JP5877466B2 - Terpenoid-derived retinoid compounds - Google Patents
Terpenoid-derived retinoid compounds Download PDFInfo
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- JP5877466B2 JP5877466B2 JP2012043411A JP2012043411A JP5877466B2 JP 5877466 B2 JP5877466 B2 JP 5877466B2 JP 2012043411 A JP2012043411 A JP 2012043411A JP 2012043411 A JP2012043411 A JP 2012043411A JP 5877466 B2 JP5877466 B2 JP 5877466B2
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Description
本発明は、核内受容体であるレチノイドX受容体（retinoid X receptor; RXR）に対し作用する新規化合物に関する。さらにはその利用に関する。 The present invention relates to a novel compound that acts on a nuclear receptor, retinoid X receptor (RXR). Furthermore, it relates to its use.
核内受容体は、細胞増殖や免疫応答、糖・脂質代謝等の生理機能、恒常性の維持を担っているリガンド依存性の転写調節因子のひとつである。核内受容体に対応するリガンドにより、その下流にある遺伝子の転写を制御している。核内受容体は、同一の原初遺伝子から派生しており、スーパーファミリーを形成する（非特許文献１）。 Nuclear receptors are one of ligand-dependent transcriptional regulators that are responsible for maintaining cell proliferation, immune response, physiological functions such as sugar / lipid metabolism, and homeostasis. The ligand corresponding to the nuclear receptor controls the transcription of the downstream gene. Nuclear receptors are derived from the same primitive gene and form a superfamily (Non-patent Document 1).
RXRは、作動性物質（以下、アゴニストと記す）の結合により遺伝子転写を制御する核内受容体の一種で、他の核内受容体であるレチノイン酸受容体（RAR）、ビタミンD受容体（VDR）、ペルオキシソーム増殖活性受容体（PPAR）、肝X受容体（LXR）などとヘテロダイマーを形成し、ヘテロダイマー毎にその生理作用が異なっている。またRXRにはα、β、γの３つのサブタイプが存在し、サブタイプ毎にその体内局在が異なっている（非特許文献１，２）。 RXR is a type of nuclear receptor that controls gene transcription through the binding of agonists (hereinafter referred to as agonists). Other nuclear receptors are retinoic acid receptor (RAR), vitamin D receptor ( VDR), peroxisome proliferative activity receptor (PPAR), liver X receptor (LXR) and other heterodimers are formed, and the physiological actions of each heterodimer are different. RXR has three subtypes, α, β, and γ, and their localization in the body is different for each subtype (Non-Patent Documents 1 and 2).
RXRαは肝臓、腎臓および脾臓、RXRβは全身、RXRγは骨格筋、心筋、皮膚および脳に局在することが知られている。またPPARγは脂肪細胞分化や糖代謝制御を司ることから、PPARγ/RXRα選択的アゴニストは糖尿病治療薬および脂質代謝異常症治療薬のターゲットとして魅力的である（非特許文献２，３）。 It is known that RXRα is localized in the liver, kidney and spleen, RXRβ is localized throughout the body, and RXRγ is localized in skeletal muscle, cardiac muscle, skin and brain. In addition, since PPARγ controls adipocyte differentiation and sugar metabolism control, PPARγ / RXRα selective agonists are attractive as targets for antidiabetics and dyslipidemia (Non-patent Documents 2 and 3).
既存のRXR選択的アゴニストの多くは、その脂溶性部位にテトラメチルシクロヘキサン環を主とするかさ高い脂溶性の置換基を導入することでRXR選択性を生み出すことに成功している（非特許文献２，３，４，５）。 Many of the existing RXR selective agonists have succeeded in producing RXR selectivity by introducing a bulky fat-soluble substituent mainly consisting of a tetramethylcyclohexane ring into the fat-soluble site (Non-patent literature). 2, 3, 4, 5).
代表的なRXRアゴニストの分子構造を以下に示す。
これらの化合物のいずれもがその脂溶性部位にテトラメチルシクロヘキサン環とベンゼン環からなる二環性骨格を主とするかさ高い脂溶性の置換基を導入している。しかしながら、これらの化合物はLXR/RXRの活性化による血中トリグリセリド(TG)の上昇が問題点として挙げられる（非特許文献６，７）。 In any of these compounds, a bulky fat-soluble substituent mainly comprising a bicyclic skeleton composed of a tetramethylcyclohexane ring and a benzene ring is introduced into the fat-soluble portion. However, these compounds have a problem in that blood triglyceride (TG) is increased by activation of LXR / RXR (Non-patent Documents 6 and 7).
RXRのリガンドはその構造の違いにより遺伝子発現に違いを生じさせる、すなわちヘテロダイマー選択的に活性化できることが知られており、RXRリガンドのバリエーションを増やすことでLXR/RXRの活性化を避けPPARγ/RXRを活性化し得るRXRアゴニストが創出できる可能性がある。 It is known that RXR ligands cause differences in gene expression due to differences in their structure, that is, they can be activated selectively by heterodimers.By increasing RXR ligand variations, activation of LXR / RXR can be avoided and PPARγ / There is a possibility that an RXR agonist capable of activating RXR can be created.
RXRのリガンド結合部位は高度な三次元環境下にあることから、RXRアゴニストの脂溶性部位として光学活性な置換基が導入されたシクロヘキサン環とベンゼン環からなる新規二環性骨格を有するRXRアゴニストに興味が持たれた。 Since the RXR ligand binding site is in an advanced three-dimensional environment, the RXR agonist has a novel bicyclic skeleton consisting of a cyclohexane ring and a benzene ring into which an optically active substituent is introduced as a lipophilic site of the RXR agonist. I was interested.
本発明は、従来のRXRアゴニストとは脂溶性部位が異なる，さらには従来のRXRアゴニストとは遺伝子発現の異なる新規なRXRリガンドを提供することを課題とする。 An object of the present invention is to provide a novel RXR ligand having a lipophilic site different from that of a conventional RXR agonist, and further having a gene expression different from that of a conventional RXR agonist.
本発明者らは、上記課題を解決するために鋭意研究を重ねた結果、テルペノイド由来二環性骨格を有するレチノイド化合物の合成に成功し、本化合物が既存のRXRアゴニストに比較してLXRα/RXRα活性化を抑え、PPARγ/RXRαを活性化し得ることを見出し、本発明を完成した。 As a result of intensive studies to solve the above problems, the present inventors have succeeded in synthesizing a retinoid compound having a terpenoid-derived bicyclic skeleton, and this compound is LXRα / RXRα compared with existing RXR agonists. It was found that activation could be suppressed and PPARγ / RXRα could be activated, and the present invention was completed.
即ち、本発明は以下よりなる。
１．一般式III：
R 2 は、Ｈ、アルキル基、フェニル基から選択され、
Zは、カルボン酸、カルボン酸エステル、ヒロドキサム酸から選択される。）
で示される化合物。
２．前記１に記載の化合物からなるレチノイドX受容体（RXR）リガンド作用調節剤。
３．前記１に記載の化合物又は前記２に記載のレチノイドX受容体（RXR）リガンド作用調節剤を有効成分として含有する薬剤。
４．薬剤が、糖尿病治療剤及び脂質代謝異常症治療剤／又は抗がん剤，又は抗炎症剤であることを特徴とする前記３に記載の薬剤。
５．有効成分として、さらに糖尿病治療剤を含む前記３又は４に記載の薬剤。
６．有効成分として、さらに脂質代謝異常症治療剤を含む前記３又は４に記載の薬剤。
７．有効成分として、さらに抗がん剤を含む前記３又は４に記載の薬剤。
８．有効成分として、さらに抗炎症剤を含む前記３又は４に記載の薬剤。
９．前記３〜８のいずれか１に記載の薬剤、並びに薬理学的及び製剤学的に許容される担体を含む医薬組成物。
That is, this invention consists of the following.
1. Formula III:
R 2 is selected from H, an alkyl group, and a phenyl group;
Z is selected from carboxylic acids, carboxylic acid esters, and hydroxamic acids. )
A compound represented by
2. A retinoid X receptor (RXR) ligand action modulator comprising the compound according to 1 above.
3. A drug comprising the compound according to 1 or the retinoid X receptor (RXR) ligand action regulator according to 2 as an active ingredient.
4). 4. The drug according to 3 above, wherein the drug is a therapeutic agent for diabetes and a therapeutic agent for dyslipidemia / or an anticancer agent, or an anti-inflammatory agent.
5. 5. The drug according to 3 or 4 above, further comprising a therapeutic agent for diabetes as an active ingredient.
