JPH0568466B2 - - Google Patents

Description

[Detailed description of the invention]

<Industrial Application Field> The present invention relates to a novel quinoline derivative having antibacterial properties and an antibacterial agent containing the new quinoline derivative as an active ingredient. <Prior art> Certain quinoline compounds exhibit antibacterial properties;
especially certain 7-piperazinyl-4-oxo-
It is known that 1,4-dihydroquinoline-3-carboxylic acid exhibits antibacterial properties. US Patent No.
No. 4017622 describes certain 7s substituted with an alkyl, benzyl or acetyl substituent in the 1 position.
-Piperazinyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid derivatives are disclosed. US Pat. No. 4,292,317 discloses 7-piperazinyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid derivatives substituted in the 1-position with an alkyl or vinyl substituent. U.S. Pat. No. 4,284,629 describes various 4-oxo-
1,4-dihydroquinoline-3-carboxylic acid is disclosed. <Characteristics of the present invention> The present invention relates to a novel antibacterial agent having the following formula:

[Formula] However, R is a halogen-selected or hydroxy-substituted phenyl. R ₁ is hydrogen or a carboxy protecting group. Z is the formula:

[Formula] [However, R ₆ is hydrogen or C ₁ to C ₁₀ alkyl or a corresponding substituted derivative thereof, and
R ₇ is the alkyl or substituted alkyl shown above for R ₆ , or an amino group, mono-(C ₁ -
_C6 ) alkylamino group or di-( _C1 - _C6 ) alkylamino group]. Alternatively, Z can be a pyridyl group or an aliphatic heterocycle containing 4 to 7 atoms and preferably 5 to 6 atoms and substituted derivatives thereof. W and X are independently selected from hydrogen or halogen; when Z is not pyridyl, W is halogen. Furthermore, X and Z can be taken together to form a methylenedioxy bridge, in which case W is hydrogen. As used herein, the term "halogen" refers to chloro, bromo, fluoro and iodo groups, and the term "C ₁ to C ₆ alkyl" refers to lower alkyl groups including methyl, ethyl, propyl, isopropyl, butyl, etc. Point. As used herein, the term "carboxy-protecting group" refers to and includes the residue of a carboxylic ester group. Such carboxy-protecting groups are well known to those skilled in the art and are described in U.S. Pat.
It is widely used in the field of penicillins and cephalosporins to protect carboxyl groups, as described in No. 3,719,667, the disclosure of which is incorporated herein by reference. Ordinarily, such carboxy-protecting groups are relatively easily cleaved to yield the corresponding free carboxy group. Typical protecting groups include C ₁ to C ₃ alkyl (e.g. methyl, ethyl, tert-butyl), benzyl and substituted derivatives thereof such as alkoxy and nitrobenzyl groups; acyloxyalkyl groups such as hivaloyloxymethyl groups are also included. preferable. According to a preferred embodiment of the present invention, the aliphatic heterocycle represented by Z contains one or two heteroatoms selected from the group consisting of S, O, N and combinations thereof; Aliphatic heterocycles in which the remaining (ring) atoms of the group heterocycles are carbon atoms, and substituted derivatives thereof. According to the practice of this invention, the aliphatic heterocycle has the formula:

[However, R ₈ is dimethylene and the formula −CH ₂ −R ₉ −
CH ₂ - (wherein R ₉ is -S-, -O-, -N- and -
selected from the group consisting of CH ₂ -). In addition, one or more substituents
_C1 to _C6 alkyl group, formula:

[Formula] [However, R ₁₀ and R ₁₁ are each independently hydrogen, C ₁ to C ₆ alkyl, C ₁ to C ₆ hydroxyalkyl, hydroxy, alkanoyl containing 1 to 6 carbon atoms, 1 to Also included are substituted derivatives of such heterocycles having an amine group selected from the group consisting of alkanoylamides containing 6 carbon atoms. Examples of such heterocyclic groups include azetidinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholino, thiomorpholino and homopiperazinyl (ie, hexahydro-1-H-1,4-diazepinyl). The pyridyl group representing Z is of the formula

