KR100332527B1 - Pyridon carbonate derivative, salt thereof and method for manufacturing the same - Google Patents

Abstract

PURPOSE: Provided are pyridon carbonate derivatives, salt thereof and a method for manufacturing the same. The novel pyridon carbonate derivatives have antibacterial activity and are thus used as medicines and drugs for animals and fishes. CONSTITUTION: Pyridon carbonate derivative is represented by the formula(1), wherein R1 is a lower alkyl group, a halogen substituted lower alkyl group, a C3-6 cycloalkyl group or a phenyl group by 1-2 of fluoro groups; R2 is hydrogen, a lower alkyl group or an amino group; A is nitrogen, or C-X(wherein, X is hydrogen, halogen, a lower alkyl group or a alkoxy group); and Z is represented by the formula, wherein R3 and R4 represent hydrogen respectively; R5 is a methyl group; and B is an amino group or a lower alkyl group substituted amino group.

Description

Pyridone carboxylic acid derivative or its salt and manufacturing method thereof

The present invention relates to a novel pyridone carboxylic acid derivative which can be used as a medicine, animal medicine, fish disease medicine as a new antibacterial substance having excellent antibacterial activity, a preparation method thereof and a pharmacological preparation thereof.

The compound of this invention is a pyridone carboxylic acid derivative represented by the following general formula (I), and its salt.

In which R ₁ represents a lower alkyl group, a halogen substituted lower alkyl group, a C _3-6 cycloalkyl group or a phenyl group substituted with 1 to 2 fluoro groups;

R ₂ means hydrogen, lower alkyl group or amino group;

A means nitrogen or C-X, where X means hydrogen, halogen, lower alkyl group or alkoxy group;

Z is represented by the following general formula;

Wherein R ₃ and R ₄ each represent hydrogen,

R ₅ is a methyl group,

B is an amino group substituted with an amino group or a lower alkyl group.

In the present invention, the halogen atom means chloro, bromo, fluoro, and the lower alkyl group includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl and the like.

Lower alkenyl groups include, for example, vinyl, allyl, 1-propenyl and isopropenyl.

Cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. Examples of the substituent in the phenyl group which may have a substituent include halogen, lower alkyl, lower ilkylooxy, halogeno lower alkyl, hydroxy, nitro, amino and the like.

Salts of the compounds of the present invention include salts with inorganic acids such as hydrochloric acid, sulfuric acid, and an acid, acetic acid, lactic acid, oxalic acid, succinic acid, methanesulfonic acid, maleic acid, malonic acid, salts with organic acids such as gluconic acid, aspartic acid, glutamic acid and the like. Salts with acidic amino acids or metal salts of sodium, potassium, calcium, magnesium, zinc and silver of the general formula (I) compounds, and salts with organic bases such as dimethylamine, triethylamine, dicyclohexylamine and benzylamine And salts with basic amino acids such as lysine and arginine.

The ester of the compound of the general formula (I) is a lower alkyl ester such as methyl ester or ethyl ester of the compound of the general formula (I), or is hydrolyzed or easily released in vivo to form a compound of the general formula (I). Known esters such as acetoxymethyl esters, pivaloyloxymethyl esters, ethoxycarbonyls, ethyl esters, choline esters, dimethylaminoethyl esters or 1-piperidinyl ethyl esters; -Indanyl ester, phthalidinyl ester, or the like.

The compound of the present invention is also obtained as a hydrate, which of course is included in the compound of the present invention.

In the compound of the present invention, since the substituent at the 7-position has a subsidiary carbon atom, it can also be obtained as an optically active substance, and such an optically active substance is also included in the compound of the present invention.

Hereinafter, the manufacturing method of the compound of this invention is demonstrated.

The compound of the present invention can be prepared by reacting a compound represented by the following general formula (II) with a novel compound represented by the following general formula (III) and isolating the product by a conventional method.

Z-H (III)

Wherein Y is halogen, R ₆ is hydrogen or lower alkyl group, A, R ₁ and R ₂ are as described above and Z is as described above.

This reaction is carried out with crude compounds (II) and (III), alcohols such as ethanol, dioxane, tetrahydrofuran, ethers such as 1,2-dimethoxyethane, aromatic hydrocarbons such as benzene, toluene and xylene, acetonitrile And inert organic solvents such as dimethylformamide, dimethylsulfoxide, pyridine and water at a temperature of 0 to 200 캜 for 10 minutes to 24 hours.

This reaction generally uses the equivalent or excessive amount of the source compound (III) to the source compound (II) in the presence of an acid acceptor, but may also serve as the acid acceptor by using the excess of the source compound (III).

As the acid acceptor, hydroxides such as sodium hydroxide or potassium hydroxide, carbonates such as sodium carbonate or potassium carbonate, bicarbonates such as sodium bicarbonate or potassium bicarbonate, triethylamine, dimethylaniline, N, N-diisopropylethylamine, 1,8- Organic salts such as diazabicyclo [5,4,0] undec-7-ene (DBU) can be used.

The raw material compound (III) used in the above reaction may be used by itself, but may be used in the form of protecting an amine group not involved in the reaction. In this case, the protecting group is removed according to a conventional method after the reaction is completed. As a protecting group, what can be removed without destroying the structure of the compound of this invention formed by reaction is a protecting group normally used by a peptide, an amino acid, hexane, or a beta lactam type compound. Preferred protecting groups include, for example, hydrolyzable groups such as acetyl, trifluoroacetyl, ethoxycarbonyl groups, or benzyl groups.

Raw material compound (II) is manufactured according to the method as described above, for example according to the method described below, or a method equivalent thereto [J. Med. Chem., 1988, 31 , 503; J. Org. Chem., 1981, 46 , 846; EP 0132845 (1985); USP 4826987 (1989); EP 0271275 (1987); JP 01-268662; JP 64-16746; J. Heterocyclic Chem., 1990. 27 , 1609; J. Heterocyclic Chem., 1991. 28, 541].

