JP7195362B2 - 有機化合物 - Google Patents
有機化合物 Download PDFInfo
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- JP7195362B2 JP7195362B2 JP2021053242A JP2021053242A JP7195362B2 JP 7195362 B2 JP7195362 B2 JP 7195362B2 JP 2021053242 A JP2021053242 A JP 2021053242A JP 2021053242 A JP2021053242 A JP 2021053242A JP 7195362 B2 JP7195362 B2 JP 7195362B2
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Description
本願は、2016年3月25日に出願された米国仮特許出願番号第62/313,629号の優先権および利益を主張する(その内容は出典明示によりその全体として本明細書の一部を構成する)。
本発明は、本明細書に記載の遊離形態、薬学的に許容される塩形態および/または実質的に純粋な形態の、特定の重水素化複素環縮合γカルボリン、ならびに5-HT2A受容体、セロトニン輸送体(SERT)および/またはドパミンD1/D2受容体シグナル伝達系が関わる経路が関わる疾患、例えば、不安、精神病、統合失調症、睡眠障害、性障害、片頭痛、頭部痛と関連する状態、社会恐怖症、胃腸管運動の機能障害のような胃腸障害、および肥満症;精神病またはパーキンソン病と関連するうつ病および気分障害;うつ病と関連する統合失調症のような精神病;双極性障害;および他の精神医学的状態および神経学的状態などの疾患または障害の治療における使用方法、ならびに他の薬剤との組合せに関する。
特許文献14には、ケトンおよび/またはN-メチル置換基の代謝を部分的に制限することによって代謝分解を減少させる目的のための一般的な重水素化複素環縮合γカルボリンが記載されている。
R1は、CH3またはCD3であり;
R2およびR3は、ともにHであるか、またはともにDであり;
ただし、R1がCH3である場合、R2およびR3はともにDである]
で示される化合物を提供する。
1.1 化合物が遊離形態または薬学的に許容される塩形態である、式I~IVのいずれかの化合物;
1.2 塩形態が薬学的に許容される酸の酸付加塩である、式1.1の化合物;
1.3 酸がトルエンスルホン酸である、式1.2の化合物;
1.4 化合物が実質的に純粋なジアステレオマー形態である(すなわち、他のジアステレオマーを実質的に含まない)、式I~IVまたは1.1~1.3のいずれかの化合物;
1.5 化合物が、70%を超えるジアステレオマー過剰率、好ましくは80%を超えるジアステレオマー過剰率、より好ましくは90%を超えるジアステレオマー過剰率、最も好ましくは95%を超えるジアステレオマー過剰率を有する、式I~IVまたは1.1~1.4のいずれかの化合物;
1.6 化合物が、構造式の所定の重水素位置での重水素の取り込みが天然のものよりも多い(すなわち、0.0156%を超える)、式I~IVまたは1.1~1.5のいずれかの化合物;
1.7 化合物が、構造式の所定の重水素位置での重水素の取り込みが天然のものよりも実質的に多い(例えば、0.1%を超えるか、または0.5%を超えるか、または1%を超えるか、または5%を超える)、式I~IVまたは1.1~1.6のいずれかの化合物;
1.8 化合物が、構造式の所定の重水素位置での重水素の取り込みが50%を超える(すなわち、50原子%Dを超える)、例えば、60%を超えるか、または70%を超えるか、または80%を超えるか、または90%を超えるか、または95%を超えるか、または96%を超えるか、または97%を超えるか、または98%を超えるか、または99%を超える、式I~IVまたは1.1~1.7のいずれかの化合物。
7.1 中枢神経系障害が、認知症と関連する1つ以上の障害、例えば、老人性認知症、アルツハイマー病、ピック病、前頭側頭型認知症、核上性麻痺(parasupranuclear palsy)、レビー小体型認知症、血管性認知症、ハンチントン病、パーキンソン病、多発性硬化症、筋萎縮性側索硬化症、ダウン症候群、高齢うつ病、ウェルニッケ・コルサコフ症候群、大脳皮質基底核変性症およびプリオン病、自閉症および注意欠陥多動症障害を包含する軽度認知障害および認知症性疾患と関連する障害である、方法I;
7.2 認知症と関連する障害が、(1)行動または気分障害、例えば激越/過敏、攻撃的行動(aggressive/assaultive behavior)、怒り、身体的または感情的爆発;(2)精神病;(3)うつ病;および(4)睡眠障害からなる群から選択される、方法Iまたは7.1;
