ANTIRHEUMATIC AGENTS - NOVEL METHOTREXATE DERIVATIVES BEARING A BENZOXAZINE OR BENZOTHIAZINE MOIETY

Novel methotrexate (MTX) derivatives bearing dihydro-2H-1,4-benzothiaz ine or dihydro-2H,1,4-benzoxazine were synthesized and tested for in v itro antiproliferative activities against human synovial cells (hSC) a nd human peripheral blood mononuclear cells (hPBMC) obtained from pati ents with rheumatoid arthritis and healthy volunteers, respectively. I n vivo antiarthritic activities of these derivatives were also evaluat ed in a rat adjuvant arthritis model. ydro-2H-1,4-benzothiazin-7-yl]ca rbonyl]-L-glutamic acid (3c) exhibited more potent antiproliferative a ctivities in hSC and hPBMC than MTX in vitro, Antiproliferative activi ties of ro-2H-1,4-benzoxazin-7-yl]carbonyl]-L-homoglutamic acid (3b) a nd -2H-1,4-benzothiazin-7-yl]carbonyl]-L-homoglutamic acid (3d) (MX-68 ) were comparable to that of MTX in these in vitro assays. Compounds 3 b,d (MX-68) significantly suppressed progression of the adjuvant arthr itis in a dose-dependent manner ranging from 0.5 to 2.5 mg/kg (po). In addition, 3d (MX-68) completely suppressed this progression at the do se of 2.5 mg/kg (po). Importantly, 3d (MX-68) having benzothiazine and homoglutamate, as expected, did not undergo polyglutamation, a proces s which may be responsible for the associated side effects of MTX. The se results suggest that 3d (MX-68) is a potent and safe candidate anti rheumatic agent, absent of the side effects of MTX.