US 6,555,555 B1 · Fused thiophone derivatives and drugs containing the same as the active ingredient

Abstract

The present invention relates to a fused thiophene derivative of the formula (I) (wherein all the symbols are defined as described in the specification) and an inhibitor of producing interleukin-6 and/or interleukin-12 comprising the said derivative as an active ingredient. A fused thiophene derivative of the formula (I) is useful as an agent for the prevention and/or treatment of various inflammatory diseases, sepsis, multiple myeloma, plasma cell leukemia, osteoporosis, cachexia, psoriasis, nephritis, renal cell carcinoma, Kaposi's sarcoma, rheumatoid arthritis, gammopathy, Castleman's disease, atrial myxoma, diabetes mellitus, autoimmune diseases, hepatitis, multiple sclerosis, colitis, graft versus host immune diseases, infectious diseases.

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)
or
(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,
is
(i) benzene ring or
(ii) 6-membered monocyclic hetero aryl containing 1-2 nitrogen atom(s),
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 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) —A1—A2—A3,
A1 is
(i) single bond,
(ii) C1-8 alkylene,
(iii) C2-8 alkenylene or
(iv) C2-8 alkynylene,
A2 is
(i) —O—,
(ii) —NR3—,
(iii) —C(O)—,
(iv) —CH(OH)—,
(v) —C(O)NR4—,
(vi) —NR5C(O)—,
(vii) —C(O)O—,
(viii) —OC(O)—,
(ix) —SO2NR6—,
(x) —NR7SO2—,
(xi) —C(O)NR9O—,
(xii) —OC(O)NR10—,
(xiii) —NR11C(O)NR12—,
(xiv) —NR13C(O)O— or
(xv) —OC(O)O—
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, —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) —P(O)(R15)2,
(d) —Si(R16)3,
(e) Cyc1,
(f) —C(O)R17,
(g) —OR18,
(h) —NR19R20,
(i) —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) —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) —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) —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) —OR31, (xiv) —SR32, (xv) —NR33R34, (xvi) —SO2NR35R36, (xvii) —C(O)R37 or (xviii) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with Cyc2, hydroxy, halogen or —C(O)—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 —C(O)—Cyc2,
R35 is hydrogen or C1-8 alkyl,
R36 is hydrogen, C1-8 alkyl or Cyc2,
R37 is hydrogen, C1-8 alkyl, —OR38, —NR39R40, Cyc2, or C1-8 alkyl substituted with Cyc2 or —C(O)—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) —OR41, (xi) —SR42, (xii) —NR43R44, (xiii) —SO2NR45R46, (xiv) —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) —OR48,
(v) —NR49R50,
(vi) —C(O)R51,
(vii) nitro,
(viii) cyano,
(ix) halogen or
(x) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with —OR48, —NR49R50, —C(O)R51, halogen or Cyc3,
R48 is
(i) hydrogen,
(ii) C1-8 alkyl,
(iii) C2-8 alkenyl,
(iv) C2-8 alkynyl,
(v) Cyc3 or
(vi) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with halogen, —OR52, —NR53R54, —C(O)R55 or Cyc3,
R49 and R50 are each independently, hydrogen, C1-8 alkyl or —COR59,
R51 is hydrogen, C1-8 alkyl, hydroxy, C1-8 alkoxy or —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 —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 —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) —NR62R63, (ix) —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, —NR62R63 or —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) —NR5C(O)—, (x) —NR7SO2—, (xiv) —NR13C(O)O— or (xv) —OC(O)O—, then A3 is not hydrogen,
an N-oxide derivative thereof or a non-toxic salt thereof.

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Fused thiophone derivatives and drugs containing the same as the active ingredient

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Fused thiophone derivatives and drugs containing the same as the active ingredient

Life of this patent

Abstract

Claims4