JP2021515011A - 小分子核内受容体モジュレータのアミドプロドラッグ - Google Patents
小分子核内受容体モジュレータのアミドプロドラッグ Download PDFInfo
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- JP2021515011A JP2021515011A JP2020545672A JP2020545672A JP2021515011A JP 2021515011 A JP2021515011 A JP 2021515011A JP 2020545672 A JP2020545672 A JP 2020545672A JP 2020545672 A JP2020545672 A JP 2020545672A JP 2021515011 A JP2021515011 A JP 2021515011A
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- C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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Abstract
Description
核内受容体モジュレータは、ステロイドホルモン、親油性ビタミン、ステロール、及び胆汁酸に対する受容体を含み、治療上の関心が大きい重要な種類の治療法の標的である(米国食品医薬品局によって承認された新薬の10〜15%を包含する)。最も重要な関心領域には、中枢神経系疾患、たとえばアルツハイマー病、パーキンソン病、脱髄疾患、及び膠芽腫がある。
一実施形態では、チラトリコールのアミド類似体(トライアック、Triacana、及び2−(4−(4−ヒドロキシ−3−ヨードフェノキシ)−3,5−ジヨードフェニル)酢酸としても知られている)またはその薬学的に許容される塩が提供され、それは以下の構造を有している:
ここで、R1は、C1〜C4の直鎖または分岐アルキルである。
ここで、R1は、C1〜C4の直鎖または分岐アルキルである。
ここで、R1は、C1〜C4の直鎖または分岐アルキルである。
ここで、R1は、C1〜C4の直鎖または分岐アルキルである。
ここで、R1は、C1〜C4の直鎖または分岐アルキルである。
ここで、R1は、C1〜C4の直鎖または分岐アルキルである。
ここで、R1は、C1〜C4の直鎖もしくは分岐アルキルまたはその薬学的に許容される塩である。
プロドラッグN−メチルアミドのモジュラー合成が開発された。親薬物のカルボン酸をカルボニルジイミダゾール(CDI)を用いて活性化させた後に、THF中の過剰なメチルアミンを添加することによって、N−メチルアミドプロドラッグが中程度から良好な収率で得られる。この方法の利点は、このような割高な親薬物出発物質のアミド結合に対する温和な条件に関係している。これによって、典型的に、アミド生成物と出発物質のみの生成物混合物が生じる。
すべての親薬物は商業的供給源から購入した。例外はNH−3で、これは本発明者らの実験室で合成した1。
概略的な合成法:
35mg(1当量)の親薬物のカルボン酸を、カルボニルジイミダゾール(CDI、1.2当量)、撹拌棒、及び3mLの乾燥THFを含む厚肉管の中に入れた。管をシールし、真空下に置いて、アルゴンを3回補充した。アルゴン下で混合物を50℃で2時間加熱した後に、室温まで冷却した。3回のさらなる真空/アルゴン補充を行った後に、過剰なメチルアミン(約10当量、THF中に2M)を注射器によって添加した。混合物を室温で2時間撹拌した後に、約14時間50℃に加熱した。冷却したら、生成物混合物をジクロロメタンを用いて希釈して、1NのHCl及び塩水を用いて洗浄した。すべての有機層を混合して、硫酸ナトリウムを用いて乾燥させ、乾燥状態まで蒸発させて、典型的に出発物質と生成物のみを含む粗生成物混合物を得た。生成物を、DCM中の1〜10%MeOHを用いて、通常は第1のバンドとして、シリカ上で分離した。
2−(4−(4−ヒドロキシ−3−ヨードフェノキシ)−3,5−ジヨードフェニル)−N−メチルアセタミド
35mgのトライアック(0.056mmol)から30.45mg(0.048mmol、87%)の生成物が、オフホワイトの粉末として得られた。
2−(4−(4−ヒドロキシ−3−イソプロピル−5−((4−ニトロフェニル)エチニル)ベンジル)−3,5−ジメチルフェノキシ)−N−メチルアセタミド
