JPS60163866A - Quinoline fungicidal compound - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION <Field of Industrial Applications> 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> It is publicly available that certain quinoline compounds exhibit antibacterial properties, particularly that certain 7-biperazinyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acids exhibit antibacterial properties. be. U.S. Pat. No. 4,017,622 describes certain 7-biperazinyl-4-oxo-1,4
-dihydroquinoline-3-carboxylic acid derivatives are disclosed. U.S. Pat. No. 4,292,317 describes 7-biperazinyl-4-oxo-1,4-dihydroquinoline-substituted with an alkyl or vinyl substituent in the 1-position.
3-carboxylic acid derivatives are disclosed. US Patent No. 4
, 284,629 discloses various 4-oxo-1,4-dihydroquinoline-3-carboxylic acids substituted at the 1-position with a cycloalkyl substituent.

Features of the Invention The present invention relates to a novel antibacterial agent having the following formula: where R is 5 to 7 ring atoms having at least one S10 and N heteroatoms and the remainder being carbon atoms. aromatic heterocycle containing atoms; 13- (wherein R6 is one or more hydrogen, halogen, C1 to C including substituted derivatives thereof, alkyl, nitro,
carboxyl, cyano, methylenedioxy, formula -Y-R
, (in the same formula, -Y- is 10- or -8-, and R3 is hydrogen or C1 to C6 alkyl, and an amine having the formula: (in the same formula, R4 and R5 are each independently hydrogen or CI to C, alkyl)) phenyl groups;

R3 is hydrogen or a carboxy protecting group.

14- [where LARe is hydrogen or C8 to C1o alkyl and corresponding substituted derivatives thereof, and R1 is Ro
an amine group, a mono-(C,-C6)alkylamino group, or a di-(c,-c,)alkylamino group].

Alternatively, Z can be a pyridyl group or an aliphatic heterocycle containing 4 to 7 atoms and preferably 5 to 6 (1i!d) 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.

The term "aromatic hetero" used herein by Toyonaka refers to 5 to 7 rings.
Refers to a heterocyclic ring containing 3 atoms in the ring and selected from the group consisting of S, Q or N (or containing up to 2 heteroatoms and the remaining (ring) atoms being carbon atoms). Representative heterocyclic groups include pyridyl, pyrazinyl, thiazolyl, furyl, chenyl and substituted derivatives thereof. Substituents that may be present on the heterocycle include C1 to C6 alkyl groups, halogen groups or groups of the formula -Y- R, (wherein Y is as described above, and R5 is hydrogen or C1 to C, alkyl) are included.

As used herein, the term "halogen" refers to chloro, bromo, fluoro and iodo groups, and the term "C8 to C6
"Alkyl" refers to lower alkyl groups including methyl, ethyl, propyl, inpropyl, butyl, and the like.

As mentioned above, R1 can be C1 to C0 branched or straight chain alkyl and hydroxy and halo substituted derivatives thereof. Such groups include chloromethyl, chloroethyl, chloropropyl, hydroxyethyl, trifluoromethyl and the like.

Rt can also be a group of formula -y-R. Typical groups of this type include hydroxy groups, mercapto groups, lower alkoxy groups such as methoxy, ethoxy, propoxy, etc.
and its thio analogues, ie, methylmercapto and ethylmercapto groups.

As used herein, the term ``carboxy-protecting group'' refers to and includes the residue of a carboxylic acid ester group; however, carboxy-protecting groups are well known to those skilled in the art, as described in U.S. Pat. 840,556 and Kffi No. 3,719,667, it is used in the field of nipenicillins and cephalosporins to protect carboxyl groups, and the disclosure thereof is referred to. Carboxy-protecting groups that are incorporated into the screen are relatively easily cleaved to yield the corresponding free carboxy group. Typical protecting groups include C1 to C8 alkyl (e.g., methyl, ethyl, tertiary butyl), benzyl and its substituted derivatives such as alkoxy and nitrobenzyl groups; acyloxyalkyl groups such as hivaloyloxymethyl groups are also preferred.

According to a preferred embodiment of the invention, the aliphatic heterocycle represented by Z contains one or two heteroatoms selected from the group consisting of 8% O, N and combinations thereof; These include aliphatic heterocycles in which the remaining (ring) atoms of the aliphatic heterocycles are carbon atoms, and substituted derivatives thereof. According to the practice of the present invention [where R8 is dimethylene and the formula -〇Hx R
e CHt (wherein the group consisting of R, S-1-o-1-N- and -CH,- is selected from 18-); ]. Also, a C1 to C6 alkyl group having one or more substituents, formula: [However, R
Io and R1 are each independently hydrogen, C3 to C
, alkyl, CI to C, hydroxyalkyl, hydroxy, alkanoyl containing 1 to 6 carbon atoms,
Also included are substituted heterocyclic conductors with an amine group selected from the group consisting of alkanoylamides containing 1 to 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 has the formula [where R1 is one or more hydrogen, halogen, C1 to C6
alkyl (including derivatives thereof)].

