JP6773820B2 - Bace仲介性appプロセシングを調節するヒダントイン - Google Patents
Bace仲介性appプロセシングを調節するヒダントイン Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/88—Nitrogen atoms, e.g. allantoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4168—1,3-Diazoles having a nitrogen attached in position 2, e.g. clonidine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
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- A—HUMAN NECESSITIES
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Description
本出願は、すべての目的のために参照により本明細書に組み込まれる、2013年2月12日出願のUSSN61/763,830の利益および該USSN61/763,830に対する優先権を請求する。
該当なし。
LY2811376およびCTS21166などのいくつかのBACE阻害薬が臨床試験に入ったが、安全性の理由から第I相を越えて前進することはなかった。BACEに関する他の生理学的基質の発見は、BACE阻害薬またはBACE調節薬に関する臨床開発における主要な懸念をもたらし、かつ該疾患のための療法としてのこれらの阻害薬の進展における有意な障害であり得る。
(式中、Mは
別段の記載がない限り、化合物に対する(例えば、本明細書に説明されるヒダントインに対する)引用は、示される構造名または化学名の化学実体の医薬として許容し得る塩、プロドラッグ、互変異性体、代替固体形態、非共有結合複合体、およびこれらの組み合わせを含むよう広範に解釈されるべきである。
種々の実施形態において、活性薬(例えば、本明細書に説明されるヒダントイン、またはその互変異性体もしくは立体異性体、または該ヒダントイン、該立体異性体、もしくは該互変異性体の医薬として許容し得る塩もしくは溶媒和化合物、またはそれらの類似体、誘導体、もしくはプロドラッグ)を利用する治療法および/または予防法が提供される。典型的には、該方法は、1つ以上の活性薬を対象へ(例えば、該方法を要するヒトへ)、望ましい治療結果または予防結果を実現させるのに十分な量で投与することを包含する。
ある実施形態において、活性薬(本明細書に説明されるヒダントインもしくはその互変異性体もしくは立体異性体、または該ヒダントイン、該立体異性体、もしくは該互変異性体の医薬として許容し得る塩もしくは溶媒和化合物、またはそれらの類似体、誘導体、もしくはプロドラッグ)は種々の予防の脈絡において利用される。したがって、例えば、ある実施形態において、該活性薬は、前臨床期アルツハイマー型認知障害の発症を予防もしくは遅延させ、ならびに/または前臨床期アルツハイマー容態および/もしくは認知障害のさらに1つの症状を寛解させ、ならびに/または前臨床期アルツハイマー容態および/もしくは認知障害からアルツハイマー病への進行を予防もしくは遅延させるのに使用することができる。
軽度認知障害(MCI)(初期認知症または記憶分離障害(isolated memory impairment)としても公知)は、年齢および教育に対して期待されるものを超える認知障害であるが典型的には日常活動を有意に妨害しない認知障害を有する個体へ与えられた診断である(例えば、Petersenら(1999)Arch.Neurol.56(3):303〜308を参照されたい。)。多くの場合において、正常な加齢と認知症の間の境界または移行期であると考えられている。MCIは、種々の症状とともに存在する可能性があるが、記憶喪失が主たる症状である場合、「健忘性MCI」と呼ばれ、アルツハイマー病についての危険因子として頻繁に見られる(例えば、Grundmanら(2004)Arch.Neurol.61(1):59〜66、およびインターネットにおいては、en.wikipedia.org/wiki/Mild_cognitive_impairment−cite_note−Grundman−1を参照されたい)。個体が記憶以外の領域における障害を有する場合、しばしば非健忘性単一領域または多重領域MCIとして分類され、これらの個体は、他の認知症(例えば、レヴィ小体を伴う認知症)へと転換しそうなエビデンスがある。健忘性MCI患者がアルツハイマー病についての神経病理学的基準に合わないことがあるものの、患者がアルツハイマー病を進展させる移行期にあることがあることを示唆するエビデンスがあり、この仮定した移行期にある患者は、新皮質におけるびまん性アミロイドおよび内側側頭葉における頻繁な神経原線維変化を示した(例えば、Petersenら(2006)Arch.Neurol.63(5):665〜72を参照されたい。)。
ある実施形態において、活性薬(例えば、本明細書に説明されるヒダントインまたはその互変異性体もしくは立体異性体、または該ヒダントイン、該立体異性体、もしくは該互変異性体の医薬として許容し得る塩もしくは溶媒和化合物、またはそれらの類似体、誘導体、もしくはプロドラッグ)は、アルツハイマー病の治療に企図される。このような場合において、本明細書に説明される方法は、アルツハイマー病(AD)の発症を予防もしくは遅延させる上で、前記対象が臨床的AD診断へと移行した場合のADの重症度を低下させる上で、および/またはアルツハイマー病の1つ以上の症状を緩和する上で有用である。
本明細書に説明される方法は、1つ以上の活性薬(例えば、本明細書に説明されるヒダントイン、またはその互変異性体もしくは立体異性体、該ヒダントイン、該立体異性体、もしくは該互変異性体の医薬として許容し得る塩もしくは溶媒和化合物、またはそれらの類似体、誘導体、もしくはプロドラッグ)の投与が、脳におけるアミロイド沈着物を特徴とする疾患、例えば、軽度認知障害、アルツハイマー病、黄斑変性症、およびこれらに類するものの治療および/または予防における使用を認めるという発見に一部基づいている。
かつR7は、C=O、C=S、C−NH2およびC=NHからなる群から選択され、波線によって表される結合は、R7がC=O、C=S、またはC=NHである場合に単結合であり、R7がC−NH2である場合に二重結合であり、R8およびR9は独立して、H、アルキル、シクロアルキル、およびアリールからなる群から選択され、但し、波線によって表される結合が二重結合である場合、R9は非存在であることを条件とし、R0は、アリール、置換アリール、二置換アリール、ヘテロアリール、置換ヘテロアリール、二置換ヘテロアリール、アルキル、ハロアルキル、シクロアルキル、アルケニル、およびアルキニルからなる群から選択され、X1は、C−ハロゲン、CH、およびNからなる群から選択され、AはメチルまたはHであり、R5およびR6は独立して、ハロゲン、H、アルキル、トリクロロメチル、およびトリフルオロメチルから選択され、R3およびR4は独立して非存在でありまたはアルキル、シクロアルキル、アルコキシ、チオアルキ(thioalky)、かつX1がCの場合、R0はパラ位で−OCHF2と単置換されたフェニルではない。また、その医薬として許容し得る塩、その互変異性体、その互変異性体の医薬として許容し得る塩、その鏡像異性体、その鏡像異性体の医薬として許容し得る塩、およびこれらに類するものも企図される。
ある実施形態において、本明細書に説明される1つ以上の活性薬(例えば、本明細書に説明されるヒダントイン、またはその互変異性体もしくは立体異性体、または該 ヒダントイン、該立体異性体、もしくは該互変異性体の医薬として許容し得る塩もしくは溶媒和化合物、またはそれらの類似体、誘導体もしくはプロドラッグ)は、該活性薬を必要とする哺乳類動物へ、例えばアミロイド前駆体タンパク質の異常なプロセシングを特徴とする病状についての危険にあるもしくは該状態を罹患している哺乳類動物、MCIからアルツハイマー病への進行についての危険にある哺乳類動物、などへ投与される。ある実施形態において、該活性薬は、前臨床期アルツハイマーの容態および/または認知障害の発症を予防もしくは遅延させ、および/または前臨床期アルツハイマー認知障害の1つ以上の症状を寛解させ、および/または前臨床期アルツハイマーの容態もしくは認知障害からアルツハイマー病への進行を予防もしくは遅延させ、および/または非アミロイド形成性経路によるアミロイド前駆体タンパク質(APP)のプロセシングを促進するために投与される。
