz), 3.22 (1H, q, J=6.6 Hz), 3.6-3.9 (1H, m), 4.7- 5.2 (1H, width d), 7.27 (5H, s)

Elemental analysis: C19H28N2O2

Calculated: C 72.12 H 8.92 N 8.85

Found: C 71.86 H 9.36 N 8.68

6) 7-(tert.-butoxycarbonylamino-5-azaspiro[2,4]heptane (compound 11a and compound 11b, optical isomer of compound 11)

We added 650 mg of compound 16b and 500 mg of palladium on charcoal (soaked with 50% water) to 30 ml of ethanol and catalytically reduced it under a pressure of 4.1 bar and heated the reaction vessel with a tungsten lamp. We performed the reduction for 6 hours. The catalyst was smeared and filtered 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 alkylated with 15% sodium hydroxide and extracted with 3 portions of chloroform. The chloroform layers were combined, washed with water, dried and the solvent separated to obtain 440 mg of the title compound 11b as a crude product. We also prepared the title compound 11a in a convenient manner.

1H-NMR spectra of compounds 11b and 11a completely matched.

17b: 1H- NMR (CDCl3) δ ppm: 0.4-1.0 (4H, m), 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, J010.8, 5.4 Hz), 3.5-3.9 (1H, M), 5.0-5.4 (1H, width d)

REFERENCE Example 3

Synthesis of 4,7-diazaspiro[2,5]octane

1) Cyclopropane-1.1-dibromoamide (compound 18)

We suspended 14.1 g of cyclopropane-1,1-diamide 17 in 35 g of bromine and added 130 ml of aqueous potassium hydroxide, prepared using 14 g of potassium hydroxide, while stirring at room temperature. After 1 hour of mixing, the reduction mixture was cooled with ice and the formed 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 obtain 28.6 g of the title compound 18.

2) 4,6-diazaspiro[2,4]heptane-5,7-dione (compound 19)

To the sodium methoxide solution, prepared from 9.1 g of metallic sodium and dry methanol, we added 26 g of compound 18 while cooling with ice and stirring. After separating the ice bath, we continued to stir the mixture, after which the internal temperature rose from about 5°C degree by degree and then at about 20°C it suddenly rose to the boiling point of methanol. The reaction mixture was refluxed for 10 minutes and then cooled to room temperature. The reaction mixture was then concentrated to dryness under reduced pressure and acetone was added to the residue. The crystals were collected by filtration and washed with acetone. The washing liquid and the filtrate were combined and concentrated under reduced pressure. The procedure afforded the title compound 19 as a crude product. We used this product without purification in the next reaction.

3) 1-aminocyclopropanecarboxylic acid 20 i

1-tert.-butoxycarbonylaminocyclopropanecarboxylic acid (compound 21)

We dissolved the above crude compound 19 in 60 ml of water, then added 15 g of barium hydroxide. The mixture was heated in a stainless steel autoclave at an internal temperature of 170°C for 2 hours. The reaction mixture was then allowed to stand overnight and the excreted barium carbonate was filtered off. Therefore, we added ammonium carbonate to the filtrate and filtered off the precipitated barium carbonate. The filtrate was concentrated to obtain the title amino compound 20 as a crude product. That compound 20 was tert.-butoxycarbonylated without purification with BOC-ON to obtain 2.5 g of the title compound 21.

1H-NMR (CDCl3) δ ppm: 2.05 (9H, s), 2.15 (2H, 7)

4) Ethyl (1-tert.-butoxycarbonylamino-1-cyclopropylcarbonylamino)acetate (compound 22)

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

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

To 680 mg of compound 22, add 10 ml of trifluoroacetic acid and 0.5 g of anisole. Stir the mixture at room temperature for 2 hours. The solvent was removed under reduced pressure. Add aqueous potassium carbonate to the residue and adjust the pH above 10. Saturate the mixture with sodium chloride and extract with chloroform. The chloroform compound is dried over anhydrous sodium sulfate and the solvent is removed under reduced pressure. The process yields 410 mg of compound 23.

1H-NMR (CDCl3) δ ppm: 0.85 (2H, 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 we heat 500 mg of compound 23 in an oil bath at 220°C, it foams and then solidifies. Continue heating for 20 minutes and at the end of that time cool the reaction system to room temperature. The procedure gives the title compound 24 as a crude product.

1H-NMR (DMSO-d6) δ ppm: 0.96 (2H, t), 1.17 (2H, t, J=4 Hz), 3.86 (2H, J=3 Hz), 8.0, 8.25 (each 1H, wid. s )

7) 4,7-diazaspiro[2,5]octane (compound 25)

350 mg of compound 24 was suspended in 200 ml of dry tetrahydrofuran, then 0.6 g of lithium aluminum hydride was added. We refluxed the mixture for 14 hours. We then added 0.6 g of water, 0.6 g of 15% aqueous sodium hydroxide, and 1.8 g of water to the reaction mixture in the above order while cooling with ice, and the resulting precipitate was removed by filtration. The precipitate was washed with tetrahydrofuran and ether, and the washings and filtrate were combined. The solvent was then removed under reduced pressure to obtain the title compound 4,7-diazaspiro[2,5]octane 25 as a crude product. We reacted this product without purification with a substitution reaction.

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 with stirring and heating at 60°C, 11 g of 3-amino-2,4,5-trifluorobenzoic acid 26 (commercial product ). We stirred the mixture for 20 minutes. After cooling, we added 500 ml of 15% hydrochloric acid and extracted the mixture with ethyl acetate. We dried the extract over anhydrous sodium sulfate and then separated the solvent under reduced pressure. Finally, the residue was chromatographed on a silica gel column (100 g) using chloroform as eluent. The procedure gives 8.4 g of 3-chloro-2,4,5-trifluorobenzoic acid 27 as colorless needles.

Melting point: 114-115°C

Elemental analysis: C7H2CIF3O2

Calculated: C 39.93, H 0.96

Found: C 39.87, H 1.04

1H-NMR (CDCl3) δ ppm: 7.76 (1H, ddd, J=6.5, 8.5, 9.9 Hz), 8.6-9.2 (1H, width s)

2) 2,4,5-trifluoro-3-iodobenzoic acid (compound 28)

10 g of copper(I) iodide and 8.8 g of tert.-butyl nitrite were added to 150 ml of acetonitrile and, with stirring at 60°C, 11 g of 3-amino-2,4,5-trifluorobenzoic acid was added. We continued stirring for 20 minutes and after cooling, added 500 ml of 15% hydrochloric acid. The mixture was then extracted with ethyl acetate. We dried the organic layer over anhydrous sodium sulfate and separated the solvent under reduced pressure. The residue was chromatographed on a silica gel column (100 g) with chloroform as eluent. We collected the fractions containing the title compound and separated the solvent under reduced pressure. Finally, the residue was recrystallized from n-hexane to obtain 8.4 g of the title compound 28 as colorless crystals.

Melting point: 121-122°C

Elemental analysis: C7H2F3IO2. 1/4 H2O

Calculated: C 28.26, H 0.51

Found: C 28.19, H 0.76

MS m/z: 302 (M+)

Using anhydrous copper(I) bromide in approximately the same way as above, we synthesized 3-bromo-2,4,5-trifluorobenzoic acid (compound 29).

Melting point: 124-125°C

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

3-1 Direct demining

We dissolved 1.8 g of tert.-butyl nitrite in 5 ml of dry dimethylformamide and added 2.0 g of 3-amino-2,4,5-trifluorobenzoic acid while stirring at 60°C. We continued to stir the mixture 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 anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was chromatographed on a silica gel column using chloroform as eluent. The procedure yields 1.1 g of crystals of the title compound 30.

3-2 Reduction of a bromo compound

The mixture composed 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 a hydrogen atmosphere for 4 hours. The catalyst was then filtered 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 obtain 3.2 g of the title compound 30 as colorless crystals.

