JP2022510467A - ムスカリンm1および/またはm4受容体アゴニストとしてのキノリノンおよびベンゾオキサジン誘導体 - Google Patents
ムスカリンm1および/またはm4受容体アゴニストとしてのキノリノンおよびベンゾオキサジン誘導体 Download PDFInfo
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- JP2022510467A JP2022510467A JP2021532237A JP2021532237A JP2022510467A JP 2022510467 A JP2022510467 A JP 2022510467A JP 2021532237 A JP2021532237 A JP 2021532237A JP 2021532237 A JP2021532237 A JP 2021532237A JP 2022510467 A JP2022510467 A JP 2022510467A
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- propyl
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- dihydroisoxazole
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
Abstract
Description
本発明は、ムスカリンM1またはM1およびM4受容体アゴニストとしての活性を有する化合物を提供する。より詳細には、本発明は、M2およびM3受容体サブタイプに比べた、M1受容体に対する選択性を示す化合物を提供する。
nは、1、2、3または4であり;
X1は、CH2またはOであり;
Yは、NまたはCHであり;
X2およびX3は、合わせると合計で4~6個の炭素原子を含有する飽和炭化水素基であって、以下の部分:
nは、1、2、3または4であり;
X1は、CH2またはOであり;
Yは、NまたはCHであり;
X2およびX3は、合わせると合計で4~6個の炭素原子を含有する飽和炭化水素基であって、以下の部分:
nは、1、2、3または4であり;
X1は、CH2またはOであり;
Yは、NまたはCHであり;
X2およびX3は、合わせると合計で4~6個の炭素原子を含有する飽和炭化水素基であって、以下の部分:
1.13 Yが、CHである、実施形態1.1~1.11のいずれかによる化合物。
1-[3-[4-[2-(4,5-ジヒドロイソオキサゾール-3-イルオキシ)エチル]-1-ピペリジル]プロピル]-3,4-ジヒドロキノリン-2-オン、
1-[3-[4-[4-(4,5-ジヒドロイソオキサゾール-3-イルオキシ)ブチル]-1-ピペリジル]プロピル]-3,4-ジヒドロキノリン-2-オン、
1-[3-[3-[2-(4,5-ジヒドロイソオキサゾール-3-イルオキシ)エチル]-8-アザビシクロ[3.2.1]オクタン-8-イル]プロピル]-3,4-ジヒドロキノリン-2-オン、
1-[3-[3-[3-(4,5-ジヒドロイソオキサゾール-3-イルオキシ)プロピル]-8-アザビシクロ[3.2.1]オクタン-8-イル]プロピル]-3,4-ジヒドロキノリン-2-オン、
1-[3-[(1R,5S)-3-[2-(4,5-ジヒドロイソオキサゾール-3-イルオキシ)エトキシ]-8-アザビシクロ[3.2.1]オクタン-8-イル]プロピル]-3,4-ジヒドロキノリン-2-オン、
1-[3-[3-[3-(4,5-ジヒドロイソオキサゾール-3-イルオキシ)プロピル]-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル]プロピル]-3,4-ジヒドロキノリン-2-オン、
4-[3-[4-[2-(4,5-ジヒドロイソオキサゾール-3-イルオキシ)エチル]-1-ピペリジル]プロピル]-7-フルオロ-1,4-ベンゾオキサジン-3-オン、
