JP2001502706A

JP2001502706A - Novel trans-3,4 chroman derivatives useful for prevention or treatment of estrogen-related diseases or syndromes

Info

Publication number: JP2001502706A
Application number: JP10519940A
Authority: JP
Inventors: ヤコブセン，ポウル; トレッペンダール，スベン; スタンレイバリー，ポール; カンストルプ，アンデルス; クリスティアンセン，リゼブロウン
Original assignee: Novo Nordisk AS
Current assignee: Novo Nordisk AS
Priority date: 1996-10-28
Filing date: 1997-10-28
Publication date: 2001-02-27
Also published as: ZA979643B; WO1998018774A1; CA2269936A1; NO992009D0; EP0937059A1; AU4771897A; IL129623A0; NO992009L; AU744403B2

Abstract

(57)【要約】本発明は式（Ｉ）の治療活性を有する化合物、該化合物ならびに該化合物を含む医薬調合剤の調整方法に関する。本新規化合物はエストロゲン関連病または症候群の予防または治療に有用である。 (57) [Summary] The present invention relates to a method for preparing a compound of formula (I) having therapeutic activity, said compound and a pharmaceutical preparation comprising said compound. The novel compounds are useful for preventing or treating estrogen-related diseases or syndromes.

Description

【発明の詳細な説明】エストロゲン関連病あるいは症候群の予防または治療に有用な新規トランス−３，４クロマン誘導体発明の分野本発明は、新規トランス−３，４クロマン誘導体、およびエストロゲン関連病または症候群、特にほ乳類に於けるエストロゲン欠乏状態に起因する病気あるいは症候群、特に骨消失、骨粗鬆症、心臓血管病、知覚障害、アルツハイマー型老人性痴呆、潮紅や生殖器萎縮を含む更年期障害、月経困難、切迫性および習慣性流産、不正子宮出血、座瘡、男性型多毛症、前立腺癌、分娩後授乳の予防または治療への当該発明の化合物の利用、ならびに避妊法あるいは卵巣の発達補助法へのこれら化合物の応用に関する。発明の背景閉経に伴うオステオペニアは公衆衛生上の大きな問題である。チェックを怠ると骨消失が進み、その結果骨格筋の構造の健全性が大きく損なわれ、痛みの強い衰弱骨折が腰部、脊椎、大腿骨に起こる。この骨折のリスクと頻度を下げようと主に骨吸収を阻害し骨量を保存する治療法の開発が集中し行われている。各種治療法の中にあって、エストロゲン代償療法は現在も閉経後の骨粗鬆症発生防止法として良く利用されており（ＬｉｎｄｓｅｙＲ，ＨａｒｔＤＭ、ＭａｃＣｌｅａｎＡ１９８７、”閉経後治療に於けるエストロゲン／プロゲストゲンの役割（Ｔｈｅｒｏｌｅｏｆｅｓｔｒｏｇｅｎ／ｐｒｏｇｅｓｔｏｇｅｎｉｎｔｈｅｍａｎａｇｅｍｅｎｔｏｆｔｈｅｍｅｎｏｐａｕｓｅ）”、ＣｏｏｋｅＩＤ、編集、ＰｒｏｃｅｅｄｉｎｇｓｏｆＵｎｉｖｅｒｓｉｔｙｏｆＳｃｈｅｆｆｉｅｌｄｓｙｍｐｏｓｉｕｍｏｎｔｈｅｒｏ１ｅｏｆｅｓｔｒｏｇｅｎａｎｄｐｒｏｇｅｓｔｏｇｅｉｎｔｈｅｍａｎａｇｅｍｅｎｔｏｆｔｈｅｍｅｎｏｐａｕｓｅ，ＵＫ：ＭＴＰＰｒｅｓｓＬｔｄ．ｐｐ．９−２５；ＭａｒｓｈａｌｌＤＨ，ＨｏｒｓｍａｎｎＡ，ＮｏｒｄｉｎＢＥＣ１９７７、”閉経後骨粗鬆症の防止と治療（Ｔｈｅｐｒｅｖｅｎｔｉｏｎａｎｄｍａｎａｇｅｍｅｎｔｏｆｐｏｓｔ−ｍｅｎｏｐａｕｓａｌｏｓｔｅｏｐｏｒｏｓｉｓ）”、ＡｃｔａＯｂｓｔｅｔＧｙｎｅｃｏ１Ｓｃａｎｄ（Ｓｕｐｐｌ）６５：４９−５６；ＲｅｃｋｅｒＲＲ、ＳａｖｉｌｌｅＰＤ、ＨｅａｎｅｙＲＰ１９７７，”閉経後女性の骨消失に及ぼすエストロゲンと炭酸カルシウムの作用（Ｅｆｆｅｃｔｏｆｅｓｔｒｏｇｅｎａｎｄｃａｌｃｉｕｍｃａｒｂｏｎａｔｅｏｎｂｏｎｅｌｏｓｓｉｎｐｏｓｔ−ｍｅｎｏｐａｕｓａｌｗｏｍｅｎ）、ＡｎｎＩｎｔｅｒｎＭｅｄ．８７：６４９−６５５；ＮａｃｈｔｉｇａｌｌＬＥ，ＮａｃｈｔｉｇａｌｌＲＨ、ＮａｃｈｔｉｇａｌｌＲＤ，ＢｅｃｋｍａｎＥＭ１９７９、”エストロゲン代償治療（Ｅｓｔｒｏｇｅｎｒｅｐｌａｃｅｍｅｎｔｔｈｅｒａｐｙ”、ＯｂｓｔｅｔＧｙｎｅｃｏｌ．５３：２７７−２８１）、そして現在エストロゲンは骨折発生の頻度とリスクを大きく下げると考えられている（ＫｒｉｅｇｅｒＮ，ＫｅｌｓｅｙＪＬ、ＨｏｌｆｏｒｄＴＲ，Ｏ’ＣｏｎｎｏｒＴ１９８２、”閉経後女性の臀部骨折に関する疫学調査（Ａｎｅｐｉｄｅｍｉｏｌｏｇｉｃａｌｓｔｕｄｙｏｆｈｉｐｆｒａｃｔｕｒｅｉｎｐｏｓｔｍｅｎｏｐａｕｓａｌｗｏｍｅｎ）”、ＡｍＪＥｐｉｄｅｍｉｏ．１１６：１４１−１４８；ＨｕｔｃｈｉｎｓｏｎＴＡ、ＰｏｌａｎｓｋｙＳＭ、ＦｅｉｎｓｔｅｉｎＡＲ１９７９，”閉経後のエストロゲンは臀部および遠位撓骨の骨折を防ぐ（Ｍｅｎｏｐａｕｓａ１ｅｓｔｒｏｇｅｎｔｈｅｒａｐｙａｎｄｈｉｐｆｒａｃｔｕｒｅｓ）”、ＡｎｎＩｎｔｅｒｎＭｅｄ．９５：２８−３１；ＷｅｉｓｓＮＳ，ＵｒｅＣＬ、ＢａｌｌａｒｄＪＨ、ＷｉｌｌｉａｍｓＡＲ、ＤａｌｉｎｇＪＲ１９８０、”エストロゲンの閉経後投与による臀部および下前腕部骨折リスクの低下（Ｄｅｃｒｅａｓｅｄｒｉｓｋｏｆｆｒａｃｔｕｒｅｓｏｎｔｈｅｈｉｐａｎｄｌｏｗｅｒｆｏｒｅａｒｍｗｉｔｈｐｏｓｔ−ｍｅｎｏｐａｕｓａｌｕｓｅｏｆｅｓｔｒｏｇｅｎ）”、ＮＥｎｇＪＭｅｄ．３０３：１１９５−１１９８）。エストロゲン代償治療が骨格に有益な効果を示すことは明らかであるが、同時にエストロゲンが心臓血管系にも有益な作用を持っていることを示すデータもある。これまでの研究は血清脂質へのエストロゲンの効果についてのものであったが、最近エストロゲンは脂質プロフィールだけでなく血管壁の伸展性にも直接作用し、末梢抵抗を低下しアテローム性動脈硬化を防止するデータもある（ＬｏｂｏＲＡ１９９０、”エストロゲン代償治療と心臓血管の関連（Ｃａｒｄｉｏｖａｓｃｕｌａｒｉｍｐｌｉｃａｔｉｏｎｏｆｅｓｔｒｏｇｅｎｒｅｐｌａｃｅｍｅｎｔｔｈｅｒａｐｙ”、ＯｂｓｔｅｔｒｉｃｓａｎｄＧｙｎａｅｃｏｌｏｇｙ，７５：１８Ｓ−２４Ｓ；ＭｅｎｄｅｌｓｏｎＭＥ、ＫａｒａｓＲＨ１９９４、”エストロゲンと血管壁”、ＣｕｒｒｅｎｔＯｐｉｎｉｏｎｉｎＣａｒｄｉｏｌｏｇｙ，１９９４（９）：６１９−６２６）。疫学データによれば、エストロゲンのもつこれら生理学的、薬理学的作用が総合された結果、女性では年齢と無関係に心臓血管病の罹病率と死亡率が下がる（ＫａｎｎｅｌＷＨ、ＨｊｏｒｔｌａｎｄＭ，ＭｃＮａｍａｒａＰＭ１９７６”閉経と心臓血管病のリスク：フラミンガム研究（Ｍｅｎｏｐａｕｓｅａｎｄｒｉｓｋｏｆｃａｒｄｉｏｖａｓｃｕｌａｒｄｉｓｅａｓｅ：ＴｈｅＦｒａｍｉｎｇｈａｍＳｔｕｄｙ）、ＡｎｎＩｎｔＭｅｄ，８５：４４７−５５２）。さらに、最近の分析は閉経後のエストロゲン代償治療が心臓血管病のリスクをおよそ５０％低下させると結論している（ＳｔａｍｐｆｅｒＭＪ，ＣｏｌｄｉｔｚＧＡ１９９１、”エストロゲン代償治療と冠動脈性心疾患：疫学データの定量分析（Ｅｓｔｒｏｇｅｎｒｅｐｌａｃｅｍｅｎｔｔｈｅｒａｐｙａｎｄｃｏｒｏｎａｒｙｈｅａｒｔｄｉｓｅａｓｅ：ａａｕａｎｔｉｔａｔｉｖｅａｓｓｅｓｓｍｅｎｔｏｆｔｈｅｅｐｉｄｅｍｉｏｌｏｇｉｃａｌｅｖｉｄｅｎｃｅ”、ＰｒｅｖｅｎｔｉｖｅＭｅｄｉｃｉｎｅ，２０；４７−６３．）。骨と心臓血管系に及ぼすエストロゲンの有益な作用に加え、エストロゲン代償療法には中枢神経系にも有益であるというデータもある。ヒトを対象とした短期試験より、閉経後女性ではエストロゲンのレベルが高くなるに従い記憶スコアも高くなることが示されている（ＫａｍｐｅｎＤＬ、ＳｈｅｒｗｉｎＢＢ１９９４，”閉経後の健康女性に於けるエストロゲン投与と言語記憶（Ｅｓｔｒｏｇｅｎｕｓｅａｎｄｖｅｒｂａｌｍｅｍｏｒｙｉｎｈｅａｌｔｈｙｗｏｍｅｎ）、ＯｂｓｔｅｔｒｉｃｓａｎｄＧｙｎｅｃｏｌｏｇｙ，８３（６）：９７９−９８３）。更に、手術により閉経した女性に外来性にエストロゲンを投与すると短期記憶が増強された。また、エストロゲン治療が女性に於けるアルツハイマー型老人性痴呆症のリスクを明瞭に低下させることを示す疫学所見があることから、認識力に及ぼすエストロゲンの作用は、短期の作用に限定されないと考えられる（Ｐａｇａｎｉｎｉ−ＨｉｌｌＡ，ＨｅｎｄｅｒｓｏｎＶＷ、１９９４，”女性に於けるエストロゲン欠乏とアルツハイマー病（ＥｓｔｒｏｇｅｎｄｅｆｉｃｉｅｎｃｙａｎｄｒｉｓｋｏｆＡｌｚｈｅｉｍｅｒ’ｓｄｉｓｅａｓｅｉｎｗｏｍｅｎ）”、ＡｍＪＥｐｉｄｅｍｉｏｌ，１４０：２５６−２６１；ＯｈｋｕｒａＴ，ＩｓｓｅＫ、ＡｋａｚａｗａＫ、ＨａｍａｍｏｔｏＭ、ＹｏｓｈｉｍａｓａＹ、ＨａｇｉｎｏＮ，１９９５，” アルツハイマー型痴呆症の女性患者に於ける長期エストロゲン代償治療：７症例報告（Ｌｏｎｇ−ｔｅｒｍｅｓｔｒｏｇｅｎｒｅｐｌａｃｅｍｅｎｔｔｈｅｒａｐｙｉｎｆｅｍａｌｅｐａｔｉｅｎｔｓｗｉｔｈｄｅｍｅｎｔｉａｏｆｔｈｅＡｌｚｈｅｉｍｅｒＴｙｐｅ：７ｃａｓｅｒｅｐｏｒｔｓ）”、Ｄｅｍｅｎｔｉａ，６：９９−１０７）。エストロゲンが認知機能を高めるメカニズムは不明であるが、エストロゲンが脳血流（ＧｏｌｄｍａｎＨ，ＳｋｅｌｌｅｙＥｂ，ＳａｎｄｍａｎＣＡ，ＫａｓｔｉｎＡＪ、ＭｕｒｐｈｙＳ，１９７６，”ホルモンと大脳の局所血流（Ｈｏｒｍｏｎｅｓａｎｄｒｅｇｉｏｎａｌｂｒａｉｎｂｌｏｏｄｆｌｏｗ”、ＰｈａｒｍａｃｏｌＢｉｏｃｈｅｍＲｅｖ，５（ｓｕｐｐｌ１）：１６５−１６９；ＯｈｋｕｒａＴ，ＴｅｓｈｉｍａＹ、ＩｓｓｅＫ，ＭａｔｓｕｄａＨ、ＩｎｏｕｅＴ，ＳａｋａｉＹ、ＩｗａｓａｋｉＮ，ＹａｏｉＹ、１９９５，”エストロゲンは閉経後女性の局所の大脳および小脳の血流を増加させる（Ｅｓｔｒｏｇｅｎｉｎｃｒｅａｓｅｓｃｅｒｅｂｒａｌａｎｄｃｅｒｅｂｅｌｌａｒｂｌｏｏｄｆｌｏｗｓｉｎｐｏｓｔｍｅｎｏｐａｕｓａｌｗｏｍｅｎ）”、Ｍｅｎｏｐａｕｓｅ：ＪＮｏｒｔｈＡｍＭｅｎｏｐａｕｓｅＳｏｃ．２（１）：１３−１８）および神経細胞に対する直接作用（ＳｉｎｇｈＭ，ＭｅｙｅｒＥＭ，ＳｉｍｐｋｉｎｓＪＷ，１９９５、”雌のＳｐａｒｇｕｅ−Ｄａｗｌｅｙラットの脳皮質および海馬域に於ける脳由来神経栄養性因子のメッセンジャーリボ核酸の発現に及ぼす卵巣摘出とエストラジオールの作用（Ｔｈｅｅｆｆｅｃｔｏｆｏｖａｒｉｅｃｔｏｍｙａｎｄｅｓｔｒａｄｉｏｌｒｅｐｌａｃｅｍｅｎｔｏｎｂｒａｉｎ−ｄｅｒｉｖｅｄｎｅｕｒｏｔｒｏｐｈｉｃｆａｃｔｏｒｍｅｓｓｅｎｇｅｒｒｉｂｏｎｕｃｌｅｉｃａｃｉｄｅｘｐｒｅｓｓｉｏｎｉｎｃｏｒｔｉｃａｌａｎｄｈｉｐｐｏｃａｍｐａｌｂｒａｉｎｒｅｇｉｏｎｓｏｆｆｅｍａｌｅＳｐｒａｇｕｅ−Ｄａｗｌｅｙｒａｔｓ）、Ｅｎｄｏｃｒｉｎｏｌｏｇｙ，１３６；２３２０−２３２４；ＭｃＭｉｌｌａｎＰＪ，ＳｉｎｇｅｒＣＡ，ＤｏｒｓａＤＭ，１９９６， ”成熟雌Ｓｐｒａｇｕｅ−Ｄａｗ１ｅｙラットの基底前脳に於けるｔｒｋＡおよびコリンアセチルトランスフェラーゼのｍＲＮＡ発現に及ぼす卵巣摘出とエストロゲン代償療法の効果（ＴｈｅｅｆｆｅｃｔｓｏｆｏｖａｒｉｅｃｔｏｍｙａｎｄｅｓｔｒｏｇｅｎｒｅｐｌａｃｅｍｅｎｔｏｎｔｒｋＡａｎｄｃｈｏｌｉｎｅａｃｅｔｙｌｔｒａｎｓｆｅｒａｓｅｍＲＮＡｅｘｐｒｅｓｓｉｏｎｉｎｔｈｅｂａｓａｌｆｏｒｅｂｒａｉｎｏｆｔｈｅａｄｕｌｔｆｅｍａｌｅＡｐｒａｇｕｅ−Ｄａｗｌｅｙｒａｔ）”、ＪＮｅｕｒｏｓｃｉ．，１６（５）：１８６０−１８６５）がこれら有益な活性の効果因子であると推測することができる。天然エストロゲンならびに、単独あるいは併用によりエストロゲン活性を示す合成製剤の治療への応用は前記の慢性症状に限定されるものではない。さらに次のようなエストロゲンの応用例が従来よりある：閉経症状の軽減（例えば、潮紅や生殖器萎縮）；経口避妊薬；切迫あるいは習慣性流産の予防；月経困難症の軽減；機能不全性子宮出血の軽減；卵細胞発育の補助；座瘡治療；女性に於ける体毛の過剰成長（男性型多毛症）の低下；前立腺癌治療；分娩後乳汁分泌の抑制［ＧｏｏｄｍａａｎｄＧｉｌｍａｎ，ＴｈｅＰｈａｒｍａｃｏｌｏｇｉｃａｌＢａｓｉｓｏｆＴｈｅｒａｐｅｕｔｉｃｓ（ＳｅｖｅｎｔｈＥｄｉｔｉｏｎ）ＭａｃｍｉｌｌａｎＰｕｂｌｉｓｈｉｎｇＣｏｍｐａｎｙ，１９８５，１４２１−１４２３ページ］。エストロゲン代償療法は広範囲の器官系や組織に対して有益な効果を持つことは明らかであるが、エストロゲン治療に伴う投薬量や期間によっては子宮内膜の過形成や癌化のリスクの増大ももたらす。サイクリックプロゲスチンを同時に使用すると子宮内膜病のリスクは下がるが、同時に多くの患者に受け入れがたい定期性の子宮出血を再発させることになる。エストロゲンには子宮内膜に対する刺激作用に加えて、長期のエストロゲン代償治療と乳癌のリスク上昇との関係の報告については議論が続いている（ＢｅｒｇｋｖｉｓｔＬ、ＡｄａｍｉＨＯ，ＰｅｒｓｏｓｏｎＩ，ＨｏｏｖｅｒＲ、ＳｃｈａｉｒｅＣ、１９８９、” エストロゲンとエストロゲン−プロゲスチン代償後の乳癌のリスク（Ｔｈｅｒｉｓｋｏｆｂｒｅａｓｔｃａｎｃｅｒａｆｔｅｒｅｓｔｒｏｇｅｎａｎｄｅｓｔｒｏｇｅｎ−ｐｒｏｇｅｓｔｉｎｒｅｐｌａｃｅｍｅｎｔ）、ＮＥｎｇＪＭｅｄ、３２１：２９３−２９７；ＣｏｌｄｉｔｚＧＡ、ＨａｎｋｉｎｓｏｎＳＥ、ＨｕｎｔｅｒＤＪ、ＷｉｌｅｔｔＷＣ，ＭａｎｓｏｎＪＥ、ＳｔａｍｐｆｅｒＭＪ，ＨｅｎｎｅｋｅｎｓＣ，ＲｏｓｎｅｒＢ，ＳｐｅｉｚｅｒＦＥ、１９９５、”閉経後女性に於けるエストロゲンとプロゲスチンの利用と乳癌のリスク（Ｔｈｅｕｓｅｏｆｅｓｔｒｏｇｅｎｓａｎｄｐｒｏｇｅｓｔｉｎｓａｎｄｔｈｅｒｉｓｋｏｆｂｒｅａｓｔｃａｎｃｅｒｉｎｐｏｓｔｍｅｎｏｐａｕｓａｌｗｏｍｅｎ）、ＮＥｎｇＪＭｅｄ、３２２（２４）：１５８９−１５９３）。さらに、生命を脅かすほどではないが、エストロゲン利用が禁忌となり、また患者の同意を妨げる別の副作用がエストロゲン代償治療にはある。前記の如く、子宮および乳房に対して不利益な副作用を示すことなく、エストロゲンの持つ骨、心臓血管系、および中枢神経系に対する有効作用を再現できる治療を可能にすることが「安全なエストロゲン」を実現するためには必要であり、これが実現できればエストロゲン代償治療の持つ利益を享受できる患者の数を大きく増やすことができる。従って、体の様々な部分や病症状に対してエストロゲンが有益な作用をもつことが明らかになる中で、様々な体組織を選択的に標的とする強力なエストロゲンアゴニストの開発が求められている。発明の詳細な説明本発明は、式中の置換基Ｒ²とＲ³がトランス型に配置される式（Ｉ）の化合物、並びに、これの光学および立体異性体、薬物として利用可能なエステル、エーテルおよびその塩を提供する。該式中のＲ¹はＨ、ＣＯＲ⁴、ＣＯＮＨＲ⁴、ＣＯＮＲ⁴ ₂、ＳＯ₂ＮＲ⁴ ₂あるいはＳＯ₂ＮＨＲ⁴であり、Ｒ²は、場合により、ＯＨ、ハロゲン、ニトロ、シアノ、ＳＨ、ＳＲ⁴、トリハロ −Ｃ₁−Ｃ₆−アルキル、Ｃ₁−Ｃ₆−アルキル、Ｃ₁−Ｃ₆−アルコキシおよびフェニルからなるグループより独立に選択された１から５の置換基で置換されるフェニルであり、そしてＲ³は、（ａ）−Ｘ−（ＣＨ₂）_n−Ｙで置換されたフェニルであり、当該式中のＸは原子価結合、ＯあるいはＳであり、ｎは１から１２の整数であり、ＹはＨ、ハロゲン、ＯＨ、ＯＲ⁴、ＮＨＲ⁴、ＮＲ⁴ ₂、ＮＨＣＯＲ⁴、ＮＨＳＯ₂Ｒ⁴、ＣＯＮＨＲ⁴、ＣＯＮＲ⁴ ₂、ＣＯＯＨ、ＣＯＯＲ⁴、ＳＯ₂Ｒ⁴、ＳＯＲ⁴、ＳＯＮＨＲ⁴、ＳＯＮＲ⁴ ₂、飽和型あるいは不飽和型のＣ₃−Ｃ₇複素環であり、該複素環はＯ、ＳおよびＮよりなるグループより独立に選択された１つあるいは２つのヘテロ原子を含み、場合によってはＨ、ＯＨ、ハロゲン、ニトロ、シアノ、ＳＨ、ＳＲ⁴、トリハロ−Ｃ₁−Ｃ₆−アルキル、Ｃ₁−Ｃ₆−アルキル、ならびにＣ₁−Ｃ₆−アルコキシからなるグループより独立に選択される１から３個の置換基で置換されるものであり、あるいは（ｂ）式中のｎおよびＹが（ａ）に同じである−（ＣＨ₂）_n−Ｙ、あるいは（ｃ）Ｏ、ＳおよびＮよりなるグループから独立して選択される１つあるいは２つのヘテロ原子を含み、場合によってはＨ、ＯＨ、ハロゲン、ニトロ、シアノ、ＳＨ、ＳＲ⁴、トリハロ−Ｃ₁−Ｃ₆−アルキル、Ｃ₁−Ｃ₆−アルキル、ならびにＣ₁−Ｃ₆−アルコキシからなるグループより独立に選択される１から３個の置換基と置換されることもある飽和あるいは不飽和型Ｃ₃−Ｃ₇複素環と縮合したフェニル、のいずれかであり、またＲ⁴はＣ₁−Ｃ₆−アルキルである。前記式中の化学一般用語は通常の意味にて用いられている。例えばＣ₁−Ｃ₆−アルキルという語はメチル、エチル、プロピル、イソプロピル、ブチル、ｓ−ブチルまたはイソブチルの様な直鎖状ならびに分枝状のアルキル基を含む。ハロゲンという語は塩素、臭素、ヨウ素とフッ素を意味する。Ｃ₃−Ｃ₇−複素環という語には、ピロリジニル、ピロリニル、イミダゾリル、イミダゾリジニル、ピラゾリル、ピラゾリジニル、ピラゾリニル、ピペリジル、ピペラジニル、ピロール、２Ｈ−ピロール、トリアゾリル、ピリジル、ピラジニル、ピリミジニル、ピリダジニル、モルフォリノ、チオモルフォリノ、イソチアゾリル、イソキサゾリル、オキサゾリル、オキサジアゾリル、チアジアゾリル、ならびにチアゾリルなどの基を含む。本発明の化合物は新規エストロゲンアゴニストであり、女性に於ける骨消失の予防と治療、骨粗鬆症の予防と治療、心臓血管病の予防と治療、神経ペプチドＹの過剰に伴う生理的障害の治療と予防（例えば、肥満、抑鬱など）、そして非インシュリン依存型糖尿病などの糖代謝の制御、そしてアルツハイマー型老人性痴呆症の予防と治療に有用である。さらに、これらエストロゲンアゴニストは経口避妊薬、閉経症状の軽減（例えば潮紅、生殖器萎縮、うつ病、躁病、分裂症など）、失禁、切迫または習慣性流産の防止、月経困難の軽減、機能不全性子宮出血の軽減、卵巣発達の補助、座瘡の治療、女性の体毛の過剰生育（男性型多毛症）の軽減、前立腺癌の治療、ならびに分娩後乳汁分泌の抑制に有用である。これら薬剤はまた血清コレステロールを低下し、血漿の脂質プロフィールに有益な効果を示す。本発明の化合物は骨組織と心臓血管系組織ではエストロゲンのアゴニストであるが、その他のエストロゲン標的器官では抗エストロゲンとしても機能する。例えば、これらの化合物は乳房組織や結腸では抗エストロゲンとして作用でき、そのために乳癌や結腸癌の様なエストロゲン依存型の癌の予防と治療に有用であろう。式Ｉの置換基Ｒ¹Ｏは６−または７−の位置でフェニル環と結合することが好ましい。即ち、次の式ＩａまたはＩｂのいずれかである本発明の化合物が好ましい。または当該式中のＲ¹、Ｒ²、およびＲ³は前記に同じである。本発明の好適な実施態様の一つは次式で表されるトランス型化合物である。当該式中のＲはＨまたはＣ₁−Ｃ₆アルキルである。本発明の他の好適な実施態様は次式で表されるトランス型化合物である。当該式中のｍは０から１０の間の整数である。本発明の他の好適な実施態様は次式で表されるトランス型化合物である。当該式中のｍは前記に同じである。本発明の他の好適な実施態様は、次式で表されるトランス型化合物である。当該式中のｍは前記に同じである。本発明の他の好適な実施態様は次式で表されるトランス型化合物である。当該式中のｍは前記に同じであり、２ヶ所のＲ⁴は前記に同じであり、相互に独立に選択される。本発明の他の好適な実施態様は次式で表されるトランス型化合物である。当該式中のＲ⁴は前記に同じである。本発明の他の好適な実施態様は次式で表されるトランス型化合物である。当該式中のＲ⁴は前記に同じである。本発明の他の好適な実施態様は次式で表されるトランス型化合物である。当該式中のＲ⁶は、１つ以上の置換基：メトキシ、ヒドロキシ、トリフルオロメチル、フルオロ、ならびにクロロである。最も好適な化合物は次のものである。（＋）−トランス−４−（４−（カルボキシメトキシ）フェニル）−７−ヒドロキシ−３−フェニルクロマン、（−）−トランス−４−（４−（カルボキシメトキシ）フェニル）−７−ヒドロキシ−３−フェニルクロマン、（＋）−トランス−７−ヒドロキシ−４−（４−（メトキシカルボニルメトキシ）フェニル）−３−フェニルクロマン、（−）−トランス−７−ヒドロキシ−４−（４−（メトキシカルボニルメトキシ）フェニル）−３−フェニルクロマン、（＋）−トランス−４−（４−（エトキシカルボニルメトキシ）フェニル）−７ −ヒドロキシ−３−フェニルクロマン、（−）−トランス−４−（４−（エトキシカルボニルメトキシ）フェニル）−７ −ヒドロキシ−３−フェニルクロマン、（＋）−トランス−４−（４−（ベンジルオキシカルボニルメトキシ）フェニル）−７−ヒドロキシ−３−フェニルクロマン、（−）−トランス−４−（４−（ベンジルオキシカルボニルメトキシ）フェニル）−７−ヒドロキシ−３−フェニルクロマン、（＋）−トランス−７−ヒドロキシ−３−フェニル−４−（４−（２−ピロリジノエトキシ）フェニル）クロマン（−）−トランス−７−ヒドロキシ−３−フェニル−４−（４−（２−ピロリジノエトキシ）フェニル）クロマン（＋）−トランス−７−ヒドロキシ−３−フェニル−４−（４−（３−ピロリジノプロポキシ）フェニル）クロマン（−）−トランス−７−ヒドロキシ−３−フェニル−４−（４−（３−ピロリジノプロポキシ）フェニル）クロマン（＋）−トランス−７−ヒドロキシ−３−フェニル−４−（４−（４−ピロリジノブトキシ）フェニル）クロマン（−）−トランス−７−ヒドロキシ−３−フェニル−４−（４−（４−ピロリジノブトキシ）フェニル）クロマン（＋）−トランス−７−ヒドロキシ−３−フェニル−４−（４−（５−ピロリジノペントキシ）フェニル）クロマン、（−）−トランス−７−ヒドロキシ−３−フェニル−４−（４−（５−ピロリジノペントキシ）フェニル）クロマン、（＋）−トランス−７−ヒドロキシ−３−フェニル−４−（４−（６−ピロリジノヘキシルオキシ）フェニル）クロマン、（−）−トランス−７−ヒドロキシ−３−フェニル−４−（４−（６−ピロリジノヘキシルオキシ）フェニル）クロマン、（＋）−トランス−７−ヒドロキシ−３−フェニル−４−（４−（７−ピロリジノヘプチルオキシ）フェニル）クロマン、（−）−トランス−７−ヒドロキシ−３−フェニル−４−（４−（７−ピロリジノヘプチルオキシ）フェニル）クロマン、（＋）−トランス−７−ヒドロキシ−３−フェニル−４−（４−（８−ピロリジノオクチルオキシ）フェニル）クロマン、（−）−トランス−７−ヒドロキシ−３−フェニル−４−（４−（８−ピロリジノオクチルオキシ）フェニル）クロマン、（＋）−トランス−７−ヒドロキシ−３−フェニル−４−（４−（９−ピロリジノノニルオキシ）フェニル）クロマン、（−）−トランス−７−ヒドロキシ−３−フェニル−４−（４−（９−ピロリジノノニルオキシ）フェニル）クロマン、（＋）−トランス−７−ヒドロキシ−３−フェニル−４−（４−（１０−ピロリジノデシルオキシ）フェニル）クロマン、（−）−トランス−７−ヒドロキシ−３−フェニル−４−（４−（１０−ピロリジノデシルオキシ）フェニル）クロマン、（＋）−トランス−７−ヒドロキシ−３−フェニル−４−（４−（１１−ピロリジノウンデシルオキシ）フェニル）クロマン、（−）−トランス−７−ヒドロキシ−３−フェニル−４−（４−（１１−ピロリジノウンデシルオキシ）フェニル）クロマン、（＋）−トランス−７−ヒドロキシ−３−フェニル−４−（４−（１２−ピロリジノドデシルオキシ）フェニル）クロマン、（−）−トランス−７−ヒドロキシ−３−フェニル−４−（４−（１２−ピロリジノドデシルオキシ）フェニル）クロマン、（＋）−トランス−７−ヒドロキシ−３−フェニル−４−（４−（２−ピペリジノエトキシ）フェニル）クロマン（−）−トランス−７−ヒドロキシ−３−フェニル−４−（４−（２−ピペリジノエトキシ）フェニル）クロマン（＋）−トランス−７−ヒドロキシ−３−フェニル−４−（４−（３−ピペリジノプロポキシ）フェニル）クロマン（−）−トランス−７−ヒドロキシ−３−フェニル−４−（４−（３−ピペリジノプロポキシ）フェニル）クロマン（＋）−トランス−７−ヒドロキシ−３−フェニル−４−（４−（４−ピペリジノブトキシ）フェニル）クロマン（−）−トランス−７−ヒドロキシ−３−フェニル−４−（４−（４−ピペリジノブトキシ）フェニル）クロマン（＋）−トランス−７−ヒドロキシ−４−（４−（２−ペルヒドロアゼピノエトキシ）フェニル）−３−フェニルクロマン（−）−トランス−７−ヒドロキシ−４−（４−（２−ペルヒドロアゼピノエトキシ）フェニル）−３−フェニルクロマン（＋）−トランス−７−ヒドロキシ−４−（４−（３−ペルヒドロアゼピノプロポキシ）フェニル）−３−フェニルクロマン（−）−トランス−７−ヒドロキシ−４−（４−（３−ペルヒドロアゼピノプロポキシ）フェニル）−３−フェニルクロマン（＋）−トランス−７−ヒドロキシ−４−（４−（４−ペルヒドロアゼピノブトキシ）フェニル）−３−フェニルクロマン（−）−トランス−７−ヒドロキシ−４−（４−（４−ペルヒドロアゼピノブトキシ）フェニル）−３−フェニルクロマン（＋）−トランス−４−（４−（２−ジメチルアミノエトキシ）フェニル）−７ −ヒドロキシ−３−フェニルクロマン（−）−トランス−４−（４−（２−ジメチルアミノエトキシ）フェニル）−７ −ヒドロキシ−３−フェニルクロマン（＋）−トランス−４−（４−（２−ジエチルアミノエトキシ）フェニル）−７−ヒドロキシ−３−フェニルクロマン（−）−トランス−４−（４−（２−ジエチルアミノエトキシ）フェニル）−７ −ヒドロキシ−３−フェニルクロマン（＋）−トランス−４−（４−（２−（Ｎ−エチル−Ｎ−メチルアミノ）エトキシ）フェニル）−７−ヒドロキシ−３−フェニルクロマン（−）−トランス−４−（４−（２−（Ｎ−エチル−Ｎ−メチルアミノ）エトキシ）フェニル）−７−ヒドロキシ−３−フェニルクロマン（＋）−トランス−４−（４−（３−ジメチルアミノプロポキシ）フェニル）− ７−ヒドロキシ−３−フェニルクロマン（−）−トランス−４−（４−（３−ジメチルアミノプロポキシ）フェニル）− ７−ヒドロキシ−３−フェニルクロマン（＋）−トランス−４−（４−（４−ジエチルアミノブトキシ）フェニル）−７ −ヒドロキシ−３−フェニルクロマン（−）−トランス−４−（４−（４−ジエチルアミノブトキシ）フェニル）−７ −ヒドロキシ−３−フェニルクロマン（＋）−トランス−４−（２，３−ジヒドロ−１，４−ベンゾキシアジン−６− イル）−７−ヒドロキシ−３−フェニルクロマン（−）−トランス−４−（２，３−ジヒドロ−１，４−ベンゾキシアジン−６− イル）−７−ヒドロキシ−３−フェニルクロマン（＋）−トランス−７−ヒドロキシ−４−（４−メチル−２，３−ジヒドロ−１，４−ベンゾキサジン−６−イル）−３−フェニルクロマン、（−）−トランス−７−ヒドロキシ−４−（４−メチル−２，３−ジヒドロ−１，４−ベンゾキサジン−６−イル）−３−フェニルクロマン、（＋）−トランス−４−（４−エチル−２，３−ジヒドロ−１，４−ベンゾキサジン−６−イル）−７−ヒドロキシ−３−フェニルクロマン（−）−トランス−４−（４−エチル−２，３−ジヒドロ−１，４−ベンゾキサジン−６−イル）−７−ヒドロキシ−３−フェニルクロマン（＋）−トランス−７−ヒドロキシ−３−（４−ヒドロキシフェニル）−４−（４−（２−ピロリジノエトキシ）フェニル）クロマン、（−）−トランス−７−ヒドロキシ−３−（４−ヒドロキシフェニル）−４−（４−（２−ピロリジノエトキシ）フェニル）クロマン、（＋）−トランス−７−ヒドロキシ−３−（４−トリフルオロメチルフェニル） −４−（４−（２−ピロリジノエトキシ）フェニル）クロマン、（−）−トランス−７−ヒドロキシ−３−（４−トリフルオロメチルフェニル） −４−（４−（２−ピロリジノエトキシ）フェニル）クロマン、（＋）−トランス−７−ヒドロキシ−３−（４−フルオロフェニル）−４−（４ −（２−ピロリジノエトキシ）フェニル）クロマン、（−）−トランス−７−ヒドロキシ−３−（４−フルオロフェニル）−４−（４ −（２−ピロリジノエトキシ）フェニル）クロマン、（＋）−トランス−３−（４−クロロフェニル）−７−ヒドロキシ−４−（４− （２−ピロリジノエトキシ）フェニル）クロマン、（−）−トランス−３−（４−クロロフェニル）−７−ヒドロキシ−４−（４− （２−ピロリジノエトキシ）フェニル）クロマン、（＋）−トランス−３−（３，４−ジメトキシフェニル）−７−ヒドロキシ−４−（４−（２−ピロリジノエトキシ）フェニル）クロマン、（−）−トランス−３−（３，４−ジメトキシフェニル）−７−ヒドロキシ−４ −（４−（２−ピロリジノエトキシ）フェニル）クロマン、（＋）−トランス−７−ヒドロキシ−３−（ペンタフルオロフェニル）−４−（４−（２−ピロリジノエトキシ）フェニル）クロマン、（−）−トランス−７−ヒドロキシ−３−（ペンタフルオロフェニル）−４−（４−（２−ピロリジノエトキシ）フェニル）クロマン、（＋）−トランス−４−（４−カルボキメトキシ）フェニル）−６−ヒドロキシ −３−フェニルクロマン、（−）−トランス−４−（４−カルボキメトキシ）フェニル）−６−ヒドロキシ −３−フェニルクロマン、（＋）−トランス−６−ヒドロキシ−４−（４−（メトキシカルボニルメトキシ）フェニル）−３−フェニルクロマン、（−）−トランス−６−ヒドロキシ−４−（４−（メトキシカルボニルメトキシ）フェニル）−３−フェニルクロマン、（＋）−トランス−４−（４−エトキシカルニルメトキシ）フェニル）−６−ヒドロキシ−３−フェニルクロマン、（−）−トランス−４−（４−エトキシカルニルメトキシ）フェニル）−６−ヒドロキシ−３−フェニルクロマン、（＋）−トランス−４−（４−ベンジルオキシカルニルメトキシ）フェニル）− ６−ヒドロキシ−３−フェニルクロマン、（−）−トランス−４−（４−ベンジルオキシカルニルメトキシ）フェニル）− ６−ヒドロキシ−３−フェニルクロマン、（＋）−トランス−６−ヒドロキシ−３−フェニル−４−（４−（２−ピロリジノエトキシ）フェニル）クロマン、（−）−トランス−６−ヒドロキシ−３−フェニル−４−（４−（２−ピロリジノエトキシ）フェニル）クロマン、（＋）−トランス−６−ヒドロキシ−３−フェニル−４−（４−（３−ピロリジノプロポキシ）フェニル）クロマン、（−）−トランス−６−ヒドロキシ−３−フェニル−４−（４−（３−ピロリジノプロポキシ）フェニル）クロマン、（＋）−トランス−６−ヒドロキシ−３−フェニル−４−（４−（４−ピロリジノブトキシ）フェニル）クロマン、（−）−トランス−６−ヒドロキシ−３−フェニル−４−（４−（４−ピロリジノブトキシ）フェニル）クロマン、（＋）−トランス−６−ヒドロキシ−３−フェニル−４−（４−（５−ピロリジノペントキシ）フェニル）クロマン、（−）−トランス−６−ヒドロキシ−３−フェニル−４−（４−（５−ピロリジノペントキシ）フェニル）クロマン、（＋）−トランス−６−ヒドロキシ−３−フェニル−４−（４−（６−ピロリジノヘキシルオキシ）フェニル）クロマン、（−）−トランス−６−ヒドロキシ−３−フェニル−４−（４−（６−ピロリジノヘキシルオキシ）フェニル）クロマン、（＋）−トランス−６−ヒドロキシ−３−フェニル−４−（４−（７−ピロリジノヘプチルオキシ）フェニル）クロマン、（−）−トランス−６−ヒドロキシ−３−フェニル−４−（４−（７−ピロリジノヘプチルオキシ）フェニル）クロマン、（＋）−トランス−６−ヒドロキシ−３−フェニル−４−（４−（８−ピロリジノオクチルオキシ）フェニル）クロマン、（−）−トランス−６−ヒドロキシ−３−フェニル−４−（４−（８−ピロリジノオクチルオキシ）フェニル）クロマン、（＋）−トランス−６−ヒドロキシ−３−フェニル−４−（４−（９−ピロリジノニルオキシ）フェニル）クロマン、（−）−トランス−６−ヒドロキシ−３−フェニル−４−（４−（９−ピロリジノニルオキシ）フェニル）クロマン、（＋）−トランス−６−ヒドロキシ−３−フェニル−４−（４−（１０−ピロリジノデシルオキシ）フェニル）クロマン、（−）−トランス−６−ヒドロキシ−３−フェニル−４−（４−（１０−ピロリジノデシルオキシ）フェニル）クロマン、（＋）−トランス−６−ヒドロキシ−３−フェニル−４−（４−（１１−ピロリジノウンデシルオキシ）フェニル）クロマン、（−）−トランス−６−ヒドロキシ−３−フェニル−４−（４−（１１−ピロリジノウンデシルオキシ）フェニル）クロマン、（＋）−トランス−６−ヒドロキシ−３−フェニル−４−（４−（１２−ピロリジノドデシルオキシ）フェニル）クロマン、（−）−トランス−６−ヒドロキシ−３−フェニル−４−（４−（１２−ピロリジノドデシルオキシ）フェニル）クロマン、（＋）−トランス−６−ヒドロキシ−３−フェニル−４−（４−（２−ピペリジノエトキシ）フェニル）クロマン、（−）−トランス−６−ヒドロキシ−３−フェニル−４−（４−（２−ピペリジノエトキシ）フェニル）クロマン、（＋）−トランス−６−ヒドロキシ−３−フェニル−４−（４−（３−ピペリジノプロポキシ）フェニル）クロマン、（−）−トランス−６−ヒドロキシ−３−フェニル−４−（４−（３−ピペリジノプロポキシ）フェニル）クロマン、（＋）−トランス−６−ヒドロキシ−３−フェニル−４−（４−（４−ピペリジノブトキシ）フェニル）クロマン、（−）−トランス−６−ヒドロキシ−３−フェニル−４−（４−（４−ピペリジノブトキシ）フェニル）クロマン、（＋）−トランス−６−ヒドロキシ−４−（４−（２−ペルヒドロアゼピノエトキシ）フェニル）−３−フェニルクロマン（−）−トランス−６−ヒドロキシ−４−（４−（２−ペルヒドロアゼピノエトキシ）フェニル）−３−フェニルクロマン（＋）−トランス−６−ヒドロキシ−４−（４−（３−ペルヒドロアゼピノプロポキシ）フェニル）−３−フェニルクロマン（−）−トランス−６−ヒドロキシ−４−（４−（３−ペルヒドロアゼピノプロポキシ）フェニル）−３−フェニルクロマン（＋）−トランス−６−ヒドロキシ−４−（４−（４−ペルヒドロアゼピノブトキシ）フェニル）−３−フェニルクロマン（−）−トランス−６−ヒドロキシ−４−（４−（４−ペルヒドロアゼピノブトキシ）フェニル）−３−フェニルクロマン（＋）−トランス−４−（４−（２−ジメチルアミノエトキシ）フェニル）−６ −ヒドロキシ−３−フェニルクロマン（−）−トランス−４−（４−（２−ジメチルアミノエトキシ）フェニル）−６ −ヒドロキシ−３−フェニルクロマン（＋）−トランス−４−（４−（２−ジエチルアミノエトキシ）フェニル）−６ −ヒドロキシ−３−フェニルクロマン（−）−トランス−４−（４−（２−ジエチルアミノエトキシ）フェニル）−６ −ヒドロキシ−３−フェニルクロマン（＋）−トランス−４−（４−（２−（Ｎ−エチル−Ｎ−メチルアミノ）エトキシ）フェニル）−６−ヒドロキシ−３−フェニルクロマン（−）−トランス−４−（４−（２−（Ｎ−エチル−Ｎ−メチルアミノ）エトキシ）フェニル）−６−ヒドロキシ−３−フェニルクロマン（＋）−トランス−４−（４−（３−ジメチルアミノプロポキシ）フェニル）− ６−ヒドロキシ−３−フェニルクロマン（−）−トランス−４−（４−（３−ジメチルアミノプロポキシ）フェニル）− ６−ヒドロキシ−３−フェニルクロマン（＋）−トランス−４−（４−（４−ジエチルアミノブトキシ）フェニル）−６ −ヒドロキシ−３−フェニルクロマン（−）−トランス−４−（４−（４−ジエチルアミノブトキシ）フェニル）−６ −ヒドロキシ−３−フェニルクロマン（＋）−トランス−４−（２，３−ジヒドロ−１，４−ベンゾキサジン−６−イル）−６−ヒドロキシ−３−フェニルクロマン（−）−トランス−４−（２，３−ジヒドロ−１，４−ベンゾキサジン−６−イル）−６−ヒドロキシ−３−フェニルクロマン（＋）−トランス−６−ヒドロキシ−４−（４−メチル−２，３−ジヒドロ−１，４−ベンゾキサジン−６−イル）−３−フェニルクロマン、（−）−トランス−６−ヒドロキシ−４−（４−メチル−２，３−ジヒドロ−１，４−ベンゾキサジン−６−イル）−３−フェニルクロマン、（＋）−トランス−４−（４−エチル−２，３−ジヒドロ−１，４−ベンゾキサジン−６−イル）−６−ヒドロキシ−３−フェニルクロマン（−）−トランス−４−（４−エチル−２，３−ジヒドロ−１，４−ベンゾキサジン−６−イル）−６−ヒドロキシ−３−フェニルクロマン（＋）−トランス−６−ヒドロキシ−３−（４−ヒドロキシフェニル）−４−（４−（２−ピロリジノエトキシ）フェニル）クロマン、（−）−トランス−６−ヒドロキシ−３−（４−ヒドロキシフェニル）−４−（４−（２−ピロリジノエトキシ）フェニル）クロマン、（＋）−トランス−６−ヒドロキシ−３−（４−トリフルオロメチルフェニル） −４−（４−（２−ピロリジノエトキシ）フェニル）クロマン、（−）−トランス−６−ヒドロキシ−３−（４−トリフルオロメチルフェニル） −４−（４−（２−ピロリジノエトキシ）フェニル）クロマン、（＋）−トランス−６−ヒドロキシ−３−（４−フルオロフェニル）−４−（４ −（２−ピロリジノエトキシ）フェニル）クロマン（−）−トランス−６−ヒドロキシ−３−（４−フルオロフェニル）−４−（４ −（２−ピロリジノエトキシ）フェニル）クロマン、（＋）−トランス−３−（４−クロロフェニル）−６−ヒドロキシ−４−（４− （２−ピロリジノエトキシ）フェニル）クロマン、（−）−トランス−３−（４−クロロフェニル）−６−ヒドロキシ−４−（４− （２−ピロリジノエトキシ）フェニル）クロマン、（＋）−トランス−３−（３，４−ジメトキシフェニル）−６−ヒドロキシ−４ −（４−（２−ピロリジノエトキシ）フェニル）クロマン、（−）−トランス−３−（３，４−ジメトキシフェニル）−６−ヒドロキシ−４ −（４−（２−ピロリジノエトキシ）フェニル）クロマン、（＋）−トランス−６−ヒドロキシ−３−（ペンタフロオロフェニル）−４−（４−（２−ピロリジノエトキシ）フェニル）クロマン、（−）−トランス−６−ヒドロキシ−３−（ペンタフロオロフェニル）−４−（４−（２−ピロリジノエトキシ）フェニル）クロマン、ならびにラセミ体混合体を含む当該化合物の混合体である。