KR970000950B1 - Benzoheterocyclic compounds and their preparing method - Google Patents

Abstract

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Description

Method for preparing benzoheterocyclic compound

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

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

The benzoheterocyclic compound of formula (I) and its salts have excellent antimicrobial activity against a variety of picture-positive and gram-negative bacteria and the effects of various infectious diseases caused by various bacteria in humans, other animals and fish. It is also useful as an external disinfectant or disinfectant for things like medical instruments.

There is much literature showing 4-oxoquinoline-3-carboxylic acid derivatives useful as antimicrobial agents.

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

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

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

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

Wherein R 'is H, CH ₃ , C ₂ H ₅ , or CH ₂ CH ₂ OH, and R ² is H, CI, or F.

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

Wherein X ¹ and X ² may each be CI or F, and R ¹ and R ² 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 or phenyl and R ² is H or F.

Similarly, dihydroquinolinecarboxylic acid derivatives substituted with 1-cyclopropyl-7-heterocyclic groups are known 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 195316 South Africa Patent 8504792, Spain Patent 8602674 and 8601968 and Portugal Patent 90546.

However, the compound shown in this document differs from the compound of the present invention in that it does not have an alkyl substituent at No. 8.

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

For example, Japanese Patent Publication No. 126271/1985 (= Portugal Patent 79616) shows the following quinoline carboxylic acid derivatives.

Wherein R is H, CH ₃ , P-nitobenzyl or P-aminobenzyl, and Y is CI, F or CH ₃ but this document shows no specific example of 8-CH ₃ derivatives. (All examples relate to 8-Cl or 8-F derivatives.) In addition, German Patent 3441788 (= Japanese Patent Laid-Open No. 122272/1986) discloses 1-cyclopropyl-4-oxoquinoline-3-carboxylic acid derivatives. Shows.

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) and salts thereof which have good antibacterial action and good water absorption.

Another object of the present invention is to provide a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable salt thereof, which are useful as active ingredients for the treatment of various infectious diseases. And another object of the invention will become more apparent to the person 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 salts which are pharmaceutically acceptable for this. In particular, the term halogen atom in the description includes fluorine, chlorine, bromine or iodine atoms. The term cyclopropyl, which may be substituted by an optional 1-3 substituent from a group consisting of (lower) alkyl and halogen atoms, includes a cyclopropyl group, which is cyclopropyl, 2-fluoro-1-cyclopropyl, 2 -Chloro-1-cyclopropyl, 2-brofo-1-cyclopropyl, 2-iodine-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, -dimethylcyclopropyl, 2,3-dimethylcyclopropyl, 2,2,3, -trimethylcyclopropyl, 2-fluoro-3-methylcyclopropyl, 2, Straight, such as 2-diethylcyclopropyl, 2-methyl-3-propylcyclopropyl, etc. With 1 to 3 substituents selected from the group been dew or branched chain alkyl group and a halogen atom configurations may be substituted. (Lower) alkyl includes straight chain or branched chain C ₁ -C ₆ alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and the like.

5-9 saturated or unsaturated heterocyclic rings which may be substituted represent 5-9 membered cyclic saturated or unsaturated heterocyclic rings which may be substituted by the following: (lower) alkyl: phenyl ring ( Phenyl: lower which may be substituted by lower) alkoxy, nitro or amino: Phenyl: lower which may be substituted by halogen atom, (lower) alkyl, or (lower) acyl substituted by 1-3 halogen atom (Lower) alkyl having 1-3 substituents selected from the group consisting of oxy, amino, (lower) alkoxy and halogen atoms wherein said amino is any (lower) alkyl, (lower) alkanoyl, cycloalkyl or (lower) alkoxy carbano May be substituted by: (lower) alkynyl: (lower) alkanoyl which may be substituted by halogen atoms of 1-7: having 1-3 substituents selected from the group consisting of halogen atoms and carboxy (Lower) alkenylcarbonyl: (lower) alkoxycarbonyl: (lower) alkoxycarbonyl: aminocarbonyl which may be substituted by (lower) alkyl: phenyl (lower) alkoxycarbonyl: phenyl (lower) alkoxy Amino (lower) alkanoyl which may be substituted by carbonyl: (lower) alkoxycarbonyl (lower) alkyl: carboxy (lower) alkyl: anilinocarbonyl (lower) alkyl: (lower) alkyl, phenyl (lower) (Lower) alkylsulfonyl optionally substituted by halogen atom of amino, hydroxy: 1-3 which may be substituted by alkyl (lower) alkoxycarbonyl or (lower) alkanoyl 2 (5H) -furanonesulfo (lower) alkyl which may be substituted by halogen atom: oxo (lower) alkoxy: (lower) alkenyl: halogen atom: (lower) alkanoyloxy phenyl or (lower) alkyl 2-oxo-1,3-dioxolene methyl which may be substituted: phenyl or (lower) al The term 2-oxo-1,3-dioxolenemethylamino: cycloalkylamino: (lower) alkylthio: or thio, etc., which may be substituted by means of 5-9 membered ring saturated or unsaturated heterocyclic ring, which may be substituted by More specific 5-9 membered ring saturated or unsaturated heterocyclic rings which may be substituted with 1-3 substituents selected from the group consisting of:

Straight chain or branched chain C ₁ -C ₆ alkyl group C ₃ -C ₈ cycloalkyl group: The phenyl ring may be substituted with a straight chain or branched chain C ₁ -C ₆ alkoxy group nitro group or amino group and the alkyl moiety is a straight chain Or a phenylalkyl group having a branched chain C ₁ -C ₆ alkyl group, wherein the phenyl ring is substituted by a straight chain or a branched chain C ₁ -C ₆ alkyl group which may be substituted by a halogen atom or a halogen atom of 1-3; a phenyl group which may: a pyridyl group: hydroxyl group, amino group, straight chain or branched chain C ₁ -C ₆ alkoxy group and a halogen atom group consisting of straight chain or branched chain, which have a substituent selected from 1-3 C ₁ -C ₆ Alkyl groups The amino groups mentioned above are straight or branched chain C ₁ -C ₆ alkyl groups, straight chain or branched chain C ₁ -C ₆ alkanoyl groups, C ₃ -C ₈ cycloalkyl groups and straight chains. And optionally substituted by a 1 or 2 substituent group selected from the group consisting of a chain or branched chain C ₁ -C ₆ alkoxycarbonyl group.

Straight or branched chain C ₁ -C ₆ alkynyl group: straight or branched chain C ₁ -C ₆ alkanoyl group which may be substituted by halogen atoms of 1-7: by halogen atom or carboxy group of 1-3 Substituted straight or branched chain C ₁ -C ₆ alkenylcarbonyl group: straight chain or branched chain C ₁ -C ₆ alkoxycarbonyl group: substituted by 1 or 2 straight chain or branched chain C ₁ -C ₆ alkyl group Aminocarbonyl groups which may be: phenylalkoxycarbonyl groups in which the alkoxy moiety is a straight chain or branched chain C ₁ -C ₆ alkoxy group: alkoxy moieties may be substituted by a phenylalkoxycarbonyl group in which the alkoxy moiety is a straight chain or branched chain C ₁ -C ₆ alkoxy group straight chain or branched chain C ₁ -C ₆ amino-alkanoyl group: the alkoxy and alkyl parts are C ₁ -C ₆ alkoxy and the alkyl group, straight chain or branched chain alkoxy carbonyloxy Alkyl group: it is not a chain C ₁ -C ₆ alkyl group with the alkyl moiety is straight chain or branched Reno carbonyl group: 1 or a straight chain or branched chain of 2 C ₁ -C ₆ alkyl groups and straight chain or branched chain C ₁ - C ₆ alkyl group, straight chain or branched chain C ₁ -C ₆ alkyl group Amino group which may be substituted by a phenylalkyl group which is a carbonyl group or a straight chain or branched chain C ₁ -C ₆ alkanoyl group: Halogen of hydroxy group: 1-3 Straight chain or branched chain C ₁ -C ₆ alkylsulfonyl group which may be substituted by atoms: phthalide group: 2 (5H) -furanone group which may be substituted by 1 or 2 halogen atoms: Sulfoalkyl groups which are straight chain or branched chain C ₁ -C ₆ alkyl group: Oxo group: Straight chain or branched chain C ₁ -C ₆ Alkoxy group: Gordon chain or branched chain C ₁ -C ₆ Alkenyl group: Halogen atom: Straight chain or branches Chain C ₁ -C ₆ alkanoyloxy group: or a phenyl group, a straight chain or branched chain C ₁ -C ₆ alkyl 2-oxo-1,3-dioxide solren methyl group which may be substituted by: C ₃ -C ₈ cycloalkyl Alkylamino: straight chain or branched chain C ₁ -C ₆ alkylthio: thio: and 2-oxo which may be substituted by a phenyl group or a straight chain or branched chain C ₁ -C ₆ alkyl group as -1,3-dioxolenemethylamino group-piperazinyl, piperadinyl, pyrrolidinyl, homopiperazinyl, morpholinothio morpholino, 1,2,5,6-tetrahydropyridyl imidazoryl , 1,4-diazabicyclo- (4,3,0) nona-4-yl (1,4-diazabicyclo- (4,3,0) nona-yl) thiomorpholin-4-oxide, Thiomorpholino-4,4-dioxide parazolidinyl, hexahydro pyridazinyl, pyridyl.thiazolidinyl, 2-thio-1-imidazolidinyl, 2-oxo-1-imidazolidinyl, 3 , 7-diaz Dicyclo (4,3,0) nona-3-yl, 4methyl-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-trimethyl-1-piperazinyl, 2,4,5-trimethyl-piperazinyl, 3-methyl-1-piperazinyl, 3-propyl-4- Methyl-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-butynyl-1-piperazinyl, 4-pentanoyl-1-piperazinyl, 4-hexanoyl-1-piperazinyl, 4- (α, α, α-trifluoroacetyl) -1-piperazinyl, 4 (β, β, β-trifluoro-α, α-difluoropropionyl) -1-piperazinyl, 4- (α, α, α-trifluoro-β, β-difluoro-α, α-difluorobutyryl) -1-piperazinyl, 4- (α, α-dichloroacetyl) -1 -blood Lazinyl, 4- (α-bromacetyl) -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-chloropentanoyl) -1 -Piperazinyl, 4-benzyl-1-piperazinyl, 4- (2-phenylethyl) -1-piperazinyl, 4- (1-phenylpropyl) -1-piperazinyl, 4- (3- Phenylethyl) -1-piperazinyl, 4- (4-phenylbutyl) -1-piperazinyl, 4- (1,1-dimethyl-2-phenylethyl) -1-piperazinyl, 4- (5 -Phenylpentyl) -1-piperazinyl, 4- (6-phenylhexyl) -1-piperazinyl, 4- (2-methyl-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-ethyl Amino-1-piperazinyl, 4-propylamino-1-piperazinyl, 4-tert-butylamino-1-piperazinyl, 3-pentylamino-1-pipera Neyl, 2-hexylamino-1-piperazinyl, 4-diethylamino-1-piperazinyl, 4- (N-methyl-Nn-butylamino) -1-piperazinyl, 3- (N-methyl -N-pentylamino) -1-piperazinyl, 2- (N-ethyl-N-hexylamino) -1-piperazinyl, 4-acetylamino-1-piperazinyl, 3-formylamino-1- Piperazinyl, 2-propionylamino-1-piperazinyl, 4-butyrylamino-1-piperazinyl, 3-pentanoylamino-1-piperazinyl, 2-hexanoylamino-1-pipera Genyl, 4- (N-methyl-N-acetylamino) -1-piperazinyl, 3- (N-ethyl-N-propionylamino) -1-piperazinyl, 4-hydroxy-1-pipera Genyl, 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-tri Fluoromethylsulfonyl-1-piperazinyl, 4- (3-fluoro Phil-sulfonyl) -1-piperazinyl, 4- (4,4,4-trifluoro butylsulfonyl) -1-piperazinyl, 4-sulfonyl-1-piperazinyl, 4- (phthal Ryde-3-yl) -1-piperazinyl, 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-hydroxymethyl-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-pipera Genyl, 4- (4-methoxybenzyl) -1-piperazinyl, 4- (3-ethoxybenzyl) -1-piperazinyl, 4- (2-propoxybenzyl) -1-piperazinyl, 4- (4-n-butoxybenzyl) -1-piperazinyl, 4- (3-pentyloxybenzyl) -1-pipera Neyl, 4- (2-hexyloxybenzyl) -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-cyclohexyl-1-piperazinyl, 4-cyclooctyl-1-piperazinyl, 4-phenyl-1 -Piperazinyl, 4- (4-fluorophenyl) -1-piperazinyl, 4- (3-bromophenyl) -1-piperazinyl, 4- (2-chlorophenyl) -1-pipera Genyl, 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-hexyl Phenyl) -1-piperazinyl, 4- (4-trifluoromethylphenyl) -1-piperazinyl, 4- (3- (3-chloromethyl) phenyl) -1-piperazinyl, 4- (2 -3, 3-dibromopropyl) phenyl) -1-piperazinyl, 4- (4- (4-chlorobutyl) phenyl) -1-piperazinyl, 4-hydroxymethyl-1-piperazinyl, 4- (2-hydroxymethyl) -1-piperazinyl, 4- (3-hydroxypropyl) -1-piperazinyl, 4- (3-chloropropyl) -1-piperazinyl, 4- (bromo Methyl) -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- (trifluoro Methyl) -1-piperazinyl, 4- (aminomethyl) -1-piperazinyl, 4- (3-dimethyl-aminopropyl) -1-piperazinyl, 4- (2-ethylaminoethyl) -1 -Piperazinyl, 4- (4-propylaminobutyl) -1-piperazinyl, 4- (5-butylaminofetyl) -1-piperazinyl, 4- (6-pentylaminohexyl) -1-pi Ferrazinyl, 4- (N-methyl-N-methylaminomethyl) -1-piperazinyl, 4- (N-methyl-N-propylaminomethyl) -1-piperazinyl, 4- (2-di Ethylaminoethyl) -1-piperazinyl, 4- (methoxymethyl) -1-piperazinyl, 4- (ethoxymethyl) -1-piperazinyl, 4- (2-propoxyethyl) -1 -Piperazinyl, 4- (3-butoxypropyl) -1-piperazinyl, 4- (4-pentyloxybutyl) -1-piperazinyl, 4- (5-hexyloxypentyl) -1- Piperazinyl, 4- (6-methoxyhexyl) -1-piperazinyl, 4-propazyl-1-piperazinyl, 4- (2-butynyl) -1-piperazinyl, 4- ( 3-butynyl) -1-piperazinyl, 4- (1-methyl-2-propynyl) -1-piperazinyl, 4- (2-pentynyl) -1-piperazinyl, 4- (2 -Hexynyl) -1-piperazinyl, 4-ethenyl-1-piperazinyl, 4-vinyl-1-piperazinyl, 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-piperazin, 4 -4dimethyl-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-ethylamino Carbonyl-1-piperazinyl, 4-propylaminocarbonyl-2-piperazinyl, 4-butylaminocarbonyl-1-piperazinyl, 4-pentylaminocarbonyl-1-piperazinyl, 4- Hexylaminocarbonyl-1-piperazinyl, 4-dimethylaminocarbonyl-1-piperazinyl, 4- (N-methyl-N-propylaminocarbonyl) -1-piperazinyl, 4-methoxycarbon Bonyl-1-piperazinyl, 4-ethoxy-carbonyl-2-piperazinyl, 4-propoxycarbonyl-1-piperazinyl, 4- (3-butoxycarbonyl-1-piperazinyl , 4-pentyloxycarbonyl-1-piperazinyl, 4-hexyloxycarbonyl-1-piperazinyl, 4-benzyloxycarbonyl-1-piperazinyl, 4- (2-phenylethoxycarbon Bonyl) -1-piperazinyl, 4- (3-phenylpropoxycarbonyl) -1-piperazinyl, 4- (4-phenylbutoxycarbonyl) -1-piperazinyl, 4- (5- Phenyl Tyloxycarbonyl) -1-piperazinyl, 4 (6-phenylhexyloxycarbonyl) -1-piperazinyl, 4- (2-aminoacetyl) -1-piperazinyl, 4- (3- Aminopropionyl) -1-piperazinyl, 4- (4-aminobutyryl) -1-piperazinyl, 4- (5-aminopentanoyl) -1-piperazinyl, 4- (6-aminohexa Noyl) -1-piperazinyl, 4- (2-benzyloxycarbonylaminoacetyl) -1-piperazinyl, 4- [2- (2-phenylethoxycarbonylamino) acetyl] -1-pipera Genyl, 4- [2- (3-phenylpropoxycarbonylamino) acetyl] -1-piperazinyl, 4-ethoxy carbonylmethyl-1-piperazinyl, 4- (2-methoxy carbonylethyl ) -1-piperazinyl, 4- (3-propoxycarbonylpropyl) -1-piperazinyl, 4- (4-butoxycarbonylbutyl) -1-piperazinyl, 4- (5-pentyl Oxycarbonylpentyl) -1-piperazinyl, 4- (6-hexyloxycarbonylhexyl) -1-piperazinyl, 4-carbonylmethyl-1-piperazinyl, 4- (2-carboxyethyl ) -1-piperazinyl, 4- (3-carboxypropyl) -1-pipe Lazinyl, 4- (4-carboxybutyl) -1-piperazinyl, 4- (5-carboxypentyl) -1-piperazinyl, 4- (6-carboxyhexyl) -1-piperazinyl, 4- (anilinocarbonylmethyl) -1-piperazinyl, 4- (2-anilinocarbonylethyl) -1-piperazinyl, 4- (3-anilinocarbonylpropyl) -1-pipera Genyl, 4- (4-anilinocarbonylpropyl) -1-piperazinyl, 4- (5-anilinocarbonylpropyl) -1-piperazinyl, 4- (6-anilinocarbonylhexyl)- 1-piperazinyl, 4- (3-carboxycyloyl) -1-piperazinyl, 4- (3-carboxy-2,3-dichloroacryloyl) -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-methoxy-1-piperazinyl, 4-ethoxy-1-piperazinyl, 4-propoxy-1-piperazinyl, 4-n-butoxy-1 Piperazinyl, 4-pentyloxy-1-piperazinyl, 4-hexyloxy-1-piperazinyl, 4-acetyloxy- 1-piperazinyl, 4-propionyloxy-1-piperazinyl, 4-butyryloxy-1-piperazinyl, 4-pentanoyloxy-1-piperazinyl, 4-ethoxycarbonyl-1 -Piperazinyl, 4-propoxy-carbonyl-1-piperazinyl, 4-n-butoxycarbonyl-1-piperazinyl, 4-pentyloxycarbonyl-1-piperazinyl, 4-hex Siloxycarbonyl-1-piperazinyl, 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- (5-phenylpentyl) -1-piperazinyl, 4- (6 -Phenylhexyl) -1-piperazinyl, 4-hydroxy-1-piperazinyl, 3-hydroxy-1-piperazinyl, 2-hydroxy-1-piperazinyl, 4-amino-1- Piperadinyl, 3-amino-1-piperazinyl, 2-amino-1-piperidinyl, 4-dimethylamino-1-piperazinyl, 4-methylamino-1-piperazinyl, 3-methylamino -1-piperazinyl, 2-propylamino-1-piperazinyl, 4-neo-butylamino-1 -Piperazinyl, 3-pentylamino-1-piperazinyl, 4-hexylamino-1-piperidinyl, 3-diethylamino-1-piperazinyl, 4- (N-methyl-N-propylamino ) -1-piperazinyl, 4-carbamoyl-1-piperazinyl, 3-carabamoyl-1-piperazinyl, 3,5-dimethyl-1-piperazinyl, 2,5-dimethyl- 1-piperazinyl, 4-oxo-1-piperazinyl, 3-oxo-1-piperazinyl, 3-hydroxy-1-pyrrolidinyl, 3-amino-1-pyrrolidinyl, 2-hydride Oxy-1-pyrrolidinyl, 2-amino-1-pyrrolidinyl, 3-methylamino-1-pyrrolidinyl, 3-dimethyl amino-pyrrolidinyl, 2-ethylamino-1-pyrrolidinyl, 3 -Propylamino-1-pyrrolidinyl, 2-butylamino-1-pyrrolidinyl, 3-pentylamino-1-pyrrolidinyl, 2-hexylamino-1-pyrrolidinyl, 3-diethylamino-1 -Pyrrolidinyl, 3- (N-ethyl-N-propylamino) -1-pyrrolidinyl, 2- (N-ethyl-N-neo-butylamino) -1-pyrrolidinyl, 3-acetylamino- 1-pyrrolidinyl, 3-propionylamino-1-pyrrole Ridinyl, 2-Butylamino-1-pyrrolidinyl, 3-pentanoylamino-1-pyrrolidinyl, 2-hexanoylamino-1-pyrrolidinyl, 3-hydroxymethyl-2-pyrrolidinyl , 2- (2-hydroxyethyl) -1-pyrrolidinyl, 3- (3-hydroxypropyl) -1-pyrrolidinyl, 2- (4-hydroxybutyl) -1-pyrrolidinyl 3- (5-hydroxyphenyl) -1-pyrrolidinyl, 3- (6-hydroxyhexyl) -1-pyrrolidinyl, 3-aminomethyl-1-pyrrolidinyl, 3- (2-aminoethyl)- 1-pyrrolidinyl, 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 -Propylaminopropyl) -1-pyrrolidinyl, 2- (4-n-butylaminobutyl) -1-pyrrolidinyl, 3- (5-pentylaminopentyl) -1-pyrrolidinyl, 3- (6 -Hexylaminohexyl-1-pyrrolidinyl, 3- (dimethyl aminomethyl) -1-pyrrolidinyl, 2- (N-methyl-N-ethyl Mino methyl) -1-pyrrolidinyl, 3- (N-methyl-N-neobutylaminomethyl) -1-pyrrolidinyl, 3-methylaminomethyl-4-methyl-1-pyrrolidinyl, 3- Methylaminoethyl-4-fluoro-1-pyrrolidinyl, -3-methylamino-4-methyl-1-pyrrolidinyl, 3-methylamino-4-chloro-1-pyrrolidinyl, 3-methylamino Methyl-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-hexyl Aminomethyl-5-chloro-1-pyrrolidinyl, 3-propylamino-5-chloro-1-pyrrolidinyl, 3-neo-butylamino-5-hexyl-pyrrolidinyl, 3-pentylamino-4- Methyl-1-pyrrolidinyl, 3-hexylamino-4-fluoro-1-pyrrolidinyl, 4-ethyl-1-homopiperazinyl, 4-methyl-1-homopiperazinyl, 4-propyl- 1-homopiperazinyl, 4- O-butyl-1-homopiperazinyl, 4-pentyl-1-homopiperazinyl, 4-hexyl-1-homopiperazinyl, 4-formyl-1-homopiperazinyl, 4-acetal-1- Homopiperazinyl, 4-propionyl-1-homopiperazinyl, 4-butyryl-1-homopiperazinyl, 4-pentanoyl-1-homopiperazinyl, 4-hexanoyl-1-homopi Ferrazinyl, 2-methyl-1-hexahydropyridazinyl, 2-ethyl-1-hexahydropyridazinyl, 2-methyl-1-hexahydropyridazinyl, 2-ethyl-1-hexahydropyridazinyl , 2-propyl-1-1hexahydropyridazinyl, 2-hexyl-1-hexahydropyridazinyl, 2-formyl-1-hexahydropyridazinyl, 2-acetyl-1-hexahydropyridazinyl, 2-propionyl-1-hexahydropyridazinyl, 2-butyryl-1-hexahydropyridazinyl, 2-pentanoyl-1-hexahydropyridazinyl, 2-hexahydropyridazinyl, 2-methyl -1-pyrazolidinyl, 2-ethyl-1-pyrazolidinyl, 2-propyl-1-pyrazolidinyl, 2-neo-butyl-1-pyrazoli Nyl 2-pentyl-1-pyrazolidinyl, 2-hexyl-1-pyrazolidinyl, 2-formyl-1-pyrazolidinyl, 2-acetyl-1-pyrazolidinyl, 2-propionyl-1-pyrazoli Diyl, 2-butyryl-1-pyrazolidinyl, 2-pentanoyl-1-pyrazolidinyl, 2-hexanoyl-1-pyrazolidinyl, 3,5-dimethyl monopolyno, 3-methylmorpholino, 3-ethylmorpholino, 2-propylmorpholino, 3-n-butylmorpholino, 3-pentyl-5-methylmorpholino, 3-hexyl-5-ethylmorpholino, 2-ethylaminomethylmo Polyno, 3-propylamimethylmorpholino, 3-n-butylaminomethylmorpholino, 2-pentylaminomethylmorpholino, 3-hexylaminomethylmorpholino, 3- (2-methylaminoethyl) -Morpholino, 3- (3-methylaminopropyl) morpholino, 3- (4-methylaminobutyl) morpholino, 2- (5-methyl-2-oxo-1,3-dioxolene-4 -Yl) methyl-1-piperazinyl, 4- (5-t-butyl-2-oxo-1,3-dioxolen-4-yl) methyl-1-piperazinyl, 4- (5-phenyl- 2-oxo-1,4-dioxolen-4-yl) methyl-1-peperazinyl, 4- (2-ox -1,3-dioxolen-4-yl) -methyl-1-piperazinyl, 3- (5-methyl-2-oxo-1,3-dioxolen-4-yl) methylamino-1-pipera Genyl, 4- (5-methyl-2-oxo-1,3-dioxolen-4-yl) methylamino-1-piperazinyl, 3-5- (5-phenyl-2-oxo-1,3- Dioxolen-4-yl) methylaminomorpholino, 3,5-dimethyl-1-piperazinyl, 3,3-dimethyl-1-piperazinyl, 4-acetyl-3-methyl-1-piperazinyl , 3-ethyl-4-piperazinyl, 3-ethyl-1-methyl-1-piperazinyl, 3- (trifluoromethyl) -1-piperazinyl, 3- (fluoromethyl) -1- Piperazinyl, 3-methylthio-1-piperazinyl, 4-methylthio-1-piperazinyl, 3-ethylthio-1-piperazinyl, 3-methylthiomorpholino, 4-flfuuro- 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-pyrrolidinyl, 3-amino-4-fluoro-1-piperazinyl, 3-amino-4-hydroxy-1-piperazinyl , 3-amino-4-methyl-1-pyrrolidinyl, 4-benzyl-3-methyl-1-piperazinyl, 3-fluoromethyl morpholino, 3-chloromethyl morpholino, 4-oxo- 1-piperidinyl, 3-oxo-1-piperazinyl, 2-oxo-1-piperidinyl, 3-acetylaminomethyl-1-pyrrolidinyl3- (N-ethyl-N-acetylamino)- Methyl-1-pyrrolidinyl, 3-3-t-butoxycarbonylaminomethyl-1-pyrrolidinyl, 3-ethylaminomethyl-1-pyrrolidinyl, 4-cycloamino-1-piperazinyl, 3-cyclopropylamino-1-pyrrolidinyl, 4-cycloamino-1-piperazinyl, 4-cyclohexylamino-1-piperazinyl, 3-cycloheptylamino-1-pyrrolidinyl, 4-cyclo Octylamino-1-piperazinyl, 4-cyclooxtipamino-1-piperidinyl, 4-cyclopropylamino-1-piperidinyl, 3-cyclopropyl aminomorpholino, 4-thio-1-pipera Genyl, 3-thio-1-piperazinyl 3-thiomorpholino, 4-cyclopropylaminomethylpiperazinyl, 3-cyclopropyl aminomethyl-1-pyrrolidinyl, 4-cyclopropylaminomethyl-1-piperazinyl, 3-cyclopropylaminomethylmorpholino, 3- (4-cyclobutylaminobutyl) -1-pi Lolidinyl, 4- (5-cyclooctylaminopentyl) -1-piperazinyl, 4- (6-cyclopropylaminohexyl) morpholino, 3-acetylaminomethyl-1-piperazinyl, 4- (2 -Propionylaminoethyl) -1-piperazinyl, 4- (3-butyrylaminopropyl) -1-piperazinyl, 3- (4-pentanoylaminobutyl) morpholino, 4- (5-hexa Noylaminopentyl) -piperazinyl, 3- (6-acetylaminohexyl) -1-piperazinyl, 4- (N-acetyl-N-ethylamino) methyl-1-piperazinyl, 4- (N- Cyclopropyl-N-acetylamino) methyl-1-pyrrolidinyl, 4- (methoxycarbonylaminomethyl) -1-piperazinyl, 4- (2-ethoxycarbonylaminoethyl) -1-pipera Genyl, 3- (3-propoxycarbonylaminopropyl) morpholino, 4- (6-t-butoxycarbonylami Hexyl) -1-piperazinyl, 3- (Nt-butoxycarbonyl-N-ethylaminomethyl) -1-piperidinyl, 3- (Nt-butoxycarbonyl-N-methylaminomethyl) -1 -Pyrrolidinyl, 3- (Nt-butoxycarbonyl-N-cyclopropylaminomethyl) -1-pyrrolidinyl, 4- (N-methoxycarbonyl-N-cyclopropylaminomethyl) -1-pi Ferrazinyl, 4- (N-propoxycarbonyl-N-cyclohexylaminomethyl) -1-piperazinyl and the like.

