JP2015526475A - ベンゾフラザン抗アミロイド化合物および方法 - Google Patents
ベンゾフラザン抗アミロイド化合物および方法 Download PDFInfo
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- JP2015526475A JP2015526475A JP2015528656A JP2015528656A JP2015526475A JP 2015526475 A JP2015526475 A JP 2015526475A JP 2015528656 A JP2015528656 A JP 2015528656A JP 2015528656 A JP2015528656 A JP 2015528656A JP 2015526475 A JP2015526475 A JP 2015526475A
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 86
- 238000000034 method Methods 0.000 title claims abstract description 24
- AWBOSXFRPFZLOP-UHFFFAOYSA-N 2,1,3-benzoxadiazole Chemical compound C1=CC=CC2=NON=C21 AWBOSXFRPFZLOP-UHFFFAOYSA-N 0.000 title 1
- -1 benzylamino, N-methylbenzylamino Chemical group 0.000 claims abstract description 133
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 33
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 9
- 238000011282 treatment Methods 0.000 claims abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 6
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/12—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4245—Oxadiazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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Abstract
Description
本出願は、2012年8月24日に出願された米国仮出願第61/693,011号の利益を主張するものであり、該仮出願は参照によってその全体が本明細書に組み込まれる。
式中、R11は、ベンジルアミノ、N−メチルベンジルアミノ、N−メチル(4−フルオロベンジル)アミノ、N−メチル(4−メトキシベンジル)アミノ、N−メチル(3,5−ジメトキシベンジル)アミノ、N−メチル(ピリジン−2−イル)アミノ、N−メチル(ピリジン−3−イル)アミノ、ピペリジノ、4−メチルピペラジン−1−イル、モルホリノ、チオモルホリノ、ピロリジノ、3−メチルピロリジン−1−イル、3−メトキシピロリジン−1−イル、ピロリジン−3−オール−1−イル、2−(2−メタノール−1−イル)ピロリド−1−イル、2−(ピロリジン−1−イルメチル)ピロリジン−1−イル、2−(2−プロパノール−2−イル)ピロリジン−1−イル、イソインドリン−2−イル、4−(ピロリジン−1−イル)ピペリジン−1−イル、Ν,Ν−ジエチルアミノ、N−メチル−N−エチルアミノ、N−メチル−N−イソプロピルアミノ、N−メチル−N−シクロプロピルアミノ、N−メチル−N−エチニルアミノ、N−(2−メトキシエチル)−N−メチルアミノ、N−(チアゾール−2−イルメチル)−N−メチルアミノ、アゼチジン−1−イル、3−メチル−3−オール−アゼチジン−1−イル、3−(エタノール−2−イル)アゼチジン−1−イル、3−メトキシアゼチジン−1−イル、3−ヒドロキシアゼチジン−1−イル、3−エトキシアゼチジン−1−イル、3−イソプロポキシアゼチジン−1−イル、3−(2−プロパノール−2−イル)アゼチジン−1−イル、3−(モルホリノメチル)アゼチジン−1−イル、3−モルホリノアゼチジン−1−イル、3−(ピロリジン−1−イル)アゼチジン−1−イル、3−(ピロリジン−1−イルメチル)アゼチジン−1−イル、または3−(1−メトキシエチル)アゼチジン−1−イルであり;
