JP6518270B2 - Gsk−3阻害剤としての新規チアジアゾリジンジオン - Google Patents
Gsk−3阻害剤としての新規チアジアゾリジンジオン Download PDFInfo
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- JP6518270B2 JP6518270B2 JP2017000211A JP2017000211A JP6518270B2 JP 6518270 B2 JP6518270 B2 JP 6518270B2 JP 2017000211 A JP2017000211 A JP 2017000211A JP 2017000211 A JP2017000211 A JP 2017000211A JP 6518270 B2 JP6518270 B2 JP 6518270B2
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- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/08—1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles
-
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Description
グリコーゲン合成酵素キナーゼ−3(GSK−3)は、別個の遺伝子によってそれぞれコードされるαおよびβアイソフォームで構成されるセリン/スレオニンタンパク質キナーゼである(Chemistry & Biology,2000,7(10),793−803。Selective small molecule inhibitors of glycogen synthase kinase−3 modulate glycogen metabolism and gene transcription.Coghlanら;Curr.Opinion Genetics Dev.,2000,10(5),508−514.GSK3,a master switch regulating cell−fate specification and tumorigenesis.Kim,L.&Kimmel,A.R.)。GSK−3は、発育、代謝ホメオスターシス、神経の成長および分化、細胞極性、細胞運命およびアポトーシスの可能性の調整にとって重要な役割を果たす。
GSK−3活性の異常調節(通常は、増加する)は、神経変性疾患[Physiol.Rev.,2004,84,361−84.Role of tau protein in both physiological and pathological conditions.Avila,J.ら]、心血管疾患[Circ Res.,2009,104(11),1240−52;Role of glycogen synthase kinase−3beta in cardioprotection.Juhaszova M.ら;Circ J.,2009,73(7),1184−92。GSK−3beta, a therapeutic target for cardiomyocyte protection.Miura T.&Miki T.]、糖尿病[Trends.Mol.Med.,2002,8,126−32.Glycogen synthase kinase 3:an emerging therapeutic target.Eldar−Finkelman,H.]またはウイルス感染[Virus Res.,2008,132,160−73.Residues in human respiratory syncytial virus P protein that are essential for its activity on RNA viral synthesis.Asenjo,A.ら]のような異なる重要な障害に何らかの役割を果たすと考えられている。
GSK−3阻害剤のさらなる総説、およびこれらの病状に対して見込みのある治療としてのこれらの使用について、Nature Reviews,2004,3,479−487.GSK3 inhibitors:development end therapeutic potential.Cohen,P.& Goedert,M.;Mini−Reviews in Medicinal Chemistry,2009,9(9),1024−1029.GSK3 inhibitors and Disease.Hernandez,F.ら;Curr.Opin.Drug Discov.Develop.,2008,11(4),533−543.Glycogen synthase kinase−3(GSK−3)inhibitors reach the clinic.Medina,M.& Castro,A.;John Wiley & Sons,Inc.,2006.Glycogen Synthase Kinase 3(GSK−3) and its inhibitors.Chapter 14.Eds:Martinez,A.,Castro,A.& Medina,Mを参照。
