KR100210006B1 - 7-substituted piperazinylamino-3-quinolonecarboxylic acid derivatives and the process for preparation thereof - Google Patents

Abstract

The present invention provides novel novel 7-substituted piperazinylamino-3-quinolone carboxylic acid derivatives of the general formula (I) and pharmaceutically acceptable salts thereof, which exhibit potent antimicrobial activity against both Gram positive and negative bacteria It relates to a production method and an antimicrobial composition containing these compounds as an active ingredient.

Wherein R is substituted or unsubstituted straight, branched or cyclic alkyl of 1 to 4 carbon atoms, or substituted or unsubstituted phenyl, and R ₁ is a hydrogen atom or a carboxy protecting group; R ₂ is a hydrogen atom, a halogen atom, nitro, cyano, substituted or unsubstituted amino, lower alkyl or lower alkoxy; R ₃ hydrogen atom, halogen atom, lower alkoxy, nitro, amino unsubstituted or substituted by lower alkyl, cyano, lower alkyl unsubstituted or substituted by halogen, or alkoxythio; R ₄ and R ₅ are the same or different and represent a hydrogen atom, straight, branched or cyclic alkyl, amino or alkyl amino of 1 to 3 carbon atoms; R ₆ and R ₇ are the same or different and represent 1 to 3 hydrogen atoms, lower acyl, unsubstituted or substituted straight chain, branched or cyclic alkyl having 1 to 7 carbon atoms, or heteroatoms selected from N, 0 and S; The containing 3-6 membered heterocyclic group is shown.

Description

7-substituted piperazinyl amino-3-quinolone carboxylic acid derivatives and preparation method thereof

The present invention relates to novel quinolone carboxylic acid derivatives represented by the following general formula (I) and salts thereof, methods for their preparation, and pharmaceutical compositions containing these compounds.

Wherein R is substituted or unsubstituted C1-C4 linear, branched or cyclic alkyl, or substituted or unsubstituted phenyl, and R ₁ is a hydrogen atom or a carboxy protecting group; R ₂ is a hydrogen atom, a halogen atom, nitro, cyano, substituted or unsubstituted amino, lower alkyl or lower alkoxy; R ₃ is a hydrogen atom, halogen atom, lower alkoxy, nitro, amino, cyano, lower alkyl unsubstituted or substituted by lower alkyl, or alkoxythio; R ₄ and R ₅ are the same or different and represent a hydrogen atom, straight, branched or cyclic alkyl, amino or alkyl amino of 1 to 3 carbon atoms; R ₆ and R ₇ are the same or different and represent 1 to 3 hydrogen atoms, lower acyl, unsubstituted or substituted straight chain, branched or cyclic alkyl having 1 to 7 carbon atoms, or heteroatoms selected from N, 0 and S; The containing 3-6 membered heterocyclic group is shown.

Since nalidixic acid was introduced as a treatment for urethritis caused by Gram-negative bacteria in 1963, a number of quinolone antibacterial agents have been developed that exhibit excellent antimicrobial activity and broad antimicrobial spectrum. Among them, 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -3-quinoline carboxylic acid having a common name cyprofloxacin is the Federal Republic of Germany. It is known that the quinolone antibacterial antibiotic described in Patent Application No. 3314854 shows very strong antibacterial activity against both Gram-positive bacteria and Gram-negative bacteria.

In addition, many compounds, such as oploxacin, difloxacin, lomefloxacin, have been developed and are currently in clinical or commercial market. However, these known compounds of the prior art have a strong antibacterial effect, strong toxicity to the central nervous system, low oral absorption or poor solubility has not been completely satisfactory.

The present inventors have been concentrating their research efforts on the development of a novel compound that complements the disadvantages of the antibacterial activity and the existing quinoline compounds as described above, and the piperazine ring is directly substituted at the 7 position of the quinolone base nucleus. Unlike most known compounds of the prior art, the introduction of a 4-amino piperazinyl group crosslinked with an amino group at position 7 not only against Gram-positive bacteria but also Gram-negative bacteria is equivalent to much better than cyprofloxacin. A new quinolone derivative exhibiting antimicrobial activity and excellent oral absorption and half-life has been prepared.

