KR19990052328A - New Quinolone Carboxylic Acid Derivatives - Google Patents

Abstract

The present invention relates to a novel quinolonecarboxylic acid derivative of formula (I) and a pharmaceutically acceptable salt thereof, a method for preparing the same, and an antimicrobial composition containing the same as an active ingredient, wherein the compound of formula (I) It is excellent as an antibacterial agent and has a broad antibacterial spectrum, which is useful as an antibacterial agent.

(Wherein R ₁ , R ₂ , R ₃ , R ₄ and X are as defined in the specification).

Description

New Quinolone Carboxylic Acid Derivatives

The present invention relates to a novel quinolonecarboxylic acid derivative having excellent antimicrobial activity, a pharmaceutically acceptable salt thereof, a preparation method thereof, and an antimicrobial composition containing the same as an active ingredient.

The quinolone derivatives reported so far and the quinolone antimicrobial agents used in the clinic are known to have excellent antimicrobial activity, but the antimicrobial activity against gram-negative bacteria is inferior to that of gram-negative bacteria, or the gram-negative bacteria is excellent. There is a problem such as poor or showing cytotoxicity, phototoxicity and the like.

Accordingly, the present inventors have an excellent antimicrobial activity, a broad antimicrobial spectrum, an improved antimicrobial activity against quinone derivatives, particularly gram-positive bacteria and methicillin-resistant bacteria, with low solubility in water and low cytotoxicity. As a result of further research to develop an antimicrobial agent, the quinolone derivatives having 3-carbamoylpyrrolidine derivatives at position 7 of the quinolone nucleus, which are prepared by condensation of quinolonecarboxylic acid and amine derivatives, are not only Gram negative bacteria but also Gram positive bacteria and The antimicrobial activity against methicillin resistant strains was found to be very good and low selectivity, leading to the completion of the present invention.

Accordingly, an object of the present invention is to provide a quinolone carboxylic acid derivative having excellent antimicrobial activity and broad antibacterial spectrum, low solubility in water and low cytotoxicity, a preparation method thereof, and an antimicrobial composition comprising the same as an active ingredient.

In order to achieve the above object, the present invention provides a novel quinolonecarboxylic acid derivative of the general formula (I) and a pharmaceutically acceptable salt thereof:

Formula 1

In the above formula,

R ₁ means a C ₁ -C ₄ lower alkyl group such as ethyl, cyclopropyl, 1-t-butyl group, or a C ₁ -C ₄ lower alkyl group, phenyl group or pyridyl group substituted with halogen;

R ₂ means hydrogen, amino or methyl group;

R ₃ and R ₄ each represent hydrogen, a C ₁ -C ₄ lower alkyl group, or a C ₁ -C ₄ lower alkyl group substituted with phenyl or halogen;

X means a methine group substituted with nitrogen, methine (CH), or a halogen, a C ₁ -C ₄ lower alkyl group or a C ₁ -C ₄ lower alkoxy group.

According to this another object, the present invention provides a method for preparing a compound of formula (I) by condensation reaction of a quinolone derivative of formula (II) with an amine derivative of formula (III):

Wherein R ₁ , R ₂ , R ₃ , R ₄ , and X are as defined above, and Y means a fluorine, chlorine or sulfonyl group.

In accordance with another object, the present invention provides an antimicrobial composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Hereinafter, the present invention will be described in more detail.

Compounds of formula (I) of the invention include their racemic compounds, enantiomers and mixtures thereof.

In the compound of formula (I), R ₁ is a C _1-4 lower alkyl group such as ethyl, cyclopropyl, 1-t-butyl group, C _1-4 lower alkyl group substituted by halogen, phenyl group or pyridyl group, R ₂ is hydrogen, amino or methyl, R ₃ and R ₄ are each hydrogen, a C _1-4 lower alkyl group, or a C _1-4 lower alkyl group substituted with phenyl or halogen, X is nitrogen, methine, halomethyl, Preference is given to compounds which are methoxymethine or methylmethine.

Among the compounds of formula (I), in particular R ₁ is cyclopropyl or 2,4-difluorophenyl, R ₂ is hydrogen or amino, R ₃ and R ₄ are each hydrogen or methyl, X is nitrogen, More preferred are compounds that are methine, fluormethine, chlormethine or methoxymethine.

Among the compounds of the general formula (I) of the present invention, the most preferred compounds are as follows:

1-cyclopropyl-6,8-difluoro-7-[(3-amino-3-carbamoylpyrrolidin) -1-yl] -4-oxo-1,4-dihydroquinoline-3-carboxyl mountain;

1-cyclopropyl-6-fluoro-8-chloro-7-[(3-amino-3-carbamoylpyrrolidin) -1-yl] -4-oxo-1,4-dihydroquinoline-3-carbox Acid;

1-cyclopropyl-6-fluoro-8-methoxy-7-[(3-amino-3-carbamoylpyrrolidin) -1-yl] -4-oxo-1,4-dihydroquinoline-3- Carboxylic acid;

1-cyclopropyl-5-amino-6,8-difluoro-7-[(3-amino-3-carbamoylpyrrolidin) -1-yl] -4-oxo-1,4-dihydroquinoline- 3-carboxylic acid;

1-cyclopropyl-6-fluoro-7-[(3-amino-3-carbamoylpyrrolidin) -1-yl] -4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

9-Fluoro-2,3-dihydro-3- (S) -methyl-10-[(3-amino-3-carbamoylpyrrolidin) -1-yl] -7-oxo-7H-pyrido [ 1.2.3-de] -1,4-benzooxazine-6-carboxylic acid;

1-cyclopropyl-6-fluoro-7-[(3-amino-3-carbamoylpyrrolidin) -1-yl] -4-oxo-1,4-dihydro-1,8-naphthyridine-3 -Carboxylic acid;

