CN105153129A - 1,3,5-三嗪类衍生物及其制备方法和抗肿瘤用途 - Google Patents
1,3,5-三嗪类衍生物及其制备方法和抗肿瘤用途 Download PDFInfo
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- CN105153129A CN105153129A CN201510464404.0A CN201510464404A CN105153129A CN 105153129 A CN105153129 A CN 105153129A CN 201510464404 A CN201510464404 A CN 201510464404A CN 105153129 A CN105153129 A CN 105153129A
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- CN
- China
- Prior art keywords
- morpholinyl
- imidazol
- triazin
- difluoromethyl
- benzo
- Prior art date
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- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims description 36
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- Chemical & Material Sciences (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及通式Ⅰ所示新的1,3,5-三嗪类衍生物及其药学上可用盐、水合物、溶剂化物、前药,其中取代基R1和R2具有在说明书中给出的含义。本发明还涉及通式Ⅰ化合物的制备方法和抗肿瘤药物中的应用。
Description
技术领域
本发明属药物化学技术领域,1,3,5-三嗪类衍生物及其制备方法,还涉及该类衍生物在制备治疗肿瘤药物中的应用。
背景技术
癌症严重威胁着人类的生命和健康,是人类最主要的死亡原因之一,治疗难度极大。20世纪后期以来癌症发病率一直呈上升趋势,且患者呈现低龄化趋势。据世界卫生组织统计,全球每年死于癌症的病人约有500万,预测至2020年将有2000万新发癌症病例,其中死亡人数将达1200万。近一个世纪以来,癌症的药物治疗取得了显著成绩,开发出了几十种抗肿瘤药物,有效地延长了患者的生命或提高了患者的生存质量,但大多数药物为细胞毒药物,选择性不高且存在耐药性问题。因此抗肿瘤的药物研究和开发仍面临巨大挑战,抗肿瘤药物的研究依然是医药领域的重要任务之一。为了提高肿瘤治疗的疗效,取得新的突破性进展,药学家必须更加深入的研究肿瘤发生发展的机制,从而发现抗肿瘤作用新的靶点,并以此为突破口,设计新的更加有效的药物。
最近,越来越多的研究表明,PI3K(磷脂酰肌醇三磷酸激酶)通路是癌症中被激活的信号通路之一,与肿瘤的发生发展、肿瘤细胞周期改变相关,使用PI3K抑制剂,阻断这一通路将会成为癌症治疗的一个很有前景的策略。
本发明人设计并合成了一系列新的1,3,5-三嗪类衍生物。经过体外活性筛选,表明该类化合物具有抗肿瘤活性。
发明内容
本发明的目的在与提供1,3,5-三嗪类衍生物及其制备方法。本发明还提供上述化合物的细胞水平及靶点水平的活性筛选结果及其抗肿瘤应用。
本发明涉及结构如通式Ⅰ所示的化合物,包括其药学上可接受的盐,通式Ⅰ如下:
其中,
R1和R2相同或不同,分别独立地选自氢、(C1-C10)烷基、(C3-C7)环烷基、(C2-C10)烯基和(C2-C10)炔基,它们可以被1-3个相同或不同的R3任选取代;
或R1和R2与和它们所连接的氮原子一起形成5-10元杂环基或5-10元杂芳基,所述杂环基和杂芳基可以任选被1-3个相同或不同的R4取代;
除了R1和R2所连接的氮原子外,所述杂环基和杂芳基可以任选含有1-4个选自N、O和S的杂原子,所述杂环基还可以任选包括1或2个碳碳双键或叁键,
R3、R4为(C1-C4)烷基、(C1-C4)烷氧基、卤代、羟基、氰基、羧基、(C1-C10)酯基;
本发明优选涉及如下结构的化合物及其药学上可接受的盐:
其中,
R1和R2相同或不同,分别独立地选自氢、(C1-C4)烷基、(C3-C7)环烷基、(C2-C4)烯基和(C2-C4)炔基,它们可以被1-3个相同或不同的R3任选取代;
