JPH01165589A - Antimicrobial agent for marine - Google Patents
Antimicrobial agent for marineInfo
- Publication number
- JPH01165589A JPH01165589A JP32439787A JP32439787A JPH01165589A JP H01165589 A JPH01165589 A JP H01165589A JP 32439787 A JP32439787 A JP 32439787A JP 32439787 A JP32439787 A JP 32439787A JP H01165589 A JPH01165589 A JP H01165589A
- Authority
- JP
- Japan
- Prior art keywords
- pyrido
- methyl
- group
- lower alkyl
- dihydro
- 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.)
- Granted
Links
- 239000004599 antimicrobial Substances 0.000 title 1
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims abstract description 5
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 4
- 229910052717 sulfur Inorganic materials 0.000 claims abstract 2
- 239000003242 anti bacterial agent Substances 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 239000004480 active ingredient Substances 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 125000001589 carboacyl group Chemical group 0.000 claims description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 2
- 150000005130 benzoxazines Chemical class 0.000 claims 1
- 125000004430 oxygen atom Chemical group O* 0.000 claims 1
- 125000004434 sulfur atom Chemical group 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 36
- 241000251468 Actinopterygii Species 0.000 abstract description 31
- 235000019688 fish Nutrition 0.000 abstract description 31
- 208000015181 infectious disease Diseases 0.000 abstract description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 12
- 208000035473 Communicable disease Diseases 0.000 abstract description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 6
- 235000015170 shellfish Nutrition 0.000 abstract description 6
- XNIVKSPSCYJKBL-UHFFFAOYSA-N 2h-1,2-benzoxazine-6-carboxylic acid Chemical compound O1NC=CC2=CC(C(=O)O)=CC=C21 XNIVKSPSCYJKBL-UHFFFAOYSA-N 0.000 abstract description 3
- 238000002360 preparation method Methods 0.000 abstract description 3
- QMEZUZOCLYUADC-UHFFFAOYSA-N hydrate;dihydrochloride Chemical compound O.Cl.Cl QMEZUZOCLYUADC-UHFFFAOYSA-N 0.000 abstract description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 abstract 1
- 238000012360 testing method Methods 0.000 description 20
- 230000000694 effects Effects 0.000 description 14
- -1 4-hydroxypiperidinyl Chemical group 0.000 description 10
- 201000010099 disease Diseases 0.000 description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
- 241000894006 Bacteria Species 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 230000000844 anti-bacterial effect Effects 0.000 description 7
- 235000014102 seafood Nutrition 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 241001600434 Plectroglyphidodon lacrymatus Species 0.000 description 5
- 230000001580 bacterial effect Effects 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 5
- NFTOEHBFQROATQ-UHFFFAOYSA-N 2,3-dihydrofuran-5-carboxylic acid Chemical compound OC(=O)C1=CCCO1 NFTOEHBFQROATQ-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 241000607598 Vibrio Species 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 229960000321 oxolinic acid Drugs 0.000 description 4
- 241000861914 Plecoglossus altivelis Species 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 230000007059 acute toxicity Effects 0.000 description 3
- 231100000403 acute toxicity Toxicity 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 2
- 241000252073 Anguilliformes Species 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241001474374 Blennius Species 0.000 description 2
- 239000005973 Carvone Substances 0.000 description 2
- 241000252233 Cyprinus carpio Species 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 244000052769 pathogen Species 0.000 description 2
- 230000001717 pathogenic effect Effects 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- RCIMBBZXSXFZBV-UHFFFAOYSA-N piromidic acid Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CN=C1N1CCCC1 RCIMBBZXSXFZBV-UHFFFAOYSA-N 0.000 description 2
- 229960004444 piromidic acid Drugs 0.000 description 2
- 239000013535 sea water Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- FUBFWTUFPGFHOJ-UHFFFAOYSA-N 2-nitrofuran Chemical class [O-][N+](=O)C1=CC=CO1 FUBFWTUFPGFHOJ-UHFFFAOYSA-N 0.000 description 1
- 241000607534 Aeromonas Species 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 241000473391 Archosargus rhomboidalis Species 0.000 description 1
- 241000512259 Ascophyllum nodosum Species 0.000 description 1
- 241000972773 Aulopiformes Species 0.000 description 1
- 241000252229 Carassius auratus Species 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 244000018436 Coriandrum sativum Species 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 241000238557 Decapoda Species 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- 241000861915 Plecoglossus Species 0.000 description 1
- 241000589516 Pseudomonas Species 0.000 description 1
- 241000277331 Salmonidae Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- 241000544286 Vibrio anguillarum Species 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000009360 aquaculture Methods 0.000 description 1
- 244000144974 aquaculture Species 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 238000003287 bathing Methods 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960005091 chloramphenicol Drugs 0.000 description 1
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 1
- 239000004020 conductor Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000009313 farming Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000013505 freshwater Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 244000000003 plant pathogen Species 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 235000019515 salmon Nutrition 0.000 description 1
- 230000000276 sedentary effect Effects 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- BWMISRWJRUSYEX-SZKNIZGXSA-N terbinafine hydrochloride Chemical compound Cl.C1=CC=C2C(CN(C\C=C\C#CC(C)(C)C)C)=CC=CC2=C1 BWMISRWJRUSYEX-SZKNIZGXSA-N 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 229940040944 tetracyclines Drugs 0.000 description 1
- 201000004647 tinea pedis Diseases 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Landscapes
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
〔座業上の利用分野］
本発明は次の式（Ｉ）
〔式中Ｘは低級アルキルアミノ基又は
Ｙ
又は低級アルキル基を、２はメチレン基、メチン基、ｒ
Ｒ素原子、イオウ原子、窒素原子を、Ｒ１は２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金示
す〕
で表わされるピリド（Ｉ，２，３−ｄｅ）［１，４］ベ
ンゾオキサシン誘導体もしくはその塩又はそれら水和物
を有効成分とする魚介類の感染症の予防・治療又は処置
に便用するための水産用抗菌剤に関する。Detailed Description of the Invention [Field of Sedentary Application] The present invention relates to the following formula (I) [wherein X is a lower alkylamino group, Y or a lower alkyl group, and 2 is a methylene group, a methine group, r
When 2 is a nitrogen atom, R represents a hydrogen atom, a lower alkyl group, a formyl group, or an alkanoyl alkyl group, and in the case of a methine group, represents a lower alkyl group or a hydroxyl group. , n and m are the same or different integers of 1 to 3), and R is a hydrogen atom or a lower alkyl group] pyrido (I,2,3-de ) [1,4] It relates to an antibacterial agent for marine products, which contains a benzoxacin derivative, a salt thereof, or a hydrate thereof, as an active ingredient and is conveniently used for the prevention, treatment, or treatment of infectious diseases of fish and shellfish.
