SE501371C2 - New 4-oxo:quinoline-3-carboxylic acid cpds. - having antimicrobial activity against Gram positive and Gram negative bacteria and other microorganisms - Google Patents

Abstract

22.5.86, 23.7.86, 19.8.86, 30.9.86, 15.10.86, 18.12.86-JP-105655, 118568, 173370, 193838, 233837, 246050, 303515) (1703KM) 4-Oxoquinoline-3-carboxylic acid cpds. of formula (I) and their salts are new. R1 is cyclopropyl opt. substd. by 1-3 substits. selected from lower alkyl and halogen; R2 is 5-9 membered opt. unsatd. heterocyclic ring which may be substd. R3 is lower alkyl which may be substd. by 1-3 substits. selected from a 5- or 6-membered satd. heterocyclic ring, lower alkylthio, amino, lower-alkylamino, lower alkanoyloxy, OH, lower alkoxy and halogen; and X is halogen. Pref. R2 is opt. substd. 1-piperidinyl, 1-pyrrolidinyl, 1-homopiperazinyl, thiomorpholino, 1,4-diazabicyclo (4.3.0) nona-4-yl, thiomorpholino-4-oxide, thiomorpholino-4,4-dioxide, 1-hexahydropyridazinyl, 2-thiazolidinyl, 1-imidazolidinyl or 3,7-diazabicyclo (4.3.0) nona-3-yl. 10 Cpds. of (I) including 7-(4-(5-methyl) 2-oxo-1,3-dioxolen -4-yl) methyl-1-piperazinyl) -1-cyclopropyl-6-fluoro- 8-methyl-1,4-dihydro-4-oxoquinoline -3-carboxylic acid are described.

Description

From the group consisting of -NH 2 and a halogen atom, or a 1-piperidinyl group, which may have 1 to 3 substituents, selected from the group consisting of oxo group, hydroxy group, a halogen atom and a C 1 -C 6 alkyl group, R 3 represents a C 1 -C 6 alkyl group, which may be substituted by 1 to 3 substituents, selected from the group consisting of a 1-pyrrolidinyl group, a C 1 -C 6 alkylthio group, hydroxy group, a C 1 -C 6 alkoxy group and provided that R 3 represents a C 1 -C 6 alkyl group. when R 2 represents a group of the formula: a halogen atom, and X represents a halogen atom, R 9 pnf] - LJN-RA '-KJN-RB' -IÖ-RH or -bi '' or R 3 represents a C 1 -C 6 alkyl group having 1 to 3 substituents selected from the group consisting of a pyrrolidinyl group, a C 1 -C 6 alkylthio group, hydroxy group, a C 1 -C 5 alkoxy group and the halogen atom, when R 2 represents a group of the formula: RD f "\ / _ <- - -k / N-RC or -N O 'or a pharmaceutically acceptable salt thereof.

The benzoheterocyclic compounds of formula (1) and salts thereof have excellent antibacterial effects against various gram-positive and gram-negative bacteria and are useful for the treatment of various infectious diseases caused by various bacteria in humans, other animals and fish and are also useful. as an external anti-microbial or disinfectant for medical instruments or the like.

Background Art There is much literature describing 4-oxoquinoline-3-carboxylic acid derivatives useful as antibacterial agents. Among these literatures, European patent publication no. 113092 and 113093 and US-PS-4 S59 342 1-Cyclopropyl-7-piperazino-dihydroquinolinecarboxylic acid derivatives of the formula: o coon H2 33 | 7-4 R1-NNN German Patent Specification 3248507 describes 1-cyclopropyl-di-hydroquinoline-carboxylic acid derivatives of the formula: wherein R1 represents H, F, Cl, Br or NO2, R2 represents H, Cl, F or NR 3 R 4, well-123 and 124 together 124 * may form 5- or 6-membered saturated or partially unsaturated heterocycles.

South African Patent Specification 8504087 discloses 1-cyclopropyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid derivative of the formula: OF COOH 1 '\ NR -NN UZA R wherein R 1 represents H, CH 3, C 255 or -CH 2 CH 2 OH, H2 represents H, Cl or F.

German Patent Specification 3420743 describes 7-amino-1-cyclopropyl-3-quinoline-carboxylic acid derivatives of the formula: wherein X 1 or X 2 each represent Cl or F, R 1 and R 2 can be combined together with N-atom to form a 5- or 6 -leaded heterocyclic ring.

German Patents 3420770 and 3420798 describe 1-cyclopropyl-7-piperazinyl-dihydroquinoline-carboxylic acid derivatives of the formula: OF COOH III-N NN §_ / R R2 wherein R represents oxo or phenyl, etc. and R2 represents H- or F. Similarly, 1-cyclopropyl-7-heterocyclic group-substituted dihydroquinoline carboxylic acid derivatives such as Japanese First Patent Publication 36265/1986, 91183/1986, 186379/1986, 205240! - 218585 / are also described. 1986, in many other literature, the cations (Kokai> Nos. 214777/1985, 122272/1986, 143363/1986, 143364/1986, 1986, 205259/1986, 218574/1986, 218575/1986, 225181/1986 and 229877/1986 European Patent Publication Nos. 178388, 183129, 187085, 191185 and 195316, Patent 8504792, Spanish Patents 8602674 and 8601968 and Portuguese Patent 80546. South African However, the compounds described in these bibliographies are distinct from the present invention. taking into account that they have no alkyl substituent at the 8-position. 1-Cyclopropyl-7-heterocyclic group-8-alkyl-dihydroquinoline-carboxylic acid derivatives are described in some literature. For example, Japanese First Patent Publication (Kokai) 126271/1985 (= Portuguese Patent 79616) discloses quinolone carboxylic acid derivatives of the formula: wherein R represents H, CH 3, p-nitrobenzyl or p-aminobenzyl, Y represents Cl, some specific example of 8- CH3 derivatives (all examples refer to F or CH3, but this literature does not describe 8-Cl or 8-F derivatives).

In addition, German Patent Specification 3441788 (= Japanese First Patent Publication (Kokai) 122272/1986) discloses 1-cyclopropyl-4-oxo-quinoline-3-carboxylic acid derivatives of the formula: X 'coon in X2 "P X3 wherein X1, X2 and X3 each denote H or C 1-3 alkyl, but these compounds do not have a heterocyclic group such as X 2, wherein the phenyl ring may be substituted with a lower alkoxy [Brief Description of the Invention The object of the present invention is to provide novel benzoheterocyclic compounds of formula [1] and salts thereof having excellent antimicrobial activity and excellent absorbability Another object of the invention is to provide a pharmaceutical composition which contains as active ingredient a compound of formula [L7 or a pharmaceutically acceptable salt which and other objects of the invention will be apparent to those skilled in the art from the following description. ing.

Detailed Description of the Invention The novel benzoheterocyclic compounds of the present invention have the formula [17 stated above and comprise pharmaceutically acceptable salts thereof.

In the specification, the term "halogen atom" includes fluorine, chlorine, bromine or iodine atoms.

The term "cyclopropyl which may be substituted with 1 to 3 substituents selected from the group consisting of a lower alkyl and a halogen atom" includes cyclopropyl groups which may be substituted with 1 to 3 substituents selected from the group consisting of a C1- C 5 -alkyl group straight chain or branched chain and a halogen atom such as cyclopropyl, 2-fluoro-1-cyclopropyl, 2-chloro-1-cyclopropyl, 2-bromo-1-cyclopropyl, 2-iodo-1-cyclopropyl , 2,2-dichlorocyclopropyl, 2,2-dibromocyclopropyl, 2,2,3-trichlorocyclopropyl, 2-methyl-1-cyclopropyl, 2-ethyl-1-cyclopropyl, 2-propyl-1-cyclopropyl, 2-butyl- 1-cyclopropyl, 2-pentyl-1-cycloproyl, 2-hexyl-1-cyclopropyl, 2,2-dimethylcyclopropyl, 2,3-dimethylcyclopropyl, 2,2,3-trimethylcyclopropyl, A2-fluoro-3-methylcyclopropyl, 2,2-diethylcyclopropyl, 2-methyl-3-propylcyclopropyl and the like.

The term "lower alkyl" embraces straight or branched chain C 1 -C 5 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, etc.

The term "É- to 9-membered saturated or unsaturated heterocyclic ring, which may be substituted", denotes a 5- to 9-membered saturated or unsaturated heterocyclic ring, which may be - substituted by a lower alkyl; a cycloalkyl; a phenyl-lower al-ff k) 10 15 20 25 30 35 40 501 371 nitro or amino; a phenyl which may be substituted by a lower alkyl or lower alkyl substituted by a lower alkyl having 1 to 3 halogen atoms, to 3 halogen atoms; a pyridyl; substituents selected from the group consisting of hydroxy, amino, a legal alkoxy or a halogen atom, wherein amino is optionally substituted with a lower alkyl, a lower alkanoyl, a cycloalkyl or a lower alkoxycarbonyl; a lower alkynyl or a lower alkanoyl which may be substituted by 1 to 7 halogen atoms; a lower alkenyl carbonyl having 1 to 3 substituents selected from the group consisting of a halogen atom and a car a lower alkoxycarbonyl; which may be boxy; an aminocarbonyl, substituted with a lower alkyl; and phenylalkalkoxycarbonyl; an aminol lower alkanoyl which may be substituted by a phenyl lower alkoxycarbonyl; a carboxyl lower alkyl; substituted with a lower alkyl, a lower alkoxycarbonyl lower alkyl; an anilinocarbonyl lower alkyl; an amino, which may be a sub- a phenyl lower alkyl, a lower alkoxycarbonyl or lower alkanoyl; hydroxy; a lower alkylsulfonyl which may be substituted by 1 to 3 halogen atoms; pthalid; a 2 (5H) -furanone, which may be substituted by 1 or 2 halogen atoms; and sulfolagalkyl; oxo; and alkoxy; and lower alkenyl; a halogen atom; a lower alkanoyloxy; a 2-oxo-1,3-dioxolenmethyl, which may be substituted by phenyl or a lower alkyl; 2-oxo--1,3-dioxolenemethylamino, which may be substituted by phenyl or a lower alkyl; a cycloalkylamino; and lower alkylthio; or ten, and more specifically comprises 5- to 9-membered saturated or unsaturated heterocyclic rings, which may be substituted with 1 to 3 substituents selected from the group consisting of a straight or branched C 1 -C 8 alkyl group chain; a C3-C3 cycloalkyl group; a phenylalkyl group in which the phenyl ring may be substituted by a straight or branched chain C 1 -C 5 alkoxy group, nitro group or amino group and alkyl moieties are a straight or branched chain C 1 -C 5 alkyl group; a phenyl group, wherein the phenyl ring may be substituted by a halogen atom or by a straight or branched chain C 1 -C 5 alkyl group, which may be substituted by 1 to 3 halogen atoms; a pyridyl group; a straight or branched chain C 1 -C 6 alkyl group having 1 to 3 substituents selected from the group consisting of hydroxy group, an amino group, a straight or branched chain C 1 -C 5 alkoxy group and a halogen atom, wherein amino group option is substituted with 1 or 2 substituents, which are selected from the group consisting of a C1-C5 straight or branched chain C1-C5 alkyl group, a straight or straight chain C1-C5 alkanoyl group chain, a C3-C8 cycloalkyl group and a C1-C5 alkoxycarbonyl group straight or branched chain; a straight or branched chain C2-C5 alkynyl group; a straight or branched chain C 1 -C 5 alkanoyl group, which alkanoyl group may be substituted by 1 to 7 halogen atoms; a C 2 -C 5 straight or branched chain alkenylcarbonyl group and substituted with 1 to 3 halogen atoms or carboxy groups; a straight or purified C1-C5 alkoxycarbonyl group; an aminocarbonyl group which may be substituted by 1 or 2 of a straight or branched chain C 1 -C 5 alkyl group; a phenylalkoxycarbonyl group in which the alkoxy moiety is a straight or branched chain C 1 -C 5 alkoxy group; a straight or branched chain C2-C5 aminoalkanoyl group which may be substituted by a phenylalkoxycarbonyl group, wherein the alkoxy moiety is a straight or branched chain C1-C5 alkoxy group; an alkoxycarbonylalkyl group, wherein alkoxy and alkyl moieties are C 1 -C 5 alkoxy and resp. straight or branched chain alkyl groups; a carboxyalkyl group, wherein the alkyl moiety is a straight or branched chain C 1 -C 5 alkyl group; an anilinocarbonylalkyl group, wherein the alkyl moiety is a straight or branched chain C 1 -C 5 alkyl group; an amino group which may be substituted by 1 or 2 of a straight or branched chain C 1 -C 5 alkyl group; a phenylalkyl group, wherein the alkyl moiety is a straight or branched chain C 1 -C 5 alkyl group, a straight or branched chain C 1 -C 5 alkoxycarbonyl group or a straight or branched chain C 1 -C 5 alkanoyl group; hydroxy group; a straight or branched chain C 1 -C 5 alkylsulfonyl group which may be substituted by 1 to 3 halogen atoms; phthalide group; a 2 (5H) -furanone group which may be substituted by 1 or 2 halogen atoms; a sulfoalkyl group, wherein the alkyl moiety is a straight or branched chain C 1 -C 5 alkyl group; oxo group; a straight or branched chain C1-C5 alkoxy group; a straight or branched chain C2-C5 alkenyl group; a halogen atom; a straight or branched chain C2-C5 alkanoyloxy group; a 2-oxo-1,3-dioxolenemethyl group which may be substituted by a straight or branched chain enyl group or a C1-C5-alkyl group; C3-C8-cycloalkylamino; a straight-chain or branched C1-C5-alkylthio chain; thio; and a 2-oxo-1,3-dioxolenylmethylamino group; which may be substituted by a methylphenyl group G fï or a C1-C3-straight chain alkyl group such as ¿¿¿¿10 15 20 25 30 35 40 501 371 piperazinyl, piperidinyl, pyrrolidinyl, homopiperazinyl, morpholino, thiomorpholino, 1,2,5,6-tetrahydropyridyl, imidazolyl, 1,4-diazabicyclo [Ä.3.Q] nona-4-yl, folino-4,4 dioxide, py} azolidinyl, hexahydropyridazinyl, pyridyl, dinyl, 3,7-diazabicyclo [c.3.Q] nona-3-71, 4-methyl-1-piperazithiomorpholino-4-oxide, thiomorthiazolidinyl , 2-thio-1-cmidazolidinyl, 2-oxo-1-imidazolinyl, 4-ethyl-1-piperazinyl, 4-propyl-1-piperazinyl, A4-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, 3, 4,5-trimethyl-1-piperazinyl, 3-ethyl-1-piperazinyl, 3-propyl-4-methyl-1-piperazinyl, 2-n-butyl-5-methyl-1-piperazinyl, 2-pentyl -5-hexyl-1-piperazinyl, 4-formyl-1-piperazinyl, 4-acetyl-1-piperazinyl, 4-propionyl-1-piperazinyl, 4-butyryl-1-piperazinyl, 4-pentanoyl-1- piperazinyl, 4-hexanoyl-1-piperazinyl, 4- (α, α, α-trifluoroacetyl) -1-piperazinyl, 4- (β, β, β-trifluoro-α, α-difluoropropionyl) -1-piperazinyl, 4- (Y, Y, Y -trifluoro-β, B-difluoro-G, G-difluorobutyryl) -1-piperazinyl, 4- (α, u-dichloroacetyl) -1-piperazinyl, 4- (U -bromoacetyl) -1-piperazinyl, 4- (α-iodoacetyl) -1-piperazinyl, 4- (B-fluoropropionyl) -1-piperazinyl, 4- (B-fluoro-G-fluoropropionyl) -1-piperazinyl, 4- (6-fluoro-hexanoyl) -1-piperazinyl, 4- (4-chloropentanoyl) -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- (1-1, -dimethyl-2-phenylethyl) -1 -piperazinyl, 4- (5-phenylpentyl) -piperazinyl, 4- (6-phenyl-hexyl) -1-pipe razinyl, 4- (2-methyl-3-phenylpropyl) -1-pipgrazinyl, 4-amino-1-piperazinyl, 3-amino-1-piperazinyl, 2-amino-1-piperazinyl, 4-methylamino-1- piperazinyl, 3-dimethylamino-1-piperazinyl, 2-ethylamino-1-piperazinyl, 4-propylamino-1-piperazinyl, 4-t-butylamino-1-piperazinyl, 3-pentylamino-1-piperazinyl, 2-hexylamino-1-piperazinyl, 4-diethylamino-1-piperazinyl, 4- (N-methyl-Nn-betylamino) -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-pipernzinyl, 4- (N-methyl-N-acetylamino) -1-piperazinyl, 3- (N-ethyl-N-propionylamino) -1-piperazinyl, -4 -hydroxy-1-piperazinyl, 3: hydroxy-phenyl-1-piperazinyl, 2-hydroxy-1-piperazinyl, 4-methylulfonylylpiperidine perazinyl, 4-ethylsulfonyl-1-piperazinyl, 4-propylsulfonyl 1-piperazinyl, 4-n-butylsulfonyl-1-piperazinyl, 4-pentylsulfonyl- 1-piperazinyl, 4-hexylsulfonyl-1-piperazinyl, 4-trifluoromethylsulfonyl-1-piperazinyl, 4- (2-fluoroethylsulfonyl) -1-piperazinyl, 4- (3-fluoropropylsulfonyl) -1-piperazinyl, 4- (4,4,4- '-trifluorobutylsulfonyl) -1-piperazinyl, 4-sulfonyl-1-piperazinyl, 4- (phthalid-3-yl) -1-piperazinyl, 4-β / 3,4-diblozo 2 (5H) -fufanon-5-yl) -1-piperazinyl, 4- (3,4-dichloro-2 (5H) -furanon-5-yl) -1-piperazinyl, 4-2 (5H) - furanon-5-yl) -1-piperazinyl, 4- (3-chloro: 2- (5H) -furanon-5-yl) -1-piperazinyl, 4-formyl-3-methyl-1--piperazinyl, 4- acetyl-3-ethyl-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-piperazinyl, 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-piperazinyl, 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-cycloobutyl-1-piperazinyl, 4-cyclopentyl-1-piperazinyl, 4-cyclohexyl- 1-piperazinyl, 4-cycloheptyl-1-piperazinyl, 4-cyclooctyl-1-piperazinyl, 4-phenyl-1-piperazinyl, 4- (4-fluorophenyl) -1-piperazinyl, 4- (3 -bromophenyl) -1-piperazinyl, 4- (2-chlorophenyl) -1-piperazinyl, 4- (4-iodophenyl) -1-piperazinyl, 4- (4-methylphenyl) -1-pi- 4- (2 -propylphenyl) -1- 4- (3-pentyl-4- (4-trifluoromethylphenyl) -1-piperazinyl, 4- [3- (2-chloroethyl) phenyl] perazinyl, 4- (3-ethylphenyl) -1- piperazinyl, -piperazinyl, 4- (4-n-butylphenyl) -1-piperazinyl, phenyl) -1-piperazinyl, 4- (2-hexylphenyl) -1-piperazinyl, -1-piperazinyl, 4- / 2- (3 , 3-dibromopropyl) phenyl / -1-piperazinyl, 4- [4- (4-chlorobutyl) phenyl] -1-piperazinyl, 4-hydroxymethyl-1-piperazinyl, 4- (2-hydroxyethyl) -1-piperazinyl , 4- (3-hydroxypropyl) -1-piperazinyl, 4- (3-chloropropyl) -1-piperazinyl, 4- (bromo-ethyl) -1-piperazine, 4- (2-fluoroethyl) -1-piperazinyl, 4- (4-chlorobutyl) -1-piperazinyl, 4- ( 3-fluoropentyl) -1-piperazinyl, -4- (2,3-cyclohexyl) -1-piperazinyl, -4- (2,2,2-trifluoroethyl) -1- -piperazinyl, 4-fluorofluoromethyl-5-pipe; aziny1; Ü4- (§minoàe-fl yl) -1-piperazinyl; 4- (3-dimethylaminoposoyl) -1-piperazinyl, 10 501 371 10 15 20 25 30 35 40 4- (2-ethylaminoethyl) -1-piperazinyl, 4- <4-propylaminobutyl) -1-piperazinyl, 4 - (5-n-butylaminopentyl) -1-piperazinyl, 4- (6-pentylaminohexyl) -1-piperazinyl} 4- (N-methyl-N-ethylaminomethyl) -1-piperazinyl, 4- (N-methyl -N-propylaminomethyl) -1-piperazinyl, 4- (2-diethylaminoethyl) piperazinyl, 4% hetoxymethyl) -1-piperazinyl, 4- (ethoxymethyl) -p-piperazinyl, 4- (2-propoxyethyl) -1- -piperazinyl, 4- (3-butoxypropyl) -1-piperazinyl, 4- (4-pentyloxybutyl) -1-piperazinyl, 4- (5-hexyloxypectyl) -1-piperazinyl, 4- (6-methoxyhexyl ) -1-piperazinyl; 4-propargyl-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-ethynyl-1-piperazinyl, 4-vinyl-1-piperazinyl, 4-allyl-1-piperazinyl, 4 - (2-butenyl) -1- -piperazinyl, 4- (3-butenyl) -1-piperazinyl, 4- (1-methylalanyl) -1- -piperazinyl, 4- (2-pentenyl) -1-piperazinyl, 4 - (2-hexenyl) -1-piperazinyl, 2-oxo-1-piparazinyl, 3-oxo-1-piperazinyl, 4-oxo--3-methyl-1-piperazinyl, 4,4-dimethyl-1-piperazinyl , 4- (2-pyridyl) -1-piperazinyl, 4- (3-pyridyl) -1-piperazinyl, 4- (4-pyridyl) -1-piperazinyl, 4-carbamoyl-1-piperazinyl, 4-dimethylamino carbonyl-1-piperazinyl, 4-ethylaminocarbonyl-1-piperazinyl, 4-propylaminocarbonyl-1-piperazinyl, 4-butylaminocarbonyl-1-piperazinyl, 4-pentylaminocarbonyl-1-piperazinyl, 4-hexylaminocarbonyl-1-piperazinyl, 4-diethylaminocarbonyl-1-piperazinyl, 4- (N-methyl-N-propylaminocarbonyl) -1-piperazinyl, 4-methoxycarbonyl-1-piperazinyl, 4-ethoxycarbonyl-1-pipera zinyl, 4-propoxycarbonyl-1-piperazinyl, 4-tert-butoxycarbonyl-1-piperazinyl, 4-pentyloxycarbonyl-1-piperazinyl, 4-hexoxycarbonyl-1-piperazinyl, 4-benzyloxycarbonyl-1-piperazinyl, 4- (2-phenylethoxycarbonyl) -1-piperazinyl, 4- (3-phenylpropoxycarbonyl) -1- -piperazinyl, 4- (4-phenylbutoxycarbonyl) -1-piperazinyl, 4- (5-phenylpentyloxycarbonyl) -1- piperazinyl, 4- (6-phenylhexyloxycarbonyl) -1-piperazinyl, 4- (2-aminoacetyl) -1-piparazinyl, 4- (3-aminopropionyl) # 1-piperazinyl, 4- (4-aminobutyryl) -1 -piperazinyl, 4- (5-aminopentanoyl) -1-piperazinyl, 4- (6-aminohaxanoyl) -1-piperazinyl, 4- (2-benayloxycarbonylaminoacetyl) -1-piperazinyl, 4- / 2- ( 2-phenylethoxycarbonyl (mino) acetyl / -1-piperazinyl, 4-12- (3-phenylpropycycarbonylamino) acetyl] -1-piperazinyl, 4- [2- (α-phenylbutoxycarbonylamino) acetyl] fl-piperazinyl, 4-methylphosphonyl] > §Oxika; b9ny1methylf; -pip§; gz¿qy1Q, 4-ethoxycarbonylmethyl-1fPiperf, ÜL azinyl, §j} 2-ethoxicasbdnylqtfl) -Qjpibet fi zinfl, h4- (3-propoxy- 10 15 20 25 30 35 40 ll 501 4- (4-butoxycarbonylbutyl) -1-p 1- 4- (6-carbonylpropyl) -1-piperazinyl, perazinyl, 4- (5-pentyloxycarbonylpentyl) -1-piperazinyl, α-hexyloxycarbonylhexyl) -1-piperazinyl, 4-carbonylmethyl-1-piperazinyl, 4- ( 2-carboxyethyl) -1-piperazinyl, 4- (3-carboxypropyl) -1-piperazinyl, 4- (4-capboxybutyl) -1-piperazinyl, 4- (5f-carboxypentyl) -1-piperazinyl, 4- ( 6-carboxyhexyl) -1-piperazinyl, 4- (anilinocarbonylmethyl) -1-piperazinyl, 4- (2-aminocarbonylethyl) -1-piperazinyl, 4- (3-anilinocafbonylpropyl) -1: piperazinyl, 4 - (4-anilinocarbonylbutyl) -1-piperazinyl, 4- (5-anilinocarosynylpentyl) -1-piperazinyl, 4- (6-anilinocarbonylhexyl) -1- -piperazinyl, 4- (3-carboxyacryloyl) -1-piperazinyl, 4- (3-carboxy-2,3-dichloroacryloyl) -1-piperazinyl, 4-methyl-1-piperidinyl, 4-ethyl-1-piperidinyl, 4-propyl-1-piperidinyl, 4-n- butyl-1-piperidinyl, 4-pentyl-1-piperidinyl, 4-hexyl-1-piperidinyl, 4-methoxy-1-piperidinyl, 4-ethoxy-1-piperidinyl, 4-propoxy-1-piperidinyl, 4 -n-butoxy-1-piperidinyl, 4-pentyloxy-1-piperidinyl, 4-hexyloxy-1-piperidinyl, 4-acetyl loxy-1-piperidinyl, 4-propionyloxy-1-piperidinyl, 4-butyryloxy-1-piperidinyl, 4-pentanoyloxy-1-piperidinyl, 4-hexanoyloxy-1-piperidinyl, 4-methoxycarbonyloxy-1-piperidinyl 1-piperidinyl, 4-propoxycarbonyl-1-piperidinyl, 4-n-butoxycarbonyl-1-piperidinyl, 4-pentyloxycarbonyl-1-piperidinyl, 4-hexyloxycarbonyl-1-piperidinyl, 4-benzyl-1 Piperidinyl, 4- (2-phenylethyl) -1-piperidinyl, 4- (1-phenylethyl) -1-piperidinyl, 4- (3-phenylpropyl) -1-piperidinyl, 4- (4-phenylbutyl) - 1-piperidinyl, 4- (5-phenylpentyl) -1-piperidinyl, 4- (6-phenylhexyl) -1-piperidinyl, 4-hydroxy-1-piperidinyl, 3-hydroxy-1-piperidinyl, 2-hydroxy-1- -piperidinyl, 4-amino-1-piperidinyl, 3-amino-1-piperidinyl, 2-amino-1-piperidinyl, 4-dimethylamino-1-piperidinyl, 4-methylamino-1-piperidinyl, 3-ethylamino-1 -piperidinyl, 2-propylamino-1-piperidinyl, 4-n-butylamino-1-piperidinyl, 3-pentylamino-1-piperidinyl, 4-hexylamino-1-piperidinyl, 3-diethylamino-1-piperidinyl, 4 - (N-methyl-N-propylamino) -1-piperidinyl, 4-carba moyl-1-piperidinyl, 3-carbamoyl-1-hyperidinyl, 3,5-dimethyl-1-piperidinyl, 2,5-dimethyl-1-piperidinyl, 4-oxo-1-piperidinyl, 3-oxo-1- piperidinyl, 3-hydroxy-1-pyrrolidinyl, 3-amino-1-pyrrolidinyl, 2-hydroxy-1-pyrrolidinyl, 2-amino-1-pyrrolidinyl, 3-methylamino-1-pyrrolidinyl, 3-dimethylamino-1- pyrrolidinyl, 2-ethylamino-1-pyrrolidinyl, 3-propylamino-1-pyrrolidinyl, 2-n-butylamino-1-pyrrolidinyl, 3-pentylamino-1-pyrrolidinyl, “10 15 20 25 30 35 40 12 501 371 2- hexylamino-1-pyrrolidinyl, 3-diethylamine-1-pyrrolidinyl, 3- (N-methyl-N-propylamino) -1-pyrrolidinyl, 2- (N-ethyl-Nn-butylamino) -1-pyrrolidinyl, 3- acetylamino-1-pyrrolidinyl, 3-propionylamino-1-pyrrolinyl, 2-butyrylamino-1-pyrrolidinyl, 3-pentanoylamino-1-pyrrolidinyl, 2-hexanoylamino-1-pyrrolidinyl, 3-hydroxymethyl-1-pyrrolidine 2- (2-hydroxethyl) -1-pyrrolidinyl, 3- (3-hydroxypropyl) -1-pyrrolidinyl, 2- (4-hydroxybutyl) -1-pyrrolidinyl, 3- (5-hydroxypentyl) 41-pyrrolidinylT 3 - (6-hydroxyhexyl) -1-pyrrolidinyl, 3-aminomethyl-1-pyrr olidinyl, 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- (methylminomethyl) -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- (dimethylaminomethyl) -1-pyrrolidinyl, 2-pyrrolidinyl, 3- (N-ethyl-Nn-butylaminomethyl) -1-pyrrolidinyl, 3-methylaminomethyl-4-methyl-1-pyrrolidinyl, 3-methylaminomethyl-4-fluoro -1-pyrrolidinyl, 3-methylamino-4-methyl-1-pyrrolidinyl, 3-methylamino-4-chloro-1-pyrrolidinyl, 3-methylaminomethyl-4-fluoro-1-pyrrolidinyl, 3-methylamino-4-fluoro- 1-pyrrolidinyl, 3-ethylaminomethyl-4-ethyl-1-pyrrolidinyl, 3-propylaminomethyl-4-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-propylam ino-5-chloro-1-pyrrolidinyl, 3-n-butylamino-5-hexyl-1-pyrrolidinyl, -B-pentylamino-4-ethyl-1-pyrrolidinyl, 3-hexylamino-4-fluoro-1-pyrrolidinyl lidinyl, 4-methyl-1-homopiperazinyl, 4-ethyl-1-homopiperazinyl, 4-propyl-1-homopiperazinyl, 4-n-butyl-1-homopiperazinyl, 4-pentyl-1-homopiperazinyl, 4-hexyl-1 -homopiperazinyl, 4-formyl-1-homopiperazinyl, 4-acetyl-1-homopiperazinyl, 4-propionyl-1-homopiperazinyl, 4-butyryl-1-homopiperazinyl, 4-pentanoyl-1-homopiperazinyl, 4 -hexanoyl-1-homopiperazinyl, 2-methyl-1-hexahydropyridazinyl, 2-ethyl-1-hexahydropyridazinyl, 2-propyl-1-hexahydropyridazinyl, 2-n-butyl-1-hexahydropyridazinyl, 2-pentyl-1- hexahydropyridazinyl, 2-hexyl-1-hexahydropyridazinyl, 2-formyl-1-hexahydropyridazinyl, 2-acetyl-1-hexahydropyridazinyl, 2-ptopionyl-1-hexahydropyridazinyl, 2-butyryl-1 + - - hexahydropyridazinyl, 2-pentanoyl-1-hexahydropyridazinyl, 2-hexanoyl-1-hexahydropyridazinyl, 2-methyl-1-pyrazolidinyl, 2-ethyl-1-pyrazolidinyl, 2-propyl- 1 -pyrazolidinyl, 2-n-butyl-1-pyrazolidinyl, 2-pentyl-1-pyrazolidinyl, 2-hexyl-1-pyrazolidinyl, 2-formyl-1-pyrazolidinyl, 2-acetyl-1-pyrazolidinyl, 2- propionyl-1-pyrazolidinyl, 2-butyryl-1-pyrazolidinyl, 2-pentanoyl-1-pyrazolidinyl, 2-hexanoyl-1-pyrazolidinyl, §, 5-dimethylmorpholino, 3-methylmorpholino, 3-ethylmorpholino, 2 -propyl-morpholino, 3-n-butylmorpholino, 3-pentyl-S-methylmorpholino, 3-hexyl-5-ethylmorpholino, 3-aminomethylmorpholino, 3-methylamino-methylmorpholino, 2-ethylaminomethylmorpholino, 3-propylaminomethyl-morpholino, 3-propylaminomethyl-morpholino , 2-pentylaminomethyl-morpholino, 3-hexylaminomethyl-morpholino, 3- (2-methylaminoethyl) -morpholino, 3- (3-methylaminopropyl) morpholino, 3- (4-methylaminobutyl) morpholino, 2- (5-methylaminopentyl) morpholino, 3- (6-methyl-aminohexyl) morpholino, 4- (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl-1-piperazinyl, 4- (5-tert-butyl-2 oxo-1,3-dioxolen-4-yl) methyl-1-piperazinyl, 4- (5-phenyl-2-oxo-1,3-dioxolen-4-yl) methyl-1-piperazinyl, 4- (2-oxo-1,3-dioxolen-4-yl) methyl-1-p Iperazinyl, 3- (5-methyl-2-oxo-1,3-dioxolen-4-yl) methylamino-1-pyrrolidinyl, 4- (5-methylph2-oxo-1,3-dioxolen-4- yl) methylamino-1-piperidinyl, 3- (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-1-piperazinyl, 3-ethyl--4-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-fluoro-1-piperidinyl, 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-pyrroli dinyl, 3-amino-4-fluoro-1-piperidinyl, 3-amino-4-hydroxy-1-piperidinyl, 3-amino-4-methyl-1-pyrrolidinyl, 4-benzyl-3-methyl-1 - -piperazinyl, 3-fluoromethylmorpholino, 3-chloromethylmorpholino, 4-oxo-1-piperidinyl, 3-oxo-1-piperidinyl, 2-oxo-1-piperidinyl, 3-acetylaminomethyl-1-pyrrolidinyl, 3- (N -ethyl-N-acetylamino) methyl-1-pyrrolide vinyl, 3-t-butoxycarbonylaminomethyl-1-pyrrolidinyl, 3-ethylaminomethyl-1-pyrrolidinyl, 4-cyclopropylmino-1-piperazinyl} 3-cyclopropylamino-1-pyrrolidinyl, 04-cyclopentylamino-1-pipiazinyl, 4- cyclohexylamino-1-piperazinyl, 3-cycloheptylamino-1-pyrrolidinyl, 4-cyclooctamino-1-piperidinyl, γ-β-4-cyclopropylamino-1-piperidinyl, β-cyclopropylgiminophorfolino, 14 501 371 4-thio-1-piperidinyl, 3-thio-1-piperazinyl, 3-thiomorpholino, 4-cyclopropylaminomethyl-1-piperazinyl, 3-cyclopropylaminomethyl-1-pyrrolidinyl, 4-cyclopropylaminomethyl-1-piperidinyl, 3- cyclopropylaminomethylmethylmorpholino, 4- (2-cyclopentylaminoethyl) -1-piperazinyl, 4- (3-cyclohexylaminopropyl) -1-piperazinyl, 3- (4-cyclobutylaminobutyl) -1-pyrrolidinyl, 4- (S-cyclooctylaminopentyl) ) -1-piperidinyl, 4- (6-cyclopropylaminohexyl) -morpholino, 3-acetylaminomethyl-1-pyrrolidinyl, 4- (2-propionylaminoethyl) -1-piperazinyl, 4- (3-butyrylaminopropyl) -1-piperidinyl nyl, 3: (4-pentanoylaminobutyl) morpholino, 4- (5-hexanoyl aminopentyl> -1-piperazinyl, 3- (6-acetylaminohexyl) -1-pyrrolidinyl, 4- (N-acetyl-N-ethylamino) methyl-1-piperazinyl, 4- (N-cyclopropyl-N-acetylamino) methyl-1-pyrrolidinyl, 4- (methoxycarbonylaminomethyl) -1-piperazinyl, 4- <2-ethoxycarbonylaminoethyl> -1-piperidinyl, 3- (3-propoxycarbonylaminopropyl) morpholino, t3- (4-pentyloxycarbonylaminobutyl) -1-pyrrolidinyl, 3- (5-hexyloxycarbonylaminopentyl) -1-pyrrolidinyl, 4- (6-t-butoxycarbonylaminohexyl) -1-piperazinyl, 3- (Nt-butoxycarbonyl-N-ethylaminomethyl) -1-pyrrolidinyl rolidinyl, 3- (Nt-butoxycarbonyl-N-methylaminomethyl) -1-pyrrolidinyl, 3- (Nt-butoxycarbonyl-N-cyclopropylaminomethyl) -1-pyrrolidinyl, 4- (N-methoxycarbonyl-N-cyclopropylaminomethyl) - 1-piperazinyl, 4- (N-propoxycarbonyl-N-cyclohexylaminomethyl) -1-piperidinyl and the like.

