TWI810185B - 一種ezh2抑制劑與btk抑制劑聯合在製備治療腫瘤的藥物中的用途 - Google Patents
一種ezh2抑制劑與btk抑制劑聯合在製備治療腫瘤的藥物中的用途 Download PDFInfo
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- TWI810185B TWI810185B TW107116782A TW107116782A TWI810185B TW I810185 B TWI810185 B TW I810185B TW 107116782 A TW107116782 A TW 107116782A TW 107116782 A TW107116782 A TW 107116782A TW I810185 B TWI810185 B TW I810185B
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Abstract
本發明涉及一種EZH2抑制劑與BTK抑制劑聯合在製備治療腫瘤的藥物中的用途。
Description
本發明涉及一種EZH2抑制劑與BTK抑制劑聯合以及其在製備治療腫瘤的藥物中的用途。
淋巴瘤是一種原發於淋巴結和(或)結外淋巴組織的淋巴細胞惡性腫瘤。根據病理中有無裡-斯細胞(Reed-Sternberg Cell,R-S細胞),分為:霍奇金淋巴瘤(Hodgkin Lymphoma,HL)和非霍奇金淋巴瘤(Non-Hodgkin Lymphoma,NHL)。2015年我國惡性淋巴瘤發病率為8.82/10萬,居各類腫瘤發病的第11位。男性惡性淋巴瘤的發病率高於女性,分別為5.30/10萬和3.52/10萬。2015年我國惡性淋巴瘤死亡率為5.21/10萬,在腫瘤死亡病例構成中排列第10位。
在亞洲,90%患者為NHL,病理上主要是分化程度不同的淋巴細胞、組織細胞或網狀細胞,根據NHL的自然病程,可以歸為三大臨床類型,即高度侵襲性、侵襲性和惰性淋巴瘤;根據不同的淋巴細胞起源,可以分為B細胞、 T細胞和自然殺傷(natural killer,NK)細胞淋巴瘤,其中B細胞的主要功能是分泌各種抗體幫助人體抵禦各種外來的侵入。
EZH2基因編碼的組蛋白甲基轉移酶是多梳蛋白抑制性複合體2(PRC2)的催化組分。與正常組織相比,EZH2水準在癌組織異常升高,而在腫瘤晚期或不良預後中,EZH2的表達水準最高。在一些腫瘤類型中,EZH2表達過剩與EZH2基因的擴增同時發生。大量si/shRNA實驗研究發現在腫瘤細胞株中減少EZH2表達,可抑制腫瘤細胞的增殖,遷移和侵襲或血管生成,並導致細胞凋亡。WO2017084494(PCT/CN2016/104318,申請日2016.11.02)中公開了一種EZH2抑制劑,結構如下所示:
Bruton酪胺酸蛋白激酶(BTK)是酪胺酸蛋白激酶亞家族的成員之一,屬於Tec家族激酶,主要在B細胞中表達,分佈於淋巴系統、造血及血液系統。B細胞受體(BCR)對於包括慢性淋巴細胞性白血病(CLL)和非霍奇金淋巴瘤的(NHL)亞型,套細胞淋巴瘤(MCL),和彌漫性大B細胞淋 巴瘤(DLBCL)在內的多種淋巴瘤的增殖及生存具有至關重要的調控作用,此外,B細胞在類風濕關節炎,系統性紅斑狼瘡,多發性硬化症,以及其他免疫疾病的發病機制中的作用已被臨床證實。Bruton酪胺酸蛋白激酶(BTK)是BCR信號通路中的一個關鍵的蛋白激酶。能夠調節正常B細胞的成熟、分化,也與多種B細胞淋巴組織失調疾病密切相關。因此,靶向小分子抑制劑BTK可對B細胞惡性腫瘤和自身免疫疾病的治療提供效益。WO2016007185A1(公開日2014.01.14)公開了BTK抑制劑,結構如下所示:
位於生發中心的B細胞,稱為生發中心B細胞(GC B cell)。GC B細胞***速度極快,並設法生成高親和力抗體,協助對抗入侵感染,剩餘的GC B細胞則凋亡。由於GC B細胞的高速***,同時在進行VDJ重排,減弱了DNA修復。所以生發中心就是淋巴瘤形成的引擎,不幸的是,這種情況發生時,許多其他基因也產生突變,最終導致了淋巴瘤的形成。例如,生發中心B細胞樣彌漫大B細胞淋巴瘤和濾泡性淋巴瘤。
已被證明在生發中心來源的B細胞淋巴瘤存在BTK的持續啟動和EZH2的突變(Y641,Y646,A682,和A692等) 或過表達。聯合BTK抑制劑和EZH2抑制劑,可以同時抑制由BTK異常(或過度)啟動和EZH2突變(或過表達)引起的腫瘤細胞增殖,產生抗腫瘤的協調作用。
專利申請WO2014168975A1(公開日2014.10.16)、WO2014166820A1(公開日2014.10.16)、WO2015146159A1(公開日2015.10.01)中公開了EZH2抑制劑與BTK抑制劑聯用治療B細胞增殖性疾病,本發明提供一種結構新穎的、具備協同作用的EZH2抑制劑與BTK抑制劑聯合治療腫瘤藥物中的用途。
本發明要解決的技術問題是提供一種EZH2抑制劑與BTK抑制劑聯合後,具備協同作用在製備治療腫瘤的藥物中的用途。
本發明的技術方案如下:本發明提供一種EZH2抑制劑與BTK抑制劑聯合在製備治療腫瘤的藥物中的用途,其特徵在於,該EZH2抑制劑為式(I)所示化合物、其可藥用的鹽或其立體異構體,
其中,環A選自雜環基和環烷基;R1相同或不同,且各自獨立地選自氫原子、鹵素、烷基、鹵烷基、烷氧基、鹵烷氧基、胺基、硝基、羥基、氰基、環烷基、雜環基、芳基、雜芳基、-OR6、-C(O)R6、-C(O)OR6、-S(O)mR6、-S(O)mNR7R8和-(CH2)xRa,其中該烷基、鹵烷基、雜環基、芳基和雜芳基各自獨立地視需要經選自烷基、鹵烷基、鹵素、胺基、硝基、氰基、羥基、烷氧基、鹵烷氧基、羥烷基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代;Ra選自鹵素、環烷基、雜環基和-NR7R8,其中該的環烷基和雜環基各自獨立地視需要經選自烷基、鹵烷基、鹵素、胺基、硝基、氰基、羥基、烷氧基、鹵烷氧基、羥烷基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代;R2為氫原子或烷基,其中該烷基視需要經選自鹵素、羥基、氰基、環烷基和雜環基中的一個或多個取代基所取代;R3選自氫原子、烷基、鹵素、氰基、烷氧基和鹵烷基;R4相同或不同,且各自獨立的選自氫原子、烷基、鹵烷基、羥基、胺基、烷氧基、鹵烷氧基、環烷基、雜環基、芳基、雜芳基、-OR6、-C(O)R6、-C(O)OR6、-S(O)mR6、-S(O)mNR7R8和-NR7R8;R5相同或不同,且各自獨立的選自氫原子、烷基、氧 基、鹵素、鹵烷基、羥基、胺基、烷氧基、鹵烷氧基、環烷基、雜環基、芳基、雜芳基、-OR6、-C(O)R6、-C(O)OR6、-S(O)mR6、-S(O)mNR7R8和-NR7R8;R6選自氫原子、烷基、鹵烷基、烷氧基、羥烷基、羥基、胺基、環烷基、雜環基、芳基和雜芳基;R7和R8相同或不同,且各自獨立地選自氫原子、烷基、烷氧基、羥烷基、羥基、胺基、羧酸酯基、環烷基、雜環基、芳基和雜芳基,其中該烷基、胺基、環烷基、雜環基、芳基和雜芳基各自獨立地視需要經選自烷基、鹵素、羥基、胺基、羧酸酯基、硝基、氰基、烷氧基、羥烷基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代;m為0、1或2;n為0、1、2或3;p為0、1、2、3、4或5;q為0、1或2;且x為0、1、2或3。