35mgのNH−3(0.074mmol)から18.7mg(0.038mmol、52%)の生成物が、黄色い粉末として得られた。
2−(3−(3−((2−クロロ−3−(トリフルオロメチル)ベンジル)(2,2−ジフェニルエチル)アミノ)プロポキシ)フェニル)−N−メチルアセタミド
35mgのGW3965(0.06mmol)から13.6mg(0.023mmol、38%)の生成物が、無色の残留物として得られた。注意:ワークアップ中に、未精製の反応性混合物を0.5MのNaOH(水溶液)を用いて洗浄し、カラム上で分離して、電荷中性種を得た。
N−メチル−4−(1−(3,5,5,8,8−ペンタメチル−5,6,7,8−テトラヒドロナフタレン−2−イル)ビニル)ベンズアミド
35mgのベキサロテン(0.1mmol)から29.3mg(0.081mmol)の生成物が、白色粉末として得られた。
(E)−3−(4−((E)−1−(4−ヒドロキシフェニル)−2−フェニルブタ−1−エン−1−イル)フェニル)−N−メチルアクリルアミド
35mgのGW7604(0.094mmol)から8.3mg(0.021mmol、23%)の生成物が、黄色がかった残留物として得られた。
N−メチル−2−(2−メチル−4−(((4−メチル−2−(4−(トリフルオロメチル)フェニル)チアゾール−5−イル)メチル)チオ)フェノキシ)アセトアミド
35mgのGW501516(0.077mmol)から27.7mg(0.059mmol、77%)の生成物が、オフホワイトの粉末として得られた。
(S)−4−(2−(4−(2−エトキシ−3−(メチルアミノ)−3−オキソプロピル)フェノキシ)エチル)メタンスルホン酸フェニル
35mgのテサグリタザール(0.086mmol)から15.6mg(0.037mmol、43%)の生成物が、黄色油として得られた。
4−クロロ−N−(4−((2−メチル−1−(メチルアミノ)−1−オキソプロパン−2−イル)オキシ)フェネチル)ベンズアミド
35mgベザフィブラート(0.097mmol)から29.8mg(0.079mmol、82%)の生成物が、白色粉末として得られた。
2−(3−クロロ−4−((3−((7−プロピル−3−(トリフルオロメチル)ベンゾ[d]イソキサゾール−6−イル)オキシ)プロピル)チオ)フェニル)−N−メチルアセタミド
35mgのF3MethylAA(0.072mmol)から11.2mg(0.022mmol、31%)の生成物が、白色粉末として得られた。
6−((4,4−ジメチルチオクロマン−6−イル)エチニル)−N−メチルニコチンアミド
35mgのタザロテン酸(0.11mmol)から29.2mg(0.087mmol、79%)の生成物が、黄色い粉末として得られた。
用語「治療有効量」または「薬学的有効量」は、治療を必要とする対象(たとえば、哺乳動物、たとえばヒト)に投与したときに、以下に規定するように、治療に効果をもたらすのに十分な量を指す。治療または薬学的有効量は、治療している対象及び病状、対象の体重及び年齢、病状の重症度、投与の方法など(これらは当業者によって容易に判定することができる)に応じて変化する。たとえば、本明細書で説明する化合物または薬学的に許容される塩もしくはその共結晶の「治療有効量」または「薬学的有効量」は、意図する生理学的標的の発現または活性を調節し、その結果、兆候に苦しむ対象(たとえば、ヒト)を治療するかまたは兆候の既存の症状を改善もしくは軽減するのに十分な量である。たとえば、治療または薬学的有効量は、意図する生理作用の阻害に応答して疾患または状態の症状を軽減するのに十分な量であってもよい。
本明細書で説明する化合物またはその薬学的に許容される塩または共結晶は通常、医薬組成物の形態で投与される。したがって、本開示で提供される医薬組成物には、活性成分として、説明した化合物のうちの1つ以上、またはその薬学的に許容される塩、薬学的に許容される共結晶、もしくは薬学的に許容されるエステル、及び1つ以上の薬学的に許容されるビヒクル、たとえば、賦形剤、担体、たとえば、不活性固体希釈剤及び充填剤、希釈剤、たとえば、滅菌水溶液及び種々の有機溶媒、透過促進剤、可溶化剤、及びアジュバントが含まれる。医薬組成物を単独でまたは他の治療薬と組み合わせて投与してもよい。このような組成物を製薬分野で良く知られた方法で調製する(たとえば、Remington’s Pharmaceutical Sciences,Mace Publishing Co.,Philadelphia,Pa.17th Ed.(1985)及びModern Pharmaceutics,Marcel Dekker,Inc.3rd Ed.(G.S.Banker&amp;C.T.Rhodes,Eds.)を参照)。
