JP3703009B2 - Bacterial signaling inhibitor - Google Patents

Description

(式中、
Ｒは、水素原子、炭素数１〜２０のアルキル基、炭素数２〜２０のアルケニル基または炭素数２〜２０のアルキニル基を示し、
Ｒ₁、Ｒ₂、Ｒ₃、Ｒ₄、Ｒ₅およびＲ₆は、それぞれ独立して、水素原子、炭素数１〜２０のアルキル基、炭素数２〜２０のアルケニル基、炭素数２〜２０のアルキニル基、炭素数１〜２０のアルコキシ基、炭素数２〜２０のアルケニルオキシ基または炭素数２〜２０のアルキニルオキシ基を示すか、または、Ｒ₁およびＲ₂、Ｒ₃およびＲ₄、および、Ｒ₅およびＲ₆は、それぞれ独立して、一緒になってエポキシ環を形成するか、または、結合を形成してもよく、
破線は、一重結合または二重結合を示し、
Ｘは、ハロゲンを示す）
で示される化合物またはその塩、および、該化合物またはその塩を含有するヒスチジンキナーゼ阻害剤を提供する。
本発明はまた、式（Ｉ）で示される化合物の製造方法を提供する。
【０００６】
【発明の実施の形態】
一般式（Ｉ）のＲ、Ｒ₁、Ｒ₂、Ｒ₃、Ｒ₄、Ｒ₅およびＲ₆における炭素数１〜２０のアルキル基とは、直鎖もしくは分枝鎖のアルキル基を包含し、メチル、エチル、ｎ−プロピル、イソプロピル、ｎ−ブチル、イソブチル、sec−ブチル、tert−ブチル、ｎ−ペンチルなどを挙げることができ、炭素数１〜１０のものが好ましく、炭素数１〜５のものが特に好ましい。
【０００７】
炭素数２〜２０アルケニル基とは、直鎖もしくは分枝鎖のアルケニル基を包含し、ビニル、プロぺニル、イソプロぺニル、ブテニル、イソブテニル、プレニル、ブタジエニル、ペンテニル、イソペンテニル、ペンタジエニルなどを挙げることができ、炭素数１〜１０のものが好ましく、炭素数１〜５のものが特に好ましい。
【０００８】
炭素数２〜２０アルキニル基とは、直鎖もしくは分枝鎖のアルキニル基を包含し、エチニル、ｎ−プロピニル、ｎ−ブチニル、ｎ−ペンチニル、イソペンチニルなどを挙げることができ、炭素数１〜１０のものが好ましく、炭素数１〜５のものが特に好ましい。
【０００９】
炭素数１〜２０のアルコキシ基とは、上記したアルキル基を有する基を包含し、例えば、メトキシ、エトキシ、ｎ−プロポキシ、イソプロポキシ、ｎ−ブトキシ、イソブトキシ、ｓｅｃ−ブトキシ、ｔｅｒｔ−ブトキシ、ｎ−ペントキシなどを挙げることができ、炭素数１〜１０のものが好ましく、炭素数１〜５のものが特に好ましい。
【００１０】
炭素数２〜２０のアルケニルオキシとは、上記したアルケニル基を有する基を包含し、例えば、ビニルオキシ、ｎ−プロペニルオキシ、ｎ−ブテニルオキシ、イソブテニルオキシ、ｓｅｃ−ブテニルオキシ、ｎ−ペンテニルオキシ、イソペンテニルオキシ、ブタジエニルオキシ、ペンタジエニルオキシなどを挙げることができ、炭素数１〜１０のものが好ましく、炭素数１〜５のものが特に好ましい。
【００１１】
低級アルキニルオキシとは、上記したアルキニル基を有する基を包含し、例えば、エチニルオキシ、ｎ−プロピニルオキシ、ｎ−ブチニルオキシ、ｎ−ペンチニルオキシおよびイソペンチニルオキシなどを挙げることができ、炭素数１〜１０のものが好ましく、炭素数１〜５のものが特に好ましい。
ハロゲンとは、臭素、塩素、フッ素またはヨウ素を意味し、特に臭素が好ましい。
【００１２】
本発明の式（Ｉ）で示される化合物としては、例えば、１１−ブロモ−４，４，７−トリメチル−２，６，１０−ドデカトリエン酸メチル、１１−ブロモ−４，４，７−トリメチル−２，６，１０−ドデカトリエン酸エチル、１１−ブロモ−４，４，７−トリメチル−２，６，１０−ドデカトリエン酸オクチル、１１−ブロモ−４，４，７−トリメチル−２，６，１０−ドデカトリエン酸、１１−ブロモ−６，７−エポキシ−４，４，７−トリメチル−２，１０−ドデカジエン酸メチル、１１−ブロモ−６，７−エポキシ−４，４，７−トリメチル−２，１０−ドデカジエン酸エチル、１１−ブロモ−６，７−エポキシ−４，４，７−トリメチル−２，１０−ドデカジエン酸オクチル、１１−ブロモ−６，７−エポキシ−４，４，７−トリメチル−２，１０−ドデカジエン酸などが挙げられる。
【００１３】
式（Ｉ）で示される化合物のうち、式（Ｉａ）：
【化１０】

（式中、Ｒ、Ｒ₃、Ｒ₄およびＸは、式（Ｉ）における定義と同一である。）
で示される化合物が特に好ましい。
さらに特に好適な化合物としては、１１−ブロモ−６，７−エポキシ−４，４，７−トリメチル−２，１０−ドデカジエン酸および１１−ブロモ−４，４，７−トリメチル−２，６，１０−ドデカトリエン酸を挙げることができる。
【００１４】
式（Ｉ）の化合物は塩の形態で用いることもできる。式（Ｉ）の化合物の塩には、無機酸または有機酸、あるいは無機塩基または有機塩基との塩が含まれ、例えば、ナトリウム、カリウム、リチウム、バリウム、マグネシウム、マグネシウム、モノ、ジまたはトリアルキルアミンとの塩等が挙げられる。
また、式（Ｉ）の化合物が１またはそれ以上の不斉炭素原子を含有する場合、ラセミ体および光学活性な形態で存在してもよく、本発明の式（Ｉ）の化合物には、これらすべての異性体およびこれらの混合物が含まれる。
【００１５】
本発明の式（Ｉ）および（Ｉａ）の化合物は、東南アジアに広く自生する生姜の一種である南洋ハナショウガ（Zingiber zerumbet Smith）の精油成分中に含まれるゼルンボン（Zerumbone）を出発物質として、製造することができる。スキーム１に、式（Ｉａ）の化合物のうち、Ｘが臭素であり、Ｒ₃とＲ₄が一緒になってエポキシを形成する化合物、および、結合を形成する化合物の製造例を示す。
【００１６】
【化１１】