1- (2,4-difluorophenyl) -6-fluoro-7-[(3-amino-3-carbamoylpyrrolidin) -1-yl] -4-oxo-1,4-dihydro-1 , 8-naphthyridine-3-carboxylic acid;

1-cyclopropyl-6,8-difluoro-7-[(3-amino-3-N-methylcarbamoylpyrrolidin) -1-yl] -4-oxo-1,4-dihydroquinoline-3 -Carboxylic acid;

1-cyclopropyl-6-fluoro-8-chloro-7-[(3-amino-3-N-methylcarbamoylpyrrolidin) -1-yl] -4-oxo-1,4-dihydroquinoline- 3-carboxylic acid;

1-cyclopropyl-6-fluoro-8-methoxy-7-[(3-amino-3-N-methylcarbamoylpyrrolidin) -1-yl] -4-oxo-1,4-dihydroquinoline -3-carboxylic acid;

1-cyclopropyl-5-amino-6,8-difluoro-7-[(3-amino-3-N-methylcarbamoylpyrrolidin) -1-yl] -4-oxo-1,4-di Hydroquinoline-3-carboxylic acid;

1-cyclopropyl-5-amino-6,8-difluoro-7-[(3-N-methylamino-3-carbamoylpyrrolidin) -1-yl] -4-oxo-1,4-di Hydroquinoline-3-carboxylic acid;

9-Fluoro-2,3-dihydro-3- (S) -methyl-10-[(3-amino-3-N-methylcarbamoylpyrrolidin) -1-yl] -7-oxo-7H- Pyrido [1.2.3-dec] -1,4-benzooxazine-6-carboxylic acid;

1-cyclopropyl-6-fluoro-7-[(3-N-methylamino-3-carbamoylpyrrolidin) -1-yl] -4-oxo-1,4-dihydro-1,8-naphthy Lidine-3-carboxylic acid;

1-cyclopropyl-5-amino-6,8-difluoro-7-[(3-N-methylamino-3-N-methylcarbamoylpyrrolidin) -1-yl] -4-oxo-1, 4-dihydroquinoline-3-carboxylic acid; And

1- (2,4-difluorophenyl) -6-fluoro-7-[(3-amino-3-N-methylcarbamoylpyrrolidin) -1-yl] -4-oxo-1,4-di Hydro-1,8-naphthyridine-3-carboxylic acid.

The compound of general formula (I) according to the present invention can be prepared by condensation reaction of a quinolonecarboxylic acid of general formula (II) with an amine derivative of general formula (III) as shown in Scheme (1) below.

Wherein R ₁ , R ₂ , R ₃ , R ₄ , X and Y are as defined above.

In the condensation reaction of Scheme 1, the compound of Formula (II) and the compound of Formula (III) are dissolved or suspended in water or an organic solvent in a molar ratio of 1: 1 to 1: 1.3, and an inorganic or organic base is added thereto. After the addition, it may be carried out by reacting at a temperature of 20 to 120 ℃.

In this case, acetonitrile, dimethylformamide, dimethyl sulfoxide, pyridine, and the like may be used as the organic solvent, and triethylamine, pyridine, diazabicyclo [5,4,0] undec-7-ene, Tertiary amines, such as diisopropylamine, are suitable.

Compounds of the general formula (II) used as starting materials for preparing compounds of general formula (I) of the present invention are described in Chem. Pharm. Bull. , 34, 4098 (1986); J. Med. Chem. , 34, 168 (1991); J. Med. Chem. , 23, 1358 (1980); J. Med. Chem. , 31, 503 (1988); Japanese Patent Laid-Open No. 62-25772; European Patent Application Publication No. 0 183 129 A1; And PCT International Publication No. WO 95/10519.

The compounds of the general formula (III), which are also used as starting materials for the preparation of the compounds of the general formula (I) of the present invention, are represented by the methods (i), (ii) and (iii) It can be prepared by three methods of, these racemic compounds, each enantiomer can be prepared separately.

Method (i)

Method (ii)

Method (iii)

Wherein R ₃ and R ₄ are as defined above, W is a leaving group, Boc is a t-butoxycarbonyl group, and Bn is benzyl.

Pharmaceutically acceptable salts of the compounds of general formula (I) of the invention include their alkali metal and alkaline earth metal salts, such as sodium salts, potassium salts, magnesium salts and calcium salts.

Compounds of formula (I) or pharmaceutically acceptable salts thereof of the present invention are useful as antibacterial agents. The present invention therefore also provides an antimicrobial composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The pharmaceutical compositions of the invention can be formulated in oral or injection dosage forms. Formulations for oral administration include, for example, tablets, capsules, etc. These formulations, in addition to the active ingredient, may contain diluents (e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants ( Eg silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols). Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpicolidine, optionally starch, agar, alginic acid or its Disintegrants or boiling mixtures such as sodium salts and / or absorbents, colorants, flavors and sweeteners may be contained. Injectable formulations are preferably aqueous isotonic solutions or suspensions.

These formulations may be sterile and / or contain preservatives, stabilizers, hydrating or emulsifying accelerators, auxiliaries such as salts and / or buffers for osmotic pressure control and other therapeutically valuable substances.

The compositions of the present invention may be formulated by conventional mixing, granulating or coating methods and the active ingredient may be contained in the range of about 1 to 99.5%, preferably about 5 to 95%. The unit dosage form for about 1 to 300 kg mammals contains about 20 to 3000 mg of active ingredient.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, these preparation examples and examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Preparation Example 1 Preparation of 3-Amino-3-carbamoylpyrrolidine Dihydrochloride

Step 1) Preparation of N-benzyl-3-ethoxycarbonyl-4-oxopyrrolidine

600 g of N-benzyl-N-ethoxycarbonylmethyl-β-alanine ethyl ester was placed in 3 L of anhydrous toluene, and the temperature of the reaction vessel was lowered to 0 ° C., and 165 g of sodium ethoxide was added thereto several times. After stirring at room temperature for about 5 hours, when the reaction was completed, 30 ml of ice water was added and the mixture was stirred vigorously, and the resulting solid was filtered, washed with hexane and ether, dissolved in water and adjusted to pH 7 with concentrated sulfuric acid, Extract with 2 liters of ethyl acetate and dry over anhydrous magnesium sulfate. Subsequently, the solvent was distilled under reduced pressure to obtain 295 g of a target compound (yield: 58%).

