JPH09249568A - Medicinal composition containing trifluoromethyl-quinolinecarboxylic acid derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a medicinal composition which contains trifluoromethyl- quinolinecarboxylic acid derivative and is useful as a proliferation inhibitor against human immunodeficiency virus particularly. SOLUTION: This medicinal composition contains as an active ingredient, a compound of formula I (R<1> is a lower alkyl, a halogeno-lower-alkyl, a cycloalkyl; R<2> is a phenyl which may be substituted with R<0> , a heteroaromatic ring which contains hetero atoms selected from N, O, S and may be substituted with R<0> ; R<0> is a halogen, a lower alkyl; R<3> is H, a lower alkyl; m is 2, 3) or its salt or ester. The compound of formula I is given by coupling reaction between a quinoline carboxylic acid of formula II and a cyclic diamine of formula III, when necessary, using an acid acceptor such as pyridine in a solvent (for example, DMSO). The compound of formula I is exemplified by 1- cyclopropyl-6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-7-[4-(2-pyrid iyl)piperazin-1- yl]quinoline-3-carboxylic acid.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel 8 which inhibits the growth of human immunodeficiency virus (hereinafter referred to as HIV).
-A trifluoromethylquinolinecarboxylic acid derivative, or a pharmaceutical composition containing a pharmacologically acceptable salt or ester thereof.

[0002]

2. Description of the Related Art HIV mainly infects CD ₄ positive lymphocytes (helper / inducer) and gradually reduces the number of cells, eventually causing severe acquired immunodeficiency syndrome (hereinafter referred to as AIDS). Provoke. Although many efforts have been made to treat AIDS, the development of vaccines is extremely difficult and antiviral agents are expected to be developed. However, the currently approved antiviral agents having an inhibitory effect on the virus-specific reverse transcriptase have a life prolonging effect on AIDS patients, but they have not been completely cured. Moreover,
These inhibitors have strong side effects such as bone marrow disorders and digestive disorders, and have many problems such as high frequency isolation of drug-resistant virus from long-term patients.Development of new drug and multi-drug combination therapy Is in a hurry.

Recently, DR-33, which is an optically active substance of ofloxacin, which is a synthetic antibacterial agent having a quinolinecarboxylic acid skeleton,
Anti-HIV activity was reported for 55 (J. Nozak
i, Renard et al., AIDS 4, 1283 (1990)) found that DR-3355 was tested for its cytotoxicity-inhibiting activity against HIV-infected cells by the method described below such as R. Pauwel. Was not recognized. Also, anti-HIV activity is described for norfloxacin, enoxacin, ciprofloxacin, lomefloxacin, difloxacin, tosufloxacin and the like (WO90 / 135).
42), however, no anti-HIV activity was observed for these compounds as well.

[0004]

The present inventors have investigated the anti-HIV activity of various quinolinecarboxylic acid derivatives. As a result, a trifluoromethyl group was introduced at the 8-position and a phenyl group or a heteroaromatic group was added at the 7-position. A quinolinecarboxylic acid derivative having enhanced antifouling activity by introducing cyclic diamines substituted with a cyclic group (for example, an optionally substituted piperazinyl group or homopiperazinyl group) to weaken the antibacterial activity is present in HIV-infected cells. In contrast, it suppresses HIV proliferation specifically, and further, the cytopathic effect of HIV (CP
The present invention was completed by discovering that it has an activity of suppressing E).

[0005]

The present invention has the general formula (I)
A pharmaceutical composition containing the 8-trifluoromethylquinolinecarboxylic acid derivative represented by or a pharmacologically acceptable salt or ester thereof.

[0006]

Embedded image

(Wherein R ¹ represents a lower alkyl group, a halogeno lower alkyl group or a cycloalkyl group, and R ² represents R ⁰
A 5- or 6-membered heteroaromatic monocyclic group containing 1 or 2 heteroatoms selected from N, O and S, which may be substituted with R ⁰ It represents a heteroaromatic condensed ring group in which an aromatic single ring and a benzene ring are condensed, R ⁰ represents a group selected from halogen, lower alkyl, fluorine-substituted lower alkyl, lower alkoxy or lower alkylthio, and R ³ represents hydrogen or lower alkyl. Represents a group, and m represents an integer of 2 or 3. )

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION Examples of the lower alkyl group for R ¹ in the above general formula (I) include C ₁ -C such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl and t-butyl. ₄ Alkyl groups can be mentioned, of which methyl, ethyl, propyl and isopropyl groups are preferable, and methyl and ethyl groups are particularly preferable. Examples of the halogeno lower alkyl group for R ¹ include, for example,
Fluoromethyl, chloromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2,2.
2-trifluoroethyl, 3-fluoropropyl, 3-
Mention may be made of halogeno C ₁ -C ₄ alkyl groups such as chloropropyl, 3-bromopropyl and 4-fluorobutyl, preferably 2-fluoroethyl, 2-chloroethyl and 2,2,2-trifluoroethyl groups. And a 2-fluoroethyl group is particularly preferable.

