JPH0616678A - Quinolinecarboxylic acid derivative - Google Patents

Abstract

PURPOSE:To provide a new quinolinecarboxylic acid derivative useful for improving an infections disease caused by a Gram-positive bacterium including a methicillin-resistant Staphylococcus and a new quinolone-resistant and methicillin-resistant Staphylococcus. CONSTITUTION:The derivative of formula I [Z is a (substituted) aromatic hetero group; R<1> is H, an alkyl or a (substituted) phenyl; R<2> is H, an alkyl, a halogen, etc.; R<3> is H or an alkyl; R<4> is H, an alkyl, hydroxy, etc.] and its pharmaceutically permissible salt, e.g. 6-fluoro-7-(4-pyridyl)-4-oxo-4H-[1,3]thiazeto[3,2- a]quinoline-3-carboxylic acid. The compound of formula I is obtained, e.g. by a cyclization reaction between a compound of formula II [R<8> is an alkyl; Z<0> is a (substituted) aromatic heterocyclic group] and a compound of formula III (D and E are each a halogen) in the presence of a deacidification agent (e.g. sodium carbonate) in an inert solvent at 0 to 120 deg.C and, as necessary, a subsequent hydrolysis reaction.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel quinolinecarboxylic acid derivative having an antibacterial action and useful as a therapeutic agent for various infectious diseases. The compounds of the invention are particularly useful for treating infections by Gram-positive bacteria, including methicillin-resistant staphylococci (MRSA) and new quinolone-resistant methicillin-resistant staphylococci (MRSA, PCA ^r ).

The compound of the present invention is represented by the following general formula [I].

[Chemical 2] In the formula, Z represents a substituted or unsubstituted aromatic heterocyclic group. R ¹ represents hydrogen, alkyl, or substituted or unsubstituted phenyl. R ² represents hydrogen, alkyl, alkoxy, amino or halogen. R ³ represents hydrogen or alkyl. R ⁴ represents hydrogen, alkyl, hydroxy, halogen or amino.

[0003]

2. Description of the Related Art As synthetic antibacterial agents for treating bacterial infections, nalidixic acid, pyromidic acid, pipemidic acid, enoxacin (AT-2266), ofloxacin (DL-8280), etc. have been widely used. Has been. However, these are mainly effective against Gram-negative bacteria,
It is not satisfactory for the treatment of infectious diseases caused by Gram-positive bacteria and methicillin-resistant Staphylococcus which is an intractable disease which has been increasing in recent years.

At present, the best therapeutic drug for methicillin-resistant staphylococcus is said to be the antibiotic vancomycin. However, since this drug has very strong nephrotoxicity, serious side effects are feared. recent years,
A completely new type of new quinolone-resistant methicillin-resistant staphylococcus, which is also resistant to new quinolone synthetic antibacterial agents, has appeared and has become a social problem due to nosocomial infection. A drug that can be expected to have a sufficient therapeutic effect has not been found.

Thus, no effective drug has been found for the treatment of infectious diseases caused by methicillin-resistant staphylococci and new quinolone-resistant methicillin-resistant staphylococci. By the way, 6-fluorothiazetoquinolinecarboxylic acid derivatives, JP-A-63-107990, JP-A 1-294680,
It is disclosed in Japanese Patent Application Laid-Open No. 1-230584, International Publication WO91 / 07412 and the like. However, each of the applied compounds has a nitrogen-carbon bond with the substituent at the 7-position.

New quinolone type synthetic antibacterial agents having pyridyl at the 7-position are disclosed in JP-A-60-163866 and JP-A-60-11.
2790, JP 60-166678, JP 1-100166
Publication, JP-A-3-145487, US-4959363, US-47974
90, EP-0417669A2 and the like. However,
The basic skeleton of any of the applied compounds is not thiazetoquinoline.

The compounds described in these prior art are not 6-fluoro-7-aromatic heterocycle-substituted thiazetoquinolinecarboxylic acid derivatives. Regarding the new quinolone synthetic antibacterial agents and their antibacterial spectra, it has been clarified that their effects are exhibited depending on the chemical structural characteristics, and it is also clear that they have completely different antibacterial activities even if their structural formulas are very similar. It has become. The above new quinolone synthetic antibacterial agents do not have sufficient antibacterial activity against methicillin-resistant staphylococci and new quinolone-resistant methicillin-resistant staphylococci.

[0008]

The object of the present invention is to provide a compound effective against various infectious diseases, and particularly effective for the treatment of infectious diseases caused by Gram-positive bacteria including methicillin-resistant staphylococcus and new quinolone-resistant methicillin-resistant staphylococcus. Was to get.

