JP2631854B2 - Novel 1,8-naphthyridine derivative - Google Patents

Description

The present invention relates to a novel 1,8-naphthyridine derivative and a pharmacologically acceptable salt thereof.

More specifically, the present invention relates to a compound represented by the general formula (I): (Wherein, X represents a hydrogen atom or a halogen atom,
R ₁ is a lower alkyl group, a lower alkenyl group or a lower cycloalkyl group, and R ₂ is a group represented by the formula Wherein R ₃ is a hydrogen atom, an acetyl group, a formyl group, or a lower alkyl group which may be substituted with a hydroxyl group, and A is a C 3-4 carbon atom which may be substituted.
Wherein X is a fluorine atom and R ₂ is A pyrazolidinyl group or 2-pyrazolin-1 represented by
Yl group, wherein R ₄ and R ₅ are the same or different and are each a hydrogen atom or a lower alkyl group, unless otherwise specified), and a pharmaceutically acceptable salt thereof. Things.

Here, R ₂ includes a pyrazolidinyl group, a hexahydropyridazinyl group or a pyrrolidinylamino group. Examples of the lower alkyl group and lower alkenyl group include methyl, ethyl, n-propyl, isopropyl, and 2-propenyl group, and examples of the lower cycloalkyl group include cyclopropyl, cyclobutyl, and cyclopentyl group. Specific examples of the salt include salts with inorganic acids such as hydrochloric acid, sulfuric acid, and methanesulfonic acid, and organic acids such as gluconic acid and tartaric acid, and sodium, potassium, and ammonium salts of carboxylic acids.

2) Prior Art At present, nalidix (US Pat. No. 3590036) or pipemidic acid (West German patent 2341146) is widely used as a synthetic antibacterial agent as a therapeutic agent for infections caused by Gram-negative bacteria.
However, they are ineffective against Pseudomonas aeruginosa infection, one of the intractable diseases that has been increasing in recent years.

On the other hand, in order to solve these drawbacks, antibacterial agents such as norfloxacin and ciprofloxacin have recently been developed and used clinically. However, although the antibacterial activity is excellent in a test tube, it is pointed out that, unlike nalidixic acid or pipemidic acid, the bioavailability is poor and the compound does not work effectively in vivo.

3) Problems to be Solved by the Invention As described above, the conventional antibacterial agents have activity but have poor absorption, and have good absorption but low activity. Therefore, in order for a synthetic antibacterial agent to effectively act on a living body, it is necessary that both antibacterial properties and bioavailability are selected, and the present invention has solved such a problem. .

4) Means for Solving the Problems We have begun to develop antibacterial agents having excellent antibacterial activity and good bioavailability. Then, a heterocycle having a nitrogen-nitrogen bond, such as pyrazolidines, is found to have low toxicity, and an appropriate hydrophilicity and lipophilic balance, and quinoline carboxylic acid, which is the core of existing synthetic antibacterial agents, and Many compounds in which pyrazolidines were introduced at the 7-position of 1,8-naphthyridine carboxylic acid were synthesized. As a result, the general formula (Wherein Y represents CH, CF, N, R ₁ represents a lower alkyl group or a lower cycloalkyl group, and R ₂ represents a group represented by the following formula: Wherein R ₄ and R ₅ are the same or different and each represent a hydrogen atom or a lower alkyl group), which has strong antibacterial activity against not only Gram-negative bacteria such as Pseudomonas aeruginosa but also Gram-positive bacteria. And it was found to be very excellent in terms of bioavailability (Japanese Patent Application No. 61-214258). The present invention
An object of the present invention is to provide a novel 1,8-naphthyridine derivative having excellent antibacterial activity.

5) Action The compound represented by the above general formula (I) is produced by various methods. A preferred example thereof is, for example, the following known method [J. Med. Chem., 27 , 292 (1984) )].

General formula (II) (Wherein X and R ₁ are the same as described above, and Y represents a group that can be substituted with pyrazolidines, 1-aminopyrrolidines, and the like) and a carboxylic acid or an ester thereof represented by the following formula: Pyrazolidines, 1-aminopyrrolidines or hydrochlorides thereof represented by (Wherein R ₃ and A have the same meanings as described above), and the product is isolated by a conventional method.

