JPH08505359A - レチノイドx受容体に対する選択性を有する化合物 - Google Patents
レチノイドx受容体に対する選択性を有する化合物Info
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- JPH08505359A JPH08505359A JP5518708A JP51870893A JPH08505359A JP H08505359 A JPH08505359 A JP H08505359A JP 5518708 A JP5518708 A JP 5518708A JP 51870893 A JP51870893 A JP 51870893A JP H08505359 A JPH08505359 A JP H08505359A
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Abstract
Description
Claims (1)
- 【特許請求の範囲】 1.レチノイン酸受容体よりも優先的にレチノイドX受容体を選択的に活性化す るリガンド。 2.レチノイン酸受容体よりも優先的に、レチノイドX受容体に選択的に仲介さ れる工程を調節するリガンド。 3.該リガンドが、レチノイン酸受容体よりもレチノイドX受容体に対して少な くとも5倍強い活性の活性化物質である請求項1記載のリガンド。 4.該リガンドのレチノイン酸受容体に対する効果が20%以下である請求項3 記載のリガンド。 5.式: または または または または または または [式中、R1およびR2はそれぞれ独立して水素または炭素原子数1−4個の低級 アルキルまたはアシルを表し; YはC、O、S、N、CHOH、CO、SO、SO2、または製剤学的に許容 し得る塩を表し; R3は水素または炭素原子数1−4個の低級アルキルであり、YはCまたはN を表し; R4は水素または炭素原子数1−4個の低級アルキルであり、YはCを表す。 ただし、YがNであるとき、R4は存在せず、またYがO、S、CHOH、CO 、SOまたはSO2であるとき、R3またはR4のいずれも存在しない。; R’およびR"は水素、炭素原子数1−4個の低級アルキルまたはアシル、O H、炭素原子数1−4個のアルコキシ、チオールまたはチオエーテル、またはア ミノを表し; あるいはR'およびR"は一緒になってオキソ(ケト)、メタノ、チオケト、H O−N=、NC−N=、(R7R8)N−N=、エポキシ、シクロプロピルまたは シクロアルキル基を形成し、ここにエポキシ、シクロプロピルおよびシクロアル キル基は炭素原子数1−4個の低級アルキルまたはハロゲンで置換されていても よい。; R'"およびR""は水素、ハロゲン、炭素原子数1−4個の低級アルキルまたは アシルを表す; またはR'"およびR""は一緒になって炭素原子数3−10個のシクロアルキル 基を形成し、ここに該シクロアルキル基は炭素原子数1−4個の低級アルキルま たはハロゲンで置換されていてもよい; R5は水素、炭素原子数1−4個の低級アルキル、ハロゲン、ニトロ、OR7、 SR7、NR7R8、または(CF)nCF3を表す。ただし、R6、R10、R11、R12 、R13の全てが共に水素でありZ、Z'、Z"、Z'"、またはZ""が全部炭素で あるとき、R5は水素ではあり得ない; R6、R10、R11、R12、R13はそれそれ独立して水素、炭素原子数1−4個 の低級アルキル、ハロゲン、ニトロ、OR7、SR7、NR7R8または(CF)n CF3を表し、それが結合しているZ、Z'、Z"、Z'"、またはZ""がCである 場合のみ存在し、あるいはそれが結合しているZ、Z'、Z"、Z'"、またはZ"" がNであり、R6、R10、R11、R12またはR13のいずれか1つがXである場合 、それぞれ独立して水素または炭素原子数1−4個の低級アルキルを表し; R7は水素または炭素原子数1−6個の低級アルキルを表し; R8は水素または炭素原子数1−6個の低級アルキルを表し; R14は水素、炭素原子数1−4個の低級アルキル、オキソ、ヒドロキシ、炭素 原子数1−4個のアシル、ハロゲン、チオールまたはチオケトンを表し; XはCOOH、テトラゾール、PO3H、SO3H、CHO、CH2OH、CO NH2、COSH、COOR9、COSR9、CONHR9、またはCOOWを表す 。