TWI774699B - 外顯子20***突變型egfr之選擇性抑制劑 - Google Patents
外顯子20***突變型egfr之選擇性抑制劑 Download PDFInfo
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- TWI774699B TWI774699B TW106135203A TW106135203A TWI774699B TW I774699 B TWI774699 B TW I774699B TW 106135203 A TW106135203 A TW 106135203A TW 106135203 A TW106135203 A TW 106135203A TW I774699 B TWI774699 B TW I774699B
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Abstract
本發明是一種用以治療惡性腫瘤患者之抗腫瘤劑，該惡性腫瘤患者表現出具有外顯子20***突變之EGFR，該抗腫瘤劑含有選自於由說明書記載之化合物A~D所構成群組之化合物或其鹽。
Description
發明領域
本發明有關於一種針對具有外顯子20***突變型表皮生長因子受體(Epidermal Growth Factor Receptor，以下亦稱為「EGFR」)之癌的抗腫瘤劑。
發明背景
EGFR是受體酪胺酸激酶，在正常組織中透過與配位子之表皮生長因子(Epidermal Growth Factor，以下亦稱為「EGF」)結合來發揮生理機能，並在表皮組織中參與增殖及細胞自戕抑制(非專利文獻1)。又，EGFR基因之體細胞突變是已知的癌之原因基因，例如，缺失EGFR外顯子19區域第746~750胺基酸者(以下亦稱為「外顯子19缺失突變」)，及外顯子21區域第858胺基酸從白胺酸突變成精胺酸者(以下亦稱為「L858R突變」)會不依賴EGF而恆常的誘發激酶活性，而參與癌細胞的增殖及生存(非專利文獻2)。有報告指出，該等突變，在東亞中，例如可在30~50%的非小細胞肺癌被觀察到，又，在歐美中亦可在約10%的非小細胞肺癌中被觀察到，而可認為是癌的原因因子之1(非專利文獻3)。
因此，針對EGFR抑制劑之抗腫瘤劑的研究
開發從以往便活躍在進行，並有導入到EGFR突變陽性肺癌之治療中。例如，吉非替尼、厄洛替尼及阿法替尼在治療用量當中會表現出廣泛認為是起因於抑制野生型EGFR所致而作為副作用的皮膚異常及消化道失調，另一方面，對外顯子19缺失突變型及L858R突變型EGFR陽性肺癌則顯示出高抗腫瘤效果。該等治療效果可認為是起因於與野生型EGFR相比，EGFR抑制劑會選擇性的抑制突變型EGFR(非專利文獻4)。
但是近年來明確了解到，在癌之中存在著具有在外顯子20區域有1個以上胺基酸被***之突變(以下亦稱為「外顯子20***突變」)的EGFR，且該等癌對以往EGFR抑制劑是呈低感受性。例如，有報告指出，阿法替尼對EGFR突變陽性肺癌的臨床抗腫瘤效果，與外顯子19缺失突變及L858R突變相比，在外顯子20***突變上是顯著較低(非專利文獻5)。有鑑於此，在該等患者上一般雖可使用化學療法，然治療法之選項受限，以及無法獲得充分的治療效果，因此需要治療效果更高的抗腫瘤劑。
專利文獻1記載一種化合物，可用於治療特徵在於外顯子20***突變型EGFR的疾病。但是，該文獻1所記載之化合物與有關本發明之化合物在結構上是差異甚，此外，亦未揭示到基於與野生型EGFR比較的選擇性以及在in vivo模式中的有效性。
又，專利文獻2記載一種喹啉取代化合物，然未記載對外顯子20***突變型EGFR的抑制活性。
習知技術文獻
專利文獻
專利文獻1：WO2015/175632A1
專利文獻2：WO2015/025936A1
非專利文獻
非專利文獻1：Nat. Rev. Cancer, vol. 6, pp803-812 (2006)
非專利文獻2：Nature Medicine, vol.19, pp1389-1400 (2013)
非專利文獻3：Nat. Rev. Cancer, vol.7, pp169-181 (2007)
非專利文獻4：Lancet Oncol. vol. 13, e23-31(2012)
非專利文獻5：Lancet Oncol. vol.16, pp830-838 (2015)
發明概要
本發明之課題在於提供一種對在以往EGFR抑制劑上治療效果不充分且外顯子20***突變型EGFR之選擇性高的抑制劑，並且降低因抑制野生型EGFR所致副作用的抗腫瘤劑。
本案發明人等精心研究，結果發現，外顯子20***突變型EGFR是妥當之癌的治療標的，且同時發現，導入
以往治療之EGFR抑制劑缺乏對野生型EGFR與外顯子20***突變型EGFR之間的選擇性。又確認到，特定的化合物對外顯子20***突變型EGFR顯示出選擇性及腫瘤增殖抑制效果，且比代表性之EGFR突變陽性癌治療藥的阿法替尼還要優異，進而完成本發明。
因此，本發明包含以下態樣。
項1. 一種用以治療惡性腫瘤患者之抗腫瘤劑，該惡性腫瘤患者表現出具有外顯子20***突變之EGFR，該抗腫瘤劑含有選自於由如下所構成群組之化合物或其鹽：(S)-N-(4-胺基-6-甲基-5-(喹啉-3-基)-8,9-二氫嘧啶并[5,4-b]吲
-8-基)丙烯醯胺(以下亦稱為「化合物A」)；(S)-N-(4-胺基-6-亞甲基-5-(喹啉-3-基)-7,8-二氫-6H-嘧啶并[[5,4-b]吡
-7-基)丙烯醯胺(以下亦稱為「化合物B」)；(S,E)-N-(4-胺基-6-亞甲基-5-(喹啉-3-基)-7,8-二氫-6H-嘧啶并[[5,4-b]吡
-7-基)-3-氯丙烯醯胺(以下亦稱為「化合物C」)；及(R)-N-(4-胺基-6-甲基-5-(喹啉-3-基)-8,9-二氫嘧啶并[5,4-b]吲
-8-基)-N-甲基丙烯醯胺(以下亦稱為「化合物D」)。
項2. 如項1記載之抗腫瘤劑，其中化合物為(S)-N-(4-胺基-6-甲基-5-(喹啉-3-基)-8,9-二氫嘧啶并[5,4-b]吲
-8-基)丙烯醯胺。
項3. 如項1或2記載之抗腫瘤劑，其中表現出具有外顯子20***突變之EGFR的惡性腫瘤患者是肺癌、乳癌、頭頸部癌、腦腫瘤、子宮癌、造血器官腫瘤、或皮膚癌之患者。
項4. 如項1~3中任一項記載之抗腫瘤劑，其中表現出具有外顯子20***突變之EGFR的惡性腫瘤患者是肺癌患者。
項5. 如項1~4中任一項記載之抗腫瘤劑，其中外顯子20***突變是在外顯子20區域***有1個以上胺基酸的突變。
項6. 如項1~5中任一項記載之抗腫瘤劑，其中外顯子20***突變是在外顯子20區域***有1至7個胺基酸的突變。
項7. 如項1~6中任一項記載之抗腫瘤劑，其中外顯子20***突變是在外顯子20區域***有1至4個胺基酸的突變。
項8. 如項1~7中任一項記載之抗腫瘤劑，其中外顯子20***突變為A763_Y764insFQEA、V769_D770insASV、D770_N771insSVD、D770_N771insNPG、D770_N771insG、D770>GY、N771_P772insN、P772_R773insPR、H773_V774insNPH、H773_V774insPH、H773_V774insAH、H773_V774insH、V774_C774insHV、或A761_E762insEAFQ。
項9. 如項1~8中任一項記載之抗腫瘤劑，其中外顯子20***突變為V769_D770insASV、D770_N771insSVD、D770_N771insG、H773_V774insNPH、H773_V774insPH。
項10. 一種惡性腫瘤患者之治療方法，包含以下步驟：對表現出具有外顯子20***突變之EGFR的惡性腫瘤患者投予抗腫瘤劑，該抗腫瘤劑含有有效量之選自於由如下所構成群組之化合物或其鹽：(S)-N-(4-胺基-6-甲基-5-(喹啉-3-基)-8,9-二氫嘧啶并[5,4-b]吲
-8-基)丙烯醯胺；(S)-N-(4-胺基-6-亞甲基-5-(喹啉-3-基)-7,8-二氫-6H-嘧啶并[[5,4-b]吡
-7-基)丙烯醯胺；(S,E)-N-(4-胺基-6-亞甲基-5-(喹啉-3-基)-7,8-二氫-6H-嘧啶并[[5,4-b]吡
-7-基)-3-氯丙烯醯胺；及(R)-N-(4-胺基-6-甲基-5-(喹啉-3-基)-8,9-二氫嘧啶并[5,4-b]吲
-8-基)-N-甲基丙烯醯胺。
項11. 一種用以治療表現出具有外顯子20***突變之EGFR的惡性腫瘤患者之化合物或其鹽，該化合物或其鹽是選自於由如下所構成群組：(S)-N-(4-胺基-6-甲基-5-(喹啉-3-基)-8,9-二氫嘧啶并[5,4-b]吲
-8-基)丙烯醯胺；(S)-N-(4-胺基-6-亞甲基-5-(喹啉-3-基)-7,8-二氫-6H-嘧啶并[[5,4-b]吡
