TW201006814A - Substituted N-oxide pyrazine derivatives - Google Patents
Substituted N-oxide pyrazine derivatives Download PDFInfo
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- TW201006814A TW201006814A TW098121234A TW98121234A TW201006814A TW 201006814 A TW201006814 A TW 201006814A TW 098121234 A TW098121234 A TW 098121234A TW 98121234 A TW98121234 A TW 98121234A TW 201006814 A TW201006814 A TW 201006814A
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- -1 N-oxide pyrazine derivatives Chemical class 0.000 title claims abstract description 13
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 7
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Description
201006814 六、發明說明： 【發明所屬之技術領域】 本發明係關於用作藥劑活性成份之化合物，該藥劑可用 於預防性及/或治療性治療由GSK3p活性異常引起之神經 退化性疾病。 【先前技術】 GSK3 0(糖原合酶激酶3β)係脯胺酸引導之絲胺酸、蘇胺 酸激酶，其在控制新陳代謝、分化及存活方面起重要作 用。起初將其鑒定為能夠磷酸化並因此抑制糖原合酶的 酶。後來認識到GSK3P與tau蛋白激酶1(ΤΡΚ1)相同，ΤΡΚ1 係使表位中之tau蛋白質磷酸化的酶，亦發現該等表位在 阿滋海默氏病（Alzheimer's disease)及若干蛋白病 (taupathy)中過度磷·酸化。 令人感興趣的是，GSK3P之蛋白質激酶B(AKT)磷酸化 導致其激酶活性喪失，且已猜測此抑制可調節神經營養因 子之一些作用。另外，GSK3P使β-連環蛋白（與細胞存活有 關之蛋白質）磷酸化藉由遍在蛋白化依賴性蛋白酶體途徑 使β-連環蛋白降解。 因此，似乎抑制GSK3P活性可獲得神經營養活性。實際 上，有證據表明，經由引入諸如Bcl-2等存活因子並抑制 諸如p53及Bax等促凋亡因子之表現，鋰（GSK30之非競爭 性抑制劑）在一些模型中可增強神經發生且亦可增加神經 元存活。 最新研究證明β-澱粉樣蛋白可增加GSK3 0活性及tau蛋白 140533.doc 201006814 質磷酸化。另外，藉由氯化鋰及GSK3p反義mRNA來阻斷 β-澱粉樣蛋白之此過度磷酸化及神經毒性作用。該等觀察 結果有力地表明GSK30可能係阿滋海默氏病中兩個主要病 理過程間之紐帶：APP(澱粉樣前體蛋白）加工異常及tau蛋 白質過度磷酸化。 儘管tau過度磷酸化使得神經元細胞骨架不穩定，但 GSK3P活性異常之病理學後果很可能不僅係由於tau蛋白質 之病理磷酸化且如上文所述，亦係由於此激酶之過度活性 φ 可經由調節細胞凋亡因子及抗細胞凋亡因子之表現而影響 存活。另外，已顯示由β-澱粉樣蛋白誘導的GSK3P活性增 加導致丙酮酸脫氫酶之磷酸化且因此對其產生抑制作用， 丙酮酸脫氫酶係能量產生及乙醯膽鹼合成中之關鍵酶。 全部該等實驗觀察結果表明，發現GSK3P可用於治療與 阿滋海默氏病相關之神經病理後果及認知及注意缺陷、以 及其他急性與慢性神經退化性疾病及其他GSK3p失調之病 理（Nature reviews 第 3 卷，2004 年 6 月，第 479-487 頁； ❿ Trends in Pharmacological Sciences，第 25 卷第 9期，2004 年 9 月，第 471-480 頁；Journal of neurochemistry 2004，89, 1313-1317 ; Medicinal Research Reviews，第 22卷，第 4 期，373-384, 2002)。 神經退化性疾病以非限制性方式包含：帕金森氏病 (Parkinson's disease)、tau蛋白病變（例如額顧葉癡呆、皮 質基底核退化症、皮克氏病（Pick's disease)、進行性核上 麻療）、威爾森氏病（Wilson's disease)、亨庭頓氏病 140533.doc 201006814 (Huntington's disease)(The Journal of biological chemistry，第277卷，第37期，9月13日發行，第33791-33798 頁，2002)、朊病毒病（Biochem. J. 372，第 129-136 頁，2003)及其他癡呆症（包含血管性癡呆）；急性中風及其 他創傷性損傷；腦血管意外（例如年齡相關性黃斑變性）； 腦及脊髓創傷；肌萎縮性側索硬化（European Journal of Neuroscience，第 22卷，第 301-309 頁，2005)周邊神經病 變；視網膜病變及青光眼。最新研究亦顯示抑制GSK30可 導致胚胎幹細胞（ESC)之神經元分化並支持人類與小鼠 ESC之更新並維持其多能性。此表明GSK3p抑制劑可用於 再生醫學（Nature Medicine 10，第 55-63 頁，2004)。 亦發現GSK3P抑制劑可用於治療其他神經系統病症，例 如雙相型障礙（躁狂性抑鬱症）。舉例而言，已使用鋰作為 情緒穩定劑及雙相型障礙之初步治療有50餘年。在一定劑 量（1-2 mM)下可觀察到鋰的治療作用，其中鋰係GSK3P之 直接抑制劑。儘管尚不清楚鋰的作用機制，但可使用 GSK30抑制劑來模擬鋰的情緒穩定作用。Akt-GSK3P信號 傳導之改變亦與精神分裂症之發病機理有關。 