The term "cycloalkyl" embraces C 3 -C 5 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.

The term "phenyl lower alkyl, substituted with a lower alkoxy, nitro or amino" includes phenyl wherein the phenyl ring may be subalkyl groups, wherein the phenyl ring may be substituted with a straight or branched chain C1-C5 alkoxy group, nitro group or amino group and the alkyl moiety is a C1 -C 5 -alkyl group straight or as benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenyl-1,1-dimethyl-2-phenylethyl, 6-phenylhexyl, 2-methyl-3-phenylpropyl, 4-methoxybenzyl, 3- Ethoxy branched chain, propyl, 4-phenylbutyl, 5-phenylpentyl, benzyl, 2-propoxybenzyl, 4-n-butoxybenzyl, 3-pentyloxyhenzyl, 2-hexyloxybenzyl, 4-nitrobenzyl, 3-nitrobeneyl, 4-aminobenzyl, 2-aminobenzyl , 2- (4-methoxyphenyl) ethyl, 1- (3-ethoxyphenyl) ethyl, N- (2-propoxyphenyl) propyl, 4- (4-n-butoxyphenyl) butyl, 5- (2- 'n. - (a-aminçsfenyunæxyl; ~ ¿q'c; = -'_ 1ik§ai1dq ~; ,, _-;.;.

The term "phenyl which may be unsubstituted; having a halogen atom, a lower alkyl or a lower alkyl substituted with 1 to 3 halogen atoms" includes phenyl groups wherein the phenyl ring may be substituted by a halogen atom or with a straight or branched chain C 1 -C 5 alkyl group, which alkyl group may be substituted by 1 to 3 halogen atoms, such as phenyl, 4-fluorophenyl, 3-bromophenyl, 2-chlorophenyl, 4-iodophenyl, α-methylphenyl , 3-ethylphenyl, 2-propylphenyl, 4-n-butylphenyl, p-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-trifluoroethyl) phenyl, 4- (2,2, 2-trifluoroethyl) phenyl and the like.

The term "lower alkyl having 1 to 3 substituents selected from the group consisting of hydroxy, amino, a lower alkoxy and a halogen atom, wherein amino is optionally substituted with a lower alkyl, a lower alkanoyl, a cycloalkyl or a lower alkoxycarbonyl" includes Cl Straight or branched chain C5 alkyl groups having 1 to 3 substituents selected from the group consisting of hydroxy group; an amino group which may be substituted with 1 to 2 substituents selected from the group consisting of a C1-C5 alkyl group straight or branched chain C1-C5 straight or branched chain C1-C5 alkanoyl group, a C1-C5 cycloalkyl group or a straight or branched chain C1-C5 alkoxycarbonyl group; a straight or branched chain C1-C5 alkoxy group and a halogen atom such as hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl, 6-hydroxyhexyl, 3-chloropropyl, bromomethyl, 2-fluoroethyl, 4-chlorobutyl, 3-fluoropentyl, 2 , 3-dichlorohexyl, 2,2,2-trifluoroethyl, trifluoromethyl yl, aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, 3-dimethylaminopropyl, 2-ethylaminoethyl, 4-propylaminobutyl, 5-n-butylaminopentyl, 6-pentylaminohexyl , methylaminomethyl, diethylaminomethyl, 2-dipropylaminoethyl, 1-di-n-butylaminoethyl, 3-dipentylaminopropyl, 4-dihexylaminobutyl, N-methyl-N-ethylaminomethyl, N-methyl-N-propylaminomethyl, methoxymethyl, ethoxymethyl , 2-propoxyethyl, 3-butoxypropyl, 4-pentyloxybutyl, Svhexyloxypentyl, 6-methoxyhexyl, propoxymethyl, 1-ethoxyethyl, 2-hexyloxyethyl, formylaminomethyl, acetylaminomethyl, 2-propanoylaminoethyl, 3-butyrylenaminopropyl, 4-butyrylenaminopropyl, , S-hexanoylaminopentyl, 6-acetylaminohexyl, propanoylaminaminethyl, -1-acetylaminoethyl, 2-hexanoylaminoethyl, N-acetylamino, N-acetylaminoethyl, N-acetylaminoethyl N-ethylaminomethyl, N-acetyl-N-cyclopropylaminomethyl, N, N-dicyclopropylaminomethyl, cyclopropylaminomethyl, 2-cyclobutylaminoethyl, 3-cyclopentyl, 1-cyclopropylaminoethyl, 2-cyclo lopropylaminoethyl, aminopropyl, 4-cyclohexylaminobutyl, 5-cycloheptylaminopentyl, 6-cyclooctylaminohexyl, N-methyl-N-cyclopropylaminomethyl, N-ethyl-N-cyclopropylaminomethyl, methoxycarbonylaminomethyl, 2-ethoxycarbonylaminopropylamino 4-t-butoxycarbonylamino-butyl, nohexyl, t-butoxycarbonylaminomethyl, 2-t-butoxycarbonylamino-5-pentyloxycarbonylaminopentyl, 8-hexyloxycarbonylamethyl, 1-t-butoxycarbonylaminoethyl, Nt-butoxycarbonylamino-N-methoxycarbonylamino-amino -ethylaminomethyl, Nt-butoxycarbonylamino-N-cyclopropylaminomethyl and the like.

The term "lower alkanoyl which may be substituted by 1 to 7 halogen atoms" includes straight or branched chain C 1 -C 5 alkanoyl groups which alkanoyl groups may be substituted by 1 to 7 halogen atoms such as formyl, acetyl, propionyl, butyryl , pentanoyl, hexanoyl, α, α, α-trifluoroacetyl, ÅB, B-trifluoro-G, G-difluoropropionyl, Y, Y, Y-trifluoro-B, B-difluoro-G, G-difluorobutyryl, Q, u dichloroacetyl, Q-bromoacetyl, G-iodoacetyl, B-fluoropropionyl, B-fluoro-Q-fluoropropionyl, 6-fluorohexanoyl, 4-chloropentanoyl, 3,3,3-trifluoropropionyl and the like.

The term selected from the group consisting of a halogen atom and "lower alkenylcarbonyl having 1 to 3 substituents, a carboxy" includes C 2 -C 5 straight or branched chain alkenylcarbonyl groups having 1 to 3 substituents selected from the group consisting of a halogen atom and a carboxy group, 3-car- 4-carboxyisocro-4-car- such as 3-carboxyacryloyl, 3-carboxy-2,3-dichloroacryloyl, boxi-2,3-dibromoacryloyl, 4-carboxycrotonoyl, tonoyl, 5-carboxy 3-pentenoyl, 6-carboxy-4-hexenoyl, boxi-3-fluorocrotonoyl, 5-carboxy-3,4-dichloro-3-hexenoyl and the like.

The term "lower alkoxycarbonyl" embraces straight or branched chain C1-C5 alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbononyloxycarbonyl and the like.

The term "aminocarbonyl", which may be substituted by ~. a lower alkyl ”includes aminocarbonyl groups which may be substituted with 1 or 2 of a straight or branched chain C 1 -C 5 alkyl group such as carbamoyl, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, n -butylaminocarbonyl, pentylaminocarbonyl, hexylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, dipentylaminocarbonyl, dihexylaminocarbonyl, N-methyl-N-propylaminocarbonyl, N-methyl-N-tert-butylaminocarbonyl and similar. - The term "phenyl-1α-alkoxycycarbonyl" embraces phenylalkoxycarbonyl groups, wherein the alkoxy moiety is a straight or branched chain C1-C5 alkoxy group, such as benzyloxycarbonyl, 2-phenylethoxycarbonyl, 1-phenylethoxycarbonyl, 3-phenoxycarbonyl, 3-phenoxycarbonyl , 1-dimethyl-2-phenylethoxycarbonyl, 5-phenylpentyloxycarbonyl, 6-phenylhexyloxycarbonyl, 2-methyl-3-phenylpropoxycarbonyl and the like.

The term "aminol-alkanoyl which may be substituted by a phenyl-alkoxycarbonyl" includes straight or branched chain C2-C5 aminoalkanoyl groups, which groups may be substituted by a phenylalkoxycarbonyl group in which the alkoxy moiety is a straight or branched C1-C5 alkoxy group chain, such as 2-aminoacetyl, 3-aminopropionyl, 4-aminobutyryl, 5-aminopentanoyl, 6-aminohexanoyl, 2-benzyloxycarbonylaminoacetyl, 2- (2-phenylethoxycarbonylamino) acetyl, 2- (3-phenylpropoxycarbonylamino) acetyl , 3- (4-phenylbutoxycarbonylamino) propionyl, 4- (1,1-dimethyl-2-phenylethoxycarbonylamino) butyryl, 5- (5-phenylpentyloxycarbonylamino) pentanoyl, 6- (6-phenylhexylcarbonylamino) hexanoyl, 2- ( 2-methyl-3-phenylpropoxycarbonylamino) acetyl and the like.

The term "lower alkoxycarbonyl lower alkyl" includes alkoxycarbonylalkyl groups, wherein the alkoxy and alkyl moieties are C 1 -C 5 alkoxy- and straight or branched chain alkyl groups, such as methoxycarbonylmethyl, ethoxycarbonylmethyl, 2-ethoxycarbonylbutylcarbonylbutylcarbonylalkyl, α 5-pentyloxycarbonylpentyl, 6-hexyloxycarbonylhexyl, 2-methoxycarbonylethyl, 3-methoxycarbonylpropoxypropyl, 3-ethylcarbonylpropoxypropyl, 4-ethylcarboxybutoxybutyl and the like The term "carboxylagalkyl" embraces carboxylalkylcarbalkylcarbalkyl straight or branched chain, such as carhokimethyl, 2-carboethyl, 3-carboxypropyl, -4-carboxybutyl, 5-carboxypentyl, -6-carboxyhexyl, .1-carboxy-ethyl. , 1,1-dimethyl-2-carboxyethyl, 2-methyl-3-carboxypropyl and the like.

The term "anilinocarbonyl lower alkyl" embraces anilinocarbonylalkyl groups, wherein the alkyl moiety is a straight or branched chain C 1 -C 5 alkyl group, such as anilinocarbonylmethyl, 2-anilinocarbonylethyl, 1-anilinocarbonylethyl, 3-aninocinylpropylinylcarbonyl G-anilinocarbonylhexyl, 1,1-dimethyl-2-anilinocarbonylethyl, 2-methylph3-anilinocarbonylpropyl and the like.

The term "amino which may be substituted by a lower alkyl or a lower alkanoyl" embraces amino groups which may be substituted by 1 or 2 of a straight or branched chain C1-C5 alkyl group or a straight or branched C1-C5 alkanoyl group branched chain such as 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-acetylamino, N-ethyl-N-propionylamino, N-methyl- N-buryrylamino, Nn- -propyl-N-pentanoylamino, N-ethyl-N-hecanoylamino and the like.

The term "2 (SH) -furanone, which may be substituted by 1 or 2 halogen atoms" includes 2 (5H) -furanone groups, which may be substituted by 1 or 2 halogen atoms, such as 2 (5H) -furanon-5-yl, 3 4-dibromo-2 (5H) -furanon-5-yl, 3,4-dichloro-2 (5H} -furanon-5-yl, 3-chloro-2 (5H) -furanon-5-yl 4-fluoro-2 (5H) -furanon-5-yl, 3-iodo-2 (5H) -furanon-5-yl and the like.

The term "sulfoalkalkyl" embraces sulfoalkyl groups, wherein the alkyl moiety is a C 1 -C 5 alkyl group having straight or branched 1-sulfoethyl, 3-sulfopro-1,1-dimethyl-2-chain, such as sulfomethyl, 2-sulfoethyl, pyl, 4-sulfobutyl , 5-sulfopentyl, 6-sulfohexyl, -sulfoethyl, 2-methyl-3-sulfopropyl and the like.

The term "lower alkylsulfonyl which may be substituted by 1 to 3 halogen atoms" includes C 1 -C 5 alkylsulfonyl straight or branched chain groups which groups may be substituted by 1 to 3 halogen atoms such as methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, pentylsulfonyl, nexylsulfonyl, trifluoromethylsulfonyl, 2-fluoroethylsulfonyl, 3-fluoropropylsulfonyl, 4,4,4-trifluorobutylsulfonyl, 5-chloro-pentylsulfonyl, 6-bromohexylsulfonyl, 6 2,2-difluoroethylsulfonyl, 2,3-dibromopropylsulfonyl and the like.

The term "lower alkoxy" embraces straight or branched chain C 1 -C 5 alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy and the like; The term "lower alkanoyloxy" embraces straight or branched chain C2-C5 alkanoyloxy groups, such as acetyloili, propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy, hexanoyloxy and the like.

The term "lower alkenyl" embraces straight or branched chain C 2 -C 5 alkenyl groups such as vinyl, allyl, 2-butenyl, 3-butenyl, 1-methylallyl, 2-pentenyl, 2-hexenyl and the like.

The term "lower alkynyl" embraces straight or branched chain C2-C5 alkynyl groups such as ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 2-hexynyl and the like .

The term "2-oxo-1,3-dioxolenmethyl, which may be substituted by phenyl or a lower alkyl" includes 2-oxo-1,3-dioxolenylmethyl groups, which may be substituted by phenyl group or a C1-C5 straight or branched chain alkyl group, such as (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl, (5-tert-butyl-2-oxo--1,3-dioxolen-4- yl) methyl, (5-phenyl-2-oxo-1,3-dioxolen-4-yl) methyl, oxolen-4-yl) methyl, (2-oxo-1,3-dioxolen-4-yl) methyl, (5-pentyl-2-oxo-1,3-di- (S-hexyl-2-oxo-1,3-dioxolen-4-yl) methyl, (5-ethyl-2-oxo-1,3) -dioxolen-4-yl) methyl, (5-propyl-2-oxo-1,3--dioxolen-4-yl) methyl and the like.

The term "lower alkyl, which may be substituted with 1 to 3 substituents selected from the group consisting of a 5- or 6-membered saturated heterocyclic ring, a lower alkylthio, amino, a lower alkylamino, a lower alkanoyloxy, hydroxy, a lower alkoxy and a the halogen atom 'comprises, in addition to the above-mentioned lower alkyl C1-C5 straight or branched chain alkyl groups, which groups are substituted by 1 to 3 substituents selected from the group consisting of a 5- or 6-membered saturated heterocyclic ring, a C 1 -C 5 straight or branched chain alkylthio group, hydroxy group, amino group, one amino group having 1 or 2 straight or branched chain C 1 -C 5 alkyl groups, one straight or branched chain C 1 -C 5 alkoxy group, one C1-C5 straight or branched chain alkanoyloxy group and a halogen atom, such as ff hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 6-hydroxyhexyl, 4-chlorobutyl , 3-fluo-4-hydroxybutyl, 5-hydroxypentyl, fluoromethyl, 3-chloropropyl, bromomethyl, 2-flu oroethyl, ropentyl, difluoromethyl, 2,3-dichlorohexyl, 2,2,2-trifluoron-iododomethyl, diethyl, trifluoromethyl, chloromethyl, dibromomethyl, chloromethyl, methoxymethyl, ethoxymethyl, 2-propoxyethyl, 3-butoxypropyl, 4-pentyloxybutyl, 5-hexyloxypentyl, 6-methoxinexyl, propoxymethyl, 1-ethoxyethyl, 2-hexyloxyethyl, aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6- aminohexyl, 3-dimethylaminopropyl, 2-ethylaminoethyl, 4-propylaminobutyl, 5-n-butylaminopentyl, 6-pentylaminohexyl, methylaminomethyl, diethylaminomethyl, 2-dipropylaminoethyl, 1-di-n-butylaminoethyl, 3-dipentylaminopropyl, 3-dipentylaminopropyl Tyl, N-methyl-N-ethylaminomethyl, N-methyl-N-propylaminomethyl, formyloxymethyl, acetyloxymethyl, 2-propionyloxyethyl, 3-butyryloxypropyl, 4-pentanoyloxybutyl, 5-hexanoyloxypentyl, 6-acetylpoxylohexyl -acetyloxyethyl, 2-hexanoyloxyethyl, (1-pyrrolidinyl) methyl, 1- (1-piperazinyl) ethyl, 2- (1-piperidinyl) ethyl, 3-morpholinopropyl, 4-thiomorpholinobutyl, 5- (1- - pyrroli dinyl) pentyl, 6- (1-piperazinyl) hexyl, methylthiomethyl, ethylthiomethyl, 2-propylthioethyl, 1-isopropylthioethyl, 3-butylthiopropyl, 4-tert-butylthiobutyl, 5-pentylthiopentyl, 6-hexylthiohexyl and the like.

The term "2-oxo-1,3-dioxolenemethylamino which may be substituted by phenyl or a lower alkyl" includes 2-oxo-1,3-dioxolenmethylamino groups which may be substituted by phenyl group or a C 1 -C 5 alkyl group by straight or branched chain, such as (5-methyl-2-oxo-1,3-dioxolen-4-yl) methylamino, (5-tert-butyl-2-oxo-1,3-dioxolen-4-yl) methylamino, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methylamino, (2-oxo-1,3-dioxolen-4-yl) methylamino, (5-pentyl-2-oxo-1 , 3-dioxolen-4-yl) methylamino, (5-hexyl-2-oxo-1,3,3-dioxolen-4-yl) methylamino, (5-ethyl-2-oxo-1,3-dioxolen-4- -yl) methylamino, (5-propyl-2-oxo-1,3-dioxolen-4-yl) methylamino and the like.

The term "cycloalkylamino" embraces C 3 -C 8 cycloalkylamino groups such as cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino, cyclooctylamino and the like. The term "lower alkylthio" includes straight or branched chain C1-C5 alkylthio groups such as methylthio, ethylthio, propyl / thio, isopropylthio, butylthio, tert-butylthio, pentylthio, hexylthio 371 ten and the like.

The compounds of the present invention of the above general formula (1) can be prepared by various methods and are conveniently prepared, for example, by the methods shown in the following reaction scheme.

(Reaction Scheme-I) x coo fl x cox3 Halogenation, g R2 'X2 R2', X2 -_R3 H3 [2] [3] O u R ”cH cooR5 [H] x Q-ca '/ R 2“ / | \\ cooR5 / R2 '\\ x2 H3 [S] fi Bo ttagande 1) rav “xc cooR5 2) oR7 I, \\ í // R -cH (: H2 X2 fa OR8. R3 H6 [6] [7] o H 5 nl-NH2 [8] xc coon Cyk1íSeríng._ .______________ +> ------ e> R2 'X2 NHR * 33 [9] 0 OX C00R5 Hydrolysis x C005 ------ +> II N 112 ”f H2 I, 33 R] 33 R

[10] [Ia] wherein R 1, R 2, R 3 and X are defined as above, R 2 'represents a halogen atom having an R 2 group (R 2 is defined as above), R 4 represents a group of the formula: -COR 9 (wherein R 9 represents a lower alkyl) or a group of the formula: -COOR 10 (wherein Rlu represents a lower alkyl), R 5 represents a lower alkyl, R 5 represents a group of the formula: 11¿ _ -N // R 1, R 1, 2 i (wherein R 11 and R 12 each represent a lower alkyl) or a lower alkoxy, X 2 and X 3 each represent a halogen atom, E 7 and R 8 each represent a lower alkyl. The halogenation of the compound (2) is carried out by reacting with a halogenating agent in the presence or absence of a solvent. The solvent includes aromatic hydrocarbons (eg benzene, toluene, xylene, etc.), halogenated hydrocarbons (eg dichloromethane, chloroform, carbon tetrachloride, etc.), ethers (eg dioxane, tetrahydrofuran, diethyl ether, etc.), dimethylformamide (DMF), dimethylsulfoxide (DMSO), and the like. The halogenating agent may be any conventional halogenating agent which can convert hydroxy in the carboxy group to a halogen atom, and comprises e.g. thionyl chloride, phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride, phosphorus pentabromide and the like. The amount of the compound (2) and the halogenating agent are not specified, but in case no solvent is used, the halogenating agent is usually used in a large excess amount and in case of using a solvent, the halogenating agent is usually used in an amount of at least 1 mol, preferably 2 -4 mol, per 1 mol of the compound (2). The reaction temperature and reaction time are also not indicated, but the reaction is usually carried out at a temperature from room temperature to 10 ° C for 30 minutes. to 6 hours.

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

The solvent may be any conventional solvent unless it has an undesirable effect on the reaction, and comprises e.g. water, ethers (eg diethyl ether, dioxane, tetrahydrofuran, monoglyme, diglyme, etc.), alcohols (eg methanol, ethanol, isopropanol, etc.), aromatic hydrocarbons (eg benzene, toluene, xylene , etc.), aliphatic hydrocarbons ft.ex. n-hexane, heptane, cyclohexane, ligroin, etc.), amines (eg pyridine, N, N-dimethylaniline, etc.), halogenated hydrocarbons (eg chloroform, dichloromethane, carbon tetrachloride, = etc. ), 10 15 20 25 30 35 40 23 501 371 aprotic polar solvents (eg DMF, DMSO, hexamethylphosphoramide (HMPA), etc.) and a mixture of these solvents.

The basic compound comprises inorganic bases (eg metallic sodium, metallic potassium, metallic magnesium, sodium hydride, sodium amide, sodium hydroxide, potassium hydroxide; sodium carbonate, potassium carbonate, sodium bicarbonate, etc.), metal alcoholates (eg sodium methylate, sodium ethylate, etc.) and organic bases (eg pyridine, piperidine, quinoline, triethylamine, N, N-dimethylaniline, etc.). The reaction is usually carried out at a temperature of from 0 ° to 150 ° C, preferably from room temperature to 120 ° C, usually used in an amount of at least 1 mol, preferably 1-2 for 0.5 to 15 hours. The compound (4) moles, per 1 mole of the compound (3). The basic compound is usually used in an amount of at least 1 mole, preferably 1-2 moles, per 1 mole of the compound (3).

The compound (5), wherein R 4 represents the group: -COR 9 is subjected to a reaction to remove the group -COR 9 in a suitable solvent in the presence of a basic compound. The solvent comprises ethers (eg diethyl ether, dioxane, tetrahydrofuran, monoglyme, diglyme, etc.). aromatic hydrocarbons benzene, toluene, xylene, etc.), aliphatic hydrocarbons (eg n-hexane, heptane, cyclohexane, etc.) aprotic polar solvents (eg DMF, DMSO, HMPA, etc.) and similar. The basic compound comprises ammonia gas, aqueous ammonia, primary or secondary amines (eg ethylamine, diethylamine, piperidine, etc.) and the like. The reaction is usually carried out at a temperature of from 0 ° to 150 ° C, preferably from room temperature to 100 ° C, for 1-20 hours.

The compound (5), wherein R4 represents a group: -COOR1 ° is subjected to a reaction to remove the group -COOR1Û in an aqueous solution in the presence of an acid catalyst. The acid catalyst comprises mineral acids (eg hydrochloric acid, sulfuric acid, etc.) and organic acids (eg p-toluenesulfonic acid, etc.).

The reaction is usually carried out at a temperature of from 0 ° to 150 ° C, preferably from room temperature to 100 ° C, for 1-20 hours. The reaction of the R4 group-removed compound and the compound (G) is carried out in a suitable solvent. The solvent may be any solvent used in the above reaction to remove the R 4 group. The reaction is usually carried out at a temperature of from 0 ° to 200 ° C, suitably from 0 ° to 150 ° C, for 0.5-10 hours. The compound (6) is usually used in an equimolar to a large excess amount, preferably 1-2 moles of 1 mole of the compound (5). In the case of using a compound (6) in which Re represents a lower alkoxy group, the reaction can also be carried out using acid anhydrides (eg acetic anhydride) as a solvent as well as the above-mentioned solvents at a temperature of from 0 °. to 200 ° C, preferably 0 ° to 170 ° C. The reaction of the compound (7) and the compound (8) is carried out in a suitable solvent. The solvent can be any conventional solvent unless it has an undesirable effect on the reaction, and comprises e.g. alcohols (eg methanol, ethanol, propanol, etc.), ethers (eg diethyl ether, dioxane, tetrahydrofuran, monoglyme, diglyme, etc.), aromatic hydrocarbons (eg benzene, toluene, xylene, etc.), aliphatic hydrocarbons (e.g. n-hexane, heptane, cyclohexane, ligroin, etc.), halogenated hydrocarbons (eg chloroform, methylene chloride, carbon tetrachloride, etc.), aprotic polar solvents (e.g. eg DNF, DMSO, HMPA, is usually carried out at a temperature from Û to 150 ° C, suitable, etc.), and the like. The reaction takes place from room temperature to 100 ° C, for 0.5 - 15 hours. The compound (8) is usually used in an amount of at least 1 mole, preferably 1-2 moles, per mole of the compound (7). In the reaction, a basic compound may optionally be added, and such a basic compound may be any basic compound used in the above reaction of the compound (3) and the compound (4).

