CN115703734A - 二芳基甲基吡啶类化合物及其制备方法和应用 - Google Patents
二芳基甲基吡啶类化合物及其制备方法和应用 Download PDFInfo
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- CN115703734A CN115703734A CN202110898403.2A CN202110898403A CN115703734A CN 115703734 A CN115703734 A CN 115703734A CN 202110898403 A CN202110898403 A CN 202110898403A CN 115703734 A CN115703734 A CN 115703734A
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- compound
- pharmaceutically acceptable
- diarylmethylpyridine
- substituted
- squamous cell
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- -1 Diaryl methyl pyridine compound Chemical class 0.000 title claims abstract description 53
- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- 150000001875 compounds Chemical class 0.000 claims abstract description 80
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 claims abstract description 15
- 201000000459 head and neck squamous cell carcinoma Diseases 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 12
- 206010018338 Glioma Diseases 0.000 claims abstract description 8
- 208000008443 pancreatic carcinoma Diseases 0.000 claims abstract description 8
- 208000032612 Glial tumor Diseases 0.000 claims abstract description 7
- 208000003445 Mouth Neoplasms Diseases 0.000 claims abstract description 5
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims description 29
- 238000006243 chemical reaction Methods 0.000 claims description 24
- 239000003814 drug Substances 0.000 claims description 17
- 206010028980 Neoplasm Diseases 0.000 claims description 16
- 238000011282 treatment Methods 0.000 claims description 11
- 229940125904 compound 1 Drugs 0.000 claims description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 229940125782 compound 2 Drugs 0.000 claims description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 239000000243 solution Substances 0.000 claims description 7
- 239000004480 active ingredient Substances 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
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- 125000003118 aryl group Chemical group 0.000 claims description 5
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- BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 claims description 4
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 4
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- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
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- UNXISIRQWPTTSN-UHFFFAOYSA-N boron;2,3-dimethylbutane-2,3-diol Chemical compound [B].[B].CC(C)(O)C(C)(C)O UNXISIRQWPTTSN-UHFFFAOYSA-N 0.000 claims description 2
