JP2013521325A - グルタミニルシクラーゼ(qc、ec2.3.2.5)の複素環阻害剤 - Google Patents
グルタミニルシクラーゼ(qc、ec2.3.2.5)の複素環阻害剤 Download PDFInfo
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- JP2013521325A JP2013521325A JP2012556515A JP2012556515A JP2013521325A JP 2013521325 A JP2013521325 A JP 2013521325A JP 2012556515 A JP2012556515 A JP 2012556515A JP 2012556515 A JP2012556515 A JP 2012556515A JP 2013521325 A JP2013521325 A JP 2013521325A
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Classifications
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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
- C07D403/02—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 two hetero rings
- C07D403/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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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
- A61K31/41—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
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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Abstract
【選択図】なし
Description
本発明は、グルタミニルシクラーゼ(QC、EC 2.3.2.5)の阻害剤としての新規複素環誘導体に関する。QCは、アンモニアの遊離下でのN-末端グルタミン残基のピログルタミン酸(5-オキソ-プロリル、pGlu*)への分子内環化、及び水の遊離下でのN-末端グルタミン酸残基のピログルタミン酸への分子内環化を触媒する。
グルタミニルシクラーゼ(QC, EC 2.3.2.5)は、アンモニアを遊離しながらの、N-末端グルタミン残基のピログルタミン酸(pGlu*)への分子内環化を触媒する。QCは、1963年にMesserにより熱帯植物カリカ・パパイヤ(Carica papaya)のラテックスから最初に単離された(Messer, M.の文献(1963 Nature 4874, 1299))。24年後、対応する酵素活性が、動物の下垂体において発見された(Busby, W. H. J.らの文献(1987 J Biol Chem 262, 8532-8536);Fischer, W. H.及びSpiess, J.の文献(1987 Proc Natl Acad Sci USA 84, 3628-3632))。哺乳動物のQCに関して、QCによるGlnのpGluへの転化を、TRH及びGnRHの前駆体について示すことができた(Busby, W. H. J.らの文献(1987 J Biol Chem 262, 8532-8536);Fischer, W. H.及びSpiess, J.の文献(1987 Proc Natl Acad Sci USA 84, 3628-3632))。加えて、初期のQC局在化実験は、ウシ下垂体における触媒の推定産物との共局在を明らかにし、ペプチドホルモン合成において示唆された機能をさらに改良した(Bockers, T. M.らの文献(1995 J Neuroendocrinol 7, 445-453))。対照的に、植物のQCの生理機能は、これほど明確ではない。C.パパイヤ由来の酵素の場合、病原性微生物に対する植物防御における役割が示唆された(El Moussaoui, A.らの文献(2001 Cell Mol Life Sci 58, 556-570))。他の植物に由来する推定上のQCが、配列比較により最近同定された(Dahl, S. W.らの文献(2000 Protein Expr Purif 20, 27-36))。しかしこれらの酵素の生理機能は依然曖昧である。
用語「ki」又は「KI」及び「KD」は結合定数であり、これは阻害剤の酵素への結合及び酵素からのその後の放出を説明するものである。別の尺度は「IC50」値であり、これは、所与の基質濃度で、50%の酵素活性を生じる阻害剤濃度を反映するものである。
好ましい実施態様において、QC阻害との相関関係を考慮し、本対象となる方法及び医学的用途は、QC阻害のIC50が10μM以下、より好ましくは1μM以下、さらにより好ましくは0.1μM以下若しくは0.01μM以下、又は最も好ましくは0.001μM以下である作用物質を利用する。実際、Ki値が、より低いμM、好ましくはnM、さらにより好ましくはpMの範囲である阻害剤が意図されている。したがって、本明細書においては便宜上「QC阻害剤」として活性作用物質が説明されているが、そのような命名は、本発明の対象を特定の作用機構に限定するものではないことは理解されるであろう。
一般に、本対象となる方法又は医学的用途のQC阻害剤は、例えば、分子量が500g/モル以下、400g/モル以下、好ましくは350g/モル以下、さらにより好ましくは300g/モル以下、及びさらには250g/モル以下である小分子であろう。
表現「アルキレン」は、式-(CH2)n-の鎖を意味し、式中nは、特に限定しない限りは、整数であり、例えば2〜5である。
請求項記載の化合物の可能性のある全ての立体異性体が、本発明に含まれる。
本発明の化合物の製造プロセスが立体異性体の混合物を生じる場合、これらの異性体は、分取クロマトグラフィーなどの通常の技術により分離され得る。該化合物は、ラセミ体の形態で製造されてもよいか、又は個別の鏡像異性体が、鏡像特異的合成若しくは分割のいずれかにより製造されてもよい。該化合物は、例えば、(-)-ジ-p-トルオイル-d-酒石酸及び/又は(+)-ジ-p-トルオイル-l-酒石酸などの光学活性のある酸との塩形成、それに続く分別結晶及び遊離塩基の再生によるジアステレオマー対の形成などの、標準技術により、該化合物の成分鏡像異性体に分割され得る。また、該化合物は、ジアステレオマー的エステル又はアミドの形成、それに続くクロマトグラフィーによる分離、及びキラル補助基の除去によっても分割され得る。或いは、該化合物は、キラルHPLCカラムを用いて分割され得る。
遊離化合物とそれらの塩又は溶媒和物の形態の化合物の間の密接な関係を考慮すると、化合物がこの文脈において言及される限りは、対応する塩、溶媒和物、又は多形体も意図されるが、但しその状況下でそのようなものが可能又は適切であることを条件とする。
本発明の化合物の医薬として許容し得る酸付加塩の形は全て、本発明の範囲により包含されるものとする。
さらに、該化合物の結晶形の一部は、多形体として存在することがあり、かつそれ自体、本発明に含まれるものとする。さらに、該化合物の一部は、水と(すなわち水和物)又は一般的な有機溶媒と溶媒和物を形成することができ、そのような溶媒和物も本発明の範囲内に包含されるものとする。また、該化合物の塩を含む該化合物は、それらの水和物の形で得ることができるか、又はそれらの結晶化に使用される他の溶媒を含むことがある。
本発明はさらに、その範囲内に、本発明の化合物のプロドラッグを含む。一般に、そのようなプロドラッグは、所望の治療活性のある化合物にインビボで容易に転化可能である化合物の官能基誘導体であろう。したがって、これらの場合、本発明の治療法で、用語「投与する」は、請求項記載の化合物の1種以上のプロドラッグ型による、記載された様々な障害の治療を包含するものとし、該プロドラッグ型は、対象への投与後にインビボで先に明記された化合物に転化する。好適なプロドラッグ誘導体の選択及び製造の通常の手順は、例えば、H. Bundgaard編「プロドラッグの設計(Design of Prodrugs)」(Elsevier, 1985)に説明されている。
本発明の化合物の製造プロセスの間に、着目される任意の分子上の感応性のある基又は反応基を保護することが必要及び/又は望ましいことがある。このことは、J.F.W. McOmie編「有機化学における保護基(Protective Groups in Organic Chemistry)」(Plenum Press, 1973);並びに、T.W. Greene及びP. G. M. Wutsの文献「有機合成における保護基(Protective Groups in Organic Synthesis)」(John Wiley & Sons, 1991)に記載されているものなど、通常の保護基により実現することができ、これらの文献は引用により本明細書中に完全に組み込まれている。保護基は、その後の都合良い工程において、当該技術分野由来の公知の方法を用いて除去することができる。
