US20030073706A1 - Fused thiophone derivatives and drugs containing the same as the active ingredient - Google Patents

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

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US20030073706A1
US20030073706A1 US10/127,409 US12740902A US2003073706A1 US 20030073706 A1 US20030073706 A1 US 20030073706A1 US 12740902 A US12740902 A US 12740902A US 2003073706 A1 US2003073706 A1 US 2003073706A1
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thiophene
dioxidebenzo
dihydro
phenylsulfonyl
oxy
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Mikio Konishi
Nobuo Katsube
Mitoshi Konno
Tadamitsu Kishimoto
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to fused thiophene derivatives and inhibitors of producing Interleukin-6 (abbreviated as IL-6 hereafter) and/or Interleukin-12 (abbreviated as IL-12 hereafter) containing fused thiophene derivatives as an active ingredient.
  • IL-6 Interleukin-6
  • IL-12 Interleukin-12
  • the present invention relates to inhibitors of producing IL-6 and/or IL-12 comprising, as an active ingredient, fused thiophene derivatives of the formula (I)
  • the present invention relates to a method for preparation of a compound of the formula (XI) which is an intermediate for the compounds of the formula (I).
  • Cytokine is a multifunctional factor which plays an important role in the host defence system of living body and it relates to various life phenomena. However, there are many diseases which may be caused by overproduction thereof or by overresponse thereto.
  • IL-6 is a cytokine produced from various cells, e.g. T cells, B cells, macrophages, kidney mesangial cells, fibroblasts etc., and its various physiological effects are known e.g. induction of B cell differentiation to antibody-producing cells, activation of T cells, increase of platelets, and production of acute phase protein from liver cells etc.
  • T cells e.g. T cells, B cells, macrophages, kidney mesangial cells, fibroblasts etc.
  • various physiological effects e.g. induction of B cell differentiation to antibody-producing cells, activation of T cells, increase of platelets, and production of acute phase protein from liver cells etc.
  • an abnormal production of IL-6 has been observed in various inflammations, autoimmune diseases and neoplastic diseases and it is suggested that IL-6 plays a certain role in the causes of such pathophysiological situations.
  • IL-12 is a cytokine produced from macrophages and dendritic cells etc. and its effects are known; e.g. activation of natural killer (abbreviated as NK hereafter) cells, induction of Interferon- ⁇ (abbreviated as IFN- ⁇ hereafter) production from NK cells and T cells, and regulation of Th1 and Th2 balance etc.
  • NK natural killer
  • IFN- ⁇ Interferon- ⁇
  • Helper T cells are classified into Th1 which stimulates cellular-mediated immunity and Th2 which assists humoral immunity.
  • IL-12 functions to induce Th1 from helper T cell precursors.
  • IL-12 induces production of IFN- ⁇ from Th1 cells (which are further differentiated) and accelerates killer activity, so that IL-12 plays a role as a main cytokine causing inflammatory immune reaction which leads to organ disorders (Blood, 84, 4008 (1994)).
  • Clinical application of the compounds of the present invention involves those diseases which may be caused and be changed to worse by abnormal production of IL-6 and/or IL-12 or by overresponse to them.
  • Inhibitors of producing IL-6 may be used 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 (J. Immunol., 145, 4185 (1990), J. Exp.
  • Inhibitors of producing IL-12 may be used for the prevention and/or treatment of various inflammatory diseases, diabetes mellitus, hepatitis, multiple sclerosis, colitis, graft versus host immune diseases, rheumatoid arthritis, infectious diseases, autoimmune diseases (J. Exp. Med., 181, 817 (1995), J. Exp. Med., 181, 381 (1995), J. Exp.
  • a compound of the formula (Xl) is an important intermediate of pharmaceutical agents and an efficient method for preparation thereof has been desired.
  • Y x is hydrogen, lower alkyl, lower alkoxy, halogen or hydroxy
  • Z x is alkyl, alkoxy, halogen, carboxy, haloalkyl or nitro,
  • aX is 0 or an integer of 2
  • bX is an integer of 2
  • cX is 0 or an integer of 1 ⁇ 5 or
  • dX is 0 or an integer of 1 ⁇ 4.
  • [0020] has an anti-fungal and anti-vital activities.
  • R 1Y is hydrogen, halogen or C1 ⁇ 3 alkyl; R 2Y and R 3Y are hydrogen or C1 ⁇ 3 alkyl) is described as an intermediate of diuretic agent, but there is no description about its biological activity.
  • R 1U and R 2U are each hydrogen or C1 ⁇ 6 alkyl, C3 ⁇ 6 cycloalkyl or phenyl which may be substituted with 1-2 of halogen, hydroxy, C1 ⁇ 6 alkyl or alkoxy
  • R 3U is hydrogen or Z U
  • Z U is C1 ⁇ 6 alkyl or CR 4U
  • R 5U R 6U R 4U and R 5U are hydrogen or C1 ⁇ 6 alkyl
  • R 6U is COOH, CH 2 —OH, C1 ⁇ 6 alkoxycarbonyl or hydroxyaminocarbonyl
  • X U is hydrogen, halogen or C1 ⁇ 6 alkyl
  • nU is 1 or 2
  • mU is 0 ⁇ 2
  • R 1V is t-butyl
  • R 1V is hydrogen, lower alkyl or acyl
  • a broken line is arbitrary bond
  • R 2V and R 3V are hydrogen, alkyl which may be substituted or alkenyl which may be substituted
  • R 4V does not represent anything when arbitrary bond exists and represents the same meaning as R 1V when arbitrary bond does not exist and nV is 0 ⁇ 2.
  • LDL low-density lipoprotein
  • Z W is oxygen atom or sulfur atom
  • R 1W , R 2W , R 3W and R 4W are the same or different, are hydrogen etc.
  • E W and F W are the same or different, are nitrogen atom or CH which may be substituted with X W or Y W
  • X W is straight or branched C1-6 alkyloxy, C3-8 cycloalkyloxy or straight or branched C1-3 alkyloxy substituted with C3 ⁇ 8 cycloalkyl
  • Y is
  • G W is —CONH—, O(O)O—, —NHCO— or —OC(O)—;
  • R 5W is (a) straight or branched C1-6 alkyl, (b) C3-8 cycloalkyl, (c) C7-12 spiroalkyl, (d) C7-12 bicycloalkyl, (e) aryl, (f) aralkyl, (g) heteroarylalkyl, (h) non-aromatic heterocyclic ring which may be substituted with phenyl or (i) C3-8 cycloalkyl-C1 ⁇ 3 alkyl.
  • Each of them may be substituted with one or more of substituent selected from a group consisting of i) straight or branched C1-6 alkyl, ii) straight or branched C1-8 alkyloxy, iii) C1-3 haloalkyl, iv) halogen, v) C3-8 cycloalkyl, vi) carboxy, vii) alkyloxycarbonyl, viii) acyl, ix) formyl and x) nitro; nW is an integer of 1-3, pW is an integer of 1-3, (CH 2 ) w and (CH 2 ) pW may be substituted with a straight or branched C1-6 alkyl or C1-3 haloalkyl) has an antagonistic activity against dopamine receptor.
  • substituent selected from a group consisting of i) straight or branched C1-6 alkyl, ii) straight or branched C1-8 alkyloxy, iii) C1-3 haloalky
  • R 1T and R 3T are independently hydrogen, —CH 3 , —C(O)—(C1 ⁇ 6 alkyl), or —C(O)—Ar T (Ar T is phenyl which may optionally be substituted);
  • R 2T is selected from a group consisting of pyrrolidino, hexamethyleneimino and piperidino], a pharmaceutically acceptable salt thereof or a solvent additive has an activity of inhibiting the effect of IL-6.
  • each R 1S and R 2S is hydrogen or hydrocarbon group which may contain substituent(s) or R 1S and R 2S taken together with the neighboring carbon atom represents 3- to 8-membered homo or heterocyclic ring which may contain substituent(s)
  • R 3S is hydrogen or lower alkyl which may contain subtstituent(s) or aromatic group which may contain substituent(s)
  • R 4S is (1) aromatic group which may contain substituent(s), (2) aliphatic hydrocarbon which contains aromatic group (this group is unsubstituted or substituted.) and which may contain additional substituent(s) or (3) acyl
  • X S and Y S are each oxygen atom or sulfur atom which may be oxidized, is single bond or double bond
  • ring A S is benzene ring which contains a group of the formula —X S R 4S (wherein each symbols represent the same meaning as defined hereinbefore) and which may contain additional substituent(s), with the proviso that when is single bond and both XS
  • TMS is trimethylsilyl
  • DDQ is 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.
  • This reaction is a method for preparation of aromatic nitrile of the formula (XI-C-2) which comprises that cyclic ketone of the formula (XI-C-1) is converted into cyanohydrin, followed by dehydration to give nitrile of the formula (XI-C-2), and then followed by dehydrogenation by an oxidizer.
  • the present inventors have investigated to find new compounds possessing an inhibitory activity of producing IL-6 and/or IL-12, so that the present inventors have found that the purpose has been achieved by fused thiophene derivatives of the formula (I).
  • Fused heterocyclic compounds of the formula (I) of the present invention has not been known as inhibitors of producing IL-6 and/or IL-12 at all. Further, a fused thiophene derivative of the formula (IA) is a novel compound which is not known at all.
  • the present invention relates to
  • an inhibitor of producing Interleukin-6 and/or Interleukin-12 comprising, as an active ingredient, a fused thiophene derivative of the formula (I)
  • n 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,
  • each R 1 of (R 1 )p is independently,
  • R 3 , R 4 , R 5 , R 6 R 7 , R 9 , R 10 , R 11 , R 12 and R 13 are each independently, hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted with Cyc 1 , —OR 14 (wherein R 14 is hydrogen or C1-8 alkyl.) or cyano, with the proviso that the linkage of the right side of each group represented by A 2 binds to A 3 .
  • a 3 is
  • R 15 s are each independently, hydroxy or C1-8 alkoxy
  • R 16 s are each independently C1-8 alkyl
  • R 17 is
  • R 31 and R 32 are each independently, hydrogen, C1-8 alkyl or Cyc 2 ,
  • R 33 is hydrogen or C1-8 alkyl
  • R 34 is hydrogen, C1-8 alkyl or —C(O)-Cyc 2 ,
  • R 37 is hydrogen or C1-8 alkyl
  • R 36 is hydrogen, C1-8 alkyl or Cyc 2 ,
  • R 37 is hydrogen, C1-8 alkyl, —OR 38 , —NR 39 R 40 , Cyc 2 , or C1-8 alkyl substituted with Cyc 2 or —C(O)-Cyc 2 ,
  • R 38 , R 39 and R 40 are each independently, hydrogen, C1-8 alkyl, or C1-8 alkyl substituted with Cyc 2 ,
  • 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) —OR 41 , (xi) —SR 42 , (xii) —NR 43 R 44 , (xiii) —SO 2 NR 45 R 46 , (xiv) —C(O)R 47 , (xv) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with hydroxy or halogen or (xvi) phenyl,
  • R 41 , R 42 , R 43 , R 44 , R 45 and R 46 are each independently, hydrogen or C1-8 alkyl
  • R 47 is hydrogen, C1-8 alkyl or C1-8 alkoxy
  • each R 2 of (R 2 )q is independently,
  • R 48 is
  • R 49 and R 50 are each independently, hydrogen, C1-8 alkyl or —COR 59 ,
  • R 51 is hydrogen, C1-8 alkyl, hydroxy, C1-8 alkoxy or —NR 50 R 61 ,
  • R 52 is hydrogen, C1-8 alkyl, Cyc 3 , or C1-8 alkyl substituted with Cyc 3 ,
  • R 53 and R 54 are each independently, hydrogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl or —C(O)R 56 (wherein R 56 is C1-8 alkyl, C1-8 alkoxy, Cyc 3 , or C1-8 alkyl substituted with Cyc 3 ),
  • R 55 is hydroxy, C1-8 alkoxy, or —NR 57 R 58 (wherein R 57 and R 58 are each independently, hydrogen, C1-8 alkyl, or C1-8 alkyl substituted with Cyc 3 ),
  • R 59 is C1-8 alkyl or C1-8 alkoxy
  • R 60 and R 61 are each independently, hydrogen or C1-8 alkyl
  • 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) —NR 62 R 63 , (ix) —COOR 64 , (x) trihalomethyl, (xi) trihalomethoxy, (xii) phenyl, (xiii) phenoxy, (xiv) phenylthio, (xv) C1-8 alkyl or C1-8 alkoxy substituted with phenyl, phenoxy, phenylthio, hydroxy, —NR 62 R 63 or —COOR 64 ,
  • R 62 and R 63 are each independently, hydrogen or C1-8 alkyl
  • R 64 is hydrogen or C1-8 alkyl
  • n 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,
  • each R 1 of (R 1 )p is independently,
  • a 1 is
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , R 10 , R 11 , R 12 and R 13 are each independently, hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted with Cyc 1 , —OR 14 (wherein R 14 is hydrogen or C1-8 alkyl.) or cyano, with the proviso that the linkage of the right side of each group represented by A 2 binds to A 3 .
  • R 15 s are each independently, hydroxy or C1-8 alkoxy
  • R 16 s are each independently C1-8 alkyl
  • R 17 is
  • R 20 is
  • 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) Cyc 2 , (xiii) —OR 31 , (xiv) —SR 2 , (xv) —NR 33 R 34 , (xvi) —SO 2 NR 35 R 36 , (xvii) —C(O)R 37 or (xviii) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with Cyc 2 , hydroxy, halogen or —C(O)-Cyc
  • R 31 and R 32 are each independently, hydrogen, C1-8 alkyl or Cyc 2 ,
  • R 33 is hydrogen or C1-8 alkyl
  • R 34 is hydrogen, C1-8 alkyl or —C(O)-Cyc 2 ,
  • R 36 is hydrogen or C1-8 alkyl
  • R 36 is hydrogen, C1-8 alkyl or Cyc 2 ,
  • R 37 is hydrogen, C1-8 alkyl, —OR 38 , —NR 39 R 40 , Cyc 2 , or C1-8 alkyl substituted with Cyc 2 or —C(O)—Cyc 2 ,
  • R 36 , R 39 and R 40 are each independently, hydrogen, C1-8 alkyl, or C1-8 alkyl substituted with Cyc 2 ,
  • 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) —OR 41 , (xi) —SR 42 , (xii) —NR 43 R 44 , (xiii) —SO 2 NR 45 R 46 , (xiv) —C(O)R 47 , (xv) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with hydroxy or halogen or (xvi) phenyl,
  • R 41 , R 42 , R 43 , R 44 , R 45 and R 46 are each independently, hydrogen or C1-8 alkyl, R 47 is hydrogen, C1-8 alkyl or C1-8 alkoxy
  • each R 2 of (R 2 q is independently,
  • R 48 is
  • R 49 and R 51 are each independently, hydrogen, C1-8 alkyl or —COR 59 ,
  • R 51 is hydrogen, C1-8 alkyl, hydroxy, C1-8 alkoxy or —NR 6 “R 6 ,
  • R 52 is hydrogen, C1-8 alkyl, Cyc 3 , or C1-8 alkyl substituted with Cyc 3 ,
  • R 53 and R 54 are each independently, hydrogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl or —C(O)R 56 (wherein R 56 is C1-8 alkyl, C1-8 alkoxy, Cyc 3 , or C1-8 alkyl substituted with Cyc 3 ),
  • R 55 is hydroxy, C1-8 alkoxy, or —NR 57 R 58 (wherein R 57 and R 58 are each independently, hydrogen, C1-8 alkyl, or C1-8 alkyl substituted with Cyc 3 ),
  • R 59 is C1-8 alkyl or C1-8 alkoxy
  • R 60 and R 61 are each independently, hydrogen or C1-8 alkyl
  • 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) —NR 62 R 63 , (ix) —COOR 64 , (x) trihalomethyl, (xi) trihalomethoxy, (xii) phenyl, (xiii) phenoxy, (xiv) phenylthio, (xv) C1-8 alkyl or C1-8 alkoxy substituted with phenyl, phenoxy, phenylthio, hydroxy, —NR 62 R 63 or —COOR 64 ,
  • R 62 and R 63 are each independently, hydrogen or C1-8 alkyl
  • R 64 is hydrogen or C1-8 alkyl
  • a 3 is not hydrogen
  • n 2
  • m is 0 or 2
  • p is O or an integer of 1-4
  • ring A and ring B are benzene ring
  • R 1 is C1-8 alkyl, C1-8 alkoxy, halogen, carboxy, nitro or C1-8 alkyl substituted with halogen, then q is not 0,
  • n 2
  • m is 0 or 2
  • p is 0 or an integer of 1-4
  • ring A and ring B are benzene ring
  • R 1 is C1-8 alkyl, C1-8 alkoxy, halogen, carboxy, nitro or C1-8 alkyl substituted with halogen
  • q is an integer of 1-5
  • R 2 is not C1-8 alkyl, C1-8 alkoxy, halogen, carboxy, nitro or C1-8 alkyl substituted with halogen
  • R 1 is not halogen, C1-8 alkyl, phenylsulfonylamino, 2-methylphenylsulfonylamino, 3-methylphenylsulfonylamino, 4-methylphenylsulfonylamino, hydroxy, C1-8 alkoxy, nitro, or C1-8 alkoxy substituted with carboxy, hydroxy, C1-8 alkoxycarbonyl or hydroxyaminocarbonyl,
  • alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylene, alkenylene and alkynylene group include straight or branched ones.
  • isomers on double bond, ring, fused ring (E—, Z—, cis-, trans-isomer), isomers generated from asymmetric carbon atom(s) (R—, S—, ⁇ —, ⁇ -isomer, enantiomer, diastereomer), optically active isomers (D—, L—, d-, I-isomer), polar compounds generated by chromatographic separation (more polar compound, less polar compound), equilibrium compounds, mixtures thereof at voluntary ratios and racemic mixtures are also included in the present invention.
  • an N-oxide derivative of a compound of the formula (I) and (IA) means a compound wherein nitrogen atom(s) in a compound containing nitrogen atom(s) of the formula (I) and (IA) is (are) oxidized.
  • C1-8 alkyl means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and the isomers thereof.
  • C2-8 alkenyl means vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, butadienyl, pentadienyl, hexadienyl, heptadienyl, octadienyl, hexatrienyl, heptatrienyl, octatrienyl and the isomers thereof.
  • C2-8 alkynyl means ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl and the isomers thereof.
  • C1-8 alkylene means methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene and the isomers thereof.
  • C2-8 alkenylene means ethenylene, propenylene, butenylene, pentenylene, hexenylene, heptenylene, octenylene and the isomers thereof.
  • C2-8 alkynylene means ethynylene, propynylene, butynylene, pentynylene, hexynylene, heptynylene, octynylene and the isomers thereof.
  • Halogen means chloride, bromide, fluoride and iodide.
  • C1-8 alkoxy means methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy and the isomers thereof.
  • Trihalomethyl means methyl substituted with three atoms selected from group consisting of chloride, bromide, fluoride and iodide atom.
  • Trihalomethoxyl means methoxyl substituted with three atoms selected from group consisting of chloride, bromide, fluoride and iodide atom.
  • C2-5 acyl means acetyl, propionyl, butyryl, valeryl and isomers thereof.
  • 6Membered monocyclic hetero aryl containing 1-2 nitrogen atom(s) includes, for example, pyridine, pyridine-N-oxide, pyrazine, pyrazine-N-monoxide, pyrazine-N-dioxide, pyrimizine, pyrimizine-N-monoxide, pyrimizine-N-dioxide, pyridazine, pyridazine-N-monoxide, pyridazine-N-dioxide ring etc.
  • Mono-, bi- or tricyclic carbo ring includes, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclopenten, cyclohexen, cyclopentadien, cyclohexadien, benzene, penthalene, indene, naphthalene, azulene, florene, phenanthrene, anthracene, acenaphthylene, biphenylene, perhydropentalene, perhydroindene, dihydronaphthalene, tetrahydronaphthalene, perhydronaphthalene, perhydroazulene, perhydrofluorene, perhydrophenanthrene, perhydroanthracene, perhydroacenaphthylene, perhydrobiphenylene ring etc.
  • 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 includes 4-18 membered mono-, bi- or tricyclic hetero aryl containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom or corresponding hetero ring in which ring is saturated partially or fully.
  • the said 4-18 membered mono-, bi- or tricyclic hetero aryl containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom includes, for example, pyrrole, pyrrole-N-oxide, imidazole, triazole, tetrazole, pyrazole, pyridine, pyridine-N-oxide, pyrazine, pyrazine-N-monoxide, pyrazine-N-dioxide, pyrimizine, pyrimizine-N-monoxide, pyrimizine-N-dioxide, pyridazine, pyridazine-N-monoxide, pyridazine-N-dioxide, azepine, diazepine, furan, pyran, oxepine, oxazepine, thiophene, thiain (thiopyran), thie
  • the said 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 in which ring is saturated partially or fully includes, for example, pyrroline, pyrrolidine, pyrrolidine-N-oxide, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, dihydropyridine, dihydropyridine-N-oxide, dihydropyrazine, dihydropyrazine-N-monoxide, dihydropyrazine-N-dioxide, dihydropyrimizine, dihydropyrimizine-N-monoxide, dihydropyrimizine-N-dioxide, dihydropyridazine, dihydropyridazine-N-monoxide, dihydropyridazine-N-monoxide, dihydropyridazine
  • m is, preferably, 0 or 2 and most preferably, 2.
  • n is, preferably, 0 or 2 and most preferably, 2.
  • p is, preferably, 1 or 2 and most preferably, 2.
  • q is, preferably, 0 or 1.
  • Z is, preferably, single bond or C1-8 alkylene, and most preferably, single bond.
  • [0444] is, preferably, pyridine or benzene ring, and most preferably, benzene ring.
  • [0445] is, preferably, C5-10 mono- or bicyclic carbo ring or 5-10 membered mono- or bicyclic hetero ring containing 1-3 nitrogen atom(s), one oxygen atom and/or one sulfur atom, more preferably, benzene, cyclohexane, thiophene, furan, pyridine, pyrimizine, imidazole ring, and most preferably, benzene or thiophene ring.
  • R 1 is, preferably, C1-8 alkyl, nitro, cyano, halogen, Cyc 1 or C1-8 alkyl substituted with halogen or Cyc 1 , or A 1 —A 2 —A 3 , and most preferably, C1-8 alkyl substituted with Cyc 1 or A 1 —A 2 —A 3 .
  • a 1 is, preferably, single bond, C1-8 alkylene, C2-8 alkenylene, and most preferably, single bond or C1-8 alkylene.
  • a 2 is, preferably, —O—, —NR 3 —, —C(O)—, —C(O)NR 4 —, —NR 5 C(O)—, —C(O)O—, —NR 13 C(O)O—, and most preferably, O—, —NR 3 —, —C(O)—, —C(O)NR 4 —, —NR 5 C(O)—.
  • a 3 is, preferably, C1-8 alkyl, Cyc 1 , or C1-8 alkyl or C2-8 alkenyl substituted with Cyc 1 , —C(O)R 7 , —NR 19 R 20 or —OR 18 , and most preferably, C1-8 alkyl substituted with Cyc 1 or NR 19 R 20 .
  • Cyc 1 is, preferably, C5-10 mono- or bicyclic carbo ring or 5-10 membered mono- or bicyclic hetero ring containing 1-3 nitrogen atom(s), one oxygen atom and/or one sulfur atom, and more preferably, C5-10 monocyclic carbo ring or 5-10 membered monocyclic hetero ring containing 1-2 nitrogen atom(s) and/or one oxygen atom, and most preferably, benzene, piperidine, piperazine, pyrrolidine, pyridine or morpholine ring.
  • R 19 , R 20 is, preferably, hydrogen or C1-8 alkyl, and most preferably, methyl, ethyl, propyl or isopropyl.
  • non-toxic salts include all such salts, for example, ordinal salts, acid-addition salts and hydrate salts.
  • the compounds of the present invention of the formula (I) may be converted into the corresponding salts by known method.
  • Non toxic and water-soluble salts are preferable.
  • Suitable salts include the salts of alkalimetal (sodium, potassium etc.), alkaline-earth metal (calcium, magnesium etc.), ammonium salts, salts of organic amine which is pharmaceutically permitted (tetramethyl ammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenetylamine, piperidine, monoethanolamine, diethanolamine, tris(hydroxymethyl)amine, lysine, arginine, N-methyl-D-gulcamine etc.).
  • the compounds of the present invention of the formula (I) may be converted into the corresponding acid-addition salts by known method.
  • Non toxic and water-soluble acid-addition are preferable.
  • Suitable acid-addition salts include the salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfonic acid, phosphonic acid, nitric acid and the salts with organic acids such as acetic acid, trifluoroacetic acid, lactic acid, tartaric acid, oxalic acid, fumaric acid, maleic acid, citric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, isethionic acid, glucuronic acid and gluconic acid.
  • R 1′ is C1-8 alkyl substituted with Cyc 1 , or
  • a 1′ is single bond or C1-8 alkylene
  • a 2 ′ is —O—, —NR 3 —, —C(O)—, —C(O)NR 4 — or NR 5 C(O)— and the other symbols are the same meanings as hereinbefore described.) and the other symbols are the same meanings as hereinbefore described.) is most preferable.
  • More preferable compounds are the following known compounds and the compounds shown in the Tables 1 to 78 and described in Examples and non-toxic salts thereof.
  • the above oxidation is known per se.
  • it may be carried out in an adequate organic solvent (e.g., methylene chloride, chloroform, benzene, hexane, t-butyl alcohol etc.), in the presence of an 1-1.2 equivalent amount of oxidizing agent (e.g., hydrogen peroxide, sodium periodate, acyl nitrite, sodium perborate, peracid (e.g., 3-chloroperbenzoic acid, peracetic acid etc.), potassium peroxymonosulfate, potassium permanganate, chromic acid etc.), at -40° C. ⁇ 0° C.
  • an adequate organic solvent e.g., methylene chloride, chloroform, benzene, hexane, t-butyl alcohol etc.
  • an oxidizing agent e.g., hydrogen peroxide, sodium periodate, acyl nitrite, sodium perborate, peracid (e.g., 3-chloroperbenz
  • the above oxidation is known per se. For example, it may be carried out in an adequate organic solvent (e.g., methylene chloride, chloroform, benzene, hexane, t-butyl alcohol etc.), in the presence of an excess amount of oxidizing agent (e.g., hydrogen peroxide, sodium periodate, acyl nitrite, sodium perborate, peracid (e.g., 3-chloroperbenzoic acid, peracetic acid etc.), potassium peroxymonosulfate, potassium permanganate, chromic acid etc.), at 20° C. ⁇ 60° C.
  • an adequate organic solvent e.g., methylene chloride, chloroform, benzene, hexane, t-butyl alcohol etc.
  • an excess amount of oxidizing agent e.g., hydrogen peroxide, sodium periodate, acyl nitrite, sodium perborate, peracid (e.g., 3-chloroper
  • R 1-1-2 is the same meanings as hereinbefore described for R 1 , provided that at least one of R R 1-1-2 (s) is a substituted oxy group or a group containing substituted oxy and the other symbols are the same meaning as hereinbefore described.
  • [0577] may be also prepared by the following methods (a) ⁇ (b).
  • the compounds of the present invention of the formula (I-1-2) may be prepared by etherification of the compounds of the formula (I-1 -2) in which at least one of R 1 (s) is a hydroxy or a group containing hydroxy, i.e., the compounds of the formula (I-1-2a)
  • R R 1-1-2a is the same meanings as hereinbefore described for R 1 , provided that at least one of R R 1-1-2a (s) is a hydroxy or a group containing hydroxy and the other symbols are the same meaning as hereinbefore described.) with the corresponding compounds containing a group which is removal (chloride, bromide, iodide, mesyl or tosyl etc.).
  • This etherification is well known. For example, it may be carried out in an organic solvent (dimethylformamide, dimethylsulfoxide, chloroform, methyhlene chloride, diethyl ether, tetrahydrofuran etc.) in the presence of hydroxide of an alkalimetal (sodium hydroxide, potassium hydroxide, lithium hydroxide etc.), hydroxide of an alkaline earth metal (barium hydroxide, calcium hydroxide etc.) or carbonate (sodium carbonate , potassium carbonate etc.) or an aqueous solution thereof or a mixture thereof at 0 ⁇ 100° C.
  • an organic solvent dimethylformamide, dimethylsulfoxide, chloroform, methyhlene chloride, diethyl ether, tetrahydrofuran etc.
  • hydroxide of an alkalimetal sodium hydroxide, potassium hydroxide, lithium hydroxide etc.
  • hydroxide of an alkaline earth metal barium hydroxide, calcium hydrox
  • the compounds of the present invention of the formula (I-1-2) may be prepared by etherification of the compounds of the formula (1-1 -2) in which at least one of R 1 (s) is a hydroxy or a group containing hydroxy, i.e., the compounds of the formula (I-1-2b)
  • R R 1-1-2b is the same meanings as hereinbefore described for R 1 , provided that at least one of R R 1-1-2b (s) is a hydroxy or a group containing hydroxy and the other symbols are the same meaning as hereinbefore described.) with the corresponding compounds containing hydroxy.
  • This etherification is well known. For example, it may be carried out in an organic solvent (methylene chloride, diethyl ether, tetrahydrofuran, acetonitrile, benzene, toluene etc.) in the presence of azo compounds (diethyl azodicaroxylate, diisopropyl azodicaroxylate, 1,1′-(azodicarbonyl)dipiperidine, 1,1′-azobis(N,N-dimethylformamide) etc.) and phosphine compounds (triphenylphosphine , tributylphosphine , trimethylphosphine etc.), with the corresponding alcohol compounds at 0 ⁇ 60° C.
  • organic solvent methylene chloride, diethyl ether, tetrahydrofuran, acetonitrile, benzene, toluene etc.
  • azo compounds diethyl azodicaroxylate, diisopropyl azodica
  • R 1-1-3 is the same meanings as hereinbefore described for R 1 , provided that at least one of R R 1-1-3 (s) is a substituted amino or a group containing substituted amino and the other symbols are the same meaning as hereinbefore described.
  • [0586] may be prepared by the following methods (a) ⁇ (d).
  • the compounds of the present invention of the formula (I-1-3) may be prepared by reacting the compounds of the formula (I-1-3) in which at least one of R 1 (s) is halogen (chloride, bromide, iodide) or a group containing halogen, i.e., the compounds of the formula (I-1-3a)
  • R R 1-1-3 is the same meanings as hereinbefore described for R 1 , provided that at least one of R R 1-1-3a (s) is a halogen (chloride, bromide, iodide) or a group containing halogen and the other symbols are the same meaning as hereinbefore described.)
  • This reaction is well known. For example, it may be carried out in an organic solvent (dimethylformamide, dimethylsulfoxide, chloroform, methyhlene chloride, diethyl ether, tetrahydrofuran, acetonitrile etc.) in the presence or absence of base (triethylamine, pyridine etc.) at 0 ⁇ 100° C.
  • organic solvent dimethylformamide, dimethylsulfoxide, chloroform, methyhlene chloride, diethyl ether, tetrahydrofuran, acetonitrile etc.
  • base triethylamine, pyridine etc.
  • the compounds of the present invention of the formula (I-1-3) may be prepared by reacting the compounds of the formula (I-1-3) in which at least one of R 1 (s) is an amino or a group containing amino, i.e., the compounds of the formula (I-1-3b)
  • R R 1-1-3b is the same meanings as hereinbefore described for R 1 , provided that at least one of R R 1-1-3b (s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing halogen (chloride, bromide, and iodide).
  • the compounds of the present invention of the formula (I-1-3) may be prepared by reductive amidation of the compounds of the formula (I-1-3) in which at least one of R 1 (s) is an amino or a group containing amino, i.e., the compounds of the formula (I-1-3c)
  • R R 1-1-3c is the same meanings as hereinbefore described for R 1 , provided that at least one of R R 1-1-3 (s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) with the corresponding compounds containing carbonyl.
  • This reductive amidation is well known. For example, it may be carried out in an organic solvent (methanol, ethanol, dimethylformamide, dimethylsulfoxide etc,) in the presence of reductant (sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, Pd-C etc.) and in the presence of acid (acetic acid, hydrochlolride solution etc.), if necessary, at ⁇ 20 ⁇ 60° C.
  • reductant sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, Pd-C etc.
  • acid acetic acid, hydrochlolride solution etc.
  • the compounds of the present invention of the formula (I-1-3) may be prepared by reductive amidation of the compounds of the formula (I-1-3) in which at least one of R 1 (s) is a carbonyl or a group containing carbonyl, i.e., the compounds of the formula (I-1-3d)
  • R R 1-1-3d is the same meanings as hereinbefore described for R 1 , provided that at least one of R R 1-1-3d (s) is a carbonyl or a group containing carbonyl and the other symbols are the same meaning as hereinbefore described.