30:1H-NMR (CDCl3) δ ppm: 7.10 (1H, ddd, J=6.5, 9 Hz), 7.96(1H, ddd, J=6.3, 8.5, 9.8 Hz), 9.2-9.6 (1H, width )

Example 1

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

(connection 31)

300 mg of 7-amino-5-azaspiro[2,4]heptane 7 and 250 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid were added to 5 ml dimethyl sulfoxide. We heated the mixture for 30 minutes at 100°C. After cooling, we separated the solvent by distillation under reduced pressure and crystallized the residue with the addition of ethanol. The resulting crude crystals were collected by filtration, suspended in ethanol and dissolved with the addition of 28% aqueous ammonia. We added 50 mg of activated carbon to that solution and filtered the mixture. The filtrate was concentrated by heating and the resulting crystals were collected by filtration. The process yields 170 mg of the title compound 31.

Melting point: 238-245°C

Elemental analysis: C19H19F3O2. 1/2 H2O

Calculated: 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, after adding 66 mg of triethylamine and further to the excess amount of aqueous solution of the optically active amino compound 7a. We heated the mixture at 120°C for 3 hours. The solvent was then removed under reduced pressure and the residue purified by preparative TLC (developed with chloroform-methanol-water 7:3:1 separation layers). The resulting crystals were recrystallized from ethanol-28% aqueous ammonia to obtain 4.5 mg of compound 31a as light yellow crystals.

With the use of compound 7b, we also obtained 34 mg of compound 31b in approximately the same way.

(+)-7-(7-amino-5-azaspiro[2,4]heptan-5-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic

acid 31a

Melting point: 221-235°C (decomposition)

[α]D + 116.2° (c=0.575, concentrated aqueous ammonia)

Elemental analysis: C19H19F2O3⋅1/2 H2O

Calculated: C 59.37, H 5.24, N 10.93

Found: C 59.31, H 5.02 N 10.93

(-)-7-(7-amino-5-azaspiro[2,4]heptan-5-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 31b

Melting point: 227-240°C (decomposition)

[α]D -106.3° (c=0.365, concentrated aqueous ammonia)

Elemental analysis: C19H19F2N3O3. 1/2 H2O

Calculated: 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

(connection 32)

200 mg of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 150 mg of compound 11 and 70 mg of triethylamine were added to 5 ml of acetonitrile and the mixture was refluxed for 24 hours . After cooling, we separated the solvent under reduced pressure and added water to the residue. The precipitate was collected by filtration and washed sequentially with water, acetonitrile, ethanol and ether and dried. The procedure gave 245 mg of 7-(7-tert.-butoxycarbonylamino-5-azaspiro[2,4]heptan-5-yl)-8-chloro-1-cyclopropyl-6-fluoro1,4-dihydro-4-oxoquinoline- 3-carboxylic acids with a melting point of 205-207°C.

To 200 mg of this carboxylic acid, we added 0.3 ml of anisole and 5 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 30 minutes. We separated the solvent under reduced pressure and added water to the residue. The mixture was alkylated 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 portions of chloroform. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was then separated under reduced pressure and the residue was recrystallized from ethanol-concentrated aqueous ammonia. The process yields 105 mg of the title compound 32.

Melting point: 235.240°C (decomposition)

Elemental analysis: C19H19 CIFN3O 1/4 H2O

Calculated: 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-6-fluoro-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 11 were added to 4 ml of dimethyl sulfoxide and the mixture was heated at 120°C for 2 hours. After cooling, we separated the solvent under reduced pressure and crystallized the residue with the addition of ethanol. We collected the crystals by filtration. The procedure gives 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.

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

Melting point: 249-252°C (decomposition)

Elemental analysis: C19H20 FN3O3

Calculated: C 63.85, H 5.64 N 11.76

Found: C 63.61, H 5.94, N 11.71

Examples 5 and 6

In essentially the same way as in example 4, we synthesized 7-(7-amino-5-azaspiro[2,4]heptan-5-yl)-6-fluoro-1-(2,4-difluorophenyl)-1,4 -dihydro-4-oxoquinoline-3-carboxylic acid (compound 34) with a melting point of 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) with a melting point of 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, 2,3de][1,4] benzoxazine-6-carboxylic acid (compound 36)

300 mg BF2-ketal 9,10-difluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3de][1,4]benzoxazine-6-carboxylic acid and 250 mg of compound 11 was added to 5 ml of dimethylacetamide and the mixture was stirred at room temperature for 3 hours. The solvent was then separated under reduced pressure and 1 ml of triethylamine and 30 ml of 95% methanol were added to the residue. We refluxed the mixture for 6 hours. After cooling, we separated the solvent under reduced pressure and triturated the residue with ethanol. The resulting crystals were collected by filtration and processed, as described in example 4, to separate the tert.-butoxycarbonyl group. The procedure gives 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 obtain 110 mg of the title compound 36.

Melting point: 236-237°C.

Example 8

1-cyclopropyl-7-(4,7-diazaspiro[2,5]octan-7-yl)-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (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 we added 0.3 ml of triethylamine. The mixture was heated in a bath at 120°C for 2 hours. The solvent was then separated under reduced pressure and the residue was chromatographed on silica gel column with chloroform-methanol-water 15:3:1 as eluent. The crude product, obtained from the fraction containing the desired compound, was recrystallized from ethanol-concentrated aqueous ammonia to obtain 160 mg of the title compound 37.

Melting point: 243-245°C (decomposition)

Elemental analysis: C19H20 N3O2F ⋅ 1/4 H2O

Calculated: C 63.08, H 5.71, N 11.61

Found: C 62.88, H 5.99, N 11.64

1H-NMR ( NaOD-DDS ) δ ppm: 0.97 (2H, t, J=6 Hz), 1.12 (2H, m) 1.36 (2H, lat. t), 1.48 (2H, lat. 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-cyclopropyl-6,7-difluoro-3-oxo-3,4-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 was refluxed for 2.5 days. (After 3 hours we added another 400 m of upper azaspiro-heptane). The reaction mixture was diluted with chloroform and the organic compound was washed with 10% aqueous citric acid and dried. The solvent was then separated under reduced pressure.

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

We collected the fractions containing the desired compound and separated the solvent under reduced pressure. We added a small amount of ethanol to the residue and heated the mixture and let it stand. The resulting crystals were collected by filtration and washed with diisopropyl ether to obtain 174 mg of the title compound 38.

Melting point: 179-182°C

1H-NMR (CDCl3 ) δ ppm: 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-amino-5-azaspiro[2,4]heptan-5-yl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

(connection 39)

174 mg 7-(7-acetoxy-5-azaspiro[2,4]heptan-5-yl)-8-chloro-1-cyclopropyl-1-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 38 was suspended in 8 ml of ethanol, then we added 1.5 ml of 1 N aqueous sodium hydroxide. 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. We washed the mixture with water. The aqueous layer was acidified with 1 N hydrochloric acid and extracted with chloroform. We dried the extract and separated the solvent under reduced pressure. Finally, the residue was recrystallized from aqueous ammonia-ethanol to obtain 127 mg of the title compound 39.

Melting point: 242-244°C

1H-NMR ( 1 N NaOD ) δ: 0.53-1.17 (8H, m), 2.98, 3.35 & 3.74 (each 1H), 4.09-4.13 (3H, m), 7.59 (1H, m), 8.45 (1H, s )

Elemental analysis: C19H18 N2O4CIF

Calculated: C 58.10, H 4.62, N 7.13

Found: C 58.39, H 4.65, N 7.27

Example 11

7-(7-hydroxyimino-5-azaspiro[2,4]heptan-5-yl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (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), and to this was added 5 ml of trifluoroacetic acid while cooling with ice. The mixture was stirred at the same temperature for 30 minutes. The solvent was then separated under reduced pressure and 100 ml of dry acetonitrile was added to the residue. Then we added 300 mg of 8-chloro-1-cyclopropyl-6,7-difluoro-4-oxo-3,4-dihydroquinoline-3-carboxylic acid and 1 ml of triethylamine and refluxed the mixture for 9 hours. The solvent was then separated under reduced pressure, methanol was added to the residue and the insoluble part was filtered off. We let the mother liquor stand for 2 days and collected the resulting crystals by filtration and recrystallized from aqueous ammonia-ethanol to obtain 58 mg of the title compound 40.