Raw material compound (III) is a novel compound synthesized in the present invention, an example of which is 6-endoamino-7-exo-methyl-3-azabicyclo [3,1,1] heptane prepared by the following method. Can be.

(Wherein R ₇ is hydrogen or methyl group)

In other words, a known compound, Np-toluenesulfonyl-7-exo-methyl-6-oxo-3-azabicyclo [3,1,1] heptane (Heterocycles, 1989, 25 , 29), was prepared in the presence of methoxy. Reduction of the methoxyamine or hydroxyimine compound (IV) produced by condensation reaction with a hydrochloride salt of imine or hydroxyamine with a reducing agent forms an amino compound (V). 6-endo-amino-7-exo-methyl-3-azabicyclo [3,1,] heptane (VI) can be prepared.

In addition, Np-toluenesulfonyl-7-exo-methyl-6-oxo-3-azabicyclo [3,1,1] heptane as a reducing compound is reduced with a reducing agent to obtain an alkoxy compound VI). 6-endo-hydroxy-7-exo-methyl-3-azabicyclo [3,1,1] heptane (VIII) can be obtained.

When the compound of the present invention obtained by the above method is an ester, the ester moiety is hydrolyzed in a conventional manner to change the compound of the general formula (I). On the other hand, if necessary, the compound of the general formula (I) may be esterified by a conventional method to produce an ester of the compound of the general formula (I).

The compound of the present invention prepared as described above is isolated and purified according to a conventional method. In isolation and refining conditions, they are obtained in the form of a salt or in a free form, but these are mutually converted according to the purpose and the compound of the present invention is produced in the desired form.

The compounds of the present invention represented by the general formula (I), esters thereof, or salts thereof are novel compounds and especially compounds (I) or salts thereof exhibit a wide range of strong antimicrobial activities as well as grams Because of its strong antibacterial activity against benign bacteria and methicillin resistant bacteria, its value as an antimicrobial agent is sufficient.

CPEX: Ciprofloxacin, OFLX: Ofloxacin

* 1 The minimum growth inhibition concentration (MIC: mcg / ml) was measured in accordance with the method described in Chemotheraphy, 29 (1), 76 (1981), and the results are shown in the table.

* 2 A: Staphylococcus aureus smith

B: Streptococcus pyogenes C4003

C: MRSA C2208

D: Escherichia coli A10536

E: Klebsiella pneumonise A10031

The compound of the general formula (I) or a salt thereof can be used not only for human or animal drugs but also as a fish disease drug, pesticide, food preservative, and the like. In addition, esters of general formula (I) are of course valuable as synthetic raw materials of compounds of general formula (I), and in addition, when the compound is easily converted into a compound of general formula (I) in vivo, It is also useful as an antimicrobial agent because it has the same effect as the compound.

When the compound of the present invention is used as an antimicrobial agent in humans, the dosage varies depending on age, weight, symptoms, route of administration, etc., but 5 mg to 5 g per day may be administered from once to several times, and the route of administration is oral or parenteral. Both sides are possible.

Although the compound of this invention may be used as it is, it is normally administered in the form of preparation like a carrier for formulation. Specific examples thereof include tablets, liquids, capsules, fine granules, powders, syrups, injections and ointments.

As a carrier of the oral preparation, a substance which does not react with the compound of the present invention is used in the field of preparations such as starch, mannitol, crystalline cellulose, CMC, Na, water and ethanol. Injectable carriers include commercially available carriers used in the field of injectables, such as water, saline, glucose solution, and fluids.

In addition, the solution or ointment is also used for the purpose of treatment in otolaryngology and ophthalmology.

The following examples specifically illustrate the preparation of the compounds of the present invention.

Example

Reference Example 1 :

6-methoxyimino-7-exo-methyl-3- (p-toluenesulfonyl) -3-azabicyclo [3,1,1] heptane

7-exo-methyl-6-oxo-3- (p-toluenesulfonyl) -3-azabicyclo [3,1,1] heptane

A mixture of 20.0 g, 7.20 g of methoxylamine hydrochloride and 200 mL of pyridine was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 500 ml of ethyl acetate, washed twice with 20 ml of 5% aqueous hydrochloric acid solution and once with 200 ml of saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solid was removed by filtration under reduced pressure, and the filtrate was concentrated under reduced pressure, dissolved in a small amount of ethanol and recrystallized with distilled water to obtain 20 g of the titled compound. (Yield 94%)

Melting Point: 115 ℃ to 117 ℃

¹ H-NMR (CDC13) δ: 7.7 (2H, d. J = 8.0 Hz), 7.3 (2H, d, J = 8.2 Hz),

3.77 (4H, m), 3.75 (3H, s), 3.0 (1H, m), 2.75 (1H, m), 2.43 (3H, s),

1.96 (1H, m), 1.08 (3H, d, J = 6.8 Hz)

Reference Example 2 :

6-endo-amino-7-exo-methyl-3- (p-toluenesulfonyl) -3-azabicyclo [3,1,1] heptane

12.0 g of NaBH ₄ was suspended in 150 mL of THF and 30. mL of trifluoroacetic acid (TFA) dissolved in 150 mL of THF and added at room temperature over 2 hours. 20.0 g of the title compound of Reference Example 1 was dissolved in 200 ml of THF, added at room temperature over 2 hours, the reaction solution was stirred at room temperature for 3 hours, and 50 ml of water and 30 ml of 40% sodium hydroxide aqueous solution were added for 5 hours. It was heated to reflux. The reaction solution was concentrated under reduced pressure to remove THF, extracted three times with 200 ml of dichloromethane, and the organic layer was washed with 200 ml of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate.

