SI8910875A - Optically active pyridone carboxylic acid derivatives - Google Patents

Abstract

Shown are Ni- (1,2-cis-2-halogenocyclopropyl) - substituted pyridone carboxylic acid derivatives shown of formula (I) and salts thereof. These compounds have strong antibacterial properties effectiveness against very diverse infectious bacteria and are useful as antibacterial agents in oral or parenteral administration. Prepare with 7-halogen-1- (2-cis-2-fluorocyclopropyl) -pyridone a cyclic amine carboxylic acid of formula Rz-H, which may be protected by a conventional protecting group, with residues R1, X1, X2, A, X and R2 of claim 1 defined meaning.

Description

Optically active pyridonecarboxylic acid derivatives

FIELD OF THE INVENTION

The present invention relates to an antimicrobial compound useful as a medicament in human and veterinary medicine and in fisheries, agricultural chemicals and antiseptics.

BACKGROUND OF THE INVENTION

Quinolone derivatives with a condensed pyridonecarboxylic acid framework are known as synthetic antimicrobial agents and in that they provide active antimicrobial compounds in substitution of their position 1 with the cyclopropyl group.

It is further known that even 1-cyclopropyl-quinolone derivatives having introduced a fluorine atom to the 2-position of the cyclopropyl group in the cis configuration with a portion of pyridonecarboxylic acid also exhibit potent antimicrobial efficacy, as shown in JP-A-87-12760 (term JP-A, as used herein, means an untested, published Japanese patent application). They are thought to have not only strong antimicrobial efficacy but also improved safety. One example of a quinolone derivative with a cis-fluorocyclopropyl group in position 1 is shown below.

Quinolone derivatives with the cis-halogen-cyclopropyl group, including the cis-fluorocyclopropyl group, in position 1, as indicated above, have excellent properties for antimicrobial efficacy and safety. With these compounds, even when the substituent without stereo-isomerism at the 7-position of part of the pyridonecarboxylic acid, the halogen-cyclopropane ring itself offers 2 enantiomers attributed to the steric ratio of the part of the pyridone carboxylic acid to the halogen atom with respect to the cyclopropane ring, such as is explained below

and

wherein R ¹ , R ² , A, X ¹ and X ^{2 have the} meanings defined below. These quinolone derivatives can be used as medicaments to the extent that they are racemic. On the other hand, for the stereoisomerism of the substituent at position 7 of the pyridone carboxylic acid moiety, such quinolone derivatives contain 4 types of diastereomers.

With diastereomer mixtures, it is difficult to specify excellent specimens and make them available as drugs.

Description of the invention

In view of the above situation, the inventors have made great efforts to obtain the individual isomers of 1- (1,2-cis 2-fluorocyclopropyl) -substituted quinolone derivatives within their diastereomers. They were able to obtain each of the enantiomers of cis-2-fluorocyclopropylamine as a pure isomer. In further studies, they were also fortunate to synthesize each of the enantiomers of the quinolone derivative, attributable only to the steric configuration of the fluorocyclopropane ring based on the amine described above.

The success of obtaining the enantiomeric quinolone derivatives useful as an intermediate has enabled the synthesis of an optically active quinolone derivative comprising one type of diastereomer by metabolizing a single amine isomer by introducing a cyclic amino group to position 7. Each of these diastereomers has proven to be more antimicrobially effective in the case of the corresponding quinolone derivatives substituted with the cyclopropyl group only, and very safe with markedly improved selective toxicity. The present invention was completed on the basis of these findings.

The present invention relates to the N, N - (1,2-cis-2-halogenocyclopropyl) -substituted pyridone carboxylic acid derivative represented by formula (I):

R ¹ 0

wherein R ¹ represents a substituted or unsubstituted amino group, hydroxyl group, thiol group, or hydrogen atom 2; R represents a substituted or unsubstituted cyclic amino group which may contain at least one hetero atom selected from a nitrogen, oxygen or sulfur atom in its ring; A represents CX or a nitrogen atom; X and X, which may each be the same or different, each represent a halogen atom and Χ ^ represents a halogen atom, an alkyl group of 1 to 6 carbon atoms, an alkoxyl group of 1 to 6 carbon atoms, a cyano group, a trifluoromethyl group or a hydrogen atom; sv "with 1 reservation to exclude the case where R is a hydrogen atom and 2

R is a piperazine or 4-alkyl-substituted piperazine residue, or a salt thereof.

Specific representatives of the compounds of formula v

(I), and salts thereof, are those wherein R is a cyclic amino 2 group which is optionally substituted; those wherein R is a 4- to 7-membered cyclic amino group which may be substituted by a hydroxyl group, an alkyl group of 1 to 6 carbon atoms, or a substituted or unsubstituted amino group; those wherein R is a pyrrolidine, piperidine, piperazine, diazabicycloheptane or diazabicyclooctane residue; one where R is a cyclic amino group comprising a single stereoisomer; one where R is a 3-amino pyrrolidinyl group; one where R is a 7-amino-5-azaspiro / 2,4 / -heptan-5-yl group; and one where X is a fluorine atom. More specifically, the compounds of the present invention comprise 7- [3- (S) -amino-1-pyrrolidinyl] -6-fluoro-1- (1,2-cis-2-fluorocyclopropyl) -4-oxo-1, 4-Dihydroquinoline-3-carboxyl, 7- [3- (S) -amino-1-pyrrolidinyl] -8-chloro-6-fluoro-1- (1,2-cis-fluorocyclopropyl) -4-oxo-1,4-dihydroquinoline-3- carboxyl, 7- [7-amino-5-azaspiro / 2,4 / heptane

5-yl] -8-chloro-6-fluoro-1- (1,2-cis-2-fluorocyclopropyl) -4oxo-1,4-dihydroquinoline-3-carboxylic, 5-amphno-7- / 3- (S ) -amino-1-pyrrolidinyl] -6,8-difluoro-1- (1,2-cis-2-fluorocyclopropyl) 4-oxo-1,4-dihydroquinoline-3-carboxyl, 7- / 4- (S) -amino -2- (S) methyl-1-pyrrolidinyl] -6-fluoro-1- (1,2-cis-2-fluorocyclopropyl) 4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxyl, 7- [3- (R) - [1 (S) -aminoethyl] -1-pyrrolidinyl] -8-chloro-6-fluoro-1- (1,2-cis2-fluorocyclopropyl) -4-oxo-1,4 -Dihydroquinoline-3-carboxyl _; 7- (3-amino-4-methyl-1-pyrrolidinyl) -6-fluoro-1- (1,2-cis-2fluorocyclopropyl) -8-methoxy-4-oxo-1,4-dihydroquinoline-3carboxyl, 7- [4- (S) -amino-2- (S) -methyl-1- pyrrolidinyl] -6-fluoro-1- (1,2-cis-2-fluorocyclopropyl) -8-methyl-4-oxo-1,4-dihydroquinoline -3-carboxyl, 5-amino-7- (7-amino-5azaspiro) 2,4-heptan-5-yl) -6,8-difluoro-1- (1,2-cis-2fluorocyclopropyl) -4- oxo-1,4-dihydroquinoline-3-carboxylic acid and their salts.

DETAILED DESCRIPTION OF THE INVENTION

1

In formula (I), when X represents a halogen atom, X and X each preferably represent a fluorine atom or

1 chlorine atom; X preferably represents a fluorine atom. R represents a substituted or unsubstituted amino group, a hydroxyl group, a thiol group or a hydrogen atom / preferably an unsubstituted amino group, a methylamino group or a hydrogen atom.

R represents a cyclic amino group, preferably 4- to

A 7-membered, and more preferably a 5- to 6-membered, cyclic amino group. The cyclic amino group may further comprise one or more oxygen, sulfur and / or nitrogen atoms, such as in the oxazolidine, morpholine, thiazolidine, thiomorpholine imidazolidine, pyrazolidine and piperazine residues. Of these cyclic amino groups, the pyrrolidine and piperazine residues are preferred. The cyclic amino group may have substituents, such as a polar group (e.g., substituted or unsubstituted amino group, substituted or unsubstituted aminoalkyl group, 5-substituted 2-oxo-1,3-dioxol-4yl methyl group, hydroxyl group) and a straight, branched or a cyclic alkyl group of up to 6 carbon atoms. Preferred polar groups are an unsubstituted amino group, aminomethyl

1-aminoethyl and hydroxyl group. Preferred alkyl groups are methyl, ethyl, propyl, gem-dimethyl and gem-7 diethyl groups, and further, these gem-alkyl groups may preferably form a cyclopropane or cyclobutane ring which is spiro-linked to the cyclic amine framework. The cyclic amino group further includes a bicyclic amino group formed by crosslinking to 4- to 7-membered cyclic amino groups.

Explanatory examples for these cyclic amino groups, especially those containing a second amine moiety, are shown below:

d7

R «-N IMR ⁹ V

R ^ Πΐ * ii r 6 where R, R, R, R, which may be the same or different, each represent a hydrogen atom or an alkyl group of 1 to 6 carbon atoms; R ', R and R, which may be the same or different, in each case represent a hydrogen atom or an alkyl group of 1 to 6 carbon atoms, with the exception that,

8 9 when R, R and R each represent a hydrogen atom, m ^{7 *}

9 is an example where R and R each represent a hydrogen atom

- 8 Ο and R represents an alkyl group of 1 to 6 carbon atoms;

R ¹⁰ and R ¹¹ , which may be the same or different, each represent a hydrogen atom or an alkyl group of 1 to 6 carbon atoms; R and R, which may be the same or different, each represent a hydrogen atom or an alkyl group of 1 to 6 carbon atoms, or bonded together to form a 3 to 6 membered ring formed of methylene chains, with an asterisk marking the center asymmetries.

Examples of these cyclic amino groups are 3-aminopyrrolidinyl,

3-methylaminopyrrolidinyl, 3-dimethylaminopyrrolidinyl, 3-ethylaminopyrrolidinyl, 3-propylaminopyrrolidinyl, 3-isopropylaminopyrrolidinyl, 3-amino-4-methylpyrrolidinyl, 3-amino-5-methylpyrrolidinyl, 3-amino-4,5-dimethyl-4,5-dimethyl-4,5-dimethyl-4,5-dimethyl 4-methylpyrrolidinyl, 3-methylamino-5-methylpyrrolidinyl, -3-raethylamino-4,5-dimethylpyrrolidinyl, 3-dimethylamino-4-methylpyrrolidinyl,

3- dimethylamino-5-methylpyrrolidinyl, 3-dimethylamino-4,5-dimethylpyrrolidinyl, 3-methylpiperazinyl, 4-methylpiperazinyl, 3,4-dimethylpiperazinyl, 3,5-dimethylpiperazinyl, 3,4,5-trimethylpiperazinyl,

4-ethyl-3,5-dimethylpiperazinyl, 4-isopropyl-3,5-dimethylpiperazinyl, 3-aminomethylpyrrolidinyl, 3-methylaminomethylpyrrolidinyl,

3- (1-amino) ethylpyrrolidinyl, 3- (1-methylamino) ethylpyrrolidinyl,

3- (1-ethylamino) ethylpyrrolidinyl, 3- (1-amino) propylpyrrolidinyl,

3- (1-methylamino) propylpiperazinyl, 3-aminopyrrolidinyl,

3-amino-4,4-dimethylpyrrolidinyl, 7-amino-5-azaspiro / 2,4 / heptan5-yl, 8-amino-6-azaspiro / 3,4-octan-6-yl, 3,4-diazabicyclo (3,2,1) octan-3-yl, 9-methyl-3,9-diazabicyclo / 3,2,1 / octan-3-yl and 9-ethyl-3,9-diazabicyclo / 3,2,1 / octan-3-yl.

The structure of the cyclic amino group at position 7 has a major influence on antimicrobial efficacy, toxicity, oral absorption, and physical properties, such as e.g. water solubility. So e.g. quinolones substituted with 3-aminopyrrolidinyl groups are known to have strong antimicrobial spectra against a wide range of microorganisms, covering both Gram positive and Gram negative bacteria. However, some quinolone derivatives of this type are sensitive to metabolism or exhibit low water solubility.

The 3-aminopyrrolidinyl groups with a spiro ring on the carbon atom adjacent to its amino group offer quinolone derivatives with improved oral absorption and improved in vivo metabolism stability while maintaining strong antimicrobial efficacy. Compounds of this type have also proven to be minor contractors of spasms, which is a known side effect of synthetic quinolone-type antimicrobials.

Furthermore, 3-aminomethylpyrrolidinyl groups, where the amino group is attached to the pyrrolidinyl group via a carbon atom, give quinolone derivatives exhibiting improved antimicrobial efficacy against Gram-positive bacteria. Particularly quinolones of this type, in which the carbon atom that binds the amino to the pyrrolidinyl group substituted with 1 or 2 alkyl groups, have been distinguished by their improved oral absorption, safety and water solubility, compared to those without such or such substituents.

Additionally preferred as cyclic amino groups are piperazine residues such as alkylpiperazine residues and piperazine residues with a spiro ring.

Examples of cyclic amino groups with substituents other than the amino group are 3-hydroxypyrrolidinyl, 3-mercaptopyrrolidinyl, 3-hydroxy-4-methylpyrrolidinyl,

3-mercapto-4-methylpyrrolidinyl, morpholine, thiomorpholine,

2-methylmorpholine, 2-methylthiomorpholine, 2,6-dimethylmorpholine, 2,6-dimethylthiomorpholine, 2,2-dimethylmorpholine and

2,2-dimethylthiomorpholine group.

The cyclic amino group is attached to position 7 of the pyridone carboxylic acid framework, preferably at the nitrogen atom of the cyclic amino group. Of course, it can also be attached to another atom.

The stereoisomerism of the moiety of the cyclic amine at position 7 is explained below. In cases where the cyclic amine has isomers, when metabolized in the form of an isomeric mixture of a 1- (1,2-cishalogenocyclopropyl) quinolone derivative, the quinolone derivative should be a mixture of diastereomers based on an ethereal relationship with the 1,2-cis2-halogenocyclopropyl group in position 1. In these cases, therefore, it is necessary to metabolize only one of the isomers of the starting amine.

Cyclic amino group functional group in position

7, such as the amino, hydroxy and thiol groups, can be protected by a conventional protecting group against substitution with the quinolone framework. Examples of such protecting groups include alkoxy carbonyl groups such as t-butoxycarbonyl and

A 2,2,2-trichloroethoxycarbonyl group and the like; aralkyloxycarbonyl groups such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl and the like; acyl groups such as acetyl, methoxyacetyl, trifluoroacetyl, chloroacetyl, pivaloyl, formyl, benzoyl groups and the like; alkyl or aralkyl groups such as t-butyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, triphenylmethyl and the like; ethers such as methoxymethyl, t-butoxymethyl, 2,2,2-trichloroethoxymethyl, tetrahydrofuran2-yl group and the like; silyl groups such as trimethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl groups and the like.

The 1,2-cis-2-halogenocyclopropyl group in the position is described below. The introduction of a halogen atom into the cyclopropyl group, in particular fluorine atoms, results in a decrease in the lipophilicity of the whole molecule. Medicines are known to prefer distribution in the central nervous system as their lipophilicity increases. In this regard, the introduction of the 1,2-cis-2-halogenocyclopropyl group of quinolones is of reduced toxicity, while maintaining excellent antiraicrobial efficacy, in comparison with the corresponding 1-cyclopropylquinolones. The halogen atom to be introduced includes fluorine and chlorine atoms, the fluorine atom being preferred.

Particularly preferred is that they are atom halogens and part pyridonecarboxylic acids v position cis z with regard to ciklopro panski ring. Whatever that, but there is 7-cycle amino

group stereoisomers or not, quinolone derivatives of formula (I) are enantiomeric vapors attributed to the cis-2-halogenocyclopropyl moiety at position 1, as explained below. Strong activity and high safety were observed with any of these enantiomers.

