JPH0146512B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel and useful quinoline derivatives having antibacterial activity. Certain 7-piperazinyl-4-oxo-1,
It is known that 4-dihydroquinoline-3-carboxylic acid exhibits antibacterial activity. For example, in US Pat. No. 4,017,622, the substituent at the 1-position is alkyl,
Certain 7-piperazinyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid derivatives that are benzyl or acetyl are disclosed. U.S. Pat. No. 4,292,317 describes certain 7-piperazinyl-6-halo-4-oxo-
1,4-dihydroquinoline-3-carboxylic acid derivatives are disclosed. U.S. Patent No. 4,284,629 includes
Various 4-oxo-1,4-dihydroquinolines in which the 1-position substituent may be cycloalkyl
Although 3-carboxylic acids are disclosed, corresponding derivatives containing 7-piperazinyl substituents are not. GB 1147336 discloses certain 4-oxo-1,4-dihydroquinoline-3-carboxylic acids in which the substituent in the 1-position is a (substituted) phenyl group. While the compounds of the patent may be useful in some respects, the search continues for new quinoline derivatives that have improved properties or are otherwise useful in treating bacterial infections. The present invention provides novel 7-substituted 6-fluoro-1,
4-dihydro-4-oxo-quinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof. The compound of the present invention can be represented by the following formula (). [However, R ₁ is hydrogen or a carboxy protecting group; R is a phenyl group, and the phenyl group is
each independently selected from the group consisting of halogen, C _1-6 alkyl, and groups having the formula -O-R ₃ , where R ₃ is hydrogen or C _1-6 alkyl.
may be substituted by ~3 groups (R ₂ ); and Z has the formula -NR ₄ R ₅ {where R ₄ and R ₅ are
Each is independently hydrogen or C _1-6 alkyl, or combined with the nitrogen atom to which they are bonded, with or without an oxygen atom, sulfur atom, or nitrogen atom, a 5- or 6-membered , and the aliphatic heterocycle is a C _1-6 alkyl and a formula -NR ₁₀ R ₁₁ (where R ₁₀ and R ₁₁ are each independently hydrogen, a C _1-6 alkyl or C _1-6 alkanoyl), and pharmaceutically Its salt acceptable. As used herein, the term "halogen" refers to chloro, bromo, fluoro and iodo groups, while the term " _C1 - _C4 alkyl" refers to lower alkyl groups, including methyl, ethyl, propyl, isopropyl, butyl. to be called. As mentioned above, _R2 can be a straight chain or branched _C1 - _C4 alkyl. R ₂ may also be a group of the formula -O-R ₃ . Representative groups of this type include hydroxy groups, lower alkoxy groups such as methoxy, ethoxy, propoxy. The term "carboxy-protecting group" as used herein refers to and includes the residue of a carboxylic acid ester group. Such carboxy-protecting groups are well known to those skilled in the art and are widely used in the penicillin and cephalosporin art to protect carboxyl groups, as described in US Pat. Nos. 3,840,556 and 3,719,667. The descriptions of these patents are inserted into the main text for reference. Generally, such carboxy-protecting groups are relatively easily cleaved to yield the corresponding free carboxy group. 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 S, O and N, and the remaining atoms of the ring is a carbon atom, and its substituted derivatives. According to an embodiment of the invention, the aliphatic heterocycle has the formula [In the formula, R ₈ is dimethylene and the formula −CH ₂ −R ₉ −
_CH2- , where _R9 is selected from the group consisting of -S-, -O-, -N-, and _-CH2- . Also included are substituted derivatives of these heterocycles, and the substituents are
_C1 - _C4 alkyl group or formula (where R ₁₀ and R ₁₁ are independently hydrogen, C ₁ −
C ₄ alkyl and alkanoyl containing 1-4 carbon atoms). Specific examples of such heterocyclic groups include piperazinyl, piperidinyl, pyrrolidinyl, morpholino and thiomorpholino groups. Preferred compounds of the invention have the formula (In the formula, R is phenyl or substituted phenyl, and the substituent of the phenyl group is one or more of alkyl, halogen, or hydroxy,
R ₁ is as defined above, preferably hydrogen, and Z is piperazinyl, substituted piperazinyl or substituted pyrrolidinyl as defined above)
It is a compound with Representative of such preferred compounds include 1-phenyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid, 1-phenyl- 6-Fluoro-1,4-dihydro-4-oxo-7-
(1-(4-methyl)piperazinyl)-quinoline-
3-carboxylic acid, 1-p-fluorophenyl-6
-Fluoro-1,4-dihydro-4-oxo-7
-(1-piperazinyl)-quinoline-3-carboxylic acid, 1-p-fluorophenyl-6-fluoro-
1,4-dihydro-4-oxo-7-(1-(4-
methyl)-piperazinyl)-quinoline-3-carboxylic acid, 1-p-bromophenyl-6-fluoro-
1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid, 1-p
-Hydroxyphenyl-6-fluoro-1,4-
Dihydro-4-oxo-7-(1-piperazinyl)
-Quinoline-3-carboxylic acid, 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-
Quinoline-3-carboxylic acid, 1-p-fluorophenyl-6-fluoro-1,4-dihydro-4-
Oxo-7-(3-amino-1-pyrrolidinyl)-
Quinoline-3-carboxylic acid, 1-p-fluorophenyl-6-fluoro-1,4-dihydro-4-
Oxo-7-(3-methylamino-1-pyrrolidinyl)-quinoline-3-carboxylic acid, 1-p-fluorophenyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-dimethyl Amino-1
-pyrrolidinyl)-quinoline-3-carboxylic acid,
and 1-(2,4-difluorophenyl)-6-
Fluoro-1,4-dihydro-4-oxo-7-
