CN1325390A - 2-脲基噻唑衍生物及其制备方法和作为抗肿瘤剂的应用 - Google Patents
2-脲基噻唑衍生物及其制备方法和作为抗肿瘤剂的应用 Download PDFInfo
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- CN1325390A CN1325390A CN99812929A CN99812929A CN1325390A CN 1325390 A CN1325390 A CN 1325390A CN 99812929 A CN99812929 A CN 99812929A CN 99812929 A CN99812929 A CN 99812929A CN 1325390 A CN1325390 A CN 1325390A
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- thiazoles
- urea
- propyl
- sec
- phenyl
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Abstract
式(Ⅰ)的2-脲基-1,3-噻唑衍生物或其可药用盐用于治疗与细胞依赖性激酶活性改变有关的细胞增殖性疾病,其中R是卤原子、硝基、可任选地取代的氨基或可任选地进一步取代的选自下列的基团:ⅰ)直链或支链C1-C6烷基;ⅱ)C3-C6环烷基;ⅲ)芳基或者直链或支链烷基链部分具有1-6个碳原子的芳烷基;R1是可任选地取代的选自下列的基团:ⅰ)直链或支链C1-C6烷基;ⅱ)3-6元碳环或5-7元杂环;ⅲ)芳基或芳基羰基;ⅳ)直链或支链烷基链部分具有1-6个碳原子的芳烷基;R2是氢、直链或支链C1-C4烷基或C2-C4链烯基或炔基;或者和与其相连的氮原子一起,R1和R2形成取代的或未取代的选自下列的基团:ⅰ)可任选地苯并稠合的或桥连的5-7元杂环;或ⅱ)9-11元螺杂环化合物。
Description
本发明涉及2-脲基噻唑衍生物,更具体地说,是涉及2-脲基-1,3-噻唑及其制备方法、含有这些化合物的药物组合物和它们作为治疗剂,尤其用于治疗癌症和细胞增殖性疾病的治疗剂的应用。
数种细胞毒性药物,例如氟尿嘧啶(5-FU)、阿霉素和喜树碱都产生破坏DNA或影响细胞代谢途径的作用,它们在许多情况下间接地阻断细胞周期。因此,由于对正常或肿瘤细胞都产生了不可逆的破坏作用,这些药物产生明显的毒副作用。基于这种原因,需要通过选择性俘获肿瘤细胞和使肿瘤细胞凋亡而具有高度特异性的抗肿瘤化合物,与目前使用的药物相比,它们具有显著的疗效和降低的毒性。
众所周知,通过细胞周期的进化受到一系列关卡控制点的支配,关卡控制点还被称为限制点,它们受一类已知称为依赖于细胞周期蛋白的蛋白激酶(cdk)的调节。cdk本身在多个方面受到调节,例如在与细胞周期蛋白的结合方面。通过细胞周期的正常进化受不同细胞周期蛋白/cdk复合物的协调活化或失活的调控。在G1期,人们认为细胞周期蛋白D/cdk4和E/cdk2介导了S期的开始。通过S期的进化需要活性细胞周期蛋白A/cdk2,而分裂中期又要求细胞周期蛋白A/cdc2(cdk1)和细胞周期蛋白B/cdc2活化。
关于细胞周期蛋白和依赖于细胞周期蛋白的蛋白激酶的概括性文献,参见,例如Kevin R.Webster等,药物研究实验观点(Exp.Opin.Invest.Drugs),1998,Vol,7(6),865-887。
肿瘤细胞中的关卡控制点不完善,这部分原因是由于cdk活性的失调。例如,已在肿瘤细胞中观察到了细胞周期蛋白E和cdk的表达发生变化,在小鼠中还发现cdk抑制剂p27KIP基因的缺失导致癌症的高发率。这种癌症高发现象支持了cdk是细胞周期进化中的速率限制性酶的看法,因此可作为这类治疗性干预的代表性分子靶。特别是,直接抑制cdk/细胞周期蛋白激酶的活性将有助于限制肿瘤细胞的无规增殖。
现在发现,本发明的2-脲基-1,3-噻唑具有cdk/细胞周期蛋白激酶抑制活性,因此可作为抗肿瘤剂用于治疗,同时这些化合物不具有目前使用的抗肿瘤药的已知毒性和副作用。更具体地说,本发明的化合物可用于各种癌症的治疗,所述癌症包括,但不限于:癌症,例如膀胱癌、乳腺癌、结肠癌、肾癌、肝癌、包括小细胞肺癌的肺癌、食管癌、胆囊癌、卵巢癌、胰腺癌、胃癌、宫颈癌、甲状腺癌、前列腺癌和包括鳞状细胞癌的皮肤癌;淋巴谱系造血肿瘤,包括白血病、急性淋巴细胞白血病、急性成淋巴细胞白血病、B细胞淋巴瘤、T细胞淋巴瘤、何杰金氏淋巴瘤、非何杰金氏淋巴瘤、多毛细胞淋巴瘤和Burkett淋巴瘤;骨髓谱系造血肿瘤,包括急慢性骨髓性白血病、脊髓发育不良性综合症和早幼粒细胞白血病、间充质源性肿瘤,包括纤维肉瘤和横纹肌肉瘤;中枢和外周神经系统肿瘤,包括星形细胞瘤、成神经细胞瘤、神经胶质瘤和神经鞘瘤;其它肿瘤,包括黑素瘤、精原细胞瘤、畸胎瘤、骨肉瘤、xenoderoma pigmentosum、角化棘皮瘤、甲状腺滤泡癌和卡波西肉瘤。
由于cdk在细胞增殖调节中的关键作用,这些2-脲基-1,3-噻唑衍生物可用于治疗各种细胞增殖性疾病,例如良性前列腺增生、家族性腺瘤病、息肉病、神经纤维瘤病、牛皮癣、与动脉粥样硬化有关的血管平滑细胞增殖、肺纤维化、关节炎、肾小球性肾炎以及术后狭窄和再狭窄。根据cdk5涉及tau蛋白磷酰化的事实(生物化学杂志(J.Biochem.),117,741-749,1995),本发明的化合物可用于治疗阿尔茨海默氏症。作为细胞凋亡的调节剂,本发明的化合物可用于治疗癌症、病毒感染、防止感染HIV个体的AIDS发展、自身免疫疾病和神经变性性疾病。本发明的化合物可用于抑制肿瘤的血管生成和迁移。
本发明的化合物还用作其它蛋白激酶的抑制剂,例如蛋白激酶C、her2、raf1、MEK1、MAP激酶、EGF受体、PDGF受体、IGF受体、PI3激酶、weel激酶、Src、Abl的抑制剂,因此可有效地治疗与其它蛋白激酶有关的疾病。
几种2-脲基-1,3-噻唑衍生物是现有技术中已知的,它们特别可作为除草剂或作为制备除草剂的合成中间体[概述性文献参见:ShellCo.的US3726891和C.A.83(1975):114381]。其中的一些实例是N’-甲基-和N’-乙基-N-(5-溴-2-噻唑基)-脲;N’-甲基-、N’-乙基-或N’-苯基-N-(5-溴-2-噻唑基)-脲;N-(5-氯-2-噻唑基)-N’,N’-二甲基-脲;N-(5-溴-2-噻唑基)-N’,N’-二甲基-脲;N’-甲基-和N’-苯基-N-(5-甲基-2-噻唑基)-脲。现有技术中还记载了作为治疗剂的其它2-脲基-1,3-噻唑衍生物。其中有FR M.7428(Melle-bezons)中作为镇静剂和抗炎剂描述的N-甲基-和N-苯基-N’-(5-氯-2-噻唑基)-脲或者WO97/40028(Vertex Pharmaceuticals Inc.)中作为5’-一磷酸肌苷脱氢酶抑制剂(IMPDH)描述的N-[4-(5-噁唑基)苯基]-N’-(5-甲基-2-噻唑基)-脲。
本发明提供式(Ⅰ)的2-脲基-1,3-噻唑衍生物或其可药用盐在制备治疗与改变的细胞依赖性激酶活性有关的细胞增殖性疾病的药物中的应用,
其中
R是卤原子、硝基、可任选地取代的氨基或可任选地进一步取代的选自下列的基团:
ⅰ)直链或支链C1-C6烷基;
ⅱ)C3-C6环烷基;
ⅲ)芳基或直链或支链烷基链部分具有1-6个碳原子的芳烷基;
R1是可任选地进一步取代的选自下列的基团:
ⅰ)直链或支链C1-C6烷基;
ⅱ)3-6元碳环或5-7元杂环;
ⅲ)芳基或芳基羰基;
ⅳ)直链或支链烷基链部分具有1-6个碳原子的芳烷基;
R2是氢、直链或支链C1-C4烷基或C2-C4链烯基或炔基;或者和与其结合的氮原子一起,
R1和R2形成取代的或未取代的选自下列的基团:
ⅰ)可任选地苯并稠合的或桥连的5-7元杂环;或
ⅱ)9-11元螺杂环化合物。
根据本发明的优选实施方案,所述细胞增殖性疾病选自癌症、阿尔茨海默氏症、病毒感染、自身免疫疾病或神经变性的疾病。
癌症(cancer)优选选自癌(carcinoma)、鳞状细胞癌、骨髓或淋巴谱系造血肿瘤、间充质源性肿瘤、中枢和外周神经系统肿瘤、黑素瘤、精原细胞瘤、畸胎瘤、骨肉瘤、xenoderomapigmentosum、角化棘皮瘤、甲状腺滤泡癌和卡波西肉瘤。
根据本发明的另一个优选实施方案,细胞增殖性疾病选自良性前列腺增生、家族性腺瘤病、息肉病、神经纤维瘤病、牛皮癣、与动脉粥样硬化有关的血管平滑细胞增殖、肺纤维化、关节炎、肾小球性肾炎以及术后狭窄和再狭窄。
另外,由于可用于治疗与改变的细胞依赖性激酶活性有关的细胞增殖性疾病,进而用于细胞周期抑制或cdk/细胞周期蛋白依赖性抑制,因此本发明的式(Ⅰ)化合物还能抑制肿瘤的血管生成和迁移。
如上所述,现有技术中已报道了作为有用治疗剂,例如抗炎剂、镇静剂和镇痛剂的本发明的某些式(Ⅰ)化合物。
因此,本发明的另一个目的是提供作为药物使用的式(Ⅰ)的2-脲基-1,3-噻唑衍生物或其可药用盐,其中
R是卤原子、硝基、可任选地取代的氨基或可任选地进一步取代的选自下列的基团:
ⅰ)直链或支链C1-C6烷基;
ⅱ)C3-C6环烷基;
ⅲ)芳基或直链或支链烷基链部分具有1-6个碳原子的芳烷基;
R1是可任选地进一步取代的选自下列的基团:
ⅰ)直链或支链C1-C6烷基;
ⅱ)3-6元碳环或5-7元杂环;
ⅲ)芳基或芳基羰基;
ⅳ)直链或支链烷基链部分具有1-6个碳原子的芳烷基;
R2是氢、直链或支链C1-C4烷基或C2-C4链烯基或炔基;或者和与其结合的氮原子一起,
R1和R2形成取代的或未取代的选自下列的基团:
ⅰ)可任选地苯并稠合的或桥连的5-7元杂环;或
ⅱ)9-11元螺杂环化合物;
条件是:
a)当R是氯原子并且R2是氢时,则R1不是甲基、苯基或三氟甲基苯基;和
b)当R是甲基并且R2是氢时,则R1不是4-(5-噁唑基)苯基。
在上述式(Ⅰ)化合物中,有数种衍生物是新的。
其中
R是卤原子、硝基、可任选地取代的氨基或可任选地进一步取代的选自下列的基团:
ⅰ)直链或支链C1-C6烷基;
ⅱ)C3-C6环烷基;
ⅲ)芳基或直链或支链烷基链部分具有1-6个碳原子的芳烷基;
R1是可任选地进一步取代的选自下列的基团:
ⅰ)直链或支链C1-C6烷基;
ⅱ)3-6元碳环或5-7元杂环;
ⅲ)芳基或芳基羰基;
ⅳ)直链或支链烷基链部分具有1-6个碳原子的芳烷基;
R2是氢、直链或支链C1-C4烷基或C2-C4链烯基或炔基;或者和与其结合的氮原子一起,
R1和R2形成取代的或未取代的选自下列的基团:
ⅰ)可任选地苯并稠合的或桥连的5-7元杂环;或
ⅱ)9-11元螺杂环化合物;
条件是:
a)当R是氯或溴并且R2是氢时,则R1不是未取代的C1-C3烷基、苯基、三氟甲基苯基或可任选地取代的苯基羰基;
b)当R是甲基并且R2是氢时,则R1不是甲基、苯基或4-(5-噁唑基)苯基;
c)当R是硝基苯基并且R2是氢时,则R1不是卤代烷基;
d)当R是溴或氯时,R1和R2不同时为甲基。
式(Ⅰ)化合物可具有非对称碳原子,因此可以外消旋混合物或单个的旋光异构体形式存在。因此,式(Ⅰ)化合物的所有可能的异构体及其混合物以及它们的代谢产物和可药用的生物学前体(也称为前药),以及它们的应用均包括在本发明的范围之内。
在本说明书中,除非另有说明,术语卤原子是指氯、溴、氟或碘原子。
术语可任选地取代的氨基是指其中一个或两个氢原子被其它取代基任选地取代的氨基,所述取代基可以相同或不同(如下所述)。
术语直链或支链C1-C6烷基是指,例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基和正己基等。
术语直链或支链C2-C4链烯基或炔基是指,例如乙烯基、烯丙基、异丙烯基、1-、2-或3-丁烯基、异丁烯基、乙炔基、1-或2-丙炔基和丁炔基等。
术语C3-C6环烷基是指环丙基、环丁基、环戊基或环己基。
术语芳基,无论是其本身,或芳烷基或芳基羰基等中的芳基,均是指单、双或多碳环以及杂环烃,具有1-4个环部分,所述环部分可以彼此稠合或通过单键相连,其中至少有一个碳环或杂环是芳香的。芳基的实例包括苯基、联苯基、α-或β-萘基、四氢萘基、茚基、二氢茚基、吡啶基、吡嗪基、嘧啶基、哒嗪基、吲哚基、异吲哚基、二氢异吲哚基、咪唑基、咪唑并吡啶基、苯并咪唑基、二氢苯并咪唑基、1,2-亚甲二氧基苯基、噻唑基、异噻唑基、苯并噻唑基、吡咯基、吡唑基、呋喃基、苯并四氢呋喃基、苯并呋喃基、二氢苯并呋喃基、噁唑基、异噁唑基、噻吩基、苯并噻吩基、四唑基、喹啉基、异喹啉基、二氢异喹啉基、喹喔啉基、二氢喹喔啉基、噁二唑基和四氢苯并二氮杂基等。
术语3-6元碳环包括,但不限于C3-C6环烷基,还指不饱和碳环烃,例如环戊烯或环己烯。
术语5-7元杂环,包括芳香杂环(也称为芳基),还指其中的一个或多个碳原子是被例如氮、氧或硫的杂原子置换的饱和或部分不饱和的5-7元碳环。
5-7元杂环的实例是1,3-二氧戊环、吡喃、吡咯烷、吡咯啉、咪唑烷、吡唑烷、吡唑啉、哌啶、哌嗪、N-烷基哌嗪、吗啉和四氢呋喃等,它们可任选是苯并稠合的或进一步被取代的。
术语桥连杂环是指至少包括具有两个或多个共同环原子的两个环(其中一个环是含氮杂环)并且的系统,例如氮杂双环[3.2.2]壬烷。
术语9-11元螺杂环是指至少包括具有一个共同环碳原子的两个环(其中一个环是含氮杂环)的系统,例如1,4-二氧杂-8-氮杂螺[4.5]癸烷和1,3,8-三氮杂螺[4.5]癸烷。
根据如上所示的取代基的含义,任何R、R1和R2基团可在任何自由位置被一个或多个,例如1-6个选自下列的取代基任选地取代:卤素、硝基、氧代(=O)、羧基、氰基、烷基、全氟烷基、链烯基、炔基、环戊基、芳基、杂环基、氨基和其衍生基团,例如烷基氨基、烷氧羰基烷基氨基、二烷基氨基、芳基氨基、二芳基氨基、烷基磺酰氨基或芳基脲基;羰基氨基和其衍生基团,例如甲酰氨基、烷基羰基氨基、链烯基羰基氨基、芳基羰基氨基、烷氧羰基氨基;氧取代的肟,例如烷氧羰基烷氧基亚氨基或烷氧基亚氨基;羟基及其衍生基团,例如烷氧基、芳氧基、烷基羰氧基、芳基羰氧基、环烯氧基;羰基及其衍生基团,例如烷基羰基、芳基羰基、烷氧羰基、芳氧羰基、环烷氧羰基、氨基羰基、烷基氨基羰基、二烷基氨基羰基;含硫的衍生基团,例如烷硫基、芳硫基、烷基磺酰基、芳基磺酰基、烷基亚磺酰基、芳基亚磺酰基、芳基磺酰氧基、氨基磺酰基、烷基氨基磺酰基或二烷基氨基磺酰基。如果合适,R、R1和R2上的上述可能的取代基也可进一步被一个或多个上述基团取代。下面给出了其中R、R1和R2被一个或多个上述取代基(如上所述,这些取代基也可任选地进一步被取代)取代的式(Ⅰ)化合物的实例。
式(Ⅰ)化合物的可药用盐是无机或有机酸的酸加成盐,例如硝酸、盐酸、氢溴酸、硫酸、高氯酸、磷酸、乙酸、三氟乙酸、丙酸、乙醇酸、乳酸、草酸、丙二酸、苹果酸、马来酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、苦杏仁酸、甲磺酸、羟乙磺酸和水杨酸的酸加成盐;以及与无机或有机碱形成的盐,例如与碱金属或碱土金属,尤其是钠、钾、钙或镁的氢氧化物、碳酸盐或碳酸氢盐形成的盐,与非环的或环状胺,优选甲胺、乙胺、二乙胺、三乙胺或哌啶形成的盐。
式(Ⅰ)化合物可存在非对称碳原子,因此可以外消旋混合物或单个旋光异构体形式存在。
因此,利用式(Ⅰ)化合物的所有可能的异构体和其混合物或者它们的代谢物和可药用生物学前体(也称为前药)作为抗肿瘤剂也都包括在本发明的范围之内。
本发明的优选化合物是式(Ⅰ)化合物,其中R是卤原子、直链或支链的C1-C4烷基、苯基或环烷基;R2是氢并且R1是可任选地取代的选自烷基、芳基或芳烷基的基团。
这类化合物中更优选的是式(Ⅰ)化合物,其中R是溴或氯、直链或支链C1-C4烷基、苯基或环烷基;R2是氢并且R1是可任选地取代的芳基或者烷基链部分具有1-4个碳原子的芳烷基或杂环基-烷基。
其中
R是卤原子或选自下列的基团:硝基、氨基、烷基氨基、羟烷基氨基、芳基氨基、C3-C6环烷基、直链或支链C1-C6烷基、可任选地下列基团取代:羟基、烷硫基、烷氧基、氨基、烷基氨基、烷氧羰基烷基氨基、烷基羰基、烷基磺酰基、烷氧羰基、羧基、芳基、可任选地被一个或多个羟基、卤素、硝基、烷氧基、芳氧基、烷硫基、芳硫基、氨基、烷基氨基、二烷基氨基、N-烷基哌嗪基、4-吗啉基、芳基氨基、氰基、烷基、苯基、氨基磺酰基、氨基羰基、烷基羰基、芳基羰基、烷氧羰基或羧基取代,或者R是芳基、可任选地被一个或多个羟基、卤素、硝基、烷氧基、芳氧基、烷硫基、芳硫基、氨基、烷基氨基、二烷基氨基、N-烷基哌嗪基、4-吗啉基、芳基氨基、氰基、烷基、苯基、氨基磺酰基、氨基羰基、烷基羰基、芳基羰基、烷氧羰基或羧基取代;
R1是直链或支链C1-C6烷基或者芳基,各自可任选地如上述R所述的被取代;
R2是氢原子;
条件是:
a)当R是氯或溴时,R1不是未取代的C1-C3烷基、苯基、三氟甲基苯基或任选地取代的苯基羰基;
b)当R是甲基时,R1不是甲基、苯基或4-(5-噁唑基)苯基;
c)当R是硝基苯基时,R1不是卤代烷基。
另一类优选的化合物是式(Ⅰ)化合物,其中R是直链或支链C1-C6烷基,并且R1、R2和与它们结合的氮原子一起形成取代的或未取代的、可任选地苯并稠合的或桥连的5-7元杂环或9-11元螺杂环。
另一类优选的式(Ⅰ)化合物是化合物,其中R是直链或支链C1-C6烷基;R2是直链或支链C1-C4烷基或者C2-C4链烯基或炔基并且R1是芳基或者支链或直链烷基链具有1-4个碳原子的芳烷基。
本发明的优选化合物在适当的时候可以呈可药用盐,例如氢溴酸盐或盐酸盐形式,它们是下列化合物:
1)N-(5-异丙基-1,3-噻唑-2-基)-N’-苯基脲;
2)N-(5-溴-1,3-噻唑-2-基)-N’-苯基脲;
3)N-(5-苯基-1,3-噻唑-2-基)-N’-苯基脲;
4)N-(5-环丙基-1,3-噻唑-2-基)-N’-苯基脲;
5)N-(5-溴-1,3-噻唑-2-基)-N’-(4-氨磺酰-苯基)脲;
6)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-氨磺酰-苯基)脲;
7)N-(5-苯基-1,3-噻唑-2-基)-N’-(4-氨磺酰-苯基)脲;
8)N-(5-环丙基-1,3-噻唑-2-基)-N’-(4-氨磺酰-苯基)脲;
9)N-(5-异丙基-1,3-噻唑-2-基)-N’-(3-甲氧基-苯基)脲;
10)N-(5-溴-1,3-噻唑-2-基)-N’-(3-甲氧基-苯基)脲;
11)N-(5-苯基-1,3-噻唑-2-基)-N’-(3-甲氧基-苯基)脲;
12)N-(5-环丙基-1,3-噻唑-2-基)-N’-(3-甲氧基-苯基)脲;
13)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-氯-苯基)脲;
14)N-(5-溴-1,3-噻唑-2-基)-N’-(4-氯-苯基)脲;
15)N-(5-苯基-1,3-噻唑-2-基)-N’-(4-氯-苯基)脲;
16)N-(5-环丙基-1,3-噻唑-2-基)-N’-(4-氯-苯基)脲;
17)N-(5-异丙基-1,3-噻唑-2-基)-N’-(3-氯-苯基)脲;
18)N-(5-溴-1,3-噻唑-2-基)-N’(3-氯-苯基)脲;
19)N-(5-苯基-1,3-噻唑-2-基)-N’-(3-氯-苯基)脲;
20)N-(5-环丙基-1,3-噻唑-2-基)-N’-(3-氯-苯基)脲;
21)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2-氯-苯基)脲;
22)N-(5-溴-1,3-噻唑-2-基)-N’-(2-氯-苯基)脲;
23)N-(5-苯基-1,3-噻唑-2-基)-N’-(2-氯-苯基)脲;
24)N-(5-环丙基-1,3-噻唑-2-基)-N’-(2-氯-苯基)脲;
25)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-甲氧基-苯基)脲;
26)N-(5-溴-1,3-噻唑-2-基)-N’-(4-甲氧基-苯基)脲;
27)N-(5-苯基-1,3-噻唑-2-基)-N’-(4-甲氧基-苯基)脲;
28)N-(5-环丙基-1,3-噻唑-2-基)-N’-(4-甲氧基-苯基)脲;
29)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-羟基-苯基)脲;
30)N-(5-溴-1,3-噻唑-2-基)-N’-(4-羟基-苯基)脲;
31)N-(5-苯基-1,3-噻唑-2-基)-N’-(4-羟基-苯基)脲;
32)N-(5-环丙基-1,3-噻唑-2-基)-N’-(4-羟基-苯基)脲;