That is, the novel quinolone derivatives of the general formula (I) according to the present invention in which fluorine at position 6 and substituted 4-aminopiperazinyl amino group at position 7 are introduced, are both Gram-positive bacteria and Gram-negative bacteria. In particular, the compound of formula (I) having an amino group introduced at position 5 (R ₂ ) exhibits excellent antibacterial activity against methicillin resistant Staphylococcus aureus.

In addition, the novel compounds of general formula (I) according to the present invention have a much lower toxicity than oploxacin and can be used safely, and the oral absorption and half-life are much better than the conventional quinolone antibacterial agents.

The carboxy protecting groups which may be present in R ₁ in the compounds of formula (I) of the present invention are conventional carboxy protecting groups which are known to be able to produce freely decomposed free carboxyl groups, for example in the form of carboxylic esters.

Preferred compounds of formula (I) of the present invention are those wherein R ₁ represents a hydrogen atom or lower alkyl such as methyl or ethyl; R is cycloalkyl unsubstituted or substituted by fluoro, for example cyclopropyl, cyclobutyl or fluorocyclopropyl, straight or branched C ₁ -C ₄ alkyl unsubstituted or substituted by fluoro, for example Methyl, ethyl, tert-butyl or fluoroethyl, or phenyl unsubstituted or mono- or disubstituted by fluoro, for example phenyl, 4-fluorophenyl or 2,4-difluorophenyl; R ₂ represents a hydrogen atom, a halogen atom, lower alkyl such as methyl, amino unsubstituted or substituted by lower alkyl such as methyl or ethyl, or lower alkoxy such as methoxy; R ₃ is a hydrogen atom, a halogen atom, lower alkoxy, for example methoxy, lower alkyl unsubstituted or substituted by one to three halogens, for example methyl, unsubstituted or mono-substituted or disubstituted by methyl Or methoxythio; R ₄ and R ₅ are the same or different and represent a hydrogen atom, C ₁ -C ₂ alkyl, for example methyl or ethyl, cycloalkyl, for example cyclopropyl, or C ₁ -C ₃ alkylamino, for example methyl Amino, ethylamino or propyl amino; R ₆ and R ₇ are the same or different and are hydrogen, unsubstituted or mono- or di-substituted C ₁ -C ₇ alkyl, for example methyl, ethyl, propyl, hydroxy methyl, hydroxy ethyl, 3 to 6 members containing 1 to 3 heteroatoms selected from hydroxy propyl, butyl, pentyl, hexyl or heptyl, cycloalkyl, eg cyclopropyl, lower acyl, eg acetyl, or N, 0 and S Heterocyclic groups such as aziridine, azetidine, piperazine, morpholine, thiomorpholine, imidazole, triazole, tetrazole, thiazole group.

More preferred compounds of formula (I) are those wherein R is cyclopropyl, cyclobutyl, 2-fluorocyclopropyl, ethyl, 2-fluoroethyl, tert-butyl, phenyl, 4-fluorophenyl or 2,4 -Difluoro phenyl; R ₁ represents hydrogen; R ₂ represents a hydrogen atom or amino; R ₃ represents a hydrogen atom, fluoro or methoxy; R ₄ and R ₅ represent a hydrogen atom; R ₆ and R ₇ are the same or different and represent a hydrogen atom, acetyl or methyl.

Particularly preferred compounds of formula (I) according to the invention are those wherein R represents cyclopropyl, 2-fluorocyclopropyl or 2,4-difluoro phenyl; R ₁ represents a hydrogen atom; R ₂ represents a hydrogen atom or amino; R ₃ represents a hydrogen atom, fluoro; R ₄ and R ₅ represent a hydrogen atom; R <_6> and R <_7> is a compound which shows a hydrogen atom.

Particularly preferred compounds according to the invention are specifically the following compounds. 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- [N- (4-amino piperazin-1-yl) amino] -3-quinoline carboxylic acid; 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7- [N- (4-aminopiperazin-1-yl) amino] -3-quinoline carboxylic acid; 1-cyclopropyl-5-amino-6,8-difluoro-1,4-dihydro-4-oxo-7- [N- (4-aminopiperazin-1-yl) amino] -3-quinoline Carboxylic acid; 1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-7- [N- (4-aminopiperazin-1-yl) amino] -3- Quinoline carboxylic acid; 1- (2-fluorocyclopropyl) -6-fluoro-1,4-dihydro-4-oxo-7- [N- (4-aminopiperazin-1-yl) amino] -3-quinolinecarr Acid; And 1- (2-fluorocyclopropyl) -6,8-difluoro-1,4-dihydro-4-oxo-7 [N- (4-aminoperazine-1 yl) amino] 3- Quinoline carboxylic acid.