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Abstract
本发明公开了一种二芳基甲基吡啶类化合物及其制备方法和应用。该二芳基甲基吡啶类化合物具有式(I)所示结构。本发明的化合物对肿瘤细胞(尤其是头颈部鳞状细胞癌细胞系、胰腺癌细胞系、神经胶质瘤和口腔癌的细胞)的生长具有一定的抑制作用,具有较好的抗肿瘤活性,尤其是对头颈部鳞状细胞癌细胞表现出很好的抑制效果。本发明制备的二芳基甲基吡啶类化合物可应用于制备抗肿瘤药物,尤其是用作制备治疗头颈部鳞状细胞癌的抗肿瘤药物。本发明制备二芳基甲基吡啶类化合物的方法简单高效,化学选择性高,无金属催化,合成成本低。
Description
技术领域
本发明涉及化学医药技术领域,具体涉及一种二芳基甲基吡啶类化合物及其制备方法和应用。
背景技术
癌症是起源于上皮组织的恶性肿瘤,是以细胞的快速增殖和转移为特点的疾病,死亡率很高,是严重威胁人类生命和社会发展的重大疾病,因此,与癌症治疗有关的研究一直被全世界密切关注。
临床上治疗癌症的方式主要有:手术治疗、放射线治疗、化学治疗和免疫治疗等。恶性肿瘤有很多种,其性质类型各异、累及的组织和器官不同、病期不同、对各种治疗的反应也不同,因此大部分肿瘤患者需要进行综合治疗,就是根据患者的身体状况、肿瘤的病理类型、侵犯范围等情况,综合采用手术、化疗、放疗、免疫治疗、中医中药治疗、介入治疗、微波治疗等手段,以期较大幅度地提高治愈率,并改善患者的生活质量。
其中,化学治疗是用可以杀死癌细胞的药物治疗癌症。目前,在我国临床上治疗癌症疾病的传统药物有很多,但是往往具有特异性低,选择性差,毒副作用大,容易产生耐药等缺点。例如蒽环类抗肿瘤药物阿霉素,其抗瘤谱较广,可广泛用于肝癌、肺癌、乳腺癌、卵巢癌等的化疗;但其同时具有包括消化道、心脏的不良反应及骨髓抑制等毒副作用。因此,研发新的小分子抗肿瘤药物具有非常重要的意义。
发明内容
基于此,本发明提供了一类新的二芳基甲基吡啶类化合物,该类化合物具有良好的抗肿瘤活性,有发展成为抗肿瘤药物的潜力。
具体技术方案如下:
具有式(1)所示结构的二芳基甲基吡啶类化合物或者其药学上可接受的盐或者其立体异构体:
其中:
Ar选自:C6-C10芳基、一个或多个R2取代的C6-C12芳基、5-10元杂芳基、一个或多个R2取代的5-10元杂芳基;
R1选自:H、C1-C6烷基、C1-C6烷氧基;
R2选自:C1-C8烷基、C1-C8烷氧基、卤素、C1-C8烷氧基羰基、氰基、卤素取代的C1-C8烷基;
R选自:H、C1-C8烷基、C1-C8烷氧基、卤素;
n选自:1、2、3、4。
在其中一些实施例中,所述二芳基甲基吡啶类化合物具有式(II)所示结构:
在其中一些实施例中,Ar选自:苯基、一个或两个R2取代的苯基、萘基、一个或两个R2取代的萘基、噻吩基、一个或两个R2取代的噻吩基、吲哚基、一个或两个R2取代的吲哚基。
在其中一些实施例中,R2选自:C1-C4烷基、C1-C4烷氧基、卤素、C1-C4烷氧基羰基、氰基、三氟甲基。
在其中一些实施例中,Ar选自:苯基、4-甲氧基苯基、2-甲基苯基、3-甲基苯基、2-甲氧基苯基、3,4-二甲基苯基、4-氟苯基、4-氯苯基、4-溴苯基、2-溴苯基、4-甲氧羰基苯基、4-氰基苯基、4-三氟甲基苯基、2-萘基、4-溴噻吩-2-基、2-甲基-1H-吲哚-3-基。
在其中一些实施例中,R选自:H、溴、氟、氯。
本发明还提供了上述的二芳基甲基吡啶类化合物的制备方法。
具体技术方案如下:
一种上述的二芳基甲基吡啶类化合物的制备方法,包括如下步骤:
(1)在惰性气体或者氮气的保护下,化合物1和化合物2在联硼酸频那醇酯的作用下反应;
(2)将步骤(1)得到的反应混合液冷却至室温,然后加入饱和碳酸氢钠溶液,在空气氛围下搅拌,即得;
所述化合物1和化合物2的结构式如下:
在其中一些实施例中,所述化合物1、化合物2和联硼酸频那醇酯的摩尔比为1:1-2:1.0-1.5。
在其中一些实施例中,所述化合物1、化合物2和联硼酸频那醇酯的摩尔比为1:1.4-1.6:1.1-1.3。
在其中一些实施例中,所述反应的溶剂为甲基叔丁基醚。
在其中一些实施例中,所述溶剂的用量与所述化合物1的配比为1mmol:4-8mL。
在其中一些实施例中,所述反应的温度为50℃-80℃,反应的时间为18h-30h。
在其中一些实施例中,所述反应的温度为70℃-80℃,反应的时间为22h-26h。
在其中一些实施例中,所述饱和碳酸氢钠溶液的用量与所述化合物1的配比为1mmol:8-16mL。
在其中一些实施例中,步骤(2)中所述搅拌的时间为12分钟-18分钟。
本发明还提供了上述的二芳基甲基吡啶类化合物或者其药学上可接受的盐或者其立体异构体的应用。
具体技术方案如下:
上述的二芳基甲基吡啶类化合物或者其药学上可接受的盐或者其立体异构体在制备预防和/或治疗肿瘤的药物中的应用。
在其中一些实施例中,所述肿瘤为:头颈部鳞状细胞癌、胰腺癌、神经胶质瘤。
在其中一些实施例中,所述头颈部鳞状细胞癌为口腔癌、人舌鳞状细胞癌。
本发明还提供了一种预防和/或治疗肿瘤的药物组合物。
具体技术方案如下:
一种预防和/或治疗肿瘤的药物组合物,包括活性成分以及药学上可接受的辅料和/或载体,所述活性成分包括有上述的二芳基甲基吡啶类化合物或者其药学上可接受的盐或者其立体异构体。
本发明开发了一种简单高效的无金属催化的自由基交叉偶联方法,通过B2(pin)2和4-氰基吡啶反应体系的自由基加成/偶联途径,以优异的化学选择性合成了一系列新的二芳基甲基吡啶类化合物。这类化合物对肿瘤细胞(尤其是头颈部鳞状细胞癌细胞系、胰腺癌细胞系和神经胶质瘤的细胞)的生长具有一定的抑制作用,具有较好的抗肿瘤活性,尤其是对头颈部鳞状细胞癌细胞表现出很好的抑制效果。本发明制备的二芳基甲基吡啶类化合物可应用于制备抗肿瘤药物,尤其是用作制备治疗头颈部鳞状细胞癌的抗肿瘤药物。
本发明制备二芳基甲基吡啶类化合物的方法简单高效,化学选择性高,无金属催化,合成成本低。
附图说明
图1为10μM的化合物3a-3s对人舌鳞状细胞癌细胞系、胰腺癌细胞系和神经胶质瘤细胞的生长能力影响。
图2为不同浓度的化合物3o对头颈部鳞状细胞癌细胞活力的影响。
图3为5μM的化合物3o对SCC15细胞活力的影响。
