JP6817073B2 - セロトニン受容体を標的にする化合物および方法 - Google Patents
セロトニン受容体を標的にする化合物および方法 Download PDFInfo
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- JP6817073B2 JP6817073B2 JP2016568912A JP2016568912A JP6817073B2 JP 6817073 B2 JP6817073 B2 JP 6817073B2 JP 2016568912 A JP2016568912 A JP 2016568912A JP 2016568912 A JP2016568912 A JP 2016568912A JP 6817073 B2 JP6817073 B2 JP 6817073B2
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Description
本願は、出願日:2014年5月19日の米国仮特許出願62/000,286号の利益を請求し、その内容はその全体を参照によってここに組み入れられる。
本発明は、1つには、特定のセロトニン受容体を立体選択的に調節して、次に、これらの症状によって特徴づけられる常同症および障害を処置することに有用である、新規な化合物の発見に基づく。関連化合物は、劣った(H1)受容体結合特性を考慮して、キラール分割を保証しない旨報告された(例えば、Ghoneim, Bioorg & Med. Chem.14 (2006):6640参照。それらの全部においてその内容は本願明細書に組み入れられる)。
用語「アシル」は式Rx─C(O)─の両方の置換基を意味し、ここで、Rxはアルキル、ヘテロアルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクロアルキル、アリール、アリールアルキル、ヘテロアリールおよびヘテロアリールアルキルである。
例1:5−PAT合成
本願明細書において記載される化合物の合成は、スキーム1に示され、そして、それは6つのステップを含む。簡潔には、1−テトラロンを臭素/AlCl3と反応することによって得られる5−Br−テトラロン(1)は、還元して対応するアルコールを与え、pTSAと処理してオレフィン(3)、エポキシド(4)を得、pTSAと処理してキーとなる中間体の5−Br−2―テトラロン(5)を得る。5−Br−2−テトラロンは、多種多様な商業的に入手可能なボロン酸誘導体(6)と反応し得る。これらの有機ホウ素はスズキ―ミヤウラ クロスカップリング反応で使われるとき、本願明細書において記載される化合物の合成を可能にする。このように、スキーム1において、5−Br−2−テトラロン(5)はテトラキス トリフェニルホスフィン Pd[0]と反応し、混合物は脱ガスされ、そして、2’−F−または2’−Cl−フェニルボロン酸が添加された。反応混合物は、80℃で3時間撹拌され、そうすると、H2O2を加える前に、室温に冷却し、過剰なボロン酸を急冷し、5−(2’−F−または2’−Cl)−フェニル−2−テトラロン(7)を得た。ジメチルアミンと還元性アミノ化を行うと、5−(2’[o]−FまたはCl)−フェニル−2−ジメチルアミノテトラリン ラセミ化合物(8)を与え、多糖類ベースのキラル固定相(CSP)−HPLCによって溶解し、それぞれ25mgの(2R)および(2S)−o−F―PAT、および―o―Cl−5−PATを得た。本願明細書において合成される他の化合物は、この一般的プロセスを包含する。
1HNMR(500MHz、CDCl3): δ 12.82 (brs, 1H), 7.36-7.31 (m, 1H), 7.23-7.15 (m, 4H), 7.11-7.07 (m, 2H), 3.56-3.47 (m, 1 H), 3.38-3.33 (m, 1 H), 3.20 (t, J = 12.0 Hz, 1 H), 2.84-2.74 (brs, 7H), 2.65- 2.56 (m, 1H), 2.38 (dd, J = 11.0, 5.0 Hz, 1H), 1.90-1.76 (m, 1 H). M.P: 232-235 °C. HPLC (s-prep): solv. sys = EtOH:Hexane (10:90) + 0.1% of diethylamine (modifier) + 0.1% triフロロacetic acid (modifier); flow rate = 2.0 ml/min. (+)-(25)-o-F-5-PAT: t =24.2 min [α]22 D = (+) 5.65° (c 0.32, CH2CI2). (-)-(2R)-o-F-5-PAT: t = 26.5 min. [α]25 D = (-) 5.45° (c 0.22, CH2CI2)。