[Formula] [However, R ₁₂ is one or more hydrogen, halogen, C ₁ ~
C ₆ alkyl (including derivatives thereof)]
has. As will be understood by those skilled in the art, the pyridyl group at position 7 may be substituted or unsubstituted. Suitable substituents on the pyridine ring include _C1 - _C6 alkyl, halogen, -Y- _R3 groups of the above formula, C1 _{-C6 alkyl} ,
Included are _C6 alkanoyl or _C1 - _C6 alkanoylamide. Included within the scope of this invention are pharmaceutically acceptable salts of the aforementioned compounds. The term "pharmaceutically acceptable salts" as used herein refers to non-toxic acid addition salts and alkaline earth metal salts of compounds of formula.
These salts can be prepared in-house during the final release and purification of the compound of formula, or separately by reacting the free base or acid function with a suitable organic acid or base. Typical oxidative addition salts include hydrochloride, hydrobromide, sulfate, bisulfate, acetate, oxalate, vallate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, mesylate, citrate, maleate, Included are fumarate, succinate, tartrate, glucohepetonate, lactobionate, lauryl sulfonate salts and the like. Representative alkali or alkaline earth metal salts include sodium, calcium, potassium and magnesium salts, and the like. It has been found that the compounds of the invention have antibacterial activity against a broad spectrum of Gram-positive and Gram-negative bacteria as well as enterobacteria. Accordingly, the compounds of the present invention are useful in the antibiotic treatment of infectious bacterial infections in humans as well as in animals. Furthermore, in view of its in vitro activity, this compound can be used as a cleaning solution for surface inhibition of microbial growth. Infectious bacteria, the growth of which can be inhibited by the compounds of the invention, include generally Gram-positive and Gram-negative, aerobic and anaerobic bacteria such as Staphylococcus, Lactobacillus, Streptococcus, Sarcina, Escherichia, Entrobacter, Klebsiella. , Pseudomonas, Acinetobacter,
Included are Proteus, Citrobacter, Nitzeria, Bacillus, Bacteroides, Peptococcus, Clostridium, Salmonella, Shigella, Serratia, Haemophilus, Brucella and other microorganisms. In addition to exhibiting highly effective antibiotic activity, the compounds of the present invention are superior to the prior art quinoline-
Shows increased and improved solubility compared to 3-carboxylic acid compounds. The compounds of the formula can also be formulated into compositions with pharmaceutically acceptable carriers for oral administration, rectal administration, etc. in parenteral injection solid and liquid forms. Compositions for parenteral injection according to the invention may be pharmaceutically acceptable sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of suitable non-aqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable organic esters such as ethyl oleate. Such compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. They can be sterilized, for example, by passing through sterile paper or by including a disinfectant in the composition. They can also be prepared in the form of sterile solid compositions that can be dissolved in sterile water or other sterile injectable media immediately before use. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is combined with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may, in common embodiments, also include third substances other than diluents, such as lubricants such as magnesium stearate. Buffers may also be included in the dosage form in the case of capsules, tablets, and pills. Tablets and pills can also be prepared in enteric coated form. Liquid dosage forms for oral administration include active diluents commonly used in the art, such as water.
pharmaceutically acceptable emulsions, solutions, suspensions,
Includes syrups and elixirs. Besides such inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents. Compositions for rectal administration are preferably suppositories which may contain, in addition to the active substance, excipients such as cocoa butter or suppository waxes. The actual dosage of active ingredient in the compositions of the invention may vary to obtain an amount of active ingredient effective to achieve antibiotic activity depending on the desired method of administration.
The selected dosage will therefore vary depending on the nature of the active compound administered, the route of administration, the desired duration of treatment and other factors. Generally, when administered orally to a mammalian subject suffering from an infection caused by a contagious bacterium, about 0.1 to 750, more preferably about 0.25 to 500, and most preferably about