(3-dimethylamino-1-pyrrolidinyl)-quinoline-3-carboxylic acid is included. The term "pharmaceutically acceptable salt" as used herein means a non-toxic acid addition salt, alkali metal salt or alkaline earth metal salt of a compound of formula (). These salts can be prepared in situ or separately during the final isolation and purification of the compound of formula () by reacting the base or acid function with the appropriate organic or inorganic acid or base, respectively. Typical acid addition salts include hydrochloride, hydrobromide, sulfate, bisulfate, acetate, tartrate, valerate, oleate, palmitate, stearate, and laurate. , borate, benzoate,
Lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, oxalate, napsylate, glucoheptonate, lactobionate, lauryl sulfate salt etc. are included. Representative alkali metal or alkaline earth metal salts include sodium, calcium, potassium and magnesium salts, and the like. Preferred compounds of the invention have been found to have antibacterial activity against a broad spectrum of Gram-positive and Gram-negative bacteria. The compounds of the invention are therefore useful in the antibiotic treatment of susceptible bacterial infections in both humans and animals. Additionally, the compounds can be used in cleaning solutions, for example on counter surfaces, for surface inhibition of bacterial growth. Susceptible microorganisms, the growth of which may be inhibited by the compounds of the invention, generally include Gram-positive and Gram-negative, aerobic and anaerobic microorganisms, such as Staphylococcus, Lactobacillus, Streptococcus. (Streptococcus), Sarcina, Eocherichia, Enterobacter, Klebsiella,
Pseudomonas, Acinetobacter, Proteus,
Citrobacter, Nisseria, Baccullus, Bacteroides, Peptococcus, Clostridium, Salmonella, Shigella, Serratia, Haemophilus , Brucella
and other microorganisms. In addition to exhibiting highly effective antimicrobial activity, the compounds of the present invention exhibit increased and improved solubility properties compared to prior art quinoline-3-carboxylic acid compounds. The compounds of formula () can also be formulated into compositions with pharmaceutically acceptable carriers for parenteral injection, oral administration in solid or liquid form, enteral administration, and the like. Compositions of the compounds of the invention for parenteral injection can be prepared in pharmaceutically acceptable sterile aqueous or non-aqueous solutions;
It can consist of a suspension or an emulsion. 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 contain adjuvants such as preservatives,
Wetting agents, emulsifying agents and dispersing agents may also be included. These compositions may be sterilized, for example, by passage through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition which may be dissolved in sterile water or some other sterile injectable medium immediately before use. can. Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In solid dosage forms, the active compound is mixed with at least one inert diluent such as sucrose, lactose or starch. The dosage form may also include additional substances other than inert diluents in normal practice, such as lubricants such as magnesium stearate. For capsules, tablets, and pills, the dosage form may also include a buffering agent. Tablets and pills can additionally be prepared with enteric coatings. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents such as water, commonly used by those skilled in the art. Ru. Besides such inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, and sweetening, seasoning, and flavoring agents. Compositions for enteral 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 compositions containing the compounds of this invention can be varied to obtain an amount of active ingredient effective to achieve antimicrobial activity according to the desired mode of administration. The selected dosage will therefore depend on the nature of the active compound being administered, the route of administration, the desired duration of treatment and other factors. Generally about 0.1-750, more preferably about 0.25
-500, most preferably about 0.5-300 mg of active ingredient/Kg of body weight per day of a compound of formula ().
It is effective when administered orally to mammals suffering from infections caused by susceptible bacteria. If desired, the daily dosage can also be divided into 2-4 doses per day. The compound of formula () can be produced according to the following reaction formula. According to the above reaction formula, 2,4-dichloro-5
-Fluoro-acetophenone (1) is reacted with dialkoxycarbonate (2) in the presence of a strong base to give the corresponding β-ketoester (3). In dialkoxycarbonate (2) R ₆ can be, for example, an alkyl group of 1-10 carbon atoms, but is preferably lower alkyl, such as ethyl. Suitable bases include metal hydrides such as sodium hydride, potassium hydride, etc. as well as metal alkoxides in alcohols such as sodium ethoxide in ethanol. A currently preferred base for this purpose is sodium hydride. The formation of β-ketoester (3) is achieved by combining acetophenone (1) with dialkoxycarbonate (2) at an elevated temperature e.g.
This is easily carried out by reacting at 120°C, preferably about 30°C to about 90°C, until the reaction is complete.
The β-ketoester can then be separated from the reaction mixture in a conventional manner. The β-ketoester (3) is then treated with a trialkylorthoformate (4) in the presence of an acid anhydride, preferably acetic anhydride, and then reacted with a substituted or unsubstituted aniline (5) to form the enaminoketoester (3). 6). In trialkyl orthoformate (4),
