JPH09323932A - Therapeutic agent or preventive for aids - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a therapeutic agent and a preventive for AIDS by using a quinolonecarboxylic acid-based anti-HIV agent and a reverse transcriptase inhibitor and/or a HIV protease inhibitor. SOLUTION: This medicine comprises (1) a quinolonecarboxylic acid-based anti-HIV agent and a reverse transcriptase inhibitor, (2) the quinolonecarboxylic acid-based anti-HIV agent and a HIV protease inhibitor or (3) the quinolonecarboxylic acid-based anti-HIV agent, the reverse transcriptase inhibitor and the HIV protease inhibitor as active ingredients. A compound of the formula (X is H or a halogen; Y is H, a halogen, a 1-4C alkylene, amino, etc.; Z is protectable carboxy or 5-tetrazolyl; Q is N, etc., R' is H, a 1-4C alkyl, etc.; R is 4-(2-pyrimidinyl)piperazin-1-yl, etc.) may be cited as the quinolonecarboxylic acid-based anti-HIV agent. An excellent synergistic effect is shown in the proliferation suppressing activity against HIV by using the combination.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to one or more drugs of a quinolonecarboxylic acid anti-HIV agent and one or more drugs of a reverse transcriptase inhibitor for treating or preventing AIDS. Combined use with, quinolonecarboxylic acid anti-HI
Combined use of one or more agents of V agent and one or more agents of HIV protease inhibitor, and reverse transcription with one or more agents of quinolonecarboxylic acid anti-HIV agent One or more enzyme inhibitors and HIV
Use in combination with one or more drugs with protease inhibitors, and one or more drugs of quinolonecarboxylic acid anti-HIV agents and one or more drugs of reverse transcriptase inhibitors AIDS therapeutic agent or prophylactic agent, which is contained as an active ingredient, and one or more agents of quinolonecarboxylic acid anti-HIV agent and one or more agents of HIV protease inhibitor, as an active ingredient One or more agents of AIDS therapeutic or preventive agents and quinolonecarboxylic acid anti-HIV agents and one or more agents of reverse transcriptase inhibitors and one or two agents of HIV protease inhibitors The present invention relates to an AIDS therapeutic agent or preventive agent containing the above-mentioned agents as active ingredients.

[0002]

2. Description of the Related Art Many drugs have been marketed, developed or studied for the purpose of treating AIDS or preventing the onset of AIDS. For example, it is known that a drug that inhibits reverse transcriptase and a drug that inhibits HIV protease are effective in treating AIDS and preventing its onset. However, there is a limit to the treatment or prevention with a single agent, and treatment with a plurality of agents or prevention of onset has been attempted.

On the other hand, the present inventors have already found that quinolonecarboxylic acid compounds have anti-HIV activity and are effective in treating or preventing the onset of AIDS (EP5).
72,259 publication, WO96 / 02512 publication).

[0004]

DISCLOSURE OF THE INVENTION The present inventors have conducted various studies in view of the importance of treating or preventing the onset of AIDS, and as a result, one or more quinolonecarboxylic acid anti-HIV agents have been obtained. , And one or more kinds of reverse transcriptase inhibitors, and one or more kinds of quinolonecarboxylic acid anti-HIV agents and HIV protease inhibitors 1 or 2 or more kinds of agents, and further, 1 or 2 or more kinds of quinolonecarboxylic acid anti-HIV agents and 1 or 2 or more kinds of reverse transcriptase inhibitors. It has been found that the effective use of AIDS treatment or prevention of the onset of AIDS can be achieved by the combined use of these agents and one or more agents of HIV protease inhibitors.

[0005]

The present invention provides a quinolonecarboxylic acid anti-HIV agent for treating or preventing AIDS.
Or two or more drugs and one or two reverse transcriptase inhibitors
Combined use with one or more drugs, combined use of one or more drugs of quinolonecarboxylic acid anti-HIV agents and one or more drugs of HIV protease inhibitors, and quinolonecarboxylic acid compounds Anti-HIV agent, one or more agents, reverse transcriptase inhibitor, one or more agents, and H
Use of IV protease inhibitor in combination with one or more drugs and quinolonecarboxylic acid anti-HIV agent
Or two or more drugs and one or two reverse transcriptase inhibitors
Aids therapeutic agent or prophylactic agent containing one or more agents as active ingredients, one or more agents of quinolonecarboxylic acid anti-HIV agents and one or more agents of HIV protease inhibitors are effective AIDS therapeutic or prophylactic agent and quinolonecarboxylic acid anti-HIV agent as one component, one or more agents and one or more reverse transcriptase inhibitors, and one or more HIV protease inhibitors or Provided is a therapeutic or prophylactic agent for AIDS containing two or more kinds of drugs as active ingredients.

The active ingredient of the present invention used in combination for the treatment or prevention of AIDS and the active ingredient of the therapeutic or prophylactic agent for AIDS are as follows: 1) One or more quinolonecarboxylic acid anti-HIV agents A drug and one or more drugs of reverse transcriptase inhibitors, 2) one or more drugs of quinolonecarboxylic acid anti-HIV agents and one or more drugs of HIV protease inhibitors; Or 3) one or more kinds of quinolonecarboxylic acid anti-HIV agents and one or more kinds of reverse transcriptase inhibitors and one or more kinds of HIV protease inhibitors And the drug.

The quinolonecarboxylic acid anti-HIV agent which is the active ingredient of the present invention is typically represented by the quinolonecarboxylic acid represented by the following general formula (Ia), (Ib) or (Ic) or a pharmacologically acceptable compound. That is the salt.

[0008]

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The above formula (Ia), (Ib) or (Ic)
Wherein X represents a hydrogen atom or a halogen atom, and Y is substituted with 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 of 1 to 4 Mono or dialkyl substituted amino group or 1
Or 2 represents a mono- or diaralkyl-substituted amino group substituted with an aralkyl group having 7 to 14 carbon atoms,
Z represents an optionally protected carboxy group or 5-tetrazolyl group, Q represents a nitrogen atom or a 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.
To indicate the four alkylene group or having 1 to 4 carbon atoms which may be substituted with alkyl 2 to 4 alkenylene group having a carbon of, R ¹ is a hydrogen atom; a substituted C 1 to carbon atoms, which may have 4 alkyl groups [Substituents of said alkyl groups 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 N, O and S
A group represented by 3 to 7-membered hetero-saturated monocyclic ring containing a hetero atom selected from
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 carbon atoms, alkyl having 1 to 4 carbon atoms substituted with fluorine, alkoxy having 1 to 4 carbon atoms, 1 to 4 carbon atoms) Alkylthio, amino, and a group selected from mono- or dialkyl-substituted amino substituted with 1 to 2 alkyl having 1 to 4 carbons), optionally substituted with 6 to 10 carbons A heterocyclic monocyclic group of 5 to 6 members containing 1 to 2 heteroatoms selected from N, O and S or a heteroaromatic condensed ring group obtained by condensing these heteroaromatic monocycles with a benzene ring. shown; R ^4, R ⁵ and R ⁷ indicates each hydrogen or C 1 to 4 alkyl group having a carbon; R ⁸ is a hydrogen atom, a hydroxyl group, 1 to 4 alkyl groups or C 1 to 4 carbon atoms
Represents 1 alkoxy group; n represents 1 or 2; m represents 0
Or 1; n'represents 1 or 2; n "is 1, 2,
3 or 4 is shown].

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

[0021]

[Chemical 21]

(In each general 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 the general formulas (Ia), (Ib) and (Ic), preferable compounds are the general 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)

[0024]

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[0025]

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(In each general formula, A, X, Y, Z,
W, R, T and R ¹ have the same meanings as described above, and are —O.
R ¹² represents an alkoxy group having 1 to 4 carbon atoms which may be substituted with halogen (especially fluorine) (especially difluoromethoxy group), and R ¹³ is substituted with a hydrogen atom, a halogen atom or halogen (especially fluorine). Optionally substituted alkyl group having 1 to 4 carbon atoms (especially trifluoromethyl group)
Further, A'includes a hydrogen atom or an alkyl group having 1 to 4 carbon atoms which may be substituted with halogen (especially fluorine).

In the present invention, 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 above 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 above 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.

Examples of the protecting group for the carboxy group in the "optionally protected carboxy group" for Z in the above general formulas (Ia) and (Ic) include methyl, ethyl, propyl, isopropyl, butyl and isobutyl groups. An alkyl group having 1 to 4 carbon atoms; benzyl, 1-phenylethyl,
Aralkyl group having 7 to 14 carbon atoms such as 1-naphthylmethyl group; alkanoyloxyalkyl group having 1 to 4 carbon atoms such as acetoxymethyl and pivaloyloxymethyl group; 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 above general formulas (Ia) and (Ic) is preferably a carboxy group which may be protected, and more preferably a carboxy group.

The above 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 above general 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 above general formulas (Ia), (Ib) and (I)
When 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 is, for example, methoxy, ethoxy, propoxy, isopropoxy or butoxy group. Alkoxy group; fluorine-substituted alkoxy group such as fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-fluoropropoxy, 3-fluoropropoxy, 4-fluorobutoxy group; 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.

The general formulas (Ia), (Ib) and (I
When Q in c) is represented by 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 with 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.

As W in the general formula (Ib),
It is preferably a sulfur atom.

As T in the general formula (Ic),
Methylene, ethylidene [-CH (CH ₃₎ -], ethylene, trimethylene, propylene, alkylene group which may having 1 to 4 carbons optionally substituted with C 1 to 4 alkyl carbons such as a tetramethylene group; -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.

