CN110452229B - 氘代Defactinib化合物及其用途 - Google Patents
氘代Defactinib化合物及其用途 Download PDFInfo
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- CN110452229B CN110452229B CN201910373081.2A CN201910373081A CN110452229B CN 110452229 B CN110452229 B CN 110452229B CN 201910373081 A CN201910373081 A CN 201910373081A CN 110452229 B CN110452229 B CN 110452229B
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- pharmaceutically acceptable
- amino
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Abstract
本发明公开了式(I)所示的化合物或其光学异构体、药学上可接受的盐、水合物或溶剂合物,其中,R1‑R18分别独立选自氢、氘,且不全为氢。本发明提供的化合物及其盐类、水合物或溶剂合物,能够作为FAK抑制剂,用于制备抗癌药物,并且,与未氘代的对照化合物Defactinib相比,本发明的化合物的代谢稳定性和药代动力学性能显著提高,应用前景优良。
Description
技术领域
本发明涉及氘代Defactinib化合物及其用途。
背景技术
氘代药物是指将药物分子中的部分氢原子替换为氘。由于氘在药物分子中形状和体积与氢极为接近,氘代药物会保留原来药物的体外生物活性和选择性。由于C-D键比C-H键更稳定,使得氘代药物在代谢反应过程中,C-D键更不容易断裂,其半衰期可能会延长。
但是,由于生物系统的代谢过程复杂,药物在生物体内的药代动力学性质受到多方面因素影响,也表现出相应的复杂性。与相应的非氘代药物相比,氘代药物药代动力学性质的变化表现出极大的偶然性和不可预测性。某些位点的氘代非但不能延长半衰期,反而可能会使其缩短(Scott L.Harbeson,Roger D.Tung.Deuterium in Drug Discovery andDevelopment,P405-406。),劣化其药代动力学性质;另一方面,药物分子上某些位置的氢被氘取代也有极大难度。因此,药物的适合氘代的位点并非显而易见的,氘代效果也是不可预期的。
因此,对Defactinib化合物进行氘代,得到一类具有更佳的药代动力学性质、降低使用剂量、降低代谢产物毒副作用的氘代药物,对于得到更有效、更安全的新药物至关重要。
发明内容
本发明的目的在于提供一种代谢稳定性和药代动力学性能更佳的有效、安全的治疗癌症的新药物。
本发明首先提供了式(I)所示的化合物或其光学异构体、药学上可接受的盐、水合物或溶剂合物:
其中,R1-R18分别独立选自氢、氘,且不全为氢。
进一步地,所述化合物具有式(II)所示结构:
进一步地,所述化合物具有式(III)所示结构:
进一步地,所述化合物具有式(IV)所示结构:
进一步地,所述化合物具有式(V)所示结构:
进一步地,所述化合物为如下化合物之一:
进一步地,所述药学上可接受的盐为所述化合物的磷酸盐、右旋樟脑磺酸盐,盐酸盐、氢溴酸盐、氢氟酸盐、硫酸盐、硝酸盐、甲酸盐、乙酸盐、丙酸盐、草酸盐、丙二酸盐、琥珀酸盐、富马酸盐、马来酸盐、乳酸盐、苹果酸盐、酒石酸盐、柠檬酸盐、苦味酸盐、甲磺酸盐、苯甲磺酸盐、苯磺酸盐、天冬氨酸盐或谷氨酸盐,优选为盐酸盐。
本发明还提供了上述的化合物或其光学异构体、药学上可接受的盐、水合物或溶剂合物在制备治疗癌症的药物中的用途。
进一步地,所述癌症选自胰腺癌,实体瘤,非小细胞肺癌,间皮瘤,卵巢癌。