R ₇ may be, for example, an alkyl group of 1-10 carbon atoms, preferably lower alkyl, such as ethyl. The reaction with the trialkyl orthoformate is preferably carried out at elevated temperatures, e.g. from about 50°C to about
carried out at 150°C, preferably from about 100°C to about 140°C, as an unisolated intermediate (shown in parentheses in the reaction scheme).
Obtain an oily liquid. The reaction of the latter with substituted or unsubstituted aniline (5) is preferably carried out in a suitable aprotic or protic solvent, preferably methylene chloride or tetrahydrofuran, and optionally at room temperature or at a suitable elevated temperature. It can be implemented. The enaminoketo ester (6) is then ring-closed, e.g. by treatment with a strong base, preferably sodium hydride, as defined above to produce a 1-aryl-1,4
-dihydro-4-oxo-quinoline-3-carboxylic acid ester (7) is obtained. Ring closure is carried out in the presence of an aprotic solvent such as dimethoxyethane, dimethylformamide, tetrahydrofuran or chlorobenzene, and preferably at a temperature of about 20°C to about
It is carried out at a temperature of 145°C, more preferably at the reflux temperature of the solvent used. Ester (7) is hydrolyzed to the free acid, for example by treatment with sodium hydroxide, and then the 7-chloro group is converted to a substituted or unsubstituted piperazine or heterocyclic amine (as described above) by techniques well known in the art. 8) to the desired 1-aryl-6-fluoro-7-substituted amino-1,4-dihydroxy-
4-oxo-quinoline-3-carboxylic acid (9) is obtained. 1-Aryl-6-fluoro-7-substituted amino-1,4-dihydro-4-oxo-quinoline-3
- The carboxylic acid (9) is then optionally converted into the free acid (9) by conventional esterification operations such as by treating the free acid (9) with a suitable alcohol in the presence of an acid catalyst.
to the corresponding acid chloride and then replacing the chloro group with a suitable alcohol, or by treating the sodium salt of acid (9) with a suitable reactive halide such as chloromethyl pivalate in dimethoxyethane. For example, pivaloyloxymethyl ester (1) can be converted to the ester (10)
[ _R1 is _-CH2OCO -C( _CH3 ) ₃ ] can be obtained. The foregoing can be better understood from the following examples. These examples are presented for illustrative purposes only and are not intended to limit the scope of the invention. Descriptions of compounds used in the following examples, e.g. (1), (2), (3), etc., and descriptions of substituents, e.g. R, R ₁ , R ₂ , etc., are the corresponding compounds in the above reaction formula and This indicates the amount to be replaced. Example 1 1-Phenyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)quinoline-3-carboxylic acid a 2,4-dichloro- in 300 ml of diethyl carbonate
In a cold solution of 20.5 g of 5-fluoroacetophenone
Slowly add 8.2 g of 60% sodium hydride suspension in oil. The mixture is heated to 80° C. for 1-1/2 hours and then poured into 700 ml of an ice-cold aqueous solution containing 25 ml of acetic acid. The mixture is extracted three times with 400 ml portions of ether. The organic phase is dried with MgSO ₄ , evaporated and the resulting liquid is distilled at 100° C. and 0.7 mm Hg pressure, yielding 22.2 g of (3) with R ₆ =C ₂ H ₅ . b 14 ml of triethyl orthoformate and 35 ml of acetic anhydride
β-Ketoester (3) (R ₆ = C ₂ H ₅ ) in ml 15.18
The solution of g is heated to 135 DEG C. for 1-1/2 hours to remove the ethyl acetate formed during the reaction. The solution is evaporated under reduced pressure to a fluid oil. Next, dissolve this oil in 150 ml of methylene chloride and add 7.5 ml of aniline to the solution. 1 hour later
The solution is evaporated to dryness and crystallized from 200 ml hexane and 5 ml ether, R ₆ =
(6) with C ₂ H ₅ and R=phenyl is obtained in 89% yield. Melting point 96-97°C c A 60% suspension of sodium hydride in oil in a cold solution of 13.9 g of the above product (6), R ₆ = C ₂ H ₅ , R = phenyl, in 140 ml of dimethoxymethane (DME) 1.49
Add g slowly. The mixture is refluxed for 4-1/2 hours, cooled and diluted to 1.5 volumes with water. The mixture was then filtered and the solids removed 1:
R ₆ = C ₂ H ₅ when washed with 1 hexane/ether solution
and 10.4 g of (7) where R = phenyl, yield 81%
It can be obtained with d To a suspension of 5.4 g of (7) (R ₆ =C ₂ H ₅ , R=phenyl) in 30 ml of THF is added sodium hydroxide solution (0.73 g in 20 ml of H ₂ O). 1 of the mixture
Heating to 80°C for an hour gives a clear solution, which is evaporated to dryness under reduced pressure. solid in H ₂ O
Dissolve in 200ml and add 2ml of acetic acid. The resulting precipitate is filtered and washed with cold water and crystallized from dimethylformamide to give 7-chloro-1
-Phenyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (7)
4.6 g (R ₆ =hydrogen, R=phenyl) are obtained.
Melting point 271-273℃ e 15ml of 1-methyl-2-pyrrolidinone at 115℃
7-chloro-1-phenyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-
2 ml of piperazine in a solution of 1.25 g of 3-carboxylic acid
Add. After stirring at 100°C for 20 hours, the solvent is removed under reduced pressure and dried. Add ethanol to the residue and filter the resulting mixture,
Wash with ether and then with a very small amount of cold water.
The resulting dry solid is suspended in 30 ml of _H2O and 2.35 ml of 1NHCl is added and warmed to dissolve. Removal of the solvent under reduced pressure yields 1-phenyl-6
-Fluoro-1,4-dihydro-4-oxo-
7-(1-piperazinyl)quinoline-3-carboxylic acid (9) (R=phenyl,

