JP4995203B2 - 精神病および神経変性障害の処置のための、n−AChRのコリン作動性リガンドとしての(1−アザ−ビシクロ[3.3.1]ノン−4−イル)−[5−(1H−インドール−5−イル)−ヘテロアリール]−アミン - Google Patents
精神病および神経変性障害の処置のための、n−AChRのコリン作動性リガンドとしての(1−アザ−ビシクロ[3.3.1]ノン−4−イル)−[5−(1H−インドール−5−イル)−ヘテロアリール]−アミン Download PDFInfo
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- AYSDPAWSPJSWSA-UHFFFAOYSA-N C(C1)CN(CC2)CC1C2Nc(cc1)nnc1-c1ccc2[nH]ccc2c1 Chemical compound C(C1)CN(CC2)CC1C2Nc(cc1)nnc1-c1ccc2[nH]ccc2c1 AYSDPAWSPJSWSA-UHFFFAOYSA-N 0.000 description 1
- LUDCMWIPNPIYST-UHFFFAOYSA-N C(C1)CN(CC2)CC1C2Nc(nc1)ccc1-c1c(cc[nH]2)c2ccc1 Chemical compound C(C1)CN(CC2)CC1C2Nc(nc1)ccc1-c1c(cc[nH]2)c2ccc1 LUDCMWIPNPIYST-UHFFFAOYSA-N 0.000 description 1
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Description
nは0、1、2、3、4または5を意味し、
Rは互いに独立してヒドロキシル、シアノ、ニトロ、ハロゲン、アルキル、アルコキシアルキルカルボニル、アルコキシカルボニル、アルキルアミン、ジアルキルアミン、アルキルカルボニルアミン、アルキルカルバメートを意味し、
Yは下記基
の化合物を提供する。
「置換もしくは非置換」なる用語は、本明細書において使用するとき、それぞれの基が1個以上、好ましくは3個まで、とりわけ1または2個の置換基によって置換されていてもよいことを意味する。置換基は好ましくは、アミノ、C1−C4アルキルアミノ、ジ(C1−C4アルキル)−アミノ、C3−C5シクロアルキルアミノ、ジ(C3−C5)シクロアルキルアミノ、N−C1−C4アルキル−N−C3−C5シクロアルキルアミノ、ハロゲン、C1−C4アルキル、C4−C6シクロアルキル、ヒドロキシ、C1−C4アルコキシ、C3−C5シクロアルキルオキシ、C1−C4アルコキシC1−C4アルコキシ、ジ(C1−C4アルキル)−アミノC1−C4アルコキシ、カルバモイル、N−C1−C4アルキル−カルバモイル、N,N−ジ(C1−C4アルキル)−カルバモイル、ニトロ、シアノ、カルボキシ、C1−C4アルコキシカルボニル、C1−C4アルカノイル、C1−C4アルカノイルオキシ、ベンゾイル、アミジノ、グアニジノ、ウレイド、メルカプト、C1−C4アルキルチオ、ピリジル、フェニル、フェノキシ、C1−C4アルコキシフェニル、フェニルチオ、フェニル−C1−C4アルキルチオ、C1−C4アルキルスルホニル、フェニルスルホニル、C1−C4アルキルフェニルスルホニル、C1−C4アルケニル、C1−C4アルカノイル、環の隣接する炭素原子で結合しているC1−C4アルキレンジオキシ、およびハロゲン、ヒドロキシ、C1−C4アルコキシ、ニトロ、シアノ、カルボキシ、C1−C4アルコキシカルボニル、C1−C4アルカノイルまたはC1−C4アルカノイルオキシで置換されたC1−C4アルキルからなる群から選択される。
nは好ましくは0または1を意味する。
nはとりわけ好ましくは0を意味する。
i)式(VIII)
R−Y−Z (VIII)
〔式中、Rは
Yは下記基
ZはCl、Br、Iまたはトシレートのような脱離基を意味する〕
の化合物を式(IX)
XB(OR)2 (IX)
〔式中、Xは好適にはRnで置換されているインドリル基(例えば5−インドリル、4−インドリル、5−1,3−ジヒドロ−インドール−2−オン−イル)を意味し、そしてRはHまたはC1−C4アルキルを意味するか、またはRO基が両方、それらが結合しているホウ素原子と一体となってヘテロ環式環を形成する〕
の化合物と反応させる工程;
ii)遊離塩基形または酸付加塩形の得られた式(I)の化合物を回収する工程;および
