JP3650199B2 - Antifungal agent and composition containing the same - Google Patents
Antifungal agent and composition containing the same Download PDFInfo
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- JP3650199B2 JP3650199B2 JP34919495A JP34919495A JP3650199B2 JP 3650199 B2 JP3650199 B2 JP 3650199B2 JP 34919495 A JP34919495 A JP 34919495A JP 34919495 A JP34919495 A JP 34919495A JP 3650199 B2 JP3650199 B2 JP 3650199B2
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- 239000012871 anti-fungal composition Substances 0.000 title claims description 10
- 229940121375 antifungal agent Drugs 0.000 title claims description 9
- 239000003429 antifungal agent Substances 0.000 title claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 31
- 150000003839 salts Chemical class 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 8
- 238000003898 horticulture Methods 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical group C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 229940125904 compound 1 Drugs 0.000 description 11
- 241000196324 Embryophyta Species 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 230000000843 anti-fungal effect Effects 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 239000002609 medium Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 206010017533 Fungal infection Diseases 0.000 description 5
- 240000007594 Oryza sativa Species 0.000 description 5
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- OOLYZFSILFGXCC-GQCTYLIASA-N (e)-1-bromo-6,6-dimethylhept-2-en-4-yne Chemical compound CC(C)(C)C#C\C=C\CBr OOLYZFSILFGXCC-GQCTYLIASA-N 0.000 description 2
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- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
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- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
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- MZSAMHOCTRNOIZ-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-phenylaniline Chemical group NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(NC2=CC=CC=C2)C=CC=1 MZSAMHOCTRNOIZ-UHFFFAOYSA-N 0.000 description 1
- AUEIOPXLEWSKBS-JTQLQIEISA-N 4-[(5s)-5-(acetamidomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluoro-n-methylbenzamide Chemical compound C1=C(F)C(C(=O)NC)=CC=C1N1C(=O)O[C@@H](CNC(C)=O)C1 AUEIOPXLEWSKBS-JTQLQIEISA-N 0.000 description 1