Melting point: 239-240°C

1H-NMR ( 1 N NaOD ) δ: 0.70-1.05 (8H, m), 3.50 (2H, s), 4.09-4.12 (1H, m), 4.29 (2H, s), 7.65 (1H, d, J=15 Hz), 8.46 (1H, s)

Elemental analysis: C19H17 N3O4FCI

Calculated: 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-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H- pyrido[1,2,3,de][1,4]

benzoxazine-6-carboxylic acid (compound 36 b)

280 mg BF2-calate (-)-9,10-difluoro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3,-de][1,4]-benzoxazine-6- carboxylic acids were suspended in 4 ml of dry dimethyl sulfoxide, then 450 mg of compound 68b and 520 mg of triethylamine were added at room temperature. We stirred the mixture for 45 minutes. Then, while cooling with ice, we slowly added water to the reaction mixture and collected the resulting crystals by filtration. We added 30 ml of 90% methanol and 2 ml of triethylamine to the crystals and refluxed the mixture for 17 hours. The solvent was removed under reduced pressure and the residue was recrystallized from aqueous ammonia-ethanol to obtain 73 mg of the title compound 36b.

Melting point: 217-238°C

[α]D -109.22° (c=0.683, 1 N NaOH)

1H-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: C19H20 N3O4F ⋅ 1 1/4 H2O

Calculated: C 57.64, H 5.73, N 10.61

Found: C 57.64, H 5.21, N 10.81

Example 13

(-)-7-(7-amino-5-azaspiro[2,4]heptan-5-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4dihydro-1,8-naphthyrid-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 . The mixture was stirred at 110°C for 1 hour. We separated the solvent under reduced pressure, and added diethyl ether to the residue. We collected the resulting precipitate by filtration and added 1 N hydrochloric acid to it. The mixture was washed with chloroform. The aqueous solution was alkylated with 1 N aqueous sodium hydroxide and washed again with chloroform. The alkyl solution was then cooled with ice and adjusted with concentrated hydrochloric acid to pH 7.1 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 ammonia-ethanol to obtain 283 mg of the title compound 35b as colorless fine needles.

Melting point: 240-250°C (decomposition)

[α]D -13.6° (c=0.66, 1 N NaOH)

Elemental analysis: C18H19 N4O3F ⋅ 1/4 H2O

Calculated: 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-3-carboxylic acid (compound 41b)

We suspended 200 mg of compound 68b in 15 ml of acetonitrile, then added 3 ml of triethylamine and, under reflux, in smaller portions, 327 mg of ethyl 7-chloro1,4-dihydro-6-fluoro-1-(2-methyl-2-propyl)- 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. We connected the organic compounds and separated the solvents. Diethyl ether was added to the residue and the resulting precipitate was collected by filtration to obtain 516 mg of a colorless powder.

1H-NMR ( DMSO-d6 ) δ: 0.77-1.05 (4H, m), 1.27 (3H, t, J=7 Hz), 1.82 (9H, s), 2.86-3.36 (4H, m), 4.20 (1H, m), 4.21 (2H, q, J=7 Hz), 7.91 (1H, d, J=13 Hz), 8.68 (1H, s)

510 ml of 1 N aqueous sodium hydroxide and the mixture was refluxed for 40 minutes. We added 5 ml of water to the reaction mixture and adjusted the pH to 7.5 with 0.25 N hydrochloric acid. The resulting crystals were collected by filtration and washed with water. The crystals were dried and recrystallized from ethanol to obtain 171 mg of the title compound 41b as a colorless powder.

Melting point: 243-247°C (decomposition)

[α]D –16.7° (c=0.504, 1 N NaOH)

1H-NMR ( DMSO-d6 ) δ: 0.45-0.82 (4H, m), 1.87 (9H, s), 2.80-3.80 (4H, m), 4.00 (1H, m), 7.98 (1H, d, J= 13 Hz), 8.82 (1H, s)

Elemental analysis: C19H23 N4O3F ⋅ 1/2 H2O

Calculated: 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-methybenzoic acid

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

We dissolved 200 g of dimethyl tetrafluorophthalate in 400 ml of nitromethane (Ishikawa, Suzuki & tanabe: Nippon Kagaku Kaishi, 1976, 200) and cooled the solution in an ice and salt bath. At an internal temperature of 15 to 20°C, 171 g of 1,8-diazabicyclo[5,4,0]-7-undecene were added in drops over 30 minutes. After the complete addition in drops, the mixture was stirred at an internal temperature of 10°C for another 30 minutes and the mixture was then 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 separated under reduced pressure and the residue was chromatographed on a silica gel column (500 g) with benzene as eluent. The procedure afforded 195 g of the title compound 42 as a yellow oil.

1H-NMR ( CDCl3 ) 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, we reduced for 2 hours a mixture of 5.0 g of compound 42, 20 ml of Raney's nickel, 15 ml of 35% formalin and 70 ml of ethanol. 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, and we obtained 5.2 g of the title compound 43 as a light yellow oil.

1H-NMR ( CDCl3 ) 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)-phenyl-methylenetrimethylammonium iodide (compound 44)

We dissolved 5.2 g of compound 42 in 50 ml of ethanol, then added 5 ml of methyl iodide and let the mixture stand for 1.5

an hour. The resulting crystals were collected by filtration. The procedure yields 3.6 g of colorless crystals of the title compound 44.

Melting point: 186-190°C (decomposition)

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

a) The mixture of 4.6 g of compound 42, 6.8 g of tributyltin hydride, 300 mg of α,αʹ-azobisisobutyronitrile and 70 ml of benzene was refluxed for 4 hours. The reaction mixture was then concentrated under reduced pressure and the residue was chromatographed on a silica gel column (59 g), with benzene as eluent. The procedure afforded 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's nickel and 350 ml of ethanol was reduced at atmospheric pressure under irradiation with a tungsten lamp for 25.5 hours.

The catalyst was then separated by filtration and the filtrate was concentrated under reduced pressure. We added water to the residue and extracted it with chloroform. We dried the organic layer over anhydrous sodium sulfate. The solvent was then removed under reduced pressure to obtain 9.62 g of the title compound 45 as a yellow oil.

1H-NMR ( CDCl3 ) δ: 2.29 (3H, t, J=2 Hz), 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. We dried the extract over colorless sodium sulfate. The solvent was then removed under reduced pressure to obtain 2.1 g of the title compound 46 as colorless crystals.

Melting point: 155-160°C

6) 2,4,5-trifluoro-3-methylbenzoic acid (compound 47)

We dissolved 10.1 g of compound 46 in 40 ml of water and heated the mixture in a sealed tube in a bath 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 obtain 6.2 g of the title compound 47 as light yellow crystals.

Melting point: 89-90°C

1H-NMR ( CDCl3 ) δ: 2.29 (3H, t, J=2 Hz), 7.56-7.84 (1H, m), 8.1-8.6 (1H, broad)

REFERENCE Example 6

Ethyl 2,45-trifluoro-3-methylbenzylacetate (compound 48)

We dissolved 9.89 g of 2,4,5-trifluoro-3-methylbenzoic acid 47 in 200 ml of benzene, then added 40 ml of thionyl chloride and refluxed the mixture 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 again concentrated to dryness under reduced pressure and the obtained crude acid chloride was dissolved in 200 ml of diethyl ether. The 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 at the end of that time, 50 ml of a diethyl solution of 8.34 g of diethyl malonate was added dropwise. 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 was dissolved in 300 ml of diethyl ether. To that solution, we added the above-prepared diethyl ether solution of acid chloride in drops over the course of 10 minutes, and the mixture was stirred at room temperature for 4 days. Then we added 100 ml of 1 N hydrochloric acid and after mixing took the ether layer, washed it with water and dried it over anhydrous sodium sulfate. The solvent was then separated under reduced pressure. We added 500 ml of water and 500 mg of p-toluenesulfonic acid to the residue and refluxed the mixture for 7 hours. The reaction mixture was extracted with chloroform, the organic compound was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was chromatographed on a silica gel column using benzene as eluent. The procedure afforded 6.1 g of the title compound 48 as a colorless oil. If left to stand, the oil partially crystallizes.