The cyclization of the compound (9) is carried out in a suitable solvent in the presence of a basic compound. The solvent may be any conventional solvent unless it has an undesirable effect on the reaction and comprises e.g. ethers (eg diethyl ether, dioxane, tetrahydrofuran, monoglyme, diglyme, etc.), aliphatic hydrocarbons (eg 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. The basic compound comprises inorganic bases (eg metallic sodium, metallic potassium, sodium hydride, sodium amide, sodium hydroxide, potassium hydroxide, etc.), metal alcoholates (eg sodium methylate, sodium ethylate, etc.) and organic bases (e.g. eg 1,8-diazobicyclo / S, 4,0 / undecene-7 (DBU), N-benzoyltrimethylamine, tetrabutylammonium hydroxide, etc.), The reaction is usually carried out at a temperature from 0 ° to 150 ° C, preferably from room temperature to 120 ° C, for 0.5-5 hours. The basic compound is usually used in an amount of at least 1 mole, preferably 1-2 moles, per 1 mole of the compound (9).

Hydrolysis of the compound (10) can be carried out under the conditions of conventional hydrolysis, e.g. in the presence of a basic compound roxide, potassium carbonate, etc.), a mineral acid (eg sulfuric acid, hydrochloric acid, nitric acid, etc.) or an organic acid (eg acetic acid, aromatic sulfonic acids, etc.) in a solvent, such as water, alcohols (eg methanol, ethanol, isopropanol, etc.), ketones (eg acetone, methyl ethyl ketone, etc.), ethers (eg dioxane, ethylene glycol, etc. .), acetic acid or a mixture thereof. The reaction is usually carried out at a temperature of from room temperature to 200 ° C, preferably from room temperature to 150 ° C, for 0.1 to 30 hours. By the reaction, the compound (Ia) is prepared.

(Reaction Scheme-II) q 13 2 ° X coon '1 ,, R H [11] X coon 3 m \ I | 1 '"N' 2 N 3 '1 R 1 [1b] [1b'] wherein R 1, R 3 and X are defined as above, X 4 represents a halogen atom and R 13 represents a hydrogen atom or a group of the formula: /// 0coR1q -B (R14 and R15 each represent an alkyl).

The reaction of the compound (1b) and the compound (11) is carried out in an inert solvent, wherein both compounds are used in a wide range of ratios, and the compound (11) is usually used in an amount of at least 1 mol, preferably 1-5 mol, per 1 mole of the compound <1b). The solvent comprises e.g. water, alcohols (eg methanol, ethanol, isopropanol, butanol, amyl alcohol, isoamyl alcohol, etc.), aromatic hydrocarbons (eg benzene, toluene, xylene, etc.), ethers (eg tetra hydrofuran, dioxane, diglyme, etc.), dimethylacetamide, DMF, DMSO, HMPA, N-methylpyrrolidone and a mixture thereof. Among these solvents, a suitable one is a DMF, DMSO, HMPA and N-methylpyrrolidine. The reaction can also be carried out in the presence of an acid scavenger, such as inorganic carbonates (eg sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, etc.) or organic bases (eg pyridine, quinoline, triethylamine, etc.). An alkaline metal halide (eg potassium fluoride, etc.) can also be added to the reaction mixture. The reaction is usually carried out under a pressure of from 1 to 20 atm, preferably from 1 to 10 atm, at a temperature from room temperature to 250 ° C. preferably from room temperature to 200 ° C, The compound (1b ') wherein R 13 represents a group: for 0.5 - 30 hours. "/, - oconl" -B \\ ocoR'5 can be converted to the corresponding compound (1b '), wherein R13 represents a hydrogen atom, by treating the former compound with an acid or a base to decompose the chelate compound.

The acid comprises mineral acids (eg hydrochloric acid, sulfuric acid, etc.) and organic acids (eg acetic acid, p-toluenesulfonic acid, etc.) and the base comprises mineral bases (eg sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, ca lium carbonate, etc.) and organic bases (eg triethylamine, etc.). The reaction is conveniently carried out at a temperature of from 0 ° C to 150 ° C, preferably from 0 ° C to 100 ° C. The acid or base may be used in an amount of at least 1 mole, preferably 1-10 hbl, per 1 mole of the starting compound.

(Reaction Scheme-III) O nlóxs [12] x coon lf-2; I w N? (cH 2) n R 3 R '[1d] wherein R 1, R 3 and X are defined as above, either Z or W represents -CH 2 - and the other represents -NH, n represents an integer 1-3, R 16 represents a lower alkyl; a cycloalkyl; a phenyl lower alkyl, in which the phenyl ring may be substituted by a lower alkoxy, nitro or amino; a phenyl which may be substituted by a halogen atom, a lower alkyl or a lower alkyl substituted by 1-3 halogen atoms; a pyridyl; a lower alkyl having 1-3 substituents, a lower alkyl having 1-3 substituents selected from the group consisting of hydroxy, amino, a lower alkoxy and a halogen atom, the amine being optionally substituted by a lower alkyl, a lower alkanoyl, a cycloalkyl or legalcoxycarbonyl; a lower alkanoyl which may be substituted by 1-7 halogen atoms; a lower alkenylcarbonyl having 1-3 substituents selected from the group consisting of a halogen atom and an aminocarbonyl which may be a carboxy; a lower alkoxycarbonyl; be substituted with a lower alkyl; a phenyl-lower alkoxycarbonyl; an aminol-alkanoyl, which may be substituted by a phenyl- a carboxyl-alkoxycarbonyl; a lower alkoxycarbonyl lower alkyl; lower alkyl; an anilinocarbonyl lower alkyl; a lower alkylsulfonyl which may be substituted by 1-3 halogen atoms; and sulfolagalkyl; a lower alkenyl or a lower alkynyl, X 5 represents a halogen atom and either 2 'or W' represents -CH 2 - and the other represents - NR 16 - The reaction of the compound (1c) and the compound (12) is carried out in a suitable solvent in the presence of a hydrogen halide. alcohols, ketones (eg, removing agents. The solvent includes water, (eg, methanol, ethanol, isopropanol, etc.), acetone, methyl ethyl ketone, etc.), ethers (eg, diethyl ether, aromatic hydrocarbons, e.g. eg toluene, the hydrogen halide-removing agent potassium hydroxane, etc.), benzene, xylene, etc.) and the like. includes inorganic bases (eg sodium hydroxide, roxide, sodium carbonate, potassium carbonate, etc.), alkaline metals (eg sodium, potassium, etc.) and organic bases (eg pyridine, piperidine, etc. ). If necessary, copper etc.) or etc.) couple powders, copper halides (eg copper iodide, alkali metal halides (eg sodium iodide, potassium iodide) can be used The compound (lc) is usually used in one equimolar per 1 mol of to large excess amount, preferably 1-3 moles, of the compound (12) The reaction is usually carried out at a temperature from room temperature to 100 ° C, preferably 50 ° C to 120 ° C, for 1-12 hours 28,501,371 10 15 20 25 30 (Reaction Scheme-IV) x coon R'7coR'8 [13] / '_ Z \ I. W NNII (cH2) n 33 H1

[10] 'o - x coon [___ Z || Wherein R 1, R 3, Z, W, n and X are as defined above, R 17 and R 18 each represent a hydrogen atom or a lower alkyl, and either is present in the presence or the absence of a solvent and in the presence of a reducing agent The solvent comprises, for example, water, alcohols (eg methanol, ethanol, isopropanol, etc.), lower alkanoic acids (eg formic acid, acetic acid, etc. ), ethers (eg dioxane, diethyl ether, diolyme, tetrahydrofuran, etc.), aromatic hydrocarbons, (eg benzene, xylene, toluene, etc.) and the like.

The reducing agent comprises formic acid, alkali metal and alkaline earth metal salts of formic acid (eg sodium formate, hydrating agents (eg sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, etc.), catalysts for catalytic reduction (eg palladium black, , platinum oxide, platinum black, Raney nickel, etc.) and at a temperature from -300 to 100 ° C, preferably from 00 to 70 ° C, for 30 minutes to 12 hours. The reducing agent for the hydrogenation is usually used in an amount of from 1 to 20 moles, preferably from 1 to 6 moles, per 1 mole of the compound (1c) In the case of using lithium aluminum hydride as a reducing agent, a suitable solvent comprises ethers (e.g. eg diethyl ether, dioxane, tetrahydrofuran, diglyme, etc.), aromatic hydrocarbons (eg benzene, toluene, xylene, etc.) etc. In the case of using a catalytic reduction catalyst, the reaction is usually carried out under a hydrogen atmosphere. i from 1-20 at, suitable gene from 1-10 atm, at a temperature from -30 ° to 100 ° C, preferably from 0 ° to 60 ° C, for 1-12 hours. The catalyst is usually used in an amount of from 0.1 to 40% by weight, preferably from 0.1 to 20% by weight, of the compound (1c). The compound (13) is usually used in an amount of at least 1 mole, preferably 1 mole to a large excess amount, per 1 mole of the compound (1c).

In Reaction Scheme I, the starting compounds of formula (2) are new or known compounds which can be prepared, for example, by the process shown in the following Reaction Scheme-V.

(Reaction Scheme-V) I X X5 X 5 // Halogenating agent X \ I 'à H2 NH; 122 'NH-xó [In] [1üa] R19 X X5 1 2 c fl zsn ° [15] «' \ à Rz '» m2 McN D71; cnsa2 ° 1.19

[16] 10 15 20 25 30 35 40 5E) 1 371 3 ° x cN X CN '/ | H2 '\\ Naz ä R2' “H2 cHsR2 ° CH2 Å19 L * 9 X CN x coon x 2 RZI X2 i Ra 'I x CH2 ï fl z Å19 R19

[20] [23] wherein X, R 2 'and X 2 are defined as above, X 5 and X 6 each represent a halogen atom, R 19 represents a hydrogen atom or a lower alkyl and R 20 represents a lower alkyl, wherein R 19 and R 20 may be taken together to form a to 7-membered ring, and M represents an alkali metal (eg sodium, potassium, etc.) or a metal (eg silver, calcium, copper, etc.). In the case where R19 and R2 ° of the compound <1s> are taken together to form a 5- to 7-membered ring, R19 in the compound (20) is -R19-R2 ° -H.

The compound (16) can be prepared by reacting a starting aniline derivative of the formula (14) with a halogenating agent and then reacting the obtained compound of the formula (14a) with a thio compound of the formula (15).

The reaction of an aniline derivative (14) and a halogenating agent is usually carried out in a suitable solvent. The solvent may be any conventional solvent unless it has an undesirable effect on the reaction, and comprises e.g. halogenated hydrocarbons (eg chloroform, dichloromethane, etc.), ethers (eg dioxane, diethyl ether, tetrahydrofuran, etc.), aromatic hydrocarbons (eg benzene, toluene, isopropaxylene, etc. ). legal alcohols (eg methanol, ethanol, zero, etc.) and polar solvents (eg DHSO, HMPA, acetonitrile, etc.). The halogenating agent can be any conventional halogenating agent and comprises e.g. N-bromosuccinimide, N-chlorosuccinimide, sodium hypobromide, sodium hypo-chlorite, bleaching powder, thionyl chloride, tert-butyl hypochlorite and the like. The halogenating agent is usually used in an amount of at least 1 mole, preferably 1-6 moles, per 1 mole of the starting material. The reaction is usually carried out at a temperature of from -78 ° C to room temperature, preferably from -60 ° to 15 ° C, and is usually completed within a few minutes. The reaction produces the intermediate of formula (14a). While the resulting compound (14a) can be separated from the reaction mixture to provide it for a subsequent reaction, the reaction mixture is usually provided for the reaction with a thio compound of formula (15) without separating it from the reaction mixture.

The reaction of the compound (14a) and the compound (15) is carried out in the same solvent as indicated above in the presence of a basic compound. The basic compound comprises inorganic bases (eg potassium carbonate, sodium carbonate, sodium hydroxide, sodium bicarbonate, sodium amide, sodium hydride, etc.) and organic bases such as tertiary amines (eg triethylamine, tripropylamine, pyridine, quinoline, etc.). The compound (15) is used in an amount of at least 1 mole, preferably 1-1.5 moles, per 1 mole of the compound (14a). The reaction is usually carried out at a temperature from room temperature to 150 ° C, preferably from room temperature to 100 ° C, for 1-5 hours. The reaction of the compound (16) and the compound (17) is carried out in a suitable solvent in the presence or absence of a basic compound. The solvent includes water, alcohols (eg methanol, ethanol, isopropanol, etc.), aromatic hydrocarbons (eg benzene, toluene, xylene, etc.), ethers (eg dioxane, tetrahydrofuran, diglyme, etc.), polar solvents (eg DMF, DMSO, HMPA, N-methylpyrrolidone, etc.) or a mixture thereof. The basic compound comprises inorganic carbonates (eg sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, etc.), organic bases (eg pyridine, quinoline, triethylamine, etc.), phase transfer catalysts (eg phenyltriethylammonium chloride, tetramethylammonium chloride, etc.) and the like. The compound (17) is usually used in an amount of at least 1 mole, preferably 1-2 moles, per 1 mole of the compound (16). The reaction is usually carried out at a temperature of from room temperature to 200 ° C, preferably from room temperature to 180 ° C, for 0.5 to 10 hours, desulphurizing the compound (18) to produce The compound (19) is usually carried out in a solvent in the presence of a suitable catalyst. The catalyst comprises e.g. aluminum amalgam, lithium lower alkylamine, Raney nickel, Raney cobalt, triethyl phosphite, triphenylphosphine and the like and a suitable one is Raney nickel; The solvent includes alcohols (eg, methanol, ethanol, isopropanol, etc.), ethers (eg, diethyl ether, dioxane, tetrahydrofuran, etc.) and the like. The reaction is usually carried out at a temperature of from 0 ° to 20 ° C, preferably from room temperature to 100 ° C, for 10 minutes to 5 hours. The catalyst is usually used in an amount from 1-10 times the weight. of the compound (18).

The reaction of converting the compound (19) into the compound (20) is carried out by reacting the compound (19) with a metallic salt of nitric acid (eg sodium nitrite, potassium nitrite, etc.) in a suitable solvent in the presence of a acid and then react the product obtained with a metal halide (eg potassium iodide, copper (I) chloride, copper (I) bromide, etc.) without separating it from the reaction mixture.

The acid comprises mineral acids such as hydrochloric acid, sulfuric acid and hydrobromic acid. The solvent includes water, alkanoic acids (eg acetic acid, etc.), ethers (eg dioxane, tetrahydrofuran, etc.), aromatic hydrocarbons (eg benzene, toluene, xylene, etc.), alcohols (e.g. eg methanol, ethanol, isopropanol, etc.), halogenated hydrocarbons (eg chloroform, dichloromethane, dichloroethane, etc.), aprotic polar solvents (eg DMF, DMSO, HMPA, nitric acid and the metal halide were used each ice, etc.) and a mixture thereof. The metallic salt in an amount of at least 1 mole, preferably 1-1.5 moles, per 1 mole of the compound (19). The reaction is usually carried out at a temperature of from 0 ° to 150 ° C, preferably from 0 ° to 100 ° C, for up to 5 hours.

Hydrolysis of the compound (20) can be carried out in the presence of a suitable hydrolysis catalyst for 10 minutes, e.g. a mineral acid (eg sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, etc.) or a basic compound (eg sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, etc.) in the presence or absence of a solvent. The solvent comprises e.g. water and a mixture of water and a legal alcohol (eg methanol, ethanol, etc.) ¿The reaction is carried out: §Also at a temperature from 50 ° C to 200 ° C, preferably 70 ° to 10 ° C. 33 351 501 371 180 ° C, for 1-10 hours.

In Reaction Scheme-II, the compounds of formula (Ib), 1313 wherein R represents a group /// OCOR1uw -B \\\ ocoR15 can be prepared, for example, by the procedure shown in the following Reaction Scheme-VI.

(Reaction Scheme-VI) ~ o x cooR5 ', ocoR1 “1” B-ocoR15 [21] Ä \\ | I \ ocoR21 x> N R3 ål Uf] O I x cooR13 I u X ff R3 RT

[13] wherein R 1, R 3, X, X 4, R 14 and R 15 are as defined above, R 5 'represents a lower alkyl or a hydrogen atom, R 13' represents a group: 'ocon' '\\ ocon'5 and R 21 represents a lower alkyl .

The reaction of the compound (If) and the compound (21) is carried out in a suitable solvent. The solvent comprises e.g. use solvents in the reaction of the R4 group-removed compound and the compound (6) in the above Reaction Scheme-I. The reaction is usually carried out at a temperature from room temperature to 200 ° C, suitably from room temperature to 150 ° C, for 10 minutes to 5 hours. The compound (21) is usually used in an amount of at least 1 mole, preferably 1-10 moles, per 1 mole of the compound (lf).

The compounds (8) used in Reaction Scheme I are new or known compounds which can be prepared, for example, by the procedure shown in Reaction Scheme VII. 10 15 20 25 30 35 40 34 501 371 (Reaction Scheme-VII) 7 m (X) mE :: M-N; t23] ¿CO H CON3 (221 2 f2 “1 M" N3 [23a] (x1) m \ lx7> m n22'on ______ i>

[26] [27] wherein X7 represents a halogen atom, R22 represents a phenylgaalkoxycarbonyl ,. R22 'represents a phenyl lower alkyl, m represents an integer from 1-3, M' represents potassium, potassium and the like, and H "represents a hydrogen atom or represents an alkali metal, such as nat- M '.

The reaction of the compound (22) and the compound (23) can be carried out under a reaction relationship which is usually used in a reaction to form an amide bond. Methods for forming an amide formation include e.g. (a) a mixed acid anhydride process: a process which is composed of reacting the carboxylic acid (22) with an alkyl halocarboxylate to obtain a mixed acid anhydride and then reacting the obtained anhydride with azide (23); (b) an active ester process: a process which is composed of converting carboxylic acid (22) to an active ester such as p-nitrophenyl ester, N-hydroxysuccinimide ester or 1-hydroxybenzotriazole ester, and then reacting the resulting ester with azide ( 23); (c) a carbodiimide process: a process composed of condensing the carboxylic acid (22) and the azide (23) in the presence of an activating agent such as dicyclohexylcarbodiimide, carbonyldiimidazole or the like; and (d) the other methods: a method comprising converting the carboxylic acid (22) to carboxylic anhydride using a hydrogenating agent, such as acetic anhydride, and then reacting the resulting anhydride with the azide (23); a process composed of reacting an ester of the carboxylic acid (22) and a legal alcohol with the azide (23) under a high pressure at a high temperature; or a process consisting of reacting an acid halide of the carboxylic acid (22) (ie acyl halide) with azide (23). The mixed acid anhydride is obtained by a conventional Schotten-Baumann reaction and the anhydride obtained is allowed to react with the azide (23), usually without separating it from the reaction mixture, to prepare the compound (24 ).

The Schotten-Baumann reaction is carried out in the presence of a basic compound commonly used in the reaction. The basic compound comprises e.g. organic bases (eg triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo [3], quinone-5 (DBN), 1,8-diazabicyclo cen-7 (DBU), 1,4-diazabicyclo [2,2,27-octane (DABCO), etc.) and inorganic bases (eg, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, etc.). The reaction is usually carried out at a temperature of from -20 ° to 100 ° C, suitably from 0 ° - 50 ° C, for 5 minutes to 10 hours, preferably 5 minutes to 2 hours. The reaction of the resulting mixed acid anhydride and azide (23) is usually carried out at a temperature of from -20 ° to 150 ° C, preferably from 0 ° to 50 ° C, for 5 minutes to 10 hours, preferably 5 minutes. to 5 hours. The mixed acid anhydride process is usually carried out in a solvent commonly used in the process. The solvent includes water, halogenated hydrocarbons (eg dichloromethane, chloroform, dichloroethane, etc.), aromatic hydrocarbons (eg benzene, toluene, xylene, etc.), ethers (eg diethyl ether, tetrahydrofuran , dimethoxyethane, etc.), esters (eg methyl acetate, ethyl acetate, etc.) ketones (eg acetone, etc.), aprotic polar solvents (e.g.

DMF, DMSO, HMPA, etc.) and a mixture thereof. The alkyl halocarboxylate used in the mixed acid anhydride process comprises e.g. methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate and the like. Azide (23) is usually used in an amount of at least 1 mole, preferably 1-1.5 moles, per 1 mole of the carboxylic acid (22).

In the case of using the process, which consists in reacting an acyl halide with azide (23), the reaction is carried out in the presence of a basic compound in a suitable solvent.

The basic compound may be any known basic compound and comprises e.g. sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, silver carbonate and metal alcoholates, such as sodium methylate and sodium ethylate, in addition to the basic compound used in the above Schotten-Baumann reaction. The solvent comprises e.g. alcohols (eg 10 15 20 25 30 35 36 501 371 methanol, ethanol, propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolv, methylcellosolv, etc.), pyridine, acetone, acetonitrile, solvents , used in the above mixed acid anhydride process, and a mixture thereof. Although the ratio of azide (23) to an acyl halide used is not limited, the acyl halide is usually used in an amount of at least 1 mole, preferably 1-5 moles, per 1 mole of azide (23). The reaction is usually carried out at a temperature of from -30 to 180 ° C, preferably from -0 ° to 150 ° C, for 5 minutes to 30 hours. Compound (24) thus prepared can be used in a subsequent reaction without separating it from the reaction mixture.

The reaction of the compound (24) and the compound (25) is usually carried out at a temperature of from 0 ° to 150 ° C, preferably from room temperature to 100 ° C, for 1-15 hours, in the presence or absence of a suitable solvent. The compound (25) is usually used in an amount of at least 1 mole, preferably 1-2 moles, per 1 mole of the compound (24).

The reaction of converting the compound (26) into the compound (27) can be carried out under the same reaction conditions as used in a reaction to remove a phenyl lower alkyl group or a phenyl lower alkoxycarbonyl group on the heterocyclic ring attached to the above compound (1).

The reaction of directly converting the compound (22) to the compound (27) is usually referred to as Schmidt reaction and is carried out in a suitable solvent in the presence of an acid.

The acid includes mineral acids (eg sulfuric acid, hydrochloric acid, etc.), phosphorus compounds (eg phosphorus oxychloride, chloride, phosphorus trichloride, phosphorus pentoxide, etc.), thionyl chloride, iron / III / chloride, aluminum chloride, tin (IV) chloride, sulfoacetic acid, phosphorus pentaphosphoric acid and the like. The solvent includes aromatic hydrocarbons (eg, hensen, toluene, xylene, etc.), halogenated hydrocarbons (eg, chloroform, dichloromethane, carbon tetrachloride, etc.) and the like. The reaction is usually carried out at a temperature of from 0 ° to 150 ° C, preferably from 0 ° to 100 ° C, for 0.5 to 10 hours. The compound (23a) is usually used in an amount of at least 1 mole, preferably 1-2 moles, per 1 mole of the compound (22). 10 15 20 25 30 35 40 37 i 501 371 (Reaction Scheme-VIII) 2 rr-Z l // |! ÄH / 0 \ ¿/ O W \\ N / ÅQ \ 'N 6 - \ (CH2) n H3 åï [28] i då

[10] wherein R23 represents phenyl, a lower alkyl or hydrogen atom, X8 represents a halogen atom, either 2 "'or W"' represents -CH2- and the other represents a group I E23 I * N “CH2-T ::: ï_ 0 OYO and R1, R3, Z, W, X and n are defined as above.

The reaction of the compound (1c) and the compound (28) can be carried out under the same reaction conditions as used in the reaction of the compound (Ib) and the compound (11) in the above reaction scheme II.

In the compounds (1), the compound in which the heterocyclic ring is substituted by (a) a phenyl lower alkyl, wherein the phenyl ring may be substituted by a lower alkoxy, nitro or amino; (b) a lower alkanoyl which may be substituted by 1-7 halogen atoms, a lower alkenyl carbonyl having 1-3 substituents selected from the group consisting of a halogen atom and a carboxy; (c) a lower alkoxycarbonyl; (d) an aminocarbonyl which may be substituted with a lower alkyl; (e) a phenyl-gal- (E) an aminol-alkanoyl, which may be substituent- (g) phthalide; (h) one which may be subatitated with 1 or 2 halocoxycarbonyl; row with a phenyl lower alkoxycarbonyl; 2 (5H) -furanone, gene atoms or (i) a 2-oxo-1,3-dioxolenmethyl, which may be substituted by phenyl or a lower alkyl, may be converted into the compound (1), in which the heterocyclic ring is not. f? 10 15 20 25 30 35 40 38 501 371 substituted, e.g. using the following methods.

The compound (1) in which the heterocyclic ring is substituted by (a) or (e) may be converted into the compound (1) by treating the former compound in a suitable solution in which the heterocyclic ring is unsubstituted. , such as water, a lower alcohol (eg methanol, ethanol, isopropanol, etc.) an ether (eg dioxane, tetrahydrofuran, etc.), acetic acid or a mixture thereof, in the presence of a catalyst for a catalytic reduction, such as palladium carbon, palladium black or the like, under a hydrogen pressure of from 1 to 10 atm, at a temperature from 0 ° to 100 ° C, for 0.5 to 10 hours (wherein a mineral acid such as hydrochloric acid , can be added to the reaction mixture) or by heating the former compound in an aqueous hydrobromic acid solution to remove phenyl lower alkyl (eg benzyl) or phenyl lower alkoxycarbonyl.

The compound (1) in which the heterocyclic ring is substituted by 1 or more of the substituents (b) to (i) can be converted into the compound (1) in which the heterocyclic ring is not substituted by hydrolyzing the former compound under the same reaction conditions used in the hydrolysis of the above compound (10).

The compound (1) in which the heterocyclic ring is substituted by amino can be converted to the compound (1) in which the heterocyclic ring is substituted by a group: R 23 f -CH 2 NH-OOY 0 using the same reaction conditions as used in the reaction. of the compound (Ic) and the compound (28) of the above Reaction Scheme VIII, and the compound (1) in which the heterocyclic ring is substituted with a group:: Fia-augus-O 0 If can also be converted into the compound (1 ), in which the heterocyclic ring is substituted with amino, by hydrolysis of the former compound under the same reaction conditions as used in the hydrolysis of the above compound (10). 10 15 20 25 30 35 40 39 501 371 (Reaction Scheme-IX) Naga * [8]

[37] R25o-cH = c (cooR2 ") 2 [goa] x No cooR2" 2 cooßz "I o R2 'N-ca o H25 3. | Rzßoc fl> <RR * [31] o B27 _ _ 0 l Cyclization [30b] o 214 x /, coon J / \ 'I H2 N x No 3- I 2 o R n * [11] o R26 H2-' N_CH > <\ LHydrolysis.

R3 | o R27 'R1 oo' x coon L32] Cyclization 47§ \ F / I z R2I \ N 3 'i I ....- RR * [13] wherein R1, R2', X9 and X are defined as above, R3 'represents a group: 319 I -cHsa2 ° (veri R19 and RZÛ are defined as above) or R3 (wherein R3 is defined as above) and 1224, Rzás, 1125, R27 and Rza each represent a lower alkyl and X9 represents a halogenetom.

The reaction of the compound (37) and the compound (8) can be carried out under the same reaction conditions as used in the reaction of the compound (ibš and the compound iii) in the reaction scheme II. The reaction of the compound (29) and the compound ((30a) or (30b) is carried out in the presence or absence of a solvent, the compound preferably comprises, for example, in the absence of any Solvent alcohols (eg methanol, ethanol, isopropanol, etc.), aromatic hydrocarbons (eg benzene, toluene, etc.), polar solvents (eg acetonitrile, DMF, DMSO, HMPA, etc.) The compound (30a) or (30b) is usually used in an amount of at least 1 mole, preferably 1-1.5 moles, per 1 mole of the compound (29), temperature to 200 ° C, preferably from 60 ° C. ° to 200 ° C, in 0.5 - The reaction is usually carried out at a temperature of about 25 hours.

The cyclization of the compound (31) or (32) can be carried out according to various known methods, such as a heating method, a method of using an acidic compound (eg phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, thionyl chloride, concentrated sulfuric acid , polyphosphoric acid, etc.). In the case of using the heating method, the reaction is usually carried out in a high-boiling solvent, such as a high-boiling hydrocarbon or a high-boiling ether (eg tetralin, diphenyl ether, diethylene glycol dimethyl ether, etc.) at a temperature of from 100 ° to 250 ° C. ° C, preferably 150 ° to 200 ° C. In the case of using the method using an acidic compound, the acidic compound is usually used from an equimolar to a large excess, suitably 10-20 moles, per 1 mole of the compound (31) or (32), and the reaction is usually carried out in the presence or absence of a suitable solvent at a temperature from room temperature to 150 ° C for 0.1 - 6 hours. The solvent comprises acid anhydrides (eg acetic anhydride, etc.) in addition to solvents used in the cyclization of the above compound (9).

Hydrolysis of compound (II) can be carried out under the same reaction conditions as used in hydrolysis of compound (10) in the above Reaction Scheme-I.

The compound (ij), wherein R 3 'represents a group: can be converted to the corresponding compound, in which R 3' represents -CH 2 R 19, by treating the former compound under the same reaction conditions as used in the reaction, wherein the compound ( 18) is converted to the compound (19) in the above Reaction Scheme-V. The compound (Ij), in which R2 'represents a 5- or 9-membered saturated or unsaturated heterocyclic ring with a lower alkoxycarbonyl on the secondary nitrogen atom, can be converted to the corresponding compound, wherein R2' represents a to a 9-membered saturated or unsaturated heterocyclic ring with no snubstituent on the secondary nitrogen atom, by treating the former compound under the same reaction conditions as used in hydrolysis of the compound (10) in the above reaction scheme.