或R1和R2与和它们所连接的氮原子一起形成5-10元杂环基或5-10元杂芳基,所述杂环基和杂芳基可以任选被1-3个相同或不同的R4取代;
除了R1和R2所连接的氮原子外,所述杂环基和杂芳基可以任选含有1-4个选自N、O和S的杂原子;
R3、R4为(C1-C4)烷基、(C1-C4)烷氧基、卤代、羟基、氰基、羧基、(C1-C10)酯基;
本发明还优选涉及如下结构的化合物及其药学上可接受的盐:
其中,
R1和R2相同或不同,分别独立地选自氢、(C1-C4)烷基,它们可以被1-3个相同或不同的R3任选取代;
或R1和R2与和它们所连接的氮原子一起形成5-10元杂环基或5-10元杂芳基,所述杂环基和杂芳基可以任选被1-3个相同或不同的R4取代;
除了R1和R2所连接的氮原子外,所述杂环基和杂芳基可以任选含有1-4个选自N、O和S的杂原子;
R3、R4为(C1-C4)烷基、(C1-C4)烷氧基、卤代、羟基、氰基、羧基、(C1-C10)酯基;
本发明还优选涉及如下结构的化合物及其药学上可接受的盐:
其中,
R1和R2相同或不同,分别独立地选自氢、(C1-C4)烷基、羟基取代的(C1-C4)烷基;
或R1和R2与和它们所连接的氮原子一起形成吗啉基、4-哌啶酮基、4-羟基哌啶基、咪唑基、哌啶基、4-甲基哌啶基、3-甲基哌啶基、2-甲基哌啶基、4-甲基-1-哌嗪基;
本发明优选涉及如下结构的化合物及其药学上可接受的盐:
R1和R2相同或不同,分别独立地选自氢、(C1-C4)烷基,羟乙基;
或R1和R2与和它们所连接的氮原子一起形成吗啉基、4-哌啶酮基、4-羟基哌啶基、咪唑基、哌啶基、4-甲基哌啶基、3-甲基哌啶基、2-甲基哌啶基、4-甲基-1-哌嗪基。
本发明还优选涉及如下结构的化合物及其药学上可接受的盐:
其中,
当R1和R2相同时,均为乙基;
当R1和R2不同时,R1,R2独立地为氢、羟乙基;
或R1和R2与和它们所连接的氮原子一起形成吗啉基、4-哌啶酮基、4-羟基哌啶基、咪唑基、哌啶基、4-甲基哌啶基、3-甲基哌啶基、2-甲基哌啶基、4-甲基-1-哌嗪基。
本发明通式Ⅰ化合物及其药学上可接受的盐、水合物、溶剂化物或前药优选以下化合物,但这些化合物并不意味着对本发明的任何限制:
M-01:1-{4-[4-(4-(2-(二氟甲基)-1H-苯并[d]咪唑-1-基)-6-吗啉基-1,3,5-三嗪-2-基]哌嗪-1-基}-2-吗啉基-1-酮;
M-02:1-{2-[4-(4-(2-(二氟甲基)-1H-苯并[d]咪唑-1-基)-6-吗啉基-1,3,5-三嗪-2-基)哌嗪-1-基]-2-氧代乙基}哌啶-4-酮;
M-03:1-{4-[4-(2-(二氟甲基)-1H-苯并[d]咪唑-1-基)-6-吗啉基-1,3,5-三嗪-2-基]哌嗪-1-基}-2-(4-羟基哌啶-1-基)乙-1-酮;
M-04:1-{4-[4-(2-(二氟甲基)-1H-苯并[d]咪唑-1-基)-6-吗啉基-1,3,5-三嗪-2-基]哌嗪-1-基}-2-(1H-咪唑-1-基)乙-1-酮;
M-05:1-{4-[4-(2-(二氟甲基)-1H-苯并[d]咪唑-1-基)-6-吗啉基-1,3,5-三嗪-2-基]哌嗪-1-基}-2-((2-羟基乙基)氨基)乙-1-酮;
M-06:1-{4-[4-(2-(二氟甲基)-1H-苯并[d]咪唑-1-基)-6-吗啉基-1,3,5-三嗪-2-基]哌嗪-1-基}-2-(2-(哌啶-1-基))乙-1-酮;
M-07:1-{4-[4-(2-(二氟甲基)-1H-苯并[d]咪唑-1-基)-6-吗啉基-1,3,5-三嗪-2-基]哌嗪-1-基}-2-(4-甲基哌啶-1-基)乙-1-酮;
M-08:1-{4-[4-(2-(二氟甲基)-1H-苯并[d]咪唑-1-基)-6-吗啉基-1,3,5-三嗪-2-基]哌嗪-1-基}-2-(3-甲基哌啶-1-基)乙-1-酮;
M-09:1-{4-[4-(2-(二氟甲基)-1H-苯并[d]咪唑-1-基)-6-吗啉基-1,3,5-三嗪-2-基]哌嗪-1-基}-2-(2-甲基哌啶-1-基)乙-1-酮;
M-10:1-{4-[4-(2-(二氟甲基)-1H-苯并[d]咪唑-1-基)-6-吗啉基-1,3,5-三嗪-2-基]哌嗪-1-基}-2-(4-甲基哌嗪-1-基)乙-1-酮;
M-11:1-{4-[4-(2-(二氟甲基)-1H-苯并[d]咪唑-1-基)-6-吗啉基-1,3,5-三嗪-2-基]哌嗪-1-基}-2-(二乙基氨基)乙-1-酮;
