Solid-phase Parallel Synthesis of a Novel N-[Alkylsulfonamido-spiro(2H-1-benzopyran-2,4-piperidine)-6-yl] substituted Amide and Amine Drug-like Libraries

Abstract

We report the solid-phase library construction of 222 number of a novel N-[alkyl sulfonamido-spiro(2H-1-benzopyran-2,4-piperidine)-6-yl] substituted amide 1A and amine 1B derivatives. The polymer-bound N-[alkylsulfonamido-spiro(2H-1-benzopyran-2,4-piperidine)-6-yl] substituted amide 9 and amine 10 derivatives were obtained by first diversity generation with various acid chlorides and alkyl halides. Further reactions on the resins 9 and 10 with substituted sulfonyl chlorides produced the desired N-[alkylsulfonamido-spiro(2H-1-benzopyran-2,4-piperidine)-6-yl] substituted amide 1A and amine 1B analogues.

Solid-Phase Parallel Synthesis of Drug-Like Artificial 2H-Benzopyran Libraries

“…The drug-like small molecule library with variously substituted benzopyrans was constructed by Gong and co-workers [79,80]. An orally active 5-LO [81,82,83,84,85,86,87] inhibitor KRH-102140 [30,31] with the benzopyran moiety (see Figure 1) was discovered as a lead compound on the drug discovery program via HTS of in-house small molecule library by Gong et al [88].…”

“…On the basis of the biological activities of the benzopyran moiety with KRH-102140, Gong and co-workers demonstrated the solid-phase synthesis of a 222-number library of 2,6-difunctionalized 2 H -benzopyran 65 and 66 for the lead optimization as a 5-LO inhibitor [80].…”

“…Solid-phase synthesis of 6-amido- and 6-amino-substituted-2-functionalized benzopyrans 65 and 66 by Gong et al [80]. …”

“…they possess physiological properties that allow them to be absorbed into the gastrointestinal system. Lipinski’s Rule [76] and similar formulations [77,78] served as guidelines to estimate the physicochemical properties of the synthesized 222-member library of 6-amido- and 6-amino-substituted-2-functionalized benzopyrans 65 and 66 , respectively [80].…”