MX2007008844A

MX2007008844A - Fluoroalkylpyrrolidine derivative.

Info

Publication number: MX2007008844A
Application number: MX2007008844A
Authority: MX
Inventors: Makoto Takemura; Hisashi Takahashi; Rie Miyauchi
Original assignee: Daiichi Sankyo Co Ltd
Priority date: 2005-01-21
Filing date: 2006-01-20
Publication date: 2007-10-15
Also published as: ATE493398T1

Abstract

A compound represented by the following formula (1), a salt thereof, or a hydrate of either. [Chemical formula 1] (1) [In the formula, R1 represents hydrogen, optionally substituted alkyl, or cycloalkyl or represents substituted carbonyl derived from an amino acid, dipeptide, or tripeptide; R2 represents hydrogen, optionally substituted alkyl, or cycloalkyl; R3 represents alkyl or haloalkyl; R4 represents cycloalkyl or halogenated cycloalkyl; R5 represents hydrogen, phenyl, acetoxymethyl, pivaloyloxymethyl, ethoxycarbonyl, choline, dimethylaminoethyl, 5-indanyl, phthalidyl, 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl, 3-acetoxy-2-oxobutyl, or phenylalkyl constituted of alkylene and phenyl; X1 and X2 each independently represents hydrogen or halogeno; and X represents hydrogen or halogeno.] The compound has potent antibacterial activity against a wide range of gram-positive bacteria and gram-negative bacteria and is highly safe. It is useful as a quinolone antibacterial drug and a preventive and/or therapeutic agent for infectious diseases.

Description

DERIVATIVE OF FLUOROALQUILPIRROLIDINE TECHNICAL FIELD OF THE INVENTION This invention relates to a fluoroalkylpyrrolidine derivative having excellent antibacterial activity for Gram-positive and Gram-negative bacteria, and a drug containing the same as an effective component.

TECHNICAL BACKGROUND Since the discovery of norfloxacin, synthetic quinolone antibacterial drugs have been significantly improved with respect to antibacterial and pharmacokinetic activity, and have made great progress in the use of chemotherapy for infections including systemic infections, and many compounds are in clinical use. However, bacteria with low sensitivity to synthetic quinolone antibacterial drugs have been increasingly observed in clinical fields. For example, bacteria that are resistant to drugs other than synthetic quinolone antibacterial drugs and that have low sensitivity to synthetic quinolone antibacterial drugs are on the rise, as can be seen in the case of Gram-positive bacteria, such as Gram-Cocos. -positives such as Staphylococcus aureus (MRSA) and pneumococci (PRSP) insensitive to p-lactam antibiotics and enterococci (VRE) insensitive to aminoglycoside antibacterial drugs. Therefore, there is a strong demand for a much more effective drug against Gram-positive cocci, especially from the clinical point of view. There is also a demand for the development of quinolone synthetic antibacterial drugs with improved safety, since it is known that the use of said drug in combination with non-steroidal anti-inflammatory drugs (NSAIDs) induces side effects such as seizures, central action (mild central neuropathy such such as shivering, headache and insomnia, as well as severe side effects such as seizures), phototoxicity (photosensitivity), hepatotoxicity, cardiotoxicity (abnormality observed by abnormal electrocardiogram that can induce fatal arrhythmia), and abnormal blood glucose level (See documents that are not patent 1 and 2). Meanwhile, it is known that the structure of the substituent at position 7 of the quinolone base structure has a great influence on the antibacterial activity, pharmacokinetics, and safety of the quinolone synthetic antibacterial drugs. For example, it is known that quinolone derivatives having 3-aminopyrrolidin-1-yl group as a substituent have more favorable antibacterial activity for Gram-negative and Gram-positive bacteria, compared to quinolone derivatives having piperazine derivative as the substituent (see documents that are not patent 3 and 4). In spite of the strong antibacterial activity, many of the quinolone depots having 3-aminopyrrolidin-1-yl group as the substituent have stronger cytotoxicity and micronucleus induction in erythrocyte cells and lower selective toxicity, compared to those depvados of quinolone having piperazine derivative as the substituent (see document which is not patent 4). Said quinolone derivatives also affect eukaryotic cells and therefore it is difficult for them to be used as drugs for humans and animals. Therefore, a drug designed to have an improved selective toxicity is of great need. Accordingly, there is an increasing demand for the development of a compound having strong antibacterial activity and high selective toxicity, from the clinical point of view. Patent document 1 and non-patent document 5 describe a depollution of quinolonecarboxylic acid (A) having a cis-3-amino-4- (fluoro-substituted methyl) pyrrolidin-1-yl group as a substituent on the position 7. (note that the definitions of the substituents for the formula (A) are taken from the patent document 1, and a symbol that is the same as that used in the present invention can designate a substituent different from that defined in the present invention ).

The substituent at the 8-position of the quinolone base structure (corresponding to the group R2) is limited to the halogenomethoxy group and an alkoxy group, and there is no definite indication of a quinolonecarboxylic acid derivative wherein the substituent at the 7-position of The base structure of the quinolone is a cis-3-amino-4- (fluoro-substituted methyl) pyrrolidin-1-yl group and the substituent at the 8-position is an alkyl group or a halogen-substituted alkyl group. The non-patent document 6 deciphers a quinolonecarboxylic acid derivative wherein the 7-position substituent is a cis-3-amino-4- (fluoro-substituted methyl) pyrrolidin-1-yl group, and the illustrative compounds described in FIG. they include 8-methoxyquinolone derivative (B) having cis-3-amino-4-trifluoromethylpyrrolidin-1-yl as its substituent.

However, in the compound described in the document which is not patent 6, the substituent at position 8 of the quinolone base structure is limited to methoxy group, and there is no particular indication of the quinolonecarboxylic acid derivative wherein the substituent at the 7-position of the quinolone base structure is a cis-3-amino-4- (fluoro-substituted meth) pyrrolidin-1-yl group and the substituent at the 8-position is an alkyl group or a halogen-substituted alkyl group. The document which is not patent 7 discloses a depollution of quinolonecarboxylic acid wherein the substituent in the 7-position is a cis-3-amino-4- (fluoro-substituted methyl) pyrrolidin-1-yl group, and the illustrative compounds described in they include 2-pyridone derivative (9-methyl-4H-4-oxoquinolizin-3-carboxylic acid derivative) (C) having cis-3-amino-4-trifluoromethylpyrrolidin-1-yl group as the substituent.

However, in the compound described in the document which is not patent 7, the quinolone base structure is limited to the 2-pyridone derivative (9-methyl-4H-4-oxoquinolizin-3-carboxylic acid derivative), which is different in chemical structure from the 1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid derivative within the scope of the present invention. [Patent Document 1] WO98 / 58923 [Document that is not patent 1] Hiroyuki Kobayashi Ed., "Clinical Applications of New-quinolone Agents", lyaku- Journal-Sha (2001) [Document that is not patent 2] Drugs, Vol. 62, No.1, page 13 (2002) [Document that is not patent 3] International Journal of Antimicrobial Agents, Vol. 16, page 5 (2000) [Document that is not patent 4] Journal of Antimicrobial Chemotherapy, Vol. 33, page 685 (1994) [ Document that is not patent 5] Journal Pharmaceutical Bulletin, Vol. 48 (No. 11), page 1667 (2000) [Document that is not patent 6] Bioorganic Medicinal Chemistry Letters, Vol. 8, page 2833 (1998) [Document that it is not patent 7] Bioorganic Medicinal Chemistry Letters, Vol. 8, page 1953 (1998) BRIEF DESCRIPTION OF THE INVENTION Problems to be Resolved by the Invention In view of the situation as described above, it is an object of the present invention to provide a quinolone antibacterial drug and a prophylactic and / or therapeutic drug for an infection exhibiting broad and strong antibacterial activity. both for Gram-positive and Gram-negative bacteria and which are also highly safe.

Means for solving the problems The inventors of the present invention found that the compound represented by the following formula (1) has broad and strong antibacterial activity for both Gram-positive and Gram-negative bacteria and that said compound is also highly safe in use for an antibacterial drug or a prophylactic and / or therapeutic drug for an infection. The present invention has been completed on the basis of said findings. Accordingly, this invention provides a compound represented by the following formula (1): or its salt or a hydrate thereof, wherein R 1 represents a hydrogen atom, an alkyl group containing 1 to 6 carbon atoms, a cycloalkyl group containing 3 to 6 carbon atoms, or a substituted carbonyl group derived from a amino acid, a dipeptide or a tripeptide, wherein the alkyl group is optionally substituted with a group selected from the group consisting of hydroxy group, amino group, halogen atom, alkylthio group containing 1 to 6 carbon atoms, and alkoxy group which contains 1 to 6 carbon atoms; R2 represents hydrogen atom, an alkyl group which contains 1 to 6 carbon atoms, or a cycloalkyl group containing 3 to 6 carbon atoms, wherein the alkyl group is optionally substituted with a group selected from the group consisting of hydroxy group, amino group, halogen atom, alkylthio group containing 1 to 6 carbon atoms, and alkoxy group containing 1 to 6 carbon atoms; R3 represents an alkyl group containing 1 to 6 carbon atoms or a halogen-substituted alkyl group containing 1 to 6 carbon atoms; R4 represents a cycloalkyl group containing 3 to 6 carbon atoms or a halogen-substituted cycloalkyl group containing 3 to 6 carbon atoms; R5 represents hydrogen atom, phenyl group, acetoxymethyl group, pivaloyloxymethyl group, ethoxycarbonyl group, choline group, dimethylaminoethyl group, 5-indanyl group, phthalidyl group, 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl group , 3-acetoxy-2-oxobutyl group, an alkyl group containing 1 to 6 carbon atoms, an alkoxymethyl group containing 2 to 7 carbon atoms, or an alkylphenyl group comprising an alkylene group containing 1 to 6 carbon atoms. carbon and phenyl group; X1 and X2 independently represent hydrogen atom or a halogen atom; and X represents a hydrogen atom or a halogen atom. This 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, or its salt or a hydrate thereof; and 7 - [(3S, 4S) -3-fluoromethyl-4-methylaminopyrrolidin-1-yl] -6-fluoro-1 - [(2S, 1 R) -2-fluorocyclopropyl] -1,4-dihydro-8 acid -methyl-4-oxoquinoline-3-carboxylic acid, its salt or a hydrate thereof. This invention also provides a drug containing the compound represented by the formula (1), its salt or a hydrate thereof as an effective component. This invention also provides a pharmaceutical composition containing the compound represented by the formula (1), its salt or a hydrate thereof, and a pharmaceutically acceptable carrier. This invention also provides a method for treating a disease, which comprises administering an effective amount of the compound represented by the formula (1), its salt or a hydrate thereof. This invention also provides a method for producing a drug, which comprises mixing the compound represented by the formula (1), its salt or a hydrate thereof, as an effective component in the drug. This invention also provides the use of the compound represented by the formula (1), its salt or a hydrate thereof for the production of a drug.