Examples of the cycloalkyl group for R ¹ include C ₃ -C ₆ cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, preferably cyclopropyl, cyclobutyl and cyclopentyl groups, A cyclopropyl group is particularly preferable. Examples of the heteroaromatic monocyclic group or heteroaromatic condensed ring group for R ² (hereinafter referred to as heteroaromatic ring group) include, for example,
2-thienyl, 2-furyl, 2-oxazolyl, 2-thiazolyl, 2-imidazolyl, 2-, 3- or 4-
Pyridyl, 2-, 4- or 5-pyrimidinyl, 2-
Pyrazinyl, 3-pyridazinyl, 2-benzoxazolyl, 2-benzothiazolyl and 2-benzimidazolyl are mentioned, preferably 2-thienyl, 2-furyl and 2
-Oxazolyl, 2-thiazolyl, 2-imidazolyl,
2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl, 3-pyridazinyl, 2-benzothiazolyl and 2-benzoxazolyl groups, especially 2-pyridyl, 2-pyrimidinyl And 2
-The benzothiazolyl group is preferred.

The substituent R ⁰ on the phenyl and heteroaromatic ring of R ² is, for example, a halogen atom such as fluorine, chlorine, bromine or iodine; methyl, ethyl, propyl, isopropyl, butyl, s-butyl, isobutyl and C ₁ -C ₄ alkyl group such as t- butyl; mono -, di- - or trifluoromethyl, 2-fluoroethyl, 2- or 3
- fluoropropyl, 2-, fluorine-substituted C ₁ -C ₄ alkyl group such as 3- or 4-fluoro-butyl; methoxy, C ₁ ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, etc. s- butoxy and t- butoxy -C ₄ alkoxy groups; methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, C ₁ ~ such s- butylthio and t- butylthio
C ₄ alkylthio groups may be mentioned, preferably fluorine, chlorine, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, methylthio and ethylthio groups, particularly fluorine, chlorine, methyl, trifluoromethyl,
Methoxy and methylthio groups are preferred.

The lower alkyl group for R ³ is, for example,
Mention may be made of C ₁ -C ₄ alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl and t-butyl, preferably methyl, ethyl, propyl and isopropyl groups, especially methyl and The ethyl group is preferred.

The carboxyl group of the compound represented by the above general formula (I) may be protected with a protecting group to form an ester. Examples of such a protecting group include methyl,
C ₁ -C ₄ alkyl groups such as ethyl, propyl, isopropyl, butyl and isobutyl groups or aralkyl groups such as benzyl and phenylethyl groups; or acetoxymethyl and pivalo which are easily hydrolyzed in vivo to convert to a carboxy group. yl C ₂ -C ₅ alkanoyloxy group such as pivaloyloxymethyl group; 1- (ethoxycarbonyloxy) ethyl and 1- C ₁ -C ₄ alkoxycarbonyloxy group such as (isopropoxycarbonyloxy) ethyl group; N, N, N-dialkyl-substituted aminocarbonylalkyl group such as N-dimethylaminocarbonylmethyl group; N, N-dialkyl-substituted aminoalkyl group such as 2- (N, N-dimethylamino) ethyl group; 2-morpholinoethyl, 2 -Piperidinoethyl and 2- (4-methylpiperidino) eth 5-membered or 6-membered hetero-saturated monocyclic-substituted alkyl group containing 1 or 2 heteroatoms selected from N, O and S, such as a vinyl group or (5-methyl (or 5-phenyl) -2-oxo Groups which form prodrugs such as -1,3-dioxolen-4-yl) methyl groups are mentioned.

In the present invention, the compound represented by the general formula (I) may be a pharmacologically acceptable salt, if necessary. Examples of such salts include acid addition salts of mineral acids such as hydrochloride, hydrobromide, hydroiodide, sulfate and phosphate; methanesulfonate, ethanesulfonate, benzenesulfonate. Salt, p-toluenesulfonate, oxalate, maleate, fumarate, acetate,
Examples thereof include acid addition salts of organic acids such as tartrate and citrate; and metal salts of carboxylic acids such as sodium, potassium, calcium, magnesium, manganese, iron and aluminum salts. The compound (I) of the present invention
Can also be present as a hydrate. Suitable compounds represented by the general formula (I) are illustrated in Tables 1 to 10.

[0014]

[Table 1]

[0015]

[Table 2]

[0016]

[Table 3]

[0017]

[Table 4]

[0018]

[Table 5]

[0019]

[Table 6]

[0020]

[Table 7]

[0021]

[Table 8]

[0022]

[Table 9]

[0023]

[Table 10]

A more preferable compound represented by the general formula (I) is 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) 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-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) piperazine-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,

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) piperazin-1-yl] quinoline-3
-Carboxylic acid, 6-fluoro-1- (2-fluoroethyl) -8-trifluoromethyl-1,4-dihydro-4
-Oxo-7- [4- (2-pyridyl) piperazine-1
-Yl] quinoline-3-carboxylic acid, 6-fluoro-1
-(2-Fluoroethyl) -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-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) piperazine-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) piperazin-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) piperazine-1-
Yl] quinoline-3-carboxylic acid, 1-ethyl-6-fluoro-8-trifluoromethyl-1,4-dihydro-
4-oxo-7- [4- (2-fluorophenyl) piperazin-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) homopiperazine-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, and 6
-Fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-1-methyl-7- [4- (2-benzoxazolyl) piperazin-1-yl] quinoline-3-
carboxylic acid

And more preferred compounds include:
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) piperazine-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, and 6-fluoro- 8-trifluoromethyl-1,
4-dihydro-4-oxo-1-methyl-7- [4-
(2-Benzothiazolyl) piperazin-1-yl] quinoline-3-carboxylic acid

And particularly preferable compounds include:
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, and 6-fluoro-8
-Trifluoromethyl-1,4-dihydro-4-oxo-1-methyl-7- [4- (2-benzothiazolyl) piperazin-1-yl] quinoline-3-carboxylic acid.

