A quinolone derivative represented by formula (I): ##STR1## wherein R.sup.1 represents a cycloalkyl group; R.sup.2 represents a hydrogen atom, an amino group, a hydroxyl group, a thiol group, a halogenomethyl group, an alkyl group, an alkenyl group, an alkynyl group, or an alkoxyl group; R.sup.3 represents an amino group, a halogenomethyl group, a halogenomethoxyl group, an alkyl group, an alkenyl group, an alkynyl group, or an alkoxyl group; R.sup.4 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; R.sup.5 represents a cycloalkyl group having 3 to 6 carbon atoms; the above R.sup.1 to R.sup.5 may be substituted; X represents a halogen atom or a hydrogen atom; and Y represents a hydrogen atom, a phenyl group, an acetoxymethyl group, a pivaloyloxymethyl group, an ethoxycarbonyl group, a choline group, a dimethylaminoethyl group, a 5-indanyl group, a phthalidinyl group, a 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl group, a 3-acetoxy-2-oxobutyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms, or a phenylalkyl group having 1 to 6 carbon atoms in the alkyl moiety thereof, or a salt thereof. The compound exhibits high and broad antimicrobial activity against various bacteria including bacteria resistant to drugs and high safety.

TECHNICAL FIELD
 This invention relates to an antimicrobial compound useful as a drug for
 humans, animals or fishes or an antimicrobial preservative, an
 antimicrobial agent or preparation containing the same, and a method for
 treating and/or preventing various infectious diseases using the same.
 BACKGROUND ART
 Quinolone derivatives having a 3-(cyclopropyl-aminomethyl)pyrrolidinyl
 group are disclosed in JP-A-59-67269 (the term "JP-A" as used herein means
 an "unexamined published Japanese patent application"), but a quinolone
 derivative according to the present invention which has a substituent
 derived from the cycloalkylaminomethylpyrrolidine compound at the
 7-position and a substituent other than a halogen atom at the 8-position
 and may also have a substituent at the 5-position is unknown.
 Recently, many synthetic quinolone antimicrobial agents excellent in not
 only antimicrobial activity but also in oral absorbability, distribution
 property to organ, and excretion rate have been developed and provided for
 clinical use as a chemotherapeutic agent effective on various infectious
 diseases.
 However, low sensitive bacteria resistant to these drugs have recently been
 increasing in the medicinal field. Further, bacteria resistant to drugs
 other than quinolone antimicrobial agents have also been acquiring
 resistance to quinolone antimicrobial agents, as .beta.-lactam resistant
 Staphylococcus aureaus (MRSA). Therefore more effective drugs have been
 keenly demanded in the field of medicine.
 The antimicrobial activity, efficacy and safety of quinolone antimicrobial
 agents are largely influenced by the substituents at the 7- and
 1-positions. And at the same time, the substituents at the 5- and
 8-positions also have considerable role to those features. The inventors
 of the present invention have considered that proper assortment of proper
 substituents to these positions could provide compounds excellent in
 antimicrobial activity, efficacy and safety. They have extensively studied
 seeking a compound exhibiting high antimicrobial activity on a broad range
 of bacteria including quinolone-resistant bacteria. As a result, it has
 been found that a quinolone compound having a substituent derived from a
 cycloalkylaminomethylpyrrolidine compound at the 7-position and having a
 substituent other than a halogen atom at the 8-position exhibits potent
 antimicrobial activity toward Gram negative bacteria and Gram positive
 bacteria, especially Gram positive bacteria including MRSA. It has also
 been found that the compound additionally having a substituent at the
 5-position shows similarly excellent antimicrobial activity.
 It has further been found that the compound having a halogenocyclopropyl
 group, particularly a fluorocyclopropyl group, at the 1-position is
 excellent in efficacy and safety as well as antimicrobial activity. The
 present invention has been completed based on these findings.
 Of the quinolone derivatives of the present invention having a substituted
 cyclic alkyl group, e.g., a halogenocyclopropyl group, at the 1-position,
 a pair of enantiomers attributed only to the halogenocyclopropane ring are
 present even when there is no stereoisomerism in the substituent at the
 other position. This is ascribed to the steric relationship between the
 pyridonecarboxylic acid moiety and the halogen atom on the cyclopropane
 ring. It is possible to apply a racemic mixture of the enantiomers as a
 drug as such.
 Where stereoisomerism exists at other position in addition to the
 halogenocyclopropane moiety, particularly at the 7-positioned substituent,
 such a quinolone derivative embraces diastereomers, that is, at least 4
 kinds of stereoisomers are possible. A mixture of diastereomers is a
 mixture of isomers having different physical properties and is hardly
 applicable as a drug as such.
 The present inventors have made an effort to obtain a quinolone compound as
 a pure stereoisomer even if there are diastereomers, particularly a pure
 stereoisomer of 1-(1,2-cis-2-fluorocyclopropyl)-substituted quinolone
 derivative.
 As a result, the present inventors have succeeded in separately obtaining
 each enantiomer of cis-2-fluorocyclopropylamine as a pure isomer. Starting
 with this cis-fluorocyclopropylamine, they separately obtained each
 enantiomer of a quinolone derivative attributed only to the steric
 configuration of the fluorocyclopropane ring thereof. They also succeeded
 in obtaining each enantiomer of a cycloalkylaminomethylpyrrolidine
 compound having an asymmetric carbon atom as a pure isomer.