O R '

R ¹ O

and

HOO

Pyridonecarboxylic acid derivatives according to the present invention include, respectively, the free acid, its acid addition salts, and salts of its carboxylic group. Acid addition salts include salts of inorganic acids, e.g. hydrochlorides, sulfates, nitrates, hydrobromides, hydroiodides and phosphates; organic acid salts, e.g. acetates, methanesulfonates, benzenesulfonates, toluenesulfonates, citrates, maleates, fumarates and lactates.

Carboxyl group salts may be organic or inorganic and include alkali metal salts, e.g. lithium salts, sodium salts and potassium salts, alkaline earth metal salts, e.g. magnesium and calcium salts; ammonium salts, triethylamine salts, N-methylglucamates and tris (hydroxymethyl) aminomethane salts.

Some of these free acids and salts may exist as hydrates.

The esterification of a carboxylic acid moiety of pyridonecarboxylic acid derivatives of formula (I) provides compounds that are useful as synthesis intermediates or pro-drugs. So e.g.

alkyl esters, benzyl esters, alkoxyalkyl esters, phenylalkyl esters and phenyl esters are useful as synthesis intermediates. Esters that break down easily in the body to form free carboxylic acids are useful as pro-drugs. Examples of such esters are acetoxymethyl esters, pivaloyloxymethyl esters, ethoxycarbonyloxyesters, chlorine esters, dimethylaminoethyl esters, 5-indanyl esters, phthalidinyl esters and oxoalkyl esters (e.g. 5-substituted 2-oxo-1,3-dioxol-4-yl-methyl-esters

3-acetoxy-2-oxobutyl esters).

The process for the synthesis of pyridone carboxylic acid derivatives of formula (I) is explained below, taking 112 8 e.g. a compound wherein A = C-H; R = H; X = X = F; and R ~ = Et (ethyl group, hereinafter the same)

acid al ^ alkali

lila, Hib removal of the protecting group acid or alkali simultaneous removal of the protecting group

IVa, IVb

2 wherein R has the same meaning as R, or a cyclic amino group, of the same structure as R but protected.

1- (1,2-cis-2-fluorocyclopropyl) 6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (6a) or (6b) optically active ethyl ester is hydrolyzed under acidic or alkaline conditions to give the free carboxylic acid derivative (7a) or (7b). The free acid (7a) or (7b) is reacted with the cyclic amine R1-H to give the desired compound (lila) or (Illb). If necessary, the protecting group is removed from the resulting compound under suitable conditions selected depending on the protecting group to give the desired compound (IVa) or (IVb).

The cyclic amine substitution reaction can be carried out in a solvent such as dimethylsulfoxide, pyridine, acetonitrile and 3-methoxybutanol at a temperature from room temperature to 150 ° C, preferably from 40 to 120 ° C, for 0.5 to 5 hours, typically 0. 5 to 2 p.m.

Alternatively, the compound (6a) or (6b) is reacted with the cyclic amine under the same conditions as above, and the resulting compound, (Iia) or (Ilb) as prepared, is then hydrolyzed under acidic or alkaline conditions, and optionally remove the protecting group to give the desired compound (lilac) or (Illb) or (IVa) or (IVb).

Optically active ci3-2-fluorocyclopropylamine can be synthesized as follows. The 2-fluorocyclopropanecarboxylic acid is reacted with (R) - (+) - oi-methylbenzylamine to give N- / 1- (R) -phenylethyl / -1,2-cis-fluorocyclopropanecarboxamide

- 15 The reaction can be carried out in tetrahydrofuran in the presence of N, Ncarbonyldiimidazole. The reaction may also be carried out in accordance with a mixed anhydride process, in which the carboxylic acid is dissolved in an aprotic solvent and reacted with a halogen ester in the presence of a base at low temperatures, then reacted with benzylamine to give the carboxamide. The resulting carboxamide can be separated on each of the isomers by chromatographic techniques.

The aprotic solvent to be used in the mixed anhydride process is not specifically limited and includes ethers, e.g. diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; halogenated hydrocarbons, e.g. dichloromethane, chloroform, 1,2-dichloroethane, and 1,1,2,2-tetra chloroethane; aromatic hydrocarbons, e.g. benzene, toluene, and xylene; and aliphatic hydrocarbons, e.g. pentane, hexane, heptane, and cyclohexane. Usually tetrahydrofuran or chloroform is used. The water contained in the solvent to be used is usually pre-removed.

The halogen atom in the halogen ester is normally a chlorine atom. The halogenomic ester includes methyl, ethyl, 2,2,2-trichloroethyl, phenyl, p-nitrophenyl and benzyl esters.

The base to be used can be either organic or inorganic. The inorganic base includes hydroxides, carbonates, and alkali metal hydrogen carbonates, e.g. lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium, sodium and potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate. The organic base includes trialkylamines, e.g. triethylamine, tripropylamine, tributylamine, N, N-diisopropyl ethylamine; dialkylanilines, e.g. diethylaniline and dimethylaniline. and heterocyclic compounds, e.g. N-methylmorpholine, pyridine, and N, N-dimethylaminopyridine.

Separation of carboxamide into optical isomers can be carried out by known techniques, such as by chromatography on a silica gel column under normal pressure or under pressure, preparative thin layer chromatography and high performance liquid chromatography (HPLC). Separation into optical isomers can also be carried out by other separation techniques that are commonly used, such as recrystallization and conversion.

Such a separate, optically active carboxamide can be converted to optically active cis-2-fluorocyclopropane carboxylic acid by hydrolysis. The reaction can be carried out by dissolving the carboxamines, e.g. in concentrated hydrochloric acid, followed by heating. Hydrochloric acid can be replaced by sulfuric acid or hydrochloric acid. The solvent may be used as acetic acid or lower alcohol.

The resulting carboxylic acid can be immediately converted by Curtius reaction in the presence of t-butanol into protected cis-1- (t-butoxycarbonylamino) -2-fluoro-cyclopropane. The reaction can be conveniently carried out using diphenylphosphorylase, except that synthesis of the intermediate azide compound is not limited thereto, and general synthesis methods can be used.

The resulting optically active cis-2-fluoro-cyclopropyl amine derivative can be used in the preparation of a quinolone derivative with the cis17 fluoro-cyclopropyl group at position 1 as a single isomer. The quinolone derivative of the present invention can then be obtained by reacting this isomer with a cyclic amine as described above.

The pyridone carboxylic acid derivatives of the present invention exhibit potent antimicrobial efficacy and can therefore be used as medicines for humans and animals, e.g. fish, such as agricultural chemicals and food preservatives.

The dose of pyridonecarboxylic acid derivatives for human use is in the range of 50 mg to 1 g, preferably 100 to 300 mg, daily for an adult. The dose intended for use as a veterinary medicinal product is generally in the range of 1 to 200 mg, preferably 5 to 100 mg, per kg body weight per day, although it may be greater or less, depending on the purpose of administration (therapeutic or preventive use, etc.). ), the species and size of the animal, the type of pathogen and the symptoms. The above daily dose can be divided into 2 to 4 doses per day. If necessary, the daily dose may deviate slightly from the above range.

The pyridonecarboxylic acid derivatives of the present invention are effective against a variety of microorganisms that cause various infectious diseases and are suitable for treating or alleviating and / or preventing diseases caused by such pathogens.

Explanatory examples of bacteria or bacterial-like microorganisms against which pyridonecarboxylic acid derivatives of the invention are effective are Staphylo-18 coccus sp., Streptococcus pyogenes, Streptococcus Haemolyticus, enterococci, Streptococcus pneumoniae, Peptostorheriaocococaeaeococaeaeococaea Citrobacter sp., Shigella sp., Klebsiella pneumoniae, Enterobacter sp., Serratia sp., Proteus sp., Pseudomonas aeruginosa, Haemophilus influenzae, Acinetobacter sp., Campylobacter sp., And Chlamidiae.

Examples of diseases caused by these pathogens include folliculitis, furunculosis, carbunculosis, erysipelas, phlegmon, lymphangiitis / lymphadenitis, felon (abscess on the finger pad), subcutaneous abscess, spiradenitis, acne of globules, infectious atheroma, mastitis, pyrian secondary infections after trauma, burns or surgical trauma, pharyngolaryngitis, acute bronchitis, tonsilitis, chronic bronchitis, bronchiectasis, diffuse panbronchiolitis, secondary infections of chronic respiratory diseases, pneumonia, pyelonephritis, cystitis, prostatitis, epidocitis, epidocitis, epidocitis , cholecystitis, cholangiitis, bacillary dysentery, enteritis, adnexitis, intrauterine infections, bartolinitis, blepharitis, hordeolum, dacryocystitis tarzadenitis, keratohelcosis, otitis media, sinusitis, paradentitis, pericoronitis, circulitis, gnatitis, peritonitis, coronitis, peritonitis, peritonitis.

Examples of microorganisms sensitive to the compounds of the invention causing veterinary infectious diseases include poultry such as Escherichia sp., Salmonella sp., Pasteurella sp., Haemophilus sp.,

Bordetella sp.,

Staphylococcus sp., And Mycoplasma sp. specific examples of veterinary diseases caused by these micro-organisms include colibacillosis, pullorum disease, avian paratyphosis, poultry cholera, infectious maize, staphylococcal infections and mycoplasma diseases; further pigs such as colibacillosis, malmonellosis, pasteurellosis, haemophilus infection, atropic rhinitis, exudative epidermitis, and mycoplasmic diseases. Bovine, such as colibacillosis, salmonellosis, hemorrhagic on septicemia, mycoplasma diseases, bovine infectious pleuropneumonia and bovine mastitis; canines such as coriform sepsis, salmonellosis, hemorrhagic septicemia, pyometra and cystitis; and feline, such as hemorrhagic pleurisy, cystitis, chronic rhinitis, haemophilus infection, diarrhea in young cats, and mycoplasma diseases.

The compound of the present invention can be formulated into antimicrobial preparations, in a suitable dosage form, in a route of administration selected by conventional methods of preparation. The dosage form for oral administration includes tablets, powders, granules, capsules, solutions, syrups, elixirs and oily or aqueous suspensions. Injections may contain, in addition to the effective ingredient, stabilizers, antiseptics and solvents. A solution that may contain such additives is placed in a container and further the solution may be subjected to lyophilization or the like to produce soluble, soluble preparations when used. The container may contain a single dose or several doses.

Dosage forms for external action include solutions of suspension, emulsions, ointments, gels, creams, lotions and sprays.

In the preparation of solid preparations, the active ingredient may be admixed with suitably selected, pharmaceutically acceptable additives such as fillers, volume enhancers, binders, disintegrators, solubilizers, wetting agents and lubricants.

Liquid preparations include solutions, suspensions and emulsions. They may contain additives such as suspension stabilizers and emulsifiers.

The compound of the present invention can be administered to animals orally either directly or mixed with feed, or a solution thereof either directly or mixed with water or feed. The compound can also be administered orally, e.g. by injection.

The compound of the invention can be formulated into animal preparations such as powders, fine granules, solubilized powders, syrups, solutions and injections, using commonly used preparative methods.

Examples of formulations are given below, but for illustrative purposes only and not by way of limitation.

EXAMPLES FOR FORMULATION NO. 1

Capsule:

Example 8 compound 100,0 mg Corn starch 23.0 mg Calcium carboxymethyl cellulose 22.5 mg Hydroxypropylmethyl cellulose 3.0 mg Magnesium stearate 1.5 mg total: 150,0 mg FORMULATION EXAMPLE NO. 2 Solutions _a : Compound of Example 7 1 to 10 Mr Rücker Acetic acid or sodium hydroxide 0.5 to 2 Mr Rücker Ethyl p-hydroxybenzoate 0.1 Mr Rücker Purified water 88,9 to 98.4 Mr Rücker

total: 100 g

EXAMPLES FOR THE FORMULATION OF ŽT. 3

Feed powder for mixing:

Compound of Example 6

Corn starch

Lightly anhydrous silicic acid up to 10 g 88.5 to 98.5 g

0.5 g total: 100 g

The present invention is now explained in more detail with the following examples and reference examples, but it should be understood that we do not mean to limit the present invention to them. Reference examples describe syntheses of optically active cis-2-fluoro-cyclopropane carboxylic acid frameworks.

The antimicrobial efficacy of the optically active compounds prepared in the examples was evaluated according to the standard method set out in Nippon Kagakuryoho gakkai and the results obtained are shown in Table 1 below, expressed as minimum inhibitory concentration (MIC: pg / ml).

REFERENCE EXAMPLE 1

N- [1- (R) -phenylethyl] -1,2-cis-2-fluorocyclopropane-carboxamide (2a, 2b);

1-1. Carbonyldiimidazole Method:

One gram of cis-2-fluorocyclopropanecarboxylic acid was dissolved in 30 ml of tetrahydrofuran (THF), and 1.78 g of N, N'-carbonyldiimidazole were added, and the mixture was stirred for 1 hour at room temperature. 1.45 g (R) - (+) -? L-methylbenzylamine was added to the solution and stirred for 2 hours. The solvent was removed under reduced pressure and the residue was extracted with chloroform. The extract was washed successively with 10% aqueous citric acid and water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. Each of the isomers was isolated from the remaining viscous oily snotfi by HPLC under the conditions shown below. Each of the isomers was recrystallized from diisopropylether to give the title compound (2a) or (2b).

HPLC conditions:

Column

Kagaku) ethyl acetate-THF (9: 1 by volume) 9.0 ml / min

Solvent

Flow

Retention Time: 11 min, for compound min. for compound ( ^2b )

Compound (2a):

Melting point:

108 ° C

Elemental analysis for C ₁₂ H ₁₄ FNO:

Calc. (%) j C 69.55; H, 6.81; N, 6.76

Found .. (%): C 69.31; H 7.01; N, 6.65 [a] _D ; + 61.96 ° (c = 0.965, chloroform) ¹ H-NMR (CDCl ₃ ) 6 ppm:

0.92-1.34 (2H, m), 1.50 (3H, d, J = 7Hz), 1.501.96 (1H, m), 4.68 (1H, dm, J = 64Hz), 5.14 (1H, m), 7.40 (5H , s)

Physicochemical properties of compound (2b):

M.p .: 102 ° C

Elemental analysis for: C ₁₂ H ₁₄ FNO:

Calc .: (%): C 69.55; H, 6.81; N 6.76 Found: (%): C 69.45; H, 6.87; * N 6.70 [a] _D : + 143.61 ° (c = 0.830, chloroform) ¹ H-NMR (CDCl ₃ ) δ ppm:

0.98 = 1.34 (2H, m), 1.52 (3H, d, J = 7Hz), 1.641.96 (1H, m), 4.58 (1H, dm, J = 66Hz), 5.24 (1H, m), 7.40 (5H) , m)

1-2. The mixed anhydride method

4.19 g of clopropanecarboxylic acid (ois-trans mixture) and 4.07 g of triethylamine were dissolved in 50 ml of tetrahydrofuran and then the solution was cooled to -10 ° C. A solution of 4.73 g of ethylchloroformate in 20 ml of tetrahydrofuran was added and the mixture was stirred for 10 minutes. A solution of 4.88 g of (R) - (+) -cyl-methyl-benzylamine in 30 ml of tetrahydrofuran at this temperature was then added dropwise to the solution, then the mixture was stirred at room temperature for 15 hours. The solvent was removed under reduced pressure and the residue was extracted with benzene. The extract was washed successively with 10% aqueous citric acid,

N aqueous sodium hydroxide solution and water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the resulting pale yellow oily material was purified by silica gel column chromatography using a benzene / ethyl acetate mixed solvent as eluent for each of the title compounds (2a) and (2b).

