CN112778217B - 一种喹唑啉类化合物及其应用 - Google Patents
一种喹唑啉类化合物及其应用 Download PDFInfo
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- CN112778217B CN112778217B CN201911084758.7A CN201911084758A CN112778217B CN 112778217 B CN112778217 B CN 112778217B CN 201911084758 A CN201911084758 A CN 201911084758A CN 112778217 B CN112778217 B CN 112778217B
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- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/88—Oxygen atoms
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
Abstract
本发明涉及通式(I)所示的含喹唑啉类化合物及其药学上可接受的盐、溶剂化物和前药，其中取代基R1、R2、R3、R4、R5、R6、p、m、n具有在说明书中给出的含义。本发明还涉及通式(I)所示的化合物作为制备抗肿瘤药物的应用，并且还涉及该类化合物及其药学上可接受的盐、溶剂化物和前药在制备和/或预防、缓解人体组织或器官肿瘤细胞引起的癌症。所指癌症优选结肠癌、肝癌、淋巴瘤、肺癌、食管癌、乳腺癌、中枢神经***肿瘤、黑色素瘤、皮肤癌、卵巢癌、***、肾癌、白血病、***癌、胰腺癌、膀胱癌、直肠癌、骨肉瘤、鼻咽癌或胃癌等。
Description
技术领域
本发明属于医药领域，具体地涉及一种喹唑啉类化合物及其在预防和/或治疗癌症中的应用。
背景技术
文献European Journal of Medicinal Chemistry 107(2016)12-25中涉及喹唑啉类化合物抑制HepG2、MGC-803,、A549肿瘤细胞增殖机制研究，但并未对肺癌、膀胱癌、结肠癌、白血病等其他癌症的抑制研究。
专利CN 102977014B涉及的通式化合物A的体外抗肿瘤抑制活性研究,但化合物结构与本发明化合物结构存在明显差异。
专利CN106632287A涉及喹唑啉类化合物对人皮肤鳞状细胞癌细胞株A431、人肺癌细胞株A549具有一定的抗癌活性。
尽管已有多篇专利提及相关介绍，但仍需要不断研发新的抗癌化合物以控制癌症对人类的危害。上述专利中所有公开的化合物均与本发明化合物结构上存在显著的不同。
发明内容
本发明旨在提供一种新型结构的喹唑啉类化合物，以及将该化合物在预防和/或治疗癌症中的应用。
为实现上述目的，本发明采用以下技术方案：
一种喹唑啉类化合物，化合物为通式(Ι)所示，
式中，
R1选自氢、卤素、羟基、氰基、硝基、氨基、未取代或被至少一个如下基团取代的C1-C12烷基、C1-C12烷氧基、C3-C12环烷基、杂环基、芳基、杂芳基、C1-C12烷硫基、C1-C12烷基磺酰基、C1-C12烷基羰基或C1-C12烷氧基羰基，如下基团为卤素、羟基、氨基、氰基或硝基；
R2选自氢、C1-C12烷基、C1-C12烷氧基、C3-C12环烷基、杂环基、芳基或杂芳基；
R3选自氢、C1-C12烷基、C1-C12烷氧基、C3-C12环烷基、杂环基、芳基或杂芳基；
R4选自氢、卤素、羟基、氨基、氰基、硝基、未取代或被至少一个如下基团取代的C1-C12烷基、C1-C12烷氧基、C3-C12环烷基、杂环基、芳基或杂芳基，其中，如下基团为卤素、羟基、氨基、氰基或硝基；