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- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
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- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
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- SZJQXQICJDHRJE-UHFFFAOYSA-N [3-(bromomethyl)phenyl]-phenylmethanone Chemical compound BrCC1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 SZJQXQICJDHRJE-UHFFFAOYSA-N 0.000 description 1
- WJALQGDUKNPCNE-UHFFFAOYSA-N [3-(methylaminomethyl)phenyl]-phenylmethanone Chemical compound CNCC1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 WJALQGDUKNPCNE-UHFFFAOYSA-N 0.000 description 1
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- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Description
【０００１】
【発明の属する技術分野】
本発明は新規化合物、当該新規化合物からなる抗真菌剤及びこれらを含有する抗真菌組成物に関する。
【０００２】
【従来の技術】
農園芸に於いて、植物の真菌に由来する病気はこれらの真菌を除去するのが困難なため大きな問題となっている。これは、未だに稲の栽培に於いて稲熱病の発生が不作の原因になっていることからも明かである。又、植物に寄生する真菌の内には、中毒性産物を産生し食中毒を起こすもの、又産生物が強いアレルゲンであるものなど人間にとっても好ましからぬものが少なくない。この為、多くの人々によって、様々な稲熱病をはじめとする植物真菌症の為の薬剤の開発が試みられ、多くの薬物が開発されたが、これらの植物真菌症への著しい効果のあるものは得られていなかった。即ち、新規の抗真菌剤が求められていたのである。
【０００３】
一方、後記一般式（Ｉ）に表される化合物は何れも新規化合物である。又、これらの化合物と類似構造の化合物としては、構造式２に示すテルビナフィンが知られているが、テルビナフィンはトリコフィトン等の動物の真菌症の原因菌に対して抗真菌作用を有することは知られているが、植物の真菌症の病原菌に対する作用は知られていない。
【０００４】
【化３】
【０００５】
【発明が解決しようとする課題】
本発明は、この様な状況のもとに為されたものであり、新規の植物の真菌症の予防と治療に好適な化合物を提供することを課題とする。
【０００６】
【課題を解決するための手段】
この様な状況に鑑み、本発明者等は抗真菌作用を有する新規化合物を求めて、鋭意、合成・スクリーニングの研究を重ねた結果、一般式（Ｉ）に示す化合物にその様な作用を見いだし、発明を完成させた。以下、本発明について詳細に説明する。
【０００７】
【化３】
（但し、ここでＡｒはベンゾフェノン残基を表し、Ｒ 1 はメチレン基を表わし、Ｒ 2 は６，６−ジメチル−２−ヘプテン−４−イン−１−イル基を表わし、Ｒ 3 は炭素数１〜４のアルキル基を表わす。）
【０００８】
（１）本発明の化合物
本発明の化合物は、上記一般式（Ｉ）に示す構造を有する。この様な化合物は何れも文献未記載の新規化合物である。この様な本発明の化合物を具体的に例示するならば、例えば、トランス−３−（６，６−ジメチル−２−ヘプテン−４−イン−１−イル）−Ｎ−メチル−３−アミノメチルベンゾフェノン（化合物１）、シス−３−（６，６−ジメチル−２−ヘプテン−４−イン−１−イル）−Ｎ−メチル−３−アミノメチルベンゾフェノン（化合物２、構造式３）等が挙げられる。これらの内最も好ましいものは構造式１に示される、トランス−３−（６，６−ジメチル−２−ヘプテン−４−イン−１−イル）−Ｎ−メチル−３−アミノメチルベンゾフェノン（化合物１）である。これらの化合物は次のような手順で合成できる。即ち、化７に示す様に、３−メチルベンゾフェノンをＮ−ブロモサクシイミド等のブロモ化剤でブロモ化シ、３−ブロモメチルベンゾフェノンと為し、これをメチルアミンと反応させ、３−（アミノメチル）ベンゾフェノンと為し、１−ブロモ−６，６−ジメチル−２−ヘプテン−４−インと反応させれば、化合物１と化合物２の混合物が得られ、これをシリカゲルカラムクロマトグラフィー等の通常の手段で精製すれば容易にこれら２つが分離できる。
【０００９】
【化５】
【００１０】
【化６】
【００１１】
【化７】
（２）本発明の抗真菌剤
