CN100500663C - 作为抗增殖化合物的n-(4-(4-甲基噻唑-5-基)嘧啶-2-基)-n-苯胺 - Google Patents
作为抗增殖化合物的n-(4-(4-甲基噻唑-5-基)嘧啶-2-基)-n-苯胺 Download PDFInfo
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- CN100500663C CN100500663C CNB028187296A CN02818729A CN100500663C CN 100500663 C CN100500663 C CN 100500663C CN B028187296 A CNB028187296 A CN B028187296A CN 02818729 A CN02818729 A CN 02818729A CN 100500663 C CN100500663 C CN 100500663C
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- pyrimidine
- methyl
- phenyl
- thiazole
- amino
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Abstract
本发明涉及2-取代的4-杂芳基-嘧啶,还涉及它们的制备方法、含有它们的药物组合物和它们作为细胞周期蛋白依赖性激酶(CDK)抑制剂的用途,并因此也涉及它们在治疗诸如癌、白血病和牛皮癣等增殖性疾病中的用途。
Description
本发明涉及2-取代的4-杂芳基-嘧啶、它们的制备方法、含有它们的药物组合物及它们在治疗诸如癌、白血病和牛皮癣等增殖性疾病中的用途。
现有技术的介绍和概述
在EP-A-233,461中公开了某些具有抗哮喘性能的4,5,6-取代的-N-(取代的苯基)-2-嘧啶胺。在WO95/09847中公开了某些4-杂芳基-N-(3-取代的苯基)-2-嘧啶胺,这类化合物具有抗增殖性能并抑制蛋白激酶C、与表皮生长因子受体有关的酪氨酸蛋白激酶(EGF-R-TPK)和CDK1/细胞周期蛋白B,其中,列举的杂芳基是吡啶基和吲哚基。
Paul,R.等人在J.Med.Chem.(1993)Vol.36,p.2716-2725中公开了另一类具有抗炎活性的苯基氨基嘧啶。所述化合物包括在嘧啶环4-位上的单取代的2-噻吩基和在该位置上的二甲基-3-呋喃基。
PCT/GB01/01423公开了许多2-取代的4-杂芳基-嘧啶,这类化合物能抑制细胞周期蛋白依赖性激酶(CDK),并用于治疗诸如癌、白血病和牛皮癣等增殖性疾病。
本发明的目的是提供另一类N-苯基-2-嘧啶抗增殖化合物。出人意料地发现,本发明化合物不是蛋白激酶C抑制剂。正如下文所讨论的那样,通过抑制细胞系中的细胞增殖和/或抑制细胞周期蛋白依赖性激酶可以证明本发明化合物的活性。
发明概述
第一方面,本发明涉及选自下述化合物:
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-硝基-苯基)-胺[1];
N-[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-N′,N-二甲基-苯-1,4-二胺[2];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-氯-苯基)-胺[3];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-甲氧基-苯基)-胺[4];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-氟-苯基)-胺[5];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-三氟甲基-苯基)-胺[7];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-甲氧基-苯基)-胺[8];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-氯-苯基)-胺[9];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-碘-苯基)-胺[10];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-碘-苯基)-胺[11];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-氟-苯基)-胺[12];
3-[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基氨基]-苯酚[13];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-碘-3-;硝基-苯基)-胺[14];
2-{4-[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基氨基]-苯基}-乙醇[15];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-溴-苯基)-胺[16];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-溴-苯基)-胺[17];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-氯-3-三氟甲基-苯基)-胺[18];
N1-[4-(2,4-二甲基-噻唑-5-基)-嘧啶-2-基]-4-[β-(苯氧基)-三乙基胺]-胺[20];
2-{4-[4-(2,4-二甲基-噻唑-5-基)-嘧啶-2-基氨基]-苯基}-乙醇[21];
2-({4-[4-(2,4-二甲基-噻唑-5-基)-嘧啶-2-基氨基]-苯基}-乙基-氨基)-乙醇[22];
(3,4-二甲氧基-苯基)-[4-(2,4-二甲基-噻唑-5-基)-嘧啶-2-基]-胺[23];
5-[4-(2,4-二甲基-噻唑-5-基)-嘧啶-2-基氨基]-2-甲氧基-苯酚[24];
N4-[4-(2,4-二甲基-噻唑-5-基)-嘧啶-2-基]-N1,N1-二甲基-2-硝基-苯-1,4-二胺[25];
2-[N-(4-N,N-二甲基氨基-3-氯-苯基)]-4-(2,4-二甲基噻唑-5-基)嘧啶胺[26];
N4-[4-(2,4-二甲基-噻唑-5-基)-嘧啶-2-基]-N1,N1-二甲基-2-三氟甲基-苯-1,4-二胺[27];
N1-[4-(2,4-二甲基-噻唑-5-基)-嘧啶-2-基]-4-甲氧基-N3,N3-二甲基-苯-1,3-二胺[28];
N,N-二甲基-N′-[4-(4-甲基-2-甲基氨基-噻唑-5-基)-嘧啶-2-基]-苯-1,4-二胺[29];
(4-碘-3-硝基-苯基)-[4-(4-甲基-2-甲基氨基-噻唑-5-基)-嘧啶-2-基]胺[30];
4-[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基氨基]-苯酚[31];
[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-硝基-苯基)-胺[32];
(4-碘-苯基)-[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-胺[33];
(4-氟-苯基)-[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-胺[34];
(4-氯-苯基)-[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-胺[35];
[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-甲氧基-苯基)-胺[36];
3-[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基氨基]-苯酚[37];
(4-氟-3-硝基-苯基)-[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-胺[38];
(4-氯-3-甲基-苯基)-[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-胺[39];
(3-碘-4-甲基-苯基)-[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-胺[40];
(4-氟-3-甲基-苯基)-[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-胺[41];
[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-甲基-3-硝基-苯基)-胺[42];
N-[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-N′,N′-二甲基-苯-1,4-二胺[43];
[4-(2-乙基氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-硝基-苯基)-胺[44];
(4-氯-苯基)-[4-(2-乙基氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-胺[45];
[4-(2-乙基氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-三氟甲基-苯基)-胺[47];
[4-(2-乙基氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-甲氧基-苯基)-胺[48];
(3-氯-苯基)-[4-(2-乙基氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-胺[49];
[4-(2-乙基氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-甲基-3-硝基-苯基)胺[50];
[4-(2-丁基氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-氟-苯基)-胺[51];
[4-(2-二甲基氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-硝基-苯基)-胺[52];
(4-氯-苯基)-[4-(2-二甲基氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-胺[53];
[4-(2-二甲基氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-氟-苯基)-胺[54];
(3-氯-苯基)-[4-(2-二甲基氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-胺[55];
N-{4-甲基-5-[2-(3-硝基-苯基氨基)-嘧啶-4-基]-噻唑-2-基}-甲磺酰胺[56];
2-{4-甲基-5-[2-(3-硝基-苯基氨基)-嘧啶-4-基]-噻唑-2-基氨基}-乙醇[58];
2-{5-[2-(4-氟-苯基氨基)-嘧啶-4-基]-4-甲基-噻唑-2-基氨基}-乙醇[59];
2-氯-N-{4-甲基-5-[2-(3-硝基-苯基氨基)-嘧啶-4-基]-噻唑-2-基}-乙酰胺[60];
2-氯-N-{5-[2-(4-氟-苯基氨基)-嘧啶-4-基]-4-甲基-噻唑-2-基}-乙酰胺[61];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-硝基-苯基)-胺[63];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(苯基)-胺[64];
4-[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-苯磺酸[65];和
4-[4-(2,4-二甲基-噻唑-5-基)-嘧啶-2-基氨基]-苯磺酸[66]。
第二方面,本发明涉及选自下述化合物:
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-硝基-苯基)-胺[1];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-三氟甲基-苯基)-胺[7];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-甲氧基-苯基)-胺[8];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-氯-苯基)-胺[9];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-碘-苯基)-胺[10];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-碘-苯基)-胺[11];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-氟-苯基)-胺[12];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-溴-苯基)-胺[16];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-溴-苯基)-胺[17];
N-{4-甲基-5-[2-(3-硝基-苯基氨基)-嘧啶-4-基]-噻唑-2-基}-甲磺酰胺[56];
2-{4-甲基-5-[2-(3-硝基-苯基氨基)-嘧啶-4-基]-噻唑-2-基氨基}-乙醇[58];
2-{5-[2-(4-氟-苯基氨基)-嘧啶-4-基]-4-甲基-噻唑-2-基氨基}-乙醇[59];
2-氯-N-{4-甲基-5-[2-(3-硝基-苯基氨基)-嘧啶-4-基]-噻唑-2-基}-乙酰胺[60];
2-氯-N-{5-[2-(4-氟-苯基氨基)-嘧啶-4-基]-4-甲基-噻唑-2-基}-乙酰胺[61];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-硝基-苯基)-胺[63];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(苯基)-胺[64];
4-[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-苯磺酸[65];和
