KR950005201B1 - 8-alkoxyquinolonecarboxylic acid derivatives - Google Patents

Abstract

No content.

Description

8-alkoxyquinolonecarboxylic acid derivative

The present invention is directed to novel 8-alkoxyquinolonecarboxylic acid derivatives of formula (I), hydrates and pharmaceutically acceptable acid addition salts or alkali salts thereof useful as antibacterial agents, methods for preparing them, and antimicrobial agents containing these novel compounds. It is about.

Wherein R is a hydrogen atom or a lower alkyl group, R ¹ is a lower alkyl group, R ² is a hydrogen atom, an amino group or a nitro group, X is a halogen atom, Z is a halogen atom, a pyrerazino group, N -Methylpiperazino group, 3-methylpiperazino group, 3-hydroxypyrrolidino group or a pyrrolidino group of the following general formula.

Wherein n is 0 or 1, R is a hydrogen atom or a lower alkyl group, R is a hydrogen atom, a lower alkyl group or a substituted lower alkyl group, and R ⁵ is a hydrogen atom, a lower alkyl group, an acyl group or an alkoxy Carbonyl group.)

Compounds of the invention are characterized by having a cyclopropyl group in the 1-position of the quinolonecarboxylic acid and an alkoxy group in the 8-position.

In the 8-alkoxyquinolone carboxylic acid derivatives, 8-methoxy derivatives of the following general formulas are already described in Japanese Patent Application Laid-Open No. 60-214773, which has not been examined.

Wherein R is a hydrogen atom or a methyl group.

However, the antimicrobial activity of these compounds is weak and their utility as antimicrobial agents is not described.

Recently, norfloxacin developed by the present inventors shows high antimicrobial activity against Gram-negative bacteria and Gram-positive bacteria, including Psudomonas aeruginosa. This compound is widely used clinically as a novel quinolonecarboxylic acid antibacterial agent with a wide range of antibacterial activity. Since then, intensive studies have been conducted to improve the bioavailability of norfloxacin and to enhance its antimicrobial activity.

As a result, quinolonescarboxylic acid derivatives with similar substituents, such as opfloxacin and cyprofloxacin, have been developed. These new quinolonecarboxylic acid derivatives showed superior antimicrobial activity against Gram-negative bacteria than other antimicrobial agents such as β-lactam and aminoglycoside antibiotics. Moreover, the progress and extension of resistance to new quinolonecarboxylic acids was not easy compared to other antibacterial agents. However, their activity against Gram-positive bacteria was weak compared to activity against Gram-negative bacteria. Thus, these quinolonecarboxylic acids unfortunately did not solve the clinical problem of increasing the frequency of separation of Gram-positive bacteria from clinical substances. As a result of various studies, the inventors have found that some of the quinolonecarboxylic acid derivatives having excellent antimicrobial activity cannot be used as pharmaceuticals due to their toxicity, and excellent selective toxicity is an important factor as well as antimicrobial activity.

As a result of continuous research to solve these problems and to develop useful new medical products, the inventors of the present invention show that the novel compounds of the present invention exhibit very excellent activity against aerobic Gram-negative bacteria and Gram-positive bacteria and are less sensitive to conventional quinolonecarboxylic acids. It has also been shown to have very good activity against Mycoplasma and anaerobic bacteria. Moreover, these compounds show high selective toxicity between primitive and eukaryotic cells as well as excellent absorbency upon oral administration in animals. The compounds of the present invention show no toxicological effect after oral or parenteral administration.

This indicates that the compounds of the present invention are very useful as pharmaceuticals for humans and livestock, and as antibacterial agents for fish, shellfish and plants.

The present invention provides 8-alkoxyquinolonecarboxylic acid derivatives of the following general formula (I), hydrates thereof, and pharmaceutically acceptable acid addition salts or alkali salts.

Wherein R is a hydrogen atom or a lower alkyl group, R¹ is a lower alkyl group, R² is a hydrogen atom, an amino group or a nitro group, X is a halogen atom, Z is a halogen atom, a pyrerazino group, N- Methylpiperazino group, 3-methylpiperazino group, 3-hydroxypyrrolidino group or a pyrrolidino group of the following general formula.

Wherein n is 0 or 1, R is a hydrogen atom or a lower alkyl group, R is a hydrogen atom, a lower alkyl group or a substituted lower alkyl group, and R ⁵ is a hydrogen atom, a lower alkyl group, an acyl group or an alkoxy Carbonyl group.) In this specification, a lower alkyl group is a straight or branched chain alkyl group having 1 to 5 carbon atoms, for example, methyl, ethyl, isopropyl, n-butyl, tert-butyl, amyl, isoamyl group. And the like.

Halogen atoms represent fluorine, chlorine, bromine or iodine atoms, preferably fluorine, chlorine or bromine atoms.

Acyl groups represent aliphatic and aromatic acyl groups having 1 to 10 carbon atoms, such as formyl, acetyl, benzoyl group and the like.