【００１７】
ゼルンボン（ＩＩ）は、南洋ハナショウガの根茎の水蒸気蒸留により、約０．５％の収率で単離することができる。ゼルンボンに、ＣＣｌ₄中の臭素を加えることにより、位置選択的に臭素化が起こり、１０，１１−ジブロモ−４，４，７，１１−テトラメチル−２，６−シクロウンデカジエノン（ＩＩＩ）を得る（ J. Org. Chem., Vol. 64, No. 8, 1999）。この臭素化では、主にトランス付加が起こる（トランス：シス＝９．２：０．８）。（ＩＩＩ）に、１％ＫＯＨ、ＣＨ₃ＣＮおよびα−シクロデキストリン（α−ＣＤ）を反応させると、１１員環が開環した１１−ブロモ−４，４，７−トリメチル−２，６，１０−ドデカトリエン酸（Ｉａ’）が得られる。この反応は、水酸基がカルボニル基へ求核攻撃した後、開裂して臭素が脱離するものと考えられる。
【００１８】
これとは別に、ゼルンボン（ＩＩ）に、ｍ−クロロ過安息香酸（ｍＣＰＢＡ）を反応させると、位置選択的にエポキシ化が起こり、６，７−エポキシ−２，６，９，９−テトラメチル−２，１０−シクロウンデカジエノン（ＩＶ）が得られる。これを臭素化すると、２，３位のみが反応し、１０，１１−ジブロモ−６，７−エポキシ−４，４，７，１１−テトラメチル−２−シクロウンデセノン（Ｖ）が得られる。この臭素化では、主にトランス付加が起こる（トランス：シス＝９：１）。これに１％ＫＯＨ、ＣＨ₃ＣＮおよびα−ＣＤを反応させると、１１員環が開環した１１−ブロモ−６，７−エポキシ−４，４，７−トリメチル−２，６，１０−ドデカトリエン酸（Ｉａ”）が得られる。この反応も、水酸基がカルボニル基へ求核攻撃した後、開裂して臭素が脱離するものと考えられる。
式（Ｉ）のその他の化合物は、スキーム１に示した反応および化学物質の製造において一般的な反応を適宜利用して、製造することができる。
【００１９】
式（Ｉ）の化合物は、以下の実施例において示すように、グラム陽性菌におけるＹｙｃＦおよびＹｙｃＧが関与する情報伝達系、特にセンサーであるＹｙｃＧのヒスチジンキナーゼ活性を阻害することにより、グラム陽性菌に対して抗菌活性を示す。これまでの抗菌剤のスクリーニング方法として、細菌の情報伝達機構である二成分制御系に着目したものはなく、したがって、本発明の抗菌剤は従来のものとは全く異なる新規な抗菌活性を有するものである。
【００２０】
式（Ｉ）の化合物を抗菌剤として用いる場合、式（Ｉ）の化合物またはその塩を、通常の経口または非経口製剤として用いてもよい。経口投与製剤としては、錠剤、カプセル剤、顆粒剤、散剤、シロップ剤、液剤などの種々の固形製剤、液体製剤を用いることができる。非経口投与としては、溶液、懸濁液、乳濁液などの注射剤、用時溶解または懸濁して使用する凍結乾燥または粉末状の製剤などを用いることができる。また、軟膏剤、パスタ剤などの経皮投与用製剤、坐剤等の非経口製剤を用いることもできる。
【００２１】
これらの製剤は、医薬品製剤における通常の担体、添加剤等を含有していてもよく、また、通常の方法により製造することができる。
式（Ｉ）の化合物を含有する医薬品製剤を投与する場合、その投与量は、患者の性別、年齢、体重、症状の重篤性などに応じて、適宜決定することができるが、経口投与の場合、式（Ｉ）の化合物を１日当たり０．０１〜１０００ｍｇ、好ましくは、０．１〜１０ｍｇ、非経口投与の場合、０．０００１〜１００ｍｇ、好ましくは０．０１〜１０ｍｇの量で投与する。
【実施例】
【００２２】
以下、実施例により本発明をさらに具体的に説明するが、本発明はこれに限定されるものではない。
実施例において、融点（ｍｐ）は修正していない。特記しない限り、ＮＭＲスペクトルは、内部標準としてテトラメチルシランを用い、ＣＤＣｌ₃中で、¹Ｈについては２７０ＭＨｚ、¹³Ｃについては５００ＭＨｚにて測定した。マススペクトルは、７０ｅｖにて記録し、高分解能マススペクトル（ＨＲＭＳ）は直接注入により測定した。特記しない限り、分析および分取ＨＰＬＣは、Wakosil-II 5C18 HC (158 x 8 mm) または Wakosil 5C18 HC (300 x 8 mm) のカラムに連結するシステムを用い、２１５ｎｍでモニターし、アセトニトリルおよび水（７：３）の混合物で溶出させて行った。用いた化学物質は、和光純薬工業（株）より購入した。
【００２３】
実施例１ ［２Ｅ，６Ｅ，１０（Ｅ／Ｚ）］−１１−ブロモ−４，４，７−トリメチル−２，６，１０−ドデカトリエン酸の製造
（１０Ｓ^*，１１Ｒ^*）−ジブロモ−４，４，７，１１−テトラメチル−２，６−シクロウンデカジエノン（３．１ｇ，８．２ｍｍｏｌ、J. Org. Chem., Vol. 64, No. 8, 1999に記載の方法にしたがって製造）、ＫＯＨ（０．８３ｇ，１４．８ｍｍｏｌ）およびα−ＣＤ（８．０ｇ，８．２ｍｍｏｌ）のアセトニトリルおよび水（それぞれ、４０ｍＬおよび４０ｍＬ）中溶液を室温にて５時間攪拌した。水（５０ｍＬ）を混合物中に加え、混合物をＨＣｌで酸性化した。酸性溶液をＥｔＯＡｃで抽出した（５０ｍＬｘ３回）。有機層を水（５０ｍＬｘ３回）および飽和水性ＮａＣｌ（５０ｍＬｘ２回）で洗浄し、無水硫酸ナトリウム上で乾燥させ、減圧下濃縮した。残渣をシリカゲル上カラムクロマトグラフィーに付し、溶離剤としてＣＨＣｌ₃およびメタノールの１５：１混合物を用いて、標記化合物を得た（２．８ｇ，９０％）。
IR (KBr) 3050, 1695, 1647 cm^-1; ¹H NMR: δ 1.07 (s, 6H, 2CH₃ at C4), 1.58 (s, 3H, CH₃ at C7), 2.20 (s, 3H, 3H at C12), 2,05-2.16 (m, 6H, 2H at C5, C8 および C9), 5.10 (dd, 1H, J = 7.6 および 8.9 Hz, H at C6), 5.73 (d, 1H, J = 15.9 Hz, H at C3), 5.77 (m, 1H, H at C10), 7.06 (d, 1H, J = 16.2 Hz, H at C2); ¹³C NMR: δ 16.0 (CH₃ at C7), 23.2 (C12), 25.9 (2CH₃ at C4), 28.1 (C9), 37.9 (C4), 39.0 (C8), 40.0 (C5), 117.1 (C3), 119,2 (C7), 120.8 (C6), 131.7 (C10), 136.6 (C11), 161.0 (C2), 172.7 (C1); HRMS m /z C₁₅H₂₂O₂Br についての計算値 (M-H) 313.0803, 実測値 313.0780.
【００２４】
実施例２ ［２Ｅ，６Ｅ，１０（Ｅ／Ｚ）］−１１−ブロモ−６，７−エポキシ−４，４，７−トリメチル−２，１０−ドデカジエン酸の製造
（ａ）６，７−エポキシ−２，６，９，９−テトラメチル−２，１０−シクロウンデカジエノン（ゼルンボン−オキシド）
塩化メチレン（５０ｍＬ）中のｍ−クロロ過安息香酸（ｍＣＰＢＡ，２．０ｇ，１２ｍｍｏｌ）の溶液を、同じ溶媒（３０ｍＬ）中のゼルンボン（２．２ｇ，１０ｍｍｏｌ、J. Org. Chem., Vol. 64, No. 8, 1999に記載の方法にしたがって製造）の攪拌溶液に−５℃にて徐々に加えた。混合物を３次間攪拌し、炭酸ナトリウム溶液（２０ｍＬ，５％）を加えた。有機層を分離し、無水硫酸ナトリウム上で乾燥させ、減圧下濃縮し、黄色結晶性固体を得た。この固体をヘキサン：酢酸エチル（ＥｔＯＡｃ）中で再結晶し、標記化合物を得た（２．３ｇ，９９％）。
融点９６．０〜９６．５℃；
IR (KBr), 1657, 1263 cm^-1; ¹H NMR: δ 1.10 (s, 3H, CH₃ at C11), 1.22 (s, 3H, CH₃ at C3), 1.31 (s, 3H, CH₃ at C11), 1.27-1.36 (m, 1H, H at C4), 1.45 (dd, 1H, J = 11.3 および 14.0 Hz, H at C1), 1.85 (s, 3H, CH₃ at C7), 1.93 (d, 1H, J = 14.0 Hz, H at C1), 2.26-2.43 (m, 3H, H at C3 および 2H at C4), 2.72 (dd, 1H, J = 1.4 および 11.3 Hz, H at C2), 6.07-6.1 2 (m, 3H, 3H at C6, C9 および C10); ¹³C NMR: δ 12.3 (CH₃ at C7), 15.8 (CH₃ at C3), 23.9 (CH₃ at C11), 24.8 (C5), 30.0 (CH₃ at C11), 36.1 (C11), 38.2 (C4), 42.8 (C1), 61.2 (C3), 62.8 (C2), 128.6 (C9), 139.3 (C7), 147.6 (C6), 159.3 (C10), 202.3 (C8); C₁₅H₂₂O₂ について計算値: C, 76.88; H, 9.46; 実測値: C, 76.96; H, 9.41