此外，抑制GSK3P可用於治療癌症，例如結腸直腸癌、 前列腺癌、乳癌、非小細胞肺癌、曱狀腺癌、T或B-細胞 白血病及若干病毒誘導之腫瘤。舉例而言，已顯示結腸直 腸癌患者之腫瘤中GSK3P之活性形式升高，抑制結腸直腸 癌細胞中之GSK3P可活化p53-依賴性細胞凋亡並拮抗腫瘤 生長。抑制GSK30亦增強前列腺癌細胞系中TRAIL誘導之 140533.doc 201006814 細胞凋亡。GSK3P亦在有絲分裂紡錘體動力學中起作用， GSK30抑制劑可阻止染色體運動，導致微管穩定及前中期 樣停滯（prometaphase-like arrest)，類似於使用低劑量紫杉 醇（Taxol)所觀察者。GSK3P抑制劑之其他可能應用包含治 療非胰島素依賴性糖尿病（例如II型糖尿病）、肥胖症及脫 髮症。 人類GSK3P抑制劑亦可抑制pfGSK3，pfGSK3係於惡性 癦原蟲（尸中所發現之此酶之同源 .物，因此其可用於治療癌疾（Biochimica et Biophysica Acta 1697, 181-196, 2004)。 最近，人類遺傳學及動物研究二者均指出Wnt/LPR5途 徑為骨質增加之主要調節因子。抑制GSK3P導致隨後活化 典型Wnt信號傳導。由於Wnt信號傳導缺乏與骨質減少之 病症有關，故GSK30抑制劑亦可用於治療骨質減少之病 症、與骨相關之病狀、骨質疏鬆症。 根據最近資料，GSK3P抑制劑可用於治療或預防尋常天 馨 跑瘡（Pemphigus vulgaris)。 最近研究顯示GSK3 β抑制劑治療可增進嗜中性粒細胞與 巨核細胞恢復。因此，GSK30抑制劑可用於治療癌症化學 療法所引發之嗜中性白血球減少症。 先前研究已顯示GSK3P活性使LTP(記憶鞏固之電生理相 關物）減少，表明此酶之抑制劑可能具有促認知（pro-cognitive)活性。 發現化 合物之 促認知 作用可 用於治 療特徵 為記憶缺陷之阿滋海默氏病、帕金森氏病、年齡相關記憶 140533.doc 201006814 損傷、輕度認知損傷、腦創傷、精神分裂症及其他可觀察 到該等缺陷之病況。 亦發現GSK3p抑制劑可用於治療實質性腎病（Nels〇n PJ > Kidney International Advance online publication > 2007年12月19日）及預防或治療肌肉萎縮（J Bi〇丨chem (283) 2008, 358-366)。 【發明内容】 本發明目的係提供用作藥劑活性成份之化合物，該藥劑 係用於預防性及/或治療性治療由GSK3p活性異常引起的 疾病（更具體而言為神經退化性疾病）。更具體而言，該目 的係提供用作能夠預防及/或治療諸如阿滋海默氏病等神 經退化性疾病之藥劑活性成份的新穎化合物。 因此，本發明者已鑑別出對GSK3P具有抑制活性之化合 物。因此，其發現由下式⑴代表之化合物具有期望活性且 可用作用以預防性及/或治療性治療上述疾病之藥劑活性 化物t井衍生物或其Μ、其溶合物或其水合物： 因此’作為本發明目的，本發明提供由式⑴代表之N_氧
140533.doc 201006814 R2代表氫原子； R3代表氩原子； R4代表： -苯基c〗—3烷基，該基團視需要經丨至4個選自Ci 6烷基、鹵 素原子、C〗.2全自化烷基、Cl_3南化烷基、羥基、Ci 6烷氧 基、心_2全_化烷氧基、C1·6烷基磺醯基、硝基、氰基、 胺基、C!·6單烷基胺基或二烷基胺基、乙醯氧基、胺 基磺醯基之取代基取代；
R5代表氫原子； 其係呈游離鹼形式或與酸形成之加成鹽形式。 根據本發明另一態樣，提供一種藥劑，其包括選自由以 下物質組成之群之物質作為活性成份：由式⑴代表之N-氧 化物》比啡衍生物及其生理上可接受u其溶合物及其 水合物。作為藥劑之較佳實施例’其提供用於預防性及/ 或治療性治療由GSK邛活性異常引起之疾病的上述藥劑， 且提供用於預防性及/或治療性治療神經退化性疾病及（此 外）諸如以下等其他疾病的上述藥劑：非騰島素依賴性糖 尿病（例如_糖尿病）及肥胖症；心；雙相型障礙（躁狂 杜抑鬱症），精神分裂症；脫髮症或癌症（例如結腸直腸 癌、前列腺癌、乳癌、非小細胞性肺癌、甲狀腺癌、了或 B-細胞性自血病、若干病毒料之腔瘤及與骨相關之病 狀)」實質性腎病及肌肉萎縮；認知及記憶缺陷”亦發現 该藥劑可用於再生醫學中。 作為本發明之其他實施例，其提供上述藥劑，其令該等 140533.doc 201006814 疾病係神經退化性疾病並選自由以下疾病組成之群：阿滋 海默氏病、帕金森氏病、tau蛋白病變（例如額顳葉癡呆、 皮質基底核退化症、皮克氏病、進行性核上麻癖）、威爾 森氏病、亨庭頓氏病、脱病毒病及其他癡呆症（包含血管 性癡呆）；急性中風及其他創傷性損傷；腦血管意外（例如 年齡相關性黃斑變性）；腦及脊髓創傷；肌萎縮性側余硬 化；周圍神經病變；視網膜病變及青光眼，且上述藥劑呈 醫藥組合物形式，該醫藥組合物含有上述物質作為活性成 份連同一或多種醫藥添加劑。 作為本發明之其他實施例，其提供上述藥劑，其中與骨 相關之病狀係骨質疏鬆症。 本發明另外提供GSK3 β活性抑制劑，其包括選自由式⑴ 之Ν-氧化物吡畊衍生物及其鹽、及其溶合物及其水合物組 成之群之物質作為活性成份。 根據本發明其他態樣，提供用於預防性及/或治療性治 療由GSK3P活性異常引起之神經退化性疾病的方法，其^ 括向患者技與預防及/或治療有效量之物質的步驟，該物 質係選自由以下物質組成之群：式⑴之冰氧化物吡畊衍生 物及其生理上可接受之鹽、及其溶合物及其水合物；且提 供選自由式（I)之Ν-氧化物吡畊衍生物及其生理上可接受之 鹽、及其溶合物〗其水合物組成之群之物質在製造上述藥 劑中之用途。 本文所用之Cw烷基代表具有丨至6個碳原子之直鏈或具 支鏈基團或環烷基，其視需要經直鏈、具支鏈或環狀 140533.doc 201006814 烷基取代，例如甲基、乙基、正丙基、異丙基、正丁基、 異丁基、第二-丁基、第三-丁基、正戊基、異戊基、新戊 基、1，卜二曱基丙基、正己基、異己基、環丙基甲基及諸 如此類。 