More preferred among the abovementioned particularly preferred compounds are 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7- [N- (4-amino piperazin-1-yl ) Amino] -3-quinoline carboxylic acid and 1-cyclopropyl-5-amino-6,8-difluoro-1,4-dihydro-4-oxo-7- [N- (4-aminopiperazin -1-yl) amino] -3-quinoline carboxylic acid.

According to the present invention, a 7-substituted pipera of general formula (I) is also condensed by reacting a quinolone carboxylic acid derivative of general formula (II) with a 4-amino piperazinyl amine derivative of general formula (III) A method for preparing a genyl amino-3-quinolone carboxylic acid derivative is provided.

Wherein R is substituted or unsubstituted straight, branched or cyclic alkyl of 1 to 4 carbon atoms, or substituted or unsubstituted phenyl; R ₁ is a hydrogen atom or a carboxy protecting group; R ₂ is a hydrogen atom, a halogen atom, nitro, cyano, substituted or unsubstituted amino, lower alkyl or lower alkoxy; R ₃ is a hydrogen atom, halogen atom, lower alkoxy, nitro, amino, cyano, lower alkyl unsubstituted or substituted by lower alkyl, or alkoxythio; R ₄ and R ₅ are the same or different and represent a hydrogen atom, straight, branched or cyclic alkyl, amino or alkyl amino of 1 to 3 carbon atoms; R ₆ and R ₇ are the same or different and represent 1 to 3 hydrogen atoms, lower acyl, unsubstituted or substituted straight, branched or cyclic alkyl having 1 to 7 carbon atoms, or heteroatoms selected from N, 0 and S; Containing 3 to 6 membered heterocyclic group, and X represents a halogen atom.

The reaction of the compound of formula (II) with the compound of formula (III) can be carried out in the presence or absence of a solvent. In terms of reaction kinetics, compound (II) and compound (III) may be By reacting at a mixing ratio, the desired novel quinolone derivative can be obtained in the best yield.

Solvents that can be used in the process of the invention are preferably alcohols, acetonitrile, dimethylformamide, dimethylsulfoxide, hexamethyl phosphoric triamide, pyridine, picoline, dioxane, chlorobenzene, toluene and the like Is preferably used in an amount of 5 to 10 times by weight based on the amount of the compound of formula (II).

The reaction of the present invention may also be carried out in the presence of a catalyst.

Examples of catalysts that can be used are tetraphenylphosphonium bromide and iodine, benzyltriethyl ammonium bromide and iodine, hexacarbonyl chromium, or salts in transition metals such as CuCl, CuCl ₂ , CoCl ₂ , NiCl ₂ , or Cu, Ni And metals such as Co. The amount of the catalyst used is 10 to 150% by weight, preferably 20 to 100% by weight based on the compound of formula (II).

In addition, the process of the present invention may be carried out using triethylamine, pyridine, quinoline, diazabicyclo [5.4.0] undec-7-ene, or the like as the acid binder in the absence of a catalyst.

In the method of the present invention, the reaction temperature is from room temperature to 150 , Preferably 50 to 140 The reaction time is 1 hour to overnight, most preferably 2 to 6 hours.

Compounds of general formula (I), which are the target compounds of the present invention, are pharmaceutically useful non-toxic acid addition salts or alkalis by conventional methods, for example, by separation with organic or inorganic acids or bases in the separation or purification of the final compound. It can be converted into salts with metals or earth metals. Representative acid addition salts include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and organic acid addition salts such as acetate, oxalate, tosylate, benzoate, stearate, laurate, succinate, fumarate, tartrate, and the like. Alkali metal or earth metal salts include sodium salts, potassium salts, calcium salts, magnesium salts, and the like.

The quinoline carboxylic acid derivatives of the novel general formula (I) of the present invention can be usefully used as an antimicrobial agent having a broad and strong antimicrobial spectrum against gram positive and gram negative bacteria. For this purpose, the compound (I) of the present invention may be formulated into a parenteral or intramuscular injection for parenteral administration or a composition for oral administration in solid or liquid form using a pharmaceutically useful carrier.