The solid was removed by filtration under reduced pressure, and the filtrate was concentrated under reduced pressure to give 16.0 g of the title compound as a tan oil (98% yield).

Melting Point: 290 ℃ (Decomposition)

¹ H-NMR (CDC13) δ: 7.7-7.1 (4H, m), 3.4-2.0 (10H, m), 2.3 (3H, s),

1.3 (3H, s)

Reference Example 3 :

6-endo-amino-7-exo-methyl-3-azabicyclo [3,1,1] heptane

A mixture of 5.0 g of the title compound of Reference Example 2 and 30 ml of an aqueous 48% HBr solution was heated to reflux for 5 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in 5 ml of water, 3 ml of 40% aqueous sodium hydroxide solution was added thereto, and the mixture was extracted three times with 100 ml of chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure to remove solids, and concentrated under reduced pressure to obtain 1.8 g of a pale yellow oily title compound. (Yield 80%)

¹ H-NMR (CDC13) δ: 3.7-2.3 (8H, m), 1.41 (3H, s),

Example 1

7- (6-endo-amino-7-exo-methyl-3-azabicyclo [3,1,1] heptan-3-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4 -Dihydro-1,8-naphthyridine-3-carboxylic acid

220 mg of 7-chloro-6-fluoro-1-cyclopropyl-1,4-dihydro4-oxo-1,8-naphthyridine-3-carboxylic acid is suspended in 4 ml of acetonitrile and 6-endo-amino 180 mg of -7-exo-methyl-3-azabicyclo [3,1,1] heptane and 140 mg of DBU were added and stirred at room temperature for 5 hours. The resulting solid was filtered, washed with acetonitrile and dried to give 200 mg of white title compound (yield 68%).

Melting Point: 300 ℃ or higher

¹ H-NMR (DMSO-d6 + TFA-d) δ: 15.44 (2H, s), 8.53 (1H, s), 7.9 (1H, d, J = 16.8 Hz), 4.23-1.43 (12H, m), 1.14 (4 H, m)

Example 2

7- (6-endo-amino-7-exo-methyl-3-azabicyclo [3,1,1] heptan-3-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4 -Dihydro-4-oxoquinoline-3-carboxylic acid

120 mg of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid is suspended in 7 ml of acetonitrile and 6-endo-amino-7-exo-methyl 125 mg of -3-azabicyclo [3,1,1] heptane and 100 mg of DBU were added and refluxed at room temperature for 3 hours. After cooling to room temperature, the precipitated solid was filtered, washed with acetonitrile and dried to obtain 160 mg of a white title compound. (95% yield)

Melting Point: 226-299 ℃

¹ H-NMR (DMSO-d6 + TFA-d) δ: 15.33 (2H, s), 8.30 (1H, s), 7.75 (1H, d, J = 15.7 Hz), 7.18 (2H, d, J = 7.9 Hz), 4.04-1.43 (12H, m), 1.11 (4H, m)

Example 3

7- (6-endo-amino-7-exo-methyl-3-azabicyclo [3,1,1] heptan-3-yl) -1-cyclopropyl-6-fluoro-8-methoxy-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid

1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 130 mg, 6-endo-amino-7-exo-methyl-3 150 mg of azabicyclo [3,1,1]) heptane and 130 mg of DBU were added to 10 ml of acetonitrile and stirred at 60 ° C. for 17 hours. The reaction solution was treated in the same manner as in Example 2 to obtain 90 mg of the title compound. (Yield 54%)

Melting Point: 226-299 ℃

¹ H-NMR (DMSO-d6 + TFA-d) δ: 8.98 (1H, s), 8.00 (1H, d, J = 12.5 Hz),

4.44-4.05 (5H, m), 4.02 (3H, s), 3.71-2.50 (4H, m),

1.70 (2H, d, J = 7.6 Hz), 1.65-1.25 (4H, m)

Example 4

9-fluoro-3-methyl-10- (6-endo-amino-7-exo-methyl-3-azabicyclo [3,1,1] heptan-3-yl) -7-oxo-2,3- Dihydro-7H-pyrido [1,2,3-dec] -1,4-benzoxazin-6-carboxylic acid

9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] -1,4-benzoxazin-6-carboxylic acid 201 mg and 140 mg of DBU were added to 7 ml of acetonitrile and refluxed at 50 ° C. for 12 hours. The reaction solution was treated in the same manner as in Example 2 to obtain 120 mg of the title compound. (Yield 54%)

Melting Point: 198 to 203 ° C

¹ H-NMR (DMSO-d6 + TFA-d) δ: 9.01 (1H, s), 7.64 (1H, d, J = 12.1 Hz),

4.96 (1H, m), 4.53 (2H, dd), 3.83-2.28 (8H, m), 1.47-1.41 (6H, m)

Example 5

7- (6-endo-amino-7-exo-methyl-3-azabicyclo [3,1,1] heptan-3-yl) -8-chloro-1-cyclopropyl-6-fluoro-1,4 -Dihydro-4-oxoquinoline-3-carboxylic acid

8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 270 mg, 6-endo-amino-7-exo-methyl-3- 140 mg of azabicyclo [3,1,1] heptane and 130 mg of DBU were added to 8 ml of acetonitrile and refluxed at 70 ° C. for 12 hours. The reaction solution was treated in the same manner as in Example 2 to obtain 130 mg of the title compound (yield 66%).