ヒダントイン、該立体異性体、もしくは該互変異性体の医薬として許容し得る塩もしくは溶媒和化合物、またはそれらの類似体、誘導体もしくはプロドラッグ)は、該活性薬を必要とする哺乳類動物へ、例えばMCIのアルツハイマー病以外の容態における アミロイド前駆体タンパク質の異常なプロセシングを特徴とする病状についての危険にあるもしくは該状態を罹患している哺乳類動物へ投与される。実例となる容態には、ダウン症候群患者のAD型症状、緑内障、黄斑変性症(例えば、加齢関連黄斑変性(AMD))、アミロイド形成と関連した糖尿病、スクレイピー、ウシ海綿状脳症(例えば、BSE)、外傷性脳損傷(「TBI」)、クロイツフェルト・ヤコブ病、およびこれらに類するものなどの神経変性疾患を含むII型糖尿病の治療における嗅覚障害、II型糖尿病を含むが、これらに限定されない。アミロイド形成/沈着を特徴とすることを特徴とする他の容態は考慮に入れられる。このような容態には、ハンチントン病、甲状腺の髄様癌、不整脈、孤立性心房アミロイドーシス、粥状硬化症、関節リウマチ、大動脈中膜アミロイド、プロラクチノーマ、家族性アミロイド多発ニューロパチー、遺伝性の非ニューロパチー性全身アミロイドーシス、透析関連アミロイドーシス、フィンランド人型アミロイドーシス、格子状角膜ジストロフィー、脳アミロイド血管症(例えば、アイスランド人型)、全身性ALアミロイドーシス、孤発性封入体筋炎、脳血管性認知症、およびこれらに類するものが含まれるが、それらに限定されない。
ある実施形態において、本明細書に説明される活性薬(例えば、本明細書に説明されるヒダントイン、またはその互変異性体もしくは立体異性体、または該ヒダントイン、該立体異性体、もしくは該互変異性体の医薬として許容しる塩もしくは溶媒和化合物、またはその類似体、誘導体、もしくはプロドラッグ)の「長時間放出」製剤が企図される。種々の実施形態において、このような長時間放出製剤は、静脈内および従来の即時放出経口剤形の高いピークの血漿水準を回避するよう設計されている。
化合物を放出する。治療用反応剤の化学的性質および生物学的安定性に応じて、安定化のための追加的な戦略を採用することができる。
本明細書に説明される長時間放出(徐放性)経口(胃腸管または経粘膜)製剤の1つの利点は、固体剤形であろうと液体ベースの剤形であろうと、即時放出製剤よりも長い持続時間で標的とされる治療ウィンドウ内に血漿薬剤濃度を維持することができるという点である。このような従来の即時放出製剤について典型的に観察される高いピークの血漿水準は典型的には、1〜12時間もしくはそれより長い時間にわたる薬剤の長時間放出によって鈍化される。加えて、血漿水準の迅速な低下は、該薬剤が錠剤の溶解時間の長さの間に口腔から血流中へと連続的に通過しているので、回避され、したがって、より安定した平衡状態を血漿薬物動態に提供する。加えて、本明細書に説明される剤形は、治療の安全性を損なう薬剤血漿薬物動態におけるピークおよびトラフが減少することにより、潜在的に有害な副作用を最小限にすることによって、治療の安全性を改善することがある。
ある実施形態において、本明細書に説明される1つ以上の活性薬(例えば、本明細書に説明されるヒダントイン、またはその互変異性体もしくは立体異性体、または該ヒダントイン、該立体異性体、もしくは該互変異性体の医薬として許容し得る塩もしくは溶媒和化合物、またはこれらの類似体、誘導体、もしくはプロドラッグ)は、該活性薬を必要とする哺乳類動物へ、例えば、アミロイド前駆体タンパク質の異常なプロセシングを特徴とする病状についての危険にあるもしくは該状態を罹患している哺乳類動物、MCIからアルツハイマー病への進行についての危険にある哺乳類動物などへ投与される。ある実施形態において、活性薬は、アルツハイマー病の前段階の認知機能障害の発症を予防もしくは遅延させるために、および/またはアルツハイマー病の前段階の認知機能障害の1つ以上の症状を寛解させるために、および/またはアルツハイマー病の前段階の容態もしくは認知障害からアルツハイマー病への進行を予防もしくは遅延させるために、および/または非アミロイド形成性経路によってアミロイド前駆体タンパク質(APP)のプロセシングを促進するために投与される。ある実施形態において、1つ以上の活性薬は、初期、中期、または後期アルツハイマー病の治療のために、例えば、該疾患の重症度を低下させ、および/または該疾患の1つ以上の症状を寛解させ、および/または該疾患の進行を遅延させるために投与される。
ある実施形態において、本明細書に説明される活性薬(例えば、本明細書に説明されるヒダントイン、またはその互変異性体もしくは立体異性体、または該ヒダントイン、該立体異性体、もしくは該互変異性体の医薬として許容し得る塩もしくは溶媒和化合物、またはこれらの類似体、誘導体、もしくはプロドラッグ)は、MCIおよび/またはADを含む脳におけるアミロイド沈着を特徴とする疾患を治療または予防するのに使用される他の治療薬またはアプローチと併用することができる。したがって、ある実施形態において、本明細書に説明される少なくとも活性薬(例えば、本明細書に説明されるヒダントイン、またはその互変異性体もしくは立体異性体、または該ヒダントイン、該立体異性体、もしくは該互変異性体の医薬として許容し得る塩もしくは溶媒和化合物、またはこれらの類似体、誘導体、もしくはプロドラッグ)を少なくとも1つの追加的な治療薬、および医薬として許容し得る担体もしくは希釈剤とともに含む医薬組成物が企図される。ある実施形態において、本明細書に説明される少なくとも活性薬を少なくとも1つの追加的な治療薬とともに投与することを含む治療法または予防法が企図される。
の組み合わせ、γセクレターゼ調節薬、γセクレターゼ阻害薬、非ステロイド性抗炎症薬、神経炎症を低下させることのできる抗炎症薬、抗アミロイド抗体(Wyeth社/Elan社製バピネオゼマブ(bapineuzemab)など)、ビタミンE、ニコチン性アセチルコリン受容体アゴニスト、CB1受容体インバースアゴニストもしくはCB1受容体アンタゴニスト、抗生物質、成長ホルモン分泌促進因子、ヒスタミンH3アンタゴニスト、AMPAアゴニスト、PDE4阻害薬、GABAAインバースアゴニスト、アミロイド凝集阻害薬、グリコーゲンシンターゼキナーゼβ阻害薬、αセクレターゼ活性プロモーター、PDE−10阻害薬、タウキナーゼ阻害薬(例えば、GSK3β阻害薬、cdk5阻害薬、またはERK阻害薬)、タウ凝集阻害薬(例えば、REMBER(登録商標)、RAGE阻害薬(例えば、TTP488(PF−4494700)))、抗Aβワクチン、APPリガンド、インスリンを上方制御する薬剤、HMG−CoA還元酵素阻害薬(例えば、アトルバスタチン、フルバスタチン、ロバスタチン、メバスタチン、ピタバスタチン、プラバスタチン、ロスバスタチン、シムバスタチンなどのスタチン類)および/もしくはコレステロール吸収阻害薬(エゼチミブなど)、またはHMG−CoA還元酵素阻害薬およびコレステロール吸収阻害薬の組み合わせ(例えば、VYTORIN(登録商標)など)などのコレステロール降下薬、フィブラート類(例えば、クロフィブラート、クロフィブライド、エトフィブラート、およびアルミニウムクロフィブラートなど)、フィブラートならびにこれステロース降下薬および/またはコレステロール吸収阻害薬の組み合わせ、ニコチン性受容体アゴニスト、ナイアシン、ナイアシンならびにこれステロース吸収阻害薬および/またはコレステロール降下薬の組み合わせ(例えば、SIMCOR(登録商標)(Abbott Laboratories社から入手可能なナイアシン/シムバスタチン))、LXRアゴニスト、LRP模倣薬、H3受容体アンタゴニスト、ヒストンデアセチラーゼ阻害薬、hsp90阻害薬、5−HT4アゴニスト(例えば、PRX−03140(Epix Pharmaceuticals製))、5−HT6受容体アンタゴニスト、mGluR1受容体調節薬もしくはアンタゴニスト、mGluR5受容体調節薬もしくはアンタゴニスト、mGluR2/3アンタゴニスト、プロスタグランジンEP2受容体アンタゴニスト、PAI−1阻害薬、ゲルゾリンなどのAβ流出を誘導することのできる薬剤、金属−タンパク質減弱化合物(例えば、PBT2)、ならびにGPR3調節薬、ならびにジメボリン(例えば、DIMENBON(登録商標)、Pfizer製)などの抗ヒスタミン薬を含む。
またはα1−アドレナリン受容体アンタゴニストである。
(加齢関連黄斑変性および緑内障におけるヒダントインの使用)
種々の実施形態において、APP結合性BACE阻害薬(ABBI)、例えば本明細書に説明される種々のヒダントインの使用は、アルツハイマー病の前段階の容態および/もしくは認知機能障害の発症を予防もしくは遅延させること、ならびに/またはアルツハイマー病の前段階の容態および/もしくは認知機能障害の1つ以上の症状を寛解させること、またはアルツハイマー病の前段階の容態もしくは認知機能障害からアルツハイマー病への進行を予防もしくは遅延させることに対して、ならびに/またはアルツハイマー病の治療に対して企図されてはいるが、ABBIに関する他の使用も企図される。特に、ある実施形態において、ABBIの使用は、加齢関連黄斑変性および/または緑内障の治療および/または予防に企図される。