The "C1 to C4 alkyl group" of the optionally substituted C1 to C4 alkyl group of R ^{1 in} the above formulas (Ia) and (Ib) is methyl or ethyl. Alkyl groups such as propyl, isopropyl, butyl, isobutyl, s-butyl and t-butyl groups are preferred, and methyl, ethyl, propyl and isopropyl groups are preferred, and methyl and ethyl groups are more preferred. Is.

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

The alkoxy group having 1 to 4 carbon atoms, which is a substituent of the substituted alkyl group having 1 to 4 carbon atoms of R ^{1 in} the general formulas (Ia) and (Ib), is methoxy, ethoxy, Examples thereof include a propoxy group, an isopropoxy group, and a butoxy group, and a methoxy group and an ethoxy group are preferable, and a methoxy group is more preferable.

The cycloalkyl group having 3 to 6 carbon atoms, which is the substituent of the substituted alkyl group having 1 to 4 carbon atoms of R ^{1 in} the general formulas (Ia) and (Ib), is cyclopropyl, Examples thereof include a cyclobutyl group, a cyclopentyl group and a cyclohexyl group, and a cyclopropyl group is preferable.

Examples of the alkanoyloxy group having 2 to 5 carbon atoms which is a substituent of the alkyl group having 1 to 4 carbon atoms substituted by R ^{1 in} the above general formulas (Ia) and (Ib) include acetoxy and propionyl. An oxy or brityloxy group is mentioned, and an acetoxy group is preferable.

R ⁹ and R ¹⁰ in the above formula (e), which is a substituent of R ¹ substituted alkyl group having 1 to 4 carbons in the above formulas (Ia) and (Ib), has 1 carbon atom.
To 4 alkyl groups have the carbon number of R ¹ of 1
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.

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

The above formula (e), which is a substituent of the substituted C ¹ -C 4 alkyl group for R ^{1 in} the above formulas (Ia) and (Ib), is preferably amino or methylamino. , Dimethylamino, piperidino and morpholino groups, and more preferably dimethylamino group.

6 to 10 carbon atoms which may be substituted with R ⁰ , which is a substituent of R ¹ substituted alkyl group having 1 to 4 carbon atoms in the above general formulas (Ia) and (Ib). Examples of the "aryl group having 6 to 10 carbon atoms" of the aryl group include a phenyl group, a 1-naphthyl group, a 2-naphthyl group and the like, and a phenyl group is preferable.

N, O and S, which may be substituted by R ⁰ , which is a substituent of the alkyl group having 1 to 4 carbon atoms, which is substituted by R ^{1 in} the above general formulas (Ia) and (Ib). A 5- to 6-membered heteroaromatic monocyclic group containing 1 to 2 heteroatoms selected from or a heteroaromatic condensed ring group obtained by condensing these heteroaromatic monocyclic groups with a benzene ring (hereinafter referred to as a heteroaromatic monocyclic group Together with a heteroaromatic ring group, it is also called a heteroaromatic ring group)
As a "5- to 6-membered heteroaromatic monocyclic group containing 1 to 2 heteroatoms selected from N, O and S or a heteroaromatic condensed ring group in which these heteroaromatic monocyclic groups are condensed with a benzene ring" 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- Pyrazinyl, 3-pyridazinyl, 2-benzoxazolyl, 2
-Benzothiazolyl, 2-benzimidazolyl, 3-benzisoxazolyl, 3-benzisothiazolyl group and the like, and preferably 2-thienyl, 2-furyl, 2
-Pyridyl and 2-pyrimidinyl groups, more preferably a 2-pyridyl group.

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

As the whole alkyl group which may be substituted and has 1 to 4 carbon atoms represented by R ^{1 in} the above general formulas (Ia) and (Ib), 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, 4
-Fluorobutyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl; cyclopropylmethyl; 2-acetoxyethyl, 2-acetoxypropyl, 3-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-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.

2 to 5 carbon atoms which may be substituted with halogen of R ^{1 in} the above general formulas (Ia) and (Ib).
As the alkenyl group, 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 can be mentioned, preferably vinyl, 2-propenyl and 3,3.
-Dimethyl-2-propenyl and 3,3-dichloro-2
-Propenyl, more preferably vinyl and 2-
It is a propenyl group.

The alkynyl group having 2 to 4 carbon atoms represented by R ^{1 in} the above formulas (Ia) and (Ib) includes 2 to 4 carbon atoms such as ethynyl, 1-propynyl, 2-propynyl and 2-butynyl groups. 4 alkynyl groups can be mentioned, preferably ethynyl and 2-propynyl groups,
More preferably, it is a 2-propynyl group.

Examples of the mono- or dialkyl-substituted amino group substituted with 1 to 2 alkyl groups having 1 to 4 carbon atoms for R ^{1 in} the above general formulas (Ia) and (Ib) include methylamino, ethylamino, Monoalkyl-substituted amino groups such as propylamino, isopropylamino, butylamino groups; dialkyl-substituted amino groups such as dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino groups, and preferably methylamino. , Ethylamino and dimethylamino groups, and more preferably a methylamino group.

3 to 6 carbon atoms which may be substituted by halogen of R ^{1 in} the above general formulas (Ia) and (Ib).
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 of R ^{1 in} the above general formulas (Ia) and (Ib) include alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy and butoxy groups. Are methoxy, ethoxy and propoxy groups, and more preferably methoxy and ethoxy groups.

[0058] Formula (Ia) and hereinafter R ⁰ having 6 to carbon atoms which may be substituted with one of R ¹ in (Ib)
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.

C ¹ to C ¹ which may be substituted with R ⁰ described later in R ^{1 in} the above general formulas (Ia) and (Ib).
A 5- or 6-membered heteroaromatic monocyclic group containing 0 aryl groups and 1 or 2 heteroatoms selected from N, O and S, or a condensed heteroaromatic condensed ring of these heteroaromatic monocycles and a benzene ring As R ⁰ of the group, the above-mentioned 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, 3 -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 are taken together to form the bond represented by the formula (f), "A" in the formula (f) "A 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" includes methyl, ethyl, propyl,
Alkyl groups such as isopropyl and butyl groups; fluoromethyl, chloromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2
-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 are taken together to form the bond represented by the formula (f), A in the formula (f) is , Preferably a hydrogen atom, methyl, fluoromethyl and hydroxymethyl group.

In the general formulas (Ia) and (Ib), when R ¹ and R ² are taken together to form the bond represented by the formula (f), G in the formula (f) is And preferably a group represented by the formula (g), and having 1 to 4 carbon atoms of R ¹¹ of —N (R ¹¹ ) — of G ¹ of the formula (f).
Examples of the alkyl group 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 are taken together to form the bond represented by the formula (f), p in the formula (f) is It is preferably 1.

The above general formulas (Ia), (Ib) and (I
Substituent R on the above aryl group and heteroaromatic ring group of R ³ and R ⁶ in formulas (h) and (i) of R in c)
⁰ is a heteroaromatic which may be substituted by R ⁰ described below, which is a substituent of the alkyl group having 1 to 4 carbon atoms which is substituted by R ¹ in the above general formulas (Ia) and (Ib). Examples of the ring group include the same as R ⁰ , preferably fluorine, chlorine atom; methyl, ethyl; trifluoromethyl; methoxy, ethoxy; methylthio, ethylthio group, and more preferably fluorine, chlorine atom. Methyl; trifluoromethyl; methoxy; methylthio group.

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

The above general formulas (Ia), (Ib) and (I
Examples of the heteroaromatic ring group of R ³ and R ⁶ in the formulas (h) and (i) of R in c) include 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 -Benzisoxazolyl and 3-benzisothiazolyl groups can be mentioned, preferably 2-thiazolyl, 4-pyrimidinyl, 2-pyrazinyl, 3-benzisothiazolyl, 2-pyridyl, 2-pyrimidinyl, 2
-Benzothiazolyl and 2-benzoxazolyl groups, more preferably 2-pyrimidinyl, 2-pyridyl, 2-benzothiazolyl and 2-benzoxazolyl groups.

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

The above general formulas (Ia), (Ib) and (I)
Examples of the alkyl group having 1 to 4 carbon atoms of R ⁸ in the 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 above general formulas (Ia), (Ib) and (I)
As R ⁸ of R in c), a hydrogen atom, a hydroxyl group, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy and propoxy groups are preferable, and a hydrogen atom, a hydroxyl group, methyl, ethyl and methoxy are particularly preferable. 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 above general 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 general formula (Ia), (Ib) or (I
When c) has a carboxy group in the molecule, those carboxy groups may be protected by a protecting group to form an ester, and such a protecting group may be the above-mentioned "protection group of Z". The same as those mentioned for the “good carboxy group” can be mentioned.

The above general formulas (Ia), (Ib) and (I
The compound shown by c) can be a pharmacologically acceptable salt as needed.

Examples of 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 benzene sulfonate, p-toluene sulfonate, oxalate, maleate, fumarate, tartrate, citrate; or sodium salt,
Examples thereof include metal salts of carboxylic acids such as potassium salt, calcium salt, magnesium salt, manganese salt, iron salt and aluminum salt.

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

Formulas (Ia) and (I
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 which is a CH-group, 8) a compound where 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-benzoxazolyl) 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 above-mentioned general formulas (Ia) and (Ib) which are the active ingredients of the present invention
The compounds represented by the formula (Ic) can be exemplified in Tables 1 to 38.