Daily dosages of a compound of formula 0.5 to about 300 mg of active ingredient are effective. If desired, the daily dose may be divided into several doses for administration, eg, 2 to 4 doses per day. The above description will be better understood from the following examples, which are given for illustrative purposes and are not intended to limit the scope of the inventive concept. <Example> Example 1 1-phenyl-6,8-difluoro-1,4-
Dihydro-4-oxo-7-(1-piperidinyl)-quinoline-3-carboxylic acid (a) 30 g of 2, in 400 ml of diethyl carbonate
To a cold solution of 3,4,5-tetrafluoroacetophenone was added variously 12.5 g of a suspension of 60% sodium hydride in oil. this mixture
It was heated at 80° C. for 11/2 hours and then poured into 700 ml of ice-cold water containing 25 ml of acetic acid. This mixture was extracted three times with 400 ml each of ether. The organic phase was dried over MgSO ₄ and the evaporated liquid was distilled to give ethyl 2,3,4,5-tetrafluorobenzoylacetate. (b) 18.5 ml of triethyl orthoformate and
A solution of the above product (a) in 45 ml of acetic anhydride was dissolved at 135 ml.
C. for 11/2 hours, this heating being done to remove the ethyl acetate formed during the reaction. The solution was evaporated under reduced pressure to obtain a fluid oil. This oil was then dissolved in 200 ml of methylene chloride and 9.9 ml of aniline was added to this solution. After 1 hour the solution was evaporated to dryness and crystallized from 200 ml hexane and 5 ml ether to give ethyl 3-anilino-2.
-(2,3,4,5-tetrafluorobenzoyl)acrylate was obtained. (c) To a cold solution of 15 g of the above acrylate (b) in 150 ml of tetrahydrofuran (THF) is added 1.63 g of
A suspension of 60% sodium hydride in oil was slowly added. The mixture was refluxed for 6 hours, then cooled and diluted to 1.5 volumes with water. The mixture was then washed with a 1:1 hexane/ether solution to give ethyl 1-phenyl-6,7,
8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate was obtained. (d) A suspension of 7 g of product (c) in 30 ml of THF,
Sodium hydroxide solution (0.88 in 20 ml H ₂ O
g) was added. The mixture was heated at 80° C. for 1 hour to obtain a clear solution. The solution was evaporated to dryness under reduced pressure. The resulting solid was dissolved in 200 ml of water and 2.5 ml of acetic acid was added. The generated precipitate was washed with cold water and recrystallized from dimethylformamide to obtain 1-phenyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid. (e) 2.5 g of 1-phenyl-6,7,8-trifluoro-1,4-dihydro-4-oxo- in 15 ml of 1-methyl-2-pyrrolidinone at 115°C.
To the solution of quinoline-3-carboxylic acid was added 3 ml of piperazine. After stirring at 100℃ for 2 hours,
The solvent was removed under reduced pressure and dried. Ethanol was added to the residue and the resulting mixture was filtered and washed with ether and then a very small amount of cold water to give a solid. This was suspended in 30ml H ₂ O and 7.8ml
of IN-HCl and dissolved by heating. Remove the solvent under reduced pressure to give 1-phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7.
-(1-piperazinyl)quinoline-3-carboxylic acid hydrochloride was obtained. To this hydrochloride was added 1 molar equivalent of an aqueous sodium hydroxide solution, and the resulting 1-phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)- Quinoline-3-carboxylic acid was obtained. (f) Alternatively, the title compound was prepared as follows. A suspension of 5 g of 1(d) product in 40 ml of 1-methyl-2-pyrrolidinone was added under nitrogen atmosphere.
At 120°C, 9.5 ml of N-carboethoxy
Piperazine was added. After 20 hours, the solvent was removed under reduced pressure and the residue was suspended in 150 ml of ethanol and refluxed for 1/2 hour. The reaction mixture was then cooled and filtered. The resulting solid was washed with cold ethanol and water to give 1-phenyl-6,8-difluoro-
7-(4-carboethoxy-1-piperazinyl)
-1,4-dihydro-4-oxo-quinoline-
3-carboxylic acid was obtained. To a suspension of 5 g of the above compound in 25 ml of ethanol at 80° C., 50 ml of 10% NaOH solution was added.
The solution was heated at 80°C for 6 hours. The solvent was removed and the solid was dissolved in 100ml water. The pH of the solution was adjusted to PH7 by addition of 10% acetic acid. The precipitate was filtered and washed with cold water to give 1-phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7.
-(Piperazinyl)-quinoline-3-carboxylic acid was obtained. (g) As an alternative to method 1(a), ethyl-2,3,
4,5-tetrafluorobenzoyl acetate was produced as follows. To a solution of 39 g of 2,3,4,5-tetrafluorobenzoic acid in 200 ml of methylene chloride was added 40 ml of thionyl chloride and 2 drops of dimethylformamide. After 3 hours of reflux, the reaction mixture was evaporated to dryness to yield the corresponding acid chloride. 379 of 1.4 M n-butyllithium in THF to a dry ice-cooled solution of 35 g malonic acid monoethyl ether in 350 ml of tetradrofuran.