ここにR9は炭素原子数1−4個の低級アルキル、フェニル、芳香族アルキル またはq-ヒドロキシフェニル、q-ブロモフェニル、q-クロロフェニル、q-フルオ ロフェニル、またはq-ヨードフェニルを表し、ここにqは2−4、Wは製剤的に 許容される塩であり、Xは環上の任意のCまたはNと結合していてよい。; Z、Z'、Z"、Z'"およびZ""はそれそれ独立してC、S、O、Nまたは製剤 的に許容される塩を表す。ただし、別のZと2重結合で結合しているかOまたは Sである他のZと結合しているとき、それはOまたはSではなく、他のNである Zと1重結合で結合しているとき、それはNではない; nは0−3;そして 第2および第7の構造式における点線は2重結合であってもよいことを表す。 ]で示される化合物。 6.レチノイン酸受容体よりも優先的にレチノイドX受容体を選択的に活性化す 請求項5記載の化合物。 7.4-[(3,5,5,8,8-ペンタメチル-5,6,7,8−テトラヒドロ-2-ナフチル)カル ボニル]安息香酸、4-[1-(3,5,5,8,8-ペンタメチル-5,6,7,8−テトラヒドロ-2 -ナフチル)エテニル]安息香酸、4-[1-(3,5,5,8,8-ペンタメチル-5,6,7,8− テトラヒドロ-2-ナフチル)シクロプロピル]安息香酸、4-[1-(3,5,5,8,8-ペ ンタメチル-5,6,7,8−テトラヒドロ-2-ナフチル)エテニル]ベンゼンテトラゾ ール、2-[1 -(5,5,8,8-テトラメチル-5,6,7,8−テトラヒドロ-2-ナフチル)エテニル]ピリ ジン-5-カルボン酸、2-[1-(3,5,5,8,8-ペンタメチル-5,6,7,8−テトラヒドロ- 2-ナフチル)エテニル]ピリジン-5-カルボン酸、エチル2-[1-(3,5,5,8,8-ペ ンタメチル-5,6,7,8−テトラヒドロ-2-ナフチル)エテニル]ピリジン-5-カルボ キシレート、5-[1-3,5,5,8,8-ペンタメチル-5,6,7,8−テトラヒドロ-2-ナフチ ル)エテニル]ピリジン-2-カルボン酸、2-[1-(3,5,5,8,8-ペンタメチル-5,6, 7,8−テトラヒドロ-2-ナフチル)シクロプロピル]ピリジン-5-カルボン酸、メ チル2-[1-(3,5,5,8,8-ペンタメチル-5,6,7,8−テトラヒドロ-2-ナフチル)シ クロプロピル]ピリジン-5-カルボキシレートおよび4-[1-3,5,5,8,8-ペンタメ チル-5,6,7,8−テトラヒドロ-2-ナフチル)エテニル]-N-(4-ヒドロキシフェニ ル)ベンズアミドからなる群から選択される化合物。 8.4-[(3,5,5,8,8-ペンタメチル-5,6,7,8−テトラヒドロ-2-ナフチル)エテ ニル]安息香酸。 9.2-[1-(3,5,5,8,8-ペンタメチル-5,6,7,8−テトラヒドロ-2-ナフチル)エ テニル]ピリジン-5-カルボン酸。 10.2-[1-(3,5,5,8,8-ペンタメチル-5,6,7,8−テトラヒドロ-2-ナフチル) シクロプロピル]ピリジン-5-カルボン酸。 11.経腸投与、非経口投与、または局所投与に適した製剤的に許容されるビヒ クル中に1またはそれ以上の請求項2記載の化合物を含有する医薬組成物。 12.経腸投与、非経口投与、または局所投与に適した製剤的に許容されるビヒ クル中に1またはそれ以上の請求項5記載の化合物を含有する医薬組成物。 13.1またはそれ以上のレチノイドX受容体に選択的に仲介される工程を調節 する方法であって、レチノイン酸受容体よりも優先的に該1またはそれ以上のレ チノイドX受容体を選択的に活性化するリガンドの存在下で該工程を行わせるこ とからなる方法。 14.該リガンドが、レチノイン酸受容体よりもレチノイン酸受容体に対して少 なくとも5倍強い活性の活性化物質である請求項13記載の方法。 15.該リガンドのレチノイン酸受容体に対する効果が20%以下である請求項 14記載の方法。 16.1またはそれ以上のレチノイドX受容体に仲介される工程を調節する方法 であって、該工程を少なくとも1個の請求項2記載のリガンドの存在下で行わせ ることからなる方法。 17.1またはそれ以上のレチノイドX受容体に仲介される工程を調節する方法 であって、該工程を少なくとも1個の請求項5記載の化合物の存在下で行わせる ことからなる方法。 18.1またはそれ以上のレチノイドX受容体に仲介される工程を調節する方法 であって、該工程を少なくとも1個の下記の式で示される化合物の存在下で行わ せることからなる方法。 