下記の化合物ならびにその純粋な鏡像異性体もまた本発明の開示の一部である。（±）−トランス−７−ヒドロキシ−３−フェニル−４−（４−（２−ピロリジノエトキシ）フェニル）クロマン、（±）−トランス−７−ヒドロキシ−３−（４−フルオロフェニル）−４−（４ −（２−ピロリジノエトキシ）フェニル）クロマン、（±）−トランス−７−ヒドロキシ−３−（４−フルオロフェニル）−４−（４ −（２−ピペリジノエトキシ）フェニル）−クロマン。本発明の化合物は、例えばＰ．Ｋ．Ａｒｏｒａ，Ｐ．Ｋ．ＫｏｌｅとＳ．Ｒａｙ、ＩｎｄｉａｎＪ．Ｃｈｅｍ．２０Ｂ、４１−５，１９８１；Ｓ．Ｒａｙ、Ｐ．Ｋ．ＧｒｏｖｅｒとＮ．Ａｎａｎｄ，ＩｎｄｉａｎＪ．Ｃｈｅｍ．９，７２７−８、１９７１；Ｓ．Ｒａｙ、Ｐ．Ｋ．Ｇｒｏｖｅｒ、Ｖ．Ｐ．Ｋａｍｂｏｊ，Ｓ．Ｂ．Ｂｅｔｔｙ，Ａ．Ｂ．ＫａｒとＮ．Ａｎａｎｄ，Ｊ．Ｍｅｄ．Ｃｈｅｍ．１９、２７６−９，１９７６；Ｍｄ．Ｓａｌｍａｎ，Ｓ．Ｒａｙ，Ａ．Ｋ．Ａｇａｒｗａｌ，Ｓ．Ｄｕｒａｎｉ，Ｂ．Ｓ．Ｂｅｔｔｙ、Ｖ．Ｐ．ＫａｍｂｏｊとＮ．Ａｎａｎｄ、Ｊ．Ｍｅｄ．Ｃｈｅｍ．２６，５９２−５、１９８３；Ｔｅｏ，Ｃ．，Ｓｉｍ、Ｋ．，ＳｉｎｇａｐｏｒｅＮａｔｌ．Ｉｎｓｔ．Ｃｈｅｍ．２２，６９−７４，１９９４の様な当業者公知のクロマン化学によって調製することも可能だろう。しかし、さらに本発明は下記工程よりなる式（Ｉ）の化合物を調製するための一般的方法にも関する。ａ）式（ＩＩ）の化合物を、式中のＲ⁵がＨ，ＯＨ，ハロゲン、ニトロ、シアノ、ＳＨ、ＳＲ⁴、トリハロ−Ｃ₁ −Ｃ₆−アルキル、Ｃ₁−Ｃ₆−アルキルとＣ₁−Ｃ₆−アルコキシより成るグループから独立に選択される１から３個の置換基であり、Ｒ⁴が前記に同じである式（ＩＩＩ）の化合物と、トリエチルアミンと無水酢酸存在下に反応せしめ、式中のＲ⁵が前記に同じである式（ＩＶ）の化合物を形成させ、ｂ）式（ＩＶ）の化合物を適当な水素化物還元剤と反応せしめ、式中のＲ⁵が前記に同じである式（Ｖ）の化合物を形成させ、ｃ）式（Ｖ）の化合物を適当な触媒存在下に水素化し、式中のＲ⁵が前記に同じである３，４−シス型の式（ＶＩ）の化合物を形成させ、ｄ）式（ＶＩ）の化合物を適当な求電子体によりアルキル化し、式中のｎ、Ｒ⁵ ならびにＹが前記に同じである式（ＶＩＩ）の化合物を形成させ、ｅ）式（ＶＩＩ）の化合物を適当な塩基でエピマー化して、式中のｎ，Ｒ⁵とＹが前記に同じである３，４−トランス型の式（ＶＩＩＩ）の化合物を形成させ、ｆ）式（ＶＩＩＩ）の化合物を適当な脱保護剤、好ましくはピリジン塩酸塩縮合により脱保護化し、式中のＲ¹が水素である式（Ｉ）の化合物を形成させる。または、ｇ）式（ＶＩ）の化合物を適当なニトロ化剤によりニトロ化し、式中のＲ⁵が前記に同じである式（ＩＸ）の化合物を形成させ、ｈ）式（ＩＸ）の化合物を適当な還元剤、好ましくは触媒により水素化して還元し、式中のＲ⁵が前記に同じである式（Ｘ）の化合物を形成させ、ｉ）式（Ｘ）の化合物を適当な薬剤により環状化して、式中のＲ⁵ とＲ⁴が前記に同じである式（ＸＩ）または（ＸＩＩ）の化合物を形成させ、ｊ）式（ＸＩ）または（ＸＩＩ）の化合物を適当な塩基により鏡像異性体化して、式中のＲ⁵とＲ⁴が前記に同じである３，４−トランス型の式（ＸＩＩＩ）または（ＸＩＶ）の化合物を形成させ、またはｋ）式（ＸＩＩＩ）または（ＸＩＶ）の化合物を適当な脱保護剤、好ましくはピリジン塩素塩縮合により脱保護し、式中のＲ¹が水素である式（Ｉ）の化合物を形成させる。または、ｌ）式（ＶＩ）の化合物をトリフルオロメタンスルフォン酸無水物と反応せしめ、式中のＲ⁵が前記に同じである式（ＸＶ）の化合物を形成させ、ｍ）式（ＸＶ）の化合物を適当な架橋相手と架橋反応せしめ、式中のｎ，Ｒ⁵とＹが前記に同じである式（ＸＶＩ）の化合物を形成させ、ｎ）式（ＸＶＩ）の化合物を適当な塩基を用いて鏡像異性体化し、式中のｎとＲ⁵ が前記に同じである３，４−トランス型の式（ＸＶＩＩ）の化合物を形成させ、ｏ）式（ＸＶＩＩ）の化合物を適当な脱保護剤、好ましくはピリジン塩酸塩縮合により脱保護化せしめ、式中のＲ¹が水素である式（Ｉ）の化合物を形成させる。または、ｐ）式中のＲ⁵が前記に同じである式（ＸＶＩＩＩ）の化合物をジメチルアミン存在下にパラフォルムアルデヒドと反応せしめ環状化し、式中のＲ⁵が前記に同じである式（ＸＩＸ）の化合物を形成させ、ｑ）式（ＸＩＸ）の化合物を適当なグリニャール試薬と反応せしめ、式中のｎ，Ｒ⁵とＹが前記に同じである式（ＸＸ）の化合物を形成させ、ｒ）式（ＸＸ）の化合物を適当な触媒を用い水素化せしめ、式中のｎ，Ｒ⁵とＹが前記に同じである３．４−シス型の式（ＸＸＩ））の化合物を形成させ、ｓ）式（ＸＸＩ）の化合物を適当な塩基を用いて鏡像異性体化し、式中のｎ，Ｒ⁵ とＹが前記に同じである３，４−トランス型の式（ＸＸＩＩ）の化合物を形成させ、ｔ）式（ＸＸＩＩ）の化合物を適当な脱保護剤、好ましくはピリジン塩素塩縮合により脱保護し、式中のＲ¹が水素である式（Ｉ）の化合物を形成させる。または、ｕ）式中のＲ¹が水素である式（Ｉ）の化合物を適当なカルボン酸またはスルフォン酸誘導体と反応せしめ、式中のＲ¹がＣＯＲ⁴、ＣＯＮＨＲ⁴、ＣＯＮＲ⁴ ₂、ＳＯ₂ＮＲ⁴ ₂、またはＳＯ₂ＮＨＲ⁴であり、当該式中のＲ⁴が前記に同じである式（Ｉ）の化合物を形成させ、ｖ）式（ＶＩ）の化合物をメタンスルフォニルクロライドと反応せしめ、式中のＲ⁵が前記に同じである式（ＸＸＩＩＩ）の化合物を形成させ、ｗ）式（ＸＸＩＩＩ）の化合物をピリジン塩酸塩または三臭化硼酸塩の様な適当な脱保護剤を用いて脱保護し、Ｒ⁵が前記に同じである式（ＸＸＩＶ）の化合物を形成させ、ｘ）式（ＸＸＩＶ）の化合物をベンジル臭化体または４−メチルベンジル臭化体の様な適当な保護剤と反応させて式中のＲ⁵が前記に同じで、Ｒ⁶がＨまたはメトキシ基である式（ＸＸＶ）の化合物を形成させ、ｙ）式（ＸＸＶ）の化合物を水酸化ナトリウムまたは水酸化カリウムのアルコール液の様な適当な脱保護剤を用いて脱保護化し、式中のＲ⁵が前記に同じであり、Ｒ⁶がＨまたはメトキシ基である式（ＸＸＶＩ）の化合物を形成させ、ｚ）式（ＸＸＶＩ）の化合物を適当な求電子体を用いてアルキル化し、式中のｎ，Ｒ⁵とＹが前記に同じであり、Ｒ⁶がＨまたはメトキシ基である式（ＸＸＶＩＩ）の化合物を形成させ、ａａ）式（ＸＸＶＩＩ）の化合物を適当な脱保護剤、好ましくはＲ⁶がＨの場合は触媒による水素化を、またはＲ⁶がメトキシ基の場合は強酸を用い脱保護化し、式中のｎ，Ｒ⁵とＹが前記に同じである式（ＸＸＶＩＩＩ）の化合物を形成させ、ｂｂ）式（ＸＸＶＩ）の化合物を１，２−ジブロモエタン、１−ブロモ−２−クロロエタン、１，４−ジブロモブタン、１，６−ジブロモヘキサン、１，８−ジブロモオクタン、１，１０−ジブロモデカンの様な二ハロゲン化物、好ましくはヨウ化カリウムにより触媒し、式中のＲ⁵が前記に同じであり、Ｒ⁶がＨまたはメトキシ基であり、Ｈａｌがクロロ、ブロモ、またはヨードである式（ＸＸＩＸ）の化合物を形成させ、ｃｃ）式（ＸＸＩＸ）の化合物を適当な求核性試薬、好ましくはアミンと反応せしめ、式中のＲ⁶はＨまたはメトキシ基であり、ＺはＮＨＲ⁴、ＮＲ⁴ ₂、またはＣ₃ −Ｃ₇複素環アミンであり、該複素環アミンは酸素または窒素を含むこともあり、さらにＨ、ＯＨ、ハロゲン、ニトロ、シアノ、トリハロ−Ｃ₁−Ｃ₆−アルキル、Ｃ₁−Ｃ₆−アルキルとＣ₁−Ｃ₆−アルコキシよりなるグループから独立に選択される１から３個の置換基で置換されることもあり、そしてｎ，Ｒ⁴とＲ⁵は前記に同じである式（ＸＸＸ）の化合物を形成し、ｄｄ）式（ＸＸＸ）の化合物を適当な脱保護剤、好ましくはＲ⁶がＨの場合は触媒による水素化を、またはＲ⁶がメトキシ基の場合は強酸を用い脱保護化し、式中のＲ⁶はＨまたはメトキシ基であり、そしてＺはＮＨＲ⁴、ＮＲ⁴ ₂、またはＣ₃ −Ｃ₇複素環アミンであり、該複素環アミンは酸素または窒素を含むこともあり、さらにＨ、ＯＨ、ハロゲン、ニトロ、シアノ、トリハロ−Ｃ₁−Ｃ₆−アルキル、Ｃ₁−Ｃ₆−アルキルとＣ₁−Ｃ₆−アルコキシよりなるグループから独立に選択される１から３個の置換基で置換されることもある、そしてｎ，Ｒ⁴とＲ⁵は前記に同じである式（ＸＸＸＩ）の化合物を形成させる。式（ＩＩ）の出発ベンゾフェノン体は、適当なジメチルエーテルをｐ−ヒドロキシ安息香酸によってＦｒｉｅｄｅｌ−Ｃｒａｆｔアシル化反応させ、ついで酢酸中で選択的に１つの基を脱メチル化せしめることで容易に調製できる。式（ＸＶＩＩＩ）の出発デオキシベンゾイン体は、適当なジメチルエーテルと適当な置換型フェニル酢酸誘導体とをＨｏｅｓｃｈ反応させ、ついで酢酸中で臭化水素酸で選択的に１つの基を脱メチル化せしめることで容易に調製できる。光学的に純粋な式（Ｉ）の化合物は、前記方法に分離工程を一つ導入することで得ることができる。該分離は鏡像異性体のラセミ混合体が生成されるいかなる工程の後にも実施可能である。ジアステレオマー塩形成またはキラルＨＰＬＣ法を含む分離法法を利用することで（−）−鏡像異性体と／または(＋)−鏡像異性体を異性体混合物から分離することができる。 ”適当な求電子体”とは、典型的には式中のＹが前記と同じであり、ＨｌｇがＣｌ，ＢｒまたはＩである式Ｙ−（ＣＨ₂）ｎ−Ｈｌｇで表されるアルキルハロゲン化物を意味している。前記方法にある環状化の工程は、例えば適当な活性化カルボン酸誘導体を水素化して実施しうる。 ”適当な架橋相手”とは、典型的には、例えばＮｉ（Ｏ）触媒が入ったグリニャール試薬の様な遷移金属触媒と一緒になった有機金属試薬を意味する。 ”適当なグリニャール試薬”とは、典型的には式中のＭがＭｇＨｇで、ＨｌｇがＣｌ、Ｂｒ、またはＩで、Ｙが前記に同じである式Ｍ−（ＣＨ₂）−Ｙの有機金属化合物を意味する。塩基を用いて３，４−シス型クロマンを３，４−トランス型クロマンに鏡像異性体化する方法はすでにＡ．Ｋ．Ｓｃｒｉｖａｓｔａｖａ，Ｊ．Ｌａｌ，Ｒ．Ｃ．．ＧｕｐｔａとＰ．Ｋ．ＧｒｏｖｅｒによりＩｎｄｉａｎＪ．Ｃｈｅｍ．３３３，７７３−４，１９９４に記載されている。本発明は、本発明の化合物を効果量と医薬品用賦形剤または希釈液を含む医薬品にも関する。これら医薬品は経口投与体または非経口投与体の形状であることが好ましい。さらに本発明は、エストロゲン関連病または症候群、好ましくは哺乳動物に於けるエストロゲン欠乏状態を原因とする病気または症候群を、本発明の化合物の効果量をそれを必要とする患者に投与することで、治療または予防する方法でもある。本発明の化合物は新規のエストロゲンアゴニストであり、骨消失の予防と治療、骨粗鬆症の予防と治療、心臓血管病の予防と治療、ニューロペプチドＹ過剰に伴う生理学的障害（例えば肥満や抑鬱症など）の治療と予防や例えば非インシュリン依存型糖尿病の様な糖代謝の制御や女性に於けるアルツハイマー型老人性痴呆症の予防と治療に有用である。さらに、これらエストロゲンアゴニストは経口避妊薬、閉経後症状（例えば紅潮、性器萎縮、抑鬱、躁病、精神分裂病など）の軽減、失禁、切迫または習慣性流産の予防、月経困難症の軽減、機能障害性子宮出血の軽減、卵巣発達の補助、アクネの治療、女性に於ける体毛の過剰生育の低減（男性型多毛症）、前立腺癌の治療や分娩後乳汁分泌の抑制にも有用である。これらの化合物は血清コレステロールも低下させ、血漿の資質プロフィールにも有効な作用を持つ。本発明の化合物は骨および心臓血管系ではエストロゲンアゴニストであるが、これら化合物はエストロゲン標的器官では抗エストロゲンとしても作用できる。例えば、これらの化合物は乳房組織や結腸内では抗エストロゲンとして作用できるので、乳ガンや結腸癌の様なエストロゲン依存型の癌の防止および治療に有用である。Ｉｎｖｉｔｒｏエストロゲンレセプター結合試験ｉｎｖｉｔｒｏレセプター結合試験を利用して本発明の化合物のエストロゲンレセプターへの親和性を測定した。本アッセーは、本発明の化合物の持つ、ウサギの子宮から得たエストロゲンレセプター（ＥＲ）から３Ｈ−１７β−エストラジオール（１７β−Ｅ２）を解離させる力を測定するものである。実験では、ウサギの子宮より得たＥＲに富む細胞質を、ウサギの筋肉から得たＥＲに乏しい細胞質で０．５ｎＭの³Ｈ −１７β−Ｅ２の最大結合の２０−２５％になるまで希釈した。アッセー毎に分析日当日に細胞質の一部を新たに解凍し、アッセーバッファーでおよそ３ｍｇ細胞質蛋白量／ｍｌになるように希釈した。アッセーバッファー（ＰＢ）の組成は以下の通りである：１０ｍＭＫ₂ＨＰＯ₄／ＫＨ₂ＰＯ₄、１．５ｍＭＫ₂ＥＤＴＡ、１０ｍＭモノチオグリセロール、１０ｍＭＮ_a２ＭｏＯ₄．２Ｈ₂Ｏ、１０％グリセロール（ｖ／ｖ）；ｐＨ７．５。非放射活性型１７β−Ｅ２はＳｉｇｍａ（シグマ社）より得た。試験液は適当な溶媒中に８×１０−３Ｍになるように調整してから、ＰＢまたはＤＭＳＯで希釈し希釈系列を作製した。各試験濃度について、１０μｌの試験液を２つづつ取り、２０μｌの³Ｈ−１７β−Ｅ２（アッセー濃度０．４ｎＭに等しい）と５０μｌの細胞質が加えておいたマイクロタイタープレートのなかに入れて反応させた。対照サンプルと最大結合サンプルについては試験化合物の代わりに１０μｌのＰＢを加えた。４℃で１８−２０時間反応させた後、１００μｌのＤＣＣスラリー［０．５％活性炭（Ｓｉｇｍａ）と０．００５％デキストランＴ７０（Ｐｈａｒｍａｃｉａ）のＰＢ液］をサンプルに加えて停止し、さらに４℃で１５分間攪拌しつづけた。細胞質の代わりに０．３％のＢＳＡのＰＢ液を５０μｌ加えて、ＤＣＣの持つバックグランドの数値を調べた。結合型の³Ｈ−１７β−Ｅ２と遊離型の³Ｈ−１７β−Ｅ２を分離するために、Ｔｉｔｅｒｔｅｋ社製プレートを４℃で１０分間遠心分離し（８００×ｇ）、サンプルの一部１００μｌを取りＯｐｔｉｆｌｏｕｒシンチレーション液を用いシンチレーション測定を行った。標準サンプルと対照サンプルは４重測定したが、試験サンプルについては２重測定した。各サンプルについて１分当たりの平均カウント（ｃｐｍ）を計算し、値からバックグランド（ＤＣＣ）を引いて最大３Ｈ−１７β−Ｅ２結合のパーセントを求めた。得られたｃｐｍを対応する試験化合物の推定濃度に対してプロットし（対数スケール）、最大結合の５０％を置き換えるために必要な化合物濃度をＩＣ５０とした。骨ミネラル密度骨ミネラル含有量（ＢＭＣ）を表す骨ミネラル密度（ＢＭＤ）は骨強度の８０％以上を担うものである。高齢化に伴うＢＭＤの喪失や閉経による加速は骨格強度を低下させ、特定の箇所をより骨折しやすくする；例えば最も顕著な箇所は脊椎、手首、臀部である。真の骨密度の測定はＡｒｃｈｉｍｅｄｅ（アルキメデス）の原理を利用した重量測定により可能である（侵襲法）。ＢＭＤはまた二波長Ｘ−線吸光法（ＤＥＸＡ）により非侵襲性に測定することもできる。当研究室では重量測定法を用い、卵巣摘出した齧歯動物に於けるエストロゲン欠乏によるＢＭＤの変化を調べた。卵巣を摘出してから（卵巣を手術により取り除く）、動物に賦形剤、陽性コントロールである１７β−Ｅ２と／あるいはその他のエストロゲンアゴニストを投与した。これらの研究の目的は、ヒトの病気の齧歯類モデルにおける本発明の化合物の骨喪失の防止能力を調べることである。雌のＳｐｒａｇｕｅ−Ｄａｗｌｅｙラット（およそ３から５ヶ月齢）または雌のＳｗｉｓｓ−Ｗｅｂｓｔｅｒマウス（およそ３から５ヶ月齢）の卵巣を両側とも切除するか、またはシャム手術した。麻酔からさめた後に、動物を無作為に次の群に８匹以上割り付けた：賦形剤を投与しシャム手術した動物賦形剤を投与し卵巣を摘出した動物２５μｇエストラジオール／ｋｇを投与し卵巣を摘出した動物、と試験化合物２００μｇ／ｋｇを投与し卵巣を摘出した動物。化合物は重量を測ってから賦形剤溶媒の無菌生理食塩水液に溶解し、３５日間毎日動物に皮下注射して投与した。３５日のプロトコールの終了時に動物を屠殺し、大腿骨を切り出してから付着した軟組織を除いた。ラットの場合、ダイヤモンド製回転ソーを使って肉をとった大腿部の端部を１ｃｍ切り取り、７０％エチルアルコールで固定し（マウスの場合には端部．５ｃｍを切り取り固定した）。７０％エチルアルコール（ＥｔＯＨ）で固定してから自動組織プロセッサーを用いて骨標本をアルコール濃度１００％まで順次移して脱水した。脱水してからクロロフォルムで脂質を除き、そして蒸留水に入れて水和させた。自動組織標本作製の工程は全て真空下で行った。水和した骨の重量を空気中で測定し、ついで密度測定キットを装備したＭｅｔｔｌｅｒバランスを用いて水中に懸架してた状態で重量を測定した。各サンプルの空気中重量を、空気重量と水中重量の差で除して総骨密度を求めた；即ち組織単位容積当たりの有機マトリックス＋ミネラル量。総骨密度を求めた後でサンプルを一晩マッフル炉に入れて６００℃に熱し灰化する。それから各サンプルの灰重量を組織容積（即ち空気重量−水中懸架重量）で除してミネラル密度を求めた。各群について平均骨密度（総骨密度とミネラル骨密度）を計算し、賦形剤投与群とエストロゲン投与対照群との統計有意差をコンピューター統計プログラムを利用して求めた。コレステロール低下活性総コレステロールの血清レベルに及ぼす本発明の化合物の作用を前記骨密度測定に共した動物より得た血液サンプル、あるいは２８日間以上の化合物を投与した卵巣摘出ラットまたはマウスより得た血液サンプルを利用して調べた。それぞれの実験では、化合物投与動物からの血液は心臓穿刺により採取し、血液１ｍｌ当たり３０μｌの５％ＥＤＴＡを含む試験管の中に入れた。２０℃ 、２５００ｒｐｍで１０分間遠心分離した後、血漿を取り出し、測定まで−２０ ℃に保管した。コレステロールはＳｉｇｍａＤｉａｇｎｏｓｔｉｃｓより市販されている標準的な酵素法によるキット（キット番号３５２）を利用して測定した。製剤調整本発明の化合物を一般的なアジュバント、キャリアー、または希釈液と一緒にして、また薬剤に利用可能な酸の添加が必要な場合には当該酸の塩を加えて製剤の形状にし、またその投与単位形状にすることができ、また錠剤や充填カプセルの様な固形製剤または溶液、懸濁液、乳剤、エリキシル剤の様な薬液、またはその充填カプセルなど経口投与に適する全ての形状に成形することができる。または非経口投与用（皮下投与や注入を含む）として滅菌された注射可能な溶液にすることもできる。この様な医薬製剤とその投与単位形状体には通常の賦形剤を通常の割合で含でおり、その他の活性化合物あるいは成分については含むことも、また含まないこともあり、そしてこれら投与単位形状体は毎日の投与範囲量として適当な効果量の本発明の化合物を含んでいる。投与単位形状体の好適な例としては活性成分１０ミリグラムを含む錠剤、より広範囲には１錠当たり１０から１００ミリグラムを含む錠剤がある。本発明の化合物は医薬製剤の処方、例えば生薬の一般的な投与法によるヒトを含む哺乳動物への経口および非経口投与に利用できる。通常の賦形剤とは、活性化合物と反応し有害になることがない非腸管的投与にも、また腸管的投与にも好適な薬物に利用可能な有機または無機のキャリアーである。この様なキャリアーの例としては水、塩溶液、アルコール、ポリエチレングリコール、ポリヒドロキシエトキシ化ひまし油、ゼラチン、乳糖アミロース、ステアリン酸マグネシウム、タルク、ケイ酸、脂肪酸モノグリセリド、脂肪酸ジグリセリド、ペンタエリスリトール脂肪酸エステル、ヒドロキシメチルセルロースやポリビニルピロリドンがある。医薬製剤は滅菌し、必要であれば活性化合物と反応し有害とならない補助剤、乳化剤、浸透圧調整用の塩、緩衝剤や／または着色剤などを混合することができる。非腸管的投与としては、特に注射液または注射懸濁液が好適であり、ポリヒドロキシ化されたひまし油に溶解された活性物質を含む水溶液が好ましい。投与単位形状体としてはアンプルが便利である。タルクや／または炭水化物キャリアーまたは結合剤等を含み、キャリアーがラクトースや／またはコーンスターチや／またはポテトスターチであることが好ましい錠剤、糖衣錠、またはカプセルは、特に経口投与に好適である。シロップ、エリキシル剤等は甘味賦形剤が利用可能な時に利用できる。一般に本発明の化合物は、投与単位当たり薬物として利用可能なキャリアーに含まれる形で０．０５−１００ｍｇを調剤される。本発明の化合物の投与量は、例えばヒトの患者に医薬品として投与する場合には０．１−３００ｍｇ／日で、好適には１０−１００ｍｇ／日である。通常の錠剤製造法により調整される典型的な錠剤には次のものが含まれる：活性化合物５．０ｍｇＬａｃｔｏｓｕｍ６７．０ｍｇＰｈ．ＥｕｒＡｖｉｃｅｌ^TM ３１．４ｍｇＡｍｂｅｒｌｉｔｅ^TMＩＲＰ８８１．０ｍｇＭａｇｎｅｓｉｌｓｔｅａｒａｓ０．２５ｍｇＰｈ．Ｅｕｒ本発明の化合物は、例えばヒトを含む生きている動物体で本発明の化合物を必要としている患者に投与することができ、また必要に応じて医薬品として利用可能な当該化合物の酸添加塩の形にして（ヒドロブロマイド、塩酸塩、またはスルフォン酸塩等は、液を酸を含む溶液の中の遊離塩基を蒸発して乾燥させる等の通常または一般的な方法で調整できる）、通常医薬品として利用可能なキャリアーまたは希釈液、特にそして好ましくは医薬品成分の形状をした該キャリアーまたは希釈液を併用し、または同時に、または混ぜて経口、直腸、または非腸管（皮下を含む）経路より病気の治療に有効な量を投与することができる。好適な投与量は１−２００ミリグラム／日、１０−１００ｍｇ／日で、好ましくは３０−７０ｍｇ／日であり、その量は通常投与方法、投与される形状、投与が指示された適用の内容、患者そして患者の体重と担当の医師や獣医師の経験から決められる。以下実施例により本発明を詳細に説明する。もとより本実施例は請求項により規定される本発明の範囲を限定するものではない。実施例１（±）−トランス−７−ヒドロキシ−３−フェニル−４−（４−（２−ピロリジノエトキシ）フェニル）クロマンステップ１：４−（４−ヒドロキシフェニル）−７−メトキシ−３−フェニル−３−クロマン４−（４−アセトフェニル）−７−メトキシ−３−フェニル−３−クマリン（１８０ｇ）をトルエン（２．１１）に７０℃で溶解してから水素化リチウムアルミニウム（３５．４ｇ）のテトラヒドロフラン（２．１１）懸濁液に加えた。添加中は反応混合液の温度を６０℃以下に保った。反応混合液を室温まで冷却した。水（４５ｍｌ）を注意しながら加え、続いて５Ｍの塩酸（１．２１）を加えた。混合液を６０−６５℃に加熱しながら３時間攪拌した。有機相が分離した。水相をトルエン（２５０ｍｌ）で抽出した。有機相を一つにしてから水（２５０ｍｌ）で洗浄し、油になるまで蒸発させ。この油を沸騰エタノール（６００ｍｌ）に溶解した。溶解液を冷却した後、ゆっくりと水（４００ｍｌ）を加え、この混合液に種付けした。結晶を濾過して除き、水／エタノール；２５／７５（２００ｍｌ）で洗浄してから乾燥した。収量４−（４−ヒドロキシフェニル）−７−メトキシ−３−フェニル−３−クロマン１２６ｇ（８１％）；融点１５６−１５７℃。ステップ２：シス−４−（４−ヒドロキシフェニル）−７−メトキシ−３−フェニルクロマン４−（４−ヒドロキシフェニル）−７−メトキシ−３−フェニル−３−クロマン’７７．７ｇ）をエタノール（１５００ｍｌ）に５０℃で溶解した。パラジウム黒、１０％、水分５０％（６ｇ）を溶解液に加え、この混合液を５５℃、１気圧下に８時間おいて水素化した。懸濁液が暖かい間に触媒を濾過して除き、濾過液を油まで蒸発させたがこの油は蒸発中に固化した。収量７４．３ｇ（９５％）、融点１６８−１９０℃。産物は¹Ｈ−ＮＭＲと元素分析にて確認した。ステップ３：（±）−シス−７−メトキシ−３−フェニル−４−（４−（２−ピロリジノエトキシ）フェニル）クロマンシス−４−（４−ヒドロキシフェニル）−７−メトキシ−３−フェニルクロマン（７４．３ｇ）をトルエン（７００ｍｌ）、水（１２ｍｌ）と水酸化ナトリウム（２４，３ｇ）の混合液に加え７５℃まで加温した。これに２−クロロエチルピロリジン塩酸塩（４６．２ｇ）を３０分に１回の割合で６回に分けて７５℃で加えた。最後の添加がおわった後に、混合液を７５℃で４時間加温した。水（１０００ｍｌ）を加えてから、全ての塩が溶解するまで混合液を攪拌した。水相を分離し、もう一度新たにトルエン（３００ｍｌ）を加えて抽出した。有機相を一つにまとめ炭酸カリウム上で乾燥し、油になるまで蒸発させた。油を還流メタノール（１０００ｍｌ）中に溶解し、これを氷槽中にて冷却して結晶化した。（±）−シス−７−メトキシ−３−フェニル−４−（４−（２−ピロリジノエトキシ）フェニル）クロマンの収量７９．６ｇ（８３％）、融点１１３−１１４ ℃。産物は¹Ｈ−ＮＭＲと元素分析にて確認した。ステップ４：（±）−トランス−７−メトキシ−３−フェニル−４−（４−（２−ピロリジノエトキシ）フェニル）クロマンシス−７−メトキシ−３−フェニル−４−｛４−［２−（ピロリジン−１−イル）ノエトキシ］フェニル｝クロマン（５．２ｇ）をジメチルスルフォキシド（１２．５ｍｌ）と水酸化カリウム（０．５５ｇ）の液の中で７０−８０℃に５時間入れて溶解した。反応混合液は室温まで冷却した。水（５０ｍｌ）を加えた。混合液を３０分間攪拌し、生じた粘着性の沈殿を濾過して除き、次の反応に進む前に水で数回洗浄した。（±）−トランス−７−メトキシ−３−フェニル−４−（４−（２−ピロリジノエトキシ）フェニル）クロマンの収量２．３ｇ（４４％）。産物は¹Ｈ−ＮＭＲで確認した。ステップ５：（±）−トランス−７−ヒドロキシ−３−フェニル−４−（４−（２−ピロリジノエトキシ）フェニル）クロマントランス−７−メトキシ−３−フェニル−４−｛４−［２−（ピロリジン−１ −イル）ノエトキシ］フェニル｝クロマン（２ｇ）を、ピリジン（１０ｍｌ）と１４０℃で蒸留して水を除いて得た濃塩酸より混合液より調整した融解塩化ピリミジニウムに溶解した。混合液を７５分間加熱した。室温まで冷却した。水（１５ｍｌ）を加え、水酸化ナトリウム（３２．５％）でｐＨを１２に調整した。混合液をトルエン（１５ｍｌ）で抽出した。有機相を分離してから、炭酸カリウムの上で乾燥させ、蒸発させた。得られた油は２本の連続したシリカゲル６０カラムをもちいて、まず酢酸エチル／メタノール１：１を溶出液とし、つぎにジクロロメタン／メタノール１：１を溶出液とするカラムクロマトグラフィーにて生成した。（±）−トランス−７−ヒドロキシ−３−フェニル−４−（４−（２−ピロリジノエトキシ）フェニル）クロマンの収量０．１４ｇ（７％）。産物は¹Ｈ−ＮＭＲと元素分析で確認した。実施例２（±）−トランス−７−ヒドロキシ−３−（４−フルオロフェニル）−４−（４ −（２−ピロリジノエトキシ）フェニル）クロマンステップ１：４−（４−アセトキシフェニル）−３−（４−フルオロフェニル）−７−メトキシ−クマリン（２−ヒドロキシ−４−メトキシフェニル）−（４−ヒドロキシフェニル）− メタノン（７．３３ｇ、３０．０ｎｎｍｏｌ）、無水酢酸（１５ｍｌ）、トリエチルアミン（５．５ｍｌ、３９．５ｍｍｏｌ）と４−フルオロフェニル酢酸（４．６３ｇ、３０．０ｍｍｏｌ）の混合液を１３５℃で１８時間攪拌し、得られたオレンジ色の液を水（１２０ｍｌ）に注ぎ入れ、さらに３時間攪拌した。得られた粘着性固形物を含む水性混合体を酢酸エチル（３００ｍｌ）で希釈して固形物を溶解し、有機相を分離した。水相をさらに酢酸エチルル（２×１００ｍｌ）で抽出した。有機相を一つにまとめ、水で洗い、飽和塩化ナトリウム液で洗い、それから硫化ナトリウム上で乾燥させて黄色／オレンジ色の固形物になるまで蒸発し、それをエタノール：水（６００ｍｌ）、１：１の液から再結晶化して灰色がかった白色の固形を得、真空下に乾燥した。４−（４−アセトキシフェニル）−３−（４−フルオロフェニル）−７−メトキシークマリンの収量７．９８ｇ（６５％）。融点１７３−１７６℃。¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，３００ＭＨｚ）δ：２．３２（ｓ，３Ｈ）；３．８９（ｓ，３Ｈ）；６．７８（ｄｄ，１Ｈ）；６．８２−６．９５（ｍ，３Ｈ）；７．０３ −７．１４（ｍ，６Ｈ）；７．１５（ｄ，１Ｈ）。ＬＲＭＳ（ＥＩ）４０４（Ｍ⁺ ）、３６２，３３４，３１９，４３。元素分析；Ｃ₂₄Ｈ₁₇ＦＯ₅についての計算値：Ｃ、７１．２８；Ｈ，４．２４％；実測値Ｃ、７１．２６；Ｈ、４．２５％ステップ２：３−（４−フルオロフェニル）−４−（４−ヒドロキシフェニル）−７−メトキシ−クロム−３−エネ水素化リチウムアルミニウム（０．７６ｇ，２０．０３ｍｍｏｌ）を少量に分けて、４−（４−アセトキシフェニル）−３−（４−フルオロフェニル）−７− メトキシ−クマリン’４．０４ｇ、９．９９ｍｍｏｌ）のテトラヒドロフラン（１５０ｍｌ）液に攪拌しながら加えた。全て加え終わったら、混合液を室温で３０分間攪拌し、それから６Ｍの塩酸（３０ｍｌ）を滴下した。得られた混合液を６０−６５℃で３時間加温した後、冷却して水（１００ｍｌ）と酢酸エチル（５０ｍｌ）で希釈した。水相を分離し、さらに酢酸エチル（３×１００ｍｌ）で抽出した。有機相を一つにまとめてから塩化ナトリウム飽和液で洗浄し、硫酸ナトリウム上で乾燥、蒸発させてオレンジ色の固体を得た。これをエタノール／水（４：１、７５ｍｌ）より再結晶化し、第一産物である無色の針型の固形物を得た。母液を蒸発させてオレンジ色のゴム体を得、これから二回目の水エタノール再結晶をおこなって無色の針型の第二産物を得た。前記固形物を一つにまとめてから真空下に乾燥させた。３−（４−フルオロフェニル）−４−（４−ヒドロキシフェニル）−７−メトキシークロム−３−エネの収量２．４７ｇ（７０％）。融点１５５−１５６．５ ℃。¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，３００ＭＨｚ）δ：３．７９（ｓ，３Ｈ）；４．８０（ｂｓ，１Ｈ）；５．２０（ｓ，２Ｈ）；６．４０（ｄｄ，１Ｈ）；６．５１（ｄ，１Ｈ）；６．７０−７．００（ｍ，９Ｈ）。ＬＲＭＳ（ＥＩ）３４８（Ｍ⁺）、２５５（Ｍ−ＰｈＯＨ）、２５３（Ｍ−ＰｈＦ）。ステップ３：（±）−シス−３−（４−フルオロフェニル）−４−（４−ヒドロキシフェニル）−７−メトキシ−クロマンパラジウム黒（１０％、０，２０ｇ、０．１９ｍｍｏｌ）を攪拌中の３−（４ −フルオロフェニル）−４−（４−ヒドロキシフェニル）−７−メトキシークロム−３−エネ（１．７４ｇ，４．９９ｍｍｏｌ）のエタノール液（１５０ｍｌ）に加え、混合液を室温で２０時間水素化する。触媒を濾過により除き、溶媒を蒸発させて灰色がかった白色の固形物を得、これを水エタノールから再結晶して精製した。これにより得た無色の固形物を真空下に乾燥して、結晶エタノールの０．７５当量を含む無色の板状物を得た。（±）−シス−３−（４−フルオロフェニル）−４−（４−ヒドロキシフェニル）−７−メトキシ−クロマンの収量１．２９ｇ（７３％）。融点１６４−１６５℃（水エタノール）。¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，３００ＭＨｚ）ｄ：１．２５（ｔ，２．４Ｈ、０．７５ＥｔＯＨ）、３．５５（ｄｄｄ，１Ｈ）、３．７３（ｑ，１．６Ｈ、０．７５ＥｔＯＨ）、３．８１（ｓ，３Ｈ）、４．１６−４．２５（ｍ，２Ｈ）、４．３８（ｄｄ，１Ｈ）、４．９０（ｂｓ，１Ｈ）、６．４４ −６．５８（ｍ，６Ｈ）、６．５９−６．６８（ｍ，２Ｈ）、６．８０−６．９０（ｍ、３Ｈ）。ＬＲＭＳ（ＥＩ）３５０（Ｍ⁺）、２２７、２１１。元素分析；Ｃ₂₂Ｈ₁₉ＦＯ₃・０．７５ＥｔＯＨ換算の計算値：Ｃ、７３．３３；Ｈ，６．１３％；実測値Ｃ、７３．３２；Ｈ、６．１１％ステップ４：（±）−シス−３−（４−フルオロフェニル）−７−メトキシ−４−（４−（２ −ピロリジノエトキシ）フェニル）−クロマン（±）−シス−３−（４−フルオロフェニル）−４−（４−ヒドロキシフェニル）−７−メトキシ−クロマン（０．５３ｇ，１．５１ｍｍｏｌ）と炭酸カリウム（２．１０ｇ、１５．２ｍｍｏｌ）、ヨウ化ナトリウム（０．０１ｇ，０．０７ｍｍｏｌ）、１−（２−クロロエチエル）ピロリジン塩酸塩（０．２８ｇ，１．６５ｍｍｏｌ）とアセトン（３５ｍｌ）の混合体を６０℃で還流しながら２４時間攪拌した。得られた混合体を濾過し、溶媒を蒸発させて無色のゴム体を得、これを冷却して固化した。この粗固形体を水エタノールから再結晶化して無色の針状の産物を得、真空下に乾燥させた。（±）−シス−３−（４−フルオロフェニル）−７−メトキシ−４−（４−（２−ピペリジノエトキシ）フェニル）−クロマンの収量０．５７ｇ（８３％）。融点９３．５−９４．５℃（水エタノール）。¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，３００ＭＨｚ）δ：１．７５−１．８５（ｍ，４Ｈ）、２．５５−２．６５（ｍ，４Ｈ）、２．８５（ｔ，２Ｈ）、３．５５（ｄｄｄ，１Ｈ）、３．８１（ｓ，３Ｈ）、４．０８（ｔ，２Ｈ）、４．１６−４．２３（ｍ，２Ｈ）、４．３７（ｄｄ，１Ｈ）、６．４３−６．５３（ｍ，４Ｈ）、６．５７−６．６６（ｍ、４Ｈ）、６．８０−６．８８（ｍ，３Ｈ）。ＬＲＭＳ（ＥＩ）４４７（Ｍ⁺）、８４（Ｃ₅ Ｈ₁₀Ｎ）ステップ５：（±）−トランス−３−（４−フルオロフェニル）−７−メトキシ−４−（４− （２−ピロリジノエトキシ）フェニル）−クロマン（±）−シス−３−（４−フルオロフェニル）−７−メトキシ−４−（４−（２−ピロリジノエトキシ）フェニル）−クロマン（１．０ｇ、２．３３ｍｍｏｌ）とパウダー状の塩化カリウム（０．２５ｇ，４．４６ｍｍｏｌ）を乾燥ＤＭＳＯ中に混合したものを３時間８０℃に加温した。混合体を水（１００ｍｌ）で希釈し、産物を酢酸エチル中（３×１００ｍｌ）に抽出した。抽出物を一つにまとめてから水、ブラインで洗浄し、硫酸マグネシウム上で乾燥させてから蒸発してオレンジ色のガム状の粗複合化合物を得た。表題の化合物はシリカゲル６０カラムと５％メタノールのジクロロメタン液を溶媒に用いたカラムクロマトグラフィーにより部分精製した。表題化合物の蒸発させて、表題化合物と未反応のシス型イソマーの出発材料との混合体を分離した。さらに表題化合物は調整ＨＰＬＣ：カラム：ＹＭＣ１２０オングストローム、１５μｍ、２５０×１０ｍｍ；溶出液：６０％メタノールの５０ｍＭ酢酸アンモニウム液；流速：１０ｍｌ／分；２２０ｎｍでのＵＶ検出、を用いて完全に精製した。相当する分画を乾燥させ無色の蝋状の表題化合物を得た。