¹ H NMR (CDCl ₃ ): δ 1.25 (3H, t) 2.80-3.50 (4H, m) 3.72 (2H, s) 4.05-4.40 (3H, m) 7.30 (5H, m).

Step 2) Preparation of N-benzyl-3-oxopyrrolidine

295 g (1.19 mol) of N-benzyl-3-ethoxycarbonyl-4-oxopyrrolidine was dissolved in 6N hydrochloric acid solution and stirred at 60-70 ° C. overnight. The mixture was neutralized with caustic soda solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography (eluent: hexane: ethyl acetate = 1: 1) to obtain 156 g of the target compound.

¹ H NMR (CDCl ₃ ): δ 2.35-2.81 (6H, m), 3.71 (2H, q), 7.3 (5H, m)

Step 3) Preparation of N-benzyl-3-amino-3-cyanopyrrolidine

3.25 g of potassium cyanide and 3 g of ammonium chloride were dissolved in 20 ml of water in an ice bath, and 15 ml of ammonium hydroxide was added. Then, a solution of 8.65 g of N-benzyl-3-oxopyrrolidine dissolved in 40 ml of ethanol was slowly added dropwise. . The reactor was sealed and then heated to 60-70 ° C. for 15 hours. The solvent was removed, water and ethyl acetate were added, followed by extraction, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (eluent: hexane: ethyl acetate = 1: 1) to obtain 3.37 g of the target compound.

¹ HNMR (CDCl ₃ ): δ 1.85-1.97 (1H, m) 2.37-2.47 (1H, m) 2.56-2.78 (3H, m) 2.96 (1H, d) 3.58 (2H, s) 7.17-7.28 (5H, m)

Step 4) Preparation of N-benzyl-3-t-butoxycarbonylamino-3-carbamoylpyrrolidine

After 50 ml of concentrated sulfuric acid was cooled in an ice bath, 2 g of N-benzyl-3-amino-3-cyanopyrrolidine was added thereto, followed by stirring at room temperature for 3 hours. After the reaction was completed, the temperature was neutralized at 20 占 폚 or lower with caustic soda solution. The resulting sodium sulfate was filtered off and the solvent was evaporated under reduced pressure. 50 ml of methanol and 2.5 g of di-t-butyldicarbonate were sequentially added to the residue, followed by stirring for 5 hours, and then the solvent was removed. Water was added, extraction was performed twice with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, followed by column chromatography (eluate: hexane: ethyl acetate = 1: 4) to obtain 2.41 g of the target compound.

¹ H NMR (CDCl ₃ ): δ 1.42 (9H, s) 2.13-2.27 (1H.m) 2.32-2.47 (1H, m) 2.69-2.80 (1H, m) 2.91-3.03 (3H, m) 3.68 (2H m) 5.61 (1 H, b) 5.96 (1 H, s) 7.22-7.34 (5 H, m) 7.95 (1 H, s)

Step 5) Preparation of N-1-butoxycarbonyl-3-t-butoxycarbonylamino-3-carbamoylpyrrolidine

2.41 g of N-benzyl-3-t-butoxycarbonylamino-3-carbamoylpyrrolidine was dissolved in methanol and hydrogenated (initial pressure 60 psi) by adding 300 mg of 10% Pd-C. Pd-C was removed by filtration through celite, and 2.0 g of di-t-butyldicarbonate was added to the filtrate and stirred for 5 hours. After the solution was removed, the solution was solidified with ethyl acetate to obtain 1.4 g of the target compound.

¹ H NMR (CDCl ₃ -CD ₃ OD): δ 1.39 (18H, s) 2.02-2.43 (2H.m) 3.23-3.61 (3H, m) 3.77 (1H, m)

Step 6) Preparation of 3-amino-3-carbamoylpyrrolidine dihydrochloride

700 mg of N-1-butoxycarbonyl-3-t-butoxycarbonylamino-3-carbamoylpyrrolidine was dissolved in 5 ml of a mixed solvent of methanol and chloroform, and then a hydrogen chloride gas was dissolved in ethanol. 10 ml of solution was added and stirred for 3 hours. The resulting solid was filtered to give 330 mg of the target compound.

¹ H NMR (D ₂ O): δ 2.37-2.48 (2H, m), 2.56-2.67 (2H, m), 3.46-3.62 (3H, m), 3.88 (1H, d), 5.63 (1H, b) , 6.01 (1H, s)

Preparation Example 2 Preparation of 3-Amino-3-N-methylcarbamoylpyrrolidine Dihydrochloride

Step 1) Preparation of N-1-butoxycarbonyl-3-t-butoxycarbonylamino-3-N-methylcarbamoylpyrrolidine

Dissolve 3.1 g of N-1-butoxycarbonyl-3-t-butoxycarbonylamino-3-carbamoylpyrrolidine in 10 ml of dimethylformamide, add 1.1 g of potassium t-butoxide at room temperature Stir for hours. 1 ml of dimethyl sulfate was added thereto and stirred for 10 hours. The reaction mixture was poured into 100 mL of ice-water, stirred well, extracted with ethyl ether, evaporated under reduced pressure, and the residue was subjected to column chromatography (eluent: methanol: ethyl acetate = 1: 5) to obtain 2.8 g of the target compound.