m选自1-4；
R5选自氢、卤素、羟基、氨基、氰基、硝基、未取代或被至少一个如下基团取代的C1-C12烷基、C1-C12烷氧基、C3-C12环烷基、杂环基、芳基或杂芳基，其中如下基团为卤素、羟基、氨基、氰基或硝基；
p选自1-4；
R6选自氢、卤素、羟基、氨基、氰基、硝基、未取代或被至少一个如下基团取代的C1-C12烷基、C1-C12烷氧基、C3-C12环烷基、杂环基、芳基、杂芳基、C1-C12烷硫基、C1-C12烷基磺酰基、C1-C12烷基羰基或C1-C12烷氧基羰基，如下基团为卤素、羟基、氨基、氰基、硝基；
n选自1-5；
或，通式(Ι)所示的化合物的异构体、及其药学上可接受的盐、溶剂化物或前药。
优选的所述通式(Ι)中，
R1选自氢、卤素、羟基、氨基、氰基、硝基、未取代或被至少一个如下基团取代的C1-C4烷基、C1-C4烷氧基、C3-C6环烷基、杂环基、芳基、杂芳基、C1-C4烷硫基、C1-C4烷基磺酰基、C1-C4烷基羰基或C1-C4烷氧基羰基，其中如下基团为卤素、羟基、氰基、硝基或氨基；
R2选自氢、C1-C4烷基或C3-C12环烷基；
R3选自氢、C1-C4烷基或C3-C12环烷基；
R4选自氢、卤素、羟基、氨基、氰基、硝基、C1-C4烷基、C1-C4烷氧基或C3-C6环烷基；
m选自1-4；
R5选自氢、卤素、羟基、氨基、氰基、硝基、C1-C4烷基、C1-C4烷氧基或C3-C6环烷基；
p选自1-4；
R6选自氢、卤素、羟基、氨基、氰基、硝基、未取代或被至少一个卤素取代的C1-C4烷基、C1-C4烷氧基、C3-C6环烷基、杂环基、芳基或杂芳基；
n选自1-5；
或，通式(Ι)所示的化合物的异构体、及其药学上可接受的盐、溶剂化物或前药。
进一步优选的所述通式(Ι)中，
R1选自氢、卤素、羟基、氨基、氰基、硝基、C1-C4烷基、C1-C4烷氧基、被一个或多个卤素取代的C1-C4烷基、C1-C4烷氧基；
R2选自氢、甲基、乙基或环丙基；
R3选自氢、甲基、乙基或环丙基；
R4、选自氢、氟、氯、甲基、乙基或环丙基；
m选自1-4；
R5、选自氢、氟、氯、甲基、乙基、环丙基、甲氧基、乙氧基和丙氧基；
p选自1-4；
R6选自氢、卤素、羟基、氨基、氰基、硝基、未取代或被至少一个卤素取代的C1-C4烷基、C1-C4烷氧基；
n选自1-5；
或，通式(Ι)所示的化合物的异构体、及其药学上可接受的盐、溶剂化物或前药。
再进一步优选的所述通式(Ι)中，
R1选自氢、三氟甲基或甲基；
R2选自氢或甲基；
R3选自氢或甲基；
R4选自氢；
R5选自氢或甲氧基；
R6选自氢、卤素、羟基、氰基、甲氧基、乙氧基、甲基、乙基、异丙基；
n选自1-5；
或，通式(Ι)所示的化合物的异构体、及其药学上可接受的盐、溶剂化物或前药。
所述通式I的化合物或其异构体对应的盐为盐酸盐、硫酸盐、硝酸盐、碳酸氢盐、碳酸盐、磷酸盐、甲酸盐、醋酸盐、三氟乙酸盐、苯磺酸盐、对甲苯磺酸盐、甲基磺酸盐、苯甲酸盐、柠檬酸盐、苹果酸盐、酒石酸盐、马来酸盐、琥珀酸盐、抗坏血酸盐或草酸盐。
依据本发明，通式(I)的化合物的前药是通式(I)化合物的衍生物，它们自身可能具有较弱的活性或甚至没有活性，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。
通式(I)的化合物溶剂化物为通式(I)的化合物或其异构体与甲醇、乙醇、异丙醇、正丁醇、乙酸乙酯、二氯甲烷、石油醚、乙腈。
一种化合物的应用，所述通式(Ι)所示的化合物、其异构体、及其药学上可接受的盐、溶剂化物或前药在制备治疗细胞增殖类疾病的药物中的应用。
所述细胞增殖类疾病选自癌症、感染、炎症或自身免疫性疾病。