[0009]

[Means for Solving the Problems] In order to achieve the above object, the inventors of the present invention happened to be in the process of synthesizing and examining various 6-fluorothiazetoquinolinecarboxylic acid derivatives effective against various infectious diseases. Has an aromatic heterocyclic group at the 7-position
The inventors have found that the 6-fluorothiazetoquinolinecarboxylic acid derivative is a compound group that is extremely effective and has low toxicity against methicillin-resistant staphylococci and new quinolone-resistant methicillin-resistant staphylococci, and completed the present invention.

The gist of the present invention resides in that the 7-position of the 6-fluorothiazetoquinolinecarboxylic acid derivative is substituted with a substituted or unsubstituted aromatic heterocyclic group. The structural feature of such a compound is that the carbon at the 7-position is directly bonded to the carbon of the substituent. Hereinafter, the present invention will be described in detail.

In the general formula [I], Z represents a substituted or unsubstituted aromatic heterocyclic group. Examples of such an aromatic heterocyclic group include those having 5 to 10 members.
Examples of such an aromatic heterocyclic group include those having a nitrogen atom.

Examples of such compounds include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, quinolyl and isoquinolyl. Especially, pyridyl, pyrimidyl, quinolyl and the like are preferable. Such an aromatic heterocyclic group as a substituent
When binding to the 7-position of the 6-fluorothiazetoquinolinecarboxylic acid derivative, any carbon of such an aromatic heterocyclic group is bound.

As the substituent of the aromatic heterocyclic group,
Examples thereof include alkyl and amino. As the alkyl as the substituent, a linear or branched lower alkyl having 1 to 4 carbon atoms is preferable, and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like can be mentioned.

The alkyl represented by R ¹ , R ² , R ³ and R ⁴ is preferably linear or branched one having 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl or isopropyl. , N-butyl, isobutyl, sec-butyl, tert-
Butyl etc. can be mentioned.

Examples of the substituted phenyl for R ¹ include halogenophenyl and the like. Examples of the halogen and the halogen represented by R ² and R ⁴ include fluorine, chlorine, bromine and iodine. The alkoxy represented by R ² is preferably a linear or branched lower alkoxy having 1 to 4 carbon atoms, and examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and sec-butoxy. , Tert-
Butoxy etc. can be mentioned.

The salt of the compound [I] included in the present invention includes, for example, salts of mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, hydrobromic acid, formic acid, acetic acid, tartaric acid, Organic acid salts such as lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, camphorsulfonic acid, sodium, potassium, calcium, etc. Examples thereof include salts of alkali metals or alkaline earth metals.

As the compounds of the present invention, the following compounds can be exemplified in addition to the compounds of Examples relating to the production method described below. (1) 6-Fluoro-7- (4-pyridyl) -4-oxo-4H- [1,3]
Thiazeto [3,2-a] quinoline-3-carboxylic acid (2) 6-fluoro-1-ethyl-7- (4-pyridyl) -4-oxo-4
H- [1,3] thiazeto [3,2-a] quinoline-3-carboxylic acid

(3) 6-Fluoro-1-phenyl-7- (4-pyridyl) -4-oxo-4H- [1,3] thiazeto [3,2-a] quinoline-3-carboxylic acid (4) 6-Fluoro-1- (4-fluorophenyl) -7- (4-pyridyl) -4-oxo-4H- [1,3] thiazeto [3,2-a] quinoline-3-carboxylic acid (5) 6 , 8-Difluoro-1-methyl-7- (4-pyridyl) -4-oxo-4H- [1,3] thiazeto [3,2-a] quinoline-3-carboxylic acid

(6) 6-Fluoro-8-methoxy-1-methyl-7
-(4-Pyridyl) -4-oxo-4H- [1,3] thiazet [3,2-a
] Quinoline-3-carboxylic acid (7) 6-fluoro-1-methyl-7- (4-amino-3-pyridyl)-
4-oxo-4H- [1,3] thiazeto [3,2-a] quinoline-3-
Carboxylic acid (8) 6-Fluoro-1-methyl-7- (3-methyl-2-pyridyl)-
4-oxo-4H- [1,3] thiazeto [3,2-a] quinoline-3-
carboxylic acid

(9) 6-Fluoro-1-methyl-7- (4-isoquinolyl) -4-oxo-4H- [1,3] thiazeto [3,2-a] quinoline-3-carboxylic acid (10) 6-Fluoro-1-methyl-7- (2-pyrimidyl) -4-oxo-4H- [1,3] thiazeto [3,2-a] quinoline-3-carboxylic acid (11) 6-Fluoro-1- Methyl-7- (2-amino-5-pyrimidyl) -4-oxo-4H- [1,3] thiazeto [3,2-a] quinoline-
3-carboxylic acid

