JP5616345B2 - 小胞モノアミン輸送体2のベンゾキノリン阻害剤 - Google Patents
小胞モノアミン輸送体2のベンゾキノリン阻害剤 Download PDFInfo
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- JP5616345B2 JP5616345B2 JP2011527995A JP2011527995A JP5616345B2 JP 5616345 B2 JP5616345 B2 JP 5616345B2 JP 2011527995 A JP2011527995 A JP 2011527995A JP 2011527995 A JP2011527995 A JP 2011527995A JP 5616345 B2 JP5616345 B2 JP 5616345B2
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
- C07D455/06—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine containing benzo [a] quinolizine ring systems
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/002—Heterocyclic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
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- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
治療剤等の外来の基質を削除するために、動物の体は、シトクロムP450酵素(CYP)、エステラーゼ、プロテアーゼ、リダクターゼ、デヒドロゲナーゼおよびモノアミンオキシダーゼ等の種々の酵素を発現して、それらの外来基質と反応し、腎排出のために、より極性の中間体または代謝物に変換する。かかる代謝反応はたびたび、炭素−酸素(C−O)−結合または炭素−炭素(C−C)π−結合のいずれか一方への、炭素−水素(C−H)−結合の酸化が含まれる。結果として得られた代謝物は、生理学的条件下で、安定であるか、または不安定であり、親化合物と比べて、実質的に異なる薬物動態学的、薬力学的、および急性および長期毒性特性を有し得る。ほとんどの薬物では、このような酸化は一般的に迅速であり、最終的に、複数回投与または高い一日用量の投与をもたらす。
またはその塩、溶媒和物、もしくはプロドラッグであって、式中、
R1〜R27は、独立して水素および重水素より成る群から選択され、
R1〜R27のうちの少なくとも1つが重水素である。
本明細書に開示される化合物はまた、VMAT2媒介性疾患の治療において、他の薬剤と組み合わせて使用、または併用され得る。または、例としてのみ、ここに記述される化合物の内の1つの治療有効性は、アジュバントの投与によって増強され得る(すなわち、それ自体で、アジュバントは、最小の治療的利益のみを示し得るが、別の治療剤との組み合わせで、患者に対する全体的治療利益が増強される)。
水素同位体は、取り込み率が先に決定される、重水素化試薬を利用する合成技術によって、および/または、取り込み率が平衡条件により決定され、反応条件に依存して非常に変化し得る、交換技術によって、本明細書に開示される化合物内に導入可能である。トリチウムまたは重水素を直接、および特異的に、公知の同位体含量のトリチウム化または重水素化薬剤によって挿入する合成技術が、高いトリチウムまたは重水素の存在をもたらし得るが、しかし、要求される化学反応によって制限され得る。変換技術は、一方で、より低いトリチウムまたは重水素取り込みをもたらし、たびたび、同位体は分子上の多くの部位で分散する。
スキームI
スキームII
実施例1
3−イソブチル−9,10−ビス(メチルアミノ)−3,4,6,7−テトラヒドロ−1H−ピリド[2,1−a]イソキノリン−2(11bH)−オン(テトラベナジン)
ステップ1
ステップ2
ステップ3
ステップ4
3−イソブチル−9,10−d6−ジメトキシ−3,4,6,7−テトラヒドロ−1Η−ピリド[2,1−a]イソキノリン−2(11bH)−オン(d6−テトラベナジン)
ステップ1
ステップ2
ステップ3
ステップ4
ステップ5
生体外肝ミクロソーム安定性アッセイ