小さなヘテロ環のチアジアゾリジンジオンである非可逆性GSK−3阻害剤は、アルツハイマー病および他の病状の有効な治療のための新しい疾患修飾薬として提案されてきており、この関連する事実は、これらの化合物に対する顕著な興味を与える。
Raは、ヒドロキシル、ヘテロシクリルまたはC(O)OR’によって場合により置換されていてもよい1〜3個の炭素原子を有するアルキル基であり、ここでR’は、アルキル基であり、
Rbは、−(CHR1)n−(Z)m−アリールであり、
R1は、水素、アルキルまたはC(O)OR”から選択され、ここでR”は、アルキル基であり、
Zは、−C(R2)(R3)−であり、ここでR2およびR3は、独立して、水素およびアルキルから選択され、
nは、0または1であり、
mは、1または2である)
または、これらの薬学的に許容され得る塩、溶媒和物またはプロドラッグに関する。
(1)式(II)のイソチオシアネート:
(2)式(III)のイソシアネート:
を添加することを含んでなるもの、である。
「アルキル」は、1〜6個の炭素原子、好ましくは、1〜3個の炭素原子を含み、不飽和部分を含まず、分子の残りの部分に単結合によって接続する直鎖または分枝鎖の炭化水素鎖基を指し、例えば、メチル、エチル、n−プロピル、i−プロピル、n−ブチル、t−ブチル、n−ペンチルなどである。
利用可能な手順によって、本発明の化合物を合成することができる[Martinez,A.ら,Bioorg.Med.Chem.,1997、5、1275−1283]。
(1)式(II)のイソチオシアネート:
(2)式(III)のイソシアネート:
を加えることを含んでなる。
好ましい実施形態によれば、上述の用途および治療方法において、認知機能の疾患または状態、神経変性疾患または神経変性状態、または神経の疾患または状態は、以下から選択される。すなわち、アルツハイマー病、パーキンソン病、中程度の認知機能不全、前頭側頭型認知症、ピック体に関連する前頭側頭葉変性症、ピック病、進行性核上性麻痺、亜急性硬化性全脳炎 、脳炎後パーキンソニズム、ボクシング認知症、グアムのパーキンソン認知症複合、大脳皮質基底核変性症、嗜銀顆粒性疾患、家族性前頭側頭型認知症およびtau遺伝子の変異に起因する17番染色体(FTDP−17−tau)に関連するパーキンソニズム、AIDSに関連する認知症、ハンチントン病、レビー小体疾患、双極性障害、鬱病、統合失調症、てんかん、気分障害、自閉症、注意欠陥多動性障害、ダウン症候群、脆弱X症候群(FXS)、虚血/再潅流、ショック、脳損傷、多発性硬化症、CNSに罹患する自己免疫疾患および炎症性疾患、脊髄小脳変性症1型、孤立性脳アミロイド血管症に起因する脳出血、筋萎縮性側索硬化症、プリオン病、ゲルストマン・ストロイスラー・シャインカー病、ハラーフォルデン−シュパッツ病、多系統萎縮症および筋緊張性ジストロフィーから選択される。
本発明は、さらに、患者に投与するための、本発明の式(I)の化合物、またはその塩、溶媒和物またはプロドラッグと、少なくとも1つの薬学的に許容され得る担体、アジュバント、および/またはビヒクルとを含む医薬組成物を提供する。
−バインダー、例えば、トウモロコシデンプン、アルファ化トウモロコシデンプン、ポビドン、ゼラチンなど。
−希釈剤またはフィラー、例えば、微結晶性セルロース、ラクトース、リン酸ナトリウム、二塩基性リン酸カルシウム二水和物、二塩基性リン酸カルシウム無水物(Emcompress、Di−tab、Di−cal−fos)など。
−崩壊剤、例えば、クロスカルメロースナトリウム(Acdisol、Explocel、Vivasol)、ナトリウムデンプングリコレート(Glycolis、Explotab、Primojel、Vivastar)、架橋したポビドン、ゴムなど。
−滑剤、例えば、タルクまたはコロイド状シリカ。
−滑沢剤、例えば、ステアリン酸マグネシウム、ステアリン酸、フマル酸ステアリルナトリウムなど。
−膜形成剤、例えば、ヒドロキシプロピルセルロース(Klucel、Metocel)、ヒプロメロース(Metocel、Metolose、Pharmacoat)、ヒドロキシ−プロピルメチルセルロースなど。
