JPH10316570A - Tnf-alpha inductive effect inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a medicine capable of inhibiting effects, such as those of disorders associated with inflammation induced by TNF-α (tumor necrosis factor) and those of gene expression suppression by HIV, by including a carboxylic acid derivative as an active ingredient. SOLUTION: This inhibitor comprises a compound or its salt of the formula [R<1> is a 1-6C alkyl, halogen, aryl, etc.; R<2> is H, 1-6C alkylthio, etc.; R<3> is H, amino, a halogen, etc.; R<4> and R<6> is H, a 1-6C alkyl; R<5> is a halogen, 1-6C alkyl, etc.; X is H or a halogen; A is N or C-R<7> (R<7> is H, a halogen, etc.); (m) is 2 or 3; Y is OH or O-R<8> (R<8> is phenyl, etc.); (z) is C or N]. The compound of the formula is effective for the treatment of chronic rheumatoid arthritis, septic shock, ulcerative colitis, etc., and suppression of development of AIDS caused by accelerated replication and transcription of HIV gene.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to TNF-α (tumor necrosis factor), such as various phenomena observed during inflammation such as cell differentiation / activation, fever, and enhancement of HIV gene replication / transcription.
The present invention relates to a TNF-α-inducing effect inhibitor that inhibits various effects induced by NF.

[0002]

2. Description of the Related Art TNF-α is a cytokine mainly produced from cells such as macrophages and acts on various kinds of cells to induce antitumor activity by inhibiting or inhibiting the division of tumor cells, suppress hematopoiesis, and induce apoptosis. Etc., regulation of differentiation / proliferation, increase in viscosity of lymphocytes, bridging to the immune system by division of T lymphocytes, etc., pyrogenic factor, phospholipase A
2 causes various functions and biological phenomena such as inflammation and tissue repair by activation.

Among these functions, for example, with regard to inflammation, TNF-α acts on almost all cells involved in inflammation, and IL-6, IL-8, G-CSF, GM-CSF,
Induces production of cytokines such as M-CSF and cell adhesion molecules such as ICAM-1, and many other phenomena observed during inflammation, such as induction of production of prostaglandin E2, protease, acute phase protein, ACTH, etc. It is thought to be involved in differentiation / activation, bone resorption, synovial proliferation, etc. (Masatoshi Yamazaki: Cytokine 94-from basic to the latest information-; Japan Medical Center, 109-117 (1994))
etc).

On the other hand, TNF-α is AID of HIV-infected persons.
It has been pointed out that S may be deeply involved in the onset or extension of S. That is, when HIV infects a cell, it is first integrated into the DNA of the host cell and replicates its own gene from there. It is considered that cytokines such as TNF-α may promote the gene expression at that time. (Grut
ers, RA, Otto, SA, Al, BJM, Verhoeven,
AJ, Verweij, CL, Van Lier, RA, W., Miedam
a, F .: Fur. J. Immunol., 21, 167-172 (1991) and the like). In fact, persistently infected cells into which the HIV gene has been
It has been confirmed that treatment with NF-α markedly enhances the replication and transcription of the HIV gene (Butera, ST, F
olks, TM: AIDS Res. Hum. Retroviruses, 8, 991-9
95 (1992)).

[0005]

From the above findings, TN
Any compound that can selectively inhibit various cytokines and the like induced to be produced by F-α, TN
It is considered that F-α may be effective for inducing effects, for example, various diseases involving inflammation, suppression of gene expression of HIV, and the like.

Accordingly, an object of the present invention is to provide an inhibitor of the induction effect by TNF-α.

[0007]

Means for Solving the Problems In view of such circumstances, the present inventors have conducted intensive studies to achieve the above object, and as a result, a compound represented by the following general formula (1) or a salt thereof has been converted to TN
The present inventors have found that various effects induced by F-α are effectively inhibited, and completed the present invention.

That is, the present invention provides a compound represented by the general formula (1):

[0009]

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[Wherein, R ¹ is a linear or branched C _1-6 alkyl group which may have a substituent; a C _3-6 cyclic alkyl group which may have a substituent; Atom, C _1-6
An alkyl group, a C _1-6 alkyl group having a fluorine atom as a substituent, a C _1-6 alkoxyl group, a C _1-6 alkylthio group, a di (C _1-6 alkyl) amino-C _1-6 alkyl group,
_1-6 alkylamino-C _1-6 alkyl group, amino C _1-6 alkyl group, imidazolyl-C _1-6 alkyl group, pyrrolyl-C _1-6 alkyl group, (1,2,3-triazole-1
-Yl) -C _1-6 alkyl group, (1,2,3-triazol-2-yl) -C _1-6 alkyl group, (1,2,4-
A triazol-1-yl) -C _1-6 alkyl group, (1,
An aryl group optionally having a substituent selected from the group consisting of a 2,4-triazol-4-yl) -C _1-6 alkyl group and a (1-morpholyl) -C _1-6 alkyl group; or

A 5- or 6-membered heteroaromatic monocycle containing one or two heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, or a heteroaromatic in which these heteroaromatic monocycles are condensed with a benzene ring A heterocyclic substituent which is a condensed ring is shown, wherein the heterocyclic substituent is a halogen atom, C _1-6
It may have a substituent selected from the group consisting of an alkyl group, a C _1-6 alkyl group having a fluorine atom as a substituent, a C _1-6 alkoxyl group, and a C _1-6 alkylthio group:

R ² represents a hydrogen atom or a C _1-6 alkylthio group. This R ² and R ¹ may be integrated to form a cyclic structure including a part of the quinolone skeleton. Preferably, the ring may contain a sulfur atom as a ring constituent atom, and the ring may have a C _1-6 alkyl group as a substituent. Alternatively, R ² and Y may be integrated so as to form a cyclic structure including a part of the quinolone skeleton:

R ³ represents a hydrogen atom, an amino group, a C _1-6 alkyl group, a C _1-6 alkoxyl group, or a halogen atom, wherein the amino group is a formyl group, a C _1-6 alkyl group, And may have as substituents one or more groups selected from the group consisting of: and C _2-6 acyl groups: R ⁴ and R ⁶ represent a hydrogen atom or a C _1-6 alkyl group:

R ⁵ is selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a C _1-6 alkyl group having a fluorine atom as a substituent, a C _1-6 alkoxyl group, and a C _1-6 alkylthio group. A 5- or 6-membered heteroaromatic monocyclic ring containing one or two heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom; A heterocyclic substituent is a heteroaromatic condensed ring in which an aromatic condensed monocyclic ring and a benzene ring are condensed, and the heterosubstituent includes a halogen atom,
C _1-6 alkyl group, C having a fluorine atom as a substituent
_It may have a substituent selected from the group consisting of a _1-6 alkyl group, a C _1-6 alkoxyl group, and a C _1-6 alkylthio group: X represents a hydrogen atom or a halogen atom:

A is a nitrogen atom or formula (2)

[0016]

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(Wherein, R ⁷ represents a hydrogen atom, a halogen atom, or a C 7 which may have a halogen atom as a substituent.
_1-6 alkyl group, a halogen atom good C _{1 -6} alkoxy group as a substituent or one or two C _1-6 alkyl groups optionally aminomethyl group as a substituent, a Show.

This R ⁷ and the above R ¹ may be integrated so as to form a cyclic structure including a part of the quinolone skeleton, but this ring has an oxygen atom or a sulfur atom as a constituent atom of the ring. This ring may further have a C _1-6 alkyl group as a substituent. )); M represents an integer of 2 or 3;
Hydroxyl group or formula (3):

[0019]

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(Wherein R ⁸ represents a phenyl group, an acetoxymethyl group, a pivaloyloxymethyl group, an ethoxycarbonyl group, a choline group, a dimethylaminoethyl group, a 5-indanyl group, a phthalidinyl group, a 5-alkyl-2 -Oxo-1,3-dioxol-4-ylmethyl group, 3-acetoxy-2-oxobutyl group, C _1-6 alkyl group, C _1-6
And a phenylalkyl group comprising an alkoxy-methyl group or a C _1-6 alkylene group and a phenyl group. )
Shows;

Z represents a partial structure represented by a carbon atom or a nitrogen atom. Or a salt thereof as an active ingredient.

[0022]

BEST MODE FOR CARRYING OUT THE INVENTION The substituent of the compound represented by the general formula (1) having the ability to inhibit the TNF-α-inducing effect of the present invention will be described below. In the present specification, for example, a "C _1-6", indicating that the carbon number of 6 to 1.

The substituent R ¹ represents a linear or branched C _1-6 alkyl group, C _3-6 cyclic alkyl group, aryl group or heterocyclic substituent which may have a substituent. ,
Here, a linear or branched C _1-6 alkyl group and C
Examples of the substituent in the _1-6 cyclic alkyl group include a halogen atom and a hydroxyl group. Of these, a halogen atom is preferable, and a fluorine atom is particularly preferable. Also,
As the alkyl group, a methyl group and an ethyl group are preferable, and as the cyclic alkyl group, a cyclopropyl group is preferable. As the alkyl group having a substituent, a 2-fluoroethyl group, a 2-chloroethyl group and a 2,2,2-
A trichloroethyl group is preferable, and a 2-halogenocyclopropyl group is preferable as the cyclic alkyl group having a substituent.

The aryl group which may have a substituent is not particularly limited as long as it is a group derived from various aromatic hydrocarbon compounds, and the number of substituents on these aryl groups is 1 When there are a plurality of substituents, they may be all composed of the same species, or may be a mixture of a plurality of species. Further, these substituents may be present at any position on the aryl group. Examples of the substituent on the aryl group include a halogen atom, a C _1-6 alkyl group, a C _1-6 alkyl group having a fluorine atom as a substituent, a C _1-6 alkoxyl group,
_1-6 alkylthio group, di (C _1-6 alkyl) amino-C
_1-6 alkyl group, C _1-6 alkylamino -C _{1 -6} alkyl group, C _1-6 aminoalkyl group, imidazolyl -C _1-6 alkyl group, pyrrolyl -C _1-6 alkyl group, (1,2 , 3-
A triazol-1-yl) -C _1-6 alkyl group, (1,
2,3-triazol-2-yl) -C _1-6 alkyl group, (1,2,4-triazol-1-yl) -C _1-6
Alkyl group, (1,2,4-triazol-4-yl)
-C _1-6 alkyl group, and (1-morpholyl) -C
_1-6 alkyl group, and the like, of which preferably is a chlorine atom or a fluorine atom as a halogen atom, C _1-6
The alkyl group may be linear, branched or cyclic. A C atom having a fluorine atom as a substituent;
_1-6 alkyl group, C _1-6 alkoxyl group, C _1-6 alkylthio group, di (C _1-6 alkyl) amino-C _1-6 alkyl group, C _1-6 alkylamino-C _1-6 alkyl group , C _1-6 aminoalkyl group, imidazolyl-C _1-6 alkyl group, pyrrolyl-C _1-6 alkyl group, (1,2,3-triazol-1-yl) -C _1-6 alkyl group, (1 , 2,3-Triazol-2-yl) -C _1-6 alkyl group, (1,
2,4-triazol-1-yl) -C _1-6 alkyl group, (1,2,4-triazol-4-yl) -C _1-6
Similarly, the alkyl group and the respective alkyl moieties of the (1-morpholyl) -C _1-6 alkyl group may be linear, branched or cyclic. The two alkyl groups in the di (C _1-6 alkyl) amino-C _1-6 alkyl group may be the same or different.