本発明の抗真菌剤は上記一般式（Ｉ）に表される化合物及び／又は生理的に許容されるこれらの塩からなる。生理的に許容される塩としては、通常医薬品で用いられている酸の塩であれば特段の限定を受けずに用いることが出来る。この様な酸としては、塩酸、硫酸、硝酸、燐酸等の鉱酸塩、クエン酸、乳酸、蓚酸等の有機酸等が好ましく例示できる。本発明の上記一般式（Ｉ）に表される化合物は何れも、植物の病原真菌に対して優れた抗真菌作用を有する。又、後記実施例に示すように優れた安全性も有する。
【００１３】
（３）本発明の抗真菌組成物
本発明の抗真菌組成物は、上記一般式（Ｉ）に表される化合物及び／又は生理的に許容されるこれらの塩を含有することを特徴とする。本発明の抗真菌組成物の種類としては、園芸用の消毒剤、植物の真菌症の予防のための農薬、植物の真菌症の治療のための農薬などが好ましく例示できる。本発明のこれらの植物の真菌症の治療のための抗真菌組成物が適用しうる疾病は、例えば、アルテルナリア属の真菌（Alternaria sp.）による、稲の稲熱病、綿、木瓜、隠元豆等のクロロシス、芍薬、杉、唐松等の芽枯病、リンゴ斑点病、ヘルミントスポリウム属（Helminthosporiumu sp.）によるトウモロコシごま葉枯病等である。これらの内、本発明の抗真菌組成物が好ましく処置しうるのは、アルテルナリア属の真菌（Alternariasp.）による、稲の稲熱病、綿、木瓜、隠元豆、唐松等の芽枯病である。本発明の抗真菌組成物は一般式（Ｉ）に表される化合物及び／又は生理的に許容されるこれらの塩以外に、通常前記農園芸用の組成物で用いられる任意成分を含有することが出来る。この様な任意成分としては、溶媒、界面活性剤、安定剤、ｐＨ調整剤、増粘剤、紫外線吸収剤、抗酸化剤等である。他の抗真菌剤を配合しても構わない。本発明の抗真菌組成物における一般式（Ｉ）に示される化合物及び／又は生理的に許容されるこれらの塩の好ましい含有量は、０．０１〜２０重量％であり、０．１〜１５重量％がより好ましく、０．５〜１０重量％が更に好ましい。一般式（Ｉ）に表される化合物及び／又は生理的に許容されるこれらの塩はただ一種を含有させても良いし、二種以上を含有させても良い。
【００１４】
【発明の実施の形態】
以下に例を挙げて、発明の実施の形態について詳細に説明するが、本発明がこれら実施の形態の例にのみ限定されないことは言うまでもない。
【００１５】
（例１）製造例（化合物１及び２）
四塩化炭素９０ｍｌに３−メチルベンゾフェノン９．７ｇ、Ｎ−ブロモサクシイミド８．８ｇ、過酸化ベンゾイル０．１５ｇを溶解させ、３時間加熱還流し、反応物を濃縮し、シリカゲルカラムクロマトグラフィーで精製し（溶出溶媒；ヘキサン：酢酸エチル＝２０：１→４：１）黄色オイル状化合物を７．３１ｇ得た。このもの４．９３ｇをメタノール４０ｍｌに懸濁し、これを予め氷冷しておいた４０％メチルアミン−メタノール溶液に氷冷しながら加えた。混合物を室温に戻し１７時間攪拌した後、減圧濃縮した。これに１Ｎの塩酸を加え溶解し、この溶液をジエチルエーテルで２回洗浄し、３ＮのＮａＯＨでアルカリ性にし、ジエチルエーテル１００ｍｌで２回抽出した。これを溶媒溜去し、シリカゲルカラムクロマトグラフィーで精製し（溶出溶媒；クロロホルム：メタノール＝１００：１→５０：１）２．１６ｇの３−（メチルアミノメチル）ベンゾフェノンを得た。このものの１．５３ｇをジメチルホルムアミド１０ｍｌに溶解させ、炭酸ナトリウム０．７４５ｇを加えた。これを氷冷下攪拌しながら、１−ブロモ−６，６−ジメチル−２−ヘプテン−４−インの１．２８をジメチルホルムアミド１．５ｍｌに溶かしたものを滴下した。室温に戻して２０時間反応させた後、ジメチルホルムアミドを溜去し水とジエチルエーテルを加えて抽出し、ジエチルエーテルの層を取り、水で洗浄した。これを濃縮し、シリカゲルカラムクロマトグラフィーで精製し（溶出溶媒；ヘキサン：酢酸エチル＝１０：１→５：１）化合物１を１．１０ｇと化合物２を０．３８ｇ得た。ＮＭＲ（δｐｐｍ）は次に示すとおりであった。
（化合物１）１．２４（９Ｈ，ｓ）、２．２０（３Ｈ，ｓ）、３．０６（２Ｈ，ｄｄ）、３．５５（２Ｈ，ｓ）、５．６５（１Ｈ，ｄｔ）、６．０７（１Ｈ，ｄｔ）、７．４〜７．８５（９Ｈ，ｍ）
（化合物２）１．２４（９Ｈ，ｓ）、２．２４（３Ｈ，ｓ）、３．２９（２Ｈ，ｄｄ）、３．５９（２Ｈ，ｓ）、５．６３（１Ｈ，ｄｔ）、５．９４（１Ｈ，ｄｔ）、７．４〜７．８７（９Ｈ，ｍ）
化合物１の１．１ｇを酢酸エチル３．５ｍｌに溶解させ、４Ｎの塩酸の酢酸エチル溶液０．８８ｍｌを加え、室温で１５分間攪拌し析出した結晶にジエチルエーテルを加え濾取しジエチルエーテルで洗浄し、乾燥させて１．０５ｇのトランス−３−（６，６−ジメチル−２−ヘプテン−４−イン−１−イル）−Ｎ−メチル−３−アミノメチルベンゾフェノンの塩酸塩を得た。ＮＭＲは次に示すとおりであった。
（化合物１の塩酸塩）１．２５（９Ｈ，ｓ）、２．６６（３Ｈ，ｄ）、３．５〜３．６５（１Ｈ，ｍ）、３．６８〜３．８５（１Ｈ，ｍ）、４．０８（１Ｈ，ｄｄ）、４．３３（１Ｈ，ｄｄ）、５．８７（１Ｈ，ｄ）、６．２８（１Ｈ，ｄｔ）７．５２（２Ｈ，ｍ）、７．６４（２Ｈ，ｔ）、７．７５〜７．９（４Ｈ，ｍ）、８．２４（１Ｈ，ｄ）、１３．１３（１Ｈ，ｂ）
【００１６】
（例２）配合例（園芸用消毒剤）
以下に示す成分を８０℃で加熱溶解し、冷却して園芸用消毒剤を得た。