ml was added and the flask was warmed to -5°C and then cooled again to -70°C. The acid chloride obtained above in 100 ml of THF was added to the resulting solution. The cooling bath was removed and the solution was allowed to warm to room temperature after one hour. The solution was then partitioned between 1N HCl and ether. Wash the ether part with _NaHCO3 ,
Drying over MgSO ₄ and then evaporation gave ethyl 2,3,4,5-tetrafluorobenzoylacetate. Example 2 1-phenyl-6,8-difluoro-1,4-
Dihydro-4-oxo-7-(1-(4-methyl)piperazinyl)-quinoline-3-carboxylic acid The procedure of Example 1 was repeated by replacing piperazine in Example 1(e) with N-methylpiperazine, and 1-phenyl -5,8-difluoro-1,4-dihydro-4
-Oxo-7-(1-(4-methyl)piperazinyl)-quinoline-3-carboxylic acid and its hydrochloride were obtained. Example 3 1-phenyl-6,8-difluoro-1,4-
Dihydro-4-oxo-7-(1-pyrrolidinyl)-quinoline-3-carboxylic acid Replacing piperazine in Example 1(e) with pyrrolidine,
In the same manner as in Example 1, 1-phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(pyrrolidinyl)-quinoline-3-carboxylic acid was obtained in good yield. Example 4 1-phenyl-6,8-difluoro-1,4-
Dihydro-4-oxo-7-(3-hydroxy-1-pyrrolidinyl)-quinoline-3-carboxylic acid Example 1 is repeated by replacing piperazine in Example 1(e) with 3-hydroxy-pyrrolidine, and 1-
Phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3-hydroxy-1-pyrrolidinyl)-quinoline-3-carboxylic acid was obtained. Example 5 1-phenyl-6,8-difluoro-1,4-
dihydro-4-oxo-7-(3-amino-1
-pyrrolidinyl)-quinoline-3-carboxylic acid 1-Phenyl-6,8-difluoro-1,4-dihydro-
4-oxo-7-(3-acetamido-1-pyrrolidinyl)-quinoline-3-carboxylic acid was obtained in good yield. (b) The above reaction product was then hydrolyzed with hydrochloric acid at 80°C to obtain 1-phenyl-6,8-difluoro-
1,4-dihydro-4-oxo-7-(3-amino-1-pyrrolidinyl)-quinoline-3-carboxylic hydrochloride was obtained. Example 6 1-phenyl-6,8-difluoro-1,4-
Dihydro-4-oxo-7-(1-piperidinyl)-quinoline-3-carboxylic acid 1-phenyl-6,8
-difluoro-1,4-dihydro-4-oxo-
7-(1-piperidinyl)-quinoline-3-carboxylic acid was obtained. Example 7 1-phenyl-6,8-difluoro-1,4-
Dihydro-4-oxo-7-(4-morpholinyl)-quinoline-3-carboxylic acid Replacing piperazine in Example 1(e) with morpholine,
1-phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(4
-morpholinyl)-quinoline-3-carboxylic acid was obtained in good yield. Example 8 1-phenyl-6,8-difluoro-1,4-
Dihydro-4-oxo-7-(4-thiomorpholinyl)-quinoline-3-carboxylic acid 1-Phenyl-6,8-
Difluoro-1,4-dihydro-4-oxo-7
-(4-thiomorpholinyl)quinoline-3-carboxylic acid was obtained. Example 9 1-phenyl-6,8-difluoro-1,4-
Dihydro-4-oxo-7-(3,5-dimethyl-1-piperazinyl)-quinoline-3-carboxylic acid 1 as in Example 1, replacing piperazine in Example 1(e) with 2,6-dimethylpiperazine. -phenyl-6,8-difluoro-1,4-dihydro-4-
Oxo-7-(3,5-dimethyl-1-piperazinyl)-quinoline-3-carboxylic acid and its hydrochloride were obtained. Example 10 1-phenyl-6,8-difluoro-1,4-
Dihydro-4-oxo-7-1-homopiperazinyl)-quinoline-3-carboxylic acid 1-phenyl-
6,8-difluoro-1,4-dihydro-4-oxo-7-(1-homopiperazinyl)-quinoline-3-carboxylic acid and its hydrochloride were obtained. Example 11 1-phenyl-6,8-difluoro-1,4-
Dihydro-4-oxo-7-(dimethylamino)
-Quinoline-3-carboxylic acid 1-Phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-
(Dimethylamino)quinoline-3-carboxylic acid was obtained. Example 12 1-phenyl-6,8-difluoro-1,4-
Dihydro-4-oxo-7-(N-2-hydroxyethylamino)-quinoline-3-carboxylic acid Repeat Example 1 by replacing piperazine in Example 1(e) with N-2-hydroxyethylamine;
1-phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(N-2-hydroxyethylamino)-quinoline-3-carboxylic acid was obtained. Example 13 1-phenyl-6,8-difluoro-1,4-
Dihydro-4-oxo-7-hydrazyl-quinoline-3-carboxylic acid Replacing piperazine in Example 1(e) with hydrazine,
In the same manner as in Example 1, 1-phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(hydrazyl)-quinoline-3-carboxylic acid and its hydrochloride were obtained. Example 14 1-phenyl-6,8-difluoro-1,4-
1-Phenyl -6,8-difluoro-1,4-dihydro-4-oxo-7-(2,2-dimethylhydrazyl)-quinoline-3-carboxylic acid and its hydrochloride were obtained. Example 15 1-p-fluorophenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1
-piperazinyl)-quinoline-3-carboxylic acid (a) Ethyl 3-(p-fluoroanilino)-2-(2,3,4 , 5-tetrafluorobenzoyl) acrylate was obtained. (b) Compound (a) above was treated analogously to Example 1(c) and Example 1(d) to obtain 7-fluoro-1-p-fluorophenyl-6,8-difluoro-1,4-dihydro- 4-oxo-quinoline-3-carboxylic acid was obtained. (c) Compound (b) above was treated in the same manner as in Example 1(e) to give 1-
p-fluorophenyl-6,8-difluoro-
1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid and hydrochloride were obtained. Example 16 The acid is replaced by the acid of the product of Example 15(b) and the piperazine is replaced with a suitable amine such as n-methylpiperazine, pyrrolidine, 3-hydroxy-pyrrolidine, 3-acetaminopyrrolidine, piperidine,
