KR0166179B1 - Novel quinolone carboxylic acid derivative and process for the preparation thereof - Google Patents

Abstract

The present invention provides a quinoline carboxylic acid derivative of the general formula (I) and a pharmaceutically acceptable salt thereof, a preparation method thereof, and an antimicrobial composition containing the same as an active ingredient, which exhibits strong antibacterial activity against Gram-positive bacteria as well as Gram-positive bacteria. It is about.

Wherein R ¹ is optionally selected from lower alkyl of 1 to 4 carbon atoms, lower haloalkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkenyl of 2 to 4 carbon atoms, or 1 or 2 fluorine atoms A substituted phenyl group or AO (or S) CH ₂ CH (CH ₃ ) -N or the like which is ring-closed at the A position to form a thiazole or oxazole ring, and R ² is a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms, Z Is

Where R ³ is a fluoro atom or a hydroxy group, X is a hydrogen atom, a halogen atom, a methyl or an amino group, and A is a nitrogen atom or CY (wherein Y is a hydrogen atom, a halogen atom, or a hydroxy group). , Methoxy or methyl group.).

Description

New quinoline carboxylic acid derivatives and preparation method thereof

The present invention relates to a quinoline carboxylic acid derivative of the general formula (I) and a pharmaceutically acceptable salt thereof, a preparation method thereof, and a pharmaceutical preparation containing the same, which exhibit a strong antibacterial activity against Gram-negative bacteria as well as Gram-positive bacteria. .

Wherein R ¹ is optionally selected from lower alkyl of 1 to 4 carbon atoms, lower haloalkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkenyl of 2 to 4 carbon atoms, or 1 or 2 fluorine atoms A substituted phenyl group or AO (or S) CH ₂ CH (CH ₃ ) -N or the like which is ring-closed at the A position to form a thiazole or oxazole ring, and R ² is a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms, Z Is

Where R ³ is a fluoro atom or a hydroxy group, X is a hydrogen atom, a halogen atom, a methyl or an amino group, and A is a nitrogen atom or CY (wherein Y is a hydrogen atom, a halogen atom, or a hydroxy group). , Methoxy or methyl group.).

The quinoline carboxylic acid-based antimicrobial substances currently used have strong activity against Gram-negative bacteria, but have weak activity against Gram-positive bacteria, and thus, strong activity of Gram-positive bacteria as well as Gram-positive bacteria is required. The present inventors conducted a study of introducing an amine derivative having a haloalkylamino group as a substituent at the 7 position of the quinoline carboxylic acid mother nucleus to improve the problems of the conventional quinolone antibacterial substances, the excellent antibacterial activity to Gram-positive bacteria The present invention was completed by synthesizing a new compound having.

Accordingly, an object of the present invention is to overcome the drawbacks of conventional quinoline carboxylic acid-based antimicrobial substances and to produce novel quinoline carboxylic acid derivatives and drugs represented by the above general formula (I), which have excellent antibacterial activity against Gram-negative bacteria as well as Gram-positive bacteria. To provide a salt that is academically acceptable.

Another object of the present invention is to provide a quinoline carboxylic acid derivative represented by the general formula (I) and a method for producing a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide an antibacterial agent containing a quinoline carboxylic acid derivative represented by the general formula (I) and a pharmaceutically acceptable salt thereof as an active ingredient.

Still another object of the present invention is to provide amine derivatives of the following general formula (VI) which are useful intermediates for the preparation of quinoline carboxylic acid derivatives of the general formula (I).

In the above formula, R ³ is as defined above.

Hereinafter, the present invention will be described in detail.

The present invention relates to a novel quinoline carboxylic acid derivative represented by general formula (I), and specific examples of R ¹ in general formula (I) include ethyl, fluoroethyl, cyclopropyl, tertiary butyl, 2,4-difluorophenyl, AO (or s) made of a tooth or a sol-oxa jolhwan ring closure to a phenyl group, a position-fluoro CH may be mentioned ₂ CH (CH ₃₎ -N, etc., of R ² Specific examples thereof include a hydrogen atom, methyl and an ethyl group.