835 mg of hydrochloride of [formula]) is obtained. Melting point >275℃. C ₂₀ H ₁₈ FN ₃ O ₃・HCl・1/4
Analysis for H ₂ O Calculated values: C 58.82, H 4.79, N 10.29 Measured values: C 58.82, H 4.70, N 10.48. When 1 molar equivalent of an aqueous sodium hydroxide solution is added to the hydrochloride and the resulting precipitate is filtered, 1-
Phenyl-6-fluoro-1,4-dihydro-
4-oxo-7-(1-piperazinyl)quinoline-3-carboxylic acid is obtained. f Alternatively, the title compound is prepared as follows. Compound (7) (R ₆ = H, R = phenyl; product of 1(d)) 5.87 g of 1-methyl-2-
Suspension in 40 ml of pyrrolidinone under nitrogen atmosphere
N-carboethoxy-p-piperazine at 120°C
Add 9.5ml. 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 cooled and filtered. The obtained solid was washed with cold ethanol and water to yield compound (9) (R=phenyl,

[Formula]) 6.15 g was obtained with a yield of 87%. The above compound (9) (R=phenyl,

[Formula]) Add 50 ml of 10% NaOH solution to 5.5 g of suspension. Heat the solution to 80°C for 6 hours. The solvent is removed and the solid is dissolved in 100 ml of water. Adjust the pH of the solution to 7 by adding 10% acetic acid. The precipitate was filtered and washed with cold water to give 1-phenyl-6-fluoro-
1,4-dihydro-4-oxo-7-(1-piperazinyl)quinoline-3-carboxylic acid (9) (R
= phenyl,

[Formula]) 4.26g is obtained. Example 2 1-Phenyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-(4-methyl)-piperazinyl)quinoline-3-carboxylic acid Piperazine in Example 1(e) By repeating the procedure of Example 1 by substituting N-methyl-piperazine, 1-phenyl-6-fluoro-1,4-dihydro-4-oxo-7(1-(4-methyl)-piperazinyl)-quinoline-3 -Carboxylic acid (9) (R=phenyl,

[Formula]) and its hydrochloride are obtained. Example 3 1-Phenyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-(4-ethyl)-piperazinyl)quinoline-3-carboxylic acid Piperazine in Example 1(e) By repeating the procedure of Example 1 by substituting N-ethylpiperazine, 1-phenyl-6-fluoro-1,4-dihydro-4-oxo-7(1-(4-ethyl)-piperazinyl)-quinoline-3- Carboxylic acid (9) (R=phenyl,

[Formula]) and its hydrochloride are obtained. Example 4 1-p-fluorophenyl-6-fluoro-
1,4-dihydro-4-oxo-(1-piperazinyl)quinoline-3-carboxylic acid a Enaminoketoester (6) (R ₆ = _-C2H5 , R ₌ p-fluorophenyl) is obtained in a yield of 78%. Melting point 108°C b According to Examples 1(c) and 1(d), the above compound
(6) (R ₆ = C ₂ H ₅ , R = p-fluorophenyl)
to 7-chloro-1-p-fluorophenyl-
6-Fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (7) (R ₆ = H, R
=p-fluorophenyl) is obtained. c The above acid (7) (R ₆ =
H, R=p-fluorophenyl) to the desired 1
-p-fluorophenyl-6-fluoro-1,
4-dihydro-4-oxo-7-(1-piperazinyl)quinoline-3-carboxylic acid (9)
(

[Formula R=p-fluorophenyl] and its hydrochloride are obtained. Melting point>
275°C (decomposition) Example 5 1-p-fluorophenyl-6-fluoro-
1,4-dihydro-4-oxo-7(1-(4-
methyl)-piperazinyl)quinoline-3-carboxylic acid The acid in Example 4(b) in the manner described in Example 1(e) replacing piperazine with N-methylpiperazine.
(7) (R ₆ = H, R = p-fluorophenyl) to the desired 1-p-fluorophenyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-(4
-methyl)-piperazinyl)quinoline-3-carboxylic acid (9) (