較佳地,該EZH2抑制劑為式(IA)所示化合物、其可藥用的鹽或其立體異構體,
其中,G選自CRbRc、C=O、NRd、S(O)m和氧原子;Rb和Rc各自獨立地選自氫原子、烷基、烷氧基、鹵素、胺基、硝基、羥基、氰基、環烷基、雜環基、芳基、雜芳基、-OR6、-C(O)R6、-C(O)OR6、-S(O)mR6和-NR7R8;Rd選自氫原子、烷基、環烷基、鹵烷基、羥烷基、雜環基、芳基、雜芳基、-C(O)R6、-C(O)OR6和-S(O)mR6;且R1至R4、R6至R8、n、m和q如申請專利範圍第1項中所定義。
進一步較佳地,該EZH2抑制劑為式(IB)所示化合物或其可藥用的鹽,
其中, E為CH或N原子;F選自CRbRc、C=O、NRd和氧原子;Rb和Rc各自獨立地選自氫原子、烷基、烷氧基、鹵素、胺基、硝基、羥基、氰基、環烷基、雜環基、芳基、雜芳基、-OR6、-C(O)R6、-C(O)OR6、-S(O)mR6和-NR7R8;Rd選自氫原子、烷基、環烷基、鹵烷基、羥烷基、雜環基、芳基、雜芳基、-C(O)R6、-C(O)OR6和-S(O)mR6;Re相同或不同,且各自獨立地選自氫原子、烷基、鹵烷基、鹵素、胺基、硝基、氰基、羥基、烷氧基、鹵烷氧基、羥烷基、環烷基、雜環基、芳基和雜芳基;t為0、1、2、3、4或5;x為0、1、2或3;y為0、1、2或3;且R2至R4、R6至R8、m和n如申請專利範圍第1項中所定義。
進一步較佳地,該EZH2抑制劑為式(IC)所示化合物或其可藥用的鹽,
其中, Re相同或不同,且各自獨立地選自氫原子、烷基和鹵素;t為0、1、2、3、4或5;R2至R4和n如申請專利範圍第1項中所定義。
進一步較佳地,該EZH2抑制劑為式(ID)所示化合物或其可藥用的鹽,
其中,Re選自氫原子、烷基、鹵烷基、鹵素、胺基、硝基、氰基、羥基、烷氧基、鹵烷氧基、羥烷基、環烷基、雜環基、芳基和雜芳基;R2至R4和n如申請專利範圍第1項中所定義。
上述方案中,該BTK抑制劑為式(II)所示化合物、其可藥用的鹽或其立體異構體,
其中,A選自CR1或N;R1選自氫原子、鹵素、視需要經取代的烷基,該取代基選自鹵素、羥基、氰基、硝基、羧基、胺基、烷基、烷氧基或鹵烷基;Ra、Rb、Rc、Rd分別獨立地選自氫原子、鹵素、羥基、氰基、硝基、視需要經取代的烷基、視需要經取代的烷氧基,該取代基選自鹵素、羥基、氰基、硝基、羧基、胺基、烷基、烷氧基或鹵烷基;B選自氫原子,視需要經取代的環烷基、雜環基、芳基或雜芳基,該取代基選自鹵素、羥基、氰基、硝基、羧基、胺基、烷基、烷氧基或鹵烷基;L選自鍵、視需要經取代的烷基;且Y選自視需要經取代的環烷基、雜環基、芳基或雜芳基,該取基選自鹵素、羥基、氰基、硝基、羧基、胺基、烷基、烷基羰基、炔基羰基或鹵烷基。
在本發明一個方案中,該可藥用的鹽選自磷酸鹽、鹽酸鹽、甲磺酸鹽、馬來酸鹽、蘋果酸鹽、對甲苯磺酸鹽或苯磺酸鹽。
在本發明另一個方案中,該BTK抑制劑選自依魯替尼、Acalabrutinib、MSC-2364447、Spebrutinib、HM-71224、Plevitrexed、GS-4059、GDC-0853、SNS-062、CGP-53716、Idoxifene、BTG-511、Banoxantrone、Glucarpidase、Anti-digoxin polyclonal antibody、Crotalidae polyvalent immune Fab(ovine,BTG)或Otelixizumab。
上述方案中,該聯合視需要包含第三組分,該第三組分選自HDAC抑制劑、CDK4/6抑制劑、ALK抑制劑、JAK2抑制劑、Bcl-2抑制劑、Hsp90抑制劑、糖皮質激素、長春花生物鹼、抗代謝物、DNA損傷劑、來那度胺、利妥昔單抗、PKC干擾原、Lyn/Fyn抑制劑、Syk抑制劑、PI3K抑制劑、PKCβ抑制劑、IKK抑制劑、20s蛋白酶體、IRF-4、IRAK4抗體、CXCR4抗體、CXCR5抗體、GLS抗體、PLK 抗體、CD20抗體、Topo Ⅱ抑制劑、DNA甲基轉移酶抑制劑、Ras/MAPK抑制劑或FGFR1抑制劑;該HDAC抑制劑,較佳為帕比司他乳酸、貝利司他、西達本胺、羅米地辛、伏立諾他、倍賽諾他或恩替諾特;該CDK4/6抑制劑較佳為Palbociclib、Blinatumomab、Tiagabine Hydrochloride或Itolizumab;該Bcl-2抑制劑較佳為Venetoclax、安普利森鈉、ABT-737或HA14-1,該Hsp90抑制劑,較佳Sebelipase alfa或Retaspimycin Hydrochloride;該JAK2抑制劑較佳為枸櫞酸托法替尼、Ruxolitinib Phosphate、Lestaurtinib、Momelotinib Dihydrochloride、Peficitinib或Filgotinib;該PKC干擾原較佳為替普瑞酮、Truheal、HO/03/03、Sotrastaurin、恩紮妥林或GF109203X;該ALK抑制劑較佳為Alectinib Hydrochloride、色瑞替尼、克唑替尼、苯達莫司汀、卡莫司汀、洛莫司汀、鹽酸氮芥或NVP-TAE684;該PI3K抑制劑較佳為GS-1101、IPI-145、BKM120、BEZ235、GDC-0941、AMG319、CAL-101或A66;且該IKK抑制劑較佳為金諾芬、BAY 86-9766或RDEA-119。
上述方案中,該聯合具有協同藥效作用。
在本發明中,提供了一種治療腫瘤的辦法,包括向患者施用上述EZH2抑制劑與BTK抑制劑。
本發明所述的用途,該腫瘤選自淋巴瘤,較佳非霍奇金淋巴瘤,更佳為B細胞增殖性疾病,該B細胞增殖性疾病選自彌漫性大B細胞淋巴瘤(DLBCL)、慢性淋巴細胞白血病(CLL)、小淋巴細胞淋巴瘤(SLL)、高危CLL或非 CLL/SLL淋巴瘤、濾泡性淋巴瘤(FL)、套細胞淋巴瘤(MCL)、前體B細胞腫瘤、前體B淋巴母細胞白血病(或淋巴瘤)、成熟(外周)B細胞腫瘤、淋巴漿細胞淋巴瘤(或免疫母細胞瘤)、結外黏膜相關淋巴瘤、毛細胞白血病、漿細胞瘤(或漿細胞骨髓瘤)、瓦爾登斯特倫巨球蛋白血症、多發性骨髓瘤、邊緣區淋巴瘤、伯基特淋巴瘤(BL)、非伯基特高度B細胞淋巴瘤或結外邊緣區B細胞淋巴瘤、急性或慢性髓性(或髓樣)白血病、骨髓增生異常綜合症或急性淋巴母細胞白血病。
