JPS6028978A - 1,8-naphthyridine derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R and R1 are H or lower alkyl), its ester or its salt. EXAMPLE:7-( 3-Amino-1-pyrrolidinyl )-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1, 8- naphthyridine-3-carboxylic acid. USE:An antibacterial agent. PREPARATION:The objective compound is prepared by reacting the carboxylic acid of formula II (X is functional group substitutable with pyrrolidine derivative) or its ester (preferably lower alkyl ester) [e.g. 7-(p-toluylsulfonyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naph thyridine-3-carboxylic acid ethyl ester] with the pyrrolidine derivative of formula III (e.g. 3-acetylaminopyrrolidine) preferably in an inert solvent at 50-150 deg.C for 20-60min.

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 (in which R
and R1 means a hydrogen atom or a lower alkyl group. ) A 1,8-naphthyridine derivative, an ester thereof, or a salt thereof.

Among the compounds of the present invention, preferred compounds are those in formula [■] in which R is a hydrogen atom and R1 is a hydrogen atom or a methyl group, and particularly preferred are compounds in which R and R1 are both hydrogen atoms.

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

Salts with organic acids such as methanesulfonic acid, maleic acid, malonic acid and gluconic acid, amino acids such as aspartic acid and glutamic acid, or salts with inorganic acids such as hydrochloric acid and phosphoric acid, or all of the compounds of formula [I]. ) Metal salts such as IJum, potassium, zinc, silver, etc., or salts with organic bases.

The ester of the compound of the formula [■] refers to a lower alkyl ester such as methyl ester or ethyl ester of the compound [I], or an ester that is easily eliminated by hydrolysis or in vivo to become the compound [I]. It refers to known esters such as pivaloyloxymethyl ester, ethoxycarbonyloxyethyl 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.

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

iti The compound of the present invention comprises a carboxylic acid or its ester (preferably a lower alkyl ester) represented by the following general formula (wherein X means a functional group that can be substituted with the pyrrolidine derivative described below) and the following general formula (formula It can be produced by reacting a pyrrolidine derivative represented by (wherein R and R1 are the same as above) and isolating the product by a conventional method.

The reactive functional group represented by X in formula (II) is arylsulfonyl or lower alkylsulfonyl.

Halogen atom, lower alkoxy, lower alkylthio, lower alkylsulfinyl, arylsulfonyloxy,
Examples include lower alkylsulfonyloxy.

This reaction uses ethanol, acetonitrile, dioxane,
20-180°C, preferably 50-150°C in an inert solvent such as dimethylformamide, toluene, xylene
In this step, starting compound (II) and (IIll) are mixed in 5 to 1
This can be carried out by mixing and stirring for 20 minutes, usually 20 to 60 minutes. The amount of the raw material compound [■] used relative to the raw material compound (n) is not an equivalent amount, but an excessive amount. Depending on the type of functional group of X in the starting compound [■], an acid such as hydrochloric acid may be produced as a by-product as a result of the reaction, so in such cases it is common to use an acid acceptor. ] may be used in excess to serve as an acid acceptor.

Further, the starting material compound (][] used in this reaction may be used with its 3-position substituent protected with acetyl or the like, and after the completion of the reaction, the protecting group may be removed by a conventional method.

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

(2) The ester form of the compound CI) of the present invention can also be represented by the following general formula (wherein Y is the same or different and means a lower alkyl group, and R and R1 are the same as above.

) is subjected to the Dinickman reaction (D
The compound (V) is heated in the presence of a base catalyst commonly used in the Ieckmann Reaction) to produce a compound represented by the following general formula (in which R, R1 and Y are the same as above), and then this compound (V) is dehydrogenated. It can be manufactured by

When producing compound [■], starting material compound [IV]
Compound [■] is obtained by heat reaction in a solvent in the presence of a base catalyst such as metallic sodium, sodium hydride, sodium ethylate, or potassium t-butyralate to cause intramolecular ring closure. At this time, the reaction can be more effectively achieved by adding a catalytic amount of lower alcohols such as methanol, ethanol, and t-butanol. benzene.

