JPS60260577A - 1,8-naphthyridine derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (X is halogen; R<1> and R<2> are H, lower alkyl or R<1> and R<2> together form a 3-7-membered ring; R<3> is H or lower alkyl; R<4> is lower alkyl, R<5> is lower alkyl, alkenyl or cycloalkyl). EXAMPLE:7-( 3-Amino-4-methyl-1-pyrrolidinyl )-1-cyclopropyl-6-fluoro-1,4-dihydro- 4-oxo-1,8-naphthyridine-3-carboxylic acid. USE:An antibacterial agent. PREPARATION:The compound of formula I can be prepared by reacting the pyrrolidine derivative of formula III with the carboxylic acid of formula II (Z is functional group which can be substituted with said pyrrolidine derivative) or its ester, in a solvent such as ethanol, acetonitrile, etc. at 20-180 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel 1,8-naphthyridine derivatives that exhibit extremely excellent antibacterial activity.

More specifically, the compound of the present invention has the following general formula (wherein X
R1 and R2 mean a hydrogen atom or a lower alkyl group, or R1 and R
2 may combine with each other to form a 3- to 7-membered ring, and R3
means a hydrogen atom or a lower alkyl group, R4 means a lower alkyl group, and R5 means a lower alkyl group, an alkenyl group, or a cycloalkyl group. ) A 1,8-naphthyridine derivative, an ester thereof, or a salt thereof.

The salts of the compounds of the present invention are acetic acid, lactic acid, -monoacid.

These are salts with organic acids such as methanesulfonic acid, maleic acid, malonic acid, and gluconic acid, metal salts such as aspartic acid, glutamipotassium, zinc, and silver, or salts with organic bases.

The ester of the compound of formula (1) refers to a lower alkyl ester such as methyl ester or ethyl ester of compound CI), or a compound that is easily eliminated by hydrolysis or in vivo to form compound [1]. Known esters, such as pivaloyloxymethyl ester.

It means ethoxycarbonyloxyethyl ester, aminoethyl esters such as dimethylamine ethyl 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.

The compound of the present invention has an asymmetric carbon atom on its pyrrolidine ring and therefore can exist as optical isomers.

Therefore, these optical isomers are included in the compounds of the present invention.

Furthermore, certain compounds of the invention may have two asymmetric carbon atoms on their pyrrolidine ring and therefore exist as different stereoisomers (cis, trans). These stereoisomers are also included in the compounds of the present invention.

Among the compounds of the present invention, preferred compounds are as follows.

7-(3-amino-4-methyl-1-pyrrolidinyl)-
1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxy-1,8-naphthyridine-3-carboxylic acid 7-(3-amino-2-methyl-1-pyrrolidinyl)-
1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridi/-3-carboxylic acid 7-(3-amino-3-methyl-1-pyrrolidinyl)-
1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 7-(+-amino-2-methyl-1-pyrrolidinyl)-
1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 7-(3-amino-4,4-dimethyl-1-pyrrolidinyl)-1-cyclo Propyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 7-(4-methyl-3-methylamino-1-pyrrolidinyl)-1-cyclopropyl-6- Fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid'r-(3-dimethylamino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1 ，
4-dihydro-4-oxy-1,8-naphthyridine-3
-Carboxylic acid 7-(3-amino-4-methyl-1-pyrrolidinyl)-
1-Ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 7-(3-amino-4-methyl-1-pyrrolidinyl)-
1-vinyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid and esters and salts thereof.

The method for producing the compound of the present invention will be explained below.

(1) The compound of the present invention is a carboxylic acid or its ester (preferably It can be produced by reacting a pyrrolidine derivative represented by the following general formula (in which R1, R2, R3 and R4 are the same as above) and isolating the product by a conventional method.

The reactive functional group represented by Z in formula CI is arylsulfonyl, lower alkylsulfonyl, halogen atom,
Lower alkoxy, lower alkylthio.

Examples include lower alkylsulfinyl, arylsulfonyloxy, lower alkylsulfonyloxy, and the like.

This reaction uses ethanol, acetonitrile, dioxane,
20-180°C, preferably 50-150°C in an inert solvent such as dimethylformamide, toluene, xylene
In, the raw material compound [■] or its ester and [■
] and stirring for 5 to 120 minutes, usually 20 to 60 minutes. The amount of raw material compound (1) used relative to the raw material compound (It) and its ester is equivalent to or in excess. Depending on the type of Z functional group in the raw material compound CII) or its ester, an acid such as hydrochloric acid may be produced as a by-product of the reaction. Compound [■] may be used in excess to serve as an acid acceptor.

