JPH0142947B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel 2-sulfanylamide pyrazine derivatives. More specifically, the present invention relates to 2-sulfanylamide pyrazine represented by the following formula (). (In the formula, R represents a branched or straight-chain lower alkyl group, which may be the same or different.) This compound is a new compound that has not been described in any literature, and
It has excellent antibacterial activity, especially against Gram-negative rods. As is clear from the test examples described below, for example, the present compound is used in Escherichia coli. Stapylococous aureus.
Klebsiella pneumoniae.Corynebacterium
It has excellent antibacterial activity against diphtheriae, Bacillus subtilis, etc., and is particularly effective against Klebsiella bacteria. The compounds therefore have utility as highly effective fungicides. An example of the method for producing the novel compound according to the present invention is represented by the following reaction formula. That is, by first condensing 2-amino-3,6-dialkylpyrazine () with P-acetylaminosulfonyl chloride (FC) (hereinafter abbreviated as FC) in pyridine, 2-acetylsulfanilamide-3, 6-dialkylpyrazine () was obtained, and then this was hydrolyzed with NaOH to obtain 2-sulfanilamide-3,6-dialkylpyrazine Na salt (), which was further
By neutralizing with _H2SO4 , the target compound, 2-sulfanilamide-3,6-dialkylpyrazine ( ₂ ), is obtained. The physical properties of the novel sulfanilamide pyrazine derivatives obtained by such a method are, as detailed in the Examples below, all of them are white and slightly yellowish crystalline solids. In carrying out the above method, first, 2-
As a solvent for dissolving amino-3,6-dialkylpyrazine () in a solvent and adding FC to it for reaction, a solvent normally used as a dehydrochlorination agent is appropriately used, and among them, triethylamine, trimethylamine, etc. , acetone, chlorophor,
Preference is given to using organic solvents such as and pyridine, or water. Particular preference is given to using pyridine. The reaction conditions are appropriately selected within the range of conditions for ordinary condensation reactions, but the reaction temperature is 10 to 80°C, preferably 20 to 50°C, and the reaction time is 30 minutes to 10 hours, usually 2 to 80°C. 4 hours is sufficient. After the reaction is completed, the acetyl compound () is obtained by dispersing with water and filtering it. The acetyl compound thus obtained, ie, 2-acetylsulfanilamide-3,6-dialkylpyrazine (2), is dissolved in an alkaline solution and subjected to an alkaline hydrolysis reaction. As alkali, KOH,
Although NaOH etc. can be used, it is not limited to this. Usually, NaOH is used because of its availability and ease of handling. This reaction is carried out at 50 to 100°C for 30 minutes to 8 hours, but usually is completed at a temperature of 90°C or around 90°C for 1 to 4 hours. In this case, since the various acetyl forms () are difficult to dissolve in an alkaline solution such as a NaOH solution, methanol is added as necessary to dissolve the acetyl forms (). In this way, 2-sulfanilamide-3,
The sodium salt of 6-dialkylpyrazine () is produced. Next, the pH of this reaction solution is adjusted to 8 to 11, preferably 10, and then decolorized with activated carbon and filtered. The resulting filtrate is cooled. The pH was adjusted to 6 using a mineral acid, and crystals of the target compound, 2-sulfanylamide-3,6-dialkylpyrazine (2), were crystallized. This mineral acid treatment step is carried out at 5 to 30°C, preferably 10 to 20°C. As the mineral acid, sulfuric acid, hydrochloric acid, phosphoric acid, etc. can be used as appropriate, but it is usually preferable to use sulfuric acid. be. The crystals thus precipitated are all in the form of yellow fine powder, but white crystals can be obtained by recrystallization using an appropriate recrystallization solvent such as methanol or ethanol. Examples and test examples showing the excellent antibacterial properties of this compound will be described below. Example 1 1.4 g of 2-amino-3,6-dinorpropylpyrazine was dissolved in 5 ml of pyridine, and P-
2.7 g of acetylaminosulfonyl chloride was continuously added. Next, the internal temperature was adjusted to 40°C, and after stirring for 2 hours as a post-reaction, it was dispersed in 100ml of water.
The precipitated crystals were collected by filtration to obtain 2-acetylsulfanilamide-3,6-dinormalpropylpyrazine. Next, dissolve 4 g of NaOH in 36 ml of water, add this acetyl compound to this solution, and place it in a water bath for 90 minutes.
The temperature was raised to .degree. C., and the mixture was stirred for 2 hours to carry out hydrolysis.
After hydrolysis, adjust the pH to 10, decolorize with 0.5g of activated carbon, cool the decolorized liquid, and add 30% H ₂ SO ₄ .
The pH was adjusted to 6 to precipitate crystals, which were collected by filtration to obtain 1.7 g of yellow powder 2-sulfanilamide-3,6-dinorpropylpyrazine. Yield 73.9% 2-sulfanilamide-3,6-dinormalpropylpyrazine C ₁₆ H ₂₂ O ₂ N ₄ S MW334 mp169℃

