JP3068175B2 - Isothiazolo [5,4-b] pyridine derivatives - Google Patents

Description

The present invention relates to a novel isothiazolo [5,
4-b] pyridine derivatives and salts thereof.

Prior art JP-A-59-80665 and JP-A-60-89472 describe:
Various monocyclic pyridonecarboxylic acid compounds have been disclosed. However, compounds having a structure in which the carboxylic acid moiety is condensed and cyclized, such as the compounds of the present invention, are not yet known.

OBJECT OF THE INVENTION The present invention provides a novel isothiazolo [5,4-b] pyridine derivative having excellent antibacterial activity.

Constitution of the Invention The compound of the present invention has the following general formula (I) (Wherein, R ₁ represents a lower alkyl group, a lower alkenyl group, a halogeno lower alkyl group, a cycloalkyl group or a phenyl group which may have a substituent, and R ₂ represents a hydrogen atom, a halogen atom, a mono or A di-lower alkylamino group or a cyclic amino group) and a salt thereof.

In the present specification, examples of the halogen atom include fluorine, chlorine and bromine. Examples of the lower alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl and the like. Examples of the lower alkenyl group include vinyl, allyl, 1-propenyl, isopropenyl and the like. Examples of the cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. Examples of the substituent in the optionally substituted phenyl group include halogen,
Lower alkyl, lower alkyloxy, halogeno lower alkyl, hydroxy, nitro, amino and the like. The cyclic amino group may further contain one or more nitrogen, oxygen or sulfur atoms, for example, a 5- to 7-membered group such as 1-pyrrolidinyl, piperidino, 1-piperazinyl, morpholino, thiomorpholino, 1-homopiperazinyl and the like. And a cyclic amino group of a ring. The cyclic amino group is selected from a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a hydroxyl group, a benzyl group, an acyl group, an optionally substituted amino group and an optionally substituted amino lower alkyl group. It may be substituted with one or more substituents.

Salts of the compounds of the present invention include salts with inorganic acids such as hydrochloric acid and phosphoric acid; salts with organic acids such as acetic acid, lactic acid, oxalic acid, succinic acid, methanesulfonic acid, maleic acid, malonic acid and gluconic acid; It is a salt with acidic amino acids such as aspartic acid and glutamic acid.

The compound represented by the general formula (I) has the following formula (Wherein R ₁ and R ₂ are the same as described above.), And such tautomers are also encompassed in the compounds of the present invention.

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

The compounds of the present invention include those having asymmetric carbon atoms, which may exist as optically active forms. Therefore,
These optically active substances are included in the compound of the present invention.

Furthermore, some of the compounds of the present invention have multiple asymmetric carbon atoms, which may exist as different stereoisomers. These stereoisomers are also included in the compounds of the present invention.

 Hereinafter, the method for producing the compound of the present invention will be described.

(1) The compound of the present invention has the following general formula (II) (Wherein, R represents a lower alkyl group, and R ₁ and R ₂ are the same as those described above.) A 2-mercapto-4-oxonicotinic acid derivative represented by the following formula: And isolating the product by a conventional method.

In this reaction, the starting compound (II) is converted to an inert solvent such as alcohols such as methanol, ethers, 1,2-diethoxyethane, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, or water and these solvents. In a mixed solvent, hydroxides such as sodium hydroxide and potassium hydroxide, carbonates such as sodium carbonate and potassium carbonate, bicarbonates such as sodium bicarbonate and potassium bicarbonate, potassium fluoride, sodium hydride, sodium ethoxy , Potassium t-butoxide, butyllithium, triethylamine, 1,8-diazabicyclo [5.4.
0.] It can be carried out by stirring with an electrophilic aminating agent in the presence of a base such as -7-undecene (DBU), preferably in a nitrogen stream. The reaction temperature is usually -20 to 150 ° C,
Preferably it is in the range of -10 to 100 ° C.

Examples of the electrophilic aminating agent include O-alkylhydroxylamine, O-arylhydroxylamine, O-
Acylhydroxylamine, hydroxylamine-O-
Known hydroxylamines such as sulfonic acid, O-diphenylphosphinylhydroxylamine, chloramine and the like can be mentioned.

If possible, the starting compound (II) used in this reaction may be used in a form in which an amino group that does not participate in the reaction is protected, and the protecting group may be removed by a conventional method after the reaction. Any protecting group may be used as long as it can be removed without destroying the structure of the compound of the present invention formed by the reaction, such as a peptide, amino sugar, nucleic acid, or β-
A protective group usually used as a protective group in the field of lactam compound chemistry is used. Preferred protecting groups include, for example, easily hydrolyzable groups such as acetyl, trifluoroacetyl and ethoxycarbonyl, or benzyl groups.

Starting compound (II) is a novel compound and can be produced according to the following reaction formula.

(In the formula, R ′ represents a lower alkyloxymethyl group or a substituted benzyl group, and R, R ₁ and R ₂ are the same as those described above.) According to this reaction, β-ketoester (1) is reacted in the presence of a base. Is reacted with a substituted isothiocyanate and a substituted methyl halide to obtain an enaminoketoester (2).
Next, this is cyclized in the presence of a base and then oxidized to obtain a pyridine derivative (3). The starting compound (II) can be produced by treating the compound (3) with an acid.

