Patent ID: 6555555
Filing Date: 2003-04-29
Classification: C07D

Abstract:
An inhibitor of interleukin-6 and/or interleukin-12 production comprising, as an active ingredient, a fused thiophene derivative of the formula (I) wherein  is a single or double bond, Y is (i) â€ƒor (ii) hydrogen (with the proviso that when  is a double bond, Y is hydrogen, and when  is a single bond, Y is m and n are each independently 0 or an integer of 1-2, p is 0 or an integer of 1-4, q is 0 or an integer of 1-5, Z is single bond, C1-8 alkylene, C2-8 alkenylene or C2-8 alkynylene, â€ƒis (i) benzene ring or (ii) 6-membered monocyclic hetero aryl containing 1-2 nitrogen atom(s), â€ƒis (i) C3-15 mono-, bi- or tricyclic carbo ring or (ii) 4-18 membered mono-, bi- or tricyclic hetero ring containing 1-4 nitrogen atoms, 1-2 oxygen atoms and/or one sulfur atom, each R1 of (R1)p is independently, (i) C1-8 alkyl, (ii) C2-8 alkenyl, (iii) C2-8 alkynyl, (iv) nitro, (v) cyano, (vi) halogen, (vii) Cyc1, (viii) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with halogen or Cyc1 or (ix) â€”A1â€”A2â€”A3, A1 is (i) single bond, (ii) C1-8 alkylene, (iii) C2-8 alkenylene or (iv) C2-8 alkynylene, A2 is (i) â€”Oâ€”, (ii) â€”NR3â€”, (iii) â€”C(O)â€”, (iv) â€”CH(OH)â€”, (v) â€”C(O)NR4â€”, (vi) â€”NR5C(O)â€”, (vii) â€”C(O)Oâ€”, (viii) â€”OC(O)â€”, (ix) â€”SO2NR6â€”, (x) â€”NR7SO2â€”, (xi) â€”C(O)NR9Oâ€”, (xii) â€”OC(O)NR10â€”, (xiii) â€”NR11C(O)NR12â€”, (xiv) â€”NR13C(O)Oâ€” or (xv) â€”OC(O)Oâ€”wherein R3, R4, R5, R6, R7, R9, R10, R11, R12 and R13 are each independently, hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted with Cyc1, cyano, â€”OR14, wherein R14 is hydrogen or C1-8 alkyl, with the proviso that the linkage of the right side of each group represented by A2 binds to A3, A3 is (i) hydrogen, (ii) C1-8 alkyl, (iii) C2-8 alkenyl, (iv) C2-8 alkynyl, (v) Cyc1 or (vi) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with 1-3 groups selected from the following (a)-(i): (a) halogen, (b) cyano, (c) â€”P(O)(R15)2, (d) â€”Si(R16)3, (e) Cyc1, (f) â€”C(O)R17, (g) â€”OR18, (h) â€”NR19R20, (i) â€”SR21; each R15 is independently, hydroxy or C1-8 alkoxy, each R16 is independently C1-8 alkyl, R17 is (i) hydrogen, (ii) C1-8 alkyl, (iii) hydroxy, (iv) C1-8 alkoxy, (v) Cyc1 or (vi) â€”NR22R23, (wherein R22 is hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted with phenyl, and wherein R23 is hydrogen, C1-8 alkyl, Cyc1 or C1-8 alkyl substituted with Cyc1 or NR24R25, wherein R24 and R25 are each independently hydrogen, C1-8 alky, phenyl, C1-8 alkyl substituted with phenyl, R18 is (i) hydrogen, (ii) C1-8 alkyl, (iii) C2-8 alkenyl, (iv) Cyc1 or (v) C1-8 alkyl substituted with (a) Cyc1, (b) Si(R26)3 wherein each R26 is independently C1-8 alkyl, or (c) â€”OR27, wherein R27 is hydrogen, C1-8 alkyl or C2-5 acyl, R19 is (i) hydrogen, (ii) C1-8 alkyl, (iii) phenyl or (iv) C1-8 alkyl substituted with phenyl, R20 is (i) hydrogen, (ii) C1-8 alkyl or (iii) â€”C(O)R28, wherein R28 is C1-8 alkyl, C1-8 alkoxy, Cyc1 or NR29R30, wherein R29 and R30 are each independently, hydrogen or C1-8 alkyl, (iv) Cyc1 or (v) C1-8 alkyl substituted with Cyc1 or cyano, R21 is (i) hydrogen, (ii) C1-8 alkyl or (iii) Cyc1, Cyc1 is (i) C3-15 mono-, bi- or tricyclic carbo ring or (ii) 4-18 membered mono-, bi- or tricyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom, wherein the said carbocyclic ring or heterocyclic ring may be substituted with one or more of (i) C1-8 alkyl, (ii) C2-8 alkenyl, (iii) C2-8 