JPH0635458B2 - Pyridonecarboxylic acid derivatives, their esters and their salts - Google Patents

Description

The present invention relates to a novel pyridonecarboxylic acid derivative having excellent antibacterial activity, its ester and its salt.

More specifically, the compounds of the present invention have the general formula (In the formula, X represents a halogen atom, and R ₁ and R ₂ represent a hydrogen atom or a lower alkyl group.), A pyridonecarboxylic acid derivative, a lower alkyl ester thereof and a salt thereof.

Here, examples of the halogen atom include fluorine and chlorine, and examples of the lower alkyl group include methyl, ethyl,
Examples thereof include propyl, isopropyl, butyl, isobutyl, pentyl and the like, with methyl and ethyl being particularly preferred.

Salts of the compounds of the present invention include acetic acid, lactic acid, succinic acid,
Salts with organic acids such as methanesulfonic acid, maleic acid, malonic acid and gluconic acid, salts with amino acids such as aspartic acid and glutamic acid, or salts with inorganic acids such as hydrochloric acid and phosphoric acid, or of the formula [I] Examples thereof include metal salts of compounds such as sodium, potassium, zinc and silver, and salts with organic bases.

The compounds of the present invention may also exist as hydrates. Therefore, such forms are naturally included in the compound of the present invention.

The compound of the present invention has an asymmetric carbon atom in the substituent at the 7-position, and therefore can exist as an optically active substance. Therefore, these optically active substances are included in the compound of the present invention.

Furthermore, since the compound of the present invention may have two asymmetric carbon atoms in the substituent at the 7-position, it can exist as different stereoisomers (cis type, trans type). These stereoisomers and mixtures thereof are also included in the compound of the present invention.

Among the compounds of the present invention, compounds suitable as antibacterial agents include the following compounds and salts thereof.

* 7- (3-aminomethyl-4-fluoro-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4
-Dihydro-4-oxo-1,8-naphthyridine-3-
Carboxylic acid, 7- (3-aminomethyl-4-chloro-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-
Dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 1-cyclopropyl-7- (3-ethylaminomethyl-4-fluoro-1-pyrrolidinyl) -6-fluoro-
1,4-Dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid. The production method of the compound of the present invention is described below.

The compound of the present invention has the following general formula: (In the formula, Z means a functional group capable of substituting for the cyclic amine derivative described below.) And a lower alkyl ester thereof and the following general formula: (In the formula, R ₁ , R ₂ and X are the same as those mentioned above.) The compound can be produced by reacting with a cyclic amine derivative and isolating the product by a conventional method.

Examples of the reactive functional group represented by Z in the formula [II] include a halogen atom, arylsulfonyl, arylsulfinyl, lower alkylsulfonyl, lower alkoxy, lower alkylthio, lower alkylsulfinyl, arylsulfonyloxy, lower alkylsulfonyloxy and the like. To be

This reaction consists of ethanol, acetonitrile, dioxane,
In an inert solvent such as dimethylformamide, toluene, xylene, at 10 to 180 ° C, preferably 20 to 150 ° C,
Starting material compound [III] or its ester and [III] 5
It can be carried out by mixing and stirring for up to 120 minutes, usually for 20 to 60 minutes. The amount of the raw material compound [III] used is an equivalent amount to a slight excess amount with respect to the raw material compound [II] or its ester. Z of the starting compound [II] or its ester
Acids such as hydrochloric acid may be by-produced as a result of the reaction depending on the type of the functional group of, so in such a case, an acid acceptor is generally used, but the starting compound [III] is used in excess. , May also serve as an acid acceptor.

The starting compound [III] used in this reaction is, if possible, The moiety may be used in a form protected with an acyl group such as acetyl or trifluoroacetyl, and the protecting group may be removed by a conventional method after completion of the reaction.

The starting compound [II] or its ester can be prepared by the method described in Reference Example 1 or a method analogous thereto, or according to JP-A-55-3.
It can be produced by the method described in 1042 or JP-A-57-142983 or a method analogous thereto.

