JP5771237B2 - 選択的グリコシダーゼ阻害剤およびその使用 - Google Patents
選択的グリコシダーゼ阻害剤およびその使用 Download PDFInfo
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- JP5771237B2 JP5771237B2 JP2013123917A JP2013123917A JP5771237B2 JP 5771237 B2 JP5771237 B2 JP 5771237B2 JP 2013123917 A JP2013123917 A JP 2013123917A JP 2013123917 A JP2013123917 A JP 2013123917A JP 5771237 B2 JP5771237 B2 JP 5771237B2
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- Prior art keywords
- tetrahydro
- thiazole
- pyrano
- acetoxymethyl
- hydroxymethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Description
本出願は、2006年8月31日出願の米国仮出願第60/841,196号および2007年3月19日出願の米国仮出願第60/895,663号の利益を主張する。これらの仮出願は参照により本明細書に組み込まれる。
本出願はグリコシダーゼを選択的に阻害する化合物およびそれらの使用に関する。
[式中、R1はそれぞれ独立して非妨害性の置換基であり;R2はアルキル、アリール、ヘテロアリール、OR4、NR4 2およびNR4OR4であり、それぞれ非妨害性の置換基により置換されていてもよく;R3はOR4、N3またはNR4 2であり;R4はそれぞれ独立して非妨害性の置換基であり、ただし、それぞれのR1がHであってR3がOHである場合、R2はCH3、CH2CH3、(CH2)2CH3、(CH2)3CH3、(CH2)4CH3、(CH2)6CH3、CH(CH3)2、CH2CH(CH3)2、NH(フェニル)、NH(4-メトキシフェニル)、N(CH3)2、(CH2)2P(O)(OH)(OCH3)および(CH2)2P(O)(OH)(O(CH2)7CH3)を除くものであり;また、それぞれのR1がCOCH3であってR3がOC(O)CH3である場合、R2はCH3、CH2CH3、(CH2)2CH3、(CH2)3CH3、(CH2)4CH3、(CH2)6CH3、CH(CH3)2、CH2CH(CH3)2、NH(フェニル)、NH(4-メトキシフェニル)、N(CH3)2、(CH2)2P(O)(OH)(OCH3)および(CH2)2P(O)(OH)(O(CH2)7CH3)、NHCH3、NH(CH2)2CH3、NHCH(CH3)2、NH(CH2)3CH3、NH(シクロヘキシル)、NH(ベンジル)、CH2Br、CHBr2、CH2P(O)(OCH2CH3)2、(CH2)2P(O)(OCH3)(O(CH2)7CH3)、(CH2)2P(O)(OCH3)2;(CH2)2P(O)(OCH3)2、N(COCH3)(フェニル)およびN(COCH3)(4-メトキシフェニル)を除くものであり;また、式(I)は表2に記載の化合物74〜85を除くものである]。
[式中、R1はそれぞれ独立して非妨害性の置換基であり得;R2はアルキル、アリール、ヘテロアリール、OR4、NR4 2およびNR4OR4であり得、それぞれ非妨害性の置換基によって置換されていてもよく;R3はOR4、N3またはNR4 2であり得;R4はそれぞれ独立して非妨害性の置換基であり得、ただし、それぞれのR1がHであってR3がOHである場合、R2はCH2CH3、(CH2)2CH3、(CH2)3CH3、(CH2)4CH3、CH(CH3)2およびCH2CH(CH3)2を除くものであり;また、それぞれのR1がCOCH3であってR3がOC(O)CH3である場合、R2はCH2CH3、(CH2)2CH3、(CH2)3CH3、(CH2)4CH3、CH(CH3)2およびCH2CH(CH3)2を除くものである]。症状は、アルツハイマー病、筋萎縮性側索硬化症(ALS)、認知障害を伴う筋萎縮性側索硬化症(ALSci)、嗜銀顆粒性認知症、Bluit病、大脳皮質基底核変異症(CBD)、拳闘家認知症、石灰化を伴うびまん性神経原線維変化病、ダウン症候群、家族性英国型認知症、家族性デンマーク型認知症、17番染色体に連鎖しパーキンソニズムを伴う前頭側頭型認知症(FTDP-17)、ゲルストマン・ストロイスラー・シャインカー病、グアダループ人パーキンソニズム(Guadeloupean parkinsonism)、ハラーホルデン・スパッツ病(脳の鉄沈着を伴う神経変性1型(neurodegeneration with brain iron accumulation type 1))、多系統萎縮症、筋緊張性ジストロフィー、ニーマン・ピック病(C型)、淡蒼球・橋・黒質の変性、グアムのパーキンソン認知症複合(Parkinsonism-dementia complex of Guam)、ピック病(PiD)、脳炎後パーキソニズム(PEP)、プリオン病(クロイツフェルト・ヤコブ病(CJD)、異型クロイツフェルト・ヤコブ病(vCJD)、致死性家族性不眠症およびクールー病を含む)、進行性超皮質性グリオーシス(Progressive supercortical gliosis)、進行性核上性麻痺(PSP)、リチャードソン症候群、亜急性硬化性全脳炎、神経原線維型認知症(Tangle-only dementia)、ハンチントン病またはパーキンソン病であり得る。ストレスは、心障害、例えば、虚血;出血;血液量減少性ショック;心筋梗塞;心血管インターベンション処置;心臓バイパス術;線溶療法;血管形成術;またはステント留置であり得る。
[式中、R1はそれぞれ独立して非妨害性の置換基であり得;R2はアルキル、アリール、ヘテロアリール、OR4、NR4 2およびNR4OR4であり得、それぞれ非妨害性の置換基によって置換されていてもよく;R3はOR4、N3またはNR4 2であり得;R4はそれぞれ独立して非妨害性の置換基であり得る]。いくつかの実施形態において、その症状は、炎症性またはアレルギー性疾患、例えば、喘息、アレルギー性鼻炎、過敏性肺疾患、過敏性肺炎、好酸球性肺炎、遅延型過敏症、アテロ−ム性動脈硬化症、間質性肺疾患(ILD)(例えば、特発性肺線維症、または関節リウマチ、全身性エリテマトーデス、強直性脊椎炎、全身性硬化症、シェーグレン症候群、多発性筋炎もしくは皮膚筋炎を伴うILD);全身性アナフィラキシーまたは過敏性反応、薬物アレルギー、昆虫刺傷アレルギー;自己免疫疾患、例えば、関節リウマチ、乾癬性関節炎、多発性硬化症、全身性エリテマトーデス、重症筋無力症、糸球体腎炎、自己免疫性甲状腺炎、移植片拒絶反応(同種移植片拒絶反応または移植片対宿主病を含む);炎症性腸疾患、例えば、クローン病および潰瘍性大腸炎;脊椎関節症;強皮症;乾癬(T細胞媒介性乾癬を含む)および炎症性皮膚疾患、例えば、皮膚炎、湿疹、アトピー性皮膚炎、アレルギー性接触性皮膚炎、じん麻疹;血管炎(例えば、壊死性、皮膚性および過敏性血管炎);好酸球性筋炎(eosinphilic myotis)および好酸球性筋膜炎;移植片拒絶反応、限定しないが特に、臓器移植、例えば、心臓、肺、肝臓、腎臓および膵臓移植(例えば、腎臓および肺の同種異系移植);てんかん;痛み;卒中、例えば、卒中後の神経保護であり得る。
