JP4166433B2 - Hormone-dependent disease treatment - Google Patents

Description

本発明薬剤は１７β−ＨＳＤ阻害活性を有し、その活性により男性及び女性ホルモン依存性疾患の予防及び／又は治療剤、具体的には前立腺癌、前立腺肥大症、男性化症、乳癌、乳腺症、子宮癌、子宮内股症、卵巣癌などの予防及び／又は治療剤として有用である。
本発明薬剤に用いる化合物は、オーロン骨格を有する化合物であり、特に以下の化合物が用いられる。
（１）６−ヒドロキシ−２−（フェニルメチレン）−３（２Ｈ）−ベンゾフラノン
（２）２−〔（４−ヒドロキシフェニル）メチレン〕−６−ヒドロキシ−３（２Ｈ）−ベンゾフラノン
（３）２−〔（３−ヒドロキシ−４−メトキシフェニル）メチレン〕−６−ヒドロキシ−３（２Ｈ）−ベンゾフラノン
（４）２−〔（４−ヒドロキシ−３−メトキシフェニル）メチレン〕−６−ヒドロキシ−３（２Ｈ）−ベンゾフラノン
（５）２−〔（３，４−ジメトキシフェニル）メチレン〕−６−ヒドロキシ−３（２Ｈ）−ベンゾフラノン
（６）２−〔（４−ブロモフェニル）メチレン〕−６−ヒドロキシ−３（２Ｈ）−ベンゾフラノン
（７）２−〔（４−フルオロフェニル）メチレン〕−６−ヒドロキシ−３（２Ｈ）−ベンゾフラノン
（８）２−〔（４−クロロフェニル）メチレン〕−６−ヒドロキシ−３（２Ｈ）−ベンゾフラノン
（９）２−〔（３−ヒドロキシ−４−メトキシフェニル）メチレン〕−６−ヒドロキシ−３（２Ｈ）−ベンゾフラノン
（１０）６−ヒドロキシ−２−ピペロニリデン−３（２Ｈ）−ベンゾフラノン
（１１）２−〔（４−メトキシフェニル）メチレン〕−６−アセトキシ−３（２Ｈ）−ベンゾフラノン
（１２）２−〔（３，４−ジメトキシフェニル〕メチレン〕−６−メトキシ−３（２Ｈ）−ベンゾフラノン
（１３）２−〔（４−メトキシフェニル）メチレン〕−６−メトキシ−３（２Ｈ）−ベンゾフラノン
（１４）２−〔（３，５−ジメトキシフェニル）メチレン〕−６−メトキシ−３（２Ｈ）−ベンゾフラノン
（１５）６−メトキシ−２−ピペロニリデン−３（２Ｈ）−ベンゾフラノン
（１６）２−〔（３，４−ジヒドロキシフェニル）メチレン〕−６−ヒドロキシ−３（２Ｈ）−ベンゾフラノン（一般名：スルフレチン）
（１７）２−〔（３，４，５−トリメトキシフェニル）メチレン〕−６−ヒドロキシ−３（２Ｈ）−ベンゾフラノン
（１８）２−〔（２，３−ジメトキシフェニル）メチレン〕−６−ヒドロキシ−３（２Ｈ）−ベンゾフラノン
これらの化合物はすべて公知の物質であり、Ｊ．Ｃｈｒｏｍａｔｏｇｒａｐｈｙ，５７，１６６（１９７１）（化合物（１）〜（５）、（１０）、（１７）及び（１８））、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，３５，１３３０（１９９２）（化合物（６）〜（８））、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，７９，２１４（１９５７）（化合物（９））、Ｍａｇｙ．Ｋｅｍ．Ｆｏｌｙ，，７４，５８２（１９６８）（化合物（１１））、Ｏｒｉｅｎｔ．Ｊ．Ｃｈｅｍ．，１１，１８９（１９９５）（化合物（１２）及び（１３））、Ｂｕｌｌ．Ｃｈｅｍ．Ｓｏｃ．Ｊｐｎ．，５４，６３５（１９８１）（化合物（１４））、Ｂｕｌｌ．Ｃｈｅｍ．Ｓｏｃ，Ｊｐｎ．，４２，１４５６（１９９６）（化合物（１５））それぞれの文献に従った合成方法により得ることができる。又は、核置換ベンゾフラノンと核置換ベンズアルデヒドをメタノール、エタノール、又はプロパノールなどの溶媒に溶解し、濃塩酸を加え１〜２４時間加熱還流した後冷却し、析出した結晶を濾過することにより得ることができる。この時、結晶が析出しない場合には、水あるいは有機溶媒などを用い、常法により結晶として析出させ、析出した結晶を濾過することにより得ることができる。叉、（１６）の化合物は一般に市販されており入手可能であり、あるいは公知の方法に従って植物より抽出精製（Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，７５，１９００（１９５３））、又は化学的合成（Ｂｅｒ．，９２，２８４７（１９５９））により得ることができる。
本発明薬剤は、ヒト及び動物に対し、医薬として経口的及び非経口的に安全に投与される。非経口的投与には、例えば静脈注射、筋肉内注射、皮下注射、腹腔内注射、経皮投与、経肺投与、経鼻投与、経腸投与、口腔内投与、経粘膜投与、経膣投与等が挙げられ、これらの製剤が投与される。例えば注射剤、坐剤、エアゾール剤、経皮吸収テープなどが挙げられる。経口投与製剤として例えば錠剤（糖衣錠、コーティング錠、バッカル錠を含む）、散剤、カプセル剤（ソフトカプセルを含む）、顆粒剤（コーティングされたものも含む）、丸剤、トローチ剤、液剤、又はこれらの製剤学的に許容され得る徐放化製剤等が挙げられる。経口投与用液剤には懸濁剤、乳剤、シロップ剤（ドライシロップを含む）、エリキシル剤などが挙げられる。これらの製剤は公知の製剤学的製法に準じ、製剤として薬理学的に許容され得る担体、賦形剤、崩壊剤、滑沢剤、着色剤等と共に医薬組成物として投与される。これらの製剤に用いる担体や賦形剤としては、例えば乳糖、ブドウ糖、白糖、マンニトール、馬鈴薯デンプン、トウモロコシデンプン、炭酸カルシウム、リン酸カルシウム、硫酸カルシウム、結晶セルロース、カンゾウ末、ゲンチアナ末など、結合剤としては例えばデンプン、トラガントゴム、ゼラチン、シロップ、ポリビニルアルコール、ポリビニルエーテル、ポリビニルピロリドン、ヒドロキシプロピルセルロース、メチルセルロース、エチルセルロース、カルボキシメチルセルロースなど、崩壊剤としては例えばデンプン、寒天、ゼラチン末、カルボキシメチルセルロースナトリウム、カルボキシメチルセルロースカルシウム、結晶セルロース、炭酸カルシウム、炭酸水素ナトリウム、アルギン酸ナトリウムなど、滑沢剤としては例えばステアリン酸マグネシウム、タルク、水素添加植物油、マクロゴールなど、着色剤としては医薬品に添加することが許容されているものを、それぞれ用いることができる。錠剤、顆粒剤は必要に応じ白糖、ゼラチン、ヒドロキシプロピルセルロース、精製セラック、ゼラチン、グリセリン、ソルビトール、エチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、フタル酸セルロースアセテート、ヒドロキシプロピルメチルセルロースフタレート、メチルメタクリレート、メタアクリル酸重合体などで被膜しても良く、又これらの２種以上を用いた層で被膜しても良い。さらにエチルセルロースやゼラチンのような物質のカプセルでも良い。又、注射剤を調製する場合は、主薬に、必要に応じｐＨ調整剤、緩衝剤、安定化剤、可溶化剤などを添加して、常法により各注射剤とする。
本発明薬剤を患者に投与する場合、症状の程度、患者の年齢、健康状態、体重などの条件によって異なり特に限定はされないが、成人１日当たり約１ｍｇ〜１０００ｍｇ、好ましくは５０〜２００ｍｇを経口或いは非経口的に１日１回若しくはそれ以上投与すれば良い。
発明を実施するための最良の形態
以下の実施例により本発明をより詳細に説明するが、これらは単に例示したのみであり、本発明はこれらによって何ら限定されるものではない。
実施例１
６−ヒドロキシ−２−（フェニルメチレン）−３（２Ｈ）−ベンゾフラノンの製造
６−ヒドロキシ−２Ｈ−ベンゾフラン−３−オン１ｇ、ベンズアルデヒド８４８ｍｇをメタノール２０ｍｌに溶解した後、水酸化ナトリウム６ｇを水６ｍｌに溶解した溶液を加え、窒素気流下、１６時間撹拌後、水４００ｍｌを加え濃塩酸でｐＨ４とした。析出した結晶は、ロ別した後、６０℃のメタノール２５ｍｌに溶解し、５℃で４時間放置後、結晶をロ別し、五酸化リン上、６０℃で８時間減圧下乾燥し、目的化合物（化合物（１））４３２．６ｍｇ（ｍｐ１４１℃）を得た。
ＦＡＢ ＭＡＳＳ；２３９（Ｍ＋１）
^１Ｈ−ＮＭＲ（ｐｐｍ，ｉｎ ＤＭＳＯ−ｄ_６）；６．７２（１Ｈ，ｄｄ，Ｊ＝１０．３，１．９Ｈｚ），６．７４（１Ｈ，ｓ），６．７８（１Ｈ，ｄ，Ｊ＝１．５Ｈｚ），７．４０（１Ｈ，ｔ，７．６Ｈｚ），７．４７（１Ｈ，ｔ，７．６Ｈｚ），７．６０（１Ｈ，ｄ，８．５Ｈｚ），７．９１（１Ｈ，ｄ，７．６Ｈｚ），１０．９５（１Ｈ，ｓ）
実施例２
２−〔（４−ヒドロキシフェニル）メチレン〕−６−ヒドロキシ−３（２Ｈ）−ベンゾフラノンの製造