X may be a hydrogen atom, methyl, amino group, A represents a nitrogen atom or CY, where Y is a hydrogen atom, fluorine, chloro atom, hydroxy, methoxy, methyl group, R Specific examples of ³ are a fluoro group, a hydroxyl group and the like.

Such a compound of the general formula (I) of the present invention and salts thereof are very useful as antibacterial agents as compounds which exhibit very strong antibacterial activity against gram-negative bacteria as well as gram-positive bacteria.

According to the present invention, specific examples of the new amine derivative introduced at the 7 position of the quinoline carboxylic acid nucleus represented by the general formula (I) are [3- (N-fluoroethyl) amino-3-hydroxymethyl] py; Rollidinyl and [3- (N-fluoroethyl) amino-3-fluoromethyl] pyrrolidinyl.

Specific examples of the compound for general formula (I) may be enumerated as follows, but the present invention is not limited to the compounds described below.

And pharmaceutically acceptable salts thereof.

Looking at the preparation method of the compound of formula (I) according to the present invention as described above, by reacting the quinoline carboxylic acid of the following formula (II) in an inert solvent or a basic solvent with the amine of the following formula (VI) It can manufacture.

In the above formulas, R ¹ , R ² , R ³ , X, and A are as defined above, and R ⁷ is a halogen atom.

Examples of suitable solvents here include tetrahydrofuran, pyridine, ethanol, propanol, butanol, chloroform, dimethylsulfoxide, dimethylformamide, water, acetonitrile, dioxane or mixtures thereof.

According to the present invention, when the solvent used in this method is not a basic solvent such as pyridine, it is preferable to add a base to the reaction mixture, in which the base reacts with hydrogen halide generated in the reaction to promote completion of the reaction. It serves as a main, and for example, 1,8-diazabicyclo [5.4.0] undes-7-ene (DBU), triethylamine, potassium carbonate or a mixture thereof may be used as the organic base and the inorganic base.

According to the present invention, a preferred solvent of the solvent is acetonitrile, and as a preferred base, 1,8-diazabicyclo [5.4.0] undes-7-ene (DBU), triethylamine or a mixture thereof is used. Especially preferred is an acetonitrile solvent containing 1 to 3 equivalents of base.

In general, such a method is more preferably prepared under atmospheric pressure at a temperature of 50 to 190 ° C, and the reaction time is prepared by reacting for 1 hour to 58 hours, and the produced product is separated by a conventional method.

For example, the resulting precipitate can be separated by filtration or by adding water to the reaction mixture and adjusting the pH to 7.0-7.4, collecting the resulting precipitate by filtration, washing with water or organic solvent and drying the precipitate. have.

On the other hand, the compounds of the formula (II) used in the preparation of the compound of the formula (I) of the present invention can be prepared by a known method.

Further, the amine compounds of the general formula (VI) are novel compounds useful for the preparation of the quinolone carboxylic acid derivatives having antimicrobial activity according to the present invention, wherein the amine compounds of the general formula (VI) are known starting materials, For example, it may be prepared from the benzylamine and the ethyl acrylate derivative through the reaction of the following reaction formula (I).

Compound (1) may be obtained by reacting ethyl acrylate and benzylamine in a methanol solvent in the process of preparing the compound of Scheme (I), and compound (2) is obtained by reacting compound (1) with ethylchloroacetate in a pyridine solvent. It can obtain by reaction, and compound (3) can be obtained by ring-closing compound (2) with a suitable base. For example, a known base can be used, and sodium hydride, potassium-tert-butoxide and the like can be preferably used.

Compound (4) can be obtained by appropriate decarboxylation of the ketoester group of compound (3) in the reaction process. For example, it can be obtained by stirring under reflux for several hours in the presence of p-toluenesulfonyl chloride or hydrochloric acid.