¹ H NMR (CDCl ₃ ): δ 1.55 (9H, s), 2.35 (2H, m), 2.88-3.10 (7H, m), 3.73 (2H, q), 7.3 (5H, m)

Step 2) Preparation of 3-amino-3-N-methylcarbamoylpyrrolidine dihydrochloride

2.4 g of N-1-butoxycarbonyl-3-t-butoxycarbonylamino-3-N-methylcarbamoylpyrrolidine was reacted in the same manner as in step 6) of Preparation Example 1 to give 1.1 g of the target compound. Got it.

¹ H NMR (D ₂ O): δ 2.20 (1H, m) 2.37 (1H, m) 2.82 (3H, s) 3.35-3.58 (4H, m)

Preparation Example 3: Preparation of 3-methylamino-3-N-carbamoylpyrrolidine dihydrochloride

Step 1) Preparation of N-benzyl-3-t-butoxycarbonylamino-3-cyanopyrrolidine

10.5 g of N-benzyl-3-amino-3-cyanopyrrolidine was dissolved in 100 ml of methanol, and 15 g of di-t-butyldicarbonate was added thereto, followed by stirring at 30 ° C. for 15 hours. After evaporating the solvent under reduced pressure, the residue was chromatographed (eluent: hexane: ethyl acetate = 1: 1) to obtain 12.6 g of the target compound.

¹ H NMR (CDCl ₃ ): δ 1.44 (9H, s), 2.21 (1H.m), 2.40 (1H, m), 2.69-2.80 (1H, m), 2.91-3.03 (3H, m), 3.68 ( 2H, m), 7.22-7.34 (5H, m)

Step 2) Preparation of N-benzyl-3- (N-methyl-N-t-butoxycarbonyl) amino-3-cyanopyrrolidine

12.0 N-benzyl-3-t-butoxycarbonylamino-3-cyanopyrrolidine was dissolved in 10 ml of dimethylformamide, and 2.5 g of 60% sodium hydride was added thereto, followed by stirring at room temperature for 1 hour. Then 6.2 g of methane iodide was added and stirred for 10 hours. The reaction mixture was poured into 500 mL of ice-water, stirred well, and extracted with ethyl ether. The solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography (solvent: hexane: ethyl acetate = 1: 1) to obtain 10.1 g of the target compound.

¹ H NMR (CDCl ₃ ): δ 1.44 (9H, s), 2.21-2.38 (2H, m), 2.52 (3H, s), 2.75 (1H, m), 2.91-3.03 (3H, m), 3.70 ( 2H, m), 7.31 (5H, m)

Step 3) Preparation of N-benzyl-3- (N-methyl-N-t-butoxycarbonyl) amino-3-carbamoylpyrrolidine

9.4 g of N-benzyl-3- (N-methyl-N-t-butoxycarbonyl) amino-3-cyanopyrrolidine was added to 50 ml of concentrated sulfuric acid in an ice bath, followed by stirring at room temperature for 3 hours. After the reaction was completed, the mixture was neutralized with caustic soda solution at a temperature of 20 ° C. or lower. The resulting sodium sulfate was filtered off, the filtrate was extracted twice with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and the residue was subjected to column chromatography (eluent: hexane: ethyl acetate = 1: 4) to obtain 6.8 g of compound was obtained.

¹ H NMR (CDCl ₃ ): δ 1.44 (9H, s), 2.19 (1H.m), 2.43 (1H, m), 2.69-2.80 (4H, m), 2.91-3.03 (3H, m), 3.68 ( 2H, m), 5.61 (1H, b), 5.96 (1H, s), 7.22-7.34 (5H, m)

Step 4) Preparation of N-1-t-butoxycarbonyl-3- (N-methyl-N-t-butoxycarbonyl) amino-3-carbamoylpyrrolidine

6.0 g of N-benzyl-3- (N-methyl-Nt-butoxycarbonyl) amino-3-carbamoylpyrrolidine is dissolved in methanol, and 1.2 g of 10% Pd-C is added to hydrogen (initial pressure 60 psi). Mad. After Pd-C was removed by filtration through celite, 2.0 g of di-t-butyldicarbonate was added to the filtrate and stirred for 5 hours. After the solution was removed, the solution was solidified with ethyl acetate to obtain 4.4 g of the target compound.

¹ H NMR (CDCl ₃ ): δ 1.43-46 (18H, s), 2.23 (1H.m), 2.51 (1H, m), 2.71-2.86 (4H, m), 2.96-3.13 (3H, m), 3.68 (2H, m), 5.63 (1H, b), 6.01 (1H, s)

Step 5) Preparation of 3-methylamino-3-carbamoylpyrrolidine dihydrochloride

3.6 g of 1-N-butoxycarbonyl-3- (N-methyl-Nt-butoxycarbonyl) amino-3-carbamoylpyrrolidine was treated in the same manner as in step 6 of Preparation Example 1 to obtain a target compound. 2.7 g were obtained.

¹ H NMR (D ₂ O): δ 2.23 (1H.m), 2.41-2.51 (4H, m), 2.71-2.86 (1H, m), 2.96-3.13 (3H, m), 5.62 (1H, b) , 5.98 (1H, s)

Preparation Example 4 Preparation of 3-methylamino-3-N-methylcarbamoylpyrrolidine dihydrochloride

Step 1) Preparation of 1-N-butoxycarbonyl-3- (N-methyl-N-t-butoxycarbonyl) amino-3-N-methylcarbamoylpyrrolidine

3.1 g of 1-N-butoxycarbonyl-3-t-butoxycarbonylamino-3-N-methylcarbamoylpyrrolidine is dissolved in 10 ml of dimethylformamide, and 0.57 g of 60% sodium hydride is added thereto. Was added and stirred at room temperature for 1 hour. Then, 1.1 g of methane iodide was added and stirred for 10 hours. The reaction mixture was poured into 100 mL of ice-water, stirred well, and extracted with ethyl ether, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography (eluent: hexane: ethyl acetate = 1: 5) to obtain 2.1 g of the target compound.