4-[4-(2,4-二甲基-噻唑-5-基)-嘧啶-2-基氨基]-苯磺酸[66]。
第三方面,本发明提供了含有一种或多种所述化合物以及可药用载体、赋形剂或稀释剂的药物组合物。
另一方面,本发明涉及一种或多种所述化合物在治疗增殖性疾病中的用途。
发明详述
在本发明第一方面的优选实施方案中,所述化合物选自下述化合物:
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-硝基-苯基)-胺[1];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-氯-苯基)-胺[9];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-碘-苯基)-胺[10];
3-[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基氨基]-苯酚[13];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-碘-3-硝基-苯基)-胺[14];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-溴-苯基)-胺[16];
(3,4-二甲氧基-苯基)-[4-(2,4-二甲基-噻唑-5-基)-嘧啶-2-基]-胺[23];
N4-[4-(2,4-二甲基-噻唑-5-基)-嘧啶-2-基]-N1,N1-二甲基-2-硝基-苯-1,4-二胺[25];
2-[N-(4-N,N-二甲基氨基-3-氯-苯基)]-4-(2,4-二甲基噻唑-5-基)嘧啶胺[26];
N,N-二甲基-N′-[4-(4-甲基-2-甲基氨基-噻唑-5-基)-嘧啶-2-基]-苯-1,4-二胺[29];
4-[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基氨基]-苯酚[31];
[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-硝基-苯基)-胺[32];
(4-氟-苯基)-[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-胺[34];
[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-甲基-3-硝基-苯基)-胺[42];
N-{4-甲基-5-[2-(3-硝基-苯基氨基)-嘧啶-4-基]-噻唑-2-基}-甲磺酰胺[56];
2-{4-甲基-5-[2-(3-硝基-苯基氨基)-嘧啶-4-基]-噻唑-2-基氨基}-乙醇[58];
2-氯-N-{4-甲基-5-[2-(3-硝基-苯基氨基)-嘧啶-4-基]-噻唑-2-基}-乙酰胺[60];和
2-氯-N-{5-[2-(4-氟-苯基氨基)-嘧啶-4-基]-4-甲基-噻唑-2-基}-乙酰胺[61]。
在本发明第一方面的更优选实施方案中,所述化合物选自:
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-硝基-苯基)-胺[1];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-氯-苯基)-胺[9];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-碘-苯基)-胺[10];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-溴-苯基)-胺[16];
N4-[4-(2,4-二甲基-噻唑-5-基)-嘧啶-2-基]-N1,N1-二甲基-2-硝基-苯-1,4-二胺[25];
2-[N-(4-N,N-二甲基氨基-3-氯-苯基)]-4-(2,4-二甲基噻唑-5-基)嘧啶胺[26];
4-[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基氨基]-苯酚[31];
[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-硝基-苯基)-胺[32];
N-{4-甲基-5-[2-(3-硝基-苯基氨基)-嘧啶-4-基]-噻唑-2-基}-甲磺酰胺[56];和
2-{4-甲基-5-[2-(3-硝基-苯基氨基)-嘧啶-4-基]-噻唑-2-基氨基}-乙醇[58]。
在本发明第一方面的另一个优选实施方案中,所述化合物选自下述化合物:
3-[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基氨基]-苯酚[13];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-碘-3-硝基-苯基)-胺[14];
(3,4-二甲氧基-苯基)-[4-(2,4-二甲基-噻唑-5-基)-嘧啶-2-基]-胺[23];
N,N-二甲基-N′-[4-(4-甲基-2-甲基氨基-噻唑-5-基)-嘧啶-2-基]-苯-1,4-二胺[29];
(4-氟-苯基)-[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-胺[34];
[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-甲基-3-硝基-苯基)-胺[42];
2-氯-N-{4-甲基-5-[2-(3-硝基-苯基氨基)-嘧啶-4-基]-噻唑-2-基}-乙酰胺[60];和
2-氯-N-{5-[2-(4-氟-苯基氨基)-嘧啶-4-基]-4-甲基-噻唑-2-基}-乙酰胺[61]。
在本发明第一方面的特别优选实施方案中,所述化合物是[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-硝基-苯基)-胺[32]或2-{4-甲基-5-[2-(3-硝基-苯基氨基)-嘧啶-4-基]-噻唑-2-基氨基}-乙醇[58]。
在本发明第二方面的优选实施方案中,所述化合物选自下述化合物:
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-硝基-苯基)-胺[1];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-氯-苯基)-胺[9];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-碘-苯基)-胺[10];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-溴-苯基)-胺[16];
N-{4-甲基-5-[2-(3-硝基-苯基氨基)-嘧啶-4-基]-噻唑-2-基}-甲磺酰胺[56];
2-{4-甲基-5-[2-(3-硝基-苯基氨基)-嘧啶-4-基]-噻唑-2-基氨基}-乙醇[58];
2-氯-N-{4-甲基-5-[2-(3-硝基-苯基氨基)-嘧啶-4-基]-噻唑-2-基}-乙酰胺[60];和
2-氯-N-{5-[2-(4-氟-苯基氨基)-嘧啶-4-基]-4-甲基-噻唑-2-基}-乙酰胺[61]。
在本发明第二方面的更优选实施方案中,所述化合物选自:
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-硝基-苯基)-胺[1];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-氯-苯基)-胺[9];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-碘-苯基)-胺[10];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-溴-苯基)-胺[16];
N-{4-甲基-5-[2-(3-硝基-苯基氨基)-嘧啶-4-基]-噻唑-2-基}-甲磺酰胺[56];和
2-{4-甲基-5-[2-(3-硝基-苯基氨基)-嘧啶-4-基]-噻唑-2-基氨基}-乙醇[58]。
在本发明第二方面的更进一步优选实施方案中,所述化合物选自下述化合物:
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-硝基-苯基)-胺[1];
N-{4-甲基-5-[2-(3-硝基-苯基氨基)-嘧啶-4-基]-噻唑-2-基}-甲磺酰胺[56];和
2-{4-甲基-5-[2-(3-硝基-苯基氨基)-嘧啶-4-基]-噻唑-2-基氨基}-乙醇[58]。
在本发明第二方面的另一个优选实施方案中,所述化合物选自下述化合物:
2-氯-N-{4-甲基-5-[2-(3-硝基-苯基氨基)-嘧啶-4-基]-噻唑-2-基}-乙酰胺[60];和
2-氯-N-{5-[2-(4-氟-苯基氨基)-嘧啶-4-基]-4-甲基-噻唑-2-基}-乙酰胺[61]。
在本发明第二方面的特别优选实施方案中,所述化合物是[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-硝基-苯基)-胺[1]。
现已发现,本发明化合物具有抗增殖活性,因此,本发明化合物被认为可用于治疗增殖性疾病,如癌、白血病和与未受控制的细胞增殖有关的其它疾病,如牛皮癣和再狭窄。正如本发明限定的,通过体外全细胞测定,例如,使用A549、HT29、Saos-2、HeLa或MCF-7中的任一细胞系,测定抑制细胞增殖的能力,或者,通过适当的测定显示对CDK酶(例如,CDK2或CDK4)的抑制作用,可以证实本发明化合物的抗增殖效果。在随后的实施例中更详细地描述了这些测定方法,包括测定其性能的方法。使用所述的细胞系测定和酶测定,可以确定本发明化合物是否具有抗增殖活性。
不希望受到理论上的限制,但认为本发明化合物是以非蛋白激酶C(PKC)依赖性的方式发挥其抗增殖作用。本发明的多种化合物能抑制与细胞周期控制有关的细胞周期蛋白依赖性激酶(CDK)。所述CDK包括CDK2和CDK4以及特别是它们分别与细胞周期蛋白E和细胞周期蛋白D1之间的相互作用。本发明的这些化合物还被认为具有对增殖性疾病中涉及的CDK酶具有选择性的优点。术语“选择性”是指:尽管本发明化合物对其它酶(例如,PKC)可能具有某些抑制作用,但优选对增殖性疾病中涉及的酶具有抑制作用。
本发明化合物可抑制细胞周期中的任何步骤或阶段,例如,核被膜的形成、退出细胞周期休止期(G0)、G1期、染色体解凝集、核被膜崩解、START、DNA复制的引发、DNA复制期、DNA复制的终止、中心体复制、G2期、有丝分裂或减数分裂功能的活化、染色体凝集、中心体分离、微管成核、纺锤体形成和功能产生、与微管动力蛋白的相互作用、染色单体的分离和隔离、有丝分裂功能的灭活、收缩环的形成和胞质分裂功能。本发明化合物尤其可影响某些基因功能,例如,染色质结合、复制复合体的形成、复制许可、磷酸化或其它二级修饰活性、蛋白水解降解、微管结合、肌动蛋白结合、septin结合、微管组织中心成核活性以及结合细胞周期信号通路的组分。
因此,本发明的一个实施方案涉及一种或多种本发明化合物在治疗增殖性疾病中的用途。所述增殖性疾病优选是癌或白血病。术语增殖性疾病是广义词,包括任何一种需要控制细胞周期的疾病,例如,诸如再狭窄和心肌病的心血管疾病,诸如肾小球性肾炎和类风湿性关节炎的自身免疫疾病,诸如牛皮癣的皮肤病,诸如痢疾、气肿和脱发的抗炎、抗真菌、抗寄生物疾病。在上述疾病中,本发明化合物可根据需要在所需细胞内诱导编程性细胞凋亡或维持停滞。
在一个特别优选的实施方案中,本发明涉及一种或多种本发明化合物在治疗CDK依赖性或敏感性疾病中的用途。CDK依赖性疾病与上述一种或多种CDK酶活性高于正常水平有关。所述疾病优选与CDK2和/或CDK4活性的非正常水平有关。CDK敏感性疾病是这样一种疾病,其主要病因不在于CDK水平异常,而在于初级代谢失常的下游。在这种情况下,可认为CDK2和/或CDK4是敏感性代谢途径的一部分,因此,CDK抑制剂可具有治疗上述疾病的活性。所述疾病优选是癌和白血病。
本发明的第三方面涉及一种或多种本发明化合物和其可药用盐在制备用于治疗增殖性疾病的药物中的用途。
术语“增殖性疾病”已在上文讨论,并且同样的定义也适用于本发明的第二方面。
在一个特别优选的实施方案中,将一种或多种本发明化合物与一种或多种其它抗癌剂组合给药。在这种情况下,本发明化合物可以与一种或多种其它抗癌剂连续、同时或依次给药。
本发明使用的短语“药物的制备”除了包括本发明化合物用于其它抗增殖性药剂的筛选程序或用于制备所述药物的任一阶段外,还包括本发明化合物直接用作药物。
本发明化合物可以盐或酯的形式存在,尤其可以可药用盐或酯的形式存在。
本发明化合物的可药用盐包括其合适的酸加成盐或碱盐。关于合适的可用药盐的综述可参见Berge等人,J Pharm Sci,66,1-99(1977)。例如,与强无机酸(例如,诸如硫酸、磷酸或氢卤酸的无机酸)形成的盐;与强有机羧酸(例如,未取代的或取代(例如,被卤素取代)的1-4个碳原子的链烷羧酸,如乙酸)形成的盐;与饱和或不饱和的二羧酸(例如,草酸、丙二酸、丁二酸、马来酸、富马酸、邻苯二甲酸或对苯二甲酸(tetraphthalic acid))形成的盐;与诸如抗坏血酸、乙醇酸、乳酸、苹果酸、酒石酸或柠檬酸的羟基羧酸形成的盐;与诸如天冬氨酸或谷氨酸的氨基酸形成的盐;与苯甲酸形成的盐;与有机磺酸(例如,未取代的或取代(例如,被卤素取代)的(C1-C4)-烷基或芳基磺酸,如甲磺酸或对甲苯磺酸)形成的盐。
根据被酯化的官能团,酯是用有机酸或用醇/氢氧化物形成的酯。有机酸包括羧酸,例如,未取代的或取代(例如,被卤素取代)的1-12个碳原子的链烷羧酸,如乙酸;饱和或不饱和的二羧酸,例如,草酸、丙二酸、丁二酸、马来酸、富马酸、邻苯二甲酸或均苯四酸(tetraphthalic acid);诸如抗坏血酸、乙醇酸、乳酸、苹果酸、酒石酸或柠檬酸的羟基羧酸;诸如天冬氨酸或谷氨酸的氨基酸;苯甲酸;或有机磺酸,如未取代的或取代(例如,被卤素取代)的(C1-C4)-烷基或芳基磺酸,例如,甲磺酸或对甲苯磺酸。合适的氢氧化物包括无机氢氧化物,例如,氢氧化钾、氢氧化钠、氢氧化钙、氢氧化铝。醇包括未取代的或取代(例如,被卤素取代)的1-12个碳原子的链烷醇。
在上文讨论的本发明的所有方面中,在适当情况下,本发明包括本发明化合物的所有对映异构体和互变异构体。本领域熟练技术人员能够识别具有旋光特性(一个或多个手性碳原子)或互变异构特征的化合物。采用本领域的已知方法可以分离/制得相应的对映异构体和/或互变异构体。
本发明还涉及以各种晶形、多晶型和无水或含水形式存在的本发明化合物或其用途。在所述化合物的合成制备中,对从所用溶剂中提纯和/或分离的方法稍加改变,可以分离出上述任意一种形式的化合物,在制药工业中已完善地建立了这种方法。