 Now that the above-mentioned quinolone derivative and
 cycloalkylaminomehylpyrrolidine compound useful as an intermediate have
 been obtained, it is possible to synthesize an optically active quinolone
 derivative substantially comprising a pure diastereomer.
 DISCLOSURE OF INVENTION
 The present invention relates to a compound represented by formula (I):
 ##STR2##
 wherein R.sup.1 represents a substituted or unsubstituted cyclic alkyl
 group having 3 to 6 carbon atoms;
 R.sup.2 represents a hydrogen atom, an amino group, a hydroxyl group, a
 thiol group, a halogenomethyl group, an alkyl group having 1 to 6 carbon
 atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group
 having 2 to 6 carbon atoms, or an alkoxyl group having 1 to 6 carbon
 atoms, and said amino group may have at least one substituent selected
 from a group of a formyl group, an alkyl group having 1 to 6 carbon atoms
 and an acyl group having 2 to 5 carbon atoms;
 R.sup.3 represents an amino group, a halogenomethyl group, a
 halogenomethoxyl group, an alkyl group having 1 to 6 carbon atoms, an
 alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6
 carbon atoms, or an alkoxyl group having 1 to 6 carbon atoms, and said
 amino group may have at least one substituent selected from a group of a
 formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group
 having 2 to 6 carbon atoms;
 R.sup.4 represents a hydrogen atom or an alkyl group having 1 to 6 carbon
 atoms, and said alkyl group may have at least one substituent selected
 from a group of a hydroxyl group, a halogen atom, an alkylthio group
 having 1 to 6 carbon atoms and an alkyloxyl group having 1 to 6 carbon
 atoms;
 R.sup.5 represents a cyclic alkyl group having 3 to 6 carbon atoms;
 X represents a halogen atom or a hydrogen atom; and
 Y represents a hydrogen atom, a phenyl group, an acetoxymethyl group, a
 pivaloyloxymethyl group, an ethoxycarbonyl group, a choline group, a
 dimethylaminoethyl group, a 5-indanyl group, a phthalidinyl group, a
 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl group, a 3-acetoxy-2-oxobutyl group,
 an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having 2
 to 7 carbon atoms, or a phenylalkyl group having 1 to 6 carbon atoms in
 the alkyl moiety thereof, and a salt thereof.
 Further, the present invention relates to the followings:
 the compound of formula (I), wherein R.sup.1 is a 2-halogenocyclopropyl
 group, and a salt thereof;
 the compound of formula (I), wherein R.sup.1 is a
 1,2-cis-2-halogenocyclopropyl group, and a salt thereof;
 the compound of formula (I), wherein R.sup.1 is a substantially
 stereochemically pure substituent, and a salt thereof;
 the compound of formula (I), wherein R.sup.1 is a
 (1R,2S)-2-halogenocyclopropyl group, and a salt thereof;
 the compound of formula (I), wherein R.sup.1 is a fluorocyclopropyl group,
 and a salt thereof;
 the compound of formula (I), wherein the compound is a substantially
 stereochemically pure compound, and a salt thereof;
 an antimicrobial agent and/or preparation containing the compound of
 formula (I) or a salt thereof as an active ingredient; and
 a method for treating and/or preventing an infectious disease by using the
 compound of formula (I) or a salt thereof.
 EMBODIMENTS OF INVENTION
 The substituents disclosed in the formula (I) of the present invention are
 explained below.
 The substituent R.sup.1 represents a substituted or unsubstituted cyclic
 alkyl group having 3 to 6 carbon atoms. The cyclic alkyl group is
 preferably a cyclopropyl group. The substituent of the substituted cyclic
 alkyl group is preferably a halogen atom, particularly a fluorine atom.
 Where R.sup.1 is a halogenocyclopropyl group, the halogen atom and the
 pyridonecarboxylic acid moiety are preferably in a cis-configuration with
 respect to the cyclopropane ring.
 The substituent R.sup.2 represents a hydrogen atom, an amino group, a
 hydroxyl group, a thiol group, a halogenomethyl group, an alkyl group
 having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms,
 an alkynyl group having 2 to 6 carbon atoms, or an alkoxyl group having 1
 to 6 carbon atoms, and said amino group may have at least one substituent
 selected from a group of a formyl group, an alkyl group having 1 to 6
 carbon atoms and an acyl group having 2 to 5 carbon atoms.
 The alkyl group as R.sup.2 can be straight or branched of from 1 to 6
 carbon atoms and preferably includes a methyl group, an ethyl group, an
 n-propyl group, and an isopropyl group. The alkenyl group as R.sup.2 can
 be straight or branched of from 2 to 6 carbon atoms and is preferably a
 vinyl group. The alkynyl group as R.sup.2 can be straight or branched of
 from 2 to 6 carbon atoms and is preferably an ethynyl group. The halogen
 atom of halogenomethyl group as R.sup.2 is preferably a fluorine atom and
 the number of the halogen atom is from 1 to 3. The alkoxyl group as
 R.sup.2 can be of from 1 to 6 carbon atoms and is preferably a methoxyl
 group.