特定の理論に結び付けられることなく、本明細書に説明される活性薬(例えば、本明細書に説明されるヒダントインなどのABBI)は、非アミロイド形成性経路によるAPPのプロセシングを促進し、および/またはアミロイド形成性経路によるAPPのプロセシングを低下もしくは阻害すると考えられている。非アミロイド形成性経路において、APPは、APPsα外部ドメイン(「sAPPα」)を放出するAβ配列内のαセクレターゼによってまず開裂する。対照的に、アミロイド形成性毛色は、βセクレターゼがAβのアミノ末端でAPPを開裂する場合に惹起し、それによりAPPsβ外部ドメイン(「sAPPβ」)を放出する。非アミロイド形成性経路およびアミロイド形成性経路によるAPPプロセシングは、当該技術分野で公知であり、例えば、Xu(2009)J Alzheimers Dis.,16(2):211〜224、およびDe Strooperら(2010)Nat Rev Neurol 6(2):99〜107によって総説されている。
本明細書に説明される化合物のうちの何らかのAPP結合性BACE阻害薬(ABBI)活性は、例えば本明細書に説明されるアッセイを用いて容易に検証することができる。基礎的には、ある実施形態において、一対のアッセイを利用して、MBP−C125 APP基質のBACE開裂を阻害するABBI化合物を識別し、結果的にC99およびβ部位ペプチド基質(P5−P5’)の生成の阻害を生じ、また、例えば表面プラズモン共鳴(SPR)分析によって測定されるように、APPと相互作用もする。
前記活性薬の阻害活性を示すのに使用することのできる実例となるアッセイは、例えば、WO2000/017369、WO2000/0003819、ならびに米国特許第5,942,400号および第5,744,346号に説明されている。このようなアッセイは、無細胞インキュベーションにおいて、またはαセクレターゼおよび/もしくはβセクレターゼならびにαセクレターゼおよびβセクレターゼの開裂部位を有するAPP基質を発現する細胞を用いた細胞インキュベーションにおいて実施することができる。
数多くの細胞系アッセイを使用して、関心対象の薬剤の活性をβセクレターゼ活性に対する相対的なαセクレターゼ活性に関して、および/またはアミロイド形成性Aβオリゴマー対非アミロイド形成性Aβオリゴマーを放出するためのAPPのプロセシングに関して評価することができる。細胞内でのかつ該薬剤の存在下または非存在下でのAPP基質とαセクレターゼおよび/またはβセクレターゼ酵素との接触を使用して、該薬剤のαセクレターゼ促進および/またはβセクレターゼ阻害活性を示すことができる。好ましくは、該薬剤の存在下でのアッセイは、阻害されていない対照と比較した場合、酵素活性の少なくとも約30%、最も好ましくは少なくとも約50%の阻害を提供する。
種々の動物モデルを使用して、関心対象の薬剤の活性を相対的αセクレターゼおよび/またはβセクレターゼ活性に関してならびに/またはAβを放出するためのAPPプロセシングに関して分析することができる。例えば、APP基質、αセクレターゼおよび/またはβセクレターゼ酵素を発現するトランスジェニック動物を使用して、該薬剤の阻害活性を示すことができる。あるトランスジェニック動物モデルは例えば、米国特許第5,877,399号、第5,612,486号、第5,387,742号、第5,720,936号、第5,850,003号、第5,877,015号、および第5,811,633号において、ならびにGanesら(1995)Nature 373:523において説明されている。ADの病理生理学と関連した特徴を呈する動物が好ましい。本明細書に説明されるトランスジェニックマウスへの該薬剤の投与は、該薬愛の阻害活性を示すための代替的な方法を提供する。医薬として有効な担体におけるかつ適切な治療的量で標的組織に到達する投与経路を介した薬剤の投与も好ましい。
種々の実施形態において、治療の有効性は、前記薬剤(例えば、本明細書に説明されるヒダントイン、またはその互変異性体もしくは立体異性体、または該ヒダントイン、該立体異性体、もしくは該互変異性体の医薬として許容し得る塩もしくは溶媒和化合物、またはこれらの類似体、誘導体、もしくはプロドラッグ)の投与が始まる前の疾患のパラメータの基線の程度を、薬剤(類)または類似体が投与された後の1つ以上の時点の同じパラメータと比較することによって判定することができる。測定することのできる1つの実例となるパラメータは、APPプロセシングのバイオマーカー(例えば、ペプチドオリゴマー)である。このようなバイオマーカーには、血液、血漿、血清、尿、粘液または脳脊髄液(CSF)中の高水準のsAPPα、p3(Aβ17−42またはAβ17−40)、sAPPβ、可溶性Aβ40、および/または可溶性Aβ42を含むがこれらに限定されない。高水準のsAPPαおよび/またはp3、ならびに低水準のsAPPβおよび/またはAPPネオの検出は、該処置が有効であるという指標である。逆に、低水準のsAPPαおよび/またはp3、ならびに/あるいは高水準のsAPPβ、APPネオ、タウまたはホスホタウ(pTau)の検出は、該処置が有効ではないという指標である。
種々の実施形態において、本明細書に説明される活性薬(例えば、ヒダントイン)は、複数回用量または単回用量の容器に封入することができる。封入した薬剤は、例えば、使用のために組み立てることのできる構成要素部分を含むキットにおいて提供することができる。例えば、凍結乾燥した形態の活性薬および適切な希釈剤は、使用前の組み合わせのために別個の構成要素として提供されてもよい。キットには、同時投与のための活性薬および第二の治療薬を含んでもよい。該活性薬および第二の治療薬は、別個の構成要素部分として提供されてもよい。キットには、複数の容器を含んで、各容器が該化合物の1以上の単位用量を保持してもよい。該容器は好ましくは、所望の投与様式に適応しており、該投与様式には、例えば、本明細書に説明されるように、経口投与のための錠剤、ゲルカプセル、持効性カプセル、およびこれらに類するもの、非経口投与のためのデポー製剤、事前に充填された注射器、アンプル、バイアル、およびこれらに類するもの、ならびに局所的投与のためのパッチ、医用パッド、クリーム、およびこれらに類するものを含むがこれらに限定されない。
以下の実施例は、請求する発明を説明するために提案するが、該発明を限定するものではない。
(化合物1:5−(3,5−ジフルオロフェニル)−5−フェニルイミダゾリジン−2,4−ジオン(ヒダントイン−1)の合成)
(工程1:(3,5−ジフルオロフェニル)(2−フェニル−1,3−ジチアン−2−イル)メタノールの合成)
(FAH−2の合成:2−アミノ−4−(4−(ジフルオロメトキシ)フェニル)−4−(3,5−ジフルオロフェニル)−1−メチル−1H−イミダゾール−5(4H)−オン))
(工程1:2−(3,5−ジフルオロフェニル)−1,3−ジチアン)
(FAH−3の合成:2−アミノ−4−(4−(ジフルオロメトキシ)フェニル)−4−(3,5−ジフルオロフェニル)−1−メチル−1H−イミダゾール−5−(4H)−オン)
(工程1:2−(3,5−ジフルオロフェニル)−1,3−ジチアンの合成)
DMF(8ml)および水(2ml)の混合物中のクロロジフルオロ酢酸ナトリウム(3.23g、21.15mmol)および4−ヒドロキシ−3−メチルベンズアルデヒド(1.44g、10.58mmol)、炭酸カリウム(2.19g、15.87mmol)の溶液を100℃で2時間加熱した。該反応混合物を水(20ml)で希釈し、酢酸エチル(3×25ml)で抽出した。有機抽出物を10%(m/v)LiCl水溶液(3×25ml)で洗浄し、硫酸ナトリウムで乾燥させ、濾過および蒸発させ、残渣を得、該残渣をフラッシュクロマトグラフィー(15%EtOAc/ヘキサン)で処理して、4−(ジフルオロメトキシ)−3−メチルベンズアルデヒド(0.244g、1.31mmol、12%)を褐色の油として得、4−ヒドロキシ−3−メチルベンズアルデヒド(1.164g、8.55mmol、81%)を褐色の固体として回収した。
DMF(15ml)中のクロロジフルオロ酢酸ナトリウム(2.60g、17.04mmol)および4−ヒドロキシ−3−メチルベンズアルデヒド(1.16g、8.52mmol)の溶液を3時間かけて、炭酸カリウム(1.77g、12.78mmol)を含有するDMF(15ml)の溶液へ95℃で添加した。該反応物をさらに15分間寝かせておいた後、冷却した。該反応混合物を水(50ml)で希釈し、酢酸エチル(3×50ml)で抽出した。有機抽出物を10%(m/v)LiCl溶液(3×25ml)で洗浄し、硫酸ナトリウム上で乾燥させ、濾過および蒸発させて、残渣を得、該残渣をフラッシュクロマトグラフィー(15%EtOAc/ヘキサン)で処理して、4−(ジフルオロメトキシ)−3−メチルベンズアルデヒド(021GLM−053_1(2)、1.00g、5.37mmol、63%)を黄色の油として得た。この油を先行実験の油と組み合わせ、パスツールピペットカラムを通過させて10%EtOAC/ヘキサンで溶出して、油を得、該油を直立位で凝固させた(1.315g、7.06mmol、2回の反応を通じて67%)。プロトンNMRは、提案した構造と一致していた。
(FAH−5の合成:2−アミノ−4−(3,5−ジフルオロフェニル)−4−(3,5−ジメチルフェニル)−1−メチル−1H−イミダゾール−5(4H)−オン)
(2−(3,5−ジフルオロフェニル)−1,3−ジチアンの合成)
(FAH−4(ITH002329)の合成)
(2−(3,5−ジフルオロフェニル)−1,3−ジチアンの合成)