(12) 8-amino-6-fluoro-1-methyl-7
-(4-Pyridyl) -4-oxo-4H- [1,3] thiazet [3,2-a
] Quinoline-3-carboxylic acid (13) 8-chloro-6-fluoro-1-methyl-7- (4-pyridyl) -4-oxo-4H- [1,3] thiazet [3,2-a] quinoline -3-carboxylic acid (14) 6-fluoro-1,8-dimethyl-7- (4-pyridyl) -4-oxo-4H- [1,3] thiazeto [3,2-a] quinoline-3-carboxylic acid acid

(15) 5-amino-6-fluoro-1-methyl-7
-(4-Pyridyl) -4-oxo-4H- [1,3] thiazet [3,2-a
] Quinoline-3-carboxylic acid (16) 5-amino-8-chloro-6-fluoro-1-methyl-7-
(4-Pyridyl) -4-oxo-4H- [1,3] thiazet [3,2-a
] Quinoline-3-carboxylic acid (17) 5-amino-6,8-difluoro-1-methyl-7- (4-pyridyl) -4-oxo-4H- [1,3] thiazet [3,2-a ] Quinoline-3-carboxylic acid

(18) 5-amino-6-fluoro-8-methoxy
-1-Methyl-7- (4-pyridyl) -4-oxo-4H- [1,3] thiazeto [3,2-a] quinoline-3-carboxylic acid (19) 5,6-difluoro-1-methyl -7- (4-Pyridyl) -4-oxo-4H- [1,3] thiazeto [3,2-a] quinoline-3-carboxylic acid (20) 5,6,8-trifluoro-1-methyl- 7- (4-pyridyl)-
4-oxo-4H- [1,3] thiazeto [3,2-a] quinoline-3-
carboxylic acid

(21) 6-Fluoro-5-hydroxy-1-methyl-7- (4-pyridyl) -4-oxo-4H- [1,3] thiazet [3,
2-a] quinoline-3-carboxylic acid (22) 6,8-difluoro-5-hydroxy-1-methyl-7- (4-
Pyridyl) -4-oxo-4H- [1,3] thiazeto [3,2-a] quinoline-3-carboxylic acid (23) 6-fluoro-1,5-dimethyl-7- (4-pyridyl) -4 -Oxo-4H- [1,3] thiazeto [3,2-a] quinoline-3-carboxylic acid (24) 6,8-difluoro-1,5-dimethyl-7- (4-pyridyl)-
4-oxo-4H- [1,3] thiazeto [3,2-a] quinoline-3-
Carboxylic Acid The compound of the present invention can be produced, for example, by the following method.

Method A:

[Chemical 3] In the formula, R ¹ , R ² and R ⁴ are the same as above. R ⁸ represents alkyl, and D and E represent the same or different halogen. Z ⁰ represents a substituted or unsubstituted aromatic heterocyclic group. Examples of the substituent of the aromatic heterocyclic group represented by Z ⁰ include alkyl and protected amino. Examples of the amino-protecting group include alkoxycarbonyl, acyl, piperidinylcarbonyl, benzyloxycarbonyl, alkenyl, aralkyl and the like which are usually used as the amino-protecting group.

The alkyl represented by R ⁸ and the alkyl as the substituent of Z ⁰ are linear or branched and have 1 carbon atoms.
To 4 are preferred, and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like. Examples of the halogen represented by D and E include fluorine, chlorine, bromine, iodine and the like.

A quinolinecarboxylic acid derivative [II] and a dihalide (eg, methylene iodide, ethylidene bromide, benzylidene bromide, etc.) in a solvent inert to the reaction are used as a deoxidizing agent (eg, sodium carbonate, potassium carbonate, [Ia] is produced by reacting the compound at 0 to 120 ° C. in the presence of triethylamine or the like) and cyclizing. As the solvent, for example, aprotic solvents such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide, dimethylsulfoxide (DMSO) and sulfolane are preferable. The amount of the dihalide and the deoxidizer used is at least equimolar with respect to 1 mol of [II], preferably
1.1 to 2.5 mol is good. 0.01 to accelerate the reaction
The reaction may be carried out by adding ~ 3.0 molar equivalents of sodium iodide or potassium iodide.

Method B:

[Chemical 4] In the formula, Z ⁰ , R ¹ , R ² , R ⁴ , R ⁸ , D and E are the same as defined above. That is, [III] and a dihalide are treated with an inert solvent (eg, N, N, etc.) in the presence of a deoxidizing agent (eg, potassium carbonate, etc.).
N-dimethylformamide). [IV] is then closed to produce [Ia]. This ring-closing reaction can be carried out by a method known per se. For example, a method by heating, a method using an acidic substance such as phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, thionyl chloride, concentrated sulfuric acid, polyphosphoric acid, polyphosphoric acid ester and the like can be mentioned. For example, when an acidic substance is used, 1 mol to a large excess amount, preferably 20 to 30 mol, of an acidic substance is used with respect to 1 mol of [IV], and usually 0 to 100 ° C., preferably 0 to 60 ° C.