したがって、例えば懸濁剤、エリキシル剤、及び液剤などの液体経口製剤に関して、好適な担体及び添加剤には、有利なことに、水、グリコール、油類、アルコール、香味料、保存料、着色料などがあり;例えば散剤、カプセル剤、ゲルキャップ剤、及び錠剤などの固形経口製剤に関して、好適な担体及び添加剤には、デンプン、糖類、希釈剤、造粒剤、滑沢剤、結合剤、崩壊剤などがある。
R1は、水素、ハロゲン、-C1-6アルキル、C2-6アルケニル、C2-6アルキニル、-アリール、-C1-6アルキルアリール、-シクロアルキル、-C1-6アルキルシクロアルキル、-ヘテロアリール、-C1-6アルキルヘテロアリール、-ヘテロシクリル、-C1-6アルキルヘテロシクリル、フェニルにより置換された-シクロアルキル、フェノキシにより置換された-シクロアルキル、シクロアルキルにより置換された-フェニル、フェノキシにより置換された-フェニル、フェニルにより置換された-フェニル、フェニルにより置換されたヘテロシクリル、フェニルにより置換されたヘテロアリール、ヘテロシクリルにより置換されたフェニル、ヘテロアリールにより置換されたフェニル、-O-シクロアルキルにより置換されたフェニル、又は-シクロアルキル-ヘテロシクリルにより置換されたフェニルを表し;
かつ、上記のアリール、シクロアルキル、ヘテロシクリル、ヘテロアリール、フェニル、又はフェノキシ基のいずれも、C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C1-6ハロアルキル、-C1-6チオアルキル、-SOC1-4アルキル、-SO2C1-4アルキル、C1-6アルコキシ-、-O-C3-8シクロアルキル、C3-8シクロアルキル、-SO2C3-8シクロアルキル、-SOC3-6シクロアルキル、C3-6アルケニルオキシ-、C3-6アルキニルオキシ-、-C(O)C1-6アルキル、-C(O)OC1-6アルキル、C1-6アルコキシ-C1-6アルキル-、ニトロ、ハロゲン、シアノ、ヒドロキシル、-C(O)OH、-NH2、-NHC1-4アルキル、-N(C1-4アルキル)(C1-4アルキル)、-C(O)N(C1-4アルキル)(C1-4アルキル)、-C(O)NH2、-C(O)NH(C1-4アルキル)、及び-C(O)NH(C3-10シクロアルキル)から選択される1個以上の基により任意に置換されていてよく;
R2は、-C1-6アルキル、ハロゲン、C1-6ハロアルキル、-アリール、-C1-6アルキルアリール、-シクロアルキル、-C1-6アルキルシクロアルキル、-ヘテロアリール、-C1-6アルキルヘテロアリール、-ヘテロシクリル、又は-C1-6アルキルヘテロシクリルを表し:
かつ、上記のアリール、ヘテロアリール、又はヘテロシクリル基のいずれも、C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C1-6ハロアルキル、-C1-6チオアルキル、-SOC1-4アルキル、-SO2C1-4アルキル、C1-6アルコキシ-、-O-C3-8シクロアルキル、C3-8シクロアルキル、-SO2C3-8シクロアルキル、-SOC3-6シクロアルキル、C3-6アルケニルオキシ-、C3-6アルキニルオキシ-、-C(O)C1-6アルキル、-C(O)OC1-6アルキル、C1-6アルコキシ-C1-6アルキル-、ニトロ、ハロゲン、シアノ、ヒドロキシル、-C(O)OH、-NH2、-NHC1-4アルキル、-N(C1-4アルキル)(C1-4アルキル)、-C(O)N(C1-4アルキル)(C1-4アルキル)、-C(O)NH2、-C(O)NH(C1-4アルキル)、及び-C(O)NH(C3-10シクロアルキル)から選択される1個以上の基により任意に置換されていてよく;
R3は、C1-6アルキル又はC1-6ハロアルキルを表し;
nは、0〜3から選択される整数を表し;かつ
Raは、C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C1-6ハロアルキル、-C1-6チオアルキル、-SOC1-4アルキル、-SO2C1-4アルキル、C1-6アルコキシ-、-O-C3-8シクロアルキル、C3-8シクロアルキル、-SO2C3-8シクロアルキル、-SOC3-6シクロアルキル、C3-6アルケニルオキシ-、C3-6アルキニルオキシ-、-C(O)C1-6アルキル、-C(O)OC1-6アルキル、C1-6アルコキシ-C1-6アルキル-、ニトロ、ハロゲン、シアノ、ヒドロキシル、-C(O)OH、-NH2、-NHC1-4アルキル、-N(C1-4アルキル)(C1-4アルキル)、-C(O)N(C1-4アルキル)(C1-4アルキル)、-C(O)NH2、-C(O)NH(C1-4アルキル)、及び-C(O)NH(C3-10シクロアルキル)を表す)。
シクロアルキル及びヘテロシクリルが置換される場合、典型的には、これらは1又は2個の置換基(例えば、1個の置換基)により置換される。典型的には、該置換基はC1-6アルキル(例えばメチル)又はハロゲン(例えば、塩素又はフッ素)である。より典型的には、シクロアルキル基及びヘテロシクリル基は非置換である。
一実施態様において、R3はC1-6アルキル(例えばメチル又はエチル)を表す。さらなる実施態様において、R3はC1-6アルキル(例えばメチル)を表す。
好適には、R3はC1-6ハロアルキルを表す。
一実施態様において、R3はC1-6ハロアルキル(例えば、2,2,2-トリフルオロエチル又は2,2,3,3-テトラフルオロプロピル)を表す。
本発明のさらなる態様によると、下記を含む、式(I)の化合物の製造プロセスが提供される:
新規中間体は、本発明の態様として請求項に記載されている。
哺乳動物におけるQC(EC)の生理的基質は、例えば、アミロイドβ-ペプチド(3-40)、(3-42)、(11-40)及び(11-42)、ABri、ADan、ガストリン、ニューロテンシン、FPP、CCL2、CCL7、CCL8、CCL16、CCL18、フラクタルカイン、オレキシンA、[Gln3]-グルカゴン(3-29)、[Gln5]-サブスタンスP(5-11)、及びペプチドQYNADである。さらなる詳細については、表1を参照されたい。本発明の化合物及び/又は組み合わせ並びに、少なくとも1種のQC(EC)阻害剤を含む医薬組成物は、QC活性の調節により治療することができる病態の治療に有用である。
3、11及び/又は22位にピログルタミン酸残基を伴うβ-アミロイドペプチドは、アミロイドβ-ペプチド1-40(42/43)よりも、より細胞傷害性があり、かつより疎水性であることが説明されている(Saido T.C.の文献(2000 Medical Hypotheses 54(3): 427-429))。
複数のN-末端変種、例えばAβ(3-40)、Aβ(3-42)、Aβ(11-40)、及びAβ(11-42)は、異なる部位でのβ-セクレターゼ酵素β部位アミロイド前駆体タンパク質切断酵素(BACE)によるか(Huse J.T.らの文献(2002 J. Biol. Chem. 277 (18):16278-16284))、及び/又は完全長ペプチドAβ(1-40)及びAβ(1-42)からのアミノペプチダーゼ処理若しくはジペプチジルアミノペプチダーゼ処理により、作製することができる。全ての場合において、その後N-末端に生じるグルタミン酸残基の環化は、QCにより触媒される。
好ましい実施態様において、本発明は、少なくとも1種のQC阻害剤を、向知性薬、神経保護薬、抗パーキンソン病薬、アミロイドタンパク質沈着阻害剤、βアミロイド合成阻害剤、抗うつ薬、抗不安薬、抗精神病薬、及び抗多発性硬化症薬からなる群から選択される少なくとも1種の他の薬剤と任意に組み合わせて含む、組成物、好ましくは医薬組成物を提供する。
(a)ベンゾジアゼピン、例えば、アルプラゾラム、クロルジアゼポキシド、クロバザム、クロナゼパム、クロラゼペート、ジアゼパム、フルジアゼパム、ロフラゼペート、ロラゼパム、メタカロン、オキサゼパム、プラゼパム、トランゼン、
(b)選択的セロトニン再取り込み阻害剤(SSRI)、例えば、シタロプラム、フルオキセチン、フルボキサミン、エスシタロプラム、セルトラリン、パロキセチン、
(c)三環系抗うつ薬、例えば、アミトリプチリン、クロミプラミン、デシプラミン、ドキセピン、イミプラミン、
(d)モノアミンオキシダーゼ(MAO)阻害剤、
(e)アザピロン系薬、例えば、ブスピロン、タンドプシロン、
(f)セロトニン-ノルエピネフリン再取り込み阻害剤(SNRI)、例えば、ベンラファキシン、デュロキセチン、
(g)ミルタザピン、
(h)ノルエピネフリン再取り込み阻害剤(NRI)、例えば、レボキセチン、
(i)ブプロピオン、
(j)ネファゾドン、
(k)β-遮断薬、
(l)NPY-受容体リガンド:NPYアゴニスト又はアンタゴニスト。
a)ジヒドロオロト酸デヒドロゲナーゼ阻害剤、例えば、SC-12267、テリフルノミド、MNA-715、HMR-1279(HMR-1715、MNA-279と同義)、
b)自己免疫抑制薬、例えば、ラキニモド、
c)パクリタキセル、
d)抗体、例えば、AGT-1、抗顆粒球−マクロファージコロニー刺激因子(GM-CSF)モノクローナル抗体、Nogo受容体モジュレーター、ABT-874、アレムツズマブ(CAMPATH)、抗-OX40抗体、CNTO-1275、DN-1921、ナタリズマブ(AN-100226、Antegren、VLA-4 Mabと同義)、ダクリツマブ(Zenepax、Ro-34-7375、SMART抗-Tacと同義)、J-695、プリリキシマブ(Centara、CEN-000029、cM-T412と同義)、MRA、Dantes、抗-IL-12-抗体、