C2-u二烷基胺基代表經2個(^-6烷基取代之胺基，例如， -一曱基胺基、乙基甲基胺基、二乙基胺基、甲基丙基胺基 及二異丙基胺基及諸如此類； 「苯基Cw院基，該基團可視需要經取代」代表可選擇 φ 性地取代苯基Cw烷基之烷基部分或苯基部分。 離去基團L代表可易於斷裂及取代之基團；例如，此一 基團可為甲苯磺醯基、甲磺醯基、溴及諸如此類。 由上述式（I)代表之化合物可形成鹽。當存在酸性基團 時，鹽之實例包含鹼金屬及鹼土金屬（例如鋰、鈉、鉀、 鎂、及鈣）之鹽；氨及胺（例如甲基胺、二曱基胺、三甲基 胺、二環己基胺、叁（羥甲基）胺基曱烷、Ν,Ν-雙（羥乙基） 六氫吡畊、2-胺基·2-甲基-1-丙醇、乙醇胺、Ν-甲基葡萄 Φ 糖胺、及L-葡萄糖胺）之鹽；或與鹼性胺基酸（例如離胺 酸、δ-羥基離胺酸及精胺酸）形成之鹽。酸性化合物之鹼加 成鹽係藉由此項技術中所熟知之標準程序製得。 當存在鹼性基團時，實例包含與無機酸（例如氫氣酸、 氫溴酸）形成之鹽；與有機酸（例如乙酸、丙酸、酒石酸、 富馬酸、馬來酸、蘋果酸、草酸、琥珀酸、檸檬酸、苯曱 酸及諸如此類）形成之鹽。 鹼性化合物之酸加成鹽係藉由此項技術中所熟知之標準 140533.doc -11 - 201006814 ^ 其匕3(但不限於）將游離驗溶於含有適當酸之 醇水溶液中並藉由蒸發溶液分離出鹽，或藉由使游離驗與 酸在有機溶劑巾反應，在此情況下直接分離出帛，或使其 利用第—有機溶劑進行賴，或可藉由濃縮溶液獲得。可 用來製備酸加成鹽之酸較佳包含彼等當與游離驗結合時產 生醫藥上可接受之鹽（亦即其陰離子在鹽之醫藥劑量下對 動物有機體相對無害的鹽）的酸，以使游離鹼之固有有益 性質不因陰離子之副作用而受到損害^儘管較佳為驗性化 合物之醫學上可接受之鹽’但所有酸加成鹽均在本發明之 範圍内。 除由上述式⑴代表之N-氧化物吡畊衍生物及其鹽之外， 其溶合物及水合物亦屬於本發明之範圍。 由上述式（I)代表之N_氧化物吡啡衍生物可具有一或多個 不對稱碳原子。就該等不對稱碳原子之立體化學而言其 可獨立地呈（R)或（S)構型，且衍生物可作為立體異構體（例 如光學異構體、或非對映異構體）存在。任何純淨形式之 立體異構肖、任何立體異構體之混合物、外消旋異構體及 諸如此類均屬於本發明之範圍。 在本發明第一實施例_，提供化合物
其中： 140533.doc 201006814 R1代表4_吡啶環、鹵素原子； R2代表氫原子； R3代表氫原子； R4代表·苯基Ci _3烧基’該基團視需要經1至4個選自鹵素 原子、羥基之取代基取代； - R5代表氫原子； • 其係呈游離鹼形式或與酸形成之加成鹽形式。 本發明各化合物之實例顯示於下文表1中。然而，本發 • 明範圍並不限於該等化合物。命名法係根據IUPAC規則給 出。 本發明之又一目的包含表i如下文所定義之式之化合物 群： 1. N-(2-苯乙基）-6-0比咬-4-基η比哨·_2-胺4-氧化物 2· (+/-)2·[(4-氧離子基（oxid〇)-6-"比啶-4-基。比，井-2-基）胺基]- 1-苯乙醇 3· (+/-)6-2-[(6-氣-4-氧離子基η比畊_2_基）胺基]_卜苯乙醇 ® 4· 6_氣-Ν-(2-苯乙基）吡畊-2-胺4-氧化物 作為再一目的，本發明亦係關於製備由上述式⑴代表之 Ν-氧化物吡畊化合物的方法。 該等化合物可根據例如下文所闡釋之方法製得。 【實施方式】 由上述式（I)代表之Ν-氧化物吡畊化合物可根據反應圖！ 中所述之方法製得。 140533.doc -13· 201006814 ci
Cl
R3 (II) „ H R5—N \ R4 (III) R1 (IV)
反應圈1 (在以上反應圖中，R1、R2、R3、R4、R5之定義與對於 式（I)化合物已闡述之彼等定義相同）。 根據該方法，使式（III)之胺（其中R5及R4係如義式⑴之 ❹ 化合物所定義）與式（II)之化合物在常態空氣中在介於25。〇 至1 80°C間之適宜溫度下反應以獲得式（1)化合物。 當R1代表鹵素原子時，使式（H)化合物與式（IV)化合物 (其中Μ代表硼酸或甲錫烷基）反應。該反應可以眾所周知 之偶合反應（例如Suzuki或Stille反應）來實施以獲得式（〗）之 化合物。 馨 式（II)、（III)及（IV)之化合物可自市場購得或可根據熟習 此項技術者所熟知之方法合成。 本發明之化合物對GSK3p具有抑制活性。因Λ，本發明 化合物可作為活性成份用於製備藥劑，該_能夠預防性 及/或治療性治療由GSK3P活性異常引起的疾病且更具體 而言為諸如阿滋海默氏病等神經退化性疾病。此外，本發 明之化合物亦可作為活性成份本發 治療性治瘠以下左t达 用於預防性及/或 下疾病之_:神經退化性疾病，例如帕金 140533.doc -14. 201006814 森氏病、tau蛋白病變（例如額顳葉癡呆皮質基底核退化 症皮克氏病、進行性核上麻癖）、咸爾森氏病、亨庭頓 氏病、朊病毒病及其他癡呆症(包含血管性癡呆）；急性中 風及其他創傷性損傷；腦血管意外（例如年齡相關性黃斑 變座），腦及脊趙創傷；肌萎縮性側索硬化、周圍神經病 變；視網膜病變及青光眼；及其他疾病，例如非狹島素依 賴性糖尿病（例如^型糖尿病）及肥胖症；瘧疾、躁狂性抑 營症’精神刀裂症，脫髮症；癌症，例如結腸直腸癌、前 ❿ ~腺癌乳癌、非小細胞性肺癌、甲狀腺癌、T或B·細胞 性白血病、若干由病毒誘導之腫瘤及與骨相關之病狀；實 質性腎臟病或肌肉萎縮。亦發現該藥 *。亦發現該藥劑可用於治療或預防尋常型：炮:生Π 現該藥劑可用於治療由癌症化學療法引發之嗜中性白血球 減少症。亦發現該藥劑可用於治療性治療以認知與記憶缺 陷為特徵之疾病，例如阿滋海默氏病、帕金森氏病、年齡 才目關性記憶損傷、輕度認知損傷、腦創傷、精神分裂症及 ® 其他可觀察到該等缺陷之病況。 本發明進-步係關於治療GSK3 β活性異常所引起的神經 退化性疾病及上述疾病之方法，其包括向有需要之哺乳動 物投與有效量的式（I)化合物。 作為本發明藥劑之活性成份，可使用選自上述式（1)所表 之化合物及其藥理學上可接受之鹽、&其溶合物及其水合 物組成之群之物質。該物質本身可作為本發明之藥劑投 與，然而，期望以醫藥組合物形式投與該藥劑，該醫藥組 140533.doc 15 201006814 合物包括上述物質作為活性成份及一或多種醫藥添加劑。 