The C _1-6 alkyl group having a fluorine atom as a substituent is preferably a straight-chain C _1-6 alkyl group having a fluorine atom. The number of fluorine atoms to be substituted is not particularly limited, but may be one in which all hydrogen atoms are substituted from monosubstitution, for example, monofluoromethyl group, difluoromethyl group, trifluoromethyl group, 2,2,2-trimethyl group, And a fluoroethyl group.

Di (C _1-6 alkyl) amino-C _1-6 alkyl group, C _1-6 alkylamino-C _1-6 alkyl group, C _1-6
Aminoalkyl group, imidazole-C _1-6 alkyl group,
Pyrrolyl-C _1-6 alkyl group, (1,2,3-triazol-1-yl) -C _1-6 alkyl group, (1,2,3-
A triazol-2-yl) -C _1-6 alkyl group, (1,
2,4-triazol-1-yl) -C _1-6 alkyl group, (1,2,4-triazol-4-yl) -C _1-6
In the alkyl group and the (1-morpholyl) -C _1-6 alkyl group, each substituent may be on any carbon atom of the alkyl group, but is more preferably on the terminal carbon atom of the alkyl group. . The alkyl moiety of these substituents is most preferably a methyl group.
_1-6 alkyl) aminomethyl group, C _1-6 alkylamino methyl group, aminomethyl group, imidazolylmethyl group, and the like as an example.

Examples of the aryl moiety in the optionally substituted aryl group include a phenyl group and a naphthyl group, and a phenyl group is preferred.

Of the aryl group which may have a substituent,
More preferred are, for example, a fluorine atom, a chlorine atom, a halogen atom such as a bromine atom, a C _1-6 alkyl group,
And a phenyl group which may be substituted by 1 to 3 substituents selected from the group of C _1-6 alkoxyl group and the like. Of these, a phenyl group, a 2-fluorophenyl group and a 4-fluorophenyl group And a 2,4-difluorophenyl group are particularly preferred.

The heterocyclic substituent is a 5- or 6-membered heteroaromatic monocyclic ring containing one or two heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, or a heteroaromatic ring thereof. A heterocyclic substituent is a heteroaromatic condensed ring in which an aromatic condensed monocyclic ring and a benzene ring are condensed.Examples include a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, and a furyl group. Thienyl group, oxazolyl group, thiazolyl group, isoxazolyl group, isothiazolyl group, oxadiazolyl group, thiadiazolyl group, benzoxazolyl group, benzothiazolyl group, benzoimidazolyl group and the like.

These heterocyclic substituents include a halogen atom,
C _1-6 alkyl group, C having a fluorine atom as a substituent
_It may have a substituent selected from the group consisting of a _1-6 alkyl group, a C _1-6 alkoxyl group, and a C _1-6 alkylthio group. Specific examples of the substituent on the heterocyclic substituent include those corresponding to each of the specific examples of the substituent used for R ¹ described above. The number of substituents on these heterocyclic substituents may be one or more. When there are a plurality of substituents, they may be the same or different.

In the general formula (1), R ² is a hydrogen atom or an alkylthio group having 1 to 6 carbon atoms, or R 2
¹ and R ² include a nitrogen atom to which R ¹ is bonded and a carbon atom to which R ² is bonded, and are integrated so as to form a cyclic structure including a part of the quinolone skeleton which is a mother nucleus. It may be. The ring thus formed may contain a sulfur atom as a ring constituent atom, and the ring may further comprise a C
_It may have a _1-6 alkyl group as a substituent. The ring formed here may be any one having a size of four to six members, and this ring may be saturated or unsaturated.

[0032] In the general formula (1), R ³ represents a hydrogen atom, an amino group, represents a C _1-6 alkyl group or a C _{1 -6} alkoxy group, an amino group of which formyl groups, C _{1 -6}
It may be substituted by one or more substituents selected from the group consisting of an alkyl group, a C _2-5 acyl group, and a halogen atom. Here, the C _1-6 alkyl group includes a linear or branched one, and preferably a methyl group,
An ethyl group, a normal propyl group and an isopropyl group. The alkyl moiety of the alkoxyl group may be the same as the alkyl group used for R ³ .

In the general formula (1), R ⁴ and R ⁶ represent a hydrogen atom or a C _1-6 alkyl group, and the C _1-6 alkyl group may be either a straight chain or a branched chain. A methyl group, an ethyl group, a normal propyl group or an isopropyl group is preferred. Note that R ⁴ and R ⁶ may be the same or different.

In the general formula (1), R ⁵ represents a nitro group, a hydroxyl group, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkyl group substituted by a fluorine atom, a C _1-6 alkoxyl group and a C _1-6 alkoxyl group. _{It represents a} phenyl group or a heterocyclic substituent which may be substituted by a substituent selected from the group consisting of _1-6 alkylthio groups. Here, the heterocyclic substituent may be either monocyclic or bicyclic. The monocyclic heterocyclic substituent has a 5- or 6-membered aromatic ring containing one or two hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. Examples include a substituent derived from a heterocyclic compound. Examples of the bicyclic heterocyclic substituent include a substituent derived from a bicyclic, aromatic heterocyclic compound formed by condensing the above monocyclic heterocyclic compound and a benzene ring. . Examples of these heterocyclic substituents include, for example, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a furyl group, a thienyl group, an oxazolyl group, a thiazolyl group, an isoxazolyl group, an isothiazolyl group, Examples thereof include an oxadiazolyl group, a thiadiazolyl group, a benzoxazolyl group, a benzothiazolyl group, and a benzimidazolyl group. Further, the heterocyclic group may have the same substituent as the phenyl group, and the number of substituents on the phenyl group or the heterocyclic group may be one or more. When there are groups, they may be the same or different. Further, these substituents may be present at any position on the phenyl group or the heterocyclic ring.

The halogen atom is a chlorine atom
And a fluorine atom or a fluorine atom is preferable. _1-6The alkyl group is
It may be straight or branched, but is preferably
Methyl, ethyl, normal propyl and isop
It is a ropyl group. Al having a fluorine atom as a substituent
The alkyl group is preferably a straight-chain alkyl group. Also replace
The number of fluorine atoms is not particularly limited.
Hydrogen atoms may be substituted, specifically,
Oromethyl group, difluoromethyl group, trifluoromethyl
A 2,2,2-trifluoroethyl group and the like.
You.

X is a halogen atom or a hydrogen atom. In the case of a halogen atom, a fluorine atom is preferable, and among these, a fluorine atom or a hydrogen atom is preferable.

A is a nitrogen atom or formula (2):

[0038]

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(R⁷Is the same as above)
Is shown. R⁷The halogen atom represented by
And fluorine atoms are preferred, and fluorine atoms are particularly preferred.
New C which may have a halogen atom as a substituent
_1-6Alkyl group or C_1-6Halo in alkoxyl group
As a gen atom, a fluorine atom or a chlorine atom is preferred.
And a fluorine atom is particularly preferred. A fluorine atom as a substituent
As an alkyl group or an alkoxyl group having
A linear alkyl group or alkoxyl group is preferred.
A fluorine atom on such an alkyl or alkoxyl group
Although there is no particular limitation on the number of
It may be replaced. Specifically, a monofluoromethyl group, diflu
Oromethyl group, trifluoromethyl group, 2,2,2-to
Fluoroalkyl group such as trifluoroethyl group; monoflu
Oromethoxy group, difluoromethoxy group, trifluoro
Methoxy group, trifluoromethoxy group, 2,2,2-to
Examples include fluoroalkoxy groups such as trifluoroethoxy groups.
Can be Furthermore, this R⁷And R¹Is R¹Are combined
Nitrogen atom and R⁷Including the carbon atom to which it is attached
In this way, the nucleus containing a part of the quinolone skeleton
Form a 7-membered ring from a sum, partially saturated or unsaturated 4-membered ring
And the ring may be an oxygen atom,
Including nitrogen or sulfur atoms as ring constituent atoms
In addition, this ring has an alkyl group having 1 to 6 carbon atoms.
You may have it as a substituent.

Y is a hydroxyl group or formula (3):

[0041]

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Is a substituent having the structure shown by
⁸ is a phenyl group, an acetoxymethyl group, a pivaloyloxymethyl group, an ethoxycarbonyl group, a choline group, a dimethylaminoethyl group, a 5-indanyl group, a phthalidinyl group, a 5-alkyl-2-oxo-1,3-dioxole -4-ylmethyl group, 3-acetoxy-2-oxobutyl group, C _1-6 alkyl group, C _1-6 alkoxy-methyl group,
And a substituent selected from the group consisting of a phenylalkyl group comprising a C _1-6 alkylene group and a phenyl group.

When A is a partial structure represented by the formula (2), in R ³ and R ⁷ of the formula (1), R ³ is selected from a hydrogen atom, an amino group, a hydroxyl group or a C _1-6 alkyl group.
R ⁷ is preferably a combination selected from a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxyl group and a halogenomethoxyl group. A more preferred combination is a case where R ³ is an amino group, a hydrogen atom, a hydroxyl group or a methyl group, and R ⁷ is a methyl group, a methoxyl group, a difluoromethoxyl group, a trifluoromethyl group, or a hydrogen atom.

Z is either a carbon atom or a nitrogen atom.

Preferred specific examples of the compound represented by the formula (1) used as an active ingredient in the TNF-α-inducing effect inhibitor of the present invention include compounds represented by the following formulas (4) to (7) or a compound thereof. Salts.

[0046]

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The compound of the formula (1) can be produced, for example, according to the following reaction formula.