e)ペプチド核酸(PNA)調製物、例えば、レチクロース(reticulose)、
f)インターフェロンα、例えば、アルファフェロン、ヒトαインターフェロン(Omniferon、Alpha Leukoferonと同義)、
g)インターフェロンβ、例えば、Frone、アボネックス、べトロン(Betron)(レビフ)のようなインターフェロンβ-1a、インターフェロンβアナログ、インターフェロンβ-トランスフェリン融合タンパク質、ベタセロンのような組換えインターフェロンβ-1b、
h)インターフェロンτ、
i)ペプチド、例えば、AT-008、AnergiX.MS、イムノカイン(α-イムノカイン-NNSO3)、ZD-7349のような環状ペプチド、
j)治療的酵素、例えば、可溶性CD8(sCD8)、
k)多発性硬化症特異的自己抗原をコードするプラスミド及びサイトカインをコードするプラスミド、例えば、BHT-3009;
l)TNF-αの阻害剤、例えば、BLX-1002、サリドマイド、SH-636、
m)TNFアンタゴニスト、例えば、ソリマスタット、レネルセプト(RO-45-2081、Tenefuseと同義)、オネルセプト(sTNFR1)、CC-1069、
n)TNFα、例えば、エタネルセプト(エンブレル、TNR-001と同義)、
o)CD28アンタゴニスト、例えば、アバタセプト、
p)Lckチロシンキナーゼ阻害剤、
q)カテプシンK阻害剤、
r)ニューロンを標的とする膜輸送体タンパク質タウリン及び植物由来のカルパイン阻害剤ロイペプチンのアナログ、例えば、Neurodur、
s)ケモカイン受容体-1(CCR1)アンタゴニスト、例えば、BX-471、
t)CCR2アンタゴニスト、
u)AMPA受容体アンタゴニスト、例えば、ER-167288-01及びER-099487、E-2007、タランパネル、
v)カリウムチャネル遮断薬、例えば、ファムプリジン、
w)VLA-4/VCAM相互作用のトシル-プロリン-フェニルアラニン低分子アンタゴニスト、例えば、TBC-3342、
x)細胞接着分子阻害剤、例えば、TBC-772、
y)アンチセンスオリゴヌクレオチド、例えば、EN-101、
z)マスト細胞受容体に結合する遊離免疫グロブリン軽鎖(IgLC)のアンタゴニスト、例えば、F-991、
aa)アポトーシス誘導性抗原、例えば、Apogen MS、
bb)アドレナリンα-2受容体アゴニスト、例えば、チザニジン(ザナフレックス、テルネリン、シルダルボ(Sirdalvo)、シルダルード、ミオニジン(Mionidine)と同義)、
cc)L-チロシン、L-リシン、L-グルタミン酸、及びL-アラニンのコポリマー、例えば、酢酸ガラティラメル(コパクソン、COP-1、コポリマー-1と同義)、
dd)トポイソメラーゼIIモジュレーター、例えば、塩酸ミトキサントロン、
ee)アデノシンデアミナーゼ阻害剤、例えば、クラドリビン(ロイスタチン、Mylinax、RWJ-26251と同義)、
ff)インターロイキン-10、例えば、イロデカキン(テノビル、Sch-52000、CSIFと同義)、
gg)インターロイキン-12アンタゴニスト、例えば、リソフィリン(CT-1501 R、LSF、リソフィリンと同義)、
hh)エタンアミニウム、例えば、SRI-62-834(CRC-8605、NSC-614383と同義)、
ii)免疫調節物質、例えば、SAIK-MS、PNU-156804、α-フェトプロテインペプチド(AFP)、IPDS、
jj)レチノイド受容体アゴニスト、例えば、アダパレン(ディフェリン、CD-271と同義)、
kk)TGF-β、例えば、GDF-1(増殖分化因子1)、
ll)TGF-β-2、例えば、ベタカイン、
mm)MMP阻害剤、例えば、グリコメド(glycomed)、
nn)ホスホジエステラーゼ4(PDE4)阻害剤、例えば、RPR-122818、
oo)プリンヌクレオシドホスホリラーゼ阻害剤、例えば、9-(3-ピリジルメチル)-9-デアザグアニン、ペルデシン(BCX-34、TO-200と同義)、
pp)α-4/β-1インテグリンアンタゴニスト、例えば、ISIS-104278、
qq)アンチセンスα4インテグリン(CD49d)、例えば、ISIS-17044、ISIS-27104、
rr)サイトカイン-誘導性物質、例えば、ヌクレオシド、ICN-17261、
ss)サイトカイン阻害剤、
tt)熱ショックタンパク質ワクチン、例えば、HSPPC-96、
uu)ニューレグリン増殖因子、例えば、GGF-2(ニューレグリン、グリア増殖因子2と同義)、
vv)カテプシンS-阻害剤、
ww)ブロピリミンアナログ、例えば、PNU-56169、PNU-63693、
xx)単球走化性タンパク質-1阻害剤、例えば、ベンゾイミダゾール様MCP-1阻害剤、LKS-1456、PD-064036、PD-064126、PD-084486、PD-172084、PD-172386。
βアミロイドペプチドに対するモノクローナル抗体は、WO 2007/068412に開示されている。それぞれのキメラ抗体及びヒト化抗体はWO 2008/011348に開示されている。アミロイド関連疾患を治療するためのワクチン組成物を製造する方法は、WO2007/068411に開示されている。
(i)WO 1999/61431に開示されたジペプチド-様化合物、例えば、N-バリルプロリル、O-ベンゾイルヒドロキシルアミン、アラニルピロリジン、L-アロ-イソロイシルチアゾリジンのようなイソロイシルチアゾリジン、L-トレオ-イソロイシルピロリジン及びそれらの塩、特にフマル酸塩、並びにL-アロ-イソロイシルピロリジン及びそれらの塩;
(ii)WO 2003/002593に開示されたペプチド構造、例えばトリペプチド;
(iii)WO 2003/033524に開示されたペプチジルケトン;
(vi)WO 2003/040174に開示された置換アミノケトン;
(v)WO 2001/14318に開示された局所的活性DP IV-阻害剤;
(vi)WO 1999/67278及びWO 1999/67279に開示されたDP IV-阻害剤プロドラッグ;並びに
(v)WO 2003/072556及びWO 2004/099134に開示されたグルタミニルベースのDP IV-阻害剤。
PF-4360365、m266、バピネオズマブ、R-1450、Posiphen、(+)-フェンセリン、MK-0752、LY-450139、E-2012、(R)-フルルビプロフェン、AZD-103、AAB-001(バピネオズマブ)、トラミプロセート、EGb-761、TAK-070、ドキソフィリン、テオフィリン、シロミラスト、トフィミラスト、ロフルミラスト、テトミラスト、チペルカスト、イブジラスト、HT-0712、MEM-1414、オグレミラスト、リネゾリド、ブジピン、イソカルボキサジド、フェネルジン、トラニルシプロミン、インダンタドール、モクロベミド、ラサジリン、ラドスチギル、サフィナミド、ABT-239、ABT-834、GSK-189254A、シプロキシファン、JNJ-17216498、Fmoc-Ala-Pyrr-CN、Z-Phe-Pro-ベンゾチアゾール、Z-321、ONO-1603、JTP-4819、S-17092、BIBP3226;(R)-N2-(ジフェニルアセチル)-(R)-N-[1-(4-ヒドロキシフェニル)エチル]アルギニンアミド、セビメリン、サブコメリン、(PD-151832)、ドネペジル、リバスチグミン、(-)-フェンセリン、ラドスチギル、ガランタミン、タクリン、メトリホナート、メマンチン、トピラマート、AVP-923、EN-3231、ネラメキサン、バルサルタン、ベナゼプリル、エナラプリル、ヒドロクロロチアジド、アムロジピン、ジルチアゼム、イスラジピン、ニカルジピン、ニフェジピン、ニモジピン、ニソルジピン、ニトレンジピン、ベラパミル、アムロジピン、アセブトロール、アテノロール、ベタキソロール、ビソプロロール、カルテオロール、カルベジロール、エスモロール、ラベタロール、メトプロロール、ナドロール、オクスプレノロール、ペンブトロール、ピンドロール、プロプラノロール、ソタロール、チモロール、PLAVIX(登録商標)(クロピドグレル重硫酸塩)、PLETAL(登録商標)(シロスタゾール)、アスピリン、ZETIA(登録商標)(エゼチミブ)及びKT6-971、スタチン、アトルバスタチン、ピタバスタチン、又はシムバスタチン;デキサメタゾン、クラドリビン、ラパマイシン、ビンクリスチン、タキソール、アリスキレン、C-243、ABN-912、SSR-150106、MLN-1202、及びベータフェロン。
−アテローム性動脈硬化の治療及び/又は予防のための、QC阻害剤、好ましくは式(I)のQC阻害剤、より好ましくは実施例1〜35のいずれか一つより選択されるQC阻害剤と、アトルバスタチンとの組み合わせ、
−再狭窄の予防及び/又は治療のための、QC阻害剤、好ましくは式(I)のQC阻害剤、より好ましくは実施例1〜35のいずれか一つより選択されるQC阻害剤と、免疫抑制薬、好ましくはラパマイシンとの組み合わせ、
−再狭窄の予防及び/又は治療のための、QC阻害剤、好ましくは式(I)のQC阻害剤、より好ましくは実施例1〜35のいずれか一つより選択されるQC阻害剤と、免疫抑制薬、好ましくはパクリタキセルとの組み合わせ、
−アルツハイマー病の予防及び/又は治療のための、QC阻害剤、好ましくは式(I)のQC阻害剤、より好ましくは実施例1〜35のいずれか一つより選択されるQC阻害剤と、AChE阻害剤、好ましくはドネペジルとの組み合わせ、