ヒビテングルコネート ０．１ 重量部
化合物１ ５ 重量部
カルボキシメチルセルロース ０．０１重量部
水 ９４．８９重量部
【００１７】
【実施例】
実施例１
安全性
化合物１の１０％ワセリン軟膏を背部を剃毛したハートレー系白色種モルモット（雌性、３００〜４００ｇ）６匹に２４時間クローズドパッチした。パッチ除去後１時間に皮膚反応をドレーズの基準（−：無反応、±：微弱な紅斑、＋：明瞭な紅斑、＋＋：浮腫を伴う反応）に従って判定した。結果は何れの動物も−（無反応）であった。これより本発明の化合物は安全性が高いことが判る。
【００１８】
実施例２
抗菌作用
化合物１について寒天平板希釈法により抗真菌作用を最小発育阻止濃度（ＭＩＣ)として測定した。即ち、病原真菌としてアルテルナリア・アルテルナータＴＩＭＭ１２８９（Alternaria alternata TIMM1289）を用い、これを増殖用培地で培養した後、分生子数を１０5個／ｍｌに調整し、予め１００μｇ／ｍｌより２倍希釈して各種濃度の化合物１を含んだサブロー培地に５μｌ接種した。化合物１はメタノール溶液にして培地に配合し、以後は培地で希釈して培地に含有させた。２８℃、７日間培養し、目視にて観察し完全に発育が阻止された最小濃度をＭＩＣとした。対照には構造式２に表されるテルビナフィンを用いた。結果は、化合物１が２５μｇ／ｍｌであったのに対し、テルビナフィンは１００μｇ／ｍｌでも発育が阻止されていなかった。これより本発明の抗真菌剤は植物の病原真菌に対して優れた抗真菌作用を有することが判る。
【００１９】
実施例３
抗菌作用
トリコフィトンに対する化合物１の抗真菌作用も実施例２と同様に求めた。即ち、トリコフィトン・メンタグロファイテス（T.mentagrophytes TIMM1189）及びトリコフィトン・ラブラム（T.rubrum IFO5808）をそれぞれ予めサブロー寒天培地の斜面に２７℃で２週間培養して分生子を充分つくらせる。これをツィーン８０を０．０５重量／容量％含有する滅菌生理食塩水で白金耳で擦りながら洗浄し分生子を浮遊させる。これを二枚重ねのガーゼで濾過し分生子のみを生理食塩水に浮遊する形で取り出した。分生子の濃度を１０5個／ｍｌになるように調整し試験菌菌液とした。一方、化合物１を４ｍｇとり、ジメチルスルホキサイド１ｍｌを加え原液とし、これを順次ジメチルスルホキサイドで２倍希釈し希釈薬剤液を調整した。組織培養用９６穴マイクロプレートの各ウェルにサブロー・デキストロース培地１７５μｌ、薬剤溶液５μｌ、試験菌菌液２０μｌを加え、良く混和した後、２７℃で１週間培養し目視にて完全に発育を阻止する最小濃度を探し、最小生育阻止濃度とした。結果は、トリコフィトン・メンタグロファイテス（T.mentagrophytes TIMM1189）に対しては、１２．５μｇ／ｍｌ、トリコフィトン・ラブラム（T.rubrum IFO5808）に対しては６．２５μｇ／ｍｌであった。これより、本発明の化合物はトリコフィトンに対しても優れた抗菌作用を有していることが判る。即ち、本発明の化合物には広い抗真菌スペクトルが期待できる。
【００２０】
【発明の効果】
本発明によれば、植物の病原真菌に対して優れた抗真菌作用を有する新規化合物が提供できる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a novel compound, an antifungal agent comprising the novel compound, and an antifungal composition containing these.
[0002]
[Prior art]
In agriculture and horticulture, diseases derived from plant fungi are a major problem because it is difficult to remove these fungi. This is clear from the fact that rice fever is still a cause of crop failure in rice cultivation. In addition, among fungi parasitic on plants, there are many things that are unfavorable for humans, such as those that produce toxic products and cause food poisoning, and those whose products are strong allergens. For this reason, many people have tried to develop drugs for phytomycosis, including various rice fever diseases, and many drugs have been developed, but these have significant effects on phytomycosis. Was not obtained. That is, a new antifungal agent has been demanded.