The compounds of the present invention may be formulated into injectable preparations, for example, sterile aqueous solutions, non-aqueous solutions, suspensions or emulsions, according to the usual methods for the preparation of injectables, which are suitable only with suitable non-aqueous carriers, diluents, solvents. But may also contain injectable organic esters such as propylene glycol, polyethylene glycol, vegetable oils, ethyl oleate. These injectables may also contain adjuvants such as preservatives, wetting agents, emulsifiers, dispersants and the like.

Solid preparations for oral administration include capsules, tablets, pills, powders, granules, and the like, which contain, in addition to the active compound, suspending agents such as starch, lactose, sucrose, and the like, and other adjuvants commonly used in the preparation of these preparations. can do. Tablets and pills may also be prepared in enteric preparations.

Liquid formulations for oral administration may be prepared from pharmaceutically available emulsions, solutions, suspensions, syrups and the like, including extracts containing siblings such as water commonly used in their formulation. In addition, in addition to excipients, these oral solutions may contain auxiliaries such as wetting agents, emulsifiers, suspending agents, sweetening agents, fragrances, and the like.

The present invention will be described in more detail with reference to the following Examples.

Example 1

Preparation of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- [N- (4-amino piperazin-1-yl) amino] -3-quinoline carboxylic acid

To 2 g of 6,7-difluoro-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinoline carboxylic acid 3.5 g of 1,4-diaminopiperazine hydrochloride, pyridine 2.8 , Triethylamine 1.4 And dimethyl sulfoxide 8.4 After warming up slowly and 80 Stir for 6 hours. After the reaction is complete, the reaction mixture is cooled and distilled under reduced pressure to remove the low boiling solvent. Water left over 10 Was added, stirred at room temperature, filtered and dried. After decomposing the crystals well again, methylene chloride solution 10 Slurry was added followed by filtration to afford 2 g (81.6%) of pure title compound.

Example 2

Preparation of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- [N- (4-acetylaminopiperazin-1-yl) amino] -3-quinoline carboxylic acid

100 mg of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- [N- (4-aminopiperazin-1-yl) amino] -3-quinoline carboxylic acid 2 After stirring for 1 hour at room temperature and gradually warmed to 20 to 40 Stir for 2 hours while maintaining. Distillation under reduced pressure to remove excess solvent and acetic acid Is added and the pH of the mixture is adjusted to 7. The resulting crystals are filtered off and dried to give 95 mg of pure title compound.

Example 3

Of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7- [N- (4-aminopiperazin-1-yl) amino] -3-quinoline carboxylic acid Produce

To 1 g of 6,7,8-trifluoro-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinoline carboxylic acid, 1.64 g of 1,4-diaminopiperazine hydrochloride, pyridine 2.8 , Triethylamine 1.4 And dimethyl sulfoxide 8 After warming up slowly, Stir for 4 hours. After the reaction was completed, the low boiling solvent was distilled off under reduced pressure to remove water 2 Is added and the pH is adjusted to 5.5-6.0. The product is filtered off and dried to yield 2.2 g (91%) of the pure title compound.

Example 4

1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7- [N- (4-acetylaminopiperazin-1-yl) amino] -3-quinoline carboxylic acid Manufacture

150 mg of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7- [N- (4-aminopiperazin-1-yl) amino] -3-quinoline carboxylic acid Acetic anhydride 3 Addition and treatment in the same manner as in Example 2 gave 130 mg of the title compound.

Example 5

1-cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxo-7- [N- (4-aminopiperazin-1-yl) amino] -3-quinoline carboxyl Manufacture of acid

200 mg of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7- [N- (4-aminopiperazin-1-yl) amino] -3-quinoline carboxylic acid In Dimethyl Formamide 7 And 126 mg of sodium methoxide were added and 120 to 140 Stir for 2 hours. After cooling, distillation under reduced pressure under high vacuum to remove dimethylformamide and water 2 Is added and the pH is adjusted to 4.

The resulting crystals were filtered off and dried to give 180 mg (87%) of the title compound.