Melting Point: 237 ~ 240 ℃

¹ H-NMR (DMSO-d6 + TFA-d) δ: 8.87 (1H, s), 7.93 (1H, d, J = 13.3 Hz),

4.39 (1H, m), 4.10-2.10 (8H, m), 1.40 (3H, d, J = 7.2 Hz), 1.25-1.03 (4H, m)

Example 6

5-amino-6,8-difluoro-7- (6-endo-amino-7-exo-methyl-3-azabicyclo [3,1,1] heptan-3-yl) -1-cyclopropyl- 1,4-dihydro-4-oxoquinoline-3-carboxylic acid

5-amino-6,7,8-trifluoro-1-cyclopropyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 150 mg, 6-endo-amino-7-exo-methyl- 150 mg of 3-azabicyclo [3,1,1] heptane and 100 mg of DBU were added to 10 ml of acetonitrile and refluxed at 70 ° C. for 8 hours. The resulting solid was filtered after cooling to room temperature, washed with cold methanol and acetonitrile, and Drying gave 130 mg of the title compound (yield 66%).

Melting Point: 145-150 ℃

¹ H-NMR (DMSO-d6 + TFA-d) δ: 8.53 (1H, s), 4.03 (1H, m), 3.81-2.24 (8H, m),

1.39 (3H, d), 1.10 (4H, m)

Example 7

7- (6-endo-amino-7-exo-methyl-3-azabicyclo [3,1,1] heptan-3-yl) -1-cyclopropyl-6-fluoro-5-methyl-1,4 -Dihydro-4-oxoquinoline-3-carboxylic acid

1-cyclopropyl-6,7-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 140 mg, 6-endo-amino-7-exo-methyl-3- 150 mg of azabicyclo [3,1,1] heptane and 100 mg of DBU were added to 3 ml of acetonitrile and refluxed for 3 hours. 160 mg of the title compound was obtained in the same manner as the Example 2 solution. (Yield 81%)

Melting Point: 260 ~ 265 ℃

¹ H-NMR (DMSO-d6 + TFA-d) δ: 8.48 (1H, s), 7.1 (1H, d, J = 9 Hz),

4.1-2.2 (12H, m), 1.4 (3H, d, J = 7 Hz), 1.2 (4H, m)

Example 8

1- (2,4-difluorophenyl) -7- (6-endo-amino-7-exo-methyl-3-azabicyclo [3,1,1] heptan-3-yl) -6-fluoro -1,4-dihydro-4-oxo-1,8-naphpyridine-3-carboxylic acid

10 ml of acetonitrile 200 mg of 1- (2,4-difluorophenyl) 6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid After dissolving in 194 mg of 6-endo-amino-7-exo-methyl-3-azabicyclo [3,1,1] heptane and 255 mg of DBH were added and stirred at room temperature for 7 hours. 10 ml of water and 3 ml of acetonitrile were added to the reaction solution to dissolve it, and then adjusted to pH 7 with a 5% aqueous hydrochloric acid solution and stirred at room temperature for 2 hours.

The resulting solid is filtered, washed with 50 ml of water and dried to give 200 mg of the title compound (yield 80%).

Melting Point: 146 ~ 150 ℃

¹ H-NMR (DMSO-d6 + TFA-d) δ: 8.95 (1H, s), 8.09 (1H, d, J = 13 Hz),

7.85 (1H, m), 7.5 (1H, m), 7.3 (1H, m), 4.05 (4H, s), 3.39 (1H, br),

2.59 (2H, s) 2.0 (1H, s), 1.3 (1H, d, J = 7.2 Hz)

Example 9

1- (4-fluorophenyl) -7- (6-endo-amino-7-exo-methyl-3-azabishiro [3,1,1] heptan-3-yl) -6-fluoro-1 , 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid

200 mg of 1- (4-fluorophenyl) -7-chloro-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid are suspended in 80 ml of acetonitrile. 206 mg of 6-endo-amino-7-exo-methyl-3-azabicyclo [3,1,1] heptane dihydrochloride and 272 mg of DBU were added to give 210 mg of the title compound in the same manner as in Example 8. 82%).

Melting Point: 260 ℃ or higher (decomposition)

¹ H-NMR (DMSO-d6 + TFA-d) δ: 8.95 (1H, s), 8.3 (1H, d, J = 13.5 Hz),

7.9-7.4 (4H, m), 4.1 (4H, s), 3.4 (1H, br), 2.7 (2H, s), 2.5 (1H, q)

Example 10

1-cyclopropyl-7- (6-endo-aminomethyl-7-exo-methyl-3-azabicyclo [3,1,1] heptan-3-yl) -6-fluoro-1,4-dihydro 4-oxo-1,8-naphthyridine-3-carboxylic acid

200 mg of 1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid was suspended in 10 ml of acetonitrile and then 6-endo 181 mg of aminomethyl-7-exo-methyl-3-azabicyclo [3,1,1] heptane dihydrochloride and DBU235 mg are added and stirred at room temperature for 7 hours. The solid formed was filtered, washed with 50 ml of acetonitrile and dried to obtain 180 mg of the target compound (yield 65%).

Melting Point: 300 ℃ (Decomposition)

¹ H-NMR (DMSO-d6 + TFA-d) δ: 8.60 (1H, s), 7.92 (1H, d, J = 16.5 Hz),

4.3-1.42 (9H, m), 2.6 (3H, d), 1.6 (3H, d), 1.5 (4H, m)

Example 11

1- (2,4-Difluorophenyl) -7- (6-endo-aminomethyl-7-exo-3-azabicyclo [3,1,1] heptan-3-yl) -6-fluoro- 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid

200 mg of 1- (2,4-difluorophenyl) -7-chloro-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid acetonitrile 10 After adding to mL, 144 mg of 6-endo-aminomethyl-7-exo-methyl-3-azabicyclo [3,1,1] heptane dihydrochloride and 255 mg of DBH were added and stirred at room temperature for 7 hours. The reaction solution was obtained in the same manner as in Example 8 to obtain 200 mg of the title compound (yield 78%).