6). 5. The drug according to 3 or 4 , further comprising a therapeutic agent for dyslipidemia as an active ingredient.
7). 5. The drug according to 3 or 4 further comprising an anticancer drug as an active ingredient.
8). 5. The drug according to 3 or 4 further comprising an anti-inflammatory agent as an active ingredient.
9. 9. A pharmaceutical composition comprising the drug according to any one of 3 to 8 above and a pharmacologically and pharmaceutically acceptable carrier.
本発明の化合物は、LXRα/RXRα活性化を抑え、かつPPARγ/RXRα活性化能を有するＲＸＲ作動性物質である。従って、本化合物は高濃度においてもLXRα/RXRα活性化にともなうトリグリセリド血中濃度の上昇を回避してＲＸＲアゴニスト作用を発揮しうることから、副作用が軽減された新規な糖尿病治療薬、脂質代謝異常症治療薬、抗がん剤の有効成分としての作用が期待できる。 The compound of the present invention is an RXR agonist that suppresses LXRα / RXRα activation and has the ability to activate PPARγ / RXRα. Therefore, since this compound can exert an RXR agonist action by avoiding an increase in the blood concentration of triglycerides associated with LXRα / RXRα activation even at high concentrations, a novel antidiabetic agent with reduced side effects, lipid metabolism abnormality It can be expected to act as an active ingredient of anti-inflammatory agents and anticancer agents.
具体的には、以下の実施例で示す化合物のうち、化合物１が挙げられる。本発明の化合物のうち、PPARγ/RXRαヘテロダイマーアゴニストとして好適には化合物１が挙げられる。 Specifically, compound 1 is mentioned among the compounds shown in the following Examples. Among the compounds of the present invention, compound 1 is preferably used as a PPARγ / RXRα heterodimer agonist.
本発明において、一般式IIIで表される化合物は、さらに、薬学的に許容される塩であってもよい。また、一般式IIIの化合物又はその塩において、異性体（例えば光学異性体、幾何異性体及び互換異性体）などが存在する場合は、本発明はそれらの異性体を包含し、また溶媒和物、水和物及び種々の形状の結晶を包含するものである。 In the present invention, the compound represented by the general formula III may further be a pharmaceutically acceptable salt. In addition, in the compound of the general formula III or a salt thereof, when there are isomers (for example, optical isomers, geometrical isomers and interchangeable isomers), the present invention includes these isomers, and solvates. , Hydrates and crystals of various shapes.
本発明において、薬学的に許容される塩とは、薬理学的及び製剤学的に許容される一般的な塩が挙げられる。そのような塩として、具体的には以下が例示される。
塩基性付加塩としては、例えばナトリウム塩、カリウム塩等のアルカリ金属塩；例えばカルシウム塩、マグネシウム塩等のアルカリ土類金属塩；例えばアンモニウム塩；例えばトリメチルアミン塩、トリエチルアミン塩；ジシクロヘキシルアミン塩、エタノールアミン塩、ジエタノールアミン塩、トリエタノールアミン塩、ブロカイン塩等の脂肪族アミン塩；たとえばＮ，Ｎ−ジベンジルエチレンジアミン等のアラルキルアミン塩；例えばピリジン塩、ピコリン塩、キノリン塩、イソキノリン塩等の複素環芳香族アミン塩；例えばテトラメチルアンモニウム塩、テトラエチルアンモニウム塩、ベンジルトリメチルアンモニウム塩、ベンジルトリエチルアンモニウム塩、ベンジルトリブチルアンモニウム塩、メチルトリオクチルアンモニウム塩、テトラブチルアンモニウム塩等の第４級アンモニウム塩；アルギニン塩；リジン塩等の塩基性アミノ酸塩等が挙げられる。
In the present invention, the pharmaceutically acceptable salt includes general pharmacologically and pharmaceutically acceptable salts. Specific examples of such salts are as follows.
Examples of basic addition salts include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; ammonium salts; trimethylamine salts and triethylamine salts; dicyclohexylamine salts and ethanolamines. Aliphatic amine salts such as salts, diethanolamine salts, triethanolamine salts and brocaine salts; Aralkylamine salts such as N, N-dibenzylethylenediamine; and heterocyclic aromatics such as pyridine salts, picoline salts, quinoline salts and isoquinoline salts For example, tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, benzyltributylammonium salt, methyltrioctylammonium salt Quaternary ammonium salts such as tetrabutylammonium salts; arginine; basic amino acid salts such as lysine salt and the like.
酸付加塩としては、例えば塩酸塩、硫酸塩、硝酸塩、リン酸塩、炭酸塩、炭酸水素塩、過塩素酸塩等の無機酸塩；例えば酢酸塩、プロピオン酸塩、乳酸塩、マレイン酸塩、フマル酸塩、酒石酸塩、リンゴ酸塩、クエン酸塩、アスコルビン酸塩等の有機酸塩；例えばメタンスルホン酸塩、イセチオン酸塩、ベンゼンスルホン酸塩、ｐ−トルエンスルホン酸塩等のスルホン酸塩；例えばアスパラギン酸塩、グルタミン酸塩等の酸性アミノ酸等を挙げることができる。 Examples of the acid addition salt include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, hydrogen carbonate, perchlorate; for example, acetate, propionate, lactate, maleate , Organic acid salts such as fumarate, tartrate, malate, citrate and ascorbate; sulfonic acids such as methanesulfonate, isethionate, benzenesulfonate, p-toluenesulfonate Salts; for example, acidic amino acids such as aspartate and glutamate.
本明細書において用いる用語は、単独で又は他の用語と一緒になって以下の意義を有する。
「アルキル」は、炭素数１〜２０、好ましくは１〜１０個の直鎖状又は分枝状のアルキル基を意味し、例えば、メチル、エチル、n-プロピル、イソプロピル、n-ブチル、イソブチル、sec-ブチル、tert-ブチル、n-ぺンチル、イソぺンチ ル、ネオぺンチル、tert-ぺンチル、n-ヘキシル、イソヘキシル、n-ヘプチル、n-オクチル、n-ノニル、n-デシル等が挙げられる。好ましくは、 炭素数１〜６個のアルキルであり、例えば、メチル、エチル、n-プロピル、イソプロピル、n-ブチル、イソブチル、sec-ブチル、tert-ブチル、n-ぺンチル、イソぺンチル、ネオぺンチル、tert-ぺンチル、n-ヘキシル、イソヘキシルが挙げられる。炭素数１〜６個の低級アルキルが特に好ましい。
The terms used herein have the following meanings alone or in combination with other terms.
“Alkyl” means a linear or branched alkyl group having 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, etc. Can be mentioned. Preferred is alkyl having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neo Examples include pentyl, tert-pentyl, n-hexyl, and isohexyl. A lower alkyl having 1 to 6 carbon atoms is particularly preferred.
「アルケニル」は、上記「アルキル」に１個又はそれ以上の二重結合を有する炭素数２〜２０個、好ましくは２〜８個の直鎖状又は分枝状のアルケニルを意味し、例えば、ビニル、1-プロペニル、2-プロペニル、1-ブテニル、2-ブテニル、3-ブテニル、1,3-ブタジエニル、3-メチル-2-ブテニル等が挙げられる。 “Alkenyl” means linear or branched alkenyl having 2 to 20 carbon atoms, preferably 2 to 8 carbon atoms, having one or more double bonds to the above “alkyl”. Examples include vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 3-methyl-2-butenyl and the like.
「アリール」 は、単環芳香族炭化水素基（フェニル）及び多環芳香族炭化水素基（例えば、1-ナフチ ル、2-ナフチル、1-アントリル、2-アントリル、9-アントリル、1-フェナントリル、2-フェナントリル、3-フェナントリル、4-フェナントリ ル、9-フェナントリル等）を意味する。好ましくは、フェニル又はナフチル（1-ナフチル、2-ナフチル）が挙げられる。 “Aryl” refers to monocyclic aromatic hydrocarbon groups (phenyl) and polycyclic aromatic hydrocarbon groups (eg, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl). , 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 9-phenanthryl and the like. Preferable is phenyl or naphthyl (1-naphthyl, 2-naphthyl).
「アルキニル」は、上記アルキルに１個又はそれ以上の三重結合を有する炭素数２〜２０個、好ましくは２〜１０個のアルキニルを意味し、例えば、エチニル、1-プロピニル、2-プロピニル、1-ブチニル、2-ブチニル、3-ブチニル等が挙げられる。 “Alkynyl” means alkynyl having 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms, having one or more triple bonds in the above alkyl. For example, ethynyl, 1-propynyl, 2-propynyl, 1 -Butynyl, 2-butynyl, 3-butynyl and the like.
