TW200838502A - Triazole derivative - Google Patents
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- TW200838502A TW200838502A TW097101845A TW97101845A TW200838502A TW 200838502 A TW200838502 A TW 200838502A TW 097101845 A TW097101845 A TW 097101845A TW 97101845 A TW97101845 A TW 97101845A TW 200838502 A TW200838502 A TW 200838502A
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- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Description
200838502 九、發明說明: 【發明所屬之技術領域】 本發明係基於發現具有有價值特性之新穎化合物之目 標’尤其彼等可用於製備藥物者。 本發明係關於與HSP90之抑制、調控及/或調節作用相關 之化合物,此外係關於包含此化合物之醫藥組合物,且係 關於該化合物用於治療與HSP9〇相關之疾病的用途。 【先前技術】 細胞中蛋白之正確摺疊及構形係由分子伴隨蛋白確保且 對於蛋白合成與降解之間的平衡調控而言至關重要。伴隨 蛋白對細胞之許多主要功能之調控而言為重要的,諸如細 胞增殖及細胞凋亡(Jolly及M〇rimoto,2000 ; Smith等人, 1998 ; Smith, 2001) 〇 熱休克蛋白(HSP) 組織之細胞對諸如熱、低氧、氧化應力或毒性物質(諸 如重金屬或醇)之外應力起反應,使稱為術語,,熱休克蛋白,, (HSP)之眾多伴隨蛋白活化。 HSP之活化保護細胞免受由該等應力因素引發之破壞, 加速生理學狀態之恢復且導致細胞對應力耐受之狀態。 除此初始發現的由HSP促進之對抗外應力之保護機制 外’其他重要伴隨蛋白功能亦已描述於個別^81>在正常無 應力條件下之時間過程中。因此,各種HSp調控(例如)細 胞之眾多生物重要蛋白的正確摺疊、胞内定位及功能或受 調控降解。 127120.doc 200838502 HSP形成一個基因家族,其中個別基因產物之細胞表 現、功能及定位在不同細胞中不同。該家族之命名及分類 係基於其分子量而進行,例如HSP27、HSP70及HSP90。 一些人類疾病係基於錯誤蛋白摺疊(參見(例如)Tytell等 人,2001 ; Smith等人,1998之綜述)。與伴隨蛋白依賴性 蛋白摺疊之機制吻合的療法研發因此可適用於該等狀況 下。舉例而言,錯誤摺疊之蛋白導致在阿茲海默症 (Alzheimer's disease)、朊病毒症或亨廷頓症候群(Himtington’s syndrome)狀況中神經退化性進展之蛋白聚集。錯誤蛋白 摺疊亦可導致喪失野生型功能,此可具有錯誤調控分子及 生理學功能之結果。 HSP在腫瘤疾病中亦具有較大重要性。舉例而言,存在 某些HSP關係之表現與腫瘤進展階段相關之指示(Martin等 人,2000 ; Conroy 等人,1996 ; Kawanishi 等人,1999 ; Jameel 等人,1992 ; Hoang 等人,2000 ; Lebeau 等人, 1991) 〇 HSP90在細胞中及某些具有抑癌活性標靶HSP90之天然 產物的眾多主要致癌信號轉導路徑中起作用之事實已產生 如下概念:HSP90之功能抑制在腫瘤疾病治療中將為明智 的。HSP90抑制劑17-烯丙基胺基-17-去甲氧基格爾德黴素 (17AAG)(格爾德黴素(geldanamycin)衍生物)目前正經歷臨 床試驗。 HSP90 HSP90代表約1-2%總細胞蛋白質量。其一般在細胞内為 127120.doc 200838502 二聚體形式且與蛋白多樣性有關,稱作輔助伴隨蛋白(參 見(例如)Pratt,1997)。HSP90對細胞生命力而言必不可少 (Young等人,2001),且藉由與許多天然摺疊已由外應力 (諸如,熱休克)修飾之蛋白相互作用而在對細胞應力之反 應中起關鍵作用,從而儲存原始摺疊或防止蛋白聚集 (Smith等人,1998)。 亦表明由突變引起之錯誤蛋白摺疊之校正推測,HSP90 作為針對突變作用之緩衝劑具有重要性(Rutherford及 Lindquist,1998)。此外,HSP90亦具有調控重要性。在生 理學條件下,HSP90以及其内質網同系物GRP94在確保各 種關鍵客戶蛋白之構形穩定性及成熟的細胞平衡中起作 用。此等可分為三組:類固醇激素之受體,Ser/Thr或酪胺 酸激酶(例如ERBB2、RAF-1、CDK4及LCK)及多種蛋白之 集合(諸如突變p53或端粒酶hTERT之催化子單元)。此等蛋 白中之每一者在細胞之生理學及生化過程之調控中起關鍵 作用。人體内之保留HSP90家族由四種基因組成,即胞質 HSP90oc、誘導性HSP90p同功異型物(Hickey等人, 1989)、内質網中之GRP94(Argon等人,1999)及粒線體基 質中之HSP75/TRAP1 (Felts等人,2000)。假定該家族之所 有成員具有類似作用模式,但視其在細胞内之定位而與不 同客戶蛋白結合。舉例而言,ERBB2為GRP94之特異性客 戶蛋白(Argon等人,1999),同時已發現腫瘤壞死因子之1 型受體(TNFR1)或視網膜母細胞瘤蛋白(Rb)為TRAP1之客 戶(Song等人,1995 ; Chen等人,1996)。 127120.doc 200838502 HSP90涉及大量客戶蛋白及調控蛋白之眾多複雜相互作 用(Smith,2001)。儘管尚未闡明精確分子細節,但近年來 藉助於X光結晶學之生化實驗及研究已愈加能夠譯解 HSP90之伴隨蛋白功能的細節(Prodromoii等人,1997 ; Stebbins等人,1997)。因此,HSP90為一種ATP依賴性分 子伴隨蛋白(Prodromoii等人,1997),其中二聚作用對ATP 水解而言為重要的。ATP之結合導致環形二聚體結構之形 成,其中兩個N末端結構域彼此緊密接觸且在構形中起開 關作用(Prodromou及 Pearl,2000)。 已知HSP90抑制劑 待發現之第一類HSP90抑制劑為苯醌安莎黴素 (ansamycin)及化合物除莠黴素A(herbimycin A)及格爾德黴 素(geldanamycin)。最初,對其摘測到由v-Src致癌基因之 轉型作用引發之纖維母細胞中之惡性表型的反轉(Uehara 等人,1985)。 隨後,在動物模型内活體外(Schulte等人,1998)及活體 内(Supko等人,1995)證明有強抗腫瘤活性。 接著,免疫沈澱及對親和基質之研究展示格爾德黴素作 用之主要機制涉及與HSP90結合(Whitesell等人,1994 ; Schulte及Neckers,1998)。此外,X光結晶學研究已展示格 爾德黴素為ATP結合部位而競爭且抑制118?90之固有 ATPase 活性(Prodromoii 等人,1997 ; Panaretou 等人, 1998)。藉此防止多聚體HSP90錯合物之形成,其特性為充 當客戶蛋白之伴隨蛋白。因此,客戶蛋白經泛素蛋白酶體 127120.doc 200838502 路徑降解。 格爾德黴素衍生物17-烯丙基胺基_17-去甲氧基格爾德黴 素(17AAG)在HSP90抑制、客戶蛋白之降解及細胞培養及 異種移植腫瘤模型中之抗腫瘤活性中展示不變之特性 (Schulte等人,1998 ; Kelland等人,1999),但比格爾德黴 素具有顯著低之肝細胞毒性(Page等人,1997)。17AAG目 ^ 前正經歷I/II期臨床試驗。 根赤殼菌素(Radicicol)(—種巨環抗生素)同樣展示V-Src ⑩ 及v-Ha_Ras引發之纖維母細胞惡性表型的反轉(Kwon等 人,1992 ; Zhao等人,1995)。根赤殼菌素因HSP90抑制而 使大量信號蛋白降解(Schulte等人,1998)。X光結晶學研 究已展示根赤殼菌素同樣與HSP90之N末端結構域結合且 抑制固有ATPase活性(Roe等人,1998)。 如已知,香豆素型抗生素在細菌中與HSP90同系DNA旋 轉酶之ATP結合部位結合。香豆素、新生黴素(Novobiocin) 0 與HSP90之羧基末端結合,亦即與不同於苯醌安莎黴素及 根赤殼菌素(其與HSP90之N末端結合)之HSP90部位結合 (Marcu等人,2000b)。 • 新生黴素對HSP90之抑制導致大量HSP90依賴性信號蛋 . 白降解(Marcu等人,2000a)。 證明例如ERBB2之信號蛋白之降解使用衍生自嘌呤之 HSP90抑制劑PU3。PU3引起乳癌細胞株之細胞週期停滯及 分化(Chiosis等人,2001)。 作為治療標靶之HSP90 127120.doc -10- 200838502 由於HSP90參與大量信號轉導路徑之調控(其對腫瘤表型 具有至關重要性)且發現某些天然產物經HSP90之活性抑制 發揮其生物作用,因此HSP90目前測試為腫瘤治療劑研發 之新穎標靶(Neckers等人,1999)。 格爾德黴素、17AAG及根赤殼菌素之主要作用機制包括 抑制ATP與ATP結合部位在蛋白N末端之結合及HSP90之固 有ATPase活性的所得抑制(參見(例如)Prodromoii等人, 1997 ; Stebbins 等人,1997 ; Panaretou 等人,1998) 〇 HSP90之ATPase活性抑制防止輔助伴隨蛋白的募集且有利 於形成HSP90雜絡物,此使客戶蛋白經由泛素-蛋白酶體路 徑經歷降解(參見(例如)Neckers等人,1999 ; Kelland等 人,1999)。以HSP90抑制劑處理腫瘤細胞導致對諸如細胞 增殖、細胞週期調控及細胞凋亡之過程具有基本重要性的 重要蛋白的選擇性降解。此等過程通常在腫瘤中解除(參 見(例如)Hostein等人,2001)。HSP90抑制劑研發值得關注 的基本原理為可藉由複數種與經轉型表型有關的蛋白之同 時降級達成強腫瘤治療作用。 詳言之,本發明係關於一種抑制、調控及/或調節HSP90 之化合物,係關於包含此化合物之組合物,且係關於將其 用於治療HSP90引發之疾病的方法,該等疾病諸如腫瘤疾 病、病毒疾病(諸如B型肝炎(Waxman,2002));移植之免疫 抑制(Bijlmakers,2000及Yorgin,2000);發炎引發之疾病 (Bucci,2000),諸如類風濕性關節炎、哮喘、多發性硬 化、1型糖尿病、紅斑性狼瘡症、牛皮癣及發炎性腸病; 127120.doc -11. 200838502 囊腫性纖維化(Fuller,2000) ’·與血管生成有關之疾病 2002及Kurebayashi,2001),諸如糖尿病性視網膜病變、血 管瘤、子宮内膜異位症及腫瘤血管生成;傳染病;自體免 疫疾病,·局部缺血;促進神經再生(R〇sen等人,w〇