The alkoxycarbonyl group represents an aliphatic or aromatic alkoxycarbonyl group having 1 to 10 carbon atoms, for example, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl group, and the like.

Substituted lower alkyl groups represent, as previously defined, hydroxy groups or alkyl groups substituted by halogen atoms, such as hydroxyethyl, fluoroethyl groups and the like.

Compounds of the present invention are prepared by the following method: Compounds of formula (IV) are prepared by condensation of compounds of formula (II) with cyclic amines of formula (III).

Wherein R, R ¹ , R ² and X are as defined above, Y is a halogen atom, Z ¹ is piperazino, N-methylpiperazino, 3-methylpiperazino, 3-hydroxy Cypirolidino group or the pyrrolidino group of the following general formula.

Where n, R ³ , R ⁴ and R ⁵ are as defined above

The reaction of the compound of formula (II) with the compound of formula (III) is carried out in the absence of a solvent or in polar solvents such as water, alcohols, acetonitrile, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), Hexamethylphosphoric acid amide (HMPA), pyridine, picoline and the like]. The reaction temperature is selected in the range of room temperature to 200 ° C, preferably room temperature to 160 ° C. More specifically, the compound of formula (II) may be reacted with 1 to 5 times molar of the compound of formula (III) with 1 to 5 times the molar amount of the compound of formula (II) It is suitable to react at room temperature to 120 ° C for a time.

At this time, it is also preferable to use deoxidizing agents such as triethylamine, diazabicyclo base and potassium carbonate.

In addition, among the compounds of the general formula (I), compounds in which R is a lower alkyl group, that is, the compound of the general formula (V), can be converted into the quinolonecarboxylic acid derivative of the general formula (VI) by hydrolysis in a conventional manner.

Wherein R ¹ , R ² , X and Z are as defined above and Alk is a lower alkyl group.

Such hydrolysis can be easily performed at room temperature to the boiling point of the solvent using an alkali such as sodium hydroxide and potassium hydroxide, or an acid such as hydrochloric acid and sulfuric acid in water, alcohol or a mixed solution thereof.

In addition, among the compounds of the general formula (I), the compounds of the general formula (VII) can be converted into the compounds of the general formula (VIII) by deacylating.

Wherein R, R ¹ , R ² and X are as defined above, Z ² is a pyrrolidino group of the general formula

Where R ⁶ is an acyl or alkoxycarbonyl group and n R ³ and R ⁴ are as defined above.

Z ³ is a pyrrolidino group of the following general formula.

Where R ³ and R ⁴ are as defined above.

The reaction can be easily carried out by conventional methods such as hydrolysis, catalytic reduction using an acid or alkali catalyst.

Synthetic intermediates of formula (II) used to prepare compounds of the present invention are also novel compounds, which can be prepared via the following reaction pathways:

Wherein Hal¹ is a halogen atom and Alk, R, R ¹ , R ² , X and Y are as defined above.

The compounds of the present invention of general formula (I) may also be prepared by reacting a compound of general formula (IX) with an alcohol of general formula (X) as in the following reaction route:

Wherein Hal is a halogen atom and R, R ¹ , R ² , X and Z ¹ are as defined above.

The reaction is preferably carried out under anhydrous conditions to prevent side reactions in the absence of a solvent or in the presence of a deoxidizing agent in a solvent such as alcohol, acetonitrile, DMSO, DMF, HMPA, dioxane, benzene and the like. . Alkali fluoride, alkali metal alcoholate, alkali hydride and the like can be used as the deoxidizing agent, but it can be reacted with alkali metal (e.g. sodium, potassium, lithium, etc.) using an alcohol of the general formula R ¹ OH as a solvent. It is suitable to provide to the reaction.

More specifically, the compound of formula (IX) is at least 1 per volume of compound of formula (IX) for 1 to 200 hours at room temperature to 200 ° C. with at least the above-mentioned deoxidizing agent of the animal and the alcohol of formula R ¹ OH. It is suitable to react in the above-mentioned 50 to 50 times the volume, and when using a low boiling point solvent, it is more preferable to react at high temperature in a closed tube.

The compound of general formula (I) can be converted into its salt, if necessary, according to a conventional method. As salts, salts with inorganic acids (e.g. hydrochloric acid, sulfuric acid, phosphoric acid, etc.), salts with organic acids (e.g. methanesulfonic acid, lactic acid, oxalic acid, acetic acid, etc.) or sodium, potassium, magnesium, calcium, aluminum, cerium, chromium And salts such as cobalt, copper, iron, zinc, platinum, and silver.

When administering the compounds of the present invention to humans, animals and plants, the form and route of administration utilize those known to date in the pharmaceutical art. These compounds can be administered orally or parenterally in the form of powders, tablets, capsules, ointments, injections, syrups, solutions, ophthalmic drops, suppositories, and the like.

The following examples illustrate the invention, which is not intended to limit the invention.

