KR19980015377A - New quinolone carboxylic acid compounds and methods for their preparation - Google Patents

Abstract

The present invention relates to a novel quinolone carboxylic acid derivative represented by the following general formula (I) useful as an antimicrobial agent, a pharmaceutically acceptable salt thereof, and a process for producing the same.

Wherein R1 is a lower alkyl group of 1-6 carbon atoms, a halogen-substituted phenyl group, a halogen substituted-alkyl group, or a t-O group in which X is C-Y when X is C-Y,

R2 and R3 are the same or different and each represents a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms, Z represents a hydrogen atom, a halogen atom, an amino group or a methyl group, X is a nitrogen atom or CY, Y is a halogen atom, M and n are integers of 1 or 2, and m + n is 3 or less.

Description

New quinolone carboxylic acid compounds and methods for their preparation

The present invention relates to a novel quinolone carboxylic acid derivative represented by the following general formula (I), a pharmaceutically acceptable salt thereof, and a process for producing the same.

Wherein R1 is a lower alkyl group having 1-6 carbon atoms such as methyl, ethyl or cyclopropyl, a halogen-substituted phenyl group, a halogen-substituted alkyl group or a t-O group in which CY forms an oxazole ring when X is CY, . R2 and R3 are the same or different and each represents a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms, and Z represents a hydrogen atom, a halogen atom, an amino group or a methyl group. X is a nitrogen atom or C-Y, wherein Y is a halogen atom, a methoxy group or a methyl group, m and n are each an integer of 1 or 2, and m + n is 3 or less.

The compound represented by the general formula (I) includes an optical isomer due to the asymmetric carbon at the 3-position. All optical isomers and mixtures thereof are therefore conveniently indicated by a single structure and are within the scope of the present invention.

In general, quinolone carboxylic acid antimicrobial agents are widely used as antimicrobial active compounds having broad antibacterial activity and broad antibacterial activity. Typical examples thereof include noproxacin, ciprofloxacin, and oproxacin. However, these antimicrobial agents show excellent antimicrobial activity against Gram-negative bacteria, but their antimicrobial activity against Gram-positive bacteria is considerably lowered, and development of new antimicrobial agents has been demanded due to the expression of resistant bacteria.

The present inventors have carried out a long study to overcome the shortcomings of the conventional quinolone antibacterial agent, and as a result, the present invention has been completed.

The novel compounds of the general formula (I) of the present invention are completed by introducing an amine represented by the general formula (II) into the C-7 position of the quinolone carboxylic acid.

Wherein R2, R3 and n and n are as described above.

The compound of general formula (I) of the present invention is prepared by reacting an amine ring compound of the above general formula (II) with a quinolone compound of the following general formula (III).

In the above formula, R 1, R 2, R 3, X, Z, n and m are as defined above, and R 4 is a halogen atom, a mesyl group or a tosyl group.

The reaction of the present invention can be carried out by reacting a compound of general formula (II) and a compound of general formula (III) with a suitable base such as 1,8-diazabicyclo [5.4.0] 7-ene, triethylamine or mixtures thereof.

The quinolonecarboxylic acid derivative represented by the general formula (I) has more excellent antibacterial activity than ciprofloxacin, which is known to have excellent antibacterial activity, and can be used as an antimicrobial agent.

The quinolone derivatives of the general formula (I) can be used as antimicrobial agents by preparing pharmaceutical preparations in a conventional manner with excipients, diluents, lubricants and the like which are conventionally used in pharmaceuticals.

Hereinafter, the present invention will be described in more detail by way of examples.

Example 1

Preparation of 1-cyclopropyl-6,8-difluoro-7- [3-aminohydroxypyrrolidinyl] -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (KL- .

100 mg (0.35 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 1,8-diazabicyclo [ (3-pyrrolidinyl) hydroxyamine (130 mg, 1.27 mmol) was added to the solution, and the mixture was refluxed for 8 hours. The solvent was removed under reduced pressure and dissolved in a mixed solvent of chloroform and methanol, then solidified using acetonitrile and the solid washed with acetonitrile. 52 mg of the aimed compound was obtained. (Yield: 40.8%)

1 H-NMR (DMSO-d 6, ppm)

(1H, s), 1.66 (1H, s), 1.65 (1H, m) ) 8.57 (1H, s)

mp. 269 ° C

Example 2

Preparation of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (3-aminohydroxypyrrolidinyl) -1,8-naphthyridine-3-quinolinecarboxylic acid KL-307).

