JPH0826029B2 - Preventive and therapeutic agents for fish infectious diseases - Google Patents

Preventive and therapeutic agents for fish infectious diseases

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Publication number
JPH0826029B2
JPH0826029B2 JP62324397A JP32439787A JPH0826029B2 JP H0826029 B2 JPH0826029 B2 JP H0826029B2 JP 62324397 A JP62324397 A JP 62324397A JP 32439787 A JP32439787 A JP 32439787A JP H0826029 B2 JPH0826029 B2 JP H0826029B2
Authority
JP
Japan
Prior art keywords
group
fish
pyrido
benzoxazine
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
JP62324397A
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Japanese (ja)
Other versions
JPH01165589A (en
Inventor
利幸 吉岡
進一 井上
俊弘 高畠
正和 武井
秀信 板鼻
Original Assignee
第一製薬株式会社
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Priority to JP62324397A priority Critical patent/JPH0826029B2/en
Publication of JPH01165589A publication Critical patent/JPH01165589A/en
Publication of JPH0826029B2 publication Critical patent/JPH0826029B2/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Description

【発明の詳細な説明】 〔産業上の利用分野〕 本発明は次の式(I) 〔式中Xは低級アルキルアミノ基又は (但し、Yは水素原子、又は低級アルキル基を、Zはメ
チレン基、メチン基、酸素原子、イオウ原子、窒素原子
を、R1はZが窒素原子の場合、水素原子、低級アルキル
基、ホルミル基、アルカノイルアルキル基を、又、メチ
ン基の場合、低級アルキル基、ヒドロキシル基を示し、
n及びmは同一かもしくは異なった1〜3の整数を示
す)で示される脂環状アミノ基を示し、Rは水素原子又
は低級アルキル基を示す〕 で表わされるピリド〔1,2,3−de〕〔1,4〕ベンゾオキサ
ジン誘導体もしくはその塩又はそれらの水和物を有効成
分とする魚類感染症の予防・治療剤に関する。
DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention provides the following formula (I): [Wherein X is a lower alkylamino group or (However, Y is a hydrogen atom or a lower alkyl group, Z is a methylene group, a methine group, an oxygen atom, a sulfur atom or a nitrogen atom, and R 1 is a hydrogen atom, a lower alkyl group or a formyl group when Z is a nitrogen atom. Group, an alkanoylalkyl group, and in the case of a methine group, a lower alkyl group and a hydroxyl group,
n and m are the same or different and each represents an integer of 1 to 3), and R represents a hydrogen atom or a lower alkyl group]], a pyrido [1,2,3-de] The present invention relates to a prophylactic / therapeutic agent for fish infectious diseases, which comprises a [1,4] benzoxazine derivative or a salt thereof or a hydrate thereof as an active ingredient.

〔従来の技術及びその問題点〕[Conventional technology and its problems]

近年水産業界では、養殖漁業が盛んになり、魚介類の
効率のよい生産努力がなされている。殊にブリ、タイ、
ウナギ、アユ、コイ等の淡海水魚やアワビ等の貝類の高
密度養殖がなされ、これらに於ては魚介類の伝染病の集
団的発生の頻度が高く時には全滅に近い被害を招き、
又、例え全滅をまぬがれても経済的損失が大きいので水
産業界ではその早期且つ有効な解決策が強く要望されて
いる。
In recent years, the aquaculture industry has become popular in the fishery industry, and efforts have been made to efficiently produce seafood. Especially yellowtail, Thailand,
High-density aquaculture of freshwater fish such as eel, sweetfish, carp and shellfish such as abalone has been carried out.In these cases, the frequency of contagious diseases of seafood is high and the damage is almost complete.
Further, even if it is not completely wiped out, the economic loss is large, so that the fishery industry is strongly demanding an early and effective solution.

魚介類の感染症の予防又は治療のため、従来からサル
フア剤、ニトロフラン、合成ペニシリン、テトラサイク
リン、マクロライド抗生物質、ナリジクス酸、オキソリ
ン酸、ピロミド酸、クロラムフエニコールなどの抗菌剤
を飼料に添加して魚類を経口投与したり、又はこれらの
抗菌剤の溶液に薬浴することが行われている。しかし、
これらの水産用抗菌剤は抗菌スペクトルがせまい、治療
効果が少ない、安全域がせまい、副作用がある、経済的
でない等の欠点があり、十分に満足のゆくものではなか
つた。
For the prevention or treatment of infectious diseases of seafood, antibacterial agents such as sulfa drugs, nitrofuran, synthetic penicillin, tetracycline, macrolide antibiotics, nalidixic acid, oxophosphoric acid, pyromidic acid and chloramphenicol have been used as feedstuffs. In addition, orally, fish is orally administered or a bath of these antibacterial agents is medicated. But,
These antibacterial agents for marine products have drawbacks such as a narrow antibacterial spectrum, a small therapeutic effect, a small safety margin, side effects and uneconomical, and have not been fully satisfactory.

〔問題点を解決するための手段〕[Means for solving problems]

斯る実情において本発明者らは、抗菌スペクトルが広
く且つ各種の魚の感染症に有効で毒性が少なく安全な水
産用抗菌剤について鋭意研究を行つた結果、前記一般式
(I)で表わされるピリド〔1,2,3−de〕〔1,4〕ベンゾ
オキサジン誘導体が魚類の感染症に対し広範囲に亘り優
れた予防・治療効果を発揮し、且つ毒性も少く安全なも
のであることを見い出し、本発明を完成するに至つた。
Under such circumstances, the present inventors have conducted earnest research on an antibacterial agent for marine products, which has a broad antibacterial spectrum, is effective against various infectious diseases of fish, has low toxicity, and is safe, and as a result, the pyrido compound represented by the general formula (I) was obtained. It was found that the [1,2,3-de] [1,4] benzoxazine derivative exerts a wide range of excellent preventive and therapeutic effects against infectious diseases of fish, and is safe with little toxicity, The present invention has been completed.