−多発性硬化症の予防及び/又は治療のための、QC阻害剤、好ましくは式(I)のQC阻害剤、より好ましくは実施例1〜35のいずれか一つより選択されるQC阻害剤と、インターフェロン、好ましくはアロネックス(Aronex)との組み合わせ、
−多発性硬化症の予防及び/又は治療のための、QC阻害剤、好ましくは式(I)のQC阻害剤、より好ましくは実施例1〜35のいずれか一つより選択されるQC阻害剤と、インターフェロン、好ましくはベータフェロンとの組み合わせ、
−多発性硬化症の予防及び/又は治療のための、QC阻害剤、好ましくは式(I)のQC阻害剤、より好ましくは実施例1〜35のいずれか一つより選択されるQC阻害剤と、インターフェロン、好ましくはレビフとの組み合わせ、
−多発性硬化症の予防及び/又は治療のための、QC阻害剤、好ましくは式(I)のQC阻害剤、より好ましくは実施例1〜35のいずれか一つより選択されるQC阻害剤と、コパクソンとの組み合わせ、
−再狭窄の予防及び/又は治療のための、QC阻害剤、好ましくは式(I)のQC阻害剤、より好ましくは実施例1〜35のいずれか一つより選択されるQC阻害剤と、デキサメタゾンとの組み合わせ、
−アテローム性動脈硬化の予防及び/又は治療のための、QC阻害剤、好ましくは式(I)のQC阻害剤、より好ましくは実施例1〜35のいずれか一つより選択されるQC阻害剤と、デキサメタゾンとの組み合わせ、
−関節リウマチの予防及び/又は治療のための、QC阻害剤、好ましくは式(I)のQC阻害剤、より好ましくは実施例1〜35のいずれか一つより選択されるQC阻害剤と、デキサメタゾンとの組み合わせ
−再狭窄の予防及び/又は治療のための、QC阻害剤、好ましくは式(I)のQC阻害剤、より好ましくは実施例1〜35のいずれか一つより選択されるQC阻害剤と、HMG-CoA-レダクターゼ阻害剤との組み合わせ、ここでHMG-CoA-レダクターゼ阻害剤は、アトルバスタチン、セリバスタチン、フルバスタチン、ロバスタチン、ピタバスタチン、プラバスタチン、ロスバスタチン、及びシンバスタチンから選択される、
−アテローム性動脈硬化の予防及び/又は治療のための、QC阻害剤、好ましくは式(I)のQC阻害剤、より好ましくは実施例1〜35のいずれか一つより選択されるQC阻害剤と、HMG-CoA-レダクターゼ阻害剤との組み合わせ、ここでHMG-CoA-レダクターゼ阻害剤は、アトルバスタチン、セリバスタチン、フルバスタチン、ロバスタチン、ピタバスタチン、プラバスタチン、ロスバスタチン、及びシンバスタチンから選択される
−関節リウマチの予防及び/又は治療のための、QC阻害剤、好ましくは式(I)のQC阻害剤、より好ましくは実施例1〜35のいずれか一つより選択されるQC阻害剤と、HMG-CoA-レダクターゼ阻害剤との組み合わせ、ここでHMG-CoA-レダクターゼ阻害剤は、アトルバスタチン、セリバスタチン、フルバスタチン、ロバスタチン、ピタバスタチン、プラバスタチン、ロスバスタチン、及びシンバスタチンから選択される、
−軽度認知障害の予防及び/又は治療のための、QC阻害剤、好ましくは式(I)のQC阻害剤、より好ましくは実施例1〜35のいずれか一つより選択されるQC阻害剤と、アミロイド-β抗体との組み合わせ、ここでアミロイド-β抗体はAcl-24である
−アルツハイマー病の予防及び/又は治療のための、QC阻害剤、好ましくは式(I)のQC阻害剤、より好ましくは実施例1〜35のいずれか一つより選択されるQC阻害剤と、アミロイド-β抗体の組み合わせ、ここでアミロイド-β抗体はAcl-24である、
−ダウン症候群における神経変性の予防及び/又は治療のための、QC阻害剤、好ましくは式(I)のQC阻害剤、より好ましくは実施例1〜35のいずれか一つより選択されるQC阻害剤と、アミロイド-β抗体との組み合わせ、ここでアミロイド-β抗体はAcl-24である、
−軽度認知障害の予防及び/又は治療のための、QC阻害剤、好ましくは式(I)のQC阻害剤、より好ましくは実施例1〜35のいずれか一つより選択されるQC阻害剤と、βセクレターゼ阻害剤との組み合わせ、ここでβセクレターゼ阻害剤は、WY-25105、GW-840736X、及びCTS-21166から選択される、
−アルツハイマー病の予防及び/又は治療のための、QC阻害剤、好ましくは式(I)のQC阻害剤、より好ましくは実施例1〜35のいずれか一つより選択されるQC阻害剤と、βセクレターゼ阻害剤との組み合わせ、ここでβセクレターゼ阻害剤は、WY-25105、GW-840736X、及びCTS-21166から選択される、
−ダウン症候群における神経変性の予防及び/又は治療のための、QC阻害剤、好ましくは式(I)のQC阻害剤、より好ましくは実施例1〜35のいずれか一つより選択されるQC阻害剤と、βセクレターゼ阻害剤との組み合わせ、ここでβセクレターゼ阻害剤は、WY-25105、GW-840736X、及びCTS-21166から選択される
−軽度認知障害の予防及び/又は治療のための、QC阻害剤、好ましくは式(I)のQC阻害剤、より好ましくは実施例1〜35のいずれか一つより選択されるQC阻害剤と、γ-セクレターゼ阻害剤との組み合わせ、ここでγ-セクレターゼ阻害剤は、LY-450139、LY-411575、及びAN-37124から選択される、
−アルツハイマー病の予防及び/又は治療のための、QC阻害剤、好ましくは式(I)のQC阻害剤、より好ましくは実施例1〜35のいずれか一つより選択されるQC阻害剤と、γ-セクレターゼ阻害剤との組み合わせ、ここでγ-セクレターゼ阻害剤は、LY-450139、LY-411575、及びAN-37124から選択される、
−ダウン症候群における神経変性の予防及び/又は治療のための、QC阻害剤、好ましくは式(I)のQC阻害剤、より好ましくは実施例1〜35のいずれか一つより選択されるQC阻害剤と、γ-セクレターゼ阻害剤との組み合わせ、ここでγ-セクレターゼ阻害剤は、LY-450139、LY-411575、及びAN-37124から選択される。
本発明の医薬組成物を製造するために、少なくとも1種の式(I)の化合物を、少なくとも1種のその他の上記の薬剤と任意に組み合わせて、有効成分(類)として使用することができる。この有効成分(類)は、従来の医薬配合技術に従い、医薬担体と密に混合され、該担体は、例えば経口投与又は筋肉内投与などの非経口投与に望ましい製剤の形に応じ多種多様な形をとることができる。経口剤形での組成物の製造において、通常の医薬媒体のいずれを使用してもよい。したがって、例えば懸濁剤、エリキシル剤、及び液剤などの液体経口製剤に関して、好適な担体及び添加物には、水、グリコール、油類、アルコール、香味料、保存料、着色料などがあり;例えば散剤、カプセル剤、ゲルキャップ剤、及び錠剤などの固形経口製剤に関しては、好適な担体及び添加物には、デンプン、糖類、希釈剤、造粒剤、滑沢剤、結合剤、崩壊剤などがある。錠剤及びカプセル剤は、投与の容易さのために最も有利な経口単位剤形であり、その場合固形医薬担体が明らかに使用される。所望の場合、錠剤は、標準の技術により、糖衣されるか、又は腸溶性コーティングされてよい。非経口に関しては、該担体は通常、滅菌水を含むが、例えば溶解の補助又は保存の目的に他の成分を含んでよい。
1-(1H-ベンゾ[d]イミダゾール-5-イル)-5-(2,3-ジフルオロフェニル)-3-ヒドロキシ-4-メチル-1H-ピロール-2-(5H)-オン塩酸塩(4.77 g, 12.6 mmol, 1当量)をTHF(150 ml)に懸濁させた。トリエチルアミン(1.94 ml, 13.9 mmol, 1.1当量)及びBoc2O(2.97 ml, 13.9 mmol, 1.1当量)を加え、該混合物を一晩還流加熱した。溶媒を蒸発させ、残渣を、CHCl3/MeOH勾配を使用するシリカのフラッシュクロマトグラフィーにより精製した。収量:2.74 g (49.2%)。
tert-ブチル5-(2-(2,3-ジフルオロフェニル)-4-ヒドロキシ-3-メチル-5-オキソ-2H-ピロール-1(5H)-イル)-1H-ベンゾ[d]イミダゾール-1-カルボキシラート(1当量)をMeCN(1 mmolの場合10 ml)に溶解させた。P1-tBu(1.5当量)及びそれぞれのハロゲン化アルキル(1当量)を加え、TLCモニタリングしながら該混合物を70℃に加熱した(3〜6時間)。周囲温度に冷却した後、反応を水でクエンチし、EtOAc(3×25 ml)で抽出した。合わせた有機層をNa2SO4で乾燥させ、蒸発乾固させた。残渣をTFA/CH2Cl2(6:4)(10 ml)に溶解させ、室温で2〜4時間攪拌した。該混合物を、飽和NaHCO3水溶液で塩基性化し、EtOAc(3×25 ml)で抽出した。合わせた有機層をNa2SO4で乾燥させ、蒸発させた。残渣を、CHCl3/MeOH勾配を使用するシリカのフラッシュクロマトグラフィーにより精製した。
(実施例1:1-(1H-ベンゾ[d]イミダゾール-6-イル)-5-シクロヘキシル-3-メトキシ-4-メチル-1H-ピロール-2(5H)-オン)
該化合物は、KOH(15当量、水溶液)、ジアザルド(8当量)、エチレングリコール/Et2O(1/2 v/v, 30 ml)、1-(1H-ベンゾ[d]イミダゾール-6-イル)-5-シクロヘキシル-3-ヒドロキシ-4-メチル-1H-ピロール-2(5H)-オン(1.00 g, 3.22 mmol, 1当量)、及びMeOH(10 ml)から出発して合成した;収量:0.250 g (25%);
