JPH0586392B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel phenyl-substituted 1,8-naphthyridine derivatives, esters thereof, or salts thereof, which exhibit extremely excellent antibacterial activity. More specifically, the compound of the present invention has the following general formula:

[Formula, X ₁ and X ₂ are the same or different and mean a halogen atom, R ₁ and R ₂ are the same or different and mean a hydrogen atom or a lower alkyl group, and R ₃ and R ₄
and R ₅ are the same or different and mean a hydrogen atom, a halogen atom or a trifluoromethyl group,
m means an integer 1, and n means an integer 4. ) A phenyl-substituted 1,8-naphthyridine derivative, an ester thereof, or a salt thereof. In this specification, halogen atoms include fluorine,
It means chlorine, bromine or iodine, and lower alkyl means an alkyl group having 1 to 5 carbon atoms. Salts of the compounds of the present invention include acetic acid, lactic acid, succinic acid, methanesulfonic acid, maleic acid, malonic acid,
Salts with organic acids such as gluconic acid, aspartic acid,
Salts with amino acids such as glutamic acid, or hydrochloric acid,
These are salts with inorganic acids such as phosphoric acid, metal salts of the compound of formula [I] such as sodium, potassium, zinc, silver, etc., or salts with organic bases. The ester of the compound of formula [I] refers to a lower alkyl ester such as methyl ester or ethyl ester of compound [I], or a compound [I] that is easily eliminated by hydrolysis or in vivo.
Known esters such as acetoxymethyl ester, pivaloyloxymethyl ester, ethoxycarbonyloxyethyl ester,
It means choline ester, aminoethyl esters such as dimethylaminoethyl ester and 1-piperidinylethyl ester, 5-indanyl ester, phthalidyl ester, and the like. Compounds of the invention may also exist as hydrates. Therefore, such forms are naturally included in the compounds of the present invention. Since the compound of the present invention has an asymmetric carbon atom in the substituent at the 7-position, it can exist as an optically active form. Therefore, these optically active substances are included in the compounds of the present invention. Furthermore, since the compound of the present invention has 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 compounds of the present invention. The method for producing the compound of the present invention will be explained below. The compound of the present invention has the following general formula:

(In the formula, Z means a functional group that can be substituted with the cyclic amine derivative described below, and X ₁ , R ₃ , R ₄ and R ₅ are the same as above.) or an ester thereof (preferably is lower alkyl ester) and the following general formula

It can be produced by reacting a cyclic amine derivative represented by [Chemical formula] (wherein X ₂ , R ₁ , R ₂ , m and n are the same as above) and isolating the product by a conventional method. can. The reactive functional group shown by Z in formula [] is
Examples include halogen atom, arylsulfonyl, arylsulfinyl, lower alkylsulfonyl, lower alkoxy, lower alkylthio, lower alkylsulfinyl, arylsulfonyloxy, and lower alkylsulfonyloxy. In this reaction, the raw material compound [ ] or its ester and [ 120 minutes, usually
This can be carried out by mixing and stirring for 20 to 60 minutes.
