KR940007309B1 - 3-carboxylic acid 4-oxoquinoline derivatives - Google Patents

Abstract

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Description

Benzoheterocyclic compounds

The present invention relates to a novel antimicrobial benzoheterocyclic compound represented by formula (I).

[1]

[One]

Wherein R ¹ is cyclopropyl which may be substituted by 1 to 3 substituents selected from the group consisting of (lower) alkyl and halogen atoms, and R ² is 5 to 9 saturated or unsaturated heterocyclic rings which may be substituted R ³ is a group consisting of 5 or 6 saturated heterocyclic rings and (low) alkylthio, amino, (low) alkylamino, (low) alkanoyloxy, hydroxy, (low) alkoxy and halogen atoms (Low) alkyl which may be substituted by 1 to 3 substituents selected from X, X is a halogen atom and a pharmaceutically acceptable halogen salt.

The benzoheterocyclic compounds of formula (I) and salts thereof have excellent antimicrobial activity against various Gram-positive and Gram-negative bacteria and are effective against the effects of various infectious diseases caused by various bacteria in humans, other animals and fish. It is also useful as an external antimicrobial or disinfectant for things like medical devices.

There is a lot of literature showing 4-oxoquinoline-3-carboxylate derivatives useful as antimicrobial drugs.

In these documents, European Patent Publication Nos. 113092 and 113093 and US Pat. No. 4,559,342 disclose 1-cyclopropyl-7-piperazino-dihydroquinoline carboxylate derivatives.

German patent 3248507 shows a 1-cyclopropyl-dihydroquinoline carboxylic acid derivative.

Wherein R ¹ is H, F, Cl, Br or NO ₂ , and R ² is H, Cl, F or NR ³ R ⁴ , where R ³ and R ^{4 form} 5-6 saturated or partially unsaturated hetero cycles You may.

South African Patent 8504087 shows a 1-cyclopropyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid derivative.

Wherein R ¹ is _{H, CH 3, C 2 H} 5 or ^- is CH ₂ CH ₂ OH, and, R ² is H, Cl or F.

German Patent 3420743 shows a 7-amino-1-cyclopropyl-3-quinoline carboxylic acid derivative.

Wherein X ¹ and X ² are each Cl or F, and R ¹ and R ³ may be combined such as N to form 5-6 heterocyclic rings.

German patents 3420770 and 3420798 show 1-cyclopropyl-7-piperazinyl-dihydroquinoline carboxylic acid derivatives.

Wherein R is oxo (OXO) or phenyl and R ² is H or F. Similarly, 1-cyclopropyl-7-heterocyclic group-substituted dihydro quinolinecarboxylic acid derivatives are also shown in many of the following documents.

Japanese Patent Publication No. 214777/1985, 36265/1986, 91183/1986, 122272/1986 143363/1986, 133364/1986, 186379/1986, 205240/1986, 205259/1986, 218574/1986, 218575/1986, 218585/1986 , 225181/1986, and 229877/1986 European Patent Publication Nos. 178388/183129, 187-85, 191185 and 196316 South Africa Patent 8504792.

Spanish patents 8602674 and 8601968 and Portuguese patent 90546.

However, the compound shown in this document differs from the compound of this invention in other respects without having an alkyl substituent at No. 8.

Some documents show 1-cyclopropyl-7-heterocyclic group-8-alkyl-dihydroquinoline carboxylic acid derivatives.

For example, Japanese Patent Laid-Open No. 126271/1985 (= Portuguese Patent 79616) shows the following quinoline carboxylic acid derivatives.

Wherein R is H, CH ₃ , P-nitobenzyl or P-aminobenzyl, and Y is Cl, F or CH _3, but this document does not show any specific examples of 8-CH ₃ derivatives (all examples are 8 -Cl or 8-F derivatives.) In addition, German patent 3441788 (= Japanese Patent Laid-Open No. 122272/1986) shows a 1-cyclopropyl-4-oxoquinoline-3-carboxylic acid derivative.

Wherein X ¹ , X ² and X ³ are each H or C _1-3 alkyl but these compounds do not have a heterocyclic group such as X ² .

It is an object of the present invention to provide novel benzoheterocyclic compounds of formula (I) having a good antimicrobial activity and good absorbency and salts thereof. Another object of the invention is to provide a pharmaceutical modifier comprising a compound of formula (I) and a pharmaceutically acceptable salt thereof, which is useful as an active ingredient in the treatment of various infectious diseases. These and other objects of this invention will be apparent to those skilled in the art from the following description.

The new benzoheterocyclic compounds of the present invention have the formula (I) as mentioned above and include pharmaceutically acceptable salts therefor.

In particular, the term "halogen atom" in the description includes fluorine, chlorine, bromine or iodine atoms.

The term "cyclopropyl", which may be substituted by a substituent of 1-3 optionally from a group consisting of (low) alkyl and halogen atoms, includes a cyclopropyl group, which is a cyclopropyl, 2-fluoro-1- Cyclopropyl, 2-chloro-1-cyclopropyl, 2-bromo-1-cycloporophyll, 2-iodo-1-cyclopropyl, 2,2-dichlorocyclopropyl, 2,2-dibromocyclopropyl , 2,2,3-trichlorocyclopropyl, 2-methyl-1-cyclopropyl, 2-methyl-1-cyclopropyl, 2-propyl-1-cyclopropyl, 2-butyl-1-cyclopropyl, 2- Pentyl-1-cyclopropyl, 2-hexyl-1-cyclopropyl, 2,2-dimethylcyclophosphophil, 2,3-dimethylmethylpropyl, 2,2,3-trimethylcyclopropyl, 2-fluoro -3-methylcyclopropyl, 2,2-dimethylcyclopropyl, 2-methyl-3-propylcycle It may be substituted by a substituent of 1-3 selected from the group consisting of an alkyl group which is a linear or branched form such as ropropyl, etc. and a halogen atom. The term "(low) alkyl" includes C ₁ -C ₆ alkyl groups which are linear or branched such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and the like.

The term "substituted 5 to 9 saturated or unsaturated heterocyclic rings" refers to 5-9 saturated or unsaturated heterocyclic rings which may be substituted by: (low) alkyl Phenyl (low) alkyl, wherein the phenyl ring may be substituted by (low) alkoxy, nitro or amino, by halogen atom, (low) alkyl, or (low) alkyl substituted by halogen atom of 1-3 Phenyl which may be substituted: hydroxy, amino, (low) alkyl having 1-3 substituents selected from the group consisting of (low) alkoxy and halogen atoms wherein the amino is any (low) alkyl, (low) alkanoyl, It may be substituted by cycloalkyl or (low) alkoxycarbanoyl or the like: (low) alkynyl: (low) alkanoyl which may be substituted by halogen atoms of 1-7-: consisting of halogen atom and carboxy (Low) alkenylcarbonyl having 1-3 substituents selected from the group: (low) alkoxycarbonyl: aminocarbonyl which may be substituted by (low) alkyl: phenyl (low) alkoxycarbonyl: phenyl (low Amino, hydroxy: may be substituted by halogen atoms of 1-3, which may be substituted by phenyl (low) alkyl (low) alkoxycarbonyl or (low) alkanoyl, which may be substituted by alkoxycarbonyl (Low) alkylsulfonyl: phthalide: 2 (5H) -furanonesulfo (low) alkyl, which may be substituted by one or two halogen atoms, oxo (OXO): (low) alkoxy: (low) alkenyl : Halogen atom: 2-oxo-1,3-dioxolenemethyl which may be substituted by (low) alkanoyloxyphenyl or (low) alkyl: 2-oxo which may be substituted by phenyl or (low) alkyl 1,3-dioxolene methylamino: cycloalkylamino: (low) alkylthio: again The term thio and “substituted 5-9 saturated or unsaturated heterocyclic rings” refers to the more specific 5-9 substituents that may be substituted for 1-3 substituents selected from the group consisting of: Saturated or unsaturated heterocyclic rings include: linear or branched C ₁ -C ₆ alkyl groups: C ₃ -C ₈ cycloalkyl groups: phenyl rings are linear or branched C ₁ -C ₆ alkoxy groups A phenylalkyl group which may be substituted with a nitro group or an amino group and the alkyl moiety is a straight or branched C ₁ -C ₆ alkyl group: the phenyl ring being substituted by a halogen atom or a halogen atom of 1-3 Phenyl group which may be substituted by C ₁ -C ₆ alkyl group which may be linear or branched form: Pyridyl group: C ₁ -C ₆ alkoxy group which is hydroxy group, amino group, straight chain or branched group Linear or branched C ₁ -C ₆ alkyl group having 1-3 substituents selected from the group consisting of high halogen atoms wherein the amino groups mentioned above are linear or branched C ₁ -C ₆ alkyl groups, straight Optionally by 1 or 2 substituents selected from the group consisting of a C ₁ -C ₆ alkanoyl group which is a chain or branched form, a C ₂ -C ₈ cycloalkyl group and a C ₁ -C ₈ alkoxycarbonyl group which is a straight or branched form May be substituted.

C ₁ -C ₆ alkynyl group, straight or branched: C ₁ -C ₆ alkanoyl group, straight or branched, which may be substituted by a halogen atom of 1-7: halogen atom or carboxy group of 1-3 C ₁ -C ₆ alkenylcarbonyl group which is a linear or branched form substituted by C ₁ -C ₆ alkoxycarbonyl group which is a linear or branched form: C ₁ -which is a straight or branched form of 1 or 2 Aminocarbonyl group which may be substituted by C ₆ alkyl group: C ₁ -C ₆ alkoxy group wherein the alkoxy moiety is linear or branched. Phenyl alkoxy carbonyl group: C ₁ -wherein the alkoxy moiety is linear or branched. C ₆ alkoxy group, phenyl-straight line alkoxycarbonyl which may be substituted by a carbonyl group or branched polymorph C ₁ -C ₆ alkanoyl-amino group: the alkoxy and alkyl moieties are each linear or branched C ₁ -C ₆ alkoxy polymorphs And alkoxycarbonyl akyls which are alkyl groups Carboxyalkyl group wherein the alkyl moiety is a linear or branched C ₁ -C ₆ alkyl group: an alinocarbonylalkyl group wherein the alkyl moiety is a straight or branched C ₁ -C ₆ alkyl group: 1 or 2 Linear or branched C ₁ -C ₆ alkyl group and alkyl group are linear or branched C ₁ -C ₆ alkyl group, linear or branched C ₁ -C ₆ alkoxycarbonyl group or linear or polymorph of the C ₁ -C ₆ alkanoyl group, an amino group which may be substituted by a phenylalkyl group: hydroxyl group: a linear or branched shape which may be substituted by a halogen atom 1-3 C ₁ - C ₆ alkylsulfonyl group: phthalide group: 2 (5H) -furanone group which may be substituted by 1 or 2 halogen atoms: sulfo whose alkyl moiety is linear or branched C ₁ -C ₆ alkyl group Alkyl Group: Oxo Group: C ₁ -C ₆ Alkoxy group: linear or branched C ₁ -C ₆ alkenyl group: halogen atom: straight chain or branched C ₁ -C ₆ alkanoyloxy group: phenyl group or linear or branched C _1- 2-oxo-1,3-dioxolenemethyl group which may be substituted by C ₆ alkyl group: C ₃ -C ₈ cycloalkylamino: C ₁ -C ₆ alkylthio which is a straight chain or branched form: And 2-oxo-1,3-dioxolene methylaminogroup-piperazinyl, piperadinyl, which may be substituted by a phenyl group or a linear or branched C ₁ -C ₆ alkyl group, such as , Pyrrolidinyl, homopiperazinyl, morpholinothio morpholino, 1,2,5,6-tetrahydro pyridyl amidazolyl, 1,4-diazabicyclo-4 (4,3,0 ) Nona-4-yl (1,4-diazabicyclo- (4,3,0) nona-yl) thiomorpholin-4-oxide, thiopolyno-4,4-da Oxidepyrazolidininyl, hexahydro pyridazinyl, pyridyl, thiapolydinyl, 2-thio-1-imidazolidinyl, 2-oxo-1-imidazolidinyl, 3,7-diazabicyclo (4,3,0) nona-3-yl, 4-methyl-1-piperazinyl, 4-ethyl-1-piperazinyl, 4-propyl-1-piperazinyl, 4-t-butyl-1 -Piperazinyl, 4-pentyl-1-piperazinyl, 4-hexyl-1-piperazinyl, 3-methyl-1-piperazinyl, 3,4-dimethyl-1-piperazinyl, 2, 5-dimethyl-1-piperazinyl, 2,4,5-primethyl-1-piperazinyl, 3,4,5-trimethyl-1-piperazinyl, 3-methyl-1-piperazinyl, 3-propyl-4-methyl-1-piperazinyl, 2-n-butyl-5-methyl-1-piperazinyl, 2-pentyl-5-hexyl-1-piperazinyl, 4-formyl-1- Piperazinyl, 4-acetyl-1-piperazinyl, 4-propionyl-1-piperazinyl, 4-butyryl-1-piperazinyl, 4-pentanoyl-1-piperazinyl, 4-hexa Noyl-1-piperazinyl, 4- (α, α, α- Trifluoroacetyl) -1-piperazinyl, 4-α, α, α-trifluoro-β, β-difluoro-α, α-difluorobutyryl) -1-piperazinyl, ( 4- (β, β, β-trifluoro-α, α-difluoro propionyl) -1-piperazinyl, 4- (α, α-dichloroacetyl) -1-piperazinyl, 4- (α-bromoacetyl) -1-piperazinyl, 4- (α-iodoacetyl) -1-piperazinyl, 4- (β-fluoro propionyl) -1-piperazinyl, 4- ( β-fluoro-α, -fluoropropionyl) -1-piperazinyl, 4- (6-fluorohexanoyl) -1-piperazinyl, 4- (4-chloropentayl) -1-piper Lazinyl, 4-benzyl-1-piperazinyl, 4- (2-phenylethyl) -1-piperazinyl, 4- (1-phenylethyl) -1-piperazinyl, 4- (3- Phenylpropyl) -1-piperazinyl, 4- (4-phenylbutyl) -1-piperazinyl, 4,-(1,1-dimethylmethylphenyl) -1-piperazinyl, 4 -(5-phenylpentyl) -1-piperazinyl, 4- (6-phenylhexyl) -1-piperazinyl, (4,2-meth -3-phenylpropyl) -1-piperazinyl, 4-amino-1-piperazinyl, 3-amino-1-piperazinyl, 2-amino-1-piperazinyl, 4-methylamino-1- Piperazinyl, 3-Dimethylamino-1-piperazinyl, 2-ethylamino-1-piperazinyl, 4-propylamino-1-piperazinyl, 4-tert-butylamino-1-piperazinyl , 3-pentylamino-1-piperazinyl, 2-hexylamino-1-piperazinyl, 4-dimethylamino-1-piperazinyl, 4- (N-methyl-Nn-butylamino) -1 -Piperazinal, 3- (N-methyl-Npentylimino) -1-piperazinyl, 2- (N-ethyl-N-hexylamino) -1-piperazinyl, 4-acetylamino-1 -Piperazinyl, 3-formylamino-1-piperazinyl, 2-propionylamino-1-piperazinyl, 4-butylylamino-1-piperazinyl, 3-pentanoylamino-1-pipera Genyl, 2-hexanoylamino-1-piperazinyl, 4- (N-methyl-N-acetylamino) -1-piperazinyl, 3- (N-ethyl-N-propionyl Mino) -1-piperazinyl, 4-hydroxy-1-piperazinyl, 3-hydroxy-1-piperazinyl, 2-hydroxy-1-piperazinyl, 4-methyl-sulfonyl-1 -Piperazinyl, 4-ethylsulfonyl-1-piperazinyl, 4-propylsulfonyl-1-piperazinyl, 4-n-butylsulfonyl-1-piperazinyl, 4-pentylsulfonyl-1 -Piperazinyl, 4-hexylsulfonyl-1-piperazinyl, 4-trifluoro methylsulfonyl-1-piperazinyl, 4- (3-fluoropropyl-sulfonyl) -1-piperazinyl , 4- (4,4,4-trifluoro butylsulfonyl) -1-piperazinyl, 4-sulfonyl-1-pyriperrazinyl, 4- (phthalide-3-yl) -1-piper Lazinyl, 4- (3,4-dibromo-2 (5H) -furanone-5-yl) -1-piperazinyl, 4- (2 (5H) -furanone-5-yl) -1- Piperazinyl, 4- (3-chloro-2 (5H) -furanone-5-yl) -1-piperazinyl, 4-formyl-3-methyl-1-piperazinyl, 4-acetyl-3- Methyl-1-piperazinyl-4-acetyl-2-methyl-1-piperazinyl, 4-methyl-3-hydroxymeth -1-piperazinyl, 3-hydroxymethyl-1-piperazinyl, 4-ethyl-3- (2-hydroxyethyl) -1-piperazinyl, 3- (3-hydroxypropyl)- 1-piperazinyl, 4-methyl-2- (4-hydroxybutyl) -1-piperazinyl, 4-ethyl-3- (5-hydroxypentyl) -1-piperazinyl, 3- (6 -Hydroxyhexyl) -1-piperazinyl, 4- (4-methoxybenzyl) -1-piperazinyl, 4- (3-ethoxybenzyl) -1-piperazinyl, 4- (2-prop Roxybenzyl) -1-piperazinyl, 4- (4-n-butoxybenzyl) -1-piperazinyl, 4- (3-pentyloxybenzyl) -1-piperazinyl, 4- (2-hex Siloxybenzyl) -1-piperazinyl, 4- (4-nitrobenzyl) -1-piperazinyl, 4- (3-nitrobenzyl) -1-piperazinyl, 4- (4-aminobenzyl ) -1-piperazinyl, 4- (2-aminobenzyl) -1-piperazinyl, 4-cyclopropyl-1-piperazinyl, 4-cyclobutyl-1-piperazinyl, 4-cyclopentyl- 1-piperazinyl, 4-cyclohexyl-1-piperazinyl, 4-cyclohep Tyl-1-piperazinyl, 4-cyclooctyl-1-piperazinyl, 4-phenyl-1-piperazinyl, 4- (4-fluorophenyl) -1-piperazinyl, 4- (3- Bromophenyl) -1-piperazinyl, 4- (2-chlorophenyl) -1-piperazinyl, 4- (4-iodophenyl) -1-piperazinyl, 4- (4-methylphenyl) -1-piperazinyl, 4- (3-ethylphenyl) -1-piperazinyl, 4- (2-propylphenyl) -1-piperazinyl, 4- (4-n-butylphenyl) -1- Piperazinyl, 4- (3-pentylphenyl) -1-piperazinyl, 4- (2-hexylphenyl) -1-piperazinyl, 4- (4-trifluoromethylphenyl) -1-pipera Genyl, 4- (3- (3-chloromethyl) phenyl) -1-piperazinyl, 4- (3,3-dibromopropyl) phenyl) -1-piperazinyl, 4- (4-4- ( Chlorobutylphenyl) -1-piperazinyl, 4-hydroxymethyl-1-piperazinyl, 4- (2-hydroxymethyl) -1-piperazinyl, 4- (3-hydroxypropyl) -1 -Piperazinyl, 4- (3-chloropropyl) -1-piperazinyl, 4- (bromomethyl) -1-piperazinyl, 4 -(2-fluoroethyl) -1-piperazinyl, 4- (4-chlorobutyl) -1-piperazinyl, 4- (3-fluoropentyl) -1-piperazinyl, 4- ( 2,3-dichlorohexyl) -1-piperazinyl, 4- (2,2,2-trifluoromethyl) -1-piperazinyl, 4- (trifluoromethyl) -1-piperazinyl , 4- (aminomethyl) -1-piperazinyl, 4- (3-aimethyl-aminopropyl) -1-piperazinyl, 4- (2-ethylaminoethyl) -1-piperazinyl, 4 -(4-propylaminobutyl) -1-piperazinyl, 4- (5-n-butylaminofetyl) -1-piperazinyl, 4- (6-pentylaminohexyl) -1-piperazinyl, 4 -(N-methyl-N-methylaminomethyl) -1-piperazinyl, 4- (N-methyl-N-propylaminomethyl) -1-piperazinyl, 4- (2-dimethylaminoethyl ) -1-piperazinyl, 4- (methoxymethyl) -1-piperazinyl, 4- (ethoxymethyl) -1-piperazinyl, 4- (2-propoxyl) -1-piper Lazinyl, 4- (3-butoxypropyl) -1-piperazinyl, 4- (4-pentyloxybutyl) -1-pipera Neyl, 4- (5-hexyloxypentyl) -1-piperazinyl, 4- (6-methoxyhexyl) -1-piperazinyl, 4-propazyl (4-propazyl) -1- Piperazinyl, 4- (2-butynyl) -1-piperazinyl, 4- (3-butynyl) -1-piperazinyl, 4- (1-methyl-2-propynyl) 1-pipera Genyl, 4- (2-pentynyl) -1-piperazinyl, 4- (2-hexynyl) -1-piperazinyl, 4-ethynyl-1-piperazinyl, 4-vinyl-1-piper Lazinyl, 4-allyl-1-piperazinyl, 4- (2-butenyl) -1-piperazinyl, 4- (3-butenyl) -1-piperazinyl, 4- (1-methylallyl ) -1-piperazinyl, 4- (2-pentenyl) -1-piperazinyl, 4- (2-hexenyl) -1-piperazinyl, 2-oxo-1-piperazinyl, 3- Oxo-1-piperazinyl, 4-oxo-3-methyl-1-piperazinyl, 4,4-dimethyl-1-piperazinyl, 4- (2-pyridyl) -1-piperazinyl, 4- (3-pyridyl) -1-piperazinyl, 4- (4-pyridyl) -1-piperazinyl, 4-carbamoyl-1-piperazinyl, 4-dimethylaminocarbonyl- 1-piperazinyl, 4-Ethylaminocarbonyl-1-piperazinyl, 4-propylaminocarbonyl-2-piperazinyl, 4-butylaminocarbonyl-1-piperazinyl, 4-pentylaminocarbonyl-1-pipera Genyl, 4-hexylaminocarbonyl-1-piperazinyl, 4-pymethylaminocarbonyl-1-piperazinyl, 4- (N-methyl-N-propylamino carbonyl) -1-piperazinyl, 4-methoxycarbonyl-1-piperazinyl, 4-ethoxy-carbonyl-2-piperazinyl, 4-propoxycarbonyl-1-piperazinyl, 4- (3-butoxycarbonyl- 1-piperazinyl, 4-pentyloxy carbonyl-1-piperazinyl, 4-hexyloxy carbonyl-1-piperazinyl, 4-benzyloxy carbonyl-1-piperazinyl, 4- (2 -Phenylethoxycarbonyl) -1-piperazinyl, 4- (3-phenylpropoxy carbonyl) -1-piperazinyl, 4- (4-phenylbutoxy carbonyl) -1-piperazinyl, 4- (5-phenylpentyloxycarbonyl) -1-piperazinyl, 4- (6-phenylhexyl oxycarbonyl) -1-piperazinyl, 4- (2-aminoacetyl) -1-pi Furazinyl, 4- (3-aminopropionyl) -1-piperazinyl, 4- (4-aminobutyryl) -1-piperazinyl, 4- (5-aminopentanoyl) -1-piperazinyl , 4- (6-aminohexanoyl) -1-piperazinyl, 4- (2-benzyloxycarbonyl aminoacetyl) -1-piperazinyl, 4- (2- (2-phenylethoxycarbonyl amino ) Acetyl) -1-piperazinyl, 4- (2- (3-phenylpropoxycarbonylamino) acetyl) -1-piperazinyl, 4- (2- (4-phenylbutoxy carbonylamino) acetyl ) -1-piperazinyl, 4-methoxycarbonylmethyl-1-piperazinyl, 4-ethoxycarbonylmethyl-1-piperazinyl, 4- (2-methoxycarbonyl ethyl) -1- Piperazinyl, 4- (3-propoxycarbonylpropyl) -1-piperazinyl, 4- (4-butoxycarbonylbutyl) -1-piperazinyl, 4- (5-pentyloxy carbonylpentyl ) -1-piperazinyl, 4- (6-hexyloxycarbonyl hexyl) -1-piperazinyl, 4-carbonylmethyl-1-piperazinyl, 4- (2-carboxymethyl) -1-piper Lazinyl, 4- (3-carboxypropyl)- 1-piperazinyl, 4- (4-carboxybutyl) -1-piperazinyl, 4- (5-carboxypentyl) -1-piperazinyl, 4- (6-carboxyhexyl) -1-piperazinyl , 4- (anilinocarbonylmethyl) -1-piperazinyl, 4- (2-anilino carbonyl ethyl) -1-piperazinyl, 4- (3-anilino carbonylpropyl) -1-piper Lazinyl, 4- (4-anilinocarbonyl propyl) -1-piperazinyl, 4- (5-anilinocarbonyl propyl) -1-piperazinyl, 4- (6-anilinocarbonyl hexyl) -1-piperazinyl, 4- (3-carboxycaylyl) -1-piperazinyl, 4- (3-carboxy-2,3-dichloro acyloyl) -1-piperazinyl, 4 Methyl-1-piperazinyl, 4-ethyl-1-piperazinyl, 4-propyl-1-piperazinyl, 4-n-butyl-1-piperazinyl, 4-pentyl-1-piperazinyl , 4-hexyl-1-piperazinyl, 4-ethoxy-1-piperedinyl, 4-pentyloxy-1-piperadinyl, 4-hexyloxy-1-piperadinyl, 4-acetyloxy- 1-piperadinyl, 4-propionyloxy-1-wave Perradinyl, 4-butyryloxy-1-piperadinyl, 4-pentanoyloxy-1-piperadinyl, 4-ethoxycarbonyl-1-piperadinyl, 4-pentyloxycarbonyl-1- Piperadinyl, 4-hexyloxycarbonyl-1-piperadinyl, -benzyl-1-piperadinyl, 4- (2-phenylethyl) -1-piperadinyl, 4- (5-phenylethyl ) -1-piperadinyl, 4- (3-phenylpropyl) -1-piperadinyl, 4- (4-phenylbutyl) -1-piperadinyl, 4- (5-phenylpentyl) -1-piper Radiinyl, 4- (6-phenylhexyl) -1-piperadinyl, 4-hydroxy-1-piperadinyl, 3-hydroxy-1-piperadinyl, 2-hydroxy-1-piperadinyl , 4-amino-1-piperazinyl, 3-amino-1-piperadinyl, 2-amino-1-piperadinyl, 4-dimethylamino-1-piperadinyl, 4-methylamino-1- Piperadinyl, 3-methylamino-1-piperadinyl, 2-propylamino-1-piperadinyl, 4-neo-butylamino-1-piperadinyl, 3-pentylamino-1-piperadinyl, 4-hexyl Mino-1-Piperadiinyl, 3-Diethylamino-1-piperadinyl, 4- (N-methyl-N-propylamino) -1-piperadinyl, 4-carbamoyl-1-piperaradi Nil, 3-carabamoyl-1-piperadinyl, 3,5-dimethylmethyl-1-piperadinyl, 2,5-dimethylmethyl-piperadinyl, 4-oxo-1-piperadinyl, 3-oxo-1-piperadinyl, 3-hydroxy-1-pyrrolidinyl, 3-amino-1-pyrrolidinyl, 2-hydroxy-1-pyrrolidinyl, 2-amino-1-pyrroli Diyl, 3-methylamino-1-pyrrolidinyl, 3-dimethylamino-1-pyrrolidinyl, 2-ethylamino-1-pyrrolidinyl, 3-propylamino-1-pyrrolidinyl, 2-butyl Amino-1-pyrrolidinyl, 3-pentylamino-1-pyrrolidinyl, 2-hexylamino-1-pyrrolidinyl, 3-dimethylamino-1-pyrrolidinyl, 3- (N-ethyl- N-propylamino) -1-pyrrolidinyl, 2- (N-ethyl-N-neo-butylamino) -1-pyrrolidinyl, 3-acetylamino-1-pyrrolidinyl, 3-propionylamino- 1-pyrrolidinyl, 2-part Tylylamino-1-pyrrolidinyl, 3-pentanoylamino-1-pyrrolidinyl, 2-hexanoylamino-1-pyrrolidinyl, 3-hydromethyl-2-pyrrolidinyl, 2- (2-hydro Hydroxyethyl) -1-pyrrolidinyl, 3- (3-hydroxypropyl) -1-pyrrolidinyl, 2- (4-hydroxybutyl) -1-pyrrolidinyl, 3- (5-hydroxy Pentyl) -1-pyrrolidinyl, 3- (6-hydroxyhexyl) -1-pyrrolidinyl, 3-aminomethyl-1-pyrrolidinyl, 3- (2-hydroxyethyl) -1-py Lolidinyl, 2- (3-aminopropyl) -1-pyrrolidinyl, 3- (4-aminobutyl) -1-pyrrolidinyl, 3- (5-aminopentyl) -1-pyrrolidinyl, 3- (6-aminohexyl) -1-pyrrolidinyl, 3- (methylaminomethyl) -1-pyrrolidinyl, 3- (2-ethylaminoethyl) -1-pyrrolidinyl, 3- (3-propyl Aminopropyl) -1-pyrrolidinyl, 2- (4-n-butylaminobutyl) -1-pyrrolidinyl, 3- (5-pentylaminopentyl) -1-pyrrolidinyl, 3- (6-hexyl Aminohexyl) -1-pyrrolidinyl, 3- (dimethylaminomethyl) -1-pyrrolidinyl, 2- (N-methyl -N-ethylaminomethyl) -1-pyrrolidinyl, 3- (N-methyl-N-neo-butylaminomethyl) -1-pyrrolidinyl, 3-methylaminomethyl-4-methyl-1-pyrroli Diyl, 3-methylaminoethyl-4-fluoro-1-pyrrolidinyl, 3-methylamino-4-methyl-1-pyrrolidinyl, 3-methylamino-4-chloro-1-pyrrolidinyl, 3-methylaminomethyl-4-chloro-1-pyrrolidinyl, 3-methylamino-4-fluoro-1-pyrrolidinyl, 3-ethylaminomethyl-4-ethyl-1-pyrrolidinyl, 3- Propylaminomethyl-5-propyl-1-pyrrolidinyl, 3-n-butylaminomethyl-5-fluoro-1-pyrrolidinyl, 3-pentylaminomethyl-5-n-butyl-1-pyrrolidinyl , 3-hexylaminomethyl-5-chloro-1-pyrrolidinyl, 3-propylamino-4-chloro-1-pyrrolidinyl, 3-neo-butylamino-5-hexyl-pyrrolidinyl, 3-pentyl Amino-4-methyl-1-pyrrolidinyl, 3-hexylamino-4-fluoro-1-pyrrolidinyl, 4-methyl-1-homopiperazinyl, 4-ethyl-1-homopiperazinyl, 4-propyl-1-homo pie Furazinyl, 4-neo-butyl-1-homopiperazinyl, 4-pentyl-1-homopiperazinyl, 4-hexyl-1-homopiperazinyl, 4-homopiperazinyl, 4-acetyl-1 Homopiperazinyl, 4-propionyl-1-homopiperazinyl, 4-butylyl-1-homopiperazinyl, 4-pentanoyl-1-homopiperazinyl, 4-hexanoyl-1-homo Piperazinyl, 2-methyl-1-hexahydro pyridazinyl, 2-ethyl-1-hexahydro pyridazinyl, 2-methyl-1-hexahydro pyridazinyl, 2-ethyl-1-hexahydro pyrida Genyl, 2-propyl-1-hexahydro pyridazinyl, 2-n-butyl-1-hexahydro pyridazinyl, 2-pentyl-1-hexahydro pyridazinyl, 2-hexyl-1-hexahydro pyrida Genyl, 2-formyl-1-hexahydro pyridazinyl, 2-acetyl-1-hexahydro pyridazinyl, 2-propionyl-1-hexahydro pyridazinyl, 2-butyryl-1-hexahydro pyrida Genyl, 2-pentanoyl-1-hexahydro pyri Genyl, 2-hexanoyl-1-hexahydro pyridazinyl, 2-methyl-1-pyrazolidinyl, 2-ethyl-1-pyrazolidinyl, 2-propyl-1-pyrazolidinyl, 2-neo-butyl -1-pyrazolidinyl, 2-pentyl-1-pyrazolidinyl, 2-hexyl-1-pyrazolidinyl, 2-formyl-1-pyrazolidinyl, 2-acetyl-1-pyrazolidinyl, 2-propy Onyl-1-pyrazolidinyl, 2-butyryl-1-pyrazolidinyl, 2-pentanoyl-1-pyrazolidinyl, 2-hexanoyl-1-pyrazolidinyl, 3,5-dimethylmorepolyno , 3-methylmorpholino, 3-ethylmoreolino, 2-propylmoreolino, 3-n-butylmorpholino. 3-pentyl-5-methylmorefolio, 3-hexyl-5-ethylmorelino, 2-ethylaminomethyl morpholino, 3-propylaminomethyl morpholino, 3-n-butylaminomethyl morpholino , 2-pentylaminomethyl morpholino, 3-hexylaminomethyl morpholino, 3- (2-methylaminoethyl)-morpholino, 3- (3-methylamino propyl) morpholino, 3- ( 4-Methylaminobutyl) morefolio, 2- (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl-1-piperazinyl, 4- (5-tert-butyl- 2-oxo-1,3-dioxolen-4-yl) methyl-1-piperazinyl, 4- (5-phenyl-2-oxo-1,4-dioxolen-4-yl) methyl-1-piper Lazinyl, 4- (2-oxo-1,3-dioxolen-4-yl) methyl-1-piperazinyl, 3- (5-methyl-2-oxo-1,3-dioxolen-4-yl Methylamino-1-piperazinyl, 4- (5-methyl-2-oxo-1,3-dioxolen-4-yl) methylamino-1-piperazinyl, 3- (5-phenyl-2- Oxo-1,3-dioxolen-4-yl-methylamino morpholino, 3,5-dimethyl-1-piperage , 3,3-Dimethyl-1-piperazinyl, 4-acetyl-3-methyl-1-piperazinyl, 3-ethyl-1-piperazinyl, 3-ethyl-4-methyl-1-pipera Genyl, 3- (trifluoromethyl) -1-piperazinyl, 3- (fluoromethyl) -1-piperazinyl, 3-methylthio-1-piperazinyl, 4-methylthio-1 -Piperazinyl, 3-ethylthio-1-piperazinyl, 3-methylthio morpholino, 4-fluoro-1-piperazinyl, 3-fluoro-1-piperazinyl, 3- Chloro-1-piperazinyl, 3-amino-4-fluoro-1-pyrrolidinyl, 3-amino-4-hydroxy-1-pyrrolidinyl, 3-amino-4-methoxy-1-py Lolidinyl, 3-amino-4-fluoro-1-piperazinyl, 3-amino-4-hydroxy-1-piperadinyl, 3-amino-4-methyl-1-pyrrolidinyl, 4-benzyl -3-methyl-1-piperazinyl, 3-fluoromethyl morpholino, 3-chloromethyl morpholino, 4-oxo-1-piperadinyl, 3-oxo-1-piperadinyl, 2- Oxo-1-piperadinyl, 3-acetylaminomethyl-1-pyrrolididyl, 3- (N-ethyl-N-acetylamino) -1-methyl-1-pyrrolidinyl, 3,3-t-butoxycarbonyl aminomethyl-1- Pyrrolidinyl, 3-ethylaminomethyl-1-pyrrolidinyl, 4-cyclopropylamino-1-piperazinyl, 3-cyclopropylamino-1-pyrrolidinyl, 4-cyclopentylamino-1-pipera Genyl, 4-cyclohexylamino-1-piperazinyl, 3-cycloheptylamino-1-pyrrolidinyl, 4-cyclooctylamino-1-piperadinyl, 4-cyclopropylamino-1-piperadinyl, 3-cyclopropyl aminomorepolyno, 4-thio-1-piperazinyl, 3-thio-1-piperazinyl, 3-thiomorpholino, 4-cyclopropyl aminomethyl piperazinyl, 3 -Cyclopropyl aminomethyl-1-pyrrolidinyl, 4-cyclopropyl aminomethyl-1-piperidinyl, 3-cyclopropyl aminomethyl morpholino, 4- (2-cyclopentyl amino Chill) -1-piperazinyl, 4- (3-cyclohexyl aminopropyl) -1-piperazinyl, 3- (4-cyclobutyl aminobutyl) -1-pyrrolidinyl, 4- (5-cyclooctyl Aminopentyl) -piperidinyl, 4- (6-cyclopropyl aminohexyl) morepolyno, 3-acetylaminomethyl-1-pyrrolidinyl, 4- (2-propylonyl aminoethyl) -1-pipera Genyl, 4- (3-butyryl aminopropyl) -1-piperidinyl, 3- (4-pentanoyl aminobutyl) morepolyno, 4- (5-hexanoyl aminopentyl) -piperazinyl, 3- (6-acetylaminohexyl) -1-pyrrolidinyl, 4- (N-acetyl-N-ethylamino) methyl-1-piperazinyl, 4- (N-cyclopropyl-N-acetylamino) methyl-1 -Pyrrolidinyl, 4- (methoxycarbonyl aminomethyl) -1-piperazinyl, 4- (2-ethoxycarbonyl aminoethyl) -1-piperadinyl, 3- (3-propoxycarbon Nylaminopropyl) morepolyno, 3- (4-pentyloxycarbonyl aminobutyl) -1-pyrrolidinyl, 3- (5-hexyloxyca Nyl aminopentyl) -1-pyrrolidinyl, 4- (6-t-butoxycarbonyl aminohexyl) -1-piperazinyl, 3- (Nt-butoxycarbonyl-N-ethylaminomethyl) -1 -Pyrrolidinyl, 3- (Nt-butoxycarbonyl-N-methylaminomethyl) -1-pyrrolidinyl, 3- (Nt-butoxycarbonyl-N-cyclopropyl aminomethyl) -1-pyrroli Diyl, 4- (N-methoxycarbonyl-N-cyclopropyl aminomethyl) -1-piperazinyl, 4- (N-propoxycarbonyl-N-cyclohexyl aminomethyl) -1-piperidinyl and The term “cycloalkyl” includes C ₃ -C ₈ cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