６−ヒドロキシ−２Ｈ−ベンゾフラン−３−オン１ｇ、４−ヒドロキシベンズアルデヒド０．８１３ｇをメタノール７５ｍｌに溶解した後、濃塩酸５０ｍｌを加え２時間リフラックスした後、本溶液を室温まで冷却し、水を４００ｍｌ加え１時間放置した。析出した結晶をロ別し、五酸化リン上、６０℃で５時間減圧下乾燥し、目的化合物（化合物（２））１．０８ｇ（ｍｐ２８７℃）（分解）を得た。
ＦＡＢ ＭＡＳＳ；２５５（Ｍ＋１）
^１Ｈ−ＮＭＲ（ｐｐｍ，ｉｎ ＤＭＳＯ−ｄ_６）；６．７１（１Ｈ，ｄｄ，Ｊ＝８．２，１．８Ｈｚ），６．７０（１Ｈ，ｓ），６．７９（１Ｈ，ｄ，Ｊ＝１．８Ｈｚ），６．８８（１Ｈ，ｄ，１０．８Ｈｚ），７．５８（１Ｈｔ，８．５Ｈｚ），７．７９（１Ｈ，ｄ，８．６Ｈｚ）
実施例３
２−〔（３−ヒドロキシ−４−メトキシフェニル）メチレン〕−６−ヒドロキシ−３（２Ｈ）−ベンゾフラノンの製造
６−ヒドロキシ−２Ｈ−ベンゾフラン−３−オン１ｇ、３−ヒドロキシ−４−メトキシベンズアルデヒド１．０１ｇをメタノール７５ｍｌに溶解した後、濃塩酸５０ｍｌを加え２時間リフラックスした後、本溶液を室温まで冷却し、水を４００ｍｌ加え２時間放置した。析出した結晶をロ別後、五酸化リン上、６０℃で５時間減圧下乾燥し、目的化合物（化合物（３））１．２７ｇ（ｍｐ２４０〜２４２℃）を得た。
ＦＡＢ ＭＡＳＳ；２８５（Ｍ＋１）
^１Ｈ−ＮＭＲ（ｐｐｍ，Ｈｚ，ｉｎ ＤＭＳＯ−ｄ_６）；３．８３（３Ｈ，ｓ），６．６３（１Ｈ，ｓ），６．７１（１Ｈ，ｄｄ，Ｊ＝１０．６，２．２Ｈｚ），６．７７（１Ｈ，ｄ，Ｊ＝２．１Ｈｚ），７．０１（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．３３（１Ｈ，ｄｄ，Ｊ＝８．２，２．１Ｈｚ），７．４７（１Ｈ，ｄ，Ｊ＝２．１Ｈｚ），７．５８（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ）
実施例４
２−〔（４−ヒドロキシ−３−メトキシフェニル）メチレン〕−６−ヒドロキシ−３（２Ｈ）−ベンゾフラノンの製造
６−ヒドロキシ−２Ｈ−ベンゾフラン−３−オン１ｇ、４−ヒドロキシ−３−メトキシベンズアルデヒド１．０１ｇをメタノール７５ｍｌに溶解した後、濃塩酸５０ｍｌを加え２時間リフラックスした後、本溶液を室温まで冷却し、水を４００ｍｌ加え２時間放置した。析出した結晶をロ別後、五酸化リン上、６０℃で５時間減圧下乾燥し、目的化合物（化合物（４））０．８５１ｇ（ｍｐ２６２〜２６３℃）を得た。
ＦＡＢ ＭＡＳＳ；２８５（Ｍ＋１）
^１Ｈ−ＮＭＲ（ｐｐｍ，ｉｎ ＤＭＳＯ−ｄ_６）；３．８５（３Ｈ，ｓ），６．７０（１Ｈ，ｓ），６．７１（１Ｈ，ｄｄ，Ｊ＝８．２，１．８Ｈｚ），６．７８（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４４（１Ｈ，ｄｄ，Ｊ＝８．５，２．１Ｈｚ），７．５０（１Ｈ，ｄ，Ｊ＝２．１Ｈｚ），７．５７（１Ｈ，ｄ，Ｊ＝９．６Ｈｚ）
実施例５
２−〔（３，４−ジメトキシフェニル）メチレン〕−６−ヒドロキシ−３（２Ｈ）−ベンゾフラノンの製造
６−ヒドロキシ−２Ｈ−ベンゾフラン−３−オン１ｇ、３、４−ジメトキシベンズアルデヒド１．２３ｇをメタノール７５ｍｌに溶解した後、濃塩酸５０ｍｌを加え１．５時間リフラックスした後、本溶液を室温まで冷却し、水４００ｍｌを加えた。析出した結晶をロ別後、五酸化リン上、６０℃で７時間減圧下乾燥し目的化合物（化合物（５））０．８５ｇ（ｍｐ２２１℃）を得た。
ＦＡＢ ＭＡＳＳ；２９９（Ｍ＋１）
^１Ｈ−ＮＭＲ（ｐｐｍ，ｉｎ ＤＭＳＯ−ｄ_６）；３．８０（３Ｈ，ｓ），３．８１（３Ｈ，ｓ），６．６８（１Ｈ，ｓ），６．７２（１Ｈ，ｄｄ，Ｊ＝８．２，１．８Ｈｚ），６．８１（１Ｈ，ｄ，Ｊ＝２．１Ｈｚ），７．０２（１Ｈ，ｄ，Ｊ＝９．６Ｈｚ），７．４９（２Ｈ，ｍ）７．５５（１Ｈ，ｄ，Ｊ＝８．５Ｈｚ）
実施例６
２−〔（４−ブロモフェニル）メチレン〕−６−ヒドロキシ−３（２Ｈ）−ベンゾフラノンの製造
６−ヒドロキシ−２Ｈ−ベンゾフラン−３−オン１ｇ、４−ブロモベンズアルデヒド１．３６ｇをメタノール７５ｍｌに溶解した後、濃塩酸５０ｍｌを加え１．５時間リフラックスした後、本溶液を室温まで冷却し、水４００ｍｌを加えた。析出した結晶をロ別後、五酸化リン上、６０℃で４時間減圧下乾燥し、目的化合物（化合物（６））１．１６ｇを得た。
ＦＡＢ ＭＡＳＳ；３１８（Ｍ＋１）
^１Ｈ−ＮＭＲ（ｐｐｍ，ｉｎ ＤＭＳＯ−ｄ_６）；６．６９（１Ｈ，ｄｄ，Ｊ＝７．９，１．５Ｈｚ），６．７２（３Ｈ，ｓ），６．７５（１Ｈ，ｄ，Ｊ＝１．８Ｈｚ），７．５９（１Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．６２（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．８２（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），１１．２１（１Ｈ，ｓ）
実施例７
２−〔（４−フルオロフェニル）メチレン〕−６−ヒドロキシ−３（２Ｈ）−ベンゾフラノンの製造
６−ヒドロキシ−２Ｈ−ベンゾフラン−３−オン１ｇ、４−フルオロベンズアルデヒド０．７８ｍｌをメタノール７５ｍｌに溶解した後、濃塩酸５０ｍｌを加え１．５時間リフラックスした。本溶液を室温まで冷却後、水４００ｍｌを加えた。析出した結晶をロ別後、五酸化リン上、６０℃で４時間減圧下乾燥し、目的化合物（化合物（７））０．７４ｇを得た。
ＦＡＢ ＭＡＳＳ；２５７（Ｍ＋１）
^１Ｈ−ＮＭＲ（ｐｐｍ，Ｈｚ，ｉｎ ＤＭＳＯ−ｄ_６）；６．７０（１Ｈ，ｄｄ，Ｊ＝８．５，１．８Ｈｚ），６．７７（１Ｈ，ｄ，Ｊ＝１．８Ｈｚ），６．７８（１Ｈ，ｓ），７．３０（２Ｈ，ｔ，Ｊ＝８．８Ｈｚ），７．６０（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．９７（２Ｈ，ｄｄ，Ｊ＝８．８，５．４Ｈｚ），１１．２０（１Ｈ，ｓ）
実施例８
２−〔（４−クロロフェニル）メチレン〕−６−ヒドロキシ−３（２Ｈ）−ベンゾフラノンの製造
６−ヒドロキシ−２Ｈ−ベンゾフラン−３−オン１ｇ、４−クロロベンズアルデヒド１．０３８ｇをメタノール７５ｍｌに溶解した後、濃塩酸５０ｍｌを加え１．５時間リフラックスした。本溶液を室温まで冷却し、水４００ｍｌを加えた。析出した結晶をロ別後、五酸化リン上、６０℃で５時間減圧下乾燥し、目的化合物（化合物（８））０．８２ｇを得た。
^１Ｈ−ＮＭＲ（ｐｐｍ，ｉｎ ＤＭＳＯ−ｄ_６）；６．６８（１Ｈ，ｄｄ，Ｊ＝８．５，１．５Ｈｚ），６．７２（１Ｈ，ｓ），６．７４（１Ｈ，ｄ，Ｊ＝１．８Ｈｚ），７．３０（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．５７（１Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．８７（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），１１．２０（１Ｈ，ｓ）
実施例９
２−（（４−メトキシフェニル）メチレン〕−６−ヒドロキシ−３（２Ｈ）−ベンゾフラノンの製造
６−ヒドロキシ−２Ｈ−ベンゾフラン−３−オン１ｇ、４−メトキシベンズアルデヒド１．１２５ｇをメタノール７５ｍｌに溶解した後、濃塩酸５０ｍｌを加え１．５時間リフラックスした。本溶液を室温まで冷却し、析出した結晶をロ別後、五酸化リン上、６０℃で４時間減圧下乾燥し、目的化合物（化合物（９））０．９８３ｇを得た。
ＦＡＢ ＭＡＳＳ；２６９（Ｍ＋１）
^１Ｈ−ＮＭＲ（ｐｐｍ，ｉｎ ＤＭＳＯ−ｄ_６）；３．７９（３Ｈ，ｓ），６．６９（１Ｈ，ｄｄ，Ｊ＝８．５，２．１Ｈｚ），６．７３（１Ｈ，ｓ），６．７６（１Ｈ，ｄ，Ｊ＝１．８Ｈｚ），７．００（２Ｈ，ｄ，Ｊ＝９．１Ｈｚ），７．５８（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．８６（２Ｈ，ｄ，Ｊ＝９．１Ｈｚ），１１．１１（１Ｈ，ｓ）
実施例１０
６−ヒドロキシ−２−ピペロニリデン−３（２Ｈ）−ベンゾフラノンの製造
６−ヒドロキシ−２Ｈ−ベンゾフラン−３−オン１ｇ、ピペロナール１．１１ｇをメタノール７５ｍｌに溶解した後、濃塩酸５０ｍｌを加え１．５時間リフラックスした。本溶液を室温まで冷却し、析出した結晶をロ別後、五酸化リン上６０℃で４時間減圧下乾燥し、目的化合物（化合物（１０））１．３７ｇを得た。
