用于治疗flt3突变型增殖性疾病的crenolanib的制作方法
【专利说明】用于治疗FLT3突变型增殖性疾病的CRENOLANIB 技术领域 本发明涉及使用的一种药学上可接受的crenolanib盐治疗由组成性激活型突变FLT3 驱动的增殖性疾病，以及一种治疗恒温动物(特别是人类)的方法，其中给予患有所述疾病 或病情的对象有效治疗剂量的crenolanib。 【背景技术】 在不限制本发明范围的情况下，其背景与FLT3酪氨酸激酶相关。 FMS样酪氨酸激酶3(FLT3)基因编码了一种膜结合受体的酪氨酸激酶，其影响导致血液 疾病和恶性肿瘤的造血过程。请参阅Drexler,HG et al .Expression of FLT3 receptor and response to FLT31igand by leukemic cells.Leukemia.1996；10:588-599； Gilli land,DG and JD Griff in.The roles of FLT3 in hematopoiesis and leukemia.Blood.2002；100:1532-1542；Stirewalt,DL and JP Radich.The role of FLT3 in hematopoietic malignancies.Nat Rev Cancer.2003;3:650_665DFLT3配体（FLT3-L) 结合FLT3受体可启动激活FLT3受体酪氨酸激酶，这也称作干细胞酪氨酸激酶I (STK-1)和胎 儿肝细胞激酶2(flk-2)，其在造血前体和干细胞上表达。 FLT3是造血恶性疾病中最常见的一种突变基因，约30%成人急性髓性白血病(AML)中 存在该突变。请参阅Nakao M，S Yokota and T Iwai .Internal tandem duplication of the FLT3 gene found in acute myeloid leukemia·Leukemia·1996;10:1911-1918;H KiyoijM Towatari and S Yokota.Internal Tandem duplication of the FLT3 gene is a novel modality of elongation mutation,which causes constitutive activation of the product.Leukemia.1998；12:1333-1337；PD KottaridisjRE Gale,et al.The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia(AML)adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy:analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials.Blood.200I； 98:1742-1759；Yamamoto YjKiyoi HjNakano Y.Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies.Blood.2001；97: 2434-2439；Thiede CjC SteudeljMohr B.Analysis of FLT3_activating mutations in 979patients with acute myelogenous leukemia:association with FAB subtypes and identification of subgroups with poor prognosis.Blood.2002；99:4326-4335〇 最常见的FLT3突变是内部串联复制（IT'D)，这会导致FLT3受体近膜区内的框内插入。目 前在15%-35%成人AML患者中已报告存在FLT3-m)突变。请参阅Nakao M，S Yokota and T Iwai.Internal tandem duplication of the FLT3 gene found in acute myeloid leukemia.Leukemia.1996；10:191 1-1918;H Kiyoi，M Towatari and S Yokota·Internal Tandem duplication of the FLT3 gene is a novel modality of elongation mutation,which causes constitutive activation of the product.Leukemia.1998； 12:1333-1337；H KiyoijT Naoe and S Yokota.Internal tandem duplication of FLT3 associated with leukocytosis in acute promyelocytic leukemia.Leukemia Study Group of the Ministry of Health and Welfare(Kohseisho).Leukemia.1997；11:1447-1452；S SchnittgerjC Schoch and M Duga.Analysis of FLT3 length mutations in 1003patients with acute myeloid leukemia:correlation to cytogenetics,FAB subtype,and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease.Blood.2002;100:59-66DFLT3_ITD突变时一种 预测患者预后较差的独立预测因子，并与标准化疗后复发风险增高、无疾病生存期和总生 存期下降相关。请参阅FM Abu_Duhier，Goodeve AC，Wilson GA，et al.FLT3 internal tandem duplication mutations in adult acute myeloid leukemia define a high risk group.British Journal of Haematology.2000；11 I:190-195;H Kiyoi，T Naoe，Y Nakano,et al.Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia.Blood.1999；93:3074-3080〇 发生率较低的是FLT3点突变，其主要存在于FLT3受体的活化环区^最常见受影响的密 码子是天冬氨酸835(D835h在约5-10%成人AML患者中存在D835残基的核苷酸替换现象。 请参阅DL Stirewalt and JP Radich. The role of FLT3 in haematopoietic malignancies.Nature Reviews Cancer·2003;3:650-665;Y Yamamoto，H Kiyoi and Y Nakano,et al.Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies·Blood.2001;97:2434-2439;C Thiede，Steudal C， Mohr B，et al.Analysis of FLT3_activating mutations in 979patients with acute myelogenous leukemia:association with FAB subtypes and identification of subgroups with poor prognosis.Blood.2002；99:4326-4335；U BacherjHaferlach CjW Kern,et al.Prognostic relevance of FLT3-TKD mutations in AML:the combination matters-an analysis of 3082patients.Blood.2008；111:2527-2537〇 成人AML患者中组成性激活型FLT3的高突变频率使FLT3基因成为此类肿瘤治疗中的一 个具有高度吸引力的药物靶点。目前已经或正在研究数种对该靶点具有不同亲和力和选择 性的FLT3抑制剂，并在AML患者中进行试验。请参阅T Kindler,Lipka DB,and Fischer T.FLT3 as a therapeutic target in AML:stiII challenging after all these years. Blood. 2010 ; I 16:5089-102。目前已知的FLT3抑制剂包括来他替尼（也称作CEP 701，之前的KT-555，Kyowa Hakko，已授权给Cephalon); CHIR-258(Chiron Corp ·) ;EB10和 IMC_EB10(ImClone Systems Inc.) ;Midostaurin(也称作 PKC412，Novartis AG);坦度替尼 (也称作 MLN-518,之前 COR Therapeutics Inc.的 CT53518,已授权给 Millennium Pharmaceuticals Inc.);舒尼替尼（也称作SU11248, Pfizer USA);奎扎替尼（也称作 AC220，Ambit Biosciences) ;XL 999(Exelixis USA，已授权给Symphony Evolution, Inc.);GTP 14564(Merck Biosciences UK);AG1295和AG1296;CEP-5214和CEP-7055 (Cephalon)。以下PCT国际申请和美国专利申请公开了其他激酶调节剂，包括FLT3调节剂： WO 2002032861,WO 2002092599,WO 2003035009,WO 2003024931,WO 2003037347,WO 2003057690,WO 2003099771,WO 2004005281,WO 2004016597,WO 2004018419,WO 2004039782,WO 2004043389,WO 2004046120,WO 2004058749,WO 2004058749,WO 2003024969和美国专利申请号20040049032。请参阅Levis M，KF Tse，et al.2001〃A FLT3 tyrosine kinase inhibitor is selectively cytotoxic to acute myeloid leukemia blasts harboring FLT3 internal tandem duplication mutations·"Blood 98(3):885-887；Tse K F，et al.,Inhibition of FLT3_mediated transformation by use of a tyrosine kinase inhibitor.Leukemia.July 2001；15(7):1001-1010；SmithjB-Douglas et al,Single agent CEP-701，a novel FLT3 inhibitor,shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leuk