REFERENCE EXAMPLE 2 (+) - cis-2-fluorocyclopropanecarboxylic acid (3a):

530 mg of the amide compound (2a) was dissolved in 15 ml of concentrated hydrochloric acid as prepared in Reference Example 1, and then the solution was heated to 5 tfr with stirring at 100-110 ° C. 20 ml of water were added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was then extracted with aqueous sodium hydrogen carbonate solution and this aqueous extract was washed with ethyl acetate. The aqueous extract was adjusted to pH 5 with concentrated hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent removed under reduced pressure to give the title compound (3a) as a pale yellow oil.

[α] _D : -23.13 ° (c = 1.020, chloroform) ¹ H-NMR (CDCl ₃ ) δ ppm:

1.0-1.42 (1H, m), 1.60-2.10 (2H, m), 4.82 (1H, dm, J = 65Hz), 12.0 (1H, s)

REFERENCE EXAMPLE 3 (+) - cis-2-fluorocyclopropanecarboxylic acid (3b) ^;

1.65 g of the amide compound (2b) was dissolved in 30 acre of concentrated hydrochloric acid as prepared in Reference Example 1, and then the solution was heated for 5 hours with stirring at 100-110 ° C. The pH of the reaction mixture was adjusted to a value between 8 and 9 with sodium hydrogen carbonate and then washed with chloroform. The pH of the aqueous layer was adjusted to 4 with hydrochloric acid concentrated and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent removed under reduced pressure to give the title compound (3t>) as a pale yellow oil.

[a] _D : + 21.56 ° (c = 1.113, chloroform) 1 H-NMR (CDCl ₃ ) δ ppm:

1.0-1.42 (1H, m), 1.56-1.98 (2H, ra, 4.76 (1H, days, J = 66Hz), 11-32 (1H, s)

REFERENCE EXAMPLE 4 (+) - cis-1- (t-butoxycarbonylamino) -2-fluorocyclopropane (4a):

Dissolve 200 mg of carboxylic acid (3a) in 5 ml of t-butanol as in Reference Example 2, 603 mg of diphenylphosphorylazide and 203 rag of triethylamine, and then reflux for 4.5 hours. After removal of the solvent under reduced pressure, the residue was extracted with chloroform. The extract was washed sequentially with 10% aqueous citric acid, 2% aqueous sodium hydroxide and water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was chromatographed on a silica gel column using chloroform as eluent to give the title compound (4a) as colorless crystals.

Melting point: 73 ° C (a] _D : + 65.57 ° (c = 0.610, chloroform) 1 H-NMR (CDCl ₃ ) 5 ppm:

0.6-1.3 (2H, m), 1.46 (9H, s), 2.48-2.74 (1H, m), 4.62 (1H, dm. J = 65Hz), 4.6-5.1 (1H, broad).

REFERENCE EXAMPLE 5 (-) - cis-1- (t-butoxycarbonylamino) -2-fluorocyclopropane (4b):

In 6 ml of t-butanol 265 mg of carboxylic acid (3b) was obtained as in Reference Example 3, 800 mg of diphenylphosphorylazide and 270 mg of triethylamine. The solution was allowed to react and treated in the same manner as in Reference Example 4 to give the title compound (4b).

Melting point: 63 ° C [a] _D : -60.27 (c = 0.740, chloroform)

- 27a ¹ H-NMR (CDCl ₃ ) δ ppm:

0.66-1.3 (2H, m), 1.46 (9H, s), 2.48-2.74 (1H, m), 4.58 (1H- dm, J = 65Hz), 4.6-5.1 (1H, broad)

REFERENCE EXAMPLE 6 (-) - Ethyl-2 - / (1,2-cis-2-fluorocyclopropan-1-yl) aminomethylene / 3-oxo-3- (2,4,5-trifluorophenyl) propionate (5a):

Ethyl 2,4,5-trifluorobenzoyl acetate (234 mg), 2 ml of ethyl orthoformate and 4 ml of acetanhydride were mixed and the mixture heated for 2 hours with stirring at 110-120 ° C. The solvent was removed under reduced pressure and the residue dissolved in 10 ml of dichloromethane.

Compound (4a) obtained in Reference Example 4 (167 mg) and 5 ml of trifluoroacetic acid were mixed and the mixture stirred for 20 minutes at room temperature, then concentrated to dryness under reduced pressure, using the resulting amine trifluoroacetate without purification). . The residue was dissolved in 10 ml of dichloromethane and cooled to -10 ° C. A solution of 230 mg of triethylamine and 10 ml of dichloromethane was then added dropwise to the mixture. The above dichloromethane solution was added dropwise, followed by stirring overnight at room temperature. The solvent was evaporated to dryness under reduced pressure and the residue was chromatographed on a silica gel column using a benzene / ethyl acetate (2: 1 vol.) Mixed solvent. The yellow oily substance was obtained from the eluent after removal of the solvent. The product was recrystallized from diisopropyl ether / n-hexane to give the title compound (5a) as colorless crystals.

Melting point: 69-70 ° C (aJ _D : -10.29 ° (c = J.O88, chloroform)

REFERENCE EXAMPLE 7 (+) - Ethyl-2 - [(1,2-cis-2-fluorocyclopropan-1-yl) aminomethylene] -3-oxo-3- (2,4,5-trifluorophenyl) propionate (5b):

Ethyl 2,4,5-trifluorobenzoyl acetate (337 mg) ml of ethylorthophore mat and 4 ml of acetanhydride were mixed, and the mixture was heated for 2 hours with stirring at 110-120 ° C. The solvent was removed under reduced pressure and the residue dissolved in 10 ml of dichloromethane.

Compound (4b) as obtained in Reference Example 5 (240 mg) and 5 ml of trifluoroacetic acid were stirred and the mixture stirred at room temperature for 1 hour, followed by concentration under reduced pressure (amine trifluoroacetate was used without purification) . The residue was dissolved in 10 ml of dichloromethane and cooled to -10 ° C. A solution of 230 mg of triethylamine in 10 ml of dichloromethane was added dropwise and the dichloromethane solution prepared above was further added to the mixture, followed by stirring overnight at room temperature. The solvent was removed under reduced pressure and the residue was chromatographed on a silica gel column using a mixed solvent of benzene and ethyl acetate (2: 1 vol). The yellow oily substance was obtained from the eluent after removal of the solvent. Recrystallization from diisopropyl ether / n-hexane gave the title compound (5b) as colorless crystals _{do not.}

I

Melting point: 69-70 ° C [a] _D ; +12.09 (c = 0.645, chloroform)

REFERENCE EXAMPLE 8 (+) - 6,7-difluoro-1- (1,2-cis-2-fluorocyclopropyl) -4-oxo,4,4-dihydroquinoline-3-carboxylate (6a):

Dissolve 180 mg of compound (5a) in 15 ml of anhydrous dioxane as obtained in Reference Example 6 and add 200 mg of 60% sodium hydride to the solution, followed by stirring for 2 hours at room temperature. The reaction mixture was added to a 10% aqueous citric acid solution, followed by concentration under reduced pressure. The residue was extracted with chloroform and the extract was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by preparative TLC on silica gel using benzene / ethyl acetate (1: 2 vol.) As the developing solvent to give the title compound (6a) as colorless crystals.

Melting point: 231-232 ° C [<x] _D : + 27.20 ° (c = 0.610, chloroform) ¹ H-NMR (CDCl ₃ ) 5 ppm:

1.20 (3H, t, J = 7Hz), 1.6-1.9 (2H, m), 3.28-3.56 (1H, m), 4.42 (2H, q, J = 7Hz), 5.11 (1H, dm.

J = 63Hz), 7.60 (1H, dd, J = 11Hz & 7Hz), 8.28 (1H, dd, J = 10Hz & 11Hz), 8.58 (1H, s)

REFERENCE EXAMPLE 9 (-) - Ethyl 6,7-difluoro-1- (1,2-cis-2-fluorocyclopropyl) -4-oxo 1,4,4-dihydroquinoline-3-carboxylate (6b):

In 15 ml of anhydrous dioxane dissolved 267 mg of compound (5b) as obtained in Reference Example 7 and 200 mg of 60% sodium hydride was added thereto, and the mixture was stirred for 2 days at room temperature. The reaction mixture was added to a 10% aqueous citric acid solution, followed by concentration under reduced pressure. The residue was extracted with chloroform and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by preparative TLC on silica gel using benzene / ethyl acetate (1: 2 vol.). "- as a developing solvent to give the title compound (6b) as colorless crystals.

Melting point: 226-227 ° C [a] _D : -31.36 ° (c = 0.610, chloroform)

1 H-NMR (CDCl ₃ ) δ ppm:

1.22 {3H, t, J = 7Hz), 1.5-1.9 (2H, m), 3.26-3.52 (1H, m), 4.40 (2H, q, J = 7Hz), 5.10 (1H, dm.

J = 63Hz), 7.58 (1H, dd, J = 11Hz & 7Hz), 8.26 (1Ή, dd, J = 10Hz & 11Hz), 8.55 (1H, s)

REFERENCE EXAMPLE 10 (+) - 6,7-Difluoro-1- (1,2-cis-2-fluorocyclopropyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (7a);

Dissolve 106 mg of ester (6a) in 15 ml of concentrated hydrochloric acid as obtained in the reference example.

8, after which the solution was heated for 2 hours with stirring at 100-110 ° C. 15 ml of water were added to the reaction mixture and the precipitate was collected by filtration to give the title compound (7a) as a colorless crystal e.

Melting point: 265-270 ° C [ct] _D : + 3.66 ° (c = 0.383, acetic acid) ¹ H-NMR (CDCl ₃ ) δ ppm:

1.75-1.95 (2H, m), 3.58 (1H, m), 5.18 (1H, dm,

J = 64Hz), 7.82 (1H, dd, J = 12Hz, & 7Hz), 8.37 (1H, dd, J = 18Hz & 8Hz), 8.94 (1H, s)

REFERENCE EXAMPLE 11 (-) - 6,7-Difluoro-1- (1,2-cis-2-fluorocyclopropyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (7b):

Dissolve 150 mg of extra (6b) in 10 ml of concentrated hydrochloric acid as was obtained in the reference case

9, after which the solution was heated for 2 hours with stirring at 110 ° C. 20 ml of water were added to the reaction mixture and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent removed under reduced pressure. The residue was recrystallized from ethanol to give the title compound (7b) as colorless crystals.

Melting point: 261-264 ° C [<x] _D ; -4.08 ° (c = 0.343, acetic acid) 1 H-NMR (CDCl ₃ ) δ ppm:

1.75-1.95 (2H, m), 3.58 (1H, m), 5.18 (1H, dm, J = 64Hz), 7.82 (1H, dd, J = 12Hz & 7Hz), 8.37 (1H, dd, J = 12Hz δ 8 Hz), 8.94 (1H s)

EXAMPLE 1

7- [3- (S) -t-Butoxycarbonylamino-1-pyrrolidinyl] -6-fluoro- (1,2-cis-2-fluorocyclopropyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (8a ):

mg of carboxylic acid (7a) as obtained in Reference Example 10, 150 mg (S) -3- (t-butoxycarbonylamino) pyrrolidine, 200 mg triethylamine and 20 ml acetonitrile were stirred and the mixture heated at reflux for 4 hours. The solvent was removed under reduced pressure and a 10% aqueous citric acid solution was added to the residue, followed by extraction with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent removed under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (8a) as yellow crystals.

Melting point: 236-239 ° C [a] _D : + 1.0 ° (c = 0.200, chloroform) ¹ H-NMR (CDCl ₃ ) δ ppms

1.2-1.7 (2H, m), 1.46 (9H, s), 1.7-1.9 (1H, m),

2.0-2.36 (1H, m), 3.3-4.0 (5H, m), 4.2-4.4 (1H, m), 5.06 (1H, dm, J = 68Hz), 6.68 (1H, d, J = 7Hz).

7.84 (1H, d, J = 14Hz), 8.46 (1H, s)

EXAMPLE 2

7- [3- (S) -t-butoxycarbonylamino-1-pyrrolidinyl] -6-fluoro-1- (1,2-cis-2-fluorocyclopropyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (8b ):

- 34 Carboxylic acid as obtained in Reference Example 11 (7b) (112 mg), 200 mg (S) -3- (t-butoxycarbonylamino) pyrrolidine, 220 mg triethylamine, and 15 ml acetonitrile were mixed and the mixture warmed 4 hours at reflux. The solvent was removed under reduced pressure and a 10% aqueous citric acid solution was added to the residue, followed by extraction with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent removed under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (8b) as yellow crystals.

Melting point: 242-243 ° C (a) _D : -4.0 ° (c = 0.448, chloroform) ¹ H-NMR (CDCl ₃ ) δ ppm:

1.0-1.7 (2H, m), 1.40 (9H, s), 1.6-1.8 (1H, ra),

1.9-2.1 (1H, m), 3.3-3.9 (5H, m), 4.2-4.5 (1H, ra), 5.00 (1H, dm, J = 68Hz), 6.58 (1H, d, J = 7Hz),

7.72 (1H, d, J = 14Hz1. 8.32 (1H, s)

EXAMPLE 3

7- [3- (S) -amino-1-pyrrolidinyl] -6-fluoro-1- (1,2-cis-2fluorocyclopropyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (9a):

Dissolve 80 mg of carboxylic acid (8a) in 10 ml of trifluoroacetic acid as was obtained in Example 1.

After stirring for 20 minutes, the reaction mixture was evaporated under reduced pressure to dryness. 5 ml of water was added to the residue and further added 1 N aqueous sodium hydroxide solution to dissolve the residue. The pH of the aqueous layer was adjusted to 7.5 with 1 N hydrochloric acid, followed by extraction with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent removed under reduced pressure. Recrystallization of the residue from ethanol gave the title compound as colorless crystals.

Melting point: 248-252 ° C [α] _θ : -31.35 ° (c = 0.370, IN NaOH exercise * d? Assfe & pin) ¹ H-NMR (CDC1 ₃ ) δ ppm:

1.52-1.68 (2H, m), 1.68-1.80 (1H, m), 2.05-Ϊ.15 (1H, m), 3.13-3.22 (1H, m), 3.25-3.45 (2H, m).

3.45-3.65 (3H, m), 5.12 (1H, dm, J = 65Hz), 6.58 (1H, d, J = 7Hz), 7.58 (1H, d, J = 14Hz), 8.29 (1H, s)

EXAMPLE 4

7- [3- (S) -amino-1-pyrrolidinyl] -6-fluoro-1- (1,2-cis-2-fluorocyclopropyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (9a ):

To 10 ml of trifluoroacetic acid was added 80 mg of carboxylic acid (8b) as was obtained in Example 2. After 20 minutes of stirring, the reaction mixture was evaporated to dryness under reduced pressure. of hydroxide to dissolve the residue. The pH of the aqueous layer was adjusted to 7.5 with 1 N hydrochloric acid followed by extraction with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent removed under reduced pressure. Recrystallization of the residue from ethanol gave the title compound (9b) as colorless crystals.

Melting point: 236-240 ° C [a] _D : +23.72 (c = 0.413, IN NaOH aqueous solution) 1 H-NMR (CDCl ₃ ) δ ppm:

1.55-1.69 (2H, m), 1.69-1.77 (1H, m), 2.07-2.15 (1H, m), 3.15-3.22 (1H, m), 3.37-3.47 (2H, m).

3.52-3.58 (2H, m), 3.58-3.66 (1H, m), 5.13 (1H, dm, J = 65Hz), 6.62 (1H, d, J ⁼ 7Hz), 7.61 (1H, d.