ＦＡＢ ＭＡＳＳ；２８３（Ｍ＋１）
^１Ｈ−ＮＭＲ（ｐｐｍ，ｉｎ ＤＭＳＯ−ｄ_６）；６．０８（２Ｈ，ｓ），６．７０（１Ｈ，ｄｄ，Ｊ＝８．２，１．８Ｈｚ），６．７０（１Ｈ，ｓ），７．０１（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．４４（１Ｈ，ｄｄ，Ｊ＝８．２，１．８Ｈｚ），７．５２（１Ｈ，ｄ，Ｊ＝１．５Ｈｚ），７．５８（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），１０．９９（１Ｈ，ｓ）
実施例１１
２−〔（４−メトキシフェニル）メチレン］−６−アセトキシ−３（２Ｈ）−ベンゾフラノンの製造
２−〔（４−メトキシフェニル）メチレン〕−６−ヒドロキシ−３（２Ｈ〕−ベンゾフラノン０．５ｇをピリジン５ｍｌに溶解後、塩化アセチル０．１７２ｍｌを加え２．５時間リフラックスした。本溶液を室温まで冷却後、酢酸エチル４０ｍｌを加え２Ｎ−塩酸１５ｍｌで２回、飽和食塩水１５ｍｌで３回洗浄した。酢酸エチル溶液は、硫酸マグネシウムで脱水し、減圧濃縮した。得られた粉末を、シリカゲルカラムクロマログラフィー（シリカゲル１００ｇ，溶出溶媒ヘキサン；酢酸エチル＝１：１で５００ｍｌで溶出）で分画し、減圧下４０℃で濃縮乾固し、結晶を得た。結晶は、酢酸エチル１０ｍｌに溶解した後、室温に２時間放置後、析出した結晶をロ別し、五酸化リン上、６０℃で５時間減圧下乾燥し、目的化合物（化合物（１１））３５４．４ｍｇを得た。
ＦＡＢ ＭＡＳＳ；３１１（Ｍ＋１）
^１Ｈ−ＮＭＲ（ｐｐｍ，ｉｎ ＣＤＣｌ_３）；２．３３（３Ｈ，ｓ），３．８４（３Ｈ，ｓ），６．８５（１Ｈ，ｓ），６．９１（１Ｈ，ｄ，Ｊ＝８．５，１．８Ｈｚ），６．９６（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．１３（１Ｈ，ｄ，Ｊ＝１．５Ｈｚ），７．７８（２Ｈ，ｄ，Ｊ＝８．２４Ｈｚ），７．８４（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ）
実施例１２
２−〔（３，４−ジメトキシフェニル）メチレン〕−６−メトキシ−３（２Ｈ）−ベンゾフラノンの製造
２−〔（３，４−ジメトキシフェニル）メチレン〕−６−ヒドロキシ−３（２Ｈ）−ベンゾフラノン０．５０３ｇ及び炭酸カリウム０．５８３ｇにジメチルホルムアミド５ｍｌを加えた溶液にメチル ｐ−トルエンスルフォネート０．２５４ｇを加え６０℃、２時間撹拌後、水１００ｍｌを加え、酢酸エチル５０ｍｌで２回抽出した後、飽和食塩水５０ｍｌで２回洗浄後硫酸マグネシウムで脱水ロ別し、４０℃で減圧濃縮し粗目的化合物を粉末で得た。得られた粉末は、シリカゲルカラムクロマトグラフィー（シリカゲル５０ｇ、溶出溶媒ヘキサン：酢酸エチル＝１：１で５００ｍｌで溶出）で分画し、減圧下４０℃で濃縮乾固し結晶を得た。本結晶は酢酸エチル２ｍｌ、ヘキサン１０ｍｌに溶解し室温で２時間放置した。析出した結晶をロ別後、五酸化リン上、６０℃で４時間減圧下乾燥し、目的化合物（化合物（１２））４３５．３ｍｇを得た。
ＦＡＢ ＭＡＳＳ；３１３（Ｍ＋１）
^１Ｈ−ＮＭＲ（ｐｐｍ，ｉｎ ＣＤＣｌ_３）；３．９０（３Ｈ，ｓ），３．８１（３Ｈ，ｓ），３．９５（３Ｈ，ｓ），６．７２（２Ｈ，ｓ），６．７６（１Ｈ，ｓ），６．９０（１Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．４４（１Ｈ，ｄｄ，Ｊ＝８．２，２．４Ｈｚ），７．４５（１Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．６７（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ）
実施例１３
２−〔（４−メトキシフェニル）メチレン〕−６−メトキシ−３（２Ｈ）−ベンゾフラノンの製造
２−〔（４−メトキシフェニル）メチレン〕−６−ヒドロキシ−３（２Ｈ）−ベンゾフラノン０．４５２ｇ及び炭酸カリウム０．５８３ｇにジメチルホルムアミド５ｍｌを加えた溶液にメチル ｐ−トルエンスルフォネート０．２５４ｇを加え６０℃、２時間撹拌後、水１００ｍｌを加え、酢酸エチル５０ｍｌで２回抽出した後、飽和食塩水５０ｍｌで２回洗浄後硫酸マグネシウムで脱水ロ別し、４０℃で減圧濃縮し粗目的化合物を粉末で得た。得られた粉末は、シリカゲルカラムクロマトグラフィー（シリカゲル５０ｇ、溶出溶媒ヘキサン：酢酸エチル＝１：１で５００ｍｌで溶出）で分画し、減圧下４０℃で濃縮乾固し結晶を得た。本結晶は酢酸エチル２ｍｌ、ヘキサン１０ｍｌに溶解し室温で２時間放置した。析出した結晶をロ別後、五酸化リン上、６０℃で４時間減圧下乾燥し、目的化合物（化合物（１３））３１５．０ｍｇを得た。
ＦＡＢ ＭＡＳＳ；２８３（Ｍ＋１）
^１Ｈ−ＮＭＲ（ｐｐｍ，ｉｎ ＣＤＣｌ_３）；３．８４（３Ｈ，ｓ），３．９０（３Ｈ，ｓ），６．７２（２Ｈ，ｍ），６．７８（１Ｈ，ｓ），６．９４（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．６７（１Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．８３（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ）
実施例１４
２−（（３，５−ジメトキシフェニル）メチレン〕−６−メトキシ−３（２Ｈ）−ベンゾフラノンの製造
２−〔（３，５−ジメトキシフェニル）メチレン〕−６−ヒドロキシ−３（２Ｈ）−ベンゾフラノン０．５０３ｇ及び炭酸カリウム０．５８３ｇにジメチルホルムアミド５ｍｌを加えた溶液にメチル ｐ−トルエンスルフォネート０．２５４ｇを加え６０℃、２時間撹拌後、水１００ｍｌを加え、酢酸エチル５０ｍｌで２回抽出した後、飽和食塩水５０ｍｌで２回洗浄後硫酸マグネシウムで脱水ロ別し、４０℃で減圧濃縮し粗目的化合物を粉末で得た。得られた粉末は、シリカゲルカラムクロマトグラフィー（シリカゲル５０ｇ、溶出溶媒ヘキサン：酢酸エチル＝１：１で５００ｍｌで溶出）で分画し、減圧下４０℃で濃縮乾固し結晶を得た。本結晶は酢酸エチル２ｍｌ、ヘキサン１０ｍｌに溶解し室温で２時間放置した。析出した結晶をロ別後、五酸化リン上、６０℃で４時間減圧下乾燥し、目的化合物（化合物（１４））４１１．６ｍｇを得た。
ＦＡＢ ＭＡＳＳ；３１３（Ｍ＋１）
^１Ｈ−ＮＭＲ（ｐｐｍ，ｉｎ ＣＤＣｌ_３）；３．９３（６Ｈ，ｓ），３．９５（３Ｈ，ｓ），６．７２（２Ｈ，ｓ），６．７６（１Ｈ，ｓ），６．９０（１Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．４４（１Ｈ，ｄｄ，Ｊ＝８．２，２．４Ｈｚ），７．４５（１Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．６７（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ）
実施例１５
６−メトキシ−２−ピペロニリデン−３（２Ｈ）−ベンゾフラノンの製造
６−ヒドロキシ−２−ピペロニリデン−３（２Ｈ）−ベンゾフラノン０．５０３ｇ及び炭酸カリウム０．４７６ｇにジメチルホルムアミド５ｍｌを加えた溶液にメチル ｐ−トルエンスルフォネート０．２５４ｍｌを加え６０℃、２時間撹拌後、水１００ｍｌを加え、酢酸エチル５０ｍｌで２回抽出した後、飽和食塩水５０ｍｌで２回洗浄後硫酸マグネシウムで脱水ロ別し、４０℃で減圧濃縮し粗目的化合物を粉末で得た。得られた粉末は、シリカゲルカラムクロマトグラフィー（シリカゲル５０ｇ、溶出溶媒ヘキサン：酢酸エチル＝１：１で５００ｍｌで溶出）で分画し、減圧下４０℃で濃縮乾固し結晶を得た。本結晶は酢酸エチル２ｍｌ、ヘキサン１０ｍｌに溶解し室温で２時間放置した。析出した結晶をロ別後、五酸化リン上、６０℃て４時間減圧下乾燥し、目的化合物（化合物（１５））３３６．７ｍｇを得た。
ＦＡＢ ＭＡＳＳ；２９７（Ｍ＋１）