[0048]

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Wherein X ′ is a leaving group such as a fluorine atom, a chlorine atom, a bromine atom, a C _1-3 alkylsulfonyl group, or an arylsulfonyl group such as a benzenesulfonyl group or a toluenesulfonyl group. Wherein Y ′ is the same as Y in the formula (1) or a compound represented by the formula (10):

[0050]

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(Wherein R ⁹ and R ¹⁰ represent a fluorine atom or a lower alkylcarbonyloxy group), and are R ¹ , R ² , R ³ , R ^3
4 , R ⁵ , R ⁶ , m, X and A are the same as described above]

That is, it can be produced by reacting the compound represented by the general formula (8) with the compound represented by the formula (9) or an acid addition salt thereof.

Y ′ is represented by the formula (3), wherein R ⁸ in the formula (3) is a C _1-6 alkyl group, a C _1-6 alkoxymethyl group,
In the case of a C _1-6 alkylene group or a phenyl group, conversion to the corresponding carboxylic acid is performed in the presence of an acid or a base used for hydrolysis of a usual carboxylic acid ester. By removing the protecting group under appropriate conditions corresponding to the above, the target compound represented by the formula (1) can be obtained.

In the compound of the formula (8), Y 'is a group represented by the formula (1)
In the case of the compound represented by formula (0), the compound can be converted to the corresponding carboxylic acid by reacting with the compound of formula (9) and then treating the compound with an acidic or basic compound.

The reaction of the compound of the formula (8) with the compound of the formula (9) can be carried out without solvent or in an inert solvent.
Here, examples of the inert solvent include dimethyl sulfoxide, pyridine, acetonitrile, triethylamine, ethanol, chloroform, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, water, and 3-methoxybutanol. Alternatively, these solvents may be used as a mixture.

The reaction temperature is usually in the range from room temperature to 200 ° C., preferably in the range from 25 ° C. to 150 ° C. The reaction time is 30 minutes to 48 hours, and is usually completed in about 30 minutes to 2 hours.

The reaction may be carried out with an acid acceptor such as an inorganic or organic base, for example, an alkali metal or alkaline earth metal carbonate or bicarbonate, or triethylamine, pyridine, 1,8-diazabicycloundecene and the like. It is advantageous to work in the presence of an organic basic compound.

The compound of the formula (1) may exist as an enantiomer or a diastereomer. When the compound of the present invention is administered to humans or animals, it is necessary to administer the compound consisting of a single enantiomer or diastereomer. Is preferred. Incidentally, the term "consisting of a single enantiomer or diastereomer" means not only a case where no other enantiomer or diastereomer is contained, but also a physical constant or a degree which does not affect the biological activity. It means that other enantiomers or diastereomers may be included.

The compound (1) may be in a free form, or as an acid addition salt of an inorganic acid or an organic acid or a salt of a carboxyl group. Examples of the acid addition salt include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, and phosphate, or acetate, methanesulfonate, and benzene. Organic acid salts such as sulfonate, toluene sulfonate, citrate, maleate, fumarate, lactate and the like can be mentioned.

Examples of the salt of the carboxyl group include alkali metal salts such as lithium salt, sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, ammonium salt, triethylamine salt and N salt.
-Methylglucamine salt, tris- (hydroxylmethyl) aminomethane salt and the like.

The free form, acid addition salt and carboxyl group salt of compound (1) may exist as hydrates.

On the other hand, the compounds of the present invention in which the carboxylic acid moiety is an ester are useful as synthetic intermediates and prodrugs. When used as a synthetic intermediate here, for example, alkyl esters, benzyl esters, alkoxyalkyl esters, phenylalkyl esters, phenyl esters, and the like are preferable.

When used as a prodrug,
Esters which are easily cleaved in the living body to produce a free form of carboxylic acid are preferred, and include, for example, acetoxymethyl ester, pivaloyloxymethyl ester, ethoxycarbonyl ester, choline ester, dimethylaminoethyl ester, 5-yne Preferred are oxoalkyl esters such as danyl ester, phthalidinyl ester, 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl ester, and 3-acetoxy-2-oxobutyl ester.

Compound (1) has a TNF-α-inducing effect inhibitory effect, and various diseases associated with inflammation caused by TNF-α, such as rheumatoid arthritis, septic shock, ulcerative colitis, etc. Or, it is effective for the onset of AIDS due to promotion of the replication and transcription of the HIV gene.

The compound (1) also has an inhibitory action on ICAM-1 production caused by TNF-α, and inhibits various cell adhesions. For example, it is useful as a therapeutic agent for inflammatory diseases such as rheumatoid arthritis and arthritis, ischemia-reperfusion injury of myocardium, bronchial asthma, glomerulonephritis, rejection at the time of organ transplantation, and the like.

When compound (1) is used as a TNF-α-inducing effect inhibitor, the dose varies depending on the age, sex, symptoms, etc. of the patient, but is in the range of 5 mg to 2 g, preferably 50 mg to 1000 mg per day for an adult. It is preferred that
In this case, the daily dose may be administered once a day, or may be divided into two or three times a day, and the daily dose may exceed the above-mentioned amount if necessary.

The TNF-α-inducing effect inhibitor containing the compound (1) is not particularly limited in its administration method and dosage form, and may be used in the preparation of various commonly used preparations according to its administration method. It just needs to be a mold.

Examples of oral preparations include tablets, powders,
Examples include granules, capsules, solutions, syrups, elixirs, and oily or aqueous suspensions.

As an injection, a solution prepared by putting the solution in a container and then freeze-drying or the like may be prepared as a solid preparation at the time of use, and a stabilizer, a preservative and a solubilizing agent may be used as necessary. Also, it may be stored in a container for each dose,
Also, multiple doses may be stored in the same container.

Examples of external preparations include solutions, suspensions, emulsions, ointments, gels, creams, lotions, sprays and the like.

Solid preparations include pharmaceutically acceptable additives together with the active compound, such as fillers, extenders, binders, disintegrants, dissolution enhancers, wetting agents, lubricants And the like can be selected and mixed as needed to form a formulation.

Examples of the liquid preparation include solutions, suspensions, and emulsions, and may contain a suspending agent, an emulsifier, and the like as additives.

[0073]

EXAMPLES Next, the present invention will be described in more detail by way of examples, but the present invention is not limited to the following examples.

Example 1 8-difluoromethoxy-1,4-dihydro-6-fur
Oro-1- (trans-2-fluorocyclopropyl)
-7- [4- (2-methoxyphenyl) -1-piperazine
Nyl] -4-oxoquinoline-3-carboxylic acid (4)
Synthesis

[0075]

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8-Difluoromethoxy-1,4-dihydro-6,7-difluoro-1- (trans-2-fluorocyclopropyl) -4-oxoquinoline-3-carboxylic acid (1-8) (100 mg, 0 .286 mmol), 1-
(2-methoxyphenyl) piperazine (1-9) (11
0 mg, 0.572 mmol), triethylamine (0.25
ml) and acetonitrile (5 ml) were mixed and heated under reflux for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was crystallized from ethanol and collected by filtration to give 83.3 mg of the title compound (4) as colorless crystals. Physical properties of compound (4) obtained are as described below.

Melting point: 218-220 ° C.¹ H-NMR (CDCl_Three) Δ: 1.42-1.50 (1
H, m), 1.90-2.01 (1H, m), 3.16
-3.30 (4H, m), 3.50-3.37 (2H,
m), 3.69-3.76 (2H, m), 3.91 (3
H, s, -OCH _Three), 4.43-4.50 (1H,
m, N-CH), 4.64 (1H, dm, J = 61H)
z, -CHF-), 6.61 (1H, dd, J = 77H)
z, 72Hz, -OCHF_Two), 6.91-7.22
(4H, m, aromatic H), 8.07 (1
H, d, J = 12 Hz), 8.71 (1H, s, H-
2), 14.34 (1H, broad, -COOH) Elemental analysis: C_{twenty five}H_{twenty three}F_FourN_ThreeO_FiveCalculated value: C, 57.58; H, 4.45; N, 8.06 Analytical value: C, 57.37; H, 4.51; N, 7.90

Reference Example 1 3,4-dehydro-4-phenylpiperidine (A-9)
Synthesis of

[0079]

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4-Hydroxy-4-phenylpiperidine (497 mg, 2.80 mmol) was dissolved in toluene (50 ml), and p-toluenesulfonic acid monohydrate (800 mg,
4.21 mmol), and the mixture was heated under reflux for 23 hours to dehydrate. The reaction solution was evaporated to dryness under reduced pressure, 1N aqueous sodium hydroxide solution (50 ml) was added to the residue, and the mixture was extracted with chloroform (2.
× 50 ml). The organic layer was washed with saturated saline (2 × 50 ml), dried over anhydrous sodium sulfate, and evaporated to remove the solvent.
47 mg (quantitative) of the title compound (A-9) were obtained as a pale yellow oil. Physical properties of obtained compound (A-9) are as described below.

¹ H-NMR (CDCl ₃ ) δ: 2.47
_{(2H, m, -CH 2 -} ), 3.11 (2H, t, J =
_{6Hz, -CH 2 -), 3.53} (2H, m, -CH
_{2 -), 6.14 (1H,} m, = CH -), 7.22-
7.40 (H, m, aromaticH)

Reference Example 2 Synthesis of 4-phenylpiperidine (B-9)

[0083]

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3,4-dehydro-4-phenylpiperidine (447 mg, 2.81 mmol), ethanol (50 m
l) 5% palladium on carbon (325 mg) was mixed and stirred at room temperature under a 1 atm hydrogen atmosphere for 15 hours. The catalyst was removed by filtration, and the filtrate was dried under reduced pressure to give 425 mg (94%) of the title compound (B-9) as colorless crystals. Physical properties of compound (B-9) obtained are as described below.

¹ H-NMR (CDCl ₃ ) δ: 1.60
1.75 (2H, m), 2.58-2.66 (1H,
m), 2.72-2.78 (2H, m), 3.18-
3.21 (2H, m), 7.18-7.32 (5H,
m)

Example 2 6-Fluoro-1-methyl-4-oxo-7- (4-f
Enyl-1-piperidinyl) -8-trifluoromethoxy
1,4-dihydroquinoline-3-carboxylic acid (2-
Synthesis of 1)

[0087]

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6,7-Difluoro-1-methyl-4-oxo-8-trifluoromethyl-1,4-dihydroquinoline-3-carboxylic acid (2-8) (87.2 mg, 0.2
84 mmol; JP-A-8-183775), 4-phenylpiperidine (B-9) (68.6 mg, 0.425 mmol)
l), triethylamine (119 μl, 0.852 mmol)
l) and acetonitrile (4 ml) were mixed and heated under reflux for 17 hours. The reaction solution was allowed to cool, and the precipitated crystals were collected by filtration and recrystallized from ethanol to give 64.2 mg (50%) of the title compound (2-1) as colorless crystals. Physical properties of compound (2-1) obtained are as described below.