−乳白剤、例えば、二酸化チタン。
−着色剤、例えば、サンセットイエロー、酸化鉄、インジゴカルミン、エリスロシンなど。
−可塑剤、例えば、ポリエチレングリコールトリアセチンなど。
−酸性化剤、例えば、クエン酸。
−緩衝化剤、例えば、クエン酸、クエン酸ナトリウム。
−希釈剤またはフィラー、例えば、マンニトール(Pearlitol)、ソルビトール(Neosorb、Parteck)、スクロース、マルトース(Advantose)など。
−甘味剤、例えば、スクラロース、アスパルテーム、アセスルファム、ナトリウムサッカリンなど。
−滑剤、例えば、コロイド状二酸化ケイ素(Aerosil,Cabosil,Aeroperl)。
−香味剤、例えば、ストロベリーフレーバー、レモンフレーバー、コーラフレーバー、オレンジフレーバーなど
−増粘剤または安定化剤、例えば、改質セルロース(ヒドロキシプロピルセルロース、カルボキシメチルセルロースナトリウム)、ポビドン、ゴムなど。
−抗菌性および溶媒剤、例えば、エタノール、プロピレングリコールなど。
−甘味剤、例えば、ソルビトールまたはスクロース。
−抗菌性防腐剤、例えば、安息香酸ナトリウム、ソルビン酸カリウム。
−酸性化剤、例えば、クエン酸またはアスコルビン酸。
−緩衝化剤、例えば、クエン酸およびクエン酸ナトリウム、ホスフェート、酢酸および酢酸ナトリウム。
−香味剤、例えば、バニラフレーバー、ストロベリーフレーバー、コーラフレーバー、ピーチフレーバーなど。
−着色剤、例えば、タートラジン、クルクミン、キノリンイエロー、サンセットイエローなど。
−希釈剤、例えば、微結晶性セルロース、ラクトース、炭酸カルシウム、二塩基性リン酸カルシウム、一塩基性リン酸カルシウム、硫酸カルシウム。
−崩壊剤、例えば、ナトリウムデンプングリコレート、架橋したポビドン。
−滑沢剤、例えば、タルク、ステアリン酸マグネシウム、ステアリン酸、フマル酸ステアリルナトリウム、ポリエチレングリコールなど。
−カプセルフィラー、例えば、微結晶性セルロース、白糖球状顆粒。
−バインダーおよび膜形成剤、例えば、コポリマー、メタクリル酸、ポリマーメタクリレート(Eudragit、Kollicoat)。
−可塑剤および膜形成剤、例えば、フタル酸ジブチル。
−着色剤、例えば、エリスロシン、サンセットイエロー、インジゴカルミンなど。
−溶媒、例えば、アセトン、イソプロピルアルコールなど。
−抗菌性防腐剤、例えば、メチルパラベン、プロピルパラベンなど。
−酸化防止剤、例えば、メタ重亜硫酸ナトリウム、没食子酸プロピルなど。
−安定化剤および懸濁剤、例えば、可溶性または膨潤性になるように調整されたセルロース、例えば、カルボキシメチルセルロースナトリウム(Aquasorb、Blanose、Nymcel)。
−等張化剤、例えば、塩化ナトリウム。
−可溶化剤、例えば、プロピレングリコールまたはポリエチレングリコール。
実施例1:一般化手順
方法A:
1H NMR(400MHz,CDCl3,δ ppm):7.37(m,3H),7.31(m,2H),4.78(s,2H),3.77(q,J=7.18Hz,2H),1.29 (t,J=7.17Hz,3H)。
13C NMR(100MHz,CDCl3,δ ppm):165.83,153.07,134.56,129.01,128.77,128.43,48.60,37.84,13.17。
MS (ES+):m/z=237(M+H)+。
1H NMR(400MHz,DMSO−d6,δ ppm):7.36(m,5H),4.80(AB System,SAB=15.6Hz,2H),4.12(m,1H),3.67(m,3H),3.54(dd,J=13.79,4.90Hz,1H),1.85(m,3H),1.60(m,1H)。
13C NMR(100MHz,DMSO−d6,δ ppm):165.65,152.77,135.42,128.69,128.12,127.96,74.43,66.88,47.34,45.50,28.42,24.68。
MS (ES+):m/z=293(M+H)+。
1H NMR(400MHz,DMSO−d6,δ ppm):7.31(m,3H),7.22(m,2H),4.62(dd,J=7.0,5.0Hz,1H),4.20(q,J=7.07Hz,2H),3.05(ABX system,JAB=13.8Hz,2H),1.23(t,J=7.12Hz,3H)。
13C NMR(100MHz,DMSO−d6,δppm):170.30,135.72,129.26,128.25,126.94,126.32,62.06,57.75,38.45,13.84。
