Napththalene derivatives which inhibit the cytokine or biological activity of microphage migration inhibitory factor (mif)

A method of inhibiting cytokine or biological activity of MIF comprising contacting MIF with a cytokine or biological activity inhibiting effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof

• wherein
• Y is O, NR9 or S(O)q,
• R1 is selected from hydrogen, C1-6alkyl, —(CR10R10′)nhalo, —(CR10R10′)nOR11, —(CR10R10′)n—SR11, —(CR10R10′)n—N(R12)2, —(CR10R10′)nS(O)R11, —(CR10R10′)nS(O)2R11, —(CR10R10′)n—S(O)3R11, —(CR10R10′)nC(O)R13, —(CR10R10′)n—C(═NR14)R15 or —(CR10R10′)nR16;
• R2 is selected from hydrogen, C1-20alkyl, C2-20alkenyl, C2-20alkynyl, —(CR10R10′)mOR17, —(CR10R10′)mSR17, —(CR10R10′)mNR18R19, —(CR10R10′)mS(O)R20, (CR10R10′)mS(O)2R20, —(CR10R10′)mC(O)R20, —(CR10R10′)mC(S)R20, —(CR10R10′)mC(═NR11)R15 or —(CR10R10′)mR16;
• R3, R4 and R5 are independently selected from hydrogen, C1-3alkyl, —(CR10R10′)nN(R)4)2, —(CR10R)nOR14, —(CR10R10′)n—SR14 or —(CR10R10′)nhalo;
• R6 is selected from hydrogen, C1-6alkyl, —C(O)C1-6alkyl, —C(O)N(R9)2—, —C(S)N(R9)2—, —(CR10R10′)nR21, or R6Y and R5 together may form —X—(CH2)r-Z-, where X and Z may be independently selected from O, S or NR14;
• R7 and R8 are independently selected from hydrogen, C1-3alkyl, C2-3alkenyl, C2-3alkynyl or —(CR10R10′)nR22;
• Each R9 is independently selected from H or C1-6alkyl;
• Each R10 and R10′ is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, halogen, OR11, SR11, C1-3alkoxy, CO2R14, N(R14)2, —CN, NO2, aryl or heterocyclyl;
• R11 is hydrogen or C1-6alkyl;
• Each R12 is independently selected from hydrogen, C1-6alkyl, NH—C(═NR14)R15, C(O)R14 or C(S)R14;
• R13 is hydrogen, C1-6alkyl, OR14, SR14 or N(R14)2;
• Each R14 is independently selected from hydrogen or C1-3alkyl;.
• R15 is C1-6alkyl, NH2, NH(C1-3alkyl) or N(C1-3alkyl)2, OR23 or SR23;
• R16 is hydroxy, C1-3alkoxy, SH, SC1-3alkyl, halo, C(O)R31, C(R24)3, CN, aryl or heterocyclyl;
• R17 is selected from hydrogen, C1-20alkyl, C2-20alkenyl, C2-20alkynyl, (CR26R26′)s—R 27, C(O)R25, CO2R25, C(S)R25, C(S)OR25, S(O)R25, S(O)2R25, [C(O)CH(R29)NH]r—R23 or [sugar]r;
• R18 and R19 are independently selected from hydrogen, C1-20alkyl, C2-20alkenyl, C2-20alkynyl, (CR26R26′)sR27, C(O)R25, C(S)R25, S(O)R25, S(O)2R25, [C(O)CH(R29)NH]r—R23, [sugar]r, C(═NR23)NH2 or NH—C(═NR23)NH2;
• R20 is selected from hydrogen, C1-20alkyl, C2-20alkenyl, C2-20alkynyl, OR28, SR28, N(R28)2, [NH—CHR29C(O)]r—OR23, [sugar]r or (CR26R26′)sR27;
• R21 is OR28, SR28, halo or N(R25)2;
• R22 is halo, CO2H, SO3H, NO2, NH2, CO2C1-3alkyl, SO3C1-3alkyl or C(R24)3;
• R23 is hydrogen or C1-3alkyl;
• Each R24 is independently selected from hydrogen, Cl or F;
• Each R25 is independently selected from hydrogen, C1-20alkyl, C2-20alkenyl, C2-20alkynyl, aryl or (CR26R26′)sR27;
• Each R26 and R26′ is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, halogen, hydroxy, C1-3alkoxy, CO2H, CO2C1-3alkyl, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, CN, NO2, aryl or heteroaryl;
• R27 is hydroxy, C1-3alkoxy, SH, SC1-3alkyl, halo, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C(O)R31, aryl or heterocyclyl;
• Each R28 is independently selected from hydrogen, C1-20alkyl, C2-20alkenyl, C2-20alkynyl or (CR26R26′)R30;
• R29 is the characterising group of an amino acid;
• R30 is halogen, hydroxy, C1-3alkoxy, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C(O)R31, aryl or heterocyclyl;
• R31 is C1-3alkyl, OH, C1-3alkoxy, aryl, aryloxy, heterocyclyl or heterocyclyloxy;
• q is 0, 1, 2 or 3;
• n is 0, 1, 2 or 3;
• m is 0 or 1 to 20;
• r is b 1 to 5;
• s is 1 to 10;
• and
• t is 1 or 2;
• wherein an alkyl, alkenyl, alkynyl, alkyloxy, aryl or heterocyclyl group may be optionally substituted one or more times.