4-[3-[4-[4-(4,5-ジヒドロイソオキサゾール-3-イルオキシ)ブチル]-1-ピペリジル]プロピル]-7-フルオロ-1,4-ベンゾオキサジン-3-オン、
3-[3-[8-[3-(3,4-ジヒドロ-2H-キノリン-1-イル)プロピル]-8-アザビシクロ[3.2.1]オクタン-3-イル]プロポキシ]-4,5-ジヒドロイソオキサゾール、
2-[2-[1-[3-(2-オキソ-3,4-ジヒドロキノリン-1-イル)プロピル]-4-ピペリジル]エチル]イソオキサゾリジン-3-オン、
2-[4-[1-[3-(2-オキソ-3,4-ジヒドロキノリン-1-イル)プロピル]-4-ピペリジル]ブチル]イソオキサゾリジン-3-オン、
2-[5-[1-[3-(2-オキソ-3,4-ジヒドロキノリン-1-イル)プロピル]-4-ピペリジル]ペンチル]イソオキサゾリジン-3-オン、
2-[3-[8-[3-(2-オキソ-3,4-ジヒドロキノリン-1-イル)プロピル]-8-アザビシクロ[3.2.1]オクタン-3-イル]プロピル]イソオキサゾリジン-3-オン、
から選択される、実施形態1.1による化合物、またはその塩。
定義
本出願では、特に示さない限り、以下の定義が適用される。
塩
式(I)、式(II)または式(III)の多数の化合物は、塩、例えば、酸付加塩、またはある種の場合、カルボン酸塩、スルホン酸塩およびリン酸塩などの有機塩基および無機塩基の塩の形態で存在し得る。このような塩のすべてが、本発明の範囲内にあり、式(I)、式(II)または式(III)の化合物の言及は、実施形態1.27~1.29に定義されている化合物の塩形態を含む。
立体異性体
立体異性体は、同じ分子式および結合原子の配列を有するが、それらの原子の空間における三次元配向のみが異なる、異性体分子である。立体異性体は、例えば、幾何異性体または光学異性体とすることができる。
幾何異性体
幾何異性体の場合、異性は、炭素-炭素二重結合に関するシスおよびトランス(ZおよびE)異性のような、二重結合に関する原子または基の異なる配向、またはアミド結合に関するシスおよびトランス異性体、または炭素と窒素の二重結合(例えば、オキシムにおけるもの)に関するシンおよびアンチ異性、または回転の制限がある結合に関する回転異性、またはシクロアルカン環などの環に関するシスおよびトランス異性によるものがある。
光学異性体
本文脈が特に必要としない限り、式の化合物が、1個または複数のキラル中心を含有し、2つ以上の光学異性体の形態で存在し得る場合、化合物の言及には、個々の光学異性体、または混合物(例えば、ラセミ混合物)、または2つ以上の光学異性体のいずれかとして、そのすべての光学異性体(例えば、鏡像異性体、エピマーおよびジアステレオ異性体)を含む。
1.36 光学異性体のラセミ混合物の形態にある、実施形態1.31による化合物。
同位体
実施形態1.1~1.37のいずれか1つにおいて定義されている本発明の化合物は、1種または複数の同位体置換を含有してもよく、特定の元素を言う場合、その元素のすべての同位体をその範囲内に含む。例えば、水素を言う場合、その範囲内に、1H、2H(D)および3H(T)を含む。同様に、炭素および酸素を言う場合、それぞれ、その範囲内に、12C、13Cおよび14C、ならびに16Oおよび18Oを含む。
溶媒和物
実施形態1.1~1.39のいずれか1つにおいて定義されている式(I)、式(II)または式(III)の化合物は、溶媒和物を形成することがある。好ましい溶媒和物は、非毒性の薬学的に許容される溶媒の分子の、本発明の化合物の固体状態構造(例えば、結晶構造)への組込みによって形成される溶媒和物である(以下において、溶媒和する溶媒と称される)。このような溶媒の例には、水、アルコール(エタノール、イソプロパノールおよびブタノールなど)およびジメチルスルホキシドが含まれる。溶媒和物は、本発明の化合物を、溶媒和する溶媒を含有する溶媒または溶媒の混合物と共に再結晶することによって調製することができる。溶媒和物が、所与のいずれかの例で形成されているか否かは、化合物の結晶を、熱重量分析(TGE)、示差走査熱量測定(DSC)およびX線結晶学などの周知な標準技法を使用する分析に施すことによって決定され得る。溶媒和物は、化学量論量の溶媒和物とすることができるか、または非化学量論量の溶媒和物とすることができる。特に、好ましい溶媒和物は、水和物であり、水和物の例には、半水和物、一水和物および二水和物が含まれる。