すなわち、本発明は、前記式(I)で表わされるピリ
ド〔1,2,3−de〕〔1,4〕ベンゾオキサジン誘導体もしく
はその塩又はそれらの水和物を有効成分として含有する
エロモナス属、エドワードジエラ属又はビブリオ属の細
菌による魚類感染症の予防・治療剤を提供するものであ
る。
That is, the present invention relates to the genus Aeromonas containing the pyrido [1,2,3-de] [1,4] benzoxazine derivative represented by the above formula (I) or a salt thereof or a hydrate thereof as an active ingredient, The present invention provides a preventive and / or therapeutic agent for fish infections caused by Edward Giera or Vibrio sp.

前記一般式(I)において、Xの低級アルキルアミノ
基の低級アルキル部分には、直鎖状もしくは分枝鎖状の
C1〜C6までのアルキル基、ジアルキル基が包合され、例
えばメチル、ジメチル、エチル、ジエチル、n−プロピ
ル、イソプロピル、ジ−n−プロピル等が挙げられる。
又、YおよびR1での低級アルキル基も直鎖状もしくは分
枝鎖状のC1〜C6までのアルキル基であり、メチル、エチ
ル、2−ヒドロキシエチル、アミノメチル、n−プロピ
ル、イソ−プロピル、n−ブチル等が挙げられ、これら
を含む を有する脂環状アミノ基としては例えばモルホニル、チ
オモルホニル、ピロリジニル、ピペリジニル、4−ヒド
ロキシピペリジニル、3−メチルピペラジニル、ピペラ
ジニル、4−メチル−ピペラジニル、4−エチルピペラ
ジニル、4−(2−ヒドロキシエチル)ピペラジニル、
4−n−プロピル−ピペラジニル、4−イソプロピルピ
ペラジニル、4−アセトニルピペラジニル、4−n−ブ
チルピペラジニル、4−ホルミルピペラジニル等が挙げ
られる。
In the general formula (I), the lower alkyl portion of the lower alkylamino group for X may be a straight chain or branched chain.
Alkyl group of up to C 1 -C 6, a dialkyl group is engaged follicle, for example methyl, dimethyl, ethyl, diethyl, n- propyl, isopropyl, di -n- propyl, and the like.
The lower alkyl group for Y and R 1 is also a linear or branched C 1 to C 6 alkyl group, and is methyl, ethyl, 2-hydroxyethyl, aminomethyl, n-propyl, iso -Propyl, n-butyl, etc. are included, and these are included. Examples of the alicyclic amino group having is morphonyl, thiomorphonyl, pyrrolidinyl, piperidinyl, 4-hydroxypiperidinyl, 3-methylpiperazinyl, piperazinyl, 4-methyl-piperazinyl, 4-ethylpiperazinyl, 4- (2 -Hydroxyethyl) piperazinyl,
4-n-propyl-piperazinyl, 4-isopropylpiperazinyl, 4-acetonylpiperazinyl, 4-n-butylpiperazinyl, 4-formylpiperazinyl and the like can be mentioned.

又基Rの例としては、水素原子、メチル及びエチル基
が好適なものとして挙げられる。
Further, examples of the group R include a hydrogen atom, a methyl group and an ethyl group.

本発明の抗菌剤に於て有効成分として使用される一般
式(I)の代表例を示せば次の通りである。
Typical examples of the general formula (I) used as an active ingredient in the antibacterial agent of the present invention are as follows.