图4为不同浓度的化合物3o对SCC15细胞的增殖能力的影响。
具体实施方式
本发明所述化合物中,当任何变量(例如R等)在任何组分中出现超过一次,则其每次出现的定义独立于其它每次出现的定义。同样,允许取代基及变量的组合,只要这种组合使化合物稳定。自取代基划入环系统的线表示所指的键可连接到任何能取代的环原子上。如果环系统为多环,其意味着这种键仅连接到邻近环的任何适当的碳原子上。要理解本领域普通技术人员可选择本发明化合物的取代基及取代型式而提供化学上稳定的并可通过本领域技术和下列提出的方法自可容易获得的原料容易的合成的化合物。如果取代基自身被超过一个基团取代,应理解这些基团可在相同碳原子上或不同碳原子上,只要使结构稳定。
本文所用术语“烷基”意指包括具有特定碳原子数目的支链的和直链的饱和脂肪烃基。例如,“C1-C6烷基”中“C1-C6”的定义包括以直链或支链排列的具有1、2、3、4、5或6个碳原子的基团。例如,“C1-C6烷基”具体包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、戊基、己基。
术语“烷氧基”指烷基与氧直接连接的基团,即具有-O-烷基结构的基团,如-OCH3、-OCH2CH3、-OCH2CH2CH3、-O-CH2CH(CH3)2、-OCH2CH2CH2CH3、-O-CH(CH3)2等。
术语“杂芳基”指含有1个或多个选自O、N或S的杂原子的芳香环,本发明范围内的杂芳基包括但不限于:喹啉基、吡唑基、吡咯基、噻吩基、呋喃基、吡啶基、嘧啶基、吡嗪基、三氮唑基、咪唑基、噁唑基、异噁唑基、哒嗪基、苯并呋喃基、苯并噻吩基、苯并恶唑、吲哚基等;“杂芳基”也理解为包括任何含有氮的杂芳基的N-氧化物衍生物。
术语“取代的”是指用指定取代基的基团置换特定结构中的氢基。
正如本领域技术人员所理解的,本文中所用“卤素”(“halo”)或“卤”意指氯、氟、溴和碘。
本发明包括式(Ⅰ)或者式(ⅠI)化合物的游离形式,也包括其药学上可接受的盐及立体异构体。可通过常规化学方法自含有碱性部分或酸性部分的本发明化合物合成本发明的药学上可接受的盐。通常,通过离子交换色谱或通过游离碱和化学计算量或过量的所需盐形式的无机或有机酸在适当溶剂或多种溶剂的组合中反应制备碱性化合物的盐。类似的,通过和适当的无机或有机碱反应形成酸性化合物的盐。
因此,本发明化合物的药学上可接受的盐包括通过碱性本发明化合物和无机或有机酸反应形成的本发明化合物的常规无毒盐。例如,常规的无毒盐包括得自无机酸例如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等的盐,也包括自有机酸例如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、扑酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、2一乙酰氧基一苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙基磺酸、三氟乙酸等制备的盐。
如果本发明化合物为酸性的,则适当的“药学上可接受的盐”指通过药学上可接受的无毒碱包括无机碱及有机碱制备的盐。得自无机碱的盐包括铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐、锌盐等。特别优选铵盐、钙盐、镁盐、钾盐和钠盐。得自药学上可接受的有机无毒碱的盐,所述碱包括伯胺、仲胺和叔胺的盐,取代的胺包括天然存在的取代胺、环状胺及碱性离子交换树脂例如精氨酸、甜菜碱、咖啡因、胆碱、N,N'-二苄基乙二胺、二乙胺、2一二乙基氨基乙醇、2一二甲基氨基乙醇、氨基乙醇、乙醇胺、乙二胺、N一乙基吗啉、N一乙基哌啶、葡萄糖胺、氨基葡萄糖、组氨酸、羟钴胺、异丙基胺、赖氨酸、甲基葡萄糖胺、吗啉、哌嗪,哌啶、呱咤、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨基丁三醇等。
Berg等,“Pharmaceutical Salts,”J.Pharm.Sci.’1977:66:1-19更详细描述了上文所述药学上可接受的盐及其它典型的药学上可接受的盐的制备。
在一个实施方案中,本发明提供了一种利用具有式(Ⅰ)或者式(ⅠI)所示结构的化合物及其药学可接受的盐或者立体异构体治疗人或其它哺乳动物肿瘤等过渡增殖性疾病或症状。
在一个实施方案中,本发明的化合物及其药学上可接受的盐可以用于治疗或控制头颈部鳞状细胞癌(优选为口腔癌、人舌鳞状细胞癌)、胰腺癌、神经胶质瘤。
联合用药:式Ⅰ-II化合物可以与已知的治疗或改进相似病状的其它药物联用。联合给药时,原来药物的给药方式&剂量保持不变,而同时或随后服用式Ⅰ-II化合物。当式Ⅰ-II化合物与其它一种或几种药物同时服用时,优选使用同时含有一种或几种已知药物和式I-II化合物的药用组合物。药物联用也包括在重叠的时间段服用式Ⅰ-II化合物与其它一种或几种已知药物。当式Ⅰ-II化合物与其它一种或几种药物进行药物联用时,式Ⅰ-II化合物或已知药物的剂量可能比它们单独用药时的剂量较低。
可以与式Ⅰ-II化合物进行药物联用的药物或活性成分包括但不局限为:
雌激素受体调节剂、雄激素受体调节剂、视网膜样受体调节剂、细胞毒素/细胞抑制剂、抗增殖剂、蛋白转移酶抑制剂、HMG-CoA还原酶抑制剂、HIV蛋白激酶抑制剂、逆转录酶抑制剂、血管生成抑制剂、细胞增殖及生存信号抑制剂、干扰细胞周期关卡的药物和细胞凋亡诱导剂,细胞毒类药物、酪氨酸蛋白抑制剂、EGFR抑制剂、VEGFR抑制剂、丝氨酸/苏氨酸蛋白抑制剂、Bcr-Abl抑制剂,c-Kit抑制剂,Met抑制剂,Raf抑制剂,MEK抑制剂,MMP抑制剂,拓扑异构酶抑制剂、组氨酸去乙酰化酶抑制剂、蛋白酶体抑制剂、CDK抑制剂,Bcl-2家族蛋白抑制剂,MDM2家族蛋白抑制剂、IAP家族蛋白抑制剂、STAT家族蛋白抑制剂、PI3K抑制剂、AKT抑制剂、整联蛋白阻滞剂、干扰素-α、白介素-12、COX-2抑制剂、p53、p53激活剂、VEGF抗体、EGF抗体等。