近年水腫業界では、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。In recent years, aquaculture has become popular in the edema industry, and efforts are being made to efficiently produce seafood.
殊にブリ、タイ、ウナギ、アユ、コイ等の炎海水魚やア
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＾く時には全滅に近
い板書を招き、父、例え全滅をまぬがれてもｍＨ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
頻＜安望されている。In particular, high-density farming of seawater fish such as yellowtail, sea bream, eel, sweetfish, and carp, and shellfish such as abalone is carried out, and in these cases, outbreaks of infectious fish and shellfish diseases occur frequently, and in some cases, they are close to extinction. As a result of this, the fisheries industry is in high demand for an early and effective solution, as even if the fish are prevented from being completely wiped out, there will be a large mH loss.
魚介類の感染症の予防又は治療のため、匠米からサルフ
ァ剤、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、ナリゾクス酸、オキンリン
酸、ピロミド酸、クロラムフェニコールなどの抗菌剤を
飼料に添加して魚類に経口投与したり、又はこれらの抗
菌剤の溶液に薬浴することが打われている。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っ
た。To prevent or treat infectious diseases in seafood, Takumai uses antibacterial agents such as sulfa drugs, nitrofurans, synthetic penicillins, tetracyclines, macrolide antibiotics, nalizoxic acid, oxinphosphate, pyromidic acid, and chloramphenicol in feed. It has been proposed to add these antibacterial agents and administer them orally to fish, or to bathe them in solutions of these antibacterial agents. However, these antibacterial agents for fisheries have shortcomings such as narrow antibacterial spectrum, low therapeutic effect, narrow safety margin, side effects, and uneconomical properties, and are not fully satisfactory.
貼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った結果、前記一般式（
りで表わされるピリド（Ｉ１２＋３−ｄｅＪ（Ｉ１４）
ベンゾオキサシン誘導体が魚類の感染症に対し広範囲に
亘り浚れた予防・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、本発明を児成するに至
った。The present inventors conducted intensive research on a safe marine antibacterial agent with a wide antibacterial spectrum, effective against various fish infections, low toxicity, and found that the general formula (
Pyrido (I12+3-deJ(I14)
The present inventors have discovered that benzoxacin derivatives exhibit extensive preventive and therapeutic effects over a wide range of infectious diseases in fish, and are safe with little toxicity, leading to the creation of the present invention.
すなわち、本発明は、前記式（Ｉ）で表わされるピリド
（Ｉ，２，３−ｄｅ）（Ｉ；４）ベンゾオキサシン誘導
体もしくはその垣又はそれらの水利物を有効成分として
含有する水産用抗菌剤を提供するものである。That is, the present invention provides a marine antibacterial product containing the pyrido(I,2,3-de)(I;4) benzoxacin derivative represented by the above formula (I) or its derivatives or aquatic products thereof as an active ingredient. The purpose is to provide an agent for
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Ｃ
１〜Ｃ６までのアルキル基、シ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 、０
ロピル、インゾロビル、シー−ｎ−ゾロビル等が挙けら
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′１でのアルキル基でアシ
、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、。In the general formula (I), the lower alkyl moiety of the lower alkylamino group of X has a linear or branched C
1 to C6 alkyl groups and sialkyl groups are included,
For example, methyl, dimethyl, ethyl, diethyl, n, 0
Examples include lopil, inzolovir, c-n-zolovir, and the like. Further, the lower alkyl group at Y and R1 is also a linear or branched alkyl group at C1 to C6'1 such as acyl, methyl, ethyl, 2-hydroxyethyl, aminomethyl, n-propyl.
脂環状アミン基としては例えばモルホニル、チオモルホ
ニル、ピロリゾニル、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−エチルビペラゾニル、
４−（２−ヒドロキシエチル）ピペラジニル、４−ｎ−
プロピルービペラゾニル、４−インゾロビルピペリジニ
ル、４−アセトニルピペラジニル、４−ｎ−プチルビペ
ラゾニル、４−ホルミルビペラゾニル等が埜げられる。Examples of alicyclic amine groups include morphonyl, thiomorphonyl, pyrrolizonyl, piperidinyl, 4-hydroxypiperidinyl, 3-methylpiperazinyl, piperazinyl,
4-methyl-piperazinyl, 4-ethylbiperazonyl,
4-(2-hydroxyethyl)piperazinyl, 4-n-
Examples include propylubiperazonyl, 4-inzolobylpiperidinyl, 4-acetonylpiperazinyl, 4-n-butylbiperazonyl, 4-formylbiperazonyl, and the like.
