CN1379668A - 3(5)-脲基-吡唑衍生物、其制备方法及其作为抗肿瘤剂的用途 - Google Patents
3(5)-脲基-吡唑衍生物、其制备方法及其作为抗肿瘤剂的用途 Download PDFInfo
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- CN1379668A CN1379668A CN00812736A CN00812736A CN1379668A CN 1379668 A CN1379668 A CN 1379668A CN 00812736 A CN00812736 A CN 00812736A CN 00812736 A CN00812736 A CN 00812736A CN 1379668 A CN1379668 A CN 1379668A
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- pyrazoles
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Abstract
式(I)所示的3-脲基-吡唑衍生物或其可药用盐:其中R、R1和R2如文中所描述;该化合物可用于,例如,治疗癌症、细胞增殖性疾病、早老性痴呆、病毒感染、自身免疫疾病或神经变性疾病。
Description
发明背景
发明领域:
本发明涉及3(5)-脲基-吡唑衍生物、其制备方法、含有该化合物的药物组合物以及该化合物作为治疗剂、特别是在治疗癌症和细胞增殖性疾病中的用途。
背景技术
许多细胞毒药物,例如氟尿嘧啶(5-FU)、阿霉素和喜树碱,可以损伤DNA或影响细胞代谢途径,从而在许多情况下引起对细胞周期的间接的阻断。因此,由于对正常细胞以及肿瘤细胞均会产生不可逆的损伤,这些药物会引起明显的毒性和副作用。
因此,需要能够作为高度特异性的抗肿瘤剂而选择性地引起肿瘤细胞生长停止和编程性细胞死亡的、与目前可以采用的药物效力相当但毒性降低了的化合物。
众所周知,细胞周期的进程受一系列关卡控制点(也可以称其为限制点)的控制,这些限制点受一族称为细胞周期蛋白依赖性蛋白激酶(cdk)的酶的控制。而cdk本身又在许多水平(例如与细胞周期蛋白的结合)上受到控制。
不同细胞周期蛋白/cdk复合物的协调地激活和失活是正常细胞周期进程所必需的。关键性的G1-S和G2-M转变均受到不同细胞周期蛋白/cdk活性的激活的控制。在G1中,细胞周期蛋白D/cdk4和细胞周期蛋白E/cdk2被认为可以调节S-期的开始。经过S-期的进程需要细胞周期蛋白A/cdk2的活性,而细胞周期蛋白A/cdc2(cdk1)的激活需要细胞周期蛋白B/cdc2来使分裂中期开始。
关于细胞周期蛋白和细胞周期蛋白依赖性蛋白激酶的一般性文献可以参见,例如,Kevin R.Webster等,Exp.Opin.Invest.Drugs,1998,Vol.7(6),865-887。
肿瘤细胞中的关卡控制点是有缺陷的,部分原因是由于cdk活性的失控所引起的。例如,在肿瘤细胞中观察到了细胞周期蛋白E和cdk表达的改变,并且证实了小鼠cdk抑制剂p27 KIP基因的缺失会引起更高的癌症发病率。
有越来越多的证据支持cdk是细胞周期进程的限速酶的观点,它因此代表了治疗性干预的分子靶点。具体地讲,对cdk/细胞周期蛋白激酶活性的直接抑制将有助于限制失控的肿瘤细胞增殖。
发明概述
本发明的目的是提供可用于治疗与改变的细胞依赖型激酶活性有关的细胞增殖性疾病的化合物。本发明的另一个目的是提供具有cdk/细胞周期蛋白激酶抑制活性的化合物。
本发明的另一个目的是提供可用作抗肿瘤剂但没有以上讨论的现有抗肿瘤药物所存在的缺点、包括毒性和副反应的化合物。
本发明人发现,3-脲基-吡唑化合物具有cdk/细胞周期蛋白激酶抑制活性,因此可以用作抗肿瘤剂并且没有已知的抗肿瘤药物所存在的上述缺点、包括毒性和副反应。
更具体地讲,本发明的化合物可用于治疗各种癌症,包括但不仅限于:癌,例如膀胱癌、乳腺癌、结肠癌、肾癌、肝癌、肺癌,包括小细胞肺癌、食道癌、胆囊癌、卵巢癌、胰腺癌、胃癌、宫颈癌、甲状腺癌、前列腺癌和皮肤癌,包含鳞状细胞癌;淋巴系的造血系统肿瘤,包括白血病、急性淋巴细胞白血病、急性淋巴母细胞白血病、B细胞淋巴瘤、T细胞淋巴瘤、Hodgkin淋巴瘤、非Hodgkin淋巴瘤、毛细胞淋巴瘤和Burkett淋巴瘤;骨髓系的造血系统肿瘤,包括急性和慢性骨髓性白血病、骨髓增生异常综合征和早幼粒细胞白血病;源于间质的肿瘤,包括纤维肉瘤和横纹肌肉瘤;中枢和外周神经系统的肿瘤,包括星形细胞瘤神经母细胞瘤、神经胶质瘤和神经鞘瘤;其它肿瘤,包括黑色素瘤、精原细胞瘤、畸胎瘤、骨肉瘤、着色性干皮病(xenoderomapigmentosum)、角化棘皮瘤(keratoctanthoma)、甲状腺滤泡癌和卡波济氏肉瘤。
由于cdk在调节细胞增殖中的重要作用,这些3-脲基-吡唑衍生物还可用于治疗各种细胞增殖性疾病,例如良性前列腺增生、家族性息肉状腺瘤病、神经纤维瘤病、牛皮癣、与动脉粥样硬化有关的血管平滑肌细胞增殖、肺纤维化、关节炎肾小球肾炎以及手术后的狭窄和再狭窄。
由于cdk5与微管相关蛋白的磷酸化有关(J.Biochem.117,741-749,1995),本发明的化合物还可用于治疗早老性痴呆。
作为细胞编程性细胞死亡的调节剂,本发明的化合物还可用于治疗癌症、病毒感染、在HIV感染的个体中预防AIDS的出现、以及治疗自身免疫疾病和神经变性疾病。
本发明的化合物还可用于抑制肿瘤血管生成和转移。
本发明的化合物还可用作其它蛋白激酶例如蛋白激酶C、her2、rafl、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,因此可以有效地治疗与这些蛋白激酶有关的疾病。
R是C1-C6烷基、芳基或芳基烷基,该基团选择性地被一个或多个羟基、卤素、硝基、氰基、氧代、羧基、氨基、烷基氨基、二烷基氨基、烷基羰基氨基、烷氧基羰基氨基、烷氧基羰基烷基氨基、氨基羰基烷基氨基、N-烷基-N-羰基氨基、N-环烷基-N-烷基氨基烷基、氨基烷基、氨基羰基、烷基、环烷基、烷硫基、烷氧基、烷基羰基、烷基磺酰基、烷基磺酰基氨基、氨基磺酰基、烷氧基羰基、芳基、芳基烷基、芳氧基、芳硫基、芳基磺酰基、芳基氨基、芳基羰基、N-烷基-哌嗪基、4-吗啉基、全氟代的C1-C4烷基、C1-C4链烯基、C2-C4炔基、C2-C4氨基炔基或C2-C4羟基炔基取代基所取代;
R1是-(CH2)n-R3;
n是0或1至4的整数;
R3是氢、羟基、氨基,或者选自环烷基、芳基和杂环基,所述环烷基、芳基和杂环基选择性地被一个或多个羟基、卤素、硝基、氰基、氧代、羧基、氨基、烷基氨基、二烷基氨基、烷基羰基氨基、烷氧基羰基氨基、烷氧基羰基烷基氨基、氨基羰基烷基氨基、N-烷基-N-羰基氨基、N-环烷基-N-烷基氨基烷基、氨基烷基、氨基羰基、烷基、环烷基、烷硫基、烷氧基、烷基羰基、烷基磺酰基、烷基磺酰基氨基、氨基磺酰基、烷氧基羰基、芳基、芳基烷基、芳氧基、芳硫基、芳基磺酰基、芳基氨基、芳基羰基、N-烷基-哌嗪基、4-吗啉基、全氟代的C1-C4烷基、C2-C4链烯基、C2-C4炔基、C2-C4氨基炔基或C2-C4羟基炔基取代基所取代;
R2是氢,或者
R2和R1与它们所连接的氮原子合在一起形成杂环基或杂芳基,所述杂环基或杂芳基选择性地被一个或多个羟基、卤素、硝基、氰基、氧代、羧基、氨基、烷基氨基、二烷基氨基、烷基羰基氨基、烷氧基羰基氨基、烷氧基羰基烷基氨基、氨基羰基烷基氨基、N-烷基-N-羰基氨基、N-环烷基-N-烷基氨基烷基、氨基烷基、氨基羰基、烷基、环烷基、烷硫基、烷氧基、烷基羰基、烷基磺酰基、烷基磺酰基氨基、氨基磺酰基、烷氧基羰基、芳基、芳基烷基、芳氧基、芳硫基、芳基磺酰基、芳基氨基、芳基羰基、N-烷基-哌嗪基、4-吗啉基、全氟代的C1-C4烷基、C2-C4链烯基、C2-C4炔基、C2-C4氨基炔基或C2-C4羟基炔基取代基所取代;
条件是,当n是0并且R2是氢时,R是选择性地被直链或支链C1-C6烷基取代的C3-C6环烷基。
根据本发明的优选实施方案,细胞增殖性疾病选自癌症、早老性痴呆、病毒感染、自身免疫疾病和神经变性疾病。
可以进行治疗的癌症类型的例子包括癌、鳞状细胞癌、骨髓或淋巴系的造血系统肿瘤、源于间质的肿瘤、中枢和外周神经系统的肿瘤、黑色素瘤、精原细胞瘤、畸胎瘤、骨肉瘤、着色性干皮病、keratoctanthoma、甲状腺滤泡癌和卡波济氏肉瘤。
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、家族性息肉状腺瘤病、神经纤维瘤病、牛皮癣、与动脉粥样硬化有关的血管平滑肌细胞增殖、肺纤维化、关节炎肾小球肾炎以及手术后的狭窄和再狭窄。
此外,本发明的方法还可以抑制肿瘤血管生成和转移。本发明的方法还可以提供细胞周期抑制作用或cdk/细胞周期蛋白依赖型的抑制。
R是C1-C6烷基、芳基或芳基烷基,该基团选择性地被一个或多个羟基、卤素、硝基、氰基、氧代、羧基、氨基、烷基氨基、二烷基氨基、烷基羰基氨基、烷氧基羰基氨基、烷氧基羰基烷基氨基、氨基羰基烷基氨基、N-烷基-N-羰基氨基、N-环烷基-N-烷基氨基烷基、氨基烷基、氨基羰基、烷基、环烷基、烷硫基、烷氧基、烷基羰基、烷基磺酰基、烷基磺酰基氨基、氨基磺酰基、烷氧基羰基、芳基、芳基烷基、芳氧基、芳硫基、芳基磺酰基、芳基氨基、芳基羰基、N-烷基-哌嗪基、4-吗啉基、全氟代的C1-C4烷基、C1-C4链烯基、C2-C4炔基、C2-C4氨基炔基或C2-C4羟基炔基取代基所取代;
R1是-(CH2)n-R3;
n是0或1至4的整数;
R3是氢、羟基、氨基,或者选自环烷基、芳基和杂环基,所述环烷基、芳基和杂环基选择性地被一个或多个羟基、卤素、硝基、氰基、氧代、羧基、氨基、烷基氨基、二烷基氨基、烷基羰基氨基、烷氧基羰基氨基、烷氧基羰基烷基氨基、氨基羰基烷基氨基、N-烷基-N-羰基氨基、N-环烷基-N-烷基氨基烷基、氨基烷基、氨基羰基、烷基、环烷基、烷硫基、烷氧基、烷基羰基、烷基磺酰基、烷基磺酰基氨基、氨基磺酰基、烷氧基羰基、芳基、芳基烷基、芳氧基、芳硫基、芳基磺酰基、芳基氨基、芳基羰基、N-烷基-哌嗪基、4-吗啉基、全氟代的C1-C4烷基、C2-C4链烯基、C2-C4炔基、C2-C4氨基炔基或C2-C4羟基炔基取代基所取代;
R2是氢,或者
R2和R1与它们所连接的氮原子合在一起形成杂环基或杂芳基,所述杂环基或杂芳基选择性地被一个或多个羟基、卤素、硝基、氰基、氧代、羧基、氨基、烷基氨基、二烷基氨基、烷基羰基氨基、烷氧基羰基氨基、烷氧基羰基烷基氨基、氨基羰基烷基氨基、N-烷基-N-羰基氨基、N-环烷基-N-烷基氨基烷基、氨基烷基、氨基羰基、烷基、环烷基、烷硫基、烷氧基、烷基羰基、烷基磺酰基、烷基磺酰基氨基、氨基磺酰基、烷氧基羰基、芳基、芳基烷基、芳氧基、芳硫基、芳基磺酰基、芳基氨基、芳基羰基、N-烷基-哌嗪基、4-吗啉基、全氟代的C1-C4烷基、C2-C4链烯基、C2-C4炔基、C2-C4氨基炔基或C2-C4羟基炔基取代基所取代;