Advantageous Effect of the Invention The fluoroalkylpyrrolidine derivative of the present invention has excellent antibacterial activity for both Gram-positive and Gram-negative bacteria as well as safety with weak acute toxicity. Accordingly, the fluoroalkylpyrrolidine derivative of the present invention is useful as an antibacterial drug or as a prophylactic and / or therapeutic drug for an infection.

DETAILED DESCRIPTION OF THE INVENTION Next, the substituents of the compound of the present invention represented by the formula (1) are described. The substituent R1 represents a hydrogen atom, an alkyl group containing 1 to 6 carbon atoms, a cycloalkyl group containing 3 to 6 carbon atoms, or a substituted carbonyl group derived from an amino acid, a dipeptide or a tripeptide. The substituent R2 can be a hydrogen atom, an alkyl group containing 1 to 6 carbon atoms, or a cycloalkyl group containing 3 to 6 carbon atoms. When R1 or R2 is an alkyl group, it may have a substituent selected from the group consisting of hydroxy group, amino group, halogen atom, alkylthio group containing 1 to 6 carbon atoms, and alkoxy group containing 1 to 6 carbon atoms. carbon.

When R1 or R2 is an alkyl group, it may be a straight chain alkyl group such as methyl group, ethyl group, n-propyl group, n-butyl group, or n-pentyl group; or a branched alkyl group such as isopropyl group, isobutyl group, sec-butyl group, or tert-butyl group. Among these, the preferred ones are methyl group and ethyl group, and the most preferred one is methyl group. When said alkyl group has hydroxy group or amino group as its substituent, the hydroxy group or the amino group is preferably a substituent on the terminal carbon atom of the alkyl group. The alkyl group in the alkyl group having the hydroxy group is preferably an alkyl group containing up to 3 carbon atoms, and preferred illustrative alkyl groups having the hydroxy group include hydroxymethyl group, 2-hydroxyethyl group, 2-hydroxypropyl group, and 3-hydroxypropyl group. The alkyl group in the alkyl group having the amino group is preferably an alkyl group containing up to 3 carbon atoms, and preferred illustrative alkyl groups having the amino group include aminomethyl group, 2-aminoethyl group, 2-aminopropyl group, and 3-aminopropyl group. When said alkyl group has a halogen atom as its substituent, the alkyl group can be a straight or branched chain alkyl group containing 1 to 6 carbon atoms. Illustrative halogen atoms include fluorine atom, chlorine atom and iodine atom, and fluorine atom is preferred. The alkyl group may be mono-, di-, or trisubstituted by fluorine atoms, and examples include monofluoromethyl group, difluoromethyl group, trifluoromethyl group and 2,2,2-trifluoroethyl group.

When said alkyl group has an alkylthio group or an alkoxy group as its substituent, the alkyl group may be a straight or branched chain alkyl group containing 1 to 6 carbon atoms, and the alkyl portion in the alkylthio group or the alkoxy group it can also be a straight chain or a branched portion. The alkyl group having an alkylthio group is preferably an alkylthiomethyl group, an alkylthioethyl group or an alkylthiopropyl group, and the alkylthio group is preferably one having 1 to 3 carbon atoms. Preferable examples of the alkyl group having an alkylthio group include methylthiomethyl group, ethylthiomethyl group and methylthioethyl group. 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 one having 1 to 3 carbon atoms. Preferable examples of the alkyl group having an alkoxy group include methoxymethyl group, ethoxymethyl group and methoxyethyl group. When R1 or R2 is a cycloalkyl group, it is preferably cyclopropyl group or cyclobutyl group, and most preferably cyclopropyl. Preferred combinations of R1 and R2 include combinations of R1 which is a hydrogen atom, an alkyl group, a cycloalkyl group or a substituted carbonyl group derived from an amino acid, a dipeptide or a tripeptide with R2 which is a hydrogen atom. Among these, preferred are those wherein R 1 is a hydrogen atom, an alkyl group or a cycloalkyl group and R 2 is a hydrogen atom. In this case, the alkyl group is preferably methyl group or ethyl group, and most preferably, methyl group. The cycloalkyl group is preferably cyclopropyl group or cyclobutyl group, and most preferably, cyclopropyl group. The most preferable combinations are combinations wherein both R1 and R2 are hydrogen, and the combination wherein R1 is methyl group and R2 is hydrogen atom. A quinolone derivative wherein the substituent R1 is a substituted carbonyl group derived from an amino acid, a dipeptide, or a tripeptide and the substituent R2 is a hydrogen atom is particularly preferable to be used as a prodrug. The amino acid, the dipeptide, or the tripeptide used to produce said prodrug can be one that produces free amine compound under digestion of the amide bond between the carboxyl group and the nitrogen atom of the amino group in the 3-position of the pyrrolidine ring in a living body. Examples of said substituents include substituted carbonyl groups depleted of 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-glycine-alanine, or glycine-alanine-alanine. The substituent R3 represents an alkyl group containing 1 to 6 carbon atoms or a halogen-substituted alkyl group containing 1 to 6 carbon atoms. Examples of an alkyl group containing 1 to 6 carbon atoms include those mentioned above. Among these, the preferred one is an alkyl group containing 1 to 3 carbon atoms, and the most preferred is methyl group. Illustrative halogen groups contained in the halogen-substituted alkyl group containing 1 to 6 carbon atoms include fluorine atom and chlorine atom, and the number of the halogen atom is preferably 1 to 3. The substituent R4 represents a cycloalkyl group containing 3 to 6 carbon atoms or a halogen-substituted cycloalkyl group containing 3 to 6 carbon atoms. Exemplary cycloalkyl groups containing 3 to 6 carbon atoms include those mentioned above. Among these, the preferred is cyclopropyl group. Exemplary halogeno-substituted cycloalkyl groups containing 3 to 6 carbon atoms include cycloalkyl groups as mentioned above substituted with 1 or 2 halogen atoms. Illustrative halogen atoms include fluorine atom and chlorine atom, and the preferred one is the fluorine atom. Among the halogen-substituted cycloalkyl groups, monohalogenocyclopropyl groups and dihalogenocyclopropyl groups are preferred, and monofluorocyclopropyl groups are most preferred. The substituent R5 represents a hydrogen atom, phenyl group, acetoxymethyl group, pivaloyloxymethyl group, ethoxycarbonyl group, choline group, dimethylaminoethyl group, 5-indanyl group, phthaldinyl group, 5-alkyl-2-oxo-1,3-dioxole group -4-ylmethyl, 3-acetoxy-2-oxobutyl group, an alkyl group containing 1 to 6 carbon atoms, an alkoxymethyl group containing 2 to 7 carbon atoms, or an alkylphenyl group comprising an alkylene group containing 1 to 6 carbon atoms and phenyl group.

When the compound of the present invention (1) is used for an antibacterial purpose, the compound is preferably a carboxylic acid compound wherein the R5 substituent is a hydrogen atom. On the other hand, quinolonecarboxylic acid derivatives produced by esterifying a carboxylic acid are useful as a synthetic intermediate or a prodrug. Esters that are useful as a synthetic intermediate include alkyl esters, benzyl esters, alkyl alkoxyesters, alkyl phenyl esters, and phenyl esters. Esters that are useful as a prodrug include those that are readily digested in a living body to produce a free carboxylic acid such as acetoxymethyl ester, pivaloyloxymethyl ester, ethoxycarbonyl ester, choline ester, dimethylaminoethyl ester, 5-indanyl ester, phthaloyl ester , 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl ester, and 3-acetoxy-2-oxobutyl ester. The substituents X1 and X2 independently represent a hydrogen atom or a halogen atom. The particularly preferable halogen atom is the fluorine atom. Preferable combinations of X1 and X2 include the combination wherein both X1 and X2 are hydrogen atom, and the combination wherein one is a hydrogen atom and the other is a fluorine atom. The substituent X represents a hydrogen atom or a halogen atom. The particularly preferable halogen atom is the fluorine atom. The compound (1) of the present invention has 4 isomers opticals since the methylpyrrolidin-1-yl 3-amino-4-fluoro-substituted group (formula (3)): which is the substituent at the 7-position has asymmetric carbon atoms at the 3-position and the 4-position. Among those isomers, the preferred 3-cis-form is preferred, those having a configuration (3S, 4S) or (3S.4R), and the most preferred one is one having configuration (3S, 4S) (formula (3-1)): In formula (3) and formula (3-1), R1, R2, X1 and X2 are as defined above. When R 4 is a halogeno-substituted cycloalkyl group in the compound of the present invention (1), a preferable stereochemical environment is such that the halogen atom and the quinolonecarboxylic acid base structure are in the 1,2-cis configuration in relation to the cycloalkane ring. The term "cis configuration" means that the halogen atom and the quinolonecarboxylic acid base structure are in cis configuration relative to the cycloalkane ring. Of the cis (1 R, 2S) and (1 S.2R) configurations, the preferred configuration is (1 R, 2S).

When the compound of the present invention represented by the formula (1) is one having diastereomers, and the compound of the present invention is administered to an animal including a human, the compound administered is preferably one comprising a single diastereomer. The "compound comprising a single diastereomer" includes not only the free compound of the other diastereomer, but also the compound that contains the other diastereomer to the extent that it does not affect the constant or physical activity. In addition, when the compound of the present invention is administered, the compound administered preferably comprises the individual stereochemically compound. The "compound comprising individual stereochemically compound" includes not only the compound comprising only an optically active substance but also the compound containing another optimally active substance to the extent that it does not affect the constant or physical activity when optical isomers are present. The compound of the present invention (1) is most preferably one having the substituent of the 7-position wherein the 3-position and the 4-position are in the (3S, 4S) configuration, and the halogenocycloalkyl group R4 which is in the configuration (1). R, 2S). The compound of the present invention (1) can be used as a free substance, but also as an acid addition salt or a salt of the carboxyl group. Exemplary addition acid salts include salts of an inorganic acid such as hydrochloride salt, sulfate salt, nitrate salt, hydrobromide salt, iohydrate salt and phosphate salt; sulfonate salts such as methanesulfonate salt, benzenesulfonate salt, and p-toluenesulfonate salt; and salts of an organic salt such as salts of a carboxylic acid such as acetate salt, citrate salt, maleate salt, fumarate salt, and lactate salt. Exemplary carboxyl group salts include alkali metal salt such as lithium salts, sodium salts, potassium salts; alkaline earth metal salts such as magnesium salts and calcium salts, ammonium salts such as triethylamine salt, N-methylglucamine salt, and tris- (hydroxymethyl) aminomethane salt. The free substance, the acid addition salt, or the carboxyl group salt may also be present as a hydrate. Examples of the compound of the present invention (1) include 7 - [(3S, 4S) -3-amino-4-fluoromethyl-1-pyrrolidinyl] -1-cyclopropyl-6-fluoro-1,4-dihydro-8- methyl-4-oxoquinoline-3-carboxylic acid, or a salt 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, or a salt or a hydrate of the same (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, or a salt or a hydrate thereof (compound No.3); 7 - [(3S, 4S) -3-fluoromethyl-4-methylaminopyrrolidin-1-yl] -6-fluoro-1 - [(2S, 1 R) -2-fluorocyclopropyl] -1,4-dihydro-8- methyl-4-oxoquinoline-3-carboxylic acid, or a salt 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, or a salt or a hydrate thereof (compound No. 5); 7 - [(3S, 4S) -3-amino-4-difluoromethylpyrrolidin-1 -yl] -6-fluoro-1 - [(1 R, 2S) -2- acid fluorocyclopropyl] -8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, its salt or a hydrate thereof (compound No.6). Among these, 7 - [(3S, 4S) -3-amino-4-fluoromet? L-1-pyrrolidinyl] -6-fluoro-1 - [(2S, 1R) -2-fluorocyclopropyl] is most preferred. -1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, or a salt or a hydrate thereof (compound No.3) and 7 - [(3S, 4S) -3-fluoromethyl-4- acid methylaminopyrrolidin-1-yl] -6-fluoro-1 - [(2S, 1R) -2-fluorocyclopropyl] -1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, its salt or a hydrate thereof (compound No.4). In producing the compound of the present invention (1), the substituent in the 7-position can be formed by reacting the following intermediate (formula (A)) with a suitable starting compound.