^１Ｈ−ＮＭＲ（ｐｐｍ，ｉｎ ＣＤＣｌ_３）；３．９０（３Ｈ，ｓ），３．８１（３Ｈ，ｓ），３．９５（３Ｈ，ｓ），６．７２（２Ｈ，ｓ），６．７６（１Ｈ，ｓ），６．９０（１Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．４４（１Ｈ，ｄｄ，Ｊ＝８．２，２．４Ｈｚ），７．４５（１Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．６７（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ）
実施例１６
２−〔（３，４，５−トリメトキシフェニル）メチレン）−６−ヒドロキシ−３（２Ｈ）−ベンゾフラノンの製造
６−ヒドロキシ−２Ｈ−ベンゾフラノン−３−オン１７ｇ及び３，４，５−トリメトキシベンズアルデヒド２５ｇをメタノール２００ｍｌに溶解した後、濃塩酸２００ｍｌを加え１．５時間リフラックスした。本溶液を室温まで冷却後、析出した結晶はロ別後、五酸化リン上、６０℃で１８時間減圧下乾燥し、目的化合物（化合物（１７））３６．０ｇを得た。
ＦＡＢ ＭＡＳＳ；３２９（Ｍ＋１）
^１Ｈ−ＮＭＲ（ｐｐｍ，ｉｎ ＤＭＳＯ−ｄ_６）；３．７２（３Ｈ，ｓ），３．８３（６Ｈ，ｓ），６．７０（２Ｈ，ｍ），６．７８（１Ｈ，ｍ），７．２５（１Ｈ，ｓ），７．２７（１Ｈ，ｓ），７．５６〜７．５９（２Ｈ，ｍ），１１．１１（１Ｈ，ｓ）
実施例１７
２−〔（２，３−ジメトキシフェニル）メチレン〕−６−ヒドロキシ−３（２Ｈ）−ベンゾフラノンの製造
６−ヒドロキシ−２Ｈ−ベンゾフラノン−３−オン２０ｇ及び２，３−ジメトキシベンズアルデヒド２５ｇをメタノール２５０ｍｌに溶解した後、濃塩酸２５０ｍｌを加え１．５時間リフラックスした後、水２００ｍｌを加えた。本溶液を室温まで冷却後、析出した結晶はロ別後、五酸化リン上、６０℃で１８時間減圧下乾燥し、目的化合物（化合物（１８））３３．３ｇを得た。
ＦＡＢ ＭＡＳＳ；２９９（Ｍ＋１）
^１Ｈ−ＮＭＲ（ｐｐｍ，ｉｎ ＤＭＳＯ−ｄ６）；３．８０（３Ｈ，ｔ），３．８１（２Ｈ，ｓ），６．６９（１Ｈ，ｄｄ，Ｊ＝８．５，１．８Ｈｚ），６．７６（１Ｈ，ｄ，Ｊ＝１．８Ｈｚ），６．９５（１Ｈ，ｓ），７．０９（１Ｈ，ｄｄ，Ｊ＝８．２，１．２Ｈｚ），７．１６（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．６０（１Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．５４（１Ｈ，ｄｄ，Ｊ＝７．９，１．２Ｈｚ），１１．２０（１Ｈ，ｓ）
実施例１８

各成分を混合し、実施例で得られた化合物５０ｍｇを含む５００ｍｇの錠剤４００個を製造した。
実施例１９

各成分を混合した後圧縮成形し、粉砕、整粒して２０〜５０メッシュの５％顆粒剤を製造した。
実施例２０

上記の実施例で得られた化合物を生理食塩水に溶解し、バイアルに充填し加熱殺菌を行い、静注用注射剤とした。
実施例２１
ｉｎ ｖｉｔｒｏ １７β−ＨＳＤ阻害活性試験
実施例１〜１７で得られた化合物（化合物１〜１５、１７、１８）及びスルフレチン（フナコシ社、Ｃａｔ．Ｎｏ．８２−００００−８：化合物１６）（以下、被験物質）の１７β−ＨＳＤ阻害活性を試験した。即ち、被験物質をそれぞれエタノールに溶解し、最終濃度が２６０ｎＭとなるように試験管に入れ、窒素ガスにより乾固させた。これに１００ｍＭ塩化カリウム、１ｍＭエチレンジアミンテトラ酢酸、０．５ｍＭ還元型ニコチンアミドアデニンジヌクレオチドリン酸（全て和光純薬社）、１μＭ〔４−^１４Ｃ〕エストロン（ＮＥＮ Ｒｅｓｅａｒｃｈ Ｐｒｏｄｕｃｔｓ社）を含む１０ｍＭリン酸緩衝液（ｐＨ７．５）５９０μｌ、及びＥ．Ａ．Ｔｈｏｍｐｓｏｎらの方法（Ｊ．Ｂｉｏｌ．Ｃｈｅｍ．、２４９巻、５３６４〜５３７２頁、１９７４年）に準じてヒト胎盤より得られたミクロソーム画分１０μｌを加え、３７℃、３０分間振盪下で反応させた。反応終了後、直ちにジクロロメタン２ｍｌを加えて充分撹拌し、３０００ｒｐｍで５分間遠心処理を行い、得られた下層（ジクロロメタン層）を別の試験管に移し、窒素ガスにて乾固させた。これに２０μｇのエストロン及び２０μｇのエストラジオールを含むエタノール１００μｌを添加し、うち２０μｌをＴＬＣプレート（シリカゲル６０Ｆ_２５４、メルク社）にスポットした。このＴＬＣプレートをベンゼン：アセトン（４：１）にて展開した後、紫外線下でエストロン、エストラジオールに相当するスポットを切り出し、液体シンチレーションカクテル（フィルターカウント（登録商標）；ヒューレットパッカード社）を加え、液体シンチレーションカウンターにて残存している〔４−^１４Ｃ〕エストロン量、及び１７β−ＨＳＤ酵素活性によって生成された〔４−^１４Ｃ〕エストラジオール量を求めた。又、被験物質を加えないで同様の操作を行ったものを対照群とした。対照群の１７β−ＨＳＤ酵素活性を阻害率０％として、被験物質の１７β−ＨＳＤ酵素阻害率を百分率にて求めた。結果を図１及び２に示す。
実施例２２
ｉｎ ｖｉｖｏ血清エストラジオール量測定試験
性腺刺激ホルモン処置幼若雌ラットを用いて、血清エストラジオール量を測定した。即ち、１４日齢のＳＤ系雌ラットを哺乳親とともに予備飼育し、２０日齢にて離乳させ、翌２１日齢に体重１ｋｇあたり生理食塩水に溶解させた妊馬血清性腺刺激ホルモンを６００国際単位皮下投与した。２４時間後に、生理食塩水に溶解させた０．５％カルボキシルメチルセルロースに被験物質を懸濁させたものを、体重１ｋｇあたり１００ｍｇ単回経口投与した。被験物質投与４及び２４時間後にエーテル麻酔下にて後大静脈より全採血を行い、３０００ｒｐｍ、３０分間の遠心処理にて血清を分離した。被験物質投与ラットの血清中に含まれるエストラジオール量の測定には、Ｅ２キット「第一」ＩＩ（第一ラジオアイソトープ研究所社）を用いた。被験物質投与ラットの血清または標準曲線用の既知濃度のエストラジオール（和光純薬社）を１００μｌずつ試験管に添加し、３ｍｌのジエチルエーテルを加え、充分に撹拌したのち暫く静置した。エーテル層と水層が明確に分離したらドライアイス−メタノールに底部を浸して水層のみを凍結させ、エーテル層を別の試験管に移し、３７℃にて窒素ガスで乾固させた。ここにキットに含まれる１００μｌ^１２５Ｉ−エストラジオールと抗エストラジオール抗体を加え、室温で９０分反応させた。反応終了後二次抗体を１ｍｌ加え、室温でさらに１５分反応させたのち、３０００ｒｐｍで１５分間遠心処理を行い、上清をアスピレーターで完全に除去し、γカウンターにて沈渣に存在する^１２５Ｉ−エストラジオールを測定した。既知濃度のエストラジオールによる^１２５Ｉ−エストラジオール量から標準曲線を描き、被験物質投与ラットの血清中に含まれるエストラジオール量（Ｅ２量）を測定した。結果を図１及び２に示す。
産業上の利用可能性
以上の結果より、本発明によりオーロン骨格を有する化合物を有効成分とする、ホルモン依存性疾患治療剤が提供される。本発明薬剤は１７β−ＨＳＤ阻害活性を有し、その活性より男性及び女性ホルモン依存性疾患の予防及び／又は治療剤、具体的には前立腺癌、前立腺肥大症、男性化症、乳癌、乳腺症、子宮癌、子宮内膜症、卵巣癌などの予防及び／又は治療剤として有用である。
【図面の簡単な説明】
図１は、実施例の結果を示す図。
図２は、実施例の結果を示す図。Technical field
The present invention relates to a hormone-dependent disease therapeutic agent comprising a compound having an aurone skeleton as an active ingredient. The drug of the present invention has 17β-HSD inhibitory activity, and due to its activity, a prophylactic and / or therapeutic agent for male and female hormone-dependent diseases, specifically prostate cancer, benign prostatic hyperplasia, androgenism, breast cancer, and mastopathy It is useful as a preventive and / or therapeutic agent for uterine cancer, endometriosis, ovarian cancer and the like.