The term "phenyl (low) alkyl wherein phenyl ring may be substituted by (low) alkoxy, nitro or amino" is a C ₁ -C ₆ alkoxy group, a nitro group or amino, wherein the phenyl ring is linear or branched. Which may be substituted by a group, the alkyl moiety being benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1,1-dimethylmethylphenyl, 5- Phenylpentyl, 6-phenylhexyl, 2-methyl-3-phenylpropyl, 4-methoxybenzyl, 3-ethoxybenzyl, 2-propoxybenzyl, 4-n-butoxybenzyl, 3-tentyloxybenzyl, 2 -Hexyloxybenzyl, 4-nitrobenzyl, 3-nitrobenzyl, 4-aminobenzyl, 2-aminobenzyl, 2- (4-ethoxyphenyl) ethyl, 1- (3-ethoxyphenyl) ethyl, 3 Straight chains such as-(2-propoxyphenyl) -propyl, 4- (4-n-butoxyphenyl) butyl, 5- (2-nitrophenyl) pentyl, 6- (3-aminophenyl) hexyl or the like or Phenylalkyl group which is a branched C ₁ -C ₆ alkyl group.

"Phenyl ring in diphenyl group which may be bound by halogen atom (low) alkyl or (low) alkyl substituted by halogen atom of 1-3 may be substituted by halogen atom, or phenyl, 4-fluoro Rophenyl, 3-bromophenyl, 2-chlorophenyl, 4-n-butylphenyl, 3-pentylphenyl, 2-hexylphenyl, 4-trifluoromethylphenyl, 3- (2-chloroethyl) phenyl, 2- (3,3-dibromopropyl) phenyl, 4- (4-chlorobutyl) phenyl, 3- (5-iodopentyl) phenyl, 4- (6-fluorohexyl) phenyl, 2- (1, C, straight or branched, which may be substituted by 1-3 halogen atoms, such as 2,2-trifluoroethyl) phenyl, 4- (2,2,2-trifluoroethyl) phenyl, and the like This phenyl ring may also be substituted by a ₁ -C ₆ alkyl group.

"Hydroxy, amino, (low) alkoxy and halogen atoms, wherein the amino mentioned above are optionally (low) alkyl, (low) alkanoyl, cycloalkyl or (low) alkoxycarbonyl and are selected from the group consisting of these compounds The term (lower) alkyl having 1-3 substituents includes a C ₁ -C ₆ alkyl group which is a straight or branched group having 1-3 substituents selected from the group consisting of the following compounds.

Hydroxy group: C ₁ -C ₆ alkyl group which is linear or branched, C ₁ -C ₆ alkanoyl group which is linear or branched, C ₃ -C ₈ cycloalkyl group and C ₁ which is linear or branched Amino groups which may be substituted by one or two substituents selected from the group consisting of -C ₆ alkoxycarbonyl groups: hydroxymethyl, 2-hydroxyethyl, l-hydroxyethyl, 2-hydroxy Propyl, 4-hydroxybutyl, 5-hydroxypentyl, 6-hydroxyhexyl, 3-chloropropyl, bromomethyl, 2-fluoromethyl, 4-chlorobutyl, 3-fluoropentyl, 2,5- Dichlorohexyl, 2,2,2-trifluoroethyl, trifluoromethyl, aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl , 6-aminohexyl, 3-dimethylaminopropyl, 2-ethylaminoethyl, 4-propylaminobutyl, 5-n-butylaminopentyl, 6-pen Aminohexyl, methylaminomethyl, ethylaminoethyl, 2-dipropylaminomethyl, 1-di-n-butylaminoethyl, 3-dipentylaminopropyl, 4-dihexylaminobutyl, N-methyl- N-ethylaminomethyl, N-methyl-N-propylaminomethyl, methoxymethyl, ethoxymethyl, 2-propoxylyl, 3-butoxypropyl, 4-pentyloxybutyl, 5-hexyloxypentyl, 6 -Methoxyhexyl, propoxymethyl, 1-ethoxyethyl, 2-hexyloxyethyl, formylaminomethyl, acetylaminomethyl, 2-propanoylaminoethyl, 3-butyrylaminopropyl, 4-penta Noylaminobutyl, 5-hexanoyl aminopentyl, 6-acetyl aminohexyl, propanoylaminoethyl, N-acetyl-N-methylaminomethyl, N-acetyl-N-ethylaminomethyl, N-acetyl-N- Cyclopropylaminomethyl, N, N-dicyclopropyl aminomethyl, cyclopropyl aminomethyl, 2-cyclobutyl aminoethyl, 3-cyclopentyl, 1- between Ropropyl aminoethyl, 2-cyclopropyl aminoethyl, aminopropyl, 4-cyclohexyl aminobutyl, 5-cycloheptyl aminopentyl, 6-cyclooctyl aminohexyl, N-methyl-N-cyclopropylaminomethyl, N -Ethyl-N-cyclopropyl aminomethyl, methoxycarbonylaminomethyl, 2-methoxycarbonylaminoethyl, 3-propoxycarbonyl aminopropyl, 4-t-butoxycarbonyl aminobutyl, 5-pentyl Oxycarbonyl aminopentyl, 6-hexyloxycarbonyl aminohexyl, t-butoxycarbonyl aminoethyl, 2-t-butoxycarbonyl aminoethyl, 1-t-butoxycarbonylaminoethyl, Nt Straight-chain or branched forms such as butoxycarbonylamino-N-ethylaminomethyl, Nt-butoxycarbonyl amino-N-ethylaminoethyl, Nt-butoxycarbonylamino-N-cyclopropyl aminomethyl, etc. C ₁ -C ₆ alkoxy groups and halogen atoms.

The term "(low) alkanoyl, which may be substituted by 1-7 halogen atoms," refers to formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, α, α, α-trifluoroacetyl, β , β, β-trifluoro-α, α-difluoropropionyl, α, α, α-trifluoro-β, β-difluoro-α, α-difluorobutyryl, α, α -Dichloroacetyl, α-bromoacetyl, α-ioacetyl, β-fluoropropionyl, β-fluoro-α-fluoropropionyl, 6-fluorohexanoyl, 4-chloropentanoyl, 3, C ₁ -C ₆ alkanoyl groups which are linear or branched which may be substituted by 1-7 halogen atoms such as 3,3-trifluoro propionyl and the like.

The term "(low) alkenylcarbonyl having 1-3 substituents selected from the group consisting of halogen atoms and carboxy" refers to 3-carboxyacryloyl, 3-carboxy-2,3-dichloroacryloyl, 3- 1 selected from the group consisting of halogen atoms and carboxy groups such as carboxy-2,3-dibromoacryloyl, 4-carboxycrotonoyl, 5-carboxy-3,4-dichloro-3-hexenoyl, and the like Linear or branched C ₁ -C ₆ alkenylcarbonyl groups having a substituent of -3.

The term "(low) alkoxycarbonyl" refers to methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, C ₁ -C ₆ alkoxycarbonyl groups which are linear or branched forms such as hexyloxycarbonyl and the like.

The term "aminocarbonyl which may be substituted by (low) alkyl" refers to carbamoyl, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, n-butylaminocarbonyl, ethylaminocarbonyl, Dipropylaminocarbonyl, Dipentylaminocarbonyl, Diethylaminocarbonyl, Dipropylaminocarbonyl, Dipentylaminocarbonyl, Dihexylaminocarbonyl, N-Methyl-N-propylaminocarbonyl, N- Aminocarbonyl groups which may be substituted by one or two linear or branched C ₁ -C ₆ alkyl groups such as methyl-N-tert-butylaminocarbonyl, N-ethyl-N-pentylaminocarbonyl It includes.

The term "phenyl (low) alkoxycarbonyl" means that the alkoxy moiety is benzyloxy carbonyl, 2-phenyloxycarbonyl, 1-phenylethoxycarbonyl, 3-phenylpropoxycarbonyl, 4-phenylbutoxycarbonyl Or chains such as 1,1-dimethyl-2-phenylethoxycarbonyl, 5-phenylpentyloxycarbonyl, 6-phenylhexyloxycarbonyl, 2-methyl-3-phenylpropoxycarbonyl, or the like Phenylalkoxycarbonyl group, which is a C ₁ -C ₆ alkoxy group, which is a form.

The term "amino (low) alkanoyl which may be substituted by phenyl (low) alkoxy carbonyl" means that the alkoxy moiety is 2-aminoacetyl, 3-aminopropionyl, 4-aminobutyryl, 5-aminopentanoyl, 6-aminohexanoyl, 2-benzylacetyl, 2- (3-phenylpropoxycarbonylamino) acetyl, 3- (4-phenylbutoxycarbonylamino) propionyl, 4- (1,1-dimethyl- 2-phenylethoxycarbonylamino) butyryl, 5- (5-phenylpentyloxy carbonylamino) pentanoyl, 6- (6-phenylhexyloxy carbonylamino) hexanoyl, 2- (2-methyl- 3-phenyl-propoxy-carbonyl-amino) acetyl such as a linear or branched shape such as a C ₁ -C ₆ alkoxy group, a phenyl-alkoxycarbonyl which may be substituted by a linear or branched shape with carbonyl group C ₁ -C ₆ amino Alkanoyl groups.

The term "(low) alkoxycarbonyl (low) alkyl" means that the alkoxy and alkyl moieties are methoxycarbonylmethyl, ethoxycarbonylmethyl, 2-ethoxycarbonylethyl, 3-propoxycarbonylpropyl, 4 Straight chains or branched bodies such as hexyloxycarbonylhexyl, 2-methoxycarbonylethyl, 3-methoxycarbonylpropoxypropyl, 3-ethylcarbonyl propoxypropyl, 4-ethylcarboxybutoxy butyl, etc. Phosphorus C ₁ -C ₆ alkoxy and an alkoxycarbonyl group which is an alkyl group.

The term "carboxy (low) alkyl" means that the alkyl moiety is carboxymethyl, 2-carboxyl, 3-carboxypropyl, 4-carboxybutyl, 5-carboxypentyl, 6-carboxyhexyl, 1-carboxyl, 1, Carboxyalkyl groups which are linear or branched C ₁ -C ₆ alkyl groups such as 1-dimethyl, 2-carboxyl, 2-methyl-3-carboxypropyl and the like.

The term "anilinocarbonyl (lower) alkyl" is not an alkyl moiety of anilinocarbonylmethyl 2-anilinocarbonylethyl, 1-anilinocarbonylmethyl, 3-anilinocarbonylpropyl, 4-anilino Straight lines such as carbonylbutyl, 5-anilinocarbonylpentyl, 6-anilinocarbonylhexyl, 1,1-dimethyl-2-anilinocarbonylethyl, 2-methyl-3-anilinocarbonylpropyl, etc. An anilinocarbonylalkyl group that is a C ₁ -C ₆ alkyl group that is a chain or branched body.

The term "amino which may be substituted by (low) alkyl or (low) alkanoyl" refers to amino, methylamino, ethylamino, propylamino, t-butylamino, pentylamino, hexylamino, dimethylamino, die Cylamino, di-n-propylamino, di-n-butylamino, dipentylamino, dihexylamino, N-methyl-Nn-butylamino, N-methyl-N-pentylamino, N-ethyl-N-hexyl Amino, acetylamino, formylamino, propionylamino, butyrylamino, pentanoylamino, hexanoylamino, N-methyl-N-butyrylamino, N-ethyl-N-propionylamino, N-methyl-N- C ₁ -C ₆ alkyl group or linear or branched form, such as butyrylamino, Nn-propyl-N-pentanoylamino, N-ethyl-N-hexanoylamino, etc. Amino groups which may be substituted by C ₁ -C ₆ alkanoyl groups.

The term "2 (5H) -furanone which may be substituted by one or two halogen atoms" refers to 2 (5H) -furanone-5-yl, 3.4-dibromo-2 (5H) -furanone-5 Which may be substituted by one or two halogen atoms, such as -yl, 4-fluoro-2 (5H) -furanone-5-yl, 3-iodo-2 (5H) -furanone-5-yl, etc. 2 (5H) -furanone group.

The term "sulfo (low) alkyl" means that the alkyl moiety is sulfomethyl, 2-sulfoethyl, 3-sulfopropyl, 4-sulfobutyl, 5-sulfopentyl, 6-sulfohexyl, 1,1-dimethyl-2 -Sulfoalkyl groups which are linear or branched C ₁ -C ₆ alkyl groups such as sulfoethyl, 2-methyl-3-sulfopropyl and the like.

The term "(lower) alkylsulfonyl which may be substituted by 1-3 halogen atoms" means methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, pentylsulfonyl, hexylsulfonyl, Trifluoromethylsulfonyl, 2-fluoromethylsulfonyl, 3-fluoropropylsulfonyl, 4,4,4-trifluoro butylsulfonyl, 5-chloropentylsulfonyl, 6-bromohexylsulfonyl, C, straight or branched, which may be substituted by 1-3 halogen atoms such as 6-iodohexylsulfonyl, 2,2-difluoroethylsulfonyl, 2,3-dibromopropyl sulfonyl, and the like _1- C ₆ alkylsulfonyl group.

The term "(low) alkoxy" refers to C ₁ -C ₆ which is a linear or branched body such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like. Alkoxy groups.

The term "(low) alkanoyloxy" refers to C ₂ -C ₆ alkanoyloxy, which is a linear or branched body such as acetyloxy, propionyloxy, butyryloxy isobutyryloxy, pentanoyloxy, hexanoyloxy Include a group.

The term "(low) alkenyl" refers to C ₂ -which is a linear or branched body such as vinyl, allyl, 2-butenyl, 3-butyl, 1-methylallyl, 2-pentenyl, 2-hexenyl, etc. C ₆ alkenyl groups.

The term "(low) alkynyl" refers to straight lines such as ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 2-hexynyl, etc. Chain or branched C ₂ -C ₆ alkenyl groups.

The term "2-oxo-1,3-dioxorenmethyl, which may be substituted by phenyl or (low) alkyl" (5-methyl-2-oxo-1,3-dioxoren-4-yl) -methyl , (5-tert-butyl-2-oxo-1,3-dioxoren-4-yl) methyl, (5-phenyl-2-oxo-1,3-dioxoren-4-yl) ethyl, (2- Oxo-1,3-dioxoren-4-yl) methyl, (5-pentyl-2-oxo-1,3-dioxoren-4-yl) methyl, (5-hexyl-2-oxo-1,3- Dioxoren-4-yl) methyl, (5-ethyl-2-oxo-1,3-dioxoren-4-yl) methyl, (5-propyl-2-oxo-1,3-dioxoren-4-yl 2-oxo-1,3-dioxorenmethyl group which may be substituted by a phenyl group such as methyl) or a C ₁ -C ₆ alkyl group which is a linear or branched body.

"1-5 selected from the group consisting of 5 or 6 saturated heterocyclic, (low) alkylthio, amino, (low) alkylamino, (low) alkanoyloxy, hydroxy, (low) alkoxy and halogen atoms The term (lower) alkyl ", which may be substituted by a substituent of 3, refers to hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 4 in addition to the (low) alkyl mentioned above. -Hydroxybutyl, 5-hydroxypentyl, 6-hydroxyhexyl, fluoromethyl, 3-chloropropyl, bromomethyl, 2-fluoroethyl, 4-chlorobutyl, 3-fluoropentyl, difluoro Chloromethyl, 2,3-dichlorohexyl, 2,2,2-trifluoroethyl, trifluoromethyl, chloromethyl, dibromomethyl, iodomethyl, dichloromethyl, methoxymethyl, ethoxymethyl , 2-propoxyl, 3-butoxypropyl, 4-pentyloxybutyl, 5-hexyloxypentyl, 6-methoxyhex Yarn, propoxymethyl, 1-ethoxyethyl, 2-hexyloxyethyl, aminoethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl , 6-aminohexyl, 3-dimethylaminopropyl, 2-ethylaminoethyl, 4-propylaminobutyl, 5-n-butylaminopentyl, 6-pentylaminohexyl, methylaminomethyl, dimethylaminomethyl, 2-dipropylaminoethyl, 1-di-n-butylaminoethyl, 3-dipentylaminopropyl, 4-di-hexylaminobutyl, N-methyl-N-ethylaminomethyl, N-methyl-N- Propylaminomethyl, formyloxymethyl, acetyloxymethyl, 2-propionyloxyethyl, 3-butyryloxypropyl, 4-pentanoyloxybutyl, 5-hexanoyloxypentyl, 6-acetyloxyhexyl, propionyloxy Methyl, 1-acetyloxyethyl, 2-hexanoyloxyethyl, (1-pyrrolidinyl) methyl, 1- (1-piperazinyl) ethyl, (1-piperazinyl) ethyl, 3-morphopoly Nopropyl, 4-thiomorpholino Tyl, 5- (1-pyrrolidinyl) pentyl, 6- (1-piperazinyl) hexyl, methylthiomethyl, ethylthioethyl, 2-propylthiomethyl, 1-isopropylthioethyl, 3 -butyl thio-propyl, 4-tert-butyl-thio-butyl-5-pentyl-thiophene-naphthyl, 6-hexyl-thio-hexyl, etc. and cyclic saturated heterocyclic five or six ring such as, linear or branched C ₁ polymorph of -C ₆ alkylthio group, hydroxy group, amino group having linear or branched amino group 1 or 2 amino group having C ₁ -C ₆ alkyl group, straight chain or branched C ₁ -C ₆ alkyl group And a linear or branched C ₁ -C ₆ alkyl group substituted by a substituent of 1-3 selected from the group consisting of a C ₁ -C ₆ alkanoyloxyethyl group which is a linear or branched group and a halogen atom .

The term "2-oxo-1,3-dioxorenmethyl amino which may be substituted by phenyl or (low) alkyl" refers to (5-methyl-2-oxo-1,3-dioxoren-4-yl) methyl Amino, (5-tert-butyl-2-oxo-1,3-dioxoren-4-yl) methylamino, (5-phenyl-2-oxo-1,3-dioxoren-4-yl) methylamino, (2-oxo-1,3-dioxoren-4-yl) methylamino, (5-pentyl-2-oxo-1,3-dioxoren-4-yl) methylamino, (5-hexyl-2-oxo -1,3-dioxoren-4-yl) methylamino, (5-yl-2-oxo-1,3-dioxoren-4-yl) methylamino, (5-propyl-2-oxo-1,3 2-oxo-1,3-dioxophene methylamino group which may be substituted by a phenyl group such as -dioxoren-4-yl) methylamino, or a C ₁ -C ₆ alkyl group which is a linear or branched form. Include.

The term "cycloalkylamino" includes C ₃ -C ₈ cycloalkylamino groups such as cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino, cyclooctylamino and the like.

The term "(low) alkylthio" refers to straight chains such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, tert-butylthio, pentylthio, hexylthio, etc. Or a branched C ₁ -C ₆ alkylthio group.

The present invention compounds of the general formula (I) above can be made by several processes, for example, by the process shown in the following reaction scheme.

Reaction Scheme-I

(여기서 R¹¹과 R^l2는 각각 낮은 알킬) 또는 낮은 알콕시, 그리고 X²와 X³는 각각 할로겐 원자이고, R⁷과 R⁸은 각각 낮은 알킬이다.Where R ¹ , R ² , R ³ and X are as defined above, R ^{2 '} is a halogen atom or R ² is a group (R ² is as defined above), and R ⁴ is a group of formulas: -COR ⁹ (where R ⁹ is low alkyl) or group of formulas: -COOR ¹⁶ where R ¹⁰ is low alkyl) and R ⁵ is low alkyl, R ⁶ is a group of formulas:

(Wherein R ¹¹ and R ^l2 are each lower alkyl) or lower alkoxy, and X ² and X ³ are each a halogen atom, R ⁷ and R ⁸ are each lower alkyl.

Halogenation of compound (2) is carried out by reacting the solvent with a halogenation reagent in the presence or absence.

The solvent may be aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.) halogenated hydrocarbons (e.g. dichloromethane, chloroform, carbon, tetrachloride, etc.), ethers (e.g. dioxane, tetrahydrofuran, die Chill ether, etc.), dimethylformamide (DMF), die sulphoxide (DMSO) and the like. Halogenation reagents can be conventionally used for any halogenation reagent, as long as they can convert the hydroxy of the carboxy group to a halogen atom. For example, thionyl chloride, phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride, phosphorus Pentabromide and the like.

Although the amount of the compound of the halogenating reagent is not particularly determined, a very large amount of halogenating reagent is used when using a solvent, and at least one mole of the halogenating reagent is used when using a solvent. It is to use 2-4 moles.

The reaction temperature and reaction time were also not specifically determined, but the reaction usually proceeds between 100 ° C. at ambient temperature for 30 minutes to 6 hours.

The reaction of compounds (3) and (4) is carried out using a suitable solvent in the presence of a base compound.

Solvents should be used as long as they do not adversely affect the reaction of water, ethers (e.g., diester ether, dioxane, tetrahydrofuran, monoglyme, niglyme, etc.) aromatic hydrocarbons (e.g. benzene, toluene, xylene Aliphatic hydrocarbons (e.g. hexane, heptane, cyclohexane, ligroin, etc.) amines (e.g. pyridine, N, N-dimethylaminoline, etc.) halogenated hydrocarbons (e.g. chloroform, dichloromethane, carbon tetra) Aprotic polar solvents (eg, DMF, DMSO, hexamethylphosphoamide (HMPA), etc.) and mixtures of such solvents. Base compounds are inorganic bases (e.g., metal sodium, metal calcium, metal magnesium, sodium hydride, amide sodium, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, etc.) metal alcohols (e.g. sodium methacrylate, sodium Acrylates, etc.) and organic bases such as pyridine, piperidine, quinoline, triethamine, N, N-dimethylaniline, and the like.

The reaction is always carried out for 30 minutes to 15 hours at 120 ° C., preferably at ambient temperature of 0 ° C.-150 ° C.

At least one mole of compound (4) is used, more preferably at least one mole per one mole of compound (3) and even more preferably 1-2 moles per one mole of compound (3).

Compound (5), wherein R ⁴ is a COR ⁹ group, is added to the reaction to remove the COR ⁹ group under a basic compound and a suitable solvent.

The solvent may be an ether (e.g., diester ether, dioxane, tetrahydrofuran, monoglyme, diglyme, etc.), an aromatic hydrocarbon (e.g. benzene, toluene, xylene, etc.) aliphatic hydrocarbon (e.g. n-hexane, heptane) , Cyclohexane, etc.) Includes such as aprotic polar solvents (eg DMF, DMSO, HMPA, etc.).

Base solvents include ammonia gas, liquid ammonia, primary or secondary amines (eg methylamine, dietamine, piperidine, etc.).

The reaction is carried out at 0 ° C.-150 ° C. and preferably at ambient temperature up to 100 ° C. for 1-20 hours.

Compound (5), wherein R ⁴ is a COOR ¹⁰ group, is added to the reaction to remove ¹⁰ moles of COOR from the aqueous solution under acid catalyst.

Acid catalysts include inorganic acids (eg hydrochloric acid, sulfuric acid) and organic acids (eg p-toluene sulfonic acid).

The reaction is carried out at ambient temperature −10 ° C. for 0-20 ° C. and more preferably 1-20 hours. The reaction of the compound (6) with the compound from which the R ⁴ group has been removed is carried out in a suitable solvent.

The solvent may be any solvent used in the above reaction for removing the R ⁴ group. The reaction is carried out at 0 ° C.-200 ° C. and preferably at 0 ° C.-150 ° C. for 30 minutes-10 hours. A large amount of compound (6) is used in the same amount, but more preferably 1-2 mole is used per 1 mole of compound (5).

In the case of using compound (6) in which R ⁶ is a low alkoxy group, the reaction is not only as many as the above-mentioned solvents at temperatures of 0 ° C-200 ° C and more preferably 0 ° C-170 ° C, but also acid anhydrides as solvents Anhydride).

The reaction of compounds (7) and (8) is carried out in a suitable solvent.

The solvent may be any conventional solvent as long as it does not have an undesirable effect on the reaction, for example alcohols (e.g. methanol, ethanol, propanol, etc.), ethers (e.g. diethether, dioxane, tetrahydrofuran, monoglyme, Diglyme) aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.) aliphatic hydrocarbons (e.g., n-hexane, heptane, cyclohexane, ligroin, etc.) halogenated hydrocarbons (e.g., chlororom, methylene chloride, carbon tetra Chlorides) aprotic polar solvents (eg DMF, DMSO, HMPA, etc.).

The reaction is always carried out at ambient temperature -100 ° C for 0 minutes-150 ° C and even better for 30 minutes-15 hours.

Compound (8) is used at least 1 mole, more preferably 1-2 moles per 1 mole of compound (7). The base compound in the reaction may be optionally added, and such base compound may be any base compound used in the above reactions of compounds (3) and (4).

Cyclization of compound (9) proceeds in a suitable solvent in the presence of a base compound. The solvent may be any conventional compound as long as it does not have an undesirable effect on the reaction and for example aliphatic hydrocarbons (e.g., ethers, eg, ether, dioxane, tetrahydrofuran, monoglyme, diglyme, etc.) , Heptane, ligroin, etc.) Halogenated hydrocarbons (eg chloroform, methylene chloride, carbon tetrachloride, etc.) and aprotic polar solvents (eg DMF, DMSO, HMPA, etc.).

Base compounds include inorganic bases (e.g. metal sodium, metal potassium, sodium hydrogen, amide sodium, sodium hydroxide, potassium hydroxide, etc.) metal alcoholates (e.g. sodium methacrylate, sodium acrylate, etc.) and organic bases (e.g. 1 , 8-diazabicyclo (5,4,0) undecene-7 (DBU), N-benzyltrimethylammonium hydroxide, tetrabutylammonium hydroxide and the like.

The reaction is always carried out at ambient temperature -120 ° C. for 30 minutes-5 hours, in order to improve 0 ° C.-150 ° C. better.

At least 1 mole of the basic compound, more preferably, 1-2 moles are used for 1 mole of the compound (9).

Dehydration of compound (10) can be accomplished by conventional dehydration conditions, for example, basic compounds (e.g. sodium hydroxide, potassium hydroxide, barium hydroxide, potassium carbonate, etc.), inorganic monic acid (e.g. sulfuric acid, hydrochloric acid, nitric acid, etc.) or organic monic acid (acetic acid, In the presence of water, alcohols (e.g. methanol, ethanol, isopropanol) ketones (e.g. acetone, methyl ketone, etc.) ethers (e.g. dioxane, ethylene glycol, etc.) It is carried out in the same solvent as the mixture.

The reaction is always carried out at ambient temperature -150 ° C for 10-30 hours.

Compound (la) is produced by the reaction.

[Schematic diagram of the reaction- II]

(여기서 R¹⁴와 R¹⁵는 각각 알킬이다)이다.Wherein R ¹ , R ³ and X are as defined above, X ⁴ is a halogenated atom and R ¹³ is a halogen atom or

Wherein R ¹⁴ and R ¹⁵ are each alkyl.

The reaction of compound (lb) with (11) is carried out in an inert solvent, in which two compounds are used in large proportions, where compound (11) is at least 1 mole more preferably 1-5 for 1 mole of compound (1b) Moles are used.

The solvent may be, for example, water, alcohols (e.g. methanol, ethanol, isopropanol, butanol, amyl alcohol, isoamyl alcohol, etc.) aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.) ethers (e.g. tetrahydrofuran, dioxane , Diglyme, etc.) dimethylacetamide, DMF, DMSO, HMPA, N-methylpyrrolidine and mixtures thereof.

Among these solvents, DMF, DMSO, HMPA and N-methylpyrrolidine are one of the good solvents.

The reaction is carried out in the presence of acid removal reagents such as inorganic carbonates (e.g. sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, etc.) or organic bases (e.g. pyridine, quinoline, triethylamine, etc.).

