887247-31-6Relevant articles and documents
Solid-phase synthetic method for N-alkyl-4-alkylamino-6-arylthieno[3,2-d]pyrimidine-2-carboxamide derivatives
Ahn, Seohyeon,Jeon, Moon-Kook
, (2021/06/12)
Herein, we describe a solid-phase synthetic method for synthesizing N-alkyl-4-alkylamino-6-arylthieno[3,2-d]pyrimidine-2-carboxamide derivatives. The derivatives consist of the biologically active 6-phenylthieno[3,2-d]pyrimidine scaffold. The template mediated synthetic strategy involving Suzuki coupling reactions between methyl 3-amino-5-bromothiophene-2-carboxylate and arylboronic acids afforded methyl 3-amino-5-arylthiophene-2-carboxylates. Cyclocondensation reactions involving methyl 3-amino-5-arylthiophene-2-carboxylates and methyl cyanoformate afforded esters, that when subjected to hydrolysis reactions yielded 6-aryl-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-carboxylic acids (template compounds). These carboxylic acid templates were coupled with primary alkylamine-loaded acid-sensitive methoxybenzaldehyde (AMEBA) resins. The amide coupling reactions were followed by direct amination reactions mediated by benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP). The compounds were subsequently cleaved from the solid support, purified using the reverse phase-high performance liquid chromatography technique (RP-HPLC), and passed through a strong anion exchange (SAX) resin pretreated with water to yield the N-alkyl-4-alkylamino-6-arylthieno[3,2-d]pyrimidine-2-carboxamide derivatives. The reaction conditions for the solid-phase transformations were optimized using a solution-phase model using 2,4-dimethoxybenzyl-protected isobutylamine as a reactant. 2,4-Dimethoxybenzyl-protected isobutylamine, and not AMEBA resin-loaded isobutylamine was used during the process. Substituent variation experiments were performed using 6-aryl-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-carboxylic acids and a variety of primary and secondary amine building blocks. Additionally, we could include the Suzuki coupling step in a modified solid-phase synthetic sequence.
Potent, selective, and orally efficacious antagonists of melanin-concentrating hormone receptor 1
Tavares, Francis X.,Al-Barazanji, Kamal A.,Bigham, Eric C.,Bishop, Michael J.,Britt, Christy S.,Carlton, David L.,Feldman, Paul L.,Goetz, Aaron S.,Grizzle, Mary K.,Guo, Yu C.,Handlon, Anthony L.,Hertzog, Donald L.,Ignar, Diane M.,Lang, Daniel G.,Ott, Ronda J.,Peat, Andrew J.,Zhou, Hui-Qiang
, p. 7095 - 7107 (2008/04/18)
The high expression of MCH in the hypothalamus with the lean hypophagic phenotype coupled with increased resting metabolic rate and resistance to high fat diet-induced obesity of MCH KO mice has spurred considerable efforts to develop small molecule MCHR1 antagonists. Starting from a lead thienopyrimidinone series, structure-activity studies at the 3- and 6-positions of the thienopyrimidinone core afforded potent and selective MCHR1 antagonists with representative examples having suitable pharmacokinetic properties. Based on structure-activity relationships, a structural model for MCHR1 was constructed to explain the binding mode of these antagonists. In general, a good correlation was observed between pKas and activity in the right-hand side of the template, with Asp123 playing an important role in the enhancement of binding affinity. A representative example when evaluated chronically in diet-induced obese mice resulted in good weight loss effects. These antagonists provide a viable lead series in the discovery of new therapies for the treatment of obesity.