本發明提供上述EZH2抑制劑聯合上述BTK抑制劑作為治療腫瘤的藥物。
本發明所述的用途,其中,該EZH2抑制劑與BTK抑制劑的比例為0.001至1000,較佳為0.01至100,進一步較佳為0.1至10,且更佳為1:1、1:2、1:3、1:4、1:5、1:6、1:7、1:8、1:9、1:10、1:11、1:12、1:13、1:14、1:15、1:16、1:17、1:18、1:19、1:20、1:21、1:22、1:23、1:24、1:25、1:26、2:1、2:3、2:5、2:7、2:9、2:11、2:13、2:15、2:17、2:19、2:21、3:1、3:2、3:4、3:5、3:7、3:8、3:10、3:11、3:13、3:14、3:16、3:17、3:19、3:20、4:1、4:3、4:5、4:7、4:9、4:11、4:13、4:15、4:17、4:19、4:21、5:1、5:2、5:3、5:4、5:6、5:7、5:8、5:9、5:11、5:12、5:13、5:14、5:16、5:17、5:18、5:19、5:21、6:1、6:5、6:7、6:11、6:13、6:17、6:19、7:1、7:2、7:3、7:5、7:6、7:8、7:9、7:10、7:11、7:12、7:13、7:15、7:16、7:17、7:18、7:19、7:20、8:1、 8:3、8:5、8:7、8:9、8:11、8:13、8:15、8:17、8:19、9:1、9:2、9:4、9:5、9:7、9:8、9:10、9:11、9:13、9:14、9:16、9:17、9:19、9:20、10:1、10:3、10:7、10:9、10:11、10:13、10:17或10:19。
本發明所述的用途,其中,該EZH2抑制劑為0.1-5000mg,較佳1-2000mg。
本發明所述的用途,其中,該BTK抑制劑為0.1-2000mg,較佳1-1000mg。
本發明還提供EZH2抑制劑的給藥劑量為0.1-5000mg,較佳10mg、50mg、100mg、150mg、200mg、250mg、300mg、350mg、400mg、400mg、500mg、550mg、600mg、650mg、700mg、750mg、800mg、8500mg、900mg、950mg、1000mg、1200mg、1250mg、1300mg、1400mg、1500mg、1600mg、1700mg、1800mg、1900mg、2000mg、2100mg、2200mg、2300mg、2400mg、2500mg、2600mg、2700mg、2800mg、2900mg、3000mg、3500mg、4000mg、4500mg或5000mg,BTK抑制劑的給藥劑量為0.1-2000mg,且較佳10mg、20mg、30mg、50mg、80mg、90mg、100mg、150mg、160mg、200mg、250mg、300mg、350mg、500mg或650mg、700mg、750mg、800mg、850mg、900mg、950mg、1000mg、1200mg、1300mg、1400mg、1500mg、1600mg、1800mg、1900mg或2000mg。
本發明所述聯合的給藥方式選自:同時給藥、獨立地配製並共給藥或獨立地配製並相繼給藥。
本發明進一步涉及一種EZH2抑制劑與BTK抑制劑聯 合在製備治療腫瘤的藥物中的用途,其中,EZH2抑制劑推薦一天一次或一天兩次,BTK抑制劑推薦一天一次。
顯著地,本發明的EZH2抑制劑與BTK抑制劑聯合應用具有協同藥效作用。
本發明的還涉及一種EZH2抑制劑與BTK抑制劑的醫藥組成物,包含視需要的一種或多種藥用載體、賦形劑和/或稀釋劑。該醫藥組成物可以製成藥學上可接受的任一劑型。例如,EZH2抑制劑與BTK抑制劑的藥物製劑可以配製為片劑、膠囊劑、丸劑、顆粒劑、溶液劑、混懸劑、糖漿劑、注射劑(包括注射液、注射用無菌粉末與注射用濃溶液)、栓劑、吸入劑或噴霧劑。
此外,本發明的所述醫藥組成物還可以以任何合適的給藥方式,例如口服、腸胃外、直腸、經肺或局部給藥等方式施用於需要這種治療的患者或受試者。當用於口服給藥時,該醫藥組成物可製成口服製劑,例如口服固體製劑,如片劑、膠囊劑、丸劑、顆粒劑等;或,口服液體製劑,如口服溶液劑、口服混懸劑、糖漿劑等。當製成口服製劑時,該藥物製劑還可包含適宜的填充劑、黏合劑、崩解劑、潤滑劑等。
本發明的EZH2抑制劑與BTK抑制劑醫藥組成物可以單獨給藥,或者與一種或多種治療劑聯合使用。因此,在某些較佳地實施方案中,該醫藥組成物還含有一種或多種治療劑。
待組合的各成分(例如,EZH2抑制劑與BTK抑制劑抑 制劑及第二治療劑)可同時給藥或依次順序地分開用藥。例如,可以在將本發明EZH2抑制劑與BTK抑制劑聯用之前、同時或之後,施用第二治療劑。此外,待組合的各成分還可以以同一製劑形式或以分開的不同製劑的形式聯合給藥。
本發明中,所謂“聯合或聯用”是一種給藥方式,其包括兩種藥物先後,或同時給藥的各種情況,此處所謂“同時”是指在同一給藥週期給予EZH2抑制劑與BTK抑制劑,例如在2天內,或1天內給予兩種藥物。所謂“先後或相繼”給藥,則包括在不同給藥週期內分別給予EZH2抑制劑與BTK抑制劑的情況。這些給藥方式,均屬於本發明所述的聯合給藥。
本發明所述的“有效量”包含足以改善或預防醫字病症的症狀或病症的量。有效量還意指足以允許或促進診斷的量。用於特定患者或獸醫學受試者的有效量可依據以下因素而變化:如待治療的病症、患者的總體健康情況、給藥的方法途徑和劑量以及副作用嚴重性。有效量可以是避免顯著副作用或毒性作用的最大劑量或給藥方案。
在本申請的說明書和申請專利範圍中,除非另有說明,否則本文中使用的科學和技術名詞具有本領域技術人員所通常理解的含義。然而,為了更好地理解本發明,下面提供了部分相關術語的定義和解釋。另外,當本申請所提供的術語的定義和解釋與本領域技術人員所通常理解的含義 不一致時,以本申請所提供的術語的定義和解釋為准。
本發明所述“鹵素或鹵素原子”是指氟原子、氯原子、溴原子、碘原子等。
本發明所述“氰基”是指-CN等基團。
本發明所述“羥基”是指-OH等基團。
本發明所述“胺基”是指-NH等基團。
本發明所述“羧基”是指-COOH等基團。
本發明所述“羰基”是指-CO-等基團。
本發明所述“硝基”是指-NO2等基團。