Alkali metal halogens (eg potassium fluoride) may be added to the reaction mixture. The reaction is always carried out at 1-20 atm, preferably 1-10 atm and atmospheric temperature of -250 ° C.

그룹인 화합물(1b')은 상응하는 화합물(1b')로 변할 수 있는데 여기서 R¹³은 킬레이트 화합물을 분해하기 위해서 전자의 화합물을 산이나 염기로 처리함에 의해서 수소이다.R ¹³ is

Compound (1b '), which is a group, can be converted to the corresponding compound (1b'), wherein R ¹³ is hydrogen by treating the former compound with an acid or a base to decompose the chelate compound.

Acids include inorganic acids (e.g. hydrochloric acid, sulfuric acid, etc.) and organic acids (e.g. acetic acid, p-toluenesulfonic acid, etc.), and bases are inorganic bases (e.g. sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, carbonate) Potassium, etc.) and organic bases (such as triethylamine, etc.) are performed well. Acids and bases may be used in amounts of at least 1 mole per mole of starting compound, at least 1 mole.

[Schematic Diagram-III]

이다.Where R ^l , R ³ and X are as defined above, one of Z or W is -CH ₂ -and the other is

to be.

n is an index of 1-3, R ¹⁶ is (low) alkyl: cycloalkyl: phenyl (low) alkyl: halogen atom, (low) wherein the phenyl ring can be substituted by (low) alkoxy, nitro or amino Phenyl which may be substituted by alkyl or substituted (low) alkyl by one to three halogen atoms: hydroxy, amino, (low) alkoxy and halogen atoms, wherein amino is (low) alkyl, (low) alkanoyl Which may be optionally substituted by cycloalkyl or (low) alkoxycarbonyl (low) alkyl having 1 to 3 substituents selected from the group consisting of these compounds: which may be substituted by halogen atoms of 1-7 ( (Low) alkanoyl: (low) alkenyl carbonyl having 1-3 substituents selected from the group consisting of halogen atoms and carboxy: (low) alkoxycarbonyl: aminocarbonyl which may be substituted by (low) alkyl: Phenyl (daytime Silver) amino (low) alkanoyl (low) alkoxycarbonyl (low) alkyl which may be substituted by alkoxycarbonyl: carboxy (low) alkyl: anilinocarbonyl (low) alkyl: by 1-3 halogen atoms (Low) alkylsulfonyl which may be substituted: sulfo (low) alkyl: (low) alkenyl or (low) alkynyl.

이다.X ⁵ is a halogen atom, one of Z ^l or W ² is —CH ₂ — and the other is

to be.

The reaction of compound (1c) with (12) is carried out in a suitable solvent in the presence of a hydrohalide reagent.

The solvent is water, alcohol (e.g. methanol, ethanol, isopropanol, etc.) ketone (e.g. acetone, methyl ethyl ketone, etc.) ether (e.g., ethyl ether, dioxane, etc.) aromatic hydrocarbons (e.g. benzene, toluene, xylene And the like).

If necessary, copper powder, copper halides (eg iodogoli), or alkali metal halides may be used.

Compound (1c) is in very large amounts in the same amount. Preferably compound (12) is used in an amount of 1-3 moles per 1 mole.

The reaction is always carried out at 50 ° C. −20 ° C. for atmospheric temperature −150 ° C. and preferably 1-2 hours.

[Schematic Diagram-IV]

이다.Where R ¹ , R ³ , Z, W, n and X are as defined above, R ¹⁷ and R ¹⁸ are each hydrogen or lower alkyl and one of Z "or W" is -CH ₂ -and the other is

to be.

The reaction of compounds (1c) and (13) is carried out under conditions in which a solvent may or may not be present in the presence of a reducing agent.

Solvents are for example water, alcohols (e.g. methanol, ethanol, isopropanol, etc.) and low alkanoic acids (e.g. formic acid, acetic acid, etc.) ethers (e.g. dioxane, iethylether, diglyme, tetrahydrofuran, etc.) ) Aromatic hydrocarbons such as benzene, xylene, toluene, etc.

The reducing agent is a catalyst for catalytic reduction (e.g. sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, etc.) for formic acid, alkali metal or alkaline earth metal salt of formic acid (e.g. sodium formate) : Palladium black, palladium carbon, platinum oxide, platinum black, nickel, etc.).

In the case of using formic acid as the reducing agent, the reaction is always carried out at 50 ° C.-150 ° C. for atmospheric temperature −200 ° C. and more preferably 1-10 hours.

Formic acid is better used in very large amounts compared to compound (1c).

In the case of using a hydrogenation reagent elsewhere, the reaction is carried out at 0 ° C.-70 ° C. for 30 min.

As a reducing reagent for hydrogenation, 1-2 moles are used, more preferably 1-6 moles per 1 mole of compound (1c).

When lithium aluminum hydride is used as the reducing reagent, a good solvent is an ether (e.g., diester ether, dioxane, tetrahydrofuran, diglyme, etc.) aromatic hydrocarbon (e.g., benzene, toluene, xylene, etc.). It is included.

In the case of using a catalyst for catalytic reduction, the reaction is always carried out at -30 ° C, -100 ° C and more preferably 0 ° C-60 ° C for 1-22 hours under hydrogen pressure of 1-20 atm, preferably 1-10 atm. do.

The catalyst is always used in an amount of 0.1-40%, more preferably 0.1-30% by weight of compound (1c). Compound (13) is always used at least 1 mole, more preferably 1 mole per 1 mole of compound (1c).

The starting compound of formula (2) in Reaction Scheme I is a sample cloud or known compound that can be prepared, for example, by the process shown in the following Reaction Scheme-V.

[Schematic Diagram-V]

Where X, R ²¹ and X ² are as defined above, X ⁵ and X ⁶ are each halogen, R ¹⁹ is hydrogen or low alkyl, R ²⁰ is low alkyl, where R ¹⁹ and R ²⁰ are grouped together Create a ring of seven to seven, and M is an alkali metal (e.g. sodium potassium) or a metal (e.g. silver, calcium, copper, etc.).

When R ¹⁹ and R ²⁰ of Compound (16) come together to form 5-7 rings, R ¹⁹ of Compound (20) is -R ¹⁹ -R ²⁰ -H.

Compound (16) is made by reacting the starting aniline derivative of formula (14) with a halogenating reagent and then reacting the compound of formula (14a) with the thio compound of formula (15).

The reaction of the aniline derivative 14 with the halogenating reagent is always carried out in a suitable solvent. Solvents may be any conventional solvent as long as no unwanted effects are given to the reaction, for example halogenated hydrocarbons (e.g. chloroform, dichloromethane, etc.) ethers (e.g. dioxane, diethether, tetrahydrofuran, etc.) Hydrocarbons (eg benzene, toluene, xylene etc.) and low alcohols (eg methanol, ethanol, isopropanol etc.) and polar solvents (eg DMSO, HMPA, acetone nitro etc.).

Halogenated reagents can be any conventional halogenated reagent, such as N-bromosuccinimide, N-chlorosuccinimide, sodium hypobromide, sodium hypochloride, bleaching powder, thionyl chloride, tert-butyl hypochloride, etc. Includes such as

Halogenation reagents are always used at least 1 mole, preferably 1-6 moles per mole of starting material.

The reaction is always carried out at -78 ° C ambient temperature, preferably -60 ° C-15 ° C and within minutes the reaction is complete.

The reaction produces an intermediate of formula 14a.

The resulting compound 14a can be separated from the reaction mixture to be fed to a subsequent reaction, but the reaction mixture is provided to react with the thio compound of formula 15 without separating it.

The reaction of the compounds (14a) and (15) is carried out in the same solvent as the above-mentioned solvents in the presence of basic compounds.

Base compounds include inorganic bases (e.g. potassium carbonate, sodium carbonate, sodium hydroxide, sodium bicarbonate, amide sodium, sodium hydride, etc.) and tertiary amines (e.g. triethamine, tripropylamine, pyridine, quinoline, etc.) Contains organic bases.

Compound (15) is always used at least 1 mole, preferably 1-1.5 moles, per mole of compound (14a). The reaction is always carried out at ambient temperature -150 ° C, preferably at ambient temperature -100 ° C for 1-5 hours.

The reaction of compounds (16) and (17) is carried out in a suitable solvent with or without a base compound. The solvent is water, alcohol (e.g. methanol, ethanol, isopropanol, etc.) aromatic hydrocarbon (e.g. benzene, toluene, xylene, etc.) ether (e.g. dioxane, tetrahydrofuran, diglyme, etc.) polar solvent (e.g. DMF , DMSO, HMPA, N-methylpyrrolidine, etc.) or mixtures of the above.

Base compounds include inorganic carbonates (e.g. sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.) and organic bases (e.g. pyridine, quinoline, triethylamine, etc.) phase inversion catalyst (e.g. phenyltriethylammonium chloride) And tetramethylammonium chloride).

Compound (17) is always used at least 1 mole, preferably 1-2 moles per 1 mole of compound (16).

The reaction is always carried out at ambient temperature of -200 ° C and preferably at ambient temperature of -180 ° C for 30 minutes-10 hours.

Desulfurization of compound (18) to make compound (19) is always carried out in a solvent under a suitable catalyst.

Catalysts include, for example, aluminum-amalgam, lithium low alkylamines, rannickel, ranicobalt, triethylphosphite, triphenylphosphine, and the like, and the best is rannickel.

Solvents include alcohols (e.g. methanol, ethanol, isopropanol, etc.) ethers (e.g. diethether, dioxane, tetrahydrofuran, etc.).

The reaction is always carried out at ambient temperature -100 ° C for 0 minutes-200 ° C and more preferably 10 minutes-5 hours. The catalyst is always used in an amount of 1-10 times the weight of the compound (18).

The conversion of compound (19) to compound (20) is carried out by reacting compound (19) with a metal salt of nitrous acid (e.g. sodium nitrite, potassium nitrite, etc.) in a suitable solvent in the presence of an acid and reacting the resulting product with a reaction mixture. By reaction with a metal halide (eg potassium iodide, copper chloride (I), copper bromide (I), etc.) without separation from it.

Acids include inorganic acids such as hydrochloric acid, sulfuric acid and hydrobromic acid.

The solvent is halogenated with water, alkanoic acid (such as acetic acid), ethers (such as dioxane, tetrahydrofuran, etc.) aromatic hydrocarbons (such as benzene, toluene, xylene, etc.) alcohols (such as methanol, ethanol, isopropanol) Hydrocarbons (eg chloroform, dichloromethane, dichloroethane, etc.) aprotic polar solvents (eg DMF, DMSO, HMPA, etc.) and mixtures of these.

Metal salts of nitrous acid and halide metals are always used at least 1 mole, preferably 1-1.5 moles per 1 mole of compound (19).

The reaction is always carried out at 0 ° C.-150 ° C., preferably at 0 ° C.-100 ° C. for 10-5 hours. Hydrolysis of the compound (20) can be carried out with a suitable hydrolysis catalyst, for example inorganic acids (e.g. sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, etc.) or base compounds (e.g. sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, hydrogen carbonate). Sodium) and the presence or absence of a solvent.

Solvents include, for example, mixtures of water and low alcohols (eg methanol, ethanol, etc.). The reaction is always carried out at 70 ° C.-180 ° C. for 50 ° C.-200 ° C. and more preferably 1-10 hours.

그룹인 공식(1b)의 화합물은 예를들면 다음 반응모식도-VI에 보여진 과정에 의해 만들어질 수 있다.In Schematic-II, R ¹³ is

Compounds of formula (1b), which are groups, can be made, for example, by the procedure shown in Scheme-VI.

[Application Formula-VⅠ]

이고, R²¹은 낮은 알킬이다.Wherein R ¹ , R ³ , X, X ⁴ , R ¹⁴ and R ¹⁵ are as defined above, R ⁵¹ is a lower alkyl or hydrogen atom,

And R ²¹ is low alkyl.

The reaction of compound (1f) with (21) is carried out in a suitable solvent.

The solvent includes, for example, a solvent used in the reaction of the R ⁴ group removing compound with compound (6) in Scheme-I.

The reaction is always carried out at ambient temperature -200 ° C, preferably at ambient temperature -150 ° C for 10-5 hours.

Compound (21) is used at least 1 mole, more preferably 1-10 moles per 1 mole of compound (1f). Compound (8) used in Scheme I is a new or known compound that can be made, for example, by the process shown in the following Scheme VII.

[Schematic diagram-Ⅶ]

Wherein X ¹¹ is a halogen atom, R ²² is phenyl (low) alkoxycarbonyl, R ^{22 '} is phenyl (low) alkyl, m is an index of 1-3, M' is an alkali metal such as sodium, potassium, and M Is hydrogen or M '.

The reaction of compounds (22) and (23) can be carried out under the reaction conditions which are always used for the reaction to form amide bonds.

The process of making the amide bond is, for example, (a) a mixed acid anhydride process: reacting the carboxylic acid (22) with an alkyl halo carboxylate to obtain a mixed acid anhydride and then resulting anhydride and azide (23). Process comprising: (b) active ester process: converting carboxylic acid (22) to an active ester such as p-lightrophenyl ester, N-hydroxysuccinimide ester or 1-hydroxybenzotriazole ester Process comprising reacting the resulting ester with azide (23): (c) Carbodiimide process: Carboxylic acid (22) and aza under an activation reagent such as dicyclohexylcarbodiimide, carbonyldiimidazole, etc. A process comprising the condensation of id 23: and (d) its process: carboxyl using a dehydrating agent such as acetic anhydride Converting acid (22) to carboxylic anhydride and reacting the resulting anhydride with azide (23): azide of carboxylic acid (22) and ester of low alcohol under high temperature and high pressure A process comprising reacting with (23): or a process comprising reacting azide (23) with halogen acid (i.e., axyl halide) of carboxylic acid (22).

The mixed acid anhydride is obtained by the traditional Shotton-Bauman reaction, and the resulting anhydride can react with the azide 23 to obtain compound 24 at all times without being separated from the reaction mixture.

The Shotton-Baumann reaction is always carried out in the presence of the base compound used in the abovementioned reaction.

Base compounds are, for example, organic bases (e.g., triethylamine, trimethylamine, pyridine, dimethylanyl and N-methylmorpholine, 1,5-diazabicyclo (4,3,0) nonene-5- (DBO) 1,8-diazabicyclo (5,4,0) undecene-7 (DBU) 1,4-diazabicyclo (2,2,2) oxane (DABCO) and other inorganic bases (eg carbonic acid) Potassium, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate and the like).

The reaction is always carried out at -20 ° C-100 ° C and preferably at 0 ° C-50 ° C for 5 minutes-10 hours and even more preferably 5 minutes-2 hours.

The reaction of the resulting mixed acid anhydride and azide 23 is always carried out for 5 minutes-10 hours at -20 ° C-150 ° C and more preferably 0 ° -50 ° C for 5 minutes-5 hours. The mixed acid anhydride process is always performed in the solvent used in the above process.

The solvent is water, halogenated hydrocarbons (e.g. dichloromethane, chloroform, dichloroethane, etc.) aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.) ethers (e.g., die ether, tetrahydrofuran, etc.) ketones Aprotic polar solvents (eg DMF, DMSO, HMPA, etc.) and mixtures of the above.

Alkylhalocarboxylates used in the mixed acid anhydride process include, for example, methylchloroformate, methylbromoformate, ethylchloroformate, ethylbromoformate, ethylchloroformate and the like.

Azide (23) is always used at least 1 mole, preferably 1-1.5 moles per mole of carboxylic acid (22).

When using a process involving reacting an axyl halide with an azide 23, the reaction is carried out in the presence of a base compound in a suitable solvent. The base compound may be any known compound, for example sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, silver carbonate and metal alcohol compounds such as sodium methacrylate and sodium acrylate, in addition to the Schotten-Baumann reaction. Contains basic compounds used in

The solvent is, for example, alcohol (e.g. methanol, ethanol, propanol, butanol, 3-methoxy-1-butanol, methylcellosolve, methylcellosolve, etc.) pyridine, acetone, acetonitrile, mixed acid from above Solvents used in the anhydride process and mixtures of the above. Although the ratio of the azide 23 to the used acyl halide is not limited, at least one mole of the axyl halide is preferably used in an amount of 1-5 moles per 1 mole of the azide 23. The reaction is always carried out at 0 ° -180 ° C. for -30 ° C.-180 ° C. and more preferably 5 minutes-30 hours.

The compound (24) thus made is used in the next reaction without being separated from the reaction mixture. The reaction of compounds (24) with (25) is carried out with or without a suitable solvent at ambient temperature -100 ° C. for 1-15 hours, preferably at 0 ° C.-150 ° C.

Compound (25) is always used at least 1 mole, preferably 1-2 moles per 1 mole of compound (24). The reaction for converting compound (26) to compound (27) is used in the reaction for removing phenyl (low) alkyl group or phenyl (low) alkoxycarbonyl group on the heterocyclic ring attached to compound (1) above. Can be performed under exactly the same conditions.

The reaction of direct conversion from compound (22) to compound (27) is generally considered to be a suit reaction and is carried out in a suitable solvent in the presence of an acid. Acids are inorganic acids (e.g. sulfuric acid, hydrochloric acid, etc.) Phosphorus compounds (e.g. phosphorus oxychloride, phosphorus pentoxide, etc.) Thionyl chloride, iron (III) chloride, aluminum chloride, stanic chloride, sulfoacetic acid, phosphoric acid And the like.

Solvents include such hydrocarbons as aromatic hydrocarbons (eg benzene, toluene, xylene, etc.) and halogenated hydrocarbons (eg chloroform, dichloromethane, carbon tetrachloride, etc.).

The reaction is always carried out for 30 minutes-10 hours at 0 ° C-150 ° C and preferably 0 ° C-100 ° C.

Compound (23) is always used at least 1 mole, preferably 1-2 moles per 1 mole of compound (22).

[Schematic diagram-Ⅷ]

이고, R^l, R³, Z, W, X 그리고 m은 위에서 정의한 바와같다.Wherein R ²³ is phenyl, low alkyl or hydrogen, X ⁸ is a halogen atom, one of Z '''orW''' is CH ₂ and the other is

R ¹ , R ³ , Z, W, X and m are as defined above.

The reaction of the compounds (1c) and (28) can be carried out under the same conditions as the reaction conditions used in the reaction of the compounds (1b) and (11) in Reaction Scheme-II above.

Compounds in which heterocycling is substituted by (a)-(i) in compound (1) can be converted to compound (1) in which heterocycling is not substituted, for example, using the following method.

(a) phenyl ring can be substituted by (low) alkoxy, nitro or amino by phenyl (low) alkyl, (b) halogen atoms of 1-7, (low) alkenyl carbonyl (Low) alkanoyl, wherein (low) alkenylcarbonyl has 1-3 substituents selected from the group consisting of halogen atoms and carboxy: (c) (low) alkoxycarbonyl: (d) (low) Aminocarbonyl, which may be substituted by alkyl, (e) phenyl (low) alkoxycarbonyl: (f) amino (low) alkanoyl, which may be substituted by phenyl (low) alkoxycarbonyl: (f) phenyl ( Low) alkoxycarbonyl which may be substituted by alkoxycarbonyl: (g) phthalide: (h) 2 (5H) -furanone which may be substituted by a halogen atom of 1-2: or (i ) A compound in which 2-OXO-1,3-dioxoleneethyl heterocycling, which may be substituted by phenyl or (low) alkyl, is substituted by (a) or (e) (1) refers to palladium carbon, palladium black, etc. in a suitable solvent such as acetic acid or a mixture of water, low alcohol (e.g. ethanol, ethanol, isopropanol), ether (e.g. dioxane, tetrahydrofuran, etc.) By treatment at a temperature of 0 ° C.-100 ° C. for 30 minutes to 10 hours (in which inorganic acids such as hydrochloric acid may be added to the reaction mixture) or under a catalytic reduction catalyst such as phenyl (low) alkyl (eg benzyl) or phenyl The heterocycling can be converted to unsubstituted compound (I) by heating the electronic compound in an aqueous hydrobromic acid solution to remove the (low) alkoxycarbonyl. Compound (1) in which at least one heterocyclic ring is substituted by a (b)-(i) substituent is used to hydrolyze the electronic compound under the same reaction conditions as those used in the hydrolysis of compound (10) above. Heterocycling can be converted to unsubstituted compound (1).

그룹에 의해 치환되는 화합물(I)로 전환될 수 있다.Compound (I) in which the heterocycling is substituted by amino is obtained by using the same reaction conditions as those used in the reaction of Compounds (1c) and (28) in Scheme VII above.

It can be converted into compound (I) substituted by a group.

그룹에 의해 치환되는 화합물(I)은 전자화합물을 위의 화합물(10)의 가수분해때 사용한 똑같은 반응조건하에서 가수분해 시킴에 의해서 헤테로사이클릭링이 아미노에 의해 치환되는 화합물(1)로 역시 전환될 수 있다.And heterocycling

Compound (I) substituted by a group is also converted to Compound (1) where heterocycling is substituted by amino by hydrolyzing the electronic compound under the same reaction conditions used in the hydrolysis of Compound (10) above. Can be.

[Schematic Diagram-IX]

그룹(여기서 R¹⁹와 R²⁰은 위에서 정의한 바와 같다) 또는 R³(여기서 R³은 위에서 정의한 바와 같다)이고, 그리고 R²⁴, R²⁵, R²⁶, R²⁷그리고 R²⁸은 각각 알킬이며 X⁹는 수소원자이다.Where R ^l , R ^{2 '} , X ⁹ and X are as defined above and R ³¹ is

Group (where R ¹⁹ and R ²⁰ are as defined above) or R ³ (where R ³ is as defined above), and R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ and R ²⁸ are each alkyl and X ⁹ Is a hydrogen atom.

The reaction of compounds (37) and (8) can be carried out under the same reaction conditions used in the reaction of compounds (1b) and (11) in Scheme-II above.

The reaction of compound (29) with (30a) or (30b) is carried out with or without solvents and preferably without any solvent.

Solvents include, for example, alcohols (eg methanol, ethanol, isopropanol, etc.) aromatic hydrocarbons (eg benzene, toluene, etc.) polar solvents (eg acetonitrile, DMF, DMSO, HMPA, etc.).

Compound (30a) or (30b) is always used at least 1 mole, preferably 1-1.5 moles, per 1 mole of compound (29).

The reaction is always carried out at 60 ° C.-200 ° C. for atmospheric temperature −200 ° C. and more preferably for 30 minutes-25 hours.

Solidification of the compound (31) or (32) is the same as the heating method, a method using an acidic compound (e.g., phosphorus oxychloride, phosphorus pentachloride, phosphorus chloride, thionyl chloride, concentrated sulfuric acid, polyphosphoric acid, etc.) This is done according to several known methods.

In the case of the heating method, the method can be used in solvents with high boiling points, such as hydrocarbons with high boiling points or high boiling ethers (eg tetralin, diphenyl ether, dieglyce nitryl ether, etc.). C is always carried out at 250 ° C., preferably at 150 ° C.-200 ° C.

When using acidic compounds, the same amount of acidic compound is used. If the amount is much higher, 10-20 moles are always used for 1 mole of compound (31) or (32). It is always carried out at 150 ° C. with or without a suitable solvent. The solvent includes acid anhydrides (e.g. acetic anhydride) in addition to the solvents used in the solidification of compound (9) above.

The hydrolysis of the compound (1i) can be carried out under the same conditions as the reaction conditions used for the hydrolysis of the compound (10) in the above reaction scheme-I.

그룹인 화합물(1j)은 위의 반응모식도-V에서 화합물(19)로 전환된 반응에서 사용되어진 반응조건과 똑같은 조건하에서 전자화합물을 처리함에 의해서 R^3'가 -CH₂R¹⁹인 상응하는 화합물로 전환될 수 있다. R^2'가 2차 질소원자에 (낮은)알콕시카보닐을 갖고 있는 5-9개로 된 포화 또는 불포화 헤테로사이클릭링인 화합물(1j)는 위의 반응모식도 I에서 화합물(10)의 가수분해시 사용되었던 똑같은 조건하에서 전자화합물을 처리함에 의해서 R^2'가 2차 질소원자에 어떠한 치환기도 갖지 않는 5-9개로 된 포화 또는 불포화 헤테로사이클릭링과 상응하는 화합물로 전환될 수 있다.R ^{3 '}

Compound (1j), which is a group, corresponds to the corresponding compound in which R ^{3 ′} is —CH ₂ R ¹⁹ by treating the electronic compound under the same conditions as those used in the reaction converted from Scheme-V to Compound (19) above. Can be switched to. Compound (1j) wherein R ^{2 '} is a 5-9 saturated or unsaturated heterocyclic ring having (low) alkoxycarbonyl at a secondary nitrogen atom is obtained by the hydrolysis of compound (10) in Scheme I above. By treating the electronic compound under the same conditions used, R ^{2 '} can be converted to a compound corresponding to 5-9 saturated or unsaturated heterocyclings having no substituents on the secondary nitrogen atom.

Compound (29) used as a starting material in Reaction Scheme-XI above can be made, for example, by the process shown in X-XII.

If the starting material in the solidification of compound (31) or (32) is a compound in which R ^{3 '} is a (low) alkyl having at least one substituent selected from halogen atoms, hydroxy or (low) alkoxy and the solvent is an acid anhydride, The (low) alkyl can be liquefied to give a compound wherein R ^{3 '} is (low) alkyl with at least one (low) alkanoyloxy in such a reaction.

However, such compounds can be easily removed from the reaction mixture.

[Schematic Diagram-X]

Where R ¹ , R ²¹ , R ¹³ , R ²⁰ , X and X ⁶ are as defined above, R ²⁷ is (low) alkanoyl and X ⁹ is a halogen atom.

Desulfurization of compound (16) or (29b) can be carried out under the same conditions as the reaction conditions used in desulfurization of compound (13) above.

The reaction of converting compound (33) to compound (34) is a (low) alkanoic acid (e.g. formic acid, acetic acid, propionic acid, etc.) (low) alkanoic anhydride (e.g. acetic anhydride, etc.) (low) It is carried out in the presence of (low) alkanoylating reagents such as canoic acid halides (e.g., acetylchloride, propionylbromide, etc.).

Base compounds may be used when acid anhydrides or halogen acids are used as the (low) alkanoylating reagents.

Base compounds include, for example, alkali metals (eg sodium metal, potassium) and hydroxide carbonates or their hydrogen carbonates, organic bases (eg pyridine, piperidine, etc.).

The reaction can be carried out with or without a solvent but is always carried out in the presence of a suitable solvent. Solvents include, for example, ketones (e.g. acetone, methyl ketone, etc.) ethers (e.g., dimethyl ether, dioxane, etc.) aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.) acetic acid, acetic anhydride, water, pyridine, etc. And the like.

The (low) alkanoylating reagent is used at least 1 mole with respect to 1 mole of compound (33), but always in the same amount-very high.

The reaction is always carried out at 0 ° C.-100 ° C., preferably at 0 ° C.-100 ° C. for 5 minutes-10 hours. Dehydrating agents are well used when (lower) alkanoic acid is used as the (lower) alkanoylating reagent.

Dehydrating agents include such things as inorganic acids (eg sulfuric acid, hydrochloric acid) and sulfonic acids (eg p-toluenesulphonic acid, benzenesulphonic acid, ethanesulphonic acid, etc.).

The reaction is well performed at 50 ° C.-120 ° C. temperature.

The nitric acid treatment of compounds (33) or (34) may be carried out by the aforementioned compounds, fuming nitric acid, concentrated nitric acid, mixed acids (e.g. nitric acid + sulfuric acid, fuming sulfuric acid, phosphoric acid or acetic anhydride), alkali metal nitrate + sulfuric acid, nitrate anhydride and Organic acids (e.g., acetyl nitric acid, benzoyl nitric acid, etc.) are treated with nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, alkyl nitric acid, sulfuric acid, phosphoric acid, and other solvents such as acetic acid, acetic anhydride, and sulfuric acid. With or without

Nitrification reagents are best used in amounts of 1-1.5 moles per 1 mole of compound (33) or (34). The reaction is always carried out at a temperature of −10 ° C.-70 ° C. for 1-24 hours. Hydrolysis of the compound (35) is carried out under the same conditions as the reaction conditions used for the hydrolysis of the compound (10) above.

The reaction of Compound (37a) or (38) with Compound (8) is carried out under the same conditions as the reaction conditions used in the reaction of Compounds (1b) and (11) in Scheme-II above.

The halogenation of compound (39) can be carried out under the same conditions as the reaction conditions used in the halogenation of compound (14) above.

The reaction of the compounds (39a) and (15) can be carried out under the same conditions as the reaction conditions used in the reaction of the compounds (14a) and (5).

The conversion of compound (29b) to compound (29a) can be carried out under the same conditions as the reaction conditions when compound (18) is converted to (19).

The conversion of compound (36) to (37) is performed by the reaction of sodium nitrite with acid (e.g. sulfuric acid, hydrochloric acid, hydrobromic acid, boron fluoride, etc.) in a solvent such as (low) alkanoic acid (e.g. acetic acid) water, etc. The electronic compounds are used to convert their diazozium salts and then to the diazonium salts in the presence of halogenated acids (e.g. hydrobromic acid, hydrochloric acid, etc.), copper powder or copper halides (e.g. copper bromide, copper chloride, guprricchlorite). Etc.) or with or without copper powder or by reacting with potassium iodir, or better with halide copper in the presence of hydrochloric acid. Sodium nitrate is preferably 1 to 1.5 moles per 1 mole of compound (36), preferably 1-2 moles, and 1-5 moles of halide copper is preferably 1 to 4 moles per 1 mole of compound (36). The reaction is always carried out at -5 ° C-100 ° C for -10 ° C-100 ° C and more preferably 10 minutes-5 hours.

The halogen atoms of X ⁹ of compound 37a can each be converted.

[Schematic Diagram-XI]

Wherein R ²¹ , R ¹⁹ , R ²⁰ , R ²⁹ , X, X ⁶ and X ⁹ are as defined above.

Hydrolysis of the compound (40) can be carried out under the same conditions as the reaction conditions used in the hydrolysis of the compound (10) above.

The reaction may be carried out under the same conditions as used in the halogenation of the compound (41). The reaction of the compounds (42) and (15) can be carried out under the same conditions as the reaction conditions used in the reaction of the compounds (14a) and (15).

Desulfurization of the compound (43) can be carried out under the same conditions as the reaction conditions used in the desulfurization of the compound (18) in the above reaction scheme-V.

[Schematic Diagram-XII]

[Schematic diagram of the reaction-XIII]

Wherein R ¹ , R ²¹ , X and X ⁷ are as defined above, A is (low) alkylene, m is 0 or 1 and X ¹⁰ is phenylsulfonyl which may be substituted by halogen atom or low alkyl Oxy, R ³⁰ is (low) alkyl, R ²¹ is (low) alkanoyloxy, R ³² and R ³³ are the same or different, each represents hydrogen or (low) alkyl, and R ³⁴ is (low) alkyl , R ³⁵ is hydrogen or nitro group.

The nitric acid treatment of compound 44 in Scheme-XII above can be carried out under the same conditions as the reaction conditions used in the nitric acid treatment of compound 34 in Scheme-X above. The reaction of compound (44) or (45) is always carried out using a hydride reducing agent such as sodium borohydride, lithium aluminum hydride or diborane and the reducing agent is at least one mole better than compound (44) or (45). 1-3 moles are always used per mole.

Reduction reactions are suitable solvents such as water (low) alcohols (e.g. methanol, ethanol, isopropanol, etc.) ethers (e.g. tetrahydrofuran, diethether, diglyme, etc.) DMSO, etc. ℃ -80 ° C It is always carried out at -30 ° C-50 ° C, preferably for 10 minutes-15 hours.

In the case of using lithium aluminum hydride diborane as the reducing reagent, anhydride solvents such as die ether, tetrahydrofuran or diglyme are well used. Conversion of compound (46) by halogenation to compound (47) wherein X ¹⁰ is a halogen atom is carried out under any reaction conditions used in halogenation of hydroxy groups, for example with or without a suitable solvent. It may also be carried out by reaction with.

Halogenated reagents include, for example, hydrochloric acid (e.g. hydrochloric acid, hydrobromic acid, etc.) N, N-dimethyl-1,2,2-trichloro vinylamide, phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride, Thionyl chloride, diethylaminosulfur trifluoride (DAST) and the like.

Inert solvents include, for example, ether (eg dioxane, tetrahydrofuran, etc.) halogenated hydrocarbons (eg chloroform, dichloromethane, carbon tetrachloride, etc.). Halogenation reagents are used at least 1 mole per mole of compound (46), always in the same amount-very large amounts and the reaction always takes place at 0 ° C.-80 ° C. for 10 minutes-15 hours.

When DAST is used as the halogenation reagent, a basic compound such as triethylamine can be used.