J = 14Hz), 8.3_D LIH, s),

REFERENCE EXAMPLE 12 ^{* 7} (-) - Ethyl-2 - // 1,2-cis-2-fluoro-1-cyclopropyl) amino] -methylene / 3-oxo-3- (3-chloro-2,4,5 -trifluorophenyl) propionate (10a):

Ethyl 3-chloro-2,4,5-trifluorobenzoyl acetate (1.5 g), 6 ml ethyl orthophorophoate, ^{and 10} acetanhydride were mixed and the mixture was heated to 110-120 ° C for 1.5 hours with stirring. The reaction mixture was concentrated to dryness under reduced pressure and the residue was dissolved in 5 ml of dichloromethane.

ml of trifluoroacetic acid was cooled with ice and dissolved in 480 mg of (+) - cis-1- (t-butoxycarbonylamino) -2-fluorocyclopropane (4a). The solution was stirred at room temperature for 20 minutes, followed by evaporation under reduced pressure to dryness. The residue was suspended in 10 ml of dichloromethane and 3 ml of triethylamine were added while cooling with ice.

After stirring for 20 minutes, the dichloromethane solution prepared above was added thereto and the mixture was stirred for 1 hour. The reaction mixture was washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was subjected to flash column flash chromatography using a benzene / ethyl acetate (5: 1 vol.) Mixed solvent as eluent. The solvent was removed under reduced pressure and the residue was washed with diisopropylether to give 620 mg of the title compound (10a).

Melting point: 98-100 ° C (a) p: -6.66 ° (c = 0.998, chloroform)

Elemental analysis for C ₁₅ H ₁₂ C1F ₄ NO ₃ :

Calc. (%): C 49.26; H, 3.31; N 3.83 Found. (%): * C 49.39; H, 3.22; N 3.86 1 H-NMR (CDCl ₃ ) 6 ppm;

0.95, 1.08 (3H, 1: 2.5, each t, J = 7HZ), 1.0-1.5 (2H, m), 2.8-3.15 (1H, m), 4.03, 4.07 (2H,

1: 2.5, each q, J = 7Hz), 4.78 (1H, dm, J = 65Hz),

7.13 (1H, ddd, J = 5.9, 8.6, & 9.5Hz), 8.20, 8.25 (1H, 1: 2.5, each d, J = 14HZ)

- 38 REFERENCE EXAMPLE 13 (+) - 2 - // 1,2-cis-2-fluoro-1-cyclopropyl) amino / methylene / 3-oxo-3- (3-chloro-2,4 _> 5-trifluorophenyl) propionate (10b):

Ethyl 3-chloro-2,4,5-trifluorobenzoyl acetate (1.5 g), 6 ml ethyl orthoformate, and 10 ml acetal anhydride were mixed and the mixture heated for 1.5 hours with stirring at 110-120 ° C. The reaction mixture was concentrated to dryness under reduced pressure and the residue dissolved in 10 ml of dichloromethane. 10 ml of trifluoroacetic acid were cooled with ice and 1.12 g (-) - cis-1- (t-butoxycarbonylamino) -2-fluorocyclopropane (4b) dissolved therein, and the mixture was evaporated to dryness after 20 hours at room temperature. at reduced pressure. The residue was suspended in 20 ml of dichloromethane and 2.0 g of triethylamine was added to the suspension while cooling with ice. To this was then added a dichloromethane solution prepared above, followed by stirring for 1 hour. The reaction mixture was washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was subjected to flash column chromatography, then eluted with a benzene / ethyl acetate mixed solvent (4: 1 vol.). The solvent was removed from the eluent under reduced pressure. The residue was washed with diisopropylether / n-hexane to give 1.74 g of the crystals of the title compound (10 b).

Melting point: 99-100 ° C [a] _n : + 6.70 ° (c = 0.895, chloroform)

Elemental analysis for C ₁₅ H ₁₂ C1F ₄ NO ₃ :

Calc. (%): C 49.26; H, 3.31; N 3.83 Found. (%): C 49.41; H, 3.60; N 4.06 ¹ H-NMR (CDCl ₃ ) δ ppm:

0.95, 1.08 (3H, 1: 2.5, each t, J = 7HZ), 1.0-1.5 (2H, m), 2.8-3.15 (1H, m), 4.03, 4.07 (2H,

1: 2.5, each q, J = 7Hz), 4.78 (1H, dm, J = 65Hz),

7.13 (1H, ddd, J = 5.9, 8.6, δ 9.5Hz), 8.20, 8.25 (1H, 1: 2.5, each d, J = 14HZ)

REFERENCE EXAMPLE 14 (+) - Ethyl 8-chloro-6,7-difluoro-1- (1,2-cis-2-fluoro-1-cyclopropyl) -4-oxo-1,4-dihydroquinoline-3-carboxylate ( 1 la):

620 mg of compound (10a) as prepared in Reference Example 12 was dissolved in 7 ml of anhydrous dioxane, and 80 mg of 60% sodium hydride was added to the solution, followed by stirring at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture and the mixture was washed successively with 10% aqueous citric acid solution and water. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed from it under reduced pressure. The residue was washed with n-hexane to give 551 mg of the title compound (11a) as colorless crystals.

Melting point: 18l-184 ° C [a] _D : + 45.1 ° (c = 1.18, chloroform)

Elemental analysis for 'C ₁₅ H ₁₂ ClF ₄ NO ₃ :

Calc. (%): C 52.12; H, 3.21; N 4.05 Found. (%): C 52.09; H, 3.33; N 4.01 ¹ H-NMR (CDCl ₃ ) δ ppm:

1.40 (3H, t, J = 7HZ), 1.4-1.9 (2H, m), 4.08 (1H, m), 4.39 (2H, q, J = 7HZ), 4.90 (1H, dm, J = 65Hz).

8.24 (1H, dd, J = 10 & 11 Hz)

REFERENCE EXAMPLE 15 (-) - Ethyl 8-chloro-6,7-difluoro-1- (1,2-cis-2-fluoro-1-cyclopropyl) 4-oxo-1,4-dihydroquinoline-3-carboxylate (11b ):

560 mg of 60% sodium hydride was suspended in 10 ml of anhydrous dioxane, which was washed twice with anhydrous n-hexane. The suspension was added to a solution of 1.70 g of compound (10b) in 20 ml of anhydrous dioxane, followed by stirring at room temperature for 2 hours. The solvent was removed under reduced pressure and 0.1 N hydrochloric acid was added to the residue. The precipitated crystals were collected by filtration, washed successively with water and diethyl ether and dried under reduced pressure to give 1.44 g of the title compound (11b) as colorless crystals.

Melting point: 174 ° C [a] _D : -45.3 ° (c = 1.05, 'chloroform')

Elemental analysis for C ₁₅ H ₁₁ C1F ₄ NO ₃ :

Calc. (%): C 52.12; H, 3.21; N, 4.05

Found. (%): C 51.80; H 3.45? N 4.15 ¹ H-NMR (CDCl 3) δ ppm:

1.40 (3H, t, J = 7HZ), 1.4-1.9 (2H, m), 4.08 (1H, m), 4.39 (2H, q, J = 7HZ), 4.90 (1H, dm, J = 65Hz).

8.24 (1H, dd, J = 10 & 11 Hz)

IR (KBr); in _max cm ^-1 : 3100, 2998, 1731, 1638, 1614,

1470, 1317

- 41 REFERENCE EXAMPLE 16 (+) - 8-Chloro-6,7-difluoro-1- (1,2-cis-2-fluoro-1-cyclopropyl) 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (12a):

The ester (11a) (540 mg), 5 ml of concentrated hydrochloric acid and 5 ml of acetic acid were mixed, then the mixture was heated for 2 hours with stirring at 120 to 130 ° C. 50 ml of water were added to the reaction mixture and the precipitated crystals were collected by filtration, washed successively with water and diethyl ether and dried under reduced pressure to give 420 mg of the title compound (12a) as colorless crystals.

Melting point: 17O-171 ° C [q] _D ; + 30.4 ° (c = Q.54, chloroform)

Elemental analysis for C ₁₃ H ₇ C1F ₃ NO ₃ : calc. (%): C 49.16; H 2.22? N 4.41 Found. (%): C 49.21; H, 2.49; N 4.27 ¹ H-NMR (CDCl ₃ ) δ ppm:

1.3-2.0 (2H, m), 4.12-4.34 (1H, m), 4.95 (1H, dm, J = 63Hz), 8.27 (1H, dd, J = 8 & 8Hz), 8.87,

8.89 (1H, s each, split 1: 1).

REFERENCE EXAMPLE 17 (-) - 8-Chloro-6,7-difluoro-1- (1,2-cis-2-fluoro-1-cyclopropyl) -4 oxo-1,4-dihydroquinoline-3-carboxylic acid (12b );

Ester (11b) (1.40 g) was mixed and 10 ml of concentrated hydrochloric acid was added and the mixture was heated for 2.5 hours with stirring at 110 ° C. 50 ml of water were added to the reaction mixture, and the precipitated crystals were collected by filtration, washed with water and diethyl ether and dried under reduced pressure to give 1.16 g

- 42 title compounds (12 b) as colorless crystals.

Mp 177-182 ° C [a] _D : -26.8 (c = 0.90, chloroform)

Elemental analysis for c ₁₃ H ₇ C1F ₃ NO ₃ :

Calc .: (%): C 49.16? H, 2.22; N 4.41 Found: (%): C 49.28; H 2.40; N-4.66 ¹ H-NMR (CDCl ₃ ) δ ppm:

1.3-2.0 (2H, m), 4.12-4.34 (1H, m), 4.95 (1H, dm, J = 63Hz), 8.27 (1H, dd, J = 8 & 8Hz), 8.87,

8.89 (1H, s each, split 1: 1).

EXAMPLE 5 (+) - 7- [3- (S) -amino-1-pyrrolidinyl] -8-chloro-6-fluoro-1- (1,2cis-2-fluoro-1-cyclopropyl) -4-oxo- 1,4-Dihydroquinoline-3carboxylic acid (13a):

ml of trifluoroacetic acid was cooled with ice and dissolved in 230 mg of 3- (S) -1-t-butoxycarbonyl-3- (t-butoxycarbonylamino) pyrrolidine, followed by stirring for 20 minutes at room temperature. The reaction mixture was evaporated to dryness under reduced pressure and the residue was dissolved in 15 ml of acetonitrile. 170 mg of carboxylic acid (12a) and 400 mg of triethylamine were added to the solution, followed by 6.5 hours of reflux. The reaction mixture was evaporated to dryness under reduced pressure and 1N hydrochloric acid was added to the residue. The mixture was washed with chloroform. The pH of the aqueous layer was adjusted to 12 z

- 43 1Ν aqueous sodium hydroxide solution and washed with chloroform. The pH of the aqueous layer was again adjusted to 7.6 with hydrochloric acid and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was recrystallized from aqueous ammonia / ethanol to give 138 mg of the title compound (13a) as colorless crystals.

Melting point:. 214-217 ° C (decomposition) [aJ _D : + 120.8 ° (c = 0.475, 0.1N NaOH aqueous solution)

Elemental analysis for C ₁₇ H ₁₆ C1F ₂ N ₃ O ₃ «1 / 2H ₂ O:

Calc. : (%) '· C 51.98; H, 4.36; N 10.70 Found :(%): C 52.07; H 4.71; N 10.72 ¹ H-NMR (NaOD) δ ppm:

1.28 (1H, dm, J = 27Hz), 1.69-1.78 (2H, m), 3.393.42 (1H, m), 3.51-3.61 (3H, m), 3.69-3.72 (1H, m), 4.13-4.17 (1H, m), 4.99 (1H, dm, J = 70Hz),

7.72 (1H, d, J = 14Hz), 8.44, 8.45 (1H, each s, split, 1: 1) *

EXAMPLE 6 (-) - 7- / 3- (S) -amino-1-pyrrolidinyl] -8-chloro-6-fluoro-1- (1,2-cis2-fluoro-1-cyclopropyl) -4-oxo- 1,4-Dihydroquinoline-3-carboxylic acid (13a):

ml of trifluoroacetic acid was cooled with ice and dissolved in 230 mg of 3- (S) -t-butoxycarbonyl-3- (t-butoxycarbonylamino) pyrrolidine, followed by stirring at room temperature for 20 minutes. The reaction mixture was evaporated to dryness under reduced pressure and the residue was dissolved in 15 ml of acetonitrile. 170 mg of carboxylic acid (12b) and 400 mg of triethylamine were added to the solution and the mixture was heated at reflux for 6.5 hours. The reaction mixture was evaporated to dryness under reduced pressure. 1N hydrochloric acid was added to the residue and the mixture was washed with chloroform. The aqueous layer was adjusted to pH 12 with 1N aqueous sodium hydroxide solution and the aqueous layer was adjusted to pH 7.6 with hydrochloric acid and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was recrystallized from aqueous ammonia / ethanol to give 158 mg of the title compound (13b) as colorless crystals.

Melting point: 247-252 ° C (decomposition) [a] _D : -94.7 ^e (c = 0.378, 0.1N HaOH aqueous solution)

Elemental analysis for C ₁₇ H ₁₆ C1F ₂ N ₃ O ₃ * H ₂ O:

Calc .: (%): C 50.82; H, 4.52; N, 10.46 Found: (%) · 'C 50.97; H, 5.14; N 10.42 ¹ H-NMR (NaOD) δ ppm:

1.32 (1H, dm, J = 27Hz), 1.73-1.80 (2H, m), 2.152.19 (1H, m), 3.19-3.22 (1H, m), 3.45-3.50 (1H, m), 3.58-3.62 (1H, m), 3.85-3.88 (2H, m), 4.164.20 (1H, m), 4.99 (1H, dm, J = 63Hz), 7.76 (1H, d, J = 14Hz), 8.54, 8.44 ( IH, each s, split, 1: 1)

REFERENCE EXAMPLE 18 (-) - Ethyl-2 - [(1,2-cis-2-fluoro-1-cyclopropyl) amino] -methylene / 3-oxo-3- (2,3,4,5-tetrafluoro- 6-nitrophenyl) -propionate (I4a):

Ethyl 2,3,4,5-tetrafluoro-6-nitrobenzoyl acetate (1.5 g), 6 ml of ethylorthoformate and 10 ml of acetanhydride were mixed and the mixture was heated at 120 ° C for 2 hours. The reaction mixture was concentrated to dryness and the residue dissolved in 10 ml of dichloromethane.

ml of trifluoroacetic acid was cooled with ice and dissolved 1.1 g (+) - cis-1- (t-butoxycarbonylamino) -2fluorocyclopropane (4a). The solution was stirred at room temperature for 2 hours, followed by evaporation to dryness under reduced pressure. The residue was suspended in 20 ml of dichloromethane and 2.0 g of triethylamine were added while cooling with ice, followed by stirring for 20 minutes. The dichloromethane solution prepared above was then added, followed by stirring for 30 minutes. The reaction mixture was washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was subjected to flash chromatography using benzene as eluent. The fractions of compound (I4a) were combined and the solvent was removed under reduced pressure. The residue was washed with n-hexane to give 1.57 g of crystals of the title compound (I4a).

Melting point: 99-100 ° C [a] _D : -10.3 ° (c = 1.25, chloroform)

Elemental analysis for ^C 15 ^H 11 ^F 5 ^N 2 ° 5

Calc .: (%): C 45.70; H 2.81; N, 7.10 Found: (%): C 45.60; H 3.01; N 7.03 ¹ H-NMR (CDCl ₃ ) δ ppm:

1.10 (3H, t, J = 7Hz), 1.2-1.55 (2E, m), 2.88-3.16 (1H, m), 4.09 (2H, q, J = 7Hz), 4.45 (1H, dm.