Melting point: 268.5-270 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.97 (4H, bro
_{ad, 2 × -CH 2 -)} , 2.79-2.87 (1H,
m), 3.79 (2H, broad d, J = 12.7)
_{Hz, -CH 2 -), 4.02} (2H, broad, -
_{CH 2 -), 7.23-7.37 (5H} , m, arom
atic H), 8.16 (1H, d, J = 12 Hz,
H-5), 8.63 (1H, s, H-2), 14.63
(1H, broad, -COOH) IR: ν _max (KBr): 1734, 1618, 1488 (cm
^-1 ) Elemental analysis: as C ₂₃ H ₂₀ F ₄ N ₂ O ₃ .1 / 4H ₂ O Calculated: C, 60.99; H, 4.56; N, 6.19 Analysis: C, 60 .94; H, 4.63; N, 6.24

Example 3 7- (3,4-Dehydro-4-phenyl-1-piperidi)
Nyl) -1,4-dihydro-6-fluoro-1-methyl
-8-trifluoromethyl-4-oxoquinoline-3-
Synthesis of carboxylic acid (5)

[0091]

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6,7-Difluoro-1-methyl-4-oxo-8-trifluoromethyl-1,4-dihydroquinoline-3-carboxylic acid (2-8) (90 mg, 0.293)
mmol), 3,4-dehydro-4-phenylpiperidine (A-9) (70 mg, 0.44 mmol), triethylamine (0.08 ml), and acetonitrile (5 ml) were mixed,
The mixture was heated under reflux for 12 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1). The obtained crude crystals were recrystallized from ethanol to give 15 mg (11%) of the title compound (5). Was obtained as pale yellow crystals. Compound (5) obtained
Are as follows.

Melting point: 227.5-229 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.79 (2H, bs,
_{-CH 2 -), 3.78 (2H} , bs, -CH 2 -),
_{4.03 (3H, s, -CH 3} ), 4.20 (2H, b
_{s, -CH 2 -), 6.12} (1H, bs), 7.25
−7.45 (5H, m, Ar), 8.16 (1H, d,
J = 12 Hz, H-5), 8.60 (1H, s, H-)
2), 14.6 (1H, s, COOH) IR: ν _max (KBr): 1762, 1734, 1620, 1
562 (cm ^-1 ) Elemental analysis: C ₂₃ H ₁₈ F ₄ N ₂ O ₃ Calculated: C, 61.88; H, 4.06; N, 6.28 Analysis: C, 61.74; H, 4.14; N, 6.24

Example 4 8-Difluoromethoxy-1,4-dihydro-6-fur
Oro-7- (4-phenyl-1-piperidinyl) -1-
[4- (1,2,4-triazol-1-yl) methyl
Phenyl] -4-oxoquinoline-3-carboxylic acid
Synthesis of (6)

[0095]

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8-Difluoromethoxy-1,4-dihydro-6,7-difluoro-1- [4- (1,2,4-triazol-1-yl) methylphenyl] -4-oxoquinoline-3-carboxylic acid Acid (4-8) (81.1 mg,
0.181 mmol; DE-A-4425659), 4-
Phenylpiperidine (B-9) (43.7 mg, 0.27
1 mmol), triethylamine (50 ml, 0.362 mmol)
l) and acetonitrile (3 ml) were mixed and heated under reflux for 24 hours. The reaction solution was cooled on ice, and the precipitated crystals were collected by filtration.
The filtrate was concentrated and the residue was crystallized from ethanol and collected by filtration. The collected crystals were collected and recrystallized from ethanol to give 38.6 mg (35%) of the title compound (6) as colorless crystals. Physical properties of compound (6) obtained are as described below.

Melting point: 180-183 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.80 (2H, m, −
CH ₂ —), 1.93 (2H, m, —CH ₂ —), 2.6
9 (1H, m, -CHPh-), 3.26 (2H, m,
_{-CH 2 -), 3.44 (2H} , m, -CH 2 -), 5.
_{48 (2H, s, -CH 2} -), 6.21 (1H, t,
_{J = 75Hz, -OCHF 2),} 7.21-7.26
(2H, m, aromatic H), 7.31-7.
36 (2H, m, aromatic H), 7.43
(1H, d, aromatic H), 8.03 (1
H, s, triazole H), 8.13 (1H,
d, J = 12 Hz, H-5), 8.14 (1H, s, t)
riazole H), 8.62 (1H, s, H-2) IR: ν _max (KBr): 1730, 1622, 1600, 1
504 (cm ^-1 ) Elemental analysis: C ₃₁ H ₂₆ F ₃ N ₅ O ₄ .3 / 4H ₂ O Calculated: C, 61.74; H, 4.58; N, 11.61 Analytical: C, 61.78; H, 4.87; N, 11.01

Reference Example 3 Methyl 3-ethenyl-2,4,5-trifluoroben
Synthesis of Zoate (C)

[0099]

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To a mixture of tetrakistriphenylphosphine palladium (6.18 g), lithium chloride (25.9 g) and anhydrous dioxane (500 ml) was added methyl 2,4,4.
5-trifluoro-3-trifluoromethanesulfonyloxybenzoate (C ') (57.37 g, 0.17
0 mmol) and a solution of tetravinyltin (33.6 ml) in anhydrous dioxane (500 ml) were added dropwise over 15 minutes under a nitrogen atmosphere, and the mixture was heated under reflux for 15 hours. The reaction solution was concentrated under reduced pressure,
An aqueous potassium fluoride solution (1 liter) was added to the residue, followed by ether extraction (3 × 500 ml). The extract was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was applied to a silica gel column and eluted with n-hexane-ethyl acetate (98: 2) to obtain a fraction containing the desired product. Distillation under reduced pressure gave 21.8 g (59%) of a colorless oil (C) having a boiling point of 82 ° C./2 mmHg. Physical properties of compound (C) obtained are as described below.

¹ H-NMR (CDCl ₃ ) δ: 3.93
(3H, s, COOCH ₃ ), 5.73 (1H, d, J
= 11 Hz, CH = CHcisH), 6.12 (1H,
d, J = 18 Hz, CH = CHtransH), 6.7.
0 (1H, dd, J = 11, 18 Hz, CH = C
H ₂ ), 7.65 (1H, ddd, J = 6, 9, 10H)
z, H-6)

Reference Example 4 Methyl 3-formyl-2,4,5-trifluoroben
Synthesis of Zoart (D)

[0103]

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Methyl 3-ethenyl-2,4,5-trifluorobenzoate (C) (21.8 g, 0.101)
mol) was dissolved in methanol (500 ml), cooled to -78 ° C, and ozone was blown for 2 hours. Excess ozone is removed by bubbling nitrogen gas, and dimethyl sulfide (14 m
l) was added and the temperature was raised to room temperature. After further adding dimethyl sulfide (14 ml) and stirring for 30 minutes, the reaction solution was concentrated under reduced pressure. Water (500 ml) was added to the residue, and the mixture was extracted with ether (500 ml). The extract is water (300 ml),
The extract was washed with saturated saline (2 × 300 ml), dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 21.4 g of a pale yellow oil containing the compound (D). This is -CHO +
It is a mixture of -OTf (3: 2). The physical properties of the obtained mixture are as follows.

¹ H-NMR (CDCl ₃ ) δ: 3.98
_{(3H, s, -COOCH 3)} , 8.04 (1H, dd
d, J = 7, 9, 9 Hz, H-6), 10.35 (1
H, s, -CHO)

Reference Example 5 2,3,6-trifluoro-5-methoxycarbonyl ammonium
Synthesis of benzoic acid (E)

[0107]

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Methyl 3-formyl-2,4,5-trifluorobenzoate (D) (21.2 g) and 2-methyl-2-butene (156 ml) were added to tert-butanol (50 ml).
0 ml), and an aqueous solution (200 ml) of NaClO ₂ (15.6 g) and sodium dihydrogen phosphate (15.6 g).
Was added dropwise over 20 minutes, and the mixture was further stirred at room temperature for 1 hour. 2-methyl-2-butene in the reaction solution was distilled off under reduced pressure,
Tertiary butanol was distilled off under reduced pressure using a vacuum pump. Saturated aqueous sodium bicarbonate (200 ml) was added to the residue, and the mixture was washed with dichloromethane (3 × 200 ml). The aqueous layer was adjusted to pH 2 with concentrated hydrochloric acid and extracted with ethyl acetate (300 ml + 200 ml). The organic layer was washed with 5% sodium thiosulfate (Na ₂ S ₂ O ₃ , 2 × 2
After washing with water (2 × 250 ml) and drying over anhydrous sodium sulfate, the solvent was distilled off to obtain 9.31 g of the title compound (E) as colorless crystals. Physical properties of compound (E) obtained are as described below.

Melting point: 94-99 ° C. ¹ H-NMR (CDCl ₃ ) δ: 3.96 (3H, s,-
_{COOCH 3), 7.94 (1H,} ddd, J = 6.3
5, 8.79, 9.76 Hz, H-6)

Reference Example 6 3-carbamoyl-2,4,5-trifluorobenzoic acid
Synthesis of methyl ester (F)

[0111]

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2,3,6-trifluoro-5-methoxycarbonylbenzoic acid (E) (2.21 g, 9.77 mmol)
l), dimethylformamide (catalytic amount, 2 drops) was dissolved in dichloromethane (40 ml), and oxalyl chloride (2.56 ml, 29.3 mmol) was added dropwise over 5 minutes.
Stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ether (30 ml). 28% aqueous ammonia (5 ml) was added to the ether solution under ice-cooling, followed by stirring for 10 minutes (crystal precipitation). The reaction solution was concentrated under reduced pressure, and the crystals were collected by filtration. The crystals were dissolved in dichloromethane, dried over anhydrous sodium sulfate, and the solvent was distilled off. The remaining crystals were washed with isopropyl ether to give 1.74 g (76%) of the title compound (F) as colorless crystals. Compound (F) obtained
Are as follows.