The compound (29) used as a starting material in the above Reaction Scheme-IX can be prepared, for example, by the procedures shown in the following Reaction Schemes-X to XII.

In the cyclization of the compound (31) or (32), if the starting material is a compound, wherein R 3 'represents lower alkyl having at least one substituent selected from a halogen atom, hydroxy or a lower alkoxy, and the solvent is an acid anhydride, lower alkyl is acylated to give a compound, wherein R 3 'represents a lower alkyl having at least one lower alkanoyloxy in such a reaction. However, such a compound can be easily removed from the reaction mixture. 501 371 42 (Reaction Scheme-X) 10 15 20 25 30 35 40 X X5 'x A H2% NH2 R2' _ CH NH2 cHsR2 ° | 2 "19 Å19 R f161 [33] x R2 'NHR29 CH2 ÅIQ Nitration C314] Nitration v x NO2 x NO2: I ;;;: I: Hxdrolgs.

P2 v »R19 R19

[35] [35] X "Oz x NO2 ____> NH2-R '[8] 2' ~ R b X9 7 R? Na-R * CH2 cH2 '19 'IR R19 [37a] ¶ [29a] 10 15 20 25 30 35 40 43 501 371 T x NO2 H19 x NO2 cH2sR2 ° [15] H2 'T-X6> R2 NHR * RI cHsR2 ° '19 [39a] __ R [29b] _ "Halogenation x NO2 x NO2 NH2-R '[8] R2' NHR * f "" "" “" "-_- R2 'X9

[39] (333 wherein R1, R2 ', R19, R2, X and X5 are defined as above, R29 represents a lower alkanoyl and X9 represents a halogen atom.

Desulfurization of the compound (16) or (29b) can be carried out under the same reaction conditions as used in the desulfurization of the above compound (18).

The reaction of converting the compound (33) into the compound (34) is carried out in the presence of a lower alkanoylating agent, such as a lower alkanoic acid (eg, formic acid, acetic acid, propionic acid, etc.), a lower alkanoic anhydride (eg, acetic anhydride, etc.). a lower alkanoic acid halide (eg, acetyl chloride, propionyl bromide, etc.), or the like. In the case of using an acid anhydride or acid halide as the lower alkanoylating agent, a basic compound can be used. The basic compound comprises e.g. alkali metals (eg metallic sodium, metallic potassium, etc.) and hydroxides, carbonates or bicarbonates thereof, organic bases (eg pyridine, piperidine, etc.) and the like.

The reaction is carried out in the presence or absence of a solvent, usually in the presence of a suitable solvent. The solvent comprises e.g. ketones (eg acetone, methyl ethyl ketone, etc.), ethers (eg diethyl ether, dioxane, etc.), aromatic hydrocarbons (eg benzene, toluene, xylene, etc.), acetic acid , acetic anhydride, water, pyridine and the like. The lower alkanoylating agent is used in an amount of at least 1 mole down 1 mole of the compound (33), usually in equimolar to a large excess of 10 15 20 25 30 35 40 44 501 371. The reaction is usually carried out at a temperature of from 0 ° to 150 ° C, preferably from 0 ° to 100 ° C, for 5 minutes to 10 hours.

In the case of using a lower alkanoic acid such as the lower alkanolylating agent, a dehydrating agent is suitably used.

The dehydrating agent includes mineral acids (eg, sulfuric acid, hydrochloric acid, etc.), sulfonic acids (eg, p-toluenesulfonic acid, benzenesulfonic acid, ethanesulfonic acid, etc.) and the like. The reaction is conveniently carried out at a temperature of from 50 ° to 120 ° C.

The nitration of the compound (33) or (34) is carried out by treating the compound with a nitrating agent, such as fuming nitric acid, conc. nitric acid, a mixed acid (eg nitric acid plus sulfuric acid, fuming sulfuric acid, phosphoric acid or acetic anhydride, etc.), an alkali metal nitrate plus sulfuric acid, an anhydride of nitric acid and an organic acid (eg acetyl nitrate, benzoyl nitrate , etc.), nitrogen tetraoxide, nitric acid plus mercury nitrate, nitrate of acetone cyanohydrin, an alkyl nitrate plus sulfuric acid or a polyphosphoric acid or the like, in the presence or absence of a solvent such as acetic acid, acetic anhydride, sulfuric acid or the like.

The nitrating agent is suitably used in an amount of 1 to 1.5 moles per 1 mole of the compound (33) or (34). The reaction is usually carried out at a temperature of from -10 ° to 70 ° C for 1-24 hours.

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

The reaction of the compound (37a) or (38) with the compound (8) can be carried out under the same reaction conditions as used in the reaction of the compound (1b) and the compound (11) in the above reaction scheme II.

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

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

The conversion of the compound (29b) into the compound (29a) can be carried out under the same conditions as the conversion of the compound (18) into the compound (19). In the reaction of converting the compound (36) into the compound 10, the compound can be carried out by converting the former compound into a diazonium salt thereof using sodium nitrite and an acid (eg, sulfuric acid, hydrochloric acid, hydrobromic acid, boron fluoride, etc.) in a solvent such as a lower alkanoic acid (e.g. acetic acid), water, etc. and then cause the diazonium salt to react with a copper powder or a copper halide (eg; copper - (I) bromide, copper (I) chloride, copper (II) chloride, etc.) in the presence of a hydrohalic acid (eg hydrobromic acid or hydrochloric acid, etc.) or with potassium iodide in the presence or absence of a copper powder: suitably with a copper halide in the presence of a hydrohalic acid. Sodium nitrite is usually used in an amount of 1-2 moles, preferably 1 to 1.5 moles, per 1 mole of the compound (36) and copper halide is usually used in an amount of 1-5 moles, preferably 1-4 moles, per 1 mole of the compound (36). The reaction is usually carried out at a temperature of from -20 ° to 100 ° C, suitably from -5 ° to 100 ° C. The halogen atom X9 in the compound (37a) can be converted to for 10 minutes to 5 hours. each other.

(Reaction Scheme-XI) X NO 2 X NO 2 Hydrolzs. ;] ::;: Iï Halogenation.

R2 '9 R2' NH2 NHR? , [H0] [H1] B19 x No 1 x No 2 cH2sR2 ° [15] 2 - - R2 'NH_x6 R2' NHZ En J cHsR2 ° 2 ån x NO2 [u3] ---> Ra- X9 Åw

[37] wherein R 2 ', R 19, R 20, R 29, X, X 5 and X 9 are defined as OVaF1.

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

The halogenation of the compound (41) can be carried out under the same reaction conditions as used in the halogenation of the compound (14) in the above reaction scheme V.

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

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

(Reaction Scheme-XII) X / lx NO2 H2 '\ X9 Ra' i X9 (ßnmcoo fl (A) mCO0H [H14] [H5] ReductionX 'Reduction' X R3sL X Ras R2 'x9 H2' X9 mcH2on mcH2X1 ° [H6] [ '47] X Ras x NO2 NH2-R1 [8] 32 'X9 "': _'__"> RZ 'min * (A) mc fl3 (A) mCH3 [ha] [29b] 10 15 20 25 30 35 40 47 501 371 (Reaction Scheme-XIII) x NO2 ------ e> (A) mcH2oH us m / I 1 / H32 “HN [52] \ R33 [52] 'fx No Hydrolysis .Acyle ring / I 2 - \\ R2 X9 R32 A CH ”() m 2N \ R33

[51] W [sz] [sz] x NO2 x NO2 (A) mcH2a31 (A) mcH¿x1 °

[50] _ Ln7] x N 02 ns-H3 ”R2, X9 3 [SU] (A) mcH2sR3" '

[53] wherein R 1, R 2 ', X and X 9 are defined as above, A represents a lower alkylene, m represents 0 or 1, X 10 represents a halogen atom or a phenylsulfonyloxy, which may be substituted by a lower alkyl, R 3 ° represents a lagelkyr, R31 denotes a 1ege1xeney1cxi, R32 and R33 are 1ixe or clixe een each denotes a hydrogen atom or a legal alkyl, R34 denotes a lower alkyl and R35 denotes a hydrogen atom or a nitro group.

The nitration of the compound (44) in the above reaction scheme XII can be carried out under the same reaction conditions as used in the nitration of the compound (34) in the above reaction scheme X. The reaction of the 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 usually used in an amount of at least 1 mol. preferably 1-3 moles, per 1 mole of the compound (44) or (45). The reduction reaction is usually carried out in a suitable solvent isodium agent, e.g. water, lower alcohols (eg methanol, ethanol, propanol, etc.), ethers (eg glyme, etc.), DMSO or the like, at a temperature from -60 ° to 80 ° C, suitably from - 30 ° C - 50 ° C, to 15 hours. In the case of using lithium aluminum hydride or tetrahydrofuran, diethyl ether, for 10 minutes. mar. diborane as a reducing agent, an anhydrous solvent such as diethyl ether, tetrahydrofuran or diglyme is suitably used.

The reaction of converting the compound (46) into the compound (47), wherein Xiu represents a halogen atom, is carried out by halogenation under any reaction conditions commonly used in the halogenation of hydroxy group, and may be carried out, for example, by reacting the compound (46) with a halogenating agent in the presence or absence of a suitable inert solvent. The halogenating agent comprises e.g. hydrohalic acids (eg hydrochloric acid, hydrobromic acid, etc.), N, N-diethyl-1,2,2-trichlorovinylamide, phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride, thionyl chloride, diethylamino sulfur trifluoride (DAST) and the like. The inert solvent comprises e.g. ethers (eg dioxane, tetrahydrofuran, etc.), halo-carbon tetrachloro The halogenating agent is used in a lowered hydrocarbon (eg chloroform, dichloromethane, rid, etc.) and the like. amount of at least 1 mole per 1 mole of the compound (46), usually in an equimolar amount to an excess amount, the reaction is usually carried out at a temperature from 0 ° - 150 ° C, preferably from 0 ° - 80 ° C, to 15 hours. for 10 min. In the case of using DAST as a halogenating agent, a basic compound such as triethylamine can be used.

When the compound (46) phonyl halide is reacted with a phenylaul- which may have a lower alkyl substituent on the phenyl ring, it may be converted into a compound (47), wherein X10 represents a phenylsulfonyloxy, which may be substituted by a lower alkyl.

The reaction can be carried out on the addition of the compound (46) to the compound (49) as hereinafter referred to as: in method <1) for the conversion of W 10 15 20 25 30 35 40 49 501 371.

The compound <4s>, wherein R35 represents the vapor atom, first converts to a compound (48), wherein R35 represents nitro, by the same nitration reaction of the compound (44), and then it is reacted with the compound (8). Thus converted reaction of the compound (48) and the compound (8) can be carried out under the same reaction conditions as used in the reaction of the compound (1b) and the compound (11) in the above reaction scheme-II.

The reaction of converting the compound (47) into the compound (48) can be carried out under the same reaction conditions as used in the reduction of the above compound (45).

The reaction of converting the compound (46) into the compound (49) of the above reaction scheme XIII can be carried out by various methods, e.g. (i) by reacting the compound (46) with a compound: R 34 X 11 (wherein R 34 represents a lower alkyl and X 11 represents a halogen atom) in a suitable solvent in the presence of a basic compound, or (ii) by reacting the compound (46) to react with a lower alcohol (ie a straight or branched chain C1-C5 alcohol, such as methanol, ethanol, isopropanol, butanol or the like) in the presence of an acid.

The solvent used in the above method (i) comprises e.g. ethers (eg diethyl ether, dioxane, tetrahydrofuran, monoglyme, diglyme, etc.), alcohols (eg methanol, ethanol, isopropanol, etc.), aromatic hydrocarbons (eg benzene, toluene, xylene, etc. .), aliphatic hydrocarbons (eg n-hexane, heptane, cyclohexane, ligroin, etc.), amines (eg pyridine, N, E-dimethylaniline, etc.), halogenated hydrocarbons (eg chloroform, dichloromethane, carbon tetrachloride, etc.), aprotic polar solvents (eg DMF, DMSO, HMPA, etc.) and a mixture thereof.

The basic compound comprises inorganic bases (eg metallic sodium, metallic potassium, metallic magnesium, sodium hydride, sodium amide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, etc.), metal alcoholates (eg sodium methylate, sodium ethylate, etc.), organic bases (eg pyridine, piperidine, quinoline, triethylamine, N, N-dimethylaniline, etc.) and the like. The reaction is usually carried out at a temperature of from 0 DEG to 120 DEG C., suitably from room temperature to 100 DEG C., in 0.1 to 5 hours of time. R34X11 is usually used in an amount of at least 1 mole, except for 10 moles. 40 25 50 40 50 501 371 mol, per 1 mol of the compound (46).

The acid used in the above method (ii) comprises e.g. mineral acids (eg hydrochloric acid, sulfuric acid, hydrobromic acid, etc.).

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

The low alcohol is usually used in a large excess amount. The acylation of the compound (46) can be carried out under the same reaction conditions as used in the reaction to convert the compound (33) to the compound (34) in the above reaction scheme: X.

The reaction of the compound (46), (49), (50) or (47) with the compound (52) and the reaction of the compound (47) with the compound (54) can both be carried out in the presence or absence of a suitable solvent in the presence or absence of a basic compound. The solvent and the basic compound may be the same solvent and basic compounds used in the reaction of the compound (3) and the compound (4) in the above Reaction Scheme-I. In the reaction of the compound (46), (49), (50) or (47) with the compound (52), the compound (52) can be used in a large excess amount, which also functions as a basic compound.

Compounds (52) and (54) are each used in an amount of at least 1 mole per 1 mole of the starting material, specifically pre- (49), (50) or (47), batch. The reaction is carried out at a temperature of from 0 ° to 150 ° C, for 3-15 hours. The reaction (46), preferably in a large range preferably from room temperature to 100 ° C, The hydrolysis of the compound (50) can be carried out under the same reaction conditions as used in the hydrolysis of the above compound (10).

Among the above compounds (3), (5), (Ia), (Ib), (1b '), (29), R 3 represents a lower alkyl substituted with hydroxy, can convert- (7), (9), (10) , (31) and (32), the compounds, wherein added to the corresponding compounds, wherein R 3 represents a lower alkyl, which may be substituted with 1-3 substituents selected from the group consisting of a saturated 5- or 6- articulated heterocyclic ring, a lower alkylthio, a lower alkanoyloxy, amino, a lower alkylamino, a lower alkoxy and a halogen atom, by reacting the former compounds under the same reaction conditions as indicated above.) 10 15 20 25 30 35 40 51 501 371 Among the above compounds (3), (5), (7), (9), (10), (Ia), (1b ', (1b'), (29), wherein R 3 represents a lower alkyl substituted with a lower alkanoyl - (31) and (32), the compounds, oxy, can be converted to the compounds, wherein R 3 represents a lower alkyl with hydroxy group, by hydrolyzing the former compounds under the same reaction conditions as indicated above.

Among the above compounds (3), (5), (7), (9), (10), (ia), (lb), (1b '), (29), (31) and (§2), wherein R 2 represents a saturated or unsaturated 5- or 9-membered compound, oxo-group heterocyclic ring can be converted into compounds wherein R 2 represents a saturated or unsaturated 5- to 9-membered hydroxy group with hydroxy group, by reducing the former the associations. The reduction can be carried out in a suitable solvent in the presence of a reducing agent for hydrogenation.

The reducing agent comprises e.g. sodium borohydride, lithium aluminum hydride, diborane and the like, and is usually used in an amount of at least 1 mole, preferably 1-5 moles, per 1 mole of the starting material to be reduced. The solvent comprises e.g. ethanol, isopropanol, water, lower alcohols (eg methanol, etc.), ethers (eg tetrahydrofuran, diethyl ether, diglyme, etc.) and the like. The reaction is usually carried out at a temperature of from -60 ° to 50 ° C, preferably from -30 ° C to room temperature, for 10 minutes to 5 hours. In the case of using lithium aluminum hydride or diborane as reducing agent, it is convenient to use an anhydrous solvent such as diethyl ether, tetrahydrofuran, diglyme. In the case where sodium borohydride is used as the reducing agent, an organic base, such as sodium hydride, can also be added to the reaction mixture.

The compounds wherein R 2 represents a saturated or unsaturated 5- to 9-membered heterocyclic ring substituted with a lower alkyl having at least one of a lower alkanoyl or a lower alkoxycarbonyl may be converted to the compounds wherein R 2 represents a saturated or unsaturated 5- with a lower alkyl having at least one carboxyl group, by hydrolysis of or 9-membered heterocyclic ring substituted by the former compounds. The hydrolysis can be carried out under the same reaction conditions as used in hydrolysis of the compound (10) in the above Reaction Scheme-I.

The compounds in which R? denotes a saturated or unsaturated gsj- s- un s-ieaaa heeerocyuic ringmea "mines one, -_ uo '-' j, i ___ ¿'f;' ig1gsq * 10 15 20 25 30 35 40 501 371" can be converted into compounds wherein R 2 denotes a saturated or unsaturated 5- to 9-membered heterocyclic ring substituted with at least one lower alkanoyl, by reacting the former compounds under the same reaction conditions as used in the reaction to convert the compound (33) to the compound (34) of the above reaction scheme-X.

The compounds (46), (47) and (48), wherein R35 represents hydrogen atom, can be converted to the corresponding compounds, wherein R35 represents nitro, by the same nitration reaction of the compound (44).

The compounds (44) and (45) can be prepared by the procedure shown in the following reaction scheme.

(Reaction Scheme-XIV) x 1 /, B35 Reaction X R35 I ----- +> R2v; I;% ;; 1: x9 R2, X9 (ÅI) mCÛÛH / (A |) mCH2OH

[55] [56] X 335 R2 ', X9 (A') mcH2x1 *

[57], cooR36 CH2 \ CO0R36 [S8] MGN [17] 4 X R35 X 335 Ra 'X9 cooR36 R2' X9 / (ÅI) mCH2CH \ CO0R36 (A |) mcH2CN

[59] [60] V Hydrølys L Hyaroiys., X R35 X 335 R2 'X9 R2' X9 (A ') mcH2cH2cooH

[61] (A ') mcH 2 cooH

[62] wherein R 2 ', R 35, X, X 9, M and m are defined as above, and A' represents a lower alkylene, provided that the groups (A ') mCH 2 - and (A ') mCH2CH2- does not have more than 6 carbon atoms, R35 represents a lower alkyl and X11 represents a halogen atom.

The reduction of the compound (55) is carried out under the same conditions as in the reduction of the compound (44) or (45).

In addition, the halogenation of the compound (S6) can be carried out under the same conditions as in the halogenation of the compound (46). The reaction of the compound (57) and the compound (58) is usually carried out in a suitable solvent in the presence of a basic compound at a temperature from room temperature to 200 ° C, preferably from 60-120 ° C, for 1 to 24 hours. The solvent omethylene glyphate contains e.g. ethers (eg dioxane, tetrahydrofuran, carbon dimethyl ether, diethyl ether, etc.), aromatic hydrocarbons (eg benzene, toluene, xylene, etc.), lower alcohols (eg methanol, ethanol, isopropanol, etc.) , polar solvents (e.g. dimethylformamide, dimethylsulfoxide, etc.) and the like. The basic compound comprises e.g. inorganic bases (eg calcium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, sodium amide, sodium hydride, potassium hydride, sodium methylate, sodium ethylate, etc.), amines (eg triethylamine, tripropylamine, pyridine, quinoline, etc. .) and similar. The reaction proceeds favorably by using an alkali metal iodide (eg potassium iodide, sodium iodide, etc.).

The compound (58) is used in an equimolar amount to excess per 1 mole amount, preferably 1-5 moles, more preferably 1-1.2 moles, of the compound (57). The reaction of the compound (57) and the compound (17) can be carried out under the same conditions as in the reaction of the compound (18) and the compound (17). In addition, hydrolysis of the compound (59) or (60) can be carried out under the same conditions as in hydrolysis of the compound (20).

The compounds (10) of Reaction Scheme-I and the compounds (ib) and (1b ') of Reaction Scheme-II are useful not only as an intermediate to prepare the present compounds (1) with antimicrobial effects, but also as a Vantimicrobial agent on because they also have antimicrobial effects.

In the compounds of the present invention, there are optical and geometric isomers, and the present invention also encompasses these isomers.

Among the present compounds (1), suitable compounds are those compounds wherein R 1 represents unsubstituted cyclopropyl, X represents chlorine or fluorine atom (especially fluorine atom) and or R 3 represents methyl or ethyl (especially methyl).

The compounds (1) can be easily converted into a salt thereof by treating them with a pharmaceutically acceptable acid or base. The acid comprises inorganic acids 1t.ex. hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, etc.) and organic acids (eg: oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, lactic acid, benzoic acid, methanesulfonic acid, propionic acid, etc.). The base comprises sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium bicarbonate and the like.

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

The compounds <1) of the present invention or salts thereof show excellent antimicrobial activity against Pseudomonas aeruginosa, anaerobic bacteria, resistant cells against various antimicrobial agents, clinically isolated bacteria and gram-negative and gram-positive bacteria (eg Enterococcus faecalis, Staphylococcus, etc.) .) and are consequently useful as an antimicrobial agent for the treatment of diseases caused by these microorganisms. These compounds also show low toxicity and less side effects and are characterized by good absorbency and prolonged action. In addition, the compounds are excreted to a large extent via urine and are consequently useful for the treatment of infectious urinary diseases, and furthermore they are also useful for the treatment of infectious intestinal diseases due to their easy excretion via bile. In addition, the compounds of the present invention show improved absorbability in the body by using them in the form of a salt, such as lactate, hydrochloride, etc.

The compounds of the present invention are commonly used in the form of a conventional pharmaceutical preparation. The pharmaceutical composition may be prepared in admixture with conventional pharmaceutically acceptable diluents or carriers such as fillers, weighting agents, binders, wetting agents, disintegrating agents, surfactants, lubricants and the like. The pharmaceutical preparation comprises various preparations suitable for the treatment of the diseases, e.g. tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc.) and the like. In the manufacture of tablets any conventional carrier can be used, e.g. excipients (eg lactose, white sugar, sodium chloride, glucose, urea, starches, calcium carbonate, kaolin, crystalline cellulose: silicate, etc.), binders (eg water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, etc.), disintegrants, (eg dry starch, sodium alginate, agar powder, laminoreabitecarbonate, sodium oxycarbonate, sodium oxycarbonate; , sodium lauryl sulphate, stearic acid monoglyceride, starches, lactose, etc.), decomposition inhibitors (eg white sugar, stearin, cocoa butter, hydrogenated oils, etc.), absorption promoters (eg quaternary ammonium salts, sodium lauryl sulphate, etc.), wetting agents (eg glycerol, starch lactose, kaolin, ser, etc.), adsorbents (eg starches, bentonite, colloidal silicates, etc.), lubricants (eg purified talc, stearates, boric acid powder, polyethylene glycol, etc.) and the like the. The tablets can also be coated with conventional coating agents, e.g. may be in the form of a sugar-coated tablet, a gelatin-coated tablet, led, a film-coating tablet or a double or multi-enteric-coating tablet-layer tablet. In the manufacture of pills, conventional carriers can be used, such as excipients (eg glucose, lactose, starches, cocoa butter, hydrogenated vegetable oils, kaolin, talc, etc.), binders (eg gum arabic powder, tragacanth powder, gelatin, ethanol, etc.), disintegrants (e.g. laminaria, agar, etc.) and the like. In the preparation of suppositories, conventional carriers such as polyethylene glycol, cocoa butter, higher alcohols, higher alcohol esters, gelatin, semi-synthesized glycerides and the like can be used.

In the preparation of injections, the solutions, emulsions or suspensions of the compounds are sterilized and suitably made isotonic with the body fluid. These solutions, emulsions and suspensions are prepared by mixing the active compound with a conventional diluent, such as water, aqueous lactic acid solution, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like. The preparations may also incorporate sodium chloride, glucose or glycerol in an amount sufficient to render them isotonic with the body fluid. The preparations may also incorporate conventional solubilizers, buffering agents, anesthetics and sweeteners, preservatives, perfumes, perfumes, flavoring agents, and other drugs. The preparations in the form of a paste, cream or gel can be prepared as a diluent in white Vaseline, paraffin, glycerol, cellulose derivatives, polyethylene glycol, silicone, bentonite or the like.

The pharmaceutical composition of the present invention may also be in the form of an infusible or injectable solution containing the above compound (1) or a salt thereof (eg lactate, etc.) and an acid which does not produce a precipitate. The acid, which does not produce a precipitate, comprises hydrochloric acid, succinic e.g. lactic acid, methanesulfonic acid, propionic acid, tartaric acid and the like, preferably lactic acid. In the case of lactic acid, the acid is usually used in an amount of from 0.1 to 10% by weight, preferably from 0.5 to 2% by weight, of the above infusible or injectable solution. In the case of using an acid other than lactic acid, the acid is usually used in an amount of from 0.05 to 4% by weight, preferably from 0.3 to 2% by weight, based on the weight of the above solution. In addition, a conventional additive may optionally be added to the above infusible or injectable solution. The additive includes e.g. a thickener, an absorption promoter or inhibitor, a crystallization inhibitor, a complexing agent, an antioxidant, an isotonicity enhancing agent or a hydrating agent and the like. The pH of the solution can be conveniently adjusted by the addition of an alkali, such as sodium hydroxide, and is usually adjusted in the range of 2.5-7.

The infusible or injectable solution thus prepared has excellent stability and can be stored and stored for a long time without maintaining the state of solution.

The active compounds (1) or salts thereof may be present in any amount in the preparations and are usually contained in an amount of 1-70% by weight, based on the total weight of the preparations. by weight, the pharmaceutical compositions of the present invention may be administered by any of the methods. Suitable method of administration can be selected according to the form, age and sex of the preparation in the patients, degree of severity of the diseases and the like. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally. In the case of injection, the injection is administered intravenously alone or together with a helper, etc.). The fluid injections (eg glucose, amino acid solution) can also be administered intramuscularly, intracutaneously, subcutaneously or intraperitoneally. Suppositories can be administered intrarectally.

The dosage of the pharmaceutical compositions of the present invention may vary according to the methods of administration, the age and sex of the patients, the severity of the diseases and the like, but is usually in the range of about 0.2-100 mg of the active compound (1) or a salt thereof per 1 kg of body weight of the patient per day. The preparation is usually administered in divided doses of two to four times a day.

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

Reference Example 1 To a solution of 2-bromo-4,5-difluoroaniline (100 g) and dimethyl sulfide (49 ml) in anhydrous dichloromethane (1.2 liters) is slowly added N-chlorosuccinimide (90 g) at below 15 ° C and then is further added in portions of triethylamine (93 ml) at 15 ° C. After the addition, the mixture is refluxed for seven hours. After cooling, 10% aqueous sodium hydroxide (1 liter) is added to the reaction mixture and the mixture is extracted with dichloromethane. The extract is dried over magnesium sulphate and concentrated and the resulting residue is purified by silica gel column chromatography (solvent, dichloromethane: n-hexane = 1: 2). The product is recrystallized from n-hexane to give 6-bromo-3,4-difluoro-2-methylthiomethylaniline (52 g) as a white crystal, m.p. 60-61 ° C.

Reference Example 2 A mixture of 6-bromo-3,4-difluoro-2-methylthiomethyl-aniline (999), HMPA (130 g) and copper cyanide (48 g) is heated to 150 ° C for four hours. After cooling, the reaction mixture is poured into a solution of ethylenediamine (50 ml) in water (500 ml) and the mixture is heated to 60 ° C for one hour. After cooling, the mixture is extracted with ethyl acetate and the extract is dried over magnesium sulphate and concentrated. The resulting residue is purified by silica gel column chromatography (solvent, dichloromethane: n-hexane = 1: 1), and the product is recrystallized from ethanol to give 2-amino-4,5-difluoro-3-methylthiomethylhensonitrile (28 g) such as a white crystal, m.p.

Reference Example 3 To a solution of 2-amino-4,5-difluoro-3-methylthiomethylbenzonitrile (4.0 g) in ethanol (80 ml) is added Raney nickel (40 ml) with ethanol (80 ml). The mixture is stirred at 40-50 ° C for 30 minutes and then filtered. To the filtrate is added water, the reaction mixture is extracted with ethyl acetate. The extract is dried over magnesium sulphate and concentrated. The product is recrystallized from n-hexane to give 2-amino-4,5-difluoro-3-meth 114-116 ° C. tylbenzonitrile (2.4 g) as a white crystal, m.p.

Reference Example 4 Sodium nitrite (5.6 g) is added to conc. sulfuric acid (58 ml) at below 70 ° C. The mixture is heated to 70 ° C for 10 minutes and then cooled and to this is added dropwise a solution of 2-amino-4,5-difluoro-3-methylbenzonitrile (12.3 g) in acetic acid (123 ml) at below 40 ° C. The mixture is stirred at the same temperature for 30 minutes and then added in portions to a solution of copper (I) chloride (20 g) in conc. hydrochloric acid (200 ml) and then heated to 80 ° C for 30 minutes. After cooling, ice water is added to the reaction mixture and ethyl acetate is distilled off. The residue obtained is purified by silica gel column chromatography (solvent, dichloromethane: n-hexane = 1: 1) to give 2-chloro-4,5-difluoro-3-methylbenzonitrile (8.0 g) as a white crystal, m.p. 59-61 ° C.

Reference Example 5 To 2-chloro-4,5-difluoro-3-methylbenzonitrile (4.0 g) was added 60% sulfuric acid (20 ml) and the mixture was heated at 140-150 ° C for three hours. After cooling, the reaction mixture is poured into ice water and the mixture is extracted with dichloromethane.

The extract is dried over magnesium sulphate and the solvent is distilled off. To the residue is added n-hexane and the precipitate is separated by filtration to give 2-chloro-4,5-difluoro-3-methylbenzoic acid (3.1 ~ g) as a white crystal; p mp A121-122 ° C. 10 15 20 25 30 35 40 59 501 371 Reference Example 6 To 2-chloro-4,5-difluoro-3-methylbenzoic acid (3.1 g) was added thionyl chloride (6 ml) and the mixture was refluxed for one hour. The mixture is concentrated under reduced pressure to give 2-chloro-4,5-difluoro-3-methylbenzoyl chloride (3.3 g).