The asymmetry at position 3 and position 4 of this intermediate compound is as described above. Therefore, the compound used in the reaction is preferably one having configuration (3S.4S) or configuration (3S, 4R), and in particular, one having configuration (3S, 4S) (formula (A-1)) .

In the compound of the formula (A) and the formula (A-1), X1 and X2 are as defined before. On the other hand, R11 and R21 are the substituents as defined above for R1 and R2 to which a protecting group for the amino group (nitrogen atom) has been added. The protecting group of the amino group is not particularly limited as long as the protection and deprotection can be easily achieved without influencing the reactions of the subsequent steps or the protecting group itself does not undergo any reaction. Said amino protecting group may be a protector commonly used in the art selected from optionally substituted alkoxycarbonyl groups, optionally substituted aralkyloxycarbonyl groups, optionally substituted acyl groups, optionally substituted aralkyl groups, and substituted silyl groups. More specifically, illustrative optionally substituted alkoxycarbonyl groups include methoxycarbonyl group, ethoxycarbonyl group, tert-butoxycarbonyl group and 2,2,2-trichloroethoxycarbonyl group; and illustrative optionally substituted acyl groups include acetyl group, methoxyacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, formyl group, and benzoyl group; Illustrative optionally substituted aralkyloxycarbonyl groups include benzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, and para-nitrobenzyloxycarbonyl group; and illustrative optionally substituted silyl groups include trimethylsilyl group, isopropyldimethylsilyl group, tert-butyldimethylsilyl group, tribenzylsilyl group, and tert-butyldimethylsilyl group. Among these, the preferred protecting groups used for said intermediate compound are optionally substituted alkoxycarbonyl groups, optionally substituted aralkyloxycarbonyl groups, and acyl group optionally substituted, and most preferred are methoxycarbonyl group, ethoxycarbonyl group, tert-butoxycarbonyl group, benzyloxycarbonyl group, acetyl group, and trifluoroacetyl group, and the most preferred is terbutoxycarbonyl group. The nitrogen atom in the 1-position of the pyrrolidine ring can also be produced as a compound wherein the nitrogen atom (amino group) has been protected by a protecting group. The protecting group used in said compound for the protection of position 1 can also be selected from those described above. As described above, the intermediate compound can have 3 amino group protecting groups at most. Said protecting groups can be selected as desired by the selection criteria commonly known in the art. Illustrative preferable methods for producing the compound of the present invention represented by the formula (1) are the methods as described below. Next, the production method is described in detail using the compound of Example 3 (compound No.3) as an example.

Compound No.3 The compound of the present invention can be produced by two methods, namely, by a method wherein the 7-halogeno-1,4-d-h-dro-4-oxoquinoline-3-carboxylic acid derivative is reacted with a pyrrolidine compound to introduce the pyrro-dine substituent, or a method wherein the pyrrolidine compound is reacted with a 4-halobenzoic acid derivative and subsequently closing the quinoline ring. The last method is described first.

[Step to Reaction of Pyrrolidine Compound with a Benzoic Acid Derivative: Compound (II) The benzoic acid derivative used in this reaction is preferably a 4-halobenzoic acid derivative, and most preferably, an acid derivative 2,4- dihalogenobenzoic The benzoic acid substituent in a position other than said position is also acceptable as long as it corresponds to the substituent of the quinolone compound to be produced. For example, an 8-methylquinolone derivative can be produced using a 2,4-dihalogeno-3-methylbenzoic acid derivative. The halogen in the 2-position and 4-position can be a fluorine atom or a chlorine atom, and most preferably, a fluorine atom. The substituent at position 4 and position 2, however, is not limited to said halogen atom as long as it has the residual group function. The carboxy group portion of the benzoic acid may be either free carboxy group (-COOH) or an ester group (-COOR). Among these, the preferred one is an ester group. Exemplary ester groups include alkyl esters, aryl esters, aralkyl esters, phenyl esters (wherein the phenyl group is optionally substituted), and benzyl esters. Among these, the use of an alkyl ester is convenient, and most preferred are methyl ester, ethyl ester, propyl ester, and the like. The reaction of the pyrrolidine compound (I) with a benzoic acid derivative is preferably conducted in the presence of a base, and the base used in this reaction is not particularly limited so long as it does not inhibits the reaction. Illustrative bases include organic bases such as trialkylamines (trimethylamine, triethylamine, etc.) and heterocyclic compounds (4- (dimethylamino) pyridine, N-methylmorpholine, 1,8-diazabicyclo [5.4.0] -7-undecene (DBU), etc.), and inorganic salts such as ammonia, ammonium salts, alkali metal carbonate salts, alkaline earth metal carbonate salts (potassium carbonate, sodium carbonate, etc.), and alkali metal hydroxides (sodium hydroxide) , potassium hydroxide, etc.). Among these, preferred are organic bases such as a tertiary amine, and in particular triethylamine, and a heterocyclic compound such as 1,8-diazabicyclo [5.4.0] -7-undecene (DBU). The base is preferably used in an amount of 1 equivalent or more. further, HF occurs in this step with the progress of the reaction, and it is estimated that this HF causes problems such as discontinuation of the necessary protective group, formation of a salt with the amine compound to inhibit the reaction with the benzoic acid compound, corrosion of the metal reaction container, and generation of pollution problems. Accordingly, this step is preferably conducted in the presence of a base to avoid these problems. When this step is conducted using an acid addition product of pyrrolidine compound, a base is also required for the purpose of producing the free base of this salt. The reaction of the benzoic acid derivative with the compound of pyrrolidine is preferably conducted in the presence of a solvent, and the solvent that can be used in this reaction is not particularly limited as long as it does not inhibit the reaction. Illustrative solvents include N-alkylamides such as N, N-dimethylacetamide and N-methylpyrrolidone; polar aprotic solvent such as N, N-dimethylformamide, dimethyl sulfoxide, and sulfolane; and acetonitrile; and the preferred ones are acetonitrile, and N, N-dimethylacetamide (to N-alkylamide). A suitable reaction temperature in the range between the freezing point and the boiling point can be selected. However, the preferable reaction temperature is in the range of room temperature and the boiling point of the reaction solution. The reaction time which is the time from the start to the confirmation of the disappearance of the starting material is generally in the range of 1 hour to 100 hours, and preferably 10 hours to 30 hours.

[Step bl Reaction of compound (II) with a malonic acid hemi-ester: compound (III) Next, the benzoic acid derivative (II) having the introduced pyrrolidine substituent is converted to benzoyl acetate ester, compound ( III). In this step, the benzoate ether can be first hydrolyzed to produce free benzoic acid, and then reacted with the malonic acid hemi-ester. Hydrolysis can be conducted under the conditions commonly used in the art for hydrolysis of an ester, and conditions can be selected by considering the nature of the protecting groups and substituents at other sites in the compound. In addition to the hydrolysis, this reaction can also be conducted by hydrogenolysis depending on the type of the ester. The hydrolysis is typically conducted under alkaline hydrolytic conditions, and for the convenience of handling, an aqueous solution in an alkali metal hydroxide is preferably reacted at room temperature in a solvent that does not inhibit the reaction and is miscible with water. This reaction usually proceeds under mild conditions, and at room temperature, the reaction is typically completed in a few hours. The benzoic acid derivative can be separated by extracting under acidic conditions after removing the solvent, and subsequently purified by a chromatographic procedure, recrystallization, or the like. However, the product is usually useful in the subsequent step (the reaction with the malonic acid hemi-ester) without further purification. The conversion to benzoylacetic acid compound by reaction with the malonic acid hemi-ester can be carried out as described below. The malonic acid hemi-ester used can be a commercially available product or one prepared from a diester, and preferably, an alkyl ester in view of the convenience of the preparation. The ester used can be suitably selected considering the situation of the protecting groups and the substituents in other sites in the compound. The malonic acid hemi-ester can be reacted with a base first to be converted to a salt, and then it can be mixed with the benzoic acid derivative which has been obtained in order to carry out the reaction. The base used to prepare the malonate salt is preferably a metal alkoxide in view of the convenience of handling, and most preferred are magnesium compounds such as magnesium ethoxide and magnesium chloride. Magnesium alkoxide compounds that are often used in the art can also be used. This reaction can be conducted using a solvent that does not inhibit the reaction, and illustrative solvents that can be used include anhydrous aprotic solvents such as aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane, tetrahydrofuran, and diethyl ether, and dimethylformamide (DMF) and dimethyl sulfoxide (DMSO). An alcohol corresponding to the alcohol constituting the hemi-ester can also be used. The reaction between the base and the hemi-ester proceeds quickly, and at room temperature, the reaction is typically completed in a few hours. The reaction of the hemi-ester salt and the benzoic acid derivative can be conducted by activating the benzoic acid derivative, and mixing the activated benzoic acid derivative with the hemi-ester salt. The activation of the benzoic acid derivative can be achieved by the acid chloride method using thionyl chloride, oxalyl bichloride, phosphorus oxychloride, or the like; a method using a coupling agent such as N, N'-dicyclohexylcarbodiimide (DCC) or 1,1-carbonyldiimidazole (CDl); a method that uses an azide; a method using mixed acid anhydrides; or a method that uses an active ester. The method used can be suitably selected from those mentioned above depending on the type and nature of the substituents and protecting groups in the compound used in the reaction based on common knowledge of the art. The reaction with the hemi-ester salt can be conducted using a solvent that does not inhibit the reaction, and illustrative solvents that can be used include anhydrous aprotic solvents such as aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as dioxane, tetrahydrofuran, and diethyl ether; and dimethylformamide (DMF), and dimethyl sulfoxide (DMSO). The reaction can be carried out at a temperature in the cold temperature range of the ice at 200 ° C, and preferably, at a cold temperature of the ice at 100 ° C. The mixing of the hemi-ester salt and the activated benzoic acid derivative is preferably conducted in an ice bath. After mixing, the reaction can be promoted at a temperature in the range of room temperature to 200 ° C; preferably, at room temperature at 100 ° C, and most preferably at room temperature.