Aromatic hydrocarbons such as toluene, dioxane, tetrahydrofuran, 1,2-dimethoxyethane.

Ethers such as diethylene glycol dimethyl ether are suitable as reaction solvents. The heating temperature is not particularly limited, but a temperature of 60 to 180'C is usually preferred.

In addition, compound (V) is also a compound represented by the following general formula.

H To dehydrogenate compound (V), compound [V] is mixed with an inert solvent (eg, benzene, toluene).

2 in xylene, ethyl acetate, dioxane, t-butyl alcohol, dimethylformamide, ethanol, etc.)
, 3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), tetrachloro-1,4-benzoquinone (chloranil), te)lacyanoethylene, palladium-carbon p N-bromosuccinimide (N B S )
s A common dehydrogenating agent such as 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 directly heated above its melting point, or benzene, toluene,
Dioxane, ethanol, n-hexane, carbon tetrachloride,
Simply heating in an inert solvent such as dimethylformamide or diphenyl ether may be sufficient.

The raw material compound (IVI) used in this reaction is the method described above (
As in the case of 1), the substituent at the 3-position of the pyrrolidine moiety may be used in a protected form with an acetyl group, etc., and after the 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.

In addition, the compound (ester form) obtained by the above method is
The ester moiety can be converted into the compound of formula (I) by hydrolyzing it by a conventional method. Furthermore,
If necessary, the compound of formula (I) can be esterified by a conventional method to give an 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 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.

Compound [I] thus obtained, its ester and its monosalt are all new compounds. Especially compound [I]
shows extremely excellent antibacterial activity even in vivo,
It is valuable as an antibacterial agent. Compound [I] 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 CI) is of course valuable as a raw material for the synthesis of compound [I), but in addition, when this compound is easily converted into compound [I] in vivo, compound CI] It is a useful compound from a pharmaceutical standpoint because it can exhibit similar effects.

Next, data regarding the antibacterial activity of the main compounds of the present invention are listed below.

In the margin below, the antibacterial effect in vitro - Minimum inhibitory concentration (MIC: μyymir) is Ch
emotherapy.

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.

*Mine experimental conditions Test drug: Compound of Example 1 Animal used: aay=s male macus (average weight 202
) Infectious bacteria load and infection method: Streptococcus pyogenes; 3 x 10' live bacteria/Max (i, p,) Escherichia coli; 9 x 10' live bacteria/Max (i, p,) Pseudomonas aeruginosa; 4 x 103 live bacteria/Max ( i, p,) Medication method: The drug was suspended in 0.2% CMCNaK, and this was orally administered immediately after infection and 6 hours later.

Method for determining results: From the survival rate 7 days after infection, Behre
Calculate the EDso value by the ns-Kaerber method,
The values are 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 5 mg to 5 g per day once or in 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 synthesizing the compound of the present invention will be explained in more detail by giving examples and reference examples.

Example 1 Synthesis method of 7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid fl) 7 -(p-tolylsulfonyl)-1-cyclopropyl-6-fluoro1,4-dihydro-4
-Ethyl oxo-1,8-naphthyridine-3-carboxylate 800 my, 3-acetylaminopyrrolidine 300 m
g, triethylamine 236 mfl and ethanol 25
The mixture of me is heated to reflux for 2 hours. The solvent was distilled off under reduced pressure, and the resulting crude crystals were recrystallized from a mixture of ethanol and isopropyl ether to give m and p.