33)N-(5-异丙基-1,3-噻唑-2-基)-N’-(3-羟基-苯基)脲;
34)N-(5-溴-1,3-噻唑-2-基)-N’-(3-羟基-苯基)脲;
35)N-(5-苯基-1,3-噻唑-2-基)-N’-(3-羟基-苯基)脲;
36)N-(5-环丙基-1,3-噻唑-2-基)-N’-(3-羟基-苯基)脲;
37)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2-甲氧基-苯基)脲;
38)N-(5-溴-1,3-噻唑-2-基)-N’-(2-甲氧基-苯基)脲;
39)N-(5-苯基-1,3-噻唑-2-基)-N’-(2-甲氧基-苯基)脲;
40)N-(5-环丙基-1,3-噻唑-2-基)-N’-(2-甲氧基-苯基)脲;
41)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2-羟基-苯基)脲;
42)N-(5-溴-1,3-噻唑-2-基)-N’-(2-羟基-苯基)脲;
43)N-(5-苯基-1,3-噻唑-2-基)-N’-(2-羟基-苯基)脲;
44)N-(5-环丙基-1,3-噻唑-2-基)-N’-(2-羟基-苯基)脲;
45)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-硝基-苯基)脲;
46)N-(5-溴-1,3-噻唑-2-基)-N’-(4-硝基-苯基)脲;
47)N-(5-苯基-1,3-噻唑-2-基)-N’-(4-硝基-苯基)脲;
48)N-(5-环丙基-1,3-噻唑-2-基)-N’-(4-硝基-苯基)脲;
49)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-氨基-苯基)脲;
50)N-(5-溴-1,3-噻唑-2-基)-N’-(4-氨基-苯基)脲;
51)N-(5-苯基-1,3-噻唑-2-基)-N’-(4-氨基-苯基)脲;
52)N-(5-环丙基-1,3-噻唑-2-基)-N’-(4-氨基-苯基)脲;
53)N-(5-异丙基-1,3-噻唑-2-基)-N’-(3-硝基-苯基)脲;
54)N-(5-溴-1,3-噻唑-2-基)-N’-(3-硝基-苯基)脲;
55)N-(5-苯基-1,3-噻唑-2-基)-N’-(3-硝基-苯基)脲;
56)N-(5-环丙基-1,3-噻唑-2-基)-N’-(3-硝基-苯基)脲;
57)N-(5-异丙基-1,3-噻唑-2-基)-N’-(3-氨基-苯基)脲;
58)N-(5-溴-1,3-噻唑-2-基)-N’-(3-氨基-苯基)脲;
59)N-(5-苯基-1,3-噻唑-2-基)-N’-(3-氨基-苯基)脲;
60)N-(5-环丙基-1,3-噻唑-2-基)-N’-(3-氨基-苯基)脲;
61)N-(5-异丙基-1,3-噻唑-2-基)-N’-苄基脲;
62)N-(5-溴-1,3-噻唑-2-基)-N’-苄基脲;
63)N-(5-苯基-1,3-噻唑-2-基)-N’-苄基脲;
64)N-(5-环丙基-1,3-噻唑-2-基)-N’-苄基脲;
65)N-(5-异丙基-1,3-噻唑-2-基)-N’-(吡啶-3-基)脲;
66)N-(5-溴-1,3-噻唑-2-基)-N’-(吡啶-3-基)脲;
67)N-(5-苯基-1,3-噻唑-2-基)-N’-(吡啶-3-基)脲;
68)N-(5-环丙基-1,3-噻唑-2-基)-N’-(吡啶-3-基)脲;
69)N-(5-溴-1,3-噻唑-2-基)-N’-(吡啶-4-基)脲;
70)N-(5-异丙基-1,3-噻唑-2-基)-N’-(吡啶-4-基)脲;
71) N-(5-苯基-1,3-噻唑-2-基)-N’-(吡啶-4-基)脲;
72)N-(5-环丙基-1,3-噻唑-2-基)-N’-(吡啶-4-基)脲;
73)N-(5-异丙基-1,3-噻唑-2-基)-N’-(吡啶-2-基)脲;
74)N-(5-溴-1,3-噻唑-2-基)-N’-(吡啶-2-基)脲;
75)N-(5-苯基-1,3-噻唑-2-基)-N’-(吡啶-2-基)脲;
76)N-(5-环丙基-1,3-噻唑-2-基)-N’-(吡啶-2-基)脲;
77)N-(5-异丙基-1,3-噻唑-2-基)-N’-(苯并噻吩-2-基)脲;
78)N-(5-溴-1,3-噻唑-2-基)-N’-(苯并噻吩-2-基)脲;
79)N-(5-苯基-1,3-噻唑-2-基)-N’-(苯并噻吩-2-基)脲;N-(5-环丙基-1,3-噻唑-2-基)-N’-(苯并噻吩-2-基)脲;
80)N-(5-异丙基-1,3-噻唑-2-基)-4-吗啉甲酰胺;
81)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-甲基苯基)脲;
82)N-(5-异丙基-1,3-噻唑-2-基)-N’-(3-氟苯基)脲;
83)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-氰基苯基)脲;
84)N-(5-异丙基-1,3-噻唑-2-基)-N’-(3-氰基苯基)脲;
85)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2,6-二甲基苯基)脲;
86)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-氟苯基)脲;
87)N-(5-异丙基-1,3-噻唑-2-基)-N’-(3-乙酰基苯基)脲;
88)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-乙酰基苯基)脲;
89)3-({[(5-异丙基-1,3-噻唑-2-基)氨基]羰基}氨基)苯甲酸;
90)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-异丙基苯基)脲;
91)3-({[(5-异丙基-1,3-噻唑-2-基)氨基]羰基}氨基)苯甲酰胺;
92)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-甲氧基苄基)脲;
93)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-丁基苯基)脲;
94)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-三氟甲基苯基)脲;
95)N-(5-异丙基-1,3-噻唑-2-基)-N’-3-溴苯基)脲;
96)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-环己基苯基)脲;
97)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-苯氧基苯基)脲;
98)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-苄氧基苯基)脲;
99)N-(5-异丙基-1,3-噻唑-2-基)-N’-(3,5-二甲基苯基)脲;
100)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2,3-二甲基苯基)脲;
101)N-(5-异丙基-1,3-噻唑-2-基)-N’-(3-甲氧基[1,1’-联苯]-4-基)脲;
102)N-(5-异丙基-1,3-噻唑-2-基)-3,4-二氢-2(1H)-异喹啉甲酰胺;
103)N-苄基-N’-(5-异丙基-1,3-噻唑-2-基)-N-甲基脲;
104)N-(5-异丙基-1,3-噻唑-2-基)-6,7-二甲氧基-3,4-二氢-2(1H)-异喹啉甲酰胺;
105)N-(5-异丙基-1,3-噻唑-2-基)-N’-[(3-氯-4-甲基)-苯基]脲;
106)N-(5-异丙基-1,3-噻唑-2-基)-N’-[(3-氯-6-甲基)-苯基]脲;
107)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2,5-二甲氧基苯基)脲;
108)N-(5-异丙基-1,3-噻唑-2-基)-N’-(3,4-二甲氧基苯基)脲;
109)N-(5-异丙基-1,3-噻唑-2-基)-N’-[(2-甲氧基-5-氯)-苯基]脲;
110)N-(5-异丙基-1,3-噻唑-2-基)-N’-((2-氯-4-甲氧基苯基)脲;
111)N-(5-异丙基-1,3-噻唑-2-基)-N’-(3,5-二氯苯基)脲;
112)N-[(1,1’-联苯)-2-基]-N’-(5-异丙基-1,3-噻唑-2-基)脲;
113)N-乙基-N’-(5-异丙基-1,3-噻唑-2-基)-N-苯基脲;
114)N-[4-({[(5-异丙基-1,3-噻唑-2-基)氨基]羰基}氨基)-2-甲氧基苯基]乙酰胺;
115)2-({[(5-异丙基-1,3-噻唑-2-基)氨基]羰基}氨基)-N-苯基苯甲酰胺;
116)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2-吗啉代苯基)脲;
117)N-[4-({[(5-异丙基-1,3-噻唑-2-基)氨基]羰基}氨基)苯基]-N-甲基乙酰胺;
118)N-[2-{[环己基(甲基)氨基]甲基}苯基]-N’-(5-异丙基-1,3-噻唑-2-基)脲;
119)N-[3-({[(5-异丙基-1,3-噻唑-2-基)氨基]羰基}氨基)-4-甲氧基苯基]乙酰胺;
120)N-(5-异丙基-1,3-噻唑-2-基)-4-(4-甲氧基苯基)-1-哌嗪甲酰胺;
121)N-(2-呋喃甲基)-N’-(5-异丙基-1,3-噻唑-2-基)脲;
122)N-(4-氟苯基)-N’-(5-异丙基-1,3-噻唑-2-基)脲;
123)N-(2-甲氧基苄基)-N’-(5-异丙基-1,3-噻唑-2-基)脲;
124)N-(5-异丙基-1,3-噻唑-2-基)-N’-[2-(1-甲基-1H-吡咯-2-基)乙基]脲;
125)N-(3,4-二甲氧基苄基)-N’-(5-异丙基-1,3-噻唑-2-基)脲;
126)N-(5-异丙基-1,3-噻唑-2-基)-4-氧代-1-苯基-1,3,8-三氮杂螺[4.5]癸烷-8-甲酰胺;
127)n-(5-异丙基-1,3-噻唑-2-基)-1,4-二氧代-8-氮杂螺[4.5]癸烷-8-甲酰胺;
128)N-(5-异丙基-1,3-噻唑-2-基)-N’-[2-(1-哌啶基)乙基]脲;
129)N-(5-异丙基-1,3-噻唑-2-基)-N’-[2-(1-吗啉基)乙基]脲;
130)4-(4-氟苯基)-N-(5-异丙基-1,3-噻唑-2-基)-1-哌嗪甲酰胺;
131)N-[4-(4-氯苯基)-3-乙基-5-异噁唑基]-N’-(5-异丙基-1,3-噻唑-2-基)脲;
132)4-[(4-氟苯基)(羟基)甲基]-N-(5-异丙基-1,3-噻唑-2-基)-1-哌嗪甲酰胺;
133)N-(3-乙炔基苯基)-N’-(5-异丙基-1,3-噻唑-2-基)脲;
134)N-(2-甲氧基-3-氟苯基)-N’-(5-异丙基-1,3-噻唑-2-基)脲;
135)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-氧代-1-哌啶基)脲;
136)N-(3-乙酰氨基苯基)-N’-(5-异丙基-1,3-噻唑-2-基)脲;
137)N-[3-(2-呋喃基)-1H-吡唑-5-基]-N’-(5-异丙基-1,3-噻唑-2-基)脲;
138)N-{4-[乙基(异丙基)氨基]苯基}-N’-(5-异丙基-1,3-噻唑-2-基)脲;
139)N-(1,3-苯并间二氧杂环戊烯-5-基)-N’-(5-异丙基-1,3-噻唑-2-基)脲;
140)5-({[(5-异丙基-1,3-噻唑-2-基)氨基]羰基}氨基)-1-苯基-1H-吡唑-4-甲酰胺;
141)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-吡啶甲基)脲;
142)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2-吡嗪基)脲;
143)n-(5-异丙基-1,3-噻唑-2-基)-N’-(5-苯基-1,3,4-噁二唑-2-基)脲;
144)N-(5-异丙基-1,3-噻唑-2-基)-4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)-1-哌啶甲酰胺;
145)N-(1,3-苯并噻唑-6-基)-N’-(5-异丙基-1,3-噻唑-2-基)脲;
146)N-(1,3-二甲基-1H-吡唑-5-基)-N’-(5-异丙基-1,3-噻唑-2-基)脲;
147)N-(3-苯基-1-甲基-1H-吡唑-5-基)-N’-(5-异丙基-1,3-噻唑-2-基)脲;
148)N-(5-异丙基-1,3-噻唑-2-基)-3-羟基-1-哌啶甲酰胺;
149)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2-甲基-1,3-二氧代-2,3-二氢-1H-异吲哚-5-基)脲;
150)N-(5-异丙基-1,3-噻唑-2-基)-4-苄基-1-哌嗪甲酰胺;
151)N-(5-异丙基-1,3-噻唑-2-基)-4-甲基-1-哌嗪甲酰胺;
152)4-羟基-N-(5-异丙基-1,3-噻唑-2-基)-1-哌啶甲酰胺;
153)N-(5-异丙基-1,3-噻唑-2-基)-3-氮杂双环[3.2.2]壬烷-3-甲酰胺;
154)N-(5-异丙基-1,3-噻唑-2-基)-4-(4-乙酰基苯基)-1-哌嗪甲酰胺;
155)4-[二(4-氟苯基)-N-(5-异丙基-1,3-噻唑-2-基)-1-哌嗪甲酰胺;
156)N-(5-异丙基-1,3-噻唑-2-基)-4-氧代-2,3,4,5-四氢-1H-1,5-苯并二氮杂-1-甲酰胺;
157)N-(5-异丙基-1,3-噻唑-2-基)-N’-(5,6,7,8-四氢-1-萘基)脲;
158)N-(4-苯基-2-噻唑基)-N’-(5-异丙基-1,3-噻唑-2-基)脲;
159)4-(4-氟苯甲酰基)-N-(5-异丙基-1,3-噻唑-2-基)-1-哌啶甲酰胺;
160)N-(5-异丙基-1,3-噻唑-2-基)-N’-(1,3-二氢-2-苯并呋喃-5-基)脲;
161)N-(5-异丙基-1,3-噻唑-2-基)-4’-(2-嘧啶基)-1-哌嗪甲酰胺;
162)N-(5-异丙基-1,3-噻唑-2-基)-3-氧代-3,4-二氢-1(2H)-喹喔啉;
163)N-(5-异丙基-1,3-噻唑-2-基)-N’-(1H-吲唑-6-基)脲;
164)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2-氯苄基)脲;
165)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2,4-二氯苄基)脲;
166)N-(5-异丙基-1,3-噻唑-2-基)-N’-(3-氟苄基)脲;
167)N-(5-异丙基-1,3-噻唑-2-基)-N’-(3,4-二氯苄基)脲;
168)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2,4-二氟苄基)脲;
169)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2,5-二氟苄基)脲;
170)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2,6-二氟苄基)脲;
171)N-(5-异丙基-1,3-噻唑-2-基)-N’-[(4-羟基-3-甲氧基)苄基]脲;
172)N-(5-异丙基-1,3-噻唑-2-基)-N’-(5-甲基-2-呋喃基)脲;
173)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-甲基磺酰基苄基)脲;
174)N-[(1R,2R)-2-羟基-2,3-二氢-1H-茚-1-基]-N’-(5-异丙基-1,3-噻唑-2-基)脲;
175)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-氯苄基)脲;
176)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2-吡啶甲基)脲;
177)N-(5-异丙基-1,3-噻唑-2-基)-N’-(3,5-二甲氧基苄基)脲;
178)N-(5-异丙基-1,3-噻唑-2-基)-N’-(3-吡啶甲基)脲;
179)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-三氟苄基)脲;
180)N-(5-异丙基-1,3-噻唑-2-基)-N’-(3,4,5-三甲氧基苄基)脲;
181)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2,4-二甲氧基苄基)脲;
182)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-二甲基氨基苄基)脲;
183)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2,5-二甲氧基苄基)脲;
184)N-(5-异丙基-1,3-噻唑-2-基)-N’-[(2-氯-6-苯氧基)苄基]脲;
185)N-(5-异丙基-1,3-噻唑-2-基)-N’-[(1R,2S)-2-羟基-2,3-二氢-1H-茚-1-基]-脲;
186)N-(5-异丙基-1,3-噻唑-2-基)-N’-[(3-羟基-4-甲基)苯基]脲;
187)N-(5-异丙基-1,3-噻唑-2-基)-N’-[4-(1H-苯并咪唑-2-基)苯基]脲;
188)N-(5-异丙基-1,3-噻唑-2-基)-N’-(3-苯基-1H-吡唑-5-基)脲;
189)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2-甲基-6-喹啉基)脲;
190)N-(5-异丙基-1,3-噻唑-2-基)-N’-[4-(氰基甲基)苯基]脲;
191)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2-喹啉基)脲;
192)N-(5-异丙基-1,3-噻唑-2-基)-N’-(1-氧代-2,3-二氢-1H-茚-5-基)脲;
193)N-(5-异丙基-1,3-噻唑-2-基)-N’-(3-氧代-1,3-二氢-2-苯并呋喃-5-基)脲;
194)N-(5-异丙基-1,3-噻唑-2-基)-N’-(5-氧代-5,6,7,8-四氢-2-萘基)脲;
195)3-({[(5-异丙基-1,3-噻唑-2-基)氨基]羰基}氨基)-4-甲基苯甲酸甲酯;
196)4-({[(5-异丙基-1,3-噻唑-2-基)氨基]羰基}氨基)-3-甲基苯甲酸甲酯;
197)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-咪唑并[1,2-a]吡啶-2-基-苯基)脲;
198)4-({[(5-异丙基-1,3-噻唑-2-基)氨基]羰基}氨基)-苯甲酸乙酯;
199)(2R)-1-苄基-2-({[(5-异丙基-1,3-噻唑-2-基)氨基]羰基}氨基)丙酰胺;
200)2-羟基-5-({[(5-异丙基-1,3-噻唑-2-基)氨基]羰基}苯甲酸;
201)2-氯-5-({[(5-异丙基-1,3-噻唑-2-基)氨基]羰基}氨基)苯甲酸;
202)3-({[(5-异丙基-1,3-噻唑-2-基)氨基]羰基}氨基)苯甲酸;
203)N-(5-异丙基-1,3-噻唑-2-基)-N’-(5-甲基-3-异噁唑基)脲;
204)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2,6-二甲氧基苯基)脲;
205)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2,3-二甲氧基苄基)脲;
206)N-(5-异丙基-1,3-噻唑-2-基)-N’-(3,4-二氟苄基)脲;
207)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2,4-二甲基苯基)脲;
208)N-(5-异丙基-1,3-噻唑-2-基)-N’-(1H-苯并咪唑-5-基)脲;
209)N-(5-异丙基-1,3-噻唑-2-基)-N’-[(R)-苯基甘氨酰氨基]脲;
210)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2-苯氧基乙酰氨基)脲;