1.40 溶媒和物形態にある、実施形態1.1~1.39のいずれか1つによる化合物。
結晶およびアモルファス形態
実施形態1.1~1.42のいずれか1つの化合物は、結晶性または非結晶性(例えばアモルファス)状態で存在することがある。化合物が結晶状態で存在しているか否かは、X線粉末回折(XRPD)などの標準技法によって容易に決定することができる。結晶およびその結晶構造は、単結晶X線結晶学、X線粉末回折(XRPD)、示差走査熱量測定(DSC)、および赤外分光法、例えばフーリエ変換赤外分光法(FTIR)を含めた、いくつかの技法を使用して特徴付けることができる。様々な湿度の条件下での結晶の挙動は、重量測定蒸気吸着検討、およびやはりまたXRPDによって分析され得る。化合物の結晶構造の決定は、本明細書に記載されている方法、およびFundamentals of Crystallography、C.Giacovazzo、H.L.Monaco、D.Viterbo、F.Scordari、G.Gilli、G.Zanotti and M.Catti(International Union of Crystallography/Oxford University Press、1992年 ISBN 0-19-855578-4(p/b)、0-19-85579-2(h/b))に記載されている方法などの従来の方法に準拠して行うことができる、X線結晶学によって行われ得る。この技法は、単結晶のX線回折の分析および解釈を含む。アモルファス固体では、結晶形態で通常、存在する三次元構造は存在せず、アモルファス形態において、互いに対する分子の位置は、実質的にランダムであり、例えば、Hancockら J.Pharm.Sci.(1997年)、86巻、1頁を参照されたい。
1.43 結晶形態にある、実施形態1.1~1.42のいずれか1つによる化合物。
(a)50%~100%の結晶性、より詳細には、少なくとも50%の結晶性、または少なくとも60%の結晶性、または少なくとも70%の結晶性、または少なくとも80%の結晶性、または少なくとも90%の結晶性、または少なくとも95%の結晶性、または少なくとも98%の結晶性、または少なくとも99%の結晶性、または少なくとも99.5%の結晶性、または少なくとも99.9%の結晶性、例えば100%の結晶性である、
実施形態1.1~1.42のいずれか1つによる化合物。
プロドラッグ
実施形態1.1~1.39のいずれか1つに定義されている式(I)、式(II)または式(III)の化合物は、プロドラッグの形態で存在することがある。「プロドラッグ」とは、例えば、インビボで、実施形態1.1~1.39のいずれか1つに定義されている、式(I)、式(II)または式(III)の生物活性化合物に変換される任意の化合物を意味する。
錯体および包接化合物
同様に、実施形態1.1~1.46の化合物の錯体(例えば、シクロデキストリンなどの化合物との包接錯体もしくは包接化合物、または金属との錯体)が、実施形態1.1~1.46における式(I)、式(II)または式(III)によって包含される。
生物活性および治療的使用
本発明の化合物は、ムスカリンM1受容体アゴニストとして活性を有する。本化合物のムスカリン活性は、以下の実施例Aに記載されているホスホ-ERK1/2アッセイを使用して決定され得る。
2.1 医薬における使用のための、実施形態1.1~1.47のいずれか1つによる化合物。
2.18 認知障害または精神病性障害の処置における使用のための、実施形態1.1~1.47のいずれか1つによる化合物。
式(I)、式(II)または式(III)の化合物は、当業者に周知の合成法、および本明細書に記載されている合成法に準拠して調製され得る。
医薬製剤