Melting Point: 218 ℃

¹ H-NMR (DMSO-d6 + TFA-d) δ: 9.0 (1H, s), 8.2 (1H, d, J = 13 Hz),

7.8 (1H, m), 7.6 (1H, m), 7.2 (1H, m), 4.0 (4H, br), 3.5-2.0 (4H, m),

2.6 (3H, s) 1.5) 3H, d, J = 7 Hz)

Example 12

1- (4-fluorophenyl) -7- (6-endo-aminomethyl-7-exo-methyl-3-azabicyclo [3,1,1] heptan-3-yl) -6-fluoro-1, 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid

200 mg of 1- (4-difluorophenyl) -7-chloro-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid in 10 ml of acetonitrile After suspension, 152 mg of 6-endo-aminomethyl-7-exo-methyl-3-azabicyclo [3,1,1] heptane dihydrochloride and 270 mg of DBU are added and allowed to react at room temperature for 8 hours. Thereafter, 210 mg of the target compound was obtained in the same manner as in Example 8 (yield 80%).

Melting Point: 270 ℃

¹ H-NMR (DMSO-d6 + TFA-d) δ: 8.90 (1H, s), 8.43 (1H, d),

8.0-7.4 (4H, m), 4.1-2.5 (8H, m), 2.7 (3H, d), 1.52 (3H, d)

Example 13

1-cyclopropyl-7- (6-endo-aminomethyl-7-exo-methyl-3-azabicyclo [3,1,1] heptan-3-yl) -6-fluoro-1,4-dihydro 4-oxo-1,8-naphthyridine-3-carboxylic acid

200 mg of 1-cyclopropyl-6,7difluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid is suspended in 10 ml of acetonitrile and then 6-endo-amino 190 mg of methyl-7-exo-methyl-3-azabicyclo [3,1,1] heptane dihydrochloride and 335 mg of DBU are added and refluxed for 7 hours. The reaction solution was cooled to room temperature, concentrated, dissolved in 20 ml of water and 5 ml of acetotrile, adjusted to pH 7 with a 5% aqueous hydrochloric acid solution, and stirred at room temperature for 2 hours. The resulting solid was filtered and then water Wash with 50 mL to give 200 mg (72.4%) of the title compound.

Melting Point: 235 ~ 238 ℃

¹ H-NMR (DMSO-d6 + TFA-d) δ: 8.6 (1H, s), 7.8 (1H, d, J = 11 Hz),

7.3 (1H, d, J = 6 Hz), 4.0 (4H, br), 3.8-1.8 (5H, m), 2.65 (3H, d),

1.63 (3H, d, J = 7 Hz), 1.3 (4H, m)

Example 14

1-tert-butyl-7- (6-endo-aminomethyl-7-exo-methyl-3-azabicyclo [3,1,1] heptan-3-yl) -6-fluoro-1,4-di Hydro-4-oxo-1,8-naphthyridine-3-carboxyl

200 mg of 1-tert-butyl-7-chloro-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid was suspended in 10 ml of acetonitrile and then 6- 180 mg of endo-aminomethyl-7-exo-methyl-3-azabicyclo [3,1,1] heptane dihydrochloride and 317 mg of DBU were added to obtain 215 mg of the title compound in the same manner as in Example 8. (79% yield)

Melting Point: 255 ℃

¹ H-NMR (DMSO-d6 + TFA-d) δ: 8.86 (1H, s), 8.05 (1H, d, J = 13.0 Hz),

4.5-2.0 (8H, m), 2.53 (3H, d), 1.90 (9H, s), 1.5 (3H, d)

Example 15

1- (2-fluoroethyl) -7- (6-endo-amino-7-exo-methyl-3-azabischloro [3,1,1] heptan-3-yl) -6-fluoro-1 , 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid

200 mg of 1- (2-fluoroethyl) -7-chloro-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid is suspended in 10 ml of acetonitrile. After adding 255 mg of 6-endo-amino-7-exo-methyl-3-azabicyclo [3,1,1] heptane dihydrochloride and 336 mg of DBU, 203 mg of the title compound was obtained in the same manner as in Example 8 (yield) 68%).

Melting Point: 213 ° C to 214 ° C

¹ H-NMR (DMSO-d6 + TFA-d) δ: 8.85 (1H, s), 8.0 (1H, d, J = 14 Hz),

4.9-2.5 (11H, m), 2.05 (1H, m), 1.45 (3H, d, J = 8 Hz)

Example 16

1- (2-fluoroethyl) -7- (6-endo-amino-7-exo-methyl-3-azabicyclo [3,1,1] heptan-3-yl) -6-fluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid

200 mg of 1- (2-fluoroethyl) -6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was suspended in 10 mg of acetonitrile and then 6-endo-amino- 144 mg of 7-exo-methyl-3-azabicyclo [3,1,1] heptane dihydrochloride and 255 mg of DBU were added and refluxed for 7 hours. Thereafter, 180 mg of the target compound was obtained by the same method as in Example 8. (Yield 65%)

Melting Point: 250 ℃ or higher (decomposition)

¹ H-NMR (DMSO-d6 + TFA-d) δ: 8.90 (1H, s), 8.05 (1H, d),

7.25 (1H, d), 5.0-2.6 (11H, m), 2.1 (1H, m), 1.52 (3H, d)

Example 17

1-((s) -1-methyl-2-fluoroethyl) -7- (6-endo-amino-7-exo-methyl-3-azabicyclo [3,1,1] heptan-3-yl) -6-Fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid

1-((s) -1-Methyl-2-fluoroethyl) -7-chloro-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 200 mg was suspended in 10 ml of acetonitrile, followed by the addition of 220 mg of 6-endo-amino-7-exo-methyl-3-azabicyclo [3,1,1] heptane dihydrochloride and 290 mg of DBU. Obtain 210 mg of compound. (Yield 80%)

Melting Point: 250 ℃ or higher (decomposition)

¹ H-NMR (DMSO-d6 + TFA-d) δ: 8.8 (1H, s), 8.0 (1H, d, J = 13 Hz),

5.7 (1H, m), 4.3 (2H, m), 3.6 (4H, m), 3.45 (1H, s),

2.5-2.29 (3H, m), 1.4-1.3 (6H, m)

Example 18

1-((s) -1-methyl-2-fluoroethyl) -7- (6-endo-amino-7-exo-methyl-3-azabicyclo [3,1,1] heptan-3-yl) -6-fluoro-1,4-dihydro-4-oxoquirroline-3-carboxylic acid

200 mg of 1-((s) -1-methyl-2-fluoroethyl) -6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid in 10 ml of acetonitrile After suspension, 242 mg of 6-endo-amino-7-exo-methyl-3-azabicyclo [3,1,1] heptane dihydrochloride and 317 mg of DBU are added. The reaction solution was refluxed at 50 ° C. for 6 hours to obtain 211 mg of the title compound in the same manner as in Example 8 (yield 77%).