02/09696 ; Degranco 等人,WO 99/51223 ; Gold,US 6,210,974 Bl);致纖維化疾病,諸如硬皮症、多發性肌 炎、全身性狼瘡症、肝硬化、瘢痕瘤形成、間質性腎炎及 肺纖維化(Strehlow,WO 02/02123)。本發明亦係關於本發 明化合物用於保護正常細胞免於化學療法引起之毒性的用 途,且係關於在錯誤蛋白摺疊或聚集為主要誘因之疾病中 的用途,該等疾病諸如綿羊癢病、庫賈氏病(Creutzfeldt_ Jakob disease)、亨廷頓症或阿茲海默症(siuler,Hum. M〇1
Genet” 10,1307,2001 ; Tratzelt等人,?1*0(:.心1八。&(1·
Sci·,92, 2944, 1995 ; Winklhofer等人,J· Biol· Chem·, 276, 45160, 2001)。WO 01/72779描述嘌呤化合物及其用於 冶療GRP94(HSP90之同系物或旁系同源物)引發之疾病(諸 如腫瘤疾病)的用途,其中癌症組織包括選自由以下癌症 組成之群的肉瘤或癌瘤:纖維肉瘤、黏液肉瘤、脂肉瘤、 軟骨肉瘤、骨肉瘤、脊索瘤、血管肉瘤、内皮肉瘤、淋巴 管肉瘤、淋巴管内皮瘤、滑膜瘤、間皮瘤、尤因氏瘤 (Ewing’s tumour)、平滑肌瘤、橫紋肌肉瘤、結腸癌、胰腺 癌、乳癌、卵巢癌、前列腺癌、鱗狀細胞癌、基底細胞 癌、腺癌、汗腺癌、皮脂腺癌、乳頭狀癌、乳頭狀腺癌、 囊腺癌、骨髓癌、支氣管癌、腎細胞癌、肝癌、膽管癌、 127120.doc -12- 200838502 賊膜癌、精原細胞瘤、胚胎癌、威姆氏瘤(Wilm,s tumour)、子宮頸癌、睾丸瘤、肺癌、小細胞肺癌、膀胱 癌、上皮癌、膠質瘤、星形細胞瘤、神經管胚細胞瘤、顱 咽管瘤、室管膜瘤、松果體瘤、血管母細胞瘤、聽神經 瘤、少枝膠質瘤、腦膜瘤、黑素瘤、神經母細胞瘤、視網 膜胚細胞瘤、白血病、淋巴瘤、多發性骨髓瘤、瓦爾登斯 特倫巨球蛋白血症(Waldenstr6m,s macroglobulinaemia)及 重鏈疾病。 A· Kamal 等人在 Trends in Molecular Medicine,第 1〇 卷’第6期,2004年6月中描述HSP90活化之治療及診斷應 用’尤其用於治療中樞神經系統疾病及心血管疾病。 特異性抑制、調控及/或調節HSP9〇之小化合物的鑑別因 此為所要的且為本發明之一目標。 已發現5-[4-(2-曱基苯基羥基-4H-1,2,4-噻唑-5-基> 2,4-二羥基-N-曱 基—N—丁基苯甲醯胺及其鹽具有極有價值 的藥理學特性,同時係良好耐受的。詳言之,其展示 HSP90抑制特性。 本發明因此係關於在該等疾病之治療及/或預防中作為 藥物及/或藥物活性成份之5-[4_(入甲基苯基)·3•羥基·4h_ 1,2,4-三唑-5-基]_2,4-二羥基_N_甲基_N-丁基苯曱醯胺,且 係關於5·[4-(2-甲基苯基)·3_羥基_4H-1,2,4_三唑_5_基]·2,‘ 二羥基·Ν-甲基-N•丁基苯曱醯胺用於製備供治療及/或預防 該等疾病用之藥物的用途,且亦係關於一種用於治療該等 疾病之方法’其包含將5-[4_(2_曱基笨基)_3_羥基-4仏 127120.doc -13- 200838502 1,2,4-三唑-5-基]-2,4-二羥基-N-曱基-N-丁基苯曱醯胺投與 需要該投與之患者。 該主體或患者可屬於任何哺乳動物種類,例如靈長類, 尤其為人類;齧齒類,包括小鼠、大鼠及倉鼠;兔;馬、 牛、犬、貓等。因實驗研究而關注動物模型,其中其提供 治療人類疾病之模型。 先前技術 WO 2006/087077描述作為HSP90抑制劑之其他三唑衍生 物。應認為本發明係其選擇性發明。由此應提及之最接近 先前技術為化合物5-[4-(2-甲基苯基)-3-羥基-4H-1,2,4-三 唑-5-基]-2,4-二羥基-N-甲基-N-丙基苯甲醯胺(ΠΑ47Π)。 WO 00/53 169描述以香豆素或香豆素衍生物進行HSP90 抑制。 WO 03/041643 Α2描述HSP90抑制性玉米赤黴醇衍生 物。 在3-位或5-位經芳族基團取代之HSP90抑制性吡唑衍生 物揭示於 WO 2004/050087 Α1 及 WO 2004/056782 Α1 中。 WO 03/055860 Α1描述作為HSP90抑制劑之3,4·二芳基吡 σ坐 〇 具有HSP90抑制特性之嘌呤衍生物揭示於WO 02/36075 Α2中。 WO 01/72779描述嘌呤化合物及其用於治療GRP94 (HSP90之同系物或旁系同源物)引發之疾病(諸如腫瘤疾病) 的用途,其中癌症組織包括選自由以下癌症組成之群的肉 127120.doc •14- 200838502 瘤或癌瘤:纖維肉瘤、黏液肉瘤、脂肉瘤、軟骨肉瘤、骨 肉瘤、脊索瘤、血管肉瘤、内皮肉瘤、淋巴管肉瘤、淋巴 官内皮瘤、滑膜瘤、間皮瘤、尤因氏瘤、平滑肌瘤、橫紋 肌肉瘤、結腸癌'胰腺癌、乳癌、卵巢癌、前列腺癌、鱗 • 狀細胞癌、基底細胞癌、腺癌、汗腺癌、皮脂腺癌、乳頭 狀癌、乳頭狀腺癌、囊腺癌、骨髓癌、支氣管癌、腎細胞 癌、肝癌、膽管癌、絨膜癌、精原細胞瘤、胚胎癌、威姆 _ 氏瘤、子宮頸癌、睾丸瘤、肺癌、小細胞肺癌、膀胱癌、 上皮癌膠貝瘤、星形細胞瘤、神經管胚細胞瘤、顧咽管 至$膜瘤、松果體瘤、血·管母細胞瘤、聽神經瘤、少 枝膠貝瘤、腦膜瘤、黑素瘤、神經母細胞瘤、視網膜胚細 胞瘤、白血病、淋巴瘤、多發性骨髓瘤、瓦爾登斯特倫巨 球蛋白血症及重鏈疾病。 WO 01/72779另外揭示其中所提及之化合物用於治療病 毒疾病之用途,其中病毒病原體係選自由以下各病原體組 • 成之群:A型肝炎、㈣肝炎、C型肝炎、流感、水痘、腺 病毒、第一型單純疱疹(HSVq)、第二型單純疱疹(hsv_ )牛疫鼻病毒、埃可病毒(echovirus)、輪狀病毒 (rotav_)、呼吸道融合性病毒(RSV)、乳頭瘤病毒、腫瘍 • 病毋、巨細胞病毒、艾奎諾病毒(equin〇virus)、節足動物 攜帶性病、亨特病毒(huntavinis)、科沙奇病毒如 ^)、月思腺炎病毒、麻療病毒、風療病#、小兒麻痒病 毒、人免疫缺陷病毒1型洱以屮及人免疫缺陷病毒^型 (鮮⑴。W〇 01/72779此外描述其中提及之化合物用於 127120.doc -15· 200838502 GRP94調即之用途,其中經調節生物GRP94活性引起個體 内之免疫反應、蛋白自内質網之輸送、自低氧/缺氧應力 m自營養不良之恢復、自熱應力之恢復或其組合, 及/或’、中該病症為一定類型之癌症、傳染病、與經破壞 蛋白自内f網之輸送有關之病症、與局部缺血/再灌注有 關之病症’或其組合,纟中與局部缺血/再灌注有關之病 症為心跳驟停、心博停止及延遲心室心律不整、心臟手 術、心肺繞道手術、器官移植、脊髓損傷、頭部外傷、中 風、栓塞性中風、出血性中a、腦血管痙攣、張力減退、 低血糖、癲癇持續狀態、癲癇發作、焦慮、精神分裂症、 神經退化性病症、阿兹海默症、亨廷頓氏病、肌萎縮性側 索硬化(ALS)或新生應力所引起之結果。 最後,WO 01/72779描述有效量iGRP94蛋白調節劑在 製備用以在個體組織部位中改變隨後至缺血狀態之細胞反 應之藥物中的用途’藉由以GRP94蛋白調節劑處理組織部 位之細胞從而使細胞内GRP94活性增加至隨後至缺血狀態 之細胞反應得以改變的程度,其中隨後缺血狀況較佳為心 跳驟停、心博停止及延遲心室心律不整、心臟手術、心肺 繞道手術、器官移植、脊髓損傷、頭部外傷、中風、栓塞 性中風、出血性中風、腦血管痙攣、張力減退、低血糖、 癲癇持續狀態、癲癇發作、焦慮、精神分裂症、神經退化 性病症、阿兹海默症、亨廷頓氏病、肌萎縮性側索硬化 (ALS)或新生應力所引起之結果,或其中組織部位為移植 之供體組織。 127120.doc -16 - 200838502 以下提及之說明書描述HSP90抑制劑格爾德黴素與其他 藥物活性成份之組合·· WO 2004/108080 A2、WO 2005/002506 A2 > WO 2005/000211 A2 > WO 2005/000212 A2、WO 2005/000213 A2、WO 2005/000214 A2、WO 2005/000314 A1 〇 其他文獻:
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Zhao JF、Nakano H及 Sharma S· 1995 "Suppression of RAS and MOS transformation by radicicol”,Oncogene,第 11卷,第 161-173 頁。 【發明内容】 本發明係關於化合物5-[4-(2-曱基苯基)-3-羥基-4H-1,2,4-三唑-5-基]-2,4-二羥基甲基-N-丁基苯曱醯胺及其 醫藥學上可用之衍生物、鹽、溶劑合物、互變異構體及立 體異構體,包括其所有比率之混合物。 詳言之’本發明係關於化合物5_[4_(2_甲基苯基>3_羥 基-4H-1,2,4-三唑-5·基]·2,4_二羥基甲基·N_丁基苯甲醯 胺及其醫藥學上可用之衍生物、互變異構體及立體異構 體’包括其所有比率之混合物。 本發明尤其較佳係關於化合物5-[4-(2-甲基苯基)_3…羥 基-4H-1,2,4-二唑。-基]。,扣二羥基_N_甲基_N•丁基苯甲醯 胺及其單魏及二射衍生物、翻基衍生物、單葡糖盤 酸及二葡糖醛酸衍生物、互變異構體及立體異構體,包括 其所有比率之混合物。 本發明極尤其較佳係關於化合物5-[4·(2-甲基苯基)_3•經 基11’2’4-三唾_5_基]_2,4_二經基_Ν-甲基·ν_ 丁基苯甲醯 胺。 本毛月亦係關於此等化合物之水合物及溶劑合物,化合 物之溶劑合物意謂惰性溶劑分子與化合物由於其相互引: 而加合,溶劑合物為(例如)單水合物或二水合物或醇合 I27120.doc -26- 200838502 本發明化合物為亦可以如下互變異構形式存在