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 CI'' C11 alkyl, halogen, a group of the above formula -Y-R, C1-C6 alkanoyl or C1
~C6 alkanoylamide is included.

Included within the scope of this invention are pharmaceutically acceptable salts of the aforementioned compounds. As used herein, the term "pharmaceutically acceptable salts" refers to non-toxic acid addition salts and alkaline earth metal salts of compounds of formula I. These salts are used in the final release and purification of compounds of formula They can sometimes be prepared in-house or separately by reacting the free base or acid function with a suitable organic acid or base. Typical acid addition salts include idrochloride, idrobromide, sulfate, and pisulfate. , acetate, oxalate, valerate,
Olate, palmitate, stearate, laurate,
borate, benzoate, lactate, phosphate,
tosylate, mesylate, cytolate, maleate,
Included are fumarate, succinate, tartrate, glucohepetonate, lactobionate, lauryl sulfonate salts and the like. Typical alkali or alkaline earth metal salts include sodium, calcium,
Included are 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 invention are useful in the antibiotic treatment of infectious bacterial infections in humans as well as in animals.

Additionally, in view of their in vitro activity, these compounds can be used as cleaning solutions for the inhibition of microbial growth on surfaces. Infectious bacteria, the growth of which can be inhibited by the compounds of the present invention, are generally gram-positive and gram-negative. , aerobic and anaerobic bacteria such as Staphylococcus, Lactobacillus, Streftococcus, Sarcina, Escherichia, Enlobacter, Klebsiella, Pseudomonas, Acinetobacter,
Proteus, Citrobacter, Nilaceria, Bacillus,
Bacteroides, Peptococcus, Clostridium,
Includes Salmonella, Shigella, Serratia, Haemophilus, Pulsella and other microorganisms. In addition to exhibiting highly effective antibiotic properties, the compounds of the present invention exhibit increased and improved solubility compared to prior quinoline-3-carboxylic acid compounds in the art.

Compounds of formula I can also be formulated into compositions with pharmaceutically acceptable carriers for oral administration, rectal administration, etc. in solid and liquid forms for parenteral injection.

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, and 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 filtration through sterile paper or by including a bactericide 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 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 pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents such as water commonly used in the art. 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 suppositories which may conveniently 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 effective amount of active ingredient 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 infectious disease caused by infectious bacteria, about 0.1 to 750 per body weight,
More preferably, a daily dosage of about 0.25 to about 500 and most preferably about 0.5 to about 300 m9 of active ingredient of a compound of formula I is 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 presented for illustrative purposes and are not intended to limit the scope of the inventive concept.

25- Examples Example L Carboxylic acid ((L) 400- to a cold solution of 30 g of 2.3.4.5-tetrafluoroacetophenone in diethyl carbonate to 12.59 of 60% sodium hydride in oil The suspension was added slowly.The mixture was heated to 13A at 80°C.
After heating for an hour, the mixture was poured into 700 ml of ice-cold water containing 25-acetic acid. This mixture was extracted three times with 400 ml of ether each time. The organic phase was Mg5O.

(b) 18. The resulting liquid was distilled to obtain ethyl 2°3.4.5-tetrafluorobenzoyl acetate. A solution of the above product (a) in s-triethyl orthoformate and 45-acetic anhydride was added to 1
Heating was carried out at 35° C. for 26 hours at 1% while removing 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-methylene chloride and α9-aniline was added to the solution. After 1 hour, the solution was evaporated to dryness and 2
Crystallization from 00-hexane and 5-ether gave ethyl 3-anilino-2-(2,3,4,5-tetrafluorobenzoyl)acrylate.

(c) To a cold solution of 15 g of the above acrylate (b) in 150 d of tetrahydrofuran (THF), 1.63 g
A suspension of 60% sodium hydride in oil was slowly added. The mixture was refluxed for 6 hours and then cooled to 1.51
! Diluted to volume with water. Then add 1 of this mixture
=1 hexane/ether A411F! iT: Washed ethyl 1-phenyl-6,7,8-)refluoro-1,4
-dihydro-4-oxo-quinoline-3-carboxylate was obtained.

(d) To a suspension of 7 g of product (c) in 30 THF was added sodium hydroxide solution (0.88.9 in 20 t111 H,O). The mixture was heated at 80° C. for 1 hour to obtain a clear solution. The solution was evaporated to dryness under reduced pressure. Add the generated solid to 2,001 tl of water.
A 2.5-acetic acid was added. The formed precipitate was washed with cold water and recrystallized from dimethylformamide to give 1-phenyl-6,7,8-)lifluoro-1,4-dihydro-
4-Kagisoquinoline-3-carboxylic acid was obtained.