211)N-(5-异丙基-1,3-噻唑-2-基)-N’-[(S)-苯基甘氨酰氨基]脲;
212)N-(5-异丙基-1,3-噻唑-2-基)-N’-{2-[(1-甲基-1H-咪唑-2-基)甲氧基]苯基}脲;
213)N-(3-碘苯基)-N’-(5-异丙基-1,3-噻唑-2-基)脲;
214)N-(5-异丙基-1,3-噻唑-2-基)-N’-[3-(3-甲氧基-1-丙炔基)苯基]脲;
215)N-{3-[3-(二甲基氨基)-1-丙炔基]苯基}-N’-(5-异丙基-1,3-噻唑-2-基)脲;
216)N-[4-({[(5-异丙基-1,3-噻唑-2-基)氨基]羰基}氨基)苯基]甲磺酰胺;
217)2-[3-({[(5-异丙基-1,3-噻唑-2-基氨基)羰基]氨基]苯胺基]乙酰胺;
218)N-[3-(3-羟基-1-丁炔基)苯基]-N’-(5-异丙基-1,3-噻唑-2-基)脲;
219)N-(咪唑并[1,2-a]吡啶-2-基-甲基)-N’-(5-异丙基-1,3-噻唑-2-基)脲;
220)2-[({[(5-异丙基-1,3-噻唑-2-基)氨基]羰基}(2-丙炔基)氨基)甲基]苯磺酰胺;
221)N-[1H-吲哚-6-基]-N’-(5-异丙基-1,3-噻唑-2-基)脲;
222)N-[(1S)-2-羟基-1-苯基乙基]-N’-(5-异丙基-1,3-噻唑-2-基)脲;
223)N-[1H-吲哚-5-基]-N’-(5-异丙基-1,3-噻唑-2-基)脲;
224)N-[(1R-2-羟基-1-苯乙基]-N’-(5-异丙基-1,3-噻唑-2-基)脲;
225)N-(5-异丙基-1,3-噻唑-2-基)-N’-丁基脲;
226)N-(5-异丙基-1,3-噻唑-2-基)-N’-苯甲酰基脲;
227)N-(5-甲基-1,3-噻唑-2-基)-N’-(2,6-二甲基苯基)脲;
228)N-(5-甲基-1,3-噻唑-2-基)-N’-苄基脲;
229)N-(5-甲基-1,3-噻唑-2-基)-N’-丁基脲;
230)N-(5-甲基-1,3-噻唑-2-基)-4-吗啉甲酰胺;
231)N-(5-甲基-1,3-噻唑-2-基)-N’-苯基脲;
232)N-(5-甲基-1,3-噻唑-2-基)-N’-(4-甲氧基苄基脲;
233)N-(5-甲基-1,3-噻唑-2-基)-N’-(4-氟苯基)脲;
234)N-[(1-乙基-2-吡咯烷基)甲基]-N’-(5-甲基-1,3-噻唑-2-基)脲;
235)N-(5-甲基-1,3-噻唑-2-基)-N’-(5-羟基-1H-吡唑-3-基)脲;
236)N-(5-甲基-1,3-噻唑-2-基)-N’-(3-吡啶基)脲;
237)N-(4-氟苯基)-N’-(5-甲基-1,3-噻唑-2-基)脲;
本发明的式(Ⅰ)化合物及其盐可通过,例如包括下列步骤的方法获得:
a)当R2是氢原子时
将其中R定义如上的式(Ⅱ)化合物
与其中R1定义如上的式(Ⅲ)化合物
R1-NCO (Ⅲ)
反应;或者
b)当R2是氢原子时或具有如上所述的含义时
并且如果需要,可将式(Ⅰ)的2-脲基-1,3-噻唑衍生物转化为另一种此类的式(Ⅰ)衍生物和/或其盐。
或者,使(Ⅰ)化合物可通过包括下列步骤的方法获得:
将其中R定义如上的式(Ⅱ)化合物与4-硝基苯基-氯甲酸酯或其聚合物支持形式反应,得到其中R定义如上的式(Ⅵ)化合物或其聚合物的支持形式;
并且如果需要,可将式(Ⅰ)的2-脲基-1,3-噻唑衍生物或其聚合物支持形式转化为另一种此类的式(Ⅰ)衍生物和/或其盐。
再者,使用聚合物支持物进行的方法的常规反应条件是本领域技术人员所熟知的。
如果按照上述方法制备的式(Ⅰ)化合物是以异构体混合物的形式获得的,则可按照常规技术将它们分离为式(Ⅰ)异构体单体,这种技术对于本领域技术人员来说是显而易见的,并且包括于本发明的范围之内。同样,按照本领域熟知的方法,将相应的盐转化为游离2-脲基-1,3-噻唑衍生物(Ⅰ)的方法也包括在本发明的范围之内。
上述方法的变化方法是可按照熟知方法进行的类似方法。
式(Ⅱ)化合物与式(Ⅲ)化合物之间的反应,或者式(Ⅳ)化合物与式(Ⅴ)化合物之间的反应可在适合的溶剂,例如二氯甲烷、氯仿、四氢呋喃、乙醚、1,4-二噁烷、乙腈、甲苯或丙酮中在室温至回流温度下进行约1-96小时。
由式(Ⅱ)化合物与4-硝基苯基氯甲酸酯或其聚合物支持形式得到式(Ⅵ)化合物的反应在叔胺碱,例如三乙胺、N-甲基吗啉、N,N-二异丙基乙胺或吡啶的存在下,在适合的溶剂,例如甲苯、二氯甲烷、氯仿、乙醚、四氢呋喃、乙腈、二噁烷或N,N-二甲基甲酰胺中,在约-10℃至室温下进行。
式(Ⅵ)化合物与式(Ⅴ)化合物得到式(Ⅰ)化合物的反应在适合的溶剂,例如甲苯、二氯甲烷、氯仿、乙醚、四氢呋喃、乙腈、1,4-二噁烷或N,N-二甲基甲酰胺中,在室温至回流温度下进行。在上述路线中,至于涉及到固相方法,式(Ⅷ)化合物可如下制备:在一种碱,例如叔丁醇钾、碳酸钾或者钾或钠的氢氧化物的存在下,式(Ⅶ)化合物与4-巯基苯酚在适合的溶剂,例如N,N-二甲基甲酰胺的存在下在40-60℃下进行反应。化合物(Ⅷ)和对硝基苯基氯甲酸酯得到化合物(Ⅸ)的反应可在一种碱,例如N-甲基吗啉、三乙胺或N,N-二异丙基乙胺的存在下,在适合的溶剂,例如二氯甲烷、氯仿、1,4-二噁烷或N,N-二甲基甲酰胺中在室温下进行。
化合物(Ⅸ)与其中R如上所述的化合物(Ⅱ)获得式(Ⅹ)化合物的反应可在适合的溶剂,例如二氯甲烷、氯仿、甲苯或N,N-二甲基甲酰胺中在室温下进行约2-22小时。
其中R如上所述的式(Ⅹ)与其中R1和R2如上所述的式(Ⅴ)化合物反应获得式(Ⅰ)化合物,该反应可在一种碱,例如三乙胺、N,N-二异丙基乙胺或N-甲基吗啉的存在下,在适合的溶剂,例如甲苯、乙腈或N,N-二甲基甲酰胺中,在室温至100℃的温度下进行。
式(Ⅰ)化合物向另一种式(Ⅰ)化合物之间的任选的转化可按照熟知的方法进行。
例如,通过用如浓盐酸中的氯化亚锡处理,或者如果合适,在室温至约100℃下使用有机溶剂,例如乙酸、1,4-二噁烷和四氢呋喃可将式(Ⅰ)化合物的硝基转化为氨基。
同样,通过,例如在适合的溶剂,例如二氯甲烷或氯仿中在约-5℃至室温下,与间氯过苯甲酸反应可将烷硫基或芳硫基转化为相应的烷基磺酰基和芳基磺酰基。
式(Ⅰ)化合物的任选的成盐反应或盐向游离化合物的转化反应以及将异构体混合物分离为单一异构体的技术可按照常规方法进行。
按照上述方法,式(Ⅱ)和(Ⅳ)化合物是已知的,或者它们可通过已知方法获得。
例如,其中R定义如上的式(Ⅱ)化合物可如下制备:将其中X是溴或氯原子的式(Ⅺ)化合物
与硫脲在适合溶剂,例如甲醇、乙醇、四氢呋喃、1,4-二噁烷或甲苯在室温至回流温度下进行约1-约24小时。
式(Ⅳ)化合物可如下获得:例如将其中R定义如上的式(Ⅱ)与二(三氯甲基)碳酸酯或三氯甲基氯甲酸酯在(如果合适)叔胺碱,例如三乙胺、N,N-二异丙基乙胺或吡啶的存在下,在适合的溶剂,例如二氯甲烷、氯仿或甲苯中,在约-20℃至回流温度下进行反应。
式(Ⅲ)、(Ⅴ)和(Ⅺ)化合物是已知有市售的化合物,或者它们可通过有机化学的已知方法按常规制备。
当按照本发明的方法制备式(Ⅰ)化合物时,在原料或中间体上的可能会产生不希望的副反应的任选的功能基需按照常规技术适当加以保护。
同样,可按照已知的方法将这些保护的化合物转化为游离的脱保护的化合物。
药理学
当按照下列方法进行试验时,式(Ⅰ)化合物得到阳性结果,因此式(Ⅰ)化合物具有cdk/细胞周期蛋白抑制剂活性。
因此,式(Ⅰ)化合物可用于限制肿瘤细胞的无规增殖,因而可用于治疗各种肿瘤,例如癌症,如乳腺癌、肺癌、膀胱癌、结肠癌、卵巢和子宫内膜癌;肉瘤,如软组织和骨肉瘤;以及血液系统的噁性肿瘤,如白血病。
另外,式(Ⅰ)化合物还可用于治疗其它细胞增殖性疾病,例如牛皮癣、与动脉粥样硬化和术后狭窄和再狭窄有关的平滑肌细胞增殖和阿尔茨海默氏症。
通过基于使用MultiScreen-PH 96孔板(Millipore)的分析方法测定推定的cdk/细胞周期蛋白抑制剂的抑制活性和所选择的化合物的效力,其中将磷酸纤维素滤纸放入各孔底部,在洗涤/过滤步骤后,使其与带正电荷的底物结合。
当通过ser/threo激酶将放射性标记的磷酸酯部分转移到滤纸结合的组蛋白上时,用闪烁计算器测定发射的光。
按照下列方案进行cdk2/细胞周期蛋白A活性的抑制分析:
激酶反应:在96孔U型底板的各孔种加入1.5μm组蛋白H1底物、25μM ATP(0.5μCi P33γ-ATP)、30ng细胞周期蛋白A/cdk2复合物、终体积为100μl缓冲液中的10μM抑制剂(TRIS HCl10mM PH7.5,MgCl210mM,7.5mM DTT)。在37℃保温10分钟后,用20μl120mM EDTA使反应停止。
捕获:从各孔取100μl转移到MultiScreen板中,使底物与磷酸纤维素滤纸结合。然后将该板用150μl/孔不含Ca++/Mg++的PBS洗涤三次并通过MultiScreen过滤系统过滤。
检测:在37℃下干燥滤纸,然后以100μl/孔的量加入闪烁剂,通过用Top-Count仪器放射性计数测定33P标记的组蛋白H1。
结果:分析数据并以相对于酶的总活性(=100%)的抑制百分数表示。为研究和确定其效力(IC50)以及通过Ki计算的动力学曲线,对表现出抑制≥50%的所有化合物都进行进一步的分析。
IC50测定:采用与上面相同的方案,但在0.0045~10μM浓度范围内进行试验。通过GraphPad Prizm计算机程序分析实验数据。
Ki的计算:在有或没有抑制剂(两种不同的适当选择的浓度)的存在下,改变ATP或组蛋白H1底物的浓度,ATP:4、8、12、24、48μM(含成比例稀释的P33γ-ATP);组蛋白:0.4、0.8、1.2、2.4、4.8μM。
使用随机双反应物系统方程式:
其中A=ATP,B=组蛋白H1,
通过SigmaPlot计算机程序分析实验数据以测定Ki值。
按照上述方法,本发明的代表性的式(Ⅰ)化合物,N-(5-异丙基-1,3-噻唑-2-基)-N’-(3,5-二甲基苯基)脲,对cdk2/细胞周期蛋白A复合物的表现出的抑制活性,相当于0.56μM(IC50)。
另外,通过基于使用SPA(Scintillation ProximityAssay)96孔板的分析方法可测定推定的cdk/细胞周期蛋白抑制剂的抑制活性和所选择的化合物的效力。基于链霉抗生物素包被的SPA珠捕获由组蛋白的磷酰化位点衍生的生物素化肽的能力进行分析。
当通过ser/threo激酶将放射性标记的磷酸酯部分转移到生物素化的组蛋白肽上时,用闪烁计算器测定发射的光。
按照下列方案进行cdk5/p25活性的抑制分析:
激酶反应:在96孔U型底板的各孔种加入1.0μM生物素化组蛋白肽底物、0.25μCi P33g-ATP、4nM cdk2/p25复合物、终体积为100μl缓冲液中的0-100μM抑制剂(Hepes 20mM PH7.5,MgCl2 15mM,1mM DTT)。在37℃保温20分钟后,加入在含0.1%Triton X-100,50μM和5mM EDTA的磷酸盐缓冲盐水中的500μg SPA珠用使反应停止。将小珠放置好,在Top Count闪烁计数器中测定结合于33P-标记肽的放射活性。
结果:分析数据并以下式表示%抑制:
100X(1-(未知-背景)/(酶对照-背景))
用改变的四参数对数方程式计算IC50值:
Y=100/1[1+10((LogEC50-X)*斜率)]
其中X=log(μM),Y=%抑制。
因此,本发明的式(Ⅰ)化合物可用于限制肿瘤细胞的无规增殖,因而用于治疗各种肿瘤,例如癌症,如乳腺癌、肺癌、膀胱癌、结肠癌、卵巢和子宫内膜癌;肉瘤,如软组织和骨肉瘤;以及血液系统的噁性肿瘤,如白血病。
另外,式(Ⅰ)化合物还可用于治疗其它细胞增殖性疾病,例如牛皮癣、与动脉粥样硬化和术后狭窄和再狭窄有关的平滑肌细胞增殖和阿尔茨海默氏症。
本发明的化合物可以化合物本身或与已知的抗癌治疗,例如放疗或使用细胞凋亡剂或细胞毒性剂的化疗方案联合应用。
例如,上述化合物可与一种或多种例如下列的化疗剂联合应用:紫杉烷、紫杉烷衍生物、CPT-11、喜树碱衍生物、蒽环类糖苷(如阿霉素或表阿霉素、依托泊苷、navelbine、长春碱、卡铂和顺铂等,并任选以其脂质体制剂形式使用。
适于给药于哺乳动物,如人类的本发明的式(Ⅰ)化合物可通过常见的途径给药,给药剂量取决于患者的年龄、体重、适应症及给药途径。
例如,式(Ⅰ)化合物的适于口服给药的适合剂量可以是约10-500mg/剂,1-5次/天。本发明的化合物可以不同剂型给药,例如以片剂、胶囊、糖衣片或膜包衣片、液体溶液或悬浮液形式口服给药;以栓剂直肠给药;通过肌内或静脉内和/或鞘内和/或脊髓内注射或输注经非胃肠给药。
本发明还包括含有式(Ⅰ)化合物或其可药用盐和可药用赋形剂(可以是载体或稀释剂)的药物组合物。含本发明化合物的药物组合物通常按照下列常规方法制备并以药学上适合的形式给药。例如固体口服形式可含有活性化合物、蔗糖、纤维素、玉米淀粉或土豆淀粉;润滑剂,如硅石、滑石、硬脂酸、硬脂酸镁或硬脂酸钙,和/或聚乙二醇;粘合剂,例如淀粉、阿拉伯胶、明胶、甲基纤维素、羧甲基纤维素或聚乙烯吡咯烷酮;崩解剂,如淀粉、藻酸、藻酸盐或淀粉甘醇酸钠;泡藤混合物;色素;甜味剂;润湿剂,如卵磷脂、土温、月桂基硫酸盐;和原则上无毒的和用于药物制剂的可药用惰性物质。所述药物制剂可以常规方法,例如通过混合、制粒、压片、包糖衣或包膜衣方法制备。口服给药的液体分散体可以是,例如糖浆、乳液或悬浮液。糖浆可含有载体,例如蔗糖或蔗糖和甘油和/或甘露醇和/或山梨醇。悬浮液或乳液可含有载体,例如天然胶、琼脂、藻酸钠、果胶、甲基纤维素、羧甲基纤维素或聚乙烯醇。用于肌内注射的悬浮液或溶液可含有活性化合物和可药用载体,如无菌水、橄榄油、油酸乙酯、甘醇类(如丙二醇),如果需要,还可含有适量的盐酸利多卡因。静脉注射或输注的溶液可含有载体,例如无菌水、等渗盐水溶液或还可含有载体丙二醇。
栓剂可含有活性化合物和可药用载体,如可可脂、聚乙二醇、聚氧乙烯脱水山梨醇脂肪酸酯或卵磷脂。
下列实施例用于说明而非限制本发明。
实施例1
环丙基乙酸甲酯的制备
将环丙基乙酸(1.08g,10.57mmol)溶于50ml甲醇中。将该溶液冷却到0℃并在搅拌下滴加5ml 96%的硫酸。使该溶液在室温放置过夜后倾入冰水中,用30%氨水碱化,最后用二氯甲烷萃取。有机层经硫酸钠干燥并蒸发至干,得到1.1g油状产物(90%产率),该产物无需纯化即可使用。
实施例2
2-环丙基乙醇的制备
将钠(85mg,0.004mmol)溶于50ml甲醇中并加入8.7g(0.23mol)硼氢化钠。在搅拌下,将按照实施例1制备的3.7g(00.032mol)环丙基乙酸甲酯在20ml甲醇中的溶液滴加到该混合物中。使反应在回流下保持6小时,然后加入300ml盐水,用二氯甲烷萃取粗产物。
有机层经硫酸钠干燥并蒸发至干,得到1.52g(55%产率)的标题化合物。
实施例3
式(Ⅵ)化合物:2-环丙基乙醛的制备
将草酰氯(1.24ml;14.18mmol)溶于10ml二氯甲烷;冷却到-60℃后,滴加按照实施例2制备的1.02g(11.9mmol)2-环丙基乙醇在10ml二氯甲烷中的溶液。使该混合物在相同的温度下搅拌30分钟,然后加入8.3ml(59.5mmol)三乙胺。
2小时后,在0℃下,加入水。该混合物用二氯甲烷稀释并用1M盐酸、水、饱和碳酸氢钠和盐水顺序洗涤。有机层经硫酸钠干燥并蒸发至干,得到0.31g(30%产率)的标题化合物。
实施例4
式(Ⅱ)化合物:2-氨基-5-异丙基-1,3-噻唑的制备
将3-甲基丁醛(2ml,18.6mmol)溶于15ml二噁烷中。在0℃下,往其中滴加2% v/v溴的二噁烷(47.81ml;18.6mmol)溶液。使该混合物在室温下搅拌2小时,然后加入2.83g(37.2mmol)硫脲和10ml乙醇。在室温下保持6小时后,将溶液蒸发至干,残余物溶于二氯甲烷,用1M盐酸萃取产物;用30%氨水使水层呈碱性并用二氯甲烷再次萃取。
有机相经硫酸钠干燥并真空蒸发。残余物经硅胶柱色谱,用环己烷-乙酸乙酯洗脱,得到1.1g(42%产率)的标题化合物。1H-NMR(DMSO-d6)δppm:6.6(s,2H,NH2);6.58(s,1H,噻唑CH);2.9(m,1H,CHMe2);1.18(s,3H,MeCHMe);1.17(s,3H,MeCHMe).
采用类似方法可制备下列化合物:
2-氨基-5-苯基-1,3-噻唑;和
2-氨基-5-环丙基-1,3-噻唑。
实施例5
式(Ⅰ)化合物:N-(5-溴-1,3-噻唑-2-基)-N’-苯基脲的制备
在室温和磁力搅拌下,将异氰酸苯基酯(1.7ml;15.6mmol)加到2-氨基-5-溴-1,3-噻唑氢溴酸盐(4g;15.6mmol)和三乙胺(2.1ml;15.6mmol)在二氯甲烷(70ml)中的溶液中。4天后,加入甲醇(7ml)并用盐水洗涤该反应混合物,经硫酸钠干燥并蒸发。残余物经柱硅胶柱色谱纯化(依次用二氯甲烷和二氯甲烷/甲醇=90∶10洗脱)得到1.9g(52%产率)无色固体的标题化合物(m.p.166-169℃/分解)。1H-NMR(CDCl3)δppm:10.50(bs,1H,-NHCONHPh);8.50(bs,1H,-NHCONHPh);7.45(d,J=7.6Hz,2H,o-Ph氢);7.36(dd,J=7.3和7.6Hz,2H,m-Ph氢);7.29(s,1H,噻唑CH);7.16(t,J=7.3Hz,1H,p-Ph氢).
采用类似方法,以相应的异氰酸酯为原料可制备下列化合物:
N-(5-苯基-1,3-噻唑-2-基)-N-苯基-脲
1H-NMR(DMSO-d6)δppm:10.56(bs,1H,-NHCONHPh);8.99(bs,
1H,NHCONHPh);7.77(s,1H,噻唑CH);7.6-7.0(m,10H,
苯基);
N-(5-溴-1,3-噻唑-2-基)-N’-(4-氨磺酰-苯基)-脲;
N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-氨磺酰-苯基)-脲;
m.p.>200℃
1H-NMR(DMSO-d6)δppm:10.58(bs,1H,-NHCONHPh);9.38(bs,
1H NHCONHPh);7.75(d,2H,H3和H5 Ph);7.61(d,2H,H2
和H6 Ph);7.21(s,2H,SO2NH2);7.02(s,1H,噻唑CH);
3.02(m,1H,CH(Me)2);1.22(s,3H,MeCHMe);1.21(s,3H,
MeCHMe):
ESI(+)-MS:m/z 341(100,(M+H)+).
N-苯甲酰基-N-(5-异丙基-1,3-噻唑-2-基)脲
m.p.217-219℃1H-NMR(400 MHz-DMSO-d6)δppm:1.27(d,6H,J=6.8,CH3CHCH3);3.11(m,1H,CH3CHCH3);7.18(d,1H,J=0.9,H噻唑);7.54(m,2H,m-苯基);7.66(m,1H,p-苯基);8.00(m,2H,o-苯基);11.50(bs,1H,NH);11.80(bs,1H,NH).ESI(+)MS: m/z 290(70,(M+H)+;m/z 169(100,(MH-C6H5CONH2)+);
N-(5-苯基-1,3-噻唑-2-基)-N’-(4-氨磺酰-苯基)脲;
N-(5-环丙基-1,3-噻唑-2-基)-N’-(4-氨磺酰-苯基)-脲;
N-(5-异丙基-1,3-噻唑-2-基)-N’-(3-甲氧基-苯基)-脲
m.p.149-150℃
1H-NMR(400 MHz-DMSO-d6)δppm:1.23(d,6H,J=6.8,
CH3CHCH3);3.06(m,1H,CH3CHCH3);3.72(s,3H,CH3);7.02(s,
1H,H噻唑);6.57(dd,1H,J=8.3,2.4,H-4-苯基);
6.93(d,1H,J=8.3,H-6-苯基);7.18(m,2H,H-5,H-2-
苯基);8.94(s,1H,NH);10.35(bs,1H,NH).
ESI(+)MS:m/z 292(100,(M+H)+);
N-(5-溴-1,3-噻唑-2-基)-N’-(3-甲氧基-苯基)-脲
m.p.190-191℃
1H-NMR(400 MHz-DMSO-d6)δppm:7.44(s,1H,H噻唑);
3.72(s,3H,CH3);6.61(dd,1H,J=2.4,7.8,H-4′-苯基);
6.94(dd,1H,J=2.0,7.8,H-6′-苯基);7.13(dd,1H,J=2.0,
2.0,H-2′-苯基);7.20(dd,1H,J=7.8,7.8,H-5′-苯基);
8.95(s,1H,NH);10.80(s,1H,NH).