The compound represented by the above general formula (I) is produced by Method A or Method B shown below.

[0032]

Embedded image

(In the formula, R ¹ , R ² , R ³ and m have the same meanings as described above, and L represents a fluorine atom or an acetoxy group.)

In method A, quinolinecarboxylic acid compound (II)
In the presence or absence of a deoxidizing agent and in the presence or absence of a solvent, the cyclic diamines (III) are coupled to produce the target compound (I).

The solvent used in this reaction is
Aprotic polar solvents such as dimethylsulfoxide, N, N-dimethylformamide, hexamethylphosphoric triamide and N, N-dimethylacetamide are preferred, but other ketones such as acetone and methylethylketone;
It is also possible to use ethers such as diethyl ether, tetrahydrofuran, dioxane; esters such as ethyl acetate; alcohols such as methanol, ethanol, propanol, isopropanol, butanol; nitriles such as acetonitrile. As a deoxidizer, 1,8
-Diazabicyclo [5.4.0] -7-undecene,
1,5-diazabicyclo [4.3.0] -5-nonene,
Tertiary amines such as triethylamine, tributylamine, pyridine, picoline, lutidine and collidine; sodium methoxide, sodium ethoxide and potassium-
Metal alkoxides such as t-butoxide; or inorganic bases such as sodium carbonate and potassium carbonate can be used.

The amount of the deoxidizing agent used is preferably equimolar to 5 times the molar amount of the compound (II), but in the case of the tertiary amines, it can be used in a large excess as a solvent. Further, since the excess cyclic diamine (III) also acts as a deoxidizing agent, the reaction proceeds smoothly even if no other deoxidizing agent is added. The reaction is carried out in the range of 0 ° C to 200 ° C, usually 0.5
It takes from 24 hours to 24 hours.

In the method B, the boron chelate compound (IV) of carboxyquinoline is added to the cyclic diamine (III) in the same manner as in the method A in the presence or absence of a deoxidizing agent and in the presence or absence of a solvent. Coupling below gives compound (V),
Then, this is reacted in a hydroalcohol in the presence of a base to dechelate to produce the target compound (I). B
The coupling reaction in the method is performed under the same conditions as those described in the method A.

As the base used for dechelation in the above method B, alkali hydroxide such as sodium hydroxide and potassium hydroxide; alkali carbonate such as sodium carbonate and potassium carbonate; 1,8-diazabicyclo [5.4.
0] -7-undecene, 1,5-diazabicyclo [4.
3.0] -5-nonene, tertiary amines such as triethylamine and 4-dimethylaminopyridine; or sodium methoxide, sodium ethoxide and potassium-t-.
Mention may be made of metal alkoxides such as butoxide.

The amount of the base used is preferably equimolar to 5 times the molar amount of the compound (V), but a large excess amount can also be used. As the hydrous alcohol used as the solvent, for example, methanol, ethanol, propanol, isopropanol and / or butanol containing 5 to 90% by weight of water can be used. The reaction is 0
The temperature is in the range of 150 to 150 ° C., and it is 0.5 to 24 hours.

In the above reaction, after completion of the reaction, the target compound of this reaction is obtained by treating the reaction mixture according to a conventional method, and if necessary, an ordinary purification means such as recrystallization method or column chromatography may be used. Can be used for purification. The compound (I) thus obtained is converted into a desired salt according to a conventional method, if necessary.
The compound (I ′) in which the substituent R ² of the general formula (I) is a heteroaromatic ring group is also produced by the method C shown below.

[0041]

Embedded image

(In the formula, R ¹ , R ³ and m have the same meanings as described above, R ² 'is a heteroaromatic ring group, and Hal represents a halogen atom.) It is performed in the same manner as described above.

That is, the quinolinecarboxylic acid compound (VI) and an equimolar to 5-fold molar amount of the compound (VII) are coupled in the presence of a deoxidizer in the presence or absence of a solvent to give the compound (I ') is produced.

Solvents used in Method C include dimethyl sulfoxide, N, N-dimethylformamide,
Although aprotic polar solvents such as hexamethylphosphoric triamide and N, N-dimethylacetamide are preferred,
Other ketones such as acetone and methyl ethyl ketone; ethers such as diethyl ether, tetrahydrofuran and dioxane; esters such as ethyl acetate; methanol,
It is also possible to use alcohols such as ethanol, propanol, isopropanol and butanol; and nitriles such as acetonitrile.