[Step Cl ring closure of compound (III): compound (IV) The benzoyl acetate ester (III) is first reacted with a dialkyl acetal of N, N-dialkyl formaldehyde, and then with fluorocyclopropylamine. The ring is then cyclized to produce 1,4-dihydro-4-oxoquinoline-3-carboxylate, compound (IV). The N, N-dialkyl formaldehyde dialkylacetal compound used is preferably one in which the alkyl groups are independently a lower alkyl group containing 1 to 6 carbon atoms in view of the convenience of handling. Illustrative of this compound is N, N-dimethylformaldehyde dimethylacetal. The reaction between the dialkylacetal compound of N, N-dialkylformaldehyde and the benzoyl acetate derivative can be conducted in a suitable solvent. The solvent that can be used includes 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 polar aprotic solvents such as DMF, DMSO and HMPA. The solvent used may also be an anhydrous lower alkane acid such as acetic anhydride. The reaction is generally conducted at a temperature of 0 ° C to 200 ° C, and most preferably, at 0 ° C to 150 ° C. The reaction is typically completed in approximately 0.5 to 10 hours. N, N-dialkylformaldehyde dialkylacetal can be used in equimolar amount in significant excess, and preferably in quantity equimolar to 2 times the molar excess of the benzoyl acetate compound. The subsequent reaction with the fluorocyclopropylamine can be conducted by reacting the reactants in a suitable solvent. The solvent used in this step is not particularly limited as long as it does not inhibit the reaction, and illustrative solvents 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 ligloin; halogenated hydrocarbons such as chloroform, methylene chloride, and carbon tetrachloride, and polar aprotic solvents such as DMF, DMSO, and HMPA. The reaction is generally conducted at a temperature of 0 ° C to 150 ° C, and most preferably, at room temperature at 100 ° C. The reaction is typically completed in about 0.5 to 15 hours. The amine compound can be used at least in equimolar amount, and preferably at an equimolar amount to 2 times the molar excess of the quinolone compound. If desired, a basic compound can be added to the reaction system. Illustrative basic compounds that can 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 bicarbonate, alcoholates of metal such as sodium methylate and sodium ethylate, and organic bases such as heterocyclic compounds (pyridine, piperidine, quinoline, N-methylmorpholine, etc.), trialkylamines (triethylamine, methyldiisopropylamine, etc.), and arylamines (N, N-dimethylaniline). When the fluorocyclopropylamine is used in the form of a salt, a further required amount of the base as mentioned above can be added for conversion of the amine salt to the free amine. The cyclization to the quinolone compound can be conducted in a suitable solvent and in the presence of a basic compound. The solvent used in this step is not particularly limited as long as it does not inhibit the reaction, and illustrative solvents include ethers such as diethyl ether, dioxane, tetrahydrofuran, monoglyme and diglyme; aliphatic hydrocarbons such as n-hexane, heptane and ligroin; halogenated hydrocarbons such as chloroform, methylene chloride and carbon tetrachloride; and polar aprotic solvents such as DMF, DMSO and HMPA. Illustrative basic compounds used include inorganic bases such as metallic sodium, metallic potassium, sodium hydride, sodium amide, sodium hydroxide and potassium hydroxide, metal alcoholates such as sodium methylate and sodium ethylate; and organic bases such as 1,8-diazabicyclo [5.4.0] undecene-7 (DBU), N-benzyltrimethylammonium hydroxide, and tetrabutylammonium hydroxide. The reaction is generally conducted at a temperature of 0 ° C to 150 ° C, and most preferably, at room temperature at 120 ° C. The The reaction is typically completed in approximately 0.5 to 5 hours. The basic compound is typically used at least in an equimolar amount, and preferably in an equimolar amount at 2 times the molar excess of the starting compound.

[Step d] Hydrolysis of compound (IV): compound No.3 Hydrolysis of the 1,4-dihydro-4-oxoquinoline-3-carboxylate ester, compound (IV) in the carboxylic acid compound can be achieved under the reaction conditions commonly used in the art for hydrolysis. More specifically, the reaction can be conducted in the presence of a basic compound such as sodium hydroxide, potassium hydroxide, barium hydroxide, or potassium carbonate, a mineral acid such as sulfuric acid, hydrochloric acid, or nitric acid, or an organic acid such as acetic acid, an alkylsulfonic acid, or an aromatic sulfonic acid; in the presence of water, an alcohol such as methanol, ethanol or isopropanol, a ketone such as acetone, methyl ethyl ketone, an ether such as dioxane or ethylene glycol, acetic acid; or a mixture of them. The reaction typically proceeds at about room temperature at 200 ° C, and most preferably at about room temperature at 150 ° C. The reaction is typically completed in about 0.5 to 30 hours. Next, the first method is described. The method as described before (the last method) where ring closure of the quinoline is conducted after introducing the portion of the pyrrolidine substituent is conducted on the benzoic acid derivative before introducing the pyrrolidine substituent portion to thereby build the quinolone base structure and obtain 7-halogen acid -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, and the pyrrolidine substituent is therefore introduced into 7-halogeno-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. Alternatively, the benzoic acid derivative can be reacted with a compound of malonic acid compound, and the resulting benzoyl acetate compound can be reacted with the pyrrolidine compound.

[Step Introduction of pyrrolidine substituent: compound No.3 In this step, 7-halogeno-1,4-dihydro-4-oxoquinoline-3-carboxylic acid or a compound (boron compound compound) wherein the portion of carboxyl group of 7-halogeno-1,4-dihydro-4-oxoquinoline-3-carboxylic acid has been converted to the oxycarbonyl structure of disubstituted boron is reacted with the pyrrolidine compound to introduce the substituent. In the reaction of 7-halogeno-1,4-dihydro-4-oxoquinoline-3-carboxylic acid or its boron chelate compound with the pyrrolidine compound, the reagents can be used in any selected ratio over a wide range. However, the pyrrolidine compound is typically it uses at least about equimolar amount, and preferably, in equimolar amount to 5 times the molar excess of 7-halogeno-1,4-dihydro-4-oxoquinoline-3-carboxylic acid or its boron chelate compound. This reaction can be carried out in a solvent that does not inhibit the reaction. Examples of said solvents include water; alcohols such as methanol, ethanol, isopropanol, butanol, amyl alcohol, and isoamyl alcohol; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as tetrahydrofuran, dioxane and diglyme; aprotic (polar) solvents such as dimethylacetarnide, DMF, DMSO, HMPA; and N-methylpyrrolidone; and mixtures thereof. Among these, the preferred ones are DMF, DMSO, HMPA and N-methylpyrrolidone. The reaction can also be conducted in the presence of a deoxidant such as an inorganic carbonate salt such as sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate; or an organic base such as pyridine, quinoline, or triethylamine. An alkali metal halide such as potassium fluoride can also be added to the reaction system. This reaction is typically conducted at a pressure of 1 to 20 atm., And preferably at 1 to 10 atm. and at a temperature of room temperature at about 250 ° C, and preferably at room temperature at 200 ° C. The reaction is typically completed in approximately 0.5 to 30 hours. When the carboxylic acid moiety has a boron-containing structure, the compound can be treated with an acidic compound or basic to decompose the chelate and derive the corresponding carboxylic acid compound. Acids which can be used in said step include mineral acids such as hydrochloric acid and sulfuric acid; and organic acids such as acetic acid and p-toluenesulfonic acid. The basic compounds that can be used include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, and potassium carbonate and organic bases such as triethylamine. The reaction proceeds at a temperature of about 0 to 1 50 ° C, and preferably at about 0 to 100 ° C. The acidic or basic compound is typically used at least in an equimolar amount, and preferably in an equimolar amount to 10 times the molar excess of the starting compound. Examples of the compound (boron chelate compound) having the di-substituted boron oxycarbonyl structure include dihalogenoboro and dialkanoyloxyboron. Preferable examples of the dihalogen compound include difluoroboron, and preferable examples of dialkanoyl oxyboron include diacetoxy boron. Among these, the preferred one is difluoroboron in view of the convenience of handling. The difluoroboron oxy compound (difluoroboron chelate compound) can be produced by reacting the carboxylic acid compound with a boron trifluoride ether complex, for example, diethyl ether complex or tetrahydrofuran complex, or alternatively, treating the compound of carboxylic acid with tetrafluoroboric acid.

This portion of boron chelate must be digested at a certain stage to regenerate the carboxy group, and digestion can be achieved by hydrolysis under basic or acidic conditions. This step can be achieved by any of the known methods. Since the compound of the present invention (1) has strong antibacterial activity and high safety with reduced side effects such as heart toxicity, it can be used as a drug for humans, animals and fish, or as a preservative of agricultural chemical compounds and foods. The dose of the compound of the present invention (1) when administered as a drug may vary according to the age, sex, and symptoms of the patients. However, the dose is typically 50 mg to 1 g, and most preferably 100 mg to 500 mg per day per adult. When the compound of the invention is administered to an animal, the dose is typically 1 mg to 200 mg, and most preferably 5 mg to 100 mg per day per kg of animal weight, although the dose may vary according to the size of the animal to be treated, type of the pathogenic microorganism , and severity of the condition. The daily dose can be administered in a single dose or in 2 to 4 divided doses. If necessary, a dose that exceeds the daily dose can be administered. The compound of the present invention (1) has excellent antibacterial activity for a wide range of microorganisms that cause various infections, and therefore, the present compound is capable of treating, preventing or mitigating the diseases caused by said pathogenic microorganisms. The compound of the present invention (1) is effective for bacteria and microorganisms similar to bacteria including Staphylococcus, Streptococcus pyogenes, hemolytic streptococci, enterococci, pneumococci, Peptostreptococcus, Neisseria gonorrhoeae, Escherichia coli (Citrobacter, Shigella, Klebsiella pneumoniae, Enterobacter , Serratia, Proteus, Pseudomonas aeruginosa, Haemophilus influenzae, Acinetobacter, Campylobacter, and Chlamydia trachomatis Diseases caused by such pathogenic microorganisms include secondary secondary infections such as folliculitis, furuncle, anthrax, erysipelas, cellulitis, lymphangitis, whitlow, subepithelial abscess, hidradenitis , acne conglobata, infectious atheroma, perianal abscess, mastitis, and injury, burns and surgical wounds, secondary infections of laryngopharyngitis, acute bronchitis, tonsillitis, chronic bronchitis, bronchiiectasis, diffuse panbronchiolitis, and chronic respiratory diseases; nia, pyelonephritis, cystitis, prostatitis, epididymitis, gonorrheal unteritis, urethritis, non-gonococcal urethritis, cholecystitis, cholangitis, shigellosis, enteritis, adnexitis, intrautarine infection, bartholinitis, blepharitis, hordeolum, dacryocystitis, meibomianitis, corneal ulcer, otitis media, sinusitis, periodontal inflammations, pericoronitis, inflammation of the jaw, peritonitis, endocarditis, sepsis, meningitis, and skin infections. The compound of the present invention (1) is also effective for acid resistant bacteria such as M. tuberculosis complex (Mycobacterium tuberculosis, M. bovis and M. africans) and atypical mycobacteria.