Example 6

1-cyclopropyl-5-amino-6,8-difluoro-1,4-dihydro-4-oxo-7- [N- (4-aminopiperazin-1-yl) amino] -3-quinoline Preparation of Carboxylic Acids

0.3 g of 1,4-diaminopiperazine to 0.3 g of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid, Pyridine 1 , Triethylamine 0.4 And dimethyl sulfoxide 2.5 Was added followed by the same procedure as in Example 1 to yield 252 mg (70%) of the title compound.

Example 7

Preparation of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- [N- (4-aminopiperazin-1-yl) amino] -3-quinoline carboxylic acid

To 2.04 g of 1-ethyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid, 3.5 g of 1,4-diaminopiperazine hydrochloride was added to Example 1 and Treatment in the same manner affords 2 g of the title compound.

Example 8

Preparation of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- [N- (4-methylaminopiperazin-1-yl) amino] -3-quinoline carboxylic acid

1.3 g of 1-methylamino-4-aminopiperazine was added to 1.4 g of 1-ethyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid and Example 1 The same procedure as in the above yields 1 g of the title compound.

Example 9

Preparation of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7- [N- (4-aminopiperazin-1-yl) amino] -3-quinoline carboxylic acid

1.64 g of 1,4-diaminopiperazine hydrochloride was added to 2.7 g of 6,7,8-trifluoro-1-ethyl-1,4-dihydro-4-oxo-3-quinoline carboxylic acid and Example 3 The same procedure as in 3.2 g (87.2%) of the title compound was obtained.

Example 10

Of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7- [N- (4-methylaminopiperazin-1-yl) amino] -3-quinoline carboxylic acid Produce.

2.6 g of 1-methylamino-4-aminopiperazine was added to 2.7 g of 6,7,8-trifluoro-1-ethyl-1,4-dihydro-4-oxo-3-quinoline carboxylic acid and Example Treatment in the same manner as 3 affords 2 g of the title compound.

Example 11

1-ethyl-6-fluoro-8-ethoxy-1,4-dihydro-4-oxo-7- [N- (4-aminopiperazin-1-yl) amino] -3-quinoline carboxylic acid Manufacture

3.7 g of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7- [N- (4-aminopiperazin-1-yl) amino] -3-quinoline carboxylic acid Sodium methoxide 2.5 g and dimethylformamide 140 Was added and treated in the same manner as in Example 5 to obtain 3.2 g of the title compound.

Example 12

1-ethyl-5-amino-6,8-difluoro-1,4-dihydro-4-oxo-7- [N- (4-aminopiperazin-1-yl) amino] -3-quinolinecarr Preparation of Acids

0.3 g of 1,4-diaminopiperazine was added to 0.31 g of 1-ethyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid. The same procedure as in Example 6 gave 0.27 g of the title compound.

Example 13

Preparation of 1-phenyl-6-fluoro-1,4-dihydro-4-oxo-7- [N- (4-aminopiperazin-1-yl) amino] -3-quinoline carboxylic acid

To 2.27 g of 6,7-difluoro-1-phenyl-1,4-dihydro-4-oxo-3-quinoline carboxylic acid, 3.5 g of 1,4-diaminopiperazine hydrochloride was added and the same as in Example 1 Treatment is carried out to give 2.8 g of the title compound.

Example 14

1- (4-fluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-7- [N- (4-aminopiperazin-1-yl) amino] -3-quinoline carboxyl Manufacture of acid

To 2.4 g of 6,7-difluoro-1- (4-fluorophenyl) -1,4-dihydro-4-oxo-3-quinoline carboxylic acid, 3.5 g of 1,4-diaminopiperazine hydrochloride was added. Addition and treatment in the same manner as in Example 1 yielded 3.0 g of the title compound.

Example 15

1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-7- [N- (4-aminopiperazin-1-yl) amino] -3- Preparation of Quinoline Carboxylic Acid

1,4-diaminopiperazine hydrochloride in 2.55 g of 1- (2,4-difluorophenyl) -6,7-difluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid 3.5 g was added and treated in the same manner as in Example 1 to obtain 2.2 g of the title compound.

Example 16

1- (2-fluoroethyl) -6-fluoro-1,4-dihydro-4-oxo-7- [N- (4-aminopiperazin-1-yl) amino] -3-quinoline carboxyl Manufacture of acid

To 2.05 g of 1- (2-fluoroethyl) -6,7-difluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid, 3.5 g of 1,4-diaminopiperazine hydrochloride was added. Addition and treatment in the same manner as in Example 1 yielding 1.95 g of the title compound.