(2) The compound of the present invention wherein R ₂ is a mono- or di-lower alkylamino or cyclic amino group is represented by the following general formula (II)
I) (Wherein X represents a halogen atom, and R ₁ is the same as described above.) A compound represented by the following general formula (IV) R ₂ ′ -H (IV) (where R ₂ ′ is mono or A di-lower alkylamino group or a cyclic amino group.), And isolating the product by a conventional method.

This reaction is carried out in an inert solvent at 10 to 180 ° C, preferably 20 to 1
At 30 ° C., the starting compounds (III) and (IV) are mixed for 10 minutes to 5 minutes.
It can be carried out by stirring for 0 hour.

Examples of the solvent include dimethylformamide, dimethylsulfoxide, ethanol, methanol, acetonitrile, water, chloroform, pyridine and the like. These solvents may be used alone or as a mixture.

This reaction is generally carried out in the presence of an acid acceptor using the starting compound (IV) in an equivalent amount or a slightly excessive amount relative to the starting compound (III). It may be used to also serve as an acid acceptor.

Examples of the acid acceptor include organic bases such as triethylamine, dimethylaniline, N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene (DBU), pyridine, sodium hydroxide and potassium hydroxide. And the like, carbonates such as sodium carbonate and potassium carbonate, and bicarbonates such as sodium bicarbonate and potassium bicarbonate.

The starting compound (IV) used in this reaction is used, if possible, in a form in which amino acids not involved in the reaction are protected, as described in (1) above. After the completion of the reaction, the protecting group is removed by a conventional method. May be.

The starting compound (III) can be produced by the reaction (1).

The compound of the present invention thus produced is isolated and purified according to a conventional method. Depending on the conditions for isolation and purification, the compound of the present invention can be obtained in the form of a salt or in a free form.

The stereoisomers of the compounds of the present invention can be separated from each other by conventional methods, for example, fractional crystallization, chromatographic separation and the like. In addition, the compound of the present invention having the corresponding specific configuration can also be produced by the above method using the starting compound having the specific configuration.

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

Effects of the Invention The compounds (I) and salts thereof thus obtained are all novel compounds and exhibit excellent antibacterial activity and are therefore valuable as antibacterial agents. The compound (I) or a salt thereof can be used as a preservative for fish disease drugs, agricultural chemicals, and foods, as well as pharmaceuticals for humans and animals.

Next, data on the antibacterial activity of the compound of the present invention will be described below.

The compounds of the present invention show excellent antibacterial activity and a broad antibacterial spectrum in in vitro tests.

In addition, the compounds of the present invention show an excellent in vivo protective effect against local or systemic infections caused by various bacteria and show good safety in general toxicity tests in animals.

When the compound of the present invention is used as an antibacterial agent in humans,
The dose varies depending on age, body weight, symptoms, administration route and the like, but it is recommended to administer 5 mg to 5 g per day in one or several divided doses. The administration route may be oral or parenteral.

The compounds of the present invention may be in the neat powder form, but are usually administered in a form prepared with a pharmaceutical carrier. Specific examples include tablets, solutions, capsules, granules, fine granules, powders,
Syrups, injections, ointments and the like can be mentioned. These preparations are prepared according to a conventional method. Pharmaceutical carriers for oral use include starch, mannitol, microcrystalline cellulose, CMC Na,
Substances that are commonly used in the pharmaceutical field such as water and ethanol and do not react with the compound of the present invention are used. Injectable carriers include carriers commonly used in the field of injectables, such as water, physiological saline, glucose solutions, and fluid solutions.

Further, the above-mentioned liquid preparations and ointments can also be used for treatment in otolaryngology and ophthalmology.

EXAMPLES Next, the production method of the compound of the present invention will be described more specifically with reference to Examples and Reference Examples.

Reference Example 1 Methyl 3-cyclopropylamino-2- (4-fluorocinnamoyl) -3- (4-methoxyphenyl) methylthioacrylate: Known 5- (4-fluorophenyl) -3-oxo-
Dissolve 10 g of methyl 4-pentenoate in 250 ml of dioxane,
At 5-10 ° C., 2.0 g of 60% sodium hydride is added and stirred for 10 minutes. To this mixture is added 5 g of cyclopropylisothiocyanate, and the mixture is stirred at room temperature for 30 minutes. Further, 7.8 g of 4-methoxybenzyl chloride was added, and the mixture was heated at 70 ° C for 1 hour at room temperature.
Stir for 1.5 hours. After evaporating the solvent under reduced pressure, water is added to the residue, and the mixture is extracted with chloroform. The chloroform layer is separated, the solvent is distilled off under reduced pressure, the residue is purified by silica gel column chromatography, and recrystallized from isopropyl ether to obtain 14.2 g of the desired product. mp 120-121 ° C. Reference Example 2 3- (4-fluorophenyl) amino-2- (4-fluorocinnamoyl) -3- (4-methoxyphenyl)
Methyl methylthioacrylate: In the same manner as in Reference Example 1, the desired product is obtained using 4-fluorophenylisothiocyanate.