[式中、R1はそれぞれ独立して非妨害性の置換基であり得;R2はアルキル、アリール、ヘテロアリール、OR4、NR4 2およびNR4OR4であり得、それぞれ非妨害性の置換基によって置換されていてもよく;R3はOR4、N3またはNR4 2であり得;R4はそれぞれ独立して非妨害性の置換基であり得、ただし、式(I)の化合物は表2および3に記載の化合物を除くものである]。本医薬は、O-GlcNAcアーゼを選択的に阻害するため、O-GlcNAcのレベルを増加させるため、O-GlcNAcアーゼにより変調する症状を処置するため、神経変性疾患、タウオパチー、癌またはストレスを処置するためものであり得る。
[式中、R1はそれぞれ独立して非妨害性の置換基であり得;R2はアルキル、アリール、ヘテロアリール、OR4、NR4 2およびNR4OR4であり得、それぞれ非妨害性の置換基によって置換されていてもよく;R3はOR4、N3またはNR4 2であり得;R4はそれぞれ独立して非妨害性の置換基であり得る]、
c)第1および第2のサンプルにおいてO-GlcNAcアーゼの阻害レベルを測定することにより、O-GlcNAcアーゼの選択的阻害剤をスクリーニングする方法を提供する、ここで試験化合物が式(I)の化合物と比較して同等またはより強くO-GlcNAcアーゼの阻害を示す場合、その試験化合物はO-GlcNAcアーゼの選択的阻害剤である。
本発明は、部分的には、O-グリコプロテイン2-アセトアミド-2-デオキシ-β-D-グルコピラノシダーゼ(O-GlcNAcアーゼ)を阻害することができる新規化合物を提供する。いくつかの実施形態において、O-GlcNAcアーゼは、哺乳類O-GlcNAcアーゼ、例えば、ラット、マウスまたはヒトO-GlcNAcアーゼである。いくつかの実施形態において、β-ヘキソサミニダーゼは、哺乳類β-ヘキソサミニダーゼ、例えば、ラット、マウスまたはヒトβ-ヘキソサミニダーゼである。
により一般的に記載される化合物、ならびにその塩、プロドラッグおよび立体異性体を提供する。
本発明は、O-GlcNAcアーゼ酵素またはO-GlcNAc修飾タンパク質レベルにより、直接または間接的に変調する症状、例えば、O-GlcNAcアーゼ酵素の阻害またはO-GlcNAc修飾タンパク質レベルの上昇により利益が得られる症状を処置する方法を提供する。そのような症状には、限定しないが、タウオパチー、例えば、アルツハイマー病、神経変性疾患、心臓脈管疾患、炎症を伴う疾患、免疫抑制を伴う疾患および癌が含まれる。本発明の化合物はまた、O-GlcNAcアーゼの欠乏もしくは過剰発現またはO-GlcNAcの蓄積もしくは枯渇に関連する疾患または障害、あるいはグリコシダーゼ阻害治療に反応するいずれかの疾患または障害の処置に有用である。そのような疾患および障害には、限定しないが、神経変性障害、例えば、アルツハイマー病(AD)および癌が含まれる。そのような疾患および障害には、酵素OGTアーゼの蓄積または欠乏に関連する疾患または障害も含まれ得る。O-GlcNAc残基により修飾される(その修飾の調節不全により疾患または病態が起こる)タンパク質を発現する標的細胞を保護するまたは処置する方法も含まれる。「処置」なる用語は本明細書において用いられる場合、治療、予防および寛解を含む。
本発明による化合物、または本発明による使用のための化合物を含む医薬組成物は、本発明の範囲内にあることを意図する。いくつかの実施形態において、有効量の式(I)の化合物を含む医薬組成物を提供する。
・NMDA受容体拮抗剤、例えば、ナメンダ(Namenda)(登録商標)(Axura(登録商標)、Akatinol(登録商標)、エビクサ(Ebixa)(登録商標)、メマンチン(Memantine))、ディメボン、SGS-742、ネラメキサン(Neramexane)、Debio-9902 SR(ZT-1 SR)など;
・ガンマ-セクレターゼ阻害剤および/または変調剤、例えば、FlurizanTM(Tarenflurbil、MPC-7869、R-フルルビプロフェン(R-flurbiprofen))、LY450139、MK 0752、E2101、BMS-289948、BMS-299897、BMS-433796、LY-411575など;
・ベータ-セクレターゼ阻害剤、例えば、ATG-Z1など;
・α-セクレターゼ活性化剤、例えば、NGX267など;
・タウ凝集阻害剤、例えば、メチレンブルーなど;
・微小管安定剤、例えば、AL-108、AL-208、パクリタキセルなど;
・RAGE阻害剤、例えば、TTP488など;
・5-HT1a受容体拮抗剤、例えば、キサリプロデン(Xaliproden)、レコゾタン(Lecozotan)など;
・5-HT4受容体拮抗剤、例えば、PRX-03410など;
・キナーゼ阻害剤、例えば、SRN-003-556、amfurindamide、LiCl、AZD1080、NP031112、SAR-502250など;
・ヒト化モノクローナル抗Aβ抗体、例えば、バピネオズマブ(Bapineuzumab)(AAB-001)、LY2062430、RN1219、ACU-5A5など;
・神経保護剤、例えば、Cerebrolysin、AL-108、AL-208、ヒューペルジンAなど;
・L-型カルシウムチャネル拮抗剤、例えば、MEM-1003など;
・ニコチン受容体拮抗剤、例えば、AZD3480、GTS-21など;
・ニコチン受容体刺激剤、例えば、MEM 3454、ネフィラセタム(Nefiracetam)など;
・ペルオキシソーム増殖剤活性化受容体(PPAR)ガンマ刺激剤、例えば、アバンディア(Avandia)(登録商標)(ロシグリタゾン(Rosglitazone))など;
・ホスホジエステラーゼIV(PDE4)阻害剤、例えば、MK-0952など;
・ホルモン補充療法、例えば、エストロゲン(プレマリン(Premarin))など;
・AMPA受容体変調剤、例えば、Ampalex(CX 516)など;
・神経成長因子またはNGF増強剤、例えば、CERE-110(AAV-NGF)、T-588、T-817MAなど;
・脳下垂体による黄体形成ホルモン(LH)の放出を防止する薬剤、例えば、ロイプロリド(VP-4896)など;
・GABA受容体変調剤、例えば、AC-3933、NGD 97-1、CP-457920など;
・ベンゾジアゼピン受容体逆刺激薬、例えば、SB-737552(S-8510)、AC-3933など;
・ノルアドレナリン放出剤、例えば、T-588、T-817MAなど。
式(I)の化合物は、グリコシダーゼ酵素、好ましくはO-GlcNAcアーゼ酵素の活性を変調する化合物についてのスクリーニングアッセイに用いてもよい。試験化合物のモデル基質からのO-GlcNAcのO-GlcNAcアーゼ依存性の切断を阻害する能力は、本明細書に記載のような、または当業者に既知のいずれかのアッセイを用いて測定され得る。例えば、当業者に既知の蛍光またはUVに基づくアッセイを用いることができる。「試験化合物」は天然のまたは人工のいずれかの化合物である。試験化合物は、限定しないが、ペプチド、ポリペプチド、合成有機分子、天然有機分子および核酸分子を含み得る。試験化合物は、式(I)の化合物のような既知の化合物と、例えば、O-GlcNAcのO-GlcNAcアーゼ依存性の切断の阻害を妨害することにより、または式(I)の化合物により誘導されるいずれかの生物学的反応を妨害することにより、「競合」し得る。