本發明所述“烷基”是指直鏈或支鏈的含有1-20個碳原子的烷基,包括例如“C1-6烷基”、“C1-4烷基”等,具體實例包括,但不限於:甲基、乙基、正丙基、異丙基、正丁基、異丁基、第二丁基、第三丁基、正戊基、異戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、異己基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、1,2-二甲基丙基等。
本發明所述“炔基”是指含有至少一個三鍵且碳原子數為2-20的直鏈或支鏈的炔基,包括例如“C2-6炔基、C2-4炔基”等。其實例包括,但不限於:乙炔基、丙炔基、2-丁炔基、2-戊炔基、3-戊炔基、4-甲基-2-戊炔基、2-己炔基、3-己炔基、5-甲基-2-己炔基等。
本發明所述的“環烷基”指飽和或部分不飽和單環或多環環狀烴取代基,其包括3至14個碳原子,較佳為包括3 至12個碳原子,更佳為環烷基環包含3至8個碳原子,最佳為環烷基環包含5至6個碳原子,最佳為環丙基。單環環烷基的非限制性實施例包含環丙基、環丁基、環戊基、環戊烯基、環己基、環己烯基、環己二烯基、環庚基、環庚三烯基、環辛基等,較佳環丙基、環己烯基。多環環烷基包括螺環、稠環和橋環的環烷基。
本發明所述的“稠環基”是指由兩個或兩個以上環狀結構彼此共用兩個相鄰的原子所形成的、含有4-15個碳原子的環狀結構,包括例如“6-11元稠環基”、“5-9元稠環基”、“7-10元稠環基”、“9-10元稠環基”等,視需要地,環狀結 構中的碳原子可以被氧化。其實例包括,但不限於:、
等。
本發明所述的“螺環基”是指由兩個或兩個以上環狀結構彼此共用一個碳原子所形成的、含有5-15個環碳原子的環狀結構。視需要地,環狀結構中的碳原子可以被氧化。包括例“6-11元螺環基”、“5-10元螺環基”、“7-8元螺環基”、 “9-10元螺環基”等。具體實例包括,但不僅限於:、
、、、、等。
本發明所述的“橋環基”是指由兩個或兩個以上環狀結構彼此共用兩個非相鄰碳原子所形成的、含有5-15個環碳原子的環狀結構。視需要地,環狀結構中的碳原子可以被氧。包括例如“6-11元橋環基”、“7-10元橋環基”、“9-10 元橋環基”等。具體實例包括,但不僅限於:、、
、、、等。
本發明所述的“雜環基”指飽和或部分不飽和單環或多環環狀烴取代基,其包括3至14個環原子,其中一個或多個環原子選自氮、氧或S(O)m(其中m是整數0至2)的雜原子,但不包括-O-O-、-O-S-或-S-S-的環部分,其餘環原子為碳。較佳包括3至12個環原子,其中1-4個是雜原子,更佳為雜環基環包含3至8個環原子,更佳為雜環基環包 含5至6個環原子。單環雜環基的非限制性實施例包含吡咯烷基、哌啶基、哌嗪基、嗎啉基、硫嗎啉基、高哌嗪基、吡喃基、四氫呋喃基等。多環雜環基包括螺環、稠環和橋環的雜環基。
本發明所述的“稠雜環基”是指由兩個或兩個以上環狀結構彼此共用兩個相鄰的原子所形成的、含有4-15個環原子(其中至少一個環原子為雜原子,例如氮原子、氧原子或硫原子)的環狀結構。視需要地,環狀結構中的環原子(例如碳原子、氮原子或硫原子)可以被氧化。包括例如“4-12元稠雜環基”、“5-9元稠雜環基”、“6-11元稠雜環基”、“7-9元稠雜環基”、“9-10元稠雜環基”等。具體實例包括,但不僅限於:吡咯烷基並環丙基、環戊基並氮雜環丙基、吡咯烷基並環丁基、吡咯烷基並吡咯烷基、吡咯烷基並哌啶基、吡咯烷基並哌嗪基、吡咯烷基並嗎啉基、哌啶基並嗎啉基、苯並吡咯烷基、四氫咪唑並[4,5-c]吡啶基、3,4-二氫喹唑啉基、1,2-二氫喹喔啉基、苯並[d][1,3]二氧雜環戊烯基、1,3-二氫異苯並呋喃基、2H-色原烯基、2H-色原烯-2-酮基、4H-色烯基、4H-色烯-4-酮基、色滿基、4H-1,3-苯並噁嗪基、4,6-二氫-1H-呋喃並[3,4-d]咪唑基、3a,4,6,6a-四氫-1H-呋喃並[3,4-d]咪唑基、4,6-二氫-1H-噻吩並[3,4-d]咪唑基、4,6-二氫-1H-吡咯並[3,4-d]咪唑基、苯並咪唑烷基、八氫-苯並[d]咪唑基、十氫喹啉基、六氫噻吩並咪唑基、六氫呋喃並咪唑基、4,5,6,7-四氫-1H-苯並[d]咪唑基、八氫環戊烯並[c]吡咯基、二氫吲哚基、二氫異吲哚基、苯並噁唑烷基、 苯並噻唑烷基、1,2,3,4-四氫異喹啉基、1,2,3,4-四氫喹啉基、4H-1,3-苯並噁嗪基等。
本發明所述的“螺雜環基”是指由兩個或兩個以上環狀結構彼此共用一個環原子所形成的、含有5-15個環原子(其中至少一個環原子為雜原子,例如氮原子、氧原子或硫原子)的環狀結構,視需要地,環狀結構中的環原子(例如碳原子、氮原子或硫原子)可以被氧化。包括例如“5-11元螺雜環基”、“6-11元螺雜環基”、“6-9元螺雜環基”、“9-10 元螺雜環基”等。具體實例包括,但不僅限於:、
、、等。
本發明所述的“橋雜環基”是指由兩個或兩個以上環狀結構彼此共用兩個非相鄰的環原子所形成的、含有5-15個環原子(其中至少一個環原子為雜原子,例如氮原子、氧原子或硫原子)的環狀結構,視需要地,環狀結構中的環原子(例如碳原子、氮原子或硫原子)可以被氧化。包括例如“5-10元橋雜環基”、“6-11元橋雜環基”、“6-9元橋雜環基”、 “7-9元橋雜環基”等。具體實例包括,但不僅限於:、
、、等。
本發明所述的“鹵烷基”指一個或多個“鹵素原子”取代“烷基”上的一個或多個氫原子所衍生的基團,該“鹵素原子”和“烷基”如前文所定義。
本發明所述的“羥基烷基”指一個或多個“羥基”取代“烷基”上的一個或多個氫原子所衍生的基團,該“烷基”如前文所定義。
本發明所述的“烷氧基、鹵烷氧基、烷基羰基、烷氧羰基、烷基羰基胺基、烷基胺基羰基、二烷基胺基羰基、烷基胺基羧基、鹵烷基羰基、環烷基烷基、環烷基羰基、雜環基羰基、烷基胺基、烷基胺基烷基或二烷基胺基”是指以烷基-O-、鹵烷基-O-、烷基-C(O)-、烷基-O-C(O)-、烷基-C(O)-NH-、烷基-NH-C(O)-、(烷基)2-NH-C(O)-、烷基 -C(O)-O-、鹵烷基-C(O)-、環烷基-烷基-、環烷基-C(O)-、雜環基-C(O)-、烷基-NH-、烷基-NH-烷基-、(烷基)2-N-方式連接的基團,其中“烷基、鹵烷基、環烷基、雜環基”如前文所定義。
本發明所述的“芳基”指具有共軛的π電子體系的6至14元全碳單環或稠合多環(也就是共用毗鄰碳原子對的環)基團,較佳為6至8元的芳基,更佳為苯基、蒽基、菲基,最佳為苯基。該芳基環可以稠合於雜芳基、雜環基或環烷基環上,其中與母體結構連接在一起的環為芳基環,非限制性實施例包含:
本發明所述的“雜芳基”指具有共軛的π電子體系的5至15元全碳單環或稠合多環基團,進一步包含1至4個雜原子的,其中雜原子選自一個或多個氧、硫或氮。較佳為5至8元的雜芳基,更佳為5元至6元的雜芳基,具體實例包括但不僅限於呋喃基、噻吩基、吡咯基、噻唑基、異噻唑基、噻二唑基、噁唑基、異噁唑基、噁二唑基、咪唑基、吡唑基、1,2,3-***基、1,2,4-***基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、吡啶基、 2-吡啶酮基、4-吡啶酮基、嘧啶基、噠嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基、1,2,4,5-四嗪基、氮雜環庚三烯基、1,3-二氮雜環庚三烯基、氮雜環辛四烯基等。該雜芳基環可以稠合於芳基、雜環基或環烷基環上,其中與母體結構連接在一起的環為雜芳基環,非限制性實施例包含:
本發明所述的“碳原子、氮原子或硫原子被氧代”是指形成C=O、N=O、S=O或SO2的結構。
“取代的”指基團中的一個或多個氫原子,較佳為最多5個,更佳為1至3個氫原子彼此獨立地被相應數目的取代基取代。不言而喻,取代基僅處在它們的可能的化學位置,本領域技術人員能夠在不付出過多努力的情況下確定(藉由實驗或理論)可能或不可能的取代。例如,具有游離氫的胺基或羥基與具有不飽和(如烯屬)鍵的碳原子結合時可能是不穩定的。
與現有技術相比,本發明的技術方案具有以下優點:本發明EZH2抑制劑與BTK抑制劑聯合用藥對SU-DHL-4和SU-DHL-6細胞增殖的抑制作用顯著、並且具備協同作用;對B細胞淋巴瘤DOHH-2細胞增殖的抑制作用顯著、並且具備顯著的協同作用。
第1圖為本發明的EZH2抑制劑與BTK抑制劑聯合用藥(化合物A:化合物B=1:2,莫耳濃度比)與單一組分(化合物B、化合物A)對SU-DHL-4細胞增殖的抑制作用;第2圖為本發明的EZH2抑制劑與BTK抑制劑聯合用藥(化合物A:化合物B=1:4,莫耳濃度比)與單一組分(化合物B、化合物A)對SU-DHL-6細胞增殖的抑制作用;第3圖為本發明的EZH2抑制劑與BTK抑制劑聯合用藥(化合物B與化合物A聯合)與單一組分(化合物B、化合物A)對淋巴瘤DOHH-2裸小鼠皮下移植瘤的療效;第4圖為本發明的EZH2抑制劑與BTK抑制劑聯合用藥(化合物B與化合物A聯合)與單一組分(化合物B、化合物A)對淋巴瘤DOHH-2裸小鼠皮下移植瘤體重的影響;第5圖為本發明的EZH2抑制劑與BTK抑制劑聯合用藥(化合物B與化合物A聯合)與單一組分(化合物B、化合物A)對B細胞淋巴瘤SU-DHL-4小鼠皮下移植瘤的療效。
以下提供本發明的組成物在糖尿病醫藥用途中的示例性試驗方案,以顯示本發明組成物的有利活性或有益技術效果。但是應當理解,下述試驗方案僅僅是對本發明內容的示例,而不是對本發明範圍的限制。本領域技術人員在本說明書的教導下,能夠對本發明的技術方案進行適當的修改或改變,而不背離本發明的精神和範圍。
將2-乙基苯甲酸1a(20.0g,133mmol,採用“Journal of the American Chemical Society,1991,113(13),4931-6”公開的方法製備而得)加入150mL硫酸中,冰浴下,分批加入硝酸鈉(11.3g,133mmol),攪拌反應3小時,分批加入N-溴丁二醯亞胺(2.6g,14.5mmol),反應體系於60℃攪拌反應1小時。反應結束後,將反應液倒入冰水中,攪拌均勻,過濾,濾液用水洗滌,減壓濃縮,得到粗品標題產物3-溴-2-乙基-5-硝基苯甲酸1b(35g,白色固體),產品不經純化直接進行下一步反應。
將粗品3-溴-2-乙基-5-硝基苯甲酸1b(35g,128mmol)溶於200mL N,N-二甲基甲醯胺中,加入碘甲烷(21.8g,153mmol),碳酸鉀(35.3g,255mmol),反應體系於室溫下攪拌反應2小時。反應結束後,將反應液減壓濃縮,加入過量水,用乙酸乙酯萃取,合併有機相,用水洗滌,飽和氯化鈉溶液洗滌,無水硫酸鈉乾燥,過濾,濾液減壓濃縮,得粗品標題產物3-溴-2-乙基-5-硝基苯甲酸甲酯1c(36g,黃色油狀物),產物不經純化直接進行下一步反應。
將粗品3-溴-2-乙基-5-硝基苯甲酸甲酯1c(35.0g,121 mmol)加入250mL乙醇和150mL水中,加熱至70℃,加入氯化銨(52.8g,969mmol),分批加入鐵粉(34g,606mmol),反應體系於70℃攪拌反應2小時。反應結束後,加矽藻土趁熱過濾,用熱乙醇洗滌濾餅,合併濾液,將濾液減壓濃縮,加入乙酸乙酯和飽和碳酸氫鈉溶液分層,水相用乙酸乙酯萃取,合併有機相,用飽和氯化鈉溶液洗滌,無水硫酸鈉乾燥,過濾,濾液減壓濃縮,用矽膠管柱色譜法以正己烷和乙酸乙酯為洗脫劑純化所得殘留物,得到標題產物5-胺基-3-溴-2-乙基苯甲酸甲酯1d(22.0g,黃色固體),產率70%。
將5-胺基-3-溴-2-乙基苯甲酸甲酯1d(15.0g,58mmol)溶於10mL乙腈中,加入200mL 10%的硫酸,攪拌均勻,冰鹽浴冷卻至3℃,滴加10mL預製的亞硝酸鈉(4.4g,64mmol)溶液,保溫攪拌4小時,加入200mL 50%的硫酸,於90℃反應1小時。反應結束後,反應液用乙酸乙酯萃取三次,合併有機相,用飽和氯化鈉溶液洗滌,無水硫酸鈉乾燥,過濾,濾液減壓濃縮,用矽膠管柱色譜法以正己烷和乙酸乙酯為洗脫劑純化所得殘留物,得到標題產物3-溴-2-乙基-5-羥基苯甲酸甲酯1e(5.5g,棕色固體),產率37%。
將3-溴-2-乙基-5-羥基苯甲酸甲酯1e(35g,135mmol) 溶於200mL N,N-二甲基甲醯胺中,加入2-溴-1,1-二乙氧基乙烷(40g,202mmol),碳酸鉀(37g,269mmol),反應體系於120℃下攪拌反應12小時。反應結束後,將反應液減壓濃縮除去N,N-二甲基甲醯胺,加入水,用乙酸乙酯萃取三次,合併有機相,用飽和氯化鈉溶液洗滌,無水硫酸鈉乾燥,過濾,濾液減壓濃縮,用矽膠管柱色譜法以正己烷和乙酸乙酯為洗脫劑純化所得殘留物,得標題產物3-溴-5-(2,2-二乙氧基乙氧基)-2-乙基苯甲酸甲酯1f(40g,淡黃色油狀物),產率80%。
將30g多聚磷酸加入400mL甲苯中,加熱至100℃,攪拌下加入50mL預製的3-溴-5-(2,2-二乙氧基乙氧基)-2-乙基苯甲酸甲酯1f(40g,107mmol)的甲苯溶液,於100℃反應16小時。反應結束後,倒出上層清液,殘留物中加入水和乙酸乙酯分層,水相用乙酸乙酯萃取,合併有機相,用飽和碳酸鈉溶液洗滌,飽和氯化鈉溶液洗滌,無水硫酸鈉乾燥,過濾,濾液減壓濃縮,用矽膠管柱色譜法以正己烷和乙酸乙酯為洗脫劑純化所得殘留物,得到標題產物6-溴-5-乙基苯並呋喃-4-羧酸甲酯1g(11.8g,黃色固體),產率39%。