1H NMR(400MHz,DMSO−d6,δ ppm):7.27(m,5H),5.26(dd,J=10.3,5.3Hz,1H),4.34(AB System,SAB=17.2Hz,2H),4.14(m,4H),3.32(dd,J=14.5,5.3Hz,1H),3.10(dd,J=14.5,10.3Hz,1H),1.18(t,J=7.1Hz,3H),1.18(t,J=7.1Hz,3H)。
13C NMR(100MHz,DMSO−d6,δ ppm):168.53,166.38,165.59,152.13,135.60,128.89,128.39,126.93,61.63,61.40,57.68,42.34,35.38,13.81,13.77。
MS (ES+):m/z=381(M+H)+。
13C−NMR(100MHz,CDCl3,δ ppm):163.63,139.28,61.57,54.52,14.11。
1H NMR(400MHz,DMSO−d6,δ ppm):8.01(m,2H),7.69(tt,J=7.4,1.2Hz,1H),7.56(t,J=7.4Hz,2H),4.50(t,J=4.8Hz,2H),4.06(t,J=4.8Hz,2H)。
13C NMR(100MHz,DMSO−d6,δ ppm):165.22,133.53,129.14,129.10,128.72,62.62,44.42。
方法B:最終生成物を白色固体として得た。収率85%。
方法C:最終生成物を白色固体として得た。収率92%。
1H NMR(400MHz,DMSO−d6,δ ppm):7.93(m,2H),7.66(tt,J=7.6,1.2Hz,1H),7.51(m,2H),7.32(m,3H),7.26(m,2H),4.79(s,2H),4.50(t,J=5.2Hz,2H),4.02(t,J=5.2Hz,2H)。
13C NMR(100MHz,DMSO−d6,δ ppm):165.75,165.48,152.55,135.40,133.32,129.25,129.11,128.59,128.03,127.78,61.25,47.20,41.20。
13C−NMR(100MHz,CDCl3,δ ppm):166.61,136.27,133.34,130.12,129.91,128.63,63.36,52.67。
1H NMR(400MHz,DMSO−d6,δ ppm):7.41−7.31(m,5H),4.91(t,J=5.85Hz,1H),4.80(s,2H),3.66(m,2H),3.58(m,2H).
13C NMR(100MHz,DMSO−d6,δ ppm):165.77,152.87,135.47,128.67,128.09,127.96,57.08,47.33,44.58。
MS (ES+):m/z=253(M+H)+。
実施例9:GSK−3アッセイ
Life Technologies(カールスバッド、CA、USA)から入手可能なZ’−LYTE(登録商標)技術に基づく市販のシステムを用い、Millipore(ビレリカ、MA、USA)製のヒト組み換えGSK3β(H350L変異を有する、N末端6Hisがタグ化された組み換え酵素)を酵素源として用い、GSK3βの酵素活性を決定した。この技術は、フルオレセインとクマリンの蛍光共鳴エネルギー移動(「FRET」)過程を利用している。このアッセイの原理は、リン酸化ペプチドと非リン酸化ペプチドの蛋白質分解開裂に対する感受性の差に基づき、開裂部位の両側に接続する2個のフルオロフォア間のエネルギー移動過程が起こらないようにする。したがって、GSK3βのリン酸化によってホスホペプチドを得て、このホスホペプチドは、適切なプロテアーゼによって加水分解することができず、2個のフルオロフォア間のエネルギー移動が起こるだろう。逆に、リン酸化が不足すると、ペプチドの加水分解が起こるため、エネルギー移動がなくなる。このアッセイは、384ウェルブラックプレート中、最終的な容積10μlで行われ、50mM Hepes(pH7.5)中の酵素濃度2nM、50mM MgCl2、5mM EGTAおよび0.05% Brij−35を含み、12.5μM ATPおよび2μM基質ペプチドを含む。後者は合成ペプチドであり、Invitrogenによって商品名「Ser/Thr 9ペプチド」で与えられ、Ser−641を含むGSK3β基材タンパク質(グリコーゲンシンターゼI)の配列に由来する。このペプチドは、末端がフルオレセインおよびクマリンで標識されている。異なる濃度の試験化合物存在下、最終DMSO濃度1%(v/v)でアッセイを行う。室温で60分間インキュベーションした後、5μlの市販のプロテアーゼ溶液(アッセイキットと同じ業者によって販売)を加え、その後、室温で1時間のインキュベーションを行った後、適切なキットと同じ業者によって提供される「停止溶液」5μlを加えた。その後に、蛍光強度を記録し、400nmで励起させたときに、445nmおよび520nmで発光をモニタリングした。445nmでの発光を520nmでの発光で割った商を用い、発光比を最終的に計算する。