(g) 2.5 g of 1-phenyl-6,7,8-)lifluoro-x,4-dihydro-4-oxo-quinoline-3- in 15-1-methyl-2-pyrrolidinone at 115°C.
To the solution of carboxylic acid was added 3t11t of piperazine. After stirring at 100° C. for 2 hours, the solvent was removed under reduced pressure and the mixture was dried. Ethanol was added to the residue and the resulting mixture was filtered, washed with ether and then a very small amount of cold water to give a solid. 7. Suspend this in 30-〇H,O.
The mixture was added to 8 liters of 1N-HC4 and dissolved by heating. Remove the solvent under reduced pressure to give 1-phenyl-6,8-difluoro-
The hydrochloride of 1,4-dihydro-4-oxo-7-(1-piperazinyl)quinoline-3-carboxylic acid was obtained.

To this hydrochloride was added 1 molar equivalent of an aqueous IJ solution, and the resulting precipitate was filtered to give 1-phenyl-6,8
-difluoro-1,4-dihydro-4-oxo-7-(
1-piperazinyl)-quinoline-3-carboxylic acid was obtained.

ω Alternatively, the title compound is prepared as follows: f, 1 in 40-1-methyl-2-pyrrolidinone
(d) Product 5! i suspension at 120°C under nitrogen atmosphere.
At , 9.5d of N-carboethoxy-piperazine was added. After 20 hours, the solvent was removed under reduced pressure and the residue was suspended in 150ml of ethanol and refluxed for 29% of the time. 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. I got it.

To a suspension of the above compound 5I in 25 d of ethanol at 80<0>C was added a 50-10X NaOH solution. 8 of the solution
Heated at 0°C for 6 hours. The solvent was removed and the solid was dissolved in 100-m water. The p of the solution is reduced by the addition of 10516 acetic acid.
The precipitate adjusted to pH 7 was washed with filtered cold water.
-Phenyl=6,8-difluoro-1,4-dihydro-
4-oxo-7-(piperazinyl)-quinoline-3-carboxylic acid was obtained.

(17) As an alternative method to method 1(α), ethyl-2,3
, 4,5-tetrafluorobenzoyl acetate was produced as follows. To a solution of 39 g of 2.3,4°30-5-tetrafluorobenzoic acid in 200-methylene chloride, 40-
of thionyl chloride and 2 drops of dimethylformamide were added. After 3 hours of reflux, the reaction mixture was evaporated to dryness to yield the corresponding acid chloride.

350ff17! of 35 g of malonic acid monoethyl ether in tetrahydrofuran, cooled with dry ice.
1.4M n-butyllithium 379 in THF was added and the flask was warmed to -5°C and then cooled again to -70°C. The acid chloride obtained above in THEIO - was added to the resulting solution.

The cooling bath was removed and the solution was allowed to warm to room temperature 1 after 1 hour. The solution was then partitioned between 1N-HCII and ether. Wash the ether part with NaHCO31. , M(
Dry over flo4 and evaporate to ethyl 2,3.4
．． 5-tetrafluorobenzoylacetate-I? I was.

Example 2 1-phenyl-6,8-difluoro-1,4-dihydro-Example 1 Repeat the procedure of Example 1 by replacing piperazine in (e) with N-methylbiperazine to obtain LA 1-phenyl-
6,8-difluoro-1,4-dihydro-4-oxo-
7-(1-(4-methyl)piperazinyl)-quinoline-
3-carboxylic acid and its hydrochloride were obtained.

Example a Carboxylic acid Example 1 Piperazine in (e) was replaced with pyrrolidine, and 1-phenyl-6,8-difluoro-1 was prepared in the same manner as in Example 1.
,4-dihydro-4-oxo-7-(pyrrolidinyl)-
Quinoline-3-carboxylic acid was obtained in good yield.

Example Repeat the procedure of Example 1 by substituting 3-hydroxy-pyrrolidine for piperazine in Example 1(e). 1-Phenyl-
6,8-difluoro-1,4-dihydro-4-oxo-
7-(3-hydroxy-1-pyrrolidinyl)-quinoline-3-carboxylic acid was obtained.

Example & 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 give 1-phenyl-6,8-difluoro-1+ 4
-dihydro-4-oxo-7-(3-amino-1-pyrrolidinyl)-quinoline-3-carboxylic hydrochloride was obtained.
Example 6 Example 1 by replacing piperazine in monocarboxylic acid Example 1 (6) with piperidine
The following procedure yielded 1-phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-piperidinyl)34-quinoline-3-carboxylic acid.

Example 7 Carboxylic Acid Example 1 Replace piperazine in (g) with morpholine and prepare 1-phenyl-6+ 8-difluoro-
1,4--)hydro-4-oxo-7-(4-morpholinyl)-quinoline-3-carboxylic acid was obtained in good yield.

Example a 3-Carboxylic acid Example 1 The procedure of Example 1 was repeated by replacing piperazine in (g) with thiomorpholine to give 1-phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(4 −
thiomorpholinyl)quinoline-3-carboxylic acid was obtained.