J = 63Hz), 8.29 (1H, d, J = 14Hz)

IR (KBr): in _ma x cnr ¹ : 3454 1734, 1626, 1566, 1521,

1482

REFERENCE EXAMPLE 19 (+) - Ethyl-2 - [(1,2-cis-2-fluoro-1-cyclopropyl) amino] -methylene / 3-oxo-3- (2,3,4,5-tetrafluoro- 6-nitrophenyl) propionate (14b):

Ethyl 2,3,4,5-tetrafluoro-6-nitrobenzoyl acetate (1.5 g), 6 ml of ethyl orthophore mat and 10 ml of acetanhydride were mixed and the mixture was heated for 1 hour with stirring at 110-120 ° C. The reaction mixture was concentrated to dryness and the residue dissolved in 10 ml of dichloromethane.

ml of trifluoroacetic acid was cooled with ice and 1.10 g (-) - cis-1- (t-butoxycarbonylamino) -2-fluorocyclopropane (4b) was dissolved in it, followed by stirring at room temperature for 20 minutes. The reaction mixture was evaporated to dryness under reduced pressure and the residue was suspended in 20 ml of dichloromethane. 1.8 g of triethylamine were added to the suspension under ice-cooling, followed by stirring for 20 minutes. The dichloromethane solution prepared above was added to the mixture, followed by stirring for 2 hours. The reaction mixture was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was subjected to flash column chromatography using benzene as eluent. Product fractions (I4b) were combined and the solvent was removed under reduced pressure. The residue was washed with n-hexane to give 1.50 g of crystals of the title compound (I4b).

- 47 Melting point: 98-100 ° C

-10.1 "(c = 2.09, chloroform)

Elemental analysis for ^c i5 ^H iiF ₅ N ₂ ^O 5 Calc: (%) with C 45.70; H 2.81; N, 7.10

Found: (%) ·. c 45.77; H, 3.38; N 7.18 ¹ H-NMR (CDCl ₃ ) δ ppm:

1.10 (3H, t, J = 7Hz), 1.2-1.5 (2H, m), 2.88-3.12 (1H, m), 4.09 (2H, q, J = 7Hz), 4.45 (1H, dm.

J = 63Hz), 8.30 (1H, d, J = 14Hz)

IR (KBr): in _max cm-1; 3454 1695, 1638, 1554, 1515

REFERENCE EXAMPLE 20 (+) - ethyl 6,7,8-trifluoro-1- (1,2-cis-2-fluoro-1-ocyclopropyl) -5nitro-4-oxo-1,4-dihydroquinoline-3-carboxylate ( 15a):

580 mg of 60% sodium hydride was suspended in 20 ml of anhydrous dioxane, which was washed twice with n-hexane. The suspension was added to a solution of 1.90 g of compound (I4a) in 20 ml of anhydrous dioxane. The mixture was stirred for 1 hour at room temperature and the solvent was removed from the reaction mixture under reduced pressure. 0.1N hydrochloric acid was added to the residue. The crystals thus formed were collected by filtration, washed successively with water and diethyl ether and dried under reduced pressure to give 1.65 g of the title compound (15a) as colorless crystals.

Melting point: I72-176 "C! <?]": + 10.7 ° (c = 1.12, chloroform,

Elemental analysis for i ^c is ^h io ^F 4 ^N 2 ° 5 Calc: (%): c 48.14; H 2.69; N, 7.49 Found: (%): C 48.29; H, 2.78; N 7.20 N-NMR (CDCl ₃ ) δ ppm:

1.36 (3H, t, J = 7Hz), 1.4-1.92 (2H, m), 3.80-4.08 (1H, m), 4.34 (2H, q, J = 7Hz), 4.99 (1H, dm.

J = 63Hz), 8.55 (1H, s)

IR (KBr): Vmax cm ^@ -1: 3454 1734, 1626, 1566, 1521 1482

REFERENCE EXAMPLE 21 (-) - Ethyl 6,7,8-trifluoro-1- (1,2-cis-2-fluoro-1-cyclopropyl) -5 nitro-4-oxo-1,4-dihydroquinoline-3-carboxylate (15b):

In 10 ml of anhydrous dioxane was suspended 440 mg of 60% sodium hydride, which was washed twice with n-hexane. The suspension was added to a solution of 1.45 g of compound (I4b) in 20 ml of anhydrous dioxane, followed by stirring at room temperature for 30 minutes. The solvent was removed from the reaction mixture under reduced pressure. 0.1N hydrochloric acid was added to the residue and the crystals formed were collected by filtration, washed sequentially with water and diethyl ether and dried under reduced pressure to give 1, 18 g of the title compound (15b) as colorless crystals.

Melting point: 17l-175 ° C [a] _D with -11.1 · (c = 0.27, chloroform)

Elemental analysis for ^< -ΐ5 ^Η ιο ^Ρ 4 ^Ν 2θ5 Calcd: (%) _: C 48.14; H 2.69; N 7.49 Found: _(% ). c 48.44; H 3.17; N-7.48 ¹ H-NMR (CDCl ₃ ) 6 ppm:

1.36 (3H, t, J = 7Hz), 1.4-1.92 (2H, m), 3.74-4.02 (1H, m), 4.36 (2H, g, J = 7Hz), 4.94 (1H, dm.

J = 62 Hz), 8.54 (1H, s)

IR (KBr): in _raax cm-1: 1731, 1626, 1566, 1485, 1323,

1275

REFERENCE EXAMPLE 22 (+) - Ethyl 5-amino-6,7,8-trifluoro-1- (1,2-cis-2-fluoro-1-cyclopropyl) -4-oxo-1,4-dihydroquinoline-3- carboxylic acid (l6a):

The nitro compound (15a) (1.60 g) was mixed with 6 ml of Raney nickel and 200 ml of ethanol, after which the mixture was shaken for 2.5 hours under a hydrogen atmosphere, the catalyst was removed by filtration / Celite and the filtrate was concentrated under reduced pressure. The residue was chromatographed on a silica gel column using chloroform as eluent. The product fractions (16a) were combined and the solvent removed under reduced pressure. The residue was recrystallized from ethanol to give 770 mg of the title compound (16a) as pale yellow crystals.

Melting point: 190-191 ^e C [a] o: + 26.0 ° (c = 0.76, chloroform)

Elemental analysis for ^c i5 ^H i2 ^F 4 ^N 2 ° 3

Calc. (%): C 52.33; H 3.51; N, 8.14. Found :'(%): C 52.13; H, 3.95; N 3.13 ¹ H-NMR (CDCl ₃ ) δ ppm:

1.39 (3H, t, J = 7Hz), 1.4-1.8 (2H, m), 3.60-3.88 (1H, m), 4.38 (2H, q, J = 7Hz), 4.87 (1H, dm.

J = 63Hz, 6.8-7.1 (2H, m), 8.37 (1H, s)

IR (KBr): in _m ax cm-1: 3436, 1683, 1653, 1557, 1461,

1284

- 50 --- ---- -:

REFERENCE EXAMPLE 23 (-) - Ethyl-5-aryano-6,7,8-trifluoro-1- (1,1 '2-cis-2-fluoro-1-cyclopropyl) -4-oxo-1,4-dihydroquinoline- 3-carboxylate (16b)

The nitro compound (15b) (1.60 g), 3 acre of Raney nickel and 120 ml of ethanol were mixed and the mixture was shaken for 4.5 hours under hydrogen atmosphere. The catalyst was removed by filtration through Celite and the filtrate was concentrated under reduced pressure. The residue is chromatographed on a silica gel column with chloroform as eluent. Combine the fractions with product (16b) and remove the solvent under reduced pressure. The residue was recrystallized from ethanol to give 620 mg of the title compound (16b) as pale yellow crystals.

'faiisee: 191-193 ° C (<x] _D : -25.9 ° (c = 0.65, chloroform)

Elemental analysis for ^ ₁₅ H ₁₂ ^F 4 ^N 2 ° 3

Izrac .; (%): C 52.33; H 3.51; N, 8.14. Found: (%): C 52.16; H, 3.54; N, 8.08. 1 H-NMR (CDCl ₃ ) δ ppm:

1.39 (3H, t, J = 7Hz), 1.4-1.8 (2H, m), 3.60-3.88 (1H, m), 4.38 (2H, q, J = 7Hz), 4.87 (1H, dm.

J = 63Hz, 6.8-7.1 (2H, m), 8.38 (1H, s)

IR (KBr): in _max cm-1; 3436, 1683, 1653, 1593, 1464,

1284

REFERENCE EXAMPLE 24

5-Amino-6,7,8-trifluoro-1- (1,2-cis-2-fluoro-1-cyclopropyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (17a)

The ester (1-6a) (750 mg) and 10 ml of concentrated hydrochloric acid were stirred and the mixture was heated at 100 ° C for 2 hours while stirring. 20 ml of water was added to the reaction mixture and the precipitated crystals were collected by filtration to give 610 mg of the title compound (17a) as colorless crystals.

Melting point: 297-300 ° C

Elemental analysis for C ^HgF ^N NP P Iz Izfac .: (%): C 49.38; H 2.55? N, 8.86 Found: (%): C 49.43; H, 2.91; N. 8.84 ¹ H-NMR (DMSO-d ₆ ) δ ppm:

1.4-2.1 (2H, m), 3.9-4.2 (1H, m), 5.08 (1H, dm,

J = 65Hz), 7.72 (1H, s), 8.62 (1H, s)

IR (KBr): in _max cm-1: 3448, 3334, 1725, 1656, 1596,

1566, 1518

REFERENCE EXAMPLE 25

5-Amino-6,7,8-trifluoro-1- (1,2-cis-2-fluoro-1-cyclopropyl) 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (17b)

The ester (16b) (588 mg) and 10 ml of concentrated hydrochloric acid were mixed and the mixture was heated to 100 to

110 ° C for 2 hours while stirring. 20 ml of water was added to the reaction mixture and the precipitated crystals were collected by filtration to give 514 mg of the title compound (17b) as colorless crystals.

Melting point: 295-300 ° C

Elemental analysis for ^c i3 ^H 8 ^F 4 ^N 2 ° 3

Calc .: (%) · * C 49.38; H 2.55? N, 8.86

Found :(%): C 49.41? H 2.81; N, 8.88

- 52 .-. 7 / ./ /. ¹ H-NMR (CDCl ₃ ) δ ppm:

1.4-2.1 (2H, m), 3.9-4.2 (1H, m), 5.08 (1H, dm,

J = 65Hz), 7.72 (1H, s), 8.62 (1H, s)

IR: in _max cm: 3448, 3334, 1725, 1656, 1596,

1566, 1518

EXAMPLE 7 (S) -5-Amino-7- [3- (S) -amino-1-pyrrolidinyl] -6,8-difluoro-1- (1,2-cis-2-fluoro-1-cyclopropyl) -4- oxo-1,4-dihydroquinoline-3-carboxylic acid (I8a) ml of trifluoroacetic acid is cooled in ice and dissolved in it 230 mg of 3- (S) -1-t-butoxycarbonyl-3- (t-butoxycarbonylamino) pyrrolidine and then stirred at room temperature for a further 30 minutes. The reaction mixture was evaporated to dryness under reduced pressure and the residue was dissolved in 25 ml of acetonitrile. To the solution was added 160 mg of carboxylic acid (17a) and 400 mg of triethylamine and the mixture was heated at reflux for 12 hours. The reaction mixture was evaporated to dryness under reduced pressure and 1 N hydrochloric acid was added to the residue. After washing the mixture with chloroform, the pH of the aqueous layer was adjusted to 12 with 1 N aqueous sodium hydroxide and then washed with chloroform. The pH of the aqueous layer was then adjusted to 7.6 with hydrochloric acid and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent removed under reduced pressure. The residue was recrystallized from aqueous ammonia / ethanol to give 128 mg of the title compound (18a) as colorless crystals.

Melting point: 224-230 ° C faL ·: -4.72 ° (c = 0.888, 0.1N NaOH aqueous solution ^{1 J} D t *

Elemental analysis for C ^ H ^ FgN ^ Og 'Calc. : (%): C 53.40; H, 4.48; N 14.65 Found :(%): C 53.28; H, 4.08; N 14.54 ¹ H-NMR (NaOD)) δ ppm:

1.47-1.58 (1H, m),, 1.67-1.78 (2H, m), 2.072.11 (1H, m), · 3.28-3.44 (1H, m), 3.48-3.52 (1H, m), 3.60-3.66 (1H, m), 3.71-3.78 (2H, m), 4.92 (1H, dm, J = 72Hz), 8.18 (1H, s)

IR: in _roa x cm-l: 3400, 1728, 1635, 1605, 1518,

1433, 1350, 1308

EXAMPLE 8 (+) - 5-amino-7- / 3- (S) -amino-1-pyrrolidinyl) -6,8-difluoro-1 (1,2-cis-2-fluoro-1-cyclopropyl) -4 -oxo-1,4-dihydroquinoline-3-carboxylic acid (I8b) ml of trifluoroacetic acid is cooled in ice and dissolved in it 230 mg of 3- (S) -1-t-butoxycarbonyl-3- (t-butoxycarbonylamino) pyrrolidine, then stirred at room temperature for another 30 minutes. The reaction mixture was evaporated to dryness under reduced pressure and the residue was dissolved in 25 ml of acetonitrile. To the solution was added 160 mg of carboxylic acid (17b) and 400 mg of triethylamine and the mixture was refluxed for 12 hours. The reaction mixture was evaporated to dryness under reduced pressure and 1 N hydrochloric acid was added to the residue. After washing the mixture with chloroform, the pH of the aqueous layer was adjusted to 12 with 1 N aqueous sodium hydroxide and then washed with chloroform. The pH of the aqueous layer was then adjusted to 7.6 with hydrochloric acid, and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent removed under reduced pressure. The residue was recrystallized from aqueous ammonia / ethanol to give 68 mg of the title compound (I8b) as colorless crystals.

Melting point: 214-217 ° C [a) _D : + 31.3 ° (c = 0.268, 0.1N NaOH aqueous solution Elemental analysis for C ₁₇ H ₁₇ F ₃ N ₄ O ₃ · 1 / 2Η ₂ Ο:

Calc .: (%): C 52.18; H 4.64; N, 14.32; Found :(%): C 52.22; H, 4.93; N 14.23 ¹ H-NMR (NaOD) δ ppm:

1.48-1.58 (1H, m),, 1.66-1.79 (2H, m), 2.062.12 (1H, m), 3.29-3.32 (1H, ra), 3.48-3.52 (1H, m), 3.60-3.64 ( 1H, m), 3.70-3.78 (2H, ra), 4.92 (1H, dm, J = 72Hz), 8.19 (1H, s)

IR: in _max cm-1: 3490, 1716, 1635, 1521, 1437,

1356, 1305

REFERENCE EXAMPLE 26

Synthesis of optically active 7-amino-5-azaspiro- (2,4) -heptane ¹ ) 5 - / (1R) -phenylethyl) -4,7-dioxo-5-azaspiro / 2,4 / -heptane (19)

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

Any insoluble matter is removed by filtration and the filtrate is evaporated to dryness under reduced pressure. Water was added to the residue and the mixture was extracted with chloroform. The chloroform extract was dried over anhydrous sodium sulfate and the solvent removed under reduced pressure. The resulting pale yellow oily substance was distilled off under reduced pressure to give 7.5 g of ethyl 1-acetyl-1-cyclopropanecarboxylate at a boiling point of 70 to 71 ° C / 2 to 3 mmHg. (T-3-3-9 mbar).

¹ H-NMR (CDCl 3) δ ppm:

1.30 (3H, t, J = 7Hz), 1.48 (4H, s), 2.49 (3H, s), 4.24 (2H, q, J = 7Hz)

Dissolve 35.7 g of the above compound in 200 ml of ethanol and add 40 g of bromine dropwise at room temperature while stirring. The mixture was then stirred at room temperature for 2 hours and then the excess bromine and solvent removed under reduced pressure to give ethyl 1-bromoacetyl-1-cyclopropanecarboxylate, which was then dissolved in 200 ml of ethanol without further purification. 33 g of R - (+) - 1-phenylethylamine and 27 g of triethylamine are added dropwise to the solution simultaneously while stirring and cooling with ice over a period of 1 hour. After the addition is complete, allow the reaction temperature to reach room temperature and continue stirring at room temperature for 2 days. Any insoluble matter removed by filtration _? ethanol was removed from the filtrate under reduced pressure. The residue was dissolved in 300 ml of ethyl acetate and the solution was washed successively with 1 N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride ^ in that order. The organic layer was dried over anhydrous sodium sulfate

- 56 - and removed under reduced pressure. The residue is chromatographed on a 200 g silica gel column, which is washed with 0 to 2% methanol chloroform to give the title compound (19) as colorless crystals.