Example 1

Synthesis of 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7- (1-piperazinyl) -3-quinolinecarboxylic acid

1-cyclopropyl-6.7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (200 mg), piperazine anhydrous (180 mg) and dimethyl sulfoxide anhydrous (DMSO: 3 ml ) Is stirred for 2.5 h at 70-80 ° C. in an oil bath. The reaction mixture is concentrated under reduced pressure and cold water is added to the residue. The precipitate was collected by filtration and recrystallized from a mixed solution of dichloromethane-methanol (1: 1) to give the title compound (40 mg) as a pale yellow prism having a melting point of 187 ° C. (decomposition).

Elemental Analysis for C ₁₈ H ₂ FN ₃ O ₄ · 2H ₂ O (%):

Calculated value: found C; 54.40 (53.96), H; 6.09 (5.99), N; 10.57 (10.34).

Example 2

Synthesis of 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7- (4-methyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid

1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (200 mg), N-methyl-piperazine (140 mg) and anhydrous DMSO ( 3 mg) is stirred for 5 h at 70-95 ° C. in an oil bath. The reaction mixture is concentrated under reduced pressure. The resulting residue was eluted with chloroform-methanol-rich aqueous ammonia (20: 6: 1) and purified by silica gel column chromatography, and the residue was recrystallized from methanol to give a colorless color having a melting point of 221 to 222 ° C. (decomposition). The title compound (50 mg) is obtained as a needle.

Elemental Analysis for C ₁₉ H ₂₂ FN ₃ O ₄ (%):

Calculated value: found C; 60.79 (60.82), H; 5.91 (5.90), N; 11.19 (11.24).

Example 3

Synthesis of 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7- (3-methyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid

1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (200 mg), 2-methyl-piperazine (140 mg) and anhydrous DMSO ( 3 ml) is stirred for 2 h at 70-95 ° C. in an oil bath. The reaction mixture is concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluting with chloroform-methanol-rich aqueous ammonia (20: 6: 1), and the residue was recrystallized from methanol to give a white powdery crystal with a melting point of 162 ° C. 50 mg of compound is obtained.

Elemental Analysis for C ₁₉ H ₂₂ FN ₃ O ₄ · 1 / 2H ₂ O:

Calculated value: found C; 59.37 (59.95), H; 6.03 (6.01), N; 10.93 (10.81).

Example 4

Synthesis of 7- (3-amino-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid

3-tert-part to a suspension of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (3 g) in anhydrous acetonitrile Toxylcarbonylaminopyrrolidine (1.86 g) and 1,8-diazabicyclo [5,4,0] are added to deck-7-ene (DBU, 1.02 g) and then the mixture is refluxed for 3 hours. The reaction mixture is concentrated under reduced pressure and the residue is dissolved in chloroform (50 ml). The resulting solution is continuously washed with 10% aqueous citric acid solution (20 ml) and saturated brine. The organic layer is dried over anhydrous sodium sulfate and then concentrated. The residue is dissolved in hot methanol (20 ml) and then cooled. The resulting crystals were collected by filtration to obtain 7- (3-tert-butoxycarbonylamino-1-pyrrolidinyl) -1-cyclopropyl-1,4-diahydro-6-fluoro-8-methoxy 4-oxo-3-quinolinecarboxylic acid (2.25 g) is obtained as an off-white prism having a melting point of 224 to 226 ° C (decomposition).

Elemental analysis for C ₂₃ H ₂₈ FN ₃ O ₆ 1 / 4H ₂ O (%):

Calculated value: found C; 59.28 (59.18), H; 6.22 (6.08), N; 9.02 (8.82).

To the suspension of these crystals (2.23 g) in methanol (16 ml) is added dropwise concentrated hydrochloric acid (16 ml). After stirring for 3 hours at room temperature, the reaction mixture is cooled and neutralized with concentrated aqueous ammonia. The resulting precipitate is collected by filtration and washed continuously with methanol and ether to give the title compound (1.52 g) as a white powder with a melting point of 217-218 ° C.

Elemental analysis for C ₁₅ H ₂₀ FN ₃ O ₄ 1 / 2H ₂ O (%):

Calculated value: found C; 58.37 (58.68), H; 5.71 (6.10), N; 11.35 (11.14).

Example 5

7- (cis-3-amino-4-methyl-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid Synthesis of

1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (200 mg), cis-3-tert-butoxycarbonylamino- A mixture of 4-methylpyrrolidine (150 mg), DBU (110 ml) and anhydrous acetonitrile (3 ml) is refluxed for 5 hours. After cooling, the resulting precipitate is collected by filtration. This precipitate is added to a mixture of concentrated hydrochloric acid-methanol (1: 1,6 ml) and stirred at room temperature for 1.5 hours. The reaction mixture is neutralized with concentrated aqueous ammonia and left in the refrigerator. The resulting crystals are collected by filtration and washed with cold water to give the title compound (90 mg) as a colorless prism having a melting point of 185-188 ° C. (decomposition).

