JPS61148179A - Novel naphthyridine derivative, ester and salt thereof - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [X is halogen; R1 is group of formula II (R3 is H or lower alkyl) or formula III (R4-R6 are R3); R2 is cyclobutyl or cyclopentyl; when R6 is H, R4 and R5 are not H at the same time], its ester, and its salt. EXAMPLE:7-( 3-Amino-1-pyrrolidinyl )-1-cyclobutyl-6-fluoro-1,4-dihydro-4 -oxo-1,8- naphthyridine-3-carboxylic acid hydrochloride. USE:Medicinal drug having excellent antibacterial activity and useful as an antibacterial agent. It can be used as a medicinal drug for man, animal and fish, agricultural chemical, preservative for food, etc. PREPARATION:The compound of formula I can be prepared by reacting the carboxylic acid of formula IV (Z is functional group which can be substituted with a cyclic amine mentioned hereafter) or its ester, preferably a lower alkyl ester with a cyclic amine derivative, of formula R1-H in an inert solvent at 10-180 deg.C for 20-60min under agitation.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel naphthyridine derivatives, esters thereof, and salts thereof, which exhibit extremely excellent antibacterial activity.

More specifically, the compound of the present invention has the following general formula (wherein X
means a halogen atom, RI means 6 in the group represented by the following formula, where Ra, Ran Rs and Rs are the same or different and mean a hydrogen atom or a lower alkyl group, and R1 is a cyclobutyl group or a cyclopentyl group. means base. However, when R@ is a hydrogen atom, R4 and R11 are simultaneously water atoms. ), novel naphthyridine derivatives, esters thereof, and salts thereof.

In this specification, halogen atom means fluorine.

It means chlorine, bromine or iodine, and lower alkyl means an alkyl group containing 1 to 3 carbon atoms.

Salts of the compounds of the present invention include acetic acid, lactic acid, and succinic acid.

Methanesulfonic acid, maleic acid, malonic acid, glucone l
! Salt with IW*m, aspartic acid, glutamine l
! A salt of IvI with an amino acid, or a salt with an m-acid such as hydrochloric acid or phosphoric acid, or a metal salt such as sodium, potassium, zinc, or silver of the compound of formula [11], or a salt with a **m group. .

The ester of the compound of formula [I] refers to lower alkyl esters such as methyl ester and ethyl ester of compound [1],
Alternatively, known esters that are easily eliminated by hydrolysis or in vivo to form compound [I], such as pivaloyloxymethyl ester, ethoxycarbonyloxyethyl ester, dimethylaminoethyl ester, and 1-pivaloyloxymethyl ester, ethoxycarbonyloxyethyl ester, dimethylaminoethyl ester, It means aminoethyl esters such as peridinyl ethyl esters, 5-indanyl esters, phthalidyl esters, 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.

The compound of the present invention in which R1 is a substituted pyrrolidinyl group has an asymmetric carbon atom on the pyrrolidine ring, and therefore can exist as optical isomers. Therefore, these optical isomers are included in the compounds of the present invention.

Furthermore, RI is a substituted pyrrolidinyl group, and R8
Some of the compounds of the present invention, in which is a lower alkyl group, have two asymmetric carbon atoms on the pyrrolidine ring, resulting in different stereoisomers (cis form).

trans form). These stereoisomers 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 is a carboxylic acid represented by the following general formula (wherein 2 means a functional group that can be substituted with the cyclic amine derivative described later, and or lower alkyl ester) and a cyclic amine derivative represented by the following general formula % [11] (where RI is the same as above), and the product is isolated by a conventional method. I can do that.

Examples of the reactive functional group represented by the formula [2] include halogen atom, arylsulfonyl, arylsulfinyl, lower alkylsulfonyl, lower alkoxy, lower alkylthio, lower alkylsulfinyl, arylsulfonyloxy, lower alkylsulfonyloxy, etc. It will be done.

This reaction uses ethanol, acetonitrile, dioxane,
in an inert solvent such as dimethylformamide, toluene, xylem, etc. from 10 to 180°C, preferably from 20 to 150°C.
It can be carried out by mixing and stirring the raw material compound [111 or its ester and [1] for 5 to 120 minutes, usually for 20 to 00 minutes.

The amount used for the starting compound [1+11] relative to the starting compound [,11] or its ester is an equivalent amount or an excess amount. As a result of the reaction, an acid such as hydrochloric acid is produced as a by-product due to the functional group 2 of the starting compound [111 or its ester. ] may be used in excess to serve as an acid acceptor.