Background art
In recent years, an increase in the prevalence of male hormone-dependent diseases such as prostate cancer and prostatic hypertrophy and female hormone-dependent diseases such as breast cancer and endometriosis has become a problem in Japan. For example, the mortality rate for prostate cancer was 3.9 per 100,000 population in the 1984 statistics, which was about 1/10 that of non-white people in the United States. It has been gradually increasing due to the westernization of daily life, and in 1993 it was gradually approaching the Western level with 6.7 people per 100,000 population. Incidentally, the number of deaths from prostate cancer in 2015 is expected to be about four times the number of deaths in 1990, which is the worst increase in all cancers.
It has already been clarified from many findings that male hormone-dependent diseases are expected to improve subjective and objective symptoms by lowering blood male hormones. For this reason, the male hormone in the blood has been lowered by castration, or an agonist of the gonadotropin-releasing hormone LH-RH secreted from the pituitary gland has been administered so far, and the LH secretion ability has been increased by desensitization of the pituitary gland. Attempts have been made to treat these diseases by lowering blood male hormones to castration level by lowering them or by administering anti-androgen drugs that antagonize androgen receptors to suppress the action of male hormones. Effects are widely recognized. However, castration leads to a reduction in QOL, so it is currently only performed in very limited cases. In addition, LH-RH agonists have problems such as side effects such as bone pain and dysuria caused by flare phenomenon (temporary increase in male hormone), and relapse due to the continued presence of adrenal-derived male hormone. . Furthermore, it has been pointed out that anti-androgen drugs have a reduced therapeutic effect due to mutations in androgen receptors during medication. For this reason, “male hormone complete blocking therapy” has recently been proposed for more effective endocrine therapy. This is intended to completely block male hormones in the blood by combining several endocrine therapies, and is expected to have a therapeutic effect that is higher than ever.
C with androgenic activity₁₉Testosterone having the strongest androgenic activity among steroids is biosynthesized with androstenedione as a substrate by 17β-Hydroxysteroid dehydrogenase (17β-HSD). Therefore, by inhibiting this 17β-HSD, it is possible to directly reduce blood testosterone, so that a high therapeutic effect on the male hormone-dependent disease can be expected. This enzyme is also a female hormone activity C₁₈Since it is also a biosynthetic enzyme of estradiol, which has the strongest female hormone activity among steroids, it is also expected to have therapeutic effects on female hormone-dependent diseases such as breast cancer and endometriosis.
To date, steroidal and non-steroidal compounds have been presented as 17β-HSD inhibitors. Non-steroidal compounds include, for example, flavones and isoflavones described in Biochemical and Biophysical Research Communications (Vol.215, pp. 1137-1144, 1995), and Journal of Steroid Biochemistry. (23, 357-363, 1985) is known. However, the activity of these compounds is never satisfactory, and a substance with higher activity has been expected.
Disclosure of the invention
In view of the above situation, as a result of intensive investigations, the present inventors have found that a compound having an aurone skeleton has an activity of inhibiting 17β-HSD causing a hormone-dependent disease. Therefore, an object of the present invention is to provide a hormone-dependent disease therapeutic agent containing a compound having an aurone skeleton as an active ingredient.
The present invention relates to a hormone-dependent disease therapeutic agent comprising a compound having an aurone skeleton as an active ingredient. The auron skeleton is represented by the following formula.

The drug of the present invention has 17β-HSD inhibitory activity, and due to its activity, a prophylactic and / or therapeutic agent for male and female hormone-dependent diseases, specifically prostate cancer, benign prostatic hyperplasia, androgenism, breast cancer, and mastopathy It is useful as a preventive and / or therapeutic agent for uterine cancer, endometriosis, ovarian cancer and the like.
The compound used for the drug of the present invention is a compound having an aurone skeleton, and the following compounds are particularly used.
(1) 6-hydroxy-2- (phenylmethylene) -3 (2H) -benzofuranone
(2) 2-[(4-Hydroxyphenyl) methylene] -6-hydroxy-3 (2H) -benzofuranone
(3) 2-[(3-hydroxy-4-methoxyphenyl) methylene] -6-hydroxy-3 (2H) -benzofuranone
(4) 2-[(4-Hydroxy-3-methoxyphenyl) methylene] -6-hydroxy-3 (2H) -benzofuranone
(5) 2-[(3,4-Dimethoxyphenyl) methylene] -6-hydroxy-3 (2H) -benzofuranone
(6) 2-[(4-Bromophenyl) methylene] -6-hydroxy-3 (2H) -benzofuranone
(7) 2-[(4-Fluorophenyl) methylene] -6-hydroxy-3 (2H) -benzofuranone
(8) 2-[(4-Chlorophenyl) methylene] -6-hydroxy-3 (2H) -benzofuranone
(9) 2-[(3-Hydroxy-4-methoxyphenyl) methylene] -6-hydroxy-3 (2H) -benzofuranone
(10) 6-hydroxy-2-piperonylidene-3 (2H) -benzofuranone
(11) 2-[(4-Methoxyphenyl) methylene] -6-acetoxy-3 (2H) -benzofuranone
(12) 2-[(3,4-Dimethoxyphenyl] methylene] -6-methoxy-3 (2H) -benzofuranone
(13) 2-[(4-Methoxyphenyl) methylene] -6-methoxy-3 (2H) -benzofuranone
(14) 2-[(3,5-dimethoxyphenyl) methylene] -6-methoxy-3 (2H) -benzofuranone
(15) 6-methoxy-2-piperonylidene-3 (2H) -benzofuranone
(16) 2-[(3,4-Dihydroxyphenyl) methylene] -6-hydroxy-3 (2H) -benzofuranone (generic name: sulfretin)
(17) 2-[(3,4,5-trimethoxyphenyl) methylene] -6-hydroxy-3 (2H) -benzofuranone
(18) 2-[(2,3-Dimethoxyphenyl) methylene] -6-hydroxy-3 (2H) -benzofuranone
All of these compounds are known substances. Chromatography, 57, 166 (1971) (compounds (1) to (5), (10), (17) and (18)), J. Org. Med. Chem. , 35, 1330 (1992) (compounds (6) to (8)), J. Am. Am. Chem. Soc. 79, 214 (1957) (compound (9)), Magy. Chem. Foly, 74, 582 (1968) (compound (11)), Orient. J. et al. Chem. , 11, 189 (1995) (compounds (12) and (13)), Bull. Chem. Soc. Jpn. , 54, 635 (1981) (compound (14)), Bull. Chem. Soc, Jpn. , 42, 1456 (1996) (compound (15)) can be obtained by a synthesis method according to each literature. Alternatively, it can be obtained by dissolving nucleus-substituted benzofuranone and nucleus-substituted benzaldehyde in a solvent such as methanol, ethanol, or propanol, adding concentrated hydrochloric acid, heating to reflux for 1 to 24 hours, cooling, and filtering the precipitated crystals. . At this time, if crystals do not precipitate, it can be obtained by using water or an organic solvent to precipitate as crystals by a conventional method and filtering the precipitated crystals. In addition, the compound (16) is generally commercially available and can be obtained, or extracted from a plant according to a known method (J. Am. Chem. Soc., 75, 1900 (1953)), or chemically synthesized ( Ber., 92, 2847 (1959)).
The drug of the present invention is safely administered orally and parenterally as a medicine to humans and animals. For parenteral administration, for example, intravenous injection, intramuscular injection, subcutaneous injection, intraperitoneal injection, transdermal administration, pulmonary administration, nasal administration, enteral administration, buccal administration, transmucosal administration, vaginal administration, etc. And these formulations are administered. For example, injections, suppositories, aerosols, transdermal tapes and the like can be mentioned. For example, tablets (including sugar-coated tablets, coated tablets, buccal tablets), powders, capsules (including soft capsules), granules (including coated ones), pills, troches, liquids, or these Examples include pharmaceutically acceptable sustained release preparations. Liquid preparations for oral administration include suspensions, emulsions, syrups (including dry syrups), elixirs and the like. These preparations are administered as pharmaceutical compositions together with carriers, excipients, disintegrants, lubricants, colorants and the like that are pharmacologically acceptable as preparations in accordance with known pharmaceutical manufacturing methods. Carriers and excipients used in these formulations include, for example, lactose, glucose, sucrose, mannitol, potato starch, corn starch, calcium carbonate, calcium phosphate, calcium sulfate, crystalline cellulose, licorice powder, gentian powder, For example, starch, tragacanth gum, gelatin, syrup, polyvinyl alcohol, polyvinyl ether, polyvinyl pyrrolidone, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, carboxymethyl cellulose, etc. Examples of lubricants are crystalline cellulose, calcium carbonate, sodium bicarbonate, sodium alginate, etc. Magnesium stearate, talc, hydrogenated vegetable oil, macrogol, those which are allowed to added to pharmaceuticals as coloring agents, can be used respectively. Tablets and granules are sucrose, gelatin, hydroxypropylcellulose, purified shellac, gelatin, glycerin, sorbitol, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, cellulose phthalate acetate, hydroxypropylmethylcellulose phthalate, methyl methacrylate as required The film may be coated with a methacrylic acid polymer or the like, or may be coated with a layer using two or more of these. Furthermore, capsules of substances such as ethyl cellulose and gelatin may be used. Moreover, when preparing an injection, a pH adjuster, a buffer, a stabilizer, a solubilizer, etc. are added to the main drug as necessary, and each injection is prepared by a conventional method.
