JP7460369B2 - Gpr6のテトラヒドロピリドピラジンモジュレーター - Google Patents
Gpr6のテトラヒドロピリドピラジンモジュレーター Download PDFInfo
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- JP7460369B2 JP7460369B2 JP2019563277A JP2019563277A JP7460369B2 JP 7460369 B2 JP7460369 B2 JP 7460369B2 JP 2019563277 A JP2019563277 A JP 2019563277A JP 2019563277 A JP2019563277 A JP 2019563277A JP 7460369 B2 JP7460369 B2 JP 7460369B2
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Description
本出願は、2017年6月15日に出願された米国仮特許出願第62/520,430号、2017年11月28日に出願された米国仮特許出願第62/591,247号、2018年3月29日に出願された米国仮特許出願第62/649,856号および2018年5月16日に出願された米国仮特許出願第62/672,261号に対する優先権を主張するものであり、それら各々の全内容を参照により本明細書に援用する。
の化合物およびその医薬的に許容される塩を提供する。式1は、化合物(R)-1-(2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-3-((テトラヒドロフラン-3-イル)アミノ)-7,8-ジヒドロピリド[3,4-b]ピラジン-6(5H)-イル)エタン-1-オンを表す。
別段の指示がない限り、本開示では以下に提供される定義が使用される。
式中、ARおよびASは、サンプルにおけるRおよびS鏡像体の量である。
以下に記載されるように、本開示は、式1の化合物およびその医薬的に許容される塩に関する。本開示はまた、式1の化合物を調製するための材料および方法、それを含有する医薬組成物、ならびにパーキンソン病を含めたCNSの疾患、傷害または病状およびGPR6と関連する他の疾患、傷害または病状を治療するための、当該式1の化合物およびその医薬的に許容される塩の(場合により他の薬理活性剤と組み合わせた)使用に関する。
式1の化合物は、以下の技術を用いて調製することができる。スキームおよび実施例のあるものについては、有機化学の当業者には公知である、酸化、還元などの一般的反応、分離方法(抽出、蒸発、沈殿、クロマトグラフィー、濾過、研和、結晶化など)、ならびに解析手順の詳細を省く場合もある。このような反応および技術の詳細は、多数の論文に見出すことができ、このような論文としては、以下のものが挙げられる:Richard Larock, Comprehensive Organic Transformations(1999)およびthe multi-volume series edited by Michael B. Smith and others, Compendium of Organic Synthetic Methods(1974 et seq.)(それらの全内容を参照により本明細書に援用する)。出発材料および試薬は、市販のものから入手してもよいし、文献に記載の方法を用いて調製してもよい。反応スキームの中には、化学的変換により生成された微量の生成物(例えば、エステルの加水分解からのアルコール、二酸の脱カルボン酸からのCO2)を無視してよいものもある。更に、場合によっては、反応中間物を単離または精製せずに(すなわち、インサイチュで)次の工程で用いてもよい。
式1の化合物(その医薬的に許容される錯体、塩、溶媒和物および水和物を含む)は、適切な剤形および投与経路を選択するために、溶解度およびpHによる溶液安定性、透過性などの生物製剤特性を評価すべきである。医薬用途を目的とする化合物は、結晶性または非晶性製品として投与してもよく、例えば、沈殿、結晶化、凍結乾燥、噴霧乾燥、蒸発乾燥、マイクロ波乾燥、または高周波乾燥などの方法により、固体プラグ、粉末、もしくはフィルム剤として得ることもできる。
GPR6モジュレーターとしての化合物の活性は、インビトロおよびインビボ方法を含む様々な方法によって測定することができる。
この細胞ベースのアッセイは、試験化合物がCHO-K1細胞に発現するGPR6受容体の構成cAMP活性を阻害する能力を測定する。CHO細胞はGPR6受容体を安定して発現し、その発現はテトラサイクリン誘導性要素により制御される。細胞を、F12K、10%FBS、1%Penn/Strep、200μg/mLのハイグロマイシンを含有する培地で培養した。GPR6受容体発現を、増殖培地中の2μg/mLのドキシサイクリン(Sigma D9891)を用いて20時間誘導する。ドキシサイクリンを添加した後、細胞を、1ウェル当たり細胞450~750の密度で96ウェル半量黒色組織培養プレート(Costar)において平板培養し(plated)、cAMPアッセイ前に、20時間、インキュベーター(37℃、5%CO2)中に静置する。