將6-溴-5-乙基苯並呋喃-4-羧酸甲酯1g(11.0g,39 mmol),四氫-2H-吡喃-4-胺(5.89g,58mmol),三(二亞苄基丙酮)二鈀(3.6g,3.9mmol),(.9mmol)雙-(二苯膦基)-1,1'-聯萘(4.86g,7.8mmol),碳酸銫(38g,117mmol)溶於100mL甲苯中,於100℃攪拌反應12小時。反應結束後,墊矽藻土過濾,濾餅用乙酸乙酯洗滌,合併有機相,用無水硫酸鈉乾燥,過濾,濾液減壓濃縮,用矽膠管柱色譜法以正己烷和乙酸乙酯為洗脫劑純化所得殘留物,得到標題產物5-乙基-6-((四氫-2H-吡喃-4-基)胺基)苯並呋喃-4-羧酸甲酯1h(10.0g,黃色固體),產率85%。
將5-乙基-6-((四氫-2H-吡喃-4-基)胺基)苯並呋喃-4-羧酸甲酯1h(10.0g,0.033mmol)溶於150mL 1,2-二氯乙烷中,加入乙醛(7.2g,0.165mmol),乙酸(9.9g,0.165mmol),攪拌反應1小時,加入三乙醯氧基硼氫化鈉(20.8g,0.1mmol),室溫下攪拌反應12小時。反應結束後,將反應液減壓濃縮,用飽和碳酸氫鈉溶液中和,乙酸乙酯萃取,合併有機相,用飽和氯化鈉溶液洗滌,無水硫酸鈉乾燥,過濾,濾液減壓濃縮,用矽膠管柱色譜法以正己烷和乙酸乙酯為洗脫劑純化所得殘留物,得到標題產物5-乙基-6-(乙基(四氫-2H-吡喃-4-基)胺基)苯並呋喃-4-羧酸甲酯1i(7.8g,白色固體),產率71%。
MS m/z(LC-MS):332.4[M+1]
將5-乙基-6-(乙基(四氫-2H-吡喃-4-基)胺基)苯並呋喃-4-羧酸甲酯1i(1.6g,4.8mmol)溶於25mL四氫呋喃中,氬氣氛下,降溫至-70℃,滴加2.0M的二異丙基胺基鋰(3.6mL,7.3mmol),攪拌90分鐘,加入N,N-二甲基甲醯胺(536mg,7.3mmol),攪拌2小時,緩慢升至室溫後,加入過量的氯化銨,攪拌均勻,用乙酸乙酯萃取三次,合併有機相,用飽和氯化鈉溶液洗滌,無水硫酸鈉乾燥,過濾,濾液減壓濃縮,用矽膠管柱色譜法以正己烷和乙酸乙酯為洗脫劑純化所得殘留物,得到標題產物5-乙基-6-(乙基(四氫-2H-吡喃-4-基)胺基)-2-甲醯基苯並呋喃-4-羧酸甲酯1j(1.3g,黃色油狀物),產率75%。
MS m/z(ESI):360.2[M+1]
將5-乙基-6-(乙基(四氫-2H-吡喃-4-基)胺基)-2-甲醯基苯並呋喃-4-羧酸甲酯1j(1.4g,3.9mmol)溶於5mL四氫呋喃和10mL甲醇中,加入硼氫化鈉(222mg,5.8mmol),室溫下攪拌30分鐘。反應結束後,將反應液減壓濃縮,加入水,飽和碳酸氫鈉溶液,用乙酸乙酯萃取三次,合併有機相,用飽和氯化鈉溶液洗滌,無水硫酸鈉乾燥,過濾, 濾液減壓濃縮,用矽膠管柱色譜法以正己烷和乙酸乙酯為洗脫劑純化所得殘留物,得標題產物5-乙基-6-(乙基(四氫-2H-吡喃-4-基)胺基)-2-(羥基甲基)苯並呋喃-4-羧酸甲酯1k(1.4g,黃色油狀物),產率99%。
將5-乙基-6-(乙基(四氫-2H-吡喃-4-基)胺基)-2-(羥基甲基)苯並呋喃-4-羧酸甲酯1k(1.0g,2.8mmol)溶於30mL四氫呋喃中,滴加三溴化磷(1.12g,4.2mmol),室溫下攪拌反應12小時。反應結束後,用飽和碳酸氫鈉溶液中和,乙酸乙酯萃取三次,合併有機相,飽和氯化鈉溶液洗滌,無水硫酸鈉乾燥,過濾,濾液減壓濃縮,得到粗品標題產物2-(溴甲基)-5-乙基-6-(乙基(四氫-2H-吡喃-4-基)胺基)苯並呋喃-4-羧酸甲酯11(1.15g,黃色油狀物),產品不經純化直接進行下一步反應。
將粗品2-(溴甲基)-5-乙基-6-(乙基(四氫-2H-吡喃-4-基)胺基)苯並呋喃-4-羧酸甲酯11(1.15g,2.7mmol)溶於15mL乙腈中,滴入預製的10mL的哌啶(362mg,4.3mmol)的乙腈溶液中,室溫下攪拌30分鐘。反應結束後,將反應液減壓濃縮,加入乙酸乙酯和飽和碳酸氫鈉溶液分層,水 相用乙酸乙酯萃取,合併有機相,飽和氯化鈉溶液洗滌,無水硫酸鈉乾燥,過濾,濾液減壓濃縮,用矽膠管柱色譜法以二氯甲烷和甲醇為洗脫劑純化所得殘留物,得到標題產物5-乙基-6-(乙基(四氫-2H-吡喃-4-基)胺基)-2-(哌啶-1-基甲基)苯並呋喃-4-羧酸甲酯1m(1.2g,黃色油狀物),產率99%。
MS m/z(LC-MS):429.2[M+1]
將5-乙基-6-(乙基(四氫-2H-吡喃-4-基)胺基)-2-(哌啶-1-基甲基)苯並呋喃-4-羧酸甲酯1m(1.2g,2.7mmol)溶於5mL四氫呋喃和20mL甲醇中,加入5mL 4M的氫氧化鈉溶液,於60℃攪拌反應12小時。反應結束後,用濃鹽酸調節反應液pH至4,減壓濃縮,用二氯甲烷和甲醇的混合溶劑(V:V=5:1)溶解殘留物,過濾,濾餅用二氯甲烷和甲醇的混合溶劑(V:V=5:1)洗滌,合併濾洗液,濾液減壓濃縮,得到粗品標題產物5-乙基-6-(乙基(四氫-2H-吡喃-4-基)胺基)-2-(哌啶-1-基甲基)苯並呋喃-4-羧酸1n(1.1g,黃色固體),產品不經純化直接進行下一步反應。
MS m/z(LC-MS):415.2[M+1]
將5-乙基-6-(乙基(四氫-2H-吡喃-4-基)胺基)-2-(哌啶 -1-基甲基)苯並呋喃-4-羧酸1n(1.0g,2.4mmol)溶於30mL N,N-二甲基甲醯胺中,加入1-乙基-3(3-二甲基丙胺)碳二亞胺(696mg,3.6mmol),1-羥基苯並***(490mg,3.6mmol),N,N-二異丙基乙基胺(1.56g,12.1mmol),攪拌反應1小時,加入3-(胺基甲基)-4,6-二甲基吡啶-2(1H)-酮鹽酸鹽2a(593mg,3.0mmol,採用專利申請“WO2014097041”公開的方法製備而得),室溫下攪拌反應12小時。反應結束後,加入過量水,用二氯甲烷和甲醇的混合溶劑(V:V=8:1)萃取,合併有機相,用水洗滌,飽和氯化鈉溶液洗滌,無水硫酸鈉乾燥,過濾,濾液減壓濃縮,用矽膠管柱色譜法以二氯甲烷和甲醇為洗脫劑純化所得殘留物,得到標題產物N-((4,6-二甲基-2-羰基-1,2-二氫吡啶-3-基)甲基)-5-乙基-6-(乙基(四氫-2H-吡喃-4-基)胺基)-2-(哌啶-1-基甲基)苯並呋喃-4-甲醯胺2(750mg,白色固體),產率:57%。
MS m/z(ESI):549.7[M+1]
1H-NMR(400MHz,DMSO-d 6):δ 11.48(s,1H),8.15(t,1H),7.39(s,1H),6.46(s,1H),5.86(s,1H),4.32(d,2H),3.83(d,2H),3.54(s,2H),3.21(t,2H),3.01-3.07(m,2H),2.92-2.97(m,1H),2.77-2.82(m,2H),2.39(brs,4H),2.23(s,3H),2.11(s,3H),1.64-1.67(brd,2H),1.47-1.55(m,6H),1.36-1.37(brd,2H),1.02(t,3H),0.82(t,3H).
