[发明专利]LSD1抑制剂的制剂

说明书

本申请涉及赖氨酸特异性去甲基酶‑1(LSD1)抑制剂或其药学上可接受的盐、溶剂合物或水合物的药物制剂和剂型，包括其制备方法，所述药物制剂和剂型适合用于治疗LSD1介导的疾病，诸如癌症。

技术领域

本申请涉及赖氨酸特异性去甲基酶-1(LSD1)抑制剂或其药学上可接受的盐、溶剂合物或水合物的药物制剂和固体剂型，包括其制备方法，所述药物制剂和固体剂型适合用于治疗LSD1介导的疾病，诸如癌症。

背景技术

在许多类型的癌症中经常观测到赖氨酸特异性去甲基酶-1(LSD1)的过表达，包括膀胱癌、NSCLC、乳腺癌、卵巢癌、神经胶质瘤、结肠直肠癌、肉瘤(包括软骨肉瘤、尤文氏肉瘤(Ewing's sarcoma)、骨肉瘤以及横纹肌肉瘤)、成神经细胞瘤、前列腺癌、食道鳞状细胞癌瘤以及乳头状甲状腺癌瘤。值得注意地，研究发现LSD1的过表达显著地与临床侵袭性癌症相关，例如复发性前列腺癌、NSCLC、神经胶质瘤、乳腺癌、结肠癌、卵巢癌、食道鳞状细胞癌瘤以及成神经细胞瘤。在这些研究中，LSD1表达的敲低或使用LSD1的小分子抑制剂治疗使得癌细胞增殖减少和/或诱导凋亡。参见例如Hayami,S.等,Overexpression ofLSD1contributes to human carcinogenesis through chromatin regulation invarious cancers.Int J Cancer,2011.128(3):第574-86页；Lv,T.等,Over-expressionof LSD1 promotes proliferation,migration and invasion in non-small cell lungcancer.PLoS One,2012.7(4):第e35065页；Serce,N.等,Elevated expression of LSD1(Lysine-specific demethylase 1)during tumour progression from pre-invasive toinvasive ductal carcinoma of the breast.BMC Clin Pathol,2012.12:第13页；Lim,S.等,Lysine-specific demethylase 1(LSD1)is highly expressed in ER-negativebreast cancers and a biomarker predicting aggressive biology.Carcinogenesis,2010.31(3):第512-20页；Konovalov,S和I.Garcia-Bassets,Analysis of the levels oflysine-specific demethylase 1(LSD1)mRNA in human ovarian tumors and theeffects of chemical LSD1inhibitors in ovarian cancer cell lines.J OvarianRes,2013.6(1):第75页；Sareddy,G.R.等,KDM1is a novel therapeutic target for thetreatment of gliomas.Oncotarget,2013.4(1):第18-28页；Ding,J.等,LSD1-mediatedepigenetic modification contributes to proliferation and metastasis of coloncancer.Br J Cancer,2013.109(4):第994-1003页；Bennani-Baiti,I.M.等,Lysine-specific demethylase 1(LSD1/KDM1A/AOF2/BHC110)is expressed and is anepigenetic drug target in chondrosarcoma,Ewing's sarcoma,osteosarcoma,andrhabdomyosarcoma.Hum Pathol,2012.43(8):第1300-7页；Schulte,J.H.等,Lysine-specific demethylase 1is strongly expressed in poorly differentiatedneuroblastoma:implications for therapy.Cancer Res,2009.69(5):第2065-71页；Crea,F.等,The emerging role of histone lysine demethylases in prostatecancer.Mol Cancer,2012.11:第52页；Suikki,H.E.等,Genetic alterations andchanges in expression of histone demethylases in prostate cancer.Prostate,2010.70(8):第889-98页；Yu,Y.等,High expression of lysine-specific demethylase1 correlates with poor prognosis of patients with esophageal squamous cellcarcinoma.Biochem Biophys Res Commun,2013.437(2):第192-8页；Kong,L.等,Immunohistochemical expression of RBP2 and LSD1 in papillary thyroidcarcinoma.Rom J Morphol Embryol,2013.54(3):第499-503页。