[Formula R=p-fluorophenyl] and its hydrochloride are obtained. Melting point>275°C (decomposition) Example 6 1-p-chlorophenyl-6-fluoro-1,
4-dihydro-4-oxo-(1-piperazinyl)quinoline-3-carboxylic acid a Enaminoketoester (6) (R ₆ = C ₂ H ₅ , R = p-chlorophenyl)
is obtained with a yield of 60%. b According to Examples 1(c) and 1(d), the above compounds
(6) (R ₆ = C ₂ H ₅ , R = p-chlorophenyl) to 7-chloro-1-p-chlorophenyl-6-
Fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (7) (R ₆ = H, R = p
-chlorophenyl) is obtained. c The above acid (7) (R ₆ =
H, R=p-chlorophenyl) to the desired 1-
p-chlorophenyl-6-fluoro-1,4-
Dihydro-4-oxo-7-(piperazinyl)
Quinoline-3-carboxylic acid (9)
(

[Formula R=p-chlorophenyl] and its hydrochloride are obtained. Example 7 1-p-chlorophenyl-6-fluoro-1,
4-dihydro-4-oxo-7-(1-(4-methyl)-piperazinyl)quinoline-3-carboxylic acid Example 1 as described in Example 1(e) replacing piperazine with N-methylpiperazine. Acid in 6(b)
(7) (R ₆ = H, R = p-chlorophenyl) to the desired 1-p-chlorophenyl-6-fluoro-
1,4-dihydro-4-oxo-7-(1-(4-
methyl)-piperazinyl)quinoline-3-carboxylic acid (9) (

[Formula R=p-chlorophenyl] and its hydrochloride are obtained. Melting point>
275°C (decomposition) Example 8 1-p-methoxyphenyl-6-fluoro-
1,4-dihydro-4-oxo-7-(1-piperazinyl)quinoline-3-carboxylic acid a The enaminoketoester (6 ) (R ₆ =C ₂ H ₅ , R = p-OCH ₃ -phenyl) is obtained in a yield of 77% (melting point 105°C). b According to Examples 1(c) and 1(d), the above compounds
(6) (R ₆ = C ₂ H ₅ , R = p-methoxyphenyl)
to 7-chloro-1-p-methoxyphenyl-
6-Fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (7) (R ₆ = H, R
=p-methoxyphenyl) is obtained. c The above acid (7) (R ₆
=H, R=p-methoxyphenyl) to the desired 1-p-methoxyphenyl-6-fluoro-
1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid (9)
(

[Formula R=p-methoxyphenyl] and its hydrochloride are obtained. Example 9 1-p-methoxyphenyl-6-fluoro-
1,4-dihydro-4-oxo-7-(1-(4
-methyl)-piperazinyl)quinoline-3-carboxylic acid The acid in Example 8(b) in the manner described in Example 1(e) replacing piperazine with N-methylpiperazine.
(7) (R ₆ = H, R = p-methoxyphenyl) to the desired 1-p-methoxyphenyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-(methyl) -piperazinyl)quinoline-3-carboxylic acid (9) (

[Formula R=p-methoxyphenyl] and its hydrochloride are obtained. Melting point>
275°C (decomposition) Example 10 1-p-methylphenyl-6-fluoro-1,
4-dihydro-4-oxo-7-(piperazinyl)quinoline-3-carboxylic acid a Enaminoketoester (6) (R ₆ = C ₂ H ₅ , R = p-methylphenyl)
is obtained in 80% yield (melting point 115.5°C). b According to Examples 1(c) and 1(d), the above compounds
(6) (R ₆ = C ₂ H ₅ , R = p-methylphenyl) to 7-chloro-1-p-methylphenyl-6-
Fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (7) (R ₆ = H, R = p
-methylphenyl) is obtained. c The above acid (7) (R ₆
=H, R=p-methylphenyl) to the desired 1
-p-methylphenyl-6-fluoro-1,4
-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid (9)
(

[Formula R=p-methylphenyl] and its hydrochloride are obtained. Example 11 1-p-methylphenyl-6-fluoro-1,
4-dihydro-4-oxo-7-(1-(4-methyl)-piperazinyl)quinoline-3-carboxylic acid The acid ( 7)(R ₆ =H,
R = p-methylphenyl) (Example 10(b)) to the desired 1-p-methylphenyl-6-fluoro-
1,4-dihydro-4-oxo-7-(1-(4-
methyl)-piperazinyl)quinoline-3-carboxylic acid (9) (

[Formula R=p-methylphenyl] and its hydrochloride are obtained. Example 12 1-p-hydroxyphenyl-6-fluoro-
1,4-dihydro-4-oxo-(1-piperazinyl)quinoline-3-carboxylic acid a Enaminoketoester (6) ( R ₆ =C ₂ H ₅ , R = p-hydroxyphenyl) is obtained with a yield of 84%. b According to Examples 1(c) and 1(d), the above compounds
(6) (R ₆ = C ₂ H ₅ , R = p-hydroxyphenyl)
7-chloro-1-p-hydroxyphenyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (7) in good yield from
(R ₆ =H, R=p-hydroxyphenyl) is obtained. c The above acid (7) (R ₆
=H,R=p-hydroxyphenyl) to the desired 1-p-hydroxyphenyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-
piperazinyl)-quinoline-3-carboxylic acid (9)
(