[0082]

[Table 1]

[0083]

[Table 2]

[0084]

[Table 3]

[0085]

[Table 4]

[0086]

[Table 5]

[0087]

[Table 6]

[0088]

[Table 7]

[0089]

[Table 8]

[0090]

[Table 9]

[0091]

[Table 10]

[0092]

[Table 11]

[0093]

[Table 12]

[0094]

[Table 13]

[0095]

[Table 14]

[0096]

[Table 15]

[0097]

[Table 16]

[0098]

[Table 17]

[0099]

[Table 18]

[0100]

[Table 19]

[0101]

[Table 20]

[0102]

[Table 21]

[0103]

[Table 22]

[0104]

[Table 23]

[0105]

[Table 24]

[0106]

[Table 25]

[0107]

[Table 26]

[0108]

[Table 27]

[0109]

[Table 28]

[0110]

[Table 29]

[0111]

[Table 30]

[0112]

[Table 31]

[0113]

Embedded image

[0114]

[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 ────────────────────────────────

[0115]

Embedded image

[0116]

[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 ──────────────────────────────

[0117]

[Chemical formula 26]

[0118]

[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 ────────────────────────────────

[0119]

Embedded image

[0120]

[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 ───────────────────────────────────

[0121]

Embedded image

[0122]

[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 ────────────────────────────────────

[0123]

[Chemical 29]

[0124]

[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 ────────────────────────────────────

[0125]

Embedded image

[0126]

[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.

[0127]

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 reverse transcriptase inhibitor, which is the active ingredient of the present invention, refers to a drug that inhibits the reverse transcriptase encoded by the HIV gene. Typical examples are nucleoside compounds and dipyridodiene. It may be an azepine compound, and is preferably ZDV (zidobucin), DDI (didanocin), DDC (zarcitabine), d4T (stavudine), 3TC (lamivudine), FTC (524W91).
And nevirapine, more preferably ZDV and DD.
I and nevirapine, most preferably ZDV.

The structural formulas of typical reverse transcriptase inhibitors are shown below.

[0130]

[Chemical 31]

ZDV (Zidobucin) is EP287,2
No. 15 publication, the chemical name is 1- (3
-Azido-2,3-dideoxy- [beta] -D-erythro-pentofuranosyl) -5-methyl-2 (1H) -pyrimidone.

DDI (didanocin) is a product of US Pat.
35, 104, etc., the chemical name is
It is 2 ', 3'-dideoxyinosine.

DDC (Zalcitabine) is EP285,
No. 884, the chemical name is 2 ',
It is 3'-dideoxycytidine.

D4T (stavudine) is EP334,3
No. 68 publication, its chemical name is 2 ',
It is 3'-dideoxy-2 ', 3'-dehydrothymidine.

3TC (lamivudine) is WO91 / 17
159, etc., and its chemical name is 4-amino-1- (2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H) -pyrimidin-2-one.

The FTC (524W91) is EP526,
No. 253, the chemical name of which is 4-amino-5-fluoro-1- (2-hydroxymethyl-
1,3-oxathiolane)-(1H) -pyrimidine-2
-On.

Nevirapine is described in EP 429,987, which has a chemical name of 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido [3,2-b: 2 ', 3'-e] [1,4] diazepin-6-one.

The reverse transcriptase inhibitor of the present invention also includes hydrates of the above compounds.

The HIV protease inhibitor, which is the active ingredient of the present invention, refers to a drug that inhibits HIV protease, and representative ones thereof may be dipeptide compounds and tripeptide compounds, preferably, VX-47
8, KNI-272, AG-1343, saquinavir,
Ritonavir, indiavir and compound A, more preferably AG-1343, saquinavir, ritonavir and indinavir.

The structural formulas of typical HIV protease inhibitors are shown below.

[0141]

Embedded image

[0142]

[Chemical 33]

VX-478 is described in WO94 / 05639, WO95 / 33464 and the like, and its chemical name is [2R-hydroxy-3-[[(4-aminophenyl) sulfonyl] (2-methylpropyl). ) Amino]-
1S- (phenylmethyl) propyl] carbamic acid 3
S-tetrahydrofuranyl ester.

KNI-272 is described in EP 574,135, and its chemical name is [4R- [3 [2
S ^* , 3 ^* S (R ^* )], 4R ^* ]]-N- (1,1-
Dimethylethyl) -3- [2-hydroxy-3-[[2
-[[5-isoquinolinyloxy) acetyl] amino]
-3- (Methylthio) -1-oxopropyl] amino]
-1-oxo-4-phenylbutyl-4-carboxamide.

AG-1343 is described in WO95 / 09843.
The chemical name is [3S- (3R
^* , 4aR ^* , 8aR ^* , 2'S ^* , 3'S ^* )]-2
-[2'-hydroxy-3'-phenylthiomethyl]-
4'-aza-5'-oxo-5 '-(2''-methyl-
3 ″ -hydroxyphenyl) pentyl] decahydroisoquinoline-3-Nt-butylcarboxamide.

Saquinavir is described in EP 432,695 and the like, and its chemical name is Nt-butyl-
Decahydro-2- [2 (R) -hydroxy-4-phenyl-3 (S)-[[N- (2-quinolylcarbonyl)-
L-asparagyl] amino] butyl]-(4aS, 8a
S) -isoquinoline-3 (S) -carboxamide.

Ritonavir is described in WO94 / 14436 and the like, and its chemical name is (2S, 3S, 5S).
-5- (N- (N-((N-methyl-N-((2-isopropyl-4-thiazolyl) methyl) amino) carbonyl) valinyl) amino) -2- (N-((5-thiazolyl) methoxy) Carbonyl) amino) -1,6-diphenyl-3-hydroxyhexane.

Indinavir is described in EP 541,168, etc., and its chemical name is N- (2 (R)-
Hydroxy-1 (S) -indanyl) -2 (R) -phenylmethyl-4 (S) -hydroxy-5- (1- (4-
(3-pyridylmethyl) -2 (S) -N '-(t-butylcarboxamido) -piperazinyl))-pentanamide.

Compound A is described in WO96 / 28423, and its chemical name is (2S, 3S) -3- (3
-Hydroxy-2-methylbenzoyl) amino-2-hydroxy-4-phenylbutanoyl- [4 (S) -chloro] -L-proline tert-butyramide.

The HIV protease inhibitors of the present invention also include hydrates of the above compounds. In the present invention,
The quinolonecarboxylic acid anti-HIV agent is used in one kind or two or more kinds, the reverse transcriptase inhibitor is used in one kind or two kinds or more, and the HIV protease inhibitor is used in one kind or two kinds or more. , Preferably 1) one drug of quinolonecarboxylic acid anti-HIV agent and one drug of reverse transcriptase inhibitor, 2) one drug of quinolonecarboxylic acid anti-HIV drug and H
1 drug of IV protease inhibitor, 3) 1 drug of quinolonecarboxylic acid anti-HIV drug, 1 drug of reverse transcriptase inhibitor, and 1 drug of HIV protease inhibitor are used in combination.

The therapeutic or prophylactic agent for AIDS of the present invention is preferably: 1) a therapeutic agent in which the quinolonecarboxylic acid anti-HIV agent as an active ingredient is of the above formula (Ia), (Ib) or (Ic) or Prophylactic agent, 2) A therapeutic or preventive agent in which the quinolonecarboxylic acid anti-HIV agent of active ingredient is the above formula (Ia), 3) A quinolonecarboxylic acid anti-HIV agent of active ingredient 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 a carboxy group which may be protected, and Q
Is a formula (d), and R ² of the formula (d) is a methoxy, difluoromethoxy or trifluoromethyl group, R ¹ is a hydrogen atom; methyl, ethyl, propyl, isopropyl; 2-hydroxy Ethyl; 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; or 2-propynyl group, and 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-
A therapeutic or prophylactic agent which is a compound having a (2-pyridyl) piperazin-1-yl group, 4) The quinolonecarboxylic acid anti-HIV agent as an active ingredient has the formula (Ia), wherein X is a fluorine atom, and 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
Is a formula (d), and R ² of the formula (d) is a methoxy, difluoromethoxy or trifluoromethyl group, and R ¹ is methyl, ethyl, 2-hydroxyethyl,
It is a 2-fluoroethyl, cyclopropyl or methylamino group, and R is 4- (2-pyrimidinyl) piperazin-1-yl, 4- (2-benzothiazolyl) piperazin-1-yl, 4- (2-pyridyl). Piperazin-1-yl, 4- (2-benzoxazolyl) piperazin-1-
Or 4- (6-methoxy-2-benzothiazolyl)
5. A therapeutic or prophylactic agent which is a compound having a piperazin-1-yl group, 5) The active ingredient, a quinolonecarboxylic acid anti-HIV agent, 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) piperazine-
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-1-methylamino-7- [4- (2-benzooxa Zolyl) piperazin-1-yl] quinoline-3-carboxylic acid, a therapeutic or prophylactic agent, 6) a reverse transcriptase inhibitor as an active ingredient is ZDV (didobucin), DDI (didanocin), DDC (zarcitabine), d4T (stavudine), 3TC (lamivudine),
FTC (524W91) or nevirapine is a therapeutic or preventive agent, 7) The active ingredient reverse transcriptase inhibitor is ZDV, DDI and nevirapine is a therapeutic or prophylactic agent, 8) The active ingredient reverse transcriptase inhibitor is , A therapeutic agent or a preventive agent which is ZDV, 9) The HIV protease inhibitor as an active ingredient is VX-4.
78, KNI-272, AG-1343, saquinavir, ritonavir, indinavir and a compound A as a therapeutic or prophylactic agent and 10) an HIV protease inhibitor as an active ingredient is AG-
1343, saquinavir, ritonavir or indinavir may be mentioned as a therapeutic or prophylactic agent.

Further, the active ingredient quinolonecarboxylic acid anti-HIV agent is selected from 1) to 5), and the active ingredient reverse transcriptase inhibitor is selected from 6) to 8).
A therapeutic agent or prophylactic agent obtained by selecting a V protease inhibitor from 9) to 10) and combining these is also suitable, and examples thereof include the following.