作為本發明藥劑之活性成份，兩種或更多種上述物質可組 合使用。上述醫療組合物可補充用於治療上述疾病之另一 藥劑之活性成份。醫藥組合物類型沒有特別限制，該組合 物可以口服或非經腸投與之任何調配物提供。舉例而言， 該醫藥組合物可調配例如呈口服投與之醫藥組合物形式， 例如顆粒、細顆粒、粉末、硬膠囊、軟膠囊、糖漿、乳 『心浮液/谷液及諸如此類；或呈非經腸投與之醫藥組 合物形式，例如靜脈内、肌肉内、或皮下投與之注射劑、 點滴輸注液、經皮製劑、經黏膜製劑、鼻滴劑、吸入劑、 栓劑及諸如此類。注射劑或點滴輸注液可製成粉末製劑， 諸如呈凍乾製劑形式，可在即將使用前溶於諸如生理鹽水 等適宜水性介質中來使用。持續釋放製劑（例如塗佈聚合 物者）可直接經大腦内投與。 彼等熟習此項技術者可適當選擇用於製造醫藥組合物之 醫藥添加劑類型、醫藥添加劑相對於活性成份之含量比 率、及醫藥組合物之製備方法。可使用無機物或有機物或 固體物質或液體物質作為醫藥添加劑。通常，醫藥添加劑 可以基於活性成份重量介於i重量％至90重量％間之比率納 入0 用於製備固體醫藥組合物之賦形劑之實例包含（例如）乳 糖、蔗糖、殿粉、滑石粉、纖維素、糊精、高嶺土、碳酸 鈣及諸如此類。可使用諸如水或植物油等習用惰性稀釋劑 來製備口服投與用之液趙組合物。除惰性稀釋劑外，液體 140533.doc •16· 201006814 組合物可含有助劑，例如濕潤劑、懸浮助劑、甜味劑、芳 香著色劑 '及防腐劑。液體組合物可填充於由諸如明 膠等易吸收材料製成之膠囊中。用於製備非經腸投與組合 物（例如注射劑、栓劑）之溶劑或懸浮介質之實例包含水、 丙一醇、聚乙二醇、苄醇、油酸乙酯、卵磷脂及諸如此 類。栓劑所用基本材料之實例包含（例如）可可脂、乳化可 可脂、月桂酸脂質、威特普索（witepsol)。 對本發明藥劑之投與劑量及頻率並無特別限制，且可根 ® 據（例如）預防性及/或治療性治療之目的、疾病類型、患者 體重或年齡、疾病嚴重程度及諸如此類等狀況對其進行適 當選擇。通常’成人口服投與的曰劑量可為0.01-1，〇〇〇 mg(活性成份重量且該劑量可每天投與一次或作為分開 部分每天投與若干次，或若干天投與一次。當該藥劑用作 主射劑時，對成人較佳可以〇〇〇11〇〇 mg(活性成份重量） 之曰劑量連續或間歇地實施投與。 化學實例 ® 資例1 (表1之4號化合物） 6-氣_N-(2-笨乙基）吡畊_2•胺4_氧化物 將存於0.485 g(4.〇 mm〇l)苯乙胺中之〇.330 g(2 〇 mmol)2,6-二氣-吡_4_氧化物懸浮液在回流下攪拌1〇 min 〇 添加冷卻水且使用二氣曱烷來萃取混合物，藉由硫酸鈉 進行乾燥並將其蒸發至乾燥狀態。 藉由在矽膠上之使用比例為97/3/0.3之二氣甲烷/曱醇/二 140533.doc 201006814 乙胺混合物洗脫之層析來純化所得殘餘物，使用二乙醚進 行研磨’然後可得到0.370 g(74%)灰色固體純淨產物。
Mp: 142-143〇G RMN lH (CDC13; 200 MHz): δ (ppm) : 7.50 (s, 1H), 7.30-7.10 (m, 5H), 5.10 (br s, 1H), 3.60 (dd，2H)，2.90 (dd, 2H)。 實例2 (表1之1號化合物） N-(2-笨乙基）·6·吡啶_4_基吡畊-2-胺4-氧化物 將存於5 mL比例為5/1之乙醇/水混合物中之含有0.250 g (1.0 mmol)6-氣-N-(2-苯乙基）吡畊_2_胺4_氧化物、0.296 g (2.40 mm〇l)4-吡啶硼酸、0.60 mL(1.2 mmol)2 μ碳酸鈉水 溶液及0.116 g(〇.l mmol)四（三苯基膦）鈀的混合物在回 流下授拌16h。添加冷卻水且使用二氣甲烷來萃取混合 物’藉由硫酸鈉進行乾燥並將其蒸發至乾燥狀態。藉由在 矽膠上之使用比例為98/2/0.2之二氣甲烷/甲醇/二乙胺混合 物洗脫之層析來純化所得殘餘物，使用二乙醚進行研磨， 然後可得到0.05 8 g(20%)黃色固體純淨產物。
Mp: 184-185〇C RMN *H (CDCI3； 200 MHz): δ (ppm) : 8.70 (d，2H); 7.90 (s，1H); 7.70 (d, 2H); 7.45 (s, 1H); 7.30-7.00 (m, 5H); 4.80 (br t, 1H), 3.70 (m, 2H); 2.90 (t, 2H)。 為闌釋本發明，上述式（I)各化合物之化學結構及物理數 據之列表於表1中給出。該等化合物已根據各實例之方法 140533.doc 201006814 製得。 在表中，（Rot.)指示對映異構體化合物之左旋性或右旋 編猇 Rot R5\ r/ R1 R3 R2 Mp*C 亶 1 CU 1 Η 9 H H 184-185 游離鹼 2 (+/-) OH Η 9 H H 224-225 游離鹼 3 (+/-) OH Η Cl H H 175-176 游離鹼 4 CU 1 H Cl H H 142-143 游離鹼
測試實例；本發明藥劑對GSK3p之抑制活性： 可使用4種不同方案。 在第一方案中：在室溫下在GSK3P存在下將7.5 μΜ預填 140533.doc •19- 201006814 酸化 GS1 肽與 10 μΜ ATP(含有 300,000 cpm 33Ρ-ΑΤΡ)於 25 mM Tris-HCl(pH 7.5)、0.6 mM DTT、6 mM MgCl2、0.6 mM EGTA、0_05 mg/ml BSA緩衝液中培養1小時（總反應體 積：100微升）。 在第二方案中：在室溫下在GSK3p存在下將4.1 μΜ預磷 酸化 GS1 肽與 42 μΜ ΑΤΡ(含有 260,000 cpm 33Ρ-ΑΤΡ)於 80 mM Mes-NaOH(pH 6.5)、1 mM 乙酸镁、0.5 mM EGTA、5 mM 2-毓基乙醇、0.02% Tween 20、10%甘油緩衝液中培