Melting Point: 200 ℃ or higher (decomposition)

¹ H-NMR (DMSO-d6 + TFA-d) δ: 8.7 (1H, s), 7.75 (1H, d, J = 15 Hz),

7.18 (1H, d, J = 8 Hz), 5.5 (1H, m), 4.3 (2H, m), 3.5 (4H, m),

3.4 (1H, s), 2.35 (2H, s) 2.0 (1H, m), 1.4-1.2 (6H, m)

Example 19

7- (6-endo-amino-7-exo-methyl-3-azabicyclo [3,1,1] heptan-3-yl) -1-trifluoroethyl-6-fluoro-4-oxo-1 , 4-dihydro-1,8-naphthyridine-3-carboxylic acid

Suspend 500 mg of 7-chloro-1-trifluoroethyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid in 10 ml of acetonitrile. 529 mg of endo-amino-7-exo-methyl-3-azabicyclo [3,1,1] heptane dihydrochloride and 0.84 ml of DBU were added and stirred at room temperature for 2 hours. 430 mg of the target compound were obtained in the same manner as in Example 8 (yield 67%).

Melting Point: Above 270 ℃ (Decomposition)

¹ H-NMR (DMSO-d6 + TFA-d) δ: 9.00 (1H, s), 8.00 (1H, d, J = 13 Hz),

5.60-5.43 (2H, m), 4.40-4.05 (4H, m), 3.38 (1H, m), 2.60 (2H, m),

1.43 (3H, d)

Example 20

7- (6-Endo-amino-7-exo-methyl-3-azabicyclo [3,1,1] heptan-3-yl) -1- (tert-butyl) -6-fluoro-4-oxo- 1,4-dihydro-1,8-naphthyridine-3-carboxylic acid

200 mg of 7-chloro-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid is suspended in 8 ml of acetonitrile and 6-endo-amino-7-exo 200 mg of the title compound was obtained in the same manner as in Example 8, after adding 200 mg of methyl-3-azabicyclo [3,1,1] heptane dihydrochloride and 325 mg of DBU. (Yield 67%)

Melting Point: 270 ° C to 272 ° C

¹ H-NMR (DMSO-d6 + TFA-d) δ: 8.9 (1H, s), 8.1 (1H, d, J = 14 Hz),

4.25-2.2 (8H, m), 1.9 (9H, s), 1.35 (3H, d)

Example 21

1-cyclopropyl-7- (6-endo-7-exo-methyl-3-azabicyclo [3,1,1] heptan-3-yl) -6, 8-difluoro-1,4-dihydro 4-oxoquinoline-3-carboxylic acid

1-cyclopropyl-6,7,8-4-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid suspended in 5 ml of acetonitrile and 6-endo-amino-7- 230 mg of exo-methyl-3-azabicyclo [3,1,1] heptane 2HBr salt and 280 mg of DBU are added. The reaction solution is cooled to room temperature, the resulting solid is filtered, washed with distilled water and isopropyl alcohol and dried. 140 mg of the title compound is obtained. (Yield 68%)

Melting Point: 215-220 ℃

¹ H-NMR (DMSO-d6 + TFA-d) δ: 8.71 (1H, s), 8.41 (2H, d, J = 4.9 Hz),

7.88 (1H, dd, J = 10.5 Hz), 4.14-2.27 (9H, m), 1.43 (3H, d, J = 7.6 Hz),

1.20 (4 H, m)

Example 22

1-cyclopropyl-7- (6-endo-aminoethyl-7-exo-methyl-3-azabicyclo [3,1,1] heptan-3-yl) -6-fluoro-1,4-dihydro 4-oxo-1,8-naphthyridine-3-carboxylic acid

200 mg of 1-cyclopropyl-7-chloro-6-fluoro-1,4-oxo-8-naphthyridine-3-carboxylic acid is suspended in 8 ml of acetonitrile and 6-endo-aminoethyl-7-exo- Add 230 mg of methyl-3-azabicyclo [3,1,1] heptane and 210 mg of DBU. The reaction solution was stirred at room temperature for 3 hours and then treated in the same manner as in Example 21 to obtain 160 mg of the title compound (yield 57%).

Melting Point: 217 ℃ (Decomposition)

¹ H-NMR (DMSO-d6 + TFA-d) δ: 8.88 (1H, s), 8.02 (1H, d, J = 14 Hz),

4.25-3.12 (8H, m), 2.67-2.08 (3H, m), 1.42 (3H, d, J = 8 Hz),

1.27-1.08 (7H, m)

Example 23

1- (2,4-difluorophenyl) -7- (6-endo-aminoethyl-7-exo-methyl-3-azabicyclo [3,1,1] heptan-3-yl) -6-fluoro Rho-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid

125 mg of 1- (2,4-difluorophenyl) -7-chloro-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid acetonitrile 4 Suspend in ml and add 100 mg of 6-endo-aminoethyl-7-exo-methyl-3-azabicyclo [3,1,1] heptane and 120 mg of DBU. The reaction solution was stirred at room temperature for 3 hours to obtain 120 mg of the title compound in the same manner as in Example 21 (yield 72%).