而且,按照本发明所属领域的一些通常方法,
本发明中上式Ⅰ1,3,5-三嗪类衍生物可以与酸生成药学上可接受的盐。其中药学上可接受的盐系指化合物与酸成盐,包括无机酸和有机酸;与碱成盐,碱为碱金属的氢氧化物。与酸形成的可药用加成盐包括无机酸和有机酸加成盐,与下列酸加成的盐是特别优选的:盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘二磺酸、乙酸、丙酸、乳酸、三氟乙酸、马来酸、柠檬酸、富马酸、草酸、酒石酸、苯甲酸等。
此外,本发明还包括本发明衍生物的前药。本发明衍生物的前药是通式Ⅰ的衍生物,它们自身可能具有较弱的活性甚至没有活性,但是在给药后,在生理条件下(例如通过代谢、溶剂分解或另外的方式)被转化成相应的生物活性形式。
本发明可以含有上式Ⅰ的1,3,5-三嗪类衍生物及其药学上可接受的盐、水合物或溶剂化物作为活性成份,与药学上可接受的载体或赋形剂混合制备成组合物,并制备成临床上可接受的剂型,上述药学上可接受的赋形剂是指任何可用于药学领域的稀释剂、辅助剂和/或载体。本发明的衍生物可以与其他活性成份组合使用,只要它们不产生其他不利的作用,例如过敏反应。
本发明上式Ⅰ的1,3,5-三嗪类衍生物用于患者的临床剂量可以根据:活性成分在体内的治疗功效和生物利用度、它们的代谢和排泄速率和患者的年龄、性别、疾病期来进行适当调整,不过成人的每日剂量一般应当为10-1000mg,优选为50-500mg。因此,当本发明的药物组合物被制成单位剂型时,考虑到上述有效剂量,每单位制剂应当含有10-500mg上式Ⅰ1,3,5-三嗪类衍生物,优选为50-300mg。按照医生或药师的指导,这些制剂可以以一定间隔分若干次给药(优选为一至六次)。
本发明的药用组合物可配制成若干种剂型,其中含有药物领域中一些常用的赋形剂。如上所述的若干种剂型可以采用注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、外用搽剂、软膏剂等剂型药物。
用于本发明药物组合物的载体是药物领域中可得到的常见类型,包括:粘合剂、润滑剂、崩解剂、助溶剂、稀释剂、稳定剂、悬浮剂、无色素、矫味剂、防腐剂、加溶剂和基质等。药物制剂可以经口服或胃肠外方式(例如静脉内、皮下、腹膜内或局部)给药,如果某些药物在胃部条件下不稳定的,可将其配制成肠衣片剂。
本发明的活性化合物或其可药用盐及其溶剂化物可作为唯一的抗增生性药物单独使用,或者可以与现已上市的抗增生性药物联合使用,用于治疗和/或预防增生性疾病,如牛皮癣、良性前列腺肥大、动脉粥样硬化和再狭窄。
我们已发现本发明化合物体外具有抑制肿瘤细胞生长活性,因此,它可以用作制备治疗和/或预防癌症的药物,如乳腺、肺、肝脏、肾脏、结肠、直肠、胃、前列腺、膀胱、子宫、胰腺、骨髓、睾丸、卵巢、淋巴、软组织、头颈、甲状腺、食道的癌和白血病、成神经细胞瘤等。
通过体外抑制非小细胞肺癌细胞株H1975,人体肺腺癌上皮细胞株A549,非小细胞肺癌细胞株PC9,人结肠癌细胞株HCT116,人乳腺癌细胞株BT549,鼻咽癌细胞株CNE2,人结肠癌细胞株SW945活性试验,本发明化合物对肺癌细胞、结肠癌细胞、乳腺癌以及鼻咽癌细胞具有显著抑制作用。
本发明的活性化合物或其可药用盐及其溶剂化物可作为唯一的抗肿瘤药物单独使用,或者可以与现已上市的抗肿瘤药物(如铂类药物顺铂、喜树碱类药物伊立替康、长春花碱类药物诺维本、脱氧胞昔类药物吉西他滨、足叶乙甙、紫杉醇等)联合使用。联合治疗通过将各个治疗组分同时、顺序或隔开给药来实现。
下文中提供的实施例和制备例进一步阐明和举例说明本发明化合物及其制备方法。应当理解,下述实例和制备例的范围并不以任何方式限制本发明的范围。
下面的合成路线(路线1)描述了本发明的式Ⅰ衍生物的制备,所有的原料都是通过这些合成路线中描述的方式、通过有机化学领域普通技术人员熟知的方法制备的或者可商购。本发明的全部最终衍生物都是通过这些合成路线中描述的方法或通过与其类似的方法制备的,这些方法是有机化学领域普通技术人员熟知的。这些合成路线中应用的全部可变因数如下文的定义或如权利要求中的定义。
路线1
按照本发明的式Ⅰ衍生物,均可按照路线1的方法由相应的中间体反应制备得到,中间体的取代基R1和R2如权利要求中所定义。
本发明提供了一系列结构新颖的新型1,3,5-三嗪类衍生物及其制备方法,并对所合成的化合物进行生物活性测试,所述化合物具有抗肿瘤的性质。发现了部分衍生物的抗肿瘤活性较好,从而对该类化合物进行了较为深入的研究,达到了本发明的目的。