Melting point: 145 ° -147 ° C. ¹ H-NMR (CDCl ₃ ) δ: 3.95 (3H, s, −
COOCH ₃ ), 6.00 (broad s, -CON)
H ₂ ), 7.88 (1H, ddd, J = 7, 9, 9H)
z, H-6)

Reference Example 7 Methyl 3-cyano-2,4,5-trifluorobenzoate
Synthesis of ester (G)

[0115]

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3-carbamoyl-2,4,5-trifluorobenzoic acid methyl ester (F) (1.72 g, 7.
38 mmol) and pyridine (1.49 ml, 18.4 mmol) were dissolved in 1,4-dioxane (20 ml), and trifluoroacetic anhydride (1.15 ml, 8.11 mmol) was added under ice-cooling. After stirring at room temperature for 4 hours, pyridine (1.49 ml,
18.4 mmol), trifluoroacetic anhydride (1.15 ml,
8.11 mmol), and the mixture was further stirred for 13 hours. The reaction solution was washed with 2N hydrochloric acid (2 × 50 ml), water (50 ml), saturated aqueous sodium bicarbonate (50 ml) and water (50 ml), dried over anhydrous sodium sulfate, and evaporated to remove the solvent, thereby obtaining 1.04 g (66%). ) Was obtained as a pale yellow solid. Physical properties of compound (G) obtained are as described below.

Melting point: 42-44 ° C. ¹ H-NMR (CDCl ₃ ) δ: 3.98 (3H, s,-)
COOCH ₃ ), 8.08 (1H, ddd, J = 6).
9,10Hz, H-6)

Reference Example 8 3-cyano-2,5-difluoro-4- [4- (2-meth
Toxiphenyl) -1-piperazinyl] methyl benzoate
Synthesis of ester (H)

[0119]

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3-Cyano-2,4,5-trifluorobenzoic acid methyl ester (G) (3.11 g, 14.5 mm)
ol), 1- (2-methoxyphenyl) piperazine (2.
98 g, 15.5 mmol), triethylamine (3.29)
ml, 21.7 mmol) with dimethyl sulfoxide (15 ml)
And stirred at room temperature for 2 hours. Water (300
ml) and extracted with ethyl acetate (200 ml + 2 × 100 ml). The organic layer was washed with water (3 × 150 ml), dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was washed with isopropyl ether to give 5.18 g (92%) of the title compound (H) as pale yellow crystals. Physical properties of compound (H) obtained are as described below.

Melting point: 130-134 ° C. ¹ H-NMR (CDCl ₃ ) δ: 3.22-3.24 (4
_{H, m, -CH 2 - ×} 2), 3.73-3.75 (4
_{H, m, -CH 2 - ×} 2), 3.89 (3H, s, -O
_{CH 3), 3.93 (3H,} s, -COOCH 3), 6.
94-6.98 (3H, m, aromatic H),
7.02-7.06 (1H, m, aromatic
H), 7.76 (1H, dd, J = 6.8, 13 Hz,
H-6) IR: ν _max (KBr): 1730, 1710 (cm ⁻¹ ) Elemental analysis: C ₂₀ H ₁₉ F ₂ N ₃ O ₃ Calculated: C, 62.01; H, 4.94; N, 10.89 Analytical value: C, 61.77; H, 5.00; N, 10.65

Reference Example 9 3-Aminomethyl-2,5-difluoro-4- [4-
(2-methoxyphenyl) -1-piperazinyl] benzoate
Synthesis of acid methyl ester (I)

[0123]

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3-cyano-2,5-difluoro-4-
[4- (2-methoxyphenyl) -1-piperazinyl]
Benzoic acid methyl ester (H) (5.18 g, 13.4
mmol), Raney nickel (20 ml), ethanol (20
0 ml) and stirred under a 1 atm hydrogen atmosphere for 23 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was washed with isopropyl ether to obtain 4.08 g (78%) of colorless crystals. The mother liquor was dried under reduced pressure to give 683 mg (13%) of the title compound (I) as colorless crystals. The physical properties of the obtained compound (I) are as follows.

Melting point: 115-116 ° C. ¹ H-NMR (CDCl ₃ ) δ: 3.20 (4H, bro
_{ad s, -CH 2 - × 2} ), 3.38 (4H, m, -
CH ₂ − × 2), 3.89 (3H, s, —OCH ₃ ),
_{3.92 (3H, s, -COOCH 3} ), 4.00 (2
H, d, J = 2Hz, -CH 2 NH 2), 6.88-7.
03 (4H, m, aromatic H), 7.53
(1H, dd, J = 6.8, 12Hz, H-6)

Reference Example 10 3-tert-butoxycarbonylaminomethyl-2,5-
Difluoro-4- [4- (2-methoxyphenyl) -1
-Piperazinyl] benzoic acid methyl ester (J)

[0127]

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3-Aminomethyl-2,5-difluoro-
4- [4- (2-methoxyphenyl) -1-piperazinyl] benzoic acid methyl ester (I) (4.71 g, 1
2.0 mmol) was dissolved in tetrahydrofuran (150 ml), and a solution of Boc ₂ O (2.63 g, 12.0 mmol) in tetrahydrofuran (30 ml) was added dropwise.
Stirred for hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography, and eluted with chloroform to obtain 6.01 g (quantitative) of the title compound (J) as a colorless amorphous. Physical properties of compound (J) obtained are as described below.

¹ H-NMR (CDCl ₃ ) δ: 1.43
(9H, s, -COOC (CH 3) 3) 3.23 (4H,
_{broad s, -CH 2 - × 2} ), 3.34 (4H,
broad s, —CH ₂ — × 2), 3.89 (3H,
_{s, -OCH 3), 3.92 (} 3H, s, -COOC
_{H 3), 4.55 (2H,} broad, -CH 2 NHBo
c), 5.06 (1H, broad, -NHBoc),
6.88-7.05 (4H, m, aromatic
H), 7.57 (1H, dd, J = 6.8, 12 Hz,
H-6)

Reference Example 11 3-tert-butoxycarbonylaminomethyl-2,5-
Difluoro-4- [4- (2-methoxyphenyl) -1
Synthesis of [piperazinyl] benzoic acid (K)

[0131]

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3-tert-butoxycarbonylaminomethyl-2,5-difluoro-4- [4- (2-methoxyphenyl) -1-piperazinyl] benzoic acid methyl ester (J) (6.01 g, 12.2 mmol) ) With methanol (2
00 ml) and a 1N aqueous solution of sodium hydroxide (1 ml).
8.3 ml) and stirred at room temperature for 17 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water (100 ml). 1
Acidify with 0% citric acid aqueous solution, and add ethyl acetate (200m
Extracted in l). The organic layer was washed with water (2 × 200 ml) and dried over anhydrous sodium sulfate.
(97%) of the title compound (K) was obtained as a colorless amorphous. Physical properties of compound (K) obtained are as described below.

¹ H-NMR (CDCl ₃ ) δ: 1.44
(9H, s, -COOC (CH 3) 3), 3.22 (4
_{H, broad s, -CH 2 -} × 2), 3.38 (4
_{H, broad s, -CH 2 -} × 2), 3.89 (3
_{H, s, -OCH 3),} 4.55 (2H, broad
_{s, -CH 2 NHBoc), 5.10} (1H, broa
ds, -NHBoc), 6.88-7.05 (4H,
m, aromatic H), 7.64 (1H, dd,
J = 6.8, 12 Hz, H-6)

Reference Example 12 Ethyl 3-tert-butoxycarbonylaminomethyl-
2,5-difluoro-4- [4- (2-methoxyphenyi
L) -1-piperazinyl] benzoylacetaate
Synthesis of (L)

[0135]

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Magnesium (0.340 g, 14.0 mm
ol) and ethanol (50 ml) were added, carbon tetrachloride (0.5 ml) was added, and the mixture was stirred at room temperature for 1 hour. Ethyl hydrogen malonate (1.85 g, 14.0 mmol)
Was added dropwise and stirred at room temperature for 2 hours. The reaction solution was dried under reduced pressure, and the residue was dissolved in tetrahydrofuran (150 ml). 3-tert-butoxycarbonylaminomethyl-2,5-difluoro-4
-[4- (2-Methoxyphenyl) -1-piperazinyl] benzoic acid (K) (5.57 g, 11.7 mmol) was dissolved in tetrahydrofuran (80 ml), and N, N'-carbonyldiimidazole (2.08 g) was dissolved. , 12.8 mmol) and stirred at room temperature for 6 hours. To this was added dropwise a solution of ethyl hydrogen malonate magnesium salt in tetrahydrofuran, and the mixture was stirred at room temperature for 16 hours. The reaction solution was evaporated to dryness under reduced pressure, and chloroform (200 ml) and a 10% aqueous citric acid solution (200 ml) were added to the residue, followed by stirring. The organic layer was separated, and the aqueous layer was extracted with chloroform (100 ml). The combined organic layer was washed with water (200 ml), dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (3: 1) to give 3.58 g (56%) of the title compound (L) as a pale yellow amorphous. Physical properties of compound (L) obtained are as described below.

[0137] _{^{1 H-NMR (CDCl 3)}} δ: keto-form (4: 1) enol-form -CH 2 C H 3 1.28 (t, J = 7.3Hz) 1.26 (t, J = 7.3H z) - COOC (CH ₃ ) ₃ 1.44 (s) -CH _2- × 2 3.22 (broad s) -CH _2- × 2 3.36 (broad s) -OCH ₃ 3.89 (s) -COCH ₂ COOEt 3.96 (d, J = 3.5 _{Hz) -C H 2 CH 3 4.22} (q, J = 7.3Hz) 4.26 (q, J = 7.3Hz) -C H 2 NHBoc 4.53 (broad s) -NHBoc 5.70 (broad s) -C (OH) = C H COOEt 5.87 (s) aromatic H 6.88-7.03 (m) H-6 7.50-7.60 (m) -C (O H) = CHCOOEt 12.66 (s)

Reference Example 13 Ethyl 2- [3-tert-butoxycarbonylaminomethyl
Tyl-2,5-difluoro-4- [4- (2-methoxy
Phenyl) -1-piperazinyl] benzoyl] -3-me
Synthesis of tylamino acrylate (M)

[0139]

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Ethyl 3-tert-butoxycarbonylaminomethyl-2,5-difluoro-4- [4- (2-methoxyphenyl) -1-piperazinyl] benzoylacetaate (L) (703 mg, 1.28 mmol) Was dissolved in benzene (30 ml), and dimethylformamide dimethyl acetal (0.852 ml, 6.42 mmol) was added to give 1
Reflux with heating for hours. Dimethylformamide Dimethyl acetal (0.852 ml, 6.42 mmol) was added, and the mixture was further heated under reflux for 2.5 hours, and then the solvent was distilled off. The residue was dissolved in toluene and methylamine hydrochloride (402 m
g, 4.93 mmol), triethylamine (1.03 ml,
7.39 ml) and stirred at room temperature for 17 hours. The reaction solution was washed with water (50 ml), dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was applied to a flash column and eluted with n-hexane-ethyl acetate (1: 1) to give 643 mg (8
6%) of the title compound (M) was obtained as a colorless amorphous. Physical properties of compound (M) obtained are as described below.