本发明还包括前药形式的本发明化合物或其用途。所述前药一般是一个或多个合适基团被修饰的本发明化合物,并且这种修饰在一经对人类和哺乳动物患者给药后可以发生逆转。这种逆转通常是通过天然存在于患者体内的酶来进行,当然也可以将所述前药与另一种药剂一起给药以实现体内逆转。所述修饰的实例包括酯(例如,上述任一种酯),其中上述逆转可以通过酯酶等进行。其它的这种体系对本领域技术人员而言是众所周知的。
本发明还包括含有本发明化合物的药物组合物。就此而言,尤其是对于人类治疗而言,即使本发明化合物(包括其可药用盐、酯和可药用溶剂化物)能被单独给药,但通常也总是与根据预期给药途径和标准用药方法选择的药用载体、赋形剂或稀释剂混合给药。
因此,本发明还涉及含有一种或多种本发明化合物或其可药用盐或酯和至少一种可药用赋形剂、稀释剂或载体的药物组合物。
作为例子,在本发明药物组合物中,本发明化合物可以与任何合适的粘合剂、润滑剂、悬浮剂、包衣剂和/或增溶剂混合。用于本发明的各种不同剂型药物组合物的合适赋形剂的实例可参见“Handbook of PharmaceuticalExcipients”,2nd Edition,(1994),Edited by A Wade and PJ Weller。
本发明药物组合物可经口服、直肠、阴道、肠胃外、肌内、腹膜内、动脉内、鞘内、支气管内、皮下、皮内、静脉内、鼻、口含或舌下的途径给药。
对于口服给药,特别使用的是压制片剂、丸剂、片剂、凝胶、滴剂或胶囊。所述组合物优选每剂含有1-250mg活性组分,更优选每剂含有10-100mg活性组分。
其它给药剂型包括可通过静脉内、动脉内、鞘内、皮下、皮内、腹膜内或肌内注射给药的溶液或乳剂,所述溶液或乳剂可由无菌或灭菌溶液制得。本发明药物组合物还可是栓剂、阴道栓、悬浮剂、乳剂、洗剂、软膏、霜剂、凝胶、喷雾剂、溶液或粉剂。
另一种透皮给药方式是使用皮肤贴剂。例如,可将活性组分掺入到由聚乙二醇或液体石蜡的水乳状液组成的乳膏中。也可以将活性组分以1-10重量%的浓度掺入到由白蜡或白软石蜡基质与可能需要的稳定剂和防腐剂组成的软膏中。
注射剂每剂可含有10-1000mg活性组分,优选每剂含有10-250mg活性组分。
本发明组合物可配制成单位剂型,即,含有单位剂量或含有多单位剂量或亚单位剂量的离散份额的形式。
无需进行过多的实验,本领域熟练技术人员能容易地确定向患者给药本发明中一种组合物的合适剂量的。一般,主治医师会确定对个体患者最适合的实际剂量,且该剂量随具体患者的年龄、体重和反应的不同而变化。本发明公开的剂量是典型的病例平均值。对于个别情况当然要考虑更高或更低剂量,这些也应当属于本发明范围之内。
在一个示范性的实施方案中,对治疗癌的患者每天给药一剂或多剂10-150mg剂量。
本发明药物组合物还可含有一种或多种其它抗癌剂,例如,现有的市售抗癌药物。
组合使用抗癌药物通常会更有效。特别是,为了避免严重毒性、作用机理和抗性机理的叠加,需要采用组合疗法。而且,最好是在所述剂量之间的最短时间间隔内以最大耐受剂量给药大多数药物。组合化疗药物的主要优点是通过生化相互作用可促进相加的或可能的协同效应,还可以降低早期肿瘤细胞中出现耐药性,而这些早期肿瘤细胞对用单一药物的初期化疗已有了别样的反应。在选择药物组合中,利用生物化学相互作用的实例是通过给药亚叶酸来提高5-氟脲嘧啶的活性胞内代谢物与其靶(即,胸苷酸合成酶)的结合能力,从而提高其细胞毒性作用。
目前,许多组合用药被用于治疗癌和白血病。有关医疗实践的更全面综述可参见“Oncologic Therapies”,edited by E.E.Vokes and H.M.Golomb,published by Springer。
在某种特定的早期癌症或由这种癌症衍生的细胞系的治疗中,通过对试验化合物和已知的或预期有效的药物一起产生的生长抑制活性进行研究,可提出一些有效的组合用药方法。该方法也可用于确定药物的给药顺序,即,在给药本发明化合物之前、同时或之后给药。这种时间表的制定可以是本发明确定的所有循环作用药物的一个特点。
可以与至少一种本发明化合物组合使用的合适的抗增殖性药物包括DNA损伤剂、抗代谢药、抗肿瘤抗生素、天然产物及其类似物、二氢叶酸还原酶抑制剂、嘧啶类似物、嘌呤类似物、细胞周期蛋白依赖性激酶抑制剂、胸苷酸合成酶抑制剂、DNA嵌入剂、DNA裂解剂、拓扑异构酶抑制剂、蒽环类抗生素、长春花属药物、丝裂霉素、博来霉素、细胞毒性核苷、喋啶类药物、diynenes、足叶草毒素、含铂药物、分化诱发剂和紫杉碱(taxans)。这类药物中特别有用的药物包括,例如,氨甲喋呤、甲喋呤、二氯氨甲喋呤、5-氟脲嘧啶、6-巯基嘌呤、诸如olomoucine、roscovitine、bohemine和Purvalanol的三取代嘌呤、Flavopiridol、星形孢素菌、阿糖胞苷、苯丙氨酸氮芥、环氧长春碱、放线菌素、柔红霉素、阿霉素、丝裂霉素D、丝裂霉素A、Carninomycin、氨基喋呤、太利苏霉素、足叶草毒素(及其衍生物)、依托泊甙、顺铂、卡铂、长春花碱、长春新碱、长春碱酰胺、紫杉酚、多西他赛、泰索帝视黄酸、丁酸、乙酰精脒、它莫昔芬、伊立替康和喜树碱。最优选的药物选自氨甲喋呤、足叶草毒素(及其衍生物)、依托泊甙、喜树碱、紫杉酚、阿霉素、roscovitine和bohemine。
作为例子,本发明化合物可通过下述反应图解1所示的路线合成:
反应图解1
正如反应图解中说明的那样,通过杂环甲基酮1与二甲基甲酰胺二甲基缩醛缩合,制得丙烯酸酯2。
胍3(反应图解2)可通过本领域的许多已知方法合成。
对本发明来说,最有效的路线是用苯胺5胺化氨腈4。
反应图解2
通过实施例并参照附图1进一步描述本发明,其中附图1表示本发明化合物的化学结构。
实施例
缩略语
DE MALDI-TOF MS,延迟提取基体辅助激光解吸电离飞行时间质谱法;DMF,N,N-二甲基甲酰胺;NMR,核磁共振波谱;RP-HPLC,反相高效液相色谱;r.t.,室温;PE,石油醚(40-60℃沸点馏分);DMSO,二甲亚砜。
一般方法
用Varian INOVA 500MHz仪记录NMR谱。化学位移用与四甲基硅烷峰之间的距离表示,单位为ppm(δ)。硅胶60(0.040-0.063mM)用于柱色谱法。
实施例1
[4-(2-氨基-4-甲基-噻唑-5基)-嘧啶-2-基]-(3-硝基-苯基)-胺[1]
搅拌在无水MeOH(20mL)中的硫脲(5.18g,0.068mol)混合物,并在冰浴冷却。加入吡啶(2mL),然后滴加3-氯-2,4-戊二酮(9.15g,0.068mol)。滴加完毕后,使反应混合物升至室温,并连续搅拌4小时。滤出沉淀,用EtOAc洗涤,得到白色固体1-(2-氨基-4-甲基-噻唑-5-基)-乙酮。
在N2气氛下,将该原料(3.35g,0.021mol)的N,N-二甲基甲酰胺二甲基缩醛(10mL)溶液回流4-6小时。蒸发反应混合物至干。向残余物中加入EtOAc,过滤收集沉淀,并用EtOAc/PE(5:1,v/v)洗涤,得到橙色固体N’-[5-(3-二甲基氨基-丙烯酰基)-4-甲基-噻唑-2-基]-N,N-二甲基-甲脒(50-79%)。1H-NMR(CDCl3)δ:2.64(s,3H,CH3),3.08(s,6H,CH3),3.11(s,6H,CH3),5.35(d,1H,J=12.2Hz,CH),7.67(d,1H,J=12.2Hz,CH),8.23(s,1H,N=CH)。DE MALDI-TOFMS:[M+H]+=267.49(C12H18N6OS计算值266.36)。
用NaOH(0.33g)处理该物料(2.19g,8.2mmol)与3-硝基-苯基胍硝酸盐(2.00g,8.2mmol)在2-甲氧基乙醇(10mL)中的混合物。在N2气氛下回流20小时后,浓缩反应混合物,并用硅胶色谱提纯(用EtOAc/PE(7:1)进行洗脱),得到浅黄色固体目标化合物(1.95g,72%),然后将该化合物从EtOAc/MeOH中重结晶。1H-NMR(DMSO-d6)δ:3.13(s,3H,CH3),7.02(d,1H,J=5.5Hz,Py-H),7.59(m,4H,Ph-H和NH2),7.82(m,1H,Ph-H),8.16(m,1H,Ph-H),8.44(d,1H,J=5.5Hz,Py-H),8.86(br.s,1H,NH)。
实施例2
用类似于上述实施例1的方法制得下述化合物:
N-[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-N′,N′-二甲基-苯-1,4-二胺[2]
黄色固体;RP-HPLC分析:tR=9.83分钟(在0.1%三氟乙酸水溶液中的0-60%乙腈,20分钟,1mL/分钟,纯度>95%)。1H-NMR(CDCl3)δ:2.58(s,3H,CH3),3.28(s,6H,CH3),7.08(d,1H,J=5.5Hz,嘧啶基-H),7.56(m,2H,Ph-H),7.89(m,2H,Ph-H),8.45(d,1H,J=5.5Hz,嘧啶基-H)。MS(DE MALDI-TOF)m/z=326.0[M+H]+(C16H18N6S计算值326.4)。
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-氯-苯基)-胺[3]
棕色固体;1H-NMR(DMSO-d6)δ:2.42(s,3H,CH3),6.88(d,1H,J=5.0Hz,嘧啶基-H),7.28(m,2H,Ph-H),7.51(br.s,2H,NH2),7.77(m,2H,Ph-H),8.32(d,1H,J=5.1Hz,嘧啶基-H),9.56(br.s,1H,NH)。MS(DE MALDI-TOF)m/z=318.4[M+H]+(C14H12ClN5S计算值317.8)。
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-甲氧基-苯基)-胺[4]
浅黄色固体;1H-NMR(DMSO-d6)δ:2.41(s,3H,CH3),3.72(s,3H,CH3),6.50(m,1H,Ph-H),6.88(d,1H,J=5.5Hz,嘧啶基-H),7.14(t,1H,J=8.0Hz,Ph-H),7.30(m,1H,Ph-H),7.47(m,1H,嘧啶基-H),7.48(br.s,2H,NH2),8.31(d,1H,J=5.5Hz,嘧啶基-H),9.41(br.s,1H,NH)。
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-氟-苯基)-胺[5]
灰色固体;1H-NMR(DMSO-d6)δ:2.43(s,3H,CH3),6.71(m,1H,Ph-H),6.92(d,1H,J=5.5Hz,嘧啶基-H),7.27(m,1H,Ph-H),7.44(m,1H,Ph-H),7.557(br.s,2H,NH2),7.84(m,1H,Ph-H),8.35(d,1H,J=5.5Hz,嘧啶基-H),9.69(sr.1H,NH)。
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-三氟甲基-苯基)-胺[7]
棕色固体;1H-NMR(DMSO-d6)δ:2.44(s,3H,CH3),6.96(d,1H,J=5.0Hz,嘧啶基-H),7.53(br.s,2H,NH2),7.60(d,2H,J=9.0Hz,Ph-H),7.97(d,2H,J=8.5Hz,Ph-H),8.38(d,1H,J=5.0Hz,嘧啶基-H),9.86(br.s,H,NH)。MS(DEMALDI-TOF)m/z=352.0[M+H]+(C15H12F3N5S计算值351.4)。
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-甲氧基-苯基)-胺[8]
棕色固体;1H-NMR(DMSO-d6)δ:2.41(s,3H,CH3),3.71(s,3H,CH3),6.80(d,1H,J=5.5Hz,嘧啶基-H),6.84(m,2H,Ph-H),7.44(br.s,1H,NH),7.63(m,2H,Ph-H),8.26(d,1H,J=5.5Hz,嘧啶基-H)和9.20(br.s,H,NH)。MS(DE MALDI-TOF)m/z=312.9[M+H]+(C15H15N5OS计算值313.4)。
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-氯-苯基)-胺[9]
棕色固体;1H-NMR(DMSO-d6)δ:2.43(s,3H,CH3),6.91(d,1H,J=5.5Hz,嘧啶基-H),6.94(m,1H,Ph-H),7.26(m,1H,Ph-H),7.55(br.s 2H,NH2),7.64(m,1H,Ph-H),8.02(s,1H,Ph-H),8.34(d,1H,J=5.5Hz,嘧啶基-H),9.64(br.s,1H,NH)。
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-碘-苯基)-胺[10]
暗色固体;1H-NMR(DMSO-d6)δ:2.44(s,3H,CH3),6.90(d,1H,J=5.5Hz,嘧啶基-H),7.04(t,1H,J=7.5Hz,Ph-H),7.25(m,1H,Ph-H),7.51(br.s,2H,NH2),7.65(m,1H,Ph-H),8.26(s,1H,Ph-H),8.34(d,1H,J=5.5Hz,嘧啶基-H),9.64(br.s,1H,NH)。MS(DE MALDI-TOF)m/z=408.9(C14H12IN5S计算值409.3)。
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-碘-苯基)-胺[11]
黄色固体;1H-NMR(DMSO-d6)δ:2.48(s,3H,CH3),7.04(d,1H,J=5.5Hz,嘧啶基-H),7.59(s,2H,NH2),8.01(m,2H,Ph-H),8.17(m,2H,Ph-H),8.43(d,1H,J=5.5Hz,嘧啶基-H),10.27(br.s,1H,NH)。
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-氟-苯基)-胺[12]
灰色固体;1H-NMR(DMSO-d6)δ:2.42(s,3H,CH3),6.86(d,1H,J=5.5Hz,嘧啶基-H),7.08(m,2H,Ph-H),7.48(br.s,2H,NH2),7.74(m,2H,Ph-H),8.30(d,1H,J=5.5Hz,嘧啶基-H),8.50,9.42(br.s 1H,NH)。MS(DE MALDI-TOF)m/z=299.6[M+H]+(C14H12FN5S计算值301.3)。
3-[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基氨基]-苯酚[13]