The amount of the starting compound [] to be used is equivalent to or slightly in excess of the starting compound [] or its ester. Depending on the type of Z functional group in the starting compound [] or its ester, an acid such as hydrochloric acid may be produced as a by-product as a result of the reaction.In such cases, it is common to use an acid acceptor; ] may be used in excess to serve as an acid acceptor. In addition, the raw material compounds used in this reaction []
If possible, that

The moiety represented by [Formula] may be used in a protected form with acetyl or the like, and after the reaction is completed, the protecting group may be removed by a conventional method. The starting compound [ ] or its ester can be produced by the method described in Reference Examples 1 and 2 or a method analogous thereto. The starting compound [ ] can be produced by the method described in Reference Examples 3 and 4 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 moiety by a conventional method. Furthermore, if necessary, the compound of formula [I] can be esterified by a conventional method to obtain an ester of the compound of formula [I]. The compound of the present invention produced in this manner is isolated and purified according to conventional methods. Depending on the isolation and purification conditions, it can be obtained in the form of a salt, a free carboxylic acid, or a free amine, but these can be mutually converted depending on the purpose to produce the compound of the present invention in the desired form. Ru. Stereoisomers (cis, trans) of the compounds of the invention can be separated from each other by conventional methods, such as fractional crystallization, chromatographic separation, and the like. In addition, the compound of the present invention having a cis-type or trans-type configuration can also be produced by the above-mentioned method using a raw material compound [] having a cis-type or a trans-type configuration, respectively. Optically active forms of the compounds of the present invention can be separated by applying known methods. The compound [I] thus obtained, its ester, and its salt are all new compounds. In particular, compound [I] and its salts exhibit extremely excellent antibacterial activity and are therefore valuable as antibacterial agents. Compound [I] or a salt thereof can be used not only as a medicine for the human body and animals, but also as a medicine for fish diseases, an agricultural chemical, a food preservative, and the like. In addition, the ester form of compound [I] is of course valuable as a raw material for the synthesis of compound [I], but if this compound is easily converted into compound [I] in vivo, the compound [I] ]
It is also a useful compound as an antibacterial agent because it can exhibit the same effect as that of antibacterial agents. Next, data regarding the antibacterial activity of the compounds of the present invention are listed below.

[Table] When the compound of the present invention is used as an antibacterial agent in humans, the dosage varies depending on age, body weight, symptoms, administration route, number of administrations, etc.
It is recommended to administer 5g in one or several divided doses. The route of administration may be either oral or parenteral. Although the compound of the present invention may be administered as a bulk powder, it is usually administered in a prepared form together with a pharmaceutical carrier. Specific examples include tablets, capsules, granules,
Examples include fine granules, powders, syrups, and injections. These formulations are prepared according to conventional methods. Oral preparation carriers include starch, mannitrate,
Substances commonly used in the pharmaceutical field, such as crystalline cellulose and CMC Na, and which do not react with the compound of the present invention are used. Examples of the carrier for injection include carriers commonly used in the field of injections such as water, physiological saline, glucose solution, and infusion preparations. Next, the method for producing the compound of the present invention will be explained in more detail with reference to Examples and Reference Examples. Reference example 1 7-chloro-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-
Ethyl 1,8-naphthyridine-3-carboxylate: (1) 60 g of 2,6-dichloro-5-fluoronicotinonitrile, a known compound, is heated in concentrated sulfuric acid at 65 to 75°C for 1 hour. Add water and further heat at 100-110°C for 2 hours to obtain 59.8 g of 2,6-dichloro-5-fluoronicotinic acid. mp155-156℃ (2) Treat 45.2g of this compound with thionyl chloride,
47.5 g of 2,6-dichloro-5-fluoronicotinic acid chloride are obtained as an oil. (3) 47.5 g of this compound is reacted with diethyl ethoxymagnesium malonate in anhydrous ether to obtain diethyl 2,6-dichloro-5-fluoronicotinoylmalonate as an oil. Add water and a catalytic amount of p-toluenesulfonic acid to this and heat at 140°C for 2 hours to obtain 46 g of ethyl 2,6-dichloro-5-fluoronicotinoyl acetate.
get. mp69-70℃ (4) Treat 40g of this compound with ethyl orthoformate and acetic anhydride to obtain 2-(2,6-dichloro-5-
42 g of ethyl fluoronicotinoyl)-3-ethoxyacrylate are obtained as an oil. (5) Dissolve 6.0 g of this compound in ethanol, react with 4-fluoroaniline at room temperature, and react with 2-fluoroaniline.