Melting Point: 190 ℃

¹ H-NMR (DMSO-d6 + TFA-d) δ: 8.83 (1H, s), 8.12 (1H, d, J = 14 Hz),

7.82-7.33 (3H, m), 4.25-3.05 (7H, m), 2.5-2.0 (3H, m), 1.34 (3H, m),

1.20 (3 H, m)

Example 24

1-cyclopropyl-7- (6-endo-aminoethyl-7-exo-methyl-3-azabicyclo [3,1,1] heptan-3-yl) -6-fluoro-1,4-dihydro 4-oxoquinoline-3-carboxylic acid

94 mg of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxolinoline-3-carboxylic acid is suspended in 4 ml of acetonitrile and 6-endo-aminoethyl-7-exo- Add 80 mg of methyl-3-azabicyclo [3,1,1] heptane and 85 mg of DBU. The reaction solution was refluxed at 70 ° C. for 10 hours, cooled to room temperature, the resulting solid was filtered, washed with distilled water and isopropyl ether, and dried to obtain 70 mg of the target compound (yield 52%).

Melting Point: 220 ~ 225 ℃

¹ H-NMR (DMSO-d6 + TFA-d) δ: 8.57 (1H, s), 7.82 (1H, d, J = 16 Hz),

7.21 (1H, d, J = 8 Hz), 4.07-3.40 (6H, m), 3.13-2.10 (5H, m),

1.43 (3H, m), 1.3-1.1 (7H, m)

Example 25

1- (4-fluorophenyl) -7- (6-endo-aminoethyl-7-exo-methyl-3-azabicyclo [3,1,1] heptan-3-yl) -6-fluoro-1 , 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid

110 mg of 1- (4-fluorophenyl) -7-chloro-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid is suspended in 4 ml of acetonitrile. 120 mg of 6-endo-aminoethyl-7-exo-methyl-3-azabicyclo [3,1,1] heptane and 110 mg of DBU are added. The reaction solution was stirred at room temperature for 4 hours, and 110 mg of the title compound was obtained in the same manner as in Example 21. (74% yield)

Melting Point: 255 ℃ (Decomposition)

¹ H-NMR (DMSO-d6 + TFA-d) δ: 8.68 (1H, s), 8.2 (1H, d),

7.7-7.4 (4H, m), 4.1-3.06 (7H, m), 2.5-2.0 (3H, m),

1.35 (3H, d, J = 7 Hz), 1.19 (3H, t, J = 7 Hz)

Example 26

1- (tert-butyl) -7- (6-endo-aminoethyl-7-exo-methyl-3-azabicyclo [3,1,1] heptan-3-yl) -6-fluoro-4-oxo -1,4-dihydro-1,8-naphthyridine-3-carboxylic acid

210 mg of 1- (tert-butyl) -7-chloro-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid is suspended in 8 ml of acetonitrile and 6 -160 mg of endo-abinoethyl-7-exo-methyl-3-azabicyclo [3,1,1] heptane dihydrochloride and 190 mg of DBU are added. After stirring the reaction solution at room temperature for 3 hours, 240 mg of the target compound was obtained in the same manner as in Example 21. (Yield 86%)

Melting Point: 100 ℃

¹ H-NMR (DMSO-d6 + TFA-d) δ: 8.71 (1H, s), 4.23 (4H, m),

3.4 (1H, m), 3.12 (2H, m), 2.66-2.09 (3H, m), 1.83 (9H, s),

1.41 (3H, d, J = 8 Hz), 1.27 (3H, m)

Example 27

1- (2-fluoroethyl) -7- (6-endo-aminoethyl-7-exo-methyl-3-azabicyclo [3,1,1] heptan-3-yl) -6-fluoro-4 Oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid

10 mg of 1- (2-fluoroethyl) -7-chloro-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid is suspended in 4 ml of acetonitrile. Add 100 mg of 6-endo-aminoethyl-7-exo-methyl-3-azabicyclo [3,1,1] heptane and 90 mg of DBU. After stirring the reaction solution at room temperature for 3 hours, 66 mg of the target compound was obtained in the same manner as in Example 21. (Yield 47%)

Melting Point: 300 ℃ (Decomposition)

¹ H-NMR (DMSO-d6 + TFA-d) δ: 8.89 (1H, s), 8.04 (1H, d, J = 14 Hz),

4.9-4.79 (4H, m), 4.20 (4H, m), 3.34-3.09 (3H, m), 2.66-2.9 (3H, m),

1.4 (3H, d, J = 8 Hz), 1.25 (3H, t, J = 7 Hz)

Example 28

1-cyclopropyl-7- (6-endo-aminoethyl-7-exo-methyl-3-azabicyclo [3,1,1] heptan-3-yl) -6,8-difluoro-1,4 -Dihydro-4-oxoquinoline-3-carboxylic acid

100 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid is suspended in 4 ml of acetonitrile and 6-endo-aminoethyl-7- Add 90 mg of exo-methyl-3-azabicyclo [3,1,1] heptane and 100 mg of DBU. The reaction solution was refluxed at 70 ° C. for 5 hours to obtain 60 mg of the title compound in the same manner as in Example 21. (Yield 41%)

Melting Point: 200-205 ℃

¹ H-NMR (DMSO-d6 + TFA-d) δ: 8.70 (1H, s), 8.40 (1H, d),

7.90 (1H, dd), 4.30-2.25 (1H, m), 1.52 (3H, d), 1.35-1.16 (7H, m)

Example 29

1-ethyl-7- (6-endo-aminoethyl-7-exo-methyl-3-azabicyclo [3,1,1] heptan-3-yl) -6-fluoro-1,4-dihydro- 4-oxo-1,8-naphthyridine-3-carboxylic acid