The starting compound [III] can be produced by the method described in Reference Examples 2 to 8 or a method analogous thereto.

When the compound of the present invention obtained by the above method is an ester, it can be converted to the compound of formula [I] by hydrolyzing the ester portion by a conventional method.
Further, if necessary, the compound of the formula [I] can be esterified by a conventional method to give an ester of the compound of the formula [I].

The compound of the present invention produced in this manner is isolated and purified by a conventional method. Depending on isolation and purification conditions, salt form,
It is obtained in the form of a free carboxylic acid or a free amine, which are mutually converted depending on the purpose to produce the desired form of the compound of the present invention.

Stereoisomers of the compound of the present invention (cis type, trans type)
Can be separated from each other by conventional methods such as fractional crystallization, chromatographic separation and the like. The compound [III] having a cis-type or trans-type configuration can also be used to produce the compound of the present invention having a cis-type or trans-type configuration, respectively.

The optically active form of the compound of the present invention can be separated by applying a known method.

Thus obtained compound [I], its ester and its salt are all novel compounds. In particular, the compound [I] and its salt exhibit extremely excellent antibacterial activity and have good solubility, and thus are valuable as antibacterial agents.
The compound [I] or a salt thereof can be used not only as a medicine for humans and animals, but also as a fish disease drug, an agricultural chemical, a preservative for foods, and the like. In addition, the compound [I]
The ester form of is a valuable raw material for the synthesis of compound [I].

Next, data will be given below on the antibacterial activity of the compounds of the present invention.

When the compound of the present invention is used as an antibacterial agent for humans, its dose varies depending on age, body weight, symptoms, administration route, number of administrations, etc., but 5 mg to 5 g per day is administered once or in several divided doses. Is recommended. The route of administration may be oral or parenteral.

Although the compound of the present invention may be used as a bulk, it is usually administered in a form prepared with a carrier for formulation. Specific examples thereof include tablets, capsules, granules, fine granules, powders, syrups, injections and the like. These preparations are prepared according to a conventional method. As the oral pharmaceutical carrier, substances commonly used in the manufacturing field such as starch, mannitol, crystalline cellulose and CMC Na and which do not react with the compound of the present invention are used. Examples of carriers for injection include carriers commonly used in the field of injectables such as water, physiological saline, glucose solutions, and infusions.

Next, the present invention will be described more specifically with reference to Examples and Reference Examples.

Reference Example 1 7-chloro-1-cyclopropyl-6-fluoro-1,
4-dihydro-4-oxo-1,8-naphthyridine-3
-Ethyl carboxylate: (1) 60 g of 2,6-dichloro-5-fluoronicotinonitrile, a known compound, is heated in concentrated sulfuric acid at 65-75 ° C for 1 hour. Add water and heat at 100-110 ℃ for 2 hours,
59.8 g of dichloro-5-fluoronicotinic acid were obtained.

mp155-156 ℃ (2) Treat 45.2g of this compound with thionyl chloride to give 2,
6-Dichloro-5-fluoronicotinic acid chloride 47.5 g
Was obtained as an oil.

(3) 47.5 g of this compound was reacted with diethyl ethoxymagnesium malonate in anhydrous ether to obtain diethyl 2,6-dichloro-5-fluoronicotinoyl malonate as an oil. Water and a catalytic amount of p-toluenesulfonic acid were added thereto, and the mixture was heated at 140 ° C. for 2 hours to obtain 46 g of ethyl 2,6-dichloro-5-fluoronicotinoyl acetate.

mp69-70 ° C (4) 12 g of this compound was treated with ethyl orthoformate and acetic anhydride to give ethyl 2- (2,6-dichloro-5-fluoronicotinoyl) -3-ethoxyacrylate, then this compound Then, cyclopropylamine and triethylamine were reacted in ethanol at room temperature to obtain 12.7 g of ethyl 3-cyclopropylamino-2- (2,6-dichloro-5-fluoronicotinoyl) acrylate.

