JPH05279364A - New tricyclic compound or its salt and antimicrobial agent comprising the same - Google Patents

Abstract

PURPOSE:To obtain a new compound useful as an antimicrobial agent, an agent for fish diseases, an agricultural chemical and a preservative for foods. CONSTITUTION:The objective compound of formula I [R<1> is H or carboxy- protecting group; R<2> is (substituted)lower alkyl, (substituted)OH or nitro; R<3> is (substituted)lower alkyl; X is halogen; Y is halogen or (substituted)cyclic amino], e.g. ethyl-1-[N-{2,2-bis(t-butyloxycarbonyl)ethyl}-N-methyl]amino-5,6,7,8- tetrafluoro-1,4-dihydro-4-oxyquinoline-3-carboxylate. This compound of formula I is obtained by starting from a compound of formula II (R<2a> is halogen or nitro; Z<1> and Z<2> are releasable groups; Y<1> is halogen) and passing the compound of formula II through a compound of formula III (R<11> and R<12> are H or carboxy- protecting group), etc.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel tricyclic compound having excellent antibacterial activity and oral absorbability or a salt thereof, and an antibacterial agent containing the same.

[0002]

2. Description of the Related Art Many compounds having pyridonecarboxylic acid as a basic skeleton are known to be useful as synthetic antibacterial agents because of their excellent antibacterial activity and broad antibacterial spectrum. Among them, norfloxacin (JP-A-53-141286) and enoxacin (JP-A-5-141).
5-31042), ofloxacin (JP-A-57 / 57)
No. 46986), ciprofloxacin (Japanese Patent Laid-Open No. 5 (1993) -58,051).
8-76667) and the like are widely used clinically as therapeutic agents for infectious diseases.

[0003]

However, these compounds are not yet sufficiently satisfactory in terms of antibacterial activity, intestinal absorbability, metabolic stability, side effects, etc., and new compounds satisfying these requirements are not Creation was desired.

[0004]

Under the circumstances, the inventors of the present invention have conducted diligent research to provide a clinically excellent synthetic antibacterial agent which has improved the above-mentioned requirements, and as a result, the following general formula (1) The compound having a 1,8-bridged quinolinecarboxylic acid structure represented by) shows excellent antibacterial activity against Gram-negative bacteria and Gram-positive bacteria and satisfies other requirements, and is useful as a synthetic antibacterial agent. Heading, completed the present invention. That is, the present invention provides the following general formula (1)

[0005]

[Chemical 2]

[In the formula, R ¹ represents a hydrogen atom or a carboxy protecting group, R ² represents a lower alkyl group which may have a substituent, an optionally protected hydroxyl group or a nitro group, and R 2 ³ represents a lower alkyl group which may have a substituent, X represents a halogen atom, and Y represents a halogen atom or a cyclic amino group which may have a substituent]. A compound or salt thereof.

In the present invention, the term "lower" used for the explanation of each substituent of the formula (1) has 1 to 7 carbon atoms, preferably 1 when the substituent is a linear or branched group. ~
5 means a group having 5 to 3 carbon atoms when it is a cyclic group.
Means the group of.

The carboxy protecting group represented by R ¹ refers to an ester residue of a carboxylic acid ester, and means any group which is cleaved relatively easily to generate a corresponding free carboxyl group. Specific examples thereof include lower alkyl groups (eg, methyl group, ethyl group, n-propyl group, t-butyl group, etc.), aralkyl groups (eg, benzyl group) or aryl groups (eg, phenyl group). Those which are eliminated by treatment under mild conditions such as hydrolysis or catalytic reduction; etc .; or lower alkanoyloxy lower alkyl groups (eg acetoxymethyl group, pivaloyloxymethyl group etc.), lower alkoxycarbonyloxy Lower alkyl group (eg, methoxycarbonyloxymethyl group, 1-ethoxycarbonyloxyethyl group, etc.), lower alkoxymethyl group (eg,
Methoxymethyl group etc.), lactonyl group (eg phthalidyl group etc.), di-lower alkylamino lower alkyl group (eg 1-dimethylaminoethyl group etc.), (5-
Methyl-2-oxo-1,3-dioxol-4-yl) methyl group and the like which are easily eliminated in vivo are mentioned.

The lower alkyl group which may have a substituent represented by R ² includes, for example, methyl group, ethyl group,
In addition to lower alkyl groups such as isopropyl group, t-butyl group, t-pentyl group, etc., lower alkyl groups substituted with hydroxyl group, halogen atom, lower alkoxy group, carboxyl group, lower alkoxycarbonyl group etc. (eg hydroxymethyl Group, fluoromethyl group, trifluoromethyl group, methoxymethyl group, t-butoxycarbonylmethyl group, etc.) and the like, and preferably a methyl group.

Suitable "protecting group" for the optionally protected hydroxyl group represented by R ² is benzyl group,
Examples thereof include an aralkyl group such as a phenethyl group and a lower alkyl group such as a methyl group and an ethyl group.

The lower alkyl group which may have a substituent represented by R ³ includes the same ones as those represented by R ² .

Examples of the halogen atom represented by X include a fluorine atom, a chlorine atom and a bromine atom, and among these, a fluorine atom is preferable.

Examples of the halogen atom represented by Y include the same ones represented by X.

The cyclic amino group represented by Y, which may have a substituent, may be either a saturated cyclic amino group or an unsaturated cyclic amino group, and one or more cyclic amino groups may be present in the ring. It may contain a heteroatom such as a nitrogen atom, an oxygen atom, a sulfur atom and a carbonyl carbon, and may be a monocyclic ring or a bicyclic or tricyclic ring. Such cyclic amino groups include, for example, acetylidin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, pyrrolin-1-yl, pyrrol-1-yl, dihydropyridin-1-yl, piperidino, dihydroazepine-. 1-yl, perhydroazepin-1-yl, etc., a saturated or unsaturated monocyclic 3- to 7-membered cyclic amino group having one nitrogen atom, for example,
Imidazol-1-yl, imidazolidin-1-yl,
Imidazolin-1-yl, pyrazolidin-1-yl, piperazin-1-yl, 1,4-dihydropyridin-1-
Saturated, unsaturated monocyclic 3 to 7 having 2 nitrogen atoms, such as yl, 1,2-dihydropyrimidin-1-yl, perhydropyrazin-1-yl, homopiperazin-1-yl and the like.
Membered cyclic amino groups, for example 1,2,4-triazol-1-yl, 1,2,3-triazol-1-yl,
Saturated or unsaturated monocyclic 3- to 7-membered ring having 3 or more nitrogen atoms such as 1,2-dihydro-1,2,4-triazin-1-yl and perhydro-S-triazin-1-yl Amino group, for example, oxazolidin-3-yl, isoxazolidin-2-yl, morpholino, 1,3-oxazin-3-yl, thiazolidin-1-yl, isothiazolidin-1-yl, thiomorpholin-1-yl, Homothiomorpholin-1-yl, 1,2,4-thiadiazolin-2-yl, 1,2,3-thiadiazolidin-2-
Saturated or unsaturated monocyclic 3- to 7-membered cyclic amino group having 1 to 4 heteroatoms selected from oxygen atom and sulfur atom other than nitrogen atom such as yl, for example, isoindoline-
2-yl, indoline-1-yl, 1H-indazol-1-yl, purin-7-yl, tetrahydroquinolin-1-yl and the like saturated or unsaturated 2-3 cyclic cyclic amino groups, for example 2, 8-diazaspiro [4,4] nonane-
2-yl, 7-azabicyclo [2,2,1] heptane-
7-yl and other spiro- and cross-linked saturated or unsaturated 5
A 12-membered cyclic amino group and the like are included. More preferably, those represented by the following formulas (a) to (t) can be mentioned.

[0015]

[Chemical 3]

[0016]

[Chemical 4]

[0017]

[Chemical 5]

[0018]

[Chemical 6]

[Wherein D is an oxygen atom, a sulfur atom, -NR
⁴ or —CONR ⁴ (wherein R ⁴ represents a hydrogen atom, a hydroxyl group, a lower alkyl group, a cyclo lower alkyl group, an aralkyl group, an alkenyl group, an acyl group or a hydroxyl lower alkyl group), and E represents CH or N indicates, e indicates a number of 3 to 5, f indicates a number of 1 to 3, g
Represents a number of 0 to 2, h represents a number of 3 to 4, and i represents 1 to
Indicates the number of 2]

The ring atom of these cyclic amino groups may be substituted with an appropriate substituent, and examples of such a substitutable group include a lower alkyl group, a lower alkenyl group,
Lower aralkyl group, aryl group, hydroxyl group, hydroxy lower alkyl group, substituted or unsubstituted amino group, substituted or unsubstituted amino lower alkyl group, said cyclic amino group, alkoxy group, alkoxy lower alkyl group, halogen atom, Halo lower alkyl group, acyloxy group, acyloxy lower alkyl group, acyl group, carboxyl group,
Examples thereof include a carboxy lower alkyl group, an alkoxycarbonyl lower alkyl group, a mercapto group, a lower alkylthio group, a cyano group and a nitro group.

Here, the lower alkyl group is, for example, a methyl group, an ethyl group, an n-propyl group, etc., the lower alkenyl group is, for example, a vinyl group, an allyl group, etc., and the lower aralkyl group is, for example, a benzyl group, 1- An aryl group such as a phenylethyl group is, for example, a phenyl group, a hydroxy lower alkyl group is, for example, a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, etc., and an amino lower alkyl group is, for example, an aminomethyl group, 1- Examples of the alkoxy group such as aminoethyl group, 2-aminoethyl group and 1-amino-1-methylethyl group include methoxy group, ethoxy group and n-propoxy group, and examples of the alkoxy lower alkyl group include methoxymethyl group. , Ethoxymethyl group, etc. Elemental atom, chlorine atom, bromine atom and the like, halo lower alkyl group, for example, fluoromethyl group, trifluoromethyl group and the like, acyloxy group, for example, acetoxy group, benzoyloxy group and the like, as acyloxy lower alkyl group, For example, acetoxymethyl group, benzoyloxymethyl group and the like, examples of the acyl group include lower alkanoyl group such as formyl and acetyl, lower alkoxycarbonyl group such as methoxycarbonyl and ethoxycarbonyl, aromatic acyl group such as benzoyl and phenoxycarbonyl, and the like. Examples of the carboxy lower alkyl group include a carboxymethyl group and a carboxyethyl group, and examples of the alkoxycarbonyl lower alkyl group include a methoxycarbonyl methyl group,
Examples of the lower alkylthio group such as t-butoxycarbonylmethyl group include methylthio group and ethylthio group.

