Oestrone sulfatase inhibiting estrone sulfamate compounds and associated pharmaceutical composition and uses thereof

摘要

New estrone sulfamate derivatives (I), their salts and esters are useful for treating estrogen-dependent disorders, particularly breast cancer in post-menopausal women. Compounds (I), their salts and esters are new: r : single or double bond; R1,R2, R4, R9,R10H or 1-6C alkyl; or R1+R2piperidino, morpholino or piperazino; R3H, cyano, nitro, COOR4, (CH2)nNR6R7 or (CH2)nOR5; R5H or lower alkyl; n : 0-6; R6, R7R1, or 1-6C acyl; or R6+R7R1+R2; and R8H, nitro or NR6R7; When r : single bond, then one of R11 and R12 is H, and the other : 1-6C alkyl, 2-6C alkenyl, 2-6C alkynyl, 1-6C alkoxy, 1-6C acyl, 1-6C acyloxy or (CH2)mO(CH2)qNR6R7; m : 0-6; q : 1-6 or; R11+R12O or =CR13R14; R13, R14R1, cyano, (CH2)mO(CH2)qNR6R7 or COOR4; When r : double bond, then one of R11 and R12 is absent, and the other : H, 1-6C alkyl, 2-6C alkenyl, 2-6C alkynyl, 1-6C alkoxy, 1-6C acyl, 1-6C acyloxy or (CH2)mO(CH2)qNR6R7; m : 0-6; q : 1-6. Independent claims are included for pharmaceutical compositions comprising (I) and suitable carriers. ACTIVITY : Anti-estrogenic. MECHANISM OF ACTION : Estrone sulfatase inhibitor. Estrone sulfatase inhibition of (Ia) was measured in female Sprague-Dawley rats (40-50 g) using the method described by Wakeling et al in Endocrinology:99:447-453 (1983). (Ia) had an IC50 of 16 picomolar with no observed estrogenic activity.