mp129-130 ° C (5) 12 g of this compound was added to potassium t- in anhydrous dioxane.
Reacted with butoxide to give 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-
10 g of ethyl 1,8-naphthyridine-3-carboxylate was obtained.

mp176-178 ° C Reference Example 2 3-Acetylaminomethyl-4-fluoropyrrolidine: (1) Known compound 1-benzyl-3-hydroxy-4-hydroxymethylpyrrolidine [J.Org.Chem., 30,740 (196)
5)] Reference] 110 g was reacted with 60.9 g of methanesulfonyl chloride in the presence of triethylamine in chloroform to obtain 81 g of oily 1-benzyl-3-hydroxy-4-methanesulfonyloxymethylpyrrolidine.

IR spectrum (liquid film) cm ^-1 : 3370,1350,1170. Mass spectrum m / z: 285 (M ⁺ ), 208,190,91. (2) 120 g of this compound and 22.8 g of sodium azide in 120 g of dimethylformamide. React at ~ 130 ° C to give an oily 3-
30 g of azidomethyl-1-benzyl-4-hydroxypyrrolidine was obtained.

IR spectrum (liquid film) cm ⁻¹ : 3350,2100,1450,1265. Mass spectrum m / z: 232 (M ⁺ ), 175,158,91. (3) Hexafluoropropene-diethylamine in 32 g of this compound in chloroform. 64 g of the reagent was added and reacted, and the crude product was separated and purified by silica gel column chromatography to obtain the following product.

3.5 g of oily 3-azidomethyl-1-benzyl-4-fluoropyrrolidine (stereoisomer B) as initial effluent
Got

IR spectrum (liquid film) cm ⁻¹ : 2100,1450,1270. Mass spectrum m / z: 234 (M ⁺ ), 177,91. NMR spectrum (CDCl ₃ ) δ: 3.64 (2H, s, CH ₂ Ph ),
4.5 and 7.30 (5H, s, C ₆ H ₅ ). 3.0 g of oily 3-azidomethyl-1-benzyl-4-fluoropyrrolidine (stereoisomer A) as a rear effluent.
Got

IR spectrum (liquid film) cm ⁻¹ : 2100,1450,1270. Mass spectrum m / z: 234 (M ⁺ ), 177,91. NMR spectrum (CDCl ₃ ) δ: 3.68 (2H, s, CH ₂ Ph ),
4.75 and . 7.30 (5H, s, C 6 H 5) as an intermediate spillage, 3-azidomethyl-1-benzyl -
7.3 g of a mixture of stereoisomers A and B of 4-fluoropyrrolidine were obtained.

(4) 3.1 g of the above compound (stereoisomer B) was reduced with sodium bis (2-methoxyethoxy) aluminum hydride and then acetylated to give oily 3-acetylaminomethyl-1-benzyl-4-fluoropyrrolidine (stereoisomer). 2.2 g of isomer B) was obtained.

IR spectrum (liquid film) cm ⁻¹ : 3270,1650,1550. Mass spectrum m / z: 250 (M ⁺ ), 158,91. NMR spectrum (CDCl ₃ ) δ: 1.96 (3H, s, COC
H ₃ ), 3.61 (2H, s, CH ₂ Ph), 4.52 and 7.30 (5H, s, C ₆ H ₅ ). Similarly, from the above compound (stereoisomer A), an oily 3
-Acetylaminomethyl-1-benzyl-4-fluoropyrrolidine (stereoisomer A) was obtained.

IR spectrum (liquid film) cm ⁻¹ : 3270,1650,1550. Mass spectrum m / z: 250 (M ⁺ ), 158,91. NMR spectrum (CDCl ₃ ) δ: 1.98 (3H, s, COC
H ₃ ), 3.66 (2H, s, CH ₂ Ph), 4.75 and 7.31 (5H, s, CH ₆ H ₅ ). Similarly, from the mixture of stereoisomers A and B of 3-azidomethyl-1-benzyl-4-fluoropyrrolidine, 3
A mixture of stereoisomers A and B of -acetylaminomethyl-1-benzyl-4-fluoropyrrolidine was obtained.