以下の実施例は本発明の実施形態を例証することを意図し、限定的に解釈されることは意図していない。以下の実施例における多くの化合物はスキーム1において概要を示す合成経路によって調製された。
一般手順A:2-アミド糖(B)の合成。(2S,3R,4R,5S,6R)-6-(アセトキシメチル)-3-アミノ-テトラヒドロ-2H-ピラン-2,4,5-トリイルトリアセテート・塩酸塩(2.0g、5.2mmol)/CH2Cl2(50mL)の懸濁物に、トリエチルアミン(1.45mL、10.4mmol)を加え、その時出発物質が溶解した。反応混合物を0℃に冷却し、1.5当量の適切な酸塩化物(7.8mmol)をシリンジによって加えた。得られた混合物を室温にて2時間撹拌した。TLC分析によって反応混合物の反応が完了したことが判定されたら、EtOAc(200mL)を加えた。有機相を水、1 M水性NaOHおよび塩水により連続的に洗浄した。有機相を乾燥させ(MgSO4)、濃縮して白色の結晶性固体を得た。こうして得られた物質を再結晶し(EtOAc/ヘキサン類)、目的とするN-アシル化物質を得た。
(2S,3R,4R,5S,6R)-6-(アセトキシメチル)-3-アミノ-テトラヒドロ-2H-ピラン-2,4,5-トリイルトリアセテート・塩酸塩(250mg、0.65mmol)/CH2Cl2(5mL)の撹拌溶液にトリエチルアミン(90μL、0.65mmol)を加えた。その溶液を飽和水性NaHCO3(20mL)により希釈し、次いで得られた混合物をCH2Cl2(3×10mL)により抽出し、合わせた有機抽出物を乾燥させ(Na2SO4)、濃縮し、おそらく(2S,3R,4R,5S,6R)-6-(アセトキシメチル)-3-アミノ-テトラヒドロ-2H-ピラン-2,4,5-トリイルトリアセテート(220mg)を得、さらに精製は行わずに用いた。
速度論的解析における実験手順: PBS緩衝液(pH 7.4)において基質としてpNP-GlcNAc(0.5mM)を用いて酵素反応を行い、ペルチェ(Peltier)温度調節器を備えたCary 3E UV-VIS分光光度計を用いて400nm、37℃にて持続的にモニターした。反応物を500μL石英キュベットにおいて予め約5分間加熱し、次いでシリンジを用いて酵素10μLを加えた(最終酵素濃度0.002mg/mL)。反応速度を、反応進行曲線の1分〜3分の間の直線領域の直線回帰により測定した。それぞれの場合においてKIの1/5〜5倍の濃度範囲の阻害剤を用いた。
速度論的解析における実験手順:酵素学的アッセイは全て、400nmにおける吸収測定により決定する遊離した4-ニトロフェノラートの量を測定するストップドアッセイ手順を用いて37℃にて3回繰り返し行った。反応(50μL)は、酵素(3μL)をシリンジを用いて加えることにより開始した。β-ヘキソサミニダーゼの時間依存的アッセイにより、酵素は、アッセイ期間にわたって緩衝液中において安定であることが分かった:50mMクエン酸、100mM NaCl、0.1% BSA、pH 4.25。β-ヘキソサミニダーゼは、濃度0.036mg/mLのものを、基質として濃度0.5mMのpNP-GlcNAcとともに用いた。阻害剤はKIの5〜1/5倍の範囲の5つの濃度にて試験した。KI値はDixonプロットからのデータの直線回帰により決定した。
KI(β−ヘキソサミニダーゼ)/KI(O-GlcNAcアーゼ)
一般に、本明細書の実施例に記載の化合物は、約1000〜100000の範囲の選択性の比率を示す。例えば表3の化合物と比較すると、本明細書の実施例に記載の化合物の多くは、O-GlcNAcアーゼに対してより高い選択性を示す。よって、本発明の化合物はβ-ヘキソサミニダーゼに対してO-GlcNAcアーゼの阻害について高い選択性を示す。
Sprague-Dawley系ラットの脳および筋肉組織におけるO-GlcNAc修飾レベルに対する(3aR,5R,6S,7R,7aR)-5-(ヒドロキシメチル)-2-プロピル-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジオール(化合物54;以後NAG-Btと称する)の静脈内(IV)投与の効果を測定した。動物は、Charles-Riverから5週齢の健康なオスのSprague-Dawley系ラットを入手した。動物を1週間気候に順応させ、6週齢の時点で適切な処置を開始した。8匹の動物の尾静脈に、様々な濃度のNAG-Btまたは媒体のみ(PBS)の静脈内注射を行った;NAG-Btの用量には0、2、5、10、25、50、100および250mg/kgが含まれた。7時間後、動物を屠殺し、死後の遅れを最小限にするために動物から組織をできる限り素早く摘出した。組織を直ちに液体窒素において凍結させ、後に用いるまで−80℃にて保管した。組織のホモジナイズは、手作業で粉砕して行い、次いで細胞溶解緩衝液(50mMトリス、pH 8.0、1mM PMSF、0.1% NP-40、1mM NAG-Bt)において、組織ホモジナイザー(IKA)を用いて4℃にてホモジナイズした。不溶性細胞の細片を17,900×g、4℃にて20分間遠心分離して除去し、得られた上清を使用するまで−20℃にて保管した。
Sprague-Dawley系ラットの脳組織におけるタウのリン酸化レベルに対するNAG-Btの経口投与の効果を測定した。動物は全てCharles-Riverから5週齢の健康なオスのSprague-Dawley系ラットを入手した。動物を1週間気候に順応させ、6週齢の時点で適切な処置を開始した。4匹の動物に100mg/kg/日のNAG-Btを含有する飼料を5日間与えた。阻害剤を含有しない飼料を与えたさらなる4匹の動物を対照として用いた。5日間の終わりに、動物を11時間絶食させ、次いでNAG-Btを含む飼料を与えた4匹の動物の尾静脈にそれぞれ50mg/kgのNAG-Btを静脈内投与した。全ての動物をさらに5時間絶食させ、次いでそれらを屠殺し、脳を摘出し、保管し、実施例29に記載のように実験した。
Sprague-Dawley系ラットの心臓組織におけるO-GlcNAcレベルに対する(3aR,5R,6S,7R,7aR)-2-(エチルアミノ)-5-(ヒドロキシメチル)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジオール(化合物25、以後NAG-AEと称する)の静脈内(IV)投与の効果を測定した。動物はCharles-Riverから5週齢の健康なオスのSprague-Dawley系ラットを入手した。動物を1週間気候に順応させ、6週齢の時点で適切な処置を開始した。9匹の動物の尾静脈に、50mg/kgのNAG-AEを静脈内注射し、注射後、以下の時間の経過後にそれぞれ1匹の動物を屠殺した:0、1、2、4、7、10、13、16および20時間。さらに、1匹の動物に媒体(PBS−pH 7.4)を注射し、2時間後に屠殺して対照として用いた。屠殺した動物から、死後の遅れを最小限にするためにできる限り素早く組織を摘出した。それぞれの動物からの心臓を直ちに液体窒素において凍結させ、後に用いるまで−80℃にて保管した。心臓組織のホモジナイズを手作業で粉砕して行い、次いで細胞溶解緩衝液(50mMトリス、pH 8.0、1mM PMSF、0.1% NP-40、1mM NAG-Bt)において4℃にて組織ホモジナイザー(IKA)を用いてホモジナイズした。不溶性細胞の細片を17,900×g、4℃にて20分間遠心分離して除去し、得られた上清を使用するまで−20℃にて保管した。