具体实施方式
实施例旨在阐述而不是限制本发明的范围。
(一)中间体的制备:
(1)4-(4,6-二氯-1,3,5-三嗪-2-基)吗啉(2)的合成
在500mL三颈瓶中依次加入10.60g(100mmol)无水碳酸钠、120mL水,搅拌溶解后,0℃下加入18.44g(100mmol)2,4,6-三氯-1,3,5-三嗪(1),搅拌均匀后,将含有8.71g(100mol)吗啉的水(25mL)溶液缓慢滴入体系中,30min内滴加完毕,并保持温度0-5℃,反应3h,减压过滤,滤饼以少量水洗,干燥,得白色粉末状固体18.54g,粗品收率78.94%。
(2)4-{4-氯-6-[2-(二氟甲基)-1H-苯并[d]咪唑-1-基]-1,3,5-三嗪-2-基}吗啉(4)的合成
500mL单口瓶中依次加入4-(4,6-二氯-1,3,5-三嗪-2-基)吗啉(2)11.33g(48.2mmol)、无水碳酸钾6.66g(48.2mmol)、DMF150mL搅拌下加入2-二氟甲基-1H-苯并咪唑(3)8.10g(48.2mmol),室温反应2h,加水200mL,静置,析出固体,减压过滤,以少量水洗,干燥,得白色粉末状固体15.21g,粗品收率86.03%。
(3)叔丁基-4-{4-[2-(二氟甲基)-1H-苯并[d]咪唑-1-基]-6-(吗啉基)-1,3,5-三嗪-2-基}哌嗪基-1-羧酸酯(5)的合成
100mL单口瓶中加入4-{4-氯-6-[2-(二氟甲基)-1H-苯并[d]咪唑-1-基]-1,3,5-三嗪-2-基}吗啉(4)1.47g(4mmol),无水碳酸钾1.10g(8mmol),N-叔丁氧羰基哌嗪1.49g(8mmol),四氢呋喃50mL,回流反应1h,冷却,减压蒸干溶剂,加水50mL,乙酸乙酯50mL×3萃取,合并有机相,以无水硫酸钠干燥,过滤,滤液减压蒸干,得白色粉末状固体0.83g,40.08%。
(4)4-{4-(哌嗪-1-基)-6-[2-(二氟甲基)-1H-苯并[d]咪唑-1-基]-1,3,5-三嗪-2-基}吗啉(6)的合成
50mL单口瓶中加入中间体50.80g(1.55mmol),二氯甲烷:三氟乙酸(1:1)15mL,室温下搅拌30min,减压蒸除二氯甲烷,加水20mL,以2NNaOH调pH至中性,过滤,以少量水洗,干燥,得白色粉末状固体0.62g,96.76%。1HNMR(400MHz,DMSO-d6)δppm8.33(d,J=8.0Hz,1H),7.84(d,J=8.3Hz,1H),7.72(t,JHF=53.8Hz,1H),7.53-7.38(m,2H),7.42(s,1H),3.82-3.77(m,4H),3.77-3.72(m,4H),3.31(brs,4H),2.78(brs,4H);MS(ESI)m/z417.2[M+H]+。
(5)2-氯-1-(4-(4-(2-(二氟甲基)-1H-苯并[d]咪唑-1-基)-6-吗啉基-1,3,5-三嗪-2-基)哌嗪-1-基)乙基-1-酮(7)的合成
50mL单口烧瓶中,加入0.83g(2mmol)中间体6,二氯甲烷20mL,三乙胺0.56mL(4mmol),冰盐浴下滴加氯乙酰氯0.32mL(4mmol)的二氯甲烷溶液5mL,5min内滴加完毕,冰盐浴下搅拌1h,室温搅拌2h。反应完毕,蒸干溶剂及酰氯,加水20mL,并二氯甲烷20mL×3萃取,合并有机层,以饱和氯化钠溶液洗涤,再以无水硫酸钠干燥,过滤,滤液减压蒸干,得白色粉末状固体0.79g,产率80.0%,粗品直接投入下一步,MS(ESI)m/z507.1[M+H]+。
(二)目标产物的合成制备:
合成通法一:
50mL单口烧瓶中加入中间体70.70g(1.42mmol),四氢呋喃15mL,Na2CO30.31g(2.82mmol),KI0.01g(0.06mmol),搅拌下加入仲胺或伯胺2.84mmol,回流反应1h.。
实施例1:1-{4-[4-(2-(二氟甲基)-1H-苯并[d]咪唑-1-基)-6-吗啉基-1,3,5-三嗪-2-基]哌嗪-1-基}-2-吗啉基-1-酮(M-01)的合成
以吗啉为原料,按合成通法一,反应完毕后,冷却至室温,加水25mL,静置,析出固体,减压过滤,以少量水洗,干燥,粗品以95%乙醇重结晶,产率77.9%。1HNMR(400MHz,DMSO-d6)δ8.33(d,J=8.1Hz,1H),7.84(d,J=7.9Hz,1H),7.74(t,J=53.40Hz,1H),7.46(m,2H),3.83-3.52(m,22H),2.46-2.38(brs,4H).
