JPH10130149A - Tnf production inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a TNF-α production inhibitor useful as a treating agent for various diseases caused by excess production of the TNF-α by including at least one kind of specific three kinds of quinolonecarboxylic acids as an active ingredient. SOLUTION: This TNF-α production inhibitor includes at least one kind of quinolonecarboxylic acid of formulas I, II and III X is H or a halogen; Y is X, a 1-4C alkyl, etc.; Z is a (protected) COOH, etc.; Q is N, a group of formula IV [R<2> is H, a 1-4C alkyl (substituted by a halogen), etc.]; W is O or S; T is a 1-4C alkylene (substituted by a 1-4C alkyl), etc.; R<1> is H, a 1-4C alkyl (substituted by OH, etc.), etc.; R is a group of formula V [R<3> is a 6-10C arly (substituted by nitro, etc.), etc.; R<4> and R<5> are each H or a 1-4C alkyl; (n) is 1 or 2], etc.}. The compound of formulas I, II or III is produced by a method written in a laid open patent application of EP572,259 (Japan laid open patent application 6-116241) and/or a patent of WO/02512, or a method corresponding to these methods.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a TNF-α production inhibitor.

[0002]

2. Description of the Related Art TNF-α plays an important role in immunostimulatory functions in normal humans and is a kind of cytokine that is also important for living organisms.

However, excessive or uncontrolled production of TNF-α induces or promotes diseases such as sepsis, cachexia, and autoimmune diseases.

It is known that a compound having a quinolone carboxylic acid skeleton suppresses the production of TNF-α (Japanese Patent Application Laid-Open No. 8-73453), but its production inhibitory activity is not always satisfactory. It was not something.

[0005]

The present inventors have conducted intensive studies on a more effective TNF-α production inhibitor for many years, and as a result, the quinolone carboxylic acid derivative described below has been used as a TNF-α production inhibitor. Useful and T
The present inventors have found that they are useful as therapeutic agents for various diseases caused by overproduction of NF-α, and completed the present invention.

[0006]

Means for Solving the Problems The present invention is a TNF-α production inhibitor containing at least one of the following quinolone carboxylic acids as an active ingredient.

The quinolone carboxylic acid as an active ingredient of the present invention is a quinolone carboxylic acid represented by the following general formula (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt thereof.

[0008]

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The above formula (Ia), (Ib) or (Ic)
In the formula, X represents a hydrogen atom or a halogen atom, and Y represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, an amino group, or an alkyl group having 1 to 2 carbon atoms having 1 to 4 carbon atoms. Mono- or dialkyl-substituted amino group or 1
Represents two to two mono- or diaralkyl-substituted amino groups substituted with an aralkyl group having 7 to 14 carbon atoms,
Z represents a carboxy group or a 5-tetrazolyl group which may be protected, and Q represents a nitrogen atom or formula (d)

[0010]

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[In the formula (d), R ² represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms which may be substituted by halogen, or a carbon atom having 1 to 4 carbon atoms which may be substituted by halogen. Represents 4 alkoxy groups], W represents an oxygen atom or a sulfur atom, and T represents 1 carbon atom which may be substituted by alkyl having 1 to 4 carbon atoms.
Represents an alkylene group having 1 to 4 carbon atoms or an alkenylene group having 2 to 4 carbon atoms which may be substituted with alkyl having 1 to 4 carbon atoms, wherein R ¹ is a hydrogen atom; 4 alkyl groups [substituents of the alkyl group include hydroxy, carboxy, halogen, alkoxy having 1 to 4 carbons, cycloalkyl having 3 to 6 carbons, alkanoyloxy having 2 to 5 carbons, formula (E)

[0012]

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(In the formula (e), R ⁹ and R ¹⁰ each represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms,
Alternatively, R ⁹ and R ¹⁰ together with the nitrogen atom to which they are attached, optionally further containing N, O and S
Or a 3- to 7-membered saturated monocyclic ring containing a heteroatom selected from the group consisting of:
A 5- or 6-membered heteroaromatic monocyclic group containing 1 or 2 heteroatoms selected from N, O and S, which may be substituted with ⁰ , A heteroaromatic condensed ring group in which a monocyclic ring and a benzene ring are condensed]; an alkenyl group having 2 to 5 carbon atoms which may be substituted by halogen; an alkynyl group having 2 to 4 carbon atoms; an amino group; A mono- or di-alkyl-substituted amino group substituted with 1 to 4 alkyl groups having 1 to 4 carbon atoms; a cycloalkyl group having 3 to 6 carbon atoms which may be substituted with halogen; An alkoxy group; or an aryl group having 6 to 10 carbon atoms which may be substituted by R ⁰ , or a 5- to 6-membered heteroaromatic monocyclic ring containing 1 or 2 heteroatoms selected from N, O and S Groups or their heteroaromatics Or showing a heteroaromatic fused ring wherein the ring and the benzene ring is condensed, and R ^1, and R ² of formula (d) in the Q together formula (f)

[0014]

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[In the formula (f), A represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms which may be substituted with halogen, hydroxy or alkoxy having 1 to 4 carbon atoms, and G represents a nitrogen atom. Or equation (g)

[0016]

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Wherein G ¹ is a methylene group, a carbonyl group, an oxygen atom, a sulfur atom or a —N (R ¹¹ ) — group (wherein
R ¹¹ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms), p represents 0 or 1, and R represents a group represented by the formula (h) or the formula (i)

[0018]

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In the formulas (h) and (i), R ³ and R ⁶
Is R ⁰ (R ⁰ is halogen, nitro, hydroxy, alkyl having 1 to 4 carbons, alkyl having 1 to 4 carbons substituted with fluorine, alkoxy having 1 to 4 carbons, 1 to 4 carbons Alkylthio, amino, and mono- or dialkyl-substituted amino substituted with 1 to 2 alkyl having 1 to 4 carbons, which may be substituted with 6 to 10 carbons An aryl group, a 5- or 6-membered heteroaromatic monocyclic group containing one or two heteroatoms selected from N, O and S, or a heteroaromatic condensed ring group obtained by condensing a benzene ring with these heteroaromatic monocycles. R ⁴ , R ⁵ and R ⁷ each represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; R ⁸ represents a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 4 carbon atoms or an alkyl group having 1 to 4 carbon atoms;
N represents 1 or 2; m represents 0
Or 1; n ′ represents 1 or 2; n ″ represents 1, 2,
3 or 4].

Further, the present invention relates to the above formulas (1a) and (1a).
A therapeutic agent for a disease selected from the following group A, which contains at least one compound of b) or (1c) as an active ingredient. Further, the present invention is the use of the compound of the above formula (1a), (1b) or (1c) for producing a therapeutic agent for a disease selected from the following group A.

[Group A] sepsis, cachexia, autoimmune disease,
Chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption disease.

That is, the compounds represented by formulas (Ia), (Ib) and (Ic) include compounds represented by formula (Ia-1):
(Ib-1) and (Ic-1) and the general formula (Ia-
2) The following compounds represented by (Ib-2) and (Ic-2)

[0023]

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(In each formula, X, Y, Z, W,
Q, T, R ¹ and R ^{3 to} R ^{8 and} m, n, n ′ and n ″ are as defined above).

Further, among the compounds represented by formulas (Ia), (Ib) and (Ic), preferred compounds are those represented by formulas (Ia-3), (Ib-3) and (Ic-3):
General formulas (Ia-4), (Ib-4) and (Ic-4),
The following compounds represented by formulas (Ia-5), (Ib-5) and (Ic-5) and formulas (Ia-6) and (Ia-7)

[0026]

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[0027]

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(In each general formula, A, X, Y, Z,
W, R, T and R ¹ are as defined above, and
R ¹² represents an alkoxy group having 1 to 4 carbon atoms (especially difluoromethoxy group) which may be substituted by halogen (especially fluorine), and R ¹³ is substituted by hydrogen atom, halogen atom or halogen (especially fluorine). Alkyl group having 1 to 4 carbon atoms (particularly trifluoromethyl group)
And A ′ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms which may be substituted by a halogen atom (particularly fluorine).

In the present invention, the compounds represented by the general formulas (Ia-3) and (Ib)
-3), (Ic-3), (Ia-4) and (Ia-6)
The compound represented by the formula (Ia) is particularly preferable.
3), (Ia-4) and compounds represented by the general formula (Ia-6), wherein A ′ is an alkyl group having 1 to 4 carbon atoms and substituted with fluorine, are preferred.

The general formulas (Ia), (Ib) and (I
Examples of the halogen atom for X in c) include a fluorine, chlorine, bromine or iodine atom, preferably a fluorine and chlorine atom, and more preferably a fluorine atom.

The general formulas (Ia), (Ib) and (I
X in c) is preferably hydrogen, fluorine and chlorine atom, more preferably fluorine and chlorine atom, and most preferably fluorine atom.

The general formulas (Ia), (Ib) and (I
Y in c) is a hydrogen atom; a halogen atom such as fluorine, chlorine, bromine or iodine; an alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl or isobutyl group; A monoalkyl-substituted amino group substituted with alkyl having 1 to 4 carbon atoms such as methylamino, ethylamino, propylamino, isopropylamino, and butylamino groups; dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutyl 1 to 4 carbon atoms such as amino group
A dialkyl-substituted amino group substituted with an alkyl group; a monoaralkyl-substituted amino group substituted with an aralkyl group having 7 to 14 carbon atoms, such as a benzylamino or phenylethylamino group; a dibenzylamino or di (phenylethyl) amino group; Examples thereof include a diaralkyl-substituted amino group substituted with an aralkyl having 7 to 14 carbon atoms, preferably a hydrogen atom, fluorine, an amino group, a methyl group or an ethyl group, and more preferably a hydrogen atom. Is an atom.

The protecting group for the carboxy group of the "optionally protected carboxy group" of Z in the above general formulas (Ia) and (Ic) includes methyl, ethyl, propyl, isopropyl, butyl and isobutyl groups. An alkyl group having 1 to 4 carbon atoms; benzyl, 1-phenylethyl,
An aralkyl group having 7 to 14 carbon atoms such as 1-naphthylmethyl group; an alkanoyloxyalkyl group having 1 to 4 carbon atoms such as acetoxymethyl and pivaloyloxymethyl groups; 1- (ethoxycarbonyloxy) ethyl ,
An alkoxycarbonyloxyalkyl group having 1 to 4 carbon atoms such as a 1- (isopropoxycarbonyloxy) ethyl group; an N, N-dialkyl-substituted aminocarbonylalkyl group such as an N, N-dimethylaminocarbonylmethyl group; N, N-dialkyl-substituted aminoalkyl groups such as-(N, N-dimethylamino) ethyl group; N, O and S such as 2-morpholinoethyl, 2-piperidinoethyl, 2- (4-methylpiperidino) ethyl group A 5- or 6-membered heterosaturated monocyclic group-substituted alkyl group containing 1 or 2 heteroatoms selected from; or (5-methyl-2-
A carboxy group which is easily deprotected in vivo such as an oxo-1,3-dioxolen-4-yl) methyl group or a (5-phenyl-2-oxo-1,3-dioxolen-4-yl) methyl group And a group which can be converted into

Z in the general formulas (Ia) and (Ic) is preferably a carboxy group which may be protected, and more preferably a carboxy group.

The general formulas (Ia), (Ib) and (I
When Q in c) is represented by the formula (d), examples of the halogen atom of R ² include a fluorine, chlorine, bromine or iodine atom, and preferred are a fluorine and chlorine atom.

The formulas (Ia), (Ib) and (I
When Q in c) is represented by the formula (d), examples of the alkyl group having 1 to 4 carbon atoms which may be substituted with a halogen of R ² include methyl, ethyl, propyl, isopropyl and butyl. Alkyl group; fluorine-substituted alkyl group such as fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, 4-fluorobutyl group; chloromethyl, dichloromethyl, trichloromethyl, 2-chloroethyl, 3 A chloro-substituted alkyl group such as -chloropropyl or 4-chlorobutyl group, preferably an unsubstituted alkyl group or a fluorine-substituted alkyl group, more preferably methyl, fluoromethyl, difluoromethyl And a trifluoromethyl group, most preferably a trifluoromethyl group.

The general formulas (Ia), (Ib) and (I
In the case where Q in c) is represented by the formula (d), the alkoxy group having 1 to 4 carbon atoms which may be substituted with a halogen of R ² includes methoxy, ethoxy, propoxy, isopropoxy and butoxy groups. Alkoxy groups; fluorine-substituted alkoxy groups such as fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-fluoropropoxy, 3-fluoropropoxy, and 4-fluorobutoxy groups; 2-chloroethoxy, 2-chloro Propoxy, 3-chloropropoxy, 4
And a chlorine-substituted alkoxy group such as -chlorobutoxy group, preferably an unsubstituted alkoxy group and a fluorine-substituted alkoxy group (especially methoxy, ethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy and 2-fluoroethoxy group). And more preferably methoxy, fluoromethoxy, difluoromethoxy and trifluoromethoxy groups, even more preferably methoxy and difluoromethoxy groups, and most preferably difluoromethoxy groups.

Formulas (Ia), (Ib) and (I)
When Q in c) is represented by the formula (d), R ² is preferably a hydrogen atom; a halogen atom; an alkyl group having 1 to 4 carbon atoms which may be substituted by a fluorine atom;
An alkoxy group having 1 to 4 carbon atoms which may be substituted by fluorine, particularly preferably a fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy and trifluoromethoxy group; More preferred are methoxy, difluoromethoxy and trifluoromethyl groups, most preferred are difluoromethoxy and trifluoromethyl groups.

The above general formulas (Ia), (Ib) and (I
Q in c) is preferably formula (d) wherein R ^{2 in} formula (d) is a methoxy, difluoromethoxy and trifluoromethyl group.

In the general formula (Ib), W is
Preferably, it is a sulfur atom.

In the general formula (Ic), T is
Alkylene groups having 1 to 4 carbon atoms which may be substituted by alkyl having 1 to 4 carbon atoms, such as methylene, ethylidene [-CH (CH ₃ )-], ethylene, trimethylene, propylene and tetramethylene groups; -CH = CH-,
Alkylene groups having 2 to 4 carbon atoms which may be substituted by alkyl having 1 to 4 carbon atoms, such as -C (CH ₃ ) = CH- group, are preferably ethylidene, -C
H ＝ CH— and —C (CH ₃ ) ＝ CH— groups, particularly preferably an ethylidene group.

In the general formulas (Ia) and (Ib), the “C1-4 alkyl group” of the optionally substituted C1-4 alkyl group represented by R ¹ includes methyl, ethyl And alkyl groups such as propyl, isopropyl, butyl, isobutyl, s-butyl and t-butyl groups, preferably methyl, ethyl, propyl and isopropyl groups, more preferably methyl and ethyl groups. It is.

Examples of the halogen atom as the substituent of the substituted alkyl group having 1 to 4 carbon atoms for R ^{1 in} the general formulas (Ia) and (Ib) include a fluorine, chlorine, bromine or iodine atom. , Preferably a fluorine and chlorine atom, and more preferably a fluorine atom.

[0044] Examples of the general formula (Ia) and (Ib) in the substituted substituent at a number of 1 to 4 carbon alkoxy group having a carbon number of 1 to 4 alkyl groups of carbon atoms in R ^1, methoxy, ethoxy, Examples include propoxy, isopropoxy and butoxy groups, preferably methoxy and ethoxy groups, and more preferably methoxy groups.

In the general formulas (Ia) and (Ib), the cycloalkyl group having 3 to 6 carbon atoms which is a substituent of the substituted alkyl group having 1 to 4 carbon atoms for R ¹ includes cyclopropyl, Examples thereof include a cyclobutyl, cyclopentyl and cyclohexyl group, preferably a cyclopropyl group.

In general formulas (Ia) and (Ib), R ^{1 is} a substituted C ¹ -C 4 alkyl group, and the C 2 -C 5 alkanoyloxy group is acetoxy or propionyl. An oxy or brityloxy group is mentioned, and an acetoxy group is preferred.

In formulas (Ia) and (Ib), R ^{1 is} a substituted alkyl group having 1 to 4 carbon atoms, and R ⁹ and R ¹⁰ in formula (e) are 1 to 4 carbon atoms.
As the 1 to 4 alkyl groups, the above-mentioned R ¹ has 1 carbon atom.
The same groups as those described above for the four to four alkyl groups can be mentioned, and preferred are a methyl group and an ethyl group.

In the general formulas (Ia) and (Ib), R ⁹ and R ¹⁰ in the above formula (e), which are the substituents of the substituted alkyl group having 1 to 4 carbon atoms, of R ¹ together And optionally a 3- to 7-membered saturated monocyclic ring containing a heteroatom selected from N, O and S together with a nitrogen atom to which they are bonded, aziridino, azetidino, pyrrolidino, piperidino, morpholino, Thiomorpholino or piperazino groups are preferred, preferably piperidino and morpholino groups.

In the general formulas (Ia) and (Ib), the above-mentioned formula (e) which is a substituent of R ¹ substituted alkyl group having 1 to 4 carbon atoms is preferably amino, methylamino , Dimethylamino, piperidino and morpholino groups, more preferably a dimethylamino group.

In formulas (Ia) and (Ib), R ^{1 is} a substituent of a substituted alkyl group having 1 to 4 carbon atoms, and may have 6 to 10 carbon atoms which may be substituted by R ⁰ described below. Examples of the "aryl group having 6 to 10 carbon atoms" of the aryl groups include phenyl, 1-naphthyl, and 2-naphthyl groups, and a phenyl group is preferable.

In the formulas (Ia) and (Ib), N, O and S, which may be substituted by R ⁰ , which is a substituent of a substituted alkyl group having 1 to 4 carbon atoms of R ¹ , A 5- or 6-membered heteroaromatic monocyclic group containing 1 or 2 heteroatoms selected from the group consisting of a heteroaromatic condensed ring obtained by condensing a heteroaromatic monocyclic group and a benzene ring (hereinafter referred to as a heteroaromatic monocyclic group; A heteroaromatic group is also referred to as a heteroaromatic group.)
As a "5- or 6-membered heteroaromatic monocyclic group containing 1 or 2 heteroatoms selected from N, O and S or a heteroaromatic condensed ring group obtained by condensing a benzene ring with these heteroaromatic monocyclic groups" Is, for example, 2-thienyl, 2-furyl, 2-oxazolyl, 2-thiazolyl, 2-imidazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyridinyl Pyrazinyl, 3-pyridazinyl, 2-benzoxazolyl, 2
-Benzothiazolyl, 2-benzimidazolyl, 3-benzisoxazolyl, 3-benzisothiazolyl group and the like, preferably 2-thienyl, 2-furyl,
-Pyridyl and 2-pyrimidinyl groups, more preferably a 2-pyridyl group.