1H NMR: δ 12.56 (brs, 1H), 7.44-7.38 (m, 1H), 7.30-7.27 (m, 2H), 7.21-7.18 (dt, J = 7.0, 2.5 Hz, 1H), 7.15-7.10 (m, 2H), 6.99 (t, J = 6.0 Hz, 1H), 3.52-3.44 (m, 1H), 3.38-3.33 (m, 1H), 3.18 (t, J = 13.5 Hz, 1 H), 2.78-2.83 (m, 6H), 2.72-2.45 (m, 2H), 2.34 (dd, J = 9.5, 2.0 Hz, 1 H), 1.88-1.79 (m, 1 H). M. P: 228-230 °C. HPLC (same conditions): (+)-(25)-o-CI-5-PAT: t =22.4 min [α]25 D= (+) 6.53° (c 0.196, CH2CI2). (-)( 2R)-o-CI-5-PAT: t = 25.3 min [α]21 D = (-) 6.80° (c 0.42, CH2CI2)。
例2:(+)−5−FPTは、立体選択的高親和力5−HT 7 および5−HT 1A 部分アゴニストである
5−HT7受容体、例えば5−o−F−PATおよび5−o−Cl−PAT(図1A)を目的とする新規な5−置換−フェニル−2−ジメチルアミノテトラリン化合物が、開発された。
(+)−5−FPTは、各々有効性の異なる尺度を有する常同症の3つの異質なモデルにおいて試験された:1)C58/Jマウスの原因不明の常同症的なジャンプ;2)(±)−2,5−ジメトキシ−4−ヨードアンフェタミン(DOI)が引き起こす常同症的な頭の単収縮;3)そして、(5R,10S)−(+)−5−メチル−10,11−ジヒドロ−5H−ジベンゾ[a,d]シクロヘプタン−5,10−イミン(MK―801)が引き起こすC57Bl/6Jマウスにおける常同症的な回転。(+)−5−FPTも、精神刺激性の濫用のための潜在的薬理学的有用性を評価するために、C57Bl/6Jマウスのd―アンフェタミン(AMP)が引き起こす超運動を減らすために、有効性が試験された。C58/Jマウスは、標準ラボ状態の下に収納されるとき、自然に反復性の、常同症的なジャンプを発現し、そして、この行動は薬物処置に応答する常同症のモデルとして使われて来た。図5に示すように、(+)−5−FPTは、運動に関する行動を変えずに、用量に依存するやり方で、C58/Jマウスの常同症的なジャンプを強力に除去した(図8を参照)。(+)−5−FPTは、ASDを処置するために開発中だった、最近報告されたmGluR5陰性アロステリック調節剤、GRN―529より大きなこのモデルの有効性を示した。
図9に示すように、(+)−5−FPT(5.6mg/kg)はC57Bl/6Jマウスにおいて始められた社会的相互作用の数を著しく増加させ、一方で身繕いも減少させた。さらに、表3に示すように、(+)−5−FPTは、最も高い行動的に有効な用量で試験され(5.6mg/kg)、平らな体、前足の踏み、ムーン・ウォーキング、立毛、ストラブテール、または揺すりを含むセロトニン症候群の症状を結果的にもたらさず、後ろ足立ちを著しく減少させ、5―HT1A活性化を示唆した。注の中で、行動の試験が終了したあと、ブラインド・スコアラは後ろ足立ちの数に基づいてマウスを2つのグループに分類し、社会的相互作用を始め、そして、2つのグループは100%の精度でビヒクルを(+)―5―FPT処置されたマウスと区別した。
図10および11にそれぞれ示すように、(+)−5−FPTは、皮下のおよび口頭の投与の後、著しくDOI HTRを減少させた。加えて、(+)−5−FPTは、全身投与の30、60および90分後に、μgレベルの検出によって証明されたように、血液脳関門を容易に横断する(表4)。特に、(+)−5−FPTのレベルは、30分の事後投与直後の脳組織と比較してプラズマにおいて実質的により低く、(+)−5−FPTが末梢において急速にクリアされることを示した。一方、DOI HTR上の(+)−5−FPT(5.6mg/kg)の減少する効果は、2時間までの事後投与の間、顕著なままだった;3時間の事後投与で、(+)−5−FPTは、DOI HTRを阻害しなかった。