实施例2:1-{2-[4-(4-(2-(二氟甲基)-1H-苯并[d]咪唑-1-基)-6-吗啉基-1,3,5-三嗪-2-基)哌嗪-1-基]-2-氧代乙基}哌啶-4-酮(M-02)的合成
以4-哌啶酮为原料,按合成通法一,反应完毕后,冷却至室温,加水25mL,静置,析出固体,减压过滤,以少量水洗,干燥,粗品以95%乙醇重结晶,产率77.4%。1HNMR(400MHz,CDCl3)δ8.32(d,J=7.9Hz,1H),7.88(d,J=7.8Hz,1H),7.55(t,J=53.60Hz,1H),7.47-7.38(m,2H),3.99-3.71(m,18H),2.88(t,J=5.8Hz,4H),2.50(t,J=5.8Hz,4H).
实施例3:1-{4-[4-(2-(二氟甲基)-1H-苯并[d]咪唑-1-基)-6-吗啉基-1,3,5-三嗪-2-基]哌嗪-1-基}-2-(4-羟基哌啶-1-基)乙-1-酮(M-03)的合成
以4-羟基哌啶为原料,按合成通法一,反应完毕后,冷却至室温,加水25mL,静置,析出固体,减压过滤,以少量水洗,干燥,粗品以95%乙醇重结晶,产率75.4%。1HNMR(400MHz,DMSO-d6)δ8.38(d,J=8.0Hz,1H),7.89(d,J=7.7Hz,1H),7.78(t,J=52.60Hz,1H),7.51(m,2H),3.96-3.69(m,18H),2.51(m,4H).
实施例4:1-{4-[4-(2-(二氟甲基)-1H-苯并[d]咪唑-1-基)-6-吗啉基-1,3,5-三嗪-2-基]哌嗪-1-基}-2-(1H-咪唑-1-基)乙-1-酮(M-04)的合成
以咪唑为原料,按合成通法一,反应完毕后,冷却至室温,加水25mL,静置,析出固体,减压过滤,以少量水洗,干燥,粗品以95%乙醇重结晶,产率84.6%。1HNMR(400MHz,DMSO-d6)δ8.34(s,1H),7.85(s,1H),7.75(s,1H),7.66-7.54(brs,1H),7.53-7.37(m,2H),7.09(s,1H),6.90(s,1H),5.10(s,2H),3.95-3.64(m,16H).
实施例5:1-{4-[4-(2-(二氟甲基)-1H-苯并[d]咪唑-1-基)-6-吗啉基-1,3,5-三嗪-2-基]哌嗪-1-基}-2-((2-羟基乙基)氨基)乙-1-酮(M-05)的合成
以2-氨基乙醇为原料,按合成通法一,反应完毕后,冷却至室温,加水25mL,静置,析出固体,减压过滤,以少量水洗,干燥,粗品以95%乙醇重结晶,产率75%。1HNMR(400MHz,CDCl3)δ8.32(d,J=7.7Hz,1H),7.89(d,J=7.8Hz,1H),7.55(t,J=53.40Hz,1H),7.48-7.38(m,2H),3.98-3.59(m,20H),2.88(s,2H).
实施例6:1-{4-[4-(2-(二氟甲基)-1H-苯并[d]咪唑-1-基)-6-吗啉基-1,3,5-三嗪-2-基]哌嗪-1-基}-2-(2-(哌啶-1-基))乙-1-酮(M-06)的合成
以4-哌啶酮盐酸盐一水合物为原料,按合成通法一,反应完毕后,冷却至室温,加水25mL,静置,析出固体,减压过滤,以少量水洗,干燥,粗品以95%乙醇重结晶,产率74.8%。1HNMR(400MHz,CDCl3)δ8.33(d,J=7.9Hz,1H),7.89(d,J=7.7Hz,1H),7.57(t,J=53.20Hz,1H),7.48-7.38(m,2H),3.95-3.71(m,18H),2.45(brs,4H),1.64-1.44(m,6H).
实施例7:1-{4-[4-(2-(二氟甲基)-1H-苯并[d]咪唑-1-基)-6-吗啉基-1,3,5-三嗪-2-基]哌嗪-1-基}-2-(4-甲基哌啶-1-基)乙-1-酮(M-07)的合成
以4-甲基哌啶为原料,按合成通法一,反应完毕后,冷却至室温,加水25mL,静置,析出固体,减压过滤,以少量水洗,干燥,粗品以95%乙醇重结晶,产率75.4%。1HNMR(400MHz,DMSO-d6)δ8.38(d,J=8.0Hz,1H),7.89(d,J=7.7Hz,1H),7.78(t,J=52.60Hz,1H),7.51(m,2H),3.95-3.60(m,18H),0.91(s,3H).