醫藥學上可用之衍生物意謂(例如)本發明化合物之鹽亦 及所謂前藥化合物。
前藥衍生物意謂經(例如)烷基或醯基、糖或募肽改質之 本發明化合物’且其在生物體内迅速裂解而產生本發明之 活性化合物。其亦包括本發明化合物之生物可降解的聚合 物衍生物’如(例如)Int. L Pharm. 115, 6i 67(i995)中所 述。 尤其較佳之前藥為鱗酸酉旨衍生物,諸如單構酸醋及/或 t磷酸醋衍生物;糖衍生物,諸如單葡萄糖普酸及/或二 葡萄糖音酸或5 -硫®g基衍生物。 表述"有效量"意謂引起研究者或内科醫師在組織、系 統、動物或人體内探尋或期望之生物或醫學反應的藥物或 醫藥活性成份之量。此外,表述"治療有效量"意謂具有以 消未接受此量之相應個體相比): s疾病、疾病形態、疾病狀況、病痛(C〇mplaint)、病症或 Μ作用之改良治癒治療、治癒、預防或㈣,亦或降低疾 病、病痛或病症的進展。 術語"治療有效量"亦涵蓋有效增加正常生理學功能之 127120.doc -27· 200838502
本發明亦係關於本發明化合物之混合物,例如兩種非對 映異構體之混合物,例如比率為1:1、1:2、1:3、1:4、 1:5、1:1〇、ι:ι00或1:10〇〇。此等為立體異構化合物之尤 其較佳混合物。 此外’本發明化合物亦及用於其製備之起始物質係由描 述於文獻(例如在標準著作中,諸如H〇uben-Weyl,
Methoden der organischen Chemie [Methods of Organic
Chemistry],Georg-Thieme-Verlag,Stuttgart)中之本身已知 方法在已知且適於該等反應之反應條件下製備。本文亦可 使用本文中未更詳細提及之本身已知之變體。 若需要,起始物質亦可藉由不自反應混合物分離而代之 以將其立即進一步轉化為本發明化合物從而原位形成。 一起始物質一般為已知的。然而,若其為新穎❸,則其可 藉由本身已知之方法加以製備。 本發明化合物係藉由wo 2006/087077中所述之方 備。 汉應係猎由熟習此項技術者已知之方法進行。 反應係在合適惰性溶劑中 Τ進仃合適惰性溶劑之實例為 烴,诸如己烷、石油醚、苯、 ,_ ^ x T本或一曱本;氯化烴,諸 如 一^風i 乙^fji、1 2 -二_ 备 ^ LA> ? 一、、元、四氯化碳、氯仿或二氯甲 烷,知,诸如甲醇、乙醇、 -丁 ,、丙知、正丙醇、正丁醇或第 一丁%,醚,諸如乙醚、二里 -椏γ ^ 一 t ,、丙基醚、四氫呋喃(THF)或 一心机,〇 —醇_,埃L 7 一 & 一醇單曱基醚或乙二醇單乙基 127120.doc -28- 200838502 醚、乙二醇二甲醚(二乙二醇二曱醚);酮,諸如丙酮或丁 酮;醢胺’諸如乙蕴胺、二甲基乙醯胺 (讀);腈,諸如乙腈;㈣,諸如二甲亞卿咖甲)= 硫化碳;錢’諸如甲酸或乙酸;磺基化合物,諸如石肖基 甲烧或硝基苯;醋’諸如乙酸乙_,或該等溶劑之混合 物。溶劑尤其較佳為(例如)四氫呋喃。
視所用之條件而定’反應時間係介於數分鐘與μ天之 間’且反應溫度係介於約_3(rcw4(rc之間,通常介於_1〇 t與130°C之間,尤其介於約3〇〇c與約125。〇之間。 藉由熟習此項技術者已知之方法移除保護基。 醚(例如甲基醚)之裂解係如上文所指$,在合適溶劑 中、較佳藉由添加三溴化硼而進行。 反應尤其較佳係在二氯甲烷中在介於約·3〇它與5〇(>c之 間、通常介於-2(TC與2(rc之間、尤其介於約_ir(:與約代 之間的反應溫度下進行。 此外,本發明化合物可藉由溶劑解(尤其水解)或藉由氫 解自其功能衍生物而將其釋放獲得。 溶劑解或氫解之較佳起始物質為彼等含有相應經保護胺 基及/或經基代替一或多個游離胺基及/或羥基者,較佳為 彼等攜帶胺基保護基代替與N原子鍵結之H原子者,例如 彼等符合式I但含有!^^^,基團(其中尺,表示胺基保護基,例 如BOC或CBZ)代替NH2基團者。 此外,較佳為攜帶羥基保護基代替羥基之Η原子的起始 物質,例如彼等符合式j但含有R”〇-苯基(其中Rn表示羥基 127120.doc -29- 200838502 保濩基)代替羥基苯基者。 。物貝刀子中亦可能存在複數個相同或不同經保護胺 土及/或羥基。若所存在之保護基彼此不同,則在許多狀 况下其可選擇性裂解。 - ^胺基保遵基在通用術語中為已知的且係關於適於 ^ ㈣(阻斷)胺基使其免於化學反應之基團,但其易於在分 子其他部位之所要化學反應已進行後移除。詳言之,該等 φ 1團中之典型者為未經取代或經取代之ϋ基、芳基、芳烧 氧基甲基或芳烧基。因為胺基保護基在所要反應(或反應 序列)後移除,所以此外其類型及尺寸並不關鍵;然而, U為彼等具有12()個、尤其卜8個碳原子者。應瞭解術語 醯基係在廣義上與本發明方法有關。其包括衍生自以下 各物之ι基·脂族、芳脂族、芳族或雜環魏酸或石黃酸,且 尤,、為垸氧魏基、芳氧幾基及尤其芳燒氧魏基。該等酸基 κ例為燒基’諸如乙g盘基、丙醯基及丁醯基;芳燒酿 馨基諸如苯基乙酸基;芳醯基,諸如苯甲酿基及甲苯基; 芳氧基燒醯基,諸如P0A ;院氧幾基,諸如甲氧幾基、乙 箪.土 2,2’2-_氣乙氧羰基、B〇c及蛾乙氧幾基;芳 ’ ⑥氧幾基,諸如CBZ(”苯甲氧絲,·)、4-甲氧基苯甲氧羰 、基及FM〇C,及芳基磺基,諸如Mtr、Pbf或pmc。較佳 之胺基保護基為B0C及Mtr,此外為CBZ、Fm〇c、苯甲基 及乙醯基。 土 術語’,經基保護基,,在通用術語中同樣為已知的且係關於 適於保護羥基使其免於化學反應之基團,但其易於在分子 127120.doc -30- 200838502 1他部位之所要化學反應已進行後移除。該等基團中之典 型者為上述未經取代或經取代之芳基、芳烷基或醯基,此 外亦為烷基。羥基保護基之種類及尺寸並不關鍵,此係因 為其在所要化學反應或反應序列後被移除。較佳為具有 2〇個、尤其1.10個碳原子之基團。經基保護基之實例尤其 為苯甲基、對硝基苯甲醯基、對甲苯磺醯基、第三丁基及
乙醯基,其中苯甲基及第三丁基尤其較佳。COOH基團較 佳以其第三丁酯形式經保護。 視所用保護基而定,使用以下各物將本發明化合物自其 B月b衍生物釋放:例如使用強酸,有利地使用TF A或過氯 酉文但亦使用其他無機強酸(諸如鹽酸或硫酸)、有機強羧 酸(諸如三氯乙酸)或磺酸(諸如苯磺酸或對甲苯磺酸)。其 他惰性溶劑之存在為可能的,但並非總是必要。合適惰性 >谷劑較佳為有機溶劑,例如羧酸(諸如乙酸)、醚(諸如四氫 呋喃或二噁烷)、醯胺(諸如〇]^17)、鹵化烴(諸如二氯曱 烷),此外亦為醇(諸如甲醇、乙醇或異丙醇)及水。此外, 上述溶劑之混合物亦合適。TFA較佳為過量使用而不添加 其他溶劑,且過氣酸較佳以乙酸與7〇%過氯酸之9:1比率之 混合物形式使用。裂解之反應溫度有利地介於約與約 50°C之間,較佳介於15°c與30cC(室溫)之間。 B〇C、OBut、Pbf、Pmc及Mtr基團可(例如)較佳在15 3〇 °c下使用二氯甲烷中之TFA或使用二噁烷中約3^至51^ HC1 裂解,且FMOC基團可在15-30°C下使用二甲胺、二乙胺或 哌啶於DMF中之約5%至50%溶液裂解。 127120.doc -31 - 200838502 可氫解移除之保護基(例>CBZ或苯甲基)可(例如)藉由 在催A例如’有利地在諸如碳之载體上的貴金屬催化 劑⑼如纪))存在下以氫處理而得以裂解。此處之合適溶劑 為彼等上文所指示者,尤其(例如)醇,諸如甲醇或乙醇; 或醯胺,諸如卿。氫解一般係在介於約代與⑽。c之溫 度下及"於約1巴與200巴之屢力下進行,較佳在2〇_抑 及M0巴下進行。CBZ基團之氫解在(例如)2〇销下在甲 鮮中之 5% 至 1〇% PH/Γ* u 斗、«η /0 Pd/C上或使用甲酸銨(代替氫)在甲醇 /DMF中之Pd/C上良好進行。 醫樂用鹽及其他形式 本發明之該化合物可呈其最終非鹽形式使用。另一方 面,本發明亦涵蓋以醫藥學上可接受之鹽形式使用此化合 物之用途’該等鹽可藉由此項技術中已知之程料生自各 種有機及無機酸及驗。本發明化合物之醫㈣上可接受之 皿形式大。P刀係猎由習知方法製備。合適鹽可藉由使化合 物與合適驗反應產生相應驗加成鹽而形成。該等驗為(例 如)驗金屬氫氧化物,包括氫氧切、氫氧錢及氯氧化 !醇:土t屬氫氧化物’諸如氫氧化鋇及氫氧化約;驗金 屬知鹽,tj如乙醇鉀及丙醇納;及各種有機驗,諸如派 乙醇胺及N·甲基麩醯胺。同樣包括本發明化合物之 =而nt由化合物經醫藥學上可接受之有機及無機酸 處理而形成酸加成鹽’例如’齒化氣,諸如氯化氯、淳化 氫或t氯;其他無機酸及其相應鹽,諸如硫酸鹽、硝酸 鹽或%酉文鹽及其類似物,及院基及單芳基石黃酸鹽,諸如乙 127120.doc -32- 200838502 磺酸鹽、甲苯磺酸及苯磺酸鹽;及其他有機酸及其相應 鹽,諸如乙酸鹽、三氟乙酸鹽、酒石酸鹽、順丁烯二酸 鹽、琥珀酸鹽、檸檬酸鹽、苯曱酸鹽、水楊酸鹽、抗壞血 酸鹽及其類似物。因此,本發明化合物之醫藥學上可接受 之酸加成鹽包括以下各物:乙酸鹽、己二酸鹽、海藻酸 ^ 鹽、精胺酸鹽、天冬胺酸鹽、苯曱酸鹽、苯磺酸鹽、硫酸 。 氫鹽、亞硫酸氫鹽、溴化物、丁酸鹽、樟腦酸鹽、樟腦磺 酸鹽、辛酸鹽、氯化物、氯苯甲酸鹽、檸檬酸鹽、環戊烷 _ 丙酸鹽、二葡糖酸鹽、磷酸二氫鹽、二硝基苯甲酸鹽、十 二烷基硫酸鹽、乙磺酸鹽、反丁烯二酸鹽、半乳糖二酸鹽 (galacterate,來自黏液酸)、半乳糖酸酸鹽、葡糖庚酸 鹽、葡糖酸鹽、麩胺酸鹽、甘油磷酸鹽、半琥珀酸鹽、半 硫酸鹽、庚酸鹽、己酸鹽、馬尿酸鹽、鹽酸鹽、氫溴酸 鹽、氫碘酸鹽、2-羥基乙磺酸鹽、碘化物、羥乙基磺酸 鹽、異丁酸鹽、乳酸鹽、乳糖酸鹽、蘋果酸鹽、順丁烯二 0 酸鹽、丙二酸鹽、扁桃酸鹽、偏磷酸鹽、甲磺酸鹽、甲基 苯曱酸鹽、磷酸氫鹽、2-萘磺酸鹽、菸酸鹽、硝酸鹽、草 酸鹽、油酸鹽、棕櫚酸鹽、果膠酸鹽、過氧硫酸鹽、苯基 0 乙酸鹽、3-苯基丙酸鹽、磷酸鹽、膦酸鹽、對苯二甲酸 . 鹽,但此不代表其限制範圍。 此外,本發明化合物之驗性鹽包括銘鹽、銨鹽、約鹽、 銅鹽、鐵(III)鹽、鐵(II)鹽、鋰鹽、鎂鹽、錳(III)鹽、錳 (Π)鹽、鉀鹽、鈉鹽及鋅鹽,但此不欲代表限制。上述鹽 中,較佳為銨鹽;鹼金屬鹽(鈉鹽及鉀鹽),及鹼土金屬鹽 127120.doc -33- 200838502 (舞鹽及鎂鹽)。衍生自醫藥學上可接受之有機無毒鹼之本 發明化合物之鹽包括以下各物之鹽:第一、第二及第三 胺、經取代之胺(亦包括天然存在之經取代胺)、環胺及鹼 性離子交換樹脂,例如精胺酸、甜菜鹼、咖啡鹼、氯普魯 卡因、膽鹼、N,N,-二苯甲基乙二胺(苄星青黴素)、二環己 胺、二乙醇胺、二乙胺、2-二乙胺基乙醇、2-二甲胺基乙 醇、乙醇胺、乙二胺、N-乙基嗎啉、N_乙基哌啶、葡萄 胺、葡糖胺、組胺酸、海卓胺、異丙胺、利多卡因 (lidocaine)、離胺酸、葡甲胺、N-甲基_D-葡萄胺、嗎|、 旅嗪、旅唆、聚胺樹脂、普魯卡因、σ票呤、可可豆驗、三 乙醇胺、三乙胺、三曱胺、三丙胺及參(羥基甲基)曱胺(緩 血酸胺),但此不欲代表限制。 含有驗性含氮基團之本發明化合物可使用以下試劑季銨 化:諸如(CpC:4)烧基鹵化物,例如甲基、乙基、異丙基及 第二丁基之氯化物、溴化物及埃化物;硫酸二烧基 酯,例如硫酸二甲酯、硫酸二乙酯及硫酸二戊酯;(c『 Cl8)烷基鹵化物,例如癸基、十二烷基、月桂基、肉豆蔻 基及硬脂酷基之氯化物、溴化物及換化物;及芳基(Cl 烷基i化物,例如苯甲基氯及苯乙基溴。可使用該等鹽製 備水溶性及油溶性之本發明化合物。 較佳之上述醫藥鹽包括乙酸鹽、三氟乙酸鹽、苯磺酸 鹽、檸檬酸鹽、反丁烯二酸鹽、葡糖酸鹽、半琥珀酸鹽、 馬尿酸鹽、鹽酸鹽、氫溴酸鹽、羥乙基磺酸鹽、扁桃酸 鹽、葡甲胺鹽、硝酸鹽、油酸鹽、膦酸鹽、特戊酸鹽、磷 127120.doc -34- 200838502 酸鈉、硬脂酸鹽、硫酸鹽、次水揚酸鹽、酒石酸鹽、硫蘋 果酸鹽、甲苯磺酸鹽及緩血酸胺鹽,但此不欲代表限制。
