HK1113571A - Fluoroalkylpyrrolidine derivative - Google Patents

Description

Fluoroalkyl pyrrolidine derivatives

Technical Field

The present invention relates to fluoroalkyl pyrrolidine derivatives having excellent antibacterial activity against gram-positive and gram-negative bacteria, and pharmaceuticals containing the derivatives as an active ingredient.

Background

Since the invention of norfloxacin, quinolinone synthetic antibacterial agents have been used to improve antibacterial activity and in vivo kinetics, and have been developed as chemotherapeutic agents effective for almost systemic infections, and many compounds have been used clinically.

However, in recent years, there has been an increase in low-susceptibility bacteria for quinolinone synthesis antibacterial agents in clinical practice. For example, among gram-positive bacteria, bacteria which are not sensitive to β -lactam antibiotics, such as staphylococcus aureus (MRSA) and pneumococcus (PRSP), and bacteria which are not sensitive to aminoglycoside antibiotics, such as gram-positive bacteria, e.g., enterococci (VRE), are bacteria which have developed resistance to drugs other than quinolinone synthesis antibacterial drugs, and bacteria which have low sensitivity to quinolinone synthesis antibacterial drugs are increasing.

Therefore, there is a particular clinical desire for pharmaceutical preparations with increased effectiveness against gram-positive cocci.

Further, it has been clarified that taking non-steroidal anti-inflammatory drugs (NSAIDs) together causes side effects such as spasticity, central action (mild central nervous disorders such as tremor, headache, and insomnia, and severe side effects such as spasticity), phototoxicity (photosensitivity), hepatotoxicity, cardiotoxicity (abnormality detected as electrocardiographic abnormality that induces fatal arrhythmia), and abnormal blood glucose level, and development of a quinolinone synthetic antibacterial agent with higher safety has been desired (see non-patent documents 1 and 2).

On the other hand, it is known that the structure of the 7-position substituent of the quinolinone skeleton has a great influence on the antibacterial activity, in vivo dynamics and safety of quinolinone synthetic antibacterial drugs. Among them, quinolinone derivatives substituted with a 3-aminopyrrolidin-1-yl group are known to exhibit better antibacterial activity against gram-negative bacteria and gram-positive bacteria than quinolinone derivatives substituted with a piperazine derivative, for example (see non-patent documents 3 and 4).

However, although the quinolinone derivatives having 3-aminopyrrolidin-1-yl as a substituent exhibit strong antibacterial activity, most of them have not only strong cytotoxicity and erythrocytic micronucleus-inducing action but also low selective toxicity as compared with quinolinone derivatives having piperazine derivatives as a substituent (see non-patent document 4).

Therefore, a compound having both strong antibacterial activity and high selective toxicity is desired clinically.

On the other hand, patent document 1 and non-patent document 5 disclose quinolinone carboxylic acid derivatives (a) in which the 7-position substituent is a cis-3-amino-4- (fluoro-substituted methyl) pyrrolidin-1-yl group (the substituent in formula (a) is as defined in patent document 1, and the same reference numerals are not used to refer to the definition of the substituent in the specification of the present application).

A substituent at the 8-position of the quinolinone skeleton (corresponding to the group R)²) Specifically disclosed are quinolinone carboxylic acid derivatives wherein the 7-position substituent of the quinolinone skeleton is not a cis-3-amino-4- (fluorine-substituted methyl) pyrrolidin-1-yl group, and the 8-position substituent is an alkyl group or a halogen-substituted alkyl group, but is limited to a halomethoxy group or an alkoxy group.

Further, non-patent document 6 discloses quinolinone carboxylic acid derivatives having a 7-position substituent as the cis-3-amino-4- (fluoro-substituted methyl) pyrrolidin-1-yl group, and describes, as a specific example thereof, 8-methoxyquinolinone derivatives (B) having a cis-3-amino-4-trifluoromethylpyrrolidin-1-yl group as a substituent.

However, the compound described in non-patent document 6 is limited to a methoxy group as the substituent at the 8-position of the quinolinone skeleton, and there is no specific description of quinolinone carboxylic acid derivatives in which the substituent at the 7-position of the quinolinone skeleton is a cis-3-amino-4- (fluorine-substituted methyl) pyrrolidin-1-yl group, and the substituent at the 8-position is an alkyl group or a halogen-substituted alkyl group.

Further, non-patent document 7 describes quinolinone carboxylic acid derivatives having a cis-3-amino-4- (fluoro-substituted methyl) pyrrolidin-1-yl group as a 7-position substituent, and specifically describes 2-pyridone derivatives (9-methyl-4H-4-oxoquinolizin-3-carboxylic acid derivatives) (C) having a cis-3-amino-4-trifluoromethylpyrrolidin-1-yl group as a substituent.

However, the quinolinone skeleton of the compound described in non-patent document 7 is limited to a 2-pyridone derivative (9-methyl-4H-4-oxoquinolizine-3-carboxylic acid derivative), and is different from the chemical structure of the 1, 4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid derivative included in the invention of the present application.

Patent document 1: international publication No. 98/58923

Non-patent document 1: honghuo edition of Xiaolin, clinical application of New quinolinone drug, journal of medicine society (2001)

Non-patent document 2: medicine, vol 62, page 1, 13 (2002)

Non-patent document 3: international Journal of antimicrobial Agents (International Journal of antimicrobial Agents), Vol.16, p5(2000)

Non-patent document 4: journal of antimicrobial chemotherapy (Journal of antimicrobial chemotherapy), Vol.33, p685(1994)

Non-patent document 5: journal of drug reporting (Journal Pharmaceutical Bulletin), Vol.48(No.11), p1667(2000)

Non-patent document 6: biopharmacochemistry patents (Bioorganic Medicinal chemistry letters), Vol.8, p2833(1998)

Non-patent document 7: biopharmacochemistry patents (Bioorganic Medicinal chemistry letters), Vol.8, p1953(1998)

Disclosure of The Invention

Accordingly, an object of the present invention is to provide quinolinone antibacterial agents exhibiting broad-spectrum potent antibacterial activity against gram-positive bacteria and gram-negative bacteria and having high safety, and agents for preventing and/or treating infectious diseases.

The present inventors have found that a compound represented by the following formula (1) exhibits a broad-spectrum potent antibacterial activity against gram-positive bacteria and gram-negative bacteria and is highly safe as an antibacterial agent and a prophylactic/therapeutic agent for infectious diseases, and have completed the present invention.

Namely, the present invention provides a compound represented by the following formula (1), a salt thereof, or a hydrate thereof.

In the formula, R¹Represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms, or a substituted carbonyl group derived from an amino acid, a dipeptide or a tripeptide, the alkyl group having a substituent selected from the group consisting of a hydroxyl group, an amino group, a halogen atom, an alkylthio group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms;

R²represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms, and the alkyl group may have a substituent selected from the group consisting of a hydroxyl group, an amino group, a halogen atom, an alkylthio group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms;

R³represents an alkyl group having 1 to 6 carbon atoms or an alkyl group substituted with a halogen having 1 to 6 carbon atoms;

R⁴represents cycloalkyl having 3 to 6 carbon atoms or cycloalkyl substituted with halogen having 3 to 6 carbon atoms;

R⁵represents a hydrogen atom, a phenyl group, an acetoxymethyl group, a trimethylacetoxymethyl group, an ethoxycarbonyl group, a choline group, a dimethylaminoethyl group, a 5-indanyl group, a phthalone 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 comprising an alkylene group having 1 to 6 carbon atoms and a phenyl group;

X¹and X²Each independently represents a hydrogen atom or a halogen atom;

x represents a hydrogen atom or a halogen atom.

The present invention also provides 7- [ (3S, 4S) -3-amino-4-fluoromethylpyrrolidin-1-yl ] -6-fluoro-1- [ (2S, 1R) -2-fluorocyclopropyl ] -1, 4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, a salt thereof or a hydrate thereof; 7- [ (3S, 4S) -3-fluoromethyl-4-methylaminopyrrolidin-1-yl ] -6-fluoro-1- [ (2S, 1R) -2-fluorocyclopropyl ] -1, 4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, a salt thereof, or a hydrate thereof.

The present invention also provides a pharmaceutical containing the compound represented by the above formula (1), a salt or hydrate thereof, or a hydrate of the salt as an active ingredient.

The present invention also provides a pharmaceutical composition containing the compound represented by the above formula (1), a salt or hydrate thereof, and a pharmaceutically acceptable carrier.

The present invention also provides a method for preventing and/or treating a disease, which is characterized by administering an effective amount of the compound represented by the above formula (1), a salt thereof, or a hydrate thereof.

The present invention also provides a method for producing a pharmaceutical, which is characterized by incorporating the compound represented by the formula (1), a salt thereof, or a hydrate thereof as an active ingredient.

The present invention also provides use of a compound represented by the above formula (1), a salt or hydrate thereof, or a hydrate of the salt in the preparation of a pharmaceutical.

The fluoroalkyl pyrrolidine derivative has excellent antibacterial activity on gram-positive bacteria and gram-negative bacteria, low acute toxicity and high safety. Therefore, the fluoroalkyl pyrrolidine derivative of the present invention is useful as an antibacterial agent and a prophylactic and/or therapeutic agent for infectious diseases.

Best Mode for Carrying Out The Invention

The substituents of the compound of the present invention represented by the above formula (1) will be described.

Substituent R¹Represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or a substituted carbonyl group derived from an amino acid, a dipeptide or a tripeptide.

Substituent R²Represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms.

R¹Or R²When they are alkyl groups, they may have a substituent selected from the group consisting of a hydroxyl group, an amino group, a halogen atom, an alkylthio group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms.

R¹Or R²Examples of the "alkyl" may include a linear alkyl such as methyl, ethyl, n-propyl, n-butyl and n-pentyl, and a branched alkyl such as isopropyl, isobutyl, sec-butyl and tert-butyl. Among them, methyl and ethyl groups are preferable, and methyl is more preferable.

When the alkyl group has a hydroxyl group or an amino group as a substituent, it is preferable that the substituent is substituted at a terminal carbon atom of the alkyl group. The alkyl group having a hydroxyl group is preferably an alkyl group having a carbon number of at most 3, and is preferably a hydroxymethyl group, a 2-hydroxyethyl group, a 2-hydroxypropyl group, a 3-hydroxypropyl group or the like. The alkyl group having an amino group is preferably an alkyl group having a carbon number of at most 3, and is preferably an aminomethyl group, a 2-aminoethyl group, a 2-aminopropyl group, a 3-aminopropyl group or the like.