11) The quinolonecarboxylic acid anti-HIV agent as the active ingredient is of the above formula (Ia), (Ib) or (Ic), and the reverse transcriptase inhibitor as the active ingredient is ZDV or DD.
I, DDC, d4T, 3TC, FTC or a nevirapine therapeutic or prophylactic agent, 12) a quinolonecarboxylic acid anti-HIV agent as an active ingredient,
The above-mentioned formula (Ia), wherein the reverse transcriptase inhibitor of the active ingredient is ZDV, DDI, DDC, d4T, 3TC, FTC.
Or a therapeutic or prophylactic agent which is nevirapine, 13) an active ingredient quinolonecarboxylic acid anti-HIV agent,
In the formula (Ia), 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 an optionally protected carboxy group,
Q is formula (d), R ^{2 of} formula (d) is a methoxy, difluoromethoxy or trifluoromethyl group, 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; or 2-propynyl group, and 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-
A compound having a (2-pyridyl) piperazin-1-yl group, wherein the reverse transcriptase inhibitor as an active ingredient is ZDV, DD
The therapeutic or prophylactic agent which is I and nevirapine, 14) The quinolonecarboxylic acid anti-HIV agent as an active ingredient,
In the formula (Ia), 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 an optionally protected carboxy group,
Q is the formula (d), R ² of the formula (d) is a methoxy, difluoromethoxy or trifluoromethyl group, and R ¹ is methyl, ethyl, 2-hydroxyethyl, 2-fluoroethyl. , Cyclopropyl or methylamino group, and R is 4- (2-pyrimidinyl) piperazin-1-yl, 4- (2-benzothiazolyl) piperazin-1-yl, 4- (2-pyridyl) piperazine-1.
-Yl, 4- (2-benzoxazolyl) piperazine-
A therapeutic or prophylactic agent which is a compound which is 1-yl or 4- (6-methoxy-2-benzothiazolyl) piperazin-1-yl group, wherein the reverse transcriptase inhibitor of the active ingredient is ZDV, DDI and nevirapine. 15) The active ingredient quinolonecarboxylic acid anti-HIV agent 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-1-methylamino-7- [4- (2- Benzoxazolyl) piperazin-1-yl] quinoline-3-carboxylic acid,
The active ingredient reverse transcriptase inhibitor is ZDV, DDI, DD
A therapeutic or prophylactic agent which is C, d4T, 3TC, FTC or nevirapine, 16) The quinolonecarboxylic acid anti-HIV agent 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) 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-1-methylamino-7- [4- (2- Benzoxazolyl) piperazin-1-yl] quinoline-3-carboxylic acid,
A therapeutic or preventive agent in which the reverse transcriptase inhibitor of the active ingredient is ZDV, DDI and nevirapine, 17) The quinolonecarboxylic acid anti-HIV agent of 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-1-methylamino-7- [4- (2- Benzoxazolyl) piperazin-1-yl] quinoline-3-carboxylic acid,
A therapeutic or preventive agent in which the reverse transcriptase inhibitor of the active ingredient is ZDV, 18) The quinolonecarboxylic acid anti-HIV agent of the active ingredient is
The HIV protease inhibitor of the above formula (Ia), (Ib) or (Ic) is VX-478 or KN.
I-272, AG-1343, saquinavir, ritonavir, indinavir and a compound A, a therapeutic or preventive agent, 19) a quinolonecarboxylic acid anti-HIV agent as an active ingredient,
The HIV protease inhibitor of the above formula (Ia) is VX-478, KNI-272, AG-13.
43, a therapeutic or prophylactic agent which is succinavir, ritonavir, indinavir and compound A, 20) a quinolonecarboxylic acid anti-HIV agent as an active ingredient
In the formula (Ia), 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 an optionally protected carboxy group,
Q is formula (d), R ^{2 of} formula (d) is a methoxy, difluoromethoxy or trifluoromethyl group, 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; or 2-propynyl group, and 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-
A compound which is a (2-pyridyl) piperazin-1-yl group, wherein the active ingredient HIV protease inhibitor is VX
-478, KNI-272, AG-1343, saquinavir, ritonavir, indinavir and compound A are therapeutic or prophylactic agents, 21) The quinolonecarboxylic acid anti-HIV agent of the active ingredient is
In the formula (Ia), 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 an optionally protected carboxy group,
Q is the formula (d), R ² of the formula (d) is a methoxy, difluoromethoxy or trifluoromethyl group, and R ¹ is methyl, ethyl, 2-hydroxyethyl, 2-fluoroethyl. , Cyclopropyl or methylamino group, and R is 4- (2-pyrimidinyl) piperazin-1-yl, 4- (2-benzothiazolyl) piperazin-1-yl, 4- (2-pyridyl) piperazine-1.
-Yl, 4- (2-benzoxazolyl) piperazine-
A compound which is a 1-yl or 4- (6-methoxy-2-benzothiazolyl) piperazin-1-yl group, wherein the active ingredient HIV protease inhibitor is VX-478, K
NI-272, AG-1343, saquinavir, ritonavir, indinavir and a therapeutic or prophylactic agent which is compound A. 22) The quinolonecarboxylic acid anti-HIV agent 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) 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-1-methylamino-7- [4- (2- Benzoxazolyl) piperazin-1-yl] quinoline-3-carboxylic acid,
The active ingredient HIV protease inhibitor is VX-47
8, KNI-272, AG-1343, saquinavir,
A therapeutic or prophylactic agent which is ritonavir, indinavir and compound A. 23) A quinolonecarboxylic acid anti-HIV agent as an active ingredient,
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-1-methylamino-7- [4- (2- Benzoxazolyl) piperazin-1-yl] quinoline-3-carboxylic acid,
The active ingredient HIV protease inhibitor is AG-134
3. A therapeutic or prophylactic agent which is saquinavir, ritonavir or indinavir, 24) a quinolonecarboxylic acid anti-HIV agent as an active ingredient,
In the formula (Ia), (Ib) or (Ic), the active ingredient reverse transcriptase inhibitor is ZDV, DDI, DDC, d
4T, 3TC, FTC or nevirapine, and the active ingredient HIV protease inhibitor is VX-478, KNI
-272, AG-1343, saquinavir, ritonavir, indinavir and compound A are therapeutic or prophylactic agents, 25) The quinolonecarboxylic acid anti-HIV agent of the active ingredient is
The above-mentioned formula (Ia), wherein the reverse transcriptase inhibitor of the active ingredient is ZDV, DDI, DDC, d4T, 3TC, FTC.
Or nevirapine, the active ingredient HIV protease inhibitor is VX-478, KNI-272, AG-13.
43, a therapeutic or prophylactic agent which is succinavir, ritonavir, indinavir and compound A. 26) A quinolonecarboxylic acid anti-HIV agent as an active ingredient
In the formula (Ia), 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 an optionally protected carboxy group,
Q is formula (d), R ^{2 of} formula (d) is a methoxy, difluoromethoxy or trifluoromethyl group, 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; or 2-propynyl group, and 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-
A compound having a (2-pyridyl) piperazin-1-yl group, wherein the reverse transcriptase inhibitor as an active ingredient is ZDV, DD
I and nevirapine, the active ingredient HIV protease inhibitors are VX-478, KNI-272, AG-1.
343, saquinavir, ritonavir, indinavir and compound A as a therapeutic or prophylactic agent, 27) an active ingredient quinolonecarboxylic acid anti-HIV agent,
In the formula (Ia), 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 an optionally protected carboxy group,
Q is the formula (d), R ² of the formula (d) is a methoxy, difluoromethoxy or trifluoromethyl group, and R ¹ is methyl, ethyl, 2-hydroxyethyl, 2-fluoroethyl. , Cyclopropyl or methylamino group, and R is 4- (2-pyrimidinyl) piperazin-1-yl, 4- (2-benzothiazolyl) piperazin-1-yl, 4- (2-pyridyl) piperazine-1.
-Yl, 4- (2-benzoxazolyl) piperazine-
1-yl or 4- (6-methoxy-2-benzothiazolyl) piperazin-1-yl group, the active ingredient reverse transcriptase inhibitors are ZDV, DDI and nevirapine, and the active ingredient HIV protease The inhibitor
VX-478, KNI-272, AG-1343, saquinavir, ritonavir, indinavir and compound A are therapeutic or prophylactic agents, 28) The quinolonecarboxylic acid anti-HIV agent of the active ingredient is
In the formula (Ia), 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 an optionally protected carboxy group,
Q is the formula (d), R ² of the formula (d) is a methoxy, difluoromethoxy or trifluoromethyl group, and R ¹ is methyl, ethyl, 2-hydroxyethyl, 2-fluoroethyl. , Cyclopropyl or methylamino group, and R is 4- (2-pyrimidinyl) piperazin-1-yl, 4- (2-benzothiazolyl) piperazin-1-yl, 4- (2-pyridyl) piperazine-1.
-Yl, 4- (2-benzoxazolyl) piperazine-
1-yl or 4- (6-methoxy-2-benzothiazolyl) piperazin-1-yl group, the active ingredient reverse transcriptase inhibitors are ZDV, DDI and nevirapine, and the active ingredient HIV protease The inhibitor
29. A therapeutic or prophylactic agent which is AG-1343, saquinavir, ritonavir or indinavir, 29) a quinolonecarboxylic acid anti-HIV agent as an active ingredient,
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-1-methylamino-7- [4- (2- Benzoxazolyl) piperazin-1-yl] quinoline-3-carboxylic acid,
The active ingredient reverse transcriptase inhibitor is ZDV, and the active ingredient HIV protease inhibitor is VX-478, KN
I-272, AG-1343, saquinavir, ritonavir, indinavir and a compound A as a therapeutic or prophylactic agent, 30) The quinolonecarboxylic acid anti-HIV agent as an active ingredient,
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-1-methylamino-7- [4- (2- Benzoxazolyl) piperazin-1-yl] quinoline-3-carboxylic acid,
The therapeutic or prophylactic agent wherein the reverse transcriptase inhibitor of the active ingredient is ZDV, and the HIV protease inhibitor of the active ingredient is AG-1343, succinavir, ritonavir or indinavir.