 The substituent R.sup.3 represents an amino group, a halogenomethyl group,
 a halogenomethoxyl group, an alkyl group having 1 to 6 carbon atoms, an
 alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6
 carbon atoms, or an alkoxyl group having 1 to 6 carbon atoms, and said
 amino group may have at least one substituent selected from a group of a
 formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group
 having 2 to 6 carbon atoms.
 The alkyl group as R.sup.3 can be straight or branched of from 1 to 6
 carbon atoms and is preferably a methyl group or an ethyl group. The
 alkenyl group as R.sup.3 can be straight or branched of from 2 to 6 carbon
 atoms and is preferably a vinyl group. The alkynyl group as R.sup.3 can be
 straight or branched of from 2 to 6 carbon atoms and is preferably an
 ethynyl group. The halogen atom of halogenomethyl group as R.sup.3 is
 preferably a fluorine atom and the number of the halogen atom is from 1 to
 3. The alkoxyl group as R.sup.3 is preferably a methoxyl group. The
 halogen atom of halogenomethoxyl group as R.sup.3 is preferably a fluorine
 atom and the number of the halogen atom is from 1 to 3.
 The substituent R.sup.4 represents a hydrogen atom or an alkyl group having
 1 to 6 carbon atoms, and said alkyl group may have at least one
 substituent selected from a group of a hydroxyl group, a halogen atom, an
 alkylthio group having 1 to 6 carbon atoms and an alkyloxy group having 1
 to 6 carbon atoms.
 The alkyl group as R.sup.4 can be straight or branched of from 1 to 6
 carbon atoms and preferably includes a methyl group, an ethyl group, an
 n-propyl group, and an isopropyl group. The hydroxyl-substituted alkyl
 group as R.sup.4 can be straight or branched of from 1 to 6 carbon atoms
 and is preferably a hydroxyethyl group or a hydroxypropyl group.
 The substituent R.sup.5 represents a cyclic alkyl group having 3 to 6
 carbon atoms, preferably a cyclopropyl group or a cyclobutyl group.
 The substituent X represents a halogen atom or a hydrogen atom. The halogen
 atom as X is preferably a fluorine atom.
 The substituent Y represents a hydrogen atom, a phenyl group, an
 acetoxymethyl group, a pivaloyloxymethyl group, an ethoxycarbonyl group, a
 choline group, a dimethylaminoethyl group, a 5-indanyl group, a
 phth~alidinyl group, a 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl group, a
 3-acetoxy-2-oxobutyl group, an alkyl group having 1 to 6 carbon atoms, an
 alkoxymethyl group having 2 to 7 carbon atoms, or a phenylalkyl group
 having 1 to 6 carbon atoms in the alkyl moiety thereof.
 Where R.sup.2 or R.sup.3 is an amino group, a hydroxyl group or a thiol
 group, it may be protected with a protective group used in this field.
 Examples of such protective groups include an alkoxycarbonyl group, e.g., a
 t-butoxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group; an
 aralkyloxycarbonyl group, e.g., a benzyloxycarbonyl group, a
 p-methoxybenzyloxycarbonyl group, and a p-nitrobenzyloxycarbonyl group; an
 acyl group, e.g., an acetyl group, a methoxyacetyl group, a
 trifluoroacetyl group, a chloroacetyl group, a pivaloyl group, a formyyl
 group, and a benzoyl group; an alkyl or aralkyl group, e.g., a t-butyl
 group, a benzyl group, a p-nitrobenzyl group, a p-methoxybenzyl group, and
 a triphenylmethyl group; an ether group, e.g., a methoxymethyl group, a
 t-butoxymethyl group, a tetrahydropyranyl group, and a
 2,2,2-trichloroethoxymethyl group; and a silyl group, e.g., a
 trimethylsilyl group, an isopropyldimethylsilyl group, a
 t-butyldimethylsilyl group, a tribenzylsilyl group, and a
 t-butyldiphenylsilyl group. The compound of the invention having such
 protected substituents are particularly useful as an intermediate.
 A preferable assortment of R.sup.2 and R.sup.3 in the compound of formula
 (I) is as follows: R.sup.2 is an amino group, a hydrogen atom, a hydroxyl
 group or an alkyl group having 1 to 6 carbon atoms while R.sup.3 is an
 alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6
 carbon atoms or a halogenomethoxyl group.
 It is still preferred that R.sup.2 is an amino group, a hydrogen atom, a
 hydroxyl group or a methyl group while R.sup.3 is a methyl group, a
 methoxyl group or a difluoromethoxyl group.
 Where R.sup.2 and R.sup.3 are selected from the above assortments, X is
 preferably a fluorine atom.
 The compound of formula (I) in which R.sup.1 is a halogenocyclopropyl group
 will be described in detail.
 The halogen atom on the cyclopropyl group includes a fluorine atom and a
 chlorine atom, with a fluorine atom being particularly preferred. The
 halogen atom and the pyridonecarboxylic acid moiety are preferably in a
 cis-configuration with respect to the cyclopropane ring. Regardless of
 stereoisomerism of the 7-positioned substituent, the 1-positioned
 cis-2-halogenocyclopropyl moiety makes a pair of enantiomers, each of
 which was observed to exhibit potent antimicrobial activity and high
 safety.