ESI(+)MS:m/z 328(100,(M+H)+);
N-(5-苯基-1,3-噻唑-2-基)-N’-(3-甲氧基-苯基)-脲;
N-(5-环丙基-1,3-噻唑-2-基)-N’-(3-甲氧基-苯基)-脲;
N-(5-异丙基-1,3-噻唑-2-基)-N’-苯基-脲1H-NMR(400 MHz-DMSO-d6)δppm:1.24(d,6H,J=6.8,CH3CHCH3);3.07(m,1H,CH3CHCH3);7.03(m,2H,H-噻唑+H-4′-苯基);7.29(m,2H,H-5′,H-3′-苯基);7.43(m,2H,H-2′,H-6-苯基);8.91(s,1H,NH);10.30(bs,1H,NH).ESI(+)-MS:m/z 262(100,(M+H)+);N-(5-苯基-1,3-噻唑-2-基)-N’-苯基-脲;N-(5-环丙基-1,3-噻唑-2-基)-N’-苯基-脲;N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-氯-苯基)-脲m.p.191-193℃1H-NMR(300 MHz-DMSO-d6)δppm:1.16(d,6H,J=6.8,CH3CHCH3);3.00(m,1H,CH3CHCH3);6.95(d,1H,J=1.0,H噻唑);7.40(d,2H,J=8.9m-苯基);7.26(d,2H,J=8.9o-苯基);9.01(bs,1H,NH);10.40(bs,1H,NH).ESI(+)MS:m/z 296(100,(M+H)+);N-(5-溴-1,3-噻唑-2-基)-N’-(4-氯-苯基)-脲;N-(5-苯基-1,3-噻唑-2-基)-N’-(4-氯-苯基)-脲;N-(5-环丙基-1,3-噻唑-2-基)-N’-(4-氯-苯基)-脲;N-(5-异丙基-1,3-噻唑-2-基)-N’-(3-氯-苯基)-脲;N-(5-溴-1,3-噻唑-2-基)-N’-(3-氯-苯基)-脲;N-(5-苯基-1,3-噻唑-2-基)-N’-(3-氯-苯基)-脲;N-(5-环丙基-1,3-噻唑-2-基)-N’-(3-氯-苯基)-脲;N-(5-异丙基-1,3-噻唑-2-基)-N’-(2-氯-苯基)-脲1H-NMR(400 MHz-DMSO-d6)δppm:1.24(d,6H,J=6.8,CH3CHCH3);3.07(m,1H,CH3CHCH3);7.07(m,2H,H-噻唑+H-4′-苯基);7.31(dd,1H,J=7.8,7.8,H-5′-苯基);7.47(d,1H,J=7.8H-3′-苯基);8.14(d,1H,J=7.8,H-6′-苯基);8.80(bs,1H,NH);11.01(bs,1H,NH).ESI(+)MS:m/z 296(100,(M+H)+);N-(5-溴-1,3-噻唑-2-基)-N’-(2-氯-苯基)-脲m.p.210-212℃1H-NMR(300 MHz-DMSO-d6)δppm:7.29(s,1H,H-噻唑);7.02(ddd,1H,J=1.6,7.6,7.6,H-4′-苯基);7.25(ddd,1H,J=1.6,7.6,7.6,H-5′-苯基);7.41(dd,1H,J=1.6,7.6,H-3′-苯基);8.03(dd,1H,J=1.6,7.6,H-6′-苯基);8.58(s,1H,NH);11.31(bs,1H,NH).ESI(+)MS:m/z 332(100,(M+H)+):N-(5-苯基-1,3-噻唑-2-基)-N’-(2-氯-苯基)-脲;N-(5-环丙基-1,3-噻唑-2-基)-N’-(2-氯-苯基)-脲;N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-甲氧基-苯基)-脲;N-(5-溴-1,3-噻唑-2-基)-N’-(4-甲氧基-苯基)-脲;N-(5-苯基-1,3-噻唑-2-基)-N’-(4-甲氧基-苯基)-脲;N-(5-环丙基-1,3-噻唑-2-基)-N’-(4-甲氧基-苯基)-脲;N-(5-溴-1,3-噻唑-2-基)-N’-(4-羟基-苯基)-脲;N-(5-苯基-1,3-噻唑-2-基)-N’-(4-羟基-苯基)-脲;N-(5-环丙基-1,3-噻唑-2-基)-N’-(4-羟基-苯基)-脲;N-(5-溴-1,3-噻唑-2-基)-N’-(3-羟基-苯基)-脲;N-(5-苯基-1,3-噻唑-2-基)-N’-(3-羟基-苯基)-脲;N-(5-环丙基-1,3-噻唑-2-基)-N’-(3-羟基-苯基)-脲;N-(5-异丙基-1,3-噻唑-2-基)-N’-(2-甲氧基-苯基)-脲m.p.184-185℃;1H-NMR(400 MHz-DMSO-d6)δppm:1.23(d,6H,J=6.7,CH3CHCH3);3.07(m,1H,CH3CHCH3);3.85(s,3H,OCH3);6.92(m,1H,H-苯基);7.01(m,3H,H-苯基+H-噻唑);8.07(d,1H,J=8.3,H-6′-苯基);8.80(bs,1H,NH);10.82(s,1H,NH).ESI(+)-MS:m/z 292(100,(M+H)+);N-(5-溴-1,3-噻唑-2-基)-N’-(2-甲氧基-苯基)-脲m.p.218-220℃1H-NMR(300MHz-DMSO-d6)δppm:3.79(s,3H,CH3O);6.90-7.98(2m,4H,苯基);7.36(s,1H,H噻唑);8.57(s,1H,NH);11.13(bs,1H,NH).ESI(+)MS:m/z 328(100,(M+H)+N-(5-苯基-1,3-噻唑-2-基)-N’-(2-甲氧基-苯基)-脲;N-(5-环丙基-1,3-噻唑-2-基)-N’-(2-甲氧基-苯基)-脲;N-(5-溴-1,3-噻唑-2-基)-N’-(2-羟基-苯基)-脲;N-(5-苯基-1,3-噻唑-2-基)-N’-(2-羟基-苯基)-脲;N-(5-环丙基-1,3-噻唑-2-基)-N’-(2-羟基-苯基)-脲;N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-硝基-苯基)-脲1H-NMR(400 MHz-DMSO-d6)δppm:1.23(d,6H,J=6.8,CH3CHCH3);3.14(m,1H,CH3CHCH3);7.04(s,1H,H-噻唑);7.74(d,2H,J=9.3,H-2′,H-6′-苯基);8.18(d,2H,J=9.3,H-3′,H-5′-苯基);9.65(bs,1H,NH);11(bs,1H,NH).ESI(+)-MS:m/z 307(100,(M+H)+);N-(5-溴-1,3-噻唑-2-基)-N’-(4-硝基-苯基)-脲;N-(5-苯基-1,3-噻唑-2-基)-N’-(4-硝基-苯基)-脲;N-(5-环丙基-1,3-噻唑-2-基)-N’(4-硝基-苯基)-脲;N-(5-异丙基-1,3-噻唑-2-基)-N’-(3-硝基-苯基)-脲m.p.220-222℃1H-NMR(400MHz-DMSO-d6)δppm:1.24(d,6H,J=6.9,CH3CHCH3);3.05(m,1H,CH3CHCH3);7.04(s,1H,H噻唑);7.56(dd,1H,J=8.2,8.2,H-5-苯基);7.77(d,1H,J=8.2,H-6′-苯基);7.83(dd,1H,J=8.2,1.5,H-4′苯基); 8.58(d,1H,J=1.5,H-2′-苯基);9.45(s,1H,NH);10.60(bs,1H,NH).ESI(+)MS:m/z 307(100,(M+H)+);N-(5-溴-1,3-噻唑-2-基)-N’-(3-硝基-苯基)-脲;N-(5-苯基-1,3-噻唑-2-基)-N’-(3-硝基-苯基)-脲;N-(5-环丙基-1,3-噻唑-2-基)-N’-(3-硝基-苯基)-脲;N-(5-异丙基-1,3-噻唑-2-基)-N’-苄基-脲1H-NMR(400 MHz-DMSO-d6)δppm:1.21(d,6H,J=6.8,CH3CHCH3);3.03(m,1H,CH3CHCH3);4.31(d,2H,J=6.35,CH2);6.96(m,1H,NH-CH2);7.27(m,5H,苯基).ESI(+)MS:m/z 276(100,(M+H)+);N-(5-溴-1,3-噻唑-2-基)-N’-苄基-脲;N-(5-苯基-1,3-噻唑-2-基)-N’-苄基-脲;N-(5-环丙基-1,3-噻唑-2-基)-N’-苄基-脲;N-(5-异丙基-1,3-噻唑-2-基)-N’-(吡啶-3-基)-脲;N-(5-溴-1,3-噻唑-2-基)-N’-(吡啶-3-基)-脲;N-(5-苯基-1,3-噻唑-2-基)-N’-(吡啶-3-基)-脲;N-(5-环丙基-1,3-噻唑-2-基)-N’-(吡啶-3-基)-脲;N-(5-溴-1,3-噻唑-2-基)-N’-(吡啶-4-基)-脲;N-(5-异丙基-1,3-噻唑-2-基)-N’-(吡啶-4-基)-脲;N-(5-苯基-1,3-噻唑-2-基)-N’-(吡啶-4-基)-脲;N-(5-环丙基-1,3-噻唑-2-基)-N’-(吡啶-4-基)-脲;N-(5-异丙基-1,3-噻唑-2-基)-N’-(吡啶-2-基)-脲;N-(5-溴-1,3-噻唑-2-基)-N’-(吡啶-2-基)-脲;N-(5-苯基-1,3-噻唑-2-基)-N’-(吡啶-2-基)-脲;N-(5-环丙基-1,3-噻唑-2-基)-N’-(吡啶-2-基)-脲;
N-(5-异丙基-1,3-噻唑-2-基)-N’-(苯并噻吩-2-基)-脲;
N-(5-溴-1,3-噻唑-2-基)-N’-(苯并噻吩-2-基)-脲;
N-(5-苯基-1,3-噻唑-2-基)-N’-(苯并噻吩-2-基)-脲;和
N-(5-环丙基-1,3-噻唑-2-基)-N’-(苯并噻吩-2-基)-脲;
实施例6
式(Ⅵ)化合物:4-硝基苯基-5-异丙基-1,3-噻唑-2-基
氨基甲酸酯的制备
在0℃和氮气氛下,往4g(28.13rnmol)5-异丙基-2-氨基-1,3-噻唑在30ml无水二氯甲烷中的溶液中滴加5.7g(28.13mmol)4-硝基苯基氯甲酸酯。然后加入2.3ml吡啶。使该反应混合物在室温搅拌过夜,然后过滤,得到6.96g(80%产率)的白色固体的标题化合物。
m.p.157-159℃
1H-NMR(400 MHz-DMSO-d6)δppm:1.23(d,6H,J=6.8,
CH3CHCH3);3.06(m,1H,CH3CHCH3);7.05(s,1H,H噻唑);
6.91(d,2H,J=9.2,H-3′,5′-苯基);8.10(d,2H,J=9.2,H-
2′,6′-苯基);11.00(bs,1H,NH).
EI-MS:m/z 307(0.5,M+);m/z 168((CH3)2-CH-噻唑-NCO)+;
m/z 153(100,(CH3-CH-噻唑-NCO)+);m/z 139(45,(OH-C6H4-NO2)+).
实施例7式(Ⅰ)化合物:N-(5-异丙基-1,3-噻唑-2-基)-N’-(3-碘苯基)脲的制
备
在氩气氛下,将1g(3.25mmol)4-硝基苯基-5-异丙基-1,3-噻唑-2-基氨基甲酸酯和0.39ml(3.25mmol)3-碘苯胺悬浮到25ml乙腈中。在70℃保持2小时后,将所得溶液冷却,得到0.923g标题化合物,然后在乙醚/戊烷1/1的混合液中重结晶。
m.p.160-162℃
1H-NMR(300 MHz-DMSO-d6)δppm:1.23(d,6H,J=6.8,
CH3CHCH3);3.05(m,1H,CH3CHCH3);7.03(d,1H,J=O.8,H
噻唑); 7.07(t,1H,J=8.0,H-5′-苯基);7.35(m,2H,H-
4′,6′-苯基);8.00(t,1H,J=1.8,1.8,H-2′-苯基);9.06
(bs,1H,NH);10.50(bs,1H,NH).
ESI(+)-MS:m/z 388(100,(M+H)+).
采用类似方法,用2-[(2-丙炔基氨基)甲基]苯磺酰胺可制备2-{[{[(5-异丙基-1,3-噻唑-2-基)氨基]羰基}(2-丙炔基)氨基]甲基}苯磺酰胺。
m.p.90-92℃
1H-NMR(400 MHz-DMSO)δppm:1.19(d,6H,J=6.8,CH3CHCH3);
2.93(m,1H,CH≡C-);3.13(m,1H,CH3CHCH3);4.18,5.08(2m,
4H,CH2Ph+CH2C≡C);6.89(m,1H,H-噻唑);7.22(m,1H,
H-3′-苯基);7.41,7.53(2m,2H,H-5′,H-4′-苯基);7.86
(m,1H,H-6′-苯基);11.90(bs,1H,NH).
ESI(+)-MS:m/z 415(100,(M+Na)+);m/z393(50,(M+H)+.
采用类似方法,但用1H-苯并咪唑-6-胺为原料,可获得N-(1H-苯并咪唑-5-基)N’-(5-异丙基-1,3-噻唑-2-基)脲。
1H-NMR(400 MHz-DMSO-d6)δppm:1.27(d,6H,J=6.8,
CH3CHCH3);3.09(m,1H,CH3CHCH3);7.01(s,1H,H-噻唑);
7.13(d,1H,H-6′-苯并咪唑);7.49(d,1H,H-7′-
苯并咪唑);7.81(s,1H,H-4′-苯并咪唑);8.03(s,
1H,H-2′-苯并咪唑).
ESI(+)-MS:m/z 302(100,(M+H)+).
采用类似方法,但使用1H-吲哚-6-胺为原料,可制备N-(1H-吲哚-6-基)-N’-(5-异丙基-1,3-噻唑-2-基)脲。
1H-NMR(400 MHz-DMSO-d6)δppm:1.24(d,6H,J=6.8,
CH3CHCH3);3.06(m,1H,CH3CHCH3);7.03(bs,1H,H噻唑);
6.33(m,1H,H-3′-吲哚);6.84(d,1H,J=8.3,H-5′-吲哚);
7.23(t,1H,J=2.4,2.4,H-2-吲哚);7.42(d,1H,J=8.3,H-
4′-吲哚);7.77(s,1H,H-7′-吲哚);8.82(s,1H,NH);
10.18(bs,1H,NH);10.95(s,1H,NH-吲哚).
ESI(+)-MS:m/z 301(100,(M+H)+).
采用类似方法,但使用1H-吲哚-5-胺,可制备N-(1H-吲哚-5-基)-N’-(5-异丙基-1,3-噻唑-2-基)脲。
1H-NMR(400 MHz-DMSO-d6)δppm:1.24(d,6H,J=6.8,
CH3CHCH3);3.06(m,1H,CH3CHCH3);7.02(s,1H,H噻唑);
6.35(m,1H,H-3′-吲哚);7.05(dd,1H,J=2.0,J=8.5,H-6′-
吲哚);7.30(m,2H,H-2′,H-7′-吲哚);7.67(d,1H,
J=2.0,H-4′-吲哚);8.68(s,1H,NH);10.15(s,1H,NH);
10.98(s,1H,NH-吲哚).
ESI(+)-MS:m/z 301(100,(M+H)+).
采用类似方法,但使用咪唑并[1,2-a]吡啶-2-基甲酰胺,可制备N-(咪唑并[1,2-a]吡啶-2-基-甲基)-N’-(5-异丙基-1,3-噻唑-2-基)脲。
1H-NMR(400 MHz-DMSO-d6)δppm:1.21(d,6H,J=6.8,
CH3CHCH3);3.04(m,1H,CH3CHCH3);4.40(d,2H,J=5.6,
CH2);6.96(d,1H,J=1.2,H噻唑);6.84(dt,1H,J=2.2,
6.8,H-6′-咪唑并吡啶);7.20(m,1H,H-5-
咪唑并吡啶);7.47(m,1H,H-7′-咪唑并吡啶);7.78
(s,1H,H-3′-咪唑并吡啶);8.49(m,1H,H-4-
咪唑并吡啶);7.01(t,1H,J=5.4,NH-CH2);10.23(bs,
1H,NH-CO).
ESI(+)-MS:m/z 316(100,(M+H)+);m/z338(85,(M+Na)+).
采用类似方法,但使用1-甲基-2-[(2-氨基苯氧基)甲基-1H-咪唑,可制备N-(5-异丙基-1,3-噻唑-2-基)-N’-{2-[(1-甲基-1H-咪唑-2-基)甲氧基]苯基}脲。
1H-NMR(300 MHz-DMSO-d6)δppm:1.23(d,6H,J=6.8,
CH3CHCH3);3.05(m,1H,CH3CHCH3);3.70(s,3H,N-CH3);5.21
(s,2H,CH2);6.92(bs,1H,H噻唑);6.90-8.20(m,6H,
咪唑+苯基);8.10(bs,1H,NH);10.96(s,1H,NH).
ESI(+)-MS:m/z 372(95,(M+H)+);m/z 410(100,(M+K)+).
采用类似方法,但使用2-(2-氨基苯氧基)乙酰胺,可制备N-(5-异丙基-1,3-噻唑-2-基)-N’-(2-苯氧基乙酰氨基)脲。
1H-NMR(400MHz-DMSO-d6)δppm: 1.24(d,6H,J=7.0,
CH3CHCH3); 3.07(m,1H,CH3CHCH3);4.50(s,2H,CH2);7.05(d,
1H,J=1.0,H噻唑);6.50-7.00(m,3H,苯基);8.10(m,
1H,苯基),7.55(s,2H,NH3),8.67(bs,1H,NH);10.86(s,
1H,NH).
ESI(+)-MS:m/z 335(50,(M+H)+);.m/z 373(100,(M+K)+).
采用类似方法,但使用(2S)-2-氨基-2-苯基乙酰胺,可制备N-(5-异丙基-1,3-噻唑-2-基)-N’-[(S)苯基甘氨酰氨基)脲。
1H-NMR(300 MHz-DMSO-d6)δppm:1.19(d,6H,J=6.8,
CH3CHCH3);3.01(m,1H,CH3CHCH3);5.26(d,1H,J=7.7CH):
6.95(s,1H,H-噻唑);7.20-7.60(m,6H,NH-CH+苯基);
7.20-7-80(s,2H,NH2),10.26(bs,1H,NH).
ESI(+)-MS:m/z 319(25,(M+H)+);.m/z 357(100,(M+K)+);
采用类似方法,但使用(2R)-2-氨基-2-苯基乙酰胺,可制备N-(5-异丙基-1,3-噻唑-2-基)-N’-[(R)-苯基甘氨酰氨基]脲。
1H-NMR(400 MHz-DMSO-d6)δppm:1.19(d,6H,J=7.0,
CH3CHCH3);3.01(m,1H,CH3CHCH3);5.26(d,1H,J=7.6CH);
6.95(d,1H,J=1.3,H噻唑);7.20-7.50(m,6H,NH-
CH+苯基);7.21-7.79(s,2H,NH2),10.20(bs,1H,NH).
ESI(+)-MS:m/z 319(100,(M+H)+);m/z 357(65,(M+K)+).
采用类似方法,但使用2-氨基苯酚,可制备N-(2-羟基苯基)-N’-(5-异丙基-1,3-噻唑-2-基)脲。
m.p.204-206℃
1H-NMR(400 MHz-DMSO-d6)δppm:1.23(d,6H,J=6.8,
CH3CHCH3);3.06(m,1H,CH3CHCH3);7.02(s,1H,H-噻唑);
6.74(m,1H,H-5′-苯基);6.82(m,2H,H-3′,H-4′-苯基);
7.98(d,1H,J=7.6,H-6′-苯基);8.60(bs,1H,NH);10.0
(bs,1H,NH);10.80(bs,1H,OH).
ESI(+)-MS:m/z 278(100,(M+H)+).
采用类似方法,但使用3-氨基苯酚,可制备N-(3-羟基苯基)-N’-(5-异丙基-1,3-噻唑-2-基)脲。
m.p.185-187℃
1H-NMR(400 MHz-DMSO-d6)δppm:1.23(d,6H,J=6.8,
CH3CHCH3);3.05(m,1H,CH3CHCH3);7.03(m,3H,H-噻唑+
H-2′,H-5′-苯基);6.39(d,2H,J=8.0,H-4′-苯基);6.77(d,
2H,J=8.0,H-6′-苯基);8.81(s,1H,NH);9.37(s,1H,NH).
ESI(+)-MS:m/z 278(100,(M+H)+).
采用类似方法,但使用4-氨基苯酚,可制备N-(4-羟基苯基)-N’-(5-异丙基-1,3-噻唑-2-基)脲。
m.p.130-132℃
1H-NMR(400 MHz-DMSO-d6)δppm:1.23(d,6H,J=6.8,
CH3CHCH3);3.05(m,1H,CH3CHCH3);7.00(s,1H,H-噻唑);
6.68(d,2H,J=8.8,H-3’,H-5′-苯基);7.21(d,2H,J=8.8,
H-2′,H-6′-苯基);8.60(s,1H,NH);9.14(s,1H,NH);10.18
(bs,1H,OH).
ESI(+)-MS:m/z 278(100,(M+H)+).
采用类似方法,但使用(2R)-2-氨基-2-苯基-1-乙醇,可制备N-[(1S)-2-羟基-1-苯乙基]-N’-(5-异丙基-1,3-噻唑-2-基)脲。
1H-NMR(400 MHz-DMSO-d6)δppm:1.20(d,6H,J=7.0,
CH3CHCH3);3.01(m,1H,CH3CHCH3);3.60(m,2H,CH2);4.73(m,
1H,CH);5.00(t,1H,J=5.1,5.1,OH);6.95(d,1H,J=1.1,
H噻唑);7.10-7.40(m,6H,NH-CH+苯基),10.15(s,1H,
NH).
