TWI803541B - 對於蛋白激酶具抑制活性之噻吩并[3,2-d]嘧啶化合物 - Google Patents
對於蛋白激酶具抑制活性之噻吩并[3,2-d]嘧啶化合物 Download PDFInfo
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Abstract
本發明係關於一種對於蛋白激酶具抑制活性之化合物4-胺基-N-(1-((3-氯-2-氟-4-羥基苯基)胺基)-6-甲基異喹啉-5-基)噻吩并[3,2-d]嘧啶-7-甲醯胺及其醫藥學上可接受之鹽。
Description
本發明係關於一種對蛋白激酶具抑制活性之噻吩并[3,2-d]-嘧啶化合物、4-胺基-N-(1-((3-氯-2-氟-4-羥基苯基)胺基)-6-甲基異喹啉 -5-基)噻吩并[3,2-d]嘧啶-7-甲醯胺及其醫藥學上可接受之鹽;及包含其作為活性成份之醫藥組合物,該醫藥組合物用於治療起因於異常細胞生長之疾病。
蛋白激酶為在經由酪胺酸、絲胺酸或蘇胺酸殘基中存在之羥基之磷酸化介導信號轉導方面發揮關鍵作用之酶,且因此涉及調節細胞生長、分化及增殖。
眾所周知,細胞內信號傳導路徑之「開啟狀態」及「關閉狀態」之間的平衡對於維持細胞穩態而言為至關重要的。當歸因於特定蛋白激酶之過度表現或突變細胞內信號之常用細胞內信號傳導路徑中斷(例如「開啟狀態」之大部分延續部分)時,其會引起爆發各種疾病,諸如癌症、發炎疾病、代謝疾病及大腦疾病。據估計,人類基因組含有518種蛋白激酶,其構成所有人類基因之約1.7% [Manning等人, Science, 298, (2002), 1912]。蛋白激酶可分成酪胺酸蛋白激酶(90或多於90種類型)及絲胺酸/蘇胺酸蛋白激酶。酪胺酸蛋白激酶可分成:受體酪胺酸激酶,其包括58種不同激酶,其可進一步分成20種亞型;及細胞質/非受體酪胺酸激酶,其包括32種不同激酶,其可進一步分成10種亞型。受體酪胺酸激酶具有表面上其可結合生長因子之激酶區域及酪胺酸殘基之磷酸化發生之活性位點。生長因子結合至受體之細胞外結構域可使得受體酪胺酸激酶形成聚合物,其可導致細胞質域中之特定酪胺酸殘基之自體磷酸化。此可經由細胞內蛋白質磷酸化觸發級聯事件,最終將細胞外信號傳輸至細胞核,由此使得可能涉及細胞生長、分化、增殖及其類似者之各種基因轉錄及合成。
在各種細胞質激酶中,RAF為參與受體蛋白激酶(其藉由生長因子活化)引發之線性Ras-RAF-MEK-ERK有絲分裂原活化蛋白激酶(MAPK)路徑之激酶中之一者[Solit, D. B.等人, Nature, 439,(2006), 358]。存在已知的三種類型之RAF同功異型物A-RAF、B-RAF及C-RAF (RAF-1) [Jansen HW,等人, EMBO J, 2, (1983), 1969;Marais R.等人, Cancer Surv, 27, (1996), 101]。因為已在約30%人類癌症組織中觀測到MAPK路徑中之異常活化,且顯示異常活化之B-RAF及C-RAF之基因突變已確認在癌症組織中,一般認可RAF在癌症組織之MAPK路徑中發揮極其重要的作用。
因此,已提出使用對於RAF激酶之異常活動具有抑制作用之化合物來治療癌症之方法。因此,多種RAF及經修飾之RAF激酶抑制劑目前處於開發中或正在進行中的臨床研究中測試。此類RAF激酶抑制劑之實例包括用於治療肝癌之索拉非尼(sorafenib) (Nexavar®,Bayer)及已批准用於治療黑色素瘤之維羅非尼(vemurafenib) (ZELBORAF®、PLX-4032、RG7204,Roche)。目前正在臨床試驗中測試之RAF激酶抑制劑之其他實例包括:瑞戈非尼(regorafenib)及Bayer之RDEA119;Novartis之RAF265;Advan Chem之E3810;Deciphera Pharma.之DCC2036;Chugai Pharma.之CKI-27;及Roche之RO-5126766。
然而,此類藥物之療效在歷經持續時間投與時受到質疑,儘管其良好初始效能、耐藥性已在初次投與藥物之後約7個月的某些患者中觀測到。
已假定,此類降解可歸因於B-RAF抑制劑之耐藥性,其起因於歸因於RAF變化之MAPK路徑之異常活化、不同RAF同功異型物中之互補信號傳導系統之活化或由於Ras之不同路徑之活化除MAPK外的各種受體激酶之活化、信號轉導級聯中使用之關鍵蛋白質(其由K-Ras、N-Ras及H-Ras亞型組成)。
不涉及RAF激酶之信號傳導路徑中之一者為C-FMS (細胞貓類McDonough肉瘤),亦稱為群落刺激因子-1受體(CSF-1R),其為原先自貓類肉瘤病毒之Susan McDonough病毒株分離之基因家族之成員。FMS為由C-FMS原癌基因編碼之巨噬細胞-群落刺激因子(M-CSF)之受體,其屬於種類III RTK以及Kit、Flt-3及PDGFR。已報導,FMS酪胺酸激酶涉及癌轉移。
另一實例為稱作盤狀結構域受體(DDR)之受體蛋白酪胺酸激酶,其為具有與網柄菌凝集素(lectin discoidin)相關之細胞外結構域之受體酪胺酸激酶子族。在諸如人類之動物之情況下,存在兩種類型之DDR蛋白質(DDR1類型及DDR2類型),其具有類似胺基酸序列,但由不同基因編碼。已報導,DDR蛋白質可涉及癌症生長及轉移之過程。另外,DDR之上調表現已在某些腫瘤細胞中觀測到,以及報導DDR之上調表現升高的已知涉及癌症生長之MMP-1及MMP-2之表現。因此,據相信,抑制此類激酶會引起對於各種類型的癌症之治療效果。
具有改良的蛋白激酶抑制活性之化合物揭示於國際公告號WO 2013/100632中。
此項技術中繼續需要對於RAF、FMS及DDR1及DDR2激酶具抑制活性且相比於習知RAF激酶抑制劑提供各種癌症(包括耐藥性癌症)之改良治療的化合物。
因此,本發明提供一種化合物及包含其之醫藥組合物,其具有有效藥物動力學及藥力學特性,用於藉由抑制RAF (細胞生長、分化及增殖之關鍵調節劑)、FMS及DDR1及DDR2激酶來預防或治療難治性癌症(包括耐藥性癌症)。
本發明之一個實施例係關於一種式(I)之化合物4-胺基 -N-(1-((3-氯-2-氟-4-羥基苯基)胺基)-6-甲基異喹啉-5-基)噻吩并[3,2-d]嘧啶-7-甲醯胺或其醫藥學上可接受之鹽或水合物:。 如本文關於式(I)化合物所使用,術語「其鹽或水合物」及其變化形式涵蓋式(I)化合物之鹽、式(I)化合物之水合物及式(I)化合物之鹽之水合物。 在一些實施例中,式(I)化合物或其醫藥學上可接受之鹽或水合物具有至少95.0%之純度。
在各種實施例中之任一者中,式(I)化合物及其醫藥學上可接受之鹽及水合物具有對於蛋白激酶之抑制活性。
在一個實施例中,抑制活性係針對A-RAF、B-RAF、 C-RAF、DDR1、DDR2及FMS中之一或多者。
在一個實施例中,式(I)為pan-RAF抑制劑。在此類實施例中,抑制活性係針對A-RAF、B-RAF及C-RAF。
在另一實施例中,抑制活性係針對FMS。
在再一實施例中,活性係針對DDR1及DDR2激酶。
本發明之另一態樣亦關於一種包含式(I)化合物或其醫藥學上可接受之鹽或水合物的醫藥組合物。
本發明之另一態樣亦關於用於預防或治療一或多種蛋白激酶之異常活化介導之疾病的方法,該方法包含向有需要之哺乳動物投與化合物或包含本發明之該等化合物之組合物中之任一者。
相關申請案之交叉參考
本申請案主張2017年11月30日申請之美國臨時申請案第62/592679號之優先權。臨時申請案之全文以引入方式併入本申請案中。
現將詳細參考本發明之某些實施例,其實例在隨附結構及式中說明。雖然本發明將結合所列舉之實施例描述,但應瞭解其不欲將本發明限於彼等實施例。相反地,本發明意欲涵蓋替代方案、修改及等效物,其可包括在申請專利範圍所界定之本發明範疇內。熟習此項技術者將能識別類似或等效於本文所描述之多種方法及材料,其可用於本發明之實踐中。本發明決不限於所描述之方法及材料。在所併入之文獻、專利及類似材料中之一或多者不同於本申請案(包括(但不限於)所定義之術語、術語用法、所描述之技術或其類似物)或與其矛盾之情況下,以本申請案為準。除非另外定義,否則本文所用之所有技術及科學術語均具有與本發明所屬領域之一般技術者通常所理解相同之含義。儘管類似於或等效於本文所述之彼等方法及材料之方法及材料可用於實踐或測試本發明,但下文描述適合之方法及材料。所有公開案、專利申請案、專利及所提及之其他參考案均以全文引用的方式併入本文中。
本發明之化合物具有針對蛋白激酶之抑制活性。在一個實施例中,化合物為具有針對A-RAF、B-RAF及C-RAF同功異型物中之至少一者之抑制活性的RAF抑制劑。在一個實施例中,化合物為針對超過一種A-RAF、B-RAF及C-RAF同功異型物具抑制活性之pan-RAF抑制劑。在另一實施例中,該抑制活性係針對FMS。在另一實施例中,該活性係針對DDR1及DDR2激酶。在另一實施例中,該活性為pan-RAF,係針對DDR1及DDR2激酶,且係針對FMS。
在一些實施例中,本發明之式(I)化合物及其醫藥學上可接受之鹽及水合物呈固體形式。
在一些實施例中,本發明之式(I)化合物及其醫藥學上可接受之鹽及水合物在醫藥載劑中呈溶液形式。在一些此類實施例中,溶液中式(I)之濃度為至少0.01 mg/mL、至少0.05 mg/mL、至少0.1 mg/mL、至少0.5 mg/mL、至少1 mg/mL、至少2 mg/mL、至少3 mg/mL、至少4 mg/mL或至少5 mg/mL。
在各種實施例中之任一者中,式(I)化合物或其醫藥學上可接受之鹽或水合物之純度為至少95%、至少96%、至少97%、至少98%、至少98.5%、至少99%或至少99.5 %,其係藉由HPLC所量測。在各種實施例中之任一者中,式(I)化合物或其醫藥學上可接受之鹽或水合物之含量為至少95%、至少96%、至少97%、至少98%、至少98.5%、至少99%或至少99.5 %,其係藉由HPLC所量測。
本發明化合物亦可形成醫藥學上可接受之鹽。此類鹽可為含有陰離子之醫藥學上可接受之無毒性酸加成鹽,但不限於此。舉例而言,該鹽可包括藉由以下酸形成之酸加成鹽:無機酸,諸如鹽酸、硫酸、硝酸、磷酸、氫溴酸、氫碘酸及其他酸;有機碳酸,諸如酒石酸、甲酸、檸檬酸、乙酸、三氯乙酸、三氟乙酸、葡糖酸、苯甲酸、乳酸、反丁烯二酸、順丁烯二酸及其他酸;及磺酸,諸如甲磺酸、苯磺酸、對甲苯磺酸、萘磺酸及其他酸。在一特定實施例中,酸加成鹽為藉由硫酸、甲磺酸或氫鹵酸(例如鹽酸)形成之酸加成鹽。在一個實施例中,式(I)鹽為雙氫氯酸鹽。
另外,式(I)化合物之水合物涵蓋在本發明之範疇內。
本發明化合物可經由通用流程1,分別藉由使用下文所示通用流程1中所獲得之中間物或市售之起始物質或中間物獲得。另外,所獲得之4-胺基-N-(1-((3-氯-2-氟-4-羥基苯基)胺基)-6-甲基異喹啉-5-基)噻吩并[3,2-d]嘧啶-7-甲醯胺之質量分析可藉由使用MicroMass ZQ™ (Waters)進行。
包含4-胺基-N-(1-((3-氯-2-氟-4-羥基苯基)胺基)-6-甲基異喹啉-5-基)噻吩并[3,2-d]嘧啶-7-甲醯胺或其鹽或水合物作為活性成份之醫藥組合物可用於預防或治療起因於一或多種蛋白激酶之異常活化的異常細胞生長疾病。
另外,本發明係關於一種用於預防或治療藉由一或多種蛋白激酶之異常活化介導之疾病之方法,該方法包括向有需要之個體投與本發明化合物。舉例而言,該個體為哺乳動物。
蛋白激酶之實例包括ALK、AMPK、Aurora A、Aurora B、Aurora C、Axl、Blk、Bmx、BTK、CaMK、CDK2/細胞週期蛋白E、CDK5/p25、CHK1、CK2、A-RAF、B-RAF、C-RAF、DDR1、DDR2、DMPK、EGFR1、Her2、Her4、EphA1、EphB1、FAK、FGFR2、FGFR3、FGFR4、Flt-1、Flt-3、Flt-4、FMS (CSF-1)、Fyn、GSK3β、HIPK1、IKKβ、IGFR-1R、IR、Itk、JAK2、JAK3、KDR、Kit、Lck、Lyn、MAPK1、MAPKAP-K2、MEK1、Met、MKK6、MLCK、NEK2、p70S6K、PAK2、PDGFRα、PDGFRβ、PDK1、 Pim-1、PKA、PKBα、PKCα、Plk1、Ret、ROCK-I、Rsk1、SAPK 2a、SGK、Src、Syk、Tie-2、Tec、Trk或ZAP-70。在一些實施例中,一或多種蛋白激酶包括A-RAF、B-RAF、C-RAF、DDR1、DDR2及FMS中之一或多者。在一些實施例中,一或多種蛋白激酶包括A-RAF、B-RAF及C-RAF中之一或多者。在一些實施例中,一或多種蛋白激酶包括DDR1及/或DDR2。在一些實施例中,蛋白激酶為FMS。根據本發明之醫藥組合物針對上述激酶具有抑制活性。
由本發明醫藥組合物可以有效對抗之一或多種蛋白激酶因異常活化導致之異常細胞生長疾病實例包括胃癌、肺癌、肝癌、結腸直腸癌、小腸癌、胰臟癌、腦癌、骨癌、黑色素瘤、乳癌、硬化性腺病、子宮癌、子宮頸癌、頭頸癌、食道癌、甲狀腺癌、副甲狀腺癌、腎癌、肉瘤、前列腺癌、尿道癌、膀胱癌、血癌、淋巴瘤、纖維腺瘤、發炎、糖尿病、肥胖症、牛皮癬、類風濕性關節炎、血管瘤、急性及慢性腎臟疾病、冠狀動脈再狹窄、自體免疫疾病、哮喘、神經變性疾病、急性感染及起因於血管生成之眼部疾病。在一些實施例中,癌症為黑色素瘤或肝癌。
本發明之醫藥組合物可包含選自由以下組成之群的藥物:細胞信號轉導抑制劑、有絲分裂抑制劑、烷基化劑、抗代謝物、抗生素、生長因子抑制劑、細胞週期抑制劑、拓樸異構酶抑制劑、生物反應調節劑、抗激素劑、抗雄激素、細胞分化/增殖/存活抑制劑、細胞凋亡抑制劑、發炎抑制劑及P-醣蛋白抑制劑。在本發明醫藥組合物研發成調配物之情況下,其可與該藥物組合使用或研發成具有該藥物之組合調配物。
在一些實施例中,該藥物為細胞信號轉導抑制劑。在某些此類態樣中,細胞信號轉導抑制劑為MEK抑制劑。MEK抑制劑藥物之非限制性實例包括以下。COTELLIC® (考比替尼(cobimetinib));(GDC-0973;Genentech);[3,4-二氟-2-(2-氟-4-碘苯胺基)苯基]-[3-羥基 -3-[(2S)-哌啶-2-基]氮雜環丁烷-1-基]甲酮;CAS號934660-93-2。GDC-0623 (Genentech);5-((2-氟-4-碘苯基)胺基)-N-(2-羥基乙氧基)咪唑并[1,5-A]吡啶-6-甲醯胺;CAS號1168091-68-6。RO4987655 (Hoffman-La Roche);CH4987655;3,4-二氟-2-(2-氟-4-碘苯胺基)-N-(2-羥基乙氧基) -5-[(3-側氧基氧氮雜環己烷-2-基)甲基]苯甲醯胺;CAS號874101-00-5。RO5126766 (Hoffman-La Roche);3-[[2-[(甲基胺基磺醯基)胺基]-3-氟吡啶-4-基]甲基]-4-甲基-7-[(嘧啶-2-基)氧基]-2H-1-苯并吡喃-2-酮;CAS號946128-88-7。曲美替尼(Trametinib) (GlaxoSmithKline);GSK1120212;N-[3-[3-環丙基-5-[(2-氟-4-碘苯基)胺基]-3,4,6,7-四氫 -6,8-二甲基-2,4,7-三側氧基吡啶并[4,3-d]嘧啶-1(2H)-基]苯基]-乙醯胺;CAS號871700-17-3。皮馬瑟替(Pimasertib) (Array BioPharma及AstraZeneca);AS-703026;Merck。司美替尼(Selumetinib);AZD6244;6-(4-溴-2-氯苯胺基)-7-氟-N-(2-羥基乙氧基)-3-甲基苯并咪唑-5-甲醯胺;CAS號606143-52-6。瑞法美替尼(Refametinib) (Bayer);RDEA119;Bay 86-9766;N-[3,4-二氟-2-(2-氟-4-碘苯胺基)-6-甲氧基苯基]-1-[(2S)-2,3-二羥基丙基]環丙烷-1-磺醯胺;CAS號923032-37-5。PD184352 (Pfizer);CI-1040;(2-氯-4-碘苯基胺基)-N-環丙基甲氧基 -3,4-二氟苯甲醯胺;CAS號212631-79-3。畢尼替尼(Binimetinib) (Array BioPharma及Novartis);MEK162;5-((4-溴-2-氟苯基)胺基)-4-氟-N-(2-羥基乙氧基)-1-甲基-1H-苯并[d]咪唑-6-甲醯胺;CAS號606143-89-9。PD0325901 (Pfizer);N-[(2R)-2,3-二羥基丙氧基]-3,4-二氟-2-[(2-氟-4-碘苯基)胺基]-苯甲醯胺;CAS號391210-10-9。AZD8330 (AstraZeneca);2-(2-氟-4-碘苯基胺基)-N-(2-羥基乙氧基)-1,5-二甲基-6-側氧基-1,6-二氫吡啶-3-甲醯胺;CAS號869357-68-6。TAK-733 (Millennium Pharmaceutical and Takeda Pharmaceutical Company);(R)-3-(2,3-二羥基丙基)-6-氟-5-(2-氟-4-碘苯基胺基)-8-甲基吡啶并[2,3-d]嘧啶 -4,7(3H,8H)-二酮;CAS號1035555-63-5。WX-554 (Wilex, AG)。HL-085 (Binjiang Pharma)。瑞戈非尼(Regorafenib) (Bayer);4-(4-(3-(4-氯-3-(三氟甲基)苯基)脲基)-3-氟苯氧基)-N-甲基吡啶甲醯胺;CAS號755037-03-7。RAF265 (Novartis);CHIR-265;1-甲基-5-[2-[5-(三氟甲基)-1H-咪唑-2-基]吡啶-4-基]氧基-N-[4-(三氟甲基)苯基]苯并咪唑-2-胺;CAS號927880-90-8。魯西坦布(Lucitanib) (Advan Chem);E3810;6-((7-((1-胺基環丙基)甲氧基)-6-甲氧基喹啉-4-基)氧基)-N-甲基-1-萘甲醯胺;CAS號1058137-23-7。雷巴塔尼(Rebastanib) (Deciphera Pharm);DCC2036;4-[4-[[[[3-(1,1-二甲基乙基)-1-(6-喹啉基)-1H-吡唑-5-基]胺基]羰基]胺基]-3-氟苯氧基]-N-甲基-2-吡啶甲醯胺;CAS號1020172-07-9。CK-127 (Chugai Pharma);RG7304;(E)-5-(2-苯亞甲基-1-甲基肼基)噠嗪-3(2H)-酮;CAS號213406-50-9。在一些實施例中,藥物為考比替尼(cobimetinib)。
本發明醫藥組合物可包含習知醫藥學上可接受之賦形劑,包括載劑、稀釋劑、佐劑、添加劑及媒劑。醫藥組合物可根據習知方法調配,且可以口服調配物,諸如錠劑、丸劑、散劑、膠囊、糖漿、乳液、微乳劑及其他或非經腸調配物,諸如肌肉內、靜脈內或皮下投與形式製備。
當根據本發明之醫藥組合物製備為用於經口投與之調配物時,待使用載劑可包括例如且不限於纖維素、矽酸鈣、玉米澱粉、乳糖、蔗糖、右旋糖、磷酸鈣、硬脂酸、硬脂酸鎂、硬脂酸鈣、明膠、滑石、界面活性劑、懸浮劑、乳化劑、稀釋劑及其組合。另外,當醫藥組合物製備為用於經口投與之調配物時,待使用稀釋劑可包括例如且不限於乳糖、甘露糖醇、醣、微晶纖維素、纖維素衍生物、玉米澱粉及其組合。用於經口投與之調配物亦可包括例如且不限於聚合物(例如親水性聚合物,諸如聚乙烯吡咯啶酮)、抗氧化劑、防腐劑、潤濕劑、潤滑劑、助流劑、加工助劑、成粒劑、分散劑、著色劑及調味劑。
壓製錠劑可藉由在適合的機器中壓縮視情況與黏合劑、潤滑劑、惰性稀釋劑、防腐劑、表面活性劑或分散劑混合之自由流動形式(諸如粉末或顆粒)的活性成分來製備。模製錠劑可藉由在適合的機器中模製經惰性液體稀釋劑濕潤之粉末狀活性成分的混合物來製造。錠劑可視情況經塗佈或評分。錠劑可未包覆包衣或可藉由已知技術(包括微囊封裝)包覆包衣以延遲在胃腸道中崩解及吸收,且藉此提供較長時期的持久作用。舉例而言,可採用時間延遲材料,諸如單獨單硬脂酸甘油酯或二硬脂酸甘油酯或與蠟一起且視情況經調配以便提供由其得到之活性成份之減緩或控制釋放。
當根據本發明之醫藥組合物製備為用於注射之調配物時,待使用載劑可包括例如且不限於水、生理食鹽水、含水葡萄糖溶液、含水糖類溶液、醇、二醇(例如聚乙二醇400)、醚、油、脂肪酸、脂肪酸酯、甘油酯、界面活性劑、懸浮劑、乳化劑及其組合。
實例
實例1:製備化合物式(I)
可根據如下步驟1至4製備化合物式(I)。
本發明之式(I)化合物可經由通用流程1藉由使用下文所示通用流程1中所獲得之中間物或分別市售之起始物質或中間物製備。
上述反應方法例示於以下分步反應中。
將15.1 g鐵粉(0.27 mol,3.0當量)及0.3 mL濃HCl (0.005 mol,0.05當量)添加至300 mL 1:1乙醇/純水混合溶液(15 v/w)中。將反應混合物加熱至90℃,繼而攪拌1小時。將20.0 g 1-氯-6-甲基-5-硝基異喹啉(0.09 mol,1.0當量)添加至反應混合物中且在回流下攪拌5小時。在減壓下經由Celite® (矽藻土)墊過濾反應混合物,且用100 mL 4:1氯仿/異丙醇混合溶液(5 v/w)洗滌。在減壓下蒸發濾液,且使殘餘物溶解於200 mL 4:1氯仿/異丙醇混合溶液(10 v/w)中。有機層用100 mL碳酸氫鈉水溶液(5 v/w)及100 mL鹽水(5 v/w)洗滌。所獲得之有機層經無水硫酸鎂乾燥且在減壓下濃縮。在45℃烘箱中乾燥已濃縮之固體12小時,獲得呈棕色固體狀之所需化合物(14.3 g,83%)。
1
H-NMR譜(300 MHz, DMSO-d 6
) δ 8.12 (m, 2H), 7.48 (q, 2H), 5.87 (s, 2H), 2.28 (s, 3H)。
使4-胺基噻吩并[3,2-d]嘧啶-7-甲酸28.5 g (0.15 mol,1.0當量)溶解於300 mLN,N-
二甲基甲醯胺(10 v/w)中,繼而在20-30℃下添加25.7 g 4-氯-2,6-二甲氧基-1,3,5-三嗪(0.15 mol,1.0當量)及16.1 mL 4-甲基嗎啉(0.15 mol,1.0當量),繼而攪拌20分鐘。隨後在20-30℃下將28.1 g 1-氯-6-甲基異喹啉-5-胺(0.15 mol,1.0當量)添加至反應混合物中,繼而攪拌12小時。向反應混合物中添加300 mL純水(10 v/w)且攪拌反應混合物1小時。在減壓下過濾反應混合物,且用90 mL純水(3 v/w)洗滌。在45℃烘箱中乾燥所得固體12小時,獲得呈棕色固體狀之所需化合物(33.2 g,61%)。
1
H-NMR譜(300 MHz, DMSO-d 6
) δ 11.69 (s, 1H), 8.95 (s, 1H), 8.65 (s, 1H), 8.37 (m, 2H), 7.95 (s, 2H), 7.88 (m, 2H), 2.49 (s, 3H)。
將20 g 4-胺基-N-(1-氯-6-甲基異喹啉-5-基)噻吩并[3,2-d
]嘧啶-7-甲醯胺(54.1 mmol,1.0當量)及17.4 g 4-胺基-2-氯-3-氟苯酚(108.2 mmol,2.0當量)添加至密封管中且在20-25℃下將200 mL異丙醇(10 v/w)及13.5 mL濃HCl (162.2 mmol,3.0當量)添加至反應混合物中。將反應混合物加熱直至130℃,繼而攪拌12小時。使反應物溶液冷卻至20-30℃。在減壓下過濾固體,繼而用50 mL異丙醇100 mL (5 v/w)洗滌以獲得呈深棕色固體狀之所需化合物(23.5 g,77%)。
將23.5 g 4-胺基-N-(1-((3-氯-2-氟-4-羥基苯基)胺基)-6-甲基異喹啉-5-基)噻吩并[3,2-d
]嘧啶-7-甲醯胺二鹽酸鹽(41.4 mmol,1.0當量)添加至1 L圓底燒瓶中且添加470 mL甲醇(20 v/w)。在20-25℃下將12.7 mL三乙胺(91.0 mmol,2.2當量)添加至反應混合物中,繼而攪拌2小時。在減壓下過濾固體,繼而用100 mL甲醇(5 v/w)洗滌。在45℃烘箱中乾燥經過濾之固體12小時以獲得呈棕色固體狀之所需化合物(11.7 g,57%)。
1
H-NMR譜(300 MHz, DMSO-d 6
) δ 11.53 (s, 1H), 10.48 (br, 1H), 8.97 (s, 1H), 8.92 (d, 1H), 8.50 (s, 1H), 8.32 (d, 1H), 7.94 (s, 2H), 7.79 (d, 1H), 7.55 (d, 1H), 7.20 (t, 1H), 7.04 (d, 1H), 6.82 (d, 1H), 2.41 (s, 3H)。
實例2:製備化合物式(I)雙氫氯酸鹽
將11.7 g 4-胺基-N-(1-((3-氯-2-氟-4-羥基苯基)胺基)-6-甲基異喹啉-5-基)噻吩并[3,2-d
]嘧啶-7-甲醯胺(23.6 mmol,1.0當量)添加至500 mL圓底燒瓶中且添加240 mL 80%乙醇(20 v/w),繼而在20-25℃下將5.9 mL濃HCl (70.9 mmol,3.0當量)添加至反應混合物中。將反應混合物加熱直至90℃,繼而攪拌2小時。使反應物溶液冷卻至20-30℃。在減壓下過濾固體,繼而用58.5 mL乙醇(5 v/w)洗滌。在烘箱中在45℃下乾燥經過濾之固體12小時以獲得呈棕色固體狀之所需化合物(10.9 g,81%)。
將10.9 g 4-胺基-N-(1-((3-氯-2-氟-4-羥基苯基)胺基)-6-甲基異喹啉-5-基)噻吩并[3,2-d
]嘧啶-7-甲醯胺二鹽酸鹽添加至3 L圓底燒瓶中且在20-25℃下添加2 L甲醇(200 v/w)。將反應混合物加熱直至50℃,繼而攪拌30分鐘。使反應混合物冷卻至20-30℃。添加1.1 g活性碳,繼而攪拌3小時。在減壓下經由矽藻土墊過濾反應混合物,繼而用100 mL甲醇(10 v/w)洗滌。在減壓下過濾濾液(使用膜濾紙),繼而用100 mL甲醇(10 v/w)洗滌。在減壓下蒸發濾液。向殘餘物中添加甲醇(200 mL),繼而攪拌2小時。在減壓下過濾固體,繼而用50 mL甲醇(5 v/w)洗滌。在烘箱中在45℃下乾燥經過濾之固體12小時以獲得呈淡棕色固體狀之所需化合物(7.7 g,71%)。
將7.7 g 4-胺基-N-(1-((3-氯-2-氟-4-羥基苯基)胺基)-6-甲基異喹啉-5-基)噻吩并[3,2-d
]嘧啶-7-甲醯胺二鹽酸鹽(13.6 mmol,1.0當量)添加至250 mL圓底燒瓶中且在20-25℃下將150 mL 80%乙醇(20 v/w)及2.3 mL濃HCl (27.1 mmol,2.0當量)添加至反應混合物中。將反應混合物加熱直至90℃,繼而攪拌1小時。使反應物溶液冷卻至20-30℃。在減壓下過濾固體,繼而用38.5 mL乙醇(5 v/w)洗滌。向所得固體中添加385 mL甲醇(50 v/w)。將反應混合物加熱直至40℃,繼而攪拌3小時。在減壓下過濾固體,繼而用38.5 mL甲醇(5 v/w)洗滌。在45℃下乾燥經過濾之固體12小時。隨後在25℃,90% RH下乾燥固體化合物12小時。吸濕性固體隨後在室溫下乾燥6小時以獲得呈灰白色粉末狀之所需化合物(4.8 g,62%)。
純度:藉由 HPLC 之97.0%
分析:藉由HPLC之96.8%
水分:4.7%
1H-NMR譜(300MHz, DMSO-d6) δ 11.60 (s, 1H), 11.42 (s, 1H), 9.47 (s, 1H), 8.88 (d, 1H), 8.62 (s, 1H), 7.88 (d, 1H), 7.56 (d, 1H), 7.42 (t, 1H), 7.32 (d, 1H), 7.10 (d, 1H), 2.50 (s, 3H)。
實驗實例3:評估RAF激酶活性
使用Kinase Profiling Service (Thermo Fisher Scientific,此前為Invitrogen,美國),根據製造商的說明書測試實例2中製備之式(I)雙氫氯酸鹽(在下文中稱為「化合物·2HCl」)針對三種RAF亞型(亦即,RAF1 (C-RAF)Y340D/Y341D
、B-RAF野生型及B-RAFV600E
)之抑制活性。化合物之酶促抑制水準經計算為各種濃度下之抑制百分比。基於抑制百分比,使用GraphPad Prism軟體繪製劑量反應曲線。化合物·2HCl針對 C-RAFYY340D/Y341D
、B-RAFWT
及B-RAFV600E
之IC50
值在表1中列出,其中ZELBORAF® (維羅非尼,PLX-40 32,Roche)用作對照組。
實驗實例4:評估對N-RASQ61K
突變細胞株SK-MEL-30 (人類黑素瘤細胞)之細胞生長之抑制
如下測試本發明化合物對增殖異常細胞之抑制活性。
N-RASQ61K
突變SK-MEL-30黑色素瘤細胞株(ACC-151)獲自DSMZ (Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH,德國)。SK-MEL30細胞表現野生型B-RAF及突變N-RAS (Q61K)。在37℃,5% CO2及95%空氣下在補充有10% FBS及1%青黴素/鏈黴素(Gibco BRL)之RPMI培養基中培育SK-MEL-30細胞。以5,000個細胞/孔之密度將細胞接種於96孔板中,且培養18小時或大於18小時。隨後用0.1-10 μM (1/10連續稀釋液)測試化合物處理細胞,且培育72小時。
為了評估細胞活力,用10% TCA (三氯乙酸)固定SK-MEL-30細胞株,用SRB (磺醯羅丹明B)染色,且在540 nm處量測吸收率。隨後由其計算GI50
,亦即,使得癌細胞增殖減少50%之藥物濃度。藉由方程式1或2計算癌細胞之生長速率。
方程式1
[(Ti-Tz)/(C-Tz)] × 100 (對於Ti ≥ Tz)
方程式2
[(Ti-Tz)/Tz] × 100 (對於Ti < Tz)
在方程式1及2中,『Tz』係指未經處理之細胞之密度,其為0%細胞生長組中之吸收率。『C』係指藉由僅添加培養基培養之細胞密度,且『Ti』係指用測試化合物處理之細胞密度。
GI50
值為當方程式1之值為50時測試化合物之濃度,其指示使癌細胞生長減少至50%所需的測試化合物濃度。在每次量測時,將測試化合物與維羅非尼(PLX-4032)對照組進行比較。量測每一化合物之GI50
值且展示於表2中。
如上文所證明,對於蛋白激酶具有抑制活性之本發明化合物4-胺基-N-(1-((3-氯-2-氟-4-羥基苯基)胺基)-6-甲基異喹啉-5-基)噻吩并[3,2-d]嘧啶-7-甲醯胺可有效地抑制包括RAF之各種蛋白激酶,且因此可單獨或組合使用,其用於預防及治療與起因於RAS蛋白質突變或過度表現或其相關蛋白激酶過度活化之異常細胞生長相關的疾病。
Claims (19)
- 如請求項1之式(I)化合物或其醫藥學上可接受之鹽或水合物,其具有至少95.0%之純度。
- 如請求項1或2之式(I)化合物或其醫藥學上可接受之鹽或水合物,其中該式(I)化合物或其醫藥學上可接受之鹽或水合物為固體。
- 一種醫藥組合物,其包含如請求項1至3中任一項之式(I)化合物或其醫藥學上可接受之鹽或水合物,及至少一種醫藥學上可接受之賦形劑。
- 如請求項4之醫藥組合物,其中該醫藥組合物用於預防或治療起因於一或多種蛋白激酶之異常活化之疾病。
- 如請求項5之醫藥組合物,其中該一或多種蛋白激酶中之至少一者選自:ALK、AMPK、Aurora A、Aurora B、Aurora C、Axl、Blk、Bmx、BTK、CaMK、CDK2/細胞週期蛋白E、CDK5/p25、CHK1、 CK2、A-RAF、B-RAF、C-RAF、DDR1、DDR2、DMPK、EGFR1、Her2、Her4、EphA1、EphB1、FAK、FGFR2、FGFR3、FGFR4、Flt-1、Flt-3、Flt-4、FMS(CSF-1)、Fyn、GSK3β、HIPK1、IKKβ、IGFR-1R、IR、Itk、JAK2、JAK3、KDR、Kit、Lck、Lyn、MAPK1、MAPKAP-K2、MEK1、Met、MKK6、MLCK、NEK2、p70S6K、PAK2、PDGFRα、PDGFRβ、PDK1、Pim-1、PKA、PKBα、PKCα、Plk1、Ret、ROCK-I、Rsk1、SAPK 2a、SGK、Src、Syk、Tie-2、Tec、Trk及ZAP-70。
- 如請求項6之醫藥組合物,其中該一或多種蛋白激酶中之至少一者選自:A-RAF、B-RAF、C-RAF、DDR1、DDR2及FMS。
- 如請求項5至7中任一項之醫藥組合物,其中該疾病選自由以下組成之群:胃癌、肺癌、肝癌、結腸直腸癌、小腸癌、胰臟癌、腦癌、骨癌、黑色素瘤、乳癌、硬化性腺病、子宮癌、子宮頸癌、頭頸癌、食道癌、甲狀腺癌、副甲狀腺癌、腎癌、肉瘤、前列腺癌、尿道癌、膀胱癌、血癌、淋巴瘤、纖維腺瘤、發炎、糖尿病、肥胖症、牛皮癬、類風濕性關節炎、血管瘤、急性及慢性腎臟疾病、冠狀動脈再狹窄、自體免疫疾病、哮喘、神經變性疾病、急性感染及起因於血管生成之眼部疾病。
- 如請求項4之醫藥組合物,其中該醫藥組合物進一步包含選自由以下組成之群的藥物:細胞信號轉導抑制劑、有絲分裂抑制劑、烷基化劑、抗代謝物、抗生素、生長因子抑制劑、細胞週期抑制劑、拓樸異構酶抑制 劑、生物反應調節劑、抗激素劑、抗雄激素、細胞分化/增殖/存活抑制劑、細胞凋亡抑制劑、發炎抑制劑及P-醣蛋白抑制劑。
- 如請求項9之醫藥組合物,其中該藥物為細胞信號轉導抑制劑。
- 如請求項10之醫藥組合物,其中該細胞信號轉導抑制劑為MEK抑制劑。
- 如請求項4之醫藥組合物,其中該醫藥組合物為口服組合物。
- 如請求項4之醫藥組合物,其中該醫藥組合物呈錠劑、丸劑、散劑、膠囊、糖漿、乳液或微乳劑形式。
- 一種如請求項1至3中任一項之式(I)化合物或其醫藥學上可接受之鹽或水合物或如請求項4至13中任一項之醫藥組合物之用途,其用於製造預防或治療受到一或多種蛋白激酶異常活化所介導之疾病之醫藥品。
- 如請求項14之用途,其中該一或多種蛋白激酶中之至少一者選自:ALK、AMPK、Aurora A、Aurora B、Aurora C、Axl、Blk、Bmx、BTK、CaMK、CDK2/細胞週期蛋白E、CDK5/p25、CHK1、CK2、A-RAF、B-RAF、C-RAF、DDR1、DDR2、DMPK、EGFR1、Her2、Her4、EphA1、EphB1、FAK、FGFR2、FGFR3、FGFR4、Flt-1、Flt-3、Flt-4、FMS(CSF-1)、Fyn、GSK3β、HIPK1、IKKβ、IGFR-1R、 IR、Itk、JAK2、JAK3、KDR、Kit、Lck、Lyn、MAPK1、MAPKAP-K2、MEK1、Met、MKK6、MLCK、NEK2、p70S6K、PAK2、PDGFRα、PDGFRβ、PDK1、Pim-1、PKA、PKBα、PKCα、Plk1、Ret、ROCK-I、Rsk1、SAPK 2a、SGK、Src、Syk、Tie-2、Tec、Trk及ZAP-70。
- 如請求項15之用途,其中該一或多種蛋白激酶中之至少一者選自:A-RAF、B-RAF、C-RAF、DDR1、DDR2及FMS。
- 如請求項14至16中任一項之用途,其中該疾病選自由以下組成之群:胃癌、肺癌、肝癌、結腸直腸癌、小腸癌、胰臟癌、腦癌、骨癌、黑色素瘤、乳癌、硬化性腺病、子宮癌、子宮頸癌、頭頸癌、食道癌、甲狀腺癌、副甲狀腺癌、腎癌、肉瘤、前列腺癌、尿道癌、膀胱癌、血癌、淋巴瘤、纖維腺瘤、發炎、糖尿病、肥胖症、牛皮癬、類風濕性關節炎、血管瘤、急性及慢性腎臟疾病、冠狀動脈再狹窄、自體免疫疾病、哮喘、神經變性疾病、急性感染及起因於血管生成之眼部疾病。
- 如請求項14至16中任一項之用途,其中該醫藥品與選自由以下組成之群的共藥物組合使用或研發成組合調配物:細胞信號轉導抑制劑、有絲分裂抑制劑、烷基化劑、抗代謝物、抗生素、生長因子抑制劑、細胞週期抑制劑、拓樸異構酶抑制劑、生物反應調節劑、抗激素劑、抗雄激素、細胞分化/增殖/存活抑制劑、細胞凋亡抑制劑、發炎抑制劑及P-醣蛋白抑制劑。
- 如請求項18之用途,其中該藥物為信號轉導抑制劑,其為MEK抑制劑。
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