REFERENCE Example 7

Ethyl 2-cyclopropylaminoethylene-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 3 hours. The reaction mixture was then concentrated to dryness under reduced pressure. We dissolved the residue in 25 ml of 1,2-dichloromethane, then added 10 ml of a solution prepared with a solution of 400 mg of cycloporpilamine in 1,2-dichloromethane. The mixture was stirred at room temperature for 14 hours. The reaction mixture was then concentrated to dryness under reduced pressure to obtain 2 g of the title compound 49 as colorless crystals, melting 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)

We dissolved 1.97 g of compound 49 in 30 ml of dry dioxane, then added 360 mg of 60% sodium hydride and stirred the mixture at room temperature for 18 hours. After adding 10 ml of 1 N hydrochloric acid, the reaction mixture was concentrated under reduced pressure and water was added to the residue. The resulting crystals were collected by filtration and washed with water and small amounts of ethanol and diethyl ether. The procedure gives 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 50 ml of water was added to the reaction mixture. The resulting crystals were collected by filtration and washed with water and ethanol to obtain 1.12 g of the title compound 51.

Melting point: 241-242°C

REFERENCE Example 10

BF2 -ketal 1-cyclopropyl-6,7-difluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (compound 52)

420 mg of compound 50 was suspended in 30 ml of diethyl ether, then 2 ml of boron trifluoride-diethyl 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 procedure afforded 487 mg of the title compound 52 as yellow crystals.

Melting point: 275-278°C

Example 15

(-)-7-(7-amino-5-azaspiro[2,4]heptan-5-yl)-8-chloro-1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4- dihydroquinoline-3

-carboxylic acid (compound 45b)

A mixture of 340 mg of compound 52, 330 mg of 7-tert.-butoxycarbonylamino-5-azaspiro-[2,3]heptane (compound 11b), 150 mg of triethylamine and 5 ml of dimethyl sulfoxide was mixed at room temperature for 5 days. The reaction mixture was then dissolved in 100 ml of chloroform and the solution was washed with water. We dried the organic compound over anhydrous sodium sulfate and separated the solvent under reduced pressure. The residue was chromatographed on a silica gel column (30 g), using chloroform-methanol (95:5) as eluent. The resulting BF2-ketal of 7-(7-tert.-butoxycarbonylamino-5-azaspiroheptan-5-yl)-1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was dissolved in 30 ml of 70% methanol, then added 1 ml of triethylamine and refluxed the mixture 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 compound was dried over anhydrous sodium sulfate. The solvent was then separated under reduced pressure. 10 ml of trifluoroacetic acid was added to the residue and the mixture was stirred at room temperature for 20 minutes and then concentrated to dryness under reduced pressure. We added hydrochloric acid to the residue and washed the mixture with chloroform. After cooling with ice, the aqueous layer was adjusted to pH 12 with aqueous sodium hydroxide and washed with chloroform. The aqueous layer was adjusted to pH 7.4 and extracted with chloroform. We dried the organic layer over anhydrous sodium sulfate and separated the solvent. The residue was recrystallized twice from aqueous ammonia-ethanol to obtain 52 mg of the title compound 55b as colorless crystals.

Melting point: 180-182°C

[α]D –128.0° ( c=0.125, 1 N NaOH )

1H-NMR (CDCl3) δ : 0.61-0.63 (1H, m), 0.64-0.74 (2H, m), 0.84-0.88 (1H, m), 0.90-0.97 (2H, m), 1.19-1.28 (2H, m), 2.62 (3H, s), 3.19-3.21(1H, m), 3.29 (1H, d, J=9 Hz), 3.36-3.39 (1H, m), 3.84 (1H, d, J=9 Hz ), 3.99-4.03 (1H, m), 4.05-4.08 (1H, m), 7.85 (1H, d, J=13.5 Hz), 8.86 (1H, s)

Example 16

Optically active 7-(7-tert.-butoxycarbonylamino)-5-azaspiro[2,4]heptan-5-yl]-8-chloro-1-cyclopropyl-6-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 separated under reduced pressure and the resulting precipitate was collected by filtration, washed sequentially with water, acetonitrile, ethanol and ether and dried under reduced pressure. The procedure afforded 560 mg of the title compound 56b as light yellow crystals. Using compound 11a, we also synthesized the title compound 56a in an almost identical way.

56b: light yellow crystals

Melting point: 216-217°C

[α]D-134.7.° (c=1.653, chloroform)

1H-NMR (CDCl3) δ: 0.4 -1.6 (8H, m), 1.45 (9H, s), 3.33 (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, width d), 7.95 (1H, d, J=12.9 Hz), 8.87 (1H, s)

Elemental analysis: C24H27 N3O5CIF

Calculated: C 58.60, H 5.53, N 8.54

Found: C 58.43, H 5.59, N 8.40

56a: light yellow crystals

Melting point: 215-216°C

[α]D +131.4 ° (c=0.77, chloroform)

Elemental analysis: C24H27 N3O5CIF

Calculated: C 58.60, H 5.53, N 8.54

Found: C 58.37, H 5.58, N 8.44

The NMR spectrum of compound 56a completely matches that of compound 56b.

Example 17

Optically active 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 a and compound 32 b))

0.5 ml of anisole and 10 ml of trifluoroacetic acid were added under ice cooling to 520 mg of compound 56b. Then we stirred the mixture at room temperature for 30 minutes. The solvent was then separated under reduced pressure, and water was added to the residue. We adjusted the mixture to a pH of about 11-12 with 1 N aqueous sodium hydroxide while cooling with ice. We washed that aqueous solution twice with chloroform and adjusted it 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 residue was recrystallized from ethanol-aqueous ammonia to give 32 mg of the title compound 32b as light yellow crystals. We have suitably prepared compound 32a from compound 56a.

Compound 32b: light yellow crystals

Melting point: 166-170°C (decomposition)

[α]D -112.6 ° ( c=0.43, 1 N aqueous NaOH )

1H-NMR (CDCl3, 500 MHz) δ ppm: 0.6-1.25 (8H, m), 3.08 (1H, t, J=4.4 Hz), 3.30 (1H, d, J010.3 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: C19H19 N3O3CIF ⋅1/2 H2O

Calculated: C 56.93, H 5.03, N 10.48

Found: C 57.16, H 5.44, N 10.46

Compound 32a: light yellow crystals

Melting point: 160-165°C (decomposition)

[α]D +110.3 ° ( c=0.435, 1 N aqueous NaOH )

Elemental analysis: C19H19 N3O3CIF 1/2 H2O

Calculated: C 56.93, H 5.03, N 10.48

Found: C 56.87, H 5.37, N 10.32

The NMR spectrum of compound 32a completely coincides with that of compound 32b.

REFERENCE Example 11

BF2-chelate of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (compound 57)

15 ml of boron trifluoride-diethyl ether complex was added to a suspension of 3 g of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid in 30 ml of 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 obtain 3.35 g of the title compound 57 as a colorless powder.

Melting point: 245-260°C (decomposition)

Elemental analysis: C13H7 NO3CIF4

Calculated: C 44.94, H 2.03, N 4.03

Found: C 45.07, 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-oxoquinolin-3- carboxylic acid (compound 32a)

Mixtures of 700 mg of compound 57, 450 mg of 7-amino-5-azaspiro[2,4]heptane dihydrochloride (compound 68b), 610 mg of triethylamine and 7 ml of dimethyl sulfoxide were mixed 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. We separated the solvent under reduced pressure and added 1 N hydrochloric acid to the residue. The mixture was washed with chloroform and the aqueous compound was alkylated with 1 N aqueous sodium hydroxide. The aqueous layer was washed again with chloroform. We adjusted the pH of the alkaline aqueous solution by cooling it with concentrated hydrochloric acid to pH 7.1. The aqueous solution was extracted three times with chloroform. The extract was washed with saturated aqueous sodium chloride and dried. The solvent was separated under reduced pressure. The residue was recrystallized from concentrated ammonia, water and ethanol to obtain 601 mg of the title compound 32a as colorless crystals.