Melting point: 98-103 ° C. @ 1 H-NMR (CDCI3) δ ppm:

1.62 (3H, d, J = 7.2Hz), 3.5 (1H, d, J = 18Hz), 3.9 (1H, d, J = 18Hz), 5.82 (1H, q, J = 7.2Hz), 7.36 (5H. s)

2) 5 - [(1R) -phenylethyl] -7-hydroxyimino-4-oxo-5-azaspiro / 2,4 / heptane (20)

To 3.35 g of compound (19) was added 1.6 g of hydroxylamine hydrochloride 2.3 g of triethylamine and 80 ml of ethanol and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and chloroform was added to the residue. The mixture was washed successively with 10% citric acid aqueous solution and saturated aqueous sodium chloride solution. Organic layer

dried over anhydrous sodium sulfate. Solvent removed under reduced pressure so that to get 3,5 g the title compounds (20) in the form colorless of crystals. Melting point: 188-194 ° C ¹ H-NMR (CDCl 3) δ ppm: 1.2-1.4 (2H, m), 1.53 (3H, d, J = 7 .2Hz & 2H, m),

3.8 (1H, d, J = 18Hz), 4.16 (1H _r d, J = 18Hz), 5.63 (1H, q, J = 7.2Hz), 7.32 (5H, s)

- -5-7 · 3) 7-amino-4-oxo-5 - [(1R) -phenylethyl] -5-azaspiro / 2,4 / -heptane (21a, 21b)

3.5 g of compound (20) and 7.5 ml of Raney nickel were added to 150 ml of methanol and the catalytic reduction was carried out at room temperature for 12 hours. After removal of the catalyst by filtration, the solvent is removed from the filtrate under reduced pressure. The residue was chromatographed on 100 g of a silica gel column, which was washed with a mixed solvent of 5% methanol in chloroform to give 1.0 g of the title compound (21b) from the early fractions and 0.8 g of the title compound (21a) from the subsequent fractions, each as a colorless oily substance.

Compound (21b):

1 H-NMR (CDCl ₃ )? Ppm:

0.8-1.4 (4H, m), 1.52 (3H, d, J = 7Hz), 2.87 (1H, dd, J = 10, & 3Hz), 3.3-3.9 (2H, m) ', 4.27 (2H, airo ), 5.42 (1H, q, J = 7Hz), 7.29 (5H, s)

Compound (21a):

¹ H-NMH (CDCl 3) δ ppm:

0.6-1.3 (4H, m), 1.40 (2H, s), - 1.53 (3H, d,

J = 7.2Hz), 2.99 (1H, dd, J = 12.8, & 7.2Hz),

3.15-3.45 (2H, m), 5.52 (1H, q, J = 7.2Hz), 7-30 (5H, s)

4) 7-amino-5 - [(1R) -phenylethyl] -5-azaspiro / 2,4 / heptane (22a, 22b)

To 50 ml of anhydrous tetrahydrofuran was added 1.0 g of compound (21b) and 500 mg of lithium aluminum hydride and the mixture was refluxed for 17 hours. After cooling the reaction mixtures

- 58 ml of water, 0.5 ml of 15% aqueous sodium hydroxide solution and 1.5 ml of water in this order are added consecutively, then stirred well at room temperature for another 30 minutes. Any insoluble matter is removed by filtration and washed well with tetrahydrofuran. The filtrate and washings are combined and dried. The solvent was removed under reduced pressure to give 940 mg of the title compound (22b) as a pale yellow oily substance. In the same manner, 755 mg of the title compound (22a) was obtained from 800 mg of the compound (21a).

Compound (21b):

¹ H-NMR (CDCl 3) δ ppm:

0.2-0.8 (4H, m), 1.35 (3H, d, - J = 6.6Hz), 1.6-2.0 (2H, width m), 2.2-3.1 (4H, m), 3.24 (1H, q.

J = 6.6Hz), 3.5-3.9 (1H, m), 7.28 (5H, broad s)

Compound (22a):

¹ H-NMR (CDCl 3) δ ppm:

0.3-0.9 (4H, m), 1.36 (3H, d, J = 6.7Hz), 1.8-2.2 (2H, m), 2.2-3.2 (4H, m), 3.24 (1H, q, J = 6.7Hz) , 3.6-3.9 (1H, m), 7.28 (5H, broad)

5) 7- (t-Butoxycarbonylamino) -5- (1R) -phenylethyl / -5-azaspiro / 2,4 / heptane (23a, 23b)

To 20 ml of anhydrous tetrahydrofuran was added 764 mg of compound (22b) and 1.3 g of Boc-ON / Boc-ON; 2- (t-Butoxycarbonyl oxyimino / -2-phenylacetonitrile

CN (CH ₃ ) ₃ COCOON =

r

5′9 ′ and the mixture was stirred at room temperature for 4 hours. Ethyl acetate was added to the reaction mixture and washed twice with 1 N aqueous sodium hydroxide solution and then once with water, followed by extraction with 10% aqueous citric acid. The aqueous extracts were washed once with ethyl acetate and a 15% aqueous solution of sodium hydroxide was added to the aqueous layer during cooling to make it alkaline. The mixture was extracted three times with chloroform and then the organic layer was washed with saturated aqueous sodium chloride solution and then dried. The solvent was removed under reduced pressure and the residue was chromatographed on a silica gel column (silica gel: 20 g; eluent: chloroform: methanol = 20: 1, 10: 1) to give 690 mg of the title compound (23b). This compound was allowed to crystallize and washed with n-hexanes. The title compound (23a) is obtained in the same manner.

Compound (23b) (Colorless Crystals):

Melting point: 1Q3-1O5 ° C [a] _D : -15.2® (c = 1.475, chloroform) ¹ H-NMR (CDCl ₃ ) 6 ppm:

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

Elemental analysis for C ₁₉ H ₂₈ N ₂ O ₂ :

Calc. X%): C 72.12; H, 8.92; N, 8.85; Found: O): C, 71.63; H, 9.07; N, 8.64

Compound (23a) (Colorless Crystals):

Melting point: 94-97 ° C [a] _D : + 47.6 ° (c = 0'.89, chloroform) ¹ H-NMR (CDCl ₃ ) δ ppm:

0.4-0.9 (4H, m), 1.33 (3H, d, J = 6.6Hz), 1.40 (9H, s), 2.29 (1H, d, J = 9Hz), -2.44 (1H, dd, J = 10.8 & 3.6Hz), 2.77 (1H, d, J = 9Hz), 2.88 (1H, dd, J = 10.8 & 5.3Hz), 3.22 (1H, q, J = 6.6Hz), 3.63.9 (1H, m). 4.7-5.2 (1H, broad d), 7.27 (5H, s)

Elemental analysis for C _ig H ₂₈ N ₂ O ₂ :

Calc .: (%): C 72.12; H, 8.92; N, 8.85; H, 9.36; N, 8.68

6) 7-t-Butoxycarbonylamino-5-azaspiro / 2,4 / heptane (24a, 24b)

650 mg of compound (23b) and 500 mg of 50% hydrogenated palladium on charcoal were added to 30 ml of ethanol and catalytic reduction was obtained at 4.2 bar heating and pressure. After 6 hours, the catalyst was filtered off and the solvent removed under reduced pressure. Ethyl acetate was added to the oily residue and extracted twice with 10% aqueous citric acid. The aqueous extract was basified with 15% aqueous sodium hydroxide solution and extracted three times with chloroform. The chlorophyll layer was washed with water and dried. The solvent was removed under reduced pressure to give 440 mg of the title compound (24b) as a crude product. The title compound (24a) is obtained in the same manner as above. The NMR spectra of compounds (24b) and (24a) are in perfect agreement with each other.

Compound (24) ¹ H-NMR (CDCl ₃ ) δ ppm:

0.4-1.0 (4H, m), 1.42 (9H, s), 2.71 (1H, d.

J = 10.2Hz), 2.92 (1H, dd, J = 10.8 & 3.6 Hz), 3.01 (1H, d, J = 10.2Hz), 3.33 (1H, dd, J = 10.8 & 5.4 Hz), 3.5-3.9 ( 1H, m), 5.0-5.4 (1H, sir d)

EXAMPLE 9

7- (7-t-butoxycarbonylamino-5-azaspiro / 2,4 / heptan-5-yl) -8chloro-6-fluoro-1- (1,2-cis-2-fluoro-1-cyclopropyl) -1. 4-Dihydro-4-oxoquinoline-3-carboxylic acid (25 bb)

Dissolve 160 mg of 8-chloro-6,7-difluoro-1- (1,2-cis-2-fluoro-1-cyclopropyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid in 0.6 ml of acetonitrile (12b) , 150 mg of the amine of compound (24b), and 0.5 ml of triethylamine, and the solution heated at reflux for 5 hours. After cooling, the precipitated colorless crystals were collected by filtration. The mother liquor was removed under reduced pressure and the residue was purified by preparative thin layer chromatography on silica gel (TLC) using chloroform-methanol as the developing solvent (5: 1 by volume). The purified product and the crystals obtained above were combined to give 255 mg of the title compound (25bb).

Melting point: 213-218 ° C. ¹ H-NMR (CDCl ₃ ) 6 ppm:

0.6-1.0 (6H, m), 1.45 (9H, s) _r 7.99 (12H,

J = 13.1Hz), 8.74, 8.78 (each 0.5H, s)

EXAMPLE 10 (-) - 7- (7-amino-5-azaspiro / 2,4 / heptan-5-yl) -8-chloro-6-fluoro- (1,2-cis-2-fluoro-1-cyclopropyl ) -1,4-Dihydro-4-oxoquinoline3-carboxylic acid (26bb)

To the 255 mg of Boc compound (25bb) obtained in Example 9, 0.5 ml of anisole and 10 ml of trifluoro-62-acetic acid were added during ice-cooling. After warming to room temperature, the mixture was stirred for a further 30 minutes. The solvent was removed under reduced pressure and the residue was added with 1 N aqueous sodium hydroxide solution to adjust the pH from 11 to 12. The alkaline aqueous solution was washed twice with chloroform. The aqueous layer was adjusted to about 7 with concentrated hydrochloric acid and 10% aqueous citric acid and extracted three times with chloroform. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the remaining solid was recrystallized from ethanol / concentrated aqueous ammonia to give 142 mg of the title compound (26bb) as colorless crystals.

Melting point 127-14O ° C (decomposition) [a] ': -199.2® (c = 0.24, IN NaOH)

Elemental analysis for C ₁₉ H ₁₈ N ₃ O ₃ F ₂ C1'1 / 4H ₂ O: rzrac. : (%) and C 55.08; H, 4.50; N, 10.14 Found:: (%): C 54.86; H 4.80; -N 10.03

EXAMPLE 11

Compound Synthesis (26ab)

Compound (26ab) is obtained from compound (12a) and compound (24b) in the same manner as described in Examples 9 and 10. Melting point: 123-128 ° C (decomposition) [a] _D : + 21.5 ° (c = 0.195, IN NaOH)

Elemental analysis for C ₁₉ H ₁₈ N ₃ O ₃ F ₂ C1-1 / 2H ₂ O:

Calc'd.: (%): C 54.49; H, 4.57; N, 10.03 Ht .: (%): C 54.33; H, 4.73; N, 9.81

EXAMPLE 12

Synthesis of compound (26a)

The compound (26a) was synthesized and the compounds (12b) and the compounds (24a) in the same manner as described in examples 9 and

10.

Melting point: 121-127 ° C (decomposition) [q] _D i -21,1 ° (c = 0.275, IN NaOH)

Elemental analysis for C ₁₉ H ₁₈ N ₃ O ₃ F ₂ C1'1 / 2H ₂ O:

Calc .: (%): C 54.49; H, 4.57; N 10.03 Found :(%): C 54.77; H, 4.43; N, 9.86

EXAMPLE 13

Synthesis of compound 26aa)

The compound (26aa) was synthesized from compound (12a) and compound (24a) in the same manner as in Examples 9 and 10.

Melting point: 126-145 ° C (decomposition) [a] _D : + 186.6 ° (c = 0.228, IN NaOH)

Elemental analysis for C _ig H ₁₈ N ₃ O ₃ F ₂ Cl * 3 / 4H ₂ O:

Calc .: (%): C 53.91; H 4.64; N 9.93 Found :(%)j £ 53.80, γ H 4.47; N, 9.82

REFERENCE EXAMPLE 27 (-) - Ethyl-8-chloro-7-fluoro-1- (1,2-cis-2-fluoro-1-cyclopropyl) 4-oxo-1,4-dihydro-1,8-naphthyridine- 3-carboxylate (29a)

A mixture of 1 g of ethyl 2,6-dichloro-5-fluoro-nicotinoyl acetate (27), 3 ml of ethyl orthoformate and 6 ml of acetanhydride was heated at 120 ° C for 1 hour with stirring. The reaction mixture was evaporated to dryness under reduced pressure and the residue was dissolved in 10 ml of dichloromethane.

ml of trifluoroacetic acid was cooled with ice and dissolved 750 mg of (+) - cis-1- (t-butoxycarbonylamino) 2-fluorocyclopropane (4a). The solution was stirred at room temperature for 20 minutes and then evaporated to dryness under reduced pressure. The residue was suspended in 20 ml of dichloromethane and 2.0 g of triethylamine were added while cooling with ice. The suspension of dichloromethane prepared above was then added to the suspension and stirred at room temperature for 30 minutes.

The reaction mixture was washed with water and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure. The residue was column chromatographed on 50 g of silica gel using chloroform as eluent to give 1.29 g of ethyl 2- (2,6-dichloro-5-fluoronicotinoyl) -3- (1,2-cis-2fluoro-1-cyclopropyl) acrylate (28a) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ ppms'

1.06 (3H, t, J = 7Hz), 1.1-1.6 (2H, m), 2.86-3.18 (1H, m), 4.05 (2H, q, J = 7Hz), 4.78 (1H, dm.

J = 63Hz), 7.36 (1H, d, J = 7Hz), 8.31 (1H, d, J = 14 Hz)

Dissolve 1.29 g of compound (28a) in 25 ml of anhydrous dioxane and add 300 mg of 60% sodium hydride to the solution and stir for 1 hour. The reaction mixture was concentrated under reduced pressure and 0.1 N hydrochloric acid was added to the residue. The precipitated crystals were collected by filtration and washed sequentially with water and diethyl ether to give 860 mg of the title compound (29a) as colorless crystals.

- 65 Melting point: 184-185 ^e C [α] η: -1.26 ° (c = 0.793, chloroform) 'Elemental analysis for - ₁ F ₂ ^W 2 ° 3

Calc .: (%): C 51.16; H, 3.37; N, 8.52. Found :(%): C 51.12; H, 3.26; N, 8.52. ¹ H-NMR (CDCl ₃ ) 6 ppm:

1.41 (3H, t, J = 7Hz), 1.4-1.84 (2H, m), 3.50 (1H, m), 4.40 (2H, q, J = 7Hz), 5.02 (1H, dm, J = 65Hz).

8.43 (1H, d, J = 7 $ z), 8.66 (1H, s)

REFERENCE EXAMPLE 28 (+) - Ethyl 8-chloro-7-fluoro-1- (1,2-cis-2-fluoro-1-cyclopropyl) 4-oxo-1,4-dihydro-1,8-naphthyl, iridine -3-carboxylate (29b)

A mixture of 1.0 g of ethyl 2,6-dichloro-5-fluoronicotinoyl acetate (27), 3 ml of ethyl orthoformate and 6 ml of ethyl acetate is heated at 120 ° C for 1.5 hours under stirring. The reaction mixture was evaporated to dryness under reduced pressure and the residue was dissolved in 10 ml of dichloromethane.

ml of trifluoroacetic acid was cooled with ice and dissolved 750 mg of (-) - cis-1- (t-butoxycarbonylamino) 2-fluorocyclopropane (4b). The solution was stirred at room temperature for 20 minutes and evaporated to dryness under reduced pressure. The residue was suspended in 30 ml of dichloromethane and 2.0 g of triethylamine were added while cooling with ice. The dichloromethane solution prepared above was then added to the suspension and the mixture was stirred at room temperature for 30 minutes.