7-(3-acetylamino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1 at 246-248°C
,4-dihydro-4-oxo-1,8-naphthyridine-
Obtain 600 ml of ethyl 3-carboxylate (2) A mixture of 600 mg of the compound obtained in the previous section and 10% of a 20% aqueous hydrochloric acid solution is heated under reflux for 10 hours. The solvent was concentrated to dryness under reduced pressure, ethanol was added, the precipitated crystals were separated, and 7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo -1,8-naphthyridine-3-carboxylic acid hydrochloride 460 m'j tl-(1 l.

m, p, 275-280°C (decomposition): Recrystallization solvent (water/ethanol mixture) Reference Example 1 7-(p-)ruylsulfonyl)-1-cyclopropyl-6- used as the starting material in Example 1 Fluoro-1,
4-dihydro-4-oxo-1゜8-naphthyridine-3
- Synthesis method of ethyl carboxylate (1) Known compound -2,6-dichloro-5-fluoronicotinonitrile 32.5F was added to 400 liters of ethanol.
In e, p-thiocresol 23.2! i' and the potassium salt of p-thiocresol obtained from 12.2 P of potassium hydroxide are reacted at room temperature, m, p, 124-125
2-chloro-6-(p-)ruylthio)-5-fluoronicotinonitrile at °C 42.4 f! get.

(2) 36 g of this compound was dried with dimethyl sulfoxyl.
' Dissolved in 180me, anhydrous potassium fluoride 22.2
Add V and heat and stir at 130-135°C for 1 hour.

The solvent was distilled off under reduced pressure, water was added to the residue, and the resulting crude crystals were recrystallized from ethanol to give m and p. 120-12
2,5-difluoro-6-(p-)ruylthio) at 1°C
Nicotinonitrile 305' is obtained.

(3) 4 g of this compound is reacted with dry hydrogen chloride in anhydrous ethanol to obtain ethyl 2,5-difluoro-6-(p-)rutilethio)nicotinate 32.

(4) Repeat the above reaction to obtain ethyl 2,5-difluoro-6-(p-1ruylthio)nicotinate 25
2 was dissolved in 400 me of dimethylformamide, and ethyl N-cyclopropylaminopropionate 25.
Add 42 and 14g of sodium hydrogen carbonate, and make 100 to 11
Heat and stir at 0°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 with anhydrous sulfuric acid and IJum. Toluene was removed under reduced pressure, and a viscous monocyclic liquid, ethyl 6-(p-)ruylthio)-2-(N-cyclopropyl-N-(2-ethoxycarbonylethyl)aminoco-5-fluoronicotinate 32S" f = get.

(5) Add 50 me of this compound 3,2 to dry toluene.
l) Add 0.325' of rum and stir the mixture for 10 minutes. Add a catalytic amount of absolute ethanol and stir for an additional 2 hours. Then, after heating at 50-60℃ for 1 hour, water was added to make 10%
- Neutralize with aqueous acetic acid. The organic layer is separated, dried over anhydrous sulfuric acid (IJ), and toluene is distilled off under reduced pressure. The obtained crude crystals were recrystallized from a mixture of n-hexane and isopropyl ether to give m, P.

7-(p-)ruylthio)-1-cyclopropyl-6-fluoro-1,2,3°4-tetrahydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl/v at 124-125°C We get 2.59.

(6) Dissolve 2.0 g of this compound in 50 me of toluene, and add 2,3-dichloro-5,6-dicyano-p
- Add 1.25 g of benzoquinone - and leave at room temperature for 2 hours.
Then, the mixture is heated and stirred at 50 to 60°C for 1 hour. Thereafter, the precipitated crystals are dissolved in chloroform, washed successively with IN sodium hydroxide and water, and the chloroform layer is dried over anhydrous sodium sulfate. Chloroborum was distilled off, and the resulting crude crystals were recrystallized from a mixture of ethanol and isopropyl ether to give m, p, 7-(p-)ruylthio)-1-cyclopropyl-6-fluoro-1,4 at 148°C. −
1,7 g of ethyl dihydro-4-oxo-1,8-naphthyridine-3-carboxylate is obtained.