  • R 1-1-4 is the same meanings as hereinbefore described for R 1 , provided that at least one of R R 1-1-4 (s) is an amide or a group containing amide and the other symbols are the same meaning as hereinbefore described.
  • R 1-1-4 may be prepared by the following methods (a) ⁇ (b).
  • the compounds of the present invention of the formula (I-1-4) may be prepared by amidation of the compounds of the formula (I-1) in which at least one of R 1 (s) is a —COOH or a group containing —COOH, i.e., the compounds of the formula (I-1-4a)
  • R R 1-1-4a is the same meanings as hereinbefore described for R 1 , provided that at least one of R R 1-1-4a (s) is a —COOH or a group containing —COOH and the other symbols are the same meaning as hereinbefore described.) with the corresponding compounds containing amino.
  • amidation is well known. For example, it may be carried out
  • (1) method with using acid halide may be carried out, for example; carboxylic acid is reacted with an acid halide (oxalyl chloride or thionyl chloride etc.) in an organic solvent (chloroform, methylene chloride, diethyl ether or tetrahydrofuran etc.) or without solvents at from ⁇ 20° C. to a refluxing temperature to give an acid halide.
  • an acid halide oxalyl chloride or thionyl chloride etc.
  • organic solvent chloroform, methylene chloride, diethyl ether or tetrahydrofuran etc.
  • the obtained acid halide and an amine are reacted in an organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran etc.) in the presence of tertiary amine (pyridine, triethylamine, dimethylaniline or dimethylaminopyridine etc.) at 0-40° C.
  • organic solvent chloroform, methylene chloride, diethyl ether, tetrahydrofuran etc.
  • tertiary amine pyridine, triethylamine, dimethylaniline or dimethylaminopyridine etc.
  • (2) method with using mixed acid anhydride may be carried out, for example; carboxylic acid is reacted with an acid halide (pivaloyl chloride, tosyl chloride, mesyl chloride etc.) or an acid derivative (ethyl chloroformate, isobutyl chloroformate etc.) in an organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran. etc.) or without solvents, in the presence of tertiary amine (pyridine, triethylamine, dimethylaniline or dimethylaminopyridine etc.), at 0-40° C.
  • an acid halide pivaloyl chloride, tosyl chloride, mesyl chloride etc.
  • an acid derivative ethyl chloroformate, isobutyl chloroformate etc.
  • organic solvent chloroform, methylene chloride, diethyl ether, tetrahydrofuran. etc
  • (3) method with using condensing agent may be carried out, for example; a carboxylic acid and an amine are reacted in an organic solvent (chloroform, methylene chloride, dimethylformamide, diethyl ether or tetrahydrofuran.
  • an organic solvent chloroform, methylene chloride, dimethylformamide, diethyl ether or tetrahydrofuran.
  • tertiary amine pyridine, triethylamine, dimethylaniline or dimethylaminopyridine etc.
  • condensing agent (1,3-dicyclohexylcarbodiimido (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimido (EDC), 1,1′-carbonydimidazole (CDI), 2-chloro-1-methylpyridinium iodide, propane phosphate cyclic anhydride etc.) using or without 1-hydroxybenztriazole (HOBt) at 0-40° C. (etc.)
  • DCC dicyclyclohexylcarbodiimido
  • EDC 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimido
  • CDI 1,1′-carbonydimidazole
  • 2-chloro-1-methylpyridinium iodide propane phosphate cyclic anhydr
  • the above reactions (1), (2) and (3) described above are carried out under an atmosphere of an inert gas (argon, nitrogen etc.) on anhydrous condition.
  • an inert gas argon, nitrogen etc.
  • the compounds of the present invention of the formula (I-1-4) may be prepared by amidation of the compounds of the formula (I-1) in which at least one of R 1 (s) is an amino or a group containing amino, i.e., the compounds of the formula (I-1-4b)
  • R R 1-1-4b is the same meanings as hereinbefore described for R 1 , provided that at least one of R R 1-1-4b (s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.)with the corresponding compounds containing carboxy.
  • R 1-1-5 is the same meanings as hereinbefore described for R 1 , provided that at least one of R 1-1-5 (s) is an ester or a group containing ester and the other symbols are the same meaning as hereinbefore described.
  • R 1-1-5 may be prepared by the following methods (a) ⁇ (b).
  • the compounds of the present invention of the formula (I-1-5) may be prepared by esterification of the compounds of the formula (I-1) in which at least one of R 1 (s) is a —COOH or a group containing —COOH, i.e., the compounds of the formula (I-1-5a)
  • R 1-1-5a is the same meanings as hereinbefore described for R 1 , provided that at least one of R 1-1-5a (s) is a —COOH or a group containing —COOH and the other symbols are the same meaning as hereinbefore described.) with the corresponding compounds containing hydroxy.
  • Esterification is well known. For example, it may be carried out
  • (1) method with using acid halide may be carried out, for example; carboxylic acid is reacted with an acid halide (oxalyl chloride or thionyl chloride -etc.) in an inert organic solvent (chloroform, methylene chloride, diethyl ether or tetrahydrofuran etc.) or without solvents at from ⁇ 20° C. to a refluxing temperature to give an acid halide.
  • an acid halide oxalyl chloride or thionyl chloride -etc.
  • an inert organic solvent chloroform, methylene chloride, diethyl ether or tetrahydrofuran etc.
  • the obtained acid halide and an alcohol are reacted in an inert organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran etc.) in the presence of tertiary amine (pyridine, triethylamine, dimethylaniline or dimethylaminopyridine etc.) at 0-40° C.
  • chloroform methylene chloride, diethyl ether, tetrahydrofuran etc.
  • tertiary amine pyridine, triethylamine, dimethylaniline or dimethylaminopyridine etc.
  • (2) method with using mixed acid anhydride may be carried out, for example; carboxylic acid is reacted with an acid halide (pivaloyl chloride, tosyl chloride, mesyl chloride etc.) or an acid derivative (ethyl chloroformate, isobutyl chloroformate etc.) in an inert organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran. etc.) or without solvents, in the presence of tertiary amine (pyridine, triethylamine, dimethylaniline or dimethylaminopyridine etc.), at 0-40° C. to give an acid halide.
  • the obtained acid halide and an alcohol are reacted in an inert organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran etc.) at 0-40° C.
  • (3) method with using condensing agent may be carried out, for example; a carboxylic acid and an alcohol are reacted in an organic solvent (chloroform, methylene chloride, dimethylformamide, diethyl ether or tetrahydrofuran.
  • an organic solvent chloroform, methylene chloride, dimethylformamide, diethyl ether or tetrahydrofuran.
  • tertiary amine pyridine, triethylamine, dimethylaniline or dimethylaminopyridine etc.
  • condensing agent (1,3-dicyclohexylcarbodiimido (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimido (EDC), 1,1′-carbonydimidazole (CDI), 2-chloro-1-methylpyridinium iodide, propane phosphate cyclic anhydride etc.
  • HOBt 1-hydroxybenztriazole
  • the reactions (1), (2) and (3) described above are carried out under an atmosphere of inert gas (argon, nitrogen etc.) on anhydrous condition.
  • inert gas argon, nitrogen etc.
  • the compounds of the present invention of the formula (1-1-5) may be prepared by esterification of the compounds of the formula (I-1) in which at least one of R 1 (s) is a hydroxy or a group containing hydroxy, i.e., the compounds of the formula (I-1-5b)
  • R 1-1-5b is the same meanings as hereinbefore described for R 1 , provided that at least one of R 1-1-5b (s) is a hydroxy or a group containing hydroxy and the other symbols are the same meaning as hereinbefore described.) with the corresponding compounds containing carboxy.
  • esterification may be carried out by the same procedure for preparation of the said compounds of the formula (I-1-5a).
  • R 1-1-6 is the same meanings as hereinbefore described for R 1 , provided that at least one of R 1-1-6 (s) is a sulfonamide or a group containing sulfonamide and the other symbols are the same meaning as hereinbefore described.
  • R 1-1-6 may be prepared by the following methods (a) ⁇ (b).
  • the compounds of the present invention of the formula (I-1-6) may be prepared by sulfonamidation of the compounds of the formula (I-1) in which at least one of R 1 (s) is a —SO 3 H or a group containing —SO 2 H, i.e., the compounds of the formula (II)
  • R 1-1-6a is the same meanings as hereinbefore described for R 1 , provided that at least one of R 1-1-6a (s) is a —SO 3 H or a group containing —SO 3 H and the other symbols are the same meaning as hereinbefore described.) with the corresponding compounds containing amino.
  • the sulfonamidation is well known. For example, it may be carried out by reacting sulfonic acid with acid halide (oxazolyl chloride, thionyl chloride etc.) in an inert organic solvent (chloroform, methyhlene chloride, diethyl ether, tetrahydrofuran etc.) or without solvent, at ⁇ 20° C.
  • acid halide oxazolyl chloride, thionyl chloride etc.
  • an inert organic solvent chloroform, methyhlene chloride, diethyl ether, tetrahydrofuran etc.
  • the compounds of the present invention of the formula (I-1-6) may be prepared by sulfonamidation of the compounds of the formula (1-1) in which at least one of R 1 (s) is an amino or a group containing amino, i.e., the compounds of the formula (I-1-6b)
  • R 1-1-6b is the same meanings as hereinbefore described for R 1 , provided that at least one of R 1-1-6b (s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) with the corresponding compounds containing sulfo.
  • R R 1-1-7 is the same meanings as hereinbefore described for R 1 , provided that at least one of R R 1-1-7 (s) is a substituted aminocarbonyloxy or a group containing a substituted aminocarbonyloxy and the other symbols are the same meaning as hereinbefore described.
  • R R 1-1-7a may be prepared by reacting the compounds of the formula (I-1) in which at least one of R 1 (s) is a hydroxy or a group containing hydroxy, i.e., the compounds of the formula (I-1-7a)
  • R 1-1-7a is the same meanings as hereinbefore described for R 1 , provided that at least one of R 1-1-7a (s) is a hydroxy or a group containing hydroxy and the other symbols are the same meaning as hereinbefore described.) with the corresponding compounds containing isocyanate.
  • This reaction is well known. For example, it may be carried out in an organic solvent (tetrahydrofuran, methyhlene chloride, diethyl ether etc.) in the presence of base (1,8-diazabicyclo[5.4.0]undec-7-en (DBU), triethylamine, sodium hydride etc.) at 0 ⁇ 100° C.
  • organic solvent tetrahydrofuran, methyhlene chloride, diethyl ether etc.
  • DBU 1,8-diazabicyclo[5.4.0]undec-7-en
  • R 1-1-8 is the same meanings as hereinbefore described for R 1 , provided that at least one of R 1-1-8 (s) is a substituted aminocarbonyl or a group containing a substituted aminocarbonyl and the other symbols are the same meaning as hereinbefore described.
  • R 1-1-8 may be prepared by reacting the compounds of the formula (I-1) in which at least one of R 1 (s) is an amino or a group containing amino, i.e., the compounds of the formula (I-1-8a)
  • R R 1-1-8 is the same meanings as hereinbefore described for R 1 , provided that at least one of R R 1-1-8a (s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) with the corresponding compounds containing isocyanate.
  • R R 1-1-9 is the same meanings as hereinbefore described for R 1 , provided that at least one of R R 1-1-9 (s) is a substituted oxycarbonylamino or a group containing a substituted oxyocarbonylamino and the other symbols are the same meaning as hereinbefore described.
  • R R 1-1-9 may be prepared by esterification of the compounds of the formula (I-1) in which at least one of R 1 (s) is an amino or a group containing amino, i.e., the compounds of the formula (I-1-9a)
  • R R 1-1-9a is the same meanings as hereinbefore described for R 1 , provided that at least one of R 1-1-9a (s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) with the corresponding halo formic acid ester.
  • This reaction is well known. For example, it may be carried out in an organic solvent (tetrahydrofuran, methyhlene chloride, diethyl ether etc.) in the presence of base (triethylamine, pyridine etc.) at ⁇ 78 ⁇ 40° C.
  • organic solvent tetrahydrofuran, methyhlene chloride, diethyl ether etc.
  • base triethylamine, pyridine etc.
  • R 1-1-10 is the same meanings as hereinbefore described for R 1 , provided that at least one of R 1-1-10 (s) is a substituted oxycarbonyloxy or a group containing a substituted oxycarbonyloxy and the other symbols are the same meaning as hereinbefore described.
  • R 1-1-10 may be prepared by esterification of the compounds of the formula (I-1) in which at least one of R 1 (s) is a hydroxy or a group containing hydroxy, i.e., the compounds of the formula (I-1-10a)
  • R 1-1-10a is the same meanings as hereinbefore described for R 1 , provided that at least one of R 1-1-10a (s) is a hydroxy or a group containing hydroxy and the other symbols are the same meaning as hereinbefore described.) with the corresponding halo formic acid ester.
  • R 1-1-11 is the same meanings as hereinbefore described for R 1 , provided that at least one of R 1-1-11 (s) is a substituted (hydroxy)methyl or a group containing a substituted (hydroxy)methyl and the other symbols are the same meaning as hereinbefore described.
  • R 1-1-11 may be prepared by the following methods (a) ⁇ (b).
  • R 1-1-11aa is the same meanings as hereinbefore described for R 1 , provided that at least one of R 1-1-11a (s) is a formyl and the other symbols are the same meaning as hereinbefore described.
  • This reaction is well known. For example, it may be carried out in an organic solvent (tetrahydrofuran, diethyl ether etc.) at ⁇ 78 ⁇ 0° C.
  • organic solvent tetrahydrofuran, diethyl ether etc.
  • n-1-11b is an integer of 1 ⁇ 2 and the other symbols are the same meaning as hereinbefore described.
  • [0666] may be prepared by oxidizing the said compounds of the formula (I-1-11a) as described in [1].
  • R 1-1-12 is the same meanings as hereinbefore described for R 1 , provided that at least one of R 1-1-12 (s) is an substituted carbonyl or a group containing substituted carbonyl and the other symbols are the same meaning as hereinbefore described.
  • [0669] may be prepared by oxidizing the said compounds of the formula (I-1-11).
  • This oxidation is well known. For example, it may be carried out in an organic solvent (methyhlene chloride, chloroform etc.) using oxidant (manganese dioxide, oxazolyl chloride, pyridinium dichromate etc.) at ⁇ 78 ⁇ 40° C.
  • oxidant manganese dioxide, oxazolyl chloride, pyridinium dichromate etc.
  • R 1-1-13 is the same meanings as hereinbefore described for R 1 , provided that at least one of R 1-1-13 (s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.
  • R 1-1-13a may be prepared by reducing nitro in the compounds of the formula of (I-1) in which at least one of R 1 (s) is a nitro or a group containing nitro, i.e., the compounds of the formula (I-1-13a)
  • R R 1-1-13a is the same meanings as hereinbefore described for R 1 , provided that at least one of R 1-1-13a (s) is a nitro or a group containing nitro and the other symbols are the same meaning as hereinbefore described.).
  • the reduction of nitro is well known. For example, it may be carried out by hydrogenolysis and reduction using organic metal.
  • This hydrogenolysis is well known. For example, it may be carried out in inert solvent [ethers (e.g., tetrahydrofuran, dioxane, dimethoxy ethane, diethyl ether etc.), alcohols (e.g., methanol , ethanol etc.), benzenes (e.g., benzene, toluene etc.), ketones (e.g., acetone, methyl ethyl ketone etc.), nitriles (e.g., acetonitrile etc.), amides (e.g., dimethylformamide etc.), water, ethyl acetate, acetic acid or mixture of the said two or more solvents etc.], in the presence of catalyst to hydrogenate (e.g., Pd-C, palladium black, Pd, palladium hydroxide, platinum oxide, Ni, Raney nickel, ruthenium chloride etc.), in the presence or absence
  • the reduction using an organic metal is well known. For example, it may be carried out in a water-admissible solvent (ethanol , methanol etc.) in the presence or absence of an aqueous hydrochloric acid solution, using an organic metal (Zn, Fe, Sn, SnCl 2 , FeCl 2 etc.) at 50 ⁇ 150° C.
  • a water-admissible solvent ethanol , methanol etc.
  • an organic metal Zn, Fe, Sn, SnCl 2 , FeCl 2 etc.
  • R 1-1-14 is the same meanings as hereinbefore described for R 1 , provided that at least one of R R 1-1-14 (s) is a —COOH, hydroxy or amino or a group containing —COOH, hydroxy or amino and the other symbols are the same meaning as hereinbefore described.
  • R 1-1-14 may be prepared by removal of protecting group in the compounds of the formula (I-1) containing a protected COOH, hydroxy or amino, i.e., the compounds of the formula (I-1-14a)
  • R 1-1-14a is the same meanings as hereinbefore described for R 1 , provided that at least one of R 1-1-14a (s) is a protected COOH (e.g., it is protected by methyl, ethyl, t-butyl and benzyl etc.), protected hydroxy (e.g., it is protected by methoxymethyl, tetrahydropyranyl, t-butyldimethylsilyl, acetyl, benzyl etc.) or protected amino (e.g., it is protected by benzyloxycarbonyl, t-butoxycarbonyloxy, trifluoroacetyl etc.) or a group containing such a group, and the other symbols are the same meaning as hereinbefore described.) according to alkaline hydrolysis, removal of protecting group in an acidic condition, removal of silyl or hydrogenolysis.
  • a protected COOH e.g., it is protected by methyl, ethyl, t-but
  • the removal of a protecting group according to alkaline hydrolysis is well known. For example, it may be carried out in an organic solvent (methanol, tetrahydrofuran, dioxane etc.), using hydroxide of an alkaline metal (sodium hydroxide, potassium hydroxide , lithium hydroxide etc.), hydroxide of an alkaline earth metal (barium hydroxide, calcium hydroxide etc.) or carbonate (sodium carbonate , potassium carbonate etc.) or an aqueous solution thereof or a mixture thereof at 0 ⁇ 40° C.
  • an organic solvent methanol, tetrahydrofuran, dioxane etc.
  • hydroxide of an alkaline metal sodium hydroxide, potassium hydroxide , lithium hydroxide etc.
  • hydroxide of an alkaline earth metal barium hydroxide, calcium hydroxide etc.
  • carbonate sodium carbonate , potassium carbonate etc.
  • the removal of a protecting group in an acidic condition is well known.
  • it may be carried out in an organic solvent (methyhlene chloride, chloroform, dioxane, ethyl acetate, anisole etc.), organic acid (acetic acid, trifluoroacetic acid, methanesulfonic acid, trimethylsilyliodide etc.) or inorganic acid (hydrochloric acid, sulfuric acid etc.) or a mixture thereof (bromohydroacetic acid etc.) at 0 ⁇ 100° C.
  • organic solvent methyhlene chloride, chloroform, dioxane, ethyl acetate, anisole etc.
  • organic acid acetic acid, trifluoroacetic acid, methanesulfonic acid, trimethylsilyliodide etc.
  • inorganic acid hydroochloric acid, sulfuric acid etc.
  • bromohydroacetic acid etc. at 0 ⁇ 100° C.
  • silyl is well known. For example, it may be carried out in a water-admissible organic solvent (tetrahydrofuran, acetonitrile etc.), using tetrabutylammonium fluoride at 0 ⁇ 40° C.
  • a water-admissible organic solvent tetrahydrofuran, acetonitrile etc.
  • [0685] may be prepared by the following methods [15] ⁇ [ 17 ].
  • n-2-15a is an integer of 1 ⁇ 2 and the other symbols are the same meanings as hereinbefore described.
  • n-2-15a is an integer of 1 ⁇ 2 and the other symbols are the same meanings as hereinbefore described.
  • This reaction is known one (to see J. Am. Chem. Soc., 72, 1985 (1950), J. Org. Chem., 54, 4232 (1989).
  • it may be carried out in an inert organic solvent (tetrahydrofuran, diethyl ether, methylene chloride, chloroform, benzene, toluene, dimethylformamide, dimethylsulfoxide, acetonitrile etc.) using hydride of an alkaline metal, hydroxide of an alkaline metal (sodium hydroxide, potassium hydroxide, lithium hydroxide etc.), hydroxide of an alkaline earth metal (barium hydroxide, calcium hydroxide etc.) or tertiary amine (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine etc.) or an aqueous solution thereof, or a mixture thereof at 0 ⁇ 40° C.
  • an inert organic solvent tetrahydrofuran, diethy
  • This reduction reaction is well known.
  • this reaction may be carried out in an organic solvent (diethyl ether, tetrahydrofuran etc.) using reductant (lithium aluminum hydride, aluminum diisobutylhydride etc.) at 0 ⁇ 80° C.
  • organic solvent diethyl ether, tetrahydrofuran etc.
  • reductant lithium aluminum hydride, aluminum diisobutylhydride etc.
  • n-2-17a is an integer of 1 ⁇ 2 and the other symbols are the same meaning as hereinbefore described.
  • [0703] may be prepared by reacting the said compounds of the formula (I-11-a) or the compounds of the formula (I-1-1b) and the compounds of the formula (IV)
  • This reaction may be carried out by the same procedure described in the reaction of the compounds of the formula (I-2-15a) and the compounds of the formula (III) in [15].
  • This reduction is known one.
  • it may be carried out by hydrogenation or by the method using triethylsilane.
  • This hydrogenation is known reaction.
  • it may be carried out in inert solvent [ethers (e.g., tetrahydrofuran, dioxane, dimethoxy ethane, diethyl ether etc.), alcohols (e.g., methanol, ethanol etc.), benzenes (e.g., benzene, toluene etc.), ketones (e.g., acetone, methyl ethyl ketone etc.), nitrites (e.g., acetonitrile etc.), amides (e.g., dimethylformamide etc.), water, ethyl acetate, acetic acid or mixture of the said two or more solvents etc.], in the presence of catalyst to hydrogenate (e.g., Pd-C, palladium black, Pd, palladium hydroxide, platinum oxide, Ni, Raney nickel, ruthenium chloride etc.), in the presence or absence of an ether to hydrogen
  • This reduction using triethylsilane is well known. For example, it may be carried out in trifluoroacetic acid, in the presence of triethylsilane at 0 ⁇ 100° C.
  • the compounds of the present invention of the formula (I-2) may be also prepared by not only the methods described in [15] ⁇ [17] but also the following methods [18] ⁇ [30].
  • R 1-2-18 and R 2-2-18 are the same meanings as hereinbefore described for R 1 and R 2 , respectively, provided that at least one of R 1-2-18 (s) and R 2-2-18 (s) is a substituted oxy or a group containing substituted oxy and the other symbols are the same meaning as hereinbefore described.
  • R 1-2-18 and R 2-2-18 are the same meanings as hereinbefore described for R 1 and R 2 , respectively, provided that at least one of R 1-2-18 (s) and R 2-2-18 (s) is a substituted oxy or a group containing substituted oxy and the other symbols are the same meaning as hereinbefore described.
  • the compounds of the present invention of the formula (I-2-18) may be prepared by eterification of the compounds of the formula (I-2) in which at least one of R 1 (s) or R 2 (s) is hydroxy or a group containing hydroxy, i.e., the compounds of the formula (I-2-18a)
  • R 1-2-18a and R 2-2-18a are the same meanings as hereinbefore described for R 1 and R 2 , respectively, provided that at least one of R 1-2-18a (s) and R 2-2-18a (s) is a hydroxy or a group containing hydroxy and the other symbols are the same meaning as hereinbefore described.
  • the compounds of the present invention of the formula (I-2-18) may be prepared by eterification of the compounds of the formula (I-2) in which at least one of R 1 (s) is a hydroxy or a group containing hydroxy, i.e., the compounds of the formula (I-2-18b)
  • R 1-2-18b and R 2-2-18b are the same meanings as hereinbefore described for R 1 and R 2 , respectively, provided that at least one of R 1-2-18b (s) and R 2-2-18b (s) is a hydroxy or a group containing hydroxy and the other symbols are the same meaning as hereinbefore described.
  • R 1-2-19 and R 2-2-19 are the same meanings as hereinbefore described for R 1 and R 2 , respectively, provided that at least one of R 1-2-19 (s) and R 2-2-19 (s) is a substituted amino or a group containing substituted amino and the other symbols are the same meaning as hereinbefore described.
  • R 1-2-19 and R 2-2-19 are the same meanings as hereinbefore described for R 1 and R 2 , respectively, provided that at least one of R 1-2-19 (s) and R 2-2-19 (s) is a substituted amino or a group containing substituted amino and the other symbols are the same meaning as hereinbefore described.
  • the compounds of the present invention of the formula (I-2-19) may be prepared by reacting the compounds of the formula (I-2) in which at least one of R 1 (s) or R 2 (s) is a halogen (chloride, bromide, iodide) or a group containing halogen, i.e., the compounds of the formula (I-2-19a)
  • R 1-2-19a and R 2-2-19a are the same meanings as hereinbefore described for R 1 and R 2 , respectively, provided that at least one of R 1-2-19a (s) and R 2-2-19a (s) is a halogen (chloride, bromide, iodide) or a group containing halogen and the other symbols are the same meaning as hereinbefore described.)
  • the compounds of the present invention of the formula (I-2-19) may be prepared by reacting the compounds of the formula (I-2) in which at least one of R 1 (s) or R 2 (s) is an amino or a group containing amino, i.e., the compounds of the formula (I-2-19b)
  • R 1-2-19b and R 2-2-19b are the same meanings as hereinbefore described for R 1 and R 2 , respectively, provided that at least one of R 1-2-19b (s) and R 2-2-19b (s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing halogen (chloride, bromide, and iodide).
  • the compounds of the present invention of the formula (I-2-19) may be prepared by reacting the compounds of the formula (I-2) in which at least one of R 1 (s) or R 2 (s) is an amino or a group containing amino, i.e., the compounds of the formula (I-2-19c)
  • R 1-2-19c and R 2-2-19c are the same meanings as hereinbefore described for R 1 and R 2 , respectively, provided that at least one of R 1-2-19c (s) and R 2-2-19c (s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing carbonyl.
  • the compounds of the present invention of the formula (I-2-19) may be prepared by reductive amidation of the compounds of the formula (I-2) in which at least one of R 1 (s) or R 2 (s) is a carbonyl or a group containing carbonyl, i.e., the compounds of the formula (I-2-19d)
  • R 1-2-19d and R 2-2-19d are the same meanings as hereinbefore described for R 1 and R 2 , respectively, provided that at least one of R 1-2-19d (s) and R 2-2-19d (s) is a carbonyl or a group containing carbonyl and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing amino.
  • R 1-2-20 and R 2-2-20 are the same meanings as hereinbefore described for R 1 and R 2 , respectively, provided that at least one of R 1-2-20 (s) and R 2-2-20 (s) is an amide or a group containing amide and the other symbols are the same meaning as hereinbefore described.
  • R 1-2-20 and R 2-2-20 are the same meanings as hereinbefore described for R 1 and R 2 , respectively, provided that at least one of R 1-2-20 (s) and R 2-2-20 (s) is an amide or a group containing amide and the other symbols are the same meaning as hereinbefore described.
  • the compounds of the present invention of the formula (I-2-20) may be prepared by amidation of the compounds of the formula (I-2) in which at least one of at least one of R 1 (s) or R 2 (s) is a —COOH or a group containing —COOH, i.e., the compounds of the formula (I-2-20a)
  • R 1-2-20a and R 2-2-20a are the same meanings as hereinbefore described for R 1 and R 2 , respectively, provided that at least one of R 1-1-20a (s) and R 2-2-20a (s) is a —COOH or a group containing —COOH and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing amino.
  • amidation may be carried out by the same procedure for preparation of the compounds of the formula (I-1-4) in [4].
  • the compounds of the present invention of the formula (I-2-20) may be prepared by amidation of the compounds of the formula (I-2) in which at least one of R 1 (s) or R 2 (s) is an amino or a group containing amino, i.e., the compounds of the formula (I-2-20b)
  • R 1-2-20b and R 2-2-20b are the same meanings as hereinbefore described for R 1 and R 2 , respectively, provided that at least one of R 1-2-20b (s) and R 2-2-20b (s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing carboxy.
  • amidation may be carried out by the same procedure for preparation of the compounds of the formula (I-1-4) in [4].
  • R 1-2-21 and R 2-2-1 are the same meanings as hereinbefore described for R 1 and R 2 , respectively, provided that at least one of R 1-2-2 (s) and R 2-2-21 (s) is an ester or a group containing ester and the other symbols are the same meaning as hereinbefore described.
  • R 1-2-2 (s) and R 2-2-21 (s) is an ester or a group containing ester and the other symbols are the same meaning as hereinbefore described.
  • the compounds of the present invention of the formula (I-2-21) may be prepared by esterification of the compounds of the formula (I-2) in which at least one of R 1 (s) or R 2 (s) is a —COOH or a group containing —COOH, i.e., the compounds of the formula (I-2-21a)
  • R 1-2-21a and R 2-2-21a are the same meanings as hereinbefore described for R 1 and R 2 , respectively, provided that at least one of R 1-2-21a (s) and R 2-2-21a (s) is a —COOH or a group containing —COOH and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing hydroxy.
  • the compounds of the present invention of the formula (I-2-21) may be prepared by esterification of the compounds of the formula (I-2) in which R 1 (s) or R 2 (s) is a hydroxy or a group containing hydroxy, i e., the compounds of the formula (I-2-21b)
  • R 1-2-21 and R 2-2-21b are the same meanings as hereinbefore described for R 1 and R 2 , respectively, provided that at least one of R 1-2-21b (s) and R 2-2-21b (s) is a hydroxy or a group containing hydroxy and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing carboxy.
  • R 1-2-22 and R 2-2-22 are the same meanings as hereinbefore described for R 1 and R 2 , respectively, provided that at least one of R 1-2-22 (s) and R 2-2-22 (s) is a sulfonamide or a group containing sulfonamide and the other symbols are the same meaning as hereinbefore described.
  • R 1-2-22 and R 2-2-22 are the same meanings as hereinbefore described for R 1 and R 2 , respectively, provided that at least one of R 1-2-22 (s) and R 2-2-22 (s) is a sulfonamide or a group containing sulfonamide and the other symbols are the same meaning as hereinbefore described.
  • the compounds of the present invention of the formula (I-2-22) may be prepared by sulfonamidation of the compounds of the formula (I-2) in which at least one of R 1 (s) or R 2 (s) is a —SO 3 H or a group containing —SO 3 H, i.e., the compounds of the formula (VI)
  • R 1-2-22a and R 2-2-22a are the same meanings as hereinbefore described for R 1 and R 2 , respectively, provided that at least one of R 1-2-22a (s) and R 2-2-22a (s) is a —SO 3 H or a group containing —SO 3 H and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing amino.
  • the compounds of the present invention of the formula (I-2-22) may be prepared by sulfonamidation of the compounds of the formula (I-2) in which at least one of R 1 (s) or R 2 (s) is an amino or a group containing amino, i.e., the compounds of the formula (I-2-22b)
  • R 1-2-22b and R 2-2-22b are the same meanings as hereinbefore described for R 1 and R 2 , respectively, provided that at least one of R 1-2-22b (s) and R 2-2-22b (s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing sulfo.
  • R 1-2-23 and R 2-2-23 are the same meanings as hereinbefore described for R 1 and R 2 , respectively, provided that at least one of R 1-2-23 (s) and R 2-2-23 (s) is a substituted aminocarbonyloxy or a group containing a substituted aminocarbonyloxy and the other symbols are the same meaning as hereinbefore described,) may be prepared by reacting the compounds of the formula (I-2) in which at least one of R 1 (s) or R 2 (s) is a hydroxy or a group containing hydroxy, i.e., the compounds of the formula (I-2-23a)
  • R 1-2-23a and R 2-2-23a are the same meanings as hereinbefore described for R 1 and R 2 , respectively, provided that at least one of R 1-2-23a (s) and R 2-2-23a (s) is a hydroxy or a group containing hydroxy and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing isocyanate.
  • R 1-2-24 and R 2-2-24 are the same meanings as hereinbefore described for R 1 and R 2 , respectively, provided that at least one of R 1-2-24 (s) and R 2-2-24 (s) is a substituted aminocarbonylamino or a group containing a substituted aminocarbonylamino and the other symbols are the same meaning as hereinbefore described.
  • R 1 (s) or R 2 (s) is an amino or a group containing amino, i.e., the compounds of the formula (I-2-24a)
  • R 1-2-24a and R 2-2-24a are the same meanings as hereinbefore described for R 1 and R 2 , respectively, provided that at least one of R 1-2-24a (s) and R 2-2-24a (s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing isocyanate.
  • R 1-2-25 and R 2-2-25 are the same meanings as hereinbefore described for R 1 and R 2 , respectively, provided that at least one of R 1-2-25 (s) and R 2-2-25 (s) is a substituted oxycarbonylamino or a group containing a substituted oxyocarbonylamino and the other symbols are the same meaning as hereinbefore described.