In the formula (II), specific examples of the functional group represented by Y include a halogen atom, a lower alkoxy group, a lower alkylthio group, a lower alkylsulfonyl group, a lower alkylsulfonyloxy group, and the like.

This reaction is carried out in an inert solvent such as ethanol, acetonitrile, dioxane, dimethylformamide (DMF), dimethylsulfoxide, pyridine, toluene, or xylene at room temperature to 200 ° C, preferably at room temperature to 150 ° C, with the compound (II) and the pyrazolidine. And 1-aminopyrrolidine for 0.25 to 24 hours, usually 0.5 to 5 hours. The amounts of the pyrazolidines and 1-aminopyrrolidines used are preferably slightly excessive (1.1 to 5 equivalents) compared to the compound (II). When a hydrochloride is used, a base such as an alkali carbonate, an alkali metal alcoholate, and triethylamine is generally used as an acid acceptor. Incidentally, pyrazolidines and hexahydropyridazines can be obtained, for example, by the method of [Chem. Ber., 91 , 1982 (1958)].

Depending on the choice of Y in the compound (II), an acid is by-produced as a result of the reaction. In such a case, a base is used as an acid acceptor. It is convenient to have a double role. In the compound (I), R ₃ is an acetyl group, a formyl group, or a lower alkyl group which may be substituted with a hydroxyl group, and the corresponding compound in which R ₃ is a hydrogen atom is acetic anhydride, formic acid, an alkyl halide, It can also be obtained by reacting with an aldehyde or the like.

The thus-obtained target compound (I) and salts thereof are effective against a wide variety of Gram-negative bacteria and positive bacteria, exhibit excellent antibacterial activity, and have excellent absorbability and are useful as therapeutic agents for urinary tract infections and the like.

6) Examples Next, the compounds of the present invention will be described more specifically with reference to examples.

Example 1. 1-Ethyl-1,4-dihydro-4-oxo-7-pyrazolidinyl-1,8-naphthyridine-3-carboxylic acid.

1.85 g (7.3 mmol) of 7-chloro-1-ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid
l) Pyrazolidine 0.56 g (7.8 mmol) in ethanol 20 ml
And reflux for 1 hour. After the reaction, the precipitated crystals are collected by filtration, washed with ethanol, and recrystallized from ethanol (yield 1.
7g).

Mp: 279-81 ℃ Elemental _{analysis: C 14 H 16 N 4 O} 3 (MW = 288.307) theory H 5.59%, C 58.32%, N 19.43% Found H 5.68%, C 58.52%, N 19.59% Example 2. 1-ethyl-1,4-dihydro-4-oxo-7- (2
-Pyrazolin-1-yl) -1,8-naphthyridin-3-
carboxylic acid.

0.33 g (1.3 mmo) of 7-chloro-1-ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid
l), 0.1 g (1.4 mmol) of pyrazolidine, and 0.288 g (2.1 mmol) of anhydrous potassium carbonate are added to 10 ml of DMF and heated at 95 ° C. for 2 hours. The reaction mixture is concentrated under reduced pressure, the residue is dissolved in a small amount of water, neutralized with 1N hydrochloric acid, and the precipitated crystals are collected by filtration, washed with water, dried and recrystallized from DMF (yield 0.18 g).

Mp: 289 ° C. Elemental _{analysis: C 14 H 14 N 4 O} 3 · 1 / 4H 2 O Theoretical value H 5.03%, C 57.83%, N 19.27% Found H 4.75%, C 57.92%, N 19.30% Example 3 . 1,4-dihydro-1-methyl-4-oxo-7-pyrazolidinyl-1,8-naphthyridine-3-carboxylic acid.

As in Example 1, 7-chloro-1,4-dihydro-1
It is synthesized from -methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid and pyrazolidine, and recrystallized from a mixed solvent of ethanol and DMF (yield 58%).