この細胞ベースのアッセイは、化合物がCHO-K1細胞に発現するGPR6受容体の構成cAMP活性を阻害する能力を測定する。CHO細胞はGPR6受容体を安定して発現し、その発現はテトラサイクリン誘導性要素により制御される。当該細胞を、F12K、10%FBS、1%Penn/Strep、200μg/mLのハイグロマイシンを含有する培地で培養する。GPR6受容体発現を、増殖培地中の1μg/mLのドキシサイクリン(Sigma D9891)を用いて20時間誘導する。ドキシサイクリンを添加した後、細胞を、1ウェル当たり細胞250~500の密度で半量黒色透明底プレート(Costar)において平板培養し(plated)、cAMPアッセイ前に、20時間、インキュベーター(37℃、5%CO2)中に静置する。
濾過ベースのフォーマットを使用する競合的結合アッセイを用いて、GPR6逆作動薬の結合特性を検討する。当該方法は、ドキシサイクリン誘発性プロモーターにより駆動されるヒトGPR6cDNAを発現するCHO-K1細胞から調製した膜を使用する。試験化合物の段階希釈物(試験リガンド1μL/ウェル)を含有するアッセイレディ96ウェルプレート(651201、Greiner、米国)を、液体ハンドラ(5μM、最終アッセイ最高濃度)を用いてDMSOにおいて調製する。アッセイ緩衝液(50mM Tris、pH7.4、50mM NaCl、6mM MgCl2、脂肪酸不含0.1%BSA、1:100プロテイナーゼ阻害剤カクテル、Sigma、米国)を加え(39μL/ウェル)、プレートをプレートシェーカー上で10分間混合する。GPR6特異的3H放射性リガンドをアッセイ緩衝液中で調製し、各ウェルに加える(40μL、2.4nM最終アッセイ濃度)。
パーキンソン病の運動症状としては、運動低下症、運動緩慢、強直、振戦および姿勢異常が挙げられ、線条体ドーパミン作動性細胞の損失および線条体ドーパミンレベルの低下と関連している。げっ歯類へのハロペリドールの投与は、レボドパおよびパーキンソン病を治療するために臨床的に検証された他の薬物の投与により回復する一過性のパーキンソン病様状態を導く。Duty, S. & Jenner, P. Br. J. Pharmacol. 164:1357-1391(2011)(その全内容を参照により本明細書に援用する)を参照のこと。ハロペリドールは、運動回路の間接的および直接的経路を含む中型有棘ニューロンにおいて、それぞれ、ドーパミンD2受容体、およびより少ない程度で、ドーパミンD1受容体を拮抗する。結果として得られる線条体ドーパミン伝達の遮断は、筋肉の硬直およびカタレプシーの症状として発現する基底核回路内での異常な下流燃焼をもたらす。カタレプシーがパーキンソン病の臨床的特徴をもたらすと仮定されており、それにより、患者は、運動を開始する能力がないと感じる。
自動化全細胞パッチクランプシステム(QPATCH(登録商標)16)を用いて、単一細胞から外向きカリウム電流を記録する。アッセイは、ヒトhERG cDNAを安定にトランスフェクトしたCHO-K1(チャイニーズハムスター卵巣)細胞を使用する。細胞をトリプシン処理により収穫し、無血清培地中に室温で維持してから、記録する。細胞を洗浄し、細胞外溶液で再懸濁してから、自動化パッチクランプサイトに適用する。パッチクランプアッセイの日に、水性細胞外溶液(137mM NaCl、4mM KCl、1.8mM CaCl2、1mM MgCl2、10mM D(+)-グルコース、10mM HEPES、NaOHで7.4に調整したpH)中で試験溶液を調製する。7種の濃度(0.03、0.1、0.3、1、3、10および30μM)の試験化合物を用いてIC50を測定する。水性細胞内溶液は、130mM KCl、10mM NaCl、1mM MgCl2、10mM EGTA、5mM MgATPおよび10mM HEPES(KOHで7.2に調製したpH)を含有する。
以下の実施例は説明のためのものであって、限定ではなく、本発明の具体例を示す。
以下の実施例における化合物の多くについて、1H NMRスペクトルを得た。特徴的な化学シフト(δ)は、s(一重項)、d(二重項)、t(三重項)、q(四重項)、m(多重項)およびbr(ブロード)を含む主要なピークの名称に関する従来の略語を用いて、テトラメチルシランからの100万分の1のダウンフィールドで表される。一般的な溶媒に関して、以下の略語を使用する:CDCl3(ジュウテロクロロホルム)、DMSO-d6(ジュウテロジメチルスルホキシド)、CD3OD(ジュウテロメタノール)、CD3CN(ジュウテロアセトニトリル)およびTHF-d8(ジュウテロテトラヒドロフラン)。エレクトロスプレーイオン化(ESI-MS)または大気圧化学イオン化(APCI-MS)質量分析のいずれかを用いて質量スペクトル([M+H]+についてはm/z)を記録した。