Compound (5) can be obtained by reacting compound (4) with ammonium carbonate, potassium cyanide and ethanol solvent, and compound (6) is obtained by reacting compound (5) with barium hydroxide in water solvent. Can be. Compound (7) can be obtained by esterification of compound (6) in methanol solvent and compound (8) can be prepared by reducing compound (7) with a suitable reducing agent.

For example, a well-known reducing agent can be used, Preferably sodium borohydride, lithium aluminum hydride, sodium cyanoborohydride, etc. can be used.

Compound (9) is obtained by reacting compound (8) with 2-fluoroethylsilate. Compound (10) is a diethylaminosulfatrifluoride after protecting the secondary amine group of compound (9) with a t-butyl carbamate group. It can be obtained by reacting with (Dast) and acid treatment to remove t-butyl carbamate group, and hydrogenated reacting compound (9) and compound (10) under palladium catalyst to form the desired compound in general formula (VI). A compound can be obtained.

On the other hand, pharmaceutically acceptable acid addition salts of the novel compounds of general formula (I) prepared as described above are prepared in a conventional manner to prepare a solution or suspension of the free base of general formula (I) in about 1 chemical equivalent Prepared by treatment with a scientifically acceptable acid.

Here, conventional concentration and recrystallization methods are used for the separation of salts, and examples of suitable acids include acetic acid, lactic acid, succinic acid, maleic acid, tartaric acid, citric acid, gluconic acid, ascorbic acid, benzic acid, methanesulfonic acid, shin Namsan, fumaric acid, phosphonic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, etc. are mentioned. In addition, pharmaceutically acceptable cationic salts of the compounds of general formula (I) are prepared by conventional methods from the corresponding acids, for example, can be prepared with about 1 equivalent molar base, and examples of cationic salts Alkali metals such as sodium or potassium, alkaline earth metals such as magnesium or calcium or diethanolamine, ammonium or organic amine salts such as N-methylglucan phosphorus or arginine.

According to the invention, these compounds of formula (I) and their pharmaceutically acceptable salts have been found to be antimicrobial agents with a wide range of effects useful in the treatment of bacterial infections, in particular in the treatment of Gram-positive bacteria infections.

The compound of the present invention can be administered to humans and animals alone for the treatment of bacterial diseases, but can usually be administered in combination with a pharmaceutical carrier selected in consideration of the route of administration and standard pharmaceutical practices.

For example, it can be administered orally in the form of tablets containing excipients such as starch or lactose, alone or in the form of capsules in admixture with excipients, in the form of elisers, or in the form of suspensions containing flavoring or coloring agents. Can be.

In addition, sterile aqueous solutions may be injected parenterally, intramuscularly, intravenously or subcutaneously and may contain other solutes (eg, sufficient amounts of salt or glucose) for preparing equivalent solutions for parenteral administration. The form of is used most satisfactorily.

In order to elucidate the pharmacological usefulness of the compound of the formula (I) of the present invention, the antimicrobial activity was performed on the representative compounds in the compound (I) of the present invention.

Experimental Example 1. Antimicrobial Activity Test

The test method of the antimicrobial test was performed by the standard method of the Japanese Chemotherapy Society (refer to Chemotherapy, Vol. 29, 76 ~ 79, (1981)), which is an agar plate dilution method.

Test strains were cultured three times or more continuously (37 ° C., 18 hours) in Mueller-Hinton Agar to have optimal activity, and then again in Mueller-Hinton broth. Inoculation was incubated for 18 hours at 37 ℃. The culture solution was diluted to about 10 ⁷ concentrations (CFU) of bacteria per ml, and the Mueller-Hinton agar medium (100-0.006 µg) containing the test compound diluted in twofold steps using a microorganism inoculator. / Ml) was inoculated at a concentration of 5 μl.

Thereafter, the medium was incubated at 37 ° C. for 18 hours, and the agar plates inoculated by diluting stepwise two times were arranged in a row and visually observed to determine the concentration of the antimicrobial material whose growth was inhibited as the minimum growth inhibition concentration (MIC). [10% sheep blood was added at the time of subculture and 10% horse serum was used at the time of liquid culture to maintain optimal activity of some specific bacteria.]