The compound (R ⁸
Can be converted to a carboxylic acid (R ³ is hydrogen) by hydrolysis, if desired. This hydrolysis reaction is carried out at room temperature using a large excess of acid (eg, sulfuric acid, hydrochloric acid, hydrobromic acid, hydrobromic acid / acetic acid, chlorosulfonic acid, polyphosphoric acid, etc.), preferably 10 to 20 times as much acid. Perform at ~ 110 ° C. Or 1 to 5 of 2 to 30 times (preferably 5 to 10 times)
% Potassium hydroxide or sodium hydroxide in a hydroalcoholic solution (methanol, ethanol, propanol, butanol, preferably tert-butanol) at room temperature to 100
It can also be hydrolyzed by stirring at ℃, preferably at the boiling point of the solvent used. The protecting group can be removed by a known method if necessary.

Further, the ester is heated and stirred at a temperature of 60 to 150 ° C., preferably 100 to 110 ° C., in the presence of a catalytic amount of concentrated sulfuric acid in an alcohol corresponding to 10 to 100 times the amount of the desired ester. It can be converted into an ester form. The protecting group can be removed by a known method if necessary.

Further, in the case of carboxylic acid (R ³ is hydrogen), it can be converted into an ester (R ³ is alkyl) by esterification if necessary. This esterification reaction can be carried out by a known esterification such as thionyl chloride and alcohol, alcohol and condensing agent (eg, dicyclohexylcarbodiimide), alkyl halide or substituted alkyl halide and alcoholate, and the like. In the case of carboxylic acid, it can be used in the form of a pharmacologically acceptable salt (eg, sodium, potassium, etc.) by a method known per se. The protecting group can be removed by a known method if necessary.

The target compound [I] thus produced is
It can be isolated and purified by a means known per se, for example, concentration, liquid conversion, phase transfer, solvent extraction, crystallization, recrystallization, fractional distillation, chromatography and the like. When the compound of the present invention contains an asymmetric carbon, an optically active substance is present due to them, and these and a mixture thereof are also included in the present invention.

The starting compounds [II] and [III] can be produced by the following reaction formula, which will be described later as a reference example.

[Chemical 5] (In the formula, Z ⁰ , R ² , R ⁴ and R ⁸ are the same as the above. (P)
Represents a protecting group for S), as a protecting group for sulfur, alkyl, alkoxymethyl, substituted benzyl, 2,4-dinitrophenyl, disulfide as a dimer of [II], alkylthiomethyl, substituted carbamoyl, diphenylmethyl, Examples thereof include triphenylmethyl, picolyl, acetamidomethyl, acyl and the like, which are usually used as a protective group for sulfur. Substituted or non-substituted fluorobenzene [V] is treated with a suitable solvent (eg, dialkyl ether, THF,
Dioxane) to react with sec-butyllithium at −78 ° C. to the boiling point of the solvent to produce fluorobenzene-o-lithium salt. Further, it is reacted with anhydrous zinc chloride to carry out metal exchange to produce fluorobenzene-o-zinc salt. This is reacted with a substituted or unsubstituted bromo-substituted aromatic heterocyclic compound in the presence of a metal catalyst (eg, palladium, nickel, copper, etc.) to produce an o-fluorophenyl-substituted aromatic heterocyclic compound [VI]. .

The o-fluorophenyl-substituted aromatic heterocyclic compound [VI] is nitrated by a conventional method to obtain nitrobenzene [VII], which is further hydrogenated in the presence of a metal catalyst (eg, palladium, nickel, iron, copper, etc.). The amino compound [VIII] is produced by reduction with a gas or an acid (eg, acetic acid, hydrochloric acid, etc.).

The amino compound [VIII] is treated with a suitable solvent (eg,
Dithiocarbamic acid salt [IX] by reacting with carbon disulfide in the presence of a large excess of triethylamine or other amine or an alkali metal in benzene, dioxane, chloroform or the like or without a solvent.
(B represents a base). The isothiocyanate [X] is produced by reacting this with ethyl chlorocarbonate in the presence of triethylamine in a solvent (eg, chloroform, methylene chloride, etc.) or by reacting with copper sulfate, lead nitrate, iron sulfate, zinc sulfide, etc. To do. Alternatively, the amino form [VI
II] in a suitable solvent (eg, chloroform, THF, etc.),
Reaction with thiophosgene in the presence of triethylamine produces [X]. This is reacted with an alkali salt of dialkyl malonate (eg, sodium salt, potassium salt) to produce phenylaminomercaptomethylene malonic acid dialkyl ester. Protect the thiol group [X
I] and heat-ring-close in a high boiling point solvent (eg, dichlorobenzene, tetralin, diphenyl ether, diethylene glycol dimethyl ether, etc.) to give [XII]. At this time, when the reverse ring-closure [XII ′] is produced as a by-product, it is purified and separated by a method such as recrystallization or column chromatography to obtain [XII].