7.0 g of ethyl (2,6-dichloro-5-fluoronicotinoyl)-3-(4-fluorophenylamino)acrylate is obtained. mp111-112℃ (6) 6.0g of this compound was reacted with potassium t-butoxide in anhydrous dioxane to give 7-chloro-
6-Fluoro-1-(4-fluorophenyl)-
5.1 g of ethyl 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate are obtained.
mp227-228℃ (7) Hydrolyze 3.0g of this compound with a mixture of 2ml of acetic acid, 5ml of sulfuric acid and 12ml of water to obtain 7-chloro-6
-Fluoro-1-(4-fluorophenyl)-
2.6 g of 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid are obtained. m.
p.273-276°C Reference Example 2 According to the method of Reference Example 1, the following compound is obtained. (1) Ethyl 7-chloro-6-fluoro-1-(2-fluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, mp212-213°C. (2) 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4
-Ethyl oxo-1,8-naphthyridine-3-carboxylate, mp 212-213°C. (3) Ethyl 7-chloro-6-fluoro-1-(3-trifluoromethylphenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, mp210-211°C. (4) 7-chloro-1-(4-chlorophenyl)-6
-Fluoro-1,4-dihydro-4-oxo-
Ethyl 1,8-naphthyridine-3-carboxylate, mp 197-198°C. (5) 7-chloro-6-fluoro-1-phenyl-
Ethyl 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, mp221~
222℃. (6) Ethyl 7-chloro-6-fluoro-1-(3-fluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, mp242-243°C. (7) 7-chloro-1-(3,4-difluorophenyl)-6-fluoro-1,4-dihydro-4
-Ethyl oxo-1,8-naphthyridine-3-carboxylate, mp 246-247°C. Reference example 3 3-acetylaminomethyl-4-fluoropyrrolidine: (1) Known compound 1-benzyl-3-hydroxy-
4-Hydroxymethylpyrrolidine [J.Org.
Chem., 30 , 740 (1965)] 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) 50 g of this compound and 22.8 g of sodium azide were reacted in dimethylformamide at 120-130°C to form an oily 3-azidomethyl-1-benzyl-
30 g of 4-hydroxypyrrolidine are obtained. IR spectrum (liquid film) cm ^-1 : 3350, 2100, 1450,
1265.Mass spectrum m/z: 232 (M ⁺ ),
175, 158, 91. (3) 64 g of hexafluoropropene-diethylamine reagent is added to a chloroform solution of 32 g of this compound and reacted, and the crude product is separated and purified by silica gel column chromatography to obtain the following product. 3.5 g of oily trans-3-azidomethyl-1-benzyl-4-fluoropyrrolidine are obtained as initial effluent. 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 5.2 (1H, br, H〓F), 7.30 (5H, s, C _6
H5 ). 3.0 g of oily cis-3-azidomethyl-1-benzyl-4-fluoropyrrolidine are obtained as a backflow. 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 5.45
(1H, br, H+F), 7.30 (5H, s, C ₆ H ₅ ). As the intermediate effluent, 3-azidomethyl-1-
7.3 g of a mixture of cis and trans isomers of benzyl-4-fluoropyrrolidine is obtained. (4) 3.1 g of the above compound (trans form) was reduced with sodium bis(2-methoxyethoxy)aluminum hydride and then acetylated to form an oily trans-3-acetylaminomethyl-1-
2.2 g of benzyl-4-fluoropyrrolidine are obtained. IR spectrum (liquid film) cm ^-1 : 3270, 1650,
1550.Mass spectrum m/z: 250 (M ⁺ ),
158, 91.NMR spectrum ( _CDCl3 ) δ: 1.96
(3H, s, COCH ₃ ), 3.61 (2H, s, CH ₂ Ph),
4.52 and 5.22 (1H, br, H+F), 7.30 (5H,
s, C ₆ H ₅ ). Similarly, oily cis-3-acetylaminomethyl-1-benzyl-4-fluoropyrrolidine is obtained from the above compound (cis form). 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,
COCH ₃ ), 3.66 (2H, s, CH ₂ Ph), 4.75 and
5.48 (1H, br, H+F), 7.31 (5H, s, C _6