100 mg (0.35 mmol) of 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3- quinolinecarboxylic acid, 0.08 ml (0.53 mmol ) And O- (3-pyrrolidinyl) hydroxyamine (120 mg, 1.18 mmol) were reacted in the same manner as in Example 1 to obtain the desired compound (43 mg).

1 H-NMR (DMSO-d 6, ppm)

(1H, m), 3.43 (1H, m), 3.42 (1H, (1H, s)

mp. 267 ° C

Example 3

: 10- [3-aminohydroxypyrrolidinyl] -9-fluoro-2,3-dihydro-3- (S) -methyl-7-oxo-7H-pyrido [ ] [1,4] -benzoxazine-6-carboxylic acid (KL-305).

9,10-difluoro-2,3-dihydro-3- (S) -methyl-7-oxo-7H-pyrido [ (0.39 mmol) of the carboxylic acid, 0.08 ml (0.53 mmol) of DBU and 80 mg (0.78 mmol) of O- (3-pyrrolidinyl) hydroxyamine were reacted in the same manner as in Example 1 to give 65 mg .

1 H-NMR (DMSO-d 6, ppm)

: 1.41-1.44 (3H, m) 1.80-1.90 (2H, m) 3.61 (1H, m) 3.93 (2H, m) 4.25-4.32 (2H, m) 4.49-4.51 , d) 7.49-7.53 (1 H, d) 8.86 (1 H, s)

mp. 266 ° C

Example 4

Preparation of 1-cyclopropyl-5-amino-7- (3-aminohydroxypyrrolidinyl) -6,8-difluoro-1,4-dihydroquinoline-4-oxo-3-carboxylic acid.

120 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydroquinoline-4-oxo-3-carboxylic acid, 0.08 ml of DBU and 0.10 ml of O- (3-pyrrolidinyl) 138 mg of hydroxyamine were reacted in the same manner as in Example 1 to obtain the desired compound (72 mg).

1 H-NMR (DMSO-d 6, ppm)

: 1.16 (4H, m) 1.96 (2H, m) 3.72 (1H, m) 3.87-3.92 (2H, m) 4.05-4.17

mp. 273 DEG C

Experimental Example 1: Antibacterial test

The in vitro bactericidal potencies of the compounds of Examples 1, 2 and 3 prepared as described above were measured by agar medium dilution method and are shown in Table 1 below. As a result, it showed more excellent antibacterial activity against gram - positive strains than ciprofloxacin, which is a conventional quinolone antibacterial agent.

Table 1. In vitro antibacterial activity of quinoline compounds (minimum inhibitory concentration: mg / ml)

Experimental Example 2: Acute Toxicity Test

The acute toxicity test was carried out using the compounds of the present invention prepared in the above Examples, and the results are shown in Table 2 below. As a result, the compounds of the present invention appeared to have little characteristics.

Table 2. LD50 (mg / kg)

As described above, the compound of the general formula (I) according to the present invention has an excellent antimicrobial activity against Gram-positive bacteria, and is extremely expected to be a novel antimicrobial agent because of its extremely low toxicity compared with the existing quinolinecarboxylic acid antibacterial agent .

Claims (2)

A quinolinecarboxylic acid derivative represented by the following general formula (I) and a pharmaceutically acceptable salt thereof Wherein R 1 is a lower alkyl group having 1 to 6 carbon atoms, a halogen-substituted phenyl group, a halogen-substituted alkyl group, or a t-O group in which CY forms an oxazole ring when X is CY, Z is a hydrogen atom, a halogen atom, an amino group or a methyl group, X is a nitrogen atom or CY, Y is a halogen atom, a methoxy group or a methyl group, and m and n each independently represent a hydrogen atom or a lower alkyl group of 1 to 3 carbon atoms, Is an integer of 1 or 2, and m + n is 3 or less. A pyrrolidine derivative represented by the following structural formula (II) and a quinolone carboxylic acid derivative represented by the following structural formula (III) are subjected to a condensation reaction using a base in the presence of a solvent to obtain a quinolinecarboxylic acid derivative of general formula (I) Methods for preparing pharmaceutically acceptable salts Wherein R 1 is a lower alkyl group having 1 to 6 carbon atoms, a halogen-substituted phenyl group, a halogen-substituted alkyl group, or a t-O group in which CY forms an oxazole ring when X is CY, Z is a hydrogen atom, a halogen atom, an amino group or a methyl group, X is a nitrogen atom or CY, Y is a halogen atom, a methoxy group or a methyl group, and m and n each independently represent a hydrogen atom or a lower alkyl group of 1 to 3 carbon atoms, Is an integer of 1 or 2, m + n is 3 or less, and R 4 is a halogen atom, a mesyl group or a tosyl group.