養2小時。 在第三方案中：在室溫下在GSK3P存在下將7.5 μΜ預磷 酸化 GS1 肽與 10 μΜ ΑΤΡ(含有 300,000 cpm 33Ρ-ΑΤΡ)於 50 mM Hepes(pH 7.2)、1 mM DTT、1 mM MgCl2、1 mM EGTA、0.01% Tween 20緩衝液中培養1小時（總反應體積： 100微升）。
在第四方案中：在室溫下在市售GSK3p(Millipore)存在 下將7.5 μΜ預磷酸化GS1肽與10 μΜ ATP(含有3 00,000 cpm 33P-ATP)於 50 mM Hepes(pH 7.2)、1 mM DTT、1 mM MgCl2、1 mM EGTA、0.01% Tween 20緩衝液中培養90分 鐘（總反應體積：100微升）。 將抑制劑溶於DMSO中（反應介質中之最終溶劑濃度為 1%)。 用100微升由25 g聚磷酸（85% P205)組成之溶液、126 ml 85%1^3?04終止反應，用1120補足至500 〇11且然後在使用前 將其稀釋至1:1〇〇。然後將反應混合物之等分試樣轉移至 140533.doc -20- 201006814
Whatman P8 1陽離子交換過濾器中並用上述溶液進行沖 洗。藉由液體閃爍光譜測定所納入之33P放射性。 磷酸化GS-1肽具有以下序列： NH2-YRRAAVPPSPSLSRHSSPHQS(P)EDEE-COOH.(Woodgett, J. R. (1989) Analytical Biochemistry 180, 237-241). 用IC5〇表示本發明化合物之GSK30抑制活性，且如表1中 各化合物之IC5〇範圍所示，其介於0.1毫微莫耳至3微莫耳 濃度之間。 ^ 舉例而言， 0.506 μΜ 〇 在第3方案中，表1之2號化合物顯示IC50為 調配物實例 (1)錠劑 藉由常用方法混合以下成份並使用習用裝置將其壓製。 實例1化合物 30 mg 結晶纖維素 60 mg 玉米澱粉 100 mg # 乳糖 200 mg 硬脂酸鎂 4 mg (2)軟膠囊 藉由常用方法混合以下成份並將其填充至軟膠囊中。 實例1化合物 30 mg 橄欖油 300 mg 卵填脂 20 mg (3)非經腸製劑 140533.doc -21 - 201006814 藉由常用方法混合以下成份以製備包含於i mi安瓿中之 注射劑。 實例1化合物 3 mg 氣化納 4 mg 注射用蒸館水 1 ml 工業應用性 本發明化合物具有GSK3p抑制活性並可用作藥劑之活性 成份’該藥劑可用於預防性及/或治療性治療由仍聯活 欧異常引起的疾病且更具體而言係神經退化性疾病。
140533.doc 22·
Claims (1)
- 201006814 七、申請專利範困： 1. 一種式（I)所表之N_氧化物吡畊衍生物或其鹽或其溶合 物或其水合物：(I) 其中： R1代表4-吡啶環、鹵素原子； R2代表氫原子； R3代表氫原子； R4代表： 苯基C!—3烷基，該基團視需要經1至4個選自c16烧基、_ 素原子、Cw全鹵化烧基、c!—3鹵化烧基、羥基、（^_6院 氧基、Ck全鹵化烷氧基、Cl_6烷基磺醯基、硝基、氰 基、胺基、Cw單烷基胺基或Cm二烷基胺基、乙醯氧 基、胺基續酿基之取代基取代； R5代表氫原子； 呈游離鹼形式或與酸之加成鹽形式。 2. 一種式（I)所表之N-氧化物吡畊衍生物或其鹽、或其溶合 物或其水合物R4 R3 ⑴ 140533.doc 201006814 其中： R1代表4-吡啶環、鹵素原子； R2代表氫原子； R3代表氫原子； R4代表：笨基Cl3烷基，該基團視需要經1至4個選自鹵 素原子、羥基之取代基取代； R5代表氫原子； 呈游離驗形式或與酸之加成鹽形式。 3 ·如請求項1或2之N-氧化物吡畊衍生物或其鹽、或其溶合 物或其水合物，其係選自由下列組成之群： N-(2-苯乙基）_6_吡啶_4_基吡畊_2_胺4_氧化物 (+/-)2-[(4-氧離子基（oxid〇)-6-"比咬-4-基吼畊_2_基）胺基]· 1-苯乙醇 (+/-)6-2·[(6-氣-4-氧離子基》比啡基）胺基]]_笨乙醇 6-氣-Ν-(2-苯乙基）吼ρ井_2_胺4·氧化物。 4. 一種藥劑，其包含一種選自由下列組成之群的物質作為 活性成份：如請求項丨至3中任一項之式⑴所表之Ν氧化 物吼畊衍生物或其鹽、或其溶合物或其水合物。 5. —種GSK3(3抑制劑’其係選自如請求項i之式⑴所表之 N-氧化物㈣衍生物或其鹽、或其溶合物或其水合物之 6. 如請求項1或2之化合物，其係用於預防性及/或 療由GSK3P活性異常所引起的疾病。 治療性治如請求項1或2之化合物 其係用於預防性及/或治療性治 140533.doc -2- 201006814 療神經退化性疾病。 8.如請求項1或2之化合物，其中該神經退化性疾病係選自 由下列組成之群：阿滋海默氏病（Alzheimer's disease)、 帕金森氏病（Parkinson’s disease)、tau蛋白病變 (tauopathies)、血管性癡呆；急性中風、創傷性損傷； 腦血管意外、腦髓創傷、脊髓創傷；周圍神經病變；視 網膜病變或青光眼。 9·如請求項1至2之化合物，其係用於預防性及/或治療性治 ❿ 療非胰島素依賴型糖尿病；肥胖症；躁鬱（manic depressive)症；精神分裂症；脫髮症（al〇pecia);癌症； 實質性腎臟病或肌肉萎縮。 1〇·如請求項9之化合物，其中癌症係乳癌、非小細胞肺 癌甲狀腺癌、T或B-細胞白血病或由病毒誘導之腫 瘤。 11.如請求項丨或2之化合物，其係用於預防性及/或治療性治 療瘧疾。 鲁12·如請求項1或2之化合物，其係用於預防性及/或治療性治 療骨疾病。 13. 如明求項丨或2之化合物，其係用於預防性及/或治療性治 療尋常型天皰瘡（Pemphigus vulgaris)。 。 14. 如明求項丨或2之化合物，其係用於預防性及/或治療性治 療癌症化學療法所引發之嗜中性白血球減少症。 〇 15·如„月求項！或2之化合物其係用於治療性治療以認知與 記憶缺陷為特徵之疾病。 、 140533.doc 201006814 四、指定代表圖： (一) 本案指定代表圖為：（無） (二) 本代表圖之元件符號簡單說明： 五、本案若有化學式時，請揭示最能顯示發明特徵的化學式： ❹ ❹ R1140533.doc