【００２５】
（ｂ）（１０Ｓ^*，１１Ｒ^*）−ジブロモ−６，７−エポキシ−４，４，７，１１−テトラメチル−２−シクロウンデセノン
ＣＣｌ₄（１０ｍＬ）中の臭素（０．７５ｇ，４．７ｍｍｏｌ）をＣＣｌ₄（５ｍＬ）中の６，７−エポキシ−２，６，９，９−テトラメチル−２，１０−シクロウンデカジエノン（１．０ｇ，４．３ｍｍｏｌ）の攪拌溶液に−１５〜−１０℃にて滴下した。¹ＨＮＭＲにより、ゼルンボン中の不飽和Ｃ３プロトンの存在を測定することにより臭素の添加を滴定した。溶液を減圧下濃縮し、結晶性（１０Ｓ^*，１１Ｒ^*）−ジブロモ−６，７−エポキシ−４，４，７，１１−テトラメチル−２−シクロウンデセノン（１．６９ｇ，９５％）をトランス：シス＝５：１のジアステレオマー比で得た。固体をＥｔＯＡｃ：ヘキサンから再結晶し、１．４４ｇ（８５％）の標記化合物を得た。
IR (KBr), 2964, 1695, 1628 cm^-1; ¹H NMR: δ 1.10 (d, 1H, J = 9.0 Hz, H at C4), 1.12 (s, 3H, CH₃ at C11 ), 1 .20 (s, 3H, CH₃ at C3), 1.30 (dd, 1H, J = 6.0 および 11.5 Hz, H at C1), 1.30 (d, 1H, J = 6.5 Hz, H at C5), 1.32 (s, 3H, CH₃ at C11 ), 1.84 (s, 3H, CH₃ at C7), 1.92 (d, 1H, J = 6.0 Hz, H at C1), 2.10 (dd, 1H, 6.5 および 9.0 Hz, H at C6), 2.20 (d, 1H, J = 9.0 Hz, H at C4), 2.62 (d, 1H, J = 11.5 Hz, H at C2), 4.21 (d, 1H, J = 9.0 Hz, H at C6), 6.43 (d, 1H, J = 16.0 Hz, H at C10), 6.87 (d, 1H, J = 16.0 Hz, H at C9); ¹³C NMR: δ 17.1 (CH₃ at C11), 20.7 (CH₃ at C7), 23.5 (CH₃ at C11), 29.7 (CH₃ at C3), 31.3 (C5), 36.7 (C11), 36.8 (C4), 39.0 (C1), 59.9 (C2), 60.7 (C3), 62.4 (C6), 69.1 (C7), 124.3 (C9), 154.7 (C10), 192.8 (C8); Anal. calcd for C₁₅H₂₂O₂Br₂についての計算値: C, 45.71 ; H, 5.63;実測値: C 45.79; H. 5.64.
【００２６】
（ｃ）［２Ｅ，６Ｅ，１０（Ｅ／Ｚ）］−１１−ブロモ−６，７−エポキシ−４，４，７−トリメチル−２，１０−ドデカジエン酸
（１０Ｓ^*，１１Ｒ^*）−ジブロモ−６，７−エポキシ−４，４，７，１１−テトラメチル−２−シクロウンデセノン（１．２ｇ，３．０ｍｍｏｌ）、ＫＯＨ（０．３ｇ，５．４ｍｍｏｌ）およびα−ＣＤ（２．８ｇ，３，０ｍｍｏｌ）のアセトニトリルおよび水（それぞれ、１５ｍＬおよび１５ｍＬ）中溶液を室温にて５時間攪拌した。水（１５ｍＬ）を混合物中に加え、混合物をＨＣｌで酸性化した。酸性溶液をＥｔＯＡｃで抽出した（５０ｍＬｘ３回）。有機層を水（５０ｍＬｘ３回）および飽和水性ＮａＣｌ（５０ｍＬｘ２回）で洗浄し、無水硫酸ナトリウム上で乾燥させ、減圧下濃縮した。残渣をシリカゲル上カラムクロマトグラフィーに付し、溶離剤としてＣＨＣｌ₃およびメタノールの１５：１混合物を用いて、標記化合物を得た（０．９５ｇ，８０％）。
IR (KBr) 3070, 1697, 1651 cm^-1; ¹H NMR: δ 1.15 (s, 3H, CH₃ at C4), 1.18 (s, 3H, CH₃ at C4), 1.23 (s, 3H, CH₃ at trans C12), 1.26 (S, 3H, CH₃ at cis C12), 1.59 (dt, 2H, J = 6.6 および 7.9 Hz, H at C8), 1.68 (dd, 2H, J = 5.6 および 6.9 Hz, H at C5), 2.10 (dt, 2H, J = 7.6 および 7.9 Hz, H at trans C9), 2.23 (dt, 2H, J = 6.6 および 7.6 Hz, H at cis C9), 2.27 (s, 3H, CH₃ at C7), 2.69 (dd, 3H, J = 5.6 および 5.9 Hz, H at C6), 5.58 (dt, 1H, J = 1.3 および 6.6 Hz, H at cis C10), 5.78 (dt, 1H, J = 1.3 および 7.6 Hz, H at trans C10), 5.79 (d, 1H, J = 16.2 Hz, H at C3), 7.07 (d, 1H, J = 15.8 Hz, H at C2); ¹³C NMR: δ 16.6 (CH₃ at C12), 23.1 (CH₃ at C7), 25.1 (C9), 26.1 (CH₃ at C4), 27.0 (CH₃ at C4), 36.5 (C4), 37.7 (C5), 40.6 (C8), 59.4 (C7), 59.9 (C6), 118.1 (C3), 120.0 (C11), 131.0 (C10), 158.9 (C2), 171.7 (C1); C₁₅H₂₃O₃Br についての計算値: C, 54.39; H, 7.00;実測値: C, 54.21 ; H, 7.13.
【００２７】
実施例３ ヒスチジンキナーゼ阻害活性
枯草菌（B. subtilis）のＹｙｃＧに対する本願発明化合物の活性を調べた。
ヒスチジンキナーゼ活性の測定は、Biosci. Biotechnol. Biochem., 64, 919-923, 2000 に報告された方法にしたがって行った。ＹｙｃＧのキナーゼ活性ドメインのみを含む領域（Ｎ−末端から２０４番目のアミノ酸から６１１番目のアミノ酸を含む）をＰＣＲ法により枯草菌の染色体ＤＮＡから調製し、発現ベクターｐＱＥ３０にクローニングした。このようにして得られたプラスミドｐＱＥ３０−ＹｙｃＧを大腸菌に形質転換した株の培養液から、ＹｙｃＧのヒスチジンキナーゼ活性ドメインのみを発現させたタンパク質（ＹｙｃＧ−２０４−６１１）を精製した。ヒスチジンキナーゼ活性測定のための反応溶液の組成は、１０μＭ ＹｙｃＧ−２０４−６１１、５０ｍＭ Ｔｒｉｓ−ＨＣｌ（ｐＨ７．５）、５０ｍＭ ＫＣｌ、１０ｍＭ ＭｇＣｌ₂、２．５μＭ ＡＴＰであり、この反応溶液１０μｌに１０μＣｉの［γ−³²Ｐ］ＡＴＰを加え、反応を開始し、室温で１０分間インキュベート後、反応を終了させ、ＳＤＳ−ポリアクリルアミドゲル電気泳動を行うことにより、枯草菌のＹｙｃＧに対する５０％阻害濃度（ＩＣ₅₀）を求めた。
【００２８】
また、大腸菌（E. coli）および枯草菌に対する最小生育阻止濃度（ＭＩＣ）についても調べた。
ＭＩＣの測定には、液体培地希釈法を用いた。接種菌液としてＬＢ培地（Bacto tryptone １０ｇ、Bacto yeast extract ５ｇ、ＮａＣｌ １０ｇ／ｌ）で一昼夜培養した細菌を用いた。ＬＢ培地に薬剤濃度５００μｇ／ｍｌから順次２倍希釈系列を作成し、それらに接種菌液を１０⁶細胞／ｍｌとなるように植菌し、３７℃にて一昼夜培養後、完全に増殖が阻止されている最小濃度を記録した。
前記スキーム１中の化合物（ＩＩ）、（ＩＩＩ）、（ＩＶ）、（Ｖ）、（Ｉａ’）および（Ｉａ”）について調べた結果を表１に示す。
【００２９】
【表１】