Example 17

1- (tert-butyl) -6-fluoro-1,4-dihydro-4-oxo-7- [N- (4-aminopiperazin-1-yl) amino] -3-quinoline carboxylic acid Manufacture

To 2.1 g of 1- (tert-butyl) -6,7-difluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid, 3.5 g of 1,4-diaminopiperazine hydrochloride was added thereto. The same procedure as in Example 1 gave 1.05 g of the title compound.

Example 18

1- (2-fluorocyclopropyl) -6-fluoro-1,4-dihydro-4-oxo-7- [N- (4-aminopiperazin-1-yl) amino] -3-quinolinecarr Preparation of Acids

3.5 g of 1,4-diaminopiperazine hydrochloride was added to 2 g of 1- (2-fluorocyclopropyl) -6,7-difluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid. Addition and treatment in the same manner as in Example 1 yielding 1.8 g of the title compound.

Example 19

Preparation of 1- (cyclobutyl) -6-fluoro-1,4-dihydro-4-oxo-7- [N- (4-aminopiperazin-1-yl) amino] -3-quinoline carboxylic acid

3.5 g of 1,4-diaminopiperazine hydrochloride was added to 2.1 g of 1- (cyclobutyl) -6,7-difluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid and Treatment in the same manner as 1 affords 1.95 g of the title compound.

Example 20

Preparation of 1-phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7- [N- (4-aminopiperazin-1-yl) amino] -3-quinoline carboxylic acid

1.64 g of 1,4-diaminopiperazine hydrochloride was added to 2.26 g of 6,7,8-trifluoro-1-phenyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and Example 3 The same procedure as in the above yields 2.02 g of the title compound.

Example 21

1- (4-fluorophenyl) 6,8-difluoro-1,4-dihydro-4-oxo-7- [N- (4-aminopiperazin-1-yl) amino] -3-quinoline Preparation of Carboxylic Acids

1.64 g of 1,4-diaminopiperazin hydrochloride to 2.38 g of 6,7,8-trifluoro-1- (4-fluorophenyl) 1,4-dihydro-4-oxo-3-quinoline carboxylic acid Was added and treated in the same manner as in Example 3 to obtain 2.0 g of the title compound.

Example 22

1- (tert-butyl) -6,8-difluoro-1,4-dihydro-4-oxo-7- [N- (4-aminopiperazin-1-yl) amino] -3-quinoline Preparation of Carboxylic Acids

1.64 g of 1,4-diaminopiperazin hydrochloride in 2.1 g of 1- (tert-butyl) -6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid Was added and treated in the same manner as in Example 3 to yield 1.85 g of the title compound.

Example 23

1- (2-fluorocyclopropyl) -6,8-difluoro-1,4-dihydro-4-oxo-7- [N- (4-aminopiperazin-1-yl) amino] -3 Preparation of -quinoline carboxylic acid

1,4-diaminopiperazine hydrochloride in 1.9 g of 1- (2-fluorocyclopropyl) -6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid 1.64 g was added and treated in the same manner as in Example 3 to obtain 1.5 g of the title compound.

Example 24

1- (4-fluorophenyl) -6-fluoro-8-methoxy-1,4-dihydro-4-oxo-7- [N- (4-aminopiperazin-1-yl) amino]- Preparation of 3-quinoline carboxylic acid

1- (4-fluorophenyl) -6,8-difluorophenyl-1,4-dihydro-4-oxo-7- [N- (4-aminopiperazin-1-yl) amino] -3 0.25 g of -quinoline carboxylic acid was treated in the same manner as in Example 5 to obtain 0.22 g of the title compound.

Example 25

1-phenyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxo-7- [N- (4-aminopiperazin-1-yl) amino] -3-quinoline carboxylic acid Manufacture

0.24 g of 1-phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7- [N- (4-aminopiperazin-1-yl) amino] -3-quinoline carboxylic acid Was prepared as a starting material in the same manner as in Example 5 to obtain 0.2 g of the title compound.