7.3 中枢神経系障害が、激越/過敏、攻撃的行動(aggressive/assaultive behavior)、怒り、身体的または感情的爆発である、方法Iまたは7.1;
7.4 中枢神経系障害が、肥満症、不安、うつ病(例えば、難治性うつ病および大うつ病性障害(MDD))、精神病、統合失調症、睡眠障害(特に、統合失調症ならびに他の精神および神経疾患と関連する睡眠障害)、性障害、片頭痛、頭部痛と関連する状態、社会恐怖症、認知症における激越(例えば、アルツハイマー病における激越)、自閉症および関連自閉症性障害における激越、ならびに胃腸管運動の機能障害のような胃腸障害からなる群から選択される障害である、方法I;
7.5 中枢神経系障害が、国際公開第2009/145900号に同様に記載されるような(その記載内容は出典明示によりその全体として本明細書の一部を構成する)、セロトニン5-HT2A、ドパミンD1/D2受容体系および/またはセロトニン再取り込み輸送体(SERT)経路が関与する障害である、方法I、または7.2~7.4のいずれか;
7.6 中枢神経系障害が、セロトニン再取り込み輸送体(SERT)経路が関与する障害である、方法I、または式7.2~7.5のいずれか;
7.7 中枢神経系障害が、以下のものから選択される障害である、方法I、または式7.2~7.6のいずれか:(1)うつ病に罹患している患者における精神病(例えば、統合失調症);(2)精神病(例えば、統合失調症)に罹患している患者におけるうつ病;(3)精神病(例えば、統合失調症)またはパーキンソン病と関連する気分障害;および(4)精神病(例えば、統合失調症)またはパーキンソン病と関連する睡眠障害;(5)うつ病;(6)不安;(7)心的外傷後ストレス障害;または(8)衝動制御障害、例えば、間欠性爆発性障害;
7.8 中枢神経系障害が精神病(例えば、統合失調症)であり、該患者がうつ病に罹患している患者である、方法I、または式7.2~7.7のいずれか;
7.9 該患者が、慣用の統合失調症治療薬(例えば、クロルプロマジン、ハロペリドール、ドロペリドール、フルフェナジン、ロキサピン、メソリダジン、モリンドン、ペルフェナジン、ピモジド、プロクロルペラジン、プロマジン、チオリダジン、チオチキセチン、トリフロペラジン、クロザピン、アリピプラゾール、オランザピン、クエチアピン、リスペリドンおよびジプラシドン)の副作用に耐えられない、方法I、または式7.2~7.8のいずれか;
7.10 該患者が、慣用の統合失調症治療薬(例えば、ハロペリドール、アリピプラゾール、クロザピン、オランザピン、クエチアピン、リスペリドンおよびジプラシドン)の副作用に耐えられない、方法I、または式7.2~7.9のいずれか;
7.11 該障害がうつ病であり、該患者が精神病(例えば、統合失調症)またはパーキンソン病に罹患している患者である、方法I、または式7.2~7.10のいずれか;
7.12 該障害が睡眠障害であり、該患者がうつ病に罹患している、方法I、または式7.2~7.6のいずれか;
7.13 該1つ以上の障害が睡眠障害であり、該患者が精神病(例えば、統合失調症)に罹患している、方法I、または7.2~7.6のいずれか;
7.14 該1つ以上の障害が睡眠障害であり、該患者がパーキンソン病に罹患している、方法I、または7.2~7.6のいずれか;
7.15 該1つ以上の障害が睡眠障害であり、該患者がうつ病と精神病(例えば、統合失調症)またはパーキンソン病に罹患している、方法I、または7.2~7.6のいずれか;
7.16 該中枢神経系障害が、精神病(例えば、統合失調症(例えば、残遺亜型)、妄想性障害(例えば、身体型)、精神病を伴う大うつ病、精神病症状を伴う双極性障害、短期精神病性障害、統合失調症様障害、統合失調感情障害、または内科的疾患もしくは物質使用によって引き起こされる精神病)の残遺症状である、方法I、または7.1~7.6のいずれか。好ましくは、患者が統合失調症の残遺症状に罹患している;
7.17 該残遺期症状が下記のものを包含する、方法I、または7.1~7.6のいずれか:陰性症状、例えば、感情鈍麻、感情離脱、対人関係不良、受動的なまたは無欲性の社会離脱、抽象思考困難、会話の自発性および流暢さの欠如、ならびに常同思考;一般的な精神病理学的症状、例えば、身体的関心、不安、罪悪感、緊張、癖(mannerisms)および不自然な姿勢、うつ病、運動発達遅滞、非協力的、異常な思考内容、見当識障害、注意力不良、判断および洞察の欠如、意志の障害、衝動制御不良、先入観および能動的社会回避;認知機能障害および睡眠障害(例えば、不眠症);
7.18 有効量が、1mg~1000mg、好ましくは2.5mg~50mg、さらに好ましくは1~40mg、例えば、1~10mg、例えば、10mg、20mg、または20mg超、例えば、30mg、40mgである、上記の方法のいずれか;