(5) The above compound (stereoisomer B) was dissolved in ethanol and subjected to hydrogenolysis using 5% palladium-carbon as a catalyst. The catalyst was filtered off and 3-acetylaminomethyl-4-
An ethanol solution of fluoropyrrolidine (stereoisomer B) was obtained. This solution was used for the next substitution reaction.

Similarly, a solution containing 3-acetylaminomethyl-4-fluoropyrrolidine (stereoisomer A) was obtained from the above compound (stereoisomer A).

Similarly, from the mixture of the stereoisomers A and B of 3-acetylaminomethyl-1-benzyl-4-fluoropyrrolidine, the mixture of the stereoisomers A and B of 3-acetylaminomethyl-4-fluoropyrrolidine is included. A solution was obtained.

Reference Example 3 3-Acetylaminomethyl-4-chloropyrrolidine: (1) 3-azidomethyl-1-benzyl-4-hydroxypyrrolidine was reacted with thionyl chloride in chloroform, and then separated and purified by column chromatography. The following product was obtained.

3-Azidomethyl-1-benzyl-4-chloropyrrolidine (stereoisomer A).

IR spectrum (liquid film) cm ^-1 : 2800,2100,740,700. Mass spectrum m / z: 250 (M ⁺ ), 158,91. NMR spectrum (CDCl ₃ ) δ: 2.6 (1H, m, C _3- H),
2.5 ~ 3.0 (2H, m, C ₂ -H), 2.8 ~ 3.4 (2H, m, C ₅ -H), 3.3 ~ 3.7 (2
H, m, CH ₂ N ₃ ), 3.73 (2H, s, CH ₂ Ph), 4.5 (1H, m, C ₄ -H), 7.34 (5
_{H, s, C 6 H 5} ). 3- azidomethyl-1-benzyl-4-chloro-pyrrolidine (stereoisomer B).

IR spectrum (liquid film) cm ^-1 : 2800,2100,740,700. Mass spectrum m / z: 250 (M ⁺ ), 158,91. NMR spectrum (CDCl ₃ ) δ: 2.58 (1H, m, C _3- H),
2.45 ~ 2.8 (2H, m, C ₂ -H), 2.8 ~ 3.2 (2H, m, C ₅ -H), 3.44 (2H,
m, CH ₂ N ₃ ), 3.66 (2H, br s, CH ₂ Ph), 4.05 (1H, m, C ₄ -H), 7.34
(5H, s, C ₆ H ₅ ). (2) The above compound (stereoisomer A) was added to sodium bis (2
After reduction with -methoxyethoxy) aluminum hydride, treatment with acetic anhydride and an aqueous solution of caustic soda gave oily 3-acetylaminomethyl-1-benzyl-4-chloropyrrolidine (stereoisomer A).

IR spectrum (liquid film) cm ⁻¹ : 3300,2800,1650,700. Mass spectrum m / z: 266 (M ⁺ ), 231,171,158,91. NMR spectrum (CDCl ₃ ) δ: 1.97 (3H, s, COC
H ₃ ), 2.5 to 2.9 (2H, m, C ₂ -H), 2.72 (1H, m, C ₃ -H), 2.8 to 3.3 (2
H, m, C ₅ -H), 3.3 to 3.7 (2H, m, CH ₂ NHCOCH ₃ ), 3.71 (2H, s, CH ₂ P
h), 4.48 (1H, m, C ₄ -H), 7.33 (5H, s, C ₆ H ₅ ). Similarly, from the above compound (stereoisomer B), oily 3
-Acetylaminomethyl-1-benzyl-4-chloropyrrolidine (stereoisomer B) was obtained.