实施例8:1-{4-[4-(2-(二氟甲基)-1H-苯并[d]咪唑-1-基)-6-吗啉基-1,3,5-三嗪-2-基]哌嗪-1-基}-2-(3-甲基哌啶-1-基)乙-1-酮(M-08)的合成
以3-甲基哌啶为原料,按合成通法一,反应完毕后,冷却至室温,加水25mL,静置,析出固体,减压过滤,以少量水洗,干燥,粗品以95%乙醇重结晶,产率75.4%。1HNMR(400MHz,DMSO-d6)δ8.34(d,J=8.2Hz,1H),7.84(d,J=7.8Hz,1H),7.74(s,1H),7.61(s,1H),7.53(s,2H),3.88-3.53(m,18H),0.82(d,J=5.4Hz,4H).
实施例9:1-{4-[4-(2-(二氟甲基)-1H-苯并[d]咪唑-1-基)-6-吗啉基-1,3,5-三嗪-2-基]哌嗪-1-基}-2-(2-甲基哌啶-1-基)乙-1-酮(M-09)的合成
以2-甲基哌啶为原料,按合成通法一,反应完毕后,冷却至室温,加水25mL,静置,析出固体,减压过滤,以少量水洗,干燥,粗品以95%乙醇重结晶,产率75.4%。1HNMR(400MHz,CDCl3)δ8.34(d,J=8.0Hz,1H),7.90(d,J=7.8Hz,1H),7.58(s,1H),7.44(m,2H),4.14-3.54(m,18H)1.12(d,J=6.2Hz,3H).
实施例10:1-{4-[4-(2-(二氟甲基)-1H-苯并[d]咪唑-1-基)-6-吗啉基-1,3,5-三嗪-2-基]哌嗪-1-基}-2-(4-甲基哌嗪-1-基)乙-1-酮(M-10)的合成
以N-甲基哌嗪为原料,按合成通法一,反应完毕后,冷却至室温,加水25mL,静置,析出固体,减压过滤,以少量水洗,干燥,粗品以95%乙醇重结晶,产率73.8%。1HNMR(400MHz,CDCl3)δ8.33(d,J=7.8Hz,1H),7.89(d,J=7.6Hz,1H),7.56(s,1H),7.47-7.37(m,2H),3.95-3.66(m,18H),2.58(brs,8H),2.30(s,3H).
实施例11:1-{4-[4-(2-(二氟甲基)-1H-苯并[d]咪唑-1-基)-6-吗啉基-1,3,5-三嗪-2-基]哌嗪-1-基}-2-(二乙基氨基)乙-1-酮(M-11)的合成
以二乙胺为原料,按合成通法一,反应完毕后,冷却至室温,加水25mL,静置,析出固体,减压过滤,以少量水洗,干燥,粗品以95%乙醇重结晶,产率76.1%。1HNMR(400MHz,CDCl3)δ8.33(d,J=8.1Hz,1H),7.88(d,J=7.8Hz,1H),7.56(t,J=53.30Hz,1H),7.47-7.36(m,2H),3.96-3.66(m,18H),2.64-2.54(m,4H),1.06(t,6H).
本发明产物的抗肿瘤活性研究
体外抗肿瘤细胞活性
体外抗肿瘤活性研究方法:MTT法,全称为四甲基偶氮唑盐(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide)比色法。此方法操作简单、快速而且灵敏度高,在体外抗肿瘤活性实验中经常使用。我们应用了此方法,对所合成的13个目标化合物进行了抗肿瘤活性测试。选用非小细胞肺癌细胞株H1975,人体肺腺癌上皮细胞株A549,非小细胞肺癌细胞株PC9,人结肠癌细胞株HCT116,人乳腺癌细胞株BT549,鼻咽癌细胞株CNE2,人结肠癌细胞株SW945七种细胞。
实验原理:MTT比色法是用来检测细胞存活和生长的方法。MTT是一种黄颜色的染料,它易被水溶解,透过细胞膜进入细胞内部。在活细胞内,线粒体中的琥珀脱氢酶可以将MTT还原,形成蓝紫色结晶甲瓒(Formazan),此结晶不溶于水,沉积在细胞中。在死细胞内,上述的还原反应不会发生,因此也不会有甲瓒生成。甲瓒结晶可溶于酸性异丙醇、二甲基亚砜等有机溶剂,通过酶联免疫检测仪,在490nm波长处测定光吸收度(OD值),由于甲瓒结晶形成的量与活细胞数量成正比例相关,因此光吸收度的大小可间接反应活细胞的数量。
实验方法:1.在96孔板中加入浓度为1×105μg/mL的细胞悬液,每孔100μL,将上述孔板置于5%CO2培养箱中,37℃孵育24h。