7.19 有効量が、1mg~100mg/日、好ましくは2.5mg~50mg/日、さらに好ましくは1~40mg/日、例えば、1~10mg/日、例えば、10mg/日、20mg/日、または20mg超/日、例えば、30mg/日、40mg/日である、上記の方法のいずれか;
7.20 処置しようとする状態が、ジスキネジア、例えば、ドパミン作用薬、例えば、レボドパおよびレボドパ補助剤(カルビドパ、COMT阻害剤、MAO-B阻害剤)、ドパミンアゴニストから選択される薬物、例えば、レボドパ、および抗コリン薬を受けている患者におけるジスキネジアである、上記の方法のいずれか;
7.21 該患者がパーキンソン病に罹患している、上記の方法のいずれか;
7.22 該患者が、例えばシタロプラム(Celexa、Cipramil、Cipram、Dalsan、Recital、Emocal、Sepram、Seropram、Citox、Cital);ダポキセチン(Priligy);エスシタロプラム(Lexapro、Cipralex、Seroplex、Esertia);フルオキセチン(Depex、Prozac、Fontex、Seromex、Seronil、Sarafem、Ladose、Motivest、Flutop、Fluctin(EUR)、Fluox(NZ)、Depress(UZB)、Lovan(AUS)、Prodep(IND));フルボキサミン(Luvox、Fevarin、Faverin、Dumyrox、Favoxil、Movox);インダルピン(Upstene);パロキセチン(Paxil、Seroxat、Sereupin、Aropax、Deroxat、Divarius、Rexetin、Xetanor、Paroxat、Loxamine、Deparoc);セルトラリン(Zoloft、Lustral、Serlain、Asentra);ビラゾドン(Viibryd);またはジメリジン(Zelmid、Normud)の1つ以上から選択される選択的セロトニン再取り込み阻害剤に反応しない、上記の方法のいずれか;
7.23 該患者が、例えばシタロプラム(Celexa、Cipramil、Cipram、Dalsan、Recital、Emocal、Sepram、Seropram、Citox、Cital);ダポキセチン(Priligy);エスシタロプラム(Lexapro、Cipralex、Seroplex、Esertia);フルオキセチン(Depex、Prozac、Fontex、Seromex、Seronil、Sarafem、Ladose、Motivest、Flutop、Fluctin(EUR)、Fluox(NZ)、Depress(UZB)、Lovan(AUS)、Prodep(IND));フルボキサミン(Luvox、Fevarin、Faverin、Dumyrox、Favoxil、Movox);インダルピン(Upstene);パロキセチン(Paxil、Seroxat、Sereupin、Aropax、Deroxat、Divarius、Rexetin、Xetanor、Paroxat、Loxamine、Deparoc);セルトラリン(Zoloft、Lustral、Serlain、Asentra);ビラゾドン(Viibryd);またはジメリジン(Zelmid、Normud)の1つ以上から選択される選択的セロトニン再取り込み阻害剤も受けている、上記の方法のいずれか;
7.24 該患者が、自閉症スペクトラム症、例えば、自閉症またはアスペルガー症候群に罹患している、上記の方法のいずれか;
7.25 該患者が、認知症、例えば、老人性認知症、アルツハイマー病、ピック病、前頭側頭型認知症、核上性麻痺(parasupranuclear palsy)、レビー小体型認知症、血管性認知症、ハンチントン病、パーキンソン病、多発性硬化症、筋萎縮性側索硬化症、ダウン症候群、高齢うつ病、ウェルニッケ・コルサコフ症候群、大脳皮質基底核変性症およびプリオン病、自閉症および注意欠陥多動症障害を包含する、軽度認知障害および認知症性疾患と関連する障害に罹患している、上記の方法のいずれか;
7.26 該患者が、遊離形態または薬学的に許容される塩形態の、コリンエステラーゼ阻害剤(例えば、アセチルコリンエステラーゼ阻害剤)またはNメチルDアスパラギン酸(NMDA)受容体アンタゴニストも受けている、上記の方法のいずれか;
7.27 該コリンエステラーゼ阻害剤(例えば、アセチルコリンエステラーゼ阻害剤)が、遊離形態または薬学的に許容される塩形態の、タクリン、リバスチグミン(Exelon)、ドネペジル(Aricept)、およびガランタミン(Razadyne、以前はReminylと称されていた)からなる群から選択される、方法7.26;
7.28 該コリンエステラーゼ阻害剤(例えば、アセチルコリンエステラーゼ阻害剤)が遊離形態または薬学的に許容される塩形態のドネペジルである、方法7.26;
