JP2019048829A - Vmat2のベンゾキノロン阻害剤 - Google Patents
Vmat2のベンゾキノロン阻害剤 Download PDFInfo
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- JP2019048829A JP2019048829A JP2018201331A JP2018201331A JP2019048829A JP 2019048829 A JP2019048829 A JP 2019048829A JP 2018201331 A JP2018201331 A JP 2018201331A JP 2018201331 A JP2018201331 A JP 2018201331A JP 2019048829 A JP2019048829 A JP 2019048829A
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Abstract
Description
治療薬などの異物を排除するために、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、レダクターゼ、デヒドロゲナーゼ、およびモノアミンオキシダーゼなどの種々の酵素を発現し、これらの異物と反応して、腎***のためにより極性の中間体または代謝産物に変換する。このような代謝反応は、炭素−水素(C−H)結合から炭素−酸素(C−O)または炭素−炭素(C−C)π結合のいずれかへの酸化を含むことが多い。結果として生じる代謝産物は生理的条件下で安定なことも不安定なこともあり、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、ならびに急性および長期的な毒性プロファイルを有し得る。大部分の薬物について、このような酸化は通常急速であり、最終的に、複数回または多量の日々の投与につながる。
R1〜R19およびR21〜R29は、水素および重水素からなる群から独立して選択され、
R20は、水素、重水素、−C(O)O−アルキルおよび−C(O)−C1〜6アルキル、または生理的条件下で切断可能な基からなる群から選択され、前記アルキルまたはC1〜6アルキルは、任意選択で、−NH−C(NH)NH2、−CO2H、−CO2アルキル、−SH、−C(O)NH2、−NH2、フェニル、−OH、4−ヒドロキシフェニル、イミダゾリル、およびインドリルからなる群から選択される1つまたは複数の置換基によって置換され、そして任意のR20置換基はさらに任意選択で重水素によって置換され、そして
R1〜R29の少なくとも1つは重水素であるか、あるいは重水素を含有する。
構造式II:
R1〜R19およびR21〜R39は、水素および重水素からなる群から独立して選択され、
R1〜R19およびR21〜R39の少なくとも1つは重水素である。
R20は、−C(O)O−アルキルおよび−C(O)−C1〜6アルキル、または生理的条件下で切断可能な基からなる群から選択され、前記アルキルまたはC1〜6アルキルは、任意選択で、−NH−C(NH)NH2、−CO2H、−CO2アルキル、−SH、−C(O)NH2、−NH2、フェニル、−OH、4−ヒドロキシフェニル、イミダゾリル、およびインドリルからなる群から選択される1つまたは複数の置換基によって置換され、そして任意のR20置換基はさらに、任意選択で、重水素によって置換される。
a. 統一パーキンソン病評定尺度(Unified Parkinson’s Disease Rating Scale)のスコアの改善、
b. 異常な不随意運動の尺度(Abnormal Involuntary Movement Scale)のスコアの改善、
c. ゲッツジスキネジア評定尺度(Goetz Dyskinesia Rating Scale)のスコアの改善、
d. 統一ジスキネジア評定尺度(Unified Dyskinesia Rating Scale)のスコアの改善、
e. PDQ−39パーキンソン病質問票(PDQー39 Parkinson’s Disease Questionnaire)のスコアの改善、および
f. 包括的な霊長類ジスキネジア評定尺度(Global Primate Dyskinesia Rating Scale)のスコアの改善
が挙げられるが、これらに限定されない。
a. 攻撃性の低下、
b. 癇癪を起す出来事の割合または重症度の低下、
c. 大人と口論する出来事の割合または重症度の低下、
d. 大人の要求または規則に従うことに対する反抗または拒否の出来事の割合または重症度の低下、
e. 自分の不作法または間違いを他者のせいにする出来事の割合または重症度の低下、
f. 神経過敏または他者によって容易に苛立つことの減少、
g. 怒りおよび/または憤慨の減少、
h. 意地悪および/または執念深さの低下、
i. 口論の出来事の割合または重症度の低下、
j. 否定的な行動の結果として権利を失うことについて気にしないことを主張する出来事の割合または重症度の低下、
k. 他者のせいにする出来事の割合または重症度の低下、
l. 行為に対する責任を認めない出来事の割合または重症度の低下、
m. 命令を無視する出来事の割合または重症度の低下、
n. 大人が互いに争うように仕向ける出来事の割合または重症度の低下、