【００３０】
実施例４ 薬剤耐性病原菌に対する作用
本願発明の式（Ｉａ’）の化合物の各種薬剤耐性病原菌に対するＭＩＣを調べた。ＭＩＣの測定は、実施例３と同様に行った。
調べた結果を表２に示す。
【００３１】
【表２】

【００３２】
実施例５ 本発明化合物を含有する医薬の処方例（注射剤）
化合物（Ｉａ’） １部
非イオン性界面活性剤 ２部
生理食塩水 ９７部
上記成分を加温混合後、滅菌して注射剤とした。
【００３３】
【発明の効果】
本発明の式（Ｉ）で示される化合物は、グラム陽性菌の二成分制御系であるＹｙｃＦおよびＹｙｃＧが関与する情報伝達系の阻害、特にセンサーであるＹｙｃＧのヒスチジンキナーゼを阻害することができ、グラム陽性菌に有効な抗菌剤として有用である。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a novel dodecanoic acid derivative, a histidine kinase inhibitor containing the compound, and a method for producing the compound.
[0002]
[Prior art]
Conventionally, many antibacterial agents have been used as therapeutic agents for bacterial infections. Many of the antibacterial agents known so far act by inhibiting bacterial nucleic acid synthesis, protein synthesis, peptidoglycan synthesis and the like. Since these target sites are single and mainly intended to inhibit the metabolic synthesis pathway, resistant bacteria to these antibacterial agents are likely to appear, and in recent years, in particular, they have many resistances to multiple antibiotics. The emergence of drug-resistant bacteria is a problem.
In recent years, Staphylococcus aureus, Streptococcus pneumoniae, etc., which are multi-drug resistant bacteria, which are a multidrug resistant bacterium, are Gram-positive bacteria. With the advent of these, development of new antibacterial agents (antibiotics) against Gram-positive bacteria by new screening different from conventional antibacterial agents is desired.
[0003]
In bacteria, on the other hand, receptors that accept changes in response to the environment and information transmission mechanisms that control the expression of each gene are known. A typical example is two-component systems. The two-component control system is an environmentally responsive gene expression control system composed of a sensor protein exhibiting histidine kinase activity and a regulator that is a DNA-binding protein. Bacteria are used in various ways to cope with various environmental changes. It has a sensor and a regulator (see Bioscience and Industry, Vol. 58, No. 4). As a two-component control system of Gram-positive bacteria, there is an information transmission system involving YycF (regulator) and YycG (sensor), and it is known that inhibition of this will kill the bacteria (Fablet, C. and Hoch, AA, J. Bacteriol., 180, 6375-6383, 1998, Marti, PK, Li, T., Sun, D., Biek, DP and Schmid, MB, J. Bacteriol., 181, 3666-3673, 1999, Lange, R., Wagner, C., DeSaizieu, A., Flint, N., Monos, J., Stiger, M., Caspers, P., Kamber, M., Keck wolfgang, Amrein, KE, Gene , 237, 223-234, 1999, Beier, D. and Frank, R., J. Bacteriol., 182, 2068-2076, 2000).
[0004]
[Problems to be solved by the invention]
The present invention has been made in view of the above prior art, and an object thereof is to provide an antibacterial agent effective against Gram-positive bacteria by using a screening method different from conventional antibiotics.
[0005]
[Means for Solving the Problems]
The present inventors have focused on the two-component control system, which is the main information transmission mechanism of bacterial cells, and as a result of extensive research, the information transmission system involving YycF and YycG, which are two-component control systems for Gram-positive bacteria. We succeeded in developing an antibacterial agent effective against Gram-positive bacteria by screening using the inhibition of histidine kinase of YycG as an index.
That is, the present invention relates to the formula (I):
[Chemical 9]