所述癌症选自结肠癌、肝癌、淋巴瘤、肺癌、食管癌、乳腺癌、中枢神经***肿瘤、黑色素瘤、皮肤癌、卵巢癌、***、肾癌、白血病、***癌、胰腺癌、膀胱癌、直肠癌、骨肉瘤、鼻咽癌或胃癌。
一种药物组合物，含有治疗有效剂量的所述通式(I)的化合物或其异构体、及其药学上可接受的盐、溶剂化物或前药，以及一种或多种药学上可接受的载体或赋形剂。
所述的药物组合物在制备治疗细胞增殖类疾病的药物中的应用。
上面给出的通式(I)化合物的定义中，汇集所用术语一般代表如下取代基：
卤素：指氟、氯、溴或碘。烷基：直链或支链烷基，例如甲基、乙基、丙基、异丙基或叔丁基。卤代烷基：直链或支链烷基，在这些烷基上的氢原子可部分或全部被卤原子所取代，例如氯甲基、二氯甲基、三氯甲基、氟甲基、二氟甲基、三氟甲基等。烷氧基：直链或支链烷基，经氧原子键连接到结构上。环烷基：取代或未取代的含杂原子的环状烷基，例如环丙基、环戊基或环己基。取代基如甲基、卤素等。经氧原子键连接到结构上。烷氧基：直链或支链烷基，经氧原子键连接到结构上。烷硫基：直链或支链烷基，经硫原子键连接到结构上。烷基羰基：直链或支链烷基经羰基(-CO-)连接到结构上，如乙酰基。烷氧基羰基：烷氧基经羰基连接到结构上。如-COOCH3，-COOCH2CH3。烷基磺酰基：直链或支链烷基经砜基(-SO2-)连接到结构上，如甲基磺酰基。芳基包括苯基或萘基等。杂芳基是含1个或多个N、O、S杂原子的五元环或六元环。例如呋喃基、吡咯基、吡唑基、噻唑基、吡啶基、嘧啶基等。
本发明的部分通式I化合物中(R6)n取代基列举于表1，但并不限定本发明。
表1
进一步的说通式(I)所示的部分化合物可由表2表示，
表2
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本发明所涉及的通式(I)化合物可以按照以下方法制备。反应式如下，式中各基团除另有说明外定义同前：
通式(I)的合成路线：
制备过程为：
步骤一：将cpd.1和cpd.2加入甲酸中，加热至135℃搅拌5小时。将反应液倒入水浴中析出产品，过滤得到cpd.3。
步骤二：将cpd.3溶于溶剂中，加入氯化试剂，加热回流反应3h。反应结束后脱溶得到产品cpd.4。
步骤三：将cpd.4和cpd.5溶于溶剂中，加入碱、水、和TBAB 100℃反应4h，反应结束后柱层析纯化得到产品cpd.6。
步骤四：将cpd.6和cpd.7溶于溶剂中，加入碱和HBTU室温搅拌6小时，柱层析得到cpd.8。
上述氯化试剂可选自如二氯亚砜、三氯化磷、五氯化磷、三氯氧磷、Vilesmier-Haack试剂、磺酰氯等。
碱可选自如氢氧化钠、氢氧化锂、碳酸钠、碳酸氢钠、氢氧化钾、碳酸钾、碳酸氢钾。
上述各步骤采用的溶剂均可选自如乙醇、乙腈、四氢呋喃、甲苯、二甲苯、苯、N,N-二甲基甲酰胺、N-甲基吡咯烷酮、二甲亚砜、丙酮或丁酮等。
上述各步骤的反应温度可在室温至溶剂沸点温度之间，优选范围为20-150℃。
上述反应中的中间体cpd.1、cpd.2、cpd.5和cpd.7为市售商品。
通式(I)化合物的盐可以由通式(I)化合物与对应的酸按常规方法制得。适宜的酸选自盐酸、硫酸、硝酸、碳酸、磷酸、甲酸、醋酸、三氟乙酸、苯磺酸、对甲苯磺酸、甲基磺酸、苯甲酸、柠檬酸、苹果酸、酒石酸、马来酸、琥珀酸、抗坏血酸或草酸等；进一步优选盐酸、硫酸、磷酸、三氟乙酸、甲磺酸或对甲苯磺酸等。
本发明包括以上述通式(I)所包含的化合物为活性成分配制成的制剂以及其制剂组成的配制。制剂制备方法为：将本发明所涵盖的化合物溶解到水溶性的有机溶剂、非离子性的表面活性剂、水溶性的类脂、各种环糊精、脂肪酸、脂肪酸酯、磷脂或其组合溶剂中而制得制剂溶液；加入生理盐水获1-20％的碳水化合物。所述有机溶剂包括聚乙二醇(PEG),乙醇，丙二醇或这些溶剂的组合溶剂。