2.将不同浓度的受试目标化合物溶液加到上一步的孔板中,继续培养24h。
3.弃除培养液,加入0.05%MTT应用液,每孔100μL,培养4h。
4.弃除培养液,每孔加入100μLDMSO,振荡5min使甲瓒颗粒完全溶解,测定490nm处的吸光度(OD值)。
按照如下方法处理实验数据:
公式:抑制率(%)=(空白对照组OD平均值-样品组OD平均值度)/空白对照组OD平均值×100%计算。再经软件计算,得出受试药物对各种肿瘤细胞生长的半数抑制浓度(IC50)。
(结果列于表1中)
表1.本发明的部分化合物的体外细胞毒活性结果
本发明的化合物的PI3Kα酶活性试验
用于测量PI3Kα激酶活性的试验基于酶联免疫吸附试验(ELISA)。具体操作是:
室温下,在0.25mg/mLPGT包被的板上,将实施例化合物、50pMPI3Kα和5μMATP在试验缓冲液中(25mMMOPS,pH7.4,0.5mMMgCl2,0.5mMMnCl2,100μM原钒酸钠,0.01%TritonX-100,1mMDTT,最后DMSO浓度1%(v/v))温育20分钟。通过冲洗除去反应混合物并用0.2μg/mL缀合辣根过氧化物酶(HRP)的磷酸酪氨酸特异性单克隆抗体(PY20)检测磷酸化聚合物底物。加入1M磷酸终止显色后,于450nm处通过分光光度法定量显色的底物(TMB)的颜色。实施例化合物对PI3Kα激酶的抑制数据见表2。
表2
从上述试验结果可以清楚地看出,本发明所要保护的通式Ⅰ的化合物,具有良好的体外抗肿瘤活性。
典型的制剂:
其中的1,3,5-三嗪类衍生物可以以任意一个化合物作为活性成分。
实施例1
每片含10mg活性成分的片剂制备如下:
将活性成分,淀粉和纤维素过筛,并充分混合,将聚乙烯吡咯烷酮溶液与上述的粉混合,过筛,制得湿颗粒于50-60℃干燥,将羧甲基淀粉钠盐,硬脂酸镁和滑石粉预先过筛,然后加入到上述的颗粒中压片。
实施例2
每囊含100mg活性成分的胶囊的制备如下:
Claims (10)
1.通式Ⅰ的化合物及其药学上可接受的盐、水合物、溶剂化物或前药,
其中:
R1和R2相同,分别独立地选自氢、(C1-C10)烷基、(C3-C7)环烷基、(C2-C10)烯基和(C2-C10)炔基,它们可以被1-3个相同或不同的R3任选取代;
或R1和R2与和它们所连接的氮原子一起形成5-10元杂环基或5-10元杂芳基,所述杂环基和杂芳基可以任选被1-3个相同或不同的R4取代;
除了与R1和R2连接的氮原子外,所述杂环基和杂芳基可以任选含有1-4个选自N、O和S的杂原子,所述杂环基还可以任选包括1或2个碳碳双键或叁键;
R3、R4为(C1-C4)烷基、(C1-C4)烷氧基、卤代、羟基、氰基、羧基、(C1-C10)酯基。
2.权利要求1所述的通式Ⅰ所示的1,3,5-三嗪类化合物及其药学上可接受的盐、水合物、溶剂化物或前药,
其中,
R1和R2相同或不同,分别独立地选自氢、(C1-C4)烷基、(C3-C7)环烷基、(C2-C4)烯基和(C2-C4)炔基,它们可以被1-3个相同或不同的R3任选取代;
或R1和R2与和它们所连接的氮原子一起形成5-10元杂环基或5-10元杂芳基,所述杂环基和杂芳基可以任选被1-3个相同或不同的R4取代;
除了R1和R2所连接的氮原子外,所述杂环基和杂芳基可以任选含有1-4个选自N、O和S的杂原子。
3.权利要求1或2所述的通式Ⅰ所示的1,3,5-三嗪类化合物及其药学上可接受的盐、水合物、溶剂化物或前药,
其中,
R1和R2相同或不同,分别独立地选自氢、(C1-C4)烷基,它们可以被1-3个相同或不同的R3任选取代;
或R1和R2与和它们所连接的氮原子一起形成5-10元杂环基或5-10元杂芳基,所述杂环基和杂芳基可以任选被1-3个相同或不同的R4取代;
除了R1和R2所连接的氮原子外,所述杂环基和杂芳基可以任选含有1-4个选自N、O和S的杂原子。
4.权利要求1-3任何一项所述的通式Ⅰ所示的1,3,5-三嗪类化合物及其药学上可接受的盐、水合物、溶剂化物或前药,
其中,
R1和R2相同或不同,分别独立地选自氢、(C1-C4)烷基、羟基取代的(C1-C4)烷基;
或R1和R2与和它们所连接的氮原子一起形成吗啉基、4-哌啶酮基、4-羟基哌啶基、咪唑基、哌啶基、4-甲基哌啶基、3-甲基哌啶基、2-甲基哌啶基、4-甲基-1-哌嗪基。