(Where
R represents a hydrogen atom, an alkyl group having 1 to 20 carbon atoms, an alkenyl group having 2 to 20 carbon atoms, or an alkynyl group having 2 to 20 carbon atoms,
R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are each independently a hydrogen atom, an alkyl group having 1 to 20 carbon atoms, an alkenyl group having 2 to 20 carbon atoms, or 2 to 20 carbon atoms. Or an alkynyl group having 1 to 20 carbon atoms, an alkenyloxy group having 2 to 20 carbon atoms, or an alkynyloxy group having 2 to 20 carbon atoms, or R ₁ and R ₂ , R ₃ and R ₄ , And R ₅ and R ₆ may each independently form an epoxy ring or form a bond,
The dashed line indicates a single bond or a double bond,
X represents halogen)
Or a salt thereof, and a histidine kinase inhibitor containing the compound or a salt thereof.
The present invention also provides a process for producing the compound represented by formula (I).
[0006]
DETAILED DESCRIPTION OF THE INVENTION
The alkyl group having 1 to 20 carbon atoms in R, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ in the general formula (I) includes a linear or branched alkyl group, Examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and the like, preferably those having 1 to 10 carbon atoms, and those having 1 to 5 carbon atoms. Those are particularly preferred.
[0007]
The alkenyl group having 2 to 20 carbon atoms includes linear or branched alkenyl groups such as vinyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl and the like. And those having 1 to 10 carbon atoms are preferred, and those having 1 to 5 carbon atoms are particularly preferred.
[0008]
The alkynyl group having 2 to 20 carbon atoms includes a straight-chain or branched alkynyl group, and examples thereof include ethynyl, n-propynyl, n-butynyl, n-pentynyl, isopentynyl and the like. The thing of C1-C5 is especially preferable.
[0009]
The alkoxy group having 1 to 20 carbon atoms includes a group having the above-described alkyl group. For example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n -A pentoxy etc. can be mentioned, A C1-C10 thing is preferable and a C1-C5 thing is especially preferable.
[0010]
The alkenyloxy having 2 to 20 carbon atoms includes a group having the above alkenyl group. For example, vinyloxy, n-propenyloxy, n-butenyloxy, isobutenyloxy, sec-butenyloxy, n-pentenyloxy, iso Examples thereof include pentenyloxy, butadienyloxy, pentadienyloxy and the like, preferably those having 1 to 10 carbon atoms, and particularly preferably those having 1 to 5 carbon atoms.
[0011]
Lower alkynyloxy includes the above-described group having an alkynyl group, and examples thereof include ethynyloxy, n-propynyloxy, n-butynyloxy, n-pentynyloxy, isopentynyloxy, and the like. The thing of 1-10 is preferable and a C1-C5 thing is especially preferable.
Halogen means bromine, chlorine, fluorine or iodine, with bromine being particularly preferred.
[0012]
Examples of the compound represented by the formula (I) of the present invention include methyl 11-bromo-4,4,7-trimethyl-2,6,10-dodecatrienoate, 11-bromo-4,4,7-trimethyl. -2,6,10-dodecatrienoic acid ethyl, 11-bromo-4,4,7-trimethyl-2,6,10-dodecatrienoic acid octyl, 11-bromo-4,4,7-trimethyl-2,6 , 10-dodecatrienoic acid, 11-bromo-6,7-epoxy-4,4,7-trimethyl-2,10-methyl dodecadienoate, 11-bromo-6,7-epoxy-4,4,7-trimethyl -2,10-dodecadienoic acid ethyl, 11-bromo-6,7-epoxy-4,4,7-trimethyl-2,10-dodecadienoic acid octyl, 11-bromo-6,7-epoxy-4,4,7 -Trimmer Such as Le 2,10 dodecadiene acid.
[0013]
Of the compounds represented by formula (I), formula (Ia):
[Chemical Formula 10]