本发明所述通式(I)中所涵盖的化合物及其盐和前药用于制备治疗、预防或缓解抗肿瘤药物或药物制剂，药物活性成分为一种或两种以上通式(I)所示的喹唑啉类化合物。尤其适用于治疗或缓解人体组织或器官肿瘤细胞引起的癌症。所指癌症优选结肠癌、肝癌、淋巴瘤、肺癌、食管癌、乳腺癌、中枢神经***肿瘤、黑色素瘤、卵巢癌、***、肾癌、白血病、***癌、胰腺癌、膀胱癌、直肠癌、骨肉瘤、鼻咽癌或胃癌等。
本发明合成的化合物可用于抗肿瘤药物的活性成分，可以单独使用，也可以与其它抗肿瘤、抗病毒药物联合用药。本发明所指的联合用药治疗过程中，包括运用至少一种本发明化合物以及其活性衍生物与其他一种或多种抗肿瘤抗病毒药物一起使用以增加总体疗效。联合用药时的药量和给药时间应根据不同的情况下所取得的最合理治疗效果而定。
所涵盖的药剂配伍包括通式(I)中的化合物的有效剂量。此处的“有效剂量”指的是对于所治疗对象能产生治疗效果所需要该化合物的用量。该有效剂量或剂量可以由有经验者根据不同情况的建议而不同。比如，所治疗的肿瘤种类不同，药物的用法不同；是否与其它的治疗方法如其他抗肿瘤药物或抗病毒药物共用等，剂量均可发生改变。可以制成任何可使用的制剂剂型。如果某些具有碱性或酸性化合物并可形成无毒性的酸或盐，可以使用该化合物的盐的形式。药学中可使用的有机酸盐包括生理上可使用的负离子盐，如对甲基苯磺酸盐、甲基磺酸盐、乙酸盐、苯甲酸盐、柠檬酸盐、苹果酸盐、酒石酸盐、马来酸盐、琥珀酸盐、抗坏血酸盐或甘油磷酸盐等；可使用的无机盐包括氯化物、溴化物、氟化物、碘化物、硫酸盐、硝酸盐、碳酸氢盐、碳酸盐或磷酸盐等；如有像胺这样的碱性的化合物与合适的酸可以制成所述的盐的形式；羧酸类的化合物可以与碱金属或碱土金属形成可使用的盐。
本发明中通式(I)中涵盖的化合物一般易溶解到有机溶剂、水溶性溶剂以及有机溶剂和水溶性溶剂与水的混合溶剂中。水溶性溶剂优选醇、多聚乙二醇、N-甲基-2-吡咯啉酮、N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、二甲亚砜、乙腈以及其合用。所述的醇优选甲醇，乙醇，异丙醇，丙三醇或乙二醇。本发明化合物可以与常用的制剂载体混合而制成制剂。化合物溶解到水溶性的有机溶剂、非质子性溶剂、水溶性类脂、环糊精、脂肪酸、磷脂中或这些溶剂的混合溶剂中而制得药物溶液；再加入生理盐水获1-20％的碳水化合物，如葡萄糖的水溶液。由此而制得的制剂稳定并用于动物和临床。
以上述通式(I)中化合物为活性成分制备成的产品药物，可以通过口服或非肠道途径给药，也可通过体内移植药物泵以及其他方法给药，此处所指的非肠道途径给药是指灌注、皮下皮内、肌肉内、静脉内、动脉内、心房内、滑膜内、胸骨内、鞘内、创伤部位内、颅内注射或滴注技术等。由技术人员运用常规的方法配比，混合最终成为所需要的药物剂型。可以是片剂、丸剂、胶囊、冲剂、糖浆、注射液、冻干粉针剂型、乳剂、粉剂、冻干粉、滴丸、乳悬液、水悬溶液、水溶液、胶体、胶体溶液、缓释制剂、纳米制剂或以其他形式的剂型用于动物或临床。
本发明通式(I)中的化合物用于治疗或缓解某一组织或器官的癌症药物的制备。所指癌症包括但不只限于结肠癌、肝癌、淋巴瘤、肺癌、食管癌、乳腺癌、中枢神经***肿瘤、黑色素瘤、卵巢癌、***、肾癌、白血病、***癌、胰腺癌、膀胱癌、直肠癌、骨肉瘤、鼻咽癌或胃癌等。
具体实施方式
以下具体实施例用来进一步说明本发明，但本发明并非限于这些例子。(除另有注明外，所用原料均有市售)
合成实施例
实施例1：化合物1的制备
步骤一：将中间体a(20g,101mmol),甲酸胺(80mL)和甲酸(8mL)加入250mL单口瓶中，加热至135℃搅拌5小时。将反应液倒入水浴中析出产品，过滤得到产品23g。