動物への投与および組織収集。ヒト変異タウタンパク質(P301L)を過剰発現するヘミ接合性トランスジェニックメスJNPL3マウスおよび野生型対照マウスをTaconic Farms, Inc.から入手した(それぞれモデル番号001638-T-Fおよび001638-W-F)。マウスは配達時に10-12週齢であり、本研究において「1週」と名付けた。1週において、これらのマウスを4つのグループに分けた:グループA(トランスジェニックマウス)には研究を通して媒体のみを投与する;グループB(トランスジェニックマウス)には1〜15週に100mg/kg/日のNAG-Btを含む飼料を与え、次いで16〜32週に1000mg/kg/日のNAG-Btを含む飲料水に切り替えた;グループD(トランスジェニックマウス)には1〜15週に媒体のみを、次いで16〜32週に500mg/kg/日のNAG-AEを含む飲料水を与えた;グループE(野生型)には研究を通して媒体のみを与えた。32週において、グループ毎に3匹の動物を屠殺し、組織を収集した。トランスジェニックマウスおよび対照はCO2チャンバーを用いて屠殺した。呼吸が止まってから約45秒後に、0.9%NaCl緩衝液30mL、次いで4%パラホルムアルデヒド(1×リン酸緩衝生理食塩水、PBS、pH 7.4におけるw/v)30mLを経心的に灌流した。次いで脳を慎重に解剖し、4%パラホルムアルデヒドにおいて後固定し、20%スクロース(1×PBSにおけるw/v)において4℃にて24時間寒冷保護した。
Sprague-Dawley系ラットに(3aR,5R,6S,7R,7aR)-5-(ヒドロキシメチル)-2-プロピル-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジオール(NAG-Bt)を8ヶ月にわたり繰り返し経口投与する毒性学的効果を測定した。動物は全てCharles-Riverから5週齢の健康なオスのSprague-Dawley系ラットを入手した。動物を1週間気候に順応させ、6週齢の時点で適切な処置を開始した。8匹の動物に、100mg/kg/日のNAG-Btを含有する飼料を8ヶ月にわたり与えた。阻害剤を含まない飼料を与えたさらに8匹の動物を対照として用いた。この期間、体重、飼料消費量、水消費量および血糖値を、各グループの動物についてモニターした(図5A-D;それぞれ、対照ラットのデータは四角で表され、投与ラットのデータは丸で表される);2グループ間に有意差は見られなかった。この期間、NAG-Btを投与したグループにおいて、肉眼による病理学的異常または行動の違いは観察されなかった。4ヶ月間投与した後、各グループにつき4匹のラットから血液および尿サンプルを収集した。これらのサンプルを血液学的に(CBC)、血液生化学的に、および尿分析により解析した(表5および6);グループ間において統計学的有意差は検出されなかった。
Sprague-Dawley系ラットの脳組織におけるタウのリン酸化レベルに対する(3aR,5R,6S,7R,7aR)-2-(エチルアミノ)-5-(ヒドロキシメチル)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジオール(化合物25、NAG-AE)を経口投与する効果を測定した。全ての動物はCharles-Riverから5週齢の健康なオスのSprague-Dawley系ラットを入手した。動物を1週間気候に順応させ、6週齢の時点で適切な処置を開始した。3匹の動物に200mg/kg/日のNAG-AEを含む飲料水を1日間与えた。NAG-AEを含有しない飲料水を与えた3匹のさらなる動物を対照として用いた。投与期間後直ちに、全ての動物を屠殺し、脳を摘出し、保管し、実施例29に記載のように実験した。
(3aR,5R,6S,7R,7aR)-5-(ヒドロキシメチル)-2-プロピル-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジオール(NAG-Bt)および(3aR,5R,6S,7R,7aR)-2-(エチルアミノ)-5-(ヒドロキシメチル)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジオール(NAG-AE)を、野生型JNPL3マウスへ9ヶ月にわたって繰り返し経口投与する毒物学的効果を測定した。動物は全てTaconic Farms, Inc.から入手し(モデル番号001638-W-F)、それらは配達時に10-12週齢であり、本研究において「1週」と名付けた。1週において、マウスを3つのグループに分けた:グループEには研究を通して媒体のみを投与した;グループF1には1〜15週に100mg/kg/日のNAG-Btを含む飼料を与え、次いで16〜40週に500mg/kg/日のNAG-AEを含む飲料水に切り替えた;グループF2には1〜15週に100mg/kg/日のNAG-Btを含む飼料を与え、次いで16〜40週に1000mg/kg/日のNAG-Btを含む飲料水に切り替えた。この期間、各グループにおける動物について、体重、飼料消費量、および水消費量をモニターした;グループ間において有意差は見られなかった。この期間、肉眼による病理学的異常または行動の違いは、NAG-BtまたはNAG-AEを与えたグループにおいて観察されなかった。40週において、血液および尿サンプルを各グループにおける動物から収集した;各グループの動物の尿サンプルは分析の前にプールしておき、血液サンプルは個々に分析した。これらのサンプルを、血液学的に(CBC)、血液生化学的に、および尿分析により解析した(表7および8);グループ間で統計学的有意差は検出されなかった。
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Claims (26)
- 式(I):
R1はそれぞれ独立してHまたはC(O)CH3であり;
R2はNR4 2またはNR4OR4であり、ここで、R4はそれぞれ独立して、H、C1-10アルキル、C2-10アルケニル、およびシクロアルキルからなる群から選択され、H以外のこれらの基は、F、OHおよびOC(O)CH3からなる群から選択される1個から置換可能な最大個数までの置換基で置換されていてもよく;
R3はOHおよびOアシルからなる群から選択される;
ただし、それぞれのR1がHであってR3がOHである場合、R2はN(CH3)2、NHCH2CH3およびNH(CH2)2CH3を除くものであり;
また、それぞれのR1がCOCH3であってR3がOC(O)CH3である場合、R2はN(CH3)2、NHCH3、NH(CH2)2CH3、NHCH(CH3)2、NH(CH2)3CH3およびNH(シクロヘキシル)を除くものである]
で示される化合物またはその医薬上許容される塩。 - R2が、NH2、NHCH3、NHCH2CH3、NH(CH2)2CH3、NH(CH2)3CH3、NHCH2CH=CH2、NHシクロプロピル、NHCH2CH2F、NHCH2CHF2、NHCH2CF3、NHCH2CH2OH、NHCH2CH2OC(O)CH3、N(CH3)2、N(CH3)(CH2CH3)またはNHOCH3である、請求項1の化合物またはその医薬上許容される塩。
- 化合物が
(3aR,5R,6S,7R,7aR)-2-アミノ-5-(ヒドロキシメチル)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジオール;
(3aR,5R,6S,7R,7aR)-5-(ヒドロキシメチル)-2-(メチルアミノ)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジオール;