条件是,当n是0并且R2是氢时,R是选择性地被直链或支链C1-C6烷基取代的C3-C6环烷基。
本发明还提供了制备3-脲基-吡唑衍生物或其可药用盐的方法,该方法包括:
R1-NCO (III)
其中R和R1如上所定义,生成式(IV)所示的化合物:
其中R和R1如上所定义;然后
(b)将式(IV)所示的化合物在碱性介质中进行选择性地水解,生成式(I)所示的3-脲基-吡唑衍生物。
本发明还提供了如下制备3-脲基-吡唑衍生物或其可药用盐的方法,该方法包括:
其中R如上所定义;
(d)将式(VI)所示的化合物与式(VII)所示的化合物反应:
R1R2NH (VII)
其中R1和R2如上所定义,生成式(VIII)所示的化合物:
其中R、R1和R2如上所定义;
(e)将式(VIII)所示的化合物在酸性介质中水解生成式(I)所示的3-脲基-吡唑衍生物;以及,选择性地将式(I)所示的3-脲基-吡唑衍生物转化成式(I)所示的另一种3-脲基-吡唑衍生物和/或转化成它的盐。
本发明还提供了含有3-脲基-吡唑衍生物和至少一种可药用载体和/或稀释剂的药物组合物。
参照如下详细描述,可以更完整地理解本发明,并且可以更好地理解本发明所具有的许多优点。
发明详述
有许多3-脲基-吡唑衍生物是已知的杀虫剂、除草剂或治疗剂。其中包括具有p38激酶抑制剂活性的杂芳基-吡唑化合物(WO 98/52941,G.D.Searle及其合作者)。芳基-脲基-吡唑例如苯基-脲基吡唑也是本领域已知的p38激酶抑制剂(WO 99/32111,Bayer Co.)。有许多5-芳基-(1H-吡唑-5-基)-脲衍生物是本领域已知的神经肽Y拮抗剂,可用作降脂剂(WO 98//24768,Banyu制药公司)。
因此,在只给出了式(I)化合物的一种互变异构体的如下说明书中,另一种互变异构体(Ia)也包括在本发明的范围内。
若无另外说明,本说明书中所用的术语卤原子包括氟、氯、溴或碘原子。
若无另外说明,本文中所用的术语烷基和烷氧基包括C1-C6烷基和C1-C6烷氧基。术语直链或支链的C1-C6烷基或C1-C6烷氧基包括选自下列的基团: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、正己基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基等。
同样,术语烷硫基、烷基氨基、二烷基氨基、烷氧基羰基、烷氧基羰基氨基、烷基羰基、烷基磺酰基、烷氧基羰基、N-烷基哌嗪基等,是指其中的烷基和烷氧基部分表示C1-C6烷基或烷氧基的上述基团。
若无另外说明,术语环烷基包括C3-C6环烷基,例如环丙基、环丁基、环戊基和环己基,以及含有最多10个碳原子的环烷基和桥接的环烷基。
术语芳基表示含有1至4个环部分的单环、二环或多环的碳环或杂环烃,其中至少有一个环是芳香族的,这些环可以是稠合的或彼此通过单键连接。这些基团可以含有5至20个碳原子,优选6至20个碳原子。
根据以上描述,本领域技术人员很容易理解,术语芳基还包括芳香族杂环,也称为杂芳基。
术语杂环是指其中的一个或多个碳原子被一个或多个选自氮、氧和硫的原子代替了的5或6元饱和或不饱和的碳环。杂原子的数量没有限制,可以是例如一个、两个、三个或更多。
芳基的例子包括苯基、1-萘基、2-萘基、二氢化茚基、茚基、联苯、苯并环烷基,例如二环[4.2.0]辛-1,3,5,-三烯、苯并杂环基,例如苯并间二氧杂环戊烯基、喹啉基、异喹啉基、喹喔啉基、吲哚基、选择性地与苯稠合的吡咯基、呋喃基、噻吩基、咪唑基、吡唑基、噻唑基、噁唑基、异噁唑基、吡啶基、吡嗪基、嘧啶基等。
杂环的例子是吡咯烷、哌啶、哌嗪、吗啉等。
术语C2-C4链烯基或炔基包括选自乙烯基、烯丙基、1-丙烯基、异丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、乙炔基、丙炔基、丁炔基等的基团。
术语氧代是指羰基(>C=O)基团。
术语全氟代烷基包括被一个以上的氟原子取代的C1-C4烷基,例如三氟甲基、2,2,2-三氟乙基、1,1,2,2,2-五氟乙基等。
式(I)化合物的可药用盐包括与无机或有机酸例如硝酸、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、扁桃酸、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例如碱金属或碱土金属、特别钠、钾、钙或镁的氢氧化物、碳酸盐或碳酸氢盐、无环或环状的胺、优选甲胺、乙胺、二乙胺、三乙胺或哌啶的盐。
式(I)化合物可以含有不对称碳原子,因此可以以外消旋混合物或单个的光学异构体的形式存在。
因此,式(I)化合物的所有可能的异构体及其混合物以及代谢物和可药用生物前体(也称为前药)作为抗肿瘤剂的用途也包括在本发明的范围内。
优选的本发明的式(I)化合物是如下化合物:其中R是C3-C6环烷基或选择性取代的直链或支链C1-C4烷基、环烷基或芳基或芳基烷基,R1是选择性地按照如上定义被取代的C1-C4烷基或苯基、苯基烷基、杂芳基、杂芳基烷基或杂环基。
更优选的化合物是如下化合物:其中R是C3-C6环烷基,R1是被羟基或氨基取代的C1-C4烷基,或是芳基、芳基烷基、杂环基或杂环基烷基,其中的芳基或杂环基部分选自苯基或选择性地与苯稠合的吡啶、吲哚、噻吩、噻唑、异噁唑、呋喃、哌啶、吗啉,这些基团均可以选择性地被进一步取代。
另一类优选的式(I)化合物是如下化合物:其中R1和R2形成选择性取代的杂环基环,例如1-哌啶基、1-哌嗪基或4-吗啉基。
当上述基团被取代时,取代基的数量没有具体的限制。例如,上述基团可以被例如一个、两个、三个或更多的取代基所取代。若无另外说明,这些取代基可以相同或不同,即,它们是彼此独立地进行选择的。
优选的本发明化合物(可以是可药用盐例如氢溴酸盐或盐酸盐的形式)的例子包括:N-(3-环丙基-1H-吡唑-5-基)-N’-[2-(1-哌啶基)乙基]脲;4-[({[(3-环丙基-1H-吡唑-5-基)氨基]羰基}氨基)甲基]苯磺酰胺;N-(3-环丙基-1H-吡唑-5-基)-N’-[2-(2-吡啶基)乙基]脲;N-(3-环丙基-1H-吡唑-5-基)-N’-[2-(1-吡咯烷基)乙基]脲;N-(3-氯苯乙基)-N’-(3-环丙基-1H-吡唑-5-基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(2,3-二甲氧基苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(4-氯苄基)脲;N-[3-(叔丁基)-1H-吡唑-5-基)]-N’-(4-哌啶基甲基)脲;N-[3-(叔丁基)-1H-吡唑-5-基)]-N’-(3-氟苄基)脲;N-[3-(叔丁基)-1H-吡唑-5-基)]-N’-(3,4-二甲氧基苄基)脲;N-[3-(叔丁基)-1H-吡唑-5-基)]-N’-(4-氯苄基)脲;N-[3-(叔丁基)-1H-吡唑-5-基)]-N’-(3,4-二羟基苄基)脲;N-[3-(叔丁基)-1H-吡唑-5-基)]-N’-(3,4-二甲基苄基)脲;N-[3-(叔丁基)-1H-吡唑-5-基)]-N’-(3-氯苯乙基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(4-哌啶基甲基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3-氟苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3,4-二甲氧基苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3,4-二甲基苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(2-羟基-1-甲基-2-苯基乙基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-[(1-乙基-2-吡咯烷基)甲基]脲;N-(3-环丙基-1H-吡唑-5-基)-N’-[2-(2H-咪唑-4-基)乙基]脲;N-(3-环丙基-1H-吡唑-5-基)-N’-[2-(5-甲氧基-1H-吲哚-3-基)乙基]脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(1H-吲哚-6-基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(1,3-苯并间二氧杂环戊烯-5-基甲基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(2-(4-吗啉基)乙基]脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(2-氯苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(2,4-二氯苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(2-乙氧基苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3,4-二氯苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3-甲氧基苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(4-氟苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3-三氟甲基苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(4-甲基苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-4-吗啉甲酰胺;N-环丁基-N’-(3-环戊基-1H-吡唑-5-基)脲;N-(3-环戊基-1H-吡唑-5-基)-1-吡咯烷甲酰胺;4-(1,3-苯并间二氧杂环戊烯-5-基甲基)-N-(3-环戊基-1H-吡唑-5-基)-1-哌嗪甲酰胺;N-(3-环戊基-1H-吡唑-5-基)-1-哌嗪甲酰胺;N-(3-环戊基-1H-吡唑-5-基)-4-苯基-1-哌嗪甲酰胺;N-(3-环戊基-1H-吡唑-5-基)-4-甲基-1-哌嗪甲酰胺;N-(3-环戊基-1H-吡唑-5-基)-4-苄基-1-哌嗪甲酰胺;N-(3-环戊基-1H-吡唑-5-基)-4-吗啉甲酰胺;N-(3