Melting point: 300 ° C or higher Elemental analysis: C ₁₃ H ₁₄ N ₄ O ₃ (MW = 274.28) Theoretical value H 5.15%, C 56.93%, N 20.43% Observed value H 5.12%, C 56.83%, N 20.31% Example 4 1,4-dihydro-4-oxo-1- (2-propenyl) -7-pyrazolidinyl-1,8-naphthyridine-3-
carboxylic acid.

7-Chloro-1,4-dihydro-4 as in Example 1.
-Oxo-1- (2-propenyl) -1,8-naphthyridine-3-carboxylic acid and pyrazolidine are obtained and recrystallized from ethanol (yield 71%).

Melting point: 235-5 ° C Elemental analysis: C ₁₅ H ₁₆ N ₄ O ₃ (MW = 300.318 Theoretical value H 5.37%, C 59.99%, N 18.66% Actual value H 5.13%, C 59.92%, N 18.51% Example 5 6-chloro-1-ethyl-1,4-dihydro-4-oxo-7-pyrazolidinyl-1,8-naphthyridine-3-carboxylic acid.

As in Example 1, 6,7-dichloro-1-ethyl-1.4
-Dihydro-4-oxo-7-pyrazolidinyl-1,8-
Synthesized from 0.1 g (0.35 mmol) of naphthyridine-3-carboxylic acid and 0.05 g (0.7 mmol) of pyrazolidine, ethanol / DM
Obtained by recrystallization from a mixed solvent of F (yield 0.07 g) Melting point: 280 ° C. (decomposition) Elemental analysis: C ₁₄ H ₁₅ ClN ₄ O ₃ (MW = 322.752) Theoretical H 4.68%, C 52.10%, N 17.36 % Found 4.54% H, 52.53% C, 17.17% N Example 6. 1-Ethyl-1,4-dihydro-7- (2-methylpyrazolidinyl) -4-oxo-1,8-naphthyridine- 3-
carboxylic acid.

As in Example 1, 6,7-chloro-1-ethyl-1,4-
0.253 g (1 mmol) of dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid and 0.258 of 1-methylpyrazolidine
g (3 mmol) and recrystallized from ethanol (yield 0.17 g) Melting point: 235-6 ° C. Elemental analysis: C ₁₅ H ₁₈ N ₄ O ₃ (MW = 302.334 theoretical value H 6.00%, C 59.59%) , N 18.53% Found H 5.90%, C 59.54%, N 18.71% Example 7. 1-Ethyl-1,4-dihydro-7- [2- (2-hydroxyethyl) pyrazolidinyl] -4-oxo-1 , 8−
Naphthyridine-3-carboxylic acid.

1-ethyl-1,4-dihydro-4-oxo-7-pyrazolidinyl-1,8-naphthyridin-3- obtained in Example 1.
0.144 g (0.5 mmol) of carboxylic acid, 0.313 g (2.5 mmol) of ethylene bromohydrin and 50% sodium hydride are added to 2 ml of dry DMF and heated at 95 ° C. for 3 hours. After the reaction, insolubles were filtered off, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate (yield 0.07 g). Melting point: 181-3 ° C Elemental analysis: C ₁₆ H ₂₀ N ₄ O ₄ (MW = 332.36) Theoretical H 6.07%, C 57.82%, N 16.86% Found H 6.11%, C 57.42%, N 16.75% Example 8. 1-Ethyl-7- (2-formylpyrazolidinyl)-
1,4-dihydro-4-oxo-1,8-naphthyridine-3-
carboxylic acid.

1-ethyl-1,4-dihydro-4-oxo-7-pyrazolidinyl-1,8-naphthyridin-3- obtained in Example 1.
Heat 0.07 g (0.24 mmol) of carboxylic acid and 0.3 ml of formic acid at 95 ° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure, ethanol was added to the residue, and the insoluble material was filtered off.
It is obtained by recrystallization from a mixed solvent of F (yield 0.07 g).