o. 「タイムアウト」になることを拒否する出来事の割合または重症度の低下、
p. 指図に対して抵抗する出来事の割合または重症度の低下、
q. 頑固さの低減、
r. 限界を試す出来事の割合または重症度の低下、および
s. 大人または仲間と妥協、降参、または交渉する気がない出来事の割合または重症度の低下
が挙げられるが、これらに限定されない。
また本明細書に開示される化合物は、VMAT2媒介性障害の治療において有用な他の薬剤と組み合わせる、あるいは組み合わせて使用することができる。あるいは、単なる例として、本明細書に記載される化合物の1つの治療有効性は、補助剤の投与によって増強され得る(すなわち、補助剤は、それ自体は最小限の治療的有用性しか有することがでないが、別の治療薬と組み合わせられると、患者に対する全体的な治療的有用性が増強される)。
同位体水素は、重水素化試薬を用いる合成技術(取込み率が予め決定される)によって、そして/あるいは交換技術(取込み率は平衡条件によって決定され、反応条件に応じて大きく異なり得る)によって、本明細書に開示される化合物中に導入することができる。既知の同位体含量を有するトリチウム化または重水素化試薬によってトリチウムまたは重水素が直接かつ特異的に挿入される合成技術は、高いトリチウムまたは重水素存在量をもたらすことができるが、必要とされる化学によって制限され得る。一方、交換技術は、より低いトリチウムまたは重水素の取込みをもたらし、多くの場合、同位体は、分子の多数の部位に分配され得る。
インビトロヒト肝ミクロソーム安定性アッセイ
アッセイにおけるさらなる希釈のために試験化合物を50%アセトニトリル/50%H2O中に溶解させる。NADPH再生系(NRS)の存在下、二度繰り返して、37℃のインキュベーションのために、指示される種の肝臓から得られたミクロソームと試験化合物を混ぜ合わせた。重水素化されていない試験化合物については、内部標準は重水素化された類似体であった。重水素化された試験化合物については、内部標準は重水素化されていない形態であった。次のLC/MS/MS分析のために、サンプルを−70℃で貯蔵した。
アッセイにおけるさらなる希釈のために試験化合物を50%アセトニトリル/50%H2O中に溶解させる。NADPH再生系(NRS)の存在下、二度繰り返して、上記のような37℃で60分間のインキュベーションのために、試験化合物を肝S9フラクションまたは肝サイトゾルと混ぜ合わせる。重水素化されていない試験化合物については、内部標準は重水素化された類似体である。重水素化された試験化合物については、内部標準は重水素化されていない形態である。次のLC/MS/MS分析のために、サンプルを−70℃で貯蔵する。
アッセイにおけるさらなる希釈のために50%アセトニトリル/50%H2O中に試験化合物を溶解させる。NADPH再生系(NRS)の存在下、37℃で0、15、30、45または60分間のインキュベーションのために、0.25μMの最終濃度の試験化合物を、バキュロウイルスに感染した昆虫細胞由来のミクロソーム(SupersomesTM、Gentest,Woburn,MA)中の組換えヒトCYP1A2、CYP3A4またはCYP2D6と混ぜ合わせる。CYPアイソザイムの濃度は、25〜200pmol/mLの範囲である。各時点で、内部標準を含有する100μLのACNの添加により反応を停止させる。重水素化された試験化合物については、内部標準は重水素化されていない形態である。ボルテックスの後、サンプルを14,000rpm(室温)で10分間遠心分離し、LC/MS/MS分析のために上清をHPLCバイアルに移す。次のLC/MS/MS分析のために、サンプルを−70℃で貯蔵する。
Weyler,Journal of Biological Chemistry 1985,260,13199−13207(参照によってその全体が本明細書に援用される)に記載される方法を用いて、手順を実行する。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について、314nmの吸光度の増大をモニターすることによって分光光度的に測定される。0.2%のTriton X−100を含有する50mMのNaPi緩衝液、pH7.2(モノアミンオキシダーゼアッセイ緩衝液)に、1mMのキヌラミン、および所望の量の酵素を加えた総容積1mLの溶液中、30℃で測定を実行した。
Uebelhack,Pharmacopsychiatry 1998,31(5),187−192(参照によってその全体が本明細書に援用される)に記載されるように手順を実行する。
Roberts et al.,Journal of Chromatography, Biomedical Applications 1981,226(1),175−82(参照によってその全体が本明細書に援用される)に記載されるように手順を実行する。
Mehvar,et al.,Drug Metabolism and Disposition 1987,15(2),250−5(参照によってその全体が本明細書に援用される)に記載されるように手順を実行する。
Schwartz,et al.,Biochemical Pharmacology 1966,15(5),645−55(参照によってその全体が本明細書に援用される)に記載されるように手順を実行する。 .