「アルコキシ」とは、炭素数１〜２０の直鎖状または分枝（鎖）状のアルコキシ基を意味し、例えばメトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基、ブトキシ基、イソブトキシ基、sec-ブトキシ基、tert-ブトキシ基、ペンチルオキシ基、ヘキシルオキシ基、オクタデカノキシ基、アリルオキシ基などが挙げられる。Ｃ1〜Ｃ6の直鎖状または分枝状の低級アルコキシが好ましい。 “Alkoxy” means a linear or branched (chain) alkoxy group having 1 to 20 carbon atoms, such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, sec -Butoxy group, tert-butoxy group, pentyloxy group, hexyloxy group, octadecanoxy group, allyloxy group and the like. C 1 -C 6 linear or branched lower alkoxy is preferred.
「アシル」とは、アルカノイルおよびアロイルなどを意味する。該アルカノイルとしては、例えば、炭素数１〜６個、好ましくは１〜４個のアルキルを有するアルカノイル（ホルミル、アセチル、トリフルオロアセチル、プロピオニル、ブチリルなど）が挙げられる。アロイルとしては、例えば、炭素数７〜１５個のアロイル、具体的には、例えばベンゾイル、ナフトイルなどが挙げられる。 “Acyl” means alkanoyl, aroyl and the like. Examples of the alkanoyl include alkanoyl having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms (formyl, acetyl, trifluoroacetyl, propionyl, butyryl, etc.). Examples of aroyl include aroyl having 7 to 15 carbon atoms, and specific examples include benzoyl and naphthoyl.
本発明において、一般式IIIで表される化合物は、RXRに対し作動性を有する。RXRはDNAの転写に関わる核内受容体であることから、本発明の化合物は転写調節化合物ということもできる。本明細書において「調節作用」という用語又はその類似語は、作用の増強又は抑制を含めて最も広義に解釈する必要がある。本発明の化合物が増強作用又は抑制作用のいずれを有するかは、本明細書の実験例に具体的に示した方法に従って容易に検定可能である。 In the present invention, the compound represented by the general formula III has an activity against RXR. Since RXR is a nuclear receptor involved in DNA transcription, the compound of the present invention can also be referred to as a transcriptional regulatory compound. In the present specification, the term “modulating action” or an analog thereof should be interpreted in the broadest sense including the enhancement or suppression of action. Whether the compound of the present invention has an enhancing action or an inhibiting action can be easily assayed according to the method specifically shown in the experimental examples of the present specification.
本発明において、一般式IIIで表される化合物のうちRXR作動性物質は、脂肪細胞分化作用、糖代謝制御作用、抗がん作用，抗炎症作用などを有する。そのため、これらの化合物は脂質代謝異常症、糖尿病、及びある種の癌の治療や予防，炎症に対しに有用であると考えられる。 In the present invention, among the compounds represented by the general formula III , the RXR agonist has an adipocyte differentiation action, a sugar metabolism control action, an anticancer action, an anti-inflammatory action and the like. Therefore, these compounds are considered useful for the treatment and prevention of dyslipidemia, diabetes, and certain types of cancer, and for inflammation.
上記の化合物は、細胞の核内に存在する核内受容体・スーパーファミリーに属するRXRとヘテロダイマーを構築する受容体に結合して生理活性を発現する物質、例えば、活性型ビタミンA代謝物（all-trans-レチノイン酸）を含むレチノイド化合物、エイコサノイド類、ビタミンD3などのビタミンD化合物、またはチロキシンやリガンド不明のオーファン受容体リガンドなどの作用を増強もしくは抑制することができる。 The above compound is a substance that expresses physiological activity by binding to a receptor that builds heterodimer with RXR belonging to the nuclear receptor superfamily existing in the nucleus of the cell, for example, active vitamin A metabolite ( all-trans-retinoic acid) -containing retinoid compounds, eicosanoids, vitamin D compounds such as vitamin D3, or thyroxine and orphan receptor ligands with unknown ligands can be enhanced or suppressed.
本発明の化合物を有効成分とする試薬又は医薬等の薬剤も、本発明の範囲に含まれる。医薬品として用いる場合には、例えば、糖尿病治療剤及び脂質代謝異常症治療剤／又は抗がん剤，又は抗炎症剤として用いることができる。 Also included within the scope of the present invention are reagents such as reagents and medicaments containing the compound of the present invention as an active ingredient. When used as a pharmaceutical, for example, it can be used as a therapeutic agent for diabetes and a therapeutic agent for dyslipidemia / or anticancer agent or anti-inflammatory agent.
本発明の化合物を有効成分とする医薬として用いる場合には、投与量は特に限定されない。例えばレチノイン酸などのレチノイドを有効成分として含む医薬と本発明の化合物とを併用してレチノイドの作用を調節する場合、あるいは、レチノイドを含む医薬を併用せずに、生体内に既に存在するレチノイン酸の作用調節のために本発明の薬剤を投与する場合など、あらゆる投与方法において適宜の投与量が容易に選択できる。例えば、経口投与の場合には有効成分を成人一日あたり０．０１〜１０００ｍｇ程度の範囲で用いることができる。レチノイドを有効成分として含む医薬と本発明の薬剤とを併用する場合には、レチノイドの投与期間中、及び／又はその前若しくは後の期間のいずれにおいても本発明の薬剤を投与することが可能である。 When used as a pharmaceutical comprising the compound of the present invention as an active ingredient, the dosage is not particularly limited. For example, when the action of a retinoid is regulated by using a compound containing a retinoid such as retinoic acid as an active ingredient in combination with the compound of the present invention, or without using a medicine containing a retinoid, retinoic acid already present in the living body Appropriate doses can be easily selected for all administration methods, such as when administering the drug of the present invention for the purpose of regulating the action of the drug. For example, in the case of oral administration, the active ingredient can be used in the range of about 0.01 to 1000 mg per adult day. When a drug containing a retinoid as an active ingredient is used in combination with the drug of the present invention, the drug of the present invention can be administered either during the retinoid administration period and / or before or after that period. is there.
本発明の薬剤として、上記一般式IIIで表される化合物から選ばれる１種又は２種以上の物質をそのまま投与してもよいが、好ましくは、上記の物質の１種又は２種以上を含む、経口用あるいは非経口用の医薬組成物として投与することが好ましい。経口用あるいは非経口用の医薬組成物は、当業者に利用可能な製剤用添加物、即ち薬理学的及び製剤学的に許容しうる担体を用いて製造することができる。例えば、レチノイン酸などのレチノイドを有効成分として含む医薬に上記の物質の１種又は２種以上を配合して、いわゆる合剤の形態の医薬組成物として用いることもできる。 As the drug of the present invention, one or more substances selected from the compounds represented by the above general formula III may be administered as they are, but preferably contain one or more of the above substances. It is preferable to administer as an oral or parenteral pharmaceutical composition. Oral or parenteral pharmaceutical compositions can be prepared using pharmaceutical additives available to those skilled in the art, that is, pharmacologically and pharmaceutically acceptable carriers. For example, one or more of the above substances can be blended in a medicine containing a retinoid such as retinoic acid as an active ingredient, and used as a pharmaceutical composition in the form of a so-called mixture.
経口投与に適する医薬用組成物としては、例えば、錠剤、カプセル剤、散剤、細粒剤、顆粒剤、液剤、及びシロップ剤等を挙げることができ、非経口投与に適する医薬組成物としては、例えば、注射剤、点滴剤、坐剤、吸入剤、点眼剤、点鼻剤、軟膏剤、クリーム剤、及び貼付剤等を挙げることができる。上記の医薬組成物の製造に用いられる薬理学的及び製剤学的に許容しうる担体としては、例えば、賦形剤、崩壊剤ないし崩壊補助剤、結合剤、滑沢剤、コーティング剤、色素、希釈剤、基剤、溶解剤ないし溶解補助剤、等張化剤、ｐＨ調節剤、安定化剤、噴射剤、及び粘着剤等を挙げることができる。 Examples of the pharmaceutical composition suitable for oral administration include tablets, capsules, powders, fine granules, granules, liquids, and syrups. The pharmaceutical composition suitable for parenteral administration includes For example, injections, drops, suppositories, inhalants, eye drops, nasal drops, ointments, creams, patches and the like can be mentioned. Examples of pharmacologically and pharmaceutically acceptable carriers used in the production of the above pharmaceutical composition include, for example, excipients, disintegrating agents or disintegrating aids, binders, lubricants, coating agents, dyes, Diluents, bases, solubilizers or solubilizers, isotonic agents, pH adjusters, stabilizers, propellants, adhesives, and the like can be mentioned.