在一个实施方案中,可以与式Ⅰ-II化合物进行药物联用的药物或活性成分包括但不局限为:阿地白介素、阿仑膦酸、干扰素、阿曲诺英、别嘌醇、别嘌醇钠、帕洛诺司琼盐酸盐、六甲蜜胺、氨基格鲁米特、氨磷汀、氨柔比星、安丫啶、阿纳托唑、多拉司琼、aranesp、arglabin、三氧化二砷、阿诺新、5-氮胞苷、硫唑嘌呤、卡介苗或tice卡介苗、贝他定、醋酸倍他米松、倍他米松磷酸钠制剂、贝沙罗汀、硫酸博来霉素、溴尿甘、bortezomib、白消安、降钙素、阿来佐单抗注射剂、卡培他滨、卡铂、康士得、cefesone、西莫白介素、柔红霉素、苯丁酸氮芥、顺铂、克拉屈滨、克拉屈滨、氯屈磷酸、环磷酰胺、阿糖胞昔、达卡巴嗪、放线菌素D、柔红霉素脂质体、地塞米松、磷酸地塞米松、戊酸雌二醇、地尼白介素2、狄波美、地洛瑞林、地拉佐生、己烯雌酚、大扶康、多西他奇、去氧氟尿苷、阿霉素、屈大麻酚、钦-166-壳聚糖复合物、eligard、拉布立酶、盐酸表柔比星、阿瑞吡坦、表阿霉素、阿法依伯汀、红细胞生成素、依铂、左旋咪唑片、雌二醇制剂、17-β-雌二醇、雌莫司汀磷酸钠、炔雌醇、氨磷汀、羟磷酸、凡毕复、依托泊甙、法倔唑、他莫昔芬制剂、非格司亭、非那司提、非雷司替、氟尿苷、氟康唑、氟达拉滨、5-氟脱氧尿嘧啶核苷一磷酸盐、5-氟尿嘧啶、氟甲睾酮、氟他胺、福麦斯坦、1-β-D-阿糖呋喃糖胞噻啶-5’-硬脂酰磷酸酯、福莫司汀、氟维司群、丙种球蛋白、吉西他滨、吉妥单抗、甲磺酸伊马替尼、卡氮芥糯米纸胶囊剂、戈舍瑞林、盐酸格拉尼西隆、组氨瑞林、和美新、氢化可的松、赤型-羟基壬基腺嘌呤、羟基脲、替坦异贝莫单抗、伊达比星、异环磷酰胺、干扰素α、干扰素-α2、干扰素α-2A、干扰素α-2B、干扰素α-nl、干扰素α-n3、干扰素β、干扰素γ-la、白细胞介素-2、内含子A、易瑞沙、依立替康、凯特瑞、硫酸香菇多糖、来曲唑、甲酰四氢叶酸、亮丙瑞林、亮丙瑞林醋酸盐、左旋四咪唑、左旋亚叶酸钙盐、左甲状腺素钠、左甲状腺素钠制剂、洛莫司汀、氯尼达明、屈大麻酚、氮芥、甲钴胺、甲羟孕酮醋酸酯、醋酸甲地孕酮、美法仑、酯化雌激素、6-琉基嘌呤、美司钠、氨甲蝶呤、氨基乙酰丙酸甲酯、米替福新、美满霉素、丝裂霉素C、米托坦、米托葱醌、曲洛司坦、柠檬酸阿霉素脂质体、奈达铂、聚乙二醇化非格司亭、奥普瑞白介素、neupogen、尼鲁米特、三苯氧胺、NSC-631570、重组人白细胞介素1-β、奥曲肽、盐酸奥丹西隆、去氢氢化可的松口服溶液剂、奥沙利铂、紫杉醇、泼尼松磷酸钠制剂、培门冬酶、派罗欣、喷司他丁、溶链菌制剂、盐酸匹鲁卡品、毗柔比星、普卡霉素、卟吩姆钠、泼尼莫司汀、司替泼尼松龙、泼尼松、倍美力、丙卡巴脐、重组人类红细胞生成素、雷替曲塞、利比、依替膦酸铼-186、美罗华、力度伸-A、罗莫肽、盐酸毛果芸香碱片剂、奥曲肽、沙莫司亭、司莫司汀、西佐喃、索布佐生、唬钠甲强龙、帕福斯酸、干细胞治疗、链佐星、氯化锶-89、左旋甲状腺素钠、他莫昔芬、坦舒洛辛、他索那明、tastolactone、泰索帝、替西硫津、替莫唑胺、替尼泊苷、丙酸睾酮、甲睾酮、硫鸟嘌呤、噻替哌、促甲状腺激素、替鲁膦酸、拓扑替康、托瑞米芬、托西莫单抗、曲妥珠单抗、曲奥舒凡、维A酸、甲氨喋呤片剂、三甲基密胺、三甲曲沙、乙酸曲普瑞林、双羟萘酸曲普瑞林、优福定、尿苷、戊柔比星、维司力农、长春碱、长春新碱、长春酰胺、长春瑞滨、维鲁利秦、右旋丙亚胺、净司他丁斯酯、枢复宁、紫杉醇蛋白质稳定制剂、acolbifene、干扰素r-lb、affinitak、氨基喋呤、阿佐昔芬、asoprisnil、阿他美坦、阿曲生坦、BAY43-9006、阿瓦斯丁、CCI-779、CDC-501、西乐葆、西妥昔单抗、克立那托、环丙孕酮醋酸酯、地西他滨、DN-101、阿霉素-MTC、dSLIM、度他雄胺、edotecarin、依氟鸟氨酸、依喜替康、芬维A胺、组胺二盐酸盐、组氨瑞林水凝胶植入物、钬-166DOTMP、伊班膦酸、干扰素γ、内含子-PEG、ixabepilone、匙孔形血蓝蛋白、L-651582、兰乐肽、拉索昔芬、libra、lonafamib、米泼昔芬、米诺屈酸酯、MS-209、脂质体MTP-PE、MX-6、那法瑞林、奈莫柔比星、新伐司他、诺拉曲特、奥利默森、onco-TCS、osidem、紫杉醇聚谷氨酸酯、帛米酸钠、PN-401、QS-21、夸西洋、R-1549、雷洛昔芬、豹蛙酶、13-顺维A酸、沙铂、西奥骨化醇、T-138067、tarceva、二十二碳六烯酸紫杉醇、胸腺素αl、嘎唑呋林、tipifarnib、替拉扎明、TLK-286、托瑞米芬、反式MID-lo7R、伐司朴达、伐普肽、vatalanib、维替泊芬、长春氟宁、Z-100和唑来麟酸或它们的组合。
合成方法:除在文献中已知的或在实验程序中例证的标准方法外,可采用如下合成方案中的方法制备本发明化合物。结合下述的合成方案,能够对本发明中所述的化合物以及合成方法进行更好的理解。所述的合成方案描述了可以用于制备本发明中所述的化合物的方法,所述的方法仅仅是为说明目的的说明性方案描述,并不构成对本发明所具有的范围的限制。
联硼酸频哪醇酯(B2pin2)的B-B键可以活化4-氰基吡啶,得到吡啶稳定的硼自由基,该自由基具有Lewis酸性,能选择性的加成到C=X(X=O或N)的氧或氮上,进而诱导一系列的吡啶官能化的转化。目前文献报道的该策略合适的底物主要局限于含羰基的化合物如:醛、酮以及α,β-不饱和酮,得到相应的加成产物(吡啶化物);并且,当底物为共轭烯酮时,其化学选择性较差,会得到1,2或者1,4加成产物,难以控制以得到一种主产物。即,现有的B2pin2/4-氰基吡啶反应体系如下:
由此可以预见,对于更长的共轭烯酮底物,其化学选择性会更加难以调控,比如,对于双烯酮底物,可预知会有三种不同化学选择性产物:1,2加成产物,1,4加成产物和1,6加成产物,这将大大限制B2pin2/4-氰基吡啶反应体系在更长共轭烯酮底物的应用前景。因此,目前为止还没有将该反应策略应用到这一类底物的文献报道。长共轭烯酮底物的化学选择性如下:
如何将B2pin2/4-氰基吡啶反应体系运用到长共轭反应底物的同时能控制反应过程中的化学选择性是该合成策略目前遇到的重要挑战和难题。而本发明意外地发现,在合适的反应条件下,以对亚甲基苯醌(p-QMs)为反应原料,通过B2pin2/4-氰基吡啶反应体系可以高选择性的制备得到一系列的二芳基甲烷类化合物(1,6加成产物),而不会有1,2加成产物或1,4加成产物的产生。从而得到本发明实施例中的二芳基甲基吡啶类化合物的合成方法如以下反应式所示:
其中,Ar分别为:苯基、4-甲氧基苯基、2-甲基苯基、3-甲基苯基、2-甲氧基苯基、3,4-二甲基苯基、4-氟苯基、4-氯苯基、4-溴苯基、2-溴苯基、4-甲氧羰基苯基、4-氰基苯基、4-三氟甲基苯基、2-萘基、4-溴噻吩-2-基、2-甲基-1H-吲哚-3-基;R分别为:H或者溴、氟、氯。
以下实施例中化合物的合成方法具体包括如下步骤:
(1)10mL反应管中依次加入化合物1(0.2mmol)、化合物2(0.3mmol)、联硼酸频那醇酯(B2pin2,0.24mmol)和干燥的甲基叔丁基醚(MTBE,1mL),在氮气保护条件下,将所得混合物加热至80℃,反应24h。
(2)反应液冷却至室温,加入2mL饱和碳酸氢钠溶液,在空气中搅拌15分钟。然后将反应液用乙酸乙酯萃取(3×5mL),合并有机相,用无水硫酸钠干燥,旋干,残留物通过柱层析纯化得到目标化合物3。
以下实施例中制备的化合物的结构鉴定条件如下:
1HNMR,19F NMR和13CNMR均通过Bruker400M核磁共振仪测定,均以CDCl3为溶剂。1HNMR数据报告如下:化学位移,以ppm(δ)为单位,多重性(s=单峰,d=双重峰,t=三重峰,m=多重峰),偶合常数(Hz);13C NMR数据报告如下:化学位移(ppm)。HRMS以ESI源测得。
本发明合成方法中所述室温的温度范围为20℃-35℃。
以下为具体实施例。
实施例1:化合物3a的制备,得到无色油状化合物3a,产率为86%,其结构式如下:
1H NMR(400MHz,CDCl3)δ(ppm)=8.49(d,J=5.1Hz,2H),7.30(t,J=7.4Hz,2H),7.24(d,J=7.3Hz,1H),7.09(d,J=7.5Hz,2H),7.04(d,J=5.3Hz,2H),6.87(s,2H),5.39(s,1H),5.14(s,1H),1.36(s,18H);13C NMR(100MHz,CDCl3)δ(ppm)=153.80,152.51,149.67,142.92,135.84,132.42,129.31,128.44,126.62,125.91,124.64,56.27,34.38,30.28;HRMS(ESI)for C26H32NO+[M+H]+calcd.374.2478,found 374.2478.
实施例2:化合物3b的制备,得到无色油状化合物3b,产率为74%,其结构式如下:
1H NMR(400MHz,CDCl3)δ(ppm)=8.48(s,2H),7.00(dd,J=14.1,6.0Hz,4H),6.92–6.78(m,4H),5.34(s,1H),5.14(s,1H),3.79(s,3H),1.36(s,18H);13CNMR(100MHz,CDCl3)δ(ppm)=158.23,154.14,152.44,149.65,135.82,135.10,132.76,130.25,125.81,124.56,113.79,55.47,55.26,34.38,30.29;HRMS(ESI)for C27H34NO2 +[M+H]+calcd.404.2584,found 404.2588.
实施例3:化合物3c的制备,得到无色油状化合物3c,产率为79%,其结构式如下:
1H NMR(400MHz,CDCl3)δ(ppm)=8.42(s,2H),7.07(m,4H),6.93(s,2H),6.73(s,2H),5.45(s,1H),5.09(s,1H),2.14(s,3H),1.28(s,18H);13C NMR(100MHz,CDCl3)δ(ppm)=153.63,152.45,149.55,141.35,136.50,135.86,131.82,130.53,129.16,126.68,126.13,125.91,124.79,52.89,34.38,30.30,19.98;HRMS(ESI)for C27H34NO+[M+H]+calcd.388.2635,found 388.2635.
实施例4:化合物3d的制备,得到无色油状化合物3d,产率为85%,其结构式如下:
1H NMR(400MHz,CDCl3)δ(ppm)=8.49(d,J=5.1Hz,2H),7.18(t,J=7.6Hz,1H),7.04(d,J=5.3Hz,3H),6.93(s,1H),6.87(d,J=5.5Hz,3H),5.35(s,1H),5.14(s,1H),2.30(s,3H),1.36(s,18H);13C NMR(100MHz,CDCl3)δ(ppm)=153.93,152.48,149.65,142.82,138.01,135.80,132.48,130.12,128.28,127.36,126.31,125.90,124.63,56.27,34.38,30.29,21.46;HRMS(ESI)for C27H34NO+[M+H]+calcd.388.2635,found 388.2634.
实施例5:化合物3e的制备,得到无色油状化合物3e,产率为74%,其结构式如下:
1H NMR(400MHz,CDCl3)δ(ppm)=8.74(d,J=5.3Hz,1H),8.39(s,1H),7.45(d,J=5.7Hz,1H),7.16–7.13(m,1H),6.96(s,2H),6.83–6.74(m,4H),5.67(s,1H),5.08(s,1H),3.63(s,3H),1.28(s,18H);13C NMR(100MHz,CDCl3)δ(ppm)=156.96,154.26,152.37,150.81,149.25,135.67,132.08,131.58,130.09,127.90,126.18,126.09,125.28,120.36,110.61,55.45,49.32,34.39,34.30,30.32,30.23;HRMS(ESI)for C27H34NO2 +[M+H]+calcd.404.2584,found 404.2580.