暗棕色固体;1H-NMR(DMSO-d6)δ:2.41(s,3H,CH3),6.34(m,1H,Ph-H),6.84(d,1H,J=5.5Hz,嘧啶基-H),7.01(m,1H,Ph-H),7.19(s,1H,Ph-H),7.23(m,1H,Ph-H),7.48(br.s,2H,NH2),8.29(d,1H,J=5.5Hz,嘧啶基-H),9.26(br.s,2H,NH & OH)。
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-碘-3-硝基-苯基)-胺[14]
暗色固体;RP-HPLC分析:tR=15.5分钟(在0.1%三氟乙酸水溶液中的0-60%乙腈,20分钟,1mL/分钟,纯度>95%)。1H-NMR(DMSO-d6)δ:2.48(s,3H,CH3),6.92(d,1H,J=5.5Hz,嘧啶基-H),7.37(m,1H,Ph-H),7.82(m,1H,Ph-H),8.19(m,1H,Ph-H),8.36(d,1H,J=5.5Hz,嘧啶基-H),8.68(br.s,2H,NH2),9.86(br.s,1H,NH)。
2-{4-[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基氨基]-苯基}-乙醇[15]
浅黄色固体;RP-HPLC分析:tR=10.9分钟(在0.1%的三氟乙酸水溶液中的0-60%乙腈,20分钟,1mL/分钟,纯度>95%)。1H-NMR(DMSO-d6)δ:2.85(s,3H,CH3),3.04(t,2H,J=7.32Hz,CH2),3.94(t,2H,J=7.32Hz,CH2),7.35(d,1H,J=5.5Hz,嘧啶基-H),7.50(d,2H,J=8.5Hz,Ph-H),7.96(d,2H,J=8.5Hz,Ph-H),8.76(d,1H,J=5.5Hz,嘧啶基-H),8.68(br.s,2H,NH2),9.12(br.s,2H,NH和OH)。
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-溴-苯基)-胺[16]
黄色固体;1H-NMR(DMSO-d6)δ:2.44(s,3H,CH3),6.91(d,1H,J=5.4Hz,PyH),7.08(m,1H,Ph-H),7.20(m,1H,Ph-H),7.53(m,1H,Ph-H),7.68(m,1H,Ph-H),8.15(br.s,2H,NH2),8.35(d,1H,J=5.4Hz,嘧啶基-H),9.62(br.s 1H,NH)。MS(DE MALDI-TOF)m/z=362.2(C14H12BrN5S计算值362.3)。
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-溴-苯基)-胺[17]
棕色固体;1H-NMR(DMSO-d6)δ:2.43(s,3H,CH3),6.89(d,1H,J=5.5Hz,嘧啶基-H),7.42(m,2H,Ph-H),7.47(br.s,2H,NH2),7.73(m,2H,Ph-H),8.33(d,1H,J=5.5Hz,嘧啶基-H),9.57(br.s,1H,NH)。MS(DEMALDI-TOF)m/z=362.2(C14H12BrN5S计算值362.3)。
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-氯-3-三氟甲基-苯基)-胺[18]
棕色固体;1H-NMR(DMSO-d6)δ:2.43(s,3H,CH3),6.96(d,1H,J=5.6Hz,嘧啶基-H),7.76(m,2H,Ph-H/NH),8.00(m,1H,Ph-H),8.38(m,2H,Py-H/PhH),9.89(br.s,1H,NH)。MS(DE MALDI-TOF)m/z=388.8[M+H]+(C15H11ClF3N5S计算值385.8)。
实施例3
N-[4-(2,4-二甲基-噻唑-5-基)-嘧啶-2-基]-N′,N′-二甲基-苯-1,4-二胺[19]
在N2气氛下,回流1-(2,4-二甲基-噻唑-5-基)乙酮(10g,0.06mol)的N,N-二甲基甲酰胺二甲基缩醛(10mL)溶液。18小时后,真空蒸发反应混合物至干。将残余固体物料从最少量的异丙醚/CH2Cl2中结晶,得到9.94g棕色粉末状3-二甲基氨基-1-(2,4-二甲基-噻唑-5-基)-丙烯酮(79%)。1H-NMR(CDCl3)δ:2.66(s,6H,CH3),2.70(s,6H,CH3),5.37(d,1H,J=12.2Hz,CH),7.66(d,1H,J=12.2Hz,CH)。
将NaOH(80mg)加入到该化合物(0.21g,1.0mmol)和N-(4-二甲基氨基-苯基)胍硝酸盐(50mg)(由N,N-二甲基-苯-1,4-二胺和氨腈制得)的2-甲氧基乙醇(3mL)溶液中。回流反应混合物8小时。真空蒸发溶剂,用SiO2快速色谱法(EtOAc)提纯残余物,得到黄色固体2-[N-(4-N,N-二甲基氨基-苯基)]-4-(2,4-二甲基噻唑-5-基)-嘧啶胺[19](26mg,79%)。RP-HPLC分析:tR=11.2分钟(在0.1%的三氟乙酸水溶液中的0-60%乙腈,20分钟,1mL/分钟,纯度>95%)。1H-NMR(DMSO-d6)δ:2.60(s,3H,CH3),2.62(s,3H,CH3),2.82(s,6H,CH3),6.70(d,2H,J=8.8Hz,Ph-H),6.95(d,1H,J=5.3Hz,嘧啶基-H),7.53(d,2H,J=8.9Hz,Ph-H),8.40(d,1H,J=5.3Hz,嘧啶基-H),9.26(br.s,1H,NH)。MS(ESI+)m/z=326.2[M+H]+(C17H19N5S计算值325.4)。
实施例4
用类似于上述实施例3的方法制得下述化合物:
N1-[4-(2,4-二甲基-噻唑-5-基)-嘧啶-2-基]-4-[β-(苯氧基)-三乙基胺]胺[20]
浅黄色固体;1H-NMR(CD3OD)δ:1.11(t,6H,J=7.3Hz,CH3),2.66(s,3H,CH3),2.68(s,3H,CH3),2.70(q,4H,J=7.1Hz,CH2),2.93(t,2H,J=5.6Hz,CH2),4.10(t,2H,J=5.9Hz,CH2),6.91(d,2H,J=9.3Hz,Ph-H),6.99(d,1H,J=5.4Hz,嘧啶基-H),7.56(d,2H,J=9.3Hz,Ph-H),8.37(d,1H,J=5.1Hz,嘧啶基H)。MS(DEMALDI-TOF)m/z=397.2[M+H]+(C21H27N5OS计算值397.5)。
2-{4-[4-(2,4-二甲基-噻唑-5-基)-嘧啶-2-基氨基]-苯基}-乙醇[21]
浅黄色固体;RP-HPLC分析:tR=13.1分钟(在0.1%的三氟乙酸水溶液中的0-60%乙腈,20分钟,1mL/分钟,纯度>95%)。1H-NMR(DMSO-d6)δ:2.89(s,3H,CH3),3.07(m,2H,CH2),3.98(t,2H,J=7.5Hz,CH2),7.46(d,1H,J=5.5Hz,嘧啶基-H),7.55(d,2H,J=8.5Hz,Ph-H),8.06(d,2H,J=8.5Hz,Ph-H),8.90(d,1H,J=5.5Hz,嘧啶基-H)。MS(ESI+)m/z=326.7(C17H18N4OS计算值326.4)。
2-({4-[4-(2,4-二甲基-噻唑-5-基)-嘧啶-2-基氨基]-苯基}-乙基-氨基)乙醇[22]
黄色固体;1H-NMR(CDCl3)δ:1.08(t,3H,J=7.1Hz,CH3),2.61(s,3H,CH3),2.64(s,3H,CH3),3.34(q,2H,J=7.1Hz,CH2),3.46(br.s,1H,OH),6.36(t,2H,J=5.9Hz,CH2),6.70(t,2H,J=5.4Hz,CH2),6.76(d,2H,J=9.0Hz,Ph-H),6.79(d,1H,J=5.1Hz,嘧啶基-H),6.84(br.s,1H,NH),7.39(d,2H,J=9.0Hz,Ph-H),8.30(d,1H,J=5.1Hz,嘧啶基-H)。
(3,4-二甲氧基-苯基)-[4-(2,4-二甲基-噻唑-5-基)-嘧啶-2-基]-胺[23]
棕色固体;1H-NMR(CDCl3)δ:2.69(s,3H,CH3),2.70(s,3H,CH3),3.89(s,3H,CH3),3.95(s,3H,CH3),6.87(d,1H,J=8.5Hz,Ph-H),6.92(d,1H,J=5.1Hz,嘧啶基-H),7.04(dd,1H,J=8.5,2.2Hz,Ph-H),7.14(br.s,1H,NH),7.36(m,1H,Ph-H),8.38(d,1H,J=5.4Hz,嘧啶基-H)。
5-[4-(2,4-二甲基-噻唑-5-基)-嘧啶-2-基氨基]-2-甲氧基-苯酚[24]
黄色固体;1H-NMR(DMSO-d6)δ:2.61(s,3H,CH3),2.63(s,3H,CH3),3.72(s,3H,CH3),6.83(d,1H,J=8.8Hz,Ph-H),6.99(d,1H,J=5.4Hz,嘧啶基-H),7.15-7.19(m,2H,Ph-H,NH),8.44(d,1H,J=5.6Hz,嘧啶基-H),8.82(br.s,1H,OH),9.34(d,1H,J=1.5Hz,Ph-H)。
实施例5
N4-[4-(2,4-二甲基-噻唑-5-基)-嘧啶-2-基]-N1,N1-二甲基-2-硝基-苯-1,4-二胺[25]
在室温,将HNO3(69%水溶液,24μL,0.36mmol)滴加至Ac2O(1mL)中,保持其内部温度低于25℃。室温搅拌混合物15分钟,然后在冰-MeOH浴中冷却至-5℃。使化合物N-[4-(2,4-二甲基-噻唑-5-基)-嘧啶-2-基]-N1,N1-二甲基-苯-1,4-二胺(50mg,0.15mmol)悬浮在Ac2O(1mL)中,并将其滴加至已冷却的硝酸乙酰酯溶液中。冷却下搅拌该混合物1小时,然后室温下搅拌2小时。将混合物倾入冰水(20mL)中,加入饱和NaHCO3水溶液调节其pH至7-8。用EtOAc萃取混合物。用盐水洗涤合并的有机物,用MgSO4干燥并过滤。真空蒸发溶剂,得到暗色固体,用快速色谱法提纯(用庚烷/EtOAc洗脱),得到32mg浅红色固体目标化合物。RP-HPLC:tR=12.7分钟(在0.1%三氟乙酸水溶液中的10-70%乙腈,20分钟,1mL/分钟,纯度>95%)。1H-NMR(DMSO-d6)δ:2.62(s,3H,CH3),2.64(s,3H,CH3),2.74(s,6H,CH3),7.09(d,1H,J=5.1Hz,嘧啶基-H),7.23(d,1H,J=8.8Hz,Ph-H),7.77(dd,1H,J=8.7,2.7Hz,Ph-H),8.39(d,1H,J=2.7Hz),8.51(d,1H,J=5.1Hz,嘧啶基-H),9.81(br.s,1H,NH)。
用另一种制备方法:将4-氟-3-硝基-苯胺(20g,128mmol)溶解在EtOH(300mL)中,并以稳定的流速加入二甲基胺(5.6M的EtOH溶液,360mL,2.02mol)。回流18小时后,冷却反应混合物并加入100mL水。蒸发除去EtOH,残余物用Et2O(3 x 100mL)萃取。用盐水洗涤合并的有机物,过滤并蒸发溶剂,得到22.8g黑色油状4-(二甲基氨基)-3-硝基苯胺。将该产物溶解在EtOH(80mL)中,并滴加HNO3(69%水溶液,18.5mL,22.1mmol),然后滴加氨腈(50重量%水溶液,37mL,476mmol)。加热回流混合物18小时。一经冷却,将该混合物倾入Et2I(1L)中。滗析醚状上清液,残余物用丙-2-醇处理,然后用Et2O处理,得到19.0g相应的胍硝酸盐黄褐色固体。将该产物与K2CO3(15.04g,108.8mmol)在2-甲氧基乙醇(250mL)中搅拌10分钟,然后加入3-二甲基氨基-1-(2,4-二甲基噻唑-5-基)-丙烯酮(9.53g,45.33mmol)。在125℃加热混合物18小时。浓缩反应混合物,并用EtOAc稀释,经二氧化硅垫过滤并蒸发,得到暗色油状产物,用色谱法提纯,用EtOAc洗脱,得到微红色固体目标化合物。从甲苯中重结晶,得到7.3g纯目标化合物。
实施例6
2-[N-(4-N,N-二甲基氨基-3-氯-苯基)-4-(2,4-二甲基噻唑-5-基)-嘧啶胺[26]
在105℃,将3-氯-4-氟硝基苯(3.0g,17.1mmol)、二甲基胺盐酸盐(1.53g,18.8mmol)和K2CO3(4.96g,35.9mm0l)的Me2SO(20mL)溶液在密封管中加热18小时。一经冷却,将反应混合物倾入水(200mL)中并用EtOAc萃取。用盐水洗涤合并的有机物,用MgSO4干燥,过滤并蒸发,得到3.47g黄色固体3-氯-4-(二甲基氨基)硝基苯。在加热条件下,将该产物的等分试样(3.4g,16.95mmol)溶解在20mL EtOH/AcOH(1:1,v/v)中。将铁粉(-325目,9.5g,170mmol)分小份加入。然后在蒸汽浴上加热混合物30分钟。冷却混合物,用塞力特硅藻土垫过滤并蒸发滤液,得到3.33g暗色固体3-氯-4-(二甲基氨基)苯胺。通过依次滴加HNO3(69%水溶液,2.6mL,40.6mmol)和氨腈(50%水溶液,5.3mL,67.78mmol),处理该化合物的EtOH(10mL)溶液。加热回流18小时后,冷却反应混合物至室温,并将其倾入Et2O(100ml)中,用NaOH溶液(2N,100mL)碱化。分离醚层。水相用Et2O萃取。用盐水洗涤合并的有机相,用MgSO4干燥、过滤并蒸发,得到黑色油状物,静置固化,得到1.6g目标化合物。RP-HPLC分析:tR=12.7分钟(在0.1%三氟乙酸水溶液中的10-70%乙腈,20分钟,1mL/分钟,纯度>95%)。1H-NMR(CD3OD)δ:2.68(s,3H,CH3),2.70(s,3H,CH3),2.75(s,6H,CH3),7.05(d,1H,J=5.1Hz),7.15(d,1H,J=8.8Hz,嘧啶基-H),7.49(dd,1H,J=8.8,2.4Hz,Ph-H),7.94(d,1H,J=2.4Hz,Ph-H),8.43(d,1H,J=5.4Hz,嘧啶基-H)。MS(ESF)m/z=393[M+Na](C17H18N6O2S计算值370.4)。
实施例7
用类似于上述实施例6的方法制得下述化合物:
N4-[4-(2,4-二甲基-噻唑-5-基)-嘧啶-2-基]-N1,N1-二甲基-2-三氟甲基苯-1,4-二胺[27]
黄白色固体:1H-NMR(CDCl3)δ:2.62(s,3H,CH3),2.64(s,9H,CH3),6.91(d,1H,J=5.5Hz),7.16(br.s,1H,NH),7.31(d,1H,J=8.5Hz,嘧啶基-H),7.63(dd,1H,J=9.0,2.5Hz,Ph-H),7.94(d,1H,J=2.5Hz,Ph-H),8.36(d,1H,J=5.0Hz,嘧啶基-H)。