REFERENCE Example 12

Alternative synthesis of 4,7-dioxo-5-[1-(R)-phenyl-ethyl]-5-azaspiro[2,4]heptane 12

1) 1-acetylcyclopropane-1-carboxylic acid (compound 58)

An aqueous solution of 75.67 g of sodium hydroxide in 200 ml of water was added dropwise to a solution of 268.6 g of compound 2 in 400 ml of ethanol at room temperature over 20 minutes. The mixture was stirred at room temperature for 2 hours. We added 1500 ml of dichloromethane and 500 ml of water to the mixture. We shook the mixture and then separated the aqueous layer. 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 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 separated under reduced pressure. The residue was distilled under reduced pressure to obtain 232 g of the title compound 58 as a colorless oil.

1H-NMR ( CDCl3 ) δ ppm: 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 was added dropwise to the solution over the course of 20 minutes. We mixed the mixture while cooling, during which we maintained the internal temperature for 40 minutes at about -30°C. The mixture was cooled to an internal temperature of -40°C and 241.1 g of R-(+)-1-phenylethylamine was added to the mixture. We stirred the mixture 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 obtain 489.3 g of the title compound 59 as a colorless oil.

1H-NMR ( CDCl3 ) δ ppm: 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. We separated the water that disappeared during the reaction. After cooling, we added 500 ml of water and 500 ml of benzene to the mixture. We then shook the mixture. The organic layer was separated and washed with a saturated aqueous solution of sodium bicarbonate and water. We dried the organic layer over anhydrous sodium sulfate and removed the solvent under reduced pressure to obtain 227.8 g of the title compound 60.

1H-NMR ( CDCl3 ) δ ppm: 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 ), 5.11 (1H, q, J=7.2 Hz ), 7.31 (5H, s ), 7.75 (1H, width s )

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

We added 145.4 g of bromine in drops to 436 ml of dioxane at room temperature in 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 an aqueous solution of sodium trisulfate and water. We dried the organic layer over anhydrous sodium sulfate and removed the solvent under reduced pressure to obtain 326.0 g of the title compound 61.

1H-NMR ( CDCl3 ) δ ppm: 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, width s )

5) 4,7-dioxo-5-[1-(R)-phenylethyl]-5-azaspiro[2,4]heptane-7-ethylene acetal (compound 62)

43 g of 60% sodium hydride was added at room temperature over 1.5 hours in three portions to a solution of 293 g of compound 61 in 1500 ml of N,N-dimethylformamide. After adding sodium hydride, we cooled the mixture to maintain the internal temperature at around 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. We dried the organic layer over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain 203.3 g of the title compound 62 as a dark oil.

1H-NMR ( CDCl3 ) δ ppm: 0.98-1.3 (4H, m), 1.5 (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. Then the solvent was separated under reduced pressure and the residue was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. We decolorized the extract with activated charcoal and separated the solvent under reduced pressure. The residue was purified by chromatography on a silica gel column (1300 g), using chloroform as an eluent, which contained 0-10% ethyl acetate, to obtain 65.7 g of the title compound 12 as a colorless crystal.

1H-NMR ( CDCl3 ) δ ppm: 1.61 (3H, d, J=7.2 Hz ), 1.41-1.75 ( 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-5-azaspiro[2,4]heptane (compound 67)

1) 7,7-ethylenedioxy-5-[1-(R)-phenylethyl]-5-azaspiro[2,4]heptane (compound 63)

We added 2.5 g of lithium aluminum hydride to solution 7.1. g of compound 62 in 150 ml of anhydrous tetrahydrofuran and the mixture was refluxed for 3.5 hours. We cooled the mixture with ice and added 2.5 ml of water, 2.5 ml of 15% aqueous sodium hydroxide solution and 7.5 ml of water in that order. The insoluble material was separated by filtration and the solvent was separated from the filtrate. The residue was purified by chromatography on a silica gel column (100 g), eluting with a mixture of n-hexane and ethyl acetate (3:2), to obtain 5.67 g of the title compound 63.

1H-NMR ( CDCl3 ) δ ppm: 0.40-0.60 (2H, m), 0.76-0.96 (2H, m), 1.36 (3H, d, J=7.2 Hz), 2.40-2.88 (4H, m), 3.77 ( 4H, s ), 7.18-7.50 (5H, m )

2) 7,7-ethylenedioxy-5-azaspiro[2,4]heptane (compound 64)

We shook a mixture of 3.89 g of compound 63, 50 ml of ethanol and 4 g of 5% palladium on charcoal in a hydrogen atmosphere at 3.9 bar. During the reduction reaction, we heated the reaction vessel from the inside with a tungsten lamp. We continued the reduction reaction for 3 hours. We separated the catalyst by filtration. The solvent was separated by filtration under reduced pressure to obtain 2 g of the title compound 64.

1H-NMR ( CDCl3 ) δ ppm: 0.44-0.64 ( 2H, m ), 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 separated under reduced pressure. The residue was extracted with chloroform and the extract was washed with water. The solvent was separated under reduced pressure. The residue was purified by chromatography on a silica gel column (50 g), eluting with a mixture of n-hexane and ethyl acetate (3:1), to obtain 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 separated under reduced pressure. We extracted the residue with chloroform and dried the extract. The solvent was removed under reduced pressure to obtain 1.94 g of the title compound 66.

1H-NMR (CDCl3) δ ppm: 1.00-1.2 & 1.30-1.50 (2H, each, m), 4.49 (9H, s), 3.78 (2H, m), 3.85 (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 solution 1.9. g of compound 66. The mixture was stirred at room temperature for 1 day. We separated the solvent under reduced pressure and added a 10% aqueous solution of citric acid to the residue. The mixture was extracted with chloroform and the extract was washed with water. We dried the extract and removed the solvent under reduced pressure to obtain 1.86 g of the title compound 67.

Melting point: 117-119°C

1H-NMR ( CDCl3 ) δ ppm: 0.90-1.10 ( 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)

The 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 at 3.9 bar. During the reduction reaction, we heated the reaction vessel from the inside with a tungsten lamp. We continued the reduction reaction for 3.5 hours. The catalyst was separated by filtration and the solvent was removed to obtain 350 mg of the title compound 68b.

Melting point: 230-240°C (decomposition, decomposition started at about 190°C)

[α]D -41.5 ° ( c= 1.616, H2O )

Elemental analysis: C6H14 N2CI2 ⋅ 1/2 H2O

Calculated: 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)

1H-NMR (D2O) 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 )

REFERENCE Example 15

7-tert.-butoxycarbonylamino-5-azaspiro[2,4]heptane (compound 11b)

We shook the mixture of 11.8 g of compound 16b, 200 ml of ethanol and 1 g of 5% palladium on charcoal under a hydrogen atmosphere at 3.9 bar. In the reduction reaction, we heated the reaction vessel with a tungsten lamp. We performed the reduction reaction for 6 hours. The catalyst was separated by filtration and the solvent was separated from the filtrate under reduced pressure. The residue was dissolved in ethyl acetate and the solution was extracted with a 10% aqueous solution of citric acid. The aqueous layer was washed with ethyl acetate. The aqueous layer was alkalized with aqueous sodium hydroxide solution and extracted with chloroform. We dried the extract and removed the solvent under reduced pressure to obtain 7.6 g of the title compound 11b.

Melting point: 56-59°C

[α]D - 68.54 ° ( c = 1.742, CHCl3 )

REFERENCE Example 16

1) Diethyl cyclobutylidenemalonate (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 we cooled to -30°C. We added 5 g of cyclobutanone and 10.83 g of diethyl manolate to the mixture. Then, over the course of 1 hour, we added a solution of 23.1 ml of pyridine in 50 ml of tetrahydrofuran in drops, during which we maintained the temperature of the reaction mixture below -10°C. We stirred the mixture for 18 hours, during which we maintained the temperature of the mixture around 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, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. We dried the organic layer over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain 17,265 g of the title compound 70 as a colorless oil.