[Formula R=p-hydroxyphenyl] and its hydrochloride are obtained. Example 13 1-p-hydroxyphenyl-6-fluoro-
1,4-dihydro-4-oxo-7(1-(4-
methyl)-piperazinyl)quinoline-3-carboxylic acid The acid in Example 12(b) in the manner described in Example 1(e) replacing piperazine with N-methylpiperazine.
(7) (R ₆ = H, R = p-hydroxyphenyl) to the desired 1-p-hydroxyphenyl-6-fluoro-1,4-dihydro-4-oxo-7(1-
(4-Methyl)-piperazinyl)quinoline-3-carboxylic acid (9) (

[Formula R=p-hydroxyphenyl] and its hydrochloride are obtained. Melting point>275°C (decomposition) Example 14 1-o-fluorophenyl-6-fluoro-
1,4-dihydro-4-oxo-(1-piperazinyl)quinoline-3-carboxylic acid a Enaminoketoester (7) ( R ₆ = C ₂ H ₅ , R = o-fluorophenyl) is obtained in a yield of 78.8% (melting point 90-92
℃). b According to Examples 1(c) and 1(d), the above compounds
(6) (R ₆ = C ₂ H ₅ , R = o-fluorophenyl)
to 7-chloro-1-o-fluorophenyl-
6-Fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (7) (R ₆ = H, R
=o-fluorophenyl) is obtained. c The above acid (7) (R ₆
=H, R=o-fluorophenyl) to the desired 1-o-fluorophenyl-6-fluoro-
1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid (9)
(

[Formula R=o-fluorophenyl] and its hydrochloride are obtained. Example 15 1-o-fluorophenyl-6-fluoro-
1,4-dihydro-4-oxo-(1-(4-methyl)-piperazinyl)quinoline-3-carboxylic acid Example 1 as described in Example 1(e) replacing piperazine with N-methylpiperazine Acid in 14(b)
(7) (R ₆ =H, R=o-fluorophenyl) to the desired 1-o-fluorophenyl-6-fluoro-1,4-dihydro-4-oxo-7(1-(4-
methyl)-piperazinyl)quinoline-3-carboxylic acid (9) (

[Formula R=o-fluorophenyl] and its hydrochloride are obtained. Example 16 1-m-fluorophenyl-6-fluoro-
1,4-dihydro-4-oxo-(1-piperazinyl)quinoline-3-carboxylic acid a Enaminoketoester (6) ( R ₆ = C ₂ H ₅ , R = m-fluorophenyl) is obtained in a yield of 68.5% (melting point 103-104
℃). b According to Examples 1(c) and 1(d), the above compounds
(6) (R ₆ = C ₂ H ₅ , R = m-fluorophenyl)
to 7-chloro-1-m-fluorophenyl-
6-Fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (7) (R ₆ = H, R
= m-fluorophenyl) is obtained. c The above acid (7) (R ₆
=H, R=m-fluorophenyl) to the desired 1-m-fluorophenyl-6-fluoro-
1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid (9)
(

[Formula R=m-fluorophenyl] and its hydrochloride are obtained. Example 17 In a manner analogous to Example 1, substituting various substituted anilines and the appropriate N-substituted piperazine in place of aniline, the following additional compounds and their hydrochloride salts are prepared as summarized in the table.

[Table] Roxyaniline
droxyphenil
Example 18 1-p-fluorophenyl-6-fluoro-
1,4-dihydro-4-oxo-7-thiomorpholino-quinoline-3-carboxylic acid 7-chloro-1-p-fluorophenyl-6-fluoro-1,4 in 35 ml of 1-methyl-2-pyrrolidinone -dihydro-4-oxo-quinoline-3
- To a solution of 3.36 g of carboxylic acid (product of Example 4(b)) at 115 DEG C. are added 4.13 g of thiomorpholine. 115
After stirring for 20 hours at °C, the solvent is removed under reduced pressure and dried. Methanol is added to the residue and the resulting mixture is filtered and washed with ethyl acetate and then water. When the solid is dried, 1-p-fluorophenyl-6-fluoro-1,4-dihydro-4
-oxo-7-thiomorpholino-quinoline-3-
Carboxylic acid(9)

2.51 g of R=p-fluorophenyl are obtained with a yield of 62%. Melting point >275℃. Analysis of C ₂₀ H ₁₆ F ₂ N ₂ SO ₃・1/4H ₂ O Calculated values: C 59.03, H 4.21, N 6.80 Actual values: C 59.36, H 3.89, N 6.85. Example 19 1-phenyl-6-fluoro-1,4-dihydro-4-oxo-7-thiomorpholino-quinoline-3-carboxylic acid 7-chloro-1-p-fluorophenyl-6-
Fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid was replaced by 7-chloro-1-phenyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid. By repeating the procedure of Example 18, 1-phenyl-6-fluoro-1,4-dihydro-4-oxo-7-thiomorpholino-quinoline-3-carboxylic acid (9)
(