The term cycloalkyl includes C ₃ -C ₈ cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

The term phenyl (lower) alkyl, wherein the phenyl ring may be substituted by (lower) alkoxy, nitro or amino, means that the phenyl ring may be substituted by a straight chain or branched chain C ₁ -C ₆ alkoxy group, nitro group or amino group. The alkyl moiety may benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1,1-dimethyl-2-phenylethyl, 5-phenylpentyl, 6-phenylhexyl, 2 -Methyl-3-phenylpropyl, 4-methoxybenzyl, 3-ethoxybenzyl, 2-propoxybenzyl, 4-n-butoxybenzyl, 3-pentyloxybenzyl, 2-hexyloxybenzyl, 4-nitrobenzyl 3-nitrobenzyl, 4-aminobenzyl, 2-aminobenzyl, 2- (4-methoxyphenyl) ethyl, 1- (3-ethoxyphenyl) ethyl, 3- (2-propoxyphenyl) -propyl, Phenyl which is a straight chain or branched chain C ₁ -C ₆ alkyl group such as 4- (4-n-butoxyphenyl) butyl, 5- (2-nitrophenyl) -pentyl, 6- (3-aminophenyl) hexyl, etc. It includes an alkyl group.

In this phenyl group which may be substituted by halogen atom, (lower alkyl or (lower) alkyl substituted by halogen atom of 1-3), phenyl ring may be substituted by halogen atom, or phenyl, 4-fluorophenyl , 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- (1,2,2 Straight chain or branched chain C ₁ -C ₆ alkyl group which may be substituted by 1-3 halogen atoms such as -trifluoroethyl) phenyl, 4- (2,2,2-trifluoroethyl) phenyl, etc. This phenyl ring may also be substituted.

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

Hydroxy group: straight chain or branched chain C ₁ -C ₆ alkyl group, straight chain or branched chain C ₁ -C ₆ alkanoyl group, C ₃ -C ₈ cycloalkyl group and straight chain or branched chain C ₁ -C ₆ alkoxy Amino groups which may be substituted by one or two substituents selected from the group consisting of carbonyl groups: hydroxymethyl, 2-hydroethylethyl, 1-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 5- Hydrocipentyl, 6-hydrohexyl, 3-chloropropyl, bromomethyl, 2-fluoromethyl, 4-chlorobutyl, 3-fluoropentyl, 2,3-dichlorohexyl, 2,2,2-tri Fluoromethyl, trifluoroethyl, aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, 3-methylaminopropyl, 2- Ethylaminoethyl, 4-propylaminobutyl, 5-n-butylaminopentyl, 6-pentylaminohexyl, methylaminomethyl, ethyl Minoethyl 2-propylaminomethyl, 1-n-butylaminoethyl, 3-pentylaminopropyl, 4-hexylaminobutyl, N-methyl-N-ethylaminomethyl, N-methyl-N-propylaminomethyl, methoxy Methyl, ethoxymethyl, 2-propoxyethyl, 3-butoxypropyl, 4-pentyloxybutyl, 5-hexyloxypentyl, 6-methoxyhexyl, propoxymethyl, 1-ethoxyethyl, 2-hexyloxy Ethyl, formylaminomethyl, acetylaminomethyl, 2-propanoylaminoethyl3-butyrylaminopropyl, 4-pentanoylaminobutyl, 5-hexanoylaminopentyl, 6-acetylaminohexyl, propanoylaminoethyl, N-acetyl-N-methylaminomethyl, N-acetyl-N-ethylaminomethyl N-acetyl-N-cyclopropylaminomethyl, N, N-dicyclopropylaminomethyl, cyclopropylaminomethyl, 2-cyclobutylamino Ethyl, 3-cyclopentyl, 1-cyclopropylaminoethyl, 2-cyclopropyl aminoethyl, aminopropyl, 4- Cyclohexylaminobutyl, 5-cycloheptylaminopentyl, 6-cyclooctylaminohexyl, N-methyl-N-cyclopropylaminomethyl, N-ethyl-N-cyclopropylaminomethyl, methoxycarbonylaminomethyl, 2- Ethoxycarbonylaminoethyl, 3-propoxycarbonylaminopropyl, 4-t-butoxycarbonylaminobutyl, 5-pentyloxycarbonylaminopentyl, 6-hexyloxycarbonylaminohexyl, t-butoxy Carbonylaminoethyl, 2-t-butoxycarbonylaminoethyl, 1-t-butoxycarbonylaminoethyl, Nt-butoxycarbonylamino-N-ethylaminomethyl, Nt-butoxycarbonylamino-N Straight chain or branched chain C ₁ -C ₆ alkoxy groups such as -ethylaminomethyl, Nt-butoxycarbonylamino-N-cyclopropylaminomethyl and the like.

The term (lower) alkanoyl which may be substituted by halogen atoms of 1-7 refers to formyl, acetyl, propionyl, butynyl, pentanoyl, hexanoyl, α, α, α-trifluoroacetyl, β, β , β-trifluoro-α, α-difluoropropionyl α, α, α-trifluoro-β, β-difluoro-α, α-difluorobutytilyl, α, α-dichloroacetyl , α-bromoacetyl, α-iodoacetyl, β-fluoropropionyl, β-fluoro-α-fluoropropionyl, 6-fluorohexanoyl, 4-chloropentanoyl, 3,3,3 A straight chain or branched chain C ₁ -C ₆ alkanoyl group which may be substituted by 1-7 halogen atoms such as -trifluoropropionyl and the like.

The term (lower) 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-carboxy-2 1-3 substituents selected from the group consisting of halogen atoms and carboxyl groups such as, 3-dibromoacryloyl, 4-carboxycrotonoyl, 5-carboxy-3,4-dichloro-3-hexenoyl Straight chain or branched chain C ₁ -C ₆ alkenylcarbonyl group having

The term (lower) alkoxycarbonyl is methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, hexyloxyca Straight chain or branched chain C ₁ -C ₆ alkoxycarbonyl groups such as carbonyl and the like.

The term aminocarbonyl, which may be substituted by (lower) alkyl, refers to carbamoyl, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, n-butylaminocarbonyl, diethylaminocarbonyl, dipropylamino Carbonyl, dipentylaminocarbonyl, dihexylaminocarbonyl, N-methyl-N-propylaminocarbonyl, N-methyl-N-tertbutylaminocarbonyl, N-ethyl-N-pentylaminocarbonyl And aminocarbonyl groups which may be substituted by the same 1 or 2 straight chain or branched chain C ₁ -C ₆ alkyl group.

The term phenyl (lower) alkoxycarbonyl means that the alkoxy moiety is benzyloxy carbonyl, 2-phenylepoxycarbonyl, 1-phenylethoxycarbonyl, 3-phenylpropoxycarbonyl, 4-phenylbutoxycarbonyl, 1 Straight or branched chains such as 1-dimethyl-2-phenylethoxycarbonyl, 5-phenylpentyloxycarbonyl, 6-phenylhexyloxycarbonyl, 2-methyl-3-phenylpropoxycarbonyl and the like And a phenylalkoxycarbonyl group which is a C ₁ -C ₆ alkoxy group.

The term amino (lower) alkanoyl which may be substituted by phenyl (lower) alkoxycarbonyl 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-phenyl Ethoxycarbonylamino) butyryl, 5- (5-phenylpentyloxycarbonylamino) pentanyl, 6- (6-phenylhexyloxycarbonylamino) hexanoyl, 2- (2-methyl-3-phenyl propoxy include carbonyl amino) acetyl such as straight chain or branched chain C ₁ -C ₆ alkoxy group, straight chain or branched chain alkoxy phenyl which may be substituted by a carbonyl group C ₁ -C ₆ alkanoyl-amino group, such as.

Alkoxy and alkyl moieties (lower) alkoxycarbonyl (lower) alkyl are methoxycarbonylmethyl, ethoxycarbonylmethyl, 2-ethoxycarbonylethyl, 3-propoxycarbonylpropyl, 4-hexyloxycarbon Straight chain or branched chain C ₁ -C such as nilohexyl, 2-methoxycarbonylethyl, 3-methoxycarbonyl propoxypropyl, 3-ethylcarbonyl propoxypropyl, 4-ethylcarboxybutoxy butyl, etc. ₆ alkoxy and an alkoxycarbonylalkyl group which is an alkyl group.

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

The term anilinocarbonyl (lower) alkyl is not an alkyl moiety anilinocarbonylmethyl, 2-anilinocarbonylethyl. 1-anilinocarbonylmethyl, 3-anilinocarbonylpropyl, 4-anilinocarbonylbutyl, 5-anilinocarbonylpentyl, 6-anilinocarbonylhexyl, 1,1-dimethyl-2-anilino An anilino carbonylalkyl group which is a straight chain or branched chain C ₁ -C ₆ alkyl group such as carbonylethyl, 2-methyl-3-anilinocarbonylpropyl, or the like.

The term amino, which may be substituted by (lower) alkyl or (lower) alkanoyl, refers to amino, methylamino, ethylamino, propylamino, t-butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, di -n-propylamino, di-n-butylamino, dipentylamino, dihexylamino, N-methyl-nn-butylamino, N-methyl-N-pentylamino, N-ethyl-N-hexylamino, acetylamino Formylamino, propionylamino, butyrylamino, pentanoylamino, hexanoylamino, N-methyl-N-butylylamino, N-ethyl-N-propionylamino, N-methyl-N-butyrylamino, 1 or 2 straight chain or branched chain C ₁ -C ₆ alkyl group or straight chain or branched chain C ₁ -C such as Nn-propyl-N-pentanoyltanoylamino, N-ethyl-N-hexanoylamino, etc. Amino groups which may be substituted by 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- May be substituted by one or two halogen atoms such as 5-yl, 4-fluoro-2 (5H) -furanone-5-yl, 3-iodo-2 (5H) -furanone-5-yl, and the like Containing 2 (5H) -furanone groups.

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

The term (lower) alkylsulfonyl which may be substituted by halogen atoms of 1-3 is methylsulfonyl, ethylsulfonyl, isopropylpropsulfonyl, n-butylsulfonyl, pentylsulfonyl hexylsulfonyl, trifluor Chloromethylsulfonyl, 2-fluoromethylsulfonyl, 3-fluoropropylsulfonyl, 4,4,4-trifluoro butylsulfonyl, 5-chloropentylsulfonyl, 6-bromohexylsulfonyl, 6- Straight chain or branched chain C ₁ -C which may be substituted by 1-3 halogen atoms such as iodinehexylsulfonyl, 2,2-difluoroethylsulfonyl, 2,3-dibromopropylsulfonyl, and the like _{It includes 6} alkylsulfonyl group.