Of the above, examples of the substituent in the substituted amino group and the substituted amino lower alkyl group include a lower alkyl group (eg, methyl group, ethyl group, etc.), a cyclo lower alkyl group (eg, cyclopropyl group, cyclobutyl group,
Cyclopentyl group etc.), lower alkenyl group (eg vinyl group, allyl group etc.), lower aralkyl group (eg benzyl group, 1-phenylethyl group etc.), aryl group (eg phenyl group etc.), acyl group (eg formyl, acetyl) Such as lower alkanoyl group, lower alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, etc.), amino acid residue or peptide residue (eg glycyl, leucyl, valyl, alanyl, phenylalanyl, alanyl-alanyl, glycyl-valyl, glycyl -Glycyl-valyl etc.) and these functional groups are protected by an amino group or a peptide residue, or a cyclic amino group, etc., which are protected by a protecting group commonly used in peptide chemistry such as acyl group or lower aralkyl, and their substitutions are included. The group is 1
The two can be arbitrarily selected from the same kind or different kinds. Compounds protected by such amino acid residues or peptide residues are expected to have improved water solubility. Particularly preferred examples of these substituted amino groups and substituted amino lower alkyl groups are methylamino group, ethylamino group, dimethylamino group, methylaminomethyl group, ethylaminomethyl group, dimethylaminomethyl group, glycyl-amino group, leucyl. -Amino group, valyl-amino group, alanyl-amino group, alanyl-alanyl-amino group and the like.

The lower alkyl group represented by R ⁴ is
For example, a methyl lower group, an ethyl group, etc., a cyclo lower alkyl group such as a cyclopropyl group, a cyclobutyl group, etc., an aralkyl group such as a benzyl group, a 1-phenylethyl group, etc., and an alkenyl group such as a vinyl group, allyl group. Examples of the acyl group such as a group include a formyl group, acetyl group, methoxycarbonyl group and ethoxycarbonyl group, and examples of the hydroxy lower alkyl group include a hydroxymethyl group and a hydroxyethyl group. Among the groups represented by the formulas (a) and (b), preferable groups include those represented by the following formulas (a ′) and (b ′).

[0024]

[Chemical 7]

(Wherein D, e, f and g mean the same as those defined in the formulas (a) and (b), and J ¹ ,
J ² and J ³ may be the same or different, and may be a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower aralkyl group, an aryl group, a hydroxyl group, a hydroxy lower alkyl group or an amino group which may have a substituent. Group, an amino lower alkyl group which may have a substituent, a pyrrolidinyl group, a piperidino group, an azetidinyl group, an alkoxy group,
Alkoxy lower alkyl group, halogen atom, halo lower alkyl group, acyloxy group, acyloxy lower alkyl group, acyl group, carboxyl group, carboxy lower alkyl group, alkoxycarbonyl lower alkyl group, mercapto group, lower alkylthio group, cyano group, nitro group The definition of the substituents of J ¹ , J ² and J ³ and preferable examples thereof are the same as those explained for the group capable of substituting the cyclic amino group. Examples of the heterocyclic group represented by the formula (a ′) include an azetidinyl group, a pyrrolidinyl group and a piperidino group, and the heterocyclic group represented by the formula (b ′) includes, for example, a piperazinyl group, a morpholino group, Thiomorpholino group, homopiperazinyl group, thiazolidinyl group, oxazolidinyl group, 3
Examples include -oxo-1-piperazinyl group.

Particularly preferred specific examples of the groups represented by the formulas (a ') and (b') are as follows. 3-hydroxyazetidinyl group, 3-aminoazetidinyl group, 3
-(Nt-butoxycarbonylamino) azetidinyl group, 3-acetylaminoazetidinyl group, 3-methylaminoazetidinyl group, 3-dimethylaminoazetidinyl group, 3-methylazetidinyl group, 3- Amino-2-methylazetidinyl group,

Pyrrolidinyl group, 3-hydroxypyrrolidinyl group, 3,4-dihydroxypyrrolidinyl group, 3-methoxypyrrolidinyl group, 3-methylpyrrolidinyl group, 3
-Hydroxy-4-methyl-pyrrolidinyl group, 3-aminopyrrolidinyl group, 3-methylaminopyrrolidinyl group,
3-dimethylaminopyrrolidinyl group, 3-ethylaminopyrrolidinyl group, 3-diethylaminopyrrolidinyl group,
3-acetylaminopyrrolidinyl group, 3-t-butoxycarbonylaminopyrrolidinyl group, 3- (N-acetyl) methylaminopyrrolidinyl group, 3- (t-butoxycarbonyl) methylaminopyrrolidinyl group, 3-aminomethylpyrrolidinyl group, 3-methylaminomethylpyrrolidinyl group, 3-dimethylaminomethylpyrrolidinyl group,
3-ethylaminomethylpyrrolidinyl group, 3-diethylaminomethylpyrrolidinyl group, 3- (N-acetyl) aminomethylpyrrolidinyl group, 3- (t-butoxycarbonyl) aminomethylpyrrolidinyl group, 3- (N-acetyl) methylaminomethylpyrrolidinyl group, 3- (t-butoxycarbonyl) methylaminomethylpyrrolidinyl group, 3- (1-aminoethyl) pyrrolidinyl group, 3-
(2-aminoethyl) pyrrolidinyl group, 3- (1-amino-1-methylethyl) pyrrolidinyl group, 3- (1-methylaminoethyl) pyrrolidinyl group, 3- (1-dimethylaminoethyl) pyrrolidinyl group, 3- Amino-3-methylpyrrolidinyl group, 3-amino-4-methylpyrrolidinyl group, 3-amino-5-methylpyrrolidinyl group, 3-
Methylamino-4-methylpyrrolidinyl group, 3-dimethylamino-4-methylpyrrolidinyl group, 3-ethylamino-4-methylpyrrolidinyl group, 3-diethylamino-
3-methylpyrrolidinyl group, 3-diethylamino-4-
Methylpyrrolidinyl group, 3-aminomethyl-4-methylpyrrolidinyl group, 3-methylaminomethyl-4-methylpyrrolidinyl group, 3-dimethylaminomethyl-4-methylpyrrolidinyl group, 3-ethyl Aminomethyl-4-methylpyrrolidinyl group, 3- (1-aminoethyl) -4-methylpyrrolidinyl group, 3- (2-aminoethyl) -4-
Methylpyrrolidinyl group, 3-amino-4-ethylpyrrolidinyl group, 3-methylamino-4-ethylpyrrolidinyl group, 3-dimethylamino-4-ethylpyrrolidinyl group,
3-ethylamino-4-ethylpyrrolidinyl group, 3-diethylamino-4-ethylpyrrolidinyl group, 3-aminomethyl-4-ethylpyrrolidinyl group, 3-methylaminomethyl-4-ethylpyrrolidinyl group Group, 3-dimethylaminomethyl-4-ethylpyrrolidinyl group, 3-amino-3
-Methylpyrrolidinyl group, 3-methylamino-3-methylpyrrolidinyl group, 3-dimethylamino-3-methylpyrrolidinyl group, 3-amino-3,4-dimethylpyrrolidinyl group, 3-amino -4,4-dimethylpyrrolidinyl group, 3-amino-4,5-dimethylpyrrolidinyl group, 3
-Amino-2,4-dimethylpyrrolidinyl group, 3-methylamino-3,4-dimethylpyrrolidinyl group, 2-methyl-3-aminopyrrolidinyl group, 2-methyl-3-dimethylaminopyrrolidini group Group, 3-amino-4-vinylpyrrolidinyl group, 3-amino-4-methoxypyrrolidinyl group, 3-amino-4-methoxymethylpyrrolidinyl group,
3-methylamino-4-methoxypyrrolidinyl group, 3-
Dimethylamino-4-methoxypyrrolidinyl group, 3-ethylamino-4-methoxypyrrolidinyl group, 3-diethylamino-4-methoxypyrrolidinyl group, 3-benzylamino-4-methoxypyrrolidinyl group, 3 -Aminomethyl-4-methoxypyrrolidinyl group, 3-methylaminomethyl-4-methoxypyrrolidinyl group, 3-dimethylaminomethyl-4-methoxypyrrolidinyl group, 3-ethylaminomethyl-4-methoxypyrrolidyl group Dinyl group, 3-aminomethyl-3-methoxypyrrolidinyl group, 3-methylaminomethyl-3-methoxypyrrolidinyl group, 3-dimethylaminomethyl-3-methoxypyrrolidinyl group, 3-amino-4 -Ethoxypyrrolidinyl group, 3-methylamino-
4-ethoxypyrrolidinyl group, 3-dimethylamino-4
-Ethoxypyrrolidinyl group, 3-methylamino-4-ethoxypyrrolidinyl group, 3-aminomethyl-4-ethoxypyrrolidinyl group, 3-dimethylaminomethyl-4-ethoxypyrrolidinyl group, 3-amino -4-aminocarbamoylpyrrolidinyl group, 3-amino-4-dimethylaminocarbamoylpyrrolidinyl group, 3-amino-4-hydroxypyrrolidinyl group, 3-amino-4-hydroxymethylpyrrolidinyl group, 3 -Amino-4-hydroxyethylpyrrolidinyl group, 3-amino-4-methyl-4-hydroxymethylpyrrolidinyl group, 3-aminomethyl-4-
Hydroxypyrrolidinyl group, 3-dimethylaminomethyl-4-hydroxypyrrolidinyl group, 3,4-dihydroxypyrrolidinyl group, 3,4-dimethoxypyrrolidinyl group, 3-hydroxy-4-methylpyrrolidinyl group Group, 3-
Amino-4-fluoropyrrolidinyl group, 3-amino-4
-Fluoromethylpyrrolidinyl group, 3-amino-4-trifluoromethylpyrrolidinyl group, 3-methylamino-
4-fluoropyrrolidinyl group, 3-dimethylamino-4
-Fluoropyrrolidinyl group, 3-aminomethyl-4-fluoropyrrolidinyl group, 3-methylaminomethyl-4-
Fluoropyrrolidinyl group, 3-dimethylaminomethyl-
4-fluoropyrrolidinyl group, 3-methylamino-4-
Chloropyrrolidinyl group, 3-aminomethyl-4-chloropyrrolidinyl group, 3-methylaminomethyl-4-chloropyrrolidinyl group, 3- (2-hydroxyethyl) aminomethylpyrrolidinyl group, 3- (2-Fluoroethyl) aminomethylpyrrolidinyl group, 3-amino-4-methylthiopyrrolidinyl group, 3-amino-4-methylsulfinylpyrrolidinyl group, 3-formimidoylaminopyrrolidinyl group, 3 -(2-Dimethylhydrazino) pyrrolidinyl group, 3-amino-4-methylenepyrrolidinyl group, 3-
(T-Butoxycarbonylaminoacetyl) amino-4
-Methylpyrrolidinyl group, 3-aminoacetylamino-
4-methylpyrrolidinyl group, 3- (2-aminopropanoyl) amino-4-methylpyrrolidinyl group, 3- (2-
Amino-3-phenylpropanoyl) amino-4-methylpyrrolidinyl group, 3- (2-benzyloxycarbonylamino-3-methylbutanoylamino-4-methylpyrrolidinyl group, 3- (2-amino- 3-Methylbutanoyl) amino-4-methylpyrrolidinyl group, 3- (2-amino-2-methylpropanoyl) amino-4-methylpyrrolidinyl group, 7-amino-5-azaspiro [2.4 ]
A heptan-5-yl group,

