JP6567515B2 - ジヒドロキシフェニル神経伝達物質の化合物、組成物、および方法 - Google Patents
ジヒドロキシフェニル神経伝達物質の化合物、組成物、および方法 Download PDFInfo
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Description
治療剤などの外来物質を排除するために、動物体は、シトクロムP450酵素(CYP)、エステラーゼ、プロテアーゼ、レダクターゼ、デヒドロゲナーゼ、モノアミンオキシダーゼなどの種々の酵素を発現することにより、これらの外来物質と反応してより極性のある中間体または代謝物に変換し、腎排泄に供する。そのような代謝反応は、多くの場合、炭素−酸素(C−O)または炭素−炭素(C−C)のπ−結合のいずれかに至る炭素−水素(C−H)結合の酸化を含む。得られる代謝物は、生理学的条件下で安定なこともあれば不安定なこともあり、親化合物と対比して実質的に異なる薬動学的プロファイル、薬力学的プロファイル、ならびに急性および長期の毒性プロファイルを有しうる。ほとんどの薬剤では、そのような酸化は、一般的には迅速であるため、最終的には多数回または多量の一日用量の投与が行われることになる。
R1〜R2は、独立して、水素、ジュウテリウム、メチル、ペルジュウテロメチル、エチル、ペルジュウテロエチル、プロピル、ペルジュウテロプロピル、ブチル、ペルジュウテロブチル、C1〜C6−アルキル、およびC5〜C6−シクロアルキルからなる群から選択され、前記C1〜C6−アルキルおよびC5〜C6−シクロアルキルは、任意選択で、ジュウテリウムで置換されていてもよく、
R3〜R8は、独立して、水素およびジュウテリウムからなる群から選択され、
R9〜R11は、独立して、水素、ジュウテリウム、メチル、ペルジュウテロメチル、エチル、ペルジュウテロエチル、プロピル、ペルジュウテロプロピル、ブチル、ペルジュウテロブチル、C1〜C6−アルキル、およびC5〜C6−シクロアルキルからなる群から選択され、前記C1〜C6−アルキルおよびC5〜C6−シクロアルキルは、任意選択で、ジュウテリウムで置換されていてもよく、かつ
R3〜R6およびR8のうちの少なくとも1つはジュウテリウムである)
またはその塩を有する。
R1〜R11は、独立して、水素およびジュウテリウムからなる群から選択され、かつ
R1〜R11のうちの少なくとも1つはジュウテリウムである
またはその塩を有する。
約2〜約18%の本明細書に開示された化合物と、
約70%〜約96%の1種以上の希釈剤と、
約1%〜約10%の水溶性結合剤と、
約0.5〜約2%の界面活性剤と
を含む長期放出医薬製剤である。
約60%〜約70%のマンニトールまたはラクトースと、
約15%〜約25%の微結晶セルロースと、
約5%のポリビニルピロリドンK29/32と、
約1〜約2%のTween80と
を含む。
約4%〜約9%の本明細書に開示された化合物と、
約60%〜約70%のマンニトールまたはラクトースと、
約20%〜約25%の微結晶セルロースと、
約5%のポリビニルピロリドンK29/32と、
約1.4%のTween80と
を含む。
約70〜約95%の本明細書に開示された化合物の顆粒であって、活性成分が顆粒の約1〜約15%を構成する、顆粒と、
約5%〜約15%の1種以上の希釈剤と、
約5%〜約20%の持続放出ポリマーと、
約0.5〜約2%の滑沢剤と
を含む長期放出医薬製剤である。
約5%〜約15%の1種以上のスプレー乾燥マンニトールまたはスプレー乾燥ラクトースと、
約5%〜約20%の持続放出ポリマーと、
約0.5〜約2%のマグネシウムステアレートと
を含む。
本明細書に開示された化合物はまた、組み合わせうるか、またはチロシンキナーゼ媒介障害の治療に有用な他の作用剤と組み合わせて使用されうる。または単なる例にすぎないが、本明細書に記載の化合物のうちの1種の治療有効性は、補助剤の投与により向上しうる(すなわち、補助剤は、それ自体では、最小限の治療効果を有するにすぎないが、治療剤との組合せで、患者への全治療効果が向上する)。
同位体水素は、取込み速度があらかじめ決められているジュウテリウム化試薬を利用する合成技術により、および/または取込み速度が平衡状態により決定され、反応条件に依存してかなり変動しうる交換技術により、本明細書に開示された化合物中に導入可能である。既知の同位体含有率のトリチウム化試薬またはジュウテリウム化試薬により直接かつ特定的にトリチウムまたはジュウテリウムが挿入される合成技術は、トリチウムまたはジュウテリウムの高い存在量を生成するが、必要な化学により制約を受ける可能性がある。一方、交換技術は、トリチウムまたはジュウテリウムの低い取込み生成する可能性があり、多くの場合、分子上の多くの部位にわたり同位体が分布する。