(3aR,5R,6S,7R,7aR)-5-(アセトキシメチル)-2-(エチルアミノ)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジイルジアセテート;
(3aR,5R,6S,7R,7aR)-2-(ブチルアミノ)-5-(ヒドロキシメチル)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジオール;
(3aR,5R,6S,7R,7aR)-5-(アセトキシメチル)-2-(アリルアミノ)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジイルジアセテート;
(3aR,5R,6S,7R,7aR)-2-(アリルアミノ)-5-(ヒドロキシメチル)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジオール;
(3aR,5R,6S,7R,7aR)-5-(アセトキシメチル)-2-(シクロプロピルアミノ)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジイルジアセテート;
(3aR,5R,6S,7R,7aR)-2-(シクロプロピルアミノ)-5-(ヒドロキシメチル)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジオール;
(3aR,5R,6S,7R,7aR)-5-(アセトキシメチル)-2-(2-フルオロエチルアミノ)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジイルジアセテート;
(3aR,5R,6S,7R,7aR)-2-(2-フルオロエチルアミノ)-5-(ヒドロキシメチル)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジオール;
(3aR,5R,6S,7R,7aR)-5-(アセトキシメチル)-2-(2,2-ジフルオロエチルアミノ)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジイルジアセテート;
(3aR,5R,6S,7R,7aR)-2-(2,2-ジフルオロエチルアミノ)-5-(ヒドロキシメチル)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジオール;
(3aR,5R,6S,7R,7aR)-5-(アセトキシメチル)-2-(2,2,2-トリフルオロエチルアミノ)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジイルジアセテート;
(3aR,5R,6S,7R,7aR)-5-(ヒドロキシメチル)-2-(2,2,2-トリフルオロエチルアミノ)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジオール;
(3aR,5R,6S,7R,7aR)-2-(2-アセトキシエチルアミノ)-5-(アセトキシメチル)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジイルジアセテート;
(3aR,5R,6S,7R,7aR)-2-(2-ヒドロキシエチルアミノ)-5-(ヒドロキシメチル)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジオール;
(3aR,5R,6S,7R,7aR)-5-(アセトキシメチル)-2-(エチル(メチル)アミノ)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジイルジアセテート;
(3aR,5R,6S,7R,7aR)-2-(エチル(メチル)アミノ)-5-(ヒドロキシメチル)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジオール;
(3aR,5R,6S,7R,7aR)-5-(アセトキシメチル)-2-(メトキシアミノ)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジイルジアセテート;および
(3aR,5R,6S,7R,7aR)-5-(ヒドロキシメチル)-2-(メトキシアミノ)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジオール
からなる群から選択される化合物;またはその医薬上許容される塩である、請求項1の化合物またはその医薬上許容される塩。 - (3aR,5R,6S,7R,7aR)-5-(アセトキシメチル)-2-(メチルアミノ)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジイルジアセテート;
(3aR,5R,6S,7R,7aR)-5-(アセトキシメチル)-2-(プロピルアミノ)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジイルジアセテート;
(3aR,5R,6S,7R,7aR)-5-(アセトキシメチル)-2-(ブチルアミノ)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジイルジアセテート;
(3aR,5R,6S,7R,7aR)-5-(アセトキシメチル)-2-(ジメチルアミノ)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジイルジアセテート;
(3aR,5R,6S,7R,7aR)-2-(ジメチルアミノ)-5-(ヒドロキシメチル)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジオール;
(3aR,5R,6S,7R,7aR)-5-(アセトキシメチル)-2-(イソプロピルアミノ)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジイルジアセテート;および
(3aR,5R,6S,7R,7aR)-5-(アセトキシメチル)-2-(シクロヘキシルアミノ)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジイルジアセテート
を除くことを条件とする、請求項1の化合物またはその医薬上許容される塩。 - R1がC(O)CH3である、請求項1の化合物またはその医薬上許容される塩。
- O-グリコプロテイン2-アセトアミド-2-デオキシ-β-D-グルコピラノシダーゼ(O-GlcNAcアーゼ)を選択的に阻害する、請求項1〜5のいずれかの化合物またはその医薬上許容される塩。
- O-GlcNAcアーゼに選択的に結合する、請求項1〜6のいずれかの化合物またはその医薬上許容される塩。
- 2-アセトアミド-2-デオキシ-β-D-グルコピラノシド(O-GlcNAc)の切断を選択的に阻害する、請求項1〜7のいずれかの化合物またはその医薬上許容される塩。
- O-GlcNAcアーゼが哺乳類O-GlcNAcアーゼである、請求項6の化合物またはその医薬上許容される塩。
- 哺乳類β-ヘキソサミニダーゼを実質的に阻害しない、請求項1〜9のいずれかの化合物またはその医薬上許容される塩。
- 請求項1〜10のいずれかの化合物または医薬上許容される塩を医薬上許容される担体と組み合わせて含む、医薬組成物。