本明細書で説明する化合物またはその薬学的に許容される塩もしくは共結晶を含む組成物(たとえば、製剤及び単位用量を含む)を調製して適切な容器内に配置し、指示された条件の治療用にラベル付けすることができる。したがって、製造物品も提供される。たとえば、化合物またはその薬学的に許容される塩もしくは共結晶の単位剤形を含む容器、及び化合物の使用上の注意を含むラベルである。いくつかの実施形態では、製造物品は、化学式Iの化合物またはその薬学的に許容される塩もしくは共結晶の単位剤形を含む容器、及び少なくとも1つの薬学的に許容されるビヒクルである。製造物品は、ボトル、バイアル、アンプル、1回だけ使う使い捨てのアプリケータなどに、本開示で提供される医薬組成物が含まれたものであってもよい。容器は、種々の材料、たとえばガラスまたはプラスチックから形成してもよく、一態様では、容器上にまたは容器に付随して、がんまたは炎症状態の治療における使用方法を示すラベルが含まれていてもよい。当然のことながら、活性成分を、化学的及び物理的安定性を改善することができる任意の材料(たとえば、アルミホイルバッグ)に封入してもよい。いくつかの実施形態では、ラベル上に示される疾患または状態には、たとえば、がんの治療を含めることができる。
動物実験
実験プロトコルは、National Institutes of Health Guide for the Care and Use of Laboratory Animalsに従うものであり、Oregon Health&Science University Institutional Animal Care&Use Committeeにより承認された。生後8〜10週の野生型雄C57Bl/6マウスを、12時間の明暗サイクルの環境制御された部屋に、食物及び水を自由に摂取できる状態で収容した。マウスに、9.14μモル/kgの親薬物またはプロドラッグの腹腔内(i.p.)注射を1回行った。3匹のマウスを以下の時点:0.5時間、2時間、及び6時間(別に表記されていない限り)で安楽死させ、組織及び血液を採取した。組織をすぐに凍らせて、血液を氷の上に最低でも30分間保持した後に、7500×gで15分間遠心沈殿させた。血清(100μL)を収集して、サンプルを処理するまで組織とともに−80℃で保管した。
血清サンプルを室温に加温して、10μLの2.99μM内部標準(d6−ソベチロム)を添加した。アセトニトリル(500μL)を添加して、サンプルを20秒間ボルテックスした。次にサンプルを、4℃にて10,000gで15分間遠心分離した。次に上澄みの90%をガラス試験管に移し、45℃で1.5時間SpeedVacを用いて濃縮した。次に、乾燥したサンプルを、400μLの10%ACN中DMFに溶解して、20秒間ボルテックスした。結果として得られる混合物をエッペンドルフに移して、10,000gで15分間遠心分離した。上澄みを0.22μm遠心ろ過機を用いてろ過して、LC−MS/MS分析にかけた。ビヒクル(DMSO)のみを注射した生後8〜10週のマウスから得た100μLの血清を用いて標準曲線を形成した。サンプルをろ過した後に7バイアルに分けた以外は、処理を正確に同じに行った。7バイアルのうちの6バイアルに親薬物を添加して、マトリクス中の終濃度を形成した(0.1pg/μL、0.5pg/μL、1pg/μL、10pg/μL、100pg/μL、及び500pg/μL)。
脳サンプルを室温に加温して、3つのGoldSpec1/8クロム鋼球を含む事前に重量を計ったホモジナイザーチューブ(Applied Industrial Technologies)に移した。結果として得られるチューブの重量を計ってから、1mLのH2Oを添加し、続いて10μLの2.99μM内部標準(d6−ソベチロム)を添加した。チューブをBead Bugを用いて30秒間均質化した後に、3mLのACNを含むファルコンチューブに移した。ACN(1mL)を用いてホモジナイザーチューブを洗浄し、溶液をファルコンチューブに戻した。次にサンプルを、血清処理と同じ方法を用いて処理した。ただし、45℃で4時間SpeedVacを用いてサンプルをガラス管内で濃縮した。
3匹のマウスの2つのコホートに、9.14μmol/kgのプロドラッグを1回腹腔内注射した(i.p.)。1つのコホートには、プロドラッグを投与する1時間前に、FAAH阻害剤PF−3845を1mg/kg投与量で注射した。プロドラッグを注射した1時間後に各コホートを安楽死させ、組織及び血液を採取した。組織をすぐに凍らせて、血液を氷の上で最低でも30分間保持した後に、7500×gで15分間遠心沈殿させた。血清(100μL)を収集して、サンプルを処理するまで組織とともに−80℃で保管した。前述したようにサンプルを処理した。