本发明还提供了上述的化合物或其光学异构体、药学上可接受的盐、水合物或溶剂合物在制备FAK抑制剂中的用途。
本发明还提供了一种治疗癌症的药物,它是以上述的化合物或其光学异构体、药学上可接受的盐、水合物或溶剂合物为活性成分,再加上药学上可接受的辅料制备而成的制剂。
实验证明,本发明提供的化合物及其盐类、水合物或溶剂合物,能够作为FAK抑制剂,用于制备抗癌药物,并且,与未氘代的对照化合物Defactinib相比,本发明的化合物的代谢稳定性和药代动力学性能显著提高,应用前景优良。
如本文所用,“氘代”指化合物或基团中的一个或多个氢被氘所取代。氘代可以是一取代、二取代、多取代或全取代。在另一优选例中,氘在氘取代位置的氘同位素含量是大于天然氘同位素含量(0.015%),更佳地大于50%,更佳地大于75%,更佳地大于95%,更佳地大于97%,更佳地大于99%,更佳地大于99.5%。
如本文所用,术语“本发明化合物”指式(I)所示的化合物。该术语还包括及式(I)化合物的各种光学异构体、药学上可接受的盐、水合物或溶剂合物。
如本文所用,术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于:
磷酸、右旋樟脑磺酸,盐酸、氢溴酸、氢氟酸、硫酸、硝酸、甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸、苯磺酸、天冬氨酸或谷氨酸。
进一步地,形成药学上可接受的盐的酸为盐酸。
本文所述药学上可接受的辅料,它具有一定生理活性,但该成分的加入不会改变上述药物组合物在疾病治疗过程中的主导地位,而仅仅发挥辅助功效,这些辅助功效仅仅是对该成分已知活性的利用,是医药领域惯用的辅助治疗方式。若将上述辅助性成分与本发明药物组合物配合使用,仍然应属于本发明保护的范围。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
本发明所用原料、仪器均为已知产品,通过购买市售产品所得。
以下采用下述合成方法1或2所述的路线,制备本发明的化合物:
合成方法1:
合成方法2:
实施例1、N-(三氘代甲基)-4-((4-(((3-(N-甲基甲基磺酰基)吡嗪-2-基)甲基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯甲酰胺(化合物1)的合成
(1)化合物叔丁基(4-((叔丁氧羰基)(4-((叔丁氧羰基)((3-(N-甲基甲磺酰胺基)吡嗪-2-基)甲基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯甲酰基)(甲基)氨基甲酸酯的合成
将N-甲基-4-((4-(((3-(N-甲基甲磺酰基)吡嗪-2-基)甲基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯甲酰胺(200.0mg,0.39mmol;即化合物1-1,购自成都恒汇化成医药科技有限公司),DMAP(1.3g,10.57mmol)加入到10mL二氯甲烷中,再滴加(Boc)2O(1.7g,7.83mmol)。体系在45℃的油浴中回流反应24h。翌日,冷却至室温,加入二氯甲烷和HCl(0.1M)溶液,萃取,后静置分层,有机相用饱和食盐水洗涤,无水硫酸钠干燥,抽滤后旋蒸除去溶剂,柱层析分离初品,得类白色固体叔丁基(4-((叔丁氧羰基)(4-((叔丁氧羰基)((3-(N-甲基甲磺酰胺基)吡嗪-2-基)甲基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯甲酰基)(甲基)氨基甲酸酯136.0mg,收率:42.8%。MS(ESI)m/e 811.2(M+H)+。
(2)化合物叔丁基(4-((叔丁氧羰基)((3-(N-甲基甲磺酰胺基)吡嗪-2-基)甲基)氨基)-5-(三氟甲基)嘧啶-2-基)(4-(甲基氨甲酰基)苯基)氨基甲酸酯的合成