 Where the compound of formula (I) has such a structure that contains
 diastereomers, it is preferable to administer to humans or animals a
 compound substantially comprising a pure diastereomer. The term "a
 compound substantially comprising a pure diastereomer" as used herein is
 construed as including not only a compound containing no other
 diastereomer but a compound containing other diastereomers to such an
 extent that the compound is recognized to be stereochemically pure as a
 whole. In other words, it is construed as meaning that other diastereomers
 may exist to some extent as long as the existence gives no substantial
 influence on physiological activities or physicochemical constants.
 The term "substantially stereochemically pure" as used herein is intended
 to mean that a compound substantially comprising a single steric isomer of
 the compound ascribed to its asymmetric carbon atom. The latitude of the
 term "pure" in "pure diastereomer" also applies here.
 The pyridonecarboxylic acid derivative of the present invention may have
 either a free form or a form of an acid addition salt or a carboxylic acid
 salt. Acid addition salts include inorganic acid salts, such as
 hydrochlorides, sulfates, nitrates, hydrobromides, hydroiodides, and
 phosphates; and organic acid salts, such as acetates, methanesulfonates,
 benzenesulfonates, toluenesulfonates, citrates, maleates, fumarates, and
 lactates.
 The carboxylic acid salts include both inorganic salts and organic salts,
 such as alkali metal salts, e.g., lithium salts, sodium salts, and
 potassium salts; alkaline earth metal salts, e.g., magnesium salts and
 calcium salts; ammonium salts; triethylamine salts, N-methylglucamine
 salts, and tris-(hydroxymethyl)aminomethane salts.
 The free pyridonecarboxylic acid derivatives, acid addition salts thereof,
 and carboxylic acid salts thereof may be present as a hydrate.
 On the other hand, quinolone derivatives with the carboxylic acid moiety
 thereof having an ester form are useful as a synthetic intermediate or a
 pro-drug (a drug precursor). For example, alkyl esters, benzyl esters,
 alkoxyalkyl esters, phenylalkyl esters, and phenyl esters are useful as
 synthetic intermediates.
 Esters which can be used as pro-drugs are esters which are easily cleaved
 in vivo to produce a free carboxylic acid, including acetoxymethyl esters,
 pivaloyloxymethyl esters, ethoxycarbonyl esters, choline esters,
 dimethylaminoethyl esters, 5-indanyl esters, phthalidinyl esters,
 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl esters, and oxoalkyl esters, such as
 3-acetoxy-2-oxobutyl esters.
 The compound of formula (I) can be prepared through various processes. A
 preferred process comprises reacting a compound represented by formula
 (II):
 ##STR3##
 wherein R.sup.1, R.sup.2, R.sup.3, and X are as defined above; A represents
 a substituent serves as a leaving group, such as a fluorine atom, a
 chlorine atom, a bromine atom, an alkylsulfonyl group having 1 to 3 carbon
 atoms or an arylsulfonyl group (e.g., a benzenesulfonyl group or a
 toluenesulfonyl group); and Y has the same meaning as Y in formula (I) and
 additionally represents a substituent of formula (III):
 ##STR4##
 wherein R.sup.11 and R.sup.12 each represent a fluorine atom or a lower
 alkylcarbonyloxy group, with a compound represented by formula (IV):
 ##STR5##
 wherein R.sup.4 has the same meaning as R.sup.4 in formula (I) and
 additionally represents a nitrogen protective group Rx; and R.sup.5 is as
 defined above, or an acid addition salt thereof.
 The nitrogen protective group Rx are those ordinary used in this field.
 Examples of Rx are; an alkyloxycarbonyl group, e.g., a t-butoxycarbonyl
 group and a 2,2,2-trichloroethoxycarbonyl group; an aralkyloxycarbonyl
 group, e.g., a benzyloxycarbonyl group, a paramethoxybenzyloxycarbonyl
 group, and a paranitrobenzyloxycarbonyl group; an acyl group, e.g., an
 acetyl group, a methoxyacetyl group, a trifluoroacetyl group, a
 chloroacetyl group, a pivaloyl group, a formyl group, and a benzoyl group;
 an alkyl group or an aralkyl group, e.g., a t-butyl group, a benzyl group,
 a paranitrobenzyl group, a paramethoxybenzyl group, and a triphenylmethyl
 group; an ether group, e.g., a methoxymethyl group, a t-butoxymethyl
 group, a tetrahydropyranyl group, and a 2,2,2-trichloroethoxymethyl group;
 and a silyl group, e.g., a trimethylsilyl group, an isopropyldimethylsilyl
 group, a t-butyldimethylsilyl group, a tribenzylsilyl group, and a
 t-butyldiphenylsilyl group.
 The resulting compound in which Y is an alkyl group having 1 to 6 carbon
 atoms, an alkoxymethyl group having 2 to 7 carbon atoms or a phenylalkyl
 group having 1 to 6 carbon atoms in the alkyl moiety thereof can be
 converted to the corresponding carboxylic acid by hydrolysis under an
 acidic or basic condition commonly used for hydrolysis of carboxylic
 esters. The protective group, if any, is removed under properly selected
 conditions to obtain a desired compound (I).
 The compound obtained by the substitution reaction between the compound
 (II) wherein Y is the group (III) and the compound (IV) can be converted
 to the corresponding carboxylic acid by treatment with an acidic or basic
 compound.