ESI(+)-MS:m/z 306(100,(M+H)+).
采用类似方法,但使用(2S)-2-氨基-2-苯基-1-乙醇,可制备N-[(1R)-2-羟基-1-苯乙基]-N’-(5-异丙基-1,3-噻唑-2-基)脲。
1H-NMR(400 MHz-DMSO-d6)δppm:1.19(d,6H,J=6.9,
CH3CHCH3);3.01(m,1H,CH3CHCH3);3.59(m,2H,CH2);4.73(m,
1H,CH);5.02(t,1H,J=5.1,5.1,OH);6.95(d,1H,J=0.7,
H噻唑);7.20-7.40(m,6H,NH-CH+苯基),10.17(s,1H,
NH).
ESI(+)-MS:m/z 306(100,(M+H)+).
实施例8
式(Ⅰ)化合物:N-[3-(3-羟基-1-丁炔基)苯基]-
N’-5-异丙基-1,3-噻唑-2-基)脲的制备
在氩气氛下,往0.2g(0.56mmol)N-(5-异丙基-1,3-噻唑-2-基)-N’-(3-碘苯基)脲在3ml无水N,N-二甲基甲酰胺的溶液中顺序加入0.6ml四甲基胍,0.088ml(1.126mmol)D,L-1-丁炔-3-醇,19mg(0.027mmol)二(三苯基膦)钯(Ⅱ)二盐酸盐和5.8mg(0.03mmol)rameous碘。5小时后,加入水并用乙酸乙酯萃取该混合物。有机层用盐水洗涤,硫酸钠干燥并蒸发0.116g黄色固体的标题化合物,m.p.71-73℃。
1H-NMR(400MHz-DMSO-d6)δppm:1.24(d,6H,J=6.9,
CH3CHCH3);3.06(m,1H,CH3CHCH3);1.37(d,3H,J=6.6,
CH3);4.57(m,1H,CH);5.43(d,1H,J=5.1,OH);7.03(s,1H,
H噻唑);7.02(d,1H,J=8.0,H-4′-苯基);7.27(t,1H,
J=8.0,8.0,H-5′-苯基);7.34(d,1H,J=8.0,H-6′-苯基);
7.65(s,1H,H-2′-苯基);8.02(s,1H,NH);10.40(bs,1H,
NH).
ESI(+)-MS:m/z 330(100,(M+H)+).
采用类似方法,但使用N,N-二甲基-2-丙基-1-胺为原料,可制备N-{3-[3-(二甲基氨基)-1-丙炔基]苯基}-N’-(5-异丙基-1,3-噻唑-2-基)脲;
1H-NMR(400 MHz-DMSO-d6)δppm:1.23(d,6H,J=6.8,
CH3CHCH3);3.05(m,1H,CH3CHCH3);2.23(s,6H,N(CH3)2);3.44
(s,2H,CH2);7.03(s,1H,H-噻唑);7.05(d,1H,J=7.8,
H-4′-苯基);7.27(t,1H,J=7.8,7.8,H-5′-苯基);7.36(d,
1H,J=7.8,H-6′-苯基);7.64(s,1H,H-2′-苯基);9.04
(bs,1H,NH);10.45(bs,1H,NH).
ESI(+)-MS:m/z 343(100,(M+H)+).
采用类似方法,但以3-甲氧基-1-丙炔为原料,可制备N-[3-(3-甲氧基-1-丙炔基]苯基]-N’-(5-异丙基-1,3-噻唑-2-基)脲。
1H-NMR(400 MHz-DMSO-d6)δppm:1.23(d,6H,J=6.8,
CH3CHCH3);3.05(m,1H,CH3CHCH3);3.32(s,3H,CH3);4.31(s,
2H,CH2);7.03(s,1H,H-噻唑);7.08(d,1H,J=8.3,H-
4-苯基);7.29(t,1H,J=8.3,8.3,H-5′-苯基);7.39(d,
1H,J=8.3,H-6′-苯基);7.67(s,1H,H-2′-苯基);9.03(s,
1H,NH);10.40(bs,1H,NH).
ESI(+)-MS:m/z 330(100,(M+H)+).
实施例9式(Ⅰ)化合物:N-(5-异丙基-1,3-噻唑-2-基)-N’-(3-氨基苯基)的制
备
在氩气氛下,将1.55g(5.05mmol)如实施例5所述制备的(5-异丙基-1,3-噻唑-2-基)-N’-(3-硝基苯基)脲和0.98g(17.7minol)铁粉与2.02ml(35.35mmol)冰醋酸在50ml乙醇中的混合物搅拌回流。5小时后,加入1.5L水并用乙酸乙酯萃取产物。有机层用盐水洗涤,硫酸钠干燥并蒸发。残余物经硅胶柱色谱纯化(氯仿/甲醇47/3),得到0.84g白色固体的标题化合物。
m.p.113-115℃
1H-NMR(400 MHz-DMSO-d6)δppm:1.23(d,6H,J=6.8,
CH3CHCH3);3.05(m,1H,CH3CHCH3);5.07(s,2H,NH2);7.02(s,
1H,H-噻唑);6.20(dd,1H,J=2.0,7.8,H-4′-苯基);6.52
(dd,1H,J=1.5,8.3,H-6′-苯基);6.76(bs,1H,H-2′-
苯基);6.89(t,1H,J=8.3,8.3,H-5′-苯基);8.61(s,1H,
NH);10.13(bs,1H,NH).
ESI(+)-MS:m/z 277(100,(M+H)+).
采用类似方法,但分别以N-(5-异丙基-1,3-噻唑-2-基)-N’-(2-硝基苯基)脲和N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-硝基苯基)脲为原料,可制备下列化合物:
N-(5-异丙基-1,3-噻唑-2-基)-N’-(2-氨基苯基)脲;
N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-氨基苯基)脲;
1H-NMR(400 MHz-DMSO-d6)δppm:1.22(d,6H,J=6.8,
CH3CHCH3);3.04(m,1H,CH3CHCH3);4.83(s,2H,NH2);6.99(s,
1H,H-噻唑);6.50(d,2H,J=8.7,H-3′,H-5′-苯基);
7.05(d,2H,J=8.7,H-2′,H-6′-苯基);8.42(s,1H,NH);
10.09(bs,1H,NH).
ESI(+)-MS:m/z 277(100,(M+H)+).
仍采用类似方法,并分别以6-硝基-1H-吲哚和6-硝基-1H-苯并咪唑为原料,可制备1H-吲哚-6-胺和1H-苯并咪唑-6-胺。
实施例10
式(Ⅰ)化合物:N-[4-({[(5-异丙基-1,3-噻唑-2-基)氨基]苯基]
甲磺酰胺的制备
将0.2g(0.724mmol)N-(5-异丙基-1,3-噻唑-2-基)-N’-(3-氨基苯基)脲溶于10ml无水乙醇中,并顺序加入0.2g(1.95mmol)碳酸氢钾和124.3mg(1.0855mmol)甲磺酰氯。使该混合物在氩气氛下和80℃下保持7小时,然后蒸发。将残余物分配到水和二氯甲烷中。有机层经硫酸钠干燥,浓缩并冷却后,得到104mg白色固体的标题化合物。
m.p.246-248℃
1H-NMR(400MHz-DMSO-d6)δppm:1.23(d,6H,J=6.8,
CH3CHCH3);3.06(m,1H,CH3CHCH3);2.97(s,3H,CH3);7.03(s,
1H,H-噻唑);6.84(d,1H,J=6.8,H-6′-苯基);7.19(m,
2H,H-4′,H-5′-苯基);7.39(s,1H,H-2′-苯基);9.00(s,
1H,NH);9.72(bs,1H,NH);10.18(bs,1H,NHSO2).
ESI(+)-MS:m/z 355(100,(M+H)+).
实施例11
式(Ⅰ)化合物:2-[3-({[5-异丙基-1,3-噻唑-2-基]氨基}
羰基}氨基)苯胺基]乙酰胺的制备
往0.2g(0.724mmol)N-(5-异丙基-1,3-噻唑-2-基)-N-(3-氨基苯基)脲的2ml N,N-二甲基甲酰胺溶液中顺序加入100mg(0.724mmol)2-溴乙酰胺和108.6mg(1.95mmol)碳酸氢钾。在氩气氛下,在40℃下使该混合物保持8小时,然后倾入水中并用二氯甲烷萃取。有机层用盐水洗涤,硫酸钠干燥并浓缩,冷却后得到160mg标题化合物。
m.p.133-135℃
1H-NMR(400MHz-DMSO-d6)δppm:1.23(d,6H,J=6.8,
CH3CHCH3);3.06(m,1H,CH3CHCH3);3.54(d,2H,J=5.4,CH2);
7.02(s,1H,H-噻唑);5.88(m,1H,NH-CH2);.6.21(d,1H,
J=7.8,H-4′-苯基);6.65(d,1H,J=7.8,H-6-苯基);6.69
(s,1H,H-2′-苯基);6.98(t,1H,J=7.8,7.8,H-5-
苯基);8.71(s,1H,NH);10.11(s,1H,NH);7.08,7.29
(s,2H,NH2).
ESI(+)-MS:m/z334(100,(M+H)+).
实施例12
(2R)-2-氨基-2-苯基乙酰胺的制备
将3.025g(15mmol)(2R)-2-氨基-2-苯基乙酸酯盐酸盐悬浮在45ml二噁烷中,然后加入45ml氨水。在室温搅拌8小时后,蒸发溶剂,将残余物再溶于氯仿并用水洗涤。有机层浓缩,得到1.7g白色固体的标题化合物。
采用类似方法,以(2S)-2-氨基-2-苯基乙酸酯为原料,可制备(2S)-2-氨基-2-苯基乙酰胺。
实施例13
1-甲基-2-[(2-硝基苯氧基)甲基]-1H-咪唑的制备
将1.92g(11.97mmol)邻硝基苯酚钠盐,3.8g(35.9mmol)碳酸钠,2g(11.97mmol)1-甲基-2-氯甲基咪唑盐酸盐30mlN,N-二甲基甲酰胺中的溶液在50℃加热2小时。然后将该混合物倾入水中并用乙酸乙酯萃取。有机层用盐水洗涤,经硫酸钠干燥并蒸发,得到1.17g标题化合物,用乙醚重结晶。
m.p.172-174℃
1H-NMR(400 MHz-DMSO-d6)δppm:3.67(s,3H,CH3);5.34(s,
2H,OCH2);6.86(s,1H,H-4-咪唑);7.13(m,1H,H-6-
苯基);7.19(s,1H,H-5-咪唑);7.60(m,1H,H-3
苯基).
ESI(+)MS:m/z 234(100,(M+H)+).
采用类似方法,以2-氯乙酰胺为原料,可制备2-(2-硝基苯氧基)乙酰胺。
m.p.190-192℃
1H-NMR(400 MHz-DMSO-d6)δppm:4.65(s,2H,CH2);7.14(ddd,
1H,J=1.0,7.5,7.9,H-4);7.22(dd,1H,J=1.0,8.7);H-6);
7.32,7.47(2bs,2H,CONH2);7.64(ddd,J=1.5,7.5,8.7,H-
5);7.90(dd,1H,J=1.5,7.9,H-3).
ESI(+)MS:m/z 197(100,(M+H)+).
实施例14
1-甲基-2-[(2-氨基苯氧基)甲基]-1H-咪唑的制备
在室温下,将1.13g 1-甲基-2-[(2-硝基苯氧基)甲基]-1H-咪唑在70ml甲醇中的溶液与0.14g 10%钯碳在50psi压力下氢化6小时。然后过滤分离催化剂并蒸发溶剂。残余物经硅胶柱色谱纯化(洗脱剂:氯仿/甲醇48/2)得到0.856g红色油状的标题化合物。
1H-NMR(400 MHz-DMSO-d6)δppm:3.72(s,3H,CH3);3.80(bs,
2H,NH2);5.15(s,2H,H-3+H-4-苯基);6.81(m,1H,H-5-
苯基);6.90(s,1H,H-4-咪唑);7.02(m,2H,H-6-
苯基+H-5-咪唑).
ESI(+)MS:m/z 204(100,(M+H)+).
采用类似方法,以2-(2-硝基苯氧基)乙酰胺为原料,可制备2-(2-氨基苯氧基)乙酰胺。
m.p.114-116℃
1H-NMR(400 MHz-DMSO-d6)δppm:4.30(s,2H,CH2CO);5.03(s,
2H,NH2);6.45(m,1H,H-5);6.61(m,1H,H-3);6.67(m,1H,
H-4);6.72(m,1H,H-6);7.45(s,1H,CONH);7.73(s,1H,
CONH2).
ESI(+)MS:m/z 167(100,(M+H)+).
实施例152-(咪唑并[1,2-a]吡啶-2-基甲基)-1H-异吲哚-1,3-(2H)-二酮的制
备
将4g(0.024mol)2-(氯甲基)咪唑并[1,2-a]吡啶溶于140mlN,N-二甲基甲酰胺中并分次加入4.81g(0.026mol)potassiumftalimide。将该混合物在60℃加热20小时。过滤沉淀,顺序用水、乙醚和四氢呋喃洗涤,得到4.8g标题化合物。
m.p.230-232℃
1H-NMR(400 MHz-DMSO-d6)δppm:4.88(s,2H,CH2);6.82(m,
1H,H-6-咪唑并吡啶);7.17(m,1H,H-5-
咪唑并吡啶);7.44(m,1H,H-7-咪唑并吡啶);7.88
(m,4H,H-苯基);8.42(m,1H,H-4-咪唑并吡啶).
ESI(+)MS:m/z 278(100,(M+H)+).
实施例16
咪唑并[1,2-a]吡啶-2-基甲胺的制备
将1.37g(4.94mmol)2-(咪唑并[1,2-a]吡啶-2-基甲基)-1H-异吲哚-1,3(2H)-二酮在14ml 98%水合肼和1ml乙醇中的溶液在室温搅拌1小时。将该混合物倾入25ml 35%氢氧化钠溶液中并用二氯甲烷萃取。有机层经硫酸钠干燥并蒸发,得到0.426g结晶于乙醚的标题化合物。
m.p.91-93℃
1H-NMR(400 MHz-DMSO-d6)δppm:1.98(bs,2H,NH2);3.78(s,
2H,CH2);6.80(m,1H,H-6);7.15(m,1H,H-5);7.41(m,1H,
H-7);7.73(s,1H,H-3);8.46(m,1H,H-4).
ESI(+)MS:m/z 148(100,(M+H)+).
实施例17
聚合物负载化合物(Ⅷ)的制备
在5℃和氩气氛下,用20分钟时间,将8.72g(69.1mmol)4-巯基苯酚在20ml无水N,N-二甲基甲酰胺中的溶液滴加到7.76g(69.1mmol)叔丁醇钾在120ml相同溶剂中的溶液中。将25g(19.75mmol)Merrifield树脂(Ⅶ)(Novabiochem,载量0.79mmol/g)加到该溶液中并使该温度保持在60℃。使该混合物在60℃轻轻搅拌18小时并在22℃搅拌24小时。将该树脂过滤,用N,N-二甲基甲酰胺、二氯甲烷、甲醇洗涤并蒸发。由通过微量分析测定的硫百分含量计算树脂上4-巯基苯酚的载量:S2.64%;载量为0.755mmolS/g。通过DRIFTS证实OH基团的存在(宽而强的带:3180-3520nm)。
实施例18
聚合物负载的化合物(Ⅸ)的制备
在氩气氛下,将7.98g(39.6mmol)加到4-硝基苯基氯甲酸酯和4.35ml(39.6mmol)N-甲基吗啉加到溶胀于200ml二氯甲烷中的24g(19.8mmol)聚合物负载的化合物(Ⅷ)中。将该混合物在22℃搅拌22小时。过滤所得化合物(Ⅸ),用二氯甲烷、甲醇洗涤并真空蒸发。由通过微量分析测定的硫百分含量计算树脂上4-硝基苯基氯甲酸酯的载量:S2.34%;载量为0.731mmol S/g。通过DRIFTS检测OH带的消失(宽而强的带:3400nm)和碳酸酯基带(强带:1785nm)的出现。
实施例19
聚合物负载的化合物(Ⅹ)的制备
在氢气氛下,将2-氨基-5-异丙基-1,3-噻唑(39.6mmol)在12.5ml二氯甲烷中的溶液加到溶胀于200ml二氯甲烷中的聚合物负载的化合物(Ⅸ)(19.8mmol)中。将该混合物在22℃搅拌22小时。过滤所得化合物(Ⅸ),用二氯甲烷、甲醇洗涤并真空蒸发。由通过微量分析测定的硫百分含量计算树脂上2-氨基-5-异丙基-1,3-噻唑的载量:S4.21%;载量为0.724mmol S/g。通过DRIFTS证实氨基甲酸酯基的存在(强带:1742nm)的出现。
实施例20
通过平行合成法制备式(Ⅰ)化合物
在Argonaut Quest 210设备容器中,将胺(Ⅴ)(0.236mmol)和N,N-二异丙基乙胺(0.236mmol)加到溶胀于3ml甲苯中的聚合物负载的化合物(Ⅹ)中。当胺的盐形成时,使用128mg(4eq)N,N-二异丙基乙胺树脂结合物(PS-DIEA载量为3.68mmol/g)。将该反应物在60℃搅拌22小时,然后过滤反应混合物并用二氯甲烷洗涤树脂。在氮气氛和35℃下,在Liebisch Termochem Metal-block恒温箱,蒸发回收到Climax试管中的液相。所得粗产物用乙醚-二氯甲烷研制,所得固体经安装有陶瓷滤芯的注射器(Alitech 1.5ml萃取净化管,1.5ml管使用Alltech Teflon陶瓷滤芯)过滤。最终真空干燥产物。
采用该方法,用适宜的胺制备下列化合物:
N-(5-异丙基-1,3-噻唑-2-基)-4-吗啉甲酰胺;
N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-甲基苯基)脲;
N-(5-异丙基-1,3-噻唑-2-基)-N’-(3-氟苯基)脲;
N-(5-异丙基-1,3-噻唑-2-yl)-N’-(4-氰基苯基)脲;
N-(5-异丙基-1,3-噻唑-2-基)-N’-(3-氰基苯基)脲;
N-(5-异丙基-1,3-噻唑-2-基)-N’-(2,6-二甲基苯基)脲;
N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-氟苄基)脲;
N-(5-异丙基-1,3-噻唑-2-基)-N’-(3-乙酰基苯基)脲;
1H-NMR(400 MHz-DMSO-d6)δppm:1.24(d,6H,J=7.0,
CH3CHCH3);3.06(m,1H,CH3CHCH3);2.55(s,3H,COCH3);7.32
(t,1H,J=7.6,H-5′-苯基);7.44(t,1H,J=7.9,H-5′-
苯基);7.5-7.8(m,2H,H-4′,H-6′-苯基);8.08(s,1H,
H-2′-苯基);7.04(s,1H,H-噻唑);9.2(bs,1H,CONH-
苯基);10.5(bs,1H,NHCONHPh);
N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-乙酰苯基)脲;
3-({[(5-异丙基-1,3-噻唑-2-基)氨基]羰基}氨基)苯甲酸;
N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-异丙基苯基)脲;
3-({[(5-异丙基-1,3-噻唑-2-基)氨基]羰基}氨基)苯甲酰胺
1H-NMR(400 MHz-DMSO-d6)δppm: 1.24(d,6H,J=6.8,
CH3CHCH3);3.05(ept,1H,J=6.8,CH3CHCH3);7.32(t,1H,
J=7.6,H-5′-苯基);7.35(t,1H,J=1.5,H-2′-苯基);7.49
(d,1H,J=7.6,H-6′-苯基);7.62(dd,1H,J=7.6,1.5,H-4-
苯基);7.04(s,1H,H-噻唑);9.64(s,1H,CONH-
苯基);10.36(s,1H,NHCONHPh);
N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-甲氧基苄基)脲;
N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-丁基苯基)脲;
N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-三氟甲基苯基)脲;
N-(5-异丙基-1,3-噻唑-2-基)-N’-(3-溴苯基)脲;
N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-环己基苯基)脲;
N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-苯氧基苯基)脲
1H-NMR(400 MHz-DMSO-d6)δppm:1.24(d,6H,J=7.0,
CH3CHCH3);3.05(m,1H,CH3CHCH3);6.96(m,4H,H-3′,H-5-
苯基H-2′H-6′-苯氧基);7.02(s,1H,H-噻唑);7.08
(m,1H,H-4′-苯氧基);7.35(m,2H,H-3′H-5′-苯氧基);7.47
(m,2H,H-2′,H-6′-苯基);8.95(bs,1H,CONH-苯基);10.3
(bs,1H,NHCONH);
N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-苄氧基苯基)脲;
N-(5-异丙基-1,3-噻唑-2-基)-N’-(3,5-二甲基苯基)脲
1H-NMR(300 MHz-DMSO-d6)δppm:1.23(d,6H,J=6.8,
CH3CHCH3);3.05(ept,1H,J=6.8,CH3CHCH3);2.22(s,6H,2
CH3);6.65-7.06(m,3H,H-苯基);7.02(s,1H,H-噻唑);
6.71(s,1H,H-苯基);6.72(s,1H,H-苯基);8.75(bs,
1H,CONH-苯基);10.3(bs,1H,NHCONH).