(1)9−フルオロ−2,3−ジヒドロ−3−メチル−10
−ジメチルアミノ−7−オキソ−7H−ピリド〔1,2,3−d
e〕〔1,4〕ベンゾオキサジン−6−カルボン酸 (2)9−フルオロ−2,3−ジヒドロ−3−メチル−10
−(1−モルホニル)−7−オキソ−7H−ピリド〔1,2,
3−de〕〔1,4〕ベンゾオキサジン−6−カルボン酸 (3)9−フルオロ−2,3−ジヒドロ−3−メチル−10
−(1−ピロリジニル)−7−オキソ−7H−ピリド〔1,
2,3−de〕〔1,4〕ベンゾオキサジン−6−カルボン酸 (4)9−フルオロ−2,3−ジヒドロ−3−メチル−10
−(1−ピペリジニル)−7−オキソ−7H−ピリド〔1,
2,3−de〕〔1,4〕ベンゾオキサジン−6−カルボン酸 (5)9−フルオロ−2,3−ジヒドロ−3−メチル−10
−(4−ヒドロキシ−1−ピペリジニル)−7−オキソ
−7H−ピリド〔1,2,3−de〕〔1,4〕ベンゾオキサジン−
6−カルボン酸 (6)9−フルオロ−2,3−ジヒドロ−3−メチル−10
−(3−メチル−1−ピペラジニル)−7−オキソ−7H
−ピリド〔1,2,3−de〕〔1,4〕ベンゾオキサジン−6−
カルボン酸 (7)9−フルオロ−2,3−ジヒドロ−3−メチル−10
−(1−ピペラジニル)−7−オキソ−7H−ピリド〔1,
2,3−de〕〔1,4〕ベンゾオキサジン−6−カルボン酸ジ
ハイドレート (8)9−フルオロ−2,3−ジヒドロ−3−メチル−10
−(4−メチル−1−ピペラジニル)−7−オキソ−7H
−ピリド〔1,2,3−de〕〔1,4〕ベンゾオキサジン−6−
カルボン酸 (9)9−フルオロ−2,3−ジヒドロ−3−メチル−10
−(4−エチル−1−ピペラジニル)−7−オキソ−7H
−ピリド〔1,2,3−de〕〔1,4〕ベンゾオキサジン−6−
カルボン酸 (10)9−フルオロ−2,3−ジヒドロ−3−メチル−10
−(4−エチル−1−ピペラジニル)−7−オキソ−7H
−ピリド〔1,2,3−de〕〔1,4〕ベンゾオキサジン−6−
カルボン酸エチルエステル (11)9−フルオロ−2,3−ジヒドロ−3−メチル−10
−(4−ホルミル−1−ピペラジニル)−7−オキソ−
7H−ピリド〔1,2,3−de〕〔1,4〕ベンゾオキサジン−6
−カルボン酸 (12)9−フルオロ−2,3−ジヒドロ−3−メチル−10
−(4−ヒドロキシエチル−1−ピペラジニル)−7−
オキソ−7H−ピリド〔1,2,3−de〕〔1,4〕ベンゾオキサ
ジン−6−カルボン酸 (13)9−フルオロ−2,3−ジヒドロ−3−メチル−10
−(4−n−プロピル−1−ピペラジニル)−7−オキ
ソ−7H−ピリド〔1,2,3−de〕〔1,4〕ベンゾオキサジン
−6−カルボン酸 (14)9−フルオロ−2,3−ジヒドロ−3−メチル−10
−(4−iso−プロピル−1−ピペラジニル)−7−オ
キソ−7H−ピリド〔1,2,3−de〕〔1,4〕ベンゾオキサジ
ン−6−カルボン酸 (15)9−フルオロ−2,3−ジヒドロ−3−メチル−10
−(4−アセトニル−1−ピペラジニル)−7−オキソ
−7H−ピリド〔1,2,3−de〕〔1,4〕ベンゾオキサジン−
6−カルボン酸 (16)9−フルオロ−2,3−ジヒドロ−3−メチル−10
−(4−n−ブチル−1−ピペラジニル)−7−オキソ
−7H−ピリド〔1,2,3−de〕〔1,4〕ベンゾオキサジン−
6−カルボン酸 (17)9−フルオロ−2,3−ジヒドロ−3−メチル−10
−(4−エチル−1−ピペラジニル)−7−オキソ−7H
−ピリド〔1,2,3−de〕〔1,4〕ベンゾオキサジン−6−
カルボン酸塩酸塩ヘミハイドレート(mp285〜290℃(分
解)) (18)3S−9−フルオロ−2,3−ジヒドロ−3−メチル
−10−(4−メチル−1−ピペラジニル)−7−オキソ
−7H−ピリド〔1,2,3−de〕〔1,4〕ベンゾオキサジン−
6−カルボン酸ヘミハイドレート (19)3S−9−フルオロ−2,3−ジヒドロ−3−メチル
−10−(4−ヒドロキシ−1−ピペリジニル)−7−オ
キソ−7H−ピリド〔1,2,3−de〕〔1,4〕ベンゾオキサジ
ン−6−カルボン酸 本発明の一般式(I)のピリド〔1,2,3−de〕〔1,4〕
ベンゾオキサジン誘導体は10位置換基Xの塩基性によ
り、酸付加塩としても使用することができ、その酸付加
塩の例としては塩酸塩、臭化水素酸塩、ヨウ化水素酸
塩、硫酸塩などの無機塩類:或いは、酢酸塩、メタンス
ルホン酸塩、クエン酸塩、ベンゼンスルホン酸塩、乳酸
塩などの有機酸塩が挙げられる。
(1) 9-fluoro-2,3-dihydro-3-methyl-10
-Dimethylamino-7-oxo-7H-pyrido [1,2,3-d
e] [1,4] benzoxazine-6-carboxylic acid (2) 9-fluoro-2,3-dihydro-3-methyl-10
-(1-morphonyl) -7-oxo-7H-pyrido [1,2,
3-de] [1,4] benzoxazine-6-carboxylic acid (3) 9-fluoro-2,3-dihydro-3-methyl-10
-(1-Pyrrolidinyl) -7-oxo-7H-pyrido [1,
2,3-de] [1,4] benzoxazine-6-carboxylic acid (4) 9-fluoro-2,3-dihydro-3-methyl-10
-(1-Piperidinyl) -7-oxo-7H-pyrido [1,
2,3-de] [1,4] benzoxazine-6-carboxylic acid (5) 9-fluoro-2,3-dihydro-3-methyl-10
-(4-Hydroxy-1-piperidinyl) -7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-
6-carboxylic acid (6) 9-fluoro-2,3-dihydro-3-methyl-10
-(3-Methyl-1-piperazinyl) -7-oxo-7H
-Pyrido [1,2,3-de] [1,4] benzoxazine-6-
Carboxylic acid (7) 9-fluoro-2,3-dihydro-3-methyl-10
-(1-Piperazinyl) -7-oxo-7H-pyrido [1,
2,3-de] [1,4] benzoxazine-6-carboxylic acid dihydrate (8) 9-fluoro-2,3-dihydro-3-methyl-10
-(4-Methyl-1-piperazinyl) -7-oxo-7H
-Pyrido [1,2,3-de] [1,4] benzoxazine-6-
Carboxylic acid (9) 9-fluoro-2,3-dihydro-3-methyl-10
-(4-Ethyl-1-piperazinyl) -7-oxo-7H
-Pyrido [1,2,3-de] [1,4] benzoxazine-6-
Carboxylic acid (10) 9-fluoro-2,3-dihydro-3-methyl-10
-(4-Ethyl-1-piperazinyl) -7-oxo-7H
-Pyrido [1,2,3-de] [1,4] benzoxazine-6-
Carboxylic acid ethyl ester (11) 9-fluoro-2,3-dihydro-3-methyl-10
-(4-Formyl-1-piperazinyl) -7-oxo-
7H-pyrido [1,2,3-de] [1,4] benzoxazine-6
-Carboxylic acid (12) 9-fluoro-2,3-dihydro-3-methyl-10
-(4-Hydroxyethyl-1-piperazinyl) -7-
Oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid (13) 9-fluoro-2,3-dihydro-3-methyl-10
-(4-n-Propyl-1-piperazinyl) -7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid (14) 9-fluoro-2, 3-dihydro-3-methyl-10
-(4-iso-propyl-1-piperazinyl) -7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid (15) 9-fluoro-2, 3-dihydro-3-methyl-10
-(4-acetonyl-1-piperazinyl) -7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-
6-carboxylic acid (16) 9-fluoro-2,3-dihydro-3-methyl-10
-(4-n-Butyl-1-piperazinyl) -7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-
6-carboxylic acid (17) 9-fluoro-2,3-dihydro-3-methyl-10
-(4-Ethyl-1-piperazinyl) -7-oxo-7H
-Pyrido [1,2,3-de] [1,4] benzoxazine-6-
Carboxylic acid hydrochloride hemihydrate (mp285-290 ° C (decomposition)) (18) 3S-9-fluoro-2,3-dihydro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo -7H-pyrido [1,2,3-de] [1,4] benzoxazine-
6-Carboxylic acid hemihydrate (19) 3S-9-fluoro-2,3-dihydro-3-methyl-10- (4-hydroxy-1-piperidinyl) -7-oxo-7H-pyrido [1,2, 3-de] [1,4] benzoxazine-6-carboxylic acid The pyrido [1,2,3-de] [1,4] of the general formula (I) of the present invention
The benzoxazine derivative can also be used as an acid addition salt due to the basicity of the 10-position substituent X, and examples of the acid addition salt include hydrochloride, hydrobromide, hydroiodide and sulfate. Inorganic salts such as: or organic acid salts such as acetate, methanesulfonate, citrate, benzenesulfonate and lactate.