(In the formula, R, R ₃ , R ₄ and X are the same as defined in formula (I).)
The compound shown by is especially preferable.
More particularly preferred compounds include 11-bromo-6,7-epoxy-4,4,7-trimethyl-2,10-dodecadienoic acid and 11-bromo-4,4,7-trimethyl-2,6,10. Mention may be made of dodecatrienoic acid.
[0014]
The compounds of formula (I) can also be used in the form of salts. Salts of compounds of formula (I) include inorganic acids or organic acids, or salts with inorganic bases or organic bases, such as sodium, potassium, lithium, barium, magnesium, magnesium, mono, di or trialkyl. Examples include salts with amines.
Also, when the compound of formula (I) contains one or more asymmetric carbon atoms, it may exist in racemic and optically active forms, and the compounds of formula (I) of the present invention include these All isomers and mixtures thereof are included.
[0015]
The compounds of the formulas (I) and (Ia) of the present invention are produced by using zerumbone, which is contained in the essential oil component of Zingiber zerumbet Smith, a kind of ginger widely growing in Southeast Asia as a starting material. can do. Scheme 1 shows a production example of a compound of formula (Ia) in which X is bromine, R ₃ and R ₄ together form an epoxy, and a compound that forms a bond.
[0016]
Embedded image

[0017]
Zerumbon (II) can be isolated in a yield of about 0.5% by steam distillation of Southern Ocean Ginger rhizomes. By adding bromine in CCl _{4 to} zerumbone, regioselective bromination occurs, and 10,11-dibromo-4,4,7,11-tetramethyl-2,6-cycloundecadienone (III) (J. Org. Chem., Vol. 64, No. 8, 1999). In this bromination, trans addition mainly occurs (trans: cis = 9.2: 0.8). When (III) is reacted with 1% KOH, CH ₃ CN and α-cyclodextrin (α-CD), 11-bromo-4,4,7-trimethyl-2,6 having an 11-membered ring opened. 10-dodecatrienoic acid (Ia ′) is obtained. In this reaction, it is considered that bromine is eliminated by cleavage after the nucleophilic attack on the carbonyl group.
[0018]
Separately, when zerumbone (II) is reacted with m-chloroperbenzoic acid (mCPBA), epoxidation occurs regioselectively and 6,7-epoxy-2,6,9,9-tetramethyl. -2,10-cycloundecadienone (IV) is obtained. When this is brominated, only the 2,3-positions react to give 10,11-dibromo-6,7-epoxy-4,4,7,11-tetramethyl-2-cycloundecenone (V). In this bromination, trans addition mainly occurs (trans: cis = 9: 1). When this was reacted with 1% KOH, CH ₃ CN and α-CD, 11-bromo-6,7-epoxy-4,4,7-trimethyl-2,6,10-dodeca with 11-membered ring opened. Trienoic acid (Ia ″) is obtained. This reaction is also considered to be brominated by cleavage after the nucleophilic attack of the hydroxyl group on the carbonyl group.
Other compounds of the formula (I) can be produced by appropriately utilizing the reactions shown in Scheme 1 and general reactions in the production of chemical substances.
[0019]
As shown in the following examples, the compound of the formula (I) inhibits the histidine kinase activity of YycG, a signal transduction system involving YycF and YycG in Gram-positive bacteria. Antibacterial activity is shown. No screening method for antibacterial agents so far has focused on the two-component control system, which is a bacterial information transmission mechanism. Therefore, the antibacterial agent of the present invention has a novel antibacterial activity that is completely different from conventional ones. It is.
[0020]
When the compound of formula (I) is used as an antibacterial agent, the compound of formula (I) or a salt thereof may be used as a normal oral or parenteral preparation. As a preparation for oral administration, various solid preparations such as tablets, capsules, granules, powders, syrups, and liquids, and liquid preparations can be used. For parenteral administration, injections such as solutions, suspensions, and emulsions, freeze-dried or powdered preparations that are dissolved or suspended at the time of use, and the like can be used. Also, preparations for transdermal administration such as ointments and pasta preparations and parenteral preparations such as suppositories can be used.
[0021]
These preparations may contain usual carriers, additives and the like in pharmaceutical preparations, and can be produced by ordinary methods.
When a pharmaceutical preparation containing a compound of formula (I) is administered, the dosage can be determined as appropriate according to the sex, age, weight, severity of symptoms, etc. of the patient. In the case, the compound of formula (I) is administered in an amount of 0.01 to 1000 mg per day, preferably 0.1 to 10 mg, in the case of parenteral administration, 0.0001 to 100 mg, preferably 0.01 to 10 mg. .
【Example】
[0022]
EXAMPLES Hereinafter, although an Example demonstrates this invention further more concretely, this invention is not limited to this.
In the examples, the melting point (mp) is not corrected. Unless otherwise specified, NMR spectra were measured at 270 MHz for ¹ H and 500 MHz for ¹³ C in CDCl ₃ using tetramethylsilane as an internal standard. Mass spectra were recorded at 70 ev and high resolution mass spectra (HRMS) were measured by direct injection. Unless otherwise noted, analytical and preparative HPLC were monitored at 215 nm using a system coupled to a Wakosil-II 5C18 HC (158 x 8 mm) or Wakosil 5C18 HC (300 x 8 mm) column, acetonitrile and water ( Elution with a mixture of 7: 3). The chemical substances used were purchased from Wako Pure Chemical Industries.
[0023]
Example 1 Preparation of [2E, 6E, 10 (E / Z)]-11-bromo-4,4,7-trimethyl-2,6,10-dodecatrienoic acid (10S ^* , 11R ^* )-dibromo-4 4,7,11-tetramethyl-2,6-cycloundecadienone (3.1 g, 8.2 mmol, prepared according to the method described in J. Org. Chem., Vol. 64, No. 8, 1999) ), KOH (0.83 g, 14.8 mmol) and α-CD (8.0 g, 8.2 mmol) in acetonitrile and water (40 mL and 40 mL, respectively) were stirred at room temperature for 5 hours. Water (50 mL) was added into the mixture and the mixture was acidified with HCl. The acidic solution was extracted with EtOAc (3 x 50 mL). The organic layer was washed with water (3 × 50 mL) and saturated aqueous NaCl (2 × 50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel using the 15: 1 mixture of CHCl ₃ and methanol as eluent to give the title compound (2.8 g, 90%).
IR (KBr) 3050, 1695, 1647 cm ^-1 ; ¹ H NMR: δ 1.07 (s, 6H, 2CH ₃ at C4), 1.58 (s, 3H, CH ₃ at C7), 2.20 (s, 3H, 3H at C12), 2,05-2.16 (m, 6H, 2H at C5, C8 and C9), 5.10 (dd, 1H, J = 7.6 and 8.9 Hz, H at C6), 5.73 (d, 1H, J = 15.9 Hz , H at C3), 5.77 (m, 1H, H at C10), 7.06 (d, 1H, J = 16.2 Hz, H at C2); ¹³ C NMR: δ 16.0 (CH ₃ at C7), 23.2 (C12) , 25.9 (2CH ₃ at C4), 28.1 (C9), 37.9 (C4), 39.0 (C8), 40.0 (C5), 117.1 (C3), 119,2 (C7), 120.8 (C6), 131.7 (C10) , 136.6 (C11), 161.0 (C2), 172.7 (C1); calculated for HRMS m / z C ₁₅ H ₂₂ O ₂ Br (MH) 313.0803, measured 313.0780.