（±）−トランス−３−（４−フルオロフェニル）−７−メトキシ−４−（４ −（２−ピロリジノエトキシ）フェニル）−クロマンの収量０．１１ｇ（１１％）。¹Ｈ−ＮＭＲ（ＣＤＣｌ₃，３００ＭＨｚ）δ：１．７３−１．８８（ｍ，４Ｈ）、２．６０−２．７２（ｍ，４Ｈ）、２．９０（ｔ，２Ｈ）、３．２０（ｄｄｄ，１Ｈ）、３．７５（ｓ，３Ｈ）、４．０４（ｔ，２Ｈ）、４．０５−４．２５（ｍ，２Ｈ）、４．３０（ｄｄ，１Ｈ）、６．４０（ｄｄ，１Ｈ）、６．４５（ｄ、１Ｈ）、６．６７（ｄ，１Ｈ）、６．７４（ｄｍ，２Ｈ）、６．８０− ６．９５（ｍ，４Ｈ）、６．９５−７．０４（ｍ，２Ｈ）。ＬＲＭＳ（ＥＩ）４４７（Ｍ⁺）、８４（Ｃ₅Ｈ₁₀Ｎ、１００％）。分析ＨＰＬＣ、Ｒｔ＝５．６２分。（ＬｉＣｈｒｏｓｏｒｂＲＰ−１８（７μｍ）、２５０×４ｍｍカラム）；溶出液９０％メタノール／１０％（ｐＨ７，０．２５％トリエチルアミン／リン酸液）緩衝液；検出２２０ｎｍＵＶ；流速０．９ｍｌ／分。ステップ６：（±）−トランス−７−ヒドロキシ−３−（４−フルオロフェニル）−４−（４ −（２−ピロリジノエトキシ）フェニル）−クロマン無水塩酸ピリジン（０．２８９ｇ，２．５０ｍｍｏｌ）と（±）−トランス− ３−（４−フルオロフェニル）−７−メトキシ−４−（４−（２−ピロリジノエトキシ）フェニル）−クロマン（０．１１ｇ、０．２５ｍｍｏｌ）の混合体を３時間１３５℃に加熱した。えられた暗い茶色の固形体をメタノール（１０ｍｌ）、水（５０ｍｌ）、炭酸水素ナトリウム液（５ｍｌ）の混合液に溶解し、産物をジクロロメタン／メタノールの９：１液（３×５０ｍｌ）に抽出した。抽出物を一つにまとめてから水、ブラインで洗浄し、硫酸マグネシウム上で乾燥させてから蒸発してオレンジ色のガム状の粗複合化合物を得た。産物はシリカゲル６０カラムと５％メタノールのジクロロメタン液を溶媒に用いたカラムクロマトグラフィーにより精製し、無色の蝋状物を得た。（±）−トランス−７−ヒドロキシ−３−（４−フルオロフェニル）−４−（４−（２−ピロリジノエトキシ）フェニル）−クロマンの収量４０ｍｇ（３７％）。¹Ｈ−ＮＭＲ（ＭｅＯＨ−ｄ₄，２００ＭＨｚ）δ：１．８５−２．１０（ｍ，４Ｈ）、３．００−３．１８（ｍ，４Ｈ）、３．１８−３．３８（ｍ，３Ｈ）、４．０５−４．２５（ｍ，５Ｈ）、６．２２（ｄｄ，１Ｈ）、６．３０（ｄ，１Ｈ）、６．４６（ｄ、１Ｈ）、６．８０（ｄｍ，２Ｈ）、６．８４−６．９８（ｍ，４Ｈ）、６．８４−６．９８（ｍ，４Ｈ）、７．０４−７．１６（ｍ，２Ｈ）。ＬＲＭＳ（ＥＩ）４３３（Ｍ⁺）、８４（Ｃ₅Ｈ₁₀Ｎ、１００％）。実施例３：（±）−トランス−７−ヒドロキシ−３−（４−フルオロフェニル）−４−（４ −（２−ピペリジノエトキシ）フェニル）−クロマン表題の化合物は、実施例２のステップ４で求電子体として用いた１−（２−クロロエチル）ピペラジンを１−（２−クロロエチル）ピロリジン塩酸塩に変更する以外は実施例２記載の方法と同一方法で調整された。中間体の（±）−トランス−３−（４−フルオロフェニル）−７−メトキシ− ４−（４−（２−ピペリジノエトキシ）フェニル）− クロマン（７０ｍｇ、０．１５２ｍｍｏｌ）を塩酸ピペラジン（０．１７６ｇ，１５２ｍｍｏｌ）と一緒に１８時間加熱して脱メチル化した後精製して無色の表題化合物を得た。（±）−トランス−７−ヒドロキシ−３−（４−フルオロフェニル）−４−（４−（２−ピペリジノエトキシ）フェニル）−クロマンの収量２５ｍｇ。¹Ｈ− ＮＭＲ（ＭｅＯＨ−ｄ₄，２００ＭＨｚ）δ：１．４０−１．５５（ｍ，２Ｈ）、１．５５−１．７０（ｍ、４Ｈ）、２．５０−２．６２（ｍ，４Ｈ）、２．７８（ｔ，２Ｈ）、３．１５−３．３０（ｍ，１Ｈ）、４．０５（ｔ，２Ｈ）、４．１０−４．２５（ｍ，３Ｈ）、６．２３（ｄｄ、１Ｈ）、６．２８（ｄ，１Ｈ）、６．４９（ｄ，１Ｈ）、６．７５（ｄｍ，２Ｈ）、６．８５−６．９８（ｍ，４Ｈ）、７．０５−７．１６（ｍ，２Ｈ）。フェノールのＯＨは観察されなかった。ＬＲＭＳ（ＥＩ）４４７（Ｍ⁺）、９８（Ｃ₆Ｈ₁₂Ｎ、１００％）。DETAILED DESCRIPTION OF THE INVENTION Novel trans-3 useful for prevention or treatment of estrogen-related diseases or syndromes , 4 chroman derivatives Field of the invention The present invention relates to novel trans-3,4 chroman derivatives, and estrogen-related diseases. Or syndromes, especially those caused by estrogen deficiency in mammals Is a syndrome, especially bone loss, osteoporosis, cardiovascular disease, paresthesia, Alzheimer's disease Human dementia, menopause including flushing and genital atrophy, dysmenorrhea, urgency and habit Prevent abortion, irregular uterine bleeding, acne, hirsutism, prostate cancer, postpartum lactation or Use of the compound of the present invention for treatment, contraception method or ovarian development support method On the application of these compounds. Background of the Invention Osteopenia associated with menopause is a major public health problem. Neglect checking Bone loss, which results in a significant loss of skeletal muscle structural integrity and is painful Weak fractures occur in the lumbar region, spine, and femur. To reduce the risk and frequency of this fracture The development of treatments that mainly inhibit bone resorption and preserve bone mass has been concentrated. Various cures Estrogen replacement therapy is still used in post-menopausal osteoporosis prevention (Lindsey R, Hart DM, MacCl ean A 1987, "Estrogen / progestogen in postmenopausal treatment Role (The role of estrogen / progestogeni) n the management of the menopause) ", C oook I D, Editing, Proceedings of University of Sc heffield symposium on the role of es trogen and process in the management ent of the menopause, UK: MTP Press Lt d. pp. 9-25; Marshall DH, Horsmann A, No rdin BEC 1977, "Prevention and treatment of postmenopausal osteoporosis (The pre vention and management of post-menop ausal osteoporosis) ", Acta Obstet Gyn eco1 Scan (Suppl) 65: 49-56; Recker RR, Savile PD, Heaney RP 1977, "Bone Loss in Postmenopausal Women Effect of Estrogen and Calcium Carbonate on Ethanol gen and calcium carbonate on bone lo ss in post-menopausal woman), Ann Int ern Med. 87: 649-655; Nachtigall LE, Nac htigall RH, Nachtigall RD, Beckman EM 1979, "Estrogen replacement. t therapy ", Obstet Gynecol. 53: 277-281. ), And now estrogen appears to significantly reduce the frequency and risk of fractures (Krieger N, Kelsey JL, Holford TR, O'Connor T 1982, "An epidemiological study on hip fractures in postmenopausal women ( An epidemiological study of hip frac cure in postmenopausal woman) ", Am J Epidio. 116: 141-148; Hutchinson TA, Polansky SM, Fe instine AR 1979, "Postmenopausal estrogen has hip and distal flexion Prevent bone fracture (Menopausa1 estrogen therapy) and hip fractures) ", Ann Intern Med. 9 5: 28-31; Weiss NS, Ure CL, Ballard JH, W illiams AR, Daling JR 1980, "Estrogen Menopause Lower risk of hip and lower forearm fractures by post-administration (Decreed ri sk of frctures on the hip and lower forearm with post-menopausal use of estrogen) ", N Eng J Med. 303: 1195-119. 8). It is clear that estrogen replacement therapy has a beneficial effect on the skeleton, Some data show that estrogen also has a beneficial effect on the cardiovascular system. You. Previous studies have been on the effects of estrogens on serum lipids However, recently estrogen directly affects not only the lipid profile but also the extensibility of the vascular wall. Data to reduce peripheral resistance and prevent atherosclerosis (Rob o RA 1990, "Estrogen replacement therapy and cardiovascular association (Cardio vasculal implication of estrogen rep replacement therapy ”, Obstrictrics and Gyn aecology, 75: 18S-24S; Mendelson ME, Kar as RH 1994, "Estrogen and blood vessel walls", Current Opin ion in Cardiology, 1994 (9): 619-626). Epidemic According to scientific data, these physiology of estrogen The combined pharmacologic and pharmacological effects have resulted in women having cardiovascular disease regardless of age. Morbidity and mortality are reduced (Kannel WH, Hjortland M, McN amara PM 1976 "Menopause and the Risk of Cardiovascular Disease: The Framingham Study ( Menopause and risk of cardiovascular disease: The Framingham Study), Ann I nt Med, 85: 447-552). In addition, recent analysis shows postmenopausal est Concludes that rogen replacement therapy reduces cardiovascular disease risk by approximately 50% (Stampfer MJ, Colditz GA 1991, "Estrogen Compensatory treatment and coronary heart disease: quantitative analysis of epidemiological data (Estrogen rep) license therapy and coronary heart disease: a automatic assessment of the epidemiological evidence ", Preve active Medicine, 20; 47-63. ). Estrogen compensation in addition to the beneficial effects of estrogen on bone and cardiovascular system Some data suggest that therapy may also benefit the central nervous system. Short-term for humans Studies show that memory scores increase with estrogen levels in postmenopausal women High (Kampen DL, Sherwin BB 1 994, Estrogen administration and verbal memory in healthy postmenopausal women gen use and verbal memory in healthy woman), Obstreets and Gynecology, 83 (6): 979-983). In addition, women who have undergone surgery have a foreign Administration of Gen increased short-term memory. Also, estrogen treatment is Alzhai Epidemiological findings that clearly reduce the risk of Mer-type senile dementia Suggests that estrogen's effects on cognition are not limited to short-term effects (Paganini-Hill A, Henderson VW, 1994) Estrogen Deficiency and Alzheimer's Disease in Women (Estrogend efficiency and risk of Alzheimer's di case in women) ", Am J Epidemiol, 140: 256-261; Ohkura T, Issue K, Akazawa K, Ha mamoto M, Yoshimasa Y, Hagino N, 1995, " Long-term estrogen replacement therapy in female patients with Alzheimer's dementia: 7 cases Report (Long-term estrogen replacement th erapy in female patents with dement ia of the Alzheimer Type: 7 case repo rts) ", Dementia, 6: 99-107. Estrogen is a cognitive function The mechanism by which estrogen increases cerebral blood flow (Goldman) is unknown. H, Skelley Eb, Sandman CA, Kastin AJ, M urphy S, 1976, "Hormones and cerebral local blood flow (Hormones and regional brain blood flow ", Pharm acol Biochem Rev, 5 (suppl 1): 165-169; Ohkura T, Teshima Y, Isse K, Matsuda H, Inoue T, Sakai Y, Iwasaki N, Yaoi Y, 199 5, "Estrogen increases regional cerebral and cerebellar blood flow in postmenopausal women ( Estrogens concerns cerebral and cere bellar blood flow s in postmenopausal woman) ", Menopaus e: J North Am Menopause Soc. 2 (1): 13-1 8) and direct action on nerve cells (Singh M, Meyer EM, S impkins JW, 1995, "Female Spargue-Dawley rats Ribonucleic acid of brain-derived neurotrophic factor in rat brain cortex and hippocampus Of ovariectomy and estradiol on the expression of f ovaryectomy and estradiol replacem ent on brain-driven neurotropic fa ctor messenger ribonicular acid expr ession in cortical and hippocampal b rain regions of female Sprague-Dawle y rates), Endocrinology, 136; 2320-2324; McMillan PJ, Singer CA, Dorsa DM, 1996, "TrkA and basal forebrain in adult female Sprague-Dawley rats Of ovariectomy and est on mRNA expression of choline acetyltransferase The effects of varigen replacement therapy (The effects of ovaryectom) y and estrogen replacement on trkA a nd choline acyltransferase mRNA ex press in inbasal forbrain of th eadult female Agre-Dawley rat) ", J Neurosci. , 16 (5): 1860-1865). It can be speculated that this is a sexual effect factor. Natural estrogens and estrogen alone or in combination Therapeutic applications of synthetic preparations that exhibit antitumor activity are not limited to the aforementioned chronic conditions. No. In addition, there are several applications of estrogen: For example, flushing and genital atrophy); birth control pills; prevention of imminent or habitual miscarriage; Reducing dysmenorrhea; Reducing dysfunctional uterine bleeding; Assisting egg cell development; Acne treatment; Reduced overgrowth of hair (sexual hirsutism) in sex; treatment of prostate cancer; postpartum milk Inhibition of secretion [Goodma and Gilman, The Pharmaco logical Basis of Therapeutics (Event h Edition) Macmillan Publishing Comp any, 1985, pp. 1421-1423]. Estrogen replacement therapy may have beneficial effects on a wide range of organ systems and tissues It is clear, but depending on the dosage and duration of estrogen treatment, It also increases the risk of hyperplasia and cancer. Use cyclic progestin simultaneously Use reduces the risk of endometriosis, but at the same time is unacceptable to many patients. Recurrent uterine bleeding. Estrogen has a sting to the endometrium Report on relationship between long-term estrogen replacement therapy and increased risk of breast cancer, in addition to intense effects Controversy continues over the report (Bergkvist L, Adami HO, Person I, Hoover R, Chaire C, 1989, " Risk of breast cancer after estrogen and estrogen-progestin compensation (Ther isk of breast cancer after estrogen and estrogen-progestin replacement), N Eng J Med, 321: 293-297; Colditz GA, H ankinson SE, Hunter DJ, Wilett WC, Mans on JE, Stam pfer MJ, Hennekens C, Rosner B, Speizer FE, 1995, "Estrogen and progestin use in postmenopausal women. The risk of breast cancer (The use of estrogens and prog estins and the risk of breast cancer in postmenopausal woman), N Eng J Me d, 322 (24): 1589-1593). Moreover, not life threatening However, estrogen use is contraindicated and other side effects that hinder patient consent There is a strogen replacement treatment. As described above, without any adverse side effects on the uterus and breast, Reproduce the beneficial effects of Rogen on bone, cardiovascular and central nervous systems Enabling treatment is necessary to realize "safe estrogen" If this can be achieved, the number of patients who will be able to benefit from estrogen replacement therapy Can be greatly increased. Therefore, estrogen treatment for various parts of the body and disease symptoms Gen has been shown to have beneficial effects, selectively targeting various body tissues There is a demand for the development of powerful estrogen agonists. Detailed description of the invention The present invention relates to a compound of the formula^TwoAnd R^ThreeOf the formula (I) in which is arranged in the trans form And its optical and stereoisomers, esters and Provide Teru and its salts. R in the formula¹Is H, COR^Four, CONHR^Four, CONR^Four _Two, SO_TwoNR^Four _TwoOr S O_TwoNHR^FourAnd R^TwoIs optionally OH, halogen, nitro, cyano, SH, SR^Four, Trihalo -C₁-C₆-Alkyl, C₁-C₆-Alkyl, C₁-C₆-Alkoxy and phenyl Substituted with 1 to 5 substituents independently selected from the group consisting of Nil, and R^ThreeIs (A) -X- (CH_Two)_n-Phenyl substituted with -Y, wherein X is an atom Valence bond, O or S, n is an integer from 1 to 12, Y is H, halogen , OH, OR^Four, NHR^Four, NR^Four _Two, NHCOR^Four, NHSO_TwoR^Four, CONHR^Four, CONR^Four _Two, COOH, COOR^Four, SO_TwoR^Four, SOR^Four, SONHR^Four, SON R^Four _Two, Saturated or unsaturated C_Three-C₇A heterocycle, wherein the heterocycle is O, S and And one or two heteroatoms independently selected from the group consisting of H, OH, halogen, nitro, cyano, SH, SR^Four,bird Halo-C₁-C₆-Alkyl, C₁-C₆-Alkyl, and C₁-C₆-Alkoki Substituted with one to three substituents independently selected from the group consisting of Or (B) wherein n and Y in the formula are the same as in (a),-(CH_Two)_n-Y, or (C) one or two independently selected from the group consisting of O, S and N Containing two heteroatoms, optionally H, OH, halogen, nitro, cyano, SH, SR^Four, Trihalo-C₁-C₆-Alkyl, C₁-C₆-Alkyl, and C₁-C₆-1 to 3 substitutions independently selected from the group consisting of alkoxy Base and place Saturated or unsaturated C_Three-C₇Phenyl fused with a heterocycle, One of R^FourIs C₁-C₆-Alkyl. The general chemical terms in the above formulas are used in their ordinary meaning. For example, C₁-C₆-The term alkyl means methyl, ethyl, propyl, isopropyl Linear and branched alkyls such as butyl, butyl, sec-butyl or isobutyl Containing a hydroxyl group. The term halogen means chlorine, bromine, iodine and fluorine. C_Three-C₇The term heterocycle includes pyrrolidinyl, pyrrolinyl, imidazolyl, Imidazolidinyl, pyrazolyl, pyrazolidinyl, pyrazolinyl, piperidyl, Piperazinyl, pyrrole, 2H-pyrrole, triazolyl, pyridyl, pyrazini , Pyrimidinyl, pyridazinyl, morpholino, thiomorpholino, isothia Zolyl, isoxazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, And groups such as thiazolyl. The compounds of the present invention are novel estrogen agonists and have been shown to reduce bone loss in women. Prevention and treatment, osteoporosis prevention and treatment, cardiovascular disease prevention and treatment, neuropeptide Y Treatment and prevention (eg, obesity, depression, etc.) of physiological disorders associated with Control of glucose metabolism such as insulin-dependent diabetes, and Alzheimer's senile dementia Useful for prevention and treatment of dementia. In addition, these estrogen agonists are Contraceptives, relief of menopausal symptoms (eg flushing, genital atrophy, depression, mania, schizophrenia, etc.) ), Prevention of incontinence, imminent or habitual miscarriage, relief of dysmenorrhea, dysfunctional uterine bleeding Alleviates ovarian development, treats acne, overgrows female hair (hirsutism) It is useful for alleviating prostate cancer, treating prostate cancer, and suppressing postpartum lactation. these The drug also lowers serum cholesterol and has a beneficial effect on the lipid profile of plasma Is shown. The compounds of the present invention are estrogen agonists in bone and cardiovascular tissues. However, it also functions as an anti-estrogen in other estrogen target organs. An example For example, these compounds can act as antiestrogens in breast tissue and the colon, Be useful in the prevention and treatment of estrogen-dependent cancers such