步骤二：将中间体b(5g,24.3mmol)加入SOCl2(50mL)中，加热回流反应3h。反应结束后脱溶得到产品5.3g。
步骤三：将中间体c(5.3g,23.7mmol)和中间体d(2.8g,25.69mmol)溶于丁酮(100mL)中，加入NaOH(3g,75mmol)、H2O(20mL,1.1mol)、和TBAB(4g,12mmol),加热至100℃反应4h，反应结束后柱层析纯化得到产品2.6g。
步骤四：将中间体e(100mg，0.337mmol)和中间体f(50mg,0.325mmol)溶于THF(10mL)中，加入DIPEA(200mg，1.55mmol)和HBTU(130mg,0.343mmol)室温搅拌6小时，柱层析得到化合物1产品100mg。
1H NMR(600MHz,DMSO-d6)δ10.34(s,1H),8.54(s,1H),7.73–7.67(m,2H),7.56(s,1H),7.43(td,J＝7.6,1.7Hz,1H),7.39(s,1H),7.33(ddd,J＝7.4,5.6,1.9Hz,1H),7.28–7.24(m,2H),7.23–7.17(m,2H),3.99(d,J＝8.9Hz,6H),3.77(s,2H).MS:433.44.
实施例2：化合物2的制备
中间体e的制备方法同实施例1。化合物2的制备方法如下：
步骤一：将中间体e(100mg，0.337mmol)和中间体f(54mg,0.325mmol)溶于THF(10mL)中，加入DIPEA(200mg，1.55mmol)和HBTU(130mg,0.343mmol)室温搅拌6小时，柱层析得到化合物2产品100mg。
1H NMR(600MHz,DMSO-d6)δ10.23(s,1H),8.53(s,1H),7.71–7.66(m,2H),7.55(s,1H),7.37(s,1H),7.30–7.26(m,2H),7.25–7.22(m,2H),6.92–6.88(m,2H),3.99(s,3H),3.97(s,3H),3.74(s,3H),3.59(s,2H).MS:445.16.
实施例3：化合物3的制备
中间体e的制备方法同实施例1。化合物3的制备方法如下：
步骤一：将中间体e(100mg，0.337mmol)和中间体f(54mg,0.325mmol)溶于THF(10mL)中，加入DIPEA(200mg，1.55mmol)和HBTU(130mg,0.343mmol)室温搅拌6小时，柱层析得到化合物3产品100mg。
1H NMR(600MHz,DMSO-d6)δ10.17(s,1H),8.53(s,1H),7.74–7.66(m,2H),7.55(s,1H),7.38(s,1H),7.28–7.22(m,4H),6.99(dd,J＝8.1,1.1Hz,1H),6.92(td,J＝7.4,1.1Hz,1H),3.99(s,3H),3.97(s,3H),3.79(s,3H),3.66(s,2H).MS:445.16.
实施例4：化合物4的制备
中间体e的制备方法同实施例1。化合物4的制备方法如下：
步骤一：将中间体e(100mg，0.337mmol)和中间体f(55mg,0.325mmol)溶于THF(10mL)中，加入DIPEA(200mg，1.55mmol)和HBTU(130mg,0.343mmol)室温搅拌6小时，柱层析得到化合物4产品100mg。
1H NMR(600MHz,DMSO-d6)δ10.30(s,1H),8.53(s,1H),7.72–7.66(m,2H),7.55(s,1H),7.43–7.35(m,5H),7.28–7.22(m,2H),3.99(s,3H),3.97(s,3H),3.68(s,2H).MS:499.84.