Separately, metallic magnesium (0.38 g) in anhydrous ethanol (0.8 ml) is suspended and a few drops of carbon tetrachloride are added thereto. When starting the reaction, a mixture of diethyl malonate (2.3 ml), anhydrous ethanol (1.5 ml) and anhydrous toluene (6 ml) is added portionwise at 50-60 ° C. To this is added dropwise a solution of the above 2-chloro-4,5-difluoro-3-methylbenzoyl chloride (3.3 g) in anhydrous toluene (5 ml) at 0 ° C.

After the addition, the mixture is stirred at room temperature for 30 minutes. To the reaction mixture is added a mixture of conc. sulfuric acid (0.4 ml) and water (8 ml) and the mixture is extracted with diethyl ether. The extract is dried over magnesium sulphate and the solvent is then distilled off to give diethyl -2-chloro-3-methyl-4,5-difluorobenzoyl malcnate (5.1 g).

Reference Example 7 To diethyl 2-chloro-3-methyl-4,5-difluorobenzoylmalonate (5.1 g) are added water (10 ml) and p-toluenesulfonic acid (30 ml) and the mixture is refluxed for four hours. After cooling, the mixture is extracted with diethyl ether and the extract is dried over magnesium sulphate. The diethyl ether is de-distilled to give ethyl -2-chloro-4,5-difluoro-3-methylbenzoyl acetate (3.9 g).

Reference Example 8 To ethyl 2-chloro-4,5-difluoro-3-methylbenzoyl acetate (3.9 g) was added triethoxymethane (3.1 g) and acetic anhydride (3.4 g) and the mixture was heated to 150 ° C for one hour. . The mixture is concentrated to give ethyl 2- (2-chloro-3-methyl-4,5-difluorobenzoyl) -3-ethoxyacrylate. To the product was added ethanol (50 ml) and to this was added cyclopropylamine (1.1 ml) at room temperature and the mixture was stirred for 30 minutes. Ethanol is distilled off to give ethyl 2- (2-chloro-3-methyl-4,5-difluorobenzoyl) -3-cyclopropylaminoacrylate. To the product was added anhydrous dioxane (30 ml) and to this was added portionwise 60% sodium hydride (0.6 g). The mixture is stirred at room temperature for 30 minutes and then refluxed for 1 hour. The reaction mixture is poured into aqueous saturated ammonium chloride and extracted with dichloromethane. The extract is dried over magnesium sulfate and concentrated to give ethyl 1-cyclopropyl-6,7-difluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate. (2.2 g).

NMR (CDCl 3) δ: 8.64 (1H, s), 8.10 (1H, t, J = 10 Hz), 4.36 (2H, g, J = 7.5 Hz) 3.76-4 (1H, m), 2.76 (3H, d, J = 4.5 Hz), 1.37 (3H, t, J =?, 5 Hz), 0.86-1.30 (4H, m).

Reference Example 9. To ethyl 1-cyclopropyl-6,7-difluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (2.2 g) is added conc. hydrochloric acid (5 ml), water (2 ml) and acetic acid (20 ml) and the mixture is refluxed for two hours. After cooling, precipitated crystals are separated by filtration and washed with water, ethanol and diethyl ether in this order to give 1-cyclopropyl-6,7--difluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3- carboxylic acid (1.8 g) as white crystals, m.p. 240-243 ° C.

Reference Example 10 To 1-cyclopropyl-6,7-difluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.0 g) is added triacetylboro / B (OCOCH 3) 3 / (1.0 g ) and acetic anhydride (10 ml) and the mixture is heated at 140 ° C for 15 minutes. After the reaction, the mixture is concentrated and to the residue are added diethyl ether and the crystals are separated by filtration to give 6,7-difluoro-1-cyclopropyl-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate. boxyl acid-B (OCOCH 3) 2-chelate (1.2 g).

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

Reference Example Gel 11 2,2-Dichloro-1-cyclopropylcarboxylic acid (4.0 g) is suspended in water (5 ml) and an appropriate amount of acetone is added thereto to give a completely homogeneous solution. The solution is cooled to 0 ° C and to this is added a solution of triethylamine (3.0 g) in acetone (60 ml). While maintaining the temperature of the mixture at 0 ° C, a solution of ethyl chlorocarbonate (3.54 g) in acetone (15 ml) is added dropwise thereto. After the addition, the mixture is stirred at 0 ° C for 30 minutes and to this is added dropwise a solution of sodium azide (2.51 g) in water (10 ml).

The mixture is further stirred at 0 ° C for one hour and then the reaction mixture is poured into ice water and the mixture is extracted with diethyl ether. The extract is dried over magnesium sulfate and concentrated. To the obtained 2,2-dichloro-1-cyclopropylcarbonyl azide are added benzyl alcohol (3.35 g) and anhydrous benzene (50 ml) and the mixture is refluxed with stirring for 10 hours. After complete completion of the reaction, the reaction mixture is concentrated and the residue obtained is purified by silica gel column chromatography (solvent, ethyl acetate: n-hexane 1:30) and then recrystallized from dichloromethane to give 2,2-dichloro-1-benzyloxycarbonylamine cyclopylcarbonylamine cyclopyl , 8 g) as colorless needles, m.p. 79.5-80.5 ° C.

Using appropriate starting materials, the following compounds are prepared in the same manner as described in Reference Example 11. 2-Chloro-1-benzyloxycarbonylaminocyclopropane (a mixture of cis and trans isomers).

NMR (CDCl 3) δ: 1.10-1.32 (2H, m), 2.76-3.10 (2H, m), 4.73-5.13 (1H, m), 5.11 (2H , s), 7.35 (5H, s) 2-fluoro-1-benzyloxycarbonylaminocyclopropane (a mixture of cis and trans isomers).

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

Reference Example 12 To 2,2-dichloro-1-benzyloxycarbonylaminocyclopropane (1.5 g) is added 5% Pd-C (0.15 g), ethanol (15 ml) and conc. hydrochloric acid (1.5 ml) and the mixture is subjected to catalytic reduction at room temperature under atmospheric pressure. After the reaction, the catalyst is removed by filtration and the filtrate is concentrated. The obtained residue is recrystallized from ethanol-diethyl ether to give 2,2-dichloro-1-aminocyclopropane hydrochloride (0.7 g) as a white powder, m.p. 147-148 ° C (dec.).

Using appropriate starting materials, the following compounds are prepared in the same manner as described in Reference Example 12. 2-Chloro-1-aminocyclopropane hydrochloride (a mixture of cis and trans isomers).

NMR (DMSO-d 6) δ: 1.16-1.73 (2H, m), 2.83-3.10 (13, m), 3.57-3.00 (1H, m), 8.60 -9.26 (SH, m). 2-fluoro-1-aminocyclopropane hydrochloride (a mixture of cis and trans isomers). NMR (DMSO-d 6, 200 MHz) δ: I, O-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).

Reference Example fl13 To a solution of ethyl 2- (2,4,5-trifluorobenzoyl) -3-ethoxyacrylate (I, 78 g) and triethylamine (0.60 g) in ethanol (10 ml) was added dropwise a solution of 2-fluoro -I-cyclopropylamine hydrochloride (0.80 g) in ethanol (10 ml) at room temperature with stirring. After the addition, the mixture is stirred at the same temperature for one hour and concentrated to give ethyl 2- (2,4,5--trifluorobenzoyl) -3- (2-fluoro-1-cyclopropyl) aminoacrylate.

To the product is added 60% sodium hydride (0.3 g) and anhydrous dioxane (30 ml) and the mixture is stirred at room temperature for one hour. After concentrating the reaction mixture, the water is added to the residue obtained and the mixture is extracted with dichloromethane. The extract is washed with water and dried, and then the solvent is distilled off to give ethyl 1- (2-fluoro-1-cyclopropyl) -6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate ( a mixture of cis and trans isomers) (1.02 g).

NMR (CDCl 3, 60 MHz) δ: 1.36 (3H, t, J = 8 Hz), 1.44-2.27 (2H, m), 3.50-3.83 (1H, m), δ 28 (2H, q, J = 8 Hz), 4.55-4.86 and 5.26-5.53 (1H, m), 7.58 (1H, dd, J = II Hz, 6Hz), 7.98 (1H, dd, J = 10 Hz, 9 Hz), 8.31 and 8.51 (1H, s).

Using suitable starting materials, the following compounds are prepared in the same manner as described in Reference Example I3. Ethyl I- (2-chloro-1-cyclopropyl) -6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (a mixture of cis and trans isomers).

NMT (CDCl 3, 60 MHz) δ: 1.37 (3H, t, J = 7 Hz), 1.70-2.20 (2H, m), 3.40-3.80 (2H, m), 4 31 (2H, q, J = 7 Hz), 7.55 (1H, dd, J = 14 Hz, 6 Hz), 8.07 (1H, dd, J = 9 Hz, 9 Hz), 8.32 and 8.34 (1H, s).

Ethyl 1- (2-methyl-1-cyclopropyl) -6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (a mixture of cis- and trans-isomers).

NMR (CDCl 3, 60 M 2) δ: 1.00-2.00 (3H, m), 1.39 (3H, t, J = 7 Hz), I4I (3H, s), 3.00- 2.27 (1H, m), 4.37 "" (1H, q, J = 7 Hz), 7.55 (1H, dd, J = II Hz, B Hz), 8.20 35 40 63 501 371 <1H, dd, J = 9 Hz, 9 Hz), 6.51 <1H, s>.

Reference Example 14 To ethyl I- (2-fluoro-1-cyclopropyl) -6,7-difluoro-1,4-dihydro-4-oxoquinoline-8-carboxylate (1.02 g) is added 90% acetic acid - conc . hydrochloric acid (4: 1, 20 ml) and the mixture is refluxed with stirring for one hour. After concentration, water was added to the residue. Precipitated crystals are separated by filtration and washed with ethanol and diethyl ether and then dried to give 1- (2-fluoro-1-cyclopropyl) -6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (a mixture of cis and trans isomers) (0.58 g).

NMR (DMSO-d 6, 200 MHz) δ: 1.63-2.17 (2H, m), 3.75-3.97 and 4.20-4.50 (1H, m), 5.09-5 , 35 and 5.41-5.63 (1H, m), 8.12 (dd, J = 11.85 Hz, 6.67 Hz), 8.39 (dd, J = 12.08 Hz, 7.3 Hz ) (1H), 8.30 (dd, J = I0.38 Hz 8.62 Hz), 8.28 (dd, J = I2, I8 Hz, 10.42 Hz) (1H), 8.73 and 8 , 65 (1H, s).

Using appropriate starting materials, the following compounds are prepared in the same manner as described in Reference Example 14. 1- <2-chloro-1-cycloprepropyl> -6,4-difluoro-1,4-dihydro-4- oxoquinoline-3-carboxylic acid (a mixture of cis and trans isomers). 1 H NMR (DMSO-d 5, 200 MHz) δ: 1.80-1.99 and 2.04-2.23 (2H, m), 3.94-4.07 (1H, m), 4.19- 4.34 (1H, m), 7.98 (1H, dd, J = I1.84 Hz, 6.64 Hz), 8.31 (1H, dd, J = I0.34 Hz, 8.66 Hz) , 8.69 (1H, s).

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

NMR (trifluoroacetic acid-d 5, 60 MHz) δ: 1.33-2.10 (3H, m), 1.58 (3H, s), 3.66-4.00 (1H, m), 8.38 ( 1H, dd, J = 10 Hz, 6 Hz), 8.53 (1H, dd, J = 0 Hz, 9 Hz), 9.48 (1H, s).

Reference Example 15 To a solution of ethyl 7- (4-methyl-1-piperazinyl) -1-cyclopropyl-6-fluoro-8-methylthiomethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (8, 09 g) in ethanol (60 ml) add Raney nickel (40 ml) together with ethanol (80 ml), stir the mixture at 40-50 ° C for 30 minutes and then filter. To the resulting filtrate, water is added and the mixture is extracted with ethyl acetate.

The extract is dried over magnesium sulfate and concentrated to give ethyl 7- (4-methyl-1-piperazinyl) -1-cyclopropyl-6-fluoro-8-methyl-1,1-dinydro-1z-oxoquinoline-α-carboxylate : (2.5 g>.

Reference Example Gel 16 In a solution of 6-bromo-3,4-difluoro-2-methylthiomethylaniline (6.00 g) in ethanol (120 ml), Raney nickel (70 ml) is suspended and the mixture is stirred at 50 ° C for 30 minutes. ~ minutes. After removal of Raney nickel by filtration, the filtrate is concentrated to give 3,4-difluoro-2-methylaniline (3.77 g) as a colorless oil.

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

Reference Example 17 To 3,4-difluoro-2-methylaniline (3.27 g) is added acetic anhydride (50 ml) and the mixture is stirred for 10 minutes.

After distilling off acetic anhydride, the residue obtained is extracted with dichloromethane. The extract is washed with water, aqueous saturated sodium bicarbonate and aqueous saturated sodium chloride in this order and then dried over anhydrous magnesium sulfate. After distilling off the dichloromethane, the residue is recrystallized from ethyl acetate-n-hexane to give 3,4-difluoro-2-methylacetanilide (3.86 g) as colorless needles, m.p. 145.5-146.0 ° C.

Reference Example 18 3,4-Difluoro-2-methylacetanilide (100 mg) is added to ice-cooled conc. nitric acid (0.1 ml) under ice-cooling and the mixture is stirred with sulfuric acid (0.3 ml) and to this is added conc. room temperature for 2 hours. To the mixture is added additional conc. nitric acid (0.1 ml) and the mixture is stirred at room temperature overnight. To the reaction mixture is added a large amount of water, and the mixture is extracted with dichloromethane.

The extract is washed with water, aqueous saturated sodium bicarbonate and aqueous saturated sodium chloride in this order and then dried over anhydrous magnesium sulfate.

After distilling off the dichloromethane, the residue is recrystallized from ethyl acetate-n-hexane to give 4,5-difluoro-6-methyl-2-nitroacetanilide (80.7 mg) as yellow needles, amp. 152.1 ° -152.6 ° C. 10 15 20 25 30 35 40 65 501 371 Reference Example 19 4,5-Difluoro-6-methyl-2-nitroacetanilide (81 mg) is dissolved in acetic acid (2 ml) and to this is added conc. hydrochloric acid (1 ml) at 0 ° C) The mixture is stirred at 100 ° C overnight and then concentrated. The residue is neutralized with aqueous saturated sodium bicarbonate and extracted with dichloromethane. The extract is washed with aqueous saturated sodium chloride and dried over anhydrous magnesium sulfate. Dichloromethane is distilled off to give 4,5-difluoro-6-methyl-2-nitroaniline (59 mg) as orange prisms, m.p. 87.2-88.0 ° C.

Reference Example 20 Sodium nitrite (30 mg) is added portionwise to conc. hydrochloric acid (0.32 ml) and the mixture is stirred at 70 ° C for 10 minutes and cooled to room temperature to which is added dropwise a solution of 4,5-difluoro-6-methyl-2-nitroaniline (59 mg) in acetic acid ( 6.5 ml) at the same temperature. The mixture is stirred at room temperature for 30 minutes and to this is added dropwise a solution of copper (I) chloride (107 mg) in conc. hydrochloric acid (1.0 ml).

The mixture is stirred at 80 ° C for 30 minutes. To the reaction mixture is added water and the mixture is extracted with ethyl acetate. The extract is washed with water, aqueous saturated sodium bicarbonate and aqueous saturated sodium chloride in this order and then dried over anhydrous magnesium sulfate. Ethyl acetate is distilled off to give 2-chloro-5,6-difluoro--3-nitrotoluene (54 mg).

NHR (CDCl 3) δ: 7.58 (1H, dd, J = 11.0 Hz, 8.0 Hz), 2.40 (3H, s).

Reference Example 21 To 2-chloro-5,6-difluoro-3-nitrotoluene (S4 mg) is added ethanol (0.3 ml) and water (0.03 ml) at 0 ° C and to this is further added dropwise a solution of 1-methylpiperazine (0.04 ml) and triethylamine (0.06 ml) in ethanol (0.1 ml) at room temperature. The mixture is stirred at room temperature for 5 hours, at 60 ° C for 5 hours and further at 80 ° C overnight. The reaction mixture is acidified with 2N hydrochloric acid and washed with a small amount of diethyl ether and then neutralized with aqueous saturated sodium bicarbonate and extracted with dichloromethane. The extract is washed with water and aqueous saturated sodium chloride in this order and dried over anhydrous magnesium sulfate, and then dichloromethane is distilled off to give 2-chloro-5-fluoro-6- (4-methyl- 1-piperazinyl) -3-nitrotoluene (35 mg).

NMR (CDCl 3) δ: 7.46 (1H, d, J = 11.2 Hz), 3.15 (4H, br), 2.55 (4H, br), 2.46 (3H, s), 2 , 73 (BH, s).

Reference Example 22 To a solution of 2-chloro-5-fluoro-6- (4-methyl-1-piperazinyl) -3-nitrotoluene (17 mg) in dimethyl sulfoxide (1.5 ml) was added potassium fluoride (110 mg ) and cyclopropylamine (1.0 ml) and the mixture is stirred at 100 ° C for 13 hours. The reaction mixture is diluted with dichloromethane and the mixture is washed with water, aqueous saturated sodium bicarbonate and aqueous saturated sodium chloride in this order and dried over anhydrous magnesium sulfate and then dichloromethane is distilled off. The product is purified by preparative thin layer chromatography (developing agent, methanol-dichloromethane 1:20) to give 1-cyclopropyl-4-fluoro-2-methyl-3- (Q-methyl-1-piperazinyl) -6-nitrotoluene (11 mg) .

NMR (CDCl 3) δ: 7.69 (1H, d, J = 13 Hz), 7.59 (1H, br), 3.45-3.08 (4H, m), 2.85-2.75 ( 1H, m), 2.70-2.43 (4H, m), 2.45 (3H, s), 2.36 (3H, s), 1.0-0.5 (4H, m) Reference Example 23 To a solution of 3,4-difluoroacetanilide (85.5 g) in sulfuric acid (850 ml) is slowly added with stirring potassium nitrate (55.5 g) at room temperature, during which the temperature rises to 60 ° C. The mixture is stirred at 60 ° C for one hour. The reaction mixture is poured into ice water and precipitated crystals are taken by filtration. The precipitates are dissolved in dichloromethane and washed with aqueous sodium bicarbonate, water and aqueous saturated sodium chloride in this order and dried.

The solvent is removed by concentration and washed with n-hexane. The obtained crystals are taken by filtration and dried to give 2-nitro-4,5-difluoroaniline (54 g).

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

Reference Example Gel 24 To a solution of 2-nitro-4,5-difluoroaniline (1.0 g) and dimethyl sulfide (1.79 g) in dichloromethane (40 ml) is slowly added N-chlorosuccinimide (3.82 g) with stirring at below 15 ° C.

The mixture is stirred for 30 minutes and triethylamine (2.89 g) is added thereto and the mixture is refluxed for 21 hours. 10 15 20 25 30 35 40 6 "'501 371 After allowing the reaction mixture to cool, the reaction mixture is washed with 10% aqueous sodium hydroxide, water and aqueous sodium chloride in this order and dried.

The solvent is removed by concentration and the residue obtained is purified by silica gel column chromatography (solvent, n-hexane: ethyl acetate = 30: 1) and then recrystallized from n-hexane to give 2-nitro-4,5-difluoro-6-methylthiomethylaniline (0.47 g) as yellow needles, 119-111.5 ° C.

Reference Example 25 Sodium nitrite (0.15 g) is added to conc. sulfuric acid (15 m.p. ml) and the mixture is stirred at 70 ° C for 10 minutes. To the mixture is added dropwise a solution of 2-nitro-4,5-difluoro-6-methylthiomethylaniline (0.45 g) in acetic acid (4.5 ml). The mixture is stirred at the same temperature for 45 minutes and to this is added a further dropwise solution of copper (I) chloride (0.52 g) in conc. hydrochloric acid (5.2 ml). The mixture is stirred at 80 ° C for 1.5 hours and the reaction mixture is poured into the ice water and extracted with ethyl acetate. The extract is washed with water and aqueous saturated sodium chloride in this order and dried and then the solvent is distilled off. The obtained residue was purified by silica gel column chromatography (solvent, n-hexane: ethyl acetate = 30: 1) to give 2-chloro-3-methylthio-4,5-difluoro-1-nitrobenzene (0.16 g).

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

Reference Example 26 2,3,6-Trifluorobenzoic acid (21.0 g) is added to conc. sulfuric acid (120 ml) under ice-cooling. To the mixture is added dropwise a solution of potassium nitrate (14.5 g) in conc. sulfuric acid (30 ml) at below 20 ° C. After the addition, the mixture is stirred at room temperature for one hour. The reaction mixture is poured into ice water and extracted with diethylates. The extract is dried over magnesium sulphate and then the solvent is distilled off. The residue is recrystallized from dichloromethane-n-hexane to give 2,5,6-trifluoro-3-nitrobenzoic acid (22 g) as colorless prisms, m.p. 98-99 ° C.

NHR (CDCl 3) δ: 8.11-8.23 (1H, m), 9.10 (1H, good) Reference Example 27 To a solution of sodium boron hydroxide (44 g) in anhydrous tetrahydrofuran is added a solution of 2.5.6 -trifluoro-3-nitro-benzoic acid (22 g) in anhydrous tetrahydrofuran (40 ml) at below 10 ° C and to this is further added dropwise a solution of boron trifluoride telate (20 ml) in anhydrous tetrahydrofuran (40 ml) at below 10 ° C. After the addition, the mixture is stirred at room temperature for one hour. The reaction mixture is kept in ice-water and extracted with diethyl ether. The extract is dried and then the solvent is distilled off to give 2,5,6-trifluoro--3-nitrobenzyl alcohol (14 g). NMR (CDCl 3) δ: 2.56 (1H, brs), 4.88 (2H, t, 2 7.92-a, o4 un, m).

Reference Example 28 To a solution of 2,5,6-trifluoro-3-nitrobenzyl alcohol J = 1.8 Hz), (14 g) in ethanol (64 ml) and water (7 ml) is added a mixture of 4-ethoxycarbonylpiperazine (11 g). g), triethylamine (12.5 g) and ethanol (18 ml) at once. The mixture is stirred at room temperature overnight and the precipitates obtained are separated by filtration. The crystals are washed with a small amount of diethyl ether and recrystallized from ethanol to give 3,6-difluoro-2- (4-ethoxycarbonyl-1-piperazinyl) -5-nitrobenzyl alcohol (8.7 g), such as yellow needles, 147-149 ° C.

Reference Example 29 To a solution of 3,6-difluoro-2- (4-ethoxycarbonyl-1-m.p. perazinyl) -5-nitrobenzyl alcohol (8.5 g) in chloroform (85 ml) is added thionyl chloride (2.7 ml ) at room temperature. The mixture is stirred at the same temperature for 30 minutes and the reaction mixture is poured into ice water and then neutralized with sodium bicarbonate and extracted with diethyl ether. The extract is dried over magnesium sulfate and then the solvent is distilled off to give 2- (4-ethoxycarbonyl-1-piperazinyl) -3,6-difluoro-5-nitrobenzyl chloride (8.1 g).

NMR (CDCl 3) δ: 1.28 (3H, t, J = 7.1 Hz), 3.08-3.33 (4H, m), 3.46-3.75 (4H, m), 4, 18 (2H, q, J = 7.1 Hz), 4.77 (2H, d, J = 2.5 Hz), 7.82 (1H, dd, J = 9.2 Hz, 7.2 Hz) .

Reference Example 30 To a solution of 3,6-difluoro-2- (4-ethoxycarbonyl-1-piperazinyl) -5-nirobenzyl chloride (8.1 g) in dimethyl sulfoxide (90 ml) is slowly added sodium borohydride (1.8 g). at below 30 ° C.

The mixture is stirred at the same temperature for 1 hour and the reaction mixture is poured into ice water and then acidified with conc. hydrochloric acid and extracted with diethyl ether. The solvent is distilled off to give 2- (4-ethoxycarbonyl-1-piperazinyl) -3,6-difluoro-5-nitrotoluene (7.1 g).

NMR (CDCl 3) δ: 1.26 (3H, t, J = ?, 1 Hz), 2.30 (3H, d, J = 3 Hz), 2.26-3.27 (SH, m), 3 50-3.75 (4H, m), 4.17 (2H, q, J = 7.1 Hz), 7.60 (1H, dd, J = 9.3 Hz, 7.2 Hz).

Reference Example Gel 31 V To 3,6-difluoro-2- (4-ethoxycarbonyl-1-piperazinyl) -5-nitrotoluene (7.1 g) are added anhydrous dimethyl sulfoxide (23 ml), potassium fluoride (2.0 g) and cyclopropylamine (1 .5 g) and the mixture is heated to 60 ° C for 6 hours. The reaction mixture is poured into ice 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) as orange-red prisms. m.p. 97-98 ° C.

NMR (CDCl 3) δ: 0.50-0.54 (2H, m), 0.66-0.74 (2H, m), 1.28 (BH, t, J = 7.1 Hz), 2, 43 (3H, s), 2.63-2.90 (1H, m), 3.07-3.28 (4H, m), 3.47-3.77 (4H, m), 4.20 ( 2H, q, J = 7.1 Hz), 7.53 (1H, brs), 7.70 (1H, dd, J = 13 Hz).

Reference Example 32 To N-cyclopropyl-2-methyl-3- (4-ethoxycarbonyl-1-piperazinyl) -4-fluoro-6-nitroaniline (7.1 g) is added diethylethoxymethylene malonate (4.6 g) and the mixture reacted at 150-170 ° C for 17 hours. After cooling, the solvent is distilled off and the residue obtained is subjected to silica gel column chromatography (solvent, dichloromethane n-hexane = 2: 19 = dichloromethane) to give diethyl [N-cyclopropyl-N: 73- (4-ethoxycarbonyl- 1-piperazinyl) -2-methyl-4-fluoro-6-nitrophenylaminaminethylene] malonate (5.4 g).

Reference Example 33 To a solution of diethyl [N-cyclopropyl-N-L3- (4-ethoxycarbonyl-1-piperazinyl) -2-methyl-4-fluoro-6-nitrophenylaminomethylene malonate (1.0 g) in acetic anhydride (5 ml) is added conc. sulfuric acid (2 ml) while maintaining at 50-70 ° C. After stirring for 30 minutes, the reaction mixture is poured into ice water and neutralized with potassium carbonate. The mixture is extracted with ethyl acetate and the solvent is distilled off and the obtained residue is purified by silica gel column chromatography (solvent, dichloromethane methanol = 10: 1) and then recrystallized from ethyl acetate to give ethyl acetate 1- cyclopropyl 7- (4-ethoxycarbonyl-1-piperazinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (0.19 g) as colorless prisms, m.p. 200-202 ° C.

In the same manner as described in Reference Example 33, but using suitable starting materials, the same compounds are prepared as in Reference Examples 8, 15 and 13.

Reference Example 34 In the same manner as described in Reference Example 28, but using the appropriate starting material, the following compound is prepared: 3,6-difluoro-2- (4-benzyl-3-methyl-1-piperazinyl) -5-nitrobenzyl alcohol NHR ( CDCl 3) δ: 2.55-2.72 (1H, m), (5H, m), 4.09 (1H, d, J = 13 Hz), 7.12-7.40 (SH, m), 7.71 (1H, dd, 1.18 (3H, d, J = 6 Hz), 2.20-2.38 (1H, m) 2.72-2.91 (1H, m), 3.06 -3.44 4.77 (2H, br), J = 9.5 Hz, 7.2 Hz).

Reference Example 35 In the same manner as described in Reference Example 29 but using the appropriate starting material, the following compound is prepared: 2- (4-Benzyl-3-methyl-1-piperazinyl) -3,6-difluoro-5-nitrobenzyl chloride NMR (CDCl Δ: 1.21 (BH, d, J = 6 Hz), 2.24-2.50 (1H, m), 2.60-3.00 (2H, m), 3.00-3.46 (SH, m), 4.11 (1H, d, J = 13 Hz), 4.75 (2H, brs), 7.26-7.45 (SH, m), 7.79 (1H, dd, J = 9.5 Hz, 7.3 Hz).

Reference Example 36 In the same manner as described in Reference Example 30, but using the appropriate starting material, the following compound is prepared: 2- (4-Benzyl-3-methyl-1-piperazinyl) -3,6-difluoro-5-nitrotoluene NMR (CDCl 3 Δ: 1.18 (3H, d, J = 6 Hz), 2.25 (3H, d, J = 3.3 Hz), 2.30-2.48 (1H, m), 2.50 3.38 (7H, m), 4.08 (1H, d, J = 13 Hz), 7.15-7.46 (SH, m), 7.58 (1H, dd, J = 7.5 Hz , 9.5 Hz).

Reference Example 37 Have the same procedure as described in Reference Example 31, but using the appropriate starting material, the following compound is prepared: N-cyclopropyl-2-methyl-3- (4 -benzyl-3-methyl-1-piperazinyl% -4-fluoro-6-nitroaniline NMR (CDCl 3) δ: 0.52-0.68 (2H, m), 0.70-0.8? (2H, m ), 1.28 (3H, d, J = 6 Hz), 2.22-2.40 (1H, m), 2.38 (3H, s), 2.58-3.37. (8H, m ), 7.26-7.44 (SH, m), 7.60 (1H, brs), 4.11 (1H, d, J = 13 Hz), 7.77 (1H, dd, J = 1a, 2 Reference Example 38 - In the same manner as described in Reference Examples 32 and 33 but using the appropriate starting material, the following compound is prepared: ethyl 1-cyclopropyl-7- (4-benzyl-3-methyl-1-piperazinyl ) - 6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate, mp 172-173 ° C, white powder (recrystallized from ethyl acetate).

Reference Example 39 In the same manner as described in Reference Example 28 but using the appropriate starting material, the following compound is prepared: 3,6-difluoro-2- (3-amino-1-pyrrolidinyl) -5-nitrobenzyl alcohol, 117.0- 118.5 ° C, orange prisms (recrystallized m.p. from ethyl acetate-n-hexane).

Reference Example 40 To 3,6-difluoro-2- (3-amino-1-pyrrolidinyl) -5-nitrobenzyl alcohol (43 mg) is added acetic anhydride (0.5 ml) at room temperature. The mixture is stirred at the same temperature for 10 minutes and the reaction mixture is diluted with water and extracted with dichloromethane. The organic layer is washed with water and aqueous saturated sodium chloride in this order and dried over anhydrous magnesium sulfate, and then the solvent is distilled off. The obtained residue is purified by silica gel column chromatography (solvent, dichloromethane 9-methanol: dichloromethane = 1:12) and then recrystallized from dichloromethane to give 2- (3-acetylamino-1-pyrrolidinyl) -3,6-difluoro -5-nitrobenzyl alcohol (40 mg) such as yellow prisms, m.p. 142.5- -143.5 ° C.