Example 26

1- (tert-butyl) -6-fluoro-8-methoxy-1,4-dihydro-4-oxo-7- [N- (4-aminopiperazin-1-yl) amino] -3 Preparation of -quinoline carboxylic acid

0.23 g of the compound prepared in Example 22 was treated as a starting material in the same manner as in Example 5 to obtain 0.19 g of the title compound.

Example 27

1- (4-fluorophenyl) -5-amino-6,8-difluoro-1,4-dihydro-4-oxo-7- [N- (4-aminopiperazin-1-yl) amino ] -3-Quinoline Carboxylic Acid

1,4-diamino to 0.35 g of 1- (4-fluorophenyl) -5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid 0.3 g of piperazine hydrochloride was added and treated in the same manner as in Example 6 to obtain 0.3 g of the title compound.

Example 28

1-phenyl-5-amino-6,8-difluoro-1,4-dihydro-4-oxo-7- [N- (4-aminopiperazin-1-yl) amino] -3-quinolinecarr Preparation of Acids

0.3 g of 1,4-polyaminopiperazine hydrochloride to 0.33 g of 1-phenyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid Addition and treatment in the same manner as in Example 6 yielding 0.28 g of the title compound.

Example 29

1- (tert-butyl) -5-amino-6,8-difluoro-1,4-dihydro-4-oxo-7- [N- (4-aminopiperazin-1-yl) amino] Preparation of 3-Quinoline Carboxylic Acid

1,4-diaminopipe to 0.31 g of 1- (tert-butyl) -5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid 0.3 g of azine hydrochloride was added and treated in the same manner as in Example 6 to yield 0.25 g of the title compound.

The target compound (I) of the present invention exhibits excellent antimicrobial activity against both Gram-positive and Gram-negative bacteria. Table (I) shows the minimum inhibitory concentrations (MIC,) of the representative general formula (I) compounds prepared in Examples 1 to 12 Of ). The minimum inhibitory concentration was determined by testing the antimicrobial activity using an in vitro dilution method according to the Japanese Chemotherapy Society standard method. I.e. Brain Heart Infusion (pH7.0) badge 5 Serial dilution of test compound in water (0.0313-4.0 Of ) And inoculate about 10 test bacteria It was determined after 18 hours of incubation at.

Table 2 also shows the antimicrobial activity (MIC value) of methicillin resistant Staphylococcus aureus of the compound of formula (I) of the present invention.

Claims (15)