实施例6:化合物3f的制备,得到无色油状化合物3f,产率为81%,其结构式如下:
1H NMR(400MHz,CDCl3)δ(ppm)=8.40(d,J=5.1Hz,2H),7.03–6.93(m,3H),6.81(s,3H),6.72(d,J=7.6Hz,1H),5.24(s,1H),5.07(s,1H),2.16(s,3H),2.13(s,3H),1.29(s,18H);13C NMR(100MHz,CDCl3)δ(ppm)=156.96,154.26,152.37,150.81,149.25,135.67,132.08,131.58,130.09,127.90,126.18,126.09,125.28,120.36,110.61,55.45,49.32,34.39,34.30,30.32,30.23;HRMS(ESI)for C28H36NO+[M+H]+calcd.402.2791,found402.2792.
实施例7:化合物3g的制备,得到无色油状化合物3g,产率为76%,其结构式如下:
1H NMR(400MHz,CDCl3)δ(ppm)=8.51(d,J=4.9Hz,2H),7.09–6.93(m,6H),6.84(s,2H),5.38(s,1H),5.18(s,1H),1.36(s,18H);13C NMR(100MHz,CDCl3)δ(ppm)=162.80,160.36,153.53,152.60,149.78,138.72,138.69,135.99,132.28,130.80,130.72,125.78,124.51,115.36,115.15,55.46,34.39,30.26;19FNMR(376MHz,CDCl3)δ(ppm)=-116.2--116.3(m);HRMS(ESI)for C26H31FNO+[M+H]+calcd.392.2384,found 392.2384.
实施例8:化合物3h的制备,得到无色油状化合物3h,产率为72%,其结构式如下:
1H NMR(400MHz,CDCl3)δ(ppm)=8.51(d,J=4.3Hz,2H),7.27(d,J=8.4Hz,2H),7.02(d,J=7.5Hz,4H),6.84(s,2H),5.36(s,1H),5.18(s,1H),1.36(s,18H);13C NMR(100MHz,CDCl3)δ(ppm)=153.19,152.67,149.80,141.52,136.04,132.48,131.94,130.63,128.59,125.77,124.50,55.62,34.40,30.26;HRMS(ESI)for C26H31ClNO+[M+H]+calcd.408.2089,found 408.2091.
实施例9:化合物3i的制备,得到无色油状化合物3i,产率为76%,其结构式如下:
1H NMR(400MHz,CDCl3)δ(ppm)=8.51(d,J=5.0Hz,2H),7.42(d,J=8.2Hz,2H),7.02(d,J=5.4Hz,2H),6.97(d,J=8.3Hz,2H),6.84(s,2H),5.34(s,1H),5.18(s,1H),1.36(s,18H);13C NMR(100MHz,CDCl3)δ(ppm)=153.11,152.68,149.80,142.06,136.05,131.85,131.55,131.02,125.77,124.50,120.60,55.69,34.40,30.26,30.17;HRMS(ESI)for C26H31BrNO+[M+H]+calcd.452.1584,found452.1592.
实施例10:化合物3j的制备,得到无色油状化合物3j,产率为80%,其结构式如下:
1H NMR(400MHz,CDCl3)δ(ppm)=8.50(d,J=5.1Hz,2H),7.58(d,J=7.9Hz,1H),7.23(d,J=7.7Hz,1H),7.12(t,J=7.6Hz,1H),7.00(d,J=5.1Hz,2H),6.94(d,J=7.7Hz,1H),6.83(s,2H),5.80(s,1H),5.16(s,1H),1.36(s,18H);13C NMR(100MHz,CDCl3)δ(ppm)=152.64,152.42,149.71,142.35,135.91,133.17,131.27,131.04,128.35,127.37,126.19,125.49,124.68,55.35,34.39,30.28;19FNMR(376MHz,CDCl3)δ(ppm)=-67.0(s);HRMS(ESI)for C26H31BrNO+[M+H]+calcd.452.1584,found 452.1581.
实施例11:化合物3k的制备,得到无色油状化合物3k,产率为70%,其结构式如下:
1H NMR(400MHz,CDCl3)δ(ppm)=8.51(s,2H),7.97(t,J=6.8Hz,2H),7.17(t,J=7.0Hz,2H),7.01(d,J=6.0Hz,2H),6.84(d,J=6.7Hz,2H),5.44(s,1H),5.18(s,1H),3.91(s,3H),1.36(s,18H);13C NMR(100MHz,CDCl3)δ(ppm)=166.92,152.84,152.72,149.86,148.25,136.07,131.67,129.77,129.36,128.59,125.83,124.52,56.21,52.10,34.40,30.25;HRMS(ESI)for C28H34NO3 +[M+H]+calcd.432.2533,found 432.2528.
实施例12:化合物3l的制备,得到无色油状化合物3l,产率为72%,其结构式如下:
1H NMR(400MHz,CDCl3)δ(ppm)=8.46(d,J=3.5Hz,2H),7.53(d,J=7.9Hz,2H),7.14(d,J=7.9Hz,2H),6.94(d,J=4.5Hz,2H),6.75(s,2H),5.37(s,1H),5.14(s,1H),1.29(s,18H);13C NMR(100MHz,CDCl3)δ(ppm)=152.93,152.19,149.95,148.49,136.29,132.31,131.03,130.07,125.76,124.46,118.79,110.65,56.21,34.42,30.22;HRMS(ESI)for C27H31N2O+[M+H]+calcd.399.2431,found399.2429.
实施例13:化合物3m的制备,得到无色油状化合物3m,产率为67%,其结构式如下:
1H NMR(400MHz,CDCl3)δ(ppm)=8.46(s,2H),7.49(d,J=8.1Hz,2H),7.15(d,J=8.1Hz,2H),6.96(d,J=4.5Hz,2H),6.78(s,2H),5.38(s,1H),5.14(s,1H),1.29(s,18H);13CNMR(100MHz,CDCl3)δ(ppm)=152.81,149.77,147.02,136.16,131.46,129.63,125.81,125.44,124.58,125.3(q,J=248.5Hz),56.04,34.41,30.24;19F NMR(376MHz,CDCl3)δ(ppm)=-62.4(s);HRMS(ESI)for C27H31F3NO+[M+H]+calcd.442.2352,found 442.2357.