(M. kansasii, M. marianum, M. scrofulaceum, M. avium, M. intracellulare, M. xenopi, M. fortuitum and M. chelonae). Mycobacterial infections caused by these pathogenic microorganisms are divided into three categories of tuberculosis, atypical mycobacteriosis and leprosy. Mycobacterial infections affect not only the lung but also the thoracic cavity, trachea and bronchi, lymph nodes, systemic dissemination, joints and bones, meninges and brain, digestive organs (intestine and liver), skin, mammary glands, eyes, auris media and throat, urinary tract, male genitalia and female genitalia. The average organ affected by atypical mycobacteriosis (non-tuberculous mycobacteriosis) is the lung. Atypical mycobacteriosis, however, also affects topical lymphadenitis, soft tissues of the skin, bones and joints, and systemic spread. The compound of the present invention is also effective for several microorganisms that cause infections in animals such as Escherichia, Salmonella, Pasteurella, Haemophilus, Bordetella, Staphylococcus and mycoplasmas. Examples of diseases include, colibacillosis, pullorum disease, avian paratyphoid, avian cholera, infectious diarrhea, staphylococcosis, mycoplasma infection, and the like for birds; colibacillosis, salmonellosis, pasteurellosis, hemophilosis, atrophic rhinitis, exudative epidermitis, infection by mycoplasmas and the like for pigs; colibacillosis, salmonellosis, hemorrhagic septicemia, mycoplasma infection, pleuropneumonia and mastitis for cows; Sepsis by Esche? chia coli, Salmonnella infection, hemorrhagic septicemia, pyometra, cystitis and the like for dogs; and exudative pleurisy, cystitis, chronic rhinitis, hemophilosis, diarrhea in small cats, mycoplasma infection, and the like for cats. The drug of the present invention contains the compound of the present invention (1), or a salt or a hydrate thereof as its effective component, and the non-limiting dosage form can be suitably selected. Exemplary dosage forms include solid and liquid oral preparations such as tablets, powder, granules, capsules, solution, syrup, elixir and oil-based and water-based suspension; non-oral preparations such as injection and suppository; external preparation, instillation and patch. The dosage form can be prepared by any of a common method used to produce various preparations by mixing with a pharmaceutically acceptable carrier. In the case of an injection, the preparation may contain a stabilizer, an antiseptic, a solubilizer, and the like and with the preparation optionally supplemented with said additives a container may be filled, and then freeze-dried to produce a solid preparation that It must be hydrated immediately before use. The container can be filled with either a single dose or multiple doses. In the case of an external preparation, the preparation can be, for example, a solution, a suspension, an emulsion, an ointment, a gel, a cream, a lotion or a spray.

In the case of a solid preparation, the preparation can contain a pharmaceutically acceptable carrier with the compound (1), and Examples of vehicles include fillers, expanders, binders, disintegrants, solubilizers, wetting agents and lubricants. The Liquid preparation can be a solution, a suspension, an emulsion, or similar that a suspension or emulsifier agent may contain as a additive.

The compound of the present invention (1) can be administered to animals, for example, by direct oral administration, adding the compound to the food for oral administration, dissolving the compound and adding the solution to the drinking water or food for oral administration, or by injection.

Illustrative preparations are described below.

Preparation 1 (capsule) Compound of example 1 100.0 mg Corn starch 23.0 mg CMC calcium 22.5 mg Hydroxymethylene cellulose 3.0 mg Magnesium stearate 1.5 mg Total 150.0 mg Preparation 2 (solution) Compound of Example 1 1 to 10 mg Acetic acid or sodium hydroxide 0.5 to 2 g Ethyl para-oxybenzoate 0.1 g Purified water 88.9 to 98.4 g Total 100.0 g Preparation 3 (powder for animal feed) Compound of example 1 1 to 10 g Corn starch 98.5 to 89.5 g Light anhydrous silicic acid 0.5 g Total 100.0 g EXAMPLES Next, the present invention is described in furtdetail with reference to reference examples and examples which in no way limit the scope of the present invention.

EXAMPLE 1 7 - [(3S, 4S) -3-amino-4-fluoromethyl-1-pyrrolidinyl-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinolin- 3-carboxylic acid (Compound Mo.1) Complex of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid-difluoroboron (654 mg, 2 mmol) and dihydrochloride (3S, 4S) -3-amino-4-fluoromethylpyrrolidine (764 mg, 4 mmol) was dissolved in anhydrous dimethyl sulfoxide (10 ml), and triethylamine (2.23 ml, 16 ml) was added. mmoles) to the solution. The mixture was stirred at 50 ° C for 24 hours in nitrogen atmosp. The solvent was distilled off under reduced pressure, and 90% ethanol (10 ml) and triethylamine (0.5 ml) were added to the residue. After heating under reflux for 3 hours, the solvent was distilled under reduced pressure. Concentrated hydrochloric acid (6 ml) was added in an ice bath, and the mixture was stirred for 30 minutes, and washed three times with chloroform. The resulting aqueous layer was adjusted to pH 12 by the addition of saturated aqueous sodium hydroxide solution in an ice bath, and the solution was stirred for 1 hour. Then, dilute hydrochloric acid was added to adjust the pH to 7.4, and the solution was stirred for 12 hours. The solution was extracted with chloroform, and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the concentrate was purified by recrystallization from a mixed solvent of diethyl etand 2-propanol, and dried under reduced pressure at 50 ° C for 14 hours to tby obtain 274 mg (0.72 mmol, 36%) of the title compound as white crystals. H-NMR (400 MHz, DMSO-d6) d: 0.82-0.97 (2H, m), 1.02-1.03 (1 H, m), 1.15-1.23 (2H, m), 2.49 (3H, s), 2.59-2.66 (1 H, m), 2.75-2.76 (1 H, m), 3.18-3.30 (2H, m ), 3.46-3.53 (1 H, m), 3.60-3.66 (2H, m), 3.82-3.85 (1 H, m), 4.28-4.32 (1 H, m), 4.52-4.84 (2H, m), 7.69 (1 H, d, J = 13.69 Hz), 8.76 (1 H, s). Melting point: 160-165 ° C (diethyl et/ 2-propanol) Elemental analysis: as C? 9H2? F2N3 O3. 0.25H2O Calculated: C, 59.76%; H, 5.67%; N, 1 1.00%. Measured: C, 59.86%; H, 5.63%, N, 10.99%.

EXAMPLE 2 7 - [(3S, 4S) -3-Amino-4-fluoromethyl-1-pyrrolidinyl] -1-cyclopropyl-V-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-difluoroboron acid complex (618 mg, 2 mmol) and (3S, 4S) -3-amino-1-dihydrochloride 4-fluoromethylpyrrolidine (764 mg, 4 mmol) were dissolved in anhydrous dimethyl sulfoxide (10 ml), and triethylamine (2.23 ml, 16 mmol) was added to the solution. The mixture was stirred at 50 ° C for 13 hours under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, and 90% ethanol (10 ml) and triethylamine (0.5 ml) were added to the residue. After heating under reflux for 2.5 hours, the solvent was distilled under reduced pressure. Concentrated hydrochloric acid (6 ml) was added in an ice bath, and the mixture was stirred for 15 minutes, and washed three times with chloroform. The resulting aqueous layer was adjusted to pH 12 by the addition of saturated aqueous sodium hydroxide solution in an ice bath, and the solution was stirred for 1 hour. Then, dilute hydrochloric acid was added to adjust the pH to 7.4, and the solution was stirred for 12 hours. The solution was extracted with chloroform, and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the concentrate was purified by recrystallization from a mixed solvent of diethyl ether and 2-propanol, and dried under reduced pressure at 70 ° C for 24 hours to thereby obtain 490 mg (1.35 mmol, 67%) of the title compound as yellow crystals. 1 H-NMR (400 MHz, DMSO-d 6) d: 0.82-0.93 (2H, m), 1.02-1.03 (1 H, m), 1.18-1.22 (2H, m), 2.49 (3H, S), 2.61-2.66 (1 H, m), 3.13-3.15 (1 H, m), 3.28-3.40 (2H, m ), 3.54-3.59 (1 H, m), 3.63-3.66 (1 H, m), 3.70-3.74 (1 H, m), 4.27 (1 H, m), 4.52-4.84 (2H, m), 7.08 (1 H, d, J = 9.05 Hz), 7.98 (1 H, d, J = 9.05 Hz), 8.73 (1 H, s). Melting point: 203-205 ° C (diethyl ether / 2-propanol) Elemental analysis: as C? 9H22FN3O3. 0.25H2O Calculated; C, 62.71%; H, 6.23%, N, 11.55%. Measured: C, 62.59%; H, 6.16%; N, 11.44%.