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。Suitable examples of the group R include a hydrogen atom, methyl and ethyl groups.
本発明の抗菌剤に於てＭ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シである。Representative examples of general formula (I) used as the M active ingredient in the antibacterial agent of the present invention are as follows.
（Ｉ）９−フルオロ−２，３−ジヒドロ−３−メチル−
１０−ゾメチルアミンー７−オキンー７Ｈ−ピリド［１
，２，３−ｄｅｌ［１，４〕ベンゾオキサノン−６−カ
ルボンば
（２）９−フルオロ−２，３−ジヒドロ−３−メチル−
１０−＜１−モルホニル）−７−ｙ！−キ７−７１４−
ピリドＣ１、２、３−ｄｅ〕［１，４］ベンゾオキサシ
ン−６−カルボン酸
（３）９−フルオロ−２，３−ジヒドロ−３−メチル−
１０−（Ｉ−ピロリゾニル）−７−オキンー７Ｈ−ピリ
ド［１，２，３−ｄｅ〕（Ｉ？４３ベンゾオキサシン−
６−カルダン酸
（４）９−フルオロ−２，３−ジヒドロ−３−メチル−
１０−（Ｉ−ピペリジニル）−７−オキンー７Ｈ−ピリ
ド（Ｉ，２，３−ｄｅｌ［１，４３ベンゾオキサノン−
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
キンー７Ｈ−ピリド（Ｉ，２，３−ｄｅ）（Ｉ，４）ペ
ンジオ牟すゾンー６−カルビンぼ
（６）９−フルオロ−２，３−ジヒドロ−３−メチル−
１０−（３−メチル−１−ビペラゾニ、ル）−７−オキ
ンー７に′１−ピリド（Ｉ゜２．３−ｄｅＪｃｌ、４）
ベンゾ、ｔ−＋？シンー６−カルボン酸
（７）９−フルオロ−２，３−ジヒドロ−３−メチル−
１０−（Ｉ−ピペリジニル）−７−オキンー７Ｈ−ピリ
ド（Ｉ，２，３−ｄｅ、）（Ｉ，４）ベンゾオキサシン
−６−カルボン鍍シバイドレート
（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−オキン
ー７Ｈ−ピリド〔１゜２．３−ｄｅｌ（Ｉ，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゛ゾニル）−７−オキ
ソ−７Ｈ−ピリド〔１゜２．３−ｄｅＪ［１，４，］］
ベンゾオキサシンー６−カルボン
酸Ｉｔ）ｌ 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
−オキンー７Ｈ−ピリド〔１゜２．３−ｄｅＪ（Ｉ，４
）ベンゾオキサシン−６−カルボン酸エチルエステル
Ｕυ 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
ンー７Ｈ−ピリド［１１２１３−ｄｅＪ［１１４）ベア
／、＋ｌ−？サゾンー６−カルゴン酸
（Ｉ２１９−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−オキンー７Ｈ−ピリド［１，２，３−ｄｅ）（Ｉ
，４］ベンゾオキサシン−６−カルボン酸
Ｑ四 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−
オキンー７ｄ−ピリド（Ｉ，２，３−ｄａ、）［１，４
］ベンゾオキサシン−６−カルボン酸
ｌＩ４１ ９−フルオロ−２，３−ジヒドロ−３−メチ
ル−１０−（４−１ｓｏ−ゾロビル−１＝ビペラゾニル
）−７−オキンー７Ｈ−ピリド（Ｉ，２，３−ｄｅＪ［
１，４）ベンゾオキサシン−６−カルボン酸
１５ ９−フルオロ−２，３−ジヒドロ−３−メチル−
１０−（４−７セトニルー１−ピペラジニル）−７−オ
千ンー７）ｉ−ピリド（Ｉ１２＋３−ｄｅｎ（Ｉ１４］
べ／ジオキサジン−６−カルボン酸
ｕｌ１９ 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
−オキンー７Ｈ−ピリド（Ｉ，２，３−ｄｅ）（Ｉ，４
）ベンゾオキサシン−６−カルｌン酸
ｑ７）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−オキン
ー７Ｈ−ピリド〔１゜２ 、３− ｄｅ ） （Ｉ、４
）ベンゾオキサシン−６−カルボン酸塩酸塩へミハイド
レート（ｍｐ２８５〜２９０Ｃ（分′Ｓ））
賭 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
キンー７Ｈ−ピリド（Ｉ，２，３−ｄｅ）［１，４，］
］ベンゾオキサシンー６−カルボンｒへミハイドレート
（Ｉ１３Ｓ−９−７ｈオＩ：Ｉ−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−オキンー７Ｈ−ピリド（Ｉ，２，３−ｄｅＪＩ
：１，４）ベンゾオキサシン−６−カルボン酸
本発明の一般式（Ｉ）のぎりドＣ１、２、３−ｄｅ Ｊ
［１、４〕ベンゾオキサシン誘誘体は１０位置換基Ｘ
の塩基性により、酸付加塩としても夏用することができ
、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ｃＲ項などの無機塩類：或いは、酢酸
項、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けられる。(I) 9-fluoro-2,3-dihydro-3-methyl-
10-zomethylamine-7-okine-7H-pyrido[1
,2,3-del[1,4]benzoxanone-6-carboxylic acid (2)9-fluoro-2,3-dihydro-3-methyl-
10-<1-morphonyl)-7-y! -Ki7-714-
Pyrido C1,2,3-de][1,4]benzoxacin-6-carboxylic acid (3) 9-fluoro-2,3-dihydro-3-methyl-
10-(I-pyrrolizonyl)-7-okine-7H-pyrido[1,2,3-de](I?43benzoxacin-
6-Cardanic acid (4) 9-fluoro-2,3-dihydro-3-methyl-
10-(I-piperidinyl)-7-okine-7H-pyrido(I,2,3-del[1,43benzoxanone-
6-Carboxylic acid (5) 9-fluoro-2,3-dihydro-3-methyl-
10-(4-Hydroxy-1-piperidinyl)-7-okine-7H-pyrido(I,2,3-de)(I,4)pendio-6-carbinbo(6)9-fluoro-2,3 -dihydro-3-methyl-
'1-pyrido (I゜2.3-deJcl, 4) to 10-(3-methyl-1-biperazoni,l)-7-okine-7
Benzo, t-+? Syn-6-carboxylic acid (7) 9-fluoro-2,3-dihydro-3-methyl-
10-(I-piperidinyl)-7-okine-7H-pyrido(I,2,3-de,)(I,4)benzoxacin-6-carboxybidelate (8) 9-fluoro-2,3- dihydro-3=methyl-
