JP6830671B6 - γ−ヒドロキシ酪酸(GHB)のプロドラッグ、その組成物および使用 - Google Patents
γ−ヒドロキシ酪酸(GHB)のプロドラッグ、その組成物および使用 Download PDFInfo
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- JP6830671B6 JP6830671B6 JP2018533996A JP2018533996A JP6830671B6 JP 6830671 B6 JP6830671 B6 JP 6830671B6 JP 2018533996 A JP2018533996 A JP 2018533996A JP 2018533996 A JP2018533996 A JP 2018533996A JP 6830671 B6 JP6830671 B6 JP 6830671B6
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Description
1つの態様では、本開示は、式Iの化合物またはその薬学的に許容される塩、エステル、水和物、もしくは溶媒和物を提供し:
式中、
Bは
ここで、
R1およびR3は独立してC1−12アルキル、C2−12アルケニル、C5−12アラルキル、C6−12アラルケニル、C2−12アルキニル、C5−10アリール、C3−8シクロアルキル、3−10員複素環アルキル、5−10員複素環アリール、または
R2はC1−6アルキレンまたはC1−6アルキレンオキシルであり、これらのいずれも、C1−6アルキルにより任意でさらに置換され;
R4は結合、C1−6アルキレン、C5−10アリーレン、またはC5−12アリーレンアルキレンであり、これらのいずれも、C1−3アルキルにより任意でさらに置換され、およびR5は水素またはC1−12アルキルであり、
Rgは水素、C1−6アルキル、フェニル、またはフェニルメチルであり、これらのいずれも、ハロゲン、ヒドロキシル、メチルチオ、C1−4アルキル、またはC5−8アリールにより任意で一置換され、または独立して多置換され;ならびにRhおよびRfは独立して水素、C1−6アルキル、C1−6アルキルカルボニル、C1−6アルコキシルカルボニル、C3−6シクロアルコキシルカルボニル、またはアミノ保護基であり;
あるいは
RfおよびRgはC、O、NまたはS原子と一緒に4−8員複素環アルキルまたは
式中、
Rgは水素、C1−6アルキル、フェニル、またはフェニルメチルであり、これらのいずれも、ハロゲン、ヒドロキシル、メチルチオ、C1−4アルキル、またはC5−8アリールにより任意で一置換され、または独立して多置換され;ならびにRhおよびRfは独立して水素、C1−6アルキル、C1−6アルキルカルボニル、C1−6アルコキシルカルボニル、C3−6シクロアルコキシルカルボニルまたはアミノ保護基である。
式中、
RfおよびRgは、C、O、またはN原子と一緒に4−6員複素環アルキルまたは
Rhは水素、C1−3アルキルまたはアミノ保護基である。
式中、
Rhは水素、C1−3アルキルまたはアミノ保護基である。
式中、
Riは水素、C1−4アルキルまたはアミノ保護基である。
式中、
R1はC1−8アルキル、C5−8アリール、C5−12アラルキル、3−10員複素環アルキルまたは
であり、およびR1cは水素、C1−12アルキルまたはハロゲンである。
式中、
Ra、Rb、Rc、RdおよびReは独立して水素、ハロゲン、C1−12アルキル、C1−12アルコキシ、シアノ、C1−12アルキルスルホニル、C1−6アルキルカルボニルオキシル、C1−4アルキルオキシカルボニル、モノ、ジ、もしくはトリハロ−C1−6アルキル、C5−10アリールオキシルまたはC5−10アリールカルボニルであり;ならびに
Ra、Rb、Rc、RdおよびReが全て水素である場合、Ra、Rb、Rc、RdおよびReの少なくとも1つはプロチウムではない。
式中、
R2は−(CR6R7)m−であり、ここでm=1−6であり、ならびにR6およびR7は独立して水素またはC1−3アルキルであり;
R3はC1−12アルキル、C5−8アリール、3−8員複素環アルキル、または5−8員複素環アリールであり、それらは各々、ハロゲン、非置換または置換アミノ、C1−6アルキルまたはC1−6アルコキシにより任意で一置換され、または独立して多置換され;ここで、アミノが置換される場合、それは、C1−6アルキル、またはC1−6アルキルカルボニルにより任意で一置換され、または独立して多置換され得る。
式中、
R3a、R3b、R3c、R3dおよびR3eは独立して水素、ハロゲン、C1−6アルキル、またはC1−6アルコキシである。
式中、
R9およびR10は独立して水素、C1−6アルキルまたはC1−6アルキルカルボニルであり;ならびにR8は水素またはC1−6アルキルである。