Elemental analysis for C ₁₉ H ₂₂ FN ₃ O ₄ · 2 / 2H ₂ O (%):

Calculated value: found C; 56.71 (56.53), H; 6.26 (6.17), N; 10.44 (10.37).

Example 6

7- (trans-3-amino-4-methyl-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid Synthesis of

1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (0.40 g), trans-3-tert-butoxycarbonylamino- A mixture of 4-methylpyrrolidine (0.41 g), DBU (0.21 g) and acetonitrile (5 ml) was refluxed for 2.5 hours, then the reaction mixture was concentrated under reduced pressure. The residue is dissolved in chloroform (40 ml) and washed continuously with 10% aqueous citric acid solution (20 ml) and saturated brine (20 ml). The organic layer is dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was crystallized with ethanol to give 7- (trans-3-tert-butoxycarbonylamino-4-methyl-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro -8-methoxy-4-oxo-3-quinolinecarboxylic acid is obtained. To the suspension of these crystals in methanol (5 ml) is added dropwise concentrated hydrochloric acid (5 ml). After stirring at room temperature for 1.5 hours, the reaction mixture was neutralized with concentrated aqueous ammonia, the resulting crystals were collected by filtration and washed sufficiently with water to give the title compound (0.29 g) as a colorless powder with a melting point of 214 to 215 ° C. To obtain.

Elemental Analysis for C ₁₉ H ₂₂ FN ₃ O ₄ (%):

Calculated value: found C; 60.07 (60.41), H; 5.97 (5.80), N; 11.06 (11.05).

Reference Example 1

Synthesis of 3-methoxy-2,4,5-trifluorobenzoic acid

According to the method described in Bardon et al., Tetrahedron, 22, 2541 (1966), 1,2,3,4-tetrafluorobenzene (50 g) is brominated and methoxylated to 1-bromo 3-Methoxy-2,4,6-trifluorobenzene (22.2 g) is obtained as a colorless oil.

The mixture of oily product (22 g), cuprous cyanide (10 g) and N-methyl-2-pyrrolidone (37 ml) in a sealed tube is heated at 140-150 ° C. for 4.5 hours. After cooling, ferric chloride in water (60 ml). A solution of hexahydrate (44 g) and concentrated hydrochloric acid (11 ml) is added to the reaction mixture and stirred at 50-60 ° C. for 20 minutes. The reaction mixture is extracted with ether and the organic layer is washed continuously with dilute aqueous hydrochloric acid, water and saturated brine solution, then dried over anhydrous sodium sulfate and concentrated. The residue is distilled off under reduced pressure to give 3-methoxy-2,4,5-trifluorobenzonitrile (14.25 g) as a colorless oil having a boiling point of 94 ° C./8 mm Hg.

Concentrated sulfuric acid (8.5 ml) and water (40 ml) are added to the oily product (14.2 g) thus obtained, and the mixture is stirred at 110 ° C for 1 hour. After cooling, the reaction mixture was poured into ice water (50 ml), the resulting precipitate was collected by filtration, washed with water and recrystallized from a solution of dichloromethane-n-hexane to give 3-methoxy-2,4, 5-trifluorobenzoamide (11.59 g) is obtained as a white needle having a melting point of 130 to 133 캜.

18 N sulfuric acid (150 ml) is then added to this crystal and the mixture is heated at 100 ° C. for 3.5 h. After cooling, water (400 ml) was added to the mixture and the resulting crystals were recrystallized from n-hexane to give the title compound (9.61 g) as a colorless needle with a melting point of 98 to 101 ° C.

Elemental Analysis for C ₈ H ₅ F ₃ O ₃ (%):

Calculated value: found C; 46.62 (46.68), H; 2.45 (2.48)

Reference Example 2

Synthesis of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid 3-methoxy-2,4,5-trifluorobenzoic acid To (9.4 g) thionylchloride (50 ml) is added and the mixture is refluxed for 3 h and then concentrated. Purification of the residue by distillation under reduced pressure yields 3-methoxy-2,4,5-trifluoro benzoyl chloride (8.86 g) as a yellow oil having a boiling point of 108 to 112 ° C / 20 mmHg.

Diethyl malonate (7 g) in anhydrous toluene (35 ml) is added dropwise to magnesium ethoxide (5.9 g) and the mixture is warmed at 50-60 ° C. for 12 hours and then cooled to -10 ° C. To the mixture is added dropwise a solution of acid chloride (8.86 g) in anhydrous toluene (10 ml) over 15 minutes. After stirring at −5 to 0 ° C. for 1 hour, ice water (30 ml) containing concentrated sulfuric acid (8 ml) is added to the mixture and the organic layer is separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give diethyl-3-methoxy-2,4,5-trifluorobenzoylmalonate (13.64 g) as brown oil.