The quinolonecarboxylic acid anti-HI used in combination with the present invention or as a therapeutic or prophylactic agent for AIDS
Specific examples of the combination of the V agent and / or the reverse transcriptase inhibitor and / or the HIV protease inhibitor include the following combinations, but the present invention is not limited to these combinations.

In Table 39, the quinolonecarboxylic acid type anti-HIV agents are shown by production example numbers.

[0156]

[Table 39] ──────────────────────────────────── Number quinolonecarboxylic acid reverse transcriptase inhibitor Protease Inhibitor ──────────────────────────────────── 1 117 ZDV-2 144 ZDV-3 3 147 ZDV- No. ZDV AG-1343 16 149 ZDV AG-1343 17 151 ZDV AG-1343 18 156 ZDV AG-1343 19 117 Z V saquinavir 20 144 ZDV saquinavir 21 147 ZDV saquinavir 22 149 ZDV saquinavir 23 151 ZDV saquinavir 24 156 ZDV saquinavir 25 117 ZDV Ritonavir 26 144 ZDV Ritonavir 27 147 ZDV Ritonavir 28 149 ZDV Ritonavir 29 151 ZDV Ritonavir 30 156 ZDV Ritonavir ──── ──────────────────────────────── According to the present invention, a quinolonecarboxylic acid anti-HIV agent and a reverse transcriptase inhibitor The combined use of the agent and the HIV protease inhibitor shows superior effects as compared with each single agent.

Further, such an effect is brought about even if the drugs of 2 to 3 systems are not necessarily present in the body at the same time. That is, the drugs of two to three systems are effective even if they do not have a blood concentration above a certain level at the same time.

In the treatment of AIDS, it is convenient to direct a combination therapy and to administer these two or three agents simultaneously.
V agent, reverse transcriptase inhibitor and / or HIV protease inhibitor can be administered in the form of a combination. When it is not preferable to mix both drugs physically simultaneously due to the formulation technique, each single drug can be administered simultaneously. Further, as described above, since the drugs of 2 to 3 systems exert excellent effects even if they are not simultaneously administered, it is also possible to administer each single drug before and after at appropriate intervals. The maximum 2 allowed to achieve the superior effect produced by such a couple of drugs
The administration intervals of the drugs of 3 to 3 systems can be confirmed clinically or by animal experiments.

The administration route for the quinolonecarboxylic acid anti-HIV agent, reverse transcriptase inhibitor and HIV protease inhibitor used in the present invention is an oral route or a parenteral route.

Therefore, the drugs of the two to three systems can be individually prepared in separate unit dosage forms, or can be mixed and physically prepared in one unit dosage form. Such a unit dosage form may be, for example, an oral administration agent such as tablets, capsules, granules, powders, syrups, etc., or a parenteral administration agent such as intravenous injection, intramuscular injection, suppository, etc. It can be prepared by the pharmaceutical technology of.

The doses and administration ratios of the quinolonecarboxylic acid anti-HIV agents, reverse transcriptase inhibitors and HIV protease inhibitors used in the present invention are determined by the activity of each drug, symptom of patient, age, body weight and the like. It can vary significantly depending on various conditions.

Further, a quinolonecarboxylic acid anti-HIV agent,
The doses of the reverse transcriptase inhibitor and the HIV protease inhibitor are lower than those of the single agents due to the excellent effect of the combination of these two or three agents.

For example, in the case of a quinolonecarboxylic acid type anti-HIV agent and a reverse transcriptase inhibitor, it is 15 mg and 100 mg, respectively, and in the case of a quinolonecarboxylic acid type anti-HIV agent and an HIV protease inhibitor, 5 mg each.
And 300 mg, quinolonecarboxylic acid anti-HIV
In the case of the agent, reverse transcriptase inhibitor, and HIV protease inhibitor, the doses are 3 mg, 20 mg, and 180 mg, respectively.

The doses of the quinolonecarboxylic acid anti-HIV agents, reverse transcriptase inhibitors, HIV protease inhibitors used in the present invention can vary widely, but generally speaking, those doses (mg dose / mg dose / Days) are about 1 to 100 mg, 10 to 500 mg and 10 to 500, respectively.
It can be mg.

The dose ratios of these two or three drugs can also vary greatly, but generally speaking, in the case of quinolonecarboxylic acid anti-HIV agents and reverse transcriptase inhibitors, the weight ratio is Can be in the range of 1: 500 to 1: 5, and in the case of quinolonecarboxylic acid anti-HIV agents and HIV protease inhibitors, it can be in the range of 1: 500 to 1: 5. Acid-based anti-HIV agents, reverse transcriptase inhibitors and HIV protease inhibitors may have a ratio of maximum drug to minimum drug in the range of 1: 500 to 1: 5.

In the present invention, the above-mentioned doses of the quinolonecarboxylic acid anti-HIV agent, reverse transcriptase inhibitor and HIV protease inhibitor are each divided into once a day or several times a day, and each of them is treated simultaneously. Alternatively, they are administered separately at different times.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the scope of the present invention is not limited thereto.

[0168]

【Example】

(Example) In vitro combination test 1) Cell and virus strain Human T cell transformed cell line MT4 is 10%
Cultured in RPMI1640 medium containing fetal bovine serum was used. The HIV-1 _IIIB strain was recovered as a culture supernatant of Molt-4 cells persistently infected with the strain and used as a virus solution. The virus titer of the virus solution was 50% tissue by performing titration on MT4 cells by limiting dilution.
It was expressed as a culture infectious dose (TCID ₅₀ ).

2) Drug combination test Using 6 96-well plates, the compound of Production Example 117 was added in the longitudinal direction according to a serial dilution series, and ZDV was performed.
(Manufactured by SIGMA) was added in the lateral direction according to a serial dilution series to prepare a diluted solution in which compounds of various concentrations were mixed on a 96-well plate (n = 4).

Multiplicity of infection in MT4 cells
HIV-1 _IIIB was added so that the (moi) was 0.001 TCID ₅₀ / ml, and the cells were allowed to adsorb at 37 ° C for 1 hour, and then the cells were added to PBS for 2 hours.
After washing twice, add 5 to the well plate containing the above-mentioned chemicals.
It was dispensed so as to have x10 ⁴ cells / well. After culturing for 6 days, the survival rate of infected MT4 cells was determined by performing a cell survival test by MTT. In the test, OD540nm
The absorbance was measured by a plate reader and a cell survival curve was drawn to determine the survival rate.

3) Analysis of combined test data Analysis was carried out according to the method of Barenbaum and an isobologram.
This was done using the Combination index (CI) (Barenbau
m, MC Pharmacol. Rev., 41, 93-141, 1989). The CI value was obtained by the general isobole equation. Synergistic, additive and competitive inhibition were determined by isobologram curve patterns and / or CI experimental values and typical additive effect CI values (CI values when the same compounds were used together).
(0.85 ± 0.11, Taylor, DL et al. Antiviral Chem. Ch.
emother., 6, 143-152, 1995)).

The IC ₅₀ values of the compound of Production Example 117 used in combination with ZDV were plotted in an isobologram. The line connecting the plotted points was located below the straight line showing the theoretical additive effect. And a curve showing a typical synergistic effect was drawn (Fig. 1). In this case, 0.55
A CI value of -0.75 was shown, indicating a statistically significant synergistic effect. Similarly, when the compound of Production Example 117 and DDI and Production Examples 117 and 3TC were used in combination, a synergistic effect was observed.

[0173]

[Table 40] ──────────────────────────────────── Manufacturing Example 117 ZDV Combination Student t-Test Judgment [ng / ml] [ng / ml] index ──────────────────────────────────── 39.0 0- 28.0 0.78 0.75 25.0 1.20 0.69 24.1 1.56 0.69 16.2 3.13 0.55 12.5 5.60 0.57 P <0.001 Synergistic effect 11.1 6.25 0.56 6.25 11.6 0.67 5.30 12.5 0.69 3.13 13.9 0.69 1.56 14.5 0.68 0 22.7-───────────── ────────────────────────

[0174]

[Table 41] ──────────────────────────────────── Manufacturing Example 117 3TC Combination Student t-Test Judgment [ng / ml] [μg / ml] index ──────────────────────────────────── 0 0.60- 0.96 0.50 0.89 0.38 0.50 0.86 0.78 0.52 0.92 1.56 0.43 0.81 3.13 0.34 0.76 P <0.001 Synergistic effect 4.57 0.25 0.70 6.25 0.19 0.71 8.0 0.125 0.71 12.4 0.063 0.88 12.7 0.0313 0.85 13.0 0.0156 0.84 16.0 0-───────── ────────────────────────────

[0175]

[Table 42] ──────────────────────────────────── Manufacturing Example 117 DDI Combination Student t- test Judgment [ng / ml] [μM] index ──────────────────────────────────── 0 5.40-0.39 4.27 0.82 0.78 4.38 0.87 1.56 3.65 0.79 3.13 2.80 0.74 3.85 2.50 0.74 P <0.001 Synergistic effect 6.25 1.67 0.76 7.70 1.25 0.78 10.0 0.63 0.83 10.5 0.313 0.81 11.0 0.156 0.81 14.0 0-────────────── ────────────────────── The following are formulation examples, production examples, and reference examples.