(7) This compound 1.5952 and m-chloroperbenzoic acid (80%) 1.905' are dissolved in 50 mf' of chloroform and heated under reflux for 30 minutes. Thereafter, it 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, 216
7-(p-)ruylsulfonyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4- at ~218°C
1.55 fI of ethyl oxo-1,8-naphthyridine-3-carboxylate are obtained.

Example 2 6-(3-acetylamino-1-pyrrolidinyl)-2-
By reacting ethyl (N-cyclopropyl-N-(2-ethoxycarbonylethyl)aminoco-5-fluoronicotinate as a raw material in accordance with the method described in Reference Example 1, Example 1 Hydrolyze 7-(3) in the same manner as method (2).
-amino-1-pyrrolidinyl)-1-cyclopropyl-
6-fluoro-1,4-dihydro-4-oxo-1,8
-Naphthyridine-3-carboxylic hydrochloride is obtained.

Reference Example 2 6-(p-)ruylthio)-2-( obtained in Reference Example 1
N-cyclopropyl-N-(2-ethoxycarbonylethyl)aminoco-5-fluoronicotinate ethyl
Oxidized using chloroperbenzoic acid, the obtained 6-(p-
) luenesulfonyl)-2-[N-cyclopropyl-N
6-(3-acetylamino-1-pyrrolidinyl)-2-(N-cyclopropyl-N
-(2-ethoxycarbonylethyl)aminogo ethyl 5-fluoronicotinate is obtained.

Example 3 7-(p-tolylsulfonyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,
Using ethyl 8-naphthyridine-3-carboxylate and 3-methylaminopyrrolidine as raw materials, reaction treatment was carried out in the same manner as in Example 1 to obtain 7-(3-methylamino-1-pyrrolidinyl)-1-cyclopropyl-6- Fluoro-1,4-
Dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid is obtained in the form of its hydrochloride.

Patent Applicant: Dainippon Pharmaceutical Co., Ltd. Representative Patent Attorney Yu Tsuboi 4th Part Procedural Amendment (Spontaneous) September 20, 1980 1. Indication of the Case 1980 Patent Order No. 138000 2. Name of the Invention 1.8 -Relationship with the Naphthyridine Derivative A Amendment Case Patent Applicant Address 3-25 Doshomachi, Higashi-ku, Osaka Name 291
Dainippon Pharmaceutical Co., Ltd. Representative Director Tomio Fuji 4, Agent 564 Address 33-94 Enohonmachi, Suita City, Osaka Prefecture Dainippon Pharmaceutical Co., Ltd. General Research Laboratory 5 Detailed explanation of the invention in the specification subject to amendment Contents of the amendment in column 0 (1) In the 5th page, line 15 of the specification, the notation 0 of ``for reference examples'' is corrected to 1 for reference examples 1''.

(2) Structural formula (IV) on page 6, line 1 of the specification is corrected as follows.

(3) r m on page 18, line 14 of the specification,
rm, p, 186-18
Correct it to 7℃J.

Written amendment to the above procedures (voluntary) 1. Indication of the case Patent Application No. 138000 of 1988 2. Name of the invention 1.8 - Naphthyridine derivative 3. Person making the amendment Relationship with the case Patent applicant address Suita, Osaka Prefecture Ichienokicho 33-94 No. 5, Detailed explanation of the invention column 6 of the specification subject to amendment, Contents of amendment (1) Page 5, line 2, page 5, line 5 of the specification , 5th
The description of "raw material compound [■]" in page 6, line 6 and page 5, line 15 is corrected to "raw material compound [■] or its ester."

(2) The statement "p-toluylthio" on page 16, line 17 of the specification is corrected to "p-toluylthio."

that's all

Claims (2)

[Claims] (1) A 1,8-naphthyridine derivative represented by the general formula (R and R1 in the formula mean a hydrogen atom or a lower alkyl group), an ester thereof, or a salt thereof (2) 7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6- as described in claim f1)
Fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid or salt thereof