In addition, if possible, the raw material compound CI) used in this reaction is used in a form in which R: and N are partially protected with acetyl, etc., and after the completion of the reaction, the protecting group is removed by a conventional method. Good too.

The starting compound (Ti) or its ester in which R5 is a lower alkyl group or a cycloalkyl group can be produced by the method described in Reference Example 1 or a method analogous thereto.

The starting compound [■] in which R5 is an alkenyl group or its ester can be produced by the method disclosed in JP-A-57-142983 or a method analogous thereto.

(2) The ester form of the compound CI) of the present invention in which R5 is a lower alkyl group or a cycloalkyl group can also be obtained by the following general formula (wherein Y is the same or different and means a lower alkyl group, and 15m is a lower alkyl group). or cycloalkyl group, and X, R', R2, R3 and R4 are the same as above.) was subjected to the Dinickman reaction (D
A compound represented by the following general formula (in the formula, X, R', R2, R3, R4, R'., and Y are the same as above) is heated in the presence of a base catalyst commonly used for This compound (
V) can be produced by dehydrogenating.

When producing compound (V), starting material compound (IV)
In the solvent, sodium metal, sodium hydride.

Compound [v] is obtained by carrying out a heating reaction in the presence of a basic catalyst such as sodium ethylate or potassium t-butyralate to cause intramolecular ring closure.

At this time, the reaction can be achieved more effectively by adding a catalytic amount of lower alcohols such as methanol, ethanol, and -butanol. Aromatic hydrocarbons such as benzene and toluene, and ethers such as dioxane, tetrahydrofuran, 1,2-dimethoxyethane, and diethylene glycol dimethyl ether are suitable as reaction solvents. Although the heating temperature is not particularly limited, a temperature of 60 to 180°C is usually preferred.

In addition, compound [V] is also represented by the following general formula.

In order to dehydrogenate R 4 compound (V), compound [■] must be added with ? 2,3-dichloro-5,6-dinara-1°4-benzoquinone (DDQ) in a medium (e.g. benzene, toluene, xylene, ethyl acetate, dioxane, t-butyl alcohol, dimethylformamide, ethanol, etc.)
, Tetranoo-1゜4-benzoquinone (chloranil)
, tetracyanoethylene, palladium-charcoal i, N-7'
Common dehydrogenating agents such as romosuccinimide (NBS), manganese dioxide or gelene dioxide may be reacted by heating for a short time at room temperature or near the boiling point of the solvent used, or the compound [■] may be heated above its melting point. Heat it directly or
or benzene, toluene, dioxane, ethanol,
n-hexane, carbon tetrachloride.

Simply heating in an inert solvent such as dimethylformamide or diphenyl ether may be sufficient.

1 minute of R2-N is used in a form protected with an acetyl group, etc.,
After completion of this reaction, the protecting group may be removed by a conventional method.

Starting compound (IV) can be produced by the method described in Reference Example 2 or a method analogous thereto.

The compound (ester form) obtained by the above method [(1) and (2)] can be converted into the compound of formula [1] by hydrolyzing the ester moiety by a conventional method. can. Furthermore, if necessary, the compound [Anaguchi] can be esterified by a conventional method to lead to an ester of the compound of formula CD.

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 a free carboxylic acid or a free amine, these can be mutually converted 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. In addition, the compound of the present invention having a cis-type or trans-type configuration can also be produced by using the compound (III) having a cis-type or a trans-type configuration, respectively, by the above method (1).

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

Compound [1] thus obtained, its ester, and its salt are all new compounds. In particular, compound [1] exhibits extremely excellent antibacterial activity and is therefore valuable as an antibacterial agent. Compound [1] or a salt thereof can be used not only as a medicine for humans and animals, but also as a medicine for fish diseases, an agricultural chemical, a food preservative, and the like. still,
The ester form of compound CI) is of course valuable as a raw material for the synthesis of compound [1], but if this compound is easily converted into compound (1) in vivo, it is equivalent to compound [1]. It is a useful compound from a pharmaceutical standpoint as well.