10-(4-Methyl-1-piperazinyl)-7-okyne-7H-pyrido[1°2.3-del(I,4]benzoxazine-6-carboxylic acid (9) 9-fluoro-2,3-dihydro -3-methyl-
10-(4-ethyl-1-piperazonyl)-7-oxo-7H-pyrido [1°2.3-deJ[1,4,]]
Benzoxacin-6-carboxylic acid It)l 9-Fluoro-2,3-dihydro-3-
Methyl-10-(4-ethyl-1-piperazinyl)-7
-Okin-7H-pyrido [1゜2.3-deJ(I,4
) Benzoxacin-6-carboxylic acid ethyl ester Uυ 9-fluoro-2,3-dihydro-3-methyl-
10-(4-formyl-1-piperazinyl)-7-okine-7H-pyrido [11213-deJ[114) bare/, +l-? Sazon-6-cargonic acid (I219-fluoro-2,3-dihydro-3-methyl-10-(4-hydroxyethyl-1-piperazinyl)
-7-okine-7H-pyrido[1,2,3-de)(I
,4]Benzoxacin-6-carboxylic acid Q4 9-fluoro-2,3-dihydro-3-methyl-
10-(4-n-propyl-1-piperazinyl)-7-
Oquin-7d-pyrido (I,2,3-da,) [1,4
]Benzoxacin-6-carboxylic acid lI41 9-fluoro-2,3-dihydro-3-methyl-10-(4-1so-zorobyl-1=biperazonyl)-7-okine-7H-pyrido(I,2,3 -deJ[
1,4) Benzoxacin-6-carboxylic acid 15 9-fluoro-2,3-dihydro-3-methyl-
10-(4-7cetonyl-1-piperazinyl)-7-othine-7)i-pyrido(I12+3-den(I14)
dioxazine-6-carboxylic acid ul19 9-fluoro-2,3-dihydro-3-methyl-10-(4-n-butyl-1-piperazinyl)-7
-okine-7H-pyrido(I,2,3-de)(I,4
) Benzoxacin-6-carlinic acid q7) 9-fluoro-2,3-dihydro-3-methyl-
10-(4-ethyl-1-piperazinyl)-7-okine-7H-pyrido[1°2,3-de) (I,4
) Benzoxacin-6-carboxylic hydrochloride hemihydrate (mp285-290C (min'S)) )-7-okine-7H-pyrido(I,2,3-de)[1,4,]
] Benzoxacin-6-carvone r hemihydrate (I13S-9-7hI:I-2,3-dihydro-3
-Methyl-10-(4-hydroxy-1-piperidinyl)-7-okine-7H-pyrido(I,2,3-deJI
:1,4) Benzoxacin-6-carboxylic acid General formula (I) of the present invention Nogiri de C1,2,3-de J
[1,4] Benzoxacin derivative has a 10-position substituent X
Due to its basicity, it can also be used as an acid addition salt. Examples of acid addition salts include inorganic salts such as hydrochloride, hydrobromide, hydroiodide, and sulfuric acid. Examples include organic acid salts such as acetic acid, 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ってもよく、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。Furthermore, when R is a hydrogen atom, the carboxyl group at position 6 in formula (I) may be in the form of a salt, such as alkali metal salts such as sodium salts and potassium salts; magnesium salts, calcium salts, etc. 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〕（Ｉ，４
，）ベンゾオキサシ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, pyrido[1,2,3-de](I,4
,) Benzoxacin derivatives or salts thereof can also be used in the form of hydrates.
また、本発明化合’ａｔ （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３８体を利
用することもできる。Further, the compound 'at (I) of the present invention has several optical isomers, and not only the racemic form but also the 38-isomer can be used.
一般式（Ｉ）のピリド（Ｉ，２，３−ｄｅ〕［１，４］
ベンゾオキサシン訪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６２−２５２７９０号には３８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。Pyrido (I,2,3-de][1,4] of general formula (I)
Most of the benzoxacin visiting conductors are, for example, disclosed in Japanese Patent Application Laid-open No. 57-
46986 and JP-A No. 58-72589 as a racemate, and JP-A No. 62-252790 as a 38-form compound, which is known per se, and can be produced according to the methods described in these publications. can do.