又、Rが水素原子である場合の式(I)における6位
のカルボキシル基は塩の形であつてもよく、例えばナト
リウム塩、カリウム塩のようなアルカリ金属塩;マグネ
シウム塩、カルシウム塩などのアルカリ土類金属塩;ア
ンモニウム塩、トリエチルアミン塩などの有機塩類が包
合される。
When R is a hydrogen atom, the 6-position carboxyl group in the formula (I) may be in the form of a salt, for example, an alkali metal salt such as sodium salt or potassium salt; magnesium salt, calcium salt or the like. Alkaline earth metal salts; organic salts such as ammonium salts and triethylamine salts are included.

さらに式(I)のピリド〔1,2,3−de〕〔1,4〕ベンゾ
オキサジン誘導体又はその塩は水和物の形態で用いるこ
ともできる。
Furthermore, the pyrido [1,2,3-de] [1,4] benzoxazine derivative of the formula (I) or a salt thereof can be used in the form of a hydrate.

また、本発明化合物(I)には、いくつかの光学的異
性体が存在するが、ラセミ体のみならず3S体を利用する
こともできる。
Further, although the compound (I) of the present invention has some optical isomers, not only the racemate but also the 3S isomer can be used.

一般式(I)のピリド〔1,2,3−de〕〔1,4〕ベンゾオ
キサジン誘導体の大部分は例えば特開昭57−46986号、
特開昭58−72589号にラセミ体として、特開昭62−25279
0号には3S体として記載されているそれ自体既知の化合
物であり、これら公報に記載された方法に準じて製造す
ることができる。
Most of the pyrido [1,2,3-de] [1,4] benzoxazine derivatives of the general formula (I) are disclosed, for example, in JP-A-57-46986.
As a racemate in JP-A-58-72589, JP-A-62-25279
No. 0 is a compound known per se described as 3S isomer, and can be produced according to the methods described in these publications.

叙上の式(I)の化合物、もしくはその塩又はその水
和物(以下、単に「活性化合物(I)」と略称する)を
魚類に投与する方法としては、活性化合物(I)を直接
あるいは飼料中に混合して経口的に投与する方法、活性
化合物(I)の溶液中に魚類を薬浴させる方法(魚類を
1定時間浸漬する)等があり、場合によつては、注射に
より投与することも可能である。
The method of administering the compound of the above formula (I), or a salt thereof or a hydrate thereof (hereinafter simply referred to as “active compound (I)”) to fish includes directly or directly administering the active compound (I). There are a method of orally administering by mixing with a feed, a method of bathing a fish in a solution of the active compound (I) (immersing the fish for a fixed time), and the like. In some cases, administration by injection It is also possible to do so.