示されている場合、質量トリガHPLC(例えば、ポンプ:WATER(商標)2525;MS:ZQ(商標);ソフトウェア:MASSLYNX(商標))、フラッシュクロマトグラフィーまたは分取薄層クロマトグラフィー(TLC)によって特定の調製および実施例の生成物を精製する。典型的には、CH3CN、ならびに0.035%および0.05%トリフルオロ酢酸(TFA)をそれぞれ含有する水移動相で溶出する酸性条件(「酸モード」)、または水および20/80(v/v)水/アセトニトリル移動相で溶出する塩基条件(「塩基モード」)(いずれも10mM NH4HCO3を含有する)下、カラム(例えば、Phenomenex GEMINI(商標) 5μ、C18、30mm×150mm;AXIA(商標)、5μ、30mm×75mm)上で逆相クロマトグラフィーを実施する。典型的にはシリカゲル60F254プレート上で分取TLCを実施する。クロマトグラフィーによる単離後、溶媒を除去し、遠心エバポレーター(例えば、GeneVac(商標))、ロータリーエバポレーター、排気したフラスコなどでの乾燥により生成物を得る。典型的には、約1大気圧(14.7psi)の圧力にて、不活性(例えば、窒素)または反応性(例えば、H2)雰囲気での反応を実施する。
調製1:(R)-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-N-(テトラヒドロフラン-3-イル)ピリド[3,4-b]ピラジン-3-アミン
(R)-テトラヒドロフラン-3-アミン(ArkPharm、AK-75910、ロットWZG082316-PB01)(5.32mL、61.0mmol)を、DMSO(50mL)中の3-クロロ-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)ピリド[3,4-b]ピラジン(10g、26.5mmol)の溶液に加えた。溶液を70℃で10時間加熱した後、水(300mL)で希釈し、iPrOAc(300mL)で抽出した。水相を更にiPrOAc(100mL)で抽出した。有機層を合わせ、飽和NH4Cl水溶液(300mL)および塩水(200mL)で洗浄し、MgSO4で乾燥させ、真空下で濃縮し、ハウスバキュームで乾燥させて、淡黄色の固体(11.4g)を得た。固体を撹拌および加熱還流しながらiPrOAc(55mL)に溶解した。沈殿を防ぐために、ヘプタン(33mL)をゆっくりと少しずつ加熱しながら加えた。次に、溶液を攪拌しながら(約400rpm)20℃に冷却させ、その間に沈殿物が形成された。混合物をゆっくりと周囲温度まで冷却させ、一晩撹拌した。固体を真空濾過により収集し、ヘプタン中の氷冷20%iPrOAcですすぎ、フィルターケーキを通して少なくとも30分間真空引きすることにより乾燥させ、収集して、表題化合物を淡黄色固体として得た(9.771g、86%)。1H NMR(500MHz,DMSO-d6) δppm 1.84-1.96(m,2H),2.01-2.16(m,3H),2.20-2.31(m,1H),3.22-3.31(m,2H),3.64-3.80(m,4H),3.85-3.93(m,1H),4.00(dd,J=9.28,6.35Hz,1H),4.55-4.67(m,2H),6.94(d,J=5.86Hz,1H),6.99-7.06(m,1H),7.25-7.37(m,2H),7.46(d,J=5.37Hz,1H),8.31(d,J=5.37Hz,1H),8.79(s,1H);ESI-MS m/z [M+H]+ 428。
(S)-テトラヒドロフラン-3-アミン(AstaTechカタログ番号37021)(0.578mL、6.64mmol)を、DMSO(5mL)中の3-クロロ-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)ピリド[3,4-b]ピラジン(1.0g、2.65mmol)の溶液に加えた。溶液を、密封されたマイクロ波バイアル内で70℃にて22時間加熱し、その時点でHPLC-MSは反応が完了したことを示した。反応混合物(5mL)を水(150mL)で希釈し、iPrOAc(150mL)で抽出した。水相を更にiPrOAc(50mL)で抽出した。有機層を合わせ、飽和NH4Cl水溶液(150mL)および塩水(100mL)で洗浄し、MgSO4で乾燥させ、CELITE(登録商標)で真空濃縮した。粗生成物をヘプタン中0~60%EtOAcの勾配で溶出するカラムクロマトグラフィー(30g NHシリカゲルカラム)により精製し、白色固体として表題化合物を得た(1.05g、93%)。1H NMR(500MHz,DMSO-d6) δppm 1.90(td,J=8.54,3.91Hz,2H),2.01-2.