EXAMPLE 3 7-f (3S, 4S) -3-amino-4-fluoromethyl-1-pyrrolidinyl) -6-fluoro-1-r (2S, 1R) -2-fluorocyclopropyl) -1,4-dihydro-8 acid -methyl-4-oxoquinoline-3-carboxylic acid (Compound No.3) To a solution of 6,7-difluoro-1 - [(2S, 1 R) -2- acid complex fluorocyclopropyl] -1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid-difluoro-boron (2.23 g, 6.46 mmol) in dimethyl sulfoxide (11 ml) were added 3- (S) -tert-butoxycarbonylamino -4- (S) -fluoromethylpyrrolidine (1.67 g, 7.65 mmol) and triethylamine (2.16 ml, 15.5 mmol) and the mixture was stirred at 35 to 40 ° C for 7 days. The reaction solution was concentrated under reduced pressure, and the concentrate was dissolved in a mixed solution of ethanol and water (9: 1) (150 ml). After the addition of triethylamine (5 ml), the mixture was heated under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure, and the concentrate was dissolved in ethyl acetate (100 ml x 2), and washed with water (50 ml x 3) and saturated aqueous sodium chloride solution (50 ml). The organic layer was dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in concentrated hydrochloric acid (20 ml) in an ice bath, and the aqueous solution was washed with chloroform (50 ml x 3). To the aqueous layer was added 10 mol / l aqueous sodium hydroxide solution to adjust the pH to 12.0, and the basic aqueous solution was adjusted with hydrochloric acid to pH 7.4. The solution was extracted with chloroform (100 ml x 2) and a mixed solution of chloroform and methanol (9: 1) (100 ml x 5). The organic layer was dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by preparative chromatography, and further purified by recrystallization from ethanol, and subsequently, dried under reduced pressure to yield the title compound 175 mg (7%) as pale yellow crystals. 1 H-NMR (400 MHz, 0.1 N-NaOD) d: 1.19-1.31 (1 H, m), 1.56-1.66 (1 H, m), 2.50 (3 H, s), 2.75-2.85 (1 H, m), 3.17-3.21 (1 H, m), 3.41 (1 H, t, J = 8.8 Hz), 3.61-3.72 (2H, m), 3.95-4.11 (2H, m), 4.79-4.88 (3H, m), 7.68 (1 H, d, J = 14. 2 Hz), 8.46 (1 H, s). IR (ATR) 3404, 3336, 3076, 2879, 1707, 1618, 1514, 1468, 1437, 1398, 1363, 1309, 1236 cm "1 Melting point: 214-216 ° C (decomposition) Elemental analysis: as C? GH20F3N3O3 0.25H2O Calculated: C, 57.07%; H, 5.17%; F, 14.25%; N, 10.51% Measured: C, 56.92%; H, 5.07%; F, 14.17%; N, 10.41% EXAMPLE 4 7-f (3S, 4S) -3-fluoromethyl-4-methylaminopyrrolidin-1-n-6-fluoro-1-f (2S, 1R) -2-fluorocyclopropin-114-dihydro-8- acid methyl-4-oxoquinoline-3-carboxylic acid (Compound No.4) To a solution of (3S, 4S) -3- (N-tert-butoxycarbonyl-N-methyl) amino-4-fluoromethylpyrrolidine (8.62 g, 37.1 mmol) in sulfolane (45 mL) were added triethylamine (2.22 mL, 17.4 mmol. ) and complex of 6,7-difluoro-1 - [(1 R, 2S) -2-fluorocyclopropyl] -8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid-difluoroboron (4.59 g, 13.3) mmoles), and the mixture was stirred at 35 to 39 ° C for 4 days. To the reaction solution was added a mixed solution of ethanol and water (5: 1) (240 ml) and triethylamine (5 ml), the mixture was heated under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, and the concentrate was dissolved in ethyl acetate (400 ml), and washed with 10% aqueous solution of citric acid (100 ml), water (100 ml x 3) and saturated aqueous sodium chloride (100 ml). The organic layer was dried with 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), and dissolved in concentrated hydrochloric acid (20 ml) in an ice bath. The solution was stirred at room temperature for 30 minutes, and the reaction solution was washed with chloroform (100 ml x 6). 10 moles / l of aqueous sodium hydroxide solution was added to the aqueous layer in an ice bath adjust the pH to 12.0, and then hydrochloric acid was added to adjust the pH to 7.4. The solution was extracted with chloroform (200 ml x 4). The organic layer was dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by recrystallization from ethanol (using activated carbon), and dried under reduced pressure to yield 1.39 g (26%) of the title compound as pale yellow crystals. Melting point: 1 73-175 ° C. 1 H-NMR (400 MHz, 0.1 N-NaOD) d: 1.26-1.38 (1 H, m), 1.58-1.69 (1 H, m), 2.36 (3 H, s), 2.54 (3H, s), 2.82-2.93 (1 H, m), 3.41 (1 H, q, J = 5.0 Hz), 3.49 (1 H, q, J = 5.8 Hz), 3.58 (2H, d, J = 6.9 Hz), 3.79 (1 H, ddd, J = 9.6, 6.1, 1.5 Hz), 4.12 (1 H, dt, J = 8.6, 5.4 Hz), 4.72-4.80 (2H, m), 5.00 (1 H, d, J = 65.0 Hz), 7.70 (1 H, d, J = 14.0 Hz), 8.48 (1 H, d, J = 2.7 Hz). Elemental analysis: as C20H22F3N3O3. 0.25H2O Calculated: C, 58.04; H, 5.48; F, 13.77, N, 10.15. Measured: C, 58.25; H, 5.52, F, 13.76; N, 10.03. IR (ATR): 3329, 2945, 2893, 1726, 1610, 1547, 1502, 1429, 1 354, 1315, 1263, 1221 cm "1.

EXAMPLE 5 1-Cyclopropyl-6-fluoro-7-f (3S, 4S) -3-fluoromethyl-4-methylaminopyrrolidin-1-in-8-methyl-1,4-dihydro-4-oxoquinolin-3- acid carboxylic (Compound No.5) To a solution of (3S, 4S) -3- (N-tert-butoxycarbonyl-N-methyl) amino-4-fluoromethylpyrrolidine (651 mg, 2.80 mmol) in sulfolane (3.5 ml) were added triethylamine (293 μl, 2.10 mmol) ) and 1-cyclopropyl-6,7-difluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid-difluoroboron acid complex (458 mg, 1.40 mmol), and the mixture was stirred from 31 to 35 ° C for 6 days. Cold water (200 ml) was added to the reaction solution, and the precipitated solid was collected by filtration, and washed with water. A solution was added to this solid mixed ethanol and water (10: 1) (165 ml) and triethylamine (3 ml), and the mixture was heated under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, and the concentrate was dissolved in ethyl acetate (400 ml), and the solution was washed with 10% aqueous solution of citric acid (100 ml), water (100 ml x 2). , and saturated aqueous solution of sodium chloride (100 ml). The organic layer was dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in concentrated hydrochloric acid (5 ml) in an ice bath, and the solution was stirred at room temperature for 30 minutes. The reaction solution was washed with chloroform (100 ml x 3). 10 moles / l of aqueous sodium hydroxide solution was added to the aqueous layer in an ice bath to adjust the pH to 12.0, and then hydrochloric acid was added to adjust the pH to 7.4. The solution was extracted with chloroform (200 ml x 4). The organic layer was dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by recrystallization from ethanol, and dried under reduced pressure to yield 161 mg (29%) of the title compound as pale yellow crystals. Melting point: 156-158 ° C. 1 H-NMR (400 MHz, 0.1 N-NaOD) d: 0.75-0.88 (2H, m), 1.11 -1.22 (2H, m), 2.37 (3H, s), 2.55 (3H, s), 2.79-2.91 ( 1 H, m), 3.47 (3 H, dq, J = 21.4.5.1 Hz), 3.61-3.67 (1 H, m), 3.73 (1 H, t, J = 8.5 Hz), 4.09-4.15 (1 H, m), 4.59-4.77 (2H, m), 7.66 (1 H, d, J = 14.0 Hz), 8.57 (1 H, s). Elemental analysis: as C2oH23F2N3O3 Calculated: C, 61.37; H, 5.92; F, 9.71; N, 10.74.

Measured: C, 61.18; H, 6.06; F, 9.85; N, 10.68. IR (ATR): 2889, 1720, 1614, 1545, 1504, 1452, 1429, 1360, 1 313, 1259, 1227 cm "1.

EXAMPLE 6 7-r (3S, 4S) -3-amino-4-difluoromethylpyrrolidin-1-n-6-fluoro-1-r (1R.2S) -2-fluorocyclopropyl-8-methyl-114-dihydroxy acid 4-Oxoquinoline-3-carboxylic acid (Compound No.6) To a solution of (3S, 4S) -3- (tert-butoxycarbonyl) amino-4-difluoromethylpyrrolidine (501 mg, 2.12 mmol) in sulfolane (2.5 mL) were added triethylamine (197 μL, 1.41 mmol) and 6-chloro-6-methoxy-3-methoxy-3-methoxyphenyl complex. , 7-difluoro-1 - [(1 R, 2S) -2-fluorocyclopropyl] -8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid-difluoroboron (406 mg, 1.18 mmol), and the mixture it was stirred at room temperature for 5 days, and at 35 ° C for 7 days. Cold water (100 ml) was added to the reaction solution, and the precipitated solid was collected by filtration and washed with water. To this solid was added a mixed solution of ethanol and water (9: 1) (100 ml) and triethylamine (1 ml), and the mixture was heated under reflux for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (300 ml), and washed with 10% aqueous solution of citric acid (100 ml), water (100 ml x 3), and saturated aqueous sodium chloride solution (100 ml). The organic layer was dried with anhydrous sodium sulfate, and the solvent was distilled under reduced pressure. The residue was dissolved in concentrated hydrochloric acid (5 ml) in an ice bath, and the solution was stirred at room temperature for 30 minutes, and the reaction solution was washed with chloroform (50 ml x 3). 10 mol / l of aqueous sodium hydroxide solution was added to the aqueous layer in an ice bath to adjust the pH to 12.0, and hydrochloric acid was then added to adjust the pH to 7.4. The solution was extracted with chloroform (150 ml x 4). The organic layer was dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developed in the lower layer of chloroform: methanol: water, 7: 3: 1), and further purified by recrystallization from ethanol-diethyl ether, and dried under reduced pressure to yield 85 mg (17%) of the title compound which was produced as pale yellow crystals. Melting point: 214-216 ° C. 1 H-NMR (400 MHz, 0.1 N-NaOD) d: 1.28 (1 H, d, J = 27.3 Hz), 1. 57-1.68 (1 H, m), 2.56 (3H, s), 2.92 (1 H, brs), 3.22 (1 H, d, J = 10.7 Hz), 3.45 (1 H, t, J = 9.0 Hz), 3.81 (1 H, brs), 3.90 (1 H, t, J = 9.5 Hz), 3.98-4.03 (1 H, m), 4.08-4.15 (1 H, m), 5.02 (1 H, d, J = 66.4 Hz), 6.22 (1 H, td, J = 55.7, 6.3 Hz), 7. 72 (1 H, d, J = 13.9 Hz), 8.47 (1 H, d, J = 3.2 Hz). Elemental analysis: as C19H19F4N3O3. 0.25H2O Calculated: C, 54.61; H, 4.70, F, 18.19; N, 10.06.

Measured: C, 54.37, H, 4.51; F, 17.71; N, 10.02. IR (ATR): 3408, 3336, 3072, 3030, 2947, 2891, 1711, 1618, 1514, 1468, 1439, 1402, 1352, 1306, 1232 cm "1.