  • R 1 (s) or R 2 (s) is an amino or a group containing amino, i.e., the compounds of the formula (I-2-25a)
  • R 1-2-25a and R 1-2-25a are the same meanings as hereinbefore described for R 1 and R 2 , respectively, provided that at least one of R 1-2-25a (s) and R 2-2-25a (s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing haloformic acid ester.
  • R 1-2-26 and R 2-2-26 are the same meanings as hereinbefore described for R 1 and R 2 , respectively, provided that at least one of R 1-2-26 (s) and R 2-2-26 (s) is a substituted oxycarbonyloxy or a group containing a substituted oxycarbonyloxy and the other symbols are the same meaning as hereinbefore described.
  • R 1 (s) or R 2 (s) is a hydroxy or a group containing hydroxy, i.e., the compounds of the formula (I-2-26a)
  • R 1-2-26a and R 2-2-26a are the same meanings as hereinbefore described for R 1 and R 2 , respectively, provided that at least one of R 1-2-26a (s) and R 2-22-6a (s) is a hydroxy or a group containing hydroxy and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing haloformic acid ester.
  • R 1-2-27 and R 2-2-27 are the same meanings as hereinbefore described for R 1 and R 2 , respectively, provided that at least one of R 1-2-27 (s) and R 2-2-27 (s) is a substituted (hydroxy)methyl or a group containing a substituted (hydroxy)methyl and the other symbols are the same meaning as hereinbefore described.
  • R 1 (s) or R 2 (s) is a formyl, i.e., the compounds of the formula (I-2-27a)
  • R 1-2-27a and R 2-2-27a are the same meanings as hereinbefore described for R 1 and R 2 , respectively, provided that at least one of R 1-2-27a (s) and R 2-2-27a (s) is a formyl and the other symbols are the same meaning as hereinbefore described.) and Grignard's reagents or corresponding derivatives containing lithium.
  • R 1-2-28 and R 2-2-28 are the same meanings as hereinbefore described for R 1 and R 2 , respectively, provided that at least one of R 1-2-28 (s) and R 2-2-28 (s) is a substituted carbonyl or a group containing a substituted carbonyl and the other symbols are the same meaning as hereinbefore described.
  • R 1-2-28 and R 2-2-28 may be prepared by oxidizing the said compounds of the formula (I-2-27).
  • R 1-2-29 and R 2-22-29 are the same meanings as hereinbefore described for R 1 and R 2 , respectively, provided that at least one of R 1-2-29 (s) and R 2-2-29 (s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.
  • R 1 (s) or R 2 (s) is a nitro or a group containing nitro, i.e., the compounds of the formula (I-2-29a)
  • R 2-2-29a and R 2-2-29a are the same meanings as hereinbefore described for R 1 and R 2 , respectively, provided that at least one of R 1-2-29a (s) and R 2-2-29a (s) is a nitro or a group containing nitro and the other symbols are the same meaning as hereinbefore described.).
  • R 1-2-30 and R 2-2-30 are the same meanings as hereinbefore described for R 1 and R 2 , respectively, provided that at least one of R 1-2-30 (s) and R 2-2-30 (s) is a —COOH, hydroxy or amino or a group containing —COOH, hydroxy or amino and the other symbols are the same meaning as hereinbefore described.
  • R 1-2-30 and R 2-2-30 (s) may be prepared by removal of protecting group in the compounds of the formula (I-2) in which —COOH, hydroxy or amino which is protected by a protecting group or a group containing —COOH, hydroxy or amino which is protected by a protecting group, i.e., the compounds of the formula (I-2-30a)
  • R 1-2-30a and R 2-2-30a are the same meanings as hereinbefore described for R 1 and R 2 , respectively, provided that at least one of R 1-2-30a (s) and R 2-2-30a (s) is a protected —COOH (e.g., it is protected by methyl, ethyl, t-butyl and benzyl etc.), protected hydroxy (e.g., it is protected by methoxymethyl, tetrahydropyranyl, t-butyldimethylsilyl, acetyl, benzyl etc.) or protected amino (e.g., it is protected by benzyloxycarbonyl, t-butoxycarbonyloxy, trifluoroacetyl etc.) or a group containing such a group and the other symbols are the same meaning as hereinbefore described.) by an alkaline hydrolysis, by removal of protecting group in an acidic condition, by removal of silyl or by removal of protecting
  • Reaction for removal of protecting group in the present invention means an ordinal one which is well known to the person in the art, for example, alkaline hydrolysis, removal of protecting group in an acidic condition and hydrogenolysis.
  • the aimed compounds of the present invention may be prepared easily by choice of these reactions.
  • a protecting group of carboxy includes, for example, methyl, ethyl, t-butyl and benzyl.
  • such a group includes the other protecting group which is removable selectively and easily, for example, one described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1991.
  • a protecting group of hydroxy includes, for example, methoxymethyl, tetrahydropyranyl, t-butyidimethylsilyl, acetyl, and benzyl.
  • such a group includes the other protecting group which is removable selectively and easily, for example, one described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1991.
  • a protecting group of amino includes, for example, benzyloxycarbonyl, t-butoxycarbonyl, trifluoroacetyl.
  • such a group includes the other protecting group which is removable selectively and easily, for example, one described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1991.
  • the compounds of the formula (I-1-1 c) in which A is benzene, R 1 is carboxy, p is 1 and R 1 is bonded at 4-position, i.e., the compounds of the formula (XI) are important intermediates of the compounds of the formula (I) of the present invention.
  • the methods for preparation of the compounds of the formula (XI) are shown in the mentioned Reaction Scheme 5. Next, each step is explained in detail.
  • reaction to synthesis of the compounds of the formula (XIII) from the compounds of the formula (XII) is well known.
  • it may be carried out in an inert organic solvent (acetonitrile, benzene, toluene, xylene, methyhlene chloride, chloroform, dimethoxy ethane, tetrahydrofuran, tetrahydropyran, dioxane, diethyl ether, acetone etc.) or mixture thereof, in the presence of Lewis acid (Znl 2 , ZnCl 2 , aluminum chloride, TiCl 2 , lithium hypochloric acid, lithium borotetrafluoride, lithium hexafluoride etc.) and cyanide derivatives (trimethylsilylcyanide, diethyl aluminum cyanide, or diethyl cyanophosphonate etc.) at 0 ⁇ 40°C.
  • Lewis acid Znl 2 , ZnCl 2 , aluminum chloride, TiC
  • reaction to synthesis of the compounds of the formula (XIV) from the compounds of the formula (XIII) is well known.
  • it may be carried out in an inert organic solvent (benzene, toluene, ethyl acetate, dioxane, dimethoxy ethane, diethyl ether, tetrahydrofuran, tetrahydropyran, the mixture thereof etc.) in the presence of oxidant (2,3-dichloro-5,6-dicyano-1,4-benzoquinon, chloranil (2,3,5,6-tetrachloro-1,4-benzoquinon) etc.) at room temperature to refluxing temperature.
  • an inert organic solvent benzene, toluene, ethyl acetate, dioxane, dimethoxy ethane, diethyl ether, tetrahydrofuran, tetrahydropyran, the mixture thereof etc.
  • oxidant 2,
  • an organic solvent ethylene glycol, oleic acid, diethylene glycol, dimethyl ether, toluene, benzene, xylene etc.
  • hydrogen acceptor nitrobenzene, maleic acid, cyclohexen, oleic acid, 1,5-cycloctadien, phenylacetylene, 2-butylic acid etc.
  • metal catalyst Pd—C, palladium hydroxide, palladium black, Pd, platinum oxide, Ni, Raney nickel, ruthenium chloride etc.
  • reaction to synthesis of the compounds of the formula (XI) from the compounds of the formula (XIV) is well known.
  • it may be carried out in alcohol solvent (ethylene glycol, t-butanol, benzyl alcohol, methanol ethanol , propanol, isopropanol etc.) in the presence of alkali (sodium hydroxide, potassium hydroxide, lithium hydroxide etc.) at 60° C. ⁇ refluxing temperature.
  • obtained products may be purified by conventional techniques. For example, purification may be carried out by distillation at atmospheric or reduced pressure, by high performance liquid chromatography, by thin layer chromatography or by column chromatography using silica gel or magnesium silicate, by washing or by recrystallization. Purification may be carried out after each reaction, or after a series of reactions.
  • optical isomers of the compounds of the present invention of the formula (I) may be obtained by an ordinal optical separation (e.g., separation by gas chromatography or by high performance liquid chromatography, separation by crystallization to diastermeric salt or clathrate compounds or separation by preferential crystallization etc.) or by ordinal method for preparation of racemic compound.
  • an ordinal optical separation e.g., separation by gas chromatography or by high performance liquid chromatography, separation by crystallization to diastermeric salt or clathrate compounds or separation by preferential crystallization etc.
  • A549 cells human lung epithelial cell line
  • DMEM dalbeco-modified eagle medium
  • FBS 0.5% fetus bovine serum
  • the test compound dissolved in various kinds of solvents at various concentrations (20 ⁇ l) and Tumor Necrosis Factor- ⁇ (TNF- ⁇ (Genzyme Co, Cat. No. TNF-H)) dissolved in DMEM at the concentration of 12.5 ng/ml (80 ⁇ l) were added thereto.
  • TNF- ⁇ Tumor Necrosis Factor- ⁇
  • EXAMPLE 20(4) possessed an inhibitory activity on IL-6 production with an IC 50 value of 4.4 ⁇ M and showed no cellular toxicity at 10 ⁇ M.
  • lipopolysaccharide (6 ⁇ g/ml) dissolved in RPMI1640 medium containing 10% FBS (LPS (Difco Co., Cat. No. 3120-25-0)) (10 ⁇ l) was added thereto. After incubation for 20 hours, the supernatant (150 ⁇ l) was recovered to assay the quantity of IL-12 using ELISA Method (R&D Systems Co, Cat. No. D1200), calculate for inhibitory activity of the test compound and determine 50% inhibitory concentration (IC 50 ) (see J. Exp. Med., 183, 147 (1996)).
  • IC 50 50% inhibitory concentration
  • the compounds of the present invention possess an inhibitory activity of producing IL-6 and/or IL-12 in animal, especially human, so they are useful for prevention and/or treatment of, for example, 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.
  • various inflammatory diseases for example, various inflammatory diseases, sepsis, multiple myeloma, plasma cell leukemia, osteoporosis, cachexia, psoriasis, nephritis, renal cell carcinoma, Kaposi's sarcoma, rheumatoid arthritis,
  • non-toxic salts for the purpose above described, non-toxic salts, acid addition salts, or hydrates thereof may be normally administered systematically or locally, usually by oral or parenteral administration.
  • the doses to be administered are determined depending upon age, body weight, symptom, the desired therapeutic effect, the route of administration, and the duration of the treatment etc.
  • the doses per person per dose are generally between 1 mg and 1000 mg, by oral administration, up to several times per day, and between 0.1 mg and 100 mg, by parenteral administration (preferred into vein) up to several times per day, or continuous administration between 1 and 24 hrs. per day into vein.
  • the compounds of the present invention may be administered as inner solid composition's or inner liquid compositions for oral administration, or as injections, liniments or suppositories etc. for parenteral administration.
  • Inner solid compositions for oral administration include compressed tablets, pills, capsules, dispersible powders, and granules.
  • Capsules contain hard capsules and soft capsules.
  • one or more of the active compound(s) is or are, admixed with at least one inert diluent (lactose, mannitol, glucose, microcrystalline cellulose, starch etc.), connecting agents (hydroxypropyl cellulose, polyvinylpyrrolidone, magnesium metasilicate aluminate etc.), disintegrating agents (cellulose calcium glycolate etc.), lubricating agents (magnesium stearate), stabilizing agents, assisting agents for dissolving (glutamic acid, asparaginic acid etc.) etc. to prepare pharmaceuticals by known methods.
  • inert diluent lactose, mannitol, glucose, microcrystalline cellulose, starch etc.
  • connecting agents hydroxypropyl cellulose, polyvinylpyrrolidone, magnesium metasilicate aluminate etc.
  • disintegrating agents cellulose calcium glycolate etc.
  • lubricating agents magnesium stearate
  • stabilizing agents assisting agents for dissolving (glutamic
  • the pharmaceuticals may, if desired, be coated with material such as sugar, gelatin, hydroxypropyl cellulose or hydroxypropyl cellulose phthalate etc., or be coated with two or more films. And further, coating may include containment within capsules of absorbable materials such as gelatin.
  • Inner liquid compositions for oral administration include pharmaceutically-acceptable water-agents, emulsions, syrups and elixirs etc.
  • one or more of the active compound(s) is or are comprised in inert diluent(s) commonly used in the art (purified water, ethanol or mixture thereof etc.).
  • inert diluents such compositions may also comprise adjuvants such as wetting agents, suspending agents, sweetening agents, flavouring agents, perfuming agents and preserving agents.
  • Injections for parenteral administration include solutions, suspensions and emulsions, and solid injections.
  • Aqueous solutions or suspensions include distilled water for injection and physiological salt solution.
  • Non-aqueous solutions or suspensions include propylene glycol, polyethylene glycol, plant oil such as olive oil, alcohol such as ethanol, POLYSOLBATE80 (registered trade mark) etc.
  • Such compositions may comprise additional diluents: e.g. preserving agents, wetting agents, emulsifying agents, dispersing agents, stabilizing agent, assisting agents such as assisting agents for dissolving (for example, glutamic acid, asparaginic acid).
  • They may be sterilized for example, by filtration through a bacteria-retaining filter, by incorporation of sterilizing agents in the compositions or by irradiation. They may also be manufactured in the form of sterile solid compositions and which can be dissolved in sterile water or some other sterile diluent for injection immediately before use.
  • compositions for parenteral administration include liquids for external use, and endermic liniments, ointments, spray, suppositories and pessaries which comprise one or more of the active compound(s) and may be prepared by known methods.
  • Spray compositions may comprise additional substances other than inert diluents: e.g. stabilizing agents such as sodium hydrogen sulfate, stabilizing agents to give isotonicity, isotonic buffer such as sodium chloride, sodium citrate, citric acid.
  • stabilizing agents such as sodium hydrogen sulfate, stabilizing agents to give isotonicity
  • isotonic buffer such as sodium chloride, sodium citrate, citric acid.
  • the solvents in parenthesis show the developing or eluting solvents and the ratios of the solvents used are by volume in chromatographic separations.
  • the solvents in parentheses in NMR show the solvents used for measurement.

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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.
Figure US20030073706A1-20030417-C00001

Description

    TECHNICAL FIELD
  • The present invention relates to fused thiophene derivatives and inhibitors of producing Interleukin-6 (abbreviated as IL-6 hereafter) and/or Interleukin-12 (abbreviated as IL-12 hereafter) containing fused thiophene derivatives as an active ingredient. [0001]
  • More particularly, the present invention relates to inhibitors of producing IL-6 and/or IL-12 comprising, as an active ingredient, fused thiophene derivatives of the formula (I) [0002]
    Figure US20030073706A1-20030417-C00002
  • (wherein all the symbols are as defined hereafter.) and non-toxic salts thereof, novel fused thiophene derivatives of the said formula (IA) or non-toxic salts thereof and methods for preparation thereof. [0003]
  • Moreover, the present invention relates to a method for preparation of a compound of the formula (XI) which is an intermediate for the compounds of the formula (I). [0004]
    • BACKGROUND
  • Cytokine is a multifunctional factor which plays an important role in the host defence system of living body and it relates to various life phenomena. However, there are many diseases which may be caused by overproduction thereof or by overresponse thereto. [0005]
  • IL-6 is a cytokine produced from various cells, e.g. T cells, B cells, macrophages, kidney mesangial cells, fibroblasts etc., and its various physiological effects are known e.g. induction of B cell differentiation to antibody-producing cells, activation of T cells, increase of platelets, and production of acute phase protein from liver cells etc. But, an abnormal production of IL-6 has been observed in various inflammations, autoimmune diseases and neoplastic diseases and it is suggested that IL-6 plays a certain role in the causes of such pathophysiological situations. In the experiment using an animal model in which IL-6 was forcibly expressed, various types of diseases could be observed and such results strongly suggest the existence of relationship between the abnormal production of IL-6 and the cause of certain diseases (Biochem. J., 265, 621 (1990), Immunol. Today, 11, 443 (1990), J. Autoimmun., 5 Suppl A, 123 (1992), Clin. Immunol. Immunopathol., 62, S60 (1992)). [0006]
  • IL-12 is a cytokine produced from macrophages and dendritic cells etc. and its effects are known; e.g. activation of natural killer (abbreviated as NK hereafter) cells, induction of Interferon-γ (abbreviated as IFN-γ hereafter) production from NK cells and T cells, and regulation of Th1 and Th2 balance etc. Helper T cells are classified into Th1 which stimulates cellular-mediated immunity and Th2 which assists humoral immunity. IL-12 functions to induce Th1 from helper T cell precursors. It is thought that succeedingly, IL-12 induces production of IFN-γ from Th1 cells (which are further differentiated) and accelerates killer activity, so that IL-12 plays a role as a main cytokine causing inflammatory immune reaction which leads to organ disorders (Blood, 84, 4008 (1994)). [0007]
  • Therefore, inhibition of IL-6 and/or IL-12 production(s) is expected to improve various kinds of diseases such as inflammatory diseases as a representative The present invention is targeted for these cytokines and provides novel medicines through inhibiting the production thereof. [0008]
  • Clinical application of the compounds of the present invention involves those diseases which may be caused and be changed to worse by abnormal production of IL-6 and/or IL-12 or by overresponse to them. Inhibitors of producing IL-6 may be used 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 (J. Immunol., 145, 4185 (1990), J. Exp. Med., 172: 1505 (1990), J. Clin. Invest., 87,739 (1991), J. Clin. Invest., 89 1681 (1992), EMBO J., 1, 1189 (1994), Hematol. Oncol. Clin. North Am., 11 159 (1997)). Inhibitors of producing IL-12 may be used for the prevention and/or treatment of various inflammatory diseases, diabetes mellitus, hepatitis, multiple sclerosis, colitis, graft versus host immune diseases, rheumatoid arthritis, infectious diseases, autoimmune diseases (J. Exp. Med., 181, 817 (1995), J. Exp. Med., 181, 381 (1995), J. Exp. Med., 182 128, (1995), Ann, NY Acad. Sci., 795, 371 (1996), Int. Immunol., 8, 569 (1996), Proc. Natl. Acad. Sci. USA, 92, 4823 (1996)). [0009]
  • Further, a compound of the formula (Xl) is an important intermediate of pharmaceutical agents and an efficient method for preparation thereof has been desired. [0010]
  • For example, [0011]
  • (1) In the specifications of U.S. Pat. No. 3,629,438 and U.S. Pat. No. 3,686,216, it is disclosed that a benzothiophene-1,1-dioxide derivative of the formula (X) [0012]
    Figure US20030073706A1-20030417-C00003
  • (wherein X[0013] x is halogen, nitro, alkyl, alkoxy, haloalkyl, carboxy or sulfonylhalide,
  • Y[0014] x is hydrogen, lower alkyl, lower alkoxy, halogen or hydroxy,
  • Z[0015] x is alkyl, alkoxy, halogen, carboxy, haloalkyl or nitro,
  • aX is 0 or an integer of 2, [0016]
  • bX is an integer of 2, [0017]
  • cX is 0 or an integer of 1˜5 or [0018]
  • dX is 0 or an integer of 1˜4.) [0019]
  • has an anti-fungal and anti-vital activities. [0020]
  • (2) In the specification of FR1585930, a compound of the formula (Y) [0021]
    Figure US20030073706A1-20030417-C00004
  • (wherein R[0022] 1Y is hydrogen, halogen or C1˜3 alkyl; R2Y and R3Y are hydrogen or C1˜3 alkyl) is described as an intermediate of diuretic agent, but there is no description about its biological activity.
  • (3) In the specification of SU591474, it is described that a compound of the formula (Z) [0023]
    Figure US20030073706A1-20030417-C00005
  • (wherein R[0024] Z, R1Z, R2Z and R3Z are hydrogen or methyl.) has an anti-spasm activity.
  • (4) In the specification of EP50326, it is described that a compound of the formula (U) [0025]
    Figure US20030073706A1-20030417-C00006
  • (wherein R[0026] 1U and R2U are each hydrogen or C1˜6 alkyl, C3˜6 cycloalkyl or phenyl which may be substituted with 1-2 of halogen, hydroxy, C1˜6 alkyl or alkoxy, R3U is hydrogen or ZU, ZU is C1˜6 alkyl or CR4UR5UR6U, R4U and R5U are hydrogen or C1˜6 alkyl, R6U is COOH, CH2—OH, C1˜6 alkoxycarbonyl or hydroxyaminocarbonyl, XU is hydrogen, halogen or C1˜6 alkyl, nU is 1 or 2, mU is 0˜2) has a diuretic activity (In the explanation of groups, essential parts are extracted).
  • (5) In the specification of WO9527710, it is described that a compound of the formula (V) [0027]
    Figure US20030073706A1-20030417-C00007
  • (wherein R[0028] 1V is t-butyl, R1V is hydrogen, lower alkyl or acyl, a broken line is arbitrary bond, R2V and R3V are hydrogen, alkyl which may be substituted or alkenyl which may be substituted, R4V does not represent anything when arbitrary bond exists and represents the same meaning as R1V when arbitrary bond does not exist and nV is 0˜2.) has an activity as antioxidant of low-density lipoprotein (LDL) (In the explanation of groups, essential parts are extracted).
  • (6) In the specification of Japanese Patent Application Kokai Hei 10-298180, it is described that a compound of the formula (W) [0029]
    Figure US20030073706A1-20030417-C00008
  • (wherein Z[0030] W is oxygen atom or sulfur atom; R1W, R2W, R3W and R4W are the same or different, are hydrogen etc.); EW and FW are the same or different, are nitrogen atom or CH which may be substituted with XW or YW; XW is straight or branched C1-6 alkyloxy, C3-8 cycloalkyloxy or straight or branched C1-3 alkyloxy substituted with C3˜8 cycloalkyl; Y is
    Figure US20030073706A1-20030417-C00009
  • (wherein G[0031] W is —CONH—, O(O)O—, —NHCO— or —OC(O)—; R5W is (a) straight or branched C1-6 alkyl, (b) C3-8 cycloalkyl, (c) C7-12 spiroalkyl, (d) C7-12 bicycloalkyl, (e) aryl, (f) aralkyl, (g) heteroarylalkyl, (h) non-aromatic heterocyclic ring which may be substituted with phenyl or (i) C3-8 cycloalkyl-C1˜3 alkyl. Each of them may be substituted with one or more of substituent selected from a group consisting of i) straight or branched C1-6 alkyl, ii) straight or branched C1-8 alkyloxy, iii) C1-3 haloalkyl, iv) halogen, v) C3-8 cycloalkyl, vi) carboxy, vii) alkyloxycarbonyl, viii) acyl, ix) formyl and x) nitro; nW is an integer of 1-3, pW is an integer of 1-3, (CH2)w and (CH2)pW may be substituted with a straight or branched C1-6 alkyl or C1-3 haloalkyl) has an antagonistic activity against dopamine receptor.
  • (7) In the specification of Japanese Patent Application Kokai Hei 10-513470, it is described that a compound of the formula (T) [0032]
    Figure US20030073706A1-20030417-C00010
  • [wherein R[0033] 1T and R3T are independently hydrogen, —CH3, —C(O)—(C1˜6 alkyl), or —C(O)—ArT (ArT is phenyl which may optionally be substituted); R2T is selected from a group consisting of pyrrolidino, hexamethyleneimino and piperidino], a pharmaceutically acceptable salt thereof or a solvent additive has an activity of inhibiting the effect of IL-6.
  • (8) In the specification of Japanese Patent Application Kokai Hei 11-49765, it is described that a compound of the formula (S) [0034]
    Figure US20030073706A1-20030417-C00011
  • [wherein each R[0035] 1S and R2S is hydrogen or hydrocarbon group which may contain substituent(s) or R1S and R2S taken together with the neighboring carbon atom represents 3- to 8-membered homo or heterocyclic ring which may contain substituent(s), R3S is hydrogen or lower alkyl which may contain subtstituent(s) or aromatic group which may contain substituent(s), R4S is (1) aromatic group which may contain substituent(s), (2) aliphatic hydrocarbon which contains aromatic group (this group is unsubstituted or substituted.) and which may contain additional substituent(s) or (3) acyl, XS and YS are each oxygen atom or sulfur atom which may be oxidized,
    Figure US20030073706A1-20030417-P00900
    is single bond or double bond, ring AS is benzene ring which contains a group of the formula —XSR4S (wherein each symbols represent the same meaning as defined hereinbefore) and which may contain additional substituent(s), with the proviso that when
    Figure US20030073706A1-20030417-P00001
    is single bond and both XS and YS are oxygen atom, then R45 is not acyl.] or a salt thereof have an excellent inhibitory effect of neurodegeneration.
  • (9) Further, the following compounds are known. [0036]
  • Compound (1): 3-(Thiophen-2-yl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene (Maybridge, Catalog No. KM 08156), [0037]
  • Compound (2): 6-Nitro-3-(thiophen-2-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene (Maybridge, catalog No. KM 08165), [0038]
  • Compound (3): 3-(Thiophen-2-yl)thio-2,3-dihydro-11-dioxidebenzo[b]thiophene (Maybridge, Catalog No. KM 08138), [0039]
  • Compound (4): 3-Phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene (Maybridge, Catalog No. KM 08140), [0040]
  • Compound (5): 4,5-Dimethyl-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 102036-04-4), [0041]
  • Compound (6): 4,6-Dimethyl-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 102036-05-5), [0042]
  • Compound (7): 4,7-Dimethyl-11-dioxidebenzo[b]thiophene (CAS Registry No. 102036-06-6), [0043]
  • Compound (8): 5,6-Dimethyl-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 102036-07-7), [0044]
  • Compound (9): 5,7-Dimethyl-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 102036-08-8), [0045]
  • Compound (10) 6,7-Dimethyl-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 102036-09-9), [0046]
  • Compound (11) 4-Carboxymethyl-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 102539-83-3), [0047]
  • Compound (12): 6-(2,2-Bis(ethoxycarbonyl)ethenyl)amino-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 118675-43-7), [0048]
  • Compound (13): 4-Methylaminocarbonyloxy-1,1 -dioxidebenzo[b]thiophene (CAS Registry No. 13687-26-8), [0049]
  • Compound (14): 5-(2-(N-(5-Methoxy-1,2,3,4-tetrahydronaphthalen-1-ylmethyl)-N-methylamino)ethyl)-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 188110-86-3), [0050]
  • Compound (15): 5-(2-Hydroxyethyl)-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 188111-49-1), [0051]
  • Compound (16): 5-Bromo-7-methyl-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 19076-24-5), [0052]
  • Compound (17): 7-Bromo-5-methyl-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 19076-25-6), [0053]
  • Compound (18): 5-Bromo-6-methyl-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 19076-26-7), [0054]
  • Compound (19): 5-Bromo-4-methyl-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 19076-27-8), [0055]
  • Compound (20): 6-Bromo-5-methyl-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 19076-28-9), [0056]
  • Compound (21): 4-Bromo-5-methyl-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 19076-29-0), [0057]
  • Compound (22): 6-Amino-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 20503-40-6), [0058]
  • Compound (23): 6-Acetyamino-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 20503-41-7), [0059]
  • Compound (24): 6-(4-Diethylaminophenyl)-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 33431-95-7), [0060]
  • Compound (25): 1,1-Dioxidethieno[2,3-b]pyridine (CAS Registry No. 37049-39-1), [0061]
  • Compound (26): 1,1-Dioxidethieno[3,2-b]pyridine (CAS Registry No. 37049-40-4), [0062]
  • Compound (27): 1,1-Dioxidethieno([2,3-c]pyridine (CAS Registry No. 37049-41-5), [0063]
  • Compound (28): 5-Amino-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 51956-01-5), [0064]
  • Compound (29): 5-(3-Methyl-5-oxo-4,5-dihydropyrazol-1-yl)-1,1-dioxidebenzo[b]thiophene (GAS Registry No. 51956-06-0), [0065]
  • Compound (30): 4-(2-(1,1-Dioxidebenzo[b]thiophen-3-yl)ethyl)-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 57011-92-4), [0066]
  • Compound (31): 7-Methyl-1,1-dioxidethieno[2,3-c]pyridine (CAS Registry No. 76905-90-3), [0067]
  • Compound (32): 1,1-Dioxidebenzo[b]thiophene (CAS Registry No. 825-44-5), [0068]
  • Compound (33): 4-(4-Methoxyphenyl)-1,1 -dioxidethieno[3,2-c]pyridine (CAS Registry No. 97104-25-1). [0069]
  • (10) In addition, as to a method for preparation of a compound of the formula (XI), for example, the method of the following Reaction Scheme 2 is known. [0070]
  • These are described in detail in Nihonkagakuzasshi 1966, 87(2), 186-189, J. Org. Chem., 1953, Vol. 18, 1511 and J. Org. Chem. 1973, Vol. 38, 146. [0071]
    Figure US20030073706A1-20030417-C00012
  • In Reaction Scheme 2, Me is methyl, Ac is acetyl and NBS is N-bromosuccinimide. [0072]
  • The above method of Reaction Scheme 2 requires 5 or 6 steps in total and Ag[0073] 2O, which is an expensive reagent, in oxidation reaction from the compound of the formula (XI-A-6) to the compound of the formula (XI).
  • Further, in the specification of Japanese Patent Application Kokai Hei 6-49058, the following Reaction Scheme 3 is disclosed as a method for preparation of the compound of the formula (XI). [0074]
    Figure US20030073706A1-20030417-C00013
  • In Reaction Scheme 3, Et is ethyl. [0075]
  • The above method of Reaction Scheme 3 requires 5 steps in total and the total yield is around 2˜3%. [0076]
  • In Tetrahedron Letters, 1996, Vol. 37, No. 19, 3243 and Tetrahedron Letters 1990, Vol.31, No.28, 4011, a reaction wherein ketone is converted into nitrile, followed by dehydrogenation to give aromatic ring is disclosed (Reaction Scheme 4). [0077]
    Figure US20030073706A1-20030417-C00014
  • In Reaction Scheme 4, TMS is trimethylsilyl, DDQ is 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. [0078]
  • This reaction is a method for preparation of aromatic nitrile of the formula (XI-C-2) which comprises that cyclic ketone of the formula (XI-C-1) is converted into cyanohydrin, followed by dehydration to give nitrile of the formula (XI-C-2), and then followed by dehydrogenation by an oxidizer. [0079]
    • DISCLOSURE OF THE INVENTION
  • The present inventors have investigated to find new compounds possessing an inhibitory activity of producing IL-6 and/or IL-12, so that the present inventors have found that the purpose has been achieved by fused thiophene derivatives of the formula (I). [0080]
  • Fused heterocyclic compounds of the formula (I) of the present invention has not been known as inhibitors of producing IL-6 and/or IL-12 at all. Further, a fused thiophene derivative of the formula (IA) is a novel compound which is not known at all. [0081]
  • In addition, the present inventors have investigated to find an efficient method for preparation at a low cost, so that the present inventor have found a method of the following Reaction Scheme 5. [0082]
    Figure US20030073706A1-20030417-C00015
  • The old methods require 5-6 steps, whereas the method of the present invention diminishes to 3 steps in total, so it become possible to produce efficiently. In addition, it is also confirmed that in mass-production of it, the cost for the production is reduced, so that the present inventors have completed the present invention. [0083]
  • The present invention relates to [0084]
  • (1) an inhibitor of producing Interleukin-6 and/or Interleukin-12 comprising, as an active ingredient, a fused thiophene derivative of the formula (I) [0085]
    Figure US20030073706A1-20030417-C00016
  • [wherein [0086]
    Figure US20030073706A1-20030417-P00002
    is a single or double bond, Y is (i)
    Figure US20030073706A1-20030417-C00017
  • or [0087]
  • (ii) hydrogen [0088]
  • (with a proviso that when [0089]
    Figure US20030073706A1-20030417-P00002
    is a double bond, Y is hydrogen, and when
    Figure US20030073706A1-20030417-P00002
    is a single bond, Y is
    Figure US20030073706A1-20030417-C00018
  • m and n are each independently 0 or an integer of 1-2, [0090]
  • p is 0 or an integer of 1-4, [0091]
  • q is 0 or an integer of 1-5, [0092]
  • Z is single bond, C1-8 alkylene, C2-8 alkenylene or C2-8 alkynylene, [0093]
    Figure US20030073706A1-20030417-C00019
  • is [0094]
  • (i) benzene ring or [0095]
  • (ii) 6-membered monocyclic hetero aryl containing 1-2 nitrogen atom(s), [0096]
    Figure US20030073706A1-20030417-C00020
  • is [0097]
  • (i) C3-15 mono-, bi- or tricyclic carbo ring or [0098]
  • (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, each R[0099] 1 of (R1)p is independently,
  • (i) C1-8 alkyl, [0100]
  • (ii) C2-8 alkenyl, [0101]
  • (iii) C2-8 alkynyl, [0102]
  • (iv) nitro, [0103]
  • (v) cyano, [0104]
  • (vi) halogen, [0105]
  • (vii) Cyc[0106] 1,
  • (viii) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with halogen or Cyc[0107] 1or
  • (ix) —A[0108] 1—A2—A3,
  • A[0109] 1 is
  • (i) single bond, [0110]
  • (ii) C1-8 alkylene, [0111]
  • (iii) C2-8 alkenylene or [0112]
  • (iv) C2-8 alkynylene, [0113]
  • A[0114] 2 is
  • (i) —O—, [0115]
  • (ii) —NR[0116] 3—
  • (iii) —C(O)—, [0117]
  • (iv) —CH(OH)—, [0118]
  • (v) —C(O)NR[0119] 4—,
  • (vi) —NR[0120] 11C(O)—,
  • (vii) —C(O)O—, [0121]
  • (viii) —OC(O)—, [0122]
  • (ix) —SO[0123] 2NR6—,
  • (x) —NR[0124] 7SO2—,
  • (xi) —C(O)NR[0125] 9O—,
  • (xii) —OC(O)NR[0126] 10—,
  • (xiii) —NR[0127] 11C(O)NR12—,
  • (xiv) —NR[0128] 13C(O)O— or
  • (xv) —OC(O)O—[0129]
  • (wherein R[0130] 3, 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, —OR14 (wherein R14 is hydrogen or C1-8 alkyl.) or cyano, with the proviso that the linkage of the right side of each group represented by A2 binds to A3.