The term (lower) alkoxy includes straight chain or branched chain C ₁ -C ₆ alkoxy groups such as methoxy, ethoxy, protoxy, isopropoxy, butoxy, t-butoxy, pentyloxy, hexyloxy and the like. do.

The term (lower) alkanoyloxy is a straight chain or branched chain C ₂ -C ₆ alkanoyloxy group such as acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy, hexanoyloxy, etc. It includes.

The term (lower) alkenyl is a straight or branched chain C ₁ -C ₆ such as vinyl, allyl, 2-butenyl, 3-butenyl, 1-methylallyl, 2-pantenyl, 2-hexenyl, etc. Alkenyl groups.

The term (lower) alkynyl refers to straight chains such as ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 2-hexynyl, etc. A branched chain C ₂ -C ₆ alkynyl group.

The term 2-oxo-1,3-dioxorenmethyl, which may be substituted by phenyl or (lower) alkyl, refers to (5-methyl-2-oxo-1,3-dioxoren-4-yl) -methyl , (5-t-butyl-2-oxo-1,3-dioxoren-4-yl) methyl, (5-phenyl-2-oxo-1,3-dioxoren-4-yl) ethyl, ( 2-oxo-1,3-di which may be substituted by a phenyl group such as 5-propyl2-oxo-1,3-dioxoren-4-yl) methyl, or a straight chain or branched chain C ₁ -C ₆ alkyl group It contains an oxolenmethyl group.

1-3 substituents selected from the group consisting of 5-6 membered saturated heterocyclic rings, (lower) alkylthio, amino, (lower) alkylamino, (lower) alkanoyloxy, hydroxy, (lower) alkoxy and halogen atoms The term (lower) alkyl, which may be substituted by, in addition to the (lower) alkyl mentioned above, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 4-hydrobutyl, 5-hydroxypentyl, 6-hydroxyhexyl, fluoromethyl, 3-chloropropyl, bromomethyl, 2-fluoroethyl, 4-chlorobutyl, 3-fluoropentyl, difluoromethyl, 2,3 -Dichlorohexyl, 2,2,2-trifluoroethyl, fluoromethyl, chloromethyl, dibromomethyl, iodomethyl, dichloromethyl, methoxymethyl, ethoxymethyl, 2-propoxyethyl, 3- Butoxypropyl, 4-pentyloxybutyl, 5-hexyloxypentyl, 6-methoxyhexyl, propoxymethyl, 1-ethoxyethyl, 2-hexyloxyethyl, Minoethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, 3-dimethylaminopropyl, 2-ethylaminoethyl, 4-propylaminobutyl , 5-n-butylaminopentyl, 6-pentylaminohexyl, methylaminomethyl, diethylminomethyl, 2-dipropylaminoethyl, 1-di-n-butylaminoethyl, 3-dipentylaminopropyl, 4- Di-hexylaminobutyl, N-methyl-N-ethylaminomethyl, N-methyl-N-propylaminomethyl, butyloxymethyl, acetyloxymethyl, 2-propionyloxyethyl, 3-butyryloxypropyl, 4- Pentanoyloxybutyl, 5-hexanoyloxypentyl, 6-acetyloxyhexyl, propionyloxymethyl, 1-acetyloxyethyl, 2-hexanoyloxyethyl, (1-pyrrolidinyl) methyl, 1- (1- Piperazinyl) ethyl, (1-piperazinyl) ethyl, 3-morpholinopropyl, 4-thiomorpholinobutyl, 5- (1-pyrrolidinyl) pentyl, 6- (1-piperazinyl) Hexyl, methylthiomethyl, ethylthioethyl, 5- to 6-membered saturation heterocycles such as 2-propylthiomethyl, 1-isopropylthioethyl, 3-butylthiopropyl, 4-t-butylthiobutyl, 5-pentylthiopentyl, 6-hexylthiohexyl, etc. Clicking ring, straight chain or branched chain C ₁ -C ₆ alkylthio group, hydroxy group, amino group, amino group having 1-2 straight or branched chain C ₁ -C ₆ alkyl group, straight chain or branched chain C _1- C ₆ alkyl group, straight chain or branched chain C ₁ -C ₆ alkanoyloxyethyl group or straight chain or branched chain C ₁ -C ₆ alkyl group substituted by 1-3 substituents selected from the group consisting of halogen atoms Include.

The term 2-oxo-1,3-dioxoene methylamino, which may be substituted by phenyl or (lower) alkyl, refers to (5-methyl-2-oxo-1,3-dioxoren-4-yl) methyl Amino, (5-t-butyl-2-oxo-1,3-dioxoren-4-yl) methylamino, (5-phenyl-2-oxo-1,3-dioxoren-4-yl) methyl Amino, (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-ethyl-2-oxo-1,3-dioxoren-4-yl) methylamino, (5-propyl-2 2-oxo-1,3-dioxoene, which may be substituted by a phenyl group such as -oxo-1,3-dioxoren-4-yl) methylamino, or a straight chain or branched chain C ₁ -C ₆ alkyl group It contains a methylamino group.

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

The term (lower) alkylthio is a straight chain or branched chain C ₁ -C ₆ alkylthio group such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, tert-butylthio, pentylthio, hexylthio, and the like. Include.

The compound of the present invention of general formula (I) above may be prepared by various processes, for example, by the process shown in the following reaction scheme.

(여기서 R¹¹과 R¹²는 각각 저급알킬) 또는 저급알콕시,그리고, X²와 X³는 각각 할로겐 원자이고, R⁷과 R⁸은 각각 저급알킬이다. 화합물(2)의 할로겐화 반응은 용매가 존재하거나 또는 존재하지 않는 상태에서 할로겐화 시약과 반응시킴으로써 수행된다.R here^One, R², R³And X are as defined above and R is²Silver halogen atom or R²(R 2 is as defined above) and R⁴Is a group of the formula: -COR⁹Where R⁹Is lower alkyl) or a group of formula -COOR¹⁶Where R¹⁶Is lower alkyl) and R⁵Silver lower alkyl, R⁶Is a group of the formula:

Where R¹¹And R¹²Is lower alkyl) or lower alkoxy, and X²With X³Are each halogen atom, R⁷And R⁸Are each lower alkyl. The halogenation reaction of compound (2) is carried out by reacting with a halogenation reagent in the presence or absence of a solvent.

The solvent may be an aromatic hydrocarbon (e.g., benzene, toluene, xylene, etc.), a halogenated hydrocarbon (e.g., dichloromethane, chloroform, carbon tetrachloride, etc.) ether (e.g., dioxane tetrahydrofuran, diethyl ether, etc.), Dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and the like. As long as the halogenating reagent can convert hydroxy of the carboxy group into a halogen atom, any halogenating reagent can be used conventionally, for example, thionyl chloride, phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride, phosphorus Pentabromide and the like.

Although the amount of the compound of the halogenation reagent is not particularly determined, when the solvent is used, the halogenation reagent is used very much, and when the solvent is used, at least 1 mole of the halogenation reagent should be used, preferably for 1 mole of the compound (2). It is to use 2-4 moles.

The reaction temperature and reaction time are also not specifically determined, but the reaction is usually carried out at room temperature ˜100 ° C. for 30 minutes to 6 hours.

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

If the solvent does not adversely affect the reaction, water, ether (e.g., diethyl ether, dioxane, tetrahydrofuran, monoglyme, diglyme, etc.) aromatic hydrocarbons (e.g., benzene, toluene, xylene, etc.) ), Aliphatic hydrocarbons (e.g., hexane, heptane cyclohexane, ligroin, etc.), amines (e.g., pyridine, N, N-dimethylaniline, etc.), halogenated hydrocarbons (e.g., chloroform, dichloromethane, Aprotic polar solvents, such as carbon tetrachloride, (eg, DMF, DMSO, hexamethylphosphoamide (HMPA), etc.) and mixtures of such solvents.

Examples of the basic compound include 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.), metal alcoholates (e.g. sodium methylate, Sodium ethylate, etc.) and organic bases such as pyridine, pyridine, quinoline, triethylamine, N, N-dimethylaniline, and the like.

The reaction temperature is usually carried out for 30 minutes to 15 hours at 0 ℃ -150 ℃, preferably room temperature ~ 120 ℃.

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

When R ⁴ in the compound (5) is a COR ⁹ group, the removal of the COR ⁹ group is carried out in a suitable solvent with the base compound.

The solvent may be ether (e.g. diethyl ether, dioxane, tetrahydrofuran, monoglyme, diglyme, etc.), aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), aliphatic hydrocarbons (e.g. n-hexane, heptane, Cyclohexane, etc.), and aprotic polar solvents (eg, DMF, DMSO, HMPA, etc.).

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

The reaction is carried out for 1-20 hours at 0 ~ 150 ℃ preferably room temperature ~ 100 ℃.

When R ⁴ in the compound (5) is a COOR ¹⁰ group, the removal of the COOR ¹⁰ groups is carried out in the presence of an acid catalyst in aqueous solution.

Acid catalysts include inorganic acids (eg hydrochloric acid, sulfuric acid, etc.) and organic acids (eg P-toluenesulfonic acid, etc.).

The reaction temperature is carried out for 1-20 hours at 0 ~ 150 ℃ preferably room temperature ~ 100 ℃.

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 to 200 ° C, preferably at 0 to 150 ° C for 30 minutes-10 hours.

The compound (6) is used in the same amount or excessive amount, but preferably 1-2 mol is used per 1 mol of compound (5).

In the case of using compound (6) in which R ⁶ is a lower alkoxy group, the reaction uses an acid anhydride (e.g. acetic anhydride) as a solvent as well as the above-mentioned solvent at a temperature of 0 to 200 캜, preferably 0 to 170 캜. Is performed by

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 adversely affect the reaction, for example, alcohol (e.g. methanol, ethanol, propanol, etc.), ether (e.g. diethyl ether, dioxane, tetrahydrofutane, monoglyme) , Diglyme, etc., aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), aliphatic hydrocarbons (e.g., n-hexane, heptane, cyclohexane, ligroin, etc.), halogenated hydrocarbons (e.g., chloroform, methylene chloride, carbon tetrachloride, etc.) ) And aprotic polar solvents (eg DMF, DMSO, HMPA, etc.).

The reaction is usually carried out at ambient temperature -100 ° C for 0 minutes to 150 ° C, preferably 30 minutes-15 hours.

The compound (8) is used at least 1 mole, preferably 1-2 moles per 1 mole of the compound (7). The base compound may optionally be added in the reaction, and such base compound may be any base compound used in the above reaction 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 adversely affect the reaction, e.g. ether (e.g. diethyl ether, dioxane, tetrahydrofutane, monoclime, diglyme, etc.), aliphatic hydrocarbons (e.g. n-hexane, Heptane, ligroin, etc.), halogenated hydrocarbons (eg chloroform, methylene chloride, carbon tetrachloride, etc.), aprotic polar solvents (eg DMF, DMSO, HMPA etc.) and the like.

Base compounds include inorganic bases (e.g., metal sodium, potassium metal, sodium hydrogen, amide sodium, sodium hydroxide, potassium hydroxide, etc.), metal alcoholates (e.g. sodium methylate, sodium ethylate, etc.) and organic bases (e.g. 1 , 8-diazocyclo [5.4.0] undec-7 (DBU), N-benzyltrimethylammonium hydroxide, tetrabutylammonium hydroxide, and the like).

The reaction is usually carried out at ambient temperature -120 ° C for 30 minutes-5 hours, preferably 0 ° C-150 ° C.

The base compound is used at least 1 mole, preferably 1-2 moles per 1 mole of the compound (9).

Dehydration of compound (10) can be carried out under conventional dehydration conditions, for example, basic compounds (e.g. sodium hydroxide, potassium hydroxide, barium hydroxide, potassium carbonate, etc.), inorganic acids (e.g. sulfuric acid, hydrochloric acid, nitric acid, etc.) or organic acids (acetic acid). Solvents such as water, alcohols (e.g. methanol, ethanol, isopropanol, etc.) ketones (e.g. acetone methyl ethyl ketone, etc.) ethers (e.g. dioxane, ethylene glycol, etc.) acetic acid and mixtures thereof in the presence of Is performed inside.

The reaction is usually carried out at ambient temperature -200 ° C, preferably at ambient temperature -150 ° C for 10 minutes-30 hours.

Compound (1a) is produced by the reaction.

(여기서 R¹⁴와 R¹⁵는 각각 알킬이다)이다.Where 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 compounds (1b) and (11) is carried out in an inert solvent, in which the two compounds are used in a wide range of ratios, where compound (11) is at least 1 mole, preferably 1 mole per 1 mole of compound (1b). -5 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. petrahydrofuran, di Oxane, diglyme, etc.), diethylacetamide, DMF, DMSO, HMA, 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 an acid removal reagent such as inorganic carbonates (e.g. sodium carbonate, potassium carbonate, sodium bicarbonate, potassium carbonate, etc.) or organic bases (e.g. pyridine, quinoline, triethylamine, etc.).

Alkali metal halogens (eg potassium fluoride, etc.) may be added to the reaction mixture.

The reaction is usually performed at 1-20 atm, preferably at 1-10 atm and at room temperature to 250 ° C, more preferably at room temperature to 200 ° C for 30 minutes to 30 hours.

기인 화합물(1b')은 상응하는 화합물(1b')로 변할 수 있는데 킬레이트 화합물을 분해시켜서 R¹³이 수소원자인 화합들물로 만들 수가 있다.R ¹³ is

Compound (1b ') attributable to the compound (1b') can be converted into a compound in which R ¹³ is a hydrogen atom by decomposing the chelating compound.

Acids include inorganic acids (e.g. sulfuric acid hydrochloric acid) 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, potassium carbonate, etc.) And organic bases such as triethylamine.

Acids and bases are preferably used in an amount of at least 1 mole, preferably 1-10 moles per mole of starting material.

이다.Where R ', 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 integer of 1-3 and R ¹⁶ is (lower) alkyl: cycloalkyl: phenyl ring (lower) alkoxy, nitro or phenyl (lower) alkyl which may be substituted by amino: halogen atom, (lower) alkyl or Phenyl which may be substituted by (lower) alkyl etc. substituted by 1 to 3 halogen atoms: hydroxy, amino, (lower) alkoxy and halogen atoms where amino is (lower) alkyl, (lower) alkanoyl, cyclo Which may be optionally substituted by alkyl or (lower) alkoxy carbonyl, which may be substituted by a halogen atom of (lower) alkyl: 1-7 having 1-3 substituents selected from the group consisting of these compounds ( Lower) alkanoyl: (lower) alkenyl carbonyl having a 1-3 substituent group selected from the group consisting of halogen atoms and carboxy: (lower) alkoxycarbonyl: amino (lower) which may be substituted by (lower) alkyl Alkanoyl (lower) alkoxycar Carbonyl (Lower) Alkyl: Carboxy (Low) Alkyl: Anlinocarbonyl (Low) Alkyl: (Lower) Alkylsulfonyl: Sulfo (Lower) Alkyl: (Lower) Alkenyl Or (lower) alkynyl.

이다.X ⁵ is a halogen atom, ^one of Z ¹ or W ¹ 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.) kenon (e.g. acetone, methyl ethyl ketone, etc.), ether (e.g. diethyl ether, dioxane, etc.), aromatic hydrocarbons (e.g. benzene, toluene, xylene And the like).

If necessary, copper powder, copper halide (for example, copper iodide, etc.), or an alkali metal halide may be used.

Compound (1c) is the same amount-excess, Preferably 1-3 water is used for 1 mol of compound (12).

The reaction is usually carried out at room temperature ˜150 ° C., preferably at 50 ° C. to 120 ° C. for 1-2 hours.

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

to be.

The reaction of compounds (1c) and (13) is carried out under conditions with or without solvent in the presence of a reducing agent.

The solvent is, for example, water, alcohol, (e.g. methanol, ethanol, isopropanol) (lower) alkanoic acid (e.g. formic acid, acetic acid, etc.), ether (e.g. dioxane, diethyl ether, diglyme, tetra Hydrofuran, etc.), aromatic hydrocarbons (eg, benzene, tylene, toluene, etc.), and the like.

Reducing agents are formic acid, alkali or alkaline earth metal salts of formic acid (e.g. sodium formate), hydroxide reducing agents (e.g. sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride), catalysts for catalytic reduction (Eg, palladium carbon, platinum oxide, platinum black, Raney nickel).

When formic acid is used as the reducing agent, it is performed at room temperature to 200 ° C., preferably at 50 to 150 ° C., for 1 to 10 hours.

Formic acid is preferably used in excess in comparison to compound (1c).

In addition, when using a hydrogenation reagent, the reaction is carried out for 30 minutes to 12 hours at 30 ~ 100 ℃, preferably 0 ~ 70 ℃.

As the reducing reagent for hydrogenation, 1-2 mol is used, and preferably 1-6 mol is used per 1 mol of compound (1c).

When lithium aluminum hydride is used as the reducing reagent, preferred solvents include ethers such as diethyl ether, dioxane, tetrahydrofuran and diglyme, aromatic hydrocarbons such as benzene, toluene and xylene. Included.

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

The catalyst is usually used in an amount of 0.1-40%, preferably 0.1-30% of the weight of compound (1c).

Excess amount is normally used for compound (13) at least 1 mole, preferably for 1 mole of compound (1c).

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

Where X, R ^{2 '} and X ² are as defined above, X ⁵ and X ⁶ are each halogen, R ¹⁹ is hydrogen or lower alkyl, R ²⁰ is lower alkyl, and R ¹⁹ and R ²⁰ are Gather together to form a 5-7 membered ring, where M is an alkyl metal (e.g. sodium, potassium, etc.) or a metal (e.g. silver, calcium, copper, etc.).

When R ¹⁹ and R ²⁰ in Compound (16) combine to form a 5-7 member cyclic ring, R ¹⁹ of Compound (20) is -R ¹⁹ R ²⁰ H.

Compound (16) is prepared by using the aniline derivative represented by the general formula (14) as a starting material, reacting it with a halogenating reagent, and then reacting the compound of the general formula (14a) with the thio compound of the general formula (15).

The reaction of the aniline derivative 14 with the halogenating reagent is usually carried out in a suitable solvent.

The solvent may be any conventional solvent as long as it does not adversely affect the reaction, for example, halogenated hydrocarbons (e.g. chloroform, dichloromethane, etc.), ethers (e.g. dioxane, diethyl ether, tetrahydrofutane, etc.), aromatic hydrocarbons ( Examples include lower alcohols (e.g. methanol, ethanol, isopropanol) and polar solvents (e.g. DMSO, HMPA, acetonitrile, etc.).

Halogenation reagents may be any conventional halogenation reagent, for example, N-bromosuccinimide, N-chlorosuccinimide, sodium hypobromide, sodium hypochloride, bleaching powder, thionyl chloride, t-butyl hypochlorous It includes things such as lights.

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

The reaction is usually carried out at -78 ° C to room temperature, preferably -60 to 15 ° C, and the reaction is completed in a few minutes.

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 for reacting with the thio compound of formula 15 without separation.

The reaction of the compounds (14a) and (15) is carried out in the same solvent as described above in the presence of a base compound.

Base compounds include organic bases such as inorganic bases such as potassium carbonate, sodium carbonate, sodium hydroxide, sodium bicarbonate, sodium amide, sodium hydride and the like.

Compound (15) is usually used at least 1 mole, preferably 1-1.5 moles, per 1 mole of compound (14a).

The reaction is usually carried out at room temperature ˜150 ° C., preferably at room 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 solvents are water, alcohols (e.g. methanol, ethanol, isopropanol, etc.), aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), ethers (e.g. dioxane, tetrahydrofuran, diglyme, etc.), polar solvents (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 bicarbonate, potassium hydrogen carbonate, etc.) organic bases (e.g. pyridine, quinoline, triethylamine, etc.) phase inversion catalysts (e.g. phenyltriethylammonium chloride tetramethylammonium) Chloride, etc.), and the like.

The compound (17) is usually used at least 1 mole, preferably 1-2 moles, with respect to 1 mole of the compound (16).

The reaction is usually performed at room temperature ˜200 ° C., preferably at room temperature ˜180 ° C. for 30 minutes-10 hours.