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| SI (1) | SI2321286T1 (zh) |
| TW (1) | TW201006814A (zh) |
| WO (1) | WO2009156857A1 (zh) |
| ZA (1) | ZA201009267B (zh) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2138492A1 (en) * | 2008-06-26 | 2009-12-30 | Sanofi-Aventis | Substituted pyrimidin-4-one derivatives |
| EP2138498A1 (en) * | 2008-06-26 | 2009-12-30 | sanofi-aventis | Substituted tricyclic derivatives against neurodegenerative diseases |
| EP2138495A1 (en) * | 2008-06-26 | 2009-12-30 | sanofi-aventis | Substituted pyrimido[2,1-a]isoquinolin-4-one derivatives |
| EP2138494A1 (en) | 2008-06-26 | 2009-12-30 | Sanofi-Aventis | Substituted alkyl pyrimidin-4-one derivatives |
| EP2138488A1 (en) * | 2008-06-26 | 2009-12-30 | sanofi-aventis | 4-(pyridin-4-yl)-1H-[1,3,5]triazin-2-one derivatives as GSK3-beta inhibitors for the treatment of neurodegenerative diseases |
| EP2138493A1 (en) * | 2008-06-26 | 2009-12-30 | Sanofi-Aventis | Substituted pyrimidone derivatives |
| US8530413B2 (en) | 2010-06-21 | 2013-09-10 | Sanofi | Heterocyclically substituted methoxyphenyl derivatives with an oxo group, processes for preparation thereof and use thereof as medicaments |
| TW201215388A (en) | 2010-07-05 | 2012-04-16 | Sanofi Sa | (2-aryloxyacetylamino)phenylpropionic acid derivatives, processes for preparation thereof and use thereof as medicaments |
| TW201221505A (en) | 2010-07-05 | 2012-06-01 | Sanofi Sa | Aryloxyalkylene-substituted hydroxyphenylhexynoic acids, process for preparation thereof and use thereof as a medicament |
| TW201215387A (en) | 2010-07-05 | 2012-04-16 | Sanofi Aventis | Spirocyclically substituted 1,3-propane dioxide derivatives, processes for preparation thereof and use thereof as a medicament |
| WO2013037390A1 (en) | 2011-09-12 | 2013-03-21 | Sanofi | 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
| WO2013045413A1 (en) | 2011-09-27 | 2013-04-04 | Sanofi | 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
| WO2014106606A1 (en) * | 2013-01-05 | 2014-07-10 | F. Hoffmann-La Roche Ag | Nove phenyl/pyridine series substitued by hydroxyethylamino for the treatment of cancer |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5170780A (ja) | 1974-12-17 | 1976-06-18 | Nippon Shinyaku Co Ltd | Shinkinabenzoguanidoruino seiho |
| EG13192A (en) | 1976-02-10 | 1982-12-31 | Rhone Poulenc Ind | Nouveaux derives du dithiole-1,2 leur preparation et les compositions qui les contiennent |
| HU178496B (en) * | 1977-12-29 | 1982-05-28 | Chinoin Gyogyszer Es Vegyeszet | Process for preparing 6,7,8,9-tetrahydro-4h-pyrido/1,2-a/pyrimidine derivatives with antiallergic activity |