When the alkyl group has a halogen atom as a substituent, the alkyl group may be either straight-chain or branched-chain having 1 to 6 carbon atoms. Examples of the halogen atom include a fluorine atom, a chlorine atom and an iodine atom, and a fluorine atom is preferable. The number of fluorine atom substitution may be 1 to 3. Among them, fluoromethyl, difluoromethyl, trifluoromethyl, 2, 2, 2-trifluoroethyl and the like are exemplified.

When the alkyl group has an alkylthio group or an alkoxy group as a substituent, the alkyl group may be either straight-chain or branched-chain having 1 to 6 carbon atoms, or the alkyl group in the alkylthio group or the alkoxy group may be either straight-chain or branched-chain. Examples of the alkyl group having an alkylthio group include an alkylthiomethyl group, an alkylthioethyl group and an alkylthiopropyl group, and the alkylthio group is preferably a group having 1 to 3 carbon atoms. More preferred are methylthiomethyl, ethylthiomethyl and methylthioethyl. The alkyl group having an alkoxy group is preferably an alkoxymethyl group, an alkoxyethyl group or an alkoxypropyl group, and the alkoxy group is preferably a group having 1 to 3 carbon atoms. More preferred are methoxymethyl, ethoxymethyl and methoxyethyl.

R¹Or R²When the alkyl group is a cycloalkyl group, a cyclopropyl group and a cyclobutyl group are preferable, and a cyclopropyl group is more preferable.

As R¹And R²Preferred combinations of (1) are preferably R¹Is a hydrogen atom, an alkyl group, a cycloalkyl group or a carbonyl group derived from an amino acid, a dipeptide or a tripeptide, R²Is a combination of hydrogen atoms. Wherein, the more preferable combination is R¹Is a hydrogen atom, an alkyl group, a cycloalkyl group, R²Is a combination of hydrogen atoms. The alkyl group is preferably a methyl group or an ethyl group, particularly preferably a methyl group. The cycloalkyl group is preferably a cyclopropyl group or a cyclobutyl group, particularly preferably a cyclopropyl group. R¹And R²Is R¹And R²Are all a combination of hydrogen atoms, or R¹Is methyl, R²Is a combination of hydrogen atoms.

Substituent R¹Is a substituted carbonyl group derived from an amino acid, dipeptide or tripeptide, R²Quinolinone derivatives which are hydrogen atoms are particularly useful as prodrugs.

The amino acid, dipeptide or tripeptide used for obtaining the prodrug is an amine compound which is cleaved in vivo by an amide bond formed between a carboxyl group and a nitrogen atom of an amino group at the 3-position of the pyrrolidine ring to form a free amine compound. Examples of the substituent include a substituted carbonyl group derived from an amino acid such as glycine, alanine, or aspartic acid, a dipeptide such as glycine-glycine, glycine-alanine, or alanine-alanine, or a tripeptide such as glycine-alanine, or glycine-alanine.

Substituent R³Represents an alkyl group having 1 to 6 carbon atoms or an alkyl group substituted with a halogen having 1 to 6 carbon atoms.

Examples of the alkyl group having 1 to 6 carbon atoms include the alkyl groups described above. Among them, an alkyl group having 1 to 3 carbon atoms is preferable, and a methyl group is particularly preferable. Examples of the halogen atom of the C1-6 halogen-substituted alkyl group include a fluorine atom and a chlorine atom, and the number thereof is preferably 1 to 3.

Substituent R⁴Represents cycloalkyl having 3 to 6 carbon atoms or cycloalkyl substituted with halogen having 3 to 6 carbon atoms.

Examples of the cycloalkyl group having 3 to 6 carbon atoms include the cycloalkyl groups described above. Of these, cyclopropyl is preferred. Examples of the cycloalkyl group substituted with a halogen having 3 to 6 carbon atoms may include the cycloalkyl groups substituted with 1 or 2 halogen atoms. The halogen atom may, for example, be a fluorine atom or a chlorine atom, and particularly preferably a fluorine atom. Among them, preferred is a halogenocyclopropyl group or a dihalocyclopropyl group, particularly preferred is a fluorocyclopropyl group.

Substituent R⁵Represents a hydrogen atom, a phenyl group, an acetoxymethyl group, a trimethylacetoxymethyl group, an ethoxycarbonyl group, a choline group, a dimethylaminoethyl group, a 5-indanyl group, a phthalone 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 comprising an alkylene group having 1 to 6 carbon atoms and a phenyl group.

When the compound (1) of the present invention is used for antibacterial purposes, it is preferable to use the substituent R⁵A carboxylic acid compound which is a hydrogen atom.

On the other hand, quinolinone carboxylic acid derivatives formed as carboxylic acid esters can be used as synthesis intermediates or prodrugs. Examples of the ester which can be used as a synthesis intermediate include alkyl esters, benzyl esters, alkoxyalkyl esters, phenylalkyl esters and phenyl esters. The ester which can be used as a prodrug is an ester which is easily cleaved in vivo to form a free carboxylic acid. Examples thereof may include acetoxymethyl ester, pivaloyloxymethyl ester, acetoxycarbonyl ester, choline ester, dimethylaminoethyl ester, 5-indanyl ester, phthalidyl ester, 5-alkyl-2-oxo-1, 3-dioxol-4-ylmethyl ester, and 3-acetoxy-2-oxobutyl ester.

Substituent X¹And X²Each independently represents a hydrogen atom or a halogenThe halogen atom is particularly preferably a fluorine atom.

As X¹And X²In combination of (1), preferably X¹And X²All are combinations of hydrogen atoms or combinations of hydrogen atoms on one hand and fluorine atoms on the other hand.

The substituent X represents a hydrogen atom or a halogen atom, and the halogen atom is particularly preferably a fluorine atom.

In the compound (1) of the present invention, since 3-amino-4-fluoro as a 7-position substituent is substituted for methylpyrrolidin-1-yl (formula (3)):

there are 4 kinds of optical isomers of the asymmetric carbon atoms at the 3-position and the 4-position, and among them, the 3, 4-cis form is preferable, and the compound having the (3S, 4S) -configuration or the (3S, 4R) -configuration is more preferable, and the compound having the (3S, 4S) -configuration (formula (3-1)) is particularly preferable.

In the formulae (3) and (3-1), R¹、R²、X¹And X²As previously described.

In the compound (1) of the present invention, R⁴When it is cycloalkyl substituted by halogen, R⁴The stereochemical environment of the halocycloalkyl group of (a) is with respect to the cycloalkane ring, preferably the halogen atom and quinolinone carboxylic acid backbone are in a 1, 2-cis configuration. Here, "cis-configuration" means that the halogen atom and the quinolinone carboxylic acid skeleton are in cis-configuration with respect to the cycloalkane ring. The cis configuration includes a (1R, 2S) -configuration and a (1S, 2R) -configuration, with the (1R, 2S) -configuration being preferred.

The compound of the present invention represented by the formula (1) is a structure in which diastereoisomers existIn the case of administering the compound of the present invention to animals including humans, it is preferable to administer a compound formed from a single diastereomer. "formed from a single diastereomer" includes not only the case where it is completely free from other diastereomer, but also the case where it contains other diastereomer to such an extent that it has no influence on physical constants and activities. In addition, when the compound of the present invention is administered, it is preferable to administer a stereochemically specific compound, and here, "stereochemical uniqueness" includes not only a case where the compound is composed of only 1 optically active form but also a case where other optically active forms are contained to the extent that they do not affect physical constants and activities in the case where the optically active forms exist. The compound (1) of the present invention is particularly preferably a compound in which the 3-and 4-positions in the 7-position substituent are in the (3S, 4S) -configuration and R is⁴Halocycloalkyl of (a) is a compound of the (1R, 2S) -configuration.

The compound (1) of the present invention may be a free form or an acid addition salt or a salt of a carboxyl group. The acid addition salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide and phosphate; sulfonates such as methanesulfonate, benzenesulfonate and p-toluenesulfonate, and carboxylates such as acetate, citrate, maleate, fumarate and lactate. Examples of the salt of the carboxyl group include alkali metal salts such as lithium salt, sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, ammonium salt, triethylamine salt, N-methylglucamine salt and tris- (hydroxymethyl) aminomethane salt. Furthermore, the free form, acid addition salt or salt of carboxyl group of the compound (1) of the present invention may also exist in the form of a hydrate.

Specific examples of the compound (1) of the present invention include 7- [ (3S, 4S) -3-amino-4-fluoromethyl-1-pyrrolidinyl ] -1-cyclopropyl-6-fluoro-1, 4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, a salt thereof or a hydrate thereof (compound No. 1), 7- [ (3S, 4S) -3-amino-4-fluoromethyl-1-pyrrolidinyl ] -1-cyclopropyl-1, 4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, a salt thereof or a hydrate thereof (compound No. 2), 7- [ (3S, 4S) -3-amino-4-fluoromethyl-1-pyrrolidinyl ] -6-fluoro-1- [ (2S, 1R) -2-fluorocyclopropyl ] -1, 4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, a salt thereof or a hydrate thereof (Compound No. 3), 7- [ (3S, 4S) -3-fluoromethyl-4-methylaminopyrrolidin-1-yl ] -6-fluoro-1- [ (2S, 1R) -2-fluorocyclopropyl ] -1, 4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, a salt thereof or a hydrate thereof (Compound No. 4), 1-cyclopropyl-6-fluoro-7- [ (3S, 4S) -3-fluoromethyl-4-methylaminopyrrolidin-1-yl ] -8-methyl-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid, a salt thereof or a hydrate thereof (Compound No. 5), 7- [ (3S, 4S) -3-amino-4-difluoromethylpyrrolidin-1-yl ] -6-fluoro-1- [ (1R, 2S) -2-fluorocyclopropyl ] -8-methyl-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid, a salt thereof or a hydrate thereof (Compound No. 6).

Of these, particularly preferred are 7- [ (3S, 4S) -3-amino-4-fluoromethyl-1-pyrrolidinyl ] -6-fluoro-1- [ (2S, 1R) -2-fluorocyclopropyl ] -1, 4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, a salt or hydrate thereof (Compound No. 3), 7- [ (3S, 4S) -3-fluoromethyl-4-methylaminopyrrolidin-1-yl ] -6-fluoro-1- [ (2S, 1R) -2-fluorocyclopropyl ] -1, 4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, a salt thereof or a hydrate thereof, A salt thereof or a hydrate thereof (compound No. 4).