实施例5：化合物5的制备
中间体e的制备方法同实施例1。化合物5的制备方法如下：
步骤一：将中间体e(100mg，0.337mmol)和中间体f(67mg,0.325mmol)溶于THF(10mL)中，加入DIPEA(200mg，1.55mmol)和HBTU(130mg,0.343mmol)室温搅拌6小时，柱层析得到化合物5产品100mg。
1H NMR(600MHz,DMSO-d6)δ10.54(d,J＝7.2Hz,1H),8.80(d,J＝4.9Hz,1H),7.76–7.71(m,2H),7.65(dd,J＝4.8,2.0Hz,2H),7.61(d,J＝8.3Hz,1H),7.47(d,J＝1.6Hz,1H),7.37(dd,J＝8.3,2.0Hz,1H),7.31–7.26(m,2H),4.04–3.99(m,6H),3.75(s,2H).MS:484.33.
其他实施例化合物数据如下：
化合物6:1H NMR(600MHz,DMSO-d6)δ10.29(s,1H),8.63(s,1H),7.71(d,J＝8.6Hz,2H),7.59(s,1H),7.40(s,1H),7.26(dd,J＝8.3,5.9Hz,3H),6.97–6.93(m,2H),6.83(d,J＝2.7Hz,1H),4.00(d,J＝10.9Hz,6H),3.76(s,3H),3.64(s,2H).MS:445.16.
化合物7:1H NMR(600MHz,DMSO-d6)δ10.37(s,1H),8.54(s,1H),7.74–7.67(m,2H),7.54(s,1H),7.46(dt,J＝7.1,2.3Hz,2H),7.37(s,1H),7.35–7.30(m,2H),7.27–7.24(m,2H),3.99(s,3H),3.98(s,3H),3.88(s,2H).MS:449.11.
化合物8:1H NMR(600MHz,DMSO-d6)δ10.34(s,1H),8.65(s,1H),7.72–7.68(m,2H),7.59(s,1H),7.44(t,J＝1.9Hz,1H),7.39(s,1H),7.35–7.32(m,3H),7.28–7.25(m,2H),4.01(s,3H),3.99(s,3H),3.71(s,2H).MS:449.11.
化合物9:1H NMR(600MHz,DMSO-d6)δ10.32(s,1H),8.57(s,1H),7.69(d,J＝8.5Hz,2H),7.57(s,1H),7.39(d,J＝5.0Hz,2H),7.25(d,J＝8.6Hz,2H),7.20(d,J＝8.0Hz,2H),7.10(d,J＝2.4Hz,1H),3.99(d,J＝10.2Hz,6H),3.71(s,2H).MS:433.14.
化合物10:1H NMR(600MHz,DMSO-d6)δ8.65(s,1H),7.72–7.68(m,2H),7.59(s,1H),7.54(d,J＝8.1Hz,2H),7.52–7.48(m,2H),7.33(d,J＝8.0Hz,2H),7.28–7.25(m,2H),4.00(d,J＝11.5Hz,6H),3.67(s,2H).MS:493.06.
化合物11:1H NMR(600MHz,DMSO-d6)δ10.35(s,1H),8.54(s,1H),7.88(dd,J＝7.8,1.1Hz,1H),7.72–7.69(m,2H),7.56(s,1H),7.42–7.38(m,3H),7.28–7.24(m,2H),7.04(ddd,J＝7.8,6.7,2.3Hz,1H),3.99(d,J＝8.2Hz,6H),3.88(s,2H).MS:541.05.
化合物12:1H NMR(600MHz,DMSO-d6)δ10.31(s,1H),8.54(s,1H),7.76(t,J＝1.7Hz,1H),7.72–7.67(m,2H),7.64(dt,J＝7.9,1.4Hz,1H),7.55(s,1H),7.39(d,J＝9.7Hz,2H),7.28–7.24(m,2H),7.16(t,J＝7.8Hz,1H),3.98(d,J＝9.5Hz,6H),3.67(s,2H).MS:541.05.
化合物13:1H NMR(600MHz,DMSO-d6)δ10.30(s,1H),8.54(s,1H),7.73–7.66(m,4H),7.55(s,1H),7.38(s,1H),7.27–7.23(m,2H),7.20–7.15(m,2H),3.98(d,J＝9.9Hz,6H),3.65(s,2H).MS:541.05.
化合物14:1H NMR(600MHz,DMSO-d6)δ10.28(s,1H),8.54(s,1H),7.73–7.67(m,2H),7.55(s,1H),7.38(s,1H),7.30–7.23(m,3H),7.21–7.14(m,3H),3.99(d,J＝9.1Hz,6H),3.72(s,2H),2.33(s,3H).MS:429.17.