  • A[0131] 3 is
  • (i) hydrogen, [0132]
  • (ii) C1-8 alkyl, [0133]
  • (iii) C2-8 alkenyl, [0134]
  • (iv) C2-8 alkynyl, [0135]
  • (v) Cyc[0136] 1 or
  • (vi) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with 1-3 groups selected from the following (a)-(i): [0137]
  • (a) halogen, [0138]
  • (b) cyano, [0139]
  • (c) —P(O)(R[0140] 15)2,
  • (d) —Si(R[0141] 16)3,
  • (e) Cyc[0142] 1,
  • (f) —C(O)R[0143] 17,
  • (g) —OR[0144] 18,
  • (h) —NR[0145] 19R20,
  • (i) —SR[0146] 21;
  • plural R[0147] 15s are each independently, hydroxy or C1-8 alkoxy,
  • plural R[0148] 16s are each independently C1-8 alkyl,
  • R[0149] 17 is
  • (i) hydrogen, [0150]
  • (ii) C1-8 alkyl, [0151]
  • (iii) hydroxy, [0152]
  • (iv) C1-8 alkoxy, [0153]
  • (v) Cyc[0154] 1 or
  • (vi) —NR[0155] 22R23 (wherein R22 is hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted with phenyl, R23 is hydrogen, C1-8 alkyl, Cyc1 or C1-8 alkyl substituted with Cyc1 or NR24R25 (R24 and R25 are each independently hydrogen, C1-8 alkyl, phenyl, C1-8 alkyl substituted with phenyl.).),
  • R[0156] 18 is
  • (i) hydrogen, [0157]
  • (ii) C1 -8 alkyl, [0158]
  • (iii) C2-8 alkenyl, [0159]
  • (iv) Cyc[0160] 1 or
  • (v) C1-8 alkyl substituted with Cyc′, Si(R[0161] 26)3 (wherein plural R27 are each independently C1-8 alkyl.) or —OR27 (wherein R27 is hydrogen, C1-8 alkyl or C2-5 acyl.),
  • R[0162] 19 is
  • (i) hydrogen, [0163]
  • (ii) C1-8 alkyl, [0164]
  • (iii) phenyl or [0165]
  • (iv) C1-8 alkyl substituted with phenyl, [0166]
  • R[0167] 20 is
  • (i) hydrogen, [0168]
  • (ii) C1-8 alkyl or [0169]
  • (iii) —C(O)R[0170] 28 (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) Cyc[0171] 1 or
  • (v) C1-8 alkyl substituted with Cyc[0172] 1 or cyano,
  • R[0173] 21 is
  • (i) hydrogen, [0174]
  • (ii) C1-8 alkyl or [0175]
  • (iii) Cyc[0176] 1,
  • Cyc[0177] 1 is
  • (i) C3-15 mono-, bi- or tricyclic carbo ring or [0178]
  • (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, 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) Cyc[0179] 2, (xiii) —OR3, (xiv) —SR32, (xv) —NR33R34, (xvi) —SO2NR35 R36 (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,
  • R[0180] 31 and R32 are each independently, hydrogen, C1-8 alkyl or Cyc2,
  • R[0181] 33 is hydrogen or C1-8 alkyl,
  • R[0182] 34 is hydrogen, C1-8 alkyl or —C(O)-Cyc2,
  • R[0183] 37 is hydrogen or C1-8 alkyl, R36 is hydrogen, C1-8 alkyl or Cyc2,
  • R[0184] 37 is hydrogen, C1-8 alkyl, —OR38, —NR39R40, Cyc2, or C1-8 alkyl substituted with Cyc2 or —C(O)-Cyc2,
  • R[0185] 38, R39 and R40 are each independently, hydrogen, C1-8 alkyl, or C1-8 alkyl substituted with Cyc2,
  • Cyc[0186] 2 is
  • (i) C3-15 mono-, bi- or tricyclic carbo ring or [0187]
  • (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, [0188]
  • 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) —OR[0189] 41, (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,
  • R[0190] 41, R42, R43, R44, R45 and R46 are each independently, hydrogen or C1-8 alkyl,
  • R[0191] 47 is hydrogen, C1-8 alkyl or C1-8 alkoxy
  • each R[0192] 2 of (R2)q is independently,
  • (i) C1-8 alkyl, [0193]
  • (ii) C2-8 alkenyl, [0194]
  • (iii) C2-8 alkynyl, [0195]
  • (iv) —OR[0196] 48
  • (v) —NR[0197] 49R50,
  • (vi) —C(O)R[0198] 51,
  • (vii) nitro, [0199]
  • (viii) cyano, [0200]
  • (ix) halogen or [0201]
  • (x) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with —OR[0202] 48, —NR49R50, —C(O)R51, halogen or Cyc3,
  • R[0203] 48 is
  • (i) hydrogen, [0204]
  • (ii) C1-8 alkyl, [0205]
  • (iii) C2-8 alkenyl, [0206]
  • (iv) C2-8 alkynyl, [0207]
  • (v) Cyc[0208] 3 or
  • (vi) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with halogen, —OR[0209] 52, —NR53R54, —C(O)R55 or Cyc3,
  • R[0210] 49 and R50 are each independently, hydrogen, C1-8 alkyl or —COR59,
  • R[0211] 51 is hydrogen, C1-8 alkyl, hydroxy, C1-8 alkoxy or —NR50R61,
  • R[0212] 52 is hydrogen, C1-8 alkyl, Cyc3, or C1-8 alkyl substituted with Cyc3,
  • —R[0213] 53 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),
  • R[0214] 55 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),
  • R[0215] 59 is C1-8 alkyl or C1-8 alkoxy,
  • R[0216] 60 and R61 are each independently, hydrogen or C1-8 alkyl,
  • Cyc[0217] 3 is
  • (i) C3-15 mono-, bi- or tricyclic carbo ring or [0218]
  • (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, [0219]
  • 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) —NR[0220] 62R63, (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,
  • R[0221] 62 and R63 are each independently, hydrogen or C1-8 alkyl,
  • R[0222] 64 is hydrogen or C1-8 alkyl,
  • with the proviso that when A[0223] 2 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, [0224]
  • (2) a fused thiophene derivative of the formula (IA) [0225]
    Figure US20030073706A1-20030417-C00021
  • [wherein [0226]
    Figure US20030073706A1-20030417-P00002
    is a single or double bond,
  • Y is (i) [0227]
    Figure US20030073706A1-20030417-C00022
  • or [0228]
  • (ii) hydrogen [0229]
  • (with a proviso that when [0230]
    Figure US20030073706A1-20030417-P00002
    is a double bond, Y is hydrogen, and when
    Figure US20030073706A1-20030417-P00002
    is a single bond, Y is
    Figure US20030073706A1-20030417-C00023
  • m and n are each independently 0 or an integer of 1-2, [0231]
  • p is 0 or an integer of 1-4, [0232]
  • q is 0 or an integer of 1-5, [0233]
  • Z is single bond, C1-8 alkylene, C2-8 alkenylene or C2-8 alkynylene, [0234]
    Figure US20030073706A1-20030417-C00024
  • is [0235]
  • (i) benzene ring or [0236]
  • (ii) 6-membered monocyclic hetero aryl containing 1-2 nitrogen atom(s), [0237]
    Figure US20030073706A1-20030417-C00025
  • is [0238]
  • (i) C3-15 mono-, bi- or tricyclic carbo ring or [0239]
  • (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, [0240]
  • each R[0241] 1 of (R1)p is independently,
  • (i) C1-8 alkyl, [0242]
  • (ii) C2-8 alkenyl, [0243]
  • (iii) C2-8 alkynyl, [0244]
  • (iv) nitro, [0245]
  • (v) cyano, [0246]
  • (vi) halogen, [0247]
  • (vii) Cyc[0248] 1,
  • (viii) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with halogen or Cyc[0249] 1 or
  • (ix) —A[0250] 1—A2—A3,
  • A[0251] 1 is
  • (i) single bond, [0252]
  • (ii) C1-8 alkylene, [0253]
  • (iii) C2-8 alkenylene or [0254]
  • (iv) C2-8 alkynylene, [0255]
  • A [0256] 2 is
  • (i) —O—, [0257]
  • (ii) —NR[0258] 3—
  • (iii) —C(O)—, [0259]
  • (iv) —CH(OH)—, [0260]
  • (v) —C(O)NR[0261] 4—,
  • (vi) —NR[0262] 5C(O)—,
  • (vii) —C(O)O—, [0263]
  • (viii) —OC(O)—, [0264]
  • (ix) —SO[0265] 2NR6,
  • (x) —NR[0266] 7SO2—,
  • (xi) —C(O)NR[0267] 9O—,
  • (xii) —OC(O)NR[0268] 10—,
  • (xiii) —NR[0269] 11C(O)NR12—,
  • (xiv) —NR[0270] 13C(O)O— or
  • (xv) —OC(O)O—[0271]
  • (wherein R[0272] 3, 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, —OR14 (wherein R14 is hydrogen or C1-8 alkyl.) or cyano, with the proviso that the linkage of the right side of each group represented by A2 binds to A3.
  • A[0273] 3 is
  • (i) hydrogen, [0274]
  • (ii) C1-8 alkyl, [0275]
  • (iii) C2-8 alkenyl, [0276]
  • (iv) C2-8 alkynyl, [0277]
  • (v) Cyc[0278] 1 or
  • (vi) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with 1-3 groups selected from the following (a)-(i): [0279]
  • (a) halogen, [0280]
  • (b) cyano, [0281]
  • (c) —P(O)(R[0282] 15)2,
  • (d) —Si(R[0283] 16)3,
  • (e) Cyc[0284] 1,
  • (f) —C(O)R[0285] 17,
  • (g) —OR[0286] 18,
  • (h) —NR[0287] 19R20,
  • (i) —SR[0288] 21;
  • plural R[0289] 15s are each independently, hydroxy or C1-8 alkoxy,
  • plural R[0290] 16s are each independently C1-8 alkyl,
  • R[0291] 17 is
  • (i) hydrogen, [0292]
  • (ii) C1-8 alkyl, [0293]
  • (iii) hydroxy, [0294]
  • (iv) C1-8 alkoxy, [0295]
  • (v) Cyc[0296] 1 or
  • (vi) —NR[0297] 22R23 (wherein R22 is hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted with phenyl, R23 is hydrogen, C1-8 alkyl, Cyc1 or C1-8 alkyl substituted with Cyc1 or NR24R25 (R24 and R25 are each independently hydrogen, C1-8 alkyl, phenyl, C1-8 alkyl substituted with phenyl.).),
  • R[0298] 18 is
  • (i) hydrogen, [0299]
  • (ii) C1-8 alkyl, [0300]
  • (iii) C2-8 alkenyl, [0301]
  • (iv) Cyc[0302] 1 or
  • (v) C1-8 alkyl substituted with Cyc[0303] 1, Si(R26)3 (wherein plural R26s are each independently C1-8 alkyl.) or —OR27 (wherein R27 is hydrogen, C1-8 alkyl or C2-5 acyl.),
  • R[0304] 19 is
  • (i) hydrogen, [0305]
  • (ii) C1-8 alkyl, [0306]
  • (iii) phenyl or [0307]
  • (iv) C1-8 alkyl substituted with phenyl, [0308]
  • R[0309] 20 is
  • (i) hydrogen, [0310]
  • (ii) C1-8 alkyl or [0311]
  • (iii) —C(O)R[0312] 28 (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) Cyc[0313] 1 or
  • (v) C1-8 alkyl substituted with Cyc[0314] 1 or cyano,
  • R[0315] 21 is
  • (i) hydrogen, [0316]
  • (ii) C1-8 alkyl or [0317]
  • (iii) Cyc[0318] 1,
  • Cyc[0319] 1 is
  • (i) C3-15 mono-, bi- or tricyclic carbo ring or [0320]
  • (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, [0321]
  • 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) Cyc[0322] 2, (xiii) —OR31, (xiv) —SR2, (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,
  • R[0323] 31 and R32 are each independently, hydrogen, C1-8 alkyl or Cyc2,
  • R[0324] 33 is hydrogen or C1-8 alkyl,
  • R[0325] 34 is hydrogen, C1-8 alkyl or —C(O)-Cyc2,
  • R[0326] 36 is hydrogen or C1-8 alkyl,
  • R[0327] 36 is hydrogen, C1-8 alkyl or Cyc2,
  • R[0328] 37 is hydrogen, C1-8 alkyl, —OR38, —NR39R40, Cyc2, or C1-8 alkyl substituted with Cyc2 or —C(O)—Cyc2,
  • R[0329] 36, R39 and R40 are each independently, hydrogen, C1-8 alkyl, or C1-8 alkyl substituted with Cyc2,
  • Cyc[0330] 2 is
  • (i) C3-15 mono-, bi- or tricyclic carbo ring or [0331]
  • (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, [0332]
  • 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) —OR[0333] 41, (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,
  • R[0334] 41, 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 R[0335] 2 of (R2q is independently,
  • (i) C1-8 alkyl, [0336]
  • (ii) C2-8 alkenyl, [0337]
  • (iii) C2-8 alkynyl, [0338]
  • (iv) —OR[0339] 48,
  • (v) —NR[0340] 49R50,
  • (vi) —C(O)R[0341] 51,
  • (vii) nitro, [0342]
  • (viii) cyano, [0343]
  • (ix) halogen or [0344]
  • (x) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with —OR[0345] 48, -NR49R50, —C(O)R51, halogen or Cyc3,
  • R[0346] 48 is
  • (i) hydrogen, [0347]
  • (ii) C1-8 alkyl, [0348]
  • (iii) C2-8 alkenyl, [0349]
  • (iv) C2-8 alkynyl, [0350]
  • (v) Cyc[0351] 3 or
  • (vi) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with halogen, —OR[0352] 52, —
  • NR[0353] 53R54, —C(O)R55 or Cyc3,
  • R[0354] 49 and R51 are each independently, hydrogen, C1-8 alkyl or —COR59,
  • R[0355] 51 is hydrogen, C1-8 alkyl, hydroxy, C1-8 alkoxy or —NR6“R6,
  • R[0356] 52 is hydrogen, C1-8 alkyl, Cyc3, or C1-8 alkyl substituted with Cyc3,
  • R[0357] 53 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),
  • R[0358] 55 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),
  • R[0359] 59 is C1-8 alkyl or C1-8 alkoxy,
  • R[0360] 60 and R61 are each independently, hydrogen or C1-8 alkyl,
  • Cyc[0361] 3 is
  • (i) C3-15 mono-, bi- or tricyclic carbo ring or [0362]
  • (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, [0363]
  • 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) —NR[0364] 62R63, (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,
  • R[0365] 62 and R63 are each independently, hydrogen or C1-8 alkyl,
  • R[0366] 64 is hydrogen or C1-8 alkyl,
  • with the proviso that when [0367]
  • (1) when A[0368] 2 is (vi) —NR5C(O)—, (x) —NR7SO2—, (xiv) —NR13C(O)O— or (xv) —OC(O)O—,
  • then A[0369] 3 is not hydrogen,
  • (2) when [0370]
    Figure US20030073706A1-20030417-P00002
    is a double bond and Y is hydrogen, then n is 1 or 2,
  • (3) when [0371]
    Figure US20030073706A1-20030417-P00002
    is a single bond, Y is
    Figure US20030073706A1-20030417-C00026
  • n is 2, [0372]
  • m is 0 or 2, p is O or an integer of 1-4, ring A and ring B are benzene ring, R[0373] 1 is C1-8 alkyl, C1-8 alkoxy, halogen, carboxy, nitro or C1-8 alkyl substituted with halogen, then q is not 0,
  • (4) when [0374]
    Figure US20030073706A1-20030417-P00002
    is a single bond, Y is
    Figure US20030073706A1-20030417-C00027
  • n is 2, [0375]
  • m is 0 or 2, p is 0 or an integer of 1-4, ring A and ring B are benzene ring, R[0376] 1 is C1-8 alkyl, C1-8 alkoxy, halogen, carboxy, nitro or C1-8 alkyl substituted with halogen, and q is an integer of 1-5, then R2 is not C1-8 alkyl, C1-8 alkoxy, halogen, carboxy, nitro or C1-8 alkyl substituted with halogen,
  • (5) when [0377]
    Figure US20030073706A1-20030417-P00002
    is a double bond, Y is hydrogen, n is 2, p is 1 and ring A is benzene ring, then R1 is not halogen, C1-8 alkyl, phenylsulfonylamino, 2-methylphenylsulfonylamino, 3-methylphenylsulfonylamino, 4-methylphenylsulfonylamino, hydroxy, C1-8 alkoxy, nitro, or C1-8 alkoxy substituted with carboxy, hydroxy, C1-8 alkoxycarbonyl or hydroxyaminocarbonyl,
  • (6) when [0378]
    Figure US20030073706A1-20030417-P00002
    is a double bond, Y is hydrogen, n is 2, p is 2 and ring A is benzene ring and one R1 is phenylsulfonylamino, 2-methylphenyisulfonylamino, 3-methylphenylsulfonylamino or 4-methylphenylsulfonylamino, then the other R1 is not C1-8 alkyl,
  • (7) when [0379]
    Figure US20030073706A1-20030417-P00002
    is a double bond, Y is hydrogen, n is 2, p is 2-3, ring A is benzene ring, one R1 is hydroxy, C1-8 alkoxy, or C1-8 alkoxy substituted with carboxy, hydroxy, C1-8 alkoxycarbonyl or hydroxyaminocarbonyl, then the other R1 is neither halogen nor C1-8 alkyl,
  • (8) when [0380]
    Figure US20030073706A1-20030417-P00002
    is a double bond, Y is hydrogen, n is 2, p is 3-4 and ring A is benzene ring, then two or three R1 are not t-butyl at the same time, and
  • (9) the following compounds (1)-(32) are excluded: [0381]
  • (1) 3-(thiophen-2-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene, [0382]
  • (2) 6-nitro-3-(thiophen-2-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene, [0383]
  • (3) 3-(thiophen-2-yl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[blthiophene, [0384]
  • (4) 4,5-dimethyl-1,1-dioxidebenzo[b]thiophene, [0385]
  • (5) 4,6-dimethyl-1,1-dioxidebenzo[b]thiophene, [0386]
  • (6) 4,7-dimethyl-1,1-dioxidebenzo[b]thiophene, [0387]
  • (7) 5,6-dimethyl-1,1-dioxidebenzo[b]thiophene, [0388]
  • (8) 5,7-dimethyl-1,1-dioxidebenzo[b[thiophene, [0389]
  • (9) 6,7-dimethyl-1,1-dioxidebenzo[b]thiophene, [0390]
  • (10) 4-carboxymethyl-1,1-dioxidebenzo[b]thiophene, [0391]
  • (11) 6-(2,2-bis(ethoxycarbonyl)ethenyl)amino-1,1-ioxidebenzo[b]thiophene, [0392]
  • (12) 4-methylaminocarbonyloxy-1,1-dioxidebenzo[b]thiophene, [0393]
  • (13) 5-(2-(N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-ylmethyl)-N-methylamino)ethyl)-1,1-dioxidebenzo[b]thiophene, [0394]
  • (14) 5-(2-hydroxyethyl)-1,1-dioxidebenzo[b]thiophene, [0395]
  • (15) 5-bromo-7-methyl-1,1-dioxidebenzo[b]thiophene, [0396]
  • (16) 7-bromo-5-methyl-1,1-dioxidebenzo[b]thiophene, [0397]
  • (17) 5-bromo-6-methyl-1,1-dioxidebenzo[b]thiophene, [0398]
  • (18) 5-bromo-4-methyl-1,1-dioxidebenzo[b]thiophene, [0399]
  • (19) 6-bromo-5-methyl-1,1-dioxidebenzo[b]thiophene, [0400]
  • (20) 4-bromo-5-methyl-1, -dioxidebenzo[b]thiophene, [0401]
  • (21) 6-amino-1,1-dioxidebenzo[b]thiophene, [0402]
  • (22) 6-acetylamino-1,1-dioxidebenzo[b]thiophene, [0403]
  • (23) 6-(4-diethylaminophenyl)-1,1-dioxidebenzo[b]thiophene, [0404]
  • (24) 1,1-dioxidethieno[2,3-b]pyridine, [0405]
  • (25) 1,1 -dioxidethieno[3,2-b]pyridine, [0406]
  • (26) 1,1-dioxidethieno[2,3-c]pyridine, [0407]
  • (27) 5-amino-1,1-dioxidebenzo[b]thiophene, [0408]
  • (28) 5-(3-methyl-5-oxo-4,5-dihydropyrazol-1-yl)-1,1-dioxidebenzo[b]thiophene, [0409]
  • (29) 4-(2-(1,1-dioxidebenzo[b]thiophen-3-yl)ethyl)-1,1-dioxidebenzo[b]thiophene, [0410]
  • (30) 7-methyl-1,1-dioxidethieno[2,3-c]pyridine, [0411]
  • (31) 1,1-dioxidebenzo[b]thiophene or [0412]
  • (32) 4-(4-methoxyphenyl)-1,1-dioxidethieno[3,2-c]pyridine.], [0413]
  • an N-oxide derivative thereof or a non-toxic salt thereof, [0414]
  • (3) a method for preparation of a fused thiophene derivative of the formula (IA), an N-oxide derivative thereof or a non-toxic salt thereof and [0415]
  • (4) a method for preparation of a compound of the formula (XI) [0416]
    Figure US20030073706A1-20030417-C00028
  • which is characterized by cyanization of a compound of the formula (XII) [0417]
    Figure US20030073706A1-20030417-C00029
  • to obtain a compound of the formula (XIII) [0418]
    Figure US20030073706A1-20030417-C00030
  • then by subjecting to dehydration of the said compound of the formula (XII) to obtain a compound of the formula (XIV) [0419]
    Figure US20030073706A1-20030417-C00031
  • and then by subjecting to hydrolysis of the said compound of the formula (XIV). [0420]
    • DETAILED EXPLANATION OF THE INVENTION
  • Unless otherwise specified, all isomers are included in the present invention. For example, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylene, alkenylene and alkynylene group include straight or branched ones. In addition, isomers on double bond, ring, fused ring (E—, Z—, cis-, trans-isomer), isomers generated from asymmetric carbon atom(s) (R—, S—, α—, β-isomer, enantiomer, diastereomer), optically active isomers (D—, L—, d-, I-isomer), polar compounds generated by chromatographic separation (more polar compound, less polar compound), equilibrium compounds, mixtures thereof at voluntary ratios and racemic mixtures are also included in the present invention. [0421]
  • In the present invention, an N-oxide derivative of a compound of the formula (I) and (IA) means a compound wherein nitrogen atom(s) in a compound containing nitrogen atom(s) of the formula (I) and (IA) is (are) oxidized. [0422]
  • In the present invention, C1-8 alkyl means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and the isomers thereof. [0423]
  • C2-8 alkenyl means vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, butadienyl, pentadienyl, hexadienyl, heptadienyl, octadienyl, hexatrienyl, heptatrienyl, octatrienyl and the isomers thereof. [0424]
  • C2-8 alkynyl means ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl and the isomers thereof. [0425]
  • C1-8 alkylene means methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene and the isomers thereof. [0426]
  • C2-8 alkenylene means ethenylene, propenylene, butenylene, pentenylene, hexenylene, heptenylene, octenylene and the isomers thereof. [0427]
  • C2-8 alkynylene means ethynylene, propynylene, butynylene, pentynylene, hexynylene, heptynylene, octynylene and the isomers thereof. [0428]
  • Halogen means chloride, bromide, fluoride and iodide. [0429]
  • C1-8 alkoxy means methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy and the isomers thereof. [0430]
  • Trihalomethyl means methyl substituted with three atoms selected from group consisting of chloride, bromide, fluoride and iodide atom. [0431]
  • Trihalomethoxyl means methoxyl substituted with three atoms selected from group consisting of chloride, bromide, fluoride and iodide atom. [0432]
  • C2-5 acyl means acetyl, propionyl, butyryl, valeryl and isomers thereof. [0433]
  • 6Membered monocyclic hetero aryl containing 1-2 nitrogen atom(s) includes, for example, pyridine, pyridine-N-oxide, pyrazine, pyrazine-N-monoxide, pyrazine-N-dioxide, pyrimizine, pyrimizine-N-monoxide, pyrimizine-N-dioxide, pyridazine, pyridazine-N-monoxide, pyridazine-N-dioxide ring etc. [0434]
  • C3-15 Mono-, bi- or tricyclic carbo ring includes, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclopenten, cyclohexen, cyclopentadien, cyclohexadien, benzene, penthalene, indene, naphthalene, azulene, florene, phenanthrene, anthracene, acenaphthylene, biphenylene, perhydropentalene, perhydroindene, dihydronaphthalene, tetrahydronaphthalene, perhydronaphthalene, perhydroazulene, perhydrofluorene, perhydrophenanthrene, perhydroanthracene, perhydroacenaphthylene, perhydrobiphenylene ring etc. [0435]
  • 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 includes 4-18 membered mono-, bi- or tricyclic hetero aryl containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom or corresponding hetero ring in which ring is saturated partially or fully. [0436]
  • The said 4-18 membered mono-, bi- or tricyclic hetero aryl containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom includes, for example, pyrrole, pyrrole-N-oxide, imidazole, triazole, tetrazole, pyrazole, pyridine, pyridine-N-oxide, pyrazine, pyrazine-N-monoxide, pyrazine-N-dioxide, pyrimizine, pyrimizine-N-monoxide, pyrimizine-N-dioxide, pyridazine, pyridazine-N-monoxide, pyridazine-N-dioxide, azepine, diazepine, furan, pyran, oxepine, oxazepine, thiophene, thiain (thiopyran), thiepine, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indazole, quinoline, quinoline-N-oxide, isoquinoline, isoquinoline-N-oxide, phthalazine, naphthyridine, naphthyridine-N-monoxide, naphthyridine-N-dioxide, quinoxaline, quinoxaline-N-monoxide, quinoxaline-N-dioxide, quinazoline, quinazoline-N-monoxide, quinazoline-N-dioxide, cinnoline, benzoxazole, benzothiazole, benzoimidazole, carbazole, acridine ring etc. [0437]
  • The said 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 in which ring is saturated partially or fully includes, for example, pyrroline, pyrrolidine, pyrrolidine-N-oxide, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, dihydropyridine, dihydropyridine-N-oxide, dihydropyrazine, dihydropyrazine-N-monoxide, dihydropyrazine-N-dioxide, dihydropyrimizine, dihydropyrimizine-N-monoxide, dihydropyrimizine-N-dioxide, dihydropyridazine, dihydropyridazine-N-monoxide, dihydropyridazine-N-dioxide, piperidine, piperidine-N-oxide, piperazine, piperazine-N-monoxide, piperazine-N-dioxide, tetrahydropyrimizine, tetrahydropyrimizine-N-monoxide, tetrahydropyrimizine-N-dioxide, tetrahydropyridazine, tetrahydropyridazine-N-monoxide, tetrahydropyridazine-N-dioxide, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiain (dihydrothiopyran), tetrahydrothiain (tetrahydrothiopyran), dihydroxazole, tetrahydroxazole, dihydroisoxazole, tetrahydroisoxazole, dihydrothiazole, tetrahydrothiazole, dihydroisothiazole, tetrahydroisothiazole, morpholine, morpholine-N-oxide, thiomorpholine, thiomorpholine-N-oxide, indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, dihydroquinoline-N-oxide, tetrahydroquinoline, tetrahydroquinoline-N-oxide, perhydroquinoline, perhydroquinoline-N-oxide, dihydroisoquinoline, dihydroisoquinoline-N-oxide, tetrahydroisoquinoline, tetrahydroisoquinoline-N-oxide, perhydroisoquinoline, perhydroisoquinoline-N-oxide, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine, dihydronaphthyridine-N-monoxide, dihydronaphthyridine-N-dioxide, tetrahydronaphthyridine, tetrahydronaphthyridine-N-monoxi de, tetrahydronaphthyridine-N-dioxide, perhydronaphthyridine, perhydronaphthyridine-N-monoxide, perhydronaphthyridine-N-dioxide, dihydroquinoxaline, dihydroquinoxaline-N-monoxide, dihydroquinoxaline-N-dioxide, tetrahydroquinoxaline, tetrahydroquinoxaline-N-monoxide, tetrahydroquinoxaline-N-dioxide, perhydroquinoxaline, perhydroquinoxaline-N-monoxide, perhydroquinoxaline-N-dioxide, dihydroquinazoline, dihydroquinazoline-N-monoxide, dihydroquinazoline-N-dioxide, tetrahydroquinazoline, tetrahydroquinazoline-N-monoxide, tetrahydroquinazoline-N-dioxide, perhydroquinazoline, perhydroquinazoline-N-monoxide, perhydroquinazoline-N-dioxide, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzoimidazole, perhydrobenzoimidazole, benzoxazepine, benzoxadiazepine, benzothiazepine, benzothiadiazepine, benzoazepine, benzodiazepine, indroxoazepine, indrotetrahydroxazepine, indroxadiazepine, indrotetrahydroxadiazepine, indrothiazepine, indrotetrahydrothiazepine, indrothiadiazepine, indrotetrahydrothiadiazepine, indroazepine, indrotetrahydroazepine, indrodiazepine, indrotetrahydrodiazepine, benzofurazane, benzothiadiazole, benzotriazole, camphar, imidazothiazole, dihydrocarbazole, tetrahydrocarbazole, perhydrocarbazole, dihydroacridine, tetrahydroacridine, perhydroacridine, 1,3-dioxaindan, 1,4-dioxoindan ring etc. [0438]
  • In the present invention, m is, preferably, 0 or 2 and most preferably, 2. [0439]
  • n is, preferably, 0 or 2 and most preferably, 2. [0440]
  • p is, preferably, 1 or 2 and most preferably, 2. [0441]
  • q is, preferably, 0 or 1. [0442]
  • Z is, preferably, single bond or C1-8 alkylene, and most preferably, single bond. [0443]
    Figure US20030073706A1-20030417-C00032
  • is, preferably, pyridine or benzene ring, and most preferably, benzene ring. [0444]
    Figure US20030073706A1-20030417-C00033
  • is, preferably, C5-10 mono- or bicyclic carbo ring or 5-10 membered mono- or bicyclic hetero ring containing 1-3 nitrogen atom(s), one oxygen atom and/or one sulfur atom, more preferably, benzene, cyclohexane, thiophene, furan, pyridine, pyrimizine, imidazole ring, and most preferably, benzene or thiophene ring. [0445]
  • R[0446] 1 is, preferably, C1-8 alkyl, nitro, cyano, halogen, Cyc1 or C1-8 alkyl substituted with halogen or Cyc1, or A1—A2—A3, and most preferably, C1-8 alkyl substituted with Cyc1 or A1—A2—A3.
  • A[0447] 1 is, preferably, single bond, C1-8 alkylene, C2-8 alkenylene, and most preferably, single bond or C1-8 alkylene.