(FAH−17:2−アミノ−4−(4−(ジフルオロメトキシ)フェニル)−4−(3−フルオロフェニル)−1−メチル−1H−イミダゾール−5(4H)−オン)
(工程1:2−(4−(ジフルオロメトキシ)−3−メチルフェニル)−1,3−ジチアンの合成)
(FAH−17 HCl塩)
(FAH−22の合成)
(2−(3−フルオロ−5−メチルフェニル)−1,3−ジアチンの合成)
(FAH−23の合成:2−アミノ−4−(4−(ジフルオロメトキシ)フェニル)−4−(3−クロロフェニル)−1−メチル−1H−イミダゾール−5(4H)−オン)
(工程1:2−(3−クロロフェニル)−1,3−ジチアンの合成)
(化合物FAH−27の合成:2−アミノ−4−(4−(ジフルオロメトキシ)フェニル)−4−(3−メチルフェニル)−1−メチル−1H−イミダゾール−5(4H)−オン)
(工程1:2−(3−メチルフェニル)−1,3−ジチアンの合成)
(FAH−28の合成:2−アミノ−4−(4−(ジフルオロメトキシ)フェニル)−4−(3−(トリフルオロメチル)フェニル)−1−メチル−1H−イミダゾール−5(4H)−オン)
(工程1:2−(3−トリフルオロメチル)フェニル)−1,3−ジチアンの合成)
(SPR分析)
カルボキシメチル化デキストラン(CM−5)チップの2つのフローセルFC1およびFC2全部の表面をビアコアT−100(GE Healthcare)を用いて30μl/分の流量を1分間用いることと併行して、50mM NaOH、1mM HCl、0.05%H3PO4および20mMリン酸ナトリウム、pH7.4、125mM塩化ナトリウムで連続的に洗浄した。FC2へ20mMリン酸、125mM塩化ナトリウムpH7.4を用いてアミンカップリングを介して融合タンパク質を固定した。この融合タンパク質TRX−eAPP577〜624は、チオレドキシン(TRX)およびAPP外部ドメインの残基575〜624(20−kDa)からなる融合体を含有している。該融合タンパク質は、Libeuら(JAD 2011)において説明される通り生成される。該タンパク質を20mMリン酸pH6.5、125mM塩化ナトリウム中で2mg/mlへと濃縮した後、20mM酢酸ナトリウムpH5.0における50μg/mlの濃度へ溶解した。FC1は、緩衝液単独による擬似固定後の基準セルとして機能した。すべてのセルについて、流量は10μl/分であった。チップを1Mエタノールアミン(pH8.5)でブロッキングした。最終的なRU値を、TRX−eAPP577〜624へのBACE阻害薬結合について、DMSO中の該阻害薬の濃度を50μMまで変化させて流すことによって測定した。化合物をDMSO中の10mM溶液から1%DMSO、20mMリン酸ナトリウムpH7.4、125mM塩化ナトリウム、0.05%トゥイーン中の50μMまで希釈した後、10工程について1.5ずつ連続希釈した。結合トレースを各希釈について、60秒間の結合相および240秒間の解離相を用いて記録した。各周期を20℃で、20μl/分の定常流量で実施した。該セルにわたる60μl/分の緩衝液流量をさらに240秒間、再生相として適用して、該タンパク質からの該化合物の完全な解離を容易にした。ビアコアT100評価ソフトウェアを用いて基準信号および緩衝液信号の減算によって、センソグラムを得た。該結合曲線をPRISM(Graphpad社製)を用いてモデル化した。
(SH−SY5Y細胞におけるAβ42測定についての実験方法)
(インビトロでのAβ検査アッセイ)
SH−SY5Y神経芽細胞腫細胞を96穴プレート中に50,000個/ウェルで播種して24時間置いた。次に、該細胞の培地を、所望の濃度のヒダントイン化合物(例えば、化合物3)を補充した新鮮培地と交換した。24時間後、20μlの培地を、1μMのEDTAを含有する2μlの完全プロテアーゼ阻害薬へ添加し、以下のELISAアッセイを用いた分析まで4℃で保管しておいた。
Invitrogen製のELISAキットも使用して、Aβ1−42(KHB3544)を二つ組で定量した。Aβ1−42高感度ELISAについて、試料を1:2に希釈した(50μlのCSF+50μlのキット提供の標準希釈緩衝液)アッセイを製造元の説明書に従って実施した。簡潔には、標準物質および試料を、HuAβのアミノ末端に特異的なモノクローナル捕捉抗体で事前に被覆しておいたプレートへ入れた。試料をAβ種のカルボキシ末端に特異的なウサギ検出抗体(Ab)と同時インキュベートして、室温で3時間4°で一晩(Aβ1−42)穏やかに揺らしながらアッセイした。洗浄後、結合したウサギAbを、セイヨウワサビペルオキシダーゼ標識した抗ウサギ二次Abを用いて検出した。再度洗浄した後、結合したHRP抗ウサギAbを、基質溶液の添加によって比色測定で検出した(Spectramax 190、Molecular Devices)。1mMの4−(2−アミノエチル)ベンゼンスルホニルフルオリドヒドロクロリド(AEBSF)プロテアーゼ阻害薬(101500、Calbiochem製)を標準物質および試料へ添加した。
(脳取り込み検査(PK))
一般に、前記ヒダントインに関する中枢神経系曝露を次のとおり実施した。試験は、ヒダントイン分子10mg/kgの皮下(sc)投与後の該ヒダントインによる処置後のヘパリン処理済み血漿および脳の収集からなった。該化合物の血漿濃度および脳濃度を、Integrated Analytical Solutions(インターネットではinalytical.net)で実施する定量的LC/MS/MS法によって測定した。血漿試料を、内部標準物質を含有するアセトニトリル:メタノール(1:1)カクテルで沈殿させた。脳試料を酢酸エチル中で直接均質化し、または液体−液体法を用いた5Mグアニジン均質物から抽出した。結果として生じた上清は、蒸発して乾燥し、LC/MS/MS分析に供した。各化合物について3個体のマウスを分析に使用した。脳:血漿比および脳濃度を次に算出した。
(ABBIの選択性:APP−BACE対PSLG1−BACEまたはNRG1−BACE開裂の阻害)
(P5−P5’アッセイ)
APP−BACE1のIC50を測定するために、Sigma製BACE1基質(7−メトキシクマリン−4−アセチル−[Asn670,Lue671]−アミロイドb/A4前駆体タンパク質770断片667〜676−(2,4ジニトロフェニル)Lys−Arg−Argアミドトリフルオロ酢酸塩)を使用し、製造元のプロトコルに従った。簡潔には、0.01単位のBACE1を室温で1時間、BACE阻害薬とともにインキュベートした後、該基質を各ウェルへ添加し、蛍光度を即時および30分ごとに2時間読み取った。活性を、特異的[BACE阻害薬]での蛍光を[BACE阻害薬]=0μMでの蛍光によって除することによって測定し、%活性をlog[BACE阻害薬]に対してプロットして、GraphPad Prism5を用いてAPP−BACE1を測定した(図6A)。
簡潔には、PSGL−1−BACE1のIC50IC50を測定するために、HEK293細胞を24欠プレートに播種し、リポフェクタミン2000を用いてPSGL1/lacZまたはNRG1/lacZのいずれかのコンストラクトで一過性に同時トランスフェクトし、製造元のプロトコルに従った。該細胞へDNA−脂質複合体を添加した2時間後に、BACE阻害薬を各ウェルへ添加した後、細胞を37℃および5%CO2で一晩インキュベートした。培地を回収し、NRG1またはPSGL1を測定し、細胞を溶解してlacZ濃度を測定した。Sigma製SEAPキット標準プロトコルを培地に関して行い、PSGL1またはNRG1の濃度を検出した。プロメガ製キットの説明書に従って、lacZ濃度を測定した。PSGL1/lacz対[BACE阻害薬]の比をプロットして、GraphPad Prism 5を用いて各基質に関してBACE−IC50を測定した(図6B)。ABBI FAH17は、PSGL1よりもAPPに対して200倍超の選択性を示す。類似の検査では、FAH17は、NRG1よりもAPPに対して10倍超ほど選択的であることを示す。
Claims (16)
- 式
- 式
- 式
- R鏡像異性体である、請求項1から3のいずれか一項に記載の化合物。
- S鏡像異性体である、請求項1から3のいずれか一項に記載の化合物。
- APPへ、および/もしくは酵素BACEへ、および/もしくはAPP/BACE複合体へ結合する;または
APPへ結合し、かつ酵素BACEを阻害する、請求項1から5のいずれか一項に記載の化合物。 - 医薬として許容し得る担体および請求項1から6のいずれか一項に記載の化合物を含む、医薬製剤。
- 経口送達、イソフォレティック送達、経皮送達、非経口送達、エアゾール投与、吸入を介した投与、静脈内投与、および直腸投与からなる群から選択される経路を介する投与のために調合された、請求項7に記載の製剤。
- 経口投与のために調合された、請求項7に記載の製剤。
- 無菌化されている、請求項7に記載の製剤。
- 単位容量の製剤である、請求項7から10のいずれか一項に記載の製剤。
- 医薬として使用するための、請求項7から11のいずれか一項に記載の製剤。
- (1)アルツハイマー病の前段階の容態および/もしくは認知機能障害の発症を予防もしくは遅延させること、ならびに/または(2)アルツハイマー病の前段階の容態および/もしくは認知機能障害の1つ以上の症状を寛解させること、ならびに/または(3)アルツハイマー病の前段階の容態および/もしくは認知機能障害からアルツハイマー病への進行を予防もしくは遅延させること、における治療上の使用のための、または(4)アルツハイマー病の治療方法における使用のための、または(5)BACE活性と関連した疾患または障害の治療方法における使用のための、または(6)哺乳類動物における加齢黄斑変性(AMD)の進行を遅延させ、停止しまたは逆転させる使用のための、請求項7から11のいずれか一項に記載の製剤であって、前記使用には、前記使用を必要とする対象へ、前記製剤の有効量を投与することを含む、製剤。
- (1)アルツハイマー病の前段階の容態および/もしくは認知機能障害の発症を予防もしくは遅延させること、ならびに/または(2)アルツハイマー病の前段階の容態および/もしくは認知機能障害の1つ以上の症状を寛解させること、ならびに/または(3)アルツハイマー病の前段階の容態および/もしくは認知機能障害からアルツハイマー病への進行を予防もしくは遅延させること、における治療上の使用のための、請求項13に記載の製剤であって、
前記対象は、50歳以上の臨床上正常なヒト対象におけるAβのバイオマーカーの陽性を呈する;および/または
前記対象は、下流の神経変性および微妙な認知/行動の低下と任意に組み合わさって、無症候性脳アミロイドーシスを呈する;および/または
前記対象は、0を上回りかつ1.5を下回る評点の臨床的認知症を任意に示す、軽度認知障害と診断された対象である;および/または
前記対象は、アルツハイマー病を発症する危険がある、および/または前記対象は、アルツハイマー病を有することに対して家族性危険を有する、および/または前記対象は、家族性アルツハイマー病(FAD)突然変異を有する、および/または前記対象は、APOEε4対立遺伝子を有する;および/または
前記投与は、Aβ42、sAPPβ、総タウ(tTau)、ホスホタウ(pTau)、APPネオ、可溶性Aβ40、pTau/Aβ42比およびtTau/Aβ42比からなる群から選択される1つ以上の成分の水準のCSFにおける低下、ならびに/またはAβ42/Aβ40比、Aβ42/Aβ38比、sAPPα、sAPPα/sAPPβ比、sAPPα/Aβ40比、およびsAPPα/Aβ42比からなる群から選択される1つ以上の成分の水準のCSFにおける上昇を生じる;および/または
前記投与は、前記対象の脳における斑の量の減少を生じる;および/または
前記投与は、前記対象の脳における斑形成の速度の低下を生じる;および/または
前記投与は、前記対象の認知能力における改善を生じる;および/または
前記投与は、前記対象の臨床的認知症評点(CDR)の減少速度における改善、該減少速度の安定化、または該減少速度の低下を生じる;および/または
前記投与は生活の質における該ヒトにより知覚される改善を生じる、製剤。 - アルツハイマー病の1つ以上の症状を寛解させ、および/またはアルツハイマー病を逆転させ、および/またはアルツハイマー病の進行速度を低下させるための、請求項13に記載の製剤であって、
前記対象は、50歳以上のヒトである;または
前記対象は、初期アルツハイマー病と診断されている;または
前記対象は、中期アルツハイマー病と診断されている;または
前記対象は、後期アルツハイマー病と診断されている;および/または
前記投与は、アルツハイマー病の重症度を低下させる;または
前記投与は、アルツハイマー病の1つ以上の症状を寛解させる;または
前記投与は、アルツハイマー病の進行速度を低下させる;および/または
前記投与は、Aβ42、sAPPβ、総タウ(tTau)、ホスホタウ(pTau)、APPネオ、可溶性Aβ40、pTau/Aβ42比およびtTau/Aβ42比からなる群から選択される1つ以上の成分の水準のCSFにおける低下、ならびに/またはAβ42/Aβ40比、Aβ42/Aβ38比、sAPPα、sAPPα/sAPPβ比、sAPPα/Aβ40比、およびsAPPα/Aβ42比からなる群から選択される1つ以上の成分の水準のCSFにおける上昇を生じる;および/または
前記投与は、前記対象の脳における斑の量の減少を生じる;および/または
前記投与は、前記対象の脳における班形成の速度の低下を生じる;および/または
前記投与は、前記対象の認知能力における改善を生じる;および/または
前記投与は、前記対象の臨床的認知症評点(CDR)の減少速度における改善、該減少速度の安定化、または該減少速度における低下を生じる;および/または
前記投与は生活の質における該ヒトにより知覚される改善を生じる;および/または
前記投与は、脳アミロイドーシスおよび/または下流の神経変性の低下を結果的に生じる;および/または
前記対象は、アルツハイマー病を示す臨床的認知症評点を示す;および/または
前記対象は、アルツハイマー病を有することについての家族性危険を有する、および/または前記対象は、家族性アルツハイマー病(FAD)突然変異を有する、および/または前記対象は、APOEε4対立遺伝子を有する、製剤。 - BACE活性と関連した疾患または障害の治療を必要とする対象における該治療のための、請求項13に記載の製剤であって、前記疾患または障害は、アルツハイマー病、認知障害、ダウン症候群、HCHWA−D、認知機能低下、老年性認知症、脳アミロイド血管症、および神経変性障害からなる群から選択される、製剤。
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Family Cites Families (103)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS4995971A (ja) * | 1973-01-27 | 1974-09-11 | ||
DE2448869A1 (de) | 1973-10-19 | 1975-09-04 | Mcneilab Inc | 4-oxo-2-imidazolidinylidenharnstoffe, verfahren zu ihrer herstellung und arzneimittel |
US4025517A (en) * | 1975-06-23 | 1977-05-24 | Mcneil Laboratories, Incorporated | 4-Oxo-2-hexahydropyrimidinylidene ureas |
JPS554305A (en) | 1978-06-13 | 1980-01-12 | Nippon Zoki Pharmaceut Co Ltd | Remedy for disease caused by stress and its preparation |
US5070100A (en) | 1983-09-14 | 1991-12-03 | Alcon Laboratories, Inc. | Spiro-tricyclicaromatic succinimide derivatives |
US4864028A (en) | 1983-09-14 | 1989-09-05 | Alcon Laboratories, Inc. | Spiro-tricyclicaromatic succinimide derivatives |
GB2189699A (en) | 1986-04-30 | 1987-11-04 | Haessle Ab | Coated acid-labile medicaments |
GB2189698A (en) | 1986-04-30 | 1987-11-04 | Haessle Ab | Coated omeprazole tablets |
CH677886A5 (ja) | 1989-06-26 | 1991-07-15 | Hans Georg Prof Dr Weder | |
JPH06507782A (ja) | 1990-06-15 | 1994-09-08 | サイオス ノバ インコーポレイテッド | アルツハイマー病のアミロイド形成開症状を示すヒト以外の組換え哺乳動物 |
ES2236682T5 (es) | 1991-01-21 | 2011-03-31 | Elan Pharmaceuticals, Inc. | Ensayo y modelo para la enfermedad de alzheimer. |
WO1993014200A1 (en) | 1992-01-07 | 1993-07-22 | Tsi Corporation | Transgenic animal models for alzheimer's disease |
US5604102A (en) | 1992-04-15 | 1997-02-18 | Athena Neurosciences, Inc. | Methods of screening for β-amyloid peptide production inhibitors |