When compound (46) is reacted with phenylsulfonyl halide, which may have a low alkyl substituent on the phenyl ring, the compound may be converted to compound (47), wherein X ¹⁰ is phenylsulfonicoxy which may be substituted with lower alkyl. have.

The reaction can be carried out in the same manner as used for converting compound (46) to compound (49) below.

Compound (48) in which R ³⁵ is hydrogen is first converted to compound (48) in which R ³⁵ is nitro by the same nitric acid treatment of compound (44) and then reacted with compound (8). The reaction of the compounds (48) and (8) thus converted can be carried out under the same reaction conditions used in the reactions of compounds (1b) and (11) in Reaction Scheme-II above.

The conversion of compound (47) to compound (48) can be carried out under the same reaction conditions used in the reaction of compound (55) above. The conversion of compound (46) to compound (49) in Reaction Scheme-XIII above can be carried out by several methods, e.g. i) Compound (46) and Compound (R) in a suitable solvent in the presence of a base compound: R ^By reaction with ³⁴ X ¹¹ where R ³⁴ is (low) alkyl and X ¹¹ is a halogen atom, ii) compound (46) and low (alcohol (ie methanol, ethanol, isopropanol, butanol, etc.) in the presence of an acid By reaction with a linear or branched C ₁ -C ₆ alcohol, such as a solvent, the solvent used in the above method (i) may be, for example, ether (e.g., ethyl ether, dioxane, tetrahydrofuran). Alcohols (e.g., methanol, ethanol, isopropanol, etc.) aromatic tandem-fusos (e.g., benzene, toluene, xylene, etc.) aliphatic hydrocarbons (e.g., n-hexane, heptane, cyclohexane, Amines (eg pyridines, N, N-dimethylaniline, etc.) Halogenated hydrocarbons (eg chloroform, dichloromethane, carbon tetrachloride, etc.) aprotic polar solvents (eg DMF, DMSO, HMPA, etc.) and mixtures of these.

Base compounds are inorganic bases (e.g. metal sodium, metal potassium, metal magnesium, sodium hydride, amide sodium, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, etc.) organic bases (e.g. pyridine, pipepyridine, quinoline , Triethylamine, N, N-dimethylaminoline, etc.) and the like. The reaction is always carried out at ambient temperature -100 ° C for 0 minutes-120 ° C and even better for 10 minutes-5 hours. Compound: R ³⁴ X ¹¹ is at least 1 mole better, preferably 1-3 moles are used per mole of compound (46).

Acids used in method (ii) above include, for example, inorganic acids (eg hydrochloric acid, sulfuric acid, hydrogen bromide, etc.). The reaction is always carried out at 50 ° C.-120 ° C. for atmospheric temperature −150 ° C., preferably 1 hour-50 hours. Alcohol (low) is always used in excess.

Acceleration of compound (46) can be carried out under the same conditions as the reaction conditions used for conversion of compound (33) to (34) in Scheme-X above. Both the reaction of compound (46) (49) (50) or (47) with compound (52) and the reaction of compound (47) with mixture (54) are both carried out in the presence or absence of a suitable solvent or in the presence of a base compound. The solvent and base compound may be the same solvent and base compound as used in the reaction of compound (3) and compound (4) in the reaction scheme I above. Compounds (52) in the reaction of compounds (46) (49) (50) or (47) with compound (52) can also be used in very large amounts as a base compound due to their functional response. Compounds (52) and (54) may be used in at least one mole, more preferably in very large amounts, relative to one mole of starting material, in particular compounds 46, 49, 50 or 47.

The reaction is carried out at ambient temperature −100 ° C. for 0-15 ° C., preferably 3-15 hours. Hydrolysis of the compound (50) can be carried out under the same conditions as the reaction conditions used in the hydrolysis of the compound (10) above.

Among the above compounds (3) (5) (7) (9) (10) (1a) (1b) (1b ') (29) (31) and (32), R ³ is substituted by hydroxy (low) Heterocycling consisting of 5-6 saturated R ³ , (low) alkylthio, (low) alkanoyloxy, by reacting a compound which is an alkyl under the same conditions as mentioned above It can be converted to the corresponding compound which is (low) alkyl substituted by a substituent of 1-3 selected from the group consisting of amino, (low) alkylamino, (low) alkoxy, and halogen atoms.

In the above compounds (3) (5) (7) (9) (10) (1a) (1b) (1b ') (29) (31) and (32), R ³ is reduced by (lower) alkanoyloxy. Compounds that are substituted (low) alkyl can be converted to compounds wherein R ³ is alkyl having a hydroxy group by hydrolyzing the electronic compound under the same conditions as mentioned above.

Saturated or unsaturated in which R ² has UX0 group among the above compounds (3) (5) (7) (9) (10) (1a) (1b) (1b ') (29) (31) and (32). Compounds that are 5-9 heterocyclic rings can be converted to saturated or unsaturated 5-9 heterocyclic rings in which R ² has a hydroxy group by reducing the electronic compound. Reduction can be effected in a suitable solvent in the presence of a reducing agent for hydrogenation. Reducing agents include, for example, sodium borohydride, lithium aluminum hydride diborane, etc., at least 1 mole, preferably 1-5 moles are always used per mole of starting material to be reduced. Solvents include, for example, water (low) alcohols (e.g. methanol, ethanol, isopropanol, etc.) ethers (e.g. tetrahydrofuran, diethether, diglyme, etc.).

The reaction is always carried out for 10 minutes -5 hours at -60 ° C -50 ° C and better -30 ° C-atmosphere. In the case of using lithium aluminum hydride or diborane as the reducing agent, an inorganic base such as sodium hydride, tetrahydrofuran and diglyme may be added to the reaction mixture.

Compounds wherein R ² is a saturated or unsaturated 5-9 heterocyclic ring substituted by alkyl having at least one of (low) alkanoyl or (low) alkoxycarbonyl are R ² can be converted to a cyclic saturated or unsaturated 5-9 heterocyclic ring pieces of the compounds substituted by alkyl (lower), which have at least one carboxyl group.

The hydrolysis can be carried out under the same conditions as the reaction conditions used in the hydrolysis of compound (10) in Scheme I above. Compounds wherein R ² is a saturated or unsaturated 5-9 heterocyclic ring having at least one —NH— in the ring are used in the conversion of compound (33) to compound (34) in Scheme X above. By reacting an electronic compound under the same reaction conditions as described above, R ² can be converted into a compound having a saturated or unsaturated 5-9 heterocyclic ring substituted by at least one (low) alkanoyl. Compounds 46 (47) and (48), which are hydrogen at the top, can be converted to the corresponding compounds in which R ³⁵ is nitro by the same nitrate reaction of compound (44).

Compounds (44) and (45) can be made by the process shown in the following reaction scheme.

[Schematic Diagram-XIV]

Where R ²¹ , R ³⁵ , X, X ⁹ , M and m are as defined above and A ¹ is a group (A ') mCH ₂ ^- and (A') mCH ₂ CH ₂ ^- having 6 or more carbon atoms If not, it is low alkylene, R36 is low alkyl, and X ¹¹ is a halogen atom.

Reduction of compound (55) takes place under the same conditions as in the reduction of compound (44) or (45). In addition, the halogenation of compound (56) can be carried out under the same conditions as in the halogenation of compound (46).

The reaction of compounds (57) and (58) is always carried out in a suitable solvent in the presence of a base compound at ambient temperature -200 ° C and preferably at 60 ° C-120 ° C for 1-24 hours. The solvent may be, for example, ether (e.g. dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, dimethyl ether, etc.) aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.) low alcohol (e.g. methanol, ethanol, Isopropanol, etc.) polar solvents such as dieformamide amide dimethyl sulfoxide and the like.

Base compounds include, for example, inorganic bases (e.g. calcium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, sodium amide, sodium hydride, potassium hydride, sodium methacrylate, sodium acrylate, etc.) Such as triethylamine, tripropylamine, pyridine, quinoline, etc.).

The reaction proceeds well by using alkali metal iodide (eg potassium iodide, sodium iodide, etc.). Compound 58 is always used in the same amount—a very large amount, preferably 1-5 moles, very preferably 1-1.2 mole per 1 mole of compound 57.

The reaction of compounds (57) and (17) can be carried out under the same conditions as in the reaction of compounds (16) and (17).

In addition, hydrolysis of the compound (59) or (60) can be carried out under the same conditions as in the hydrolysis of the compound (20).

Compound (10) in Scheme I and compounds (1b) and (1b ') in Scheme II are not only useful as intermediates to make current compounds with antimicrobial activity, but also as antimicrobial agents because Because they also have antimicrobial activity.

Compounds of the present invention have optical and geometric isomers, and the present invention also includes such isomers. Among the present compounds (1) are good compounds wherein R ¹ is unsubstituted cyclopropyl, X is chlorine or fluorine atoms (particularly fluorine atoms) and R ³ is methyl or ethyl (particularly methyl).

Compound (1) can be readily converted to their salts by treating them with pharmaceutically acceptable acids or bases. Acids include inorganic acids (e.g. hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, etc.) and organic acids (e.g. oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, lactic acid, benzoic acid, methanesulfonic acid, protea Onic acid).

Bases include sodium hydroxide, potassium hydroxide, potassium hydroxide, sodium carbonate, potassium hydrogen carbonate and the like.

The compound thus obtained can be easily separated by conventional methods such as extraction with a solvent, dilution method, recrystallization, column chromatography, preparative thin layer chromatography, and the like.

Compounds of the present invention or salts thereof include Pseudomonas aeruginosa, anaerobic membrane tertiary resistant cells, clinically isolated bacteria, and gram-negative and gram-positive bacteria (e.g. enterococcus picalis, staphylo) It shows excellent antimicrobial activity against cocos pyogenes and the like and is therefore a good antimicrobial agent for the treatment of diseases caused by these microorganisms. These compounds also have good side effects and low side effects and are characterized by good absorption and sustained activity.

Furthermore, the compound is excreted a lot by urine and thus is effective for the treatment of urinary tract diseases, and is also effective for the treatment of intestinal infections because it is easy to excrete by bile.

In addition, the compounds of this invention are used in the form of salts such as lactate and hydrogen chloride to show enhanced absorption into the body. The compounds of the present invention are usually used always in the form of pharmaceutical preparations. Pharmaceutical preparations may be formulated in traditionally acceptable diluents or mixtures such as carriers, such as fillers, weighting agents, binders, wetting agents, disintegrants, surfactants, lubricating agents.

Pharmaceutic preparations include a variety of preparations suitable for treating diseases such as, for example, tablets, pills, flours, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc.).

Tablets can be formulated with any conventional carrier, e.g. excipients (e.g. lactose, white sugar, salt glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicate, etc.) binders (e.g. water, ethanol, propanol) , Simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidine, etc. Disintegrants (e.g. dry starch, sodium alginate agar powder laminaran powder, hydrogen carbonate) Absorption of disintegrating agents (e.g. white sugar, stearin, cacao butter, hydrogenated oil, etc.), sodium carbonate, calcium carbonate, polyoxyethylene sorbate fatty acid ester, lauryl sulfate sodium, stearic monoglyceride, starch, lactose Accelerators (e.g. quaternary ammonium salts, lauryl sulfate sodium, etc.) Wetting agents (e.g. glycerine, starch, etc.) Adsorbents (e.g. starch, lactose, kaolin, bentonite, colloid Is purified talc, Stella rate, boric acid powder, polyethylene glycol, etc.), such as: silicate, etc.) rubles Lee controller (eg.

Tablets may also be enveloped with traditional external preparations, for example in the form of sugar tablets, gelatin tablets, intestinal tablets, film tablets or two or more tablets.

In the preparation of pills, excipients (e.g. glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin, talc, etc.) binders (e.g. gum arabic, tragacanth powder, gelatin, ethanol, etc.) Traditional carriers such as laminaran, agar, etc. may be used.

In the preparation of suppositories, traditional carriers such as polyethylene glycol, cacao butter, high alcohols, high alcohol esters, gelatin, semisynthetic glycerides, and the like may also be used. In the preparation of injections, solutions, emulsions or suspensions of compounds are sterile and well made isotonic with body fluids. These veins, emulsions and suspensions are conventional diluents such as water soluble lactic acid solution, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty ester, etc. Is made by mixing with active compounds.

The preparation may be combined with salt, glucose or glycerin in an amount sufficient to isotonic with body fluids. Formulations may also be combined with traditional solubilizers, buffers, anesthetics, and further to colorants, arks, flavors, flavors, sweeteners and other drugs. Formulations in the form of pastes, creams or gels can be prepared using white petrolatum, paraffin, glycerin, cellulose derivatives, polyethylene glycols, silicones, bentonites, etc. as diluents.

The pharmaceutical preparations of the present invention may contain the above compound (1) or a salt thereof (e.g., lactate, etc.) and an acid that does not precipitate and may be in the form of an injectable or injectable solution.

Acids that do not precipitate include, for example, lactic acid, methanesulphonic acid, propionic acid, hydrochloric acid, succinic acid, and the like, and more preferably lactic acid. When using lactic acid, lactic acid is always used 0.1-10% by weight, preferably 0.5-2% by weight, based on the weight of the above injectable and injectable solutions. When using an acid other than lactic acid, the acid is always used as 0.05-4% by weight, preferably 0.3% -2% by weight, based on the above solution.

Moreover, traditional additives can optionally be added to the above injectable, injectable solutions. Excipients include, for example, film hardeners, absorption accelerators or blockers, solidification blockers, complexing agents, anti-oxidants, drug hydrate drugs that make isotonicity, and the like. The pH of the solution is appropriately adjusted by adding an alkali such as sodium hydroxide and is always adjusted in the range between 2.5-7. The injectable and injectable solutions thus made have excellent stability and are stored in solution for a long time. The active compound or salt thereof may be contained in any amount of the pharmaceutical preparation, and may be contained 1-70% weight based on the total pharmaceutical weight.

The pharmaceutical preparations of the present invention can be administered by any method. Appropriate methods of administration may be selected depending on the type of preparation, the age and sex of the patient and the severity of the disease. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered by mouth. Injections are given intravenously either alone or in combination with auxiliary solutions (e.g. glucose, amino acid solutions, etc.).

Injections can also be administered intramuscularly, intracutaneously, subcutaneously or intraperitoneally. Suppositories are injected rectally.

The amount of pharmaceutical preparation of the present invention varies depending on the method of administration, the age and sex of the patient, the severity of the disease, etc., but is administered in the range of 0.2-100 mg of the active compound (1) or 2 salts to 1 kg of patient weight per day. Formulations are always given in divided portions 2-4 times a day.

The present invention is illustrated by the following comparative examples, examples, preparations and experiments.

Comparative Example 1

Dimethyl sulfide (49 ml) in 2-bromo-4,5-difluoroaniline (100 g) and amorphous dichloromethane (1.2 liter) was gradually added N-chlorosuccinimide (90 g) below 15 ° C. Put in and then partially add triethylamine (93 ml) at 15 ° C. After addition the mixture was refluxed for 7 hours. After cooling, 10% liquid sodium hydroxide (1liter) is added to the reaction mixture and the mixture is extracted with dichloromethane. The extract is dried over magnesium sulfate and concentrated and the remaining residue is purified by silica gel column chromatography (solvent, dichloromethane: n-hexane = 1: 2).

The product was recrystallized from n-hexane to obtain 6-bromo-3,4-difluoro-2-methylthiomethylaniline (52 g) as white crystals with melting point 60-61 ° C.

Comparative Example 2

A mixture of 6-bromo-3,4-difluoro-2-methylthiomethylaniline (99 g) HMPA (130 g) and cyanide copper (48 g) is heated at 150 ° C. for 4 hours. After cooling the reaction mixture is poured into a solution of ethylenediamine (50 ml) in water (500 ml) and the mixture is heated at 60 ° C. for one hour. After cooling the mixture is extracted with ethyl acetate and the extract is dried over magnesium sulfate and concentrated.

The remaining residue is purified by silica gel column chromatography (solvent, dichloromethane: n-hexane = 1: 1) and the product is 2-amino-4,5-difluoro as white crystals with melting point 109-110 ° C. Recrystallized from ethanol to obtain rho-3-methylthiomethyl-benzonitrile (28 g).

Comparative Example 3

A solution of 2-amino-4,5-difluoro-3-methylthiomethylbenzonitrile (4.0 g) in ethanol is added with Ranickel (40 ml) with ethanol (80 ml). The mixture is shaken at 40-50 ° C. for 30 minutes and then filtered. Water is added to the filtrate and the reaction mixture is extracted with ethylacetate. The extract is dried over magnesium sulfate and concentrated. The product was recrystallized from n-hexane to obtain 2-amino-4,5-difluoro-3-methylbenzonitrile (2.4 g) as white crystals with melting point 114-116 ° C.

[Comparative Example 4]

To sodium nitrite (5-6 g), concentrated sulfuric acid (59 ml) is added at 70 占 폚 or lower. The mixture was heated at 70 [deg.] C. for 10 minutes and then cooled, and then there was added a solution of 2-amino-4,5-difluoro-3-methylbenzonitrile (12.3 g) in acetic acid (123 ml). Add dropwise at ℃. The mixture is shaken at the same temperature for 30 minutes, then partially added to a solution of copper chloride (20 g) in concentrated hydrochloric acid (200 ml) and heated to 80 ° C. for 30 minutes. After cooling, ice water is added to the reaction mixture, and the ethyl acetate is distilled away. As a result, the remaining residue is white crystals with a melting point of 59-61 ° C in silica gel column chromatography (solvent, dichloromethane: n-hexane = 1: 1), 2-chloro-4,5-difluoro-3-methyl Purify to obtain benzonitrile (8.0 g).

[Comparative Example 5]

To 2-chloro-4,5-difluoro-3-methylbenzonitrile (4.0 g) is added 60% sulfuric acid (20 ml) and the mixture is heated at 140-150 ° C. for 3 hours. After cooling, the reaction mixture is poured into iced water and the mixture is extracted with dichloromethane. The extract is dried over magnesium sulfate and the solvent is evaporated. Precipitation was isolated by filtration to add n-hexane to the rest and to obtain 2-chloro-4,5-difluoro-3-methylbenzoic acid (3,1) as white crystals with melting point 121-122 ° C. do.

Comparative Example 6

Thionyl chloride (6 ml) was added to 2-chloro-4,5-difluoro-3-methylbenzoyl acid (3.1 ml) and refluxed for 1 hour. The mixture is condensed at low pressure to give 2-chloro-4,5-difluoro-3-methylbenzoyl chloride (3.3 g). In addition, the metalyl magnetic wool (0.38g) is suspended in anhydrous ethanol (0.8ml), and a few drops of carbon acid chloride are added thereto. At 50-60 ° C., the mixture of diethyl malonate (2.3 ml) anhydrous ethanol (1.5 ml) and anhydrous toluene (6 ml) is partly mixed at the beginning of the reaction. A solution of 2-chloro-4,5-difluoro-3-methylbenzoyl chloride (3.3 g) mentioned above in anhydrous toleneene (5 ml) is added dropwise at 0 ° C. to this mixture. After the addition, the mixture is stirred at room temperature for 30 minutes. High concentration sulfuric acid (0.47 ml) and water (8 ml) are added to the reaction mixture, and the mixture is extracted with diethyl ether. The extract is dried over magnesium sulfate, the solvent is distilled off and blown off to yield diethyl 2-chloro-3-methyl-4,5-difluorobenzoyl malonate (5.1 g).

Comparative Example 7

Water (10 ml) and p-toluene-sulfonic acid (30 ml) are added to 2-chloro-3-methyl-4,5-difluoro benzoylmaleate (5.1 g) and refluxed for 4 hours. After cooling, the mixture is extracted with diethyl ether, and the extract is dried over magnesium sulfate. Diethyl ether is blown off by distillation to give ethyl 2-chloro-4,5-difluoro-3-methylbenzoyl acetate (3.9 g).

Comparative Example 8

Triethoxyethane (3.1 g) and saxic anhydride (3.4 g) are added to ethyl 2-chloro-4,5-difluoro-3-methylbenzoyl acetate (3.9 g) and the mixture is heated at 150 ° C. for one hour. do. The mixture is coagulated to yield ethyl 2- (2-chloro-3-ethyl-4,5-difluorobenzoyl) -3-ethoxyacrylate. Ethanol (50 ml) is added to this product, to which cyclopropylamine (1.1 ml) is added at room temperature and stirred for 30 minutes. Obtained by distilling off ethanol. Ioxane anhydride (30 ml) is mixed with this product with a slight addition of 60% sodium hydroxide (0.6 g). The mixture is stirred at room temperature for 30 minutes and refluxed for 1 hour. The reaction mixture is poured into aqueous saturated ammonium chloride and extracted with dichloromethane. The extract is dried over magnesium sulfate and condensed to ethyl 1-cyclopropyl-6,7-difluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (2.2 g) Is obtained.

NMR (CDCl ₃ ) δ: 0.64 (1H, s), 8.10 (1H, t, J = 10Hz), 4.36 (2H, g, J = 7.5Hz), 3.75-4.10 (1H, m), 2.76 (3H, d, J = 45 Hz), 1.37 (3H, t, J = 7.5 Hz), 0.86-1.30 (1H, m)

Comparative Example 9

Concentrated hydrochloric acid (5 ml), water (2 ml) and acetic acid (20 ml) were diluted with ethyl 1-cyclopropyl-6,7-difluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxyl. Add to rate (2.2 g) and reflux for 2 hours. After cooling, the precipitated crystals were filtered off, washed with water, ethanol and diethyl ether, and then washed with 1-cyclopropyl-6,7-difluoro-8-methyl-1,4-dihydro-4-oxoqui. Norin-3-carboxylic acid (1.8 g) is obtained as white crystals (mp240-243 ° C).

Comparative Example 10

After addition of triacetylboron B (OCOCH ₃ ) ₃ (1.0 g) and anoxic anhydride (10 ml), the mixture was heated to 140 ° C. for 15 minutes, after which the mixture condensed and dietierinterfere was added thereto. The crystals were filtered off to obtain 6,7 ₃ ) ₂ chelate (1.2 g).

NMR (CDCl ₃ ) δ: 9.32 (1H, 9), 8.23 (4H, t, J = 9Hz), 4.30-4.58 (1H, m), 2.97 (3H, d, J = 3Hz), 2.03 (6H, s ), 1.13-1.60 (4H, m)

Comparative Example 11

2.2-Dichloro-1-cyclopropylcarboxylic acid (4.0 g) is suspended in water (5 ml) to add a suitable amount of acetone to form a completely homogeneous solution. The solution is cooled to 0 ° C. and a solution of triethylamine (3 g) in acetone (60 ml) is added thereto.

While maintaining the mixture at 0 ° C., a solution of ethylchlorocarbonate (3.54 g) in acetone (15 ml) was added dropwise. After mixing like this, the mixture was stirred at 0 ° C. for 30 minutes, and then the solution of sodium azide (2.51 g) dissolved in water (10 ml) was dropped drop by drop. The mixture is further stirred at 0 ° C. for one hour, after which the reaction mixture is poured into iced water and extracted with diethyl ether. The extract solution is dried and condensed on magnesium sulfate. Benzyl alcohol (3.35 g) and anhydrous benzene (50 ml) are finally added to the 2.2-dichloro-1-cyclopropylcarbonyl azide obtained and the mixture is refluxed with stirring for 10 hours.

After the reaction was completed, the reaction mass was condensed and the residue was purified by silica gel column chromatography (solvent: ethyl acetate: n-hexane = 1: 30), and then recrystallized from dichloromethane to give 2.2-dichloro-l-benzyloxycarbo Nielaminocyclopropane (2.8 g) is obtained. It is a colorless needle and m.p. 79.5-80.5 ° C.

The following materials were prepared in the manner described in Comparative Example 11 using suitable starting materials.

2-chloro-1-benzyloxycarbonylaminocyclopropane (mixture of cis and tris isomers)

NMR (CDCl ₃ ) δ: 1.10-1.32 (2H, m), 2.76-3.10 (2H, m), 4.73-5.13 (1H, m), 5.11 (2H, 2), 7.35 (5H, s)

2 Fluoro-1-benzyloxycarbonylaninocyclopropane (a mixture of sea and trans isomi)

NMR (CDCl ₃ , 60 MHz) δ: 0.60-1.60 (2H, m), 2.50-3.17 (1H, m), 4.07-4.30 and 4.53-5.00 (2H, m), 5.08 and 5.11 (2H, s), 7.33 (5H, s)

Comparative Example 12

To 2.2-dichloro-1-benzyloxycarbonylamino cyclopropane (1.5 g), 5% pd-C (0.15 g), ethanol (15 ml) and concentrated hydrochloric acid (1.5 ml) were added, and the mixture was cooled to room temperature. Catalytic reduction at atmospheric pressure. After the reaction, the catalyst is filtered off to remove the filtrate. The resulting residue is recrystallized from ethanol diethyl ether and 2.2-dichloro-1-aminocyclopropane hydrogen chloride (0.7 g) is obtained as a white powder. It has an m.p. of 147-148 ° C. (decomposition).

Using a suitable starting material, the following materials were obtained according to the method described in Comparative Example 12.

2-Chloro-1-aminocyclopropanehydrochlorohydride (a mixture of sea and trans isomers)

NMR (DMSO-d ₆ ) δ: 1.16-1.73 (2H, m), 2.83-3.10 (1H, m), 3.57-3.80 (1H, m), 8.60-9.26 (3H, m)

2-fluoro-1-aminocyclopropane hydrochloride (mixture of sea and trans isomers)

NMR (DMSO-6, 200 MHz) δ: 1.00-1.60 (2H, m), 2.47-2.68 and 2.88-3.17 (1H, m), 4.65-4.88 and 4.96-5.20 (1H, m), 8.30-9.00 (3H , m)

In a solution of ethyl 2 (2,4,5-trifluorobenzoyl) -3-ethoxyacrylate (1.78 g) and triethylamine (0.60 g) in ethanol (10 ml). -Drop the solution containing fluoro-1-cyclopropylamine hydrochloride (0.60 g) drop by drop. After addition the mixture is stirred for 1 hour at room temperature and then condensed to yield ethyl 2- (2,4,5-trifluorobenzoyl) -3- (2-fluoro-1-cyclopropyl) aminoacrylate. Dioxene (30 g) and 60% sodium hydroxide (0.3 g) are added to this product, and the mixture is stirred at room temperature for one hour.

After condensation of the reaction mixture, water is added to the obtained residue, followed by extraction with dichloromethane. The extract is washed with water and dried to evaporate the solvent and then ethyl 1- (2-fluoro-1-cyclopropyl) -6,7-difluoro-1,4-dihydro-4-oxoquinoline-3 Carboxylate (a mixture of sheath and trans isomers) is obtained (1.02 g).

NMR (CDCl ₃ , 60 MHz) δ: 1.36 (3H, t, J = 8 Hz), 1.44-2.27 (2H, m), 3.50-3.83 (1H, m), 4.28 (2H, q, J = 8 Hz), 4.55 -4.86 and 5.26-5.53 (1H, m), 7.5 8 (1 H, dd, J = 11Hz, 6Hz), 7.98 (1H, dd, J = 10Hz, 9Hz), 8.31 and 8.51 (lH, s)

Using the appropriate starting material, the following material is obtained in the same manner as in Comparative Example 13.

Ethyl 1- (2-chloro-1-cyclopropyl) -6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (mixture of sheath and transisomer)

NMR (CDCl ₃ , 60 MHz) 6: 1.37 (3H, t, J = 7 Hz), 1.70-2.20 (2H, m), 3.40-3.80 (2H, m), 4.31 (2H, q, J = 7 Hz), 7.55 (1H, dd, J = 14Hz, 6Hz), 8.07 (1H, dd, J = 9Hz), 8.32 and 8.34 (1H, s)

Ethyl 1- (2-ethyl-1-cyclopropyl) -6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (mixture of sheath and trans isomer)

NMR (CDCl ₃ , 60 MHz) δ: 1.00-2.00 (3H, m), 1.39 (3H, t, J = 7 Hz), 1.41 (3H, s), 3.00-2.27 (1H, m), 4.37 (lH, q , J = 7Hz), 7.55 (lH, dd, J = 11Hz, 6Hz), 8.2 0 (1H, dd, J = 9Hz, 9Hz), 8.51 (1H, s)

Ethyl 1- (2-fluoro-1-cyclopropyl) -6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (1.02 g) in 90% acetic Seed-conc. Hydrochloric acid (4: 1.2 ml) is mixed and the mixture is refluxed with stirring for one hour. After condensation, water is added to this residue. The precipitated crystals were filtered off, washed with ethanol and diethyl ether, and then dried to give 1- (2-fluoro-1-cyclopropyl) -6,7-difluoro-1,4-dihydro-4-. Oxoquinoline 0-3-carboxylate (a mixture of cis and trans isomers) (0.58 g) is obtained.

NMR (DMSO-d ₆ , 200NMz) δ: 1.63-2M 17 (2H, m), 3.75-3.97 and 4.20-4.50 (1H, m), 5.09-5.35 and 5.41-5.63 (1H, m), 8.12 (dd , J = 11.85Hz, 6.67Hz), 8.39 (dd, J = 12.08Hz, 7.3Hz) (1H), 8.30 (dd, J = 10.38Hz, 8.62Hz), 8.28 (dd, J = 12.18Hz, 10.42 ) (lH), 8.73 and 8.65 (1H, s)

By adding an appropriate starting material, the following materials were obtained in the same manner as in Comparative Example 14.

1- (2-Chloro-1-cyclopropyl) -6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (mixture of sea and trans isomers)

NMR (DMSO-d ₆ , 200 MHz) 6: 1.80-1.99 and 2.04-2.23 (2H, m), 3.94-4.07 (1H, m), 4.19-4.34 (1H, m), 7.98- (lH, dd, J = 11.84 Hz, 6.64 Hz), 8.31 (lH, dd, J = 10.34 Hz, 8.66 Hz), 8.69 (lH, s)

1- (2-Methyl-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (mixture of cis and trans isomers)

NMR (trifluoroacetic acid-d ₆ , 60H MHz) δ: 1.33-2.10 (3H, m), 1.56 (3H, s), 3.66-4.00 (lH, m), 8.38 (lH, dd, J = 10Hz, 6Hz ), 8.53 (lH, dd, J = 9 Hz), 9.48 (1H, s)

Comparative Example 15

Ethyl 7- (4-methyl-1 piperazinyl) -1-cyclopropyl-6-fluoro-8-methylthio methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (8.09 g) Nickel (40 ml) was added to the solution dissolved in ethanol (80 ml) together with ethanol (80 ml), and the mixture was stirred at 40-50 ° C. for 30 minutes and then filtered. Water is added to this filtrate and extracted with methyl acetate. The extract was dried over magnesium sulfate and condensed to yield ethyl 7- (4-methyl-1-piperazin) -1-cyclopropyl-6-fluoro-methyl-1,4-dihydro-4-oxoquinoline 3-carboxylate (2.5 g) is obtained.

[Comparative Example 16]

A mixture of 6-bromo-3,4-difluoro-2-methyl-thiomethylanili (6.00 g) suspended in nickel (70 ml) in a solution dissolved in ethanol (120 ml) at 30 ° C. Stir for minutes.

Raney nickel is filtered off and the filtration material is then condensed to yield 3,4-difluoro-2-methyl-aniline (3,77 g) as a colorless oil condition.

NMR (CDCl ₃ ) δ: 6.72 (1H, ddd, J = 10.2 Hz, 8.7 Hz), 6.27 (1H, ddd, J = 10.2 H z, 6.0 Hz, 2.7 Hz), 3.43 (2H, br), 2.02 ( 3H, d, J = 2.4 Hz).

[Comparative Example 17]

To the 3,4-difluoro-2-ethylaniline (3.27 g) is added anhydrous acid (50 ml) and the mixture is stirred for 10 minutes. After evaporating the acetichydride, the residue is extracted with dichloromethane. The extract is washed sequentially with water, aqueous saturated sodium bicarbonate and aqueous saturated sodium chloride, and then dried over anhydrous magnesium sulfate. The dichloromethane is evaporated off and the residue is recrystallized from ethyl acetate-n-hexane to give 3,4-difluoro-2-methylacetanilide (3.86 g) as a colorless needle. m.p. is 145.5-146.0 ° C.

[Comparative Example 18]

3,4-difluoro-2-methylacetanilide (100 mg) is added to ice-cold concentrated sulfuric acid (0.3 ml), to which concentrated concentrated nitric acid (0.1 ml) is added, and the resulting mixture is brought to room temperature. Stir for 2 hours. To this mixture is further added concentrated nitric acid (0.1 ml) and stirred at room temperature throughout the day. A large amount of water is added to this reaction mixture and extracted with dichloromethane. The extract is washed with water, aqueous saturated sodium bicarbonate and aqueous saturated sodium chloride, and dried over anhydrous magnesium sulfate. The difluoromethane is evaporated off and the residue is recrystallized from methyl acetate-n hexane to give a yellow needle of 4,5-difluoro-6-methyl-2-nitroacetanilide (80.7 mg). It has an m.p. of 152.2-152.6 ° C.