本明細書の実施例に、本発明の式Iに示される好ましい化合物の製造方法を具体的に説明する。これらの製造方法において用いられた出発原料及び試薬、並びに反応条件などを適宜修飾ないし改変することにより、本発明の範囲に包含される化合物はいずれも製造可能である。本発明の化合物の製造方法は、実施例に具体的に説明されたものに限定されるものではない。 In the examples of the present specification, a method for producing a preferred compound represented by the formula I of the present invention will be specifically described. Any of the compounds included in the scope of the present invention can be produced by appropriately modifying or altering the starting materials and reagents used in these production methods and reaction conditions. The manufacturing method of the compound of this invention is not limited to what was specifically demonstrated by the Example.
以下、本発明を実施例によりさらに具体的に説明するが、本発明は下記の実施例の範囲に限定されることはない。 Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to the scope of the following examples.
[実施例１]目的化合物１の合成
本実施例における製造方法のスキームを図１、２に示した。
[Example 1] Synthesis of target compound 1 The scheme of the production method in this example is shown in Figs.
１）中間体１の合成
アルゴン雰囲気中、氷冷下ジイソプロピルアミン(3.36 mL, 24.0 mmol)に撹拌しながらn-ブチルリチウム(1.65 M, n-ヘキサン溶液, 14.4 mL, 24.0 mmol)を10分かけて滴下した後、無水テトラヒドロフラン(50 mL)に溶解させた。-78℃に冷却後、(-)-メントン(3.09 g, 20.0 mmol)の無水テトラヒドロフラン(5 mL)溶液を滴下し同温で30分撹拌した後、3-トリメチルシリル-3-ブテン-2-オン(3.70 g, 26.0 mmol)の無水テトラヒドロフラン(7 mL)溶液を滴下し-78℃で1時間、0℃で2.5時間撹拌した。TLCプレート（n-ヘキサン:酢酸エチル＝7:1）で原料消失を確認後、5%塩酸(60 mL)を加え室温で30分激しく撹拌した。氷冷下、飽和炭酸水素ナトリウム水溶液で中和後、酢酸エチルで抽出した。有機層を水と食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧下にて留去し、残渣をフラッシュカラムクロマトグラフィー（n-ヘキサン:酢酸エチル＝9:1）で精製し、無色アモルファスの中間体１(2.83 g, 63%)を得た。
1H NMR (300 MHz, CDCl3) δ : 2.62-2.51 (m, 1H), 2.41-2.29 (m, 1H), 2.13 (s, 3H), 2.10-1.97 (m, 4H), 1.90-1.73 (m, 3H), 1.58-1.28 (m, 3H), 1.07 (d, J = 6.0 Hz, 3H), 0.89 (d, J = 6.0 Hz, 3H), 0.85 (d, J = 6.0 Hz, 3H).
1) Synthesis of Intermediate 1 n-Butyllithium (1.65 M, n-hexane solution, 14.4 mL, 24.0 mmol) was stirred for 10 minutes with stirring in diisopropylamine (3.36 mL, 24.0 mmol) under argon cooling in an argon atmosphere. After dropwise addition, it was dissolved in anhydrous tetrahydrofuran (50 mL). After cooling to -78 ° C, a solution of (-)-menton (3.09 g, 20.0 mmol) in anhydrous tetrahydrofuran (5 mL) was added dropwise and stirred at the same temperature for 30 minutes, then 3-trimethylsilyl-3-buten-2-one A solution of (3.70 g, 26.0 mmol) in anhydrous tetrahydrofuran (7 mL) was added dropwise, and the mixture was stirred at -78 ° C for 1 hour and at 0 ° C for 2.5 hours. After confirming the disappearance of the raw materials on a TLC plate (n-hexane: ethyl acetate = 7: 1), 5% hydrochloric acid (60 mL) was added, and the mixture was vigorously stirred at room temperature for 30 minutes. Under ice-cooling, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by flash column chromatography (n-hexane: ethyl acetate = 9: 1) to obtain colorless amorphous intermediate 1 (2.83 g, 63%).
1 H NMR (300 MHz, CDCl 3 ) δ: 2.62-2.51 (m, 1H), 2.41-2.29 (m, 1H), 2.13 (s, 3H), 2.10-1.97 (m, 4H), 1.90-1.73 ( m, 3H), 1.58-1.28 (m, 3H), 1.07 (d, J = 6.0 Hz, 3H), 0.89 (d, J = 6.0 Hz, 3H), 0.85 (d, J = 6.0 Hz, 3H).
２）中間体２の合成
アルゴン雰囲気中、氷冷下中間体１(2.83 g, 12.6 mmol)の無水テトラヒドロフラン(110 mL)溶液に、カリウムt-ブトキシド(1.42 g, 12.6 mmol)を加え、同温で1.5時間撹拌した。TLCプレート（n-ヘキサン:酢酸エチル＝6:1）で原料消失を確認後、飽和塩化アンモニウム水溶液で中和後、ジエチルエーテルで抽出した。有機層を水と食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧下にて留去し、残渣をフラッシュカラムクロマトグラフィー（n-ヘキサン:酢酸エチル＝6:1）で精製し、無色結晶の中間体２(1.63 g, 63%)を得た。
1H NMR (300 MHz, CDCl3) δ : 5.86 (s, 1H), 2.44-2.12 (m, 3H), 2.07-1.96 (m, 2H), 1.82-1.75 (m, 4H), 1.57-1.46 (m, 1H), 1.33-1.12 (m, 2H), 1.04 (d, J = 6.3 Hz, 3H), 0.97 (d, J = 6.6 Hz, 3H), 0.89 (d, J = 6.6 Hz, 3H).
2) Synthesis of Intermediate 2 Potassium t-butoxide (1.42 g, 12.6 mmol) was added to an anhydrous tetrahydrofuran (110 mL) solution of Intermediate 1 (2.83 g, 12.6 mmol) in an argon atmosphere under ice cooling, and the same temperature. For 1.5 hours. After confirming the disappearance of the raw materials with a TLC plate (n-hexane: ethyl acetate = 6: 1), the mixture was neutralized with a saturated aqueous ammonium chloride solution and extracted with diethyl ether. The organic layer was washed with water and brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by flash column chromatography (n-hexane: ethyl acetate = 6: 1) to obtain colorless crystal intermediate 2 (1.63 g, 63%).
1 H NMR (300 MHz, CDCl 3 ) δ: 5.86 (s, 1H), 2.44-2.12 (m, 3H), 2.07-1.96 (m, 2H), 1.82-1.75 (m, 4H), 1.57-1.46 ( m, 1H), 1.33-1.12 (m, 2H), 1.04 (d, J = 6.3 Hz, 3H), 0.97 (d, J = 6.6 Hz, 3H), 0.89 (d, J = 6.6 Hz, 3H).
３）中間体３の合成
アルゴン雰囲気中、氷冷下ジイソプロピルアミン(0.862 mL, 6.15 mmol)に撹拌しながらn-ブチルリチウム(1.62 M, n-ヘキサン溶液, 3.80 mL, 6.15 mmol)を10分かけて滴下した後、無水テトラヒドロフラン(12 mL)に溶解させた。-78℃に冷却後、中間体２(1.15 g, 5.59 mmol)の無水テトラヒドロフラン(6 mL)溶液を滴下し同温で30分撹拌した後、N-t-ブチルベンゼンスルフィンイミドイルクロリド(1.45 g, 6.71 mmol)の無水テトラヒドロフラン(5 mL)溶液を滴下し-78℃で30分撹拌した。1%塩酸(34 mL)を加えて反応を止めた後、ジクロロメタンで抽出し、有機層を無水硫酸ナトリウムで乾燥した。溶媒を減圧下にて留去し、残渣をフラッシュカラムクロマトグラフィー（n-ヘキサン:ジエチルエーテル＝15:1）で精製し、淡黄色油状物質の中間体３(565 mg, 50%)を得ると共に、中間体２(418 mg, 36%)を回収した。
3) Synthesis of Intermediate 3 n-Butyllithium (1.62 M, n-hexane solution, 3.80 mL, 6.15 mmol) was added over 10 minutes with stirring in diisopropylamine (0.862 mL, 6.15 mmol) under argon cooling in an argon atmosphere. After dropwise addition, it was dissolved in anhydrous tetrahydrofuran (12 mL). After cooling to −78 ° C., a solution of intermediate 2 (1.15 g, 5.59 mmol) in anhydrous tetrahydrofuran (6 mL) was added dropwise and stirred at the same temperature for 30 minutes, and then Nt-butylbenzenesulfinimidoyl chloride (1.45 g, 6.71). mmol) in anhydrous tetrahydrofuran (5 mL) was added dropwise, and the mixture was stirred at -78 ° C for 30 minutes. The reaction was stopped by adding 1% hydrochloric acid (34 mL), followed by extraction with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by flash column chromatography (n-hexane: diethyl ether = 15: 1) to obtain a light yellow oily intermediate 3 (565 mg, 50%). Intermediate 2 (418 mg, 36%) was recovered.