供試品:式(IE)所示化合物(定義為化合物B,可按照 WO2017084494(專利申請PCT/CN2016/104318)中的方法製備,見對比例1)、式(IIA)所示化合物(定義為化合物A,可按照專利申請WO2016007185A1中的方法製備)。
細胞株:體外培養人B細胞淋巴瘤DOHH-2細胞(購自DSMZ),用含10%胎牛血清(FBS)的RPMI 1640培養基培養。
供試品溶液配製:供試品均用DMSO配成10mM的原液;使用時用不含血清的培養液配成所需濃度。
實驗方法:接種一定數量的對數生長期細胞於96孔培養板,24小時後,加入不同濃度(1-100000nM)的藥物,培養72小時,然後每孔加入MTT工作液,4小時後,三聯液溶解,酶標儀570nm波長下測定OD值。
資料分析:以下列公式計算細胞生長抑制率:抑制率=(OD值對照孔-OD值給藥孔)/OD值對照孔×100%;根據各濃度抑制率,並採用非線性回歸方法計算半數有效濃度IC50;化合物A與化合物B聯用的濃度比為1:10,藉由中位效應法,以Calcu-Syn program計算聯合指數(Combination index,CI),判斷兩藥聯用時的相互關係(CI<1為協同,CI=1為相加,CI>1為拮抗)。
實驗結論:由上表數據可知,化合物A與化合物B聯用後對體外培養DOHH-2細胞增殖有協同抑制作用。
供試品:式(IE)所示化合物(定義為化合物B,可按照WO2017084494(專利申請PCT/CN2016/104318)中的方法製備,見對比例1)、式(IIA)所示化合物(定義為化合物A,可按照專利申請WO2016007185A1中的方法製備)。
細胞株:體外培養人B細胞淋巴瘤SU-DHL-4和SU-DHL-6細胞(購自ATCC),用含10%胎牛血清(FBS)的RPMI 1640培養基培養。
供試品溶液配製:供試品均用DMSO配成10mM的原液;使用時用不含血清的培養液配成所需濃度。
實驗方法:接種一定數量的對數生長期細胞於96孔培養板。24小時後,加入不同濃度(1-40000nM)的藥物,培養72小時,然後每孔加入MTT工作液,4小時後,三聯液(10% SDS,5%異丁醇,0.012mol/L HCl)溶解,37℃過夜,酶標儀570nm波長下測定OD值。
資料分析:以下列公式計算細胞生長抑制率:抑制率=(OD值對照孔-OD值給藥孔)/OD值對照孔×100%;根據各濃度抑制率,並採用非線性回歸方法計算半數有效濃度IC50;化合物A與化合物B聯用的濃度比為1:2(SU-DHL-4)和1:4(SU-DHL-6),藉由中位效應法,以Calcu-Syn program計算聯合指數(Combination index,CI),判斷兩藥聯用時的相互關係(CI<1為協同,CI=1為相加,CI>1為拮抗)。
實驗結論:由上表數據可知,化合物A與化合物B聯用後對體外培養SU-DHL-4和SU-DHL-6細胞有協同抑制作用。
供試品:式(IE)所示化合物(定義為化合物B,可按照WO2017084494(專利申請PCT/CN2016/104318)中的方法製備,見對比例1)、式(IIA)所示化合物(定義為化合物A,可按照專利申請WO2016007185A1中的方法製備)。
實驗動物:BALB/cA-nude裸小鼠,56週,雌性,購 自上海靈暢生物科技有限公司,生產許可證號:SCXK(滬)2013-0018;動物合格證號2013001818958,飼養環境:SPF級。
供試品溶液配製:供試品均用0.2% Tween 80+0.5% CMC溶液配製並稀釋成相應濃度。
實驗方法:
(1)裸小鼠皮下接種淋巴瘤DOHH-2細胞,待腫瘤生長至100-200mm3後,將動物隨機分組(D0)。給藥劑量和給藥方案見表5。
(2)觀察與記錄:每週測2-3次瘤體積,稱鼠重,記錄資料。
(3)腫瘤測量與終點主要終點是看腫瘤生長是否可能會推遲或小鼠可能被治癒,腫瘤體積用卡尺每週測量兩次、測量兩個維度,單位為mm3;腫瘤體積(V)計算公式為:V=0.5×a×b2 其中a、b分別表示長、寬;T/C(%)=(T-T0)/(C-C0)×100 其中T、C為實驗結束時的腫瘤體積;T0、C0為實驗開始時的腫瘤體積,T/C值(百分比)作為抗腫瘤效力的指示。
(4)資料分析:匯總統計,包括平均值和平均值的標準誤差(SEM),組間腫瘤體積的差異統計分析和在最後一次給藥(分組後的第21天)後在最佳治療時間點進行的藥物相 互作用所獲得的資料分析。比較組間腫瘤體積和腫瘤重量用單向方差分析,當得到非顯著F-統計量(p<0.001,治療方差比上誤差方差),進行組間Games-Howell比較,對所有資料採用SPSS17.0進行分析,P<0.05被認為是統計學上有意義。
實驗結論:由表5數據可知,化合物A(50mg/kg,PO,QD×21)抑制DOHH-2裸小鼠皮下移植瘤的生長,抑瘤率為49%(P<0.05,與溶劑比較);化合物B(50mg/kg,PO,QD×21)對DOHH-2有一定的抑制作用,抑瘤率為35%(P>0.05,與溶劑比較);二者合用,抑瘤率提高到75%,明顯強於化合 物A、化合物B單用時的療效(P<0.05,與單藥比較,見第3圖),由附第4圖說明化合物A與化合物B聯合後沒有明顯的體重減輕等症狀發生。
綜上該,本發明的BTK抑制劑化合物A與EZH2抑制劑化合物B聯合的作用效果優於單一組分,並且具有協同的作用效果。
供試品:式(IE)所示化合物(定義為化合物B,可按照WO2017084494(專利申請PCT/CN2016/104318)中的方法製備,見對比例1)、式(IIA)所示化合物(定義為化合物A,可按照專利申請WO2016007185A1中的方法製備)。
實驗動物:SCID.BG小鼠,5-6週,雌性,購自上海靈暢生物科技有限公司,生產許可證號:SCXK(滬)2013-0018;動物合格證號2013001820833,飼養環境:SPF級。
供試品溶液配製:供試品均用0.2% Tween 80+0.5% CMC溶液配製並稀釋成相應濃度。
實驗方法:
(1)每只小鼠皮下接種SU-DHL-4細胞(B細胞淋巴瘤SU-DHL-4細胞購自ATCC),待腫瘤生長至100-150mm3後,根據腫瘤體積分組(D0)。給藥劑量和給藥方案見表6。
(2)觀察與記錄:每週測2-3次瘤體積,稱鼠重,記 錄資料。
(3)腫瘤測量與終點主要終點是看腫瘤生長是否可能會推遲或小鼠可能被治癒,腫瘤體積用卡尺每週測量兩次、測量兩個維度,單位為mm3;腫瘤體積(V)計算公式為:V=0.5×a×b2 其中a、b分別表示長、寬;T/C(%)=(T-T0)/(C-C0)×100 其中T、C為實驗結束時的腫瘤體積;T0、C0為實驗開始時的腫瘤體積,T/C值(百分比)作為抗腫瘤效力的指示;抑瘤率(TGI)(%)=100-T/C(%);當腫瘤出現消退時,抑瘤率(TGI)(%)=100-(T-T0)/T0×100
如果腫瘤比起始體積縮小,即T<T0或C<C0時,即定義為腫瘤部分消退(PR);如果腫瘤完全消失,即定義為腫瘤完全消退(CR)。
(4)資料分析:匯總統計,包括平均值和平均值的標準誤差(SEM),組間腫瘤體積的差異統計分析和在最後一次給藥(分組後的第14天)後在最佳治療時間點進行的藥物相互作用所獲得的資料分析。比較組間腫瘤體積和腫瘤重量用單向方差分析,當得到非顯著F-統計量(p<0.001,治療方差比上誤差方差),二組腫瘤體積之間的比較採用單尾Mann-Whitney統計學分析,P<0.05定義為有統計學顯著性差異。