The 20 strains used in this experiment were urinary tract infection, scarlet fever, impetigo, purulent skin disease, intestinal bacterial infection, respiratory infection, pneumonia and meningitis.

-Gram-positive bacteria-

Streptococcus Pyogenes 308 A

2. Streptococcus Pyogenes 77 A

3. Streptococcus faecium MD 8b

4. Staphylococcus aureus SG 511

5. Staphylococcus aureus 285

6. Staphylococcus aureus 503

-Gram negative bacteria-

7.Escherichia coli 078

8. Escherichia coli DC 0

9. Escherichia coli DC 2

10. Escherichia coli TEM

11.Escherichia coli 1507 E

12.Pseudomonas aeruginosa 9027

13. Pseudomonas aeruginosa 1592 E

14.Pseudomonas aeruginosa 1771

15.Pseudomonas aeruginosa 1771 M

16. Salmonella typhimurium

17.Klebsiella oxytoca 1082 E

18.Klebsiella oxytoca 1522 E

19. Enterbacter cloacae P 99

20. Enterbacter cloacae 1321 E

The antimicrobial activity test results for the test strains were measured using the preparation compounds of Examples to be described in Table 1 below.

Experimental Example 2. Acute Toxicity Test

In order to determine the usefulness of the compound according to the present invention as a drug, an acute toxicity test was conducted on the compound of Examples 8-12.

Experimental animals were 4 weeks old ICR mice were used in each group of eight mice.

The dose was set to 5000 mg / kg for the highest dose group in consideration of preliminary test results and drug solubility, and 0.5% CMC-Na solution was administered to the control group. Observations were made every hour for 6 hours after administration, and changes in general condition, poisoning symptoms, and deaths were observed once a day from the next day of administration to 14 days. The results are shown in Table 2 below.

As a result of this experiment, the LD value was 210-260 mg / kg in the intravenous injection of the compound of Example 8-12 and 2,600-3,300 mg / kg in the oral administration, clearly demonstrating the high stability as a medicine.

Hereinafter, the present invention will be described in detail with reference to Examples.

Example 1

[Preparation of 1-benzyl-3-pyrrolidinone]

11 g of 1-benzyl-3- (methoxycarbonyl) pyrrolidin-4-one was added to 45 ml of 18% hydrochloric acid solution, stirred under reflux for 3 hours, and then concentrated under reduced pressure. The residue was dissolved in 55 ml of water, cooled to 0 ° C., adjusted to pH 11-12 by adding potassium carbonate, extracted with carbon dichloride, concentrated under reduced pressure to remove the solvent and distilled under reduced pressure to give 5.1 g of the target compound as a slightly yellow oil (yield: 65.7%).

Example 2

[Preparation of 8-benzyl-1,3,8-triazaspiro [4,4] bedside]

15 g of 1-benzyl-3-pyrrolidinone and 8.36 g of potassium cyanide and 24.7 g of ammonium carbonate were dissolved in 150 ml of 50% aqueous solution of ethanol, followed by stirring for 5-6 hours while maintaining the temperature at 55-75 ° C. Let's do it. After the reaction mixture was cooled to room temperature, 200 ml of water was added thereto, and the resulting crystals were adjusted to pH 7-8 with concentrated hydrochloric acid. The resulting crystals were filtered, washed with cold water and dried to obtain 16.8 g (yield: 80.2%) of the title compound.

Example 3

[Preparation of 1-benzyl-3-amino-3-methoxycarbonylpyrrolidine]

13 g of 1-benzyl-3-amino-3-pyrrolidinecarboxylic acid is dissolved in 130 ml of methanol and stirred under reflux for 70 minutes under hydrochloric acid gas. The reaction solution was concentrated under reduced pressure, the pH was adjusted to 8-9 with 25% sodium bicarbonate solution, extracted with carbon dichloride, and concentrated under reduced pressure to obtain 9.1 g (yield: 65.8%) of the target compound.