| US4406897A (en) * | 1981-07-06 | 1983-09-27 | William H. Rorer, Inc. | 6-Aryl-4-hydrazinyl-s-triazin-2-ones |
| US4804663A (en) * | 1985-03-27 | 1989-02-14 | Janssen Pharmaceutica N.V. | 3-piperidinyl-substituted 1,2-benzisoxazoles and 1,2-benzisothiazoles |
| US5629322A (en) | 1994-11-15 | 1997-05-13 | Merck & Co., Inc. | Cyclic amidine analogs as inhibitors of nitric oxide synthase |
| EP0861238A4 (en) | 1995-11-01 | 2000-03-01 | Merck & Co Inc | HEXAHYDRO-5-IMINO-1,4-HETEROAZEPINE DERIVATIVES AS INHIBITORS OF NITROGEN OXIDE SYTHASE |
| IL123986A (en) | 1997-04-24 | 2011-10-31 | Organon Nv | Medicinal compounds |
| EP1136484A1 (en) | 2000-03-23 | 2001-09-26 | Sanofi-Synthelabo | 2-(Arylalkylamino)pyrimidone derivatives |
| CA2445697A1 (en) | 2001-04-26 | 2002-11-07 | Daiichi Pharmaceutical Co., Ltd. | Drug efflux pump inhibitor |
| US7388005B2 (en) | 2001-09-21 | 2008-06-17 | Sanofi-Aventis | Substituted 2-pyrimidinyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 7-pyrimidinyl-2,3-dihydroimidazo [1,2-a]pyrimidin-5(1H)one derivatives for neurodegenerative disorders |
| EP1537102A4 (en) | 2002-08-16 | 2010-12-08 | Astrazeneca Ab | INHIBITORS OF PHOSPHOINOSITIDE-3-KINASE BETA |
| SE0203754D0 (sv) * | 2002-12-17 | 2002-12-17 | Astrazeneca Ab | New compounds |
| EP1454909B1 (en) | 2003-03-07 | 2008-08-20 | Sanofi Aventis | 8'-pyridinyl-dihydrospiro- (cycloalkyl) -pyrimido (1,2-a) pyrimidin-6-one and 8'-pyrimidinyl-dihydrospiro (cycloalkyl) -pyrimido (1,2-a) pyrimidin-6-one derivatives and their use against neurodegenerative diseases |
| EP1460076A1 (en) | 2003-03-21 | 2004-09-22 | Sanofi-Synthelabo | Substituted 8-perfluoroalkyl-6,7,8,9-tetrahydropyrimido[1,2-a] pyrimidin-4-one derivatives |
| EP1790649A1 (en) | 2005-11-21 | 2007-05-30 | Sanofi-Aventis | Substituted bicyclic pyrimidone derivatives |
| WO2007067790A2 (en) | 2005-12-09 | 2007-06-14 | Brunswick Bowling & Billiards Corporation | Bowling ball having an rfid tag |
| EP2138494A1 (en) * | 2008-06-26 | 2009-12-30 | Sanofi-Aventis | Substituted alkyl pyrimidin-4-one derivatives |
| EP2138495A1 (en) * | 2008-06-26 | 2009-12-30 | sanofi-aventis | Substituted pyrimido[2,1-a]isoquinolin-4-one derivatives |
| EP2138492A1 (en) * | 2008-06-26 | 2009-12-30 | Sanofi-Aventis | Substituted pyrimidin-4-one derivatives |
| EP2138488A1 (en) * | 2008-06-26 | 2009-12-30 | sanofi-aventis | 4-(pyridin-4-yl)-1H-[1,3,5]triazin-2-one derivatives as GSK3-beta inhibitors for the treatment of neurodegenerative diseases |