たとえば、R3〜R5のうちの1つ以上の位置にジュウテリウムを導入するために、対応するジュウテリウム置換を有する化合物1を使用することが可能である。R6にジュウテリウムを導入するために、ジュウテリウムガスを使用することが可能である。R8にジュウテリウムを導入するために、対応するジュウテリウム置換を有する化合物4を使用することが可能である。
同一用量のL−threo−DOPSと比較した2mg/kgのL−threo−2,3ジジュウテロDOPSの静脈内投与後の麻酔ラットの平均動脈血圧の変化
L−threo−2,3−ジジュウテロDOPSの投与は、長時間にわたり増強された平均動脈血圧の増加をもたらす。
肝臓ミクロソーム安定性アッセイは、2%NaHCO3中のNADPH生成系(2.2mM NADPH、25.6mMグルコース6−リン酸、6単位/mLグルコース6−リン酸デヒドロゲナーゼ、および3.3mM MgCl2)を用いて1mg/mL肝ミクロソームタンパク質で行われる。試験化合物は、20%アセトニトリル−水の溶液として調製され、アッセイ混合物(最終アッセイ濃度5マイクログラム/mL)に添加され、37℃でインキュベートされる。アッセイでのアセトニトリルの最終濃度は<1%にすべきである。アリコート(50μL)は、0、15、30、45、および60分の時点で採取され、反応を停止させるために氷冷アセトニトリル(200μL)で希釈される。サンプルは、タンパク質を沈殿させるために12,000RPMで10分間遠心分離される。上清は、マイクロ遠心分離チューブに移され、試験化合物の分解半減期のLC/MS/MS分析のために貯蔵される。
ノルエピネフリンおよびd6−ノルエピネフリンをモノアミンオキシダーゼ−A(MAO−A)と共にインキュベートした。
シトクロムP450酵素は、バキュロウイルス発現系を用いて対応するヒトcDNAから発現される(BD Biosciences,San Jose,CA)。100ミリモルのリン酸カリウム(pH7.4)中に0.8ミリグラム/ミリリットルのタンパク質、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、0.2ミリモルの式Iで示される化合物、対応する非同位体富化化合物または標準または対照を含有する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後、適切な溶媒(たとえば、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)の添加により反応を停止させ、3分間遠心分離する(10,000g)。上清をHPLC/MS/MSにより分析する。
手順は、Weyler,Journal of Biological Chemistry 1985,260,13199−13207(その全体が参照により本明細書に組み込まれる)に記載の方法を用いて行われる。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生成を伴うキヌラミンの酸化に基づいて314nmの吸光度の増加をモニターすることにより分光測光により測定される。測定は、1mLの全体積中に0.2%のTriton X−100(モノアミンオキシダーゼアッセイ緩衝液)と、1mMのキヌラミンと、所望の量の酵素とを含有する50mMのNaPi緩衝液pH7.2中、30℃で行われる。
手順は、Uebelhack,Pharmacopsychiatry 1998,31(5),187−192(その全体が参照により本明細書に組み込まれる)に記載されるように行われる。
手順は、Verhagen−Kamerbeek et al.,Monit.Mol.Neurosci.,Proc.Int.Conf.In Vivo Methods,5th,1991,373−6(その全体が参照により本明細書に組み込まれる)に記載されるように行われる。
手順は、Yue et al.,J.Pharmacy and Pharmacol.,1992,44(12),990−5(その全体が参照により本明細書に組み込まれる)に記載されるように行われる。
手順は、Coll Mar et al.,Hepatology(Baltimore,Md.),2012,56(5),1849−60(その全体が参照により本明細書に組み込まれる)に記載されるように行われる。
Claims (39)
- 構造式:
Dとして表された各位置が、10%以上のジュウテリウム富化率を有し、炭素−13により富化されていない、
組成物。 - Dとして表された各位置が50%以上のジュウテリウム富化率を有する、請求項1に記載の組成物。
- Dとして表された各位置が90%以上のジュウテリウム富化率を有する、請求項1に記載の組成物。