Mp: 256-8 ℃ Elemental _{analysis: C 15 H 16 N 4 O} 4 (MW = 316.317 theory H 5.10%, C 56.96%, N 17.71% Found H 5.11%, C 56.69%, N 17.98% Example 9 . 1-ethyl-7- (2-acetylpyrazolidinyl)-
1,4-dihydro-4-oxo-1,8-naphthyridine-3-
carboxylic acid.

1-ethyl-1,4-dihydro-4-oxo-7-pyrazolidinyl-1,8-naphthyridin-3- obtained in Example 1.
0.4 g (1.4 mmol) of carboxylic acid is added to 5 ml of acetic anhydride and refluxed for 1 hour. The reaction mixture is concentrated under reduced pressure, ethanol is added to the residue, the insoluble matter is filtered off, then concentrated and recrystallized from ethanol (yield 0.4 g).

Melting point: 280-1 ° C Elemental analysis: C ₁₆ H ₁₈ N ₄ O ₄ (MW = 330.344 Theory H 5.49%, C 58.17%, N 16.96% Found H 5.62%, C 58.26%, N 16.83% Example 10 . 7-Hexanehydropyridazinyl-1,4-dihydro-
1-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid.

0.477 g of 7-chloro-1,4-dihydro-1-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid (2 mmo
l), 0.516 g (6 mmol) of hexahydropyritazine is added to 20 ml of ethanol and refluxed for 3 hours. After the reaction, the precipitated crystals are collected by filtration and recrystallized from a mixed solvent of ethanol and DMF (yield 0.37 g).

Mp: 275-7 ℃ Elemental _{analysis: C 14 H 16 N 4 O} 3 (MW = 288.307 theory H 5.59%, C 58.32%, N 19.43% Found H 5.69%, C 58.43%, N 19.33% Example 11 . 1-ethyl-7-hexahydropyridazinyl-1,4-
Dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid.

As in Example 10, 7-chloro-1-ethyl-1,4-
It is synthesized from dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid and hexahydropyridazine, and obtained by recrystallization from ethanol (yield: 56%).

Melting point: 260 ° C. Elemental analysis: C ₁₅ H ₁₈ N ₄ O ₃ (MW = 302.334 theoretical value H 6.00%, C 59.59%, N 18.53% actual value H 6.05%, C 59.53%, N 18.40% Example 12.7 -Hexahydropyridazinyl-1,4-dihydro-4
-Oxo-1- (2-propenyl) -1,8-naphthyridine-3-carboxylic acid.

7-Chloro-1,4-dihydro-4 as in Example 10.
-Oxo-1- (2-propenyl) -1,8-naphthyridine-3-carboxylic acid and hexahydropyridazine, which are obtained by recrystallization from ethanol (yield 70%).

Melting point: 226-9 ° C Elemental analysis: C ₁₆ H ₁₈ N ₄ O ₃ (MW = 314.345 Theory H 5.77%, C 61.14%, N 17.82% Found H 5.97%, C 61.31%, N 17.71% Example 13 . 7- (2-Acetylhexahydropyridazinyl) -1
-Ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid.

Example 11 0.4 g (1.32 mmol) of the obtained 1-ethyl-7-hexahydropyridazinyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid was added to 5 ml of acetic anhydride. Add and reflux for 1 hour. The reaction mixture is concentrated under reduced pressure, ethanol is added to the residue, insolubles are filtered off, and the mixture is concentrated and recrystallized from ethanol (yield 0.39 g).

Melting point: 286 ° C. Elemental analysis: C ₁₇ H ₂₀ N ₄ O ₄ (MW = 344.371 Theory H 5.85%, C 59.29%, N 16.27% Found H 5.95%, C 59.11%, N 16.43% Example 14.1 -Ethyl-6-fluoro-7-hexahydropyridazinyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid.

3.0 ml of hexahydropyritazine was added to 1 g (3.7 mmol) of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, and the mixture was heated at 60 ° C. Heat for 1.5 hours. The reaction mixture is concentrated under reduced pressure, water is added to the residue, and the precipitated crystals are collected by filtration, washed with water, dried and recrystallized from ethanol (yield 0.53 g). Melting point: 200-1 ° C. Elemental analysis: C ₁₅ H ₁₇ FN ₄ O ₃ (MW = 320.324) Theory H 5.35%, C 56.24%, N 17.49% Found H 5.31%, C 56.24%, N 17.38% Example 15. 1-Cyclopropyl-6-fluoro-7- Hexahydropyridazinyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid.