In formulas (Ia) and (Ib), R ^{1 is} a substituent of a substituted alkyl group having 1 to 4 carbon atoms, and may have 6 to 10 carbon atoms which may be substituted by R ⁰ described below. R ⁰ of the aryl group and the heteroaromatic ring group include, for example, halogen atoms such as fluorine, chlorine, bromine and iodine atoms; nitro group; hydroxy group; methyl, ethyl, propyl, isopropyl, butyl, s-butyl , Isobutyl, an alkyl group having 1 to 4 carbon atoms such as a t-butyl group; fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-fluoropropyl, 3-fluoropropyl, 2-fluorobutyl, 3
An alkyl group having 1 to 4 carbon atoms substituted by a fluorine atom such as -fluorobutyl and 4-fluorobutyl groups; an alkoxy group having 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy and butoxy groups An alkylthio group having 1 to 4 carbon atoms such as a methylthio, ethylthio, propylthio, isopropylthio, butylthio group; an amino group; methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, s-butyl A monoalkyl-substituted amino group substituted with an alkyl group having 1 to 4 carbon atoms such as an amino group or a t-butylamino group; dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, ethyl (methyl ) Carbon like amino group 1 to include four dialkyl substituted amino group substituted with an alkyl group, preferably, fluorine, chlorine, a methoxy group; a methyl group.

In the above general formulas (Ia) and (Ib), R ¹ as a whole may be a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl;
2-hydroxyethyl, 2-hydroxypropyl, 3-
Hydroxypropyl; carboxymethyl, 1-carboxyethyl, 2-carboxyethyl; fluoromethyl, chloromethyl, 2-fluoroethyl, 2-chloroethyl,
2-bromoethyl, 2-iodoethyl, 3-fluoropropyl, 3-chloropropyl, 3-bromopropyl,
-Fluorobutyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl; cyclopropylmethyl; 2-acetoxyethyl, 2-acetoxypropyl, 3-acetoxypropyl; 2-aminoethyl,
-Methylaminoethyl, 2-dimethylaminoethyl, 2
Morpholinoethyl, 2-piperidinoethyl; 2-methoxyethyl; phenylmethyl, 1-phenylethyl, 2
-Phenylethyl, naphthylmethyl, 2-fluorophenylmethyl, 3-fluorophenylmethyl, 4-fluorophenylmethyl, 2,4-difluorophenylmethyl, 3,4-difluorophenylmethyl, 2,6-difluorophenylmethyl, -Methylphenylmethyl, 3
-Methylphenylmethyl, 4-methylphenylmethyl,
2-chlorophenylmethyl, 3-chlorophenylmethyl, 4-chlorophenylmethyl, 2-methoxyphenylmethyl, 3-methoxyphenylmethyl, 4-methoxyphenylmethyl, 2-thienylmethyl, 2-furylmethyl, 2-pyridylmethyl and 2-chlorophenylmethyl Pyrimidinylmethyl group, more preferably methyl, ethyl, propyl,
Isopropyl, 2-hydroxyethyl, carboxymethyl, 2-fluoroethyl, 2-chloroethyl, 2,2,
2-trifluoroethyl, 2-acetoxyethyl, phenylmethyl, 2-phenylethyl, 2-pyridylmethyl, 2-dimethylaminoethyl and 2-morpholinoethyl, even more preferably methyl, ethyl,
-Hydroxyethyl and 2-fluoroethyl groups.

Most preferred are methyl, ethyl and 2-hydroxyethyl groups.

In formulas (Ia) and (Ib), R ¹ has 2 to 5 carbon atoms which may be substituted with halogen.
Alkenyl groups include vinyl, 2-propenyl,
1-butenyl, 2-butenyl, 3-butenyl, 3,3-
Dimethyl-2-propenyl, 2-fluorovinyl, 2-
(2-fluoro) propenyl, 3,3-difluoro-2
-Propenyl, 3,3-dichloro-2-propenyl and the like, preferably vinyl, 2-propenyl, 3,3
-Dimethyl-2-propenyl and 3,3-dichloro-2
-Propenyl, more preferably vinyl and 2-
It is a propenyl group.

In general formulas (Ia) and (Ib), R ¹ represents an alkynyl group having 2 to 4 carbon atoms, such as an ethynyl, 1-propynyl, 2-propynyl or 2-butynyl group. And four alkynyl groups, preferably ethynyl and 2-propynyl,
More preferably, it is a 2-propynyl group.

In the general formulas (Ia) and (Ib), the mono- or dialkyl-substituted amino group of R ¹ substituted by 1 to 2 alkyl groups having 1 to 4 carbon atoms includes methylamino, ethylamino, Monoalkyl-substituted amino groups such as propylamino, isopropylamino, and butylamino groups; and dialkyl-substituted amino groups such as dimethylamino, diethylamino, dipropylamino, diisopropylamino, and dibutylamino groups. , Ethylamino and dimethylamino groups, and more preferably a methylamino group.

In formulas (Ia) and (Ib), R ¹ has 3 to 6 carbon atoms which may be substituted with halogen.
Cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-fluorocyclopropyl, 2-chlorocyclopropyl,
Bromocyclopropyl, 2,2-difluorocyclopropyl, 2-chloro-2-fluorocyclopropyl, 2-
Fluorocyclobutyl, 2-fluorocyclopentyl,
Examples thereof include a 2-fluorocyclohexyl group and the like, preferably cyclopropyl, cyclobutyl, cyclopentyl and 2-fluorocyclopropyl, more preferably a cyclopropyl group.

Examples of the alkoxy group having 1 to 4 carbon atoms for R ^{1 in} the formulas (Ia) and (Ib) include alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy and butoxy groups. Are methoxy, ethoxy and propoxy groups, more preferably methoxy and ethoxy groups.

In the above general formulas (Ia) and (Ib), R ¹ having the carbon number of 6 to 1 which may be substituted by R ⁰ described below.
A 5- to 6-membered complex containing 1 to 2 heteroatoms selected from N, O and S which may be substituted by R ⁰ , “aryl groups having 6 to 10 carbon atoms” of 0 aryl groups A 5- or 6-membered heteroaromatic monocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, which is an aromatic monocyclic group or a heteroaromatic condensed ring group in which a heteroaromatic monocycle and a benzene ring are condensed; Examples of the group or a heteroaromatic condensed ring group in which a heteroaromatic monocyclic ring and a benzene ring are condensed ”are the same as those described above as the substituent of the substituted alkyl group having 1 to 4 carbon atoms of R ^1. And phenyl, naphthyl, 2-thiazolyl, 2-oxazolyl, and 2
-Pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-benzoxazolyl and 2-benzothiazolyl group,
More preferred are phenyl and 2-pyridyl groups.

[0061] Formula (Ia) and hereinafter R ⁰ having 6 to carbon atoms which may be substituted with one of R ¹ in (Ib)
A 5- or 6-membered heteroaromatic monocyclic group containing 0 or 2 aryl groups and 1 or 2 heteroatoms selected from N, O and S, or a condensed heteroaromatic ring obtained by condensing a benzene ring with these heteroaromatic monocycles As R ⁰ of the group, the aforementioned general formula (I)
a) and having 1 to carbon atoms substituted by R ¹ in (Ib) is a substituent of the four alkyl groups, it is the same as R ⁰ good heteroaromatic ring group optionally substituted by below R ⁰ And preferably a fluorine or chlorine atom; a methyl group.

R ¹ in the general formulas (Ia) and (Ib) is preferably a hydrogen atom; methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl;
2-hydroxyethyl, 2-hydroxypropyl, 3-
Hydroxypropyl; carboxymethyl, 1-carboxyethyl, 2-carboxyethyl; fluoromethyl, 2
-Fluoroethyl, 2-chloroethyl, 3-fluoropropyl, 3-chloropropyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl; cyclopropylmethyl; 2-acetoxyethyl, 2-acetoxypropyl, -Acetoxypropyl; 2-aminoethyl, 2-methylaminoethyl, 2-dimethylaminoethyl, 2-morpholinoethyl, 2-piperidinoethyl; 2-methoxyethyl; phenylmethyl, 1-phenylethyl, 2-phenylethyl, naphthylmethyl , 2-
Fluorophenylmethyl, 3-fluorophenylmethyl, 4-fluorophenylmethyl, 2,4-difluorophenylmethyl, 3,4-difluorophenylmethyl,
2,6-difluorophenylmethyl, 2-methylphenylmethyl, 3-methylphenylmethyl, 4-methylphenylmethyl, 2-chlorophenylmethyl, 3-chlorophenylmethyl, 4-chlorophenylmethyl, 2-methoxyphenylmethyl, 3-methoxy Phenylmethyl, 4-
Methoxyphenylmethyl; 2-thienylmethyl, 2-furylmethyl, 2-pyridylmethyl, 2-pyrimidinylmethyl; amino; methylamino, ethylamino, dimethylamino; methoxy, ethoxy, propoxy; cyclopropyl, cyclobutyl, cyclopentyl, 2- Fluorocyclopropyl; phenyl, naphthyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,
2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 2,6-difluorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl; Thiazolyl, 2-oxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl,
4-pyrimidinyl, 5-pyrimidinyl, 2-benzoxazolyl, 2-benzothiazolyl; vinyl, 2-propenyl, 3,3-dimethyl-2-propenyl, 3,3-diclo-2-propenyl; ethynyl, 2-propynyl A hydrogen atom; methyl, ethyl, propyl, isopropyl; 2-hydroxyethyl; carboxymethyl; 2-fluoroethyl, 2-chloroethyl,
2,2,2-trifluoroethyl; 2-acetoxyethyl; phenylmethyl, 2-phenylethyl; 2-pyridylmethyl; 2-dimethylaminoethyl, 2-morpholinoethyl; amino; methylamino; methoxy; cyclopropyl, cyclobutyl , Cyclopentyl, 2-fluorocyclopropyl; phenyl, 2-fluorophenyl, 3-
Fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl; vinyl, 2-propenyl; 2-propynyl, even more preferably methyl, ethyl, 2-hydroxyethyl, 2-fluoroethyl, cyclopropyl And a methylamino group, most preferably
Methyl, ethyl, 2-hydroxyethyl and methylamino groups.

In the general formulas (Ia) and (Ib), when R ¹ and R ² together form a bond represented by the formula (f), the “A” of the formula (f) Examples of the halogen atom, a hydroxy group or an alkyl group having 1 to 4 carbon atoms which may be substituted with an alkoxy group having 1 to 4 carbon atoms "include methyl, ethyl, propyl,
Alkyl groups such as isopropyl and butyl; fluoromethyl, chloromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl,
-Bromoethyl, 2-fluoropropyl, 3-fluoropropyl, 2-fluorobutyl, 3-fluorobutyl,
Halogeno-substituted alkyl groups such as 4-fluorobutyl group; hydroxy-substituted alkyl groups such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl and 4-hydroxybutyl groups; methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl And alkoxy-substituted alkyl groups such as methoxyethyl, methoxypropyl and methoxybutyl groups, preferably methyl, fluoromethyl and hydroxymethyl groups.

In the general formulas (Ia) and (Ib), when R ¹ and R ² together form a bond represented by the formula (f), A in the formula (f) represents And preferably hydrogen, methyl, fluoromethyl and hydroxymethyl.

In the general formulas (Ia) and (Ib), when R ¹ and R ² together form a bond represented by the formula (f), G in the formula (f) is Preferably, it is a group represented by the formula (g), and also has 1 to 4 carbon atoms of R ¹¹ of —N (R ¹¹ ) — of G ^{1 in} the formula (f).
Alkyl groups include methyl, ethyl, propyl,
Examples include isopropyl and butyl groups, preferably methyl and ethyl groups, and G ^{1 in} the formula (f) is preferably an oxygen atom and a sulfur atom, and more preferably an oxygen atom.

In the general formulas (Ia) and (Ib), when R ¹ and R ² together form a bond represented by the formula (f), p in the formula (f) is Preferably it is 1.

The formulas (Ia), (Ib) and (I
the substituent R on the aryl and heteroaromatic groups of R ³ and R ⁶ in formulas (h) and (i) of R in c)
⁰ represents a heteroaromatic which may be substituted by R ⁰ described below, which is a substituent of an alkyl group having 1 to 4 carbon atoms and is substituted by R ¹ in the aforementioned general formulas (Ia) and (Ib). The same groups as those described for R ^{0 in} the ring group are preferred, preferably a fluorine or chlorine atom; methyl, ethyl; trifluoromethyl; methoxy, ethoxy; a methylthio or ethylthio group, more preferably a fluorine or chlorine atom. Methyl; trifluoromethyl; methoxy; methylthio groups.

The formulas (Ia), (Ib) and (I
Examples of the aryl group having 6 to 10 carbon atoms of R ³ and R ⁶ in formulas (h) and (i) of R in c) include phenyl, 1-naphthyl, and 2-naphthyl groups. It is a phenyl group.

The formulas (Ia), (Ib) and (I
Examples of the heteroaromatic group represented by R ³ and R ⁶ in formulas (h) and (i) of R in c) include, for example, 2-thienyl,
2-furyl, 2-oxazolyl, 2-thiazolyl, 2-
Imidazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 3-pyridazinyl, 2-benzoxazolyl, 2-benzothiazolyl, 2-benzimidazolyl, 3 -Benzoisoxazolyl and 3-benzoisothiazolyl groups, preferably 2-thiazolyl, 4-pyrimidinyl, 2-pyrazinyl, 3-benzoisothiazolyl, 2-pyridyl, 2-pyrimidinyl, 2
-Benzothiazolyl and 2-benzoxazolyl groups, more preferably 2-pyrimidinyl, 2-pyridyl, 2-benzothiazolyl and 2-benzoxazolyl groups.

The formulas (Ia), (Ib) and (I
The R ³ and R ⁶ in the formula of R (h) and (i) in c), optionally heteroaromatic ring group optionally substituted by a phenyl group and R ⁰ may be substituted with R ⁰ is preferred More preferably, R is a group represented by the formula (h), and R ³ in the formula (h) is a heteroaromatic group which may be substituted by R ⁰ , and particularly preferably, R is the formula (h)
And R ³ in the formula (h) is a 5- or 6-membered heteroaromatic group containing 1 or 2 nitrogen atoms which may be substituted with R ⁰ , and more preferably Is a pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, benzothiazolyl, benzoisothiazolyl and benzooxazolyl group wherein R is formula (h) and R ³ in formula (h) may be substituted by R ⁰ It is.

More specifically, the formula (h) of R in the general formulas (Ia), (Ib) and (Ic) is used.
And R ³ and R ⁶ in (i) are preferably
Phenyl, 4-fluorophenyl; 2-pyridyl; 2-
Pyrazinyl; 2-pyrimidinyl, 4-pyrimidinyl; dimethoxy-2-pyrimidinyl; 2-thiazolyl; 2-benzoxazolyl; 2-benzothiazolyl; 3-benzoisothiazolyl; fluorine at the 2-, 3- or 4-position;
Phenyl substituted with chlorine, methoxy, nitro, trifluoromethyl, amino or dimethylamino; 2-pyridyl substituted with methoxy, amino or nitro; 2-pyrimidinyl substituted with chlorine, methyl or ethyl; substituted with chlorine, methyl or ethyl 4-pyrimidinyl; 2-benzoxazolyl substituted with chlorine, methyl or methoxy; 2-benzooxazolyl substituted with chlorine, methyl or methoxy is preferred, and phenyl, 4-
Fluorophenyl; 2-pyridyl; 2-pyrazinyl; 2
-Pyrimidinyl, 4-pyrimidinyl; 2-thiazolyl;
2-benzoxazolyl; 2-benzothiazolyl; 2
Phenyl substituted at the-, 3- or 4-position with fluorine, chlorine, methoxy, nitro, trifluoromethyl, amino or dimethylamino; 2 substituted with methoxy or nitro
2-pyrimidinyl substituted with chlorine, methyl or ethyl; 4-pyrimidinyl substituted with chlorine, methyl or ethyl; 2-benzothiazolyl substituted with methoxy; 2-benzooxazolyl group substituted with methoxy; More preferably, phenyl; 2-pyridyl; 2
2-pyazodinyl; 2-benzothiazolyl; 2-benzoxazolyl; 6-methoxybenzothiazolyl; 6-methoxybenzoxazolyl, most preferably 2-pyrimidinyl; 2-benzothiazolyl; 2-benzoxazolyl; 6-methoxybenzothiazolyl group.

The formulas (Ia), (Ib) and (I
R ⁴ in the formula of R (h) and (i) in c), R
Examples of the alkyl group having 1 to 4 carbon atoms of ⁵ and R ⁷ include:
For example, alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl and t-butyl groups can be mentioned, preferably methyl, ethyl, propyl and isopropyl groups. And particularly preferred are methyl and ethyl groups.

The formulas (Ia), (Ib) and (I
R ⁴ in the formula of R (h) and (i) in c), R
^{As 5} and R ⁷ , a hydrogen atom, a methyl, ethyl, propyl and isopropyl group are preferable, and a hydrogen atom,
Methyl and ethyl groups are preferred.

The formulas (Ia), (Ib) and (I
Examples of the alkyl group having 1 to 4 carbon atoms for R ⁸ in formula (i) of R in c) include alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and t-butyl groups. Preferred are methyl, ethyl, propyl and isopropyl groups, and more preferred are methyl and ethyl groups.

The formulas (Ia), (Ib) and (I
Examples of the alkoxy group having 1 to 4 carbon atoms for R ⁸ in formula (i) of R in c) include alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy and butoxy groups, preferably methoxy, ethoxy. And a propoxy group.

The formulas (Ia), (Ib) and (I
c) R in formula (i) ⁸ As hydrogen
Atom, hydroxyl, methyl, ethyl, propyl, isopropyl
Methoxy, ethoxy and propoxy groups are preferred.
Especially hydrogen, hydroxyl, methyl, ethyl, methoxy
And ethoxy groups are preferred.

The formulas (Ia), (Ib) and (I
In R in c), in formula (h), n is preferably 1, and in formula (i), the sum of n ′ and n ″ is preferably 3, 4 or 5, and particularly preferred. Is preferably 3 or 4, and m is preferably 0.