1H NMR (300 MHz, CDCl3) δ : 7.10 (d, J = 8.1 Hz, 1H), 6.70 (d, J = 3.0 Hz, 1H), 6.63 (dd, J = 8.1, 3.0 Hz, 1H), 4.58 (s, 1H), 2.78-2.64 (m, 2H), 2.28-2.16 (m, 1H), 1.99-1.90 (m, 1H), 1.89-1.77 (m, 1H), 1.62-1.50 (m, 1H), 1.38-1.28 (m, 1H), 1.25 (d, J = 6.9 Hz, 3H), 1.01 (d, J = 6.9 Hz, 3H), 0.71 (d, J = 6.9 Hz, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ: 7.10 (d, J = 8.1 Hz, 1H), 6.70 (d, J = 3.0 Hz, 1H), 6.63 (dd, J = 8.1, 3.0 Hz, 1H), 4.58 (s, 1H), 2.78-2.64 (m, 2H), 2.28-2.16 (m, 1H), 1.99-1.90 (m, 1H), 1.89-1.77 (m, 1H), 1.62-1.50 (m, 1H ), 1.38-1.28 (m, 1H), 1.25 (d, J = 6.9 Hz, 3H), 1.01 (d, J = 6.9 Hz, 3H), 0.71 (d, J = 6.9 Hz, 3H).
４）中間体４の合成
アルゴン雰囲気中、氷冷下中間体３(538 mg, 2.63 mmol)とピリジン(0.426 mL, 5.27 mmol)の無水ジクロロメタン(5 mL)溶液に、トリフルオロメタンスルホン酸無水物(0.532 mL, 3.16 mmol)を滴下し、室温で1時間撹拌した。TLCプレート（n-ヘキサン:酢酸エチル＝5:1）で原料消失を確認後、1%塩酸(13 mL)を加え、ジクロロメタンで抽出した。有機層を飽和炭酸水素ナトリウム水溶液で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧下にて留去し、残渣をフラッシュカラムクロマトグラフィー（n-ヘキサン）で精製し、無色油状物質の中間体４(559 mg, 63%)を得た。
4) Synthesis of intermediate 4 In an argon atmosphere, a solution of intermediate 3 (538 mg, 2.63 mmol) and pyridine (0.426 mL, 5.27 mmol) in anhydrous dichloromethane (5 mL) was added to trifluoromethanesulfonic anhydride ( 0.532 mL, 3.16 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour. After confirming the disappearance of the raw materials on a TLC plate (n-hexane: ethyl acetate = 5: 1), 1% hydrochloric acid (13 mL) was added, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by flash column chromatography (n-hexane) to obtain Intermediate 4 (559 mg, 63%) as a colorless oily substance.
1H NMR (300 MHz, CDCl3) δ : 7.29 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 2.7 Hz, 1H), 7.02 (dd, J = 8.4, 2.7 Hz, 1H), 2.85-2.70 (m, 2H), 2.27-2.12 (m, 1H), 2.04-1.94 (m, 1H), 1.91-1.81 (m, 1H), 1.66-1.53 (m, 1H), 1.42-1.30 (m, 1H), 1.28 (d, J = 6.9 Hz, 3H), 1.01 (d, J = 6.6 Hz, 3H), 0.71 (d, J = 6.9 Hz, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ: 7.29 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 2.7 Hz, 1H), 7.02 (dd, J = 8.4, 2.7 Hz, 1H), 2.85-2.70 (m, 2H), 2.27-2.12 (m, 1H), 2.04-1.94 (m, 1H), 1.91-1.81 (m, 1H), 1.66-1.53 (m, 1H), 1.42-1.30 (m , 1H), 1.28 (d, J = 6.9 Hz, 3H), 1.01 (d, J = 6.6 Hz, 3H), 0.71 (d, J = 6.9 Hz, 3H).
５）中間体５の合成
アルゴン雰囲気中、中間体４(120 mg, 0.357 mmol)、(2E,4E,6Z)-3-メチル-7-トリブチルすず-2,4,6-オクタトリエン酸エチル(218 mg, 0.464 mmol)、テトラキス(トリフェニルホスフィン)パラジウム(0)(41.2 mg, 0.0357 mmol)、ヨウ化銅(I)(13.6 mg, 0.0714 mmol)、フッ化セシウム(108 mg, 0.714 mmol)の無水N,N-ジメチルホルムアミド(3.6 mL)溶液を45℃で3時間撹拌した。TLCプレート（n-ヘキサン:ジエチルエーテル＝20:1）で原料消失を確認後、ジクロロメタン(5 mL)と水(2 mL)を加えて室温下激しく撹拌した後、セライトろ過し、ジクロロメタン:酢酸エチル＝1:1で洗い込んだ。ろ液をジクロロメタンで抽出し、有機層を無水硫酸ナトリウムで乾燥した。溶媒を減圧下にて留去し、残渣をフラッシュカラムクロマトグラフィー（カラム担体はシリカゲル：フッ化カリウム＝9:1、溶出液はn-ヘキサン:ジエチルエーテル＝40:1）で精製し、黄色油状物質の中間体５(40.9 mg, 31%)を得た。
5) Synthesis of Intermediate 5 Intermediate 4 (120 mg, 0.357 mmol), (2E, 4E, 6Z) -3-methyl-7-tributyltin-2,4,6-octatrienoic acid ethyl (in argon atmosphere) 218 mg, 0.464 mmol), tetrakis (triphenylphosphine) palladium (0) (41.2 mg, 0.0357 mmol), copper (I) iodide (13.6 mg, 0.0714 mmol), cesium fluoride (108 mg, 0.714 mmol) An anhydrous N, N-dimethylformamide (3.6 mL) solution was stirred at 45 ° C. for 3 hours. After confirming the disappearance of the raw materials on a TLC plate (n-hexane: diethyl ether = 20: 1), dichloromethane (5 mL) and water (2 mL) were added, and the mixture was vigorously stirred at room temperature, filtered through Celite, and then dichloromethane: ethyl acetate. = Washed with 1: 1. The filtrate was extracted with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by flash column chromatography (the column carrier was silica gel: potassium fluoride = 9: 1, the eluent was n-hexane: diethyl ether = 40: 1), and yellow oil Intermediate 5 of the material (40.9 mg, 31%) was obtained.
1H NMR (500 MHz, CDCl3) δ : 7.24 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 1.5 Hz, 1H), 7.04 (dd, J = 8.0, 1.5 Hz, 1H), 6.78 (dd, J = 15.0, 10.5 Hz, 1H), 6.25 (d, J = 15.0 Hz, 1H), 6.22 (d, J = 10.5 Hz, 1H), 5.74 (s, 1H), 4.15 (q, J = 7.0 Hz, 2H), 2.84-2.72 (m, 2H), 2.30-2.22 (m, 1H), 2.172 (s, 3H), 2.170 (s, 3H), 2.01-1.95 (m, 1H), 1.89-1.81 (m, 1H), 1.67-1.59 (m, 1H), 1.42-1.34 (m, 1H), 1.30 (d, J = 7.0 Hz, 3H), 1.28 (t, J = 7.0 Hz, 3H), 1.01 (d, J = 6.5 Hz, 3H), 0.74 (d, J = 7.0 Hz, 3H). 1 H NMR (500 MHz, CDCl 3 ) δ: 7.24 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 1.5 Hz, 1H), 7.04 (dd, J = 8.0, 1.5 Hz, 1H), 6.78 (dd, J = 15.0, 10.5 Hz, 1H), 6.25 (d, J = 15.0 Hz, 1H), 6.22 (d, J = 10.5 Hz, 1H), 5.74 (s, 1H), 4.15 (q, J = 7.0 Hz, 2H), 2.84-2.72 (m, 2H), 2.30-2.22 (m, 1H), 2.172 (s, 3H), 2.170 (s, 3H), 2.01-1.95 (m, 1H), 1.89- 1.81 (m, 1H), 1.67-1.59 (m, 1H), 1.42-1.34 (m, 1H), 1.30 (d, J = 7.0 Hz, 3H), 1.28 (t, J = 7.0 Hz, 3H), 1.01 (d, J = 6.5 Hz, 3H), 0.74 (d, J = 7.0 Hz, 3H).