The formula R=phenyl is obtained. Example 20 1-p-methoxyphenyl-6-fluoro-
1,4-dihydro-4-oxo-7-thiomorpholino-quinoline-3-carboxylic acid 7-chloro-1-p-fluorophenyl-6-
Fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid to 7-chloro-1-p-methoxyphenyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid 1-p-Methoxyphenyl-6-fluoro-1,4-dihydro-4-oxo-7-thiomorpholino-quinoline- by the method described in Example 18 with substitution of acid.
3-carboxylic acid (9) (

[Formula R=p-methoxyphenyl] is obtained. Example 21 1-p-hydroxyphenyl-6-fluoro-
1,4-dihydro-4-oxo-7-thiomorpholino-quinoline-3-carboxylic acid 7-chloro-1-p-fluorophenyl-6-
Fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid to 7-chloro-1-p-hydroxyphenyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid When replacing with acid and repeating the operation of Example 18, 1-p
-Hydroxyphenyl-6-fluoro-1,4-
Dihydro-4-oxo-7-thiomorpholino-quinoline-3-carboxylic acid (9) (

[Formula R=p-hydroxyphenyl] is obtained. Example 22 1-phenyl-6-fluoro-1,4-dihydro-4-oxo-7-morpholino-quinoline-
3-Carboxylic acid 7-chloro-1-phenyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid in 30 ml of 1-methyl-2-pyrrolidinone
Add 4 ml of morpholine to 2.5 g of solution at 115°C.
After stirring at 115°C for 20 hours, the solvent was removed under reduced pressure and dried. Ethanol is added to the residue and the resulting mixture is filtered and washed with ethanol and then water.
When the solid is dried, 1-phenyl-6-fluoro-
1,4-dihydro-4-oxo-7-morpholino-quinoline-3-carboxylic acid (9)

1.98 g of R = phenyl is obtained. Melting point >250℃. IR (KBr) cm ^-1 :CO1730,
1630. NMR [DMSO-d ⁶ ] δ value: 3.01 (4H, m),
3.69 (4H, m), 6.42 (1H, d, J=7.5Hz), 7.71
(5H, s), 8.00 (1H, d, J=13Hz), 8.62 (1H,
s), 15.10 (1H, bs). Example 23 1-p-fluorophenyl-6-fluoro-
1,4-dihydro-4-oxo-7-morpholino-quinoline-3-carboxylic acid 7-chloro-1-phenyl-6-fluoro-
1,4-dihydro-4-oxo-quinoline-3-
By repeating the procedure of Example 22 by replacing the carboxylic acid with 7-chloro-1-p-fluorophenyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid, 1-p- Fluorophenyl-6-fluoro-1,4-dihydro-4-
Oxo-7-morpholino-quinoline-3-carboxylic acid (9) (

[Formula R=p-fluorophenyl] is obtained. Melting point>275°C (decomposition) Example 24 1-p-hydroxyphenyl-6-fluoro-
1,4-dihydro-4-oxo-7-morpholino-quinoline-3-carboxylic acid 7-chloro-1-phenyl-6-fluoro-
1,4-dihydro-4-oxo-quinoline-3-
carboxylic acid to 7-chloro-1-p-hydroxyphenyl-6-fluoro-1,4-dihydro-4-
1-p-Hydroxyphenyl-6-fluoro-1,4-dihydro-4-
Oxo-7-morpholino-quinoline-3-carboxylic acid (9) (

[Formula R=p-hydroxyphenyl] is obtained. Example 25 1-phenyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-amino-1-pyrrolidinyl)quinoline-3-carboxylic acid (a) in 20 ml of 1-methyl-2-pyrrolidinone 7-
Chloro-1-phenyl-6-fluoro-1,4
-To a solution of 1.5 g of dihydro-4-oxo-quinoline-3-carboxylic acid at 115 DEG C. are added 3 g of 3-acetamido-pyrrolidine. After stirring at 100°C for 20 hours, the solvent was removed under reduced pressure and dried.
Add ethanol to the residue and wash with ether, then dilute with cold hydrochloric acid and then water. Dry the solid to give 1-phenyl-6-fluoro-1,4-
Dihydro-4-oxo-7-(3-acetamido-1-pyrrolidinyl)quinoline-3-carboxylic acid (9)

1.60 g of R=phenyl is obtained. (b) The above product is then hydrolyzed with hydrochloric acid at 80°C to produce 1-phenyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-amino-1-pyrrolidinyl)quinoline-3- Carboxylic acid(9)