Example a 1-phenyl-6,8-
Difluoro-1,4-dihydro-4-oxo-7-(3
,5-dimethyl-1-piperazinyl)-quinoline-3-
A carboxylic acid and its hydrochloride were obtained.

Example lα Monocarboxylic acid Example 1 The procedure of Example 1 was repeated by replacing the piperazine in (g) with homopiperazine.
Homopiperazinyl)-quinoline-3-carboxylic acid and its hydrochloride were obtained.

Example IL Rubonic Acid 91J 1 1-Phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(dimethylamino)quinoline in the same manner as in Example 1, replacing piperazine in (g) with dimethylamine. -3-carboxylic acid was obtained.

Example 12. .

37- 4-oxo-7-(N-2-hydroxyethylamino)
- Example 1 The procedure of Example 1 was repeated by replacing piperazine in (g) with N-2-hydroxyethylamine. LA l-
Phenyl-6,8-difluoro-1,4-dihydro-4
-oxo-7-(#-2-hydroxyethylamino)-
Quinoline-3-carboxylic acid was obtained.

Example 1a Example 1 Piperazine in (g) was replaced with hydrazine, and l-phenyl-6,8-difluoro-i was used in the same manner as in Example 1.
, 4-dihydro-4-oxo-7-(hydrazyl)
-Quinoline-3-carboxylic acid and its hydrochloride were obtained.

Example 14゜38- 1-phenyl-6,8-difluoro-1,4-dihydro-Example 1 The operation of Example 1 was repeated by replacing piperazine in (g) with 1,1-dimethylhydrazine, and 1-phenyl-6 ,8-difluoro-1,4-dihydro-4-oxy-7-(2,2-dimethylhydrazyl)-quinoline-
3-carboxylic acid and its hydrochloride were obtained.

Example 1 (α) ani'): y is replaced with p-fluoroaniline, Example ICe)) ethyl 3-Cp-fluoroanilino)-2-(213+ 415-te)rafluoro Benzoyl] acrylate was obtained.

(b) The above compound (α) was added to Example 1(C) and Example 1<
rt> to give 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, s-difluoro-1,
4-dihydro-4-oxo-7-(1-piperazinyl)
-Quinoline-3-carboxylic acid and its hydrochloride were obtained.

Example 1a The acid is replaced with the acid of the product of Example 15(b) and the piperazine is replaced with a suitable amine such as n-methylpiperazine,
Similar to example 1 (#), substituting pyrrolidine, 3-hydroxy-pyrrolidine, 3-acetaminopyrrolidine, piperidine, morpholine, thiomorpholine, 2,6-dimethylpiperazine, homopiperazine, diethylamine and 2,2-dimethylhydrazine The following compound was obtained.

(α) 1-p-fluorophenyl-a,S-difluoro-1,4-dihydro-4-ogiso? -(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''l-fluorophenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3-hydroxy-1-pyrrolidinyl)-quinoline-3-carboxylic acid.

(d) t-p-fluorophenyl-6,8-difluoro-1,4-dihydro-4-oxy-7-(3-acetamino-1-pyrrolidinyl)-quinoline-3-carboxylic acid.

(g) 1-p-fluorophenyl-6,8-difluoro-41-1,4-dihydro-4-oxo-7-(1-piperidinyl)-quinoline-3-carboxylic acid.

(f) 1-p-fluorophenyl-6,8-difluoro-1,4-dihydro-4-ogiso7-(4-morpholinyl)-quinoline-3-carboxylic acid.

(y) 1-p-fluorophenyl-6,8--)fluoro-1,4-dihydro-4-oxo-7-(4-thiomorpholinyl)-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-oxy-7-(1-homopiperazinyl)-quinoline-3-carboxylic acid.

(j) 1-p-fluorophenyl-6,8-difluoro-42-1,4-dihydro-4-oxo-7-(diethylamino)-quinoline-3-carboxylic acid.

(&) 1-p-Fluorophenyl-6,8-dineruol 1,4-dihydro-4-oxo-7-(2,2-dimethylhydrazyl)-quinoline-3-carboxylic acid.

Example 11 The compound of Example 16(d) was treated as in Example 5(b) to yield 1
-p-fluorophenyl-6,8-difluoro-1,4
-dihydro-4-oxo-7-(3-amino-1-pyrrolidinyl)-quinoline-3-carboxylic acid was obtained.

Example 1 & 4-dihydro-4-oxo-7-(1-piperazinyl)
Ethyl 3-(p-hydroxyaniline)-2-(2,3,4,5-tetrafluorobenzoyl)acrylate was obtained in the same manner as in Example i(b), replacing -(α)aniline with hydroxyaniline.