Reference Example 41 In the same manner as described in Reference Example 29, but using the appropriate starting material, the following compound is prepared} ï -} * - 1Ü _,>. 2- (4-Acetylamino-1-pyrrolidinyl) -3,6-difluoro-5-nitrobenzyl chloride.

NMR (CDCl 3) δ: 7.74 (1H, dd, J = I2.0 Hz, 7.5 Hz), 6.16 (1H, d, J = 5.4 Hz), 4.78 (1H, dd J = II, 3 Hz, 3.0 Hz) 4.69 (1H, dd, J = II, 3 Hz, 3.0 Hz), 4.62-4.50 (1H, m) 3.97- 3.69 (2H, m), 3.6? -3.50 (1H, m), 3.49-3.32 (1H, m), 2.40-2.18 (1H, m), 2.12-1.93 (1H, m), 1.98 (an, s). Reference Example 42 In the same manner as described in Reference Example 30 but using the appropriate starting material, the following compound is prepared: 2- (3-acetylamino-1-pyrrolidinyl) -3,6-difluoro-5-nitro-139.0 -I40.3 ° C, yellow needles (recrystallized from toluene, m.p. dichloromethane).

Reference Example 43 In the same manner as described in Reference Example 31, but using the appropriate starting material, the following compound is prepared: N-cyclopropyl-2-methyl-3- (3-acetylamino-1-pyrrolidinyl) -4-fluoro-6-nitroaniline, m.p. 162.5-164.0 ° C, orange prisms (recrystallized from ethyl acetate-n-hexane).

Reference Example 44 In the same manner as described in Reference Example 32 but using the appropriate starting material, the following compound is prepared: Diethyl- [N-cyclopropyl-N-L13-acetylamino-1-pyrrolidinyl) -4-fluoro-2-methyl-6- nitrophenyl] aminomethyleneYmalonate NMR (CDCl 3) δ: 7.73 (1H, s), 7.68 (1H, d, J = II, 6 Hz), 5.97 (1H, br), 4.62-4.45 (1H, m), 4.12 (4H, q, J = 7.2 Hz), 3.85-3.15 (SH, m), 2.42-1.95 (SH, m), 1, 98 (3H, s), 1.29 (6H, t, J = 7.2 Hz), 0.93-0.52 (4H, m).

Reference Example 45 In the same manner as described in Reference Example 33 but using the appropriate starting material, the following compound is prepared: In Ethyl-1-cyclopropyl-7- (3-acatylamino-1-pyrrolidinyl) -6-fluoro-8-methyl 1,4-dihydro-4-oxoquinoline-3-carboxylate, m.p. 215.5-27 ° C, D ° C, white powder (recrystallized from ethanol * -ethyl acetate-diethyl ether). In Reference Example 46 3,6-Difluoro-2- (4-ethoxycarbonyl-1-piperazinyl) -5-nitrobenzyl alcohol (1.5 g) is dissolved in dichloromethane (18 ml) and to this is added dropwise a solution of dimethylaminosulfur trifluoride (DAST) (0.7 ml) and triethylamine (0.78 ml) in dichloromethane (3 ml) over a period of 5 minutes with stirring at 0 ° C in an ice bath.

The mixture is stirred at 0 ° C for 1.2 hours and to this is added additional DAST (0.3 ml). After 5 minutes, the reaction mixture is poured into ice water and the organic layer is separated.

The solvent is distilled off under reduced pressure and the residue is purified by silica gel column chromatography (solvent, ethyl acetate: n-hexane = 1:10 - 1: 5 v / v) to give 2,5-difluoro-3-fluoromethyl-4- ( 4-ethoxycarbonyl-1-piperazinyl) nitrobenzene (1.1 g).

Reference Example Gel 47 3,6-Difluoro-2- (4-ethoxycarbonyl-1-piperazinyl) -5-nitrobenzyl alcohol (1.0 g) is dissolved in pyridine (10 ml) and to this is added with stirring acetic anhydride (2 ml) at room temperature and the mixture is stirred at the same temperature for two hours. To the reaction mixture is added water (20 ml) and the mixture is stirred for 5 minutes. The mixture is extracted with dichloromethane and the organic layer is washed with 10% hydrochloric acid and aqueous saturated sodium bicarbonate and then dried over magnesium sulphate. The solvent is distilled off under reduced pressure to give 3-acetoxymethyl-2,5-difluoro-4- (4-ethoxycarbonyl-1-piperazinyl) -nitrobenzene (1.2 g).

Reference Example 48 In the same manner as described in Reference Example 31, but using the appropriate starting material, the following compounds are prepared: N-cyclopropyl-2-acetoxymethyl-3- (4-ethoxycarbonyl-1-piperazinyl) -4-fluoro-6- nitroaniline N-cyclopropyl-2-methoxymethyl-3- (4-methyl-1-piperazinyl) -4-fluoro-6-nitroaniline NHR (CDCl 3) δ: 0.47-0.55 (2H, m), 0.69 -0.78 (2H, m), 2.36 (BH, s), 2.51-2.61 (4H, m), 2.88-2.98 (1H, m), 3.22-3 31 (4H, m), 3.34 (BH, s), 4.67 (2H, s), 7.29 (1H, s), 7.70 (1H, d, J = 12.7 Hz) N-cyclopropyl-2-methoxymethyl-3- (4-ethoxycarbonyl-1-piper - C'-azinyl) -4-fluoro-6-nitroaniline, orange-red needles, m.p. 89-90 ° C 10 15 20 25 30 35 40 74 501 371 (ethanol-water).

Reference Example 49 In the same manner as described in Reference Example 32, but using the appropriate starting material, the following compounds are prepared: - Diethyl / N-cyclopropyl-N- [3- (4-ethoxycarbonyl-1-piperazinyl) -2- acetoxymethyl-4-fluoro-6-nitrophenyl / aminomethylene) malonate diethyl / N-cyclopropyl-N- [3- (4-methyl = 1-piperazinyl) -2-methoxymethyl-4-fluoro-6-nitrophenyl] aminomethylene / malonate RMR (CDCl 3) δ: 0.50-1.10 (4H, m), 1.23 (3H, t, J = 7.0 Hz) 2.37 (BH, 2.39-2.60 ( 4H, m), 3.0-3.20 (1H, m), 3.10-3.50 (4H, m), 3.39 (3H, s), 4.15 (2H, q, J = 7.0 Hz), 4.30-4.55 (2H, m), 7.55-7.90 (2H, m). S), diethyl / N-cyclopropyl-n- / 3- (4- ethoxycarbonyl-1-piperazinyl) -2-methoxymethyl-4-fluoro-6-nitrophenyl / aminomethylene / malonate NMR (CDCl 3) δ: 0.55-0.73 (2H, m), 0.95-1.15 (2H, m), 1.15-1.45 (QH, m), 3.0-3.15 (1H, m), 3.15-3.35 (4H, m), 3.40 (3H , m), 3.45-3.70 (4H, m), 4.05-4.40 (GH, m), 4.40-4.60 (2H, m), 7.65-7.90 (2H, m).

Reference Example 50 In the same manner as described in Reference Example 33, using the appropriate starting material, the following compounds are prepared: Ethyl-1-cyclopropyl- 7- (4-ethoxycarbonyl-1-piperazinyl) -6-fluoro-8-acetoxymethyl-1,4-dihydro -4-oxoquinoline-3-carboxylate, 172-1,3 ° C methyl 1-cyclopropyl-7- (4-ethoxycarbonyl-1-piperazinyl) -6-yellow powder, m.p. fluoro-8-methoxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate NHR (CDCl 3) δ: 0.80-0.95 (ZH, m), 1.10-1.22 (2H, m) , 1.30 (3H, t, J = 7.1 Hz), 3.13 (3H, 3.08-3.30 (4H, m), 3.50-3.85 (SH, m), 3 92 (3H, 4.19 (ZH, q, J = 7.1 Hz), 5.12 (2H, 8.09 (1H, d, J = 12.4 Hz), 8.67 (1H, ethyl -1-cyclopropyl-7- (4-methyl-1-piperazinyl) -6-fluoro- s), s), s), s) 8-acetoxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate, m.p. 122-125 ° C, yellowish white powder V Methyl 1-cyclopropyl-7- (4-ethoxycarbonyl-1-piperazinyl) -6-fluoro-8-hydroxymethyl-1,4-dihydro-oxoquinoline-3-carboxylate ethyl-1 -cyclopropyl 7- (4-ethoxycarbonyl-1-piperazinyl) -6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate.

Reference Example 51 In the same manner as described in Reference Example 28, using a suitable starting material, the following compound is prepared: 3,6-difluoro-2- (4-methyl-1-piperazinyl) -5-nitrohenzyl alcohol, m.p. 138 ~ 139 ° C, yellow prisms. Reference Example 52 52 - 3,6-difluoro-2- (4-ethoxycarbonyl-1-piperazinyl) -5-nitrobenzyl alcohol (7.14 g) is dissolved in methanol (770 ml) and to this is added dropwise conc. sulfuric acid (145 ml) while cooling in an ice bath. The mixture is refluxed for four hours. The reaction mixture is cooled to room temperature and poured into ice water (1.5 liters) and then extracted with dichloromethane. The extract is dried over magnesium sulphate and sodium sulphate and then the solvent is distilled off under reduced pressure to give 3-methoxymethyl--2,5-difluoro-4- (4-ethoxycarbonyl-1-piperazinyl) nitrobenzene (7.39 g) as a yellow powder, m.p. . 85-6 ° C.

In the same manner as described above using a suitable starting material, the following compound is prepared. 3-Methoxymethyl-2,5-difluoro-4- (4-methyl-1-piperazinyl) -nitrobenzene NMR (CDCl 3) δ: 2.37 (3H, s), 2.45-2.60 (4H, m), 3 , 32- 3.42 (4H, m), 3.48 (3H, s), 4.53 (2H, d, J = 3.5 Hz) 7.78 (1H, dd, J = 7.3 Hz J = 11.8 Hz) Reference Example 53 To a solution of ethyl 1-cyclopropyl-7- (4-ethoxycarbonyl-1-piperazinyl) -6-fluoro-8-acetoxymethyl-1,4-dihydro-4- oxoquinoline-3-carboxylate (300 mg) in methanol (3 ml) is added 1N aqueous potassium carbonate (0.8 ml) and the mixture is stirred at room temperature for 3.25 hours. The reaction mixture is kept in water and extracted with dichloromethane and chloroform. The organic layers are combined and then dried over anhydrous sodium sulfate and the solvent is distilled off to give a mixture of methyl 1-cyclopropyl-7- (4-ethoxycarbonyl-1-pinerazinyl) -6-fluoro-20-hydroxymethyl-1 , 4-dihydro-fo-oxoquinoline-3-carboxylate and ethyl 1-cyclopropyl-7- (4-ethoxycarbonyl-1-piper-aazinyl) -6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxo-quinoline - carboxylate (2: 1) (280 mg).

Without separating them, ethanol (7A '? 10 15 20 25 30 35 40 76 501 371 ml) and conc. sulfuric acid (1.4 ml) and the mixture is refluxed for four hours. The reaction mixture is poured into ice water (50 ml) and then adjusted to below pH 8 with potassium carbonate and extracted with dichloromethane. The extract is dried over anhydrous sodium sulfate and then the solvent is distilled off under reduced pressure to give methyl 1-cyclopropyl-7f (4-ethoxycarbonyl-1-piperazinyl) -6-fluoro-8-methoxymethyl-1,1-dihydro -4-oxoquinoline-3-carboxylate (159 mg). NMR (CDCl 3) δ: 0.80-0.05 (2H, m), 1.10-1.22 (2H, m), M 1.30 (3H, t, J = 7.1 Hz), 3.13 (SH, 3.08-3.30 (4H, m), 3.50-3.85 (SH, m), 3.92 (3H, 4.19 (2H, q, J = 7, 1 Hz), 5.12 (2H, 8.09 (1H, d, J = 12.4 Hz), 8.67 (1H, s), s), s), s).

Reference Example 54 In the same manner as described in Reference Example 28, but using the appropriate starting material, the following compounds are prepared: 3,6-difluoro-2-morpholino-5-nitrobenzyl alcohol NMR (CDCl 3) δ: 7.79 (1H, dd, J = 11.9 Hz, 7.2 Hz), 4.86 (2H, 4.02-3.66 (4H, 3.42-3.20 <4H, 3.30-3.02 (1H, br)) mp 87-89 ° C (recrystallized from n-hexane-ethyl acetate), s), m), m), yellow plates 2,5-difluoro-3-methoxymethyl-4-morpholino-nitrobenzene, m.p. 61.5-62 ° C (recrystallized from n-hexane-ethyl acetate), yellow needles 3,6-difluoro-2- (3-acetamidomethyl-1-pyrrolidinyl) -5-nitrobenzyl alcohol, m.p. 120-121 ° C, yellow crystals NMR (CDCl 3 + DMSO-d 5) δ: 1.55-1.83 (1H, m), 1.95 (3H, s) 1.99-2.10 (1H, m ), 2.39-2.57 (1H, m), 3.14-3.82 (GH, m), 4.72 (2H, d, J = 2.6 Hz), 7.70 (1H, dd, J = 7.5 Hz, 13.5 Hz) 3,6-difluoro-2- (4-benzyl-1-piperazinyl) -5-nitrobenzyl alcohol NMR (CDCl 3) §: 2.50-2.72 (4H, m), 3.20 (1H, br), 3.25-s, sa an, m), a, se (an, 4,7s-4, so (za, m, 7,20-7 , 45 (SH, m), 7.76 (1H, dd, Js7.2 Hz, 11.6 Hz) 2,5-difluoro-3-methoxymethyl-4- (4-benzyl-1-piperazinyl) - 7, 31 (1H, brs), s), nitrobeneen., _.,.

NMR (CDCl 3) δ: 2.45-2.68 (4H, m), 3.30-3.45 (4H, m), δ 15 20 25 30 35 40 77 3.42 (SH, 3.58 ( 2H, 4.52 (2H, d, J = 3.4 Hz), 7.26-7.40 (SH, m), 7.78 (1H, dd, J = 7.3 Hz, 11.9 Hz ) 2,5-Difluoro-3-methoxymethyl-4- (4-benzyl-3-methyl-1-piper- s), s), azinyl) -nitrobenzene NMR (CDCl 3) δ: 7.77 (1H, d, J = 7.4 Hz, 11.9 Hz), 7.41 - 7.18 (SH, m), 4.52 (2H, s), 4.11 (1H, d, Q = 13.0 Hz ) 3.45-2.89 (4H, m), 3.42 (3H, s), 3.21 (1H, d, J = 13.0 Hz), 2.89-2.73 (1H, m ), - 2.73-2.54 (1H, m), 2.39-2.20 (1H, m), 1.19 (3H, d, J = 6.2 Hz) 3,6-difluoro- 2- [3- (N-methyl-N-benzylamino) -1-pyrrolidinyl) -5-nitrobenzyl alcohol NMR (CDCl 3) δ: 7.75 (1H, dd, J = 7.5 Hz, 7.20 ( SH, m), 3.85-3.60 (4H, m), 3.62 (1H, d, J = 13.1 Hz), 3.52 (1H, d, J = 13.1 Hz), 3.25-3.05 (1H, m), 2.35-1.92 (3H, m), 2.20 (3H, s) Reference Example 55 In the same manner as described in Reference Example 29, but 13.1 Hz), 7.41 - using the appropriate starting material, the following compounds are prepared: 2-morpholino-3,6-difluoro-5-nitrobenzyl chloride NHR (CDCl 3) δ: 7.84 (1H, dd, J = 11 , 3 Hz, 7.3 Hz), 4.79 (2H, d, J = 2.6 Hz), 4.00-3.78 (4H, m), 3.40-3.15 (4H, m ) 2,5-Difluoro-3-chloromethyl-4- [3- (N-methyl-N-benzylamino) -1-pyrrolidinyl) -nitrotoluene NHR (CDCl 3) δ: 7.78 (1H, dd, J = 7, 6 Hz, 13.4 Hz), 7.42-7.22 (SH, 4.78 (1H, dd, J = 2.7 Hz, 12.1.Hz), 4.67 (1H, 12.1 Hz), 3.92-3.55 (4H, m) 3.67 (1H, d, J = 13.1 Hz), 3.53 (1H, d, J = 13.1 Hz), 3.30 -3.10 (1H, 2.35-1.88 (2H, m), 2.22 (3H, s) 2,5-difluoro-3-chloromethyl-4- (3-acetamidomethyl-1-pyrrolidinyl) ) nitrotoluene, 94-98 ° C, yellow crystals NMR (CDCl 3 + DMCO-d 5) δ: 1.68-1.90 (1H, m), 2.07 (SH, s) 2.00-2.25 ( 1H, m), 2.50-2.68 (1H, m), 3.20-3.79 (SH, m), 4.78 (2H, d, J = 2.6 Hz), 7.78 (1H, dd, J = 7.5 Hz, 13.5 Hz), 8.18 (1H, brs) Reference Example 56 'In the same manner as described in Reference Example 30 but gem), dd, J = 2.7 Hz, m), SMP. Using suitable starting materials, the following compounds are prepared: 501 371 78 2-Morpholino-3,6-difluoro-5-nitrotoluene, orange needles, 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, 1 H NMR (CDCl 3) δ: 7.65 (1H, dd, J = 7.1 Hz, 12.8 Hz), 7.38-7.20 (5H, m), 3.79-3.45 (4H, m ), 3.62 (1H, d, J = 13.4 Hz), 3.50 (1H, d, J = 13.4 Hz), 3.30Å3.06 (1H, m), 2.35-2 13 (1H, m), 2.25 (3H, d, J = 3.2 Hz), 2.20 (3H, s), 2.11-1.88 (1H, m). Α, 6-difluoro-5-nitro-2- (3-acetamidomethyl-1-pyrrolidinyl) toluene, m.p. 82-84 ° C, yellow crystals NHR (CDCl 3) δ: 1.60-1.78 (1H, m), 2.00 (3H, s), 2.02-2.20 (1H, m), 2 24 (3H, d, J = 3.2 Hz), 2.40-2.66 (1H, m), 3.20-3.62 (6H, m), 5.67 (1H, brs), 7.63 (1H, dd, J = 7, d Hz, 13.5 Hz) Reference Example 57 In the same manner as described in Reference Example 31, but using the appropriate starting material, the following compounds are prepared: N-cyclopropyl-2- methyl-3-morpholino-4-fluoro-6-nitroaniline red flakes, m.p. 101.5-102 ° C (recrystallized from n-hexane) N-cyclopropyl-2-methoxymethyl-3- (4-benzyl-1-piperazinyl) -4-fluoro-6-nitroaniline NMR (CDCl 3) δ: 0.45 -0.57 (2H, m), 0.65-0.77 (2H, m), 2.48-2.65 (4H, m), 2.86-3.00 (1H, m), 3.20-3.30 (4H, m), 3.32 (3H, s), 3.58 (2H, s), 4.81 (2H, s), 7.25-7.38 (SH, m), 7.70 (1H, d, J = 12.8 Hz).

N-Cyclopropyl-2-methoxymethyl-3- (3-methyl-4-benzyl-1-piperazinyl) -4-fluoro-6-nitroaniline NMR (CDCl 3) δ: 7.70 (1H, d, J = I2.9 Hz), 7.40-7.19 (SH, m), 4.65 (2H, s), 4.11 (1H, d, J = I3.3 Hz), 3.32 (2H, s), 3.40-2.88 (SH, m), 3.22 (1H, d, J = I3.3 Hz) 2.88-2.72 (1H, m), 2.72-2, 53 (1H, m), 2.38-2.20 (1H, m), 1.20 (3H, d, J = 6.2 Hz), 0.80-0.63 (2H, m), 0.50-, 45 (2H, m) N-cyclopropyl-2-methyl-3- [3- (N-methyl-N-benzylamino) -1-pyrrolidinyl] -4-fluoro-6-nitroaniline.

NHR (CDCl 3) δ: 7.87 (1H, a), 7.69 (1H, d, J = II, 7 Hz), 7.40-7.22 (SH, m), 3.81-3, 41 (4H, m), 3.65 (1H, d, 40 J = I0.6 Hz), 3.55 (1H, d, J = I0.6 Hz), 3.24-3.08 79 (1H, m), 2.86-2.72 (1H, m), 2.32-2, 10 (1H, m), 2.29 (3H, s), 2.21 ( 3H, S), 2.08 ~ I, 90 (1H, m), 0.88-0.56 (3H, m), 0.5I ~ 0.4I (1H, m) N-cyclopropyl-2: methoxymethyl -3-morpholino-4-fluoro-6-nitroaniline, m.p. 75-60 ° C (crystallized from n-hexane), red powder - N-cyclopropyl-2-methyl-3- (3-acetamidomethyl-1-nyrrolidinyl) -4-fluoro-6-nitroaniline - NMR (CDCl 3) δ : 0.40-0.85 (4H, m), 1.60-1.83 (1H, m), N 2.01 (3H, s), 2.04-2.20 (1H, m), 2.28 (3H, s), 2.42-2.60 (1H, m), 2.70-2.88 (1H, m), 3.20-3.65 (GH, m), 5, 89 (1H, brs), 7.65 (1H, d, J = I4.6 Hz), 7.86 (1H, brs) Reference Example Gel 58 In the same manner as described in Reference Example 32, but using appropriate starting material, the following compounds: diethyl [N-cyclopropyl-N- [3- (4-benzyl-1-piperazinyl) -2-methoxymethyl-4-fluoro-6-nitrophenyljaminomethyl] malonate NHR (CDCl 3) 6: 0.55-0.90 ( 4H, m), 1.15-1.35 (GH, m), 2.4? -2.70 (4H, m), 3.05-3.45 (4H, m), 3.37 (3H , s), 3.58 (2H, s), 4.15 (4H, q, J = 7 Hz), 4.20-4.55 (3H, m), 7.20-7.38 (SH, m), 7.63-7.90 (2H, m) diethyl- [N-cyclopropyl-N-L3- (4-benzyl-3-methyl-1-piperazinyl) -2-methoxymethyl-4-fluoro- 6-nitrophenyl] aminomethylQ] malenate NHR (CDCl 3) δ: 7.80 (1H, d, J = I2.7 Hz), 7.78 (1H, s), 7.47-7.15 (SH, m ), 4.55-3.98 (7H, m), 3.65f2.88 (SH, m), 3.38 (3H, s), 2.86-2.70 (1H, m), 2, 70-2.4? (1H, m), 2.32-2.18 (1H, m), 1.50-1.08 (SH, m), I.19 (3H, d, J = 5.0 Hz), 1, 01-0.41 (4H, m) Diethyl [N- (cyclopropyl-N- [3-L3- (N-benzyl-N-methylamino] -1-pyrrolidinyl] -2-methyl-4-fluoro-6-nitrophenyl ] -aminomethylene7-malonate NMR (CDCl 3) δ: 7.85-7.60 (2H, m), 7.40-7.16 (5H, m), 4.25-4.06 (2H, m), 3.80 * 3.05 (8H, m), 2.19 (GH, s), 2.32-I, 89 (2H, m), 1.23 (SH, t, J = 7.1 Hz) 1,12-, 0.41 (4H, m) -diethyl [N-cyclopropyl-Nf [3-morpholino-2-methyl-4-fluoro-6-nitrophenyl] aminomethylene] malonate. Reference Example 59 In the same manner as described in Reference Example 33, using the appropriate starting material, the following compounds are prepared: β ethyl-1-cyclopropyl-7-morpholino-6-fluoro-8-methyl-1,4-di- hydro-4-oxoquinoline-3-carboxylate, 205-26 ° C (recrystallized from ethyl acetate-n-hexane) colorless powder, m.p. ethyl 1-cyclopropyl-7- (4-benzyl-1-piperazinyl) -8-acetoxy methyl 6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate, ÜMR (CDCl 3) δ: 0.85-1.00 (2H, m), 1.10-1.25 (2H, m), 1.41 (3H, t, J = 7.1 Hz), 2.03 (3H, s), 2.45-2.30 (4H, m), 3.10-3.45 (4H, m), 3.60 (? H, s), 3.85-4.03 (1H, m), 4.39 (2H, q, J = 7.1 Hz), 5.79 (ZH, s), 7.23-7.45 (SH , m), 8.11 (1H, d, J = 12.3 Hz), 8.65 (1H, s) ethyl-1-cyclopropyl-7-morpholino-8-acetoxymethyl-6-fluoro-1,4- dihydro-4-oxoquinoline-3-carboxylate, m.p. 176-178 ° C (recrystallized from ethyl acetate-diethyl ether-n-hexane), pale yellow prisms ethyl 1-cyclopropyl-7- (4-methyl-1-piperazinyl) -6-fluoro-8-hydroxymethyl-1, 4-dihydro-4-oxoquinoline-3-carboxylate, m.p. 216-218 ° C, pale yellow powder ethyl 1-cyclopropyl-7- (4-methyl-1-piperazinyl> -6-fluoro-8-methoxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate, m.p. 200-204 ° C, pale yellow powder ethyl 1-cyclopropyl-7- (4-benzyl-3-methyl-1-piperazinyl) -6-fluoro-8-acetoxymethyl-1,4-dihydro-4-oxoquinoline 3-Carboxylate, mp 170-172.5 ° C (dec.) (Recrystallized from ethyl acetate-diethyl ether), pale brown powder ethyl 1-cyclopropyl-β- (N-benzyl-N-methylamino) - 1-pyrrolidinyl7-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate, mp 145-148.5 ° C (dec.) (Recrystallized from ethyl acetate-diethyl ether>, bleached yellow powder ethyl 1-cyclopropyl-7-morpholino-6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate, amp. 212-216 ° C, bleached yellow powder ethyl 1-Cyclopropyl-7-morpholino-6-fluoro-8- (1-pyrrolidinylmethyl) -1,4-dihydro-4-oxoquinoline-3-carboxylate, mp 227-232 ° C, pale yellow powder ethyl-1 -cyclopropyl-7-morpholino-6-fluoro-8-ethylthiomethyl-1,4-dihydro-4-oxoquinoline-3-carb oxylate, m.p. 165-167 ° C (recrystallized from dichloromethane-diethyl ether), pale yellow needles ethyl 1-cyclopropyl-7- (3-acetamidomethyl-1-pyrrolidinyl) -6-fluoro-6-methyl-1,4: dihydro- 4-oxoquinoline-3-carboxylate, m.p. 208-210 ° C (recrystallized from ethanol), white crystals. Reference Example 60 To a solution of ethyl 1-cyclopropyl-7- (4-methyl-1-piperazinyl) -6-fluoro-8-acetoxymethyl-1 , 4-Dihydro-4-oxoquinoline-3-carboxylate (142 mg) in ethanol (10 ml) is added aqueous potassium carbonate (1 ml) and the mixture is stirred at room temperature for 2.5 hours. The reaction mixture is extracted with chloroform.

The extract is dried over magnesium sulphate and the solvent is distilled off. The residue is crystallized by adding thereto diethyl ether to give ethyl 1-cyclopropyl-7- (4-methyl-1-piperazinyl) -6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3- carboxylate (101 mg) as pale yellow powder, m.p. 216-218 ° C.

Reference Example 61 To a solution of ethyl 1-cyclopropyl-7- (4-methyl-1-piperazinyl) -6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (160 mg ) in methanol (10 ml) is added conc. sulfuric acid (2 ml) and the mixture is refluxed for 6.5 hours. The reaction mixture is adjusted to below pH 8 with aqueous saturated sodium bicarbonate and extracted with dichloromethane. The extract is washed with saturated aqueous sodium chloride and then dried over magnesium sulfate and the solvent is distilled off. The residue is crystallized by adding thereto diethyl ether to give methyl 1-cyclopropyl-7- (4-methyl-1-piperazinyl) -6-fluoro-8-methoxymethyl-1,4-dihydro-4-oxoquinoline-3 carboxylate (125 mg) as pale yellow powder, m.p. 200-204 ° C.

Reference Example 62 To a solution of 3,6-difluoro-2- (4-benzyl-1-piperazinyl) -S-nitrobenzyl alcohol (15.4 g) in methanol (400 ml) is slowly added conc. sulfuric acid (80 ml) with stirring under ice-cooling. After the addition, the mixture is refluxed for 30 hours and additional conc. sulfuric acid (10 ml) and the mixture is refluxed for a further 20 hours. After cooling to room temperature, the reaction mixture is adjusted to below pH 8 with aqueous saturated potassium carbonate and aqueous saturated sodium bicarbonate and then extracted with ethyl acetate. The extract is dried over magnesium sulfate and then the solvent is distilled off. The residue is purified by silica gel column chromatography (solvent, dichloromethane) to give 2,5-difluoro-4- (4-benzyl-1-piperazinyl) -3-methoxymethylnitrobenzene (12.9 g). 1 H NMR (CDCl 3) δ: 2.45-2.68 (4H, m), 3.30-3.45 (4H, m), 3.42 (3H, s), 3.58 (2H, s) 4.52 (2H, d, J = 3.4 Hz), 7.26-7.40 (SH, m), 7.78 (1H, dd, J = 7.3 Hz, 11.9 Hz Reference Example 63 To a solution of ethyl 1-cyclopropyl-7-morpholino-6-fluoro: 8-acetoxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (550 mg) in ethanol (10 ml) was added 2N aqueous potassium carbonate (1 ml) and the mixture is stirred at room temperature for four hours. The reaction mixture is diluted with water and extracted with dichloromethane. The extract is dried and concentrated. The residue is crystallized by adding thereto diethyl ether to give ethyl 1-cyclopropyl-7-morpholino-6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (353 mg) as a pale yellow powder, m.p. 212-216 ° C.

Reference Example 64 To ethyl 1-cyclopropyl-7-morpholino-6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (80 mg) is added thionyl chloride (1 ml) and the mixture is stirred at room temperature. for four hours and further at 50 ° C for one hour. The solvent is concentrated under reduced pressure to give crude ethyl -1-cyclopropyl-7-morpholino-6-fluoro-8-chloromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (84 mg).