または または または または または または [式中、R1およびR2はそれそれ独立して水素または炭素原子数1−4個の低級 アルキルまたはアシルを表し; YはC、O、S、N、CHOH、CO、SO、SO2、または製剤学的に許容 し得る塩を表し; R3は水素または炭素原子数1−4個の低級アルキルであり、YはCまたはN を表し; R4は水素または炭素原子数1−4個の低級アルキルであり、YはCを表す。 ただし、YがNであるとき、R4は存在せず、またYがO、S、CHOH、CO 、SOまたはSO2であるとき、R3またはR4のいずれも存在しない。; R'およびR"は水素、炭素原子数1−4個の低級アルキルまたはアシル、OH 、炭素原子数1−4個のアルコキシ、チオールまたはチオエーテル、またはアミ ノを表し; あるいはR'およびR"は一緒になってオキソ(ケト)、メタノ、チオケト、H O−N=、NC−N=、(R7R8)N−N=、エポキシ、シクロプロピルまたは シクロアルキル基を形成し、ここにエポキシ、シクロプロピルおよびシクロアル キル基は炭素原子数1−4個の低級アルキルまたはハロゲンで置換されていても よい。; R'"およびR""は水素、ハロゲン、炭素原子数1−4個の低級アルキルまたは アシルを表す; またはR'"およびR""は一緒になって炭素原子数3−10個のシクロアルキル 基を形成し、ここに該シクロアルキル基は炭素原子数1−4個の低級アルキルま たはハロゲンで置換されていてもよい; R5は水素、炭素原子数1−4個の低級アルキル、ハロゲン、ニトロ、OR7、 SR7、NR7R8、または(CF)nCF3を表す。ただし、R6、R10、R11、R12 、R13の全てが共に水素でありZ、Z'、Z"、Z'"、またはZ""が全部炭素で あるとき、R5は水素ではあり得ない; R6、R10、R11、R12、R13はそれそれ独立して水素、炭素原子数1−4個 の低級アルキル、ハロゲン、ニトロ、OR7、SR7、NR7R8または(CF)n CF3を表し、それが結合しているZ、Z'、Z"、Z'"、またはZ""がCである 場合のみ存在し、あるいはそれが結合しているZ、Z'、Z"、Z'"、またはZ"" がNであり、R6、R10、R11、R12またはR13のいずれか1つがXである場合 、それぞれ独立して水素または炭素原子数1−4個の低級アルキルを表し; R7は水素または炭素原子数1−6個の低級アルキルを表し; R8は水素または炭素原子数1−6個の低級アルキルを表し; R14は水素、炭素原子数1−4個の低級アルキル、オキソ、ヒドロキシ、炭素 原子数1−4個のアシル、ハロゲン、チオールまたはチオケトンを表し; XはCOOH、テトラゾール、PO3H、SO3H、CHO、CH2OH、CO NH2、COSH、COOR9、COSR9、CONHR9、またはCOOWを表す 。ここにR9は炭素原子数1−4個の低級アルキル、フェニル、芳香族アルキル またはq-ヒドロキシフェニル、q-ブロモフェニル、q-クロロフェニル、q-フルオ ロフェニル、またはq-ヨードフェニルを表し、ここにqは2−4、Wは製剤的に 許容される塩であり、Xは環上の任意のCまたはNと結合していてよい。; Z、Z'、Z"、Z'"およびZ""はそれぞれ独立してC、S、O、Nまたは製剤 的に許容される塩を表す。ただし、別のZと2重結合で結合しているかOまたは Sである他のZと結合しているとき、それはOまたはSではなく、他のNである Zと1重結合で結合しているとき、それはNではない; nは0−3;そして 第2および第7の構造式における点線は2重結合であってもよいことを表す。 ] 19.該レチノイドX受容体が、レチノイドX受容体−アルファ、レチノイドX 受容体−ベータ、またはレチノイドX受容体−ガンマである請求項18記載の方 法。 20.該工程が脂質代謝のインビボ調節、皮膚関連工程のインビボ調節、悪性細 胞増殖のインビボ調節、または前癌病巣のインビボ調節である請求項18記載の 方法。 21.該工程がインビトロ細胞増殖および分化、またはインビボ四肢形態発生で ある請求項18記載の方法。 22.1またはそれ以上のレチノイドX受容体によって仲介される工程を調節す る方法であって、該工程を少なくとも1個の請求項7記載の化合物の存在下で行 わせることからなる方法。 23.1またはそれ以上のレチノイドX受容体に仲介される工程を調節する方法 であって、該1またはそれ以上のレチノイドX受容体に仲介される該工程を調節 するに有効な量の請求項2記載の1またはそれ以上のリガンドを哺乳動物対象に 投与することを含む方法。 24.1またはそれ以上のレチノイドX受容体に仲介される工程を調節する方法 であって、該1またはそれ以上のレチノイドX受容体に仲介される該工程を調節 するに有効な量の請求項5記載の1またはそれ以上の化合物を哺乳動物対象に投 与することを含む方法。 