Comparative Example 19

4,5-Difluoro-6-methyl-2-nitroacetanilide (81 mg) is dissolved in acetic acid (2 ml), and concentrated hydrochloric acid (1 ml) is added at 0 ° C. The mixture is stirred and condensed at 100 ° C. for one day. The residue is neutralized with aqueous saturated sodium bicarbonate and extracted with dichloromethane. The extract is washed with water soluble saturated sodium chloride and dried over anhydrous magnesium sulfate.

Evaporation of dichloromethane yielded 4,5-difluoro-6-methyl-2-nitroaniline (59 mg) as an orange prism with an m.p. of 87.2-88.0 ° C.

[Comparative Example 20]

Sodium nitrite (30 mg) was added in portions to concentrated hydrochloric acid (0.32 ml), and the mixture was stirred at 70 ° C. for 10 minutes, cooled to room temperature and 4.5-difluoro-6- in acetic acid (6.5 ml). A solution of methyl-2-nitroaniline (59 mg) is added dropwise at the same temperature. The mixture is stirred at room temperature for 30 minutes, to which is added dropwise a solution of copper chloride (107 mg) dissolved in concentrated hydrochloric acid (1.0 ml). The mixture is stirred at 80 ° C. for 30 minutes. Water is added to this mixture and ethyl sulphate is extracted. The extract is washed sequentially with water, water-soluble saturated sodium hydrogen carbonate and water-soluble saturated sodium chloride, and dried over anhydrous magnesium sulfate. Distillation of the ethyl saxate yields 2-chloro-5,6-difluoro-3-nitrotoluene (54 mg).

(CDCl ₃ ) δ: 7.58 (lH, dd, J = 11.0 Hz, 8.0 Hz), 2.40 (3H, s)

Comparative Example 21

To 2-chloro-5.6-difluoro-3-nitrotoluene (54 mg) was added ethanol (0.3 ml) and water (0.03 ml) at 0 ° C., to ethanol (0.1 ml) -methyl-piperazine (0.04 ml) and triethylamine (0.06 ml) in an aqueous solution are added dropwise at room temperature.

After stirring for 5 hours at room temperature, it is stirred for 5 hours at 60 ℃ and all day at 80 ℃. The reaction mixture is oxidized with 2n hydrochloric acid, washed with a small amount of diethyl ether, neutralized with aqueous saturated sodium bicarbonate and extracted with cichloromethane. The extracts were washed sequentially with water and water-soluble saturated sodium chloride, dichloromethane was distilled off and blown. 2-chloro-5-fluoro-6- (4-methyl-1-piperazinyl) -3-nitrotoluene (35 mg ) Is obtained.

NMR (CDCl ₃ ) δ: 7.46 (lH, d, J = 11.2 Hz), 3.15 (4H, br), 2.55 (4H, br), 2.46 (3H, s), 2.73 (3H, s)

Comparative Example 22

Potassium fluoride (110 mg) was dissolved in an aqueous solution of 2-chloro-5-fluoro-6- (4-methyl-1-piperazinyl) -3-nitrotoluene (17 ml) in dimethyl sulfoxide (1.5 ml). Cyclopropylamine (1.0 ml) is added and stirred at 100 ° C. for 13 hours.

The reaction compound is diluted with dichloromethane, washed with water, aqueous saturated sodium bicarbonate and aqueous saturated sodium chloride in that order and dried over anhydrous magnesium sulfate. Dichloromethane is then distilled off and blown off. The product was purified using a preferential thin layer chromatograph (developer, 1: 20 mixture of methanol-dichloromethane) and eventually n-cyclopropyl-4-fluoro-2-methyl-3- (4-methyl- 1-pyrerazinyl) -6-nitrotoluene (11 mg) is obtained.

NMR (CDCl ₃ ) δ: 7.69 (lH, d, J = 13 Hz), 7.59 (lH, br), 3.45-3.08 (4H, m), 2.8 5-2.75 (1H, m), 2.70-2.43 (4H, m), 2.45 (3H, s), 2.36 (3H, s), 1.0-0.5 (4H, m)

Comparative Example 23

To a solution of 3,4-difluoroacetanilide (85.5 g) dissolved in sulfuric acid (850 ml), potassium nitrate (55.5 g) is added at room temperature with gentle stirring, during which the temperature is raised to 60 ° C. Stir at 60 ° C. for 1 hour. It is poured into ice water and the precipitated crystals are filtered out. The precipitate is dissolved in dichloromethane, washed with aqueous sodium bicarbonate and aqueous saturated sodium chloride and dried. The obtained crystals are filtered and dried to give 2-nitro-4,5-difluoroaniline (54 g).

NMR (CDCl ₃ ) δ: 5.76-6.40 (2H, m), 6.60 (1H, dd, J = 12Hz, 7Hz), 7.97 (1H, dd, J = 10.5Hz, 8.5Hz)

Comparative Example 24

N-chlorosuccinimide (3.82 g) is slowly added to an aqueous solution of 2-nitro-4,5-difluoro aniline (1.0 g) dissolved in dichloromethane (40 ml) with stirring at 15 占 폚 or lower. It is stirred for 30 minutes, triethylamine (2.89 g) is added and the back refluxed for 21 hours.

After cooling, the reaction mixture is washed with 10% aqueous sodium hydroxide water and aqueous sodium chloride and dried. The solvent was removed by condensation and the residue was purified by silica gel column chromatography (solvent, n-hexane: ethyl acetate = 30: 1), and then recrystallized from n = hexane to give 2-nitro-4,5-difluoro. Rho-6-methylthiomethylaniline (0.47 g) is obtained in the form of a yellow needle.

[Comparative Example 25]

Sodium nitrite (0.15 g) is added to concentrated sulfuric acid (15 ml) and stirred at 70 ° C. for 10 minutes. To this was added dropwise a solution of 2-nitro-4,5-difluoro-6-methylthiomethylaniline (0.45 g) dissolved in acetic acid (4.5 ml).

This was stirred for 45 minutes at the same temperature, and an aqueous solution of copper chloride (0.52 g) dissolved in concentrated hydrochloride acid (5.2 ml) was added dropwise thereto. It is stirred at 80 ° C. for 1.5 hours, poured into ice water and extracted with ethyl acetate. The extract is washed with water and water-soluble saturated sodium chloride, and the solvent is distilled off. The residue obtained was purified by silica gel column chromatography (solvent, n-hexane: ethyl acetate = 30: 1), followed by 2-chloro-3-methylthio-4,5-difluoro-1-nitrobenzene. (0.16 g) is obtained.

NMR (CDCl ₃ ) δ: 2.15 (3H, s), 3.92 (2H, dd, J = 3 Hz), 7.67 (1H, dd, J = 8.5 H z, 8 Hz)

Comparative Example 26

2,3,6-Crifluorobenzoic acid (21.0 g) is added to concentrated sulfuric acid (120 ml) on ice cooling. To this mixture, a solution of potassium nitrate (14.5 g) dissolved in concentrated sulfuric acid (30 ml) is added dropwise at 20 占 폚 or lower. After this addition the mixture is stirred for 1 hour at room temperature. It is poured into ice water and extracted with diethyl ether. This extract is dried over magnesium sulfate and the solvent is blown off. The residue was recrystallized from dichloromethane-n-hexane to give 2,5,6-trifluoro-3-nitrobenzophosphoric acid (22 g) in m.p. Obtained in the form of a colorless prism of 98-99 ° C.

NMR (CDCl ₃ ) δ: 8.11-8.23 (1H, m), 9.10 (1H, brs)

Comparative Example 27

To an aqueous solution of sodium borate (44 g) dissolved in anhydrous tetrahydrofuran, an aqueous solution of anhydrous tetrahydrofuran (40 ml) in 2.5,6-trifluoro-3-nitrobenzoic acid (22 g) is added at 10 DEG C or lower. . An aqueous solution of boron trifluoride ethylate (20 ml) in anhydrous tetrahydrofuran (40 ml) was added dropwise at 10 占 폚 or lower. After the addition, the mixture is stirred for 1 hour at room temperature. It is poured into ice water and extracted with diethyl ether. The extract is dried and the solvent is distilled off to give 2,5,6-trifluoro-3-nitrobenzyl alcohol (14 g).

NMR (CDCl ₃ ) δ: 2.56 (lH, brs), 4.88 (2H, t, J = 1.8 Hz), 7.92-8.04 (1H, m)

Comparative Example 28

2,5,6-trifluoro-3-nitrobenzyl alcohol (14 g) was dissolved in ethanol (64 ml) and water (7 ml) in 4-ethoxycarbonylpiperazine (11 g) and triethylamine ( 12.5 g) and ethanol (18 ml) are mixed at once. The mixture is stirred at room temperature for one day, and the resulting additive is filtered off. Recrystallization is made from ethanol and 3,5-difluoro-2- (4-ethoxycarbonyl-1-piperazinyl) -5-nitrobenzyl alcohol (8.7 g) has an mp of 147-149 ° C. Obtained in the form of a yellow needle.

Comparative Example 29

Seed oil chloride (2.7 ml) in a solution of 3,6-difluoro-2- (4-ethoxycarbonyl-1-piperazinyl) -5-nitrobenzyl alcohol (8.5 g) in chloroform (85 ml). ) Is added at room temperature. It is stirred for 30 minutes at room temperature, poured into iced water, neutralized with sodium bicarbonate and extracted with diethyl ether. The extract was dried over magnesium sulfate and the solvent was distilled off and cut off to give 2- (4-ethoxycarbonyl-1-piperazinyl) -3,6-difluoro-5-nitrobenzylide ( 8.lg) is obtained.

NMR (CDCl ₃ ) δ: 1.28 (3H, t, J = 7.1 Hz), 3.08-3.33 (4 Hz, m), 3.46-3.75 (4H, m), 4.18 (2H, q, J = 7.l Hz), 4.77 (2H, D, J = 2.5 Hz), 7.82 (1H, dd, J = 9.2 Hz, 7.2 Hz)

Comparative Example 30

Sodium borate was dissolved in an aqueous solution of 3,6-difluoro-2- (4-ethoxycarbonyl-1-piperazinyl) -5-nitrobenzylchloride (8.lg) in dimethyl sulfoxide (90 ml). 1.8 g) is slowly added below 30 ° C. It is stirred for one hour at the same temperature, the reaction mixture is poured into ice water, oxidized with concentrated hydrochloric acid and extracted with diethyl ether. After distilling off the solvent and blowing off 2- (4-ethoxycarbonyl-1-piperazinyl) -3,6-difluoro-5-nitrotoluene (7.1 g).

NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.1 Hz), 2.30 (3H, d, J = 3 Hz), 2.76-3.27 (5H, m), 3.50-3.75 (4H, m), 4.17 ( 2H, q, J = 7.1Hz), 7.60 (1H, dd, J = 9.3Hz, 7.2Hz)

Comparative Example 31

3,6-difluoro-2- (4-ethoxycarbonyl-1-piperazinyl) -5-nitrotoluene (7.1 g) with N-hydrous dimethylsulfoxide (23 ml) and potassium potassium fluoride After addition of the ride (2.0 g) and cyclopropylamine (1.5 g), the mixture is heated to 60 ° C. for 6 hours. The reaction mixture is poured into iced water and extracted with dichloromethane. The solvent is distilled off and the residue is recrystallized from ethanol to give an orange red prism with an m.p. of 97-98 ° C.

NMR (CDCl ₃ ) δ: 0.50-0.54 (2H, m), 0.66-0.74 (2H, m), 1.28 (3H, t, J = 7.1H z), 2.43 (3H, s), 2.63-2.90 (H , m), 3.07-3.28 (4H, m), 3.47-3.77 (4H, m), 4.20 (2 H, q, J = 7.1 Hz), 7.53 (1H, brs), 7.70 (1H, dd, J = 13 Hz)

Comparative Example 32

Diethyl ethoxy methylenemalonate (4.6 g) in N-cyclopropyl-2-methyl-3- (4-ethoxycarbonyl-1-piperazinyl) -4-fluoro-6-nitroaniline (7.1 g) g) is added and it is reacted at 150-17 ° C. for 17 hours. After cooling, the solvent was distilled off and the residue was passed through silica gel column chromatography (solvent, dichloromethane: n-hexane = 2: 1-> dichloromethane) to give diethyl [n-cyclopropyl-N- [3-4- Ethoxycarbonyl-1-piperazinyl) -2-methyl-4-fluoro-6-nitrophenyl] amino methylene] malonate (5.4 g) is obtained.

Comparative Example 33

Diethyl [N-cyclo-N- [3- (4-ethoxycarbonyl-1-piperazinyl) -2-methyl-4-fluoro-6-nitrophenyl] amino methylene in oxalic anhydride (50 ml) ] To a solution of malonate (1.0 g) is added concentrated sulfuric acid (2 ml) while maintaining 50-76 ° C.

After stirring for 30 minutes, the reaction mass is poured into iced water and neutralized with potassium carbonate. The mixture was extracted with ethyl acetate, the solvent was distilled off, and the residue was purified by passing through silica gel column chromatography (solvent, dichloromethane: ethanol = 10: 1), and then recrystallized from ethyl acetate to yield ethyl-1-cyclo. Propyl-7- (4-ethoxycarbonyl-1-piperazinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (0.19 g) Colorless prism mp Obtained at 200-202 ° C.

Using the appropriate starting materials in the same manner as in Comparative Example 33, the same materials as in Comparative Examples 8, 15 and 13 were obtained.

Comparative Example 34

In Comparative Example 28, the following mixture was obtained using the appropriate starting material. 3,6-difluoro-2- (4-benzyl-3-methyl-1-piperazinyl) -5-nitrobenzyl alcohol

NMR (CDCl ₃ ) δ: 1.18 (3H, d, J = 6 Hz), 2.20-3.38 (1H, m), 2.55-2.72 (1H, m), 2.72-2.91 (1H, m), 3.06-3.44 (5H , m), 4.09 (lH, d, J = 13 Hz), 4.77 (2H, br), 7.12-7.40 (5H, m), 7.71 (1H, dd, J = 9.5 Hz, 7.2 Hz)

Comparative Example 35

Using the appropriate starting materials in the same manner as in Comparative Example 29, the following compounds were obtained.

2- (4-benzyl-3-methyl-1-pyrerazinyl) -3,6-difluoro-5-nitrobenzyl chloride

NMR (CDCl ₃ ) δ: 1.21 (3H, d, J = 6 Hz), 2.24-2.50 (1H, m), 2.00-3.00 (2H, m), 3.00-3.46 (5H, m), 4.11 (1H, d , J = 13Hz), 4.7 (2H, brs, 7.26-7.45 (5H, m), 7.79 (1H, dd, J = 9.5Hz, 7.3Hz)

Comparative Example 36

Using the appropriate starting materials in the same manner as in Comparative Example 30, the following compounds were obtained.

2- (4-benzyl-3-methyl-1-piperazinyl) -3,5-difluoro-5-nitrotoluene

NMR (CDCl ₃ ) δ: l.18 (3H, d, J = 6 Hz), 2.25 (3H, d, J = 3.3 Hz), 2.30-2.48 (lH, m), 2.50-3.38 (7H, m), 4.08 (lH, d, J = 13Hz), 7.15-7.46 (5H, m), 7.58 (1H, dd, J = 7.5Hz, 9.5Hz)

Comparative Example 37

Using the appropriate starting materials in the same manner as in Comparative Example 31, the following compounds were obtained.

N-cyclopropyl-2-methyl-3- (4-benzyl-3-methyl-1-pyrerazinyl) -4-fluoro-6-nitroaniline

NMR (CDCl ₃ ) δ: 0.52-0.68 (2H, m), 0.70-0.87 (2H, m), 1.28 (3H, d, J = 6H z), 2.22-2.40 (1H, m), 2.38 (3H, S), 2.58-3.37 (8H, m), 7.26-7.44 (5H, m), 7.60 (1H, brs), 4.11 (1H, d, J = 13 Hz), 7.77 (1H, dd, J = 13.2 Hz)

[Comparative Example 38]

The following compounds were obtained using the appropriate starting materials in the same manner as in Comparative Examples 32 and 33.

Ethyl-1-cyclopropyl-7 (4-benzyl-3-methyl-1-piperazinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate Mp Obtained as a white powder (recrystallized from ethyl acetate) at 172-173 ° C.

Comparative Example 39

Using the appropriate starting material in the same manner as in Comparative Example 28 to obtain the following compound.

3,6-difluoro-2- (3-amino-1-pyrrolidinyl) -5-nitrobenzyl alcohol was used in m.p. Obtained in the orange prism phase (recrystallized from ethyl acetate-n-hexane) at 117.0-118.5 degreeC.

[Comparative Example 40]

To 3,5-difluoro-2- (3-amino-1-pyrrolidinyl) -5-nitrobenzyl alcohol (43 mg) is added acetic anhydride (0.5 g) at room temperature. The mixture is stirred at room temperature for 10 minutes and the reaction mass is diluted with water and extracted with dichloromethane. The organic layer is washed with water and aqueous saturated sodium chloride in that order, dried over anhydrous magnesium sulfate, and the solvent is evaporated to blow off. The obtained residue was purified by passing through silica gel column chromatography (solvent, dichloromethane-methanol: dichloromethane = 1: 12) to give 2- (3-acetylamino-1-pyrrolidinyl) -3,6-difluoro- 5-nitrobenzyl alcohol (40 mg) in mp Obtained in the form of a yellow prism at 142.5-143.5 ° C.

Comparative Example 41

Using the appropriate starting material in the same manner as in Comparative Example 29 to obtain the following material.

2- (4-acetylamino-1-pyrrolidinyl) -3,5-difluoro-5-nitrobenzyl chloride

NMR (CDCl ₃ ) δ: 7.74 (1H, dd, J = 12.0 Hz, 7.5 Hz), 6.16 (1H, d, J = 5.4 Hz), 4.78 (1H, dd, J = 11.3 Hz, 3.0 Hz), 4.69 (1H, dd, J = 11.3Hz, 3.0Hz), 4.62-4.50 (1H, m), 3. 9 7-3.69 (2H, m), 3.67-3.50 (1H, m), 3.49-3.32 (1H, m). 2.40-2.18 (1H, m), 2.12-1.93 (lH, m), 1.98 (3H, s)

Comparative Example 42

Using the appropriate starting material in the same manner as in Comparative Example 30 to obtain the following material.

2- (3-acetylamino-1-pyrrolidinyl) -3,5-difluoro-5-nitrotoluene, m.p. 139.0-140 ° C Yellow needle (recrystallized from dichloromethane)

Comparative Example 43

In the same manner as in Comparative Example 31, the following materials were obtained using a suitable starting material.

m.p. 162.5-164.0 ° C. orange prismatic (recrystallized from ethyl acetate-n-hexane)

Comparative Example 44

Using the appropriate starting materials in the same manner as in Comparative Example 32, the following materials were obtained.

Diethyl [N-cyclopropyl-N-[(3-acetylamino-1-pyrrolidinyl) -4-fluoro-2-methyl-6-nitropinyl] aminomethylene] malonate

NMR (CDCl ₃ ) δ: 7.73 (1H, s), 7.68 (1H, d, J = 11.6 Hz), 5.97 (1H, br), 4.62-4.45 (1H, m), 4.12 (4H, q, J = 7.2 Hz), 3.85-3.15 (5H, m), 2.42-1.95 (5H, m), 1.90 (3 H, s), 1.29 (6H, t, J = 7.2 Hz), 0.93-0.52 (4H, m)

Comparative Example 45

In the same manner as in Comparative Example 33, using a suitable starting material, the following material was obtained.

Ethyl 1-cyclopropyl-7- (3-acetylamino-1-pyrrolidinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate, mp is 215.5 -217.0 ° C. white powder (recrystallized from ethanol-ethyl acetate-diethyl ether)

Comparative Example 46

Dissolve 3,6-difluoro-2- (4-ethoxycarbonyl-1-piperazinyl) -5-nitrobenzyl alcohol (1.5 g) in dichloromethane (18 ml), and dichloromethane (3 ml ) Was dissolved in a solution of diethylaminosulfur trifluoride (DAST) (0.7ml) and triethylamine (0.78ml) dropwise into a bucket of ice at 0 ℃ for 5 minutes and mixed with stirring. The mixture is stirred for 1 hour at 0 ° C. and further DAST (to 0.3 ml) is added thereto. After 5 minutes the reaction mixture is poured into ice water and the organic layer is separated. The solvent is distilled off at low pressure, and the residue is purified by silica gel column chromatography (solvent, ethyl acetate: n-hexane = 1: 10 → 1: 5 v / v), resulting in 2,5-difluoro-3 -Fluoromethyl-4- (4-ethoxycarbonyl-1-piperazinyl) nitrobenzene (1.1 g) is obtained.

Comparative Example 47

3,6-Difluoro-2- (4-ethoxycarbonyl-1-piperazinyl) -5-nitrobenzyl alcohol (1.0 g) is dissolved in pyridine (10 ml), and there is added anhydrous acid (2 ml). ) Is added at room temperature with stirring. And it is stirred for 2 hours with stirring. Water (20 ml) is added to the reaction mixture and stirred for 5 minutes. It is extracted with dichloromethane and the organic layer is washed with 10% hydrochloric acid and aqueous saturated sodium bicarbonate and dried over magnesium sulfate. Obtained after evaporation of the solvent at low pressure.

Comparative Example 48

Using the same method as in Comparative Example 31, using a suitable starting material to obtain the following compound.

N-cyclopropyl-2-acetoxymethyl-3- (4-ethoxycarbonyl-1-pyrerazinyl) -4-fluoro-6-nitroaniline

N-cyclopropyl-2-methoxymethyl-3- (4-ethyl-1-piperazinyl) -4-fluoro-6-nitroaniline)

NMR (CDCl ₃ ) δ: 0.47-0.55 (2H, m), 0.69-0.78 (2H, m), 2.36 (3H, s), 2.51-2.61 (4H, m), 2.88-2.98 (1H, m), 3.22-3.31 (4H, m), 3.34 (3H, s), 4.67 (2H, s), 7.2 9 (1H, s), 7.70 (1H, d, J = 12.7 Hz)

N-cyclopropyl-2-methoxyethyl-3- (4-ethoxycarbonyl-1-piperazinyl) -4-fluoro-6-nitroaniline is orange red needle, m.p. 89-90 ° C (ethanol-water)

[Comparative Example 49]

Using the appropriate starting material in the same manner as in Comparative Example 42 to obtain the following compound.

Diethyl [N-cyclopropyl-N- (3- (4-ethoxycarbonyl-1-piperazinyl) -2-acetmethyl-4-fluoro-6-anitrophenyl) aminomethylene] malonate

Diethyl [N-cyclopropyl-N- (3- (4-methyl-1-piperazinyl-2-methoxymethyl-4-fluoro-6-nitrophenyl) aminomethylene] malonate

NMR (CDCl ₃ ) δ: 0.50-1.10 (4H, m), 1.23 (3H, t, J = 7.0Hz), 2.37 (3H, s), 2.39-2.60 (4H, m), 3.0-3.20 (1H, m), 3.10-3.50 (4H, m), 3.39 (3H, s), 4.15 (2H, q, J = 7.0 Hz), 4.30-4.55 (2H, m), 7.55-7.90 (2H, m)

Diethyl [N-cyclopropyl-N- (3- (4-ethoxycarbonyl-1-piperazinyl) -2-methoxymethyl-4-fluoro-6-nitrophenyl) aminomethylene] malonate

NMR (CDCl ₃ ) δ: 0.55-0.73 (2H, m), 0.96-1.15 (2H, m), 1.15-1.45 (9H, m), 3.0-3.15 (1H, m), 3.15-3.35 (4H, m ), 3.40 (3H, m), 3.45-3.70 (4H, m), 4.05-4.40 (6H, m), 4.40-4.60 (2JH, m), 7.65-7.90 (2H, m)

[Comparative Example 50]

Using a suitable starting material in the same manner as in Comparative Example 33 to obtain the following compound.

Ethyl 1-cyclopropyl-7- (4-ethoxycarbonyl-1-pyrerazinyl) -6-fluoro-8-acetoxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxyl Lane, yellow powder, mp 172-173 ℃

Methyl 1-cyclopropyl-7- (4-ethoxycarbonyl-1-pyrerazinyl) -6-fluoro-8-methoxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxyl Lane

NMR (CDCl ₃ ) δ: 0.80-0.95 (2H, m), 1.10-1.22 (2H, m), 1.30 (3H, t, J = 7.1 Hz), 3.13 (3H, s), 3.08-3.30 ( 4H, m), 3.50-3.85 (5H, m), 3.92 (3H, s), 4. 19 (2H, q, J = 7.1 Hz), 5.12 (2H, s), 8.09 (1H, d, J = 12.4 Hz), 8.67 (1 H, s)

Ethyl 1-cyclopropyl-7- (4-methyl-1-pyrerazinyl) -6-fluoro-8-acetoxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate, mp , 122-125 ℃ Yellow Powder

Methyl 1-cyclopropyl-7- (4-ethoxycarbonyl-1-pyrerazinyl) -6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxyl Lane

Ethyl 1-cyclopropyl-7- (4-ethoxycarbonyl-1-pyrerazinyl) -6-fluoro-8-hydromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate

Comparative Example 51

Using the appropriate starting material in the same manner as in Comparative Example 28 to obtain the following compound.

3,6-difluoro-2- (4-methyl-1-piperazinyl) -5-nitrobenzyl alcohol, m.p. 138-139 ℃, yellow prism form.

Comparative Example 52

Dissolve 3,5-difluoro-2- (4-ethoxycarbonyl-1-piperazinyl) -5-nitrobenzyl alcohol (7.14 g) in methanol (770 ml), and add concentrated sulfuric acid (145 ml). Place in ice bucket and add drop by drop. The mixture is refluxed for 4 hours.

After cooling the reaction mixture to room temperature, poured into ice water (1.5 L), and extracted with dichloromethane. The extract is dried over magnesium sulfate and sodium sulfate, and the solvent is distilled off at low pressure to blow off 3-methoxymethyl-2,5-difluoro-4- (4-ethoxycarbonyl-1-pi. Ferrazinyl) nitrobenzene (7.39g) in yellow powder mp Obtained at 85-86 ° C.

Use of suitable starting materials in the manner described above yields the following compounds.

3-methoxymethyl-2,5-difluoro-4- (4-methyl-1-piperazinyl) nitrobenzene

NMR (CDCl ₃ ) δ: 2.37 (3H, s), 2.45-2.60 (4H, m), 3.32-3.42 (4H, m), 3,48 (3H, s), 4,53 (2H, d, J = 3.5 Hz), 7.78 (1H, dd, J = 7.3Jz. J = 11.8 Hz)

Comparative Example 53

Methyl 1-cyclopropyl-7- (4-ethoxycarbonyl-1-piperazinyl-6-fluoro-8-acetoxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (300 mg) was dissolved in methanol (3 ml) and IN aqueous potassium carbonate (0.8 ml) was added and stirred at room temperature for 3.25 h The reaction mixture was poured into water and extracted with dichloromethane and chloroform. After the organic layers are combined, dried over Nhydrous sodium sulfate, and the solvent is evaporated, methyl ethyl 1-cyclopropyl-7- (4-ethoxycarbonyl-1-piperazinyl) -6-fluoro-8 -Hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate and ethyl 1-cyclopropyl-7- (4-ethoxycarbonyl-1-piperazinyl) -6-fluorine A mixture of rho-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (2: 1) (280 mg) is obtained.

Without fractionation, methanol (7 ml) and concentrated sulfuric acid (1.4 ml) were added and the mixture was refluxed for 4 hours. The reaction mixture is poured into ice water (50 ml), adjusted to pH 8 or less with potassium carbonate, and extracted with dichloromethane.

The extract is dried over anhydrous sodium sulfate and the solvent is evaporated under low pressure once methyl 1-cyclopropyl-7- (4-ethoxycarbonyl-1-piperazinyl) -6-fluoro-8-methoxymethyl -1,4-dihydro-4-oxoquinoline-3-carboxylate (15.9 mg)

NMR (CDCl ₃ ) δ: 0.80-0.95 (2H, m), 1.10-1.22 (2H, m), 1.30 (3H, t, J = 7.1 Hz), 3.13 (3H, s), 3.08-3.30 (4H , m), 3.50-3.85 (5H, m), 3.92 (3H, s), 4.19 (2H, q, J = 7.1 Hz), 5.12 (2H, s), 8.09 (1H, d, J = 12.4 Hz) , 8.67 (1H, s)

[Comparative Example 54]

Using the appropriate starting material in the same manner as in Comparative Example 28 to obtain the following compound.

3,6-difluoro-2-morpholino-5-nitrobenzyl alcohol

NMR (CDCl ₃ ) δ: 7,79 (1H, dd, J = 11.9 Hz, 7.2 Hz), 4.86 (2H.s), 4.02-3.66 (4H, m), 3.42-3.20 (4H, m), 3.30 -3.02 (1H, br)

m.p. 87-89 ° C. (recrystallized from n-hexane ethyl acetate), yellow plate form 2,5-difluoro-3-methoxymethyl-4-morpholino-nitrobenzene, mp61.5-62 ° C. (n-hexane ethyl Recrystallized from acetate), yellow needle form

3,6-difluoro-2- (3-acetaminomethyl-1-piperazinyl) -5-nitrobenzyl alcohol, m.p. 120-121 ° C. yellow crystals

NMR (CDCl ₃ + DMSO-d ₆ ) δ: l.55-1.83 (1H, m), 1.95 (3H, s), 1.99-2.10 (1H, m), 2.39-2.57 (1H, m), 3.14- 3.82 (6H, m), 4.72 (2H, d, J = 2.6 Hz), 7.31 (1H, brs), 7.70 (1H, dd, J = 7.5 Hz, 13.5 Hz)

3,6-difluoro-2- (4-benzyl-1-piperazinyl-5-nitrobenzyl alcohol

NMR (CDCl ₃ ) δ: 2.50-2.72 (4H, m), 3.20 (1H, br), 3.25-3.38 (4H, m), 3.58 (2H, s), 4.75-4.90 (2H, m), 7.20- 7.45 (6H, m), 7.76 (1H, dd, J = 7.2 Hz, 11.6 Hz)

2,5-difluoro-3-methoxymethyl-4- (4-benzyl-1-piperazinyl) -nitrobenzene

NMR (CDCl ₃ ) δ: 2.45-2.68 (4H, m), 3.30-3.45 (4H, m), 3.42 (3H, s), 3.58 (2H, s), 4.52 (2H, d, J = 3.4Hz) , 7.26-7,40 (5H, m), 7.78 (1H, dd, J = 7.3 H z, 11.9Hz)

2,5-difluoro-3-methoxymethyl-4- (4-benzyl-3-methyl-1-piperazinyl) -nitrobenzene

NMR (CDCl ₃ ) δ: 7.77 (1H, d, J = 7.4 Hz, 11.9 Hz), 7.41-7.18 (5H, m), 4.52 (2H, s), 4.11 (1H, d, J = 13.0 Hz), 3.45-2.89 (4H, m), 3.42 (3H, s), 3.21 (1H, d, J = 1.0 Hz), 2.89-2.73 (1H, m), 2.73-2.54 (lH, m), 2.39- 2.20 (1H, m), 1.19 (3H, d, J = 6.2 Hz)

3,6-difluoro-2- [3- (N-methyl-N-benzylamino) -1-pyrrolidinyl-5-nitrobenzyl alcohol

NMR (CDCl ₃ ) δ: 7.75 (1H, dd, J = 7.5 Hz, 13.1 Hz), 7.41-7.20 (5H, m), 3.85-3.60 (4H, m), 3.62 (1H, d, J = 13.1 Hz), 3.52 (1H, d, J = 13.1 Hz), 3.25-3.05 (1H, m), 2.35-1.92 (3H, m), 2.20 (3H, s)

Comparative Example 55

Using the appropriate starting materials in the same manner as in Comparative Example 29 to obtain the following compound.

2-morpholino-3,6-difluoro-5-nitrobenzyl chloride

NMR (CDCl ₃ ) δ: 7.84 (1H, dd, J = l1.3 Hz, 7.3 Hz), 4.79 (2H, d, J = 2.6 Hz), 4.00-3.78 (4H, m), 3.40-3.15 (4H, m)

2,5-difluoro-3-chloromethyl-4- [3- (N-methyl-N-benzylamino) -1-pyrrolidinyl] -nitrotoluene

NMR (CDCl ₃ ) δ: 7.78 (1H, dd, J = 7.6 Hz, 13.4 Hz), 7.42-7.22 (5H, m), 4.78 (1H, dd, J = 2.7 Hz, 12.1 Hz), 4.67 (1H, dd, J = 2.7 Hz, 12.1 Hz), 3.92-3.55 (4H, m), 3.67 (1H, d, J = l3.1 Hz), 3.53 (1H, d, J = 13.1 Hz), 3.30-3.10 (1H , m), 2.35-1.88 (2H, m), 2.22 (3H, s)

2,5-difluoro-3-chloromethyl-4- (3-acetamidomethyl-1-pyrrolidinyl) nitrotoluene, m.p. 94-98 ° C. yellow crystals

NMR (CDCl ₃ + DMSO-d ₆ ) δ: 1.68-1.90 (1H, m), 2.07 (3H, s), 2.00-2.25 (lH, m), 2.50-2.68 (lH, m), 3.20-3.79 ( 6H, m), 4.78 (2H, d, J = 2.6 Hz), 7.78 (1H, dd, J = 7.5 Hz, 13.5 Hz), 8.18 (lH, brs)

[Comparative Example 56]

Using the appropriate starting material in the same manner as in Comparative Example 30 to obtain the following mixture.