16(m,3H),2.20-2.31(m,1H),3.21-3.32(m,2H),3.63-3.80(m,4H),3.89(q,J=7.49Hz,1H),4.00(dd,J=9.28,6.35Hz,1H),4.54-4.67(m,2H),6.96(d,J=6.35Hz,1H),7.00-7.08(m,1H),7.26-7.39(m,2H),7.46(d,J=5.37Hz,1H),8.31(d,J=5.37Hz,1H),8.79(s,1H);ESI-MS m/z [M+H]+ 428。
HOAc(80mL)およびTHF(80mL)中(R)-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-N-(テトラヒドロフラン-3-イル)ピリド[3,4-b]ピラジン-3-アミン(16g、37.4mmol)を入れたフラスコへ、窒素下で無水酢酸(17.66mL、187mmol)を加えた。炭素上のパラジウム(10%、Aldrich 205699-10G、ロット番号MKBZ3284V)(3.19g、2.99mmol)を窒素下で添加した。フラスコを水素充填バルーンに接続し、ハウスバキュームで排気し、水素を8回再充填した。反応混合物を水素下で40時間撹拌し、その後、ケーキが乾かないように注意しながら、CELITE(登録商標)のパッドを通して濾過した。フラスコおよびフィルターケーキをEtOAc(48mL)、メタノール(48mL)およびEtOAc(48mL)ですすいだ。濾液を真空下で濃縮して、THF、EtOAcおよびメタノールを除去した(浴温≦40℃)。溶液をヘプタン(480mL)で希釈し、真空下で再濃縮してHOAcを共沸混合物とした(浴温≦45℃)。残渣をiPrOAc(320mL)に取り、10重量%K2CO3水溶液(320mL、230mmol)(洗浄前pH13、洗浄後pH10)および塩水(240mL、洗浄後pH7)で洗浄し、MgSO4で乾燥させ、真空下で濃縮し、ハウスバキューム下で少なくとも1時間乾燥させて、淡黄色の固体(16.71g)を得た。粗生成物をエタノール(84mL)に取り、撹拌しながら油浴で加熱した。固体が溶解した後、溶液を攪拌しながら油浴でゆっくりと冷却させ、その間に沈殿物が形成され始め、溶液は白濁した。混合物を油浴で周囲温度まで冷却させ、一晩撹拌した。再結晶後、白色固体を真空濾過によって収集し、氷冷エタノールですすぎ、高真空下で乾燥させて、白色固体として表題化合物を得た(13.34g、75%)。1H NMR(500MHz,DMSO-d6) δppm 1.81-2.00(m,3H),2.02-2.12(m,5H),2.14-2.24(m,1H),2.60(t,J=5.61Hz,1H),2.72(t,J=5.86Hz,1H),2.84-2.96(m,2H),3.26-3.32(m,2H),3.56(dt,J=8.79,5.13Hz,1H),3.65-3.78(m,3H),3.81-3.94(m,2H),4.33-4.47(m,3H),4.52(tt,J=8.18,4.03Hz,1H),5.91(dd,J=13.42,6.10Hz,1H),6.97-7.05(m,1H),7.24-7.36(m,2H);ESI-MS m/z [M+H]+ 474;mp150℃(DSCピーク);キラル純度(キラルカラムクロマトグラフィーによる)>98%ee。
HOAc(5mL)およびTHF(5mL)中(S)-2-(4-(2,4-ジフルオロフェノキシ)ピペリジン-1-イル)-N-(テトラヒドロフラン-3-イル)ピリド[3,4-b]ピラジン-3-アミン(1.05g、2.456mmol)を入れたフラスコに、窒素下で無水酢酸(1.159mL、12.28mmol)を加えた。炭素上のパラジウム(10%、Aldrich 205699-10G、ロット番号MKBZ3284V)(0.523g、0.491mmol)を窒素下で添加した。フラスコを水素充填バルーンに接続し、ハウスバキュームで排気し、水素を8回再充填した。反応混合物を水素下で18時間撹拌し、その後、ケーキが乾かないように注意しながら、Celite(登録商標)のパッドを通して濾過した。フラスコおよびフィルターケーキを、EtOAc(20mL)、メタノール(20mL)およびEtOAc(20mL)ですすぎ、濾液をCELITE(登録商標)で真空濃縮した。