成上の式（Ｉ）の化合物、もしくはその塩又は七の水和
＊＜以下、単に「粘性化合物（■）」と略称する）を魚
介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４故中に魚介類を楽浴させる方法（魚介
類を１定時間浸漬する）等があり％場合によっては、注
射によシ投与することも可能である。As a method for administering the compound of the above formula (I), or a salt thereof, or a hydrated compound (hereinafter simply referred to as "viscous compound (■)") to seafood, the active compound (I) is There are methods such as oral administration directly or by mixing with feed, and methods of bathing seafood in active compound (I) (soaking seafood for a certain period of time), etc. Depending on the case, Administration by injection is also possible.
活性化合物（Ｉ）を魚介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寺により異な
るが、一般的には１日当たり魚体＊ １ ｘｙに対し１
〜２００ｍｙ、好ましくは５〜１００Ｑ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。When using active compound (I) as an antibacterial agent for seafood, the dosage varies depending on the purpose of administration (prevention or treatment), the type and size of the fish to be treated, and the degree of infection, but in general is the number of fish per day * 1 for xy
~200my, preferably in an amount ranging from 5 to 100Q
It can be administered once a day or in divided doses.
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ｏＴ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って元号な効果を
得ることができる。However, of course, the above dosage is just a guideline, and it is also possible to administer an amount outside the above range depending on the age, weight, medical condition, etc. of the fish. There is also no particular restriction on the period of administration, but significant effects can usually be obtained by administration for about 1 to 10 days.
活性化合物（Ｉ）を魚介ｙＡに投与するだめの製剤とし
ては、この分封において通常用いられる技術により通宜
敢削、ｆＡ粒剤、ｏＪ’Ｆ＃故剤、シロツゾ剤、浴液あ
るいは注射剤とすることかでさる。以下にその代表的な
製４＋１処万例を記す。The preparations for administering the active compound (I) to seafood yA can be prepared according to the techniques normally used in this packaging, such as fA granules, oJ'F# decomposition, cilantro, bath solution, or injection. The monkey is the one who does it. Below is a typical example of 4+1 production.
製剤例１（ｖ＠科混合用敢刑）：
活性化付切（Ｉ）１〜１０重量部
とうもろこし澱粉 ９８．５〜８９．５ ＃＠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 ｓｉ ９９〜９０ ｌ計
１００ ｌ
製剤例３（Ｉ！Ａ料混合用又は薬浴用液剤）：活性化合
物（■）１〜１０重量部
酢 酸 ５〜２０ ｌノ９
ラオキシ安息香酸エチル ０．１１梢 製
水 ６９．９〜９３．９ １計
１００ ｌ
〔発明の効果〕
本発明によシ提供される抗菌剤は、魚介類の感染症の原
因となる各種の細菌及び水虫菌に対して広範囲な活性を
有しておシ、例えばエロモナス属、ニドワードシェラ属
、ノｑスツレラ属、シュードモナス属、連鎖球菌域、ビ
ブリオ属等の細菌に対して強力な抗菌作用を発揮する。Formulation example 1 (v@medical mixed use): Activated cut (I) 1-10 parts by weight Corn starch 98.5-89.5 #@Quality silicic anhydride 0.5〃Total 100
〃 Formulation Example 2 (Soluble powder for feed mixing or medicated bath): Active compound (I) 1-10 parts by weight (water-soluble) Milk si 99-90 l Total 100 l Formulation example 3 (I!A mixture) Liquid preparation for use or medicinal bath): Active compound (■) 1 to 10 parts by weight Acetic acid 5 to 20 parts by weight
Ethyl laoxybenzoate 0.11 Kozue Water 69.9-93.9 1 total
[Effects of the Invention] The antibacterial agent provided by the present invention has a wide range of activity against various bacteria and athlete's foot fungi that cause infectious diseases of fish and shellfish, such as Aeromonas spp. It exhibits a strong antibacterial effect against bacteria such as , Nidwardsiella spp., Noqstrella spp., Pseudomonas spp., Streptococcus spp., and Vibrio spp.
従ってプリ類、ツナギ、アユ、コイ、サケ、マス類など
の海水又は淡水性の養殖魚やアワピなどの貝類、ノリ・
コンブなどの海藻類、エビ類あるいは金魚、熱帯魚など
の観賞魚の感染症の予防、治療、処置に際して有用であ
る。Therefore, seawater or freshwater cultured fish such as puri, cutlet, sweetfish, carp, salmon, trout, shellfish such as Awapi, seaweed, etc.
It is useful in the prevention, treatment, and treatment of infectious diseases in seaweed such as kelp, shrimp, and ornamental fish such as goldfish and tropical fish.
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 explained in more detail with reference to Examples.
実施例１
各植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誉して、その培−＃液（菌数約ｘｏ
８ｍ／−）の一定量をあらかじめ各濃度段階の試験化合
物を添加しである１、５〜ｚＯ％塩化ナトリウム官有ミ
ューラーヒＸトン寒天（Ｉ）ｉｆｃｏ） 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 each plant pathogen: Each test bacterial strain was cultured overnight, and the culture solution (number of bacteria was approximately xo
A fixed amount of 8m/-) was inoculated onto a plate of 1.5-zO% sodium chloride-proprietary Mueller's X-ton agar (I) to which the test compound at each concentration level had been added in advance, and incubated at 28-30°C. The minimum concentration of test compound that inhibited the growth of the inoculum after 24-48 hours of incubation, the minimum inhibitory concentration (MIC), was determined. The results are shown in Table 1 below. The test compounds used were 1 to 9 and 19 in Table 2.