６）１の合成
中間体５(38.0 mg, 0.104 mmol)のエタノール(1.5 mL)溶液に、10%水酸化ナトリウム水溶液(1 mL)を加え、50℃で5時間撹拌した。TLCプレート（n-ヘキサン:ジエチルエーテル＝7:3）で原料消失を確認後、氷冷下5%塩酸(2.5 mL)を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧下にて留去し、残渣をフラッシュカラムクロマトグラフィー（n-ヘキサン:ジエチルエーテル＝7:3）で精製し、無色結晶の１(33.6 mg, 96%)を得た。
6) Synthesis of 1 To a solution of intermediate 5 (38.0 mg, 0.104 mmol) in ethanol (1.5 mL) was added 10% aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at 50 ° C. for 5 hr. After confirming the disappearance of the raw materials on a TLC plate (n-hexane: diethyl ether = 7: 3), 5% hydrochloric acid (2.5 mL) was added under ice cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by flash column chromatography (n-hexane: diethyl ether = 7: 3) to obtain 1 (33.6 mg, 96%) of colorless crystals.
1H NMR (300 MHz, CDCl3) δ : 7.24 (d, J = 7.8 Hz, 1H), 7.09 (br s, 1H), 7.03 (dd, J = 7.8, 1.8 Hz, 1H), 6.82 (dd, J = 15.3, 10.8 Hz, 1H), 6.27 (d, J = 15.3 Hz, 1H), 6.23 (d, J = 10.8 Hz, 1H), 5.76 (s, 1H), 2.84-2.71 (m, 2H), 2.30-2.22 (m, 1H), 2.18 (s, 6H), 2.03-1.94 (m, 1H), 1.91-1.81 (m, 1H), 1.69-1.57 (m, 1H), 1.43-1.35 (m, 1H), 1.30 (d, J = 6.6 Hz, 3H), 1.01 (d, J = 6.9 Hz, 3H), 0.74 (d, J = 6.6 Hz, 3H).
Anal. Calcd for C23H30O2: C, 81.61; H, 8.93. Found: C, 81.78; H, 9.11.
ESI-HRMS Calcd for C23H31O2 [M+H]+ 339.2319. Found 339.2311.
Mp: 149-151 ℃
[α]27 D -43.5 (c 0.380, MeOH)
1 H NMR (300 MHz, CDCl 3 ) δ: 7.24 (d, J = 7.8 Hz, 1H), 7.09 (br s, 1H), 7.03 (dd, J = 7.8, 1.8 Hz, 1H), 6.82 (dd, J = 15.3, 10.8 Hz, 1H), 6.27 (d, J = 15.3 Hz, 1H), 6.23 (d, J = 10.8 Hz, 1H), 5.76 (s, 1H), 2.84-2.71 (m, 2H), 2.30-2.22 (m, 1H), 2.18 (s, 6H), 2.03-1.94 (m, 1H), 1.91-1.81 (m, 1H), 1.69-1.57 (m, 1H), 1.43-1.35 (m, 1H ), 1.30 (d, J = 6.6 Hz, 3H), 1.01 (d, J = 6.9 Hz, 3H), 0.74 (d, J = 6.6 Hz, 3H).
Anal. Calcd for C 23 H 30 O 2 : C, 81.61; H, 8.93. Found: C, 81.78; H, 9.11.
ESI-HRMS Calcd for C 23 H 31 O 2 [M + H] + 339.2319. Found 339.2311.
Mp: 149-151 ℃
[α] 27 D -43.5 (c 0.380, MeOH)
７）中間体６の合成
アルゴン雰囲気中、中間体４(120 mg, 0.357 mmol)、(2E,4E,6Z)-3-メチル-7-トリブチルすず-2,4,6-ノナトリエン酸エチル(224 mg, 0.464 mmol)、テトラキス(トリフェニルホスフィン)パラジウム(0)(41.2 mg, 0.0357 mmol)、ヨウ化銅(I)(13.6 mg, 0.0714 mmol)、フッ化セシウム(108 mg, 0.714 mmol)の無水N,N-ジメチルホルムアミド(3.6 mL)溶液を45℃で3時間撹拌した。TLCプレート（n-ヘキサン:ジエチルエーテル＝20:1）で原料消失を確認後、ジクロロメタン(5 mL)と水(2 mL)を加えて室温下激しく撹拌した後、セライトろ過し、ジクロロメタン:酢酸エチル＝1:1で洗い込んだ。ろ液をジクロロメタンで抽出し、有機層を無水硫酸ナトリウムで乾燥した。溶媒を減圧下にて留去し、残渣をフラッシュカラムクロマトグラフィー（カラム担体はシリカゲル：フッ化カリウム＝9:1、溶出液はn-ヘキサン:ジエチルエーテル＝30:1）で精製し、淡黄色油状物質の中間体６(27.4 mg, 20%)を得た。
7) Synthesis of Intermediate 6 In an argon atmosphere, intermediate 4 (120 mg, 0.357 mmol), (2E, 4E, 6Z) -3-methyl-7-tributyltin-2,4,6-nonatrienoic acid ethyl (224 mg, 0.464 mmol), tetrakis (triphenylphosphine) palladium (0) (41.2 mg, 0.0357 mmol), copper (I) iodide (13.6 mg, 0.0714 mmol), anhydrous cesium fluoride (108 mg, 0.714 mmol) A solution of N, N-dimethylformamide (3.6 mL) was stirred at 45 ° C. for 3 hours. After confirming the disappearance of the raw materials on a TLC plate (n-hexane: diethyl ether = 20: 1), dichloromethane (5 mL) and water (2 mL) were added, and the mixture was vigorously stirred at room temperature, filtered through Celite, and then dichloromethane: ethyl acetate. = Washed with 1: 1. The filtrate was extracted with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by flash column chromatography (the column carrier was silica gel: potassium fluoride = 9: 1, the eluent was n-hexane: diethyl ether = 30: 1), and pale yellow Intermediate 6 (27.4 mg, 20%) of an oily substance was obtained.
1H NMR (300 MHz, CDCl3) δ : 7.23 (d, J = 7.8 Hz, 1H), 7.03 (br s, 1H), 6.98 (dd, J = 7.8, 1.5 Hz, 1H), 6.71 (dd, J = 15.3, 11.1 Hz, 1H), 6.26 (d, J = 15.3 Hz, 1H), 6.19 (d, J = 11.1 Hz, 1H), 5.73 (s, 1H), 4.15 (q, J = 7.2 Hz, 2H), 2.86-2.70 (m, 2H), 2.48 (q, J = 7.5 Hz, 2H), 2.30-2.18 (m, 1H), 2.15 (s, 3H), 2.04-1.94 (m, 1H), 1.92-1.82 (m, 1H), 1.68-1.58 (m, 1H), 1.44-1.32 (m, 1H), 1.30 (d, J = 6.9 Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H), 1.03 (t, J = 7.5 Hz, 3H), 1.00 (d, J = 6.9 Hz, 3H), 0.73 (d, J = 6.9 Hz, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ: 7.23 (d, J = 7.8 Hz, 1H), 7.03 (br s, 1H), 6.98 (dd, J = 7.8, 1.5 Hz, 1H), 6.71 (dd, J = 15.3, 11.1 Hz, 1H), 6.26 (d, J = 15.3 Hz, 1H), 6.19 (d, J = 11.1 Hz, 1H), 5.73 (s, 1H), 4.15 (q, J = 7.2 Hz, 2H), 2.86-2.70 (m, 2H), 2.48 (q, J = 7.5 Hz, 2H), 2.30-2.18 (m, 1H), 2.15 (s, 3H), 2.04-1.94 (m, 1H), 1.92 -1.82 (m, 1H), 1.68-1.58 (m, 1H), 1.44-1.32 (m, 1H), 1.30 (d, J = 6.9 Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H), 1.03 (t, J = 7.5 Hz, 3H), 1.00 (d, J = 6.9 Hz, 3H), 0.73 (d, J = 6.9 Hz, 3H).