(b) Compounds of (a) above in Examples 1(C) and 1(d)
) to give 7-fluoro-1-p-hydroxyphenyl-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(g) to produce 1-7+-hydroxyphenyl-6,8-difluoro-
1,4-dihydro-4-oxy-7-(1-piperazinyl)quinoline-3-carboxylic acid and its hydrochloride were obtained.

Example 1a Replace the acid with the acid of the product of Example 18(b) and replace piperazine with a suitable acid such as N-methylbiperazine, pyrrolidine, 3-hydroxypyrrolidine, 3-acetamidopyrrolidine, piperidine, morpholine, thiomorpholine, 2,
The following compound was obtained in the same manner as in Example 1 (-) except that 6-dimethylbiperazine, homopiperazine, dimethylamine and 2,2-dimethylhydrazine were substituted.

(cL) 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-difluoro45- = 1,4-dihydro-4-oxo-7-(3-hydroxy-1-pyrrolidinyl)-quinoline-3-carboxylic acid.

(d) l-p-hydroxyphenyl-6, g-difluoro-1,4-dihydro-4-oxy-7-(3-acetamido-1-pyrrolidinyl)-quinoline-3-carboxylic acid.

(g) 1-p-hydroxyphenyl-6,S-difluoro-1,4-dihydro-4-oxo-7-(1-piperidinyl)-quinoline-3-carboxylic acid.

φ 1-p-hydroxyphenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(4-morpholinyl)-quinoli/-3-carboxylic acid.

(σ) 1-p-hydro Schiff 1-ru 6,8-Schiff”
O-0-1,4-dihydro-4-oxo-7-(4-thiomolporinyl)-quinoline-3-carboxylic acid.

(n) 1-p-hydroxyphenyl-6,8-difluoro46-1,4-dihydro-4-oxy-7-(3,5-dimethyl-1-piperazinyl)-quinoline-3-carboxylic acid.

(i) 1-p-hydroxyphenyl-6,8-difluoro-1,4-dihydro-4-oxy-7-(l-homopiperazinyl)-quinoline-3-carboxylic acid.

(j) 1-p-hydroxyphenyl-6,8-difluoro-1,4-dihydro-4-oxy-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 2a The compound of Example 18(d) was treated as in Example 5(b) to yield 1
-p-hydroxyphenyl-6,8-difluoro-1,
4-dihydro-4-oxo-7-(3-amino-1-pyrrolidinyl)-quinoline-3-carboxylic acid was obtained.

Example 2L Replace aniline with the appropriate amine (R-NHt),
l-Substituted-6,7,8-1-lifluoro-1,4-dihydro-4 as shown in Table 1 below as in Example 1 (α-d)
~Oxo-quinoline-3-carboxylic acid was obtained.

α) O-fluoroaniline O-fluorophenyl b)
p-chloroaniline p-chlorophenylc)o-;9
0 loaniline O-chlorophenyl d) p-methoxyaniline p-methoxyphenyl e) o-methoxyaniline 0-methoxyphenyl f) 2,4-difluoro l
+-difluorophenyl g) 2-hydroxyanili 2-hydroxyphenylin h) 2-hydroxy-4-2-hydroxy-4-fluoroaniline fluorophenyl 5) 214-dihydroxy 2,4-dihydroxyaniline phenyl j) p- Cyanoaniline p-cyanophenyl k)2.
4-diaminoben p-aminophenylzenur0) 4-aminopyridine 4-pyridylq) 3-aminopyrazine 3-pyrazinylr) 2-aminothiazole 2-thiazoyl8) 3-amino7rane 2-furylt)3 -aminothiophene 3-thenyl49- 14) 3-chloro-4-human 3-chloro-4-hydroxyphenyl xyphenyl Example 2z Replace the acid with the acid of the compound listed in Table 1 of Example 21, and add piperazine as appropriate. amines such as N-methylpiperazine,
Replaced with pyrrolidine, 3-hydroxypyrrolidine, 3-acetamidopyrrolidine, 3-dimethylaminopyrrolidine, piperidine, morpholine, thiomorpholine, 2,6-dimethylbiperazine, homopiperazine, dimethylamine, and 2,2-dimethylhydrazine , Example 1 (
The compound shown in Part 1 was obtained in the same manner as in e).

50 - Example 2a Compounds (11) and (12) of Example 22 were converted as in Example 5(b) to compounds (al and (b) below, respectively).

(cL) l-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 25 g of a cold solution of 2-chloro-4-(4-biridylcine-5-fluoroacetophenone) in diethyl carbonate (α)350- is gradually added to 80 g of a suspension of 60% sodium hydride in oil. 80% of this mixture
℃ for 3 hours, then cooled in an ice-cold aqueous solution containing 25-acetic acid.
Injected into 00-. This mixture was extracted three times with 400 d each of ether.

The organic phase was dried over M 1804, evaporated and the resulting oil was purified in a silica gel column to give pure ethyl-2-
Chloro-4-(4-pyridyl)-5-fluorobenzoyl acetate was obtained.