称取叔丁基(4-((叔丁氧羰基)(4-((叔丁氧羰基)((3-(N-甲基甲磺酰胺基)吡嗪-2-基)甲基)氨基)-5-(三氟甲基)嘧啶-2-yl)氨基)苯甲酰基)(甲基)氨基甲酸酯(136.0mg,0.17mmol),氘代甲胺盐酸盐(189.0mg,2.68mmol)加入到5mL乙腈中,室温搅拌。再向其中加入DBU(613.0mg,4.03mmol),逐渐溶解澄清。随后将体系置于油浴中回流反应过夜。翌日,冷却至室温,旋蒸除去溶剂后,向体系中加入二氯甲烷以及HCl(0.1M)溶液,剧烈搅拌,静置分层,有机相分别用纯净水以及饱和食盐水洗涤,无水硫酸钠干燥,旋蒸除去溶剂,Pre-TLC分离纯化(PE/EA=2:1),得白色固体叔丁基(4-((叔丁氧羰基)((3-(N-甲基甲磺酰胺基)吡嗪-2-基)甲基)氨基)-5-(三氟甲基)嘧啶-2-基)(4-(甲基氨甲酰基)苯基)氨基甲酸酯42.0mg,收率:35.3%。MS(ESI)m/e 614.2(M+H)+。
(3)化合物N-(三氘代甲基)-4-((4-(((3-(N-甲基甲基磺酰基)吡嗪-2-基)甲基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯甲酰胺(化合物1)的合成
将叔丁基(4-((叔丁氧羰基)((3-(N-甲基甲磺酰胺基)吡嗪-2-基)甲基)氨基)-5-(三氟甲基)嘧啶-2-基)(4-(甲基氨甲酰基)苯基)氨基甲酸酯(42.0mg,0.06mmol)加入到2mL二氯甲烷中,室温搅拌(未能溶解澄清)。随后向其中加入0.1mL三氟乙酸,体系逐渐呈现透明澄清状,任其在室温搅拌反应过夜。翌日,旋蒸除去溶剂,向体系中加入乙酸乙酯以及饱和NaHCO3溶液,剧烈搅拌,后静置分层,测得水相的pH值约为7-8左右。有机层分别用水以及饱和食盐水各洗涤2次,无水硫酸钠干燥,旋蒸除去溶剂,得类白色固体N-氘代甲基-4-((4-(((3-(N-甲基甲基磺酰基)吡嗪-2-基)甲基)氨基)-5-(三氟甲基)嘧啶-2-)氨基)苯甲酰胺24.0mg,收率:80.0%。MS(ESI)m/e 514.2(M+H)+。
1H NMR(400MHz,DMSO-d6)δ9.86(s,1H),8.69(d,J=2.4Hz,1H),8.58(d,J=2.8Hz,1H),8.32(s,1H),8.18(s,1H),7.67-7.59(dd,J=19.6,8.8Hz,4H),7.48-7.45(t,J=5.2Hz,1H),5.00(d,J=4.8Hz,2H),3.22(s,3H),3.20(s,3H)。
实施例2、N-甲基-4-((4-(((3-(N-氘代甲基甲磺酰胺基)吡嗪-2-基)甲基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯甲酰胺(化合物2)的合成
(1)化合物N-氘代甲基甲磺酰胺的合成
称取甲基磺酰氯(3.0g,26.19mmol)置于100mL单颈圆底烧瓶中,并向其中加入二氯甲烷(30mL),室温搅拌溶解澄清。随后,将体系移置于冰水浴中继续降温冷却搅拌。15min后,向体系中缓慢加入三乙胺(6.1g,60.24mmol),加毕,体系继续保温搅拌10min。接着向体系中分批次缓慢加入氘代甲胺盐酸盐(2.0g,28.81mmol)。完毕,撤去冰浴,任体系恢复室温搅拌反应过夜。翌日,监测反应结束,旋蒸除去溶剂,再向体系中加入乙酸乙酯(30mL),搅拌10min,对其进行抽滤操作,滤饼用少量乙酸乙酯淋洗。合并滤液,减压浓缩得粗品,后经柱层析分离得无色透明油状液体N-氘代甲基甲磺酰胺2.1g,收率:71.4%。
(2)化合物N-(3-氰基吡嗪-2-基)-N-氘代甲基甲磺酰胺的合成