- 必要とする対象においてO-GlcNAcアーゼを選択的に阻害するための医薬であって、式(I)の化合物またはその医薬上許容される塩を含む医薬:
R1はそれぞれ独立してHまたはC(O)CH3であり;
R2はNR4 2またはNR4OR4であり、ここで、R4はそれぞれ独立して、H、C1-10アルキル、C2-10アルケニル、およびシクロアルキルからなる群から選択され、H以外のこれらの基は、F、OHおよびOC(O)CH3からなる群から選択される1個から置換可能な最大個数までの置換基で置換されていてもよく;
R3はOHおよびOアシルからなる群から選択される]。 - 必要とする対象においてO-GlcNAcレベルを上昇させるための医薬であって、式(I)の化合物またはその医薬上許容される塩を含む医薬:
R1はそれぞれ独立してHまたはC(O)CH3であり;
R2はNR4 2またはNR4OR4であり、ここで、R4はそれぞれ独立して、H、C1-10アルキル、C2-10アルケニル、およびシクロアルキルからなる群から選択され、H以外のこれらの基は、F、OHおよびOC(O)CH3からなる群から選択される1個から置換可能な最大個数までの置換基で置換されていてもよく;
R3はOHおよびOアシルからなる群から選択される]。 - 必要とする対象において、神経変性疾患、タウオパチー、癌およびストレスを除く、O-GlcNAcアーゼにより変調される症状を処置するための医薬であって、式(I)の化合物またはその医薬上許容される塩を含む医薬:
R1はそれぞれ独立してHまたはC(O)CH3であり;
R2はNR4 2またはNR4OR4であり、ここで、R4はそれぞれ独立して、H、C1-10アルキル、C2-10アルケニル、およびシクロアルキルからなる群から選択され、H以外のこれらの基は、F、OHおよびOC(O)CH3からなる群から選択される1個から置換可能な最大個数までの置換基で置換されていてもよく;
R3はOHおよびOアシルからなる群から選択される]。 - 症状が、炎症性疾患、アレルギー、喘息、アレルギー性鼻炎、過敏性肺疾患、過敏性肺炎、好酸球性肺炎、遅延型過敏症、アテロ−ム性動脈硬化症、間質性肺疾患(ILD)、特発性肺線維症、関節リウマチを伴うILD、全身性エリテマトーデス、強直性脊椎炎、全身性硬化症、シェーグレン症候群、多発性筋炎または皮膚筋炎、全身性アナフィラキシーまたは過敏性反応、薬物アレルギー、昆虫刺傷アレルギー、自己免疫疾患、関節リウマチ、乾癬性関節炎、多発性硬化症、全身性エリテマトーデス、重症筋無力症、糸球体腎炎、自己免疫性甲状腺炎、移植片拒絶反応、同種移植片拒絶反応、移植片対宿主病、炎症性腸疾患、クローン病、潰瘍性大腸炎、脊椎関節症、強皮症、乾癬、T細胞媒介性乾癬、炎症性皮膚疾患、皮膚炎、湿疹、アトピー性皮膚炎、アレルギー性接触性皮膚炎、じん麻疹、血管炎、壊死性、皮膚性および過敏性血管炎、好酸球性筋炎、好酸球性筋膜炎、臓器移植拒絶反応、心臓移植拒絶反応、肺移植拒絶反応、肝臓移植拒絶反応、腎臓移植拒絶反応、膵臓移植拒絶反応、腎臓同種移植片、肺同種移植片、てんかん、痛み、卒中、神経保護からなる群から選択される1以上の症状である、請求項14の医薬。
- 必要とする対象において神経変性疾患、タウオパチー、癌およびストレスからなる群から選択される症状を処置するための医薬であって、式(I)の化合物またはその医薬上許容される塩を含む医薬:
R1はそれぞれ独立してHまたはC(O)CH3であり;
R2はNR4 2またはNR4OR4であり、ここで、R4はそれぞれ独立して、H、C1-10アルキル、C2-10アルケニル、およびシクロアルキルからなる群から選択され、H以外のこれらの基は、F、OHおよびOC(O)CH3からなる群から選択される1個から置換可能な最大個数までの置換基で置換されていてもよく;
R3はOHおよびOアシルからなる群から選択される]。 - 症状が、アルツハイマー病、筋萎縮性側索硬化症(ALS)、認知障害を伴う筋萎縮性側索硬化症(ALSci)、嗜銀顆粒性認知症、Bluit病、大脳皮質基底核変異症(CBD)、拳闘家認知症、石灰化を伴うびまん性神経原線維変化病、ダウン症候群、家族性英国型認知症、家族性デンマーク型認知症、17番染色体に連鎖しパーキンソニズムを伴う前頭側頭型認知症(FTDP-17)、ゲルストマン・ストロイスラー・シャインカー病、グアダループ人パーキンソニズム、ハラーホルデン・スパッツ病(脳の鉄沈着を伴う神経変性1型)、多系統萎縮症、筋緊張性ジストロフィー、ニーマン・ピック病(C型)、淡蒼球・橋・黒質の変性、グアムのパーキンソン認知症複合、ピック病(PiD)、脳炎後パーキソニズム(PEP)、プリオン病(クロイツフェルト・ヤコブ病(CJD)、異型クロイツフェルト・ヤコブ病(vCJD)、致死性家族性不眠症およびクールー病を含む)、進行性超皮質性グリオーシス、進行性核上性麻痺(PSP)、リチャードソン症候群、亜急性硬化性全脳炎、神経原線維型認知症、ハンチントン病およびパーキンソン病からなる群から選択される1以上の症状である、請求項16の医薬。
- ストレスが心障害である、請求項16の医薬。
- 心障害が、虚血;出血;血液量減少性ショック;心筋梗塞;心血管インターベンション処置;心臓バイパス術;線溶療法;血管形成術;およびステント留置からなる群から選択される1以上の障害である、請求項18の医薬。
- R2が、NH2、NHCH3、NHCH2CH3、NH(CH2)2CH3、NH(CH2)3CH3、NHCH2CH=CH2、NHシクロプロピル、NHCH2CH2F、NHCH2CHF2、NHCH2CF3、NHCH2CH2OH、NHCH2CH2OC(O)CH3、N(CH3)2、N(CH3)(CH2CH3)またはNHOCH3である、請求項12〜19のいずれかの医薬。
- 化合物が
(3aR,5R,6S,7R,7aR)-2-アミノ-5-(ヒドロキシメチル)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジオール;
(3aR,5R,6S,7R,7aR)-5-(ヒドロキシメチル)-2-(メチルアミノ)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジオール;
(3aR,5R,6S,7R,7aR)-5-(アセトキシメチル)-2-(エチルアミノ)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジイルジアセテート;
(3aR,5R,6S,7R,7aR)-2-(エチルアミノ)-5-(ヒドロキシメチル)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジオール;
(3aR,5R,6S,7R,7aR)-5-(ヒドロキシメチル)-2-(プロピルアミノ)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジオール;
(3aR,5R,6S,7R,7aR)-2-(ブチルアミノ)-5-(ヒドロキシメチル)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジオール;
(3aR,5R,6S,7R,7aR)-5-(アセトキシメチル)-2-(アリルアミノ)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジイルジアセテート;
(3aR,5R,6S,7R,7aR)-2-(アリルアミノ)-5-(ヒドロキシメチル)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジオール;