 The substitution reaction between the compounds (II) and (IV) is carried
 out with or without a solvent. The solvent, if used, is not limited as
 long as it is inert under the reaction conditions. Suitable solvents
 include dimethyl sulfoxide, pyridine, acetonitrile, ethanol, chloroform,
 dimethylformamide, dimethylacetamide, N-methylpyrrolidone,
 tetrahydrofuran, water, and 3-methoxybutanol. These solvents may be used
 as a mixture thereof.
 The reaction is usually performed within the range of room temperature to
 200.degree. C., preferably 25 to 150.degree. C., for 0.5 to 48 hours. The
 reaction usually completes in about 0.5 to 2 hours. It is advantageous to
 conduct the reaction in the presence of an acid acceptor, such as an
 inorganic base (e.g., an alkali metal or alkaline metal carbonate or
 hydrogencarbonate) or an organic base (e.g., triethylamine or pyridine).
 The optically active cis-2-fluorocyclopropylamine, which substantially
 comprises a-pure isomer and is preferred as a starting compound for the
 synthesis of the compound (I) substantially comprising a pure isomer, can
 be synthesized by, for example, the process described in JP-A-2-231475.
 The thus obtained cis-2-fluorocyclopropylamine derivative is led to the
 compound of formula (II) substantially comprising a pure isomer by, for
 example, the process described in JP-A-2-231475.
 The compounds of the present invention have potent antimicrobial activity
 and are therefore useful as drugs for humans, animals or fishes,
 agricultural chemicals, or food preservatives.
 For use as drugs for humans, the dose of the compound is in the range of
 from 50 mg to 1 g, and preferably from 100 mg to 300 mg, per day for
 adults.
 For veterinary use, the dose is generally in the range of from 1 to 200 mg,
 and preferably from 5 to 100 mg, per kg of body weight per day while
 varying depending on the purpose of administration (e.g., for therapy or
 for prevention), etc., the kind and the size of the animal, the kind of
 the pathogenic organisms, and severity of symptom.
 The above-mentioned daily dose is given once a day or in 2 to 4 divided
 doses. If necessary, a daily dose may exceed the above-specified range.
 The compounds according to the present invention are active on a broad
 range of microorganisms causing various infectious diseases and effective
 to prevent, alleviate or cure diseases caused by these pathogenes.
 Examples of bacteria or bacterium-like microorganisms on which the
 compounds of the invention are effective include Staphylococci,
 Streptococcus pyogenes, Streptococcus haemolyticus, Streptococcus fecalis,
 Streptococcus pneumoniae, Peptostreptococci, Neisseria gonorrhoeae,
 Escherichia coli, Citrobacter sp., Shigella sp., Klebsiella pneumoniae,
 Enterobacter sp., Serratia sp., Proteus sp., Pseudomonas aeruginosa,
 Haemophilus influenzae, Acinetobacter sp., Campylobacter sp., and
 Chlamydozoon trachomatis.
 Diseases which are caused by these pathogenes include folliculitis,
 furuncle, carbuncle, erysipelas, phlegmon, lymphangitis/lymphadenitis,
 felon, subcutaneous abscess, spiradenitis, acne agminata, infectious
 atheroma, perianal abscess, mastadenitis, superficial secondary infections
 after trauma, burn or surgery trauma, pharyngolaryngitis, acute
 bronchitis, tonsillitis, chronic bronchitis, bronchiectasis, diffuse
 panbronchiolitis, secondary infections of chronic respiratory diseases,
 pneumonia, pyelonephritis, cystitis, prostatitis, epididymitis, gonococcal
 urethritis, non-gonococcal urethritis, cholecystitis, cholangitis,
 bacillary dysentery, enteritis, adnexitis, intrauterine infections,
 bartholinitis, blepharitis, hordeolum, dacryocystitis, tarsadenitis,
 keratohelcosis, otitis media, sinusitis, paradentosis, pericoronitis,
 gnathitis, peritonitis, endocarditis, septicemia, meningitis, and skin
 infections.
 The compounds of the present invention are also effective on various
 microorganisms causing veterinary diseases, such as those belonging to the
 genera Escherichia, Salmonella, Pasteurella, Haemophilus, Bordetella,
 Staphylococcus, and Mycoplasma. Illustrative examples of the veterinary
 diseases include those of fowl, such as colibacillosis, pullorum disease,
 avian paratyphosis, fowl cholera, infectious coryza, staphylomycosis, and
 mycoplasmosis; those of pigs, such as colibacillosis, salmonellosis,
 pasteurellosis, hemophilus infections, atrophic rhinitis, exudative
 epidermitis, and mycoplasmosis; those of cattle, such as colibacillosis,
 salmonellosis, hemorrhagic septicemia, mycoplasmosis, bovine contagious
 pleuropneumonia, and bovine mastitis; those of dogs, such as colisepsis,
 salmonellosis, hemorrhagic septicemia, pyometra, and cystitis; those of
 cats, such as exudative pleurisy, cystitis, chronic rhinitis, and
 hemophilus infections; and those of kittens, such as bacterial diarrhea
 and mycoplasmosis.
 Dosage forms of pharmaceutical preparations containing the compound of the
 present invention are appropriately selected according to the
 administration route and can be prepared by conventional preparation
 methods. Examples of dosage forms for oral administration include tablets,
 powders, granules, capsules, solutions, syrups, elixirs, and oily or
 aqueous suspensions.
