Preparation of oxalylaminothiophene derivatives as modulators of protein tyrosine phosphatases (PTPases).

Abstract

Oxalylaminoheterocycles (e.g., oxalylaminothiophene and oxalylaminothienopyran derivs., etc.) were prepd. as inhibitors of Protein Tyrosine Phosphatases (PTPases), such as PTP1B, TC-PTP, CD45, SHP-1, SHP-2, PTPα, PTPε, PTPμ, PTPδ, PTPσ, PTPζ, PTPβ, PTPD1, PTPD2, PTPH1, PTP-MEG1, PTP-LAR, and HePTP. These compds. are indicated in the management or treatment of a broad range of diseases such as autoimmune diseases, acute and chronic inflammation, osteoporosis, various forms of cancer and malignant diseases, and type I diabetes and type II diabetes. For instance, 2-amino-5-hydroxymethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-Bu ester (prepn. given) was reacted with phthalimide in THF, PPh3, and DIAD to form the 5-phthalimidomethyl deriv. (47%). The amine was amidated with imidazol-1-yloxoacetic acid tert-Bu ester in CH2Cl2 and TEA (99%), followed by hydrolysis of the ester function with TFA in CH2Cl2, to give 5-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)-2-(oxalylamino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid (I) in 57% yield. In an in vitro test against PTP1B expressed in E. coli and purified by known methods, Ki values at various inhibitor concns. were detd. An anal. of selectivity of two PTPase inhibitors against PTP1B, PTP-LAR, PTPε, CD45, and PTPβ showed that one compd. of the invention is a non-selective inhibitor, whereas another behaves like a selective inhibitor. [on SciFinder(R)]