活性化合物(I)を魚類の抗菌剤として使用する場
合、その投与量は投与の目的(予防又は治療)、処置す
べき魚の種類や大きさ、あるいは感染の程度等により異
なるが、一般的には1日当たり魚体重1Kgに対し1〜200
mg、好ましくは5〜100mgの範囲の量を1日1回又は数
回に分けて投与することができる。しかし勿論、上記の
投与量は一応の目安であり、魚の年齢、体重、病状等に
応じて、上記範囲外の量を投与することも可能である。
また投与の期間も特に制限はないが、通常1〜10日間程
度の投与によつて充分な効果を得ることができる。
When the active compound (I) is used as an antibacterial agent for fish, the dose varies depending on the purpose of administration (prevention or treatment), the type and size of the fish to be treated, the degree of infection, etc. 1 to 200 per 1kg of fish weight per day
The amount in the range of mg, preferably 5 to 100 mg can be administered once a day or in several divided doses. However, as a matter of course, the above dose is a rough guide, and it is also possible to administer an amount outside the above range depending on the age, weight, medical condition, etc. of the fish.
The administration period is also not particularly limited, but a sufficient effect can usually be obtained by administration for about 1 to 10 days.

活性化合物(I)を魚類に投与するための製剤として
は、この分野において通常用いられる技術により適宜散
剤、顆粒剤、可溶散剤、シロツプ剤、溶液あるいは注射
剤とすることができる。以下にその代表的な製剤処方例
を記す。
The formulation for administering the active compound (I) to fish can be appropriately prepared into powders, granules, soluble powders, syrups, solutions or injections by the techniques usually used in this field. The typical formulation examples are described below.

製剤例1(飼料混合用散剤): 活性化合物(I) 1〜10重量部 とうもろこし澱粉 98.5〜89.5 〃 軽質無水ケイ酸 0.5 〃 計 100 〃 製剤例2(飼料混合用又は薬浴用可溶散剤): 活性化合物(I) 1〜10重量部 (水可溶性のもの) 乳糖 99〜90 〃 計 100 〃 製剤例3(飼料混合用又は薬浴用液剤): 活性化合物(I) 1〜10重量部 酢酸 5〜20 〃 パラオキシ安息香酸エチル 0.1 〃 精製水 69.9〜93.9 〃 計 100 〃 〔発明の効果〕 本発明の活性化合物(I)は魚類に感染する細菌、特
にエロモナス属、エドワードジエラ属及びビブリオ属の
細菌に対して強い抗菌作用を示すので、これらの細菌に
よるウナギ、アユ、アマゴ等の感染症を予防及び治療す
ることができる。
Formulation Example 1 (Powder Mixing Powder): 1 to 10 parts by weight of active compound (I) Corn starch 98.5 to 89.5 〃 Light anhydrous silicic acid 0.5 〃 100 〃 Formulation Example 2 (Soluble powder for feed mixing or medicinal bath): Active compound (I) 1 to 10 parts by weight (water-soluble) Lactose 99 to 90 〃 Total 100 〃 Formulation example 3 (mixture for feed or liquid for medicinal bath): Active compound (I) 1 to 10 parts by weight Acetic acid 5 20 〃 Ethyl paraoxybenzoate 0.1 〃 Purified water 69.9 to 93.9 〃 Total 100 〃 [Effect of the invention] The active compound (I) of the present invention is a bacterium that infects fish, especially bacteria of the genus Aeromonas, Edward genus Diera and genus Vibrio. Since it has a strong antibacterial action against Escherichia coli, it is possible to prevent and treat infectious diseases such as eel, sweetfish, and amago caused by these bacteria.

〔実施例〕〔Example〕

次に実施例を挙げ、本発明を更に詳しく説明する。 Next, the present invention will be described in more detail with reference to examples.

実施例1 各種魚病菌に対する試験管内抗菌活性測定試験: 各試験菌株を一夜培養して、その培養液(菌数約108
個/ml)の一定量をあらかじめ各濃度段階の試験化合物
を添加してある1.5〜2.0%塩化ナトリウム含有ミユーラ
ーヒントン寒天(Difco)平板に接種し、28〜30℃で24
〜48時間培養した後接種菌の発育を阻止した試験化合物
の最小濃度、即ち最小発育阻止濃度(MIC)を決定し
た。その結果を下記第1表に示した。なお、用いた試験
化合物は第2表の1〜9及び19である。
Example 1 In vitro antibacterial activity measurement test against various fish pathogens: Each test strain was cultured overnight and the culture solution (the number of bacteria was about 10 8
Aliquots / ml) are inoculated on 1.5-2.0% sodium chloride-containing Miura-Hinton agar (Difco) plates to which test compounds at each concentration step have been added in advance, and at 28-30 ° C for 24 hours.
The minimum concentration of the test compound that inhibited the growth of the inoculum after culturing for ˜48 hours, ie the minimum inhibitory concentration (MIC), was determined. The results are shown in Table 1 below. The test compounds used are 1 to 9 and 19 in Table 2.

以上のように代表的な活性化合物(I)は、試験管内
抗菌活性試験において対照化合物のオキソリン酸やピロ
ミド酸に比較し高い抗菌活性を示した。
As described above, the representative active compound (I) showed higher antibacterial activity in the in vitro antibacterial activity test than the control compounds oxophosphoric acid and pyromidic acid.

実施例2 試験菌株を代え、実施例1と同様にして第2表の試験
化合物10〜18についての最小阻止濃度を調べた。この結
果を第3表に示す。
Example 2 The test strain was changed, and the minimum inhibitory concentrations for the test compounds 10 to 18 in Table 2 were examined in the same manner as in Example 1. The results are shown in Table 3.