¹ H NMR (CDCl ₃ ): δ 2.23 (1H, m), 2.56 (1H, m), 3.10 (1H, s), 3.21 (3H, s), 3.65-3.80 (4H, m)

Step 2) Preparation of 3-methylamino-3-N-methylcarbamoylpyrrolidine dihydrochloride

1.8 g of 1-N-butoxycarbonyl-3- (N-methyl-Nt-butoxycarbonyl) amino-3-N-methylcarbamoylpyrrolidine was treated in the same manner as in step 6 of Preparation Example 1 The desired compound 0.7g was obtained.

¹ H NMR (D ₂ O): δ 2.35-2.41 (2H, m), 2.55 (3H, s), 2.84 (3H, s), 3.30-3.60 (4H, m)

Preparation Example 5) Preparation of 3- (2-fluoroethyl) amino-3-carbamoylpyrrolidine dihydrochloride

Step 1) Preparation of N-benzyl-3- (N- (2-fluoroethyl) -N-t-butoxycarbonyl) amino-3-cyanopyrrolidine

N-benzyl-3-t-butoxycarbonylamino-3-cyanopyrrolidine 12.0 was dissolved in 10 ml of dimethylformamide, 2.5 g of 60% sodium hydride was added thereto, stirred at room temperature for 1 hour, and then 1- 5.2 g bromo-2-fluoroethane was added and stirred for 10 hours. The reaction mixture was poured into 500 mL of ice-water, stirred well, extracted with ethyl ether, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography (eluent: hexane: ethyl acetate = 1: 1) to obtain 8.1 g of the target compound.

¹ H NMR (CDCl ₃ ): δ 1.44 (9H, s), 2.21-2.42 (4H, m), 2.75 (1H, m), 2.91-3.03 (3H, m), 3.70 (4H, m), 7.31 ( 5H, m)

Step 2) Preparation of 3- (2-fluoroethyl) amino-3-carbamoylpyrrolidine dihydrochloride

6.8 g of N-benzyl-3- (N- (2-fluoroethyl) -Nt-butoxycarbonyl) amino-3-cyanopyrrolidine was reacted in the same manner as in steps 3 to 5 of Preparation Example 3. 1.1 g of the target compound were obtained.

¹ H NMR (D ₂ O): δ 2.37-2.40 (2H, m), 2.57 (2H, m), 2.81 (1H, m), 3.30-3.60 (2H, m), 3.72 (2H, m), 5.59 (1H, b), 6.03 (1H, s)

Example 1 1-cyclopropyl-6,8-difluoro-7-[(3-amino-3-carbamoylpyrrolidin) -1-yl] -4-oxo-1,4-dihydroquinoline- Preparation of 3-carboxylic Acid

280 mg of 1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 140 mg of 3-amino-3-carbamoylpyrrolidine, diazabicyclo [ 5.4.0] 200 mg of undec-7-ene was added to 5 ml of acetonitrile, refluxed for 6 hours, cooled, filtered and dried to give 324 mg of a pale yellow target compound.

Elemental Analysis (C ₁₈ H ₁₈ N ₄ O ₄ F ₂ )

Found (%); C: 55.29 H: 4.68 N: 14.37

Theoretical value (%); C: 55.38 H: 4.62 N: 14.36

Example 2: 1-cyclopropyl-6-fluoro-8-chloro-7-[(3-amino-3-carbamoylpyrrolidin) -1-yl] -4-oxo-1,4-dihydroquinoline Preparation of 3-carboxylic acid

298 mg of 1-cyclopropyl-6,7-difluoro-8-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 140 mg of 3-amino-3-carbamoylpyrrolidine 376 mg of the title compound was obtained as a white solid.

Elemental Analysis (C ₁₈ H ₁₈ N ₄ O ₄ FCl)

Found (%); C: 53.21 H: 4.43 N: 13.68

Theoretical value (%); C: 53.00 H: 4.42 N: 13.74

Example 3: 1-cyclopropyl-6-fluoro-8-methoxy-7-[(3-amino-3-carbamoylpyrrolidin) -1-yl] -4-oxo-1,4-dihydro Preparation of Quinoline-3-carboxylic Acid

293 mg of 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and 140 mg of 3-amino-3-carbamoylpyrrolidine 312 mg of the target compound were obtained in the same manner as in Example 1.

Elemental Analysis (C ₁₉ H ₂₁ N ₄ O ₅ F)

Found (%); C: 56.51 H: 5.29 N: 13.87

Theoretical value (%); C: 56.58 H: 5.21 N: 13.90

Example 4: 1-cyclopropyl-5-amino-6,8-difluoro-7-[(3-amino-3-carbamoylpyrrolidin) -1-yl] -4-oxo-1,4- Preparation of Dihydroquinoline-3-carboxylic Acid

295 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and 140 mg of 3-amino-3-carbamoylpyrrolidine 356 mg of yellow target compound was obtained in the same manner as in Example 1.

Elemental Analysis (C ₁₈ H ₁₉ N ₅ O ₄ F ₂ )

Found (%); C: 53.37 H: 4.76 N: 17.41

Theoretical value (%); C: 53.33 H: 4.69 N: 17.28

Example 5 1-cyclopropyl-6-fluoro-7-[(3-amino-3-carbamoylpyrrolidin) -1-yl] -4-oxo-1,4-dihydroquinoline-3-car Preparation of Acids

263 mg of 1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and 140 mg of 3-amino-3-carbamoylpyrrolidine were treated in the same manner as in Example 1. Treatment to give 301 mg of the target compound as a white solid.