式中、
R11はC1−8アルキルまたはC5−8アリールであり、これらのいずれも、ハロゲン、ヒドロキシル、C1−6アルキルまたはC1−4アルコキシにより任意で一置換され、または独立して多置換され;
R12は水素またはC1−6アルキルである。
本開示の化合物(その塩、エステル、水和物、または溶媒和物を含む)は、任意の公知の有機合成技術を用いて調製することができ、多くの可能な合成経路のいずれかに従い合成することができる。
本開示は本開示の1つ以上の化合物および薬学的に許容される担体を含む医薬組成物を提供する。
本開示は、被験体に、有効量の、本開示の1つ以上の化合物を投与することを含む、疾患を治療する方法を提供する。
本開示はまた、疾患を治療するための薬剤の製造における本開示の1つ以上の化合物の使用を提供する。いくつかの実施形態では、疾患はナルコレプシー、日中の過剰な眠気、カタプレキシー、神経変性疾患、睡眠障害症候群、線維筋痛症、慢性疲労、統合失調症(schizophenia)、過食性障害、パーキンソン病、遅発性ジスキネジア、またはアルツハイマー病である。いくつかの実施形態では、疾患はナルコレプシーと関連する日中の過剰な眠気またはカタプレキシーである。
下記実施例は本開示を説明するために提示される。それらは、制限することを決して意図しない。
本開示に包含される化合物は、異なるスキームにより調製され得る。様々なスキームによる90の例示的な化合物の詳細な調製プロセスが以下に記載され、キャラクタリゼーション結果が同様に各化合物について列挙される。
実施例1−30
実施例1−42
ベンジル4−(2−(2−(tert−ブトキシカルボニル)アミノアセトキシ)プロパノイルオキシ)ブタノエート
2,2,9−トリメチル−4,7,10−トリオキソ−3,8,11−トリオキサ−5−アザペンタデカン−15−酸
ラット/ヒト肝臓S9画分代謝安定性アッセイ
ラット/ヒト肝臓S9画分代謝安定性アッセイのためのプロトコルを使用して、インビトロでの本開示の化合物の半減期(T1/2)およびプロドラッグからGHBへ変換するそれらの放出効率を決定する。
ラット/ヒト全血代謝安定性アッセイのためのプロトコルを使用して、インビトロでプロドラッグからGHBへ変換する本開示の化合物の放出効率を決定する。
ラット薬物動態研究では、雄Sprague−Dawleyラットを個々に収容し、使用前一晩絶食させた。動物投与実験を国立衛生研究所実験動物の管理と使用に関するガイドラインおよび動物福祉法に従い実施した。GHBナトリウム塩については、単一用量の50mg/kgを2つの群(n=3/群)における各ラットに、それぞれ、静脈内(IV)および経口(PO)投与により投与した。GHBナトリウム塩のために使用されるビヒクルは生理食塩水である。他の試験化合物では、単一用量の各試験化合物を各ラットに経口投与した(n=3/群)。各試験化合物の投与量は表4に列挙される。試験化合物を投与するために使用されるビヒクルは0.5%(w/v)ナトリウムカルボキシルメチルセルロース(CMC−Na)を含む生理食塩水であった。血液試料を、IVおよびPO群内の個々のラットへの投与後、特定の時点で(投与前、10分、0.5時間、1時間、2時間、4時間、6時間)収集した。血液試料を氷上で直ちに凝固させ、血漿試料をその後、遠心分離により単離し、さらなる分析まで凍結保存した(−80℃)。GHBおよび全ての他の試験化合物の濃度を個々に、LC/MS/MSアッセイにより決定した。様々な薬物動態パラメータをPhoenix(商標)WinNonlin(登録商標)ソフトウェアを使用して計算した。循環系での試験化合物の生物変換効率を定量するために、PO投与後のGHBナトリウム塩の相対バイオアベイラビリティを計算した。相対バイオアベイラビリティの値を、試験化合物から変換されたGHBのAUC対用量により調整されたIVのみにより投与されたGHBナトリウム塩のAUCの比として表した。データが、下記表4において示される。
結腸吸収試験の目的は、GHBの得られた薬物動態および分布に関するプロドラッグの改善された輸送特性の効果を評価することである。研究は下記一般手順により実施されるべきである:GHBおよび本発明の化合物を各々、3〜7匹の雄ラットの群に、ボーラス注射により、直接結腸内に留置カニューレを介して投与する。投与後、血液試料を、間隔を置いて24時間にわたり入手し、直ちに処理して血漿を4℃で得る。GHBおよび全ての他の試験化合物の濃度をHPLC−MS/MSアッセイにより個々に決定する。本開示の化合物は、GHBよりも有効な結腸吸収を示す。
Claims (43)
- 前記化合物の分子量は450Da以下、または150−450Da、または150−300Daである、請求項1〜5のいずれか1項に記載の化合物。
- 前記水素はその同位体を含み、前記同位体はプロチウムおよび重水素である、請求項1〜6のいずれか1項に記載の化合物。