実施例3 マウス静脈内投与における試験化合物の急性毒性(LD
50): 代表的な試験化合物である化合物5、7、9、11及び
13について、これらをマウス静脈内に投与し、急性毒性
を調べた。
Example 3 Acute toxicity of a test compound upon intravenous administration to mice (LD
50 ): Compounds 5, 7, 9, 11 and representative test compounds
For 13, these were intravenously administered to mice and examined for acute toxicity.

実験方法:5週齢のSIc:ddyマウス(雄,体重25〜29.6
g)を用い、検体を0.1N−NaOHで溶解後、0.1N−HClでpH
を調整し、精製水で所定濃度に希釈した後、マウスの尾
静脈内に接種した。試験1においては1群6匹用い、試
験2においては1群10匹を用いた。この試験結果を第4
表に示した。
Experimental method: 5-week-old SIc: ddy mouse (male, body weight 25 to 29.6)
g), dissolve the sample with 0.1N-NaOH, then add 0.1N-HCl to
Was prepared, diluted with purified water to a predetermined concentration, and then inoculated into the tail vein of the mouse. In test 1, 6 animals were used per group, and in test 2, 10 animals were used per group. This test result is the 4th
Shown in the table.

第4表の結果から試験化合物のマウス静脈内投与にお
けるLD50値はそれぞれ次の通り算定された。
From the results shown in Table 4, the LD 50 values of the test compound intravenously administered to mice were calculated as follows.

化合物13 200〜300mg/Kg 〃 9 300〜400mg/Kg 〃 7 50mg/Kg以下 〃 11 300〜400mg/Kg 〃 5 400mg/Kg以上 実施例4 類結節症人工感染ブリにおける経口投与効果: 病魚より分離した類結節症病原菌パスツレラ・ピシシ
ダを生理食塩水に懸濁して、平均体重90gのブリ稚魚に
体重100gにつき0.01mgの菌量になるように背部筋肉内に
注射して人工感染した。感染3時間後より化合物8を6.
3,3.1,1.6,0.8mg/Kg魚体重になるようにモイストペレツ
トに混合して1日1回5日間自由摂飼で投与した。試験
は25〜26℃の水温で実施し、投薬終了後10日間観察した
結果を第5表に示した。この結果から明らかなように本
発明の化合物8は魚体内においても優れた効果を発揮し
た。
Compound 13 200 to 300 mg / Kg 〃 9 300 to 400 mg / Kg 〃 7 50 mg / Kg or less 〃 11 300 to 400 mg / Kg 〃 5 400 mg / Kg or more Example 4 Oral administration effect on artificially infected nodular disease buri: From diseased fish The isolated pathogenic nodule pathogenic fungus Pasteurella pisisida was suspended in physiological saline, and artificially infected by injecting into the back muscle of juvenile yellowtails with an average weight of 90 g so that the bacterial load was 0.01 mg per 100 g of body weight. Compound 8 was added 6 hours after infection.
3,3.1,1.6,0.8 mg / Kg fish was mixed with moist pellets so as to have a body weight and administered once a day for 5 days under free feeding. The test was carried out at a water temperature of 25 to 26 ° C., and the results of observation for 10 days after the completion of administration are shown in Table 5. As is clear from these results, the compound 8 of the present invention exhibited an excellent effect also in the fish body.

実施例5 類結節症人工感染ブリにおける経口投与効果: 病魚より分離した類結節症病原菌パスツレラ・ピシシ
ダを104CFU/ml浮遊させた菌液に平均体重21.6gのブリ稚
魚を菌浴させ人工感染した。感染3時間後より化合物8
を6.3又は3.2mg/Kg魚体重、対照薬としてオキソリン酸
を30mg/Kg魚体重になるように餌料に混ぜた後、1日1
回5日間強制投与した。試験は23〜25℃の水温で実施
し、投薬終了後10日間観察した結果を第6表に示す。こ
の結果から明らかな如く、本発明の化合物8は魚体内に
おいてオキソリン酸より優れた効果を示した。
Example 5 Oral administration effect on artificially infected yellowtail with nodular disease: Artificial liquor with an average weight of 21.6 g was bathed in a bacterial solution in which 10 4 CFU / ml of the nodular pathogenic fungus Pasteurella pisisida separated from diseased fish was artificially bathed. Infected. Compound 8 from 3 hours after infection
Was mixed with 6.3 or 3.2 mg / Kg fish body weight and oxophosphoric acid as a control drug to 30 mg / Kg fish body weight.
Forcible administration was performed once for 5 days. The test was carried out at a water temperature of 23 to 25 ° C., and the results of observation for 10 days after the completion of administration are shown in Table 6. As is clear from these results, the compound 8 of the present invention showed a superior effect to oxophosphoric acid in the fish body.

実施例6 類結節症人工感染ブリにおける経口投与効果: 病魚より分離した類結節症病原菌パスツレラ・ピシシ
ダを104CFU/ml浮遊させた菌液に平均体重18.3gのブリ稚
魚を菌浴させ人工感染した。感染3時間後より化合物9
および化合物13をそれぞれ12.5,6.3,3.2mg/Kg魚体重に
なるように餌料にまぜた後1日1回5日間強制投与し
た。試験は24.5〜27.7℃の水温で実施し、投薬終了後10
日間観察した結果を第7表に示す。この結果から明らか
な如く、本発明の化合物9及び化合物13は魚体内におい
て優れた効果を示した。
Example 6 Oral administration effect on artificially infected yellowtail with nodular disease: Artificial liquor with an average weight of 18.3 g was bathed in a bacterial solution in which 10 4 CFU / ml of the nodular pathogenic fungus Pasteurella pisisida isolated from diseased fish was subjected to artificial treatment. Infected. Compound 9 from 3 hours after infection
Compound 13 and Compound 13 were mixed with the diet so that the fish weight was 12.5, 6.3, and 3.2 mg / Kg, respectively, and then forcedly administered once a day for 5 days. The test is carried out at a water temperature of 24.5 to 27.7 ° C and 10
The results of daily observation are shown in Table 7. As is clear from these results, the compounds 9 and 13 of the present invention showed excellent effects in fish.