図12は、さまざまな合成された5−PAT化合物およびセロトニン受容体タイプ、5−HT1A、5−HT2A、5−HT2B、5−HT2Cおよび5−HT7でのそれらの親和力を示す。ヒスタミンH1受容体の親和力も含有する。
例7:4−PAT合成
本願明細書において記載する式IIaの化合物の合成は、スキーム1において示される。一般に、2−、3−、4−、2,6−または3,5置換されたスチレンのTFAAとの反応は、テトラール−2−オールに還元される、テトラレン−2−オールフェニル酢酸塩を提供し、それは、トシル化され、ジメチルアミンでSN2反転が続く。シス/トランス ラセミ化合物は、カラムクロマトグラフィによって分離され、そして、鏡像異性体分割は、キラル静止位相(CSP)−HPLCによる。
スキーム2
スキーム3
例8:化合物の結合親和力
放射性受容体競合的結合分析は、本発明の化合物の結合親和力を評価するために行なわれた。放射性リガンド競合的置換結合分析は、穴当たり膜サンプルからのタンパク質3−5μgを用いて、96穴プレートにおいて実行された。結合実験の各濃度点はサンプルの三組において実行され、そして、各実験は最低3回実行された。分析混合物の放射性リガンドの最終濃度は、〜KD濃度、すなわち2.0nM[3H]ケタンセリン(5―HT2A)、1.95nM[3H]メスラジン(5―HT2B)、1.4nM[3H]メスラジン(5―HT2C)または1.0nM[3H]メピラミン(H1))であった。非特異的結合は、全3つの5−HT2受容体のための10μMのミアンセリン、またはH1受容体のための10μMのトリプロリジンの存在下において決定された。放射性受容体結合分析混合物は37℃で1.0時間培養され、96穴セル‐ハーベスタ(Tomtec、Hamden、CT)を使用してワットマンGF/Bフィルタを通して迅速な濾過によって終了し、それは室温で、50mMのトリス−HClによって5回、その後洗浄された。結合された[3H]放射性リガンドを含有するフィルタは乾燥し、2mLのシンチレーション・カクテル(ScintiVerse)が入っているバイアルに置かれ、一晩平衡させて、そのあとで、ベックマン−コールターLS6500カウンタを使用して3Hによって誘発されたシンチレーションに対してカウントされた。
式IIおよび式IIaの化合物の生体内研究は、行動活性におけるMK−801によって誘発された増加の反転のために検討することによって、マウスにおいて行われる。注意および働くメモリの混乱を逆転させる際のこれらの化合物の効果を調べる追加の研究、およびMK―801によってできる衝動性の増加も、行われる。
本発明は、その特定の実施態様に関連して説明されているが、さらなる変更が可能であり、本出願は、一般に、本発明の原理に従って、本発明の変形、使用、 本発明が関係する技術の範囲内で知られているまたは慣例的なやり方で、本明細書に記載された本質的な特徴に適用され、添付の特許請求の範囲の範囲内で以下に記載される本開示からのそのような逸脱を含む。
本願明細書において参照されるすべての特許および刊行物は、全体として本願明細書に組み入れられる。
Claims (11)
- 式(I):
R1およびR2の各々は、独立して水素もしくはアルキルであるか、またはR1およびR2は一緒になって任意に置換されていてもよい複素環を形成し;
R3、R4、R5、R6、およびR7の各々は、独立して水素、ハロ、ヒドロキシ、アシル、アシルオキシ、アルキル、ヘテロアルキル、アルケニル、ヘテロアルケニル、アルキニル、ヘテロアルキニル、アルコキシカルボニル、シアノ、トリフルオロメチル、トリフルオロメトキシ、ニトロ、アミノ、およびアミドであり、ここで、任意の2個の隣り合うR基は、任意に一緒になって炭素環系または複素環系を形成し得る;
R8、R9およびR10の各々は、独立して水素またはアルコキシである;
で表される構造を有する、セロトニン5−HT7および5−HT1A受容体の実質的に鏡像異性的に純粋な(S)−エナンチオマー二重部分アゴニスト、または、その薬学的に許容し得る塩、水和物もしくは溶媒和物の治療上有効量、および、薬学的に許容し得る賦形剤または担体を含む、