称取3-氯吡嗪-2-腈(1.7g,12.48mmol)置于100mL单颈圆底烧瓶中,并向其中加入40mL乙腈,室温搅拌溶解澄清。尔后向体系中分批次缓慢加入碳酸铯(8.1g,24.96mmol)。加毕,开始向体系中滴加溶有N-氘代甲基甲磺酰胺(2.1g,18.72mmol)的乙腈(10mL)溶液。滴毕,将体系移置于80℃的油浴中回流搅拌反应。30min后,TLC监测原料消耗完全。撤去油浴,任体系冷却至室温,对其进行抽滤操作,滤饼用乙腈(100mL)多次淋洗。合并滤液,旋蒸除去溶剂得粗品,后经柱层析分离得浅褐色油状液体N-(3-氰基吡嗪-2-基)-N-氘代甲基甲磺酰胺1.1g,收率:42.3%。MS(ESI)m/e 233.1(M+H2O)+。
1H NMR(400MHz,CDCl3)δ8.65-8.63(dd,J=6.0,2.4Hz,2H),3.26(s,3H)。
(3)化合物N-(3-(氨甲基)吡嗪-2-基)-N-氘代甲基甲磺酰胺的合成
称取N-(3-氰基吡嗪-2-基)-N-氘代甲基甲磺酰胺(42mg,0.20mmol)置于25mL单颈圆底烧瓶中,并加入4mL甲醇以及1mL氨水,室温搅拌均匀。随后向体系中加入湿钯碳(10.0mg),对体系进行氢气置换操作,反复十次。完毕,体系在室温搅拌反应。1h后,监测反应结束。对体系进行抽滤操作,滤饼用甲醇(25mL)少量多次淋洗,合并滤液,减压浓缩除去溶剂,并用甲醇反复旋带除去体系中残留的水分得浅黄褐色油状液体N-(3-(氨甲基)吡嗪-2-yl)-N-氘代甲基甲磺酰胺,不经进一步纯化,直接用于下步反应中。MS(ESI)m/e 220.1(M+H)+。
(4)化合物叔丁基(4-(甲基氨甲酰)苯基)氨基甲酸酯的合成
称取4-((叔丁氧羰基)氨基)苯甲酸(3.0g,12.65mmol)置于250mL单颈圆底烧瓶中,并向其中加入50mL DMF,室温搅拌。随后向体系中依次加入EDCI(4.8g,25.29mmol),TEA(4.5g,44.28mmol),甲胺盐酸盐(1.3g,18.98mmol),DMAP(16.0mg,0.13mmol)。完毕,体系在室温搅拌反应过夜。翌日,监测原料消耗完毕,向体系中加入乙酸乙酯(70mL)和水(50mL),剧烈搅拌,静置分层后,水相用乙酸乙酯反萃(20mL*3),合并有机层,分别用水(20mL*3),饱和食盐水(30mL)洗涤,无水硫酸钠干燥,旋蒸除去溶剂得粗品,后经柱层析分离得类白色固体叔丁基(4-(甲基氨甲酰)苯基)氨基甲酸酯2.1g。收率:66.5%。MS(ESI)m/e 251.2(M+H)+。
(5)化合物4-氨基-N-甲基苯甲酰胺三氟乙酸盐的合成
称取叔丁基(4-(甲基氨基甲酰)苯基)氨基甲酸酯(500mg,2.00mmol)置于50mL单颈圆底烧瓶中,并向其中加入10mL二氯甲烷,室温搅拌。尔后,向体系中加入三氟乙酸(1mL),完毕,体系在室温搅拌反应过夜。翌日,TLC显示反应结束。浓缩除去溶剂以及过量的三氟乙酸,并使用二氯甲烷多次旋带除去体系中残留的三氟乙酸直到体系中呈现完全固状为止,得类白色固体4-氨基-N-甲基苯甲酰胺三氟乙酸盐(510mg),不经进一步纯化,直接用于下步反应中。
(6)化合物4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-N-甲基苯甲酰胺的合成
称取2,4-二氯-5-(三氟甲基)嘧啶(499mg,2.30mmol)于50mL单颈圆底烧瓶中,并向体系中加入1,2-二氯乙烷(5mL)和叔丁醇(5mL),室温搅拌溶解澄清。后将体系移置于冰水浴中继续降温冷却搅拌,15min后,向体系中加入溴化锌(1.4g,6.00mmol)。完毕,体系在冰水浴中继续保温搅拌30min。然后向体系中加入前步合成的4-氨基-N-甲基苯甲酰胺三氟乙酸盐以及三乙胺(648mg,6.40mmol)。加毕,撤去冰浴,体系在室温搅拌反应过夜。翌日,监测反应结束,旋蒸除去溶剂后,向体系中加入乙酸乙酯(30mL)和水(20mL),剧烈搅拌,静置分层后,水层用乙酸乙酯反萃(10mL*3),合并有机相,依次用水(15mL*3),饱和食盐水(15mL)洗涤,无水硫酸钠干燥,减压浓缩得粗品,后经柱层析分离得类白色固体4-((4-氯-5-(三氟甲基)嘧啶-2-yl)氨基)-N-甲基苯甲酰胺280mg。收率:42.3%。MS(ESI)m/e 331.0(M+H)+。