实施例14:化合物3n的制备,得到无色油状化合物3n,产率为84%,其结构式如下:
1H NMR(400MHz,CDCl3)δ(ppm)=8.55(s,2H),7.81(dd,J=19.3,10.6Hz,3H),7.50(dd,J=8.2,5.1Hz,3H),7.30(d,J=9.3Hz,1H),7.13(s,2H),6.98(s,2H),5.60(s,1H),5.23(s,1H),1.40(s,18H);13C NMR(100MHz,CDCl3)δ(ppm)=153.68,152.62,149.67,140.46,135.97,133.39,132.27,128.07,127.88,127.82,127.71,127.62,126.15,126.00,125.84,124.76,56.42,34.42,30.30;HRMS(ESI)for C30H34NO+[M+H]+calcd.424.2635,found 424.2628.
实施例15:化合物3o的制备,得到无色油状化合物3o,产率为77%,其结构式如下:
1H NMR(400MHz,CDCl3)δ(ppm)=8.47(d,J=5.0Hz,2H),7.06(d,J=1.5Hz,3H),6.89(s,2H),6.56(s,1H),5.39(s,1H),5.15(s,1H),1.31(s,18H);13CNMR(100MHz,CDCl3)δ(ppm)=153.12,152.49,149.89,148.27,136.17,131.60,129.05,125.32,123.84,122.29,109.24,51.56,34.42,30.25;HRMS(ESI)for C24H29BrNOS+[M+H]+calcd.458.1148,found458.1135.
实施例16:化合物3p的制备,得到无色油状化合物3p,产率为56%,其结构式如下:
1H NMR(400MHz,CDCl3)δ(ppm)=8.39(s,2H),7.95(s,1H),7.18(s,1H),7.08(d,J=3.8Hz,2H),6.98(dd,J=12.7,9.7Hz,4H),6.85(t,J=7.0Hz,1H),5.52(s,1H),5.06(s,1H),2.14(s,3H),1.27(s,18H);13C NMR(100MHz,CDCl3)δ(ppm)=155.14,152.40,148.71,135.84,135.30,132.15,132.01,127.94,125.73,124.55,121.00,119.33,119.26,112.92,110.26,47.25,34.37,30.30,24.88;HRMS(ESI)for C29H35N2O+[M+H]+calcd.427.2744,found 427.2739.
实施例17:化合物3q的制备,得到无色油状化合物3q,产率为65%,其结构式如下:
1H NMR(400MHz,CDCl3)δ(ppm)=8.68(d,J=4.9Hz,1H),7.26(d,J=5.0Hz,1H),7.23(s,1H),7.05(d,J=7.9Hz,2H),6.94(d,J=7.9Hz,2H),6.85(s,2H),5.51(s,1H),5.07(s,1H),2.25(s,3H),1.29(s,18H);13C NMR(100MHz,CDCl3)δ(ppm)=166.31,152.69,150.34,139.14,136.43,135.94,131.88,129.32,129.05,125.83,125.14,122.55,120.56,116.85,58.84,34.39,30.27,21.08;HRMS(ESI)for C27H33BrNO+[M+H]+calcd.466.1740,found 466.1737.
实施例18:化合物3r的制备,得到无色油状化合物3r,产率为68%,其结构式如下:
1H NMR(400MHz,CDCl3)δ(ppm)=8.37–8.16(m,2H),7.03(d,J=7.8Hz,2H),6.88(dd,J=16.0,4.9Hz,3H),6.80(s,2H),5.60(s,1H),5.08(s,1H),2.26(s,3H),1.29(s,18H);13C NMR(100MHz,CDCl3)δ(ppm)=151.57,144.50(d,J=5.1Hz),139.88(d,J=12.1Hz),137.53,136.81(d,J=24.9Hz),135.32,134.82,130.09,128.26,128.13,127.99,127.84,124.70,124.04,47.52,47.49,33.34,29.23,20.02;19F NMR(376MHz,CDCl3)δ(ppm)=-130.73(d,J=5.4Hz);HRMS(ESI)for C27H33FNO+[M+H]+calcd.406.2541,found406.2547.
实施例19:化合物3s的制备,得到无色油状化合物3s,产率为63%,其结构式如下:
1H NMR(400MHz,CDCl3)δ(ppm)=8.68(d,J=4.9Hz,1H),7.27(dd,J=5.0,1.1Hz,1H),7.23(s,1H),7.05(d,J=7.9Hz,2H),6.94(d,J=7.9Hz,2H),6.85(s,2H),5.51(s,1H),5.07(s,1H),2.26(s,3H),1.29(s,18H);13C NMR(100MHz,CDCl3)δ(ppm)=166.30,152.68,150.34,139.14,136.43,135.94,131.88,129.31,129.04,125.83,125.14,122.55,120.56,116.85,58.85,34.39,30.27,21.08;HRMS(ESI)for C27H33ClNO+[M+H]+calcd.422.2245,found 422.2241.