ESI(+)-MS:m/z 362(100,(M+H)+);
N-(5-异丙基-1,3-噻唑-2-基)-N’-(2,3-二甲基苯基)脲;
N-(5-异丙基-1,3-噻唑-2-基)-N’-(3-甲氧基[1,1’-联苯]-4-基)脲;
N-(5-异丙基-1,3-噻唑-2-基)-3,4-二氢-2(1H)-异喹啉甲酰胺;
N-苄基-N’-(5-异丙基-1,3-噻唑-2-基)-N-甲基脲;
N-(5-异丙基-1,3-噻唑-2-基)-6,7-二甲氧基-3,4-二氢-2(1H)-异喹啉甲酰胺;1H-NMR(400 MHz-DMSO-d6)δppm:1.21(d,6H,J=6.4,CH3CHCH3);2.99(ept,1H,J=6.8,CH3CHCH3);2.7(t2H,J=5.5,CH2NCH2CH2);3.68(t,2H,J=5,5,CH2NCH2CH2);3.69(s,3H,OCH3);3.71(s,3H,OCH3);4.55(s,2H,CH2NCH2CH2);6.97(s,1H,H-噻唑);6.71(s,1H,H-苯基);6.72(s,1H,H-苯基); 10.7(bs,1H,NH).ESI(+)-MS:m/z 362(100,(M+H)+);
N-(5-异丙基-1,3-噻唑-2-基)-N’-[(3-氯-4-甲基)-苯基]脲;
N-(5-异丙基-1,3-噻唑-2-基)-N’-[(3-氯-6-甲基)苯基]脲;
N-(5-异丙基-1,3-噻唑-2-基)-N’-(2,5-二甲氧基苯基)脲;
1H-NMR( 400MHz-DMSO-d6)δppm:.1.24(d,6H,J=7.0,
CH3CHCH3);3.07(m,1H,J=7.0,CH3CHCH3);3.68,3.80(双s
6H,2-OCH3);7.04(d,J=1.0,1H,H-噻唑);6.53(dd,
1H,J=3.0,8.9,H-4′-苯基);6.93(d,1H,J=8.9,H-3′-
苯基);7.79(d,1H,J=3.0,H-6′-苯基);8.7(bs,1H,
NHPh);10.9(bs,1H,NHCONHPh);
N-(5-异丙基-1,3-噻唑-2-基)-N’-(3,4-二甲氧基苯基)脲;
1H-NMR(400 MHz-DMSO-d6)δppm:1.23(d,6H,J=7.0,
CH3CHCH3);3.05(ept,1H,J=7.0,CH3CHCH3);3.7(s3H,OCH3);
3.73(s,3H,OCH3);7.02(s,1H,H-噻唑);6.8-7.2(m,
3H,H-苯基);8.76(s,1H,NHCONHPh);10.2(s,1H,
NHCONHPh);
N-(5-异丙基-1,3-噻唑-2-基)-N’-[(2-甲氧基-5-氯)苯基]脲;
N-(5-异丙基-1,3-噻唑-2-基)-N’-((2-氯-4-甲氧基苯基)脲;
N-(5-异丙基-1,3-噻唑-2-基)-N’-(3,5-二氯苯基)脲;
N-[(1,1’-联苯)-2-基]-N’-(5-异丙基-1,3-噻唑-2-基)脲;
N-乙基-N’-(5-异丙基-1,3-噻唑-2-基)-N-苯基脲;
N-[4-({[(5-异丙基-1,3-噻唑-2-基)氨基]羰基}氨基)-2-甲氧基苯基]乙酰胺;
2-({[(5-异丙基-1,3-噻唑-2-基)氨基]羰基}氨基)-N-苯基苯甲酰胺;
N-(5-异丙基-1,3-噻唑-2-基)-N’-(2-吗啉代苯基)脲;
N-[4-({[(5-异丙基-1,3-噻唑-2-基)氨基]羰基}氨基)苯基]-N-甲基乙酰胺;
1H-NMR(400 MHz-DMSO-d6)δppm:1.22(d,6H,J=6.6,
CH3CHCH3);3.08(m,1H,CH3CHCH3);1.73(s,3H,NCOCH3);
7.03(s,1H,H-噻唑);3.09(s,3H,CH3NCOCH3);7.23(d,
2H,J=8.1,H-6′,H-2′-苯基);7.51(d,2H,J=8.1,H-5′,H-
3′-苯基);9.1(bs,1H,NHCONHPh);10.4(bs,1H,NHCONHPh);
N-(2-{[环己基(甲基)氨基]甲基}苯基)-N’-(5-异丙基-1,3-噻唑-2-基)脲;
N-[3-({[(5-异丙基-1,3-噻唑-2-基)氨基]羰基}氨基)-4-甲氧基苯基]乙酰胺;
N-(5-异丙基-1,3-噻唑-2-基)-4-(4-甲氧基苯基)-1-哌嗪甲酰胺;
N-(2-呋喃甲基)-N’-(5-异丙基-1,3-噻唑-2-基)脲;
1H-NMR(400 MHz-DMSO-d6)δppm:1.24(d,6H,J=6.8,
CH3CHCH3);2.99(ept,1H,J=6.8,CH3CHCH3);4.32(d,2H,
J=5.6,NHCH2);6.26(d,1H,J=3,H-5′-呋喃基);6.4(d,1H,
J=3,H-4′-呋喃基);6.98(s,1H,H-噻唑);6.93(t,1H,
NHCH2);7.59(s,1H,H-3′-呋喃基);10.19(bs,1H,NHCO).
ESI(+)-MS:m/z 266(100,(M+H)+);
N-(4-氟苯基)-N’-(5-异丙基-1,3-噻唑-2-基)脲;
N-(2-甲氧基苄基)-N’-(5-异丙基-1,3-噻唑-2-基)脲;
N-(5-异丙基-1,3-噻唑-2-基)-N’-[2-(1-甲基-1H-吡咯-2-基)乙基]脲;
N-(3,4-二甲氧基苄基)-N’-(5-异丙基-1,3-噻唑-2-基)脲;
1H-NMR(400 MHz-DMSO-d6)δppm:1.21(d,6H,J=7.0,
CH3CHCH3);3.01(ept,1H,J=7.0,CH3CHCH3);3.69(s,3H,
OCH3);3.72(s,3H,OCH3);4.22(d,2H,J=5.0,NHCH2Ph);6.8-
6.9(m,3H,H-苯基);6.96(s,1H,H-噻唑)
N-(5-异丙基-1,3-噻唑-2-基)-4-氧代-1-苯基-1,3,8-三氮杂螺[4.5]癸烷-8-甲酰胺;
1H-NMR(400 MHz-DMSO-d6)δppm:1.23(d,6H,J=6.8,
CH3CHCH3);3.03(ept,1H,J=6.8,CH3CHCH3);1.62(d,2H,
J=13.6,H-3′eq,H-5′eq-哌啶);2.4(td,2H,J=13.6,
5.1,H-3′ax,H-5′ax-哌啶);3.46(bt,2H,J=10.4,H-
6′ax,H-2′ax-哌啶);4.14(bd,2H,J=10.4,H-6′eq,H-
2′eq-哌啶);4.58(s,2H,CONHCH2NPh);6.6-6.7(m,3H,
H-2′,H-6′,H-4′-苯基);7.14(t,2H,J=7.5,H-3′,H-5′-
苯基);6.98(bs,1H,H-噻唑);8.75(bs,1H,
CONHCH2NPh);10.85(bs,1H,噻唑-NHCON);
N-(5-异丙基-1,3-噻唑-2-基)-1,4-二氧杂-8-氮杂螺[4.5]癸烷-8-甲酰胺;
N-(5-异丙基-1,3-噻唑-2-基)-N’-[2-(1-哌啶基)乙基]脲;
N-(5-异丙基-1,3-噻唑-2-基)-N’-[2-(1-吗啉基)乙基]脲;
4-(4-氟苯基)-N-(5-异丙基-1,3-噻唑-2-基)-1-哌嗪甲酰胺;
N-[4-(4-氯苯基)-3-乙基-5-异噁唑基]-N’-(5-异丙基-1,3-噻唑-2-基)脲;
4-[(4-氟苯基)(羟基)甲基]-N-(5-异丙基-1,3-噻唑-2-基)-1-哌啶甲酰胺;
N-(3-乙炔基苯基)-N’-(5-异丙基-1,3-噻唑-2-基)脲;
N-(2-甲氧基-3-氟苯基)-N’-(5-异丙基-1,3-噻唑-2-基)脲;
N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-氧代-1-哌啶基)脲;
N-(3-乙酰氨基苯基)-N’-(5-异丙基-1,3-噻唑-2-基)脲;
N-[3-(2-呋喃基)-1H-吡唑-5-基]-N’-(5-异丙基-1,3-噻唑-2-基)脲;
N-{4-[乙基(异丙基)氨基]苯基}-N’-(5-异丙基-1,3-噻唑-2-基)脲;
N-(1,3-苯并间二氧杂环戊烯-5-基)-N’-(5-异丙基-1,3-噻唑-2-基)脲;
5-({[(5-异丙基-1,3-噻唑-2-基)氨基]羰基}氨基)-1-苯基-1H-吡唑-4-甲酰胺;
N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-吡啶甲基)脲;
N-(5-异丙基-1,3-噻唑-2-基)-N’-(2-吡嗪基)脲;
N-(5-异丙基-1,3-噻唑-2-基)-N’-(5-苯基-1,3,4-噁二唑-2-基)脲;
N-(5-异丙基-1,3-噻唑-2-基)-4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)-1-哌啶甲酰胺;
1H-NMR(400 MHz-DMSO-d6)δppm:1.23(d,6H,J=7.0,
CH3CHCH3);3.01(ept,1H,J=7.0,CH3CHCH3);1.69(bd,2H,
J=9.8,H-3′eq,H-5′eq-哌啶);2.21(m,2H,H-3′ax,H-
5′ax-哌啶);3.46(bt,2H,J=12.4,H-2′ax,H-6′ax-
哌啶);4.14(m,3H,H-2′eq,H-6′eq,H-4′ax-哌啶);
6.9-7.2(m,4H,芳香的);6.98(s,1H,H-噻唑);
10.8(bs,2H,NHCONH):
N-(1,3-苯并噻唑-6-基)-N’-(5-异丙基-1,3-噻唑-2-基)脲;
1H-NMR(400 MHz-DMSO-d6)δppm:1.24(d,6H,J=6.8,
CH3CHCH3);3.05(ept,1H,J=6.8,CH3CHCH3);7.5(dd,1H,
J=8.8,1.9,H-5′-苯并噻唑);7.98(d,1H,J=8.8,H-4′-
苯并噻唑);8.38(d,1H,J=1.9,H-7′-苯并噻唑);
9.22(s,2H,H-2′-苯并噻唑+NHCONHPh);7.04(s,1H,H-
噻唑);10.41(s,1H,NHCONHPh);
N-(1,3-二甲基-1H-吡唑-5-基)-N’-(5-异丙基-1,3-噻唑-2-基)-脲;
N-(3-苯基-1-甲基-1H-吡唑-5-基)-N’-(5-异丙基-1,3-噻唑-2-基)脲;
N-(5-异丙基-1,3-噻唑-2-基)-3-羟基-1-哌啶甲酰胺;
N-(5-异丙基-1,3-噻唑-2-基)-N’-(2-甲基-1,3-二氧代-2,3-二氢-1H-异吲哚-5-基)脲;
N-(5-异丙基-1,3-噻唑-2-基)-4-苄基-1-哌嗪甲酰胺;
N-(5-异丙基-1,3-噻唑-2-基)-4-甲基-1-哌嗪甲酰胺;
4-羟基-N-(5-异丙基-1,3-噻唑-2-基)-1-哌嗪甲酰胺;
N-(5-异丙基-1,3-噻唑-2-基)-3-氮杂双环[3.2.2]壬烷-3-甲酰胺;
N-(5-异丙基-1,3-噻唑-2-基)-4-(4-乙酰基苯基)-1-哌嗪甲酰胺;
1H-NMR(400 MHz-DMSO-d6)δppm:1.21(d,6H,J=7.0,
CH3CHCH3);2.99(ept,1H,J=7.0,CH3CHCH3);2.44(s,3H,
CH3COPh);3.29(bt,4H,CH2-2′,6′-哌嗪);3.63(bt,4H,
CH2-3′,5′-哌嗪);6.97(d,2H,J=9.2,H-3′,5′-
苯基);7.8(d,2H,J=9.2,H-2′,6′-苯基);6.97(s,1H,
H-噻唑);10.95(bs,1H,NHCON):
4-[二(4-氟苯基)-N-(5-异丙基-1,3-噻唑-2-基)-1-哌嗪甲酰胺;
N-(5-异丙基-1,3-噻唑-2-基)-4-氧代-2,3,4,5-四氢-1H-1,5-苯并二氮杂-1-甲酰胺;
N-(5-异丙基-1,3-噻唑-2-基)-N’-(5-6,7,8-四氢-1-萘基)脲;
N-(4-苯基-2-噻唑基)-N’-(5-异丙基-1,3-噻唑-2-基)脲;
4-(4-氟苯甲酰基)-N-(5-异丙基-1,3-噻唑-2-基)-1-哌啶甲酰胺;
N-(5-异丙基-1,3-噻唑-2-基)-N’-1,3-二氢-2-苯并呋喃-5-基)脲;
N-(5-异丙基-1,3-噻唑-2-基)-4-(2-嘧啶基)-1-哌嗪甲酰胺;
N-(5-异丙基-1,3-噻唑-2-基)-3-氧代-3,4-二氢-1(2H)-喹喔啉;
N-(5-异丙基-1,3-噻唑-2-基)-N’-(1H-吲唑-6-基)脲;
1H-NMR(500 MHz-DMSO-d6)δppm:1.25(d,6H,J=6.8,
CH3CHCH3);3.07(m,1H,CH3CHCH3);6.94(d,1H,J=8.4,H-5′-
吲唑);7.65(d,1H,J=8.4,H-4′-吲唑);.7.94(m,2H,
H-3′,H-7′-吲唑);7.04(s,1H,H-噻唑);9.12(bs,
1H,CONH-吲唑);10.30(bs,1H,NH-噻唑);12.87(bs,
1H,NH-吲唑).
ESI(+)-MS:m/z 302(100,(M+H)+);
N-(5-异丙基-1,3-噻唑-2-基)-N’-(2-氯苄基)脲;
1H-NMR(500 MHz-DMSO-d6)δppm:1.21(d,6H,J=6.9,
CH3CHCH3);3.03(m,1H,CH3CHCH3);4.38(d,2H,J=5.9,CH2);
7.3-7.44(m,4H,苯基);6.97(d,1H,J=0.9,H-噻唑);
7.10(bs,1H,NHCH2);10.32(bs,1H,NH-噻唑).
ESI(+)-MS:m/z 310(100,(M+H)+);N-(5-异丙基-1,3-噻唑-2-基)-N’-(2,4-二氯苄基)脲;N-(5-异丙基-1,3-噻唑-2-基)-N’-(3-氟苄基)脲;1H-NMR(500MHz-DMSO-d6)δppm:1.21(d,6H,J=6.8,CH3CHCH3);3.03(m,1H,CH3CHCH3);4.32(d,2H,J=6.1,CH2);6.97(d,1H,J=0.9,H-噻唑);7.0-7.4(m,5H,苯基+NHCH2);10.30(bs,1H,NH-噻唑).ESI(+)-MS:m/z 294(100,(M+H)+);N-(5-异丙基-1,3-噻唑-2-基)-N’-(3,4-二氯苄基)脲;1H-NMR(500 MHz-DMSO-d6)δppm:1.21(d,6H,J=6.7,CH3CHCH3);3.03(m,1H,CH3CHCH3);4.30(d,2H,J=6.1,CH2);7.28(dd,1H,J=2.0,8.2,H-6′-苯基);7.52(d,1H,J=2.0,H-2′-苯基);7.58(d,1H,J=8.2,H-5′-苯基);6.97(d,1H,J=0.9,H-噻唑);7.12(bs,1H,NHCH2);10.41(bs,1H,NH-噻唑).ESI(+)-MS:m/z 143(100,异丙基氨基噻唑+H)+);m/z344(65,(M+H)+);N-(5-异丙基-1,3-噻唑-2-基)-N’-(2,4-二氟苄基)脲;1H-NMR(300 MHz-DMSO-d6)δppm:1.21(d,6H,J=6.7 CH3CHCH3);3.03(m,1H,CH3CHCH3);4.30(d,2H,J=6.0,CH2);6.97(d,1H,J=0.9,H-噻唑);7.0-7.4(m,4H,苯基+NHCH2);10.20(bs,1H,NH-噻唑).ESI(+)-MS:m/z 312(100,(M+H)+);N-(5-异丙基-1,3-噻唑-2-基)-N’-(2,5-二氟苄基)脲;
1H-NMR(500 MHz-DMSO-d6)δppm:1.21(d,6H,J=6.9 CH3CHCH3);
3.02(m,1H,CH3CHCH3);4.35(d,2H,J=5.8,CH2);7.08(m,
2H,H-3′,H-5′-苯基);7.39(m,1H,H-4′-苯基);6.95(d,
1H,J=0.9,H-噻唑);7.04(bs,1H,NHCH2);10.08(bs,1H,
NH-噻唑).
ESI(+)-MS:m/z 312(100,(M+H)+);
N-(5-异丙基-1,3-噻唑-2-基)-N’-(2,6-二氟苄基)脲;
N-(5-异丙基-1,3-噻唑-2-基)-N’-[(4-羟基-3-甲氧基)苄基]脲;
N-(5-异丙基-1,3-噻唑-2-基)-N’-(5-甲基-2-呋喃基)脲;
1H-NMR(500 MHz-DMSO-d6)δppm:1.21(d,6H,J=6.8,
CH3CHCH3);3.03(m,1H,CH3CHCH3);2.21(s,3H,CH3);4.23(d,
2H,J=5.8,CH2);5.97,6.11(2s,2H,呋喃);6.96(d,1H,
J=1.0,H-噻唑);6.91(bs,1H,NHCH2);10.14(bs,1H,NH-
噻唑).
ESI(+)-MS:m/z 280(100,(M+H)+);
N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-甲磺酰基苄基)脲;
N-[(1R,2R)-2-羟基-2,3-二氢-1H-茚-1-基)-N’-(5-异丙基-1,3-噻唑-2-基)脲;
N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-氯苄基)脲;
1H-NMR(500 MHz-DMSO-d6)δppm:1.21(d,6H,J=6.8,
CH3CHCH3);3.03(m,1H,CH3CHCH3);4.29(d,2H,J=6.1,CH2);
7.3,7.37(2d,4H,J=8.5,苯基);6.97(d,1H,J=0.9,H-
噻唑);7.06(bs,1H,NHCH2);10.30(bs,1H,NH-
噻唑).
ESI(+)-MS:m/z 310(100,(M+H)+);
N-(5-异丙基-1,3-噻唑-2-基)-N’-(2-吡啶基甲基)脲;
N-(5-异丙基-1,3-噻唑-2-基)-N’-(3,5-二甲氧基苄基)脲;
1H-NMR(500 MHz-DMSO-d6)δppm:1.21(d,6H,J=6.8,
CH3CHCH3);3.03(m,1H,CH3CHCH3);4.24(d,2H,J=5.9,CH2);
3.71(s,6H,2OCH3);6.37(s,1H,H-4′-苯基);6.44(s,
2H,H-2′,H-6′-苯基);6.97(s,1H,H-噻唑);6.99(bs,
1H,NHCH2);10.22(bs,1H,NH-噻唑).
ESI(+)-MS:m/z 336(100,(M+H)+);
N-(5-异丙基-1,3-噻唑-2-基)-N’-(3-吡啶甲基)脲;
N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-三氟苄基)脲;
N-(5-异丙基-1,3-噻唑-2-基)-N’-(3,4,5-三甲氧基苄基)脲;
1H-NMR(300 MHz-DMSO-d6)δppm:1.21(d,6H,J=6.8,
CH3CHCH3);3.03(m,1H,CH3CHCH3);4.24(d,2H,J=5.9,CH2);
3.60,3.65(3s,9H,3 OCH3);6.60(s,2H,苯基);6.97(s,
1H,H-噻唑);6.99(bs,1H,NHCH2);10.20(bs,1H,NH-
噻唑).
ESI(+)-MS:m/z 366(100,(M+H)+);m/z 181(100,(CH3O)3-C7H4 +);
N-(5-异丙基-1,3-噻唑-2-基)-N’-(2,4-二甲氧基苄基)脲;
1H-NMR(300 MHz-DMSO-d6)δppm:1.21(d,6H,J=6.8,
CH3CHCH3);3.03(m,1H,CH3CHCH3);4.24(d,2H,J=5.9,CH2);
3.70,3.78(2s,6H,2 OCH3);6.48(dd,1H,H-5-苯基);
6.52(d,1H,H-3′-苯基);7.05(d,1H,H-6′-苯基);6.97
(s,1H,H-噻唑);6.80(bs,1H,NHCH2);10.10(bs,1H,
NH-噻唑).
ESI(+)-MS:m/z 336(100,(M+H)+);
N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-二甲氨基苄基)脲;
N-(5-异丙基-1,3-噻唑-2-基)-N’-(2,5-二甲氧基苄基)脲;
N-(5-异丙基-1,3-噻唑-2-基)-N’-[(2-氯-6-苯氧基)苄基]脲;
N-(5-异丙基-1,3-噻唑-2-基)-N’-[(1R,2S)-2-羟基-2,3-二氢-1H-茚-1-基]脲;
N-(5-异丙基-1,3-噻唑-2-基)-N’-[(3-羟基-4-甲基)苯基]脲;
N-(5-异丙基-1,3-噻唑-2-基)-N’-[4-(1H-苯并咪唑-2-基)苯基]脲;
N-(5-异丙基-1,3-噻唑-2-基)-N’-(3-苯基-1H-吡唑-5-基)脲;
N-(5-异丙基-1,3-噻唑-2-基)-N’-(2-甲基-6-喹啉基)脲;
1H-NMR(500 MHz-DMSO-d6)δppm:1.25(d,6H,J=6.8,
CH3CHCH3);3.07(m,1H,CH3CHCH3);2.61(s,3H,CH3);7.05(s,
1H,H-噻唑);7.36(d,1H,J=8.4,H-3′-喹啉);7.65
(dd,1H,J=2.0,9.0,H-7′-喹啉);7.85(d,1H,J=9.0,H-
8′-喹啉);8.14(m,2H,H-4′,H-5′-喹啉);9.22(bs,
1H,NHCONH-喹啉);10.40(bs,1H,NH-噻唑).