The following compound was obtained in the same manner as in Example 1(e), substituting morpholine, thiomorpholine, 2,6-dimethylpiperazine, homopiperazine, diethylamine and 2,2-dimethylhydrazine. (a) 1-p-fluorophenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-
(1-(4-methyl)piperazinyl)-quinoline-3-carboxylic acid. (b) 1-p-fluorophenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-
(1-pyrrolidinyl)-quinoline-3-carboxylic acid. (c) 1-p-fluorophenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-
(3-hydroxy-1-pyrrolidinyl)quinoline-3-carboxylic acid. (d) 1-p-fluorophenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-
(3-acetamino-1-pyrrolidinyl)-quinoline-3-carboxylic acid. (e) 1-p-fluorophenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-
(1-piperidinyl)-quinoline-3-carboxylic acid. (f) 1-p-fluorophenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-
(4-morpholinyl)-quinoline-3-carboxylic acid. (g) 1-p-fluorophenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-
(4-thiomorphonyl)-quinoline-3-carboxylic acid. (h) 1-p-fluorophenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-
(3,5-dimethyl-1-piperazinyl)-quinoline-3-carboxylic acid. (i) 1-p-fluorophenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-
(1-Homopiperazinyl)-quinoline-3-carboxylic acid. (j) 1-p-fluorophenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-
(diethylamino)-quinoline-3-carboxylic acid. (k) 1-p-fluorophenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-
(2,2-dimethylhydrazyl)-quinoline-3
-Carboxylic acid. Example 17 1-p-fluorophenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3
-amino-1-prolidinyl)-quinoline-3
-carboxylic acid The compound of Example 16(d) is treated as in Example 5(b) to give 1-
p-fluorophenyl-6,8-difluoro-
1,4-dihydro-4-oxo-7-(3-amino-1-pyrrolidinyl)-quinoline-3-carboxylic acid was obtained. Example 18 1-p-hydroxyphenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-
(1-piperazinyl)-quinoline-3-carboxylic acid (a) replacing aniline with hydroxyaniline,
Ethyl 3-(p-hydroxyanilino)-2-(2,3,4,5-tetrafluorobenzoyl)acrylate was obtained in the same manner as in Example 1(b). (b) The compound of (a) above is treated as in Examples 1(c) and 1(d) to give 7-fluoro-1-phydroxyphenyl-6,8-difluoro-1,4-dihydro-4 -Oxo-quinoline-3-carboxylic acid was obtained. (c) The acid of (b) above is treated as in Example 1(e) to give 1-p
-Hydroxyphenyl-6,8-difluoro-
1,4-dihydro-4-oxo-7-(1-piperazinyl)quinoline-3-carboxylic acid and its hydrochloride were obtained. Example 19 Replace the acid with the acid of the product of Example 18(b) and replace piperazine with a suitable acid such as N-methylpiperazine, pyrrolidine, 3-hydroxypyrrolidine, 3-acetamidopyrrolidine, piperidine, morpholine,
thiomorpholine, 2,6-dimethylpiperazine,
Homopiperazine, dimethylamine and 2,2-
The following compound was obtained in the same manner as in Example 1(e) except that dimethylhydrazine was substituted. (a) 1-p-hydroxyphenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-
(1-(4-methyl)piperazinyl-quinoline-
3-carboxylic acid and its hydrochloride. (b) 1-p-hydroxyphenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-
(1-pyrrolidinyl)-quinoline-3-carboxylic acid. (c) 1-p-hydroxyphenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-
(3-hydroxy-1-pyrrolidinyl)-quinoline-3-carboxylic acid. (d) 1-p-hydroxyphenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-
(3-acetamido-1-pyrrolidinyl)-quinoline-3-carboxylic acid. (e) 1-p-hydroxyphenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-
(1-piperidinyl)-quinoline-3-carboxylic acid. (f) 1-p-hydroxyphenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-
(4-Homophorinyl)-quinoline-3-carboxylic acid. (g) 1-p-hydroxyphenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-
(4-Thiohomophorinyl)-quinoline-3-carboxylic acid. (h) 1-p-hydroxyphenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-
(3,5-dimethyl-1-piperazinyl)-quinoline-3-carboxylic acid. (i) 1-p-hydroxyphenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-
(1-Homopiperazinyl)-quinoline-3-carboxylic acid. (j) 1-p-hydroxyphenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-
(diethylamino)-quinoline-3-carboxylic acid. (k) 1-p-hydroxyphenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-
(2,2-dimethylhydrazinyl)-quinoline-
3-carboxylic acid. Example 20 1-p-hydroxyphenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-
(3-amino-1-pyrrolidinyl)quinoline-
3-carboxylic acid The compound of Example 18(d) is treated as in Example 5(b) to give 1-
p-hydroxyphenyl-6,8-difluoro-
1,4-dihydro-4-oxo-7-(3-amino-1-pyrrolidinyl)-quinoline-3-carboxylic acid was obtained. Example 21 The 1 _- substituted-6,7,8-trifluoro-
1,4-dihydro-4-oxo-quinoline-3-
Carboxylic acid was obtained.