化合物15:1H NMR(600MHz,DMSO-d6)δ10.26(s,1H),8.54(s,1H),7.71–7.67(m,2H),7.56(s,1H),7.38(s,1H),7.27–7.22(m,4H),7.15(d,J＝7.8Hz,2H),3.99(d,J＝9.8Hz,6H),3.62(s,2H),2.29(s,3H).MS:429.17.
化合物16:1H NMR(600MHz,DMSO-d6)δ10.36(s,1H),8.53(s,1H),7.81(d,J＝1.8Hz,1H),7.75(dt,J＝7.7,1.4Hz,1H),7.70(td,J＝7.4,6.8,1.7Hz,3H),7.57(t,J＝7.8Hz,1H),7.54(s,1H),7.37(s,1H),7.28–7.23(m,2H),3.99(s,3H),3.97(s,3H),3.79(s,2H).MS:440.15.
化合物17:1H NMR(600MHz,DMSO-d6)δ10.36(s,1H),8.53(s,1H),7.86–7.78(m,2H),7.72–7.64(m,2H),7.60–7.50(m,3H),7.38(s,1H),7.29–7.21(m,2H),3.98(d,J＝9.8Hz,6H),3.81(s,2H).MS:440.15.
化合物18:1H NMR(600MHz,DMSO-d6)δ10.36(s,1H),8.54(s,1H),7.72–7.67(m,2H),7.56(s,1H),7.53(dd,J＝6.5,2.8Hz,1H),7.40(ddd,J＝9.0,4.6,2.9Hz,1H),7.38(s,1H),7.29–7.26(m,2H),7.26(d,J＝2.9Hz,1H),3.99(d,J＝8.9Hz,6H),3.80(s,2H).MS:467.10.
化合物19：1H NMR(600MHz,DMSO-d6)δ10.33(s,1H),8.54(s,1H),7.73–7.66(m,2H),7.58–7.53(m,2H),7.41(dd,J＝10.4,1.9Hz,1H),7.38(s,1H),7.28–7.24(m,2H),7.23(dd,J＝8.4,1.9Hz,1H),3.98(d,J＝9.7Hz,6H),3.74(s,2H).MS:467.10
化合物20:1H NMR(600MHz,DMSO-d6)δ10.31(s,1H),8.53(s,1H),7.75(t,J＝1.8Hz,1H),7.70–7.66(m,2H),7.60(d,J＝1.8Hz,2H),7.55(s,1H),7.38(s,1H),7.27–7.24(m,2H),3.98(d,J＝9.4Hz,6H),3.73(s,2H).MS:570.97.
化合物21:1H NMR(600MHz,DMSO-d6)δ10.36(s,1H),8.54(s,1H),7.70–7.68(m,2H),7.66(dd,J＝8.8,5.4Hz,1H),7.55(s,1H),7.38(s,1H),7.38–7.35(m,1H),7.28–7.24(m,2H),7.13(td,J＝8.5,3.1Hz,1H),3.98(d,J＝8.5Hz,6H),3.90(s,2H).MS:511.05.