as breast and colon cancer U. A substituent R of the formula I¹O is preferably bonded to the phenyl ring at the 6- or 7-position. Good. That is, compounds of the present invention that are either of the following formulas Ia or Ib are preferred: No. Or R in the formula¹, R^Two, And R^ThreeIs the same as above. One of the preferred embodiments of the present invention is a trans compound represented by the following formula.R in the formula is H or C₁-C₆Alkyl. Another preferred embodiment of the present invention is a trans compound represented by the following formula. M in the formula is an integer between 0 and 10. Another preferred embodiment of the present invention is a trans compound represented by the following formula. M in the formula is the same as described above. Another preferred embodiment of the present invention is a trans compound represented by the formula:M in the formula is the same as described above. Another preferred embodiment of the present invention is a trans compound represented by the following formula. M in the formula is the same as described above, and two R^FourAre the same as above, Is selected. Another preferred embodiment of the present invention is a trans compound represented by the following formula. R in the formula^FourIs the same as above. Another preferred embodiment of the present invention is a trans compound represented by the following formula.R in the formula^FourIs the same as above. Another preferred embodiment of the present invention is a trans compound represented by the following formula. R in the formula⁶Is one or more substituents: methoxy, hydroxy, trifluoromethyl Tyl, fluoro, and chloro. The most preferred compounds are: (+)-Trans-4- (4- (carboxymethoxy) phenyl) -7-hydro Xy-3-phenylchroman, (-)-Trans-4- (4- (carboxymethoxy) phenyl) -7-hydro Xy-3-phenylchroman, (+)-Trans-7-hydroxy-4- (4- (methoxycarbonylmethoxy ) Phenyl) -3-phenylchroman; (-)-Trans-7-hydroxy-4- (4- (methoxycarbonylmethoxy ) Phenyl) -3-phenylchroman; (+)-Trans-4- (4- (ethoxycarbonylmethoxy) phenyl) -7 -Hydroxy-3-phenylchroman, (-)-Trans-4- (4- (ethoxycarbonylmethoxy) phenyl) -7 -Hydroxy-3-phenylchroman, (+)-Trans-4- (4- (benzyloxycarbonylmethoxy) phenyl ) -7-Hydroxy-3-phenylchroman; (-)-Trans-4- (4- (benzyloxycarbonylmethoxy) phenyl ) -7-Hydroxy-3-phenylchroman; (+)-Trans-7-hydroxy-3-phenyl-4- (4- (2-pyrrolidine Noethoxy) phenyl) chroman (-)-Trans-7-hydroxy-3-phenyl-4- (4- (2-pyrrolidine Noethoxy) phenyl) chroman (+)-Trans-7-hydroxy-3-phenyl-4- (4- (3-pyrrolidine Nopropoxy) phenyl) chroman (-)-Trans-7-hydroxy-3-phenyl-4- (4- (3-pyrrolidine Nopropoxy) phenyl) chroman (+)-Trans-7-hydroxy-3-phenyl-4- (4- (4-pyrrolidine Nobutoxy) phenyl) chroman (-)-Trans-7-hydroxy-3-phenyl-4- (4- (4-pyrrolidine Nobutoxy) phenyl) chroman (+)-Trans-7-hydroxy-3-phenyl-4- (4- (5-pyrrolidine Nopentoxy) phenyl) chroman, (-)-Trans-7-hydroxy-3-phenyl-4- (4- (5-pyrrolidine Nopentoxy) phenyl) chroman, (+)-Trans-7-hydroxy-3-phenyl-4- (4- (6-pyrrolidine Nohexyloxy) phenyl) chroman, (-)-Trans-7-hydroxy-3-phenyl-4- (4- ( 6-pyrrolidinohexyloxy) phenyl) chroman, (+)-Trans-7-hydroxy-3-phenyl-4- (4- (7-pyrrolidine Noheptyloxy) phenyl) chroman, (-)-Trans-7-hydroxy-3-phenyl-4- (4- (7-pyrrolidine Noheptyloxy) phenyl) chroman, (+)-Trans-7-hydroxy-3-phenyl-4- (4- (8-pyrrolidine Nooctyloxy) phenyl) chroman, (-)-Trans-7-hydroxy-3-phenyl-4- (4- (8-pyrrolidine Nooctyloxy) phenyl) chroman, (+)-Trans-7-hydroxy-3-phenyl-4- (4- (9-pyrrolidine Nononyloxy) phenyl) chroman, (-)-Trans-7-hydroxy-3-phenyl-4- (4- (9-pyrrolidine Nononyloxy) phenyl) chroman, (+)-Trans-7-hydroxy-3-phenyl-4- (4- (10-pyrroli Dinodecyloxy) phenyl) chroman, (-)-Trans-7-hydroxy-3-phenyl-4- (4- (10-pyrroli Dinodecyloxy) phenyl) chroman, (+)-Trans-7-hydroxy-3-phenyl-4- (4- (11-pyrroli Diundecyloxy) phenyl) chroman, (-)-Trans-7-hydroxy-3-phenyl-4- (4- (11-pyrroli Diundecyloxy) phenyl) chroman, (+)-Trans-7-hydroxy-3-phenyl-4- (4- (12-pyrroli Dinododecyloxy) phenyl) chroman, (-)-Trans-7-hydroxy-3-phenyl-4- (4- (12-pyrroli Dinododecyloxy) phenyl) chroman, (+)-Trans-7-hydroxy-3-phenyl-4- (4- (2-piperidi Noethoxy) phenyl) chroman (-)-Trans-7-hydroxy-3-phenyl-4- (4- (2-piperidi Noethoxy) phenyl) chroman (+)-Trans-7-hydroxy-3-phenyl-4- (4- (3-piperidi Nopropoxy) phenyl) chroman (-)-Trans-7-hydroxy-3-phenyl-4- (4- (3-piperidi Nopropoxy) phenyl) chroman (+)-Trans-7-hydroxy-3-phenyl-4- (4- (4-piperidi Nobutoxy) phenyl) chroman (-)-Trans-7-hydroxy-3-phenyl-4- (4- (4-piperidi Nobutoxy) phenyl) chroman (+)-Trans-7-hydroxy-4- (4- (2-perhydroazepinoate Xy) phenyl) -3-phenylchroman (-)-Trans-7-hydroxy-4- (4- (2-perhydroazepinoate Xy) phenyl) -3-phenylchroman (+)-Trans-7-hydroxy-4- (4- (3-perhydroazepinopro Poxy) phenyl) -3-phenylchroman (-)-Trans-7-hydroxy-4- (4- (3-perhydroazepinopro Poxy) phenyl) -3-phenylchroman (+)-Trans-7-hydroxy-4- (4- (4-perhydroazepinobut) Xy) phenyl) -3-phenylchroman (-)-Trans-7-hydroxy-4- (4- (4-perhydroazepinobut) Xy) phenyl) -3-phenylchroman (+)-Trans-4- (4- (2-dimethylaminoethoxy) phenyl) -7 -Hydroxy-3-phenylchroman (-)-Trans-4- (4- (2-dimethylaminoethoxy) phenyl) -7 -Hydroxy-3-phenylchroman (+)-Trans-4- (4- (2-diethylaminoethoxy) f Enyl) -7-hydroxy-3-phenylchroman (-)-Trans-4- (4- (2-diethylaminoethoxy) phenyl) -7 -Hydroxy-3-phenylchroman (+)-Trans-4- (4- (2- (N-ethyl-N-methylamino) ethoxy) C) phenyl) -7-hydroxy-3-phenylchroman (-)-Trans-4- (4- (2- (N-ethyl-N-methylamino) ethoxy) C) phenyl) -7-hydroxy-3-phenylchroman (+)-Trans-4- (4- (3-dimethylaminopropoxy) phenyl)- 7-hydroxy-3-phenylchroman (-)-Trans-4- (4- (3-dimethylaminopropoxy) phenyl)- 7-hydroxy-3-phenylchroman (+)-Trans-4- (4- (4-diethylaminobutoxy) phenyl) -7 -Hydroxy-3-phenylchroman (-)-Trans-4- (4- (4-diethylaminobutoxy) phenyl) -7 -Hydroxy-3-phenylchroman (+)-Trans-4- (2,3-dihydro-1,4-benzoxazine-6- Yl) -7-hydroxy-3-phenylchroman (-)-Trans-4- (2,3-dihydro-1,4-benzoxyazine-6- Yl) -7-hydroxy-3-phenylchroman (+)-Trans-7-hydroxy-4- (4-methyl-2,3-dihydro-1 , 4-benzoxazin-6-yl) -3-phenylchroman, (-)-Trans-7-hydroxy-4- (4-methyl-2,3-dihydro-1 , 4-benzoxazin-6-yl) -3-phenylchroman, (+)-Trans-4- (4-ethyl-2,3-dihydro-1,4-benzoxa Zin-6-yl) -7-hydroxy-3-phenylchroman (-)-Trans-4- (4-ethyl-2,3-dihydro-1,4-benzoxa Zin-6-yl) -7-hydroxy-3-phenylchroman (+)-Trans-7-hydroxy-3- (4-hydroxyphenyl) -4- ( 4- (2-pyrrolidinoethoxy) phenyl) chroman, (-)-Trans-7-hydroxy-3- (4-hydroxyphenyl) -4- ( 4- (2-pyrrolidinoethoxy) phenyl) chroman, (+)-Trans-7-hydroxy-3- (4-trifluoromethylphenyl) -4- (4- (2-pyrrolidinoethoxy) phenyl) chroman, (-)-Trans-7-hydroxy-3- (4-trifluoromethylphenyl) -4- (4- (2-pyrrolidinoethoxy) phenyl) chroman, (+)-Trans-7-hydroxy-3- (4-fluorophenyl) -4- (4 -(2-pyrrolidinoethoxy) phenyl) chroman, (-)-Trans-7-hydroxy-3- (4-fluorophenyl) -4- (4 -(2-pyrrolidinoethoxy) phenyl) chroman, (+)-Trans-3- (4-chlorophenyl) -7-hydroxy-4- (4- (2-pyrrolidinoethoxy) phenyl) chroman, (-)-Trans-3- (4-chlorophenyl) -7-hydroxy-4- (4- (2-pyrrolidinoethoxy) phenyl) chroman, (+)-Trans-3- (3,4-dimethoxyphenyl) -7-h Droxy-4- (4- (2-pyrrolidinoethoxy) phenyl) chroman, (-)-Trans-3- (3,4-dimethoxyphenyl) -7-hydroxy-4 -(4- (2-pyrrolidinoethoxy) phenyl) chroman, (+)-Trans-7-hydroxy-3- (pentafluorophenyl) -4- ( 4- (2-pyrrolidinoethoxy) phenyl) chroman, (-)-Trans-7-hydroxy-3- (pentafluorophenyl) -4- ( 4- (2-pyrrolidinoethoxy) phenyl) chroman, (+)-Trans-4- (4-carboxymethoxy) phenyl) -6-hydroxy -3-phenylchroman, (-)-Trans-4- (4-carboxymethoxy) phenyl) -6-hydroxy -3-phenylchroman, (+)-Trans-6-hydroxy-4- (4- (methoxycarbonylmethoxy ) Phenyl) -3-phenylchroman; (-)-Trans-6-hydroxy-4- (4- (methoxycarbonylmethoxy) ) Phenyl) -3-phenylchroman; (+)-Trans-4- (4-ethoxycarnylmethoxy) phenyl) -6- Droxy-3-phenylchroman, (-)-Trans-4- (4-ethoxycarnylmethoxy) phenyl) -6-h Droxy-3-phenylchroman, (+)-Trans-4- (4-benzyloxycarnylmethoxy) phenyl)- 6-hydroxy-3-phenylchroman, (-)-Trans-4- (4-benzyloxycarnylmethoxy) phenyl)- 6-hydroxy-3-phenylchroman, (+)-Trans-6-hydroxy-3-phenyl-4- (4- (2-pyrrolidine Noethoxy) phenyl) chroman, (-)-Trans-6-hydroxy-3-phenyl-4- (4- (2-pyrrolidine Noethoxy) phenyl) chroman, (+)-Trans-6-hydroxy-3-phenyl-4- (4- (3-pyrrolidine Nopropoxy) phenyl) chroman, (-)-Trans-6-hydroxy-3-phenyl-4- (4- (3-pyrrolidine Nopropoxy) phenyl) chroman, (+)-Trans-6-hydroxy-3-phenyl-4- (4- (4-pyrrolidine Nobutoxy) phenyl) chroman, (-)-Trans-6-hydroxy-3-phenyl-4- (4- (4-pyrrolidine Nobutoxy) phenyl) chroman, (+)-Trans-6-hydroxy-3-phenyl-4- (4- (5-pyrrolidine Nopentoxy) phenyl) chroman, (-)-Trans-6-hydroxy-3-phenyl-4- (4- (5-pyrrolidine Nopentoxy) phenyl) chroman, (+)-Trans-6-hydroxy-3-phenyl-4- (4- (6-pyrrolidine Nohexyloxy) phenyl) chroman, (-)-Trans-6-hydroxy-3-phenyl-4- (4- (6-pyrrolidine Nohexyloxy) phenyl) chroman, (+)-Trans-6-hydroxy-3-phenyl-4- (4- (7-pyrrolidine Noheptyloxy) phenyl) chroman, (-)-Trans-6-hydroxy-3-phenyl-4- (4- (7-pyrrolidine Noheptyloxy) phenyl) chroman, (+)-Trans-6-hydroxy-3-phenyl-4- (4- (8-pyrrolidine Nooctyloxy) phenyl) chroman, (-)-Trans-6-hydroxy-3-phenyl-4- (4- ( 8-pyrrolidinooctyloxy) phenyl) chroman, (+)-Trans-6-hydroxy-3-phenyl-4- (4- (9-pyrrolidine Nonyloxy) phenyl) chroman, (-)-Trans-6-hydroxy-3-phenyl-4- (4- (9-pyrrolidine Nonyloxy) phenyl) chroman, (+)-Trans-6-hydroxy-3-phenyl-4- (4- (10-pyrroli Dinodecyloxy) phenyl) chroman, (-)-Trans-6-hydroxy-3-phenyl-4- (4- (10-pyrroli Dinodecyloxy) phenyl) chroman, (+)-Trans-6-hydroxy-3-phenyl-4- (4- (11-pyrroli Diundecyloxy) phenyl) chroman, (-)-Trans-6-hydroxy-3-phenyl-4- (4- (11-pyrroli Diundecyloxy) phenyl) chroman, (+)-Trans-6-hydroxy-3-phenyl-4- (4- (12-pyrroli Dinododecyloxy) phenyl) chroman, (-)-Trans-6-hydroxy-3-phenyl-4- (4- (12-pyrroli Dinododecyloxy) phenyl) chroman, (+)-Trans-6-hydroxy-3-phenyl-4- (4- (2-piperidi Noethoxy) phenyl) chroman, (-)-Trans-6-hydroxy-3-phenyl-4- (4- (2-piperidi Noethoxy) phenyl) chroman, (+)-Trans-6-hydroxy-3-phenyl-4- (4- (3-piperidi Nopropoxy) phenyl) chroman, (-)-Trans-6-hydroxy-3-phenyl-4- (4- (3-piperidi Nopropoxy) phenyl) chroman, (+)-Trans-6-hydroxy-3-phenyl-4- (4- (4-piperidi Nobutoxy) phenyl) chroman, (-)-Trans-6-hydroxy-3-phenyl-4- (4- (4-piperidi Nobutoxy) phenyl) chroman, (+)-Trans-6-hydroxy-4- (4- (2-perhydroazepinoate Xy) phenyl) -3-phenylchroman (-)-Trans-6-hydroxy-4- (4- (2-perhydroazepinoate Xy) phenyl) -3-phenylchroman (+)-Trans-6-hydroxy-4- (4- (3-perhydroazepinopro Poxy) phenyl) -3-phenylchroman (-)-Trans-6-hydroxy-4- (4- (3-perhydroazepinopro Poxy) phenyl) -3-phenylchroman (+)-Trans-6-hydroxy-4- (4- (4-perhydroazepinobut) Xy) phenyl) -3-phenylchroman (-)-Trans-6-hydroxy-4- (4- (4-perhydroazepinobuto) Xy) phenyl) -3-phenylchroman (+)-Trans-4- (4- (2-dimethylaminoethoxy) phenyl) -6 -Hydroxy-3-phenylchroman (-)-Trans-4- (4- (2-dimethylaminoethoxy) phenyl) -6 -Hydroxy-3-phenylchroman (+)-Trans-4- (4- (2-diethylaminoethoxy) phenyl) -6 -Hydroxy-3-phenylchroman (-)-Trans-4- (4- (2-diethylaminoethoxy) phenyl) -6 -Hydroxy-3-phenylchroman (+)-Trans-4- (4- (2- (N-ethyl-N-methylamino) ethoxy) C) phenyl) -6-hydroxy-3-phenylchroman (-)-Trans-4- (4- (2- (N-ethyl-N-methylamino) ethoxy) C) phenyl) -6-hydroxy-3-phenylchloro man (+)-Trans-4- (4- (3-dimethylaminopropoxy) phenyl)- 6-hydroxy-3-phenylchroman (-)-Trans-4- (4- (3-dimethylaminopropoxy) phenyl)- 6-hydroxy-3-phenylchroman (+)-Trans-4- (4- (4-diethylaminobutoxy) phenyl) -6 -Hydroxy-3-phenylchroman (-)-Trans-4- (4- (4-diethylaminobutoxy) phenyl) -6 -Hydroxy-3-phenylchroman (+)-Trans-4- (2,3-dihydro-1,4-benzoxazin-6-i ) -6-hydroxy-3-phenylchroman (-)-Trans-4- (2,3-dihydro-1,4-benzoxazin-6-i ) -6-hydroxy-3-phenylchroman (+)-Trans-6-hydroxy-4- (4-methyl-2,3-dihydro-1 , 4-benzoxazin-6-yl) -3-phenylchroman, (-)-Trans-6-hydroxy-4- (4-methyl-2,3-dihydro-1 , 4-benzoxazin-6-yl) -3-phenylchroman, (+)-Trans-4- (4-ethyl-2,3-dihydro-1,4-benzoxa Zin-6-yl) -6-hydroxy-3-phenylchroman (-)-Trans-4- (4-ethyl-2,3-dihydro-1,4-benzoxa Zin-6-yl) -6-hydroxy-3-phenylchroman (+)-Trans-6-hydroxy-3- (4-hydroxyphenyl) -4- ( 4- (2-pyrrolidinoethoxy) phenyl) chroman , (-)-Trans-6-hydroxy-3- (4-hydroxyphenyl) -4- ( 4- (2-pyrrolidinoethoxy) phenyl) chroman, (+)-Trans-6-hydroxy-3- (4-trifluoromethylphenyl) -4- (4- (2-pyrrolidinoethoxy) phenyl) chroman, (-)-Trans-6-hydroxy-3- (4-trifluoromethylphenyl) -4- (4- (2-pyrrolidinoethoxy) phenyl) chroman, (+)-Trans-6-hydroxy-3- (4-fluorophenyl) -4- (4 -(2-pyrrolidinoethoxy) phenyl) chroman (-)-Trans-6-hydroxy-3- (4-fluorophenyl) -4- (4 -(2-pyrrolidinoethoxy) phenyl) chroman, (+)-Trans-3- (4-chlorophenyl) -6-hydroxy-4- (4- (2-pyrrolidinoethoxy) phenyl) chroman, (-)-Trans-3- (4-chlorophenyl) -6-hydroxy-4- (4- (2-pyrrolidinoethoxy) phenyl) chroman, (+)-Trans-3- (3,4-dimethoxyphenyl) -6-hydroxy-4 -(4- (2-pyrrolidinoethoxy) phenyl) chroman, (-)-Trans-3- (3,4-dimethoxyphenyl) -6-hydroxy-4 -(4- (2-pyrrolidinoethoxy) phenyl) chroman, (+)-Trans-6-hydroxy-3- (pentafluorophenyl) -4- ( 4- (2-pyrrolidinoethoxy) phenyl) chroman, (-)-Trans-6-hydroxy-3- (pentafluorophenyl) -4- ( 4- (2-pyrrolidinoethoxy) phenyl) chroman, and racemic mixture And mixtures of the compounds. The following compounds as well as their pure enantiomers are also part of the disclosure of the present invention . (±) -trans-7-hydroxy-3-phenyl-4- (4- (2-pyrrolidine Noethoxy) phenyl) chroman, (±) -trans-7-hydroxy-3- (4-fluorophenyl) -4- (4 -(2-pyrrolidinoethoxy) phenyl) chroman, (±) -trans-7-hydroxy-3- (4-fluorophenyl) -4- (4 -(2-Piperidinoethoxy) phenyl) -chroman. The compounds of the present invention are described, for example, in P.S. K. Arora, P .; K. Kole and S.M. Ra y, Indian J .; Chem. 20B, 41-5, 1981; Ray, P. K. Grover and N.M. Andand, Indian J .; Chem. 9,7 27-8, 1971; Ray, P.M. K. Grover, V .; P. Kambo j, S. B. Betty, A .; B. Kar and N.M. Andand, J .; Med. Ch em. 19, 276-9, 1976; Md. Salman, S .; Ray, A .; K . Agarwal, S.M. Durani, B .; S. Betty, V .; P. Kamb oj and N.M. Anand, J. et al. Med. Chem. 26, 592-5, 1983; Teo, C.I. , Sim, K .; , Singapore Natl. Inst. Ch em. 22, 29-74, 1994 by chroman chemistry known to those skilled in the art. It could also be made. However, the present invention further provides a method for preparing a compound of formula (I) comprising the following steps: It also relates to general methods. a) A compound of formula (II) R in the formula^FiveIs H, OH, halogen, nitro, cyano, SH, SR^Four, Trihalo-C₁ -C₆-Alkyl, C₁-C₆-Alkyl and C₁-C₆A glue of alkoxy One to three substituents independently selected from^FourIs the same as above A compound of (III), Reaction with triethylamine in the presence of acetic anhydride,^FiveIs the same as above Forming a compound of formula (IV) b) reacting a compound of formula (IV) with a suitable hydride reducing agent,^FiveBefore Forming a compound of formula (V) which is the same as c) hydrogenating the compound of formula (V) in the presence of a suitable catalyst,^FiveIs the same as above 3,4-cis compound of formula (VI) d) alkylating the compound of formula (VI) with a suitable electrophile, wherein n, R^Five And forming a compound of formula (VII) wherein Y is the same as defined above,e) epimerizing the compound of formula (VII) with a suitable base to give n, R^FiveAnd Y To form a compound of formula (VIII) in the 3,4-trans form as defined above, f) condensation of the compound of formula (VIII) with a suitable deprotecting agent, preferably pyridine hydrochloride Deprotected by¹Is a hydrogen compound of formula (I). Ma Or g) nitrating the compound of formula (VI) with a suitable nitrating agent,^FiveBefore Forming a compound of formula (IX) which is the same as h) reduction of the compound of formula (IX) by hydrogenation with a suitable reducing agent, preferably a catalyst And R in the formula^FiveIs a compound of formula (X) as defined above,i) cyclizing a compound of formula (X) with a suitable agent to form a compound of the formula^Five