-环戊基-1H-吡唑-5-基)-1-哌啶甲酰胺;N-(3-环戊基-1H-吡唑-5-基)-4-(氨基甲基)-1-哌啶甲酰胺;N-(3-环戊基-1H-吡唑-5-基)-N’-(1-苄基-4-哌啶基)脲;N-(3-环戊基-1H-吡唑-5-基)-N’-苄基脲;N-(3-环戊基-1H-吡唑-5-基)-N’-苯乙基脲;N-(3-环戊基-1H-吡唑-5-基)-N’-(3,4-二甲氧基苯乙基)脲;N-(3-环戊基-1H-吡唑-5-基)-N’-(4-羟基苯乙基)脲;N-(3-环戊基-1H-吡唑-5-基)-N’-丙基脲;N-(3-环戊基-1H-吡唑-5-基)-N’-(4-羟基丁基)脲;N-(3-环戊基-1H-吡唑-5-基)-4-[2-硝基-4-(三氟甲基)苯基]-1-哌嗪甲酰胺;N-(3-苯乙基-1H-吡唑-5-基)-1-吡咯烷甲酰胺;4-(1,3-苯并间二氧杂环戊烯-5-基-甲基)-N-(3-苯乙基-1H-吡唑5-基)-1-哌嗪甲酰胺;N-(3-苯乙基-1H-吡唑-5-基)-1-哌嗪甲酰胺;N-(3-苯乙基-1H-吡唑-5-基)-4-苯基-1-哌嗪甲酰胺;N-(3-苯乙基-1H-吡唑-5-基)-4-甲基-1-哌嗪甲酰胺;N-(3-苯乙基-1H-吡唑-5-基)-4-苄基-1-哌嗪甲酰胺;N-(3-苯基-1H-吡唑-5-基)-4-吗啉甲酰胺;N-(3-苯乙基-1H-吡唑-5-基)-1-哌啶甲酰胺;N-(3-苯乙基-1H-吡唑-5-基)-4-(氨基甲基)-1-哌啶甲酰胺;N-(3-苯乙基-1H-吡唑-5-基)-N’-苄基脲;N-(3-苯乙基-1H-吡唑-5-基)-N’-苯乙基脲;N-(3-苯乙基-1H-吡唑-5-基)-N’-(3,4-二甲氧基苯乙基)脲;N-(3-苯乙基-1H-吡唑-5-基)-N’-(4-羟基苯乙基)脲;N-(3-苯乙基-1H-吡唑-5-基)-N’-丙基脲;N-(3-苯乙基-1H-吡唑-5-基)-N’-(4-羟基丁基)脲;N-(3-苯乙基-1H-吡唑-5-基)-4-[2-硝基-4-(三氟甲基)苯基]-1-哌嗪甲酰胺;N-(3-环丙基-1H-吡唑-5-基)-N’-丁基脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(2,4-二甲基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3,4-二甲氧基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3-羧基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(2,3-二甲基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3-羧基-4-氯苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3,5-二甲基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3-甲酰氨基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3-羧基-4-羟基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(2,6-二甲基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(4-氰基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3-乙酰基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(1H-苯并咪唑-6-基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(4-羟基-3-甲氧基苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-苄基脲;N-(3-环丙基-1H-吡唑-5-基)-N’-{3-[3-(二甲基氨基)-1-丙炔基]苯基}脲;N-[3-({[(3-环丙基-1H-吡唑-5-基)氨基]羰基}氨基)苯基]甲磺酰胺;2-[3-({[(3-环丙基-1H-吡唑-5-基)氨基]羰基}氨基)苯氨基]乙酰胺;N-(3-环丙基-1H-吡唑-5-基)-N’-(2-羟基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-[3-(3-羟基-1-丁炔基)苯基]脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(1H-吲哚-6-基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(1H-吲哚-5-基)脲;4-({[(3-环丙基-1H-吡唑-5-基)氨基]羰基}氨基)苯磺酰胺;N-(3-环丙基-1H-吡唑-5-基)-N’-(3-甲氧基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-苯基脲;N-[4-({[(3-环丙基-1H-吡唑-5-基)氨基]羰基}氨基)苯基]-N-甲基乙酰胺;N-(2-{[环己基(甲基)氨基]甲基}苯基)-N’-(3-环丙基-1H-吡唑-5-基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(2-甲氧基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(2-氯苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3-乙炔基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(4-氨基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3-羟基-4-甲基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-3-氧代-3,4-二氢-1(2H)-喹喔啉甲酰胺;N-(3-环丙基-1H-吡唑-5-基)-3,4-二氢-2(1H)-异喹啉甲酰胺;N-(3-环丙基-1H-吡唑-5-基)-N’-(4-吡啶基甲基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(2-呋喃基甲基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(1,3-苯并噻唑-5-基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(1,3-二甲基-1H-吡唑-5-基)脲;N-[5-({[(3-环丙基-1H-吡唑-5-基)氨基]羰基}氨基)-2-甲氧基苯基]乙酰胺;N-[3-({[(3-环丙基-1H-吡唑-5-基)氨基]羰基}氨基)-4-甲氧基苯基]乙酰胺;N-(3-环丙基-1H-吡唑-5-基)-N’-(3-氨基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(1H-咪唑-6-基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3-羟基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(4-羟基苯基)脲。
本发明的式(I)化合物及其盐可以通过例如包括如下步骤的方法制得:
b)将式(IV)化合物在碱性介质中进行选择性地水解得到式(I)化合物;或者,
(b)将式(VI)化合物与式(VII)化合物反应:
R1R2NH (VII)其中R1和R2如上所定义,由此得到式(VIII)化合物:其中R、R1和R2如上所定义,
(c)将式(VIII)化合物在酸性介质中水解生成式(I)化合物;然后,如需要,将式(I)的3-脲基-吡唑衍生物转化成式(I)的另一种衍生物和/或转化成它的盐。
式(V)化合物可以通过包括如下步骤的方法制得:
(a)将式(IX)化合物:
R-COOR4 (IX)
其中R如上所定义并且R4是烷基,与乙腈在碱性试剂的存在下反应生成式(X)的化合物:
R-CO-CH2-CN (X)其中R如上所定义;
其中R如上所定义;
(d)将式(XI)化合物与叔丁氧基羰基酐(Boc2O)反应生成式(XII)化合物:
其中R如上所定义;
(e)将式(XII)化合物还原得到式(V)化合物,其中R如上所定义。
式(I)化合物还可以通过包括如下步骤的方法制得:
其中R和R1如上所定义;
(b)在氢化钠、甲醇和过量式(III)化合物的存在下加热回流,生成式(I)化合物。
式(I)化合物还可以通过包括如下步骤的方法制得:
其中R和R1如上所定义;
(b)将式(XIV)化合物在酸性介质中水解生成式(I)化合物,其中R和R1如上所定义。
式(I)化合物还可以通过包括如下步骤的方法制得:
(b)将式(XV)化合物与式(VII)化合物反应:
式(I)化合物还可以通过包括如下步骤的方法制得:
(c)将式(XVIII)化合物与上述的式(VII)化合物反应生成式(I)化合物,其中R、R1和R2如上所定义。
本领域技术人员很容易理解,如果按照上述方法制备的式(I)化合物是以异构体的混合物形式得到的,将其按照常规方法分离成单个的式(I)的异构体也包括在本发明的范围之内。
同样,按照本领域公知的方法将相应的盐转化成游离的化合物(I)也包括在本发明的范围之内。
上述方法可以按照公知的方法进行。
式(II)或式(V)化合物和式(III)化合物之间的反应可以在碳酸氢钠或叔碱例如三乙胺、N-甲基吗啉、N,N-二异丙基乙基胺或吡啶的存在下、在适宜的溶剂例如甲苯、二氯甲烷、氯仿、乙醚、四氢呋喃、乙腈、二氧六环或N,N-二甲基甲酰胺中、在约10℃至回流的温度下进行。
从式(IV)化合物制备式(I)化合物的反应可以用碱例如氢氧化钠、氢氧化钾、碳酸钠或碳酸钾在适宜的溶剂例如甲醇或乙醇和水的混合物中、在室温下进行。
从式(II)化合物和式(III)化合物制备式(XIII)化合物的反应可以用碱例如碳酸氢钠或氢化钠在适宜的溶剂例如乙醇或甲醇中、在室温下进行。
从式(XIII)化合物制备式(I)化合物的反应可以通过在过量的式(III)化合物和碱例如氢化钠的存在下、在适宜的溶剂例如甲醇或乙醇中、在60至80℃下加热来完成。
从式(XIV)化合物制备式(I)化合物的反应可以用酸例如三氟乙酸、盐酸、甲酸在适宜的溶剂例如二氯甲烷中、在-10℃至室温下进行。
从式(IX)化合物制备式(X)化合物的反应可以用乙腈和碱例如氢化钠在适宜的溶剂例如乙醚、四氢呋喃、二氧六环中、在室温至120℃的温度下进行。