The formulas (Ia), (Ib) and (I
R in c) is preferably 4- (2-pyrimidinyl) piperazin-1-yl, 4- (2-benzothiazolyl) piperazin-1-yl, 4- (2-benzoxazolyl) piperazin-1- Yl, 4- (6-methoxy-2
-Benzoxazolyl) piperazin-1-yl, 4-
(6-methoxy-2-benzothiazolyl) piperazine-
1-yl and 4- (2-pyridyl) piperazin-1-yl groups, more preferably 4- (2-pyrimidinyl) piperazin-1-yl, 4- (2-benzothiazolyl) piperazin-1-yl , 4- (2-benzoxazolyl) piperazin-1-yl, 4- (2-pyridyl) piperazin-1-yl and 4- (6-methoxy-2-benzothiazolyl) piperazin-1-yl.

The above formula (Ia), (Ib) or (I
When c) has a carboxy group in the molecule, those carboxy groups may be protected with a protecting group to form an ester. The same as those described for the “good carboxy group” can be used.

The above formulas (Ia), (Ib) and (I
The compound represented by c) can be converted into a pharmacologically acceptable salt, if necessary.

Such salts include acid addition salts of mineral acids such as hydrochloride, hydrobromide, hydroiodide, sulfate and phosphate; methanesulfonate and ethanesulfonate. ,
Acid addition salts of organic acids such as benzenesulfonate, p-toluenesulfonate, oxalate, maleate, fumarate, tartrate, citrate; or sodium salt
Metal salts of carboxylic acids such as potassium, calcium, magnesium, manganese, iron and aluminum salts.

The compounds (Ia) and (Ib) of the present invention
And (Ic) can also exist as hydrates.

The autoimmune diseases in Group A include organ-specific and non-specific autoimmune diseases. For example, the organ-specific autoimmune diseases include Hashimoto's thyroiditis, primary myxedema, thyrotoxicosis, Pernicious anemia, Goodpasture syndrome,
Acute progressive glomerulonephritis, myasthenia gravis, pemphigus vulgaris,
Bullous pemphigoid, insulin-dependent diabetes mellitus, juvenile diabetes, Addison's disease, atrophic gastritis, male infertility, premature menopause, lensogenic uveitis, sympathetic vasculitis, multiple sclerosis, ulcerative There are colitis, primary biliary cirrhosis, chronic active hepatitis, autoimmune hemolytic anemia, paroxysmal hemoglobinuria, idiopathic thrombocytopenic purpura, and Sjogren's syndrome. There are rheumatoid arthritis, systemic lupus erythematosus, discoid lupus erythematosus, polymyositis, scleroderma, mixed connective tissue disease.

The sepsis in Group A includes sepsis shock, endotoxin shock, Gram-negative sepsis, toxic shock syndrome, etc. in addition to the usual sepsis.

The cachexia in Group A includes cachexia, cachexia due to acquired immunodeficiency syndrome (AIDS),
Includes cachexia due to infectious diseases.

The active ingredients of the formulas (Ia) and (Ia)
Among the compounds b) and (Ic), preferred are: 1) a compound wherein X is a fluorine atom, 2) a compound wherein Y is a hydrogen atom, a fluorine atom, an amino group, a methyl group or an ethyl group. 3) a compound wherein Y is a hydrogen atom; 4) a compound wherein Z is a carboxy group which may be protected; 5) Q is a compound of the formula (d) and R ^{2 of the} formula (d) But,
6) a compound in which W is a sulfur atom, 7) a compound in which T is ethylidene, -CH = CH- or -C (CH
₃ ) a compound in which ＝ CH—, 8) a compound in which T is an ethylidene group, 9) R ¹ is a hydrogen atom; methyl, ethyl, propyl, isopropyl; 2-hydroxyethyl; carboxymethyl; 2-fluoroethyl , 2-chloroethyl, 2,2
2-trifluoroethyl; 2-acetoxyethyl; phenylmethyl, phenylethyl; 2-pyridylmethyl;
-Dimethylaminoethyl, 2-morpholinoethyl; amino; methylamino; methoxy; cyclopropyl, cyclobutyl, cyclopentyl, 2-fluorocyclopropyl; phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4 - difluorophenyl; vinyl, 2-propenyl; compounds or 2-propynyl group, 10) R ¹ is methyl, ethyl, compound is 2-hydroxyethyl, cyclopropyl or methylamino group, 11) R is 4 -(2-pyrimidinyl) piperazine-1
-Yl, 4- (2-benzothiazolyl) piperazine-1
-Yl, 4- (2-benzoxazolyl) piperazine-
1-yl, 4- (6-methoxy-2-benzooxazolyl) piperazin-1-yl, 4- (6-methoxy-2-
Benzothiazolyl) piperazin-1-yl or 4- (2
-Pyridyl) piperazin-1-yl group, 12) R is 4- (2-pyrimidinyl) piperazine-1
-Yl, 4- (2-benzothiazolyl) piperazine-1
-Yl, 4- (2-benzoxazolyl) piperazine-
Examples of the compound include a 1-yl, 4- (2-pyridyl) piperazin-1-yl or 4- (6-methoxy-2-benzothiazolyl) piperazin-1-yl group. The compounds represented by the general formula (Ia), (Ib) or (Ic), which are the active ingredients of the present invention, can be exemplified in Tables 1 to 38.

[0087]

[Table 1]

[0088]

[Table 2]

[0089]

[Table 3]

[0090]

[Table 4]

[0091]

[Table 5]

[0092]

[Table 6]

[0093]

[Table 7]

[0094]

[Table 8]

[0095]

[Table 9]

[0096]

[Table 10]

[0097]

[Table 11]

[0098]

[Table 12]

[0099]

[Table 13]

[0100]

[Table 14]

[0101]

[Table 15]

[0102]

[Table 16]

[0103]

[Table 17]

[0104]

[Table 18]

[0105]

[Table 19]

[0106]

[Table 20]

[0107]

[Table 21]

[0108]

[Table 22]

[0109]

[Table 23]

[0110]

[Table 24]

[0111]

[Table 25]

[0112]

[Table 26]

[0113]

[Table 27]

[0114]

[Table 28]

[0115]

[Table 29]

[0116]

[Table 30]

[0117]

[Table 31]

[0118]

Embedded image

[0119]

[Table 32] ──────────────────────────────────── R ¹ R ³ ────── ────────────────────────────── propyl 3-benzoisoxazolyl 3-benzoisothiazolyl 6-methoxy-2- Benzoxazolyl 5-methoxy-2-benzoxazolyl 6-methoxy-2-benzothiazolyl 5-methoxy-2-benzothiazolyl 2-benzothiazolyl 2-benzoxazolyl isopropyl 3-benzoisoxazolyl 3-benzoisothiazo Ryl 6-methoxy-2-benzoxazolyl 5-methoxy-2-benzooxazolyl 6-methoxy-2-benzothiazolyl 5-methoxy-2-benzothiazolyl 2-benzothiazolyl 2-benzoxazolyl ────────────────────────────────

[0120]

Embedded image

[0121]

[Table 33] ──────────────────────────────────── R ¹ R ³ ──────ブ チ ル Butyl 3-benzoisoxazolyl 3-benzoisothiazolyl 6-methoxy-2- Benzoxazolyl 5-methoxy-2-benzoxazolyl 6-methoxy-2-benzothiazolyl 5-methoxy-2-benzothiazolyl 2-benzothiazolyl 2-benzoxazolyl isobutyl 3-benzoisoxazolyl 3-benzoisothiazo Ryl 6-methoxy-2-benzoxazolyl 5-methoxy-2-benzooxazolyl 6-methoxy-2-benzothiazolyl 5-methoxy-2-benzothiazolyl 2-benzothiazolyl 2-benzoxazolyl ──────────────────────────────

[0122]

Embedded image

[0123]

[Table 34] ──────────────────────────────────── R ¹ R ³ ──────水 素 hydrogen atom 3-benzoisoxazolyl 3-benzoisothiazolyl 6-methoxy-2 -Benzoxazolyl 5-methoxy-2-benzoxazolyl 6-methoxy-2-benzothiazolyl 5-methoxy-2-benzothiazolyl 2-benzothiazolyl 2-benzoxazolyl cyclobutyl 3-benzoisoxazolyl 3-benzoisothi Azolyl 6-methoxy-2-benzoxazolyl 5-methoxy-2-benzoxazolyl 6-methoxy-2-benzothiazolyl 5-methoxy-2-benzothiazolyl 2-benzothiazolyl 2-benzoxazolyl ────────────────────────────────

[0124]

Embedded image

[0125]

[Table 35] ──────────────────────────────────── R ¹ R ³ ──────シ ク ロ Cyclopentyl 3-benzoisoxazolyl 3-benzoisothiazolyl 6-methoxy-2- Benzoxazolyl 5-methoxy-2-benzoxazolyl 6-methoxy-2-benzothiazolyl 5-methoxy-2-benzothiazolyl 2-benzothiazolyl 2-benzoxazolyl methylamino 3-benzoisoxazolyl 3-benzoisothi Azolyl 6-methoxy-2-benzoxazolyl 5-methoxy-2-benzoxazolyl 6-methoxy-2-benzothiazolyl 5-methoxy-2-benzothiazolyl 2-benzothiazolyl 2-benzoxazolyl ───────────────────────────────────

[0126]

Embedded image

[0127]

[Table 36] ──────────────────────────────────── R ¹ R ³ ────── ────────────────────────────── 2-fluoroethyl 3-benzoisoxazolyl 3-benzoisothiazolyl 6-methoxy -2-benzoxazolyl 5-methoxy-2-benzoxazolyl 6-methoxy-2-benzothiazolyl 5-methoxy-2-benzothiazolyl 2-benzothiazolyl 2-benzoxazolyl 2-hydroxyethyl 3-benzoisoxazolyl 3-benzoisothiazolyl 6-methoxy-2-benzoxazolyl 5-methoxy-2-benzoxazolyl 6-methoxy-2-benzothiazolyl 5-methoxy-2-benzothiazolyl 2-benzothiazolyl 2-benzo Kisazoriru ────────────────────────────────────

[0128]

Embedded image

[0129]

[Table 37] ──────────────────────────────────── R ¹ R ³ R ⁴ ────メ チ ル methyl 3-benzisoxazolyl methyl 3-benzoisothiazolyl methyl 6- Methoxy-2-benzoxazolyl methyl 5-methoxy-2-benzooxazolyl methyl 6-methoxy-2-benzothiazolyl methyl 5-methoxy-2-benzothiazolyl methyl 2-benzooxazolyl methyl ethyl 3-benzoisoxazolyl Methyl 3-benzoisothiazolyl methyl 6-methoxy-2-benzoxazolyl methyl 5-methoxy-2-benzoxazolyl methyl 6-methoxy-2-benzothiazolyl methyl 5-methoxy-2-benzothia Lil methyl 2-benzothiazolyl methyl 2-benzoxazolyl methyl ────────────────────────────────────

[0130]

Embedded image

[0131]

[Table 38] ──────────────────────────────────── R ¹ R ³ ──────メ チ ル Methyl 3-benzoisoxazolyl 3-benzoisothiazolyl 6-methoxy-2- Benzoxazolyl 5-methoxy-2-benzoxazolyl 6-methoxy-2-benzothiazolyl 5-methoxy-2-benzothiazolyl 2-benzothiazolyl 2-benzoxazolyl ethyl 3-benzoisoxazolyl 3-benzoisothiazo Ryl 6-methoxy-2-benzoxazolyl 5-methoxy-2-benzooxazolyl 6-methoxy-2-benzothiazolyl 5-methoxy-2-benzothiazolyl 2-benzothiazolyl 2-benzoxazolyl ─ ──────────────────────────── Formula is the active ingredient of the present invention (Ia), (Ib)
Or as a more preferred compound represented by (Ic),
1-cyclopropyl-6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-7- [4-
(2-Pyrimidinyl) piperazin-1-yl] quinoline-3-carboxylic acid, 1-cyclopropyl-6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-7- [4- (2 -Pyridyl) piperazin-1-yl] quinoline-3-carboxylic acid, 1-cyclopropyl-
6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-7- [4- (2-methoxyphenyl) piperazin-1-yl] quinoline-3-carboxylic acid, 1-cyclopropyl-6 -Fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-7- (4
-Phenylpiperazin-1-yl) quinoline-3-carboxylic acid, 1-cyclopropyl-6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-7-
[4- (3-chlorophenyl) piperazin-1-yl]
Quinoline-3-carboxylic acid, 1-cyclopropyl-6-
Fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-7- [4- (4-fluorophenyl) piperazin-1-yl] quinoline-3-carboxylic acid, 1-
Cyclopropyl-6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-7- [4- (3-
Trifluoromethylphenyl) piperazin-1-yl]
Quinoline-3-carboxylic acid, 6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-1-methyl-7- [4- (2-pyrimidinyl) piperazine-1
-Yl] quinoline-3-carboxylic acid, 6-fluoro-8
-Trifluoromethyl-1,4-dihydro-4-oxo-1-methyl-7- [4- (2-pyridyl) piperazin-1-yl] quinoline-3-carboxylic acid, 1-ethyl-
6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-7- [4- (2-pyrimidinyl) piperazin-1-yl] quinoline-3-carboxylic acid, 1-
Ethyl-6-fluoro-8-trifluoromethyl-1,
4-dihydro-4-oxo-7- [4- (2-pyridyl) piperazin-1-yl] quinoline-3-carboxylic acid, 1-ethyl-6-fluoro-8-trifluoromethyl-1,4-dihydro -4-oxo-7- [4- (2-
Methoxyphenyl) piperazin-1-yl] quinoline-
3-carboxylic acid, 6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-1-isopropyl-7- [4- (2-pyrimidinyl) piperazin-1-yl] quinoline-3-carboxylic acid Acid, 6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-1
-Isopropyl-7- [4- (2-pyridyl) piperazin-1-yl] quinoline-3-carboxylic acid, 6-fluoro-8-trifluoromethyl-1,4-dihydro-4-
Oxo-1-isopropyl-7- [4- (2-methoxyphenyl) piperazin-1-yl] quinoline-3-carboxylic acid, 6-fluoro-1- (2-fluoroethyl)-
8-trifluoromethyl-1,4-dihydro-4-oxo-7- [4- (2-pyrimidinyl) piperazine-1-
Yl] quinoline-3-carboxylic acid, 6-fluoro-1-
(2-fluoroethyl) -8-trifluoromethyl-
1,4-dihydro-4-oxo-7- [4- (2-pyridyl) piperazin-1-yl] quinoline-3-carboxylic acid, 6-fluoro-1- (2-fluoroethyl) -8-
Trifluoromethyl-1,4-dihydro-4-oxo-
7- [4- (2-methoxyphenyl) piperazine-1-
Yl] quinoline-3-carboxylic acid, 6-fluoro-8-
Trifluoromethyl-1,4-dihydro-4-oxo-
1-methyl-7- [4- (2-methoxyphenyl) piperazin-1-yl] quinoline-3-carboxylic acid, 6-fluoro-8-trifluoromethyl-1,4-dihydro-
4-oxo-1-methyl-7- [4- (2-chlorophenyl) piperazin-1-yl] quinoline-3-carboxylic acid, 6-fluoro-8-trifluoromethyl-1,4-
Dihydro-4-oxo-1-methyl-7- (4-phenylpiperazin-1-yl) quinoline-3-carboxylic acid,
6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-1-methyl-7- [4- (4-fluorophenyl) piperazin-1-yl] quinoline-3-
Carboxylic acid, 6-fluoro-8-trifluoromethyl-
1,4-dihydro-4-oxo-1-methyl-7- [4
-(2-Thiazolyl) piperazin-1-yl] quinoline-3-carboxylic acid, 6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-1-methyl-7
-[4- (2-methylthiophenyl) piperazine-1-
Yl] quinoline-3-carboxylic acid, 1-ethyl-6-fluoro-8-trifluoromethyl-1,4-dihydro-
4-oxo-7- [4- (4-methoxyphenyl) piperazin-1-yl] quinoline-3-carboxylic acid, 1-ethyl-6-fluoro-8-trifluoromethyl-1,4
-Dihydro-4-oxo-7- [4- (4-chlorophenyl) piperazin-1-yl] quinoline-3-carboxylic acid, 1-ethyl-6-fluoro-8-trifluoromethyl-1,4-dihydro- 4-oxo-7- [4- (5-
Chloro-2-pyrimidinyl) piperazin-1-yl] quinoline-3-carboxylic acid, 1-ethyl-6-fluoro-
8-trifluoromethyl-1,4-dihydro-4-oxo-7- [4- (2-fluorophenyl) piperazine-
1-yl] quinoline-3-carboxylic acid, 1-ethyl-6
-Fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-7- [4- (3-methoxyphenyl)
Piperazin-1-yl] quinoline-3-carboxylic acid, 1
-Cyclopropyl-6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-7- [4- (2
-Pyridyl) piperazin-1-yl] quinoline-3-carboxylic acid 2-morpholinoethyl ester, 6-fluoro-8-trifluoromethyl-1,4-dihydro-4-
Oxo-1-methyl-7- [3-methyl-4- (2-pyrimidinyl) piperazin-1-yl] quinoline-3-carboxylic acid, 6-fluoro-8-trifluoromethyl-
1,4-dihydro-4-oxo-1-methyl-7- [4
-(2-Pyrimidinyl) homopiperazin-1-yl] quinoline-3-carboxylic acid 6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-1-methyl-7- [4- (2 -Benzothiazolyl) piperazin-1-yl] quinoline-3-
Carboxylic acid, 6-fluoro-8-trifluoromethyl-
1,4-dihydro-4-oxo-1-methyl-7- [4
-(2-benzoxazolyl) piperazin-1-yl]
Quinoline-3-carboxylic acid, 6-fluoro-8-difluoromethoxy-1,4-dihydro-4-oxo-1-ethyl-7- [4- (2-benzothiazolyl) piperazin-1-yl] quinoline-3- Carboxylic acid, 6-fluoro-8-difluoromethoxy-1,4-dihydro-4-oxo-1-methyl-7- [4- (2-benzothiazolyl) piperazin-1-yl] quinoline-3-carboxylic acid, 6 -Fluoro-8-difluoromethoxy-1,4-
Dihydro-4-oxo-1-methyl-7- [4- (6-
Methoxy-2-benzothiazolyl) piperazin-1-yl] quinoline-3-carboxylic acid, 6-fluoro-8-difluoromethoxy-1,4-dihydro-4-oxo-1
-(2-hydroxyethyl) -7- [4- (2-benzothiazolyl) piperazin-1-yl] quinoline-3-carboxylic acid and 6-fluoro-8-difluoromethoxy-
1,4-dihydro-4-oxo-1-methylamino-7
-[4- (2-benzoxazolyl) piperazine-1-
Yl] quinoline-3-carboxylic acid, and more preferable compound is 1-cyclopropyl-6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-7- [4- ( 2-pyridyl) piperazin-1-yl] quinoline-3-carboxylic acid, 6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-1
-Methyl-7- [4- (2-pyrimidinyl) piperazin-1-yl] quinoline-3-carboxylic acid, 6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-1-methyl- 7- [4- (2-pyridyl) piperazin-1-yl] quinoline-3-carboxylic acid, 1-ethyl-6-fluoro-8-trifluoromethyl-1,4-
Dihydro-4-oxo-7- [4- (2-pyridyl) piperazin-1-yl] quinoline-3-carboxylic acid, 6-
Fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-1-methyl-7- [4- (4-fluorophenyl) piperazin-1-yl] quinoline-3-carboxylic acid, 6-fluoro- 8-trifluoromethyl-1,
4-dihydro-4-oxo-1-methyl-7- [4-
(2-Thiazolyl) piperazin-1-yl] quinoline-
3-carboxylic acid, 6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-1-methyl-7-
[4- (2-benzothiazolyl) piperazin-1-yl] quinoline-3-carboxylic acid, 6-fluoro-8-difluoromethoxy-1,4-dihydro-4-oxo-1
-Ethyl-7- [4- (2-benzothiazolyl) piperazin-1-yl] quinoline-3-carboxylic acid, 6-fluoro-8-difluoromethoxy-1,4-dihydro-4
-Oxo-1-methyl-7- [4- (2-benzothiazolyl) piperazin-1-yl] quinoline-3-carboxylic acid, 6-fluoro-8-difluoromethoxy-1,4-
Dihydro-4-oxo-1-methyl-7- [4- (6-
Methoxy-2-benzothiazolyl) piperazin-1-yl] quinoline-3-carboxylic acid, 6-fluoro-8-difluoromethoxy-1,4-dihydro-4-oxo-1
-(2-hydroxyethyl) -7- [4- (2-benzothiazolyl) piperazin-1-yl] quinoline-3-carboxylic acid and 6-fluoro-8-difluoromethoxy-
1,4-dihydro-4-oxo-1-methylamino-7
-[4- (2-benzoxazolyl) piperazine-1-
Yl] quinoline-3-carboxylic acid, and a particularly preferred compound is 1-cyclopropyl-6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-7- [4- ( 2-pyridyl) piperazin-1-yl] quinoline-3-carboxylic acid, 6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-1
-Methyl-7- [4- (2-pyrimidinyl) piperazin-1-yl] quinoline-3-carboxylic acid, 6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-1-methyl- 7- [4- (2-pyridyl) piperazin-1-yl] quinoline-3-carboxylic acid, 6-fluoro-8-trifluoromethyl-1,4-dihydro-4
-Oxo-1-methyl-7- [4- (2-benzothiazolyl) piperazin-1-yl] quinoline-3-carboxylic acid, 6-fluoro-8-difluoromethoxy-1,4-
Dihydro-4-oxo-1-ethyl-7- [4- (2-
Benzothiazolyl) piperazin-1-yl] quinoline-
3-carboxylic acid, 6-fluoro-8-difluoromethoxy-1,4-dihydro-4-oxo-1-methyl-7-
[4- (2-benzothiazolyl) piperazin-1-yl] quinoline-3-carboxylic acid, 6-fluoro-8-difluoromethoxy-1,4-dihydro-4-oxo-1
-Methyl-7- [4- (6-methoxy-2-benzothiazolyl) piperazin-1-yl] quinoline-3-carboxylic acid, 6-fluoro-8-difluoromethoxy-1,4
-Dihydro-4-oxo-1- (2-hydroxyethyl) -7- [4- (2-benzothiazolyl) piperazin-1-yl] quinoline-3-carboxylic acid and 6-fluoro-8-difluoromethoxy-1, 4-dihydro-4-
Oxo-1-methylamino-7- [4- (2-benzoxazolyl) piperazin-1-yl] quinoline-3-carboxylic acid, and the most preferred compound is 6-
Fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-1-methyl-7- [4- (2-pyrimidinyl) piperazin-1-yl] quinoline-3-carboxylic acid, 6-fluoro-8 -Difluoromethoxy-1,4-
Dihydro-4-oxo-1-ethyl-7- [4- (2-
Benzothiazolyl) piperazin-1-yl] quinoline-
3-carboxylic acid, 6-fluoro-8-difluoromethoxy-1,4-dihydro-4-oxo-1-methyl-7-
[4- (2-benzothiazolyl) piperazin-1-yl] quinoline-3-carboxylic acid, 6-fluoro-8-difluoromethoxy-1,4-dihydro-4-oxo-1
-Methyl-7- [4- (6-methoxy-2-benzothiazolyl) piperazin-1-yl] quinoline-3-carboxylic acid, 6-fluoro-8-difluoromethoxy-1,4
-Dihydro-4-oxo-1- (2-hydroxyethyl) -7- [4- (2-benzothiazolyl) piperazin-1-yl] quinoline-3-carboxylic acid and 6-fluoro-8-difluoromethoxy-1, 4-dihydro-4-
Oxo-1-methylamino-7- [4- (2-benzoxazolyl) piperazin-1-yl] quinoline-3-carboxylic acid.