該化合物は、KOH(15当量、水溶液)、ジアザルド(8当量)、エチレングリコール/Et2O (1/2 v/v, 30 ml)、1-(1H-ベンゾ[d]イミダゾール-6-イル)-5-イソプロピル-3-ヒドロキシ-4-メチル-1H-ピロール-2(5H)-オン(0.500 g, 1.83 mmol, 1当量)、及びMeOH(10 ml)から出発して合成した;収量:0.040 g (7.6%);
該化合物は、KOH(10当量、水溶液)、ジアザルド(5当量)、エチレングリコール/Et2O(3/1 v/v)、1-(1H-ベンゾ[d]イミダゾール-6-イル)-5-(2,6-ジフルオロフェニル)-3-ヒドロキシ-4-メチル-1H-ピロール-2(5H)-オン(0.189 g, 0.5 mmol, 1当量)、及びMeOH/H2O(90/10 v/v)から出発して合成した;収量:0.058 g (32.6%);
該化合物は、KOH(15 g, 267.8 mmol、水溶液)、ジアザルド(20 g, 93.37 mmol 5当量)、エチレングリコール/Et2O(2/1 v/v, 140 mL)、1-(1H-ベンゾ[d]イミダゾール-5-イル)-5-(2,4,5-トリフルオロフェニル)-3-ヒドロキシ-4-メチル-1H-ピロール-2(5H)-オン(2 g, 5.57 mmol、1当量)、及びMeOH(50 mL)から出発して合成した;収量:1.05 g (50.55%);
該化合物は、KOH(10当量、水溶液)、ジアザルド(5当量)、エチレングリコール/Et2O(3/1 v/v)、1-(1H-ベンゾ[d]イミダゾール-6-イル)-5-(2,3,5-トリフルオロフェニル)-3-ヒドロキシ-4-フェニル-1H-ピロール-2(5H)-オン(0.230 g, 0.5 mmol, 1当量)、及びMeOH/H2O(90/10 v/v)から出発して合成した;収量:0.015 g (6.9%);
該化合物は、KOH(15 g, 267.8 mmol、水溶液)、ジアザルド(20 g, 93.37 mmol, 5当量)、エチレングリコール/Et2O(2/1 v/v, 140 mL)、1-(1H-ベンゾ[d]イミダゾール-5-イル)-5-(5-ブロモ-2-フルオロフェニル)-3-ヒドロキシ-4-メチル-1H-ピロール-2(5H)-オン(2 g, 5.57 mmol, 1当量)、及びMeOH(50 mL)から出発して合成した;収量:1.3 g (57.2%);
該化合物は、KOH(10当量、水溶液)、ジアザルド(5当量)、エチレングリコール/Et2O(3/1 v/v)、1-(1H-ベンゾ[d]イミダゾール-6-イル)-5-(2-クロロ-3,6-ジフルオロフェニル)-3-ヒドロキシ-4-フェニル-1H-ピロール-2(5H)-オン(0.103 g, 0.25 mmol, 1当量)、及びMeOH/H2O(90/10 v/v)から出発して合成した;収量:0.013 g (13.3%);
該化合物は、KOH(11 g, 196.4 mmol、水溶液)、ジアザルド(15 g, 10.00 mmol)、エチレングリコール/Et2O(2/1 v/v, 140 mL)、1-(1H-ベンゾ[d]イミダゾール-5-イル)-5-(5-ブロモ-2-フルオロフェニル)-3-ヒドロキシ-4-メチル-1H-ピロール-2(5H)-オン(1.46 g, 4.28 mmol, 1当量)、及びMeOH(50mL)から出発して合成した;収量:0.700 g (46%);
20mg/5mlの1-(1H-ベンゾ[d]イミダゾール-6-イル)-5-(2,3-ジフルオロフェニル)-3-メトキシ-4-メチル-1H-ピロール-2(5H)-オン(実施例8に従い製造可能である)を、250/21 Chirobiotic Tag(供給業者:Supelco社)、5μ、検出:214 nmでの紫外、移動相:40%酢酸アンモニウム緩衝液(pH 4.0, 40mM)/60% MeOH、均一溶媒、10ml/分、室温で半分取キラルクロマトグラフィーにかけた。収量、2番目に溶離するエナンチオマーとして8mg、旋光c= 0.5g/100 ml (MeOH) αD 20=214.1°。
20mg/5mlの1-(1H-ベンゾ[d]イミダゾール-6-イル)-5-(2,3-ジフルオロフェニル)-3-メトキシ-4-メチル-1H-ピロール-2(5H)-オン(実施例8に従い製造可能である)を、250/21 Chirobiotic Tag(供給業者:Supelco社)、5μ、検出:214 nmでの紫外、移動相:40%酢酸アンモニウム緩衝液(pH 4.0, 40mM)/60% MeOH、均一溶媒、10ml/分、室温で半分取キラルクロマトグラフィーにかけた。収量、最初に溶離するエナンチオマーとして8mg、旋光c= 0.5g/100 ml (MeOH) αD 20=215°。
該化合物は、KOH(15当量、水溶液)、ジアザルド(9当量)、エチレングリコール/Et2O(1/5 v/v, 30 ml)、1-(1H-ベンゾ[d]イミダゾール-6-イル)-4-エチル-5-(2,3-ジフルオロフェニル)-3-ヒドロキシ-1H-ピロール-2(5H)-オン(1.2 g, 2.81 mmol, 1当量)、及びMeOH(10 ml)から出発して合成し、生成物を分取HPLCによりさらに精製した;収量:0.085 g (8.2%);
該化合物は、KOH(15当量、水溶液)、ジアザルド(9当量)、エチレングリコール/Et2O(1/3 v/v, 40 ml)、1-(1H-ベンゾ[d]イミダゾール-6-イル)-5-(2,3-ジフルオロフェニル)-3-ヒドロキシ-4-プロピル-1H-ピロール-2(5H)-オン(1.0 g, 2.71 mmol, 1当量)、及びMeOH(10 ml)から出発して合成し、生成物を分取HPLCによりさらに精製した;収量: 0.120 g (11.6%);
該化合物は、KOH(15当量、水溶液)、ジアザルド(9当量)、エチレングリコール/Et2O(1/7.5 v/v, 17 ml)、1-(1H-ベンゾ[d]イミダゾール-6-イル)-5-(2,3-ジフルオロフェニル)-4-イソプロピル-3-ヒドロキシ-1H-ピロール-2(5H)-オン(0.15 g, 0.34 mmol, 1当量)、及びMeOH(10 ml)から出発して合成し、生成物を分取TLCによりさらに精製した;収量:0.040 g (10.4 %);
該化合物は、KOH(15当量、水溶液)、ジアザルド(9当量)、エチレングリコール/Et2O(1/2.8 v/v, 34 ml)、1-(1H-ベンゾ[d]イミダゾール-6-イル)-5-(2,3-ジフルオロフェニル)-3-ヒドロキシ-4-フェニル-1H-ピロール-2(5H)-オン(1 g, 2.48 mmol, 1当量)、及びMeOH(10 ml)から出発して合成した;収量:0.160 g (60%);
該化合物は、KOH (15当量、水溶液)、ジアザルド (8当量)、エチレングリコール/Et2O(1/4.2 v/v, 31 ml)、1-(1H-ベンゾ[d]イミダゾール-6-イル)-5-(2,3-ジフルオロフェニル)-4-(4-フルオロフェニル)-3-ヒドロキシ-1H-ピロール-2(5H)-オン(0.5 g , 1.2 mmol, 1当量)、及びMeOH(10 ml)から出発して合成した;収量:0.160 g (60%);
該化合物は、KOH(9.0 g,160.71 mmol、水溶液)、ジアザルド(24 g, 112.02 mmol)、エチレングリコール/Et2O(2/1 v/v, 140 mL)、1-(1H-ベンゾ[d]イミダゾール-5-イル)-5-(2,3-ジクロロフェニル)-3-ヒドロキシ-4-メチル-1H-ピロール-2(5H)-オン(3 g, 8.04 mmol, 1当量)、及びMeOH(50 mL)から出発して合成した;収量;1.2 g (38.46%);
1.2gの1-(1H-ベンゾ[d]イミダゾール-6-イル)-5-(2,3-ジクロロフェニル)-3-メトキシ-4-メチル-1H-ピロール-2(5H)-オン(実施例17に従い製造可能である)を、カラム:CHIRAL PAK IC (30×250mm) 5μ、移動相n-ヘキサン: IPA: DEA: TFA (50:50:0.1:0.05)のキラル半分取HPLC条件に付した。収量:最初に溶離するエナンチオマーとして267mgの異性体。
1.2gの1-(1H-ベンゾ[d]イミダゾール-6-イル)-5-(2,3-ジクロロフェニル)-3-メトキシ-4-メチル-1H-ピロール-2(5H)-オン(実施例17に従い製造可能である)を、カラム:CHIRAL PAK IC (30×250mm) 5μ、移動相n-ヘキサン: IPA: DEA: TFA (50:50:0.1:0.05)のキラル半分取HPLC条件に付した。収量:最初に溶離するエナンチオマーとして127mgの異性体。
該化合物は、KOH(15当量、水溶液)、ジアザルド(8当量)、エチレングリコール/Et2O(1/2 v/v, 30 ml)、1-(1H-ベンゾ[d]イミダゾール-6-イル)-3-ヒドロキシ-4-メチル-5-(4-モルホリノフェニル)-1H-ピロール-2(5H)-オン(0.500 g, 1.28 mmol, 1当量)、及びMeOH(10 ml)から出発して合成し、生成物を、クロロホルム中の4%メタノールを溶離液として使用して分取TLCにより精製した;収量:0.100 g (19.34%);