ESI(+)MS:m/z 185(100,(MH-(CH3)2-CH-氨基-噻唑)+);327
(75,(M+H)+);
N-(5-异丙基-1,3-噻唑-2-基)-N’-[4-(氰甲基)苯基]脲;
1H-NMR(500 MHz-DMSO-d6)δppm:1.24(d,6H,J=6.9,
CH3CHCH3);3.05(m,1H,CH3CHCH3);7.03(s,1H,H-噻唑);
3.94(s,2H,CH3);7.27(d,2H,H-3′,H-5′-苯基);7.48(d,
2H,J=8.5,H-2′,H-6′-苯基);9.01(bs,1H,NH-苯基);
10.30(bs,1H,NH-噻唑).
ESI(+)MS:m/z 301(100,(M+H)+);
N-(5-异丙基-1,3-噻唑-2-基)-N’-(2-喹啉基)脲;
1H-NMR(500 MHz-DMSO-d6)ppm:1.27(d,6H,J=6.8,
CH3CHCH3);3.13(m,1H,CH3CHCH3);7.17(s,1H,H-噻唑);
7.44(m,1H,H-3′-喹啉);7.50(m,1H,H-6′-喹啉);
7.75(m,1H,H-7′-喹啉);7.82(m,1H,H-8′-喹啉);
7.90(m,1H,H-5′-喹啉);8.34(m,1H,H-4′-喹啉);
10.45(bs,1H,NHCONH-喹啉);13.02(bs,1H,NHCON).
ESI(+)MS:m/z 313(100,(M+H)+).
N-(5-异丙基-1,3-噻唑-2-基)-N’-(1-氧代-2,3-二氢-1H-茚-5-基)脲;
N-(5-异丙基-1,3-噻唑-2-基)-N’-(3-氧代-1,3-二氢-2-苯并呋喃-5-基)脲;
1H-NMR(500 MHz-DMSO-d6)δppm:1.24(d,6H,J=6.8,
CH3CHCH3);3.06(m,1H,CH3CHCH3);7.04(s,1H,H-噻唑);
5.35(s,1H,CH2);7.58(d,1H,J=8.4,H-5′-苯基);7.71
(d,1H,J=8.4,H-6′-苯基); 8.08(s,1H,H-2′-苯基);9.34
(bs,1H,NHCONHPh);10.50(bs,1H,NHCON).
ESI(+)MS:m/z 318(100,(M+H)+);
N-(5-异丙基-1,3-噻唑-2-基)-N’-(5-氧代-5,6,7,8-四氢-2-萘基)脲;
3-(([(5-异丙基-1,3-噻唑-2-基)氨基]羰基}氨基)-4-甲基苯甲酸甲酯;
1H-NMR(300 MHz-DMSO-d6)δppm:1.25(d,6H,J=6.8,
CH3CHCH3);3.10(m,1H,CH3CHCH3);2.30(s,3H,CH3-苯基);
3.80(s,3H,CH3O);7.05(s,1H,H-噻唑);7.30(d,1H,
H-5′-苯基);7.58(dd,1H,H-6′-苯基);8.55(m,2H,H-2′
苯基+NHPh);10.80(bs,1H,NH-噻唑).
ESI(+)MS:m/z 334(100,(M+H)+);
4-(([(5-异丙基-1,3-噻唑-2-基)氨基]羰基}氨基)-3-甲基苯甲酸甲酯;
1H-NMR(300 MHz-DMSO-d6)δppm:1.21(d,6H,CH3CHCH3);3.03
(m,1H,CH3CHCH3);2.25(s,3H,CH3-苯基);3.83(s,3H,
CH3O);7.03(s,1H,H-噻唑);7.30(d,1H,H-3-苯基);
7.53(dd,1H,H-4′-苯基);8.50(m,2H,H-6-苯基+
NHPh);10.70(bs,1H,NH-噻唑).
ESI(+)MS:m/z 334(100,(M+H)+);
N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-咪唑并[1,2-a]吡啶-2-基-苯基)脲;
1H-NMR(300 MHz-DMSO-d6)ppm:1.21,(d,6H,J=6.8,
CH3CHCH3);3.03(m,1H,CH3CHCH3);7.03(s,1H,H-噻唑);
6.84,7.20(2m,2H,H-5′,H-6″咪唑并吡啶);7.50,7.90
(2m,5H,H-2′,H-3′,H-5′,H-6′-苯基+H-7′-
咪唑并吡啶);8.30(s,1H,H-3′-咪唑并吡啶);8.50
(d,1H,H-4′-咪唑并吡啶);9.00(bs,1H,NHCONHPh);
10.30(bs,1H,NHCON).
ESI(+)MS:m/z 236(100,(MH-(CH3)2-CH-氨基-噻唑)+);m/z
378(85,(M+H)+);
4-(([(5-异丙基-1,3-噻唑-2-基)氨基]羰基}氨基)苯甲酸乙酯;
1H-NMR(300 MHz-DMSO-d6)δppm:1.20(d,6H,CH3CHCH3);3.03
(m,1H,CH3CHCH3);7.00(s,1H,H-噻唑);1.15(t,3H,
CH3);3.58(s,2H,CH2-苯基);4.06(q,2H,CH2O);7.16,
7.38(2d,4H,苯基);8.90(bs,1H,NHCONHPh);10.30(bs,
1H,NHCON).
ESI(+)MS:m/z 348(100,(M+H)+);
(2R)-1-苄基-2-(([(5-异丙基-1,3-噻唑-2-基)氨基]羰基}氨基)丙酰胺;
2-羟基-5-({[(5-异丙基-1,3-噻唑-2-基)氨基]羰基}苯甲酸;
2-氯-5-({[{5-异丙基-1,3-噻唑-2-基}氨基]羰基}氨基)苯甲酸;
1H-NMR(400 MHz-DMSO-d6)δppm:1.24(d,6H,J=6.8,
CH3CHCH3);3.04(m,1H,CH3CHCH3);7.02(s,1H,H-噻唑);
7.35(d,1H,J=8.8,H-5′-苯基);7.55(dd,1H,H-6′-
苯基);7.88(bs,1H,H-2′苯基);9.75(bs,1H,
NHCONHPh);11.00(bs,1H,NHCON).
ESI(+)MS:m/z 340(100,(M+H)+);
3-({[(5-异丙基-1,3-噻唑-2-基)氨基]羰基}氨基)苯甲酸;
1H-NMR(500 MHz-DMSO-d6)δppm:1.24(d,6H,J=6.8,
CH3CHCH3);3.03(m,1H,CH3CHCH3);7.04(s,1H,H-噻唑);
7.40(dd,1H,J=7.9,H-5′-苯基);7.58,7.63(2d,2H,
J=7.9,H-4′,H-6′-苯基);8.13(s,1H,H-2′-苯基);9.28
(s,1H,NHCONHPh);10.50(bs,1H,NHCON).
ESI(+)MS:m/z 306(100,(M+H)+);
N-(5-异丙基-1,3-噻唑-2-基)-N’-(5-甲基-3-异噁唑基)脲;
N-(5-异丙基-1,3-噻唑-2-基)-N’-(2,6-二甲氧基苯基)脲;
N-(5-异丙基-1,3-噻唑-2-基)-N’-(2,3-二甲氧基苄基)脲;
1H-NMR(300 MHz-DMSO-d6)δppm:1.21(d,6H,J=6.8,
CH3CHCH3);3.03(m,1H,CH3CHCH3);4.32(d,2H,J=6.1,CH2);
3.72,3.75(2s,6H,2OCH3);6.8-7.0(m,3H,苯基);6.97
(s,1H,H-噻唑);6.90(bs,1H,NHCH2);10.20(bs,1H,
NH-噻唑).
ESI(+)-MS:m/z 336(100,(M+H)+);
N-(5-异丙基-1,3-噻唑-2-基)-N’-(3,4-二氟苄基)脲;
N-(5-异丙基-1,3-噻唑-2-基)-N’-(2,4-二甲基苯基)脲;
N-(5-异丙基-1,3-噻唑-2-基)-N’-丁基脲;
1H-NMR(300 MHz-DMSO-d6)δppm:1.20(d,6H,CH3CHCH3);3.00
(m,1H,CH3CHCH3);0.85(t,3H,CH3);1.20-1.40(m,4H,CH2-CH2);3.10(m,2H,CH2-NH);6.94(d,1H,J=1.0,H-噻唑);
6.49(t,1H,NHCH2);10.5(bs,1H,NH-噻唑).
ESI(+)-MS:m/z 242(100,(M+H)+);
N-(5-异丙基-1,3-噻唑-2-基)-N’-苯甲酰基脲;
N-(5-甲基-1,3-噻唑-2-基)-N’-(2,6-二甲基苯基)脲;
N-(5-甲基-1,3-噻唑-2-基)-N’-苄基脲;
N-(5-甲基-1,3-噻唑-2-基)-N’-丁基脲;
N-(5-甲基-1,3-噻唑-2-基)-4-吗啉甲酰胺;
N-(5-甲基-1,3-噻唑-2-基)-N’-苯基脲;
N-(5-甲基-1,3-噻唑-2-基)-N’-(4-甲氧基苄基脲;
N-(5-甲基-1,3-噻唑-2-基)-N’-(4-氟苯基)脲;
N-[(1-乙基-2-吡咯烷基)甲基]-N’-(5-甲基-1,3-噻唑-2-基)脲;
N-(5-甲基-1,3-噻唑-2-基)-N’-(5-羟基-1H-吡唑-3-基)脲;
N-(5-甲基-1,3-噻唑-2-基)-N’-(3-吡啶基)脲;
N-(4-氟苯基)-N’-(5-甲基-1,3-噻唑-2-基)脲。
所以化合物均以质谱(MS)表征。LC-MS证实在各种情况下,主要成分都具有相应于预期产物的分子离子。化合物显示的HPLC面积%为70-100。
HPLC分析:
仪器:Beckman System Gold Cromatographer(127 Sloventmodule,168 Detector,507e Autosampler)
流动相A:H2O/CH3CN(90/10)+0.1% TFA
流动相B:H2O/CH3CN(10/90)+0.075% TFA
流速:1.5ml/min
样品体积:20cml
柱:SupelcoTM,Discovery RP Amide C16,5-μm,(50x4.6)mm
温度:25℃
梯度:
时间(min) %A %B
0 0 100
6.5 0 100
7 100 0
10 100 0
检测:二极管阵列UV 254nm
所有化合物均使用LCQ Finnigan质谱仪进行MS谱分析(ESI)。对随机选择的37种化合物进行了1H-NMR分析。在Varian XL 400光谱仪上绘制谱图。
Claims (16)
1、式(Ⅰ)的2-脲基-1,3-噻唑衍生物或其可药用盐在制备治疗与改变的细胞依赖性激酶活性有关的细胞增殖性疾病的药物中的用途,
其中
R是卤原子、硝基、可任选地取代的氨基或可任选地进一步取代的选自下列的基团:
ⅰ)直链或支链C1-C6烷基;
ⅱ)C3-C6环烷基;
ⅲ)芳基或者直链或支链烷基链部分具有1-6个碳原子的芳烷基;
R1是可任选地进一步取代的选自下列的基团:
ⅰ)直链或支链C1-C6烷基;
ⅱ)3-6元碳环或5-7元杂环;
ⅲ)芳基或芳基羰基;
ⅳ)直链或支链烷基链部分具有1-6个碳原子的芳烷基;
R2是氢、直链或支链C1-C4烷基或C2-C4链烯基或炔基;或者
和与其结合的氮原子一起,
R1和R2形成取代的或未取代的选自下列的基团:
ⅰ)可任选地苯并稠合的或桥连的5-7元杂环;或
ⅱ)9-11元螺杂环化合物。
2、权利要求1的用途,其中所述细胞增殖性疾病选自癌症、阿尔茨海默氏症、病毒感染、自身免疫疾病或神经变性的疾病。
3、权利要求2的用途,其中所述癌症选自癌、鳞状细胞癌、骨髓或淋巴谱系造血肿瘤、间充质源性肿瘤、中枢和外周神经系统肿瘤、黑素瘤、精原细胞瘤、畸胎瘤、骨肉瘤、xenoderomapigmentosum、角化棘皮瘤、甲状腺滤泡癌和卡波西肉瘤。
4、权利要求1的应用,其中所述细胞增殖性疾病选自良性前列腺增生、家族性腺瘤病、神经纤维瘤病、牛皮癣、与动脉粥样硬化有关的血管平滑细胞增殖、肺纤维化、关节炎、肾小球性肾炎以及术后狭窄和再狭窄。
5、前述任一项权利要求的应用,其中的药物能使肿瘤的血管生成和迁移抑制。
6、用作药物的式(Ⅰ)的2-脲基-1,3-噻唑衍生物或其可药用盐,其中
R是卤原子、硝基、可任选地取代的氨基或可任选地进一步取代的选自下列的基团:
ⅰ)直链或支链C1-C6烷基;
ⅱ)C3-C6环烷基;
ⅲ)芳基或直链或支链烷基链部分具有1-6个碳原子的芳烷基;
R1是可任选地进一步取代的选自下列的基团:
ⅰ)直链或支链C1-C6烷基;
ⅱ)3-6元碳环或5-7元杂环;
ⅲ)芳基或芳基羰基;
ⅳ)直链或支链烷基链部分具有1-6个碳原子的芳烷基;
R2是氢、直链或支链C1-C4烷基或C2-C4链烯基或炔基;或者和与其结合的氮原子一起,
R1和R2形成取代的或未取代的选自下列的基团:
ⅰ)可任选地苯并稠合的或桥连的5-7元杂环;或
ⅱ)9-11元螺杂环化合物;
条件是:
a)当R是氯原子并且R2是氢时,R1不是甲基、苯基或三氟甲基苯基;和
b)当R是甲基并且R2是氢时,R1不是4-(5-噁唑基)苯基。
7、式(Ⅰ)的2-氨基-1,3-噻唑衍生物或其可药用盐,
其中
R是卤原子、硝基、可任选地取代的氨基或可任选地进一步取代的选自下列的基团:
ⅰ)直链或支链C1-C6烷基;
ⅱ)C3-C6环烷基;
ⅲ)芳基或直链或支链烷基链部分具有1-6个碳原子的芳烷基;
R1是可任选地进一步取代的选自下列的基团:
ⅰ)直链或支链C1-C6烷基;
ⅱ)3-6元碳环或5-7元杂环;
ⅲ)芳基或芳基羰基;
ⅳ)直链或支链烷基链部分具有1-6个碳原子的芳烷基;
R2是氢、直链或支链C1-C4烷基或C2-C4链烯基或炔基;或者
和与其结合的氮原子一起,
R1和R2形成取代的或未取代的选自下列的基团:
ⅰ)可任选地苯并稠合的或桥连的5-7元杂环;或
ⅱ)9-11元螺杂环化合物;
条件是:
a)当R是氯或溴并且R2是氢时,R1不是未取代的C1-C3烷基、苯基、三氟甲基苯基或可任选地取代的苯基羰基;
b)当R是甲基并且R2是氢时,R1不是甲基、苯基或4-(5-噁唑基)苯基;
c)当R是硝基苯基并且R2是氢时,R1不是卤代烷基;
d)当R是溴或氯时,R1和R2不同时为甲基。
8、权利要求7的式(Ⅰ)化合物,其中R是卤原子、直链或支链的C1-C4烷基、苯基或环烷基;R2是氢并且R1是可任选地取代的选自烷基、芳基或芳烷基的基团。
9、权利要求8的式(Ⅰ)化合物,其中R是溴或氯、直链或支链C1-C4烷基、苯基或环烷基;R2是氢并且R1是可任选地取代的芳基或者烷基链部分具有1-4个碳原子的芳烷基或杂环基-烷基。
10、权利要求7的式(Ⅰ)化合物和其可药用盐,其中R是卤原子或选自下列的基团:硝基、氨基、烷基氨基、羟烷基氨基、芳基氨基、C3-C6环烷基、直链或支链C1-C6烷基、可任选地被下列基团取代:羟基、烷硫基、烷氧基、氨基、烷基氨基、烷氧羰基烷基氨基、烷基羰基、烷基磺酰基、烷氧羰基、羧基、芳基、可任选地被一个或多个羟基、卤素、硝基、烷氧基、芳氧基、烷硫基、芳硫基、氨基、烷基氨基、二烷基氨基、N-烷基哌嗪基、4-吗啉基、芳基氨基、氰基、烷基、苯基、氨基磺酰基、氨基羰基、烷基羰基、芳基羰基、烷氧羰基或羧基取代,或者R是芳基、可任选地被一个或多个羟基、卤素、硝基、烷氧基、芳氧基、烷硫基、芳硫基、氨基、烷基氨基、二烷基氨基、N-烷基哌嗪基、4-吗啉基、芳基氨基、氰基、烷基、苯基、氨基磺酰基、氨基羰基、烷基羰基、芳基羰基、烷氧羰基或羧基取代;
R1是直链或支链C1-C6烷基或者芳基,各自可任选地如上述R所述的被取代;
R2是氢原子;
条件是:
a)当R是氯或溴时,R1不是未取代的C1-C3烷基、苯基、三氟甲基苯基或任选地取代的苯基羰基;
b)当R是甲基时,R1不是甲基、苯基或4-(5-噁唑基)苯基;
c)当R是硝基苯基时,R1不是卤代烷基。
11、权利要求7的式(Ⅰ)化合物,其中R是直链或支链C1-C6烷基,并且R1、R2和与它们结合的氮原子一起形成取代的或未取代的、可任选地苯并稠合的或桥连的5-7元杂环或9-11元螺杂环。
12、权利要求7的式(Ⅰ)化合物,其中R是直链或支链C1-C6烷基;R2是直链或支链C1-C4烷基或者C2-C4链烯基或炔基并且R1是芳基或者支链或直链烷基链具有1-4个碳原子的芳烷基。
13、前述任一项权利要求的式(Ⅰ)化合物,适当的时候可以呈可药用盐形式,它们选自下列化合物:
1)N-(5-异丙基-1,3-噻唑-2-基)-N’-苯基脲;
2)N-(5-溴-1,3-噻唑-2-基)-N’-苯基脲;
3)N-(5-苯基-1,3-噻唑-2-基)-N’-苯基脲;
4)N-(5-环丙基-1,3-噻唑-2-基)-N’-苯基脲;
5)N-(5-溴-1,3-噻唑-2-基)-N’-(4-氨磺酰-苯基)脲;
6)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-氨磺酰-苯基)脲;
7)N-(5-苯基-1,3-噻唑-2-基)-N’-(4-氨磺酰-苯基)脲;
8)N-(5-环丙基-1,3-噻唑-2-基)-N’-(4-氨磺酰-苯基)脲;
9)N-(5-异丙基-1,3-噻唑-2-基)-N’-(3-甲氧基-苯基)脲;
10)N-(5-溴-1,3-噻唑-2-基)-N’-(3-甲氧基-苯基)脲;
11)N-(5-苯基-1,3-噻唑-2-基)-N’-(3-甲氧基-苯基)脲;
12)N-(5-环丙基-1,3-噻唑-2-基)-N’-(3-甲氧基-苯基)脲;
13)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-氯-苯基)脲;
14)N-(5-溴-1,3-噻唑-2-基)-N’-(4-氯-苯基)脲;
15)N-(5-苯基-1,3-噻唑-2-基)-N’-(4-氯-苯基)脲;
16)N-(5-环丙基-1,3-噻唑-2-基)-N’-(4-氯-苯基)脲;
17)N-(5-异丙基-1,3-噻唑-2-基)-N’-(3-氯-苯基)脲;
18)N-(5-溴-1,3-噻唑-2-基)-N’-(3-氯-苯基)脲;
19)N-(5-苯基-1,3-噻唑-2-基)-N’-(3-氯-苯基)脲;
20)N-(5-环丙基-1,3-噻唑-2-基)-N’-(3-氯-苯基)脲;
21)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2-氯-苯基)脲;
22)N-(5-溴-1,3-噻唑-2-基)-N’-(2-氯-苯基)脲;
23)N-(5-苯基-1,3-噻唑-2-基)-N’-(2-氯-苯基)脲;
24)N-(5-环丙基-1,3-噻唑-2-基)-N’-(2-氯-苯基)脲;
25)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-甲氧基-苯基)脲;
26)N-(5-溴-1,3-噻唑-2-基)-N’-(4-甲氧基-苯基)脲;
27)N-(5-苯基-1,3-噻唑-2-基)-N’-(4-甲氧基-苯基)脲;
28)N-(5-环丙基-1,3-噻唑-2-基)-N’-(4-甲氧基-苯基)脲;
29)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-羟基-苯基)脲;
30)N-(5-溴-1,3-噻唑-2-基)-N’-(4-羟基-苯基)脲;
31)N-(5-苯基-1,3-噻唑-2-基)-N’-(4-羟基-苯基)脲;
32)N-(5-环丙基-1,3-噻唑-2-基)-N’-(4-羟基-苯基)脲;
33)N-(5-异丙基-1,3-噻唑-2-基)-N’(3-羟基-苯基)脲;
34)N-(5-溴-1,3-噻唑-2-基)-N’-(3-羟基-苯基)脲;
35)N-(5-苯基-1,3-噻唑-2-基)-N’-(3-羟基-苯基)脲;
36)N-(5-环丙基-1,3-噻唑-2-基)-N’-(3-羟基-苯基)脲;
37)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2-甲氧基-苯基)脲;
38)N-(5-溴-1,3-噻唑-2-基)-N’-(2-甲氧基-苯基)脲;
39)N-(5-苯基-1,3-噻唑-2-基)-N’-(2-甲氧基-苯基)脲;
40)N-(5-环丙基-1,3-噻唑-2-基)-N’-(2-甲氧基-苯基)脲;
41)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2-羟基-苯基)脲;
42)N-(5-溴-1,3-噻唑-2-基)-N’-(2-羟基-苯基)脲;
43)N-(5-苯基-1,3-噻唑-2-基)-N’-(2-羟基-苯基)脲;
44)N-(5-环丙基-1,3-噻唑-2-基)-N’-(2-羟基-苯基)脲;
45)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-硝基-苯基)脲;
46)N-(5-溴-1,3-噻唑-2-基)-N’-(4-硝基-苯基)脲;
47)N-(5-苯基-1,3-噻唑-2-基)-N’-(4-硝基-苯基)脲;
48)N-(5-环丙基-1,3-噻唑-2-基)-N’-(4-硝基-苯基)脲;
49)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-氨基-苯基)脲;
50)N-(5-溴-1,3-噻唑-2-基)-N’-(4-氨基-苯基)脲;
51)N-(5-苯基-1,3-噻唑-2-基)-N’-(4-氨基-苯基)脲;
52)N-(5-环丙基-1,3-噻唑-2-基)-N’-(4-氨基-苯基)脲;
53)N-(5-异丙基-1,3-噻唑-2-基)-N’-(3-硝基-苯基)脲;
54)N-(5-溴-1,3-噻唑-2-基)-N’-(3-硝基-苯基)脲;
55)N-(5-苯基-1,3-噻唑-2-基)-N’-(3-硝基-苯基)脲;
56)N-(5-环丙基-1,3-噻唑-2-基)-N’-(3-硝基-苯基)脲;
57)N-(5-异丙基-1,3-噻唑-2-基)-N’-(3-氨基-苯基)脲;
58)N-(5-溴-1,3-噻唑-2-基)-N’-(3-氨基-苯基)脲;
59)N-(5-苯基-1,3-噻唑-2-基)-N’-(3-氨基-苯基)脲;
60)N-(5-环丙基-1,3-噻唑-2-基)-N’-(3-氨基-苯基)脲;
61)N-(5-异丙基-1,3-噻唑-2-基)-N’-苄基脲;
62)N-(5-溴-1,3-噻唑-2-基)-N’-苄基脲;
63)N-(5-苯基-1,3-噻唑-2-基)-N’-苄基脲;
64)N-(5-环丙基-1,3-噻唑-2-基)-N’-苄基脲;
65)N-(5-异丙基-1,3-噻唑-2-基)-N’-(吡啶-3-基)脲;
66)N-(5-溴-1,3-噻唑-2-基)-N’-(吡啶-3-基)脲;
67)N-(5-苯基-1,3-噻唑-2-基)-N’-(吡啶-3-基)脲;
68)N-(5-环丙基-1,3-噻唑-2-基)-N’-(吡啶-3-基)脲;
69)N-(5-溴-1,3-噻唑-2-基)-N’-(吡啶-4-基)脲;
70)N-(5-异丙基-1,3-噻唑-2-基)-N’-(吡啶-4-基)脲;
71)N-(5-苯基-1,3-噻唑-2-基)-N’-(吡啶-4-基)脲;
72)N-(5-环丙基-1,3-噻唑-2-基)-N’-(吡啶-4-基)脲;