本活性化合物は、単独で投与することが可能であるが、医薬組成物(例えば、製剤)として供給されることが好ましい。
以下の表1に示されている実施例1~13の化合物を調製した。それらの化合物のNMRおよびLCMS特性、ならびにそれらを調製するために使用した方法を表3に記載する。実施例のそれぞれに関する出発原料は、表2に列挙される。
調製経路は含まれていない場合、関連する中間体が市販されている。市販試薬は、さらに精製することなく利用した。室温(rt)は、約20~27℃を指す。1H NMRスペクトルは、BrukerまたはJeolの機器のどちらかで400MHzで記録した。ケミカルシフト値は、百万分率(ppm)、すなわち(δ)値で表す。NMRシグナルの多重度について、以下の略称を使用する:s=シングレット、br=ブロード、d=ダブレット、t=トリプレット、q=カルテット、quint=クインテット、td=ダブレットのトリプレット、tt=トリプレットのトリプレット、qd=ダブレットのカルテット、ddd=ダブレットのダブレットのダブレット、ddt=トリプレットのダブレットのダブレット、m=マルチプレット。カップリング定数は、Hzで測定したJ値として列挙する。NMRおよび質量分光法の結果は、バックグラウンドピークを考慮して補正した。クロマトグラフィーとは、60~120メッシュのシリカゲルを使用して行い、窒素加圧下(フラッシュクロマトグラフィー)条件で実施したカラムクロマトグラフィーを指す。反応をモニタリングするためのTLCは、指定した移動相、およびMerck製の固定相としてシリカゲルF254を使用して実施したTLCを指す。マイクロ波を媒介とする反応は、Biotage開始剤またはCEM Discoverマイクロ波用反応器で行った。
方法A
機器:Waters Acquity H Class、光ダイオードアレイ、SQ検出器、カラム:BEH C18、1.7ミクロン、2.1×50mm;グラジエント[時間(分)/溶媒A中のB(%)]:0.01/5、0.40/5、0.8/35、1.20/55、2.50/100、3.30/100、3.31/5、4.00/5;溶媒:溶媒A=5mM酢酸アンモニウムおよびH2O中の0.1%ギ酸;溶媒B=MeCN中の0.1%ギ酸;注入量2μL;UV検出200~400nM;質量検出100~1200AMU(+veエレクトロスプレー);周囲温度でのカラム;流速0.55mL/分。
方法B
機器:Waters 2695、光ダイオードアレイ、ZQ-2000検出器、カラム:X-Bridge C18、5ミクロン、150×4.6mm;グラジエント[時間(分)/溶媒A中のB(%)]:0.01/10、5.00/90、7.00/100、11.00/100、11.01/10 12.00/10;溶媒:溶媒A=H2O中の0.1%アンモニア;溶媒B=MeCN中の0.1%アンモニア;注入量10μL;UV検出200~400nM;質量検出60~1000AMU(+veエレクトロスプレー);周囲温度でのカラム;流速1.0mL/分。
方法C
機器:Waters 2695、光ダイオードアレイ、ZQ-2000検出器、カラム:X-Bridge C18、3.5ミクロン、50×4.6mm;グラジエント[時間(分)/溶媒A中のB(%)]:0.01/5、5.00/90、5.80/95、7.20/95、7.21/5、10.00/5;溶媒:溶媒A=H2O中の0.1%アンモニア;溶媒B=MeCN中の0.1%アンモニア;注入量10μL;UV検出200~400nM;質量検出60~1000AMU(+veエレクトロスプレー);周囲温度でのカラム;流速1.0mL/分。
方法D
機器:Waters 2695、光ダイオードアレイ、ZQ-2000検出器、カラム:X-Bridge C18、5ミクロン、150×4.6mm;グラジエント[時間(分)/溶媒A中のB(%)]:0.01/10、5.00/90、7.00/100、11.00/100、11.01/10、12.00/10;溶媒:溶媒A=H2O中の20mM酢酸アンモニウム;溶媒B=MeOH;UV検出200~400nM;質量検出60~1000AMU(+veエレクトロスプレー);周囲温度でのカラム;流速1.0mL/分。