The protecting group is eliminated by a known method [I
I] is manufactured. Further, the protective group is removed from [XI] by a known method to produce [III]. When the compound of the present invention is administered as a medicine, the compound of the present invention is contained as it is or in a pharmaceutically acceptable non-toxic and inert carrier, for example, 0.1% to 99.5%, preferably 0.5% to 90%. The composition is administered to animals, including humans. As the carrier, one or more solid, semi-solid, or liquid diluents, fillers, and other auxiliaries for formulation are used. The pharmaceutical composition is preferably administered in dosage unit form. The pharmaceutical composition of the present invention can be administered orally, intratissueally, topically (transdermally, etc.) or rectally. It is needless to say that the dosage form is suitable for these administration methods. For example, oral administration is particularly preferred.

The dose as a therapeutic agent for infectious diseases is preferably adjusted in consideration of the patient's condition such as age and weight, administration route, nature and degree of disease, etc. The amount of the active ingredient of the present invention is 50 to 50 per day.
1000 mg / human range, preferably 100 mg-300 mg /
The human range is common. In some cases, lower doses may be sufficient, and conversely, higher doses may be required. It is also preferable to administer the drug in divided doses 2-3 times a day.

[0038]

EXAMPLES Reference examples relating to the production of the compound of the present invention will be described below.
The present invention will be described in more detail with reference to Examples and test examples of the compounds of the present invention. Reference Example 1 6-Fluoro-4-hydroxy-2-mercapto-
Synthesis of 7- (4-pyridyl) quinoline-3-carboxylic acid ethyl ester (1) 4- (2-fluorophenyl) pyridine Fluorobenzene 24.71 g was dissolved in THF 200 ml, and sec-butyllithium was added at -78 ° C under an argon stream. 283 ml of cyclohexane solution of is added dropwise and stirred at the same temperature for 1 hour and 15 minutes. To this reaction solution, a solution prepared by suspending 38.55 g of zinc chloride in 300 ml of THF was added dropwise, and the mixture was stirred at -78 ° C for 1 hour and 15 minutes. 4-bromopyridine 2
0.31 g of ether solution (100 ml) was added dropwise, followed by tetrakistriphenylphosphine palladium (Pd (PPh ₃ ) ₄ ) 1.
0 g was added, and the mixture was stirred at -78 ° C for 4 hours and reacted at room temperature for 19 hours. Pour the reaction mixture into 1,000 ml of 10% aqueous ammonium chloride solution and extract with ethyl acetate. The extract is washed with water and dried over magnesium sulfate, and the solvent is distilled off. Purification by column chromatography (SiO ₂ , chloroform) gave 12.5 g of the desired product as a pale yellow solid.

(2) 4- (2-fluoro-5-nitrophenyl)
Pyridine Fuming nitric acid 20 ml and concentrated sulfuric acid 20 ml under ice-cooled stirring,
The compound obtained in (1) (9.7 g) is added to a concentrated sulfuric acid solution (20 ml), and the reaction is continued for 1 hour. The reaction solution is poured into 300 ml of ice water, stirred well, and the precipitated sulfate salt is collected by filtration. Add this to 300 ml of 10% aqueous sodium hydroxide, stir well, and extract with chloroform. The extract was washed with water, dried over magnesium sulfate, and concentrated to obtain 10.58 g of the desired product as a colorless solid.

(3) 4- (5-amino-2-fluorophenyl)
A suspension of 3.0 g of pyridine iron, 1.35 g of acetic acid, 3.0 g of water and 15 ml of ethanol is refluxed at 100 to 110 ° C for 2 hours. To this reaction solution, a suspension of 3.27 g of the compound obtained in (2) in ethanol (30 ml) is added, and the mixture is refluxed for 4 hours. Add 2.65 g of sodium carbonate 15
Stir for minutes and filter the reaction through Celite. After the filtrate was concentrated, 100 ml of water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated to obtain 2.83 g of the desired product as a pale ocher powder.