Piperazinyl group, 4-methylpiperazinyl group, 3-methylpiperazinyl group, 2-methylpiperazinyl group, 3,4-dimethylpiperazinyl group, 3,5-dimethylpiperazinyl group, 3,3-dimethylpiperazinyl group, 3,4,5-trimethylpiperazinyl group, 4-ethoxycarbonylpiperazinyl group, 4-t-butoxycarbonylpiperazinyl group, 4-acetylpiperazinyl group,
4-benzyloxycarbonylpiperazinyl group, 4-ethylpiperazinyl group, 3,4-diethylpiperazinyl group, 3,4,5-triethylpiperazinyl group, 4-ethyl-3,5-dimethylpipepe Razinyl group, 3-methyl-4
-Acetylpiperazinyl group, 3-methyl-4-t-butoxycarbonylpiperazinyl group, 4-benzylpiperazinyl group, 4-n-propylpiperazinyl group, 4-isopropylpiperazinyl group, 4- t-butylpiperazinyl group, 4-cyclopropylpiperazinyl group, 4-cyclopentylpiperazinyl group, 4-cyclopropylmethylpiperazinyl group, 4-phenylpiperazinyl group, 4- (p-
Dimethylaminophenyl) piperazinyl group, 4- (p-
Methoxyphenyl) piperazinyl group, 4- (p-fluorophenyl) piperazinyl group, 3-phenylpiperazinyl group, 3- (p-fluorophenyl) piperazinyl group,
3- (p-chlorophenyl) piperazinyl group, 3- (p
-Hydroxyphenyl) piperazinyl group, 3- (p-methylphenyl) piperazinyl group, 4-hydroxyethylpiperazinyl group, 4-aminoethylpiperazinyl group, 4
-Allylpiperazinyl group, 4-cinnamylpiperazinyl group, 4-cyanoethylpiperazinyl group, 4-carboxyethylpiperazinyl group, 4-carboxymethylpiperazinyl group, 4- (1,2-di Carboxyethyl) piperazinyl group, 4-hydroxypiperazinyl group, 3-fluoromethylpiperazinyl group, 3-trifluoromethylpiperazinyl group, 4-formimidoylpiperazinyl group, 4-
Acetimidoylpiperazinyl group,

A piperidino group, a 4-aminopiperidino group,
4-dimethylaminopiperidino group, 4-hydroxypiperidino group, morpholino group, 2-aminomethylmorpholino group, 2-methylaminomorpholino group, 2-dimethylaminomorpholino group, thiomorpholino group, homopiperazinyl group, 4- Methylhomopiperazinyl group, thiazolidinyl group, oxazolidinyl group.

Further, the compound (1) of the present invention can form both an acid addition salt or a base addition salt. Incidentally, this salt also includes a salt formed with a chelate salt with a boron compound. Examples of the acid addition salt include (a) salts with mineral acids such as hydrochloric acid and sulfuric acid, (b) salts with organic carboxylic acids such as formic acid, citric acid, trichloroacetic acid, trifluoroacetic acid, fumaric acid and maleic acid, (C) Salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid, and examples of base addition salts include (a) sodium, potassium and the like. Salts with alkali metals, (b) salts with alkaline earth metals such as calcium and magnesium, (c) ammonium salts, (d) trimethylamine,
Triethylamine, tributylamine, pyridine, N,
N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, procaine, dibenzylamine, N-benzyl-β
Examples thereof include salts with a nitrogen-containing organic base such as phenethylamine, 1-ephenamine, and N, N'-dibenzylethylenediamine. Further, as the boron compound,
Examples thereof include boron halides such as boron fluoride and lower acyloxyboron such as acetoxyboron.

The compound (1) of the present invention can exist not only in unsolvated form but also as hydrate or solvate. Accordingly, the compounds of the present invention extend to all crystalline forms and hydrates or solvates thereof.

Further, the compound (1) of the present invention includes compounds having an asymmetric carbon atom, and therefore can exist as an optically active substance. These optically active substances are also included in the compound of the present invention. Furthermore, some of the compounds (1) of the present invention have two or more asymmetric carbon atoms, and they may exist as different stereoisomers (cis type, trans type). These stereoisomers are also included in the compound of the present invention.

The compound (1) of the present invention can be produced by any method suitable for the kind of the substituent and the like. Preferred examples thereof are as follows.

In the general formula (1), a compound having a halogen atom or a nitro group at the 6-position (position of R ² ) and a halogen atom at the 4-position (position of Y) is represented by, for example, the following. It is manufactured by a series of [Step-1] to [Step-6].

[0035]

[Chemical 8]

[0036]

[Chemical 9]

[0037]

[Chemical 10]

[In the formula, R ^2a represents a halogen atom or a nitro group, Z ¹ or Z ² represents a leaving group, Y ¹ represents a halogen atom, R ⁵ represents a lower alkoxy group or --NR ⁸ R ⁹
(Wherein R ⁸ and R ⁹ each represent a lower alkyl group), R ⁶ and R ⁷ each represent a lower alkyl group, R ¹⁰ represents an amino protecting group, and R ¹¹ and R ¹² each represent hydrogen. Represents an atom or a carboxy protecting group, and R ¹ , R ³
And X have the same meaning as above]

[Step-1] Compound (B) is compound (A)
It is obtained by reacting with an orthoformate ester (C) such as ethyl orthoformate or methyl orthoformate in acetic anhydride, and then reacting with a hydrazine derivative (D). The reaction between the compound (A) and the orthoformate ester is usually 0 to 16
It is carried out at 0 ° C., preferably 50 to 150 ° C., and the reaction time is generally 10 minutes to 48 hours, preferably 1 to 10 hours. The amount of orthoformate ester used is preferably equimolar or more, and more preferably about 1 to 10 times the molar amount of the compound (A).

The starting material (A) in [Step-1] is
It can be produced by the method described in the following documents or a method similar thereto. 1) J. Heterocyclic Chem. 22 ,
1033 (1985) 2) Liebigs Ann. Chem. 29 (198
7) 3) J. Med. Chem. 31 , 991 (1988) 4) J. Org. Chem. 35 , 930 (1970) 5) JP-A-62-246541 6) JP-A-62-26272 7) JP-A-63-145268 8) J. Med. Chem. 29 , 2363 (198)
6) 9) J. Fluorin Chem. 28, 361 (1
985) 10) JP-A-63-198664 11) JP-A-63-264461 12) JP-A-63-104974 13) European Patent Application No. 230948 Also, in the present specification, an explanation of substituents of compounds is given. Alternatively, as for suitable compounds not specifically exemplified, the same substituents as those described for the other compounds can be referred to.

The reaction with the above compound (D) is carried out in a suitable solvent. Here, a suitable "protecting group" for the amino protecting group represented by R ¹⁰ is, for example, a lower alkanoyl group such as formyl group, acetyl group, propionyl group, pivaloyl group, hexanoyl group, for example, chloroacetyl group, bromoacetyl group. Mono (or di or tri) halo (lower) alkanoyl groups such as dichloroacetyl group and trifluoroacetyl group, for example, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, t-butoxycarbonyl group, t-pentyloxycarbonyl group , A lower alkoxycarbonyl group such as a hexyloxycarbonyl group, a carbamoyl group, for example, an aroyl group such as a benzoyl group, a toluoyl group, and a naphthoyl group, for example, an ar (lower) alkanoyl group such as a phenylacetyl group and a phenylpropionyl group, such as a phenoyl group. Aryloxycarbonyl group,
Aryloxycarbonyl group such as naphthyloxycarbonyl group, for example, phenoxyacetyl group, aryloxy (lower) alkanoyl group such as phenoxypropionyl group, for example, phenylglyoxyloyl group, arylglyoxyloyl group such as naphthylglyoxyloyl group, for example , A benzyloxycarbonyl group, a phenethyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group, and the like, which may have an appropriate substituent, an ar (lower) alkoxycarbonyl group, etc., for example, a benzylidene group, a hydroxybenzylidene group, etc. Optionally substituted alk (lower) alkylidene group, for example, benzyl group, 1-phenylethyl group, benzhydryl group, alk (lower) alkyl group such as trityl group, or di- or triphenyl (lower) alkyl group
An alkyl group etc. are mentioned.

The solvent used here may be any solvent as long as it does not affect the reaction. For example, aromatic hydrocarbons such as benzene, toluene, xylene, etc .; diethyl ether, tetrahydrofuran, dioxane, monoglyme, Ethers such as diglyme; Aliphatic hydrocarbons such as pentane, hexane, heptane, ligroin, etc .; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, etc .; Dimethylformamide; Dimethyl sulfoxide, etc. Such aprotic polar solvent; alcohols such as methanol, ethanol, propanol and the like.
This reaction is usually carried out at 0 to 150 ° C., preferably 0 to 100 ° C., and the reaction time is usually 10 minutes to 48 hours.
The amount of compound (D) used is equimolar or more, preferably equimolar to 2 times the molar amount of compound (A).

Alternatively, the compound (A) may be converted into N, N-
After reacting with acetals such as dimethylformamide dimethylacetal and N, N-cimethylformamide diethylacetal, compound (D) can be reacted to lead to compound (B). As the solvent used in the reaction with the acetal, any solvent may be used as long as it is inert to the reaction, and examples thereof include those mentioned above. This reaction is generally 0 to 150 ° C., preferably room temperature to 10
It is carried out at 0 ° C., and the reaction time is generally 10 minutes to 48 hours, preferably 1 to 10 hours.