IR spectrum (liquid film) cm ⁻¹ : 3300,2800,1650,700. Mass spectrum m / z: 266 (M ⁺ ), 231,158,91. NMR spectrum (CDCl ₃ ) δ: 1.97 (3H, s, COC
H ₃ ), 2.3 to 2.8 (3H, m, C ₂ -H, C ₃ -H), 3.05 to 3.75 (4H, m, CH ₂ NH
COCH ₃ , C ₅ -H), 3.6 (2H, s, CH ₂ Ph), 4.1 (1H, m, C ₄ -H), 7.3 (5H,
s, C ₆ H ₅ ). (3) Hydrogenolysis of the above compound (stereoisomer A) in ethanol in the presence of acetic acid and 5% palladium-carbon. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give oily 3-acetylaminomethyl-4-chloropyrrolidine (stereoisomer A).

Similarly, 3-acetylaminomethyl-4-chloropyrrolidine (stereoisomer B) was obtained from the above compound (stereoisomer B).

Reference Example 4 4-Fluoro-3- (N-methyltrifluoroacetylaminomethyl) pyrrolidine (stereoisomer A): (1) 3-azidomethyl-1-benzyl-4-fluoropyrrolidine (stereoisomer A) was added to sodium After reduction with bis (2-methoxyethoxy) aluminum hydride, formylation with formic acid-acetic anhydride was performed to obtain 1-benzyl-4-fluoro-3-formylaminomethylpyrrolidine (stereoisomer A).

(2) This compound was reduced with sodium bis (2-methoxyethoxy) aluminum hydride and then treated with trifluoroacetic anhydride to give oily 1-benzyl-4-fluoro-3- (N-methyltrifluoroacetylamino). Methyl) pyrrolidine (stereoisomer A) was obtained.

IR spectrum (liquid film) cm ^-1 : 1690,1190. Mass spectrum m / z: 318 (M ⁺ ), 241,158,91. NMR spectrum (CDCl ₃ ) δ: 3.68 (2H, s, CH ₂ P
h), 5.00 (1H, br d, J = 51Hz, C ₄ -H), 7.30 (5H, s, C ₆ H ₅ ). (3) This compound was treated in the same manner as in Reference Example 3- (3). 4-
Fluoro-3- (N-methyltrifluoroacetylaminomethyl) pyrrolidine (stereoisomer A) was obtained.

Reference Example 5 4-Fluoro-3- (N-ethyltrifluoroacetylaminomethyl) pyrrolidine: (1) 3-Acetylaminomethyl-1-benzyl-4-fluoropyrrolidine (stereoisomer A) was used in Reference Example 4- ( Treated in the same manner as 2) to give oily 1-benzyl-4-fluoro-
3- (N-ethyltrifluoroacetylaminomethyl)
Pyrrolidine (stereoisomer A) was obtained.

IR spectrum (liquid film) cm ^-1 : 1690,1140. Mass spectrum m / z: 332 (M ⁺ ), 255,158,91. NMR spectrum (CDCl ₃ ) δ: 5.10 (1H, br d, J =
60Hz, C ₄ -H), 7.33 (5H, s, C ₆ H ₅ ). Similarly 3-acetylaminomethyl-1-benzyl-4-
From fluoropyrrolidine (stereoisomer B), oily 1-
Benzyl-4-fluoro-3- (N-ethyltrifluoroacetylaminomethyl) pyrrolidine (stereoisomer B)
Got

IR spectrum (liquid film) cm ^-1 : 1690,1190,1145. Mass spectrum m / z: 332 (M ⁺ ), 255,235,91. NMR spectrum (CDCl ₃ ) δ: 1.26 (3H, t, J = 7H
z), 4.90 (1H, br d, J = 52Hz, C ₄ -H), 7.34 (5H, s, C ₆ H ₅ ). (2) The above compound (stereoisomer A) was used in Reference Example 3- (3 ) Was performed in the same manner as in () to give 4-fluoro-3- (N-ethyltrifluoroacetylaminomethyl) pyrrolidine (stereoisomer A).

