Design and Synthesis of Novel Thienopyrimidine Derivatives as Potential Targeted Anticancer Agents

Abstract

According to statistics from the American Cancer Society (ACS), Cancer is the third most lethal disease after cardiovascular diseases, infectious and parasitic diseases.It may affect humans of all ages, regions and socioeconomic levels. Continuous research worldwide is focusing on developing better therapeutics as well as finding novel druggable targets for better efficacy. Small molecule tyrosine kinase inhibitors provide attractive therapeutic targets, as they are able to block cell signaling associated with many types of cancer. In this study, thienopyrimidine derivatives have been designed and synthesized as targeted EGFR/HER-2 inhibitors. The design focused on exploration of the previous revealed SAR studies, bioisosteric modifications of the lead compounds both in market and in clinical studies, and identification of the key interactions with the binding site in silico. Synthesis of the designed compounds was then accomplished & their structures were confirmed by various spectral and microanalytical data. This study involved the synthesis of the following reported intermediates: 1) 1-(Benzyloxy)-4-nitrobenzene (Ia) 2) 1-Fluoro-3-((4-nitrophenoxy) methyl)benzene (Ib) 3) 1-Fluoro-4-((4-nitrophenoxy) methyl)benzene (Ic) 4) 1-Chloro-4-((4-nitrophenoxy) methyl)benzene (Id) 5) 2-Chloro-1-((3-fluorobenzyl) oxy)-4-nitrobenzene (If) 6) 4-(Benzyloxy) aniline (IIa) 7) 4-((4-Chlorobenzyl) oxy) aniline (IId) 8) 4-(Benzyloxy)-3-chloroaniline (IIe) 9) 3-Chloro-4-((3-fluorobenzyl) oxy) aniline (IIf) 10) 3-Chloro-4-((4-fluorobenzyl) oxy) aniline (IIg) 11) 3-Chloro-4-((4-chlorobenzyl) oxy) aniline (IIh) 12) Ethyl -5-amino-4-cyano-3-methylthiophene-2-carboxylate (III) 13) 2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile(VI) 14) Ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (IX) 15) 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one (X) 16) 4-Chloro-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine (XI) 17) 1-(4-((5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-yl)amino)phenyl)ethan-1-one (XII) Also, it comprised the following new intermediates: 1) 1-(Benzyloxy)-2-chloro-4-nitrobenzene (Ie) 2) 2-Chloro-1-((4-fluorobenzyl) oxy)-4-nitrobenzene (Ig) 3) 2-Chloro-1-((4-chlorobenzyl) oxy)-4-nitrobenzene (Ih) 4) 4-((3-Fluorobenzyl) oxy) aniline (IIb) 5) 4-((4-Fluorobenzyl) oxy) aniline (IIc) 6) Ethyl.(E)-4-cyano-5-(((dimethylamino)methylene)amino)-3-methylthiophene-2-carboxylate (IV) 7) (E)-N'-(3-Cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-N,N-dimethylformimidamide (VII)