7.29 該NMDA受容体アンタゴニストが遊離形態または薬学的に許容される塩形態のメマンチンである、方法7.26;
7.30 さらなる統合失調症治療薬および/または抗うつ薬および/または睡眠薬のような1つ以上の他の治療薬を投与することを含む、上記の方法のいずれか;
7.31 該1つ以上の他の治療薬が、遊離形態または薬学的に許容される塩形態の、抗うつ薬、例えば、GABA活性を調節する(例えば、該活性を増強し、GABA伝達を促進する)化合物、GABA-Bアゴニスト、5-HT調節物質(例えば、5-HT1Aアゴニスト、5-HT2Aアンタゴニスト、5-HT2Aインバースアゴニスト等)、メラトニンアゴニスト、イオンチャネル調節物質(例えば、ブロッカー)、セロトニン-2アンタゴニスト/再取り込み阻害剤(SARI)、オレキシン受容体アンタゴニスト、H3アゴニスト、ノルアドレナリン作動性アンタゴニスト、ガラニンアゴニスト、CRHアンタゴニスト、ヒト成長ホルモン、成長ホルモンアゴニスト、エストロゲン、エストロゲンアゴニスト、ニューロキニン-1薬;および統合失調症治療薬、例えば、非定型統合失調症治療薬から選択される、方法7.30;
7.32 該1つ以上の他の治療薬が、統合失調症治療薬、例えば、クロルプロマジン、ハロペリドール、ドロペリドール、フルフェナジン、ロキサピン、メソリダジン、モリンドン、ペルフェナジン、ピモジド、プロクロルペラジン、プロマジン、チオリダジン、チオチキセチン、トリフロペラジン、クロザピン、アリピプラゾール、オランザピン、クエチアピン、リスペリドン、ジプラシドン、パリペリドン、アセナピン、ルラシドン、イロペリドン、カリプラジン、アミスルプリド、ゾテピン、セルチンドールであり、該1つ以上の他の治療薬が式I~IVもしくは1.1~1.8の化合物の補助剤として投与されるか、または式I~IVもしくは1.1~1.8の化合物が該1つ以上の他の治療薬の補助剤として投与される、方法7.30または7.31。
7.4P 遊離形態または薬学的に許容される塩形態の、式I~IVまたは1.1~1.8の化合物;
7.8P 上記の医薬組成物またはデポ組成物;または
7.11P 上記の浸透圧制御放出経口送達系組成物。
8.1 遊離形態または薬学的に許容される塩形態の式I~IVまたは1.1~1.8の化合物;
8.2 上記の医薬組成物またはデポ組成物;
8.3 上記の浸透圧制御放出経口送達系組成物。
8.11 睡眠障害が睡眠維持障害である、上記の方法のいずれか;
8.12 有効量が、1mg~10mg/日、例えば1~5mg/日、好ましくは2.5~5mg/日、さらに好ましくは10mg/日である、上記の方法のいずれか;
8.13 有効量が、2.5mg/日または5mg/日、または10mg/日である、上記の方法のいずれか;
8.14 睡眠障害が、ジスキネジアに罹患しているかまたはそのリスクがある患者、例えば、例えばレボドパおよびレボドパ補助剤(カルビドパ、COMT阻害剤、MAO-B阻害剤)、ドパミンアゴニストから選択されるドパミン作用薬を受けている患者、例えばレボドパを受けている患者、および抗コリン薬を受けている患者におけるものである、上記の方法のいずれか;
8.15 該患者がパーキンソン病に罹患している、上記の方法のいずれか。
9.1 該治療薬が、GABA活性を調節する(例えば、該活性を増強し、GABA伝達を促進する)化合物である、方法I-AまたはII-A;
9.2 該GABA化合物が、ドキセピン、アルプラゾラム、ブロマゼパム、クロバザム、クロナゼパム、クロラゼペート、ジアゼパム、フルニトラゼパム、フルラゼパム、ロラゼパム、ミダゾラム、ニトラゼパム、オキサゼパム、テマザパム、トリアゾラム、インジプロン、ゾピクロン、エスゾピクロン、ザレプロン、ゾルピデム、ガバキサドール(gabaxadol)、ビガバトリン、チアガビン、EVT 201(Evotec Pharmaceuticals)およびエスタゾラムの1つ以上からなる群から選択される、方法I-AまたはII-Aまたは9.1;
9.3 該治療薬がさらなる5HT2Aアンタゴニストである、方法I-AまたはII-A;
9.4 該さらなる5HT2Aアンタゴニストが、ケタンセリン、リスペリドン、エプリバンセリン、ボリナンセリン(Sanofi-Aventis、France)、プルバンセリン、MDL 100907(Sanofi-Aventis、France)、HY 10275(Eli Lilly)、APD 125(Arena Pharmaceuticals、San Diego、CA)およびAVE8488(Sanofi-Aventis、France)の1つ以上から選択される、方法I-AまたはII-Aまたは9.3;ピマバンセリン(ACP-103)およびピゾチフェンから選択される、方法I-AまたはII-A、9.3または9.4;
9.5 治療薬がメラトニンアゴニストである、方法I-AまたはII-A;