略称
d = 日
DCM = ジクロロメタン
DIPEA = ジイソプロピルエチルアミン
DMF = ジメチルホルムアミド
DMSO = ジメチルスルホキシド
ES = エレクトロスプレーイオン化
EtOAc = 酢酸エチル
h = 時間
HPLC = 高速液体クロマトグラフィー
LC = 液体クロマトグラフィー
MeCN = アセトニトリル
MeOH = メタノール
min = 分間
MS = 質量分析法
NMR = 核磁気共鳴
rt = 室温
sat. = 飽和
sol. = 溶液
STAB = トリアセトキシ水素化ホウ素ナトリウム
THF = テトラヒドロフラン
TLC = 薄層クロマトグラフィー
接頭語のn-、s-、i-、t-およびtert-は、その通常の意味を有する:ノルマル、二級、イソおよび三級。
実施例B
医薬製剤
(i)錠剤製剤
式(1)の化合物を含有する錠剤組成物は、50mgの化合物を、希釈剤として197mgのラクトース(BP)および滑沢剤として3mgのステアリン酸マグネシウムと混合し、公知の方法で圧縮して錠剤を形成することによって調製する。
(ii)カプセル剤製剤
カプセル剤製剤は、100mgの式(1)の化合物を、ラクトース100mgおよび場合により1重量%のステアリン酸マグネシウムと混合し、得られた混合物を標準の不透明な硬質ゼラチンカプセルに充填することによって調製する。
中間体の合成:
経路1
中間体4である1-(3-(4-(2-ヒドロキシエチル)ピペリジン-1-イル)プロピル)3,4-ジヒドロキノリン-2(1H)-オンの調製によって例示される、アルコールの調製の典型的な手順
LCMS(方法A):m/z 244(M+H)+(ES+)、2.11分、UV不活性。
LCMS(方法A):m/z 431(M+H)+(ES+)、2.45分、252.0nm。
経路2
中間体3である1-(3-クロロプロピル)-3,4-ジヒドロキノリン-2(1H)-オンの調製によって例示される、アルコールの調製の典型的な手順
経路3
中間体9である3-ニトロ-4,5-ジヒドロイソオキサゾールの調製によって例示される、ニトロの調製の典型的な手順
経路4
中間体14である3-(2-(8-アザビシクロ[3.2.1]オクタン-3-イル)エトキシ)-4,5-ジヒドロイソオキサゾールの調製によって例示される、アミンの調製の典型的な手順
LCMS(方法A):m/z 283(M+H)+(ES+)、2.54分、235nm。
LCMS(方法A):m/z 285(M+H)+(ES+)、2.46分、202nm。
LCMS(方法A):m/z 256(M+H)+(ES+)、2.03分、202nm。
LCMS(方法A):m/z 325(M+H)+(ES+)、2.28分、202nm。
経路5
中間体16であるtert-ブチル3-(3-((4,5-ジヒドロイソオキサゾール-3-イル)オキシ)プロピル)-8-アザビシクロ[3.2.1]オクタン-8-カルボキシレートの調製によって例示される、アミンの調製の典型的な手順
LCMS(方法A):m/z 240(M+H)+(ES+)、2.23分、202nm。
LCMS(方法A):m/z 240(M+H)+(ES+)、2.11分、202nm。
LCMS(方法A):m/z 296(M+H)+(ES+)、2.42分、221nm。
LCMS(方法A):m/z 298(M+H)+(ES+)、2.44分、202nm。
TLC:(5:5、EtOAc/ヘキサン、RF:0.30)。
LCMS(方法A):m/z 270(M+H)+(ES+)、2.11分、202nm。
LCMS(方法A):m/z 339(M+H)+(ES+)、2.38分、202nm。
経路6
中間体19である3-(2-((8-アザビシクロ[3.2.1]オクタン-3-イル)オキシ)エトキシ)-4,5-ジヒドロイソオキサゾールの調製によって例示される、アミンの調製の典型的な手順
LCMS(方法A):m/z 314(M+H)+(ES+)、2.53分、202nm。