1H-NMR (CDCl3) δ ppm : 1.29 (6H, t, 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)

Diethyl cyclopentylidene malonate (compound 71) was obtained by a suitable procedure

1H-NMR ( CDCl3 ) δ ppm: 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 cyclohexylidenemalonate (compound 72) 1H-NMR ( CDCl3 ) δ ppm : 1.28 (6H, t, J=7.2 Hz ), 1.4 -1.85 ( 6H, ext. ), 2.3-2.6 (4H, ext.), 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 16 hours. We added a 10% aqueous solution of citric acid to the mixture and shook the mixture. The organic layer was separated and washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain 19.03 g of the title compound 73 as a yellow oil.

1H-NMR ( CDCl3 ) δ ppm: 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 )

We obtained diethyl (1-nitromethyl-1-cyclopentyl)malonate (compound 74) 1H-NMR ( CDCl3 ) δ ppm: 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) 1H-NMR ( CDCl3 ) δ ppm : 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).

3) Ethyl 7-oxo-6-azaspiro[3,4]octane-8-carboxylate (compound 76)

We added 30 ml of Reney's nickel, washed with water and ethanol, to a solution of 19.03 g of compound 73 in 400 ml of ethanol. We performed the catalytic reduction for 2 days. They separated the catalyst by filtration and the solvent under reduced pressure. We added ethyl acetate and 1 N hydrochloric acid to the mixture and shook it. We dried the organic layer over anhydrous sodium sulfate and separated the solvent under reduced pressure. The residue was purified by chromatography on a silica gel column (100 g), eluting with chloroform, which contained 0-3% methanol, to obtain 2.97 g of the title compound 76. The hydrochloric acid layer was neutralized with sodium bicarbonate and the mixture was extracted with ethyl acetate. We dried the organic layer over anhydrous sodium sulfate and removed the solvent under reduced pressure to obtain 1.58 g of the title compound 76. Finally, we obtained a total of 4.56 g of the title compound 76.

1H-NMR ( CDCl3 ) δ ppm : 1.28 ( 3H, t, J=7.1 Hz ), 1.8 - 2.2 ( 6H, m ), 3.21 (1H, s ), 3.41 ( 1H, dd, J=9.7 & 1.4 Hz) , 3.60 (1H, d, J=9.7 Hz), 4.20 (2H, q, J=7.1 Hz), 7.21 (1H, width)

We obtained 3-oxo-2-azaspiro[4,4]nonane-4-carboxylate (compound 77) 1H-NMR ( CDCl3 ) δ ppm: 1.28 ( 3H, t, J=7.3 Hz ), 2.6 - 2.8 ( 8H, width ), 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 ) . ), 1.3 - 1.7 ( 10H, width ), 3.05 (1H, s ), 3.17 ( 1H, dd, J=9.3 & 1.4 Hz ), 4.20 ( 2H, q, J=7.3 Hz ), 7.30 (1H, width . )

7-oxo-6-azaspiro[3,4]octane-8-carboxylic acid (compound 79)

20 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. We refluxed the mixture for 2 hours. The ethanol was separated under reduced pressure and the aqueous layer was washed with chloroform. The aqueous layer was neutralized with ice cooling 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 obtain 1.57 g of the title compound 79 as colorless crystals.

1H-NMR ( CDCl3 ) δ ppm : 1.6-2.7 (6H, s ), 3.15 (1H, s ), 3.40 ( 1H, d, J=9.2 Hz ), 3.60 ( 1H, d, J=9.2 Hz ), 6.2 (1H, width)

Diethyl 3-oxo-2-azaspiro[4,4]nonane-4-carboxylic acid (compound 80) was obtained by a suitable procedure 1H-NMR (CDCl3 ) δ ppm: 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, width ) and 3-oxo-2-azaspiro[4,5]decane-4- carboxylic acid (compound 81) 1H-NMR (CDCl3) δ 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, width ).

5) 8-tert.-butoxycarbonylamino-7-oxo-6-azaspiro[3,4]octane (compound 82)

2.2 ml of diphenyl phosphorylazide and 1.55 ml of triethylamine were added with stirring to a suspension of 1.57 g of compound 79 in 20 ml of benzene. We refluxed the mixture for 1.5 hours. Then we added 4.4 to the mixture. ml of tert.-butanol and refluxed the mixture for 16 hours. The solvent was separated 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 washing liquids were extracted with ethyl acetate and the combined extracts were dried over anhydrous sodium sulfate. The solvent was separated under reduced pressure. The residue was purified by chromatography on a silica gel column (50 g), eluting with chloroform, which contained 0-3% methanol, to obtain 0.56 g of the title compound 82.

1H-NMR ( CDCl3 ) δ ppm: 1.48 (9H, s), 1.5-2.5 (6H, m), 3.27 (1H, d, J=9.9 Hz), 3.44 (1H, d, J=9.9 Hz), 4.18 (1H, d, J=7.7 Hz ), 5.20 ( 1H, d, J=7.7 Hz ), 7.13 ( 1H, width, s )

Diethyl 4-tert.-butoxycarbonylamino-3-oxo-2-azaspiro[4,4]nonane (compound 83) was obtained by a suitable procedure. , m ), 3.13 ( 2H, s ), 4.35 ( 1H, d, J=7.9 Hz ), 5.15 ( 1H, d, J=7.9 Hz ), 7.21 ( 1H, wid., s ) and 4-tert.- butoxycarbonylamino-3-oxo-2-azaspiro[4,5]decane (compound 84) 1H-NMR ( CDCl3 ) δ ppm : 1.46 ( 9H, s ), 1.0-1.8 (10H, m ), 2.9-3.4 ( 2H, m ), 4.15 (1H, d, J=8.6 Hz ), 4.89 (1H, d, J=8.6 Hz ), 6.71 (1H, width, s ).

6) 6-tert.-butoxycarbonyl-8-tert.-butoxycarbonylamino-6-azaspiro[3,4]octane (compound 87)

15 ml of trifluoroacetic acid was added while mixing to 560 mg of ice-cooled compound 82. The mixture was then stirred at room temperature for 1.5 hours. The trifluoroacetic acid was separated under reduced pressure and the residue was dissolved in 30 ml of anhydrous tetrahydrofuran. We cooled the solution with ice and added 884 mg of lithium aluminum hydride to the mixture. We refluxed the mixture for 16 hours. We cooled the mixture with ice and then added water while mixing. The insoluble material was separated by filtration and washed with tetrahydrofuran. We combined the filtrate and washing liquids and added 1.02 g of di-tert.-butyl dicarbonate. The mixture was stirred at room temperature for 16 hours. The solvent was separated under reduced pressure. The residue was purified by chromatography on a silica gel column (50 g), eluting with a mixture of ethyl acetate and n-hexane (1:10), to obtain 273 mg of the title compound 87.

1H-NMR ( CDCl3 ) δ ppm: 1.45 (18H, s ), 1.7-2.1 (6H, m ), 3.0-3.6 (4H, m ), 3.8-4.2 (1H, m ), 5.1 (1H, wid. d )

Using a suitable procedure, we obtained 2-tert.-butoxycarbonyl-4-tert.-butoxycarbonyl-amino-2-azaspiro[4,4]nonane (compound 90) 1H-NMR ( CDCl3 ) δ ppm : 1.45 (18H, s ), 1.3 -1.8 (8H, m), 3.0-3.3 (3H, m), 3.4-3.7 (1H, m), 3.7-4.1 (1H, m), 4.55 (1H, wide d) and 2-tert.-butoxycarbonyl -4-tert.-butoxycarbonylamino-2-azaspiro[4,5]decane (compound 93) 1H-NMR (CDCl3 ) δ ppm : 1.0-1.9 (28H, m ), 2.9-4.1 ( 5H, m ), 4.51 ( 1H, width d).