When the drug of the present invention is administered to a patient, it varies depending on conditions such as the degree of symptoms, the patient's age, health condition, weight, etc., and is not particularly limited, but about 1 mg to 1000 mg, preferably 50 to 200 mg per day for an adult is administered orally It may be administered orally once or more daily.
BEST MODE FOR CARRYING OUT THE INVENTION
The present invention will be described in more detail with reference to the following examples, but these are merely illustrative and the present invention is not limited thereto.
Example 1
Preparation of 6-hydroxy-2- (phenylmethylene) -3 (2H) -benzofuranone
1 g of 6-hydroxy-2H-benzofuran-3-one and 848 mg of benzaldehyde are dissolved in 20 ml of methanol, and then a solution of 6 g of sodium hydroxide in 6 ml of water is added. After stirring for 16 hours in a nitrogen stream, 400 ml of water is added. The pH was adjusted to 4 with concentrated hydrochloric acid. The precipitated crystals are separated by filtration, dissolved in 25 ml of methanol at 60 ° C., allowed to stand at 5 ° C. for 4 hours, separated from the crystals, dried over phosphorus pentoxide at 60 ° C. for 8 hours under reduced pressure, and the target compound 432.6 mg (compound (1)) (mp 141 ° C.) was obtained.
FAB MASS; 239 (M + 1)
¹H-NMR (ppm, in DMSO-d₆); 6.72 (1H, dd, J = 10.3, 1.9 Hz), 6.74 (1H, s), 6.78 (1H, d, J = 1.5 Hz), 7.40 (1H) , T, 7.6 Hz), 7.47 (1 H, t, 7.6 Hz), 7.60 (1 H, d, 8.5 Hz), 7.91 (1 H, d, 7.6 Hz), 10.95 (1H, s)
Example 2
Preparation of 2-[(4-hydroxyphenyl) methylene] -6-hydroxy-3 (2H) -benzofuranone
After dissolving 1 g of 6-hydroxy-2H-benzofuran-3-one and 0.813 g of 4-hydroxybenzaldehyde in 75 ml of methanol, adding 50 ml of concentrated hydrochloric acid and refluxing for 2 hours, the solution was cooled to room temperature, 400 ml was added and left for 1 hour. The precipitated crystals were separated by filtration and dried over phosphorus pentoxide at 60 ° C. for 5 hours under reduced pressure to obtain 1.08 g (mp 287 ° C.) (decomposition) of the target compound (compound (2)).
FAB MASS; 255 (M + 1)
¹H-NMR (ppm, in DMSO-d₆); 6.71 (1H, dd, J = 8.2, 1.8 Hz), 6.70 (1H, s), 6.79 (1H, d, J = 1.8 Hz), 6.88 (1H) , D, 10.8 Hz), 7.58 (1 Ht, 8.5 Hz), 7.79 (1 H, d, 8.6 Hz)
Example 3
Preparation of 2-[(3-hydroxy-4-methoxyphenyl) methylene] -6-hydroxy-3 (2H) -benzofuranone
1 g of 6-hydroxy-2H-benzofuran-3-one and 1.01 g of 3-hydroxy-4-methoxybenzaldehyde are dissolved in 75 ml of methanol, 50 ml of concentrated hydrochloric acid is added and refluxed for 2 hours, and then the solution is cooled to room temperature. 400 ml of water was added and left for 2 hours. The precipitated crystals were separated by filtration and then dried over phosphorus pentoxide at 60 ° C. for 5 hours under reduced pressure to obtain 1.27 g (mp 240 to 242 ° C.) of the target compound (compound (3)).
FAB MASS; 285 (M + 1)
¹H-NMR (ppm, Hz, in DMSO-d₆); 3.83 (3H, s), 6.63 (1H, s), 6.71 (1H, dd, J = 10.6, 2.2 Hz), 6.77 (1H, d, J = 2) .1 Hz), 7.01 (1H, d, J = 8.2 Hz), 7.33 (1H, dd, J = 8.2, 2.1 Hz), 7.47 (1H, d, J = 2. 1 Hz), 7.58 (1H, d, J = 8.2 Hz)
Example 4
Preparation of 2-[(4-hydroxy-3-methoxyphenyl) methylene] -6-hydroxy-3 (2H) -benzofuranone
After dissolving 1 g of 6-hydroxy-2H-benzofuran-3-one and 1.01 g of 4-hydroxy-3-methoxybenzaldehyde in 75 ml of methanol, 50 ml of concentrated hydrochloric acid was added and refluxed for 2 hours, and then the solution was cooled to room temperature. 400 ml of water was added and left for 2 hours. The precipitated crystals were separated by filtration and then dried over phosphorus pentoxide at 60 ° C. for 5 hours under reduced pressure to obtain 0.851 g (mp 262 to 263 ° C.) of the target compound (compound (4)).
FAB MASS; 285 (M + 1)
¹H-NMR (ppm, in DMSO-d₆); 3.85 (3H, s), 6.70 (1H, s), 6.71 (1H, dd, J = 8.2, 1.8 Hz), 6.78 (1H, d, J = 8) .2 Hz), 7.44 (1H, dd, J = 8.5, 2.1 Hz), 7.50 (1H, d, J = 2.1 Hz), 7.57 (1H, d, J = 9. 6Hz)
Example 5
Preparation of 2-[(3,4-dimethoxyphenyl) methylene] -6-hydroxy-3 (2H) -benzofuranone
1 g of 6-hydroxy-2H-benzofuran-3-one and 1.23 g of 3,4-dimethoxybenzaldehyde are dissolved in 75 ml of methanol, 50 ml of concentrated hydrochloric acid is added and refluxed for 1.5 hours, and then the solution is cooled to room temperature. And 400 ml of water was added. The precipitated crystals were separated by filtration and dried over phosphorus pentoxide at 60 ° C. under reduced pressure for 7 hours to obtain 0.85 g (mp 221 ° C.) of the desired compound (compound (5)).
FAB MASS; 299 (M + 1)
¹H-NMR (ppm, in DMSO-d₆3.80 (3H, s), 3.81 (3H, s), 6.68 (1H, s), 6.72 (1H, dd, J = 8.2, 1.8 Hz), 6. 81 (1H, d, J = 2.1 Hz), 7.02 (1H, d, J = 9.6 Hz), 7.49 (2H, m) 7.55 (1H, d, J = 8.5 Hz)
Example 6
Preparation of 2-[(4-bromophenyl) methylene] -6-hydroxy-3 (2H) -benzofuranone
After dissolving 1 g of 6-hydroxy-2H-benzofuran-3-one and 1.36 g of 4-bromobenzaldehyde in 75 ml of methanol, adding 50 ml of concentrated hydrochloric acid and refluxing for 1.5 hours, the solution was cooled to room temperature, 400 ml of water was added. The precipitated crystals were separated by filtration and dried over phosphorus pentoxide at 60 ° C. under reduced pressure for 4 hours to obtain 1.16 g of the desired compound (Compound (6)).
FAB MASS; 318 (M + 1)
¹H-NMR (ppm, in DMSO-d₆); 6.69 (1H, dd, J = 7.9, 1.5 Hz), 6.72 (3H, s), 6.75 (1H, d, J = 1.8 Hz), 7.59 (1H) , D, J = 8.5 Hz), 7.62 (2H, d, J = 8.5 Hz), 7.82 (2H, d, J = 8.5 Hz), 11.21 (1H, s)
Example 7
Preparation of 2-[(4-fluorophenyl) methylene] -6-hydroxy-3 (2H) -benzofuranone
After dissolving 1 g of 6-hydroxy-2H-benzofuran-3-one and 0.78 ml of 4-fluorobenzaldehyde in 75 ml of methanol, 50 ml of concentrated hydrochloric acid was added and refluxed for 1.5 hours. After cooling this solution to room temperature, 400 ml of water was added. The precipitated crystals were separated by filtration and dried over phosphorus pentoxide at 60 ° C. for 4 hours under reduced pressure to obtain 0.74 g of the desired compound (compound (7)).
FAB MASS; 257 (M + 1)
¹H-NMR (ppm, Hz, in DMSO-d₆); 6.70 (1H, dd, J = 8.5, 1.8 Hz), 6.77 (1H, d, J = 1.8 Hz), 6.78 (1H, s), 7.30 (2H) , T, J = 8.8 Hz), 7.60 (1H, d, J = 8.6 Hz), 7.97 (2H, dd, J = 8.8, 5.4 Hz), 11.20 (1H, s)
Example 8
Preparation of 2-[(4-chlorophenyl) methylene] -6-hydroxy-3 (2H) -benzofuranone
After dissolving 1 g of 6-hydroxy-2H-benzofuran-3-one and 1.038 g of 4-chlorobenzaldehyde in 75 ml of methanol, 50 ml of concentrated hydrochloric acid was added and refluxed for 1.5 hours. The solution was cooled to room temperature and 400 ml of water was added. The precipitated crystals were separated by filtration and dried over phosphorus pentoxide at 60 ° C. for 5 hours under reduced pressure to obtain 0.82 g of the desired compound (compound (8)).