REFERENCE EXAMPLE 1 4 - [(3S, 4S) -3-tert-butoxycarbonylamino-4-fluoromethyl-1-pyrrolidinip-2,5-difluoro-3-methylbenzoate ethyl To a solution of ethyl 2,4,5-trifluoro-3-methylbenzoate (1.12 g, 5.14 mmol) in dimethyl sulfoxide (5 ml) were added 3- (S) -tert-butoxycarbonylamino-4- (S) - fluoromethylpyrrolidine (0.751 g, 3.44 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (0.695 mL, 5.14 mmol), and the mixture was stirred at 60 to 65 ° C for 20 hours. The solution was allowed to cool to room temperature and the reaction mixture was dissolved in ethyl acetate (50 ml x 2), and the solution was washed with 10% aqueous solution of citric acid (50 ml), water (50 ml × 2), and saturated aqueous sodium chloride solution (50 ml). The organic layer was dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography on silica gel, and 725 mg (51%) of the title compound was obtained as oily crystals from the eluate of n-hexane and ethyl acetate (3: 1). colorless 1 H-NMR (400 MHz, CDCl 3) d: 1.38 (3 H, t, J = 7.1 Hz), 1.46 (9 H, s), 2.22 (3 H, d, J = 2.9 Hz), 2.73-2.88 (1 H, m ), 3.14-3.18 (1 H, m), 3.35-3.50 (2H, m), 3.70 (1 H, ddd, J = 9.7, 6.0, 1.9 Hz), 4.36 (2H, q, J = 7.1 Hz), 4.47-4.77 (3H, m), 4.92-4.89 (1 H, m), 7.44 (1 H, dd, J = 12.7.6.8 Hz).

REFERENCE EXAMPLE 2 4 - [(3S, 4S) -3-tert-butoxycarbonylamino-4-fluoromethyl-1-pyrrolidinyl-2,5-difluoro-3-methylbenzoylacetate in ethyl To a solution of ethyl 4 - [(3S, 4S) -3-tert-butoxycarbonylamino-4-fluoromethyl-1-pyrrolidinyl] -2,5-difluoro-3-methylbenzoate (720 mg, 1.73 mmol) in ethanol (10%). ml) was added 3 mol / l of aqueous potassium hydroxide solution (2.31 ml), and the mixture was stirred at room temperature for 1 hour. To the reaction solution were added 10% aqueous solution of citric acid (10 ml) and water (10 ml) to adjust the pH to 2 to 3, and ethanol was concentrated under reduced pressure. The solution was extracted with chloroform (30 x 2 ml), and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to yield 4 - [(3S.4S) -3-tert-butoxycarbonylamino-4-fluoromethyl-1-pyrrolidinyl] -2,5-difluoro-3-methyl benzoic acid. (718 mg, 1.73 mmol) as a yellow oily product. Monoethyl malonate (459 mg, 3.48 mmol) was dissolved in anhydrous tetrahydrofuran (5 ml), and magnesium ethoxide (370 mg, 3.23 mmol) was added in an ice bath. The mixture was stirred at room temperature for 2 hours, and the reaction solution was concentrated under reduced pressure to yield magnesium salt of monoethyl malonate. Then, 4 - [(3S, 4S) -3-tert-butoxycarbonylamino-4-fluoromethyl-1-pyrrolidinyl] -2,5-difluoro-3-methylbenzoic acid (718 mg, 1.73 mmol) was dissolved in tetrahydrofuran (10 ml. ), and 1,1-carbonyldiimidazole (365 mg, 2.25 mmol) was added in an ice bath. The mixture was stirred at room temperature for 2 hours, and to this mixture was added dropwise a solution of the magnesium salt of monoethyl malonate prepared as described above in anhydrous tetrahydrofuran (5 ml) in an ice bath. After completion of the dropwise addition, the solution was gradually allowed to return to room temperature, and the solution was stirred for 16 hours. To this reaction solution was added toluene (10 ml) and 10% aqueous solution of citric acid (10 ml) in an ice bath to acidify the reaction solution (to pH 2 to 3), and the solution was stirred at room temperature. room temperature for 1 hour. The organic layer was collected and washed with saturated aqueous sodium bicarbonate solution (10 ml) and saturated aqueous sodium chloride solution (10 ml) in that order, and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and subjected to column chromatography on silica gel to yield 334 mg (42%) of the title compound as an oily product. pale orange from the material eluted from n-hexane and ethyl acetate (1: 1). 1 H-NMR (400 MHz, CDCl 3) d: 1.25-1.35 (3H, m), 1.46 (9H, s), 2.22-2.22 (3H, m), 2.74-2.87 (1 H, m), 3.82-3.12 ( 4H, m), 3.93 (2H, d, J = 3.9 Hz), 4.19-4.29 (2H, m), 4.76-4.48 (3H, m), 4.91 (1 H, s), 5.84 (1 / 3H, s ), 7.46 (1 H, q, J = 6.7 Hz), 12.67 (1 / 3H, s).

REFERENCE EXAMPLE 3 7-f (3S, 4S) -3-tert-butoxycarbonylamino-4-fluoromethyl-1-pyrrolidinin-6-fluoro-1-f (2S, 1R) -2-fluorocyclopropyl) -1, 4- ethyl dihydro-8-methyl-4-oxoquinoline-3-carboxylate 4 - [(3S, 4S) -3-tert-butoxycarbonylamino-4-fluoromethyl-1-pyrrolidinyl) -2,5-difluoro-3-methylbenzoyl acetate (334 mg, 0.729 mmol) and NN-dimethylformamide dimethylacetal (0.194) ml, 1.46 mmoles) were dissolved in benzene (6 ml), and the mixture was stirred 3 hours by heating in an oil bath at an external temperature of 80 ° C. The reaction solution was allowed to cool, and concentrated under reduced pressure to dryness. The resulting yellow oil product was dissolved in toluene (10 ml), and to this solution was added para-toluenesulfonate salt of (1 R, 2S) -2-fluorocyclopropylamine (270 mg, 1.09 g). mmoles). The mixture was stirred at -10 ° C, and triethylamine (0.158 mL, 1.13 mmol) was added dropwise with stirring. The reaction solution was stirred at room temperature for 1 hour, and water (150 ml) and ethyl acetate (20 x 2 ml) were added to the solution. The solution was washed with saturated aqueous sodium chloride solution (15 ml), and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to dryness. The yellow oily product was dissolved in dimethylformamide (5 ml), and potassium carbonate (202 mg, 1.46 mmol) was added in an ice bath, and the solution was stirred at room temperature for 4 days. To the reaction solution was added 10% aqueous solution of citric acid (20 ml) in an ice bath, and the precipitated crystals were collected by filtration. The crystals were washed with an excessive amount of purified water, and the resulting crude crystals were subjected to column chromatography on silica gel to obtain 277 mg (73%) of the title compound as a pale yellow powder from the material eluted from a mixed solution of chloroform and methanol (95: 5). 1 H-NMR (400 MHz, CDCl 3) d: 1.20-1.34 (2H, m), 1.41 (3H, t, J = 7.1 Hz), 1.46 (9H, s), 2.57 (3H, s), 2.88 (1 H , s), 3.14-3.18 (1 H, m), 3.44-3.60 (2H, m), 3.80-3.92 (2H, m), 4.39 (2H, q, J = 7.1 Hz), 4.50-4.56 (1 H , m), 4.65-4.70 (1 H, m), 4.74-4.82 (1 H, m), 4.94-4.90 (1 H, m), 7.96 (1 H, d, J = 13.2 Hz), 8.53 (1 H, d, J = 2.9 Hz).

EXAMPLE 7 7-r (3S, 4S) -3-amino-4-fluoromethyl-1-? -rolyolidin-6-fluoro-1-r (2S, 1R) -2- (fluorocyclopropyl-1, 4-dihydro) acid -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 (3 ml) was added 1 mol / l of aqueous sodium hydroxide solution (1.06 ml), and the mixture was stirred at room temperature for 5 hours. To this reaction solution were added 10% aqueous solution of citric acid (15 ml) and water (10 ml) to adjust the pH from 2 to 3, and the precipitated solid was collected by filtration and washed with water (10 ml. ). The residue was dissolved in concentrated hydrochloric acid (5 ml) in an ice bath, and the aqueous solution was washed with chloroform (50 ml x 2). 10 moles / l of aqueous sodium hydroxide solution (6 ml) was added. to the aqueous layer to adjust the pH to 12.0, and hydrochloric acid was added to this basic aqueous solution to adjust the pH to 7.4. The solution was then extracted with chloroform (100 ml x 3) and a mixed solution of chloroform and methanol (9: 1) (100 ml x 4).

The organic layer was dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by recrystallization from Soapropyl alcohol was dried under reduced pressure to yield 100 mg (48%) of the title compound as pale yellow crystals. The 1 H-NMR data of this compound were consistent with compound No.3.

REFERENCE EXAMPLE 5 (3S, 4S) -1- (benzyloxycarbonyl) -3- (N-tert-butoxycarbonyl-N-methyl) amino-4-fluoromethylpyrrolidine To a solution of (3S, 4S) -1- (benzyloxycarbonyl) -3- (tert-butoxycarbonyl) amino-4-fluoromethylpyrrolidine (17.2 g, 48.2 mmol) in N, N-dimethylformamide (170 mL) was added sodium hydride (55% 1 for comparison with 4.21 g, 96.4 mmol), and the mixture was stirred at 0 ° C for 10 minutes. After stirring, methyl iodide (3.30 ml, 53.0 mmol) was added to the solution at the same temperature and the mixture was stirred for 30 minutes. A saturated aqueous solution of ammonium chloride (500 ml) was added to the reaction solution, and the solution was extracted with ethyl acetate (500 ml x 2), and washed with water (100 ml x 2) and aqueous solution saturated with sodium chloride (100 ml). The organic layer was dried with sodium sulfate and the solvent was distilled under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane-ethyl acetate: 4: 1 - 2: 1) to obtain 17.4 9 (98%) of the title compound as a syrup. colorless. 1 H-NMR (400 MHz, CDCl 3) d: 1.46 (9H, d, J = 1.7 Hz), 2.78-2.80. (4H, m), 3.36-3.44 (1 H, m), 3.60-3.79 (3H, m), 4.30-4.51 (1 H, m), 4.58 (1 H, d, J = 46.6 Hz), 4.79 ( 1 H, 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 (15.7 g, 42.8 mmol) was dissolved in ethanol (300 ml), and catalyst was added of 10% palladium-carbon (M, water content, 50.9%, 1.60 g). The mixture was stirred at 40 ° C for 2 hours under a stream of hydrogen. After removing the catalyst by filtration (by washing with ethanol), the filtrate was concentrated under reduced pressure to yield 9.50 g (96%) of the crude title compound as a colorless syrup. 1 H-NMR (400 MHz, CDCl 3) d: 1.47 (9H, s), 2.54-2.68 (1 H, m), 2.85 (3H, s), 2.97 (1 H, dd, J = 11.3, 7.1 Hz), 3.07 (1 H, dd, J = 11.5, 5.6 Hz), 3.16-3.23 (2H, m), 4.36 (1 H, ddd, J = 47.6, 9.3, 6.4 Hz), 4.48 (1 H, ddd, J = 46.8, 9.1, 5.1 Hz), 4.41-4.48 (1 H, m).