Malonate (13.55 g), water (20 ml) and p-toluenesulfonic acid (14 mg) are added to the oily product and the mixture is refluxed for 9 hours. After cooling, the reaction mixture was extracted with dichloromethane and the organic layer was washed with aqueous sodium bicarbonate solution and saturated brine, then dried over anhydrous sodium sulfate, and then concentrated to ethyl 3-methoxy-2,4,5-trifluoro Robenzoyl acetate (10.29 g) is obtained.

To benzoyl acetate (9.79 g) is added acetic anhydride (9.6 g) and ethyl orthoformate (8.4 g) and the mixture is refluxed for 3 hours. After addition of acetic anhydride (3.2 g) and ethyl orthoformate (8.8 g), the mixture was refluxed for 8 hours and concentrated to ethyl 2- (3-methoxy-2,4,5-trifluoro Benzoyl) -3-ethoxyacrylate (9.73 g) is obtained as a brown oil.

To a solution of acrylate (9.73 g) in ethanol (20 ml) was added dropwise while cooling cyclopropylamine (2.0 g). After stirring at room temperature for 2 hours, the reaction mixture is concentrated and the residue is purified by silica gel column chromatography, eluting with n-hexane-ethyl acetate (5: 1) to ethyl 2- (3-methoxy-2 , 4,5-trifluorobenzoyl) -3-cyclopropyl-aminoacrylate (7.52 g) is obtained as off-white crystals having a melting point of 56 to 58 ° C.

Elemental Analysis for C ₁₆ H ₁₆ F ₃ NO ₄ (%):

Calculated value: found C; 55.98 (56.07), H; 4.70 (4.66), N; 4,08 (4,07).

A mixture of aminoacrylate (6.68 g), sodium fluoride (1.31 g) and anhydrous dimethylformamide (26 ml) is refluxed for 5 hours. After cooling, the reaction mixture was poured into ice water (100 ml), the resulting precipitate was collected by filtration, washed with water, recrystallized with ethyl acetate and ethyl 1-cyclopropyl-6,7-difluoro-1 , 4-Dihydro-8-methoxy-4-oxo-3-quinolinecarboxylate (4,53 g) is obtained as a colorless needle having a melting point of 178 to 180 ° C.

Elemental Analysis for C ₁₆ H ₁₁ F ₂ NO ₄ (%):

Calculated value: found C; 59.44 (59.34), H; 4.68 (4.59), N; 4.74 (4.74)

To this crystal (4.5 g) was added a mixed solution of acetic acid (30 ml), dark yellow (4 ml) and water (22 ml) and the mixture was refluxed for 1 hour. After cooling, ice water (100 ml) is added and the resulting precipitate is collected by filtration, washed with water and dried to give the title compound (4 g) as a colorless powder with a melting point of 185 to 186 ° C.

Elemental Analysis for C ₁₄ H ₁₁ F ₂ NO ₄ (%):

Calculated value: found C; 56.95 (56.68), H; 3.76 (3.70), N; 4.74 (4.74).

Example 7

Synthesis of 3- (3-aminomethyl-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid

1-cyclopropyl-6,7-difluoro-1-4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (200 mg), 3-amino-methylpyrrolidine (80 mg), A mixture of DBU (110 mg) and anhydrous acetonitrile (3 ml) is refluxed for 2.5 hours. After cooling, the resulting precipitate was collected by filtration and recrystallized with a solution of dichloromethane-methanol (1: 1) to give the title compound (90 mg) as white powdery crystals with a melting point of 198 to 200 ° C.

Elemental Analysis for C ₁₉ H ₂₂ FN ₃ O ₄ (%):

Calculated value: found C; 60.79 (60.39), H; 5.91 (5.87), N; 11.19 (11.07)

Example 8

Synthesis of 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7- (3-methylaminomethyl-1-pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid

1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (200 mg), 3-methylaminomethyl pyrrolidine (90 mg), DBU (110 mg) and a mixture of anhydrous acetonitrile (3 ml) are refluxed for 75 minutes. After cooling, the resulting precipitate was collected by filtration and recrystallized from a solution of tichloromethane-methanol (1: 1) to give the title compound (130 mg) as white powdery crystals having a melting point of 226.5 to 230 ° C.

Elemental analysis for C ₂₀ H ₂₄ FN ₃ O ₄ 1/2 H ₂ O (%):

Calculated value: found C; 60.29 (60.49), H; 6.32 (6.08), N; 10.54 (10.48)

Example 9

Synthesis of 1-cyclopropyl-7- (3-ethylaminomethyl-1-pyrrolidinyl) -6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid

1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (200 mg), 3-ethylaminomethylpyrrolidine (100 mg), DBU (110 mg) and a mixture of anhydrous acetonitrile (3 ml) are refluxed for 6 hours. After cooling, the resulting precipitate was collected by filtration and recrystallized with methanol to give the title compound (120 mg) as a colorless prism having a melting point of 217 to 219 ° C.