¹ H-NMR (CDCl ₃ ) δ: (EZ mixture) —CH ₂ CH ₃ 1.02 (t, J = 7.3 Hz) 0.87 (t, J = 7.3 Hz) —COOC (CH ₃ ) ₃ 1.57 (s _{) -CH 2 - × 4 3.0-3.5 (} broad) -OCH 3 3.89 (s) -C H 2 CH 3 4.03 (q, J = 7.3Hz) 3.98 (q, J = 7.3Hz) -C H 2 NHBoc 4.51 (broad) -NHBoc 5.14 (broad) = CHNHMe 5.87 (s) aromatic H 6.87-7.11 (m) H-6 8.09 (d, J = 14Hz) 8.06 (d, J = 14Hz) -NHMe 10.79 (broad) 9.28 ( broad)

Example 5 Ethyl 8-tert-butoxycarbonylaminomethyl-
1,4-dihydro-6-fluoro-7- [4- (2-meth
Toxiphenyl) -1-piperazinyl] -1-methyl-
4-oxoquinoline-3-carboxylate (5-1)
Synthesis of

[0143]

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A) Ethyl 2- [3-tert-butoxycarbonylaminomethyl-2,5-difluoro-4- [4
-(2-methoxyphenyl) -1-piperazinyl] benzoyl] -3-methylaminoacrylate (M) (64
3 mg, 1.09 mmol) in dimethylformamide (10 m
l) and dissolved in 60% sodium hydride (88 mg, 2.
20 mmol) and stirred for 20 minutes. The reaction solution was poured into ice water (100 ml), and the precipitated crystals were collected by filtration. The precipitate was dissolved in chloroform, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with chloroform to obtain 248 mg of a yellow amorphous substance (structure unknown). Chloroform-
Elution with methanol (95: 5), 187 mg (30%)
The title compound (5-1) was obtained as colorless crystals. Physical properties of compound (5-1) obtained are as described below.

Melting point: 178-181 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.43 (3H, t, J
_{= 7.3Hz, -CH 2 CH 3)} , 1.56 (9H, s,
_{-COOC (CH 3) 3),} 2.9-3.8 (8H, br
_{oad, -CH 2 - × 4)} , 3.90 (3H, s, -O
CH ₃ ), 4.06 (3H, s, N ₁ -CH ₃ ), 4.4
0 (2H, q, J = 7.3Hz, -CH 2 CH 3), 4.
78 (2H, d, J = 4.4Hz, -CH 2 NHBo
c), 4.90 (1H, broad, -NHBoc),
6.90-7.04 (4H, m, aromatic
H), 8.20 (1H, d, J = 12 Hz, H-5),
8.42 (1H, s, H-2) (AX02563A) IR: ν _max (KBr): 3280, 3072, 1728, 1
698, 1620 (cm ^-1 ) Elemental analysis: as C ₃₀ H ₃₇ FN ₄ O ₆ Calculated: C, 63.37; H, 6.56; N, 9.85 Analytical: C, 62.95; H, 6.59; N, 9.43

B) Ethyl 2- [3-tert-butoxycarbonylaminomethyl-2,5-difluoro-4- [4
-(2-methoxyphenyl) -1-piperazinyl] benzoyl] -3-methylaminoacrylate (M) (1.
04 g, 1.77 mmol) in dimethylformamide (30
dissolved in potassium carbonate (488 mg, 3.53 mmol).
l) was added and the mixture was stirred at room temperature for 20 hours. The reaction solution was evaporated to dryness under reduced pressure, a 10% aqueous citric acid solution (70 ml) was added to the residue, and the mixture was extracted with ethyl acetate (200 ml). The organic layer was washed with water (2 ×
50 ml) and saturated brine (50 ml), dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was washed with isopropyl ether and 936 mg (93%) of the title compound (5
-1) was obtained as colorless crystals.

Example 6 8-tert-butoxycarbonylaminomethyl-1,4-
Dihydro-6-fluoro-7- [4- (2-methoxyph
Enyl) -1-piperazinyl] -1-methyl-4-oxo
Synthesis of soquinoline-3-carboxylic acid (6-1)

[0148]

Embedded image

Ethyl 8-tert-butoxycarbonylaminomethyl-1,4-dihydro-6-fluoro-7-
[4- (2-methoxyphenyl) -1-piperazinyl]
-1-Methyl-4-oxoquinoline-3-carboxylate (5-1) (142 mg, 0.250 mg) was dissolved in ethanol (30 ml), and a 1N aqueous sodium hydroxide solution (0.50 ml) was added thereto. After refluxing under heating for an hour, the reaction solution was concentrated under reduced pressure. A 10% aqueous citric acid solution was added to the residue, and the mixture was extracted with ethyl acetate (100 ml), and the organic layer was washed with saturated saline (2 × 50 ml). After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off to obtain 142 mg of pale yellow crystals. Wash with isopropyl ether, 124 mg (92
%) Of the title compound (6-1) as colorless crystals. Physical properties of compound (6-1) obtained are as described below.

Melting point: 163-166 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s,-
_{COOC (CH 3) 3),} 3.0-3.5 (8H, bro
_{ad, -CH 2 - × 4)} , 3.91 (3H, s, -OC
_{H 3), 4.18 (3H,} s, N 1 -CH 3), 4.85
_{(3H, broad s, -CH 2} NHBoc, -NH
Boc), 6.90-7.26 (4H, m, aroma).
tic H), 8.15 (1H, d, J = 12 Hz, H
-5), 8.64 (1H, s, H-2) IR: ν _max (KBr): 1710, 1620 (cm ^-1 ) Elemental analysis: C ₂₈ H ₃₃ FN ₄ O ₆ Calculated: C, H, 6.15; N, 10.36 Analytical value: C, 61.92; H, 6.09; N, 10.05.

Example 7 8-aminomethyl-1,4-dihydro-6-fluoro-
7- [4- (2-methoxyphenyl) -1-piperazini
1] -methyl-4-oxoquinoline-3-carboxyl
Synthesis of acid dihydrochloride (7-1)

[0152]

Embedded image

8-tert-butoxycarbonylaminomethyl-1,4-dihydro-6-fluoro-7- [4- (2
-Methoxyphenyl) -1-piperazinyl] -1-methyl-4-oxoquinoline-3-carboxylic acid (6-1)
Concentrated hydrochloric acid (5 ml) was added to (118 mg, 0.218 mmol), and the mixture was stirred at room temperature for 15 minutes. Water (20 ml) was added, and the mixture was dried under reduced pressure. The residue was recrystallized from aqueous ethanol to give 9
0.2 mg (80%) of the title compound (7-1) was obtained as colorless crystals. Physical properties of compound (7-1) obtained are as described below.

Melting point: 248-250 ° C. ¹ H-NMR (D ₂ O) δ: 3.4-4.0 (8H, br
oad, 4 × —CH ₂ —), 3.97 (3H, s, —O
CH ₃ ), 4.25 (3H, s, N ₁ -CH ₃ ), 7.1
0-7.30 (2H, m, aromatic H),
7.30-7.70 (2H, m, aromatic
H), 8.21 (1H, d, J = 12 Hz, H-5),
8.97 (1H, s, H-2) IR: ν _max (KBr): 1726, 1618, 1606, 1
502, 1468, 1432 (cm ^-1 ) Elemental analysis: C ₂₃ H ₂₅ FN ₄ O ₄ .2HCl Calculated: C, 53.81; H, 5.30; N, 10.91 Analysis: C, 53.82; H, 5.21; N, 10.72

Example 8 Ethyl 8-aminomethyl-1,4-dihydro-6- phenyl
Fluoro-7- [4- (2-methoxyphenyl) -1-pi
Perazinyl] -1-methyl-4-oxoquinoline-3-
Synthesis of carboxylate (8-1)

[0156]

Embedded image

Ethyl 8-tert-butoxycarbonylaminomethyl-1,4-dihydro-6-fluoro-7-
[4- (2-methoxyphenyl) -1-piperazinyl]
To -1-methyl-4-oxoquinoline-3-carboxylate (5-1) (75.5 mg, 0.132 mmol) was added trifluoroacetic acid (5 ml), the mixture was stirred at room temperature for 15 minutes, and then dried under reduced pressure. . Saturated aqueous sodium hydrogen carbonate (50 ml) was added to the residue, and the mixture was extracted with chloroform (3 × 50 ml). The extract was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 70.1 mg of the title compound (8-1) as a colorless amorphous. Physical properties of compound (8-1) obtained are as described below.

¹ H-NMR (CDCl ₃ ) δ: 1.42
(3H, t, J = 7.3Hz , -CH 2 CH 3), 2.8
_{-3.8 (8H, broad, -CH 2} - × 4), 3.
_{91 (3H, s, -OCH 3} ), 4.26 (2H, s,
—CH ₂ NH ₂ ), 4.29 (3H, s, N ₁ —CH ₃ ),
4.40 (2H, q, J = 7.3Hz, -CH 2 C
_{H 3), 6.90-7.06 (4H,} m, aromat
ic H), 8.15 (1H, d, J = 12 Hz, H−
5), 8.44 (1H, s, H-2)

Example 9 Ethyl 8-dimethylaminomethyl-1,4-dihydro
-6-fluoro-7- [4- (2-methoxyphenyl)
-1-piperazinyl] -1-methyl-4-oxoquinoli
Synthesis of (9-1) of N-3-carboxylate

[0160]

Embedded image

Ethyl 8-aminomethyl-1,4-dihydro-6-fluoro-7- [4- (2-methoxyphenyl) -1-piperazinyl] -1-methyl-4-oxoquinoline-3-carboxylate ( 8-1) (70.1m
g), paraformaldehyde (30 mg), 5% palladium on carbon (100 mg), and ethanol (30 ml),
The mixture was stirred for 2 days under a 1 atm hydrogen atmosphere. The catalyst is filtered off,
The filtrate was concentrated under reduced pressure. Preparative TLC of residue
(Developing solvent; chloroform-methanol 95: 5) to give 30.0 mg of the title compound (9-1) as colorless crystals. Physical properties of compound (9-1) obtained are as described below.