PT730643E (pt) | 1993-10-27 | 2001-06-29 | Lilly Co Eli | Animais transgenicos portadores do alelo de app com mutacao sueca |
US5877399A (en) | 1994-01-27 | 1999-03-02 | Johns Hopkins University | Transgenic mice expressing APP-Swedish mutation develop progressive neurologic disease |
ES2094688B1 (es) | 1994-08-08 | 1997-08-01 | Cusi Lab | Manoemulsion del tipo de aceite en agua, util como vehiculo oftalmico y procedimiento para su preparacion. |
FR2730932B1 (fr) | 1995-02-27 | 1997-04-04 | Oreal | Nanoemulsion transparente a base de lipides amphiphiles non-ioniques fluides et utilisation en cosmetique ou en dermopharmacie |
US5744346A (en) | 1995-06-07 | 1998-04-28 | Athena Neurosciences, Inc. | β-secretase |
JPH11507538A (ja) | 1995-06-07 | 1999-07-06 | アテナ ニューロサイエンシズ インコーポレイティド | β−セクレターゼ、β−セクレターゼに対する抗体、及びβ−セクレターゼ阻害を検出するためのアッセイ |
FR2742676B1 (fr) | 1995-12-21 | 1998-02-06 | Oreal | Nanoemulsion transparente a base de tensioactifs silicones et utilisation en cosmetique ou en dermopharmacie |
FR2755854B1 (fr) | 1996-11-15 | 1998-12-24 | Oreal | Nanoemulsion a base de lipides amphiphiles non-ioniques et cationiques et utilisations |
FR2760970B1 (fr) | 1997-03-18 | 2000-03-10 | Oreal | Nanoemulsions a base de lipides amphiphiles non-ioniques et de silicones aminees et utilisations |
AU5002399A (en) | 1998-07-17 | 2000-02-07 | National Broach And Machine Company | Full form roll finishing technique |
KR20070004143A (ko) | 1998-09-24 | 2007-01-05 | 파마시아 앤드 업존 캄파니 엘엘씨 | 알츠하이머병 세크레타제 |
FR2787026B1 (fr) | 1998-12-14 | 2001-01-12 | Oreal | Nanoemulsion a base d'esters mixtes d'acide gras ou d'alcool gras, d'acide carboxylique et de glyceryle, et ses utilisations dans les domaines cosmetique, dermatologique et/ou ophtalmologique |
FR2787027B1 (fr) | 1998-12-14 | 2001-01-12 | Oreal | Nanoemulsion a base d'esters gras de sucre ou d'ethers gras de sucre et ses utilisations dans les domaines cosmetique, dermatologique et/ou ophtalmologique |
FR2787326B1 (fr) | 1998-12-17 | 2001-01-26 | Oreal | Nanoemulsion a base d'esters gras de glycerol, et ses utilisations dans les domaines cosmetique, dermatologique et/ou ophtalmologique |
FR2787325B1 (fr) | 1998-12-17 | 2001-01-26 | Oreal | Nanoemulsion a base d'esters gras de sorbitan oxyethylenes ou non oxyethylenes, et ses utilisations dans les domaines cosmetique, dermatologique et/ou ophtalmologique |
FR2787728B1 (fr) | 1998-12-23 | 2001-01-26 | Oreal | Nanoemulsion a base d'esters gras d'acide phosphorique, et ses utilisations dans les domaines cosmetique, dermatologique, pharmaceutique et/ou ophtalmologique |
FR2787703B1 (fr) | 1998-12-29 | 2001-01-26 | Oreal | Nanoemulsion a base d'ethers gras ethoxyles ou d'esters gras ethoxyles, et ses utilisations dans les domaines cosmetique, dermatologique et/ou ophtalmologique |
FR2788007B1 (fr) | 1999-01-05 | 2001-02-09 | Oreal | Nanoemulsion a base de copolymeres blocs d'oxyde d'ethylene et d'oxyde de propylene, et ses utilisations dans les domaines cosmetique, dermatologique et/ou ophtalmologique |
FR2788449B1 (fr) | 1999-01-14 | 2001-02-16 | Oreal | Nanoemulsion a base de citrates d'alkylether, et ses utilisations dans les domaines cosmetique, dermatologique, pharmaceutique et/ou ophtalmologique |
FR2789076B1 (fr) | 1999-02-02 | 2001-03-02 | Synthelabo | Derives de alpha-azacyclomethyl quinoleine, leur preparation et leur application en therapeutique |
US7161962B1 (en) | 1999-05-27 | 2007-01-09 | Nuera Communications, Inc. | Method and apparatus for coding modem signals for transmission over voice networks |
FR2811564B1 (fr) | 2000-07-13 | 2002-12-27 | Oreal | Nanoemulsion contenant des polymeres non ioniques, et ses utilisations notamment dans les domaines cosmetique, dermatologique, pharmaceutique et/ou ophtalmologique |
AU2002241823A1 (en) | 2001-01-11 | 2002-07-24 | Eastman Chemical Company | Cyclodextrin sulfonates, guest inclusion complexes, methods of making the same and related materials |