H5 ). Similarly, a mixture of the cis and trans forms of 3-acetylaminomethyl-1-benzyl-4-fluoropyrrolidine is obtained from the mixture of the cis and trans forms of 3-azidomethyl-1-benzyl-4-fluoropyrrolidine. . (5) The above compound (trans form) is dissolved in ethanol and hydrolyzed using 5% palladium-carbon as a catalyst. The catalyst was filtered off and the trans-3-
An ethanol solution of acetylaminomethyl-4-fluoropyrrolidine is obtained. This solution is used in the next substitution reaction. Similarly, from the above compound (cis form), cis-
A solution containing 3-acetylaminomethyl-4-fluoropyrrolidine is obtained. Similarly, the above 3-acetylaminomethyl-
A solution containing a mixture of the cis and trans forms of 3-acetylaminomethyl-4-fluoropyrrolidine is obtained from the mixture of the cis and trans forms of 1-benzyl-4-fluoropyrrolidine. Reference Example 4 3-acetylaminomethyl-4-chloropyrrolidine: (1) After reacting 3-azidomethyl-1-benzyl-4-hydroxypyrrolidine with thionyl chloride in chloroform, it was separated and purified by column chromatography. The following product is obtained. cis-3-azidomethyl-1-benzyl-4
-Chloropyrrolidine. 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 to 3.4 (2H, m, C ₅
−H), 3.3 to 3.7 (2H, m, CH ₂ N ₃ ), 3.73 (2H,
s, CH ₂ Ph), 4.5 (1H, m, C ₄ -H), 7.34
(5H, s, C ₆ H ₅ ). trans-3-azidomethyl-1-benzyl-4-chloropyrrolidine. 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, _C2 -H), 2.8~3.2 (2H,
m _{, C5} -H), 3.44 (2H, m, _CH2N3 ), 3.66
(2H, br s, CH ₂ Ph), 4.05 (1H, m, C ₄ −
H), 7.34 (5H, s, C ₆ H ₅ ). (2) After reducing the above compound (cis form) with sodium bis(2-methoxyethoxy)aluminum hydride, the oily cis-3-
Acetylaminomethyl-1-benzyl-4-chloropyrrolidine is obtained. 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,
COCH ₃ ), 2.5-2.9 (2H, m, C ₂ -H), 2.72
(1H, m, C ₃ - H), 2.8~3.3 (2H, m, C ₅ -
H), 3.3-3.7 (2H, m, CH ₂ NHCOCH ₃ ),
3.71 (2H, s, CH ₂ Ph), 4.48 (1H, m, C ₄ −
H), 7.33 (5H, s, C ₆ H ₅ ). Similarly, from the above compound (trans form),
Oily trans-3-acetylaminomethyl-
1-Benzyl-4-chloropyrrolidine is 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, COCH ₃ ), 2.3 ~
2.8 (3H, m, _C2 -H, C3 _- H), 3.05~3.75
(4H, m, CH ₂ NHCOCH 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) The above compound (cis form) is hydrolyzed 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 an oily cis-3-acetylaminomethyl-
4-chloropyrrolidine is obtained. Similarly, from the above compound (trans form), trans-3-acetylaminomethyl-4
- Obtain chloropyrrolidine. Example 1 7-(3-aminomethyl-4-fluoro-1-
pyrrolidinyl)-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-
1,8-Naphthyridine-3-carboxylic acid and its hydrochloride: (1) 7-chloro-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-1,8- Ethyl naphthyridine-3-carboxylate 2.21g, 3-acetylaminomethyl-4-
A mixture consisting of 1.14 g of fluoropyrrolidine, 2 ml of triethylamine and 150 ml of acetonitrile is heated and stirred for 2 hours. After distilling off the solvent, the gum-like residue is washed with water and crystallized by adding ethanol and water. The crystals were collected by filtration and recrystallized from ethyl acetate to give 7-(3-acetylaminomethyl-4
-fluoro-1-pyrrolidinyl)-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-
Ethyl 3-carboxylate (approximately 1:1 of stereoisomers)
mixture) to obtain 2.0g. mp175-178°C (2) 0.95 g of the above ester is heated and stirred with 10 ml of 20% hydrochloric acid for 3 hours. The reaction solution was concentrated to dryness under reduced pressure.