- 前記化合物は、経口投与後生物学的プロセスを介して、γ−ヒドロキシ酪酸に変換され、ヒト循環系に入ることができる、請求項1〜7のいずれか1項に記載の化合物。
- 請求項1〜8のいずれか1項に記載の1つ以上の化合物、および薬学的に許容される担体を含む医薬組成物。
- 前記医薬組成物は固体である、請求項9に記載の医薬組成物。
- 前記薬学的に許容される担体は、前記化合物を溶解または分散させるための溶媒を含む、請求項9に記載の医薬組成物。
- 前記溶媒は水を含む、請求項11に記載の医薬組成物。
- 前記製剤が液体剤形である、請求項9、11および12のいずれか1項に記載の医薬組成物。
- 前記薬学的に許容される担体は、香味剤、スクロース、ラクトース、セルロース糖、マンニトール、マルチトール、デキストラン、ソルビトール、デンプン、寒天、アルギナート、キチン、キトサン、ペクチン、トラガカントゴム、アラビアゴム、ゼラチン、コラーゲン、カゼイン、アルブミン、合成もしくは半合成ポリマまたはグリセリド、メチルセルロース、ヒドロキシプロピルメチル−セルロース、またはポリビニルピロリドンを含む、請求項9〜13のいずれか1項に記載の医薬組成物。
- 前記薬学的に許容される担体は、ポリマ賦形剤を含む、請求項9〜14のいずれか1項に記載の医薬組成物。
- 前記医薬組成物は、錠剤、カプレット、カプセル、ジェルキャップ、顆粒、丸薬、粉末、ロゼンジ、サシェ、カシェ剤、懸濁液、エマルジョン、溶液、スラリーまたはシロップを含む、請求項9に記載の医薬組成物。
- 前記医薬組成物は、単位剤形で製剤化されている、請求項9〜16ののいずれか1項に記載の医薬組成物。
- 前記単位剤形は、0.5g〜30gの重量を有する、請求項17に記載の医薬組成物。
- 前記単位剤形は、1g〜18gの重量を有する、請求項18に記載の医薬組成物。
- 前記医薬組成物が液体剤形である、請求項19に記載の医薬組成物。
- 前記医薬組成物は、水酸化ナトリウム、塩酸およびリンゴ酸から選択されるpH調整剤を更に含む、請求項9〜20のいずれか1項に記載の医薬組成物。
- 前記医薬組成物は、即時放出形態を含む形態で製剤化されている、請求項9〜21のいずれか1項に記載の医薬組成物。
- 前記医薬組成物は、遅延放出形態を含む形態で製剤化されている、請求項9〜21のいずれか1項に記載の医薬組成物。
- 前記医薬組成物は、徐放形態を含む形態で製剤化されている、請求項9〜21のいずれか1項に記載の医薬組成物。
- 疾患の治療用の医薬品の製造における式(IA)の化合物またはその薬学的に許容される塩の使用であって、前記疾患は、ナルコレプシー、日中の過剰な眠気、カタプレキシー、神経変性疾患、睡眠障害症候群、線維筋痛症、慢性疲労、統合失調症、過食性障害、パーキンソン病、遅発性ジスキネジア、アルツハイマー病、ナルコレプシーに関連した日中の過剰な眠気、またはナルコレプシーに関連したカタプレキシーであり、
式中、
Rgは水素またはC1−3 アルキルであり、
RhおよびRfはそれぞれ独立して水素またはC1−3 アルキルである、疾患の治療用の医薬品の製造における式(IA)の化合物またはその薬学的に許容される塩の使用。 - 前記疾患は、ナルコレプシー、日中の過剰な眠気、カタプレキシー、線維筋痛症、慢性疲労、または遅発性ジスキネジアである、請求項25に記載の使用。
- 前記疾患は、ナルコレプシーである、請求項26に記載の使用。
- 前記疾患は、日中の過剰な眠気である、請求項26に記載の使用。
- 前記疾患は、カタプレキシーである、請求項26に記載の使用。
- 前記化合物は1日に2回以下で投与される、請求項25〜29のいずれか1項に記載の使用。
- 前記化合物は1日に1回以下で投与される、請求項25〜30のいずれか1項に記載の使用。
- 前記化合物は、経口、経鼻、静脈内、皮下、舌下、または筋肉内投与される、請求項25〜31のいずれか1項に記載の使用。
- 前記化合物は、経口投与される、請求項25〜31のいずれか1項に記載の使用。
- 前記化合物は、エマルジョン、シロップ、エリキシル、懸濁液、スラリーおよび溶液で投与される、請求項25〜33のいずれか1項に記載の使用。
- 前記化合物は、溶液で投与される、請求項25〜34のいずれか1項に記載の使用。
- 前記化合物は、0.5g〜30gの量で投与される、請求項25〜35のいずれか1項に記載の使用。
- 前記化合物は、即時放出剤形として投与される、請求項25〜36のいずれか1項に記載の使用。
- 前記化合物は、遅延放出剤形として投与される、請求項25〜36のいずれか1項に記載の使用。
- 前記化合物は、徐放剤形として投与される、請求項25〜36のいずれか1項に記載の使用。
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