140 mg of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid is suspended in 5 ml of acetonitrile and 6-endo-aminoethyl-7- Add 120 mg of exo-methyl-3-azabicyclo [3,1,1] heptane and 130 mg of DBU. The reaction solution was stirred at room temperature for 4 hours, and 120 mg of the title compound was obtained in the same manner as in Example 21. (Yield 60%)

Melting Point: 225 ~ 230 ℃

¹ H-NMR (DMSO-d6 + TFA-d) δ: 8.90 (1H, s), 8.06 (1H, d, J = 13 Hz),

4.32-3.10 (9H, m), 2.60-2.03 (3H, m), 1.52 (3H, d, J = 9 Hz),

1.32-1.09 (6H, m)

Example 30

1-ethyl-7- (6-endo-aminoethyl-7-exo-methyl-3-azabicyclo [3,1,1] heptan-3-yl) -6-fluoro-1,4-dihydro- 4-oxo-1,8-naphthyridine-3-carboxylic acid

140 mg of 1-ethyl-7-chloro-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid is suspended in 5 ml of acetonitrile and 6-endo-amino Add 180 mg of ethyl-7-exo-methyl-3-azabicyclo [3,1,1] heptane dihydrochloride and 240 mg of DBU. The reaction solution was stirred for 1 hour at room temperature and left for 5 hours to filter the resulting solid. The solution is washed with acetonitrile and dried to give 170 mg of the title compound. (91% yield)

Melting Point: 300 ℃ or higher

¹ H-NMR (DMSO-d6 + TFA-d) δ: 8.92 (1H, s), 8.07 (1H, d, J = 13 Hz),

4.32-3.08 (7H, m), 2.62-2.01 (3H, m), 1.50 (3H, d, J = 8 Hz),

1.30-1.08 (3H, m)

Example 31

1,4-dihydro-7- (6-endo-amino-7-exo-methyl-3-azabicyclo [3,1,1] heptan-3-yl) -6-fluoro-1-methyl-4 Oxo-1,8-naphthyridine-3-carboxylic acid

132 mg of 1,4-dihydro-7-chloro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid is suspended in 5 ml of acetonitrile and 6-endo-amino-7-exo Add 180 mg of methyl-3-azabicyclo [3,1,1] heptane dihydrochloride and 240 mg of DBU. After stirring the reaction solution at room temperature for 2 hours, 150 mg of the title compound was obtained in the same manner as in Example 30 (yield 86%).

Melting Point: 295 ℃ (Decomposition)

¹ H-NMR (DMSO-d6 + TFA-d) δ: 8.88 (1H, s), 8.01 (2H, d, J = 13 Hz),

4.30-3.02 (8H, m), 2.58-2.0 (3H, m), 1.55 (3H, d)

Claims (5)

Pyridone carboxylic acid derivative represented by general formula (I) or a salt thereof: In which R ₁ represents a lower alkyl group, a halogen substituted lower alkyl group, a C _3-6 cycloalkyl group or a phenyl group substituted with 1 to 2 fluoro groups; R ₂ means hydrogen, lower alkyl group or amino group; A means nitrogen or C-X, where X means hydrogen, halogen, lower alkyl group or alkoxy group; Z is represented by the following general formula; Wherein R ₃ and R ₄ each represent hydrogen, R ₅ is a methyl group, B is an amino group substituted with an amino group or a lower alkyl group. A compound represented by formula (III); Z-H (III) In the above formula, Z is represented by the following general formula, Wherein R ₃ and R ₄ each represent hydrogen, R ₅ is a methyl group, B is an amino group substituted with an amino group or a lower alkyl group. A compound represented by formula (I) characterized by condensation reaction of a compound represented by formula (II) wherein R ₆ is hydrogen with a compound represented by formula (III) or an acid addition salt thereof in an inert organic solvent A method of preparing a don carboxylic acid derivative or a salt thereof; In formula (I), R ₁ is a lower alkyl group, a halogen substituted lower alkyl group, a C _3-6 cycloalkyl group or a phenyl group substituted with 1 to 2 fluoro groups, R ₂ means hydrogen, lower alkyl group or amino group; A means nitrogen or C-X, where X means hydrogen, halogen, lower alkyl group or alkoxy group; Z is represented by the following general formula; Wherein R ₃ and R ₄ each represent hydrogen, R ₅ is a methyl group, B means an amino group substituted with an amino or lower alkyl group. A compound represented by formula (II) wherein R ₆ is lower alkyl and a compound represented by formula (III) or an acid addition salt thereof are subjected to condensation reaction in an inert organic solvent and then hydrolyzed. Method for preparing a pyridone carboxylic acid derivative or salt thereof represented by: Z-H (III) In which R ₁ represents a lower alkyl group, a halogen substituted lower alkyl group, a C _3-6 cycloalkyl group or a phenyl group substituted with 1 to 2 fluoro groups; R ₂ means hydrogen, lower alkyl group or amino group; A means nitrogen or C-X (where X means hydrogen, halogen, lower alkyl group or alkoxy group); Z is represented by the following general formula; Wherein R ₃ and R ₄ each represent hydrogen, R ₅ is a methyl group. B means an amino group substituted with an amino or lower alkyl group. An antimicrobial composition comprising a compound of formula (I) according to claim 1 and a pharmaceutically acceptable carrier: In formula (I), in formula (I), R ₁ means lower alkyl group, halogen substituted lower alkyl group, C _3-6 cycloalkyl group or phenyl group substituted with 1 to 2 fluoro groups; R ₂ means hydrogen, lower alkyl group or amino group; A means nitrogen or C-X, where X means hydrogen, halogen, lower alkyl group or alkoxy group; Z is represented by the following general formula; Wherein R ₃ and R ₄ each represent hydrogen, R ₅ is a methyl group, B means an amino group substituted with an amino or lower alkyl group.