FR2819427B1 (fr) | 2001-01-18 | 2003-04-11 | Oreal | Nanoemulsion translucide, son procede de fabrication et ses utilisations dans les domaines cosmetique, dermatologique et/ou ophtalmologique |
AU2002367976B2 (en) | 2001-06-05 | 2007-06-21 | The Regents Of The University Of Michigan | Nanoemulsion vaccines |
US7476393B2 (en) | 2002-11-29 | 2009-01-13 | L'oreal | Process for the preparation of a cationic nanoemulsion, and cosmetic composition |
EP1660443B1 (en) | 2003-08-08 | 2009-03-04 | Schering Corporation | Cyclic amine bace-1 inhibitors having a benzamide substituent |
TW200524910A (en) | 2003-08-08 | 2005-08-01 | Schering Corp | Cyclic amine BACE-1 inhibitors having a heterocyclic substituent |
US7592348B2 (en) | 2003-12-15 | 2009-09-22 | Schering Corporation | Heterocyclic aspartyl protease inhibitors |
US7763609B2 (en) | 2003-12-15 | 2010-07-27 | Schering Corporation | Heterocyclic aspartyl protease inhibitors |
CN102627609B (zh) | 2003-12-15 | 2016-05-04 | 默沙东公司 | 杂环天冬氨酰蛋白酶抑制剂 |
US7468402B2 (en) | 2004-03-17 | 2008-12-23 | Baker Hughes Incorporated | Polymeric nanoemulsion as drag reducer for multiphase flow |
WO2005096730A2 (en) | 2004-04-02 | 2005-10-20 | Merck & Co., Inc. | Methods for detecting substances which bind to the amyloid precursor protein or beta amyloid fragments, and binding compounds |
EP1740575A2 (en) | 2004-04-22 | 2007-01-10 | Eli Lilly And Company | Pyrrolidine derivatives useful as bace inhibitors |
IL162288A0 (en) | 2004-06-01 | 2005-11-20 | Future Products Man S A | Compositions and methods for treating neurodegenerative disorders |
AU2005264917A1 (en) | 2004-06-16 | 2006-01-26 | Wyeth | Diphenylimidazopyrimidine and -imidazole amines as inhibitors of B-secretase |
CN1968945A (zh) | 2004-06-16 | 2007-05-23 | 惠氏公司 | 用于抑制β分泌酶的氨基-5,5-二苯基咪唑酮衍生物 |
MX2007000760A (es) | 2004-07-22 | 2007-04-09 | Schering Corp | Amida sustituida inhibidora de b secretasa. |
ES2306200T3 (es) | 2004-07-28 | 2008-11-01 | Schering Corporation | Inhibidores macrociclicos de beta-secretasa. |
TW200624426A (en) | 2004-09-21 | 2006-07-16 | Lilly Co Eli | BACE inhibitors |
GB0500683D0 (en) | 2005-01-13 | 2005-02-23 | Novartis Ag | Organic compounds |
MX2007008507A (es) | 2005-01-13 | 2009-02-16 | Novartis Ag | Compuestos macrociclicos utiles como inhibidores de bace. |
WO2006138264A2 (en) | 2005-06-14 | 2006-12-28 | Schering Corporation | Aspartyl protease inhibitors |
CA2610812A1 (en) | 2005-06-14 | 2006-12-28 | Schering Corporation | Aspartyl protease inhibitors |
JP2008543846A (ja) | 2005-06-14 | 2008-12-04 | シェーリング コーポレイション | プロテアーゼ阻害剤として化合物の調製およびその使用 |
ATE489370T1 (de) | 2005-06-14 | 2010-12-15 | Schering Corp | Herstellung und verwendung von verbindungen als aspartylproteasehemmer |
AR056865A1 (es) | 2005-06-14 | 2007-10-31 | Schering Corp | Heterociclos nitrogenados y su uso como inhibidores de proteasas, composiciones farmaceuticas |
AU2006259609A1 (en) | 2005-06-14 | 2006-12-28 | Pharmacopeia, Inc. | Aspartyl protease inhibitors |
CN101193892A (zh) | 2005-06-14 | 2008-06-04 | 先灵公司 | 大环杂环天冬氨酰基蛋白酶抑制剂 |
TW200738683A (en) | 2005-06-30 | 2007-10-16 | Wyeth Corp | Amino-5-(5-membered)heteroarylimidazolone compounds and the use thereof for β-secretase modulation |
AU2006266167A1 (en) | 2005-06-30 | 2007-01-11 | Wyeth | Amino-5-(6-membered)heteroarylimidazolone compounds and the use thereof for beta-secretase modulation |
TW200730523A (en) | 2005-07-29 | 2007-08-16 | Wyeth Corp | Cycloalkyl amino-hydantoin compounds and use thereof for β-secretase modulation |
CA2623245A1 (en) | 2005-09-26 | 2007-04-05 | Wyeth | Amino-5- [4- (difluoromethoxy) phenyl] -5-phenylimidazolone compounds as inhibitors of the beta-secretase (bace) |
WO2007050721A2 (en) | 2005-10-27 | 2007-05-03 | Schering Corporation | Heterocyclic aspartyl protease inhibitors |
EP1943246A1 (en) | 2005-10-31 | 2008-07-16 | Schering Corporation | Aspartyl protease inhibitors |
EP1954682A4 (en) * | 2005-11-21 | 2011-11-09 | Astrazeneca Ab | NOVEL 2-AMINO-IMIDAZOLE-4-ONE COMPOUNDS AND THEIR USE IN THE MANUFACTURE OF A MEDICAMENT FOR USE IN THE TREATMENT OF COGNITIVE DEFICIENCY, ALZHEIMER'S DISEASE, NEURODEGENERATION AND DEMENTIA |