N1-[4-(2,4-二甲基-噻唑-5-基)-嘧啶-2-基]-4-甲氧基-N3,N3-二甲基-苯-1,3-二胺[28]
黄白色固体;1H-NMR(CDCl3)δ:2.58(s,3H,CH3),2.62(s,3H,CH3),2.67(s,6H,CH3),3.74(s,3H,CH3),6.84(d,1H,J=8.5Hz,嘧啶基-H),6.98(d,1H,J=5.0Hz,嘧啶基-H),7.33(m,1H,Ph-H),8.44(d,1H,J=5.0Hz,嘧啶基-H),9.33(br.s,1H,NH)。
实施例8
N,N-二甲基-N′-[4-(4-甲基-2-甲基氨基-噻唑-5-基)-嘧啶-2-基]-苯-1,4-二胺[29]
用N-甲基-2-硫脲(1.67g,19mmol)和吡啶(15mL)处理3-氯-2,4-戊酮(2.5g,19mmol)的MeOH(15mL)溶液。室温下搅拌3小时后,滤出所得沉淀,用Et2O洗涤,得到白色固体1-(4-甲基-2-甲基氨基-噻唑-5-基)乙酮(2.05g)。无需进一步提纯,在100-110℃用N,N-二甲基甲酰胺二甲基缩醛(10mL)处理该化合物22小时。浓缩反应混合物,收集沉淀,用EtOAc洗涤,得到橙色固体3-二甲基氨基-1-(4-甲基-2-甲基氨基噻唑-5-基)-丙烯酮。1H-NMR(CDCl3)δ:2.55(s,3H,CH3),2.94(s,3H,CH3),3.40(s,6H,CH3),5.29(d,1H,J=12.2Hz,CH),7.62(d,1H,J=12.2Hz,CH)。
按常规方法将3-二甲基氨基-1-(4-甲基-2-甲基氨基噻唑-5-基)-丙烯酮与N-(4-二甲基氨基-苯基)-胍硝酸盐缩合,制得目标化合物。暗棕色固体;RP-HPLC分析:tR=10.2分钟(在0.1%三氟乙酸水溶液中的0-60%乙腈,20分钟,1mL/分钟,纯度>95%)。1H-NMR(DMSO-d6)δ:2.62(s,3H,CH3),3.31(s,6H,CH3),7.11(d,1H,J=5.5Hz,嘧啶基-H),7.53(m,2H,Ph-H),7.88(m,2H,Ph-H),8.44(d,1H,J=5.5Hz,嘧啶基-H),8.68(br.s,1H,NH)。
用类似方法制得下述化合物:
(4-碘-3-硝基-苯基)-4-(4-甲基-2-甲基氨基-噻唑-5-基)-嘧啶-2-基]-胺[30]
深棕色固体;1H-NMR(DMSO-d6)δ:2.49(s,3H,CH3),3.24(s,3H,CH3),6.96(d,1H,J=6.0Hz,嘧啶基-H),7.37(d,1H,J=8.0Hz,Ph-H),7.82(m,1H,PhH),8.36(d,1H,J=6.0Hz,嘧啶基-H),8.68(s,1H,Ph-H),9.86(br.s,1H,NH)。
实施例9
4-[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基氨基]-苯酚[31]
向用冰冷却的硫氰酸钾(5.67g,58mmol)的Me2CO(45mL)溶液中滴加3-氯-戊-2,4-二酮(6.95mL,58mmol)。滴加完毕后,将反应混合物升至室温,并搅拌6小时。蒸发溶剂至干。将残余物溶解在EtOH(30mL)中,并加入HCl(浓水溶液,15mL)。加热回流混合物14小时。浓缩,收集沉淀,用冷MeOH洗涤,然后用Et2O洗涤,得到9.1g浅色固体。在100-110℃用N,N-二甲基甲酰胺二甲基缩醛(13mL)处理该化合物8小时。浓缩反应混合物,用SiO2快速色谱法(EtOAc/PE)提纯残余物,得到黄色固体3-二甲基氨基-1-(2-甲氧基-4-甲基-噻唑-5-基)-丙烯酮。1H-NMR(CDCl3)δ:2.50(s,3H,CH3),3.07(s,3H,CH3),3.21(s,6H,CH3),5.09(d,1H,J=12.0Hz,CH),7.59(d,1H,J=12.0Hz,CH)。
用N-(4-羟基-苯基)-胍硝酸盐(0.42g,2.0mmol)处理3-二甲基氨基-1-(2-甲氧基-4-甲基-噻唑-5-基)-丙烯酮(0.23g,1.0mmol)的2-甲氧基乙醇(3mL)溶液。回流20小时后,浓缩反应混合物,用SiO2快速色谱法提纯残余物(EtOAc)。从EtOAc中重结晶,得到棕色晶体目标化合物(25mg)。RP HPLC分析:tR=11.8分钟(在0.1%三氟乙酸水溶液中的0-60%乙腈,20分钟,1mL/分钟,纯度>95%)。1H-NMR(DMSO-d6)δ:2.52(s,3H,CH3),3.27(s,3H,CH3),6.68(d,2H,J=8.9Hz,Ph-H),6.81(d,1H,J=5.5Hz,嘧啶基-H),7.44(d,2H,J=8.9Hz,Ph-H),8.34(d,1H,J=5.5Hz,嘧啶基-H),9.12(br.s,1H,OH/NH),9.24(br.s,1H,NH/OH)。
实施例10
用类似于上文所述的方法制得下述化合物:
[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-硝基-苯基)-胺[32]
棕色晶体。RP-HPLC分析:tR=17.8分钟(在0.1%三氟乙酸水溶液中的0-60%乙腈,20分钟,1mL/分钟,纯度>97%)。1H-NMR(DMSO-d6)δ:2.42(s,3H,CH3),3.16(s,3H,CH3),6.92(d,1H,J=5.0Hz,嘧啶基-H),7.42(d,1H,J=8.0Hz,Ph-H)7.65(m,1H,Ph-H),7.88(m,1H,Ph-H),8.37(d,1H,J=5.0Hz,嘧啶基-H),8.72(br.s,1H,NH)。
(4-碘-苯基)-[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-胺[33]
棕色固体;RP-HPLC分析:tR=18.8分钟(在0.1%三氟乙酸水溶液中的0-60%乙腈,20分钟,1mL/分钟,纯度>95%)。1H-NMR(DMSO-d6)δ:2.83(s,3H,CH3),3.59(s,3H,CH3),7.24(d,1H,J=5.0Hz,嘧啶基-H),7.87(m,4H,Ph-H),8.71(d,1H,J=5.0Hz,嘧啶基-H)。13C-NMR(DMSO-d6)δ:14.96,30.30,85.01,109.42,109.41,110.32,121.93,137.69,137.70,138.74,140.89,158.55,159.24,159.93,170.39。
(4-氟-苯基)-[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-胺[34]
灰色固体;1H-NMR(DMSO-d6)δ:2.92(s,3H,CH3),3.67(s,3H,CH3),7.32(d,1H,J=5.0Hz,嘧啶基-H),7.51(m,2H,Ph-H),8.11(m,2H,Ph-H),8.80(d,1H,J=5.0Hz,嘧啶基-H)。
(4-氯-苯基)-[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-胺[35]
浅黄色固体:1H-NMR(DMSO-d6)δ:2.55(s,3H,CH3),3.29(s,3H,CH3),6.97(d,1H,J=5.0Hz,嘧啶基-H),7.32(d,2H,J=8.5Hz,Ph-H),7.76(d,2H,J=9.0Hz,Ph-H),8.44(d,1H,J=5.0Hz,嘧啶基-H),9.75(br.s,1H,NH)。
[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-甲氧基-苯基)-胺[36]
浅黄色固体;1H-NMR(DMSO-d6)δ:2.54(s,3H,CH3),3.28(s,3H,CH3),3.71(s,3H,CH3),6.86(m,3H,嘧啶基-H & Ph-H),7.59(d,2H,J=9.0Hz,Ph-H),8.37(d,1H,J=5.0Hz,嘧啶基-H),9.39(br.s,1H,NH)。
3-[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基氨基]-苯酚[37]
浅黄色固体;RP-HPLC分析:tR=15.4分钟(在0.1%三氟乙酸水溶液中的0-60%乙腈,20分钟,纯度>95%)。1H-NMR(DMSO-d6)δ:2.55(s,3H,CH3),3.26(s,3H,CH3),6.36(m,1H,Ph-H),6.90(d,1H,J=5.5Hz,嘧啶基-H),7.03(t,1H,J=8.5Hz,Ph-H),7.16(m,1H,Ph-H),7.22(s,1H,PhH),8.40(d,1H,J=5.5Hz,嘧啶基-H),9.39(br.s,1H,NH)。
(4-氟-3-硝基-苯基)-[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-胺[38]
棕色固体;1H-NMR(DMSO-d6)δ:2.42(s,3H,CH3),2.81(s,3H,CH3),6.36(m,1H,Ph-H),6.91(d,1H,J=5.5Hz,嘧啶基-H),7.31(m,1H,Ph-H),8.33(m,1H,Ph-H),8.48(d,1H,J=5.5Hz,嘧啶基-H),8.52和9.68(br.s,1H,NH)。
(4-氯-3-甲基-苯基)-[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-胺[39]
黄色固体:1H-NMR(DMSO-d6)δ:2.30(s,3H,CH3),2.55(s,3H,CH3),3.27(s,3H,CH3),6.96(d,1H,J=5.5Hz,嘧啶基-H),7.30(d,1H,J=9.0Hz,Ph-H),7.52(m,1H,Ph-H),7.81(m,1H,Ph-H),8.43(d,1H,J=5.5Hz,嘧啶基-H),9.69(br.s,1H,NH)。
(3-碘-4-甲基-苯基)-[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-胺[40]
棕色固体:1H-NMR(DMSO-d6)δ:2.28(s,3H,CH3),3.30(s,3H,CH3),6.96(d,1H,J=5.0Hz,嘧啶基-H),7.14(m,1H,Ph-H),7.21(m,1H,Ph-H),7.53(m,1H,Ph-H),8.42(d,1H,J=5.0Hz,嘧啶基-H),9.65(br.s,1H,NH)。
(4-氟-3-甲基-苯基)-[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-胺[41]
灰色固体;1H-NMR(DMSO-d6)δ:2.21(s,3H,CH3),2.55(s,3H,CH3),3.26(s,3H,CH3),6.92(d,1H,J=5.0Hz,嘧啶基-H),7.04(t,1H,J=9.0Hz,Ph-H),7.48(m,1H,Ph-H),7.68(m,1H,Ph-H),8.40(d,1H,J=5.5Hz,嘧啶基-H),9.54(br.s,1H,NH)。
[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-甲基-3-硝基-苯基)-胺[42]
黄色固体:1H-NMR(DMSO-d6)δ:2.44(s,3H,CH3),2.55(s,3H,CH3),3.27(s,3H,CH3),7.03(d,1H,J=5.0Hz,嘧啶基-H),7.40(t,1H,J=8.5Hz,Ph-H),7.84(m,1H,Ph-H),8.48(m,1H,Ph-H),8.59(d,1H,J=5.5Hz,嘧啶基-H),9.99(br.s,1H,NH)。
N-[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-N′,N′-二甲基-苯-1,4-二胺[43]
黄色固体;RP-HPLC分析:tR=19.6分钟(在0.1%三氟乙酸水溶液中的0-60%乙腈,20分钟,纯度>95%)。1H-NMR(DMSO-d6)δ:2.83(s,3H,CH3),2.90(s,6H,CH3),3.08(s,3H,CH3),6.73(m,2H,Ph-H),6.81(d,1H,J=5.5Hz,嘧啶基-H),7.03(m,1H,Ph-H),7.50(m,1H,Ph-H),8.32(d,1H,J=5.5Hz,嘧啶基-H),9.24(br.s,1H,NH)。
实施例11
[4-(2-乙基氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-硝基-苯基)-胺[44]
通过1-(2-乙基氨基-4-甲基-噻唑-5-基)乙酮与3-氯-戊-2,4-二酮之间的反应制备3-二甲基氨基-1-(2-乙基氨基-4-甲基-噻唑-5-基)-丙烯酮。然后用常规方法将其与N-(3-硝基-苯基)-胍硝酸盐缩合,制得目标化合物。黄色固体;1H-NMR(DMSO-d6)δ:1.14(m,3H,CH3),2.47(s,3H,CH3),3.23(m,2H,CH2),6.99(d,1H,J=5.0Hz,嘧啶基-H),7.55(m,1H,Ph-H),7.77(m,1H,Ph-H),8.02(m,1H,Ph-H),8.39(d,1H,J=5.0Hz,嘧啶基-H),8.47(s,1H,Ph-H),9.98(br.s,1H,NH)。
实施例12
用类似于上述实施例11的方法制得下述化合物:
(4-氯-苯基)-[4-(2-乙基氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-胺[45]
棕色固体;1H-NMR(DMSO-d6)δ:1.16(m,3H,CH3),2.45(s,3H,CH3),3.24(m,2H,CH2),6.90(d,1H,J=5.0Hz,嘧啶基-H),7.30(d,2H,J=9.0Hz,Ph-H),7.79(d,2H,J=9.0Hz,Ph-H),8.32(d,1H,J=5.0Hz,嘧啶基-H),9.57(sbr,1H,NH)。
[4-(2-乙基氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-三氟甲基-苯基)胺[47]
棕色固体;1H-NMR(DMSO-d6)δ:1.16(t,3H,J=7.0Hz,CH3),2.46(s,3H,CH3),3.27(m,2H,CH2),6.98(d,1H,J=5.5Hz,嘧啶基-H),7.60(d,2H,J=9.0Hz,Ph-H),7.97(d,2H,J=9.0Hz,Ph-H),8.14(br.s,1H,NH),8.37(d,1H,J=5.5Hz,嘧啶基-H),9.86(br.s,1H,NH)。
[4-(2-乙基氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-甲氧基-苯基)-胺[48]