(7)化合物N-甲基-4-((4-(((3-(N-氘代甲基甲磺酰胺基)吡嗪-2-基)甲基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯甲酰胺的合成
向装有N-(3-(氨甲基)吡嗪-2-yl)-N-氘代甲基甲磺酰胺(65.8mg,0.30mmol)的25mL单颈圆底烧瓶中加入5mL 1,2-二氯乙烷,5mL叔丁醇,室温搅拌溶解澄清。随后,向体系中依次加入4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-N-甲基苯甲酰胺(100.0mg,0.30mmol),二异丙基乙胺(116.3mg,0.90mmol),加毕,将体系移置于80℃的油浴中回流反应。8h后,TLC监测原料消耗完全。停止加热,待体系冷却至室温后,旋蒸除去溶剂得粗品,后经Prep-TLC分离纯化得类白色固体N-甲基-4-((4-(((3-(N-氘代甲基甲磺酰胺基)吡嗪-2-基)甲基)氨基)-5-(三氟甲基)嘧啶-2-yl)氨基)苯甲酰胺12mg。收率:7.8%。MS(ESI)m/e514.2(M+H)+。
1H NMR(400MHz,DMSO-d6)δ9.83(s,1H),8.69(s,1H),8.59(s,1H),8.32(s,1H),8.20(d,J=4.0Hz,1H),7.68-7.61(dd,J=14.4,8.4Hz,4H),7.41-7.39(t,J=4.4Hz,1H),5.01(d,J=3.6Hz,2H),3.20(s,3H),2.76(d,J=4.0Hz,3H)。
实施例3、N-(三氘代甲基)-4-((4-(((3-(N-氘代甲基甲磺酰胺基)吡嗪-2-基)甲基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯甲酰胺(化合物3)的合成
(1)化合物叔丁基(4-(氘代甲基氨基甲酰)苯基)氨基甲酸酯的合成
称取4-((叔丁氧羰基)氨基)苯甲酸(1.1g,4.64mmol)置于100mL单颈圆底烧瓶中,并向其中加入20mL DMF,室温搅拌。随后向体系中依次加入EDCI(1.3g,6.96mmol),TEA(1.2g,11.6mmol),氘代甲胺盐酸盐(327.2mg,4.64mmol),DMAP(28mg,0.23mmol)。完毕,体系在室温搅拌反应过夜。翌日,监测原料消耗完毕,向体系中加入乙酸乙酯(30mL)和水(20mL),剧烈搅拌,静置分层后,水相用乙酸乙酯反萃(15mL*3),合并有机层,分别用水(15mL*3),饱和食盐水(20mL)洗涤,无水硫酸钠干燥,旋蒸除去溶剂得粗品,后经柱层析分离得类白色固体叔丁基(4-(氘代甲基氨基甲酰)苯基)氨基甲酸酯953mg。收率:81.2%。MS(ESI)m/e 254.2(M+H)+。
(2)化合物4-氨基-N-氘代甲基苯甲酰胺三氟乙酸盐的合成
称取叔丁基(4-(氘代甲基氨基甲酰)苯基)氨基甲酸酯(953.0mg,3.76mmol)置于50mL单颈圆底烧瓶中,并向其中加入20mL二氯甲烷,室温搅拌。尔后,向体系中加入三氟乙酸(5mL),完毕,体系在室温搅拌反应过夜。翌日,TLC显示反应结束。浓缩除去溶剂以及过量的三氟乙酸,并使用二氯甲烷多次旋带除去体系中残留的三氟乙酸直到体系中呈现完全的固状为止。得类白色固体4-氨基-N-氘代甲基苯甲酰胺三氟乙酸盐(941mg),不经进一步纯化,直接用于下步反应中。MS(ESI)m/e 154.1(M+H)+。