As the deoxidizing agent, 1,8-diazabicyclo [5.4.0] -7-undecene, 1,5-diazabicyclo [4.3.0] -5-nonene, triethylamine,
Tertiary amines such as tributylamine, pyridine, picoline, lutidine and collidine; or inorganic bases such as sodium carbonate and potassium carbonate can be used.

The amount of the deoxidizing agent used is preferably an equimolar to 10-fold molar amount with respect to compound (VII), but when the tertiary amines are used, they can be used in a large excess as a solvent. . The reaction is carried out in the range of 0 ° C to 200 ° C, usually 1
It takes from 24 hours to 24 hours. In addition, the compound (VI) used as a starting material in the method C is prepared by using the compound (II) or (IV) as a starting material, and using the cyclic diamine (III) in which R ² is a hydrogen atom, the method (A) or the method (B). It is produced by reacting in the same manner.

The compound (II) used as a starting material in the above method A is, for example, JP-A-64-66180.
Manufactured by the method D using the compound (VII) obtained by the method described in US Pat.
55183).

[0048]

Embedded image

(In the formula, R ¹ has the same meaning as described above, R ⁴ represents a lower alkyl group, and R ⁵ and R ⁶ represent the same or different alkyl groups.)

Further, the boron chelate compound (IV) used as a raw material in the method B is the compound (II) obtained by the method D, or its lower alkyl ester compound (XIII).
To E method (for example, JP-A-63-198664 (Reference Example 8), JP-A-2-124873 (Reference Example 7), and JP-A-3-287577 (Reference Example 4)).

[0051]

[Chemical 6]

The compound represented by the general formula (I) produced as described above may have optical isomers. In such a case, the corresponding optical isomer of the target compound (I) can be obtained by carrying out the above reaction using a raw material compound optically resolved at an appropriate stage. Further, the optical isomer mixture of the compound represented by the general formula (I) can be treated according to a usual optical resolution method to obtain each optical isomer.

The carboxy group of the compound represented by the general formula (I) may be protected to form an ester as described above, and the ester forming reaction is carried out from the corresponding carboxy compound and alcohols. Conventional methods (eg,
The dehydration condensation method using an acid catalyst, the method using an acid halide, the dehydration condensation method using carbodiimides, etc.) is performed.

The compounds of general formula (I) are useful as therapeutic agents for AIDS caused by HIV. Dosage forms for that purpose include, for example, tablets, capsules, granules, powders,
Oral administration by syrup or the like, or parenteral administration by intravenous injection, intramuscular injection, suppository and the like can be mentioned. These agents are produced by a well-known method using additives such as an excipient, a binder, a disintegrating agent, a lubricant, a stabilizer, and a flavoring agent, if necessary. Although the dose varies depending on age, body weight, symptom, administration form, number of administrations, etc., usually, the compound of the general formula (I) is administered to an adult at about 10 to 500 mg per day, once or in several divided doses. To do.
In addition, the compound of the general formula (I) did not show toxicity even when the rat was orally administered at a dose several times the above dose (calculated per body weight). Next, the present invention will be described more specifically with reference to Examples and Reference Examples.

[0055]

【Example】

Example 1 1-Cyclopropyl-6-fluoro-8-trifluoro
Methyl-1,4-dihydro-4-oxo-7- [4-
(2-Pyrimidinyl) piperazin-1-yl] quinoline
Synthesis of -3-carboxylic acid 1.0 g (0.003 mol) of 1-cyclopropyl-6,7-difluoro-8-trifluoromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 1 −
1.23 g of (2-pyrimidinyl) piperazine (0.00
(75 mol) was dissolved in 20 ml of pyridine, stirred at 105 ° C. for 3 hours, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent; chloroform: methanol = 9.5: 0.5 mixture). 1-cyclopropyl-6-fluoro-8-trifluoromethyl-1,4-
0.68 g of dihydro-4-oxo-7- [4- (2-pyrimidinyl) piperazin-1-yl] quinoline-3-carboxylic acid was obtained as a yellow powder. Melting point: 285-287 ° 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)

Examples 2-31 The compounds in Table 11 were synthesized in the same manner as in Example 1.

[0057]

[Table 11]

Example 32 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 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 6
0 mg was obtained as a pale yellow powder. Melting point: 203-205 ° C MS spectrum (CI): m / e 590 (M ⁺ +1)

Example 33 6-Fluoro-8-trifluoromethyl-1,4-dihi
Dro-4-oxo-1-methyl-7- [3-methyl-4
-(2-Pyrimidinyl) piperazin-1-yl ] quinoli
Synthesis of benzene -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. Obtained 6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-1
-Methyl-7- (3-methylpiperazin-1-yl) quinoline-3-carboxylic acid 1.49 g (0.0039 mol), 2-chloropyrimidine 0.88 g (0.0077)
Mol) and 0.78 g (0.0077 mol) of triethylamine were added to 20 ml of N, N-dimethylformamide,
After stirring at 130 ° C. for 10 hours, the solvent was distilled off under reduced pressure.