从式(X)化合物制备式(II)化合物的反应可以用水合肼在溶剂例如甲醇或乙醇中、在室温至80℃的温度下进行。
从式(II)化合物制备式(XI)化合物的反应可以用oxone(过一硫酸钾)或其它氧化剂例如过氧化氢在适宜的溶剂例如水-丙酮的混合物中、在0℃至室温下进行。
从式(XI)化合物制备式(XII)化合物的反应可以用叔丁氧羰基酐在适宜的溶剂例如二氯甲烷-水混合物中、在碳酸氢钠的存在下于室温下进行。
从式(XII)化合物制备式(V)化合物的反应可以直接用氢在催化剂例如钯/炭的存在下、在适宜的溶剂例如甲醇或乙醇中于室温下进行。
从式(V)化合物制备式(VI)化合物的反应可以用氯甲酸4-硝基苯酯或其聚合物负载的形式在叔碱例如三乙胺、N-甲基吗啉、N,N-二异丙基乙基胺或吡啶的存在下、在适宜的溶剂例如甲苯、二氯甲烷、氯仿、乙醚、四氢呋喃、乙腈、二氧六环或N,N-二甲基甲酰胺中、在约-10℃至室温的温度下进行。
从式(VI)或(XV)化合物和式(VII)化合物制备式(VIII)化合物的反应可以在适宜的溶剂例如甲苯、二氯甲烷、氯仿、乙醚、四氢呋喃、乙腈、二氧六环或N,N-二甲基甲酰胺中、在约室温至回流的温度下进行。
从式(VIII)化合物制备式(I)化合物的反应可以用酸例如三氟乙酸、盐酸、甲酸在适宜的溶剂例如二氯甲烷中、在-10℃至室温的温度下进行。
从式(V)化合物制备式(XV)化合物的反应可以用1,1’-羰基二咪唑、碳酸二(三氯甲基)酯或氯甲酸三氯甲酯,如果需要,在叔碱例如三乙胺、N,N-二异丙基乙基胺或吡啶的存在下、在适宜的溶剂例如二氯甲烷、氯仿、甲苯、二氧六环或四氢呋喃中、在0℃至回流的温度下进行。
从肟树脂(XVI)和三光气制备式(XVII)化合物的反应可以在适宜的溶剂例如二氯甲烷中、在室温下进行。
从式(XVII)化合物和式(II)化合物制备式(XVIII)化合物的反应可以在适宜的溶剂例如二氯甲烷中、在室温下进行。
从式(XVIII)化合物和式(VII)化合物制备式(I)化合物的反应可以在适宜的溶剂例如甲苯、二氯甲烷、氯仿、乙醚、四氢呋喃、乙腈、二氧六环或N,N-二甲基甲酰胺中、在室温至回流的温度下进行。
此外,选择性地将式(I)化合物转化成另一种式(I)化合物也可以按照已知的方法来进行。
选择性地将式(I)化合物成盐或将盐转化成游离化合物以及将异构体的混合物分离成单个的异构体也可以通过常规的方法来完成。
式(III)、(VII)、(IX)和(X)的化合物是已知的可以购买到的产品,或者可以按照常规的合成方法制得。
在按照本发明的方法制备式(I)化合物时,在原料或其中间体中存在的可以引起不利副反应的选择性的功能基需要按照常规的方法进行保护。
同样,将这些保护的化合物转化成游离的脱保护的化合物也可以按照公知的方法来进行。
本领域技术人员可以理解,用于制备式(I)化合物的上述方法也可用于制备其它式(I)化合物,包括已知的化合物。药理学
式(I)化合物具有cdk/细胞周期蛋白抑制剂活性,因为它们在按照如下方法进行的试验中具有阳性的结果。
推定的cdk/细胞周期蛋白抑制剂的抑制活性和选定化合物的效力通过基于MultiScreen-PH 96孔板(Millipore)的测定方法来测定,其中,将磷酸纤维素滤纸置于各孔的底部,使带正电荷的底物在经过洗涤/过滤步骤后可以结合。
当放射标记的磷酸酯部分被ser/threo激酶转移到滤纸结合的组蛋白上时,在闪烁计数器中测定发射光。
cdk2/细胞周期蛋白A活性的抑制试验按照如下方法进行:
激酶反应:将1.5·M组蛋白H1底物、25·M ATP(0.5uCiP33g-ATP)、100ng细胞周期蛋白A/cdk2复合物、在最终体积为100·l的缓冲液(TRIS HCl 10mM pH 7.5,MgCl2 10mM,7.5mM DTT)中的10·M的抑制剂加入到96孔U型底的平板中。于37℃下保温10分钟后,用20·l EDTA 120mM终止反应。
捕获:从MultiScreen平板的各孔中转移出100·l,使底物结合在磷酸纤维素滤纸上。然后将平板用150·l/孔不含Ca++/Mg++的PBS洗涤3次,然后通过MultiScreen过滤系统过滤。
检测:将滤纸于37℃下干燥,然后加入100·l/孔的闪烁剂并通过在Top-Count仪中进行放射性计数来测定33P标记的组蛋白H1。
结果:将数据进行分析并用相对于酶的总活性(=100%)的抑制%来表示。
将所有显示抑制>50%的化合物进行进一步的分析,以便通过Ki计算研究和确定抑制剂的动力学特性。
除了ATP和底物的浓度外,所用的试验方法与以上描述的相同。对ATP和组蛋白H1底物的浓度均进行了改变:在含或不含两种不同的、适当选择的抑制剂浓度下,使用浓度为4、8、12、24、48·M(含有按比例稀释的P33g-ATP)的ATP和浓度为0.4、0.8、1.2、2.4、4.8·M的组蛋白。
此外,还用基于SPA(闪烁近似测定法)96孔平板测定的测定方法测定了推定的cdk/细胞周期蛋白抑制剂的抑制活性和选定化合物的效力。该测定法是基于链霉抗生物素蛋白包衣的SPA珠捕获从组蛋白的磷酸化位点衍生的生物素化的肽的能力。
当放射标记的磷酸酯部分被ser/threo激酶转移到生物素化的组蛋白肽上时,在闪烁计数器中测定发射光。
cdk5/p25活性的抑制试验按照如下方法进行:
激酶反应:将在最终体积为100·l的缓冲液(Hepes 20mM pH 7.5,MgCl2 15mM,1mM DTT)中的1.0·M生物素化的组蛋白肽底物、0.25uCiP33g-ATP、4nM cdk2/p25复合物、0-100·M的抑制剂加入到96孔U型底平板的各孔中。于37℃下保温20分钟后,通过加入在含有0.1%Triton X-100、50μM ATP和5mM EDTA的磷酸盐缓冲盐水中的500ug SPA珠来终止反应。使小珠沉降,在Top-Count闪烁计数器中检测掺入到33P标记的肽中的放射性。
结果:用如下方程式对数据进行分析并用抑制%来表示:
100 x(1-(未知-背景)/(酶对照-背景))
用四参数对数方程的改变形式计算IC50:
Y=100/[1+10^{(LogEC50-X)*斜率}]其中X=log(uM),Y=抑制%。
因此,式(I)化合物可用于限制失控的肿瘤细胞增殖,从而可用于治疗各种肿瘤,例如癌症,例如乳腺癌、肺癌、膀胱癌、结肠癌、卵巢和子宫内膜肿瘤、肉瘤,例如软组织和骨肉瘤,以及血液系统的恶性肿瘤例如白血病。
此外,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、与动脉粥样硬化有关的血管平滑肌增殖和手术后的狭窄和再狭窄,并可用于治疗早老性痴呆。
适于向哺乳动物、例如人给药的本发明的式(I)化合物可以根据患者的年龄、体重、病症以及给药途径通过常规的途径和剂量给药。
例如,适于口服给药的式(I)化合物的适宜剂量可以是约10至约500mg/剂,每天给药1至5次。
本发明的化合物可以作为单一的活性剂进行给药,或者与已知的抗癌疗法结合,例如放疗或者与细胞抑制剂或细胞毒药物、抗生素类药物、烷化剂、抗代谢剂、激素类药物、免疫学药物、干扰素类型的药物、环加氧酶抑制剂(例如COX-2抑制剂)、金属基质蛋白酶抑制剂、端粒酶抑制剂、酪氨酸激酶抑制剂、抗生长因子受体剂、抗-HER剂、抗-EGFR剂、抗血管生成剂、法尼基转移酶抑制剂、ras-raf信号传导通路抑制剂、细胞周期抑制剂、其它cdks抑制剂、微管蛋白结合剂、拓扑异构酶I抑制剂、拓扑异构酶II抑制剂等联合的化疗方案。
例如,可将本发明的化合物与一种或多种化疗剂例如紫杉烷、紫杉烷衍生物、包封的紫杉烷类、CPT-11、喜树碱衍生物、蒽环霉素(anthracycline)糖甙例如阿霉素、伊达比星、表阿霉素、依托泊甙、navelbine、长春碱、卡铂、顺铂、雌莫司汀、celecoXib、SugenSU-5416、Sugen SU-6668、Herceptin等联合给药,并且可以选择性地在脂质体制剂中给药。
如果以固定的剂量给药,该联合形式的产品采用在上述剂量范围内的本发明化合物和认可的剂量范围内的其它药物活性剂。
当联合制剂不适用时,可将式(I)化合物与已知的抗癌剂顺序给药。
可将本发明的化合物以各种剂型给药,例如,以片剂、胶囊、糖或薄膜包衣片、液体的溶液或混悬液的形式口服给药;以栓剂的形式直肠给药;胃肠外给药,例如肌肉内或静脉内和/或鞘内和/或脊柱内注射或输液。
本发明还包括含有式(I)化合物或其可药用盐以及可药用赋形剂的药物组合物,所述赋形剂可以是载体或稀释剂。
含有本发明化合物的药物组合物通常按照常规方法制备并以适宜的药物形式给药。
例如,固体口服剂型可以含有活性化合物以及稀释剂,例如乳糖、葡萄糖、蔗糖、纤维素、玉米淀粉或土豆淀粉;润滑剂,例如二氧化硅、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、阿拉伯树胶、明胶、甲基纤维素、羧甲基纤维素或聚乙烯吡咯烷酮;崩解剂,例如淀粉、藻酸、藻酸盐或淀粉甘醇酸钠;泡腾混合物;染料;甜味剂;湿润剂,例如卵磷脂、聚山梨醇酯、十二烷基硫酸盐;以及药物制剂中使用的无毒和无药理学活性的物质。这些药物制剂可以通过已知的方式,例如混合、制粒、压片、糖包衣或薄膜包衣过程进行生产。
用于口服给药的液体分散体可以是例如糖浆、乳剂和混悬剂。
糖浆可以含有载体,例如蔗糖或蔗糖加甘油和/或甘露醇和/或山梨醇。
混悬剂和乳剂可以含有载体,例如天然树胶、琼脂、藻酸钠、果胶、甲基纤维素、羧甲基纤维素或聚乙烯醇。
用于肌肉内注射的混悬液或溶液可以含有活性化合物以及可药用的载体,例如无菌水、橄榄油、油酸乙酯、二醇,例如丙二醇,并且,如需要,还可含有适宜量的利多卡因盐酸盐。
用于静脉内注射或输液的溶液可以含有例如无菌水作为载体,或者优选是无菌的等渗盐水溶液的形式,或者可以含有丙二醇作为载体。
栓剂可以含有活性化合物以及可药用载体,例如可可脂、聚乙二醇、聚氧乙烯脱水山梨醇脂肪酸酯表面活性剂或卵磷脂。
实施例
以上对本发明进行了总的描述,通过参照具体的实施例可以进一步理解本发明,本文中提供这些实施例的目的仅仅是为了说明而并非想要进行限定,除非另有说明。
实施例1
N-(3-环丙基-1H-吡唑-5-基)-N’-苯基脲
向0.4g(3.2mmol)3-环丙基-5-氨基-1H-吡唑的10ml含有0.3g碳酸氢钠的95%乙醇溶液中在数分钟内滴加0.35ml(3mmol)异氰酸苯酯。30分钟后,加入水,滤出固体,依次用10%HCl和水洗涤。将滤液真空浓缩。将粗产物用甲醇/水重结晶得到白色的5-氨基-3-环丙基-N-苯基-1H-吡唑-1-甲酰胺,
m.p.97-99℃;
MS(EI)m/z(相对强度)242(M+,13),123(99),119(86),96(74),91(86),80(85),77(53),65(61),64(79),63(52),51(51).