iii)所望により既知の方法、例えばキラルHPLCクロマトグラフィーで立体異性体を分離する工程
が含まれる。
i)式(X)
の化合物と反応させる工程;
ii)遊離塩基形または酸付加塩形の得られた式(I)の化合物を回収する工程;および
iii)所望により既知の方法、例えばキラルHPLCクロマトグラフィーで立体異性体を分離する工程
が含まれる。
a)1個以上の官能基、例えばカルボキシ、ヒドロキシ、アミノまたはメルカプトは、保護基によって出発物質において保護されている必要があり得る。使用する保護基は既に前駆体において存在していてもよく、望ましくない2次的反応、例えばアシル化、エーテル化、エステル化、酸化、加溶媒分解および同様の反応に対して官能基を保護しなければならない。容易に、すなわち望ましくない2次的反応なしに、典型的には加溶媒分解、還元、光分解または酵素活性によって、例えば生理的条件と同様の条件下で除去され、最終生成物には存在しないことが保護基の特徴である。当業者は、どのような保護基が本明細書の反応に好適であるか、既知であるか、または容易に確立することができる。保護基による官能基の保護、保護基そのもの、およびそれらの除去反応は、例えば標準的な参考文献、例えばJ. F. W. McOmie, “Protective Groups in Organic Chemistry”, Plenum Press, London and New York 1973、T. W. Greene, “Protective Groups in Organic Synthesis”, Wiley, New York 1981、“The Peptides”; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981、“Methoden der organischen Chemie” (Methods of organic chemistry), Houben Weyl, 4th edition, Volume 15/I, Georg Thieme Verlag, Stuttgart 1974、H.-D. Jakubke and H. Jescheit, “Aminosaeuren, Peptide, Proteine” (amino acids, peptides, proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982、およびJochen Lehmann, “Chemie der Kohlenhydrate: Monosaccharide und Derivate” (Chemistry of carbohydrates: monosaccharides and derivatives), Georg Thieme Verlag, Stuttgart 1974に記載されている。
「常套の抗精神病剤」なる用語は、本明細書において使用するとき、これらに限定されないが、ハロペリドール、フルフェナジン、チオチキセンおよびフルペンチキソールを含む。
「非典型的な抗精神病剤」なる用語は、本明細書において使用するとき、これらに限定されないが、クロザリル、リスペリドン、オランザピン、クエチアピン、ジプラシドンおよびアリピプラゾールを含む。
a)nAChR α7への親和性に関する機能的アッセイを、nAChR α7を安定的に発現するラット下垂体細胞系で行う。簡単に説明すると、組換えによってnAChR α7を発現するGH3細胞を、実験の72時間前に、黒色96ウェルプレートに播種し、37℃で湿潤雰囲気下で(5% CO2/95% 空気)インキュベートした。実験1日目に、プレートをフリックして培地を除去し、蛍光カルシウム感受性染料を含む増殖培地100μlと、2.5mMプロベネシド(Sigma)の存在下で置換した。細胞を、37℃で湿潤雰囲気下で(5% CO2/95% 空気)1時間インキュベートした。プレートをフリックして過剰のFluo−4を除去し、Hepes緩衝化塩溶液(mM:NaCl 130、KCl 5.4、CaCl2 2、MgSO4 0.8、NaH2PO4 0.9、グルコース 25、Hepes 20、pH 7.4;HBS)で2回洗浄し、適当である場合、アンタゴニストを含むHBS100μlで再度充填した。アンタゴニストの存在下でのインキュベーションを3〜5分継続した。プレートをイメージングプレートリーダーに置き、蛍光シグナルを記録した。このアッセイにおいて、本発明の化合物は約5〜約9のpEC50値を示す。この試験における部分および強力なアゴニストが好ましい。