実施例7 ビブリオ病人工感染アユにおける経口投与効果: ビブリオ病病原菌ビブリオ・アンギララムを1%食塩
水中に7×105/ml浮遊させた菌液に、平均体重40gのア
ユを菌浴させ人工感染した。感染3時間後より化合物8
を10,3.2mg/Kg魚体重、対照薬としてオキソリン酸を32,
10mg/Kg魚体重になるように餌料にまぜて1日1回2日
間強制投与した。試験は24℃の水温で実施し、感染後10
日間観察した結果を第8表に示した。この結果から明ら
かなように、本発明の化合物8はビブリオ病菌に対して
も魚体内において優れた効果を示した。
Example 7 Oral Administration Effect on Artificial Sweetfish with Vibrio Disease: Vibrio anguillarum, a vibrio disease-causing bacterium, was suspended in a 1% saline solution at a concentration of 7 × 10 5 / ml, and artificially infected with ayu having an average body weight of 40 g. . Compound 8 from 3 hours after infection
103.2 mg / Kg fish weight, oxophosphoric acid 32 as a control drug,
The fish was mixed with the feed so that the fish body weight was 10 mg / Kg, and was forcibly administered once a day for 2 days. The test is conducted at a water temperature of 24 ° C and 10
The results of daily observation are shown in Table 8. As is clear from these results, the compound 8 of the present invention also showed an excellent effect in the fish body against Vibrio bacterium.

実施例8 パラコロ病人工感染ウナギにおける経口投与効果: パラコロ病病原菌エドワルドジエラ・タルダを生理食
塩水に懸濁させて平均体重62.0gのニホンウナギに2×1
07CFU/尾となるように腹腔内注射して人工感染した。感
染3時間後より化合物8を10,5,2.5,1.25,0.63mg/Kg魚
体重になるよう餌料にまぜて1日1回2日間強制投与し
た。試験は23.5〜23.7℃の水温で実施し、感染後14日間
観察した結果を第9表に示す。この結果から明らかなよ
うに、本発明の化合物はパラコロ病病原菌に対しても優
れた効果を示した。
Example 8 Effect of Oral Administration on Artificially Infected Eel of Paracolo Disease: The paracolopathogenic bacterium Eduardo diella tarda is suspended in physiological saline to 2 × 1 in Japanese eel having an average weight of 62.0 g.
Artificial infection was carried out by intraperitoneal injection at 0 7 CFU / tail. Three hours after the infection, Compound 8 was forcibly administered once a day for 2 days by mixing it with the feed so that the fish weight was 10, 5, 2.5, 1.25, 0.63 mg / Kg. The test was carried out at a water temperature of 23.5 to 23.7 ° C, and the results observed for 14 days after infection are shown in Table 9. As is clear from this result, the compound of the present invention also showed an excellent effect against the pathogenic bacterium of Paracolo disease.

次に前記実施例に用いた活性化合物中、化合物10及び
17の合成例を参考のために示す。
Next, among the active compounds used in the above examples, compound 10 and
A synthetic example of 17 is shown for reference.

合成例A エタノール12ml中に9−フルオロ−2,3−ジヒドロ−
3−メチル−10−(4−エチル−1−ピペラジニル)−
7−オキソ−7H−ピリド〔1,2,3−de〕〔1,4〕ベンゾオ
キサジン−6−カルボン酸1.8gおよび濃硫酸2.4gを加え
7時間攪拌還流する。冷後、氷冷下で水25mlを加え10%
NaOHでpH11〜12としクロロホルムで抽出する。クロロホ
ルム層を水洗(2回)し芒硝で乾燥し、溶媒を留去し含
水エタノールから再結晶すれば融点240〜243℃の9−フ
ルオロ−2,3−ジヒドロ−3−メチル−10−(4−エチ
ル−1−ピペラジニル)−7−オキソ−7H−ピリド〔1,
2,3−de〕〔1,4〕ベンゾオキサジン−6−カルボン酸エ
チルエステル1.1gが得られる。
Synthesis Example A 9-Fluoro-2,3-dihydro-in 12 ml of ethanol
3-Methyl-10- (4-ethyl-1-piperazinyl)-
1.8 g of 7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid and 2.4 g of concentrated sulfuric acid are added, and the mixture is stirred and refluxed for 7 hours. After cooling, add 25 ml of water under ice cooling and add 10%
Adjust to pH 11-12 with NaOH and extract with chloroform. The chloroform layer was washed with water (twice), dried over Glauber's salt, the solvent was distilled off and the residue was recrystallized from water-containing ethanol to give 9-fluoro-2,3-dihydro-3-methyl-10- (4) having a melting point of 240-243 ° C. -Ethyl-1-piperazinyl) -7-oxo-7H-pyrido [1,
1.1 g of 2,3-de] [1,4] benzoxazine-6-carboxylic acid ethyl ester are obtained.