Next, data regarding the antibacterial activity of the compound produced in Example 1 (3) among the compounds of the present invention is listed below.

(Hereinafter F margin) Antibacterial activity in vitro This was carried out according to the method (revised draft) described in Vol. 29, No. 1, p. 76 (1981), and the results are shown in the table above.

00 Experimental conditions Test drug: Compound of Example 1 (3) Animal used: ddy-8 male mouse (average weight 20y)
Amount of infectious bacteria and method of infection: Streptococcus pneumoniae; 3X10B live bacteria/mouse (i, p,) Pseudomonas aeruginosa; 4X103 live bacteria/mouse (i,p,) Dosing method
Method: The drug was suspended in 0.2% CMCNa and administered orally immediately after infection and every 6 hours.

Method for determining results: From the survival rate 7 days after infection, Behre
The ED function value was calculated by the ns-Kaerber method, and the value is shown in the table.

When the compound of the present invention is used as an antibacterial agent in humans, the dosage depends on age, body weight, symptoms, and route of administration.

Although it varies depending on the number of administrations, etc., it is recommended to administer 5rng to 5y per day 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, and granules.

Examples include fine granules, powders, syrups, and injections. These formulations are prepared according to conventional methods. Starch and mannitol are used as carriers for oral preparations.

Substances commonly used in the pharmaceutical field, such as crystalline cellulose and CMCNa, 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-(p-tolylsulfonyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,
Ethyl 8-naphthyridine-3-carboxylate (1) Known compound 2,6-dichloro-5-fluoronicotinonitrile 32.51P was mixed with ethanol 400mf? Inside, p-thiocresol 23.2p and potassium hydroxide 12p
．． The potassium salt of p-thiocresol obtained from 27 was reacted at room temperature to give 2-chloro-6-(p-)ruylthio)-5-fluoronicotinonitrile 42.419 m, p, 124-125°C. obtain.

(2) This compound 36y was dissolved in dry dimethyl sulfoxide 180me, anhydrous potassium fluoride 222y was distilled off under pressure, water was added to the residue, the resulting crude crystals were recrystallized from ethanol, m, p, 2 of 120-121℃
,5-difluoro-6-(p-)ruylthio)nicotinonitrile 302 is obtained.

(3) This compound 4y is reacted with dry hydrogen chloride in anhydrous ethanol to obtain ethyl 2,5-difluoro-6-(p-tolylthio)nicotinate 3y1r.

(4) Repeat the above reaction to obtain ethyl 2,5-difluoro-6-(p-)ruylthio)nicotinate 25P
400ml of dimethylformamide? 25.4 ethyl N-cyclopropylaminopropionate
4;' and sodium hydrogen carbonate 142, add 100 to 1
Heat and stir at 10°C for 10 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with toluene.

After washing the toluene layer with dilute hydrochloric acid and then with water, the toluene layer is dried over anhydrous sodium sulfate. Toluene was distilled off under reduced pressure, and the viscous liquid 6-(p-)ruylthio)-2-[N
-Cyclopropyl-N-(2-ethoxycarbonylethyl)amine-5-ethyl fluoronicotinate 32p is obtained.

(5) This compound 3.217 was dissolved in 50me of dry toluene.
65% sodium hydride at room temperature.
Add 321 and stir the mixture for 10 minutes. Add a catalytic amount of absolute ethanol and stir for an additional 2 hours. Then 5
After heating at 0-60°C for 1 hour, water is added and neutralized with an aqueous solution of 10-thiacetic acid. The organic layer is separated, dried over anhydrous sodium sulfate, and then toluene is distilled off under reduced pressure.

The resulting crude crystals were recrystallized from a mixture of n-hexane and inzolovyl ether, m, p, 7 at 124-125°C.
-(p-toluylthio)-1-cyclopropyl-6-fluoro-1,2,3,4-tetrahydro-4-oxo-
Ethyl 1,8-naphthyridine-3-carboxylate 2.5y
get.