The residue was subjected to silica gel column chromatography (eluent; chloroform: methanol = 9: 1 mixture) to give 6-fluoro-8-trifluoromethyl-.
1,4-dihydro-4-oxo-1-methyl-7- [3
-Methyl-4- (2-pyrimidinyl) piperazine-1-
0.35 g of [il] quinoline-3-carboxylic acid was obtained as an ocher powder. Melting point: 283 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 Found: C: 53.47, H: 4.07, N: 14.95.

Example 34 6-Fluoro-8-trifluoromethyl-1,4-dihi
Dro-4-oxo-1-methyl-7- [4- (2-pyri
Midinyl) homopiperazin-1-yl] quinoline-3-
Synthesis of carboxylic acid 6,7-difluoro-8-trifluoromethyl-1,4
Dissolve 0.8 g (0.0026 mol) of dihydro-1-methyl-4-oxoquinoline-3-carboxylic acid and 2.1 g (0.0118 mol) of 1- (2-pyrimidinyl) homopiperazine in 12 ml of pyridine. After stirring at 105 ° C. for 3 hours, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent; chloroform: methanol = 9.5: 0.5 mixture) to give 6-fluoro-
8-trifluoromethyl-1,4-dihydro-4-oxo-1-methyl-7- [4- (2-pyrimidinyl) homopiperazin-1-yl] quinoline-3-carboxylic acid
45 g were obtained as a yellow powder. Melting point: 243 to 245 ° C MS spectrum (CI): m / e 466 (M ⁺ +1) Elemental analysis value (%); C ₂₁ H ₁₉ F ₄ N ₅ O ₃ Theoretical value; C: 54.20, H : 4.11, N: 15.05 Found: C: 54.06, H: 4.03, N: 14.96.

Example 35 The anti-HIV activity of the compound of the present invention was measured by the method of R. Pauwel et al. (J. Virologi-cal Method 20 , p. 309-321 (198).
8)). That is, MT-4 cells were centrifuged (1000 × g, 5 minutes), the obtained cell pellet was suspended in a serum-free RPMI-1640 medium, and HIV was inoculated into the cell suspension to 37 ° C. After culturing for 1 hour at 10%
Fetal bovine serum-added RPMI-1640 medium (hereinafter referred to as serum medium) was added, washed and centrifuged (1000 × g, 5 minutes). HIV-infected cells and HIV thus obtained
Uninfected cells were suspended in serum medium at a concentration of ⁴ × 10 ⁵ / ml, and 100 μl was dispensed to each well of a 96-well multiwell for tissue culture. To each of these wells, 100 μl of a compound previously serially diluted with a serum medium was dispensed, and then static culture was carried out at 37 ° C. for 5 days in the presence of 5% carbon dioxide gas. Similarly, HIV-infected cells and HI containing no compound
V uninfected cells were cultured. After culturing, MTT [3-
(4,5-dimethylthiazol-2-yl) -2,5-
[Diphenyltetrazolium bromide] was used to measure living cells, and cytotoxicity-suppressing activity (anti-HIV
Activity). It was confirmed that the cell solution and the inoculated virus solution did not contain mycoplasma.

50% cytotoxicity inhibition against HIV-infected cells, where the cytotoxicity-inhibiting activity of non-compound-added HIV-uninfected cells is 100%, and the cytotoxicity-inhibiting activity of HIV-infected cells without compound is 0%. The concentration of the compound showing the activity (EC ₅₀ ) was determined. Table 12 shows the test results.

[0064]

[Table 12]

Reference Example 1 1-Cyclopropyl-6,7-difluoro-8-trif
Fluoromethyl-1,4-dihydro-4-oxoquinoline
Synthesis of 3-carboxylic acid (II; R ¹ = cyclopropyl) 2,4,5-trifluoro-3-trifluoromethylbenzoic acid (VII) 8.5 g (0.0348 mol) in benzene 30 ml, thionyl chloride 17 ml and a few drops of N, N-dimethylformamide were added, and the mixture was heated under reflux for 3 hours. After the reaction, the benzene and the excess thionyl chloride were distilled off under reduced pressure to obtain 2,4,5
-Trifluoro-3-trifluoromethylbenzoic acid chloride (VIII) was obtained. Ethyl 3-dimethylaminoacrylate (IX; R ³ = ethyl, R ⁴ = R ⁵ = methyl) 5.47
g (0.0383 mol) of anhydrous tetrahydrofuran 30
After being dissolved in ml, 4.2 g of triethylamine (0.04
15 mol) was added, 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. 3.9 g (0.0417 mol) of cyclopropylamine (XI; R ¹ = cyclopropyl) hydrochloride was added to the filtrate, 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 mixed solution), and ethyl 2- (2,4,5-trifluoro-3-trifluoromethylbenzoyl) -3-cyclopropylaminoacrylate (XII; R ¹ = cyclopropyl, R ³ = Ethyl) 10.63 g was obtained as a pale yellow solid. This was dissolved in 100 ml of anhydrous diethyl ether, 1.6 g (0.0416 mol) of 62.4% sodium hydride-mineral oil was gradually added under ice cooling, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 1N hydrochloric acid (41.7 ml), and the mixture was vigorously stirred to acidify the whole reaction mixture, and the precipitated crystals were collected by filtration, washed with water and then with diethyl ether, and 1-cyclopropyl-6,7. - difluoro-8-trifluoromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester; yield (XIII R ¹ = cyclopropyl, R ³ = ethyl) was 7.32g as a white powder. Melting point: 184-185 ° C MS spectrum (CI): m / e 362 (M ⁺ +1)