  • A[0448] 2 is, preferably, —O—, —NR3—, —C(O)—, —C(O)NR4—, —NR5C(O)—, —C(O)O—, —NR13C(O)O—, and most preferably, O—, —NR3—, —C(O)—, —C(O)NR4—, —NR5C(O)—.
  • A[0449] 3 is, preferably, C1-8 alkyl, Cyc1, or C1-8 alkyl or C2-8 alkenyl substituted with Cyc1, —C(O)R 7, —NR19R20 or —OR18, and most preferably, C1-8 alkyl substituted with Cyc1 or NR19R20.
  • Cyc[0450] 1 is, preferably, C5-10 mono- or bicyclic carbo ring or 5-10 membered mono- or bicyclic hetero ring containing 1-3 nitrogen atom(s), one oxygen atom and/or one sulfur atom, and more preferably, C5-10 monocyclic carbo ring or 5-10 membered monocyclic hetero ring containing 1-2 nitrogen atom(s) and/or one oxygen atom, and most preferably, benzene, piperidine, piperazine, pyrrolidine, pyridine or morpholine ring.
  • R[0451] 19, R20 is, preferably, hydrogen or C1-8 alkyl, and most preferably, methyl, ethyl, propyl or isopropyl.
  • [Salts][0452]
  • In the present invention, non-toxic salts include all such salts, for example, ordinal salts, acid-addition salts and hydrate salts. [0453]
  • The compounds of the present invention of the formula (I) may be converted into the corresponding salts by known method. Non toxic and water-soluble salts are preferable. Suitable salts include the salts of alkalimetal (sodium, potassium etc.), alkaline-earth metal (calcium, magnesium etc.), ammonium salts, salts of organic amine which is pharmaceutically permitted (tetramethyl ammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenetylamine, piperidine, monoethanolamine, diethanolamine, tris(hydroxymethyl)amine, lysine, arginine, N-methyl-D-gulcamine etc.). [0454]
  • The compounds of the present invention of the formula (I) may be converted into the corresponding acid-addition salts by known method. Non toxic and water-soluble acid-addition are preferable. Suitable acid-addition salts include the salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfonic acid, phosphonic acid, nitric acid and the salts with organic acids such as acetic acid, trifluoroacetic acid, lactic acid, tartaric acid, oxalic acid, fumaric acid, maleic acid, citric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, isethionic acid, glucuronic acid and gluconic acid. [0455]
  • The compounds of the present invention of the formula (I) or salts thereof may be converted into a corresponding hydrate by known methods. [0456]
  • In the compounds of the formula (I), preferred compounds are as follows: the compound of the formula (I-A) [0457]
    Figure US20030073706A1-20030417-C00034
  • (wherein all the symbols are the same meanings as hereinbefore described.), the compound of the formula (I-B) [0458]
    Figure US20030073706A1-20030417-C00035
  • (wherein all the symbols are the same meanings as hereinbefore described.), the compound of the formula (I-C) [0459]
    Figure US20030073706A1-20030417-C00036
  • (wherein all the symbols are the same meanings as hereinbefore described.), the compound of the formula (I-D) [0460]
    Figure US20030073706A1-20030417-C00037
  • (wherein all the symbols are the same meanings as hereinbefore described.), the compound of the formula (I-E) [0461]
    Figure US20030073706A1-20030417-C00038
  • (wherein all the symbols are the same meanings as hereinbefore described.), the compound of the formula (I-F) [0462]
    Figure US20030073706A1-20030417-C00039
  • (wherein all the symbols are the same meanings as hereinbefore described.), the compound of the formula (I-G) [0463]
    Figure US20030073706A1-20030417-C00040
  • (wherein all the symbols are the same meanings as hereinbefore described.), the compound of the formula (I-H) [0464]
    Figure US20030073706A1-20030417-C00041
  • (wherein all the symbols are the same meanings as hereinbefore described.), the compound of the formula (I-J) [0465]
    Figure US20030073706A1-20030417-C00042
  • (wherein all the symbols are the same meanings as hereinbefore described.), the compound of the formula (I-K) [0466]
    Figure US20030073706A1-20030417-C00043
  • (wherein all the symbols are the same meanings as hereinbefore described.), the compound of the formula (I-L) [0467]
    Figure US20030073706A1-20030417-C00044
  • (wherein all the symbols are the same meanings as hereinbefore described.), the compound of the formula (I-M) [0468]
    Figure US20030073706A1-20030417-C00045
  • (wherein all the symbols are the same meanings as hereinbefore described.), the compound of the formula (I-N) [0469]
    Figure US20030073706A1-20030417-C00046
  • (wherein all the symbols are the same meanings as hereinbefore described.), the compound of the formula (I-O) [0470]
    Figure US20030073706A1-20030417-C00047
  • (wherein all the symbols are the same meanings as hereinbefore described.), or the compound of the formula (I-P) [0471]
    Figure US20030073706A1-20030417-C00048
  • (wherein all the symbols are the same meanings as hereinbefore described.). [0472]
  • In the compounds of the formula (I-A), the compound of the formula (I-A′) [0473]
    Figure US20030073706A1-20030417-C00049
  • (wherein, R[0474] 1′ is C1-8 alkyl substituted with Cyc1, or
    Figure US20030073706A1-20030417-C00050
  • (wherein, A[0475] 1′ is single bond or C1-8 alkylene, A2′ is —O—, —NR3—, —C(O)—, —C(O)NR4— or NR5C(O)— and the other symbols are the same meanings as hereinbefore described.) and the other symbols are the same meanings as hereinbefore described.) is most preferable.
  • In the compound of the formula (I-N), the compound of the formula (I-N′) [0476]
    Figure US20030073706A1-20030417-C00051
  • (wherein all the symbols are the same meanings as hereinbefore described.) is most preferable. [0477]
  • The following compounds (1)-(4) are known and marketed ones, but their activities as inhibitor of producing IL-6 and/or IL-12 have not been known at all. The compounds (1)-(4) and non-toxic salts thereof are also preferable ones used in the present invention. [0478]
  • For example, [0479]
  • Compound (1): 3-(thiophene-2-yl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene (Maybridge, Catalog No. KM 08156): [0480]
    Figure US20030073706A1-20030417-C00052
  • Compound (2): 6-nitro-3-(thiophene-2-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene (Maybridge, Catalog No. KM 08165): [0481]
    Figure US20030073706A1-20030417-C00053
  • Compound (3): 3-(thiophene-2-yl)thio-2,3-dihydro-1,1 -dioxidebenzo[b]thiophene (Maybridge, Catalog No. KM 08138): [0482]
    Figure US20030073706A1-20030417-C00054
  • Compound (4): 3-phenylsulfonyl-2,3-dihydro-11-dioxidebenzo[b]thiophene (Maybridge, Catalog No. KM 08140): [0483]
    Figure US20030073706A1-20030417-C00055
  • More preferable compounds are the following known compounds and the compounds shown in the Tables 1 to 78 and described in Examples and non-toxic salts thereof. [0484]
  • In the following tables, 3-Py is pyridin-3-yl, Me is methyl, Et is ethyl, n-Pr is normalpropyl, i-Pr is isopropyl, t-Bu is t-butyl and the other symbols are the same meanings as hereinbefore described. [0485]
    TABLE 1
    (I-A)
    Figure US20030073706A1-20030417-C00056
    No. p position R1 q position R2
    1 1 4 —O—(CH2)2-(3-Py) 0 — —
    2 1 5 —O—(CH2)2-(3-Py) 0 — —
    3 1 6 —O—(CH2)2-(3-Py) 0 — —
    4 1 7 —O—(CH2)2-(3-Py) 0 — —
    5 1 4 —O—(CH2)2—N(CH3)2 0 — —
    6 1 5 —O—(CH2)2—N(CH3)2 0 — —
    7 1 6 —O—(CH2)2—N(CH3)2 0 — —
    8 1 7 —O—(CH2)2—N(CH3)2 0 — —
    9 0 — — 1 2′ —O—(CH2)2-(3-Py)
    10 0 — — 1 3′ —O—(CH2)2-(3-Py)
    11 0 — — 1 4′ —O—(CH2)2-(3-Py)
    12 0 — — 2 3′, 5′ —O—(CH2)2-(3-Py)
    13 0 — — 1 2′ —O—(CH2)2—N(CH3)2
    14 0 — — 1 3′ —O—(CH2)2—N(CH3)2
    15 0 — — 1 4′ —O—(CH2)2—N(CH3)2
    16 0 — — 2 3′, 5′ —O—(CH2)2—N(CH3)2
    17 1 4 —O—(CH2)2-(3-Py) 1 2′ —O—(CH2)2-(3-Py)
    18 1 5 —O—(CH2)2-(3-Py) 1 3′ —O—(CH2)2-(3-Py)
    19 1 6 —O—(CH2)2-(3-Py) 1 4′ —O—(CH2)2-(3-Py)
    20 1 7 —O—(CH2)2-(3-Py) 2 3′, 5′ —O—(CH2)2-(3-Py)
  • [0486]
    TABLE 2
    (I-B)
    Figure US20030073706A1-20030417-C00057
    No. p position R1 q position R2
    1 1 5 —O—(CH2)2-(3-Py) 0 — —
    2 1 6 —O—(CH2)2-(3-Py) 0 — —
    3 1 7 —O—(CH2)2-(3-Py) 0 — —
    4 2 6, 7 —O—(CH2)2-(3-Py) 0 — —
    5 1 5 —O—(CH2)2—N(CH3)2 0 — —
    6 1 6 —O—(CH2)2—N(CH3)2 0 — —
    7 1 7 —O—(CH2)2—N(CH3)2 0 — —
    8 2 6, 7 —O—(CH2)2—N(CH3)2 0 — —
    9 0 — — 1 2′ —O—(CH2)2-(3-Py)
    10 0 — — 1 3′ —O—(CH2)2-(3-Py)
    11 0 — — 1 4′ —O—(CH2)2-(3-Py)
    12 0 — — 2 3′, 5′ —O—(CH2)2-(3-Py)
    13 0 — — 1 2′ —O—(CH2)2—N(CH3)2
    14 0 — — 1 3′ —O—(CH2)2—N(CH3)2
    15 0 — — 1 4′ —O—(CH2)2—N(CH3)2
    16 0 — — 2 3′, 5′ —O—(CH2)2—N(CH3)2
    17 1 5 —O—(CH2)2-(3-Py) 1 2′ —O—(CH2)2-(3-Py)
    18 1 6 —O—(CH2)2-(3-Py) 1 3′ —O—(CH2)2-(3-Py)
    19 1 7 —O—(CH2)2-(3-Py) 1 4′ —O—(CH2)2-(3-Py)
    20 2 6, 7 —O—(CH2)2-(3-Py) 1 3′ —O—(CH2)2-(3-Py)
  • [0487]
    TABLE 3
    (I-C)
    Figure US20030073706A1-20030417-C00058
    No. p position R1 q position R2
    1 1 4 —O—(CH2)2-(3-Py) 0 — —
    2 1 5 —O—(CH2)2-(3-Py) 0 — —
    3 1 6 —O—(CH2)2-(3-Py) 0 — —
    4 2 4, 5 —O—(CH2)2-(3-Py) 0 — —
    5 1 4 —O—(CH2)2—N(CH3)2 0 — —
    6 1 5 —O—(CH2)2—N(CH3)2 0 — —
    7 1 6 —O—(CH2)2—N(CH3)2 0 — —
    8 2 4, 5 —O—(CH2)2—N(CH3)2 0 — —
    9 0 — — 1 2′ —O—(CH2)2-(3-Py)
    10 0 — — 1 3′ —O—(CH2)2-(3-Py)
    11 0 — — 1 4′ —O—(CH2)2-(3-Py)
    12 0 — — 2 3′, 5′ —O—(CH2)2-(3-Py)
    13 0 — — 1 2′ —O—(CH2)2—N(CH3)2
    14 0 — — 1 3′ —O—(CH2)2—N(CH3)2
    15 0 — — 1 4′ —O—(CH2)2—N(CH3)2
    16 0 — — 2 3′, 5′ —O—(CH2)2—N(CH3)2
    17 1 4 —O—(CH2)2-(3-Py) 1 2′ —O—(CH2)2-(3-Py)
    18 1 5 —O—(CH2)2-(3-Py) 1 3′ —O—(CH2)2-(3-Py)
    19 1 6 —O—(CH2)2-(3-Py) 1 4′ —O—(CH2)2-(3-Py)
    20 2 4, 5 —O—(CH2)2-(3-Py) 1 3′ —O—(CH2)2-(3-Py)
  • [0488]
    TABLE 4
    (I-D)
    Figure US20030073706A1-20030417-C00059
    No. p position R1 q position R2
    1 1 4 —O—(CH2)2-(3-Py) 0 — —
    2 1 5 —O—(CH2)2-(3-Py) 0 — —
    3 1 6 —O—(CH2)2-(3-Py) 0 — —
    4 1 7 —O—(CH2)2-(3-Py) 0 — —
    5 1 4 —O—(CH2)2—N(CH3)2 0 — —
    6 1 5 —O—(CH2)2—N(CH3)2 0 — —
    7 1 6 —O—(CH2)2—N(CH3)2 0 — —
    8 1 7 —O—(CH2)2—N(CH3)2 0 — —
    9 0 — — 1 3′ —O—(CH2)2-(3-Py)
    10 0 — — 1 4′ —O—(CH2)2-(3-Py)
    11 0 — — 1 5′ —O—(CH2)2-(3-Py)
    12 0 — — 1 6′ —O—(CH2)2-(3-Py)
    13 0 — — 1 3′ —O—(CH2)2—N(CH3)2
    14 0 — — 1 4′ —O—(CH2)2—N(CH3)2
    15 0 — — 1 5′ —O—(CH2)2—N(CH3)2
    16 0 — — 1 6′ —O—(CH2)2—N(CH3)2
    17 1 4 —O—(CH2)2-(3-Py) 1 3′ —O—(CH2)2-(3-Py)
    18 1 5 —O—(CH2)2-(3-Py) 1 4′ —O—(CH2)2-(3-Py)
    19 1 6 —O—(CH2)2-(3-Py) 1 5′ —O—(CH2)2-(3-Py)
    20 1 7 —O—(CH2)2-(3-Py) 1 6′ —O—(CH2)2-(3-Py)
  • [0489]
    TABLE 5
    (I-E)
    Figure US20030073706A1-20030417-C00060
    No. p position R1 q position R2
    1 1 4 —O—(CH2)2-(3-Py) 0 — —
    2 1 5 —O—(CH2)2-(3-Py) 0 — —
    3 1 6 —O—(CH2)2-(3-Py) 0 — —
    4 1 7 —O—(CH2)2-(3-Py) 0 — —
    5 1 4 —O—(CH2)2—N(CH3)2 0 — —
    6 1 5 —O—(CH2)2—N(CH3)2 0 — —
    7 1 6 —O—(CH2)2—N(CH3)2 0 — —
    8 1 7 —O—(CH2)2—N(CH3)2 0 — —
    9 0 — — 1 2′ —O—(CH2)2-(3-Py)
    10 0 — — 1 4′ —O—(CH2)2-(3-Py)
    11 0 — — 1 5′ —O—(CH2)2-(3-Py)
    12 0 — — 1 6′ —O—(CH2)2-(3-Py)
    13 0 — — 1 2′ —O—(CH2)2—N(CH3)2
    14 0 — — 1 4′ —O—(CH2)2—N(CH3)2
    15 0 — — 1 5′ —O—(CH2)2—N(CH3)2
    16 0 — — 1 6′ —O—(CH2)2—N(CH3)2
    17 1 4 —O—(CH2)2-(3-Py) 1 2′ —O—(CH2)2-(3-Py)
    18 1 5 —O—(CH2)2-(3-Py) 1 4′ —O—(CH2)2-(3-Py)
    19 1 6 —O—(CH2)2-(3-Py) 1 5′ —O—(CH2)2-(3-Py)
    20 1 7 —O—(CH2)2-(3-Py) 1 6′ —O—(CH2)2-(3-Py)
  • [0490]
    TABLE 6
    (I-F)
    Figure US20030073706A1-20030417-C00061
    No. p position R1 q position R2
    1 1 4 —O—(CH2)2-(3-Py) 0 — —
    2 1 5 —O—(CH2)2-(3-Py) 0 — —
    3 1 6 —O—(CH2)2-(3-Py) 0 — —
    4 1 7 —O—(CH2)2-(3-Py) 0 — —
    5 1 4 —O—(CH2)2—N(CH3)2 0 — —
    6 1 5 —O—(CH2)2—N(CH3)2 0 — —
    7 1 6 —O—(CH2)2—N(CH3)2 0 — —
    8 1 7 —O—(CH2)2—N(CH3)2 0 — —
    9 0 — — 1 2′ —O—(CH2)2-(3-Py)
    10 0 — — 1 3′ —O—(CH2)2-(3-Py)
    11 0 — — 2 2′, 5′ —O—(CH2)2-(3-Py)
    12 0 — — 2 2′, 6′ —O—(CH2)2-(3-Py)
    13 0 — — 1 2′ —O—(CH2)2—N(CH3)2
    14 0 — — 1 3′ —O—(CH2)2—N(CH3)2
    15 0 — — 2 2′, 5′ —O—(CH2)2—N(CH3)2
    16 0 — — 2 2′, 6′ —O—(CH2)2—N(CH3)2
    17 1 4 —O—(CH2)2-(3-Py) 1 2′ —O—(CH2)2-(3-Py)
    18 1 5 —O—(CH2)2-(3-Py) 1 3′ —O—(CH2)2-(3-Py)
    19 1 6 —O—(CH2)2-(3-Py) 1 2′ —O—(CH2)2-(3-Py)
    20 1 7 —O—(CH2)2-(3-Py) 1 3′ —O—(CH2)2-(3-Py)
  • [0491]
    TABLE 7
    (I-G)
    Figure US20030073706A1-20030417-C00062
    No. p position R1 q position R2
    1 1 5 —O—(CH2)2-(3-Py) 0 — —
    2 1 6 —O—(CH2)2-(3-Py) 0 — —
    3 1 7 —O—(CH2)2-(3-Py) 0 — —
    4 2 6, 7 —O—(CH2)2-(3-Py) 0 — —
    5 1 5 —O—(CH2)2—N(CH3)2 0 — —
    6 1 6 —O—(CH2)2—N(CH3)2 0 — —
    7 1 7 —O—(CH2)2—N(CH3)2 0 — —
    8 2 6, 7 —O—(CH2)2—N(CH3)2 0 — —
    9 0 — — 1 3′ —O—(CH2)2-(3-Py)
    10 0 — — 1 4′ —O—(CH2)2-(3-Py)
    11 0 — — 1 5′ —O—(CH2)2-(3-Py)
    12 0 — — 1 6′ —O—(CH2)2-(3-Py)
    13 0 — — 1 3′ —O—(CH2)2—N(CH3)2
    14 0 — — 1 4′ —O—(CH2)2—N(CH3)2
    15 0 — — 1 5′ —O—(CH2)2—N(CH3)2
    16 0 — — 1 6′ —O—(CH2)2—N(CH3)2
    17 1 5 —O—(CH2)2-(3-Py) 1 3′ —O—(CH2)2-(3-Py)
    18 1 6 —O—(CH2)2-(3-Py) 1 4′ —O—(CH2)2-(3-Py)
    19 1 7 —O—(CH2)2-(3-Py) 1 5′ —O—(CH2)2-(3-Py)
    20 2 6, 7 —O—(CH2)2-(3-Py) 1 6′ —O—(CH2)2-(3-Py)
  • [0492]
    TABLE 8
    (I-H)
    Figure US20030073706A1-20030417-C00063
    No. p position R1 q position R2
    1 1 4 —O—(CH2)2-(3-Py) 0 — —
    2 1 5 —O—(CH2)2-(3-Py) 0 — —
    3 1 6 —O—(CH2)2-(3-Py) 0 — —
    4 2 4, 5 —O—(CH2)2-(3-Py) 0 — —
    5 1 4 —O—(CH2)2—N(CH3)2 0 — —
    6 1 5 —O—(CH2)2—N(CH3)2 0 — —
    7 1 6 —O—(CH2)2—N(CH3)2 0 — —
    8 2 4, 5 —O—(CH2)2—N(CH3)2 0 — —
    9 0 — — 1 3′ —O—(CH2)2-(3-Py)
    10 0 — — 1 4′ —O—(CH2)2-(3-Py)
    11 0 — — 1 5′ —O—(CH2)2-(3-Py)
    12 0 — — 1 6′ —O—(CH2)2-(3-Py)
    13 0 — — 1 3′ —O—(CH2)2—N(CH3)2
    14 0 — — 1 4′ —O—(CH2)2—N(CH3)2
    15 0 — — 1 5′ —O—(CH2)2—N(CH3)2
    16 0 — — 1 6′ —O—(CH2)2—N(CH3)2
    17 1 4 —O—(CH2)2-(3-Py) 1 3′ —O—(CH2)2-(3-Py)
    18 1 5 —O—(CH2)2-(3-Py) 1 4′ —O—(CH2)2-(3-Py)
    19 1 6 —O—(CH2)2-(3-Py) 1 5′ —O—(CH2)2-(3-Py)
    20 2 4, 5 —O—(CH2)2-(3-Py) 1 6′ —O—(CH2)2-(3-Py)
  • [0493]
    TABLE 9
    (I-J)
    Figure US20030073706A1-20030417-C00064
    No. p position R1 q position R2
    1 1 5 —O—(CH2)2-(3-Py) 0 — —
    2 1 6 —O—(CH2)2-(3-Py) 0 — —
    3 1 7 —O—(CH2)2-(3-Py) 0 — —
    4 2 6, 7 —O—(CH2)2-(3-Py) 0 — —
    5 1 5 —O—(CH2)2—N(CH3)2 0 — —
    6 1 6 —O—(CH2)2—N(CH3)2 0 — —
    7 1 7 —O—(CH2)2—N(CH3)2 0 — —
    8 2 6, 7 —O—(CH2)2—N(CH3)2 0 — —
    9 0 — — 1 2′ —O—(CH2)2-(3-Py)
    10 0 — — 1 4′ —O—(CH2)2-(3-Py)
    11 0 — — 1 5′ —O—(CH2)2-(3-Py)
    12 0 — — 1 6′ —O—(CH2)2-(3-Py)
    13 0 — — 1 2′ —O—(CH2)2—N(CH3)2
    14 0 — — 1 4′ —O—(CH2)2—N(CH3)2
    15 0 — — 1 5′ —O—(CH2)2—N(CH3)2
    16 0 — — 1 6′ —O—(CH2)2—N(CH3)2
    17 1 5 —O—(CH2)2-(3-Py) 1 2′ —O—(CH2)2-(3-Py)
    18 1 6 —O—(CH2)2-(3-Py) 1 4′ —O—(CH2)2-(3-Py)
    19 1 7 —O—(CH2)2-(3-Py) 1 5′ —O—(CH2)2-(3-Py)
    20 2 6, 7 —O—(CH2)2-(3-Py) 1 6′ —O—(CH2)2-(3-Py)
  • [0494]
    TABLE 10
    (I-K)
    Figure US20030073706A1-20030417-C00065
    No. p position R1 q position R2
    1 1 4 —O—(CH2)2-(3-Py) 0 — —
    2 1 5 —O—(CH2)2-(3-Py) 0 — —
    3 1 6 —O—(CH2)2-(3-Py) 0 — —
    4 2 4, 5 —O—(CH2)2-(3-Py) 0 — —
    5 1 4 —O—(CH2)2—N(CH3)2 0 — —
    6 1 5 —O—(CH2)2—N(CH3)2 0 — —
    7 1 6 —O—(CH2)2—N(CH3)2 0 — —
    8 2 4, 5 —O—(CH2)2—N(CH3)2 0 — —
    9 0 — — 1 2′ —O—(CH2)2-(3-Py)
    10 0 — — 1 4′ —O—(CH2)2-(3-Py)
    11 0 — — 1 5′ —O—(CH2)2-(3-Py)
    12 0 — — 1 6′ —O—(CH2)2-(3-Py)
    13 0 — — 1 2′ —O—(CH2)2—N(CH3)2
    14 0 — — 1 4′ —O—(CH2)2—N(CH3)2
    15 0 — — 1 5′ —O—(CH2)2—N(CH3)2
    16 0 — — 1 6′ —O—(CH2)2—N(CH3)2
    17 1 4 —O—(CH2)2-(3-Py) 1 2′ —O—(CH2)2-(3-Py)
    18 1 5 —O—(CH2)2-(3-Py) 1 4′ —O—(CH2)2-(3-Py)
    19 1 6 —O—(CH2)2-(3-Py) 1 5′ —O—(CH2)2-(3-Py)
    20 2 4, 5 —O—(CH2)2-(3-Py) 1 6′ —O—(CH2)2-(3-Py)
  • [0495]
    TABLE 11
    (I-L)
    Figure US20030073706A1-20030417-C00066
    No. p position R1 q position R2
     1 1 5 —O—(CH2)2-(3-Py) 0 — —
     2 1 6 —O—(CH2)2-(3-Py) 0 — —
     3 1 7 —O—(CH2)2-(3-Py) 0 — —
     4 2 6, 7 —O—(CH2)2-(3-Py) 0 — —
     5 1 5 —O—(CH2)2—N(CH3)2 0 — —
     6 1 6 —O—(CH2)2—N(CH3)2 0 — —
     7 1 7 —O—(CH2)2—N(CH3)2 0 — —
     8 2 6, 7 —O—(CH2)2—N(CH3)2 0 — —
     9 0 — — 1 2′ —O—(CH2)2-(3-Py)
    10 0 — — 1 3′ —O—(CH2)2-(3-Py)
    11 0 — — 2 2′, 3′ —O—(CH2)2-(3-Py)
    12 0 — — 2 2′, 5′ —O—(CH2)2-(3-Py)
    13 0 — — 1 2′ —O—(CH2)2—N(CH3)2
    14 0 — — 1 3′ —O—(CH2)2—N(CH3)2
    15 0 — — 2 2′, 3′ —O—(CH2)2—N(CH3)2
    16 0 — — 2 2′, 5′ —O—(CH2)2—N(CH3)2
    17 1 5 —O—(CH2)2-(3-Py) 1 2′ —O—(CH2)2-(3-Py)
    18 1 6 —O—(CH2)2-(3-Py) 1 3′ —O—(CH2)2-(3-Py)
    19 1 7 —O—(CH2)2-(3-Py) 2 2′, 3′ —O—(CH2)2-(3-Py)
    20 2 6, 7 —O—(CH2)2-(3-Py) 2 2′, 5′ —O—(CH2)2-(3-Py)
  • [0496]
    TABLE 12
    (I-M)
    Figure US20030073706A1-20030417-C00067
    No. p position R1 q position R2
     1 1 4 —O—(CH2)2-(3-Py) 0 — —
     2 1 5 —O—(CH2)2-(3-Py) 0 — —
     3 1 6 —O—(CH2)2-(3-Py) 0 — —
     4 2 4, 5 —O—(CH2)2-(3-Py) 0 — —
     5 1 4 —O—(CH2)2—N(CH3)2 0 — —
     6 1 5 —O—(CH2)2—N(CH3)2 0 — —
     7 1 6 —O—(CH2)2—N(CH3)2 0 — —
     8 2 4, 5 —O—(CH2)2—N(CH3)2 0 — —
     9 0 — — 1 2′ —O—(CH2)2-(3-Py)
    10 0 — — 1 3′ —O—(CH2)2-(3-Py)
    11 0 — — 2 2′, 3′ —O—(CH2)2-(3-Py)
    12 0 — — 2 2′, 5′ —O—(CH2)2-(3-Py)
    13 0 — — 1 2′ —O—(CH2)2—N(CH3)2
    14 0 — — 1 3′ —O—(CH2)2—N(CH3)2
    15 0 — — 2 2′, 3′ —O—(CH2)2—N(CH3)2
    16 0 — — 2 2′, 5′ —O—(CH2)2—N(CH3)2
    17 1 4 —O—(CH2)2-(3-Py) 1 2′ —O—(CH2)2-(3-Py)
    18 1 5 —O—(CH2)2-(3-Py) 1 3′ —O—(CH2)2-(3-Py)
    19 1 6 —O—(CH2)2-(3-Py) 2 2′, 3′ —O—(CH2)2-(3-Py)
    20 2 4, 5 —O—(CH2)2-(3-Py) 2 2′, 5′ —O—(CH2)2-(3-Py)
  • [0497]
    TABLE 13
    (I-A-1)
    Figure US20030073706A1-20030417-C00068
    No. R1 No. R1
    1
    Figure US20030073706A1-20030417-C00069
         		11
    Figure US20030073706A1-20030417-C00070
    2
    Figure US20030073706A1-20030417-C00071
         		12
    Figure US20030073706A1-20030417-C00072
    3
    Figure US20030073706A1-20030417-C00073
         		13
    Figure US20030073706A1-20030417-C00074
    4
    Figure US20030073706A1-20030417-C00075
         		14
    Figure US20030073706A1-20030417-C00076
    5
    Figure US20030073706A1-20030417-C00077
         		15
    Figure US20030073706A1-20030417-C00078
    6
    Figure US20030073706A1-20030417-C00079
         		16
    Figure US20030073706A1-20030417-C00080
    7
    Figure US20030073706A1-20030417-C00081
         		17
    Figure US20030073706A1-20030417-C00082
    8
    Figure US20030073706A1-20030417-C00083
         		18
    Figure US20030073706A1-20030417-C00084
    9
    Figure US20030073706A1-20030417-C00085
         		19
    Figure US20030073706A1-20030417-C00086
    10 
    Figure US20030073706A1-20030417-C00087
         		20
    Figure US20030073706A1-20030417-C00088
  • [0498]
    TABLE 14
    (I-A-2)
    Figure US20030073706A1-20030417-C00089
    No. R1 No. R1
    1
    Figure US20030073706A1-20030417-C00090
         		11
    Figure US20030073706A1-20030417-C00091
    2
    Figure US20030073706A1-20030417-C00092
         		12
    Figure US20030073706A1-20030417-C00093
    3
    Figure US20030073706A1-20030417-C00094
         		13
    Figure US20030073706A1-20030417-C00095
    4
    Figure US20030073706A1-20030417-C00096
         		14
    Figure US20030073706A1-20030417-C00097
    5
    Figure US20030073706A1-20030417-C00098
         		15
    Figure US20030073706A1-20030417-C00099
    6
    Figure US20030073706A1-20030417-C00100
         		16
    Figure US20030073706A1-20030417-C00101
    7
    Figure US20030073706A1-20030417-C00102
         		17
    Figure US20030073706A1-20030417-C00103
    8
    Figure US20030073706A1-20030417-C00104
         		18
    Figure US20030073706A1-20030417-C00105
    9
    Figure US20030073706A1-20030417-C00106
         		19
    Figure US20030073706A1-20030417-C00107
    10 
    Figure US20030073706A1-20030417-C00108
         		20
    Figure US20030073706A1-20030417-C00109
  • [0499]
    TABLE 15
    (I-A-3)
    Figure US20030073706A1-20030417-C00110
    No. R1 No. R1
    1
    Figure US20030073706A1-20030417-C00111
         		11
    Figure US20030073706A1-20030417-C00112
    2
    Figure US20030073706A1-20030417-C00113
         		12
    Figure US20030073706A1-20030417-C00114
    3
    Figure US20030073706A1-20030417-C00115
         		13
    Figure US20030073706A1-20030417-C00116
    4
    Figure US20030073706A1-20030417-C00117
         		14
    Figure US20030073706A1-20030417-C00118
    5
    Figure US20030073706A1-20030417-C00119
         		15
    Figure US20030073706A1-20030417-C00120
    6
    Figure US20030073706A1-20030417-C00121
         		16
    Figure US20030073706A1-20030417-C00122
    7
    Figure US20030073706A1-20030417-C00123
         		17
    Figure US20030073706A1-20030417-C00124
    8
    Figure US20030073706A1-20030417-C00125
         		18
    Figure US20030073706A1-20030417-C00126
    9
    Figure US20030073706A1-20030417-C00127
         		19
    Figure US20030073706A1-20030417-C00128
    10 
    Figure US20030073706A1-20030417-C00129
         		20
    Figure US20030073706A1-20030417-C00130
  • [0500]
    TABLE 16
    (I-A-4)
    Figure US20030073706A1-20030417-C00131
    No. R1 No. R1
    1
    Figure US20030073706A1-20030417-C00132
         		11
    Figure US20030073706A1-20030417-C00133
    2
    Figure US20030073706A1-20030417-C00134
         		12
    Figure US20030073706A1-20030417-C00135
    3
    Figure US20030073706A1-20030417-C00136
         		13
    Figure US20030073706A1-20030417-C00137
    4
    Figure US20030073706A1-20030417-C00138
         		14
    Figure US20030073706A1-20030417-C00139
    5
    Figure US20030073706A1-20030417-C00140
         		15
    Figure US20030073706A1-20030417-C00141
    6
    Figure US20030073706A1-20030417-C00142
         		16
    Figure US20030073706A1-20030417-C00143
    7
    Figure US20030073706A1-20030417-C00144
         		17
    Figure US20030073706A1-20030417-C00145
    8
    Figure US20030073706A1-20030417-C00146
         		18
    Figure US20030073706A1-20030417-C00147
    9
    Figure US20030073706A1-20030417-C00148
         		19
    Figure US20030073706A1-20030417-C00149
    10 
    Figure US20030073706A1-20030417-C00150
         		20
    Figure US20030073706A1-20030417-C00151
  • [0501]
    TABLE 17
    (I-B-1)
    Figure US20030073706A1-20030417-C00152
    No. R1 No. R1
    1
    Figure US20030073706A1-20030417-C00153
         		11
    Figure US20030073706A1-20030417-C00154
    2
    Figure US20030073706A1-20030417-C00155
         		12
    Figure US20030073706A1-20030417-C00156
    3
    Figure US20030073706A1-20030417-C00157
         		13
    Figure US20030073706A1-20030417-C00158
    4
    Figure US20030073706A1-20030417-C00159
         		14
    Figure US20030073706A1-20030417-C00160
    5
    Figure US20030073706A1-20030417-C00161
         		15
    Figure US20030073706A1-20030417-C00162
    6
    Figure US20030073706A1-20030417-C00163
         		16
    Figure US20030073706A1-20030417-C00164
    7
    Figure US20030073706A1-20030417-C00165
         		17
    Figure US20030073706A1-20030417-C00166
    8
    Figure US20030073706A1-20030417-C00167
         		18
    Figure US20030073706A1-20030417-C00168
    9
    Figure US20030073706A1-20030417-C00169
         		19
    Figure US20030073706A1-20030417-C00170
    10 
    Figure US20030073706A1-20030417-C00171
         		20
    Figure US20030073706A1-20030417-C00172
  • [0502]
    TABLE 18
    (I-B-2)
    Figure US20030073706A1-20030417-C00173
    No. R1 No. R1
    1
    Figure US20030073706A1-20030417-C00174
         		11
    Figure US20030073706A1-20030417-C00175
    2
    Figure US20030073706A1-20030417-C00176
         		12
    Figure US20030073706A1-20030417-C00177
    3
    Figure US20030073706A1-20030417-C00178
         		13
    Figure US20030073706A1-20030417-C00179
    4
    Figure US20030073706A1-20030417-C00180
         		14
    Figure US20030073706A1-20030417-C00181
    5
    Figure US20030073706A1-20030417-C00182
         		15
    Figure US20030073706A1-20030417-C00183
    6
    Figure US20030073706A1-20030417-C00184
         		16
    Figure US20030073706A1-20030417-C00185
    7
    Figure US20030073706A1-20030417-C00186
         		17
    Figure US20030073706A1-20030417-C00187
    8
    Figure US20030073706A1-20030417-C00188
         		18
    Figure US20030073706A1-20030417-C00189
    9
    Figure US20030073706A1-20030417-C00190
         		19
    Figure US20030073706A1-20030417-C00191
    10 
    Figure US20030073706A1-20030417-C00192
         		20
    Figure US20030073706A1-20030417-C00193
  • [0503]
    TABLE 19
    (I-B-3)
    Figure US20030073706A1-20030417-C00194
    No. R1 No. R1
    1
    Figure US20030073706A1-20030417-C00195
         		11
    Figure US20030073706A1-20030417-C00196
    2
    Figure US20030073706A1-20030417-C00197
         		12
    Figure US20030073706A1-20030417-C00198
    3
    Figure US20030073706A1-20030417-C00199
         		13
    Figure US20030073706A1-20030417-C00200
    4
    Figure US20030073706A1-20030417-C00201
         		14
    Figure US20030073706A1-20030417-C00202
    5
    Figure US20030073706A1-20030417-C00203
         		15
    Figure US20030073706A1-20030417-C00204
    6
    Figure US20030073706A1-20030417-C00205
         		16
    Figure US20030073706A1-20030417-C00206
    7
    Figure US20030073706A1-20030417-C00207
         		17
    Figure US20030073706A1-20030417-C00208
    8
    Figure US20030073706A1-20030417-C00209
         		18
    Figure US20030073706A1-20030417-C00210
    9
    Figure US20030073706A1-20030417-C00211
         		19
    Figure US20030073706A1-20030417-C00212
    10 
    Figure US20030073706A1-20030417-C00213
         		20
    Figure US20030073706A1-20030417-C00214
  • [0504]
    TABLE 20
    (I-C-1)
    Figure US20030073706A1-20030417-C00215
    No. R1 No. R1
    1
    Figure US20030073706A1-20030417-C00216
         		11
    Figure US20030073706A1-20030417-C00217
    2
    Figure US20030073706A1-20030417-C00218
         		12
    Figure US20030073706A1-20030417-C00219
    3
    Figure US20030073706A1-20030417-C00220
         		13
    Figure US20030073706A1-20030417-C00221
    4
    Figure US20030073706A1-20030417-C00222
         		14
    Figure US20030073706A1-20030417-C00223
    5
    Figure US20030073706A1-20030417-C00224
         		15
    Figure US20030073706A1-20030417-C00225
    6
    Figure US20030073706A1-20030417-C00226
         		16
    Figure US20030073706A1-20030417-C00227
    7
    Figure US20030073706A1-20030417-C00228
         		17
    Figure US20030073706A1-20030417-C00229
    8
    Figure US20030073706A1-20030417-C00230
         		18
    Figure US20030073706A1-20030417-C00231
    9
    Figure US20030073706A1-20030417-C00232
         		19
    Figure US20030073706A1-20030417-C00233
    10 
    Figure US20030073706A1-20030417-C00234
         		20
    Figure US20030073706A1-20030417-C00235
  • [0505]
    TABLE 21
    (I-C-2)
    Figure US20030073706A1-20030417-C00236
    No. R1
    1
    Figure US20030073706A1-20030417-C00237
    2
    Figure US20030073706A1-20030417-C00238
    3
    Figure US20030073706A1-20030417-C00239
    4
    Figure US20030073706A1-20030417-C00240
    5
    Figure US20030073706A1-20030417-C00241
    6
    Figure US20030073706A1-20030417-C00242
    7
    Figure US20030073706A1-20030417-C00243
    8
    Figure US20030073706A1-20030417-C00244
    9
    Figure US20030073706A1-20030417-C00245
    10
    Figure US20030073706A1-20030417-C00246
    11
    Figure US20030073706A1-20030417-C00247
    12
    Figure US20030073706A1-20030417-C00248
    13
    Figure US20030073706A1-20030417-C00249
    14
    Figure US20030073706A1-20030417-C00250
    15
    Figure US20030073706A1-20030417-C00251
    16
    Figure US20030073706A1-20030417-C00252
    17
    Figure US20030073706A1-20030417-C00253
    18
    Figure US20030073706A1-20030417-C00254
    19
    Figure US20030073706A1-20030417-C00255
    20
    Figure US20030073706A1-20030417-C00256
  • [0506]
    TABLE 22
    (I-C-3)
    Figure US20030073706A1-20030417-C00257
    No. R1
    1
    Figure US20030073706A1-20030417-C00258
    2
    Figure US20030073706A1-20030417-C00259
    3