(3aR,5R,6S,7R,7aR)-5-(アセトキシメチル)-2-(シクロプロピルアミノ)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジイルジアセテート;
(3aR,5R,6S,7R,7aR)-2-(シクロプロピルアミノ)-5-(ヒドロキシメチル)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジオール;
(3aR,5R,6S,7R,7aR)-5-(アセトキシメチル)-2-(2-フルオロエチルアミノ)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジイルジアセテート;
(3aR,5R,6S,7R,7aR)-2-(2-フルオロエチルアミノ)-5-(ヒドロキシメチル)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジオール;
(3aR,5R,6S,7R,7aR)-5-(アセトキシメチル)-2-(2,2-ジフルオロエチルアミノ)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジイルジアセテート;
(3aR,5R,6S,7R,7aR)-2-(2,2-ジフルオロエチルアミノ)-5-(ヒドロキシメチル)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジオール;
(3aR,5R,6S,7R,7aR)-5-(アセトキシメチル)-2-(2,2,2-トリフルオロエチルアミノ)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジイルジアセテート;
(3aR,5R,6S,7R,7aR)-5-(ヒドロキシメチル)-2-(2,2,2-トリフルオロエチルアミノ)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジオール;
(3aR,5R,6S,7R,7aR)-2-(2-アセトキシエチルアミノ)-5-(アセトキシメチル)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジイルジアセテート;
(3aR,5R,6S,7R,7aR)-2-(2-ヒドロキシエチルアミノ)-5-(ヒドロキシメチル)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジオール;
(3aR,5R,6S,7R,7aR)-5-(アセトキシメチル)-2-(エチル(メチル)アミノ)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジイルジアセテート;
(3aR,5R,6S,7R,7aR)-2-(エチル(メチル)アミノ)-5-(ヒドロキシメチル)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジオール;
(3aR,5R,6S,7R,7aR)-5-(アセトキシメチル)-2-(メトキシアミノ)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジイルジアセテート;および
(3aR,5R,6S,7R,7aR)-5-(ヒドロキシメチル)-2-(メトキシアミノ)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジオール;
(3aR,5R,6S,7R,7aR)-5-(アセトキシメチル)-2-(メチルアミノ)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジイルジアセテート;
(3aR,5R,6S,7R,7aR)-5-(アセトキシメチル)-2-(プロピルアミノ)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジイルジアセテート;
(3aR,5R,6S,7R,7aR)-5-(アセトキシメチル)-2-(ブチルアミノ)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジイルジアセテート;
(3aR,5R,6S,7R,7aR)-5-(アセトキシメチル)-2-(ジメチルアミノ)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジイルジアセテート;
(3aR,5R,6S,7R,7aR)-2-(ジメチルアミノ)-5-(ヒドロキシメチル)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジオール;
(3aR,5R,6S,7R,7aR)-5-(アセトキシメチル)-2-(イソプロピルアミノ)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジイルジアセテート;および
(3aR,5R,6S,7R,7aR)-5-(アセトキシメチル)-2-(シクロヘキシルアミノ)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジイルジアセテート
からなる群から選択される化合物またはその医薬上許容される塩である、請求項12〜19のいずれかの医薬。 - 投与により対象におけるO-GlcNAcレベルが増大する、請求項12〜21のいずれかの医薬。
- 対象がヒトである、請求項12〜22のいずれかの医薬。
- 医薬の調製における式(I)の化合物またはその医薬上許容される塩の使用(ただし、(3aR,5R,6S,7R,7aR)-5-(アセトキシメチル)-2-(ジメチルアミノ)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジイルジアセテート;および(3aR,5R,6S,7R,7aR)-2-(ジメチルアミノ)-5-(ヒドロキシメチル)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジオールを除く):
R1はそれぞれ独立してHまたはC(O)CH3であり;
R2はNR4 2またはNR4OR4であり、ここで、R4はそれぞれ独立して、H、C1-10アルキル、C2-10アルケニル、およびシクロアルキルからなる群から選択され、H以外のこれらの基は、F、OHおよびOC(O)CH3からなる群から選択される1個から置換可能な最大個数までの置換基で置換されていてもよく;
R3はOHおよびOアシルからなる群から選択されるである]。 - 医薬が、O-GlcNAcアーゼを選択的に阻害するため、O-GlcNAcレベルを増加させるため、O-GlcNAcアーゼにより変調する症状を処置するため、神経変性疾患、タウオパチー、癌またはストレスを処置するためのものである、請求項24の使用。
- (3aR,5R,6S,7R,7aR)-5-(アセトキシメチル)-2-(メチルアミノ)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジイルジアセテート;
(3aR,5R,6S,7R,7aR)-5-(アセトキシメチル)-2-(プロピルアミノ)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジイルジアセテート;
(3aR,5R,6S,7R,7aR)-5-(アセトキシメチル)-2-(ブチルアミノ)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジイルジアセテート;