R13は、3−(1−エタノール−2−イル)フェニル、3−(1−オール−2,2,2−トリフルオロエタン−2−イル)フェニル、2−(1−オール−2,2,2−トリフルオロエタン−2−イル)フェニル、4−(1−オール−2,2,2−トリフルオロエタン−2−イル)フェニル、3−(3−オール−オキセタン−3−イル)フェニル、3−メタノニルフェニル、3−((ピペラジン−1−イル)メタノン−2−イル)フェニル、3−((モルフォリン−1−イル)メタノン−2−イル)フェニル、3−((ピロリジン−1−イル)メタノン−2−イル)フェニル、3−((N−シクロプロピル)アミド−2−イル)フェニル、メタノニル、トリフルオロメタノニル、1−オール−2,2,2−トリフルオロエタン−2−イル、3−オール−オキセタン−3−イル、(1−オール−2,2,2−トリフルオロエタン−2−イル)チオフェン−2−イル、1−オール−プロパ−2−エン−3−イル、2−オール−ブタ−3−エン−4−イル、または2−オール−2−トリフルオロメチル−(1,1,1−トリフルオロ)ブタ−3−エン−4−イルであり;
R12およびR14はそれぞれ独立して水素またはアルキルである。
式中、R11は、ベンジルアミノ、N−メチルベンジルアミノ、N−メチル(4−フルオロベンジル)アミノ、N−メチル(4−メトキシベンジル)アミノ、N−メチル(3,5−ジメトキシベンジル)アミノ、N−メチル(ピリジン−2−イル)アミノ、N−メチル(ピリジン−3−イル)アミノ、ピペリジノ、4−メチルピペラジン−1−イル、モルホリノ、チオモルホリノ、ピロリジノ、3−メチルピロリジン−1−イル、3−メトキシピロリジン−1−イル、ピロリジン−3−オール−1−イル、2−(2−メタノール−1−イル)ピロリド−1−イル、2−(ピロリジン−1−イルメチル)ピロリジン−1−イル、2−(2−プロパノール−2−イル)ピロリジン−1−イル、イソインドリン−2−イル、4−(ピロリジン−1−イル)ピペリジン−1−イル、Ν,Ν−ジエチルアミノ、N−メチル−N−エチルアミノ、N−メチル−N−イソプロピルアミノ、N−メチル−N−シクロプロピルアミノ、N−メチル−N−エチニルアミノ、N−(2−メトキシエチル)−N−メチルアミノ、N−(チアゾール−2−イルメチル)−N−メチルアミノ、アゼチジン−1−イル、3−メチル−3−オール−アゼチジン−1−イル、3−(エタノール−2−イル)アゼチジン−1−イル、3−メトキシアゼチジン−1−イル、3−ヒドロキシアゼチジン−1−イル、3−エトキシアゼチジン−1−イル、3−イソプロポキシアゼチジン−1−イル、3−(2−プロパノール−2−イル)アゼチジン−1−イル、3−(モルホリノメチル)アゼチジン−1−イル、3−モルホリノアゼチジン−1−イル、3−(ピロリジン−1−イル)アゼチジン−1−イル、3−(ピロリジン−1−イルメチル)アゼチジン−1−イル、および3−(1−メトキシエチル)アゼチジン−1−イルからなる群から選択され;
R13は、3−(1−エタノール−2−イル)フェニル、3−(1−オール−2,2,2−トリフルオロエタン−2−イル)フェニル、2−(1−オール−2,2,2−トリフルオロエタン−2−イル)フェニル、4−(1−オール−2,2,2−トリフルオロエタン−2−イル)フェニル、3−(3−オール−オキセタン−3−イル)フェニル、3−メタノニルフェニル、3−((ピペラジン−1−イル)メタノン−2−イル)フェニル、3−((モルフォリン−1−イル)メタノン−2−イル)フェニル、3−((ピロリジン−1−イル)メタノン−2−イル)フェニル、3−((N−シクロプロピル)アミド−2−イル)フェニル、メタノニル、トリフルオロメタノニル、1−オール−2,2,2−トリフルオロエタン−2−イル、3−オール−オキセタン−3−イル、(1−オール−2,2,2−トリフルオロエタン−2−イル)チオフェン−2−イル、1−オール−プロパ−2−エン−3−イル、2−オール−ブタ−3−エン−4−イル、および2−オール−2−トリフルオロメチル−(1,1,1−トリフルオロ)ブタ−3−エン−4−イルからなる群から選択され;