25.レチノイドX受容体療法が必要な哺乳動物対象を治療する方法であって、 該対象に薬学的に有効な量の、1またはそれ以上の請求項2記載のリガンドを投 与することを含む方法。 26.レチノイドX受容体療法が必要な哺乳動物対象を治療する方法であって、 該対象に薬学的に有効な量の、1またはそれ以上の請求項5記載の化合物を投与 することを含む方法。 27.哺乳動物対象の高密度リポタンパク質の血漿濃度を増大する方法であって 、そのような対象に薬学的に有効な量の、1またはそれ以上の請求項5記載のリ ガンドを投与することを含む方法。 28.1またはそれ以上のレチノイドX受容体の存在を決定する方法であって、 請求項5記載の化合物を1またはそれ以上の不明の受容体を含有する試料と混合 し、該リガンドが該試料中のなんらかの受容体と結合したか否かを決定すること を含む方法。 29.レチノイドX受容体を精製する方法であって、請求項5記載の化合物を1 またはそれ以上の該レチノイドX受容体を含有する試料と混合し、該化合物とレ チノイドX受容体とを結合させ、結合した該化合物とレチノイドX受容体の組み 合わせ分離することを含む方法。 30.レチノイン酸受容体よりも優先的にレチノイドX受容体を選択的に活性化 する第1リガンドと、レチノイドX受容体よりも優先的にレチノイン酸受容体を 選択的に活性化する第2リガンドとの組み合わせを含有する組成物。 31.レチノイン酸受容体よりも優先的にレチノイドX受容体を選択的に活性化 する第1リガンドと、レチノイドX受容体以外の1またはそれ以上の細胞内受容 体を活性化する第2リガントとの組み合わせを含有する組成物。 32.特定の濃度で該組成物により哺乳動物内で生産される生理学的効果が該リ ガンドの各々を該濃度で単独使用して得られる相加的な効果よりも大きい、請求 項30または31に記載の組成物。 33.レチノイン酸受容体よりも優先的にレチノイドX受容体を選択的に活性化 する第1リガンドと、レチノイドX受容体以外の1またはそれ以上の細胞内受容 体を活性化する第2リガンドとの組み合わせを、経腸、非経口または局所投与の ための製剤的に許容されるビヒクル中に含有する医薬組成物。 34.該第2リガンドがレチノイドX受容体よりも優先的にレチノイン酸受容体 を活性化するものである請求項33記載の医薬組成物。 35.細胞内受容体によって仲介される工程を調節する方法であって、レチノイ ン酸受容体よりも優先的にレチノイドX受容体を選択的に活性化する第1リガン ドと、レチノイドX受容体以外の1またはそれ以上の細胞内受容体を活性化する 第2リガンドとを含有する組成物の存在下で該工程を行わせることを含む方法( ここに、特定の濃度の該組成物によって哺乳動物内で産生される生理学的作用が 該リガンドの各々を該濃度で単独使用して達成される相加効果よりも大きい)。 36.該第2リガンドがレチノイドX受容体よりも優先的にレチノイン酸受容体 を活性化する請求項35記載の方法。 37.該工程が脂質代謝のインビボ調節、皮膚関連工程のインビボ調節、悪性細 胞増殖のインビボ調節、前癌病巣のインビボ調節、またはプログラムされた細胞 死のインビボ調節である請求項36記載の方法。 38.該組成物中に、該第1リガンドまたは該第2リガンドのいずれもが、単独 では有意な治療応答を産生し得ない濃度で存在している請求項35記載の方法。 39.該第2リガンドがペルオキシソーム増殖因子活性化受容体を活性化する請 求項35記載の方法。 40.該第2リガンドがビタミンD受容体を活性化する請求項35記載の方法。 41.該第2リガンドがチロイドホルモン受容体、HNF4受容体、または受容 体のCOUPファミリーのメンバーを活性化する請求項35記載の方法。
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US6258811B1 (en) | 1996-10-03 | 2001-07-10 | Eisai Co., Ltd. | Methods for preventing, inhibiting or treating graft rejection reactions in graft-versus-host disease (GVHD) and organ transplantation |
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