(3)化合物4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-N-氘代甲基苯甲酰胺的合成
称取2,4-二氯-5-(三氟甲基)嘧啶(891.8mg,4.11mmol)于100mL单颈圆底烧瓶中,并向体系中加入1,2-二氯乙烷(10mL)和叔丁醇(10mL),室温搅拌溶解澄清。后将体系移置于冰水浴中继续降温冷却搅拌,15min后,向体系中加入溴化锌(2.3g,10.71mmol)。完毕,体系在冰水浴中继续保温搅拌30min。然后向体系中加入前步合成的4-氨基-N-氘代甲基苯甲酰胺三氟乙酸盐以及三乙胺(1.2g,11.41mmol)。加毕,撤去冰浴,任体系在室温搅拌反应过夜。翌日,监测反应结束,旋蒸除去溶剂后,向体系中加入乙酸乙酯(50mL)和水(20mL),剧烈搅拌,静置分层后,水层用乙酸乙酯反萃(20mL*3),合并有机相,分别用水(20mL*3),饱和食盐水(20mL)洗涤,无水硫酸钠干燥,减压浓缩得粗品,后经柱层析分离得类白色固体4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-N-氘代甲基苯甲酰胺467mg。收率:39.2%。MS(ESI)m/e334.0(M+H)+。
(4)化合物N-氘代甲基-4-((4-(((3-(N-氘代甲基甲磺酰胺基)吡嗪-2-基)甲基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯甲酰胺的合成
向装有N-(3-(氨甲基)吡嗪-2-基)-N-氘代甲基甲磺酰胺(43.8mg,0.20mmol)的25mL单颈圆底烧瓶中加入3mL 1,2-二氯乙烷,3mL叔丁醇,室温搅拌溶解澄清。随后,向体系中依次加入4-((4-氯-5-(三氟甲基)嘧啶-2-yl)氨基)-N-氘代甲基苯甲酰胺(66.7mg,0.20mmol),二异丙基乙胺(77.6mg,0.60mmol),加毕,将体系移置于80℃的油浴中回流搅拌反应。8h后,TLC监测原料消耗完全。停止加热,待体系冷却至室温后,旋蒸除去溶剂的粗品,后经Pre-TLC分离纯化得类白色固体N-氘代甲基-4-((4-(((3-(N-氘代甲基甲磺酰胺基)吡嗪-2-基)甲基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯甲酰胺35.5mg。收率:34.4%。MS(ESI)m/e 517.2(M+H)+。
1H NMR(400MHz,DMSO-d6)δ9.83(s,1H),8.69(d,J=2.8Hz,1H),8.58(d,J=2.4Hz,1H),8.31(s,1H),8.17(s,1H),7.67-7.60(dd,J=15.4,8.6Hz,4H),7.42-7.39(t,J=5.2Hz,1H),5.00(d,J=4.8Hz,2H),3.20(s,3H)。
实施例4、N-氘代甲基-4-((4-(((3-(N-氘代甲基甲磺酰胺基)吡嗪-2-基)氘代甲基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯甲酰胺(化合物5)的合成
(1)化合物N-(3-(氨基氘代甲基)吡嗪-2-基)-N-氘代甲基甲磺酰胺的合成
称取N-(3-氰基吡嗪-2-基)-N-氘代甲基甲磺酰胺(100.0mg,0.46mmol)置于25mL单颈圆底烧瓶中,并加入5mL氘代甲醇,室温搅拌溶解澄清。随后向体系中依次加入湿钯碳(使用重水处理)(20.0mg),三乙胺(188.2mg,1.86mmol),对体系进行氘气置换操作,反复十次。完毕,体系在室温搅拌反应。72h后,监测反应结束。对体系进行抽滤操作,滤饼用氘代甲醇(10mL)少量多次淋洗,合并滤液,旋蒸除去溶剂,得浅黄褐色油状液体N-(3-(氨基氘代甲基)吡嗪-2-基)-N-氘代甲基甲磺酰胺,不经进一步纯化,直接用于下步反应中。MS(ESI)m/e222.2(M+H)+。