向5-氨基-3-环丙基-N-苯基-1H-吡唑-1-甲酰胺(0.5g,2mmol)的6ml甲醇溶液中加入0.5ml(4.6mmol)异氰酸苯酯和2ml 10%NaOH。将该混合物回流2小时然后冷却,用10%HCl终止反应并用乙酸乙酯萃取。将有机相用10%HCl、水和盐水洗涤。浓缩并进行硅胶色谱,用8%至20%丙酮的二氯甲烷溶液洗脱,得到100mg(20%收率)N-(3-环丙基-1H-吡唑-5-基)-N’-苯基脲,为无色玻璃状固体。m.p.162-164℃;
m.p.162-164℃;
1H NMR(DMSO-d6)12.0(s,1H),9.2(s,1H),8.84(s,1H),7.42(app.d,2H),7.27
(app.t,2H),6.96(app.t,1H),5.86(s,1H),1.85(m,1H),0.91(m,2H),0.67(m,2H);
MS(EI)m/z(相对强度)242(M+,9),149(43),123(89),122(38),119(89),93
(99),91(54),80(46),66(47),65(40),64(34).
实施例2
N-(3-环丙基-1H-吡唑-5-基)-N’-(2.4-二氯苄基)脲
将1g(8.13mmol)3-环丙基-5-氨基-1H-吡唑溶于10ml含有1.37g(16.26mmol)碳酸氢钠和3.27g(16.26mmol)2,4-二氯苄基异氰酸酯的乙醇。室温下3小时后,加入50ml水并滤出固体。将滤液蒸发至干然后溶于10ml甲醇。加入8.2ml 1M的氢氧化钠,然后将混合物室温搅拌4小时。将甲醇蒸发,将残余物用二氯甲烷溶解并用水洗涤。将有机层用无水硫酸钠干燥然后真空浓缩得到1.5g(60%收率)标题化合物。m.p.177-179℃;1H NMR(DMSO-d6)11.9(s,1H),8.84(s,1H),7.60(d,1H),7.55(br s,1H),7.43(dd,1H),7.36(d,1H),5.67(s,1H),4.36(d,2H),1.81(m,1H),0.89(m,2H),0.61(m,2H);HRMS(FAB)计算值C14H14Cl2N4O+H 325.0623,测定值325·0621。
实施例3
3-环丙基-3-氧代-丙腈
将4.5g(0.15mol)氢化钠(80%)悬浮在200ml二氧六环中,滴加7.5ml乙腈(0.15mol),20分钟后,加入环丙烷甲酸乙酯(0.125mol)的100ml二氧六环溶液。将混合物在搅拌下回流3小时,然后加入400ml水并将未反应的原料用二氯甲烷萃取。将水层用稀盐酸酸化并用二氯甲烷萃取。将有机层用无水硫酸钠干燥然后蒸发至干得到残余物,经柱色谱(环己烷-乙酸乙酯)后得到7.8g(57%收率)标题化合物。
1H NMR(400MHZ,CDCl3)3.59(s,2H),2.12(dddd,1H,J=7.6,7.6,4.5,4.5),1.21(m,2H),1.10(m,2H).
EI-MS:m/z 69(85,M-C3H5);m/z 39(100,C3H5 +).
实施例4
3-环丙基-5-氨基-1H-吡唑
将5g(0.046mol)3-环丙基-3-氧代-丙腈溶于200ml乙醇并加入2.26ml(0.046mol)水合肼。将溶液回流5小时然后真空蒸除溶剂。将残余物溶于二氯甲烷并用盐水洗涤数次。将有机层用无水硫酸钠干燥然后蒸除溶剂得到4.53(80%收率)标题化合物。
1H NMR(400MHZ,CDCl3)6-7(b,3H,NH+NH2),5.02(s,1H),1.68(dddd,1H,J=8.3,8.3,4.9,4.9),0.76(m,2H),0.54(m,2H).
ESI(+)MS:m/z 124(100,MH+).
实施例5
3-环丙基-5-硝基-1H-吡唑
向2.7g氢氧化钠的454ml水溶液中于0℃下加入7.1g(0.058mol)3-环丙基-5-氨基-1H-吡唑和46.5g碳酸氢钠。10分钟后,在剧烈搅拌下同时滴加337ml丙酮的221ml水溶液和130g(0.21mol)oxone的580ml水溶液。在该温度下4小时后,用饱和亚硫酸钠溶液终止反应并用乙酸乙酯萃取。将有机层用无水硫酸钠干燥然后蒸发至干得到4.6g(52%收率)标题化合物。
1H NMR(400MHZ,CDCl3)6.51(s,1H),2.01(dddd,1H,J=8.2,8.2,5.1,5.1),1.10(m,2H),0.79(m,2H).
EI-MS:m/z 153(100,M+);136(60,M-OH).
实施例6
叔丁基-3-硝基-5-环丙基-1H-吡唑-1-甲酸酯
将4.9g(0.032mol)3-环丙基-5-硝基-1H-吡唑溶于200ml二氯甲烷并加入200ml饱和碳酸氢钠溶液。然后在室温搅拌下加入35g(0.16mol)叔丁氧基羰基酐。24小时后,分液并将有机层用硫酸钠干燥然后真空蒸发。将残余物进行硅胶柱色谱(环己烷-乙酸乙酯)得到7.7g(95%收率)标题化合物。
1H NMR(400MHZ,CDCl3)6.49(s,1H),2.48(dddd,1H,J=8.5,8.5,5.3,5.3),1.68(s,9H),1.13(m,2H),0.78(m,2H).
ESI(+)MS:m/z 276(100,MNa+);220[60,(MNa-C4H8)+].
实施例7
叔丁基-3-氨基-5-环丙基-1H-吡唑-1-甲酸酯
将1.2g(4.74mmol)叔丁基-3-硝基-5-环丙基-1H-吡唑-1-甲酸酯溶于20ml乙醇,然后在200mg钯/炭的(10%)的存在下于50psi和室温下氢化,用硅藻土过滤然后蒸除溶剂得到0.96g(95%收率)标题化合物。
1H NMR(400MHZ,CDCl3)5.39(s,1H),3.82(br s,2H)2.34(dddd,1H,J=8.4,8.4,5.2,5.2),1.63(s,9H),0.97(m,2H),0.64(m,2H).
ESI(+)MS:m/z 246(20,MNa+);168[100,(MH-C4H8)+];124[90,(MH-C5H8O2)+].
实施例8
聚合物负载的物质(XVIII)的制备
向1.067g(负载量0.57mmol/g,0.608mmol)肟树脂(XVI)的10ml二氯甲烷溶液中加入241mg(0.811mmol)三光气的5ml二氯甲烷溶液。将反应液搅拌过夜。将树脂收集在烧结的玻璃漏斗上并用二氯甲烷充分洗涤。将残余物在真空烘箱中干燥得到1.085g树脂。将树脂通过FT-IR分析显示在1800cm-1处有强的羰基拉伸。然后将树脂重新悬浮在10ml二氯甲烷中并加入232mg(1.88mmol)3-环丙基-5-氨基吡唑。搅拌1 2小时后,过滤收集树脂并用甲醇洗涤。在真空烘箱中干燥后,得到1.097g树脂。FT-IR分析显示在1761cm-1处有强的羰基拉伸。实施例9
N-(3-环丙基-1H-吡唑-5-基)-N’-(3-甲氧基苄基)脲
将100mg(0.1mmol)肟-氨基甲酸酯树脂(XVIII)悬浮在1ml DMSO中并加入11mg(0.08mmol)3-甲氧基苄基胺在0.2M DMSO中的溶液。将反应液于80℃加热3小时,然后过滤分离出树脂,用150μl二氯甲烷和150μl MeOH洗涤。将滤液浓缩,用乙醚研磨后得到11.4mg(50%收率)标题化合物。
按照类似的方法可以制得如下化合物:N-(3-环丙基-1H-吡唑-5-基)-N’-[(1-乙基-2-吡咯烷基)甲基]脲;N-(3-环丙基-1H-吡唑-5-基)-N’-[2-(2H-咪唑-4-基)乙基]脲;N-(3-环丙基-1H-吡唑-5-基)-N’-[2-(5-甲氧基-2H-吲哚-3-基)乙基]脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(1H-吲哚-6-基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-[2-(4-吗啉基)乙基]脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(2-氯苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(2,4-二氯苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(2-乙氧基苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3,4-二氯苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3-三氟甲基苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(4-氟苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(4-甲基苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(4-氯苄基)脲;N-(3-氯苯乙基)-N’-(3-环丙基-1H-吡唑-5-基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-[2-(2-吡啶基)乙基]脲;N-(3-环丙基-1H-吡唑-5-基)-N’-[2-(1-吡咯烷基)乙基]脲;N-(3-环丙基-1H-吡唑-5-基)-N’-丁基脲;N-(3-环丙基-1H-吡唑-5-基)-N’-[2-(1-哌啶基)乙基]脲;4-[({[(3-环丙基-1H-吡唑-5-基)氨基]羰基}氨基)甲基]苯磺酰胺;N-(3-环戊基-1H-吡唑-5-基)-4-[2-硝基-4-(三氟甲基)苯基]-1-哌嗪甲酰胺;N-(3-环戊基-1H-吡唑-5-基)-N’-丙基脲;N-(3-环戊基-1H-吡唑-5-基)-N’-(4-羟基丁基)脲;N-(3-环戊基-1H-吡唑-5-基)-N’-(3,4-二甲氧基苯乙基)脲;N-(3-环戊基-1H-吡唑-5-基)-N’-(4-羟基苯乙基)脲;N-(3-环戊基-1H-吡唑-5-基)-N’-苄基脲;N-(3-环戊基-1H-吡唑-5-基)-N’-苯乙基脲;N-(3-环戊基-1H-吡唑-5-基)-N’-(1-苄基-4-哌啶基)脲;N-(3-环戊基-1H-吡唑-5-基)-1-哌啶甲酰胺;N-(3-环戊基-1H-吡唑-5-基)-4-(氨基甲基)-1-哌啶甲酰胺;N-(3-环戊基-1H-吡唑-5-基)-4-苄基-1-哌嗪甲酰胺;N-(3-环戊基-1H-吡唑-5-基)-4-吗啉甲酰胺;N-(3-环戊基-1H-吡唑-5-基)-4-苯基-1-哌嗪甲酰胺;N-(3-环戊基-1H-吡唑-5-基)-4-甲基-1-哌嗪甲酰胺;N-(3-环戊基-1H-吡唑-5-基)-1-哌嗪甲酰胺;N-(3-环戊基-1H-吡唑-5-基)-4-(1,3-苯并间二氧杂环戊烯-5-基-甲基)-1-哌嗪甲酰胺;N-(3-环戊基-1H-吡唑-5-基)-N’-环丁基脲;N-(环戊基-1H-吡唑-5-基)-1-吡咯烷甲酰胺;N-环丁基-N’-(3-苯乙基-1H-吡唑-5-基)脲;N-(3-苯乙基-1H-吡唑-5-基)-1-吡咯烷甲酰胺;4-(1,3-苯并间二氧杂环戊烯-5-基-甲基)-N-(3-苯乙基-1H-吡唑-5-基)-1-哌嗪甲酰胺;N-(3-苯乙基-1H-吡唑-5-基)-1-哌嗪甲酰胺;N-(3-苯乙基-1H-吡唑-5-基)-4-苯基-1-哌嗪甲酰胺;N-(3-苯乙基-1H-吡唑-5-基)-4-甲基-1-哌嗪甲酰胺;N-(3-苯乙基-1H-吡唑-5-基)-4-苄基-1-哌嗪甲酰胺;N-(3-苯乙基-1H-吡唑-5-基)-4-吗啉甲酰胺;N-(3-苯乙基-1H-吡唑-5-基)-1-哌啶甲酰胺;N-(3-苯乙基-1H-吡唑-5-基)-4-(氨基甲基)-1-哌啶甲酰胺;N-(3-苯乙基-1H-吡唑-5-基)-N’-(1-苄基-4-哌啶基)脲;N-(3-苯乙基-1H-吡唑-5-基)-N’-苄基脲;N-(3-苯乙基-1H-吡唑-5-基)-N’-苯乙基脲;N-(3-苯乙基-1H-吡唑-5-基)-N’-(3,4-二甲氧基苯乙基)脲;N-(3-苯乙基-1H-吡唑-5-基)-N’-(4-羟基苯乙基)脲;N-(3-苯乙基-1H-吡唑-5-基)-N’-丙基脲;N-(3-苯乙基-1H-吡唑-5-基)-N’-(4-羟基丁基)脲;N-(3-苯乙基-1H-吡唑-5-基)-4-[2-硝基-4-(三氟甲基)苯基]-1-哌嗪甲酰胺。
所有化合物均通过质谱(MS)进行了鉴定。LC-MS证实,在所有情况下,主要的成分具有与预期产物相对应的分子离子峰。这些化合物显示的HPLC面积%为70至100。HPLC分析:
溶剂A:H2O/CH3CN=90/10+0.1%TFA
溶剂B:H2O/CH3CN=10/90+0.075%TFA
流速:1.5ml/分钟检测:UV 254nm温度:室温柱:SupelcoTM,DisGovery RP Amide C16,sum,(50×4.6)mm
时间(分钟) | %A | %B |
0 | 0 | 100 |
6.5 | 0 | 100 |
7 | 100 | 0 |
10 | 100 | 0 |
实施例10
N-(3-环丙基-1H-吡唑-5-基)-N’-
(1,3-苯并间二氧杂环戊烯-5-基-甲基)脲
氮气氛下,向1.5g(6.7mmol)叔丁基-3-氨基-5-环丙基-1H-吡唑-1-甲酸酯的15ml二氯甲烷溶液中于0℃下滴加1.41g(7mmol)氯甲酸对硝基苯酯在7ml二氯甲烷和1ml吡啶的混合物中的溶液。室温下12小时后,过滤分离出沉淀得到1.95g(75%收率)对硝基苯基-叔丁基-3-氨基-5-环丙基氨基甲酸酯。将该中间体(5mmol,不经纯化)悬浮于20ml乙腈中并加入830mg(5.5mmol)(1,3-苯并间二氧杂环戊烯-5-基)-甲基胺。80℃下3小时后,将该悬浮液过滤并将滤液真空浓缩。将残余物重新溶于乙酸乙酯并依次用饱和碳酸氢钠溶液和水洗涤。将有机层用无水硫酸钠干燥然后蒸发至干。将粗产物通过硅胶柱色谱纯化(己烷/乙酸乙酯7/3)得到1.2g(60%收率)N-(3-环丙基-1-叔丁氧羰基-吡唑-5-基)-N’-(1,3-苯并间二氧杂环戊烯-5-基-甲基)脲。最后,将前面的中间体(3mmol)溶于2 5ml 10%v/v三氟乙酸-二氯甲烷的混合物。室温下1小时后,将溶剂蒸发至干,将残余物溶于二氯甲烷并用饱和碳酸氢钠溶液洗涤。将有机层用无水硫酸钠干燥然后浓缩得到855mg(95%收率)标题化合物。
显然,可以根据以上的教导对本发明进行多种修饰和改变。因此,应当理解,在所附权利要求的范围之内,还可以通过除文中具体描述之外的其它方式来实践本发明。
Claims (23)
R是C1-C6烷基、芳基或芳基烷基,该基团选择性地被一个或多个羟基、卤素、硝基、氰基、氧代、羧基、氨基、烷基氨基、二烷基氨基、烷基羰基氨基、烷氧基羰基氨基、烷氧基羰基烷基氨基、氨基羰基烷基氨基、N-烷基-N-羰基氨基、N-环烷基-N-烷基氨基烷基、氨基烷基、氨基羰基、烷基、环烷基、烷硫基、烷氧基、烷基羰基、烷基磺酰基、烷基磺酰基氨基、氨基磺酰基、烷氧基羰基、芳基、芳基烷基、芳氧基、芳硫基、芳基磺酰基、芳基氨基、芳基羰基、N-烷基-哌嗪基、4-吗啉基、全氟代的C1-C4烷基、C1-C4链烯基、C2-C4炔基、C2-C4氨基炔基或C2-C4羟基炔基取代基所取代;
R1是-(CH2)n-R3;
n是0或1至4的整数;
R3是氢、羟基、氨基,或者选自环烷基、芳基和杂环基,所述环烷基、芳基和杂环基选择性地被一个或多个羟基、卤素、硝基、氰基、氧代、羧基、氨基、烷基氨基、二烷基氨基、烷基羰基氨基、烷氧基羰基氨基、烷氧基羰基烷基氨基、氨基羰基烷基氨基、N-烷基-N-羰基氨基、N-环烷基-N-烷基氨基烷基、氨基烷基、氨基羰基、烷基、环烷基、烷硫基、烷氧基、烷基羰基、烷基磺酰基、烷基磺酰基氨基、氨基磺酰基、烷氧基羰基、芳基、芳基烷基、芳氧基、芳硫基、芳基磺酰基、芳基氨基、芳基羰基、N-烷基-哌嗪基、4-吗啉基、全氟代的C1-C4烷基、C2-C4链烯基、C2-C4炔基、C2-C4氨基炔基或C2-C4羟基炔基取代基所取代;
R2是氢,或者
R2和R1与它们所连接的氮原子合在一起形成杂环基或杂芳基,所述杂环基或杂芳基选择性地被一个或多个羟基、卤素、硝基、氰基、氧代、羧基、氨基、烷基氨基、二烷基氨基、烷基羰基氨基、烷氧基羰基氨基、烷氧基羰基烷基氨基、氨基羰基烷基氨基、N-烷基-N-羰基氨基、N-环烷基-N-烷基氨基烷基、氨基烷基、氨基羰基、烷基、环烷基、烷硫基、烷氧基、烷基羰基、烷基磺酰基、烷基磺酰基氨基、氨基磺酰基、烷氧基羰基、芳基、芳基烷基、芳氧基、芳硫基、芳基磺酰基、芳基氨基、芳基羰基、N-烷基-哌嗪基、4-吗啉基、全氟代的C1-C4烷基、C2-C4链烯基、C2-C4炔基、C2-C4氨基炔基或C2-C4羟基炔基取代基所取代;
条件是,当n是0并且R2是氢时,R是选择性地被直链或支链C1-C6烷基取代的C3-C6环烷基。
2.权利要求1的方法,其中的细胞增殖性疾病选自癌症、早老性痴呆、病毒感染、自身免疫疾病和神经变性疾病。
3.权利要求2的方法,其中的癌症选自癌、鳞状细胞癌、骨髓或淋巴系的造血系统肿瘤、源于间质的肿瘤、中枢和外周神经系统的肿瘤、黑色素瘤、精原细胞瘤、畸胎瘤、骨肉瘤、着色性干皮病、角化棘皮瘤、甲状腺滤泡癌和卡波济氏肉瘤。
4.权利要求1的方法,其中的细胞增殖性疾病选自良性前列腺增生、家族性息肉状腺瘤病、神经纤维瘤病、牛皮癣、与动脉粥样硬化有关的血管平滑肌细胞增殖、肺纤维化、关节炎肾小球肾炎以及手术后的狭窄和再狭窄。
5.权利要求1的方法,该方法可以抑制肿瘤血管生成和转移。
6.权利要求1的方法,该方法可以抑制细胞周期或产生cdk/细胞周期蛋白依赖型的抑制作用。
7.权利要求1的方法,进一步包括对需要治疗的哺乳动物进行放疗或与至少一种细胞抑制剂或细胞毒药物联合进行化疗。
8.权利要求1的方法,其中R是选择性地被直链或支链的C1-C6烷基取代的C3-C6环烷基。
9.权利要求1的方法,其中
R是C3-C6环烷基或选择性取代的直链或支链C1-C4烷基、环烷基、芳基或芳基烷基;
R1是选择性地按照权利要求1中的定义被取代的C1-C4烷基或苯基、苯基烷基、杂芳基、杂芳基烷基或杂环基;
或其可药用盐。
10.权利要求1的方法,其中
R是C3-C6环烷基;
R1是被羟基或氨基取代的C1-C4烷基,或是芳基、芳基烷基、杂环基或杂环基烷基,其中的芳基或杂环基部分选自苯基或选择性地与苯稠合的吡啶、吲哚、噻吩、噻唑、异噁唑、呋喃、哌啶、吗啉,这些基团均可以选择性地被进一步取代;
或其可药用盐。
11.权利要求1的方法,其中R1和R2与它们连接的氮原子合在一起形成选择性取代的杂环基环。
12.权利要求11的方法,其中的杂环基环是1-哌啶基、1-哌嗪基或4-吗啉基。
13.权利要求7的方法,其中的化合物选自:N-(3-环丙基-1H-吡唑-5-基)-N’-[2-(1-哌啶基)乙基]脲;4-[({[(3-环丙基-1H-吡唑-5-基)氨基]羰基}氨基)甲基]苯磺酰胺;N-(3-环丙基-1H-吡唑-5-基)-N’-[2-(2-吡啶基)乙基]脲;N-(3-环丙基-1H-吡唑-5-基)-N’-[2-(1-吡咯烷基)乙基]脲;N-(3-氯苯乙基)-N’-(3-环丙基-1H-吡唑-5-基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(2,3-二甲氧基苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(4-氯苄基)脲;N-[3-(叔丁基)-1H-吡唑-5-基)]-N’-(4-哌啶基甲基)脲;N-[3-(叔丁基)-1H-吡唑-5-基)]-N’-(3-氟苄基)脲;N-[3-(叔丁基)-1H-吡唑-5-基)]-N’-(3,4-二甲氧基苄基)脲;N-[3-(叔丁基)-1H-吡唑-5-基)]-N’-(4-氯苄基)脲;N-[3-(叔丁基)-1H-吡唑-5-基)]-N’-(3,4-二羟基苄基)脲;N-[3-(叔丁基)-1H-吡唑-5-基)]-N’-(3,4-二甲基苄基)脲;N-[3-(叔丁基)-1H-吡唑-5-基)]-N’-(3-氯苯乙基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(4-哌啶基甲基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3-氟苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3,4-二甲氧基苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3,4-二甲基苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(2-羟基-1-甲基-2-苯基乙基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-[(1-乙基-2-吡咯烷基)甲基]脲;N-(3-环丙基-1H-吡唑-5-基)-N’-[2-(2H-咪唑-4-基)乙基]脲;N-(3-环丙基-1H-吡唑-5-基)-N’-[2-(5-甲氧基-1H-吲哚-3-基)乙基]脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(1H-吲哚-6-基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(1,3-苯并间二氧杂环戊烯-5-基甲基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(2-(4-吗啉基)乙基]脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(2-氯苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(2,4-二氯苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(2-乙氧基苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3,4-二氯苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3-甲氧基苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(4-氟苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3-三氟甲基苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(4-甲基苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-4-吗啉甲酰胺;N-环丁基-N’-(3-环戊基-1H-吡唑-5-基)脲;N-(3-环戊基-1H-吡唑-5-基)-1-吡咯烷甲酰胺;4-(1,3-苯并间二氧杂环戊烯-5-基甲基)-N-(3-环戊基-1H-吡唑-5-基)-1-哌嗪甲酰胺;N-(3-环戊基-1H-吡唑-5-基)-1-哌嗪甲酰胺;N-(3-环戊基-1H-吡唑-5-基)-4-苯基-1-哌嗪甲酰胺;N-(3-环戊基-1H-吡唑-5-基)-4-甲基-1-哌嗪甲酰胺;N-(3-环戊基-1H-吡唑-5-基)-4-苄基-1-哌嗪甲酰胺;N-(3-环戊基-1H-吡唑-5-基)-4-吗啉甲酰胺;N-(3-环戊基-1H-吡唑-5-基)-1-哌啶甲酰胺;N-(3-环戊基-1H-吡唑-5-基)-4-(氨基甲基)-1-哌啶甲酰胺;N-(3-环戊基-1H-吡唑-5-基)-N’-(1-苄基-4-哌啶基)脲;N-(3-环戊基-1H-吡唑-5-基)-N’-苄基脲;N-(3-环戊基-1H-吡唑-5-基)-N’-苯乙基脲;N-(3-环戊基-1H-吡唑-5-基)-N’-(3,4-二甲氧基苯乙基)脲;N-(3-环戊基-1H-吡唑-5-基)-N’-(4-羟基苯乙基)脲;N-(3-环戊基-1H-吡唑-5-基)-N’-丙基脲;N-(3-环戊基-1H-吡唑-5-基)-N’-(4-羟基丁基)脲;N-(3-环戊基-1H-吡唑-5-基)-4-[2-硝基-4-(三氟甲基)苯基]-1-哌嗪甲酰胺;N-(3-苯乙基-1H-吡唑-5-基)-1-吡咯烷甲酰胺;4-(1,3-苯并间二氧杂环戊烯-5-基-甲基)-N-(3-苯乙基-1H-吡唑5-基)-1-哌嗪甲酰胺;N-(3-苯乙基-1H-吡唑-5-基)-1-哌嗪甲酰胺;N-(3-苯乙基-1H-吡唑-5-基)-4-苯基-1-哌嗪甲酰胺;N-(3-苯乙基-1H-吡唑-5-基)-4-甲基-1-哌嗪甲酰胺;N-(3-苯乙基-1H-吡唑-5-基)-4-苄基-1-哌嗪甲酰胺;N-(3-苯基-1H-吡唑-5-基)-4-吗啉甲酰胺;N-(3-苯乙基-1H-吡唑-5-基)-1-哌啶甲酰胺;N-(3-苯乙基-1H-吡唑-5-基)-4-(氨基甲基)-1-哌啶甲酰胺;N-(3-苯乙基-1H-吡唑-5-基)-N’-苄基脲;N-(3-苯乙基-1H-吡唑-5-基)-N’-苯乙基脲;N-(3-苯乙基-1H-吡唑-5-基)-N’-(3