(Formulation Example 1) Compound of Production Example 117 and ZD
V mixture 1) Capsule 15 g of the compound of Production Example 117, 100 g of ZDV, 14 lactose
0.5 g, crospovidone 15 g, magnesium stearate 3 g and sodium lauryl sulphate 1.5 g are uniformly mixed to obtain a mixture, and No. 2 capsules are filled at 275 mg each.
The capsule contains 15 mg of the compound of Production Example 117 and 100 mg of ZDV per capsule.

2) Tablets 15 g of the compound of Production Example 117, 100 g of ZDV, 150 g of anhydrous lactose, 79 g of crystalline cellulose, 25 g of croscarmellose sodium, 4 g of magnesium stearate and 2 g of light anhydrous silicic acid were uniformly mixed. After that, a tablet machine is used to obtain tablets with a diameter of 10 mm and a weight of 375 mg. The tablets each contain 15 mg of the compound of Production Example 117 and 100 mg of ZDV.

3) Fine Granules 30 g of the compound of Production Example 117, 200 g of ZDV and lactose were added.
640 g and low-substituted hydroxypropyl cellulose 100 g
After being uniformly mixed, a fluidized bed granulator is used to spray and granulate an aqueous hydroxypropyl cellulose solution (30 g as solid content) to obtain a fine granule. Production Example 11 per 1 g of this fine granule
It contains 30 mg of the compound of Example 7 and 200 mg of ZDV.

4) Granules 30 g of the compound of Production Example 117, 200 g of ZDV and lactose were added.
After uniformly mixing 800 g, 275 g of crystalline cellulose, 150 g of low-substituted hydroxypropyl cellulose and 45 g of hydroxypropyl cellulose, add purified water and knead using a high speed agitation granulator, then extrud granulator. And then dried in a dryer to obtain granules. 30 mg of the compound of Production Example 117 and 200 mg of ZDV were contained per 1.5 g of this granule.

Formulation Example 2 Mixture of the compound of Production Example 117 and compound A 1) Capsule 5 g of the compound of Production Example 117, 300 g of compound A, and lactose
162.5 g, crospovidone 25 g, magnesium stearate 5 g and sodium lauryl sulfate 2.5 g are uniformly mixed to obtain a mixture, and the No. 0 capsules are filled with 500 mg each. The capsule contains 5 mg of the compound of Production Example 117 and 300 mg of compound A per capsule. 2) Tablets 5 g of the compound of Production Example 117, 300 g of compound A, 115 g of anhydrous lactose, 40 g of crystalline cellulose, 25 g of croscarmellose sodium, and 10 g of magnesium stearate.
After uniformly mixing 5 g of light anhydrous silicic acid, a tablet machine is used to obtain tablets having a major axis of 15 mm, a minor axis of 7.5 mm and a weight of 500 mg.
The tablets each contain 5 mg of the compound of Production Example 117 and 300 mg of compound A.

3) Fine Granules 10 g of the compound of Production Example 117, 600 g of compound A, 695 g of lactose and 150 g of low-substituted hydroxypropylcellulose.
After being uniformly mixed with, a fluidized bed granulator is used to spray and granulate an aqueous hydroxypropyl cellulose solution (45 g as a solid content) to obtain a fine granule. Production Example 1 per 1.5 g of this fine granule
10 mg of the compound of 17 and 600 mg of the compound A are contained.

4) Granules 10 g of the compound of Production Example 117, 600 g of compound A, 850 g of lactose, 280 g of crystalline cellulose, 200 g of low-substituted hydroxypropyl cellulose and 60 g of hydroxypropyl cellulose were uniformly mixed and then purified. After adding water and kneading using a high speed agitation granulator, granules are obtained by extruding the granules with a granulator and drying with a dryer. 10 mg of the compound of Production Example 117 and 600 mg of compound A were contained per 2 g of this granule.

Formulation Example 3 Compound of Production Example 117, ZD
Mixture of V and compound A 1) Capsule 3 g of the compound of Production Example 117, 20 g of ZDV and compound A
180g, lactose 119g, crospovidone 18g, magnesium stearate 8g and sodium lauryl sulfate 2
Mix g to obtain a mixture, and fill No. 1 capsules with 350 mg each. Production Example 1 of the capsule per capsule
Compound 17 of 3 mg, ZDV of 20 mg, Compound A of 180 mg
contains.

2) Tablets 3 g of the compound of Production Example 117, 20 g of ZDV and compound A
After uniformly mixing 180g, anhydrous lactose 190g, crystalline cellulose 67g, croscarmellose sodium 25g, magnesium stearate 10g and light anhydrous silicic acid 5g,
A tablet machine is used to obtain tablets with a major axis of 15 mm, a minor axis of 7.5 mm and a weight of 500 mg. Each of the tablets contains the compound of Production Example 117
It contains 5 mg, 20 mg of ZDV and 180 mg of compound A.

3) Fine Granules 3 g of the compound of Production Example 117, 20 g of ZDV and compound A
After uniformly mixing 180g, lactose 667g and low-substituted hydroxypropylcellulose 100g, a hydroxypropylcellulose solution (30g as solid content) is sprayed and granulated using a fluidized bed granulator to obtain a fine granule. . The compound of Production Example 117 (3 mg), ZDV (20 mg) and Compound A (180 mg) were contained per 1 g of the fine granules.

4) Granules 3 g of the compound of Production Example 117, 20 g of ZDV and compound A
180 g, lactose 827 g, crystalline cellulose 275 g, low-substituted hydroxypropyl cellulose 150 g and hydroxypropyl cellulose 45 g were uniformly mixed, after which purified water was added and kneaded using a high-speed stirring granulator, Granules are obtained by convolution using an extrusion granulator and drying with a dryer. 3 mg of the compound of Production Example 117 and 20 parts of ZDV per 1.5 g of this granule
and 180 mg of compound A.

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

[0188]

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1-Cyclopropyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 1.66 g (0.005 mol) 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 form was dissolved in 100 ml of a 4: 1 mixture of chloroform and methanol, 2 ml of concentrated hydrochloric acid was added, and the mixture was concentrated under reduced pressure. The residue was washed with a 4: 1 mixture of methanol and ethanol and dried. 1.08 g of the title object 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 3-46 were synthesized.

[0191]

[Table 43]

[0192]

[Table 44]

[0193]

[Table 45]

[0194]

[Table 46]

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

[0196]

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5.0 g (0.016 mol) of 1-ethyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
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. The mixture was stirred at room temperature for 5 hours and 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 = 7.0Hz), 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) By the same method as in Production Example 63, the compounds of Tables 47 to 49 were synthesized.

[0200]

[Table 47]

[0201]

[Table 48]

[0202]

[Table 49]

(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

[0204]

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0.81 g (0.0042 mol) of 1- (2-methoxyphenyl) piperazine was dissolved in 40 ml of ethanol, and 7-chloro-6-fluoro-1- (4-fluorophenyl) was stirred at 30 ° C. 1.02 g (0.0028 mol) of -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester was added in small portions. 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 sodium hydroxide aqueous solution, and the precipitated crystals were collected by filtration and subjected to silica gel column chromatography (eluent: chloroform: methanol = 9.5: 0.5 mixed solution). The target compound (0.87 g) was obtained 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 50 were synthesized.

[0207]

[Table 50]

(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

[0209]

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1-Ethyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 3.19 g (0.01 mol) and 2
-Methylpiperazine (3.0 g, 0.03 mol) was dissolved in pyridine (60 ml) and the mixture was stirred at 105 to 110 ° C for 2 hours, and the solvent was evaporated 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
-Chloropyrimidine 0.9 g (0.008 mol) and triethylamine 0.81 g (0.008 mol) 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 was 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 Actual value: C, 55.41, H, 4.56, N, 14.65 (Production Examples 95 to 97) The compounds in Table 51 were synthesized by the same method as in Production Example 94.

[0213]

[Table 51]

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

[0215]

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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

[0218]

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1-Ethyl-7-fluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-
The 3-carboxylic acid and 1- (2-pyrimidinyl) piperazine were reacted in the same manner as in Production Example 1 to obtain the target 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

[0220]

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6,7-Difluoro-1-methyl-4-oxo-1H, 4H- [1,3] thiazet [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. Dilute acetic acid aqueous solution was added to the reaction solution to adjust the pH to 7.2, 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: 266-268 ° 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

[0224]

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1-Ethyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 0.9 g (0.0028 mol)
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: 233-235 ° 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 Actual value: C, 57.83, H, 4.59, N, 8.80 (Production Examples 102 and 103) The compounds in Table 52 were synthesized by the same reaction as in Production Example 101.

[0227]

[Table 52]

(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

[0229]

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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 58. 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
Theoretical value as O: C, 55.38, H, 5.34, N, 14.35 Actual value: C, 55.06, H, 5.20, N, 14.26 (Production Examples 105 to 108) The compounds of Table 53 were prepared in the same manner as in Production Example 104. Synthesized.

[0232]

[Table 53]

(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

[0234]

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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-cyclopropyl-6,7-
Difluoro-8-trifluoromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 1.0 g
(0.003 mol) and 1.23 g (0.0075 mol) of 1- (2-pyrimidinyl) piperazine in 20 ml of pyridine
, And the mixture was stirred at 105 ° C. for 3 hours, the solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent; chloroform: methanol = 9.5: 0.5 mixed solution) to give 1-cyclohexyl. Propyl-6-fluoro-8-
Trifluoromethyl-1,4-dihydro-4-oxo-
0.68 g of 7- [4- (2-pyrimidinyl) piperazin-1-yl] quinoline-3-carboxylic acid was obtained as a yellow powder.