(6) Dissolve 2.02 of this compound in 50°C of toluene, add 1.25y of 2,3-dichloro-5,6-dicyano-p-benzoquinone, and keep at room temperature for 2 hours, then at 50-60°C. Heat and stir for 1 hour. Thereafter, the precipitated crystals are collected, dissolved in chloroform, washed successively with IN sodium hydroxide and water, and the chloroform layer is dried over anhydrous sodium sulfate. Chloroform was distilled off, and the resulting crude crystals were recrystallized from a mixture of ethanol and inzolovyl ether to give m, p, 7-(p-)ruylthio)-1-cyclopropyl-6-fluoro at 186-187°C. -1,
4-dihydro-4-oxo-1,8-naphthyridine-3
-1.72 of ethyl carboxylate are obtained.

(7) This compound 1.59y and m-chloroperbenzoic acid (
80% ”) 1.909 riooform50rId!
and heat under reflux for 30 minutes. Thereafter, the mixture is washed successively with 2N sodium carbonate and water, and the chloroform layer is dried over anhydrous sodium sulfate. Chloroform was distilled off and the resulting crude crystals were recrystallized from ethyl acetate to give m, p, 2
7-(p-)ruylsulfonyl)-1 at 16-218°C
-cyclopropyl-6-fluoro-1,4-dihydro-
1.55 y of ethyl 4-oxo-1,8-naphthyridine-3-carboxylate is obtained.

Example 1 7-(3-amino-4-methyl-1-pyrrolidinyl)-
1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic hydrochloride (1) 7-(p-tolylsulfonyl)-1-cyclopropyl-6- Ethyl fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate 4.3
y, 3-acetylamino-4-methylpyrrolidine (mixture of cis and trans forms) 1.85y.

Sodium hydrogen carbonate 1.26y, acetonitrile 60r
ne mixture is heated to reflux for 1 hour. Concentrate to dryness under reduced pressure, add water to the residue, and extract with chloroform. The organic layer was washed with dilute hydrochloric acid and water, and then dried over anhydrous sulfuric acid and IJum. The solvent is distilled off and the residue is subjected to silica gel chromatography to obtain the following three components.

(a) Stereoisomer A1. ly (b) A small amount of a mixture of stereoisomer A and stereoisomer B2.
9y (c) Stereoisomer BO,ly Components (a) and (c) were each recrystallized from ethanol-inzolovyl ether to give 7-(3-acetylamino-4-methyl-1-pyrrolidinyl)-1 -Stereoisomer A (m, p, 280-282.5°C) and stereoisomer B of ethyl cyclopropyl-6-fluoro-1,4-dihydro-4-oxy-1,8-naphthyridine-3-carboxylate (m, p, 209-210°C) is obtained.

(2) Stereoisomer A0.97y of the above ester and 20%
A mixture of 10 rne of hydrochloric acid is heated to reflux for 3 hours. Concentrate to dryness under reduced pressure, add ethanol, and collect one portion of the precipitated crystals. Recrystallization from water-ethanol yields the carboxylic hydrochloride salt corresponding to stereoisomer A, i.e. 7-(3-7mi/-4
-Methyl-1-pyrrolidinyl)-1-cyclopropyl-
6-Fluoro-1,4-dihydro-4-oxy1.8
-Naphthyridine-3-carboxylic acid hydrochloride 057y is obtained. m, p, 234-238°C (decomposition).

(3) Component (b) 2.9y obtained in (1) was reacted in the same manner as in (2), and 7-(3-amino-4-methyl-1
2.02y of the hydrochloride of -pyrrolidinyl)-1-cyclopropyl-6-fluoro-1°4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid is obtained. m-
p, 270-278°C (decomposed). This substance contains 6% each of carboxylic hydrochloride salts corresponding to stereoisomers A and H;
It was confirmed by high performance liquid chromatography analysis that the content was 94%.

Example 2 The following compound is obtained by carrying out the reaction treatment in the same manner as in Example 1.

7-(3-amino-2-methyl-1-pyrrolidinyl)-
1-Cycloprobyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid; Isomer A (hydrochloride, 3/2 hydrate) m, p, 215-
217°C, mixture of isomers A, B (A:B=1:4 hydrochloride, 3/2 hydrate) m, p, 276-280°C (decomposition). [The mixing ratio was measured by high performance liquid chromatography. same as below. ] 7-(3-amino-3-methyl-1-pyrrolidinyl)-
1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid; (hydrochloride, 5/4 hydrate) m, n.

285-287°C (decomposed).