,4-二甲氧基苯乙基)脲;N-(3-苯乙基-1H-吡唑-5-基)-N’-(4-羟基苯乙基)脲;N-(3-苯乙基-1H-吡唑-5-基)-N’-丙基脲;N-(3-苯乙基-1H-吡唑-5-基)-N’-(4-羟基丁基)脲;N-(3-苯乙基-1H-吡唑-5-基)-4-[2-硝基-4-(三氟甲基)苯基]-1-哌嗪甲酰胺;N-(3-环丙基-1H-吡唑-5-基)-N’-丁基脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(2,4-二甲基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3,4-二甲氧基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3-羧基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(2,3-二甲基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3-羧基-4-氯苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3,5-二甲基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3-甲酰氨基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3-羧基-4-羟基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(2,6-二甲基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(4-氰基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3-乙酰基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(1H-苯并咪唑-6-基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(4-羟基-3-甲氧基苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-苄基脲;N-(3-环丙基-1H-吡唑-5-基)-N’-{3-[3-(二甲基氨基)-1-丙炔基]苯基}脲;N-[3-({[(3-环丙基-1H-吡唑-5-基)氨基]羰基}氨基)苯基]甲磺酰胺;2-[3-({[(3-环丙基-1H-吡唑-5-基)氨基]羰基}氨基)苯氨基]乙酰胺;N-(3-环丙基-1H-吡唑-5-基)-N’-(2-羟基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-[3-(3-羟基-1-丁炔基)苯基]脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(1H-吲哚-6-基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(1H-吲哚-5-基)脲;4-({[(3-环丙基-1H-吡唑-5-基)氨基]羰基}氨基)苯磺酰胺;N-(3-环丙基-1H-吡唑-5-基)-N’-(3-甲氧基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-苯基脲;N-[4-({[(3-环丙基-1H-吡唑-5-基)氨基]羰基}氨基)苯基]-N-甲基乙酰胺;N-(2-{[环己基(甲基)氨基]甲基}苯基)-N’-(3-环丙基-1H-吡唑-5-基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(2-甲氧基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(2-氯苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3-乙炔基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(4-氨基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3-羟基-4-甲基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-3-氧代-3,4-二氢-1(2H)-喹喔啉甲酰胺;N-(3-环丙基-1H-吡唑-5-基)-3,4-二氢-2(1H)-异喹啉甲酰胺;N-(3-环丙基-1H-吡唑-5-基)-N’-(4-吡啶基甲基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(2-呋喃基甲基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(1,3-苯并噻唑-5-基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(1,3-二甲基-1H-吡唑-5-基)脲;N-[5-({[(3-环丙基-1H-吡唑-5-基)氨基]羰基}氨基)-2-甲氧基苯基]乙酰胺;N-[3-({[(3-环丙基-1H-吡唑-5-基)氨基]羰基}氨基)-4-甲氧基苯基]乙酰胺;N-(3-环丙基-1H-吡唑-5-基)-N’-(3-氨基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(1H-咪唑-6-基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3-羟基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(4-羟基苯基)脲,及其可药用盐。
14.权利要求1的方法,其中的哺乳动物是人。
R是C1-C6烷基、芳基或芳基烷基,该基团选择性地被-个或多个羟基、卤素、硝基、氰基、氧代、羧基、氨基、烷基氨基、二烷基氨基、烷基羰基氨基、烷氧基羰基氨基、烷氧基羰基烷基氨基、氨基羰基烷基氨基、N-烷基-N-羰基氨基、N-环烷基-N-烷基氨基烷基、氨基烷基、氨基羰基、烷基、环烷基、烷硫基、烷氧基、烷基羰基、烷基磺酰基、烷基磺酰基氨基、氨基磺酰基、烷氧基羰基、芳基、芳基烷基、芳氧基、芳硫基、芳基磺酰基、芳基氨基、芳基羰基、N-烷基-哌嗪基、4-吗啉基、全氟代的C1-C4烷基、C1-C4链烯基、C2-C4炔基、C2-C4氨基炔基或C2-C4羟基炔基取代基所取代;
R1是-(CH2)n-R3;
n是0或1至4的整数;
R3是氢、羟基、氨基,或者选自环烷基、芳基和杂环基,所述环烷基、芳基和杂环基选择性地被一个或多个羟基、卤素、硝基、氰基、氧代、羧基、氨基、烷基氨基、二烷基氨基、烷基羰基氨基、烷氧基羰基氨基、烷氧基羰基烷基氨基、氨基羰基烷基氨基、N-烷基-N-羰基氨基、N-环烷基-N-烷基氨基烷基、氨基烷基、氨基羰基、烷基、环烷基、烷硫基、烷氧基、烷基羰基、烷基磺酰基、烷基磺酰基氨基、氨基磺酰基、烷氧基羰基、芳基、芳基烷基、芳氧基、芳硫基、芳基磺酰基、芳基氨基、芳基羰基、N-烷基-哌嗪基、4-吗啉基、全氟代的C1-C4烷基、C2-C4链烯基、C2-C4炔基、C2-C4氨基炔基或C2-C4羟基炔基取代基所取代;
R2是氢,或者
R2和R1与它们所连接的氮原子合在一起形成杂环基或杂芳基,所述杂环基或杂芳基选择性地被一个或多个羟基、卤素、硝基、氰基、氧代、羧基、氨基、烷基氨基、二烷基氨基、烷基羰基氨基、烷氧基羰基氨基、烷氧基羰基烷基氨基、氨基羰基烷基氨基、N-烷基-N-羰基氨基、N-环烷基-N-烷基氨基烷基、氨基烷基、氨基羰基、烷基、环烷基、烷硫基、烷氧基、烷基羰基、烷基磺酰基、烷基磺酰基氨基、氨基磺酰基、烷氧基羰基、芳基、芳基烷基、芳氧基、芳硫基、芳基磺酰基、芳基氨基、芳基羰基、N-烷基-哌嗪基、4-吗啉基、全氟代的C1-C4烷基、C2-C4链烯基、C2-C4炔基、C2-C4氨基炔基或C2-C4羟基炔基取代基所取代;
条件是,当n是0并且R2是氢时,R是选择性地被直链或支链C1-C6烷基取代的C3-C6环烷基。
16.权利要求15的3-脲基-吡唑衍生物或其可药用盐,其中
R是C3-C6环烷基或选择性取代的直链或支链C1-C4烷基、环烷基、芳基或芳基烷基;
R1是选择性地按照权利要求15中的定义被取代的C1-C4烷基或苯基、苯基烷基、杂芳基、杂芳基烷基或杂环基。
17.权利要求15的3-脲基-吡唑衍生物或其可药用盐,其中
R是C3-C6环烷基;
R1是被羟基或氨基取代的C1-C4烷基,或是芳基、芳基烷基、杂环基或杂环基烷基,其中的芳基或杂环基部分选自苯基或选择性地与苯稠合的吡啶、吲哚、噻吩、噻唑、异噁唑、呋喃、哌啶、吗啉,这些基团均可以选择性地被进一步取代。
18.权利要求15的3-脲基-吡唑衍生物,其中R1和R2与它们连接的氮原子合在一起形成选择性取代的杂环基环。
19.权利要求15的3-脲基-吡唑衍生物,其中的杂环基环是1-哌啶基、1-哌嗪基或4-吗啉基。
20.权利要求15的3-脲基-吡唑衍生物,所述化合物选自:N-(3-环丙基-1H-吡唑-5-基)-N’-[2-(1-哌啶基)乙基]脲;4-[({[(3-环丙基-1H-吡唑-5-基)氨基]羰基}氨基)甲基]苯磺酰胺;N-(3-环丙基-1H-吡唑-5-基)-N’-[2-(2-吡啶基)乙基]脲;N-(3-环丙基-1H-吡唑-5-基)-N’-[2-(1-吡咯烷基)乙基]脲;N-(3-氯苯乙基)-N’-(3-环丙基-1H-吡唑-5-基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(2,3-二甲氧基苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(4-氯苄基)脲;N-[3-(叔丁基)-1H-吡唑-5-基)]-N’-(4-哌啶基甲基)脲;N-[3-(叔丁基)-1H-吡唑-5-基)]-N’-(3-氟苄基)脲;N-[3-(叔丁基)-1H-吡唑-5-基)]-N’-(3,4-二甲氧基苄基)脲;N-[3-(叔丁基)-1H-吡唑-5-基)]-N’-(4-氯苄基)脲;N-[3-(叔丁基)-1H-吡唑-5-基)]-N’-(3,4-二羟基苄基)脲;N-[3-(叔丁基)-1H-吡唑-5-基)]-N’-(3,4-二甲基苄基)脲;N-[3-(叔丁基)-1H-吡唑-5-基)]-N’-(3-氯苯乙基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(4-哌啶基甲基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3-氟苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3,4-二甲氧基苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3, 