2-morpholino-3,6-difluoro-5-nitrotoluene yellow needle form, m.p. 120.5-121.5 ° C. (recrystallized from n-hexane)

3,6-difluoro-5-nitro-2- [3- (N-methyl-N-benzylamino) -1-pyrrolidinyl] toluene.

NMR (CDCl ₃ ) δ: 7.65 (lH, dd, J = 7.1 Hz), 7.38-7.20 (5H, m), 3.79-3.45 (4H, m), 3.62 (lH, d, J = 13.4 Hz), 3.50 (lH, d, J = 13.4Hz), 3.30-3.06 (1H, m), 2.35-2.13 (1H, m), 2.25 (3H, d, J = 3.2Hz), 2.20 (3H, s), 2.11- 1.88 (lH, m)

3,6-difluoro-5-nitro-2- (3-acetamidomethyl-1-pyrrolidinyl) -toluene, m.p. 82-84 ° C., yellow crystals

NMR (CDCl ₃ ) δ: 1.60-1.78 (lH, m), 2.00 (3H, s), 2.02-2.20 (lH, m), 2.24 (3H, d, J = 3.2Hz), 2.40-2.66 (1H , m), 3.20-3.62 (6H, m), 5.67 (1H, brs), 7.63 (1H, dd, J = 7.5 Hz, 13 Hz)

[Comparative Example 57]

Using the appropriate starting material in the same manner as in Comparative Example 31 to obtain the following compound.

N-cyclopropyl-2-methyl-3-morpholino-4-fluoro-6-nitroaniline, yellow flake form, m.p. 101.5-102 ° C. (recrystallized from n-hexane)

N-cyclopropyl-2-methoxymethyl-3- (4-benzyl-1-pyrerazinyl) -4-fluoro-6-nitroaniline

NMR (CDCl ₃ ) δ: 0.45-0.57 (2H, m), 0.65-0.77 (2H, m), 2.48-2.65 (4H, m), 2.86-3.00 (lH, m), 3.20-3.30 (4H, m ), 3.32 (3H, s), 3.58 (2H, s), 4.81 (2H, s), 7.25-7.38 (5H, m), 7.70 (lH, d, J = 12.8 Hz)

N-cyclopropyl-2-methoxymethyl-3- (3-methyl-4-benzyl-1-pyrerazinyl) -4-fluoro-6-nitroaniline

NMR (CDCl ₃ ) δ: 7.70 (lH, d, J = 12.9 Hz), 7.40-7.l9 (5H, m), 4.65 (2H, s), 4.11 (lH, d, J = 13.3 Hz), 3.32 (2H, s), 3.40-2.88 (5H, m), 3.22 (lH, d, J = l3.3 Hz), 2. 8 8-2.72 (1H, m), 2.72-2.53 (1H, m), 2.38 -2.20 (1H, m), 1.20 (3H, d, J = 6.2 Hz), 0.80-0.63 (2H, m), 0.60-0.45 (2H, m)

N-cyclopropyl-2-methyl-3- [3- (N-methyl-N-benzylamino) -pyrrolidinyl] -4-fluoro-6-nitroaniline

NMR (CDCl ₃ ) δ: 7.87 (1H, s), 7.69 (lH, d, J = 11.7 Hz), 7.40-7.22 (5H, m), 3.81-3.41 (4H, m), 3.65 (1H, d, J = 10.6Hz), 3.55 (lH, d, J = 10.6Hz), 3.24-3.08 (1H, m), 2.86-2.72 (1H, m), 2.32-2.10 (1H, m), 2.29 (3H , s), 2.21 (3H, s), 2.08-1.90 (1H, m), 0.88-0.56 (3H, m), 0.51-0.41 (1H, m)

N-cyclopropyl-2-methoxymethyl-3-morpholino-4-fluoro-6-nitroaniline, m.p.57-60 ° C. (recrystallized from n-hexane), red powder

N-cyclopropyl-2-methyl-3- (3-acetamido methyl-1-pyrrolidinyl) -4-fluoro-6-nitroaniline

NMR (CDCl ₃ ) δ: 0.40-0.85 (4H, m), 1.60-1.83 (1H, m), 2.01 (3H, s), 2.04-2.20 (lH, m), 2.28 (3H, S), 2.42- 2.60 (1H, m), 2.70-2.88 (1H, m), 3.20-3.65 (6H, m), 5.89 (2H, brs), 7.65 (1H, d, J = 14.6Hz), 7.86 (lH, brs)

[Comparative Example 58]

Using the appropriate starting material in the same manner as in Comparative Example 32 to obtain the following compound.

Diethyl [N-cyclopropyl-N- (3- (4-benzyl-1-pyrerazinyl) -2-methoxymethyl-4-fluoro-6-nitrophenyl) aminomethylene] -malonate

NMR (CDCl ₃ ) δ: 0.55-0.90 (4H, m), 1.15-1.35 (6H, m), 2.47-2.70 (4H, m), 3.05-3.45 (4H, m), 3.37 (3H, s), 3.58 (2H, s), 4.15 (4H, q, J = 7 Hz), 4.20-4.55 (3H, m), 7.20-7.38 (5H, m), 7.63-7.90 (2H, m)

Diethyl [N-cyclopropyl-N- (3- (4-benzyl-3-ethyl-1-pyrerazinyl) -2-methoxymethyl-4-fluoro-6-nitrophenyl) aminomethylene] Nate

NMR (CDCl ₃ ) δ: 7.80 (1H, d, J = 12.7 Hz), 7.78 (1H, s), 7.47-7.15 (5H, m), 4.55-3.98 (7H, m), 3.65-2.88 (6H, m), 3.38 (3H, s), 2.86-2.70 (1H, m), 2.70-2.47 (1H, m), 2.32-2.13 (1H, m), 1.50-1.08 (6H, m), 1.19 (3H, d, J = 5.0 Hz), 1.01-0.41 (4H, m)

Diethyl [N-cyclopropyl-N- (3- (3-N-benzyl-N-methylamino) -pyrrolidinyl] -2-methyl-4-fluoro-6-nitrophenyl) -aminomethylene] mallo Nate

NMR (CDCl ₃ ) δ: 7.85-7.60 (2H, m), 7.40-7.16 (5H, m), 4.25-4.06 (2H, m), 3.80-3.05 (8H, m), 2.19 (6H, s), 2.32-1.89 (2H, m), 1.23 (6H, t, J = 7.1 Hz), 1.12-1.41 (4H, m)

Diethyl [N-cyclopropyl-N- (3-morpholino-2-methyl-4-fluoro-6-nitrophenyl) aminomethylene] malonate

Comparative Example 59

Using a suitable starting material in the same manner as in Comparative Example 33 to obtain the following compound.

Ethyl 1-cyclopropyl-7-morpholino-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate, colorless powder, mp205-206 ° C. (ethyl acetate recrystallized from -n-hexane)

Ethyl 1-cyclopropyl-7- (4-benzyl-1-pyrerazinyl) -8-acetoxymethyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate

NMR (CDCl ₃ ) δ: 0.85-1.00 (2H, m), 1.10-1.25 (2H, m), 1.41 (3H, t, J = 7.1 Hz), 2.03 (3H, s), 2.45-2.30 (4H , m), 3.10-3.45 (4H, m), 3,60 (2H, s), 3.85-4.03 (lH, m), 4.39 (2H, q, J = 7.1 Hz), 5.79 (2H, s), 7.23-7.45 (5H, m), 8.11 (1 H, d, J = 12.3 Hz), 8.65 (1 H, s)

Ethyl 1-cyclopropyl-7-morphoniro-3-acetoxymethyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate, mp176-178 ° C. (ethyl acetate- Recrystallized from diethylether-n-hexane), light yellow prism form

Ethyl 1-cyclopropyl-7- (4-methyl-1-piperazinyl) -6-fluoro-8-hydrophenyl-1,4-dihydro-4-oxoquinoline-3-carboxylate, mp216 -218 ℃, light yellow powder

Ethyl 1-cyclopropyl-7- (4-methyl-1-piperazinyl) -6-fluoro-8-methoxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate, mp 200-204 ℃, light yellow powder

Ethyl 1-cyclopropyl-7- (4-benzyl-3-methyl-1-piperazinyl) -6-fluoro-8-acetoxymethyl-1,4-dihydro-4-oxoquinoline-3- Carboxylate, mp170-172 ° C. (decomposition) (recrystallized from ethyl acetate-diethyl ether), light brown powder.

Ethyl 1-cyclopropyl-7- [3-N-benzyl-N-methylamino-1-pyrrolidinyl] -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3- Carboxylate, mp145-148.5 ° C. (decomposition) (recrystallized from ethyl acetate-diethyl ether), light yellow powder.

Ethyl 1-cyclopropyl-7-morpholino-6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate, m.p. 212-216 ° C., light yellow powder.

Ethyl 1-cyclopropyl-7-morpholino-fluoro-8- (1-pyrrolidinylmethyl) -1,4-dihydro-4-oxoquinoline-3-carboxylate, mp227-232 ° C, light yellow powder.

Ethyl 1-cyclopropyl-7-morpholino-6-fluoro-8-ethylthiomethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate, mp165-167 ° C. (dichlorometal- Recrystallized from diethyl ether), pale yellow needle form

Ethyl 1-cyclopropyl-7- (3-acetamidomethyl-1-pyrrolidinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate, mp 208-210 ° C. (recrystallized from ethanol) white crystals.

[Comparative Example 60]

Ethyl 1-cyclopropyl-7- (4-methyl-1-piperazinyl) -6-fluoro-8-acetoxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (142 mg ) Was added to a solution of ethanol (10 ml), and water-soluble potassium carbonate (1 ml) was added thereto and stirred at room temperature for 2,5 hours. The reaction mixture is extracted with chloroform. The extract is dried over magnesium sulfate and the solvent is evaporated.

Diethyl ether is added to this to determine the residue, which in turn is ethyl 1-cyclopropyl-7- (4-methyl-1-piperazinyl) -6-fluoro-8-hydroxymethyl-1,4 -Dihydro-4-oxoquinoline-3-carboxylate (101 mg) Light yellow powder, obtained at mp216-218 ° C.

Comparative Example 61

1-cyclopropyl-7- (4-methyl-1-piperazinyl) -6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (160 mg) To the solution dissolved in ethanol (10 ml) was added concentrated sulfuric acid (2 ml) and refluxed it for 6.5 hours. Water solubility is also adjusted to pH 8 or lower with sodium hydrogen carbonate and extracted with dichloromethane. The extract is washed with water soluble saturated sodium chloride, dried over magnesium sulfate and the solvent is evaporated.

Crystallization by addition of diethyl ether to the residue resulted in methyl 1-cyclopropyl-7- (4-methyl-1-piperazinyl) -6-fluoro-8-methoxymethyl-1,4-dihydro-4 Oxoquinoline-3-carboxylate (125 mg) as a pale yellow powder, obtained at mp200-204 ° C.

Comparative Example 62

3,6-difluoro-2- (4-benzyl-1-piperazinyl) -5-nitrobenzyl alcohol (15.4 g) was dissolved in methanol (400 ml) and stirred in iced water of solution. 80 ml) is mixed slowly. After addition the mixture is refluxed for 30 h, then further concentrated sulfuric acid (10 ml) is added and refluxed again for 20 h. After cooling to room temperature, water-soluble saturated potassium carbonate and water-soluble saturated sodium hydrogencarbonate are adjusted to pH 8 or less, and extracted with ethyl acetate.

The extract is dried over magnesium sulfate and the solute is evaporated. The residue was purified by silica gel column chromatography (solvent, dichloromethane) to give 2,5-difluoro-4- (4-benzyl-1-piperazinyl) -3-methoxymethyl-nitrobenzene (12.9 g) is obtained.

NMR (CDCl ₃ ) δ: 2.45-2.68 (4H, m), 3.30-3.45 (4H, m), 3.42 (3H, s), 3.5 8 (2H, s), 4.52 (2H, d, J = 3.4Hz ), 7.26-7.40 (5H, m), 7.78 (1 H, dd, J = 7.3 Hz, 1 1.9 Hz)

[Comparative Example 63]

Aqueous solution of ethyl 1-cyclopropyl-7-morpholino-6-fluoro-8-acetoxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (550 mg) in ethanol (10 ml) To 2N water-soluble potassium carbonate (lml) is added, which is stirred for 4 hours at room temperature. The reaction mixture is diluted with water and extracted with dichloromethane. The extract is dried and condensed. The residue is crystallized by addition of diethyl ether and eventually ethyl 1-cyclopropyl-7-morpholino-6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carbonate (353 mg) pale yellow powder, obtained at mp212-216 ° C.

[Comparative Example 64]

Thionylchloride (1 ml) is added to 1-cyclopropyl-7-morpholino-6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (80 mg) And it is stirred for 4 hours at room temperature, and further stirred for one hour at 50 ℃. Solvent condensed under reduced pressure and eventually impure ethyl 1-cyclopropyl-7-morpholino-6-fluoro-8-chloromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (84 mg) Obtained.

Pyridine (lml) is added thereto without clarification of the product, which is then stirred at room temperature for one day. The reaction mixture is extracted with dichloromethane and the extract is washed with water and aqueous saturated sodium chloride and dried over magnesium sulfate. The solvent is evaporated off and the residue is purified using silica gel column chromatography (solvent, dichloromethane: methane = 10: 1) to give 1-cyclopropyl-7-morpholino-8- (1-pyrrolidinylmethyl) -6 -Fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (31.8 mg) is obtained as a pale yellow powder at mp227-232 ° C.

[Comparative Example 65]

Ethyl 1-cyclopropyl-7-morpholino-6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (10 mg) cionyl chloride (1.5 ml) Add, and stir at room temperature for 5, 2 hours. The solvent is removed by condensation under reduced pressure. This impure ethyl 1-cyclopropyl-7-morpholino-6-fluoro-8-chloromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate and ethanethiol (1.5 ml) and tri Ethylamine (30 μl) is added and stirred at room temperature for one day. The reaction mixture is extracted with dichloromethane and the extract is washed with water and aqueous saturated sodium chloride in that order and dried over magnesium sulfate. The solvent is removed by condensation under reduced pressure, which is purified by silica gel column chromatography (solvent, dichloromethane: methanol = 15: 1), and recrystallized from dichloromethane-diethyl ether to obtain ethyl 1-cyclopropyl-7-morpholino-. 6-Fluoro-8-ethylthiomethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (49 mg) is obtained in the form of a pale yellow needle at mp165-167 ° C.

[Comparative Example 66]

Potassium fluoride (1.4 g) dried with 2-chloro-5,6-difluoro-3-nitrotoluene (1.0 g) espray, enhydrous dimethyl siloxide (10 ml) and benzene (10 ml) were added. Moisture is removed by distillation of the aotropes with benzene. The mixture is then stirred at 170-180 ° C. under argon for 3,5 hours.

After cooling, the reaction mixture is poured into iced water and extracted with diethyl ether. The extract is washed with water and dried to evaporate the solvent. The residue is purified by silica gel column chromatography (solvent, nhexane) to give 2,5,6-trifluoro-3-nitrotoluene (0.45 g).

NMR (CDCl ₃ ) δ: 2.34-2.37 (3H, m), 7.75-8.00 (1H, m)

Comparative Example 67

3-Amino-1-benzyl-4-methyl-phyllolidine (9.5 g) is added to ethanol (90 ml) at room temperature and stirred for one hour. Methanol is evaporated off under reduced pressure and water is added to the residue. Extract with dichloromethane and the extract is dried over magnesium sulfate to evaporate dichloromethane. The residue was purified by silica gel column chromatography (solvent, dichloromethane: methanol = 19: l) to be purified by 3- (t-butoxycarbonylamino) -1-benzyl-4-methylolidine (isomer A). (4.4 g) was obtained at mp131-132.7 ° C. as a colorless prism appearance.

NMR (CDCl ₃ ) δ: 1.09 (3H, d, J = 6.7 Hz), 1.43 (9H, s), 1.86-2.02 (2H, m), 2.6 2 (2H, d, J = 6.1 Hz), 2.93- 3.05 (1H, m), 3.56 (2H, s), 3.68 (1H, brs), 4.84 (1H, brs), 7. 20-7.37 (5H, m)

[Comparative Example 68]

To 3- (t-butoxycarbonylamino) -1-benzyl-4-methylpyrrolidine (3.9 g), ethanol (50 ml) and 10% Pd-C (780 mg) are added, which are then at atmospheric pressure below 60 ° C. Catalytic reduction is carried out under reduced pressure. After catalytic reduction, the catalyst is filtered off and the filter material condenses. The residue obtained was recrystallized from ethyl acetate-petroleum ether to give 3- (t-butoxyamino) -4-ethylpyrrolidine (isomer A) (2.1 g) as a colorless prism at mp86.8-87 ° C. Lose.

NMR (CDCl ₃ ) δ: 1.08 (3H, d, J = 6.8 Hz), 1.45 (9H, s), 1.83-1.97 (1H, m), 2.10 (lH, brs), 2.43-2.52 (lH, m) , 2.52-2.81 (lH, m), 3.10-3.35 (2H, m), 3.53-3.73 (lH, m), 4.69 (lH, brs)

[Comparative Example 69]

A solution of 2,5,6-trifluoro benzoic acid (120 g) dissolved in tetrahydrofuran (200 ml) was added dropwise to a solution of sodium boron hydride (51.6 g) dissolved in tetrahydrofuran (500 ml). And stirred at 10 ° C. or less, where a solution in which BF 3 ′ (C ₂ H ₅ ) ₂ O (232 ml) is dissolved in tetrahydrofuran (500 ml) is added drop by drop under ice cooling. It is stirred for 1 day at room temperature. The reaction mixture is poured into iced water (1.5) and extracted with this ethyl ether. The extract is dried over magnesium sulfate and the solvent is evaporated under reduced pressure to give 2,3,6-trifluorobenzyl alcohol (112.7 g) as a pale yellow oil at bp112 ° C. (30 mmHg).

[Comparative Example 70]

2,3,6-trifluorobenzyl alcohol (41 g) is dissolved in dichloromethane (100 ml) in a solution of cyanyl chloride (50 ml) in dichloromethane (80 ml), ice-cooled and a drop in stirring Add each and stir at room temperature for one day. Triethylamine (10 ml) was added thereto, and the solvent was evaporated under reduced pressure to give 2,3,6-trifluorobenzyl chloride (28.6 g) as colorless oil, which was obtained as b.p.63 占 폚 (13 mmHg).

NMR (CDCl ₃ ) δ: 4.66 (2H, s), 6.62-6.93 (lH, m), 7.04-7.26 (lH, m)

[Comparative Example 71]

Phenyltriethyl ammonium chloride (0.09 g) is added to a solution in which sodium cide (1.94 g) is dissolved in water (4 ml), and 2,3,6-trifluorobenzene chloride (5.0 g) is added thereto with stirring. Is added and the mixture is stirred at 90 to 100 ° C. for 40 minutes. The reaction mixture is poured into iced water (20 ml) and extracted with diethyl ether. The extract was dried over cardium carbonate and the solvent was evaporated to afford 2- (6-trifluorophenyl) acetnitrile (3.lg) at b.p. 80-85 ° C. (5 mmHg).

NMR (CDCl ₃ ) δ: 3.76 (2H, d, J = 0.8 Hz), 6.89-6.98 (lH, m), 7.11-7.26 (1H, m)

[Comparative Example 72]

Dissolve 2- (2,3,6-trifluorophenyl) acetnitrile (13.3 g) in ethanol (20 ml), and carefully add concentrated sulfuric acid (8.5 ml) to it, and then at 125 ° C for 7 hours. To countercurrent. After cooling, the reaction mixture is partitioned between diethyl ether and water. The ether layer is washed with aqueous saturated sodium chloride, dried over magnesium sulfate and condensed under reduced pressure to give ethyl 2- (2,3,6-trifluorophenyl) acetate (16.3 g) as colorless oil.

NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.1 Hz), 3.72 (2H, d, J = 1.2 Hz), 4.19 (2H, q, J = 7.1 Hz), 6.78-6.90 (lH, m ), 7.00-7.16 (lH, m)

Comparative Example 73

Dissolve ethyl 2- (2,3,6-trifluorophenyl) acetate (16.2 g) in ethanol (60 ml). It is stirred and 3N sodium hydroxide (200 ml) is added thereto and it is stirred at 70 ° C. for one hour. After cooling 6N hydrochloric acid (120 ml) is added to this mixture. The white powder precipitate obtained is dissolved by adding diethyl ether. The diethyl ether layer was separated, dried over magnesium sulfate, and then condensed under reduced pressure to yield 2- (2,3,6-trifluorophenyl) acetic acid (13.9 g) as white crystals.

NMR (CDCl ₃ ) δ: 3.79 (2H, s), 6.79-6.91 (lH, m), 7.02-7.18 (lH, m), 9.7 5 (1H, s)

[Comparative Example 74]

Richium aluminum hydride (0.8 g) is suspended in dried diethyl ether (5 ml) and the mixture is stirred.

A solution of 2- (2,3,6-trifluorophenyl) acetic acid (2.0 g) dissolved in dried diethyl ether (15 ml) is added dropwise to this mixture and refluxed for 30 minutes. To this was added water (0.8 ml), 10% water soluble sodium hydroxide (0.8 ml) and water (1.6 ml) in this order, and the mixture was stirred at room temperature. Diethyl ether (10 ml) was added thereto, and the obtained precipitate was filtered off and washed with tetrahydrofuran. The washing solution and the filtering material are combined with each other, and when condensed under reduced pressure, 2- (2,3,6-trifluorophenyl) ethyl alcohol (1.9 g) is obtained as colorless oil.

NMR (CDCl ₃ ) δ: 1.75 (1H, s), 2.98 (3H, t, J = 6.7 Hz), 3.85 (2H, t, J = 6.7 Hz), 6.74-6.87 (1H, m), 6.98 -7.09 (1H, m)

[Comparative Example 75]

P-toluenesulfonyl chloride (2.2 g) and triethylamine (2.0 ml) while stirring in a solution of 2- (2,3,6-trifluorophenyl) ethyl alcohol (1.5 g) dissolved in methylene chloride (10 ml). ) Is added and the mixture is stirred at room temperature for 5 hours. The reaction mixture is poured into iced water and extracted with diethyl ether. The ether layer is washed with water-soluble saturated sodium hydrogen carbonate and water-soluble saturated sodium chloride, dried over magnesium sulfate, and then coagulated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (solvent, methylene chloride) and recrystallized from diethyl ether-n-hexane to give 1- [2- (p-toluenesulfonyloxy) ethyl] -2,3, 6-trifluorobenzene (3.4 g) is obtained in the form of a colorless prism at mp73-74 ° C.

NMR (CDCl ₃ ) δ: 2.44 (3H, s), 3.03 (3H, t, J = 6.5Hz), 4.23 (2H, t, J = 6.5Hz), 6.70-6.82 (1H, m), 6.93 -7.09 (1H, m), 7.29 (2H, d, J = 8.5 Hz), 7.70 (2H, d, J = 8.5 Hz)

[Comparative Example 76]

Richium aluminum hydrolide (5.6 g) was suspended in dried diethyl ether (70 ml) and stirred with 1- (2- (p-toluene sulfonyloxy) ethyl) -2,3,6-tri A solution of fluorobenzene (23.3 g) dissolved in dried diethyl ether (170 ml) is added dropwise at 10 DEG C or lower, and the mixture is stirred at room temperature for one hour. To this was added water (5.6 ml), 10% water soluble sodium hydroxide (10.0 ml) and water (5.6 ml) in this order and stirred for 30 minutes at room temperature. Finally, the white precipitate obtained was filtered and the filter material was condensed at atmospheric pressure or lower to give 2,3,6-trifluoro-1-ethylbenzene (13.2 g) as colorless oil.

NMR (CDCl ₃ ) δ: 1.22 (3H, t, J = 7.1 Hz), 2.72 (2H, q, J = 7.1 Hz), 6.71-6.82 (1H, m), 6.87-7.03 (1H, m)

[Comparative Example 77]

2,3,6-trifluoro-1-ethylbenzene (1.09 g) was dissolved in concentrated sulfuric acid (5.5 ml), and a mixture of potassium nitrate (0.83 g) dissolved in concentrated sulfuric acid (4 ml) was stirred. Add and stir for 1 hour at the same temperature. The reaction mixture is poured into iced water (100 ml) and extracted with diethyl ether. The ether layer is washed with aqueous saturated sodium chloride, dried over magnesium sulphate and condensed under reduced pressure to give 3-ethyl-2,4,5-trifluoro-nitrobenzene (1.14 g) as a yellow oil.

NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.6 Hz), 2.77-2.89 (2H, m), 7.83 (1 H, dd, J = 8.0 Hz, 16.2 Hz)

[Comparative Example 78]

To 3-ethyl-2,4,5-trifluoro-nitrobenzene (1.02 g) is added ethanol (4.5 ml) and water (0..5 ml) and stirred. To this was added a mixture of 1-methylpiperazine (0.83 ml), triethylamine (1.0 ml) and ethanol (0.6 ml), and the mixture was refluxed for 5 hours.

To this reaction mixture is added l-ethylpiperazine (1.0 ml) and refluxed for 3 h. It was concentrated under reduced pressure and purified by silica gel column chromatography (solvent, methylene chloride) to give 3-ethyl-2,5-difluoro-4- (4-methyl-1-piperazinyl) nitrobenzene (1.12). g) is obtained as a yellow oil.

NMR (CDCl ₃ ) δ: 1.21 (3H, t, J = 7.5 Hz), 2.37 (3H, s), 2.42-2.67 (4H, m), 2.8 1 (2H, dq, J = 2.8 Hz, 7.5 Hz) , 3.05-2.23 (4H, m), 7.63 (1H, dd, J = 7.1Hz, 11.3Hz)

[Comparative Example 79]

3-Ethyl-2,5-difluoro-4- (4-methyl-1-piperazinyl) nitrobenzene (1.12 g) with forsyrium fluoride (0.24 g) and N, N-dimethyl sulfoxide (3.5 ml) and cyclopropylamine (0.4 ml) are added and it is stirred for 1.5 h between 80 and 85 ° C. The reaction mixture was diluted with ethyl acetate, the organic layer was washed with water and water-soluble saturated sodium chloride, dried over magnesium sulfate and condensed under reduced pressure to obtain N-cyclopropyl-2-ethyl-3- (4- Methyl-1-piperazinyl) -4-fluoro-6-nitroaniline (1.00 g) is obtained as a viscous oil.

NMR (CDCl ₃ ) δ: 0.45-0.55 (2H, m), 0.66-0.78 (2H, m), 1.14 (3H, t, J = 7.4 Hz), 2.37 (3H, s), 2.40-2.62 ( 4H, m), 2.62-2.85 (1H, m), 3.00 (2H, q, J = 7.4Hz), 3.05-3.23 (4H, m), 6.82 (lH, s), 7.54 (1H, d, J = 12.4 Hz)

[Comparative Example 80]

Using the appropriate starting material in the same manner as in Comparative Example 67 to obtain the following material.

3- (tbutoxycarbonylamino) -1-benzyl-4-methyl-pyrrolidine (isomer B) colorless needle, m.p.83-83.5 ° C (recrystallized from n-hexane)

NMR (CDCl ₃ ) δ: 0.93 (3H, d, J = 6.98 Hz), 1,44 (9H.s), 2.14-2.54 (3H, m), 2. 60-2.93 (2H, m), 3.58 (2H, dd, J = 13.03Hz, 14.91Hz), 4.07-4.31 (1H, m), 4.61-4.82 (1H, m), 7.14-7.39 (5H, m)

[Comparative Example 81]

Using the appropriate starting materials in the same manner as in Comparative Example 68, the following materials were obtained.

3 (t-butoxyamino) -4-methylpyrrolidine (isomer B), b.p. 106-109 ° C. (0.25 mmHg)

NMR (CDCl ₃ ) δ: 0.97 (3H, d, J = 6.9 Hz), 1.45 (9H, s), 1.93 (1H, brs), 2.10-2.33 (1H, m), 2.61-2.79 (1H, m) , 3.04-3.33 (2H, m), 3.97-4.21 (1H, m), 4.63-4.87 (1H, m)

Comparative Example 82

In the same manner as in Comparative Example 32, using a suitable starting material, the following compound was obtained.

Diethyl [N-cyclopropyl-N- [3 (4-methyl-1-pyrerazinyl) 2-ethyl-ethyl-4-fluoro-6-nitrophenyl] aminomethylene] malonate

[Comparative Example 83]

Using the appropriate starting material in the same manner as in Comparative Example 33 to obtain the following compound.

Ethyl 1-cyclopropyl-7- (4-methyl-1-pyrerazinyl) 6-fluoro-8-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate, mp201-203 ℃ White Powder (Recrystallized from Ethanol)

Example 1

6,7-difluoro-1-cyclopropyl-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid-B (OCOCH ₃ ) ₂ chilate (1.2 g) in benzylpiperazine ( 1.6 g) and diethylacetamide (6 ml) were added and reacted at 50 ° C. for 20 hours. After the concentration time, the residue is dissolved in acetone (20 ml), and concentrated hydrochloric acid (5 ml) is added thereto and stirred at room temperature for 30 minutes. After evaporation of the solvent, water is added to the residue and extracted with dichloromethane. The aqueous layer is taken up, neutralized with aqueous sodium hydrogen carbonate, and extracted with dichloromethane. The extract is combined and dried over magnesium sulfate. After the solvent was removed, a mixture of diethyl ether and ethanol was added to the extract, and then the precipitate was filtered off to obtain 7- (4-benzyl-1-piperazinyl) -1-cyclopropyl-6-fluoro-. 8-Methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.1 mg) is obtained as white crystals at mp209-211 ° C.

NMR (CDCl ₃ ) δ: 8.86 (1H, s), 7.85 (1H, d, J = 12Hz), 7.35 (5H, bs), 3.93-4.26 (lH, m), 3.62 (2H, s), 3.13- 3.50 (4H, m), 2.76 (3H, s), 2.53-2.83 (4H, m), 0.73-1.40 (4H, m)

Example 2

Acetic to 7- (4-benzyl-1-piperazinyl) -1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (84 mg) Acid (3 ml) and 10% pd-c (10 mg) were added and catalytic reduction at 70 ° C. for 1 hour. After catalytic reduction, the reaction mixture is cooled and the catalyst is filtered off. Concentrate the filtrate, add water-soluble sodium hydrogen carbonate thereto, and separate the obtained precipitate by filtration to obtain 7- (1-piperazinyl) -1-cyclopropyl-6-fluoro-8-methyl-1, 4-Dihydro-4-oxoquinoline-3-carboxylic acid (45 ml) as white crystals mp291-295 ℃ (decomposition)

NMR (DMSO-d ₆ ) δ: 8.84 (1H, s), 7.85 (1H, d, J = 12.5 Hz), 4.30-4.48 (1H, m), 3.16-3.50 (8H, m), 2.78 (3H, s), 1.12-1.28 (2H, m), 0.84-0.96 (2H, m)

Example 3

It is suspended in N-methylpyrrolidone (5 ml), to which piperazine (1.8 g) is added, which is stirred at 150 ° C. for 3 hours. After the reaction, the reaction mixture is concentrated and the residue is purified by silica gel column chromatography (solvent, dichloromethane: ethanol = 3: 1) to obtain white crystals, m.p.291-295 ° C (decomposition).

NMR (DMSO-d ₆ ) δ: 8.84 (1H, s), 7.85 (1H, d, J = 12.5Hz), 4.30-4.48 (1H, m), 3.16-3.50 (3H, m), 2.78 (3H, m), 1.12-1.28 (2H, m), 0.84-0.96 (2H, m)

Example 4

In the same manner as in Example 1, using a suitable starting material to obtain the following compound. 7- (4-methyl-1-pyrerazinyl) -1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, mp219-220.5 ° C. ( Recrystallized from ethanol Light yellow prism, 7- (1,4-diazabicyclo (4,3,0) nonan-4-yl) -1-cyclopropyl-6-fluoro-8-methyl-1,4-di Hydro-4-oxoquinoline-3-carboxylic acid, mp208-212 ° C. (dichloromethane-diethyl ether) light yellow powder.