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

Catalysts include, for example, aluminum-amalgam, lithium lower alkylamines, Raney nickel, Raney cobalt, triethyl phosphite, triphenylphosphine, and the most preferred is Raney nickel.

Examples of the solvent include alcohols (eg, methanol, ethanol, isopropanol) and ethers (eg, diethyl ether, dioxane, tetrahydrofuran, etc.).

The reaction is usually carried out for 10 minutes-5 hours at 0 ~ 200 ℃ preferably room temperature ~ 100 ℃.

The catalyst is usually 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 nitrite (e.g. sodium nitrite, zirconium nitrite, etc.) in a suitable solvent in the presence of an acid and reacting the resulting product By reaction with metal halides (eg potassium iodide, copper (I), copper bromide (I), etc.) without separation from it.

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

Solvents include water, alkanoic acid (e.g. acetic acid, etc.) ethers (e.g. dioxane, tetra hydrofuran, etc.), aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), alcohols (e.g. methanol, ethanol, isopropanol, etc.) , Halogenated hydrocarbons (eg chloroform, dichloromethane, dichloroethane, etc.), aprotic polar solvents (eg DMF, DMSO, HMPA, etc.) and mixtures thereof.

The metal salt of nitrous acid and the halide metal are usually used at least 1 mol, preferably 1-1.5 mol, with respect to 1 mol of compound (19).

The reaction is usually carried out for 10 minutes-5 hours at 0-150 ° C, preferably 0-100 ° C.

Hydrolysis of the compound (20) can be carried out with a suitable hydrolysis catalyst, for example inorganic acids (e.g. sulfate, hydrobromic acid, phosphoric acid, etc.) or base compounds (e.g. sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrocarbon, etc.). And may be performed under conditions with or without solvent.

The solvent includes, for example, a mixture of water and lower alcohols such as methanol and ethanol.

The reaction is usually carried out at 50-200 ° C., preferably at 70-180 ° C., for 1-10 hours.

기인 일반식(1b)의 화합물은 예를 들면 다음 반응모식도-V1에 나타낸 과정에 의해 제조될 수 있다.Schematic diagram of -II in R ¹³

The compound of general formula (1b) which is a group can be manufactured by the process shown, for example in following Reaction Scheme-V1.

이고, R²¹은 저급알킬이다.Wherein R ¹ , R ³ , X, X ⁴ , R ¹⁴ and R ¹⁵ are as defined above, R ¹⁵ is a lower alkyl or hydrogen atom, and R ^{13 '} is

And R ²¹ is lower alkyl.

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

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

The reaction is usually carried out at room temperature ˜200 ° C., preferably at room temperature ˜150 ° C. for 10 minutes-5 hours.

Compound (21) is used at least 1 mole, 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.

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

The reaction of the compounds (22) and (23) can be carried out under the reaction conditions usually 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 alkylhalocarboxylate to obtain a mixed acid anhydride and then resulting anhydride and azide (23). Process comprising: (b) active ester process: converting carboxylic acid (22) into active ester such as p-nitrophenylester, N-hydroxysuccinamide ester or 1-hydroxybenzotriazole ester and resulting (C) carbodiimide process: carboxylic (22) and azide under an activation reagent such as dicyclohexylcarbodiimide, carbonyldiimidazole, etc. And (d) converting the carboxylic acid (22) to the carboxylic anhydride using a dehydrating agent, such as acetic anhydride, as a further procedure. And then reacting the resulting anhydride with azide 23: a process comprising reacting an ester of carboxylic acid 22 and a lower alcohol with azide 23 under high temperature and high pressure: or The process of reacting the azide 23 with the halogen acid (that is, axyl halide) of the carboxylic acid 22 is mentioned.

Mixed acid anhydrides are obtained by traditional Shotton-Bieumann reactions, and the resulting anhydrides can be reacted with azide 23 to obtain compound 24, usually without being separated from the reaction mixture.

The Shotton-Bieumann reaction is carried out in the presence of a base compound commonly used in the abovementioned reactions.

Base compounds are for example organic bases (e.g. triethylamine, trimethylamine, pyridine, dimethylaniline and N-methylmorpholine, 1.5-diazabicyclo [4,3,0] nonene-5 (DBO), 1, 3-diazabicyclo [5,4,0] undecene-7 (DBU), 1,4-diazabicyclo (2,2,2) octane (DABCO) and inorganic bases (e.g. potassium carbonate, sodium carbonate, carbonic acid) Potassium hydrogen, sodium bicarbonate, and the like).

The reaction is usually carried out at -20 to 100 DEG C, preferably at 0 to 50 DEG C for 5 minutes-10 hours, preferably 5 minutes-2 hours.

The resulting reaction of the mixed acid anhydride and azide 23 is usually carried out at -20 to 150 ° C, preferably 0 to 50 ° C, for 5 minutes-10 hours, preferably 5 minutes-15 hours. The mixed acid anhydride process is usually carried out in the solvents commonly used in the above process.

The solvent may be water, halogenated hydrocarbons (e.g. dichloromethane, chloroform, dichloroethane, etc.), aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), ethers (e.g. diethyl ether, tetrahydrofuran, etc.) ketones (e.g. Acetone, etc.) 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, ethylchloromate, ethylbromoformate, ethylchloroformate and the like.

The azide 23 is usually used at least 1 mole, preferably 1-1.5 moles, per 1 mole of the 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 methylate and sodium ethylate, and in addition to the Schatten-Baumann reaction. Base compounds used are included.

The solvent can be, for example, alcohols (e.g., methanol, ethanol, propanol, butanol, 3-methoxy-butanol, ethyl cellosolve, methyl cellosolve, etc.), pyridine, acetone, acetonitrile, mixed acid anhydride processes Solvents 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, preferably 1 to 5 moles, is preferably used for one mole of the azide 23.

The reaction is usually carried out for 5 minutes to 30 hours at -30 to 180 캜, preferably 0 to 180 캜.

The compound (24) thus made is used in the next reaction without being separated from the reaction mixture.

The reaction of the compounds (24) and (25) is carried out in the presence or absence of a suitable solvent for 1-15 hours at 0 ~ 150 ℃, preferably at room temperature ~ 100 ℃.

Compound (25) is usually 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 the same as that used in the reaction for removing phenyl (lower) alkyl group or phenyl (lower) alkoxycarbonyl group on the heterocyclic attached to compound (1) above. Can be performed in

The reaction of direct conversion from compound (22) to compound (27) is generally considered to be a chute 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) chlorite, aluminum chlorite, stanic chloride, sulfoacetic acid , Phosphoric acid and the like.

Solvents include such as aromatic hydrocarbons (eg benzene, toluene, xylene, etc.) halogenated hydrocarbons (eg chloroform, dichloromethane, carbon tetrachloride, etc.). The reaction is usually carried out for 30 minutes to 10 hours at 0 to 150 캜, preferably 0 to 100 캜.

At least 1 mole of compound (23a) is preferably used, preferably 1-2 moles per 1 mole of compound (22).

이고, R¹,R³,Z,W,X및 n은 위에서 정의한 바와 같다.Wherein R ²³ is phenyl, lower alkyl or hydrogen, X ⁸ is halogenated, one of Z '''orW''' is -CH _2-

And R ¹ , R ³ , Z, W, X and n 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 the above reaction scheme -II.

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

(a) phenyl (lower) alkyl, which may be substituted by (lower) alkoxy, nitro or amino, (b) halogen atoms of 1-7, (lower) alkenyl carbonyl which may be substituted ( Lower) alkanoyl, wherein (lower) alkenylcarbonyl has 1-3 substituents selected from the group consisting of halogen atoms and carboxy. (c) (lower) alkoxycarbonyl: (d) aminocarbonyl which may be substituted by (lower) alkyl, (e) phenyl (lower) alkoxy carbonyl: (f) phenyl (lower) alkoxy carbonyl Amino (lower) alkanoyl which may be substituted by: (g) phthalide: (h) 2 (5H) -furanone which may be substituted by a halogen atom of 1-2: or (i) phenyl or (lower) Compound (1) in which 2-oxo-1,3-daxoeneethyl heterocyclic ring, which may be substituted by alkyl, is substituted by (a) or (e) may be substituted with the former compound by water, lower alcohol (e.g., 30 minutes-10 hours under a catalytic reduction catalyst such as palladium carbon, palladium black, etc. in a suitable solvent such as methanol, ethanol, isopropanol), ether (e.g. dioxane, tetrahydrofuran, etc.) acetic acid or mixtures of the above. During this time, inorganic acids such as hydrochloric acid can be added to the reaction mixture) or by treatment at a temperature of 0 to 100 ° C. Or phenyl (lower) alkoxy can in aqueous hydrobromic acid solution in order to remove the carbonyl can be converted to the compound (Ⅰ) unsubstituted heterocyclic ring click as by heating the compound.

Compound (1) in which at least one heterocyclic ring is substituted by (b)-(i) substituents hydrolyzes the electronic compound under the same reaction conditions as those used in the hydrolysis of compound (10) above. By means of which heterocycling can be converted in undisubstituted compound (1).

기에 의해 치환되는 화합물(Ⅰ)로 전환될 수 있다.Compound (I) in which the heterocyclic ring is substituted by amino is obtained by using the same reaction conditions as those used for the reaction of fluoride (IC) and (28) in the reaction scheme VII above.

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

기에 의해And heterocycling

By flag

Substituted compound (I) can also be converted to compound (1) in which heterocycling is substituted by amino by hydrolyzing the compound under the same reaction conditions used in the hydrolysis of compound (10) above. .

Wherein R ¹ , R ² , R ⁹ and X are as defined above and R ³¹ is an R ¹⁹ -CHSR ²⁰ group (where R ¹⁹ and R ²⁰ are as defined above) or R ³ (where R ³ is as defined above) And R ¹⁴ , R ²⁵ , R ²⁶ , R ²⁷ and R ²⁸ are alkyl and X ⁹ is a hydrogen atom.

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

The reaction of compound (29) with (30a) or (30b) is carried out with or without solvent and more preferably in the absence of 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 at least 1 mole, preferably 1-1.5 moles are used per mole of compound (29).

The reaction is usually carried out for 30 minutes-25 hours at room temperature ~ 200 ℃, preferably 60 ~ 200 ℃.

Solidification of the compound (31) or (32) can be carried out using a heating method, such as a method using an acidic compound (e.g., phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, thionyl chloride, concentrated sulfuric acid, polyphosphoric acid, etc.). Several known methods are performed.

When using the heating method, the process is characterized by high boiling solvents such as hydrocarbons with high boiling points or high boiling ethers (e.g. tetralin, diphenyl ether, diethylglyce nymethyl ether, etc.). At 100 ° C to 250 ° C, preferably at 150 ° C to 200 ° C.

When using the acidic compound method, the acidic compound is the same amount-a very large amount, more preferably, 10-20 moles are usually used for 1 mole of the compound (31) or (32), and the reaction is carried out at room temperature ~ 150 for 10 minutes -6 hours. It is generally carried out at or without the appropriate solvent.

Solvents include acid anhydrides (e.g. acetic anhydride, etc.) in addition to the solvents used in the solidification of compound (9) above.

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

기인 화합물(1J)은 위의 반응 모식도 -Ⅴ에서 화합물(19)로 전환된 반응에서 사용되어진 반응조건과 같은 조건하에서 상기 화합물을 처리함에 의해서 R^3'가 -CH₂R¹⁹인 상응하는 화합물로 전환될 수 있다.R ^{3 '}

Compound (1J) attributable to the corresponding compound in which R ^{3 ′} is —CH ₂ R ¹⁹ by treating the compound under the same conditions as used in the reaction converted to compound (19) in the above reaction schematic-V. Can be switched.

The reaction scheme on compound (1j) wherein R ^{2 ′} is a 5-9 membered saturated or unsaturated heterocycling having (lower) alkoxycarbonyl at a secondary nitrogen atom is the same as that used for the hydrolysis of compound (10) in I. By treating the electronic compound under conditions, R ^{2 ′} can be converted to the corresponding compound which is a 5-9 membered saturated or unsaturated heterocyclic ring having no substituents on the secondary nitrogen atom.

The compound (29) used as a starting material in the reaction scheme -X above can be made, for example, by the process shown in the following reaction scheme XIII-XII.

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

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

Wherein R ¹ , R ²¹ , R ¹³ , R ²⁰ , X and X ⁶ are as defined above and R ²⁹ is (lower) 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 the desulfurization of the mixture (18).

The reaction for converting compound (33) to compound (34) includes (lower) alkanoic acid, (e.g. formic acid, propion, etc.), (lower) alkanoic anhydride (e.g. acetic anhydride, etc.), (lower) eggs. It is carried out in the presence of (lower) alkanoylating reagents such as canoic acid halides (e.g. acetyl chloride, propionyl bromide and the like).

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

Base compounds include, for example, alkali metals (e.g., metal sodium, metal potassium, etc.), hydroxides, carbonates or their hydrogen carbonates, free bases (e.g., pyridine, pyreridine, etc.).

The reaction can be carried out with or without solvents but is usually carried out in the presence of a suitable solvent.

The solvent may be, for example, ketones (e.g. acetone, methyl ethyl ketone, etc.), ethers (e.g. dimethyl ether, dioxane, etc.), aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.) acetic acid, acetic anhydride, water, pyridine, etc. It includes.

As the (lower) alkanoylating reagent, at least 1 mole is used per 1 mole of compound (33), but usually the same amount or excess is used.

The reaction is usually carried out for 5 minutes -10 hours at 0-150 ° C, preferably 0-100 ° C.

Dehydrating agents are well used when (lower) alkanoic acid is used as the (lower) alkanoylating reagent.

Dehydrating agents include those such as inorganic acids (eg sulfuric acid, hydrochloric acid) and sulfonic acids (eg p-toluenesulfonic acid, benzenesulfonic acid, ethanesulfonic acid, etc.).

The reaction is well carried out at a temperature of 50 ℃ to 120 ℃.

The nitric acid treatment of compounds (33) or (34) may be carried out by the aforementioned compounds and 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, nitric anhydride and Organic acids (e.g., acetyl nitric acid, benzoyl nitric acid, etc.) can be treated with a solvent such as acetic acid, acetic anhydride or sulfuric acid by treating such as nitric acid, nitric acid + nitric acid or nitric acid of acetone cyanohydrin. It is performed without.

Nitrification reagents are best used in amounts of 1-1.5 moles per 1 mole of compound (33) or (34).

The reaction is usually carried out at a temperature of −10 to 70 ° C. for 1-24 hours.

Hydrolysis of the compound (35) is carried out under the same conditions as the reaction conditions used in the hydrolysis of the compound (10) above.

The reaction of the compound (37a) or (38) with the compound (8) is carried out under the same conditions as the reaction conditions used in the reaction of the compounds (1b) and (11) in the reaction 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) uses sodium nitrate and acid (e.g. sulfuric acid, hydrochloric acid, hydrobromic acid, bronfluoride, etc.) in solvents such as (lower) alkanoic acid (e.g. The compounds are converted to their diazonium salts and then the diazonium salts are converted into copper powder or copper halides (e.g. bromination (1) copper, chlorides (1) in the presence of halogenated acids (e.g. hydrobromic acid, hydrochloric acid, etc.). Copper, copper chloride (II), or the like, or with potassium iodide with or without copper powder, or better with copper halide in the presence of hydrochloric acid. Sodium nitrate is usually 1-2 mol, preferably 1-1.5 mol is used per 1 mol of compound (36), and copper halide is 1-5 mol, preferably 1-4 mol is used per 1 mol of compound (36). do. The reaction is usually carried out for 10 minutes-5 hours at -20 to 100 ° C, preferably at -5 to 100 ° C. The halogen atoms of X ⁹ of compound 37a can each be converted.

Where 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.

Wherein R ¹ , R ²¹ , X and X ⁷ are as defined above, A is (lower) alkylene, m is 0 or 1 and X ¹⁰ is phenylsulfonyl which may be substituted by halogen or lower alkyl Oxy, R ³⁰ is (lower) alkyl, R ³¹ is (lower) alkanoyloxy, R ³² and R ³³ are the same or different, each represents hydrogen or (lower) alkyl, and R ³⁴ is (lower) alkyl , R ³⁵ is hydrogen or nitro group.

The nitric acid treatment of the compound (44) in the above reaction scheme -XII can be carried out under the same conditions as the reaction conditions used in the nitric acid treatment of the compound (34) in the above reaction scheme -XIII. The reaction of compound (44) or (45) is usually 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 mol is normally used with respect to 1 mol.

Reduction reactions are suitable solvents such as water (lower) alcohols (e.g. methanol, ethanol, isopropanol, etc.) ethers (e.g. tetrahydrofuran, diethyl ether, diglyme, etc.) and solvents such as DMSO. Preferably it is usually carried out at -30 ~ 50 ℃ for 10 minutes-15 hours. In the case of using lithium aluminum hydride borane as the reducing reagent, an anhydride solvent such as diethyl ether, tetrahydrofuran or diglyme is used.

By halogenation of compound (46) the conversion to compound (47), wherein X ¹⁰ is a halogen atom, is carried out under any reaction conditions used in the halogenation of hydroxy groups, for example compound (46) with a halogen reagent with or without a suitable solvent. It may also be carried out by reaction. Halogenated reagents include, for example, hydrochloric acid (e.g. hydrochloric acid, hydrobromic acid, etc.) N, N-dimethyl-1,2,2-trichlorovinylamide, phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride, thi Onyl chloride, diethylaminosulfotrifluoride (DAST) and the like. Inert solvents include, for example, ether (eg dioxane, tetrahydrofuran, etc.) halogenated hydrocarbons (eg chloroform, dichloromethane, carbon tetrachloride, etc.). Halogen reagent is used at least 1 mole per 1 mole of compound (46), usually the same amount-excess is used and the reaction usually occurs for 10 minutes-15 hours at 0 ~ 150 ℃, preferably 0 ~ 80 ℃.

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 lower alkyl substituent on the phenyl ring, the compound may be converted to compound (47), wherein X ¹⁰ is phenylsulfonoxyoxy 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 changed can be carried out under the same reaction conditions used in the reaction of compounds (1b) and (11) in the above reaction scheme -II.

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.

In the above reaction scheme -XIII, the conversion of compound (46) to compound (49) can be carried out by various methods.

Iii) Compound (46) with compound in a suitable solvent in the presence of a base compound: R ³⁴ X ¹¹ wherein R ³⁴ is (lower) alkyl and X ¹¹ is halogen winza)

ii) the above reaction method by reaction of compound (46) with a (lower) alcohol (i.e. straight or branched chain C ₁ -C ₆ alcohol such as methanol, ethanol, isopropanol, butanol, etc.) in the presence of an acid. The solvent used in (i) may be, for example, an ether (e.g. diethyl ether, dioxane, tetrahydrofuran, monoglyme, diclime, etc.) alcohol (e.g. methanol, ethanol, isopropanol, etc.) aromatic hydrocarbon (e.g. Aliphatic hydrocarbons (e.g., n-hexane, heptane, cyclohexane, ligroin, etc.), amines (e.g. pyridine, N, N-dimethylaniline, etc.) halogenated hydrocarbons (e.g., chloroform, dichloro Methane, carbon tetrachloride, etc.), aprotic polar solvents (e.g. DMF.DMSO.HMPA) and mixtures of the above.

Base compounds are inorganic bases (e.g., metal sodium, potassium, metal magnesium, sodium hydride, amide sodium, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, etc.) organic bases (e.g. pyridine, parperidine, Quinoline, triethylamine, NN-dimethylaniline, etc.) etc. are included.

The reaction is usually carried out for 10 minutes-5 hours at 0 ~ 120 ℃ preferably room temperature ~ 100 ℃. Compound: R ³⁴ X ¹¹ is at least 1 mole, preferably 1-3 moles, per 1 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 usually carried out at room temperature ˜150 ° C., preferably at 50-120 ° C., for 1 hour-50 hours.

(Lower) alcohols are usually used in excess.