Example 19

7-(8-amino-6-azaspiro[3,4]octan-6-yl)-1-cyclopropyl-6,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (compound 94)

2.7 ml of trifluoroacetic acid was added while mixing to 173 mg of ice-cooled compound 87. The trifluoroacetic acid was separated 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. We refluxed the mixture for 16 hours. The solvent was separated 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 obtain 125 mg of the title compound 94.

Melting point: 260-263°C

Elemental analysis: C20H21 N3O 3F2

Calculated: C 58.19, H 5.76, N 10.18

Found: C 58.10, H 5.38, N 10.13

1H-NMR (0.1 N NaOD-D2O) δ ppm: 1.05 (2H, width s), 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)

Using a suitable procedure, we obtained 7-(4-amino-2-azaspiro[4,4]nonan-2-yl)-1-cyclopropyl-6,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (compound 95) and 7-(4-amino-2-azaspiro[4,5]decan-2-yl)-1-cyclopropyl-6,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (compound 96).

7-(4-amino-2-azaspiro[4,4]nonan-2-yl)-1-cyclopropyl-6,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 95:

Melting point: 249-253°C

Elemental analysis: C21H23 N3O3F2 ⋅ 0.7 H2O

Calculated: C 60.63, H 5.91, N 10.10

Found: C 60.63, H 5.69, N 9.94

1H-NMR (0.1 N NaOD-D2O) δ ppm: 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:

Melting point: 247-274°C

Elemental analysis: C22H25 N3O3F2

Calculated: C 63.30, H 6.04, N 10.07

Found: C 63.14, H 6.08, N 10.02

1H-NMR (0.1 N NaOD-D2O) 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 )

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)

The 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 separated under reduced pressure. To the residue we added 85 mg of BF2-chelate 9,10-difluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine -6-carboxylic acid, 15 ml of dimethyl sulfoxide and 1 ml of triethylamine. The mixture was stirred at room temperature overnight. The solvent was separated under reduced pressure. We added 20 ml of 95% methanol and 1.2 ml of triethylamine to the mixture and refluxed the mixture for 5 hours. We separated the solvent under reduced pressure and added diethyl ether to the residue. The resulting crystalline product was collected by filtration and recrystallized from ammonia water and ethanol to obtain 50 mg of the title compound 98.

Melting point: 229-231°C

Elemental analysis: C20H22 N3O4F ⋅ 1/2 H2O

Calculated: C 57.96, H 6.08, N 10.14

Found: C 57.66, H 5.84, N 0.24

1H-NMR (0.1 N NaOD-D2O) δ ppm: 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), (1H, d, J=19.5 Hz), 8.13 (1H, s)

REFERENCE Example 17

1) Tert-butyl 7-oxo-6-azaspiro[3,4]octane-8-carboxylate (compound 99)

2 g of compound 79 were dissolved in 30 ml of tert.-butanol while heating with 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 separated 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. We extracted the washing liquids with ethyl acetate and washed the extracts in the same way. We dried the organic layer over anhydrous sodium sulfate and separated the solvent under reduced pressure. The residue was purified by chromatography on a silica gel column (75 g), eluting with chloroform, which contains 0 to 2% methanol, to obtain 1.97 g of the title compound 99.

1H-NMR ( CDCl3 ) δ ppm: 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), 9.60 (1H, width s )

Tert-butyl 3-oxo-2-azaspiro[4,4]nonane-4-carboxylate (compound 100) was obtained by a suitable procedure 1H-NMR (CDCl3) δ ppm: 1.47 (9H, s ) 1.70 (8H, width s), 2.98 (1H, s ), 3.10 (1H, d, J=9.7 Hz ), 3.43 (1H, d, J=9.7 Hz ), 7.50 (1H, ext.) and tert.-butyl 3-oxo- 2-oxo-2-azaspiro[4,5]decane-4-carboxylate (compound 101) (1H-NMR CDCl3 ) δ ppm: 1.45 (19H, br. s), 2.93 (1H, s ), 3.13 (1H, d, J=11 Hz), 3.32 (1H, d, J=11 Hz), 6.90 (1H, width s )

2) 6-tert.-butoxycarbonyl-8-hydroxymethyl-6-azaspiro[3,4]octane (compound 103)

20 ml of ice-cooled trifluoroacetic acid was added while stirring to 1.94 g of ice-cooled compound 99. The mixture was stirred at room temperature for 1 hour and the trifluoroacetic acid was separated under reduced pressure. The residue was dissolved in 100 ml of anhydrous tetrahydrofuran and the solution was cooled in an ice bath. We slowly added 3.11 g of lithium aluminum hydride to the solution and refluxed the mixture for 18 hours. We cooled the mixture with ice and slowly added 10 ml of water to the solution. The mixture was stirred at room temperature for 30 minutes. The insoluble material was separated by filtration and washed with tetrahydrofuran. The combined filtrate and washing liquids were condensed under reduced pressure to a volume of about 50 ml. Di-tert-butyl dicarbonate was added to the solution and the mixture was stirred at room temperature for 18 hours. The solvent was separated under reduced pressure. The residue was purified by chromatography on a silica gel column (150 g), eluting with a mixture of n-hexane and ethyl acetate (3:2), to obtain 420 mg of the title compound 103.

1H-NMR ( CDCl3 ) δ ppm: 1.46 (9H, s ), 1.7-2.3 ( 8H, m ), 3.3-3.9 ( 5H, m

Using a suitable procedure, we obtained 2-tert.-butoxycarbonyl-4-hydroxymethyl-2-azaspiro[4,4]nonane (compound 105) 1H-NMR ( CDCl3 ) δ ppm: 1.46 (9H, s ) 1.61 ( 8H, s ), 3.0-3.9 (7H, m ), and 2-tert.-butoxycarbonyl-4-hydroxymethyl-2-oxo-2-azaspiro[4,5]decane (compound 107) (1H-NMR ( CDCl3 ) δ 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 during mixing to 120 mg of ice-cooled compound 103. The mixture was stirred at room temperature for 1 hour. Trifluoroacetic acid was separated under reduced pressure. The residue was dissolved in 10 ml of actonitrile and 100 mg of 1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-hydroquinoline-3-carboxylic acid and 0.22 ml of triethylamine were added to the solution. We refluxed the mixture for 18 hours. We separated the solvent under reduced pressure and added concentrated hydrochloric acid and chloroform to the residue. We shook the mixture and settled the aqueous layer. The aqueous layer was washed with chloroform and the chloroform washings were extracted with a small amount of concentrated hydrochloric acid. The combined aqueous layers were cooled with ice and the pH adjusted with sodium hydroxide to above 13. The aqueous layer was washed with chloroform. Then we washed the aqueous layer with concentrated hydrochloric acid and adjusted it to pH 7.4 with saturated sodium bicarbonate solution. The aqueous layer was extracted with chloroform and the extract was dried over anhydrous sodium sulfate. The solvent was separated under reduced pressure. The residue was recrystallized from ethanol and ammonia water to obtain 52 mg of the title compound 108 as yellow needles.