[Step-2] The compound (B) is subjected to a ring closure reaction to obtain a compound (E). Examples of the leaving group represented by Z ² include a halogen atom such as a fluorine atom.

This reaction is carried out in the presence of a basic compound in a suitable solvent. As the solvent used in this reaction, any solvent which does not affect the reaction can be used, and examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; diethyl ether, tetrahydrofuran, dioxane, monoglyme. Ethers such as; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, etc .; methanol, ethanol,
Alcohols such as propanol, butanol, etc .;
Examples include aprotic polar solvents such as dimethylformamide, dimethylsulfoxide and the like. The basic compounds used include alkali metals such as sodium metal and potassium; metal hydrides such as sodium hydride and calcium hydride; sodium hydroxide, potassium hydroxide and sodium carbonate. Inorganic bases such as; alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide and the like; metal fluorides such as sodium fluoride, potassium fluoride and the like; triethylamine, 1,8-diazabicyclo [5. 4.0] Organic bases such as undecene (DBU). The reaction temperature of this reaction is usually 0 to 2
The temperature is preferably 00 ° C, preferably room temperature to 180 ° C, and the reaction is usually completed in 5 minutes to 24 hours. The amount of the basic compound used is equimolar or more, preferably equimolar to 2 with respect to the compound (B).
Double mole is good.

[Step-3] The compound (F) can be produced by subjecting the compound (E) to the Michael addition reaction with the conjugated double bond compound (G). The reaction is carried out in the presence of base or Lewis acid. Suitable bases include
Examples thereof include alkali metal hydrides such as sodium hydride and potassium hydride, alkaline earth metal hydrides such as calcium hydride, alkali metal alkoxides such as potassium t-butoxide, potassium fluoride and the like. Suitable Lewis acid, for example, zinc bromide, zinc halide such as zinc chloride, for example magnesium bromide, magnesium halide such as magnesium chloride, for example titanium tetrachloride, tetraethoxy titanium, titanium compounds such as tetrapropoxy titanium, Examples thereof include boron trifluoride. The reaction is usually water, alcohol such as methanol, ethanol, methylene chloride, tetrahydrofuran,
It is carried out in a solvent such as N, N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone or a mixture thereof, but any other solvent can be used as long as it does not adversely influence the reaction. As a solvent or an auxiliary agent when using a Lewis acid, for example, a compound having an ether bond for modifying Lewis acidity such as diethyl ether, 1,2-epoxypropane, tetrahydrofuran, dioxane, etc. can be used. The reaction temperature is not particularly limited, but the reaction is usually performed under heating.

[Step-4] The compound (H) can be produced by subjecting the compound (F) to a ring closure reaction. Examples of the leaving group represented by Z ¹ include a halogen atom such as a fluorine atom. The ring closure reaction is carried out in the presence of a base. Examples of suitable bases and solvents are the same as those shown for [Step-3]. The reaction temperature is not particularly limited, but the reaction is usually performed under heating. Depending on the reaction conditions (for example, using dimethyl sulfoxide as a solvent), the Michael addition of [Step-3] causes the ring-closing reaction of [Step-4] to occur successively, and the reaction proceeds as a whole in one step.

[Step-5] Compound (I) can be produced by subjecting compound (H) to a solvolysis reaction. The solvolysis reaction is preferably carried out in the presence of a base or an acid (including a Lewis acid). Suitable bases include, for example, alkali metals such as sodium and potassium,
For example, alkaline earth metals such as magnesium and calcium, or hydroxides or carbonates or hydrogen carbonates thereof, such as trialkylamines such as trimethylamine and triethylamine, picoline, 1,5-diazabicyclo [4.
3.0] Non-5-ene, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] undec-7-ene, and other inorganic and organic bases. Is mentioned. Suitable acids include, for example, formic acid, acetic acid, glacial acetic acid, propionic acid, trichloroacetic acid,
Examples thereof include organic acids such as trifluoroacetic acid and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride and hydrogen bromide. The elimination using a Lewis acid such as trihaloacetic acid such as trichloroacetic acid or trifluoroacetic acid is preferably performed in the presence of a cation scavenger such as anisole and phenol. The reaction is usually carried out in a solvent such as water, alcohol such as methanol and ethanol, methylene chloride, tetrahydrofuran, N, N-dimethylformamide, dimethylsulfoxide or a mixture thereof, but a solvent which does not adversely influence the reaction. Any other solvent can be used as long as it is. Liquid bases or acids can also be used as solvents. The reaction temperature is not particularly limited, but the reaction is usually performed under cooling or heating.

[Step-6] Compound (J-1) can be produced by subjecting compound (I) to a decarboxylic acid reaction. This reaction is carried out by heating in an atmosphere of an inert gas such as nitrogen, or according to a conventional method such as reduction. The reaction is usually carried out in a solvent such as water, alcohol such as methanol and ethanol, methylene chloride, tetrahydrofuran, N, N-dimethylformamide, dimethylsulfoxide or a mixture thereof, but it does not adversely influence the reaction. Any other solvent can be used as long as it is a solvent. The reaction temperature is not particularly limited, but the reaction is usually performed under cooling or heating. If desired, the carboxy protecting group may be deprotected by an ordinary hydrolysis reaction to obtain a compound in which R ¹ is a hydrogen atom.

Among the compounds represented by the general formula (1), R
Compound (J-3) in which ² is a hydroxyl group which may be protected and Y is a halogen atom is a compound (J-
It can be obtained by subjecting 2) to the following [Step-7] and [Step-8].

[0051]

[Chemical 11]

(In the formula, R ^2b represents a halogen atom, and R ^2c
Represents an optionally protected hydroxyl group, R ¹³ represents a hydroxy protecting group, and R ¹ , R ³ , X and Y ¹ have the same meanings as described above)

[Step-7] The compound (K) is the compound (J
It can be produced by reacting -2) with the compound (L). Examples of the hydroxy protecting group represented by R ¹³ include those similar to the “protecting group” for the optionally protected hydroxyl group represented by R ² . This reaction is
It is carried out in the presence of a base such as sodium, potassium or sodium hydride. The reaction is usually benzene, toluene,
Aromatic hydrocarbons such as xylene, tetrahydrofuran,
The reaction can be carried out in any solvent which does not adversely influence the reaction, such as ethers such as dioxane, dimethylformamide, acetonitrile or pyridine. Further, the compound (L) may be used in excess to serve also as a solvent. Further, in this reaction, a compound (L) and a base-bonded reagent such as sodium methoxide and sodium ethoxide are used, and the compound (J
It can also be carried out by reacting with -2). The reaction temperature is not particularly limited, but the reaction is usually performed under cooling or heating.

[Step-8] The compound (J-3) can be produced by removing the hydroxy protecting group and / or carboxy protecting group from the compound (K), if desired. As the elimination reaction of the hydroxy protecting group and the carboxy protecting group, any of ordinary hydrolysis reaction conditions and ordinary catalytic reduction reaction conditions can be applied. Specifically, in the case of hydrolysis, basic compounds such as sodium hydroxide, potassium hydroxide, barium hydroxide and potassium carbonate, mineral acids such as sulfuric acid, hydrochloric acid and nitric acid, organic acids such as acetic acid and aromatic sulfonic acid. Etc. in the presence of water, alcohols such as methanol, ethanol and 2-propanol, ketones such as acetone and methyl ethyl ketone, ethers such as dioxane and ethylene glycol diethyl ether, solvents such as acetic acid or a mixed solvent thereof. Done. The reaction is usually at room temperature to 20
It is performed at 0 ° C., preferably room temperature to around 120 ° C. In the case of catalytic reduction, palladium carbon, palladium black, in the presence of a catalyst such as platinum dioxide, in a solvent such as methanol, ethanol, propanol, acetic acid, tetrahydrofuran, dioxane, ethyl acetate, water or a mixed solvent thereof. It is usually carried out by stirring under a hydrogen stream at atmospheric pressure to 100 atm. The reaction temperature is usually room temperature to about 100 ° C., and the reaction is usually completed in 1 to 48 hours.

Further, among the compounds represented by the general formula (1), the compound (J-4) in which R ² is a lower alkyl group which may have a substituent and Y is a halogen atom is a compound (J-2) from the following [Step-9] to [Step-1
1] can be obtained.

[0056]

[Chemical formula 12]

(In the formula, R ^2d represents a lower alkyl group which may have a substituent, and R ¹⁴ may have a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkoxy group or a substituent. A lower alkyl group is represented by R ¹ , R ^2b , R
³ , R ¹¹ , R ¹² , X and Y ¹ have the same meanings as above)

[Step-9] The compound (M) is the compound (J
It can be manufactured by reacting -2) with the compound (N). The halogen atom represented by R ¹⁴ includes
Examples thereof include a fluorine atom and a chlorine atom. Examples of the lower alkoxy group represented by R ¹⁴ include a methoxy group and an ethoxy group. Examples of the lower alkyl group which may have a substituent represented by R ¹⁴ include a methyl group, an ethyl group, a trifluoromethyl group, a hydroxymethyl group and the like. This reaction is carried out with a base such as sodium, potassium,
It is carried out in the presence of sodium hydride or the like. The reaction is usually carried out in any other solvent that does not adversely affect the reaction, such as aromatic hydrocarbons such as benzene, toluene, xylene, ethers such as tetrahydrofuran and dioxane, dimethylformamide, acetonitrile and the like. You can The reaction temperature is not particularly limited, but the reaction is usually performed under cooling or heating.

[Step-10] Compound (O) can be produced by subjecting compound (M) to a solvolysis reaction. This reaction can be performed under the same conditions as in [Step-5].

[Step-11] Compound (J-4) can be produced by subjecting compound (O) to a decarboxylic acid reaction. This reaction can be performed under the same conditions as in [Step-6].

Among the compounds represented by the general formula (1),
A compound in which R ¹ is a hydrogen atom or a lower alkyl group and Y is a cyclic amino group which may have a substituent (J-
6) is produced, for example, by the following [Step-12].

[0062]

[Chemical 13]

(In the formula, R ^1a represents a hydrogen atom or a lower alkyl group, Y ² represents a cyclic amino group which may have a substituent, M represents a hydrogen atom, an alkali metal atom or an organometallic compound. And R ² , R ³ , X and Y ¹ have the same meanings as described above.

That is, the compound (J-5) has the formula Y ² -M
The compound (J-6) is obtained by reacting the compound represented by or an alkali metal alcoholate.