    Figure US20030073706A1-20030417-C00260
    4
    Figure US20030073706A1-20030417-C00261
    5
    Figure US20030073706A1-20030417-C00262
    6
    Figure US20030073706A1-20030417-C00263
    7
    Figure US20030073706A1-20030417-C00264
    8
    Figure US20030073706A1-20030417-C00265
    9
    Figure US20030073706A1-20030417-C00266
    10
    Figure US20030073706A1-20030417-C00267
    11
    Figure US20030073706A1-20030417-C00268
    12
    Figure US20030073706A1-20030417-C00269
    13
    Figure US20030073706A1-20030417-C00270
    14
    Figure US20030073706A1-20030417-C00271
    15
    Figure US20030073706A1-20030417-C00272
    16
    Figure US20030073706A1-20030417-C00273
    17
    Figure US20030073706A1-20030417-C00274
    18
    Figure US20030073706A1-20030417-C00275
    19
    Figure US20030073706A1-20030417-C00276
    20
    Figure US20030073706A1-20030417-C00277
  • [0507]
    TABLE 23
    (I-D-1)
    Figure US20030073706A1-20030417-C00278
    No. R1
    1
    Figure US20030073706A1-20030417-C00279
    2
    Figure US20030073706A1-20030417-C00280
    3
    Figure US20030073706A1-20030417-C00281
    4
    Figure US20030073706A1-20030417-C00282
    5
    Figure US20030073706A1-20030417-C00283
    6
    Figure US20030073706A1-20030417-C00284
    7
    Figure US20030073706A1-20030417-C00285
    8
    Figure US20030073706A1-20030417-C00286
    9
    Figure US20030073706A1-20030417-C00287
    10
    Figure US20030073706A1-20030417-C00288
    11
    Figure US20030073706A1-20030417-C00289
    12
    Figure US20030073706A1-20030417-C00290
    13
    Figure US20030073706A1-20030417-C00291
    14
    Figure US20030073706A1-20030417-C00292
    15
    Figure US20030073706A1-20030417-C00293
    16
    Figure US20030073706A1-20030417-C00294
    17
    Figure US20030073706A1-20030417-C00295
    18
    Figure US20030073706A1-20030417-C00296
    19
    Figure US20030073706A1-20030417-C00297
    20
    Figure US20030073706A1-20030417-C00298
  • [0508]
    TABLE 24
    (I-D-2)
    Figure US20030073706A1-20030417-C00299
    No. R1
    1
    Figure US20030073706A1-20030417-C00300
    2
    Figure US20030073706A1-20030417-C00301
    3
    Figure US20030073706A1-20030417-C00302
    4
    Figure US20030073706A1-20030417-C00303
    5
    Figure US20030073706A1-20030417-C00304
    6
    Figure US20030073706A1-20030417-C00305
    7
    Figure US20030073706A1-20030417-C00306
    8
    Figure US20030073706A1-20030417-C00307
    9
    Figure US20030073706A1-20030417-C00308
    10
    Figure US20030073706A1-20030417-C00309
    11
    Figure US20030073706A1-20030417-C00310
    12
    Figure US20030073706A1-20030417-C00311
    13
    Figure US20030073706A1-20030417-C00312
    14
    Figure US20030073706A1-20030417-C00313
    15
    Figure US20030073706A1-20030417-C00314
    16
    Figure US20030073706A1-20030417-C00315
    17
    Figure US20030073706A1-20030417-C00316
    18
    Figure US20030073706A1-20030417-C00317
    19
    Figure US20030073706A1-20030417-C00318
    20
    Figure US20030073706A1-20030417-C00319
  • [0509]
    TABLE 25
    (I-D-3)
    Figure US20030073706A1-20030417-C00320
    No. R1
    1
    Figure US20030073706A1-20030417-C00321
    2
    Figure US20030073706A1-20030417-C00322
    3
    Figure US20030073706A1-20030417-C00323
    4
    Figure US20030073706A1-20030417-C00324
    5
    Figure US20030073706A1-20030417-C00325
    6
    Figure US20030073706A1-20030417-C00326
    7
    Figure US20030073706A1-20030417-C00327
    8
    Figure US20030073706A1-20030417-C00328
    9
    Figure US20030073706A1-20030417-C00329
    10
    Figure US20030073706A1-20030417-C00330
    11
    Figure US20030073706A1-20030417-C00331
    12
    Figure US20030073706A1-20030417-C00332
    13
    Figure US20030073706A1-20030417-C00333
    14
    Figure US20030073706A1-20030417-C00334
    15
    Figure US20030073706A1-20030417-C00335
    16
    Figure US20030073706A1-20030417-C00336
    17
    Figure US20030073706A1-20030417-C00337
    18
    Figure US20030073706A1-20030417-C00338
    19
    Figure US20030073706A1-20030417-C00339
    20
    Figure US20030073706A1-20030417-C00340
  • [0510]
    TABLE 26
    (I-D-4)
    Figure US20030073706A1-20030417-C00341
    No. R1
    1
    Figure US20030073706A1-20030417-C00342
    2
    Figure US20030073706A1-20030417-C00343
    3
    Figure US20030073706A1-20030417-C00344
    4
    Figure US20030073706A1-20030417-C00345
    5
    Figure US20030073706A1-20030417-C00346
    6
    Figure US20030073706A1-20030417-C00347
    7
    Figure US20030073706A1-20030417-C00348
    8
    Figure US20030073706A1-20030417-C00349
    9
    Figure US20030073706A1-20030417-C00350
    10
    Figure US20030073706A1-20030417-C00351
    11
    Figure US20030073706A1-20030417-C00352
    12
    Figure US20030073706A1-20030417-C00353
    13
    Figure US20030073706A1-20030417-C00354
    14
    Figure US20030073706A1-20030417-C00355
    15
    Figure US20030073706A1-20030417-C00356
    16
    Figure US20030073706A1-20030417-C00357
    17
    Figure US20030073706A1-20030417-C00358
    18
    Figure US20030073706A1-20030417-C00359
    19
    Figure US20030073706A1-20030417-C00360
    20
    Figure US20030073706A1-20030417-C00361
  • [0511]
    TABLE 27
    (I-E-1)
    Figure US20030073706A1-20030417-C00362
    No. R1
    1
    Figure US20030073706A1-20030417-C00363
    2
    Figure US20030073706A1-20030417-C00364
    3
    Figure US20030073706A1-20030417-C00365
    4
    Figure US20030073706A1-20030417-C00366
    5
    Figure US20030073706A1-20030417-C00367
    6
    Figure US20030073706A1-20030417-C00368
    7
    Figure US20030073706A1-20030417-C00369
    8
    Figure US20030073706A1-20030417-C00370
    9
    Figure US20030073706A1-20030417-C00371
    10
    Figure US20030073706A1-20030417-C00372
    11
    Figure US20030073706A1-20030417-C00373
    12
    Figure US20030073706A1-20030417-C00374
    13
    Figure US20030073706A1-20030417-C00375
    14
    Figure US20030073706A1-20030417-C00376
    15
    Figure US20030073706A1-20030417-C00377
    16
    Figure US20030073706A1-20030417-C00378
    17
    Figure US20030073706A1-20030417-C00379
    18
    Figure US20030073706A1-20030417-C00380
    19
    Figure US20030073706A1-20030417-C00381
    20
    Figure US20030073706A1-20030417-C00382
  • [0512]
    TABLE 28
    (I-E-2)
    Figure US20030073706A1-20030417-C00383
    No. R1
    1
    Figure US20030073706A1-20030417-C00384
    2
    Figure US20030073706A1-20030417-C00385
    3
    Figure US20030073706A1-20030417-C00386
    4
    Figure US20030073706A1-20030417-C00387
    5
    Figure US20030073706A1-20030417-C00388
    6
    Figure US20030073706A1-20030417-C00389
    7
    Figure US20030073706A1-20030417-C00390
    8
    Figure US20030073706A1-20030417-C00391
    9
    Figure US20030073706A1-20030417-C00392
    10
    Figure US20030073706A1-20030417-C00393
    11
    Figure US20030073706A1-20030417-C00394
    12
    Figure US20030073706A1-20030417-C00395
    13
    Figure US20030073706A1-20030417-C00396
    14
    Figure US20030073706A1-20030417-C00397
    15
    Figure US20030073706A1-20030417-C00398
    16
    Figure US20030073706A1-20030417-C00399
    17
    Figure US20030073706A1-20030417-C00400
    18
    Figure US20030073706A1-20030417-C00401
    19
    Figure US20030073706A1-20030417-C00402
    20
    Figure US20030073706A1-20030417-C00403
  • [0513]
    TABLE 29
    (I-E-3)
    Figure US20030073706A1-20030417-C00404
    No. R1
    1
    Figure US20030073706A1-20030417-C00405
    2
    Figure US20030073706A1-20030417-C00406
    3
    Figure US20030073706A1-20030417-C00407
    4
    Figure US20030073706A1-20030417-C00408
    5
    Figure US20030073706A1-20030417-C00409
    6
    Figure US20030073706A1-20030417-C00410
    7
    Figure US20030073706A1-20030417-C00411
    8
    Figure US20030073706A1-20030417-C00412
    9
    Figure US20030073706A1-20030417-C00413
    10
    Figure US20030073706A1-20030417-C00414
    11
    Figure US20030073706A1-20030417-C00415
    12
    Figure US20030073706A1-20030417-C00416
    13
    Figure US20030073706A1-20030417-C00417
    14
    Figure US20030073706A1-20030417-C00418
    15
    Figure US20030073706A1-20030417-C00419
    16
    Figure US20030073706A1-20030417-C00420
    17
    Figure US20030073706A1-20030417-C00421
    18
    Figure US20030073706A1-20030417-C00422
    19
    Figure US20030073706A1-20030417-C00423
    20
    Figure US20030073706A1-20030417-C00424
  • [0514]
    TABLE 30
    (I-E-4)
    Figure US20030073706A1-20030417-C00425
    No. R1
    1
    Figure US20030073706A1-20030417-C00426
    2
    Figure US20030073706A1-20030417-C00427
    3
    Figure US20030073706A1-20030417-C00428
    4
    Figure US20030073706A1-20030417-C00429
    5
    Figure US20030073706A1-20030417-C00430
    6
    Figure US20030073706A1-20030417-C00431
    7
    Figure US20030073706A1-20030417-C00432
    8
    Figure US20030073706A1-20030417-C00433
    9
    Figure US20030073706A1-20030417-C00434
    10
    Figure US20030073706A1-20030417-C00435
    11
    Figure US20030073706A1-20030417-C00436
    12
    Figure US20030073706A1-20030417-C00437
    13
    Figure US20030073706A1-20030417-C00438
    14
    Figure US20030073706A1-20030417-C00439
    15
    Figure US20030073706A1-20030417-C00440
    16
    Figure US20030073706A1-20030417-C00441
    17
    Figure US20030073706A1-20030417-C00442
    18
    Figure US20030073706A1-20030417-C00443
    19
    Figure US20030073706A1-20030417-C00444
    20
    Figure US20030073706A1-20030417-C00445
  • [0515]
    TABLE 31
    Figure US20030073706A1-20030417-C00446
    No. R1
    1
    Figure US20030073706A1-20030417-C00447
    2
    Figure US20030073706A1-20030417-C00448
    3
    Figure US20030073706A1-20030417-C00449
    4
    Figure US20030073706A1-20030417-C00450
    5
    Figure US20030073706A1-20030417-C00451
    6
    Figure US20030073706A1-20030417-C00452
    7
    Figure US20030073706A1-20030417-C00453
    8
    Figure US20030073706A1-20030417-C00454
    9
    Figure US20030073706A1-20030417-C00455
    10
    Figure US20030073706A1-20030417-C00456
    11
    Figure US20030073706A1-20030417-C00457
    12
    Figure US20030073706A1-20030417-C00458
    13
    Figure US20030073706A1-20030417-C00459
    14
    Figure US20030073706A1-20030417-C00460
    15
    Figure US20030073706A1-20030417-C00461
    16
    Figure US20030073706A1-20030417-C00462
    17
    Figure US20030073706A1-20030417-C00463
    18
    Figure US20030073706A1-20030417-C00464
    19
    Figure US20030073706A1-20030417-C00465
    20
    Figure US20030073706A1-20030417-C00466
  • [0516]
    TABLE 32
    Figure US20030073706A1-20030417-C00467
    No. R1
    1
    Figure US20030073706A1-20030417-C00468
    2
    Figure US20030073706A1-20030417-C00469
    3
    Figure US20030073706A1-20030417-C00470
    4
    Figure US20030073706A1-20030417-C00471
    5
    Figure US20030073706A1-20030417-C00472
    6
    Figure US20030073706A1-20030417-C00473
    7
    Figure US20030073706A1-20030417-C00474
    8
    Figure US20030073706A1-20030417-C00475
    9
    Figure US20030073706A1-20030417-C00476
    10
    Figure US20030073706A1-20030417-C00477
    11
    Figure US20030073706A1-20030417-C00478
    12
    Figure US20030073706A1-20030417-C00479
    13
    Figure US20030073706A1-20030417-C00480
    14
    Figure US20030073706A1-20030417-C00481
    15
    Figure US20030073706A1-20030417-C00482
    16
    Figure US20030073706A1-20030417-C00483
    17
    Figure US20030073706A1-20030417-C00484
    18
    Figure US20030073706A1-20030417-C00485
    19
    Figure US20030073706A1-20030417-C00486
    20
    Figure US20030073706A1-20030417-C00487
  • [0517]
    TABLE 33
    Figure US20030073706A1-20030417-C00488
    No. R1
    1
    Figure US20030073706A1-20030417-C00489
    2
    Figure US20030073706A1-20030417-C00490
    3
    Figure US20030073706A1-20030417-C00491
    4
    Figure US20030073706A1-20030417-C00492
    5
    Figure US20030073706A1-20030417-C00493
    6
    Figure US20030073706A1-20030417-C00494
    7
    Figure US20030073706A1-20030417-C00495
    8
    Figure US20030073706A1-20030417-C00496
    9
    Figure US20030073706A1-20030417-C00497
    10
    Figure US20030073706A1-20030417-C00498
    11
    Figure US20030073706A1-20030417-C00499
    12
    Figure US20030073706A1-20030417-C00500
    13
    Figure US20030073706A1-20030417-C00501
    14
    Figure US20030073706A1-20030417-C00502
    15
    Figure US20030073706A1-20030417-C00503
    16
    Figure US20030073706A1-20030417-C00504
    17
    Figure US20030073706A1-20030417-C00505
    18
    Figure US20030073706A1-20030417-C00506
    19
    Figure US20030073706A1-20030417-C00507
    20
    Figure US20030073706A1-20030417-C00508
  • [0518]
    TABLE 34
    Figure US20030073706A1-20030417-C00509
    No. R1
    1
    Figure US20030073706A1-20030417-C00510
    2
    Figure US20030073706A1-20030417-C00511
    3
    Figure US20030073706A1-20030417-C00512
    4
    Figure US20030073706A1-20030417-C00513
    5
    Figure US20030073706A1-20030417-C00514
    6
    Figure US20030073706A1-20030417-C00515
    7
    Figure US20030073706A1-20030417-C00516
    8
    Figure US20030073706A1-20030417-C00517
    9
    Figure US20030073706A1-20030417-C00518
    10
    Figure US20030073706A1-20030417-C00519
    11
    Figure US20030073706A1-20030417-C00520
    12
    Figure US20030073706A1-20030417-C00521
    13
    Figure US20030073706A1-20030417-C00522
    14
    Figure US20030073706A1-20030417-C00523
    15
    Figure US20030073706A1-20030417-C00524
    16
    Figure US20030073706A1-20030417-C00525
    17
    Figure US20030073706A1-20030417-C00526
    18
    Figure US20030073706A1-20030417-C00527
    19
    Figure US20030073706A1-20030417-C00528
    20
    Figure US20030073706A1-20030417-C00529
  • [0519]
    TABLE 35
    Figure US20030073706A1-20030417-C00530
    No. R1
    1
    Figure US20030073706A1-20030417-C00531
    2
    Figure US20030073706A1-20030417-C00532
    3
    Figure US20030073706A1-20030417-C00533
    4
    Figure US20030073706A1-20030417-C00534
    5
    Figure US20030073706A1-20030417-C00535
    6
    Figure US20030073706A1-20030417-C00536
    7
    Figure US20030073706A1-20030417-C00537
    8
    Figure US20030073706A1-20030417-C00538
    9
    Figure US20030073706A1-20030417-C00539
    10
    Figure US20030073706A1-20030417-C00540
    11
    Figure US20030073706A1-20030417-C00541
    12
    Figure US20030073706A1-20030417-C00542
    13
    Figure US20030073706A1-20030417-C00543
    14
    Figure US20030073706A1-20030417-C00544
    15
    Figure US20030073706A1-20030417-C00545
    16
    Figure US20030073706A1-20030417-C00546
    17
    Figure US20030073706A1-20030417-C00547
    18
    Figure US20030073706A1-20030417-C00548
    19
    Figure US20030073706A1-20030417-C00549
    20
    Figure US20030073706A1-20030417-C00550
  • [0520]
    TABLE 36
    Figure US20030073706A1-20030417-C00551
    No. R1
    1
    Figure US20030073706A1-20030417-C00552
    2
    Figure US20030073706A1-20030417-C00553
    3
    Figure US20030073706A1-20030417-C00554
    4
    Figure US20030073706A1-20030417-C00555
    5
    Figure US20030073706A1-20030417-C00556
    6
    Figure US20030073706A1-20030417-C00557
    7
    Figure US20030073706A1-20030417-C00558
    8
    Figure US20030073706A1-20030417-C00559
    9
    Figure US20030073706A1-20030417-C00560
    10
    Figure US20030073706A1-20030417-C00561
    11
    Figure US20030073706A1-20030417-C00562
    12
    Figure US20030073706A1-20030417-C00563
    13
    Figure US20030073706A1-20030417-C00564
    14
    Figure US20030073706A1-20030417-C00565
    15
    Figure US20030073706A1-20030417-C00566
    16
    Figure US20030073706A1-20030417-C00567
    17
    Figure US20030073706A1-20030417-C00568
    18
    Figure US20030073706A1-20030417-C00569
    19
    Figure US20030073706A1-20030417-C00570
    20
    Figure US20030073706A1-20030417-C00571
  • [0521]
    TABLE 37
    Figure US20030073706A1-20030417-C00572
    No. R1
    1
    Figure US20030073706A1-20030417-C00573
    2
    Figure US20030073706A1-20030417-C00574
    3
    Figure US20030073706A1-20030417-C00575
    4
    Figure US20030073706A1-20030417-C00576
    5
    Figure US20030073706A1-20030417-C00577
    6
    Figure US20030073706A1-20030417-C00578
    7
    Figure US20030073706A1-20030417-C00579
    8
    Figure US20030073706A1-20030417-C00580
    9
    Figure US20030073706A1-20030417-C00581
    10
    Figure US20030073706A1-20030417-C00582
    11
    Figure US20030073706A1-20030417-C00583
    12
    Figure US20030073706A1-20030417-C00584
    13
    Figure US20030073706A1-20030417-C00585
    14
    Figure US20030073706A1-20030417-C00586
    15
    Figure US20030073706A1-20030417-C00587
    16
    Figure US20030073706A1-20030417-C00588
    17
    Figure US20030073706A1-20030417-C00589
    18
    Figure US20030073706A1-20030417-C00590
    19
    Figure US20030073706A1-20030417-C00591
    20
    Figure US20030073706A1-20030417-C00592
  • [0522]
    TABLE 38
    Figure US20030073706A1-20030417-C00593
    No. R1
    1
    Figure US20030073706A1-20030417-C00594
    2
    Figure US20030073706A1-20030417-C00595
    3
    Figure US20030073706A1-20030417-C00596
    4
    Figure US20030073706A1-20030417-C00597
    5
    Figure US20030073706A1-20030417-C00598
    6
    Figure US20030073706A1-20030417-C00599
    7
    Figure US20030073706A1-20030417-C00600
    8
    Figure US20030073706A1-20030417-C00601
    9
    Figure US20030073706A1-20030417-C00602
    10
    Figure US20030073706A1-20030417-C00603
    11
    Figure US20030073706A1-20030417-C00604
    12
    Figure US20030073706A1-20030417-C00605
    13
    Figure US20030073706A1-20030417-C00606
    14
    Figure US20030073706A1-20030417-C00607
    15
    Figure US20030073706A1-20030417-C00608
    16
    Figure US20030073706A1-20030417-C00609
    17
    Figure US20030073706A1-20030417-C00610
    18
    Figure US20030073706A1-20030417-C00611
    19
    Figure US20030073706A1-20030417-C00612
    20
    Figure US20030073706A1-20030417-C00613
  • [0523]
    TABLE 39
    Figure US20030073706A1-20030417-C00614
    No. R1
    1
    Figure US20030073706A1-20030417-C00615
    2
    Figure US20030073706A1-20030417-C00616
    3
    Figure US20030073706A1-20030417-C00617
    4
    Figure US20030073706A1-20030417-C00618
    5
    Figure US20030073706A1-20030417-C00619
    6
    Figure US20030073706A1-20030417-C00620
    7
    Figure US20030073706A1-20030417-C00621
    8
    Figure US20030073706A1-20030417-C00622
    9
    Figure US20030073706A1-20030417-C00623
    10
    Figure US20030073706A1-20030417-C00624
    11
    Figure US20030073706A1-20030417-C00625
    12
    Figure US20030073706A1-20030417-C00626
    13
    Figure US20030073706A1-20030417-C00627
    14
    Figure US20030073706A1-20030417-C00628
    15
    Figure US20030073706A1-20030417-C00629
    16
    Figure US20030073706A1-20030417-C00630
    17
    Figure US20030073706A1-20030417-C00631
    18
    Figure US20030073706A1-20030417-C00632
    19
    Figure US20030073706A1-20030417-C00633
    20
    Figure US20030073706A1-20030417-C00634
  • [0524]
    TABLE 40
    Figure US20030073706A1-20030417-C00635
    No. R1
    1
    Figure US20030073706A1-20030417-C00636
    2
    Figure US20030073706A1-20030417-C00637
    3
    Figure US20030073706A1-20030417-C00638
    4
    Figure US20030073706A1-20030417-C00639
    5
    Figure US20030073706A1-20030417-C00640
    6
    Figure US20030073706A1-20030417-C00641
    7
    Figure US20030073706A1-20030417-C00642
    8
    Figure US20030073706A1-20030417-C00643
    9
    Figure US20030073706A1-20030417-C00644
    10
    Figure US20030073706A1-20030417-C00645
    11
    Figure US20030073706A1-20030417-C00646
    12
    Figure US20030073706A1-20030417-C00647
    13
    Figure US20030073706A1-20030417-C00648
    14
    Figure US20030073706A1-20030417-C00649
    15
    Figure US20030073706A1-20030417-C00650
    16
    Figure US20030073706A1-20030417-C00651
    17
    Figure US20030073706A1-20030417-C00652
    18
    Figure US20030073706A1-20030417-C00653
    19
    Figure US20030073706A1-20030417-C00654
    20
    Figure US20030073706A1-20030417-C00655
  • [0525]
    TABLE 41
    Figure US20030073706A1-20030417-C00656
    No. R1
    1
    Figure US20030073706A1-20030417-C00657
    2
    Figure US20030073706A1-20030417-C00658
    3
    Figure US20030073706A1-20030417-C00659
    4
    Figure US20030073706A1-20030417-C00660
    5
    Figure US20030073706A1-20030417-C00661
    6
    Figure US20030073706A1-20030417-C00662
    7
    Figure US20030073706A1-20030417-C00663
    8
    Figure US20030073706A1-20030417-C00664
    9
    Figure US20030073706A1-20030417-C00665
    10
    Figure US20030073706A1-20030417-C00666
    11
    Figure US20030073706A1-20030417-C00667
    12
    Figure US20030073706A1-20030417-C00668
    13
    Figure US20030073706A1-20030417-C00669
    14
    Figure US20030073706A1-20030417-C00670
    15
    Figure US20030073706A1-20030417-C00671
    16
    Figure US20030073706A1-20030417-C00672
    17
    Figure US20030073706A1-20030417-C00673
    18
    Figure US20030073706A1-20030417-C00674
    19
    Figure US20030073706A1-20030417-C00675
    20
    Figure US20030073706A1-20030417-C00676
  • [0526]
    TABLE 42
    Figure US20030073706A1-20030417-C00677
    No. R1
    1
    Figure US20030073706A1-20030417-C00678
    2
    Figure US20030073706A1-20030417-C00679
    3
    Figure US20030073706A1-20030417-C00680
    4
    Figure US20030073706A1-20030417-C00681
    5
    Figure US20030073706A1-20030417-C00682
    6
    Figure US20030073706A1-20030417-C00683
    7
    Figure US20030073706A1-20030417-C00684
    8
    Figure US20030073706A1-20030417-C00685
    9
    Figure US20030073706A1-20030417-C00686
    10
    Figure US20030073706A1-20030417-C00687
    11
    Figure US20030073706A1-20030417-C00688
    12
    Figure US20030073706A1-20030417-C00689
    13
    Figure US20030073706A1-20030417-C00690
    14
    Figure US20030073706A1-20030417-C00691
    15
    Figure US20030073706A1-20030417-C00692
    16
    Figure US20030073706A1-20030417-C00693
    17
    Figure US20030073706A1-20030417-C00694
    18
    Figure US20030073706A1-20030417-C00695
    19
    Figure US20030073706A1-20030417-C00696
    20
    Figure US20030073706A1-20030417-C00697
  • [0527]
    TABLE 43
    Figure US20030073706A1-20030417-C00698
    No. R1
    1
    Figure US20030073706A1-20030417-C00699
    2
    Figure US20030073706A1-20030417-C00700
    3
    Figure US20030073706A1-20030417-C00701
    4
    Figure US20030073706A1-20030417-C00702
    5
    Figure US20030073706A1-20030417-C00703
    6
    Figure US20030073706A1-20030417-C00704
    7
    Figure US20030073706A1-20030417-C00705
    8
    Figure US20030073706A1-20030417-C00706
    9
    Figure US20030073706A1-20030417-C00707
    10
    Figure US20030073706A1-20030417-C00708
    11
    Figure US20030073706A1-20030417-C00709
    12
    Figure US20030073706A1-20030417-C00710
    13
    Figure US20030073706A1-20030417-C00711
    14
    Figure US20030073706A1-20030417-C00712
    15
    Figure US20030073706A1-20030417-C00713
    16
    Figure US20030073706A1-20030417-C00714
    17
    Figure US20030073706A1-20030417-C00715
    18
    Figure US20030073706A1-20030417-C00716
    19
    Figure US20030073706A1-20030417-C00717
    20
    Figure US20030073706A1-20030417-C00718
  • [0528]
    TABLE 44
    Figure US20030073706A1-20030417-C00719
    No. R1
    1
    Figure US20030073706A1-20030417-C00720
    2
    Figure US20030073706A1-20030417-C00721
    3
    Figure US20030073706A1-20030417-C00722
    4
    Figure US20030073706A1-20030417-C00723
    5
    Figure US20030073706A1-20030417-C00724
    6
    Figure US20030073706A1-20030417-C00725
    7
    Figure US20030073706A1-20030417-C00726
    8
    Figure US20030073706A1-20030417-C00727
    9
    Figure US20030073706A1-20030417-C00728
    10
    Figure US20030073706A1-20030417-C00729
    11
    Figure US20030073706A1-20030417-C00730
    12
    Figure US20030073706A1-20030417-C00731
    13
    Figure US20030073706A1-20030417-C00732
    14
    Figure US20030073706A1-20030417-C00733
    15
    Figure US20030073706A1-20030417-C00734
    16
    Figure US20030073706A1-20030417-C00735
    17
    Figure US20030073706A1-20030417-C00736
    18
    Figure US20030073706A1-20030417-C00737
    19
    Figure US20030073706A1-20030417-C00738
    20
    Figure US20030073706A1-20030417-C00739
  • [0529]
    TABLE 45
    Figure US20030073706A1-20030417-C00740
    No. R1
    1
    Figure US20030073706A1-20030417-C00741
    2
    Figure US20030073706A1-20030417-C00742
    3
    Figure US20030073706A1-20030417-C00743
    4
    Figure US20030073706A1-20030417-C00744
    5
    Figure US20030073706A1-20030417-C00745
    6
    Figure US20030073706A1-20030417-C00746
    7
    Figure US20030073706A1-20030417-C00747
    8
    Figure US20030073706A1-20030417-C00748
    9
    Figure US20030073706A1-20030417-C00749
    10
    Figure US20030073706A1-20030417-C00750
    11
    Figure US20030073706A1-20030417-C00751
    12
    Figure US20030073706A1-20030417-C00752
    13
    Figure US20030073706A1-20030417-C00753
    14
    Figure US20030073706A1-20030417-C00754
    15
    Figure US20030073706A1-20030417-C00755
    16
    Figure US20030073706A1-20030417-C00756
    17
    Figure US20030073706A1-20030417-C00757
    18
    Figure US20030073706A1-20030417-C00758
    19
    Figure US20030073706A1-20030417-C00759
    20
    Figure US20030073706A1-20030417-C00760
  • [0530]
    TABLE 46
    Figure US20030073706A1-20030417-C00761
    No. R1
    1
    Figure US20030073706A1-20030417-C00762
    2
    Figure US20030073706A1-20030417-C00763
    3
    Figure US20030073706A1-20030417-C00764
    4
    Figure US20030073706A1-20030417-C00765
    5
    Figure US20030073706A1-20030417-C00766
    6
    Figure US20030073706A1-20030417-C00767
    7
    Figure US20030073706A1-20030417-C00768
    8
    Figure US20030073706A1-20030417-C00769
    9
    Figure US20030073706A1-20030417-C00770
    10
    Figure US20030073706A1-20030417-C00771
    11
    Figure US20030073706A1-20030417-C00772
    12
    Figure US20030073706A1-20030417-C00773
    13
    Figure US20030073706A1-20030417-C00774
    14
    Figure US20030073706A1-20030417-C00775
    15
    Figure US20030073706A1-20030417-C00776
    16
    Figure US20030073706A1-20030417-C00777
    17
    Figure US20030073706A1-20030417-C00778
    18
    Figure US20030073706A1-20030417-C00779
    19
    Figure US20030073706A1-20030417-C00780
    20
    Figure US20030073706A1-20030417-C00781
  • [0531]
    TABLE 47
    Figure US20030073706A1-20030417-C00782
    No. R1
    1
    Figure US20030073706A1-20030417-C00783
    2
    Figure US20030073706A1-20030417-C00784
    3
    Figure US20030073706A1-20030417-C00785
    4
    Figure US20030073706A1-20030417-C00786
    5
    Figure US20030073706A1-20030417-C00787
    6
    Figure US20030073706A1-20030417-C00788
    7
    Figure US20030073706A1-20030417-C00789
    8
    Figure US20030073706A1-20030417-C00790
    9
    Figure US20030073706A1-20030417-C00791
    10
    Figure US20030073706A1-20030417-C00792
    11
    Figure US20030073706A1-20030417-C00793
    12
    Figure US20030073706A1-20030417-C00794
    13
    Figure US20030073706A1-20030417-C00795
    14
    Figure US20030073706A1-20030417-C00796
    15
    Figure US20030073706A1-20030417-C00797
    16
    Figure US20030073706A1-20030417-C00798
    17
    Figure US20030073706A1-20030417-C00799
    18
    Figure US20030073706A1-20030417-C00800
    19
    Figure US20030073706A1-20030417-C00801
    20
    Figure US20030073706A1-20030417-C00802
  • [0532]
    TABLE 48
    Figure US20030073706A1-20030417-C00803
    No. R1
    1
    Figure US20030073706A1-20030417-C00804
    2
    Figure US20030073706A1-20030417-C00805
    3
    Figure US20030073706A1-20030417-C00806
    4
    Figure US20030073706A1-20030417-C00807
    5
    Figure US20030073706A1-20030417-C00808
    6
    Figure US20030073706A1-20030417-C00809
    7
    Figure US20030073706A1-20030417-C00810
    8