６）３の合成
中間体５(23.8 mg, 0.0625 mmol)のエタノール(1.0 mL)溶液に、10%水酸化ナトリウム水溶液(0.7 mL)を加え、50℃で5時間撹拌した。TLCプレート（n-ヘキサン:ジエチルエーテル＝7:3）で原料消失を確認後、氷冷下5%塩酸(2.5 mL)を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧下にて留去し、残渣をフラッシュカラムクロマトグラフィー（n-ヘキサン:ジエチルエーテル＝7:3）で精製し、淡黄色アモルファスの３(18.6 mg, 84%)を得た。
6) Synthesis of 3 To a solution of intermediate 5 (23.8 mg, 0.0625 mmol) in ethanol (1.0 mL) was added 10% aqueous sodium hydroxide solution (0.7 mL), and the mixture was stirred at 50 ° C. for 5 hr. After confirming the disappearance of the raw materials on a TLC plate (n-hexane: diethyl ether = 7: 3), 5% hydrochloric acid (2.5 mL) was added under ice cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by flash column chromatography (n-hexane: diethyl ether = 7: 3) to obtain pale yellow amorphous 3 (18.6 mg, 84%).
1H NMR (300 MHz, CDCl3) δ : 7.23 (d, J = 8.1 Hz, 1H), 7.03 (br s, 1H), 6.97 (dd, J = 8.1, 1.5 Hz, 1H), 6.76 (dd, J = 15.3, 11.1 Hz, 1H), 6.28 (d, J = 15.1 Hz, 1H), 6.20 (d, J = 11.1 Hz, 1H), 5.75 (s, 1H), 2.85-2.70 (m, 2H), 2.48 (q, J = 7.5 Hz, 2H), 2.29-2.18 (m, 1H), 2.15 (s, 3H), 2.04-1.94 (m, 1H), 1.92-1.82 (m, 1H), 1.68-1.56 (m, 1H), 1.45-1.34 (m, 1H), 1.30 (d, J = 7.2 Hz, 3H), 1.03 (t, J = 7.5 Hz, 3H), 1.00 (d, J = 6.9 Hz, 3H), 0.73 (d, J = 6.6 Hz, 3H).
ESI-HRMS Calcd for C24H32NaO2 [M+Na]+ 375.2295. Found 375.2296.
[α]24 D -72.2 (c 0.348, CHCl3)
1 H NMR (300 MHz, CDCl 3 ) δ: 7.23 (d, J = 8.1 Hz, 1H), 7.03 (br s, 1H), 6.97 (dd, J = 8.1, 1.5 Hz, 1H), 6.76 (dd, J = 15.3, 11.1 Hz, 1H), 6.28 (d, J = 15.1 Hz, 1H), 6.20 (d, J = 11.1 Hz, 1H), 5.75 (s, 1H), 2.85-2.70 (m, 2H), 2.48 (q, J = 7.5 Hz, 2H), 2.29-2.18 (m, 1H), 2.15 (s, 3H), 2.04-1.94 (m, 1H), 1.92-1.82 (m, 1H), 1.68-1.56 ( m, 1H), 1.45-1.34 (m, 1H), 1.30 (d, J = 7.2 Hz, 3H), 1.03 (t, J = 7.5 Hz, 3H), 1.00 (d, J = 6.9 Hz, 3H), 0.73 (d, J = 6.6 Hz, 3H).
ESI-HRMS Calcd for C 24 H 32 NaO 2 [M + Na] + 375.2295. Found 375.2296.
[α] 24 D -72.2 (c 0.348, CHCl 3 )
[実施例２] RXRならびにRXRへテロダイマー活性評価
１）測定原理
核内受容体の多くは転写調節に関わる転写因子であるため、その転写活性を測定する手段としてレポーター遺伝子アッセイ（reporter gene assay）が行われる。COS-1細胞やHeLa細胞などの細胞に、RXR受容体タンパク質発現プラスミド及びレポータープラスミドを導入し、融合タンパク質（fusion protein）を過剰発現させる。そこに、RXR作動性物質（リガンド）が受容体に結合すると、転写がリガンド依存的に起こり、その下流にある融合タンパク質が生成され、下流にあるルシフェラーゼの産生が始まる。このルシフェラーゼ活性を測ることにより、RXR作動活性を測定した。また、PPARもしくはLXRとのヘテロダイマーアッセイについては、PPARまたはLXRの発現プラスミドを併用し、かつPPARまたはLXRに対応する遺伝子配列を有するレポータープラスミドを利用した。
また、分泌型アルカリホスファターゼ（SEAP）発現プラスミドを導入し、SEAPの活性を測定することで、形質転換効率の補正を行った。
[Example 2] RXR and RXR heterodimer activity evaluation 1) Measurement principle Since many nuclear receptors are transcription factors involved in transcriptional regulation, a reporter gene assay is used as a means of measuring transcriptional activity. Done. An RXR receptor protein expression plasmid and a reporter plasmid are introduced into cells such as COS-1 cells and HeLa cells to overexpress a fusion protein. When the RXR agonist (ligand) binds to the receptor, transcription occurs in a ligand-dependent manner, a downstream fusion protein is generated, and downstream luciferase production begins. RXR agonist activity was measured by measuring the luciferase activity. For heterodimer assay with PPAR or LXR, a reporter plasmid having a gene sequence corresponding to PPAR or LXR was used in combination with an expression plasmid of PPAR or LXR.
Moreover, the transformation efficiency was corrected by introducing a secretory alkaline phosphatase (SEAP) expression plasmid and measuring the activity of SEAP.
２）宿主細胞の培養
細胞の増殖培地は、ダルベッコ変法イーグルMEM培地（DMEM）を用いた。まず、500 mLの超純水（Milli-Q(R)にて生成）にDMEM粉末を4.75 g溶解し、高圧加熱滅菌（121℃、20分間）を行った後、室温に戻し、これを非働化したウシ胎児血清（FBS）を10 % (v/v)となるように加え、さらに高圧加熱滅菌した10 % NaHCO3を10 mL添加し、その後L‐グルタミン0.292 gを8 mLの超純水に溶解したものをろ過滅菌後添加して調製した。
2) Host cell culture Dulbecco's modified Eagle MEM medium (DMEM) was used as a cell growth medium. First, 4.75 g of DMEM powder was dissolved in 500 mL of ultrapure water (produced with Milli-Q (R) ), sterilized by high-pressure heat (121 ° C, 20 minutes), then returned to room temperature. Add activated fetal bovine serum (FBS) to 10% (v / v), add 10 mL of high pressure heat-sterilized 10% NaHCO3, and then add 0.292 g of L-glutamine to 8 mL of ultrapure water. The dissolved one was prepared by adding after filtration sterilization.
各細胞の継代は、100 mm培養シャーレで培養した細胞の培養上清を除き、トリプシン処理により細胞を回収し、4 ℃、1000 rpm、3分間遠心分離後、増殖培地を加えて細胞を分散させ、100 mm培養シャーレに細胞を分散した増殖培地を15 mL加え、37℃、5 % CO2存在下で培養した。
形質転換はEffecteneTM Transection Reagent (QIAGEN社)を用いて行った。RXRの陽性コントロールにはLGD1069、PPARの陽性コントロールにはTIPP-703、LXRの陽性コントロールにはcarba-T0901317を用いた。これらは、DMSO溶解したものをストック溶液とし、アッセイするプレートにおいて計測した。
For the passage of each cell, remove the culture supernatant of cells cultured in a 100 mm culture dish, collect the cells by trypsin treatment, centrifuge at 4 ° C, 1000 rpm for 3 minutes, and then add the growth medium to disperse the cells. Then, 15 mL of a growth medium in which cells were dispersed in a 100 mm culture dish was added, and cultured in the presence of 37 ° C. and 5% CO 2 .
Transformation was performed using Effectene ™ Transection Reagent (QIAGEN). LGD1069 was used as a positive control for RXR, TIPP-703 was used as a positive control for PPAR, and carba-T0901317 was used as a positive control for LXR. These were counted in the plates to be assayed as DMSO-dissolved stock solutions.
３）転写活性の測定
（１日目）60 mm培養シャーレに、増殖培地5 mLとともにCOS-1細胞を50×104 cells播種し、一晩培養した。
（２日目）EffecteneTM Transection Reagent (QIAGEN社)を用いたリポフェクション法により形質転換を行った。形質転換には、受容体タンパク質発現プラスミド1 μg、レポータープラスミド4 μg、SEAP発現プラスミド1 μgを用いた。ヘテロダイマーアッセイの場合は、受容体タンパク質発現プラスミドとして、RXRα受容体タンパク質発現プラスミド0.5 μgに加え、PPARγ受容体タンパク質発現プラスミド0.5 μgまたはLXRα受容体タンパク質発現プラスミド0.5 μgを併用した。
（３日目）16〜18時間後、培養上清を除き、トリプシン処理により細胞を回収し、4 ℃、1000 rpm、3分間遠心分離後、増殖培地を加えて細胞を分散し、20×104 cells/wellとなるように96ウェルのホワイトプレートに播種した。その後、DMSO濃度が１％以下になるように各化合物を加えた。
（４日目）24時間後、上清25μLをSEAP測定に用い、残りの細胞液はルシフェラーゼ活性測定に用いた。
3) Measurement of transcriptional activity (Day 1) COS-1 cells were seeded in a 60 mm culture dish with 5 mL of growth medium together with 50 × 10 4 cells and cultured overnight.