This reaction is preferably carried out in an inert reaction solvent such as acetonitrile, dimethylformamide, dimethylsulfoxide, sulfolane or N-methylpyrrolidone or a mixture thereof. In addition, this reaction is carried out in the presence of a chelate compound obtained by reacting compound (J-5) with boron trifluoride or a complex thereof or tris-lower acyloxyboron in the presence of a chelate compound to obtain a chelate salt. It is also possible to react with the amine compound in the state. The reaction temperature is 50 to 200.
C is preferable, and 80 to 150 C is more preferable. This reaction comprises triethylamine, 2,6-lutidine, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,
It is preferable to use a base such as 5-diazabicyclo [4.3.0] non-5-ene or an alkali metal carbonate while neutralizing the generated hydrogen halide. It is also possible to use a method of neutralizing the generated hydrogen halide by using an alkali metal alcoholate or amine used in the reaction in excess. In this reaction, the product may be obtained in the form of a salt. If necessary, the product may be used with an acid such as acetic acid, trifluoroacetic acid or hydrochloric acid, or sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide. It is possible to convert the product to the free form by treating with a base such as.

In this reaction, when the hydroxyl group, mercapto group, carboxyl group or amino group is substituted in the compound represented by Y ² -M, the yield of compound (J-6) in the above reaction May significantly decrease, but in such a case, after the hydroxyl group, mercapto group, carboxyl group or amino group in the compound is modified with an appropriate protecting group, it is subjected to [Step-12], After that, a good yield can be obtained by deprotecting the obtained compound. As the protective group in this case, any known protective group can be used, for example, for a hydroxyl group, an acyl group, an alkoxycarbonyl group or a benzyl group; for a mercapto group, an acyl group or an ethylthio group. A benzyl group for a carboxyl group; an acyl group, an alkoxycarbonyl group, a benzyl group or the like for an amino group, and these protecting groups include acid hydrolysis, base hydrolysis or catalytic hydrogenation. Can be removed by any known method.

Among the compounds represented by the general formula (1),
The compound in which R ¹ is a carboxy protecting group is produced, for example, by the following [Step-13].

[0068]

[Chemical 14]

(In the formula, R ^1b represents a carboxy protecting group,
X ¹ represents a hydrogen atom or a halogen atom, and R ² , R ³ ,
X and Y have the same meaning as described above. That is, the compound (J-8) is obtained by reacting the compound (J-7) with a halide R ^1b -X ¹ .

The reaction is carried out in the presence of a base such as triethylamine, trimethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate, and an inert solvent such as N, N-dimethylformamide, dimethylsulfoxide and N-methylpyrrolidone. Using room temperature to 100 ℃
It is preferable to carry out at the temperature of. In this step as well, the yield may decrease due to the substituents on Y as described in [Step-12], but this problem is [Step-12].
It can be solved in the same manner as the method described in.

Further, particularly in the case of the group represented by Y, the substituents present therein can be interconverted by various known methods. In [Step-12], one example of the above-mentioned interconversion was described as application of a protecting group and deprotection, but some of the other reaction examples are as follows. These are conversion of hydroxyl groups to halogen atoms; acylation of hydroxyl groups, mercapto groups, primary and secondary amino groups; conversion of halogen atoms to amino groups or cyano groups; removal of alkoxycarbonyl groups, benzyl groups, acyl groups; hydroxyl groups , Mercapto group, carboxy group,
Alkylation of primary and secondary amino groups; conversion of alkenyl group to alkyl group; cyclization reaction by bonding of substituents.

[0072]

[Action]

(1) Antibacterial action For typical compounds of the present invention (1), the Japanese Society of Chemotherapy standard method [CHEMOTHERAPY Vol. 29,
No. 1, pp. 76-79 (1981)], the minimum inhibitory concentration [MIC: μg / ml] was measured. The results are shown in Table 1.
The compound numbers in the table are as shown in the examples.

[0073]

[Table 1]

As described above, the compound (1) of the present invention and salts thereof are novel compounds, exhibit extremely excellent antibacterial activity against Gram-negative and Gram-positive bacteria, and have a high oral absorption rate. is there.

When the compound (1) of the present invention is used as an antibacterial agent, it is combined with a pharmaceutically acceptable carrier for parenteral administration such as injection, rectal administration and eye drop administration, and oral administration in solid or liquid form. It can be prescribed as a product.

The form of the composition according to the present invention for injection includes pharmaceutically acceptable sterile water or non-aqueous solution, suspension or emulsion. Examples of suitable non-aqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate. Such compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. These compositions may be sterilized, for example, by filtration through a bacteria-retaining filter or by admixing a sterilant in the form of a sterile solid composition which may be dissolved in sterile water, or some other sterile injectable medium immediately before use. it can.
The preparation for eye drop administration may preferably contain, in addition to the present compound, a solubilizing agent, a preservative, an isotonicity agent, a thickening agent and the like.

Solid preparations for oral administration include capsules, tablets, pills, powders and granules. In preparing this solid dosage form, the compound of the invention is generally admixed with at least one inert diluent such as sucrose, lactose or starch. The formulation may also include additional substances other than an inert diluent in conventional formulation, such as a lubricant (eg magnesium stearate). Buffers may also be included in the case of capsules, tablets and pills. Tablets and pills may be further coated with an enteric coating.

Liquid formulations for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used by those skilled in the art, such as water. Included. In addition to such inert diluents, the composition can also include adjuvants such as wetting agents, emulsifying agents, suspending agents, and sweetening, flavoring and flavoring agents. Formulations for rectal administration may preferably contain, in addition to a compound of this invention, an excipient such as cocoa butter or a suppository wax.

The dose of the compound (1) of the present invention depends on the nature of the compound to be administered, the route of administration, the desired treatment period and other factors, but it is generally about 0.1-10 per day.
00 mg / kg, especially about 1-100 mg / kg is preferred. Also,
If desired, the daily dose can be divided into 2 to 4 divided doses for administration.

[0080]

INDUSTRIAL APPLICABILITY The compound (1) of the present invention and a salt thereof are extremely valuable as antibacterial agents and can be used as pharmaceuticals for humans and animals, and as preservatives for fish diseases, agricultural chemicals and foods. .. Furthermore, the compound of the present invention can be expected to have an antiviral action, particularly an anti-HIV (human immunodeficiency virus) action, and is considered to have an effect on the prevention or treatment of AIDS.

[0081]

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

Reference Example 1 Ethyl 1- (Nt-butyloxycarbonyl-N-
Methylamino) -5,6,7,8-tetrafluoro-
1,4-dihydro-4-oxoquinoline-3-carboxylate (1) 2,3,4,5,6-pentafluorobenzoyl ethyl acetate (28.6 g), ethyl orthoformate (23.2 g)
And a mixture of acetic anhydride (32.3 g) was heated under reflux for 8 hours. The solvent was distilled off. The obtained oily substance was dissolved in methylene chloride (100 ml), and a solution of N- (t-butyloxycarbonyl) -N-methylhydrazine (14.6 g) in methylene chloride (30 ml) was added dropwise under ice cooling for 2 hours. It was stirred. The solvent was distilled off. The obtained oily substance was crystallized from n-hexane and collected by filtration. 18.2 g of 2- (2,3,
4,5,6-Pentafluorobenzoyl) -3- (2-
t-butyloxycarbonyl-2-methylhydrazino)
Obtained ethyl acrylate. The obtained ethyl acrylate and anhydrous potassium carbonate (6.2 g) were added to N, N-dimethylformamide (50 ml), and the mixture was heated at 70 ° C. for 1 hour. The reaction solution was poured into ice water (200 ml) and the precipitate was collected by filtration. The precipitate was dissolved in chloroform (200 ml), washed with water and dried over magnesium sulfate, and the solvent was evaporated. The obtained oily substance was crystallized from n-hexane to obtain 13.7 g of the title compound (1).

Reference Example 2 Ethyl 1- (N-methylamino) -5,6,7,8-
Tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (2) The compound (1) (4.2 g) was dissolved in ethyl acetate (30 ml), and the solution was cooled with ice to prepare a 4N hydrochloric acid-dioxane solution. (40 ml)
Was added, and the mixture was stirred at room temperature overnight. The solvent was distilled off. The residue was dissolved in chloroform (100 ml), 10% aqueous sodium carbonate solution (50 ml) was added, and the mixture was stirred at room temperature for 30 min.
The organic layer was separated, dried over magnesium sulfate, and the solvent was evaporated. The crystals were dispersed in ether and collected by filtration to obtain 2.9 g of the title compound (2).

Example 1 Ethyl 1- [N- {2,2-bis (t-butyloxycarbonyl) ethyl} -N-methyl] amino-5,6.
7,8-Tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (3) Compound (2) (9.5 g) obtained in Reference Example 2 and di-
t-Butyl methylidene malonate (13.7 g) was dissolved in methylene chloride (90 ml), titanium tetrachloride (3.3 ml) was added dropwise over 40 minutes under ice cooling, and the mixture was further stirred for 1 hour. The reaction solution was poured into ice water, the organic layer was separated, dried over magnesium sulfate, and the solvent was evaporated. The obtained oily substance was separated by silica gel chromatography (silica gel, elution solvent; ethyl acetate: methylene chloride = 1: 20),
8.6 g of the title compound (3) was obtained. Colorless powder Melting point: 118-122 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.39 (s, 12H), 1.46 (s, 9)
H), 3.00 (s, 3H), 3.19-3.23 (m, 1H), 3.48-3.62 (m, 2H),
4.40 (q, J = 7.1Hz, 2H), 8.52 (s, 1H)

Example 2 Ethyl 3,3-bis (t-butyloxycarbonyl)
-4,5,6-trifluoro-2,3-dihydro-1-
Methyl-7-oxo-1H, 7H-pyrido [3.2.1
-Ij] Cinnoline-8-carboxylate (4) The compound (3) (10.0 g) obtained in Example 1 was dissolved in dimethyl sulfoxide (150 ml), and the mixture was stirred at room temperature, and cesium carbonate (3.0 g) was stirred. Was added and the mixture was stirred at 80 ° C. for 3 hours. After allowing to cool, the reaction solution was added with a 5% aqueous citric acid solution (5
(00 ml) and ethyl acetate (500 ml), the organic layer was separated and dried over magnesium sulfate, and the solvent was evaporated. The residue was dissolved in ether and the insoluble material was filtered off. The filtrate was evaporated, and the residue was separated by silica gel chromatography (silica gel, eluting solvent: chloroform) to give 1.6 g of the title compound (4). Colorless powder Melting point: 169-173 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.40 (t, J = 7.1Hz, 3H), 1.
49 (s, 18H), 2.76 (s, 3H), 4.04 (s, 2H), 4.39 (q, J = 7.1Hz, 2
H), 8.47 (s, 1H)