【table】

[Table] Cyaniline Cifenil
Example 22 The acid is replaced by the acid of the compound listed in the table of Example 21, and the piperazine is replaced by a suitable amine such as N-methylpiperazine, pyrrolidine, 3-hydroxypyrrolidine, 3-acetamidopyrrolidine, 3-dimethylaminopyrrolidine, piperidine, morpholine, The compounds shown in Table 1 were obtained as in Example 1(e) by substituting thiomorpholine, 2,6-dimethylpiperazine, homopiperazine, dimethylamine, and 2,2-dimethylhydrazine.

[Table] Nil
Niru

[Table] Phenyl
phenyl
Example 28 Compounds (11) and (12) of Example 22 were converted as in Example 5(b) to compounds (a) and (b) below, respectively. (a) 1-o-fluorophenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-
(3-amino-1-pyrrolidinyl)quinoline-
3-carboxylic acid. (b) 1-p-methylphenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3
-amino-1-pyrrolidinyl)quinoline-3-
carboxylic acid. Example 24 1-Phenyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-pyridyl)-quinoline-3-carboxylic acid (a) 2-chloro-4-( 25 g of a cold solution of 4-pyridyl)-5-fluoroacetophenone was slowly added to 80 g of a suspension of 60% sodium hydride in oil. The mixture was heated at 80° C. for 3 hours and then poured into 700 ml of an ice-cold aqueous solution containing 25 ml acetic acid. This mixture was extracted three times with 400 ml each of ether. The organic phase was dried over _MgSO4 , evaporated and the resulting oil was purified in a silica gel column to yield pure ethyl-2-chloro-4-(4-pyridyl)-5-fluorobenzoylacetate. (b) 14 ml of triethyl orthoformate and 35
A solution of 15 g of the above ethyl-2-chloro-4-(4+pyridyl)-5-fluorobenzoylacetate in ml of acetic anhydride was heated at 135° C. for 11/2 hours, and this heating was combined with the ethyl acetate formed during the reaction. This was done while removing. The solution was evaporated under reduced pressure to obtain a free-flowing oil, which was then dissolved in 150 ml of methylene chloride.
7.5 ml of aniline was added to this solution. After 1 hour, the solution was evaporated to dryness to give ethyl 3-anilino-
2-[2-chloro-4-(4-pyridyl)-5-
Fluorobenzoyl]acrylate was obtained. (c) To a cold solution of 13 g of the above product in 140 ml of tetrahydrofuran (THF) was slowly added 1.25 g of a 60% suspension of sodium hydride in oil. The mixture was refluxed for 6 hours, then cooled and diluted to 1.5 with water. The mixture was then filtered and the solid washed with a 1:1 hexane/ether solution to give ethyl 1-phenyl-6-fluoro-1,4-dihydro-4-oxo-7-
(4-pyridyl)quinoline-3-carboxylate was obtained. (d) To a suspension of 5 g of the above product (c) in 300 ml of THF, add sodium hydroxide solution ( ₂₀ ml H
0.63 g) in O was added. The mixture was heated at 80° C. for 2 hours to obtain a clear solution. The solution was evaporated to dryness under reduced pressure. 200ml of the obtained solids
Dissolved in H ₂ O and added 2 ml of acetic acid. The resulting precipitate was filtered and washed with cold water to obtain 1-phenyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-pyridyl)-quinoline-3-carboxylic acid. Example 25 1-p-fluorophenyl-6-fluoro-
1,4-dihydro-4-oxo-7-(4-pyridyl)quinoline-3-carboxylic acid The procedure of Example 24 was repeated by replacing aniline with p-fluorophaniline in Example 24(b), and 1-p- Fluorophenyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-pyridyl)quinoline-3-carboxylic acid was obtained. Example 26 1p-Hydroxyphenyl-6-fluoro-1,4-dihydro-4-
Oxo-7-(4-pyridyl)quinoline-3-carboxylic acid was obtained. Example 27 The procedure of Example 24 was repeated by substituting p-methoxyaniline for aniline in Example 24(b), and 1-p-methoxyphenyl-6-fluoro-1,4-dihydro-4-oxo-7-(4 -pyridyl)quinoline-
3-carboxylic acid was obtained. Example 28 The aniline of Example 24(b) can be converted to various amines (R-NH ₂ ).
and 1-substituted-6-fluoro-1,4-dihydro- as shown in the table below in the same manner as in Example 24.
4-oxo-7-(4-pyridyl)quinoline-3
-carboxylic acid was obtained.