Elemental analysis for C ₂₁ H ₂₆ FN ₃ O ₄ · 2 / 3H ₂ O (%):

Calculated value: found C; 60.71 (60.59), H; 6.63 (6.43), N; 10.11 (10.03)

Reference Example 3

Synthesis of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-5-nitro-4-oxo-3-quinolinecarboxylic acid

Stirred to a solution of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (490 mg) in concentrated sulfuric acid (5 ml) at less than 5 ° C. Potassium nitrate (235 mg) is added in fractions. After stirring for 45 minutes, the reaction mixture was poured into ice water (25 ml), the fish precipitate was collected by filtration, washed sufficiently with cold water, recrystallized from a solution of dichloromethane-methanol (1: 1) and titled Compound (329 mg) is obtained as a yellow prism with a melting point of 215.5 to 221 ° C. (decomposition).

Elemental Analysis for C ₁₄ H ₁₀ F ₂ N ₂ O ₆ (%):

Calculated value: found C; 49.42 (49.37), H; 2.96 (2.94), N; 8.23 (8.12)

Reference Example 4

Synthesis of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid

To a solution of 1-cyclopropyl-6.7-difluor-1,4-dihydro-8-methoxy-5-nitro-4-oxo-3-quinolinecarboxylic acid (322 mg) in ethanol-DMF (4: 1) 10% palladium-carbon (25 mg) is added and the mixture is stirred for 6 hours at room temperature under a hydrogen gas atmosphere. The catalyst is filtered off and washed with a solution of chloroform-methanol-condensed aqueous ammonia (10: 10: 3). Combine the filtrate and the wash and concentrate. The residue is recrystallized from a solution of chloroform-methanol-rich aqueous ammonia (2: 6: 1) to give the title compound (183 mg) as a yellow prism having a melting point of 291 to 291.5 ° C. (decomposition).

Elemental Analysis for C ₁₄ H ₁₂ F ₂ N ₂ O ₄ (%):

Calculated value: found C; 54.20 (54.46), H; 3.90 (3.89), N; 9.03 (8.97)

Example 10

Synthesis of 5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7- (1-piperazinyl) -3-quinolinecarboxylic acid

5-Amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-7- (1-piperazinyl) -3-quinolinecarboxylic acid (72 mg) The mixture of anhydrous piperazine (60 mg) and anhydrous DMSO (3 mg) is stirred at 70-80 ° C. for 2 hours and then concentrated under reduced pressure. The solution of the residue dissolved in aqueous ethanol is acidified to less than pH 1 with concentrated hydrochloric acid. Leave the solution in the refrigerator. The resulting precipitate is collected by filtration, washed with aqueous ethanol and then with ethanol to give the title compound (33 mg) as yellow flaky crystals having a melting point of 271 to 273 ° C. (decomposition).

Elemental Analysis for C ₁₈ H ₂₁ FN ₄ O ₄ HCLH ₂ O (%):

Calculated value: found C; 50.18 (50.28), H; 5.61 (5.48), N; 13.00 (12.97)

Example 11

Synthesis of 5-amino-7- (3-amino-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid

5-Amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (90 mg), tert-butoxycarbonyl A mixture of aminopyrrolidine (115 mg), DBU (50 mg) and anhydrous acetonitrile (4 ml) is refluxed for 20 hours. After cooling, the resulting precipitate is collected by filtration and added to concentrated hydrochloric acid-methanol (1: 1; 2 ml). The mixture is stirred at room temperature for 10 minutes, then neutralized with concentrated aqueous ammonia and the precipitate is collected by filtration. The solution of the precipitate dissolved in cold water is acidified to less than pH 1 using concentrated hydrochloric acid and left in the refrigerator. The resulting precipitate is collected by filtration and washed with cold dilute aqueous hydrochloric acid to give the title compound (35 mg) as a yellow needle having a melting point of 254 to 257 ° C. (decomposition).

Elemental analysis for C ₁₈ H ₂₁ FN ₄ O ₄ · 2HCL (%):

Calculated value: found C; 48.12 (48.16), H; 5.16 (5.53), N; 12.47 (12.52)

Example 12

Synthesis of 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7- (1-piperazinyl) -3-quinolinecarboxylic acid

To a solution of sodium methoxite prepared with sodium (0.2 g) and anhydrous methanol (9 ml), 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7- (1-pi Ferrazinyl) -3-quinolinecarboxylic acid (0.5 g) is added and the mixture is heated in a sealed tube at 140-150 ° C. for 72.5 hours. After cooling, the reaction mixture is concentrated and water (4 ml) is added to the residue and the solution is adjusted to pH 7 with acetic acid. Insoluble matters are filtered off and the filtrate is left in the refrigerator. The resulting precipitate is collected by filtration and recrystallized with dichloromethane-methanol (2: 1: 6 ml) to give the title compound (0.12 g) as a colorless prism having a melting point of 185 to 187.5 ° C. (decomposition).