Melting point: 187-190 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.41 (3H, t, J
_{= 7.3Hz, -CH 2 CH 3)} , 2.01 (6H, s,
_{-N (CH 3) 2),} 3.0-3.5 (8H, broa
_{d, -CH 2 - × 4)} , 3.90 (3H, s, -OC
_{H 3), 4.12 (5H,} s, -CH 2 NH 2, N 1 -CH
_{3), 4.40 (2H, q} , J = 7.3Hz, -CH 2 C
_{H 3), 6.90-7.03 (4H,} m, aromat
ic H), 8.17 (1H, d, J = 12 Hz, H−
5), 8.39 (1H, s, H-2)

Example 10 8-Dimethylaminomethyl-1,4-dihydro-6- phenyl
Fluoro-7- [4- (2-methoxyphenyl) -1-pi
Perazinyl] -1-methyl-4-oxoquinoline-3-
Synthesis of carboxylic acid (7)

[0164]

Embedded image

Ethyl 8-dimethylaminomethyl-1,
4-dihydro-6-fluoro-7- [4- (2-methoxyphenyl) -1-piperazinyl] -1-methyl-4-
Oxoquinoline-3-carboxylate (9-1) (6
5.4 mg, 0.132 mmol) was dissolved in ethanol (20 ml), and 1N aqueous sodium hydroxide solution (0.263 m
l) was added and the mixture was refluxed for 16 hours. The reaction mixture was evaporated to dryness under reduced pressure, and the residue was dissolved in water (10 ml).
263 ml) and extracted with chloroform (2 × 50 ml).
did. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off. Recrystallize the residue from isopropanol;
8 mg (66%) of the title compound (7) were obtained as colorless crystals. Physical properties of compound (7) obtained are as described below.

Melting point: 274-279 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.99 (6H, s, −
_{N (CH 3) 2),} 3.1-3.6 (8H, broad,
—CH ₂ — × 4), 3.91 (3H, s, —OCH ₃ ),
_{4.04 (3H, s, N 1} -CH 3), 6.91-7.0
7 (4H, m, aromatic H), 8.13 (1
H, d, J = 12 Hz, H-5), 8.61 (1H,
s, H-2) 14.87 (1H, s, -COOH) IR: ν _max (KBr): 1732, 1616, 1436 (cm
^-1 ) Elemental analysis: C ₂₅ H ₂₉ FN ₄ O ₄ Calculated: C, 63.42; H, 5.99; N, 12.33 Analysis: C, 63.39; H, 6.01 N, 12.18;

Example 11 Ethyl 1,4-dihydro-6-fluoro-7- [4-
(2-methoxyphenyl) -1-piperazinyl] -8-
(4-nitrophenylsulfonylaminomethyl) -1-
Methyl-4-oxoquinoline-3-carboxylate
Synthesis of (11-1)

[0168]

Embedded image

Ethyl 8-aminomethyl-1,4-dihydro-6-fluoro-7- [4- (2-methoxyphenyl) -1-piperazinyl] -1-methyl-4-oxoquinoline-3-carboxylate ( 8-1) (320 mg,
0.687 mmol) in dichloromethane (50 ml) and 2,6-lutidine (0.190 ml, 1.65 mmol).
l), p-nitrobenzenesulfonyl chloride (182 m
g, 0.825 mmol) and stirred at room temperature for 18 hours. The reaction solution was washed with water (2 × 100 ml), dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and eluted with chloroform-methanol (95: 5) to give 408 mg (91%) of the title compound (11-1) as yellow crystals. Physical properties of compound (11-1) obtained are as described below.

Melting point: 137-142 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.44 (3H, t, J
_{= 7.3Hz, -CH 2 CH 3)} , 2.5-3.8 (8
_{H, broad, -CH 2 - ×} 4), 3.88 (3H,
_{s, -OCH 3), 4.16 (} 3H, s, -N 1 -C
_{H 3), 4.35 (2H,} q, J = 7.3Hz, -CH 2
CH ₃ ), 4.66 (2H, d, J = 5.6 Hz, −C
_{H 2 NH -), 6.31 (} 1H, broad, -NHS
O ₂ −), 6.69 (1H, d, J = 7 Hz, arom
atic H), 6.90 (1H, d, J = 7 Hz, a
romantic H), 7.00 (1H, t, J = 7H)
z, aromatic H), 7.09 (1H, t, J
= 7 Hz, aromatic H), 7.85 (1H,
d, J = 12 Hz, H-5), 8.21 (2H, d, J
= 9 Hz, aromatic H), 8.35 (1H,
s, H-2), 8.36 (2H, d, J = 9 Hz, ar
matic H)

Example 12 Ethyl 1,4-dihydro-6-fluoro-7- [4-
(2-methoxyphenyl) -1-piperazinyl] -8-
(N-methyl-N-4-nitrophenylsulfonylamido
Nomethyl) -1-methyl-4-oxoquinoline-3-ca
Synthesis of ruboxylate (12-1)

[0172]

Embedded image

Ethyl 1,4-dihydro-6-fluoro-7- [4- (2-methoxyphenyl) -1-piperazinyl] -8- (4-nitrophenylsulfonylaminomethyl) -1-methyl-4-oxo Quinoline-3-carboxylate (11-1) (402 mg, 0.615 mmol)
l), dimethylformamide (10 ml), potassium carbonate (266 mg, 1.93 mmol), methyl iodide (80 μm)
1,1.29 mmol) and stirred at room temperature for 3 hours.
The reaction solution was evaporated to dryness under reduced pressure, 30 ml of water was added to the residue, and the mixture was extracted with chloroform (60 ml). After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off and the residue was washed with isopropyl ether to give 384 mg (94%) of the title compound (12-
1) was obtained as yellow crystals. The obtained compound (12-
The physical properties of 1) are as follows.

Melting point: 282-284 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.43 (3H, t, J
_{= 7.3Hz, -CH 2 CH 3)} , 2.10 (3H, s,
-NCH ₃ SO _2- ), 2.7-2.9 (4H, broa
_{d, -CH 2 - × 2)} , 3.2-3.4 (4H, bro
_{ad, -CH 2 - × 2)} , 3.86 (3H, s, -OC
_{H 3), 4.24 (3H,} s, -N 1 CH 3), 4.42
(2H, q, J = 7.3Hz , -CH 2 CH 3), 4.9
_{1 (2H, s, -CH 2} N -), 6.59 (1H, d,
J = 8 Hz, aromatic H), 6.89 (1
H, d, J = 8 Hz, aromatic H), 6.9
9 (1H, t, J = 8 Hz, aromatic H),
7.08 (1H, t, J = 8Hz, aromatic
H), 8.07 (2H, d, J = 9 Hz, aromat
ic H), 8.24 (1H, d, J = 12 Hz, H−
5), 8.45 (2H, d, J = 9 Hz, aromat
ic H), 8.46 (1H, s, H-2), IR: ν _max (KBr): 1720, 1610, 1532, 1
498, 1440 (cm ^-1 ) Elemental analysis: C ₃₂ H ₃₄ FN ₅ O ₈ S Calculated: C, 53.81; H, 5.30; N, 10.91 Analysis: C, 53.82 H, 5.21; N, 10.72

Example 13 Ethyl 1,4-dihydro-6-fluoro-7- [4-
(2-methoxyphenyl) -1-piperazinyl] -1-
Methyl-8-methylaminomethyl-4-oxoquinoline
Synthesis of -3-carboxylate (13-1)

[0176]

Embedded image

Ethyl 1,4-dihydro-6-fluoro-7- [4- (2-methoxyphenyl) -1-piperazinyl] -8- (N-methyl-N-4-nitrophenylsulfonylaminomethyl) -1 -Methyl-4-oxoquinoline-3-carboxylate (12-1) (377 mg,
0.589 mmol) was dissolved in dimethylformamide (5 ml), and potassium carbonate (244 mg, 1.77 mmol) and thiophenol (73 μl, 0.707 mmol) were added, followed by stirring at room temperature for 22 hours. The reaction solution was evaporated to dryness under reduced pressure, water (30 ml) was added to the residue, and the mixture was extracted with ethyl acetate (100 ml).
The extract was washed with water (3 × 30 ml), dried over anhydrous sodium sulfate and evaporated to give 211 mg (79%) of the title compound (13-1) as a pale yellow oil. Physical properties of compound (13-1) obtained are as described below.

¹ H-NMR (CDCl ₃ ) δ: 1.41
(3H, t, J = 7.3Hz , -CH 2 CH 3), 2.5
_{1 (3H, s, -NCH 3} ), 2.8-3.2 (4H,
_{broad, -CH 2 - × 2)} , 3.25-3.8 (4
_{H, broad, -CH 2 - ×} 2), 3.90 (3H,
_{s, -OCH 3), 4.29 (} 3H, s, N 1 -C
_{H 3), 4.42 (2H,} q, J = 7.3Hz, -CH 2
CH ₃ ), 6.90-7.07 (4H, m, aroma)
tic H), 8.16 (1H, d, J = 12 Hz, H
-5), 8.43 (1H, s, H-2)

Example 14 1,4-Dihydro-6-fluoro-7- [4- (2-meth
Toxiphenyl) -1-piperazinyl] -1-methyl-
8-methylaminomethyl-4-oxoquinoline-3-ca
Synthesis of rubonic acid (14-1)

[0180]

Embedded image

Ethyl 1,4-dihydro-6-fluoro-7- [4- (2-methoxyphenyl) -1-piperazinyl] -1-methyl-8-methylaminomethyl-4-oxoquinoline-3-carboxylate (13-1) (2
11 mg, 0.464 mmol), ethanol (20 ml), 1
Normal sodium hydroxide (0.982ml, 0.982mmo
l) was mixed and heated at reflux for 18 hours. The reaction solution was evaporated to dryness under reduced pressure, the residue was dissolved in water (10 ml), and the solution was pH 7.4 with hydrochloric acid.
And extracted with chloroform. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was recrystallized from ethanol to give 94.9 mg (44%) of the title compound (14
-1) was obtained as colorless crystals. The obtained compound (14-
The physical properties of 1) are as follows.

Melting point: 217-218 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.51 (3H, bro
_{ad, -NH (CH 3))} , 2.8-3.8 (8H, b
_{road, -CH 2 - × 4)} , 3.91 (3H, s, -
_{OCH 3), 4.42 (3H,} s, N 1 -CH 3), 6.
91-7.08 (4H, m, aromatic H),
8.14 (1H, d, J = 12 Hz, H-5), 8.6
6 (1H, s, H-2) IR: ν _max (KBr): 1728, 1616, 1500, 1
464 (cm ^-1 ) Elemental analysis: C ₂₄ H ₂₇ FN ₄ O ₄ .H ₂ O Calculated: C, 62.19; H, 6.09; N, 12.09 Analytical: C, 62. 16; H, 5.88; N, 11.89

Test Example 1 Compounds (4) to (4) produced in Examples 1, 3, 4 and 10
An ICAM-1 production inhibition test was performed using (7). The following equation as a control

[0184]

Embedded image

The benzothiophene derivative represented by the following formula was used.