In the preparation of the compound (1) of the present invention, the following intermediate compound (formula (a)) may be reacted with an appropriate starting compound in order to construct a 7-position substituent.

The asymmetry of the 3-and 4-positions of the intermediate compound is as described above. Therefore, the compound participating in the reaction is more preferably a compound in the (3S, 4S) -configuration or the (3S, 4R) -configuration, particularly preferably a compound in the (3S, 4S) -configuration (formula (A-1)).

Conversion of formula (A) and formula (A-1)In the compound, X¹And X²As defined above. In another aspect, R¹¹And R¹²Represents the aforementioned R¹And R²A substituent of a protecting group of an amino group (nitrogen atom) is added. The protecting group of the amino group may be any group as long as it is easily protected and deprotected, and it does not affect the reaction in the subsequent step or the protecting group itself does not react. The protecting group for the amino group may be selected from the group consisting of an alkoxycarbonyl group which may have a substituent, an aralkoxycarbonyl group which may have a substituent, an acyl group which may have a substituent, an aralkyl group which may have a substituent and a substituted silyl group, which are conventionally used. More specifically, examples of the alkoxycarbonyl group which may have a substituent include a methoxycarbonyl group, an ethoxycarbonyl group, a tert-butoxycarbonyl group, and a 2, 2, 2-trichloroethoxycarbonyl group. Examples of the acyl group which may have a substituent include an acetyl group, a methoxyacetyl group, a trifluoroacetyl group, a chloroacetyl group, a pivaloyl group, a formyl group, and a benzoyl group. Examples of the aralkyloxycarbonyl group which may have a substituent include a benzyloxycarbonyl group, a p-methoxyphenylmethoxycarbonyl group and a p-nitrobenzyloxycarbonyl group. Examples of the substituted silyl group include a trimethylsilyl group, an isopropyldimethylsilyl group, a tert-butyldimethylsilyl group, a tritylsilyl group, and a tert-butyldimethylsilyl group. Among the protecting groups used in the intermediate compound, preferred are an alkoxycarbonyl group which may have a substituent, an aralkyloxycarbonyl group which may have a substituent and an acyl group which may have a substituent, particularly preferred are a methoxycarbonyl group, an ethoxycarbonyl group, a tert-butoxycarbonyl group, a benzyloxycarbonyl group, an acetyl group and a trifluoroacetyl group, and more preferred is a tert-butoxycarbonyl group.

In most cases, a compound in which the nitrogen atom at the 1-position of the pyrrolidine ring is protected with a protecting group for a nitrogen atom (amino group) is easy to produce. The protecting group to be used for the compound protected at the 1-position can be selected from the protecting groups shown above.

The intermediate compound may have a protecting group of 3 amino groups at most, and the selection of such protecting group may be carried out according to necessity by a selection standard known in the art.

A preferable example of the method for producing the compound of the present invention represented by the formula (1) is, for example, the following method. The following will specifically explain the production method of the compound of example 3 (compound No. 3) as an example.

The preparation of the compounds of the invention can be carried out according to 2 methods. Namely, a method of reacting a pyrrolidine compound with a 7-halo-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid derivative and introduction of a pyrrolidine substituent, or a method of reacting the pyrrolidine compound with a 4-halobenzoic acid derivative and then ring-closing a quinoline ring.

The latter method will be explained first.

[ step a ] reaction of a pyrrolidine compound with a benzoic acid derivative; compound (II)

The benzoic acid derivative used in the reaction is preferably a 4-halobenzoic acid derivative. More preferred are 2, 4-dihalobenzoic acid derivatives. The substituent at a site other than the above-mentioned site of benzoic acid may be any substituent based on the quinolinone compound itself to be obtained. For example, to obtain 8-methylquinolinone derivatives, 2, 4-dihalo-3-methylbenzoic acid derivatives can be used. The halogen at the 2-position and the 4-position may be a fluorine atom or a chlorine atom, and is preferably a fluorine atom. The substituents at the 4-position and the 2-position are not limited to halogen atoms as long as they function as leaving groups.

The carboxylic moiety of benzoic acid may be a free carboxylic group (-COOH) or may also be an ester group (-COOR). Among them, an ester group is more preferable. Examples of the ester group include an alkyl ester, an aryl ester, an aralkyl ester, a phenyl ester which may have a substituent on the phenyl group, and a benzyl ester. Among them, alkyl esters are more convenient to use, and methyl ester, ethyl ester, propyl ester, etc. are more preferable.

The reaction with the pyrrolidine compound (I) is preferably carried out in the presence of a base. The base used herein is not particularly limited as long as it does not inhibit the reaction, and examples thereof include organic bases such as trialkylamine (e.g., trimethylamine, triethylamine) and heterocyclic compounds (e.g., 4- (dimethylamino) pyridine, N-methylmorpholine and 1, 8-diazabicyclo [5.4.0] -7-undecene (DBU)), and inorganic bases such as ammonia, ammonium salts, alkali metal carbonates, alkaline earth metal carbonates (e.g., potassium carbonate and sodium carbonate), and hydroxides (e.g., sodium hydroxide and potassium hydroxide). Among them, organic bases such as tertiary amines are preferable, triethylamine is particularly preferable, and 1, 8-diazabicyclo [5.4.0] -7-undecene (DBU) is preferable as the heterocyclic compound. The amount of the base is 1 equivalent or more.

In this step, HF is generated with the progress of the reaction, and this HF may cause problems in terms of pollution, for example, the necessary protecting group is released, a salt with an amine compound interferes with the reaction with a benzoic acid compound, and the reaction vessel is corroded. Furthermore, when an acid addition salt of a pyrrolidine compound is used in this step, a base is also required to form the salt as a free base.

The reaction with the pyrrolidine compound may be carried out in the presence of a solvent, and the solvent used herein is not particularly limited as long as it does not affect the reaction, and examples thereof include N-alkylamides such as N, N-dimethylacetamide and N-methylpyrrolidone, aprotic polar solvents such as N, N-dimethylformamide, dimethylsulfoxide and sulfolane, acetonitrile and the like, and acetonitrile and N, N-dimethylacetamide (N-alkylamides) are preferable.

The reaction temperature may be arbitrarily selected from the freezing point to the boiling point of the reaction solution, and is preferably from room temperature to the boiling point of the reaction solution. The reaction time is usually 1 hour to 100 hours, preferably 10 hours to 30 hours, as long as the disappearance of the starting material is acceptable.

[ step b ] reaction of Compound (II) with malonic acid half ester; compound (III)

Then, the benzoic acid derivative (II) having the pyrrolidine substituent introduced therein is converted into the benzoylacetate compound (III). This step may be carried out by first hydrolyzing the benzoate ester to form free benzoic acid and then carrying out the reaction with the half ester of malonic acid.

The hydrolysis reaction may be carried out under the conditions for ester hydrolysis which are generally performed in the art, and the conditions may be selected depending on the nature of the protecting group and the substituent at other sites present in the compound. In addition to hydrolysis, the esters may also be decomposed under hydrogenolysis conditions. The reaction can be carried out under alkaline hydrolysis conditions, and it is convenient to carry out the reaction in an aqueous alkali hydroxide solution at room temperature in a solvent which does not affect the reaction and is miscible with water. The reaction is almost always carried out under relatively mild conditions, and is usually completed within a few hours at room temperature.

After the solvent is removed, the benzoic acid derivative can be isolated by extraction under acidic conditions and purified by chromatography, recrystallization, or the like, but in many cases, the reaction with the malonic acid half ester in the subsequent step can be carried out without any special purification treatment.

The conversion to the benzoylacetic acid compound by reaction with the malonic acid half ester can be carried out according to the following procedure. The half-ester of malonic acid can be prepared from a commercially available product or a diester, and the alkyl ester is used relatively conveniently. The kind of ester may be appropriately selected depending on the protective group of the compound or the substituent at other sites. The half ester of malonic acid can be prepared by reacting the half ester with a base to form a salt and then mixing the benzoic acid derivative obtained previously.

As the base used for the preparation of the malonate, an alkanol metal is used relatively conveniently, and among them, a magnesium compound is preferable. For example, magnesium ethoxide, magnesium chloride, etc. may be used, and a commonly used sodium alkoxide compound may also be used.

The reaction may be carried out using a solvent which does not affect the reaction, and the solvent which may be used may be an anhydrous aprotic solvent. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane, tetrahydrofuran and diethyl ether, Dimethylformamide (DMF) and Dimethylsulfoxide (DMSO). In addition, alcohols corresponding to the alcohols constituting the half-esters may also be used.

The reaction of the base and the half-ester is usually carried out rapidly and can be completed within a few hours at room temperature.

The reaction of the half-ester salt with the benzoic acid derivative can be carried out by activating the benzoic acid derivative and mixing the half-ester salt.

Examples of the activating agent (method) for the benzoic acid derivative include a method using an acid chloride such as thionyl chloride, oxalyl chloride or phosphorus oxychloride, a method using a coupling reagent such as N, N' -Dicyclohexylcarbodiimide (DCC) or 1, 1-Carbonyldiimidazole (CDI), an azide method, a mixed acid anhydride method and an active ester method. Any one of these may be selected, or the selection may be made based on the knowledge known in the art, depending on the kind and properties of the substituent or the protecting group and the like present in the compound used for the reaction.

The reaction with the half-ester salt may be carried out in the presence of a solvent which does not affect the reaction, and the solvent which may be used may be an anhydrous aprotic solvent. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane, tetrahydrofuran and diethyl ether, Dimethylformamide (DMF) and Dimethylsulfoxide (DMSO).

The reaction temperature is a temperature in the range of ice-cold to 200 ℃, preferably in the range of ice-cold to 100 ℃. The mixing of the half-ester salt and the activated benzoic acid derivative may be carried out under ice-cooling. After mixing, the reaction can be carried out at a temperature ranging from room temperature to 200 ℃, preferably from room temperature to 100 ℃, more preferably at room temperature.

[ step c ] ring closure reaction of the compound (III); compound (IV)

The 1, 4-dihydro-4-oxoquinoline-3-carboxylate compound (IV) can be formed by reacting the benzoylacetate compound (III) with N, N-dialkylcarbaldehyde dialkyl acetal, and then reacting with fluorocyclopropylamine followed by ring closure.

Among the N, N-dialkylformaldehydedialkylacetal compounds, those in which each alkyl group is a lower alkyl group having 1 to 6 carbon atoms, for example, N, N-dimethylformaldehydedimethylacetal, are used relatively conveniently. The reaction of the compound with the benzoylacetate derivative may be carried out in a suitable solvent.