實驗結論:由表6數據可知,化合物A(50mg/kg,PO,QD×14)抑制SU-DHL-4小鼠皮下移植瘤的生長,抑瘤率為76%,有1/8腫瘤部分消退,1/8腫瘤完全消退;化合物B(50mg/kg,PO,QD×14)對SU-DHL-4的抑瘤率為60%,有2/8腫瘤部分消退,1/8腫瘤完全消退;化合物A與化合物B合用,抑瘤率提高到91%,有2/8腫瘤部分消退,1/8腫瘤完全消退,明顯強於化合物A、化合物B單用時的療效(見第5圖);二者合用顯著抑制人B細胞淋巴瘤SU-DHL-4小鼠皮 下移植瘤的生長,引起腫瘤部分或完全消退;二者合用,療效提高,荷瘤小鼠體重有所下降,但對藥物耐受。
綜上所述,本發明的BTK抑制劑化合物A與EZH2抑制劑化合物B聯合的作用效果優於單一組分,並且具有協同的作用效果。
Claims (20)
- 一種EZH2抑制劑與BTK抑制劑聯合在製備治療腫瘤的藥物中的用途,其特徵在於,該EZH2抑制劑為式(I)所示化合物、其可藥用的鹽或其立體異構體,
- 如申請專利範圍第1至5項中任一項所述的用途,其中,該BTK抑制劑為式(II)所示化合物、其可藥用的鹽或其立體異構體,
- 如申請專利範圍第5項所述的用途,其中,該可藥用的鹽選自磷酸鹽、鹽酸鹽、甲磺酸鹽、馬來酸鹽、蘋果酸鹽、對甲苯磺酸鹽或苯磺酸鹽。
- 如申請專利範圍第1項所述的用途,其中,該BTK抑制劑選自依魯替尼、Acalabrutinib、MSC-2364447、Spebrutinib、HM-71224、Plevitrexed、GS-4059、GDC-0853、SNS-062、CGP-53716、Idoxifene、BTG-511、Banoxantrone、Glucarpidase、Anti-digoxin polyclonal antibody、Crotalidae polyvalent immune Fab(ovine,BTG)或Otelixizumab。
- 如申請專利範圍第1項所述的用途,其中,該聯合視需要包含第三組分,該第三組分選自HDAC抑制劑、CDK4/6抑制劑、ALK抑制劑、JAK2抑制劑、Bcl-2抑制劑、Hsp90抑制劑、糖皮質激素、長春花生物鹼、抗代謝物、DNA損傷劑、來那度胺、利妥昔單抗、PKC干擾原、Lyn/Fyn抑制劑、Syk抑制劑、PI3K抑制劑、PKCβ抑制劑、IKK抑制劑、20s蛋白酶體、IRF-4、IRAK4抗 體、CXCR4抗體、CXCR5抗體、GLS抗體、PLK抗體、CD20抗體、Topo Ⅱ抑制劑、DNA甲基轉移酶抑制劑、Ras/MAPK抑制劑或FGFR1抑制劑。
- 如申請專利範圍第10項所述的用途,其中,該HDAC抑制劑為帕比司他乳酸、貝利司他、西達本胺、羅米地辛、伏立諾他、倍賽諾他或恩替諾特;該CDK4/6抑制劑為Palbociclib、Blinatumomab、Tiagabine Hydrochloride或Itolizumab,該Bcl-2抑制劑為Venetoclax、安普利森鈉、ABT-737或HA14-1;該Hsp90抑制劑為Sebelipase alfa或Retaspimycin Hydrochloride;該JAK2抑制劑為枸櫞酸托法替尼、Ruxolitinib Phosphate、Lestaurtinib、Momelotinib Dihydrochloride、Peficitinib或Filgotinib;該PKC干擾原為替普瑞酮、Truheal、HO/03/03、Sotrastaurin、恩紮妥林或GF109203X;該ALK抑制劑為Alectinib Hydrochloride、色瑞替尼、克唑替尼、苯達莫司汀、卡莫司汀、洛莫司汀、鹽酸氮芥或NVP-TAE684;該PI3K抑制劑為GS-1101、IPI-145、BKM120、BEZ235、GDC-0941、AMG319、CAL-101或A66;且該IKK抑制劑為金諾芬、BAY 86-9766或RDEA-119。
- 如申請專利範圍第10或11項所述的用途,其中,該腫瘤為淋巴瘤。
- 如申請專利範圍第12項所述的用途,其中,該淋巴瘤為非霍奇金淋巴瘤。
- 如申請專利範圍第10或11項所述的用途,其中,該腫瘤為B細胞增殖性疾病,該B細胞增殖性疾病選自彌漫性大B細胞淋巴瘤(DLBCL)、慢性淋巴細胞白血病(CLL)、小淋巴細胞淋巴瘤(SLL)、高危CLL或非CLL/SLL淋巴瘤、濾泡性淋巴瘤(FL)、套細胞淋巴瘤(MCL)、前體B細胞腫瘤、前體B淋巴母細胞白血病、成熟B細胞腫瘤、淋巴漿細胞淋巴瘤、免疫母細胞瘤、結外黏膜相關淋巴瘤、毛細胞白血病、漿細胞瘤、漿細胞骨髓瘤、瓦爾登斯特倫巨球蛋白血症、多發性骨髓瘤、邊緣區淋巴瘤、伯基特淋巴瘤(BL)、非伯基特高度B細胞淋巴瘤或結外邊緣區B細胞淋巴瘤、急性或慢性髓性白血病、骨髓增生異常綜合症或急性淋巴母細胞白血病。
- 如申請專利範圍第12項所述的用途,其中,該EZH2抑制劑與BTK抑制劑的比例為0.001至1000。
- 如申請專利範圍第15項所述的用途,其中,該EZH2抑制劑與BTK抑制劑的比例為0.01至100。
- 如申請專利範圍第16項所述的用途,其中,該EZH2抑制劑與BTK抑制劑的比例為0.1至10。
- 如申請專利範圍第12項所述的用途,其中,該EZH2抑制劑的給藥劑量為1-2000mg,且該BTK抑制劑的給藥劑量為1-1000mg。
- 如申請專利範圍第18項所述的用途,其中,該EZH2抑制劑的給藥劑量為10mg、50mg、100mg、150mg、 200mg、300mg、400mg、800mg或1600mg,且該BTK抑制劑的給藥劑量為10mg、20mg、50mg、80mg、100mg、150mg、160mg、200mg、250mg、300mg、350mg、500mg或650mg。
- 一種含有申請專利範圍第1至9項中任一項所述的EZH2抑制劑與BTK抑制劑的醫藥組成物,其特徵在於,該醫藥組成物包含一種或多種可藥用的賦形劑、稀釋劑或載體。
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AU2018269262A1 (en) | 2019-10-31 |
CA3058241A1 (en) | 2018-11-22 |
WO2018210296A1 (zh) | 2018-11-22 |
MX2019012938A (es) | 2019-12-16 |
CN109937041A (zh) | 2019-06-25 |
BR112019023632A2 (pt) | 2020-08-18 |
KR20200007851A (ko) | 2020-01-22 |
EP3626239A1 (en) | 2020-03-25 |
JP7125952B2 (ja) | 2022-08-25 |
CN109937041B (zh) | 2022-04-12 |
KR102635949B1 (ko) | 2024-02-14 |
JP2020519588A (ja) | 2020-07-02 |
US11065239B2 (en) | 2021-07-20 |
EP3626239A4 (en) | 2021-03-10 |
RU2762893C2 (ru) | 2021-12-23 |
MY201580A (en) | 2024-03-02 |
AU2018269262B2 (en) | 2021-12-02 |
RU2019138222A3 (zh) | 2021-07-30 |
TW201900171A (zh) | 2019-01-01 |
US20210030736A1 (en) | 2021-02-04 |
RU2019138222A (ru) | 2021-06-18 |
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