73)N-(5-异丙基-1,3-噻唑-2-基)-N’-(吡啶-2-基)脲;
74)N-(5-溴-1,3-噻唑-2-基)-N’-(吡啶-2-基)脲;
75)N-(5-苯基-1,3-噻唑-2-基)-N’-(吡啶-2-基)脲;
76)N-(5-环丙基-1,3-噻唑-2-基)-N’-(吡啶-2-基)脲;
77)N-(5-异丙基-1,3-噻唑-2-基)-N’-(苯并噻吩-2-基)脲;
78)N-(5-溴-1,3-噻唑-2-基)-N’-(苯并噻吩-2-基)脲;
79)N-(5-苯基-1,3-噻唑-2-基)-N’-(苯并噻吩-2-基)脲;N-(5-环丙基-1,3-噻唑-2-基)-N’-(苯并噻吩-2-基)脲;
80)N-(5-异丙基-1,3-噻唑-2-基)-4-吗啉甲酰胺;
81)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-甲基苯基)脲;
82)N-(5-异丙基-1,3-噻唑-2-基)-N’-(3-氟苯基)脲;
83)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-氰基苯基)脲;
84)N-(5-异丙基-1,3-噻唑-2-基)-N’-(3-氰基苯基)脲;
85)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2,6-二甲基苯基)脲;
86)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-氟苯基)脲;
87)N-(5-异丙基-1,3-噻唑-2-基)-N’-(3-乙酰基苯基)脲;
88)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-乙酰基苯基)脲;
89)3-({[(5-异丙基-1,3-噻唑-2-基)氨基]羰基}氨基)苯甲酸;
90)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-异丙基苯基)脲;
91)3-({[(5-异丙基-1,3-噻唑-2-基)氨基]羰基}氨基)苯甲酰胺;
92)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-甲氧基苄基)脲;
93)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-丁基苯基)脲;
94)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-三氟甲基苯基)脲;
95)N-(5-异丙基-1,3-噻唑-2-基)-N’-3-溴苯基)脲;
96)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-环己基苯基)脲;
97)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-苯氧基苯基)脲;
98)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-苄氧基苯基)脲;
99)N-(5-异丙基-1,3-噻唑-2-基)-N’-(3,5-二甲基苯基)脲;
100)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2,3-二甲基苯基)脲;
101)N-(5-异丙基-1,3-噻唑-2-基)-N’-(3-甲氧基[1,1’-联苯]-4-基)脲;
102)N-(5-异丙基-1,3-噻唑-2-基)-3,4-二氢-2(1H)-异喹啉甲酰胺;
103)N-苄基-N’-(5-异丙基-1,3-噻唑-2-基)-N-甲基脲;
104)N-(5-异丙基-1,3-噻唑-2-基)-6,7-二甲氧基-3,4-二氢-2(1H)-异喹啉甲酰胺;
105)N-(5-异丙基-1,3-噻唑-2-基)-N’-[(3-氯-4-甲基)-苯基]脲;
106)N-(5-异丙基-1,3-噻唑-2-基)-N’-[(3-氯-6-甲基)-苯基]脲;
107)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2,5-二甲氧基苯基)脲;
108)N-(5-异丙基-1,3-噻唑-2-基)-N’-(3,4-二甲氧基苯基)脲;
109)N-(5-异丙基-1,3-噻唑-2-基)-N’-[(2-甲氧基-5-氯)-苯基]脲;
110)N-(5-异丙基-1,3-噻唑-2-基)-N’-((2-氯-4-甲氧基苯基)脲;
111)N-(5-异丙基-1,3-噻唑-2-基)-N’-(3,5-二氯苯基)脲;
112)N-[(1,1’-联苯)-2-基]-N’-(5-异丙基-1,3-噻唑-2-基)脲;
113)N-乙基-N’-(5-异丙基-1,3-噻唑-2-基)-N-苯基脲;
114)N-[4-({[(5-异丙基-1,3-噻唑-2-基)氨基]羰基}氨基)-2-甲氧基苯基]乙酰胺;
115)2-({[(5-异丙基-1,3-噻唑-2-基)氨基]羰基}氨基)-N-苯基苯甲酰胺;
116)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2-吗啉代苯基)脲;
117)N-[4-({[(5-异丙基-1,3-噻唑-2-基)氨基]羰基}氨基)苯基]-N-甲基乙酰胺;
118)N-[2-{[环己基(甲基)氨基]甲基}苯基]-N’-(5-异丙基-1,3-噻唑-2-基)脲;
119)N-[3-({[(5-异丙基-1,3-噻唑-2-基)氨基]羰基}氨基)-4-甲氧基苯基]乙酰胺;
120)N-(5-异丙基-1,3-噻唑-2-基)-4-(4-甲氧基苯基)-1-哌嗪甲酰胺;
121)N-(2-呋喃甲基)-N’-(5-异丙基-1,3-噻唑-2-基)脲;
122)N-(4-氟苯基)-N’-(5-异丙基-1,3-噻唑-2-基)脲;
123)N-(2-甲氧基苄基)-N’-(5-异丙基-1,3-噻唑-2-基)脲;
124)N-(5-异丙基-1,3-噻唑-2-基)-N’-[2-(1-甲基-1H-吡咯-2-基)乙基]脲;
125)N-(3,4-二甲氧基苄基)-N’-(5-异丙基-1,3-噻唑-2-基)脲;
126)N-(5-异丙基-1,3-噻唑-2-基)-4-氧代-1-苯基-1,3,8-三氮杂螺[4.5]癸烷-8-甲酰胺;
127)n-(5-异丙基-1,3-噻唑-2-基)-1,4-二氧代-8-氮杂螺[4.5]癸烷-8-甲酰胺;
128)N-(5-异丙基-1,3-噻唑-2-基)-N’-[2-(1-哌啶基)乙基]脲;
129)N-(5-异丙基-1,3-噻唑-2-基)-N’-[2-(1-吗啉基)乙基]脲;
130)4-(4-氟苯基)-N-(5-异丙基-1,3-噻唑-2-基)-1-哌嗪甲酰胺;
131)N-[4-(4-氯苯基)-3-乙基-5-异噁唑基]-N’-(5-异丙基-1,3-噻唑-2-基)脲;
132)4-[(4-氟苯基)(羟基)甲基]-N-(5-异丙基-1,3-噻唑-2-基)-1-哌嗪甲酰胺;
133)N-(3-乙炔基苯基)-N’-(5-异丙基-1,3-噻唑-2-基)脲;
134)N-(2-甲氧基-3-氟苯基)-N’-(5-异丙基-1,3-噻唑-2-基)脲;
135)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-氧代-1-哌啶基)脲;
136)N-(3-乙酰氨基苯基)-N’-(5-异丙基-1,3-噻唑-2-基)脲;
137)N-[3-(2-呋喃基)-1H-吡唑-5-基]-N’-(5-异丙基-1,3-噻唑-2-基)脲;
138)N-{4-[乙基(异丙基)氨基]苯基}-N’-(5-异丙基-1,3-噻唑-2-基)脲;
139)N-(1,3-苯并间二氧杂环戊烯-5-基)-N’-(5-异丙基-1,3-噻唑-2-基)脲;
140)5-({[(5-异丙基-1,3-噻唑-2-基)氨基]羰基}氨基)-1-苯基-1H-吡唑-4-甲酰胺;
141)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-吡啶甲基)脲;
142)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2-吡嗪基)脲;
143)n-(5-异丙基-1,3-噻唑-2-基)-N’-(5-苯基-1,3,4-噁二唑-2-基)脲;
144)N-(5-异丙基-1,3-噻唑-2-基)-4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)-1-哌啶甲酰胺;
145)N-(1,3-苯并噻唑-6-基)-N’-(5-异丙基-1,3-噻唑-2-基)脲;
146)N-(1,3-二甲基-1H-吡唑-5-基)-N’-(5-异丙基-1,3-噻唑-2-基)脲;
147)N-(3-苯基-1-甲基-1H-吡唑-5-基)-N’-(5-异丙基-1,3-噻唑-2-基)脲;
148)N-(5-异丙基-1,3-噻唑-2-基)-3-羟基-1-哌啶甲酰胺;
149)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2-甲基-1,3-二氧代-2,3-二氢-1H-异吲哚-5-基)脲;
150)N-(5-异丙基-1,3-噻唑-2-基)-4-苄基-1-哌嗪甲酰胺;
151)N-(5-异丙基-1,3-噻唑-2-基)-4-甲基-1-哌嗪甲酰胺;
152)4-羟基-N-(5-异丙基-1,3-噻唑-2-基)-1-哌啶甲酰胺;
153)N-(5-异丙基-1,3-噻唑-2-基)-3-氮杂双环[3.2.2]壬烷-3-甲酰胺;
154)N-(5-异丙基-1,3-噻唑-2-基)-4-(4-乙酰基苯基)-1-哌嗪甲酰胺;
155)4-[二(4-氟苯基)-N-(5-异丙基-1,3-噻唑-2-基)-1-哌嗪甲酰胺;
156)N-(5-异丙基-1,3-噻唑-2-基)-4-氧代-2,3,4,5-四氢-1H-1,5-苯并二氮杂-1-甲酰胺;
157)N-(5-异丙基-1,3-噻唑-2-基)-N’-(5,6,7,8-四氢-1-萘基)脲;
158)N-(4-苯基-2-噻唑基)-N’-(5-异丙基-1,3-噻唑-2-基)脲;
159)4-(4-氟苯甲酰基)-N-(5-异丙基-1,3-噻唑-2-基)-1-哌啶甲酰胺;
160)N-(5-异丙基-1,3-噻唑-2-基)-N’-(1,3-二氢-2-苯并呋喃-5-基)脲;
161)N-(5-异丙基-1,3-噻唑-2-基)-4’-(2-嘧啶基)-1-哌嗪甲酰胺;
162)N-(5-异丙基-1,3-噻唑-2-基)-3-氧代-3,4-二氢-1(2H)-喹喔啉;
163)N-(5-异丙基-1,3-噻唑-2-基)-N’-(1H-吲唑-6-基)脲;
164)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2-氯苄基)脲;
165)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2,4-二氯苄基)脲;
166)N-(5-异丙基-1,3-噻唑-2-基)-N’-(3-氟苄基)脲;
167)N-(5-异丙基-1,3-噻唑-2-基)-N’-(3,4-二氯苄基)脲;
168)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2,4-二氟苄基)脲;
169)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2,5-二氟苄基)脲;
170)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2,6-二氟苄基)脲;
171)N-(5-异丙基-1,3-噻唑-2-基)-N’-[(4-羟基-3-甲氧基)苄基]脲;
172)N-(5-异丙基-1,3-噻唑-2-基)-N’-(5-甲基-2-呋喃基)脲;
173)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-甲基磺酰基苄基)脲;
174)N-[(1R,2R)-2-羟基-2,3-二氢-1H-茚-1-基]-N’-(5-异丙基-1,3-噻唑-2-基)脲;
175)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-氯苄基)脲;
176)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2-吡啶甲基)脲;
177)N-(5-异丙基-1,3-噻唑-2-基)-N’-(3,5-二甲氧基苄基)脲;
178)N-(5-异丙基-1,3-噻唑-2-基)-N’-(3-吡啶甲基)脲;
179)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-三氟苄基)脲;
180)N-(5-异丙基-1,3-噻唑-2-基)-N’-(3,4,5-三甲氧基苄基)脲;
181)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2,4-二甲氧基苄基)脲;
182)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-二甲基氨基苄基)脲;
183)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2,5-二甲氧基苄基)脲;
184)N-(5-异丙基-1,3-噻唑-2-基)-N’-[(2-氯-6-苯氧基)苄基]脲;
185)N-(5-异丙基-1,3-噻唑-2-基)-N’-[(1R,2S)-2-羟基-2,3-二氢-1H-茚-1-基]-脲;
186)N-(5-异丙基-1,3-噻唑-2-基)-N’-[(3-羟基-4-甲基)苯基]脲;
187)N-(5-异丙基-1,3-噻唑-2-基)-N’-[4-(1H-苯并咪唑-2-基)苯基]脲;
188)N-(5-异丙基-1,3-噻唑-2-基)-N’-(3-苯基-1H-吡唑-5-基)脲;
189)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2-甲基-6-喹啉基)脲;
190)N-(5-异丙基-1,3-噻唑-2-基)-N’-[4-(氰基甲基)苯基]脲;
191)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2-喹啉基)脲;
192)N-(5-异丙基-1,3-噻唑-2-基)-N’-(1-氧代-2,3-二氢-1H-茚-5-基)脲;
193)N-(5-异丙基-1,3-噻唑-2-基)-N’-(3-氧代-1,3-二氢-2-苯并呋喃-5-基)脲;
194)N-(5-异丙基-1,3-噻唑-2-基)-N’-(5-氧代-5,6,7,8-四氢-2-萘基)脲;
195)3-({[(5-异丙基-1,3-噻唑-2-基)氨基]羰基}氨基)-4-甲基苯甲酸甲酯;
196)4-({[(5-异丙基-1,3-噻唑-2-基)氨基]羰基}氨基)-3-甲基苯甲酸甲酯;
197)N-(5-异丙基-1,3-噻唑-2-基)-N’-(4-咪唑并[1,2-a]吡啶-2-基-苯基)脲;
198)4-({[(5-异丙基-1,3-噻唑-2-基)氨基]羰基}氨基)-苯甲酸乙酯;
199)(2R)-1-苄基-2-({[(5-异丙基-1,3-噻唑-2-基)氨基]羰基}氨基)丙酰胺;
200)2-羟基-5-({[(5-异丙基-1,3-噻唑-2-基)氨基]羰基}苯甲酸;
201)2-氯-5-({[(5-异丙基-1,3-噻唑-2-基)氨基]羰基}氨基)苯甲酸;
202)3-({[(5-异丙基-1,3-噻唑-2-基)氨基]羰基}氨基)苯甲酸;
203)N-(5-异丙基-1,3-噻唑-2-基)-N’-(5-甲基-3-异噁唑基)脲;
204)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2,6-二甲氧基苯基)脲;
205)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2,3-二甲氧基苄基)脲;
206)N-(5-异丙基-1,3-噻唑-2-基)-N’-(3,4-二氟苄基)脲;
207)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2,4-二甲基苯基)脲;
208)N-(5-异丙基-1,3-噻唑-2-基)-N’-(1H-苯并咪唑-5-基)脲;
209)N-(5-异丙基-1,3-噻唑-2-基)-N’-[(R)-苯基甘氨酰氨基]脲;
210)N-(5-异丙基-1,3-噻唑-2-基)-N’-(2-苯氧基乙酰氨基)脲;
211)N-(5-异丙基-1,3-噻唑-2-基)-N’-[(S)-苯基甘氨酰氨基]脲;
212)N-(5-异丙基-1,3-噻唑-2-基)-N’-{2-[(1-甲基-1H-咪唑-2-基)甲氧基]苯基}脲;
213)N-(3-碘苯基)-N’-(5-异丙基-1,3-噻唑-2-基)脲;
214)N-(5-异丙基-1,3-噻唑-2-基)-N’-[3-(3-甲氧基-1-丙炔基)苯基]脲;
215)N-{3-[3-(二甲基氨基)-1-丙炔基]苯基}-N’-(5-异丙基-1,3-噻唑-2-基)脲;
216)N-[4-({[(5-异丙基-1,3-噻唑-2-基)氨基]羰基}氨基)苯基]甲磺酰胺;
217)2-[3-({[(5-异丙基-1,3-噻唑-2-基氨基)羰基]氨基]苯胺基]乙酰胺;
218)N-[3-(3-羟基-1-丁炔基)苯基]-N’-(5-异丙基-1,3-噻唑-2-基)脲;
219)N-(咪唑并[1,2-a]吡啶-2-基-甲基)-N’-(5-异丙基-1,3-噻唑-2-基)脲;
220)2-[({[(5-异丙基-1,3-噻唑-2-基)氨基]羰基}(2-丙炔基)氨基)甲基]苯磺酰胺;
221)N-[1H-吲哚-6-基]-N’-(5-异丙基-1,3-噻唑-2-基)脲;
222)N-[(1S)-2-羟基-1-苯基乙基]-N’-(5-异丙基-1,3-噻唑-2-基)脲;
223)N-[1H-吲哚-5-基]-N’-(5-异丙基-1,3-噻唑-2-基)脲;
224)N-[(1R-2-羟基-1-苯乙基]-N’-(5-异丙基-1,3-噻唑-2-基)脲;
225)N-(5-异丙基-1,3-噻唑-2-基)-N’-丁基脲;
226)N-(5-异丙基-1,3-噻唑-2-基)-N’-苯甲酰基脲;
227)N-(5-甲基-1,3-噻唑-2-基)-N’-(2,6-二甲基苯基)脲;
228)N-(5-甲基-1,3-噻唑-2-基)-N’-苄基脲;
229)N-(5-甲基-1,3-噻唑-2-基)-N’-丁基脲;
230)N-(5-甲基-1,3-噻唑-2-基)-4-吗啉甲酰胺;
231)N-(5-甲基-1,3-噻唑-2-基)-N’-苯基脲;
232)N-(5-甲基-1,3-噻唑-2-基)-N’-(4-甲氧基苄基脲;
233)N-(5-甲基-1,3-噻唑-2-基)-N’-(4-氟苯基)脲;
234)N-[(1-乙基-2-吡咯烷基)甲基]-N’-(5-甲基-1,3-噻唑-2-基)脲;
235)N-(5-甲基-1,3-噻唑-2-基)-N’-(5-羟基-1H-吡唑-3-基)脲;
236)N-(5-甲基-1,3-噻唑-2-基)-N’-(3-吡啶基)脲;
237)N-(4-氟苯基)-N’-(5-甲基-1,3-噻唑-2-基)脲;
16、一种药物组合物,含有一种或多种可药用载体和/或稀释剂,以及有效量的作为活性成分的如权利要求1中所定义的式(Ⅰ)化合物。
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US6262096B1 (en) | 1997-11-12 | 2001-07-17 | Bristol-Myers Squibb Company | Aminothiazole inhibitors of cyclin dependent kinases |
US6407124B1 (en) | 1998-06-18 | 2002-06-18 | Bristol-Myers Squibb Company | Carbon substituted aminothiazole inhibitors of cyclin dependent kinases |
DE69923681T2 (de) * | 1998-06-18 | 2006-01-12 | Bristol-Myers Squibb Co. | Kohlenstoff substituierte aminothiazole als inhibitoren von cyclin-abhängigen kinasen |
US8124630B2 (en) | 1999-01-13 | 2012-02-28 | Bayer Healthcare Llc | ω-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors |
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WO2000026203A1 (en) | 2000-05-11 |
SK4752001A3 (en) | 2002-02-05 |
AU771166C (en) | 2005-01-13 |
GB9823873D0 (en) | 1998-12-30 |
EP1124811A1 (en) | 2001-08-22 |
US20030187040A1 (en) | 2003-10-02 |
IL142372A0 (en) | 2002-03-10 |
AR023060A1 (es) | 2002-09-04 |
AU771166B2 (en) | 2004-03-18 |
PL347506A1 (en) | 2002-04-08 |
AU1044700A (en) | 2000-05-22 |
HUP0104167A2 (hu) | 2002-03-28 |
KR20010085984A (ko) | 2001-09-07 |
NO20012058D0 (no) | 2001-04-26 |
US6863647B2 (en) | 2005-03-08 |
EA200100486A1 (ru) | 2001-12-24 |
HK1041260A1 (zh) | 2002-07-05 |
NZ510967A (en) | 2003-10-31 |
NO20012058L (no) | 2001-06-28 |
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US20040157827A1 (en) | 2004-08-12 |
HUP0104167A3 (en) | 2003-12-29 |
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