実施例10:TDZDの熱力学的溶解度
pH7.4の0.01Mリン酸緩衝化食塩水溶液(PBS)中、化合物濃度2mg/mLで、混合時間が24時間の各サンプル2つずつの熱力学的溶解度を決定した。分析および定量をLC−UVによって行った。それぞれの化合物について、アセトニトリル中、濃度1.0、0.1、0.01および0.001mg/mLで検量線を調製した。
実施例11:脳および血漿の曝露およびバイオアベイラビリティ
いくつかの式(I)の化合物と、比較化合物として以前のTDTD(化合物5)について、マウスでの薬物動態挙動を評価した。オスC57BL6Jマウス(20〜25g、8週齢、Harlan)を使用し、薬物動態試験を行った。強制経口投与(投薬量200mg/kg)によって、それぞれの薬物を、25%のPEG 400、15%のcremophorおよび適量の蒸留水の混合物に懸濁させた。血液および脳のサンプル(各サンプル点について、n=2マウス)を、特定の時間点である投薬後0.25、0.5、1、2、4、6、8および24時間で集めた。静脈投与(投薬量1mg/kg)も行い、経口投与のバイオアベイラビリティを決定した(時間点0.03、0.08、0.16、0.5、1、2および4時間;投薬量1mg/kg、1mL/kg)。
懸濁物のための粉末
−バイアルへの活性成分の充填
希釈剤
−メチルパラベン、プロピルパラベン、メタ重亜硫酸ナトリウム、塩化ナトリウムをプロピレングリコールに溶解する。適切な時間混合する。
−注射用蒸留水を加え、適切な時間混合する。
−濾過によって滅菌し、バイアルに充填する。
注射用懸濁物に適した賦形剤のリストは、上に詳細に記載した。
−ポビドンK−25を水に溶解した顆粒化溶液を調製する。
−活性成分、トウモロコシデンプン、アルファ化したトウモロコシデンプンおよび微結晶性セルロースを混合する。
−顆粒化溶液を用いて顆粒化する。
−乾燥。
−乾燥した顆粒を、適切なメッシュ径でふるい分けする。
−ラクトース、クロスカルメロースナトリウムおよびタルクを加える。
−適切な時間混合する。
−ステアリン酸マグネシウムを加える。
−適切な時間混合する。
−最終的なブレンドが終わったら、錠剤化する準備が完了する。
−錠剤の圧縮
−膜コーティング
コーティングされた錠剤に適切な賦形剤のリストは、上に詳細に記載している。
−すべての成分を適切なメッシュ径に通す。
−成分を適切なミキサーで混合する。
−最終的なブレンドを容器に取り出す。
−ブレンドを投薬量ごとに小袋に分ける。
経口溶液のための粉末に適切な賦形剤のリストは、上に詳細に記載している。
−プロピレングリコールおよびエタノールを適切な容器に入れる。
−安息香酸ナトリウムを完全に溶解するまで加える。
−クエン酸およびクエン酸ナトリウムを加え、完全に溶解するまで混合する。
−活性成分を加え、均一になるまで混合する。
−ソルビトールを加え、均一になるまで混合する。
−精製水を加え、均一になるまで混合する。
−バニラフレーバーおよびタートラジンを加え、均一になるまで混合する。
−シロップの塊が完成したら、ガラスまたはプラスチックの瓶に入れる準備が完了。
シロップに適切な賦形剤のリストは、上に詳細に記載している。
−すべての成分を適切なメッシュ径に通す。
−活性成分、微結晶性セルロース、リン酸カルシウムおよびタルクを適切なミキサーに入れる。
−適切な時間混合する。
−ステアリン酸マグネシウムを加える。
−適切な時間混合する。
−最終的なブレンドが完成したら、ゼラチンカプセル(適切な大きさ)に、投薬量に分ける準備が完成。
カプセルに適切な賦形剤のリストは、上に詳細に記載している。
−エリスロシン、フタル酸ジブチルおよびコポリマーメタクリル酸を、アセトン+イソプロピルアルコールに溶解する。
−活性成分およびポロキサマーを加え、上の溶液に溶解する。
−微結晶性セルロース球を流体床乾燥器に入れる。
−セルロース球にコーティング溶液を噴霧する。
−コーティング溶液を完全に噴霧したら、顆粒を乾燥する。
−乾燥したら、適切な容器に取り出す。
−コーティングされた球を含むゼラチンカプセルを充填する。
腸溶性カプセルに適切な賦形剤のリストは、上に詳細に記載している。
Claims (9)
- 置換基Rb中のアリール基がフェニルである、請求項1に記載の化合物。