Acceleration of compound (46) can be carried out under the same conditions as the reaction conditions used for the conversion of compound (33) to (34) in the reaction scheme -VII above.

Both the reaction of compound (46) (49) (50) or (47) with compound (52) and the reaction of compound (47) with compound (54) may be carried out in the presence of a basic compound with or without a suitable solvent. . 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 Reaction Scheme I above. In the reaction of compounds (46) (49) (50) or (47) with compound (52), compound (52) can be used in a very large amount functionally as a base compound.

Compounds (52) and (54) may be used in at least one mole, preferably in excess, relative to one mole of starting material, in particular compounds (46) (49) (50) or (47).

The reaction is carried out for 3-15 hours at 0 ~ 150 ℃ preferably room temperature ~ 100 ℃. 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.

In the above compounds (3) (5) (7) (9) (10) (1a) (1b) (1b ') (29) (31) and (32), R ³ is substituted by hydroxy (lower) A compound which is alkyl is heterocyclic, (lower) alkylthio, (lower) alkanoyloxy consisting of a 5-6 membered ring in which R ³ is saturated by reacting the above compound under the same conditions as mentioned above. , Amino, (lower) alkylamino, (lower) alkoxy, and (lower) alkyl substituted by 1-3 substituents selected from the group consisting of halogen atoms. In the above compounds (3) (5) (7) (9) (10) (1a) (1b) (1b ') (29) (31) and (32), R ³ is selected from (lower) alkanoyloxy. Substituted (lower) alkyl compounds can be converted to compounds wherein R ³ is alkyl having a hydroxy group by hydrolyzing the electronic compound under the same reaction conditions as mentioned above.

Saturated or unsaturated, in which R ² has an oxo group in the above compounds (4) (5) (7) (9) (10) (1a) (1b) (1b ') (29) (31) and (32). the heterocyclic ring compounds of -9 source may Sikkim by reducing a compound of the R ² can be converted to a heterocyclic ring, a compound of a saturated or unsaturated 5-9-reduction that has a hydroxyl group.

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, and the like, at least 1 mole, preferably 1-5 moles, per mole of starting material to be reduced. Solvents include, for example, water (lower) alcohols (eg, methanol, ethanol, isopropanol, etc.) ethers (eg, tetrahydrofuran, diethyl ether, diglyme, etc.). The reaction is usually carried out for 10 minutes-5 hours, preferably at -30 ° C to room temperature.

In the case of using lithium aluminum hydride or diborane as the reducing agent, when using anhydride solvents such as diethyl ether, tetrahydrofuran, diglyme, inorganic bases such as sodium hydride may also be added to the reaction mixture.

Compounds wherein R ² is a saturated or unsaturated 5-9 membered heterocyclic ring substituted by alkyl having at least one of (lower) alkanoyl or (lower) alkoxycarbonyl are R ² by hydrolysis of the electronic compound. Can be converted to a saturated or unsaturated 5-9 membered heterocyclic ring substituted by (lower) alkyl having at least one carboxyl group.

The hydrolysis can be carried out under the same conditions as the reaction conditions used in the hydrolysis of the compound (10) in the above scheme. Compounds wherein R ² is a saturated or unsaturated 5-9 membered 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- to 9-membered heterocycling substituted by at least one (lower) alkanoyl. .

Compounds (46) (47) and (48), wherein R ³⁵ is hydrogen, can be converted to the corresponding compounds where R ³⁵ is nitro by the same nitric acid reaction of compound (44).

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

Wherein R ²¹ , R ³⁵ , X, X ⁹ , M and m are as defined above, and A ¹ is a group (A ¹ ) mCH ₂ -and (A ¹ ) mCH ₂ CH ₂ -having 6 or more carbon atoms If not, lower alkylene, R ³⁶ is lower alkyl, and X ¹¹ is a halogen atom.

Reduction of compound (55) takes place under the same conditions as for 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 usually carried out in a suitable solvent in the presence of a base compound at atmospheric temperature -200 ° C, preferably 60 ° C-120 ° C for 1-24 hours. The solvent is, for example, ether (e.g. dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, diethyl ether, etc.) aromatic hydrocarbon (e.g. benzene, toluene, xylene, etc.) lower alcohol (e.g. methanol, ethanol, isopropanol) Polar solvents such as dimethylformamide, dimethyl sulfoxide, and the like.

Base compounds include, for example, inorganic bases (e.g. potassium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, sodium amide, sodium hydride, potassium hydride, sodium methylate, sodium ethylate, etc.) Triethylamine, tripropylamine, pyridine, quinoline, and the like.

The reaction proceeds well by using alkali metal iodide (eg potassium iodide, sodium iodide, etc.).

Compound (58) is usually used in the same amount or in excess, preferably 1-5 moles, more preferably 1-1.2 moles per 1 mole of compound (57).

The reaction with compounds (57) and (17) can be carried out under the same conditions as in the reaction of compounds (16) and (17). In addition, the hydrolysis of compound (50) or (60) can be carried out under the same conditions as in the hydrolysis of compound (20).

Compound (10) in Scheme I and compounds (1b) and (1b ') in Scheme II are not only useful as intermediates to make the compounds of the present invention with antimicrobial action, but also as antibacterial agents because they are also antibacterial agents. Because it has action.

The compounds of the present invention have optical isomers and stereoisomers and the present invention also includes these isomers.

Among the compounds (1) preferred are compounds in which R ¹ is unsubstituted cyclopropyl, X is a chlorine or fluorine atom (particularly a fluorine atom) and R ³ is methyl or ethyl (particularly methyl).

Compound (1) can be readily converted to their salts for treatment with pharmaceutically acceptable acids or bases.

Acids are inorganic acids (e.g. hydrochloric acid, sulfuric 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, propionic acid, etc.) It includes.

Bases include sodium hydroxide, potassium hydroxide, calcium 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 liquid chromatography.

Compounds of the present invention or salts thereof include Pseudomonas aeruginosa, anaerobic bacteria, cells resistant to various antimicrobial agents, clinically isolated bacteria, and Gram-negative and Gram-positive bacteria (e.g. It shows excellent antimicrobial activity against Callis, Stakilococos piogens, etc. and is therefore a good antimicrobial agent for the treatment of diseases caused by these microorganisms.

These compounds also have low toxicity and low side effects and are characterized by good absorbency and sustained effects. Moreover, since the compound is excreted a lot by urine and therefore is effective for the treatment of urinary tract diseases, and also the excretion by bile is easy, it is also effective for the treatment of enteropathy.

In addition, the compounds of this invention utilize them in the form of salts, such as lactate and hydrogen chloride, to show their constant absorption into the body.

Compounds of the present invention are commonly used in the form of pharmaceutical preparations.

Pharmaceutical preparations may be formulated in admixture such as carriers, conventionally acceptable diluents or carriers such as fillers, binders, wetting agents, disintegrants, surfactants, lubricants.

Pharmaceutical formulations include various formulations suitable for the treatment of diseases such as, for example, tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc.).

The preparation of tablets can be any common carrier, e.g. excipients (e.g. lactose, white sugar, salt, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicates, 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 Sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, lauryl sulfate sodium, stearic monoglyceride, starch, lactose, etc. Disintegration inhibitors (e.g. white sugar, stearin, cacao butter, hydrogenated oil) Absorption accelerators (e.g. quaternary ammonium salts, lauryl sulfate sodium, etc.) Wetting agents (e.g. glycerine, starch, etc.) Absorbents (e.g. starch, lactose, kaolin, bentonite, colloidal silly) It is purified talc, Stella rate, boric acid powder, polyethylene glycol, and the like) such as: byte, etc.) lubricants (e. Tablets may also be enveloped with traditional envelopes, such as sugar envelopes, gelatin envelopes, enteric envelopes, film envelopes, 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. Arabian rubber powder, tragacanth powder, gelatin, ethanol, etc.) Traditional carriers such as lamina and agar) may be used. In the preparation of suppositories, traditional carriers such as polyethylene glycol, cacao butter, higher alcohols, esters, gelatin, semisynthetic glycerides and the like may be used.

In the preparation of injections, solutions, emulsions or suspensions of compounds are sterile and well made isotonic with body fluids. These solutions, emulsions and suspensions are commonly diluted colors such as water soluble lactic acid solution, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated, isostearyl alcohol, polyoxyethylene sorbitan fatty ester, etc. By actively mixing with the compound.

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, moreover, colorants, preservatives, 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 glycol, silicone, bentonite, and the like as diluents.

The pharmaceutical preparation 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 injected or in the form of an injectable solution. Acids that do not include include, for example, lactic acid, methanesulfonic acid, propionic acid, hydrochloric acid, succinic acid, and the like, and the like, and the like.

When lactic acid is used, lactic acid is usually used at 0.1-10% by weight, preferably 0.5-2% by weight, based on the weight of the above injectable and injectable solutions.

In the case of using an acid other than lactic acid, the acid is usually used as 0.05-4% by weight, preferably 0.3-2% by weight, based on the above solution.

Furthermore, traditional additives can optionally be added to the above injectable or injectable solutions. Additives include, for example, film hardeners, absorption accelerators or blockers, solidifying deactivators, complex preparations. Antioxidants, drug isotonic drugs that create isotonicity, and the like. The pH of the solution is suitably adjusted by the addition of an alkali such as sodium hydroxide and is usually adjusted in the range of 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 in 1-70% by weight based on the total pharmaceutical weight. The pharmaceutical preparations of the 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, subcutaneously or intraperitoneally. Suppositories are injected rectally. The amount of the pharmaceutical preparation of the present invention depends on the method of administration, the age and sex of the patient, the severity of the star, etc., but is administered in the range of 0.2-100 mg of the salt of the active compound (1) or 2 per kg of body weight per day.

The preparation is usually administered 2-4 times a day.

The invention is illustrated by the following comparative examples, eg preparation and experiment.

Example

Comparative Example 1

To anhydrous dichloromethane (1.2 L) solution containing 2-bromo-4.5-difluoroaniline (100 g) and dimethyl sulfide (49 ml) is slowly added N-fluorosuccinimide (90 g) at 15 ° C or below. . Then triethylamine (ml) was added little by little at 15 ° C. After addition the mixture is refluxed for 7 hours. After cooling, 10% liquid sodium hydroxide (1 L) is added to the reaction mixture and the mixture is extracted with dichloromethane.

The extract was dried over magnesium sulfate, concentrated and the residue obtained was purified by silica gel column chromatography (eluent, dichloromethane: n-hexane = 1: 2). The product is recrystallized from n-hexane to give 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 resultant residue is purified by silica gel column chromatography (solvent, dichloromethane: n-hexane = 1: 1) and the product is a white amino acid with a melting point of 109-110 ° C. as 2-amino-4,5-difluoro-. Recrystallize from ethanol to yield 3-methylthiomethyl-benzonitrile (28 g).

Comparative Example 3

To a solution of 2-amino-4,5-difluoro-3-methylthiomethylbenzonitrile (4.0 g) in ethanol is added 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 ethyl acetate.

The extract is dried over magnesium sulfate and concentrated.

The product is recrystallized from n-hexane to give 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 ° C or below.

The mixture was heated at 70 ° C. for 10 minutes, then cooled and thereafter a solution of 2-amino-4,5-difluoro-3-methylbenzonitrile (12.3 g) contained in acetic acid (123 ml) was charged at 40 ° C. Add dropwise at.

The mixture is shaken at the same temperature for 30 minutes and 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 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-methylbenzo. Purify to obtain nitrile (8.0 g).

Comparative Example 5

60% sulfuric acid (20 ml) is added to 2-chloro-4,5-difluoro-3-methylbenzonitrile (4.0 g) 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. The precipitate was separated by filtration to add n-hexane to the rest and to give 2-chloro-4,5-difluoro-3-methylbenzoic acid (3.1 g) as white crystals with melting point 121-122 ° C.

Comparative Example 6

Thionylchloride (6 ml) was added to 2-chloro-4,5-difluoro-3-methylbenzoic acid (3.1 ml) and refluxed for 1 hour. The mixture is concentrated at low pressure to give 2-chloro-4,5-difluoro-3-methylbenzoylchloride (3.3 g).

In addition, the metalyl magnesium (0.38 g) is suspended in anhydrous ethanol (0.8 ml), and a few drops of carbon tetrachloride are added thereto. At 50-60 ° C., the mixture of diethylmalonate (2.3 ml), anhydrous ethanol (1.5 ml) and anhydrous toluene (6 ml) is mixed in portions at the beginning of the reaction. A solution of 2-chloro-4,5-difluoro-3-methylbenzoyl chloride (3.3 g) mentioned above in anhydrous toluene (5 ml) is added dropwise at 0 ° C to the mixture. After the addition, the mixture is stirred at room temperature for 30 minutes. Concentrated sulfuric acid (0.4 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 ethyl 2-chloro-3-methyl-4,5-difluorobenzoylmalonate (5.1 g).

Comparative Example 7

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

Comparative Example 8

Triethoxymethane (3.1 g) and acetic anhydride (3.4 g) are added to 2-chloro-4,5-difluoro-3-methylbenzoyl acetate (3.9 g) and the mixture is stirred at 150 ° C. for 1 hour. Heat. The mixture is concentrated to give 2- (2-chloro-3-methyl-4,5-difluorobenzoyl) -3-ethoxy acrylate.

Ethanol (50 ml) is added to this product, to which cyclopropylamine (1.1 ml) is added at room temperature and stirred for 30 minutes. Distilling off ethanol yields 2- (2-chloro-3-methyl-4,5-difluorobenzoyl) -3-cyclopropylaminoacrylate. Dioxane anhydride (30 ml) is mixed with this product and a small amount of 60% sodium hydroxide (0.6 g) is added thereto. The mixture is stirred at room temperature for 30 minutes and refluxed for 1 hour. The reaction mixture is poured into saturated aqueous ammonia chloride solution and extracted with dichloromethane. The extract was dried over magnesium sulfate, and concentrated to give 1-cyclopropyl-6,7-difluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl (2.2 g). Lose.

NMR (CDCl ₃ ) δ: 8.64 (1H.S), 8.10 (1H, t, J = 10Hz), 4.36 (2H, g, J = 7.5Hz), 3.75-4.10 (1H, m), 2.376 (3H, d, J = 45 Hz), 1.37 (3H, t, J = 7.5 Hz), 0.86-1.30 (4H, m)

Comparative Example 9

Concentrated hydrochloric acid (5 ml), water (2 ml) and acetic acid (20 ml) were mixed with 1-cyclopropyl-6,7-difluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ( 2.2 g) and reflux for 2 hours. After cooling, the precipitated crystals were filtered off and washed with water, ethanol and diethyl ether in order of 1-cyclopropyl-6,7-difluoro-8-methyl-1,4-dihydro-4-oxoquinoline 3-Carboxylic acid (1.8 g) is obtained as white crystals (mp240-243 占 폚).

Comparative Example 10

Triacetylboron [B (OCOCH ₃ ) ₃ ] (1.0 g) and acetic anhydride (10 ml) were mixed with 1-cyclopropyl-6,7-difluoro-8-methyl-1,4-dihydro-4-oxoquinoline. After addition to -3-carboxylic acid (1.0 g), the mixture was heated to 140 ° C. for 15 minutes, after which the mixture was concentrated, and diethyl ether was added thereto, and the crystals were filtered to classify 6,7-. Difluoro-1-cyclopropyl-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid-B (OCOCH ₃ ), chelate (1.2 g) is obtained.

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

A suitable amount of acetone is added to a material in which 2,2-dichloro-1-cyclopropylcarboxylic acid (4.0 g) is suspended in water (5 ml) to form a completely uniform 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) dissolved in acetone (15 ml) was added dropwise. After mixing in this manner, the mixture was stirred at 0 ° C. for 30 minutes, and then a drop of a solution of sodium azide (2.51 g) in water (10 ml) was dropped. The mixture is further stirred at 0 ° C. for one hour, after which the reaction mixture is poured into ice water and extracted with diethyl ether. The extract is dried over magnesium sulfate and concentrated. Benzyl alcohol (3.35 g) and anhydrous benzene (50 ml) were added to the resulting 2,2-dichloro-1-cyclopropylcarbonylazide and the mixture was refluxed with stirring for 10 hours.

After the reaction was completed, the reaction mixture was concentrated, and the residue was purified by Gilica gel column chromatography (solvent: ethyl acetate: n-hexane = 1: 30) and then recrystallized from difluoromethane to give 2,2-dichloro-1-. Benzyloxycarbonylaminocyclopropane (2.8 g) is obtained. It is colorless needle and has 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 trans isomers)

NMR (CDCl ₃ ) δ: 1.10-1.32 (2H, m), 2.76-3.10 (2H, m), 4.73-5.3 (1H, m), 5.11 (2H, s), 7.35 (5Hs)

2-fluoro-1-benzyloxycarbonylaminocyclopropane (mixture of cis and trans isomers)

NMR (CDCl ₃ , 60MHz) 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-benzyloxycarbonylaminocyclopropane (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 completion of the reaction, the catalyst was filtered off and the filtrate was concentrated. The residue thus obtained is recrystallized from ethanol-diethyl ether to give 2,2-dichloro-1-aminocyclopropane hydrogen chloride (0.7 g) in the form of a white powder.

It has an m.p. of 147-148 ° C. (decomposition).

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

2-chloro-1-aminocyclopropane hydrochloride (mixture of cis and trans isomers)

NMR (DMSO-d ₂ ) 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 seeds and trans isomers)

NMR (DMSO-d 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 ethanol (10 ml), 2- (2,4,5-trifluorobenzoyl) -3-ethoxy acrylate (1.78 g) and triethylamine (0.60 g) are dissolved in ethanol (10 ml). -Drop the solution containing fluoro-1-cyclopropylamine hydrochloride (0.60 g) drop by drop. After addition, the mixture was stirred for 1 hour at room temperature and then concentrated to give ethyl 2- (2,4,5-trifluorobenzoyl) -3- (2-fluoro-1-cycloproproyl) aminoacrylate. Dioxene (30 ml) and 60% sodium hydroxide (0.3 g) are added to the resulting product, and the mixture is stirred at room temperature for one hour. The reaction mixture is concentrated and water is added to the residue obtained, followed by extraction with dichloromethane. The extract is washed with water and dried to allow the solvent to evaporate, then ethyl 1- (2-fluoro-1-cyclopropyl) -6,7-difluoro-1,4-dihydro-4-oxoquinoline-3- Carboxylate (a mixture of cis and trans isomers) is obtained (1.02 g).

Using the appropriate starting materials, the following materials were obtained in the same manner as in Comparative Example 13.

1- (2-Chloro-1-cyclopropyl) -6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-ethyl carboxylate (mixture of cis and trans isomers)

1- (2-chloro-1-cyclopropyl) -6,7-difluoro1,4-dihydro-4-oxoquinoline-3-ethyl carboxylate (mixture of cis and trans isomers)

90% acetic acid-exclusive hydrochloric acid in 1- (2-fluoro-1-cyclopropyl) -6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-ethyl carboxylate (1.02 g) 4: 1) 20 ml are mixed and the mixture is refluxed with stirring for 1 hour. After concentration, water is added to this residue. Precipitated crystals were filtered off, washed with ethanol ingot diethyl ether and dried to give 1- (2-fluoro-1-cyclopropyl) -6,7-difluoro-1,4-dihydro-4- Oxoquinoline-3-carboxylic acid (mixture of cis and trans isomers) (0.58 g) is obtained.

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 cis and trans isomers)

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

Comparative Example 15

7- (4-Methyl-1-cyclopropyl-6-fluoro-8-methylthiomethyl-1,4-dihydro-4-oxoquinoline-3-ethyl carboxylate (8.09 g) is dissolved in ethanol (80 ml) To the solution was added Raney Nickel (40 ml) together with ethanol (80 ml), and the mixture was stirred for 30 minutes at 40-50 ° C. and filtered, water was added to the filtrate and extracted with ethyl acetate. The material was dried over magnesium sulfate and concentrated to give 7- (4-methyl-1-piperazinyl) -1-cyclopropyl-6-fluoro-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid Ethyl (2.5 g) is obtained.