Example 3 4,5,6-Trifluoro-2,3-dihydro-1-methyl-7-oxo-8-ethoxycarbonyl-1H, 7
H-pyrido [3.2.1-ij] cinnoline-3-carboxylic acid (5) The compound (4) (1.0 g) obtained in Example 2 was dissolved in trifluoroacetic acid (2 ml), and the mixture was heated at 60 ° C. Heated for 2 hours. The reaction solution was poured into isopropyl ether (50 ml), and the precipitated solid was collected by filtration. 0.67 g of the title compound (5) was obtained. Colorless powder Melting point: 219-223 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 1.28 (t, J = 7.1 Hz, 3)
H), 2.78 (s, 3H), 3.73-3.76 (m, 2H), 4.18-4.25 (m, 3H),
8.45 (s, 1H)

Example 4 Ethyl 4,5,6-trifluoro-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido [3.
2.1-ij] Cinnoline-8-carboxylate (6) The compound (5) (300 mg) obtained in Example 3 was dissolved in N-methylpyrrolidone (6 ml) and heated at 160 ° C for 3 hours. After allowing to cool, water was added to the reaction solution, and the mixture was extracted 3 times with chloroform. The organic layer was dried over magnesium sulfate and the solvent was evaporated. The residue was separated by silica gel chromatography (silica gel, eluting solvent: chloroform), and 1
28 mg of the title compound (6) was obtained. Colorless powder Melting point: 236-240 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.40 (t, J = 7.1Hz, 3H), 2.
83 (s, 3H), 3.00-3.08,3.44-3.51 (each m, each 2H), 4.3
8 (q, J = 7.1Hz, 2H), 8.49 (s, 1H)

Example 5 Ethyl 4,5-difluoro-6- (bis-t-butyloxycarbonyl) methyl-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido [3.2. 1-
ij] Cinnoline-8-carboxylate (7) t-butyl malonate (1.31 g) was added to toluene (14 m).
l) dissolved in sodium hydride (60%, 240mg)
Was added and reacted at room temperature for 30 minutes. This solution was added dropwise to a toluene solution (14 ml) in which the compound (6) (450 mg) obtained in Example 4 was suspended and reacted at room temperature for 30 minutes. Ethyl acetate was added to the reaction solution, which was washed with a 10% aqueous citric acid solution, dried over anhydrous magnesium sulfate, and evaporated.
The obtained residue was separated with a silica gel column (developing solvent: 1% methanol / chloroform) and then crystallized with diisopropyl ether to obtain 220 mg of the title compound (7). Melting point: 162-165 ° C ¹ H-NMR (CDCl ₃ ) δ: 8.47 (s, 1H), 7.07 (s, 1)
H), 4.36 (q, J = 7.0Hz, 2H), 3.46 (t, J = 6.0Hz, 2H), 3.08 (t,
J = 6.0Hz, 2H), 2.82 (s, 3H), 1.50 (s, 18H), 1.37 (t, J = 7.0H
z, 3H)

Example 6 4,5-Difluoro-2,3-dihydro-1-methyl-
8-Ethoxycarbonyl-7-oxo-1H, 7H-pyrido [3.2.1-ij] cinnoline-6-acetic acid (8) The compound (7) (522 mg) obtained in Example 5 was treated with trifluoroacetic acid ( 2 ml) and reacted at 80 ° C. for 1 hour. After cooling, diisopropyl ether (15 ml) was added, and the precipitated powder was collected by filtration and dried to obtain 360 mg of the title compound (8). Melting point: 205-208 ° C (decomposition) ¹ H-NMR (CDCl ₃ ) δ: 8.60 (s, 1H), 4.28-4.41
(m, 4H), 3.50 (t, J = 6.0Hz, 2H), 3.12 (t, J = 6.0Hz, 2H), 2.8
7 (s, 3H), 1.39 (t, J = 7.0Hz, 3H)

Example 7 Ethyl 4,5-difluoro-1,6-dimethyl-2,
3-dihydro-7-oxo-1H, 7H-pyrido [3.
2.1-ij] Cinnoline-8-carboxylate (9) The compound (8) (360 mg) obtained in Example 6 was dissolved in dimethyl sulfoxide (10 ml) and reacted at 160 ° C for 1 hour. After allowing to cool, it was poured into ethyl acetate (100 ml), washed with a saturated aqueous sodium hydrogen carbonate solution and water, dried over anhydrous magnesium sulfate, and then evaporated. The obtained residue was separated by silica gel chromatography (developing solvent; 1% methanol / chloroform), crystallized from diethyl ether, and dried to give 110 mg of the title compound (9).
Got Melting point: 200-201 ° C ¹ H-NMR (CDCl ₃ ) δ: 8.48 (s, 1H), 4.38 (q, J =
7.1Hz, 2H), 3.45 (t, J = 6.0Hz, 2H), 3.04 (t, J = 6.0Hz, 2H),
2.87 (d, J = 2.8Hz, 3H), 2.82 (s, 3H), 1.40 (t, J = 7.1Hz, 3H)

Example 8 4,5-Difluoro-1,6-dimethyl-2,3-dihydro-7-oxo-1H, 7H-pyrido [3.2.1-
ij] Cinnoline-8-carboxylic acid (10) A mixture of the compound (9) (110 mg) obtained in Example 7, acetic acid (4 ml) and 12N-hydrochloric acid (1 ml) was heated and refluxed for 6 hours. After allowing to cool, water was added, the mixture was extracted with chloroform, dried over anhydrous magnesium sulfate, and evaporated.
The residue obtained is washed with diethyl ether, dried and
81 mg of the title compound (10) was obtained. Melting point: 247-249 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 8.74 (s, 1H), 3.51
(t, J = 6.0Hz, 2H), 3.09 (t, J = 6.0Hz, 2H), 2.85 (s, 3H), 2.8
2 (d, J = 2.8Hz, 3H)

Example 9 4- (cis (-) 3-amino-4-methylpyrrolidine-
1-yl) -5-fluoro-1,6-dimethyl-2,3
-Dihydro-7-oxo-1H, 7H-pyrido [3.
2.1-ij] Cinnoline-8-carboxylic acid-hydrochloride (11) The compound (10) (44 mg) obtained in Example 8, cis (-) 3-amino-4-methylpyrrolidine dihydrochloride (11) A mixture of 60 mg), 1,8-diazabicyclo [5.4.0] undec-7-ene (130 mg) and acetonitrile (2 ml) was reacted under heating under reflux for 15 hours. After distilling off the solvent, ethanol was added and further 4N-hydrochloric acid / 1,
4-Dioxane (2 drops) was added, and the deposited precipitate was collected by filtration, washed with ethanol and diethyl ether, and dried to obtain 47 mg of the title compound (11). Melting point: 178-180 ° C (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 8.63 (s, 1H), 3.31-
4.00 (m, 7H), 3.02-3.03 (m, 2H), 2.87 (s, 3H), 2.76 (d, J =
3.3Hz, 3H), 2.58-2.69 (m, 1H), 1.14 (d, J = 6.6Hz, 3H)

Example 10 Benzyl 4,5-difluoro-6-benzyloxy-
2,3-dihydro-1-methyl-7-oxo-1H, 7
H-pyrido [3.2.1-ij] cinnoline-8-carboxylate (12) benzyl alcohol (500 mg), benzene (10 ml)
Sodium hydride (60%, 50 mg) was added thereto, and the mixture was reacted at room temperature for 10 minutes, then the compound (6) (326 mg) obtained in Example 4 was added, and the mixture was reacted at room temperature for 1 hour. Ethyl acetate was added to the reaction solution, which was washed with a 10% aqueous citric acid solution, dried over anhydrous magnesium sulfate, and evaporated. The obtained oily substance was crystallized from diethyl ether to obtain 172 mg of the title compound (12). Melting point: 174-177 ° C ¹ H-NMR (CDCl ₃ ) δ: 8.44 (s, 1H), 7.32-7.65
(m, 10H), 5.37 (s, 2H), 5.22 (s, 2H), 3.41 (t, J = 6.0Hz, 2
H), 2.97 (t, J = 6.0Hz, 2H), 2.78 (s, 3H)

Example 11 4,5-Difluoro-6-benzyloxy-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido [3.2.1-ij] cinnoline-8-carvone Acid (1
3) The compound (12) (400 mg) obtained in Example 10 was dissolved in tetrahydrofuran (10 ml), 1N-sodium hydroxide (1 ml) was added, and the mixture was reacted with heating under reflux for 2 hours. After cooling, water (50 ml) was added, the mixture was acidified with 12 N hydrochloric acid to acidify the hydrochloric acid, and the precipitated crystals were collected by filtration, washed successively with water, ethanol and diethyl ether, and dried to give 300 mg of the title compound (13). It was Melting point: 165-168 ° C ¹ H-NMR (CDCl ₃ ) δ: 8.80 (s, 1H), 7.36-7.62
(m, 5H), 5.22 (s, 2H), 3.49 (t, J = 6.0Hz, 2H), 3.07 (t, J = 6.
0Hz, 2H), 2.87 (s, 3H)

Example 12 4,5-Difluoro-6-hydroxy-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido [3.2.1-ij] cinnoline-8-carboxylic acid (1
4) The compound (13) (360 mg) obtained in Example 11 was dissolved in acetic acid (15 ml), and 10% palladium carbon (100%) was added.
mg) was added, and the mixture was reacted overnight at 60 ° C. under a hydrogen stream. Chloroform was added to dissolve the precipitated crystals, the catalyst was filtered off, the filtrate was evaporated, the residue was washed with ethanol and diethyl ether, and dried to obtain 190 mg of the title compound (14). Melting point: 255-259 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 8.76 (s, 1H), 3.47
(t, J = 6.0Hz, 2H), 2.96 (t, J = 6.0Hz, 2H), 2.85 (s, 3H)