9.6 該メラトニンアゴニストが、メラトニン、ラメルテオン(ROZEREM(登録商標)、武田薬品工業株式会社、日本)、VEC-162(Vanda Pharmaceuticals、Rockville、MD)、PD-6735(Phase II Discovery)およびアゴメラチンの1つ以上からなる群から選択される、方法I-AまたはII-Aまたは9.5;
9.7 該治療薬がイオンチャネルブロッカーである、方法I-AまたはII-A;
9.8 該イオンチャネルブロッカーが、ラモトリギン、ガバペンチンおよびプレガバリンの1つ以上である、方法I-AまたはII-Aまたは9.7;
9.9 該治療薬がオレキシン受容体アンタゴニストである、方法I-AまたはII-A;
9.10 該オレキシン受容体アンタゴニストが、オレキシン、1,3-ビアリール尿素、SB-334867-a(GlaxoSmithKline、UK)、GW649868(GlaxoSmithKline)およびベンズアミド誘導体からなる群から選択される、方法I-AまたはII-Aまたは9.9;
9.11 該治療薬がセロトニン-2受容体アンタゴニスト/再取り込み阻害剤(SARI)である、方法I-AまたはII-A;
9.12 該セロトニン-2受容体アンタゴニスト/再取り込み阻害剤(SARI)が、つ以上のOrg 50081(Organon-Netherlands)、リタンセリン、ネファゾドン、セルゾンおよびトラゾドンからなる群から選択される、方法I-AまたはII-Aまたは9.11;
9.13 該治療薬が5HT1aアゴニストである、方法I-AまたはII-A;
9.14 該5HT1aアゴニストが、レピノタン、サリゾタン、エプタピロン、ブスピロンおよびMN-305(MediciNova、San Diego、CA)の1つ以上からなる群から選択される、方法I-AまたはII-Aまたは9.13;
9.15 該治療薬がニューロキニン-1薬である、方法I-AまたはII-A;
9.16 該ニューロキニン-1薬がカソピタント(GlaxoSmithKline)である、方法I-AまたはII-Aまたは9.15;
9.17 該治療薬が統合失調症治療薬である、方法I-AまたはII-A;
9.18 該統合失調症治療薬が、クロルプロマジン、ハロペリドール、ドロペリドール、フルフェナジン、ロキサピン、メソリダジン、モリンドン、ペルフェナジン、ピモジド、プロクロルペラジン、プロマジン、チオリダジン、チオチキセチン、トリフロペラジン、クロザピン、アリピプラゾール、オランザピン、クエチアピン、リスペリドン、ジプラシドンおよびパリペリドンからなる群から選択される、方法I-AまたはII-Aまたは9.17;
9.19 該治療薬が抗うつ薬である、方法I-AまたはII-A;
9.20 該抗うつ薬が、アミトリプチリン、アモキセピン、ブプロピオン、シタロプラム、クロミプラミン、デシプラミン、ドキセピン、デュロキセチン、エスシタロプラム、フルオキセチン、フルボキサミン、イミプラミン、イソカルボキサジド、マプロチリン、ミルタザピン、ネファゾドン、ノルトリプチリン、パロキセチン、フェネルジン硫酸塩、プロトリプチリン、セルトラリン、トラニルシプロミン、トラゾドン、トリミプラミンおよびベンラファキシンから選択される、方法I-AまたはII-Aまたは9.19;
9.21 該統合失調症治療薬が非定型統合失調症治療薬である、方法I-AまたはII-A、9.17または9.18;
9.22 該非定型統合失調症治療薬が、クロザピン、アリピプラゾール、オランザピン、クエチアピン、リスペリドン、ジプラシドンおよびパリペリドンからなる群から選択される、方法I-AまたはII-A、または9.17~9.21のいずれか;
9.23 該治療薬が、方法9.1~9.22のいずれかから選択され、例えば、モダフィニル、アルモダフィニル、ドキセピン、アルプラゾラム、ブロマゼパム、クロバザム、クロナゼパム、クロラゼペート、ジアゼパム、フルニトラゼパム、フルラゼパム、ロラゼパム、ミダゾラム、ニトラゼパム、オキサゼパム、テマザパム、トリアゾラム、インジプロン、ゾピクロン、エスゾピクロン、ザレプロン、ゾルピデム、ガバキサドール(gabaxadol)、ビガバトリン、チアガビン、EVT 201(Evotec Pharmaceuticals)、エスタゾラム、ケタンセリン、リスペリドン、エプリバンセリン、ボリナンセリン(Sanofi-Aventis、France)、プルバンセリン、MDL 100907(Sanofi-Aventis、France)、HY 10275(Eli Lilly)、APD 125(Arena Pharmaceuticals、San Diego、CA)、AVE8488(Sanofi-Aventis、France)、レピノタン、サリゾタン、エプタピロン、ブスピロン、MN-305(MediciNova、San Diego、CA)、メラトニン、ラメルテオン(ROZEREM(登録商標)、武田薬品工業株式会社、日本)、VEC-162(Vanda