Without purifying the product, pyrrolidine (1 ml) is added thereto and the mixture is stirred at room temperature overnight. 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 distilled off and the residue is purified by silica gel column chromatography (solvent, dichloromethanesmethanol = 10: 1) to give 1-cyclopropyl-7-morpholino-8- (1-pyrrolidinylmethyl) -6-fluoro-1,4-dihydro-4-oxo quinoline-3-carboxylic acid (31.8 mg) as a bleached powder, mp 227-232 ° C.

Reference Example 65 To ethyl 1-cyclopropyl-7-morpholino-6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (101 mg) was added thionyl chloride (1.5 ml) and the mixture Stir at room temperature for 5.2 hours. The solvent is removed by concentration under reduced pressure. To the resulting ethyl 1-cyclopropyl-7-morpholino-G-fluoro-8-chloromethyl-1,4-dihydro-4-oxoquinoline-3-carhoxylate are added ethanethiol (1.5 ml) and triethylamine (30 .mu.l). and the mixture is stirred at room temperature overnight. The reaction mixture is extracted with dichloromethane and the extract is washed with water and aqueous saturated sodium chloride in this order and then dried over magnesium sulphate. The solvent is removed by concentration under reduced pressure and the residue obtained is purified by silica gel column chromatography (solvent, dichloromethanesmethanol = 15: 1) and then recrystallized from dichloromethane-diethyl ether to give ethyl 1-cyclopropyl-7-morpholino-6-fluoro -8-ethylthiomethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (49 mg), such as pale yellow needles, m.p. 165-167 ° C.

Reference Example 66 To 2-chloro-5,6-difluoro-3-nitrotoluene (1.0 g) is added spray-dried potassium fluoride (1.4 g), anhydrous dimethyl sulfoxide (10 ml) and benzene (10 ml) and the moisture is removed by azeotropic distillation. together with benzene. The mixture is then stirred at 170-180 ° C under argon flow for 3.5 hours. After cooling, the reaction mixture is poured into ice water and extracted with diethyl ether. The extract is washed with water, dried and then the solvent is distilled off. the residue is purified by silica gel column chromatography (solvent, n-hexane) to give 2,5,6-trifluoro-3-nitrotoluene (0.45 g).

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

Reference Example 6? To a solution of 3-amino-1-benzyl-4-methylpyrrolidine (9.5 g) in methanol (190 ml) is added anhydrous t-butoxycarboxylic acid (13.0 g) at room temperature and the mixture is stirred for one hour. Methanol is distilled off under reduced pressure and water is added to the residue. The mixture is extracted with dichloromethane and the extract is dried over magnesium sulphate and dichloromethane is then distilled off. The residue is purified by silica gel column chromatography (solvent, dichloromethane: methanol = 19: 1) to give 3- (t-butoxycarbonylamino) -1-benzyl-4-methylpyrrolidine (isomer A) (4.4 g) as colorless prisms, m.p. . 1s1.s-1a2.7 ° c. '_. NMR (CDCl 3) δ: 1.09 (33, d, .J = 6.7 Hz), 1.43 (9H, s), δ 15 20 25 30 35 84 501 371 1.86-2.02 ( 2H, m), 2.62 (2H, d, J = 6.1 Hz), 2.93-3.05 (1H, m), 3.56 (2H, s), 3.68 (1H, brs ), 4.84 (1H, brs), 7.20-7.37 (SH, m).

Reference Example Gel To 3- (t-butoxycarbonylamino) -1-benzyl-4-methylpyrrolidine (3.9 g) is added ethanol (50 ml) and 10% Pd-C (780 mg) and the mixture is subjected to catalytic reduction at 60 ° C. under atmospheric pressure. After the catalytic reduction, the catalyst is removed by filtration and the filtrate is concentrated. The obtained residue is recrystallized from methyl acetate-petroleum ether to give 3- (t-butoxyamino) -4-methylpyrrolidine (isomer A) (2.01 g) as colorless prisms, m.p. 86.8-87 ° C.

NHR (CDCl 3) δ: 1.08 (3H, d, J = 6.8 Hz), 1.45 (QH, s), 1.83-1.9? (1H, m), 2.10 (1H, brs), 2.43-2.52 (1H, m), 2.52-2.81 (1H, m), 3.10-3.35 (2H , m), 3.53-3.73 (1H, m), 4.69 (1H, brs).

Reference Example 69 To a solution of sodium borohydride (51.6 g) in tetrahydrofuran (500 ml) is added dropwise a solution of 2,5,6-trifluorobenzoic acid (120 g) in tetrahydrofuran (200 ml) with stirring. at below 10 ° C and to this is further added dropwise a solution of BF 3. (C 2 H 5) 2 O (232 ml) in tetrahydrofuran (500 ml) under ice-cooling. The mixture is stirred at room temperature overnight. The reaction mixture is poured into ice water (1.5 liters) and extracted with diethyl ether. The extract is dried over magnesium sulphate and the solvent is distilled off under reduced pressure to give 2,3,6, -trifluorobenzyl alcohol (112.7 g) as pale yellow oil, b.p. 112 ° C (30 mmHg).

Reference Example 70 To a solution of 2,3,6-trifluorobenzyl alcohol (41 g) in dichloromethane (100 ml) is added dropwise a solution of thionyl chloride (50 ml) in dichloromethane (80 ml) under ice-cooling with stirring and the mixture is stirred at room temperature overnight.

To the mixture was added triethylamine (10 ml) and the solvent was distilled off under reduced pressure to give 2,3,6-trifluorobenzyl chloride (28.6 g) as a colorless oil, b.p. 63 ° C (13 mmHg). NHR (CDCl 3) δ: 4.66 (2H, s), 6.62-6.93 (1H, m), 7.04-7.26 (1H, m). To a solution of sodium cyanide (1.94 g) in water (4 ml) is added phenyltriethylammonium chloride (0.09 g) and to this was added with stirring 2,3,6-trifluorobenzyl chloride ( 5.0 g) and the mixture is stirred at 90-100 ° C for 40 minutes. The reaction mixture is poured into water (20 ml) and extracted with diethyl ether.

The extract is dried over potassium carbonate and the solvent is distilled off to give 2- (2,3,6-trifluoro-enyl) acetonitrile (3.1 g), b.p. 80-8S ° C (5 mm fi g). & MR (CDCl 3) δ: 3.76 (2H, d, J = 0.8 Hz), 6.89-6.98 (1H, m), 7.11-7.26 (1H, m).

Reference Example 72 2- (2,3,6-Trifluorophenyl) acetonitrile (I3.3 g) is dissolved in ethanol (20 ml) and carefully added thereto. sulfuric acid (8.5 ml) and the mixture is refluxed at I25 ° C for seven hours. After cooling, the reaction mixture is fractionated with diethyl ether and water. The ether layer is washed with aqueous saturated sodium chloride and dried over magnesium sulfate and then concentrated under reduced pressure to give ethyl 2- - (2,3,6-trifluorophenyl) acetate (16.3 g) as a colorless oil.

NMR (CDCl 3) δ: 1.27 (3H, t, J = 7, 1 Hz), 3.72 (2H, d, J = 1, 2 Hz), 4.19 (2H, q, J = 7, 1 Hz), 6.78-6.90 (1H, m), 7.00-7.16 (1H, m).

Reference Example 73 Ethyl 2- (2,3,6-trifluorophenyl) acetate (I6.2 g) is dissolved in ethanol (60 ml). The mixture is stirred and to this is added 3N sodium hydroxide (200 ml) and the mixture is stirred at 70 ° C for one hour. After cooling, 6N hydrochloric acid (120 ml) is added to the mixture. The white powdery precipitates obtained are dissolved by adding diethyl ether thereto. The diethyl ether layer is separated and dried over magnesium sulfate and then concentrated under reduced pressure to give 2- (2,3,6-trifluorophenyl) acetic acid (I3.9 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).

Reference Example 74 Lithium aluminum hydride (0.8 g) is suspended in dry diethyl ether (5 ml) and the mixture is stirred. To the mixture was added dropwise a solution of 2- (2,3,6-trifluorophenyl) acetic acid, (2.0 g) in dry diethyl ether (1 ml) and the mixture was refluxed for 30 minutes. 10% aqueous sodium hydroxide (0.8 ml) and water (1.6 ml) To the reaction mixture is added water (0.8 ml), in this order, and the mixture is stirred at room temperature.

To the mixture is added diethyl ether (10 ml) and the precipitates obtained are separated by filtration and washed with tetrahydrofuran. The washings and filtrate are combined and then concentrated under reduced pressure to give 2- (2,3,6-trifluorophenyl) ethyl alcohol (1.9 g) as a colorless oil.

NMR (CDCl 3) δ: 1.75 (1H, s), 2.98 (3H, t, J = 6.7 Hz), 's, as <2H, t, J = e,? Hm, s,? 4-s, a7 <1n, m), 6.93- 7.09 (1H, m).

Reference Example 75 To a solution of 2- (2,3,6-trifluorophenyl) ethyl alcohol (1.5 g) in methylene chloride (10 ml) is added with stirring p-toluenesulfonyl chloride (2.2 g) and triethylamine (2.0 g). ml) and the mixture is stirred at room temperature for 5 hours. The reaction mixture is poured into water and extracted with diethyl ether. The ether layer is washed with aqueous saturated sodium bicarbonate and aqueous saturated sodium chloride and dried over magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent, methylene chloride) and recrystallized from diethyl ether-n-hexane to give 1- [2- (p-toluenesulfonyloxy) ethyl] -2,3,6-trifluorobenzene (3 , 4 g) as colorless prisms, m.p. 73-74 ° C.

NHR (CDCl 3) δ: 2.44 (3H, s), 3.03 (3H, t, J = 6.5 Hz), 4.23 (2H, t, J = 6.5 Hz), 6.70 -6.82 (1H, m), 6.93-7.09 (1H, m), 7.29 (2H, d, J = 8.5 Hz), 7.70 (2H, d, J = 8 .5 Hz) Reference Example Gel 76 Lithium aluminum hydride (5.6 g) is suspended in dry diethyl ether (70 ml) and to this is added dropwise with stirring a solution of 1- / 2- (p-toluenesulfonyloxy) ethyl / -2.3.6 -trifluorobenzene (23.3 g) in dry diethyl ether (170 ml) at below 10 ° C and the mixture is stirred at room temperature for one hour. To the reaction 10% aqueous sodium hydroxide (10.0 ml) and water (5.6 ml) in this order was added water (5.6 ml), and the mixture was stirred at room temperature for 30 minutes. The resulting white precipitates are filtered off and the filtrate is concentrated under atmospheric pressure to give 2,3,6-trifluoro-1-ethyl-benzene (13.2 g) as a colorless oil. NMR (CDCl 3) δ: 1.22 (3H, t, J = 7.1 Hz), 2.72 (2H, q, J = 7.1 Hz), δ, 71-6.82 (1H, m), 6.87-7.03 (1H, m).

Reference Example 77 2,3,6-Trifluoroyl-ethylbenzene (1.09 g) is dissolved in conc. sulfuric acid (5.5 ml) and to this is added with stirring a mixture of potassium nitrate (0.83 g) in conc. sulfuric acid (4 ml) at room temperature and the mixture is stirred at the same temperature for one hour. The reaction mixture is poured into cold water (100 ml) and extracted with diethyl ether. The ether layer is washed with aqueous saturated sodium chloride and dried over magnesium sulfate and then concentrated under reduced pressure to give 3-ethyl-2,4,5-trifluoronitrobenzene (1.14 g) as a yellow oil.

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

Reference Example 78 To 3-ethyl-2,4,5-trifluoronitrobenzene (1.02 g) is added ethanol (4.5 ml) and water (0.5 ml) and the mixture is stirred.

To the mixture is added with stirring a mixture of 1-methylpiperazine (0.83 ml), triethylamine (1.0 ml) and ethanol (0.6 ml) and the mixture is refluxed for five hours. To the reaction mixture is added additional 1-methylpiperazine (1.0 ml) and the mixture is refluxed for three hours. The mixture is concentrated under reduced pressure and the resulting residue is purified by silica gel column chromatography (solvent, methylene chloride) to give 3-ethyl-2,5-difluoro-4- (4-methyl-1-piperazinyl) -nitrobenzene (1, 12 g) such as yellow oil.

NMR (CDCl 3) δ: 1.21 (3H, t, J = 7.5 Hz), 2.37 (3H, s), 2.42-2.67 (4H, m), 2.81 (2H, dq, J = 2.8 Hz, 7.5 Hz), 3.05-3.23 (4H, m), 7.63 (1H, dd, J = 7.1 Hz, 11.3 Hz) Reference Example 79 To 3-ethyl-2,5-difluoro-4- (4-methyl-1-piperazinyl) nitrobenzene (1.12 g) is added potassium fluoride (0.24 g), N, N-dimethylsulfoxide (3, 5 ml) and cyclopropylamine (0.4 ml) and the mixture is stirred at 80-85 ° C for 1.5 hours. The reaction mixture is diluted with ethyl acetate and the organic layer is washed with water and aqueous saturated sodium chloride and dried over magnesium sulfate and then concentrated under reduced pressure to give N-cyclopropyl-2-ethyl-3- (4-methyl-1-piperazinyl) -4 -fluoro-6-nitroaniline (1.00 g) as a viscous oil. NMR (CDCl 3) δ: 0.45-0.55 (2H, m), 0.66-0.78 (2H, m), 1.14 (3H, t, J = 7.4 Hz), 2.37 (BH, s), 2.40-2.62 (4H, m), 2.62-2.85 (1H, m), 3.00 (2H, q, J = 7.4 Hz), 3.05-3.23 (4H, m), 6.82 (1H, s), 7.54 (1H, d, J = I2.4 Hz).

Reference Example 80 q In the same manner as described in Reference Example 67 using a suitable starting material, the following compound is prepared. α- (t-butoxycarbonylamino) -1-benzyl-4-methylpyrrolidine (isomer B), colorless needles, m.p. 83-83.5 ° C (recrystallized from n-hexane).

NMR (CDCl 3) δ: 0.93 (3H, d, J = 6.98 Hz), 1.44 (QH, s), 2.14-2.54 (3H, m), 2.60-2, 93 (2H, m), 3.58 (2H, dd, J = 13.03 Hz, 14.91 Hz), 4.07-4.31 (1H, m), 4.61-4.82 (1H , m), 7.14-7.39 (SH, m).

Reference Example 81 In the same manner as described in Reference Example 68, using a suitable starting material, the following compound is prepared. 3- (t-butoxyamino) -4-methylpyrrolidine (isomer B), b.p. 106-109 ° C (0.25 mmHg).

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

Reference Example 82 In the same manner as described in Reference Example 32, using a suitable starting material, the following compound is prepared.

Diethyl LN-cyclopropyl-N- [3- (4-methyl-1-piperazinyl) -2-ethyl-4-fluoro-6-nitrophenyl] aminomethylenymalonate.

Reference Example 83 In the same manner as described in Reference Example 33, using a suitable starting material, the following compound is prepared.

Ethyl 1-cyclopropyl- (4-methyl-1-piperazinyl) -6-fluoro-8-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate, m.p. 201-203 ° C, A white powder (recrystallized from ethanol). I: 10 15 20 25 30 35 40 89 501 371 Example Gel 1 To 6,7-difluoro-1-cyclopropyl-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid B (OCOCH 3) 2-chelate (1.2 g), benzylpiperazine (1.6 g) and dimethylacetamide (6 ml) are added and the mixture is reacted at 50 ° C for 20 hours. After concentration, the residue obtained is dissolved in acetone (20 ml) and conc. hydrochloric acid (5 ml) and the mixture is stirred at room temperature for 30 minutes. After the solvent was distilled off, water was added to the residue, and the mixture was extracted with dichloromethane. The aqueous layer is taken up and neutralized with aqueous sodium bicarbonate and extracted with dichloromethane. The extracts are combined and dried over magnesium sulphate. After removal of the solvent, a mixture of diethyl ether and ethanol remained to be obtained, and the resulting precipitates were separated by filtration to give 7- (4-benzyl-1-piperazinyl) -1-cyclopropyl-6-fluoro-8-methyl Tyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.1 g), such as white crystals, m.p. 209-211 ° C.

NMR (CDCl 3) δ 8.86 (1H, s), 7.85 (1H, d, J = 12 Hz), 7.35 (SH, bs), 3.93-4.26 (1H, m), 3.62 (2H, s), 3.13-3.50 (4H, m), 2.76 (3H, s), 2.53-2.83 (4H, m), 0.73-1, 40 (4H, m).

Example 2 To 7- (4-benzyl-1-piperazinyl) -1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (84 mg) is added acetic acid (3 ml) and 10% Pd-C (10 mg) and the mixture is subjected to catalytic reduction at 70 ° C for one hour. After catalytic reduction, the reaction mixture is cooled and the catalyst is filtered off. The filtrate was concentrated and to the residue was added aqueous sodium bicarbonate, and the precipitates obtained were separated by filtration to give 7- (1-piperazinyl) -1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3- carboxylic acid (45 mg) as white crystals, m.p. 291-295 ° C (dec.).

NMR (DMSO-d 5) δ: 8.84 (1H, s), 7.85 (1H, d, J = 12.5 Hz) 4.30-4.48 (1H, m), 3.16-3 , 50 (BH, m), 2.78 (3H, s), 1.12-1.28 (ZH, m), 0.84-0.96 (ZH, m).

Example 3 76,7,7-Difluoro-1-cyclopropyl-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.8 g) is suspended in 1-methylpyrrolidone. 90 501 371 (5 ml) and to this is added piperazine (1.8 g) and the mixture is stirred at 150 ° C for three hours. After the reaction, the reaction mixture is concentrated and the residue obtained is purified by silica gel column chromatography (solvent, dichloromethanesmethanol = 3: 1) to give 7- (1-piperazinyl) -1-cyclopropyl-6-fluoro-8-methyl-1,4- dihydro-4-oxoquinoline-3-carboxylic acid (0.06 g) as white crystals, m.p. 291-295 ° C (dec.). 1 H NMR (DMSO-d 5) δ: 8.84 (1H, s), 7.85 (1H, d, J = 12.5 Hz), 4.30-4.48 (1H, m), 16-3.50 (BH, m), 2.78 (BH, s), 1.12-1.28 (2H, m), 0.84-0.96 (2H, m).

Example Gel 4 In the same manner as described in Example 1 using the appropriate starting material, the following compounds are prepared: 7- (4-methyl-1-piperazinyl) -1-cyclopropyl-6-fluoro-8-methyl-1,4 -dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 219-220.5 ° C (recrystallized from ethanol), pale yellow prisms, 7- (1,4-diazabicyclo [4.3.3.7] nonan-4-yl] -1-cyclopropyl-6-fluoro-8-methyl-1,4 -dihydro-4-oxoquinoline-3-carboxylic acid, mp 208-212 ° C (recrystallized from dichloromethane-diethyl ether), pale yellow powder, 7- (1-piperazinyl-1- (2,2-dichloro-1-cyclopropyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 7- (1-piperazinyl) -1- (2-fluoro-1-cyclopropyl) -6-fluoro-8-methyl -1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

Example gel S 1-Cyclopropyl-6-fluoro-8-methyl-7- (1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.20 g) and potassium bicarbonate (70 mg ) is suspended in dimethylformamide (3 ml) and to this is added 4-bromomethyl-3-methyl-1,3-dioxolen-2-one (0.13 g) under ice-cooling and the mixture is stirred at room temperature for one hour. The reaction mixture is concentrated under reduced pressure and water is added to the residue and the mixture is extracted with dichloromethane. The extract is distilled under reduced pressure and the residue obtained is recrystallized from dichloromethane and diethyl ether to give 7- [4- (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl-1- piperazinyl] -1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.24 g) as pale yellowish white crystals, amp. 174-177 ° C.

Example 6 To 6,7-difluoro-1-cyclopropyl-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid B (OCOCH 3) 2-chelate ( 3.4 g), dimethylacetamide (10 ml) and 4-benzyl-3-methylpiperazine (6.8 g) are added and the mixture is reacted at 50 ° C for three hours.

After the reaction, the working medium is distilled off and acetone (30 ml) is added to the residue obtained and conc. hydrochloric acid (5 ml) and the mixture is stirred at room temperature for 30 minutes. After the solvent is distilled off, water is added to the residue and the crystals are separated by filtration. The aqueous layer is neutralized with sodium bicarbonate and extracted with dichloromethane. Dichloromethane is distilled off and the resulting residue is purified by silica gel column chromatography (solvent, dichloromethanesmethanol = 20: 1) and recrystallized from ethanol to give 7- (4-benzyl-3-methyl-1-piperazinyl) -1-cyclopropyl-6- fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.45 g) as pale yellow powder, 170-171 ° C.

Example 7 To 7- (4-benzyl-3-methyl-1-piperazinyl) -1-cyclopropyl-6-m.p. fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.30 g) is added acetic acid (10 ml) and 10% Pd-C (50 mg) and the mixture is subjected to catalytic reduction at 70 ° C. ° C under atmospheric pressure for one hour. After the catalytic reduction, the reaction mixture is cooled and the catalyst is removed by filtration. The filtrate is concentrated and to the residue is added water and the mixture is adjusted to approx. pH 7.5 with sodium bicarbonate and then extracted with dichloromethane. The dichloromethane is distilled off and to the residue is added diethyl ether. The resulting precipitates are 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), such as pale yellow powder, m.p. 206-208 ° C.

Example 8 In the same manner as described in Examples 1 and 3, using the appropriate starting material, the following compounds are prepared: 7- (1-piperazinyl) -1- (2-chloro-1-cyclopropyl) -6-fluoro-1,4 -dihydro-4-oxoquinoline-3-carboxylic acid (a mixture of cis and trans isomers) NHR (DMSO-d 5, 200 MHz) C: 1.79-1.96 and 2.13-2.31 (2H, '- m), 2.83-3.00 (4H, m), 3.20-3.40 (4H, m), 3.81-10 I5 20 25 30 35 40 92 501 371 3.98 (1H , m), 4.15-4.29 (1H, m), 7.36 (1H, d, J = 7.4 Hz), 7.93 (1H, d, J = I3.2 Hz), 8 65 (1H, s) 7- (1-piperazinyl) -1- (2-methyl-1-cyclopropyl) -6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (a mixture of cis- and trans isomers).

NMR (trifluoroacetic acid d5, 60 MHz) δ: 1.23-2.00 (3H, m) 1.57 m, s), s, ss "-4, so (su, m), 7.83 (m , d, J = 7 Hz), 8.31 (1H, d, J = 14 Hz), 9.33 (1H, s) 7- (4-methyl-1-piperazinyl) -1- (2-methyl- 1-Cyclopropyl) -6-fluoroocl, 4-dihydro-4-oxoquinoline-3-carboxylic acid (a mixture of cis and trans isomers) NHR (trifluoroacetic acid ds, 60 MHz) 6: 1.55 (3H, s) , 3.24 (3H, s), (1H, d, J = 7 Hz), (1H, s) 7- (1-piperazinyl) -1- (2-fluoro-1-cyclopropyl) -6-fluoro- 1.33-2.00 (3H, m) 3.36-4.50 (QH, m), 7.82 8.33 (1H, d, J = 14 Hz), 9.33 I, 4-dihydro -4-oxoquinoline-3-carboxylic acid (a mixture of cis and trans isomers) NMR (FMSO-d 6, 200 MHz) δ: 1.60-2.18 (2H, m), 2.74-3.40 (8H, m), 3.77-3.98 and 4.20-4.50 (1H, m), 5.05-5.26 and 5.38-5.57 (1H, m), 7, 39 (d, J = 7.42 Hz) and 7.46 (d, J = 7.42 Hz) (1H), 7.92 (d, J = 13.46 Hz) and 7.91 (d, J = 13.46 Hz) (1H), 8.58 and 8.75 (1H, s) 7- (4-methyl-1-piperazinyl) -1- (2-fluoro-1-cyclopropyl) -6-fluoro- 1,4-Dihydro-4-oxoquinoline-3-carboxylic acid (a mixture of cis and trans isomers) NMR (DMSO-d s, 200 MHz) δ: 1.58-2.13 (2H, m), 2.32 (3H, s), 2.44-2.67 (4H, m), 3.18-3.39 ( 4H, m), 3.33-3.50 and 3.72-3.90 (1H, m), 4.56-4.84, 4.84-4.95 and 5.13-5.24 ( 1H, m), 7.17 (d, J = 7.26 Hz) and 7.14 (d, J = 6, 14 Hz) (1H), 7.97 (d, J = 13, 18 Hz) and 7.98 (d, J = I2.6 Hz) (1H), 8.52 and 8.72 (1H, s).

Example 9 9 To ethyl 1-cyclopropyl-7- (4-ethoxycarbonyl-1-piperazinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (0.8 g ) is added 10% aqueous sodium hydroxide (7 ml) and the mixture is refluxed for 5 hours. After cooling, the mixture is diluted with dilute hydrochloric acid and extracted with dichloromethane. The aqueous layer is adjusted to about pH 7.5 with sodium bicarbonate and the precipitates obtained are separated by filtration to give 7- (1 -piperazinyl) -1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.3 g) mp 291-295 ° C (dec.).

NMR (DMSO-d 6) δ; 8.84 (1H, s), 7.85 (1H, d, J = 12.5 Hz), 4.30-4.48 (1H, m), 3.16-3.50 (8H, m ), 2.78 (3H, s), 1.12-1.28 (ZH, m), 0.84-0.96 (ZH, m). In the same manner as described in Example 9, using suitable starting materials, the same compounds as in Examples 1, 4, 5, 6, 7 and 8 are prepared.