Example 4

[Preparation of 1-benzyl- [3- (N-fluoroethyl) amino-3-hydroxymethyl] pyrrolidine]

6.5 g of 1-benzyl- (3-amino-3-hydroxymethyl) pyrrolidine and 8.25 g of 2-fluoroethyltosylate are added to 65 ml of methanol and stirred under reflux for 6 hours. The reaction solution was concentrated under reduced pressure, the residue was adjusted to pH 2-3 with 10% hydrochloric acid solution, extracted with water, adjusted to pH 7-8 with sodium bicarbonate, extracted with chloroform, concentrated under reduced pressure, and the target product was separated by column chromatography. The concentrate was concentrated under reduced pressure to give 5.6 g (yield: 70.4%) of the title compound as a pale yellow oil.

Example 5

[Preparation of 3- (N-fluoroethyl) amino-3-hydroxymethyl] pyrrolidine]

1.0 g of 1-benzyl- [3- (N-fluoroethyl) amino-3-hydroxymethyl] pyrrolidine was dissolved in 100 ml of methanol, and 0.3 g of 10% -palladium / carbon catalyst was added thereto at room temperature. Stir for 20 hours at 30 ps. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain 0.6 g of an oily compound (yield: 93.7%).

Example 6

[Preparation of 1-benzyl- [3- (N-fluoroethyl) amino-3-fluoromethyl] pyrrolidine]

5 g of a compound obtained by reacting 1-benzyl- [3- (N-fluoroethyl) amino-3-hydroxymethyl) pyrrolidine with 2-fluoroethyltosylate as in Example 4 was added to 30 ml of carbon dichloride. After dissolving, 5.4 g of di-t-dibutyldicarbonate was slowly added at 10 DEG C, stirred at room temperature for 1 hour, and 50 ml of carbon dichloride was added to the residue under reduced pressure, and then dissolved under 3.78 g of -85 DEG C. Diethylaminosulfatrifluoride (Dast) is slowly added dropwise. After dropping, the mixture is heated to room temperature, stirred at room temperature for about 3 hours, extracted with water, concentrated under reduced pressure, and stirred at room temperature for 3 hours by adding 6N-HCl aqueous solution. It is adjusted to pH 11-12 with 1N aqueous sodium hydroxide solution and extracted with carbon dichloride. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the target was separated by column chromatography. The separated solution was concentrated under reduced pressure to obtain 3.64 g (yield: 72.3%) of the target compound as a slightly yellow oil.

Example 7

[Preparation of 3- (N-fluoroethyl) amino-3-fluoromethyl] pyrrolidine]

In the same manner as in Example 5, 1-benzyl- [3- (N-fluoroethyl) amino-3-fluoromethyl] pyrrolidine was used to obtain 0.5 g (yield 88.6%) of the desired compound in the oil phase. .

Example 8

[5-amino-1-cyclopropyl-6,8-difluoro-7- [3- (N-fluoroethyl) amino-3-hydroxymethyl] pyrrolidinyl-1,4-dihydro-4 Preparation of oxo-3-quinoline carboxylic acid]

To 5 ml of acetonitrile, 0.25 g of cyclopropyl-5-amino-6,8-difluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid and 0.18 g of [3- (N-fluoro Roethyl) amino-3-hydroxymethyl] pyrrolidine is added, and 0.32 ml of 1,8-diazabicyclo- [4.4.0] -undes-7ene is added, followed by stirring under reflux for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was crystallized by adding water. The resulting crystals were filtered, washed with acetonitrile and diethyl ether, and recrystallized with methanol / dimethylformamide to yield 0.24 g of a target compound as a pale yellow solid (yield: 62.5%). Get)

m.p. : 196-198 ℃

Example 9

[1-cyclopropyl-6,8-difluoro-7- [3- (N-fluoroethyl) amino-3-hydroxymethyl] pyrrolidinyl-1,4-dihydro-4-oxo-3 Preparation of Quinoline Carboxylic Acid]

In the same manner as in Example 8, 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid was used to obtain the title compound as a pale yellow solid. .