Jindal,et al.,Journal of Chromatography, Biomedical Applications 1989,493(2),392−7(参照によってその全体が本明細書に援用される)に記載されるように手順を実行する。
Scherman et al.,Journal of Neurochemistry 1988,50(4),1131−36(参照によってその全体が本明細書に援用される)に記載されるように手順を実行する。
Kilbourn et al.,Synapse 2002,43(3),188−194(参照によってその全体が本明細書に援用される)に記載されるように手順を実行する。
Kilbourn et al.,European Journal of Pharmacology 1997,331(2−3),161−68(参照によってその全体が本明細書に援用される)に記載されるように手順を実行する。
Erickson et al.,Journal of Molecular Neuroscience 1995,6(4),277−87(参照によってその全体が本明細書に援用される)に記載されるように手順を実行する。
米国特許第8,039,627号明細書(参照によってその全体が本明細書に援用される)に記載されるように手順を実行する。
米国特許第8,039,627号明細書(参照によってその全体が本明細書に援用される)に記載されるように手順を実行する。
米国特許第8,039,627号明細書(参照によってその全体が本明細書に援用される)に記載されるように手順を実行する。
米国特許第8,039,627号明細書(参照によってその全体が本明細書に援用される)に記載されるように手順を実行する。
米国特許第8,039,627号明細書(参照によってその全体が本明細書に援用される)に記載されるように手順を実行する。
Claims (48)
- 構造式II
R1〜R19およびR21〜R39の少なくとも1つは重水素である)
の化合物、またはその塩もしくは立体異性体。 - 前記化合物が(+)−アルファ立体異性体である、請求項1に記載の化合物。
- 前記化合物が(−)−アルファ立体異性体である、請求項1に記載の化合物。
- 前記化合物が(+)−ベータ立体異性体である、請求項1に記載の化合物。
- 前記化合物が(−)−ベータ立体異性体である、請求項1に記載の化合物。
- R1〜R19およびR21〜R39の少なくとも1つが独立して約10%以上の重水素濃縮を有する、請求項1に記載の化合物。
- R1〜R19およびR21〜R39の少なくとも1つが独立して約50%以上の重水素濃縮を有する、請求項1に記載の化合物。
- R1〜R19およびR21〜R39の少なくとも1つが独立して約90%以上の重水素濃縮を有する、請求項1に記載の化合物。
- R1〜R19およびR21〜R39の少なくとも1つが独立して約98%以上の重水素濃縮を有する、請求項1に記載の化合物。
- 前記化合物が、
- 前記化合物が、
- Dで表される各位置が約10%以上の重水素濃縮を有する、請求項11に記載の化合物。
- Dで表される各位置が約50%以上の重水素濃縮を有する、請求項11に記載の化合物。
- Dで表される各位置が約90%以上の重水素濃縮を有する、請求項11に記載の化合物。
- Dで表される各位置が約98%以上の重水素濃縮を有する、請求項11に記載の化合物。
- 前記化合物が、
- 前記化合物が、
- 前記化合物が、
- 前記化合物が、
- 前記化合物が、構造式:
- 前記化合物が、構造式:
- 前記化合物が、構造式:
- 前記化合物が、構造式:
- 前記化合物が、構造式:
- 前記化合物が、構造式:
- 前記化合物が、構造式:
- 構造式III
の化合物、またはその塩もしくは立体異性体。 - 前記化合物が(+)−アルファ立体異性体である、請求項27に記載の化合物。
- 前記化合物が(−)−アルファ立体異性体である、請求項27に記載の化合物。
- 前記化合物が(+)−ベータ立体異性体である、請求項27に記載の化合物。
- 前記化合物が(−)−ベータ立体異性体である、請求項27に記載の化合物。
- 請求項1に記載の化合物と一緒に、薬学的に許容可能な担体を含む、医薬組成物。
- VMAT2媒介性障害を治療する方法であって、それを必要としている患者に、治療的に有効な量の請求項1に記載の化合物を投与することを含む方法。
- 前記障害が、慢性多動性運動障害、ハンチントン病、片側バリズム、ハンチントン病に関連する舞踏病、老人性舞踏病、チック障害、遅発性ジスキネジア、ジストニア、トゥレット症候群、うつ病、癌、関節リウマチ、精神病、多発性硬化症、喘息、パーキンソン病レボドパ誘発性ジスキネジア、運動障害、および反抗挑戦性障害からなる群から選択される、請求項33に記載の方法。
- 付加的な治療薬の投与をさらに含む、請求項33に記載の方法。
- 前記付加的な治療薬が、オランザピンおよびピモジドからなる群から選択される、請求項35に記載の方法。