Elemental Analysis (C ₁₈ H ₁₉ N ₄ O ₄ F)

Found (%); C: 57.86 H: 5.11 N: 15.12

Theoretical value (%); C: 57.91 H: 5.09 N: 15.01

Example 6: 9-Fluoro-2,3-dihydro-3- (S) -methyl-10-[(3-amino-3-carbamoylpyrrolidin) -1-yl] -7-oxo-7H Preparation of pyrido [1.2.3-dec] -1,4-benzoxazine-6-carboxylic acid

9,10-Fluoro-2,3-dihydro-3- (S) -methyl-7-oxo-7H-pyrido [1.2.3-dec] -1,4-benzooxazine-6-carboxylic acid 287 mg and 140 mg of 3-amino-3-N-methylcarbamoylpyrrolidine were treated in the same manner as in Example 1 to obtain 334 mg of the target compound.

Elemental Analysis (C ₁₈ H ₁₉ N ₄ O ₅ F)

Found (%); C: 55.47 H: 4.91 N: 14.40

Theoretical value (%); C: 55.53 H: 4.88 N: 14.40

Example 7: 1-cyclopropyl-6-fluoro-7-[(3-amino-3-carbamoylpyrrolidin) -1-yl] -4-oxo-1,4-dihydro-1,8- Preparation of Naphthyridine-3-carboxylic Acid

264 mg of 1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid, 140 mg of 3-amino-3-carbamoylpyrrolidine 293 mg of the target compound were obtained in the same manner as in Example 1.

Elemental Analysis (C ₁₇ H ₁₈ N ₅ O ₄ F)

Found (%); C: 54.51 H: 4.87 N: 18.91

Theoretical value (%); C: 54.55 H: 4.81 N: 18.72

Example 8 1- (2,4-Difluorophenyl) -6-fluoro-7-[(3-amino-3-carbamoylpyrrolidin) -1-yl] -4-oxo-1,4- Preparation of Dihydro-1,8-naphthyridine-3-carboxylic Acid

1- (2,4-difluorophenyl) -6,7-difluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid 334 mg, 3-amino-3- 140 mg of carbamoylpyrrolidine was treated in the same manner as in Example 1 to obtain 413 mg of the target compound.

Elemental Analysis (C ₂₀ H ₁₆ N ₅ O ₄ F ₃ )

Found (%); C: 54.08 H: 3.69 N: 15.71

Theoretical value (%); C: 54.05 H: 3.60 N: 15.77

Example 9: 1-cyclopropyl-6,8-difluoro-7-[(3-amino-3-N-methylcarbamoylpyrrolidin) -1-yl] -4-oxo-1,4-di Preparation of Hydroquinoline-3-carboxylic Acid

280 mg of 1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and 170 mg of 3-amino-3-N-methylcarbamoylpyrrolidine were administered. 320 mg of the target compound was obtained by the same method as in Example 1.

Elemental Analysis (C ₁₉ H ₂₀ N ₄ O ₄ F ₂ )

Found (%); C: 56.37 H: 4.91 N: 13.79

Theoretical value (%); C: 56.44 H: 4.95 N: 13.86

Example 10 1-cyclopropyl-6-fluoro-8-chloro-7-[(3-amino-3-N-methylcarbamoylpyrrolidin) -1-yl] -4-oxo-1,4- Preparation of Dihydroquinoline-3-carboxylic Acid

297 mg of 1-cyclopropyl-6,7-difluoro-8-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and 170 mg of 3-amino-3-N-methylcarbamoylpyrrolidine Was treated in the same manner as in Example 1 to obtain 362 mg of the target compound as a white solid.

Elemental Analysis (C ₁₉ H ₂₀ N ₄ O ₄ FCl)

Found (%); C: 54.01 H: 4.68 N: 13.40

Theoretical value (%); C: 54.09 H: 4.74 N: 13.29

Example 11 1-cyclopropyl-6-fluoro-8-methoxy-7-[(3-amino-3-N-methylcarbamoylpyrrolidin) -1-yl] -4-oxo-1,4 Preparation of Dihydroquinoline-3-carboxylic Acid

293 mg of 1-cyclopropyl-6,7-difluoro-8-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and 170 mg of 3-amino-3-N-methylcarbamoylpyrrolidine Was treated in the same manner as in Example 1 to obtain 320 mg of the target compound as a white solid.

Elemental Analysis (C ₂₀ H ₂₃ N ₄ O ₅ F)

Found (%); C: 57.51 H: 5.41 N: 13.38

Theoretical value (%); C: 57.55 H: 5.52 N: 13.34

Example 12 1-cyclopropyl-5-amino-6,8-difluoro-7-[(3-amino-3-N-methylcarbamoylpyrrolidin) -1-yl] -4-oxo-1 Preparation of 4-, dihydroquinoline-3-carboxylic acid

295 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and 3-amino-3-N-methylcarbamoylpyrroli 170 mg of Dean was treated in the same manner as in Example 6 to obtain 320 mg of the target compound.

Elemental Analysis (C ₁₉ H ₂₁ N ₅ O ₄ F ₂ )

Found (%); C: 54.31 H: 4.96 N: 16.68

Theoretical value (%); C: 54.42 H: 5.01 N: 16.71

Example 13: 1-cyclopropyl-5-amino-6,8-difluoro-7-[(3-N-methylamino-3-carbamoylpyrrolidin) -1-yl] -4-oxo-1 Preparation of 4-, dihydroquinoline-3-carboxylic acid

1-cyclopropyl-5-amino-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 295 mg, 3-N-methylamino-3-carbamoylpyrroli 170 mg of Dean was treated in the same manner as in Example 6 to obtain 287 mg of the target compound.