LCMS(方法A):m/z 216(M-56)+(ES+)、1.91分、202nm。
LCMS(方法A):m/z 341(M+H)+(ES+)、2.14分、214nm。
経路7
中間体22である3-(3-((1R,5S)-3,8-アザビシクロ[3.2.1]オクタン-3-イル)プロポキシ)-4,5-ジヒドロイソオキサゾールの調製によって例示される、アミンの調製の典型的な手順
LCMS(方法C):m/z 271(M+H)+(ES+)、3.81分、202nm。
LCMS(方法C):m/z 340(M+H)+(ES+)、4.69分、202nm。
経路8
中間体34である2-(4-(ピペリジン-4-イル)ブチル)イソオキサゾリジン-3-オンの調製によって例示される、アミンの調製の典型的な手順
LCMS(方法A):m/z 327(M+H)+(ES+)、2.30分、225nm。
経路9
中間体36である2-(5-(ピペリジン-4-イル)ペンチル)イソオキサゾリジン-3-オンの調製によって例示される、アミンの調製の典型的な手順
LCMS(方法C):m/z 242(M+H)+(ES+)、4.58分、202nm。
LCMS(方法C):m/z 298(M+H)+(ES+)、5.38分、210nm。
LCMS(方法C):m/z 300(M+H)+(ES+)、2.62分、210nm。
LCMS(方法C):m/z 272(M+H)+(ES+)、5.04分、210nm。
LCMS(方法C):m/z 427(M+H)+(ES+)、4.23分、225nm。
LCMS(方法C):m/z 335(M+H)+(ES+)、6.46分、202nm。
LCMS(方法C):m/z 341(M+H)+(ES+)、4.23分、254nm。
経路10
中間体37である2-(3-(8-アザビシクロ[3.2.1]オクタン-3-イル)プロピル)イソオキサゾリジン-3-オンの調製によって例示される、アミンの調製の典型的な手順
LCMS(方法A):m/z 240(M+H)+(ES+)、2.23分、202nm。
LCMS(方法A):m/z 240(M+H)+(ES+)、2.11分、202nm。
LCMS(方法A):m/z 296(M+H)+(ES+)、2.42分、221nm。
LCMS(方法A):m/z 298(M+H)+(ES+)、2.44分、202nm。
TLC:(5:5、EtOAc/ヘキサン、RF:0.30)。
LCMS(方法A):m/z 270(M+H)+(ES+)、2.11分、202nm。
LCMS(方法A):m/z 332(M+H)+(ES+)、2.94分、202nm。
LCMS(方法A):m/z 339(M+H)+(ES+)、2.24分、226nm。
一般合成手順:
経路a
実施例1である1-(3-(4-(2-((4,5-ジヒドロイソオキサゾール-3-イル)オキシ)エチル)ピペリジン-1-イル)プロピル)-3,4-ジヒドロキノリン-2(1H)-オンの調製によって例示される、ジヒドロキノリノンの調製の典型的な手順
経路b
実施例3である1-(3-((1R、5S)-3-(2-((4,5-ジヒドロイソオキサゾール-3-イル)オキシ)エチル)-8-アザビシクロ[3.2.1]オクタン-8-イル)プロピル)-3,4-ジヒドロキノリン-2(1H)-オンの調製によって例示される、ジヒドロキノリノンの調製の典型的な手順
ホスホ-ERK1/2アッセイ
機能アッセイは、Alphascreen Surefireホスホ-ERK1/2アッセイ(Crouch&Osmond、Comb. Chem.High Throughput Screen、2008年)を使用して行った。ERK1/2リン酸化は、Gq/11とGi/oタンパク質共役型受容体の活性化の両方の下流での結果であり、これにより、様々な受容体サブタイプに対する様々なアッセイフォーマットを使用するよりも、M1、M3(Gq/11共役型)およびM2、M4受容体(Gi/o共役型)の評価に、高度に好適となる。ヒトムスカリンM1、M2、M3またはM4受容体を安定して発現するCHO細胞を、MEM-アルファ+10%の透析後FBS中、96ウェル組織培養プレートでプレート培養(25K/ウェル)した。細胞が一旦、接着すると、細胞を一晩、血清飢餓させた。アゴニスト刺激は、細胞に5μLのアゴニストを添加することにより5分間、行った(37℃)。培地を取り除き、50μLの溶解緩衝液を加えた。15分間後、4μLの試料を384ウェルプレートに移し、7μLの検出用混合物を加えた。暗所中、プレートを穏やかに撹拌しながら2時間、インキュベートし、次に、PHERAstarプレートリーダーで読取りを行った。