(4) 4- (2-Fluoro-5-isothiacyanatephenyl) pyridine Compound (380 mg) obtained in (3) and 607 mg of triethylamine were dissolved in 3 ml of dioxane, and carbon disulfide was stirred with cooling with ice water. Add 761 mg dropwise. After stirring at the same temperature for 2 hours,
React at room temperature for 11 hours and 30 minutes. Under cooling with ice water again, 217 mg of ethyl chlorocarbonate was added dropwise and the reaction was carried out at the same temperature for 30 minutes. The reaction solution is poured into 20 ml of water and extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulfate, and concentrated. The concentrate was purified by column chromatography (SiO ₂ , chloroform) to obtain 270 mg of colorless powder.

(5) {4-Fluoro-3- (4-pyridyl) phenylamino} (methylthio) methylenemalonic acid diethyl ester Dissolve 4.05 g of diethyl malonate in 40 ml of dry tetrahydrofuran (THF) and cool with ice. Sodium hydride (60%) 1.0
After adding 1g and stirring for 30 minutes, under ice cooling, 50 ml of dry TH
5.30 g of 4- (2-fluoro-5-isothiocyanatophenyl) pyridine dissolved in F is added dropwise and the reaction is carried out at the same temperature for 1 hour. The reaction solution was cooled again with ice water, and 3.55 g of methyl iodide was added.
A solution of THF (15 ml) is added dropwise and the mixture is reacted at room temperature for 1 hour. The reaction mixture is poured into 200 ml of ice water, extracted with chloroform, the extract is washed with water, dried over magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , chloroform) to obtain 8.35 g of a pale yellow liquid.

(6) 6-Fluoro-4-hydroxy-2-methylthio-7- (4-pyridyl) quinoline-3-carboxylic acid ethyl ester 8.35 g of the compound obtained in (5) was dissolved in 40 g of diphenyl ether and heated at 150 ° C. Stir for 1 hour. The reaction solution was cooled and then purified by column chromatography (SiO ₂ , chloroform) to obtain 5.47 g of the desired product.

(7) 6-Fluoro-4-hydroxy-2-methylsulfinyl-7- (4-pyridyl) quinoline-3-carboxylic acid ethyl ester 1.68 g of the compound obtained in (6) was added to 15 ml of methylene chloride. ,
Furthermore, 0.89 g of m-chloroperbenzoic acid (m-CPBA) was added and the reaction was carried out at room temperature for 1 hour. 10 ml of water is added to the reaction solution, and the mixture is extracted with a mixed solvent of chloroform and methanol. The extract was washed with water, dried over magnesium sulfate, and concentrated to obtain 2.40 g of a pale yellow solid.

(8) 6-Fluoro-4-hydroxy-2-mercapto-7- (4-pyridyl) quinoline-3-carboxylic acid ethyl ester 2.70 g of the compound obtained in (7) was added to 25 ml of dry THF, Add 1.13 g of sodium hydrosulfide (NaSH.nH ₂ O) and stir at room temperature for 16 hours. THF is distilled off under reduced pressure from the reaction solution, water is added to the residue, and the mixture is neutralized with acetic acid. The precipitated crystals were collected by filtration, washed with water, ethanol and ether, and dried to give a yellow solid (1.40 g).
Got Melting point 255 ° C

Reference Example 2 6-Fluoro-4-hydroxy-2-
Mercapto-7- (3-pyridyl) quinoline-3-carboxylic acid ethyl ester To 800 ml of pyridine, while cooling with ice water, 42 g of o-fluorobenzenediazonium salt tetrafluoroborate was added dropwise at the same temperature for 30 minutes under cooling with ice water, and further. React at room temperature for 72 hours. Pyridine is distilled off from the reaction solution under reduced pressure, 300 ml of chloroform is added to the residue, and the mixture is stirred well and the insoluble matter is filtered off. The filtrate was concentrated and purified by column chromatography (SiO ₂ , chloroform) to give 3- (2-fluorophenyl) pyridine 2
I got 4.5g. Using this compound, (2) to Reference example 1
The target compound was obtained in the same manner as in (7). Melting point 183 ℃

Reference Example 3 6-Fluoro-4-hydroxy-2-
The target compound was obtained in the same manner as in Reference Example 1 using mercapto-7- (2-pyridyl) quinoline-3-carboxylic acid ethyl ester 2-bromopyridine. Melting point 195 ° C

Reference Example 4 7- (3,5-Dimethyl-4-pyridyl) -6-fluoro-4-hydroxy-2-mercaptoquinoline-3-carboxylic acid ethyl ester 2,6-dimethyl-4-bromopyridine Using it, a target compound was obtained in the same manner as in Reference Example 1. Melting point 279.5 ° C (decomposition)

Reference Example 5 6-Fluoro-4-hydroxy-2-
Mercapto-7- (3-quinolyl) quinoline-3-carboxylic acid ethyl ester 3-bromoquinoline was used to obtain the target compound in the same manner as in Reference Example 1. Melting point 290 ℃ (decomposition)