Comparative Example 16

Raney nickel (70 ml) is suspended in an ethanol (120 ml) solution containing 6-bromo-3,4-difluoro-2-methylthiomethylaniline (6.00 g) and the mixture is stirred at 50 ° C. for 30 minutes. After Raney nickel was removed by filtration, the filtrate was concentrated to give 3,4-difluoro-2-methyl-aniline (3.77 g) in the form of colorless oil.

Comparative Example 17

Acetic anhydride (50 ml) is added to 3,4-difluoro-2-methylaniline (3.27 g), and the mixture is stirred for 10 minutes. After evaporating acetic anhydride, the residue is extracted with dichloromethane. The extract is washed with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. After evaporation of dichloromethane, the residue was 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) was added to ice-cold concentrated sulfuric acid (0.3 ml), to which concentrated concentrated nitric acid (0.1 ml) was added, and at room temperature for 2 hours. Stir. Then further concentrated nitric acid (0.1 ml) is added and stirred overnight at room temperature. A large amount of water is added to the reaction mixture and extracted with dichloromethane. The extract is washed with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. After dichloromethane was distilled off, the residue was recrystallized from ethyl 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 at 100 ° C. for one day and concentrated. The residue is neutralized with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The extract is washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. When dichloromethane is evaporated off, m.p of 4,5-difluoro-6-methyl-2-nitroaniline (59 mg) obtained as an orange prism is 87.2-88.0 ° C.

Comparative Example 20

Sodium nitrite (30 mg) was added in portions to concentrated hydrochloric acid (0.32 ml), the mixture was stirred at 70 ° C. for 10 minutes, cooled to room temperature and then diluted with 4,5-difluoro-acetic acid (6.5 ml). A solution of 6-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 sulfuric acid (1.0 ml). The mixture is stirred at 80 ° C. for 30 minutes. To this mixture is added water and extracted with ethyl acetate. The extract is washed with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. When ethyl acetate is distilled off, 2-chloro-5,6-difluoro-3-nittoluene (54 mg) is obtained.

Comparative Example 21

To 2-chloro-5,6-difluoro-3-nitrotoluene (54 mg), ethanol (0,3 ml) and water (0,03 ml) were added at 0 ° C, where N was added to ethanol (0,1 ml). Add an aqueous solution of methyl-piperazine (0.04 ml) and triethylamine (0.06 ml) 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 saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The extract was washed with water and saturated aqueous sodium chloride solution and dichloromethane was removed in the middle to remove 2-chloro-5-fluoro-6- (4-methyl-1-piperazinyl) -3-nitrotoluene (35 mg). Is obtained.

22 on comparison

Potassium fluoride (110 ml) in an aqueous solution of 2-chloro-5-fluoro-6- (4-methyl-1-piperazinyl) -3-nitrotoluene (17 ml) dissolved in dimethyl sulfoxide (1.5 ml). Cyclopropylamine (1.0 ml) is added and stirred at 100 ° C. for 13 hours. The reaction mixture is diluted with dichloromethane, washed with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Dichloromethane is then distilled off. The product was purified by preparative thin layer chromatography (eluent: 1:20 mixture of methineol-dichloromethane), resulting in N-cyclopropyl-4-fluoro-2-methyl) -3- (4-methyl-1 -Piperazinyl) -6-nitrotoluene (11 mg) is obtained.

23 in comparison

To a solution of 3,4-difluoroacetanilide (85.5 g) dissolved in sulfuric acid (850 ml), slowly adding potassium nitrate (55.5 g) while stirring at room temperature, the temperature is raised to 60 ° C. After stirring at 60 ° C. for 1 hour, it was poured into ice water and the precipitated crystals were filtered out. The precipitated crystals are dissolved in dichloromethane, washed with aqueous sodium bicarbonate and saturated aqueous sodium chloride solution and dried. The solvent is distilled off when concentrated and washed with n-nucleic acid. The obtained crystals are filtered and dried to yield 2-nitro-4,5-difluoroaniline (54 g).

Comparative Example 24

N-chlorosuccinimide (3.82 g) is slowly added to an aqueous solution of 2-nitro-4,5-difluoroaniline (1.0 g) dissolved in dichloromethane (40 ml) with stirring at 15 ° C or below. It is stirred for 30 minutes, triethylamine (2.98 g) is added and refluxed for 21 hours. After cooling, the reaction mixture is washed and dried in the order of 10% aqueous sodium hydroxide solution and aqueous sodium chloride solution. The solvent was removed by concentration. The residue was purified by silica gel column chromatography (eluent, n-nucleic acid: ethyl acetate = 30: 1), and then recrystallized with n-hexane to give 2-nitro-4,5-difluoro. -5,6-methylthiomethylaniline (0.47 g) is obtained in the yellow form.

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 is stirred for 45 minutes at the same temperature, and then dropwise addition of an aqueous solution of copper chloride (0.52 g) dissolved in concentrated hydrochloric acid (5.2 ml). It is stirred at 80 ° C. for 1.5 hours, poured into ice water and extracted with ethyl acetate. The extracts are washed with water and saturated aqueous 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), and then 2-chloro-3-methylthio-4.5-difluoro-1-nitrobenzene (0.16 g) was used. Get

Comparative Example 26

2,3,6-trifluorobenzoic 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 DEG C 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. The extract is dried over magnesium sulfate and the solvent is blown off. The residue was recrystallized from dichlorometal-n-hexane to give 2,5,6-trifluoro-3-nitrobenzoic acid (22 g) in m.p. Obtained in the form of a colorless prism of 98-99 ° C.

Comparative Example 27

To an aqueous solution of sodium borate (44 g) dissolved in tetrahydrofuran anhydride, an aqueous solution of tetrahydrofuran anhydrous (40 ml) dissolved in 2,5,6-trifluoro-3-nitrobenzoic acid (22 g) is added at 10 占 폚 or lower. .

An aqueous solution of borontrofluoride ethylate (20 ml) dissolved 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 was dried and the solvent was distilled off to give 2,5,6-trifluoro-3-nitrobenzyl anticol (14 g).

Comparative Example 28

4-Ethoxycarbonylpiperazine (11 g) and triethylamine (12.5) in a solution of 2,5,6-trifluoro-3-nitrobenzyl alcohol (14 g) dissolved in ethanol (64 ml) and water (7 ml). 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. Recrystallized from ethanol to give 3,6-difluoro-2- (4-ethoxycarbonyl-1-piperazinyl) -5-nitrobenzyl alcohol (8,7 g) and m.p. Obtained in the form of a yellow needle at 147-149 ° C.

Comparative Example 29

Thionyl chloride (2,7 ml) in a solution of 2,6-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 to remove 2- (4-ethoxycarbonyl-1-piperazinyl) -3,6-difluoro-5-nitrobenzylchloride (8.1 g). Obtained.

Comparative Example 30

Sodium borate (1.8 g) in an aqueous solution of 3,6-difluoro-2- (4-ethoxycarbonyl-1-piperazinyl) -5-nitrobenzylchloride (8.1 g) in dimethyl sulfoxide (90 ml). ) Is added slowly below 30 ° C. It is stirred for one hour at the same temperature, the reaction mixture is poured into iced water, oxidized with concentrated hydrochloric acid and extracted with diethyl ether.

The solvent is distilled off to give 2- (4-ethoxacarbonyl-1-piperazinyl) -3,6-difluoro-5-nitrotoluene (7.1 g).

Comparative Example 31

To 3,6-difluoro-2- (4-ethoxycarbonyl-1-piperazinyl) -5-nitrotoluene (7.1 g) anhydrous dimethyl sulfoxide (23 ml) and potassium fluoride (2.0 g) And cyclopropylamine (1.5 g) were added, then the mixture was 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 N-cyclopropyl-2-methyl-3- (4-ethoxycarbonyl-1-piperazinyl) -4-fluoro-6-nitroaniline (7.4 g) is obtained in the form of an orange-red prism with mp of 97-98 ° C.

Comparative Example 32

Diethylethoxymethylenemalonate (4.6 g) in N-cyclopropyl-2-methyl-3- (4-ethoxycarbonyl-1-piperazinyl) -4-fluoro-6-nitroaniline (7.1 g) ) Is added and it is reacted at 150-170 ° 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 [N-cyclopropyl-N- [3- (4- Oxycarbonyl-1-piperazinyl) -2-methyl-4-fluoro-6-nitrophenyl] aminomethylene] diethyl malonate (5.4 g) is obtained.

Comparative Example 33

Acetic anhydride (50 ml) [N-cyclo-N- [3- (4-ethoxycarbonyl-1-piperazinyl) -2-methyl-4-fluoro-6-nitrophenyl] aminomethylene] malonic acid Ethyl (1.0 g) is added to the dissolved solution, maintaining concentrated sulfuric acid (2 ml) at 50-70 ° C.

After stirring for 30 minutes, the reaction mass is poured into iced water and neutralized with potassium carbonate. This was extracted with ethyl acetate, the solvent was blown off in midstream, and the residue was purified by silica gel column chromatography (eluent, dichloromethane: methane = 10: 1), and then recrystallized from ethyl acetate to yield 1-cyclopropyl. -7- (4-ethoxycarbonyl-1-piperazinyl) -6-fluoro-8-methyri-1,4-dihydro-4-oxoquinoline-3-ethyl carboxylate (0.19 g) is colorless It is obtained with the prism of mp200-202 ° C. Using the appropriate starting material in the same manner as in Comparative Example 33, the same material as in Comparative Examples 8, 15 and 13 was frozen.

Comparative Example 34

In the same manner as in Comparative Example 28, using a suitable starting material, the following mixture is obtained. 3,6-difluoro-2- (4-benzyl-3-piperazinyl) -5-nitrobenzyl alcohol

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-piperazinyl) -3,6-difluoro-5-nitrobenzylchloride

Comparative Example 36

Using the appropriate starting material in the same manner as in Comparative Example 30 to obtain the following compound. 2- (4-benzyl-3-methyl-1-piperazinyl) -3,6-difluoro-5-nitrotoluene

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-piperazinyl) -4-fluoro-6-nitroaniline

Comparative Example 38

In the same manner as in Comparative Examples 32 and 33, the following compounds were obtained using suitable starting materials. m.p. Obtained as a white powder (recrystallized from ethyl acetate) which is 172-173 degreeC.

Comparative Example 39

Using the appropriate starting material in the same manner as in Comparative Example 28 to obtain the following compound. 3,6-difluuro-2- (3-amino-1-pyrrolidinyl) -5-nitrobenzyl alcohol mp 117-118.5 ° C. in an orange prism phase (recrystallized from ethyl acetate-n-hexane) Obtained.

Comparative Example 40

To 3,6-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, diluted with water with this reaction and extracted with dichloromethane. The organic layer is washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off. The obtained residue was purified by passing through silica gel column chromatography (eluent, dichloromethane → methanol: dichloromethane = 1: 12) to give 2- (3-acetylamino-1-pyrrolidinyl) -3.6-difluoro-5 Nitrobenzyl alcohol (40 mg) is obtained as a yellow prism at mp142.5-143.5 ° 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) -3.6-difluoro-5-nitrobenzylchloride

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) -3.6-difluoro-5-nitrotoluene m.p.139-140.3 ° C. yellow needles (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.

N-cyclopropyl-methyl-3- (3-acetylamino-1-pyrrolidinyl) -4-fluoro-6-nitroaniline, mp162.5-164 [deg.] C., orange prismatic form (ethyl acetate-n-hexane Determined).

Comparative Example 44

Using the appropriate starting materials in the same way as in 32, the following materials are obtained.

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

Comparative Example 45

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

1-cyclopropyl-7- (3-acetylamino-1-pyrrolidinyl) -6-fluoro-8-methyl-1,4-dihydrodi-4-oxoquinoline-3-ethyl carboxylate, m.p. 215.5-217.0 ° C. White powder (recrystallized from ethanol-ethyl acetate-diethyl ether)

Comparative Example 46

3,6-difluoro-2- (4-ethoxycarbonyl-1-piperazinyl) -5-nitrobenzyl alcohol (1.5 g) is dissolved in dichloromethane (18 ml), and dichloromethane (3 ml) Into a solution of diethylaminosulfolifluoride (DAST) (0,7ml) and triethylamine (0.78ml) was added dropwise into a bucket of ice at 0 ° C. for 5 minutes and mixed with stirring. The mixture is stirred at 0 ° C. for 1,2 hours, to which further DAST (0.3 ml) is added. After 5 minutes, the reaction mixture is poured into ice water and the organic layer is separated.

After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent, ethyl acetate: n-hexane = 1: 10 → 1: 5V / V) to yield 2,5-difluoro-3-fluoro. Romethyl-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 acetic anhydride (2 ml) is added thereto. Add 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 saturated aqueous sodium bicarbonate solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to yield 3-acetoxymethyl-2,5-difluoro-4- (4-ethoxycarbonyl-1-piperazinyl) -4-nitrobenzene (1.2 g).

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

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

Comparative Example 49

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

[N-cyclopropyl-N- [3- (4-ethoxycarbonyl-1-piperazinyl) -2-acetmethyl-4-fluoro-6-nitrophenyl] aminomethylene] dimalonic acid diethyl

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

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

Comparative Example 50

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

1-cyclopropyl-7- (4-ethoxycarbonyl-1-piperazinyl) -6-fluoro-8-acetoxymethyl-1,4-dihydro-4-oxoquinoline-3-ethyl carboxylate, Yellow powder, mp 172-173 ° C.

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

1-cyclopropyl-7- (4-methyl-1-piperazinyl) -6-fluoro-8-acetoxymethyl-1,4-dihydro-4-oxoquinoline-3-ethyl carboxylate, m.p122 -125 ° C, yellow white powder 1-cyclopropyl-7- (4-ethoxycarbonyl-1-piperazinyl) -6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxo Quinoline-3-methylcarboxylic acid

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

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-nitrobenzylalcohol, m.p. 138-139 ° C. yellow prism form.

Comparative Example 52

Dissolve 3,6-difluoro-2- (4-ethoxycarbonyl-1-piperazinyl) -5-nitrobenzyl alcohol (7.14 g) in methanol (770 ml), and concentrated sulfuric acid (145 ml) on ice. Place in a bucket and add dropwise. The mixture is refluxed for 4 hours. The reaction mixture is cooled to room temperature, poured into ice water (1.5 L), and extracted with dichloromethane. The extract was dried over magnesium sulfate and sodium sulfate, and the solvent was concentrated under reduced pressure. 3-methoxymethyl-2,5-difluoro-4- (4-ethoxycarbonyl-1-piperazinyl) nitrobenzene ( 7.39 g) is obtained as a yellow powder at mp85-86 ° 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

Comparative Example 53

1-cyclopropyl-7- (4-ethoxycarbonyl-1-piperazinyl) -6-fluoro-8-acetoxymethyl-1,4-dahydro-4-oxoquinoline-3-carboxylmethylmethyl To a solution of (300 mg) in methanol (3 ml) was added 1N aqueous potassium carbonate (0.8 ml), which was stirred at room temperature for 3.25 hours.

The reaction mixture is poured into water and extracted with dichloromethane and chloroform. After this organic layer is combined, dried over anhydrous sodium sulfate, and the solvent is evaporated, 1-cyclopropyl-7- (4-ethoxycarbonyl-1-piperazinyl) -6-fluoro-8-hydroxymethyl -1,4-dihydro-4-oxoquinoline-3-carboxylic acid methyl and 1-cyclopropyl-7- (4-ethoxycarbonyl-1-piperazinyl) -6-fluoro-8-hydroxymethyl A mixture of -1,4-dihydro-4-oxoquinoline-3-methyl carboxylate (2: 1) (280 mg) is obtained.

Without classifying them, methanol (7 ml) and concentrated sulfuric acid (1.4 ml) were added and 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 was dried over anhydrous sodium sulfate and the solvent was evaporated under low pressure to yield 1-cyclopropyl-7- (4-ethoxycarbonyl-1-piperazinyl) -6-fluoro-8-methoxymethyl- 1,4-dihydro-4-oxoquinoline-3-methyl carboxylate (15.9 mg)

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

mp 87-89 ° C. (recrystallized from n-hexaneethylacetate acetate), yellow plate form 2,5-difluoro-3-methoxymethyl-4-morpholino-nitrobenzene, mp 61.5-62 ° C. (n Recrystallized from hexane ethyl acetate), yellow plate form.

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

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

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

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

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

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-nitrobenzylchloride

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

2,5-fluoro-3-chloromethyl-4- (3-acetamidomethyl-1-pyrrolidinyl) nitrotoluene, m.p. 94-98 ℃ Yellow Crystal

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

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

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-piperazinyl) -4-fluoro-6-nitroaniline

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

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

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-acetamidomethyl-1-pyrrolidinyl) -4-fluoro-6-nitroaniline

Comparative Example 58

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

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

[N-cyclopropyl-N- [3- (4-benzyl-3-ethyl-1-piperazinyl) -2-methoxymethyl-4-fluoro-6-nitrophenyl] aminomethylene] -malonic acid diethyl

[N-cyclopropyl-N- [3- [3- (N-benzyl-N-methylamino] -pyrrolidinyl)]-2-methyl-4-fluoro-6-nitrophenyl] -aminomethylene] malon Sandiethyl

[N-cyclopropyl-N- [3-morpholino-2-methyl-4-fluoro-6-nitrophenyl] aminomethylene] malonic acid diethyl

Comparative Example 59

Using the appropriate starting material in the same manner as in Comparative Example 33 to obtain the following compound. 1-cyclopropyl-7-morpholino-6-fluoro-8-methyl-1,4-dihydrodi-4-oxoquinoline-3-ethyl carboxylic acid, colorless powder, m.p. 205-206 ° C. (Recrystallized from ethyl acetate-n-hexane)

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

1-Cyclopropyl-7-morpholino-8-acetoxymethyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-ethyl carboxylate, mp176-178 ° C. (ethylacetate-diethyl Recrystallized from ether-n-hexane), light yellow prism form

1-cyclopropyl-7- (4-methyl-1-piperazinyl) -6-fluoro-8-hydrophenyl-1,4-dihydro-4-oxoquinoline-3-ethyl carboxylate, m.p. 216-218 ° C, light yellow powder.

1-cyclopropyl-7- (4-methyl-1-piperazinyl) -6-fluoro-8-methoxymethyl-1,4-dihydro-4-oxoquinoline-3-ethyl carboxylate, m.p. 200-204 ° C, light yellow powder.

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

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

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

1-cyclopropyl-7-morpholino-6-fluoro-8- (1-pyrrolidinylmethyl) -1,4-dihydro-4-oxoquinoline-3-ethyl carboxylate, m.p. 227-232 ° C, light yellow powder.

1-cyclopropyl-7-morpholino-6-fluoro-8-ethylthiomethyl1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl, mp165-167 ° C. (dichloromethane-diethyl ether Recrystallized from), light yellow needle form.

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

Comparative Example 60

1-cyclopropyl-7- (4-methyl-1-piperazinyl) -6-fluoro-8-acetoxymethyl-1,4-dihydro-4-oxoquinoline-3-ethyl carboxylate (142 mg) Potassium carbonate solution (1 ml) is added to a solution dissolved in ethanol (101 mg), which is stirred for 2,5 hours at room temperature. 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 eventually results in 1-cyclopropyl-7- (4-methyl-1-piperazinyl) -6-fluoro-8-hydroxymethyl-1,4- Dihydro-4-oxoquinoline-3-ethyl carboxylate (101 mg) is obtained as a light yellow powder at mp216-218 degreeC.

Comparative Example 61

1-Cyclopropyl-7- (4-methyl-1-piperazinyl) -6-fluoro-8-hydroxymethyl-1,4-dihydroxy-4-oxoquinoline-3-ethyl carboxylate (160 mg) To the solution dissolved in methanol (10 ml) was added concentrated sulfuric acid (2 ml) and refluxed for 6.5 hours. The pH is adjusted to 8 or less with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The extract is washed with water soluble sodium chloride, dried over magnesium sulfate and the solvent is evaporated.