 Injectable preparations may contain adjuvants, such as stabilizers,
 antiseptics, and solubilizers. The injectable solution which may contain
 these adjuvants may be put into a container and solidified by, for
 example, lyophilization to prepare a solid preparation which is dissolved
 on use. The container may contain either a single dose or multiple doses.
 Preparations for external application include solutions, suspensions,
 emulsions, ointments, gels, creams, lotions, and sprays.
 Solid preparations may contain, in addition to the active compound,
 pharmaceutically acceptable additives. For example, the active compound is
 mixed with additives selected according to necessity from among fillers,
 extenders, binders, disintegrators, absorption accelerators, wetting
 agents, and lubricants and formulated into solid preparations.
 Liquid preparations include solutions, suspensions, and emulsions. They may
 contain adjuvants, such as suspending agents, emulsifiers, and so forth.
 The compound can be administered to animals orally either directly or by
 mixing with feedstuff, or in a dissolved form directly given to animals or
 by mixing with water or feedstuff or non-orally by injection.
 For veterinary use, the compound can be formulated into powders, fine
 granules, soluble powders, syrups, solutions, and injections according to
 the customary methods in the art.

The present invention will now be illustrated by way of Formulation
 Examples, Reference Examples, and Examples, but the present invention
 should not be construed as being limited thereto. All the percents are by
 weight unless otherwise indicated.
 Formulation Example 1

Solution
 Compound of Example 2 1 to 10 g
 Acetic acid or sodium hydroxide 0.5 to 2 g
 Ethyl p-hydroxybenzoate 0.1 g
 Purified water 87.9 to 98.4 g
 Total 100 g
 Formulation Example 3

Powder for Mixing with Feed
 Compound of Example 2 1 to 10 g
 Corn starch 89.5 to 98.5 g
 Light anhydrous silicic acid 0.5 g
 Total 100 g
 BEST MODE FOR CARRYING OUT INVENTION
 EXAMPLES
 Reference Example 1
 (3R)-N-Cyclopropyl-1-[(R)-phenylethyl]-5-oxopyrrolidine-3-carboxamide
 To a solution of 2.33 g (10 mmol) of
 (3R)-1-[(R)-phenylethyl]-5-oxopyrrolidine-3-carboxylic acid in 20 ml of
 acetonitrile was added 1.83 g (11.5 mol) of 1,1'-carbonyldiimidazole, and
 the mixture was heated at 60.degree. C. for 1 hour. The reaction mixture
 was cooled, and 655 mg (11.5 mmol) of cyclopropylamine was added thereto
 while cooling with ice, followed by stirring at room temperature for 19
 hours. The solvent was evaporated, and chloroform was added to the
 residue. The mixture was washed successively with a 10% citric acid
 aqueous solution and water, and dried over sodium sulfate. The solvent was
 evaporated to give 2.56 g (94%) of the title compound.
 .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 0.45-0.51 (2H, m), 0.70-0.80 (2H,
 m), 1.53 (3H, d, J=6.84 Hz), 2.53-2.59 (1H, m), 2.67-2.83 (3H, m),
 3.07-3.12 (1H, m), 3.53-3.67 (1H, m), 5.44-5.49 (1H, m), 5.82 (1H, brs),
 7.25-7.35 (5H, m).
 Reference Example 2
 (3R)-3-(N-Cyclopropylaminomethyl)-1-[(R)-phenylethyl]pyrrolidine
 To a solution of 2 g (7.35 mol) of
 (3R)-N-cyclopropyl-1-[(R)-phenylethyl]-5-oxopyrrolidine-3-carboxamide in
 60 ml of tetrahydrofuran was added a 37 ml of a solution containing 1 mmol
 of a borane-tetrahydrofuran complex under ice-cooling, and the mixture was
 stirred at room temperature for 17 hours. The solvent was evaporated, and
 chloroform was added to the residue. The mixture was washed with a
 saturated sodium chloride aqueous solution and dried over sodium sulfate.
 The solvent was evaporated, and a 5N sodium hydroxide aqueous solution was
 added to the residue, followed by refluxing for 5 hours. After cooling, a
 saturated sodium chloride aqueous solution was added to the reaction
 mixture, and the mixture was extracted with chloroform. The extract was
 dried over sodium sulfate, and the solvent was evaporated to give 1.63 g
 (91%) of the title compound.
 .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 0.27-0.31 (2H, m), 0.38-0.43 (2H,
 m), 1.36-1.47 (1H, m), 1.37 (3H, d, J=6.83 Hz), 1.89-1.98 (1H, m),
 2.04-2.11 (2H, m), 2.27-2.59 (3H, m), 2.65 (2H, d, J=7.32 Hz), 2.81-2.88
 (1H, m), 3.14-3.19 (1H, m), 7.20-7.34 (5H, m).
 Reference Example 3
 (3R)-3-(N-t-Butoxycarbonyl-N-cyclopropyl-aminomethyl)-1-[(R)-phenylethyl]py
 rrolidine
 To a solution of 1.63 g (6.68 mmol) of
 (3R)-3-(N-cyclopropylaminomethyl)-1-[(R)-phenylethyl]pyrrolidine in 30 ml
 of dichloromethane were added 1.75 g (8 mol) of di-t-butyl dicarbonate, 8
 ml of triethylamine, and 10 mg of 4-dimethylaminopyridine, followed by
 stirring at room temperature for 20 minutes. The solvent was evaporated,
 and the residue was purified by silica gel column chromatography to give
 2.2 g (96%) of the title compound from a 3% methanolchloroform eluate.