Reference Example 6 6-Fluoro-4-hydroxy-2-
Mercapto-7- (5-pyrimidyl) quinoline-3-carboxylic acid ethyl ester 5-bromopyrimidine was used to obtain the target compound in the same manner as in Reference Example 1. Melting point 241.5 ° C (decomposition)

Example 1 6-Fluoro-1-methyl-4-oxo-7- (4-pyridyl) -4H
-[1,3] Thiazeto [3,2-a] quinoline-3-carboxylic acid ethyl ester To 15 ml of dry DMF are added 1.1-dibromoethane (1.50 g) and potassium carbonate (1.11 g), and the mixture is stirred at 100 ° C. In this mixture,
6-Fluoro-4-hydroxy-2- dissolved in 30 ml dry DMF
Mercapto-7- (4-pyridyl) quinoline-3-carboxylic acid ethyl ester (1.38 g) was slowly added dropwise for another 2 hours.
Stir for 30 minutes at the same temperature. DMF was distilled off under reduced pressure from the reaction solution,
The residue is dissolved in chloroform, washed with water, dried over magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , chloroform → chloroform: methanol = 50: 1) to obtain 0.55 g of the title compound.
Melting point 210 ° C Elemental analysis value (as C ₁₉ H ₁₅ FN ₂ O ₃ S) Calculated value (%) C 61.61 H 4.08 N 7.56 Measured value (%) C 58.53 H 3.58 N 7.00

Example 2 6-Fluoro-1-methyl-4-oxo-7- (4-pyridyl) -4H
-[1,3] Thiazeto [3,2-a] quinoline-3-carboxylic acid 6-fluoro-1-methyl-4-oxo-7- (4 obtained in Example 1
-Pyridyl) -4H- [1,3] thiazet [3,2-a] quinoline-3-carboxylic acid ethyl ester 0.54 g in a 1% potassium hydroxide solution (equal mixture solvent of tert-butanol and water) Melt and stir at 60 ° C. for 1 hour 30 minutes. After allowing the reaction solution to cool, it is neutralized with dilute acetic acid and the precipitated crystals are collected by filtration. It was washed with water, ethanol and ether and dried to obtain 0.35 g of colorless powder. Melting point 234 ° C Elemental analysis value (as C ₁₇ H ₁₁ FN ₂ O ₃ S) Calculated value (%) C 59.64 H 3.24 N 8.18 Measured value (%) C 59.47 H 3.14 N 8.04 As in Examples 1 and 2, Was synthesized.

Example 3 6-Fluoro-1-methyl-4-oxo-7- (3-pyridyl) -4H
-[1,3] Thiazeto [3,2-a] quinoline-3-carboxylic acid ethyl ester The title compound was obtained in the same manner as in Example 1 using the compound obtained in Reference Example 2. NMR (CDCl ₃ ) ppm 1.42 (t, 3H, J = 7Hz), 2.18 (d, 3H, J = 6.4Hz), 4.40 (
q, 2H, J = 7Hz), 5.98 (q, 1H, J = 6.4Hz), 7.00 ~ 9.00
(m, 6H),

Example 4 6-Fluoro-1-methyl-4-oxo-7- (3-pyridyl) -4H
-[1,3] Thiazeto [3,2-a] quinoline-3-carboxylic acid The title compound was obtained in the same manner as in Example 2 using the compound obtained in Example 3. Melting point 254 ° C Elemental analysis value (as C ₁₇ H ₁₁ FN ₂ O ₃ S) Calculated value (%) C 59.64 H 3.24 N 8.18 Measured value (%) C 59.13 H 3.43 N 7.73

Example 5 6-Fluoro-1-methyl-4-oxo-7- (2-pyridyl) -4H
-[1,3] Thiazeto [3,2-a] quinoline-3-carboxylic acid ethyl ester The title compound was obtained in the same manner as in Example 1 by using the compound obtained in Reference Example 3. Melting point 227 ° C Elemental analysis value (as C ₁₉ H ₁₅ FN ₂ O ₃ S) Calculated value (%) C 61.61 H 4.08 N 7.56 Measured value (%) C 61.26 H 4.04 N 7.57