Crystallization by addition of diethyl ether to the residue gave 1-cyclopropyl-7- (4-methyl-1-piperazinyl) -6-fluoro-8-methoxymethyl-1,4-dihydrodi-4 Oxoquinoline-3-methyl carboxylate (125mg) light yellow powder, mp Obtained at 200-204 ° 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 concentrated in iced water. Mix slowly).

After addition, the mixture was refluxed for 30 hours, then further concentrated sulfuric acid (10 ml) was added and refluxed for another 20 hours. After cooling to room temperature, saturated aqueous potassium carbonate solution and saturated aqueous sodium bicarbonate solution are adjusted to pH 8 or less, and extracted with ethyl acetate.

The extract is dried over magnesium sulfate and the solvent is evaporated. The residue was purified by silica gel column chromatography (eluent, dichloromethane) to give 2,5-difluoro-4- (4-benzyl-1-pyrazinyl) -3-methoxymethyl-nitrobenzene (12.90 g) is obtained.

Comparative Example 63

2N saturated in aqueous solution of 1-cyclopropyl-7-morpholino-6-fluoro-8-acetoxymethyl-1.4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl (550 mg) in methanol (10 ml) Aqueous potassium carbonate solution (1 mg) 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 concentrated. The residue was crystallized by the addition of diethyl ether and eventually 1-cyclopropyl-7-morpholino-6-fluoro-8-hydroxymethyl-1.4-dihydro-4-oxoquinoline-3-ethyl carboxylate (353 mg ) With this pale yellow powder mp Obtained at 212-216 ° C.

Comparative Example 64

To thionylchloride (1 ml) is added to 1-cyclopropyl-7-morpholino-6-fluoro-8-hydroxymethyl-1.4-dihydro-4-oxoquinoline-3-ethyl carboxylate (80 mg), It is stirred at room temperature for 4 hours and further stirred at 50 ° C. for one hour.

The solvent is concentrated under reduced pressure and eventually impure 1-cyclopropyl-7-morpholino-6-fluoro-8-chloromethyl-1.4-dihydro-4-oxoquinoline-3-ethyl carboxylate (84 mg) is obtained. .

Pyrrolidine (1 ml) is added thereto without purification 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 (eluent, dichloromethane: = 10: 1) to yield 1-cyclopropyl-7-morpholino-8 (1-pyrrolidinylmethyl) -6. -Fluoro-1.4-dihydro-4-oxoquinoline-3-carboxylate (31.8 mg) as yellow powder mp Obtained at 227-232 ° C.

Comparative Example 65

Thionyl chloride (1.5 ml) is added to 1-cyclopropyl-7-morpholino-6-fluoro-8-hydroxymethyl-1.4-dihydro-4-oxoquinoline-3-ethyl carboxylate (101 mg) This is stirred at room temperature for 5.2 hours. The solvent is removed by concentration under reduced pressure. To this impure 1-cyclopropyl-7-morpholino-6-fluoro-8-chloromethyl-1.4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ethane (1.5 ml) and triethylamine 30 After adding μl, the mixture is stirred at room temperature for one day. The reaction mixture is extracted with dichloromethane and the extract is washed in the order of water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed by concentration under reduced pressure, which was purified by silica gel column chromatography (solvent, dichloromethane: methanol = 15: 1), recrystallized from dichloromethane-diethyl ether, and cyclopropyl-7-morpholino-6-fluoro -8-ethylthiomethyl-1.4-dihydro-4-oxoquinoline-3-ethyl carboxylate (49 mg) in the form of a pale yellow saliva Obtained at 165-167 ° C.

Comparative Example 66

To 2-chloro-5,5-difluoro-3-nitrotoluene (1.0 g) was added potassium fluoride (1.4 g), dry dimethyl sulfoxide (10 ml) and benzene (10 ml) dried by spraying, Moisture is removed by boiling with benzene. The mixture is then stirred at 170-180 ° C. under argon gas 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 column chromatography (eluent, n-hexane) 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-pyrrolidine (9.5 g) is added methanol (90 ml) at room temperature, which is stirred for one hour. Methanol is evaporated off under reduced pressure and water is added to the residue. Extract with dichloromethane and extract is dried over magnesium sulfate to evaporate dichloromethane. The residue was purified using silica gel column chromatography (eluent, dichloromethane: methanol = 19: 1) to give 3- (t-butoxycarbonylamino) -1-benzyl-4-methylpyrrolidine (isomer A). (4.4g) In The Colorless Prism mp Obtained at 131.5-132.7 ° C.

Comparative Example 68

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

Comparative Example 69

To a solution of sodium boron hydrite (51.6 g) dissolved in tetrahydrofuran (500 ml), add a drop of 2,5,6-trifluorobenzoic acid (120 g) dissolved in tetrahydrofuran (200 ml) one by one. Stirring is below C, and 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. This is stirred for 1 day at room temperature, the reaction mixture is poured into ice water (1.5) and extracted with this ethyl ether. The extract was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give 2,3,6-trifluorobenzine alcohol (112.7 g) as light yellow oil at bp112 ° C. (30 mmHg).

Comparative Example 70

2,3,6-trifluorobenzyl alcohol (41 g) was dissolved in dichloromethane (10 ml) and the solution of thionyl chloride (50 ml) in dichloromethane (80 ml) was ice-cooled, dropwise with stirring. Add 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 a colorless oil at b.p.63 占 폚 (13 mmHg).

NMR (CDCl ₃ ) δ: 4.66 (2H, s), 6.62-6.93 (1H, m), 7.04-7.26 (1H, m).

Comparative Example 71

Phenyltriethylammonium chloride (0.09 g) is added to a solution of sodium cyanide (1.94 g) dissolved in water (4 ml), and 2,3,6-trifluorobenzyl chloride (5.0 g) is added thereto while stirring. 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 potassium carbonate to evaporate the solvent to give 2- (2,3,6-trifluorophenyl) acetonitrile (3.1 g) at b.p 80-85 ° C. (5 mmHg).

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

Comparative Example 72

Dissolve 2- (2,3,6-trifluorophenyl) acetonitrile (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. Reflux. After cooling, the reaction mixture is partitioned between diethyl ether and water. The ether layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure to yield 2- (2,3,6-trifluorophenyl) ethyl acetate (16.3 g) as colorless oil.

Comparative Example 73

Dissolve 2- (2,3,6-trifluorophenyl) ethyl 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 1 hour. After cooling 6N hydrochloric acid (120 ml) is added to this mixture. The obtained white powder precipitate is dissolved by adding diethyl ether. The diethyl ether layer was separated, dried over magnesium sulfate, and concentrated 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 (1H, m), 7.02-7.18 (1H, m), 9.75 (1H, s).

Comparative Example 74

Lithium 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. Water (0.8 ml), 10% aqueous sodium hydroxide solution (0.8 ml) and water (1.6 ml) are added in this order, and the mixture is stirred at room temperature. Diethyl ether (10 ml) was added thereto, and the resultant precipitate was filtered off and washed with tetrahydrofuran. The washing solution and the filtrate are combined with each other, and concentrated under reduced pressure to yield 2- (2,3,6-trifluorophenyl) ethylalkyl (1.9 g) as colorless oil.

NMR (CDCl ₃ ) δ: 1.75 (1H, s), 2.98 (3H, t, J = 6.7Hz), 3.85 (2H, t, J = 6.7Hz), 6.74-6.87 (1H, m), 6.93-7.09 (1H, m).

Comparative Example 75

P-toluenesulfonylchloride (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 saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (eluent, methylene chloride) and recrystallized from diethyl ether-n-hexane.

1- [2- (p-toluenesulfonyloxy) ethyl] -2,3,6-trifluorobenzene (3.4 g) is obtained in the form of a colorless prism at m.p 73-74 ° C.

Comparative Example 76

Lithium aluminum hydride (5.6 g) was suspended in dried diethyl ether (70 ml) and stirred with 1- [2- (p-toluenesulfonyloxy) ethyl] -2,3,6-trifluorourobenzene (23.3 g) was added to the solution of dried diethyl ether (170 ml) dropwise at 10 DEG C or lower, and the mixture was stirred at room temperature for 1 hour.

To this was added mol (5.6 ml), 10% aqueous sodium hydroxide (10.0 ml) and water (5.6 ml) in this order, which was stirred for 30 minutes at room temperature.

The white precipitate thus obtained is filtered and the filtrate is concentrated under normal pressure 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), 6.71-6.2 (1H, m), 6.87-7.03 (1H, m).

Comparative Example 77

Dissolve 2,3,6-trifluoro-1-ethylbenzene (1.09 g) in concentrated sulfuric acid (5.5 ml), add a mixture of potassium nitrate (0.83 g) in concentrated sulfuric acid (4 ml) with stirring, and Stir at temperature for 1 hour.

The reaction mixture is poured into iced water (100 ml) and extracted with diethyl ether.

The ether layer is washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated 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 (1H, dd, J = 8.0 Hz, 1.62 Hz).

Comparative Example 78

To 3-ethyl-2,3,5-trifluoro-nitrobenzene (1.02 g), ethanol (4.5 ml) and water (0.5 ml) were added, and 1-methylpiperazine (0.83 ml) and triethyl were stirred with stirring. A mixture of amine (1.0 ml) and ethanol (0.6 ml) is added and the mixture is refluxed for 5 hours.

1-ethylpyrazine (1.0 ml) was added to the reaction mixture and refluxed for 3 hours.

It was concentrated under reduced pressure and purified by silica gel column chromatography (eluent, methyl chloride) to give 3-ethyl-2,5-difluoro-4- (4-methyl-1-piperazinyl) nitrobenzene (11.2 g). ) Is obtained as a yellow oil.

Comparative Example 79

3-ethyl-2,5-difluoro-4- (4-methyl-1-piperazinyl) nitrobenzene (1.12g) in potassium fluoride (0.24g) and N, N-dimethylsulfoxide (3.5 ml) and cyclopropylamine (0.41 ml) are added and it is stirred between 80 and 85 ° C. for 1,5 hours.

The reaction mixture was diluted with ethyl acetate, the organic layer was washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. N-cyclopropyl-2-ethyl-3- (4-methyl-1 Piperazinyl) -4-fluoro-6-nitroaniline (1.00 g) is obtained as a viscous oil.

Comparative Example 80

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

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

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)

Comparative Example 82

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

[N-Cycloporophyl-N- [3- (4-methyl-1-piperazinyl) -2-ethyl-4-fluoro-6-nitrophenyl] aminomethylene] diethyl malonate

Comparative Example 83

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

1-Cycloporophyl-7- (4-methyl-1-piperazinyl) -6-fluoro-8-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl, mp 201-203 ℃ White Powder (Recrystallized from Ethanol)

Example 1

6,7-difluoro-1-cyclopropyl-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid-B- (COCOCH ₃ ) ₂ chelate (1.2 g) in benzylpiperazine ( 1.6 g) and dimethylacetamide (6 ml) were added and reacted at 50 ° C. for 20 hours.

After concentration, the residue is dissolved in acetone (20 ml), and concentrated hydrochloric acid (5 ml) is added thereto, which is stirred for 30 minutes at room temperature.

After distilling off the solvent, the merl is added and extracted with dichloromethane.

The aqueous layer is neutralized with aqueous sodium bicarbonate solution, extracted with dichloromethane and dried over magnesium sulfate.

After the solvent was removed, a mixture of diethyl ether and ethanol was added to the extract, and the precipitate was filtered again to obtain 2- (4-benzyl-1-piperazinyl) -1-cyclopropyl-6-fluoro-8-. Methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.1 g) is white crystals, mp Obtained at 209-211 ° C.

Example 2

Acetic acid (3 ml) in 7- (4-benzyl-1-piperazinyl) -1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (84 mg) ) And 10% Pd-C (10 mg) were added and the catalyst was reduced at 70 ° C. for 1 hour.

After catalytic reduction, the reaction mixture is cooled and the catalyst is filtered off.

The filtrate was concentrated, water-soluble sodium carbonate was added thereto, and the obtained precipitate was separated by filtration to obtain 7- (1-piperazinyl) -1-cyclopropyl-6-fluoro-8-methyl-1,4-di Hydro-4-oxoquinoline-3-carboxylic acid (45 ml) was converted into white crystals. p.291-295 ° C. (decomposition).

Example 3

6,7-difluoro-1-cyclopropyl-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.8 g) is suspended in N-methylpyrrolidine (5 ml), To this piperazine (1.8 g) is added, which is stirred at 150 ° C. for 3 hours.

After the reaction, the reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (eluent, dichloromethane: methanol = 3: 1) to obtain 7- (1-piperazinyl) -1-cyclopropyl-6-fluoro. -8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.06 g) is obtained as white crystals, mp 291-295 ° C. (decomposition).

Example 4

In the same manner as in Example 1, using a suitable starting material to obtain the following compound.

7- (4-methyl-1-piperazinyl) -1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, mp 219-220.5 ° C. ( Recrystallized from ethanol Light yellow prism, 7- (1,40-diazabicyclo [4.3.0] nonan-4-yl) -1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro- 4-oxoquinoline-3-carboxylic acid, mp 208-212 ° C. (dichloromethane-diethyl ether acetate yellow powder, 7- (1-piperazinyl) -1- (2,2-dichloro-1-cychloropropyl- 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) and sodium hydrogencarbonate (70 ml ) Is suspended in dimethylformamide (3 ml) and 4-bromomethyl-3-1,3-dioxoren-2-one (0.13 g) is added thereto under ice cooling, which is then cooled to 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 dimethyl ether to obtain 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 (0.24 g) is pale yellow-white crystals mp Obtained at 174-177 ° C.

Example 6

Dimethylacetamide (10 ml) in 6,7-difluoro-1-cyclopropyl-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid-B (OCOCH ₃ ) ₂ chelate (3.4 g) ) And 4-benzyl-3-methylpiperazinyl (68 g) are added and the mixture is reacted at 50 ° C for 3 hours.

After the reaction, the solvent is evaporated, and 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.

After distilling off the solvent, water is added and the crystals are filtered off.

Neutralize with aqueous sodium bicarbonate solution and extract with dichloromethane.

Dichloromethane was evaporated and the remaining residue was purified by silica gel column chromatography (eluent, dichloromethane: methanol = 20: 1), and recrystallized from ethanol 7- (4-benzyl-3-methyl-1-piperazinyl). -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-piperazinyl) -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 reaction 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 removed by filtration.

The filtrate is concentrated, thereto is added water, adjusted to pH 7.5 with sodium bicarbonate 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-piperazinyl) -1-cyclopropyl-6. -Fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.16 g) as light yellow powder mp Obtained at 206-208 ° C.

Example 8

In the same manner as in Example 1, using a suitable starting material, the following compounds were obtained.

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

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

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

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

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

Example 9

1-Cycloflofil-7- (4-ethoxycarbonyl-1-piperazinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ( 0.8 g) is added 10% aqueous sodium hydroxide (7 ml) and 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 bicarbonate, 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) Obtained at 291-295 ° C. (decomposition).

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 m.p. 201.5-203.0 ℃ 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 mp 234-235 ° C. (recrystallized from methanol), yellow needles

3) 1-cyclopropyl-7- (4-ethoxycarbonyl-1-piperazinyl) -6-fluoro-8-methoxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid mp 218-220 ° C. (recrystallized from ethanol), pale yellow prismatic

4) 1 -Cyclopropyl-7- (4-methyl-1-piperazinyl) -6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid m.p. 197-201 ℃, light yellow powder.

5) 1-cyclopropyl-7- (1-piperazinyl) -6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid m.p. 149-152 ° 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 m.p. 208-210 ° 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 mp 187- 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-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 m.p. 234-236 ° C (Recrystallized from chloroform-ethanol) Light yellow crystal

13) 1-cyclopropyl-7- (3-amino-4-methyl-1-pyrrolidinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ( Isomer A) mp 226-232 ° C yellow powder (recrystallized from ethyl acetate-ethanol)

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

14) 1 -cyclopropyl-7- (3-aminomethyl-1-pyrrolidinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 195-200 ° C (Recrystallized from ethyl acetate-methanol) Yellow crystals

15) 1-cyclopropyl-7- (3-methylamino-1-pyrrolidinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid m.p. 185-5-187.5 ° C (decomposition) (recrystallized from ethanol-diethyl ether (white powder)

16) 1 -Cyclopropyl-7- (4-cyclopropyl-1-piperazinyl) -6-fluoro-8-methyl-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid m.p. 224-225 ° C (decomposition) (recrystallized from ethanol) light yellow prism

17) 1-cyclopropyl-7- (3-5-methyl-2-oxo-1,3-dioxoren-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, m.p. 227.5-228 ° C (recrystallized from ethanol)

19) 1 -cyclopropyl-7-morpholino-6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 218-220 ° C (Recrystallized from Methanol) Light Yellow Prism

20) 1-Cyclopropyl-7- (4-benzyl-1-pyrerazinyl) -6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid m.p. 229-231 ° C. (Recrystallized from dichloromethane-diethyl ether)

21) 1-cyclopropyl-7- (4-benzyl-3-methyl-1-piperazinyl) -6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3- Carboxylic acid mp 208-209 ° C (Recrystallized from ethanol-diethyl ether) Light orange powder

22) 1-Cyclopropyl-7- (3-methyl-1-piperazinyl) -6-fluoro-8-hydroxymethyl-1,4-dihydroxy-4-oxoquinoline-3-carboxylic acid mp180 -183 ° C (Recrystallized from ethanol-ethyl acetate-diethyl ether) White powder

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

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

25) 1-Cyclopropyl-7-morpholino-6-fluoro-8-ethylthiomethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid mp206-208 ° C. (m-hexane-ethanol Recalculation from arithmetic yellow prism

26) 1-cyclopropyl-7- (4-oxo-1-pyrerazinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid mp247-250 ° C. (Crystallized with chloroform-ethanol) white crystals

27) 1-cyclopropyl-7- (3-acetamidomethyl-1-pyrrolidinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid mp192 -194 ° C (recrystallized from chloroform-methanol) white crystals

28) 1-Cyclopropyl-7- (3-t-butoxycarbonylamino-methyl-1-pyrrolidinyl) -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 ℃ (Recrystallized from ethyl acetate-methanol) White powder

30) 1-cyclopropyl-7- (3-N-ethylacetoamino) methyl-1-pyrrolidinyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid mp167-169 ° 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 mp 267-271 ° C. (recrystallized from methanol-acetonitrile) yellow powder

32) 1-Cyclopropyl-7- (4-acetyl-3-methyl-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-piperazinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid mp236- 239 ° C (Recrystallized from methanol)

34) 1-cyclopropyl-7- (3,4-dimethyl-1-piperazinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid mp181- 183 ° C (Recrystallized from ethyl acetate with burner) Light yellow powder

35) 1-cyclopropyl-7- (3,4-dimethyl-1-piperidyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid mp176- 179 ° C (Recrystallized from Ethanol) Light Yellow Prism

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

41) 1-Cyclopropyl-7- (4-fluoro-1-piperazinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid mp208-210 ℃ (Recrystallized from Ethanol) Colorless needles

42) 1 -Cyclopropyl-7- (3- (5-methyl-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 ° C. Decomposition (recrystallized from diethyl ether-ethanol) white powder

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

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

46) 1-cyclopropyl-7- (3-amino-4-methyl-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) mp209-213 ° 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), 7.70 (1H, d, J = 13.7 Hz), 8.77 (1Hs)

48) 1 -Cyclopropyl-7- (3-t-butoxycarbonylamino-4-methyl-1-pyrrolidinyl) -6-fluoro-8-methyl-1, 4-dihydro-4-oxo Quinoline-3-carboxylic acid (isomer B) mp157-160 ° C. (recrystallized from ethyl acetate) yellow powder

NMR (DCDl ₃ -d ₆ ) δ: 1.20 (3H, d, J = 6.6Hz), 2.57 (3H, s), 7.91 (1H, d, J = 13.3Hz), 9.15 (1H, s)

49) 1-cyclopropyl-7- (3-t-butoxycarbonylamino-4-methyl-1-pyrrolidinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxo Quinoline-3-carboxylic acid (isomer B) mp199-202 ° C. (recrystallized from ethyl acetate)) yellow powder

NMR (DCDl ₃ -d ₆ ) δ: 1.12 (3H, d, J = 6.6Hz), 2.58 (3H, s), 7.85 (1H, d, J = 13.6Hz), 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 mp117-120 ° C. (recrystallized from ethanol) light yellow prismatic form

51) 1-Cyclopropyl-7-morpholino-6-fluoro-8-fluoromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid mp189-192 ° C decomposition (n-hexane- Recrystallized from 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 (68mg) and ethanol (10ml) it was catalytically reduced at 60 ° C for 6.5 hours under hydrogen gas.