すべての親薬物及びd6−ソベチロム内部標準を、エレクトロスプレーイオン化(ESI)を伴うQTRAP4000ハイブリッド/トリプル四重極線形イオントラップ質量分析計(Applied biosystems)をネガティブモードで用いて、分析した。質量分析計を、Shimadzu(Columbia,MD)SIL−20ACXRオートサンプラーとそれに続く2LC−20ADXRLCポンプに接続して機能させて、Applied Biosystems/SCIEX QTRAP 4000機器(Foster City,CA)上で分析した。機器を以下の設定で動作させた。電源電圧は−4500kV、GS1は50、GS2は60、CURは15、TEM650、及びCAD MEDIUM。スケジュールされた多重反応モニタリング(MRM)遷移は、前駆イオンm/z及びその対応する診断用生成物イオンに基づいている。化合物を別個に注入して、機器パラメータを各MRM遷移に対して最適化した。MRMパラメータを補足情報に示す。勾配移動相を流量0.5mL/分で送出した。勾配移動相は2種の溶媒からなっていた。A:水中の10mMギ酸アンモニウム、及びB:90%アセトニトリル、10%水中の10mMギ酸アンモニウム。Imtakt ScherzoSS−C18、50x2mm、3μm(製品番号SS022)を、Imtakt Guard cartridge ScherzoSS−C18、5×2mm、3μmプレカラム(製品番号GCSS0S)とともに用いて、40℃で保持し、オートサンプラーを30℃で保持した。勾配は以下のようであった。Bの初期濃度は10%で、0.5分間保持した後に、4.5分間で98%Bまで増加させ、0.9分間保持して、0.1分間で10%Bまで後退させて、2分間10%Bで保持し、合計実行時間は8分であった。データをSCIEX Analyst 1.6.2 ソフトウェア(Framingham,MA,USA)を用いて取得して、Multiquant3.0.2を用いて分析した。
両側スチューデントt検定を用いて、個々の群と適切なビヒクル群とを、述べたように比較して、統計分析を行った。有意水準<0.05に設定し、P値を以下の記号を用いて例示した。ns=非有意、*P≦0.05、**P≦0.01、及び***P≦0.001。すべてのデータは平均±SEMを表す。動物群数を、以前の作業から情報を得て、実験あたりの合計動物数を必要に応じて最小限にした。AUC値を計算して、データをGraphPad Prism7を用いてプロット及び分析した。
[本発明1001]
化学式(I)、化学式(III)、化学式(V)、化学式(VII)、化学式(IX)、化学式(XI)、化学式(XIII)、化学式(XV)、及び化学式(XVII):
の群から選択される化学式を有する化合物であって、
各場合におけるR 1 が独立に、C 1 〜C 4 の直鎖もしくは分岐アルキルである、
化合物またはその薬学的に許容される塩。
[本発明1002]
以下の化学式:
の群から選択される、本発明1001の化合物またはその薬学的に許容される塩。
[本発明1003]
薬学的有効量の本発明1001の化合物またはその薬学的に許容される塩、及び薬学的に許容される担体または賦形剤を含む、医薬組成物。
[本発明1004]
前記化合物が、本発明1002の化合物またはその薬学的に許容される塩の群から選択される、本発明1003の医薬組成物。
[本発明1005]
薬剤の調製における本発明1001の化合物またはその薬学的に許容される塩の使用。
[本発明1006]
薬剤の調製において使用する前記化合物が、本発明1002の化合物またはその薬学的に許容される塩の群から選択される、本発明1003の使用。
Claims (6)
- 薬学的有効量の請求項1に記載の化合物またはその薬学的に許容される塩、及び薬学的に許容される担体または賦形剤を含む、医薬組成物。
- 前記化合物が、請求項2の化合物またはその薬学的に許容される塩の群から選択される、請求項3に記載の医薬組成物。
- 薬剤の調製における請求項1に記載の化合物またはその薬学的に許容される塩の使用。
- 薬剤の調製において使用する前記化合物が、請求項2に記載の化合物またはその薬学的に許容される塩の群から選択される、請求項3に記載の使用。
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