JPS62234076A - 5-hydroxynaphto(2,3-d)thiazole-4,9-dione - Google Patents

Abstract

NEW MATERIAL:5-Hydroxynaphtho[2,3-d]thiazole-4,9-dione shown by formula I. USE:Useful as an antibacterial agent. Showing improved antibacterial activity against pathogenic bacteria of animals including human, domestic animals such as pigs, cattle, chickens, etc., and fishes, etc. Showing excellent effects an mycoplasmal pneumonia, infectious disease of chicken with Mycoplasma gallisepticum, etc., because of strong antibacterial activity against Mycoplasma. Oral or parenteral administration. PREPARATION:For example, 5-aminonahptho[2,3-d]thiazole-1,4-dione shown by formula II is reacted with >= equimolar amount of sodium nitrite in conc. sulfuric acid at room temperature - about 150 deg.C to give a diazonium salt, which is hydrolyzed at room temperature to give a compound shown by formula I. The compound shown by formula II is synthesized by aminating compound shown by formula III with ammonia, further reacting the reaction product with sodium sulfide and formaldehyde to give a compound shown by formula IV and hydrolyzing.

Description

[Detailed Description of the Invention] [Industrial Field of Application] The present invention provides a novel antibacterial agent useful as an antibacterial agent. -Hydroxynaphthol[co,,7-d]thiazole-hiro, 9-dione.

[Conventional technology]

In recent years, livestock and poultry farming have become increasingly large-scale and intensive, and as a result, the damage caused by mycoplasma infections, which were not considered a common problem in the past, is increasing. Examples of mycoplasma infections include mycoplasmal pneumonia.
) and Mycoplasma gallisepticum infections in chickens. Conventionally, macrolide antibiotics such as tylosin and spiramycin have been used to prevent and treat these diseases, but resistance has increased significantly. As an alternative, diterpene antibiotics such as tiamulin,
Tetracycline antibiotics such as doxycycline have been developed.

However, these antibiotics are expensive compared to their medicinal efficacy, and are not sufficiently accepted by the market.

On the other hand, mycoplasma does not develop under good environmental conditions or when the health condition is good, but when some kind of stress is applied, it can spread to other bacterial species, especially gram-negative bacteria (E, Cadi, Ha
emophilue spp,, Pa5teurel
Conventional anti-mycoplasma antibacterial substances have a drawback in that they have strong antibacterial activity against mycoplasma but are weak against gram-negative bacteria.

Tokukai Sho! is an antibacterial agent that solves this problem. ;9-
/'III No. 75, naphtho-[co,,? -a) -Thiazo-router, ? -Geo/ has been proposed.

[Problem that the invention seeks to solve]

The present invention provides a novel compound useful as an antibacterial agent, which has a higher antibacterial activity against Mycoplasma and Durham negative than conventionally known compounds, and has the advantage of being inexpensive.

[Means for solving problems]

The gist of the invention is! -Hydroxynaftho [ko...?
-(1) Thea Shielder, 0 present in 9-dione The present invention will be described in more detail below.

The compound of the present invention is a new compound. It is a substance with a melting point of 1-2θ°C.

The compounds of the present invention are, for example, yo-aminonaphtho[λ,,7-
4) Thiazole-hedadione (Vl) is mixed with more than equimolar amount of sodium nitrite in concentrated sulfuric acid from room temperature to /! It is obtained by reacting at about θ°C to form a diazonium salt, which is then hydrolyzed at about room temperature.

Compound (Vl) is, for example, S-acetylamino-2
, 3-cycloluna-7-8-dadione (old) is aminated by reacting with ammonia, and further reacting with sodium sulfide and formaldede to give !-acetylamino[co, J -d )naphthothiazole-
/, lI-dione (■), and is obtained by hydrolyzing this with concentrated sulfuric acid and water.

The above reaction route is illustrated as follows.

(II) (III) (
IV)<Vl[)CI) The compound of the present invention represented by formula (I) exhibits excellent antibacterial activity against pathogens of humans, livestock such as pigs, cows, and chickens, poultry, and animals including fish. It is useful as an antibacterial agent, and has particularly strong antibacterial activity against Mycoplasma, and is therefore highly effective against epidemic pneumonia in pigs and Mycoplasma gallisepticum infection in chickens.

When using the compound of the present invention as an antibacterial agent, the compound of the present invention may be used alone or in a carrier appropriate for the formulation, but it may also be used in combination with other antibacterial agents, or may be used in advance with other antibacterial agents. It is also possible to formulate it in addition to.

Furthermore, when the compound of the present invention is used as an antibacterial agent for animals such as livestock and poultry, it can also be used by adding it to feed.

When the compound of the present invention is used as an antibacterial agent, examples of dosage forms include powders, fine granules, granules, tablets, capsules, and injections. and manufactured by conventional methods.

In other words, when preparing solid preparations for oral use, excipients are added to the herbal medicine, and if necessary, binders, disintegrants, lubricants, colorants, flavorings, etc. are added, and then the mixture is prepared using conventional methods. Tablets, coated tablets, granules, powders, white sugar, glucose, sorbitol, crystalline cellulose, etc., and binders include, for example, polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxyglobil cellulose. Disintegrants include starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, etc., and lubricants include For example, magnesium stearate, talc, polyethylene glycol, silica, hydrogenated vegetable oil, etc. are approved to be added to pharmaceuticals as colorants/fillers, but as flavoring agents, cocoa powder, peppermint, etc. Aromatic acids, peppermint oil, cybernetic acid, cinnamon powder, etc. are used. These tablets and granules are coated with sugar, gelatin,
Of course, other appropriate coatings may be applied as necessary.