 .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 0.53-0.58 (2H, m), 0.70-0.74 (2H,
 m), 1.37 (3H, d, J=6.35 Hz), 1.44 (9H, s), 1.85-1.94 (1H, m), 2.13-2.18
 (1H, m), 2.41-2.64 (4H, m), 2.78-2.82 (1H, m), 3.14-3.25 (4H, m),
 7.22-7.33 (5H, m).
 Reference Example 4
 (3R)-3-(N-t-Butoxycarbonyl-N-cyclopropylaminomethyl)pyrrolidine
 To a solution of 1.7 g (4.9 mmol) of
 (3R)-N-t-butoxycarbonyl-N-cyclopropylaminomethyl-1-[(1R)-phenylethyl]pyrro
 lidine in 50 ml of ethanol was added 1.7 g of 10% palladium-on-carbon.
 Catalytic hydrogenation was conducted under a 4 atom of hydrogen
 atmosphere, while the reaction vessel was heated by an irradiation with a
 tungsten lamp. The catalyst was removed by filtration, and the solvent was
 removed from the filtrate by evaporation to give 1.2 g (100%) of the title
 compound.
 .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 0.60 (2H, brs), 0.75-0.85 (2H, m),
 1.96 (9H, s), 1.72-1.85 (1H, m), 2.10-2.20 (1H, m), 2.45-2.54 (1H, m),
 2.65-2.79 (1H, m), 2.94-3.03 (1H, m), 3.21-3.51 (5H, m).
 Example 1
 7-[3-(R)-Cyclopropylaminomethyl-1-pyrrolidinyl]-6-fluoro-1-[(1R,2S)-2-fluor
 ocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic Acid
 To a solution of 690 mg (2 mmol) of
 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoqui
 noline-3-carboxylic acid BF.sub.2 chelate in 8 ml of dimethyl sulfoxide
 were added 960 mg (4 mmol) of
 (3R)-3-(N-t-butoxycarbonyl-N-cyclopropylaminomethyl)pyrrolidine and 1 ml
 of triethylamine, and the mixture was stirred at room temperature for 170
 hours. Triethylamine was removed by evaporation, and 10 ml of water was
 added to the residue, followed by stirring at room temperature for 15
 minutes. The precipitated crystals were washed with water and collected by
 filtration. The crystals were dissolved in 100 ml of a 4:1 mixture of
 ethanol and water, and 10 ml of triethylamine was added thereto, followed
 by refluxing for 3 hours. The solvent was evaporated, and 100 ml of
 chloroform was added to the residue. The mixture was washed with two 30 ml
 portions of 10% citric acid aqueous solution, and dried over magnesium
 sulfate. The solvent was evaporated, and 10 ml of concentrated
 hydrochloric acid was added to the residue. The mixture was stirred at
 room temperature for 5 minutes, washed with two 10 ml portions of
 chloroform, adjusted to a pH of 7.3 with a 20% sodium hydroxide aqueous
 solution, and extracted with three 80 ml portions of chloroform. The
 extract was dried over sodium sulfate, and the solvent was evaporated. The
 residue was purified by preparative thin layer chromatography (TLC)
 (developed with the lower layer of a mixture of
 chloroform:methanol:water=7:3:1) to give 181 mg (22%) of a crude product.
 Recrystallization from ethanoldiethyl ether gave 100 mg of the title
 compound.
 .sup.1 H-NMR (0.1N-NaOD) .delta. ppm: 0.30-0.36 (2H, m), 0.41-0.50 (2H, m),
 1.04-1.20 (1H, m), 1.42-1.65 (2H, m), 2.00-2.17 (2H, m), 2.28-2.46 (1H,
 m), 2.36 (3H, s), 2.63-2.75 (2H, m), 3.19-3.35 (3H, m), 3.54-3.68 (1H, m),
 3.96-4.04 (1H, m), 4.99-5.07 (0.5H, m), 7.61 (1H, d, J=14.16 Hz), 8.42
 (1H, s).
 Elementary analysis for C.sub.22 H.sub.25 F.sub.2 N.sub.3
 O.sub.3.multidot.0.25H.sub.2 O: Calcd. (%): C 62.62; H 6.09; N 9.69; Found
 (%): C 62.87; H 6.11; N 9.83; Melting point: 163-164.degree. C.
 Example 2
 5-Amino-7-[3-(R)-(N-cyclopropylaminomethyl)-1-pyrrolidinyl]-6-fluoro-1-[(1R
 ,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxocquinoline-3-carboxyli
 c Acid
 To a solution of 328 mg (1 mmol) of
 5-amino-6,7-difluoro-1-[(2S)-fluoro-(1R)-cyclopropyl]-1,4-dihydro-8-methox
 y-4-oxoquinoline-3-carboxylic acid in 10 ml of dimethyl sulfoxide were
 added 360 mg (1.5 mmol) of
 (3R)-3-(N-t-butoxycarbonyl-N-cyclopropylaminomethyl)pyrrolidine and 3 ml
 of triethylamine, and the mixture was heated at 100.degree. C. for 15
 hours. The solvent was evaporated, and 50 ml of chloroform was added to
 the residue. The chloroform solution was washed with two 20 ml portions of
 a 10% citric acid aqueous solution and dried over sodium sulfate, and the
 solvent was evaporated. To the residue was added 5 ml of concentrated
 hydrochloric acid, followed by stirring at room temperature for 5 minutes.
