Based on the potent phosphodiesterase 10 A (PDE10A) inhibitor PQ‐10, we synthesized 32 derivatives to determine relationships between their molecular structure and binding properties. Their roles as potential positron emission tomography (PET) ligands were evaluated, as well as their inhibitory potency toward PDE10A and other PDEs, and their metabolic stability was determined in vitro. According to our findings, halo‐alkyl substituents at position 2 of the quinazoline moiety and/or halo‐alkyloxy substituents at positions 6 or 7 affect not only the compounds′ affinity, but also their selectivity toward PDE10A. As a result of substituting the methoxy group for a monofluoroethoxy or difluoroethoxy group at position 6 of the quinazoline ring, the selectivity for PDE10A over PDE3A increased. The same result was obtained by 6,7‐difluoride substitution on the quinoxaline moiety. Finally, fluorinated compounds (R)‐7‐(fluoromethoxy)‐6‐methoxy‐4‐(3‐(quinoxaline‐2‐yloxy)pyrrolidine‐1‐yl)quinazoline ( 16 a ), 19 a – d , (R)‐tert‐butyl‐3‐(6‐fluoroquinoxalin‐2‐yloxy)pyrrolidine‐1‐carboxylate ( 29 ), and 35 (IC50 PDE10A 11–65 nM ) showed the highest inhibitory potential. Further, fluoroethoxy substitution at position 7 of the quinazoline ring improved metabolic stability over that of the lead structure PQ‐10. 相似文献
A highly efficient and environmentally benign procedure for the synthesis of quinazoline derivatives via the condensation of carbonyl compounds with 2-aminobenzamide using zirconium tetrakis(dodecylsulfate) [Zr(DS)4] as a highly efficient, reusable Lewis acid-surfactant-combined catalyst is described. A broad range of substrates including aldehydes and ketones are successfully condensed with 2-aminobenzamide and all reactions are completed in short times and the products are obtained in good to excellent yields. The catalyst could be recycled and reused several times without any loss of efficiency. Moreover, presented procedure has been applied successfully for the synthesis of spiro-quinazolinones and fused ring-quinazolinone derivatives. 相似文献
The one‐pot synthesis of substituted 2‐arylquinazoline derivatives and tetracylic isoindolo[1,2‐a]quinazoline via cyanation followed by rearrangement of ortho‐substituted 2‐halo‐N‐arylbenzamides is described. Using dimethyl sulfoxide (DMSO) as the solvent, the cleavage of the tetracyclic isoindole fused quinazoline leads to the formation of 2‐arylquinazoline derivatives. When 1,4‐dioxane is used as the solvent, tetracyclic isoindole fused quinazolines are produced in good yield. A wide range of products, including 2‐phenylquinazolin‐4‐amine, 4‐methyl‐2‐phenylquinazoline and long‐chain 2‐phenyl‐4‐styrylquinazoline derivatives were produced in moderate to good yields using DMSO as the solvent. However, various tetracyclic isoindole fused quinazoline derivatives were obtained in good yields when 1,4‐dioxane was used as the solvent.
Synthesis and 13C-N.M.R.-Spectroscopy of Pyrrolo-[2,1,-b]quinazoline In 6- or 7-position substituted pyrrolo-[2,1-b]quinazoline derivatives were synthesized by reacting substituted anthranilic acid derivatives with either 4-amino-butyric acid or 2-methoxy-Δ1-pyrroline. Furthermore some at C-3 substituted desoxyvasicinone derivatives were prepared. Using these compounds and different n.m.r. spectroscopie techniques the 13C resonance signals of all carbon atoms in peganine were assigned. 相似文献
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