- Dとして表された各位置が98%以上のジュウテリウム富化率を有する、請求項1に記載の組成物。
- 構造式:
- 構造式:
- 構造式:
- 請求項1に記載の組成物と共に薬学的に許容可能な担体を含む医薬組成物。
- 神経伝達物質レベルを調節することにより改善される障害の予防または治療のための医薬の製造のための、請求項1〜7のいずれか1項に記載の組成物の使用。
- 請求項9に記載の使用であって、
前記障害が、低血圧、急速眼球運動(REM)行動障害、慢性心不全、ストレス関連障害、運動障害または言語障害、発作、脳虚血、鼻閉、気分障害、注意欠陥障害(ADD)、注意欠陥多動性障害(ADHD)、家族性自律神経失調症、糖尿病性自律神経症、多発性骨髄腫の状況下のアミロイドーシス、ドーパミンβヒドロキシラーゼ欠損症、疼痛、進行性核上性麻痺、自律神経機能不全、青年期における起立不耐性、神経心臓性失神、体位性起立性頻拍症候群(POTS)、疲労、睡眠障害、抑鬱症、小児発達障害、ノルエピネフリンの合成または作用の減少が関与する遺伝病、多系統調節障害、神経変性疾患、認知機能不全、嗅覚障害、神経内分泌障害、ならびに自己免疫障害からなる群から選択される、
使用。 - 請求項9に記載の使用であって、
前記障害が、多系統萎縮症(MSA)に伴う神経原性起立性低血圧、シャイ・ドレーガー症候群に伴う起立性低血圧、家族性アミロイド多発性神経症(FAP)に伴う神経原性起立性低血圧、純粋自律神経不全(PAF)に伴う神経原性起立性低血圧、特発性起立性低血圧、交感神経非緊張性低血圧、パーキンソン病に伴う神経原性起立性低血圧、透析時低血圧(IDH)、線維筋痛症候群(FMS)に伴う低血圧、脊髄傷害における低血圧、および慢性疲労症候群(CFS)に伴う低血圧からなる群から選択される、
使用。 - 請求項11に記載の使用であって、
透析時低血圧(IDH)が、血液透析誘発性低血圧である、
使用。 - 請求項9に記載の使用であって、
前記障害は、起立性低血圧である、
使用。 - 請求項9に記載の使用であって、
前記障害が、ドーパミンβヒドロキシラーゼ欠損症、メンケス病、ビタミンC欠乏症、レビー小体病、パーキンソン病、レビー小体型認知症、純粋自律神経不全、家族性自律神経失調症、両側内視鏡下胸部交感神経切除後状態、起立不耐性、および起立性低血圧からなる群から選択される、
使用。 - 請求項9に記載の使用であって、
前記障害が、神経原性起立性低血圧、慢性疼痛、睡眠障害、ナルコレプシー、不眠症、無嗅覚症、嗅覚減退、軽度認知障害(MCI)、ダウン症候群、アルツハイマー病、自己免疫自律神経不全、食後低血圧、ライリー・デイ症候群、パーキンソン病関連自律神経失調症、血管迷走神経のおよび慢性の起立不耐性からなる群から選択される、
使用。 - 請求項9に記載の使用であって、
前記障害が、症候性神経原性起立性低血圧、パーキンソン病に起因する姿勢反射異常、線維筋痛、異痛症および痛覚過敏からなる群から選択される、
使用。 - 請求項9に記載の使用であって、
追加の治療剤をさらに含む、
使用。 - 請求項17に記載の使用であって、
前記追加の治療剤が、交感神経模倣剤、Sアルキルイソチオウロニウム誘導体、グルココルチコイド、蘇生剤、向精神剤、陽性変力剤、抗低血圧剤作用剤、L−芳香族アミノ酸デカルボキシラーゼ阻害剤、カテコール−O−メチルトランスフェラーゼ阻害剤、モノアミンオキシダーゼ阻害剤、および5−HT2Aインバースアゴニストからなる群から選択される、
使用。 - 請求項18に記載の使用であって、
前記交感神経模倣剤が、エピネフリン、ノルエピネフリン、フェニレフリン、ドブタミン、ドーパミン、エフェドリン、ミドドリン、およびアメジニウムからなる群から選択される、
使用。 - 請求項18に記載の使用であって、
前記S−アルキルイソチオウロニウム誘導体が、ジフェツルおよびイゾツロンからなる群から選択される、
使用。 - 請求項18に記載の使用であって、
前記グルココルチコイドが、ヒドロコルチゾン、プレドニゾン、プレドニゾロン、デキサメタゾン、およびベタメタゾンからなる群から選択される、
使用。 - 請求項18に記載の使用であって、
前記蘇生剤が、ベメグリド、カフェイン、カンフォラ、およびコルジアミンからなる群から選択される、
使用。 - 請求項18に記載の使用であって、
前記向精神剤が、アンフェタミン、アトモキセチン、ブプロピオン、デュロキセチン、メタンフェタミン、メチルフェニデート、レボキセチンおよびベンラファキシンからなる群から選択される、
使用。 - 請求項18に記載の使用であって、
前記陽性変力剤が、強心配糖体、ストロファンチンK、コルグリコン、ジゴキシン、アムリノン、およびミルリノンからなる群から選択される、
使用。 - 請求項18に記載の使用であって、