該化合物は、KOH (15当量、水溶液)、ジアザルド (8当量)、エチレングリコール/Et2O(1/2 v/v, 60 ml)、1-(1H-ベンゾ[d]イミダゾール-6-イル)-3-ヒドロキシ-4-メチル-5-(ビフェン-4-イル)-1H-ピロール-2(5H)-オン(1 g, 2.63 mmol, 1当量)、及びMeOH(20 ml)から出発して合成した;収量 0.070 g (17.7%);
該化合物は、(15当量、水溶液)、ジアザルド(8当量)、エチレングリコール/Et2O(1/2 v/v, 60 ml)、1-(1H-ベンゾ[d]イミダゾール-6-イル)-3-ヒドロキシ-4-メチル-5-(4-(ピペリジン-1-イル)フェニル)-1H-ピロール-2(5H)-オン (0.700 g, 1.88 mmol, 1当量)、及びMeOH(20 ml)から出発して合成した;収量:0.050 g (7%);
該化合物は、KOH(15当量、水溶液)、ジアザルド(8当量)、エチレングリコール/Et2O(1/2 v/v, 30 ml)、1-(1H-ベンゾ[d]イミダゾール-6-イル)-5-(4-(シクロヘキシルオキシ)フェニル)-3-ヒドロキシ-4-メチル-1H-ピロール-2(5H)-オン(0.500 g, 1.24 mmol, 1当量)、及びMeOH (10 ml)から出発して合成した;収量:0.050 g (10%);
該化合物は、KOH(10当量、水溶液)、ジアザルド(5当量)、エチレングリコール/Et2O(3/1 v/v)、1-(1H-ベンゾ[d]イミダゾール-6-イル)-5-(キノリン-3-イル)-3-ヒドロキシ-4-フェニル-1H-ピロール-2(5H)-オン(0.230 g, 0.5 mmol, 1当量)、及びMeOH/H2O(90/10 v/v)から出発して合成した;収量:0.003 g (1.4%);
該化合物は、KOH(15当量、水溶液)、ジアザルド (9当量)、エチレングリコール/Et2O (1/2 v/v, 30 ml)、1-(1H-ベンゾ[d]イミダゾール-6-イル)-5-(4-シクロヘキシルフェニル)-3-ヒドロキシ-4-メチル-1H-ピロール-2(5H)-オン(0.900 g, 2.32 mmol, 1当量)、及びMeOH(10 ml)から出発して合成した;収量:0.200 g (21.4%);
該化合物は、KOH(15当量、水溶液)、ジアザルド(8当量)、エチレングリコール/Et2O(1/2.5 v/v, 28 ml)、1-(1H-ベンゾ[d]イミダゾール-6-イル)-5-(4-(4,4-ジフルオロシクロヘキシル)-フェニル)-3-ヒドロキシ-4-メチル-1H-ピロール-2(5H)-オン(0.800 g, 1.88 mmol, 1当量)、及びMeOH(10 ml)から出発して合成した;収量:0.060 g (7.3%);
該化合物は、KOH(15当量、水溶液)、ジアザルド (8当量)、エチレングリコール/Et2O(1/2 v/v, 30 ml)、1-(1H-ベンゾ[d]イミダゾール-6-イル)-3-ヒドロキシ-4-メチル-5-(4-(4-モルホリノシクロヘキシル)フェニル)-1H-ピロール-2(5H)-オン(0.350 g, 0.74 mmol, 1当量)、及びMeOH(10 ml)から出発して合成した;収量:0.040 g (11%);
該化合物は、KOH(15当量、水溶液)、ジアザルド(9当量)、エチレングリコール/Et2O(1/3 v/v, 40 ml)、1-(1H-ベンゾ[d]イミダゾール-6-イル)-3-ヒドロキシ-4-メチル-5-(4-フェノキシシクロヘキシル)-1H-ピロール-2(5H)-オン(0.900 g, 2.23mmol, 1当量)、及びMeOH(10ml)から出発して合成し、分取HPLCにより精製した;収量:0.051 g (12.2%);
該化合物は、KOH(15当量、水溶液)、ジアザルド(9当量)、エチレングリコール/Et2O(1/5 v/v, 18 ml)、1-(1H-ベンゾ[d]イミダゾール-6-イル)-3-ヒドロキシ-4-メチル-5-(1-フェニルピペリジン-4-イル)-1H-ピロール-2(5H)-オン(0.280 g, 0.72 mmol, 1当量)、及びMeOH(15 ml)から出発して合成し、生成物を分取TLCによりさらに精製した;収量:0.021 g (5.2%);
該化合物は、KOH(15当量、水溶液)、ジアザルド(9当量)、エチレングリコール/Et2O(1/2 v/v, 60 ml)、1-(1H-ベンゾ[d]イミダゾール-6-イル)-3-ヒドロキシ-4-メチル-5-(4-フェニルシクロヘキシル)-1H-ピロール-2(5H)-オン(1.0 g, 2.58 mmol, 1当量)、及びMeOH(20 ml)から出発して合成した;収量:0.100 g (10%);
該化合物は、上述の方法に従い、tert-ブチル 5-(2-(2,3-ジフルオロフェニル)-4-ヒドロキシ-3-メチル-5-オキソ-2H-ピロール-1(5H)-イル)-1H-ベンゾ[d]イミダゾール-1-カルボキシラート(0.22 g, 0.5 mmol)、ブロモエタン(0.056 ml, 0.75 mmol)、及びP1-tBu(0.191 ml, 0.75 mmol)から出発して合成した。収量:0.044 g (23.8%);
該化合物は、上述の方法に従い、tert-ブチル 5-(2-(2,3-ジフルオロフェニル)-4-ヒドロキシ-3-メチル-5-オキソ-2H-ピロール-1(5H)-イル)-1H-ベンゾ[d]イミダゾール-1-カルボキシラート(0.441 g, 1 mmol)、1,1,2,2-テトラフルオロ-3-ヨードプロパン(0.17 ml, 1.5 mmol)、及びP1-tBu(0.38 ml, 1.5 mmol)から出発して合成した。収量;0.138 g (30.3%);
該化合物は、上述の方法に従い、tert-ブチル 5-(2-(2,3-ジフルオロフェニル)-4-ヒドロキシ-3-メチル-5-オキソ-2H-ピロール-1(5H)-イル)-1H-ベンゾ[d]イミダゾール-1-カルボキシラート(0.441 g, 1 mmol)、トリフルオロヨードエタン(0.15 ml, 1.5 mmol)、及びP1-tBu(1.38 ml, 1.5 mmol)から出発して合成し、半分取HPLCによりさらに精製した。収量:0.007 g (1.6%);
分析HPLCシステムは、Li-Chrospher(登録商標) 100 RP 18(5μm)、分析カラム(長さ:125mm、直径:4mm)、及び記録波長としてλ=214nmを有するダイオードアレイ検出器(DAD)を利用する、メルク-日立装置(モデルLaChrom(登録商標))から構成された。化合物は、流量1mL/分で勾配を用いて分析したが、ここで、溶離剤(A)はアセトニトリルであり、溶離剤(B)は水であり、両方とも0.1%(v/v)トリフルオロ酢酸を含有し、下記の勾配を適用した:方法[A]:0分〜5分、5%の(A);5分〜17分、5〜15%の(A);17分〜29分、15〜95%の(A);29分〜32分、95%の(A);32分〜33分、95〜5%の(A);33分〜38分、5%(A);方法[B]:0分〜25分、20〜80%の(A);25分〜30分、80〜95%の(A);30分〜31分、95〜20%の(A);31分〜40分、20%の(A)。全ての報告された化合物の純度は、214nmでのピーク面積の百分率により決定した。
ESI-Massスペクトルは、正イオン化モードを利用してSCIEX API 365分光器(Perkin Elmer社製)で得た。
(蛍光アッセイ)
全ての測定は、マイクロプレート用BioAssay Reader HTS-7000Plus(Perkin Elmer社)により30℃で行った。QC活性は、H-Gln-βNAを用い、蛍光測定により評価した。試料は、最終容積250μlにおける、20mM EDTA含有0.2Mトリス/HCl(pH8.0)中の、0.2mM蛍光発生基質、0.25Uピログルタミルアミノぺプチダーゼ(Unizyme社、ホルショルム、デンマーク)、及び適宜希釈した一定分量のQCからなった。励起/発光波長は、320/410nmであった。該アッセイ反応は、グルタミニルシクラーゼの添加により開始した。QC活性は、アッセイ条件下でのβ-ナフチルアミンの標準曲線から決定した。1単位は、記載した条件下で、1分あたりにH-Gln-βNAから1μmolのpGlu-βNAの形成を触媒するQC量と定義されている。
この新規アッセイを用いて、ほとんどのQC基質の反応速度パラメータを決定した。QC活性は、補助的な酵素としてグルタミン酸デヒドロゲナーゼを利用する、既存の不連続アッセイ(Bateman, R. C. J.の文献(1989 J Neurosci Methods 30, 23-28))を適応させることにより導いた連続法を用い、分光光度的に分析した。試料は、最終容積250μlにおける、各QC基質、0.3mM NADH、14mMα-ケトグルタル酸、及び30U/mlグルタミン酸デヒドロゲナーゼからなった。反応は、QCの添加により出発し、340nmでの吸光度の低下を8〜15分間モニタリングすることにより追跡した。
阻害剤の試験に関して、試料組成物は、推定阻害化合物を添加したこと以外は、先に説明したものと同じであった。QC-阻害に関する迅速試験について、試料は、4mMの各阻害剤及び1KMの基質濃度を含有した。阻害の詳細な研究及びKi-値の決定については、阻害剤の補助的な酵素に対する影響を最初に調べた。あらゆる場合において、いずれの酵素についても影響は検出されず、したがってQC阻害の信頼できる決定が可能であった。阻害定数は、GraFitソフトウェアを用い、反応進行曲線のセットを、競合阻害に関する一般式にあてはめることにより評価した。