[Table] Rin Niru

[Table] Cyaniline xyphenyl
Example 29 2-chloro-4-(4-pyridyl)-5 of Example 24(a)
-fluoroacetophenone to 2-chloro-4-
1-p-fluorophenyl-1,4-dihydro-4-oxo -7-
(4-pyridyl)-quinoline-3-carboxylic acid was obtained. Example 30 1-phenyl-6,8-methylenedioxy-4
-Oxo-1,4-dihydroquinoline-3-carboxylic acid (a) in 25 ml of tetrahydrofuran (THF)
To a dry ice-cooled solution of 0.85 g of malonic acid monoethyl ester was slowly added 9.2 ml of 1.4 M n-butyllithium in THF, and the flask was
Warmed to 5°C. After 5 minutes the solution was cooled again to -70°C. 1 g of acid chloride i.e. 3,
After adding 4-methylenedioxy-5-bromobenzoyl chloride, the cooling bath was removed and the mixture was warmed to room temperature over 1 hour. The solution was then partitioned between IN-HCl and ether.
The ethereal portion was washed with NaHCO ₃ , dried over MgSO ₄ and then evaporated to give 1 g of pale yellow oil. This oil was then purified on a silica gel column eluting with 15% ethyl acetate in hexane to yield 0.89 g of the β-ketoester ethyl 3,4-methylenedioxy-6-bromoacetate. (b) A solution of 1 g of the above β-ketoester dissolved in 0.8 ml of triethyl orthoformate and 5 ml of acetic anhydride was heated at 135°C for 11/2 hours, and this heating was used to remove the ethyl acetate produced during the reaction. I did it while doing so. The solution was evaporated under reduced pressure to obtain a fluid oil. Next, dissolve this oil in 5 ml of methylene chloride and add 0.3 ml.
of aniline was added to this solution. After 1 hour the solution was evaporated to dryness and crystallized from ethyl acetate, yielding 1.1 g of ethyl 3-anilino-2-
(3,4-methylenedioxy-5-bromobenzoyl)acrylate was obtained. Melting point 144-146
℃. (c) 0.19 g of 60% of the above product in a cold solution of 3 g in 30 ml of tetrahydrofuran (THF).
A suspension of sodium hydride in oil was slowly added. The mixture was refluxed for 2 hours, then cooled and diluted to a volume of 100ml with water. The mixture was then filtered and the solids washed with 1:1 hexane/ether solution to remove 2.38 g of ethyl 1-phenyl-6,7-methylenedioxy-1,4-dihydro-4-oxo-quinoline-3. -carboxylate was obtained. Melting point 275-276℃. (d) A suspension of 1.6 g of the above product in 20 ml of THF was added with sodium hydroxide solution (20 ml H ₂ O
0.23g) was added. The mixture was heated at 80° C. for 2 hours to obtain a clear solution. The solution was evaporated to dryness under reduced pressure. The resulting solid was dissolved in 200 ml of H ₂ O.
1 ml of acetic acid was added. The formed precipitate was filtered and washed with cold water to obtain 1.4 g of 1-phenyl-6,7-methylenedioxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. Melting point >300℃. Example 31 1-p-fluorophenyl-6,7-methylenedioxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid Example 30 replacing aniline in Example 30(b) with p-fluoroaniline Repeat this operation to obtain 1-p-fluorophenyl-6,7-methylenedioxy-4-
Oxo-1,4-dihydroquinoline-3-carboxylic acid was obtained. Example 32 1-p-Hydroxyphenyl-6,7-methylenedioxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid Replacing aniline in Example 30(b) with p-hydroxyaniline, Example 30 In the same manner as above, 1-p-hydroxyphenyl-6,7-methylenedioxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid was obtained. Example 33 1-p-Methoxyphenyl-6,7-methylenedioxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid Example 30 replacing aniline in Example 30(b) with p-methoxyaniline Repeat this operation to obtain 1-p-methoxyphenyl-6,7-methylenedioxy-4-
Oxo-1,4-dihydro-quinoline-3-carboxylic acid was obtained. Example 34 The aniline of Example 30(b) can be converted to various amines (R-NH ₂ ).
and 1-substituted-6,7-methylenedioxy-4- shown in the table below in the same manner as in Example 30.
Oxo-1,4-dihydroquinoline-3-carboxylic acid was obtained.