[0003]
On the other hand, any of the compounds represented by the general formula (I) described later is a novel compound. Further, terbinafine represented by structural formula 2 is known as a compound having a similar structure to these compounds, but terbinafine is known to have antifungal action against the causative fungi of animals such as trichophyton. However, its effect on pathogenic fungi of plant mycosis is not known.
[0004]
[Chemical 3]
[0005]
[Problems to be solved by the invention]
The present invention has been made under such circumstances, and an object of the present invention is to provide a compound suitable for the prevention and treatment of a novel plant mycosis.
[0006]
[Means for Solving the Problems]
In view of such circumstances, the present inventors have sought for a novel compound having antifungal activity, and as a result of intensive research on synthesis and screening, have found such an effect on the compound represented by the general formula (I). , Completed the invention. Hereinafter, the present invention will be described in detail.
[0007]
[Chemical 3]
(Wherein Ar represents a benzophenone residue, R 1 represents a methylene group, R 2 represents a 6,6-dimethyl-2-hepten-4-in-1-yl group, and R 3 represents a carbon number) Represents an alkyl group of 1 to 4 )
[0008]
(1) Compound of the present invention The compound of the present invention has a structure shown in the general formula (I). Such compounds are all novel compounds not described in any literature . Specific examples of a compound of such invention This, for example, trans-3- (6,6-dimethyl-2-heptene-4-yn-1-yl) -N- methyl-3-amino Methylbenzophenone (compound 1), cis-3- (6,6-dimethyl-2-hepten-4-in-1-yl) -N-methyl-3-aminomethylbenzophenone (compound 2, structural formula 3), etc. Can be mentioned. The most preferred of these is trans-3- (6,6-dimethyl-2-hepten-4-in-1-yl) -N-methyl-3-aminomethylbenzophenone (compound 1) as shown in Structural Formula 1. ). These compounds can be synthesized by the following procedure. That is, as shown in Chemical formula 7, 3-methylbenzophenone is brominated with 3-bromobenzoicone such as N-bromosuccinimide and 3-bromomethylbenzophenone, and this is reacted with methylamine to give 3- (amino Methyl) benzophenone and reaction with 1-bromo-6,6-dimethyl-2-hepten-4-yne gives a mixture of compound 1 and compound 2, which is usually used for silica gel column chromatography and the like. These two can be easily separated if purified by the means described above.
[0009]
[Chemical formula 5]
[0010]
[Chemical 6]
[0011]
[Chemical 7]
(2) Antifungal Agent of the Present Invention The antifungal agent of the present invention comprises the compound represented by the above general formula (I) and / or physiologically acceptable salts thereof. The physiologically acceptable salt can be used without particular limitation as long as it is an acid salt usually used in pharmaceuticals. Preferred examples of such acids include mineral acid salts such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, and organic acids such as citric acid, lactic acid and succinic acid. Any of the compounds represented by the above general formula (I) of the present invention has an excellent antifungal action against plant pathogenic fungi. Further, as shown in the examples described later, it has excellent safety.
[0013]
(3) antifungal composition antifungal composition of the present invention of the present invention is characterized by containing these salts compounds and / or physiologically acceptable represented by the general formula (I) . Preferred examples of the antifungal composition of the present invention include horticultural disinfectants, agricultural chemicals for preventing plant mycosis, and agricultural chemicals for treating plant mycosis. Diseases to which the antifungal composition for the treatment of mycosis of these plants of the present invention can be applied are, for example, rice fever caused by Alternaria sp. Chlorosis, glaze, Japanese cedar, Karamatsu, etc., bud blight, apple spot disease, corn sesame leaf blight caused by Helminthosporiumu sp. Among these, the antifungal composition of the present invention can be preferably treated for rice fever caused by Alternaria genus (Alternariasp.), Bud blight diseases such as cotton, tree culm, hidden peas, and Karamatsu. The antifungal composition of the present invention contains, in addition to the compound represented by the general formula (I) and / or physiologically acceptable salts thereof, optional components usually used in the composition for agriculture and horticulture. I can do it. Examples of such optional components include a solvent, a surfactant, a stabilizer, a pH adjuster, a thickener, an ultraviolet absorber, and an antioxidant. You may mix | blend another antifungal agent . The preferred content of these salts are generally compounds shown in (I) and / or physiologically acceptable in the antifungal composition of the present invention is 0.01 to 20 wt%, 0.1 to 15 % By weight is more preferable, and 0.5 to 10% by weight is still more preferable. The compound represented by the general formula (I) and / or physiologically acceptable salts thereof may contain only one kind or two or more kinds.