[0024]
Example 2 Preparation of [2E, 6E, 10 (E / Z)]-11-bromo-6,7-epoxy-4,4,7-trimethyl-2,10-dodecadienoic acid (a) 6,7-epoxy -2,6,9,9-tetramethyl-2,10-cycloundecadienone (Zernbon-oxide)
A solution of m-chloroperbenzoic acid (mCPBA, 2.0 g, 12 mmol) in methylene chloride (50 mL) was added to zerumbone (2.2 g, 10 mmol, J. Org. Chem., Vol. 3) in the same solvent (30 mL). 64, No. 8, 1999) was gradually added at -5 ° C. The mixture was stirred for the third time and sodium carbonate solution (20 mL, 5%) was added. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a yellow crystalline solid. This solid was recrystallized in hexane: ethyl acetate (EtOAc) to give the title compound (2.3 g, 99%).
Melting point 96.0-96.5 ° C .;
IR (KBr), 1657, 1263 cm ^-1 ; ¹ H NMR: δ 1.10 (s, 3H, CH ₃ at C11), 1.22 (s, 3H, CH ₃ at C3), 1.31 (s, 3H, CH ₃ at C11), 1.27-1.36 (m, 1H, H at C4), 1.45 (dd, 1H, J = 11.3 and 14.0 Hz, H at C1), 1.85 (s, 3H, CH ₃ at C7), 1.93 (d, 1H, J = 14.0 Hz, H at C1), 2.26-2.43 (m, 3H, H at C3 and 2H at C4), 2.72 (dd, 1H, J = 1.4 and 11.3 Hz, H at C2), 6.07-6.1 2 (m, 3H, 3H at C6, C9 and C10); ¹³ C NMR: δ 12.3 (CH ₃ at C7), 15.8 (CH ₃ at C3), 23.9 (CH ₃ at C11), 24.8 (C5), 30.0 (CH ₃ at C11), 36.1 (C11), 38.2 (C4), 42.8 (C1), 61.2 (C3), 62.8 (C2), 128.6 (C9), 139.3 (C7), 147.6 (C6), 159.3 (C10 ), 202.3 (C8); Calculated for C ₁₅ H ₂₂ O ₂ : C, 76.88; H, 9.46; Found: C, 76.96; H, 9.41
[0025]
(B) Bromine (0.75 g, 4.R) in (10S ^* , 11R ^* )-dibromo-6,7-epoxy-4,4,7,11-tetramethyl-2-cycloundecenone CCl ₄ (10 mL). 7 mmol) to a stirred solution of 6,7-epoxy-2,6,9,9-tetramethyl-2,10-cycloundecadienone (1.0 g, 4.3 mmol) in CCl ₄ (5 mL) −15 It was dripped at -10 ° C. Bromine addition was titrated by measuring the presence of unsaturated C3 protons in zerumbone by ¹ H NMR. The solution was concentrated under reduced pressure to obtain crystalline (10S ^* , 11R ^* )-dibromo-6,7-epoxy-4,4,7,11-tetramethyl-2-cycloundecenone (1.69 g, 95%). Obtained in a diastereomeric ratio of trans: cis = 5: 1. The solid was recrystallized from EtOAc: hexanes to give 1.44 g (85%) of the title compound.
IR (KBr), 2964, 1695, 1628 cm ^-1 ; ¹ H NMR: δ 1.10 (d, 1H, J = 9.0 Hz, H at C4), 1.12 (s, 3H, CH ₃ at C11), 1.20 (s, 3H, CH ₃ at C3), 1.30 (dd, 1H, J = 6.0 and 11.5 Hz, H at C1), 1.30 (d, 1H, J = 6.5 Hz, H at C5), 1.32 (s, 3H , CH ₃ at C11), 1.84 (s, 3H, CH ₃ at C7), 1.92 (d, 1H, J = 6.0 Hz, H at C1), 2.10 (dd, 1H, 6.5 and 9.0 Hz, H at C6) , 2.20 (d, 1H, J = 9.0 Hz, H at C4), 2.62 (d, 1H, J = 11.5 Hz, H at C2), 4.21 (d, 1H, J = 9.0 Hz, H at C6), 6.43 (d, 1H, J = 16.0 Hz, H at C10), 6.87 (d, 1H, J = 16.0 Hz, H at C9); ¹³ C NMR: δ 17.1 (CH ₃ at C11), 20.7 (CH ₃ at C7 ), 23.5 (CH ₃ at C11), 29.7 (CH ₃ at C3), 31.3 (C5), 36.7 (C11), 36.8 (C4), 39.0 (C1), 59.9 (C2), 60.7 (C3), 62.4 ( C6), 69.1 (C7), 124.3 (C9), 154.7 (C10), 192.8 (C8); Calculated for Anal.calcd for C ₁₅ H ₂₂ O ₂ Br ₂ : C, 45.71; H, 5.63; measured : C 45.79; H. 5.64.
[0026]
(C) [2E, 6E, 10 (E / Z)]-11-bromo-6,7-epoxy-4,4,7-trimethyl-2,10-dodecadienoic acid (10S ^* , 11R ^* )-dibromo- 6,7-epoxy-4,4,7,11-tetramethyl-2-cycloundecenone (1.2 g, 3.0 mmol), KOH (0.3 g, 5.4 mmol) and α-CD (2.8 g) , 3, 0 mmol) in acetonitrile and water (15 mL and 15 mL, respectively) were stirred at room temperature for 5 hours. Water (15 mL) was added into the mixture and the mixture was acidified with HCl. The acidic solution was extracted with EtOAc (3 x 50 mL). The organic layer was washed with water (3 × 50 mL) and saturated aqueous NaCl (2 × 50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel using the 15: 1 mixture of CHCl ₃ and methanol as eluent to give the title compound (0.95 g, 80%).
IR (KBr) 3070, 1697, 1651 cm ^-1 ; ¹ H NMR: δ 1.15 (s, 3H, CH ₃ at C4), 1.18 (s, 3H, CH ₃ at C4), 1.23 (s, 3H, CH ₃ at trans C12), 1.26 (S, 3H, CH ₃ at cis C12), 1.59 (dt, 2H, J = 6.6 and 7.9 Hz, H at C8), 1.68 (dd, 2H, J = 5.6 and 6.9 Hz, H at C5), 2.10 (dt, 2H, J = 7.6 and 7.9 Hz, H at trans C9), 2.23 (dt, 2H, J = 6.6 and 7.6 Hz, H at cis C9), 2.27 (s, 3H, CH ₃ at C7), 2.69 (dd, 3H, J = 5.6 and 5.9 Hz, H at C6), 5.58 (dt, 1H, J = 1.3 and 6.6 Hz, H at cis C10), 5.78 (dt, 1H, J = 1.3 And 7.6 Hz, H at trans C10), 5.79 (d, 1H, J = 16.2 Hz, H at C3), 7.07 (d, 1H, J = 15.8 Hz, H at C2); ¹³ C NMR: δ 16.6 (CH ₃ at C12), 23.1 (CH ₃ at C7), 25.1 (C9), 26.1 (CH ₃ at C4), 27.0 (CH ₃ at C4), 36.5 (C4), 37.7 (C5), 40.6 (C8), 59.4 (C7), 59.9 (C6), 118.1 (C3), 120.0 (C11), 131.0 (C10), 158.9 (C2), 171.7 (C1); Calculated for C ₁₅ H ₂₃ O ₃ Br: C, 54.39; H, 7.00; found: C, 54.21; H, 7.13.
[0027]
Example 3 Histidine kinase inhibitory activity The activity of the compound of the present invention against B. subtilis YycG was examined.
The measurement of histidine kinase activity was performed according to the method reported in Biosci. Biotechnol. Biochem., 64, 919-923, 2000. A region including only the kinase active domain of YycG (including amino acids 204 to 611 from the N-terminal) was prepared from Bacillus subtilis chromosomal DNA by PCR and cloned into the expression vector pQE30. A protein (YycG-204-611) in which only the histidine kinase active domain of YycG was expressed was purified from the culture solution of the strain obtained by transforming the thus obtained plasmid pQE30-YycG into E. coli. The composition of the reaction solution for measuring histidine kinase activity was 10 μM YycG-204-611, 50 mM Tris-HCl (pH 7.5), 50 mM KCl, 10 mM MgCl ₂ , 2.5 μM ATP, and 10 μCi was added to 10 μl of this reaction solution. [Γ- ³² P] ATP was added, and the reaction was started. After incubation at room temperature for 10 minutes, the reaction was terminated, and SDS-polyacrylamide gel electrophoresis was performed, whereby the Bacillus subtilis 50% inhibitory concentration against YycG ( IC ₅₀ ) was determined.
[0028]
In addition, the minimum growth inhibitory concentration (MIC) for E. coli and Bacillus subtilis was also examined.
The liquid medium dilution method was used for the measurement of MIC. Bacteria cultured overnight in LB medium (Bacto tryptone 10 g, Bacto yeast extract 5 g, NaCl 10 g / l) were used as the inoculum. A series of two-fold dilutions were prepared in LB medium starting from a drug concentration of 500 μg / ml, and the inoculum was inoculated to 10 ⁶ cells / ml and cultured at 37 ° C. overnight to completely prevent growth. Recorded the minimum density.
Table 1 shows the results of investigation on the compounds (II), (III), (IV), (V), (Ia ′) and (Ia ″) in the scheme 1.
[0029]
[Table 1]