Similarly, 4-fluoro-3- (N-ethyltrifluoroacetylaminomethyl) pyrrolidine (stereoisomer B) was obtained from the above compound (stereoisomer B).

Reference Example 6 3- (Acetyl-N-ethylaminomethyl) -4-fluoropyrrolidine (stereoisomer B): (1) 3-acetylaminomethyl-1-benzyl-4-fluoropyrrolidine (stereoisomer B) After reduction with sodium bis (2-methoxyethoxy) aluminum hydride, acetylation was performed with acetic anhydride to give oily 3- (acetyl-N-ethylaminomethyl) -1-benzyl-4-.
Fluoropyrrolidine (stereoisomer B) was obtained.

IR spectrum (liquid film) cm ⁻¹ : 1630,1450,1420. Mass spectrum m / z: 278 (M ⁺ ), 258,158,91. NMR spectrum (CDCl ₃ ) δ: 1.18 (3H, t, J = 7H
z, CH ₂ CH ₃ ), 2.10 (3H, s, COCH ₃ ), 3.61 (2H, s, CH ₂ Ph), 4.88 (1
H, br d, J = 56 Hz, C ₄ -H), 7.30 (5H, s, C ₆ H ₅ ). (2) This compound was treated in the same manner as in Reference Example 3- (3) to give 3-
(Acetyl-N-ethylaminomethyl) -4-fluoropyrrolidine (stereoisomer B) was obtained.

Reference Example 7 3-Acetylaminomethyl-3-fluoropyrrolidine: (1) 1-benzyl-3-oxopyrrolidine was reacted with oxosulfonium ylide to give 5-benzyl-5-aza-1-oxaspiro [2.4]. I got heptane. bp13
0-135 ° C / 3.5 mmHg. This compound was treated with 70% hydrofluoric acid to give 1-benzyl-3-fluoro-3-hydroxymethylpyrrolidine.

bp133-137 ° C / 1mmHg. Mass spectrum m / z: 209 (M ⁺ ), 132,118,91. (2) After treating this compound with methanesulfonyl chloride,
React with sodium azide to give 3-azidomethyl-1
-Benzyl-3-fluoropyrrolidine was obtained.

(3) This compound was treated in the same manner as in Reference Example 6- (1) to give 3-
Acetylaminomethyl-1-benzyl-3-fluoropyrrolidine was obtained.

IR spectrum (liquid film) cm ⁻¹ : 3150,2800,1650,1550. Mass spectrum m / z: 250 (M ⁺ ), 249,230,172,91. NMR spectrum (CDCl ₃ ) δ: 1.75 to 2.6 (2H, m) , C
₄ -H), 1.98 (3H, s, COCH ₃ ), 2.35-3.08 (4H, m, C ₂ -H, C ₅ -H),
3.54 (2H, q, J = 22Hz, 6Hz, CH ₂ NHCOCH ₃ ), 3.66 (2H, s, CH ₂ P
h), 6.95 (1H, NH ), 7.3 (5H, s, C 6 H 5). (4) The compound in Reference Example 3- (3) and was treated in the same manner, 3-
Acetylaminomethyl-3-fluoropyrrolidine was obtained.

Reference Example 8 3-Dimethylaminomethyl-3-fluoropyrrolidine: (1) 3-aminomethyl-1-benzyl-3-fluoropyrrolidine was reacted with 37% aqueous formaldehyde solution and formic acid to give 1-benzyl-3-dimethylamino. Methyl-
3-Fluoropyrrolidine was obtained.

bp124.5-126.5 ℃ / 1mmHg. IR spectrum (liquid film) cm ⁻¹ : 2800,1450,1040,740,70
Mass spectrum m / z: 216,172,91. NMR spectrum (CDCl ₃ ) δ: 1.75 to 2.85 (4H, m,
C ₄ -H, C ₅ -H), 2.3 (6H, s, N Me ₂ ), 2.36 (2H, d, J = 25Hz), 2.78
(2H, d, J = 24Hz), 3.68 (2H, s, CH ₂ Ph), 7.3 (5H, s, C ₆ H ₅ ). (2) This compound was treated in the same manner as in Reference Example 3- (3). And then 3-
Dimethylaminomethyl-3-fluoropyrrolidine was obtained.