[0014]
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, embodiments of the invention will be described in detail with reference to examples, but it is needless to say that the present invention is not limited to only the examples of these embodiments.
[0015]
Example 1 Production Example (Compounds 1 and 2)
Dissolve 9.7 g of 3-methylbenzophenone, 8.8 g of N-bromosuccinimide, and 0.15 g of benzoyl peroxide in 90 ml of carbon tetrachloride, heat to reflux for 3 hours, concentrate the reaction, and purify by silica gel column chromatography. (Elution solvent; hexane: ethyl acetate = 20: 1 → 4: 1) 7.31 g of a yellow oily compound was obtained. 4.93 g of this product was suspended in 40 ml of methanol, and this was added to a 40% methylamine-methanol solution that had been ice-cooled in advance with ice-cooling. The mixture was returned to room temperature and stirred for 17 hours, and then concentrated under reduced pressure. This was dissolved by adding 1N hydrochloric acid, and the solution was washed twice with diethyl ether, made alkaline with 3N NaOH, and extracted twice with 100 ml of diethyl ether. The solvent was distilled off and the residue was purified by silica gel column chromatography (elution solvent: chloroform: methanol = 100: 1 → 50: 1) to obtain 2.16 g of 3- (methylaminomethyl) benzophenone. 1.53 g of this was dissolved in 10 ml of dimethylformamide, and 0.745 g of sodium carbonate was added. A solution prepared by dissolving 1.28 of 1-bromo-6,6-dimethyl-2-hepten-4-yne in 1.5 ml of dimethylformamide was added dropwise while stirring under ice cooling. After returning to room temperature and reacting for 20 hours, dimethylformamide was distilled off and extracted by adding water and diethyl ether, and the diethyl ether layer was taken and washed with water. This was concentrated and purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 10: 1 → 5: 1) to obtain 1.10 g of Compound 1 and 0.38 g of Compound 2. NMR (δppm) was as shown below.
(Compound 1) 1.24 (9H, s), 2.20 (3H, s), 3.06 (2H, dd), 3.55 (2H, s), 5.65 (1H, dt), 6 .07 (1H, dt), 7.4-7.85 (9H, m)
(Compound 2) 1.24 (9H, s), 2.24 (3H, s), 3.29 (2H, dd), 3.59 (2H, s), 5.63 (1H, dt), 5 .94 (1H, dt), 7.4-7.87 (9H, m)
Dissolve 1.1 g of Compound 1 in 3.5 ml of ethyl acetate, add 0.88 ml of 4N hydrochloric acid in ethyl acetate, stir at room temperature for 15 minutes, add diethyl ether to the precipitated crystals, filter and wash with diethyl ether And dried to obtain 1.05 g of trans-3- (6,6-dimethyl-2-hepten-4-in-1-yl) -N-methyl-3-aminomethylbenzophenone hydrochloride. NMR was as follows.
(Hydrochloride of Compound 1) 1.25 (9H, s), 2.66 (3H, d), 3.5 to 3.65 (1H, m), 3.68 to 3.85 (1H, m) 4.08 (1H, dd), 4.33 (1H, dd), 5.87 (1H, d), 6.28 (1H, dt) 7.52 (2H, m), 7.64 (2H) , T), 7.75 to 7.9 (4H, m), 8.24 (1H, d), 13.13 (1H, b)
[0016]
(Example 2) Formulation example (horticultural disinfectant)
The components shown below were dissolved by heating at 80 ° C. and cooled to obtain a horticultural disinfectant.
Hibiten gluconate 0.1 parts by weight Compound 1 5 parts by weight Carboxymethylcellulose 0.01 parts by weight Water 94.89 parts by weight
【Example】
Example 1
A safety compound 1 10% petrolatum ointment was closed patched to 6 Hartley white guinea pigs (female, 300-400 g) shaved on the back for 24 hours. One hour after the removal of the patch, the skin reaction was determined according to the criteria for drazing (-: no reaction, ±: weak erythema, +: clear erythema, ++: reaction with edema). The result was-(no response) for all animals. This shows that the compound of the present invention is highly safe.
