Synthesis of novel 2-benzothiopyran and 3-benzothiepin derivatives and their stimulatory effect on bone formation

Citation
T. Oda et al., Synthesis of novel 2-benzothiopyran and 3-benzothiepin derivatives and their stimulatory effect on bone formation, J MED CHEM, 42(4), 1999, pp. 751-760
Citations number
28
Categorie Soggetti
Chemistry & Analysis
Journal title
JOURNAL OF MEDICINAL CHEMISTRY
ISSN journal
00222623 → ACNP
Volume
42
Issue
4
Year of publication
1999
Pages
751 - 760
Database
ISI
SICI code
0022-2623(19990225)42:4<751:SON2A3>2.0.ZU;2-J
Abstract
In a search for therapeutic agents for the treatment of osteoporosis and bo ne fracture, we found that 2-benzothiopyran-1-carboxamide derivatives I, de rived from ipriflavone as a lead compound, increase cellular alkaline phosp hatase activity in cultures of rat bone marrow stromal cells. Further modif ication of 1 has led to the discovery of more potent 3-benzothiepin-2-carbo xamide derivatives 2. Of these, 3-benzothiepin derivatives bearing a 4-(dia lkoxyphosphorylmethyl)phenyl group on the 2-carboxamide moiety such as 2h a nd 2q exhibited significant improvement of activity compared to ipriflavone . Asymmetric synthesis of 2h and 2q revealed that the (-)-isomers possessed activities superior to those of the (+)-isomers. Further evaluation of the se compounds using the mouse osteoblastic cell line MC3T3-E1 revealed that (-)-2q enhanced the effect of bone morphogenetic protein. In addition, appl ication of a sustained-release agent containing 2q increased the area of ne wly formed bone in a rat skull defect model. Based on these findings, (-)-2 q was selected for further investigation as a new drug stimulating bone for mation. Synthesis and structure-activity relationships for this novel serie s of 2-benzothiopyran and 3-benzothiepin derivatives are detailed.