Then, 0.8 g (0.0
022 mol) was suspended in a mixed solution of 5 ml of acetic acid, 3 ml of water and 0.3 ml of concentrated sulfuric acid, and the mixture was heated under reflux for 2 hours with stirring. After cooling to room temperature, water was added to collect insoluble matter by filtration, and the collected matter was washed with water and dried to give 1-cyclopropyl-6,7-difluoro-8-trifluoromethyl-1,4-. 0.7 g of dihydro-4-oxoquinoline-3-carboxylic acid (II; R ¹ = cyclopropyl) was obtained as white crystals. Melting point: 210-212 ° C MS spectrum (CI): m / e 334 (M ⁺ +1)

Reference Example 2 1-Ethyl-6,7-difluoro-8-trifluorome
Cyl-1,4-dihydro-4-oxoquinoline-3-ca
Synthesis of Rubic Acid (II; R ¹ = Ethyl) Ethylamine (XI; R ¹ = ethyl) was used instead of cyclopropylamine hydrochloride to react in the same manner as in Reference Example 1 to obtain 1-ethyl-6,7-difluoro. -8-Trifluoromethyl-1,4-dihydro-4-oxoquinoline-3
- carboxylic acids; to give the (II R ¹ = ethyl) as a white powder. Melting point: 159-162 ° C MS spectrum (CI): m / e 322 (M ⁺ +1)

Reference Example 3 6,7-Difluoro-8-trifluoromethyl-1,4
-Dihydro-1-methyl-4-oxoquinoline-3-ca
Synthesis of Rubic Acid (II; R ¹ = Methyl) Methylamine hydrochloride (XI; R ¹ = methyl) was used in place of cyclopropylamine hydrochloride and reacted in the same manner as in Reference Example 1 to obtain 6,7-difluoro- 8-Trifluoromethyl-1,4-dihydro-1-methyl-4-oxoquinoline-3-carboxylic acid (II; R ¹ = methyl) was obtained as a white powder. Melting point: 197.5-199 ° C MS spectrum (CI): m / e 308 (M ⁺ +1)

Reference Example 4 6,7-Difluoro-8-trifluoromethyl-1,4
-Dihydro-1-isopropyl-4-oxoquinoline-
Synthesis of 3-carboxylic acid (II; R ¹ = isopropyl) Instead of cyclopropylamine hydrochloride, isopropylamine hydrochloride (XI; R ¹ = isopropyl) was used and reacted in the same manner as in Reference Example 1 to obtain 6,7- Difluoro-8-trifluoromethyl-1,4-dihydro-1-isopropyl-
4-oxoquinoline-3-carboxylic acid (II; R ¹ = isopropyl) was obtained as a white powder. Melting point: 197.5-200 ° C MS spectrum (CI): m / e 336 (M ⁺ +1)

Reference Example 5 6,7-Difluoro-1- (2-fluoroethyl) -8
-Trifluoromethyl-1,4-dihydro-4-oxo
Quinoline-3-carboxylic acid (II; R ¹ = 2-fluoroe
The reaction was performed in the same manner as in Reference Example 1 using 2-fluoroethylamine hydrochloride (XI; R ¹ = 2-fluoroethyl) instead of cyclopropylamine hydrochloride, and 6,7-difluoro-1- ( 2-Fluoroethyl) -8-trifluoromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (II; R ¹ = 2-fluoroethyl) was obtained as a white powder. Melting point: 183-185 ° C MS spectrum (CI): m / e 340 (M ⁺ +1)

Reference Example 6 Synthesis of 1- (2-pyrimidyl) homopiperazine Homopiperazine 10.0 g (0.1 mol), 2-chloropyrimidine 2.9 g (0.025 mol), potassium carbonate 6.9 g (0 (0.05 mol) and a catalytic amount of potassium iodide were added with 50 ml of acetonitrile, 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 7 Synthesis of 1- (2-methylthiophenyl) piperazine 2.8 g (0.02 mol) of 2-methylthioaniline and N-bis (2-bromoethyl) amine hydrobromide 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 8 Synthesis of 1- (2-thiazolyl) piperazine 5.0 g (0.0305 mol) of 2-bromothiazole was dissolved in 50 ml of acetonitrile to give 13.1 g of piperazine.
(0.153 mol) and 8.4 g (0.06 mol) of potassium carbonate.
1 mol) and a catalytic amount of potassium iodide were added, and the mixture was heated under reflux for 5 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent; chloroform: methanol: 28% aqueous ammonia = 40: 9: 1 mixture) to obtain 1- (2 3.62 g of -thiazolyl) piperazine were obtained as a colorless liquid. MS spectrum (CI): m / e 170 (M ⁺ +1)

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07D 401/12 213 C07D 401/12 213 233 233 237 237 239 239 241 241 243 243 403 401/14 213 401 / 14 213 239 239 241 241 241 243 243 413/12 215 413/12 215 417/12 215 417/12 215 (72) Inventor Takashi Nishigaki 1-2-5 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd.