以下余白
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
ド酸に比較し萬い抗菌活性を示した。As shown in the margins below, representative active compound (I) exhibited greater antibacterial activity in an in vitro antibacterial activity test compared to the control compounds oxolinic acid and pyromidic acid.
以下余白
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。Margins below Example 2 The minimum inhibitory concentrations of test compounds 10 to 18 in Table 2 were investigated in the same manner as in Example 1, except that the test bacterial strains were changed. The results are shown in Table 3.
以下余白 実施例３ 。Below margin Example 3.
マウス静脈内投与における試験化合物の急性毒性（ＬＤ
ｓｏ ）二
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、急性猷
性を調べた。Acute toxicity (LD) of test compound upon intravenous administration in mice
So) Compounds 5.7.9.11 and 13, which are two representative test compounds, were administered intravenously to mice to examine acute vulnerabilities.
実験方法＝５週岬のＳｌｃ ： ｄｄｙマウス（雄。Experimental method = 5 weeks Cape Slc: ddy mouse (male.
体！ＩＬ２ｓ〜２９．６ Ｆ ）を用い、検体をＱ、
ｌ Ｎ −ＮａＯＨで浴解佼、Ｑ、ＩＮ−ＭＣＩでｐＨ
を調整し、精製氷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硅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。body! IL2s~29.6F), the sample was Q,
Bath dissolved with lN-NaOH, pH with Q, IN-MCI
was prepared, diluted with purified ice to a predetermined concentration, and then inoculated into the tail vein of mice. In Test 1, 6 mice were used per group, and in Test 2, 10 mice were used per group. The test results are shown in Table 4.
第４表−Ａ 急性毒性値（ＬＪ）５６、−ｒウス、ｉｖ
）以下余白
第４表−Ｂ 急性毒性ＩＩ （Ｌａ）ｓｏ 、 マウス
＊ｉｖ）＊ 投与後日数で、表中の数字は死亡四欽。Table 4-A Acute toxicity value (LJ) 56, -rus, iv
) Margin below Table 4-B Acute Toxicity II (La)so, Mouse *iv)* Numbers in the table are the number of days after administration, and the number is the number of deaths.
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ＬＤｓｏ １ｌｌｉはそれぞれ次の通り算定された。From the results shown in Table 4, the LDso 1lli in intravenous administration of the test compound to mice was calculated as follows.
化合物１３ ２００〜３００ ＩＩ９／に９＃９３００
〜４００１ｙ ／ Ｋｐ
ｐ ７ ５０ｍｇ／Ｌｙ以下
＃ １１ ３００〜４００１９／Ｌ９＃ ５ ４
００ａｇ／時以上
実施例４
類Ｍ節症人工感染ブリにおける経口投与効果：
病魚よシ分離した類結節症病原困ノＱスツレラ・ビシシ
ダを生理食塩水に懸濁して、平均体重９０ｔのプリ稚魚
に体重１００ｔにつき０．０１畔の菌量になるように背
部筋内内に注射して人工感染した。感染３時間後よシ化
合ｖｌｊ８を６．３ 、３．１ 、１．６ 、０．８ｍ
９／Ｋｌ魚体重になるようにモイストペレットに混合し
て１日１回５日間自由摂飼で投与した。試験は２５〜２
６℃の水温で実施し、投薬終了後１０日間劇祭した結果
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ｖｔＪ８は魚体内においても優れた効果を発揮し
た。Compound 13 200-300 II9/Ni9#9300
~4001y/Kp p7 50mg/Ly or less #11 300~40019/L9 #5 4
00ag/hour or more Example 4 Effect of oral administration on artificially infected Yellowtail with M-like Nodular disease: Separated from diseased fish, the Nodular-like disease-causing Q. Sturella bisicida was suspended in physiological saline, and the average weight of the yellowtail was 90 tons. Artificial infection was performed by injecting the bacteria into the back muscle at a bacterial load of 0.01 per 100 tons of body weight. 3 hours after infection, compound vlj8 at 6.3, 3.1, 1.6, 0.8 m
The fish were mixed with moist pellets at a weight of 9/Kl fish and administered once a day for 5 days with free feeding. The exam is 25-2
Table 5 shows the results of the test conducted at a water temperature of 6° C. for 10 days after the end of the drug administration. As is clear from these results, the compound vtJ8 of the present invention exhibited excellent effects even within the fish body.
以下余白
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、Ｑスッレラ・ビシシ
ダを１０’ ＣＦＵ／−浮遊させた菌液に平均体重２１
．６ ｔのプ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３．２ ｍｇ／にノ魚体
■、対照系としてオキソリン酸を３０ｊ１ｇ／Ｋｊｌ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ｌＯ日間観祭した結果を第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＃）優れた効果を示した。Below is the margin Example 5 Oral administration effect on artificially infected yellowtail with nodular disease: The average body weight of 21 kg was added to a bacterial solution in which 10' CFU/- of Q sullella biscicida, a nodular disease pathogen isolated from diseased fish, was suspended.