Example 1 7- (3-Aminomethyl-4-fluoro-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-
Dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride (stereoisomer B): (1) 2.2 g of 3-acetylaminomethyl-1-benzyl-4-fluoropyrrolidine (stereoisomer B) The ethanol 5
It was dissolved in 0 ml, 0.3% of 5% palladium-carbon was added, and hydrogenolysis was carried out at 60 to 70 ° C under a hydrogen stream. The catalyst was filtered off and the filtrate was treated with 7-chloro-1-cyclopropyl-6-fluoro-1,
4-dihydro-4-oxo-1,8-naphthyridine-3
-2.2 g of ethyl carboxylate and 3 ml of triethylamine were added, and the mixture was heated under reflux for 2 hours. The reaction mixture was concentrated to dryness, saturated aqueous sodium carbonate solution was added to the residue, and the mixture was extracted with chloroform. The chloroform extract was dried and then concentrated to dryness.
The obtained crude product was separated and purified by silica gel column chromatography to give 7- (3-acetylaminomethyl-
4-Fluoro-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-
Ethyl 1,8-naphthyridine-3-carboxylate (stereoisomer B) was obtained. mp211 to 213 ° C (2) To 1.3 g of this compound is added 40 ml of 15% hydrochloric acid, and the mixture is heated under reflux for 3 hours. Hydrochloric acid was distilled off under reduced pressure, the residue was dissolved in a small amount of water and cooled. The precipitated crystals were collected by filtration to give 7- (3-aminomethyl-4-fluoro-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-.
0.75 g of oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride (stereoisomer B) was obtained. mp269-272 ° C (decomposition). Thereafter, in the same manner as in Example 1, the compounds of Examples 2 to 10 were obtained.

Example 2 (1) 7- (3-acetylaminomethyl-4-fluoro-
1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (stereoisomer A), mp 179-181
C. (2) 7- (3-aminomethyl-4-fluoro-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,
4-dihydro-4-oxo-1,8-naphthyridine-3
-Carboxylic acid hydrochloride (stereoisomer A), mp284-286 ° C
(Disassembly). (3) Concentrated aqueous ammonia was added to the above hydrochloride to make it weakly alkaline and cooled. The precipitated crystals were collected by filtration to give 7- (3-aminomethyl-4-fluoro-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-. 3-Carboxylic acid (stereoisomer A) was obtained. mp217-218 ° C. Example 3 (1) 7- (3-acetylaminomethyl-4-chloro-1)
-Pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate ethyl (stereoisomer A), mp213
~ 214 ° C. (2) 7- (3-Aminomethyl-4-chloro-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4
-Dihydro-4-oxo-1,8-naphthyridine-3-
Carboxylic acid hydrochloride (stereoisomer A), mp 243-248 ° C
(Decomposition) (3) The above hydrochloride was dissolved in water, and saturated aqueous sodium hydrogen carbonate solution was added to adjust the pH to 7.5 to 8.0, followed by cooling. The precipitated crystals were collected by filtration to give 7- (3-aminomethyl-4-chloro-
1-Pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (stereoisomer A) was obtained.