藉由使游離鹼形式與足量之所要酸接觸,使得以習知方 式幵/成鹽’從而製備本發明化合物之酸加成鹽。可藉由使 鹽形式與驗接觸且以習知方式分離游離鹼從而產生游離 鹼。在特定態樣中’游離鹼形式與其相應鹽形式之區別在 ;某二物理特性,諸如在極性溶劑中之溶解度;然而為本 發明之目的’鹽另外對應於其各別游離鹼形式。 如所述,本發明化合物之醫藥學上可接受之鹼加成鹽係 與金屬或胺形成,諸如鹼金屬及鹼土金屬或有機胺。較佳 孟屬為鈉、鉀、鎂及鈣。較佳有機胺為N,N,_二苯甲基乙 一胺、氯普魯卡因、膽鹼、二乙醇胺、乙二胺、n_甲基_ D-葡萄胺及普魯卡因。 错由使游離酸形式與足量之所要鹼接觸,使得以習知方 式开^成1從而製備本發明化合物之驗加成鹽。可藉由使 鹽形式與酸接觸且以習知方式分離游離酸從而產生游離 酸。在特定態樣中,游離酸形式與其相應鹽形式之區別在 於某些物理特性,諸如在極性溶财之溶解度1而為本 發明之㈣,鹽另外對應於其各別游離酸形式。 鑒於上述,可見本文中之表述"醫藥學上可接受之鹽"意 謂包含以其鹽中之—者形式存在之本發明化合物的活性成 份’尤其若此鹽形式職予活性成份相較於游離形式活性成 份或先前所用之活性成份^h甘^ _ 動力、、… 何其他鹽形式有改良之藥物 動力予特性。活性成份之醫藥學上可接受之鹽形式亦可首 127120.doc -35- 200838502 次提供此活性成份以先前未具有之所要藥物動力學特性, 且甚至可對此活性成份關於其在體内之治療功效的藥物動 力學產生積極影響。 本發明此外係關於本發明化合物及/或其生理學上可接 欠之鹽之用途,其係用於(尤其)藉由非化學方法製備藥物 (醫藥組合物)。其可與至少一種固體、液體及/或半液體賦 形劑或佐劑一起,且若需要則與一或多種其他活性成份組 合而轉化為本文之合適劑型。 本發明此外係關於包含5_[4_(2_曱基苯基)_3_羥基 1’2,4—一唑_5_基]_2,4_二羥基_N_甲基·Ν·丁基苯甲醯胺及/或 其醫藥學上可用之衍生物、冑、溶劑合物、互變異構體及 立體異構體’包括其所有比率之混合物,以及視情況之賦 形或佐劑的藥物。醫藥調配物可以每劑量單位包含 預定量之活性成份的劑量單位形式投與。該單位可包人 (例如)〇.1啤至3g、較佳lmg至· mg、尤其較佳5咐 ⑽^本發明化合物,此係視所治療之疾病病況、投藥方 ^及者年齡、體重及病況而定,或醫藥調配物可以每巧 ,^立包含騎量活性成份之劑量單位形式投與。_ 1早位調配物為包含如上文所述之每日劑量或部分劑量, 或其相應分率之活性成份的調配物。此外,此類型之殺華 調配物可使用醫藥技術中-般已知之方法加以製備。 醫藥調配物可•經任何所要合適方法投與,例如夢由 口服(包括經頰或經舌下)、經直腸、經鼻、 _ 頰、經舌下或經皮)、铖 。51 (匕括經 、I陰道或非經腸(包括皮下、肌肉 127120.doc -36- 200838502 内、靜脈内或皮内)方法。該等調配物可使用醫藥技術中 已知之所有方法藉由(例如)使活性成份與賦形劑或佐劑組 合加以製備。 適於口服投與之醫藥調配物可作為單獨單位投與,諸如 膠囊或錠劑,散劑或顆粒劑;水性或非水性液體中之溶液 或懸浮液;可食用泡沫體或泡沫體食物;或水中油液體乳 液或油中水液體乳液。
/大此,舉例而言,在口服投與狀況下,在為錠劑或膠囊 幵/式¥ ’可將活性成份組份與口服、無毒且醫藥學上可接 :之丨“生賦形劑組合,諸如乙醇、甘油、水及其類似物。 糟由將化合物粉碎為合適精細尺寸且將其與以類似形式粉 碎之醫藥賦形劑(諸 ^ J 用石反水化合物,諸如澱粉或甘 鉻糖醇)混合而製備散~ 散劑及染料。可存在香料、防腐劑、分 來製造膠囊。:二::粉:混合物且以其填充成型明膠殼 及潤滑劑,諸如以^ 粉末混合物中添加助流劑 酸i伽形式酸、滑石、硬脂酸鎮、硬脂 (諸如瓊脂-•、碳酸以^同樣可添加崩解劑或增溶劑 物之可用性。 ,弓或心納)以在服用膠囊後改良藥 劑 膠 劑 潤滑劑及崩解劑以及¥料ΓΓ 合適黏 天然糖(諸如,葡萄撼,… 合劑包括搬粉、 fe萄糖或β_乳糖)、由玉 天然及合成橡膠(諸如 去、成之甜 7拉伯膠、黃耆膠或海藻 127120.doc 200838502 納、緩甲基纖維素、聚乙二醇、壤)及其類似物。此等劑 型中所用之潤滑劑包括油酸鈉、硬脂酸鈉、硬脂酸鎂、苯 甲酸鈉、乙酸鈉、氯化鈉及其類似物。崩解劑包括(但不 限於)澱粉、甲基纖維素、瓊脂、膨潤土、三仙膠及其類 似物。藉由(例如)製備粉末混合物,使該混合物粒化或乾 式壓縮,添加潤滑劑及崩解劑且將整個混合物擠壓產生錠 . 劑,從而調配錠劑。藉由將以合適方式粉碎之化合物與如 上文所述之稀釋劑或鹼及視情況之黏合劑(諸如,羧甲基 纖維素、海藻酸鹽、明膠或聚乙烯吡咯啶酮)、阻溶劑(諸 如,石蠟)、吸收促進劑(諸如,第四鹽)及/或吸收劑(諸如 膨潤土、高嶺土或墙酸二約)混合從而製備粉末混合物。 可藉由將粉末化合物以黏合劑(諸如,糖漿、澱粉糊狀 物、黏膠阿卡迪(acadia mucilage)或纖維素或聚合物材料 之/谷液)濕潤且將其經篩擠壓而使其粒化。作為粒化之替 代,可使粉末混合物流經製錠機,產生非均勻形狀之塊, • 將其研碎以形成顆粒劑。可藉由添加硬脂酸、硬脂酸鹽、 滑石粉或礦物油將顆粒劑潤滑,從而防止黏在錠劑澆鑄模 上。接著擠壓經潤滑混合物產生錠劑。亦可將本發明化合 物與無流動惰性賦形劑組合且接著直接擠壓產生鍵劑,而 ' 不進行粒化或乾式擠壓步驟。可存在由蟲膠密封層、糖或 聚口物材料層及蠟光亮層組成之透明或不透明保護層。可 向此專塗層中添加染料從而可區分不同劑量單位。 可將口服液體(諸如,溶液、糖漿及酏劑)製備為劑量單 位开y式彳疋而產生包含預指定量化合物之給定量。可藉由將 127120.doc -38· 200838502 化合物與合適香料一 係使用無毒醇媒劑二二:水溶液中製備糖漿,劑 中而調配懸浮液合物分散於無毒媒劑 氧化異硬脂醇及聚 ^加w劑及礼化劑(諸如,乙 添加劑(諸如,^由知山梨糖_)、防腐劑、香味 味劑及其類似物或天然甜味劑或糖精)或其他人工甜 中與之劑量軍位調配物可(若需要)囊封於微膠囊 以聚:以延長或延遲釋放之方式藉由(諸如)將微粒物質 …蠟及其類似物塗佈或嵌埋而製備調配物。 :亦:::發明化合物及/或其醫藥學上可用之衍生物、 /合μ 口物、互變異構體及立體異構體,包括其所有比 混合物,以及視情況之賦形劑及/或佐劑及其鹽、、容 ::物及生理學功能衍生物以脂質體傳遞系統形式投盥: ㈣平Λ小微脂粒、單層大微脂粒及多層微脂粒。可由多 體 邊如’膽固醇、硬脂胺或鱗脂醯膽鹼)形成脂質 生物使1$1^明化合物及其鹽、溶劑合物及生理學功能街 〃化°物分子偶合之單株抗體作為個別載劑來傳 將化合物與作為乾向藥物載劑之可溶聚合物偶 σ。該4聚合物可涵蓋經軟脂醯基取代之聚乙烯吼㈣ :、派喃共聚物、聚經基丙基甲基丙稀醯胺基苯"經 土乙基天冬胺醯胺基㈣或聚氧化乙烯聚離胺酸。此外, 可將化D物與-類適於達成藥物之受控制釋放的生物可降 解聚合物偶合,例如聚乳酸、聚-己内醋、聚經基丁酸、 127120.doc -39- 200838502 水原敲、聚縮醛、聚二羥基哌喃、聚氰基丙烯酸酯及水 凝膠之交聯或兩性嵌段共聚物。 適於ι皮投與之醫藥調配物可作為獨纟t藥與接受者真 皮延展、緊密接觸而投與。因此,例如,可藉由離子導入 療法自膏藥傳遞活性成份,如Pharmaeeutieai Research, 3(6),318 (1986)中之通用術語所述。 、適於局部投與之醫藥化合物可調配為軟膏、乳膏、懸浮