Claims (26)

[Claims] 1. The following general formula (I): (In the formula, R ¹ represents a lower alkyl group, a halogeno-lower alkyl group or a cycloalkyl group, R ² is a phenyl group which may be substituted with R ^0, which may be substituted with R ⁰ N, O and Represents a 5-membered or 6-membered heteroaromatic monocyclic group containing 1 or 2 heteroatoms selected from S or a heteroaromatic condensed ring group in which these heteroaromatic monocycles and a benzene ring are condensed, and R ⁰ is halogen, lower 8 represents a group selected from alkyl, fluorine-substituted lower alkyl, lower alkoxy or lower alkylthio, R ³ represents hydrogen or a lower alkyl group, and m represents an integer of 2 or 3).
-A pharmaceutical composition containing at least one trifluoromethylquinolinecarboxylic acid derivative or a pharmaceutically acceptable salt or ester thereof. 2. An 8-trifluoromethylquinolinecarboxylic acid derivative or pharmacologically acceptable, wherein R ¹ is a C ₁ -C ₄ alkyl group, a halogeno C ₁ -C ₄ alkyl group or a C ₃ -C ₆ cycloalkyl group. The pharmaceutical composition according to claim 1, which comprises a salt thereof or an ester thereof. 3. R ¹ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, fluoromethyl, chloromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl. , 2-bromoethyl, 2-iodoethyl,
Selected from the group consisting of 2,2,2-trifluoroethyl, 3-fluoropropyl, 3-chloropropyl, 3-bromopropyl, 4-fluorobutyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups, The pharmaceutical composition according to claim 1, which comprises an 8-trifluoromethylquinolinecarboxylic acid derivative or a pharmacologically acceptable salt or ester thereof. 4. R ¹ is methyl, ethyl, propyl, isopropyl, 2-fluoroethyl, 2-chloroethyl,
Contains an 8-trifluoromethylquinolinecarboxylic acid derivative selected from the group consisting of 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl and cyclopentyl groups, or a pharmacologically acceptable salt or ester thereof. The pharmaceutical composition according to claim 1. 5. An 8-trifluoromethylquinolinecarboxylic acid derivative or a pharmacologically acceptable salt thereof, wherein R ¹ is selected from the group consisting of methyl, ethyl, 2-fluoroethyl and cyclopropyl groups. The pharmaceutical composition of claim 1 containing the ester. 6. The pharmaceutical composition according to claim 1, which comprises an 8-trifluoromethylquinolinecarboxylic acid derivative in which R ² is a phenyl group, or a pharmacologically acceptable salt or ester thereof. 7. The substituent R ^{0 of} R ² is a halogen atom, C
₁ -C ₄ alkyl group, fluorine-substituted C ₁ -C ₄ alkyl group is one selected from the group consisting of C ₁ -C ₄ alkoxy groups and C ₁ -C ₄ alkylthio group, 8-trifluoromethyl quinoline carboxylic The pharmaceutical composition according to claim 1, which comprises an acid derivative or a pharmaceutically acceptable salt or ester thereof. 8. The substituent R ^{0 of} R ² is fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, s-butyl, isobutyl, t-butyl, mono-, di- or trifluoro. Methyl, 2-fluoroethyl, 2- or 3-fluoropropyl, 2-3
-Or 4-fluorobutyl, methoxy, ethoxy,
Propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, methylthio, ethylthio, propylthio, isopropylthio, butylthio,
The drug according to claim 1, which comprises an 8-trifluoromethylquinolinecarboxylic acid derivative selected from the group consisting of isobutylthio, s-butylthio and t-butylthio groups, or a pharmaceutically acceptable salt or ester thereof. Composition. 9. 8-Trifluoromethyl, wherein the substituent R ^{0 of} R ² is selected from the group consisting of fluorine, chlorine, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, methylthio and ethylthio groups. The pharmaceutical composition according to claim 1, which comprises a quinolinecarboxylic acid derivative or a pharmacologically acceptable salt or ester thereof. 10. The substituent R ^{0 of} R ² is fluorine, chlorine,
The pharmaceutical composition according to claim 1, which comprises an 8-trifluoromethylquinolinecarboxylic acid derivative selected from the group consisting of ethyl, trifluoromethyl, methoxy and methylthio groups, or a pharmaceutically acceptable salt or ester thereof. Stuff. 11. The heteroaromatic monocyclic group or heteroaromatic condensed ring group for R ² is 2-thienyl, 2-furyl, 2-oxazolyl, 2-thiazolyl, 2-imidazolyl, 2-, 3- or 4-pyridyl. , 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl, 3-pyridazinyl, 2-benzoxazolyl, 2-benzothiazolyl and 2-benzimidazolyl groups, 8-
The pharmaceutical composition according to claim 1, which comprises a trifluoromethylquinolinecarboxylic acid derivative or a pharmacologically acceptable salt or ester thereof. 12. The heteroaromatic monocyclic group or heteroaromatic condensed ring group for R ² is 2-thienyl, 2-furyl, 2-oxazolyl, 2-thiazolyl, 2-imidazolyl, 2-, 3- or 4-pyridyl. A 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl, 3-pyridazinyl and 2-benzothiazolyl group.