 The reaction mixture was washed with two 20 ml portions of chloroform. The
 hydrochloric acid solution was adjusted to a pH of 7.3 with a 20% sodium
 hydroxide aqueous solution and extracted with three 80 ml portions of
 chloroform. The extract was dried over sodium sulfate, and the solvent was
 evaporated. The residue was purified by preparative TLC (developed with
 the lower layer of a mixture of chloroform:methanol:water=7:3:1) to obtain
 a crude compound. Recrystallization from diethyl ether yielded 215 mg
 (48%) of the title compound.
 .sup.1 H-NMR (0.1N-NaOD) .delta. ppm: 0.33 (2H, brs), 0.46-0.48 (2H, m),
 1.17-1.27 (1H, m), 1.34-1.47 (1H, m), 1.57-1.59 (1H, m), 2.08-2.14 (2H,
 m), 2.39-2.43 (1H, m), 2.72 (2H, brs), 3.34-3.35 (1H, m), 3.43 (3H, 2s),
 3.56-3.65 (2H, m), 3.86-3.89 (1H, m), 5.02 (0.5H, brs), 8.21 (1H, 2s).
 Elementary analysis for C.sub.19 H.sub.20 F.sub.2 N.sub.4
 O.sub.4.multidot.0.25H.sub.2 O: Calcd. (%): 58.48; H 5.86; N 11.97; Found
 (%): 53.34; H 5.90; N 12.37; Melting point: 154-156.degree. C. (with
 decomposition)
 Example 3
 5-Amino-7-[(3R)-N-cyclopropylaminomethyl-1-pyrrolidinyl]-6-fluoro-1-[(1R,2S
 )-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic
 Acid Hydrochloride
 To a solution of 2.00 g (6.4 mmol) of
 5-amino-6,7-difluoro-1-[(2S)-fluoro-(1R)-cyclopropyl]-1,4-dihydro-8-methyl
 -4-oxoquinoline-3-carboxylic acid in 10 ml of dimethyl sulfoxide were added
 2.32 g (9.6 mmol) of
 (3R)-N-t-butoxycarbonyl-N-cyclopropylaminomethylpyrrolidine and 30 ml of
 triethylamine, and the mixture was heated at 120.degree. C. for 5 days.
 The solvent was evaporated, and to the residue was added 10 ml of
 concentrated hydrochloric acid, followed by stirring at room temperature
 for 15 minutes. The reaction mixture was washed with two 300 ml portions
 of chloroform. The hydrochloric acid solution was adjusted to a pH of 7.3
 with a 20% sodium hydroxide aqueous solution and extracted with three 200
 ml portions of chloroform. The extract was dried over sodium sulfate, and
 the solvent was evaporated. The residue was purified by preparative TLC
 (developed with the lower layer of a mixture of
 chloroform:methanol:water=7:3:1), 10 ml of 1N hydrochloric acid was added
 to the crude product, and the solvent was evaporated. Recrystallization
 from ethanol-diethyl ether yielded 1.05 g (31%) of the title compound.
 .sup.1 H-NMR (0.1N NaOD-D.sub.2 O) .delta. ppm: 0.34 (1H, brs), 0.47 (1H,
 brs), 1.03-1.16 (1H, m), 1.42-1.61 (2H, m), 2.04-2.80 (6H, m), 3.25-3.42
 (3H, m), 3.66-3.74 (1H, m), 3.88-3.97 (1H, m), 8.26 (1H, s )
 Elementary analysis for C.sub.23 H.sub.29 F.sub.2 N.sub.4
 O.sub.3.multidot.HCl.multidot.2.5H.sub.2 O.multidot.0.25EtOH: Calcd. (%):
 C 51.82; H 6.47; N 10.74; Found (%): C 51.94; H 5.91; N 10.20; Melting
 point: 145-149.degree. C.
 The antimicrobial activity of the compounds obtained in Examples 1 to 3 was
 examined in accordance with the standard method specified by the Japan
 Chemotherapeutic Society. The resulting antimicrobial spectra are shown in
 Table 1 below.
 TABLE 1
 Antimicrobial Spectra (MIC: .mu.g/ml)
 Test Microorganism Example 1 Example 2 Example 3
 E. coli, NIHJ .ltoreq.0.003 0.006 0.006
 S. flexneli, 2A 5503 0.006 0.013 0.006
 Pr. vulgaris, 08601 0.006 0.10 0.05
 Pr. mirabilis, IFO-3849 0.025 0.20 0.10
 Ser. marcescens, 10100 0.10 0.39 0.20
 Ps. aeruginosa, 32104 0.20 0.78 0.39
 Ps. aeruginosa, 32121 0.10 0.78 0.20
 Ps. maltophilia, IID-1275 0.05 0.20 0.10
 S. aureus, 209P .ltoreq.0.003 .ltoreq.0.003 .ltoreq.0.003
 S. epidermidis, 56500 0.013 0.013 0.006
 Str. pyrogenes, G-36 0.013 0.025 0.013
 Str. faecalis, ATCC-19433 0.025 0.10 0.05
 S. aureaus, 870307 0.025 0.05 0.025