粗生成物をヘプタン中0~60%EtOAcの勾配で溶出するカラムクロマトグラフィー(120g NHシリカゲルカラム、サイズ200)により精製し、白色固体(1.0g)を得た。白色の固体をエタノール(5mL)に取り、攪拌しながら油浴で80℃に加熱した。固体が溶解した後、加熱を停止し、溶液を攪拌しながら油浴中に20℃までゆっくりと冷却させた。混合物を室温で3日間撹拌した。固体を真空濾過により収集し、氷冷エタノールですすぎ、高真空下で乾燥させて、表題化合物を白色固体として得た(848mg、72.9%)。1H NMR(500MHz,DMSO-d6) δppm 1.82-2.00(m,3H),2.02-2.12(m,5H),2.13-2.24(m,1H),2.60(t,J=5.86Hz,1H),2.72(t,J=5.86Hz,1H),2.83-2.96(m,2H),3.24-3.32(m,2H),3.56(dt,J=8.79,5.25Hz,1H),3.66-3.77(m,3H),3.81-3.94(m,2H),4.33-4.47(m,3H),4.52(tt,J=8.08,3.87Hz,1H),5.93(dd,J=13.30,6.22Hz,1H),6.98-7.06(m,1H),7.24-7.35(m,2H);ESI-MS m/z [M+H]+ 474;mp 149℃(DSCピーク);キラル純度(キラルカラムクロマトグラフィーによる)>98%ee。
表1は、CHO-K1細胞で発現したGPR6受容体の構成cAMP活性を阻害する試験化合物の能力(pEC50として報告)を測定する細胞ベースのアッセイに従って試験した式1の化合物(実施例1)および化合物Aの生物学的アッセイデータ(cAMPのインビトロ阻害)を示す。このアッセイは、本明細書中では、「cAMPのインビトロ阻害(EC50)」という見出しの下で記載されている。
表2は、GPR6競合的結合アッセイからの阻害定数(Ki)と、式1(例1)の化合物および化合物AのhERG機能アッセイからのIC50値を示す。上述のように、各化合物のKiは、ヒトGPR6 cDNAを発現するCHO-K1細胞から調製した膜を利用する濾過ベースのフォーマットを採用する競合結合アッセイを用いて得られ、各化合物のIC50は、ヒトhERG cDNAをトランスフェクトしたCHO-K1細胞を利用する自動全細胞パッチクランプシステムを採用するhERG機能アッセイを用いて得られた。
運動活動を改善する化合物は、パーキンソン病の潜在的な療法として有望であると考えられる。パーキンソン病の6-OHDAモデルのラットに、6-OHDAの線条体への両側注射を施し、前-後(AP):中心-横(ML):背-腹(DV)、1±3、麻酔下のブレグマと比較して-5mmをコーディネートする。ラットを、少なくとも28日後に自発運動について試験した。式1(実施例1)またはビヒクル(対照)を投薬する前に、自発運動ボックス内で30分間動物を馴化した。
生後8か月以上、体重7~15kgの意識のあるビーグル犬(Marsahall BioResources、ノースローズ、ニューヨーク州)における式1(実施例1)の潜在的な心血管作用。ビーグル犬には、適切なCharles River Laboratories、モントリオール、QC標準操作手順(TB12-04-06)に従って、DSI PHYSIOTEL(登録商標)Digital L21トランスミッターインプラントからの遠隔測定デバイスを装備させる。生体電位リードを、修正リードII構成に配置する。動物を実験室環境に慣れさせるために、動物の到着から遠隔測定デバイスの外科的移植の開始まで、最低6日間の馴化期間を設ける。手術から治療開始までの最短回復期間は4週間とする。動物室環境の目標条件は、指定された手順中を除き、湿度30~70%で17℃~23℃、明所に12時間および暗所に12時間である。
当業者は、ルーチンの実験を超えるものを用いることなく、本明細書に記載の本発明に従って特定の実施形態の多くの等価物を認識し、または確認することができる。本発明の範囲は上記の説明に限定されることを意図せず、むしろ添付の特許請求の範囲に記載の通りである。
Claims (35)
- 式1:
- 前記組成物は前記式1の化合物またはその医薬的に許容される塩を
(a)98%ee以上;および/または、
(b)99%ee以上;および/または、
(c)100%eeに等しい;
で含む、請求項1に記載の組成物。 - 前記式1の化合物が塩の形態として存在しない、請求項1または2に記載の組成物。
- (a)請求項1~3のいずれか一項に記載の組成物;および
(b)医薬的に許容される賦形剤
を含む医薬組成物。 - 薬剤として使用するための、請求項4に記載の医薬組成物。
- 疾患、障害または病状の治療に使用するための、請求項4または5に記載の医薬組成物。
- GPR6に関連する疾患、障害または病状の治療に使用するための、請求項4~6のいずれか一項に記載の医薬組成物。
- パーキンソン病、レボドパ誘発性ジスキネシア、ハンチントン舞踏病、薬物依存、摂食障害、認知障害、統合失調症、双極性障害、癲癇、アルツハイマー病、不安症および鬱病からなる群から選択される疾患、障害または病状の治療に使用するための、請求項4~7のいずれか一項に記載の医薬組成物。
- パーキンソン病の治療に使用するための、請求項4~8のいずれか一項に記載の医薬組成物。
- 被験体におけるパーキンソン病の治療に使用するための医薬組成物であって、前記治療が前記被検体の運動症状を改善する、請求項4~9のいずれか一項に記載の医薬組成物。
- パーキンソン病の非運動性の臨床症状の治療に使用するための、請求項4~10のいずれか一項に記載の医薬組成物。
- 前記医薬組成物は、前記式1の化合物またはその医薬的に許容される塩の0.5mg/kg~5.0mg/kgの範囲内の用量での投与に適合される、請求項4~11のいずれか一項に記載の医薬組成物。
- 前記医薬組成物は、経口投与に適合される、請求項4~12のいずれか一項に記載の医薬組成物。
- 薬剤としての使用のための、請求項1~3のいずれか一項に記載の組成物。
- 疾患、障害または病状の治療における使用のための、請求項1~3のいずれか一項に記載の組成物。
- GPR6に関連する疾患、障害または病状の治療における使用のための、請求項1~3のいずれか一項に記載の組成物。
- パーキンソン病、レボドパ誘発性ジスキネシア、ハンチントン舞踏病、薬物依存、摂食障害、認知障害、統合失調症、双極性障害、癲癇、アルツハイマー病、不安症および鬱病からなる群から選択される、疾患、障害または病状の治療における使用のための、請求項1~3のいずれか一項に記載の組成物。
- パーキンソン病の治療における使用のための、請求項1~3のいずれか一項に記載の組成物。
- 被験体でのパーキンソン病の治療における使用のための組成物であって、前記治療が前記被検体の運動症状を改善する、請求項1~3のいずれか一項に記載の組成物。
- パーキンソン病の、非運動性の臨床症状の治療における使用のための、請求項1~3のいずれか一項に記載の組成物。
- 前記組成物は、前記式1の化合物またはその医薬的に許容される塩の0.5mg/kg~5.0mg/kgの範囲内の用量での投与に適合される、請求項14~20のいずれか一項に記載の組成物。
- 前記式1の化合物またはその医薬的に許容される塩は、経口投与に適合される、請求項14~21のいずれか一項に記載の組成物。
- 少なくとも1つの更なる薬理活性剤を更に含む、請求項4~13のいずれか一項に記載の医薬組成物。
- 前記更なる薬理活性剤が:
(a)レボドパ、DOPAデカルボキシラーゼ阻害剤、ドーパミン作動薬、抗コリン作動薬、選択的モノアミンオキシダーゼB阻害剤およびカテコールO-メチルトランスフェラーゼ阻害剤からなる群から選択される;および/または、
(b)アマンタジンである;および/または、
(c)DOPAデカルボキシラーゼ阻害剤と組み合わせたレボドパである;および/または、
(d)カルビドパ、ベンセラジド、メチルドパ、α-ジフルオロメチル-DOPA、3’,4’,5,7-テトラヒドロキシ-8-メチルイソフラボン、塩酸アポモルフィン、ブロモクリプチン、ロチゴチン、プラミペキソール、ロピニロール、トリヘキフェニジル、メシル酸ベンズトロピン、サフィナミド、セレジリン、ラサギリン、エンタカポンおよびトルカポンからなる群から選択される;および/または、