The TNF-α production inhibitor of the present invention is preferably: 1) the quinolone carboxylic acid as an active ingredient is represented by the formula (I)
a) a TNF-α production inhibitor which is (Ib) or (Ic); 2) the quinolone carboxylic acid as an active ingredient is represented by the formula (Ia)
3) The active ingredient quinolone carboxylic acid, wherein X is a fluorine atom and Y is a hydrogen atom, a fluorine atom, an amino group, a methyl group or an ethyl group in the formula (Ia). , Z is an optionally protected carboxy group, and Q is a group represented by the formula (d)
And R ² of the formula (d) is a methoxy, difluoromethoxy or trifluoromethyl group, and R ¹ is
Hydrogen atom; methyl, ethyl, propyl, isopropyl;
2-hydroxyethyl; carboxymethyl; 2-fluoroethyl, 2-chloroethyl, 2,2,2-trifluoroethyl; 2-acetoxyethyl; phenylmethyl, phenylethyl; 2-pyridylmethyl; 2-dimethylaminoethyl, Morpholinoethyl; amino; methylamino; methoxy; cyclopropyl, cyclobutyl, cyclopentyl, 2-fluorocyclopropyl;
-Fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl; vinyl,
2-propenyl; or a 2-propynyl group, wherein R is
4- (2-pyrimidinyl) piperazin-1-yl, 4-
(2-benzothiazolyl) piperazin-1-yl, 4-
(2-benzoxazolyl) piperazin-1-yl, 4
-(6-methoxy-2-benzoxazolyl) piperazin-1-yl, 4- (6-methoxy-2-benzothiazolyl) piperazin-1-yl or 4- (2-pyridyl)
TNF-α which is a compound which is a piperazin-1-yl group
4) The quinolone carboxylic acid as an active ingredient, in the formula (Ia), wherein X is a fluorine atom, Y is a hydrogen atom, a fluorine atom, an amino group, a methyl group or an ethyl group, and Z is protected. Is a carboxy group, and Q is a group represented by the formula (d)
And R ² of the formula (d) is a methoxy, difluoromethoxy or trifluoromethyl group, and R ¹ is
A methyl, ethyl, 2-hydroxyethyl, 2-fluoroethyl, cyclopropyl or methylamino group;
Is 4- (2-pyrimidinyl) piperazin-1-yl,
4- (2-benzothiazolyl) piperazin-1-yl,
4- (2-pyridyl) piperazin-1-yl, 4- (2
-Benzoxazolyl) piperazin-1-yl or 4-
(6-methoxy-2-benzothiazolyl) piperazine-
A TNF-α production inhibitor which is a compound which is a 1-yl group, 5) the quinolone carboxylic acid as an active ingredient is 1-cyclopropyl-6-fluoro-8-trifluoromethyl-1,4
-Dihydro-4-oxo-7- [4- (2-pyridyl)
Piperazin-1-yl] quinoline-3-carboxylic acid, 6
-Fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-1-methyl-7- [4- (2-pyrimidinyl) piperazin-1-yl] quinoline-3-carboxylic acid, 6-fluoro- 8-trifluoromethyl-1,4
-Dihydro-4-oxo-1-methyl-7- [4- (2
-Pyridyl) piperazin-1-yl] quinoline-3-carboxylic acid, 6-fluoro-8-trifluoromethyl-
1,4-dihydro-4-oxo-1-methyl-7- [4
-(2-benzothiazolyl) piperazin-1-yl] quinoline-3-carboxylic acid, 6-fluoro-8-difluoromethoxy-1,4-dihydro-4-oxo-1-ethyl-7- [4- (2- Benzothiazolyl) piperazine-
1-yl] quinoline-3-carboxylic acid, 6-fluoro-
8-difluoromethoxy-1,4-dihydro-4-oxo-1-methyl-7- [4- (2-benzothiazolyl)
Piperazin-1-yl] quinoline-3-carboxylic acid, 6
-Fluoro-8-difluoromethoxy-1,4-dihydro-4-oxo-1-methyl-7- [4- (6-methoxy-2-benzothiazolyl) piperazin-1-yl] quinoline-3-carboxylic acid, 6 -Fluoro-8-difluoromethoxy-1,4-dihydro-4-oxo-1- (2
-Hydroxyethyl) -7- [4- (2-benzothiazolyl) piperazin-1-yl] quinoline-3-carboxylic acid or 6-fluoro-8-difluoromethoxy-1,4
-Dihydro-4-oxo-1-methylamino-7- [4
-(2-benzoxazolyl) piperazin-1-yl]
And TNF-α production inhibitors which are quinoline-3-carboxylic acids.

[0133]

BEST MODE FOR CARRYING OUT THE INVENTION The compounds represented by the general formulas (Ia), (Ib) and (Ic), which are the active ingredients of the present invention, are disclosed in EP 572,259, published in Japanese Unexamined Patent Publication No.
No. 16241) and / or WO /
It is produced by the method described in JP-A-02512 and a method analogous thereto.

The compound represented by formula (Ia), (Ib) or (Ic) produced as described above may have an optical isomer or a geometric (cis, trans) isomer. is there. In such a case, the above-mentioned reaction is carried out at an appropriate stage by optical resolution or using the separated raw material compound, whereby the corresponding target compound (I
Optical isomers or geometric isomers of a), (Ib) or (Ic) can be obtained. In addition, general formulas (Ia) and (Ia)
The mixture of the optical isomers or the geometric isomers of the compound represented by b) or (Ic) can be treated according to a usual optical resolution method or separation method to obtain each stereoisomer.

When the compound represented by formula (Ia), (Ib) or (Ic) has a carboxy group in the molecule, the carboxy group is protected as described above to form an ester. The ester formation reaction may be carried out from the corresponding carboxy compound and an alcohol by a conventional method (for example, a dehydration condensation method using an acid catalyst, a method via an acid halide, a dehydration condensation method using a carbodiimide, etc.).

The compound of the general formula (Ia), (Ib) or (Ic) is useful as a TNF-α production inhibitor or a therapeutic agent for various diseases caused by overproduction of TNF-α.

The administration forms for that purpose include, for example, oral administration by tablets, capsules, granules, powders, syrups and the like, intravenous injections, intramuscular injections,
Parenteral administration with a suppository patch or the like can be mentioned.

The dose varies depending on the age, body weight, symptoms, administration form and number of administrations, but usually the adult is treated with the compound of the formula (Ia), (Ib) or (Ic) in an amount of about 0,1 per day. 1 to 1000 mg is administered once or in several divided doses.

[0139]

Next, the present invention will be described more specifically with reference to examples.

[0140]

【Example】

1) Cells and their cultures R containing 10% fetal bovine serum at 37 ° C. under 5% CO ₂
Using PMI-1640 medium, human histiocytic lympho
Ma cell line U937 (ATCC CRL 1593) was cultured.

2) TNF Production Inhibition Test TNF- containing 30 ng / ml of tetradecanoyl phorbol acetate (manufactured by Sigma) and 1 g of newborn bovine serum was used.
U937 cells in RPMI-1640 medium containing 0%
The suspension was suspended at a concentration of 1 to 2.5 × 10 ⁶ cells / ml, and 200 μl of the suspension was dispensed into each well of a 96-well multiplate and cultured at 37 ° C. under 5% CO ₂ .

After culturing for 72 hours, the medium was removed with aspirate, and RPMI-164 containing various concentrations of the test compound was used.
0 medium (containing 10% newborn calf serum) in 200 μl
Each well was dispensed to each well, and the culture was continued for 30 minutes. Then, lipopolysaccharide (manufactured by Sigma) was added at 10 ng /
ml to each well and further culture for 1
Continued for 5 hours to induce TNF-α production.

The concentration of TNF-α in the obtained culture supernatant was measured using a human TNF-α Elisa quantification kit (manufactured by Genzyme), and the TNF-α production inhibitory activity of the test compound was determined.

[0144]

３９ Production Example No. TNF-α production inhibitory activity (IC ₅₀ μg / Ml) ８ 8 0.6 19 0.5 79 1.0 11 10 1.2 112 0.8 113 0.8 114 0.5 115 115 0.8 117 0.8 118 118 0.07 120 0.3 128 0.2 0.2 130 0.1 131 0.06 132 0.05 135 135 0.2 139 0.02 140 0.1 化合物 The compound of the present invention has excellent TNF- It showed α production inhibitory activity.

(Production Example 1) 1-Cyclopropyl-6-fluoro-8-difluorome
Toxi-7- [4- (2-methoxyphenyl) piperazine
1-yl] -1,4-dihydro-4-oxoquinolyl
Synthesis of N-3-carboxylic acid and hydrochloride

[0146]

Embedded image

1.66 g (0.005 mol) of 1-cyclopropyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 1- (2-methoxy Phenyl) piperazine 2.4
g (0.0125 mol) was dissolved in 20 ml of pyridine.
After stirring at 5 to 110 ° C. for 3 hours, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: 9.5: 0.5 mixture of chloroform-methanol) to give the free form of the target compound 1.33 g were obtained. Next, 1.33 g of this free compound was dissolved in 100 ml of a 4: 1 mixture of chloroform and methanol, concentrated with 2 ml of concentrated hydrochloric acid, concentrated under reduced pressure, and the residue was washed with a 4: 1 mixture of methanol and ethanol and dried. 1.08 g of the title compound was obtained as a white powder.

Melting point: 223 to 225 ° C. NMR (DMSO-d ₆ , δ): 1.04 to 1.07 (2H, m), 1.16 to 1.17 (2
H, m), 3.30 (4H, br.s), 3.47 (4H, br.s), 3.86 (3H, s), 4.0
9 ~ 4.12 (1H, m), 6.90 ~ 7.27 (5H, m), 7.95 ~ 7.98 (1H, d,
J = 12.1 Hz), 8.79 (1H, s) MS spectrum (CI): m / e 504 (M ⁺⁺ 1) (Production Examples 2 to 62) Table 4 by a method similar to Production Example 1
Compounds 0 to 43 were synthesized.

[0149]

[Table 40]

[0150]

[Table 41]

[0151]

[Table 42]

[0152]

[Table 43]

(Production Example 63) 1-ethyl-6-fluoro-8-difluoromethoxy-
7- [4- (2-methoxyphenyl) piperazine-1-
Yl] -1,4-dihydro-4-oxoquinoline-3-
Synthesis of carboxylic acid

[0154]

Embedded image

1-ethyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 5.0 g (0.016 mol),
To a suspension of methyl isobutyl ketone (20 ml) was added boron trifluoride diethyl ether complex (4.54 g, 0.032 mol), and the mixture was stirred under reflux with heating for 6 hours. After allowing the reaction mixture to cool, the precipitated crystals were collected by filtration, washed with ether and chloroform, and then washed with 1-ethyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-oxoquinoline-3.
- to give the carboxylic acid · BF ₂ chelate compound 32g as a pale pink crystals.

0.5 g (0.00136 mol) of the chelate compound thus obtained, 1.3 g (0.0068 mol) of 1- (2-methoxyphenyl) piperazine and 2 ml of triethylamine were added to 5 ml of dimethyl sulfoxide. After stirring at room temperature for 5 hours, the mixture was left overnight. Water was added to the reaction mixture, and the precipitated yellow crystals were collected by filtration and washed with water. The crystals were dissolved in 100 ml of 80% methanol containing 2.5 ml of triethylamine, heated under reflux for 12 hours, the solvent was distilled off under reduced pressure, the residue was washed with a mixed solvent of ethanol and water, dried and dried. 5 g were obtained as a pale red powder.

Melting point: 219 to 222 ° C. NMR (DMSO-d ₆ , δ): 1.28 (3H, t, J = 7.0 Hz), 3.11 (4H, b
rs), 3.47 (4H, Br.s), 3.81 (3H, s), 4.74 (2H, q, J = 7.0H
z), 6.92-7.32 (5H, m), 8.01-8.04 (1H, d, J = 12.1Hz),
8.96 (1H, s) MS spectrum (CI): m / e 492 (M ⁺ +1) (Production Examples 64 to 89) The compounds of Tables 44 to 46 were synthesized in the same manner as in Production Example 63.

[0158]

[Table 44]

[0159]

[Table 45]

[0160]

[Table 46]

(Production Example 90) 6-Fluoro-1- (4-fluorophenyl) -7-
[4- (2-methoxyphenyl) piperazine-1-i
L] -1,4-dihydro-4-oxo-1,8-naphthy
Synthesis of lysine-3-carboxylic acid

[0162]

Embedded image

0.81 g (0.0042 mol) of 1- (2-methoxyphenyl) piperazine is dissolved in 40 ml of ethanol, and the mixture is stirred at 30 ° C. while stirring for 7-chloro-6-fluoro-1- (4-fluorophenyl). 1.02 g (0.0028 mol) of -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester was added little by little. After the addition was completed, the reaction was carried out at the same temperature for 4 hours.
After allowing the reaction solution to cool, the precipitated crystals were collected by filtration and washed with ethanol. 12 ml of a 6N hydrochloric acid aqueous solution was added to the crystals, and the mixture was refluxed for 6 hours. After cooling, the reaction solution was adjusted to pH 8.5 with a 1N aqueous sodium hydroxide solution, and the precipitated crystals were collected by filtration and subjected to silica gel column chromatography (eluent: chloroform: methanol = 9.5: 0.5 mixture). To give 0.87 g of the title compound as a pale yellow powder.