元素分析値 C21H26O4N3Fとしての 理論値:C,62.51;H,6.50;N,10.41 実測値:C,62.54;H,6.55;N,10.39 合成例B エタノール50ml中に9−フルオロ−2,3−ジヒドロ−
3−メチル−10−(4−エチル−1−ピペラジニル)−
7−オキソ−7H−ピリド〔1,2,3−de〕〔1,4〕ベンゾオ
キサジン−6−カルボン酸2.0gおよび濃塩酸2.0mlを加
え、加熱して溶解させる。減圧下で過剰のエタノールを
濃縮し、析出晶を取、エタノールで洗浄後含水エタノ
ールから再結晶すれば融点285〜290℃(分解)の9−フ
ルオロ−2,3−ジヒドロ−3−メチル−10−(4−エチ
ル−1−ピペラジニル)−7−オキソ−7H−ピリド〔1,
2,3−de〕〔1,4〕ベンゾオキサジン−6−カルボン酸塩
酸塩ヘミハイドレート1.3gが得られる。
Elemental analysis Theoretical value as C 21 H 26 O 4 N 3 F: C, 62.51; H, 6.50; N, 10.41 Actual value: C, 62.54; H, 6.55; N, 10.39 Synthesis example B 9 in 50 ml of ethanol -Fluoro-2,3-dihydro-
3-Methyl-10- (4-ethyl-1-piperazinyl)-
2.0 g of 7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid and 2.0 ml of concentrated hydrochloric acid are added and dissolved by heating. Excess ethanol was concentrated under reduced pressure, and the precipitated crystals were washed with ethanol and recrystallized from hydrous ethanol to give 9-fluoro-2,3-dihydro-3-methyl-10 having a melting point of 285 to 290 ° C (decomposition). -(4-Ethyl-1-piperazinyl) -7-oxo-7H-pyrido [1,
1.3 g of 2,3-de] [1,4] benzoxazine-6-carboxylic acid hydrochloride hemihydrate are obtained.

元素分析値 C19H22O4N3F・HCl・0.5H2Oとしての 理論値:C,54.22;H,5.75;N,9.98 実測値:C,54.20;H,5.79;N,9.85Elemental analysis value C 19 H 22 O 4 N 3 F ・ HCl ・ 0.5H 2 O theoretical value: C, 54.22; H, 5.75; N, 9.98 Found value: C, 54.20; H, 5.79; N, 9.85

───────────────────────────────────────────────────── フロントページの続き (72)発明者 武井 正和 東京都江戸川区北葛西1丁目16番13号 第 一製薬中央研究所内 (72)発明者 板鼻 秀信 東京都江戸川区北葛西1丁目16番13号 第 一製薬中央研究所内 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Masakazu Takei 1-16-13 Kitakasai, Edogawa-ku, Tokyo 1st Central Pharmaceutical Research Center (72) Hidenobu Itanabe 1-1-16 Kitakasai, Edogawa-ku, Tokyo No. 1 Central Research Institute for Pharmaceutical Sciences

Claims (1)

【特許請求の範囲】[Claims] 【請求項1】次の式(I) 〔式中Xは低級アルキルアミノ基又は (但し、Yは水素原子、又は低級アルキル基を、Zはメ
チレン基、メチン基、酸素原子、イオウ原子、窒素原子
を、R1はZが窒素原子の場合、水素原子、低級アルキル
基、ホルミル基、アルカノイルアルキル基を、又、メチ
ン基の場合、低級アルキル基、ヒドロキシル基を示し、
n及びmは同一かもしくは異なった1〜3の整数を示
す)で示される脂環状アミノ基を示し、Rは水素原子又
は低級アルキル基を示す〕 で表わされるピリド〔1,2,3−de〕〔1,4〕ベンゾオキサ
ジン誘導体もしくはその塩又はそれらの水和物を有効成
分とするエロモナス属、エドワードジエラ属又はビブリ
オ属の細菌による魚類感染症の予防・治療剤。
1. The following formula (I): [Wherein X is a lower alkylamino group or (However, Y is a hydrogen atom or a lower alkyl group, Z is a methylene group, a methine group, an oxygen atom, a sulfur atom or a nitrogen atom, and R 1 is a hydrogen atom, a lower alkyl group or a formyl group when Z is a nitrogen atom. Group, an alkanoylalkyl group, and in the case of a methine group, a lower alkyl group and a hydroxyl group,
n and m are the same or different and each represents an integer of 1 to 3), and R represents a hydrogen atom or a lower alkyl group]], a pyrido [1,2,3-de] [1] A preventive and / or therapeutic agent for a fish infectious disease caused by a bacterium of the genus Aeromonas, Edward diella or genus Vibrio, which comprises a [1,4] benzoxazine derivative or a salt thereof or a hydrate thereof as an active ingredient.
JP62324397A 1987-12-22 1987-12-22 Preventive and therapeutic agents for fish infectious diseases Expired - Lifetime JPH0826029B2 (en)

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JPH0826029B2 true JPH0826029B2 (en) 1996-03-13

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JPS62452A (en) * 1985-06-22 1987-01-06 バイエル・アクチエンゲゼルシヤフト Manufacture of 1,8-bridged-4-quinolone-3-carboxylic acids, intermediates and use as drug
JPS62145088A (en) * 1985-12-10 1987-06-29 バイエル・アクチエンゲゼルシヤフト Enantiomerically pure 1, 8-crosslinked 4-quinolone-3- carboxylic acid

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62452A (en) * 1985-06-22 1987-01-06 バイエル・アクチエンゲゼルシヤフト Manufacture of 1,8-bridged-4-quinolone-3-carboxylic acids, intermediates and use as drug
JPS62145088A (en) * 1985-12-10 1987-06-29 バイエル・アクチエンゲゼルシヤフト Enantiomerically pure 1, 8-crosslinked 4-quinolone-3- carboxylic acid

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