7-(4-amino-2-methyl-1-pyrrolidinyl)-
1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid; Isomer A (hydrochloride, 5/4 hydrate) m, p, 263-
267°C (decomposition), mixture of isomers A and H (A:B=
3:2) (hydrochloride, dihydrate) m, p.

205-208 and 241-244°C (decomposed).

7-(4-Methyl-3-methylamino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-cathyridine-3-carboxylic acid; Isomer A , H mixture (hydrochloride, 5/4 hydrate) m, p, 258-277°C (decomposition).

7-(3-amino-4-methyl-1-pyrrolidinyl)-
1-ethyl-6-fluoro-1,4-dihydro-4-oxy-1,8-naphthyridine-3-carboxylic acid; mixture of isomers A, B (A:B-2:1) (hydrochloride, 5/ dihydrate) m, p, 279-297°C (decomposition). [The mixing ratio was determined by spectral analysis. [Reference Example 6-(3-acetylamino-4-methyl-1-pyrrolidinyl)-2-(N-cyclopropyl-N-(2-ethoxycarbonylethyl)amine)-5-ethyl fluoronicotinate Reference Example 1 6-(p-)ruylthio)- obtained in (4)
Oxidation of ethyl 2-[N-cyclopropyl-N-(2-ethoxycarbonylethyl)amine-5-fluoronicotinate with m-chloroperbenzoic acid to produce 6-
By reacting ethyl (p-)fluoronicotinate with 3-acetylamino-4-methylpyrrolidine, ,6
Ethyl -(3-acetylamino-4-methyl-1-pyrrolidinyl)-2-(N-cyclopropyl-N-(2-ethoxycarbonylethyl)aminoco-5-fluoronicotinate is obtained.

Example 3 7-(3-amino-4-methyl-1-pyrrolidinyl)
-1-Cycloprobyl-6-fluoro1,4-dihydro-4-oxy-1,8-naphthyridine-3-carboxylic hydrochloride 6-(3-acetylamino-4-methyl-1-pyrrolidinyl)-2-[ 7-(3-acetylamino-4 −
Methyl-1-pyrrolidinyl)-1-cycloprobyl-6
-fluoro1,4-dihydro-4-oxy-1,8-
Ethyl naphthyridine-3-carboxylate is obtained. This was hydrolyzed in the same manner as in Example 1 (2) and (3), and 7
-(3-amino-4-methyl-1-pyrrolidinyl)-1
-cyclopropyl-6-fluoro-1,4-dihydro-
4-oxo-1,8-naphthyridine-3-carboxylic hydrochloride is obtained.

Example 4 7-(3-amino-4-methyl-1-pyrrolidinyl)-
1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-katutiridine 3-carboxylic acid ethyl ester 7-(3-amino-4-methyl −
i-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic hydrochloride 6,6y was suspended in absolute ethanol, and 7y of concentrated sulfuric acid was added. In addition, the mixture was heated under reflux for 1 hour while stirring. After about 20 mf of ethanol is distilled off, 20 mf of absolute ethanol is added and the mixture is heated to reflux again. After repeating this operation three times, the mixture was heated under reflux for 15 hours while stirring. Ethanol was distilled off under reduced pressure, and the residue was mixed with chloroform and 20%
Add an aqueous sodium hydroxide solution to adjust the pH to 9 or higher. The organic layer was separated, chloroform was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to give 7-(3-amino-4
-phthyl-l-pyrrolidinyl') -1-cycloprobyl-6-fluoro-1,4-dihydro-4-oxo-1
, 8-naphthyridine-3-carboxylic acid ethyl ester 4
Get 3y. m, p, 148-150.5°C.

Patent applicant: Dainippon Pharmaceutical Co., Ltd. Agent: Patent attorney Yu Tsuboi, Department 4

Claims (1)

Claims: (In the formula, X means a halogen atom, R1 and R2 mean a hydrogen atom or a lower alkyl group, or R1
and R2 may combine with each other to form a 3- to 7-membered ring, R3 means a hydrogen atom or a lower alkyl group, and R
4 means a lower alkyl group, R5 is a lower alkyl group,
It means an alkenyl group or a cycloalkyl group. ) A 1,8-naphthyridine derivative, an ester thereof, or a salt thereof. (2) 7-(3-amino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fur2-. 4-dihydro-4-oxo-1,8-naphthyridine-3
- The compound according to claim 1, which is a carboxylic acid, or an ester or salt thereof.