Elemental Analysis for C ₁₈ H ₂₀ FN ₃ O ₄ 1/2 H ₂ O (%):

Calculated value: found C; 58.37 (57.98), H; 5.71 (5.52), N; 11.35 (11.28)

Example 13

Synthesis of 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7- (4-methyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid

Sodium formate (22 mg), 87% formic acid (0.3 ml), 37% formalin (25μ1) and 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7- ( The mixture of 1-piperazinyl) -3-quinolinecarboxylic acid (60 mg) is stirred at 100-120 ° C. for 2 hours. After cooling, water (1 ml) is added to the reaction mixture and concentrated. Water (0.5 ml) is added to the residue, adjusted to pH 7 with 1N aqueous sodium hydroxide solution, and the solution is left in the refrigerator. The resulting precipitate is collected by filtration and washed with water to give the title compound (33 mg) as a colorless needle having a melting point of 229 to 232 ° C. (decomposition).

Elemental Analysis for C ₁₉ H ₂₂ FN ₃ O ₄ (%):

Calculated value: found C; 60.79 (60.80), H; 5.91 (5.90), N; 11.19 (11.15)

Example 14

Synthesis of 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7- (3-methyl-1-piperazinyl) -4-oxo-quinolinecarboxylic acid

To a solution of sodium methoxide made of sodium (0.4 g) and anhydrous methanol (20 ml) was dissolved in 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (3-methyl-1-pi Ferrazinyl) -4-oxo-3-quinolinecarboxylic acid (1.12 g) is added and the mixture is stirred in a sealed tube at 140-150 ° C. for 70.5 hours and then concentrated. The residue is dissolved in a small amount of water and the resulting solution is adjusted to pH 7 with acetic acid and then concentrated. The resulting residue was purified by silica gel column chromatography, eluting with chloroform-methanol-rich aqueous ammonia (20: 6: 1) and recrystallized with methanol to give the title compound (0.33 g) as light yellow with a melting point of 162 ° C. Obtained as a prism.

Elemental Analysis for C ₁₉ H ₂₂ FN ₃ O ₄ 1 / 2H ₂ O (%):

Calculated value: found C; 59.37 (59.48), H; 6.03 (5.70), N; 10.93 (11.07)

), 3.77(3H,s,OCH₃), 3.5-2.9(7H,m,피페라진), 1.3-1.0(7H,m,

)H-NMR (δ in CDCI); 8.79 (1H, s, 2-position), 7.85 (1H, m, J = 12.3 Hz, 5-position), 4.1-3.9 (1H, m,

), 3.77 (3H, s, OCH₃), 3.5-2.9 (7H, m, piperazine), 1.3-1.0 (7H, m,

)

Example 15

Synthesis of 7- (3-amino-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline acid

To a solution of sodium methoxide prepared from sodium (0.2 g) and anhydrous methanol (10 ml) 7- (3-amino-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1,4 -Dihydro-4-oxo-3-quinolinecarboxylic acid (0.47 g) is added and the mixture is stirred in a sealed tube at 140-150 ° C. for 49 hours and then concentrated. The residue was purified by silica gel column chromatography, eluting with chloroform-methanol-rich aqueous ammonia (20: 6: 1), and recrystallized with a solution of dichloromethane-methanol (1: 1) to give the title compound (6 mg). Obtained as a pale yellow prism having a melting point of 207.5 to 212 ° C.

Elemental Analysis for C ₁₈ H ₂₀ FN ₃ O ₄ H ₂ O (%):

Calculated value: found C; 56.99 (57.19), H; 5.82 (5.38), N; 11.13 (10.86)

Mass spectrometry (m / e): 361 (M ⁺ ), 362 (M ⁺ +1).

H-NMR (δ in D ₂ O, NaOD); 0.48 (1H, s, 2-position), 7.62 (1H, d, J = 14.5 Hz,

), 3.55(3H,s,OCH₃), 3.8-3.2(5H,m,

), 2.3-1.6(2H,m,

), 1.2-0.9(4H,m,

)5-position), 4.1-3.9 (1H, m,

), 3.55 (3H, s, OCH₃), 3.8-3.2 (5H, m,

), 2.3-1.6 (2H, m,

), 1.2-0.9 (4H, m,

)

Example 16

Synthesis of 7- (3-amino-4-methyl-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid

To a solution of sodium methoxide made of sodium (50 mg) and anhydrous methanol (3 ml) was added 7- (3-amino-4-methyl-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro- 1,4-Dihydro-4-oxo-3-quinolinecarboxylic acid (80 mg) is added and the mixture is stirred in a sealed tube at 140-150 ° C. for 86 hours and then concentrated. A small amount of water is added to the residue and the solution is adjusted to pH 7 with acetic acid and then concentrated. The resulting residue was purified by silica gel column chromatography, eluting with chloroform-methanol-rich aqueous ammonia (20: 6: 1) and recrystallized with a solution of dichloromethane-methanol (1: 1) to give the title compound (9 mg). ) Is obtained as a light yellow prism having a melting point of 191.5 to 193.5 ° C.