Elemental Analysis (C ₁₉ H ₂₁ N ₅ O ₄ F ₂ )

Found (%); C: 54.51 H: 4.96 N: 16.68

Theoretical value (%); C: 54.42 H: 5.01 N: 16.71

Example 14 9-Fluoro-2,3-dihydro-3- (S) -methyl-10-[(3-amino-3-N-methylcarbamoylpyrrolidin) -1-yl] -7- Preparation of oxo-7H-pyrido [1.2.3-dec] -1,4-benzooxazine-6-carboxylic acid

9,10-Fluoro-2,3-dihydro-3- (S) -methyl-7-oxo-7H-pyrido [1.2.3-dec] -1,4-benzooxazine-6-carboxylic acid 278 mg and 3-amino-3-N-methylcarbamoylpyrrolidine were treated in the same manner as in Example 1 to obtain 290 mg of the target compound.

Elemental Analysis (C ₁₉ H ₂₁ N ₄ O ₅ F)

Found (%); C: 56.51 H: 5.24 N: 13.97

Theoretical value (%); C: 56.58 H: 5.21 N: 13.90

Example 15 1-cyclopropyl-6-fluoro-7-[(3-N-methylamino-3-carbamoylpyrrolidin) -1-yl] -4-oxo-1,4-dihydro-1 Preparation of 8, naphthyridine-3-carboxylic acid

264 mg of 1-cyclopropyl-6,7-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid and 3-N-methylamino-3-carbamoylpyrrolidine 170 mg was treated in the same manner as in Example 6) to obtain 312 mg of the target compound.

Elemental Analysis (C ₁₈ H ₂₀ N ₅ O ₄ F)

Found (%); C: 55.59 H: 5.21 N: 18.11

Theoretical value (%); C: 55.67 H: 5.15 N: 18.04

Example 16: 1-cyclopropyl-5-amino-6,8-difluoro-7-[(3-N-methylamino-3-N-methylcarbamoylpyrrolidin) -1-yl] -4- Preparation of oxo-1,4-dihydroquinoline-3-carboxylic acid

1-cyclopropyl-5-amino-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 295 mg, 3-N-methylamino-3-N-methylcarba 188 mg of molypyrrolidine was treated in the same manner as in Example 6) to obtain 327 mg of the target compound.

Elemental Analysis (C ₂₀ H ₂₃ N ₅ O ₄ F ₂ )

Found (%); C: 55.48 H: 5.31 N: 16.41

Theoretical value (%); C: 55.43 H: 5.31 N: 16.17

Example 17 1- (2,4-Difluorophenyl) -6-fluoro-7-[(3-amino-3-N-methylcarbamoylpyrrolidin) -1-yl] -4-oxo-1 Preparation of, 4-dihydro-1,8-naphthyridine-3-carboxylic acid

1- (2,4-difluorophenyl) -6,7-difluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid 334 mg, 3-amino-3- 170 mg of N-methylcarbamoylpyrrolidine was treated in the same manner as in Example 6) to obtain 335 mg of the target compound.

Elemental Analysis (C ₂₁ H ₁₈ N ₅ O ₄ F ₃ )

Found (%); C: 55.08 H: 3.96 N: 15.32

Theoretical value (%); C: 55.02 H: 3.93 N: 15.28

In vitro antimicrobial activity and selective toxicity of the compounds of the present invention and comparative compounds were measured and compared according to the following test examples.

Test Example 1: In vitro antibacterial activity

In vitro antimicrobial testing of the compounds of the present invention and comparative compounds was performed by a 2-fold dilution method using Mueller Hinton agar medium. The solvent used was water or 1N-NaOH aqueous solution, the strain was Hoechst standard strain and the number of inoculated bacteria was 10 ⁷ CFU (Colony Forming Unit) / ml. After incubating at 37 ^° C. for about 18 hours using cyprofloxacine as a compound of Comparative Examples 1 and 4, the growth of the bacteria was observed and the degree of inhibition was measured.

Table 1 shows the in vitro antibacterial activity of the compounds of Examples 1 and 4 of the present invention and cyprofloxacin, a comparative compound.

Strain MIC (µg / mL) Compound of Example 1 Compound of Example 4 Cyprofloxacin Streptococcus pyogenes 308a 0.391 0.391 3.125 Streptococcus pyogenes 77A 0.195 0.195 0.781 Streptococcus faecium MD 8b 0.391 0.391 0.391 Streptococcus aureus SG 511 (Staphylococcus aureus SG 511) 0.025 0.098 0.195 Streptococcus aureus 285 0.049 0.049 0.781 Streptococcus aureus 503 0.025 0.049 0.391

Test Example 2: Selectivity Index

Selective toxicity of the test compound was determined by the inhibitory action of the test compound against topoisomerase II (IC _{100, Topo II} (µg / ml)) and by the test compound against DNA gyrase of E. Coli. The ratio of inhibitory activity (IC _{100, Gyrase} (µg / ml)) is shown. Table 2 shows the selective toxicity of the compounds of Examples 1 and 4 of the present invention, and the comparative compounds cyprofloxacin and spafloxacin.

IC _{100, Topo II} (µg / mL) IC _{100, Gyrase} (μg / ml) Selective Toxicity (IC _{100, Topo II} / IC _{100, Gyrase)} Compounds of Example 1 Compounds of Example 4 Cyprofloxacin Spafloxacin 1,0001,000500500 0.51.00.51.0 2,0001,0001,000500

From the results of Tables 1 and 2, it can be seen that the compound of the present invention has excellent antibacterial activity and low selectivity.

As described above, the quinolone derivative having 3-carbamoylpyrrolidine derivative at the position 7 of the quinolone nucleus, which is prepared by condensation of the quinolonecarboxylic acid and the amine derivative, has excellent antibacterial activity and low selectivity. It can be usefully used.