Add ethanol to the residue to crystallize it. Recrystallized from ethanol-water to give 7-(3-aminomethyl-4-fluoro-1-pyrrolidinyl)-
6-Fluoro-1-(4-fluorophenyl)-
0.68 g of 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic hydrochloride (approximately 1:1 mixture of stereoisomers) is obtained. mp207～
210℃ (3) Dissolve 0.5g of the above hydrochloride in water and neutralize by adding aqueous sodium hydrogen carbonate solution. The precipitated crystals were collected by filtration and washed with water to give 7-(3-aminomethyl-4-
Fluoro-1-pyrrolidinyl)-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3
-carboxylic acid (approx. 1:1 mixture of stereoisomers)
Get 0.43g. mp approx. 270°C (decomposition) Example 2 7-(cis-3-aminomethyl-4-fluoro-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro −
4-Oxo-1,8-naphthyridine-3-carboxylic acid and its hydrochloride: (1) 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4
-1.94 g of ethyl oxo-1,8-naphthyridine-3-carboxylate, 1.12 g of cis-3-acetylaminomethyl-4-fluoropyrrolidine, 1.5 ml of triethylamine and 150 ml of acetonitrile.
A mixture consisting of was treated in the same manner as in Example 1-(1) to obtain 7-(cis-3-acetylaminomethyl-4-fluoro-1-pyrrolidinyl)-
1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8
1.6 g of ethyl-naphthyridine-3-carboxylate are obtained. Recrystallize from ethanol-water. m.
p.239-242℃ (2) 1.24g of the above ester was reacted in the same manner as in Example 1-(2), and 7-(cis-3-aminomethyl-4-fluoro-1-pyrrolidinyl)-1-
0.95 g of (2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride is obtained. Recrystallize from ethanol-water. mp272
~276°C (decomposition) (3) 150 mg of the above hydrochloride was reacted in the same manner as in Example 1-(3) to obtain 7-(cis-3-aminomethyl-
4-fluoro-1-pyrrolidinyl)-1-(2,
4-difluorophenyl)-6-fluoro-1,
130 mg of 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid are obtained. Recrystallize from dimethylformamide-water. mp232～
236℃ (decomposition) Example 3 7-(cis-3-aminomethyl-4-chloro-
1-pyrrolidinyl)-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid: (1) 7-chloro-6-fluoro -1-(4-fluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid
1.8g, cis-3-acetylaminomethyl-4-
Chloropyrrolidine 1.3g, triethylamine 3ml
and 50 ml of acetonitrile is stirred at room temperature for 1 hour. Filter the precipitated crystals,
Wash with acetonitrile to give 7-(cis-3-acetylaminomethyl-4-chloro-1-pyrrolidinyl)-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-1. ，
2.0 g of 8-naphthyridine-3-carboxylic acid is obtained. Recrystallize from acetonitrile. mp234
-235°C (2) A mixture of 1.8 g of the above carboxylic acid and 18 ml of 20% hydrochloric acid is heated at 100-115°C for 5 hours. Concentrate to dryness under reduced pressure, add ethanol to the residue, and collect the crystals by filtration. Dissolve the crystals in warm water and treat with activated carbon, then add aqueous ammonia to neutralize. The precipitated crystals were collected by filtration and washed with water to give 7-(cis-3-aminomethyl-4
-chloro-1-pyrrolidinyl)-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3
- 1.2 g of carboxylic acid are obtained. mp220~225℃ (decomposition)

Claims (1)

[Claims] 1 General formula: (wherein, X ₁ and X ₂ are the same or different and mean a halogen atom, and R ₁ and R ₂ are the same or different and mean a hydrogen atom or a lower alkyl group , R ₃ , R ₄
and R ₅ are the same or different and mean a hydrogen atom, a halogen atom or a trifluoromethyl group,
m means an integer 1, and n means an integer 4. ) A phenyl-substituted 1,8-naphthyridine derivative, a lower alkyl ester thereof, or a salt thereof. Claim 1 in which 2 X ₁ is a fluorine atom
Phenyl-substituted 1,8-naphthyridine derivatives, lower alkyl esters thereof, or salts thereof as described in 1.