mp174-177 ° C. Example 4 (1) 7- (3-acetylaminomethyl-4-chloro-1)
-Pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate ethyl (stereoisomer B), mp203
~ 206 ° C. (2) 7- (3-aminomethyl-4-chloro-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4
-Dihydro-4-oxo-1,8-naphthyridine-3-
Carboxylic acid (stereoisomer B), mp 222-224 ° C (decomposition). Example 5 (1) 1-Cyclopropyl-6-fluoro-7- [4-fluoro-3- (N-methyltrifluoroacetylaminomethyl) -1-pyrrolidinyl] -1,4-dihydro-4
Ethyl -oxo-1,8-naphthyridine-3-carboxylate (stereoisomer A), mp 177-179 ° C. (2) 1-Cyclopropyl-6-fluoro-7- (4-fluoro-3-methylaminomethyl) -1-pyrrolidinyl)
-1,4-Dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (stereoisomer A), mp 230-240
C. Example 6 (1) 1-Cyclopropyl-7- [3- (N-ethyltrifluoroacetylaminomethyl) -4-fluoro-1-
Pyrrolidinyl] -6-fluoro-1,4-dihydro-4
Ethyl -oxo-1,8-naphthyridine-3-carboxylate (stereoisomer A), mp 198-200 ° C. (2) 1-Cyclopropyl-7- (3-ethylaminomethyl-4-fluoro-1-pyrrolidinyl ) -6-Fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride (stereoisomer A), mp275
˜280 ° C. Example 7 (1) 1-Cyclopropyl-7- [3- (N-ethyltrifluoroacetylaminomethyl) -4-fluoro-1-
Pyrrolidinyl] -6-fluoro-1,4-dihydro-4
Ethyl -oxo-1,8-naphthyridine-3-carboxylate (stereoisomer B), mp 150-153 ° C. (2) 1-Cyclopropyl-7- (3-ethylaminomethyl-4-fluoro-1-pyrrolidinyl ) -6-Fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride (stereoisomer B), mp268
˜270 ° C. Example 8 (1) 1-Cyclopropyl-7- [3- (N-ethylacetylaminomethyl) -4-fluoro-1-pyrrolidinyl] -6-fluoro-1,4-dihydro-4- Oxo-
Ethyl 1,8-naphthyridine-3-carboxylate (stereoisomer B), mp 105-107 ° C. (2) 1-cyclopropyl-7- (3-ethylaminomethyl-4-fluoro-1-pyrrolidinyl) -6 -Fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride (stereoisomer B), mp268
~ 270 ° C. Example 9 (1) 7- (3-acetylaminomethyl-3-fluoro-
1-Pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate ethyl, mp 214-215 ° C. (2) 7- (3-amino Methyl-3-fluoro-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,
4-dihydro-4-oxo-1,8-naphthyridine-3
-Carboxylic acid hydrochloride, mp 272-279 ° C. (3) 7- (3-aminomethyl-3-fluoro-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,
4-dihydro-4-oxo-1,8-naphthyridine-3
-Carboxylic acid, mp 229 to 232 ° C. Example 10 (1) 1-Cyclopropyl-7- (3-dimethylaminomethyl-3-fluoro-1-pyrrolidinyl) -6-fluoro-1,4-dihydro-4- Ethyl oxo-1,8-naphthyridine-3-carboxylate, mp 179-180 ° C. (2) 1-Cyclopropyl-7- (3-dimethylaminomethyl-3-fluoro-1-pyrrolidinyl) -6-fluoro-1. , 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, mp 174-177 ° C.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-59-67269 (JP, A) JP-A-60-28978 (JP, A) J. Med. Chem. 27 “12” (1984) P. 1543-1548

Claims (2)

[Claims] 1. A general formula (In the formula, X represents a halogen atom, and R ₁ and R ₂ represent a hydrogen atom or a lower alkyl group.) A pyridonecarboxylic acid derivative, a lower alkyl ester thereof and a salt thereof. 2. R ₁ is a hydrogen atom, R ₂ is a methyl group, X is a fluorine atom or a chlorine atom, and 1-
The pyridonecarboxylic acid derivative according to claim 1, which is located at the 4-position of the pyrrolidinyl group, a lower alkyl ester thereof and a salt thereof.