-The pharmaceutical composition according to claim 1, which comprises a trifluoromethylquinolinecarboxylic acid derivative or a pharmacologically acceptable salt or ester thereof. 13. An 8-trifluoromethylquinolinecarboxylic acid derivative or a pharmacologically acceptable compound, wherein the heteroaromatic monocyclic group or heteroaromatic condensed ring group for R ² is a 2-pyridyl, 2-pyrimidinyl or 2-benzothiazolyl group. The pharmaceutical composition according to claim 1, which comprises a salt thereof or an ester thereof. 14. An 8-trifluoromethylquinolinecarboxylic acid derivative or a pharmacologically acceptable salt or ester thereof, wherein R ³ is a hydrogen atom.
Pharmaceutical composition. 15. The pharmaceutical composition according to claim 1, which comprises an 8-trifluorotylquinolinecarboxylic acid derivative or a pharmacologically acceptable salt or ester thereof, wherein R ³ is a C ₁ -C ₄ alkyl group. 16. R ³ is selected from the group consisting of methyl, ethyl, propyl and isopropyl groups.
The pharmaceutical composition according to claim 1, which comprises an 8-trifluoromethylquinolinecarboxylic acid derivative or a pharmacologically acceptable salt or ester thereof. 17. R ³ is a methyl or ethyl group, 8
-The pharmaceutical composition according to claim 1, which comprises a trifluoromethylquinolinecarboxylic acid derivative or a pharmacologically acceptable salt or ester thereof. 18. The carboxyl group of formula (I) is C _1-
1 selected from a C ₄ alkyl group, an aralkyl group, a C _{2 to} C ₅ alkanoyloxyalkyl group, a C _{1 to} C ₄ alkoxycarbonyloxyalkyl group, an N, N-dialkyl-substituted aminocarbonylalkyl group, N, O and S, or From a 5- or 6-membered hetero-saturated monocyclic-substituted alkyl group containing 2 heteroatoms and (5-methyl (or 5-phenyl) -2-oxo-1,3-dioxolen-4-yl) methyl group The pharmaceutical composition according to claim 1, which comprises an ester of an 8-trifluoromethylquinolinecarboxylic acid derivative which is an ester protected with a protecting group selected from the group consisting of: 19. The carboxyl group of the formula (I) is methyl, ethyl, propyl, isopropyl, butyl and isobutyl, benzyl and phenylethyl, acetoxymethyl, pivaloyloxymethyl, 1- (ethoxycarbonyloxy) ethyl, 1; -(Isopropoxycarbonyloxy) ethyl, N, N-dimethylaminocarbonylmethyl group, 2- (N, N-dimethylamino) ethyl; 2-morpholinoethyl-substituted alkyl, 2-piperidinoethyl-substituted alkyl, 2- (4-methylpiperidino) ) Ethyl-substituted alkyl and (5-methyl (or 5-phenyl) -2-
The pharmaceutical of claim 1, which comprises an ester of an 8-trifluoromethylquinolinecarboxylic acid derivative which is an ester protected with a protecting group selected from the group consisting of oxo-1,3-dioxolen-4-yl) methyl groups. Composition. 20. The compound of formula (I) is an acid addition salt of a mineral acid, an acid addition salt of an organic acid or a metal salt of a carboxylic acid,
The pharmaceutical composition according to claim 1, which contains a pharmacologically acceptable salt of an 8-trifluoromethylquinolinecarboxylic acid derivative. 21. The compound of formula (I) is a hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, methanesulfonate, ethanesulfonate, benzenesulfonate, From the group consisting of p-toluenesulfonate, oxalate, maleate, fumarate, tartrate, citrate, sodium salt, potassium salt, calcium salt, magnesium salt, manganese salt, iron salt and aluminum salt. The pharmaceutical composition according to claim 1, which contains a pharmacologically acceptable salt of an 8-trifluoromethylquinolinecarboxylic acid derivative which is a selected salt. 22. 1-Cyclopropyl-6-fluoro-
8-trifluoromethyl-1,4-dihydro-4-oxo-7- [4- (2-pyridyl) piperazin-1-yl] quinoline-3-carboxylic acid or a pharmacologically acceptable salt or ester thereof A pharmaceutical composition containing the same. 23. 6-Fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-1-methyl-7-
A pharmaceutical composition comprising [4- (2-pyrimidinyl) piperazin-1-yl] quinoline-3-carboxylic acid or a pharmacologically acceptable salt or ester thereof. 24. 6-Fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-1-methyl-7-
A pharmaceutical composition comprising [4- (2-pyridyl) piperazin-1-yl] quinoline-3-carboxylic acid or a pharmacologically acceptable salt or ester thereof. 25. 6-Fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-1-methyl-7-
A pharmaceutical composition comprising [4- (2-benzothiazolyl) piperazin-1-yl] quinoline-3-carboxylic acid or a pharmacologically acceptable salt or ester thereof. 26. A human immunodeficiency virus containing at least one of the 8-trifluoromethylquinolinecarboxylic acid derivative according to any one of claims 1 to 25 or a pharmacologically acceptable salt or ester thereof. Growth inhibitor.