[Table] Example 2 2-amino-3,6-diisopropylpyrazine
1.2 g, pyridine 5 ml, P-acetylaminosulfonyl chloride 1.24 g, NaOH 4 g, H ₂ O 36 ml,
Using activated carbon 0.5 and operating in the same manner as above, 2
1.5 g of white powder of -sulfanilamide-3,6-diisopropylpyrazine was obtained. Yield 72.5% 2-sulfanilamide-3,6-diisopropylpyrazine C ₁₆ H ₂₂ O ₂ N ₄ S MW334 mp205~207℃

[Table] Example 3 2-amino-3,6-diisobutylpyrazine
1.5 g, 6 ml of pyridine, 2.5 g of P-acetylaminosulfonyl chloride, 4 g of NaOH, 36 ml of H ₂ O,
Using 0.5 g of activated carbon, operate in the same manner as above,
2 g of white powder of 2-sulfanilamide-3,6-diisobutylpyrazine was obtained. Yield 76.3% 2-sulfanilamide-3,6-diisobutylpyrazine C ₁₈ H ₂₆ O ₂ N ₄ S MW362 mp172~173℃

[Table] Example of test confirmed by mass spectrometer 10 mg of each of the coupling agents (a to c: compounds of the present invention, d: sulfur drug sulfamethoxazole currently on the market as a reference example, trade name Shinomin-Shionogi) Dissolve the total volume in 1M _{Na2CO3 solution} to 10ml
And so. (1000γ/ml) Using this solution, serially dilute it with sterile purified water (100, 25, 12.5, 6.25,
3.13, 1.56, 0.78γ/ml) and tested each concentration. On the other hand, 1 ose of the test bacterial strains (1 to 5) was inoculated into a test tube containing 5 ml of trypticase soy broth, and this was cultured at 37°C for 20 hours. This was adjusted to a concentration of 10 ^-7 and 0.1 ml of this bacterial solution was used. Antibacterial properties were determined by the disc method.
The effectiveness was evaluated based on the presence or absence of the blocking circle of the mm filter paper disk. The tested drugs, the tested bacterial species, and the experimental results obtained were as follows, and as is clear from the table below, the compounds of the present invention are very effective as antibacterial agents. Test drug (a) Compound of the present invention (obtained according to Example 1) (b) Compound of the present invention (obtained according to Example 2) (c) Compound of the present invention (obtained according to Example 3) ) (d) Shinomin (trade name) 5-methyl-3-sulfanilamide isoxazole Test bacteria (1) Escherichia coli BK (2) Staphylococcus aureus 209P (3) Klebsiella pneumoniae type M (4) Corynebacterium diphtheriae (5) Bacillus subtilis 219

【table】

Claims (1)

[Claims] Linear formula (However, R in the formula may be the same or different and represents a branched or straight-chain lower alkyl group.) A 2-sulfanylamide pyrazine derivative represented by the following formula.