Further, the starting compound [I[1] used in this reaction may be used in a protected form with acetyl or the like, and after the completion of the reaction, the protecting group may be removed by a conventional method.

The raw material compound [n] or its ester can be produced by the method α described in Reference Examples 1 and 2 or a method analogous thereto. The starting compound [1111, which is a pyrrolidine derivative, can be produced by the method α 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 [1] may be esterified by a conventional method to obtain the ester of the compound of formula CI].

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, the salt form,
Although it is obtained in the form of free carb/acid or free amine, these can be interconverted depending on the purpose to produce the compound of the present invention in the desired form.

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. The compounds of the present invention having cis or trans configuration [1!

Optical isomers of the compounds of the present invention can be separated by applying known methods.

The compound [X] thus obtained, its ester, and its salt are all new compounds. Especially compounds [! ] exhibits extremely excellent antibacterial activity and is therefore valuable as an antibacterial agent. Compound [1] or its salt can be used not only as a human body and as a veterinary drug, but also as a fish disease drug, I3 drug,
It can also be used as a food preservative. Moreover, the ester form of compound [1] is 0 of compound [];
[Of course, it is valuable as a drug, but if this compound is easily converted into compound [I] in vivo, it can exhibit the same action and effect as compound [I], so it is valuable from a pharmaceutical standpoint. ``It is a useful compound.'' First, data regarding the antibacterial activity of the compound of the present invention is listed below.

Antibacterial action in vitro "1 Experimental conditions Minimum inhibitory concentration (MIC: μg/ml)
therapy, 29(1), 76 (1981).
The results are shown in the table above.

When the compound of the present invention is used as an antibacterial □ agent in humans, the dosage should be determined according to the age, symptoms, and route of administration.

Although it varies depending on the number of administrations, etc., it is recommended to administer 5 to 5 g per day in one or several divided doses. The route of administration may be either oral or parenteral.

Although the compounds of the present invention may be administered neat, they are usually administered in a prepared form with a pharmaceutical carrier. Specific examples include tablets, capsules,! ! I granules.

Examples include fine granules, powders, syrups, and injections. These preparations are manufactured in W4 according to conventional methods. Starch as a carrier for oral preparations. Mannit.

A substance that is commonly used in the field of crystalline cellulose and CMCNa cap formulations and does not react with the compound of the present invention is 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-1-cyclobutyl-6-fluoro-1,4
-dihydro-4-oxo-1,8-naphthyridine-3-
Carboxylic acid ethyl ester: (ri) Known compound, 2.
6-Dichloro-5-fluoronicotinonitrile OOg is heated in t5 sulfuric acid at 65-75°C for 1 hour. Water is added and the mixture is further heated at 100-110°C for 2 hours to obtain 59.8 g of 2,8-dichloro-5-fluoronicotinic acid.
m, 9. 155-156°C.

■ 45.2 g of this compound was treated with thionyl chloride,
2.6-') 47.5 g of chloro-5-fluoronicotine Kuma chloride are obtained as an oil.

(3) 47.5 g of this compound was reacted with Etquin magnesium diethyl malonate in anhydrous ether, and 2
．． Diethyl 6-cyclo-5-fluoronicotinoylmalonate is obtained as an oil. Touch this with water amtvp-
Add toluenesulfonic acid and heat at 140° C. for 2 hours to obtain 40 g of ethyl 2,6-dichloro-5-fluoronicotinoyl acetate.

m, 9. 69-70℃.

(4) 40 g of this compound was treated with ethyl orthoformate and acetic anhydride to obtain ethyl 2-(2,6-dichloro-5-fluoronicotinoyl)-3-ethoxyacrylate 4.
2 g are obtained as an oil.

5) Dissolve 10.1 g of this compound in ethanol and react with cyclobutylamine at room temperature to obtain 9.0 g of ethyl 3-7 chlorobutylamino-2-(2,8-dichloro-5-fluoronicotinoyl)acrylate. .
m, 9. 90-91°C.

(6) 7.2 g of this compound was reacted with potassium t-butoxide in anhydrous dioxane to give 7-chloro-1-
Cyclobutyl-6-fluoro-1,4-dihydro-4-
5.6 g of oxo-1,8-nalatirikun-3-carbo/ethyl acid were obtained. m, p, 154-155°C.

Reference example 2 7-chloro-1-cyclobenthyl-6-fluoro-1,
4-dihydro-4-oxo-1,8-naphthyridine-3
-Carboxylic acid ethyl ester: The compound obtained in Reference Example 1-(4) and cyclopentylamine were reacted in the same manner as in Reference Example 1-■.
-Dichloro-5-fluoronicotinoyl)ethyl acrylate is obtained. m, f), 110-111
℃.

This compound was reacted in the same manner as in Reference Example 1-(61) to give 7-chloro-1-cyclobenzene-6-fluoro-1
,4-dihydro-4-oxo-1,8-naphthyridine-
Ethyl 3-carboxylate is obtained.

m, I), 135-138°C.

Reference Example 3 3-acetylamino-4-methylpyrrolisif=3-amino-1-benzyl-4-methylpyrrolidine (JP-A-1983
-22899) is reacted with acetic anhydride to obtain 3-acetylamino-1-benzyl-4-methylbiclidine as an oil. IR spectrum: 3300.
1650 cm-1, this compound is catalytically reduced in the presence of 5% palladium on carbon to give 3-acetylamino-4-methylpyrrolidine as an oil.

Reference Example 4 3-acetylamino-3-methylpyrrolidine: 1-pair')k-3-pyrrolido 7 [J, Org, Chem.

30, 740 (1905) with methylmagnesium bromide to form 1-benzyl-3-hydroxy-3
-Methylpyrrolidine is obtained as an oil.

b, 9. 1013°C/0.5**Hg, this compound is treated with a mixed solution of acetonitrile and 0 sulfuric acid under water cooling to obtain 3-acetylamide/-1-benzyl-3-methylpyrrolidine. m, p, 105~100"
C0 This is catalytically reduced in the presence of 5% palladium on carbon to give 3-acetylamino-3-methylpyrrolidine as an oil.

Example 1 7-(3-amino-1-pyrrolidinyl)-1-cyclobutyl-6-fluoro-1,4-? ) Hydro-4-oxo-1,8-naphthyridine-3-carboxylic hydrochloride: (1) 7-chloro-1-cyclobutyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine -3-Ethyl carboxylate 800 sq., 3-acedelaminopyrrolidine 420 sq., sodium hydrogen carbonate 360 sq.
, a mixture of 15 ml of acetonitrile is stirred at room temperature for 1 hour. The reaction mixture is concentrated to dryness under reduced pressure, water is added to the residue, and extracted with chloroform.

Separate the layers, wash with water, and dry. Chloroform is distilled off, and the resulting crude crystals are recrystallized from ethyl acetate.
Ethyl 3-7cetylamino-1-pyrrolidinyl)-1-cyclobutyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate 870
■ Get.

m, 9.　220~221"C.

(2) Dissolve the above ester 832 (2) in 10 ml of 20% hydrochloric acid and heat under reflux for 2 hours. After treatment with activated carbon, the reaction solution is concentrated to dryness under reduced pressure, ethanol is added to the residue, and the precipitated crystals are collected by filtration. Recrystallized from water-ethanol, 7-
(3-amino-1-pyrrolidinyl)-1-7 chlorobutyl-6-fluoro-1,4-dihydro-4-oxo-1,
8-S7Tyridine-3-carboxylic hydrochloride 018■ is obtained.

m, p, 255-260°C (decomposition).

Example 2 7-(3-amino-4-methyl-1-pyrrolidinyl)-
1-Cyclobutyl-6-fluoro-1,4-dihydro-
4-oxo-1,8-naphthyridine-3-carboxylic hydrochloride: (1) 7-chloro-1-cyclobutyl-6-fluoro-1,4-dihydro-4-oxo-1,s-decaphthyridine-3- Example 1-(
1), 7-(3-acetylamino-4-methyl-1-pyrrolidinyl)=1-cyclobutyl-6-fluoro-t, 4-dihydro-4-oxo-1
, 1.10 g of ethyl 8-naphthyridy-3-carboxylate
get. m, p, 174-175°C.

This compound is either a stereoisomer (cis type or trans type) due to the positional relationship between the amino group and the methyl group on the pyrrolidine ring! be.

■ The above ester 800■ was treated in the same manner as in Example 1-■, and 7-(3-amino-4-methyl-1-pyrrolidinyl)-1-cyclobutyl-6-fluoro-1,4
-dihydro-4-oxo-1,8-naphthyridine-3-
Obtain carboxylic hydrochloride 040 R * m, p-'
272-270°C (decomposition).

Example 3 7-(3-amino-3-methyl-1-pyrrolidinyl)-
1-Cyclobutyl-6-fluoro-1,4-dihydro-
4-Oquine-1,8-su7tylizine-3-carboxylic hydrochloride: 1(117-
1.0 g of ethyl chloro-1-cyclobutyl-6-fluoro-diridine-3-carboxylate and 40 m of 3-acetylamino-3-methylvirolidiyG were reacted in the same manner as in Example 1-(1), and ? - (3-acetylamino-3-methyl-1-pyrrolidinyl)-1-cyclobutyl-6-fluoro-1,4-dihydro-4-okyne-1. Obtain 1.1 g of ethyl 8-naphthyridine-3-carboxylate. m. p. 203-204℃.

■ The above ester 860■ was treated in the same manner as in Example 1-(2), and 7-(3-amino-3-methyl-1-pyrrolidinyl)-1-cyclobutyl-6-fluoro-1,
4-dihydro-4-oxo-1,8-naphthyridine-3
-Carboheptahydrochloride 010■ is obtained. Recrystallize from ethanol.

m. 9. 290-293°C (decomposition).

Example 4 1-Cyclobutyl-6-fluoro-7-(1-piperazinyl)-1,4-dihydro a-4-oxo-1,8-naphthyridine-3-carboxylic acid: (1) 7-chloro-1-
cyclobutyl-6-fluoro-1,4-dihydro-4-
800 μl of ethyl oxo-1.8 naphthyridine-3-carboxylate and 1.0 μl of anhydrous piperazine. oOg in Example 1-(1
1-Cyclobutyl-6-fluoro-7-(1-piperazinyl)-1,4-dihydro-
Obtain ethyl 4-oxo-1.8 naphthyridine-3-carboxylate 640 m. 9. 179-18
0℃.

■ A mixture of 600 ■ of the above ester and 51 of a 0.5N aqueous sodium hydroxide solution was heated under reflux for 30 minutes. After cooling, add vinegar to the reaction solution! l〒Neutralize and extract with chloroform. Separate the chloroform layer, dry, and condense under reduced pressure for 50 minutes. The obtained crystals were collected by cold filtration to give 1-cyclobutyl-6-fluoro-7-(1-piperazinyl)-1,4-dihydro-4-
Okin 1. 8-naphthyridine-3-carbo/acid 30
Get 0 ■.

m. l), 247-248°C.

Example 5 1-Cyclobutyl-6-fluoro-7-(4-methyl-
1-piperazinyl)-1,4-dihydro-4-oxo-
1.8-Naphthyridine-3-carboxylic acid: (1) 7-chloro-1-cyclobutyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carbo/! l! Ethyl 800, ! -4-
330 ml of methylpiperazine was reacted in the same manner as in Example 1-(1) to give 1-cyclobutyl-6-2-fluoro-7-
550 n of ethyl (4-methyl-1-piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate are obtained.

ml), 153-154°C.

■ The above ester 389■ was subjected to reaction treatment in the same manner as in Example 4-■, and 1-cyclobutyl-6-fluoro-7-(4
-methyl-1-piperazinyl)-1゜4-dihydro-4
-oxo-1,8-naphthyridine-3-carvone 111
Get 292q. Recrystallize from ethanol. m,
9. 243-244°C.

Example 6 7-(3-Amino-1-pyrrolidinyl)-1-cycloben-6-fluoro-1,4-dibFcl-4-oxo 1,8-naphthyridine-3-carboheptahydrochloride: (1 ) 1.3 g of ethyl 7-chloro-1-cyclopendel-6-fluoro-t,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate and 1.0 g of 3-acetylaminopyrrolisif, The reaction treatment was carried out in the same manner as in Example 1-0) to obtain 7-(3-acetylaminol-1-pyrrolidinyl)-1-cyclobenzene-6-fluoro-1,4-
Dihydro-4-oxo-'1,8-naphthyridine-3-
Ethyl carboxylate 1. Get ffg. Recrystallization from chloroform-ethyl acetate, I), 138-13
9℃.

■ 1.3 g of the above ester was reacted in the same manner as in Example 1-■, and 7-(3-amino-1-pyrrolidinyl)-,
1-Cyclobenyl-6-fluoro-1,4-dihydro I
1.1 g of j-4-oxo 1,8-naphthyridi-7-3-carboxylic hydrochloride are obtained.

m, P, 285-272°C (decomposition).

Claims (1)

[Claims] General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, X means a halogen atom, and R_1 is a group represented by the following formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ means R_3, R_4, R_5 and R_6
are the same or different and mean a hydrogen atom or a lower alkyl group, R_2 means a cyclobutyl group or a cyclopentyl group, provided that when R_6 is a hydrogen atom, R
_4 and R_5 are hydrogen atoms at the same time. ) Novel naphthyridine derivatives, esters thereof and salts thereof.