And R^FourIs a compound of formula (XI) or (XII) as defined above, j) enantiomerizing a compound of formula (XI) or (XII) with a suitable base , R in the formula^FiveAnd R^FourIs the same as above, in the form of a 3,4-trans-formula (XIII) Forms the compound of (XIV), Ork) converting a compound of formula (XIII) or (XIV) to a suitable deprotecting agent, Deprotection is preferably carried out by pyridine chloride salt condensation,¹Is a compound of the formula (I ) Is formed. Or 1) reacting a compound of formula (VI) with trifluoromethanesulfonic anhydride , R in the formula^FiveIs a compound of formula (XV) as defined above, m) Cross-linking the compound of formula (XV) with a suitable cross-linking partner to obtain n, R^FiveWhen Forming a compound of formula (XVI) wherein Y is the same as defined above, n) enantiomerizing the compound of formula (XVI) with a suitable base, wherein n and R^Five To form a compound of formula (XVII) in the 3,4-trans form as defined above , o) condensation of the compound of formula (XVII) with a suitable deprotecting agent, preferably pyridine hydrochloride Deprotection by means of¹To form a compound of formula (I) wherein . Or p) R in the formula^FiveIs a compound of the formula (XVIII) It reacts with paraformaldehyde in the presence of cyclization to form R in the formula^FiveIs the same as above Forming a compound of formula (XIX) q) reacting a compound of formula (XIX) with a suitable Grignard reagent, wherein n, R^FiveAnd a compound of formula (XX) wherein Y is the same as defined above, r) The compound of formula (XX) is hydrogenated using a suitable catalyst to obtain n, R^FiveAnd Y Is a 3.4-cis compound of formula (XXI)) as defined above, s) Enantiomerization of the compound of formula (XXI) using a suitable base, wherein n, R^Five Form a compound of formula (XXII) in the 3,4-trans form, wherein Y is as defined above. Let t) condensation of the compound of formula (XXII) with a suitable deprotecting agent, preferably chlorinated pyridine With deprotection, and R in the formula¹Is a hydrogen compound of formula (I). Or u) R in the formula¹Is hydrogen with a suitable carboxylic acid or sulfonate Reaction with a carboxylic acid derivative, and R in the formula¹Is COR^Four, CONHR^Four, CONR^Four _Two, SO_TwoNR^Four _TwoOr SO_TwoNHR^FourAnd R in the formula^FourIs the same as above Forming the compound of (I), v) reacting a compound of formula (VI) with methanesulfonyl chloride, wherein R^FiveIs a compound of formula (XXIII) as defined above,w) converting the compound of formula (XXIII) to a suitable compound such as pyridine hydrochloride or tribromide Deprotection using a suitable deprotecting agent,^FiveIs a compound of formula (XXIV) as defined above To form x) converting the compound of formula (XXIV) to benzyl bromide or 4-methylbenzyl bromide By reacting with a suitable protecting agent such as^FiveIs the same as above,⁶Is H or met Forming a compound of formula (XXV) which is an xy group, y) converting the compound of formula (XXV) to an alcohol of sodium hydroxide or potassium hydroxide Deprotection using a suitable deprotecting agent such as^FiveIs the same as above , R⁶Is a compound of formula (XXVI) wherein is H or a methoxy group;z) alkylating the compound of formula (XXVI) using a suitable electrophile, , R^FiveAnd Y are the same as above, and R⁶Is a compound of the formula (XXVII) wherein ) To form a compound aa) converting a compound of formula (XXVII) to a suitable deprotecting agent, preferably R⁶Is H Represents the catalytic hydrogenation, or R⁶Is a methoxy group, deprotection using a strong acid , N, R in the formula^FiveAnd Y are the same as defined above to form a compound of formula (XXVIII) Let bb) The compound of the formula (XXVI) is converted to 1,2-dibromoethane, 1-bromo-2- Loroethane, 1,4-dibromobutane, 1,6-dibromohexane, 1,8-di Dihalides such as bromooctane, 1,10-dibromodecane, preferably Catalyzed by potassium iodide, wherein R^FiveIs the same as above, and R⁶Is H or A compound of the formula (XXIX), wherein Hal is chloro, bromo, or iodo, To form a compound of cc) reacting a compound of formula (XXIX) with a suitable nucleophile, preferably an amine Shime, R in the formula⁶Is H or a methoxy group, and Z is NHR^Four, NR^Four _TwoOr C_Three -C₇A heterocyclic amine, which may contain oxygen or nitrogen. , H, OH, halogen, nitro, cyano, trihalo-C₁-C₆-Alkyl , C₁-C₆-Alkyl and C₁-C₆-Independently selected from the group consisting of alkoxy And may be substituted with one to three substituents, and n, R^FourAnd R^FiveIs To form a compound of formula (XXX) which is the same as dd) The compound of formula (XXX) is converted to a suitable deprotecting agent, preferably R⁶If H is Hydrogenation with a medium, or R⁶When is a methoxy group, deprotection using a strong acid, R in⁶Is H or a methoxy group, and Z is NHR^Four, NR^Four _TwoOr C_Three -C₇A heterocyclic amine, which may contain oxygen or nitrogen. , H, OH, halogen, nitro, cyano, trihalo-C₁-C₆-Alkyl , C₁-C₆-Alkyl and C₁-C₆-Independently selected from the group consisting of alkoxy And may be substituted with one to three substituents, and n, R^FourAnd R^FiveIs To form a compound of formula (XXXI) which is the same as The starting benzophenone of formula (II) is prepared by converting the appropriate dimethyl ether to p-hydro Friedel-Craft acylation reaction with xybenzoic acid, then vinegar It can be easily prepared by selectively demethylating one group in an acid. The starting deoxybenzoin of formula (XVIII) is An appropriate substituted phenylacetic acid derivative is Followed by selective demethylation of one group with hydrobromic acid in acetic acid. And can be easily prepared. Optically pure compounds of formula (I) can be obtained by introducing one separation step into the process. Can be obtained at The separation comprises any racemic mixture of enantiomers being formed. It can also be performed after the process. Diastereomeric salt formation or chiral HPLC method (−)-Enantiomer and / or (+)-enantiomer Isomers can be separated from a mixture of isomers. A "suitable electrophile" is typically a compound of the formula where Y is the same as above and Hlg is Formula Y- (CH which is Cl, Br or I_Two) Alkylhalo represented by n-Hlg Means gently. The cyclization step in the above method may involve, for example, converting an appropriate activated carboxylic acid derivative to hydrogen. And can be implemented. "Suitable cross-linking partners" typically include, for example, Ni (O) -catalyzed green Organometallic reagent together with a transition metal catalyst, such as Schiffer's reagent. "Suitable Grignard reagents" typically means that M is MgHg and Hlg Is Cl, Br or I, and Y is as defined above,_Two) -Y organic It means a metal compound. Using a base, the 3,4-cis chroman is mirror-imaged to the 3,4-trans chroman. The method of incorporation is described in A. K. Scrivastava, J. et al. Lal, R .; C . . Gupta and P.M. K. Grover by Indian J. et al. Chem. 3 33, 773-4, 1994. The present invention relates to a medicament comprising an effective amount of the compound of the present invention and a pharmaceutical excipient or diluent. Related to goods. These drugs must be in the form of an oral or parenteral dosage form Is preferred. Further, the present invention relates to an estrogen-related disease or syndrome, preferably in a mammal. Diseases or syndromes caused by estrogen deficiency in A method of treatment or prevention by administering an effective amount to a patient in need thereof is there. The compounds of the present invention are novel estrogen agonists and prevent and treat bone loss , Prevention and treatment of osteoporosis, prevention and treatment of cardiovascular disease, excessive neuropeptide Y Treatment and prevention of associated physiological disorders (eg obesity and depression) and non-insulin Control of glucose metabolism such as phosphorus-dependent diabetes mellitus and Alzheimer-type senile dementia in women Useful for prevention and treatment of dementia. In addition, these estrogen agonists are Contraceptives, postmenopausal symptoms (eg flushing, genital atrophy, depression, mania, schizophrenia, etc.) Relief, incontinence, prevention of imminent or habitual abortion, reduction of dysmenorrhea, dysfunctional uterus Reduces bleeding, aids ovarian development, treats acne, reduces hair overgrowth in women It is also useful for the treatment of gestational hirsutism, treatment of prostate cancer and suppression of postpartum lactation. These compounds also lower serum cholesterol and have a Has an effective action. The compounds of the present invention are estrogen agonists in the bone and cardiovascular system, These compounds can also act as antiestrogens in estrogen target organs. For example, these compounds can act as antiestrogens in breast tissue and colon. Useful for preventing and treating estrogen-dependent cancers such as breast and colon cancer It is.In vitro estrogen receptor binding test Estrogen of Compounds of the Invention Using an In Vitro Receptor Binding Assay The affinity for the receptor was measured. This assay is a compound of the present invention. 3H-17β-est from estrogen receptor (ER) obtained from heron uterus Ladiol (17β-E2 ) Is measured. In the experiment, ER obtained from rabbit uterus ER-poor cytoplasm obtained from rabbit muscle at 0.5 nM^ThreeH Diluted to 20-25% of the maximum binding of -17β-E2. Minutes per assay On the day of the analysis, a portion of the cytoplasm was newly thawed, and the cells were thinned with approximately 3 mg of Assay buffer. It was diluted to the amount of cytoplasmic protein / ml. The composition of Assay Buffer (PB) As follows: 10 mMK_TwoHPO_Four/ KH_TwoPO_Four, 1.5 mMK_TwoEDTA , 10 mM monothioglycerol, 10 mM N_a2MoO_Four. 2H_TwoO, 10% Lycerol (v / v); pH 7.5. Non-radioactive 17β-E2 was obtained from Sigma ( Sigma). The test solution was adjusted to 8 × 10 −3 M in a suitable solvent, and then PB or Was diluted with DMSO to prepare a dilution series. 10 μl test for each test concentration Take two aliquots and add 20 μl^ThreeH-17β-E2 (at an assay concentration of 0.4 nM) Equal) and 50 μl of cytoplasm in the microtiter plate The reaction was carried out. Test compound replacement for control and maximal binding samples Instead, 10 μl of PB was added. After reacting at 4 ° C. for 18-20 hours, 100 μl of DCC slurry [0.5% Activated carbon (Sigma) and 0.005% dextran T70 (Pharmacia) PB solution) was added to the sample to stop, and the mixture was further stirred at 4 ° C. for 15 minutes. . Add 50 μl of 0.3% BSA PB solution instead of cytoplasm The background values were checked. Combined^ThreeH-17β-E2 and free form^ThreeTo separate H-17β-E2, The Titertek plate was centrifuged (800 × g) at 4 ° C. for 10 minutes. Take 100 µl of the sample, Opt Scintillation measurement was performed using ifflow scintillation liquid. Standard Samples and control samples were measured in quadruplicate, but test samples were measured in duplicate. . Calculate the average counts per minute (cpm) for each sample and calculate the Background (DCC) to determine the percent of maximum 3H-17β-E2 binding. I did. The resulting cpm is plotted against the estimated concentration of the corresponding test compound (vs. (Several scales), the compound concentration required to displace 50% of the maximum binding is determined by the IC5 0 was set.Bone mineral density Bone mineral density (BMD), which represents bone mineral content (BMC), is 80% of bone strength. %. BMD loss due to aging and acceleration due to menopause are skeletal strength Reduce the degree of fracture and make certain points more prone to fractures; The vertebrae, wrists and buttocks. The measurement of true bone density is Archimede (Archimedes) ) Is possible by weight measurement using the principle of (invasive method). BMD also has two wavelengths It can also be measured non-invasively by X-ray absorption (DEXA). In our laboratory Shows that estrogen deficiency in ovariectomized rodents was measured using a gravimetric method. The change in MD was examined. After the ovaries are removed (the ovaries are surgically removed), the animals Excipient, positive control 17β-E2 and / or other estrogens Gen agonists were administered. The purpose of these studies was to investigate rodent models of human disease The purpose of the present invention is to examine the ability of the compound of the present invention to prevent bone loss in the present invention. Female Sprague-Dawley rat (approximately 3 to 5 months old) or female Ovaries from Swiss-Webster mice (approximately 3 to 5 months old) He also had resection or sham surgery. After waking from anesthesia, the animals are randomly More than 8 animals were assigned to the group: Sham-operated animals receiving vehicle Ovariectomized animal with vehicle An animal whose ovaries have been removed by administering 25 μg estradiol / kg, An animal from which ovaries were removed after administration of 200 μg / kg of a test compound. Compounds are weighed and dissolved in sterile saline solution of the excipient solvent, every 35 days Animals were dosed subcutaneously on day one. Animals were sacrificed at the end of the 35-day protocol. After the femur was cut out, the attached soft tissue was removed. For rats, diamonds 1cm cut off the end of the thigh with meat taken using It was fixed with alcohol (in the case of a mouse, the end was cut off at a length of 0.5 cm and fixed). 7 Fix with 0% ethyl alcohol (EtOH) and use an automatic tissue processor The bone specimens were sequentially transferred to an alcohol concentration of 100% and dehydrated. Dehydrated and then black The lipids were removed with roform and hydrated in distilled water. Automatic tissue preparation All steps were performed under vacuum. The weight of the hydrated bone is measured in air and then the density While suspended in water using a Mettler balance equipped with a measurement kit The weight was measured. Divide the weight in air of each sample by the difference between the weight of air and the weight in water Total bone density was determined; that is, the amount of organic matrix + mineral per unit volume of tissue. After determining the total bone density, the sample is placed in a muffle furnace overnight and heated to 600 ° C. for incineration. You. The ash weight of each sample is then calculated as the tissue volume (ie, air weight-weight suspended in water). To determine the mineral density. Average bone density for each group (total bone mineral density and mineral bone Density) and calculate the statistically significant difference between the vehicle-administered group and the estrogen-administered control group. Determined using the pewter statistics program.Cholesterol lowering activity The effect of the compounds of the present invention on serum levels of total cholesterol A blood sample obtained from the animal used for the bone density measurement, or 28 days or more Using blood samples obtained from ovariectomized rats or mice to which the compound was administered. Solid. In each experiment, blood from compound-treated animals was collected by cardiac puncture. , Into tubes containing 30 μl of 5% EDTA per ml of blood. 