-7-基)丙烯醯胺；
(S,E)-N-(4-胺基-6-亞甲基-5-(喹啉-3-基)-7,8-二氫-6H-嘧啶并[[5,4-b]吡
-7-基)-3-氯丙烯醯胺；及(R)-N-(4-胺基-6-甲基-5-(喹啉-3-基)-8,9-二氫嘧啶并[5,4-b]吲
-8-基)-N-甲基丙烯醯胺。
項12.一種選自於由如下所構成群組之化合物或其鹽之用於製造抗腫瘤劑的用途，該抗腫瘤劑是用以治療表現出具有外顯子20***突變之EGFR的惡性腫瘤患者：(S)-N-(4-胺基-6-甲基-5-(喹啉-3-基)-8,9-二氫嘧啶并[5,4-b]吲
-8-基)丙烯醯胺；(S)-N-(4-胺基-6-亞甲基-5-(喹啉-3-基)-7,8-二氫-6H-嘧啶并[[5,4-b]吡
-7-基)丙烯醯胺；(S,E)-N-(4-胺基-6-亞甲基-5-(喹啉-3-基)-7,8-二氫-6H-嘧啶并[[5,4-b]吡
-7-基)-3-氯丙烯醯胺；及(R)-N-(4-胺基-6-甲基-5-(喹啉-3-基)-8,9-二氫嘧啶并[5,4-b]吲
-8-基)-N-甲基丙烯醯胺。
與本發明有關之抗腫瘤劑不會抑制野生型EGFR，而顯示出對外顯子20***突變型EGFR之高選擇性。因此，可用於提供一種抗腫瘤劑，其降低因抑制野生型EGFR所致之副作用，並且針對在以往EGFR抑制劑上治療效果不充分且表現出具有外顯子20***突變之EGFR的惡性腫瘤患者會發揮出優異治療效果。
以往之EGFR抑制劑，與野生型EGFR相比，
對外顯子20***突變型EGFR的選擇性低，因此，發揮抗腫瘤效果的投予量與產生起因於野生型EGFR抑制之副作用(皮膚異常、消化道失調等)的投予量之間的差距小，而難以發揮充分的治療效果。另一方面，與本發明有關之抗腫瘤劑對外顯子20***突變型EGFR的選擇性高，因此，在不產生起因於野生型EGFR之副作用下而增加投予量將成為可能，而可對表現出具有外顯子20***突變之EGFR的惡性腫瘤患者發揮出優異治療效果。
圖1是顯示野生型EGFR與外顯子20***突變型EGFR之IC50比，其是從有關於化合物A、B、C、D，以及比較化合物、吉非替尼、厄洛替尼及阿法替尼對表現野生型及突變型EGFR細胞株之細胞增殖抑制的試驗結果所算出。
圖2是顯示野生型EGFR與外顯子20***突變型EGFR之GI50比，其是從有關於化合物A、比較化合物、吉非替尼、厄洛替尼及阿法替尼對表現野生型及突變型EGFR人類細胞株之細胞增殖抑制的試驗結果所算出。
圖3是顯示在皮下移植表現突變型EGFR細胞株(NIH3T3-EGFRinsASV細胞)之模式小鼠中的相對腫瘤體積(以下亦稱為「RTV」。)，其用以測定化合物A之抗腫瘤效果。
圖4是顯示將皮下移植表現突變型EGFR細胞株(NIH3T3-EGFRinsASV細胞)模式小鼠之腫瘤分組後的體重變化，其用以測定化合物A之毒性。
圖5是顯示皮下移植表現突變型EGFR細胞株(NIH3T3-EGFRinsSVD細胞)之模式小鼠中的相對腫瘤體積，其用以測定化合物A之抗腫瘤效果。
圖6是顯示將皮下移植表現突變型EGFR細胞株(NIH3T3-EGFRinsSVD細胞)模式小鼠之腫瘤分組後的體重變化，其用以測定化合物A之毒性。
圖7是顯示皮下移植表現突變型EGFR細胞株(H1975-EGFRinsSVD細胞)之模式小鼠中的相對腫瘤體積，其用以測定化合物A之抗腫瘤效果。
圖8是顯示將皮下移植表現突變型EGFR細胞株(H1975-EGFRinsSVD細胞)模式小鼠之腫瘤分組後的體重變化，其用以測定化合物A之毒性。
圖9是顯示皮下移植表現突變型EGFR細胞株(NIH3T3-EGFRinsNPH)之模式小鼠中的腫瘤體積，其用以測定化合物A之抗腫瘤效果。
圖10是顯示將皮下移植表現突變型EGFR細胞株(NIH3T3-EGFRinsNPH)模式小鼠之腫瘤分組後的體重變化，其用以測定化合物A之毒性。
圖11是顯示皮下移植表現突變型EGFR細胞株(H1975-EGFRinsSVD細胞)之模式大鼠中的腫瘤體積，其用以測定化合物A之抗腫瘤效果。
圖12是顯示將皮下移植表現突變型EGFR細胞株(H1975-EGFRinsSVD細胞)模式大鼠之腫瘤分組後的體重變化，其用以測定化合物A之毒性。
圖13是顯示皮下移植源自V769_D770insASV突變型EGFR陽性肺癌患者之腫瘤之模式小鼠中的腫瘤體積，其用以測定化合物A之抗腫瘤效果。
圖14是顯示將皮下移植源自V769_D770insASV突變型EGFR陽性肺癌患者腫瘤之模式小鼠之腫瘤分組後的體重變化，其用以測定本發明化合物A之毒性。
圖15是顯示野生型EGFR(Wild-type EGFR)之胺基酸序列(序列編號1)。
用以實施發明之形態
將於下詳細說明在說明書之上述或下述記載當中，本發明範圍所包含之各種定義的較佳例。
本說明書中所謂「EGFR」，表示人類表皮生長因子受體蛋白質，亦稱為ErbB-1或HER1。
本說明書中所謂「野生型EGFR」，表示不具有體細胞突變的EGFR，具體而言，是由序列編號1所示胺基酸序列所構成之蛋白質(GenBank登錄編號：NP_005219.2)。
本說明書中所謂「外顯子20***突變」，表示在EGFR之外顯子20區域(序列編號1中第761~823的胺基酸序列)***有1個以上(1~7個為宜，1~4個為佳)胺基酸
的突變，且宜可舉在外顯子20區域之從第763丙胺酸到第764酪胺酸之間***有胺基酸序列FQEA(從N端側依序，***酸、穀氨醯胺、穀氨醯胺酸、丙胺酸)的突變(A763_Y764insFQEA)、在外顯子20區域之從第769纈胺酸到第770天門冬胺酸之間***有胺基酸序列ASV(從N端側依序，丙胺酸、絲胺酸、纈胺酸)的突變(V769_D770insASV)、在外顯子20區域之從第770天門冬胺酸到第771天門冬胺酸之間***有胺基酸序列SVD(從N端側依序，絲胺酸、纈胺酸、天門冬胺酸)的突變(D770_N771insSVD)、在外顯子20區域之從第770天門冬胺酸到第771天門冬胺酸之間***有胺基酸序列NPG(從N端側依序，天門冬胺酸、脯胺酸、甘胺酸)的突變(D770_N771insNPG)、在外顯子20區域之從第770天門冬胺酸到第771天門冬胺酸之間***有胺基酸G(甘胺酸)的突變(D770_N771insG)、在外顯子20區域缺失第770天門冬胺酸且***有胺基酸序列GY(從N端側順序，甘胺酸、酪胺酸)以取代其的突變(D770>GY)、在外顯子20區域之從第771天門冬胺酸到第772脯胺酸之間***有胺基酸N(天門冬胺酸)的突變(N771_P772insN)、在外顯子20區域之從第772脯胺酸到第773組胺酸之間***有胺基酸序列PR(從N端側順序，脯胺酸、精胺酸)的突變(P772_R773insPR)、在外顯子20區域之從第773組胺酸到第774纈胺酸之間***有胺基酸序列NPH(從N端側依序，天門冬胺酸、脯胺酸、組胺酸)的突變
(H773_V774insNPH)、在外顯子20區域之從第773組胺酸到第774纈胺酸之間***有胺基酸序列PH(從N端側依序，脯胺酸、組胺酸)的突變(H773_V774insPH)、在外顯子20區域之從第773組胺酸到第774纈胺酸之間***有胺基酸序列AH(從N端側依序，丙胺酸、組胺酸)的突變(H773_V774insAH)、在外顯子20區域之從第773組胺酸到第774纈胺酸之間***有胺基酸H(組胺酸)的突變(H773_V774insH)、在外顯子20區域之從第774纈胺酸到第775半胱胺酸之間***有胺基酸序列HV(從N端側依序，組胺酸、纈胺酸)的突變(V774_C775insHV)、在外顯子20區域之從第761丙胺酸到第762穀氨醯胺酸之間***有胺基酸序列EAFQ(從N端側依序，穀氨醯胺酸、丙胺酸、***酸、穀氨醯胺)的突變(A761_E762insEAFQ)等。可舉下述突變為佳：在外顯子20區域之從第769纈胺酸到第770天門冬胺酸之間***有胺基酸序列ASV(從N端側依序，丙胺酸、絲胺酸、纈胺酸)的突變(V769_D770insASV)、在外顯子20區域之從第770天門冬胺酸到第771天門冬胺酸之間***有胺基酸序列SVD(從N端側依序，絲胺酸、纈胺酸、天門冬胺酸)的突變(D770_N771insSVD)、在外顯子20區域之從第770天門冬胺酸到第771天門冬胺酸之間***有胺基酸G(甘胺酸)的突變(D770_N771insG)、在外顯子20區域之從第773組胺酸到第774纈胺酸之間***有胺基酸序列NPH(從N端側依序，天門冬胺酸、脯胺酸、組胺酸)的突變
(H773_V774insNPH)、在外顯子20區域之從第773組胺酸到第774纈胺酸之間***有胺基酸序列PH(從N端側依序，脯胺酸、組胺酸)的突變(H773_V774insPH)。更佳可舉下述突變：在外顯子20區域之從第770天門冬胺酸到第771天門冬胺酸之間***有胺基酸序列SVD(從N端側依序，絲胺酸、纈胺酸、天門冬胺酸)的突變(D770_N771insSVD)、在外顯子20區域之從第770天門冬胺酸到第771天門冬胺酸之間***有胺基酸G(甘胺酸)的突變(D770_N771insG)。
本說明書中所謂「表現出具有外顯子20***突變之EGFR的惡性腫瘤患者」，表示表現出在EGFR外顯子20區域之至少1處具有外顯子20***突變之EGFR的惡性腫瘤患者，該EGFR亦可在相異的2處以上具有外顯子20***突變，然宜在1處具有外顯子20***突變。又，該EGFR亦可具有外顯子20***突變以外的突變(例如，外顯子19缺失突變、L858R突變、L790M突變等)。
本發明中，針對惡性腫瘤患者所表現之EGFR具有外顯子20***突變之檢測方法而言，若可檢測出該突變則無特別限制，可使用周知的檢測方法。在外顯子20***突變之檢測當中，EGFR基因之基因體序列、EGFR基因之轉錄產物或EGFR蛋白質之任一者皆可作為檢測對象。
供於檢測外顯子20***突變之試樣，若是源自惡性腫瘤患者之生體試樣，特別是採取自惡性腫瘤患者
且含有惡性腫瘤細胞之試樣，則無特別限定。生體試樣可例如體液(血液、尿等)、組織、其萃取物及所採取組織之培養物等。又，生體試樣之採取方法可試生體試樣之種類來適宜選擇。
生體試樣可因應檢測方法，施以適切的處理來調製。又，檢測所使用的試劑(例如，含有引子或探針的試劑)可因應檢測方法，以慣用的方法來調整。
在本發明之1態樣中，在對惡性腫瘤患者投予抗腫瘤劑之前，可進行惡性腫瘤患者表現出EGFR具有外顯子20***突變之檢測步驟。
接著，針對化合物A~D(化合物A、B、C及D)(本說明書中，有時總稱為「本發明化合物」、「關於本發明之化合物」)及其製造法進行說明。
化合物A((S)-N-(4-胺基-6-甲基-5-(喹啉-3-基)-8,9-二氫嘧啶并[5,4-b]吲
-8-基)丙烯醯胺)是以下述化學式表示。
化合物B((S)-N-(4-胺基-6-亞甲基-5-(喹啉
-3-基)-7,8-二氫-6H-嘧啶并[[5,4-b]吡
-7-基)丙烯醯胺)是以下述化學式表示。
化合物C((S,E)-N-(4-胺基-6-亞甲基-5-(喹啉-3-基)-7,8-二氫-6H-嘧啶并[[5,4-b]吡
-7-基)-3-氯丙烯醯胺)是以下述化學式表示。
化合物D((R)-N-(4-胺基-6-甲基-5-(喹啉-3-基)-8,9-二氫嘧啶并[5,4-b]吲
-8-基)-N-甲基丙烯醯胺)是以下述化學式表示。
[化學式4]
上述化合物A~D可透過例如WO2015/025936A1所記載之製造法或實施例所示方法等來製造。但化合物A~D之製造法並未受該等反應例所限定。
上述化合物A~D具有光學異構物、立體異構物、旋轉異構物、互突變構物等異構物時，在無特別明記之下，任何異構物、混合物皆包含於本發明化合物中。例如，當化合物A~D存在光學異構物時，在無特別明記之下，外消旋物及自外消旋物分割出的光學異構物皆包含在本發明化合物中。
所謂上述化合物A~D之鹽意指藥學上容許之鹽，可舉鹼加成鹽或酸加成鹽。
該鹼加成鹽可舉例如鈉鹽、鉀鹽等鹼金屬鹽；例如鈣鹽、鎂鹽等鹼土類金屬鹽；例如銨鹽；例如三甲基胺鹽、三乙基胺鹽、二環己基胺鹽、乙醇胺鹽、二乙醇胺鹽、三乙醇胺鹽、普羅卡因鹽、N,N’-二苄基乙二胺鹽等有機胺鹽等。
該酸加成鹽可舉例如鹽酸鹽、硫酸鹽、硝酸
鹽、磷酸鹽、過氯酸鹽等無機酸鹽；例如醋酸鹽、甲酸鹽、順丁烯二酸鹽、反丁烯二酸鹽、酒石酸鹽、檸檬酸鹽、抗壞血酸鹽、三氟乙酸鹽等有機酸鹽；例如甲烷磺酸鹽、2-羥乙磺酸鹽、苯磺酸酸鹽、對甲苯磺酸鹽等磺酸鹽等。
上述化合物A~D或其鹽亦包含其前藥。前藥是在生體內之生理條件下，透過酵素、胃酸等反應來轉變成化合物A~D或其鹽的化合物，亦即，是說發生酵素性的氧化、還原、水解等而變化成本發明化合物或其鹽的化合物，發生胃酸等所致水解等而變化成化合物A~D或其鹽的化合物。又，亦可做成在如廣川書店1990年刊「醫藥品之開發」第7卷分子設計163頁至198頁所記載之生理條件下變化成化合物A~D或其鹽者。
疾病之記載
作為本發明對象之腫瘤並無特別限制，可舉例如頭頸部癌、消化器官癌(食道癌、胃癌、十二指腸癌、肝臟癌、膽道癌(膽囊‧膽管癌等)、胰臟癌、結腸直腸癌(結腸癌、直腸癌等)等)、肺癌(非小細胞肺癌、小細胞肺癌、間皮瘤等)、乳癌、生殖器官癌(卵巢癌、子宮癌(子宮頸癌、子宮體癌等)等)、泌尿器官癌(腎癌、膀胱癌、***癌、***腫瘤等)、造血器官腫瘤(白血病、惡性淋巴瘤、多發性骨髓瘤等)、骨‧軟組織腫瘤、皮膚癌、腦腫瘤等。宜為肺癌、乳癌、頭頸部癌、腦腫瘤、子宮癌、造血器官腫瘤或皮膚癌。
在將上述化合物A~D或其鹽使用作為醫藥
時，可視需要摻合藥學上的載劑，並因應預防或治療目的採用各種投予形態。該形態可為例如口服劑、注射劑、栓劑、軟膏劑、貼片劑等任一，且宜採用口服劑。該等投予形態可利用各個習於此藝者周知慣用的製劑方法來製造。
針對藥學上的載劑，可使用在製劑素材方面所慣用的各種有機或無機載劑物質，並可做成固態製劑中的賦形劑、結合劑、崩解劑、潤滑劑、著色劑來摻合；做成液狀製劑中的溶劑、助溶劑、懸浮化劑、等張化劑、緩衝劑、無痛劑等來摻合。又，視需要亦可使用防腐劑、抗氧化劑、著色劑、甜味劑、穩定劑等製劑添加物。
調製口服用固態製劑時，可對化合物A~D添加賦形劑，並且視需要進一步添加結合劑、崩解劑、潤滑劑、著色劑、矯味‧氣味改善劑等，之後，依常法來製造錠劑、被覆錠劑、顆粒劑、散劑、膠囊劑等。
賦形劑可舉乳糖、白糖、D-甘露糖醇、葡萄糖、澱粉、碳酸鈣、高嶺土、微結晶纖維素、無水矽酸等。結合劑可舉水、乙醇、1-丙醇、2-丙醇、單糖漿、葡萄糖液、α-澱粉液、明膠液、D-甘露糖醇、羧甲基纖維素、羥丙基纖維素、羥丙基澱粉、甲基纖維素、乙基纖維素、蟲膠、磷酸鈣、聚乙烯吡咯啶酮等。崩解劑可舉乾燥澱粉、海藻酸鈉、寒天粉末、碳酸氫鈉、碳酸鈣、月桂基硫酸鈉、硬脂酸單甘油酯、乳糖等。潤滑劑可舉純化滑石、硬脂酸鈉鹽、硬脂酸鎂、硼砂、聚乙二醇等。著色劑可舉氧化鈦、氧化鐵等。矯味‧氣味改善劑可舉白糖、橙皮、檸檬酸、
酒石酸等。
調製口服用液體製劑時，可對化合物A~D添加口味調節劑、緩衝劑、穩定劑、氣味改善劑等，並依常法製造內服液劑、糖漿劑、酏劑等。
矯味‧氣味改善劑可使用前述所舉者。緩衝劑可舉檸檬酸鈉等。安定劑可舉黃蓍膠、***膠、明膠等。視需要，亦可實施腸溶性著衣，或在有效持續之目的下，對口服製劑利用周知方法實施著衣。如此膜衣劑可舉羥丙基甲基纖維素、乙基纖維素、羥甲基纖維素、羥丙基纖維素、聚氧乙二醇、Tween80(商標)等。
調製注射劑時，可對化合物A~D添加pH調節劑、緩衝劑、穩定劑、等張化劑、局部麻醉劑等，並依常法製造皮下、肌肉內及靜脈內用注射劑。
pH調節劑及緩衝劑可舉檸檬酸鈉、醋酸鈉、磷酸鈉等。穩定劑可舉焦亞硫酸鈉、EDTA、硫乙二醇酸、硫代乳酸等。局部麻醉劑可舉鹽酸普魯卡因、鹽酸利多卡因等。等張化劑可舉氯化鈉、葡萄糖、D-甘露糖醇、甘油等。
調製栓劑時，可對化合物A~D添加習於此藝者所周知的製劑用載劑，例如聚乙二醇、羊毛脂、可可脂、脂肪酸三甘油酯等，進一步視需要添加如Tween80(商標)之類的界面活性劑等，之後，利用常法來製造。
調製軟膏劑時，可視需要對化合物A~D摻合通常使用之基劑、安定劑、濕潤劑、保存劑等，並依常法
混合來製劑化。
基劑可舉流動石蠟、白凡士林、白蜂蠟、辛基十二烷醇、石蠟等。
保存劑可舉對羥苯甲酸甲酯、對羥苯甲酸乙酯、對羥苯甲酸丙酯等。
調製貼片劑時，可在通常的支持體透過常法塗布前述軟膏、乳霜(cream)、凝膠(gel)、糊(paste)等來製造。
支持體可舉綿、短纖維、由化學纖維所構成之織布或不織布、軟質氯乙烯、聚乙烯、聚胺基甲酸酯等的薄膜或者發泡體片。
上述各投予單位形態中所應摻合之上述化合物A~D的量，視需應用其之患者的症狀或者其劑形等而無固定，然一般在每一投予單位形態上，在口服劑宜做成0.05~1000mg、在注射劑宜做成0.01~500mg、在栓劑宜做成1~1000mg。
又，具有上述投予形態之藥劑的每1日投予量，視患者之症狀、體重、年齡、性別等有異而無法一概決定，然作為有效成分之化合物A~D在通常成人(體重50kg)可設為每1日0.05~5000mg、宜設為0.1~1000mg，並且宜將其1日1次或分成2~3次左右來投予。
本發明亦提供一種惡性腫瘤患者之治療方法，含有下述步驟：對表現出具有外顯子20***突變之EGFR的惡性腫瘤患者投予有效量之含有選自由於化合物
A~D所構成群組之化合物或其鹽的抗腫瘤劑。
本發明亦提供一種選自於由化合物A~D所構成群組之化合物或其鹽，是用以治療表現出具有外顯子20***突變之EGFR的惡性腫瘤患者。
本發明亦提供一種選自於由化合物A~D所構成群組之化合物或其鹽的用途，是用以治療表現出具有外顯子20***突變之EGFR的惡性腫瘤患者。
本發明亦提供一種選自於由化合物A~D所構成群組之化合物或其鹽之用於製造抗腫瘤劑的用途，該抗腫瘤劑是用以治療表現出具有外顯子20***突變之EGFR的惡性腫瘤患者。
本發明亦是一種含有下述步驟(1)~(2)之化學療法之治療效果的予測方法，該化學療法是對惡性腫瘤患者使用有以選自於由化合物A~D所構成之群組之化合物或其鹽作為有效成分的抗腫瘤劑：(1)檢測步驟：檢測採取自該患者之生體試樣所含有之EGFR基因有無突變，及(2)預測步驟：上述步驟(1)之檢測結果，當EGFR基因具有外顯子20***突變時，可預測該化學療法對該患者會顯示出充分治療效果的可能性很高。
本發明亦是一種含有下述步驟(1)~(3)之惡性腫瘤患者的治療方法：(1)檢測步驟：檢測採取自該患者之生體試樣所含有之EGFR基因有無突變，及
(2)預測步驟：上述步驟(1)之檢測結果，當EGFR基因具有外顯子20***突變時，可預測使用有含有以選自於由化合物A~D所構成群組之化合物或其鹽之抗腫瘤劑的化學療法對該患者會顯示出充分治療效果的可能性很高，及(3)投予步驟：對在上述步驟(2)預測出該化學療法顯示出充分治療效果之可能性高的患者投予該抗腫瘤劑。
EGFR基因之鹼基序列是周知。cDNA之鹼基序列之GenBank登錄編號是NM_005228.4。
此外，「治療效果」可根據腫瘤縮小效果、再發抑制效果、延命效果等來評價，再發抑制效果可藉由無再發生存期間之延長及/或再發率之改善的程度來表示；延命效果可藉由全生存期間及/或無惡化生存期間之中央值之延長的程度等來表示。所謂使用有含有以化合物A或其鹽作為有效成分之抗腫瘤劑的化學療法「顯示出充分治療效果」，是稱透過投予含有以化合物A或其鹽作為有效成分之抗腫瘤劑，相較於非投予之情況，可使生存期間顯著延長、顯著抑制再發之程度的優異治療效果。
實施例
以下顯示試驗例以更詳細說明本發明，然本發明並未受該等實施例(試驗例)所限制。
試驗例1
In vitro藥效試驗
對表現野生型及突變型EGFR細胞株之細胞增殖抑制效果的評價(1)
化合物對野生型EGFR及突變型EGFR之抑制活性是使用導入有人類EGFR基因之小鼠B淋巴球前驅細胞株之Ba/F3細胞來進行。Ba/F3細胞是以含有10%胎牛血清(FBS)、100U/mL盤尼西林/100μg/mL鏈黴素(Thermo Fisher Scientific)及1ng/mL小鼠介白素-3(mIL-3)(CST)的RPMI-1640培養基(Thermo Fisher Scientific)來維持，並將編碼有人類EGFR基因(野生型(WT)、V769_D770insASV(insASV)、D770_N771insSVD(insSVD)、D770_N771insG(insG)、H773_V774insNPH(insNPH)、H773_V774insPH(insPH))的PB-CMV-MCS-EF1-GFP+Puro載體或者PB-CMV-MCS-EF1-RFP+Puro載體與Super PiggyBacTransposase表現載體一起藉由利用Amaxa(商標)Cell Line Nucleofector(商標)Kit V的電穿孔法來導入，之後，以嘌黴素(SIGMA)來選擇。表現有野生型EGFR的Ba/F3細胞(以下亦稱為「Ba/F3-EGFR_WT」)在50ng/mL EGF(R&D SYSTEMS)存在下顯示出mIL-3非依賴性的增殖，又，表現有外顯子20***突變型EGFR的Ba/F3細胞(以下亦稱為「Ba/F3-EGFRinsASV」、「Ba/F3-EGFRinsSVD」、「Ba/F3-EGFRinsG」、「Ba/F3-EGFRinsNPH」、
「Ba/F3-EGFRinsPH」)在EGF非存在下顯示出mIL-3非依賴性的增殖。
在評價細胞增殖抑制效果時，將Ba/F3-EGFR_WT細胞以含有10% FBS、100U/mL盤尼西林、100μg/mL鏈黴素及50ng/mL EGF的RPMI-1640培養基來懸浮，並播種細胞懸浮液使96孔平底微量盤各孔中每1孔的細胞數為30,000個。另一方面，表現有外顯子20***突變型EGFR的Ba/F3細胞以含有10% FBS、100U/mL盤尼西林、100μg/mL鏈黴素的RPMI-1640培養基來懸浮，並播種細胞懸浮液使96孔平底微量盤各孔中每1孔的細胞數為15,000個。接著，將依照專利文獻2記載之製造方法所獲得之(S)-N-(4-胺基-6-甲基-5-(喹啉-3-基)-8,9-二氫嘧啶并[5,4-b]吲
-8-基)丙烯醯胺(化合物A)、(S)-N-(4-胺基-6-亞甲基-5-(喹啉-3-基)-7,8-二氫-6H-嘧啶并[[5,4-b]吡
-7-基)丙烯醯胺(化合物B)、(S,E)-N-(4-胺基-6-亞甲基-5-(喹啉-3-基)-7,8-二氫-6H-嘧啶并[[5,4-b]吡
-7-基)-3-氯丙烯醯胺(化合物C)、(R)-N-(4-胺基-6-甲基-5-(喹啉-3-基)-8,9-二氫嘧啶并[5,4-b]吲
-8-基)-N-甲基丙烯醯胺(化合物D)及依照WO2013/125709A1記載之製造方法所獲得之(S)-N-(4-胺基-5-(喹啉-3-基)-6,7,8,9-四氫嘧啶并[[5,4-b]吲
-8-基)丙烯醯胺(WO2013/125709A1之實施例1化合物)(以下亦稱為「比較化合物」)溶解於DMSO中，使用DMSO或者懸浮各細胞所使用之培養基來稀釋，並將其加到細胞
培養盤之各孔中，在含有5%碳酸氣體的培養器中且37℃下培養3日。培養後之細胞數的計測是使用Cell Titer-Glo(商標)Luminescent Cell Viability Assay(Promega)，並根據製造商推薦之程序(protocol)來進行。利用下式算出增殖率，並求出抑制50%之受測化合物的濃度(IC50(μM))。
增殖率(%)=T/C×100
T：添加有受測化合物之孔的發光強度
C：未添加受測化合物之孔的發光強度。
又，利用下式算出野生型EGFR與外顯子20***突變型EGFR之IC50的比。結果顯示在圖1。
IC50比(ratio)=IC50(WT)/IC50(ex20ins)
IC50(WT)：對野生型EGFR之IC50
IC50(ex20ins)：對外顯子20***突變型EGFR之IC50。
如自圖1明顯所示，化合物A~D對表現出外顯子20***突變型EGFR之細胞株顯示出細胞增殖抑制效果，且突變選擇性與比較化合物、吉非替尼、厄洛替尼、及阿法替尼相比為高。
試驗例2
對表現野生型及突變型EGFR人類細胞株之細胞增殖抑制效果(2)
為了評價化合物對野生型EGFR及突變型EGFR的抑制活性，使用了透過改變基因使D770_N771insSVD突變
型EGFR表現的人類肺腺癌細胞株之NCI-H1975細胞(以下亦稱為「H1975-EGFRinsSVD」)、表現出野生型EGFR之人類表皮癌細胞株的A431細胞。H1975-EGFRinsSVD細胞是如下來選擇：將編碼有D770_N771insSVD(insSVD)的PB-CMV-MCS-EF1-RFP+Puro載體與Super PiggyBacTransposase表現載體一起藉由利用Amaxa(商標)Cell Line Nucleofector(商標)Kit R之電穿孔法來導入NCI-H1975細胞，之後，以嘌黴素(SIGMA)來選擇，之後，將XTN(商標)TALENs Site-Specific Nucleases(Transposagen)藉由利用Amaxa(商標)Cell Line Nucleofector(商標)Kit R的電穿孔法來導入，並透過定序(sequence)以剔除內生性EGFR(T790M/L858R)之細胞來選擇。
在評價細胞增殖抑制效果時，是使各個細胞懸浮在透過ATCC所推薦的培養基中。播種細胞懸浮液使96孔平底盤各孔中每1孔的細胞數為3,000個，並在含有5%碳酸氣體的培養器中且37℃下培養1日。將化合物A、比較化合物、吉非替尼、厄洛替尼及阿法替尼溶解在DMSO中，並使用DMSO稀釋受測化合物之濃度成為終濃度的200倍。將受測化合物之DMSO溶液以用於懸浮各細胞之培養基來稀釋，將其添加至細胞培養盤之各孔中使DMSO的最終濃度為0.5%，並在含有5%碳酸氣體的培養器中且37℃下培養3日。培養開始時(day0)及培養後
(day3)之細胞數的計測是使用CellTiter-Glo(商標)Luminescent Cell Viability Assay(Promega)，並根據製造商推薦之程序來進行。利用下式來算出增殖率，並求出抑制50%之受測化合物的濃度(GI50(μM))。結果顯示在表1。
1)Tday3≧Cday0的情況
增殖率(%)=(Tday3-Cday0)/(Cday3-Cday0)×100
T：添加有受測化合物之孔的發光強度
C：未添加受測化合物之孔的發光強度
day0：添加受測化合物之日
day3：評價日。
2)Tday3<Cday0的情況
增殖率(%)=(Tday3-Cday0)/(Cday0)×100
T：添加受測化合物之孔的發光強度
C：未添加受測化合物之孔的發光強度
day0：添加受測化合物之日
day3：評價日。
又，利用下式來算出野生型EGFR與外顯子20***突變型EGFR之GI50值的比。結果顯示在圖2。
GI50比(ratio)=GI50(A431)/GI50(H1975 EGFRinsSVD)
GI50(A431)：對野生型EGFR之GI50
GI50(H1975 EGFRinsSVD)：對外顯子20***突變型EGFR之GI50。
如自表1及圖2明顯所示，化合物A對表現有外顯子20***突變型EGFR之細胞株顯示出細胞增殖抑制效果，且突變選擇性與比較化合物、吉非替尼、厄洛替尼、阿法替尼及奧希替尼(osimertinib)相比為高。
試驗例3
對表現野生型及突變型EGFR細胞株之磷酸化EGFR抑制活性的評價(1)
分別使過量表現出野生型EGFR之人類表皮癌細胞株的A431細胞、透過改變基因而表現出D770_N771insSVD突變型EGFR之人類肺腺癌細胞株的H1975-EGFRinsSVD細胞懸浮在培養基中。分別將細胞懸浮液播種到60mm培養皿中，並在含有5%碳酸氣體之培養器中且37℃下培養1日。將化合物A溶解在DMSO中，並使用DMSO將受測化合物稀釋成終濃度之1000倍的濃度。將受測化合物之DMSO溶液以懸浮各細胞所使用之培養基來稀釋，並將其添加到細胞之培養皿中使DMSO的最終濃度成為0.1%，並在含有5%碳酸氣體之培養器中
且37℃下培養6小時。培養後，回收細胞，並以丸粒(pellet)狀態在-80℃下保管直到使用時。對丸粒添加已添加蛋白酶抑制劑混合物(Protease inhibitor cocktail，Thermo Fisher Scientific)之RIPA緩衝液(Thermo Fisher Scientific)，萃取細胞內的蛋白質，之後，使用BCA蛋白質定量分析套組(BCA protein assay kit，Thermo Fisher Scientific)測定蛋白質濃度，分別將各樣品調整成適合於磷酸化EGFR表現測定的蛋白質濃度。磷酸化EGFR表現測定是使用簡易西方定量系統(Simple Western(商標)assay system)(ProteinSimple)，並根據製造商推薦的程序來進行。1次抗體是將Phospho-EGF Receptor(Tyr1068)# 3777(CST)稀釋成50分之1，並用於測定。
對各細胞做成蛋白質濃度(x軸)與磷酸化EGFR表現量(y軸)的標準曲線，並基於該標準曲線將各樣品之磷酸化EGFR表現量換算成蛋白質濃度。利用下式算出磷酸化EGFR率，並求出可將磷酸化EGFR抑制50%之受測化合物的濃度(IC50(μM))。
磷酸化EGFR率(%)=T/C×100
T：添加有受測化合物之樣品的蛋白質濃度相當量
C：未添加受測化合物之樣品的蛋白質濃度相當量。
又，利用下式算出野生型EGFR與外顯子20***突變型EGFR的選擇性。結果顯示於表2。
IC50比=IC50(A431)/IC50(H1975
EGFRinsSVD)
IC50(A431)：對野生型EGFR之IC50
IC50(H1975 EGFRinsSVD)：對外顯子20***突變型EGFR之IC50。
如自表2明顯所示，化合物A顯示出對外顯子20***突變型EGFR的選擇性抑制活性。
試驗例4
對表現野生型及突變型EGFR細胞株之磷酸化EGFR抑制活性的評價(2)
化合物之野生型EGFR及突變型EGFR的自我磷酸化抑制活性是使用導入有人類EGFR基因之小鼠纖維母細胞株的NIH-3T3細胞來進行。NIH-3T3細胞是以含有10%新生小牛血清(NBCS)、1,500mg/L碳酸氫鈉、100U/mL盤尼西林/100μg/mL鏈黴素(Thermo Fisher Scientific)之D-MEM(高葡萄糖)培養基(和光純藥)來維持，並將編碼有人類EGFR基因(WT、insASV、insSVD、insG、insNPH、insPH)的PB-CMV-MCS-EF1-RFP+Puro載體與Super PiggyBacTransposase表現載體一起藉由利用Amaxa(商標)Cell Line Nucleofector(商標)Kit R之電穿孔法導入，
之後，以嘌黴素(SIGMA)來選擇。表現有野生型EGFR之NIH-3T3細胞(以下亦稱為「NIH3T3-EGFR_WT」)在1%NBCS條件下且在50ng/mL EGF(R&D SYSTEMS)存在下顯示出增殖，又，表現有外顯子20***突變型EGFR之NIH-3T3細胞(以下亦稱為「NIH3T3-EGFRinsASV」、「NIH3T3-EGFRinsSVD」、「NIH3T3-EGFRinsG」、「NIH3T3-EGFRinsNPH」、「NIH3T3-EGFRinsPH」)在1%NBCS條件下且在EGF非存在下顯示出增殖。
評價EGFR自我磷酸化抑制活性時，使導入有人類EGFR之NIH3T3細胞分別懸浮在培養基中。分別將細胞懸浮液播種到60mm培養皿或6孔平底盤，並在含有5%碳酸氣體之培養器中且37℃下培養1日。將化合物A溶解在DMSO中，並使用DMSO稀釋受測化合物使其濃度成為終濃度的400倍。將受測化合物之DMSO溶液以懸浮各細胞所使用之培養基來稀釋，並將其添加至細胞之培養皿中使DMSO之最終濃度成為0.25%。進一步，在NIH3T3-EGFR_WT細胞之培養皿中添加EGF使其成為終濃度50ng/mL。將全部的培養皿在含有5%碳酸氣體之培養器中且37℃下培養6小時。培養後，回收細胞，並以丸粒的狀態在-80℃下保管直到使用時。對丸粒添加已添加蛋白酶抑制劑混合物(Thermo Fisher Scientific)的RIPA緩衝液(Thermo Fisher Scientific)，萃取細胞內的蛋白質，之後，使用BCA蛋白質定量分析套組(Thermo Fisher Scientific)測定蛋白質濃度，分別將各樣品調整成適合於
磷酸化EGFR表現測定的蛋白質濃度。磷酸化EGFR表現測定是使用簡易西方定量系統(Simple Western(商標)assay system)(ProteinSimple)，並根據製造商推薦的程序來進行。1次抗體是將Phospho-EGF Receptor(Tyr1068)# 3777(CST)稀釋成50分之1，並用於測定。
對各細胞做成蛋白質濃度(x軸)與磷酸化EGFR表現量(y軸)的標準曲線，並基於該標準曲線將各樣品之磷酸化EGFR表現量換算成蛋白質濃度。利用下式算出磷酸化EGFR抑制率，並求出可將磷酸化EGFR抑制50%之受測化合物的濃度(IC50(μM))。
磷酸化EGFR抑制率(%)=T/C×100
T：添加有受測化合物之樣品的蛋白質濃度相當量
C：未添加受測化合物之樣品的蛋白質濃度相當量。
又，利用下式算出野生型EGFR與外顯子20***突變型EGFR的選擇性。結果顯示於表3。
IC50比=IC50(WT)/IC50(外顯子20***突變型EGFR)
如自表3明顯所示，化合物A顯示出對各種外顯子20***突變型EGFR的選擇性抑制活性。
如自前述試驗例1至4之結果明顯所示，化合物A~D對表現有外顯子20***突變型EGFR之細胞株顯示出伴隨著EGFR抑制效果的細胞增殖抑制效果，該效果及突變選擇性與比較化合物、吉非替尼、厄洛替尼阿法替尼及奧希替尼相比為高。
試驗例5
In vivo藥效試驗
使用了皮下移植表現突變型EGFR細胞株之模式之抗腫瘤效果的評價
將導入有人類突變型EGFR之NIH3T3-EGFRinsASV細胞、NIH3T3-EGFRinsSVD細胞或者H1975-EGFRinsSVD細胞移植到裸小鼠的皮下，並當植入腫瘤之裸小鼠的腫瘤體積達到100-200mm3左右的時間點時，為使各組之腫瘤體積的平均能夠均一，透過分層隨機化(stratified randomization)將5-6隻分成1組，並將化合物A及阿法替尼進行14日、1日1次連日口服投予。
在投予用量方面，阿法替尼在正式試驗投予期間之14日中是使用最大耐藥用量(投予期間中體重減少會小於20%的最大投予用量)之20mg/kg/day、化合物A是使用200mg/kg/day(最大耐藥用量)。此外，最大耐藥用量是依照源自美國國家癌症研究所(NCI)之「Guidelines Involving Experimental Neoplasia Proposals in Mice and Rats」，並從人道觀點來設定。
為了比較各受測化合物投予時腫瘤之經時增殖推移，腫瘤之增殖比例方面，是令分組時之腫瘤體積為1並依照下式算出相對腫瘤體積(以下亦稱為「RTV」)。又，毒性指標方面，是經時的測定體重，並依照下式算出相對於分組日之平均體重變化率(Body weight change，以下亦稱為「BWC(%)」)。各個體之RTV及BWC之平均值的推移顯示在圖3-8。
RTV=(腫瘤體積計測日之腫瘤體積)/(分組時之腫瘤體積)
BWC(%)=(體重測定日之體重)/(分組時之體重)。
當最終評價日之化合物A投予組的平均RTV值比阿法替尼投予組的平均RTV值還小，且顯示出統計上顯著差異(Student-t檢定、p<0.05)時，化合物A是判定為較阿法替尼顯著有效，並在圖中顯示＊號。此外，將最終評價日之T/C(%)依照下式算出。結果顯示於表4。
如自圖3-8及表4之結果明顯所示，化合物A對移植到裸小鼠皮下之表現外顯子20***突變型EGFR之細胞株顯示出顯著的抗腫瘤效果。又，其效果比阿法替尼還高，且當時並未在小鼠上觀察到嚴重的體重減少、便異常、皮膚異常之症狀。
試驗例6
In vivo藥效試驗
使用了皮下移植表現突變型EGFR細胞株之模式之抗腫瘤效果的評價
將導入有人類突變型EGFR之NIH3T3-EGFRinsNPH細胞移植到裸小鼠的皮下。當植入腫瘤之裸小鼠的腫瘤體積達到100-200mm3左右之時間點時，為使各組之腫瘤體積的平均能夠均一，透過分層隨機化將6隻分成1組，並將化合物A及阿法替尼進行10日、1日1次連日口服投予。
在投予用量方面，阿法替尼是使用最大耐藥用量(投予期間中體重減少會小於20%的最大投予用量)之20mg/kg/day、化合物A是使用100及200mg/kg/day。此外，最大耐藥用量是依照源自美國國家癌症研究所(NCI)之「Guidelines Involving Experimental Neoplasia Proposals in Mice and Rats」，並從人道觀點來設定。
為了比較各受測化合物投予時腫瘤之經時增殖推移，將各個體之腫瘤體積(以下亦稱為「TV」)利用下式算出。又，就毒性指標而言，是經時的測定體重，並
將相對於分組日之體重變化率(Body weight change，以下亦稱為「BWC(%)」)依照下式算出。各個體之TV及BWC之平均值的推移顯示在圖9-10。
TV(mm3)=(長徑×短徑2)/2
BWC(%)=(體重測定日之體重)/(分組時之體重)。
針對抗腫瘤效果，當化合物A投予組之最終投予翌日之平均TV值是比控制組之平均TV值還小，且顯示出統計上顯著差異(Dunnett檢定、p<0.05)時，化合物A是判定為有效，並在圖中顯示＊號。此外，最終評價日之T/C(%)是依照下式算出。結果顯示在表5。
T/C(%)=(受測化合物投予組之腫瘤體積)/(控制組之腫瘤體積)。
如自圖9-10及表5明顯所示，本發明化合物A對移植到裸小鼠皮下之表現外顯子20***突變型EGFR之細胞株顯示出腫瘤增殖抑制或伴隨腫瘤退縮之顯著的抗腫瘤效果，且當時並未在評價動物上觀察到嚴重的體重減少。
試驗例7
使用了皮下移植表現突變型EGFR細胞株之大鼠模式之抗腫瘤效果的評價
將導入有人類突變型EGFR之H1975-EGFRinsSVD細胞移植到裸大鼠的皮下。當植入腫瘤之裸大鼠的腫瘤體積達到200-500mm3左右之時間點時，為使各組之腫瘤體積的平均能夠均一，透過分層隨機化將6隻分成1組，並將化合物A進行14日、1日1次連日口服投予。
在投予用量方面，在正式試驗之投予期間的14日中是使用小於最大耐藥用量(投予期間中之體重減少會小於20%的最大投予用量)的20及40mg/kg/day。此外，最大耐藥用量是依照源自美國國家癌症研究所(NCI)之「Guidelines Involving Experimental Neoplasia Proposals in Mice and Rats」，並從人道觀點來設定。
為了比較各受測化合物投予時腫瘤之經時增殖推移，將各個體之腫瘤體積(以下亦稱為「TV」)利用下式算出。又，就毒性指標而言，是經時的測定體重，並將相對於分組日之體重變化率(Body weight change，以下亦稱為「BWC(%)」)依照下式算出。各個體之TV及BWC之平均值的推移顯示在圖11-12。
TV(mm3)=(長徑×短徑2)/2
BWC(%)=(體重測定日之體重)/(分組時之體重)。
針對抗腫瘤效果，當化合物A投予組之最終評價日之平均TV值是比控制組之平均TV值還小，且顯示出統計上顯著差異(Dunnett檢定、p<0.05)時，化合物A是判定為有效，並在圖中顯示＊號。此外，最終評價日之T/C(%)是依照下式算出。結果顯示在表6。
T/C(%)=(受測化合物投予組之腫瘤體積)/(控制組之腫瘤體積)。
如自圖11-12及表6明顯所示，化合物A對移植到裸大鼠皮下之表現外顯子20***突變型EGFR之細胞株顯示出腫瘤增殖抑制或伴隨腫瘤退縮之顯著的抗腫瘤效果，且當時並未在評價動物上觀察到嚴重的體重減少。
試驗例8
使用了皮下移植源自突變型EGFR陽性肺癌患者之腫瘤之小鼠模式的抗腫瘤效果的評價
將源自V769_D770insASV突變型EGFR陽性人類肺癌患者之腫瘤的LXF 2478移植到裸小鼠之皮下。當植入腫瘤之裸小鼠的腫瘤體積達到100-200mm3左右的時間點時，為使各組之腫瘤體積的平均能夠均一，透過分層隨機化將8隻分成1組，並將化合物A及阿法替尼進行28日、1日1次連日口服投予，之後，設置2週的觀察期間。
在投予用量方面，阿法替尼是使用最大耐藥用量(投予期間中體重減少會小於20%的最大投予用量)之20mg/kg/day、化合物A是使用100及200mg/kg/day。此外，最大耐藥用量是依照源自美國國家癌症研究所(NCI)
之「Guidelines Involving Experimental Neoplasia Proposals in Mice and Rats」，並從人道觀點來設定。
為了比較各受測化合物投予時腫瘤之經時增殖推移，針對腫瘤之增殖比例，是將分組時之腫瘤體積設為1的相對腫瘤體積(以下亦稱為「RTV」)依照下式算出。又，就毒性指標而言，是經時的測定體重，並將相對於分組日之體重變化率(Body weight change，以下亦稱為「BWC(%)」)依照下式算出。各個體之RTV及BWC之平均值的推移顯示在圖13-14。
RTV=(腫瘤體積計測日之腫瘤體積)/(分組時之腫瘤體積)
BWC(%)=(體重測定日之體重)/(分組時之體重)。
當投予最終日隔日(Day28)之化合物A投予組之平均RTV值比控制組之平均RTV值還小，且顯示出統計上顯著差異(Dunnett檢定、p<0.05)時，化合物A是判定為有效，並在圖中顯示＊號。此外，將最終投予日隔日(Day28)之T/C(%)依照下式算出。結果顯示在表7。
T/C(%)=(受測化合物投予組之RTV)/(控制組之RTV)。
如自圖13-14及表7明顯所示，化合物A對移
植到裸小鼠皮下之源自外顯子20***突變型EGFR陽性肺癌患者之腫瘤顯示出伴隨腫瘤退縮之顯著的抗腫瘤效果，且在觀察期間中該效果亦有持續。在當時並未在評價動物上觀察到嚴重的體重減少。
試驗例9
使用了肺移植表現突變型EGFR細胞株之模式之延命效果的評價
建立導入人類突變型EGFR細胞株，即，在H1975-EGFRinsSVD導入有Luciferase的H1975-EGFRinsSVD-Luc株。H1975-EGFRinsSVD-Luc細胞是將編碼有Luciferase之pJTI(商標)FAST DEST載體與pJTI(商標)PhiC31 Integrase表現載體一起藉由利用Amaxa(商標)Cell Line Nucleofector(商標)Kit R的電穿孔法導入到NCI-H1975-EGFRinsSVD細胞，之後，以潮黴素B(nacalai tesque股份有限公司)來選擇。
在評價延命效果時，於培養好之H1975-EGFRinsSVD-Luc細胞之懸浮液等量添加Matrigel來調製細胞浮遊液，之後，移植到裸小鼠的右肺。在移植後6日之時間點將Luciferin以尾靜脈內投予到生存的全部小鼠，並且，為使各組之發光強度之平均值能夠均一，透過分層隨機化將9隻分成1組，並將化合物A及阿法替尼進行1日1次連日口服投予。在投予用量方面，阿法替尼是使用最大耐藥用量(投予期間中體重減少會小於20%的最大投予用量)之20mg/kg/day、化合物A是使用100及
200mg/kg/day。此外，最大耐藥用量是依照源自美國國家癌症研究所(NCI)之「Guidelines Involving Experimental Neoplasia Proposals in Mice and Rats」，並從人道觀點來設定。
針對延命效果之評價，是觀察移植後生存期間，並就各個小鼠求出生存日數。從求出的生存日數算出各組之生存日數中央值(Median survival time，以下亦稱為「MST」)，使用控制組與受測化合物投予組之MST並且利用以下之計算式算出生存期間延長效果(Increase in life span，以下亦稱為「I.L.S.(%)」)。又，就毒性指標而言，是經時的測定體重，並將相對於分組日之體重變化率(Body weight change，以下亦稱為「BWC(%)」)依照下式算出。
I.L.S.(%)=(T/C-1)×100
T：受測化合物投予組之MST
C：控制組之MST。
BWC(%)=(體重測定日之體重)/(分組時之體重)。
針對延命效果之判定，當受測化合物投予組之MST比控制組之MST還大，且顯示出統計上顯著差異(Wilcoxon檢定、p<0.05)時，化合物A是判定為有效，結果顯示在表8。
[表8]
如自表8明顯所示，化合物A在將表現外顯子20***突變型EGFR細胞株移植到裸小鼠之肺同處之模式中顯示出顯著的延命作用。另一方面，在阿法替尼並未觀察到本模式中的延命作用。又，並未觀察到因化合物A之投予所致動物之嚴重體重減少。
試驗例10
移植腫瘤及小鼠皮膚組織中磷酸化EGFR抑制活性的評價
將導入有人類突變型EGFR之NIH3T3-EGFRinsSVD細胞移植到裸小鼠的皮下，並當植入腫瘤之裸小鼠的腫瘤體積達到250-500mm3左右的時間點時，為使各組之腫瘤體積的平均能夠均一，透過分層隨機化將3隻分成1組，並進行一次口服投予化合物A及阿法替尼。投予後，在化合物A及阿法替尼各自之最高血中濃度到達時間附近之1小時及3小時的時間點採取腫瘤以
及皮膚組織。採取好之組織使用液態氮瞬間凍冷凍，保管在-80℃直到使用時。腫瘤及皮膚組織在添加已添加蛋白酶抑制劑混合物(Thermo Fisher Scientific)之RIPA衝液(Thermo Fisher Scientific)的狀態下，進行均質化並萃取細胞內的蛋白質，之後，使用BCA蛋白質定量分析套組(Thermo Fisher Scientific)測定蛋白質濃度，分別將各樣品調整成適合於磷酸化EGFR表現測定的蛋白質濃度。蛋白質是利用SDS-PAGE來分離並轉印至PVDF膜。在阻斷(blocking)之後，將一次抗體之Phospho-EGF Receptor(Tyr1068)# 2234(CST)以0.1% TBS-T緩衝液稀釋到1000分之1，並在4℃下使之反應一晚。之後，將二次抗體之HRP標識抗兔抗體# NA9340V(GE HEALTHCARE)以利用0.1% TBS-T緩衝液來調製之5%脫脂乳溶液稀釋到2500分之1，並在室溫下使之反應40分。透過ECL-Prime(GE HEALTHCARE)使之反應，之後，以LAS-3000(GE HEALTHCARE)檢測。
從上述試驗之結果明顯所示，與皮膚之野生型EGFR相比，化合物A會選擇性的抑制腫瘤之突變型EGFR。
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170 175 Ser Met Asp Phe Gln Asn His Leu Gly Ser Cys Gln Lys Cys Asp Pro 180 185 190 Ser Cys Pro Asn Gly Ser Cys Trp Gly Ala Gly Glu Glu Asn Cys Gln 195 200 205 Lys Leu Thr Lys Ile Ile Cys Ala Gln Gln Cys Ser Gly Arg Cys Arg 210 215 220 Gly Lys Ser Pro Ser Asp Cys Cys His Asn Gln Cys Ala Ala Gly Cys 225 230 235 240 Thr Gly Pro Arg Glu Ser Asp Cys Leu Val Cys Arg Lys Phe Arg Asp 245 250 255 Glu Ala Thr Cys Lys Asp Thr Cys Pro Pro Leu Met Leu Tyr Asn Pro 260 265 270 Thr Thr Tyr Gln Met Asp Val Asn Pro Glu Gly Lys Tyr Ser Phe Gly 275 280 285 Ala Thr Cys Val Lys Lys Cys Pro Arg Asn Tyr Val Val Thr Asp His 290 295 300 Gly Ser Cys Val Arg Ala Cys Gly Ala Asp Ser Tyr Glu Met Glu Glu 305 310 315 320 Asp Gly Val Arg Lys Cys Lys Lys Cys Glu Gly Pro Cys Arg Lys Val 325 330 335 Cys Asn Gly Ile Gly Ile Gly Glu Phe Lys Asp Ser Leu Ser Ile Asn 340 345 350 Ala Thr Asn Ile Lys His Phe Lys Asn Cys Thr Ser Ile Ser Gly Asp 355 360 365 Leu His Ile Leu Pro Val Ala Phe Arg Gly Asp Ser Phe Thr His Thr 370 375 380 Pro Pro Leu Asp Pro Gln Glu Leu Asp Ile Leu Lys Thr Val Lys Glu 385 390 395 400 Ile Thr Gly Phe Leu Leu Ile Gln Ala Trp Pro Glu Asn Arg Thr Asp 405 410 415 Leu His Ala Phe Glu Asn Leu Glu Ile Ile Arg Gly Arg Thr Lys Gln 420 425 430 His Gly Gln Phe Ser Leu Ala Val Val Ser Leu Asn Ile Thr Ser Leu 435 440 445 Gly Leu Arg Ser Leu Lys Glu Ile Ser Asp Gly Asp Val Ile Ile Ser 450 455 460 Gly Asn Lys Asn Leu Cys Tyr Ala Asn Thr Ile Asn Trp Lys Lys Leu 465 470 475 480 Phe Gly Thr Ser Gly Gln Lys Thr Lys Ile Ile Ser Asn Arg Gly Glu 485 490 495 Asn Ser Cys Lys Ala Thr Gly Gln Val Cys His Ala Leu Cys Ser Pro 500 505 510 Glu Gly Cys Trp Gly Pro Glu Pro Arg Asp Cys Val Ser Cys Arg Asn 515 520 525 Val Ser Arg Gly Arg Glu Cys Val Asp Lys Cys Asn Leu Leu Glu Gly 530 535 540 Glu Pro Arg Glu Phe Val Glu Asn Ser Glu Cys Ile Gln Cys His Pro 545 550 555 560 Glu Cys Leu Pro Gln Ala Met Asn Ile Thr Cys Thr Gly Arg Gly Pro 565 570 575 Asp Asn Cys Ile Gln Cys Ala His Tyr Ile Asp Gly Pro His Cys Val 580 585 590 Lys Thr Cys Pro Ala Gly Val Met Gly Glu Asn Asn Thr Leu Val Trp 595 600 605 Lys Tyr Ala Asp Ala Gly His Val Cys His Leu Cys His Pro Asn Cys 610 615 620 Thr Tyr Gly Cys Thr Gly Pro Gly Leu Glu Gly Cys Pro Thr Asn Gly 625 630 635 640 Pro Lys Ile Pro Ser Ile Ala Thr Gly Met Val Gly Ala Leu Leu Leu 645 650 655 Leu Leu Val Val Ala Leu Gly Ile Gly Leu Phe Met Arg Arg Arg His 660 665 670 Ile Val Arg Lys Arg Thr Leu Arg Arg Leu Leu Gln Glu Arg Glu Leu 675 680 685 Val Glu Pro Leu Thr Pro Ser Gly Glu Ala Pro Asn Gln Ala Leu Leu 690 695 700 Arg Ile Leu Lys Glu Thr Glu Phe Lys Lys Ile Lys Val Leu Gly Ser 705 710 715 720 Gly Ala Phe Gly Thr Val Tyr Lys Gly Leu Trp Ile Pro Glu Gly Glu 725 730 735 Lys Val Lys Ile Pro Val Ala Ile Lys Glu Leu Arg Glu Ala Thr Ser 740 745 750 Pro Lys Ala Asn Lys Glu Ile Leu Asp Glu Ala Tyr Val Met Ala Ser 755 760 765 Val Asp Asn Pro His Val Cys Arg Leu Leu Gly Ile Cys Leu Thr Ser 770 775 780 Thr Val Gln Leu Ile Thr Gln Leu Met Pro Phe Gly Cys Leu Leu Asp 785 790 795 800 Tyr Val Arg Glu His Lys Asp Asn Ile Gly Ser Gln Tyr Leu Leu Asn 805 810 815 Trp Cys Val Gln Ile Ala Lys Gly Met Asn Tyr Leu Glu Asp Arg Arg 820 825 830 Leu Val His Arg Asp Leu Ala Ala Arg Asn Val Leu Val Lys Thr Pro 835 840 845 Gln His Val Lys Ile Thr Asp Phe Gly Leu Ala Lys Leu Leu Gly Ala 850 855 860 Glu Glu Lys Glu Tyr His Ala Glu Gly Gly Lys Val Pro Ile Lys Trp 865 870 875 880 Met Ala Leu Glu Ser Ile Leu His Arg Ile Tyr Thr His Gln Ser Asp 885 890 895 Val Trp Ser Tyr Gly Val Thr Val Trp Glu Leu Met Thr Phe Gly Ser 900 905 910 Lys Pro Tyr Asp Gly Ile Pro Ala Ser Glu Ile Ser Ser Ile Leu Glu 915 920 925 Lys Gly Glu Arg Leu Pro Gln Pro Pro Ile Cys Thr Ile Asp Val Tyr 930 935 940 Met Ile Met Val Lys Cys Trp Met Ile Asp Ala Asp Ser Arg Pro Lys 945 950 955 960 Phe Arg Glu Leu Ile Ile Glu Phe Ser Lys Met Ala Arg Asp Pro Gln 965 970 975 Arg Tyr Leu Val Ile Gln Gly Asp Glu Arg Met His Leu Pro Ser Pro 980 985 990 Thr Asp Ser Asn Phe Tyr Arg Ala Leu Met Asp Glu Glu Asp Met Asp 995 1000 1005 Asp Val Val Asp Ala Asp Glu Tyr Leu Ile Pro Gln Gln Gly Phe 1010 1015 1020 Phe Ser Ser Pro Ser Thr Ser Arg Thr Pro Leu Leu Ser Ser Leu 1025 1030 1035 Ser Ala Thr Ser Asn Asn Ser Thr Val Ala Cys Ile Asp Arg Asn 1040 1045 1050 Gly Leu Gln Ser Cys Pro Ile Lys Glu Asp Ser Phe Leu Gln Arg 1055 1060 1065 Tyr Ser Ser Asp Pro Thr Gly Ala Leu Thr Glu Asp Ser Ile Asp 1070 1075 1080 Asp Thr Phe Leu Pro Val Pro Glu Tyr Ile Asn Gln Ser Val Pro 1085 1090 1095 Lys Arg Pro Ala Gly Ser Val Gln Asn Pro Val Tyr His Asn Gln 1100 1105 1110 Pro Leu Asn Pro Ala Pro Ser Arg Asp Pro His Tyr Gln Asp Pro 1115 1120 1125 His Ser Thr Ala Val Gly Asn Pro Glu Tyr Leu Asn Thr Val Gln 1130 1135 1140 Pro Thr Cys Val Asn Ser Thr Phe Asp Ser Pro Ala His Trp Ala 1145 1150 1155 Gln Lys Gly Ser His Gln Ile Ser Leu Asp Asn Pro Asp Tyr Gln 1160 1165 1170 Gln Asp Phe Phe Pro Lys Glu Ala Lys Pro Asn Gly Ile Phe Lys 1175 1180 1185 Gly Ser Thr Ala Glu Asn Ala Glu Tyr Leu Arg Val Ala Pro Gln 1190 1195 1200 Ser Ser Glu Phe Ile Gly Ala 1205 1210
(無)
Claims (8)
- 一種選自於由如下所構成群組之化合物或其鹽之用於製造醫藥的用途，該醫藥是用以治療表現出具有外顯子20***突變之EGFR的惡性腫瘤患者：(S)-N-(4-胺基-6-甲基-5-(喹啉-3-基)-8,9-二氫嘧啶并[5,4-b]吲-8-基)丙烯醯胺；(S)-N-(4-胺基-6-亞甲基-5-(喹啉-3-基)-7,8-二氫-6H-嘧啶并[5,4-b]吡
-7-基)丙烯醯胺；(S,E)-N-(4-胺基-6-亞甲基-5-(喹啉-3-基)-7,8-二氫-6H-嘧啶并[5,4-b]吡
-7-基)-3-氯丙烯醯胺；及(R)-N-(4-胺基-6-甲基-5-(喹啉-3-基)-8,9-二氫嘧啶并[5,4-b]吲
-8-基)-N-甲基丙烯醯胺。
- 如請求項1之用途，其中化合物為(S)-N-(4-胺基-6-甲基-5-(喹啉-3-基)-8,9-二氫嘧啶并[5,4-b]吲-8-基)丙烯醯胺。
- 如請求項1或2之用途，其中表現出具有外顯子20***突變之EGFR的惡性腫瘤患者是肺癌、乳癌、頭頸部癌、腦腫瘤、子宮癌、造血器官腫瘤或皮膚癌之患者。
- 如請求項1或2之用途，其中表現出具有外顯子20***突變之EGFR的惡性腫瘤患者是肺癌患者。
- 如請求項1或2之用途，其中外顯子20***突變是在外顯子20區域***有1個以上胺基酸的突變。
- 如請求項1或2之用途，其中外顯子20*** 突變是在外顯子20區域***有1至7個胺基酸的突變。
- 如請求項1或2之用途，其中外顯子20***突變是在外顯子20區域***有1至4個胺基酸的突變。
- 如請求項1或2之用途，其中外顯子20***突變為V769_D770insASV、D770_N771insSVD、D770_N771insG、H773_V774insNPH、或H773_V774insPH。
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| SG11202106986VA (en) * | 2018-12-28 | 2021-07-29 | Taiho Pharmaceutical Co Ltd | L718 and/or l792 mutant treatment-resistant egfr inhibitor |
| JP6960064B2 (ja) | 2019-02-15 | 2021-11-05 | 大鵬薬品工業株式会社 | ７Ｈ−ピロロ［２，３−ｄ］ピリミジン−４−アミン誘導体 |
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| CN113861195B (zh) * | 2020-06-30 | 2022-11-18 | 上海和誉生物医药科技有限公司 | 一种多稠环egfr抑制剂及其制备方法和应用 |
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| WO2022055895A1 (en) * | 2020-09-08 | 2022-03-17 | Cullinan Pearl Corp. | Treatment regimens for exon-20 insertion mutant egfr cancers |
| WO2022121967A1 (zh) * | 2020-12-09 | 2022-06-16 | 南京药石科技股份有限公司 | Egfr酪氨酸激酶抑制剂及其用途 |
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