新型酰基脲类Raf激酶抑制剂的合成及其抗肿瘤活性

Synthesis and Antitumor Activivties of Novel Imidazole Acyl Urea Derivatives Raf Kinase Inhibitors

以4-氯吡啶甲酸为原料,经6步反应制得两个中间体——取代基-4-【{2-[5-(三氟甲基)-1H-咪唑-2-基]吡啶-4-基}氧基】苯胺(7a和7d);7分别与取代苯甲酰基异硫氰酸酯反应,合成了6个新型的酰基脲类Raf激酶抑制剂(9a^9f),其结构经1H NMR和ESI-MS表征。用MTT法考察了9a^9f对人胃癌细胞株(BGC823)的抑制活性。结果表明:N-【3-氟-4-{2-[5-(三氟甲基)-1H-咪唑-2-基]吡啶-4-氧基}苯基】-4-氯苯甲酰硫脲(9c)和N-【4-{2-[5-(三氟甲基)-1H-咪唑-2-基]吡啶-4-氧基}苯基】-3-(吡啶-3-基)丙烯酰硫脲(9d)的抑制活性较好。在用药量为100μg时,9c和9d对BGC823的抑制率分别为66.86%和63.60%,与索拉非尼药效接近(70.97%)。

Two intermediates, N- [ 3-fluoro-4- [ { 2- [ 5- （trifluoromethyl） -1H-imidazol-2-yl ] oxy ] -phe- nyl] aeetamide（Ta） and N-[4-[ {2-[ 5-（trifluoromethyl） -1H-imidazol-2-yl ] pyridin-4-yl I oxy] -phen- yl ] acetamide（Td）, were obtained by a six-step reaction from 4-ehloropieolinie acid. Six novel imidazole acyl urea derivatives Raf kinase inhibitors （ga - 9f） were synthesized by the reaction of 7a and 7d with substituted benzoyl isothiocyanate, respectively. The structures were characterized by 1H NMR and ESI-MS. The antitumor activities of 9a - 9f against human gastric carcinoma cell line （BGC823） were investigated by MrlT method. The results showed that 4-ehloro-N-[ [ 3-fluoro-4-[ {2- [ 5- （trifluoromethyl） -1H-imidazol-2-yl ] oxy ] pyridin-4-yl t ] -phenyl ] earbamothioyl ] benzamide （9c） and N- [ [ 3 -fluoro-4- [ 12- E 5- （ trifluoromethyl ） -1H-imidazol-2-yl ] pyridin-4-yl I oxy ] -phenyl ] earbamo- thioyl]-3-（pyridin-3-yl） acrylamide （gd） exhibited similar inhibitory activities to Sorafenib （70. 97% ）. The inhibitory activities ofgc and 9d were 66.86% and 63.60% with dosage of 100 μg, respectively .