实施例20抗肿瘤活性测试
将上述实施例1-19制备的化合物3a、3b、3c、3d、3e、3f、3g、3h、3i、3j、3k、3l、3m、3n、3o、3p、3q、3r和3s进行抗肿瘤活性检测,本实施例中抗肿瘤测试所用的细胞系为U87、Cal33和BxPC3,这些细胞系均购买于美国ACTT公司。U87、Cal33和BxPC3细胞系在DMEM培养基中进行培养,上述DMEM培养基含有10%的胎牛血清和1%的青霉素-链霉素溶液(100U/ml青霉素和100μg/ml链霉素)。细胞培养条件为37℃、含5%CO2的恒温培养箱。具体实验步骤如下:
(1)用血球计数板对细胞进行计数后,各肿瘤细胞系分别用对应的培养基将其稀释至3×104个/mL,获得各肿瘤细胞的细胞悬液;
(2)在96孔板的每个孔里加入100μL细胞悬液吹打混匀,于37℃的培养箱中孵育过夜;
(3)将化合物3a、3b、3c、3d、3e、3f、3g、3h、3i、3j、3k、3l、3m、3n、3o、3p、3q、3r和3s分别稀释至浓度为10μM,分别加入培养的各肿瘤细胞系中,于37℃的培养箱中培育48h;
(4)细胞存活能力通过MTT实验进行检测,待药物处理结束后,加入浓度为5mg/mL的MTT,于37℃的培养箱中培育4h;
(5)加DMSO将细胞溶解,然后用酶标仪测试570nm处的OD值(即OD570);
(6)处理数据,根据OD值计算细胞存活率。
实验结果如图1和表1所示:10μM的化合物3a-3s对人舌鳞状细胞癌细胞系(Cal33)、胰腺癌细胞系(BxPC3)、神经胶质瘤细胞(U87)的生长能力影响如图1和表1所示所示。图1和表1的数据表明,化合物3a-3s对人舌鳞状细胞癌细胞系、胰腺癌细胞系、神经胶质瘤的细胞生长能力均具有一定程度的抑制作用,尤其是化合物3l和化合物3o对各种肿瘤细胞的抑制活性很好,尤其是对人舌鳞状细胞癌细胞表现出显著的抑制效果。由此可见,本发明的化合物可以抑制或杀死肿瘤细胞,具有一定的抗肿瘤活性,可应用于制备抗肿瘤药物,尤其是化合物3o可以用作制备治疗人舌鳞状细胞癌的抗肿瘤药物。
表1二芳基甲基吡啶类化合物的抗癌活性测试结果
实施例21化合物3o的抗肿瘤活性
本实施例的实验方法参照实施例20。
一、本实施例检测了不同浓度的化合物3o对头颈部鳞状细胞癌细胞活力的影响,将人舌鳞状细胞癌(SCC15、Cal33、Cal27)和口腔癌(UM-1)细胞系(均购买于美国ACTT公司)分别用含10%的胎牛血清和1%的青霉素-链霉素溶液(100U/ml青霉素和100μg/ml链霉素)的DMEM培养基进行稀释,稀释至3×104个/mL,然后分别接种100μl细胞悬液到96孔板中,培育过程中分别加入浓度为0μM、0.1μM、0.5μM、1μM、5μM、10μM、20μM、50μM与100μM的化合物3o处理细胞48h,检测不同浓度的化合物3o对SCC15、Cal33、Cal27和UM-1细胞生长能力的影响,结果如图2所示。图2的数据表明,不同的头颈部鳞状细胞癌细胞对化合物3o的敏感性不同,与其他细胞株相比,SCC15细胞对化合物3o最为敏感,其半数致死浓度为5μM。化合物3o对头颈部鳞状细胞癌各细胞系均具有显著的抑制效果,能够有效抑制头颈部鳞状细胞癌细胞的活性。
二、为了更加真实的反应化合物3o对头颈部鳞状细胞癌细胞生长的影响,通过高内涵药物筛选平台对细胞生长的过程进行实时拍照,检测5μM的化合物3o对SCC15细胞生长的抑制能力,结果如图3所示。图3的检测结果表明:5μM的化合物3o处理SCC15细胞48h,可以显著抑制细胞增殖。
三、在图3展示的实验结果的基础上,分别将1×103个SCC15细胞种植于6孔板中,在37℃,5%的二氧化碳细胞培养箱中培养过夜,分别加入0μM、5μM与10μM的3o化合物处理细胞,待细胞的克隆团长到大约50个细胞时终止培养,选用4%的多聚甲醛对细胞进行固定并用1%的结晶紫溶液染色,检测化合物3o对细胞生长能力的影响,结果如图4所示。图4的检测数据表明,化合物3o可以显著抑制SCC15细胞的增殖能力。
以上所述实施例的各技术特征可以进行任意的组合,为使描述简洁,未对以下实施例中的各个技术特征所有可能的组合都进行描述,然而,只要这些技术特征的组合不存在矛盾,都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对本发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
Claims (10)
3.根据权利要求1或2所述的二芳基甲基吡啶类化合物或者其药学上可接受的盐或者其立体异构体,其特征在于,Ar选自:苯基、一个或两个R2取代的苯基、萘基、一个或两个R2取代的萘基、噻吩基、一个或两个R2取代的噻吩基、吲哚基、一个或两个R2取代的吲哚基。
4.根据权利要求1或2所述的二芳基甲基吡啶类化合物或者其药学上可接受的盐或者其立体异构体,其特征在于,R2选自:C1-C4烷基、C1-C4烷氧基、卤素、C1-C4烷氧基羰基、氰基、三氟甲基;和/或,R选自:H、溴、氟、氯。
5.根据权利要求1或2所述的二芳基甲基吡啶类化合物或者其药学上可接受的盐或者其立体异构体,其特征在于,Ar选自:苯基、4-甲氧基苯基、2-甲基苯基、3-甲基苯基、2-甲氧基苯基、3,4-二甲基苯基、4-氟苯基、4-氯苯基、4-溴苯基、2-溴苯基、4-甲氧羰基苯基、4-氰基苯基、4-三氟甲基苯基、2-萘基、4-溴噻吩-2-基、2-甲基-1H-吲哚-3-基。
8.根据权利要求7所述的二芳基甲基吡啶类化合物的制备方法,其特征在于,所述化合物1、化合物2和联硼酸频那醇酯的摩尔比为1:1-2:1-1.5;和/或,
所述反应的溶剂为甲基叔丁基醚;和/或,
所述反应的温度为50℃-80℃,反应的时间为18h-30h;和/或,
步骤(2)中所述搅拌的时间为12分钟-18分钟。
9.权利要求1-6任一项所述的二芳基甲基吡啶类化合物或者其药学上可接受的盐或者其立体异构体在制备预防和/或治疗肿瘤的药物中的应用;优选地,所述肿瘤为:头颈部鳞状细胞癌、胰腺癌、神经胶质瘤;优选地,所述头颈部鳞状细胞癌为口腔癌、人舌鳞状细胞癌。
10.一种预防和/或治疗肿瘤的药物组合物,其特征在于,包括活性成分以及药学上可接受的辅料和/或载体,所述活性成分包括有权利要求1-6任一项所述的二芳基甲基吡啶类化合物或者其药学上可接受的盐或者其立体异构体。
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