The catalyst is filtered off and the filtrate is concentrated.

The obtained residue was recrystallized from ethanol-acetone-dichloromethane to 1 -cyclopropyl-70 (1-piperazinyl) -6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline- 3-carboxylic acid (342 mg) is obtained as a white powder as mp149-152.

Example 12

1% 1-cyclopropyl-7- (4-oxo-1-piperazinyl) -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 at room temperature.

It is stirred for 30 minutes at the same temperature, poured into ice water and acidified with concentrated sulfuric acid.

The mixture is extracted with dichloromethane and the solvent is distilled off.

When it was added to ethyl acetate to crystallize and recrystallized from chloroform-methanol, 1-cyclopropyl-7- (4-hydroxy-1-piperidinyl) -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) are 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 diethyl 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 (45 mg) is obtained as mp195-200 ° C as pale yellow crystals.

Example 14

1-cyclopropyl-7- (3- (N-ethylacetamido) methyl-1-pyrrolidinyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid To a chloride solution (0.22 g) is added 5% aqueous sodium hydroxide solution (10 ml) and 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 made alkaline with aqueous sodium chloride solution, to which anhydrous t-butoxycarboxylic acid (200 mg) is added.

This is stirred for 30 minutes at room temperature.

It is acidified with 10% hydrochloric acid and extracted with dichloromethane.

Concentrate to remove the solvent, then 10% hydrochloric acid (5ml) and methanol (10ml) is 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-carboxylic acid hydrogen chloride (30 mg) is obtained as yellow crystals at mp267-271 ° 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 an aqueous sodium hydroxide solution (5 ml), and acetic anhydride (0.3 ml) is added thereto at room temperature, followed by stirring at room temperature for 30 minutes.

Oxidized with concentrated hydrochloric acid, extracted with dichloromethane, concentrated to remove the solvent, purified by passing through silica gel column chromatography (eluent, dichloromethane), 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) is obtained as a white powder at mp219-221 ° 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) was added to formic acid ( 1.7 ml) and acetic anhydride (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.

Concentrate to remove the solvent and recrystallize from methanol as residue to give 1-cyclo-7- (4-formyl-3-methyl-1-piperazinyl) -6-fluoro-8-methyl-1,4-di Hydro-4-oxoquinoline-3-carboxylic acid (0.13 g) is obtained as a white powder mp236-239 ° C.

Example 17

Formic acid in 1-cyclopropyl-7- (3-methyl-1-piperazinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.4 g) 3 ml), 37% formalin (3 ml) and sodium formate (0.4 g) were added and then refluxed for 5 hours.

After cooling, the reaction mixture was adjusted to pH 8 or less using sorbent sodium bicarbonate solution in ice water and extracted with dichloromethane.

Concentration removes the solvent and the residue is recrystallized from ethyl acetate, and then 1-cyclopropyl-7- (3,4-dimethyl-1-piperazinyl) -6-fluoro-8-methyl-1,4-di Hydro-4-oxoquinoline-3-carboxylic acid (0.12 g) is obtained as a light yellow powder at mp181-183 ° 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.

Formulation 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. Was injected into a sterile ampoule which was washed with nitrogen gas and sterilized at 121 ° C. for 15 minutes to obtain an injection.

Formulation Example 2

Tablets coated with a film are obtained from the following components.

Mix and meet 7- (1-piperazinyl) -1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, Avicel, cornstarch and magnesium stearate Ha Tablets (manufactured by Kyokusui Seisakusho Co., Ltd.) are made of tablets using a conventional founder (R10mm) for sugar coating.

The tablets thus prepared are coated with a film coating additive consisting of Tc-5, polyethylene glycol 6000, castor oil and ethanol.

Formulation Example 3

Ointment is prepared from the following ingredients:

Heat to dissolve the bleached beeswax and add 7- (1-piperazinyl) -1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, Add purified lanolin and white petrolatum and dissolve it until liquid. The mixture is stirred until it becomes an ointment.

Experiment (Antibacterial Activity in Vitro)

The antimicrobial activity of the test compounds mentioned below was examined by measuring the minimum growth inhibition concentration (MIC) by serial dilution on agar plates.

(cf. Chymotherapy, 22, 126-1128 (1974) Microorganisms are used at concentrations of 1 × 10 ⁸ cells / ml (O 660 mμ 0.07-0.16) and 1 × 10 ⁶ cells / mg1 mg (100-fold dilution) It became.

When pneumococcal form II and pneumococcal form III were used as test bacteria, the medium contained 5% horse blood.

The results are shown in Table 1.

(Test compound)

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-cycloflophyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

3.7-1,4-diazabicyclo [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-cycloflophyl-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-4-4-oxoquinoline-3-carboxylic acid

11.1-Cyclopropyl-7- (3-acetamidemethyl-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-oxoquinol-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-piperazinyl) -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-piperazinyl) -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-piperazinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

24.1-cyclopropyl-7- (4-cyclopropyl-1-piperazinyl) -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-ethyl-1-pyrrolidinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride ( Isomer A)

27 1-cyclopropyl-7- (3,5-dimethyl-1-piperazinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

(Test microorganism):

Claims (55)

Wherein R ¹ is cyclopropyl, R ² is a heterocyclic group selected from the following formulas,

Wherein R ^B is a 2-oxo-1,3-dioxorenmethyl group substituted with a C ₁ -C ₆ alkyl group or a C ₃ -C ₈ cycloalkyl group, R ^C is a hydrogen atom, a C ₁ -C ₆ alkyl group, A C ₁ -C ₆ alkoxycarbonyl group or a phenyl (C ₁ -C ₆ ) alkyl group, R ^D is a hydrogen atom or a C ₁ -C ₆ alkyl group, R ^G is a C ₁ -C ₆ alkyl group, R ^H is C _1- C ₆ alkanoyl group, the group of formula

Wherein R ¹ represents amino- (C wherein the amano group is optionally substituted with 1-2 substituents selected from the group consisting of a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkanoyl group and a C ₁ -C ₆ alkoxycarbonyl group _Is an amino group which may be optionally substituted with 1-2 substituents selected from the group consisting of _1- C ₆ ) alkyl group, or C ₁ -C ₆ alkyl group, phenyl (C ₁ -C ₆ ) alkyl group or C ₁ -C ₆ alkoxycarbonyl group R ^J is a hydrogen atom or a C ₁ -C ₆ alkyl group,

(R ^K is a hydrogen atom or a C ₁ -C ₆ alkyl group), or a morpholino group substituted with 1-3 C ₁ -C ₆ alkyl groups, wherein each alkyl group is selected from a group consisting of -NH ₂ and a halogen atom. It may be substituted with 1-piperidinyl group which may have 1-3 substituents selected, or 1-3 substituents selected from the group consisting of oxo group, hydroxy group, halogen atom and C ₁ -C ₆ alkyl group. R ³ is 1-pyrrolidinyl group, C ₁ -C ₆ alkylthio group, a hydroxy group, C ₁ -C ₆ alkoxy group and a halogen atom group consisting of C ₁ -C which may be optionally substituted with 1 to 3 substituents selected from _{6 is an} alkyl group, X is a halogen atom, Provided that R ³ is:

or

When R ³ is a C ₁ -C ₆ alkyl group or R ² is a group of formula

or

Wherein R ³ is a C ₁ -C ₆ alkyl group having 1-3 substituents selected from the group consisting of a pyrrolidinyl group, a C ₁ -C ₆ alkylthio group, a hydroxy group, a C ₁ -C ₆ alkoxy group and a halogen atom A process for producing the benzoheterocyclic compound of (I) or a pharmaceutically acceptable salt thereof. The method for producing a benzoheterocyclic compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ^{1 is a} cyclopropyl group, R ³ is an unsubstituted C ₁ -C ₆ alkyl group, and X is a fluorine atom. The compound of claim 1, wherein R ¹ is a cyclopropyl group, X is a fluorine atom, and R ² is a group of the formula:

Wherein R ^D is a hydrogen atom, R ^C is a hydrogen atom, a C ₁ -C ₆ alkyl group or a phenyl (C | ₁ -C ₆ ) alkyl group, and R ³ is an unsubstituted C ₁ -C ₆ alkyl group A method for preparing a heterocyclic compound or a pharmaceutically acceptable salt thereof. The compound of claim 1, wherein R ¹ is a cyclopropyl group, X is a fluorine atom, and R ² is a group of the formula

Wherein R ^B is a 2-oxo-1,3-dioxorenmethyl group substituted by a C ₁ -C ₆ alkyl group or a C ₃ -C ₈ cycloalkyl group) or a pharmaceutically acceptable compound Method for producing a salt thereof. The method for producing a benzoheterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 3, wherein R ^C is a C ₁ -C ₆ alkyl group. The method for producing a benzoheterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 5, wherein R ³ is a methyl group. The method for producing a benzoheterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 5, wherein R ³ is an ethyl group. The preparation of a benzoheterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 4, wherein R ^B is a 2-oxo-1,3-dioxorenmethyl group which may be substituted by a C ₁ -C ₆ alkyl group. Way. The method for producing a benzoheterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 4, wherein R ^B is a C ₃ -C ₈ cycloalkyl group. The method for producing a benzoheterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 8, wherein R ³ is a methyl group. The method for producing a benzoheterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 8, wherein R ³ is an ethyl group. The compound of claim 1, wherein R ² is a group of the formula:

(Wherein R ^C is a hydrogen atom or a C ₁ -C ₆ alkyl group, R ^D is a hydrogen atom), or a method for producing a benzoheterocyclic compound or a pharmaceutically acceptable salt thereof. The group of claim 1, wherein R ² is a group of the formula:

(Wherein R ^C is a hydrogen atom and R ^D is a C ₁ -C ₆ alkyl group) a process for producing a benzoheterocyclic compound or a pharmaceutically acceptable salt thereof. The group of claim 1, wherein R ² is a group of the formula:

(Wherein R ^C is a C ₁ -C ₆ alkyl group and R ^D is a C ₁ -C ₆ alkyl group) A process for producing a benzoheterocyclic compound or a pharmaceutically acceptable salt thereof. The method for producing a benzoheterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 12, wherein R ² is a methyl group. The method for producing a benzoheterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 12, wherein R ³ is an ethyl group. The method for producing a benzoheterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 13, wherein R ³ is a methyl group. The method for producing a benzoheterocyclic compound or a pharmaceutically acceptable salt thereof, according to claim 13, wherein R ³ is an ethyl group. The method for producing a benzoheterocyclic compound or a pharmaceutically acceptable salt thereof, according to claim 14, wherein R ³ is a methyl group. The method for producing a benzoheterocyclic compound or a pharmaceutically acceptable salt thereof, according to claim 14, wherein R ³ is an ethyl group. The group of claim 1, wherein R ² is a 1-pyrrolidinyl group of the formula:

Wherein R ¹ is a C ₁ -C ₆ alkyl group having one or two amino groups optionally substituted with C ₁ -C ₆ alkyl groups or an amino group which may be substituted with one or two C ₁ -C ₆ alkyl groups: And R ^J is a hydrogen atom or a C | ₁ -C ₆ alkyl group). The method for preparing a benzoheterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 12, wherein R ^I is an amino group which may be substituted by one C ₁ -C ₆ alkyl group. The benzoyl group according to claim 12, wherein R ^I is a C ₁ -C ₆ alkyl group having one amino group, wherein the amino group may be substituted by one C ₁ -C ₆ alkyl group, and R ^J is a hydrogen atom A process for preparing a heterocyclic compound or a pharmaceutically acceptable salt thereof. The method for producing a benzoheterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 22, wherein R ³ is a methyl group. The method for producing a benzoheterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 21, wherein R ³ is a methyl group. 22. The method of claim 21 wherein, R ² is the group of Food: R ² is the group of Food:

(Wherein R ^K is a hydrogen atom or a C ₁ -C ₆ alkyl group) A method for producing a benzoheterocyclic compound or a pharmaceutically acceptable salt thereof. The method for producing a benzoheterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 26, wherein R ³ is a methyl group. The method for producing a benzoheterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ³ is a methyl group. The method for producing a benzoheterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein R ³ is a methyl group. 2. The benzoheteroside of claim 1, wherein R ² is a 1-piperidinyl group, which may have a 1-3 substituent selected from the group consisting of an oxo group, a hydroxy group, a halogen atom and a C ₁ -C ₆ alkyl group. A method for preparing a click compound or a pharmaceutically acceptable salt thereof. The method of claim 30, wherein R ² is a 1-piperidinyl group, which is a benzoheterocyclic compound substituted by one halogen atom or a pharmaceutically acceptable salt thereof. The method for producing a benzoheterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 31, wherein R ³ is a methyl group. The method for producing a benzoheterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ³ is an ethyl group. The method for producing a benzoheterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 30, wherein R ² is a 1-piperidinyl group having a substituent selected from a hydroxy group and an oxo group. The group of claim 1, wherein R ² is a group of the formula:

A method for producing a phosphorus benzoheterocyclic compound or a pharmaceutically acceptable salt thereof. The method for producing a benzoheterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 35, wherein R ³ is a methyl group. The method for producing a benzoheterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 22, wherein R ³ is a methyl group. The method for producing a benzoheterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 23, wherein R ³ is an ethyl group. 7- [4- (5-methyl-2-oxo-1,3-dioxoren-4-yl) methyl-1-piperazinyl] -1-cyclopropyl-6-fluoro-8-methyl-1 Process for the preparation of, 4-dihydro-4-oxoquinoline-3-carboxylic acid. Process for the preparation of 7- (3-methyl-1-piperazinyl) -1-cycloflophyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. Process for the preparation of 1-cyclopropyl-7- (aminomethyl-1-pyrrolidinyl) -1-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. Process for the preparation of 1-cyclopropyl-7- (3-methylamino-1-piperidinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. Process for the preparation of 1-cyclopropyl-7- (ethylaminomethyl-1-pyrrolidinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquanoline-3-carboxylic acid. Of 1-cyclopropyl-7- (3-amino-4-methyl-1-pyrrolidinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid Manufacturing method. Process for the preparation of 1-cyclopropyl-7- (4-fluoro-1-piperidinine) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. Process for the preparation of 1-cyclopropyl-7-morpholino-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. Process for the preparation of 1-cyclopropyl-7- (3-methylmorpholino) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. By cyclizing the chemical of formula (1) to obtain the compound of formula (2) and, if necessary, converting the product to a pharmaceutically acceptable salt thereof:

Wherein R ¹ , R ² , R ³ and X are as defined in claim ¹ , wherein the benzoheterocyclic compound or a pharmaceutically acceptable salt thereof is prepared.

Wherein R ¹ , R ² , R ³ and X are as defined in claim 1, X ² is a halogen atom and R ⁵ is a C ₁ -C ₆ alkyl group.

[Wherein R ¹ , R ² , R ³ and X are as defined in claim 1 and R ⁵ is as defined above and the hydrolysis of the compound is optionally accompanied.] The group of claim 1, wherein R ² is a group of the formula:

Wherein R ^G and R ^H are as defined in claim 1; a method for preparing a benzoheterocyclic compound or a pharmaceutically acceptable salt thereof. The compound of formula (3) is reacted with a compound of formula: R ² H [R ² is as defined in claim 1] to obtain a compound of formula (4) and, if necessary, the product of which Where the conversion to salt is accompanied by

Wherein R ¹ , R ² , R ³ and X are as defined in claim ¹ , wherein the benzoheterocyclic compound or a pharmaceutically acceptable salt thereof is prepared.

[Wherein R ¹ , R ³ and X are as defined in claim 1, X ⁴ is a halogen atom, and R | ¹³ is a hydrogen atom or the following formula:

Wherein R ¹⁴ and R ¹⁵ are each C ₁ -C ₆ alkyl group.

^{[Wherein, R 1, R 2, R} 3 and X are as defined in claim 1, R ¹³ is the same as was defined above, R ¹³ is the group of Food:

(Where R ¹⁴ and R ¹⁵ are as defined above), followed by conversion of the product into a compound wherein R ¹³ is a hydrogen atom.] The following formula consisting of reacting a compound of formula (5) with a compound of formula (6):

[Wherein R ¹ , R ³ and X are as defined in claim 1 and R ¹⁶ is C ₁ -C | ₆ alkyl group C ₃ -C ₈ cycloalkyl group, C ₁ -C ₆ alkoxycarbonyl group, phenyl (C ₁ -C ₆ ) alkyl group] or a pharmaceutically acceptable salt thereof.

Wherein R ¹ , R ³ and X are as defined in claim 1. R ¹⁶ X ⁵ (6) Wherein R ¹⁶ is as defined above and X ⁵ is a halogen atom, which entails converting the product, if necessary, to a pharmaceutically acceptable salt thereof.] The following formula consisting of reacting a compound of formula (7) with a compound of formula (8):

Wherein R ¹ , R ³ and X are as defined in claim 1 and R ¹⁷ and R ⁸ are each a hydrogen atom or a C ₁ -C ₆ alkyl group, or a pharmaceutically acceptable compound Method for producing a salt thereof.

Wherein R ¹ , R ³ and X are as defined in claim 1 R ¹⁷ COR ¹⁸ (8) [Wherein R ¹⁷ and R ¹⁸ are as defined above and entail converting the product, if necessary, to a pharmaceutically acceptable salt thereof.] The following formula consisting of reacting a compound of formula (9) with a compound of formula (10):

[Wherein R ¹ , R ³ are as defined in claim 1 and R ²³ is C ₁ -C | ₆ alkyl group] method for producing a benzoheterocyclic compound or a pharmaceutically acceptable salt thereof.

Wherein R ¹ , R ³ and X are as defined in claim 1.

[Wherein R ²³ is as defined above and X ⁸ is a halogen atom and involves converting the product, if necessary, to a pharmaceutically acceptable salt thereof.] The following formula consists of cyclizing the compound of formula (11) and, if necessary, converting the product into a pharmaceutically acceptable salt thereof.

Wherein R ¹ , R ² and X are as defined in claim 1 and R ^{3 ′} is

(Wherein R ¹⁹ is a hydrogen atom or a group of C ₁ -C ₆ alkyl and R ²⁰ is a C ₁ -C | ₆ alkyl group) of a benzoheterocyclic compound or a pharmaceutically acceptable salt thereof Way.

[Wherein R ¹ , R ² and X are as defined in claim 1, R ^{3 ′} is as defined above and R ²⁶ and R ²⁷ are C ₁ -C ₆ alkyl groups.] By cyclization of the compound of formula (12) to obtain the compound of formula (13), which if necessary involves the conversion of the product to a pharmaceutically acceptable salt thereof:

[Wherein R ¹ and X are as defined in claim 1, R ^{2 '} is a halogen atom or a group as defined in claim 1 for R ² and R ^3' is a group of the formula:

(Wherein R ¹⁹ is a hydrogen atom or a C ₁ -C ₆ alkyl group, R ²⁰ is a C ₁ -C ₆ alkyl group)] A process for producing a benzoheterocyclic compound or a pharmaceutically acceptable salt thereof.

Wherein R ¹ and X are as defined in claim 1, R ^{2 '} and R ^3' are as defined above, and R ²⁴ is a C ₁ -C ₆ alkyl group.

[Wherein R ¹ and X are as defined in claim 1, R ^{2 ′} , R ^{3 ′} and R ²⁴ are as defined above and are accompanied by hydrolysis of the product.]