Reference Example 3 1-cyclopropyl-6- (4-fluorophenyl)
Methyl 1,4-dihydro-2- (4-methoxyphenyl) methylthio-4-oxonicotinate: 3-cyclopropylamino-2- (4-fluorocinnamoyl) -3- (4-methoxyphenyl) methylthioacryl Methyl acid (7.1 g) is dissolved in dimethylformamide (100 ml), and the mixture is heated and stirred at 100 ° C. for 5 hours. After distilling off the solvent under reduced pressure, the residue was dissolved in 100 ml of dioxane, and 2.65 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) was added at room temperature.
Add. After stirring for 2.5 hours, insolubles were removed by filtration, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and recrystallized from ethyl acetate to obtain 4.0 g of the desired product. mp 180-181 ° C. Reference Example 4 Methyl 1,6-bis (4-fluorophenyl) -1,4-dihydro-2- (4-methoxyphenyl) methylthio-4-oxonicotinate: In the same manner as in Reference Example 3. , 3- (4-Fluorophenyl) amino-2- (4-fluorocinnamoyl) -3-
The desired product is obtained from (4-methoxyphenyl) methylthioacrylic acid methyl ester. mp 139 to 140 ° C (recrystallization solvent: isopropyl ether) Reference Example 5 1-cyclopropyl-6- (4-fluorophenyl)
Methyl 1,4-dihydro-2-mercapto-4-oxonicotinate: 1-cyclopropyl-6- (4-fluorophenyl)
Anisole was added to 3.2 g of methyl 1,4-dihydro-2- (4-methoxyphenyl) methylthio-4-oxonicotinate.
6.4 g was added, 25 ml of trifluoroacetic acid and 0.65 ml of trifluoromethanesulfonic acid were further added, and the mixture was stirred at room temperature for 6 hours. After concentrating the reaction solution under reduced pressure, the residue is dissolved in an aqueous sodium hydroxide solution and washed with chloroform. The aqueous layer is made acidic with 10% hydrochloric acid and extracted with chloroform. The solvent was distilled off under reduced pressure, and the residue was recrystallized from isopropyl ether to obtain 2.3 g of the desired product. mp 133 ° -135 ° C. Reference Example 6 Methyl 1,6-bis (4-fluorophenyl) -1,4-dihydro-2-mercapto-4-oxonicotinate: The desired product is obtained from methyl (4-fluorophenyl) -1,4-dihydro-2- (4-methoxyphenyl) methylthio-4-oxonicotinate. mp 173 to 175 ° C (recrystallization solvent: isopropyl ether) Example 1 7-cyclopropyl-6- (4-fluorophenyl)
-2,3,4,7-Tetrahydro-3,4-dioxoisothiazolo [5,4-b] pyridine: 1-cyclopropyl-6- (4-fluorophenyl)
250 ml of water is added to 2.4 g of methyl 1,4-dihydro-2-mercapto-4-oxonicotinate and 5.7 g of sodium hydrogen carbonate, and the mixture is stirred at room temperature for 1 hour. 1.7 g of hydroxyamine-O-sulfonic acid is added thereto, and the mixture is further stirred for 1.5 hours.
After adding 20% hydrochloric acid to the reaction solution to make it acidic, the precipitated crystals are collected by filtration and recrystallized from ethanol to obtain 1.92 g of the desired product. m.
p.195-197 ° C Example 2 6,7-bis (4-fluorophenyl) -2,3,4,7-tetrahydro-3,4-dioxoisothiazolo [5,4-b] pyridine: Example In the same manner as in 1, the desired product is obtained from methyl 1,6-bis (4-fluorophenyl) -1,4-dihydro-2-mercapto-4-oxonicotinate. mp266-267
° C (recrystallization solvent: ethanol) Example 3 7-Cyclopropyl-6- (4-dimethylaminophenyl) -2,3,4,7-tetrahydro-3,4-dioxoisothiazolo [5,4-b Pyridine: 7-cyclopropyl-6- (4-fluorophenyl)
500 mg of 2,3,4,7-tetrahydro-3,4-dioxoisothiazolo [5,4-b] pyridine, 2 ml of a 50% aqueous solution of dimethylamine, and 30 ml of dimethyl sulfoxide are heated in a sealed tube at 150 ° C. for 48 hours. I do. The solvent is distilled off under reduced pressure, water is added to the residue, and the precipitated crystals are collected by filtration. Recrystallize from ethyl acetate to give 420 mg of the desired product
Get. mp193 ~ 197 ℃

Continuation of front page (72) Inventor Minami Akira 42-3, Suyama-cho, Hirakata-shi, Osaka (58) Field surveyed (Int.Cl. ⁷ , DB name) C07D 513/04 A61K 31/437 A61P 31/04 CAPLUS (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] (1) General formula (Wherein, R ₁ represents a lower alkyl group, a lower alkenyl group, a halogeno lower alkyl group, a cycloalkyl group or a phenyl group which may have a substituent, and R ₂ represents a hydrogen atom, a halogen atom, a mono or An isothiazolo [5,4-b] pyridine derivative represented by the following formula: