TWI599356B - 抑制突變型c-kit的方法 - Google Patents
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- TWI599356B TWI599356B TW101135903A TW101135903A TWI599356B TW I599356 B TWI599356 B TW I599356B TW 101135903 A TW101135903 A TW 101135903A TW 101135903 A TW101135903 A TW 101135903A TW I599356 B TWI599356 B TW I599356B
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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Description
本發明涉及降低或抑制細胞或對象中突變C-KIT的激酶活性的方法,以及此類方法在預防或治療C-KIT相關的細胞疾病中的應用。
結合在治療KIT依賴性疾病中抑制突變形式KIT的能力描述了本發明的背景,但並不限制本發明的範圍。
c-kit基因位於人第四染色體的基因座q11-q12上,其編碼蛋白質KIT(也稱為CD 117),該蛋白是許多不同細胞表面表現的細胞因子受體。參見Rulina等.,生物化學Biochemistry(莫斯科).“活化的白血病致癌基因AML1-ETO和c-kit:產生急性髓性白血病的作用和目前抑制它們的方法”(Activated Leukemic Oncogenes AML1-ETO and c-kit:Role of Development of Acute Myeloid Leukemia and Current Approaches for Their Inhibition).2010;75(13):1650-1666。KIT是單體受體家族的III型受體酪氨酸激酶,和幹細胞因子的跨膜受體。參見Tefferi和Pardanani.“白血病和淋巴瘤”(Leukemia and Lymphoma),2010年3月;51(3):360-362。
KIT主要由肥大細胞、造血祖細胞、生殖細胞、黑素細胞和胃腸道中的Cajal間質細胞表現,其與正常肥大細胞發
育、造血、配子發生、黑素生成和胃慢波的調節相關。參見Miettinen等,“(KIT(CD117):正常和腫瘤組織中表現以及突變和它們的臨床病理相關性的綜述”(KIT(CD117):A Review on Expression in Normal and Neoplastic Tissues,and Mutations and their Clinicopathologic Correlation).Appl Immunohistochem Mol Morphol.2005;13:205-220。
導致KIT的配體不依賴性活化的活化突變在該基因的近膜和激酶結構域中發生。參見Hug等,“ETO相互作用蛋白”(ETO Interacting Proteins).Oncogene.2004;23(24):4270-4274。產生活化形式KIT的突變顯示在增殖性疾病中起作用,所述增殖性疾病是,例如肥大細胞增多症、急性髓性白血病、胃腸基質瘤、鼻腔鼻竇NK/T-細胞淋巴瘤、精原細胞瘤、無性細胞瘤(dysgerminomas)、黑色素瘤和胸腺腫瘤。
目前用於治療野生型和突變KIT相關疾病的靶向劑是甲磺酸伊馬替尼(也稱為GLEEVEC或GLIVIC;諾華公司,巴塞爾,瑞士)。伊馬替尼分別對某些跨膜和近膜KIT突變體,即F522C和V560G表現出活性,但該活性在共有激酶結構域突變體(包括D816V)中顯著降低。參見Akin等.“跨膜C-KIT突變相關的肥大細胞增多症新形式以及對伊馬替尼的反應”(A Novel Form of Mastocytosis Associated with a Transmembrane C-KIT Mutation and Response to Imatinib).Blood.2004;103:3222-3225;Zermati等.“酪氨酸激酶抑制劑STI571對肥大細胞瘤中發現的野生型和各種突變C-KIT
受體的激酶活性的作用”(Effect of Tyrosine Kinase Inhibitor STI571 on the Kinase Activity of Wild-type and Various MutatedC-KIT Receptors Found in Mast Cell Neoplasms).Oncogene.2003;22:660-664;Akin等.“酪氨酸激酶抑制劑STI571對攜帶野生型或突變C-KIT的人肥大細胞的作用”(Effects of Tyrosine Kinase Inhibitor STI571 on Human Mast Cells Bearing Wild-type or Mutated C-KIT).Exp Hematol.2003;31:686-692;Ma等.“導致人肥大細胞增多症的C-KIT突變對STI571和其它KIT激酶抑制劑耐受;含酶促位點突變的激酶顯示不同於野生型激酶和含調節型突變的那些激酶的抑制劑敏感性特徵”(The C-KIT Mutation Causing Human Mastocytosis is Resistant to STI571 and Other KIT Kinase Inhibitors; Kinases with Enzymatic Site Mutations Show Different Inhibitor Sensitivity Profiles than Wild-type Kinases and Those with Regulatory-type Mutations).Blood.2002;99:1741-1744。本領域中所研究的其它KIT突變激酶抑制劑包括達沙替尼(Dasatinib,百時美施貴寶公司(BMS),紐約,紐約州)、米哚妥林(Midostaurin,也稱為PKC412;諾華公司,巴塞爾,瑞士)和馬薩替尼(Masatinib,也稱為AB1010;AB Science,法國)。因此,本領域需要治療KIT活性失調所致的疾病和病症。
本發明涉及抑制結構域突變的KIT和治療突變的KIT
所驅動的此類疾病。KIT依賴性疾病包括特徵在於以下的已知KIT突變的疾病:D816F、D816H、D816N、D816Y、D816V、K642E、Y823D、Del 550-558、Del 557-561、N822K、V654A、N822H、Del 550-558+V654A、Del557-561+V654A、Ins503AY、V560G、55bNP、Del557-558、Del W559-560,F522C、Del579、R634W、K642E、T801I、C809G、D820Y、N822K、N822H、Y823D、Y823C和T670I。
本發明包括抑制或降低患有突變型C-KIT相關增殖性疾病的對象中突變C-KIT酪氨酸激酶的活性或表現的方法,包括給予患有增殖性疾病的所述對象治療有效量的式I所示化合物或其藥學上可接受的鹽或溶劑化物:
在一方面,本發明的治療有效量是每天約50-500毫克。在另一方面,所述化合物的給藥是連續、間歇、全身性或局部給藥中的至少一種。在另一方面,突變的C-KIT進一步限定為持續活化的突變C-KIT。在另一方面,所述化合物經口服、靜脈內或腹膜內給藥。在另一方面,克萊拉尼(Crenolanib)是苯磺酸克萊拉尼、磷酸克萊拉尼、乳酸克萊拉尼、鹽酸克萊拉尼、檸檬酸克萊拉尼、乙酸克萊拉尼、
甲苯磺酸克萊拉尼或琥珀酸克萊拉尼。在另一方面,所述C-KIT突變是以下之一:D816F、D816H、D816N、D816Y、D816V、K642E、Y823D、Del 550-558、Del 557-561、N822K、V654A、N822H、Del 550-558+V654A、Del557-561+V654A、Ins503AY、V560G、55bNP、Del557-558、Del W559-560、F522C、Del579、R634W、K642E、T801I、C809G、D820Y、N822K、N822H、Y823D、Y823C和T670I。在另一方面,治療有效量的所述化合物每天最多給予三次或更多次,只要對象需要治療C-KIT突變體活化的增殖性疾病。在另一方面,所述化合物與另一藥劑以順次或相伴方式中的至少一種提供給新診斷的增殖性疾病患者或復發/難治的增殖性疾病患者。在另一方面,所述化合物作為單一藥劑提供或與另一藥劑(如化療劑)組合提供給新診斷的增殖性疾病患者或復發/難治的增殖性疾病患者。在另一方面,所述化合物作為單一藥劑提供或與另一藥劑組合提供給新診斷的增殖性疾病兒科患者或復發/難治的增殖性疾病兒科患者。在另一方面,所述患者是復發患者/干擾素α、2-氯去氧腺苷或甲磺酸伊馬替尼難治的患者。
在另一實施方式中,本發明包括治療患有C-KIT突變體驅動的增殖性疾病的患者的方法,包括:給予需要此類治療的患者治療有效量的本發明化合物或其鹽,其中細胞增殖性疾病的特徵在於C-KIT突變體受體酪氨酸激酶活性,所述增殖性疾病選自以下的至少一種:肥大細胞增多症、急性髓性白血病、胃腸基質瘤、鼻腔鼻竇NK/T-細胞淋巴瘤、
精原細胞瘤、惡性胚胎瘤(dysgerminomas)、黑色素瘤和胸腺腫瘤。在另一方面,克萊拉尼是苯磺酸克萊拉尼、磷酸克萊拉尼、乳酸克萊拉尼、鹽酸克萊拉尼、檸檬酸克萊拉尼、乙酸克萊拉尼、甲苯磺酸克萊拉尼或琥珀酸克萊拉尼。在另一方面,所述C-KIT突變是以下之一:D816F、D816H、D816N、D816Y、D816V、K642E、Y823D、Del 550-558、Del 557-561、N822K、V654A、N822H、Del 550-558+V654A、Del557-561+V654A、Ins503AY、V560G、55bNP、Del557-558、Del W559-560、F522C、Del579、R634W、K642E、T801I、C809G、D820Y、N822K、N822H、Y823D、Y823C和T670I。在另一方面,克萊拉尼與另一藥劑以順次或相伴方式中的至少一種提供給新診斷的增殖性疾病或復發/難治的增殖性疾病。在另一方面,克萊拉尼作為單一藥劑提供或與另一藥劑(例如,化療劑)組合提供以便治療增殖性疾病的兒科患者。在另一方面,克萊拉尼作為單一藥劑以順次或相伴方式與化療或靶向治療提供給新診斷的增殖性疾病。在另一方面,克萊拉尼作為單一藥劑提供以治療化療或靶向治療難治的或在化療或靶向治療後復發的增殖性疾病患者。在另一方面,所述患者是干擾素α、2-氯去氧腺苷或甲磺酸伊馬替尼中至少一種難治的患者。
本發明提供降低或抑制細胞或對象中突變型C-KIT的激酶活性的方法,以及此類方法在治療突變型C-KIT驅動的細胞增殖性疾病中的應用。本發明的其它特徵和優點將從下文的本發明詳述和申請專利範圍中明白。
為更完全地瞭解本發明的特徵和優點,可參考本發明詳述和附圖,其中:圖1顯示相比於其它KIT酪氨酸激酶抑制劑,本發明苯磺酸鹽對持續活化的KIT D816H突變的結合常數;圖2顯示相比於其它KIT酪氨酸激酶抑制劑,本發明苯磺酸鹽對持續活化的KIT D816V突變的結合常數。
雖然下文詳細討論了作出和利用本發明的各種實施方式,但應該知道本發明提供了許多可適用的發明點,它們可以具體體現為各種特定的內容。本文討論的具體實施方式僅是作出和利用本發明的具體方式的說明,不限制本發明的範圍。
下文定義了許多術語以幫助理解本發明。本文定義的術語具有本發明相關領域的普通技術人員通常理解的含義。諸如“一”、“一個”和“該”等術語不應僅指單數實體,還包括可用具體例子作說明的普通種類。本文的術語用於描述本發明的具體實施方式,但利用它們並不限制本發明,除非在申請專利範圍中描述的。
本發明包括本發明化合物在抑制細胞或對象中突變型C-KIT激酶活性,或治療對象中突變型C-KIT激酶活性或表現相關疾病中的應用。
在該方面的一個實施方式中,本發明提供降低或抑制
細胞中突變型C-KIT的激酶活性的方法,包括將所述細胞與本發明化合物接觸的步驟。本發明還提供降低或抑制對象中突變型C-KIT激酶活性的方法,包括給予所述對象本發明化合物的步驟。本發明還提供抑制細胞增殖的方法,包括將所述細胞與本發明化合物接觸的步驟。
本文所用的術語“對象”指已經作為治療、觀察或實驗客體的動物,例如哺乳動物或人。
本文所用的術語“接觸”指將本發明化合物或其藥學上可接受的鹽加入到細胞,從而所述細胞攝取所述化合物。
在該方面的其它實施方式中,本發明提供治療方法以便治療具有患有細胞增殖性疾病的對象,所述疾病由突變型C-KIT的異常激酶活性驅動。
本文所用的術語“治療有效量”指研究人員、獸醫、醫生或其它臨床醫師所尋求的,引發對象中生物學或醫學反應的活性化合物或藥用鹽的用量,所述反應包括緩解所治療疾病或病症的症狀。
本領域知曉測定包含本發明化合物的藥物組合物的治療有效劑量的方法。
本文所用的術語“組合物”應包括含有特定量的特定成分的產品以及從特定量的特定成分的組合直接或間接獲得的任何產品。
本文所用的術語“突變型C-KIT相關疾病”或“C-KIT突變的受體酪氨酸激酶相關疾病”或“突變型C-KIT驅動細胞增殖性疾病”包括與突變型C-KIT活性相關或涉及突變型
C-KIT活性的疾病,例如導致C-KIT組成型活化的突變。“突變型C-KIT相關疾病”的例子包括C-KIT中突變造成C-KIT過度刺激所致的疾病。
術語“細胞增殖性疾病”指多細胞生物體中一個或多個細胞亞組的過度細胞增殖,從而對該多細胞生物體致害(即,不適或預期壽命降低)。細胞增殖性疾病可在不同類型的動物和人中發生。細胞增殖性疾病的例子是肥大細胞增多症、急性髓性白血病、胃腸基質瘤、鼻腔鼻竇NK/T-細胞淋巴瘤、精原細胞瘤、無性細胞瘤、黑色素瘤和胸腺腫瘤。
在一個實施方式中,本發明可與另一療法組合為組合治療以便治療對象中突變型C-KIT相關的細胞增殖性疾病發作。組合治療包括給予治療有效量的本發明化合物與一種或多種其它抗細胞增殖療法,包括但不限於化療和靶向療法,例如放療。
在本發明的另一實施方式中,本發明化合物可與化療組合給予。本文所用的化療指涉及化療劑的療法。各種化療劑可與本發明聯用。紫杉烷化合物,具體是多西他賽與本發明化合物以每平方米體表面積75毫克(mg/m2)的劑量安全性群組合給藥,僅是舉例。
化療是本領域技術人員已知的。化療的合適劑量和方案類似於臨床治療中早已採用的那些,其中所述化療與其它療法組合使用或單用。
在本發明的另一實施方式中,本發明化合物可與放療
組合給予。本文所用的“放療”指包括有需要的對象暴露於射線的治療。本領域技術人員已知放療。放療的合適劑量和方案類似於臨床治療中早已採用的那些,其中所述放療與其它療法組合遞送或單用。
在本發明的另一實施方式中,本發明化合物可與靶向治療組合給予。本文所用的“靶向治療”指靶向參與腫瘤產生或致癌信號傳導的特定類型蛋白質的治療。例如,抗血管內皮生長因子的酪氨酸激酶抑制劑已用於治療癌症。
本發明還包括以下方法:除了本發明化合物,該方法還利用第二化療劑,二者同時或順次(任一次序)給予。
本文所用的術語“化療劑”指與本發明聯用的化療劑。為詳細討論可與本發明聯用的化療劑以及它們的給藥劑量和方法,可參見,例如Dorr等.,《癌症化療手冊》(The Cancer Chemotherapy Handbook)(第6版)Fischer,Durivage,Knobf和Beaulieu,Mosby-Year Book,Inc.(2003),相關劑型、治療方案和操作要求通過引用納入本文。化療劑的非限制性例子選自以下的至少一種:烷化/氨基甲醯化劑;鉑衍生物;抗有絲分裂劑;微管蛋白抑制劑;拓撲異構酶抑制劑;核苷酸或核苷拮抗劑,例如嘧啶或嘌呤拮抗劑;葉酸拮抗劑、紫杉烷類、激酶抑制劑;磷酸酶抑制劑;蛋白酶體抑制劑;組蛋白脫乙醯基酶抑制劑;熱激蛋白抑制劑;血管靶向劑(VAT);單克隆抗體(例如,曲妥珠單抗(Trastuzumab)、利妥昔單抗(Rituximab)、阿萊珠單抗(Alemtuzumab)、托西莫單抗(Tositumomab)、賽圖昔單抗(Cetuxcimab)、貝伐珠單抗
(Bevacizumab))以及單克隆抗體的突變體、片段和偶聯物(例如,吉妥單抗(Gemtuzumab ozogamicin)或替伊莫單抗(Ibritumomab tiuxetan));基於寡核苷酸的療劑;Toll-樣受體激動劑;蛋白酶抑制劑;抗-雌激素激素療劑;抗-雄激素激素療劑;促黃體激素釋放激素(LHRH)劑(例如,亮丙瑞林(Leuprorelin)、戈舍瑞林(Goserelin)、曲普瑞林(Triptorelin));芳香酶抑制劑;博萊黴素;類維生素A;DNA甲基轉移酶抑制劑;丙氨菌素(alanosine);細胞因子;干擾素;和死亡受體激動劑。在還有的另一方面,所述化療劑選自以下的至少一種:放線菌素D、阿巴瑞克(Abarelix)、阿昔單抗(Abciximab)、阿柔比星(Aclarubicin)、阿達帕林(Adapalene)、阿萊珠單抗、六甲蜜胺(Altretamine)、氨魯米特、氨普立糖(Amiprilose)、氨柔比星(Amrubicin)、阿那曲唑(Anastrozole)、安西他賓(Ancitabine)、青蒿素、硫唑嘌呤(Azathioprine)、巴利昔單抗(Basiliximab)、苯達莫司汀(Bendamustine)、百克沙(Bexxar)、比卡魯胺(Bicalutamide)、博萊黴素、硼替佐米(Bortezomib)、溴尿苷(Broxuridine)、白消安、坎帕斯(Campath)、卡培他濱(Capecitabine)、卡鉑、卡波醌(Carboquone)、卡莫司汀(Carmustine)、西曲瑞克(Cetrorelix)、瘤可寧(ChloramBucil)、氮芥(Chlormethine)、順鉑、克拉屈濱(Cladribine)、氯米芬(Clomifene)、環磷醯胺、達卡巴嗪(Dacarbazine)、達利珠單抗(Daclizumab)、更生黴素、柔紅黴素、地西他濱(Decitabine)、德含瑞林(Deslorelin)、右雷佐生(Dexrazoxane)、多西他賽、多西氟
尿啶(Doxifluridine)、阿黴素、屈洛昔芬(Droloxifene)、屈他雄酮(Drostanolone)、依地福新(Edelfosine)、依洛尼塞(Eflornithine)、依米替氟(Emitefur)、表柔比星、環硫雄醇(Epitiostanol)、依鉑(Eptaplatin)、西妥昔單抗(Erbitux)、埃羅替尼(Erlotinib)、雌莫司汀(Estramustine)、依託泊甙、依西美坦(Exemestane)、法倔唑(Fadrozole)、非那雄胺(Finasteride)、氟尿苷(Floxuridine)、氟胞嘧啶、氟達拉濱(Fludarabine)、氟尿嘧啶、氟他胺(Flutamide)、福美司坦(Formestane)、膦甲酸(Foscarnet)、磷雌酚(Fosfestrol)、福莫司汀(Fotemustine)、氟維司群(Fulvestrant)、吉非替尼(Gefitinib)、吉那森斯(Genasense)、吉西他濱(Gemcitabine)、格列衛(Glivec)、戈舍瑞林(Goserelin)、胍立莫司(Gusperimus)、赫賽汀(Herceptin)、伊達比星(Idarubicin)、碘苷(Idoxuridine)、異環磷醯胺(Ifosfamide)、伊馬替尼(Imatinib)、英丙舒凡(Improsulfan)、英夫利昔單抗(Infliximab)、依立替康(Irinotecan)、伊沙匹隆(Ixabepilone)、蘭瑞肽(Lanreotide)、來曲唑(Letrozole)、亮丙瑞林(Leuprorelin)、樂巴鉑(Lobaplatin)、洛莫司汀(Lomustine)、魯珀若利得(Luprolide)、美法侖、巰嘌呤(Mercaptopurine)、甲氨蝶呤、美妥替呱(Meturedepa)、米鉑(Miboplatin)、米非司酮(Mifepristone)、米特福辛(Miltefosine)、米立司亭(Mirimostim)、米托胍腙(Mitoguazone)、二溴衛矛醇(Mitolactol)、絲裂黴素、米托蒽醌、咪唑立賓(Mizoribine)、莫特沙芬(Motexafin)、麥羅
塔(Mylotarg)、那托司亭(Nartograstim)、那巴珠單抗(Nebazumab)、奈達鉑(Nedaplatin)、尼魯米特(Nilutamide)、尼莫司汀(Nimustine)、奧曲肽(Octreotide)、奧美昔芬(Ormeloxifene)、奧沙利鉑(Oxaliplatin)、紫杉醇、帕利珠單抗(Palivizumab)、埃坡黴素(Patupilone)、培門冬酶(Pegaspargase)、聚乙二醇非格司亭(Pegfilgrastim)、培美曲唑(Pemetrexed)、噴曲肽(Pentetreotide)、噴司他丁(Pentostatin)、培磷醯胺(Perfosfamide)、呱泊舒凡(Piposulfan)、吡柔比星(Pirarubicin)、光神黴素、潑尼氮芥(Prednimustine)、丙卡巴肼(Procarbazine)、丙帕鍺(Propagermanium)、丙螺氯銨(Prospidium Chloride)、雷洛昔芬(Raloxifen)、雷替曲塞(Raltitrexed)、雷莫司汀(Ranimustine)、豹蛙酶(Ranpirnase)、拉布立酶(Rasburicase)、雷佐生(Razoxane)、利妥昔單抗、利福平、利曲舒凡(Ritrosulfan)、羅莫肽(Romurtide)、魯伯斯塔(Ruboxistaurin)、沙格司亭(Sargramostim)、沙鉑(Satraplatin)、西羅莫司(Sirolimus)、索布佐生(Sobuzoxane)、索拉非尼(Sorafenib)、螺莫司汀(Spiromustine)、鏈佐星(Streptozocin)、舒尼替尼(Sunitinib)、他莫昔芬、他索納明(Tasonermin)、替加氟(Tegafur)、替莫泊芬(Temoporfin)、替莫唑胺(Temozolomide)、替尼泊苷(Teniposide)、睾內酯酮(Testolactone)、塞替派(Thiotepa)、胸腺法新(Thymalfasin)、硫米嘌呤(Tiamiprine)、拓撲替康(Topotecan)、托瑞米芬
(Toremifene)、特雷爾(Trail)、曲奧舒凡(Treosulfan)、三亞胺醌(Triaziquone)、三甲曲沙(Trimetrexate)、曲普瑞林(Triptorelin)、曲磷胺(Trofosfamide)、烏瑞替哌(Uredepa)、戊柔比星(Valrubicin)、瓦他拉尼(Vatalanib)、維替泊芬(Verteporfin)、長春花鹼、長春新鹼、長春地辛、長春瑞濱(Vinorelbine)、伏羅唑(Vorozole)和澤娃靈(Zevalin)。
在一個實施方式中,本發明利用治療有效量的式I所示化合物或其藥學上可接受的鹽或溶劑化物抵禦增殖性疾病:
所述增殖性疾病選自以下的至少一種:肥大細胞增多症、急性髓性白血病、胃腸基質瘤、鼻腔鼻竇NK/T-細胞淋巴瘤、精原細胞瘤、無性細胞瘤、黑色素瘤和胸腺腫瘤。藥學上可接受的鹽有,例如鹽酸鹽、磷酸鹽和乳酸鹽,它們的製備方式類似於苯磺酸鹽的製備方式且是本領域普通技術人員熟知的。
可將本發明化合物經全身性,例如口服、靜脈內、皮下、肌肉內、真皮內或胃腸外給予對象。本發明化合物還可局部給予對象。
可將本發明化合物配製成緩釋或速釋製劑,其目的是
在所需時間範圍內維持本發明化合物與靶向組織的接觸。
適合口服給藥的組合物包括固體形式,例如丸劑、片劑、囊片、膠囊、粒劑和粉末,液體形式,例如溶液、乳液和混懸液。可用於胃腸外給藥的形式包括無菌溶液、乳液和混懸液。
本發明化合物的每日劑量可以在每日每位成年人50-500毫克的寬範圍內變動。對於口服給藥,組合物宜採用含有20-100毫克的片劑形式提供。本發明的化合物可採用每日最多三次或更多次的服法給予。優選每日三次。待給予的最佳劑量可由本領域技術人員決定,可依據所用的本發明化合物、給藥方式、給藥時間、製品強度、疾病細節作出改變。劑量調節取決於患者特徵相關的因素,例如年齡、體重和飲食。
本發明化合物的製備.
可用於製備式I所示化合物的通用合成方法見美國專利號5,990,146(1999年11月23日授權)(華納-蘭伯特公司Warner-Lambert Co.)和PCT公佈申請號WO 99/16755(1999年4月8日公佈)(默克公司Merck & Co.)、WO 01/40217(2001年7月7日公佈)(輝瑞公司Pfizer,Inc.)、美國專利申請號US 2005/0124599(輝瑞公司)和美國專利申請號7,183,414(輝瑞公司),相關部分通過引用納入本文。
藥學上可接受的鹽,例如鹽酸鹽、磷酸鹽和乳酸鹽採用類似於苯磺酸鹽的製備方式製備,這些鹽是本領域普通技術人員熟知的。以下本發明代表性的化合物僅是出於示
範性目的,絕非意味著限制本發明。
生物學活性.
體外試驗.
進行以下代表性的體外試驗以測定本發明化合物的C-KIT生物學活性。給出這些試驗以非限制性方式說明本發明。
抑制突變型C-KIT酶活性證明特異性抑制了突變型C-KIT酶和依賴於突變型C-KIT活性的細胞過程。本文的所有實例顯示突變型C-KIT激酶和C-KIT-依賴性細胞反應的顯著和特異性抑制作用。
競爭性結合試驗.
進行體外激酶試驗以測定本發明化合物的活性。採用KINOME掃描Kdelect試驗方案抑制突變型人C-KIT受體的激酶結構域。KINOME掃描平臺採用高通量競爭結合技術。混合DNA-標記的激酶、固定化配體和本發明化合物進行該試驗。採用DNA標籤的定量PCR檢測本發明化合物與固定化配體競爭的能力。採用競爭結合試驗評估本發明化合物對一組96個人蛋白激酶的活性。
在24-孔板塊中,將激酶-標記的T7噬菌體菌株在源自BL21菌株的大腸桿菌宿主中平行培養。將大腸桿菌培養至對數階段,用冷凍儲備物的T7噬菌體感染並在32℃振盪溫育直至裂解。然後離心並過濾裂解物。在HEK-293細胞中產生其餘激酶並用DNA標記以供定量PCR檢測。室溫下,用生物素化的小分子配體處理鏈霉親和素-包被的磁珠30
分鐘來產生用於激酶試驗的親和樹脂。用過量生物素封閉配體珠,用封閉緩衝液洗滌以減少非特異性噬菌體結合,所述封閉緩衝液由Sea Block、1%牛血清白蛋白(BSA)、0.05%吐溫20、1 mM二硫蘇糖醇(DTT)構成。在100%二甲基亞碸(DMSO)中,將本發明的11-點3-倍連續稀釋液製備成40×儲備液,稀釋成1×直接加入試驗。
通過在1x結合緩衝液中混合配體親和珠、激酶和本發明化合物活化結合反應,所述結合緩衝液由20% Sea Block、0.17磷酸緩衝鹽水(PBS)、0.05%吐溫20、6 mM DTT構成。所有反應在聚丙烯384-孔平板中進行,最終體積為0.04 mL。平板在室溫下振盪溫育1小時。親和珠用1xPBS和0.05%吐溫20緩衝液洗滌,然後重懸在由1x PBS、0.05%吐溫20、0.5 uM非生物素化的親和配體構成的洗脫緩衝液中。重懸後,室溫下振盪溫育親和珠。然後通過定量PCR檢測洗脫液的激酶濃度。
採用Hill方程,利用標準劑量-反應曲線計算結合常數(Kd)。利用非線性最小二乘與Levenberg-Marquardt演算法擬合曲線。將本發明化合物的Kd與陰性DMSO對照和陽性對照化合物的Kd作比較。利用化合物特性目測相互作用圖,TREE點(TREEspot)目測觀察本發明化合物的結合親和力。
直接酶磷酸化試驗.
採用密理博激酶IC50分析試驗(Millipore Kinase IC50 Profiler assay),對一組正常C-KIT和突變的C-KIT激酶篩選
本發明化合物。對於兩種激酶的試驗,C-KIT酶與pH 7.0的8 mM 3-(N-嗎啉基)丙磺酸(MOPS)、0.2 mM乙二胺四乙酸(EDTA)、50 uM合成的Abl肽底物EAIYAAPFAKKK、10 mM乙酸鎂和[γ-33P-ATP]溫育。加入MgATp混合物活化反應。反應混合物在室溫溫育40分鐘,加入3%磷酸溶液停止反應。將10微升反應溶液點樣在P30濾墊上,用75 mM磷酸洗滌3次,5分鐘,然後用甲醇洗滌1次,隨後乾燥並作閃爍計數。利用5.1版的XLFit分析各重複樣品(包括陽性和陰性對照)的閃爍值,以測定本發明化合物對正常和突變C-KIT的IC50值。
C-KIT-D816突變的生物學資料.
本發明的苯磺酸鹽對C-KIT酪氨酸激酶結構域突變D816H和D816V的活性示於圖1和2。所有結合常數以納摩爾濃度示出。在圖1和2中,比較了本發明化合物與本領域已知的其它抑制劑對C-KIT D816突變的活性。參見Davis MI,Hunt JP,Herrgard S等,“激酶抑制劑選擇性的綜合分析”(Comprehensive analysis of kinase inhibitor selectivity.)Nat Biotechnol 2011;29:1046-51。本發明苯磺酸鹽對C-KIT D816H突變的結合常數(Kd)是5.4 nM,對C-KIT D816V突變的結合常數(Kd)是2.5 nM。比較本發明的苯磺酸鹽對C-KIT D816H和D816V突變的Kd與本領域的其它抑制劑的Kd時,本發明的苯磺酸鹽形式對C-KIT D816H突變的親和力是其它抑制劑的1-103倍,對C-KIT D816V突變的親和力是其它抑制劑的1-392倍。與甲磺酸伊馬替尼相比,本發明的苯磺
酸鹽形式對C-KIT D816H突變的親和力是甲磺酸伊馬替尼的103倍以上,對C-KIT D816V突變的親和力是甲磺酸伊馬替尼的392倍(D816H Kd=560 nM和D816V Kd=980 nM)。
採用直接酶促密理博激酶IC50分析試驗(direct enzymatic Millipore IC50 profiler assay)測定本發明苯磺酸鹽的活性。所有IC50值以納摩爾濃度示出。在直接酶促檢測試驗中,本發明苯磺酸鹽對C-KIT D816H突變的IC50值是7 nM。
對於本發明的任何方法、試劑盒、試劑或組合物,可實施本說明書討論的任何實施方式,反之亦然。此外,可利用本發明的組合物實施本發明的方法。
應該理解,本文所述的特定實施方式是為說明目的顯示,不是對本發明的限制。本發明的主要特徵可用於各種實施方式中而不脫離本發明的範圍。僅採用常規實驗,本領域技術人員會知道或確定本文所述具體流程的許多等價方式。此類等價方式應視作落在本發明的範圍內並被申請專利範圍所覆蓋。
說明書述及的所有出版物和專利申請說明了本發明所屬領域的技術人員的技術水準。與各出版物或專利申請專門且單獨表示通過引用納入的程度一樣,所有出版物和專利申請通過引用納入本文。
當詞語“一”在申請專利範圍和/或說明書中與術語“包含”聯用時,可表示“一”,但還與“一個或多個”、“至少一個”和“一個或多於一個”的意義一致。在申請專利範圍中利用
術語“或”表示“和/或”,除非明確表示指代唯一的備選方案或者備選方案相互排斥,但本發明支持指代唯一的備選方案和“和/或”的定義。本申請通篇利用術語“約”表明某數值包括用於測定該數值的方法、裝置的固有誤差,或研究客體之間存在的偏差。
本說明書和申請專利範圍中使用的詞語“包含”(和任何形式的包含,例如“含有”和“包括”)、“具有”(和任何形式的具有,例如“有”和“擁有”)、“包括”(和任何形式的包括,例如“包括有”和“包括了”)或“含有”(任何形式的含有,例如“含”和“包含”)是非排他性的或開放式的,不排除未述及的其它元素或方法步驟。
本文所用的術語“或它們的組合”指該術語之前所列專案的所有排列和組合。例如,“A、B、C或它們的組合”應包括以下的至少一種:A、B、C、AB、AC、BC或ABC,如果在特定情況中順序是至關重要的,還包括BA、CA、CB、CBA、BCA、ACB、BAC或CAB。繼續以此為例,明顯包括的組合含有一個或多個專案或術語的重複,例如BB、AAA、MB、BBC、AAABCCCC、CBBAAA、CABABB等等。技術人員應理解任何組合中專案或術語的數量通常不作限制,除非上下文中明顯有限制。
本文所用的近似詞語,例如但不限於“約”、“實質性”或“實質性地”指這樣一種條件:當如此修飾時,應理解為不必是絕對的或完美的,但認為足夠接近本領域普通技術人員的那些條件,從而保證能指明該條件,如其存在的那
樣。說明書可變動的範圍取決於產生的改變有多大,但該改變仍使得本領域普通技術人員認識到修飾的特徵仍具有未修飾特徵的所需特徵和性能。根據前述討論,用近似詞語,例如“約”修飾的數值通常可自所述值改變至少±1、2、3、4、5、6、7、10、12或15%。
根據本說明書,可以作出和實施本文披露和要求保護的所有組合物和/或方法。雖然根據優選的實施方式描述了本發明的組合物和方法,本領域技術人員應該明白可對本文所述的組合物和/或方法以及方法的步驟或步驟次序作出改變而不脫離本發明的概念、構思和範圍。本領域技術人員顯而易見的所有此類相似的替代方式和改進應視作落在隨附申請專利範圍限定的本發明構思、範圍和概念內。
Rulina等.,Biochemistry(莫斯科).“活化的白血病致癌基因AML1-ETO和c-kit:產生急性髓性白血病的作用和目前抑制它們的方法”(Activated Leukemic Oncogenes AML1-ETO and c-kit:Role of Development of Acute Myeloid Leukemia and Current Approaches for Their Inhibition).2010;75(13):1650-1666.
Tefferi和Pardanani.“KIT816V-陽性肥大細胞增多症的靶向治療:等待原則證明”(Targeted Therapy in KIT816V-positive mastocytosis:waiting for proof-of-principle.)“白血病和淋巴瘤”(Leukemia and Lymphoma),2010年3月;51(3):360-362.
Miettinen等,“(KIT(CD117):正常和腫瘤組織中表現以及突變和它們的臨床病理相關性的綜述”(KIT(CD117):A Review on Expression in Normal and Neoplastic Tissues,and Mutations and their Clinicopathologic Correlation).Appl Immunohistochem Mol Morphol.2005;13:205-220.
Hug等,“ETO相互作用蛋白”(ETO Interacting Proteins).Oncogene.2004;23(24):4270-4274.
Akin等.“跨膜C-KIT突變相關的肥大細胞增多症新形式以及對伊馬替尼的反應”(A Novel Form of Mastocytosis Associated with a Transmembrane C-KIT Mutation and Response to Imatinib).Blood.2004;103:3222-3225.
Zermati等.“酪氨酸激酶抑制劑STI571對肥大細胞瘤中發現的野生型和各種突變C-KIT受體的激酶活性的作用”(Effect of Tyrosine Kinase Inhibitor STI571 on the Kinase Activity of Wild-type and Various Mutated C-KIT Receptors Found in Mast Cell Neoplasms).Oncogene.2003;22:660-664.
Akin等.“酪氨酸激酶抑制劑STI571對攜帶野生型或突變C-KIT的人肥大細胞的作用”(Effects of Tyrosine Kinase Inhibitor STI571 on Human Mast Cells Bearing Wild-type or Mutated C-KIT).Exp Hematol.2003;31:686-692.
Ma等.“導致人肥大細胞增多症的C-KIT突變體對STI571和其它KIT激酶抑制劑耐受;含酶促位元點突變的激酶顯示不同於野生型激酶和含調節型突變的那些激酶的抑
制劑敏感性特徵”(The C-KIT Mutation Causing Human Mastocytosis is Resistant to STI571 and Other KIT Kinase Inhibitors;Kinases with Enzymatic Site Mutations Show Different Inhibitor Sensitivity Profiles than Wild-type Kinases and Those with Regulatory-type Mutations).Blood.2002;99:1741-1744.
Davis MI,Hunt JP,Herrgard S等,“激酶抑制劑選擇性的綜合分析”(Comprehensive analysis of kinase inhibitor selectivity.)Nat Biotechnol 2011;29:1046-51.
Claims (21)
- 一種治療有效量的式I所示化合物
- 如申請專利範圍第1項所述的用途,其特徵在於,所述增殖性疾病選自以下的至少一種:肥大細胞增多症、急性髓性白血病、胃腸基質瘤、鼻腔鼻竇NK/T-細胞淋巴瘤、精原細胞瘤、惡性胚胎瘤、黑色素瘤和胸腺腫瘤。
- 如申請專利範圍第1項所述的用途,其特徵在於,所述治療有效量是每天50-500毫克。
- 如申請專利範圍第1項所述的用途,其特徵在於,所述化合物係被配製成連續、間歇、全身性或局部給藥中的至少一種。
- 如申請專利範圍第1項所述的用途,其特徵在於,所述突變型C-KIT限定為持續活化的。
- 如申請專利範圍第1項所述的用途,其特徵在於,所述化合物係被配製成經口服、靜脈內或腹膜內給藥。
- 如申請專利範圍第1項所述的用途,其特徵在於,所述化合物或其鹽是選自於下列至少一種:苯磺酸克萊拉尼(crenolanib)、磷酸克萊拉尼、乳酸克萊拉尼、鹽酸克萊拉尼、檸檬酸克萊拉尼、乙酸克萊拉尼、甲苯磺酸克萊拉尼或琥珀酸克萊拉尼。
- 如申請專利範圍第1項所述的用途,其特徵在於,所述治療有效量的化合物每天給藥多達三次或更多次,只要所述對象需要治療增殖性疾病。
- 如申請專利範圍第1項所述的用途,其特徵在於,另一藥劑係與克萊拉尼或其藥學上可接受的鹽、及一或多種適合的賦形劑組合。
- 如申請專利範圍第1項所述的用途,其特徵在於,所述對象是新診斷的增殖性疾病對象、緩解中之對象、或復發/難治的增殖性疾病對象。
- 如申請專利範圍第1項所述的用途,其特徵在於,所述對象是新診斷的增殖性疾病兒科對象、緩解中之兒科對象、或復發/難治的增殖性疾病兒科對象。
- 如申請專利範圍第1項所述的用途,其特徵在於,所述對象是干擾素α、2-氯去氧腺苷或甲磺酸伊馬替尼(Imatinib)之復發/難治的對象。
- 一種治療有效量的克萊拉尼或其藥學上可接受的鹽於製造用於治療患有增殖性疾病的對象之藥劑之用途,其中所述增殖性疾病的特徵在於源自於突變型C-KIT受體酪氨酸激酶的活性,及其中所述增殖性疾病選自以下的 至少一種:肥大細胞增多症、急性髓性白血病、胃腸基質瘤、鼻腔鼻竇NK/T-細胞淋巴瘤、精原細胞瘤、惡性胚胎瘤、黑色素瘤和胸腺腫瘤;且其中所述突變型C-KIT受體酪氨酸激酶係下列中的至少一種:C-KIT D816、D816F、D816H、D816Y及D816V。
- 如申請專利範圍第13項所述的用途,其特徵在於,所述化合物係被配製成經口服、靜脈內或腹膜內給藥。
- 如申請專利範圍第13項所述的用途,其特徵在於,所述克萊拉尼是選自於下列至少一種:苯磺酸克萊拉尼、磷酸克萊拉尼、乳酸克萊拉尼、鹽酸克萊拉尼、檸檬酸克萊拉尼、乙酸克萊拉尼、甲苯磺酸克萊拉尼或琥珀酸克萊拉尼。
- 如申請專利範圍第13項所述的用途,其特徵在於,所述治療有效量的化合物每天給予多達三次或更多次,只要所述對象需要治療增殖性疾病。
- 如申請專利範圍第13項所述的用途,其特徵在於,所述克萊拉尼或其鹽與另一藥劑以順次或相伴方式中的至少一種提供給新診斷的增殖性疾病對象、提供給一對象以維持緩解、或提供給復發/難治的增殖性疾病對象。
- 如申請專利範圍第13項所述的用途,其特徵在於,所述克萊拉尼或其鹽作為單一藥劑提供或與另一藥劑組合提供用以治療增殖性疾病的兒科對象。
- 如申請專利範圍第13項所述的用途,其特徵在於,所述克萊拉尼或其鹽在新診斷的增殖性疾病中的化療或靶 向治療中的至少一種之後作為單一藥劑提供。
- 如申請專利範圍第13項所述的用途,其特徵在於,所述克萊拉尼作為單一藥劑提供,用於在另一化療或靶向治療後難治或復發的增殖性疾病對象的治療。
- 如申請專利範圍第13項所述的用途,其特徵在於,所述對象是干擾素α、2-氯去氧腺苷或甲磺酸伊馬替尼中至少一種難治的對象。
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US10835525B2 (en) | 2012-09-26 | 2020-11-17 | Arog Pharmaceuticals, Inc. | Method of inhibiting mutant C-KIT |
US11642340B2 (en) | 2012-09-26 | 2023-05-09 | Arog Pharmaceuticals, Inc. | Method of inhibiting mutant C-KIT |
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BR112015016282A2 (pt) | 2013-01-07 | 2017-07-11 | Arog Pharmaceuticals Inc | crenolanibe para tratamento de distúrbios proliferativos de flt3 mutado |
WO2018014519A1 (zh) * | 2016-07-18 | 2018-01-25 | 北京雅康博生物科技有限公司 | 用于检测c-kit基因突变的引物、探针及试剂盒 |
US11078541B2 (en) | 2016-11-02 | 2021-08-03 | Arog Pharmaceuticals, Inc. | Crenolanib for treating FLT3 mutated proliferative disorders associated mutations |
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US11713310B2 (en) | 2020-07-20 | 2023-08-01 | Arog Pharmaceuticals, Inc. | Crystal forms of crenolanib and methods of use thereof |
US11969420B2 (en) | 2020-10-30 | 2024-04-30 | Arog Pharmaceuticals, Inc. | Combination therapy of crenolanib and apoptosis pathway agents for the treatment of proliferative disorders |
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