¹H-NMR (ppm, in DMSO-d₆); 6.68 (1H, dd, J = 8.5, 1.5 Hz), 6.72 (1H, s), 6.74 (1H, d, J = 1.8 Hz), 7.30 (2H) , D, J = 8.5 Hz), 7.57 (1H, d, J = 8.5 Hz), 7.87 (2H, d, J = 8.8 Hz), 11.20 (1H, s)
Example 9
Preparation of 2-((4-methoxyphenyl) methylene] -6-hydroxy-3 (2H) -benzofuranone
After dissolving 1 g of 6-hydroxy-2H-benzofuran-3-one and 1.125 g of 4-methoxybenzaldehyde in 75 ml of methanol, 50 ml of concentrated hydrochloric acid was added and refluxed for 1.5 hours. The solution was cooled to room temperature, and the precipitated crystals were filtered off and dried under reduced pressure on phosphorus pentoxide at 60 ° C. for 4 hours to obtain 0.983 g of the desired compound (Compound (9)).
FAB MASS; 269 (M + 1)
¹H-NMR (ppm, in DMSO-d₆); 3.79 (3H, s), 6.69 (1H, dd, J = 8.5, 2.1 Hz), 6.73 (1H, s), 6.76 (1H, d, J = 1) .8 Hz), 7.00 (2H, d, J = 9.1 Hz), 7.58 (2H, d, J = 8.2 Hz), 7.86 (2H, d, J = 9.1 Hz), 11 .11 (1H, s)
Example 10
Preparation of 6-hydroxy-2-piperonylidene-3 (2H) -benzofuranone
After dissolving 1 g of 6-hydroxy-2H-benzofuran-3-one and 1.11 g of piperonal in 75 ml of methanol, 50 ml of concentrated hydrochloric acid was added and refluxed for 1.5 hours. The solution was cooled to room temperature, and the precipitated crystals were separated and dried over phosphorus pentoxide at 60 ° C. for 4 hours under reduced pressure to obtain 1.37 g of the desired compound (compound (10)).
FAB MASS; 283 (M + 1)
¹H-NMR (ppm, in DMSO-d₆); 6.08 (2H, s), 6.70 (1H, dd, J = 8.2, 1.8 Hz), 6.70 (1H, s), 7.01 (1H, d, J = 7) .9 Hz), 7.44 (1H, dd, J = 8.2, 1.8 Hz), 7.52 (1H, d, J = 1.5 Hz), 7.58 (1H, d, J = 8. 2Hz), 10.99 (1H, s)
Example 11
Preparation of 2-[(4-methoxyphenyl) methylene] -6-acetoxy-3 (2H) -benzofuranone
After dissolving 0.5 g of 2-[(4-methoxyphenyl) methylene] -6-hydroxy-3 (2H) -benzofuranone in 5 ml of pyridine, 0.172 ml of acetyl chloride was added and refluxed for 2.5 hours. After cooling to room temperature, 40 ml of ethyl acetate was added, and the mixture was washed twice with 15 ml of 2N-hydrochloric acid and three times with 15 ml of saturated brine, and the ethyl acetate solution was dehydrated with magnesium sulfate and concentrated under reduced pressure. Fractionated by column chromatography (silica gel 100 g, elution solvent hexane; ethyl acetate = 1: 1, eluted with 500 ml) and concentrated to dryness under reduced pressure at 40 ° C. to obtain crystals. After dissolution, the mixture was allowed to stand at room temperature for 2 hours, and then the precipitated crystals were separated, dried over phosphorus pentoxide at 60 ° C. for 5 hours under reduced pressure, and the target compound (compound (1 )) Was obtained 354.4mg.
FAB MASS; 311 (M + 1)
¹H-NMR (ppm, in CDCl₃2.33 (3H, s), 3.84 (3H, s), 6.85 (1H, s), 6.91 (1H, d, J = 8.5, 1.8 Hz), 6. 96 (2H, d, J = 8.8 Hz), 7.13 (1H, d, J = 1.5 Hz), 7.78 (2H, d, J = 8.24 Hz), 7.84 (2H, d , J = 8.8 Hz)
Example 12
Preparation of 2-[(3,4-dimethoxyphenyl) methylene] -6-methoxy-3 (2H) -benzofuranone
Methyl p-toluenesulfonate 0 to a solution of 0.503 g of 2-[(3,4-dimethoxyphenyl) methylene] -6-hydroxy-3 (2H) -benzofuranone and 0.583 g of potassium carbonate in 5 ml of dimethylformamide After adding 254g and stirring at 60 ° C for 2 hours, 100 ml of water was added, extracted twice with 50 ml of ethyl acetate, washed twice with 50 ml of saturated brine, dehydrated with magnesium sulfate, and concentrated under reduced pressure at 40 ° C. The crude target compound was obtained as a powder. The obtained powder was fractionated by silica gel column chromatography (silica gel 50 g, elution solvent hexane: ethyl acetate = 1: 1, eluted with 500 ml), and concentrated to dryness at 40 ° C. under reduced pressure to obtain crystals. The crystals were dissolved in 2 ml of ethyl acetate and 10 ml of hexane and left at room temperature for 2 hours. The precipitated crystals were separated by filtration and dried over phosphorus pentoxide at 60 ° C. for 4 hours under reduced pressure to obtain 435.3 mg of the target compound (Compound (12)).
FAB MASS; 313 (M + 1)
¹H-NMR (ppm, in CDCl₃); 3.90 (3H, s), 3.81 (3H, s), 3.95 (3H, s), 6.72 (2H, s), 6.76 (1H, s), 6.90 (1H, d, J = 8.5 Hz), 7.44 (1H, dd, J = 8.2, 2.4 Hz), 7.45 (1H, d, J = 8.5 Hz), 7.67 ( 1H, d, J = 8.2Hz)
Example 13
Preparation of 2-[(4-methoxyphenyl) methylene] -6-methoxy-3 (2H) -benzofuranone
0.254 g of methyl p-toluenesulfonate was added to 0.452 g of 2-[(4-methoxyphenyl) methylene] -6-hydroxy-3 (2H) -benzofuranone and 0.583 g of potassium carbonate to 5 ml of dimethylformamide. After stirring at 60 ° C. for 2 hours, 100 ml of water was added, extracted twice with 50 ml of ethyl acetate, washed twice with 50 ml of saturated brine, dehydrated with magnesium sulfate, and concentrated under reduced pressure at 40 ° C. The compound was obtained as a powder. The obtained powder was fractionated by silica gel column chromatography (silica gel 50 g, elution solvent hexane: ethyl acetate = 1: 1, eluted with 500 ml), and concentrated to dryness at 40 ° C. under reduced pressure to obtain crystals. The crystals were dissolved in 2 ml of ethyl acetate and 10 ml of hexane and left at room temperature for 2 hours. The precipitated crystals were separated by filtration and dried over phosphorus pentoxide at 60 ° C. for 4 hours under reduced pressure to obtain 315.0 mg of the target compound (Compound (13)).
FAB MASS; 283 (M + 1)
¹H-NMR (ppm, in CDCl₃3.84 (3H, s), 3.90 (3H, s), 6.72 (2H, m), 6.78 (1H, s), 6.94 (2H, d, J = 8.); 5 Hz), 7.67 (1H, d, J = 8.5 Hz), 7.83 (2H, d, J = 8.5 Hz)
Example 14
Preparation of 2-((3,5-dimethoxyphenyl) methylene] -6-methoxy-3 (2H) -benzofuranone
Methyl p-toluenesulfonate 0 to a solution of 0.503 g of 2-[(3,5-dimethoxyphenyl) methylene] -6-hydroxy-3 (2H) -benzofuranone and 0.583 g of potassium carbonate in 5 ml of dimethylformamide After adding 254g and stirring at 60 ° C for 2 hours, 100 ml of water was added, extracted twice with 50 ml of ethyl acetate, washed twice with 50 ml of saturated brine, dehydrated with magnesium sulfate, and concentrated under reduced pressure at 40 ° C. The crude target compound was obtained as a powder. The obtained powder was fractionated by silica gel column chromatography (silica gel 50 g, elution solvent hexane: ethyl acetate = 1: 1, eluted with 500 ml), and concentrated to dryness at 40 ° C. under reduced pressure to obtain crystals. The crystals were dissolved in 2 ml of ethyl acetate and 10 ml of hexane and left at room temperature for 2 hours. The precipitated crystals were separated by filtration and dried over phosphorus pentoxide at 60 ° C. for 4 hours under reduced pressure to obtain 411.6 mg of the target compound (Compound (14)).
FAB MASS; 313 (M + 1)
¹H-NMR (ppm, in CDCl₃); 3.93 (6H, s), 3.95 (3H, s), 6.72 (2H, s), 6.76 (1H, s), 6.90 (1H, d, J = 8. 5 Hz), 7.44 (1H, dd, J = 8.2, 2.4 Hz), 7.45 (1H, d, J = 8.5 Hz), 7.67 (1H, d, J = 8.2 Hz) )
Example 15
Preparation of 6-methoxy-2-piperonylidene-3 (2H) -benzofuranone
To a solution obtained by adding 5 ml of dimethylformamide to 0.503 g of 6-hydroxy-2-piperonylidene-3 (2H) -benzofuranone and 0.476 g of potassium carbonate, 0.254 ml of methyl p-toluenesulfonate was added and stirred at 60 ° C. for 2 hours. Thereafter, 100 ml of water was added, the mixture was extracted twice with 50 ml of ethyl acetate, washed twice with 50 ml of saturated brine, dehydrated with magnesium sulfate, and concentrated under reduced pressure at 40 ° C. to obtain a crude target compound as a powder. The obtained powder was fractionated by silica gel column chromatography (silica gel 50 g, elution solvent hexane: ethyl acetate = 1: 1, eluted with 500 ml), and concentrated to dryness at 40 ° C. under reduced pressure to obtain crystals. The crystals were dissolved in 2 ml of ethyl acetate and 10 ml of hexane and left at room temperature for 2 hours. The precipitated crystals were separated by filtration and dried over phosphorus pentoxide at 60 ° C. for 4 hours under reduced pressure to obtain 336.7 mg of the target compound (Compound (15)).