Example 13 4- (cis (-) 3-amino-4-methylpyrrolidine-
1-yl) -5-fluoro-6-hydroxy-2,3-
Dihydro-1-methyl-7-oxo-1H, 7H-pyrido [3.2.1-ij] cinnoline-8-carboxylic acid
Hydrochloride (15) Compound (14) (59 mg) obtained in Example 12, cis (-) 3-amino-4-methylpyrrolidine dihydrochloride (55 mg), 1,8-diazabicyclo [5.4. A mixture of [0] undec-7-ene (127 mg) and acetonitrile (1.2 ml) was reacted under heating under reflux for 17 hours. After distilling off the solvent, ethanol was added, and 4N-hydrochloric acid / 1,4-dioxane (2 drops) was added, and the deposited precipitate was collected by filtration and washed with ethanol and diethyl ether.
After drying, 59 mg of the title compound (15) was obtained. Melting point: 243-247 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 8.62 (s, 1H), 3.33-
4.04 (m, 9H), 2.88 (s, 3H), 2.45-2.46 (m, 1H), 1.08 (d, J =
(6.6Hz, 3H)

Example 14 4,5-Difluoro-6-hydroxy-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido [3.2.1-ij] cinnoline-8-carboxylic acid -Boron difluoride complex (16) The compound (14) (70 mg) obtained in Example 12 was added to diethyl ether (2 ml), and the boron difluoride-diethyl ether solution (2 ml) was added dropwise under ice cooling. After completion of dropping, the mixture was stirred overnight at room temperature. The precipitated solid was collected by filtration and washed with diethyl ether to obtain 58 mg of the title compound (16). Melting point: 270-272 ° C (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 9.14 (s, 1H), 3,54
(d, J = 6Hz, 2H), 3.04 (d, J = 6Hz, 2H), 2.94 (s, 3H)

Example 15 5-Fluoro-6-hydroxy-2,3-dihydro-1
-Methyl-4- (4-methylpiperazin-1-yl)-
7-oxo-1H, 7H-pyrido [3.2.1-ij]
Cinnoline-8-carboxylic acid (17) Compound (16) (29 mg) and 1 obtained in Example 14
-Methylpiperazine (25 mg) was added to dimethyl sulfoxide (1 ml), and the mixture was stirred at room temperature overnight. Diethyl ether was added and the supernatant was removed. 80% Methanol (5 ml) and triethylamine (0.5 ml) were added to the residue, and the mixture was heated under reflux for 2 hours. The solvent was concentrated under reduced pressure, and ethanol and diethyl ether were added to the residue. The solid was collected by filtration and washed with ethanol and diethyl ether to obtain 16 mg of the title compound (17). Light yellow solid Melting point: 178 ° C. <(decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 2.28 (s, 3H), 2.54 (b
rs, 4H), 2.87 (s, 3H), 3.01-3.09 (m, 2H), 3.27 (brs, 4H),
3.35-3.43 (m, 2H), 8.69 (s, 1H)

Example 16 4- (trans-3-amino-2-methylazetidine-
1-yl) -5-fluoro-6-hydroxy-2,3-
Dihydro-1-methyl-7-oxo-1H, 7H-pyrido [3.2.1-ij] cinnoline-8-carboxylic acid
Hydrochloride (18) Compound (16) (29 mg) obtained in Example 14, trans-3-amino-2-methylazetidine dihydrochloride (2
7 mg) and triethylamine (43 mg) were added to dimethyl sulfoxide (1 ml), and the mixture was stirred at room temperature overnight. Diethyl ether was added and the supernatant was removed. 80% Methanol (5 ml) and triethylamine (0.5 ml) were added to the residue, and the mixture was heated under reflux for 2 hours. The solvent was concentrated under reduced pressure. Ethanol (2 ml) and concentrated hydrochloric acid (0.5 ml) were added to the residue, and the mixture was stirred at room temperature for 1 hr. The solvent was concentrated under reduced pressure, and ethanol and diethyl ether were added to the residue. The solid was collected by filtration and washed with ethanol and diethyl ether to obtain 10 mg of the title compound (18). Light yellow solid Melting point: 196 ° C. <(Decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 1.34 (d, J = 5.9Hz, 3
H), 2.80 (s, 3H), 3.24-3.55 (m, 4H), 3.71-4.48 (m, 4H),
5.84-5.95 (m, 1H), 8.56 (brs, 2H), 8.59 (s, 1H)

Reference Example 3 Ethyl 1- (Nt-butyloxycarbonyl-N-
Methylamino) -6,7,8-trifluoro-5-nitro-1,4-dihydro-4-oxoquinoline-3-carboxylate (19) In the same manner as in Reference Example 1, the title compound (19) was obtained. It was Melting point: 139-141 ° C ¹ H-NMR (CDCl ₃ ) δ: 8.38 (s, 1H), 4.36 (q, J =
7.3Hz, 2H), 3.45 (s, 3H), 1.35-1.60 (m, 12H)

Reference Example 4 Ethyl 1- (N-methylamino) -6,7,8-trifluoro-5-nitro-1,4-dihydro-4-oxoquinoline-3-carboxylate (20) Reference Example 2 The title compound (20) was obtained in the same manner as. Melting point: 215-216 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 8.70 (s, 1H), 7.02-
7.10 (m, 1H), 4.24 (q, J = 7.1Hz, 2H), 2.84 (d, J = 6.1Hz, 3H),
1.28 (t, J = 7.1Hz, 3H)

Example 17 Ethyl 1- [N- {2,2-bis (t-butyloxycarbonyl) ethyl} -N-methyl] amino-6,7,
8-trifluoro-5-nitro-1,4-dihydro-4
-Oxoquinoline-3-carboxylate (21) In the same manner as in Example 1, the title compound (21) was obtained. Colorless powder Melting point: 162-163 ° C (decomposition) ¹ H-NMR (CDCl ₃ ) δ: 1.40 (s, 12H), 1.45 (s, 9)
H), 3.03 (s, 3H), 3.19-3.24 (m, 1H), 3.50-3.68 (m, 2H),
4.40 (q, J = 6.8Hz, 2H), 8.64 (s, 1H)

Example 18 Ethyl 3,3-bis (t-butyloxycarbonyl)
4,5-Difluoro-6-nitro-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido [3.
2.1-ij] Cinnoline-8-carboxylate (2
2) In the same manner as in Example 2, the title compound (22) was obtained. Colorless powder Melting point: 172-173 ° C (decomposition) ¹ H-NMR (CDCl ₃ ) δ: 1.40 (t, J = 6.8Hz, 3H), 1.
48 (s, 18H), 2.74 (s, 3H), 4.03 (s, 2H), 4.38 (q, J = 6.8Hz, 2
H), 8.45 (s, 1H)

Example 19 4,5-Difluoro-6-nitro-2,3-dihydro-
1-methyl-7-oxo-8-ethoxycarbonyl-1
H, 7H-pyrido [3.2.1-ij] cinnoline-3
-Carboxylic acid (23) In the same manner as in Example 3, the title compound (23) was obtained. Colorless powder Melting point: 210-212 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 1.28 (t, J = 7.1 Hz, 3
H), 2.79 (s, 3H), 3.73-3.76 (m, 2H), 4.18-4.29 (m, 3H),
8.45 (s, 1H)

Example 20 Ethyl 4,5-difluoro-6-nitro-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido [3.2.1-ij] cinnoline-8-carboxy Rate (24) The title compound (24) was obtained in the same manner as in Example 4. Colorless powder Melting point: 221-225 ° C. (decomposition) ¹ H-NMR (CDCl ₃ ) δ: 1.40 (t, J = 7.2 Hz, 3 H), 2.
83 (s, 3H), 3.00-3.05,3.44-3.49 (each m, each 2H), 4.37
(q, J = 7.2Hz, 2H), 8.48 (s, 1H)

Example 21 4,5-Difluoro-6-nitro-2,3-dihydro-
1-Methyl-7-oxo-1H, 7H-pyrido [3.
2.1-ij] Cinnoline-8-carboxylic acid (25) In the same manner as in Example 8, the title compound (25) was obtained. Colorless powder Melting point: 262-266 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 2.85 (s, 3H), 3.06,
3.50 (each t, each J = 6.1Hz, each 2H), 8.78 (s, 1H)

Example 22 4-{(3S) -3-aminopyrrolidin-1-yl}-
5-fluoro-1,6-dimethyl-2,3-dihydro-
7-oxo-1H, 7H-pyrido [3,2,1-ij]
Cinnoline-8-carboxylic acid / hydrochloride (26) Similarly to Example 9, 4,5-difluoro-1,6-dimethyl-2,3-dihydro-7-oxo-1H, 7H-pyrido [3,2] , 1-ij] Cinnoline-8-carboxylic acid (10) to give the title compound (26). Melting point: 186-190 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 8.66 (s, 1H), 8.28 (b
r, 3H), 3.92-2.98 (m, 8H), 2.88 (s, 3H), 2.77 (d, J = 3Hz, 3
H), 2.38-1.96 (m, 3H)

In the same manner as in Example 15, 4,5-difluoro-6-hydroxy-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido [3,2,1-i] was used.
j] Starting from the cinnoline-8-carboxylic acid-boron difluoride complex (16) the following compounds were obtained.

Example 23 4- (Pyrrolidin-1-yl) -5-fluoro-6-hydroxy-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido [3,2,1- ij] Cinnoline-8-carboxylic acid (27) Melting point: 262-265 ° C. (decomposition) ¹ H-NMR (CDCl ₃ ) δ: 8.71 (s, 1H), 3.60-3.54
(m, 4H), 3.37 (t, J = 6Hz, 2H), 2.90 (s, 3H), 2.85 (t, J = 6Hz,
2H), 2.02-1.98 (m, 4H)

Example 24 4- (morpholin-4-yl) -5-fluoro-6-hydroxy-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido [3,2,1- ij] Cinnoline-8-carboxylic acid (28) Melting point: 270-272 ° C. (decomposition) ¹ H-NMR (CDCl ₃ ) δ: 8.78 (s, 1H), 3.86 (t, J = 5)
Hz, 4H), 3.43 (t, J = 6Hz, 2H), 3.29 (brs, 4H), 2.97 (t, J = 6H
z, 2H), 2.89 (s, 3H)

Example 25 4- (3-Hydroxyazetidin-1-yl) -5-fluoro-6-hydroxy-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido [3 2,1-i
j] Cinnoline-8-carboxylic acid (29) Melting point 277-280 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 8.53 (s, 1H), 5.71
(d, J = 6Hz, 1H), 4.72 (brs, 2H), 4.56-4.50 (m, 1H), 4.27-
4.25 (m, 2H), 3.41-3.28 (m, 2H), 2.90-2.85 (m, 2H), 2.83
(s, 3H)