(2)化合物N-氘代甲基-4-((4-(((3-(N-氘代甲基甲磺酰胺基)吡嗪-2-基)氘代甲基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯甲酰胺的合成
向装有N-(3-(氨基氘代甲基)吡嗪-2-基)-N-氘代甲基甲磺酰胺(22.1mg,0.10mmol)的25mL单颈圆底烧瓶中加入2mL 1,2-二氯乙烷,2mL叔丁醇,室温搅拌溶解澄清。随后,向体系中依次加入4-((4-氯-5-(三氟甲基)嘧啶-2-yl)氨基)-N-氘代甲基苯甲酰胺(33.4mg,0.10mmol),二异丙基乙胺(30.6mg,0.30mmol),加毕,将体系移置于80℃的油浴中回流反应。8h后,TLC监测原料消耗完全。停止加热,待体系冷却至室温后,旋蒸除去溶剂得粗品,后经Prep-TLC分离纯化得类白色固体N-氘代甲基-4-((4-(((3-(N-氘代甲基甲磺酰胺基)吡嗪-2-基)甲基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯甲酰胺8.1mg。收率:15.6%。MS(ESI)m/e 519.2(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.83(s,1H),8.69(d,J=2.0Hz,1H),8.58(d,J=2.4Hz,1H),8.31(s,1H),8.17(s,1H),7.67-7.61(dd,J=15.2,8.8Hz,4H),7.39(s,1H),3.20(s,3H)。
采用以下化合物为原料,按照化合物1-3,5以及化合物3-3相类似的合成方法,制备得到本发明化合物4,6-18:化合物A,2-3,B,2-4,3-3,N-(3-(氨基甲基)吡嗪-2-基)-N-甲基甲磺酰胺(参考文献:PCT Int.Appl.,2008129380),N-甲基甲磺酰胺,N-三氘代甲基甲磺酰胺,2,4-二氯-5-(三氟甲基)嘧啶,4-氨基-3,5-二氘苯甲酸(参考文献:Journal ofLabelled Compounds and Radiopharmaceuticals,53(11-12),668-673;2010),4-氨基-2,6-二氘苯甲酸(参考文献:Journal of Labelled Compounds and Radiopharmaceuticals,53(11-12),668-673;2010)。
以下通过试验例的方式来说明本发明的有益效果。
试验例1、本发明化合物的肝细胞微粒体代谢稳定性实验
第一步、母溶液按以下表1的成分比列配制:
表1、母溶液的配制
第二步:两个实验分别进行如下:
A)加还原型辅酶Ⅱ(NADPH):10μL浓度为20mg/mL的肝微粒体和40μL浓度为10mM的NADPH加入孵化试验中。肝微粒体和NADPH的最终浓度为0.5mg/mL和1mM。
B)不加NADPH:10μL浓度为20mg/mL的肝微粒体和40μL的高纯水加入孵化试验中。肝微粒体的最终浓度为0.5mg/mL。
第三步:加入4μL的200μM浓度的阳性对照物或者测试化合物后反应开始。本实验中的阳性对照物为Verapamil。测试化合物的最终浓度为2μM。
第四步:在0,15,30,45和60分钟的时间点由反应溶液中各取出50μL。往反应液中加入4倍体积的乙腈和IS(100nM浓度的alprazolam,200nM浓度的labetalol,200nM浓度的caffeine and 2μM浓度的ketoprofen)。样品在3220克重力下离心40分钟。上层清夜100μL中加入100μL高纯水用LC-MS/MS分析。
第五步:数据分析:从提取的离子色谱图确定峰面积。斜率值k通过母体药物的剩余百分比与孵育时间曲线的自然对数的线性回归来确定。