(HPLC:)
方法[A]:分析的HPLCシステムは、LUNA(登録商標)RP 18(5μm)、分析カラム(長さ:125mm、直径:4mm)、及び記録波長としてλ=214nmを有するダイオードアレイ検出器(DAD)を利用する、メルク-日立装置(モデルLaChrom(登録商標))から構成された。化合物は、流量1mL/分で勾配を用いて分析したが、ここで、溶離剤(A)はアセトニトリルであり、溶離剤(B)は水であり、両方とも0.1%(v/v)トリフルオロ酢酸を含有し、下記の勾配を適用した::0分〜5分→5%の(A)、5分〜17分→5〜15%の(A)、15分〜27分→15〜95%の(A)、27分〜30分→95%の(A)、方法[B]:0分〜15分→5〜60%の(A)、15分〜20分→60〜95%の(A)、20分〜23分→95%の(A)、方法[C]:0分〜20分→5〜60%の(A)、20分〜25分→60〜95%の(A)。25分〜30分→95%の(A)。
ESI-質量スペクトルは、SCIEX API 365分光器(Perkin Elmer社)で、正イオン化モードを利用して得た。
1H NMR-スペクトル(500MHz)をBRUKER AC 500で記録した。溶媒は、特に明記しない限り、DMSO-D6とした。化学シフトは、テトラメチルシランからの低周波側での百万分率(ppm)で表す。分裂パターンを次のように示した:s (一重線)、d(二重線)、dd(二重の二重線)、t(三重線)、m(多重線)及びbr(広幅のシグナル)。
マトリックス支援レーザー脱離/イオン化質量分析を、線形型飛行時間分析器を備えたHewlett-Packard社G2025 LD-TOFシステムを用いて行った。この装置は、337nm窒素レーザー、電位加速源(5kV)及び1.0m飛行管を装備した。検出器の操作は、正イオンモードであり、シグナルは、パーソナルコンピュータに接続されたLeCroy 9350Mデジタルストレージオシロスコープを用い、記録し、かつフィルタリングする。試料(5μl)は、等容積のマトリックス溶液と混合した。マトリックス溶液に関して、水を溶媒とする1mlアセトニトリル/0.1%TFA(1:1(v/v))中に、2',6'-ジヒドロキシアセトフェノン(Aldrich社)30mg及びクエン酸水素ジアンモニウム(Fluka社)44mgを溶解することにより製造した、DHAP/DAHCを使用した。少量(ほぼ1μl)のマトリックス被検体-混合物を、プローブチップに移し、直ちに真空チャンバー(Hewlett-Packard社G2024A試料製造付属品)内で蒸発させ、迅速かつ均質な試料の結晶化を確実にした。
本発明は、先に列挙した群の好ましい及びより好ましい群及び実施態様の全ての組み合わせを包含する。
(DHQ)2PHAL ヒドロキニン 1,4-フタラジンジイルジエーテル
AcOH 酢酸
DAD ダイオードアレイ検出器
DCC ジシクロヘキシルカルボジイミド
DEA ジエチルアミン
DHAP/DAHC ジヒドロキシアセトンリン酸/ジヒドロ-5-アザシチジン
DMF ジメチルホルムアミド
DMSO ジメチルスルホキシド
EDTA エチレンジアミン-N,N,N',N'-四酢酸
EtOAc 酢酸エチル
EtOH エタノール
FPLC 高性能液体クロマトグラフィー
HPLC 高速液体クロマトグラフィー
IPA イソプロパノール
LD-TOF レーザー脱離飛行時間型質量分析
ML 母液
MS 質量分析
NMR 核磁気共鳴
Pd2dba3 トリス(ジベンジリデンアセトン)ジパラジウム
TEA トリエチルアミン
TFA トリフルオロ酢酸
THF テトラヒドロフラン
TLC 薄層クロマトグラフィー
TMSCN トリメチルシリルシアニド
Claims (26)
- 全互変異性体及び立体異性体を含む、式(I)の化合物、又はその医薬として許容し得る塩、溶媒和物、若しくは多形体:
R1は、-C1-6アルキル、-アリール、-C1-6アルキルアリール、-シクロアルキル、-C1-6アルキルシクロアルキル、-ヘテロアリール、-C1-6アルキルヘテロアリール、-ヘテロシクリル、-C1-6アルキルヘテロシクリル、フェニルにより置換された-シクロアルキル、フェノキシにより置換された-シクロアルキル、シクロアルキルにより置換された-フェニル、フェノキシにより置換された-フェニル、フェニルにより置換された-フェニル、フェニルにより置換されたヘテロシクリル、フェニルにより置換されたヘテロアリール、ヘテロシクリルにより置換されたフェニル、ヘテロアリールにより置換されたフェニル、-O-シクロアルキルにより置換されたフェニル、又は-シクロアルキル-ヘテロシクリルにより置換されたフェニルを表し;
かつ、上記のアリール、シクロアルキル、ヘテロシクリル、ヘテロアリール、フェニル、又はフェノキシ基のいずれも、C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C1-6ハロアルキル、-C1-6チオアルキル、-SOC1-4アルキル、-SO2C1-4アルキル、C1-6アルコキシ-、-O-C3-8シクロアルキル、C3-8シクロアルキル、-SO2C3-8シクロアルキル、-SOC3-6シクロアルキル、C3-6アルケニルオキシ-、C3-6アルキニルオキシ-、-C(O)C1-6アルキル、-C(O)OC1-6アルキル、C1-6アルコキシ-C1-6アルキル-、ニトロ、ハロゲン、シアノ、ヒドロキシル、-C(O)OH、-NH2、-NHC1-4アルキル、-N(C1-4アルキル)(C1-4アルキル)、-C(O)N(C1-4アルキル)(C1-4アルキル)、-C(O)NH2、-C(O)NH(C1-4アルキル)、及び-C(O)NH(C3-10シクロアルキル)から選択される1個以上の基により任意に置換されていてよく;
R2は、-C1-6アルキル、C1-6ハロアルキル、-アリール、-C1-6アルキルアリール、-シクロアルキル、-C1-6アルキルシクロアルキル、-ヘテロアリール、-C1-6アルキルヘテロアリール、-ヘテロシクリル、又は-C1-6アルキルヘテロシクリルを表し:
かつ、上記のアリール、ヘテロアリール、又はヘテロシクリル基のいずれも、C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C1-6ハロアルキル、-C1-6チオアルキル、-SOC1-4アルキル、-SO2C1-4アルキル、C1-6アルコキシ-、-O-C3-8シクロアルキル、C3-8シクロアルキル、-SO2C3-8シクロアルキル、-SOC3-6シクロアルキル、C3-6アルケニルオキシ-、C3-6アルキニルオキシ-、-C(O)C1-6アルキル、-C(O)OC1-6アルキル、C1-6アルコキシ-C1-6アルキル-、ニトロ、ハロゲン、シアノ、ヒドロキシル、-C(O)OH、-NH2、-NHC1-4アルキル、-N(C1-4アルキル)(C1-4アルキル)、-C(O)N(C1-4アルキル)(C1-4アルキル)、-C(O)NH2、-C(O)NH(C1-4アルキル)、及び-C(O)NH(C3-10シクロアルキル)から選択される1個以上の基により任意に置換されていてよく;
R3は、C1-6アルキル又はC1-6ハロアルキルを表し;
nは、0〜3から選択される整数を表し;かつ
Raは、C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C1-6ハロアルキル、-C1-6チオアルキル、-SOC1-4アルキル、-SO2C1-4アルキル、C1-6アルコキシ-、-O-C3-8シクロアルキル、C3-8シクロアルキル、-SO2C3-8シクロアルキル、-SOC3-6シクロアルキル、C3-6アルケニルオキシ-、C3-6アルキニルオキシ-、-C(O)C1-6アルキル、-C(O)OC1-6アルキル、C1-6アルコキシ-C1-6アルキル-、ニトロ、ハロゲン、シアノ、ヒドロキシル、-C(O)OH、-NH2、-NHC1-4アルキル、-N(C1-4アルキル)(C1-4アルキル)、-C(O)N(C1-4アルキル)(C1-4アルキル)、-C(O)NH2、-C(O)NH(C1-4アルキル)、及び-C(O)NH(C3-10シクロアルキル)を表す)。 - R1が、-C1-6アルキル、-アリール、-シクロアルキル、-ヘテロアリール、-ヘテロシクリル、フェニルにより置換された-シクロアルキル、フェノキシにより置換された-シクロアルキル、シクロアルキルにより置換された-フェニル、フェノキシにより置換された-フェニル、フェニルにより置換された-フェニル、フェニルにより置換されたヘテロシクリル、フェニルにより置換されたヘテロアリール、ヘテロシクリルにより置換されたフェニル、ヘテロアリールにより置換されたフェニル、-O-シクロアルキルにより置換されたフェニル、又は-シクロアルキル-ヘテロシクリルにより置換されたフェニルを表す、請求項1記載の化合物。
- R1が、-C1-6アルキル、-アリール、-シクロアルキル、-ヘテロアリール、フェニルにより置換された-シクロアルキル、フェノキシにより置換された-シクロアルキル、シクロアルキルにより置換された-フェニル、フェニルにより置換された-フェニル、フェニルにより置換されたヘテロシクリル、ヘテロシクリルにより置換されたフェニル、-O-シクロアルキルにより置換されたフェニル、又は-シクロアルキル-ヘテロシクリルにより置換されたフェニルを表す、請求項2記載の化合物。