Huma was added to each well of a 96-well microplate.
8 x 10 umblical vein endotherial cells (HUBIC)
^The cells were inoculated in triplicate and pre-cultured at 37 ° C. for 48 hours in the presence of 5% CO ₂ . After 48 hours, add human-TNF-α to each well.
To a final concentration of 1000 U / ml, also, each test sample to a final concentration of 0.05,0.5,5μg / ml, was added in 50μl respectively, 5% CO ₂ presence 37 Incubation was performed at 4 ° C. for another 4 hours. 0.1% B cells
After washing five times with Hank's Balanced Salt Solution (HBSS) containing SA, the mouse anti-human ICAM-
One antibody was added to each well in an amount of 10 μl, and reacted at room temperature for 45 minutes. After completion of the reaction, the cells were washed with H containing 0.1% BSA.
After washing 5 times with BSS, peroxidase-labeled mouse Ig
100 μl of the 3000-fold diluted solution is added to each well,
The reaction was carried out at room temperature for another 90 minutes. Cells were washed with 0.1% BSA
After washing 5 times with the containing HBSS, 100 μl of ABTS Peroxidase Substrate System (ABTS) was used as a reaction substrate in each well.
Each μl was added, and the reaction was performed at room temperature for 20 minutes. Stopping the reaction is 1
This was performed by adding 50 μl of a% SDS solution to each well. After stopping the reaction, use an absorbance meter to measure the absorption wavelength to 40
The color development ratio of the solution in each well was measured at 5 nm. The results are shown in FIG.

A control compound, a benzothiophene derivative, inhibited ICAM-1 production at 0.05 μg / ml. This inhibitory effect is based on literature values (Boshelli, DH, Karmer,
JB, Connor, DT, Lesch, ME, Schrier, D.
J., Ferin, MA, Wright, CD: J. Med. Chem. 37, 7
176-718 (1994)). On the other hand, all of the test compounds (4) to (7) showed an inhibitory effect on ICAM-1 production at 5 μg / ml, of which the compound (6) showed the strongest inhibitory activity, and 0.05 μg / ml almost completely inhibited ICAM-1. -1 production was inhibited.

Test Example 2 Using the compounds (4) to (7), a test for inhibiting p24 protein production from OM-10.1 cells by TNF-α stimulation was performed. OM-10.1 cells incorporating all HIV genes were prepared at 1 × 10 ⁵ / ml, and the cells were incubated for 2 hours in the presence of the test drug.
After reincubation, TNF-α was added to a concentration of 10 U / ml to stimulate the cells. In the presence of 5% CO ₂
After culturing at 37 ° C for 3 days, the amount of p24 antigen in the culture supernatant was determined by E
The 50% inhibitory concentration was measured using an LISA kit and the EC ₅₀
Indicated by Table 1 shows the results.

[0189]

[Table 1]

Compounds (4) to (7) were all TNF-
The p24 protein produced from OM-10.1 cells by α stimulation was inhibited at a low concentration of 0.17 μM or less. Among them, compound (6) showed the strongest inhibitory activity with an EC ₅₀ value of 0.017 μM.

Test Example 3 An anti-HIV activity test was carried out using Compounds (4) to (7). To a 1 × 10 ⁵ cells / ml suspension of MT-4 cells, add M
HIV-1.IIIB was infected at a ratio of OI: 0.02, and the infected cell solution was dispensed in equal amounts into a 96-well microplate containing a two-fold serial dilution of each drug, and then incubated at 37 ° C.
For 4 days. After the culture, the MTT method (Pauwels, R.
. et al,:... J Virol Methods, 20, to measure the anti-HIV effects of each drug using 309-321 (1988)), showed a 50% inhibition concentration EC _50. Table 2 shows the results.

[0192]

[Table 2]

Compounds (4) to (7) show strong H with an EC ₅₀ value of 0.54 μM or less even in an acute infection system using MT4 cells.
It showed an IV growth inhibitory effect. Among them, compound (6) exhibited an anti-HIV effect at a low EC ₅₀ value of 0.025 μM. Further, as described above, the compounds (4) to (7) inhibit the activity of ICAM-1 production, and OM induced by TNF-α stimulation.
The activity of inhibiting p24 protein production from -10.1 cells and the strength of anti-HIV activity were almost correlated.

[0194]

According to the present invention, various diseases caused by the induction effect of TNF-α, such as rheumatoid arthritis, septic shock, ulcerative colitis, etc., or AIDS by promoting the replication and transcription of the HIV gene A TNF-α-inducing effect inhibitor, which is effective in suppressing the onset of the disease, can be obtained.

[Brief description of the drawings]

FIG. 1. ICAM by TNF-α-inducing effect inhibitor
FIG. 3 is a diagram showing production inhibition of -1.

────────────────────────────────────────────────── ─── front page continued (51) Int.Cl. ⁶ identifications FI A61K 31/47 ACD A61K 31/47 ACD ACJ ACJ ACV ACV ADU ADU ADY ADY // C07D 215/56 C07D 215/56 401/04 211 401/04 211 401/14 211 401/14 211

Claims (6)

[Claims] 1. A compound of the general formula (1) [Wherein, R ¹ represents a linear or branched C _1-6 alkyl group which may have a substituent; a C _3-6 cyclic alkyl group which may have a substituent; _1-6 alkyl group, C _1-6 alkyl group having a fluorine atom as a substituent, C _1-6 alkoxyl group, C _1-6 alkylthio group, di (C _1-6 alkyl) amino-C _1-6 alkyl group , C _1-6 alkylamino-C _1-6 alkyl group, amino C _1-6 alkyl group, imidazolyl-C _1-6
An alkyl group, a pyrrolyl-C _1-6 alkyl group, (1,2,
3-triazol-1-yl) -C _1-6 alkyl group,
(1,2,3-triazol-2-yl) -C _1-6 alkyl group, (1,2,4-triazol-1-yl) -C
_1-6 alkyl group, (1,2,4-triazol-4-yl) -C _1-6 alkyl group and (1-morpholyl) -
An aryl group optionally having a substituent selected from the group consisting of a C _1-6 alkyl group; or a 5-membered or 1- or 2-membered heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom A heterocyclic substituent is a 6-membered heteroaromatic monocyclic ring or a heteroaromatic condensed ring obtained by condensing the heteroaromatic monocyclic ring with a benzene ring. The heterocyclic substituent is a halogen atom, a C _1-6 alkyl. group, a fluorine atom C _1-6 alkyl group having as a substituent, C _1-6 alkoxyl group, and C _1-6 which may have a substituent selected from the group consisting of alkylthio radicals: R
² represents a hydrogen atom or a C _1-6 alkylthio group, and this R ² and the above R ¹ may be integrated so as to form a cyclic structure including a part of the quinolone skeleton. The ring may contain a sulfur atom as a constituent atom of the ring, and the ring may have a C _1-6 alkyl group as a substituent. Further, R ² and Y may be integrated so as to form a cyclic structure including a part of the quinolone skeleton: R 2
³ represents a hydrogen atom, an amino group, a C _1-6 alkyl group, a C _1-6 alkoxyl group, and a halogen atom. Among them, the amino group is a formyl group, a C _1-6 alkyl group, and a C _2-6 group. _It may have one or more groups selected from the group consisting of ₆ acyl groups as substituents: R ⁴ and R
⁶ represents a hydrogen atom or a C _1-6 alkyl group: R
⁵ is a substituent selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a C _1-6 alkyl group having a fluorine atom as a substituent, a C _1-6 alkoxyl group, and a C _1-6 alkylthio group. A phenyl group which may be possessed; or a 5- or 6-membered heteroaromatic monocyclic ring containing one or two heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, or a heteroaromatic condensed monocyclic ring thereof And a benzene ring are condensed to form a heteroaromatic condensed ring, wherein the heterocyclic substituent is a halogen atom, a C _1-6 alkyl group,
A C _1-6 alkyl group having a fluorine atom as a substituent,
_It may have a substituent selected from the group consisting of a _1-6 alkoxyl group and a C _1-6 alkylthio group: X represents a hydrogen atom or a halogen atom: A represents a nitrogen atom or a formula (2) Embedded image (Wherein, R ⁷ represents a hydrogen atom, a halogen atom, a C _1-6 alkyl group _optionally having a halogen atom as a substituent,
Halogen atoms which may have a substituent C _{1 -6} alkoxy group shows also good aminomethyl group optionally having or 1 or 2 C _1-6 alkyl groups as a substituent. This R ⁷ and R ¹ may be integrated so as to form a cyclic structure including a part of the quinolone skeleton,
This ring may contain an oxygen atom or a sulfur atom as a constituent atom of the ring, and this ring may have a C _1-6 alkyl group as a substituent. )), M represents an integer 2 or 3, and Y represents a hydroxyl group or a formula (3): (Wherein R ⁸ represents a phenyl group, an acetoxymethyl group, a pivaloyloxymethyl group, an ethoxycarbonyl group, a choline group, a dimethylaminoethyl group, a 5-indanyl group, a phthalidinyl group, a 5-alkyl-2-oxo- 1,3-dioxol-4-ylmethyl group, 3-acetoxy-2-
Oxobutyl group, C _1-6 alkyl group, C _1-6 alkoxy-
It represents a phenylalkyl group composed of a methyl group or a C _1-6 alkylene group and a phenyl group. Z represents a partial structure represented by a carbon atom or a nitrogen atom. Or a salt thereof as an active ingredient. 2. The TNF according to claim 1, wherein the compound represented by the general formula (1) is a compound represented by the following formula (4).
-Α-inducing effect inhibitor. Embedded image 3. The TNF according to claim 1, wherein the compound represented by the general formula (1) is a compound represented by the following formula (5).
-Α-inducing effect inhibitor. Embedded image 4. The TNF according to claim 1, wherein the compound represented by the general formula (1) is a compound represented by the following formula (6).
-Α-inducing effect inhibitor. Embedded image 5. The TNF according to claim 1, wherein the compound represented by the general formula (1) is a compound represented by the following formula (7).
-Α-inducing effect inhibitor. Embedded image 6. The method according to claim 1, wherein the TNF-α-inducing effect is ICAM-
1 (intracellularadhesion molecule-1) production, p2
The TNF-α-inducing effect inhibitor according to any one of claims 1 to 5, wherein the inhibitor is one or more selected from the group consisting of 4 protein production and HIV virus proliferation.