| EP2138493A1 (en) * | 2008-06-26 | 2009-12-30 | Sanofi-Aventis | Substituted pyrimidone derivatives |
-
2008
- 2008-06-26 EP EP08290619A patent/EP2138485A1/en not_active Withdrawn
-
2009
- 2009-06-24 AR ARP090102317A patent/AR072229A1/es unknown
- 2009-06-24 TW TW098121234A patent/TW201006814A/zh unknown
- 2009-06-25 EP EP09769668A patent/EP2321286B1/en active Active
- 2009-06-25 CN CN2009801242842A patent/CN102076669A/zh active Pending
- 2009-06-25 AT AT09769668T patent/ATE545635T1/de active
- 2009-06-25 SI SI200930255T patent/SI2321286T1/sl unknown
- 2009-06-25 JP JP2011515665A patent/JP5409783B2/ja not_active Expired - Fee Related
- 2009-06-25 WO PCT/IB2009/006445 patent/WO2009156857A1/en not_active Ceased
- 2009-06-25 EA EA201170093A patent/EA201170093A1/ru unknown
- 2009-06-25 KR KR1020117001903A patent/KR20110028367A/ko not_active Withdrawn
- 2009-06-25 PT PT09769668T patent/PT2321286E/pt unknown
- 2009-06-25 ES ES09769668T patent/ES2382677T3/es active Active
- 2009-06-25 CA CA2728680A patent/CA2728680A1/en not_active Abandoned
- 2009-06-25 DK DK09769668.6T patent/DK2321286T3/da active
- 2009-06-25 NZ NZ590047A patent/NZ590047A/en not_active IP Right Cessation
- 2009-06-25 BR BRPI0914676A patent/BRPI0914676A2/pt not_active IP Right Cessation
- 2009-06-25 AU AU2009263843A patent/AU2009263843A1/en not_active Abandoned
- 2009-06-25 MX MX2010013939A patent/MX2010013939A/es unknown
- 2009-06-25 PL PL09769668T patent/PL2321286T3/pl unknown
-
2010
- 2010-12-15 US US12/968,958 patent/US8202874B2/en not_active Expired - Fee Related
- 2010-12-22 IL IL210170A patent/IL210170A0/en unknown
- 2010-12-23 ZA ZA2010/09267A patent/ZA201009267B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CA2728680A1 (en) | 2009-12-30 |
| ATE545635T1 (de) | 2012-03-15 |
| IL210170A0 (en) | 2011-03-31 |
| US20110136828A1 (en) | 2011-06-09 |
| DK2321286T3 (da) | 2012-06-11 |
| MX2010013939A (es) | 2011-09-27 |
| ES2382677T3 (es) | 2012-06-12 |
| JP2011525903A (ja) | 2011-09-29 |
| AR072229A1 (es) | 2010-08-11 |
| CN102076669A (zh) | 2011-05-25 |
| KR20110028367A (ko) | 2011-03-17 |
| SI2321286T1 (sl) | 2012-06-29 |
| PL2321286T3 (pl) | 2012-07-31 |
| WO2009156857A1 (en) | 2009-12-30 |
| EP2138485A1 (en) | 2009-12-30 |
| NZ590047A (en) | 2011-11-25 |
| US8202874B2 (en) | 2012-06-19 |
| JP5409783B2 (ja) | 2014-02-05 |
| PT2321286E (pt) | 2012-05-02 |
| BRPI0914676A2 (pt) | 2015-10-20 |
| ZA201009267B (en) | 2012-03-28 |
| EA201170093A1 (ru) | 2011-06-30 |
| AU2009263843A1 (en) | 2009-12-30 |
| EP2321286B1 (en) | 2012-02-15 |
| EP2321286A1 (en) | 2011-05-18 |
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