．． 6 t of Puri fry were exposed to bacteria and artificially infected. Three hours after infection, Compound 8 was added to the fish body at 6.3 or 3.2 mg/kg, and as a control, oxolinic acid was mixed into the feed at a rate of 30g/Kjl fish body weight, and then forced once a day for 5 days. administered. The test was carried out at a water temperature of 23 to 25°C, and the test results were observed for 10 days after the end of the administration, and the results are shown in Table 6. As is clear from these results, Compound 8 of the present invention exhibited superior effects in the fish body compared to oxolinic acid.
実施例６
類結節症人工感染ブリにおける袖口投与効果：
病魚より分離した類結節症病原菌、ｅスツレラ・ビシシ
ダを１０４ ＣＦＵ／−浮遊させた菌液に平均体ｉｉｓ
、ａｒのプリ稚魚を菌浴させ人工感染した。感染３時間
後よシ化合ｖｌＪ９および化合＄１３をそれぞれ１！５
，６．３，３．２ｍｙ ／ Ｋｆ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
６５〜２７、７０の水温で実施し、投系終了後１０日間
症祭した結果を第７表に示す。この結果から明らかな如
く、本発明の化合′９ＩＪ９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 Effect of cuff administration on artificially infected yellowtail with tuberculoid disease: The average body mass of E. strella biscicida isolated from diseased fish was suspended in 104 CFU/-.
, ar puri fry were exposed to bacteria and artificially infected. 3 hours after infection, administered 1 to 5 doses of compound vlJ9 and compound $13, respectively.
, 6.3, 3.2 my/Kf fish weight was mixed with food and then forcefully administered once a day for 5 days. The exam is 24
Table 7 shows the results of experiments conducted at water temperatures of 65 to 27 and 70 degrees Celsius and 10 days after the end of the system injection. As is clear from these results, Compound '9IJ9 and Compound 13 of the present invention showed excellent effects in the fish body.
実施例７
ビブリオ柄人工感染アユにおける経口投与効果：
ビブリオ病病原圀ビブリオ・アンギララムを１％食塩水
中に７Ｘ１０’／−浮遊させた菌液に、平均体重４０ｒ
のアユを菌浴させ人工感染した。感染３時間後よシ化合
物８を１Ｏ９３、２ｍｙ ／に２魚体重、対照薬として
オキソリン酸を３２ 、１ ｏｍｇ／ｋｔ魚体■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日間銭祭した結果
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？！１８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 Effect of oral administration on Vibrio stalk artificially infected sweetfish: Vibrio disease pathogen Vibrio anguillarum was suspended in 1% saline solution at 7×10'/- to a bacterial solution containing an average weight of 40 r.
Ayu were bathed in bacteria and artificially infected. Three hours after infection, Compound 8 was mixed with the feed at a concentration of 1 O93, 2 my/kt/kt fish body weight, and oxolinic acid was mixed with the feed as a control drug at a concentration of 32,1 omg/kt fish body weight, and the mixture was forcibly administered once a day for two days. The test was conducted at a water temperature of 24°C, and the test results were shown in Table 8 after 10 days of infection. As is clear from this result, the compound of the present invention? ! No. 18 also showed excellent effects against Vibrio disease bacteria in fish bodies.
実施例８
、ｅラコロ病人工感染ウナギにおける経口投与効果：
ノＱラコロ病病涼菌エドワルドゾエラ・タルダを生理食
塩水に懸濁させて平均体重６２−Ｏ２の二ホンウナギに
２ Ｘ ｌ ０７ ＣＦＵ／尾となるよう腹腔内注射し
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゜０．６３１９／に９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 Ｃの水温で実施し、感染後１４
日間観祭した結果を第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、ｅラコロ調病原菌に対し
ても優れた効果を示した。Example 8, Effect of oral administration in eels artificially infected with Lakoro disease: NoQ Lakoro disease bacterium Edwardzoella tarda was suspended in physiological saline and administered to Japanese eels with an average weight of 62-O2 at 2 X l 07 CFU. Artificial infection was performed by intraperitoneal injection to obtain a tail. Compound 8 at 10.5 hours after infection
,2. ．． 5.1.25°0.6319/9 fish was mixed with feed to give a weight of 9 fish, and the mixture was forcibly administered once a day for two days. The test was carried out at a water temperature of 23.5-23.7 C and 14 hours after infection.
The results of the day-long festival are shown in Table 9. As is clear from these results, the compound of the present invention also showed excellent effects against E. lacoro pathogenic bacteria.
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, synthesis examples of compounds 10 and 17 among the active compounds used in the above examples are shown for reference.
合成例Ａ
エタノール１２−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−オキンー７Ｈ−ピリド（Ｉ，２，３−ｄｅ）［
１，４）ベンゾオキサシン−６−カルボン酸１．８？お
：び濃硫酸２．４２を加え７時間攪拌還流する。Synthesis Example A 9-Fluoro-2°3-dihydro-3-methyl-10-(4-ethyl-1-piperazinyl)-7-okine-7H-pyrido(I,2,3-de)[
1,4) Benzoxacin-6-carboxylic acid 1.8? Add 2.42 g of concentrated sulfuric acid and stir and reflux for 7 hours.
冷鏝、水冷下で水２５ｍ７！を加え、１０％ＮａＯＨで
ｐＨ１１〜１２としクロロホルムで抽出する。Cold iron, 25m7 of water under water cooling! was added, adjusted to pH 11-12 with 10% NaOH, and extracted with chloroform.