(b) Triethyl orthoformate of 14- and 35
A solution of 15.9 of the above ethyl-2-chloro-4-(4-pyridyl)-5-fluorobenzoylacetate in 111 t of acetic anhydride was heated at 135°C for 134 hours, and this heating was combined with the ethyl acetate formed during the reaction. ) + was performed while removing. The solution was evaporated under reduced pressure to give a fluid oil. The oil was then diluted with 150-l of methylene chloride and 7.5-l of aniline was added to the solution. After 1 hour, the solution was evaporated to dryness to give ethyl 3-anilino-
2-[2-chloro-4-(4-pyridylco-5-fluorobenzoyl)]acrylate was obtained.

(c) Add 6096 g of the above product to a cold solution of 140% tetrahydrofuran (THF).
1.25 g of a suspension of Jumhydride in oil was added slowly. The mixture was refluxed for 6 hours, then cooled and diluted to 1.5 A with water.

The mixture was then filtered and the solids washed with 1:1 hexane/needle solution R to obtain ethyl 1-phenyl-6-fluoro-1,4-dihydro-4-oxo-7-
(4-pyridyl)quinoline-3-carboxylate'?
Obtained f, -0(d) The above product (c) 5fI is 300-
A solution of IJ hydroxide (1639 in 1 M20) was added to the suspension in THF. 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 55- was dissolved in 200-H2O and 2-acetic acid was added. The resulting precipitate was filtered and washed with cold water to give 1-phenyl-6
-Fluoro-1,4-dihydro-4-oxo-7-(4
-pyridyl)-quinoline-3-carboxylic acid was obtained.

Example 2 Carboxylic acid The aniline in Example 24 (6) was replaced with p-fluoroaniline and the operation of Example 24 was repeated, and 1-p-fluorophenyl-6-fluoro-1,4-dihydro-4-oxo -7-(4-pyridyl)quinoline-3-carboxylic acid was obtained.

Example 2a 1-p-hydroxyphenyl-656-1-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 replacing aniline in Example 24(b) with p-methoxyaniline, and 1-p-methoxyphenyl-6-fluoro-1,4-dihydro-4-oxo-7-( 4-pyridyl)quinoline-3-carvone ef
Obtained.

Example 2 & Example 24(b) Amine (R-NH2)
), and in the same manner as Example 24, as shown in Section ① below.
1-substituted-6-fluoro-1,4-dihydro-4-oxy-7-(4-pyridyl)quinoline-3-carboxylic acid was obtained.

Chapter ■ Table R-NH, R (X=F, W=H, R, =H) Lo-
Fluoroaniline 0-Fluorophenylz p-Chloroaniline p-70 Lofenyl & o-Chloroaniline o-Chlorophenyl 4, p-71 Thylaniline p
-Methylphenyl h z+4-difluoro 2,4-difluorophenyaniline 2-hydroxyani 2-hydroxyphenyl phosphor 2-hydroxy-4-2-hydroxy-4-fluoroaniline orophenyl & 2,4-dihydroxy 2, 4-dihydroxyphenyline nyl a p-cyanoaniline p-cyanophenyl-O'/
- 1ap-aminothiopheno p-mercaptophenyl 144-aminopyridine 4-pyridyl 15 3-aminopyrazine 3-pyrazinyl la 2-aminothiazole 2-thiazoyl 173-aminofuran 3-furyl 1&3-aminothiophene 3-thenyl 113 .4-
Methylenedi 3.4-dimethylenedioxyoxyaniline Diphenyl Example 2a 2-chloro-4-(4-pyridyl)- of Example 24 (OL)
5-fluoroacetophenone was converted into 2-chloro-4-(4-
pyridyl)-acetophenone, Example 24(b)
aniline fp-fluoroaniline in Example 24
Similarly, 1-p-fluorophenyl-1,4-dihydro-4-oxo-7-(4-pyridyl)-quinoline-
3-carboxylic acid was obtained.

Example 3a 59- 58- (α)25- in tetrahydrofuran (CTHF).
To a dry ice-cooled solution of 85y malonic acid monoethyl ester was slowly added 9.2-liters of 1.4 M n-butyllithium in T, HF and the flask was warmed to -5°C. After 5 minutes the solution was cooled again to -70°C. After adding 1 g of acid chloride, 3°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-MCI and ether. The ethereal portion was washed with NaHCO, dried over MQSO4 and then evaporated to give 1y pale yellow oil.

This oil was then purified on a silica gel column in hexane.
Purified by elution with 5% ethyl acetate, 0.89 g
The β-ketoester of ethyl 3,4-methylenedioxy-6-bromoacetate was obtained.

60- (b) A solution of 1g 1O, 8d of the above β-ketoester dissolved in triethyl orthoformate and 5ml acetic anhydride is heated at 135°C for 1y2 hours, and this heat is used to remove ethyl acetate generated during the reaction. I did it while doing so. The solution was evaporated under reduced pressure to obtain a fluid oil.