(e)β-セクレターゼ阻害剤、γ-セクレターゼ阻害剤、HMG-CoAレダクターゼ阻害剤、および非ステロイド系抗炎症薬(NSAID)からなる群から選択される;および/または、
(f)アパゾン、アスピリン、セレコキシブ、ジクロフェナック(ミソプロストール含有および非含有)、ジフルニサル、エトドラク、フェノプロフェン、フルルビプロフェン、イブプロフェン、インドメタシン、ケトプロフェン、メクロフェナム酸ナトリウム、メフェナム酸、メロキシカム、ナブメトン、ナプロキセン、オキサプロジン、フェニルブタゾン、ピロキシカム、サリチル酸コリンおよびマグネシウム、サルサレート、ならびにスリンダクからなる群から選択される;および/または、
(g)ドネペジル、リバスチグミン、メマンチンおよびガランタミンからなる群から選択される;および/または、
(h)鎮痛剤、催眠薬、抗不安薬、抗精神病薬および精神安定剤からなる群から選択される;および/または、
(i)アミトリプチリン、アモキサピン、アリピプラゾール、アセナピン、ブプロピオン、クロルジアゼポキシド、シタロプラム、クロルプロマジン、クロザピン、デシプラミン、デスベンラファキシン、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、フルフェナジン、ハロペリドール、イロペリドン、イミプラミン、イソカルボキサジド、ラモトリジン、レボミルナシプラン、ルラシドン、ミルタザピン、ネファゾドン、ノルトリプチリン、オランザピン、パリペリドン、パロキセチン、ペルフェナジン、フェネルジン、プロトリプチリン、クエチアピン、リスペリドン、サフィナミド、セレギリン、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、ビラゾドン、ボルチオキセチンおよびジプラシドンからなる群から選択される;および/または、
(j)アルプラゾラム、クロルジアゼポキシド、クロバゼパム、クロナゼパム、クロラゼペート、ジアゼパム、エスタゾラム、フルラゼパム、ロラゼパム、ミダゾラム、オキサゼパム、プラゼパム、クアゼパム、テマゼパム、およびトリアゾラム、ヒドロキシジン、エスゾピクロン、ザレプロン、ゾルピデム、ゾピクロン、およびブスピロンからなる群から選択される;および/または、
(k)アセタゾラミド、カルバマゼピン、クロバザム、クロナゼパム、エスリカルバゼピン酢酸塩、エトスクシミド、ガバペンチン、ラコサミド、ラモトリジン、レベチラセタム、ニトラゼパム、オクスカルバゼピン、ペランパネル、ピラセタム、フェノバルビタール、フェニトイン、プレガバリン、プリミドン、レチガビン、ルフィナミド、バルプロ酸ナトリウム、スチリペントール、チアガビン、トピラマート、ビガバトリンおよびゾニサミドからなる群から選択される、
請求項23に記載の医薬組成物。 - 請求項4~13のいずれか一項に記載の医薬組成物と、少なくとも1つの更なる薬理活性剤を含む医薬組成物とを含む、キット。
- 前記更なる薬理活性剤が:
(a)レボドパ、DOPAデカルボキシラーゼ阻害剤、ドーパミン作動薬、抗コリン作動薬、選択的モノアミンオキシダーゼB阻害剤およびカテコールO-メチルトランスフェラーゼ阻害剤からなる群から選択される;および/または、
(b)アマンタジンである;および/または、
(c)DOPAデカルボキシラーゼ阻害剤と組み合わせたレボドパである;および/または、
(d)カルビドパ、ベンセラジド、メチルドパ、α-ジフルオロメチル-DOPA、3’,4’,5,7-テトラヒドロキシ-8-メチルイソフラボン、塩酸アポモルフィン、ブロモクリプチン、ロチゴチン、プラミペキソール、ロピニロール、トリヘキフェニジル、メシル酸ベンズトロピン、サフィナミド、セレジリン、ラサギリン、エンタカポンおよびトルカポンからなる群から選択される;および/または、
(e)β-セクレターゼ阻害剤、γ-セクレターゼ阻害剤、HMG-CoAレダクターゼ阻害剤、および非ステロイド系抗炎症薬(NSAID)からなる群から選択される;および/または、
(f)アパゾン、アスピリン、セレコキシブ、ジクロフェナック(ミソプロストール含有および非含有)、ジフルニサル、エトドラク、フェノプロフェン、フルルビプロフェン、イブプロフェン、インドメタシン、ケトプロフェン、メクロフェナム酸ナトリウム、メフェナム酸、メロキシカム、ナブメトン、ナプロキセン、オキサプロジン、フェニルブタゾン、ピロキシカム、サリチル酸コリンおよびマグネシウム、サルサレート、ならびにスリンダクからなる群から選択される;および/または、