Claims (6)

Quinolonecarboxylic acid derivative of formula (I) or a pharmaceutically acceptable salt thereof: Formula 1 In the above formula, R ₁ means a C ₁ -C ₄ lower alkyl group, or a C ₁ -C ₄ lower alkyl group, a phenyl group or a pyridyl group substituted with halogen; R ₂ means hydrogen, amino or methyl group; R ₃ and R ₄ each represent hydrogen, a C ₁ -C ₄ lower alkyl group, or a C ₁ -C ₄ lower alkyl group substituted with phenyl or halogen; X means a methine group substituted with nitrogen, methine (CH), or a halogen, a C ₁ -C ₄ lower alkyl group or a C ₁ -C ₄ lower alkoxy group. The method of claim 1, R ₁ is a C ₁ -C ₄ lower alkyl group, a C ₁ -C ₄ lower alkyl group substituted by halogen, a phenyl group or a pyridyl group, R ₂ is hydrogen, amino or methyl, and R ₃ and R ₄ are each hydrogen, C ₁ -A C ₄ lower alkyl group or a C ₁ -C ₄ lower alkyl group substituted with halogen and X is nitrogen, methine, halomethine, methoxymethine or methylmethine, or a pharmaceutically acceptable salt thereof. The method of claim 1, The following compounds or pharmaceutically acceptable salts thereof: 1-cyclopropyl-6,8-difluoro-7-[(3-amino-3-carbamoylpyrrolidin) -1-yl] -4-oxo-1,4-dihydroquinoline-3-carboxyl mountain; 1-cyclopropyl-6-fluoro-8-chloro-7-[(3-amino-3-carbamoylpyrrolidin) -1-yl] -4-oxo-1,4-dihydroquinoline-3-carbox Acid; 1-cyclopropyl-6-fluoro-8-methoxy-7-[(3-amino-3-carbamoylpyrrolidin) -1-yl] -4-oxo-1,4-dihydroquinoline-3- Carboxylic acid; 1-cyclopropyl-5-amino-6,8-difluoro-7-[(3-amino-3-carbamoylpyrrolidin) -1-yl] -4-oxo-1,4-dihydroquinoline- 3-carboxylic acid; 1-cyclopropyl-6-fluoro-7-[(3-amino-3-carbamoylpyrrolidin) -1-yl] -4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 9-Fluoro-2,3-dihydro-3- (S) -methyl-10-[(3-amino-3-carbamoylpyrrolidin) -1-yl] -7-oxo-7H-pyrido [ 1.2.3-de] -1,4-benzooxazine-6-carboxylic acid; 1-cyclopropyl-6-fluoro-7-[(3-amino-3-carbamoylpyrrolidin) -1-yl] -4-oxo-1,4-dihydro-1,8-naphthyridine-3 -Carboxylic acid; 1- (2,4-difluorophenyl) -6-fluoro-7-[(3-amino-3-carbamoylpyrrolidin) -1-yl] -4-oxo-1,4-dihydro-1 , 8-naphthyridine-3-carboxylic acid; 1-cyclopropyl-6,8-difluoro-7-[(3-amino-3-N-methylcarbamoylpyrrolidin) -1-yl] -4-oxo-1,4-dihydroquinoline-3 -Carboxylic acid; 1-cyclopropyl-6-fluoro-8-chloro-7-[(3-amino-3-N-methylcarbamoylpyrrolidin) -1-yl] -4-oxo-1,4-dihydroquinoline- 3-carboxylic acid; 1-cyclopropyl-6-fluoro-8-methoxy-7-[(3-amino-3-N-methylcarbamoylpyrrolidin) -1-yl] -4-oxo-1,4-dihydroquinoline -3-carboxylic acid; 1-cyclopropyl-5-amino-6,8-difluoro-7-[(3-amino-3-N-methylcarbamoylpyrrolidin) -1-yl] -4-oxo-1,4-di Hydroquinoline-3-carboxylic acid; 1-cyclopropyl-5-amino-6,8-difluoro-7-[(3-N-methylamino-3-carbamoylpyrrolidin) -1-yl] -4-oxo-1,4-di Hydroquinoline-3-carboxylic acid; 9-Fluoro-2,3-dihydro-3- (S) -methyl-10-[(3-amino-3-N-methylcarbamoylpyrrolidin) -1-yl] -7-oxo-7H- Pyrido [1.2.3-dec] -1,4-benzooxazine-6-carboxylic acid; 1-cyclopropyl-6-fluoro-7-[(3-N-methylamino-3-carbamoylpyrrolidin) -1-yl] -4-oxo-1,4-dihydro-1,8-naphthy Lidine-3-carboxylic acid; 1-cyclopropyl-5-amino-6,8-difluoro-7-[(3-N-methylamino-3-N-methylcarbamoylpyrrolidin) -1-yl] -4-oxo-1, 4-dihydroquinoline-3-carboxylic acid; or 1- (2,4-difluorophenyl) -6-fluoro-7-[(3-amino-3-N-methylcarbamoylpyrrolidin) -1-yl] -4-oxo-1,4-di Hydro-1,8-naphthyridine-3-carboxylic acid. The quinolone derivative of the following general formula (II) and the amine derivative of the following general formula (III) are dissolved or suspended in water or an organic solvent in a molar ratio of 1: 1 to 1: 1.3, and a base is added thereto, and then 20 to A process for preparing a compound of formula (I) according to claim 1 comprising reacting at 120 ° C .: Formula 2 Formula 3 Wherein R ₁ , R ₂ , R ₃ , R ₄ and X are as defined in claim 1 and Y means fluorine, chlorine or sulfonyl group. Amine derivatives of the general formula (III) Formula 3 Wherein R ₃ and R ₄ are as defined in claim 1. An antimicrobial composition comprising an antimicrobial effective amount of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.