- 前記付加的な治療薬が、ベンゾジアゼピンおよび抗精神病薬からなる群から選択される、請求項35に記載の方法。
- 前記ベンゾジアゼピンが、アルプラゾラム、アジナゾラム、ブロマゼパム、カマゼパム、クロバザム、クロナゼパム、クロチアゼパム、クロキサゾラム、ジアゼパム、ロフラゼプ酸エチル、エスティゾラム、フルジアゼパム、フルニトラゼパム、ハラゼパム、ケタゾラム、ロラゼパム、メダゼパム、ダゾラム、ニトラゼパム、ノルダゼパム、オキサゼパム、クロラゼプ酸カリウム、ピナゼパム、プラゼパム、トフィソパム、トリアゾラム、テマゼパム、およびクロルジアゼポキシドからなる群から選択される、請求項37に記載の方法。
- 前記抗精神病薬が、クロルプロマジン、レボメプロマジン、プロマジン、アセプロマジン、トリフルプロマジン、シアメマジン、クロルプロエタジン、ジキシラジン、フルフェナジン、ペルフェナジン、プロクロルペラジン、チオプロパザート、トリフルオペラジン、アセトフェナジン、チオプロペラジン、ブタペラジン、ペラジン、ペリシアジン、チオリダジン、メソリダジン、ピポチアジン、ハロペリドール、トリフルペリドール、メルペロン、モペロン、ピパンペロン、ブロムペリドール、ベンペリドール、ドロペリドール、フルアニソン、オキシペルチン、モリンドン、セルチンドール、ジプラシドン、フルペンチキソール、クロペンチキソール、クロルプロチキセン、チオチキセン、ズクロペンチキソール、フルスピリレン、ピモジド、ペンフルリドール、ロキサピン、クロザピン、オランザピン、クエチアピン、テトラベナジン、スルピリド、スルトプリド、チアプリド、レモキシプリド、アミスルプリド、ベラリプリド、レボスルピリド、リチウム、プロチペンジル、リスペリドン、クロチアピン、モサプラミン、ゾテピン、プリピプラゾール、およびパリペリドンからなる群から選択される、請求項37に記載の方法。
- a)非同位体濃縮化合物と比較して、前記化合物またはその代謝産物の血漿レベルにおける個体間変動の減少と、
b)非同位体濃縮化合物と比較して、その投与量単位あたりの、前記化合物の平均血漿レベルの増大と、
c)非同位体濃縮化合物と比較して、その投与量単位あたりの、前記化合物の少なくとも1つの代謝産物の平均血漿レベルの低下と、
d)非同位体濃縮化合物と比較して、その投与量単位あたりの、前記化合物の少なくとも1つの代謝産物の平均血漿レベルの増大と、
e)非同位体濃縮化合物と比較して、その投与量単位あたりの、前記被験者の治療中の臨床効果の改善と
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、請求項33に記載の方法。 - a)非同位体濃縮化合物と比較して、前記化合物またはその代謝産物の血漿レベルにおける個体間変動の減少と、
b)非同位体濃縮化合物と比較して、その投与量単位あたりの、前記化合物の平均血漿レベルの増大と、
c)非同位体濃縮化合物と比較して、その投与量単位あたりの、前記化合物の少なくとも1つの代謝産物の平均血漿レベルの低下と、
d)非同位体濃縮化合物と比較して、その投与量単位あたりの、前記化合物の少なくとも1つの代謝産物の平均血漿レベルの増大と、
e)非同位体濃縮化合物と比較して、その投与量単位あたりの、前記被験者の治療中の臨床効果の改善と
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、請求項33に記載の方法。 - 前記方法が、対応する非同位体濃縮化合物と比較して、前記被験者における少なくとも1つの多形的に発現されたシトクロムP450アイソフォームによる、その投与量単位あたりの前記化合物の代謝の減少をもたらす、請求項33に記載の方法。
- 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、請求項42に記載の方法。
- 前記化合物が、非同位体濃縮化合物と比較して、その投与量単位あたりの、前記被験者における少なくとも1つのシトクロムP450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を特徴とする、請求項33に記載の方法。
- 前記シトクロムP450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、請求項44に記載の方法。
- 前記方法が、対応する非同位体濃縮化合物と比較して、診断上の肝胆機能のエンドポイントにおける有害な変化を低減する、請求項33に記載の方法。
- 前記診断上の肝胆機能のエンドポイントが、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、ガンマ−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、および血液タンパク質からなる群から選択される、請求項46に記載の方法。
- 薬剤として使用するための、請求項1に記載の化合物。
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