Claims (12)
- 以下:
1-[3-[4-[2-(4,5-ジヒドロイソオキサゾール-3-イルオキシ)エチル]-1-ピペリジル]プロピル]-3,4-ジヒドロキノリン-2-オン、
1-[3-[4-[4-(4,5-ジヒドロイソオキサゾール-3-イルオキシ)ブチル]-1-ピペリジル]プロピル]-3,4-ジヒドロキノリン-2-オン、
1-[3-[3-[2-(4,5-ジヒドロイソオキサゾール-3-イルオキシ)エチル]-8-アザビシクロ[3.2.1]オクタン-8-イル]プロピル]-3,4-ジヒドロキノリン-2-オン、
1-[3-[3-[3-(4,5-ジヒドロイソオキサゾール-3-イルオキシ)プロピル]-8-アザビシクロ[3.2.1]オクタン-8-イル]プロピル]-3,4-ジヒドロキノリン-2-オン、
1-[3-[(1R,5S)-3-[2-(4,5-ジヒドロイソオキサゾール-3-イルオキシ)エトキシ]-8-アザビシクロ[3.2.1]オクタン-8-イル]プロピル]-3,4-ジヒドロキノリン-2-オン、
1-[3-[3-[3-(4,5-ジヒドロイソオキサゾール-3-イルオキシ)プロピル]-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル]プロピル]-3,4-ジヒドロキノリン-2-オン、
4-[3-[4-[2-(4,5-ジヒドロイソオキサゾール-3-イルオキシ)エチル]-1-ピペリジル]プロピル]-7-フルオロ-1,4-ベンゾオキサジン-3-オン、
4-[3-[4-[4-(4,5-ジヒドロイソオキサゾール-3-イルオキシ)ブチル]-1-ピペリジル]プロピル]-7-フルオロ-1,4-ベンゾオキサジン-3-オン、
3-[3-[8-[3-(3,4-ジヒドロ-2H-キノリン-1-イル)プロピル]-8-アザビシクロ[3.2.1]オクタン-3-イル]プロポキシ]-4,5-ジヒドロイソオキサゾール、
2-[2-[1-[3-(2-オキソ-3,4-ジヒドロキノリン-1-イル)プロピル]-4-ピペリジル]エチル]イソオキサゾリジン-3-オン、
2-[4-[1-[3-(2-オキソ-3,4-ジヒドロキノリン-1-イル)プロピル]-4-ピペリジル]ブチル]イソオキサゾリジン-3-オン、
2-[5-[1-[3-(2-オキソ-3,4-ジヒドロキノリン-1-イル)プロピル]-4-ピペリジル]ペンチル]イソオキサゾリジン-3-オン、
2-[3-[8-[3-(2-オキソ-3,4-ジヒドロキノリン-1-イル)
プロピル]-8-アザビシクロ[3.2.1]オクタン-3-イル]プロピル)イソオキサゾリジン-3-オン、
から選択される、請求項1に記載の化合物、またはその塩。 - 医薬における使用のための、請求項1から6のいずれか一項に記載の化合物。
- 請求項1から6のいずれか一項に記載の化合物、および薬学的に許容される賦形剤を含む医薬組成物。
- ムスカリンM1受容体アゴニスト活性を有する、請求項1から6のいずれか一項に記載の化合物。
- 認知障害もしくは精神病性障害の処置における使用のための、あるいは急性、慢性、神経性もしくは炎症性疼痛を処置するまたはそれらの重症度を軽減するための、請求項1から6に記載の化合物。
- 認知障害が、アルツハイマー病である、請求項10に記載の化合物。
- 認知障害が、レビー小体型認知症である、請求項10に記載の化合物。
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