前記L−芳香族アミノ酸デカルボキシラーゼ阻害剤が、ベンセラジド、カルビドパ、メチルドパ、およびα−ジフルオロメチル−DOPAからなる群から選択される、
使用。 - 請求項18に記載の使用であって、
前記カテコール−O−メチルトランスフェラーゼ阻害剤が、エンタカポン、トルカポン、およびニテカポンからなる群から選択される、
使用。 - 請求項18に記載の使用であって、
前記モノアミンオキシダーゼ阻害剤が、イソカルボキサジド、イソニアジド、ニアラミド、フェネルジン、トラニルシプロミン、モクロベミド、ピルリンドール、トロキサトン、ラサギリン、およびセレギリンからなる群から選択される、
使用。 - 請求項18に記載の使用であって、
前記5−HT2Aインバースアゴニストがピムバセリンである、
使用。 - 請求項17に記載の使用であって、前記追加の治療剤が、
使用。 - 請求項17に記載の使用であって、前記追加の治療剤が、
使用。 - 請求項17に記載の使用であって、前記追加の治療剤が、構造式:
使用。 - 請求項9に記載の使用であって、
a.非同位体富化化合物と比較して前記化合物またはその代謝物の血漿中レベルの個体間変動の減少、
b.前記非同位体富化化合物と比較して投与ユニットあたりの前記化合物の血漿中平均レベルの増加、
c.前記非同位体富化化合物と比較して投与ユニットあたりの前記化合物の少なくとも1種の代謝物の血漿中平均レベルの減少、
d.前記非同位体富化化合物と比較して投与ユニットあたりの前記化合物の少なくとも1種の代謝物の血漿中平均レベルの増加、および
e.前記非同位体富化化合物と比較して投与ユニットあたりの被験体の治療中の臨床効果の改善
からな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、
使用。 - 請求項9に記載の使用であって、
a.非同位体富化化合物と比較して前記化合物またはその代謝物の血漿中レベルの個体間変動の減少、
b.前記非同位体富化化合物と比較して投与ユニットあたりの前記化合物の血漿中平均レベルの増加、
c.前記非同位体富化化合物と比較して投与ユニットあたりの前記化合物の少なくとも1種の代謝物の血漿中平均レベルの減少、
d.前記非同位体富化化合物と比較して投与ユニットあたりの前記化合物の少なくとも1種の代謝物の血漿中平均レベルの増加、および
e.前記非同位体富化化合物と比較して投与ユニットあたりの被験体の治療中の臨床効果の改善
からなる群から選択される少なくとも2つの効果をさらにもたらす、
使用。 - 請求項9に記載の使用であって、
前記化合物は、対応する非同位体富化化合物と比較して、被験体において、少なくとも1種の多形発現シトクロムP450アイソフォームによる投与ユニットあたりの前記化合物の代謝の減少により特徴付けられる、
使用。 - 請求項34に記載の使用であって、
前記シトクロムP450アイソフォームが、CYP2C8、CYP2C9、CYP2C19、およびCYP2D6からなる群から選択される、
使用。 - 請求項9に記載の使用であって、
前記化合物は、非同位体富化化合物と比較して、投与ユニットあたりの被験体における少なくとも1種のシトクロムP450アイソフォームまたはモノアミンオキシダーゼアイソフォームの阻害の減少により特徴付けられる、
使用。 - 請求項36に記載の使用であって、
前記シトクロムP450アイソフォームまたはモノアミンオキシダーゼアイソフォームが、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からなる群から選択される、
使用。 - 請求項9に記載の使用であって、
前記化合物は、対応する非同位体富化化合物と比較して、診断肝胆道機能エンドポイントの有害変化の低減により特徴付けられる、
使用。 - 請求項38に記載の使用であって、
前記診断肝胆道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、アルカリホスファターゼ(「ALP」)、アンモニアレベル、ビリルビン、γグルタミルトランスペプチダーゼ(「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、および血中タンパク質からなる群から選択される、
使用。
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US11590107B2 (en) * | 2019-10-25 | 2023-02-28 | Curasen Therapeutics, Inc. | Methods for treating neurological disorders with α1A-AR partial agonists |
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