EXAMPLE OF TEST 1 The compounds of the present invention were evaluated for their antibacterial activity in accordance with the standard method defined by the Japanese Society of Chemotherapy, and the results are shown in MIC (μg / ml) in Tables 1 and 2, below. The MIC value is also shown for levofloxacin (LVFX), ciprofloxacin (CPFX) and the comparative compound (compound of Example 1 in Patent Document 1) for comparison with the MIC value of the compound of the present invention.

Comparative Compound The results reveal that the compounds of the present invention have broader and stronger antibacterial activity for both Gram-negative and Gram-positive bacteria including resistant bacteria compared to common synthetic quinolone antibacterials, and in particular, that the The compounds of the present invention have strong antibacterial activity for Gram-positive bacteria such as Staphylococcus aureus (MRSA) and pneumococci (PRSP).

TABLE 1 Compound Compound Compound Compound No 1 No 2 No 3 No 4 E coli NJ < 0003 < 0003 0006 < 0003 S flexnep, 2A 5503 < 0003 0006 < 0003 0006 Pr vulgaps 08601 < 0003 0006 < 0003 0006 Pr mirabilis, IFO-3849 0012 005 0006 0025 Ser marcescens, 10100 0025 005 0025 005 Ps aeruginosa, 32104 005 01 005 01 Ps aeruginosa, 32121 0025 0025 0025 005 S maltophi a, IID-1275 01 02 01 01 S aureus, 209P 0012 0025 0006 0012 S epidermidis 56500 0025 01 0025 005 Str pyogenes, G-36 01 02 005 01 Str faeca s, ATCC-19433 005 02 01 01 S aureus, 870307 02 078 039 039 S pneumoniae, J24 0025 01 0025 005 MIC values (μg / ml) TABLE 2 Compound Compound LVFX CPFX Compound No 5 No 6 comparative E coli NJ < 0003 < 0003 0012 < 0003 < 0003 S flexnep, 2A 5503 < 0003 < 0003 0025 0006 0006 Pr vulgaps 08601 0006 0006 0012 < 0003 0012 Pr mirabilis, IFO-3849 0025 0012 005 0012 0025 Ser marcescens, 10100 005 005 01 0025 005 Ps aeruginosa, 32104 02 02 02 005 02 Ps aeruginosa, 32121 005 005 01 0025 005 S maltophiha, IID-1275 005 005 039 078 02 S aureus, 209P 0012 0012 02 01 0012 S epidermidis, 56500 005 0025 039 02 005 Str pyogenes, G-36 01 005 078 156 01 Str faecahs, ATCC-19433 01 01 078 078 01 S aureus, 870307 039 02 > 625 > 625 02 S pneumoniae, J24 005 005 078 01 0025 MIC values (μg / ml) S aureus, 870307 Staphylococcus aureus resistant to levofloxacin, resistant to methicillin S Pneumoniae, J24. pneumococcus resistant to penicillin (moderate resistance) EXAMPLE OF TRIAL 2 The compounds of the present invention were evaluated for toxicity in a single-dose toxicity test by administering the compounds to 6-week-old male Slc: ddY mice. The compound was diluted with 0.1 mol / L NaOH / physiological saline, and filtered through a Millex GS filter (0.22 μm) for sterilization. The compound was administered at a rate of 10 ml / kg and 0.2 ml / min in a single dose by intravenous injection. The results are shown in table 3. The compound of example 1 in patent document 1 was used for the comparative compound as in the case of test example 1. The results indicate that the compounds of the present invention exhibit acute toxicity more weak compared to the comparative compound.

TABLE 3

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - A compound represented by the following formula (1): or its salt or a hydrate thereof, wherein R 1 represents a hydrogen atom, an alkyl group containing 1 to 6 carbon atoms, a cycloalkyl group containing 3 to 6 carbon atoms, or a substituted carbonyl group derived from a amino acid, a dipeptide, or a tripeptide, wherein the alkyl group is optionally substituted with a group selected from the group consisting of hydroxy group, amino group, halogen atom, alkylthio group containing 1 to 6 carbon atoms, and alkoxy group containing 1 to 6 carbon atoms; R 2 represents hydrogen atom, an alkyl group containing 1 to 6 carbon atoms, or a cycloalkyl group containing 3 to 6 carbon atoms, wherein the alkyl group is optionally substituted with a group selected from the group consisting of hydroxy group , amino group, halogen atom, alkylthio group containing 1 to 6 carbon atoms, and alkoxy group containing 1 to 6 carbon atoms; R3 represents an alkyl group containing 1 to 6 carbon atoms or an alkyl group halogen-substituted containing 1 to 6 carbon atoms; R4 represents a cycloalkyl group containing 3 to 6 carbon atoms or a halogen-substituted cycloalkyl group containing 3 to 6 carbon atoms; R5 represents hydrogen atom, phenyl group, acetoxymethyl group, pivaloyloxymethyl group, ethoxycarbonyl group, choline group, dimethylaminoethyl group, 5-indanyl group, phthalidyl group, 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl group , 3-acetoxy-2-oxobutyl group, an alkyl group containing 1 to 6 carbon atoms, an alkoxymethyl group containing 2 to 7 carbon atoms, or an alkylphenyl group comprising an alkylene group containing 1 to 6 carbon atoms. carbon and phenyl group; X1 and X2 independently represent hydrogen atom or a halogen atom; and X represents a hydrogen atom or a halogen atom.

2. The compound according to claim 1, its salt, or a hydrate thereof, further characterized in that the compound represented by the formula (1) is a compound having a structure represented by the following formula: wherein R1, R2, R3, R4, R5, X1, X2, and X are as defined above.

3. The compound according to claim 1 or 2, its salt, a hydrate thereof, further characterized in that X1 and X2 are atoms of hydrogen 4 - The compound according to claim 1 or 2, its salt, a hydrate thereof, further characterized in that one of X1 and X2 is fluorine atom and the other is hydrogen atom 5 - The compound in accordance with any of claims 1 to 4, its salt, or a hydrate thereof, further characterized in that R1 and R2 are hydrogen atoms 6 - The compound according to any of claims 1 to 4, its salt, or a hydrate thereof, further characterized in that one of R1 and R2 is hydrogen atom, and the other is methyl group 7 - The compound according to any of claims 1 to 6, its salt, or a hydrate thereof, further characterized in that X is a hydrogen atom. Fluorine 8 - The compound according to any of claims 1 to 6, its salt, a hydrate thereof, further characterized in that X is hydrogen atom 9 - The compound according to any of claims 1 to 8, its salt, or a hydrate thereof, further characterized in that R3 is an alkyl group containing 1 to 6 carbon atoms. The compound according to any of claims 1 to 8, its salt, or a hydrate thereof, further characterized in that R3 is group methyl 11 - The compound in accordance with any of the claims 1 to 10, a salt thereof or a hydrate thereof, further characterized in that R 4 is cyclopropyl group or 1,2-cis-2-halogenocyclopropyl group. 12. The compound according to any of claims 1 to 10, its salt, or a hydrate thereof, further characterized in that R4 is stereochemically uniform 1, 2-cis-2-halogenocyclopropyl group. 13. The compound according to any of claims 1 to 10, its salt, or a hydrate thereof, further characterized in that R4 is group (1 R, 2S) -2-halogenocyclopropyl. 1

4. The compound according to any of claims 1 to 10, its salt, or a hydrate thereof, further characterized in that R4 is (1 R, 2S) -2-fluorocyclopropyl group. 1

5. The compound according to any of claims 1 to 14, its salt, or a hydrate thereof, further characterized in that R5 is a hydrogen atom. 16.- 7- [3-Amino-4-fluoromethylpyrrolidin-1-yl-6-fluoro-1 - [(2S, 1 R) -2-fluorocyclopropyl] -1,4-dihydro-8-methyl-4 acid oxoquinoline-3-carboxylic acid, its salt, or a hydrate thereof. 17.- 7- [3-Fluoromethyl-4-methylaminopyrrolidin-1-yl] -6-fluoro-1 - [(2S, 1 R) -2-fluoro-1-cyclopropyl-1,4-dihydro-8- acid methyl-4-oxoquinoline-3-carboxylic acid, its salt, or a hydrate thereof. 18.- 7- [cis-3-amino-4-fluoromethylpyrrolidin-1 -yl] -6-fluoro-1 acid [(2S, 1 R) -2-fluorocyclopropyl] -1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, its salt, or a hydrate thereof. 19.- 7- (cis-3-fluoromethyl-4-methylaminopyrrolidin-1-yl-6-fluoro-1 - [(2S, 1 R) -2-fluorocyclopropyl] -1,4-dihydro-8-methyl- 4-oxoquinoline-3-carboxylic acid, its salt, or a hydrate thereof. 20. The compound according to any of claims 1 to 19, its salt, or a hydrate thereof, further characterized in that the compound of the formula (1) is stereochemically uniform compound. 21.- 7 - [(3S, 4S) -3-amino-4-fluoromethylpyrrolidin-1-yl] -6-fluoro-1 - [(2S, 1 R) -2-fluoro-cyclopropyl] -1,4 acid -dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, its salt, or a hydrate thereof. 22.- 7 - [(3S, 4S) -3-fluoromethyl-4-methylaminopyrrolidin-1-yl-6-fluoro-1 - [(2S, 1 R) -2-fluorocyclopropyl] -1,4-dihydroxy acid 8-methyl-4-oxoquinoline-3-carboxylic acid, its salt, or a hydrate thereof. 23. A drug comprising the compound according to any of claims 1 to 22, its salt, or a hydrate thereof, as an effective component. 24. An antibacterial drug comprising the compound according to any of claims 1 to 22, its salt, or a hydrate thereof, as an effective component. 25.- A prophylactic and / or therapeutic drug for infectious diseases, comprising the compound in accordance with any of Claims 1 to 22, its salt, or a hydrate thereof, as an effective component. 2

6. A pharmaceutical composition comprising the compound according to any of claims 1 to 22, its salt, or a hydrate thereof and a pharmaceutically acceptable carrier. 2

7. An antibacterial drug comprising the compound according to any of claims 1 to 22, its salt, or a hydrate thereof and a pharmaceutically acceptable carrier. 2

8. A prophylactic and / or therapeutic drug comprising the compound according to any of claims 1 to 22, its salt, or a hydrate thereof and a pharmaceutically acceptable carrier. 2

9. The use of the compound according to any of claims 1 to 22, in the manufacture of a medicament useful for preventing and / or treating an infectious disease.