GB0602951D0 (en) | 2006-02-14 | 2006-03-29 | Novartis Ag | Organic Compounds |
EP2004630A4 (en) | 2006-04-05 | 2010-05-19 | Astrazeneca Ab | 2-AMINOPYRIMIDIN-4-ONES AND THEIR USE FOR THE TREATMENT OR PREVENTION OF PATHOLOGIES RELATED TO PROTEIN A |
GB0611064D0 (en) | 2006-06-05 | 2006-07-12 | Novartis Ag | Organic compounds |
EP2032542A2 (en) | 2006-06-12 | 2009-03-11 | Schering Corporation | Heterocyclic aspartyl protease inhibitors |
TW200808796A (en) | 2006-06-14 | 2008-02-16 | Astrazeneca Ab | New compounds III |
TW200815443A (en) | 2006-06-14 | 2008-04-01 | Astrazeneca Ab | Novel compounds I |
TW200815449A (en) | 2006-06-14 | 2008-04-01 | Astrazeneca Ab | Novel compounds II |
TW200815447A (en) | 2006-06-14 | 2008-04-01 | Astrazeneca Ab | Novel compounds IV |
TW200815349A (en) | 2006-06-22 | 2008-04-01 | Astrazeneca Ab | New compounds |
CA2656869A1 (en) | 2006-07-20 | 2008-01-24 | Novartis Ag | Macrocyclic lactams |
KR20090039726A (ko) | 2006-07-20 | 2009-04-22 | 노파르티스 아게 | Bace 억제제로서 유용한 마크로시클릭 화합물 |
WO2008062044A1 (en) | 2006-11-23 | 2008-05-29 | Novartis Ag | 2-hydroxy-1,3-diaminopropane derivatives |
CN101631779A (zh) | 2006-12-12 | 2010-01-20 | 先灵公司 | 含有三环系统的天冬氨酰蛋白酶抑制剂 |
AU2007332754A1 (en) | 2006-12-12 | 2008-06-19 | Schering Corporation | Aspartyl protease inhibitors |
TW200831091A (en) * | 2006-12-20 | 2008-08-01 | Astrazeneca Ab | New compounds |
CA2680307A1 (en) | 2007-03-12 | 2008-09-18 | Merck & Co., Inc. | Monocyclic anilide spirolactam cgrp receptor antagonists |
PE20090160A1 (es) | 2007-03-20 | 2009-02-11 | Wyeth Corp | COMPUESTOS AMINO-5-[4-(DIFLUOROMETOXI)FENIL SUSTITUIDO]-5-FENILIMIDAZOLONA COMO INHIBIDORES DE ß-SECRETASA |
TW200902499A (en) | 2007-05-15 | 2009-01-16 | Astrazeneca Ab | New compounds |
US20090041201A1 (en) | 2007-08-06 | 2009-02-12 | Carestream Health, Inc. | Alignment apparatus for imaging system |
EA201000340A1 (ru) | 2007-08-23 | 2010-08-30 | Новартис Аг | Аминобензилзамещенные циклические сульфоны, полезные в качестве ингибиторов васе |
US20090062361A1 (en) | 2007-08-30 | 2009-03-05 | Allergan, Inc. | Therapeutic hydantoins |
TWI431004B (zh) | 2008-05-02 | 2014-03-21 | Lilly Co Eli | Bace抑制劑 |
AU2009268024A1 (en) | 2008-07-10 | 2010-01-14 | Novartis Ag | Cyclic sulfones with aminobenzyl substitution useful as BACE inhibitors |
JPWO2010047372A1 (ja) | 2008-10-22 | 2012-03-22 | 塩野義製薬株式会社 | Bace1阻害活性を有する2−アミノピリミジン−4−オンおよび2−アミノピリジン誘導体 |
EP2359861B1 (en) | 2008-11-11 | 2013-09-11 | CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd. | Inclusion complexes of pinocembrin with cyclodextrin or its derivatives |
AR077277A1 (es) | 2009-07-09 | 2011-08-17 | Lilly Co Eli | Compuestos de biciclo (1,3)tiazin-2-amina formulacion farmaceutica que lo comprende y su uso para la manufactura de un medicamento util para el tratamiento de la enfermedad de alzheimer |
UA108363C2 (uk) | 2009-10-08 | 2015-04-27 | Похідні імінотіадіазиндіоксиду як інгібітори bace, композиція на їх основі і їх застосування | |
EP2485591B1 (en) | 2009-10-08 | 2016-03-23 | Merck Sharp & Dohme Corp. | Iminothiadiazine dioxide compounds as bace inhibitors, compositions, and their use |
CA2808630A1 (en) | 2010-08-19 | 2012-02-23 | Buck Institute For Age Research | Methods of treating mild cognitive impairment (mci) and related disorders |
US8415483B2 (en) | 2010-12-22 | 2013-04-09 | Astrazeneca Ab | Compounds and their use as BACE inhibitors |
US20120165346A1 (en) | 2010-12-22 | 2012-06-28 | Astrazeneca Ab | Compounds and their use as BACE inhibitors |
US8877744B2 (en) | 2011-04-04 | 2014-11-04 | Hoffmann-La Roche Inc. | 1,4-Oxazepines as BACE1 and/or BACE2 inhibitors |
KR102220259B1 (ko) | 2013-02-12 | 2021-02-25 | 버크 인스티튜트 포 리서치 온 에이징 | Bace 매개 app 처리과정을 조절하는 히단토인 |
US11142505B2 (en) * | 2015-08-27 | 2021-10-12 | The Regents Of The University Of California | Compositions for APP-selective BACE inhibition and uses therefor |
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