20 ° C After centrifugation at 2500 rpm for 10 minutes, the plasma was removed and -20 until measurement. Stored in ° C. Cholesterol is commercially available from Sigma Diagnostics Using a standard enzymatic kit (kit number 352). Was.Formulation adjustment Compounds of the invention together with a common adjuvant, carrier, or diluent If it is necessary to add an acid that can be used as a drug, And can be in the form of dosage units, tablets and filled capsules Solid formulations or solutions, suspensions, emulsions, drug solutions such as elixirs, or the like. It can be formed into any shape suitable for oral administration such as a filled capsule. Also Is a sterile injectable solution for parenteral administration (including subcutaneous administration and infusion). You can also. Such excipients and their dosage unit form can be passed through conventional excipients. It contains in the usual ratio, and may contain other active compounds or ingredients, It may also be absent, and these dosage unit forms constitute a daily dosage range. And an appropriate effective amount of a compound of the present invention. As a preferred example of a dosage unit form Tablets containing 10 milligrams of active ingredient, more broadly 10 to 1 per tablet There are tablets containing 00 milligrams. The compounds of the present invention can be used to formulate pharmaceutical preparations, e.g. It can be used for oral and parenteral administration to mammals including. Ordinary excipients are intended for non-intestinal administration that do not harm the active compound Also organic or inorganic carriers available for drugs suitable for enteral administration is there. Examples of such carriers are water, saline, alcohol, polyethylene glycol. Coal, polyhydroxyethoxylated castor oil, gelatin, lactose amylose, Magnesium alate, talc, silicic acid, fatty acid monoglyceride, fatty acid diglyceride Cerides, pentaerythritol fatty acid esters, hydroxymethylcellulose There is polyvinylpyrrolidone. Pharmaceutical preparations are sterilized and, if necessary, reacted with the active compound and are not harmful, Emulsifiers, salts for adjusting osmotic pressure, buffers and / or colorants can be mixed You. For parenteral administration, injectable solutions or suspensions are particularly suitable. Aqueous solutions containing the active materials dissolved in roxified castor oil are preferred. Ampules are convenient as dosage unit forms. Contains talc and / or carbohydrate carriers or binders, making the carrier easier Preferably toast and / or corn starch and / or potato starch Tablets, dragees or capsules are particularly suitable for oral administration. Syrup, d Rixyl agents and the like can be used when sweet excipients are available. In general, the compounds of the present invention are useful as carriers that can be used as drugs per dosage unit. 0.05-100 mg is dispensed in the form included. The dose of the compound of the present invention may be, for example, when administered as a pharmaceutical to a human patient. Is 0.1-300 mg / day, preferably 10-100 mg / day. Typical tablets prepared by conventional tablet manufacturing methods include: To get: Active compound 5.0mg Lactosum 67.0 mg Ph. Eur Avicel^TM 31.4mg Amberlite^TM1.0 mg of IRP88 Magnesil stearas 0.25 mg Ph. Eur The compounds of the present invention require the compounds of the present invention in living animals, including humans, for example. Can be administered to patients in need and can be used as a pharmaceutical if needed In the form of an acid addition salt of the compound (hydrobromide, hydrochloride or sulfonate) For example, fonates are used to evaporate the free base in a solution containing an acid to dry the solution. Carriers that can be adjusted in usual or general ways), and are usually available as pharmaceuticals Or a diluent, especially and preferably said carrier in the form of a pharmaceutical ingredient. Can be used in combination with, or simultaneously with, or with a diluent, oral, rectal, or non-intestinal An effective amount for treating a disease can be administered by the following routes (including the below). Suitable administration Amounts are 1-200 mg / day, 10-100 mg / day, preferably 30-7 mg / day. 0 mg / day, the amount was usually indicated by the method of administration, dosage form, and administration Determined by application, patient and patient weight and experience of the attending physician or veterinarian . Hereinafter, the present invention will be described in detail with reference to examples. Of course, this embodiment is based on the claims. It is not intended to limit the scope of the invention as defined. Example 1 (±) -trans-7-hydroxy-3-phenyl-4- (4- (2-pyrrolidine Noethoxy) phenyl) chroman Step 1: 4- (4-hydroxyphenyl) -7-methoxy-3-phenyl-3-chroman 4- (4-acetophenyl) -7-methoxy-3-phenyl-3-coumarin ( 180 g) in toluene (2.11) at 70 ° C. Minium (35.4 g) was added to a suspension in tetrahydrofuran (2.11). Attachment During the addition, the temperature of the reaction mixture was kept at 60 ° C. or lower. The reaction mixture was cooled to room temperature . Water (45 ml) was carefully added, followed by 5M hydrochloric acid (1.21). . The mixture was stirred for 3 hours while heating to 60-65 ° C. The organic phase separated. water The phases were extracted with toluene (250ml). Combine organic phase and water (250m Wash in l) and evaporate to an oil. Add this oil to boiling ethanol (600ml) Was dissolved. After cooling the solution, water (400 ml) was slowly added. The mixture was seeded. The crystals were removed by filtration, water / ethanol; 25/75 (200 ml) and then dried. Yield 4- (4-hydroxyphenyl) -7-methoxy-3-phenyl-3-c 126 g (81%) of roman; mp 156-157 ° C. Step 2: Cis-4- (4-hydroxyphenyl) -7-methoxy-3-phenylchroman 4- (4-hydroxyphenyl) -7-methoxy-3-phenyl-3-chroma '77 .7 g) was dissolved in ethanol (1500 ml) at 50 ° C. Paraziu Black, 10% and water 50% (6 g) were added to the solution, and the mixture was heated at 55 ° C. Hydrogenation was carried out under pressure for 8 hours. The catalyst was removed by filtration while the suspension was warm, and the filtrate was evaporated to an oil. Solidified during evaporation. Yield 74.3 g (95%), mp 168-190 ° C. The product is¹H-NMR and element Confirmed by elementary analysis. Step 3: (±) -cis-7-methoxy-3-phenyl-4- (4- (2-pyrrolidinoet Xy) phenyl) chroman Cis-4- (4-hydroxyphenyl) -7-methoxy-3-phenyl chroma (74.3 g) in toluene (700 ml), water (12 ml) and sodium hydroxide (24.3 g) and heated to 75 ° C. This is 2-chloroethyl Pyrrolidine hydrochloride (46.2 g) was divided into 6 portions, once every 30 minutes, at 75 ° C. added. After the last addition was completed, the mixture was warmed at 75 ° C. for 4 hours. Water (1 000 ml) was added and the mixture was stirred until all salts were dissolved. Water phase The mixture was separated, and extracted with another portion of toluene (300 ml). One organic phase Combined, dried over potassium carbonate and evaporated to an oil. Methano reflux oil (1000 ml), which was crystallized by cooling in an ice bath. (±) -cis-7-methoxy-3-phenyl-4- (4- (2-pyrrolidinoe Yield of 79.6 g (83%) of toxic) phenyl) chroman, mp 113-114. ° C. The product is¹Confirmed by H-NMR and elemental analysis. Step 4: (±) -trans-7-methoxy-3-phenyl-4- (4- (2-pyrrolidino Ethoxy) phenyl) chroman Cis-7-methoxy-3-phenyl-4- {4- [2- (pyrrolidine-1-i Le) noethoxy] phenyl} chroman (5.2 g) is converted to dimethyl sulfoxide (5.2 g). 12.5ml) and potassium hydroxide (0.55g) at 70-80 ° C for 5 hours Dissolve with a pause. Reaction mixture The mixture was cooled to room temperature. Water (50 ml) was added. Stir the mixture for 30 minutes, The resulting sticky precipitate was filtered off and washed several times with water before proceeding to the next reaction. (±) -trans-7-methoxy-3-phenyl-4- (4- (2-pyrrolidine 2.3 g (44%) of (ethoxy) phenyl) chroman. The product is¹H-NM Confirmed by R. Step 5: (±) -trans-7-hydroxy-3-phenyl-4- (4- ( 2-pyrrolidinoethoxy) phenyl) chroman Trans-7-methoxy-3-phenyl-4- {4- [2- (pyrrolidine-1 -Yl) noethoxy] phenyl} chroman (2 g) was combined with pyridine (10 ml). The molten pyridochloride prepared from the mixture from concentrated hydrochloric acid obtained by removing water by distillation at 140 ° C. Dissolved in midinium. The mixture was heated for 75 minutes. Cooled to room temperature. Water (1 5 ml) and the pH was adjusted to 12 with sodium hydroxide (32.5%). Mixed The combined solution was extracted with toluene (15 ml). Separate the organic phase and add potassium carbonate And dried. The resulting oil was applied to two successive silica gel 60 columns, first using ethyl acetate. 1: 1 methanol / methanol as eluent, then dichloromethane / methanol 1: 1 Was produced by column chromatography using as an eluent. (±) -trans-7-hydroxy-3-phenyl-4- (4- (2-pyrroli 0.14 g (7%) of dinoethoxy) phenyl) chroman. The product is¹H-N Confirmed by MR and elemental analysis. Example 2 (±) -trans-7-hydroxy-3- (4-fluorophenyl) -4- (4 -(2-pyrrolidinoethoxy) phenyl) chroman Step 1: 4- (4-acetoxyphenyl) -3- (4-fluorophenyl) -7-methoxy Sea marine (2-hydroxy-4-methoxyphenyl)-(4-hydroxyphenyl)- Methanone (7.33 g, 30.0 nmol), acetic anhydride (15 ml), triet Tylamine (5.5 ml, 39.5 mmol) and 4-fluorophenylacetic acid (4 . (63 g, 30.0 mmol) was stirred at 135 ° C. for 18 hours to obtain a mixture. The orange liquid was poured into water (120 ml) and further stirred for 3 hours. Obtained The aqueous mixture containing the sticky solid was diluted with ethyl acetate (300 ml) Was dissolved and the organic phase was separated. The aqueous phase is further treated with ethyl acetate (2 × 100 ml) Extracted. Combine the organic phases, wash with water, wash with saturated sodium chloride solution, and Then dried over sodium sulfide and evaporated to a yellow / orange solid It was recrystallized from a 1: 1 solution of ethanol: water (600 ml) to give a gray A dark white solid was obtained and dried under vacuum. 4- (4-acetoxyphenyl) -3- (4-fluorophenyl) -7-meth 7.98 g (65%) of xyquemarin. 173-176 ° C.¹H-N MR (CDCl_Three, 300 MHz) δ: 2.32 (s, 3H); 3.89 (s, 3H); 6.78 (dd, 1H); 6.82-6.95 (m, 3H); 7.03 -7.14 (m, 6H); 7.15 (d, 1H). LRMS (EI) 404 (M⁺ ), 362, 334, 319, 43. Elemental analysis; C_{twenty four}H₁₇FO_FiveCalculation about Values: C, 71.28; H, 4.24%; found C, 71.26; H, 4.25%. Step 2: 3- (4-fluorophenyl) -4- (4-hydroxyphenyl) -7-methoxy Sea chrome-3-ene Lithium aluminum hydride (0.76 g, 20.03 mmol) was added in small portions. 4- (4-acetoxyphenyl) -3- (4-fluorophenyl) -7- Methoxy-coumarin '4.04 g, 9.99 mmol) in tetrahydrofuran ( 150 ml) with stirring. When all has been added, mix at room temperature for 3 hours. Stirred for 0 min, then added 6M hydrochloric acid (30 ml) dropwise. The resulting mixture is After heating at 60-65 ° C for 3 hours, the mixture was cooled and water (100 ml) and ethyl acetate (5 ml) were added. 0 ml). Separate the aqueous phase and extract with ethyl acetate (3 × 100 ml). Issued. Combine the organic phases and wash with saturated sodium chloride solution. Drying over lium and evaporation gave an orange solid. Ethanol / water ( 4: 1, 75 ml) to give a colorless needle-shaped solid as the first product. . The mother liquor was evaporated to give an orange rubber body, from which a second time of aqueous ethanol Crystallization gave a colorless needle-shaped second product. Do you put the solids together And dried under vacuum. 3- (4-fluorophenyl) -4- (4-hydroxyphenyl) -7-metho 2.47 g (70%) of xiechrome-3-ene. Melting point 155-156.5 ° C.¹H-NMR (CDCl_Three, 300 MHz) δ: 3.79 (s, 3H); 80 (bs, 1H); 5.20 (s, 2H); 6.40 (dd, 1H); 6.5 1 (d, 1H); 6.70-7.00 (m, 9H). LRMS (EI) 348 ( M⁺), 255 (M-PhOH), 253 (M-PhF). Step 3: (±) -cis-3- (4-fluorophenyl) -4- (4-hydroxyphenyl ) -7-Methoxy-chroman While stirring palladium black (10%, 0.20 g, 0.19 mmol), 3- (4 -Fluorophenyl) -4- (4-hydroxyphenyl) ) -7-Methoxy-chromium-3-ene (1.74 g, 4.99 mmol) To the ethanol solution (150 ml), the mixture is hydrogenated at room temperature for 20 hours. Catalyst Filter off and evaporate the solvent to give an off-white solid which is extracted with water. It was purified by recrystallization from ethanol. Dry the resulting colorless solid under vacuum Thus, a colorless plate containing 0.75 equivalents of crystalline ethanol was obtained. (±) -cis-3- (4-fluorophenyl) -4- (4-hydroxyphenyl L) -7-Methoxy-chroman yield 1.29 g (73%). Melting point 164-16 5 ° C (water ethanol).¹H-NMR (CDCl_Three, 300 MHz) d: 1.25 (T, 2.4H, 0.75 EtOH), 3.55 (ddd, 1H), 3.73 ( q, 1.6H, 0.75 EtOH), 3.81 (s, 3H), 4.16-4.2. 5 (m, 2H), 4.38 (dd, 1H), 4.90 (bs, 1H), 6.44 -6.58 (m, 6H), 6.59-6.68 (m, 2H), 6.80-6.9 0 (m, 3H). LRMS (EI) 350 (M⁺), 227, 211. Elemental analysis C_{twenty two}H₁₉FO_Three-Calculated value in terms of 0.75 EtOH: C, 73.33; H, 6. 13%; found C, 73.32; H, 6.11%. Step 4: (±) -cis-3- (4-fluorophenyl) -7-methoxy-4- (4- (2 -Pyrrolidinoethoxy) phenyl) -chroman (±) -cis-3- (4-fluorophenyl) -4- (4-hydroxyphenyl 7) -7-methoxy-chroman (0.53 g, 1.51 mmol) and potassium carbonate (2.10 g, 15.2 mmol) and sodium iodide (0.01 g, 0.0 7 mmol), 1- (2-chloroethyl) pyrrolidine hydrochloride (0.28 g, 1 . A mixture of 65 mmol) and acetone (35 ml) was refluxed at 60 ° C for 24 hours. Stirred for hours. The resulting mixture was filtered and the solvent was evaporated to give a colorless rubber, This was cooled and solidified. The crude solid was recrystallized from water ethanol to give a colorless A needle-like product was obtained and dried under vacuum. (±) -cis-3- (4-fluorophenyl) -7-methoxy-4- (4- ( 0.57 g (83%) of 2-piperidinoethoxy) phenyl) -chroman. 93.5-94.5 ° C (water ethanol).¹H-NMR (CDCl_Three, 300 MHz) δ: 1.75-1.85 (m, 4H), 2.55-2.65 (m, 4H) ), 2.85 (t, 2H), 3.55 (ddd, 1H), 3.81 (s, 3H) , 4.08 (t, 2H), 4.16-4.23 (m, 2H), 4.37 (dd, 1H), 6.43-6.53 (m, 4H), 6.57-6.66 (m, 4H), 6.80-6.88 (m, 3H). LRMS (EI) 447 (M⁺), 84 (C_Five H_TenN) Step 5: (±) -trans-3- (4-fluorophenyl) -7-methoxy-4- (4- (2-pyrrolidinoethoxy) phenyl) -chroman (±) -cis-3- (4-fluorophenyl) -7-methoxy-4- (4- ( 2-pyrrolidinoethoxy) phenyl) -chroman (1.0 g, 2.33 mmol) ) And potassium chloride in powder form (0.25 g, 4.46 mmol) in dry DMS The mixture in O was warmed to 80 ° C. for 3 hours. Dilute the mixture with water (100 ml) The product was extracted into ethyl acetate (3 × 100 ml). Put the extracts together Wash with water, brine, dry over magnesium sulfate and evaporate An orange gum-like crude compound was obtained. The title compound is silica gel 60 color Chromatography using dichloromethane and 5% methanol in dichloromethane Partially purified by Evaporation of the title compound to give unreacted cis-form with the title compound Isomer output The mixture with the starting material was separated. Further, the title compound was prepared by HPLC: Column: YM C120 Å, 15 μm, 250 × 10 mm; eluent: 60% meta In 50 mM ammonium acetate; flow rate: 10 ml / min; U at 220 nm Purified completely using V-detection. Dry the corresponding fractions to give a colorless waxy title Compound was obtained. (±) -trans-3- (4-fluorophenyl) -7-methoxy-4- (4 -(2-pyrrolidinoethoxy) phenyl) -chroman yield 0.11 g (11% ).¹H-NMR (CDCl_Three, 300 MHz) δ: 1.73-1.88 (m, 4 H) 2.60-2.72 (m, 4H), 2.90 (t, 2H), 3.20 (d dd, 1H), 3.75 (s, 3H), 4.04 (t, 2H), 4.05-4. 25 (m, 2H), 4.30 (dd, 1H), 6.40 (dd, 1H), 6.4 5 (d, 1H), 6.67 (d, 1H), 6.74 (dm, 2H), 6.80- 6.95 (m, 4H), 6.95-7.04 (m, 2H). LRMS (EI) 4 47 (M⁺), 84 (C_FiveH_TenN, 100%). Analytical HPLC, Rt = 5.62 min . (LiChrosorb RP-18 (7 μm), 250 × 4 mm column); Eluent 90% methanol / 10% (pH 7, 0.25% triethylamine / phosphorus Acid solution) buffer; detection 220 nm UV; flow rate 0.9 ml / min. Step 6: (±) -trans-7-hydroxy-3- (4-fluorophenyl) -4- (4 -(2-pyrrolidinoethoxy) phenyl) -chroman Anhydrous pyridine hydrochloride (0.289 g, 2.50 mmol) and (±) -trans- 3- (4-fluorophenyl) -7-methoxy-4- (4- (2-pyrrolidinoe Toxic) phenyl) -chroman (0.11 g, 0.25 mmol) Heated to 135 ° C. for hours. The obtained dark brown solid was dissolved in methanol (10 ml), water (50 ml), and carbonated water. Dissolve in a mixture of sodium hydrogen chloride solution (5 ml) and dilute the product with dichloromethane / methanol To a 9: 1 solution (3 × 50 ml). Combine the extracts into water, Wash in line, dry over magnesium sulfate and evaporate to orange Thus, a crude composite compound in the form of rubber was obtained. The product is silica gel 60 column and 5% methanol Purified by column chromatography using chloromethane solution as solvent, colorless A wax was obtained. (±) -trans-7-hydroxy-3- (4-fluorophenyl) -4- ( 4- (2-pyrrolidinoethoxy) phenyl) -chroman yield 40 mg (37% ).¹H-NMR (MeOH-d_Four, 200 MHz) δ: 1.85-2.10 (m , 4H), 3.00-3.18 (m, 4H), 3.18-3.38 (m, 3H) 4.05-4.25 (m, 5H), 6.22 (dd, 1H), 6.30 (d, 1H), 6.46 (d, 1H), 6.80 (dm, 2H), 6.84-6.98. (M, 4H), 6.84-6.98 (m, 4H), 7.04-7.16 (m, 2 H). LRMS (EI) 433 (M⁺), 84 (C_FiveH_TenN, 100%). Example 3 (±) -trans-7-hydroxy-3- (4-fluorophenyl) -4- (4 -(2-piperidinoethoxy) phenyl) -chroman The title compound was obtained using 1- (2-k) as the electrophile in Step 4 of Example 2. (Loroethyl) piperazine is changed to 1- (2-chloroethyl) pyrrolidine hydrochloride The preparation was carried out in the same manner as described in Example 2 except for the following. Intermediate (±) -trans-3- (4-fluorophenyl) -7-methoxy- 4- (4- (2-piperidinoethoxy) phenyl)- Chromane (70 mg, 0.152 mmol) was added to piperazine hydrochloride (0.176 g, (152 mmol) for 18 hours. The title compound was obtained. (±) -trans-7-hydroxy-3- (4-fluorophenyl) -4- ( 25 mg of 4- (2-piperidinoethoxy) phenyl) -chroman.¹H- NMR (MeOH-d_Four, 200 MHz) δ: 1.40-1.55 (m, 2H) , 1.55-1.70 (m, 4H), 2.50-2.62 (m, 4H), 2.7 8 (t, 2H), 3.15-3.30 (m, 1H), 4.05 (t, 2H), 4 . 10-4.25 (m, 3H), 6.23 (dd, 1H), 6.28 (d, 1H) ), 6.49 (d, 1H), 6.75 (dm, 2H), 6.85-6.98 (m , 4H), 7.05-7.16 (m, 2H). Phenol OH not observed Was. LRMS (EI) 447 (M⁺), 98 (C₆H₁₂N, 100%).