(3aR,5R,6S,7R,7aR)-5-(アセトキシメチル)-2-(イソプロピルアミノ)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジイルジアセテート;および
(3aR,5R,6S,7R,7aR)-5-(アセトキシメチル)-2-(シクロヘキシルアミノ)-5,6,7,7a-テトラヒドロ-3aH-ピラノ[3,2-d]チアゾール-6,7-ジイルジアセテート
からなる群から選択される1つ以上の化合物またはその医薬上許容される塩を医薬上許容される担体と組み合わせて含む、医薬組成物。
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WO2008025170A1 (en) | 2006-08-31 | 2008-03-06 | Simon Fraser University | Selective glycosidase inhibitors and uses thereof |
CA2732335A1 (en) | 2008-08-01 | 2010-02-04 | Simon Fraser University | Selective glycosidase inhibitors and uses thereof |
WO2010012107A1 (en) | 2008-08-01 | 2010-02-04 | Simon Fraser University | Selective glycosidase inhibitors and uses thereof |
US20110301217A1 (en) | 2008-09-16 | 2011-12-08 | David Jaro Vocadlo | Selective Glycosidase Inhibitors and Uses Thereof |
WO2011140640A1 (en) | 2010-05-11 | 2011-11-17 | Simon Fraser University | Selective glycosidase inhibitors and uses thereof |
WO2012061971A1 (en) | 2010-11-08 | 2012-05-18 | Alectos Therapeutics Inc. | Selective glycosidase inhibitors and uses thereof |
WO2012061927A1 (en) | 2010-11-08 | 2012-05-18 | Alectos Therapeutics, Inc. | Selective glycosidase inhibitors and uses thereof |
WO2012061972A1 (en) | 2010-11-08 | 2012-05-18 | Alectos Therapeutics Inc. | Selective glycosidase inhibitors and uses thereof |
AU2011349021B2 (en) | 2010-12-23 | 2016-12-22 | Alectos Therapeutics, Inc. | Selective glycosidase inhibitors and uses thereof |
US8927507B2 (en) | 2011-03-24 | 2015-01-06 | Ernest J. McEachern | Selective glycosidase inhibitors and uses thereof |
WO2012129651A1 (en) | 2011-03-31 | 2012-10-04 | Alectos Therapeutics Inc. | Selective glycosidase inhibitors and uses thereof |
WO2013000085A1 (en) | 2011-06-27 | 2013-01-03 | Alectos Therapeutics Inc. | Selective glycosidase inhibitors and uses thereof |
JP6147737B2 (ja) | 2011-06-27 | 2017-06-14 | アレクトス・セラピューティクス・インコーポレイテッド | 選択的グリコシダーゼ阻害剤およびその使用 |
US9701693B2 (en) | 2011-06-27 | 2017-07-11 | Alectos Therapeutics Inc. | Selective glycosidase inhibitors and uses thereof |
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2007
- 2007-08-31 WO PCT/CA2007/001554 patent/WO2008025170A1/en active Application Filing
- 2007-08-31 EP EP11157096.6A patent/EP2322529B1/en not_active Not-in-force
- 2007-08-31 CA CA2661582A patent/CA2661582C/en not_active Expired - Fee Related
- 2007-08-31 EP EP07800577A patent/EP2057171A4/en not_active Withdrawn
- 2007-08-31 AU AU2007291870A patent/AU2007291870B2/en not_active Ceased
- 2007-08-31 US US12/438,882 patent/US8334310B2/en active Active
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EP2322529A1 (en) | 2011-05-18 |
EP2057171A1 (en) | 2009-05-13 |
AU2007291870B2 (en) | 2012-12-06 |
EP2322529B1 (en) | 2017-12-06 |
JP2013213037A (ja) | 2013-10-17 |
CA2661582C (en) | 2015-09-29 |
WO2008025170A1 (en) | 2008-03-06 |
JP5380293B2 (ja) | 2014-01-08 |
US20120316207A1 (en) | 2012-12-13 |
AU2007291870A1 (en) | 2008-03-06 |
US20100016386A1 (en) | 2010-01-21 |
EP2057171A4 (en) | 2010-04-21 |
CA2661582A1 (en) | 2008-03-06 |
JP2010501598A (ja) | 2010-01-21 |
US8962664B2 (en) | 2015-02-24 |
WO2008025170B1 (en) | 2008-04-24 |
US8334310B2 (en) | 2012-12-18 |
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