7- (1-piperazinyl) -1- (2,2-dichloro-1-cyclopropyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

7- (1-piperazinyl) -1- (2-fluoro-1-cyclopropyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

Example 5

1-cyclopropyl-6-fluoro-8-methyl-7- (1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.20 g) with potassium hydrogen carbonate ( 70 ml) was suspended in dimethylformamide (3 ml), and 4-bromomethyl-3-1,3-dioxothen-2-silver (0.13 g) was added thereto under ice cooling, which was then cooled at room temperature for one hour. Stir. It is concentrated under reduced pressure, water is added, and extracted with dichloromethane. After distilling the extract under reduced pressure, the remaining residue was recrystallized from dichloromethane and diethyl ether to obtain 7- (4- (5-methyl-2-oxo-1,3-dioxoten-4-dimethyl-1 Pyrrazinyl) -1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.24 g) is pale yellow wall color crystal mp174-177 ° C Is obtained.

Example 6

Dimethylacetamide (10 ml) in 6,7-difluoro-1-cyclopropyl-8-1,4-dihydro-4-oxoquinoline-3-carboxylic acid-B (OCOCH ₃ ) ₂ chilate (3.4 g) And 4-benzyl-3-ethylpiperazinyl (68 g) are added and the mixture is reacted at 50 ° C for 3 hours. After the reaction, the solvent is evaporated, acetone (30 ml) and concentrated hydrochloric acid (5 ml) are added to the residue, and the mixture is stirred at room temperature for 30 minutes. Blow off the solvent, add water and filter to classify. The aqueous layer is neutralized with sodium hydrogencarbonate and extracted with dichloromethane. The dichloromethane was evaporated and the remaining residue was purified by silica gel column chromatography (solvent, dichloromethane: methanol = 20: 1), and recrystallized from ethanol to 7- (4-benzyl-3-methyl-1-pyrerazinyl). -1-Cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.45 g) is obtained as a light yellow powder at mp170-171 ° C.

Example 7

7- (4-benzyl-3-methyl-1-pyrerazinyl) -1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.30 g Acetic acid (10 ml) and 10% pd-c (50 ml) are added to the c), and the mixture is catalytically reduced for one hour under normal pressure at 70 ° C. After catalytic reduction, the reaction mixture is cooled and the catalyst is filtered off. The filtrate is concentrated, water is added thereto, adjusted to pH 7.5 with sodium hydrogen carbonate, and extracted with dichloromethane.

Dichloromethane was evaporated off, diethyl ether was added to the residue, the precipitate was separated by filtration and recrystallized from ethanol to give 7- (3-methyl-1-pyrerazinyl) -1-cyclopropyl-6 -Fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 80.165 g) is obtained as a light yellow powder at mp206-208 ° C.

Example 8

In the same manner as in Example 1, using a suitable starting material, the following compounds were obtained. 7- (1-piperazinyl) -1- (2-chloro-1-cyclopropyl) -6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (of seas and trans isomers) mixture)

NMR (DMSO-d ₆ , 200 MHz) δ: 1.79-1.96 and 2.13-2.31 (2H, m), 2.83-3.00 (4H, M), 3.20-3.40 (4H, m), 3.81-3.93 (1H, m) , 4.15-4.29 (1H, m), 7.36 (1H, d, J = 7.4Hz), 7.93 (1H, d, J = 13.2Hz), 8.56 (1H, m)

7- (1-piperazinyl) -1- (2-methyl-1-cyclopropyl) -6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (of seas and trans isomers mixture)

NMR (trifluoroacetic acid-d ₆ , 60 MHz) δ: 1.23-2.00 (3H, m), 1.57 (3H, s), 3.56-4.30 (9H, m), 7.83 (1H, d, J = 7 Hz), 8.31 ( lH, d, J = 14Hz), 9.33 (lH, m)

7- (4-Methyl-1-piperazinyl) -1- (2-methyl-1-cyclopropyl) -6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (ciswa Mixture of trans isomer)

_{NMR (trifluoroacetic acid-d 6,} 60MHz) δ: 1.33-2.00 (3H, m), 1.55 (3H, s), 3.24 (3H, s), 3.36-4.50 (9H, m), 7.82 (1H, d, J = 7Hz), 8.33 (1H, d, J = 14Hz), 9.3 3 (1H, d, J = 14Hz), 9.33 (1H, s)

7- (1-piperazinyl) -1- (2-fluoro-1-cyclopropyl) -6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (mixture of sheath and trans )

NMR (DMSO-d ₆ , 200 MHz) δ: 1.60-2.18 (2H, m), 2.74-3.40 (8H, m), 3.77 -3.98 and 4.20-4.50 (1H, m), 5.05-5.26 and 5.38-5.57 ( 1H, m), 7.39 (d, J = 7.42Hz) and 7.46 (d, J = 7.42Hz) (1H), 7.92 (d, J = 13.46Hz) and 7.91 (d, J = 13.4 6Hz ) (1H), 8.58 and 8.75 (1H, s)

7- (4-Methyl-1-piperazinyl) -1- (2-fluoro-1-cyclopropyl) -6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid And mixture of trans)

NMR (DMSO-d ₆ ) 200MHz) δ: 1.58-2.13 (2H, m), 2.32 (3H, s), 2.44-2.67 (4H, m), 3.18-3.39 (4H, m), 3.33-3.50 and 3.72 -3.90 (1H, m), 4.56-4.64 4.84-4.95 and 5.13-5.24 (1H, m), 7.17 (d, J = 7.26Hz) and 7.14 (d, J = 6.14Hz) (1H), 7.9 7 ( d, J = 13.18 Hz) and 7.98 (d, 12.61 Hz) (1H), 8.52 and 8.72 (1H, s)

Example 9

Ethyl 1-cyclopropyl-7- (4-ethoxycarbonyl-1-piperazinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (0.8 To g) is added 10% water soluble sodium hydroxide (7 ml), which is refluxed for 5 hours. After cooling it is oxidized with diluted hydrochloric acid and extracted with dichloromethane. The aqueous layer was adjusted to PH 7.5 with sodium hydrogen carbonate, and the precipitate was filtered off and sorted, then 7- (1-piperazinyl) -1-cyclopropyl-6-fluoro-8-methyl-1,4- Dihydro-4-oxoquinoline-3-carboxylic acid (0.3 g) is obtained at mp291-295 ° C (decomposition).

NMR (DMSO-d ₆ ) δ: 8.84 (1H, s). 7.85 (1H, d, J = 12.5 Hz), 4.30-4.48 (1H, m), 3.16-3.50 (8H, m), 2.78 (3H, s), 1.12-1.28 (2H, m), 0.84-9.96 ( 2H, m)

In the same manner as in Example 9, using a suitable starting material, the same compound as in Example 1,4,5,6,7,8 can be obtained.

Example 10

Using the appropriate starting materials in the same manner as in Examples 1, 3 and 9, the following compounds were obtained.

(1) 7- (3-amino-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid mp201.5-203.0 Light yellow powder (recrystallized from ethanol-diethyl ether)

(2) 1-cyclopropyl-7- (4-ethoxycarbonyl-1-piperazinyl) -6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3- Carboxylic acid mp234-235 ° C. (recrystallized yellow needle form from methanol.)

(3) 1-cyclopropyl-7- (4-ethoxycarbonyl) -1-piperazinyl) -6-fluoro-8-methoxymethyl-1,4-dihydro-4-oxoquinoline-3 Carboxylic acid mp218-220 ° C. (recrystallized from ethanol), in the form of a light yellow prism.

(4) 1-cyclopropyl-7- (4-methyl-1-piperazinyl) -6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid mp197 -201 ℃ pale yellow powder.

(5) 1-cyclopropyl-7- (1-piperazinyl) -6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid mp149-152 ° C ( Recrystallized from ethanol-acetone dichloromethane) white powder.

(6) 1-cyclopropyl-7- (4-methyl-1-piperazinyl) -6-fluoro-8-methoxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid mp208 -210 ° C (recrystallized from ethanol-diethyl ether) white powder.

(7) 1-cyclopropyl-7- (1-piperazinyl-6-fluoro-8-methoxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

(8) 1-cyclopropyl-7- (4-methyl-1-piperazinyl) -6-fluoro-8-fluoromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid mp187 -189 ° C. (recrystallized from diethyl ether-dichloromethane) Light yellow powder.

(9) 1-cyclopropyl-7- (1-piperazinyl) -6-fluoro-8-fluoromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

(10) 1-cyclopropyl-7- (4-methyl-1-piperazinyl) -6-fluoro-8-difluoromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

(11) 1-cyclopropyl-7- (1-piperazinyl) -6-fluoro-8-difluoromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

(12) 1-cyclopropyl-7- (4-hydroxy-1-piperazinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid mp234- 236 ° C (Recrystallized from chloroform-ethanol) Light yellow crystals

(13) 1-cyclopropyl-7- (3-amino-4-methyl-1-pyrodinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid Hydrochloride (isomer A) mp226-232 ° C. yellow powder (recrystallized from ethyl acetate-ethanol)

NMR (DMSO-d ₆ ) δ: 1.18 (3H, d, J = 6.7 Hz), 2.62 (3H, s), 7.72 (1H, d, J = 13.4 Hz), 8.79 (1H, s)

(14) 1-cyclopropyl-7- (3-aminomethyl-1-pyrrolidinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride mp . 1 95-200 ° C. (recrystallized from ethyl acetate-methanol) yellow crystal

(15) 1-cyclopropyl-7- (3-methylamino-1-pyrrolidinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid mp185.5- 187.5 ° C (decomposition) (recrystallized from ethanol-dimethyl ether) white powder

(16) 1-cyclopropyl-7- (4-cyclopropyl-1-piperazinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid mp224- 225 ° C (decomposition) (recrystallized from ethanol) light yellow prism

(17) 1-Cyclopropyl-7- (3- (5-methyl-2-oxo-1,3-dioxoten-4-yl) methylamino-1-pyrrolidinyl) -6-fluoro- 8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

(18) 1-cyclopropyl-7-morpholino-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid mp227.5-228 ° C (recrystallized from ethanol) (19) 1-cyclopropyl-7-morpholino-6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-mp 218-220 ° C (Recrystallized from Methanol) Light Yellow Prism

(20) 1-cyclopropyl-7- (4-benzyl-1-piperazinyl) -6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid mp229 -213 ° C (recrystallized from dichloromethane-diethyl ether) pale yellowish form

(21) 1-cyclopropyl-7- (4-benzyl-3-methyl-1-piperazinyl) -6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3 Carboxylic acid mp208-209 ° C (recrystallized from ethanol-diethyl ether) light orange powder

(22) 1-cyclopropyl-7- (3-methyl-1-piperazinyl) -6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-4-carboxylic acid mp180 -193 ° C (recrystallized from ethanol-ethylavitate-diethyl ether) white powder

(23) 1-cyclopropyl-7- (3-N-benzyl-N-methylamino) -1-pyrrolidinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline 3-carboxylic acid mp160.8-161.3 ° C. (recrystallized from ethanol diethyl ether) light yellow powder

(24) 1-cyclopropyl-7-morpholino-6-fluoro-8 (1-pyrrolidinylmethyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid mp232-236 ° C. (decomposition) (Recrystallized from diethyl ether-ethanol-dichloromethane) light yellow prism form

(25) 1-Cyclopropyl-7-morpholino-6-fluoro-8-ethylthiomethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid mp206-208 ° C (N-hexane- Recrystallization from Ethanol) Op Yellow Prism

(26) 1-cyclopropyl-7- (4-oxo-1-piperidyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid mp247-250 ° C (recrystallized from chloroform-ethanol) White crystal

(27) 1-cyclopropyl-7- (3-acetaminomethyl-1-pyrrodininyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid mp192 -194 ° C (Recrystallized from chloroform-methanol) White crystal

(28) 1-cyclopropyl-7- (3-t-butoxycarbonylamino-methyl-1-pyrrodininyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline 3-carboxylic acid mp131-135 ° C. (recrystallized from methanol) White powder

(29) 1-cyclopropyl-7- (3-aminomethyl-1-pyrrolidinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid mp195- 200 ° C (Recrystallized from ethyl acetate-methanol) White powder

(30) 1-cyclopropyl-7- (3- (N-ethylacetamino) methyl-1-pyrrolidinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline- 3-carboxylic acid mp167-160 ° C. (recrystallized from ethanol) light yellow crystals

(31) 1-cyclopropyl-7- (3-ethylaminomethyl-1-pyrrolidinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride mp267-271 ° C. (recrystallized from methanol-acetnitrile) yellow powder

(32) 1-cyclopropyl-7- (4-acetyl-3-methyl-1-piperazinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid mp219-220 ° C (Recrystallized from methanol) White powder

(33) 1-cyclopropyl-7- (4-formyl-3-methyl-1-piperazinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid mp236-239 ° C (Recrystallized from methanol) White powder

(34) 1-cyclopropyl-7- (3-, 4-dimethyl-1-piperazinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid mp 181-183 ° C (recrystallized from ethyl acetate) light yellow powder

(35) 1-cyclopropyl-7- (3-, 5-dimethyl-1-piperidyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid mp 176-179 ° C (Recrystallized from Ethanol) Light Yellow Prism Form

(36) 1-cyclopropyl-7- (3-methylmorpholino) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid mp199.5-201 ° C (ethanol- Recrystallized from ethyl acetate) Colorless needle form

(37) 1-cyclopropyl-7- (3-aminomethylmorpholino) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

(38) 1-cyclopropyl-7- (3-fluoromethylmorpholino) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

(39) 1-cyclopropyl-7- (3-chloromethylmorpholino) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

(40) 1-cyclopropyl-7- (4-ethyl-1-piperazinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid mp208-210 ° C. (Recrystallized from dimethylacetamide-diethyl ether) Light yellow prismatic form

(41) 1-cyclopropyl-7- (4-fluoro-1-piperazinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid mp208- 210 ° C (Recrystallized from ethanol) Colorless saliva

(42) 1-cyclopropyl-7- (3- (5-ethyl-2-oxo-1,3-dioxoren-4-yl) -methylamino-1 pyrrolidinyl) -6-fluoro-8 -Methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

(43) 1-cyclopropyl-7- (4-methyl-1-piperazinyl) -6-fluoro-8-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid mp239-242 ℃ (decomposition) (Recrystallized from diethyl ether-ethanol) White powder

(44) 1-cyclopropyl-7- (3-methyl-1-piperazinyl) -6-fluoro-8-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

(45) 1-cyclopropyl-7- (3-amino-1-pyrrolidinyl) -6-fluoro-8-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

(46) 1-cyclopropyl-7- (3-amino-4-ethylyl-1-pyrrolidinyl) -6-fluoro-8-ethyl-1,4-dihydro-4-oxoquinoline-3- Carboxylic acid

(47) 1-cyclopropyl-7- (3-amino-4-ethyl-1-pyrrolidinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid Hydrochloride (Isomer B) mp 209-213 ° C. (recrystallized from ethyl acetate-ethanol) yellow powder

NMR (DMSO-d ₆ ) δ: 1.15 (3H, d, J = 6.9 Hz), 2.76 (3H, s), 7.7 0 (1 H, d, J = 13.7 Hz), 8.77 (1H, s)

(48) 1-cyclopropyl-7- (3-t-butoxycarbonylamino-4-methyl-1-pyrrolidinyl) -6-fluoro-8-methyl-1,4-dihydro-4- Oxoquinoline-3-carboxylic acid (isomer B) mp 157-160 ° C (Recrystallized from ethyl acetate) Yellow crystals

NMR (CDCl ₃ ) δ: 1.20 (3H, d, J = 6.6 Hz), 2.57 (3H, s), 7.91 (lH, d, J = 13.3 Hz), 9.15 (lH, s)

(49) 1-cyclopropyl-7- (3-t-butoxycarbonylamino-4-methyl-1-pyrrolidinyl) -6-fluoro-8-methyl-1,4-dihydro-4- Oxoquinoline-3-carboxylic acid (isomer B) mp 199-202 ° C (Recrystallized from ethyl acetate) Yellow powder

NMR (CDCl ₃ ) δ: 1.12 (3H, d, J = 6.6 Hz), 2.58 (3H, s), 7.85 (1H, d, J = 13.6 Hz), 8.87 (1H, s)

(50) 1-cyclopropyl-7- (3-t-butoxycarbonylamino-1-pyrrolidinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3 -Carboxylic acid mp 117-120 ° C (Recrystallized from Ethanol) Light Yellow Prism Form

(51) 1-cyclopropyl-7-morpholini-6-fluoro-8-fluoromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid m.p. 189-192 ° C (decomposition) (recrystallized from n-hexane-acetonitrile) light yellow powder

Example 11

10 in 1-cyclopropyl-7- (4-benzyl-1-piperazinyl) -6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (132 mg) After addition of% Pd-C (68 mg) and ethanol (10 ml), it was catalytically reduced at 60 ° C. for 6.5 hours under water extraction. The catalyst is filtered off and the filtrate is concentrated. The obtained residue was recrystallized from ethanol-acetone-dichloromethane to obtain 1-cyclopropyl-7- (1-piperazinyl) -6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline -3-carboxylic acid (342 mg) in white powder mp Obtained at 149-152 ° C.

Example 12

1% 1-cyclopropyl-7- (4-oxo-1-piperadyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.25 g) It is dissolved in aqueous sodium hydroxide (28 ml) and sodium borate (0.1 g) is added thereto at room temperature. It is stirred for 30 minutes at the same temperature, poured into ice water and oxidized with concentrated sulfuric acid. The mixture is extracted with dichloromethane and the solvent is distilled off. Crystallization by addition of ethyl acetate and recrystallization from chloroform-methanol gave 1-cyclopropyl-7- (4-hydroxy-1-piperidyl) -6-fluoro-8-methyl-1,4- Dihydro-4-oxoquinoline-3-carboxylic acid (0.16 g) is obtained as light yellow crystals at mp234-236 ° C.

Example 13

1-cyclopropyl-7- (3-t-butoxycarbonylaminomethyl) -1-pyrrolidinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3- 10% hydrochloric acid (4 ml) and ethanol (2 ml) were added to the carboxylic acid (0.1 g), followed by reaction for 10 minutes at 70 ° C. After concentration, the residue was crystallized by addition of this ethyl ether and recrystallized from ethyl acetate-methanol to 1-cyclopropyl-7- (3-aminomethyl-1-pyrrolidinyl) -6-fluoro-8-methyl -1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride (45 mg) as light yellow crystals mp Obtained at 195-200 ° C.

Example 14

1-cyclopropyl-7- (3- (N-ethylacetamide) methyl-1-pyrrolidinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid To hydrogen chloride (0.22 g) is added 5% water soluble sodium hydroxide (10 ml), which is refluxed for 24 h. After cooling, the insoluble material is filtered off and the filtered material is oxidized with concentrated hydrochloric acid. It is extracted with dichloromethane and the aqueous sodium chloride aqueous layer is made alkaline, followed by addition of anhydrous t-butoxycarboxylic acid (200 mg). This is stirred for 30 minutes at room temperature. It is oxidized with 10% hydrochloric acid and extracted with dichloromethane. Concentrate to remove the solvent, then 10% hydrochloric acid (5ml) and methanol (10ml) are added, it is heated to 70 ℃ 30 minutes. After concentration, the residue was recrystallized from methanol-acetonitrile to yield 1-cyclopropyl-7- (3-ethylaminomethyl-1-pyrrolidinyl) -6-fluoro-8-methyl-1,4-dihydro -4-oxoquinoline-3-hydrogen carboxylate (30mg) turns yellow crystals mp Obtained at 267-271 ° C.

Example 15

10% 1-cyclopropyl-7- (3-methyl-1-piperazinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.3 g) It is dissolved in water-soluble sodium chloride (5 ml) and aceticene hydride (0.3 ml) is added thereto at room temperature, followed by stirring at room temperature for 30 minutes. Oxidized with concentrated hydrochloric acid and then extracted with dichloromethane. Concentrate to remove the solvent, purify by passing through the chromatography (solvent, dichloroethane) with silica gel column, and then recrystallized from methanol 1-cyclopropyl-7- (4-acetyl-3-methyl-1-piperazinyl) -6-Fluoro-8-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.1 g) was converted into a white powder mp Obtained at 219-221 ° C.

Example 16

1-cyclopropyl-7- (3-methyl-1-piperazinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.4 g) is formic acid (1.7 ml) and acetic hydride (2.2 ml) are added at 0 ° C. After addition it is heated to 80 ° C. for 2 hours. To this is added water and extracted with dichloromethane. Concentration removes the solvent and the residue is recrystallized from methanol to give 1-cyclopropyl-7- (4-formyl-3-methyl-1-piperazinyl) -6-fluoro-8-methyl-1,4 -Dihydro-4-oxoquinoline-3-carboxylic acid (0.13 g) is white powder mp Obtained at 236-239 ° C.

Example 17

Formic acid in 1-cyclopropyl-7- (3-methyl-1-piperazinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-4-carboxylic acid (0.4 g) (3 ml), 37% formalin (3 ml) and sodium formate (0.4 g) were added followed by reflux for 5 hours. After cooling, the reaction mixture is poured into iced water, adjusted to pH 8 or below with aqueous sodium hydrogen carbonate and extracted with dichloromethane. The solvent was concentrated to remove the solvent and the residue was recrystallized from ethyl acetate, resulting in 1-cyclopropyl-7- (3,4-dimethyl-1-piperazinyl) -6-fluoro-8-methyl-1,4-di Hydro-4-oxoquinoline-3-carboxylic acid (0.12 g) as a pale yellow powder mp Obtained at 181-183 ° C. Using the appropriate starting material in the same manner as in Example 17, the first compound of Example 4, the third and fifth compounds of Example 8, and the fourth, sixth, fifteenth, twenty-third, and thirteenth compounds of Example 10 were obtained.

[Example 1]

Injections are made from the following ingredients:

This solution was dissolved in distilled water for injection of 7- (1-piperazinyl) -1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and glucose. Is injected into a sterilized ampule which is washed with nitrogen gas and sterilized at 121 ° C. for 15 minutes.

[Example 2]

A film covered tablet is obtained from the following ingredients.

Mix and knead 7- (1-piperazinyl) -1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, Avicel, cornstarch and magnesium stearate The tablets are then made using a conventional founder (R10mm) for sugar coating (produced by Kikkusui Seisakusho, Japan). The tablets thus prepared are coated with a film coating additive consisting of TC-5, polyethylene glycol 6000, castor oil and ethanol.

[Example 3]

Ointment is prepared from the following ingredients:

Heated to melt the bleached beeswax and add 7- (1-piperazinyl) -1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid Add clarified lanolin and white petrolatum and dissolve it until it becomes a liquid. Stir until the mixture solidifies and becomes an ointment.

Experiment (antimicrobial activity in the laboratory)

As mentioned below, the antimicrobial activity of the test compounds was examined by measuring the minimum disturbance concentration (MIC) by serial dilution in agar plates (cf chymotherapy, 22, 1126-1128 (1974)). 1 × 10 ⁸ cells / ml (DD 660 μm, 0.07-0.16) and 1 × 10 ⁶ cells / ml (100-fold dilution) were used. When pneumococcal Streptococcus Form II and pneumococcal Streptococcus Form III were used as test microorganisms, the medium contained 5% horse blood. The results are shown in Table 1.

TABLE 1

[Experimental component]

1. 7- (1-Piperazinyl) -1-cyclopropyl-6-fluoro-8-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

2. 7- (4-Methyl-1-piperazinyl) -1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

3. 7- (1,4-diazabicylo (4,3,0) nonan-4-yl) × 1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4- Oxoquinoline-3-carboxylic acid.

4. 7- (4- (5-Methyl-2-oxo-1,3-dioxoren-4-yl) methyl-1-piperazinyl) -1-cyclopropyl-6-fluoro-8-methyl -1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

5. 7- (3-Methyl-1-piperazinyl) -1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

6. 7- (1-Piperazinyl) -1- (2-fluoro-1-cyclopropyl) -6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

7. 7- (3-Amino-1-pyrrolidinyl) 1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

8. 7- (4-Methyl-1-piperazinyl) -1-cyclopropyl-6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

9. 1-Cyclopropyl-7-morpholino-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

10. 1-Cyclopropyl-7-morpholino-6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

11. 1-cyclopropyl-7- (3-acetamidomethyl-1-pyrrolidinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

12. 1-Cyclopropyl-7- (3-methyl-4-benzyl-1-piperazinyl) -6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3- Carboxylic acid.

13. 1-cyclopropyl-7- (4-oxo-1-piperazinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

14. 1-cyclopropyl-7- (4-hydroxy-1-piperazinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

15. 1-Cyclopropyl-7- (3- (t-butoxycarbonylaminomethyl) -1-pyrrolidinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline 3-carboxylic acid.

16. 1-Cyclopropyl-7- (3-aminomethyl-1-pyrrolidinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

17. 1-Cyclopropyl-7- (3-N-methyl-N-benzylamino) -1-pyrrolidinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline- 3-carboxylic acid.

18. 1-Cyclopropyl-7- (3-methylamino-1-pyrrolidinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

19. 1-Cyclopropyl-7- (4-acetyl-3-methyl-1-piperadinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

20. 1-Cyclopropyl-7- (3-ethylaminomethyl) -1-pyrrolidinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

21. 1-Cyclopropyl-7- (4-formyl-3-methyl-1-piperadinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

22. 1-Cyclopropyl-7- (3,4-dimethyl-1-piperazinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

23. 1-Cyclopropyl-7- (4-ethyl-1-piperadinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

24. 1-Cyclopropyl-7- (4-cyclopropyl-1-piperadinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

25. 1-Cyclopropyl-7- (3-methylmorpholino) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

26. 1-Cyclopropyl-7- (3-amino-4-pyrrolidinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride (isomer A)

27. 1-Cyclopropyl-7- (3,5-dimethyl-1-piperadinyl) -6-fluoro-8-methyl-1,4- (test microorganism):

A: Staphylococcus aureus FDA 2094

B: Staphylococus Pyrogens IID S-23

C: Staphylococcus pneumoniae type II

D: Staphylococcus pneumoniae type III

E: Pseudomonas aeraginosa E-2

F: Bacteroides fragilis GM 7000

G: Eubacterium limosum ATCC 8496

H: Paptococcus anaerobis GM 1003

I: Propionibacterium acnes ATCC 6919

J: Propionibecterium granulcsum ATCC 25564

K: Enterococcus faecalis

[Table 1a]

[Table 1b]

[Table 1c]

[Table 1d]

[Table 1e]

Claims (74)

Wherein R 'is cyclopropyl which may be substituted by 1 to 3 substituents selected from the group consisting of (low) alkyl and halogen atoms, and R ² is a 5-9 membered saturated or unsaturated heterocyclic ring which may be substituted , R ³ is composed of 5-6 membered saturated heterocyclic, (low) alkylthio, amino, (low) alkylamino, (low) alkanoyloxy, hydroxy, (low) alkoxy and halogen atoms A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein (low) alkyl may be substituted by 1-3 substituents selected from the group, X is a halogen atom. The compound of claim 1, wherein R ′ is unsubstituted cyclopropyl, R ² is 1-piperidinyl, 1-pyrrolidinyl, 1-homopiperazinyl, thiomorpholino, 1,4-diazabicyclo (4,3,0) nona-4-yl, thiomorpholino-4-oxide, thiomorpholino-4,4-dioxide, 1-hexahydropyridazinyl, 2-thiazolidinyl, 1-imi Is a substituted or unsubstituted heterocyclic group selected from the group consisting of dazolidinyl and 3,7-diazabiacyl (4,3,0) nona-3-yl, R ² is unsubstituted C ₁ -C ₆ An alkyl group, and X is a fluorine atom, or a pharmaceutically acceptable salt thereof. The compound of claim 1, wherein R 'is unsubstituted cyclopropyl, R ² is a substituted or unsubstituted 5-9 membered unsaturated heterocyclic group, and R ³ is an unsubstituted C ₁ -C ₆ alkyl group And X is a fluorine atom or a pharmaceutically acceptable salt thereof. The compound of claim 1, wherein R 'is unsubstituted cyclopropyl, X is a fluorine atom, and R ² is a group of the general formula:

(Wherein R _A is a hydrogen atom C ₁ -C ₆ alkyl group, a phenyl (C ₁ -C ₆ ) alkyl group, wherein the phenyl ring is selected from the group consisting of a hydroxy group and a C ₁ -C ₆ alkoxy group Or a C ₁ -C ₆ alkyl group or an amino group, a natro group, a C ₁ -C ₆ alkoxy group having a substituent of ³ to ³ ), and R ³ is an unsubstituted C ₁ -C ₆ alkyl group. Phosphorus compounds and pharmaceutically acceptable salts thereof. The compound of claim 1, wherein R 'is unsubstituted cyclopropyl, X is a fluorine atom, and R ² is a group of the general formula:

Wherein R _B is a C ₃ -C ₈ cycloalkyl group: phenyl group, wherein the phenyl ring may be substituted by a C ₁ -C ₆ alkyl group or halogen atom, which may be substituted by halogen atoms 1-3 Dyl group: C ₁ -C ₆ alkyl group, which has 1-3 substituents selected from the group consisting of an amino group and a halogen atom, wherein the amino group is a C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy Optionally substituted by 1 or 2 substituents selected from the group consisting of a noyl group, a C ₃ -C ₈ cycloalkyl group and a C ₁ -C ₆ alkoxycarbonyl group: C ₂ -C ₆ alkynyl group: C ₁ -C ₆ alkanoyl group, which may be substituted by halogen atoms 1-7: C ₂ -C ₆ alkenylcarbonyl group which is substituted by halogen atom or carboxy group 1-3: C ₁ -C ₆ alkoxycarbonyl group, amino-carbonyl group, wherein the group Is C ₁ -C ₆ optionally substituted by one or two of the alkyl group: phenyl-alkoxy-carbonyl group, wherein the alkoxy part is a C ₁ -C ₆ alkoxy group: C ₂ -C ₆ alkanoyl-amino group, wherein the group The alkoxy moiety may be substituted by a phenylalkoxycarbonyl group wherein the alkoxy moiety is a C ₁ -C ₆ alkoxy group: an alkoxycarbonylalkyl group wherein the alkoxy moiety and the alkyl moiety are each C ₁ -C ₆ alkoxy and C ₁ -C ₆ Alkyl group: carboxyalkyl group wherein the alkyl moiety is a C ₁ -C ₆ alkyl group: an anilinocarbonylalkyl group, wherein the alkyl moiety is a C ₁ -C ₆ alkyl group: an amino group, wherein this group is C _1- It may be substituted by 1 or 2 substituents selected from the group consisting of a C ₆ alkyl group, a phenyl (C ₁ -C ₆ ) alkyl group, a C ₁ -C ₆ alkoxycarbonyl group or a C ₁ -C ₆ alkanoyl group: Hydroxy group: C ₁ -C ₆ alkylsulfonyl group Phthalide group: 2 (5H) -furanone group, which may be substituted by one or two halogen atoms: sulfoalkyl group, wherein the alkyl moiety is C _1- A C ₆ alkyl group: C ₁ -C ₆ alkoxy group: C ₂ -C ₆ alphenyl group: C ₂ -C ₆ alkanoyl oxy group: 2-oxo-1,3-dioxolenemethyl group, wherein this group It may be substituted by a phenyl group or a C ₁ -C ₆ alkyl group: C ₃ -C ₈ cycloalkyl amino group: and a C ₁ -C ₆ alkyl cyio group) and R ³ is unsubstituted C ₁ -C _{6 A} compound which is an alkyl group or a pharmaceutically acceptable salt thereof. The compound of claim 1, wherein R ¹ is unsubstituted cyclopropyl, X is a fluorine atom, R ² is a 4-substituted or unsubstituted 1-piperazinyl group, which group is 2-, 3-, 5 And 1-3 substituents selected from the group consisting of the groups listed below in the 6-position. C ₃ -C ₈ cycloalkyl group: phenyl (C ₁ -C ₆ ) alkyl group, wherein the phenyl ring may be substituted with a C ₁ -C ₆ alkoxy group, nitro group or amino group: pyridyl group: C ₁ -C ₆ alkyl group which has substituents 1-3 selected from the group consisting of a hydroxy group, an amino group, a C ₁ -C ₆ alkoxy group and a halogen atom. The amino group is a C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkanoyl group may be optionally substituted by 1 or 2 substituents selected from the group consisting of C ₃ -C ₈ cycloalkyl group and C ₁ -C ₆ alkoxycarbonyl group: C ₂ -C ₆ alkoxy Nyl group: C ₁ -C ₆ alkanoyl group, which may be substituted by 1-7 of halogen atom: C ₂ -C ₆ alkenyl carbonyl group which is selected from 1-3 of halogen atom and carboxy group A group substituted by an aminocarbonyl group wherein this group is a C ₁ -C ₆ alkyl group May be substituted by 1 or 2 of the phenylalkoxycarbonyl group, wherein the alkoxy moiety is a C ₁ -C ₆ alkoxy group: C ₂ -C ₆ aminoalkanoyl group wherein the alkoxy moiety is C ₁ -C _It may also be substituted by a phenylalkoxycarbonyl group which is a ₆ alkoxy group: an alkoxycarbonylalkyl group, wherein the alkoxy moiety and the alkyl moiety are each C ₁ -C ₆ alkoxy group and C ₁ -C ₆ alkyl group: carboxyalkyl group Wherein the alkyl moiety is a C ₁ -C ₆ alkyl group: an anilinocarbonylalkyl group, wherein the alkyl moiety is a C ₁ -C ₆ alkyl group: an amino group, where this group is a C ₁ -C ₆ alkyl group, phenyl It may be substituted by 1 or 2 substituents selected from the group consisting of a (C ₁ -C ₆ ) alkyl group, a C ₁ -C ₆ alkoxycarbonyl group, or a C ₁ -C ₆ alkanoyl group. Hydroxy group: C ₁ -C ₆ alkylsulfonyl group, which may be substituted by 1-3 of halogen atom: 2 (5H) -furanone group wherein this group is attached to 1 or 2 of halogen atom May be substituted by: sulfoalkyl group, wherein the alkyl moiety is a C ₁ -C ₆ alkyl group: oxo group: C ₁ -C ₆ alkoxy group: C ₂ -C ₆ alkenyl group: halogen atom: C ₂ -C ₆ alkanoyloxy group: 2-oxo-1,3-dioxolenmethyl group, which may be substituted by phenyl group or C ₁ -C ₆ alkyl group: C ₃ -C ₈ cycloalkylamino group: C ₁ -C ₆ alkylthio group: thio group: and 2-oxo-1,3-dioxorenmethyl amino group, which may be substituted by a phenyl group or a C ₁ -C ₆ alkyl group ( If the number of substituents in the piperazinyl ring is not greater than 3). And R ³ is an unsubstituted C ₁ -C ₆ alkyl group and a pharmaceutically acceptable salt thereof. The compound of claim 1, wherein R ¹ is unsubstituted cyclopropyl, X is a fluorine atom, and R ² is a 1-piperazinyl group, which is a group consisting of a C ₁ -C ₆ alkyl group and a phenyl group The selected 1-3 substituents are in the 2, 3-, 5- and 6-positions, where the phenyl ring in the phenyl group is assigned to a C ₁ -C ₆ alkyl group which may be substituted by a halogen atom or by 1-3 of a halogen atom It may also be substituted, furthermore, this phenyl ring consists of C ₁ -C ₆ alkyl, C ₁ -C ₆ alkanoyl, phenyl (C ₁ -C ₆ ) alkyl and 2-oxo-1,3-dioxorenmethyl It may also have a substituent selected from the group in the 4-position. Wherein the 2-oxo-1,3-dioxorenmethyl group may be substituted by a phenyl group or a C ₁ -C ₆ alkyl group (unless the number of substituents in piperazinyling is not greater than 3). And R ³ is an unsubstituted C ₁ -C ₆ alkyl group or a pharmaceutically acceptable salt thereof. The compound of claim 1, wherein R ¹ is unsubstituted cyclopropyl, X is a fluorine atom, R ² is a 1-pyrrolidinyl group, which is a 1-3 substituent selected from the group consisting of Have C ₁ -C ₆ alkyl group: C ₃ -C ₈ cyclo alkyl group: phenyl (C ₁ -C ₆ ) alkyl group, wherein the phenyl ring is substituted by a C ₁ -C ₆ alkoxy group, nitro group or amino group It may also be: a phenyl group, wherein the phenyl ring may be substituted by a halogen atom and may be substituted by a C ₁ -C ₆ alkyl group which may be substituted by 1-3 of a halogen atom. Pyridyl group: C ₁ -C ₆ alkyl group, which has 1-3 of the substituents selected from the group consisting of hydroxy group, amino group, C ₁ -C ₆ alkoxy group and halogen atom. Optionally substituted by 1 or 2 substituents selected from the group consisting of a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkanoyl group, a C ₃ -C ₈ cycloalkyl group and a C ₁ -C ₆ alkoxycarbonyl group : C ₂ -C ₆ alkynyl group: C ₁ -C ₆ alkanoyl group, which may be substituted by 1-7 of halogen atom: C ₂ -C ₆ alkenylcarbonyl group Is a group substituted by 1-3 of a carboxy group: C ₁ -C ₆ alkoxy carbonyl group: aminocarbonyl group, which may be substituted by 1 or 2 of C ₁ -C ₆ alkyl group: Phenylalkoxycarbonyl group, wherein the alkoxy moiety is a C ₁ -C ₆ alkoxy group A C ₂ -C ₆ aminoalkanoyl group, which may be substituted by a phenylalkoxycarbonyl group wherein the alkoxy portion of the phenylalkoxycarbonyl group is a C ₁ -C ₆ alkoxy group: alkoxycarbonylalkyl group, Wherein the alkoxy moiety and the alkyl moiety are each a C ₁ -C ₆ alkoxy group and a C ₁ -C ₆ alkyl group: a carboxyalkyl group, wherein the alkyl moiety is a C ₁ -C ₆ alkyl group: an anilinocarbonylalkyl group, wherein The alkyl moiety is a C ₁ -C ₆ alkyl group: an amino group, wherein this group is a C ₁ -C ₆ alkyl group, a phenyl (C ₁ -C ₆ ) alkyl group, a C ₁ -C ₆ alkoxycarbonyl group, or C It may be substituted by 1 or 2 substituents selected from the group consisting of _1- C ₆ alkanoyl groups: hydroxy group: C ₁ -C ₆ alkylsulfonyl group, wherein this group is substituted with 1 to 3 of the halogen atom May be substituted by: phthalide group: 2 (5H) -furanone group, two When this group may be substituted on one or two of the halogen atoms: a sulfoalkyl group, wherein the alkyl moiety is a C ₁ -C ₆ alkyl group: oxo group: C ₁ -C ₆ alkoxy group: C ₂ -C ₆ al Kenyl group: halogen atom: C ₂ -C ₆ alkanoyloxy group: 2-oxo-1,3-dioxorenmethyl group, wherein this group may be substituted by phenyl group or C ₁ -C ₆ alkyl group. C ₃ -C ₈ cycloalkylamino: C ₁ -C ₆ alkylthio group: thio group: and 2-oxo-1,3-dioxolenemethylamino group, which is a phenyl group or C ₁ -C ₆ It may be substituted by an alkyl group. And R ³ is an unsubstituted C ₁ -C ₆ alkyl group or a pharmaceutically acceptable salt thereof. _{10. The} compound of claim 8, wherein R ² is a 1-pyrrolidinyl group, which group represents a 1-3 substituent selected from the group consisting of a hydroxy group C ₁ -C ₆ alkyl group, a substituted C ₁ -C ₆ alkyl group The latter substituted C ₁ -C ₆ alkyl group may have substituents 1-3 selected from the group consisting of a hydroxy group and an amino group. Wherein the amino group is optionally substituted by C ₁ -C ₆ alkyl group 1 or 2. And 1-pyrrolidinyl may have 1-3 substituents selected from an amino group, which amino group may be substituted by C ₁ -C ₆ alkyl group 1 or 2. The compound of claim 1, wherein R ¹ is unsubstituted cyclopropyl, X is a fluorine atom, and R ² is a morpholino group, wherein the group is from a group consisting of a C ₁ -C ₆ alkyl group and a phenyl group A compound or a pharmaceutically acceptable salt thereof, which may have 1-3 substituents selected, and R ³ is an unsubstituted C ₁ -C ₆ alkyl group. The compound of claim 1, wherein R ¹ is unsubstituted cyclopropyl, X is a fluorine atom, R ² is a morpholino, wherein this group has 1-3 substituents selected from the group consisting of: C ₃ -C ₈ cycloalkyl group: phenyl (C ₁ -C ₆ ) alkyl group, wherein the phenyl ring may be substituted by a C ₁ -C ₆ alkoxy group, nitro group or amino group: phenyl group, where phenyl The ring is substituted by a C ₁ -C ₆ alkyl group which may be substituted by a halogen atom or may be substituted by 1-3- of a halogen atom: a pyridyl group: a C ₁ -C ₆ alkyl group, which is hydroxy Group 1-3 has substituents selected from the group consisting of an amino group, a C ₁ -C ₆ alkoxy group and a halogen atom, wherein the amino group is a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkanoyl group , Optionally substituted by one or two substituents selected from the group consisting of a C ₃ -C ₈ cycloalkyl group and a C ₁ -C ₆ 1 alkoxycarbonyl group: C ₂ -C ₆ alkynyl group: C ₁ -C ₆ alkanoyloxy group, wherein the group of the halogen atom in the 1-7 It may be substituted: C ₂ -C ₆ alkenyl-carbonyl group, the group is a group optionally substituted with 1 to 3 of halogen atoms or carboxy groups: C ₁ -C ₆ alkoxycarbonyl group, amino-carbonyl group, This group may then be substituted by 1 or 2 of the C ₁ -C ₆ alkyl group: a phenylalkoxycarbonyl group, wherein the alkoxy moiety is a C ₁ -C ₆ alkoxy group: C ₂ -C ₆ aminoalkanoyl group Wherein the group may be substituted by a phenylalkoxycarbonyl group wherein the alkoxy moiety of the phenylalkoxycarbonyl group is a C ₁ -C ₆ alkoxy group: an alkoxycarbonylalkyl group, wherein the alkoxy moiety and the alkyl moiety are each C ₁ -C ₆ alkoxy group and C ₁ -C ₆ alkyl group. A carboxyalkyl group, wherein the alkyl moiety is a C ₁ -C ₆ alkyl group: an anilinocarbonylalkyl group, wherein the alkyl moiety is a C ₁ -C ₆ alkyl group: an amino group, where this group is C ₁ -C ₆ alkyl It may be substituted by 1 or 2 substituents selected from the group consisting of a group, a phenyl (C ₁ -C ₆ ) alkyl group, a C ₁ -C ₆ alkoxycarbonyl group or a C ₁ -C ₆ alkanoyl group: hydroxy Group: C ₁ -C ₆ alkylsulfonyl group, in which group may be substituted by 1-3 of halogen atom: phthalide group: 2 (5H) -furanone group, wherein this group is 1 of halogen atom Or may be substituted by 2: a sulfoalkyl group, wherein the alkyl moiety is a C ₁ -C ₆ alkyl group: oxo group: C ₁ -C ₆ alkoxy group: C ₂ -C ₆ alkenyl group: halogen atom: C ₂ -C ₆ alkanoyloxy group: 2-oxo-1, 3-dioxane Soren methyl group, wherein the phenyl group is the group C ₁ -C ₆ may be substituted by alkyl group: C ₃ -C ₈ cycloalkylamino group: C ₁ -C ₆ alkylthio group: thio group: and 2-oxo-1,3-dioxane Methyl Soren Amino group, where this group may be substituted by phenyl group or C ₁ -C ₆ alkyl group. And R ³ is an unsubstituted C ₁ -C ₆ alkyl group or a pharmaceutically acceptable salt thereof. The compound of claim 4, wherein R ^A is a C ₁ -C ₆ alkyl group. The compound of claim 12, wherein R ³ is methyl. The compound of claim 12, wherein R ³ is ethyl. 6. The compound of claim 5, wherein R ^B is a 2-oxo-1,3-dioxorenmethyl group, which group may be substituted by a phenyl or C ₁ -C ₆ alkyl group. The compound of claim 5, wherein R ^B is a group other than a 2-oxo-1,3-dioxorenmethyl group, which may be substituted by phenyl or a C ₁ -C ₆ alkyl group. The compound of claim 15, wherein R ³ is methyl. The compound of claim 15, wherein R ³ is ethyl. 8. The compound of claim 7, wherein R ³ is a group of the formula:

Wherein R ^C and R ^E are each C ₁ -C ₆ alkyl group, R ^D is a hydrogen atom, a C ₁ -C ₆ alkyl group or 2-oxo- which may be substituted by phenyl or C ₁ -C ₆ alkyl group 1,3-dioxorenmethyl group. 8. The compound of claim 7, wherein R ² is a group of the formula

Wherein R ^E is a C ₁ -C ₆ alkyl group. 8. A compound according to claim 7, wherein R ² is a group of the formula:

Wherein R ^G is a C ₁ -C ₆ alkyl group and R ^H is a 2-oxo-1,3-dioxorenmethyl, which may be substituted by a C ₁ -C ₆ alkyl group or a phenyl or C ₁ -C ₆ alkyl group Compounds that are groups. The compound of claim 19, wherein R ³ is methyl. The compound of claim 19, wherein R ³ is ethyl. The compound of claim 20, wherein R ³ is methyl. The compound of claim 20, wherein R ³ is ethyl. The compound of claim 21, wherein R ³ is methyl. The compound of claim 21, wherein R ³ is ethyl. The compound of claim 9, wherein R ² is a 1-pyrrolidinyl group of the formula:

Wherein R ¹ is a C ₁ -C ₆ alkyl group, which has one amino group, which amino group is optionally substituted by 1 or 2 of the C ₁ -C ₆ alkyl group. Or R ¹ is an amino group, which may be substituted by 1 or 2 of the C ₁ -C ₆ alkyl group: and R ^J is a hydrogen atom or a C ₁ -C ₆ alkyl group. The compound of claim 28, wherein R ¹ is an amino group which may be substituted by one C ₁ -C ₆ alkyl group. 29. The method of claim 28, wherein R ¹ is C ₁ -C ₆ alkyl having one amino group, wherein the amino group may be optionally substituted by one C ₁ -C ₆ alkyl group. And R ^J is a hydrogen atom. The compound of claim 29, wherein R ³ is methyl. 32. The compound of claim 30, wherein R ³ is methyl. The compound of claim 10, wherein R ² is a group of the formula:

Wherein R ^K is a hydrogen atom or a C ₁ -C ₆ alkyl group. The compound of claim 33, wherein R ³ is methyl. The compound of claim 11, wherein R ³ is methyl. The compound of claim 1, wherein R ¹ is unsubstituted cyclopropyl, X is a fluorine atom, and R ² is a 1-piperidinyl group wherein 1-3 is selected from the group consisting of Has a substituent. C ₁ -C ₆ alkyl group: C ₃ -C ₈ cycloalkyl group: phenyl (C ₁ -C ₆ ) alkyl group, wherein the phenyl ring is to be substituted by a C ₁ -C ₆ alkoxy group, nitro group or amino group May be: phenyl group, wherein the phenyl ring may be substituted by a C ₁ -C ₆ alkyl group which may be substituted by a halogen atom or may be substituted by 1-3 of a halogen atom: a pyridyl group: C ₁ inde -C ₆ alkyl group, this group is also a hydroxyl group, amino group, C ₁ -C ₆ alkoxy group, and there have 1-3 substituents selected from the group consisting a halogen atom, the above mentioned amino groups are C ₁ - Optionally substituted by 1 or 2 substituents selected from the group consisting of a C ₆ alkyl group, a C ₁ -C ₆ alkanoyl group, a C ₃ -C ₈ cycloalkyl group and a C ₁ -C ₆ alkoxycarbonyl group: C ₂ -C ₆ alkynyl group: C ₁ -C ₆ alkanoyl Group, wherein this group may be substituted by 1-7 of a halogen atom: C ₂ -C ₆ alkenylcarbonyl group, which is substituted by 1-3 of a halogen atom or a carboxy group: C ₁ -C ₆ alkoxycarbonyl group: aminocarbonyl group, which may be substituted by 1 or 2 of C ₁ -C ₆ alkyl group: phenylalkoxy carbonyl group, wherein the alkoxy moiety is C ₁ -C ₆ Alkoxy group: C ₂ -C ₆ aminoalkanoyl group, which may be substituted by phenylalkoxy carbonyl group, wherein the alkoxy portion of the phenylalkoxy carbonyl group is a C ₁ -C ₆ alkoxy group: alkoxy Carbonyl alkyl groups, wherein the alkoxy moiety and alkyl moiety are each C ₁ -C ₆ alkoxy and C ₁ -C ₆ alkyl group: a carboxyalkyl group, where the alkyl moiety is a C ₁ -C ₆ alkyl group: anilinocarbonyl Alkyl group, wherein the alkyl moiety is a C ₁ -C ₆ alkyl group Is an amino group, wherein this group is a C ₁ -C ₆ alkyl group, a phenyl (C ₁ -C ₆ ) alkyl group C ₁ -C ₆ alkoxycarbonyl group, or C ₁ -C ₆ alkanoyl group May be substituted by: hydroxy group: C ₁ -C ₆ alkylsulfonyl group, which may be substituted by 1-3 of halogen atom: 2 (5H) -furanone group, wherein this group is May be substituted by one or two of the halogen atoms: a sulfoalkyl group, wherein the alkyl moiety is a C ₁ -C ₆ alkyl group: oxo group: C ₁ -C ₆ alkoxy group: C ₂ -C ₆ alkenyl group: Halogen atom: C ₂ -C ₆ alkanoyloxy group: 2-oxo-1,3-dioxorenmethyl group, wherein this group may be substituted by a phenyl group or a C ₁ -C ₆ alkyl group: C _3- C ₈ cycloalkyl-amino group: C ₁ -C ₆ alkylthio group: thio group: and 2-oxo-1,3-dioxane Soren methyl-amino group, wherein the phenyl group is It may be substituted with a group or C ₁ -C ₆ alkyl group. And R ³ is an unsubstituted C ₁ -C ₆ alkyl group and a pharmaceutically acceptable salt thereof. The compound of claim 36, wherein R ³ is methyl. The compound of claim 36, wherein R ² is a 1-piperidinyl group, which group may have 1-3 substituents selected from the group consisting of oxo groups, halogen atoms and C ₁ -C ₆ alkyl groups . The compound of claim 38, wherein R ² is 1-piperadinyl, wherein this group is substituted by one halogen atom. The compound of claim 39, wherein R ³ is methyl. The compound of claim 39, wherein R ³ is ethyl. The compound of claim 38, wherein R ² is a 1-piperadinyl group having a substituent selected from a hydroxy group and an oxo group. The compound of claim 2, wherein R ² is a group of the formula:

Compound. The compound of claim 2, wherein R ² is 1-homopiperazinyl or thiomorpholino, which group may be substituted by a C ₁ -C ₆ alkyl group. 45. The compound of claim 44, wherein R ³ is methyl. The compound of claim 3, wherein R ² is unsubstituted 1,2,5,6-tetrahydropyridyl, unsubstituted imidazolyl, unsubstituted pyridyl. 47. The compound of claim 46, wherein R ³ is methyl. The compound of claim 1, wherein R ¹ is cyclopropyl, wherein the compound has substituents 1-3 selected from the group consisting of a C ₁ -C ₆ alkyl group and a halogen atom, X is a fluorine atom Acceptable salt of this. The compound according to claim 1, wherein X is a fluorine atom, and R ² is a heterocyclic group selected from the group consisting of the following compounds. 1-piperazinyl, 1-piperidinyl, 1-pyrrolidinyl, 1-homopiperazinyl, morpholino, thiomorpholino, 1,2,5,6-tetrahydropyridin-1-yl, 1-imidazolyl, 1,4-diazabicyclo (4,3,0) nona-4-yl, thiomorpholin-4-oxide, thiomorpholino-4,4-dioxide, 1-pyrazoli Diyl, 1-hexahydropyridazinyl, pyridyl, 2-thiazolidinyl, 2-thio-1-imidazolidinyl, 2-oxo-1-imidazolidinyl, or 3,7-diazabi Cyclo (4,3,0) nona-3-yl, wherein the heterocyclic group described above is optionally substituted by 1-3 substituents selected from the group consisting of the groups listed below. C ₁ -C ₆ alkyl group: C ₃ -C ₈ cycloalkyl group: phenyl (C ₁ -C ₆ ) alkyl group, wherein the phenyl ring is substituted by a C ₁ -C ₆ alkoxy group, nitro group or amino group May also be a phenyl group, wherein the phenyl ring may be substituted by a halogen atom and may be substituted by a C ₁ -C ₆ alkyl group which may be substituted by 1-3 of the halogen atom: pyridyl group: C ₁ -C ₆ alkyl group wherein this group contains 1-3 of substituents selected from the group consisting of a hydroxy group, an amino group, a C ₁ -C ₆ alkoxy group and a halogen atom, wherein the amino group is C ₁ Optionally substituted by 1 or 2 substituents selected from the group consisting of a C ₆ alkyl group, a C ₁ -C ₆ alkanoyl group C ₃ -C ₈ cycloalkyl group and a C ₁ -C ₆ alkoxycarbonyl group: C ₂ -C ₆ alkynyl group: C ₁ -C ₆ alkanoyl group Wherein the group may be substituted by 1-7 of a halogen atom: C ₂ -C ₆ alkenylcarbonyl group, where this group is a group substituted by 1-3 of a halogen atom or a carboxy group: C ₁ -C ₆ alkoxycarbonyl group: aminocarbonyl group, which may be substituted by 1 or 2 of C ₁ -C ₆ alkyl group: phenylalkoxycarbonyl group, wherein the alkoxy moiety is C ₁ -C _{A 6} alkoxy group: C ₂ -C ₆ amino alkanoyl group, which may be substituted by a phenylalkoxycarbonyl group, wherein the alkoxy portion of the phenylalkoxy carbonyl group is a C ₁ -C ₆ alkoxy group: alkoxy Carbonyl alkyl groups, wherein the alkoxy moiety and alkyl moiety are each C ₁ -C ₆ alkoxy group and C ₁ -C ₆ alkyl group: a carboxyalkyl group, wherein the alkyl moiety is a C ₁ -C ₆ alkyl group: anilinocarbono Nyl alkyl group, wherein alkyl moiety C ₁ -C ₆ alkyl group: an amino group, wherein the groups are C ₁ -C ₆ alkyl group, a phenyl (C ₁ -C ₆₎ alkyl group, C ₁ -C ₆ alkoxycarbonyl group or C ₁ -C ₆ May be substituted by 1 or 2 of the alkanoyl group: hydroxy group: C ₁ -C ₆ alkylsulfonyl group, where this group may be substituted by 1-3 of halogen atom: phthalite group: 2 (5H) -furanone group, which may be substituted by one or two of the halogen atoms: sulfoalkyl group, wherein the alkyl moiety is a C ₁ -C ₆ alkyl group: oxo group: C ₁ -C ₆ Alkoxy group: C ₂ -C ₆ alkenyl group: Halogen atom: C ₂ -C ₆ Alkanoyl oxy group: 2-oxo-1,3-dioxoren methyl group, wherein this group is a phenyl group or C ₁ -C ₆ It may be substituted by alkyl group: C ₃ -C ₈ cycloalkylamino group: C ₁ -C ₆ alkylthio group: thio group: and 2-oxo-1,3-dioxane Alkylene-amino-methyl group, wherein the group may be substituted by a phenyl group or C ₁ -C ₆ alkyl group. And R ³ is an unsubstituted C ₁ -C ₆ alkyl group and a pharmaceutically acceptable salt thereof. The compound of claim 49, wherein R ² is 1-piperazinyl. 51. The compound of claim 50, wherein R ² is a group of the formula:

Wherein R ^L and R ^N are each a hydrogen atom or a C ₁ -C ₆ alkyl group, and R ^M is a hydrogen atom or a C ₁ -C ₆ alkyl group. The compound of claim 51, wherein R ³ is methyl. The group of claim 49 wherein R ² is a group of the formula:

Wherein R ⁰ is a hydrogen atom or a C ₁ -C ₆ alkyl group. The compound of claim 53, wherein R ³ is methyl. The compound of claim 49, wherein R ² is a 1-pyrrolidinyl group, wherein the group is a C ₁ -C ₆ alkyl group having an amino group which may be substituted by 1 or 2 of a C ₁ -C ₆ alkyl group And 1 or 2 substituents selected from the group consisting of amino groups which may be substituted by C ₁ -C ₆ alkyl group 1 or 2 in the 3- and 4-positions. The compound of claim 55, wherein R ³ is methyl. 13. A compound according to claim 12, wherein R ² is a 1-piperidinyl group, which group has 1-2 substituents selected from the group consisting of halogen atoms, oxo groups, hydroxy groups and C ₁ -C ₆ alkyl groups Compound. The compound of claim 27, wherein R ³ is methyl. The compound of claim 1, wherein R ¹ is unsubstituted cyclopropyl, X is a fluorine atom, and R ² is a 1-piperazinyl group wherein the group is from a group consisting of a C ₁ -C ₆ alkyl group and a phenyl group A group having 1-3 selected substituents in 2-, 3-, 5-, and 6-positions, wherein the phenyl ring in the phenyl group may be substituted by a halogen atom, or by 1-3 of a halogen atom It may also be substituted by a C ₁ -C ₆ alkyl group which may be substituted. Furthermore, this 1-piperazinyl group has a substituent selected at 4-position from the group consisting of the following groups. C ₃ -C ₈ cycloalkyl group: phenyl (C ₁ -C ₆ ) alkyl group, wherein the phenyl ring may be substituted by a C ₁ -C ₆ alkoxy group, nitro group or amino group: phenyl group, where phenyl The ring may be substituted by a halogen atom or may be substituted by a C ₁ -C ₆ alkyl group which may be substituted by 1-3 of a halogen atom: a pyridyl group: a C ₁ -C ₆ alkyl group, wherein This group has 1-3 of substituents selected from the group consisting of an amino group and a halogen atom, wherein the amino group mentioned above is a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkanoyl group, C _3- Optionally substituted by 1 or 2 substituents selected from the group consisting of a C ₈ cycloalkyl group and a C ₁ -C ₆ alkoxycarbonyl group: C ₂ -C ₆ alkynyl group: C ₁ -C ₆ alkanoyl Group, where this group is 1 It may be substituted with a -7: C ₂ -C ₆ alkenyl-carbonyl group, wherein the group is a group optionally substituted with 1 to 3 of halogen atoms or carboxy groups: C ₁ -C ₆ alkoxycarbonyl group: Aminocarbonyl groups, which may be substituted by one or two of the C ₁ -C ₆ alkyl groups: phenylalkoxy carbonyl groups, wherein the alkoxy moiety is a C ₁ -C ₆ alkoxy group: C ₂ -C ₆ Aminoalkanoyl groups, which may be substituted by phenylalkoxy-carbonyl groups, wherein the alkoxy portion of the phenylalkoxy carbonyl group is a C ₁ -C ₆ alkoxy group: alkoxycarbonyl alkyl group, wherein the alkoxy portion And the alkyl moiety are each a C ₁ -C ₆ alkoxy group and a C ₁ -C ₆ alkyl group: a carboxyalkyl group, wherein the alkyl moiety is a C ₁ -C ₆ alkyl group: an anilinocarbonyl alkyl group, wherein the alkyl moiety is C ₁ -C ₆ alkyl group is an amino group, where The group may be substituted by 1 or 2 of C ₁ -C ₆ alkyl group, phenyl (C ₁ -C ₆ ) alkyl group, C ₁ -C ₆ alkoxycarbonyl group or C ₁ -C ₆ alkanoyl group: Hydroxy group: C ₁ -C ₆ alkylsulfonyl group, which may be substituted by 1-3 of halogen atom: 2 (5H) -furanone group, wherein this group is 1 or 2 of halogen atom May be substituted by: sulfoalkyl group, wherein the alkyl moiety is a C ₁ -C ₆ alkyl group: oxo group: C ₁ -C ₆ alkoxy group: C ₂ -C ₆ alkenyl group: halogen atom: C _2- C ₆ alkanoyl oxy group: 2-oxo-1,3-dioxolenmethyl group, which may be substituted by phenyl group or C ₁ -C ₆ alkyl group: C ₃ -C ₈ cycloalkylamino group : C ₁ -C ₆ alkylthio group: and 2-oxo-1,3-dioxane Soren methyl-amino group, wherein the group value by a phenyl group or C ₁ -C ₆ alkyl group, It may be. And R ³ is an unsubstituted C ₁ -C ₆ alkyl group or a pharmaceutically acceptable salt thereof. The compound of claim 29, wherein R ³ is ethyl. 31. The compound of claim 30, wherein R ³ is ethyl. The compound of claim 1, wherein R ³ is C ₁ -C ₆ alkyl, wherein the compound is a 5- or 6-membered saturated heterocyclic group, C ₁ -C ₆ alkylthio group, amino group, C _1- Compounds or agents which may be substituted by 1-3 substituents selected from the group consisting of C ₆ alkylamino groups, C ₁ -C ₆ alkanoyloxy groups, hydroxy groups, C ₁ -C ₆ alkoxy groups, and halogen atoms Scholarly acceptable salt of this. 63. The heterocyclic group of claim 62, wherein the heterocyclic group is 1-pyrrolidinyl, 1-piperazinyl, 1-piperidinyl, morpholino, thiomorpholino, thiomorpholino-4-oxide, thiomorphoyl No-4,4-dioxide, 1-hexahydropyridazinyl, 2-thiazolidinyl, and 1-amidazolidinyl. 64. The heterocyclic group according to claim 63, wherein the heterocyclic group is optionally substituted by l-3 substitution selected from the group consisting of the groups listed below. C ₁ -C ₆ alkyl group: C ₃ -C ₈ cycloalkyl group: phenyl (C ₁ -C ₆ ) alkyl group, wherein the phenyl ring is substituted by a C ₁ -C ₆ alkoxy group, nitro group or amino group May also be a phenyl group, wherein the phenyl ring may be substituted by a halogen atom or may be substituted by a C ₁ -C ₆ alkyl group which may be substituted by 1-3 of a halogen atom: a pyridyl group: C ₁ -C ₆ alkyl group, which contains 1-3 of substituents selected from the group consisting of a hydroxy group, an amino group, a C ₁ -C ₆ alkoxy group, and a halogen atom. The amino group is selected from the group consisting of C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkanoyl group, C ₃ -C ₈ cycloalkyl group and C ₁ -C ₆ alkoxycarbonyl group. It is optionally substituted by: C ₂ -C ₆ alkynyl Groups: C ₁ -C ₆ alkanoyl group, wherein the group may be substituted by 1-7 halogen atoms: C ₂ -C ₆ alkenyl carbonyl indenyl group, the group is a halogen atom or a carboxy group 1 A group substituted by 3: a C ₁ -C ₆ alkoxy carbonyl group: an aminocarbonyl group, where this group may be substituted by 1 or 2 of a C ₁ -C ₆ alkyl group: phenylalkoxy carbonyl group Wherein the alkoxy moiety is a C ₁ -C ₆ alkoxy group: a C ₂ -C ₆ aminoalkanoyl group, which may be substituted by a phenylalkoxycarbonyl group, where the alkoxy moiety is C ₁ -C ₆ alkoxy groups: alkoxycarbonyl-alkyl group, wherein the alkoxy part and the alkyl moiety are each C ₁ -C ₆ alkoxy group and C ₁ -C ₆ alkyl group: carboxyalkyl group wherein the alkyl part is C ₁ -C _{6 is an} alkyl group: anilinocarbonylalkyl Group wherein the alkyl moiety is a C ₁ -C ₆ alkyl group: an amino group, wherein this group is a C ₁ -C ₆ alkyl group, a phenyl (C ₁ -C ₆ ) alkyl group, a C ₁ -C ₆ alkoxycarbonyl group Or may be substituted by 1 or 2 of a C ₁ -C ₆ alkanoyl group: hydroxy group: C ₁ -C ₆ alkylsulfonyl group, where this group may be substituted by 1-3 of halogen atom : Phthalide group: 2 (5H) -furanone group, which may be substituted by 1 or 2 of halogen atom: sulfoalkyl group, wherein alkyl moiety is C ₁ -C ₆ alkyl group: oxo group : C ₁ -C ₆ alkoxy group: C ₂ -C ₆ alkenyl group: halogen atom: C ₂ -C ₆ alkanoyloxy group: 2-oxo-1,3-dioxorenmethyl group, wherein this group is a phenyl group Or may be substituted by a C ₁ -C ₆ alkyl group: C ₃ -C ₈ cycloalkylamino group: C ₁ -C ₆ alkylthio group: Group: 2-oxo-1,3-dioxorenmethyl amino group, which may be substituted by a phenyl group or a C ₁ -C ₆ alkyl group. And X is a fluorine atom. 7- (4- (5-methyl-2-oxo-1,3-dioxoren-4-yl) methyl-1-piperazinyl) -1-cyclopropyl-6-fluoro-8-methyl-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid. 7- (3-Methyl-1-piperazinyl) -1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. 7- (3-amino-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. 1-cyclopropyl-7- (3-aminomethyl-1-pyrrolidinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. 1-cyclopropyl-7- (3-methylamino-1-pyrrolidinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. 1-cyclopropyl-7- (3-ethylaminomethyl-1-pyrrolidinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. 1-cyclopropyl-7- (3-amino-4-methyl-1-pyrrolidinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. 1-cyclopropyl-7- (4-fluoro-1-piperidinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. 1-cyclopropyl-7-morpholino-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. 1-cyclopropyl-7- (3-methylmorpholino) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.