The reaction mixture was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by column chromatography on 50 g of silica gel using chloroform as eluent to give 1.29 g of ethyl 2- (2,6-dichloro-5-fluoronicotinoyl) -3- (1,2-cis-2-fluoro- 1-cyclopropyl) acrylate (28b) as a colorless oil.

Compound (28b) (1.29 g) was reacted in the same way as compound (28a) to give 936 mg of the title compound (29b) as colorless crystals.

Melting point: 183-185 ^e C [aId: + 1.12 ° (c = 1.07, chloroform) 'Elemental analysis · for ^ ΐ4 ^ ιι ^Ρ 2 ^ 2θ3

Calc .: (%): C 51.16; H, 3.37; N, 8.52. Found: *: (%): C 51.39; H, 3.24; N, 8.49

REFERENCE EXAMPLE 29 (-) - 8-Chloro-7-fluoro-1- (1,2-cis-2-fluoro-1-cyclopropyl) -4oxo-1,4-dihydro-1,8-naphthyridin-3 -carboxylic acid a (30a)

A mixture of 800 mg of compound (29a) and 15 ml of concentrated hydrochloric acid was stirred at 100 ° C for 1.5 hours under stirring. Water was added to the reaction mixture and the precipitated crystals were collected by filtration to give 610 mg of the title compound (30a) as colorless crystals.

Melting point: 215-219 ° C / <A / _d : -20.65 ° (c = 0.910, chloroform)

REFERENCE EXAMPLE 30 (+) - 8-chloro-7-fluoro-1- (1,2-cis-2-fluoro-1-cyclopropyl) -4oxo-1,4-dihydro-1,8-naphthyridin-3- carboxylic acid (30b)

A mixture of 870 mg of compound (29b) and 20 ml of concentrated hydrochloric acid was heated at 100 ° C for 2 hours while stirring. Water was added to the reaction mixture and the precipitated crystals were collected by filtration to give 715 mg of the title compound (30b) as colorless crystals.

Melting point 218-22O ° C / <^ £ / _d : + 22,34 ° (c = 0.555, chloroform)

EXAMPLE 14

7- [4- (S) -amino-2- (S) -methyl-1-pyrrolidinyl] -6-fluoro-1- (1,2cis-2-fluoro-1-cyclopropyl) -4-oxo-1, 4-Dihydro-1,8-naphthyridine

3- Carboxylic acid (31a)

Dissolve 3θθ mg in 15 ml of trifluoroacetic acid

4- (S) -araino-1-t-butoxycarbonyl-2- (S) -methylpyrrolidine (32) (cf. Terry Ronson, et al., J. Med. Chem., Vol. 31, p. 1598 (1988) , and the solution was stirred at room temperature for 20 minutes and then evaporated to dryness under reduced pressure. Hydrochloric acid was added to the pressure and the mixture was washed with chloroform, sodium hydroxide was adjusted to pH 13 and washed with chloroform, then the pH was adjusted to 7.5 and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed. The residue was recrystallized from aqueous ammonia / ethanol to give 150 mg of the title compound (31a) as colorless crystals.

255-258 ° C / << 7 _d : -14.52 ° (c = O, 4l3, 0.1 N NaOH)

Elemental analysis for C ₁₇ H ₁₈ F ₂ N ₄ O ₃ * 1 / 4H ₂ O:

Calc'd (%) ^: C 55.36; H, 5.06; N, 15.19

Found :(%): C 55.09; H 5.40; N.15.04

EXAMPLE 15 (-) - 7- / 3- (R) - [1- (S) -aminoethyl] -1-pyrrolidinyl] -8-chloro-6-fluoro-1- (1,2-cis-2-fluorocyclopropyl) - 4-Oxo-1,4-dihydroquinoline-3-carboxylic acid (34b)

A mixture of 159 mg of (-) - 8-chloro-6,7-difluoro-1- (1,2-cis-2fluoro-1-cyclopropyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (12b) , 160 mg 3- (R) - (1- (S) -t-butoxycarbonylaminoethyl). of pyrrolidine (cf. JP-A-61-31 1992), 400 mg of triethylamine and 20 ml of acetonitrile were heated at reflux for 12 hours. The reaction mixture was concentrated under reduced pressure and the residue dissolved in chloroform. The organic solution was washed successively with 10% aqueous citric acid and water and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was recrystallized from ethyl acetate / isopropyl ether to give 220 mg of (-) - 7- / 3- (R) - / 1- (S) -t-butoxycarbonylaminoethyl (1-pyrrolidinyl) -8-chloro-6-fluoro -1- (1,2-cis-2-fluoro-1-cyclopropyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (33b).

Mp 189-193 ° C / pC / _D : -205 ° (c = O, 985, chloroform)

Elemental analysis for ^C 24 ^H 28 ^C 1 F ₂ ^N 3 ° 5

Calc .: (%) s C 56.31; H, 5.51; N 8.21 Found: (%): C 56.16; H, 5.48; N-8.21

- 69 Dissolve 200 mg of compound (33 b) in 10 ml of trifluoroacetic acid and stir for 30 minutes. The reaction mixture was evaporated to dryness under reduced pressure and the residue was dissolved in 1 N aqueous sodium hydroxide solution and washed with chloroform. Hydrochloric acid was adjusted to pH 7.4 and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was recrystallized from aqueous ammonia / ethanol to give 140 mg of the title compound (34b) as colorless crystals.

Melting point:. 204-207 ° C (oJd: 160.0 ° (c = 0.605, 0.1N NaOH)

Elemental analysis for ^C i9 ^H 2o ^CLF 2 ^N 3 O 3 * ^H 2 ^0J Calcd .: (%): C, 53.09; H, 5.38; N 9.?7 Found :(%): C 53.20; H, 5.17; N, 9.66

REFERENCE EXAMPLE 31

Ethyl 2- (3-acetoxy-2,4,5-trifluorobenzoyl) -3- (1,2-cis-2fluoro-N-cyclopropyl) acrylate (36b)

A mixture of 1.0 g of ethyl 3-acetoxy-2,4,5-trifluorobenzoyl acetate (35) (cf. JP-A-87-175485), 6 ml of ethyl orthoformate and 6 ml of acetanhydride was heated at 120 ° C for 3 hours under stirring. The reaction mixture was evaporated to dryness under reduced pressure and the residue was dissolved in 10 ml of dichloromethane. .

Dissolve 467 mg of (-) - cis-1-t-butoxycarbonylamino-2-fluorocyclopropane (4b) in 5 ml of trifluoroacetic acid and stir the solution for 20 minutes then evaporate to dryness under reduced pressure. The residue was suspended in 20 ml of dichloromethane and added dropwise while cooling with ice 5 ml of dichloromethane containing 500 mg of triethylamine were added and the solution was stirred for a further 10 minutes. The dichloromethane solution prepared above was added to this solution and the mixture was stirred at room temperature for 16 hours. The reaction mixture was washed successively with 10% aqueous citric acid and water. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 1.25 g of the title compound (36b).

REFERENCE EXAMPLE 32 (-) - Ethyl 6,7, -difluoro-1- (1,2-cis-2-fluoro-1-cyclopropyl) -8methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (37b )

Dissolve 1.25 g of compound (36b) and 440 mg of potassium carbonate in 40 ml of dioxane, then add 10 ml of water and stir at room temperature for 19 hours. The reaction mixture was neutralized with hydrochloric acid, concentrated under reduced pressure and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. Dissolve the residue in 40 ml of anhydrous dioxane, add 300 mg of 60% sodium hydride and 1 ml of ethyl iodide and stir at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure and the residue was extracted with chloroform, washed with water and dried over anhydrous sodium sulfate. Evaporate the solvent. The residue was recrystallized and isopropyl ether to give 235 mg of the title compound (37b) as colorless crystals.

Melting point: 163-64®C [α] ο: -22.9® (c = 0.490, chloroform) ¹ H-NMR (CDC1 ₃ ) δ ppm:

1.40 (3H, t, J = 7Hz), 1.3-1.8 (2H, m), 3.7-4.0 (1H, m), 4.10 (3H, d, J = 2Hz), '4.38 (2H, g.

J = 7Hz), 4.85 (1H, dm, J = 63Hz), 8.02 (1H, dd,

J = 9Hz, & 8.5Hz), 8.55 (1H, s)

Elemental analysis for ^c i6 ^H i4 ^P 3 ^NO 4

Calc .: (%): C 56.31; H, 4.13; N 4.10 Found :(%)? C 56.62; H, 4.18; N, 4.11

REFERENCE EXAMPLE 33-1 (+) - cis-4-aryano-1-benzyl-3-methyl-2-oxopyrrolidine (45)

A mixture of 5.13 g of ethyl 1-benzyl-3-methyl-2-oxo-3-pyrrolidinecarboxylate (42, cf. JP-A-62-4284), 40 ml of 50% ethanol and 2 g of sodium hydroxide was stirred at room temperature. 42 hours. To this reaction mixture was added 100 ml of water and the mixture was washed with chloroform. The aqueous layer was neutralized with hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated to give 3.40 g of (+) - 1-benzyl-2-oxo-3-pyrrolidine carboxylic acid (43) as colorless crystals.

Compound (43) (3.40 g), 4.45 g diphenylphosphorylazide 1.9 g triethylamine and 50 ml t-butyl alcohol were stirred and the mixture was heated at reflux for 12 hours. The reaction mixture was concentrated under reduced pressure and the residue dissolved in chloroform. The solution is washed successively with 10% aqueous solution

Cit · Citric acid, 2% aqueous sodium hydroxide solution and water, and dried over anhydrous sodium sulfate ?. The solvent was evaporated and the residue was purified by silica gel column chromatography using chloroform-methanol (97.5: 2.5 by volume) as eluant to give 1.76 g (+ -cis-1benzyl-4- t -butoxycarbonylamino-3- methyl-4-oxopyrrolidine (44) as a colorless oil.

1.76 g of compound (44) are dissolved in 15 ml of trifluoroacetic acid. After 1 hour the solution was concentrated under reduced pressure. To the residue was added 100 ml of water and the mixture was washed with benzene. The pH of the aqueous layer was adjusted to 12 with sodium hydroxide and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated to give the title compound (45) as a colorless oil.

1 H-NMR (CDCl ₃ ) δ ppm:

1.25 (3H, d, J = 7Hz), 1.44 (2H, s), 2.16 (1H, dt,

J = 7Hz), 2.83 (1H, dd, J = 6.7Hz, & 8Hz), 3.14 (1H, • m), 3.38 (1H, dd, J = 6.7Hz, & 8Hz), 4.48 (2H, s).

7.28 (5H, s)

REFERENCE EXAMPLE 33-2>

Optical separation of cis-4-amino-1-benzyl-3-methyl-2-oxopyrrolidine (45)

Dissolve 4.17 g of compound (45) and 3.3 ml of pyridine in 40 ml of dichloromethane and add a solution of 7.7 g (S) -N-p-toluenesulfonylpropyl chloride in 50 ml of dichloromethane dropwise and stir for 4 hours.

- 73 The reaction mixture was washed successively with 1 N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was chromatographed on a silica gel column using ethyl acetate as the eluent to isolate the isomers. Each of the isomers was recrystallized from ethyl acetate to give 3.3 g and 3.6 g of cis-1-benzyl-3-methyl-4 - / (S) -N-p-toluenesulfonylprolylamino / -2-oxopyrrolidine (46a) or. (46b).

Compound (46a);

Rf (silica gel tlC; ethyl acetate: 0.69 Melting point; 162 ° C [a] _D ; -87.3® (c = 0.735, chloroform)

Compound (46b);

Rf (silica gel TLC; ethyl acetate): 0.61 Melting point: 175-177 ° C

-148.6 ° (c = O, 665, chloroform)

REFERENCE EXAMPLE 33-3 (+) - cis-1-benzyl-3-t-butoxycarbonylamino-4-methyl-pyrrolidine (47a)

A mixture of 3.23 g of compound (46a) and 50 ml of concentrated hydrochloric acid was refluxed for 5 hours, then concentrated under reduced pressure. To the residue was added 1 N aqueous sodium hydroxide solution and the solution was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated to give 1.48 g of compound (45a) as a colorless oil.

- 74 The product is dissolved in 10 ml of tetrahydrofuran and a solution of dropwise 2.0 g of lithium aluminum hydride in 50 ml of tetrahydrofuran is added dropwise. The mixture was heated at reflux for 24 hours. Then 10 ml of water are added dropwise to the mixture during ice-cooling and after stirring for 30 minutes any insoluble matter is removed by filtration. 1.92 g of Boc-ON was added to the filtrate and stirred for a further 24 hours. The reaction mixture was concentrated under reduced pressure and the residue was extracted with chloroform. The extract was washed successively with 5% aqueous sodium hydroxide solution and water and dried over anhydrous sodium sulfate. The solvent was then evaporated.

The residue was purified by silica gel column chromatography using chloroform-methanol (1: 0 to 9: 1 by volume) as eluant to give 1.7 g of crystals. N-Hexane was added to the product and the mixture was stirred to yield dl compound. The crystals were collected by filtration and the filtrate was concentrated. We repeat this process twice. This gives 100 mg dl of the compound from the filter cake and 1.61 g of the title optically active compound (47a) from the mother liquor.

Melting point; 48-52 ° C [a] o: + 27.2 ° (c = 2.33, chloroform) ^X H-NMR (CDCl ₃ ) δ ppm:

1.07 (3H, d, J = 7Hz), 1.43 (9H, s), 1.78-2.02 (2H, m), 2.62 (2H, d, J = 5Hz), 2.84-3.10 (1H, m), 3.55 (2H , s), 3.5-3.8 (1H, m), 4.8-5.2 (1H, broad), 7.23 (5H, s)

REFERENCE EXAMPLE 33-4 (-) - Cis-1-benzyl-3-t-butoxycarbonylamino-4-methyl-pyrrolidine (47b)

In the same way as for the synthesis of compound (47a), but starting from 3.52 g of compound (46b), 1.72 g of the title compound (47b) is obtained.

Melting point: 57-6l ° C / dl / _D : -31.21 °.

REFERENCE EXAMPLE 33-5 cl3-3-t-butoxycarbonylamino-4-methylpyrrolidine (39a), (39b)

Compound (47a) (1.61 g), 1.5 g of 5% palladium on charcoal and 80 ml of ethanol were stirred and catalytically reduced for 5 hours while irradiating the mixture with an infrared light in a hydrogen atmosphere at a pressure of 4 bar. After the reaction was complete, the catalyst was removed by filtration and the filtrate was concentrated to give 1.09 g of crude product as a colorless oil. The product, which solidified as carbonate, was used without further purification.

In the same way as for the synthesis of compound (39a), 1.1 g of compound (39b) is obtained from 1.70g of compound (47b) as a colorless oil.

REFERENCE EXAMPLE 34

Ethyl 2- (2,4,5-trifluoro-3-methylbenzoyl) -3- (1,2-cis-2-fluoro-cyclopropyl) acrylate (50b)

Mixture of 710 mg ethyl 2,4,5-trifluoro-3-methylbenzoyl acetate (prepared from 2,4,5-trifluoro-3- methylbenzoic acid (48), cf. p-A-62-215572), 6 ml ethyl of the orthoformate and 6 ml of acetanhydride were heated at 120 ° C for 2 hours while stirring. The reaction mixture was evaporated to dryness under reduced pressure and the residue was dissolved in 10 ml of dichloromethane.