───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.⁷ 識別記号ＦＩテーマコート゛(参考）Ａ６１Ｐ 25/28 Ａ６１Ｐ 25/28 Ｃ０７Ｄ 413/04 Ｃ０７Ｄ 413/04 (81)指定国ＥＰ(ＡＴ，ＢＥ，ＣＨ，ＤＥ，ＤＫ，ＥＳ，ＦＩ，ＦＲ，ＧＢ，ＧＲ，ＩＥ，ＩＴ，ＬＵ，ＭＣ，ＮＬ，ＰＴ，ＳＥ)，ＯＡ(ＢＦ，ＢＪ，ＣＦ，ＣＧ，ＣＩ，ＣＭ，ＧＡ，ＧＮ，ＭＬ，ＭＲ，ＮＥ，ＳＮ，ＴＤ，ＴＧ)，ＡＰ(ＧＨ，ＫＥ，ＬＳ，ＭＷ，ＳＤ，ＳＺ，ＵＧ，ＺＷ)，ＥＡ(ＡＭ，ＡＺ，ＢＹ，ＫＧ，ＫＺ，ＭＤ，ＲＵ，ＴＪ，ＴＭ)，ＡＬ，ＡＭ，ＡＴ，ＡＵ，ＡＺ，ＢＡ，ＢＢ，ＢＧ，ＢＲ，ＢＹ，ＣＡ，ＣＨ，ＣＮ，ＣＵ，ＣＺ，ＤＥ，ＤＫ，ＥＥ，ＥＳ，ＦＩ，ＧＢ，ＧＥ，ＧＨ，ＨＵ，ＩＤ，ＩＬ，ＩＳ，ＪＰ，ＫＥ，ＫＧ，ＫＰ，ＫＲ，ＫＺ，ＬＣ，ＬＫ，ＬＲ，ＬＳ，ＬＴ，ＬＵ，ＬＶ，ＭＤ，ＭＧ，ＭＫ，ＭＮ，ＭＷ，ＭＸ，ＮＯ，ＮＺ，ＰＬ，ＰＴ，ＲＯ，ＲＵ，ＳＤ，ＳＥ，ＳＧ，ＳＩ，ＳＫ，ＳＬ，ＴＪ，ＴＭ，ＴＲ，ＴＴ，ＵＡ，ＵＧ，ＵＺ，ＶＮ，ＹＵ，ＺＷ (72)発明者バリー，ポールスタンレイデンマーク国，デーコー―2400 ケベンハウンエンベー，ヨルトルムスアレ 48 (72)発明者カンストルプ，アンデルスデンマーク国，デーコー―3060 エスペルゲルデ，フレドスコウバイ７セー (72)発明者ブロウンクリスティアンセン，リゼデンマーク国，デーコー―2800 リーングビー，ソフュススカンドルフスバイ４──────────────────────────────────────────────────続き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 25/28 A61P 25/28 C07D 413/04 C07D 413/04 (81) Designated countries EP (AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (GH, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ , TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI GB, GE, GH, HU, ID, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW , MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, UZ, VN, YU, ZW Barry, Paul Stanley, Denmark, Denmark-2400 Kebenhaun-Embe, Jörtrums Alle 48 (72) Inventor Kanstorp, Anders Denmark, Denmark-3060 Espel Gerde, Fredskoubai 7See (72) Inventor Blown Christiansen, Rize Denmark , DECO-2800 Leaning Be, Sofus Scandorfus by 4

Claims

[Claims] 1. Substituent R in the formula^TwoAnd R^ThreeIs a compound of formula (I) arranged in the trans form hand, R in the formula¹Is H, COR^Four, CONHR^Four, CONR^Four _Two, SO_TwoNR^Four _TwoOr S O_TwoNHR^FourAnd R^TwoIs optionally OH, halogen, nitro, cyano, SH, SR^Four, Toriha B-C₁-C₆-Alkyl, C₁-C₆-Alkyl, C₁-C₆-Alkoxy and Substituted with 1 to 5 substituents independently selected from the group consisting of Phenyl, and R^ThreeBut, (A) -X- (CH_Two)_nPhenyl substituted with -Y, wherein X in the formula is an atom Valence bond, O or S, n is an integer from 1 to 12, Y is H, halogen , OH, OR^Four, NHR^Four, NR^Four _Two, NHCOR^Four, NHSO_TwoR^Four, CONHR^Four, CONR^Four _Two, COOH, COOR^Four, SO_TwoR^Four, SOR^Four, SONHR^Four, SON R^Four _Two, Saturated or unsaturated C_Three-C₇A heterocycle, wherein the heterocycle is O, S and And one or two heteroatoms independently selected from the group consisting of H, OH, halogen, nitro, cyano, SH, SR^Four,bird Halo-C₁-C₆-Alkyl, C₁-C₆-Alkyl, and C₁-C₆-Alkoki By one to three substituents independently selected from the group consisting of Replaced or (B) wherein n and Y in the formula are the same as in (a),-(CH_Two)_n-Y, or (C) one or two independently selected from the group consisting of O, S and N Containing two heteroatoms, optionally H, OH, halogen, nitro, cyano, SH, SR^Four, Trihalo-C₁-C₆-Alkyl, C₁-C₆-Alkyl, and C₁-C₆-1 to 3 substitutions independently selected from the group consisting of alkoxy Or unsaturated C substituted with a group_Three-C₇Phenyl fused with a heterocycle, One of R in the above formula^FourIs C₁-C₆A compound which is alkyl; And its optical and stereoisomers, its esters, Ter and salt. 2. Substituent R in the formula^TwoAnd R^ThreeIs a compound of formula (I) arranged in the trans form hand, R in the formula¹Is H, COR^Four, CONHR^Four, CONR^Four _Two, SO_TwoNR^Four _TwoOr S O_TwoNHR^FourAnd R^TwoIs optionally OH, halogen, nitro, cyano, SH, SR^Four, Toriha B-C₁-C₆-Alkyl, C₁-C₆-Alkyl, C₁-C₆-Alkoxy and Substituted with one to three substituents independently selected from the group consisting of Phenyl, and R^ThreeBut, (A) -X- (CH_Two)_nPhenyl substituted with -Y, wherein X in the formula is an atom Valence bond, O or S, n is an integer of 1 to 12, and Y is H, OH, O R^Four, NHR^Four, NR^Four _Two, NHCOR^Four, NHSO_TwoR^Four, CONHR^Four, CONR^Four _Two , COOH, COOR^Four, SO_TwoR^Four, SOR^Four, SONHR^Four, SONR^Four _Two, Saturated Or unsaturated C_Three-C₇A heterocycle, wherein the heterocycle is composed of O, S and N. One or two heteroatoms independently selected from the group Therefore, H, OH, halogen, nitro, cyano, SH, SR^Four, Trihalo-C₁− C₆-Alkyl, C₁-C₆-Alkyl, and C₁-C₆-Consisting of alkoxy It is substituted by 1 to 3 substituents independently selected from the group Or (B) wherein n and Y in the formula are the same as in (a),-(CH_Two)_n-Y or Iha (C) one or two independently selected from the group consisting of O, S and N Containing two heteroatoms, optionally H, OH, halogen, nitro, cyano, SH, SR^Four, Trihalo-C₁-C₆-Alkyl, C₁-C₆-Alkyl, and C₁-C₆-1 to 3 substitutions independently selected from the group consisting of alkoxy Or unsaturated C substituted with a group_Three-C₇Phenyl fused with a heterocycle, One of R in the above formula^FourIs C₁-C₆A compound which is alkyl; And its optical and stereoisomers, its esters, Ter and salt. 3. R in the formula¹, R^Two, R^ThreeHas the following formula: Compound. 4. R in the formula¹Is H, COR^Four, CONHR^Four, CONR^Four _Two, SO_TwoNR^Four _TwoThere Is SO_TwoNHR^FourA compound according to any of the preceding claims, wherein 5. R^TwoIs phenyl, and the phenyl is optionally OH, halogen, nitro , Cyano, SH, SR^Four, Trihalo-C₁-C₆-Alkyl, C₁-C₆-Alkyl , And C₁-C₆From 1 independently selected from the group consisting of alkoxy A compound according to any of the preceding claims, optionally substituted by 5 substituents. 6. R^TwoIs phenyl, and the phenyl is optionally OH, halogen, nitro , Cyano, SH, SR^Four, Trihalo-C₁-C₆-Alkyl, C₁-C₆-Alkyl , And C₁-C₆From 1 independently selected from the group consisting of alkoxy A compound according to any one of the preceding claims, optionally substituted by three substituents. 7. R^ThreeIs -X- (CH_Two)_nPhenyl substituted with -Y, wherein X is a valence bond, O or S, n is an integer from 1 to 12, Y is H, OH, OR^Four, NHR^Four, NR^Four _Two, NHCOR^Four, NHSO_TwoR^Four, CONHR^Four, C ONR^Four _Two, COOH, COOR^Four, SO_TwoR^Four, SOR^Four, SONHR^Four, SONR^Four _Two , Saturated or unsaturated C_Three-C₇A heterocycle, wherein the heterocycle is O, S and Containing one or two heteroatoms independently selected from the group consisting of N , Optionally H, OH, halogen, nitro, cyano, SH, SR^Four, Toriha B-C₁-C₆-Alkyl, C₁-C₆-Alkyl, and C₁-C₆-Alkoxy From Substituted with 1 to 3 substituents independently selected from the group consisting of A compound according to any of the preceding claims. 8. R^ThreeIs-(CH_Two)_n-Y, before n and Y in the formula are the same as above. A compound according to any of the preceding claims. 9. R^ThreeIs a saturated or unsaturated C_Three-C₇With phenyl fused heterocycle One wherein the heterocycle is independently selected from the group consisting of O, S and N Or two heteroatoms, optionally H, OH, halogen, nitro, Cyano, SH, SR^Four, Trihalo-C₁-C₆-Alkyl, C₁-C₆-Alkyl, And C₁-C₆1 to 3 independently selected from the group consisting of alkoxy The compound of any of the preceding claims, wherein the compound is substituted with a substituent. 10. Where R is H or C₁-C₆Claim 1 or a formula of the formula: Compound of 2. 11. 3. The compound according to claim 1, wherein m is an integer from 0 to 10. 12. 3. The compound according to claim 1, wherein m is the same as defined above. 13. 3. The compound according to claim 1, wherein m is the same as defined above. 14． In the formula, m is the same as described above, and two R^FourIs independently the same as above 3. A compound of claim 1 or 2 of the formula: 15. R in the formula^FourIs a compound of claim 1 or 2 wherein 16. R in the formula^FourIs a compound of claim 1 or 2 wherein 17． R in the formula⁶Has one or more of the following substituents: methoxyhydroxy, trifur 3. A compound of claim 1 or 2 of the formula: which is olomethyl, fluoro and chloro 18. 3. A compound of claim 1 or 2 selected from: (±) -trans-7-hydroxy-3-phenyl-4- (4- (2-pyrroli Dinoethoxy) phenyl) chroman, (±) -trans-7-hydroxy-3- (4-fluorophenyl) -4- ( 4- (2-pyrrolidinoethoxy) phenyl) chroman, (±) -trans-7-hydroxy-3- (4-fluorophenyl) -4- ( 4- (2-piperidinoethoxy) phenyl) chroman, And its pure enantiomers. 19. 3. A compound according to claim 1 or 2 selected from: (+)-Trans-4- (4- (carboxymethoxy) phenyl) -7-hydro Xy-3-phenylchroman, (-)-Trans-4- (4- (carboxymethoxy) phenyl) -7-hydro Xy-3-phenylchroman, (+)-Trans-7-hydroxy-4- (4- (methoxycarbonylmethoxy ) Phenyl) -3-phenylchroman; (-)-Trans-7-hydroxy-4- (4- (methoxycarbonylmethoxy ) Phenyl) -3-phenylchroman; (+)-Trans-4- (4- (ethoxycarbonylmethoxy) f Enyl) -7-hydroxy-3-phenylchroman, (-)-Trans-4- (4- (ethoxycarbonylmethoxy) phenyl) -7 -Hydroxy-3-phenylchroman, (+)-Trans-4- (4- (benzyloxycarbonylmethoxy) phenyl ) -7-Hydroxy-3-phenylchroman; (-)-Trans-4- (4- (benzyloxycarbonylmethoxy) phenyl ) -7-Hydroxy-3-phenylchroman; (+)-Trans-7-hydroxy-3-phenyl-4- (4- (2-pyrrolidine Noethoxy) phenyl) chroman (-)-Trans-7-hydroxy-3-phenyl-4- (4- (2-pyrrolidine Noethoxy) phenyl) chroman (+)-Trans-7-hydroxy-3-phenyl-4- (4- (3-pyrrolidine Nopropoxy) phenyl) chroman (-)-Trans-7-hydroxy-3-phenyl-4- (4- (3-pyrrolidine Nopropoxy) phenyl) chroman (+)-Trans-7-hydroxy-3-phenyl-4- (4- (4-pyrrolidine Nobutoxy) phenyl) chroman (-)-Trans-7-hydroxy-3-phenyl-4- (4- (4-pyrrolidine Nobutoxy) phenyl) chroman (+)-Trans-7-hydroxy-3-phenyl-4- (4- (5-pyrrolidine Nopentoxy) phenyl) chroman, (-)-Trans-7-hydroxy-3-phenyl-4- (4- (5-pyrrolidine Nopentoxy) phenyl) chroman, (+)-Trans-7-hydroxy-3-phenyl-4- (4- (6-pyrrolidine Nohexyloxy) phenyl) chroman, (-)-Trans-7-hydroxy-3-phenyl-4- (4- (6-pyrrolidine Nohexyloxy) phenyl) chroman, (+)-Trans-7-hydroxy-3-phenyl-4- (4- (7-pyrrolidine Noheptyloxy) phenyl) chroman, (-)-Trans-7-hydroxy-3-phenyl-4- (4- (7-pyrrolidine Noheptyloxy) phenyl) chroman, (+)-Trans-7-hydroxy-3-phenyl-4- (4- (8-pyrrolidine Nooctyloxy) phenyl) chroman, (-)-Trans-7-hydroxy-3-phenyl-4- (4- (8-pyrrolidine Nooctyloxy) phenyl) chroman, (+)-Trans-7-hydroxy-3-phenyl-4- (4- (9-pyrrolidine Nononyloxy) phenyl) chroman, (-)-Trans-7-hydroxy-3-phenyl-4- (4- (9-pyrrolidine Nononyloxy) phenyl) chroman, (+)-Trans-7-hydroxy-3-phenyl-4- (4- (10-pyrroli Dinodecyloxy) phenyl) chroman, (-)-Trans-7-hydroxy-3-phenyl-4- (4- (10-pyrroli Dinodecyloxy) phenyl) chroman, (+)-Trans-7-hydroxy-3-phenyl-4- (4- (11-pyrroli Diundecyloxy) phenyl) chroman, (-)-Trans-7-hydroxy-3-phenyl-4- (4- (11-pyrroli Diundecyloxy) phenyl) chroman, (+)-Trans-7-hydroxy-3-phenyl-4- (4- (12-pyrroli Dinododecyloxy) phenyl) chroman, (-)-Trans-7-hydroxy-3-phenyl-4- (4- (12-pyrroli Dinododecyloxy) phenyl) chroman, (+)-Trans-7-hydroxy-3-phenyl-4- (4- (2-piperidi Noethoxy) phenyl) chroman (-)-Trans-7-hydroxy-3-phenyl-4- (4- ( 2-piperidinoethoxy) phenyl) chroman (+)-Trans-7-hydroxy-3-phenyl-4- (4- (3-piperidi Nopropoxy) phenyl) chroman (-)-Trans-7-hydroxy-3-phenyl-4- (4- (3-piperidi Nopropoxy) phenyl) chroman (+)-Trans-7-hydroxy-3-phenyl-4- (4- (4-piperidi Nobutoxy) phenyl) chroman (-)-Trans-7-hydroxy-3-phenyl-4- (4- (4-piperidi Nobutoxy) phenyl) chroman (+)-Trans-7-hydroxy-4- (4- (2-perhydroazepinoate Xy) phenyl) -3-phenylchroman (-)-Trans-7-hydroxy-4- (4- (2-perhydroazepinoate Xy) phenyl) -3-phenylchroman (+)-Trans-7-hydroxy-4- (4- (3-perhydroazepinopro Poxy) phenyl) -3-phenylchroman (-)-Trans-7-hydroxy-4- (4- (3-perhydroazepinopro Poxy) phenyl) -3-phenylchroman (+)-Trans-7-hydroxy-4- (4- (4-perhydroazepinobut) Xy) phenyl) -3-phenylchroman (-)-Trans-7-hydroxy-4- (4- (4-perhydroazepinobut) Xy) phenyl) -3-phenylchroman (+)-Trans-4- (4- (2-dimethylaminoethoxy) phenyl) -7 -Hydroxy-3-phenylchroman (-)-Trans-4- (4- (2-dimethylaminoethoxy) phenyl) -7 -Hydroxy-3-phenylchroman (+)-Trans-4- (4- (2-diethylaminoethoxy) phenyl) -7 -Hydroxy-3-phenylchroman (-)-Trans-4- (4- (2-diethylaminoethoxy) phenyl) -7 -Hydroxy-3-phenylchroman (+)-Trans-4- (4- (2- (N-ethyl-N-methylamino) ethoxy) C) phenyl) -7-hydroxy-3-phenylchroman (-)-Trans-4- (4- (2- (N-ethyl-N-methylamino) ethoxy) C) phenyl) -7-hydroxy-3-phenylchroman (+)-Trans-4- (4- (3-dimethylaminopropoxy) phenyl)- 7-hydroxy-3-phenylchroman (-)-Trans-4- (4- (3-dimethylaminopropoxy) phenyl)- 7-hydroxy-3-phenylchroman (+)-Trans-4- (4- (4-diethylaminobutoxy) phenyl) -7 -Hydroxy-3-phenylchroman (-)-Trans-4- (4- (4-diethylaminobutoxy) phenyl) -7 -Hydroxy-3-phenylchroman (+)-Trans-4- (2,3-dihydro-1,4-benzoxazine-6- Yl) -7-hydroxy-3-phenylchroman (-)-Trans-4- (2,3-dihydro-1,4-benzoxyazine-6- Yl) -7-hydroxy-3-phenylchroman (+)-Trans-7-hydroxy-4- (4-methyl-2,3-dihydro-1 , 4-benzoxazin-6-yl) -3-phenylchroman, (-)-Trans-7-hydroxy-4- (4-methyl-2,3-dihydro-1 , 4-benzoxazin-6-yl) -3-phenylchroman, (+)-Trans-4- (4-ethyl-2,3-dihydro-1,4 -Benzoxazin-6-yl) -7-hydroxy-3-phenylchroman (-)-Trans-4- (4-ethyl-2,3-dihydro-1,4-benzoxa Zin-6-yl) -7-hydroxy-3-phenylchroman (+)-Trans-7-hydroxy-3- (4-hydroxyphenyl) -4- ( 4- (2-pyrrolidinoethoxy) phenyl) chroman, (-)-Trans-7-hydroxy-3- (4-hydroxyphenyl) -4- ( 4- (2-pyrrolidinoethoxy) phenyl) chroman, (+)-Trans-7-hydroxy-3- (4-trifluoromethylphenyl) -4- (4- (2-pyrrolidinoethoxy) phenyl) chroman, (-)-Trans-7-hydroxy-3- (4-trifluoromethylphenyl) -4- (4- (2-pyrrolidinoethoxy) phenyl) chroman, (+)-Trans-7-hydroxy-3- (4-fluorophenyl) -4- (4 -(2-pyrrolidinoethoxy) phenyl) chroman, (-)-Trans-7-hydroxy-3- (4-fluorophenyl) -4- (4 -(2-pyrrolidinoethoxy) phenyl) chroman, (+)-Trans-3- (4-chlorophenyl) -7-hydroxy-4- (4- (2-pyrrolidinoethoxy) phenyl) chroman, (-)-Trans-3- (4-chlorophenyl) -7-hydroxy-4- (4- (2-pyrrolidinoethoxy) phenyl) chroman, (+)-Trans-3- (3,4-dimethoxyphenyl) -7-hydroxy-4 -(4- (2-pyrrolidinoethoxy) phenyl) chloro man, (-)-Trans-3- (3,4-dimethoxyphenyl) -7-hydroxy-4 -(4- (2-pyrrolidinoethoxy) phenyl) chroman, (+)-Trans-7-hydroxy-3- (pentafluorophenyl) -4- ( 4- (2-pyrrolidinoethoxy) phenyl) chroman, (-)-Trans-7-hydroxy-3- (pentafluorophenyl) -4- ( 4- (2-pyrrolidinoethoxy) phenyl) chroman, (+)-Trans-4- (4-carboxymethoxy) phenyl) -6-hydroxy -3-phenylchroman, (-)-Trans-4- (4-carboxymethoxy) phenyl) -6-hydroxy -3-phenylchroman, (+)-Trans-6-hydroxy-4- (4- (methoxycarbonylmethoxy ) Phenyl) -3-phenylchroman; (-)-Trans-6-hydroxy-4- (4- (methoxycarbonylmethoxy) ) Phenyl) -3-phenylchroman; (+)-Trans-4- (4-ethoxycarnylmethoxy) phenyl) -6- Droxy-3-phenylchroman, (-)-Trans-4- (4-ethoxycarnylmethoxy) phenyl) -6-h Droxy-3-phenylchroman, (+)-Trans-4- (4-benzyloxycarnylmethoxy) phenyl)- 6-hydroxy-3-phenylchroman, (-)-Trans-4- (4-benzyloxycarnylmethoxy) phenyl)- 6-hydroxy-3-phenylchroman, (+)-Trans-6-hydroxy-3-phenyl-4- (4- ( 2-pyrrolidinoethoxy) phenyl) chroman, (-)-Trans-6-hydroxy-3-phenyl-4- (4- (2-pyrrolidine Noethoxy) phenyl) chroman, (+)-Trans-6-hydroxy-3-phenyl-4- (4- (3-pyrrolidine Nopropoxy) phenyl) chroman, (-)-Trans-6-hydroxy-3-phenyl-4- (4- (3-pyrrolidine Nopropoxy) phenyl) chroman, (+)-Trans-6-hydroxy-3-phenyl-4- (4- (4-pyrrolidine Nobutoxy) phenyl) chroman, (-)-Trans-6-hydroxy-3-phenyl-4- (4- (4-pyrrolidine Nobutoxy) phenyl) chroman, (+)-Trans-6-hydroxy-3-phenyl-4- (4- (5-pyrrolidine Nopentoxy) phenyl) chroman, (-)-Trans-6-hydroxy-3-phenyl-4- (4- (5-pyrrolidine Nopentoxy) phenyl) chroman, (+)-Trans-6-hydroxy-3-phenyl-4- (4- (6-pyrrolidine Nohexyloxy) phenyl) chroman, (-)-Trans-6-hydroxy-3-phenyl-4- (4- (6-pyrrolidine Nohexyloxy) phenyl) chroman, (+)-Trans-6-hydroxy-3-phenyl-4- (4- (7-pyrrolidine Noheptyloxy) phenyl) chroman, (-)-Trans-6-hydroxy-3-phenyl-4- (4- (7-pyrrolidine Noheptyloxy) phenyl) chroman, (+)-Trans-6-hydroxy-3-phenyl-4- (4- (8-pyrrolidine Nooctyloxy) phenyl) chroman, (-)-Trans-6-hydroxy-3-phenyl-4- (4- (8-pyrrolidine Nooctyloxy) phenyl) chroman, (+)-Trans-6-hydroxy-3-phenyl-4- (4- (9-pyrrolidine Nonyloxy) phenyl) chroman, (-)-Trans-6-hydroxy-3-phenyl-4- (4- (9-pyrrolidine Nonyloxy) phenyl) chroman, (+)-Trans-6-hydroxy-3-phenyl-4- (4- (10-pyrroli Dinodecyloxy) phenyl) chroman, (-)-Trans-6-hydroxy-3-phenyl-4- (4- (10-pyrroli Dinodecyloxy) phenyl) chroman, (+)-Trans-6-hydroxy-3-phenyl-4- (4- (11-pyrroli Diundecyloxy) phenyl) chroman, (-)-Trans-6-hydroxy-3-phenyl-4- (4- (11-pyrroli Diundecyloxy) phenyl) chroman, (+)-Trans-6-hydroxy-3-phenyl-4- (4- (12-pyrroli Dinododecyloxy) phenyl) chroman, (-)-Trans-6-hydroxy-3-phenyl-4- (4- (12-pyrroli Dinododecyloxy) phenyl) chroman, (+)-Trans-6-hydroxy-3-phenyl-4- (4- (2-piperidi Noethoxy) phenyl) chroman, (-)-Trans-6-hydroxy-3-phenyl-4- (4- (2-piperidi Noethoxy) phenyl) chroman, (+)-Trans-6-hydroxy-3-phenyl-4- (4- (3-piperidi Nopropoxy) phenyl) chroman, (-)-Trans-6-hydroxy-3-phenyl-4- (4- (3-piperidi Nopropoxy) phenyl) chroman, (+)-Trans-6-hydroxy-3-phenyl-4- (4- (4-piperidi Nobutoxy) phenyl) chroman, (-)-Trans-6-hydroxy-3-phenyl-4- (4- ( 4-piperidinobutoxy) phenyl) chroman, (+)-Trans-6-hydroxy-4- (4- (2-perhydroazepinoate Xy) phenyl) -3-phenylchroman (-)-Trans-6-hydroxy-4- (4- (2-perhydroazepinoate Xy) phenyl) -3-phenylchroman (+)-Trans-6-hydroxy-4- (4- (3-perhydroazepinopro Poxy) phenyl) -3-phenylchroman (-)-Trans-6-hydroxy-4- (4- (3-perhydroazepinopro Poxy) phenyl) -3-phenylchroman (+)-Trans-6-hydroxy-4- (4- (4-perhydroazepinobut) Xy) phenyl) -3-phenylchroman (-)-Trans-6-hydroxy-4- (4- (4-perhydroazepinobuto) Xy) phenyl) -3-phenylchroman (+)-Trans-4- (4- (2-dimethylaminoethoxy) phenyl) -6 -Hydroxy-3-phenylchroman (-)-Trans-4- (4- (2-dimethylaminoethoxy) phenyl) -6 -Hydroxy-3-phenylchroman (+)-Trans-4- (4- (2-diethylaminoethoxy) phenyl) -6 -Hydroxy-3-phenylchroman (-)-Trans-4- (4- (2-diethylaminoethoxy) phenyl) -6 -Hydroxy-3-phenylchroman (+)-Trans-4- (4- (2- (N-ethyl-N-methylamino) ethoxy) C) phenyl) -6-hydroxy-3-phenylchroman (-)-Trans-4- (4- (2- (N-ethyl-N-methylamino) ethoxy) C) phenyl) -6-hydroxy-3-phenylchroman (+)-Trans-4- (4- (3-dimethylaminopropoxy) phenyl)- 6-hydroxy-3-phenylchroman (-)-Trans-4- (4- (3-dimethylaminopropoxy) phenyl)- 6-hydroxy-3-phenylchroman (+)-Trans-4- (4- (4-diethylaminobutoxy) phenyl) -6 -Hydroxy-3-phenylchroman (-)-Trans-4- (4- (4-diethylaminobutoxy) phenyl) -6 -Hydroxy-3-phenylchroman (+)-Trans-4- (2,3-dihydro-1,4-benzoxazin-6-i ) -6-hydroxy-3-phenylchroman (-)-Trans-4- (2,3-dihydro-1,4-benzoxazin-6-i ) -6-hydroxy-3-phenylchroman (+)-Trans-6-hydroxy-4- (4-methyl-2,3-dihydro-1 , 4-benzoxazin-6-yl) -3-phenylchroman, (-)-Trans-6-hydroxy-4- (4-methyl-2,3-dihydro-1 , 4-benzoxazin-6-yl) -3-phenylchroman, (+)-Trans-4- (4-ethyl-2,3-dihydro-1,4-benzoxa Zin-6-yl) -6-hydroxy-3-phenylchroman (-)-Trans-4- (4-ethyl-2,3-dihydro-1,4-benzoxa Zin-6-yl) -6-hydroxy-3-phenylchroman (+)-Trans-6-hydroxy-3- (4-hydroxyphenyl) -4- ( 4- (2-pyrrolidinoethoxy) phenyl) chroman, (-)-Trans-6-hydroxy-3- (4-hydroxyphenyl) -4- ( 4- (2-pyrrolidinoethoxy) phenyl) chroman, (+)-Trans-6-hydroxy-3- (4-trifluoromethylphenyl) -4- (4- (2-pyrrolidinoethoxy) phenyl) chroman, (-)-Trans-6-hydroxy-3- (4-trifluoromethylphenyl) -4- (4- (2-pyrrolidinoethoxy) phenyl) chroman, (+)-Trans-6-hydroxy-3- (4-fluorophenyl) -4- (4 -(2-pyrrolidinoethoxy) phenyl) chroman (-)-Trans-6-hydroxy-3- (4-fluorophenyl) -4- (4 -(2-pyrrolidinoethoxy) phenyl) chroman, (+)-Trans-3- (4-chlorophenyl) -6-hydroxy-4- (4- (2-pyrrolidinoethoxy) phenyl) chroman, (-)-Trans-3- (4-chlorophenyl) -6-hydroxy-4- (4- (2-pyrrolidinoethoxy) phenyl) chroman, (+)-Trans-3- (3,4-dimethoxyphenyl) -6-hydroxy-4 -(4- (2-pyrrolidinoethoxy) phenyl) chroman, (-)-Trans-3- (3,4-dimethoxyphenyl) -6-hydroxy-4 -(4- (2-pyrrolidinoethoxy) phenyl) chroman, (+)-Trans-6-hydroxy-3- (pentafluorophenyl) -4- ( 4- (2-pyrrolidinoethoxy) phenyl) chroman, (-)-Trans-6-hydroxy-3- (pentafluorophenyl) ) -4- (4- (2-pyrrolidinoethoxy) phenyl) chroman or racemic Mixtures of the above compounds, including premixes. 20. A method for preparing a compound of formula (I) comprising the following steps: a) a compound of formula (II): R in the formula^Five, Is H, OH, halogen, nitro, cyano, SH, SR^Four, Trihalo- C₁-C₆-Alkyl, C₁-C₆-Alkyl and C₁-C₆-Glue of alkoxy From 1 to 3 substituents independently selected from^FourIs the same as above A compound of the following formula (III) is reacted with triethylamine in the presence of acetic anhydride. , R in the formula^FiveForms a compound of the following formula (IV), which is the same as described above. b) reacting a compound of formula (IV) with a suitable hydride reducing agent,^FiveBefore A compound of formula (V) is formed which is the same as described above. c) hydrogenation of a compound of formula (V) in the presence of a suitable catalyst to give R^FiveIs the same as above To form a 3,4-cis compound of formula (VI) d) alkylating the compound of formula (VI) with a suitable electrophile, wherein n, R^Five And Y are as defined above to form a compound of formula (VII). e) epimerizing the compound of formula (VII) with a suitable base to give n, R^FiveAnd Y Form a 3,4-trans-formula compound of formula (VIII) as defined above. .f) condensation of the compound of formula (VIII) with a suitable deprotecting agent, preferably pyridine hydrochloride Deprotected by¹Is a hydrogen compound of formula (I). Ma Or g) nitrating the compound of formula (VI) with a suitable nitrating agent,^FiveBefore A compound of formula (IX) is formed which is the same as described above. h) reduction of the compound of formula (IX) by hydrogenation with a suitable reducing agent, preferably a catalyst And R in the formula^FiveTo form a compound of formula (X) which is the same as described above. i) cyclizing a compound of formula (X) with a suitable agent to form a compound of the formula^Five And R^FourIs a compound of formula (XI) or (XII) as defined above.j) enantiomerizing a compound of formula (XI) or (XII) with a suitable base , R in the formula^FiveAnd R^FourIs the same as above, in the form of a 3,4-trans-formula (XIII) Forms the compound of (XIV). Or k) Compound of formula (XIII) or (XIV) is converted to a suitable deprotecting agent, preferably Deprotection by lysine chloride salt condensation,¹Is a compound of formula (I) Let it form. Or 1) reacting a compound of formula (VI) with trifluoromethanesulfonic anhydride , R in the formula^FiveForm a compound of formula (XV), which is the same as described above.m) Cross-linking the compound of formula (XV) with a suitable cross-linking partner to obtain n, R^FiveWhen A compound of formula (XVI) wherein Y is the same as above is formed. n) enantiomerizing the compound of formula (XVI) using a suitable base, wherein n, R^Five To form a compound of formula (XVII) in the 3,4-trans form as defined above You. o) condensation of the compound of formula (XVII) with a suitable deprotecting agent, preferably pyridine hydrochloride Deprotection by means of¹To form a compound of formula (I) wherein . Or p) R in the formula^FiveIs a compound of the formula (XVIII) It reacts with paraformaldehyde in the presence of cyclization to form R in the formula^FiveIs the same as above To form a compound of formula (XIX). q) reacting a compound of formula (XIX) with a suitable Grignard reagent, wherein n, R^FiveAnd Y are as defined above to form a compound of formula (XX). r) The compound of formula (XX) is hydrogenated using a suitable catalyst to obtain n, R^FiveAnd Y Are the same as above, to form compounds of formula (XXI)) in 3.4-cis form. s) Enantiomerization of the compound of formula (XXI) using a suitable base, wherein n, R^Five Form a compound of formula (XXII) in the 3,4-trans form, wherein Y is as defined above. Let it.t) condensation of the compound of formula (XXII) with a suitable deprotecting agent, preferably chlorinated pyridine With deprotection, and R in the formula¹Is a hydrogen compound of formula (I). Or u) R in the formula¹Is hydrogen with a suitable carboxylic acid or sulfonate Reaction with a carboxylic acid derivative, and R in the formula¹Is COR^Four, CONHR^Four, CONR^Four _Two, SO_TwoNR^Four _TwoOr SO_TwoNHR^FourAnd R in the formula^FourIs the same as above The compound of (I) is formed. v) reacting a compound of formula (VI) with methanesulfonyl chloride, wherein R^FiveForms a compound of formula (XXIII), which is the same as described above. w) converting the compound of formula (XXIII) to a suitable compound such as pyridine hydrochloride or tribromide Deprotection using a suitable deprotecting agent,^FiveIs a compound of formula (XXIV) as defined above Is formed.x) converting the compound of formula (XXIV) to benzyl bromide or 4-methylbenzyl bromide By reacting with a suitable protecting agent such as^FiveIs the same as above,⁶Is H or met A compound of formula (XXV), which is a xy group, is formed. y) converting the compound of formula (XXV) to an alcohol of sodium hydroxide or potassium hydroxide Deprotection using a suitable deprotecting agent such as^FiveIs the same as above , R⁶Is a H or methoxy group to form a compound of formula (XXVI). z) alkylating the compound of formula (XXVI) using a suitable electrophile, , R^FiveAnd Y are the same as above, and R⁶Is a compound of the formula (XXVII) wherein ) Is formed.aa) converting a compound of formula (XXVII) to a suitable deprotecting agent, preferably R⁶Is H Is hydrogenated by a catalyst or R⁶When is a methoxy group, deprotection using a strong acid And n, R in the formula^FiveTo form a compound of formula (XXVIII), wherein Y is as defined above. Let it. bb) The compound of the formula (XXVI) is converted to 1,2-dibromoethane, 1-bromo-2- Loroethane, 1,4-dibromobutane, 1,6-dibromohexane, 1,8-di Dihalides such as bromooctane, 1,10-dibromodecane, preferably Catalyzed by potassium iodide, wherein R^FiveIs the same as above, and R⁶Is H or A compound of the formula (XXIX), wherein Hal is chloro, bromo, or iodo, Is formed. cc) reacting a compound of formula (XXIX) with a suitable nucleophile, preferably an amine Shime, R in the formula⁶Is H or a methoxy group, and Z is NHR^Four, NR^Four _TwoOr C_Three -C₇A heterocyclic amine, which may contain oxygen or nitrogen. , H, OH, halogen, nitro, cyano, trihalo-C₁-C₆-Alkyl , C₁-C₆-Alkyl and C₁-C₆-Independently selected from the group consisting of alkoxy May be substituted with 1 to 3 substituents represented by the following formula: , R^FourAnd R^FiveIs the same as the formula (XX) The compound of X) is formed. dd) The compound of formula (XXX) is converted to a suitable deprotecting agent, preferably R⁶If H is Hydrogenation with a medium, or R⁶When is a methoxy group, deprotection using a strong acid, R in⁶Is H or a methoxy group, and Z is NHR^Four, NR^Four _TwoOr C_Three -C₇A heterocyclic amine, which may contain oxygen or nitrogen. , H, OH, halogen, nitro, cyano, trihalo-C₁-C₆-Alkyl , C₁-C₆-Alkyl and C₁-C₆-Independently selected from the group consisting of alkoxy And may be substituted with one to three substituents, and n, R^FourAnd R^FiveIs To form a compound of formula (XXXI) which is the same as 21. An estrogen-related disease or syndrome, preferably estrogen deficient Claim 1 for use in preventing or treating diseases or syndromes that have occurred in animals. 20. The compound of any of 22. Bone loss, osteoporosis, cardiovascular disease, cognitive impairment, Alzheimer's disease -Postmenopausal symptoms including senile dementia, flushing, genital atrophy, depression, mania and schizophrenia Condition, incontinence, obesity, depression, glucose metabolism disorders, dysmenorrhea, imminent or recurrent miscarriage, function Impaired uterine bleeding, acne, hirsutism, prostate cancer, estrogen-dependent cancer, Use to prevent or treat postpartum lactation, or oral contraceptives or ovarian development Use as an aid, preferably for the prevention and treatment of bone loss or osteoporosis The compound according to any one of claims 1 to 19, wherein 23. 20. An effective amount of a compound of claims 1 to 19 or a compound thereof usable as a medicament. A pharmaceutical comprising a salt and a carrier or diluent that can be used for pharmaceuticals. 24. 24. The pharmaceutical of claim 23 in the form of an oral dosage unit or a parenteral dosage unit. 25. Estrogen-related diseases or syndromes, preferably due to estrogen deficiency Claims 1 to a pharmaceutical for the prevention and treatment of diseases or syndromes occurring in mammals Use of any of the compounds of any one of claims 19 to 19. 26. Bone loss, osteoporosis, cardiovascular disease, cognitive impairment, Alzheimer's senile dementia Postmenopausal signs including dementia, flushing, genital atrophy, depression, mania, schizophrenia, incontinence, fertilization Fullness, depression, impaired glucose metabolism, dysmenorrhea, imminent or recurrent miscarriage, dysfunctional uterus Blood, acne, hirsutism, prostate cancer, estrogen-dependent cancer, postpartum milk For the prevention or treatment of ligation, or as a contraceptive or ovarian development aid Pharmaceuticals for use, preferably for the prevention and treatment of bone loss or osteoporosis Use of a compound according to any of claims 1 to 19 in the combination. 27. An effective amount of the compound according to any one of claims 1 to 19 is administered to a patient in need thereof. An estrogen-related disease or syndrome, preferably estrogen A method for treating or preventing a disease or syndrome caused in a mammal due to a deficiency. 28. 20. Administration to a patient in need of an effective amount of a compound of any of claims 1 to 19. Bone loss, osteoporosis, cardiovascular disease, cognitive impairment, Alzheimer's Postmenopausal signs including senile dementia, flushing, genital atrophy, depression, mania, schizophrenia, Incontinence, obesity, depression, glucose metabolism disorders, dysmenorrhea, imminent or habitual miscarriage, dysfunction Uterine bleeding, acne, hirsutism, prostate cancer, estrogen-dependent cancer, delivery A method of preventing and treating post-lactation or assisting ovarian development, preferably with bone loss or Is a method of preventing and treating osteoporosis. 29. 20. An effective amount of a compound according to any one of claims 1 to 19, in male or female mammals. A contraceptive method consisting of administering to an object.