- R1が、-C1-6アルキル、-アリール、-シクロアルキル、-ヘテロアリール、フェニルにより置換された-フェニル、ヘテロシクリルにより置換されたフェニル、又は-O-シクロアルキルにより置換されたフェニルを表し、前記フェニル基が1個以上のハロゲン基により任意に置換されており、前記ヘテロシクリル基が1個以上のC1-6アルキル基により任意に置換されており、かつ前記シクロアルキル基が1個以上のハロゲン基により任意に置換されている、請求項3記載の化合物。
- R1が、2,3-ジフルオロフェニルなどの、1個以上のハロゲン基により任意に置換されたフェニルを表す、請求項4記載の化合物。
- R2が、-C1-6アルキル、C1-6ハロアルキル、-アリール、-シクロアルキル、-ヘテロアリール、又は-ヘテロシクリルを表す、請求項1〜5のいずれか一項記載の化合物。
- R2が、-C1-6アルキル、C1-6ハロアルキル、又は-アリールを表す、請求項6記載の化合物。
- R2が、-C1-6アルキル又は-アリールを表す、請求項7記載の化合物。
- R2が、メチル、エチル、プロピル、イソプロピル、トリフルオロメチル、又は1個以上のハロゲン基により任意に置換されたフェニルを表す、請求項8記載の化合物。
- R2が、メチルなどのメチル又は非置換フェニルを表す、請求項9記載の化合物。
- R3が、メチルなどのC1-6アルキルを表す、請求項1〜10のいずれか一項記載の化合物。
- R3が、2,2,2-トリフルオロエチル又は2,2,3,3-テトラフルオロプロピルなどのC1-6ハロアルキルを表す、請求項11記載の化合物。
- nが0を表す、請求項1〜12のいずれか一項記載の化合物。
- 全互変異性体及び立体異性体を含む、実施例1〜35のいずれか一項記載の化合物、又はその医薬として許容し得る塩、溶媒和物、若しくは多形体。
- 1-(1H-ベンゾ[d]イミダゾール-6-イル)-5-(2,3-ジフルオロフェニル)-3-メトキシ-4-メチル-1H-ピロール-2(5H)-オン、又はその医薬として許容し得る塩、溶媒和物、若しくは多形体である、請求項1記載の化合物。
- 医薬として使用するための、請求項1〜15記載の化合物。
- 請求項1〜15のいずれか一項記載の化合物を、任意に1種以上の治療上許容し得る希釈剤又は担体と組み合わせて含む医薬組成物。
- 神経保護薬、抗パーキンソン病薬、アミロイドタンパク質沈着阻害剤、βアミロイド合成阻害剤、抗うつ薬、抗不安薬、抗精神病薬、及び抗多発性硬化症薬からなる群から選択される少なくとも1種の化合物をさらに含む、請求項17記載の医薬組成物。
- PEP-阻害剤、LiCl、DP IV又はDP IV様酵素の阻害剤の阻害剤、アセチルコリンエステラーゼ(ACE)阻害剤、PIMTエンハンサー、βセクレターゼの阻害剤、γセクレターゼの阻害剤、中性エンドペプチダーゼの阻害剤、ホスホジエステラーゼ-4(PDE-4)の阻害剤、TNFα阻害剤、ムスカリン性M1受容体アンタゴニスト、NMDA受容体アンタゴニスト、σ-1受容体阻害剤、ヒスタミンH3アンタゴニスト、免疫調節薬、免疫抑制薬からなる群から選択される少なくとも1種の化合物、又はアンテグレン(ナタリズマブ)、Neurelan(ファムプリジン-SR)、カンパス(アレムツズマブ)、IR 208、NBI 5788/MSP 771(チプリモチド)、パクリタキセル、Anergix.MS(AG 284)、SH636、ディフェリン(CD 271, アダパレン)、BAY 361677(インターロイキン-4)、マトリックス-メタロプロテイナーゼ-阻害剤、インターフェロン-τ(トロホブラスチン)、及びSAIK-MSからなる群から選択される薬剤をさらに含む、請求項17又は18記載の医薬組成物。
- ケネディ病、ヘリコバクターピロリ感染を伴う又は伴わない十二指腸癌、結腸直腸癌、ゾリンジャー・エリソン症候群、ヘリコバクターピロリ感染を伴う又は伴わない胃癌、病原性精神病的病態、統合失調症、不妊、新生物、炎症性宿主反応、癌、悪性転移、メラノーマ、乾癬、液性及び細胞仲介性免疫応答障害、内皮内の白血球接着及び遊走プロセス、摂食障害、睡眠-覚醒障害、エネルギー代謝の恒常性制御障害、自律神経機能障害、ホルモン平衡障害又は体液の調節障害、多発性硬化症、ギラン・バレー症候群、及び慢性炎症性脱髄性多発性神経根症からなる群から選択される疾病の治療において使用するための、請求項1〜15のいずれか一項記載の化合物又は請求項17〜19のいずれか一項記載の医薬組成物。
- 軽度認知障害、アルツハイマー病、家族性英国型認知症、家族性デンマーク型認知症、ダウン症候群における神経変性、及びハンチントン病からなる群から選択される疾病の治療において使用するための、請求項1〜15のいずれか一項記載の化合物又は請求項17〜19のいずれか一項記載の医薬組成物。
- 関節リウマチ、アテローム性動脈硬化、膵炎、及び再狭窄からなる群から選択される疾病の治療において使用するための、請求項1〜15のいずれか一項記載の化合物又は請求項17〜19のいずれか一項記載の医薬組成物。
- ケネディ病、潰瘍疾患、ヘリコバクターピロリ感染を伴う又は伴わない十二指腸癌、結腸直腸癌、ゾリンジャー・エリソン症候群、ヘリコバクターピロリ感染を伴う又は伴わない胃癌、病原性精神病的病態、統合失調症、不妊、新生物、炎症性宿主反応、癌、悪性転移、メラノーマ、乾癬、液性及び細胞仲介性免疫応答障害、内皮内の白血球接着及び遊走プロセス、摂食障害、睡眠-覚醒障害、エネルギー代謝の恒常性制御障害、自律神経機能障害、ホルモン平衡障害又は体液の調節障害、多発性硬化症、ギラン・バレー症候群、及び慢性炎症性脱髄性多発性神経根症からなる群から選択される疾病の治療又は予防の方法であって、対象に、有効量の請求項1〜15のいずれか一項記載の化合物又は請求項17〜19のいずれか一項記載の医薬組成物を投与することを含む、前記方法。
- 軽度認知障害、アルツハイマー病、家族性英国型認知症、家族性デンマーク型認知症、ダウン症候群における神経変性、及びハンチントン病からなる群から選択される疾病の治療又は予防の方法であって、対象に、有効量の請求項1〜15のいずれか一項記載の化合物又は請求項17〜19のいずれか一項記載の医薬組成物を投与することを含む、前記方法。
- 関節リウマチ、アテローム性動脈硬化、膵炎、及び再狭窄からなる群から選択される疾病の治療又は予防の方法であって、対象に、有効量の請求項1〜15のいずれか一項記載の化合物又は請求項17〜19のいずれか一項記載の医薬組成物を投与することを含む、前記方法。
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JP2021525792A (ja) * | 2018-08-31 | 2021-09-27 | ナショナル ヘルス リサーチ インスティチューツ | ベンズイミダゾール化合物、及びアルツハイマー病又はハンチントン病の治療のためのその使用 |
JP7035275B2 (ja) | 2018-08-31 | 2022-03-14 | ナショナル ヘルス リサーチ インスティチューツ | ベンズイミダゾール化合物、及びアルツハイマー病又はハンチントン病の治療のためのその使用 |
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US20110224254A1 (en) | 2011-09-15 |
US8269019B2 (en) | 2012-09-18 |
CA2789440A1 (en) | 2011-09-15 |
WO2011110613A1 (en) | 2011-09-15 |
KR20130016208A (ko) | 2013-02-14 |
US20120283259A1 (en) | 2012-11-08 |
EP2545047A1 (en) | 2013-01-16 |
NZ602312A (en) | 2014-02-28 |
EA022420B1 (ru) | 2015-12-30 |
AU2011226074A1 (en) | 2012-10-04 |
CN102791704B (zh) | 2015-11-25 |
HK1178528A1 (zh) | 2013-09-13 |
DK2545047T3 (da) | 2014-07-28 |
ES2481823T3 (es) | 2014-07-31 |
SG183229A1 (en) | 2012-09-27 |
BR112012022478A2 (pt) | 2017-02-14 |
US8420828B2 (en) | 2013-04-16 |
JP5688745B2 (ja) | 2015-03-25 |
EP2545047B1 (en) | 2014-04-23 |
IL221243A0 (en) | 2012-10-31 |
CN102791704A (zh) | 2012-11-21 |
CA2789440C (en) | 2020-03-24 |
KR101790806B1 (ko) | 2017-11-20 |
EP2545047B9 (en) | 2015-06-10 |
EA201201275A1 (ru) | 2013-04-30 |
BR112012022478B1 (pt) | 2021-09-21 |
IL221243A (en) | 2016-06-30 |
MX2012010470A (es) | 2012-10-09 |
AU2011226074B2 (en) | 2015-01-22 |
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