alkynyl, (iv) oxo, (v) cyano, (vi) nitro, (vii) trihalomethyl, (viii) trihalomethoxy, (ix) halogen, (x) diphenylmethyl, (xi) triphenylmethyl, (xii) Cyc2, (xiii) â€”OR31, (xiv) â€”SR32, (xv) â€”NR33R34, (xvi) â€”SO2NR35R36, (xvii) â€”C(O)R37 or (xviii) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with Cyc2, hydroxy, halogen or â€”C(O)â€”Cyc2, R31 and R32 are each independently, hydrogen, C1-8 alkyl or Cyc2, R33 is hydrogen or C1-8 alkyl, R34 is hydrogen, C1-8 alkyl or â€”C(O)â€”Cyc2, R35 is hydrogen or C1-8 alkyl, R36 is hydrogen, C1-8 alkyl or Cyc2, R37 is hydrogen, C1-8 alkyl, â€”OR38, â€”NR39R40, Cyc2, or C1-8 alkyl substituted with Cyc2 or â€”C(O)â€”Cyc2, R38, R39 and R40 are each independently, hydrogen, C1-8 alkyl, or C1-8 alkyl substituted with Cyc2, CyC2 is (i) C3-15 mono-, bi- or tricyclic carbo ring or (ii) 4-18 membered mono-, bi- or tricyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom, wherein the said carbocyclic ring or heterocyclic ring may be substituted with one or more of (i) C1-8 alkyl, (ii) C2-8 alkenyl, (iii) C2-8 alkynyl, (iv) oxo, (v) cyano, (vi) nitro, (vii) trihalomethyl, (viii) trihalomethoxy, (ix) halogen, (x) â€”OR41, (xi) â€”SR42, (xii) â€”NR43R44, (xiii) â€”SO2NR45R46, (xiv) â€”C(O)R47, (xv) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with hydroxy or halogen or (xvi) phenyl, R41, R42, R43, R44, R45 and R46 are each independently, hydrogen or C1-8 alkyl, R47 is hydrogen, C1-8 alkyl or C1-8 alkoxy each R2 of (R2)q is independently, (i) C1-8 alkyl, (ii) C2-8 alkenyl, (iii) C2-8 alkynyl, (iv) â€”OR48, (v) â€”NR49R50, (vi) â€”C(O)R51, (vii) nitro, (viii) cyano, (ix) halogen or (x) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with â€”OR48, â€”NR49R50, â€”C(O)R51, halogen or Cyc3, R48 is â€ƒ(i) hydrogen, â€ƒ(ii) C1-8 alkyl, â€ƒ(iii) C2-8 alkenyl, â€ƒ(iv) C2-8 alkynyl, â€ƒ(v) Cyc3 or â€ƒ(vi) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with halogen, â€”OR52, â€”NR53R54, â€”C(O)R55 or Cyc3, R49 and R50 are each independently, hydrogen, C1-8 alkyl or â€”COR59, R51 is hydrogen, C1-8 alkyl, hydroxy, C1-8 alkoxy or â€”NR60R61, R52 is hydrogen, C1-8 alkyl, Cyc3, or C1-8 alkyl substituted with Cyc3, R53 and R54 are each independently, hydrogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl or â€”C(O)R56, wherein R56 is C1-8 alkyl, C1-8 alkoxy, Cyc3, or C1-8 alkyl substituted with Cyc3, R55 is hydroxy, C1-8 alkoxy, or â€”NR57R58, wherein R57 and R58 are each independently, hydrogen, C1-8 alkyl, or C1-8 alkyl substituted with Cyc3, R59 is C1-8 alkyl or C1-8 alkoxy, R60 and R61 are each independently, hydrogen or C1-8 alkyl, Cyc3 is (i) C3-15 mono-, bi- or tricyclic carbo ring or (ii) 4-18 membered mono-, bi- or tricyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom, wherein the said carbocyclic ring or heterocyclic ring may be substituted with one or more of (i) C1-8 alkyl, (ii) C1-8 alkoxy, (iii) nitro, (iv) halogen, (v) cyano, (vi) hydroxy, (vii) benzyloxy, (viii) â€”NR62R63, (ix) â€”COOR64, (x) trihalomethyl, (xi) trihalomethoxy, (xii) phenyl, (xiii) phenoxy, (xiv) phenylthio, (xv) C1-8 alkyl or C1-8 alkoxy substituted with phenyl, phenoxy, phenylthio, hydroxy, â€”NR62R63 or â€”COOR64, R62 and R63 are each independently, hydrogen or C1-8 alkyl, R64 is hydrogen or C1-8 alkyl, with the proviso that when A2 is (vi) â€”NR5C(O)â€”, (x) â€”NR7SO2â€”, (xiv) â€”NR13C(O)Oâ€” or (xv) â€”OC(O)Oâ€”, then A3 is not hydrogen, an N-oxide derivative thereof or a non-toxic salt thereof.