Example 6 6-Fluoro-1-methyl-4-oxo-7- (2-pyridyl) -4H
-[1,3] Thiazeto [3,2-a] quinoline-3-carboxylic acid The title compound was obtained in the same manner as in Example 2 using the compound obtained in Example 5. Melting point 300 ° C or more (decomposition) Elemental analysis value (as C ₁₇ H ₁₁ FN ₂ O ₃ S) Calculated value (%) C 59.64 H 3.24 N 8.18 Measured value (%) C 59.33 H 3.37 N 7.90 NMR (CDCl ₃ ) ppm 2.29 (d, 3H, J = 6Hz), 6.21 (q, 1H, J = 6Hz), 7.40 (d
d, 1H, J = 5Hz, 8Hz), 7.8 ~ 8.1 (m, 3H), 8.19 (d, 1
H, J = 12Hz), 8.78 (d, 1H, J = 5Hz), 13.85 (bs, 1H)

Example 7 7- (3,5-Dimethyl-4-pyridyl) -6-fluoro-1-methyl-4-oxo-4H- [1,3] thiazeto [3,2-a] quinoline-3 -Carboxylic acid ethyl ester The title compound was obtained in the same manner as in Example 1 by using the compound obtained in Reference Example 4. Melting point 276.8 ° C

Example 8 7- (3,5-Dimethyl-4-pyridyl) -6-fluoro-1-methyl-4-oxo-4H- [1,3] thiazeto [3,2-a] quinoline-3 -Carboxylic acid The title compound was obtained in the same manner as in Example 2 using the compound obtained in Example 7. Melting point 274.5 ° C Elemental analysis value (as C ₁₉ H ₁₅ FN ₂ O ₃ S) Calculated value (%) C 61.61 H 4.08 N 7.56 Measured value (%) C 61.85 H 4.10 N 6.72

Example 9 6-Fluoro-1-methyl-4-oxo-7- (3-quinolyl) -4H
-[1,3] Thiazeto [3,2-a] quinoline-3-carboxylic acid ethyl ester The title compound was obtained in the same manner as in Example 1 by using the compound obtained in Reference Example 5. Melting point 268.5 ° C (decomposition)

Example 10 6-Fluoro-1-methyl-4-oxo-7- (3-quinolyl) -4H
-[1,3] Thiazeto [3,2-a] quinoline-3-carboxylic acid The title compound was obtained in the same manner as in Example 2 using the compound obtained in Example 9. Melting point 242.3 ° C (decomposition) Elemental analysis value (as C ₂₁ H ₁₃ FN ₂ O ₃ S.3 / 4 H ₂ O) Calculated value (%) C 62.14 H 3.60 N 6.90 Measured value (%) C 62.29 H 3.66 N 6.91

Example 11 6-Fluoro-1-methyl-4-oxo-7- (5-pyrimidyl)-
4H- [1,3] Thiazeto [3,2-a] quinoline-3-carboxylic acid ethyl ester The title compound was obtained in the same manner as in Example 1 by using the compound obtained in Reference Example 6. Melting point 242.3 ° C

Example 12 6-Fluoro-1-methyl-4-oxo-7- (5-pyrimidyl)-
4H- [1,3] thiazeto [3,2-a] quinoline-3-carboxylic acid The title compound was obtained in the same manner as in Example 2 by using the compound obtained in Example 11. Melting point 263.4 ° C (decomposition) Elemental analysis value (as C ₁₆ H ₁₀ FN ₂ O ₃ S · 1/2 H ₂ O) Calculated value (%) C 54.54 H 3.15 N 11.93 Measured value (%) C 54.62 H 3.19 N 11.94

Test Examples The results of pharmacological tests showing the usefulness of representative examples of the compounds of the present invention are shown below. 2. Minimum inhibitory concentration (MIC) measurement (1) Test method: Japanese Society of Chemotherapy Standard Method (Journal of the Japanese Society of Chemotherapy)
29 (1) 76-79 (1981)), the MIC was measured by the agar plate dilution method. That is, using a broth for sensitivity measurement, the bacterial solution cultured at 37 ° C for 18 hours was treated with 10 ⁶ CFU / ml in the same medium.
Dilute. This was inoculated into agar medium for drug-containing sensitivity measurement with a micro planter and cultured at 37 ° C for 18 hours, then MI
C was measured. Ciprofloxacin (CPFX) was used as a comparative drug. The results are shown in Table 1.

[Table 1] The compound of the present invention showed extremely strong antibacterial activity against methicillin-resistant staphylococci, gram-positive bacterium and gram-negative bacterium including new quinolone-resistant methicillin-resistant staphylococcus.

Claims (1)

[Claims] 1. A quinolinecarboxylic acid derivative represented by the following general formula [I] and a physiologically acceptable salt thereof. [Chemical 1] In the formula, Z represents a substituted or unsubstituted aromatic heterocyclic group. R ¹ represents hydrogen, alkyl, or substituted or unsubstituted phenyl. R ² represents hydrogen, alkyl, alkoxy, amino or halogen. R ³ represents hydrogen or alkyl. R ⁴ represents hydrogen, alkyl, hydroxy, halogen or amino.