[Table]

[Table] Cyaniline Cifenil
It will be understood that many changes and modifications may be made in details of formulation, operation and use without departing from the spirit of the invention as claimed.

Claims (1)

[Claims] 1 Formula: [Formula] [However, R ₁ is hydrogen or a carboxy protecting group; R is a halogen-substituted or hydroxy-substituted phenyl group; Z is pyridyl or contains 4 to 7 atoms aliphatic heterocycle and substituted derivatives thereof, formula: [Formula] {wherein R ₆ is hydrogen or C ₁ to C ₁₀ alkyl and substituted derivatives thereof, and R _{7 is}
C ₁₀ alkyl and its substituted derivatives, amine groups, mono-(C ₁ to C ₆ )alkylamino groups and di-(C ₁
from the group consisting of an amino group having a C ₆ ) alkylamino group; W and X are independently selected from hydrogen or halogen; W is halogen when not pyridyl; and X and Z can also be taken together to form a methylenedioxy bridge, in which case W is hydrogen, and a pharmaceutically acceptable compound That salt. 2 Aliphatic heterocycle has the structure [Formula] [However, R ₈ is dimethylene or the formula -CH ₂ -R _9
-CH2- (wherein _R9 is selected from the group consisting of -S-, -O- and -N-)]
A compound according to claim 1 having the following. 3 aliphatic heterocycle is C ₁ to C ₆ alkyl, C ₁ to C ₆ hydroxyalkyl, hydroxy, alkanoyl containing 1 to 6 carbon atoms, alkanoylamide containing 1 to 6 carbon atoms, and the formula: [Formula] [However, R ₁₀ and R ₁₁ are each independently selected from the group consisting of hydrogen, C ₁ to C ₆ alkyl, and substituted derivatives thereof]; or The compound according to claim 1, which is substituted with two or more substituents. 4 Z is the formula [Formula] [However, R ₆ is hydrogen or a C ₁ to C ₁₀ alkyl or a substituted derivative thereof, and R ₇ is a C ₁ to C ₁₀ alkyl, a substituted derivative thereof, an amino group,
Mono-(C ₁ -C ₄ )alkylamino group or di(C ₁
The compound according to claim 1, which is an amino group having a _C4 ) alkylamino group]. 5 Z is the formula [Formula] [However, one or more hydrogen, halogen or C ₁
to C ₆ alkyl, formula -Y-R ₃ (in the formula, Y is -O
- or -S- and R ₃ is lower alkyl), hydroxy, alkanoyl containing 1 to 6 carbon atoms, alkanoylamide containing 1 to 6 carbon atoms, and groups of the formula R ₁₀ and R ₁₁ in the formula each independently represent hydrogen,
The compound according to claim 1, which is substituted with a substituent selected from the group consisting of amines selected from the group consisting of C ₁ to C ₆ alkyl and substituted derivatives thereof. 6 R is p-fluorophenyl, Z is piperazinyl, X and W are fluoro,
2. A compound according to claim 1, wherein R ₁ is hydrogen. 7 R is p-fluorophenyl and Z is 4-
The compound according to claim 1, which is methylpiperazinyl, X and W are fluoro, and R ₁ is hydrogen. 8 R is hydroxyphenyl, Z is piperazinyl, X and W are fluoro,
2. A compound according to claim 1, wherein R ₁ is hydrogen. 9 R is o,p-difluorophenyl, Z
2. A compound according to claim 1, wherein is piperazinyl, X and W are fluoro, and R ₁ is hydrogen. 10 R is p-fluorophenyl, R ₁ ,
A compound according to claim 1, wherein X and W are hydrogen and Z is 4-pyridyl. 11. The compound according to claim 1, wherein R is p-fluorophenyl, R ₁ and W are hydrogen, and Z is 4-pyridyl. 12 R is p-hydroxyphenyl, R ₁
and W is hydrogen, X is fluoro, and Z
The compound according to claim 1, wherein is 4-pyridyl. 13. The compound according to claim 1, wherein X and Z together form a methylene dioxane bridge and W is hydrogen. 14. The compound according to claim 13, wherein 14R is p-fluorophenyl and _R1 is hydrogen. 15. The compound according to claim 1, wherein R ₁ is hydrogen, R is p-fluorophenyl, X and W are fluoro, and Z is 3-amino-1-pyrrolidinyl.