Next, this oil is 57! of methylene chloride and 0.3-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.

(C) 3g%30m7 of the above product! Tetrahydrofuran (CTHF)? 0.19 in the cold solution!
7 of a suspension of 6096 sodium hydride in oil was slowly added. The mixture was refluxed for 20 hours, then cooled and diluted with water to a volume of 100 d'lf. The mixture was then filtered and washed with a 1:1 % solids hexane/ether solution to give 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) 1.6g of the above product 2011+7! TH
Sodium hydroxide solution (2 ot
(L23!9) was added in rtH,o. Add this mixture to 8
Heating at 0° C. for 2 hours gave a clear solution. The solution was evaporated to dryness under reduced pressure. The obtained solid was added to 200-H,O and LA1- acetic acid. The generated precipitate was filtered and washed with cold water to obtain 1.417 of 1-phenyl-6,7-methylenedioxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. Melting point>300℃.

Example 31 The operation of Example 30 was repeated by substituting anilino fp-fluoroaniline in Example 30(b), and 1-p-fluorophenyl-6,7-methylenedioxy-4-oxo-1,
4-dihydroquinoline-3-carboxylic acid was obtained.

Example 32 Acids 1-p-hydroxyphenyl-6,7-methylenedioxy-4-oxo-1,4-
Dihydroquinoline-3-carboxylic acid was obtained.

Example 3a = 63 = Repeat the operation of Example 30 by substituting p-methoxyaniline for aniline in Example 30(b) 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) was converted to various amines (R-NH,)
and strained in the same manner as in Example 30 to obtain 1-substituted-6,7-methylenedioxy-4-oxo-
1,4-dihydroquinoline-3-carboxylic acid.

Table ■ R-NH,R Lo-fluoroaniline p-fluorophenyl 2, p
-Chloroaniline p-chlorophenyl a Q-chloroaniline o-chlorophenyl 4, p-methylaniline p-methylphenyl 64- Fh 2.4-cyfluor” 2 + 4-cyfluorophenyaniline d 2-hydroxyani 2-hydroxy Phenylline'Z2-hydroxy-4- 2-hydroxy-4-fluoroaniline orophenyl & 2,4-dihydroxy 2,4-dihydroxyphenyline nyl a p-cyanoaniline p-cyanophenyl 144-
Aminopyridine p-pyridyl 1 & 3-aminopyrazine 3-pyrazinyl 1fL 2-aminofuran 2-thiodiyl 173-aminofuran 3-furyl 1 & 3-aminothi sec-2ene 3-chenyl The spirit of the invention as set forth in the claims It will be understood that many changes and modifications may be made in the details of formulation, operation and use without departing from the principles herein.

Continuing from page 1 ■Int, CI,' Identification symbol Internal organization r317:00
) Procedural amendment (formality) Manabu Shiga, Commissioner of the Patent Office, March 4, 1985 1 Display of the case 1985 Patent Application No. 11122 2 Name of the invention Quinoline antibacterial compound 3 Person making the amendment Related Patent applicant name Abbott Laboratories 4 agent 07 Address Akasaka Taisei Building, 1-1-18 Akasaka, Minato-ku, Tokyo (
Telephone: 582-7161) Contents of amendment to the handwritten specification 6 attached to the application As shown in the attached sheet, however, there is no amendment to the content.

Claims (1)