FAB MASS; 297 (M + 1)
¹H-NMR (ppm, in CDCl₃); 3.90 (3H, s), 3.81 (3H, s), 3.95 (3H, s), 6.72 (2H, s), 6.76 (1H, s), 6.90 (1H, d, J = 8.5 Hz), 7.44 (1H, dd, J = 8.2, 2.4 Hz), 7.45 (1H, d, J = 8.5 Hz), 7.67 ( 1H, d, J = 8.2Hz)
Example 16
Preparation of 2-[(3,4,5-trimethoxyphenyl) methylene) -6-hydroxy-3 (2H) -benzofuranone
After dissolving 17 g of 6-hydroxy-2H-benzofuranone-3-one and 25 g of 3,4,5-trimethoxybenzaldehyde in 200 ml of methanol, 200 ml of concentrated hydrochloric acid was added and refluxed for 1.5 hours. After cooling this solution to room temperature, the precipitated crystals were separated and dried over phosphorus pentoxide at 60 ° C. under reduced pressure for 18 hours to obtain 36.0 g of the target compound (compound (17)).
FAB MASS; 329 (M + 1)
¹H-NMR (ppm, in DMSO-d₆3.72 (3H, s), 3.83 (6H, s), 6.70 (2H, m), 6.78 (1H, m), 7.25 (1H, s), 7.27 (1H, s), 7.56-7.59 (2H, m), 11.11 (1H, s)
Example 17
Preparation of 2-[(2,3-dimethoxyphenyl) methylene] -6-hydroxy-3 (2H) -benzofuranone
After dissolving 20 g of 6-hydroxy-2H-benzofuranone-3-one and 25 g of 2,3-dimethoxybenzaldehyde in 250 ml of methanol, 250 ml of concentrated hydrochloric acid was added and refluxed for 1.5 hours, and then 200 ml of water was added. After cooling the solution to room temperature, the precipitated crystals were separated and dried over phosphorus pentoxide at 60 ° C. under reduced pressure for 18 hours to obtain 33.3 g of the target compound (compound (18)).
FAB MASS; 299 (M + 1)
¹H-NMR (ppm, in DMSO-d6); 3.80 (3H, t), 3.81 (2H, s), 6.69 (1H, dd, J = 8.5, 1.8 Hz), 6 .76 (1H, d, J = 1.8 Hz), 6.95 (1H, s), 7.09 (1H, dd, J = 8.2, 1.2 Hz), 7.16 (1H, t, J = 7.9 Hz), 7.60 (1H, d, J = 8.5 Hz), 7.54 (1H, dd, J = 7.9, 1.2 Hz), 11.20 (1H, s)
Example 18

Each component was mixed to produce 400 500 mg tablets containing 50 mg of the compound obtained in the example.
Example 19

Each component was mixed and then compression molded, pulverized, and sized to produce 20-50 mesh 5% granules.
Example 20

The compound obtained in the above Example was dissolved in physiological saline, filled into a vial, sterilized by heating, and used as an injection for intravenous injection.
Example 21
In vitro 17β-HSD inhibitory activity test
17β-HSD inhibition of the compounds (Compounds 1-15, 17, 18) and Sulfletin (Funakoshi, Cat. No. 82-0000-8: Compound 16) obtained from Examples 1 to 17 (hereinafter referred to as test substances) Activity was tested. That is, each test substance was dissolved in ethanol, put into a test tube so that the final concentration was 260 nM, and dried with nitrogen gas. 100 mM potassium chloride, 1 mM ethylenediaminetetraacetic acid, 0.5 mM reduced nicotinamide adenine dinucleotide phosphate (all Wako Pure Chemical Industries), 1 μM [4-¹⁴C] 590 μl of 10 mM phosphate buffer (pH 7.5) containing estrone (NEN Research Products); A. According to the method of Thompson et al. (J. Biol. Chem., 249, 5364-5372, 1974), 10 μl of the microsomal fraction obtained from human placenta was added and reacted at 37 ° C. for 30 minutes with shaking. . Immediately after completion of the reaction, 2 ml of dichloromethane was added and sufficiently stirred, and centrifuged at 3000 rpm for 5 minutes. The resulting lower layer (dichloromethane layer) was transferred to another test tube and dried with nitrogen gas. To this was added 100 μl of ethanol containing 20 μg estrone and 20 μg estradiol, 20 μl of which was added to the TLC plate (silica gel 60F).₂₅₄, Merck). After developing the TLC plate with benzene: acetone (4: 1), a spot corresponding to estrone and estradiol was cut out under ultraviolet light, and a liquid scintillation cocktail (Filter Count (registered trademark); Hewlett Packard) was added to the liquid. Remaining at the scintillation counter [4-¹⁴C] produced by the amount of estrone and 17β-HSD enzyme activity [4-¹⁴C] The amount of estradiol was determined. Moreover, what performed the same operation, without adding a test substance was made into the control group. The 17β-HSD enzyme activity of the control group was set to 0% inhibition rate, and the 17β-HSD enzyme inhibition rate of the test substance was determined as a percentage. The results are shown in FIGS.
Example 22
In vivo serum estradiol level measurement test
Serum estradiol levels were measured using gonadotropin-treated young female rats. That is, 14 day old SD female rats were preliminarily raised with a parent, weaned at 20 days of age, and the next 21 days of age were 600 international pregnant maternal serum gonadotropins dissolved in physiological saline per kg of body weight. The unit was administered subcutaneously. After 24 hours, a suspension of the test substance in 0.5% carboxymethylcellulose dissolved in physiological saline was orally administered at a single dose of 100 mg / kg body weight. Four and 24 hours after administration of the test substance, whole blood was collected from the vena cava under ether anesthesia, and serum was separated by centrifugation at 3000 rpm for 30 minutes. E2 kit “Daiichi” II (Daiichi Radioisotope Laboratories) was used to measure the amount of estradiol contained in the serum of the test substance-administered rats. Serum of test substance-administered rats or a known concentration of estradiol (Wako Pure Chemical Industries) for standard curve was added to each 100 μl test tube, 3 ml of diethyl ether was added, and the mixture was stirred well and allowed to stand for a while. When the ether layer and the aqueous layer were clearly separated, the bottom was immersed in dry ice-methanol to freeze only the aqueous layer, the ether layer was transferred to another test tube, and dried at 37 ° C. with nitrogen gas. 100 μl included in the kit here¹²⁵I-estradiol and anti-estradiol antibody were added and reacted at room temperature for 90 minutes. After completion of the reaction, add 1 ml of the secondary antibody and react at room temperature for another 15 minutes, then centrifuge at 3000 rpm for 15 minutes, completely remove the supernatant with an aspirator, and exist in the sediment with a γ counter¹²⁵I-estradiol was measured. With known concentrations of estradiol¹²⁵A standard curve was drawn from the amount of I-estradiol, and the amount of estradiol (E2 amount) contained in the serum of the test substance-administered rat was measured. The results are shown in FIGS.
Industrial applicability
From the above results, the present invention provides a therapeutic agent for hormone-dependent diseases comprising a compound having an aurone skeleton as an active ingredient. The drug of the present invention has a 17β-HSD inhibitory activity, and based on the activity, an agent for preventing and / or treating male and female hormone-dependent diseases, specifically prostate cancer, benign prostatic hyperplasia, androgenism, breast cancer, and mastopathy It is useful as a preventive and / or therapeutic agent for uterine cancer, endometriosis, ovarian cancer and the like.
[Brief description of the drawings]
FIG. 1 is a diagram showing the results of Examples.
FIG. 2 is a diagram showing results of the example.

Claims (1)

The 17β-hydroxysteroid dehydrogenase inhibitor , wherein the compound having an aurone skeleton is any one of the following:
(1) 6-hydroxy-2- (phenylmethylene) -3 (2H) -benzofuranone
(2) 2-[(4-hydroxyphenyl) methylene] -6-hydroxy-3 (2H) -benzofuranone
(3) 2-[(3-Hydroxy-4-methoxyphenyl) methylene] -6-hydroxy-3 (2H) -benzofuranone
(4) 2-[(4-Hydroxy-3-methoxyphenyl) methylene] -6-hydroxy-3 (2H) -benzofuranone
(5) 2-[(3,4-Dimethoxyphenyl) methylene] -6-hydroxy-3 (2H) -benzofuranone
(6) 2-[(4-Bromophenyl) methylene] -6-hydroxy-3 (2H) -benzofuranone
(7) 2-[(4-Fluorophenyl) methylene] -6-hydroxy-3 (2H) -benzofuranone
(8) 2-[(4-Chlorophenyl) methylene] -6-hydroxy-3 (2H) -benzofuranone
(9) 2-[(3-Hydroxy-4-methoxyphenyl) methylene] -6-hydroxy-3 (2H) -benzofuranone
(10) 6-hydroxy-2-piperonylidene-3 (2H) -benzofuranone
(11) 2-[(4-Methoxyphenyl) methylene] -6-acetoxy-3 (2H) -benzofuranone
(12) 2-[(3,4-Dimethoxyphenyl) methylene] -6-methoxy-3 (2H) -benzofuranone
(13) 2-[(4-Methoxyphenyl) methylene] -6-methoxy-3 (2H) -benzofuranone
(14) 2-[(3,5-dimethoxyphenyl) methylene] -6-methoxy-3 (2H) -benzofuranone
(15) 6-methoxy-2-piperonylidene-3 (2H) -benzofuranone
(16) 2-[(3,4-Dihydroxyphenyl) methylene] -6-hydroxy-3 (2H) -benzofuranone (generic name: sulfretin)
(17) 2-[(3,4,5-Trimethoxyphenyl) methylene] -6-hydroxy-3 (2H) -benzofuranone
(18) 2-[(2,3-Dimethoxyphenyl) methylene] -6-hydroxy-3 (2H) -benzofuranone

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