Pharmaceuticals、Rockville、MD)、PD-6735(Phase II Discovery)、アゴメラチン、ラモトリギン、ガバペンチン、プレガバリン、オレキシン、1,3-ビアリール尿素、SB-334867-a(GlaxoSmithKline、UK)、GW649868(GlaxoSmithKline)、ベンズアミド誘導体、Org 50081(Organon-Netherlands)、リタンセリン、ネファゾドン、セルゾン、トラゾドン、カソピタント(GlaxoSmithKline)、アミトリプチリン、アモキセピン、ブプロピオン、シタロプラム、クロミプラミン、デシプラミン、ドキセピン、デュロキセチン、エスシタロプラム、フルオキセチン、フルボキサミン、イミプラミン、イソカルボキサジド、マプロチリン、ミルタザピン、ネファゾドン、ノルトリプチリン、パロキセチン、フェネルジン硫酸塩、プロトリプチリン、セルトラリン、トラニルシプロミン、トラゾドン、トリミプラミン、ベンラファキシン、クロルプロマジン、ハロペリドール、ドロペリドール、フルフェナジン、ロキサピン、メソリダジン、モリンドン、ペルフェナジン、ピモジド、プロクロルペラジン、プロマジン、チオリダジン、チオチキセチン、トリフロペラジン、クロザピン、アリピプラゾール、オランザピン、クエチアピン、リスペリドン、ジプラシドンおよびパリペリドンからなる群から選択される、方法I-AまたはII-A;ここに挙げられた治療薬に加えて、方法I-AまたはII-Aは、さらに、ピマバンセリン(ACP-103)およびピゾチフェンから選択される;
9.24 該治療薬がH3アゴニストである、方法I-AまたはII-A;
9.25 該治療薬がH3アンタゴニストである、方法I-AまたはII-A;
9.26 該治療薬がノルアドレナリン作動性アゴニストまたはアンタゴニストである、方法I-AまたはII-A;
9.27 該治療薬がガラニンアゴニストである、方法I-AまたはII-A;
9.28 該治療薬がCRHアンタゴニストである、方法I-AまたはII-A;
9.29 該治療薬がヒト成長ホルモンである、方法I-AまたはII-A;
9.30 該治療薬が成長ホルモンアゴニストである、方法I-AまたはII-A;
9.31 該治療薬がエストロゲンまたはエストロゲンアゴニストである、方法I-AまたはII-A;
9.32 該治療薬が5-HT6受容体アンタゴニストである、方法I-AまたはII-A;
9.33 該治療薬がニューロキニン-1薬である、方法I-AまたはII-A;
9.34 治療薬が式(I)の化合物と組み合わされ、該治療薬が、抗パーキンソン薬、例えば、L-ドパ、コ-カレルドパ、デュオドパ、スタロバ(stalova)、シンメトレル、ベンゾトロピン、ビペリデン、ブロモクリプチン、エンタカポン、ペルゴリド、プラミペキソール、プロシクリジン、ロピニロール、セレギリンおよびトルカポンである、方法I-AまたはII-A;
9.35 式(I)の化合物が、挙げられた疾患および/またはパーキンソン病に罹患している患者における睡眠障害、うつ病、精神病またはその組合せの処置に使用され得る、方法I-AまたはII-A;
9.36 該障害が、精神病(例えば、統合失調症)、うつ病、気分障害、睡眠障害(例えば、睡眠維持および/または睡眠開始)またはその障害の組合せの少なくとも1つ以上から選択される、方法I-AまたはII-A;
9.37 該障害が睡眠障害である、上記の方法のいずれか;
9.38 該障害が、精神病(例えば、統合失調症)またはパーキンソン病と関連する睡眠障害である、遊離形態または薬学的に許容される塩形態の、上記の方法のいずれか。
11.1 遊離形態または薬学的に許容される塩形態の、式Iまたは式1~1.9のいずれかの化合物;
11.2 上記の医薬組成物;
11.3 上記のデポ組成物;または
11.4 上記の浸透圧制御放出経口送達系組成物。
12.1 上記の医薬組成物;
12.2 上記のデポ組成物;または
12.3 上記の浸透圧制御放出経口送達系組成物。
他に特記されない場合または文脈から明らかでない場合、本明細書で用いる下記の用語は、下記の意味を有する:
a.本明細書で用いる「残遺症状」としては、Kay et al., Schizophr. Bull. (1987) 13(2):261-276(出典明示によりその全体として本明細書の一部を構成する)に記載されているPositive and Negative Symptom Scale(PANSS)に記載されているような陰性症状および一般的な精神病理学的症状を包含する。陰性症状としては以下のものが挙げられる:感情鈍麻、感情離脱、対人関係不良、受動的/無欲性社会離脱、抽象思考困難、会話の自発性および流暢さの欠如および常同思考。一般的な精神病理学的症状としては、以下のものが挙げられる:身体的関心、不安、罪悪感、緊張、癖(mannerisms)および不自然な姿勢、うつ病、運動発達遅滞、非協力的、異常な思考内容、見当識障害、注意力不良、判断および洞察の欠如、意志の障害、衝動制御不良、先入観および能動的社会回避。残遺症状はまた、うつ病、認知障害および睡眠障害(例えば、不眠症)も包含し得る。本発明の化合物は、これらの残遺症状のうち、受動的な社会離脱、常同思考、身体的関心、不安、緊張、能動的社会回避およびうつ病処置に特に有用である。したがって、本発明の化合物は、統合失調症に罹患している患者における社会的統合および社会的機能の改善に特に有用である。これらの残遺症状の処置は、また、うつ病にも罹患している統合失調症患者に特に有用である。