7-substituted piperazinylamino-3-quinolone carboxylic acid derivatives of general formula (I) and pharmaceutically acceptable salts thereof. Wherein R is substituted or unsubstituted straight, branched or cyclic alkyl of 1 to 4 carbon atoms, or substituted or unsubstituted phenyl, and R ₁ is a hydrogen atom or a carboxy protecting group; R ₂ is a hydrogen atom, a halogen atom, nitro, cyano, substituted or unsubstituted amino, lower alkyl or lower alkoxy; R ₃ is a hydrogen atom, halogen atom, lower alkoxy, nitro, amino, cyano, lower alkyl unsubstituted or substituted by lower alkyl, or alkoxythio; R ₄ and R ₅ are the same or different and represent a hydrogen atom, straight, branched or cyclic alkyl, amino or alkyl amino of 1 to 3 carbon atoms; R ₆ and R ₇ are the same or different and represent 1 to 3 hydrogen atoms, lower acyl, unsubstituted or substituted straight, branched or cyclic alkyl having 1 to 7 carbon atoms, or heteroatoms selected from N, 0 and S; The containing 3-6 membered heterocyclic group is shown. The compound of claim 1, wherein R is cycloalkyl unsubstituted or substituted by fluoro, straight or branched C ₁ -C ₄ alkyl unsubstituted or substituted by fluoro, or mono-substituted or substituted by fluoro. Di-substituted phenyl; R ₁ represents a hydrogen atom or lower alkyl; R ₂ represents a hydrogen atom, a halogen atom, lower alkyl, amino or lower alkoxy unsubstituted or substituted by lower alkyl; R ₃ represents a hydrogen atom, a halogen atom, lower alkoxy, lower alkyl unsubstituted or substituted by one to three halogen atoms, amino unsubstituted or monosubstituted or substituted by methyl, or methoxythio; R ₄ and R ₅ are the same or different and represent a hydrogen atom, C ₁ -C ₂ alkyl, cycloalkyl or C ₁ -C ₃ alkylamino; R ₆ and R ₇ are the same or different and are hydrogen atom, unsubstituted or mono- or di-substituted C ₁ -C ₇ alkyl, cycloalkyl, lower acyl or hetero atoms selected from N, 0 and S Quinolone carboxylic acid derivatives of formula (I) which are three to six membered heterocyclic groups. The compound of claim 2, wherein R is cyclopropyl, cyclobutyl, 2-fluorocyclobutyl, ethyl, 2-fluoroethyl, tert-butyl, phenyl, 4-fluorophenyl or 2,4-difluorophenyl Represents; R ₁ represents a hydrogen atom; R ₂ represents a hydrogen atom or amino; R ₃ represents a hydrogen atom, fluoro or methoxy; R ₄ , and R ₅ represent a hydrogen atom; R ₆ and R ₇ are the same or different and the quinolone carboxylic acid derivative of the general formula (I) representing a hydrogen atom, acetyl or methyl. The compound of claim 3, wherein R represents cyclopropyl, 2-fluorocyclopropyl or 2,4-difluorophenyl; R ₁ represents a hydrogen atom; R ₂ represents a hydrogen atom or amino; R ₃ represents a hydrogen atom or fluoro; R ₄ and R ₅ represent a hydrogen atom; R ₆ and R ₇ are quinolone carboxylic acid derivatives of the general formula (I) representing a hydrogen atom. The compound of claim 1, wherein 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- [N- (4-aminopiperazin-1-yl) amino] -3-quinoline carbamide Acids, and 1-cyclopropyl-5-amino-6,8-difluoro-1,4-dihydro-4-oxo-7- [N- (4-aminopiperazin-1-yl) amino] Quinolone carboxylic acid derivative of formula (I) selected from 3-quinoline carboxylic acid. A condensation reaction of a quinolone carboxylic acid derivative of formula (II) with a 4-aminopiperazinyl amine derivative of formula (III), wherein 7-substituted piperazinylamino Process for preparing 3-quinolone carboxylic acid derivatives and salts thereof. Wherein R is substituted or unsubstituted straight, branched or cyclic alkyl of 1 to 4 carbon atoms, or substituted or unsubstituted phenyl; R ₁ is a hydrogen atom or a carboxy protecting group; R ₂ is a hydrogen atom, a halogen atom, nitro, cyano, substituted or unsubstituted amino, lower alkyl or lower alkoxy; R ₃ is a hydrogen atom, halogen atom, lower alkoxy, nitro, amino, cyano, lower alkyl unsubstituted or substituted by lower alkyl, or alkoxythio; R ₄ and R ₅ are the same or different and represent a hydrogen atom, straight, branched or cyclic alkyl, amino or alkyl amino of 1 to 3 carbon atoms; R ₆ and R ₇ are the same or different and represent 1 to 3 hydrogen atoms, lower acyl, unsubstituted or substituted straight, branched or cyclic alkyl having 1 to 7 carbon atoms, or heteroatoms selected from N, 0 and S; A containing 3 to 6 membered heterocyclic group; X represents a halogen atom. The method of claim 6, wherein compound (II) and compound (III) are reacted in a ratio of 1: 1.5 to 1: 3. The method of claim 6, wherein the reaction is carried out in the presence of a solvent. The method of claim 8, wherein the solvent is selected from the group consisting of alcohol, acetonitrile, dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, pyridine, picoline, dioxane, chlorobenzene and toluene. 10. The process according to claim 9, wherein the solvent is used in an amount of 5 to 10 times by weight based on the compound of formula (II). The process of claim 6 wherein the reaction is carried out in the presence of a catalyst. The process of claim 11 wherein the catalyst is selected from the group consisting of tetraphenylphosphonium bromide and iodine, benzyltriethyl ammonium bromide and iodine, hexacarbonyl chromium, CuCl, CuCl ₂ , NiCl ₂ and metals Cu, Ni and Co . The process according to claim 12, wherein the catalyst is used in an amount of 10 to 150% by weight based on the compound of formula (II). The method of claim 6, wherein the reaction is carried out in the presence of an acid binder. The method of claim 6, wherein the reaction is from room temperature to 150 The process is carried out at a temperature of 1 hour to overnight.