5.权利要求1-4任何一项所述的通式Ⅰ所示的1,3,5-三嗪类化合物及其药学上可接受的盐、水合物、溶剂化物或前药,
其中,
R1和R2相同或不同,分别独立地选自氢、(C1-C4)烷基,羟乙基;
或R1和R2与和它们所连接的氮原子一起形成吗啉基、4-哌啶酮基、4-羟基哌啶基、咪唑基、哌啶基、4-甲基哌啶基、3-甲基哌啶基、2-甲基哌啶基、4-甲基-1-哌嗪基。
6.权利要求1-5任何一项所述的通式Ⅰ的化合物及其药学上可接受的盐、水合物、溶剂化物或前药:
M-01:1-{4-[4-(4-(2-(二氟甲基)-1H-苯并[d]咪唑-1-基)-6-吗啉基-1,3,5-三嗪-2-基]哌嗪-1-基}-2-吗啉基-1-酮;
M-02:1-{2-[4-(4-(2-(二氟甲基)-1H-苯并[d]咪唑-1-基)-6-吗啉基-1,3,5-三嗪-2-基)哌嗪-1-基]-2-氧代乙基}哌啶-4-酮;
M-03:1-{4-[4-(2-(二氟甲基)-1H-苯并[d]咪唑-1-基)-6-吗啉基-1,3,5-三嗪-2-基]哌嗪-1-基}-2-(4-羟基哌啶-1-基)乙-1-酮;
M-04:1-{4-[4-(2-(二氟甲基)-1H-苯并[d]咪唑-1-基)-6-吗啉基-1,3,5-三嗪-2-基]哌嗪-1-基}-2-(1H-咪唑-1-基)乙-1-酮;
M-05:1-{4-[4-(2-(二氟甲基)-1H-苯并[d]咪唑-1-基)-6-吗啉基-1,3,5-三嗪-2-基]哌嗪-1-基}-2-((2-羟基乙基)氨基)乙-1-酮;
M-06:1-{4-[4-(2-(二氟甲基)-1H-苯并[d]咪唑-1-基)-6-吗啉基-1,3,5-三嗪-2-基]哌嗪-1-基}-2-(2-(哌啶-1-基))乙-1-酮;
M-07:1-{4-[4-(2-(二氟甲基)-1H-苯并[d]咪唑-1-基)-6-吗啉基-1,3,5-三嗪-2-基]哌嗪-1-基}-2-(4-甲基哌啶-1-基)乙-1-酮;
M-08:1-{4-[4-(2-(二氟甲基)-1H-苯并[d]咪唑-1-基)-6-吗啉基-1,3,5-三嗪-2-基]哌嗪-1-基}-2-(3-甲基哌啶-1-基)乙-1-酮;
M-09:1-{4-[4-(2-(二氟甲基)-1H-苯并[d]咪唑-1-基)-6-吗啉基-1,3,5-三嗪-2-基]哌嗪-1-基}-2-(2-甲基哌啶-1-基)乙-1-酮;
M-10:1-{4-[4-(2-(二氟甲基)-1H-苯并[d]咪唑-1-基)-6-吗啉基-1,3,5-三嗪-2-基]哌嗪-1-基}-2-(4-甲基哌嗪-1-基)乙-1-酮;
M-11:1-{4-[4-(2-(二氟甲基)-1H-苯并[d]咪唑-1-基)-6-吗啉基-1,3,5-三嗪-2-基]哌嗪-1-基}-2-(二乙基氨基)乙-1-酮。
7.一种药用组合物,包含权利要求1-6中任何一项的化合物及其药学上可接受的盐、水合物、溶剂化物或前药作为活性成分以及药学上可接受的赋形剂。
8.权利要求1-6中任何一项的化合物及其药学上可接受的盐、水合物、溶剂化物或前药在或权利要求7所述的药用组合物在制备治疗和/或预防增生性疾病药物中的应用。
9.权利要求1-6中任何一项的化合物及其药学上可接受的盐、水合物、溶剂化物或前药或权利要求7所述的药用组合物在制备治疗和/或预防癌症的药物中的应用。
10.权利要求1-6中任何一项的化合物及其药学上可接受的盐、水合物、溶剂化物或前药或权利要求7所述的药用组合物在制备治疗和/或预防肺癌、结肠癌、鼻咽癌、乳腺癌的药物中的应用。
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JO-ANNE PINSON ET AL.: "L‑Aminoacyl-triazine Derivatives Are Isoform-Selective PI3Kβ Inhibitors That Target Nonconserved Asp862 of PI3Kβ", 《ACS MEDICINAL CHEMISTRY LETTERS》 * |
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