b.式において、例えば式I~IVまたは1.1~1.8のいずれかの構造式において、および「CD3」のような用語において用いられる場合、「D」とは、同位体重水素(2H)を天然存在量よりも多く含有する水素の原子をいう。天然の化学物質はすべて、すべての水素原子に対して約0.0156原子%の重水素を含有する水素原子を包含する。本開示における「D」および「重水素」の使用は、この天然の存在量を上回り、例えば、0.1%を上回り、または1%を上回り、100%に満たない任意の値まで(例えば、99%、または99.9%、または99.99%、または99.999%)の重水素の量の任意の濃縮をいう。水素原子としての「H」の使用は、天然の存在量以下の重水素、例えば、0.0156原子%以下の重水素を含有する化学構造における水素原子をいう。
本発明の化合物の中間体は、一般的に、国際特許出願PCT/US08/03340(国際公開第2008/112280号);米国出願第10/786,935号;米国特許第6,548,493号;第7,238,690号;第6,552,017号;第6,713,471号;第7,183,282号;米国再発行特許発明第39680号および米国再発行特許発明第39679号、ならびに国際公開第2015/154025号(各記載内容は、出典明示によりその全体として本明細書の一部を構成する)の記載に従って製造し得る。本発明の化合物の塩もまた、米国特許第6,548,493号;第7,238,690号;第6,552,017号;第6,713,471号;第7,183,282号;米国再発行特許発明第39680号;米国再発行特許発明第39679号;および国際公開第2009/114181号(各記載内容は、出典明示によりその全体として本明細書の一部を構成する)の記載と同様に製造され得る。
1-(4-フルオロフェニル)-4-((6bR,10aS)-3-メチル-d3-2,3,6b,7,10,10a-ヘキサヒドロ-1H-ピリド[3',4':4,5]ピロロ[1,2,3-de]キノキサリン-8(9H)-イル)ブタン-1-オン・p-トルエンスルホン酸塩
2,2-d2-1-(4-フルオロフェニル)-4-((6bR,10aS)-3-メチル-2,3,6b,7,10,10a-ヘキサヒドロ-1H-ピリド[3',4':4,5]ピロロ[1,2,3-de]キノキサリン-8(9H)-イル)ブタン-1-オン
2,2-d2-1-(4-フルオロフェニル)-4-((6bR,10aS)-3-メチル-d3-2,3,6b,7,10,10a-ヘキサヒドロ-1H-ピリド[3',4':4,5]ピロロ[1,2,3-de]キノキサリン-8(9H)-イル)ブタン-1-オン・p-トルエンスルホン酸塩
1-(4-フルオロ(2,3,5,6-d4)フェニル)-4-((6bR,10aS)-3-メチル-2,3,6b,7,10,10a-ヘキサヒドロ-1H-ピリド[3',4':4,5]ピロロ[1,2,3-de]キノキサリン-8(9H)-イル)ブタン-1-オン・p-トルエンスルホン酸塩
実施例1~3の化合物および式Qの化合物をマウスに投与し、親化合物および主要アミド代謝物の両方のレベルを研究する。式Qの化合物の合成手順は、国際公開第2008/112280号に見ることができる。各研究の動物群における固有の代謝速度の差を制御するために、各研究において、内部標準として比較実施例4の化合物を使用する。試験化合物および内部標準の単回経口投与から0.25時間後、0.5時間後、1時間後、2時間後、4時間後および6時間後に親化合物および代謝物の血漿中レベルを測定する。親および主要アミド代謝物の両方の最大濃度、最大濃度までの時間、および曲線下面積(AUC)を測定する。各試験化合物についてのAUC値を、内部標準(実施例4)のAUCに対するその比をとることによって正規化する。かくして、各実施例X(すなわち、実施例1、実施例2、実施例3および実施例Q)について、以下のようにして相対的なアミド形成を算出する:
実施例2の重水素化化合物(式Iの化合物、トシレート塩)のインビボ代謝(脱メチル化/酸化)を、その非重水素化コンジナーである式Qの化合物(トシレート塩)のものと比べる。ラットにおける交差研究において経口(PO)投与後および静脈内(IV)投与後の両方における各化合物の薬物動態を測定する。