棕色固体;1H-NMR(DMSO-d6)δ:1.17(m,3H,CH3),2.48(s,3H,CH3),3.25(m,2H,CH2),6.49(m,1H,Ph-H),6.89(d,1H,J=5.5Hz,嘧啶基-H),7.14(t,1H,J=8.5Hz,Ph-H),7.26(m,1H,Ph-H),7.52(m,1H,Ph-H),8.31(d,1H,J=5.5Hz,嘧啶基-H),8.49(br.s,1H,NH),9.39(br.s,1H,NH)。
(3-氯-苯基)-[4-(2-乙基氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-胺[49]
棕色固体;1H-NMR(DMSO-d6)δ:1.15(m,3H,CH3),2.47(s,3H,CH3),3.22(m,2H,CH2),6.94(m,2H,Ph-H和嘧啶基-H),7.26(t,1H,J=9.0Hz,Ph-H),7.58(m,1H,Ph-H),8.10(m,1H,Ph-H),8.35(d,1H,J=5.5Hz,嘧啶基-H),9.65(br.s,1H,NH)。
[4-(2-乙基氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-甲基-3-硝基-苯基)-胺[50]
棕色固体;1H-NMR(DMSO-d6)δ:1.19(t,3H,J=7.5Hz,CH3),2.49(s,3H,CH3),3.24(m,2H,CH2),6.95(d,1H,J=5.5Hz,嘧啶基-H),7.37(d,1H,J=8.5Hz,Ph-H),7.81(m,1H,Ph-H),8.35(d,1H,J=5.5Hz,嘧啶基-H),8.66(s,1H,Ph-H),9.83(br.s,1H,NH)。
实施例13
[4-(2-丁基氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-氟-苯基)-胺[51]
用常规方法,通过1-(2-丁基氨基-4-甲基-噻唑-5-基)-3-二甲基氨基-丙烯酮与4-氟-苯基胍硝酸盐的缩合制得目标化合物。灰色固体;1H-NMR(DMSO-d6)δ:0.90(m,3H,CH3),1.33(m,2H,CH2),1.53(m,2H,CH2),2.48(s,3H,CH3),3.22(m,2H,CH2),6.87(d,1H,J=5.0Hz,嘧啶基-H),7.10(m,2H,Ph-H),7.74(m,2H,PhH),8.11(br.s,1H,NH),8.30(d,1H,J=5.5Hz,嘧啶基-H),9.42(br.s,1H,NH)。
实施例14
[4-(2-二甲基氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-硝基-苯基)-胺[52]
用NaH(0.113g,4.7mmol)处理1-(4-甲基-2-甲基氨基-噻唑-5-基)乙酮(0.40g,2.4mmol)在THF(2mL)中的混合物。在40℃加热0.5小时后,加入MeI(0.35g,2.4mmol)。再继续加热2小时。冷却后,用EtOAc稀释溶液,用盐水洗涤并用MgSO4干燥。蒸发溶剂,得到黄色固体1-(2-二甲基氨基-4-甲基-噻唑-5-基)乙酮。1H-NMR(CDCl3)δ:2.36(s,3H,CH3),2.51(s,3H,CH3),3.10(s,6H,CH3)。
在125℃将上述化合物在N,N-二甲基甲酰胺二甲基缩醛(2mL)中加热4小时。浓缩反应混合物,残余物用SiO2色谱法(EtOAc/MeOH,95:5)提纯,得到目标产物3-二甲基氨基-1-(2-二甲基氨基-4-甲基-噻唑-5-基)-丙烯酮。1H-NMR(CDCl3)δ:2.49(s,6H,CH3),3.03(s,6H,CH3),3.29(s,3H,CH3),5.23(d,1H,J=12.0Hz,CH),7.51(d,1H,J=12.0Hz,CH)。用常规方法将该化合物与N-(3-硝基-苯基)-胍硝酸盐缩合,得到棕色固体目标化合物。1H-NMR(DMSO-d6)δ:3.12(s,9H,CH3),7.02(d,1H,J=5.0Hz,嘧啶基-H),7.55(t,1H,J=8.0Hz,Ph-H),7.77(m,1H,Ph-H),7.93(m,1H,PhH),8.41(d,1H,J=6.0Hz,嘧啶基-H),8.49(s,1H,Ph-H),9.10(br.s,1H,NH)。
实施例15
用类似于上述实施例14的方法制得下述化合物:
(4-氯-苯基)-[4-(2-二甲基氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-胺[53]
棕色固体;1H-NMR(DMSO-d6)δ:3.09(s,9H,CH3),6.93(d,1H,J=5.5Hz,嘧啶基-H),7.32(d,2H,J=9.5Hz,Ph-H),7.79(d,2H,J=9.5Hz,Ph-H),8.33(d,1H,J=5.0Hz,嘧啶基-H),9.57(br.s,1H,NH)。
[4-(2-二甲基氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-氟-苯基)-胺[54]
灰色固体;1H-NMR(DMSO-d6)δ:3.08(s,9H,CH3),6.89(d,1H,J=5.0Hz,嘧啶基-H),7.11(m,2H,Ph-H),7.74(m,2H,Ph-H),8.31(d,1H,J=5.5Hz,嘧啶基-H),9.44(br.s,1H,NH)。
(3-氯-苯基)-[4-(2-二甲基氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-胺[55]
棕色固体;1H-NMR(DMSO-d6)δ:3.10(s,9H,CH3),6.96(d,2H,嘧啶基-H和Ph-H),7.27(t,1H,J=8.0Hz,Ph-H),7.52(m,1H,Ph-H),8.20(s,1H,Ph-H),8.37(d,1H,J=5.5Hz,嘧啶基-H),9.71(br.s,1H,NH)。
实施例16
N-{4-甲基-5-[2-(3-硝基-苯基氨基)-嘧啶-4-基]-噻唑-2-基}-甲磺酰胺[56]
向[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-硝基-苯基)-胺(1.0mmo1,0.33g)和甲磺酰氯(2.0mmol,0.22g)在无水DMF(2mL)中的混合物中加入Et3N(0.28mL)。室温搅拌反应混合物20小时。冷却后,用EtOAc稀释混合物,盐水洗涤并用MgSO4干燥。蒸发溶剂,残余物用制备RP-HPLC提纯,用在0.1%三氟乙酸水溶液中的10-70%乙腈进行梯度洗脱40分钟以上。得到橙色固体目标化合物。RP-HPLC分析:tR=17.4分钟(在0.1%三氟乙酸水溶液中的0-60%乙腈,20分钟,1mL/分钟,纯度>97%)。1H-NMR(DMSO-d6)δ:3.10(s,3H,CH3),3.25(s,3H,CH3),7.05(d,1H,J=5.2Hz,嘧啶基-H),7.42(m,1H,Ph-H),7.63(m,1H,PhH),7.98(m,1H,Ph-H),8.21(d,1H,J=5.2Hz,嘧啶基-H),8.42(s,1H,Ph-H),9.18(s,1H,NH)。
实施例17
2-{4-甲基-5-[2-(3-硝基-苯基氨基)-嘧啶-4-基]-噻唑-2-基氨基}-乙醇[58]
将叔丁基亚氨基-2-二乙基氨基-1,3-二甲基全氢-1,3-二氮杂磷杂因(phosphorine)(0.5mL)加入[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-硝基-苯基)-胺(0.33g,1.0mmol)和碘乙醇(0.44g,2.6mmol)在无水DMF(2mL)中的混合物中。在124℃加热反应混合物20小时。用在0.1%三氟乙酸水溶液中的10-70%乙腈进行梯度洗脱40分钟,通过制备RP-HPLC(Vydac 218TP1022,9mL/分钟)分离出棕色固体产物。RP-HPLC分析:tR=14.30分钟(Vydac218TP54,在0.1%三氟乙酸水溶液中的0-60%乙腈,20分钟,25℃,1mL/分钟,纯度>97%)。1H-NMR(CD3OD)δ:3.30(s,3H,CH3),3.91(t,2H,J=4.6Hz,CH2),4.25(t,2H,J=4.6Hz,CH2),7.21(d,1H,J=5.2Hz,嘧啶基-H),7.54(m,1H,Ph-H),7.89(m,2H,Ph-H),8.59(d,1H,J=5.2Hz,嘧啶基-H),8.90(s,1H,Ph-H)。
2-{5-[2-(4-氟-苯基氨基)-嘧啶-4-基]-4-甲基-噻唑-2-基氨基}-乙醇[59]
用类似于化合物[58]的制备方法,从[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-氟-苯基)-胺制得上述化合物。1H-NMR(DMSO-d6)δ:2.44(s,3H,CH3),3.54(m,2H,CH2),4.78(m,2H,CH2),6.87(d,1H,J=5.2Hz,嘧啶基-H),7.09(m,2H,Ph-H),7.75(m,2H,PhH),8.30(d,1H,J=5.2Hz,嘧啶基-H),8.11(m,1H,NH),9.43(s,1H,NH)。DE MALDI-TOF MS:[M+H]+=345.79(C16H16FN5OS计算值345.40)。
实施例18
2-氯-N-{4-甲基-5-[2-(3-硝基-苯基氨基)-嘧啶-4-基]-噻唑-2-基}-乙酰胺[60]
在冰-水浴中冷却[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-硝基-苯基)-胺(0.33g,1.0mmol)的无水DMF(3mL)溶液。加入氯代乙酰氯(0.22g,2.0mmol)和吡啶(80μL)。室温搅拌18小时后,用在0.1%三氟乙酸水溶液中的10-70%乙腈进行梯度洗脱40分钟,通过制备RP-HPLC(Vydac 218TP1022,9mL/分钟)分离出棕色固体产物。RP-HPLC分析:tR=20.62分钟(Vydac218TP54,在0.1%三氟乙酸水溶液中的0-60%乙腈,20分钟,1mL/分钟,25℃,纯度>97%)。1H-NMR(CD3OD)δ:2.45(s,3H,CH3),4.12(s,2H,CH2),7.03(d,1H,J=5.2Hz,嘧啶基-H),7.42(m,1H,Ph-H),7.63(m,1H,Ph-H),8.01(m,1H,Ph-H),8.41(d,1H,J=5.2Hz,嘧啶基-H),8.64(s,1H,Ph-H)。
用类似的方法制得下述化合物:
2-氯-N-{5-[2-(4-氟-苯基氨基)-嘧啶-4-基]-4-甲基-噻唑-2-基}-乙酰胺[61]
用类似于上述化合物[60]的制备方法,从[4-(2-氨基-4-甲基-噻唑-5-基)嘧啶-2-基]-(4-氟-苯基)-胺制得该化合物。1H-NMR(DMSO-d6)δ:2.94(s,3H,CH3),4.75(s,2H,CH2),7.44(m,3H,嘧啶基-H和Ph-H),8.09(m,2H,Ph-H),8.28(s,1H,NH),8.80(d,1H,J=5.2Hz,嘧啶基-H)。
根据分析筛选测定CDK抑制作用和/或使用一种或多种细胞系进行细胞毒性测定,以此说明本发明化合物的生物活性(参见表1)。
实施例19
所选择化合物的激酶特异性
研究了上述实施例化合物对多种蛋白激酶的酶活性的抑制能力。尤其测定了CDK2/细胞周期蛋白E和CDK4/细胞周期蛋白D1。
使用重组蛋白和合适的测定缓冲液(一般为25mMβ-磷酸甘油、20mMMOPS、5mM EGTA、1mM DTT和1mM Na3VO3,pH7.4)在96孔板中进行激酶测定,向其中加入2-4μg作用于合适底物的活性酶(对于CDK2,为纯组蛋白H1,对于CDK4,为重组GST-成视网膜细胞瘤蛋白(残基773-928))。加入Mg/ATP混合物(15mM MgCl2+100μM ATP,每孔30-50kBq的[γ-32P]-ATP)引发反应,根据需要,在30℃培养混合物10分钟(CDK2/细胞周期蛋白E)或45分钟(CDK4/细胞周期蛋白D1)。在冰上终止反应,然后通过p81滤板或GF/C滤板(用于CDK4)(Whatman Polyfiltronics,Kent,UK.)过滤。用75mM正磷酸水溶液洗涤3次后,将滤板干燥,掺入闪烁体,在闪烁计数器(TopCount,Packard Instruments,Pangbourne,Berks,UK)上测定掺入物放射性。将用于激酶测定的化合物配制成在DMSO中的10mM贮存液,并在测定缓冲液将其稀释到10%DMSO。使用曲线拟合软件(GraphPad Prism version3.00 for Windows,graphPad Software,San Diego California USA)分析数据以测定IC50值(抑制50%激酶活性所需的试验化合物浓度)。
或者,通过在合适体系中监测GST-Rb的磷酸化作用,可以测定CDK4/细胞周期蛋白D1、CDK2/细胞周期蛋白E和CDIK1/细胞周期蛋白B激酶。因此,在用于体外激酶测定的96-孔板中,使用放射性标记的ATP,将放射性标记磷酸盐掺入GST-Rb(772-928),测定由CDK4/细胞周期蛋白D1、CDK2/细胞周期蛋白E或CDK1/细胞周期蛋白B诱导的GST-Rb的磷酸化作用。
磷酸化的反应混合物(总体积40μl)由50mM HEPES pH7.4、20mMMgCl2、5mM EGTA、2mM DTT、20mM β-磷酸甘油、2mM NaF、1mMNa3VO4、蛋白酶抑制剂混合物(Sigma,参见上文)、BSA 0.5mg/ml、1μg纯化的酶复合物、10μl GST-Rb琼脂糖珠、100μM ATP和0.2μ Ci32P-ATP组成。在30℃连续振荡30分钟进行反应。然后,向每孔中加入100μl的50mMHEPES pH7.4和1mM ATP,并将全部反应混合物转移到GFC滤板上。滤板用200μl的50mM HEPES pH7.4和1mM ATP洗涤5次。向每孔中加入50μl闪烁液体,在闪烁计数器(Topcount,HP)上测定样品放射性。用GraFit软件计算不同肽的IC50值。
如下所述,在组蛋白3中掺入放射标记磷酸盐可测定PKCα激酶活性。反应混合物(总体积65μl)由50mM Tris-HCl、1mM乙酸钙、3mM DTT、0.03mg/ml磷脂酰丝氨酸、2.4μg/ml PMA、0.04% NP40、12mM Mg/Cl、纯PKCα-100ng、0.2mg/ml组蛋白3、100μM ATP和0.2μCi[γ-32P]-ATP组成。在37℃在微板振荡器中反应15分钟。加入10μl 75mM正磷酸并将该板置于冰上终止反应。将50μl反应混合物转移至p81滤板上,洗出游离的放射性磷酸盐(每孔用200μl 75mM正磷酸洗涤3次)后,向每孔中加入50μl闪烁液体,在闪烁计数器(Topcount,HP)上测定放射性。