- mが1である、請求項1または2のいずれか一項に記載の化合物。
- R2およびR3が水素である、請求項1〜3のいずれか一項に記載の化合物。
- 請求項1〜5のいずれか一項に記載の式(I)の化合物、またはその塩または溶媒和物と、少なくとも1つの薬学的に許容され得る担体、アジュバント、および/またはビヒクルとを含む、医薬組成物。
- 認知機能の疾患または状態、神経変性疾患または神経変性状態、または神経の疾患または状態の治療に使用するための、請求項6に記載の医薬組成物。
- 糖尿病、炎症性疾患および自己免疫性疾患、心血管障害から選択される疾患または状態、およびメタボリックシンドロームX、脱毛症、コロナウイルスによる重症呼吸器症候群、コカイン中毒、骨量の減少および緑内障から選択される病状の治療に使用するための、請求項6に記載の医薬組成物。
- 請求項1〜5のいずれか一項に記載の式(I)の化合物、またはその塩または溶媒和物を含む、GSK−3の阻害を必要とするin vitro生物学的アッセイにおける反応物。
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HUE057521T2 (hu) | 2013-03-14 | 2022-05-28 | Brigham & Womens Hospital Inc | Készítmények és eljárások epithelialis õssejtek szaporítására és tenyésztésére |
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EP3189134A1 (en) | 2014-09-03 | 2017-07-12 | The Brigham and Women's Hospital, Inc. | Compositions, systems, and methods for generating inner ear hair cells for treatment of hearing loss |
EP3400286A1 (en) | 2016-01-08 | 2018-11-14 | Massachusetts Institute Of Technology | Production of differentiated enteroendocrine cells and insulin producing cells |
US10213511B2 (en) | 2016-03-02 | 2019-02-26 | Frequency Therapeutics, Inc. | Thermoreversible compositions for administration of therapeutic agents |
US10201540B2 (en) | 2016-03-02 | 2019-02-12 | Frequency Therapeutics, Inc. | Solubilized compositions for controlled proliferation of stem cells / generating inner ear hair cells using GSK3 inhibitors: I |
US11260130B2 (en) | 2016-03-02 | 2022-03-01 | Frequency Therapeutics, Inc. | Solubilized compositions for controlled proliferation of stem cells / generating inner ear hair cells using a GSK3 inhibitor: IV |
CA3048220A1 (en) | 2016-12-30 | 2018-07-05 | Frequency Therapeutics, Inc. | 1h-pyrrole-2,5-dione compounds and methods of using them to induce self-renewal of stem/progenitor supporting cells |
US11162071B2 (en) | 2018-08-17 | 2021-11-02 | Frequency Therapeutics, Inc. | Compositions and methods for generating hair cells by upregulating JAG-1 |
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