クロロホルムノーを水況（２回）し亡硝で乾燥し、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
キンー７Ｈ−ピリド（Ｉ、２、３−ｄｅ ）（Ｉ，４）
ベンゾオキサシン−６−カルボン酸エチルエステル１．
１？が得られる。If chloroform is washed with water (twice), dried with distilled nitrogen, the solvent is distilled off, and recrystallized from aqueous ethanol, the melting point is 240~
9-Fluoro-2<3-dihydro-3-methyl-10-(4-ethyl-1-piperazinyl)-7-okine-7H-pyrido(I,2,3-de)(I,4) at 243°C
Benzoxacin-6-carboxylic acid ethyl ester 1.
1? is obtained.
元素分析値
Ｃ２ＬＨ２６０４Ｎ３Ｆとしての
理論１ｉ ： Ｃ、６Ｚ５１ ；Ｈ，６，５０；Ｎ、
１０．４１実測値： Ｃ，６２，５４；ｌ（，６，５５
ｉＮ、１０．３９合成例Ｂ
エタノール５〇−中に９−フルオロ−２゜３−ジヒドロ
−３−メチル−１０−（４−エチル−１−１？−ｅラゾ
二ル） −７−オキンー７Ｈ−ピリド［１，２，３−ｄ
ｅ〕（Ｉ，４］ベンゾオキサシン−６−カルボンｖｚｏ
ｔおよび濃塩酸２．０−を加え、加熱して溶解させる。Theory 1i as elemental analysis value C2LH2604N3F: C, 6Z51; H, 6,50; N,
10.41 Actual value: C,62,54;l(,6,55
iN, 10.39 Synthesis Example B 9-fluoro-2゜3-dihydro-3-methyl-10-(4-ethyl-1-1?-e lazonyl)-7-okine-7H in ethanol 5〇- -pyrido[1,2,3-d
e](I,4]benzoxacin-6-carvone vzo
Add 2.0-t and concentrated hydrochloric acid and heat to dissolve.
減圧下で過剰のエタノールを濃縮し、析出晶をＰ取、エ
タノールで況＃後含水エタノールから再結晶すれば融点
２８５〜２９０℃＜分Ｓ＞０９−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−オキンー７Ｈ−ピリド［１，２，３−ｄ
ｅ Ｊ［１，４Ｊベンゾオキサシン−６−カルボン酸塩
酸塩ヘミノ１イドレート１．３９が得られる。Excess ethanol is concentrated under reduced pressure, the precipitated crystals are collected, heated with ethanol, and then recrystallized from aqueous ethanol to give a melting point of 285-290°C<minS>09-fluoro-2,3-dihydro-3-methyl. -10-(4-ethyl-1-piperazinyl)-7-okine-7H-pyrido[1,2,3-d
e J[1,4J benzoxacin-6-carboxylic hydrochloride heminoliderate 1.39 is obtained.
元素分析値
Ｃ，，１（２２０４Ｎ３Ｆ−ＨＣｌ・０．５）１２０と
しての理調１直： Ｃ、５４，２２；）ｉ、 ５．７５
；Ｎ、 ９．９８実測値： Ｃ，５４，２０；ｉ−１
，５，７９；Ｎ、９．８５以上Elemental analysis value C,, 1 (2204N3F-HCl・0.5) 1st shift of barbershop as 120: C, 54, 22;)i, 5.75
;N, 9.98 Actual value: C,54,20;i-1
,5,79;N,9.85 or more
Claims (1)
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、Ｒ＿１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
しくは異なつた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
それら水和物を有効成分とする水産用抗菌剤。[Claims] 1. The following formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, X is a lower alkylamino group, or ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (However, Y is a hydrogen atom or a lower alkyl group, Z is a methylene group, methine group, oxygen atom, sulfur atom, or nitrogen atom; R_1 is a hydrogen atom, a lower alkyl group, a formyl group, or an alkanoyl alkyl group when Z is a nitrogen atom. In the case of a methine group, it represents a lower alkyl group, a hydroxyl group, n and m are the same or different integers of 1 to 3), and R is a hydrogen atom. or a lower alkyl group] pyrido[1,2,3-de] [1,4] An antibacterial agent for marine products containing a benzoxazine derivative, a salt thereof, or a hydrate thereof as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62324397A JPH0826029B2 (en) | 1987-12-22 | 1987-12-22 | Preventive and therapeutic agents for fish infectious diseases |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62324397A JPH0826029B2 (en) | 1987-12-22 | 1987-12-22 | Preventive and therapeutic agents for fish infectious diseases |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH01165589A true JPH01165589A (en) | 1989-06-29 |
| JPH0826029B2 JPH0826029B2 (en) | 1996-03-13 |
Family
ID=18165337
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP62324397A Expired - Lifetime JPH0826029B2 (en) | 1987-12-22 | 1987-12-22 | Preventive and therapeutic agents for fish infectious diseases |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0826029B2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000050428A1 (en) * | 1999-02-24 | 2000-08-31 | Samsung Electronics Co., Ltd. | Process for preparing (-)pyridobenzoxazine carboxylic acid derivatives |
Citations (2)
| 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 |
-
1987
- 1987-12-22 JP JP62324397A patent/JPH0826029B2/en not_active Expired - Lifetime
Patent Citations (2)
| 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 |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6316618B1 (en) | 1998-02-24 | 2001-11-13 | Samsung Electronics Co., Ltd. | Process for preparing (-)pyridobenzoxazine carboxylic acid derivatives |
| WO2000050428A1 (en) * | 1999-02-24 | 2000-08-31 | Samsung Electronics Co., Ltd. | Process for preparing (-)pyridobenzoxazine carboxylic acid derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0826029B2 (en) | 1996-03-13 |
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