在上述测定中使用的CDK2、CDK4和/或PKC可从现有货源得到或通过公开的重组方法制备。His6标记的重组人类CDK2/细胞周期蛋白E、CDIK1/细胞周期蛋白B、CDK4和PKCα可以在感染了适当杆状病毒构成物的sf9昆虫细胞中表达。感染两天后通过低速离心收集细胞,并用金属螯合色谱法(大于90%均匀性)从昆虫细胞沉淀中提纯蛋白。简而言之,通过超声处理将昆虫细胞沉淀溶解在缓冲液A(10mM Tris-HCl pH8.0、150mM NaCl、0.02%NP40和5mM β-巯基乙醇、1mM NaF、1mM Na3VO4和含AEBSF、胃蛋白酶抑制剂A、E64、苯丁抑制素和亮抑蛋白酶肽的蛋白酶抑制剂混合物(Sigma))中。离心澄清可溶部分,并加载于Ni-NTA-琼脂糖(Quiagen)上。用300mM NaCl、5-15mM咪唑的缓冲液A溶液洗去未结合的蛋白。结合的蛋白则用250mM咪唑的缓冲液A溶液洗涤。提纯的蛋白彻底透过被等分储存在-70℃的贮存缓冲液(20mM HEPES pH7.4、50mM NaCl、2mM DTT、1mMEDTA、1mM EGTA、0.02%NP40、10%v/v甘油)中。分别用不同的缓冲液一50mM NaH2PO4pH8.0和0.05%Trition X-100缓冲液代替Tris和NP40,用相同的方法提纯PKC-α-6×组氨酸。
下表2中的结果表明,所讨论的本发明化合物对CDK的抑制作用具有高选择性。
实施例20
MTT细胞毒性测定
使用从ATCC(American Type Culture Collection,10801 UniversityBoulevard,Manessas,VA 20110-2209,USA)得到的人类肿瘤细胞系,对上述实施例化合物进行标准细胞增殖测定。进行标准72小时MTT(噻唑蓝;溴化3-[4,5-二甲基噻唑-2-基]-2,5-二苯基四唑鎓)测定(Haselaberger,K.;Peterson,D.C.;Thomas,D.G.;Darling,J.L.Anti Cancer Druds 1996,7,331-8;Loveland,B.E.;Johns,T.G.;Mackay,I.R.;Vaillant,F.;Wang,Z.X.;Hertzog,P.J.Biochemistry international 1992,27,501-10)。简而言之,根据倍增时间将细胞接种于96孔板中,并在37℃培养过夜。将试验化合物溶解在DMSO,并用100μL细胞介质制备1/3稀释系列,将其加入细胞中(一式三份),并在37℃培养72小时。将MTT配制成5mg/mL的细胞介质贮存液,并过滤灭菌。从细胞中除去介质,然后用200μl PBS洗涤。向每孔中加入20μL MTT溶液,并在37℃在黑暗处培养4小时。除去MTT溶液,再次用200μl PBS洗涤细胞。在搅拌条件下,每孔用200μL DMSO溶解MTT染料。在540nm处读取吸光度,使用曲线拟合软件(GraphPad Prism version 3.00 for Windows,graphPad Software,San Diego California USA)分析数据,以测定IC50值(抑制50%细胞生长所需的试验化合物浓度)。
下表3中的结果表明了本发明化合物的抗增殖活性。
只要不脱离本发明的范围和精神,对本发明描述的方法进行各种改进和改变对本领域技术人员而言是显而易见的。因此,只要对本发明方法的改进对相应或相关领域的技术人员而言是显而易见的,则这种改进落在下述权利要求的范围之内。
表1:所选择化合物的生物活性
表2:所选择化合物的激酶特异性(IC50,μM)
1CDK2-细胞周期蛋白E复合体;2CDK2-细胞周期蛋白A复合体;
3CDK1-细胞周期蛋白B1复合体;4CDK4-细胞周期蛋白D1复合体;
5CDK7-细胞周期蛋白H-MAT1复合体;6胞外信号调节激酶2;
7蛋白激酶Cα;8Ableson酪氨酸激酶;9酪蛋白激酶2;10蛋白激酶B;11p70核糖体蛋白S6激酶;12应激活化蛋白激酶2a;13钙调蛋白依赖性激酶II;14polo样激酶1;15cAMP依赖性蛋白激酶;16糖原合酶激酶3β。
表3:所选择化合物的体外抗增殖活性(72-小时MTT IC50,μM)
Claims (16)
1.化合物,选自:
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-硝基-苯基)-胺[1];
N-[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-N′,N′-二甲基-苯-1,4-二胺[2];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-氯-苯基)-胺[3];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-甲氧基-苯基)-胺[4];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-氟-苯基)-胺[5];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-三氟甲基-苯基)-胺[7];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-甲氧基-苯基)-胺[8];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-氯-苯基)-胺[9];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-碘-苯基)-胺[10];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-碘-苯基)-胺[11];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-氟-苯基)-胺[12];
3-[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基氨基]-苯酚[13];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-碘-3-硝基-苯基)-胺[14];
2-{4-[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基氨基]-苯基}-乙醇[15];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-溴-苯基)-胺[16];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-溴-苯基)-胺[17];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-氯-3-三氟甲基-苯基)-胺[18];
N1-[4-(2,4-二甲基-噻唑-5-基)-嘧啶-2-基]-4-[β-(苯氧基)-三乙基胺]-胺[20];
2-{4-[4-(2,4--甲基-噻唑-5-基)-嘧啶-2-基氨基]-苯基}-乙醇[21];
2-({4-[4-(2,4-二甲基-噻唑-5-基)-嘧啶-2-基氨基]-苯基}-乙基-氨基)-乙醇[22];
(3,4-二甲氧基-苯基)-[4-(2,4-二甲基-噻唑-5-基)-嘧啶-2-基]-胺[23];
5-[4-(2,4-二甲基-噻唑-5-基)-嘧啶-2-基氨基]-2-甲氧基-苯酚[24];
N4-[4-(2,4-二甲基-噻唑-5-基)-嘧啶-2-基]-N1,N1-二甲基-2-硝;基-苯-1,4-二胺[25];
2-[N-(4-N,N-二甲基氨基-3-氯-苯基)]-4-(2,4-二甲基噻唑-5-基)嘧啶胺[26];
N4-[4-(2,4-二甲基-噻唑-5-基)-嘧啶-2-基]-N1,N1-二甲基-2-三氟甲基-苯-1,4-二胺[27];
N1-[4-(2,4-二甲基-噻唑-5-基)-嘧啶-2-基]-4-甲氧基-N3,N3-二甲基-苯-1,3-二胺[28];
N,N-二甲基-N′-[4-(4-甲基-2-甲基氨基-噻唑-5-基)-嘧啶-2-基]-苯-1,4-二胺[29];
(4-碘-3-硝基-苯基)-[4-(4-甲基-2-甲基氨基-噻唑-5-基)-嘧啶-2-基]胺[30];
4-[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基氨基]-苯酚[31];
[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-硝基-苯基)-胺[32];
(4-碘-苯基)-[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-胺[33];
(4-氟-苯基)-[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-胺[34];
(4-氯-苯基)-[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-胺[35];
[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-甲氧基-苯基)-胺[36];
3-[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基氨基]-苯酚[37];
(4-氟-3-硝基-苯基)-[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-胺[38];
(4-氯-3-甲基-苯基)-[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-胺[39];
(3-碘-4-甲基-苯基)-[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-胺[40];
(4-氟-3-甲基-苯基)-[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-胺[41];
[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-甲基-3-硝基-苯基)-胺[42];
N-[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-N′,N′-二甲基-苯-1,4-二胺[43];
[4-(2-乙基氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-硝基-苯基)-胺[44];
(4-氯-苯基)-[4-(2-乙基氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-胺[45];
[4-(2-乙基氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-三氟甲基-苯基)-胺[47];
[4-(2-乙基氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-甲氧基-苯基)-胺[48];
(3-氯-苯基)-[4-(2-乙基氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-胺[49];
[4-(2-乙基氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-甲基-3-硝基-苯基)胺[50];
[4-(2-丁基氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-氟-苯基)-胺[51];
[4-(2-二甲基氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-硝基-苯基)-胺[52];
(4-氯-苯基)-[4-(2-二甲基氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-胺[53];
[4-(2-二甲基氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-氟-苯基)-胺[54];
(3-氯-苯基)-[4-(2-二甲基氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-胺[55];
N-{4-甲基-5-[2-(3-硝基-苯基氨基)-嘧啶-4-基]-噻唑-2-基}-甲磺酰胺[56];
2-{4-甲基-5-[2-(3-硝基-苯基氨基)-嘧啶-4-基]-噻唑-2-基氨基}-乙醇[58];
2-{5-[2-(4-氟-苯基氨基)-嘧啶-4-基]-4-甲基-噻唑-2-基氨基}-乙醇[59];
2-氯-N-{4-甲基-5-[2-(3-硝基-苯基氨基)-嘧啶-4-基]-噻唑-2-基}-乙酰胺[60];
2-氯-N-{5-[2-(4-氟-苯基氨基)-嘧啶-4-基]-4-甲基-噻唑-2-基}-乙酰胺[61];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-硝基-苯基)-胺[63];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(苯基)-胺[64];
4-[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-苯磺酸[65];和
4-[4-(2,4-二甲基-噻唑-5-基)-嘧啶-2-基氨基]-苯磺酸[66]。
2.权利要求1的化合物,选自:
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-硝基-苯基)-胺[1];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-氯-苯基)-胺[9];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-碘-苯基)-胺[10];
3-[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基氨基]-苯酚[13];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-碘-3-硝基-苯基)-胺[14];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-溴-苯基)-胺[16];