体外半衰期(体外t1/2)由斜率值确定:in vitrot1/2=-(0.693/k)
放大内在清除率(Scale up CLint,以mL/min/kg为单位)通过使用以下式(重复测定的平均值)由体外t1/2(分钟)换算:
小鼠,大鼠和人肝微粒体代谢稳定性实验结果见表2:
表2、小鼠,大鼠和人肝微粒体代谢稳定性实验结果
如上表所示,本发明的化合物1、3在肝微粒体中的代谢稳定性都比非氘代对照化合物Defactinib显著提高,但是化合物2在大鼠、人肝微粒体的代谢稳定性比非氘代对照化合物Defactinib稍差。表明本发明化合物,特别是化合物1、3具有更好的代谢稳定性。并且有可能有更好的药代动力学,具有更好的安全性和有效性,这将在下面的试验例中进一步证明。
试验例2、本发明化合物的大鼠药代动力学
1)实验材料及仪器:
LC-20AD高效液相色谱系统,购自日本SHIMADZU(岛津)公司
API4000三重四极杆质谱仪,购自美国Applied Biosystem公司
PhenixWinnolin药动学软件(Version 6.3),购自美国Certara公司
高速冷冻离心机,购自Thermo Fisher Scientific
分析天平,购自赛多利斯,SECURA225D-1CN
SD大鼠,购自成都达硕实验动物有限公司
N,N-二甲基乙酰胺(DMA)(Sigma)
羧甲基纤维素钠(CMC-Na)、肝素,购自成都科龙化工
2)实验方法及结果
精密称取适量药物(相当于原形药物10mg),先加入DMA 0.25ml使之溶解,然后缓慢加入0.5%CMC-Na至5ml,超声、涡漩混匀。取配制的终溶液0.2ml,于-20℃保存,用于浓度测定。健康成年雄性SD大鼠3只(180-250g),禁食过夜(自由饮水)后,灌胃给药,给药体积5ml/kg;于给药前及给药后0.5,1,2,4,6,8,12,24h由眼眶后静脉丛采血0.1ml,4℃离心5min分离血浆,于-20℃保存待测。然后采用LC/MS/MS法测定血浆中的待测化合物浓度。
表3、本发明的药代动力学参数
可以看出,与非氘代的对照化合物Defactinib相比,本发明的化合物具有更高的达峰血药浓度,更高的暴露量,更长的半衰期,说明本发明提供的化合物具有更好的药代动力学性能。在治疗癌症中应用前景优异。
综上,本发明提供的各种氘代化合物及其盐类、水合物或溶剂合物,能够作为FAK抑制剂,用于制备抗癌药物,并且,与未氘代的对照化合物Defactinib相比,本发明的化合物的代谢稳定性和药代动力学性能显著提高,应用前景优良。
Claims (9)
2.根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于:所述药学上可接受的盐为所述化合物的磷酸盐、右旋樟脑磺酸盐,盐酸盐、氢溴酸盐、氢氟酸盐、硫酸盐、硝酸盐、甲酸盐、乙酸盐、丙酸盐、草酸盐、丙二酸盐、琥珀酸盐、富马酸盐、马来酸盐、乳酸盐、苹果酸盐、酒石酸盐、柠檬酸盐、苦味酸盐、甲磺酸盐、苯磺酸盐、天冬氨酸盐或谷氨酸盐。
3.根据权利要求2所述的化合物或其药学上可接受的盐,其特征在于:所述药学上可接受的盐为盐酸盐。
4.权利要求1~3任一项所述的化合物或其药学上可接受的盐在制备治疗癌症的药物中的用途。
5.根据权利要求4所述的用途,其特征在于:所述癌症选自胰腺癌,非小细胞肺癌,卵巢癌 。
6.根据权利要求4所述的用途,其特征在于:所述癌症为实体瘤。
7.根据权利要求4所述的用途,其特征在于:所述癌症为间皮瘤。
8.权利要求1~3任一项所述的化合物或其药学上可接受的盐在制备FAK抑制剂中的用途。
9.一种治疗癌症的药物,其特征在于:它是以权利要求1~3任一项所述的化合物或其药学上可接受的盐为活性成分,再加上药学上可接受的辅料制备而成的制剂。
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