[0018]
Example 2
The antifungal activity of antibacterial compound 1 was measured as the minimum inhibitory concentration (MIC) by the agar plate dilution method. Specifically, Alternaria alternata TIMM1289 (Alternaria alternata TIMM1289) was used as a pathogenic fungus, and after culturing it in a growth medium, the number of conidia was adjusted to 10 5 cells / ml, and it was diluted twice from 100 μg / ml in advance. Then, 5 μl was inoculated into Sabouraud medium containing various concentrations of Compound 1. Compound 1 was made into a methanol solution and mixed with the medium, and thereafter diluted with the medium and contained in the medium. The culture was incubated at 28 ° C. for 7 days, visually observed, and the minimum concentration at which growth was completely inhibited was defined as MIC. Terbinafine represented by Structural Formula 2 was used as a control. As a result, Compound 1 was 25 μg / ml, whereas terbinafine was not inhibited from growing even at 100 μg / ml. This shows that the antifungal agent of the present invention has an excellent antifungal action against pathogenic fungi of plants.
[0019]
Example 3
Antifungal action of Compound 1 against antibacterial action trichophyton was also determined in the same manner as in Example 2. That is, T. mentagrophytes TIMM1189 and T. rubrum IFO5808 are each preliminarily cultured on the slope of Sabouraud agar medium at 27 ° C. for 2 weeks to sufficiently produce conidia. This is washed with a sterilized physiological saline containing 0.05 wt / vol% of Tween 80 while rubbing with a platinum loop to float the conidia. This was filtered through two layers of gauze and only the conidia were taken out in a form floating in physiological saline. The concentration of conidia was adjusted to 10 5 cells / ml to obtain a test bacterial cell solution. On the other hand, 4 mg of Compound 1 was taken, and 1 ml of dimethyl sulfoxide was added to make a stock solution, which was successively diluted 2-fold with dimethyl sulfoxide to prepare a diluted drug solution. Add 175 μl of Sabouraud dextrose medium, 5 μl of the drug solution, and 20 μl of the test bacterial solution to each well of the 96-well microplate for tissue culture, mix well, then incubate at 27 ° C. for 1 week to completely prevent growth. The minimum concentration was searched and used as the minimum growth inhibition concentration. The result was 12.5 μg / ml for Trichophyton mentagrophytes TIMM1189 and 6.25 μg / ml for Trichophyton labrum (T.rubrum IFO5808). This shows that the compound of the present invention has an excellent antibacterial action against trichophyton. That is, the compound of the present invention can be expected to have a broad antifungal spectrum.
[0020]
【The invention's effect】
ADVANTAGE OF THE INVENTION According to this invention, the novel compound which has the outstanding antifungal action with respect to the pathogenic fungi of a plant can be provided.
Claims (5)
（但し、ここでＡｒはベンゾフェノン残基を表し、Ｒ1 はメチレン基を表し、Ｒ2 は６，６−ジメチル−２−ヘプテン−４−イン−１−イル基を表し、Ｒ3は炭素数１〜４のアルキル基を表す。）A compound represented by formula (I).
(Where, Ar represents a benzophenone residue, R 1 represents a methylene group, R 2 represents a 6,6-dimethyl-2-hepten-4-in-1-yl group, and R 3 represents a carbon number. Represents 1 to 4 alkyl groups.)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP34919495A JP3650199B2 (en) | 1995-12-20 | 1995-12-20 | Antifungal agent and composition containing the same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP34919495A JP3650199B2 (en) | 1995-12-20 | 1995-12-20 | Antifungal agent and composition containing the same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH09169710A JPH09169710A (en) | 1997-06-30 |
| JP3650199B2 true JP3650199B2 (en) | 2005-05-18 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP34919495A Expired - Fee Related JP3650199B2 (en) | 1995-12-20 | 1995-12-20 | Antifungal agent and composition containing the same |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3650199B2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2247675C (en) * | 1998-09-17 | 2009-05-05 | Pola Chemical Industries, Inc. | Antifungal agents |
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1995
- 1995-12-20 JP JP34919495A patent/JP3650199B2/en not_active Expired - Fee Related
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| Publication number | Publication date |
|---|---|
| JPH09169710A (en) | 1997-06-30 |
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