Elemental Analysis for C ₁₉ H ₂₂ FN ₃ O ₄ , 7 / 5H ₂ O (%):

Calculated value: found C; 56.96 (57.10); H; 6.24 (5.98); N; 10.49 (10.42)

H-NMR (δ in D ₂ O, NaOD); 8.47 (1H, s, 2, -position), 7.57 (1H, d, J = 14.5 Hz,

), 3.51(3H,s,OCH₃), 3.8-3.2(4H,m,

),3.2-2.9(1H,q,

),2.1-7.1(1H,m,

),1.09(3H,d,J=6.59Hz,

), 1.3-0.7(4H,m,

)5-position), 4.1-3.9 (1H, m,

), 3.51 (3H, s, OCH₃), 3.8-3.2 (4H, m,

), 3.2-2.9 (1H, q,

), 2.1-7.1 (1H, m,

), 1.09 (3H, d, J = 6.59 Hz,

), 1.3-0.7 (4H, m,

)

Example 17

Synthesis of 7- (3-aminomethyl-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid

To a solution of sodium methoxide prepared with sodium (0.2 g) and anhydrous methanol (9 ml), 7- (3-aminomethyl-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.5 g) is added and the mixture is stirred in a sealed tube at 140-150 ° C. for 86 hours and then concentrated. A small amount of water is added to the residue and the solution is adjusted to pH 7 with acetic acid and then concentrated. The resulting residue was purified by silica gel column chromatography, eluting with chloroform-methanol-rich aqueous ammonia (20: 6: 1) and recrystallized with methanol to yield the title compound (40 mg) with a melting point of 225 to 228.5 ° C. Obtained as a yellow prism.

Elemental analysis for C ₁₉ H ₂₀ FN ₃ O ₄ , 2/3 (%):

Calculated value: found C; 58.91 (58.73); H; 6.07 (5.92); N 10.85 (10.88)

Example 18

Synthesis of 1-cyclopropyl-6-fluoro-1,4-dihydro-8-ethoxy-4-oxo-7- (1-piperazinyl) -3-quinolinecarboxylic acid

To a solution of sodium ethoxide prepared with sodium (0.75 g) and anhydrous methanol (30 ml), 1cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7- (1-pipera Genyl) -3-quinolinecarboxylic acid (0.8 g) is added and the mixture is stirred at 140-150 ° C. for 52 hours in a sealed tube and then concentrated. Water (60 ml) is added to the residue, the solution is adjusted to pH 7 with acetic acid and then extracted with chloroform. The chloroform layer is washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated. The resulting residue was purified by silica gel column chromatography, eluting with chloroform-methanol (2: 1) → chloroform-methanol-condensed aqueous ammonia (20: 6: 1 → 10: 10: 1) and recrystallized with ethanol. To give the title compound (75 mg) as a light brown prism having a melting point of 119 to 122 ° C.

Elemental Analysis for C ₁₉ H ₂₂ FN ₃ O ₄ , 1 / 2H ₂ O (%):

Calculated value: found C; 59.37 (59.60); H; 6.03 (6.04); N 10.93 (10.85)

Experimental Example 1

Antimicrobial spectrum

Antimicrobial tests are performed according to the method devised by the Japan Society of Chemotherapy. The results are shown in Table 1.

TABLE 1a

Antimicrobial activity in vitro

TABLE 1b

Antimicrobial activity in vitro

TABLE 1c

Antimicrobial activity in vitro

TABLE 1d

Antimicrobial activity in vitro

TABLE 1e

Antimicrobial activity in vitro

TABLE 1f

Antimicrobial activity in vitro

Table 1g

Antimicrobial activity in vitro

Table 1h

Antimicrobial activity in vitro

Control compound

CPFX: Ciprofloxsacin

MNZ: Metronidazole

Compounds of the present invention are better against Gram-positive bacteria than ciprofloxacin known to date and exhibit high activity against anaerobic bacteria, the same as metronidazole recommended by medical experts.

Claims (2)

8-alcoholquinolonecarboxylic acid derivatives of formula (I), hydrates thereof or pharmaceutically acceptable acid addition salts or alkali salts.

Wherein R is a hydrogen atom or a lower alkyl group, R¹ is a lower alkyl group, R² is a hydrogen atom, an amino group or a nitro group, X is a halogen atom, Z is a halogen atom, a piperazino group, N-methyl Piperazino group, 3-methylpiperazino group, 3-hydroxypyrrolidino group or a pyrrolidino group of the following general formula.

Wherein n is 0 or 1, R is a hydrogen atom or a lower alkyl group, R ⁴ is a hydrogen atom, a lower alkyl group or a substituted lower alkyl group, and R ⁵ is a hydrogen atom, a lower alkyl group, an acyl group or an alkoxy Carbonyl group.) An antimicrobial agent containing at least one compound according to claim 1 as an active ingredient.