    Figure US20030073706A1-20030417-C00811
    9
    Figure US20030073706A1-20030417-C00812
    10
    Figure US20030073706A1-20030417-C00813
    11
    Figure US20030073706A1-20030417-C00814
    12
    Figure US20030073706A1-20030417-C00815
    13
    Figure US20030073706A1-20030417-C00816
    14
    Figure US20030073706A1-20030417-C00817
    15
    Figure US20030073706A1-20030417-C00818
    16
    Figure US20030073706A1-20030417-C00819
    17
    Figure US20030073706A1-20030417-C00820
    18
    Figure US20030073706A1-20030417-C00821
    19
    Figure US20030073706A1-20030417-C00822
    20
    Figure US20030073706A1-20030417-C00823
  • [0533]
    TABLE 49
    Figure US20030073706A1-20030417-C00824
    No. R1
    1
    Figure US20030073706A1-20030417-C00825
    2
    Figure US20030073706A1-20030417-C00826
    3
    Figure US20030073706A1-20030417-C00827
    4
    Figure US20030073706A1-20030417-C00828
    5
    Figure US20030073706A1-20030417-C00829
    6
    Figure US20030073706A1-20030417-C00830
    7
    Figure US20030073706A1-20030417-C00831
    8
    Figure US20030073706A1-20030417-C00832
    9
    Figure US20030073706A1-20030417-C00833
    10
    Figure US20030073706A1-20030417-C00834
    11
    Figure US20030073706A1-20030417-C00835
    12
    Figure US20030073706A1-20030417-C00836
    13
    Figure US20030073706A1-20030417-C00837
    14
    Figure US20030073706A1-20030417-C00838
    15
    Figure US20030073706A1-20030417-C00839
    16
    Figure US20030073706A1-20030417-C00840
    17
    Figure US20030073706A1-20030417-C00841
    18
    Figure US20030073706A1-20030417-C00842
    19
    Figure US20030073706A1-20030417-C00843
    20
    Figure US20030073706A1-20030417-C00844
  • [0534]
    TABLE 50
    Figure US20030073706A1-20030417-C00845
    No. R1
    1
    Figure US20030073706A1-20030417-C00846
    2
    Figure US20030073706A1-20030417-C00847
    3
    Figure US20030073706A1-20030417-C00848
    4
    Figure US20030073706A1-20030417-C00849
    5
    Figure US20030073706A1-20030417-C00850
    6
    Figure US20030073706A1-20030417-C00851
    7
    Figure US20030073706A1-20030417-C00852
    8
    Figure US20030073706A1-20030417-C00853
    9
    Figure US20030073706A1-20030417-C00854
    10
    Figure US20030073706A1-20030417-C00855
    11
    Figure US20030073706A1-20030417-C00856
    12
    Figure US20030073706A1-20030417-C00857
    13
    Figure US20030073706A1-20030417-C00858
    14
    Figure US20030073706A1-20030417-C00859
    15
    Figure US20030073706A1-20030417-C00860
    16
    Figure US20030073706A1-20030417-C00861
    17
    Figure US20030073706A1-20030417-C00862
    18
    Figure US20030073706A1-20030417-C00863
    19
    Figure US20030073706A1-20030417-C00864
    20
    Figure US20030073706A1-20030417-C00865
  • [0535]
    TABLE 51
    (I-M-2)
    Figure US20030073706A1-20030417-C00866
    No. R1 No. R1
    1
    Figure US20030073706A1-20030417-C00867
         		11
    Figure US20030073706A1-20030417-C00868
    2
    Figure US20030073706A1-20030417-C00869
         		12
    Figure US20030073706A1-20030417-C00870
    3
    Figure US20030073706A1-20030417-C00871
         		13
    Figure US20030073706A1-20030417-C00872
    4
    Figure US20030073706A1-20030417-C00873
         		14
    Figure US20030073706A1-20030417-C00874
    5
    Figure US20030073706A1-20030417-C00875
         		15
    Figure US20030073706A1-20030417-C00876
    6
    Figure US20030073706A1-20030417-C00877
         		16
    Figure US20030073706A1-20030417-C00878
    7
    Figure US20030073706A1-20030417-C00879
         		17
    Figure US20030073706A1-20030417-C00880
    8
    Figure US20030073706A1-20030417-C00881
         		18
    Figure US20030073706A1-20030417-C00882
    9
    Figure US20030073706A1-20030417-C00883
         		19
    Figure US20030073706A1-20030417-C00884
    10 
    Figure US20030073706A1-20030417-C00885
         		20
    Figure US20030073706A1-20030417-C00886
  • [0536]
    TABLE 52
    (I-M-3)
    Figure US20030073706A1-20030417-C00887
    No. R1 No. R1
    1
    Figure US20030073706A1-20030417-C00888
         		11
    Figure US20030073706A1-20030417-C00889
    2
    Figure US20030073706A1-20030417-C00890
         		12
    Figure US20030073706A1-20030417-C00891
    3
    Figure US20030073706A1-20030417-C00892
         		13
    Figure US20030073706A1-20030417-C00893
    4
    Figure US20030073706A1-20030417-C00894
         		14
    Figure US20030073706A1-20030417-C00895
    5
    Figure US20030073706A1-20030417-C00896
         		15
    Figure US20030073706A1-20030417-C00897
    6
    Figure US20030073706A1-20030417-C00898
         		16
    Figure US20030073706A1-20030417-C00899
    7
    Figure US20030073706A1-20030417-C00900
         		17
    Figure US20030073706A1-20030417-C00901
    8
    Figure US20030073706A1-20030417-C00902
         		18
    Figure US20030073706A1-20030417-C00903
    9
    Figure US20030073706A1-20030417-C00904
         		19
    Figure US20030073706A1-20030417-C00905
    10 
    Figure US20030073706A1-20030417-C00906
         		20
    Figure US20030073706A1-20030417-C00907
  • [0537]
    TABLE 53
    (I-N-1)
    Figure US20030073706A1-20030417-C00908
    No. R1 No. R1
    1
    Figure US20030073706A1-20030417-C00909
         		11
    Figure US20030073706A1-20030417-C00910
    2
    Figure US20030073706A1-20030417-C00911
         		12
    Figure US20030073706A1-20030417-C00912
    3
    Figure US20030073706A1-20030417-C00913
         		13
    Figure US20030073706A1-20030417-C00914
    4
    Figure US20030073706A1-20030417-C00915
         		14
    Figure US20030073706A1-20030417-C00916
    5
    Figure US20030073706A1-20030417-C00917
         		15
    Figure US20030073706A1-20030417-C00918
    6
    Figure US20030073706A1-20030417-C00919
         		16
    Figure US20030073706A1-20030417-C00920
    7
    Figure US20030073706A1-20030417-C00921
         		17
    Figure US20030073706A1-20030417-C00922
    8
    Figure US20030073706A1-20030417-C00923
         		18
    Figure US20030073706A1-20030417-C00924
    9
    Figure US20030073706A1-20030417-C00925
         		19
    Figure US20030073706A1-20030417-C00926
    10 
    Figure US20030073706A1-20030417-C00927
         		20
    Figure US20030073706A1-20030417-C00928
  • [0538]
    TABLE 54
    (I-N-2)
    Figure US20030073706A1-20030417-C00929
    No. R1 No. R1
    1
    Figure US20030073706A1-20030417-C00930
         		11
    Figure US20030073706A1-20030417-C00931
    2
    Figure US20030073706A1-20030417-C00932
         		12
    Figure US20030073706A1-20030417-C00933
    3
    Figure US20030073706A1-20030417-C00934
         		13
    Figure US20030073706A1-20030417-C00935
    4
    Figure US20030073706A1-20030417-C00936
         		14
    Figure US20030073706A1-20030417-C00937
    5
    Figure US20030073706A1-20030417-C00938
         		15
    Figure US20030073706A1-20030417-C00939
    6
    Figure US20030073706A1-20030417-C00940
         		16
    Figure US20030073706A1-20030417-C00941
    7
    Figure US20030073706A1-20030417-C00942
         		17
    Figure US20030073706A1-20030417-C00943
    8
    Figure US20030073706A1-20030417-C00944
         		18
    Figure US20030073706A1-20030417-C00945
    9
    Figure US20030073706A1-20030417-C00946
         		19
    Figure US20030073706A1-20030417-C00947
    10 
    Figure US20030073706A1-20030417-C00948
         		20
    Figure US20030073706A1-20030417-C00949
  • [0539]
    TABLE 55
    (I-N-3)
    Figure US20030073706A1-20030417-C00950
    No. R1 No. R1
    1
    Figure US20030073706A1-20030417-C00951
         		11
    Figure US20030073706A1-20030417-C00952
    2
    Figure US20030073706A1-20030417-C00953
         		12
    Figure US20030073706A1-20030417-C00954
    3
    Figure US20030073706A1-20030417-C00955
         		13
    Figure US20030073706A1-20030417-C00956
    4
    Figure US20030073706A1-20030417-C00957
         		14
    Figure US20030073706A1-20030417-C00958
    5
    Figure US20030073706A1-20030417-C00959
         		15
    Figure US20030073706A1-20030417-C00960
    6
    Figure US20030073706A1-20030417-C00961
         		16
    Figure US20030073706A1-20030417-C00962
    7
    Figure US20030073706A1-20030417-C00963
         		17
    Figure US20030073706A1-20030417-C00964
    8
    Figure US20030073706A1-20030417-C00965
         		18
    Figure US20030073706A1-20030417-C00966
    9
    Figure US20030073706A1-20030417-C00967
         		19
    Figure US20030073706A1-20030417-C00968
    10 
    Figure US20030073706A1-20030417-C00969
         		20
    Figure US20030073706A1-20030417-C00970
  • [0540]
    TABLE 56
    (I-N-4)
    Figure US20030073706A1-20030417-C00971
    No. R1 No. R1
    1
    Figure US20030073706A1-20030417-C00972
         		11
    Figure US20030073706A1-20030417-C00973
    2
    Figure US20030073706A1-20030417-C00974
         		12
    Figure US20030073706A1-20030417-C00975
    3
    Figure US20030073706A1-20030417-C00976
         		13
    Figure US20030073706A1-20030417-C00977
    4
    Figure US20030073706A1-20030417-C00978
         		14
    Figure US20030073706A1-20030417-C00979
    5
    Figure US20030073706A1-20030417-C00980
         		15
    Figure US20030073706A1-20030417-C00981
    6
    Figure US20030073706A1-20030417-C00982
         		16
    Figure US20030073706A1-20030417-C00983
    7
    Figure US20030073706A1-20030417-C00984
         		17
    Figure US20030073706A1-20030417-C00985
    8
    Figure US20030073706A1-20030417-C00986
         		18
    Figure US20030073706A1-20030417-C00987
    9
    Figure US20030073706A1-20030417-C00988
         		19
    Figure US20030073706A1-20030417-C00989
    10 
    Figure US20030073706A1-20030417-C00990
         		20
    Figure US20030073706A1-20030417-C00991
  • [0541]
    TABLE 57
    (I-O-1)
    Figure US20030073706A1-20030417-C00992
    No. R1 No. R1
    1
    Figure US20030073706A1-20030417-C00993
         		11
    Figure US20030073706A1-20030417-C00994
    2
    Figure US20030073706A1-20030417-C00995
         		12
    Figure US20030073706A1-20030417-C00996
    3
    Figure US20030073706A1-20030417-C00997
         		13
    Figure US20030073706A1-20030417-C00998
    4
    Figure US20030073706A1-20030417-C00999
         		14
    Figure US20030073706A1-20030417-C01000
    5
    Figure US20030073706A1-20030417-C01001
         		15
    Figure US20030073706A1-20030417-C01002
    6
    Figure US20030073706A1-20030417-C01003
         		16
    Figure US20030073706A1-20030417-C01004
    7
    Figure US20030073706A1-20030417-C01005
         		17
    Figure US20030073706A1-20030417-C01006
    8
    Figure US20030073706A1-20030417-C01007
         		18
    Figure US20030073706A1-20030417-C01008
    9
    Figure US20030073706A1-20030417-C01009
         		19
    Figure US20030073706A1-20030417-C01010
    10 
    Figure US20030073706A1-20030417-C01011
         		20
    Figure US20030073706A1-20030417-C01012
  • [0542]
    TABLE 58
    (I-O-2)
    Figure US20030073706A1-20030417-C01013
    No. R1 No. R1
    1
    Figure US20030073706A1-20030417-C01014
         		11
    Figure US20030073706A1-20030417-C01015
    2
    Figure US20030073706A1-20030417-C01016
         		12
    Figure US20030073706A1-20030417-C01017
    3
    Figure US20030073706A1-20030417-C01018
         		13
    Figure US20030073706A1-20030417-C01019
    4
    Figure US20030073706A1-20030417-C01020
         		14
    Figure US20030073706A1-20030417-C01021
    5
    Figure US20030073706A1-20030417-C01022
         		15
    Figure US20030073706A1-20030417-C01023
    6
    Figure US20030073706A1-20030417-C01024
         		16
    Figure US20030073706A1-20030417-C01025
    7
    Figure US20030073706A1-20030417-C01026
         		17
    Figure US20030073706A1-20030417-C01027
    8
    Figure US20030073706A1-20030417-C01028
         		18
    Figure US20030073706A1-20030417-C01029
    9
    Figure US20030073706A1-20030417-C01030
         		19
    Figure US20030073706A1-20030417-C01031
    10 
    Figure US20030073706A1-20030417-C01032
         		20
    Figure US20030073706A1-20030417-C01033
  • [0543]
    TABLE 59
    (I-O-3)
    Figure US20030073706A1-20030417-C01034
    No. R1 No. R1
    1
    Figure US20030073706A1-20030417-C01035
         		11
    Figure US20030073706A1-20030417-C01036
    2
    Figure US20030073706A1-20030417-C01037
         		12
    Figure US20030073706A1-20030417-C01038
    3
    Figure US20030073706A1-20030417-C01039
         		13
    Figure US20030073706A1-20030417-C01040
    4
    Figure US20030073706A1-20030417-C01041
         		14
    Figure US20030073706A1-20030417-C01042
    5
    Figure US20030073706A1-20030417-C01043
         		15
    Figure US20030073706A1-20030417-C01044
    6
    Figure US20030073706A1-20030417-C01045
         		16
    Figure US20030073706A1-20030417-C01046
    7
    Figure US20030073706A1-20030417-C01047
         		17
    Figure US20030073706A1-20030417-C01048
    8
    Figure US20030073706A1-20030417-C01049
         		18
    Figure US20030073706A1-20030417-C01050
    9
    Figure US20030073706A1-20030417-C01051
         		19
    Figure US20030073706A1-20030417-C01052
    10 
    Figure US20030073706A1-20030417-C01053
         		20
    Figure US20030073706A1-20030417-C01054
  • [0544]
    TABLE 60
    (I-P-1)
    Figure US20030073706A1-20030417-C01055
    No. R1 No. R1
    1
    Figure US20030073706A1-20030417-C01056
         		11
    Figure US20030073706A1-20030417-C01057
    2
    Figure US20030073706A1-20030417-C01058
         		12
    Figure US20030073706A1-20030417-C01059
    3
    Figure US20030073706A1-20030417-C01060
         		13
    Figure US20030073706A1-20030417-C01061
    4
    Figure US20030073706A1-20030417-C01062
         		14
    Figure US20030073706A1-20030417-C01063
    5
    Figure US20030073706A1-20030417-C01064
         		15
    Figure US20030073706A1-20030417-C01065
    6
    Figure US20030073706A1-20030417-C01066
         		16
    Figure US20030073706A1-20030417-C01067
    7
    Figure US20030073706A1-20030417-C01068
         		17
    Figure US20030073706A1-20030417-C01069
    8
    Figure US20030073706A1-20030417-C01070
         		18
    Figure US20030073706A1-20030417-C01071
    9
    Figure US20030073706A1-20030417-C01072
         		19
    Figure US20030073706A1-20030417-C01073
    10 
    Figure US20030073706A1-20030417-C01074
         		20
    Figure US20030073706A1-20030417-C01075
  • [0545]
    TABLE 61
    (I-P-2)
    Figure US20030073706A1-20030417-C01076
    No. R1
    1
    Figure US20030073706A1-20030417-C01077
    2
    Figure US20030073706A1-20030417-C01078
    3
    Figure US20030073706A1-20030417-C01079
    4
    Figure US20030073706A1-20030417-C01080
    5
    Figure US20030073706A1-20030417-C01081
    6
    Figure US20030073706A1-20030417-C01082
    7
    Figure US20030073706A1-20030417-C01083
    8
    Figure US20030073706A1-20030417-C01084
    9
    Figure US20030073706A1-20030417-C01085
    10
    Figure US20030073706A1-20030417-C01086
    11
    Figure US20030073706A1-20030417-C01087
    12
    Figure US20030073706A1-20030417-C01088
    13
    Figure US20030073706A1-20030417-C01089
    14
    Figure US20030073706A1-20030417-C01090
    15
    Figure US20030073706A1-20030417-C01091
    16
    Figure US20030073706A1-20030417-C01092
    17
    Figure US20030073706A1-20030417-C01093
    18
    Figure US20030073706A1-20030417-C01094
    19
    Figure US20030073706A1-20030417-C01095
    20
    Figure US20030073706A1-20030417-C01096
  • [0546]
    TABLE 62
    (I-P-3)
    Figure US20030073706A1-20030417-C01097
    No. R1
    1
    Figure US20030073706A1-20030417-C01098
    2
    Figure US20030073706A1-20030417-C01099
    3
    Figure US20030073706A1-20030417-C01100
    4
    Figure US20030073706A1-20030417-C01101
    5
    Figure US20030073706A1-20030417-C01102
    6
    Figure US20030073706A1-20030417-C01103
    7
    Figure US20030073706A1-20030417-C01104
    8
    Figure US20030073706A1-20030417-C01105
    9
    Figure US20030073706A1-20030417-C01106
    10
    Figure US20030073706A1-20030417-C01107
    11
    Figure US20030073706A1-20030417-C01108
    12
    Figure US20030073706A1-20030417-C01109
    13
    Figure US20030073706A1-20030417-C01110
    14
    Figure US20030073706A1-20030417-C01111
    15
    Figure US20030073706A1-20030417-C01112
    16
    Figure US20030073706A1-20030417-C01113
    17
    Figure US20030073706A1-20030417-C01114
    18
    Figure US20030073706A1-20030417-C01115
    19
    Figure US20030073706A1-20030417-C01116
    20
    Figure US20030073706A1-20030417-C01117
  • [0547]
    TABLE 63
    (I-A-1)
    Figure US20030073706A1-20030417-C01118
    No. R1
    21
    Figure US20030073706A1-20030417-C01119
    22
    Figure US20030073706A1-20030417-C01120
    23
    Figure US20030073706A1-20030417-C01121
    24
    Figure US20030073706A1-20030417-C01122
    25
    Figure US20030073706A1-20030417-C01123
    26
    Figure US20030073706A1-20030417-C01124
    27
    Figure US20030073706A1-20030417-C01125
    28
    Figure US20030073706A1-20030417-C01126
    29
    Figure US20030073706A1-20030417-C01127
    30
    Figure US20030073706A1-20030417-C01128
    31
    Figure US20030073706A1-20030417-C01129
    32
    Figure US20030073706A1-20030417-C01130
    33
    Figure US20030073706A1-20030417-C01131
    34
    Figure US20030073706A1-20030417-C01132
    35
    Figure US20030073706A1-20030417-C01133
    36
    Figure US20030073706A1-20030417-C01134
    37
    Figure US20030073706A1-20030417-C01135
    38
    Figure US20030073706A1-20030417-C01136
    39
    Figure US20030073706A1-20030417-C01137
    40
    Figure US20030073706A1-20030417-C01138
    41
    Figure US20030073706A1-20030417-C01139
    42
    Figure US20030073706A1-20030417-C01140
    43
    Figure US20030073706A1-20030417-C01141
    44
    Figure US20030073706A1-20030417-C01142
  • [0548]
    TABLE 64
    (I-A-1)
    Figure US20030073706A1-20030417-C01143
    No. R1
    45
    Figure US20030073706A1-20030417-C01144
    46
    Figure US20030073706A1-20030417-C01145
    47
    Figure US20030073706A1-20030417-C01146
    48
    Figure US20030073706A1-20030417-C01147
    49
    Figure US20030073706A1-20030417-C01148
    50
    Figure US20030073706A1-20030417-C01149
    51
    Figure US20030073706A1-20030417-C01150
    52
    Figure US20030073706A1-20030417-C01151
    53
    Figure US20030073706A1-20030417-C01152
    54
    Figure US20030073706A1-20030417-C01153
    55
    Figure US20030073706A1-20030417-C01154
    56
    Figure US20030073706A1-20030417-C01155
    57
    Figure US20030073706A1-20030417-C01156
    58
    Figure US20030073706A1-20030417-C01157
    59
    Figure US20030073706A1-20030417-C01158
    60
    Figure US20030073706A1-20030417-C01159
    61
    Figure US20030073706A1-20030417-C01160
    62
    Figure US20030073706A1-20030417-C01161
    63
    Figure US20030073706A1-20030417-C01162
    64
    Figure US20030073706A1-20030417-C01163
    65
    Figure US20030073706A1-20030417-C01164
    66
    Figure US20030073706A1-20030417-C01165
    67
    Figure US20030073706A1-20030417-C01166
  • [0549]
    TABLE 65
    (I-A-2)
    Figure US20030073706A1-20030417-C01167
    No. R1
    21
    Figure US20030073706A1-20030417-C01168
    22
    Figure US20030073706A1-20030417-C01169
    23
    Figure US20030073706A1-20030417-C01170
    24
    Figure US20030073706A1-20030417-C01171
    25
    Figure US20030073706A1-20030417-C01172
    26
    Figure US20030073706A1-20030417-C01173
    27
    Figure US20030073706A1-20030417-C01174
    28
    Figure US20030073706A1-20030417-C01175
    29
    Figure US20030073706A1-20030417-C01176
    30
    Figure US20030073706A1-20030417-C01177
    31
    Figure US20030073706A1-20030417-C01178
    32
    Figure US20030073706A1-20030417-C01179
    33
    Figure US20030073706A1-20030417-C01180
    34
    Figure US20030073706A1-20030417-C01181
    35
    Figure US20030073706A1-20030417-C01182
    36
    Figure US20030073706A1-20030417-C01183
    37
    Figure US20030073706A1-20030417-C01184
    38
    Figure US20030073706A1-20030417-C01185
    39
    Figure US20030073706A1-20030417-C01186
    40
    Figure US20030073706A1-20030417-C01187
    41
    Figure US20030073706A1-20030417-C01188
    42
    Figure US20030073706A1-20030417-C01189
    43
    Figure US20030073706A1-20030417-C01190
    44
    Figure US20030073706A1-20030417-C01191
  • [0550]
    TABLE 66
    (I-A-2)
    Figure US20030073706A1-20030417-C01192
    No. R1
    45
    Figure US20030073706A1-20030417-C01193
    46
    Figure US20030073706A1-20030417-C01194
    47
    Figure US20030073706A1-20030417-C01195
    48
    Figure US20030073706A1-20030417-C01196
    49
    Figure US20030073706A1-20030417-C01197
    50
    Figure US20030073706A1-20030417-C01198
    51
    Figure US20030073706A1-20030417-C01199
    52
    Figure US20030073706A1-20030417-C01200
    53
    Figure US20030073706A1-20030417-C01201
    54
    Figure US20030073706A1-20030417-C01202
    55
    Figure US20030073706A1-20030417-C01203
    56
    Figure US20030073706A1-20030417-C01204
    57
    Figure US20030073706A1-20030417-C01205
    58
    Figure US20030073706A1-20030417-C01206
    59
    Figure US20030073706A1-20030417-C01207
    60
    Figure US20030073706A1-20030417-C01208
    61
    Figure US20030073706A1-20030417-C01209
    62
    Figure US20030073706A1-20030417-C01210
    63
    Figure US20030073706A1-20030417-C01211
    64
    Figure US20030073706A1-20030417-C01212
    65
    Figure US20030073706A1-20030417-C01213
    66
    Figure US20030073706A1-20030417-C01214
    67
    Figure US20030073706A1-20030417-C01215
  • [0551]
    TABLE 67
    (I-A-3)
    Figure US20030073706A1-20030417-C01216
    No. R1
    21
    Figure US20030073706A1-20030417-C01217
    22
    Figure US20030073706A1-20030417-C01218
    23
    Figure US20030073706A1-20030417-C01219
    24
    Figure US20030073706A1-20030417-C01220
    25
    Figure US20030073706A1-20030417-C01221
    26
    Figure US20030073706A1-20030417-C01222
    27
    Figure US20030073706A1-20030417-C01223
    28
    Figure US20030073706A1-20030417-C01224
    29
    Figure US20030073706A1-20030417-C01225
    30
    Figure US20030073706A1-20030417-C01226
    31
    Figure US20030073706A1-20030417-C01227
    32
    Figure US20030073706A1-20030417-C01228
    33
    Figure US20030073706A1-20030417-C01229
    34
    Figure US20030073706A1-20030417-C01230
    35
    Figure US20030073706A1-20030417-C01231
    36
    Figure US20030073706A1-20030417-C01232
    37
    Figure US20030073706A1-20030417-C01233
    38
    Figure US20030073706A1-20030417-C01234
    39
    Figure US20030073706A1-20030417-C01235
    40
    Figure US20030073706A1-20030417-C01236
    41
    Figure US20030073706A1-20030417-C01237
    42
    Figure US20030073706A1-20030417-C01238
    43
    Figure US20030073706A1-20030417-C01239
    44
    Figure US20030073706A1-20030417-C01240
  • [0552]
    TABLE 68
    (I-A-3)
    Figure US20030073706A1-20030417-C01241
    No. R1
    45
    Figure US20030073706A1-20030417-C01242
    46
    Figure US20030073706A1-20030417-C01243
    47
    Figure US20030073706A1-20030417-C01244
    48
    Figure US20030073706A1-20030417-C01245
    49
    Figure US20030073706A1-20030417-C01246
    50
    Figure US20030073706A1-20030417-C01247
    51
    Figure US20030073706A1-20030417-C01248
    52
    Figure US20030073706A1-20030417-C01249
    53
    Figure US20030073706A1-20030417-C01250
    54
    Figure US20030073706A1-20030417-C01251
    55
    Figure US20030073706A1-20030417-C01252
    56
    Figure US20030073706A1-20030417-C01253
    57
    Figure US20030073706A1-20030417-C01254
    58
    Figure US20030073706A1-20030417-C01255
    59
    Figure US20030073706A1-20030417-C01256
    60
    Figure US20030073706A1-20030417-C01257
    61
    Figure US20030073706A1-20030417-C01258
    62
    Figure US20030073706A1-20030417-C01259
    63
    Figure US20030073706A1-20030417-C01260
    64
    Figure US20030073706A1-20030417-C01261
    65
    Figure US20030073706A1-20030417-C01262
    66
    Figure US20030073706A1-20030417-C01263
    67
    Figure US20030073706A1-20030417-C01264
  • [0553]
    TABLE 69
    (I-A-4)
    Figure US20030073706A1-20030417-C01265
    No. R1
    21
    Figure US20030073706A1-20030417-C01266
    22
    Figure US20030073706A1-20030417-C01267
    23
    Figure US20030073706A1-20030417-C01268
    24
    Figure US20030073706A1-20030417-C01269
    25
    Figure US20030073706A1-20030417-C01270
    26
    Figure US20030073706A1-20030417-C01271
    27
    Figure US20030073706A1-20030417-C01272
    28
    Figure US20030073706A1-20030417-C01273
    29
    Figure US20030073706A1-20030417-C01274
    30
    Figure US20030073706A1-20030417-C01275
    31
    Figure US20030073706A1-20030417-C01276
    32
    Figure US20030073706A1-20030417-C01277
    33
    Figure US20030073706A1-20030417-C01278
    34
    Figure US20030073706A1-20030417-C01279
    35
    Figure US20030073706A1-20030417-C01280
    36
    Figure US20030073706A1-20030417-C01281
    37
    Figure US20030073706A1-20030417-C01282
    38
    Figure US20030073706A1-20030417-C01283
    39
    Figure US20030073706A1-20030417-C01284
    40
    Figure US20030073706A1-20030417-C01285
    41
    Figure US20030073706A1-20030417-C01286
    42
    Figure US20030073706A1-20030417-C01287
    43
    Figure US20030073706A1-20030417-C01288
    44
    Figure US20030073706A1-20030417-C01289
  • [0554]
    TABLE 70
    (I-A-4)
    Figure US20030073706A1-20030417-C01290
    No. R1
    45
    Figure US20030073706A1-20030417-C01291
    46
    Figure US20030073706A1-20030417-C01292
    47
    Figure US20030073706A1-20030417-C01293
    48
    Figure US20030073706A1-20030417-C01294
    49
    Figure US20030073706A1-20030417-C01295
    50
    Figure US20030073706A1-20030417-C01296
    51
    Figure US20030073706A1-20030417-C01297
    52
    Figure US20030073706A1-20030417-C01298
    53
    Figure US20030073706A1-20030417-C01299
    54
    Figure US20030073706A1-20030417-C01300
    55
    Figure US20030073706A1-20030417-C01301
    56
    Figure US20030073706A1-20030417-C01302
    57
    Figure US20030073706A1-20030417-C01303
    58
    Figure US20030073706A1-20030417-C01304
    59
    Figure US20030073706A1-20030417-C01305
    60
    Figure US20030073706A1-20030417-C01306
    61
    Figure US20030073706A1-20030417-C01307
    62
    Figure US20030073706A1-20030417-C01308
    63
    Figure US20030073706A1-20030417-C01309
    64
    Figure US20030073706A1-20030417-C01310
    65
    Figure US20030073706A1-20030417-C01311
    66
    Figure US20030073706A1-20030417-C01312
    67
    Figure US20030073706A1-20030417-C01313
  • [0555]
    TABLE 71
    (I-N-1)
    Figure US20030073706A1-20030417-C01314
    No. R1 No. R1
    21
    Figure US20030073706A1-20030417-C01315
         		33
    Figure US20030073706A1-20030417-C01316
    22
    Figure US20030073706A1-20030417-C01317
         		34
    Figure US20030073706A1-20030417-C01318
    23
    Figure US20030073706A1-20030417-C01319
         		35
    Figure US20030073706A1-20030417-C01320
    24
    Figure US20030073706A1-20030417-C01321
         		36
    Figure US20030073706A1-20030417-C01322
    25
    Figure US20030073706A1-20030417-C01323
         		37
    Figure US20030073706A1-20030417-C01324
    26
    Figure US20030073706A1-20030417-C01325
         		38
    Figure US20030073706A1-20030417-C01326
    27
    Figure US20030073706A1-20030417-C01327
         		39
    Figure US20030073706A1-20030417-C01328
    28
    Figure US20030073706A1-20030417-C01329
         		40
    Figure US20030073706A1-20030417-C01330
    29
    Figure US20030073706A1-20030417-C01331
         		41
    Figure US20030073706A1-20030417-C01332
    30
    Figure US20030073706A1-20030417-C01333
         		42
    Figure US20030073706A1-20030417-C01334
    31
    Figure US20030073706A1-20030417-C01335
         		43
    Figure US20030073706A1-20030417-C01336
    32
    Figure US20030073706A1-20030417-C01337
         		44
    Figure US20030073706A1-20030417-C01338
  • [0556]
    TABLE 72
    (I-N-1)
    Figure US20030073706A1-20030417-C01339
    No. R1 No. R1
    45