Melting point: 272 ° -273 ° C. NMR (DMSO-d ₆ , δ): 2.97 (4H, br.s), 3.71 (4H, br.s),
3.80 (3H, s), 6.86 to 7.70 (8H, m), 8.17 to 8.20 (1H, d,
J = 13.6Hz), 8.70 (1H, s), 15.13 (1H, s) MS spectrum (CI): m / e 493 (M ⁺⁺ 1) (Production Examples 91 to 93) By the same method as in Production Example 90, The compounds in Table 47 were synthesized.

[0165]

[Table 47]

(Production Example 94) 1-ethyl-6-fluoro-8-difluoromethoxy-
7- [3-methyl-4- (2-pyrimidinyl) piperazine
1-yl] -1,4-dihydro-4-oxoquinolyl
Synthesis of N-3-carboxylic acid

[0167]

Embedded image

3.19 g (0.01 mol) of 1-ethyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 2
After dissolving 3.0 g (0.03 mol) of -methylpiperazine in 60 ml of pyridine and stirring at 105 to 110 ° C for 2 hours, the solvent was distilled off under reduced pressure. Water was added to the residue, and the precipitated crystals were collected by filtration, washed with water and ethanol, dried, and dried with 1-ethyl-6-fluoro-8-difluoromethoxy-7- (3
-Methylpiperazin-1-yl) -1,4-dihydro-
3.23 g of 4-oxoquinoline-3-carboxylic acid was obtained as a pale yellow powder.

1.6 g (0.004 mol) of this powder and 2
0.9 g (0.008 mol) of chloropyrimidine and 0.81 g (0.008 mol) of triethylamine were added to N, N-
The mixture was added to 20 ml of dimethylformamide, stirred at 130 ° C. for 15 hours, and the solvent was removed under reduced pressure. Ethanol was added to the residue, and the precipitated crystals were collected by filtration and subjected to silica gel column chromatography (eluent; chloroform: methanol = 9.
5: 0.5 mixture) to give the title compound of interest 0.34
g were obtained as a pale yellow powder.

Melting point: 219 to 221 ° C. MS spectrum (CI): m / e 478 (M ⁺⁺ 1) Elemental analysis value (%): C ₂₂ H ₂₂ F ₃ N ₅ O ₄ Theoretical value: C, 55.35, H , 4.64, N, 14.67 Found: C, 55.41, H, 4.56, N, 14.65 (Production Examples 95 to 97) The compounds in Table 48 were synthesized in the same manner as in Production Example 94.

[0171]

[Table 48]

(Production Example 98) 1-ethyl-6-fluoro-8-difluoromethoxy-
7- [4- (2-pyrimidinyl) piperazine-1-i
L] -3- (5-tetrazolyl) -1,4-dihydro-
Synthesis of 4-oxoquinoline

[0173]

Embedded image

3-cyano-1-ethyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4
-Oxoquinoline 4.85 g and 1- (2-pyrimidinyl) piperazine 9.49 g were reacted in the same manner as in Production Example 1 to give 3-cyano-1-ethyl-6-fluoro-8-.
Difluoromethoxy-7- [4- (2-pyrimidinyl)
Piperazin-1-yl] -1,4-dihydro-4-oxoquinoline (4.2 g) was obtained as a pale yellow powder (mp 286-290).
° C).

3-cyano-1-ethyl-6-fluoro-
8-difluoromethoxy-7- [4- (2-pyrimidinyl) piperazin-1-yl] -1,4-dihydro-4-
0.5 g (0.0011 mol) of oxoquinoline, 0.21 g (0.0033 mol) of sodium azide, and 1.07 g (0.0033 mol) of tributyltin chloride are added to 25 ml of xylene, and heated under reflux. Stir for 9 hours. After cooling to room temperature, 7 ml of a 1N aqueous hydrochloric acid solution was added. After stirring, the precipitated crystals were collected by filtration, washed with ethanol and toluene, and subjected to silica gel column chromatography (eluent; chloroform: methanol = 9: 1 mixture). 0.37 g of the title compound was obtained as a pale yellow powder. Mp: 265~268 ℃ MS spectrum (CI): m / e 488 (M + +1) Elemental analysis _{(%): C 21 H 20} F 3 N 9 O 2 · 1 / 2H 2
As O Theoretical value: C, 50.81, H, 4.06, N, 25.39 Observed value: C, 50.96, H, 4.16, N, 25.58 (Production Example 99) 1-ethyl-8-difluoromethoxy-7- [4- ( 2
-Pyrimidinyl) piperazin-1-yl] -1,4-di
Synthesis of hydro-4-oxoquinoline-3-carboxylic acid

[0176]

Embedded image

1-ethyl-7-fluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-
The same procedure as in Production Example 1 was carried out using 3-carboxylic acid and 1- (2-pyrimidinyl) piperazine to obtain the title compound as a white powder. Melting point:> 300 ° C. MS spectrum (CI): m / e 446 (M ⁺⁺ 1) Elemental analysis (%): as C ₂₁ H ₂₁ F ₂ N ₅ O ₄ Theoretical values: C, 56.63, H, 4.75, N , 15.72 Found: C, 56.70, H, 4.62, N, 15.34 (Production Example 100) 6-Fluoro-1-methyl-4-oxo-7- [4-
(2-pyrimidinyl) piperazin-1-yl] -1H,
4H- [1,3] thiazeto [3,2-a] quinoline-3
-Synthesis of carboxylic acids

[0178]

Embedded image

6,7-Difluoro-1-methyl-4-oxo-1H, 4H- [1,3] thiazeto [3,2-a]
2.0 g of ethyl quinoline-3-carboxylate (0.006
4 mol), 1- (2-pyrimidinyl) piperazine dihydrochloride 3.0 g (0.0129 mol), and 1,8-diazabicyclo [5.4.0] -7-undecene 3.9 g
(0.0256 mol) was added to 16 ml of N, N-dimethylformamide and stirred at room temperature for 5 days. The reaction solution was added to water, and the precipitated crystals were collected by filtration, washed with water, and dried.
6-fluoro-1-methyl-4-oxo-7- [4-
(2-pyrimidinyl) piperazin-1-yl] -1H,
4H- [1,3] thiazeto [3,2-a] quinoline-3
-2.8 g of ethyl carboxylate were obtained as a pale yellow powder.

0.8 g (0.0018 mol) of this powder
, 5 ml of methanol, 1 ml of dioxane, 1 ml of water and 1
7 ml of N sodium hydroxide was added, and the mixture was stirred at room temperature for 3 days. The reaction solution was adjusted to pH 7.2 by adding a dilute acetic acid aqueous solution, and the precipitated crystals were collected by filtration and subjected to silica gel column chromatography (eluent; chloroform: methanol = 20: 1).
Mixture) to give 0.22 g of the title compound as a pale yellow powder.

Melting point: 266 to 268 ° C. (decomposition) MS spectrum (CI): m / e 428 (M ⁺⁺ 1) Elemental analysis value (%): C ₂₀ H ₁₈ FN ₅ O ₃ S · 1 / 2H ₂
As O: Theoretical: C, 55.04, H, 4.39, N, 16.05 Found: C, 54.85, H, 4.19, N, 15.92 (Production Example 101) 1-ethyl-6-fluoro-8-difluoromethoxy-
7-[(4-hydroxy-3-phenylamino) pyrroli
Zin-1-yl] -1,4-dihydro-4-oxoquino
Synthesis of phosphorus-3-carboxylic acid

[0182]

Embedded image

0.9 g (0.0028 mol) of 1-ethyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid
And 1.52 g (0.0071 mol) of (4-hydroxy-3-phenylamino) pyrrolidine hydrochloride and 1.6 g (0.0142 mol) of triethylenediamine were added to 20 ml of pyridine, and the mixture was stirred at room temperature for 30 minutes. , 105-11
After stirring at 0 ° C. for 3 hours, the solvent was distilled off under reduced pressure. Water was added to the residue, and the precipitated crystals were collected by filtration, washed with ethanol, and subjected to silica gel column chromatography (eluent; chloroform: methanol = 9.5: 0.5 mixture) to give the title 0.71 g of the compound was obtained as a slightly yellowish white powder.

Melting point: 233 to 235 ° C. MS spectrum (CI): m / e 478 (M ⁺⁺ 1) Elemental analysis value (%): C ₂₃ H ₂₂ F ₃ N ₃ O ₅ Theoretical value: C, 57.86, H , 4.64, N, 8.80 Found: C, 57.83, H, 4.59, N, 8.80 (Production Examples 102 and 103) The compounds in Table 49 were synthesized by the same reaction as in Production Example 101.

[0185]

[Table 49]

(Production Example 104) 1-ethyl-6-fluoro-8-difluoromethoxy-
7- [4- (2-pyrimidinyl) piperazine-1-i
L] -1,4-dihydro-4-oxoquinoline-3-ca
Synthesis of rubonic acid-2-morpholinoethyl ester

[0187]

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1-ethyl-6-fluoro-8-difluoromethoxy-7- [4- (2-pyrimidinyl) piperazin-1-yl] -1,4-dihydro-4-oxoquinoline-3-carboxylic acid 94 g (0.127 mol)
And 4- (2-hydroxyethyl) morpholine 25.0
5 g (0.191 mol), 23.3 g (0.191 mol) of 4-dimethylaminopyridine and 1-ethyl hydrochloride
3- (3-dimethylaminopropyl) carbodiimide 4
8.8 g (0.254 mol) was added to 3 liters of methylene chloride, and the mixture was stirred at room temperature for 4 days. The residue was dissolved in chloroform, washed with a 1N aqueous hydrochloric acid solution, then with water, dried, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: chloroform: methanol: 28% aqueous ammonia =
40: 9: 1 mixture) to give the title compound of title 50.
25 g were obtained as a slightly yellowish white powder.

Melting point: 162 ° -164 ° C. MS spectrum (CI): m / e 577 (M ⁺⁺ 1) Elemental analysis value (%): C ₂₇ H ₃₁ F ₃ N ₆ O ₅ .1 / 2H ₂
As O: Theoretical: C, 55.38, H, 5.34, N, 14.35 Found: C, 55.06, H, 5.20, N, 14.26 (Production Examples 105-108) The compounds of Table 50 were prepared in the same manner as in Production Example 104. Synthesized.

[0190]

[Table 50]

(Production Example 109) 9-ethyl-6-fluoro-8-difluoromethoxy-
7- [4- (2-pyrimidinyl) piperazine-1-i
] -2,3,4,9-tetrahydroisothiazolo
[5.4-b] Synthesis of quinoline-3,4-dione

[0192]

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9-ethyl-6,7-difluoro-8-difluoromethoxy-2,3,4,9-tetrahydroisothiazolo [5.4-b] quinoline-3,4-dione 50
0 mg (1.44 mmol) and 1- (2-pyrimidinyl)
From 1.9 g (11.5 mmol) of piperazine, 10 mg of the title target compound was obtained as a pale yellow powder in the same manner as in Production Example 1.

Melting point: 259 to 262 ° C. MS spectrum (CI): m / e 493 (M ⁺ +1) Elemental analysis value (%): C ₂₁ H ₁₉ F ₃ N ₆ O ₃ S · 1 / 2H
_{As 2} O Theoretical: C, 50.30, H, 3.82, N, 16.75 Found: C, 50.56, H, 3.51, N, 17.03 (Production Example 110) 1-cyclopropyl-6-fluoro-8-trifluoro
Methyl-1,4-dihydro-4-oxo-7- [4-
(2-Pyrimidinyl) piperazin-1-yl] quinoline
Synthesis of -3-carboxylic acid 1.0 g (0.003 mol) of 1-cyclopropyl-6,7-difluoro-8-trifluoromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 1 −
1.23 g of (2-pyrimidinyl) piperazine (0.00
(75 mol) was dissolved in 20 ml of pyridine, stirred at 105 ° C. for 3 hours, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent; chloroform: methanol = 9.5: 0.5 mixture). 1-cyclopropyl-6-fluoro-8-trifluoromethyl-1,4-
0.68 g of dihydro-4-oxo-7- [4- (2-pyrimidinyl) piperazin-1-yl] quinoline-3-carboxylic acid was obtained as a yellow powder.

Melting point: 285 to 287 ° C. NMR (DMSO-d ₆ , δ): 0.91 (2H, m), 1.17 to 1.18 (2H, m),
3.49 (4H, br.s), 3.94 (4H, br.s), 4.07 (1H, m), 6.69
~ 6.71 (1H, t, J = 9.3Hz), 8.06 ~ 8.09 (1H, d, J = 11.7H
z), 8.42-8.43 (2H, d, J = 4.4Hz), 8.85 (1H, s), 14.5
8 (1H, s). MS spectrum (CI): m / e 478 (M ⁺⁺ 1) (Production Examples 111 to 140) The compounds in Table 51 were synthesized in the same manner as in Production Example 110.

[0196]

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[0197]

[Table 51] 製造 Production example R ¹ R ³
Melting point (℃) ──────────────────────────────────── 111 Cyclopropyl 2-pyridyl yellow powder 225- 226 112 Cyclopropyl 2-methoxyphenyl White pink powder 196-197 113 Cyclopropyl phenyl slightly red powder 245-247 114 Cyclopropyl 3-chlorophenyl ocher powder 235-237 115 Cyclopropyl 4-fluorophenyl pale orange powder 230.5-231.5 116 Cyclopropyl 3-trifluoromethylphenyl Off-white powder 233-234 117 Methyl 2-pyrimidinyl pale yellow powder 280-282 118 Methyl 2-pyridyl yellow powder 264-266 119 Ethyl 2-pyrimidinyl yellow powder 265.5-267 120 Ethyl 2-pyridyl yellow Powder 259-260 121 Ethyl 2-methoxyphenyl yellowish white powder 197-199 122 Isopropyl 2-pyrimidinyl Yellow powder 285-288 123 Isopropyl 2-pi Lysyl pale yellow powder 266-268 124 Isopropyl 2-methoxyphenyl ocher powder 196-198 125 2-fluoroethyl 2-pyrimidinyl yellow powder 271.5-273.5 126 2-fluoroethyl 2-pyridyl yellow powder 246-248 127 2-fluoroethyl 2-methoxyphenyl yellowish white powder 225-226 128 methyl 2-methoxyphenyl ocher powder 252-253 129 methyl 2-chlorophenyl light orange powder 275-278 130 methyl phenyl light orange powder 258.5-260.5 131 methyl 4-fluorophenyl light Orange powder 269-270 132 Methyl 2-thiazolyl Yellow powder 266-267 133 Methyl 2-methylthiophenyl Ocher powder 242-243 134 Ethyl 4-methoxyphenyl Light red powder 235-236 135 Ethyl 4-chlorophenyl Pink powder 274-276 136 Ethyl 5-chloro-2-pyrimidinyl pale yellow powder 283-285 137 ethyl 2-fluorophenyl Ocher powder 228-230 138 Ethyl 3-methoxyphenyl Light red powder 217.5-218.5 139 Methyl 2-benzothiazolyl Yellow powder 285-287 140 Methyl 2-benzoxazolyl Yellow powder 300 or more ────────── ────────────────────────── (Production Example 141) 1-cyclopropyl-6-fluoro-8-trifluoro
Methyl-1,4-dihydro-4-oxo-7- [4-
(2-Pyridyl) piperazin-1-yl] quinoline-3
Synthesis of 2-carboxylic acid 2-morpholinoethyl ester 1-cyclopropyl-6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-7- [4-
(2-Pyridyl) piperazin-1-yl] quinoline-3
-100 mg (0.21 mmol) of carboxylic acid and 4- (2
-Hydroxyethyl) morpholine 0.055 g (0.4
2 mmol) and 0.045 of 4-dimethylaminopyridine
g (0.37 mmol) and 1-ethyl-3- (3- (3-hydrochloride)
0.091 g of dimethylaminopropyl) carbodiimide
(0.48 mmol) was added to 5 ml of methylene chloride, the mixture was allowed to stand at room temperature for 7 days, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent; chloroform: methanol: 28% aqueous ammonia = 40: 9: 1).
Mixture), and 1-cyclopropyl-6-fluoro-
60 mg of 8-trifluoromethyl-1,4-dihydro-4-oxo-7- [4- (2-pyridyl) piperazin-1-yl] quinoline-3-carboxylic acid 2-morpholinoethyl ester was obtained as a pale yellow powder. Was.

Melting point: 203-205 ° C. MS spectrum (CI): m / e 590 (M ⁺ +1) (Production Example 142) 6-fluoro-8-trifluoromethyl-1,4-diphenyl
Dro-4-oxo-1-methyl-7- [3-methyl-4
-(2-Pyrimidinyl) piperazin-1-yl] quinoli
Synthesis of 1-3 -carboxylic acid 6.7-difluoro-8-trifluoromethyl-1,4
1.5 g (0.0049 mol) of -dihydro-1-methyl-4-oxoquinoline-3-carboxylic acid and 1.5 g (0.015 mol) of 2-methylpiperazine were added to pyridine 30
After stirring for 3 hours at 105 ° C., the solvent was distilled off under reduced pressure. Ethanol was added to the residue, the precipitated crystals were collected by filtration, and the obtained crystals were washed with ethanol, dried, and dried.
1.49 g of -fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-1-methyl-7- (3-methylpiperazin-1-yl) quinoline-3-carboxylic acid
Was obtained as a yellow powder.

The obtained 6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-1-methyl-
7- (3-methylpiperazin-1-yl) quinoline-3
-1.49 g (0.0039 mol) of carboxylic acid, 0.88 g (0.0077 mol) of 2-chloropyrimidine and 0.78 g (0.0077 mol) of triethylamine in N,
Add 20 ml of N-dimethylformamide, and add
After stirring for 0 hours, the solvent was distilled off under reduced pressure.

The residue was subjected to silica gel column chromatography (eluent; chloroform: methanol = 9: 1 mixture) to give 6-fluoro-8-trifluoromethyl-
1,4-dihydro-4-oxo-1-methyl-7- [3
-Methyl-4- (2-pyrimidinyl) piperazine-1-
0.35 g of [il] quinoline-3-carboxylic acid was obtained as an ocher powder.