Dissolve 580 mg of (-) - cis-1-t-butoxycarbonylamino-2-fluorocyclopropane (4b) in 5 ml of trifluoroacetic acid, stir the solution for 30 minutes and then evaporate to dryness under reduced pressure. The residue was suspended in 20 ml of dichloromethane and 700 mg of triethylamine was added while cooling with ice. The solution was stirred for 10 minutes, then the above dichloromethane solution was added and allowed to stand overnight. The reaction mixture was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was crystallized from n-hexane to give 787 mg of the title compound (50b) as pale yellow crystals.

REFERENCE EXAMPLE 35 (-) - Ethyl 6,7-difluoro-1- (1,2-cis-2-fluoro-1-cyclopropyl) -8methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate ( 51b)

Dissolve 600 mg of compound (50b) in 20 ml of anhydrous dioxane and add a suspension of 100 mg of 60% sodium hydride washed with n-hexane in a small amount of anhydrous dioxane. The solution was stirred at room temperature for 1 hour, then 10 ml of a 10% aqueous citric acid solution was added and concentrated under reduced pressure. The precipitated crystals were collected by filtration, washed successively with water, a small amount of ethanol and diethyl ether to give 480 mg of the title compound (51b) as colorless crystals.

Melting point: 230-231 ° C (α] ηϊ -80.0 ° (c = 0.350, chloroform) ¹ H-NMR (CDCl ₃ ) 6 ppm:

1.40 (3H, t, J = 7Hz), 1.1-1.7 (2H, m), 2.71 (3H, d, J = 3.3Hz), 3.77-3.98 (1H, m), 4.38 (2H, q.

J = 7Hz), 4.85 (2H, dm, J = 64Hz), 8.12 (1H, dd,

J = 10Hz), 8.54 (1H, d, J = 3Hz)

REFERENCE EXAMPLE 36 (-) - 6,7-Difluoro-1- (1,2-cis-2-fluoro-1-cyclopropyl) -8-methyl4-oxo-1,4-dihydroquinoline-3-carboxylic acid (52b )

A mixture of 480 mg of ester of compound (51 b) and 10 ml of concentrated hydrochloric acid was heated under stirring at 120 ° C for 75 minutes. The mixture was cooled and the precipitated crystals were collected by filtration and washed with water and ethanol to give 380 mg of the title compound (52b) as colorless crystals.

Melting point: 204 ° C [<x] ds 60.0 ° (c = 0.100, chloroform) ¹ H-NMR (CDCl ₃ ) δ ppm:

1.3-1.9 (2H, m), 2.80 (3H, d, J = 5.8Hz), 4.1-4.4 (1H, m,, 4.15 (1H, dm, J = 64Hz), 8.17 (1H, dd, J = 16Hz) ), 8.82 (1H, d, J = 4Hz), 14.2 (1H, s)

EXAMPLE 16

(-) - 6- / 3- (R) - (1- (S) -aminoethyl) -1-pyrrolidinyl] -6-fluoro-1- (1,2-cis-2-fluoro-1-cyclopropyl) -8 hydrochloride -methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (54b)

Mixture of 198 mg of compound (52b), 350 mg of 3- (R) - / 1- (S) -butoxycarbonylaminoethyl / pyrrolidine, 5 ml of dimethyl sulfoxide

- 78 and 1.5 g of triethylamine are stirred at 110-120 ° C for 5 hours while stirring. The reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in chloroform and the solution was washed with 10% aqueous citric acid solution and water, and dried over anhydrous sodium sulfate. Evaporate the solvent. The residue is chromatographed on a thin-layer chromatography (TLC) preparative plate, which is developed with a chloroform / methanol (95: 5 vol.) Mixed solvent, yielding 110 mg 7- / 3- (R) - / 1- (S) -t- butoxycarbonylaminoethyl / pyrrolidinyl) -6,7difluoro-8-methyl-4-dihydroquinoline-3-carboxylic acid (53b) Rot a pale yellow powder.

(CDC1 ₃ ) δ ppm:

1.24 (3H, d, J = 7Hz), 1.45 (9H, s), 1.2-1.9 ( ^2H 'm), 2.52 (3H, s), 1.9-2.7 (3H, m).> 3.2-4.2 (6 ^fl 'm), 4.73 (1H, d, J = 8Hz), 4.98 (1H, dm, J = 65H ^) r 7.77 (1H, d, J = 13Hz), 8.70 (1H, d, J = 3.5H%) )

To 110 mg of compound (53b) was added 5 m of concentrated HCl and stirred at room temperature for 10 minutes, then evaporated to dryness under reduced pressure. The residue was recrystallized from ethanol-diethyl ether to give 62 mg of the title compound (54b) as yellow crystals.

Melting point: 149-153 ° C / Λχ / θ: -34.4 ° (¢ = 0.168, 1N HCl)

EXAMPLE 17

5-amino-7- (7-amino-5-azaspiro / 2,4 / heptan-5-yl) -6,8-difluoro-1- (1,2-cis-2-fluoro-1-cyclopropyl) -4- oxo-1,4-dihydroquinoline3-carboxylic acid (56b)

A mixture of 100 mg (-) - 5-amino-6,7,8-trifluoro-1- (1,2-cis2-fluoro-1-cyclopropyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid ( 17b), 100 mg of 7-t-butoxycarbonylamino-5-azaspiro / 2,4 / heptane (24b), 300 mg of triethylamine and 20 ml of acetonitrile were heated at reflux for 23 hours.

The reaction mixture was evaporated to dryness under reduced pressure and the residue was dissolved in 100 ml of chloroform. The solution is washed successively with 10% aqueous citric acid and water. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was recrystallized from acetonitrile to give 120 mg of 5-amino-77-t-butoxycarbonylamino-5-azaspiro / 2,4 (heptan-5-yl) -6,8-difluoro-1- (1,2-cis-2- fluoro-1-cyclopropyl) -4-oxo-1,4-dihydro quinoline-3-carboxylic acid (55bb) as yellow needle-like crystals.

Melting point: 25O-253 ° C. ¹ H-NMR (CDCl ₃ ) δ ppm:

0.6-0.8 (2H, m), 0.8-1.0 (2H, m), 1.45 (9H, S),

1.3-1.8 (2H, m), 3.2-3.4 (1H, m), 3.6-3.9 (3H, m), 3.9-4.3 (2H, m), 4.85 (1H, dm, J = 63Hz), 4.75.0 (1H, broad) 8.51 (1H, s)

Dissolve 120 mg of compound (55bb) in 5 ml of trifluoroacetic acid and stir the solution for 30 minutes, then evaporate

- 80 to dry under reduced pressure. The residue was dissolved in hydrochloric acid and the solution was washed with chloroform. The pH of the aqueous layer was then adjusted to 7.4 and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was recrystallized from aqueous ammonia / ethanol to give 65 mg of the title compound (56bb) as yellow crystals.

Melting point: 213-217 ° C / i / W _D : -96.7 ° (c = 0.120, DMF).

EXAMPLE 18

7- [4- (S) -amino-2- (S) -methyl-1-pyrrolidinyl] -6-fluoro-1- (1,2cis-2-fluoro-1-cyclopropyl) -4-oxo-1, 4-Dihydro-1,8-naphthyridine

3- Carboxylic acid (31b)

Dissolve 300 mg in 15 ml of trifluoroacetic acid

4- (S) -amino-1-t-butoxycarbonyl-2- (S) -methylpyrrolidine (32) was dissolved at room temperature for 20 minutes and then evaporated to dryness under reduced pressure. The residue was dissolved in 20 ml of anhydrous acetonitrile and 150 mg of compound (30b) and 2 ml of triethylamine were added to the solution and then refluxed for 15 minutes. The reaction mixture was evaporated to dryness under reduced pressure and 1 N hydrochloric acid was added to the residue; the mixture was washed with chloroform. The aqueous layer was basified with 1 N aqueous sodium hydroxide solution and washed with chloroform. The pH of the aqueous layer was then adjusted to 7 and extracted with chloroform. The organic layer was dried and the solvent was evaporated. The residue was recrystallized from aqueous ammonia / ethanol to give 130 ng of the title compound (31b).

Melting point: 247-255 ° C (decomposition) [a] _D : + 120 ° (c = 0.950, IN NaOH)

Elemental 'analysis for c ₁₇ · 1 / 4Η ₂ Ο

Calc .: (%): C 55.36? H 5.06? N 15.19 Found _:( %) _: C 55> $ 0; H, 5.25; N, 14.97

EXAMPLE 19

5-Amino-6,8-difluoro-1- (1,2-cis-2-fluoro-1-cyclopropyl) -7-piperazinyl-4-oxo-quinoline-3-carboxylic acid (57b)

A mixture of 75 mg of compound (17b) and 45 mg of anhydrous piperazine in 5 ml of acetonitrile was heated at reflux for 2 hours.

The reaction mixture was evaporated under reduced pressure and the residue was recrystallized from ethanol to give 72 mg of the title compound (57b) as yellow crystals.

Melting point: 23O-239 ° C / cA- / _D : + 8.00 ° (c = 0.225, 1 N NaOH)

REFERENCE EXAMPLE 37

6,7-Difluoro-1- (1,2-cis-2-fluoro-1-cyclopropyl) -8-methoxy-4oxo-1,4-dihydroquinoline-3-carboxylic acid "BF2" chelate (38b)

A mixture of 230 mg of ester compound (37b) and 5 ml of 42% fluoroboronic acid was heated at 110 ° C for 2 hours while stirring. Cooled, the precipitated crystals were collected by filtration and washed with water to give 210 mg of colorless crystals of the title compound.

Melting point: 261-271 ° C.

Reaction of cis-3-t-butoxycarbonylamino-4-methylpyrrolidine (39a) and chelate of compound (38b) yields 7- (cis-3amino-4-methylpyrrolidinyl) -6-fluoro-8-methoxy-4-oxo-1. 4-Dihydro quinoline-3-carboxylic acid (40ba). Further, by reaction of amine compound (24) and chelate compound (38b), 7. (7-amino5-azaspiro / 2,4 / heptan-5-yl) -6-fluoro-8-methoxy-4-oxo-1 is obtained. 4dihydroquinoline-3-carboxylic acid (4lbb).

The process diagram is shown in the attached figure.

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

3.

Table. Antimicrobial activity

Γ3 CO., LTD CO., LTD CM <0.1 ro> 0.10 0.39 o ** - 4 o ro> 0.20 0.39 Oh X * ^ “4 «-« v — 4 T ^ 4 • —4 CM -Q • CO., LTD Oh o Oh ca. o Oh ca. Oh CM v v v v v V v ca. ^ 4 »~ 4 «* —4 ^ 4 ^ “4 • 4 Λ • CO., LTD Oh Oh Oh Oh Oh C9 ca. ca. r— « v v v v v v v ca. w ™ 4 »^ 4 4 ^ 4 + Ή ^ 4 ^ 4 CM CO., LTD 09 Oh o Oh Oh Oh «Oh Oh C9 T-4 v v v v V V v o + * “4 4 ^ “4 τΗ * -4 * “4 «-4 CM ^ 9 CO., LTD C9 C9 Oh o θ Oh ca. o ^ 4 v V V v V v v o "" 4 w - 4 ^ 4 v — l ^ 4 ^ 4 ^ 4 CM co co C9 Oh Oh Oh Oh Oh ca. Oh v v V v v v v ca. C9 03 03 ^ 4 »H + -4 »• 4 ^ 4 ^ 4 CO., LTD e— yes 03 Oh Oh Oh Oh Oh Oh ca. ca. v v v v o o 03 o o 03 t— , —4 »—4 cm CO., LTD ^ 4 ^ 4 co tn co 03 Oh Oh o Oh Oh o o »4 V co co '' * »· ca. 03 3 o · —4 o • “4 W o CM o Ή ^ 4 o r · —4 rH tn Oh 'i? Oh r — 4 CM CM cn o o co CO., LTD CO., LTD tn t- a co * cu «C Ui o tO • • • • -o C co co 03 ui • 03 Ul Ul o • * 4 Ul * - « ω Oh o o CM Ό •• 4 SC · —'4 Ul c c •• 4 • —4 CQ in 03 * «4 • «4 • ε CO., LTD • r ^ ¹ • co Oh will that ui U o «H • "Oh U SJ o = 3 03 03 P •• 4 -H co L- in 03 Ό CO., LTD m · —T 3 e 03 03 U •• 4 M-4 4-5 o > co <0 3 O. o • «0 03 • ra • in • • U 37 ♦ U 03 that ui « • 4-J LU cu tn cu C- cn that tn

Daiichi Seiyaku Co., Ltd. . ./'.OptAČTlp Active derivatives ...

REACTION SCHEME

Ph

F COOH XcH3

8a, 8b

9a,

- 1Daiichi Seiyaku Co., Ltd. "Optical .active derivatives ..."

Cl

10a, 10b

Ha. Ilb

12a, 12b

13a, 13b

NO2 o

17a, 17b 18a.18b

Daiichi Seiyaku Co., Ltd. ... Optical.active derivatives ...

20

22a, 22b

NHBoc

23a, 23b

N

H

24a, 24b

Daiichi Seiyaku Co., Ltd. Optically active derivatives ...

Ct

AAi sN F

28a, 26b

30a, 30b

H2N '

31a, 31b

33b

34b

Daiichi Seiyaku Co., Ltd. .Optically active derivatives ...

Me COOB ^ Ph

Me COOH

Me -NHBoc

Me NH 2 ° -Q ^ Ph

Ts

46a, 46b

Me NH2

45a, 45b

Me NHBoc

Me NHBoc

H

47a, 47b

39a, 39b

Daiichi Seiyaku Co., Ltd.- '<' - (TptieflQak 'Derivatives ...

Claims (7)

PATENT APPLICATIONS A process for the preparation of N, N - (1,2-cis-2-halogenocyclopropyl) subst. pyridonecarboxylic acid derivatives represented by the following formula R ¹ 0 wherein R represents a substituted or unsubstituted amino group, a hydroxyl group, a thiol group, or a hydrogen atom; R represents a substituted or unsubstituted cyclic amino group which may contain at least one hetero atom selected from a nitrogen, oxygen or sulfur atom in its 3 - 1 2 ring; A represents CX or a nitrogen atom; X and X ', which may be the same or different at each time, represent a halogen atom Oh X ^J represents a halogen atom, an alkyl group of 1 to 6 carbon atoms, an alkoxyl group of 1 to 6 carbon atoms, a cyano group, a trifluoromethyl group or a hydrogen atom; with the proviso that the case where R is a hydrogen atom and 2 is excluded R is a piperazine or 4-alkyl-substituted piperazine residue, or a salt thereof. characterized in that 7-halogeno-1- (1,2-cis-2fluorocyclopropyopyridone carboxylic acid is reacted with the following formula R ¹ 0 x 'γΛγΛ ^ εοοΗ x v2 V 112 wherein R, X, X and A have the meanings defined above and X represents a halogen atom, 2 _{to a} cyclic amine compound of formula R -H which may be protected2 to a conventional protecting group, wherein R is as defined above. A process according to claim 1, characterized in that R is a 4- to 7-membered cyclic amino group which may be substituted by one or more hydroxyl groups, alkyl groups with 1 to 6 carbon atoms or substituted or unsubstituted amino groups. Process according to claim 1 or 2, characterized in that v 2 into the framework of the cyclic amino group R is a elan selected from the group consisting of pyrrolidine, piperidine, diazabicycloheptane and diazabicyclooctane, The process of claim 1 or 2, wherein R is a cyclic amino group comprising a single stereoisomer. The process of claim 4, wherein R is a 3-amino pyrrolidinyl group. A process according to claim 4, wherein R is a 7-amino-5-azaspiro / 2.4 / heptan-5-yl group. „2 A process according to claim 1, wherein X is a fluorine atom.