Melting point: 285-287 ° C. NMR (DMSO-d ₆ , δ): 0.91 (2H, m), 1.17-1.18 (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 54 were synthesized in the same manner as in Production Example 110.

[0238]

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[0239]

[Table 54] ──────────────────────────────────── Manufacturing Example R ¹ R ³ Properties Melting point (℃ ) ──────────────────────────────────── 111 Cyclopropyl 2-pyridyl yellow powder 225-226 112 Cyclo Propyl 2-methoxyphenyl White pink powder 196-197 113 Cyclopropyl phenyl Light red powder 245-247 114 Cyclopropyl 3-chlorophenyl Ocher powder 235-237 115 Cyclopropyl 4-fluorophenyl Light 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-pyridyl 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 bright orange powder 275-278 130 Methyl phenyl bright orange powder 258.5-260.5 131 Methyl 4-fluorophenyl bright 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 Nil Pink powder 274-276 136 Ethyl 5-chloro-2-pyrimidinyl Light 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
-Carboxylic acid 100 mg (0.21 mmol) 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 then 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-
8-Trifluoromethyl-1,4-dihydro-4-oxo-7- [4- (2-pyridyl) piperazin-1-yl] quinoline-3-carboxylic acid 2-morpholinoethyl ester 60 mg was obtained as a pale yellow powder. It was

Melting point: 203 to 205 ° C. MS spectrum (CI): m / e 590 (M ⁺ +1) (Production Example 142) 6-fluoro-8-trifluoromethyl-1,4-dihi
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.

6-Fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-1-methyl-obtained
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 hour, the solvent was distilled off under reduced pressure.

The residue was subjected to silica gel column chromatography (eluent; chloroform: methanol = 9: 1 mixed solution) 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 to 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 O Theoretical value; C: 53.17, H: 4.25, N: 14.76 actual measured value; C: 53.47, H: 4.07, N: 14.95 (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: 243-245 ° 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: 15.05 Found: C: 54.06, H: 4.03, N: 14.96 (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 acids 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 (light 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-diph
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) (Production 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 ( light yellowish 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 crystals) (Production Example 156) 1-methylamino-6-fluoro-8-difluorometh
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-
The 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) (Production 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.): 188-190 160-2) 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 (pale yellow powder) (Reference Example 1) 6,7-difluoro-8-difluoromethoxy-1-
(2-pyridylmethyl) -1,4-dihydro-4-oxo
Synthesis of soquinoline-3-carboxylic acid

[0259]

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30 g (0.124 mol) of 2,4,5-trifluoro-3-difluoromethoxybenzoic acid was dissolved in 37 ml of toluene, added with 35 ml of thionyl chloride and 0.5 ml of N, N-dimethylformamide and 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, magnesium ethoxide 15.5 g
(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 described 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 form.
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) The compounds shown in Table 55 below were synthesized in the same manner as in Reference Example 1. did.

[0267]

[Table 55]

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

[0269]

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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 (M ⁺ +1) 127 (M ⁺ + 1-COCH ₃ ) 25.9 g (0.153) of 2-acetylamino-6-fluorophenol obtained as described above. 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 above was dissolved in 180 ml of ethyl alcohol. , Concentrated hydrochloric acid 50.3 ml
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.

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 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 potassium carbonate 6.9 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 to 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

[0278]

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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
Gin synthesis

[0282]

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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 was obtained as pale red crystals.

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

[0286]

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8.6 g of piperazine and 2.9 g (0.02 mol) of 2-chloro-6-methoxypyridine were charged in a sealed tube in an amount of 1.
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 mixed solution) 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

[0289]

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2-Bromothiazole 5.0 g (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

[0292]

[Chemical 51]

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

[0295]

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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 was obtained as white crystals.

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

[0298]

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(1) 1 g of 1-t-butoxycarbonyl-3-epoxypyrrolidine (0.027 mol) was dissolved in 20 ml of ethyl alcohol, and 12.6 g (0.13 g of aniline).
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 100 ml of methanol, 30 ml of 6N hydrochloric acid 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) of 3-methoxy-4-phenylaminopyrrolidine hydrochloride
Synthesis

[0302]

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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 with 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) 1- (6-ethyl-4-pyrimidinyl) piperazine combined
Success

[0306]

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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 pale red liquid.

Then, this was dissolved in 100 ml of acetonitrile and 11.5 g of 1-ethoxycarbonylpiperazine was added.
(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.
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-difluorometh
Xy-2,3,4,9-tetrahydrothiazolo [5,4
-B] Synthesis of quinoline-3,4-dione

[0311]

Embedded image

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-dimethylaminoacrylate 5.
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 form was obtained.
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 to 212 ° C. MS spectrum (CI): m / e 334 (M ⁺ +1) (Reference Example 22) 1-ethyl-6,7-difluoro-8-trifluorome
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: 197.5-200 ° 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 Homopiperazine 10.0 g (0.1 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, 50 ml of acetonitrile was added, and the mixture was 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 Hydrochloric acid N-bis (2-bromoethyl) amine 13.7
40 ml of ethanol was added to g (0.044 mol) and 1
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 added to acetonitrile. Dissolve in 50 ml and piperazine 13.1 g
(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 subsided, the temperature was raised to 80 ° C., and stirring was continued for 30 minutes at that temperature. 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-trifluorobenzoate
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 all at once to a solution prepared 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. The ether layer was extracted twice with 212 ml of 0.5N aqueous sodium hydroxide solution, and 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 to 97 ° C. MS spectrum (CI): m / e 227 (M ⁺ +1) (Reference Example 31) 1-cyclopropyl-6,7-difluoro-8-diflu
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-dimethylaminoacrylate 6.
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.
0.0% sodium hydride-mineral oil 2.36g
(0.059 mol) was added slowly, followed by stirring at room temperature for 1 hour. To the reaction mixture was added 59 ml of 1N hydrochloric acid, and the mixture was vigorously stirred to acidify the whole reaction mixture, 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 to 210 ° C. MS spectrum (CI): m / e 344 (M ⁺ +1) Then, 2.0 g (0.0058 mol) of this ester compound was obtained.
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 to 192.5 ° C. MS spectrum (CI): m / e 315 (M ⁺ +1) (Reference Example 32) 1- (3-tert-butoxycarbonylaminopropyiene
) -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

[0332]

INDUSTRIAL APPLICABILITY By using the quinolonecarboxylic acid derivative of the present invention and a reverse transcriptase inhibitor in combination,
A remarkable synergistic effect was observed for the growth inhibition of A. Therefore, the combination of the quinolonecarboxylic acid derivative of the present invention and the reverse transcriptase inhibitor is useful as an anti-HIV agent or an AIDS therapeutic agent.

[Brief description of drawings]

FIG. 1 is a graph in which the IC ₅₀ values of the compound of Production Example 117 or ZDV under a fixed concentration of ZDV or the compound of Production Example 117 are plotted. The vertical axis represents the ZDV concentration, and the horizontal axis represents the concentration of the compound of Production Example 117. A straight line shows a theoretical straight line when showing an additive effect.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area A61K 31/55 A61K 31/55 45/00 45/00 C07D 498/04 105 C07D 498/04 105 498 / 06 498/06 513/04 343 513/04 343 345 345 383 383 513/06 513/06 // C07D 215/56 215/56 401/04 243 401/04 243 401/06 215 401/06 215 401 / 12 213 401/12 213 233 233 235 235 237 237 239 239 241 241 241 401/14 207 401/14 207 211 211 211 213 213 239 239 413/12 215 413/12 215 417/12 215 417/12 215 455/04 455 / 04 471/04 114 471/04 114Z (72) Inventor Takashi Nishigaki 1-2-2 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. Within the company (72) inventor Kimura, Saitama Prefecture Niiza Tomio Shinbori 2-chome 11 address of 15 (72) inventor KATSUBE Akira嗣 Ube City, Yamaguchi Prefecture, Oaza Kogushi 1978 address of 5 Ube Kosan Co., Ltd. Ube the laboratory

Claims (26)