Melting point: 283-284.5 ° C. MS spectrum (CI): m / e 466 (M ⁺ +1) Elemental analysis value (%); C ₂₁ H ₁₉ F ₄ N ₅ O ₃ .1 / 2H ₂
As O: Theoretical; C: 53.17, H: 4.25, N: 14.7
6 actual values; C: 53.47, H: 4.07, N: 14.9
5 (Production Example 143) 6-fluoro-8-trifluoromethyl-1,4-dihi
Dro-4-oxo-1-methyl-7- [4- (2-pyri
Midinyl) homopiperazin-1-yl] quinoline-3-
Synthesis of carboxylic acid 6.7-difluoro-8-trifluoromethyl-1,4
Dissolve 0.8 g (0.0026 mol) of dihydro-1-methyl-4-oxoquinoline-3-carboxylic acid and 2.1 g (0.0118 mol) of 1- (2-pyrimidinyl) homopiperazine in 12 ml of pyridine. After stirring at 105 ° C. for 3 hours, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent; chloroform: methanol = 9.5: 0.5 mixture) to give 6-fluoro-
8-trifluoromethyl-1,4-dihydro-4-oxo-1-methyl-7- [4- (2-pyrimidinyl) homopiperazin-1-yl] quinoline-3-carboxylic acid
45 g were obtained as a yellow powder.

Melting point: 243 to 245 ° C. MS spectrum (CI): m / e 466 (M ⁺ +1) Elemental analysis value (%); Theoretical value as C ₂₁ H ₁₉ F ₄ N ₅ O ₃ ; C: 54. 20, H: 4.11, N: 15.0
5 actual values; C: 54.06, H: 4.03, N: 14.9
6 (Production Example 144) 1-ethyl-6-fluoro-8-difluoromethoxy-
1,4-dihydro-4-oxo-7- [4- (2-ben
Zothiazolyl) piperazin-1-yl] quinoline-3-
Synthesis of carboxylic acid Production Example 1 using 1-ethyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 1- (2-benzothiazolyl) piperazine The target compound was synthesized in the same manner as described above. Melting point (° C): 246-247 (ocher powder) (Production Example 145) 1-cyclopropyl-6-fluoro-8-methoxy-
1,4-dihydro-4-oxo-7- [4- (2-ben
Zothiazolyl) piperazin-1-yl] quinoline-3-
Synthesis of carboxylic acid Production Example 63 using 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 1- (2-benzothiazolyl) piperazine The target compound was synthesized in the same manner as described above. Melting point (° C): 248.5-249.5 (white powder) (Production Example 146) 1-benzyl-6-fluoro-8-difluoromethoxy
-1,4-dihydro-4-oxo-7- [4- (2-
[Nzothiazolyl) piperazin-1-yl] quinoline-3
-Synthesis of carboxylic acid 1-benzyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-
A target compound was synthesized in the same manner as in Production Example 1 using carboxylic acid and 1- (2-benzothiazolyl) piperazine. Melting point (° C): 283-285 (white powder) (Production Example 147) 1-methyl-6-fluoro-8-difluoromethoxy-
1,4-dihydro-4-oxo-7- [4- (2-ben
Zothiazolyl) piperazin-1-yl] quinoline-3-
Synthesis of carboxylic acid Production Example 1 using 1-methyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 1- (2-benzothiazolyl) piperazine The target compound was synthesized in the same manner as described above. Melting point (° C.): 251-253 (pale yellow powder) (Production Example 148) 1-methyl-6-fluoro-8-difluoromethoxy-
1,4-dihydro-4-oxo-7- [4- (6-chloro
B-2-benzothiazolyl) piperazin-1-yl] ki
Synthesis of Norin-3-carboxylic acid 1-methyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 1- (6-chloro-2-benzothiazolyl) The target compound was synthesized in the same manner as in Production Example 1 using piperazine. Melting point (° C.): 300 or more (yellow crystal, 3 / 2H ₂ O) (Production Example 149) 1-methyl-6-fluoro-8-difluoromethoxy-
1,4-dihydro-4-oxo-7- [4- (6-meth
Xy-2-benzothiazolyl) piperazin-1-yl]
Synthesis of quinoline-3-carboxylic acid 1-methyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 1- (6-methoxy-2-benzothiazolyl) The target compound was synthesized in the same manner as in Production Example 1 using piperazine. Melting point (° C.): 244-245 (yellow crystal, 1 / 2H ₂ O) (Production Example 150) 5-amino-1-cyclopropyl-6-fluoro-8-
Difluoromethoxy-1,4-dihydro-4-oxo-
7- [4- (2-benzothiazolyl) piperazine-1-
Synthesis of yl] quinoline-3-carboxylic acid 5-amino-1-cyclopropyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 1- (2 -Benzothiazolyl) piperazine was used to synthesize the target compound in the same manner as in Production Example 1.

Melting point (° C.): 300 or more (yellow powder) (Production Example 151) 1- (2-hydroxyethyl) -6-fluoro-8-di
Fluoromethoxy-1,4-dihydro-4-oxo-7
-[4- (2-benzothiazolyl) piperazine-1-i
1 ] Synthesis of quinoline-3-carboxylic acid 1- (2-hydroxyethyl) -6,7-difluoro-
The target compound was synthesized in the same manner as in Production Example 1 using 8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 1- (2-benzothiazolyl) piperazine.

Melting point (° C.): 254.5-256.5 (yellow powder) (Production Example 152) 1- (2-methoxyethyl) -6-fluoro-8-dif
Fluoromethoxy-1,4-dihydro-4-oxo-7-
[4- (2-benzothiazolyl) piperazine-1-i
1 ] Synthesis of quinoline-3-carboxylic acid 1- (2-methoxyethyl) -6,7-difluoro-8
The target compound was synthesized in the same manner as in Production Example 1 using -difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 1- (2-benzothiazolyl) piperazine.

Melting point (° C.): 229.5-231.0 (white powder) (Preparation Example 153) 6-fluoro-8-difluoromethoxy-1,4-dihi
Dro-4-oxo-7- [4- (2-benzothiazoly
Ru) piperazin-1-yl] quinoline-3-carboxylic acid
Synthesis of 6,7-difluoro-8-difluoromethoxy-1,4
The target compound was synthesized in the same manner as in Production Example 1 using -dihydro-4-oxoquinoline-3-carboxylic acid and 1- (2-benzothiazolyl) piperazine.

Melting point (° C.): 263-265 (ocher powder) (Production Example 154) 1-cyclopropyl-6-fluoro-8-methoxy-
1,4-dihydro-4-oxo-7- [4- (2-ben
Zoxazolyl) piperazin-1-yl] quinoline-3
Synthesis of carboxylic acid 6,7-difluoro-8-difluoromethoxy-1,4
The target compound was synthesized in the same manner as in Production Example 1 using -dihydro-4-oxoquinoline-3-carboxylic acid and 1- (2-benzothiazolyl) piperazine.

Melting point (° C.): 246-248 (pale yellow-brown powder) (Production Example 155) 1-cyclopropyl-6-fluoro-8-difluorome
Tyl-1,4-dihydro-4-oxo-7- [4- (2
-Pyrimidinyl) piperazin-1-yl] quinoline-3
Synthesis of carboxylic acid 1-cyclopropyl-6,7-difluoro-8-difluoromethyl-1,4-dihydro-4-oxoquinoline
A target compound was synthesized in the same manner as in Production Example 1 using 3-carboxylic acid and 1- (2-pyrimidinylbe) piperazine.

Melting point (° C.): 264-265 (yellow crystal) (Production Example 156) 1-methylamino-6-fluoro-8-difluoromethoate
Xy-1,4-dihydro-4-oxo-7- [4- (2
-Benzoxazolyl) piperazin-1-yl] quinoli
Synthesis of 1-methylamino-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-
A target compound was synthesized in the same manner as in Production Example 1 using 3-carboxylic acid and 1- (2-benzoxazolyl) piperazine.

Melting point (° C.): 227-229 (pale yellowish white powder) (Preparation Example 157) 9-fluoro-3-fluoromethyl-7-oxo-10
-[4- (2-benzothiazolyl) piperazine-1-i
L] -2,3-Dihydro-7H-pyrido- [1,2,3
-De] [1,4] benzoxazine-6-carboxylic acid
Synthesis of 9,10-difluoro-3-fluoromethyl-7-oxo-2,3-dihydro-7H-pyrido- [1,2,3-
de] [1,4] benzoxazine-6-carboxylic acid and 1- (2-benzothiazolyl) piperazine,
The target compound was synthesized in the same manner as in Production Example 63.

Melting point (° C.): 280-282 (yellow powder) (Production Example 158) 1-methyl-6-fluoro-8-trifluoromethyl-
1,4-dihydro-4-oxo-7- [4- (2-pyra
Dinyl) piperazin-1-yl] quinoline-3-carbo
Synthesis of acid Preparation example using 1-methyl-6,7-difluoro-8-trifluoromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 1- (2-pyrazinyl) piperazine In a similar manner to 110, the target compound was synthesized.

Melting point (° C.): 285-287 (yellow powder) (Production Example 159) 1-methyl-6-fluoro-8-trifluoromethyl-
1,4-dihydro-4-oxo-7- [4- (3-ben
Zoisothiazolyl) piperazin-1-yl] quinoline-
Synthesis of 3-carboxylic acid 1-methyl-6,7-difluoro-8-trifluoromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 1- (3-benzoisothiazolyl) piperazine Using this, the target compound was synthesized in the same manner as in Production Example 1.

Melting point (° C.): 296-298 (yellow powder) (Production Example 160) 1- (3-aminopropyl) -6-fluoro-8-tri
Fluoromethyl-7- [4- (2-pyrimidinyl) pipe
Razin-1-yl] -1,4-dihydro-4-oxo
Synthesis of Norin-3-carboxylic acid 160-1) 1- (3-tert-Butoxycarbonylaminopropyl) -6,7-difluoro-8-trifluoromethyl-1,4-dihydro-4-oxoquinoline-
7.56 g of 3-carboxylic acid ethyl ester (0.015
8 mol) and 1- (2-pyrimidinyl) piperazine 9.1
g (0.0554 mol) and 12.3 g (0.095 mol) of N-ethyldiisopropylamine in acetonitrile 5
The mixture was dissolved in 0 ml and stirred for 48 hours under reflux with heating. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent; a mixed solution of ethyl acetate: toluene = 7: 3) to give 1- (3-tert-butoxycarbonylaminopropyl) -6-fluoro 2.2 g of -8-trifluoromethyl-7- [4- (2-pyrimidinyl) piperazin-1-yl] -1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester was obtained as a yellow powder. .

Melting point (° C.): 188 to 190 160-2) 1- (3-tert-butoxycarbonylaminopropyl) -6-fluoro-8-trifluoromethyl-7- [4- (2-pyrimidinyl) piperazine- 1
-Yl] -1,4-dihydro-4-oxoquinoline-3
-To a solution obtained by adding 50 ml of acetonitrile to 2.2 g (0.0035 mol) of ethyl carboxylate was added 21.2 ml of a 1N aqueous solution of sodium hydroxide, and the mixture was stirred under heating and reflux for 1 hour. After completion of the reaction, the reaction solution
21.2 ml of an N hydrochloric acid aqueous solution was added, and the solvent was distilled off under reduced pressure. The residue is subjected to silica gel column chromatography (eluent; chloroform: methanol = 9: 1 mixed solution).
1- (3-tert-butoxycarbonylaminopropyl) -6-fluoro-8-trifluoromethyl-7- [4- (2-pyrimidinyl) piperazine-1-
Yl] -1,4-dihydro-4-oxoquinoline-3-
2.04 g of carboxylic acid was obtained as a yellow powder.

Melting point (° C.): 246-248 160-3) 1- (3-tert-Butoxycarbonylaminopropyl) -6-fluoro-8-trifluoromethyl-7- [4- (2-pyrimidinyl) piperazine- 1
-Yl] -1,4-dihydro-4-oxoquinoline-3
-A solution of 2.04 g (0.0034 mol) of carboxylic acid in 50 ml of methylene chloride was added with trifluoroacetic acid.
1.5 ml was added, and the mixture was stirred at room temperature for 1 hour. After evaporating the solvent under reduced pressure, water was added, the pH was adjusted to 7.5 with a saturated aqueous solution of sodium bicarbonate, the precipitated crystals were collected by filtration, washed with water, and washed with 1- (3-aminopropyl) -6- Fluoro-8
-Difluoromethyl-1,4-dihydro-4-oxo-
1.36 g of 7- [4- (2-pyrimidinyl) piperazin-1-yl] quinoline-3-carboxylic acid was obtained as a slightly yellow powder.

Melting point (° C.): 243 to 245 (Production Example 161) 1-methyl-6-fluoro-8-trifluoromethyl-
1,4-dihydro-4-oxo-7- [4- (2-ben
Zoxazolyl) -3-methylpiperazin-1-yl]
Synthesis of quinoline-3-carboxylic acid 1-methyl-6,7-difluoro-8-trifluoromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 2-methyl-1- (2-benzo The target compound was synthesized in the same manner as in Production Example 1 using oxazolyl) piperazine.

Melting point (° C.): 300 or more (light yellow powder) (Reference Example 1) 6,7-difluoro-8-difluoromethoxy-1-
(2-pyridylmethyl) -1,4-dihydro-4-oxo
Synthesis of soquinoline-3-carboxylic acid

[0219]

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30 g (0.124 mol) of 2,4,5-trifluoro-3-difluoromethoxybenzoic acid was dissolved in 37 ml of toluene, 35 ml of thionyl chloride and 0.5 ml of N, N-dimethylformamide were added, and the mixture was heated for 4 hours. Refluxed.
After the reaction, toluene and excess thionyl chloride were distilled off under reduced pressure to obtain 2,4,5-trifluoro-3-difluoromethoxybenzoic acid chloride.

On the other hand, 15.5 g of magnesium ethoxide
(0.135 mol) and malonic acid diethyl ester
9 g (0.130 mol) of anhydrous tetrahydrofuran 10
The mixture was heated under reflux with stirring in 0 ml for 2.5 hours to obtain a suspension of diethyl ethoxymagnesium malonate in tetrahydrofuran. To this was added dropwise a solution of the above acid chloride in 20 ml of tetrahydrofuran with stirring at room temperature, and the mixture was further stirred at room temperature for 2 hours. 100 ml of 1N hydrochloric acid was added to the reaction mixture, and the mixture was vigorously stirred and separated. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 2,4,5-trifluoro-3-difluoromethoxy. Benzoylmalonic acid diethyl ester 5
1.8 g were obtained as a pale red liquid.

MS spectrum (CI): m / e 385
(M ⁺ +1), 339 (M ⁺ -OC ₂ H ₅ ) Then, this was dissolved in 200 ml of dioxane, and 23.6 g (0.124 mol) of p-toluenesulfonic acid monohydrate was dissolved.
Was added and heated to reflux for 8.5 hours. The reaction solution was concentrated under reduced pressure, and water and 10.41 g of sodium hydrogen carbonate (0.
124 mol) and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 32.0 g of 2,4,5-trifluoro-3-difluoromethoxybenzoyl acetic acid ethyl ester as a yellow liquid.

MS spectrum (CI): m / e 313
(M ⁺ +1), 225 (M ⁺ -CH ₂ COOC ₂ H ₅ ) 2,4,5-trifluoro-3- obtained as above
3. Difluoromethoxybenzoyl acetic acid ethyl ester
11 g of acetic anhydride and 3.2 ml of ethyl orthoformate were added to 85 g (0.0155 mol), and the mixture was heated under reflux for 2 hours.
Excess acetic anhydride and ethyl orthoformate were distilled off under reduced pressure. The residue was dissolved in 150 ml of dichloromethane, and 2.01 g (0.0186 g) of 2-aminomethylpyridine was stirred under ice cooling.
Mol) was added dropwise, and the mixture was stirred under ice cooling for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent; toluene: ethyl acetate = 9: 1 mixture) to give 2- (2,4,5-trifluoro-3-difluoromethoxybenzoyl). 6.56 g of -3- (2-pyridylmethylamino) acrylic acid ethyl ester was obtained as a candy liquid. Recrystallization was performed using n-hexane to obtain 3.6 g of white crystals.

MS spectrum (CI): m / e 431 (M ⁺⁺ 1) 2- (2,4,5-trifluoro-3-difluoromethoxybenzoyl) -3- (2-pyridyl) obtained as above Methylamino) acrylic acid ethyl ester 5.6
g (0.013 mol) was dissolved in 50 ml of N, N-dimethylformamide, and 2.2 g (0.
026 mol) and stirred at 120 ° C. for 30 minutes.
The reaction solution was poured into 200 ml of water, and the precipitated crystals were collected by filtration. The collected product was washed with water and ethanol, and then dried to obtain 6,7.
2.6 g of -difluoro-8-difluoromethoxy-1- (2-pyridylmethyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester was obtained as yellow crystals.

MS spectrum (CI): m / e 411 (M ⁺ +1) Then, 1.7 g (0.0041 mol) of this ester compound
Was suspended in a mixture of 4.2 ml of acetic acid, 1.5 ml of water and 0.48 ml of concentrated sulfuric acid, and the mixture was heated under reflux with stirring for 2 hours. After cooling to room temperature, water was added and the insolubles were collected by filtration. The collected matter was washed with water and dried, and dried to give 6,7-difluoro-8-difluoromethoxy-1- (2-pyridylmethyl) -1,4. 1.1 g of -dihydro-4-oxoquinoline-3-carboxylic acid were obtained as white crystals.

Melting point: 207 to 213 ° C. (decomposition) MS spectrum (CI): m / e 383 (M ⁺ +1) (Reference Examples 2 to 9) Compounds shown in Table 52 below were synthesized in the same manner as in Reference Example 1. did.

[0225]

[Table 52]

Reference Example 10 1-ethyl-7-fluoro-8-difluoromethoxy-
1,4-dihydro-4-oxoquinoline-3-carboxylic
Acid synthesis

[0227]

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2-Fluoro-6-nitrophenol 2
6.4 g (0.168 mol) and 17.2 g of acetic anhydride
(0.168 mol) was dissolved in 290 ml of acetic acid and then 5%
3.0 g of palladium carbon was added, and hydrogen gas was passed for 2 hours while stirring at room temperature. After the reaction mixture was filtered and the filtrate was concentrated under reduced pressure, the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate, evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent; ethyl acetate: toluene = 1: 2 mixture) to give 2-acetylamino-6. -Fluorophenol 2
5.9 g were obtained as brown crystals.

MS spectrum (CI): m / e 170
The ^{(M + +1) 127 (M} + + 1-COCH 3) obtained as described above 2-acetylamino-6-fluorophenol 25.9 g (0.153 mol), N, N
-Dissolved in 110 ml of dimethylformamide, 25.4 g (0.184 mol) of potassium carbonate and 33.1 g (0.383 mol) of chlorodifluoromethane were added, and the mixture was stirred in an autoclave at 100 ° C for 5 hours. After completion of the reaction, the reaction solution was poured into 1 liter of water and extracted with ethyl acetate. After washing the ethyl acetate layer with water and drying over anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent; ethyl acetate: toluene = 1: 3 mixture) to obtain 30.4 g of 3-fluoro-2-difluoromethoxyacetanilide as light brown crystals. Was.