Examples of the solvent used herein include ethers such as diethyl ether, dioxane, tetrahydrofuran, monoglyme, and diglyme, aromatic hydrocarbons such as benzene, toluene, and xylene, aliphatic hydrocarbons such as n-hexane, heptane, and cyclohexane, and aprotic polar solvents such as DMF, DMSO, and HMPA. In addition to these solvents, lower alkyl anhydrides such as acetic anhydride can also be used.

The reaction temperature is usually 0 to 200 ℃, preferably about 0 to 150 ℃, and the reaction time is usually about 0.5 to 10 hours.

The N, N-dialkylformal dialkyl acetal is used in an amount generally in an equimolar to large excess, preferably in an equimolar to 2-fold molar amount, relative to the benzoylacetic acid compound.

The reaction with fluorocyclopropylamine as the subsequent step may be carried out in a suitable solvent.

The solvent used herein may be any solvent as long as it does not affect the reaction, and examples thereof include alcohols such as methanol, ethanol and propanol, ethers such as diethyl ether, dioxane, tetrahydrofuran, monoglyme and diglyme, aromatic hydrocarbons such as benzene, toluene and xylene, aliphatic hydrocarbons such as n-hexane, heptane, cyclohexane and petroleum ether, halogenated hydrocarbons such as chloroform, dichloromethane and carbon tetrachloride, aprotic polar solvents such as DMF, DMSO and HMPA. The reaction temperature is usually 0 to 150 ℃, preferably around room temperature to 100 ℃, and the reaction is generally carried out for about 0.5 to 15 hours.

The amine compound is used in an amount of at least equimolar, preferably equimolar to 2-fold molar amount, relative to the quinolinone compound.

A basic compound may be added to the reaction as required. Examples of the basic compound to be used include inorganic bases such as metallic sodium, metallic potassium, metallic magnesium, sodium hydride, sodium amide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and sodium hydrogen carbonate, metal alkoxides such as sodium methoxide and sodium ethoxide, organic bases such as heterocyclic compounds (pyridine, piperidine, quinoline and N-methylmorpholine), trialkylamines (triethylamine and methyldiisopropylamine), and arylamines (N, N-dimethylaniline). When fluorocyclopropylamine is used as a salt, the base exemplified above is further added in an amount necessary to convert the amine salt into a free amine.

The cyclization reaction to convert into a quinolinone compound can be carried out in an appropriate solvent in the presence of a basic compound.

The solvent used herein may be any solvent as long as it does not affect the reaction, and examples thereof include ethers such as diethyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether and diethylene glycol dimethyl ether, aliphatic hydrocarbons such as n-hexane, heptane and petroleum ether, halogenated hydrocarbons such as chloroform, dichloromethane and carbon tetrachloride, and aprotic polar solvents such as DMF, DMSO and HMPA.

Examples of the basic compound to be used include inorganic bases such as sodium metal, potassium metal, sodium hydride, sodium amide, sodium hydroxide and potassium hydroxide, metal alkoxides such as sodium methoxide and sodium ethoxide, and organic bases such as 1, 8-diazabicyclo [5.4.0] undecene-7 (DBU), N-benzyltrimethylammonium hydroxide and tetrabutylammonium hydroxide.

The reaction temperature is usually 0 to 150 ℃, preferably around room temperature to 120 ℃, and the reaction is generally carried out for about 0.5 to 5 hours.

The basic compound is usually used in an amount of at least equimolar, preferably equimolar to 2-fold molar amount.

[ step d ] hydrolysis of Compound (IV); compound No. 3

The hydrolysis reaction for converting the 1, 4-dihydro-4-oxoquinoline-3-carboxylic acid ester compound (IV) into a carboxylic acid compound can be carried out under ordinary hydrolysis reaction conditions, and specifically, the reaction can be carried out in the presence of a basic compound such as sodium hydroxide, potassium hydroxide, barium hydroxide, or potassium carbonate, an inorganic acid such as sulfuric acid, hydrochloric acid, or nitric acid, an organic acid such as acetic acid, an alkylsulfonic acid, or an aromatic sulfonic acid, in water, an alcohol such as methanol, ethanol, or isopropyl alcohol, a ketone such as acetone or methyl ethyl ketone, an ether such as dioxane or ethylene glycol, a solvent such as acetic acid, or a mixed solvent thereof.

The reaction is usually carried out at room temperature to 200 ℃, preferably around room temperature to 150 ℃, and the reaction time is usually about 0.5 to 30 hours.

The former method is explained below.

The method of introducing the pyrrolidine substituent moiety into a benzoic acid derivative to which no pyrrolidine substituent has been introduced and then ring-closing quinolinone (the latter method) is carried out, in which a quinolinone skeleton is first constructed to obtain 7-halo-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid, and then a pyrrolidine substituent is introduced into the compound. Alternatively, the malonic acid compound may be reacted with the benzoic acid derivative first, and then the pyrrolidine compound may be reacted with the benzoylacetate compound produced by the above reaction.

[ step e ] introduction of a pyrrolidine substituent; compound No. 3

This step is a method of reacting a pyrrolidine compound with 7-halo-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid or a compound (boron chelate) in which the carboxyl moiety thereof is formed into a disubstituted boroxycarbonyl structure in order to introduce a substituent.

In the reaction of the 7-halo-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid or the boron chelate compound with the pyrrolidine compound, the ratio of the use of both is not particularly limited and may be appropriately selected from a wide range, and usually the amount of the pyrrolidine compound to be used is at least about equimolar, preferably about equimolar to 5-fold molar relative to the former.

The reaction can be carried out in a solvent which does not affect the reaction, for example, alcohols such as water, methanol, ethanol, isopropanol, butanol, pentanol, and isopentanol, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as tetrahydrofuran, dioxane, and diglyme, aprotic (polar) solvents such as dimethylacetamide, DMF, DMSO, HMPA, and N-methylpyrrolidone, or a mixed solvent thereof. Among them, DMF, DMSO, HPMA and N-methylpyrrolidone are preferable.

The reaction may be carried out in the presence of a deacidification agent, specifically, inorganic carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate, organic bases such as pyridine, quinoline and triethylamine, and the like. Further, an alkali metal halide such as potassium fluoride may be added.

The reaction is usually carried out under a pressure of 1 to 20 atmospheres, preferably 1 to 10 atmospheres, at a temperature of about room temperature to 250 ℃, preferably about room temperature to 200 ℃, and the reaction is usually carried out for about 0.5 to 30 hours.

When the carboxylic acid moiety is formed into a boron-containing structure, the chelate compound may be decomposed by treatment with an acid or a basic compound to form a corresponding carboxylic acid compound. Examples of the acid used herein include inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as acetic acid and p-toluenesulfonic acid. Examples of the basic compound include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, potassium hydrogencarbonate and potassium carbonate, and organic bases such as triethylamine. The reaction can be carried out at a temperature of 0 to 150 ℃ and preferably at a temperature of about 0 to 100 ℃. The amount of the acid or basic compound to be used is usually at least about equimolar, preferably 1 to 10 times the molar amount of the raw material compound.

Examples of the compound (boron chelate compound) having a disubstituted boroxycarbonyl structure may include boron dihalide or dialkanoyloxyboron, the dihalo compound is preferably boron difluoride, and the dialkanoyloxyboron may be diacetoxyboron. The most convenient of these is boron difluoride.

The boron difluoride oxy compound (boron difluoride chelate compound) can be obtained by the reaction of a carboxylic acid compound with various ether complexes of boron trifluoride, such as an ether complex, a tetrahydrofuran complex, and the like, and also can be obtained by treatment with tetrafluoroboric acid.

The boron chelate moiety must be cleaved at any stage to regenerate the carboxyl group, and therefore, can be cleaved by hydrolysis reaction under alkaline or acidic conditions, and this step can be carried out according to a known method.

The compound (1) of the present invention has a strong antibacterial activity and high safety, can reduce cardiotoxicity, and has no side effects, and therefore, can be used as a pharmaceutical product for humans, animals, fishes, etc., or a preservative for agricultural chemicals and foods. When the compound (1) of the present invention is used as a pharmaceutical, the dose varies depending on the age, sex, symptoms and the like of a patient, and is 50mg to 1g, preferably 100mg to 500mg, per 1 day for an adult. The dose to be administered to an animal varies depending on the purpose of administration, the size of the animal to be treated, and the type and degree of the pathogenic bacteria to be infected, and the dose for 1 day is generally 1mg to 200mg, preferably 5mg to 100mg, based on 1kg of the animal body weight. The 1-day dose can be administered 1 time or 2-4 times per day. The amount of 1 day may be more than the above amount as required.

The compound (1) of the present invention has excellent antibacterial activity against a wide range of microorganisms causing various infectious diseases, and can treat, prevent or alleviate diseases caused by these pathogens. Examples of microorganisms of bacteria and the like useful as the compound (1) of the present invention include Staphylococcus, Streptococcus pyogenes, Streptococcus hemolyticus, enterococcus, pneumococcus, Peptostreptococcus, Escherichia coli, Citrobacter, Shigella, Klebsiella, Enterobacter cloacae, Serratia, Proteus, Pseudomonas aeruginosa, Haemophilus influenzae, Acinetobacter, Campylobacter, and Chlamydia trachomatis.

Examples of the diseases caused by these pathogens include folliculitis, furuncle, carbuncle, erysipelas, cellulitis, lymphangitis, herpes, subcutaneous abscess, hidradenitis, polymeric hemorrhoid, infectious porridge, perianal abscess, mastitis, surface secondary infection due to trauma, burn, surgical wound, etc., pharyngolaryngitis, acute bronchitis, tonsillitis, chronic bronchitis, bronchiectasis, diffuse panbronchiolitis, secondary infection due to chronic respiratory disease, pneumonia, nephropyelitis, cystitis, prostatitis, epididymitis, gonococcal urethritis, non-gonococcal urethritis, cholecystitis, cholangitis, bacillary dysentery, enteritis, adnexitis, intrauterine infection, bartholinitis, blepharitis, hordeolum, dacryocystitis, blepharitis, corneal ulcer, otitis media, paranasal sinusitis, periodontitis, maxingitis, maxillonitis, lymphadenitis, and other diseases, Peritonitis, endocarditis, septicemia, meningitis, skin infections, and the like.