液洗液、散劑、溶液、糊狀物、凝膠、喷霧、氣溶膠或 油狀物。 為…療眼睛或其他外部組織(例如口及皮膚),調配物較 佳作為局部軟膏或乳膏應用。在調配物為軟膏之狀況下, 活性成份可以石蝶抑或或水可混溶乳膏基質形式採用。或 者活!生成伤可經调配以產生具有水中油乳膏基質或油中 水基質之乳膏。 、適於局部應用至眼睛之醫藥調配物包括滴眼劑,其中將 活性成份溶解錢浮於合適载财,尤其為水性溶劑中。 適於局部應用於π中之醫藥調配物涵蓋口含劑、片劑及 漱口劑。 適於直腸投與之醫藥調配物可以栓劑或灌腸劑形式投 載劑物質為固體之適於經鼻投與之醫藥調配物包含粒徑 在(例如)20-500微米範圍内之粗輪粉末,其係以使用鼻粉 之方式投與,_由用鼻孔自固持於鼻子附近之含有粉 劑之容器迅速吸人。心作為鼻噴霧或鼻滴劑(將液體用 127120.doc 200838502 作載劑物質)投與之合適調配物涵蓋水或油中之活性成份 溶液0 习 適於藉由吸入投與之醫藥調配物涵蓋精細微粒粉塵或薄 霧,其可由各種類型之具有氣溶膠之加壓分散器、噴霧哭 或吹入器產生。 °° 適於陰道投與之醫藥調配物可作為子宮托、棉球、乳 貧、凝膠、糊狀物、泡沫體或噴霧調配物投與。 適於非經腸投與之醫藥調配物包括水性及非水性無菌注 射/合液,其包含抗氧化劑、緩衝劑、抑菌劑及溶質,調配 物藉此與待治療之接受者的血液等張;及水性及非水性無 菌懸浮液,其可包含懸浮介質及增稠劑。調配物可在單劑 ϊ或多劑量容器(例如密封安瓶及小瓶)中投與,且以冷凍 乾秌(凍乾)狀態儲存,從而在必須使用前僅需添加無菌載 劑液體(例如水)以達注射之目的。 根據處方製備之注射溶液及懸浮液可由無菌散劑、顆粒 劑及錠劑製備。 勿庸置疑’除上文特定提及之組份外,調配物亦可包含 此項技術中關於特定調配物類型可用之其他試劑;因此, 例如,適於口服投與之調配物可包含香料。 t月化s物之治療有效量係視多種因素而定,包括 (例如)人類或動物之年齡及體重,需要治療之準確疾病病 况及其嚴重程度,調配物種類及其投與方法,且由醫師或 被醫最終決定。然而,本發明化合物之有效量一般在每天 每公斤接受者(哺乳動物)體重〇·1 mg至100 mg範圍内且尤 127120.(j〇e -41 - 200838502 其通常在每天每公斤體重1 mg至10 mg範圍内。因此,體 重70 kg之成年哺乳動物每天之實際量一般介於7〇 與 700 mg之間,其中此量可作為單獨劑量每天投與或一般以 系列部分劑量(諸如,兩個、三個、四個、五個或六個)每 • 天投與’使得每日總劑量相同。有效量之鹽或溶劑合物或 其生理學功能衍生物可作為本發明化合物本身之有效量的 • 分率加以確定。可假定類似劑量適於治療上文所述之其他 病況。 此外,本發明係關於包含至少一種本發明化合物及/或 其醫藥學上可用之衍生物、溶劑合物及立體異構體,包括 其所有比率之混合物,以及至少一種其他藥物活性成份的 藥物。 其他藥物活性成份較佳為化學治療劑,尤其彼等抑制血 官生成且因此抑制腫瘤細胞生長及傳播者;本文中較佳為 VEGF受體抑制劑,包括針對VEGF受體之核酶及反義物, • 及血管抑制素及内皮抑制素。 可與本發明化合物組合使用之抗腫瘤劑之實例一般包括 烧基化抗代5射物,表鬼臼毒素(epidophyllotoxin);抗 • 腫瘤酶;拓撲異構酶抑制劑;丙卡馬肼(procarbazin);米 • 托恩S昆(mitoxantron)或鉑配位錯合物。 抗腫瘤;=j彳較彳土係選自以下類別:蒽環黴素(anthraCyCHn)、 長春花(vinca)藥物、絲裂黴素(mh〇mycin)、博萊黴素 (bleomycin)、細胞毒性核苷、埃博黴素(ep〇thii〇ne)、迪斯 德莫來(discormolide)、喋啶、二炔烯(diynene)及鬼白毒素 127120.doc -42 - 200838502 (podophyllotoxin) 〇
尤其較佳為以下該等類別:例如,洋紅黴素 (carminomycin)、道諾黴素(daunorubicin)、胺基蝶吟 (aminopterin)、甲胺嗓呤(methotrexate)、甲嗓呤 (methopterin)、二氯曱胺嗓呤、絲裂黴素C、泊非黴素 (porfiromycin)、5-氟尿嘴唆、5-氟脫氧尿_單填酸醋、阿 糖胞苷(cytarabine)、5 -氮雜胞苷、硫鳥嗓呤、硫嗤嘌呤、 腺苷、喷司他丁(pentostatin)、赤經基壬基腺嘌吟、克拉 屈濱(cladribine)、6-M 基 σ票呤、吉西他濱(gemcitabine)、 阿糖胞苷(cytosinarabinoside)、鬼臼毒素或鬼臼毒素衍生 物(諸如依託泊苷(etoposide)、磷酸依託泊苷或替尼泊甙 (teniposide))、美法侖(melphalan)、長春驗(vinblastine)、 長春瑞濱(vinorelbine)、長春新鹼(vincristine)、異長春驗 (leurosidine)、長春地辛(vindesine)、環長春驗 (leurosine)、多烯紫杉醇(docetaxel)及紫杉醇(paclitaxel) 〇 其他較佳抗腫瘤劑係選自以下各物之群:迪斯德莫來、埃 坡黴素 D(epothilone D)、雌二醇氮界、卡舶(carboplatin)、 順始(cisplatin)、奥賽力銘(oxaliplatin)、環填醯胺 (cyclophosphamide)、博萊黴素、吉西他濱、異環麟醯胺 (ifosamide)、美法侖、六甲基三聚氰胺、嗟替派(thiotepa)、 伊達曲沙(idatrexate)、三甲曲沙(trimetrexate)、達卡巴口秦 (dacarbazine)、L-天冬醯胺酶、喜樹驗(camptothecin)、 CPT-11 、 拓朴替康 (topotecan)、 阿糖胞苷 (arabinosylcytosine)、比卡魯胺(bicalutamide)、氟他胺 127120.doc -43 - 200838502 (flutamide)、亮丙瑞林Geiiprolide)、吡啶幷苯并吲哚衍生 物、干擾素及介白素。 其他藥物活性成份較佳為抗生素。較佳抗生素係選自以 下各物之群··更生黴素(daciin〇mycin)、道諾黴素、黃膽 素(idarubicm)、表柔比星(epinjbicin)、米托蒽醌 (mit〇Xantr〇ne)、博萊黴素、普卡黴素(plicamycin)、絲穿
黴素。 X 其他藥物活性成份較佳為酶抑制劑。較佳酶抑制劑係選 自乂下各物之群·組蛋白去乙醯抑制劑(例如,辛二酹苯 胺異經㈣[SAHA])及路胺酸激酶抑制劑(例如,如皿 [Iressa])。 其他藥物活性成份較佳為核輸出抑制劑。核輸出抑制劑 防止生物聚合物(例如,rna)自細胞核 抑制劑係選自以下各物之群……, 住核輸出 物之群·卡利他〉丁㈣lystatin)、細黴 (Pt+〇myCin B)、瑞特雅酮(ratjadone)。 防止味=m成μ佳為核輸出抑制劑。核輸出抑制劑 :止生物聚合物(例如,RNA)自細胞核 二 出抑制劑係選自以下^… 田μ土核輸 特_。 物之群:卡料、細黴素Β、瑞 其他藥物活性成份較佳 劑係選自以下各物之群劑。較佳之免疫抑制 (wy, ' rAD001 雷帕黴素(rapamycin)、CCI_779 心nnaceuticals)。 (N_他)、AP23573 (Ariad 本發明亦係關於一插 套件(套組),其係由以下各物單獨 127120.doc -44· 200838502 封裝組成 (a) 有效量之本發明化合物及/或其醫藥學上可用之衍生 物、溶劑合物及立體異構體,包括其所有比率之混合 物, 以及 (b) 有效量之另一藥物活性成份。 該套件包含合適容器,諸如各星猫 碎如孤早獨珉、包或安瓶。該 套件可(例如)包含獨立安瓶,其各 八合a 3有有效量之本發明 化合物及/或其醫藥學上可用夕料#仏 τ用之何生物、溶劑合物及立體 ”構體,包括其所有比率之混合物, 卿以及有效ϊ之溶解或 /東乾形式之另一藥物活性成份。 用途 本發明化合物適用作供哺乳 HSPQn, g礼動物(尤其人類)治療與 HSP90相關之疾病用的醫藥活性成份。 本發明因此係關於5_[4_(2· 、r暴本基)·3-經基-4H-1 2 4-三唑-5-基]-2,4-二羥基·Ν_τ ,2,4 &Μ u ^ m 丁基本甲醯胺,及其醫 桌予上可用之衍生物、溶劑合 女L十 月J 口物及立體異構體,包括i所 有比率之混合物之用逯,苴及m ^ n 、^、,、用於製備供治療與HSP90之 抑制、調控及/或調節作用相 ^ 關之疾病用的藥物。 本發明涵蓋5-[4-(2_甲其贫甘、 其1〇 (甲基本基基H,2,4-三唑j 基]-2,4_二羥基_;^_$基卞 丁基本甲醯胺及其醫藥學上可用 之何生物、溶劑合物及立體 合物t ^ , ”構體,包括其所有比率之混 口物之用途,其係用於製備 、商广— 侑供冶療以下疾病用之藥物··腫 瘤疾病,例如纖維肉瘤、 黏液肉瘤、脂肪肉瘤、軟骨肉 127120.doc -45· 200838502 瘤、骨肉瘤、脊索瘤、血管肉瘤、内皮肉瘤、淋巴管肉 瘤、淋巴内皮肉瘤、滑膜瘤、間皮瘤、尤因氏瘤、平滑肌 瘤、検紋肌肉瘤、結腸癌、胰腺癌、乳癌、卵巢癌、前列 腺癌、鱗狀細胞癌、基底細胞癌、腺癌、汗腺癌、皮脂腺 癌、礼頭狀癌、乳頭狀腺癌、囊腺癌、骨髓癌、支氣管 癌、腎細胞癌、肝癌、膽管癌、絨膜癌、精原細胞瘤、胚 胎癌、威姆氏瘤、子宮頸癌、睾丸瘤、肺癌、小細胞肺 癌、膀胱癌、上皮癌、膠質瘤、星形細胞瘤、神經管胚細 胞瘤、顱咽官瘤、室管膜瘤、松果體瘤、血管母細胞瘤、 聽神經瘤、少枝膠質瘤、腦膜瘤、黑素瘤、神經母細胞 瘤、視網膜胚細胞瘤、白血病、淋巴瘤、多發性骨髓瘤、 瓦爾登斯特倫巨球蛋白血症及重鏈疾病; 病毒疾病,其中病毒病原體係選自由以下各病原體組成 之群·· A型肝炎、b型肝炎、c型肝炎、流感、水痘、腺病 毒、第一型單純疱疹(HSV-I)、第二型單純疱疹、 牛疫、鼻病毋、埃可病毒、輪狀病毒、呼吸道融合性病毒 (RSV)、乳頭瘤病毒、腫瘍病毒、巨細胞病毒、艾奎諾病 毒、節足動物攜帶性病、亨特病毒、科沙奇病毒、腮腺炎 病毒、麻疹病毒、風疹病毒、小兒麻痺病毒、人免疫缺陷 病毒I型(HIV-Ι)及人免疫缺陷病毒!丨型(Ηϊν·π); 移植之免疫抑制;發炎引發之疾病,諸如類風濕性關節 炎、哮喘、多發性硬化、1型糖尿病、紅斑性狼瘡症、牛 皮癬及發炎性腸病;囊腫性纖維化;與血管生成有關之疾 病,諸如糖尿病性視網膜病變、血管瘤、子宮内膜異位 127120.doc -46- 200838502 症、腫瘤灰管峰忐·趨 、木病,自體免疫疾病;局部缺血; 致纖維化疾病,諸如硬皮症、多發性肌 肺纖維化;狼瘡症、肝硬化、瘢痕瘤形成、間質性腎炎及 HM2-甲基苯基)_3_羥基-购二‘三唑_5_基]_2,4·二羥 基4甲基·Ν_丁基苯甲酸胺尤其可抑制癌症、腫瘤細胞之 生長及腫瘤新陳代謝且因此適於腫瘤療法。
本發明此外涵蓋5_[4_(2-甲基苯基)-3-羥基-4Η-1,2,4-三 =-5-基卜2,4-二羥基_Ν_曱基丁基苯甲醯胺及/或其生理 干上可接又之鹽及溶劑合物之用途,其係用於製備供保護 正系細胞免於化學療法引起之毒性,以及供治療錯誤蛋白 摺豐或聚集為主要誘因之疾病(諸如,錦羊癢病、庫賈氏 病、予廷頓症或阿茲海默症)的藥物。 本發明亦係關於5-[4-(2-甲基苯基)-3-羥基三 唑-5-基]·2,4-二羥基甲基_N_丁基苯甲醯胺及/或其生理 學上可接受之鹽及溶劑合物之用途,其係用於製備供治療 中樞神經系統疾病、心血管疾病及惡病質的藥物。 在另一實施例中,本發明亦係關於5-[4-(2-甲基苯基)_3_ 說基-411-1,2,4_三唑_5_基]-2,4-二經基->1-甲基->^丁基苯曱 酿胺及/或其生理學上可接受之鹽及溶劑合物之用途,其 係用於製備供調節HSP90之藥物,其中所調節之生物 HSP90活性在個體内引起免疫反應、自内質網輸送蛋白 貝、自低氧/缺氧應力中恢復、自營養不良中恢復、自熱 應力中恢復,或其組合,及/或其中該病症為一種癌症、 127120.doc -47- 200838502 傳染病、與自内質網輸送之已破壞 衣贪白貝有關之病症、與 局部缺血/再灌注有關之病症,或 甘士 ^ 乂具組合,其中與局部缺 血/再灌注有關之病症為心跳驟停、心博停止及延遲心室 心律不整、心臟手術、心肺繞道手術、器官移植、脊歸指 傷、頭部外傷、中風、栓塞性中風、出血性中風、腦血管 痙攣、張力減退、低域、癲癇持續狀態、癲癇發作、焦 慮、精神分裂症、神經退化性病症、阿兹海默症 '亨廷頓 氏病、肌萎縮性側索硬化(ALS)或新生應力所引起之处 果。 、、。 〜在另-實施例中,本發明亦係關於5_[4_(2_甲基苯基 經基·4Η_1,2,4_三唾其1 9 4 -〜甘、 土 h2,4-一搜基甲基丁基苯甲 醯胺及/或其生理學上可接受之鹽及溶劑合物之用途,其 係用於製備供治療局部缺血之藥物,該局部缺血係心跳驟 停、心博停止及延遲心室心律不整、心臟手術、心肺繞道 手術、器官移才直、脊髓損傷、頭部外傷、中風、栓塞性中 風1血性中ϋ血管痙攣、張力減退、低血糖、_ 持續狀態、癲癇發作、焦慮、精神分裂症、神經退化性病 症阿β海,,,犬症、予廷頓氏病、肌萎縮性側索硬化(als) 或新生應力所引起之結果。 【實施方式】 量測HSP90抑制劑之測試方法 可利用格爾德黴素或17,丙基胺基-17_去甲氧基格爾德 徽素(17AAG)與HSP90之結合及其ϋ爭性抑制來測定本發 月化口物之抑制劑活性(Carreras等人,2〇〇3,等 127I20.doc -48- 200838502 人,2002)。在特定狀況下,使用放射性配位子過濾結合 測試。本文所用之放射性配位子為氣標記之17-烯丙基胺 基格爾德黴素,[3H]17AAG。此過濾結合測試允許干擾 ATP結合部位之抑制劑的靶向搜索。 材料 重組人類HSP90a(由大腸桿菌表現,95%純度); ^ [3H]17AAG(17-烯丙基胺基格爾德黴素,[烯丙基胺基- 2,3·3Η·特異性活性:l.llxlO12 Bq/mmol (Moravek,MT-• 1717); HEPES過濾緩衝液(50 mM HEPES,pH 7.0,5 mM MgCl2,BSA 0.01 %)
Multiscreen FB(1 μπι)過濾、培養盤(Millipore,MAFBNOB 50) 〇 方法 首先沖洗96孔微量滴定過濾培養盤且以0.1%聚伸乙基亞 ^ 胺將其塗佈。 測試係在以下條件下進行:
反應溫度22°C > 反應時間:30分鐘,在800 rpm下振盪 、 測試體積:50 μΐ 最終濃度:
50 mM HEPES HC卜 pH 7.0,5 mM MgCl2,0.01% (w/v) BSA HSP90 :每次檢定1.5 127120.doc -49- 200838502 [3H]17AAG:0.08 μΜ。 在反應結束時,藉助於真空歧管(Multiscreen Separation System,Millipore)抽吸來移除過濾培養盤中之上清液,且 將過濾器洗滌兩次。 接著將過濾培養盤在β計數器(Microbeta,Wallac)中以閃 爍計數器(Microscint 20,Packard)計數。 ”對照%”係由π每分鐘計數”值測定且化合物之IC5〇值係由 其計算。 下表展示本發明化合物與來自最接近先前技術之化合物 ”Α47Π之比較量測。本發明之化合物”0:1"在HSP90抑制上 具有高出約10倍的活性。
測試結果 表I HSP90抑制 化合物 IC5〇 [mol/1] 5-[4-(2·曱基苯基)-3-羥基-4H-1,2,4-三唑-5-基]-2,4· 二羥基-Ν-甲基-Ν-丙基苯甲醯胺(ηΑ47π) 1.60E-07 5-[4-(2-甲基笨基>)-3-經基4H-l,2,4二ϋ坐-5基]-2,4-二羥基-N-甲基-N·丁基苯甲醯胺(”CΓ) 2.90E-08 在上文及下文中,所有溫度係以°C表示。在以下實例 中,”習知處理"意謂··若必要,則添加水,若必要,則將 pH調整至介於2與10之間,其係視最終產物之組成而定, 將混合物以乙酸乙酯或二氯曱烷萃取,使各相分離,將有 機相經硫酸鎂乾燥且蒸發,且將產物藉由矽膠層析法及/ 或結晶法純化。矽膠上之Rf值;溶離劑:乙酸乙酯/甲醇 127120.doc -50- 200838502 9:1。 LC-MS條件 HP 1100系列Hewlett Packard System具有以下特徵:離 子源:電喷霧(正離子模式);掃描:100-1000 m/e ;斷裂 電壓·· 60 V ;氣體溫度:300°C,DAD : 220 nm。 • 流動速率:2.4 ml/min。所用分裂器在DAD後將MS之流 . 動速率降低至0.75 ml/min。 管柱:Chromolith SpeedROD RP-18e 50-4.6 _ 溶劑:Merck KGaA之 LiChrosolv 品質 溶劑 A ·· Η20(0·01% TFA) 溶劑Β : ACN(0.008% TFA) 梯度: 20% B— 100% Β : 0分鐘至2·8分鐘 100% Β : 2.8分鐘至3.3分鐘 100% Β->20% Β : 3.3 分鐘至 4分鐘 ⑩ 以下實例中指示之滯留時間Rf或Rt [分鐘]及Μ+Η+資料 MW為LC-MS量測之量測結果。 參考實例1 • 5-(2,4·二羥基-5-苯乙基苯基)-4-(2-氟苯基)_3_羥基-4H- . 1,2,4-三唑(,,Α1Π)之製備: 1.1將15 g 5·溴-2,4-二羥基苯甲酸、14·4 ml碘甲烷及 62.9 g石炭酸铯於1〇〇 ml N,N-二甲基甲酿胺(dmF)中之溶液 在回流下加熱16小時。使混合物經受習知處理,產生16.7 g 5·溴-2,4-二甲氧基苯甲酸(π1")。 127120.doc -51- 200838502 1·2將4 g ”1”及2滴DMF於40 ml亞硫醯氯中之混合物在室 溫下攪拌16小時。移除溶劑產生4·3 g 5-溴-2,4-二甲氧基 苯甲酿氯(,,2"),Rf 1.610 ; MW 280.5。 產物未經進一步純化即反應。 1·3在冰冷卻下將3.8 g ”2”於25 ml二氯甲烷中之溶液逐 滴添加至1.314 ml 2-氟苯胺及1.13 ml吡啶於25 ml二氯甲 烧中之溶液中,且將混合物在室溫下攪拌5小時。習知處 理且由異丙醇結晶產生4.5 g 5_溴-N_(2_氟苯基)-2,4_二甲 氧基苯曱醯胺(”3n),Rf 2.217 ; MW 3 5 5.2。 1·4在氮氣氛下將2.9 g PC15添加至4·5 g,,3"於60 ml甲苯 中之溶液中,且將混合物在回流下加熱3小時。移除溶 劑’將殘餘物溶解於1〇〇 ml THF中,且在〇。(:下將溶液逐 滴添加至1 Μ肼於THF中之138 ml溶液中。將混合物再搜 拌16小時,經受習知處理且由異丙醇結晶產生3.6 g n_(2_ 氟苯基)-3-溴-4,6-二曱氧基苯曱醯胺腙(”4"),Rf 〇 952 ; MW 369·2 〇 Η2Ν\
1·5將1·86 g 1,1,-羰基二咪唑(”5”)添加至3·6 g ”4"於別〇 ml THF中之溶液中,且將混合物再攪拌16小時。使混合物 經受習知處理’將殘餘物以MTB醚煮沸且冷卻,且分離出 晶體,產生700 mg 5-(2,4-二甲氧基溴苯基)_4·(2_氟苯 127120.doc -52- 200838502 基)-3-經基-4Η-1,2,4·三唑("6"),Rf 1.413 ; MW 395.2。 1·6將 600 mg ”6”、178·4 μΐ苯乙烯(經穩定化)、430.2 μΐ 二乙胺、14_1 mg乙酸鈀(^)(470/0 Pd)、a 17 mg三鄰甲苯 基膦及4 ml乙腈引入1〇 ml小瓶中。在i7(rc下,將混合物 在微波中照射30分鐘。添加少量催化劑,且將混合物再照 射兩次。向混合物中添加甲苯,接著將其以水萃取數次。 將有機相乾燥且蒸發。將殘餘物經由rP層析法純化,產生 140 mg ”7”(Rf 1.765 ; MW 418.4)及 40 mg "8”。
F
OH
F OH 1·7在標準條件下,將140 mg ”7”在10 ml THF中於〇.14 g Pt/C(5%)存在下氫化。隨後分離出催化劑且使其經受習知 處理,產生 140 mg,,9”,Rf 1.920,MW 420.5。
127120.doc -53· 200838502 加158_5 μΐ二溴化硼,且將混合物在室溫下再攪拌μ小 時。在〇cC下添加甲醇,且分離出溶劑,且將殘餘物經由 RP層析法純化產生 74 mg ” A1" (Rf 1537 ; mw 392.4)及 27 mg nA2”(Rf 1.884 ; MW 398.4)。
參考實例2 5-[4-(2_氟苯基)_3_羥基三唑_5_基]_2,4·二羥基_ N-甲基丙基苯甲醯胺(,,a46”)之製備 2,1在10〇 C及7·5巴下,將1〇〇 mg 5-(2,4-二曱氧基 溴苯基)-4-(2-氟苯基)·3-羥基-4H-1,2,4-三唑(,,6")、7 mg氯
化[(R)-(+)_2,2-雙-(二苯膦基)-1,1,_聯萘]!巴⑴)、57瓜卜 氧化碳及35 pi三乙胺於20 ml甲醇中之溶液在高壓釜中處 理20小時。隨後將所得溶液濃縮且由乙醇結晶,產生91 mg如下之5-[4-(2·氟苯基)·3-羥基-4H-1,2,4-三唑-5-基]-2,4· 二曱氧基苯甲酸甲酯,Rt 1.057分鐘,m/e 374。
127120.doc 200838502 2·2類似於實例1.8,使90 mg 5-[4-(2-氟苯基)-3_羥基_ 4Η-1,2,4-二嗤-5-基]-2,4-二甲氧基苯甲酸曱酯反應產生 57.2 mg化合物 5-[4-(2-氟苯基)-3-羥基-4Η-1,2,4-三唑-5- 基]-2,4-二羥基苯甲酸,Rt〇 598分鐘,m/e 332。 2.3 將 55 mg 5-[4·(2-氟苯基)-3-羥基-4H-1,2,4-三唑-5- 基]-2,4-二羥基苯甲酸、2莫耳當量第三丁基二甲基氯矽烷 及2 ml THF中之3莫耳當量咪唑在室溫下攪拌3小時,產生 如下化合物。
2,4將2.3中獲得之產物溶解於1.5 ml THF中,且添加2 ¥ II-(3-一曱胺基丙基乙基碳化二亞胺鹽酸鹽。在室 溫下1小時後,添加12當量丙基曱基胺,且將混合物再櫈 拌18小時。隨後添加3當量氟化四曱基銨,且將混合物在 室溫下攪拌2小時。濃縮後,分離出產物,產生42 mg ’’A46” ; Rt 1.139分鐘,m/e 387 ; MW 386。
127120.doc -55- 200838502 類似地獲得以下化合物: 5-[4-(2-甲基苯基)-3-羥基-4H-1,2,4-三唑-5-基]-2,4-二羥 基·Ν-曱基-N-丙基苯甲醯胺(nA47n),MW 3 83.4。 實例1 類似於"Α47"之製備獲得本發明化合物5-[4-(2-甲基苯 基)-3-羥基-4Η-1,2,4-三唑-5-基]-2,4-二羥基-Ν-甲基-Ν-丁 基笨曱醯胺(nCln);
!H NMR (500 MHz,DMSO-d6) δ 11.86 (s,1H),9·92 (s, 1Η),7.28-7.23 (m,2Η),7.14-7.10 (m,1Η),7·03-7·01 (m, 1H),6·88 (s,1H),6.26 (s,1H),3.16 (寬峰,m,2H),2.73 (寬峰,s,3H),2.14 (s,3H),1.40 (寬峰,m,2H),1.15 (寬 峰,m,2H),0.81 (寬峰,m,3H)。 實例2 可如下進行nCln之合成:
0
127120.doc -56- 200838502
2.1 5 -溴-2,4 -二經基苯甲酸(!)··
將3.55 kg 2,4-二羥基苯甲酸溶解於3〇 1冰乙酸中。隨後 在15°C下,經8小時逐滴添加1〇6〇 ml溴於1〇 1冰乙酸中之 溶液。接著在20 °C下繼續攪拌16小時,將混合物真空蒸 發’且將結晶殘餘物在201:氯甲烷中漿化且攪拌1小時。 過濾且在空氣中乾燥產生4·9 kg白色粗產物。由3〇 1甲苯/ 乙腈(1:1)再結晶且乾燥產生3 549 kg(66%產率)5_溴_2,心二 經基苯甲酸(熔點 21〇_211.5°C ; MW 233.0)。 2·2 5-溴-2,4-二羥基苯甲酸曱酯(足): 將8.9 kg 5-溴-2,4-二羥基苯甲酸溶解於70 1曱醇中且將 其加熱至55°C。隨後計量添加800 ml硫酸(w = 95_98。/〇), 且將混合物在溫和回流下攪拌4天,每日再添加5〇〇 ―硫 酸(w - 95-98%)(3次)。將反應混合物攪拌入9 kg碳酸氫鈉 於100 1水中之冷溶液(5°C)中。過濾且在50°C下真空乾燥 127120.doc -57- 200838502 產生7.87 kg(83%)5-溴-2,4_二羥基苯甲酸甲酯(白色晶體), MW 247.1 〇 2·3 2,4-雙苯曱乳基-5-漠苯甲酸曱酯(3): 在0C下,將7·86 kg(83%)5-溴-2,4-二羥基苯甲酸甲酯及 9·65 kg碳酸鉀懸浮於1〇〇 1乙腈中。隨後將混合物加熱至肋 °C,且經40分鐘由滴液漏斗添加7575如苯甲基溴。在 . °C下攪拌16小時後,過濾混合物,且將所收集之濾液真空 蒸發· 12·95 kg(95%)2,4-雙苯甲氧基-5-溴苯甲酸曱酯(微 •黃色晶體);MW 427·3。 2.4 2,4-雙苯甲氧基-5-溴苯甲酸(生): 將18 1 THF中之6·4 kg 2,4·雙苯甲氧基-5_溴苯曱酸甲酯 添加至3 kg氫氧化鈉於30 1水中之溶液中。在68。〇下攪拌 隔仪後,將混合物冷卻至1(TC,且經由滴液漏斗(pH 〇添 加7.5 1 HCl(w: 37%)。將混合物再攪拌1小時,且隨後過 濾。在60 °C下將殘餘物真空乾燥至恆定重量;5.687 • kg(91%)2,4-雙苯甲氧基-5-溴-苯甲酸(熔點15〇-152〇c ; MW 413.3)。 2·5 2,4-雙苯曱氧基-5-溴-N-鄰甲苯基笨甲醯胺(^) ·· • 將80 DMF添加至42 1亞硫醯氯中。將混合物冷卻至2_ - 9 C,且經1小時時段添加11.55 kg 2,4-雙苯曱氧基_5_溴苯 甲酸。在此溫度下再繼續攪拌1小時,且接著在25χ:下擾 拌16小時。接著真空(300毫巴,46。〇蒸餾除去亞硫醯氯。 接著將3 1曱苯添加至所得殘餘物中,且將混合物再次蒸發 至乾燥,且將此程序再重複2次。不經進一步純化而將所 127120.doc -58- 200838502 得產物用於隨後反應中。13 6kg(加上甲苯 在3 C下’將2·8 1鄰甲笑脸芬,《^ 州T本胺及2_5 1吡啶添加至50 1二氯甲 烧中。將懸浮於35 1二氯甲烷中夕w ^ ^ _ 軋Τ沉f之13.6 kg 2,4-雙苯甲氧基-
5-漠苯甲耗(甲苯職)經2小時之難添加至此溶液中。 隨後將混合物在饥下攪拌隔夜,且遽出固體且以二氯甲 烷沖洗(2χ ’每次5 〇該固體。將以此方式獲得之粗產物(8 kg)溶解於40 !二氯甲燒中且以4〇】蒸顧水、5〇 i鹽酸(約i mol/1;由5 i HC1 w: 37%與5〇 i水製備)連續萃取。隨後將 有機相以50 1水洗滌。將有機相使用6 kg硫酸鈉乾燥3天。 經吸濾器抽吸濾出乾燥劑,且將濾液在旋轉蒸發器中蒸發 至乾燥。由乙醇(35 1,65。〇再結晶且乾燥(5(rc/35毫巴) 至恆定重量產生10.84 kg(82%)2,4-雙苯甲氧基_5_溴_%鄰 甲苯基苯甲醯胺(熔點174.5°C -176°C ; MW 。 2.6 5-(2,4-雙苯甲氧基-5-溴苯基)_4_(2_甲基苯基羥基_ 411-1,2,4-三唾(色): 在3°C下,將1.75 kg五氯化麟添加至6〇 1曱苯中之3.5 kg 2,4-雙苯甲氧基-5-溴-N-鄰甲苯基苯甲醯胺中。隨後將混 合物在135°C下加熱4小時,且接著在25°C下繼續攪拌16小 時。真空蒸發產生3 · 6 kg結晶物質。將後者溶解於1 8 1 THF中且在3°C下經1.5小時之過程將其添加至^以kg Boc-肼於30 1 THF中之溶液中。溫至251且攪拌16小時後,以 抽吸濾出產物(4.3 kg白色產物-THF濕氣)且將其直接用 於隨後反應中。 將產物溶解於30 1 THF中,且在rc下經20分鐘之過程 127120.doc -59- 200838502 添加7 1鹽酸(w : 37%)。將、、日人此丄 將此合物在23t下攪拌16小時, 且冷卻至-5°C,且經1·5小時夕、两扣、r、 , 、之耘逐滴添加7·5 1氫氧化鈉 洛液(w: 32〇/〇)。使各相分離, 1將有機相以25 1飽和氯化 鈉〉谷液(由8 ·75 kg氣化鈉與25〗士制扯 1水製備)洗滌。將有機相使 用6 kg硫酸納乾燥,以抽吸渡出乾燥劑且將攄液在旋轉暮 發器中蒸發至乾燥。向殘餘物中添加2x 5 i甲苯,且進行" 峰式"蒸餾以"帶走"剩餘之水。# ^ 將以此方式獲得之殘餘物
直接進行進-步反應。將h3 kg幾基二咪唾(cdi)溶解於 1〇0 1THF中。冷卻至代後,絲自前述反應之產物緩慢 逐滴添加至25 i THF+。隨後將混合物在说下擾掉叫、 時’且以30 i飽和氣化納溶液萃取,且接著將有機相以251 IN HC1萃取。隨後將有機相以25丨飽和氣化鈉溶液洗務且 使用10 kg硫酸鈉乾燥。過濾且真空蒸發有機相產生固體 殘餘物,將其溶解於5 1甲苯中且在真空中再次蒸發至乾 燥。在70°C下由20 1 2-丙醇再結晶產生2 7 kg(76%)5_(2,4· 雙苯曱氧基-5-溴苯基)_木(2_甲基苯基>3 一羥基“札^心三 唑,MW 542.4。 2·7 5-[4-(2-甲基苯基)·3·羥基-4H-1,2,4-三唑-5-基]-2,4-雙 苯甲氧基-N-甲基-N- 丁基苯甲醢胺⑺: 在120°C及5-10巴下將2 kg 5-(2,4-雙苯曱氧基漠苯 基)-4_(2-甲基苯基)-3-經基-4Η-1,2,4·三唾、90 g氯化(1 ι,_ 雙(二苯膦基)二茂鐵)鈀(II)、83 !一氧化碳、479 g三乙胺 及400 g N-甲基丁基胺於25 1 THF中之溶液在高壓爸中處 理20小時。隨後將所得溶液蒸發且由乙醇結晶,產生1 4 127120.doc -60 - 200838502 kg(70%)5_[4-(2-甲基苯基)-3·羥基-4H-1,2,4-三唑-5-基]-2,4-雙苯甲氧基甲基-N-丁基苯甲酸胺,MW 476.7。 2.8 5-[4-(2-甲基苯基)-3-髮基-41!-1,2,4-三峻-5-基]-2,4-二 羥基-N-甲基·Ν-丁基苯甲醯胺("A1"): 在 23 C 下,將 1.1 kg 5-[4-(2-甲基苯基)_3-羥基 _4H· 二唑-5-基]-2,4-雙苯曱氧基甲基丁基苯甲醯胺、5% • Pd/q50·5。/0^^及85 1氫於10 1 THF中之溶液在高壓釜中處 理7小時。隨後將所得溶液蒸發且由乙醇結晶產生8 鲁 g(95%)5-[4-(2·甲基苯基)-3,基-4H-1,2,4-三啥 _5_基]_2,4· 二羥基-N·甲基-N-丁基苯甲醯胺("Cl") ; Mw 396 5。 可分離本發明化合物"C1"之兩種多晶型形式ai&a2。 熔點: 形式八1:熔點 238.5 士〇.1。〇(11==6) 形式 A2 ··熔點 209.6 士 〇.2°C (η = 6) 形式A1為熱力學上較穩定之形式。 • ㈣多晶型形式之粉末x光繞射譜展示於圖i中。 形式A2可(例如)藉由在諸如甲醇、乙醇、丙酮、DMF、 乙酸、曱酸、THF或異丙醇之溶劑中㈣而轉化為ai。 • 多晶型A1及A2之粉末XRD譜資料: ^ 在各狀況下將10個特徵峰用於評估。 —-—---—_ 樣本 [__ XRD原始眘姐 批次7,形式A1 RT 1 批次12,形式A2 -------- -----一 1 I xJjC^XJ / ----RT 2214-07__ 程序及結果: 127120.doc -61 - 200838502 X光粉末繞射(XRD) 所有樣本係藉由XRD量測。 RT 162-07 : • D5 000繞射儀[Bruker AXS] •透射模式
' •發生器功率30 kV/40 mA ' · CuKal-輻射1.5406 A(第一單色儀) •位置敏感偵測器 _ XRD量測條件: 範圍:3-65。20 解析度:0.05°2Θ 步長時間:1.4 s RT 2214-07 : • Stoe粉末X光繞射儀系統STADIP611KL •透射模式