肝ミクロソーム安定性アッセイを、NADPH発生系を用いて2%重炭酸ナトリウム(2.2mM NADPH、25.6mMグルコース6−リン酸、mL当たり6単位のグルコース6−リン酸脱水素酵素、および3.3mM塩化マグネシウム)中でmL当たり1mgの肝ミクロソームタンパク質で行った。試験化合物を、20%アセトミトリル‐水中の溶液として調製し、アッセイ混合液(最終アッセイ濃度が1mL当たり5マイクログラム)に添加し、37℃でインキュベートする。アッセイ中のアセトニトリルの最終濃度は、1%未満であるべきである。一定分量(50μL)を0、15、30、45、および60分で取出し、氷冷アセトニトリル(200μL)で希釈して、反応を停止させる。サンプルを、10分間、12,000RPMで遠心分離して、タンパク質を沈殿させる。上清を微量遠心管に移し、そして試験化合物の崩壊半減期のLC/MS/MS分析のために保存する。したがって、このアッセイで試験された、本明細書に開示される特定の重水素濃縮化合物を、非同位体的に濃縮した薬物と比較した場合、崩壊半減期が増大することが認められた。実施例1および2(テトラベナジンおよびd6−テトラベナジン)の崩壊半減期を、表1に示す。
生体外ヒト肝ミクロソーム(HLM)安定性アッセイの結果
シトクロムP450酵素を、バキュロウイルス発現系(BD Biosciences,San Jose,CA)を使用して、相当するヒトcDNAから発現させる。100ミリのモルリン酸カリウム(pH7.4)中の1ミリリットル当たり0.8ミリグラムのタンパク質、1.3ミリモルのNADP+、3.3ミリモルのグルコース−6−リン酸、0.4U/mLのグルコース−6−リン酸デヒドロゲナーゼ、3.3ミリモルの塩化マグネシウムおよび0.2ミリモルの式1の化合物、相当する非同位体的に濃縮した化合物、または標準物つまり対照物を、含有する0.25ミリリットルの反応混合物を、37℃で20分間インキュベートする。インキュベーションした後、適切な溶媒(例えば、アセトニトリル、20%トリクロロ酢酸、94%アセトニトリル/6%氷酢酸、70%過塩素酸、94%アセトニトリル/6%氷酢酸)の添加によってその反応を停止し、3分間遠心(10,000g)する。上清をHPLC/MS/MSによって解析する。
Weyler et al.,Journal of Biological Chemistry 1985,260,13199−13207により記載される方法を使用して、手順を実行し、その全体が参照することにより本明細書に組み込まれる。モノアミンオキシダーゼA活性は、4−ヒドロキシキノリンの形成を伴うキヌラミンの酸化の際に、314nmでの吸収の増加を監視することにより測定される。これらの測定は、30℃で、0.2%Triton−X−100(モノアミンオキシダーゼアッセイ緩衝液)に加えて、1mMキヌラミン、および所望の量の酵素を含有するpH7.2の50mMナトリウムリン酸緩衝液中、総量1mLで実行される。
本手順は、Uebelhack et al.,Pharmacopsychiatry 1998,31(5),187−192に説明されるように実行し、その全体が参照することにより本明細書に組み込まれる。
本手順は、Roberts et al.,Journal of Chromatography,Biomedical Applications 1981,226(1),175−82に説明されるように実行し、その全体が参照することにより本明細書に組み込まれる。
本手順は、Mehvar et al.,Drug Metabolism and Disposition 1987,15(2),250−5に説明されるように実行し、その全体が参照することにより本明細書に組み込まれる。
本手順は、Schwartz et al.,Biochemical Pharmacology 1966,15(5),645−55に説明されるように実行し、その全体が参照することにより本明細書に組み込まれる。
本手順は、Jindal,et al.,Journal of Chromatography,Biomedical Applications 1989,493(2),392−7に説明されるように実行し、その全体が参照することにより本明細書に組み込まれる。
本手順は、Scherman et al.,Journal of Neurochemistry 1988,50(4),1131−36に説明されるように実行し、その全体が参照することにより本明細書に組み込まれる。
本手順は、Kilbourn et al.,Synapse 2002,43(3)188−194に説明されるように実行し、その全体が参照することにより本明細書に組み込まれる。
本手順は、Kilbourn et al.,European Journal of Pharmacology 1997,331(2−3)161−68に説明されるように実行し、その全体が参照することにより本明細書に組み込まれる。
本手順は、Erickson et al.,Journal of Molecular Neuroscience 1995,6(4)277−87に説明されるように実行し、その全体が参照することにより本明細書に組み込まれる。
Claims (16)
- 下記構造式:
- Dとして表される各位置が、10%以上の重水素濃縮を有する、請求項1に記載の化合物またはその塩。
- Dとして表される各位置が、50%以上の重水素濃縮を有する、請求項1に記載の化合物またはその塩。
- Dとして表される各位置が、90%以上の重水素濃縮を有する、請求項1に記載の化合物またはその塩。
- Dとして表される各位置が、98%以上の重水素濃縮を有する、請求項1に記載の化合物またはその塩。
- 薬学的に許容される担体と共に、請求項1に記載される化合物またはその塩を含む、薬学的組成物。
- VMAT2の阻害により軽減される疾患の予防または治療のための、請求項1に記載される化合物またはその塩を含む、薬学的組成物。
- 前記VMAT2の阻害により軽減される疾患がハンチントン病である、請求項7に記載の薬学的組成物。
- a.非同位体的に濃縮した化合物と比較した場合に、前記化合物またはその代謝物の血漿レベルでの個人間の変動の減少、
b.非同位体的に濃縮した化合物と比較した場合に、その投与量単位当たりの前記化合物の平均血漿レベルの増大、
c.非同位体的に濃縮した化合物と比較した場合に、その投与量単位当たりの前記化合物の少なくとも1つの代謝物の平均血漿レベルの減少、
d.非同位体的に濃縮した化合物と比較した場合に、その投与量単位当たりの前記化合物の少なくとも1つの代謝物の平均血漿レベルの増大、
e.非同位体的に濃縮した化合物と比較した場合に、その投与量単位当たりの前記被験体の治療中の臨床効果の改善、
より成る群から選択される少なくとも1つの効果をさらにもたらす、請求項7に記載の薬学的組成物。 - 前記化合物が、相当する非同位体的に濃縮した化合物と比較した場合に、前記被験体において、少なくと
も1つの多型的に発現したシトクロムP450アイソフォームにより、その投与量単位当
たりの前記化合物の代謝の減少をもたらす、請求項7に記載の薬学的組成物。 - 前記シトクロムP450アイソフォームが、CYP2C8、CYP2C9、CYP2C19、およびCYP2D6より成る群から選択される、請求項10に記載の薬学的組成物。
- 前記化合物が、非同位体的に濃縮した化合物と比較した場合に、その投与量単位当たり、前記被験体中の少なくとも1つのシトクロムP450アイソフォームまたはモノアミン酸化酵素アイソフォームの阻害の減少により特徴付けられる、請求項7に記載の薬学的組成物。
- 前記シトクロムP450アイソフォームまたはモノアミン酸化酵素アイソフォームが、CYP1A1、CYP1A2、CYP1B1、CYP2A6、CYP2A13、CYP2B6、CYP2C8、CYP2C9、CYP2C18、CYP2C19、CYP2D6、CYP2E1、CYP2G1、CYP2J2、CYP2R1、CYP2S1、CYP3A4、CYP3A5、CYP3A5P1、CYP3A5P2、CYP3A7、CYP4A11、CYP4B1、CYP4F2、CYP4F3、CYP4F8、CYP4F11、CYP4F12、CYP4X1、CYP4Z1、CYP5A1、CYP7A1、CYP7B1、CYP8A1、CYP8B1、CYP11A1、CYP11B1、CYP11B2、CYP17、CYP19、CYP21、CYP24、CYP26A1、CYP26B1、CYP27A1、CYP27B1、CYP39、CYP46、CYP51、MAOA、およびMAOBより成る群から選択される、請求項12に記載の薬学的組成物。
- 前記化合物が、相当する非同位体的に濃縮した化合物と比較した場合に、診断の肝胆機能エンドポイントにおける悪化を低減する、請求項7に記載の薬学的組成物。
- 前記診断の肝胆機能エンドポイントが、アラニンアミノトランスフェラーゼ(「ALT」)、血清グルタミン酸ピルビン酸トランスアミナーゼ(「SGPT」)、アスパラギン酸アミノトランスフェラーゼ(「AST」、「SGOT」)、ALT/AST比、血清アルドラーゼ、アルカリフォスファターゼ(「ALP」)、アンモニアレベル、ビリルビン、ガンマグルタミントランスペプチターゼ(「GGTP」、「γ−GTP」、「GGT」)、ロイシンアミノペプチダーゼ(「LAP」)、肝生検、肝臓の超音波検査、肝臓核スキャン、5’−ヌクレオチダーゼ、および血漿タンパク質より成る群から選択される、請求項14に記載の薬学的組成物。
- 薬剤として使用するための、請求項1に記載の化合物またはその塩。
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JP2015007124A (ja) * | 2008-09-18 | 2015-01-15 | オースペックス・ファーマシューティカルズ・インコーポレイテッドAuspex Pharmaceuticals, Inc. | 小胞モノアミン輸送体2のベンゾキノリン阻害剤 |
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