Further, as the acid-fast bacteria effective for the compound (1) of the present invention, Mycobacterium tuberculosis (Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium africanum), atypical acid-fast bacteria (Mycobacterium kansasii, Mycobacterium marinum, Mycobacterium scrofulae, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium bufonis, Mycobacterium fortuitum, Mycobacterium chelonii) and the like can be exemplified. The acid-fast bacteria infections caused by these pathogens are roughly classified into 3 types, i.e., tuberculosis, atypical acid-fast bacteria, and barbadosnut, according to the bacteria causing the infections. Mycobacterium tuberculosis infection is found in the thoracic cavity, trachea, bronchi, lymph nodes, systemic dispersibility, bone joints, meninges, brain, digestive organs (intestine, liver), skin, mammary gland, eye, middle ear, throat, urinary tract, male genitalia, female genitalia, and the like, in addition to the lung. The major organ of atypical antacid (nontuberculous mycobacteria) is the lung, and other organs include regional lymphadenitis, soft tissues of the skin, bone joints, and systemic scatter type.

In addition, the composition is effective for various microorganisms causing animal infectious diseases, such as microorganisms belonging to the genus Escherichia, Salmonella, Pasteurella, Haemophilus, Bordetella, Staphylococcus, and Mycoplasma. Specific diseases include colibacillosis, pullorum disease, paratyphoid disease of fowl, fowl cholera, infectious rhinitis, staphylococcal disease, mycoplasma infection, etc. in poultry, salmonellosis, pasteurellosis, haemophilus infection, atrophic rhinitis, exudative dermatitis of piglets, mycoplasma infection, etc. in cattle, colibacillosis, salmonellosis, hemorrhagic septicemia, mycoplasma infection, bovine pleuropneumonia, mastitis, etc. in dogs, colibacillosis, salmonellosis, hemorrhagic septicemia, pyometra, cystitis, etc. in cats, exudative pleurisy, cystitis, chronic, haemophilus infection, diarrhea in kittens, mycoplasma infection, etc.

The pharmaceutical product of the present invention contains the compound (1), a salt or a hydrate thereof of the present invention as an active ingredient, and the administration form is not particularly limited, and may be appropriately selected, and examples thereof include solid and liquid preparations for oral use such as tablets, powders, granules, capsules, solutions, syrups, elixirs, oily or aqueous suspensions, non-oral preparations such as injections and suppositories, external preparations, eye drops, patches and the like. These administration forms can be prepared by incorporating a pharmaceutically acceptable carrier into the preparation of various preparations in a usual manner.

As an injection, a stabilizer, a preservative, a solubilizer, or the like may be used in the preparation, and a solution containing these adjuvants may be put into a container and freeze-dried to form a solid preparation, which is then prepared at the time of use. Further, the single dose may be contained in a container, or the multiple doses may be contained in one container.

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

The solid preparation may contain the compound (1) and a pharmaceutically acceptable carrier, and examples of the carrier include fillers, extenders, binders, disintegrants, dissolution promoters, wetting agents, and lubricants. The liquid preparation may, for example, be a solution, suspension, emulsion, etc., and may contain a suspending agent, an emulsifier, etc. as an additive.

Examples of the method of administering the compound (1) of the present invention to animals include a method of directly orally administering the compound or orally administering the compound to animals in feed, a method of directly orally administering the compound after forming a solution, a method of orally administering the compound to animals in drinking water or feed, and a method of administering the compound by injection.

Formulation examples are shown below.

Formulation example 1 [ capsule ]:

example 1 Compound 100.0mg

Corn starch 23.0mg

CMC calcium 22.5mg

Hydroxymethyl cellulose 3.0mg

Magnesium stearate 1.5mg

A total of 150.0mg

Formulation example 2 [ solution formulation ]:

1-10 g of the Compound of example 1

Acetic acid or sodium hydroxide 0.5-2 g

0.1mg of ethyl p-hydroxybenzoate

88.9-98.4 g of refined water

A total of 100.0g

Formulation example 3 [ powder for feed mixing ]:

1-10 g of the Compound of example 1

Corn starch 98.5-89.5 g

Light silicic anhydride 0.5g

A total of 100.0g

Examples

The present invention will be described in more detail with reference to the following examples and examples, but the present invention is not limited thereto.

[ example 1]

7- [ (3S, 4S) -3-amino-4-fluoromethyl-1-pyrrolidinyl ] -1-cyclopropyl-6-fluoro-1, 4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (Compound No. 1)

1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid boron difluoride complex (654mg, 2mmol), (3S, 4S) -3-amino-4-fluoromethylpyrrolidine dihydrochloride (764mg, 4mmol) was dissolved in anhydrous dimethylsulfoxide (10ml), triethylamine (2.23ml, 16mmol) was added, and the mixture was stirred at 50 ℃ for 24 hours under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, and 90% ethanol (10ml) and triethylamine (0.5ml) were added to the residue, followed by heating and refluxing for 3 hours, and then the solvent was distilled off under reduced pressure. Concentrated hydrochloric acid (6ml) was added under ice cooling, stirred for 30 minutes and washed 3 times with chloroform. Under ice-cooling, a saturated aqueous sodium hydroxide solution was added to the obtained aqueous layer to adjust the pH to 12, and the mixture was stirred for 1 hour. Then, dilute hydrochloric acid aqueous solution was added thereto to adjust the pH to 7.4, and the mixture was stirred for 12 hours. Extracted with chloroform and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting concentrated residue was recrystallized from a mixed solvent of ether/2-propanol and dried under reduced pressure at 50 ℃ for 14 hours to obtain 274mg (0.72mmol, 36%) of the title compound as white crystals.

¹H-NMR(400MHz，DMSO-d₆)δ：0.82-0.97(2H，m)，1.02-1.03(1H，m)，1.15-1.23(2H，m)，2.49(3H，s)，2.59-2.66(1H，m)，2.75-2.76(1H，m)，3.18-3.30(2H，m)，3.46-3.53(1H，m)，3.60-3.66(2H，m)，3.82-3.85(1H，m)，4.28-4.32(1H，m)，4.52-4.84(2H，m)，7.69(1H，d，J＝13.69Hz)，8.76(1H，s).

Melting point: 160 ℃ 165 ℃ (diethyl ether/2-propanol)

Elemental analysis value: c₁₉H₂₁F₂N₃O₃·0.25H₂O

Theoretical value: c, 59.76%; h, 5.67%; n, 11.00 percent.

Measured value: c, 59.86%; h, 5.63%; n, 10.99%

[ example 2]

7- [ (3S, 4S) -3-amino-4-fluoromethyl-1-pyrrolidinyl ] -1-cyclopropyl-1, 4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (Compound No. 2)

1-cyclopropyl-7-fluoro-1, 4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid boron difluoride complex (618mg, 2mmol), (3S, 4S) -3-amino-4-fluoromethylpyrrolidine dihydrochloride (764mg, 4mmol) was dissolved in anhydrous dimethylsulfoxide (10ml), triethylamine (2.23ml, 16mmol) was added, and the mixture was stirred at 50 ℃ for 13 hours under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, and 90% ethanol (10ml) and triethylamine (0.5ml) were added to the residue, followed by heating and refluxing for 2.5 hours, and then the solvent was distilled off under reduced pressure. Concentrated hydrochloric acid (6ml) was added under ice cooling, stirred for 15 minutes and washed 3 times with chloroform. Under ice-cooling, a saturated aqueous sodium hydroxide solution was added to the obtained aqueous layer to adjust the pH to 12, and the mixture was stirred for 1 hour. Then, dilute hydrochloric acid aqueous solution was added thereto to adjust the pH to 7.4, and the mixture was stirred for 1 hour. Extracted with chloroform and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting concentrated residue was recrystallized and purified from a mixed solvent of ether/2-propanol, and dried under reduced pressure at 70 ℃ for 14 hours to obtain 490mg (1.35mmol, 67%) of the title compound as yellow crystals.

¹H-NMR(400MHz，DMSO-d₆)δ：0.82-0.93(2H，m)，1.02-1.03(1H，m)，1.18-1.22(2H，m)，2.49(3H，s)，2.61-2.66(1H，m)，3.13-3.15(1H，m)，3.28-3.40(2H，m)，3.54-3.59(1H，m)，3.63-3.66(1H，m)，3.70-3.74(1H，m)，4.27(1H，m)，4.52-4.84(2H，m)，7.08(1H，d，J＝9.05Hz)，7.98(1H，d，J＝9.05Hz)，8.73(1H，s).

Melting point: 203-

Elemental analysis value: c₁₉H₂₂FN₃O₃·0.25H₂O

Theoretical value: c, 62.71%; h, 6.23%; and N, 11.55 percent.

Measured value: c, 62.59%; h, 6.16%; n, 11.44 percent.

[ example 3]

7- [ (3S, 4S) -3-amino-4-fluoromethyl-1-pyrrolidinyl ] -6-fluoro-1- [ (2S, 1R) -2-fluorocyclopropyl ] -1, 4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (Compound No. 3)

To a solution of 6, 7-difluoro-1- [ (2S, 1R) -2-fluorocyclopropyl ] -1, 4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid boron difluoride complex (2.23g, 6.46mmol) in dimethyl sulfoxide (11ml) were added 3- (S) -tert-butoxycarbonylamino-4- (S) -fluoromethylpyrrolidine (1.67g, 7.65mmol) and triethylamine (2.16ml, 15.5mmol), and the mixture was stirred at 35 to 40 ℃ for 7 days. After the reaction mixture was concentrated under reduced pressure, the residue was dissolved in a mixed solution (150ml) of ethanol and water (9: 1), and triethylamine (5ml) was added thereto, followed by reflux under heating for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (100 ml. times.2), which was washed with water (50 ml. times.3) and saturated brine (50 ml). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in concentrated hydrochloric acid (20ml) under ice cooling, and the aqueous solution was washed with chloroform (50 ml. times.3). The pH of the aqueous layer was adjusted to 12.0 by adding 10mol/l aqueous sodium hydroxide solution, the pH of the basic aqueous solution was adjusted to 7.4 by using hydrochloric acid, and the mixture was extracted with chloroform (100ml × 2) and a 9: 1 chloroform-methanol mixed solution (100ml × 5). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative chromatography, then recrystallized from ethanol and purified by drying under reduced pressure, to obtain 175mg (7%) of the title compound as pale yellow crystals.

¹H-NMR(400MHz，0.1N-NaOD)δ：1.19-1.31(1H，m)，1.56-1.66(1H，m)，2.50(3H，s)，2.75-2.85(1H，m)，3.17-3.21(1H，m)，3.41(1H，t，J＝8.8Hz)，3.61-3.72(2H，m)，3.95-4.11(2H，m)，4.79-4.88(3H，m)，7.68(1H，d，J＝14.2Hz)，8.46(1H，s).