Melting point: 273-274°C

Elemental analysis: C21H22 N2O4F2

Calculated: C 62.37, H 5.48, N 6.93

Found: C 62.31, H 5.93, N 6.96

(1H-NMR ( CDCl3 ) δ ppm: 1.11-1.31 (4H, m ), 1.89-2.13 (7H, m ), 3.63-3.99 (7H, m ), 7.75 (1H, dd, J=13.5 & 1.6 Hz) , 8.62 (1H, s )

We obtained 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) 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):

Melting point: 249-252°C

Elemental analysis: C22H24 N2O4F2

Calculated: C 63.15, H 5.78, N 6.70

Found: C 62.74, H 5.76, N 6.46

1H-NMR ( CDCl3 ) δ 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, s )

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):

Melting point: 231-234°C

Elemental analysis: C23H26 N2O4F2 ⋅ 1/2 H2O

Calculated: C 62.58, H 6.17, N 6.35

Found: C 62.92, H 6.17, N 6.25

1H-NMR ( CDCl3 ) δ ppm: 1.13-1.18 (2H, m ), 1.24-1.28 ( 2H, m ), 1.30-1.69 (11H, m ), 3.51-4.02 ( 7H, m ), 7.80 (1H, dd , J=13.5 & 1.6 Hz), 8.70 (1H, s )

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. We added 0.5 ml of water, 0.5 ml of 15% aqueous sodium hydroxide and 1.5 ml of water to the mixture in the order mentioned and stirred the mixture at room temperature for 30 minutes. The insoluble material was separated by filtration and the filtrate was concentrated to dryness to obtain 1.4 g of 7-hydroxy-5-[1-(R)-phenylethyl]-5-azaspiro[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. We added ethyl acetate to it and washed the solution with saturated aqueous sodium bicarbonate and water, and then dried over anhydrous sodium sulfate. We separated the solvent under reduced pressure to obtain 1.6 g of 7-acetoxy-5-[1-(R)-phenylethyl]-5-azaspiro[2,4]heptane and 1.2 g of palladium on charcoal (wetted with 50% water) in 20 ml of ethanol, we shook under hydrogen pressure 3.7. at least 5 hours. In the reduction reaction, we heated the reaction vessel with a tungsten lamp. The catalyst was filtered off and the solvent was removed under reduced pressure to obtain 880 mg of the title compound 69 as an oil.

In addition to the above compounds, we synthesized the following compounds. The physical data of the corresponding compounds are given.

1: (-)-7-[7-(S)-amino-5-azaspiro[2,3]heptan-5-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline- 3-carboxylic acid 33b, melting point: 259-261°C

2: (-)-7-[7-(S)-amino-5-azaspiro[2,3]heptan-5-yl)-6-fluoro-1-(2,4-difluorophenyl)-1,4- dihydro-4-oxo-1,8-naphthyride-3-carboxylate 111b, mp: 232-235°C, [α]D -20.54° (c=0.73, CHCl3).

Table: Antibacterial activity ( MIC, µg / ml )

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Table: Antibacterial activity ( MIC, µg / ml )

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From the detailed description of the invention and with reference to its specific embodiments, it will be clear to the expert that he can make various changes and modifications in it, without departing from its essence and scope.

Claims (11)

1. A spiro compound, characterized in that it is formula I [image] where a denotes an integer 0 or 1; b denotes an integer from 2 to 5 inclusive; c denotes an integer 0 or 1; and d denotes an integer from 0 to 2 inclusive; Z stands for >CHR1, >NR2, >C=NOR3, an oxygen atom or a sulfur atom, where R1 is a hydrogen atom, an amino group, a monoalkylamino group with 1 to 6 carbon atoms, a dialkylamino group containing in each alkyl 1 to 6 carbon atoms, hydroxyl group, 1 to 6 carbon atom alkoxy group or 1 to 6 carbon atom hydroxyalkyl group; R2 is a hydrogen atom, an alkyl group with 1 to 6 carbon atoms, a hydroxyalkyl group with 1 to 6 carbon atoms, a haloalkyl group with 1 to 6 carbon atoms, a formyl group or an alkylcarbonyl group with 2 to 7 carbon atoms; and R 3 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; Q represents part of the structure of formula II: [image] where R4 denotes an alkyl group with 1 to 6 carbon atoms, an alkenyl group with 2 to 6 carbon atoms, a haloalkyl group with 1 to 6 carbon atoms, a cycloalkaline group with 3 to 6 carbon atoms, cis-2-methylcyclopropyl, 2-gem-dihalocyclopropyl, 4-fluorophenyl, 2,4-di-fluorophenyl, 2.fluoro-4-pyridyl, 1 to 6 carbon atom alkoxy group or 1 to 6 carbon atom alkylamino acupine; R5 denotes a hydrogen atom or an alkyl group with 1 to 6 carbon atoms; R 6 denotes a hydrogen atom, an amino group, a mono-C 1-6 -alkylamino group, a di-C 1-6 -alkylamino group, a hydroxyl group, a halo-C 1-6 -alkyl group, an 1 to 6 carbon atom alkoxy group or a halogen atom; A denotes a nitrogen atom or ≥C-R7 where R7 is a hydrogen atom, an alkyl group with 1 to 6 carbon atoms, a halogen atom, an alkoxy group with 2 to 6 carbon atoms, a haloalkyl group with 1 to 6 carbon atoms, or a cyano group; R4 can together with R5 and/or R7 form a substituted or unsubstituted four-membered to seven-membered ring, which can contain an oxygen, nitrogen or sulfur atom, where the substituent is an alkyl group with 1 to 6 carbon atoms or a haloalkyl group with 1 to 6 carbon atoms; X denotes a halogen atom; Y denotes a hydrogen atom, an alkyl group with 1 to 6 carbon atoms, an alkoxyalkyl group with 1 to 6 carbon atoms, a phenylalkyl group, which contains in its alkyl part 1 to 6 carbon atoms, a dihaloboron group, a phenyl group, an acetoxymethyl group, a pivaloyloxymethyl group, ethoxycarbonyloxy group, choline group, dimethylaminoethyl group, 5-indanyl group, phthalidinyl group, 5-substituted-2-oxo-1,3-dioxazol-4-ylmethyl group or 3-acetoxy-2-oxobutyl group and their salts. 2. A spiro compound of formula I according to claim 1, characterized in that a is 1, b is 2, c is 0 and d is 1 and Z denotes >CH(NH2), or their salt. 3. A spiro compound of formula I according to claim 1, characterized in that a is 1, b is 3, c is 0 and d is 1 and Z denotes >CH(NH2), or their salt. 4. A spiro compound of formula I according to claim 1, characterized in that a is 1, b is 2, c is 0 and d is 2 and Z denotes >NH, or their salt. 5. Spiro compound of formula I according to claim 1, characterized in that 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-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 acids , 7-(7-amino-5-azaspiro[2,4]heptan-5-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids , 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 acids, 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-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 7-(7-hydroxy-5-azaspiro[2,4]heptan-5-yl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 7-(7-amino-5-azaspiro[2,4]heptan-5-yl)-1-(2-methyl-2-propyl)-6-fluoro-1,4-dihydro-4-oxo-1, 8-naphthyride-3-carboxylic acids, 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-2-azaspiro[4,4]nonan-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 1-cyclopropyl-6,8-difluoro-7-(4-hydroxymethyl-2-azaspiro[4,5]decan-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 7-(8-amino-6-azaspiro[3,4]octan-6-yl)-1-cyclopropyl-6,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 10-(8-amino-6-azaspiro[3,4]octan-6-yl)-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1, 2,3-de-][1,4] benzoxazine-6-carboxylic acids, 7-(4-amino-2-azaspiro[4,4]nonan-2-yl)-1-cyclopropyl-6,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 7-(7amino-5-azaspiro[2,4]heptan-5-yl)-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine- 3-carboxylic acids and their salts. 6. A spiro compound of formula i according to any of claims 1 to 5, characterized in that said spiro compound is optically (stereoisometrically) pure. 7. The process for the preparation of spiro compounds according to claims 1 to 6, characterized in that it includes the reaction of a cyclic amine containing a spiro cyclic ring of the following formula: [image] where a, b, c, d, and Z are the same as defined in claim 1, with a halogenated quinoline derivative of the following formula: [image] where A, R4, R5, R6, Y and X are as defined in claim 1 and X' represents a halogen atom. 8. Pharmaceutical preparation, characterized in that it comprises (A) an antibacterially effective amount of a spiro compound according to any one of claims 1 to 6, and (B) a pharmaceutically acceptable carrier or solvent. 9. Pharmaceutical preparation according to claim 8, characterized in that said preparation comprises an oral dosage form, selected from the group consisting of tablets, powders, granules, capsules, solutions, syrups, elixirs, oil suspensions and aqueous suspensions. 10. Pharmaceutical preparation according to claim 8, characterized in that said preparation is an injectable solution. 11. Pharmaceutical preparation according to claim 8, characterized in that said preparation comprises an external dosage form, selected from the group consisting of solution, suspension, emulsion, ointment, gel, cream, lotion and spray.