745064-65-7Relevant articles and documents
Dopamine D3 receptor antagonists. 1. Synthesis and structure-activity relationships of 5,6-Dimethoxy-N-alkyl- and N-alkylaryl-substituted 2-aminoindans
Haadsma-Svensson,Cleek,Dinh,Duncan,Haber,Huff,Lajiness,Nichols,Smith,Svensson,Zaya,Carlsson,Lin
, p. 4716 - 4732 (2007/10/03)
5,6-Dimethoxy-2-(N-dipropyl)-aminoindan (3, PNU-99194A) was found to be a selective dopamine D3 receptor antagonist with potential antipsychotic properties in animal models. To investigate the effects of nitrogen substitution on structure- activity relationships, a series of 5,6-dimethoxy-N-alkyl- and N-alkylaryl-substituted 2-aminoindans were synthesized and evaluated in vitro for binding affinity and metabolic stability. The results indicate that substitution at the amine nitrogen of the 2-aminoindans is fairly limited to the di-N-propyl group in order to achieve selective D3 antagonists. Thus, combinations of various alkyl groups were generally inactive at the D3 receptor. Although substitution with an N-alkylaryl or N-alkylheteroaryl group yields compounds with potent D3 binding affinity, the D2 affinity is also enhanced, resulting in a less than 4-fold preference for the D3 receptor site, and no improvements in metabolic stability were noted. A large-scale synthesis of the D3 antagonist 3 has been developed that has proven to be reproducible with few purification steps. The improvements include the use of 3,4-dimethoxybenzaldehyde as a low-cost starting material to provide the desired 5,6-dimethoxy-1-indanone 5c in good overall yield (65%) and the formation of a soluble silyl oxime 17 that was reduced efficiently with BH3·Me2S. The resulting amino alcohol was alkylated and then deoxygenated using a Lewis acid and Et3SiH to give the desired product 3 in good overall yield of (～65%) from the indanone 5c.