4-二甲基苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(2-羟基-1-甲基-2-苯基乙基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-[(1-乙基-2-吡咯烷基)甲基]脲;N-(3-环丙基-1H-吡唑-5-基)-N’-[2-(2H-咪唑-4-基)乙基]脲;N-(3-环丙基-1H-吡唑-5-基)-N’-[2-(5-甲氧基-1H-吲哚-3-基)乙基]脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(1H-吲哚-6-基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(1,3-苯并间二氧杂环戊烯-5-基甲基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(2-(4-吗啉基)乙基]脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(2-氯苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(2,4-二氯苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(2-乙氧基苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3,4-二氯苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3-甲氧基苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(4-氟苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3-三氟甲基苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(4-甲基苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-4-吗啉甲酰胺;N-环丁基-N’-(3-环戊基-1H-吡唑-5-基)脲;N-(3-环戊基-1H-吡唑-5-基)-1-吡咯烷甲酰胺;4-(1,3-苯并间二氧杂环戊烯-5-基甲基)-N-(3-环戊基-1H-吡唑-5-基)-1-哌嗪甲酰胺;N-(3-环戊基-1H-吡唑-5-基)-1-哌嗪甲酰胺;N-(3-环戊基-1H-吡唑-5-基)-4-苯基-1-哌嗪甲酰胺;N-(3-环戊基-1H-吡唑-5-基)-4-甲基-1-哌嗪甲酰胺;N-(3-环戊基-1H-吡唑-5-基)-4-苄基-1-哌嗪甲酰胺;N-(3-环戊基-1H-吡唑-5-基)-4-吗啉甲酰胺;N-(3-环戊基-1H-吡唑-5-基)-1-哌啶甲酰胺;N-(3-环戊基-1H-吡唑-5-基)-4-(氨基甲基)-1-哌啶甲酰胺;N-(3-环戊基-1H-吡唑-5-基)-N’-(1-苄基-4-哌啶基)脲;N-(3-环戊基-1H-吡唑-5-基)-N’-苄基脲;N-(3-环戊基-1H-吡唑-5-基)-N’-苯乙基脲;N-(3-环戊基-1H-吡唑-5-基)-N’-(3,4-二甲氧基苯乙基)脲;N-(3-环戊基-1H-吡唑-5-基)-N’-(4-羟基苯乙基)脲;N-(3-环戊基-1H-吡唑-5-基)-N’-丙基脲;N-(3-环戊基-1H-吡唑-5-基)-N’-(4-羟基丁基)脲;N-(3-环戊基-1H-吡唑-5-基)-4-[2-硝基-4-(三氟甲基)苯基]-1-哌嗪甲酰胺;N-(3-苯乙基-1H-吡唑-5-基)-1-吡咯烷甲酰胺;4-(1,3-苯并间二氧杂环戊烯-5-基-甲基)-N-(3-苯乙基-1H-吡唑5-基)-1-哌嗪甲酰胺;N-(3-苯乙基-1H-吡唑-5-基)-1-哌嗪甲酰胺;N-(3-苯乙基-1H-吡唑-5-基)-4-苯基-1-哌嗪甲酰胺;N-(3-苯乙基-1H-吡唑-5-基)-4-甲基-1-哌嗪甲酰胺;N-(3-苯乙基-1H-吡唑-5-基)-4-苄基-1-哌嗪甲酰胺;N-(3-苯基-1H-吡唑-5-基)-4-吗啉甲酰胺;N-(3-苯乙基-1H-吡唑-5-基)-1-哌啶甲酰胺;N-(3-苯乙基-1H-吡唑-5-基)-4-(氨基甲基)-1-哌啶甲酰胺;N-(3-苯乙基-1H-吡唑-5-基)-N’-苄基脲;N-(3-苯乙基-1H-吡唑-5-基)-N’-苯乙基脲;N-(3-苯乙基-1H-吡唑-5-基)-N’(3,4-二甲氧基苯乙基)脲;N-(3-苯乙基-1H-吡唑-5-基)-N’-(4-羟基苯乙基)脲;N-(3-苯乙基-1H-吡唑-5-基)-N’-丙基脲;N-(3-苯乙基-1H-吡唑-5-基)-N’-(4-羟基丁基)脲;N-(3-苯乙基-1H-吡唑-5-基)-4-[2-硝基-4-(三氟甲基)苯基]-1-哌嗪甲酰胺;N-(3-环丙基-1H-吡唑-5-基)-N’-丁基脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(2,4-二甲基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3,4-二甲氧基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3-羧基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(2,3-二甲基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3-羧基-4-氯苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3,5-二甲基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3-甲酰氨基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3-羧基-4-羟基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(2,6-二甲基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(4-氰基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3-乙酰基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(1H-苯并咪唑-6-基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(4-羟基-3-甲氧基苄基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-苄基脲;N-(3-环丙基-1H-吡唑-5-基)-N’-{3-[3-(二甲基氨基)-1-丙炔基]苯基}脲;N-[3-({[(3-环丙基-1H-吡唑-5-基)氨基]羰基}氨基)苯基]甲磺酰胺;2-[3-({[(3-环丙基-1H-吡唑-5-基)氨基]羰基}氨基)苯氨基]乙酰胺;N-(3-环丙基-1H-吡唑-5-基)-N’-(2-羟基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-[3-(3-羟基-1-丁炔基)苯基]脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(1H-吲哚-6-基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(1H-吲哚-5-基)脲;4-({[(3-环丙基-1H-吡唑-5-基)氨基]羰基}氨基)苯磺酰胺;N-(3-环丙基-1H-吡唑-5-基)-N’-(3-甲氧基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-苯基脲;N-[4-({[(3-环丙基-1H-吡唑-5-基)氨基]羰基}氨基)苯基]-N-甲基乙酰胺;N-(2-{[环己基(甲基)氨基]甲基}苯基)-N’-(3-环丙基-1H-吡唑-5-基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(2-甲氧基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(2-氯苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3-乙炔基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(4-氨基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3-羟基-4-甲基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-3-氧代-3,4-二氢-1(2H)-喹喔啉甲酰胺;N-(3-环丙基-1H-吡唑-5-基)-3,4-二氢-2(1H)-异喹啉甲酰胺;N-(3-环丙基-1H-吡唑-5-基)-N’-(4-吡啶基甲基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(2-呋喃基甲基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(1,3-苯并噻唑-5-基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(1,3-二甲基-1H-吡唑-5-基)脲;N-[5-({[(3-环丙基-1H-吡唑-5-基)氨基]羰基}氨基)-2-甲氧基苯基]乙酰胺;N-[3-({[(3-环丙基-1H-吡唑-5-基)氨基]羰基}氨基)-4-甲氧基苯基]乙酰胺;N-(3-环丙基-1H-吡唑-5-基)-N’-(3-氨基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(1H-咪唑-6-基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(3-羟基苯基)脲;N-(3-环丙基-1H-吡唑-5-基)-N’-(4-羟基苯基)脲,及其可药用盐。
22.制备权利要求15所述的3-脲基-吡唑衍生物或其可药用盐的方法,该方法包括:
其中R如权利要求15所定义;
(d)将式(VI)所示的化合物与式(VII)所示的化合物反应:
R1R2NH (VII)
其中R、R1和R2如权利要求15所定义;
(e)将式(VIII)所示的化合物在酸性介质中水解生成式(I)所示的化合物;以及,选择性地将式(I)所示的3-脲基-吡唑衍生物转化成式(I)所示的另一种衍生物和/或转化成它的盐。
23.药物组合物,该组合物含有权利要求15的3-脲基-吡唑衍生物和至少一种可药用载体和/或稀释剂。
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- 2000-08-11 KR KR1020027001815A patent/KR20020060158A/ko not_active Application Discontinuation
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Also Published As
Publication number | Publication date |
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JP2003507328A (ja) | 2003-02-25 |
EP1202734A4 (en) | 2004-09-01 |
ES2284518T3 (es) | 2007-11-16 |
ATE361070T1 (de) | 2007-05-15 |
HK1049790A1 (zh) | 2003-05-30 |
BR0013277A (pt) | 2002-06-18 |
NO20020687L (no) | 2002-04-03 |
EA200200249A1 (ru) | 2002-08-29 |
DE60034683D1 (de) | 2007-06-14 |
PL354058A1 (en) | 2003-12-15 |
EP1202734A1 (en) | 2002-05-08 |
ZA200201118B (en) | 2003-05-28 |
PE20010482A1 (es) | 2001-04-20 |
CA2380786A1 (en) | 2001-02-22 |
NZ517238A (en) | 2004-01-30 |
MXPA02001497A (es) | 2003-07-21 |
WO2001012188A1 (en) | 2001-02-22 |
NO20020687D0 (no) | 2002-02-11 |
US6387900B1 (en) | 2002-05-14 |
KR20020060158A (ko) | 2002-07-16 |
SK2082002A3 (en) | 2002-09-10 |
CO5200848A1 (es) | 2002-09-27 |
DE60034683T2 (de) | 2008-01-17 |
AU6747000A (en) | 2001-03-13 |
IL147925A0 (en) | 2002-08-14 |
AR035557A1 (es) | 2004-06-16 |
HUP0301857A2 (hu) | 2003-09-29 |
EP1202734B1 (en) | 2007-05-02 |
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