MS spectrum (CI): m / e 220 (M ⁺ +1) 30.3 g (0.138 mol) of 3-fluoro-2-difluoromethoxyacetanilide obtained as described above was dissolved in 180 ml of ethyl alcohol. , Concentrated hydrochloric acid 50.3ml
Was added and the mixture was heated under reflux for 3 hours. After completion of the reaction, ethyl alcohol and concentrated hydrochloric acid were distilled off under reduced pressure, 200 ml of water was added to the residue, the mixture was neutralized with potassium carbonate, and extracted with chloroform.
The chloroform layer was washed with brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent; chloroform) to give 3-fluoro-2-difluoromethoxy. 22.4 g of aniline were obtained as a red liquid.

The 3-fluoro-2-obtained as described above
22.4 g (0.127 mol) of difluoromethoxyaniline and 27.4 g of diethyl ethoxymethylenemalonate
(0.127 mol) was heated at 120 ° C. for 5 hours. After cooling to room temperature, n-hexane was added and the mixture was filtered. The collected matter was washed with n-hexane, dried, and dried.
37.5 g of (2,2-diethoxycarbonylvinyl) -3-fluoro-2-difluoromethoxyaniline was obtained as a white powder.

A mixture of 10.0 g (0.029 mol) of N- (2,2-diethoxycarbonylvinyl) -3-fluoro-2-difluoromethoxyaniline obtained as described above and 70 ml of diphenyl ether was added for 30 minutes. Heated to reflux. After cooling to room temperature, n-hexane was added and the precipitated crystals were collected by filtration and dried, and 7.25 g of 7-fluoro-8-difluoromethoxy-4-hydroxyquinoline-3-carboxylic acid ethyl ester was obtained as a white powder. Obtained.

Melting point: 218-219 ° C MS spectrum (CI): m / e 302 (M ⁺ +1) Ethyl 7-fluoro-8-difluoromethoxy-4-hydroxyquinoline-3-carboxylate obtained as described above 3.0 g (0.01 mol) of the ester was dissolved in 96 ml of N, N-dimethylformamide, and 6.9 potassium carbonate was added.
g (0.05 mol) and ethyl iodide 12.5 g (0.0
8 mol) and stirred at 100 ° C. for 14 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, water was added to the residue, and the precipitated crystals were collected by filtration and subjected to silica gel column chromatography (eluent; chloroform: methanol = 95: 5 mixture) to give 1-ethyl- 1.1 g of 7-fluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester was obtained as white crystals.

Melting point: 214.5-215.5 ° C. MS spectrum (CI): m / e 329 (M ⁺ +1) Then, 1.1 g (0.0033 mol) of this ester form
Was suspended in a mixture of 9 ml of acetic acid, 6.6 ml of water and 1.2 ml of concentrated sulfuric acid, and the mixture was refluxed for 2 hours with stirring. After cooling to room temperature, water was added and the insolubles were collected by filtration, the collected product was washed with water, dried and dried to give 1-ethyl-7-fluoro-8-difluoromethoxy-1,4-dihydro-4-. 0.85 g of oxoquinoline-3-carboxylic acid was obtained as white crystals.

Melting point: 169 to 170 ° C MS spectrum (CI): m / e 302 (M ⁺ +1) (Reference Example 11) 3-cyano-1-ethyl-6,7-difluoro-8-di
Fluoromethoxy-1,4-dihydro-4-oxoquino
Phosphorus synthesis

[0236]

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To 36.0 g (0.15 mol) of 2,4,5-trifluoro-3-difluoromethoxybenzoic acid, 45 ml of toluene, 15 ml of thionyl chloride and 0.2 ml of N, N-dimethylformamide were added and heated for 4 hours. Refluxed. After the reaction, toluene and excess thionyl chloride were distilled off under reduced pressure.
2,4,5-Trifluoro-3-difluoromethoxybenzoic acid chloride was obtained.

3-Dimethylaminoacrylonitrile 1
After dissolving 5.2 g (0.158 mol) in 75 ml of anhydrous tetrahydrofuran, 16.7 g of triethylamine was dissolved.
(0.165 mol), and a solution prepared by dissolving the above acid chloride in 15 ml of anhydrous tetrahydrofuran was gradually added dropwise at room temperature. After the dropwise addition, the mixture was heated under reflux for 1 hour, cooled to room temperature, and filtered. To the filtrate were added 9.7 ml of triethylamine and 14.7 g (0.18 mol) of ethylamine hydrochloride.
Stirred at 0 ° C. for 2 hours. After cooling to room temperature, filtration,
The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent; ethyl acetate: toluene = 3: 7 mixture) to give 2- (2,4,5-trifluoro-3-difluoromethoxybenzoyl)- 39.3 g of 3-ethylaminoacrylonitrile were obtained as a red liquid. This was mixed with a mixture of anhydrous diethyl ether and tetrahydrofuran 7
And then slowly add 4.9 g (0.123 mol) of 60% sodium hydride-mineral oil under ice-cooling.
The mixture was stirred at the same temperature for 1 hour. 1N hydrochloric acid 120 in the reaction mixture
ml, and the mixture was vigorously stirred to make the whole reaction solution acidic, and the precipitated crystals were collected by filtration, washed with water, then with diethyl ether, and washed with 3-cyano-1-ethyl-6,7-difluoro-8-. Difluoromethoxy-1,4-dihydro-4-
17.2 g of oxoquinoline was obtained as a white powder.

Melting point: 194 ° -195 ° C. MS spectrum (CI): m / e 301 (M ⁺ +1) (Reference Example 12) 1- (4,6-dimethoxy-2-pyrimidinyl) pipera
Synthesis of gin

[0240]

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10 g of 1-benzylpiperazine (0.05
67 g) was dissolved in 100 ml of acetonitrile, and 11.7 g (0.085 mol) of potassium carbonate and 14.8 g of 4,6-dimethoxy-2-methylsulfonylpyrimidine were dissolved.
(0.068 mol), and the mixture was heated under reflux for 5 hours. After cooling to room temperature, filtration was performed, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent; ethyl acetate: toluene = 1: 9 mixture) to give 4- (4,6-dimethoxy-2-pyrimidinyl). ) -1-Benzylpiperazine 1
7.6 g were obtained as a colorless liquid.

MS spectrum (CI): m / e 315 (M ⁺⁺ 1) 4- (4,6-dimethoxy-2- obtained as above.
3.9 g of pyrimidinyl) -1-benzylpiperazine
(0.0125 mol) was dissolved in 110 ml of ethanol, 2.5 g of 5% palladium on carbon was added, and hydrogen gas was passed in under reflux for 6 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent; chloroform: methanol = 9: 1 mixture) to give 1- (4,6-dimethoxy-
1.38 g of 2-pyrimidinyl) piperazine were obtained as pale red crystals.

MS spectrum (CI): m / e 225 (M ⁺ +1) (Reference Example 13) Synthesis of 1- (6-methoxy-2-pyridyl) piperazine

[0244]

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In a sealed tube, 8.6 g of piperazine and 2.9 g (0.02 mol) of 2-chloro-6-methoxypyridine were placed in a sealed tube.
The reaction was performed at 50 ° C. for 4 hours. After the reaction, the reaction mixture was subjected to silica gel column chromatography (eluent; chloroform: methanol: 28% aqueous ammonia = 40: 9: 1 mixture) to give 2.4 g of 1- (6-methoxy-2-pyridyl) piperazine. Was obtained as a pale yellow liquid.

MS spectrum (CI): m / e 194 (M ⁺ +1) (Reference Example 14) Synthesis of 1- (2-thiazolyl) piperazine

[0247]

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5.0 g of 2-bromothiazole (0.03
05 mol) in 50 ml of acetonitrile, 13.1 g (0.153 mol) of piperazine and 8.4 potassium carbonate.
g (0.061 mol) and a catalytic amount of potassium iodide were added, and the mixture was heated under reflux for 5 hours. After cooling to room temperature, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent; chloroform: methanol: 28).
% Ammonia water = 40: 9: 1 mixture).
3.62 g of (2-thiazolyl) piperazine were obtained as a colorless liquid.

MS spectrum (CI): m / e 170 (M ⁺ +1) (Reference Example 15) Synthesis of 1- (3-amino-2-pyridyl) piperazine

[0250]

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3.13 g (0.015 mol) of 1- (3-nitro-2-pyridyl) piperazine was added to 30 ml of methanol.
, And 2 g of 5% palladium on carbon was added, and hydrogen gas was passed for 1 hour while stirring at room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 2.56 g of 1- (3-amino-2-pyridyl) piperazine as a pale yellow liquid.

MS spectrum (CI): m / e 179 (M ⁺ +1) (Reference Example 16) Synthesis of 1- (2-benzoxazolyl) piperazine

[0253]

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33.6 g (0.39 mol) of piperazine and 10.0 g (0.065 mol) of 2-chlorobenzoxazole
Was dissolved in 200 ml of acetonitrile, 9.0 g (0.065 mol) of potassium carbonate and a catalytic amount of potassium iodide were added, and the mixture was heated under reflux with stirring for 11 hours. After cooling to room temperature, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent; chloroform: methanol = 9: 1 mixture) to give 1- (2-benzoxazolyl). 7.54 g of piperazine were obtained as white crystals.

MS spectrum (CI): m / e 204 (M ⁺ +1) (Reference Example 17) 3-hydroxy-4-phenylaminopyrrolidine hydrochloride
Synthesis of

[0256]

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(1) 1-t-butoxycarbonyl-3-epoxypyrrolidine (5 g, 0.027 mol) was dissolved in ethyl alcohol (20 ml), and aniline (12.6 g, 0.13 g) was dissolved.
5 mol) and heated under reflux for 20 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent; ethyl acetate: toluene =
1: 4 mixture) to give 1-t-butoxycarbonyl-
3-hydroxy-4-phenylaminopyrrolidine 4.8
5 g were obtained as tan crystals.

MS spectrum (EI): m / e 278
(M ⁺ ), 57 (C ₄ H ₉ ⁺ ) (2) 1-tert-butoxycarbonyl-3-hydroxy-4-phenylaminopyrrolidine obtained as above.
4 g (0.0086 mol) was dissolved in methanol (100 ml), 6N hydrochloric acid (30 ml) was added, the mixture was heated under reflux for 2.5 hours, and the solvent was distilled off under reduced pressure. The obtained residue was washed with ethanol and ether to obtain 1.52 g of 3-hydroxy-4-phenylaminopyrrolidine hydrochloride as a light brown powder.

MS spectrum (CI): m / e 179 (M ⁺ +1) (Reference Example 18) 3-methoxy-4-phenylaminopyrrolidine hydrochloride
Synthesis

[0260]

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0.34 g (0.0085 mol) of 60% sodium hydride-mineral oil was added to 10 ml of anhydrous tetrahydrofuran, and 1.21 g (0.0085 mol) of methyl iodide was added while stirring at 45 to 50 ° C. did.
To this mixture, 2.37 g of 1-tert-butoxycarbonyl-3-hydroxy-4-phenylaminopyrrolidine obtained in (1) of Reference Example 17 was added with anhydrous tetrahydrofuran 10
The solution dissolved in ml was added dropwise, and the mixture was further stirred at the same temperature for 1 hour. After cooling to room temperature, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent; methyl acetate: toluene = 1: 4 mixture) to give 1-t-butoxycarbonyl-3-methoxy-4. 1.98 g of -phenylaminopyrrolidine was obtained as white crystals.

MS spectrum (EI): m / e 292 (M ⁺ ) 1-t-butoxycarbonyl-3 obtained as above
1.98 g of -methoxy-4-phenylaminopyrrolidine
(0.0068 mol) in 100 ml of methanol,
23.5 ml of 6N hydrochloric acid was added and left at room temperature overnight. The solvent was distilled off under reduced pressure, the residue was washed with ethanol, and 3-methoxy-4-phenylaminopyrrolidine hydrochloride (1.71 g) was used.
Was obtained as a white powder.

MS spectrum (CI): m / e 193 (M ⁺ +1) (Reference Example 19) Synthesis of 1- (6-ethyl-4-pyrimidinyl) piperazine
Success

[0264]

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6-ethyl-4-hydroxypyrimidine 1
1,2-dichloroethane 50 was added to 2.4 g (0.1 mol).
After adding ml, 18.4 g (0.12 mol) of phosphorus oxychloride was added, and the mixture was heated under reflux for 3 hours. After cooling, water was added to the reaction solution, and extracted with chloroform. After the chloroform layer was washed with water and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to give 4-chloro-6-ethylpyrimidine 10.38.
g was obtained as a slightly red liquid.

Next, this was dissolved in 100 ml of acetonitrile, and 11.5 g of 1-ethoxycarbonylpiperazine was dissolved.
(0.073 mol) and potassium carbonate 20.2 g (0.1
46 mol) and a catalytic amount of potassium iodide were added, and the mixture was heated under reflux for 10 hours. After cooling to room temperature, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent; chloroform: methanol = 4: 1 mixture).
And 1- (6-ethyl-4-pyrimidinyl) -4-
20.69 g of ethoxycarbonylpiperazine were obtained as an orange liquid.

MS spectrum (CI): m / e 265 (M ⁺⁺ 1) 1- (6-ethyl-4-pyrimidinyl) -4-ethoxycarbonylpiperazine 20.69 obtained as above
200 g of 6N hydrochloric acid was added to g (0.78 mol), and the mixture was heated under reflux for 18 hours. Add sodium hydroxide to the reaction mixture
H was adjusted to 10 or more, and extracted with diethyl ether.
After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent; chloroform: methanol = 4: 1 mixture).
To give 1- (6-ethyl-4-pyrimidinyl) piperazine as a colorless liquid.

MS spectrum (CI): m / e 193 (M ⁺ +1) (Reference Example 20) 9-ethyl-6,7-difluoro-8-difluoromethoate
Xy-2,3,4,9-tetrahydrothiazolo [5,4
-B] Synthesis of quinoline-3,4-dione

[0269]

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The reaction was carried out according to the method described in Reference Example 23 of JP-A-3-209367 to obtain the title compound as a pink powder.

Melting point: 211-213 ° C. MS spectrum (CI): m / e 349 (M ⁺ +1) (Reference Example 21) 1-cyclopropyl-6,7-difluoro-8-trif
Fluoromethyl-1,4-dihydro-4-oxoquinoline
Synthesis of -3-carboxylic acid 8.5 g (0.0348 mol) of 2,4,5-trifluoro-3-trifluoromethylbenzoic acid was added to 30 m of benzene.
l, 17 ml of thionyl chloride and a few drops of N, N-dimethylformamide were added and the mixture was refluxed for 3 hours. After the reaction, benzene and excess thionyl chloride were distilled off under reduced pressure to obtain 2,4,5-trifluoro-3-trifluoromethylbenzoic acid chloride.

Ethyl 3-dimethylaminoacrylate5.
After dissolving 47 g (0.0383 mol) in 30 ml of anhydrous tetrahydrofuran, 4.2 g of triethylamine (0.
0415 mol), and a solution prepared by dissolving the above acid chloride in 7 ml of anhydrous tetrahydrofuran was gradually added dropwise at room temperature. After completion of the dropwise addition, the mixture was heated at 50 ° C. for 3 hours, cooled to room temperature, and filtered. 2. Add cyclopropylamine hydrochloride to the filtrate.
9 g (0.0417 mol) was added, and the mixture was stirred at 40 ° C. for 30 minutes. After cooling to room temperature, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent; ethyl acetate: toluene = 1: 4 mixture) to give a residue.
10.63 g of ethyl-(2,4,5-trifluoro-3-trifluoromethylbenzoyl) -3-cyclopropylaminoacrylate was obtained as a pale yellow solid. This was dissolved in anhydrous diethyl ether (100 ml), and cooled under ice cooling to 62.4.
% Sodium hydride-mineral oil 1.6 g (0.0
(416 mol) was added slowly, and the mixture was stirred at room temperature for 1 hour. 41.7 ml of 1N hydrochloric acid was added to the reaction mixture, and the mixture was vigorously stirred to make the whole reaction solution acidic, and the precipitated crystals were collected by filtration, washed with water, and then with diethyl ether to give 1-cyclopropyl-6,7. -Difluoro-8-trifluoromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester (7.32 g) was obtained as a white powder.

Melting point: 184-185 ° C. MS spectrum (CI): m / e 362 (M ⁺ +1) Then, 0.8 g (0.0022 mol) of this ester compound
Was suspended in a mixture of 5 ml of acetic acid, 3 ml of water and 0.3 ml of concentrated sulfuric acid, and heated under reflux for 2 hours with stirring. After cooling to room temperature, water was added and the insolubles were collected by filtration.
After drying, 1-cyclopropyl-6,7-difluoro-
0.7 g of 8-trifluoromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was obtained as white crystals.

Melting point: 210-212 ° C. MS spectrum (CI): m / e 334 (M ⁺ +1) (Reference Example 22) 1-ethyl-6,7-difluoro-8-trifluoromethyl
Cyl-1,4-dihydro-4-oxoquinoline-3-ca
Synthesis of rubonic acid Using ethylamine instead of cyclopropylamine hydrochloride, the reaction was carried out in the same manner as in Reference Example 21 to give 1-ethyl-6
7-Difluoro-8-trifluoromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was obtained as a white powder.

Melting point: 159 to 162 ° C. MS spectrum (CI): m / e 322 (M ⁺ +1) (Reference Example 23) 6,7-difluoro-8-trifluoromethyl-1,4
-Dihydro-1-methyl-4-oxoquinoline-3-ca
Synthesis of rubonic acid Reaction was carried out in the same manner as in Reference Example 21 using methylamine hydrochloride instead of cyclopropylamine hydrochloride, and 6,7-difluoro-8-trifluoromethyl-1,4-dihydro-1-methyl- 4-oxoquinoline-3-carboxylic acid was obtained as a white powder.

Melting point: 197.5-199 ° C. MS spectrum (CI): m / e 308 (M ⁺ +1) (Reference Example 24) 6,7-difluoro-8-trifluoromethyl-1,4
-Dihydro-1-isopropyl-4-oxoquinoline-
Synthesis of 3-carboxylic acid Reaction was carried out in the same manner as in Reference Example 21 except that isopropylamine hydrochloride was used instead of cyclopropylamine hydrochloride.
7-difluoro-8-trifluoromethyl-1,4-dihydro-1-isopropyl-4-oxoquinoline-3-
The carboxylic acid was obtained as a white powder.