[0030]
Example 4 Action on drug-resistant pathogens The MIC of the compound of formula (Ia ') of the present invention against various drug-resistant pathogens was examined. The MIC measurement was performed in the same manner as in Example 3.
The examination results are shown in Table 2.
[0031]
[Table 2]

[0032]
Example 5 Formulation Example of Pharmaceutical Containing the Compound of the Present Invention (Injection)
Compound (Ia ′) 1 part nonionic surfactant 2 parts physiological saline 97 parts The above ingredients were heated and mixed, then sterilized to give an injection.
[0033]
【The invention's effect】
The compound represented by the formula (I) of the present invention can inhibit the signal transduction system involving YycF and YycG, which are two-component regulatory systems of Gram-positive bacteria, in particular, the histidine kinase of YycG, which is a sensor, It is useful as an antibacterial agent effective against gram-positive bacteria.

Claims (8)

Formula (I):

(Where
R represents a hydrogen atom, an alkyl group having 1 to 20 carbon atoms, an alkenyl group having 2 to 20 carbon atoms, or an alkynyl group having 2 to 20 carbon atoms,
R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are each independently a hydrogen atom, an alkyl group having 1 to 20 carbon atoms, an alkenyl group having 2 to 20 carbon atoms, or 2 to 20 carbon atoms. Or an alkynyl group having 1 to 20 carbon atoms, an alkenyloxy group having 2 to 20 carbon atoms, or an alkynyloxy group having 2 to 20 carbon atoms, or R ₁ and R ₂ , R ₃ and R ₄ , And R ₅ and R ₆ may each independently form an epoxy ring or form a bond,
The dashed line indicates a single bond or a double bond,
X represents halogen)
Or a salt thereof. Formula (Ia):

(Wherein R, R ₃ , R ₄ , dashed line and X are the same as defined for formula (I) in claim 1)
The compound or its salt of Claim 1 shown by these. A histidine kinase inhibitor comprising the compound according to claim 1. The histidine kinase inhibitor according to claim 3 for use as a bacterial signal transduction inhibitor. The histidine kinase inhibitor according to claim 3 for use as an antibacterial agent. The histidine kinase inhibitor according to claim 3 for use as an antibacterial agent against Gram-positive bacteria. Formula (II):

Bromine zerumbone represented by formula (III):

To obtain a compound of formula (Ia ′): by treating with potassium hydroxide, methyl cyanide and α-cyclodextrin.

The manufacturing method of the compound shown by these. Formula (II):

The zerumbone represented by formula (IV):

To obtain a compound of formula (V):

To give a compound of formula (Ia ″) by treatment with potassium hydroxide, methyl cyanide and α-cyclodextrin:

The manufacturing method of the compound shown by these.