按照上述实施例的记载以及发明内容中通式(Ι)化合物的制备过程，可进一步的制备出通式(Ι)所示的其他化合物；
按照上述制备方式获得通式(Ι)所示化合物，所得化合物再与相应的盐反应还可获得通式(Ι)所示的化合物药学上可接受的盐。
抗肿瘤活性测定
实施例1：体外对肿瘤细胞抑制作用的检测实验(MTT法)如下：
所用人癌肿瘤细胞株：人结肠癌HT-29、人***细胞Hela。
采用体外细胞培养技术，人结肠癌HT-29、人***细胞Hela用常规MTT法测定5个浓度供试样品对各人癌细胞生长的抑制率。
MTT法：将细胞分别从培养箱中取出，用PBS液清洗两次，用0.25％胰蛋白酶溶液消化，加入RPMI1640完全培养基(含10％FBS)终止消化，离心后甩去上清，加入完全培养基吹打使之形成细胞悬液，并于倒置显微镜下进行计数。将细胞配制成浓度为5x104个/mL的细胞悬液，在96孔板每孔加入细胞100μL，放置于5％二氧化碳，37℃湿化空气中培养过夜甩去上清，加入完全培养基稀释成40μg/mL、8μg/mL、1.6μg/mL、0.32μg/mL和0.064μg/mL五个不同浓度梯度的待测上述实施例获得化合物，令其作用48h后甩去上清，加入0.5mg/mlMTT100μL，经反应4小时，活细胞将MTT tetrazolium(四氮唑)成分还原产生formazan(甲臜)甩去上清，之后加入100μL DMSO以溶解formazan，最后以96孔平板读数仪上测量490nm,630nm的吸光值。
细胞抑制率＝(1-实验组吸光值/对照组吸光值)×100％
再根据5个浓度供试样品的抑制率，用GraphPad Prism6软件采用非线性回归法计算IC50值。部分测试结果(参见表3)如下：
表3.化合物对人肿瘤细胞的细胞毒活性
从表中数据可以看出，本发明的喹唑啉类化合物1、化合物15、化合物21对Tubulin、C-Met靶点高表达细胞株具有非常明显的抑制效果，具一定的抗肿瘤活性，可以有效抑制肿瘤细胞的生长；本发明通式(Ι)化合物结构中存在喹唑啉和苯乙酰胺衍生结构；其与已经报道的化合物具有明显差异，进而通式(Ι)化合物及其药学上可接受的盐、溶剂化物和前药在制备和/或预防、缓解人体组织或器官肿瘤细胞引起的癌症。
以上所述本发明的具体实施方式，并不构成对本发明保护范围的限定。任何根据本发明的技术构思所作出的各种其他相应的改变与变形，均应包含在本发明权利要求的保护范围内。
Claims (9)
1.一种喹唑啉类化合物，其特征在于：化合物为通式(Ι)所示，
式中，
R1选自氢；
R2选自氢；
R3选自氢；
R4选自氢；
m选自1-4；
R5选自氢、C1-C12烷氧基；
p选自1-4；
R6选自卤素、未取代的C1-C12烷基；
n选自1-5；
或，通式(Ι)所示的化合物药学上可接受的盐。
2.根据权利要求1所述的喹唑啉类化合物，其特征在于：所述通式(Ι)中，
R1选自氢；
R2选自氢；
R3选自氢；
R4选自氢；
m选自1-4；
R5选自氢、C1-C4烷氧基；
p选自1-4；
R6选自卤素、未取代的C1-C4烷基；
n选自1-5；
或，通式(Ι)所示的化合物药学上可接受的盐。
3.根据权利要求2所述的喹唑啉类化合物，其特征在于：所述通式(Ι)中，
R1选自氢；
R2选自氢；
R3选自氢；
R4选自氢；
R5选自氢或甲氧基；
R6选自卤素、甲基、乙基、异丙基；
n选自1-5；
或，通式(Ι)所示的化合物药学上可接受的盐。
4.根据权利要求1-3任意一项所述的化合物，其特征在于：所述通式I的化合物对应的盐为盐酸盐、硫酸盐、硝酸盐、碳酸氢盐、碳酸盐、磷酸盐、甲酸盐、醋酸盐、三氟乙酸盐、苯磺酸盐、对甲苯磺酸盐、甲基磺酸盐、苯甲酸盐、柠檬酸盐、苹果酸盐、酒石酸盐、马来酸盐、琥珀酸盐、抗坏血酸盐或草酸盐。
5.一种权利要求1所述的化合物的应用，其特征在于：所述通式(Ι)所示的化合物在制备治疗细胞增殖类疾病的药物中的应用。
6.根据权利要求5所述的化合物的应用，其特征在于：所述细胞增殖类疾病选自癌症、感染、炎症或自身免疫性疾病。
7.根据权利要求6所述的化合物的应用，其特征在于：所述癌症选自结肠癌、肝癌、淋巴瘤、肺癌、食管癌、乳腺癌、中枢神经***肿瘤、黑色素瘤、皮肤癌、卵巢癌、***、肾癌、白血病、***癌、胰腺癌、膀胱癌、直肠癌、骨肉瘤、鼻咽癌或胃癌。
8.一种药物组合物，其特征在于：含有治疗有效剂量的所述权利要求1-4中任一项所示化合物，以及一种或多种药学上可接受的载体或赋形剂。
9.根据权利要求8所述的药物组合物在制备治疗细胞增殖类疾病的药物中的应用。
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