[Formula R=phenyl] hydrochloride is obtained. Melting point >275℃. C ₂₀ H ₁₈ FN ₃ O ₃・
Analysis of HCl/H ₂ O Calculated values: C 56.94, H 4.98, N 9.96 Actual values: C 56.75, H 4.84, N 9.88. Example 26 1-p-fluorophenyl-6-fluoro-
1,4-dihydro-4-oxo-7-(3-amino-1-pyrrolidinyl)quinoline-3-carboxylic acid 7-chloro-1-phenyl-6-fluoro-
1,4-dihydro-4-oxo-quinoline-3-
1-p as described in Example 25 replacing the carboxylic acid with 7-chloro-1-p-fluorophenyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid. -Fluorophenyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-amino-1-pyrrolidinyl)quinoline-3-carboxylic hydrochloride (9)
(

[Formula R=p-fluorophenyl] is obtained in good yield. Example 27 1-p-hydroxyphenyl-6-fluoro-
1,4-dihydro-4-oxo-7-(3-amino-1-pyrrolidinyl)quinoline-3-carboxylic acid 7-chloro-1-phenyl-6-fluoro-
1,4-dihydro-4-oxo-quinoline-3-
carboxylic acid to 7-chloro-1-p-hydroxyphenyl-6-fluoro-1,4-dihydro-4-
1-p-Hydroxyphenyl-6-fluoro-1,4-dihydro-4-
Oxo-7-(3-amino-1-pyrrolidinyl)
Quinoline-3-carboxylic hydrochloride (9)
(

[Formula R=p-hydroxyphenyl] is obtained in good yield. Example 28 1-o,p-difluorophenyl-6-fluoro-1,4-dihydro-4-oxo-7-(3
-amino-1-pyrrolidinyl)quinoline-3-
Carboxylic acid 7-chloro-1-phenyl-6-fluoro-
1,4-dihydro-4-oxo-quinoline-3-
carboxylic acid to 7-chloro-1-o,p-difluorophenyl-6-fluoro-1,4-dihydro-
1-o,p-difluorophenyl-6-fluoro-1,4-dihydro-4-oxo-7-(3 -amino-1-pyrrolidinyl)quinoline-3-carboxylic acid and its hydrochloride (9) (

[Formula R=2,4-difluorophenyl] is obtained. Example 29 1-p-fluorophenyl-6-fluoro-
1,4-dihydro-4-oxo-7-(3-dimethylamino-1-pyrrolidinyl)quinoline-
3-Carboxylic acid When the procedure of Example 18 is repeated by replacing thiomorpholine with 3-dimethylaminopyrrolidine, 1 is obtained.
-p-fluorophenyl-6-fluoro-1,4
-dihydro-4-oxo-7-(3-dimethylamino-1-pyrrolidinyl)quinoline-3-carboxylic acid and its hydrochloride (9)
(

[Formula R=4-fluorophenyl] is obtained. Example 30 1-p-fluorophenyl-6-fluoro-
1,4-dihydro-4-oxo-7-(3-methylamino-1-pyrrolidinyl)quinoline-3
-Carboxylic acid a By repeating the procedure of Example 29 by replacing 3-dimethylaminopyrrolidine with 3-N-methylacetamidopyrrolidine, 1-p-fluorophenyl-6-fluoro-1,4-dihydro-
4-oxo-7-(3-N-methylacetamidopyrrolidinyl)quinoline-3-carboxylic acid (9)
(

[Formula R=4-fluorophenyl] is obtained. b Next, when the above product is hydrolyzed with hydrochloric acid at 80°C, 1-p-fluorophenyl-6-fluoro-
1,4-dihydro-4-oxo-7-(3-methylaminopyrrolidinyl)quinoline-3-carboxylic acid is obtained. Example 31 7-chloro-1-phenyl-6-fluoro-
1,4-dihydro-4-oxo-quinoline-3-
Various 1 instead of carboxylic acid (7) (R=phenyl)
-aryl-7-chloro-6-fluoro-1,4
Using -dihydro-4-oxo-quinoline-3-carboxylic acid (7), where aryl represents R, and replacing morpholine with a suitable substituted amine, the following additional compound (9) can be obtained: They are manufactured as summarized in the table.

【table】

[Table] The melting points of compounds in which R ₁ is H and R and Z are changed in formula () are shown in the table.

It will be obvious that various changes and modifications may be made in the details of operation, formulation and use without departing from the spirit of the invention.

Claims (1)

[Claims] 1 Formula: [However, R ₁ is hydrogen or a carboxy protecting group; R is a phenyl group, and the phenyl group is
each independently selected from the group consisting of halogen, C _1-6 alkyl, and groups having the formula -O-R ₃ , where R ₃ is hydrogen or C _1-6 alkyl.
may be substituted by ~3 groups (R ₂ ); and Z has the formula -NR ₄ R ₅ {where R ₄ and R ₅ are
Each is independently hydrogen or C _1-6 alkyl, or combined with the nitrogen atom to which they are bonded, with or without an oxygen atom, sulfur atom, or nitrogen atom, a 5- or 6-membered , and the aliphatic heterocycle is a C _1-6 alkyl and a formula -NR ₁₀ R ₁₁ (where R ₁₀ and R ₁₁ are each independently hydrogen, a C _1-6 alkyl or C _1-6 alkanoyl), and pharmaceutically Its salt acceptable.