実施例2の重水素化化合物(式Iの化合物、トシレート塩)のインビボ代謝(脱メチル化およびα酸化)を、その非重水素化コンジナーである式Qの化合物(トシレート塩)のものと比較する。イヌにおける非クロスオーバー連続研究において、舌下(SL)投与および皮下(SC)投与後に各化合物の薬物動態を測定する。
表2は、3つの化合物のすべてがセロトニン、ドパミンD1、ドパミンD2およびセロトニン輸送体受容体で活性を有するが、これらの受容体でのそれらの相対的な活性は異なることを示している。代謝物Q-1Aは親Qと非常に類似している薬理学的プロファイルを有するが、表2は、代謝物Q-1がドパミンD2受容体およびセロトニン輸送体での相対活性が非常に低いという点で有意に異なることを示している。加えて、式Q-1の化合物は、QおよびQ-1Aとは異なって、強力なμオピエート受容体アンタゴニスト(約22nMのKi)であることが分かっている。それらの異なる受容体活性プロファイルのために、関連する代謝物の各々は、親薬物Qと比べて異なる機能的薬理学的効果を有する。かくして、化合物QおよびQ-1Aを代謝物Q-1に転換する代謝経路を遮断することによって、薬理学的機能に対する有意に効果を得ることができる。したがって、本発明は、親薬物によってもたらされる全薬理学的プロファイルを調節するためにこの代謝経路を阻害するのに有用である。
Claims (17)
- 化合物が塩形態である、請求項1に記載の医薬組成物。
- 塩がトルエンスルホン酸付加塩である、請求項2に記載の医薬組成物。
- 化合物が遊離形態または塩形態の式IIの化合物である、請求項1に記載の医薬組成物。
- 患者が不安、うつ病、難治性うつ病、大うつ病性障害(MDD)、精神病、統合失調症、性障害、片頭痛、社会恐怖症、激越、衝動制御障害、間欠性爆発性障害の1以上にも罹患している、請求項1~4の何れかに記載の医薬組成物。
- 患者がさらに激越/過敏、攻撃的行動(aggressive/assaultive behavior)、怒り、身体的または感情的爆発、精神病およびうつ病からなる群から選択される認知症と関連する障害に罹患している、請求項1~4の何れかに記載の医薬組成物。
- 該認知症と関連する障害が激越/過敏である、請求項6に記載の医薬組成物。
- 1以上の他の治療剤と併用することを特徴とする、請求項1~7の何れかに記載の医薬組成物。
- 1以上の他の治療剤が、遊離形態または薬学的に許容される塩形態のGABA活性を調節する化合物、GABA-Bアゴニスト、5-HT調節物質、メラトニンアゴニスト、イオンチャネル調節物質、セロトニン-2アンタゴニスト/再取り込み阻害剤(SARI)、5-HT6アンタゴニスト、オレキシン受容体アンタゴニスト、H3アゴニスト、ノルアドレナリンアンタゴニスト、ガラニンアゴニスト、CRHアンタゴニスト、ヒト成長ホルモン、成長ホルモンアゴニスト、エストロゲン、エストロゲンアゴニスト、ニューロキニン-1薬;および抗精神病薬;および抗うつ薬から選択される、請求項8に記載の医薬組成物。
- 1以上の他の治療剤がアミトリプチリン、アモキサピン、ブプロピオン、シタロプラム、クロミプラミン、デシプラミン、ドキセピン、デュロキセチン、エスシタロプラム、フルオキセチン、フルボキサミン、イミプラミン、イソカルボキサジド、マプロチリン、ミルタザピン、ネファゾドン、ノルトリプチリン、パロキセチン、フェネルジン硫酸塩、プロトリプチリン、セルトラリン、トラニルシプロミン、トラゾドン、トリミプラミンおよびベンラフェキシンの1以上から選択される抗うつ薬である、請求項9に記載の医薬組成物。
- 抗うつ薬がSSRIである、請求項9に記載の医薬組成物。
- 該認知症が軽度認知障害、老人性認知症、アルツハイマー病、ピック病、前頭側頭型認知症、核上性麻痺(parasupranuclear palsy)、レビー小体型認知症、血管性認知症、ハンチントン病、パーキンソン病、多発性硬化症、筋萎縮性側索硬化症、高齢うつ病、ウェルニッケ・コルサコフ症候群、大脳皮質基底核変性症およびプリオン病、自閉症または注意欠陥多動症障害から選択される、請求項1~11の何れかに記載の医薬組成物。
- 該認知症がアルツハイマー病である、請求項1~11の何れかに記載の医薬組成物。
- 該認知症がパーキンソン病である、請求項1~11の何れかに記載の医薬組成物。
- 治療有効量が1日あたり2.5~50mgの用量である、請求項1~14の何れかに記載の医薬組成物。
- 構造式の所定の重水素位置での重水素の取り込みが90%を超える、請求項1~15の何れかに記載の医薬組成物。
- 構造式の所定の重水素位置での重水素の取り込みが97%を超える、請求項1~15の何れかに記載の医薬組成物。
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