[Claims] Formula L: [However, R1 is hydrogen or a carboxy protecting group; an aromatic heterocycle containing 7 atoms, and of the formula: where R1 is hydrogen, halogen, nitro, carboxyl, methylenedioxy, cyan, CI to C6 alkyl and substituted derivatives thereof, of the formula Y -R. (In the same formula, -Y- is -〇- or -S-, and R8 is hydrogen or C1 to C6 alkyl.) and a group having the formula: (In the same formula, R4 and R6 is independently hydrogen or one or more groups selected from the group consisting of an amino group having C8 to Ce alkyl)
Z is pyridyl or an aliphatic heterocycle containing 4 to 7 atoms and substituted derivatives thereof, of the formula: (wherein R6 is hydrogen or and substituted derivatives thereof, and R1 is C4 to CIO
Alkyl and its substituted derivatives, amine groups, mono-(CI
to Ca) algylamino group and di(C1 to ce,
) alkylamino groups); W and X are independently selected from hydrogen or halogen, and when Z is not pyridyl; and X and Z can also be taken together to form a methylenedioxy bridge, in which case W is hydrogen], and pharmaceutically acceptable salts thereof. 2 Aliphatic heterocycle structure, where R8 is dimethylene or the formula -CH2-R, -C
2. A compound according to claim 1, having the radical H2-, in which R is selected from the group consisting of -8-1-〇- and -N-. a aliphatic heterocycle is C1 to C, alkyl, CI to C6 hydroxyalkyl, hydroxy, l to 6 carbon alkanoyl, alkanoylamide containing 1 to 6 carbon atoms and the formula: RIG and R11 are each independently hydrogen,
Claim 1 is substituted with one or more substituents selected from the group consisting of amine groups selected from the group consisting of C1 to C6 alkyl and substituted derivatives thereof. Compounds described. 4 R contains 5 to 7 atoms in the ring, and S',
l selected from the group consisting of Q, N and combinations thereof.
2. The compound according to claim 1, which is an aromatic heterocycle containing two heteroatoms from which the remaining ring atoms are carbon atoms. & Aromatic heterocycle is C1 to C6 alkyl and substituted derivatives thereof, halogen and of the formula -y-R3 [wherein Y is 10- or -S-, and R3 is halogen or C8 to C6 alkyl] 5. The compound according to claim 4, which is substituted with one or more substituents selected from the group consisting of: iz is the formula [wherein R6 is hydrogen or alkyl from C3 to CIo or a substituted derivative thereof, and R1 is from C1 to CI
o Al-5-kyl, its substituted derivative, amino group, mono~Ccr~C4
) alkylamino group or di(Ct-C4) alkylamino group]. 7 Z is a formula [however, one or more hydrogen, halogen or CI to C,
Alkyl of the formula -Y-R, (Y in the formula is 10- or -
S- and R8 is lower alkyl), hydroxy, alkanoyl containing 1 to 6 carbon atoms, 1 to 6
from the group consisting of alkanoylamides containing 5 carbon atoms, and amines of the formula (wherein R1 and RI are each independently selected from the group consisting of hydrogen, C1 to 6-C0 alkyl and substituted derivatives thereof) The compound according to claim 1, which is substituted with a selected substituent. & R is phenyl, Z is piperazinyl,
The compound according to claim 1, wherein and W is fluoro and RI is hydrogen. The compound according to claim 1, wherein a R is phenyl, Z is 4-methylpiperazinyl, X and W are fluoro, and R1 is hydrogen. ICIR is p-fluorophenyl, Z is piperazinyl, X and W are fluoro, '? A compound according to claim 1, wherein I is hydrogen. 11. The compound according to claim 1, wherein R is p-fluorophenyl, Z is 4-methylpiperazinyl, X and W are fluoro, and R1 is hydrogen. 12. The compound according to claim 1, wherein R1fi is hydroxyphenyl, Z is piperazinyl, X and W are fluoro, and RI is hydrogen. 11 Rkao, p-difluorophenyl, Z
is piperazinyl, X and W are fluoro,
2. A compound according to claim 1, wherein R1 is hydrogen. 14. The compound according to claim 1, wherein R is phenyl, R1 and W are hydrogen, X is fluoro, and Z is 4-pyridyl. lfi R cuff)-fluorophenyl, R1,
and W is hydrogen and Z is 4-pyridyl. 1 (, R is p-fluorophenyl, R1 and W
The compound according to claim 1, wherein is hydrogen and Z is 4-pyridyl. 17. The compound according to claim 1, wherein R is hydroxyphenyl, R is hydrogen, X is fluoro, and Z is 4-pyridyl. 1 & X and Z together form a methylenedioxy bridge and W is hydrogen. 19. The compound according to claim 18, wherein R is phenyl or p-fluorophenyl, and R1 is hydrogen. 2(IR, is hydrogen, R is p-fluorophenyl, X and W are fluoro, Z is 3-amino-
% of the compound according to claim 1 which is 1-pyrrolidinyl. 2L formula: [However, R1 is hydrogen or a carboxy protecting group; 9-R is 5 to 7 carbon atoms forming a ring with at least one heteroatom that is S, Q, and N and aromatic heterocycles containing atoms of the formula: (wherein R2 is hydrogen), rogen, nitro, carboxyl, methylenedioxy, cyano, CI to C6 alkyl and substituted derivatives thereof, of the formula NiY -R. (In the same formula, -Y- is -O- or -S-, and R3 is hydrogen or C1 to C, alkyl), and a group having the formula: (In the same formula, R4 and R3 are independently hydrogen or CI to 06 alkyl), -10-)
Z is pyridyl or an aliphatic heterocycle containing 4 to 7 atoms and substituted derivatives thereof, formula: (wherein R8 is hydrogen or CSO to and substituted derivatives thereof, and R7 is C0 to C7゜alkyl and substituted derivatives thereof, amine group, mono-(Ci
to CO) alkylamino group and G<C1 to C6)
(selected from the group consisting of alkylamino groups)
W and X are independently selected from hydrogen or halogen, and when Z is not pyridyl, W is halogen; and X and Z together An antibacterial agent containing as an active ingredient a compound or a pharmaceutically acceptable salt thereof, which can be used to form methylenedioxy crosslinks, in which case W is hydrogen.