R12およびR14はそれぞれ独立して水素またはアルキルである。いくつかの実施形態において、R11は、ベンジルアミノ、N−メチルベンジルアミノ、N−メチル(4−フルオロベンジル)アミノ、ピロリジノ、イソインドリン−2−イル、および4−(ピロリジン−1−イル)ピペリジン−1−イルからなる群から選択され;R13は、3−(1−エタノール−2−イル)フェニルおよび3−(1−オール−2,2,2−トリフルオロエタン−2−イル)フェニルからなる群から選択される。
別途定義がない限り、本明細書で用いられる用語は、以下で詳細に記述される以下の定義を差す。
本発明は種々の立体異性体およびそれらの混合物を企図しており、それらは本発明の範囲内に明確に含まれる。立体異性体には、鏡像異性体およびジアステレオマー、並びに鏡像異性体またはジアステレオマーの混合物が含まれる。本発明の化合物の個々の立体異性体は、不斉中心もしくはキラル中心を含有する市販の出発物質から合成によって、または当業者に周知のラセミ混合物を調製した後の分割によって、調製されてもよい。これらの分割方法は、(1)Furniss,Hannaford,Smith,and Tatchell,“Vogel’s Textbook of Practical Organic Chemistry”,5th edition(1989),Longman Scientific & Technical,Essex CM20 2JE,Englandに記載される、鏡像異性体の混合物のキラル補助基への付着、得られたジアステレオマー混合物の再結晶もしくはクロマトグラフィーによる分離、および光学的に純粋な産物の該補助基からの任意の遊離、または(2)キラルクロマトグラフィーカラム上での光学対掌体混合物の直接分離、または(3)分別再結晶法によって例証される。
特に記載がない限り、
基内に存在するキラル中心を含有する「TRV−」で示される化合物IDは、そのそれぞれのキラル中心に関するラセミ混合物として合成および試験された。以下の合成スキームおよび記載された手順を用いて、本発明の化合物は合成された。
1H NMR (DMSO, 500 MHz) δ = 7.91 (s, 1H), 7.83 (d, J = 10 Hz, 1H), 7.59 (d, J = 10 Hz, 1H), 7.55 (t, J = 10 Hz, 1H), 7.50 (s, 1H), 6.97 (d, J = 5 Hz, 1H), 6.73 (s, 1H), 5.31−5.26 (m, 1H), 4.20 (d, J = 10 Hz, 2H), 3.16 (t, J = 10 Hz, 2H), 2.52 (s, 4H), 2.26−2.22 (m, 1H), 2.00 (d, J = 10 Hz, 2H), 1.67 (s, 4H), 1.63−1.56 (m, 2H).
DCM(5mL)中の前述の材料(190mg、0.55mmol)およびルパート試薬(150mg、1.1mmol)の撹拌溶液に、0℃でTBAF(0.1mL、1M THF、0.1mmol)を加えた。低温で30分後、冷浴を取り除き、反応を室温にした。3時間後、過剰のTBAFを加え、反応をDCMで希釈した。有機相を飽和NH4Cl、ブラインで洗浄し、次にMgSO4で乾燥、真空下で濃縮した。粗材料をSiO2(DCM)のプラグに通し、次にフラッシュカラムクロマトグラフィー(2:1DCM/Hex)によって精製した。1H NMR (500 MHz, CDCl3) δ = 7.84 (s, 1H), 7.77 (dt, J = 7 Hz, 2 Hz, 1H), 7.60 (m, 2H), 7.43 (m, 4H), 7.23 (s, 1H), 6.25 (s, 1H), 5.31 (s, 4H), 5.2 (m, 1H), 2.68 (s, 1H).