(Day 2) Transformation was performed by a lipofection method using Effectene ™ Transection Reagent (QIAGEN). For transformation, receptor protein expression plasmid 1 μg, reporter plasmid 4 μg, and SEAP expression plasmid 1 μg were used. In the case of the heterodimer assay, as a receptor protein expression plasmid, 0.5 μg of PPARγ receptor protein expression plasmid or 0.5 μg of LXRα receptor protein expression plasmid was used in combination with 0.5 μg of RXRα receptor protein expression plasmid.
(Day 3) After 16 to 18 hours, the culture supernatant is removed, and the cells are collected by trypsin treatment. After centrifugation at 4 ° C. and 1000 rpm for 3 minutes, a growth medium is added to disperse the cells. It seed | inoculated to 96 well white plate so that it might become 4 cells / well. Thereafter, each compound was added so that the DMSO concentration was 1% or less.
(Day 4) After 24 hours, 25 μL of the supernatant was used for SEAP measurement, and the remaining cell solution was used for luciferase activity measurement.
SEAP測定は、Methods in molecular biology, 63, pp.49-60, 1997/ BD Great EscAPe SEAP User manual (BD bioscience)に記載の方法に従い行った。
具体的には、以下の方法で測定した。上記４日目の上清25μLに対して希釈用緩衝液を25μL加えた後、65 ℃で30分インキュベートした。その後室温に戻し、アッセイ用緩衝液 (7μL)、10×MUP (0.3 μL)、希釈用緩衝液 (2.7 μL)を加え、暗所室温で60分インキュベートした。その後、マイクロプレートリーダー（インフィニットTM (infinite)200、TECAN社製）を用い励起波長360 nm、蛍光波長465 nmにより蛍光強度を測定した。
SEAP measurement was performed according to the method described in Methods in molecular biology, 63, pp. 49-60, 1997 / BD Great EscAPe SEAP User manual (BD bioscience).
Specifically, it measured by the following method. 25 μL of dilution buffer was added to 25 μL of the supernatant on day 4, and incubated at 65 ° C. for 30 minutes. After returning to room temperature, assay buffer (7 μL), 10 × MUP (0.3 μL), and dilution buffer (2.7 μL) were added, and incubated at room temperature in the dark for 60 minutes. Thereafter, the fluorescence intensity was measured with an excitation wavelength of 360 nm and a fluorescence wavelength of 465 nm using a microplate reader (Infinite ™ (infinite) 200, manufactured by TECAN).
アッセイ用緩衝液は、以下の方法で調製した。50 mLの超純水（Milli-Qョにて生成）にL-ホモアルギニン（0.45 g）と塩化マグネシウム（0.02 g）を溶解させ、ジエタノールアミン（21 mL）を加えた。その後、塩酸を用いてpHを9.8になるように調整後、超純水を用いて全量が100 mLになるようにメスアップし、それを4 ℃で保存した。 The assay buffer was prepared by the following method. A 50 mL of ultrapure water (generated in Milli-Q ®) L-homoarginine and (0.45 g) was dissolved magnesium chloride (0.02 g), was added diethanolamine (21 mL). Then, after adjusting the pH to 9.8 with hydrochloric acid, the volume was adjusted to 100 mL with ultrapure water and stored at 4 ° C.
希釈用緩衝液は、以下の方法で調製した。90 mLの超純水（Milli-Qョにて生成）に塩化ナトリウム（4.38 g）とTris Base(2.42g)を溶解させた。その後、塩酸を用いてpHが7.2になるように調整し、5倍濃度希釈用緩衝液を作製し、それを4 ℃で保存した。使用直前にそれを5倍希釈することで希釈用緩衝液を作製した。 The dilution buffer was prepared by the following method. To 90 mL of ultra pure water (generated in Milli-Q ®) was dissolved sodium chloride (4.38 g) and Tris Base (2.42 g). Thereafter, the pH was adjusted to 7.2 with hydrochloric acid to prepare a 5-fold dilution buffer, which was stored at 4 ° C. Dilution buffer was prepared by diluting it 5-fold immediately before use.
4-メチルウンベリフェリルホスフェートを25mMになるように超純水（Milli-Qョにて生成）に溶解させ、それを-20 ℃で保存したものを、10×MUPとした。 4-methylumbelliferyl phosphate was dissolved in as ultrapure water becomes 25 mM (produced by Milli-Q ®), what it was stored at -20 ° C., was 10 × MUP.
ルシフェラーゼ活性は、NUNC社製の96穴ホワイトプレートを用い、発光基質（Steady-Gloョ Luciferase Assay System、Promega社製）との反応産物との発光強度をマイクロプレートリーダー（インフィニットTM (infinite)200、TECAN社製）を用いて測定した。 Luciferase activity using the 96-well white plate manufactured by NUNC, luminescent substrate (Steady-Glo ® Luciferase Assay System, Promega Corp.) emission intensity microplate reader with reaction products of (Infinite TM (infinite) 200, Measured using TECAN).
４）測定結果
上記の測定結果を以下の表１ならびに図３〜４に示した。
4) Measurement results The measurement results are shown in the following Table 1 and FIGS.
測定結果は、陽性コントロール（RXRには非特許文献８記載のLGD1069を、PPARには非特許文献９記載のTIPP-703を、LXRには非特許文献１０記載のcarba-T0901317）を1μM反応させたときの転写活性を1とし、相対活性を調べた。その結果、化合物１について、転写活性を認めた。 The measurement results were obtained by reacting 1 μM of a positive control (LGD1069 described in Non-Patent Document 8 for RXR, TIPP-703 described in Non-Patent Document 9 for PPAR, and carba-T0901317 described in Non-Patent Document 10 for LXR). The transcriptional activity was 1 and the relative activity was examined. As a result, transcriptional activity was observed for Compound 1.
非特許文献８：Cancer Res. 1996, 56, 5566.
非特許文献９：Bioorg. Med. Chem. Lett. 2008, 18, 4525.
非特許文献１０：Heterocycles 2008, 76, 137.
Non-Patent Document 8: Cancer Res. 1996, 56, 5566.
Non-Patent Document 9: Bioorg. Med. Chem. Lett. 2008, 18, 4525.
Non-Patent Document 10: Heterocycles 2008, 76, 137.
表1は，化合物１および非特許文献１１記載の化合物２のRXR各サブタイプに対する転写活性化能である。非特許文献１１：Bioorg Med Chem. 2011，19，939. Table 1 shows the transcription activation ability of Compound 1 and Compound 2 described in Non-Patent Document 11 for each RXR subtype. Non-Patent Document 11: Bioorg Med Chem. 2011, 19, 939.
以上詳述したように、本発明の化合物は既存のRXR作動薬の活性と比較して，それを凌ぐRXRアゴニストとして機能する。さらに、化合物１は既存のRXRアゴニストに比較して、LXRα/RXRα活性化を抑え、かつPPARγ/RXRα活性化能を有することを見出した。このことは、本化合物が高濃度においてもLXRα/RXRα活性化にともなうトリグリセリド血中濃度の上昇を回避することが期待できる。本発明の化合物は、糖尿病治療薬、脂質代謝異常症治療薬、抗がん剤の有効成分としての作用が期待できるため、このような医薬として利用することができる。また、生化学試験用試薬としても利用することができる。 As described above in detail, the compound of the present invention functions as an RXR agonist that surpasses the activity of existing RXR agonists. Furthermore, it has been found that Compound 1 suppresses LXRα / RXRα activation and has PPARγ / RXRα activation ability as compared with existing RXR agonists. This can be expected to avoid an increase in the blood triglyceride concentration associated with LXRα / RXRα activation even when the present compound is at a high concentration. Since the compound of the present invention can be expected to act as an active ingredient of a therapeutic agent for diabetes, a therapeutic agent for dyslipidemia, and an anticancer agent, it can be used as such a medicament. It can also be used as a biochemical test reagent.
Claims (9)
R 2 は、Ｈ、アルキル基、フェニル基から選択され、
Zは、カルボン酸、カルボン酸エステル、ヒロドキサム酸から選択される。）
で示される化合物。 Formula III:
R 2 is selected from H, an alkyl group, and a phenyl group;
Z is selected from carboxylic acids, carboxylic acid esters, and hydroxamic acids. )
A compound represented by
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