(g)ドネペジル、リバスチグミン、メマンチンおよびガランタミンからなる群から選択される;および/または、
(h)鎮痛剤、催眠薬、抗不安薬、抗精神病薬および精神安定剤からなる群から選択される;および/または、
(i)アミトリプチリン、アモキサピン、アリピプラゾール、アセナピン、ブプロピオン、クロルジアゼポキシド、シタロプラム、クロルプロマジン、クロザピン、デシプラミン、デスベンラファキシン、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、フルフェナジン、ハロペリドール、イロペリドン、イミプラミン、イソカルボキサジド、ラモトリジン、レボミルナシプラン、ルラシドン、ミルタザピン、ネファゾドン、ノルトリプチリン、オランザピン、パリペリドン、パロキセチン、ペルフェナジン、フェネルジン、プロトリプチリン、クエチアピン、リスペリドン、サフィナミド、セレギリン、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、ビラゾドン、ボルチオキセチンおよびジプラシドンからなる群から選択される;および/または、
(j)アルプラゾラム、クロルジアゼポキシド、クロバゼパム、クロナゼパム、クロラゼペート、ジアゼパム、エスタゾラム、フルラゼパム、ロラゼパム、ミダゾラム、オキサゼパム、プラゼパム、クアゼパム、テマゼパム、およびトリアゾラム、ヒドロキシジン、エスゾピクロン、ザレプロン、ゾルピデム、ゾピクロン、およびブスピロンからなる群から選択される;および/または、
(k)アセタゾラミド、カルバマゼピン、クロバザム、クロナゼパム、エスリカルバゼピン酢酸塩、エトスクシミド、ガバペンチン、ラコサミド、ラモトリジン、レベチラセタム、ニトラゼパム、オクスカルバゼピン、ペランパネル、ピラセタム、フェノバルビタール、フェニトイン、プレガバリン、プリミドン、レチガビン、ルフィナミド、バルプロ酸ナトリウム、スチリペントール、チアガビン、トピラマート、ビガバトリンおよびゾニサミドからなる群から選択される、
請求項25に記載のキット。 - 請求項1~3のいずれか一項に記載の組成物および医薬的に許容される賦形剤を含む医薬組成物であって、前記式1の化合物またはその医薬的に許容される塩の0.5mg/kg~5.0mg/kgの範囲内の用量での経口投与に適合される、医薬組成物。
- 疾患、障害または症状の治療用薬剤の製造における、請求項1~3のいずれか一項に記載の組成物の使用。
- GPR6に関連する疾患、障害または症状の治療用薬剤の製造における、請求項1~3のいずれか一項に記載の組成物の使用。
- パーキンソン病、レボドパ誘発性ジスキネシア、ハンチントン舞踏病、薬物依存、摂食障害、認知障害、統合失調症、双極性障害、癲癇、アルツハイマー病、不安症および鬱病からなる群から選択される、疾患、障害または病状の治療用薬剤の製造における、請求項1~3のいずれか一項に記載の組成物の使用。
- パーキンソン病の治療用薬剤の製造における、請求項1~3のいずれか一項に記載の組成物の使用。
- 被験体のパーキンソン病の治療用薬剤の製造における前記組成物の使用であって、前記治療が前記被検体の運動症状を改善する、請求項1~3のいずれか一項に記載の組成物の使用。
- パーキンソン病の、非運動性の臨床症状の治療用薬剤の製造における、請求項1~3のいずれか一項に記載の組成物の使用。
- 前記治療用薬剤は、前記式1の化合物またはその医薬的に許容される塩の0.5mg/kg~5.0mg/kgの範囲内の用量での投与に適合される、請求項28~33のいずれか一項に記載の、使用。
- 前記治療用薬剤は、経口投与に適合される、請求項28~34のいずれか一項に記載の使用。
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US62/672,261 | 2018-05-16 | ||
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