^ •發生器功率40 kV/40 mA • Cu-Kal-輻射1.5406人(第一單色儀) •位置敏感偵測器 XRD量測條件: „ 範圍:3 - 65°2Θ 解析度:0.5°2Θ 步長時間:15 s 形式 Al ; RT 162-07 · 127120.doc -62- 200838502 編號 d[A] 2Θ I/Io 1 9.3 9.5 100 2 6.8 13.0 43 3 5.3 16.8 60 4 4.7 18.9 50 5 4.6 19.5 75 6 4.1 21.8 15 7 3.6 24.7 96 8 3.4 26.4 21 9 3.2 27.8 16 10 2.5 36.6 11 形式 A2 ; RT 2214-07 : 編號 d[A] 2Θ I/Io 1 11.8 7.5 38 2 8.4 10.5 100 3 5.4 16.4 32 4 4.4 20.2 60 5 4.2 20.9 64 6 4.0 22.4 46 7 3.8 23.5 28 8 2.9 31.2 11 9 2.3 38.8 13 10 2.2 41.3 9
前藥化合物之製備 實例3 磷酸單-[2-(丁基甲基胺甲醯基)-5-羥基-4-(5-側氧基-4-鄰 甲苯基-4,5-二氫-1H-1,2,4-三唑-3-基)苯基]酯之製備 127120.doc -63 - 200838502
首先在冷卻下將700 mg 5-[4_(2-甲基苯基)_3_羥基_4h_ 1,2,4_二唑-5-基]-4-苯甲氧基-2_羥基-沁甲基卞_丁基苯甲 醯胺引入20 ml乙腈中,且添加1〇㈤丨四氯化碳。接著將〇·5 ml Ν乙基一異丙基胺及5〇 mg 4_(二曱基)吡啶及326 μ亞 膦酸二苯甲基酯在_1〇艺下緩慢逐滴添加。將混合物在此 皿度下再攪拌3〇分鐘,添加〇·5 μ ΚΗ2Ρ〇4於水中之1〇 ml 溶液,且將混合物以乙醚萃取,經硫酸鈉乾燥、過濾且蒸 發。藉由管柱層析法產生550 mg(5 1%)5-[4-(2-甲基苯基)_ 3-羥基-4Η·1,2,4-三唑-5-基]-4-苯曱氧基-2-(二苯甲基磷酸 酉曰)->^甲基-:^_丁基苯甲醯胺(1^2.196分鐘;1^\^ 746.8)。 在23°C下’將550 mg 5-[4-(2·甲基苯基)_3_羥基-4H-1,2,4-三唑-5-基]-4·苯甲氧基-2-(二苯曱基亞磷酸酯曱 基-Ν-丁基苯甲醯胺、5% Pd/c(5〇_5%4)及49·5 ml氫於1〇 ml THF中之溶液在高壓釜中處理19小時。隨後將所得溶液 蒸發且由乙醚結晶;280 mg(79.8%)磷酸單—[2-(丁基曱基 127120.doc -64- 200838502
鐘。 實例6
N-丁基-2,4-二羥基-N-甲基-5-(5-硫酮基-4-鄰甲苯基-4,5-二 氫-1Η·1,2,4-三唑-3-基)苯甲醯胺(G)之製備
實例7 "C1"葡糖醛酸衍生物之製備 127120.doc -66- 200838502
將4 ml磷酸鉀緩衝液(0.1 M/pH 7.4,具有1〇 mM MgCl2) 100 mg尿苷_5,_二膦醯葡糖醒酸納鹽、邮 m "C1"(懸浮於lml2〇%乙腈中)及^諸肝組織句衆引入樣 本小瓶中。將批料在坑下培育。24小時後乙猜, «; 將混合物離心,且接著將上清液蒸發至乾燥。 三種區位異構體之分離及分析係藉助於L(:_Ms進行。 LC-MS條件 具有以下特徵之Hewlett Packard HP 11 〇〇系列系統:離子 源:電喷霧(正離子模式);掃描:1〇0_1000 m/e ; 斷裂電壓:60 V ; 氣體溫度:300°C ; DAD : 220 nm 〇 流動速率:2·4 ml/min。所用之分裂器在DAD後將MS之 127120.doc -67- 200838502
以下實例係關於醫藥組合物 實例A ··注射小瓶 使用2 N鹽酸將100 g本菸 ^明之活性成份及5 g磷酸氫二 納於3 1再療館水中之溶液带敕 收調整至PH 6.5,將其無菌過濾, 轉移至注射小瓶,在益菌检放 牡…、囷條件下凍乾且在無菌條件下密
封。各注射小瓶含有5 mg活性成份。 實例B :栓劑 將20 g本發明之活性成份與1〇〇 g大豆印填脂及^⑽g可 可脂之混合物㈣,將其倒人模具中且使其冷卻。各检劑 含有20 mg活性成份。 實例C :溶液 由940 ml再蒸餾水中之1 g本發明之活性成份、9 38 g NaH2P04 · 2 H20、28.48 g Na2HP04 · 12 h2〇及 〇·! g氯化 苯甲烴銨製備溶液。將pH調整至6.8,且將溶液補足至1 i 127120.doc -69 - 200838502 且藉由照射將其無菌化。此溶液可以滴眼劑形式使用。 實例D :軟资 在防腐條件下將500 mg本發明之活性成份與99·5 g凡士 林(Vaseline)混合。 實例E ··錠劑 將1 kg本發明之活性成份、4 kg乳糖、1 ·2 kg馬鈴薯澱 粉、0.2 kg滑石粉及〇1 kg硬脂酸鎂之混合物以習知方式擠 L產生叙9彳’使传各錠劑含有1 〇 mg活性成份。 實例F :糖衣藥丸 類似於實例E壓縮錠劑且隨後以習知方式將其用蔗糖、 馬鈴薯澱粉、滑石粉、黃耆膠及染料之包衣將其塗佈。 實例G :膠囊 將kg本务明之活性成份以習知方式引入至硬明膠膠 囊中,使得各膠囊含有2〇mg活性成份。 實例Η :安瓶 將1 kg本發明之活性成份於6〇 1再蒸餾水中之溶液無菌 過濾,將其轉移至安瓶中,在無菌條件下凍乾且在無菌條 牛下#丄封各女瓶含有1 〇 mg活性成份。 【圖式簡單說明】
圖1展示化合物,,C1”之兩種多晶型形式A1及A2的粉末X 光繞射譜。 127120.doc
Claims (1)
- 200838502 十、申請專利範圍: 1 · 一種化合物 一 5-[4你甲基苯基,基-.R4三嗤|基卜2,4·二 搜基·N•甲基丁基笨甲醯胺, 一 w某+上可用之衍生物、鹽、溶劑合物、互變異 構體及立體異構體,包括其所有比率+物^ • 2·=求項1之化合物,其中該等醫藥學上可用之衍生物 久、乂下各物之群群··單石粦酸及二填酸衍生物、硫酮 ^ 衍生物、單葡糖趁酸及二葡糖駿酸衍生物。 3· T種藥物’其包含5K2-曱基苯基)-3,基-4H-1,2,4-三 Λ 5基]_2,4_二羥甲基·N•丁基苯甲醯胺及/或其醫 藥學上可用夕# 1 Μ λ, J用之何生物、鹽、溶劑合物、互變異構體及立 體異構體,包括其所有比率之混合物,以及視情況之賦 形劑及/或佐劑。 4·種5_[4·(2-甲基苯基)-3-羥基·4Η-1,2,4-三唑-5-基]-2,4_ 龜 一搜基_1甲基-丁基苯曱醯胺,及其醫藥學上可用之 鹽、彡谷劑合物互變異構體及立體異構體,包括 其所有比率之混合物之用途,其係用於製備供治療及/或 • 預防與HSP90之抑制、調控及/或調節作用相關之疾病用 , 的藥物。 5·如明求項4之5-[4-(2_曱基苯基)_3_羥基·4Η-1,2,4-三唑-5-基]-2,4-二經基_Ν•曱基_Ν_ 丁基苯甲醯胺及其醫藥學上可 用之街生物、鹽、溶劑合物 '互變異構體及立體異構 體’包括其所有比率之混合物的用途,其係用於製備如 127120.doc 200838502 下藥物 ;/Q療或預防腫瘤疾病、病毒疾病、移植之免疫抑 制、發炎引發之疾病、囊腫性纖維化、與血管生成有關 之疾病、傳染病、自體免疫疾病、局部缺血、致纖維化 疾病, 瘳 用於促進神經再生, 用於抑制癌症、腫瘤細胞之生長及腫瘤新陳代謝用, _ 用於保護正常細胞免於化學療法引起之毒性, 用於治療以錯誤蛋白摺疊或聚集為主要誘因之疾病。 如明求項5之用途,其中該等腫瘤疾病為纖維肉瘤、黏 液肉瘤、脂肉瘤、軟骨肉/廇、骨肉瘤、脊索瘤、血管肉 瘤、内皮肉瘤、淋巴管肉瘤、淋巴管内皮瘤、滑膜瘤、 間皮瘤、尤因氏瘤(Ewing,s tum〇ur)、平滑肌瘤、橫紋肌 肉瘤、結腸癌、胰腺癌、乳癌、卵巢癌、前列腺癌、鱗 狀細胞癌、基底細胞癌、腺癌、汗腺癌、皮脂腺癌、乳 _ 頭狀癌、乳頭狀腺癌、囊腺癌、骨髓癌、支氣管癌、腎 細胞癌、肝癌、膽管癌、絨膜癌、精原細胞瘤、胚胎 癌、威姆氏瘤(Wilm’s tumour)、子宮頸癌、睾丸瘤、肺 . 癌、小細胞肺癌、膀胱癌、上皮癌、膠質瘤、星形細胞 • 瘤、神經管胚細胞瘤、顱咽管瘤、室管膜瘤、松果體 瘤、血管母細胞瘤、聽神經瘤、少枝膠質瘤、腦膜瘤、 黑素瘤、神經母細胞瘤、視網膜胚細胞瘤、白血病、淋 巴瘤、多發性骨髓瘤、瓦爾登斯特倫巨球蛋白血症 (Waldenstr5m’s macroglobulinaemia)及重鏈疾病。 127120.doc 200838502i ’如明求項5之用途’其中該等病毒疾病之病原體係選自 由以下各病原體組成之群:A型肝炎、B型肝炎、c型肝 火、流感、水痘、腺病毒、第一型單純疱疹(j^vq)、第 二型單純疱疹(HSV-II)、牛疫、鼻病毒、埃可病毒 (ech〇vlrus)、輪狀病毒(r〇tavirus)、呼吸道融合性病毒 (RSV)乳頭瘤病毒、腫瘍病毒、巨細胞病毒、艾奎諾 病毒(equinovirus)、節足動物攜帶性病、亨特病毒 ( ^rUS)、科沙可病毒((^0乂8&〇]<^¥11*118)、肥腺炎病 毒:麻療病毒、風療病毒、小兒麻痺病毒、人免疫缺陷 病毋1型(mv·1)及人免疫缺陷病毒II型(Ηΐν-π)。 如明:項5之用途’其中該等發炎引發之疾病為類風濕 〖生關即九、哮喘、多發性硬化、1型糖尿病、紅斑性狼 瘡症、牛皮癖及發炎性腸病。 9·如明求項5之用途,其中該等與血管生成有關之疾病為 ㈣病性視網膜病f管瘤、子宮内膜異位症及腫瘤 10·如請求項田、合 ^ 、之用途,其中該等致纖維化疾病為硬皮症、 夕發性肌炎、令I 身14狼瘡症、肝硬化、瘢痕瘤形成、間 貝性腎炎及肺纖維化。 項5之用途,其中該等錯誤蛋白摺疊或聚集為主 H. § *之疾病為綿羊瘪病、庫賈氏病(Creutzfeldt-Jakob disease)、亨娃 負症(Huntington’s)或阿兹海默症 (Alzheimer,s) 〇 12· —種藥物,发 〆、 [_(2·甲基苯基)-3-經基·4Η-1,2,4-三 127120.doc 200838502 唾,*二趣基— 藥學上可用之衍生物、蹿丁基苯p醯胺及/或其醫 體異構體,包括其 i、溶劑合物、互變異構體及立 他藥物活性成份「 比率之混合物,以及至少-種其 J3. —種套件(套組 ⑷有效量之”: 下各物單獨封裝組成: 5-基]_24 _ [4_(2·甲基苯基)·3,基.!,2,4_ 三哇· 上可用之、Γ羥基-N•甲基_Ν·丁基苯甲醯胺及/或其醫藥學 構體,~ 4丁生物、鹽、溶劑合物、互變異構體及立體異 匕括其所有比率之混合物,以及 (b)有 # ^里之另一藥物活性成份。 127120.doc
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