セロトニン5−HT7および5−HT1A受容体の活性化を必要とする精神神経性の疾患または障害の処置における使用のための医薬組成物であって、疾患は、自閉症スペクトラム障害(ASD)、アスペルガー(Asperger)症候群、脆弱X症候群(FXS)、プラダー・ウィリー(Prader-Willi)症候群、レット(Rett)症候群、トゥレット(Tourette)症候群、注意欠陥多動性障害(ADHD)、強迫性障害、精神病性障害、精神刺激薬中毒および全般性不安からなる群から選択される、前記医薬組成物。 - 二重部分アゴニストが、100nM未満、または50nM未満、または25nM未満、または20nM未満、または10nM未満、または5nM未満、または2nM未満、または1nM未満の結合親和力(Ki)でセロトニン5−HT7受容体および5−HT1A受容体に対して結合する、請求項1に記載の医薬組成物。
- R1およびR2がメチルであるか;
R3、R4、R5、R6およびR7の少なくとも1つがHではないか;
R3、R4、R5、R6およびR7の少なくとも1つがハロであるか;または、
R3、R4、R5、R6およびR7の少なくとも1つがハロであり、かつハロがフルオロである;
請求項1または2に記載の医薬組成物。 - R3、R4、R5、R6およびR7の少なくとも1つがフルオロであるか;
R3のみがH以外の置換基であるか;
R3がフルオロまたはクロロなどのハロであるか;
R3がフルオロまたはクロロであり、R8、R9およびR10の少なくとも1つがメトキシであるか;
R 6およびR7、R5およびR6、R4およびR5、ならびにR3およびR4のいずれか1つが、フルオロまたはクロロなどのハロで置換されているか、または非置換のフェニル環を形成するか;
R3〜R7の置換基を含む原子の総数が、少なくとも5であり、20個の非水素原子以下であるか;または、
R3〜R7の置換基を含む原子の総数が、少なくとも5であり、20個の非水素原子以下であり、二重部分アゴニストが、CYP1A2、CYP2C19、CYP2C9、CYP2D6、CYP2E1およびCYP3A4から選択されるP450の1つ以上の形態について生理学的に関連した基質ではない;
請求項1〜3のいずれか一項に記載の医薬組成物。 - 二重部分アゴニストが、
- 式(Ib):
R1、R2、R8、およびR9の各々は、独立して水素、アルキル、アリール、ハロ、ニトロ、アミノ、ヘテロアリール、シクロアルキル、複素環式、またはアルコキシであり、
R10は、独立して水素、アルキル、アリール、ハロ、ニトロ、アミノ、ヘテロアリール、シクロアルキル、または複素環式であり、および
R3は、ハロ、アルコキシ、またはハロアルキルである、
によって表される構造の化合物、または、その薬学的に許容し得る塩、水和物、もしくは溶媒和物であって、
R 1 およびR 2 の両方がメチルであるか;または、
R 3 がフルオロ、クロロ、ブロモまたはヨードなどのハロである;
前記化合物、または、その薬学的に許容し得る塩、水和物、もしくは溶媒和物。 -
- 式(Ic):
R1およびR2の各々は、独立して水素またはアルキルであり、および
R3、R4、R5、R6、R7、R8、R9、R10、R11およびR12の各々は、独立して水素、アルキル、アリール、ハロ、ニトロ、アミノ、ヘテロアリール、シクロアルキル、複素環またはアルコキシであり、および
R3、R4、R5、R6、R7、R8およびR9の少なくとも1つは水素ではない、
によって表される構造の化合物、または、その薬学的に許容し得る塩、水和物、もしくは溶媒和物。 - R1およびR2の両方がメチルであるか;
R3が水素であるか;または、
R3、R4、R5、R6、R7、R8およびR9の1つ以上がフルオロ、クロロ、ブロモまたはヨードなどのハロである;
請求項8に記載の化合物。 -
- 請求項6〜10のいずれか一項に記載の化合物の、または、請求項1〜5のいずれか一項に記載の組成物の、セロトニン5−HT 7 および5−HT 1A 受容体の活性化を必要とする精神神経性の疾患もしくは障害を処置または予防するための医薬の製造のための使用であって、疾患は、自閉症スペクトラム障害(ASD)、アスペルガー(Asperger)症候群、脆弱X症候群(FXS)、プラダー・ウィリー(Prader-Willi)症候群、レット(Rett)症候群、トゥレット(Tourette)症候群、注意欠陥多動性障害(ADHD)、強迫性障害、精神病性障害、精神刺激薬中毒および全般性不安からなる群から選択される、前記使用。
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