On the other hand, when preparing injections, if necessary,
Add H regulator, buffering agent, stabilizer, preservative, solubilizing agent, etc., and make it into a subcutaneous, intramuscular, or intravenous injection by a conventional method.

The dosage of the compound of the present invention when administered to humans as an antibacterial agent varies depending on the type of disease, severity of symptoms, etc., but is preferably O.S. /~
/■ Administer orally or parenterally.

On the other hand, the dosage when administering the compound of the present invention to animals such as livestock and domestic animals varies depending on the type of disease, symptoms, and class 81 of the animal. , t11
9, preferably LrX, 0-/~/1'9 administered orally or parenterally.

〔Example〕

Hereinafter, the present invention will be explained in more detail with reference to Examples.
The present invention is not limited to the following examples.

Example 1 5-Hydroxynaphtho[Co, J-cL] Thea Shielder, Preparation of 9-dione, 3-dichloro-2.3, synthesized by nitration, reduction, and acetylation of II-naphthoquinone. -dichloro-/, 41-su7toquinone (forepaw formula (II)) q, o o i (2 LAmmol)
ethanol/! ; In addition to Oml, ammonia water (λzachi aqueous solution) was added dropwise at room temperature while stirring, and then 70
The reaction was allowed to take place at ℃. This reaction solution is cooled, and the precipitated crystals are separated, thoroughly washed with ethanol and water, and dried to form a mixture of r- and g-acetylaminofucoamino-3-chloro-/ and Khunaphthoquinone (mixing ratio/ : / ) A, / g I (23,lImm
ol) was obtained (yield 93.0% based on (II)K)
This mixture was purified and separated by silica gel column chromatography (developing solvent, ethyl acetate: n-hexane =/: 4I), and t-acetylaminofucoamino-3-chloro-muda-naphthoquinone (forefoot formula (■)) was purified. )
Crystals of QON (9.0 mmol) were obtained.

g-acetylamino-co-amino-3-chloro-7,4
<-Naphtokinonko, tio 11 (q, 09 mm
ol) and sodium sulfide hydrate A, 1011 (
Add 1,3 mmol) to ethanol/30- and go
'c for 1 hour to produce an intermediate represented by the forefoot formula (IV), formalindr was added, and the mixture was refluxed for 3 hours. After reaction, ethanol/θ01R
t is distilled off, the precipitated crystals are separated from each other, and thoroughly washed with ethanol and water. -acetylaminonaphtho [co, 3-
(1) Thiazoluda, Dageion (front leg type (V))
/, 901t (1?ffmmol) was obtained. ((
■ Yield for )? A, ff%) 5-acetylaminonaphtho(2,3-d)thiazo-to-4<,9-dione/
,? 01 (4.9t mmol) was dissolved in concentrated sulfuric acid (30°C) and reacted at 50°C for 7 hours, then this solution was dropped into 200°C of water, and the precipitated crystals were washed door to door with water and dried. , j-aminonaphtho(2,J-d)
Thiazole-tei, 9-dione (forefoot type (■)) crystal/
,! 1011 (A,!; / mmol) was obtained. ((
(2) Yield 9J, lI%) j-aminonaphtho[co,3-d]thiazole-tei, 9-
After dissolving dione /, t 09 (A,! / mmol) in concentrated sulfuric acid 30-, sodium nitrite o, s O,9 (
7,-! mmol) and reacted for 30 minutes at room temperature, the reaction solution was heated to 110° C. and reacted until no nitrogen gas was generated. (about 6 o minutes).

After the reaction is complete, cool to room temperature, gradually drop into water, wash the precipitated crystals with water, and dry.
Thiazole-Hiroshi, 9-dione crystal/,,701 (!
r, Aλmmo'l) was obtained. (Yield ff4.4 (%) based on (■)) The melting point of the compound of the present invention is 2/g-2
It was 0°C.

The minimum inhibitory concentration (M"°) of the six compounds of the present invention is based on the standard method of the Japanese Society of Chemotherapy.
1. by agar plate dilution method using rH1nton agar medium. It was determined by measuring after jQ hours at yt°C.

However, for the susceptibility measurement of M. galleepticum, horse serum 20% fyry ppLo was used for pre-culture.
Using Broth, J? The C12 Koji culture was used as an inoculum solution. The measurement medium contained horse serum - θ% force 0 ppr.
, using to agar medium,! After culturing at 37° C. for 7 days under carbon dioxide gas, MrO was determined. Also, H, pleuropn
Pre-culture of euuoiae was performed using 5% horse dessicated blood.
J TrypticaaeBoy Broth, p.
Pre-culture of multOcid& is carried out using Heart engineering nfus.
ion Broth for 27 hours at 37°C, and the susceptibility was measured for both strains! Chima deseni blood I
3 using DTrypticase Soy Agar
7℃! A carbon dioxide gas culture was carried out, and MC was determined after 2 hours. Similarly, 7 to [ko, 3-d) thiazo-router,? -Dione (referred to as a comparative drug) was used to determine the MC for each strain. The results are shown in the table below.

Incidentally, the results of an acute toxicity test of the compound according to the present invention using engineered OR mice (male) were as follows.

Oral LD! 0 1f) / 00 Ml/KqB
, W peritoneal cavity LDjO approx. -! ? 19/%B, W Applicant: Mitsubishi Chemical Industries, Ltd. Agent: Patent Attorney Cho Kagawa - and 1 other person

Claims (1)

[Claims] 5-hydroxynaphtho-[2,3-d]thiazole-4
,9-dione