IR(ATR)3404，3336，3076，2879，1707，1618，1514，1468，1437，1398，1363，1309，1236cm^-1

Melting point: 214 ℃ 216 ℃ (decomposition)

Elemental analysis value: c₁₉H₂₀F₃N₃O₃·0.25H₂O

Theoretical value: c, 57.07%; h, 5.17%; f, 14.25%; n, 10.51%

Measured value: c, 56.92%; h, 5.07 percent; f, 14.17%; n, 10.41%

[ example 4]

7- [ (3S, 4S) -3-fluoromethyl-4-methylaminopyrrolidin-1-yl ] -6-fluoro-1- [ (2S, 1R) -2-fluorocyclopropyl ] -1, 4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (Compound No. 4)

Triethylamine (2.22ml, 17.4mmol) and a 6, 7-difluoro-1- [ (1R, 2S) -2-fluorocyclopropyl ] -8-methyl-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid boron difluoride complex (4.59g, 13.3mmol) were added to a solution of (3S, 4S) -3- (N-tert-butoxycarbonyl-N-methyl) amino-4-fluoromethylpyrrolidine (8.62g, 37.1mmol) in sulfolane (45ml), and the mixture was stirred at 35 to 39 ℃ for 4 days. To the reaction mixture were added a 5: 1 ethanol/water mixed solution (240ml) and triethylamine (5ml), and the mixture was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (400ml), which was washed with 100% aqueous citric acid (100ml), water (100 ml. times.3) and saturated brine (100 ml). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by short silica gel column chromatography (chloroform-methanol, 49: 1 → 9: 1). The purified product was dissolved in concentrated hydrochloric acid (20ml) under ice cooling, and then stirred at room temperature for 30 minutes, and the reaction mixture was washed with chloroform (100 ml. times.6). The pH was adjusted to 12.0 by adding 10mol/l aqueous sodium hydroxide solution to the aqueous layer under ice cooling, to 7.4 by adding hydrochloric acid, and then extracted with chloroform (200 ml. times.4). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by recrystallization from ethanol (using activated carbon), and dried under reduced pressure to obtain 1.39g (26%) of the title compound as pale yellow crystals.

Melting point: 173 ℃ and 175 ℃.

¹H-NMR(400MHz，0.1N-NaOD)δ：1.26-1.38(1H，m)，1.58-1.69(1H，m)，2.36(3H，s)，2.54(3H，s)，2.82-2.93(1H，m)，3.41(1H，q，J＝5.0Hz)，3.49(1H，q，J＝5.8Hz)，3.58(2H，d，J＝6.9Hz)，3.79(1H，ddd，J＝9.6，6.1，1.5Hz)，4.12(1H，dt，J＝8.6，5.4Hz)，4.72-4.80(2H，m)，5.00(1H，d，J＝65.0Hz)，7.70(1H，d，J＝14.0Hz)，8.48(1H，d，J＝2.7Hz).

Elemental analysis value: c₂₀H₂₂F₃N₃O₃·0.25H₂O

Calculated values: c, 58.04; h, 5.48; f, 13.77; n, 10.15.

Measured value: c, 58.25; h, 5.52; f, 13.76; and N, 10.03.

IR(ATR)：3329，2945，2893，1726，1610，1547，1502，1429，1354，1315，1263，1221cm^-1.

[ example 5]

1-cyclopropyl-6-fluoro-7- [ (3S, 4S) -3-fluoromethyl-4-methylaminopyrrolidin-1-yl ] -8-methyl-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid (Compound No. 5)

Triethylamine (293. mu.l, 2.10mmol) and a 1-cyclopropyl-6, 7-difluoro-8-methyl-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid boron difluoride complex (458mg, 1.40mmol) were added to a solution of (3S, 4S) -3- (N-tert-butoxycarbonyl-N-methyl) amino-4-fluoromethylpyrrolidine (651mg, 2.80mmol) in sulfolane (3.5ml), and the mixture was stirred at 31 to 35 ℃ for 6 days. Cold water (200ml) was added to the reaction mixture, and the precipitated solid was collected by filtration and washed with water. To the solid were added a 10: 1 mixed solution (165ml) of ethanol and water and triethylamine (3ml), and the mixture was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (400ml), which was washed with 10% aqueous citric acid (100ml), water (100 ml. times.2) and saturated brine (100 ml). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in concentrated hydrochloric acid (5ml) under ice cooling, and then stirred at room temperature for 30 minutes, and the reaction solution was washed with chloroform (100 ml. times.3). The pH was adjusted to 12.0 by adding 10mol/l aqueous sodium hydroxide solution to the aqueous layer under ice cooling, to 7.4 by adding hydrochloric acid, and then extracted with chloroform (200 ml. times.4). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by recrystallization from ethanol and dried under reduced pressure to obtain 161mg (29%) of the title compound as pale yellow crystals.

Melting point: 156 and 158 ℃.

¹H-NMR(400MHz，0.1N-NaOD)δ：0.75-0.88(2H，m)，1.11-1.22(2H，m)，2.37(3H，s)，2.55(3H，s)，2.79-2.91(1H，m)，3.47(3H，dq，J＝21.4，5.1Hz)，3.61-3.67(1H，m)，3.73(1H，t，J＝8.5Hz)，4.09-4.15(1H，m)，4.59-4.77(2H，m)，7.66(1H，d，J＝14.0Hz)，8.57(1H，s).

Elemental analysis value: c₂₀H₂₃F₂N₃O₃

Calculated values: c, 61.37; h, 5.92; f, 9.71; n, 10.74.

Measured value: c, 61.18; h, 6.06; f, 9.85; n, 10.68.

IR(ATR)：2889，1720，1614，1545，1504，1452，1429，1360，1313，1259，1227cm^-1.

[ example 6]

7- [ (3S, 4S) -3-amino-4-difluoromethylpyrrolidin-1-yl ] -6-fluoro-1- [ (1R, 2S) -2-fluorocyclopropyl ] -8-methyl-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid (Compound No. 6)

To a solution of (3S, 4S) -3- (tert-butoxycarbonyl) amino-4-difluoromethylpyrrolidine (501mg, 2.12 mmol) in sulfolane (2.5ml) were added triethylamine (197. mu.l, 1.41mmol) and 6, 7-difluoro-1- [ (1R, 2S) -2-fluorocyclopropyl ] -8-methyl-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid boron difluoride complex (406mg, 1.18mmol), and the mixture was stirred at room temperature for 5 days and at 35 ℃ for 7 days. Cold water (100ml) was added to the reaction mixture, and the precipitated solid was collected by filtration and washed with water. To the solid were added a 9: 1 ethanol/water mixed solution (100ml) and triethylamine (1ml), and the mixture was refluxed for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (300ml), which was washed with 10% aqueous citric acid (100ml), water (100 ml. times.3) and saturated brine (100 ml). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in concentrated hydrochloric acid (5ml) under ice cooling, and then stirred at room temperature for 30 minutes, and the reaction solution was washed with chloroform (50 ml. times.3). The pH was adjusted to 12.0 by adding 10mol/l aqueous sodium hydroxide solution to the aqueous layer under ice cooling, to 7.4 by adding hydrochloric acid, and then extracted with chloroform (150 ml. times.4). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by preparative gel thin layer chromatography (developed in the lower layer of chloroform-methanol-water 7: 3: 1), recrystallized from ethanol-ether and dried under reduced pressure to obtain 85mg (17%) of the title compound as pale yellow crystals.

Melting point: 214 ℃ and 216 ℃.

¹H-NMR(400MHz，0.1N-NaOD)δ：1.28(1H，d，J＝27.3Hz)，1.57-1.68(1H，m)，2.56(3H，s)，2.92(1H，brs)，3.22(1H，d，J＝10.7Hz)，3.45(1H，t，J＝9.0Hz)，3.81(1H，brs)，3.90(1H，t，J＝9.5Hz)，3.98-4.03(1H，m)，4.08-4.15(1H，m)，5.02(1H，d，J＝66.4Hz)，6.22(1H，td，J＝55.7，6.3Hz)，7.72(1H，d，J＝13.9Hz)，8.47(1H，d，J＝3.2Hz).

Elemental analysis value: c₁₉H₁₉F₄N₃O₃·0.25H₂O

Calculated values: c, 54.61; h, 4.70; f, 18.19; n, 10.06.

Measured value: c, 54.37; h, 4.51; f, 17.71; and N, 10.02.

IR(ATR)：3408，3336，3072，3030，2947，2891，1711，1618，1514，1468，1439，1402，1352，1306，1232cm^-1.

[ reference example 1]

4- [ (3S, 4S) -3-tert-Butoxycarbonylamino-4-fluoromethyl-1-pyrrolidinyl ] -2, 5-difluoro-3-methylbenzoic acid ethyl ester

To a solution of ethyl 2, 4, 5-trifluoro-3-methylbenzoate (1.12g, 5.14mmol) in dimethylsulfoxide (5ml) were added 3- (S) -tert-butoxycarbonylamino-4- (S) -fluoromethylpyrrolidine (0.751g, 3.44mmol), 1, 8-diazabicyclo [5.4.0] -7-undecene (0.695ml, 5.14mmol), and the mixture was stirred at 60 to 65 ℃ for 20 hours. After cooling to room temperature, the reaction mixture was dissolved in ethyl acetate (50 ml. times.2), which was washed with 10% aqueous citric acid (50ml), water (50 ml. times.2) and saturated brine (50 ml). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography to obtain 725mg (51%) of the title compound as a colorless oil from an eluted fraction of n-hexane: ethyl acetate 3: 1.

¹H-NMR(400MHz，CDCl₃)δ：1.38(3H，t，J＝7.1Hz)，1.46(9H，s)，2.22(3H，d，J＝2.9Hz)，2.73-2.88(1H，m)，3.14-3.18(1H，m)，3.35-3.50(2H，m)，3.70(1H，ddd，J＝9.7，6.0，1.9Hz)，4.36(2H，q，J＝7.1Hz)，4.47-4.77(3H，m)，4.92-4.89(1H，m)，7.44(1H，dd，J＝12.7，6.8Hz).

[ reference example 2]

4- [ (3S, 4S) -3-tert-Butoxycarbonylamino-4-fluoromethyl-1-pyrrolidinyl ] -2, 5-difluoro-3-methylbenzoyl acetic acid ethyl ester

To a solution of ethyl 4- [ (3S, 4S) -3-tert-butoxycarbonylamino-4-fluoromethyl-1-pyrrolidinyl ] -2, 5-difluoro-3-methylbenzoate (720mg, 1.73mmol) in ethanol (10ml) was added 3mol/l aqueous potassium hydroxide solution (2.31ml), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added with 10% citric acid aqueous solution (10ml) and water (10ml) to adjust the pH to 2 to 3, and the mixture was concentrated under reduced pressure with ethanol, extracted with chloroform (30X 2ml), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give 4- [ (3S, 4S) -3-tert-butoxycarbonylamino-4-fluoromethyl-1-pyrrolidinyl ] -2, 5-difluoro-3-methylbenzoic acid (718mg, 1.73mmol) as a yellow oil.

Monoethyl malonate (459mg, 3.48mmol) was dissolved in anhydrous tetrahydrofuran (5ml), and magnesium ethoxide (370mg, 3.23mmol) was added under ice-cooling and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to prepare a magnesium salt of monoethyl malonate. Then, 4- [ (3S, 4S) -3-tert-butoxycarbonylamino-4-fluoromethyl-1-pyrrolidinyl ] -2, 5-difluoro-3-methylbenzoic acid (718mg, 1.73mmol) was dissolved in anhydrous tetrahydrofuran (10ml), and 1, 1-carbonyldiimidazole (365mg, 2.25mmol) was added under ice cooling and stirred at room temperature for 2 hours. A solution of magnesium salt of monoethyl malonate dissolved in anhydrous tetrahydrofuran (5ml) prepared in advance was added dropwise thereto under ice cooling. After completion of the dropwise addition, the temperature was slowly returned to room temperature, and the mixture was stirred for 16 hours. Toluene (10ml) and a 10% aqueous citric acid solution (10ml) were added to the reaction mixture under ice cooling to make the reaction mixture acidic (pH 2-3), followed by stirring at room temperature for 1 hour. The organic layer was extracted, which was washed successively with a saturated aqueous sodium hydrogencarbonate solution (10ml) and saturated brine (10ml), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography to obtain 334mg (42%) of the title compound as a pale orange oil from an eluted fraction of n-hexane/ethyl acetate 1: 1.

¹H-NMR(400MHz，CDCl₃)δ：1.25-1.35(3H，m)，1.46(9H，s)，2.22-2.22(3H，m)，2.74-2.87(1H，m)，3.82-3.12(4H，m)，3.93(2H，d，J＝3.9Hz)，4.19-4.29(2H，m)，4.76-4.48(3H，m)，4.91(1H，s)，5.84(1/3H，s)，7.46(1H，q，J＝6.7Hz)，12.67(1/3H，s).

[ reference example 3]

7- [ (3S, 4S) -3-tert-Butoxycarbonylamino-4-fluoromethyl-1-pyrrolidinyl ] -6-fluoro-1- [ (2S, 1R) -2-fluorocyclopropyl ] -1, 4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid ethyl ester

4- [ (3S, 4S) -3-tert-Butoxycarbonylamino-4-fluoromethyl-1-pyrrolidinyl ] -2, 5-difluoro-3-methylbenzoyl acetate (334mg, 0.729mmol) and N, N-dimethylformamide dimethyl acetal (0.194ml, 1.46mmol) were dissolved in benzene (6ml), and the mixture was stirred with heating in an oil bath at an external temperature of 80 ℃ for 3 hours. The reaction solution is cooled down, decompressed, concentrated and dried to be solid. The resulting yellow oil was dissolved in toluene (10ml), p-toluenesulfonate (270mg, 1.09mmol) of (1R, 2S) -2-fluorocyclopropylamine was added, and triethylamine (0.158ml, 1.13mmol) was added dropwise with stirring at-10 ℃. The reaction mixture was stirred at room temperature for 1 hour, and then water (150ml) and ethyl acetate (20X 2ml) were added thereto, followed by washing with saturated brine (15ml) and drying over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure, and drying to obtain the final product. The resulting yellow oil was dissolved in dimethylformamide (5ml), and potassium carbonate (202mg, 1.46mmol) was added under ice-cooling, followed by stirring at room temperature for 4 days. A10% citric acid aqueous solution (20ml) was gradually poured into the reaction mixture under ice cooling, and the precipitated crystals were collected by filtration. After washing the crystals with an excess of purified water, the resulting crude crystals were subjected to silica gel column chromatography to obtain 277mg (73%) of the title compound as a pale yellow powder from the eluted fraction of 95: 5 (chloroform: methanol).

¹H-NMR(400MHz，CDCl₃)δ：1.20-1.34(2H，m)，1.41(3H，t，J＝7.1Hz)，1.46(9H，s)，2.57(3H，s)，2.88(1H，s)，3.14-3.18(1H，m)，3.44-3.60(2H，m)，3.80-3.92(2H，m)，4.39(2H，q，J＝7.1Hz)，4.50-4.56(1H，m)，4.65-4.70(1H，m)，4.74-4.82(1H，m)，4.94-4.90(1H，m)，7.96(1H，d，J＝13.2Hz)，8.53(1H，d，J＝2.9Hz).

[ example 7]

7- [ (3S, 4S) -3-amino-4-fluoromethyl-1-pyrrolidinyl ] -6-fluoro-1- [ (2S, 1R) -2-fluorocyclopropyl ] -1, 4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (Compound No. 3)

To a solution of 7- [ (3S, 4S) -3-tert-butoxycarbonylamino-4-fluoromethyl-1-pyrrolidinyl ] -6-fluoro-1- [ (2S, 1R) -2-fluorocyclopropyl ] -1, 4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid in ethanol (3ml) was added 1mol/1 aqueous sodium hydroxide solution (1.06ml), and the mixture was stirred at room temperature for 5 hours. A10% citric acid aqueous solution (15ml) and water (10ml) were added to the reaction mixture to adjust the pH to 2 to 3, and the resulting mixture was filtered to collect a precipitated solid, which was then washed with water (10 ml). After the residue was dissolved in concentrated hydrochloric acid (5ml) under ice-cooling, the aqueous solution was washed with chloroform (50 ml. times.2). The pH of the aqueous layer was adjusted to 12.0 by adding 10mol/l aqueous sodium hydroxide solution (6ml), the pH of the aqueous alkaline solution was adjusted to 7.4 with hydrochloric acid, and the mixture was extracted with chloroform (100ml × 3) and a mixed solution of chloroform and methanol (9: 1) (100ml × 4). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by recrystallization from isopropanol and dried under reduced pressure to obtain 100mg (48%) of the title compound as pale yellow crystals. The 1H-NMR data of this compound agreed with Compound No. 3.

[ reference example 5]

(3S, 4S) -1- (Phenylmethoxycarbonyl) -3- (N-tert-butoxycarbonyl-N-methyl) amino-4-fluoromethylpyrrolidine

To a solution of (3S, 4S) -1- (benzyloxycarbonyl) -3- (tert-butoxycarbonyl) amino-4-fluoromethylpyrrolidine (17.2g, 48.2mmol) in N, N-dimethylformamide (170ml) was added sodium hydride (55%, 4.21g, 96.4mmol), and after stirring at 0 ℃ for 10 minutes, methyl iodide (3.30ml, 53.0mmol) was added at the same temperature and the mixture was stirred for 30 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution (500ml), which was extracted with ethyl acetate (500 ml. times.2), followed by washing with water (100 ml. times.2) and saturated brine (100 ml). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane-ethyl acetate, 4: 1 → 2: 1) to obtain 17.4g (98%) of the title compound as a colorless syrup.

¹H-NMR(400MHz，CDCl₃)δ：1.46(9H，d，J＝1.7Hz)，2.78-2.80(4H，m)，3.36-3.44(1H，m)，3.60-3.79(3H，m)，4.30-4.51(1H，m)，4.58(1H，d，J＝46.6Hz)，4.79(1H，brs)，5.11-5.20(2H，m)，7.26-7.38(5H，m).

[ reference example 6]

(3S, 4S) -3- (N-tert-Butoxycarbonyl-N-methyl) amino-4-fluoromethylpyrrolidine

(3S, 4S) -1- (benzyloxycarbonyl) -3- (N-tert-butoxycarbonyl-N-methyl) amino-4-fluoromethylpyrrolidine (15.7g, 42.8mmol) was dissolved in ethanol (300ml), and 10% palladium on carbon catalyst (M, water content 50.9%, 1.60g) was added to the solution, followed by stirring under a hydrogen stream at 40 ℃ for 2 hours. After the catalyst was filtered off (ethanol washing), the filtrate was concentrated under reduced pressure to obtain 9.50g (96%) of the title compound as an unrefined product in the form of a colorless syrup.

¹H-NMR(400MHz，CDCl₃)δ：1.47(9H，s)，2.54-2.68(1H，m)，2.85(3H，s)，2.97(1H，dd，J＝11.3，7.1Hz)，3.07(1H，dd，J＝11.5，5.6Hz)，3.16-3.23(2H，m)，4.36(1H，ddd，J＝47.6，9.3，6.4Hz)，4.48(1H，ddd，J＝46.8，9.1，5.1Hz)，4.41-4.48(1H，m).

[ test example 1]

The method for measuring the antibacterial activity of the compound of the present invention is performed according to the standard method specified by the japan chemical therapy society, and the results are shown in tables 1 and 2 below as MIC (μ g/ml). As a comparison of MIC values of the compounds of the present invention, MIC values of ofloxacin (LVFX), Ciprofloxacin (CPFX), and a comparative compound (the following compound of example 1 of patent document 1) are shown at the same time.

Comparative Compounds

From these results, it was found that the compound of the present invention has a broad spectrum of potent antibacterial activity against both gram-negative bacteria and gram-positive bacteria because it contains resistant bacteria, as compared with the known quinolinone synthetic antibacterial agents. In particular, it has a strong antibacterial activity against gram-positive bacteria such as Staphylococcus aureus (MRSA) and Streptococcus pneumoniae (PRSP).

TABLE 1

	Compound No.1	Compound No. 2	Compound No. 3	Compound No. 4
					Escherichia coli NIHJ	≤0.003	≤0.003	0.006	≤0.003
Shigella flexneri 2A 5503	≤0.003	0.006	≤0.003	0.006
					Proteus vulgaris 08601	≤0.003	0.006	≤0.003	0.006
Proteus mirabilis IFO-3849	00.012	0.05	0.006	0.025
					Serratia marcescens 10100	0.025	0.05	0.025	0.05
Pseudomonas aeruginosa 32104	0.05	0.1	0.05	0.1
					Pseudomonas aeruginosa 32121	0.025	0.025	0.025	0.05
Stenotrophomonas maltophilia IID-1275	0.1	0.2	0.1	0.1
					Staphylococcus aureus 209P	0.012	0.025	0.006	0.012
Staphylococcus epidermidis 56500	0.025	0.1	0.025	0.05
					Streptococcus pyogenes G-36	0.1	0.2	0.05	0.1
Streptococcus faecalis ATCC-19433	0.05	0.2	0.1	0.1
					Staphylococcus aureus 870307	0.2	0.78	0.39	0.39
Streptococcus pneumoniae J24	0.025	0.1	0.025	0.05

MIC value (μ g/ml)

TABLE 2

	Compound No. 5	Compound No. 6	LVFX	CPFX	Comparative Compounds
						Escherichia coli NIHJ	≤0.003	≤0.003	0.012	≤0.003	≤0.003
Shigella flexneri 2A 5503	≤0.003	≤0.003	0.025	0.006	0.006
						Proteus vulgaris 08601	0.006	0.006	0.012	≤0.003	0.012
Proteus mirabilis IFO-3849	0.025	0.012	0.05	0.012	0.025
						Serratia marcescens 10100	0.05	0.05	0.1	0.025	0.05
Pseudomonas aeruginosa 32104	0.2	0.2	0.2	0.05	0.2
						Pseudomonas aeruginosa 32121	0.05	0.05	0.1	0.025	0.05
Stenotrophomonas maltophilia IID-1275	0.05	0.05	0.39	0.78	0.2
						Staphylococcus aureus 209P	0.012	0.012	0.2	0.1	0.012
Staphylococcus epidermidis 56500	0.05	0.025	0.39	0.2	0.05
						Streptococcus pyogenes G-36	0.1	0.05	0.78	1.56	0.1
Streptococcus faecalis ATCC-19433	0.1	0.1	0.78	0.78	0.1
						Staphylococcus aureus 870307	0.39	0.2	＞6.25	＞6.25	0.2
Streptococcus pneumoniae J24	0.05	0.05	0.78	0.1	0.025

MIC value (μ g/ml)

Staphylococcus aureus 870307: ofloxacin-resistant methicillin-resistant staphylococcus aureus

Streptococcus pneumoniae J24: penicillin intermediate resistant pneumococcus

[ test example 2]

The mouse intravenous single dose toxicity test of the compounds of the present invention was performed as follows. Namely, six-week-old Slc: ddY male mice were diluted with 0.1mol/1 NaOH/physiological saline to dissolve the compound. Sterilized by filtration through a millex GS 0.22 μm filter. A single intravenous administration was carried out at a dosing rate of 10ml/kg, 0.2 ml/min. The results are shown in Table 3. The compound of example 1 of patent document 1 was used as a comparative compound in the same manner as in test example 1.

From the results, it was found that the compounds of the present invention were less acute toxic than the comparative compounds.

TABLE 3

	Compound No. 3	Compound No. 4	Comparative Compounds
				Administration of mg/kg	Number/total of deaths	Number/total of deaths	Number/total of deaths
100	0/5	0/5	1//5
				150	0/3	1/2	2/3

Claims (36)

1. A compound represented by the following formula (1), a salt or hydrate thereof,

in the formula, R¹Represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms, or a substituted carbonyl group derived from an amino acid, a dipeptide or a tripeptide, and the alkyl group may have a hydroxyl group, an amino group, a halogen atom, or an alkylthio group having 1 to 6 carbon atomsA group containing an alkoxy group having 1 to 6 carbon atoms as a substituent;

R²represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms, and the alkyl group may have a substituent selected from the group consisting of a hydroxyl group, an amino group, a halogen atom, an alkylthio group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms;

R³represents an alkyl group having 1 to 6 carbon atoms or an alkyl group substituted with a halogen having 1 to 6 carbon atoms;

R⁴represents cycloalkyl having 3 to 6 carbon atoms or cycloalkyl substituted with halogen having 3 to 6 carbon atoms;

R⁵represents a hydrogen atom, a phenyl group, an acetoxymethyl group, a trimethylacetoxymethyl group, an ethoxycarbonyl group, a choline group, a dimethylaminoethyl group, a 5-indanyl group, a phthalone 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 comprising an alkylene group having 1 to 6 carbon atoms and a phenyl group;

X¹and X²Each independently represents a hydrogen atom or a halogen atom;

x represents a hydrogen atom or a halogen atom.

2. The compound according to claim 1, a salt or hydrate thereof, wherein the compound represented by the formula (1) is a compound having a structure represented by the following formula,

in the formula, R¹、R²、R³、R⁴、R⁵、X¹、X²And X is as defined above.

3. The compound, the salt thereof, or the hydrate thereof according to claim 1 or 2, wherein X is¹And X²Is a hydrogen atom.

4. The compound, the salt thereof, or the hydrate thereof according to claim 1 or 2, wherein X is¹And X²One of them is a fluorine atom, and the other is a hydrogen atom.

5. The compound, the salt thereof, or the hydrate thereof according to any one of claims 1 to 4, wherein R is¹And R²Is a hydrogen atom.

6. The compound, the salt thereof, or the hydrate thereof according to any one of claims 1 to 4, wherein R is¹And R²One of them is a hydrogen atom, and the other is a methyl group.

7. The compound according to any one of claims 1 to 6, a salt or hydrate thereof, wherein X is a fluorine atom.

8. The compound according to any one of claims 1 to 6, a salt or hydrate thereof, wherein X is a hydrogen atom.

9. The compound, the salt thereof, or the hydrate thereof according to any one of claims 1 to 8, wherein R is³Is an alkyl group having 1 to 6 carbon atoms.

10. The compound, the salt thereof, or the hydrate thereof according to any one of claims 1 to 8, wherein R is³Is methyl.

11. The compound, the salt thereof, or the hydrate thereof according to any one of claims 1 to 10, wherein R is⁴Is cyclopropyl or 1, 2-cis-2-halogeno ringAnd (4) propyl.

12. The compound, the salt thereof, or the hydrate thereof according to any one of claims 1 to 10, wherein R is⁴Is a stereochemically specific 1, 2-cis-2-halocyclopropyl group.

13. The compound, the salt thereof, or the hydrate thereof according to any one of claims 1 to 10, wherein R is⁴Is (1R, 2S) -2-halogenocyclopropyl.

14. The compound, the salt thereof, or the hydrate thereof according to any one of claims 1 to 10, wherein R is⁴Is (1R, 2S) -2-fluorocyclopropyl.

15. The compound, the salt thereof, or the hydrate thereof according to any one of claims 1 to 14, wherein R is⁵Is a hydrogen atom.

7- [ 3-amino-4-fluoromethylpyrrolidin-1-yl ] -6-fluoro-1- [ (2S, 1R) -2-fluorocyclopropyl ] -1, 4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, a salt thereof or a hydrate thereof.

7- [ 3-fluoromethyl-4-methylaminopyrrolidin-1-yl ] -6-fluoro-1- [ (2S, 1R) -2-fluoro-1-cyclopropyl ] -1, 4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, a salt thereof or a hydrate thereof.

7- [ cis-3-amino-4-fluoromethylpyrrolidin-1-yl ] -6-fluoro-1- [ (2S, 1R) -2-fluorocyclopropyl ] -1, 4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, a salt thereof or a hydrate thereof.

7- [ cis-3-fluoromethyl-4-methylaminopyrrolidin-1-yl ] -6-fluoro-1- [ (2S, 1R) -2-fluorocyclopropyl ] -1, 4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, a salt thereof or a hydrate thereof.

20. The compound, the salt thereof, or the hydrate thereof according to any one of claims 1 to 19, wherein the compound of formula (1) is a stereochemically specific compound.

7- [ (3S, 4S) -3-amino-4-fluoromethylpyrrolidin-1-yl ] -6-fluoro-1- [ (2S, 1R) -2-fluorocyclopropyl ] -1, 4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, a salt thereof or a hydrate thereof.

7- [ (3S, 4S) -3-fluoromethyl-4-methylaminopyrrolidin-1-yl ] -6-fluoro-1- [ (2S, 1R) -2-fluorocyclopropyl ] -1, 4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, a salt thereof or a hydrate thereof.

23. A pharmaceutical agent comprising the compound according to any one of claims 1 to 22, a salt or hydrate thereof, or a hydrate of the salt as an active ingredient.

24. An antibacterial agent comprising the compound according to any one of claims 1 to 22, a salt or hydrate thereof, or a hydrate of the salt as an active ingredient.

25. A prophylactic and/or therapeutic agent for an infection, which comprises the compound according to any one of claims 1 to 22, a salt or hydrate thereof, or a hydrate of the salt as an active ingredient.

26. A pharmaceutical composition comprising the compound according to any one of claims 1 to 22, a salt or hydrate thereof, and a pharmaceutically acceptable carrier.

27. An antibacterial agent comprising the compound according to any one of claims 1 to 22, a salt or hydrate thereof, and a pharmaceutically acceptable carrier.

28. A prophylactic and/or therapeutic agent for an infectious disease, which comprises the compound according to any one of claims 1 to 22, a salt or hydrate thereof, and a pharmaceutically acceptable carrier.

29. A method for preventing and/or treating a disease, which comprises administering an effective amount of the compound according to any one of claims 1 to 22, a salt or hydrate thereof, or a hydrate of the salt.

30. A method for preventing and/or treating an infection, which comprises administering an effective amount of the compound according to any one of claims 1 to 22, a salt or hydrate thereof, or a hydrate of the salt.

31. A method for producing a pharmaceutical, which comprises incorporating the compound according to any one of claims 1 to 22, a salt thereof, or a hydrate thereof as an active ingredient.

32. A method for producing an antibacterial agent, characterized by incorporating the compound according to any one of claims 1 to 22, a salt thereof, or a hydrate thereof as an active ingredient.

33. A method for producing a prophylactic and/or therapeutic agent for an infectious disease, which comprises incorporating the compound according to any one of claims 1 to 22, a salt or hydrate thereof, or a hydrate of the salt as an active ingredient.

34. Use of the compound according to any one of claims 1 to 22, a salt or hydrate thereof, for the production of a pharmaceutical.

35. Use of the compound according to any one of claims 1 to 22, a salt or hydrate thereof, for producing an antibacterial agent.

36. Use of the compound according to any one of claims 1 to 22, a salt or hydrate thereof, for producing a prophylactic and/or therapeutic agent for an infectious disease.