(3,4-二甲氧基-苯基)-[4-(2,4-二甲基-噻唑-5-基)-嘧啶-2-基]-胺[23];
N4-[4-(2,4-二甲基-噻唑-5-基)-嘧啶-2-基]-N1,N1-二甲基-2-硝基-苯-1,4-二胺[25];
2-[N-(4-N,N-二甲基氨基-3-氯-苯基)]-4-(2,4-二甲基噻唑-5-基)嘧啶胺[26];
N,N-二甲基-N′-[4-(4-甲基-2-甲基氨基-噻唑-5-基)-嘧啶-2-基]-苯-1,4-二胺[29];
4-[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基氨基]-苯酚[31];
[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-硝基-苯基)-胺[32];
(4-氟-苯基)-[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-胺[34];
[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-甲基-3-硝基-苯基)-胺[42];
N-{4-甲基-5-[2-(3-硝基-苯基氨基)-嘧啶-4-基]-噻唑-2-基}-甲磺酰胺[56];
2-{4-甲基-5-[2-(3-硝基-苯基氨基)-嘧啶-4-基]-噻唑-2-基氨基}-乙醇[58];
2-氯-N-{4-甲基-5-[2-(3-硝基-苯基氨基)-嘧啶-4-基]-噻唑-2-基}-乙酰胺[60];和
2-氯-N-{5-[2-(4-氟-苯基氨基)-嘧啶-4-基]-4-甲基-噻唑-2-基}-乙酰胺[61]。
3.权利要求1或2的化合物,选自:
3-[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基氨基]-苯酚[13];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-碘-3-硝基-苯基)-胺[14];
(3,4-二甲氧基-苯基)-[4-(2,4-二甲基-噻唑-5-基)-嘧啶-2-基]-胺[23];
N,N-二甲基-N′-[4-(4-甲基-2-甲基氨基-噻唑-5-基)-嘧啶-2-基]-苯-1,4-二胺[29];
(4-氟-苯基)-[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-胺[34];
[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-甲基-3-硝基-苯基)-胺[42];
2-氯-N-{4-甲基-5-[2-(3-硝基-苯基氨基)-嘧啶-4-基]-噻唑-2-基}-乙酰胺[60];和
2-氯-N-{5-[2-(4-氟-苯基氨基)-嘧啶-4-基]-4-甲基-噻唑-2-基}-乙酰胺[61]。
4.权利要求1或2的化合物,选自:
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-硝基-苯基)-胺[1];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-氯-苯基)-胺[9];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-碘-苯基)-胺[10];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-溴-苯基)-胺[16];
N4-[4-(2,4-二甲基-噻唑-5-基)-嘧啶-2-基]-N1,N1-二甲基-2-硝基-苯-1,4-二胺[25];
2-[N-(4-N,N-二甲基氨基-3-氯-苯基)]-4-(2,4-二甲基噻唑-5-基)嘧啶胺[26];
4-[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基氨基]-苯酚[31];
[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-硝基-苯基)-胺[32];
N-{4-甲基-5-[2-(3-硝基-苯基氨基)-嘧啶-4-基]-噻唑-2-基}-甲磺酰胺[56];和
2-{4-甲基-5-[2-(3-硝基-苯基氨基)-嘧啶-4-基]-噻唑-2-基氨基}-乙醇[58]。
5.权利要求1、2或4中任一权利要求的化合物,其为:
[4-(2-甲氧基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-硝基-苯基)-胺[32]或2-{4-甲基-5-[2-(3-硝基-苯基氨基)-嘧啶-4-基]-噻唑-2-基氨基}-乙醇[58]。
6.化合物,选自:
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-硝基-苯基)-胺[1];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-三氟甲基-苯基)-胺[7];
[4-(2-氨基4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-甲氧基-苯基)-胺[8];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-氯-苯基)-胺[9];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-碘-苯基)-胺[10];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-碘-苯基)-胺[11];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-氟-苯基)-胺[12];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-溴-苯基)-胺[16];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-溴-苯基)-胺[17];
N-{4-甲基-5-[2-(3-硝基-苯基氨基)-嘧啶-4-基]-噻唑-2-基}-甲磺酰胺[56];
2-{4-甲基-5-[2-(3-硝基-苯基氨基)-嘧啶-4-基]-噻唑-2-基氨基}-乙醇[58];
2-{5-[2-(4-氟-苯基氨基)-嘧啶-4-基]-4-甲基-噻唑-2-基氨基}-乙醇[59];
2-氯-N-{4-甲基-5-[2-(3-硝基-苯基氨基)-嘧啶-4-基]-噻唑-2-基}-乙酰胺[60];
2-氯-N-{5-[2-(4-氟-苯基氨基)-嘧啶-4-基]-4-甲基-噻唑-2-基}-乙酰胺[61];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(4-硝基-苯基)-胺[63];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(苯基)-胺[64];
4-[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-苯磺酸[65];和
4-[4-(2,4-二甲基-噻唑-5-基)-嘧啶-2-基氨基]-苯磺酸[66]。
7.权利要求6的化合物,选自:
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-硝基-苯基)-胺[1];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-氯-苯基)-胺[9];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-碘-苯基)-胺[10];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-溴-苯基)-胺[16];
N-{4-甲基-5-[2-(3-硝基-苯基氨基)-嘧啶-4-基]-噻唑-2-基}-甲磺酰胺[56];
2-{4-甲基-5-[2-(3-硝基-苯基氨基)-嘧啶-4-基]-噻唑-2-基氨基}-乙醇[58];
2-氯-N-{4-甲基-5-[2-(3-硝基-苯基氨基)-嘧啶-4-基]-噻唑-2-基}-乙酰胺[60];和
2-氯-N-{5-[2-(4-氟-苯基氨基)-嘧啶-4-基]-4-甲基-噻唑-2-基}-乙酰胺[61]。
8.权利要求6或7的化合物,选自:2-氯-N-{4-甲基-5-[2-(3-硝基-苯基氨基)-嘧啶-4-基]-噻唑-2-基}-乙酰胺[60];和
2-氯-N-{5-[2-(4-氟-苯基氨基)-嘧啶-4-基]-4-甲基-噻唑-2-基}-乙酰胺[61]。
9.权利要求6或7的化合物,选自:
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-硝基-苯基)-胺[1];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-氯-苯基)-胺[9];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-碘-苯基)-胺[10];
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-溴-苯基)-胺[16];
N-{4-甲基-5-[2-(3-硝基-苯基氨基)-嘧啶-4-基]-噻唑-2-基}-甲磺酰胺[56];和
2-{4-甲基-5-[2-(3-硝基-苯基氨基)-嘧啶-4-基]-噻唑-2-基氨基}-乙醇[58]。
10.权利要求9的化合物,选自:
[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-硝基-苯基)-胺[1];
N-{4-甲基-5-[2-(3-硝基-苯基氨基)-嘧啶-4-基]-噻唑-2-基}-甲磺酰胺[56];和
2-{4-甲基-5-[2-(3-硝基-苯基氨基)-嘧啶-4-基]-噻唑-2-基氨基}-乙醇[58]。
11.权利要求6、7或9中任一权利要求的化合物,其为[4-(2-氨基-4-甲基-噻唑-5-基)-嘧啶-2-基]-(3-硝基-苯基)-胺[1]。
12.药物组合物,含有权利要求1-11中任一权利要求的化合物或其可药用盐以及可药用稀释剂、赋形剂或载体。
13.权利要求1-11中任一权利要求的化合物或其可药用盐在制备用于治疗增殖性疾病的药物中的用途。
14.权利要求13的用途,其中,增殖性疾病是癌症或白血病。
15.权利要求13或14的用途,其中,以足以抑制至少一种CDK酶的量给药所述一种或多种化合物。
16.权利要求15的用途,其中,CDK酶是CDK2和/或CDK4。
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SG47583A1 (en) | 1986-01-13 | 1998-04-17 | American Cyanamid Co | 4,5,6-Substituted-n- (substituted-phenyl) -2- pyrimidinamines |
EP0672035A1 (en) | 1993-10-01 | 1995-09-20 | Novartis AG | Pyrimidineamine derivatives and processes for the preparation thereof |
GB9523675D0 (en) * | 1995-11-20 | 1996-01-24 | Celltech Therapeutics Ltd | Chemical compounds |
CN100355751C (zh) * | 2000-03-29 | 2007-12-19 | 西克拉塞尔有限公司 | 2-取代的4-杂芳基-嘧啶、其组合物及其用途 |
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Non-Patent Citations (2)
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Phenylamino-Pyrimidine (PAP) Derivatives: A New Class ofPotent and Selective Inhibitors of Protein Kinase C( ) PKC. Jurg Zimmennann, et al.Archive Der Pharmazie,Vol.329 No.7. 1996 * |
Phenylamino-Pyrimidine (PAP) Derivatives: A New Class ofPotent and Selective Inhibitors of Protein Kinase C() PKC. Jurg Zimmennann, et al.Archive Der Pharmazie,Vol.329 No.7. 1996 |
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EP1430051A1 (en) | 2004-06-23 |
EP1430051B1 (en) | 2006-12-27 |
EP1760082A1 (en) | 2007-03-07 |
US7427627B2 (en) | 2008-09-23 |
JP4495963B2 (ja) | 2010-07-07 |
ATE349443T1 (de) | 2007-01-15 |
NZ531596A (en) | 2005-08-26 |
JP2005508931A (ja) | 2005-04-07 |
DE60217140D1 (de) | 2007-02-08 |
IL161092A0 (en) | 2004-08-31 |
CZ2004354A3 (cs) | 2004-06-16 |
CN1617870A (zh) | 2005-05-18 |
DE60217140T2 (de) | 2007-04-19 |
US20040259894A1 (en) | 2004-12-23 |
BR0212944A (pt) | 2004-10-13 |
CA2460909A1 (en) | 2003-04-10 |
US20060199830A1 (en) | 2006-09-07 |
US7388015B2 (en) | 2008-06-17 |
WO2003029248A1 (en) | 2003-04-10 |
MXPA04002914A (es) | 2005-06-20 |
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