Melting point: 197.5 to 200 ° C. MS spectrum (CI): m / e 336 (M ⁺ +1) (Reference Example 25) 6,7-difluoro-1- (2-fluoroethyl) -8
-Trifluoromethyl-1,4-dihydro-4-oxo
Synthesis of quinoline-3-carboxylic acid Reaction was carried out in the same manner as in Reference Example 21 using 2-fluoroethylamine hydrochloride instead of cyclopropylamine hydrochloride, and 6,7-difluoro-1- (2-fluoroethyl)
-8-Trifluoromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was obtained as a white powder.

Melting point: 183-185 ° C. MS spectrum (CI): m / e 340 (M ⁺ +1) (Reference Example 26) Synthesis of 1- (2-pyrimidyl) homopiperazine 10.0 g (0.1 g ) of homopiperazine Mol), 2.9 g (0.025 mol) of 2-chloropyrimidine, 6.9 g (0.05 mol) of potassium carbonate and a catalytic amount of potassium iodide were added with 50 ml of acetonitrile, and heated under reflux for 11 hours. After cooling to room temperature, the mixture was filtered, the obtained filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent; chloroform: methanol = 8: 2 mixture).
And 1- (2-pyrimidyl) homopiperazine 2.1
4 g were obtained as a pale yellow liquid.

MS spectrum (CI): m / e 179 (M ⁺ +1) (Reference Example 27) Synthesis of 1- (2-methylthiophenyl) piperazine 2.8 g (0.02 mol) of 2-methylthioaniline and odor N-bis (2-bromoethyl) amine hydrohydride 13.7
g (0.044 mol) and 40 ml of ethanol,
The mixture was refluxed for 0 hours. After cooling to room temperature, 10.2 g of potassium carbonate was added, and the mixture was heated under reflux for 10 hours. After cooling to room temperature, the mixture was filtered, the obtained filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: chloroform: methanol: 28% aqueous ammonia = 40: 40).
9: 1 mixture) to give 1.31 g of 1- (2-methylthiophenyl) piperazine as a pale yellow liquid.

MS spectrum (CI): m / e 209 (M ⁺ +1) (Reference Example 28) Synthesis of 1- (2-thiazolyl) piperazine 5.0 g (0.0305 mol) of 2-bromothiazole was acetonitrile Dissolve in 50 ml and 13.1 g of piperazine
(0.153 mol) and 8.4 g (0.06 mol) of potassium carbonate.
1 mol) and a catalytic amount of potassium iodide were added, and the mixture was heated under reflux for 5 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent; chloroform: methanol: 28% aqueous ammonia = 40: 9: 1 mixture) to obtain 1- (2 3.62 g of -thiazolyl) piperazine were obtained as a colorless liquid.

MS spectrum (CI): m / e 170 (M ⁺ +1) (Reference Example 29) 1-bromo-3-difluoromethyl-2,4,5-tri
Synthesis of fluorobenzene 1.61 g (0.01 mol) of diethylaminosulfur trifluoride was added to 2.39 g (0.01 mol) of 1-bromo-2,4,5-trifluorobenzaldehyde cooled to 3 ° C. After stirring for 30 minutes at, the temperature was carefully raised to a temperature at which heat generation started.

When the exotherm had subsided, the temperature was raised to 80 ° C., and stirring was continued at that temperature for 30 minutes. After cooling to room temperature, chloroform was added, washed with water, dried over anhydrous sodium sulfate, evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent; n-hexane) to give 1-
1.47 g of bromo-3-difluoromethyl-2,4,5-trifluorobenzene was obtained as a colorless liquid.

HS spectrum (CI): m / e 260 (M ⁺ +1) (Reference Example 30) 3-difluoromethyl-2,4,5-trifluorobenzo
Synthesis of perfumed acid 42.72 g (0.164 mol) of 1-bromo-3-difluoromethyl-2,4,5-trifluorobenzene was dissolved in 500 ml of anhydrous diethyl ether and then cooled to -70 ° C. 108 ml (0.177 mol) of a 1.63 M n-butyllithium n-hexane solution was added dropwise to this solution over 30 minutes, followed by stirring at the same temperature for 5 minutes.

The above reaction solution was added at once to a solution obtained by adding 1 kg of dry ice to 500 ml of anhydrous diethyl ether, and stirring was continued until the temperature reached room temperature. Then, 569 ml of 1N hydrochloric acid was added, and the ether layer was separated. After the ether layer was extracted twice with 212 ml of 0.5N aqueous sodium hydroxide solution, the aqueous layer was adjusted to pH 1 with 6N hydrochloric acid. The precipitated oil was extracted twice with 500 ml of diethyl ether, washed with saturated saline, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give 3-difluoromethyl-2,4,5-trifluorobenzoic acid.
0 g was obtained as white crystals.

Melting point: 95-97 ° C. MS spectrum (CI): m / e 227 (M ⁺ +1) (Reference Example 31) 1-cyclopropyl-6,7-difluoro-8-difur
Oromethyl-1,4-dihydro-4-oxoquinoline-
Synthesis of 3-carboxylic acid 10.0 g (0.0442 mol) of 2,4,5-trifluoro-3-difluoromethylbenzoic acid was added to benzene.
7 ml, 21.8 ml of thionyl chloride and several drops of N, N-dimethylformamide were added, and the mixture was heated under reflux for 3 hours. After the reaction, benzene and excess thionyl chloride were distilled off under reduced pressure.
5-trifluoro-3-difluoromethylbenzoic acid chloride was obtained.

Ethyl 3-dimethylaminoacrylate6.
After dissolving 95 g (0.0486 mol) in 38 ml of anhydrous tetrahydrofuran, 5.37 g of triethylamine was dissolved.
(0.0530 mol), and a solution prepared by dissolving the above acid chloride in 8 ml of anhydrous tetrahydrofuran was gradually added dropwise at room temperature. After completion of the dropwise addition, the mixture was heated at 50 ° C. for 3 hours, cooled to room temperature, and filtered. 6.2 g (0.0663 mol) of cyclopropylamine hydrochloride was added to the filtrate, and the mixture was stirred at 40 ° C for 20 minutes. After cooling to room temperature, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent; ethyl acetate: toluene = 1: 4 mixture) to give 2- (2,4,5-triethyl). 14.27 g of ethyl fluoro-3-difluoromethylbenzoyl) -3-cyclopropylaminoacrylate was obtained as a pale yellow solid. This was dissolved in 200 ml of anhydrous diethyl ether, and cooled under ice cooling.
2.36 g of 0.0% sodium hydride-mineral oil
(0.059 mol) was added slowly, followed by stirring at room temperature for 1 hour. To the reaction mixture was added 1N hydrochloric acid (59 ml), and the mixture was vigorously stirred to make the whole reaction solution acidic, and the precipitated crystals were collected by filtration.
After washing with water and then with diethyl ether, 11.40 g of 1-cyclopropyl-6,7-difluoro-8-difluoromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester was obtained as a white powder. As obtained.

Melting point: 208-210 ° C. MS spectrum (CI): m / e 344 (M ⁺⁺ 1) Then, 2.0 g (0.0058 mol) of this ester form
Was suspended in a mixture of 13.1 ml of acetic acid, 7.8 ml of water and 0.78 ml of concentrated sulfuric acid, and heated under reflux for 2 hours with stirring. After cooling to room temperature, water was added and the insolubles were collected by filtration, the collected product was washed with water and dried, and 1-cyclopropyl-6,7-difluoro-8-difluoromethyl-1,4-dihydromethyl was added. −
1.72 g of 4-oxoquinoline-3-carboxylic acid was obtained as white needle crystals.

Melting point: 190.5-192.5 ° C. MS spectrum (CI): m / e 315 (M ⁺ +1) (Reference Example 32) 1- (3-tert-butoxycarbonylaminopropiate )
) -6,7-difluoro-8-trifluoromethyl-
1,4-dihydro-4-oxoquinoline-3-carboxylic
Synthesis of acid ethyl ester Instead of 2,4,5-trifluoro-3-difluoromethoxybenzoic acid, use 2,4,5-trifluoro-3-trifluoromethylbenzoic acid instead of 2-aminomethylpyridine And N-tert-butoxycarbonylpropylenediamine in the same manner as in Reference Example 1 to obtain 1
-(3-tert-butoxycarbonylaminopropyl) -6,7-difluoro-8-trifluoromethyl-
1,4-Dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester was obtained as a white powder.

Melting point (° C.): 131-133

[0290]

EFFECT OF THE INVENTION By using the quinolone carboxylic acid of the present invention, a remarkable effect of suppressing TNF-α production was recognized. Therefore, the quinolone carboxylic acids of the present invention are TNF-
It is useful as an α-production inhibitor and a therapeutic agent for various diseases caused by overproduction of TNF-α.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/55 ACD A61K 31/55 ACD // C07D 215/56 C07D 215/56 401/04 207 401/04 207 257 257 401 / 12 213 401/12 213 235 235 237 237 239 239 241 241 401/14 205 401/14 205 207 207 211 211 213 213 239 239 241 241 257 257 257 405 405/12 215 405/12 215 409/12 215 409/12 215 413/12 215 413/12 215 413/14 215 413/14 215 417/12 215 417/12 215 417/14 215 417/14 215 471/04 114 471/04 114Z 498/04 105 498/04 105 498 / 06 498/06 498/14 498/14 513/04 513/04 343 343 345 345 5 513/06 513/06 513/14 513/14 (72) Inventor Takashi Nishigaki 1-258 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Fumio Kimura 2 Niibori, Niiza-shi, Saitama (11) Chome 11-15 (72) Inventor Tetsushi Katsube 1978 Kogushi, Obe-shi, Ube-shi, Yamaguchi 5 Ube Industries, Ltd.

Claims (7)

[Claims] (1) The following general formula (Ia), (Ib) or (I
quinolone carboxylic acid represented by c), a pharmaceutically acceptable salt or ester thereof In the above formula (Ia), (Ib) or (Ic), X represents a hydrogen atom or a halogen atom, and Y is a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, an amino group, or 1 to 2 A mono- or dialkyl-substituted amino group substituted by an alkyl group having 1 to 4 carbon atoms or a mono- or diaralkyl-substituted amino group substituted by 1 to 2 aralkyl groups having 7 to 14 carbon atoms; Represents a carboxy group or a 5-tetrazolyl group which may be protected, and Q is a nitrogen atom or a group represented by the formula (d): [In the formula (d), R ² represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms which may be substituted with halogen, or a C 1 to 4 carbon atom which may be substituted with halogen. W represents an oxygen atom or a sulfur atom, and T represents an alkylene group having 1 to 4 carbon atoms which may be substituted by alkyl having 1 to 4 carbon atoms or an alkyl group having 1 to 4 carbon atoms.
R ¹ is a hydrogen atom; a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms, which may be substituted with 2 alkyl groups, wherein R ¹ is a hydrogen atom; , Hydroxy, carboxy, halogen, alkoxy having 1 to 4 carbon atoms,
Cycloalkyl having 3 to 6 carbon atoms, alkanoyloxy having 2 to 5 carbon atoms, a compound represented by the formula (e): (In the formula (e), R ⁹ and R ¹⁰ each represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, or
⁹ and R ¹⁰ together with the nitrogen atom to which they are attached may optionally form a 3 to 7 membered saturated monocyclic ring containing a heteroatom selected from N, O and S) Or an aryl group having 6 to 10 carbon atoms which may be substituted by R ⁰ described below, N,
A 5- or 6-membered heteroaromatic monocyclic group containing 1 or 2 heteroatoms selected from O and S or a heteroaromatic condensed ring group obtained by condensing a heteroaromatic monocycle and a benzene ring]; An alkenyl group having 2 to 5 carbon atoms which may be substituted; an alkynyl group having 2 to 4 carbon atoms; an amino group;
A mono- or di-alkyl-substituted amino group substituted with 1 to 2 alkyl groups having 1 to 4 carbon atoms; a cycloalkyl group having 3 to 6 carbon atoms which may be substituted with halogen; An alkoxy group; or an aryl group having 6 to 10 carbon atoms and a 5- or 6-membered heteroaromatic unit containing 1 or 2 heteroatoms selected from N, O and S, which may be substituted by R ⁰ described below. A ring group or a heteroaromatic condensed ring group in which a heteroaromatic monocyclic ring and a benzene ring are condensed, or R ¹ and R ^{2 of} Q in formula (d) are taken together to form formula (f) 4] [In the formula (f), A represents a hydrogen atom or a halogen, hydroxy or an alkyl group having 1 to 4 carbon atoms which may be substituted by alkoxy having 1 to 4 carbon atoms, and G represents a nitrogen atom or a formula ( g) embedded image G ¹ represents a methylene group, a carbonyl group, an oxygen atom,
A sulfur atom or a —N (R ¹¹ ) — group (wherein R ¹¹ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms);
Represents 0 or 1], and R represents the formula (h) or the formula (i) [In the formulas (h) and (i), R ³ and R ⁶ are R ⁰ (R ⁰
Are halogen, nitro, hydroxy, alkyl having 1 to 4 carbons, alkyl having 1 to 4 carbons substituted by fluorine, alkoxy having 1 to 4 carbons, and 1 to 4 carbons
Alkylthio, amino, and mono- or dialkyl-substituted amino substituted with 1 to 2 alkyl having 1 to 4 carbons, which may be substituted with 6 to 10 carbons An aryl group or a 5- to 6-membered heteroaromatic monocyclic group containing 1 or 2 heteroatoms selected from N, O and S, or a heteroaromatic condensed ring group obtained by condensing a benzene ring with these heteroaromatic monocycles. R ⁴ , R ⁵ and R ⁷ each represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; R ⁸ represents a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 4 carbon atoms or 1 to 4 carbon atoms; N represents 1 or 2; m represents 0 or 1;
n 'represents 1 or 2; n "represents 1, 2, 3 or 4]. A TNF- [alpha] production inhibitor comprising at least one as an active ingredient. 2. The TNF-α production inhibitor according to claim 1, wherein the quinolone carboxylic acid as the active ingredient is the compound of the formula (Ia). 3. The quinolone carboxylic acid as an active ingredient is represented by the formula (I)
In a), X is a fluorine atom, Y is a hydrogen atom, a fluorine atom, an amino group, a methyl group or an ethyl group, Z is an optionally protected carboxy group, and Q is a group represented by the formula (d) And R ² of the formula (d) is a methoxy, difluoromethoxy or trifluoromethyl group, and R ¹ is a hydrogen atom; methyl, ethyl, propyl, isopropyl; 2-hydroxyethyl; carboxymethyl;
-Fluoroethyl, 2-chloroethyl, 2,2,2-trifluoroethyl; 2-acetoxyethyl; phenylmethyl, phenylethyl; 2-pyridylmethyl; 2-dimethylaminoethyl, 2-morpholinoethyl; amino; methylamino; Methoxy; cyclopropyl, cyclobutyl, cyclopentyl, 2-fluorocyclopropyl; phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl; vinyl, 2-propenyl; or 2-propynyl group R is 4- (2-pyrimidinyl) piperazin-1-yl, 4- (2-benzothiazolyl) piperazin-1-yl, 4- (2-benzoxazolyl) piperazin-1-
Yl, 4- (6-methoxy-2-benzoxazolyl)
The TNF-α according to claim 2, which is a compound that is a piperazin-1-yl, 4- (6-methoxy-2-benzothiazolyl) piperazin-1-yl or 4- (2-pyridyl) piperazin-1-yl group. Production inhibitors. 4. The quinolone carboxylic acid as an active ingredient has a formula (I)
In a), X is a fluorine atom, Y is a hydrogen atom, a fluorine atom, an amino group, a methyl group or an ethyl group, Z is an optionally protected carboxy group, and Q is a group represented by the formula (d) And R ² in the formula (d) is a methoxy, difluoromethoxy or trifluoromethyl group, and R ¹ is methyl, ethyl, 2-hydroxyethyl, 2-
A fluoroethyl, cyclopropyl or methylamino group, wherein R is 4- (2-pyrimidinyl) piperazin-1-yl, 4- (2-benzothiazolyl) piperazin-1-yl, 4- (2-pyridyl) piperazine- 1-yl, 4-
The compound according to claim 2, which is a compound which is a (2-benzoxazolyl) piperazin-1-yl or 4- (6-methoxy-2-benzothiazolyl) piperazin-1-yl group.
An NF-α production inhibitor. 5. The method of claim 1, wherein the quinolone carboxylic acid as the active ingredient is 1-cyclopropyl-6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-7- [4-
(2-Pyridyl) piperazin-1-yl] quinoline-3
-Carboxylic acid, 6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-1-methyl-7- [4- (2-pyrimidinyl) piperazin-1-yl] quinoline-3-carboxylic acid 6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-1-methyl-7- [4- (2-pyridyl) piperazin-1-yl] quinoline-3-carboxylic acid; 6- Fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-1-methyl-7- [4- (2-benzothiazolyl) piperazin-1-yl] quinoline-3-
Carboxylic acid, 6-fluoro-8-difluoromethoxy-1,4-dihydro-4-oxo-1-ethyl-7- [4- (2-benzothiazolyl) piperazin-1-yl] quinoline-3-
Carboxylic acid, 6-fluoro-8-difluoromethoxy-1,4-dihydro-4-oxo-1-methyl-7- [4- (2-benzothiazolyl) piperazin-1-yl] quinoline-3-
Carboxylic acid, 6-fluoro-8-difluoromethoxy-1,4-dihydro-4-oxo-1-methyl-7- [4- (6-methoxy-2-benzothiazolyl) piperazin-1-yl]
Quinoline-3-carboxylic acid, 6-fluoro-8-difluoromethoxy-1,4-dihydro-4-oxo-1- (2-hydroxyethyl) -7
-[4- (2-benzothiazolyl) piperazin-1-yl] quinoline-3-carboxylic acid or 6-fluoro-8-
Difluoromethoxy-1,4-dihydro-4-oxo-
The TNF-α production inhibitor according to claim 2, which is 1-methylamino-7- [4- (2-benzoxazolyl) piperazin-1-yl] quinoline-3-carboxylic acid. 6. A therapeutic agent for a disease selected from the following group A, which comprises at least one of the compounds according to claim 1 as an active ingredient. [Group A] sepsis, cachexia, autoimmune disease, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption disease. 7. Use of the compound according to claim 1 for producing a therapeutic agent for a disease selected from the following group A. [Group A] sepsis, cachexia, autoimmune disease, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption disease.