Example 26 4- (3-Hydroxypyrrolidin-1-yl) -5-fluoro-6-hydroxy-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido [3,2] , 1-i
j] Cinnoline-8-carboxylic acid (30) Melting point: 235-240 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 8.62 (s, 1H), 5.05-
5.00 (m, 1H), 4.43-4.38 (m, 1H), 3.93-3.81 (m, 2H), 3.58-
3.28 (m, 4H), 3.03-2.92 (m, 2H), 2.88 (s, 3H), 2.07-1.80
(m, 2H)

In the same manner as in Example 16, 4,5-difluoro-6-hydroxy-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido [3,2,1-i] was used.
j] Starting from cinnoline-8-carboxylic acid-boron difluoride complex (16) the following compounds were obtained:

Example 27 4-{(3R, 1'S) -3- (1'-amino) ethylpyrrolidin-1-yl} -5-fluoro-6-hydroxy-2,3-dihydro-1-methyl -7-oxo-1
H, 7H-pyrido [3,2,1-ij] cinnoline-8
-Carboxylic acid / hydrochloride (31) Melting point: 275 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 8.65 (s, 1H), 8.10 (b
r, 3H), 3.78-2.60 (m, 9H), 2.88 (s, 3H), 2.46-2.32 (m, 1
H), 2.14-2.03 (m, 1H), 1.78-1.70 (m, 1H), 1.28 (d, J = 6H
z, 3H)

Example 28 4- (Piperazin-1-yl) -5-fluoro-6-hydroxy-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido [3,2,1- ij] Cinnoline-8-carboxylic acid / hydrochloride (32) Melting point: 280-283 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 8.72 (s, 1H), 3.46 (b
rs, 4H), 3.41 (t, J = 6Hz, 2H), 3.26-3.24 (m, 4H), 2.95 (t, J
= 6Hz, 2H), 2.87 (s, 3H)

Example 29 4- (3-amino-3-methylpyrrolidin-1-yl)
-5-Fluoro-6-hydroxy-2,3-dihydro-
1-methyl-7-oxo-1H, 7H-pyrido [3,3
2,1-ij] Cinnoline-8-carboxylic acid / hydrochloride (33) Melting point: 238-242 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 8.66 (s, 1H), 8.49 (b
rs, 3H), 3.86-2.95 (m, 8H), 2.88 (s, 3H), 2.28-2.02 (m, 2
H), 1.51 (s, 3H)

Example 30 4- (cis-3-amino-4-methoxypyrrolidine-1)
-Yl) -5-fluoro-6-hydroxy-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido [3,2,1-ij] cinnoline-8-carboxylic acid hydrochloride ( 34) Melting point: 191-194 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 8.66 (s, 1H), 4.38-
2.64 (m, 10H), 3.40 (s, 3H), 2.89 (s, 3H)

Example 31 4- (3-Monomethylaminomethylpyrrolidin-1-yl) -5-fluoro-6-hydroxy-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido [3 , 2,1-ij] Cinnoline-8-carboxylic acid / hydrochloride (35) Melting point: 265-270 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 8.78 (br, 2H), 8.64
(s, 1H), 3.73-2.73 (m, 11H), 2.88 (s, 3H), 2.58 (s, 3H),
2.21-2.12 (m, 1H), 1.83-1.71 (m, 1H)

Example 32 4- (3-Aminoazetidin-1-yl) -5-fluoro-6-hydroxy-2,3-dihydro-1-methyl-
7-oxo-1H, 7H-pyrido [3,2,1-ij]
Cinnoline-8-carboxylic acid / hydrochloride (36) Melting point: 240 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 8.58 (s, 1H), 4.82-
4.74 (m, 2H), 4.54-4.48 (m, 2H), 4.12-3.61 (m, 3H), 2.88-
2.79 (m, 2H), 2.84 (s, 3H)

Example 33 4- {trans (-)-3-amino-4-methylpyrrolidin-1-yl} -5-fluoro-6-hydroxy-
2,3-dihydro-1-methyl-7-oxo-1H, 7
H-pyrido [3,2,1-ij] cinnoline-8-carboxylic acid / hydrochloride (37) Melting point: 230-235 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 8.67 (s, 1H) ), 8.28 (b
r, 3H), 3.92-2.80 (m, 9H), 2.85 (s, 3H), 2.46-2.35 (m, 1
H), 1.16 (d, J = 7Hz, 3H)

Example 34 4-{(3S) -3-aminopyrrolidin-1-yl}-
5-fluoro-6-hydroxy-2,3-dihydro-1
-Methyl-7-oxo-1H, 7H-pyrido [3,2,
1-ij] Cinnoline-8-carboxylic acid / hydrochloride (3
8) Melting point: 198 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 8.67 (s, 1H), 3.94-
2.74 (m, 9H), 2.89 (s, 3H), 2.32-2.20 (m, 1H), 2.10-1.95
(m, 1H)

Example 35 4-{(3R) -3-aminopyrrolidin-1-yl}-
5-fluoro-6-hydroxy-2,3-dihydro-1
-Methyl-7-oxo-1H, 7H-pyrido [3,2,
1-ij] Cinnoline-8-carboxylic acid / hydrochloride (3
9) Melting point: 202-207 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 8.67 (s, 1H), 3.93-
2.74 (m, 9H), 2.88 (s, 3H), 2.33-2.21 (m, 1H), 2.10-1.96
(m, 1H)

Example 36 4- (3-Dimethylaminopyrrolidin-1-yl) -5
-Fluoro-6-hydroxy-2,3-dihydro-1-
Methyl-7-oxo-1H, 7H-pyrido [3,2,1
-Ij] Cinnoline-8-carboxylic acid / hydrochloride (40) Melting point: 235-240 ° C (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 8.68 (s, 1H), 4.01-
2.78 (m, 9H), 2.89 (s, 3H), 2.82 (s, 6H), 2.46-2.21 (m, 2H)

Example 37 4- (3-monomethylaminopyrrolidin-1-yl)-
5-fluoro-6-hydroxy-2,3-dihydro-1
-Methyl-7-oxo-1H, 7H-pyrido [3,2,
1-ij] Cinnoline-8-carboxylic acid / hydrochloride (4
1) Melting point: 267-272 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 8.67 (s, 1H), 3.89-
2.84 (m, 9H), 2.89 (s, 3H), 2.63 (s, 3H), 2.39-2.08 (m, 2H)

Example 38 4- {3- (1'-monomethylamino) ethylpyrrolidin-1-yl} -5-fluoro-6-hydroxy-2,
3-dihydro-1-methyl-7-oxo-1H, 7H-
Pyrido [3,2,1-ij] cinnoline-8-carboxylic acid / hydrochloride (isomer B) (42) Melting point: 280-282 ° C (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 8.65 ( s, 1H), 8.58 (b
r, 2H), 3.80-2.62 (m, 10H), 2.89 (s, 3H), 2.57 (s, 3H), 2.
16-2.06 (m, 1H), 2.81-2.72 (m, 1H), 1.29 (d, J = 7Hz, 3H)

Example 39 4- {3- (1'-amino-1'-methyl) ethylpyrrolidin-1-yl} -5-fluoro-6-hydroxy-
2,3-dihydro-1-methyl-7-oxo-1H, 7
H-pyrido [3,2,1-ij] cinnoline-8-carboxylic acid / hydrochloride (43) Melting point: 203-208 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 8.65 (s, 1H) ), 8.16 (b
rs, 3H), 3.76-2.95 (m, 8H), 2.89 (s, 3H), 2.78-2.53 (m, 1
H), 2.09-1.78 (m, 2H), 1.31 (s, 6H)

Example 40 4- (3-Amino-4,4-dimethylpyrrolidine-1-
Yl) -5-Fluoro-6-hydroxy-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido [3,2,1-ij] cinnoline-8-carboxylic acid hydrochloride (44) ) Melting point: 157-162 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 8.65 (s, 1H), 8.37 (b)
r, 3H), 4.73-2.76 (m, 9H), 2.88 (s, 3H), 1.19 (s, 6H)

Example 41 4- {cis-2,8-diazabicyclo [4,3,0] nonan-8-yl} -5-fluoro-6-hydroxy-
2,3-dihydro-1-methyl-7-oxo-1H, 7
H-pyrido [3,2,1-ij] cinnoline-8-carboxylic acid / hydrochloride (45) Melting point: 200-205 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 9.38 (br, 1H ), 8.65
(s, 1H), 8.52 (br, 1H), 4.22-4.13 (m, 1H), 3.93-3.77 (m, 2
H), 3.62-3.18 (m, 5H), 3.03-2.92 (m, 2H), 2.89 (s, 3H),
2.76-2.62 (m, 1H), 1.84-1.63 (m, 5H)

Example 42 4-{(6S) -1,4-diazabicyclo [4,3,4]
0] nonan-4-yl} -5-fluoro-6-hydroxy-2,3-dihydro-1-methyl-7-oxo-1
H, 7H-pyrido [3,2,1-ij] cinnoline-8
-Carboxylic acid / hydrochloride (46) Melting point: 187-192 ° C (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 8.72 (s, 1H), 3.89-
2.91 (m, 13H), 2.87 (s, 3H), 2.21-1.91 (m, 3H), 1.77-1.60
(m, 1H)

Example 43 4- (cis-3,5-dimethylpiperazin-1-yl)
-5-Fluoro-6-hydroxy-2,3-dihydro-
1-methyl-7-oxo-1H, 7H-pyrido [3,3
2,1-ij] Cinnoline-8-carboxylic acid / hydrochloride (47) Melting point: 300 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 8.72 (s, 1H), 3.49-
3.16 (m, 8H), 2.99-2.92 (m, 2H), 2.88 (s, 3H), 1.28 (d, J = 6
(Hz, 6H)

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Shoji Yokomoto 1624 Shimodate, Koda-cho, Takada-gun, Hiroshima Prefecture Yukunaga Pharmaceutical Co., Ltd. In-house (72) Inventor Norihiro Hayashi 1624 Shimo-Koritsu, Koda-cho, Takada-gun, Hiroshima Prefecture Yunaga Pharmaceutical Co., Ltd.

Claims (2)

[Claims] 1. The following general formula (1): [In the formula, R ¹ represents a hydrogen atom or a carboxy protecting group,
R ² represents a lower alkyl group which may have a substituent, an optionally protected hydroxyl group or a nitro group,
R ³ represents a lower alkyl group which may have a substituent, X represents a halogen atom, Y represents a halogen atom or a cyclic amino group which may have a substituent] Compounds or salts thereof. 2. An antibacterial agent containing the tricyclic compound or its salt according to claim 1 as an active ingredient.