以下の方法論を用いた:
Αβ40(1.0mg)を1.5mLミクロチューブ内でHFIP(1mL)で前処理し、20分間超音波処理して、事前に形成されたあらゆるΑβ凝集物を分解した。HFIPをアルゴン流で除去し、Αβをトリス塩基(5.8mL、20mM、pH〜10)に溶解させた。pHを濃HC1(〜10μl)で7.4に調整し、その溶液を、使用前にシリンジフィルター(0.2μm)を用いて濾過した。
Αβ凝集に対する動態学的ThTアッセイは、Chalifour et al(Chalifour et al, 2003, J. Biol. Chem. 278 :34874−81)のそれと同様である。簡潔に説明すると、事前処理したΑβ40またはΑβ42(20mM Tris中40μΜ、pH7.4)を、等量の、Tris中8μΜチオフラビンT(ThT)(20mM、pH7.4、300mM NaCl)で希釈した。Αβ/ThT(200μl)の一定分量を黒色ポリスチレン96ウェルプレートのウェルに加え、その後、2μLのDMSO中化合物(種々の濃度)、またはDMSO単独(対照)を加えた。インキュベーションを3連で行い、20μΜ Αβ、20mM Tris(pH7.4)中の種々の濃度の化合物、150mM NaCl、1%DMSOを含有させた。プレートを透明なポリスチレン製の蓋で覆い、Tecan Geniosマイクロプレートリーダーにおいて37℃でインキュベートした。
タウ凝集に対する動態学的ThSアッセイは、ThTの代わりにThioflavinS(ThS)が使用され、タウタンパク質がΑβの代わりに使用される以外は、概ね上記の手順に従う。
ThTおよびThS凝集アッセイの解析
各読み取りの前にまず15秒間激しく振盪し、10秒間静置させた後に、蛍光読み取り(λex=450nm、λem=480nm)を15分毎に行った。活性化合物は、対照において起こった経時的な蛍光の増加を減弱させた。図1〜図7において、この手順が実行された期間は80時間(X軸の右端部)にまで及び、その時点で、蛍光の増加は漸近線に概ね達した。80時間におけるDMSO対照を100%凝集(0%阻害)として、および0時間におけるDMSO対照を0%凝集(100%阻害)として定義することで、所与の濃度の化合物について、高い程良い%阻害スコアを算出することができる。いくつかの濃度にわたってこの手順を繰り返すことで、いくつかの化合物についての以下の表に記載される、平均阻害濃度(IC50)を測定することができる。
下記のアッセイはH. LeVine III. Biotin−avidin interaction−based screening assay for Alzheimer’s β−peptide oligomer inhibitors, Anal. Biochem. 356 (2006) 265−272およびA. Frey, B. Meckelein, D. Externest, M.A. Schmidt. A stable and highly sensitive 3,3’,5,5’−tetramethylbenzidine−based substrate reagent for enzyme−linked immunosorbent assays, J. Immunol. Methods 233 (2000) 47−56からの出典であった。
Claims (11)
- 式Iの化合物またはその薬剤的に許容できる塩であって、
R11は、ベンジルアミノ、N−メチルベンジルアミノ、N−メチル(4−フルオロベンジル)アミノ、N−メチル(4−メトキシベンジル)アミノ、N−メチル(3,5−ジメトキシベンジル)アミノ、N−メチル(ピリジン−2−イル)アミノ、N−メチル(ピリジン−3−イル)アミノ、ピペリジノ、4−メチルピペラジン−1−イル、モルホリノ、チオモルホリノ、ピロリジノ、3−メチルピロリジン−1−イル、3−メトキシピロリジン−1−イル、ピロリジン−3−オール−1−イル、2−(2−メタノール−1−イル)ピロリド−1−イル、2−(ピロリジン−1−イルメチル)ピロリジン−1−イル、2−(2−プロパノール−2−イル)ピロリジン−1−イル、イソインドリン−2−イル、4−(ピロリジン−1−イル)ピペリジン−1−イル、N,N−ジエチルアミノ、N−メチル−N−エチルアミノ、N−メチル−N−イソプロピルアミノ、N−メチル−N−シクロプロピルアミノ、N−メチル−N−エチニルアミノ、N−(2−メトキシエチル)−N−メチルアミノ、N−(チアゾール−2−イルメチル)−N−メチルアミノ、アゼチジン−1−イル、3−メチル−3−オール−アゼチジン−1−イル、3−(エタノール−2−イル)アゼチジン−1−イル、3−メトキシアゼチジン−1−イル、3−ヒドロキシアゼチジン−1−イル、3−エトキシアゼチジン−1−イル、3−イソプロポキシアゼチジン−1−イル、3−(2−プロパノール−2−イル)アゼチジン−1−イル、3−(モルホリノメチル)アゼチジン−1−イル、3−モルホリノアゼチジン−1−イル、3−(ピロリジン−1−イル)アゼチジン−1−イル、3−(ピロリジン−1−イルメチル)アゼチジン−1−イル、3−(1−メトキシエチル)アゼチジン−1−イル、N−(3−(N,N−ジメチルアミノ)プロピル)−N−メチルアミノ、および4−(N,N−ジメチルアミノ)ピペリジン−1−イルからなる群から選択され;
R13は、3−(1−エタノール−2−イル)フェニル、3−(1−オール−2,2,2−トリフルオロエタン−2−イル)フェニル、2−(1−オール−2,2,2−トリフルオロエタン−2−イル)フェニル、4−(1−オール−2,2,2−トリフルオロエタン−2−イル)フェニル、3−(3−オール−オキセタン−3−イル)フェニル、3−メタノニルフェニル、3−((ピペラジン−1−イル)メタノン−2−イル)フェニル、3−((モルフォリン−1−イル)メタノン−2−イル)フェニル、3−((ピロリジン−1−イル)メタノン−2−イル)フェニル、3−((N−シクロプロピル)アミド−2−イル)フェニル,メタノニル、トリフルオロメタノニル、1−オール−2,2,2−トリフルオロエタン−2−イル、3−オール−オキセタン−3−イル、(1−オール−2,2,2−トリフルオロエタン−2−イル)チオフェン−2−イル、1−オール−プロパ−2−エン−3−イル、2−オール−ブタ−3−エン−4−イル、および2−オール−2−トリフルオロメチル−(1,1,1−トリフルオロ)ブタ−3−エン−4−イルからなる群から選択され;
R12およびR14はそれぞれ、独立して水素またはアルキルである、
上記化合物またはその薬剤的に許容できる塩。 - 式Iの化合物であって、
式中、R11はベンジルアミノ、N−メチルベンジルアミノ、N−メチル(4−フルオロベンジル)アミノ、ピロリジノ、イソインドリン−2−イル、4−(ピロリジン−1−イル)ピペリジン−1−イル、3−メチル−3−オール−アゼチジン−1−イル、3−(エタノール−2−イル)アゼチジン−1−イル、3−メトキシアゼチジン−1−イル、3−ヒドロキシアゼチジン−1−イル、および3−エトキシアゼチジン−1−イルからなる群から選択され;
R13は3−(1−エタノール−2−イル)フェニルおよび3−(1−オール−2,2,2−トリフルオロエタン−2−イル)フェニルからなる群から選択される、
式Iの化合物。 - 式Iの化合物であって、
式中、R11はベンジルアミノ、N−メチルベンジルアミノ、N−メチル(4−フルオロベンジル)アミノ、ピロリジノ、イソインドリン−2−イル、4−(ピロリジン−1−イル)ピペリジン−1−イル、3−メチル−3−オール−アゼチジン−1−イル、3−(エタノール−2−イル)アゼチジン−1−イル、3−メトキシアゼチジン−1−イル、3−ヒドロキシアゼチジン−1−イル、および3−エトキシアゼチジン−1−イルからなる群から選択される、
式Iの化合物。 - 65%以上のΑβ40(20μm)の阻害率を有する、請求項1に記載の化合物。
- 請求項1〜2のいずれか一項に記載の治療有効量の化合物を対象に投与することを含む、対象におけるアミロイド疾患を治療する方法。
- アミロイド疾患がアルツハイマー病である、請求項5に記載の方法。
- アミロイド疾患が進行性核上性麻痺である、請求項5に記載の方法。
- 請求項1〜3のいずれか一項に記載の化合物および薬剤的に許容できる担体を含む、医薬組成物。
- 記憶喪失、認知喪失およびそれらの組み合わせから選択される構成要素である状態を治療するための方法であって、治療を必要とする対象に、請求項1〜3のいずれか一項に記載の治療有効量の化合物を投与することを含む、上記方法。
- 前記状態がアルツハイマー病と関連する、請求項9に記載の方法。
- 約0.0003〜約50mg/体重kgの合計一日量が投与される、請求項9に記載の方法。
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