Example 10 In the same manner as described in Examples 1, 3 and 9 using suitable starting materials the following compounds are prepared: 1) 7- (3-amino-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-8-m.p. 201.5- -203.0 ° C, pale yellow powder (recrystallized from ethanol-dimethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, ethyl ether) 2) 1-cyclopropyl-7- (4- ethoxycarbonyl-1-piperazinyl) -6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 234-235 ° C (recrystallized from methanol), white needles 3) 1-cyclopropyl-7- (4-ethoxycarbonyl-1-piperazinyl) -6-fluoro-8-methoxymethyl-1,4-dihydro-4-oxoquinoline-3 -carboxylic acid, m.p. 218-220 ° C (recrystallized from ethanol), pale yellow prisms 4) 1-cyclopropyl-7- (4-methyl-1-piperazinyl) -6-fluoro-8-hydroxymethyl-1,4-dihydro-4- oxoquinoline-3-carboxylic acid, m.p. 197-201 ° C, pale 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 (1) 8) -cyclopropyl-7- (4-methyl-1-piperazinyl) -6-fluoro-8-fluoromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, mp; 187-18900 (decomposition) (recrystallized from diethyl ether-dichloromethane), pale yellow powder 9) 1-cyclopropyl-7- (1-piperazinyl) -6-fluoro-8-fluoromethyl. Tyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 10) 1-cyclopropyl-7- (4-methyl-1-piperazinyl) -6-fluoro-8-difluoromethyl-1,4-dihydro-4 -oxoquinoline-3-carboxylic acid 11) 1-cyclopropyl-7- (1-piperazinyl) -6-fluoro-8-difluoromethyl-1,4-dihydro-4-oxoquinoline-α-carboxylic acid 12) 1-cyclopropyl-7- (4-hydroxy-1-piperidyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 234-236 ° C (recrystallized from chloroform-ethanol), pale yellow crystals 13) 1-cyclopropyl-7- (3-amino-4-methyl-1-pyrrolidinyl) -6 fluoro-8-methyl-1,4 -dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride (isomer A), m.p. 226-232 ° C, yellow powder (recrystallized from ethyl acetate-ethanol) NMR (DMSO-d 5) δ: 1.18 (QH, d, J = 6.7 Hz), 2.62 (3H, s), 7.72 (1H, d, J = 13.4 Hz), 8.79 (1H, s) 14) 1-Cyclopropyl-7- (3-aminomethyl-1-pyrrolidinyl) -6-fluoro-8-methyl- 1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride, 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. 185.5-18.5 ° C (dec.) (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, amp. 224-225.5 ° C (decomposition) (recrystallized from ethanol) pale yellow prisms 17) 1-cyclopropyl-7- [3- (5-methyl-2-oxo-1,3-dioxolen-4-yl) methylamino] 1-pyrrolidinyl7-6-fluoro-β-methyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid 18) 1-cyclopropyl-7-morpholino-6-fluoro-8-methyl-1,4-di hydro-4-oxoquinoline-3-carboxylic acid, amp. 227.5-228 ° C (recrystallized from ethanol), pale yellow flakes 19) 1-cyclopropyl-7-morpholino-6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, amp. 218 DEG-220 DEG C. (recrystallized from methanol), pale yellow prisms 20) 1-cyclopropyl-7- (4-benzyl-1-piperazinyl) -6-fluoro-8-hydroxymethyl-1,4-dihydro-4- oxoquinoline; 5-carboxylic acid, amp. 10 15 20 25 30 35 40 95 501 371 229-231 ° C (recrystallized from dichloromethane-diethyl ether), pale yellow leaves 21) 1-cyclopropyl-7- (4-benzyl-3-methyl-1-piperazinyl) -6- fluoro-8-hydroxymethylll, 4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 208-209 ° C (recrystallized from ethanol-diethyl ether), pale orange powder 22) 1-cyclopropyl-7- (3-methyl-1-piperazinyl) -5-fluoro-8-hydroxymethyl-1,4-dihydro-4 -oxoquinoline-3-carboxylic acid, m.p. 180-183 ° C (recrystallized from ethanol-ethyl acetate-diethyl ether), white powder 23) 1-cyclopropyl-7-C3- (N-benzyl-N-methylamino) -1-pyrrolidinyL7-6-fluoro-8 -methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 160.8-161.3 ° C (recrystallized from ethanol-diethyl ether), pale yellow powder 24) 1-cyclopropyl-7-morpholino-6-fluoro-8- (1-pyrrolidinylmethyl) ~ 1,4- dihydro-4-oxoquinoline-3-carbosylic acid, m.p. 232-236 ° C (dec.) (Recrystallized from diethyl ether-ethanol-dichloromethane), pale yellow prisms 25) 1-cyclopropyl-7-morpholino-6-fluoro-8-ethylthiomethyl-1,4-dihydro-4-oxoquinoline-3 -carboxylic acid, m.p. 206-208 ° C (recrystallized from n-hexane-ethanol), pale yellow prisms 26) 1-cyclopropyl-7- (4-oxo-1-piperidyl) -8-fluoro-8-m.p. 247-250 ° C (recrystallized from chloroform-ethanol), white crystals of tyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 27) 1-cyclopropyl-7- (3-acetamidomethyl-1-pyrrolidinyl) - 6 -fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 192-194 ° C (recrystallized from chloroform-methanol), white crystals 28) 1-cyclopropyl-7-C3-t-butoxycarbonylaminomethyl-1-pyrrolidinyl) -6-fluoro-8-methyl-1,4-dihydro-4- oxoquinoline-3-carboxylic acid, m.p. 131-135 ° C (recrystallized from methanol), white powder 29) 1-cyclopropyl-7- (3-aminomethyl-1-pyrrolidinyl) -5-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3 -carboxylic acid hydrochloride, m.p. 195-200 ° C (recrystallized from ethyl acetate-methanol), white powder 30) 1-cyclopropyl-7- [3- (N-ethyl-acetamido) methyl-1-pyrrolidinyl] -Glufluoro-8-methyl-1,4- dihydro-4-oxoquinoline-3-carboxylic acid; mp 167-169 ° C (b (crystalline alloyed from ethanol), pale yellow crystals 10 15 20 25 30 35 40 96 501 371 31) 1-cyclopropyl-7- (3-ethylaminomethyl-1-pyrrolidinyl) -6-fluoro-8- methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride, m.p. 267-271 ° C (recrystallized from methanol-acetonitrine, yellow powder 32) 1-cyclopropyl-7- (4-acetyl-3-methyl-1-piperazinyl) -6-fluoro-8-methyl-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 219-220 ° C (recrystallized from methanol), white powder 33) 1-cyclopropyl-7- (4-formyl-3-methyl-1-piperazinyl) -6-fluoro-β-methyl-1,4-dihydro-4 -oxoquinoline-3-carboxylic acid, m.p. 236-233 ° C (recrystallized from methanol), white powder 34) 1-cyclopropyl-7- (3,4-dimethyl-1-piperazinyl) -8-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline -3-carboxylic acid, 181-183 ° C (recrystallized from ethyl acetate), pale yellow pulp. ver 35) 1-cyclopropyl-7- (3,5-dimethyl-1-piperidyl) -6-fluoro-176-179 ° C (recrystallized from ethanol), pale yellow prisms 8-methyl-1,4-dihydro-4 -oxoquinoline-3-carboxylic acid, m.p. 36) 1-Cyclopropyl-7- (3-methylmorpholino) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, amp. 199.5-201 ° C (recrystallized from ethanol-ethyl acetate), colorless needles 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-β- (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-m.p. 208-210 ° C pale yellow methyl 1,4-dihydro-4-oxoquinoline-3-carboxylic acid, (recrystallized from dimethylacetamide diethyl ether), prisms 41) 1-cyclopropyl-7- (4-fluoro-1-piperidinyl) - 6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 208-121 ° C (recrystallized from ethanol), colorless needles 42) 1-cyclopropyl-7- [3- (5-methyl-2-oxo-1,3-dioxolen-4-yl) methylamino-1-pyrrolidinyl] - 6-fluoro-8-methyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid Q 43) 1-cyclopropyl-7- (4-methyl-1-piperazinyl) -6-fluoro-8-ethyl- 1,4-Dihydro-4-oxoquinoline-3-carboxylic acid, amp. 239-242 ° C (decomposition) (recrystallized from diethyl ether-ethanol), white powder 10 15 20 25 30 35 40 97 501 371 44) 1-cyclopropyl-7- (3-methyl-1-piperazinyl) -6-fluoroprene 8-Ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 45) 1-Cyclopropyl-7- (3-amino-1-pyrrolidinyl) -6-fluoro-8-ethyl-1,4-dihydro-4 -o-quinoline-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-methyl-1-pyrrolidinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3: carboxylic acid hydrochloride (isomer B) , m.p. 209-213 ° C (recrystallized from ethyl acetate-ethanol), yellow powder 4 NMR (DMSO-d 5) δ: 1.15 (3H, d, J = 6.9 Hz), 2.76 (3H, s), δ , 70 (1H, d, J = 13.7 Hz), 8.77 (1H, s) 48) 1-Cyclopropyl-7- (3-t-butoxycarbonylamino-4-methyl-1-pyrrolidinyl) -6-fluoro -8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (isomer A), m.p. 157-160 ° C (recrystallized from ethyl acetate), yellow crystal NMR (CDCl 3) δ: 1.20 (3H, d, J = 6.6 Hz), 2.57 (3H, s), 7.91 (1H, d, J = 13.3 Hz), 9.15 (1H, s) 49) 1-Cyclopropyl-7- (3-t-butoxycarbonylamino-4-methyl-1-pyrrolidinyl) -6-fluoro-8-methyl- 1,4-dihydro-4-oxoquinoline-3-carboxylic acid (isomer B), m.p. 199-202 ° C (recrystallized from ethyl acetate), yellow powder NMR (CDCl 3) δ: 1.12 (SH, d, J = 6.6 Hz), 2.58 (3H, s), 7.85 (1H, d, J = 13.6 Hz), 8.87 (1H, s) 50) 1-cyclopropyl-7- (3-t-butoxycarbonylamino-1-pyrrolidinyl) -6-fluoro-8-methyl-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 117-120 ° C (recrystallized from ethanol), pale yellow prisms 51) 1-cyclopropyl-7-morpholino-6-fluoro-8-fluoromethyl-189-192 ° C (decomposition) (recrystallized from n-hexane-acetonitrile ), pale 1,4-dihydro-oxoquinoline-3-carboxylic acid, m.p. yellow powder.

Example 11 To 1-cyclopropyl-7- (4-benzyl-1-piperazinyl) -6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (132 mg) is added 10% Pd-C (68 mg) and ethanol (10 ml) and the mixture is subjected to catalytic reduction under a hydrogen atmosphere at 60 ° C for 6.5 hours. After filtering off the catalyst, the filtrate is concentrated and the residue is recrystallized from ethanol-acetone-dichloronethane to give 1 + cyclopropyl-7- (1-piperazin-3-yl) -6-fluoro-8-hydroxymethyl-1 , 4-dihydro-4-oxoquinoline-3-carboxylic acid (34.2 mg) as a white powder, m.p. 149-152 ° C.

Example 12 1-Cyclopropyl-7- (4-oxo-1-piperidyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.25 g) is dissolved in 1% aqueous sodium hydroxide (28 ml) and to this is added sodium boron hydroxide (0.1 g) at room temperature. The mixture is stirred at the same temperature for 30 minutes and the resulting mixture is poured into ice water and then acidified with conc. sulfuric acid.

The mixture is extracted with dichloromethane and the solvent is distilled off. The obtained residue is crystallized by adding ethyl acetate thereto and then recrystallized from chloroform-methanol to give 1-cyclopropyl-7- (4-hydroxy-1-piperidyl) -6-fluoro-8-methyl-1,4-dihydro-4 -oxoquinoline-3-carboxylic acid (0.16 g), m.p. 234-236 ° C.

Example 13 To 1-cyclopropyl-7- [3- (t-butoxycarbonylaminomethyl) -1- such as pale yellow crystals, pyrrolidinyl] -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate hoxylic acid (0.1 g) is added 10% hydrochloric acid (4 ml) and ethanol (2 ml) and the mixture is reacted at 70 ° C for 10 minutes.

After concentration, the resulting residue is crystallized by adding diethyl ether and then recrystallized from ethyl acetate-methanol to give 1-cyclopropyl-7- (3-aminomethyl-1-pyrrolidinyl) -6-fluoro-8-methyl-1-yl. 4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride (45 mg), such as yellow crystals, m.p. 195- -200 ° C.

Example 14 To 1-Cyclopropyl-7- [B- (N-ethylacetamido) methyl-1-pyrrolidinyl] -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride (0.22 g) is added 5% aqueous sodium hydroxide (10 ml) and the mixture is refluxed for 24 hours. After cooling, insoluble material is filtered off and the filtrate is acidified with conc. hydrochloric acid. The mixture is extracted with dichloromethane and the aqueous layer is made alkaline with aqueous sodium hydroxide and t-butoxycarboxylic acid hydride (200 mg) is added thereto. The mixture is stirred at room temperature for 30 minutes. The reaction mixture is acidified with 10% hydrochloric acid and extracted with dichloromethane. After removal of the solvent by concentration, 10% hydrochloric acid (5 ml) and methanol (10 ml) are added to the resulting residue, and the mixture is heated to 0 ° C for 30 minutes. After concentration, the residue is recrystallized from ethanol-acetonitrile to give 1-cyclopropyl-7- (3-ethylaminomethyl-1-pyrrolidinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3- carboxylic acid hydrochloride (30 mg) as yellow crystals, mp 267-271 ° C.

Example gel 1-1-Cyclopropyl-7- (3-methyl-1-piperazinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.3 g) is dissolved in 10% aqueous sodium hydroxide (5 ml) and to this is added acetic anhydride (0.3 ml) at room temperature and the mixture is stirred at the same temperature for 30 minutes. The reaction mixture is acidified with conc. hydrochloric acid and extracted with dichloromethane. After removal of the solvent by concentration, the residue obtained is purified by silica gel column chromatography (solvent, dichloromethane) and then recrystallized from methanol to give 1-cyclopropyl-7- (4-acetyl-3-methyl-1-piperazinyl) -6- fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.1 g) as a white powder, m.p. 219-221 ° C.

Example 16 1-Cyclopropyl-7- (3-methyl-1-piperazinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.4 g) is added to a mixture of formic acid (1.7 ml) and acetic anhydride (2.2 ml) at 0 ° C. After the addition, the mixture is heated to 80 ° C for 2 hours. To the reaction mixture is added water and the mixture is extracted with dichloromethane. After removal of the solvent by concentration, the residue obtained is recrystallized from methanol to give 1-cyclopropyl-7- (4-formyl-3-methyl-1-piperazinyl) -6-fluoro-8-methyl-1,4-dihydro-4- oxoquinoline-3-carboxylic acid (0.13 g), such as white powder, m.p. 236-239 ° C.

Example 17 To 1-cyclopropyl-7- (3-methyl-1-piperazinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.4 g) is added formic acid (3 ml), 37% formalin (3 ml) and sodium formate (OQ4 g) and the mixture is refluxed for five hours. After cooling, the reaction mixture is poured over ice water and adjusted to below pH 8 with aqueous sodium bicarbonate and the mixture is extracted with dichloromethane. After removal of the solvent by concentration, the residue obtained is recrystallized from ethyl acetate to give 1-cyclopropyl-7- (3,4 + di- ~ 10 15 20 25 30 40 100 methyl-1-piperazinyl) -6-fluoro-8 -methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.12 g) as pale yellow powder, 181- -183 ° C. m.p.

In the same manner as described in Example 17 using suitable starting materials, the same compounds as the 1st compound of Examples 4, 3rd and 5th compounds of Examples 8, 4th, 6th, 15th are prepared. , 23rd, 31st and 40th in Example 10.

Preparation 1 - An injection preparation is prepared from the following components: Components Amount 7- (1-piperazinyl) -1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 200 glucose 250 mg distilled water for injection in sufficient quantity A total of 5 ml of 7- (1-piperazinyl) -1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and glucose are dissolved in distilled water for injection and the solution is added to a 5 ml ampoule, which is purified with nitrogen and then subjected to sterilization at 121 ° C for 15 minutes to give an injection preparation.

Preparation 2 Film-coated tablets are prepared from the following components.

Components Amount of 7- (1-piperazinyl) -1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 100 g Avicel ® (trademark in microcrystalline cellulose, manufactured by Asahi Chemical, Japan) 40 g Corn starch 30 g Magnesium stearate 2 g TC-5 (trademark in hydroxypropyl methylcellulose, manufactured by Shinetsu Kagaku Kogyo, Japan) 10 g Polyethylene glycol 6000 3 g Castor oil 50 g. Ethanol 40 g 7- (1-piperazinyl) -1-cyclopropyl-6-fluoro-8-methyl-1Q4-dihydro-α-oxoquinoline-3-carboxylic acid, Avicel ®, corn starch 10 15 20 25 30 40 40 101 501 371 and magnesium stearate are mixed and kneaded and the mixture is tabulated under use of conventional mortar (R 10 mm) for sugar coating (manufactured by Kikusui Seisakusho Co., Ltd Japan). The tablets thus obtained are coated with a film coating agent consisting of TC-S, polyethylene glycol 6000, castor oil and ethanol to give film-coated tablets.

Preparation 3 W I An ointment is prepared from the following components.

Components Amount of 7- <epiperazinyl> -1-cyclopropyl-ef within α-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 2 g Purified lanolin g Bleached beeswax g White petrolatum 88 q Total 100 g Bleached beeswax is made liquid by heating and to this is added 7- (1-piperazinyl) -1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, purified lanolin and white petrolatum and the mixture is heated until becomes liquid. The mixture is stirred until it solidifies to give an ointment. A Exgeriment (Antimicrobial effect in vitro) The antimicrobial effect of the test compounds listed below was tested by measuring the minimum inhibitory concentration (MIC) by the series dilution method on agar plate (cf.

Chemotherapy, 22, 1126-1128 (1974)). The microorganisms were used at a concentration of 1 x 108 cells / ml (y.d. 660 nm, 0.07-0.16) and 1 x 105 cells / ml (100-fold dilution). When S. penumoniae type II and S. pneumoniae type III were used as experimental organisms, the medium contained 5% horse blood. The results are shown in Table 1.

(Test compound) 1. 7- (1-piperazinyl) -1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 2. 7- (4-methyl-1-piperazinyl ) -1-Cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 3. 7- (1,4-diazabicyclo [4.3.0] nonan-4-yl) -1 -cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 4. 7- [α- (5-methyl-2-oxo-1,3-dioxolen-4-yl) Methyl 1-giper-1 'Azinyl7-1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-1-oxoquino- 10 15 20 25 30 35 40 102 -591 371 lin-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-methylphi, 4-dihydro-4-oxoquinoline-3-carboxylic acid JI 8. 7- (4-methyl-1-piperazinyl) -1-cyclopropyl-6-fluoro-8-hydroxymethyl-1,4-dihydro-4- oxoquinoline-3-carboxylic acid QQ. 1-Cyclopropyl-7-morpholino-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 10. 1-Cyclopropyl-7-morpholino-6-fluoro-8-hydroxymethyl-1 , 4-dihydro-4-oxoquinoline-3-carboxylic acid 11. 1-cyclopropyl-7- (3-acetamidomethyl-1-pyrrolidinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3- carboxylic acid 12. 1-cyclopropyl-7- (3-methyl-4-benzyl-1-piperazinyl} -6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 13. 1-cyclopropyl- 7-C4-oxo-1-piperidinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 14. 8-methyl-1,4-dihydro-4-oxoquinoline 3-Carboxylic acid 15. pyrrolidinyl] -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-1-cyclopropyl-7- (4-hydroxy-1-piperidinyl) -5-fluoro-1- cyclopropyl-7- [3- (t-buboxycarbonylaminomethyl) -1-carboxylic acid 16. fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 17. lidinyl] -6-fluoro-8-methyl-1 , 4-dihydro-4-oxoquinoline-3-carboxyl-1-cyclopropyl-7- (3-aminomethyl-1-pyrrolidinyl) -6-1-cyclopropyl- 7- [3- (N-methyl-N-benzylamino) - 1-pyrroic acid 18. fluoro-8-methyl-1,4-dih hydro-4-oxoquinoline-3-carboxylic acid 19. fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 20. fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3- carboxylic acid 21. fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carbaxylic acid 22. fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 23. 1-cyclopropyl-7 - (3-methylamino-1-pyrrolidinyl) -6-1-cyclopropyl-7- (4-acetyl-3-methyl-1-piperazinyl) -6-1-cyclopropyl-7- (3-ethylaminomethyl-1-pyrrolidinyl) -6- 1-cyclopropyl-7- (4-formyl-3-methyl-1-piperazinyl) -6-1-cyclopropyl-7- (3,4-dimethyl-1-piperazinyl) -6-1-cyclopropyl-7 - (4-ethyl-1-piperazinyl) -5-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 24. 1-Cyclopropyl-7- (4-cyclopropyl -1-piperazinyl-6-fluoro-8-methyl-10-4-dihydro-4-oxoquinoline-3-carboxylic acid I 25. 1-Cyclopropyl-7- (3-methylmorpholino) -6-fluoro-8-methyl Tyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 26. 1-Cyclopropyl-7- (3-amino-4-methyl-1-pyrrolidinyl) -6-fluorop-8-methyl-1,4-dihydro -4-oxoquinoline-3-carboxylic acid hydrochloride (isomer A) 27. 27. 1-Cyclop Ropyl-7- (3,5-dimethyl-1-piperidinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 28. 1-Cyclopropyl-7- (4-fluoro- 1-piperidinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (test micro-organisms): A: Staphylococcus aureus FDA 209A Staphylococcus pyrogen IID S-23 Staphylococcus pneumoniae type II Staphylococcus pneumoniae type III Pseudomonas aeruginosa E-2 Bacterioides fragilis GM7000 Eubacterium limosum ATCC 8496 Peptococcus anaerobis GM1003 Propionibacterium acnes ATCC 6919 Propionibacterium granulosum ATCC 25564 KC-cß-1CUUC- - micro- __ förening förening förening Förening organisf Nr. 1 Nr. 2 Nr. 3 Nr. 4 mer 1 x 106 1 x 106 1 x 106 1 x 106 a fl h flfi ü a fl kmh fl rælkmh fl u fl Lhd A 0.2 0.1 0.1 0.05 B 0.39 0739 0.39 0.2 c 0.10 o; 39 0 .78 0.39 D 1¿56 0.39 0.39 0.39 E 0.39 0.78 1:56 0.39 F 0.78 012 0.1 0.2 G 0.78 - - - H 1.56 OKYB 0.39 0.1 I 0.39 0.2 0.2 0.05 J 0.2 0.39 0.2 0.1 K 0.39 OI39 1.56 1.55 - to be continued - 105 Table l (continued) Test- ““ Experimental- Experimental- Experimental- Experimental- micro_ association compound Association compound 4 Nr. 5 Nr. 6 Nr. 7 Nr. 8 ° r9a "iS '1 x 106 1 x 106 1 x 106 1 x 106 mer a fl kmßü u fl k flfifl a fl kï fifl cæ flfifl A 0,2 0,70 0,010; 0,39 B 0,39 0¿39 0,0ü8 0,78 C 0 , 39 _ “_ D _ _ _ E 0,78 0¿39 0,195 1f56 F Û42“ "" G _ _. _ _ H "_ I 0,2 - - - J 0,2 _ _ _ K 0478 -“ _ - to be continued - 106 501 37 1 Table l (continued) Test- ~ Trial- Trial- Trial- Trial- micro_ association association association no. 9 Nr. 10 Nr. ll Nr. 12 ”gan” 1 x 106 1 x 106 1 x 106 1 x 106 mer u fl la fl ü. cn fl en fi ü uáh flfi ü. clü fl A 07012 01048 0,02H 0,39 B 0zOÄ8 0178 0,02U 07048 C _ _ _ _ D _ _ _ _ E 0:78 - - - F _ _ _ _ G _ _ _ _ H _ _ '_ _ I _ _ _ _ J _ _ _ _ K _ _ _ _ - to be continued - 107 5 01 3 71 Table l (Cont.) Test- - Trial- Trial- Trial- Trial- micr0_ association association association Association no. 13 Nr. 14 Nr. 15 Nr. 16 ”gëmis” 1 X 106 1 x 106 1 x 106 1 x 106 mer cells / ml cells / ful oeller / Inl cell / ful A <0¿O06 0.012 0.048 <070O6 B 01097 010143 0.195 <0¿006 C _ _ _ _ D _ _ _ _ _ E 1.56 0.78 - 0; 39 F _ _ _ _ G _ _ _ _ H _ _ _ _ I _ _ _ _ J _ _ _ _ K _ _ _ _ - to be continued - 108 '501 571 Table l (continued) Test- ~ Experimental Experimental- Experimental- Experimental- micro_ association association Association no. 17 Nr. 18 Nr. 19 Nr. 20 ° r9a “is' 1 x 106 1 x 106 1 x 106 1 x 106 mer a fl km fifl a fl kmh fl u fl kmhd a fl LMü A 0,0U8 0,02Ä 0,048 <0,006 B 0,195 0,0U8 0,097 0,012 C _ _ _ _ D _ _ _ _ _ s - 0.39 - 0.78 F _ _ _ _ G _ _ _ _ H _ _ '_ _ I _ _ _ _ J _ _ _ _ K _ _ _ _ - to be continued - 1 ”501 371 Table 1 (continued) Test- “Trial- Trial- Trial- Trial- micr0_ Association association association association Nr. 21 Nr. 22 Nr. 23 Nr. 24 "gams" 1 x 106 1 x 106 1 x 106 1 x 106 more cells / ful cells / ful æller / rnl cell / ml A 0.02U 0 {097 0.097 0.0U8 B OIO97 0.39 0.39 0¿ 39 C _ _ _ _ _ D _ _ _ _ E - 1,56 1f56 - F _ _ _ _ G G _ _ _ _ H _ '_ _ _ I _ _ _ _ _ J _ _ _ _ _ _ _ _ _ att continued - 110 Table l (Cont.) Test- ~ Trial- Trial- Trial- Trial- micrO_ association association association association _ Nr. 25 Nr. 26 Nr. 27 Nr. 28 ”gams” 1 x 106 1 x 106 1 x 106 1 x 106 more - cells / ful cells / url cells / ful cell / ml A 07012 0) 02U 0.097 0.012 B 0íO97 0.024 - - c _. _ _ ._ D _ _ _ ._ E 1r56 0,195 - 0,78 F ._ _ _ _ G _. _ - ._ H - L _ ~ I ._ _ _ _ J _ _ _ _ _

Claims (48)

10 15 20 25 30 35 40 1 .. 501 Patent claims A compound of the formula X COOH 112 - [11 R 3 R 1 wherein R 1 represents cyclopropyl, R 2 represents a group of formula F. Wherein RF represents a C1-C5 alkyl group, RA represents a hydrogen atom, I a C1-C5 alkyl group or a phenyl (C1-C5) alkyl group, RB represents a 2- oxo-1,3-dioxolenemethyl substituted with a C 1 -C 5 alkyl group or a C 3 -C 8 cycloalkyl group, RC represents hydrogen atom, a C 1 -C 5 alkyl group, a C 1 -C 5 alkoxycarbonyl group or a phenyl (C 1 -C 5) alkyl group, RD represents a hydrogen atom or a C1-C5-alkyl group, R5 represents a C1-C5-alkyl group and RH represents a C1-C5-alkyl group, a phenyl (C1-C5) alkyl group or a C1-C5-alkanoyl group or I Wherein R 1 represents an amino (C 1 -C 5) allyl group, wherein the amino group is optionally substituted with 1 or 2 substituents selected from a C 1 -C 5 alkyl group, a C 1 -C 6 alkanoyl group or a C 1 -C 5 alkoxycarbonyl group or an amino group which may be substituted by 1 or 2 substituents selected from a C 1 -C 5 alkyl group and a phenyl (C 1 -C 5) alkyl group and R 1 represents hydrogen atom or a C 1 -C 5 alkyl group, 371 10 15 20 Wherein RK represents the hydrogen atom or a C1-C5-alkyl group or a morpholino group which is substituted by 1 to 3 C1-C5-alkyl groups, wherein each of the alkyl groups is substituted by 1 to 3 substituents selected from the group consisting of -NH 2 and a halogen atom, or a 1-piperidinyl group which may have 1 to 3 substituents selected from the group consisting of oxo group, hydroxy group, a halogen atom and a C 1 -C 5 alkyl- group, R 3 represents a C 1 -C 5 alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of a 1-pyrrolidinyl group, a C 1 -C 5 alkylthio group, hydroxy group, a C 1 -C 5 alkoxy group and a halogen atom, and X represents a halogen atom, provided that R 3 represents a C 1 -C 5 alkyl group, when R 2 represents a group of the formula: ip N RC "J _ MJN-RA '_ FWN-RB' -G-RH or- / F / N 'or R 3 represents a C 1 -C 5 alkyl group having 1 to 3 substituents selected from the group consisting of a pyrrolidin-γ 1 group, a C1-C5-alkylthio group, hydroxy group, an δ1; C5-4 -alkoxy group and the halogen atom, when R2 represents a group with "of e .tft" in the formula: D-1 in R lf / Ü - N-RC Å ' - 0. 'I k / or \ ___ / or a pharmaceutically acceptable salt thereof. wherein R 2 represents an osbusti or a A compound according to claim 1, a tuerated C 1 -C 6 alkyl group and X represents the fluorine atom, a pharmaceutically acceptable salt thereof. A compound according to claim 1, wherein X represents the fluorine atom, R 2 represents a group of the formula: wherein R a represents hydrogen atom, a C 1 -C 6 alkyl group or a phenyl (C 1 -C 5) alkyl group and R 3 represents an unsubstituted C 1 -C 5 alkyl group, or a pharmaceutically acceptable salt thereof. 10 15 20 25 30 35 40 QÜWRP ”ß 501 3712 A compound according to claim 1, wherein X represents the fluorine atom, R 2 represents a group of the formula: -N N_RB wherein R B represents a C 3 -C 3 cycloalkyl group or a 2-oxo-1,3-dioxolenomethyl substituted with a C 1 -C 5 alkyl group . A compound according to claim 3, wherein RA represents a C 1 -C 6 alkyl group. A compound according to claim 5, wherein R 3 represents methyl. A compound according to claim 5, wherein R 3 represents ethyl. A compound according to claim 4, wherein RB represents a 2-oxo--1,3-dioxolenmethyl group substituted with A compound according to claim 4, wherein RB represents a C 3 -C 5 cycloalkyl group. A compound according to claim 8, wherein R 3 represents methyl. A compound according to claim 8, wherein R 3 represents ethyl. A compound according to claim 1, wherein R 2 represents a group of the formula: C. R. wherein RC represents a hydrogen atom, a C1-C6-alkyl group, a C1-C8-alkoxycarbonyl group or a phenyl (C1-C5) alkyl group and RD represents a hydrogen atom or a C1-C5-alkyl group. A compound according to claim 1, wherein R 2 represents a group of the formula: F R 1 is -f where RF represents a C 1 -C 5 alkyl group. - NH \ __ / A compound according to claim 1, wherein R 2 represents a group of the formula: α 1 (R 9 wherein R 9 represents a C 1 -C 5 alkyl group and R H K -N N_RH represents a C 1 -C 5 alkyl group, a phenyl- (C 1 -C 5) alkyl group or a C 1 -C 5 alkanoyl- 15 A compound according to claim 12, wherein R 3 represents methyl. A compound according to claim 12, wherein R 3 represents ethyl. A compound according to claim 13, wherein R 3 represents methyl. A compound according to claim 13, wherein R 3 represents ethyl. A compound according to claim 14, wherein R 3 represents methyl. A compound according to claim 14, wherein R 3 represents ethyl. a C 1 -C 5 alkyl group. 10 15 20 25 30 35 40 501 371 "4 A compound according to claim 1, wherein R 2 represents a 1-pyrrolidinyl group of the formula: IR wherein R 1 represents a C 1 -C 5 alkyl group having one - 1 amino group, wherein the amino group is optionally R 1 - substituted with one or two C 1 -C 5 alkyl groups , or an amino group which may be substituted by one or two C 1 -C 5 alkyl groups; and R 1 represents hydrogen atom or a C 1 -C 5 alkyl group. A compound according to claim 21, wherein R 1 represents an amino group which may be substituted by a C 1 -C 6 alkyl group. A compound according to claim 21, wherein R 1 represents a C 1 -C 5 alkyl group having an amino group, wherein the amino group is substituted with a C 1 -C 5 alkyl group and R 1 represents a hydrogen atom. A compound according to claim 22, wherein R 3 represents methyl. A compound according to claim 23, wherein R 3 represents methyl. A compound according to claim 1, wherein R 2 represents a group of the formula: RK f-f _ \ __ / ° A compound according to claim 26, wherein R 3 represents methyl. wherein RK represents hydrogen atom or a C1-C5-alkyl group. A compound according to claim 1, wherein R 3 represents methyl. A compound according to claim 3, wherein R 3 represents methyl. A compound according to claim 1, wherein R 2 represents 1-piperidinyl group, which = may have 1 to 3 substituents selected from the group consisting of oxo group, hydroxy group, a halogen atom and a C 1 -C 5 alkyl group. A compound according to claim 30, wherein R 2 represents 2-piperidinyl group which is substituted by a halogen atom. A compound according to claim 31, wherein R 3 represents methyl. A compound according to claim 31, wherein R 3 represents ethyl. A compound according to claim 30, wherein R 2 represents 1-piperidinyl group having a substituent selected from hydroxy group and oxo group. A compound according to claim 1, wherein R 2 represents a group -QL_ <ï:]. with the formula: 10 15 20 25 30 35 40 "S 501 371 A compound according to claim 35, wherein R 3 represents methyl. A compound according to claim 22, wherein R 3 represents ethyl. A compound according to claim 23, wherein R 3 represents ethyl. A compound according to claim 1, which is 7- [4- (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl-1-piperazinyl] -1-cyclopropyl-6- fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. A compound according to claim 1, which is 7- (3-methyl-1-piperazinyl) -1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. A compound according to claim 1, which is 1-cyclopropyl-7- (3-aminomethyl-1-pyrrolidinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid . A compound according to claim 1, which is 1-cyclopropyl-7- (3-methylamino-1-pyrrolidinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid . A compound according to claim 1, which is 1-cyclopropyl-7- (3-ethylaminomethyl-1-pyrrolidinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid . A compound according to claim 1, which is 1-cyclopropyl-7- (3-amino-4-methyl-1-pyrrolidinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline -3-carboxylic acid. A compound according to claim 1, which is 1-cyclopropyl-7- (4-fluoro-1-piperidinyl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3- carboxylic acid_ A compound according to claim 1, which is 1-cyclopropyl-7-morpholino-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. A compound according to claim 1, which is 1-cyclopropyl-7- (3-methylmorpholino) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. A process for the preparation of the compound described in claim 1, wherein (a) a compound of the formula: O 'HX c YcooR-S R2 2 The hen] - R3 wherein R1 represents cyclopropyl, R2 represents a group having for ~ meln: 10 15 20 25 30 35 40 501 371 ”6 RF - / _