[Claims] 1. A combined use of one or more drugs of a quinolonecarboxylic acid anti-HIV agent and one or more drugs of a reverse transcriptase inhibitor for the treatment or prevention of AIDS. 2. One or more quinolonecarboxylic acid anti-HIV agents and HI for treating or preventing AIDS.
Combined use of V protease inhibitors with one or more drugs. 3. A quinolonecarboxylic acid-based anti-HIV agent, one or more agents, a reverse transcriptase inhibitor, one or more agents, and an HIV protease inhibitor for the treatment or prevention of AIDS. Combined use with one or more drugs. 4. An active ingredient, a quinolonecarboxylic acid anti-HIV.
The agent is a quinolonecarboxylic acid represented by the general formula (Ia), (Ib) or (Ic), a pharmacologically acceptable salt thereof or an 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 an alkyl group having 1 to 4 carbon atoms which may be substituted with halogen. Represents an alkoxy group], 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 with alkyl having 1 to 4 carbon atoms or 1 to 4 carbon atoms.
Represents an alkenylene group having 2 to 4 carbon atoms which may be substituted with 4 alkyl, R ¹ is a hydrogen atom; a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms [the substituent of the alkyl group is , Hydroxy, carboxy, halogen, alkoxy having 1 to 4 carbon atoms,
A cycloalkyl having 3 to 6 carbons, an alkanoyloxy having 2 to 5 carbons, 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,
It is a 5- or 6-membered heteroaromatic monocyclic group containing 1 to 2 heteroatoms selected from O and S or a heteroaromatic condensed ring group obtained by condensing these heteroaromatic monocycles and a benzene ring]; An optionally substituted alkenyl group having 2 to 5 carbon atoms; an alkynyl group having 2 to 4 carbon atoms; an amino group;
A mono- or dialkyl-substituted amino group substituted with 1 to 2 carbon atoms of 1 to 4; a cycloalkyl group of 3 to 6 carbon atoms which may be substituted with halogen; 1 to 4 carbon atoms An alkoxy group; or an aryl group having 6 to 10 carbon atoms which may be substituted with R ⁰ described later, a 5- to 6-membered heteroaromatic unit containing 1 to 2 heteroatoms selected from N, O and S A ring group or a heteroaromatic condensed ring group in which these heteroaromatic monocycles are condensed with a benzene ring is shown, or R ¹ and R ² of the formula (d) in Q together form a compound represented by the 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]}. 5. A quinolonecarboxylic acid anti-HIV as an active ingredient.
The combined use according to claims 1 to 3, wherein the agent is a compound of formula (Ia). 6. An active ingredient, a quinolonecarboxylic acid anti-HIV.
The agent is, in formula (Ia), 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 a carboxy group which may be protected, and Q is Is a formula (d), and R ² of the formula (d) is a methoxy, difluoromethoxy or trifluoromethyl group, 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; 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 combined use according to claim 5, wherein the compound is a piperazin-1-yl, 4- (6-methoxy-2-benzothiazolyl) piperazin-1-yl or 4- (2-pyridyl) piperazin-1-yl group. 7. A quinolonecarboxylic acid anti-HIV as an active ingredient
The agent is, in formula (Ia), 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 a carboxy group which may be protected, and Q is Is a 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-
Is a fluoroethyl, cyclopropyl or methylamino group, R is 4- (2-pyrimidinyl) piperazin-1-yl, 4- (2-benzothiazolyl) piperazin-1-yl, 4- (2-pyridyl) piperazine- 1-yl, 4-
The combined use according to claim 5, wherein the compound is a (2-benzoxazolyl) piperazin-1-yl group or a 4- (6-methoxy-2-benzothiazolyl) piperazin-1-yl group. 8. A quinolonecarboxylic acid-based anti-HIV as an active ingredient
The agent 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-1-methylamino-7- [4 -(2
-Benzoxazolyl) piperazin-1-yl] quinoline-3-carboxylic acid in combination use. 9. An active ingredient reverse transcriptase inhibitor is ZDV,
The combined use according to claim 1 or 3, which is DDI, DDC, d4T, 3TC, FTC or nevirapine. 10. The active ingredient reverse transcriptase inhibitor is ZD.
The combined use according to claim 1 or 3, which is V, DDI and nevirapine. 11. A reverse transcriptase inhibitor as an active ingredient is ZDV.
The combined use according to claim 1 or 3, wherein 12. The active ingredient HIV protease inhibitor is VX-478, KNI-272, AG-1343,
The combined use according to claim 2 or 3, which is saquinavir, ritonavir, indinavir and the following compound A. Compound A 13. The combined use according to claim 2 or 3, wherein the HIV protease inhibitor as an active ingredient is AG-1343, saquinavir, ritonavir or indinavir. 14. A therapeutic or prophylactic agent for AIDS, which comprises, as active ingredients, one or more agents of quinolonecarboxylic acid anti-HIV agents and one or more agents of reverse transcriptase inhibitors. 15. A therapeutic or prophylactic agent for AIDS, which comprises, as active ingredients, one or more agents of quinolonecarboxylic acid anti-HIV agents and one or more agents of HIV protease inhibitors. 16. One or more agents of quinolonecarboxylic acid anti-HIV agents and one or more agents of reverse transcriptase inhibitors and one or more agents of HIV protease inhibitors. A therapeutic or preventive agent for AIDS containing as an active ingredient. 17. An active ingredient, a quinolonecarboxylic acid anti-HI.
The V agent is a quinolonecarboxylic acid represented by the general formula (Ia), (Ib) or (Ic), a pharmacologically acceptable salt thereof or an ester thereof. In the above formula (Ia), (Ib) or (Ic), X represents a hydrogen atom or a halogen atom, Y represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, an amino group or 1 to 2 atoms. Represents 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 an aralkyl group having 1 to 2 carbon atoms of 7 to 14, and Z is It represents a carboxy group or a 5-tetrazolyl group which may be protected, Q is a nitrogen atom or a compound 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 an alkyl group having 1 to 4 carbon atoms which may be substituted with halogen. Represents an alkoxy group], 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 with alkyl having 1 to 4 carbon atoms or 1 to 4 carbon atoms.
Represents an alkenylene group having 2 to 4 carbon atoms which may be substituted with 4 alkyl, R ¹ is a hydrogen atom; a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms [the substituent of the alkyl group is , Hydroxy, carboxy, halogen, alkoxy having 1 to 4 carbon atoms,
A cycloalkyl having 3 to 6 carbons, an alkanoyloxy having 2 to 5 carbons, 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,
It is a 5- or 6-membered heteroaromatic monocyclic group containing 1 to 2 heteroatoms selected from O and S or a heteroaromatic condensed ring group obtained by condensing these heteroaromatic monocycles and a benzene ring]; An optionally substituted alkenyl group having 2 to 5 carbon atoms; an alkynyl group having 2 to 4 carbon atoms; an amino group;
A mono- or dialkyl-substituted amino group substituted with 1 to 2 carbon atoms of 1 to 4; a cycloalkyl group of 3 to 6 carbon atoms which may be substituted with halogen; 1 to 4 carbon atoms An alkoxy group; or an aryl group having 6 to 10 carbon atoms which may be substituted with R ⁰ described later, a 5- to 6-membered heteroaromatic unit containing 1 to 2 heteroatoms selected from N, O and S A ring group or a heteroaromatic fused ring group in which these heteroaromatic monocycles are condensed with a benzene ring, or R ¹ and R ² of the formula (d) in Q together form a group represented by the formula (f) 11] [In the formula (f), A represents a hydrogen atom or halogen, hydroxy, or an alkyl group having 1 to 4 carbon atoms which may be substituted with alkoxy having 1 to 4 carbon atoms, and G represents a nitrogen atom or a formula ( g) 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 formula (h) or formula (i) [In the formulas (h) and (i), R ³ and R ⁶ are R ⁰ (R ⁰
Is halogen, nitro, hydroxy, alkyl having 1 to 4 carbon atoms, alkyl having 1 to 4 carbon atoms substituted with a fluorine atom, alkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, amino And a group selected from mono- or dialkyl-substituted amino substituted with 1 to 2 alkyl having 1 to 4 carbons), an aryl group having 6 to 10 carbons optionally substituted with N, or N, O
And a 5- or 6-membered heteroaromatic monocyclic group containing 1 or 2 heteroatoms selected from S or a heteroaromatic condensed ring group obtained by condensing these heteroaromatic monocycles and a benzene ring; 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, or 1 carbon atom
To 4 alkyl groups or alkoxy groups having 1 to 4 carbon atoms; n is 1 or 2; m is 0 or 1; n'is 1 or 2; , 3 or 4] is shown}. 18. An active ingredient, a quinolonecarboxylic acid anti-HI.
The agent for treating or preventing AIDS according to claim 14, wherein the agent V is the compound of the formula (Ia). 19. An active ingredient, a quinolonecarboxylic acid anti-HI.
The agent V is, in the formula (Ia), 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 a carboxy group which may be protected, Q Is a formula (d), and R ² of the formula (d) is a methoxy, difluoromethoxy or trifluoromethyl group, R ¹ is a hydrogen atom; methyl, ethyl, propyl, isopropyl; 2-hydroxy Ethyl; carboxymethyl; 2
-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)
19. The therapeutic or preventive agent for AIDS according to claim 18, which is a compound having a piperazin-1-yl, 4- (6-methoxy-2-benzothiazolyl) piperazin-1-yl or 4- (2-pyridyl) piperazin-1-yl group. Agent. 20. A quinolonecarboxylic acid anti-HI as an active ingredient
The agent V is, in the formula (Ia), 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 a carboxy group which may be protected, Q Is a 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-
Is a fluoroethyl, cyclopropyl or methylamino group, and R is 4- (2-pyrimidinyl) piperazin-1-yl, 4- (2-benzothiazolyl) piperazin-1-yl, 4- (2-pyridyl) piperazine- 1-yl, 4-
The therapeutic or prophylactic agent for AIDS according to claim 18, which is a compound having a (2-benzoxazolyl) piperazin-1-yl group or a 4- (6-methoxy-2-benzothiazolyl) piperazin-1-yl group. 21. An active ingredient, a quinolonecarboxylic acid anti-HI.
V agent 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-1-methylamino-7- [4 -(2
-Benzoxazolyl) piperazin-1-yl] quinoline-3-carboxylic acid, The therapeutic or preventive agent for AIDS according to claim 18. 22. The active ingredient reverse transcriptase inhibitor is ZD.
The therapeutic or prophylactic agent for AIDS according to claim 14 or 16, which is V, DDI, DDC, d4T, 3TC, FTC or nevirapine. 23. The active ingredient reverse transcriptase inhibitor is ZD.
The therapeutic or preventive agent for AIDS according to claim 14 or 16, which is V, DDI or nevirapine. 24. The reverse transcriptase inhibitor as an active ingredient is ZDV.
The therapeutic or prophylactic agent for AIDS according to claim 14 or 16. 25. The active ingredient HIV protease inhibitor is VX-478, KNI-272, AG-1343,
The therapeutic or prophylactic agent for AIDS according to claim 15 or 16, which is saquinavir, ritonavir, indinavir and the following compound A. Compound A 26. The therapeutic or prophylactic agent for AIDS according to claim 15 or 16, wherein the HIV protease inhibitor as an active ingredient is AG-1343, saquinavir, ritonavir or indinavir.