(1)哺乳類、とりわけヒトの診断または治療処置において使用するための、とりわけアルファ−7受容体アゴニストとして使用するための、例えば1種以上の障害、とりわけ本明細書に記載の1種以上の障害の処置(緩和を含む)において使用するための、式Iの化合物および/またはその塩。
(2’)アルファ−7受容体活性化が含まれるかまたは関与する、および/またはアルファ−7受容体活性が含まれるかまたは関与する障害、とりわけ本明細書に記載の1種以上の障害のいずれかの処置または予防のための、式Iの化合物および/またはその薬学的に許容される塩、ならびに薬学的に許容される希釈剤または担体を含む医薬組成物。
(3’)処置を必要とする対象における、アルファ−7受容体活性化が含まれるかまたは関与する障害、および/またはアルファ−7受容体活性が含まれるかまたは関与する障害の処置または予防法であって、それを必要とする哺乳類に、治療上有効量の式Iの化合物、またはその薬学的に許容される塩を投与することを含んでなる方法。
AcOEt 酢酸エチル
aq. 水
EtOH エタノール
FC フラッシュクロマトグラフィー
HV 高真空
MeOH MeOH
m.p. 融点
MTBE メチルtert−ブチルエーテル
NHMDS ナトリウムヘキサメチルジシラザン
rt 室温
soln. 溶液
THF テトラヒドロフラン
実施例1 (4SR、5RS)−(1−アザ−ビシクロ[3.3.1]ノン−4−イル)−[5−(1H−インドール−5−イル)−ピリジン−2−イル]−アミン
2,5−ジブロモピリジン2.59g(10.9mmol)、tert−ブトキシドナトリウム1.57g(16.4mmol)、Pd2(dba)30.20g、およびキサントホス0.38gを乾燥トルエン40mlに溶解し、トルエン10ml中(rac.)−1−アザ−ビシクロ[3.3.1]ノン−4−イルアミン1.53g(10.9mmol)溶液で処理する。95に60分間加熱した後、反応混合物を氷に注ぎ、AcOEtで希釈する。水相をAcOEtで抽出し、合併した有機相を水および塩水で洗浄し、粉末Na2CO3で乾燥し、蒸発させる。残渣を中圧シリカゲルクロマトグラフィーでAcOEt/MeOH/NEt3 50:45:5で精製し、(4SR、5RS)−(1−アザ−ビシクロ[3.3.1]ノン−4−イル)−(5−ブロモ−ピリジン−2−イル)−アミン2.09gを、ベージュ色の粉末として得る。MS (ES+): m/e = 296/298 (MH+).
カラム:Chiralpak AD 20μm; 5×(75×21.2mm)
溶離剤:n−ヘキサン:CHCl3:MeOH 50:25:25+0.1%ジエチルアミン
流速:40ml/分
検出器:UV254nm
ピーク1:9〜13分;ピーク2:17〜30分。
分析評価:
カラム:Chiralpak AD 10 μm;4.6×250mm)
溶離剤:n−ヘキサン:CHCl3:MeOH 50:25:25+0.1%ジエチルアミン
流速:1.5ml/分
検出器:UV254nm
ピーク1:6.65分=(4R,5S)−(1−アザ−ビシクロ[3.3.1]ノン−4−イル)−[5−(1H−インドール−5−イル)−ピリジン−2−イル]−アミン;ピーク2:19.12分=(4S,5R)−(1−アザ−ビシクロ[3.3.1]ノン−4−イル)−[5−(1H−インドール−5−イル)−ピリジン−2−イル]−アミン
各々上記実施例に記載の式Iの化合物の1種を有効成分として0.05g含む5000個の軟ゼラチンカプセル剤を下記のとおり製造する:
250gの粉砕した有効成分を2リットルのLauroglykol(登録商標)(プロピレングリコールラウレート、Gattefosse S.A., Saint Priest, France)に懸濁し、湿潤粉砕機で粉砕して、約1〜3μmの粒子径とする。0.419g部の混合物をカプセル充填機を使用して軟ゼラチンカプセル剤に導入する。
Claims (9)
- 医薬として使用するための、遊離塩基形または薬学的に許容される酸付加塩形の請求項1ないし請求項7のいずれかに記載の化合物。
- 精神病および神経変性障害の予防、処置および/または進行の遅延に使用するための、遊離塩基形または薬学的に許容される酸付加塩形の請求項1ないし請求項7のいずれかに記載の化合物。
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