m.p .: 193-195 ° C

Example 10

[1-cyclopropyl-6-fluoro-7- [3- (N-fluoroethyl) amino-3-fluoromethyl] pyrrolidinyl-1,4-dihydro-4-oxo-3-quinolinecarr Preparation of Acids]

In the same manner as in Example 8, 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid was used to obtain the title compound as a pale yellow solid.

m.p .: 190-192 ° C

Example 11

[1-cyclopropyl-6,8-difluoro-7- [3- (N-fluoroethyl) amino-3-fluoromethyl] pyrrolidinyl-1,4-dihydro-4-oxo-3 Preparation of Quinoline Carboxylic Acid]

In the same manner as in Example 8, 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid was used to obtain the title compound as a pale yellow solid. .

m.p .: 194-196 ° C

Example 12

[5-amino-1-cyclopropyl-6,8-difluoro-7- [3- (N-fluoroethyl) amino-3-fluoromethyl] -pyrrolidinyl-1,4-dihydro- Preparation of 4-oxo-3-quinoline carboxylic acid]

In the same manner as in Example 8, 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid was used as a pale yellow solid. Obtain the desired compound.

m.p .: 197 ° C. (dec.)

Example 13

[1-cyclopropyl-6-fluoro-7- [3- (N-fluoroethyl) amino-3-hydroxymethyl] pyrrolidinyl-1,4-dihydro-4-oxo-3-quinolinecarr Preparation of Acids]

In the same manner as in Example 8, 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid was used to obtain the title compound as a pale yellow solid.

m.p .: 195 ° C. (dec.)

Hereinafter, the preparation examples prepared with the antimicrobial compounds of the present invention.

Preparation Example 1

Tablets were prepared by tableting the above components with 50 mg of tablets according to the conventional method for preparing tablets.

Preparation Example 2

The above-mentioned ingredients were filled into 50 mg gelatin capsules according to the conventional method for preparing capsules to prepare capsules.

Preparation Example 3

The component was prepared as an ointment according to the conventional method for preparing an ointment.

Preparation Example 4

The above components were prepared as injections according to the conventional method for preparing injections.

Preparation Example 5

The above ingredients were prepared as creams according to the conventional method for preparing creams.

Claims (3)

A quinoline carboxylic acid derivative represented by the following general formula (I) and a pharmaceutically acceptable salt thereof. Wherein R ¹ is lower alkyl having 1 to 4 carbon atoms, lower haloalkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, alkenyl having 2 to 4 carbon atoms, or a phenyl group optionally substituted by 2 fluorine atoms Or AO (or S) CH ₂ CH (CH ₃ ) -N which is ring-closed at the A position to form a thiazole or oxazole ring, R ² is a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms, and Z is (Wherein R ³ is a fluoro atom or a hydroxy group), X is a hydrogen atom, a halogen atom, a methyl or an amino group, A is a nitrogen atom or CY (wherein Y is a hydrogen atom, a halogen atom, hydroxy) , Methoxy or methyl group). A method for producing a novel quinoline carboxylic acid derivative represented by the following general formula (I) by reacting a quinoline carboxylic acid represented by the following general formula (II) with an amine represented by the following general formula (VI). Wherein R ¹ is optionally substituted by lower alkyl of 1 to 4 carbon atoms, lower haloalkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkenyl of 2 to 4 carbon atoms, or two fluorine atoms Phenyl group, or AO (or S) CH ₂ CH (CH ₃ ) -N which is ring-closed at the A position to form a thiazole or oxazole ring, R ² is a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms, R ³ is a fluoro atom or a hydroxyl group, Z is (Wherein R ³ is as defined above), X is a hydrogen atom, a halogen atom, a methyl or an amino group, A is a nitrogen atom or CY (wherein Y is a hydrogen atom, a halogen atom, hydroxy, methoxy or Methyl group), and R ⁷ is a halogen atom. An amine compound represented by the following general formula (VI). Wherein R ³ is a fluoro atom or a hydroxyl group.