7-chloro-1-cyclopropyl-6-fluoro-1,
4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 1.1 g (4.0 mmol), hexahydropyridazine 2.5
Add ml to 20 ml of ethanol and heat at 60 ° C for 1 hour. The reaction mixture is concentrated under reduced pressure, water is added to the residue, and the precipitated crystals are collected by filtration, washed with water, dried and recrystallized from ethanol to obtain 0.6 g.

Melting point: 220-1 ° C Elemental analysis: C ₁₆ H ₁₇ FN ₄ O ₃ (MW = 332.335) Theory H 5.16%, C 57.83%, N 16.86% Found H 5.17%, C 58.02%, N 16.78% 16. 1-Ethyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-pyrrolidinylamino) -1,8-naphthyridine-3-carboxylic acid.

0.41 g (1.5 mmol) of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid was added to 50 ml of ethanol.
Add 0.38 g (4.5 mmol) of aminopyrrolidine and stir at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform: carbon tetrachloride = 10: 1 → 1
0: 0), the desired fractions are collected, concentrated and recrystallized from ethanol to give (yield 0.1 g).

Melting point: 238-40 ° C (decomposition) Elemental analysis: C ₁₅ H ₁₇ FN ₄ O ₃ (MW = 320.324) Theoretical value H 5.35%, C 56.24%, N 17.49% Actual value H 5.50%, C 56.06%, N 17.35 % Example 17. 1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-pyrrolidinylamino) -1,8
-Naphthyridine-3-carboxylic acid.

As in Example 16, 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-
It is synthesized from 1.4 g (5 mmol) of naphthyridine-3-carboxylic acid and 1.3 g (15 mmol) of 1-aminopyrrolidine, and is subjected to silica gel column chromatography (chloroform: carbon tetrachloride = 4: 1 → 4:
0) and obtained by recrystallization from ethanol (yield
0.2g).

Mp: 250 ° C. (decomposition) Elemental _{analysis: C 16 H 17 FN 4 O} 3 · 1 / 4H 2 O Theoretical value H 5.24%, C 57.05%, N 16.63% Found H 5.07%, C 57.23%, N 16.57% 7) Effect of the Invention The usefulness of the compound of the present invention as an antibacterial agent was proved by the following biological tests. The in vitro antibacterial test was carried out according to the method specified by the Japan Chemotherapy Society [Journal of the Japan Chemotherapy Society, 29, (1) 76 (1981)], and nalidixic acid and norfloxacin were used as control drugs. The test results of the compounds of the present invention among the compounds of Examples 4 and 15 are shown in Table 1.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Mayumi Watanabe 1-3-40 Nishi-Otsuka, Matsubara-shi, Osaka Fujimoto Pharmaceutical Co., Ltd. (72) Inventor Masafumi Hase 2-7-14 Minamieganoso, Habikino-shi, Osaka (72) Inventor Mitsuko Hanakawa 1-16-13 285 Urashiri Nishi, Hirano-ku, Osaka-shi, Osaka

Claims (1)

(57) [Claims] 1. The compound of the general formula (I) (Wherein, X represents a hydrogen atom or a halogen atom,
R ₁ is a lower alkyl group, a lower alkenyl group or a lower cycloalkyl group, and R ₂ is a group represented by the formula Wherein R ₃ is a hydrogen atom, an acetyl group, a formyl group, or a lower alkyl group which may be substituted with a hydroxyl group, and A is a C 3-4 carbon atom which may be substituted.
Wherein X is a fluorine atom and R ₂ is A pyrazolidinyl group or 2-pyrazolin-1 represented by
A yl group, wherein R ₄ and R ₅ are the same or different and each is a hydrogen atom or a lower alkyl group, unless otherwise specified), and a pharmaceutically acceptable salt thereof.