    Figure US20030073706A1-20030417-C01340
         		57
    Figure US20030073706A1-20030417-C01341
    46
    Figure US20030073706A1-20030417-C01342
         		58
    Figure US20030073706A1-20030417-C01343
    47
    Figure US20030073706A1-20030417-C01344
         		59
    Figure US20030073706A1-20030417-C01345
    48
    Figure US20030073706A1-20030417-C01346
         		60
    Figure US20030073706A1-20030417-C01347
    49
    Figure US20030073706A1-20030417-C01348
         		61
    Figure US20030073706A1-20030417-C01349
    50
    Figure US20030073706A1-20030417-C01350
         		62
    Figure US20030073706A1-20030417-C01351
    51
    Figure US20030073706A1-20030417-C01352
         		63
    Figure US20030073706A1-20030417-C01353
    52
    Figure US20030073706A1-20030417-C01354
         		64
    Figure US20030073706A1-20030417-C01355
    53
    Figure US20030073706A1-20030417-C01356
         		65
    Figure US20030073706A1-20030417-C01357
    54
    Figure US20030073706A1-20030417-C01358
         		66
    Figure US20030073706A1-20030417-C01359
    55
    Figure US20030073706A1-20030417-C01360
         		67
    Figure US20030073706A1-20030417-C01361
    56
    Figure US20030073706A1-20030417-C01362
  • [0557]
    TABLE 73
    (I-N-2)
    Figure US20030073706A1-20030417-C01363
    No. R1 No. R1
    21
    Figure US20030073706A1-20030417-C01364
         		33
    Figure US20030073706A1-20030417-C01365
    22
    Figure US20030073706A1-20030417-C01366
         		34
    Figure US20030073706A1-20030417-C01367
    23
    Figure US20030073706A1-20030417-C01368
         		35
    Figure US20030073706A1-20030417-C01369
    24
    Figure US20030073706A1-20030417-C01370
         		36
    Figure US20030073706A1-20030417-C01371
    25
    Figure US20030073706A1-20030417-C01372
         		37
    Figure US20030073706A1-20030417-C01373
    26
    Figure US20030073706A1-20030417-C01374
         		38
    Figure US20030073706A1-20030417-C01375
    27
    Figure US20030073706A1-20030417-C01376
         		39
    Figure US20030073706A1-20030417-C01377
    28
    Figure US20030073706A1-20030417-C01378
         		40
    Figure US20030073706A1-20030417-C01379
    29
    Figure US20030073706A1-20030417-C01380
         		41
    Figure US20030073706A1-20030417-C01381
    30
    Figure US20030073706A1-20030417-C01382
         		42
    Figure US20030073706A1-20030417-C01383
    31
    Figure US20030073706A1-20030417-C01384
         		43
    Figure US20030073706A1-20030417-C01385
    32
    Figure US20030073706A1-20030417-C01386
         		44
    Figure US20030073706A1-20030417-C01387
  • [0558]
    TABLE 74
    (I-N-2)
    Figure US20030073706A1-20030417-C01388
    No. R1 No. R1
    45
    Figure US20030073706A1-20030417-C01389
         		57
    Figure US20030073706A1-20030417-C01390
    46
    Figure US20030073706A1-20030417-C01391
         		58
    Figure US20030073706A1-20030417-C01392
    47
    Figure US20030073706A1-20030417-C01393
         		59
    Figure US20030073706A1-20030417-C01394
    48
    Figure US20030073706A1-20030417-C01395
         		60
    Figure US20030073706A1-20030417-C01396
    49
    Figure US20030073706A1-20030417-C01397
         		61
    Figure US20030073706A1-20030417-C01398
    50
    Figure US20030073706A1-20030417-C01399
         		62
    Figure US20030073706A1-20030417-C01400
    51
    Figure US20030073706A1-20030417-C01401
         		63
    Figure US20030073706A1-20030417-C01402
    52
    Figure US20030073706A1-20030417-C01403
         		64
    Figure US20030073706A1-20030417-C01404
    53
    Figure US20030073706A1-20030417-C01405
         		65
    Figure US20030073706A1-20030417-C01406
    54
    Figure US20030073706A1-20030417-C01407
         		66
    Figure US20030073706A1-20030417-C01408
    55
    Figure US20030073706A1-20030417-C01409
         		67
    Figure US20030073706A1-20030417-C01410
    56
    Figure US20030073706A1-20030417-C01411
  • [0559]
    TABLE 75
    (I-N-3)
    Figure US20030073706A1-20030417-C01412
    No. R1 No. R1
    21
    Figure US20030073706A1-20030417-C01413
         		33
    Figure US20030073706A1-20030417-C01414
    22
    Figure US20030073706A1-20030417-C01415
         		34
    Figure US20030073706A1-20030417-C01416
    23
    Figure US20030073706A1-20030417-C01417
         		35
    Figure US20030073706A1-20030417-C01418
    24
    Figure US20030073706A1-20030417-C01419
         		36
    Figure US20030073706A1-20030417-C01420
    25
    Figure US20030073706A1-20030417-C01421
         		37
    Figure US20030073706A1-20030417-C01422
    26
    Figure US20030073706A1-20030417-C01423
         		38
    Figure US20030073706A1-20030417-C01424
    27
    Figure US20030073706A1-20030417-C01425
         		39
    Figure US20030073706A1-20030417-C01426
    28
    Figure US20030073706A1-20030417-C01427
         		40
    Figure US20030073706A1-20030417-C01428
    29
    Figure US20030073706A1-20030417-C01429
         		41
    Figure US20030073706A1-20030417-C01430
    30
    Figure US20030073706A1-20030417-C01431
         		42
    Figure US20030073706A1-20030417-C01432
    31
    Figure US20030073706A1-20030417-C01433
         		43
    Figure US20030073706A1-20030417-C01434
    32
    Figure US20030073706A1-20030417-C01435
         		44
    Figure US20030073706A1-20030417-C01436
  • [0560]
    TABLE 76
    (I-N-3)
    Figure US20030073706A1-20030417-C01437
    No. R1 No. R1
    45
    Figure US20030073706A1-20030417-C01438
         		57
    Figure US20030073706A1-20030417-C01439
    46
    Figure US20030073706A1-20030417-C01440
         		58
    Figure US20030073706A1-20030417-C01441
    47
    Figure US20030073706A1-20030417-C01442
         		59
    Figure US20030073706A1-20030417-C01443
    48
    Figure US20030073706A1-20030417-C01444
         		60
    Figure US20030073706A1-20030417-C01445
    49
    Figure US20030073706A1-20030417-C01446
         		61
    Figure US20030073706A1-20030417-C01447
    50
    Figure US20030073706A1-20030417-C01448
         		62
    Figure US20030073706A1-20030417-C01449
    51
    Figure US20030073706A1-20030417-C01450
         		63
    Figure US20030073706A1-20030417-C01451
    52
    Figure US20030073706A1-20030417-C01452
         		64
    Figure US20030073706A1-20030417-C01453
    53
    Figure US20030073706A1-20030417-C01454
         		65
    Figure US20030073706A1-20030417-C01455
    54
    Figure US20030073706A1-20030417-C01456
         		66
    Figure US20030073706A1-20030417-C01457
    55
    Figure US20030073706A1-20030417-C01458
         		67
    Figure US20030073706A1-20030417-C01459
    56
    Figure US20030073706A1-20030417-C01460
  • [0561]
    TABLE 77
    (I-N-4)
    Figure US20030073706A1-20030417-C01461
    No. R1 No. R1
    21
    Figure US20030073706A1-20030417-C01462
         		33
    Figure US20030073706A1-20030417-C01463
    22
    Figure US20030073706A1-20030417-C01464
         		34
    Figure US20030073706A1-20030417-C01465
    23
    Figure US20030073706A1-20030417-C01466
         		35
    Figure US20030073706A1-20030417-C01467
    24
    Figure US20030073706A1-20030417-C01468
         		36
    Figure US20030073706A1-20030417-C01469
    25
    Figure US20030073706A1-20030417-C01470
         		37
    Figure US20030073706A1-20030417-C01471
    26
    Figure US20030073706A1-20030417-C01472
         		38
    Figure US20030073706A1-20030417-C01473
    27
    Figure US20030073706A1-20030417-C01474
         		39
    Figure US20030073706A1-20030417-C01475
    28
    Figure US20030073706A1-20030417-C01476
         		40
    Figure US20030073706A1-20030417-C01477
    29
    Figure US20030073706A1-20030417-C01478
         		41
    Figure US20030073706A1-20030417-C01479
    30
    Figure US20030073706A1-20030417-C01480
         		42
    Figure US20030073706A1-20030417-C01481
    31
    Figure US20030073706A1-20030417-C01482
         		43
    Figure US20030073706A1-20030417-C01483
    32
    Figure US20030073706A1-20030417-C01484
         		44
    Figure US20030073706A1-20030417-C01485
  • [0562]
    TABLE 78
    (I-N-4)
    Figure US20030073706A1-20030417-C01486
    No. R1 No. R1
    45
    Figure US20030073706A1-20030417-C01487
         		57
    Figure US20030073706A1-20030417-C01488
    46
    Figure US20030073706A1-20030417-C01489
         		58
    Figure US20030073706A1-20030417-C01490
    47
    Figure US20030073706A1-20030417-C01491
         		59
    Figure US20030073706A1-20030417-C01492
    48
    Figure US20030073706A1-20030417-C01493
         		60
    Figure US20030073706A1-20030417-C01494
    49
    Figure US20030073706A1-20030417-C01495
         		61
    Figure US20030073706A1-20030417-C01496
    50
    Figure US20030073706A1-20030417-C01497
         		62
    Figure US20030073706A1-20030417-C01498
    51
    Figure US20030073706A1-20030417-C01499
         		63
    Figure US20030073706A1-20030417-C01500
    52
    Figure US20030073706A1-20030417-C01501
         		64
    Figure US20030073706A1-20030417-C01502
    53
    Figure US20030073706A1-20030417-C01503
         		65
    Figure US20030073706A1-20030417-C01504
    54
    Figure US20030073706A1-20030417-C01505
         		66
    Figure US20030073706A1-20030417-C01506
    55
    Figure US20030073706A1-20030417-C01507
         		67
    Figure US20030073706A1-20030417-C01508
    56
    Figure US20030073706A1-20030417-C01509
  • [Methods for Preparation of the Compounds of the Present Invention][0563]
  • The compounds of the present invention of the formula (I) of the present invention may be prepared by the following methods or the methods described in examples. [0564]
  • Among the compounds of the present invention of the formula (I), the compounds of the present invention of the formula (I-1) [0565]
    Figure US20030073706A1-20030417-C01510
  • (wherein all the symbols are the same meanings as hereinbefore described.) may be prepared by the known methods or the following methods [1]˜14]. [0566]
  • [1] The compounds of the present invention of the formula (I-1) in which n is 1 or 2 may be also prepared by the following methods (a)˜(b). [0567]
  • (a) The compounds of the present invention of the formula (I-1) in which n is 1, i.e., the compounds of the present invention of the formula (I-1-1a) [0568]
    Figure US20030073706A1-20030417-C01511
  • (wherein all the symbols are the same meanings as hereinbefore described.) may be prepared by oxidation of the compounds of the formula (I-1-1c) [0569]
    Figure US20030073706A1-20030417-C01512
  • (wherein all the symbols are the same meanings as hereinbefore described.) [0570]
  • The above oxidation is known per se. For example, it may be carried out in an adequate organic solvent (e.g., methylene chloride, chloroform, benzene, hexane, t-butyl alcohol etc.), in the presence of an 1-1.2 equivalent amount of oxidizing agent (e.g., hydrogen peroxide, sodium periodate, acyl nitrite, sodium perborate, peracid (e.g., 3-chloroperbenzoic acid, peracetic acid etc.), potassium peroxymonosulfate, potassium permanganate, chromic acid etc.), at -40° C.˜0° C. [0571]
  • (b) The compounds of the present invention of the formula (I-1) in which n is 2, i.e., the compounds of the present invention of the formula (I-1-1b) [0572]
    Figure US20030073706A1-20030417-C01513
  • (wherein all the symbols are the same meanings as hereinbefore described.) may be prepared by oxidation of the said the compounds of the formula (I-1-1c). [0573]
  • The above oxidation is known per se. For example, it may be carried out in an adequate organic solvent (e.g., methylene chloride, chloroform, benzene, hexane, t-butyl alcohol etc.), in the presence of an excess amount of oxidizing agent (e.g., hydrogen peroxide, sodium periodate, acyl nitrite, sodium perborate, peracid (e.g., 3-chloroperbenzoic acid, peracetic acid etc.), potassium peroxymonosulfate, potassium permanganate, chromic acid etc.), at 20° C.˜60° C. [0574]
  • [2] The compounds of the present invention of the formula (I-1) in which at least one of R[0575] 1 (s) is a substituted oxy group or a group containing substituted oxy, i.e., the compounds of the present invention of the formula (I-1-2)
    Figure US20030073706A1-20030417-C01514
  • (wherein, R[0576] 1-1-2 is the same meanings as hereinbefore described for R1, provided that at least one of R R1-1-2(s) is a substituted oxy group or a group containing substituted oxy and the other symbols are the same meaning as hereinbefore described.)
  • may be also prepared by the following methods (a)˜(b). [0577]
  • (a) The compounds of the present invention of the formula (I-1-2) may be prepared by etherification of the compounds of the formula (I-1 -2) in which at least one of R[0578] 1(s) is a hydroxy or a group containing hydroxy, i.e., the compounds of the formula (I-1-2a)
    Figure US20030073706A1-20030417-C01515
  • (wherein, R R[0579] 1-1-2a is the same meanings as hereinbefore described for R1, provided that at least one of R R1-1-2a(s) is a hydroxy or a group containing hydroxy and the other symbols are the same meaning as hereinbefore described.) with the corresponding compounds containing a group which is removal (chloride, bromide, iodide, mesyl or tosyl etc.).
  • This etherification is well known. For example, it may be carried out in an organic solvent (dimethylformamide, dimethylsulfoxide, chloroform, methyhlene chloride, diethyl ether, tetrahydrofuran etc.) in the presence of hydroxide of an alkalimetal (sodium hydroxide, potassium hydroxide, lithium hydroxide etc.), hydroxide of an alkaline earth metal (barium hydroxide, calcium hydroxide etc.) or carbonate (sodium carbonate , potassium carbonate etc.) or an aqueous solution thereof or a mixture thereof at 0˜100° C. [0580]
  • (b) The compounds of the present invention of the formula (I-1-2) may be prepared by etherification of the compounds of the formula (1-1 -2) in which at least one of R[0581] 1(s) is a hydroxy or a group containing hydroxy, i.e., the compounds of the formula (I-1-2b)
    Figure US20030073706A1-20030417-C01516
  • (wherein, R R[0582] 1-1-2b is the same meanings as hereinbefore described for R1, provided that at least one of R R1-1-2b(s) is a hydroxy or a group containing hydroxy and the other symbols are the same meaning as hereinbefore described.) with the corresponding compounds containing hydroxy.
  • This etherification is well known. For example, it may be carried out in an organic solvent (methylene chloride, diethyl ether, tetrahydrofuran, acetonitrile, benzene, toluene etc.) in the presence of azo compounds (diethyl azodicaroxylate, diisopropyl azodicaroxylate, 1,1′-(azodicarbonyl)dipiperidine, 1,1′-azobis(N,N-dimethylformamide) etc.) and phosphine compounds (triphenylphosphine , tributylphosphine , trimethylphosphine etc.), with the corresponding alcohol compounds at 0˜60° C. [0583]
  • [3] The compounds of the present invention of the formula (I-1) in which at least one of R[0584] 1(s) is a substituted amino or a group containing substituted amino, i.e., the compounds of the present invention of the formula (I-1-3)
    Figure US20030073706A1-20030417-C01517
  • (wherein, R[0585] 1-1-3 is the same meanings as hereinbefore described for R1, provided that at least one of R R1-1-3(s) is a substituted amino or a group containing substituted amino and the other symbols are the same meaning as hereinbefore described.)
  • may be prepared by the following methods (a)˜(d). [0586]
  • (a) The compounds of the present invention of the formula (I-1-3) may be prepared by reacting the compounds of the formula (I-1-3) in which at least one of R[0587] 1(s) is halogen (chloride, bromide, iodide) or a group containing halogen, i.e., the compounds of the formula (I-1-3a)
    Figure US20030073706A1-20030417-C01518
  • (wherein, R R[0588] 1-1-3 is the same meanings as hereinbefore described for R1, provided that at least one of R R1-1-3a(s) is a halogen (chloride, bromide, iodide) or a group containing halogen and the other symbols are the same meaning as hereinbefore described.)
  • and the corresponding compounds containing amino. [0589]
  • This reaction is well known. For example, it may be carried out in an organic solvent (dimethylformamide, dimethylsulfoxide, chloroform, methyhlene chloride, diethyl ether, tetrahydrofuran, acetonitrile etc.) in the presence or absence of base (triethylamine, pyridine etc.) at 0˜100° C. [0590]
  • (b) The compounds of the present invention of the formula (I-1-3) may be prepared by reacting the compounds of the formula (I-1-3) in which at least one of R[0591] 1(s) is an amino or a group containing amino, i.e., the compounds of the formula (I-1-3b)
    Figure US20030073706A1-20030417-C01519
  • (wherein, R R[0592] 1-1-3b is the same meanings as hereinbefore described for R1, provided that at least one of R R1-1-3b(s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing halogen (chloride, bromide, and iodide).
  • This reaction may be carried out by the same procedure for the preparation of the said compounds of the formula (I-1-3a). [0593]
  • (c) The compounds of the present invention of the formula (I-1-3) may be prepared by reductive amidation of the compounds of the formula (I-1-3) in which at least one of R[0594] 1(s) is an amino or a group containing amino, i.e., the compounds of the formula (I-1-3c)
    Figure US20030073706A1-20030417-C01520
  • (wherein, R R[0595] 1-1-3c is the same meanings as hereinbefore described for R1, provided that at least one of R R1-1-3(s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) with the corresponding compounds containing carbonyl.
  • This reductive amidation is well known. For example, it may be carried out in an organic solvent (methanol, ethanol, dimethylformamide, dimethylsulfoxide etc,) in the presence of reductant (sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, Pd-C etc.) and in the presence of acid (acetic acid, hydrochlolride solution etc.), if necessary, at −20˜60° C. [0596]
  • (d) The compounds of the present invention of the formula (I-1-3) may be prepared by reductive amidation of the compounds of the formula (I-1-3) in which at least one of R[0597] 1(s) is a carbonyl or a group containing carbonyl, i.e., the compounds of the formula (I-1-3d)
    Figure US20030073706A1-20030417-C01521
  • (wherein, R R[0598] 1-1-3d is the same meanings as hereinbefore described for R1, provided that at least one of R R1-1-3d(s) is a carbonyl or a group containing carbonyl and the other symbols are the same meaning as hereinbefore described.)
  • with the corresponding compounds containing amino. [0599]
  • This reductive amidation may be carried out by the same procedure for preparation of the said compounds of the formula (I-1-3c). [0600]
  • [4] The compounds of the present invention of the formula (I-1) in which at least one of R[0601] 1(s) is an amide or a group containing amide, i.e., the compounds of the present invention of the formula (I-1-4)
    Figure US20030073706A1-20030417-C01522
  • (wherein, R[0602] 1-1-4 is the same meanings as hereinbefore described for R1, provided that at least one of R R1-1-4(s) is an amide or a group containing amide and the other symbols are the same meaning as hereinbefore described.) may be prepared by the following methods (a)˜(b).
  • (a) The compounds of the present invention of the formula (I-1-4) may be prepared by amidation of the compounds of the formula (I-1) in which at least one of R[0603] 1(s) is a —COOH or a group containing —COOH, i.e., the compounds of the formula (I-1-4a)
    Figure US20030073706A1-20030417-C01523
  • (wherein, R R[0604] 1-1-4a is the same meanings as hereinbefore described for R1, provided that at least one of R R1-1-4a(s) is a —COOH or a group containing —COOH and the other symbols are the same meaning as hereinbefore described.) with the corresponding compounds containing amino.
  • The amidation is well known. For example, it may be carried out [0605]
  • (1) by the method with using acid halide, [0606]
  • (2) by the method with using mixed acid anhydride, [0607]
  • (3) by the method with using conducing agent etc. [0608]
  • Concrete description of these methods are as follows: [0609]
  • (1) method with using acid halide may be carried out, for example; carboxylic acid is reacted with an acid halide (oxalyl chloride or thionyl chloride etc.) in an organic solvent (chloroform, methylene chloride, diethyl ether or tetrahydrofuran etc.) or without solvents at from −20° C. to a refluxing temperature to give an acid halide. The obtained acid halide and an amine are reacted in an organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran etc.) in the presence of tertiary amine (pyridine, triethylamine, dimethylaniline or dimethylaminopyridine etc.) at 0-40° C. [0610]
  • (2) method with using mixed acid anhydride may be carried out, for example; carboxylic acid is reacted with an acid halide (pivaloyl chloride, tosyl chloride, mesyl chloride etc.) or an acid derivative (ethyl chloroformate, isobutyl chloroformate etc.) in an organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran. etc.) or without solvents, in the presence of tertiary amine (pyridine, triethylamine, dimethylaniline or dimethylaminopyridine etc.), at 0-40° C. [0611]
  • (3) method with using condensing agent may be carried out, for example; a carboxylic acid and an amine are reacted in an organic solvent (chloroform, methylene chloride, dimethylformamide, diethyl ether or tetrahydrofuran. etc.) or without solvents in the presence or absence of tertiary amine (pyridine, triethylamine, dimethylaniline or dimethylaminopyridine etc.) using with condensing agent (1,3-dicyclohexylcarbodiimido (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimido (EDC), 1,1′-carbonydimidazole (CDI), 2-chloro-1-methylpyridinium iodide, propane phosphate cyclic anhydride etc.) using or without 1-hydroxybenztriazole (HOBt) at 0-40° C. (etc.) [0612]
  • Preferably, the above reactions (1), (2) and (3) described above are carried out under an atmosphere of an inert gas (argon, nitrogen etc.) on anhydrous condition. [0613]
  • (b) The compounds of the present invention of the formula (I-1-4) may be prepared by amidation of the compounds of the formula (I-1) in which at least one of R[0614] 1(s) is an amino or a group containing amino, i.e., the compounds of the formula (I-1-4b)
    Figure US20030073706A1-20030417-C01524
  • (wherein, R R[0615] 1-1-4b is the same meanings as hereinbefore described for R1, provided that at least one of R R1-1-4b(s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.)with the corresponding compounds containing carboxy.
  • The above amidation may be carried out by the same procedure for preparation of the said compounds of the formula (I-1-4a). [0616]
  • [5] The compounds of the present invention of the formula (1-1) in which at least one of R[0617] 1(s) is an ester or a group containing ester, i.e., the compounds of the present invention of the formula (I-1-5)
    Figure US20030073706A1-20030417-C01525
  • (wherein, R[0618] 1-1-5 is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-5(s) is an ester or a group containing ester and the other symbols are the same meaning as hereinbefore described.) may be prepared by the following methods (a)˜(b).
  • (a) The compounds of the present invention of the formula (I-1-5) may be prepared by esterification of the compounds of the formula (I-1) in which at least one of R[0619] 1(s) is a —COOH or a group containing —COOH, i.e., the compounds of the formula (I-1-5a)
    Figure US20030073706A1-20030417-C01526
  • (wherein, R[0620] 1-1-5a is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-5a(s) is a —COOH or a group containing —COOH and the other symbols are the same meaning as hereinbefore described.) with the corresponding compounds containing hydroxy.
  • Esterification is well known. For example, it may be carried out [0621]
  • (1) by the method with using acid halide, [0622]
  • (2) by the method with using mixed acid anhydride, [0623]
  • (3) by the method with using conducing agent etc. [0624]
  • Concrete description of the above methods are as follows: [0625]
  • (1) method with using acid halide may be carried out, for example; carboxylic acid is reacted with an acid halide (oxalyl chloride or thionyl chloride -etc.) in an inert organic solvent (chloroform, methylene chloride, diethyl ether or tetrahydrofuran etc.) or without solvents at from −20° C. to a refluxing temperature to give an acid halide. The obtained acid halide and an alcohol are reacted in an inert organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran etc.) in the presence of tertiary amine (pyridine, triethylamine, dimethylaniline or dimethylaminopyridine etc.) at 0-40° C. [0626]
  • (2) method with using mixed acid anhydride may be carried out, for example; carboxylic acid is reacted with an acid halide (pivaloyl chloride, tosyl chloride, mesyl chloride etc.) or an acid derivative (ethyl chloroformate, isobutyl chloroformate etc.) in an inert organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran. etc.) or without solvents, in the presence of tertiary amine (pyridine, triethylamine, dimethylaniline or dimethylaminopyridine etc.), at 0-40° C. to give an acid halide. The obtained acid halide and an alcohol are reacted in an inert organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran etc.) at 0-40° C. [0627]
  • (3) method with using condensing agent may be carried out, for example; a carboxylic acid and an alcohol are reacted in an organic solvent (chloroform, methylene chloride, dimethylformamide, diethyl ether or tetrahydrofuran. etc.) or without solvents in the presence or absence of tertiary amine (pyridine, triethylamine, dimethylaniline or dimethylaminopyridine etc.) using with condensing agent (1,3-dicyclohexylcarbodiimido (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimido (EDC), 1,1′-carbonydimidazole (CDI), 2-chloro-1-methylpyridinium iodide, propane phosphate cyclic anhydride etc.) using or without 1-hydroxybenztriazole (HOBt) at 0-40° C. [0628]
  • Preferably, the reactions (1), (2) and (3) described above are carried out under an atmosphere of inert gas (argon, nitrogen etc.) on anhydrous condition. [0629]
  • (b) The compounds of the present invention of the formula (1-1-5) may be prepared by esterification of the compounds of the formula (I-1) in which at least one of R[0630] 1(s) is a hydroxy or a group containing hydroxy, i.e., the compounds of the formula (I-1-5b)
    Figure US20030073706A1-20030417-C01527
  • (wherein, R[0631] 1-1-5b is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-5b(s) is a hydroxy or a group containing hydroxy and the other symbols are the same meaning as hereinbefore described.) with the corresponding compounds containing carboxy.
  • The esterification may be carried out by the same procedure for preparation of the said compounds of the formula (I-1-5a). [0632]
  • [6] The compounds of the present invention of the formula (1-1) in which at least one of R[0633] 1(s) is a sulfonamide or a group containing sulfonamide, i.e., the compounds of the present invention of the formula (I-1-6)
    Figure US20030073706A1-20030417-C01528
  • (wherein, R[0634] 1-1-6 is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-6(s) is a sulfonamide or a group containing sulfonamide and the other symbols are the same meaning as hereinbefore described.) may be prepared by the following methods (a)˜(b).
  • (a) The compounds of the present invention of the formula (I-1-6) may be prepared by sulfonamidation of the compounds of the formula (I-1) in which at least one of R[0635] 1(s) is a —SO3H or a group containing —SO2H, i.e., the compounds of the formula (II)
    Figure US20030073706A1-20030417-C01529
  • (wherein, R[0636] 1-1-6a is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-6a(s) is a —SO3H or a group containing —SO3H and the other symbols are the same meaning as hereinbefore described.) with the corresponding compounds containing amino.
  • The sulfonamidation is well known. For example, it may be carried out by reacting sulfonic acid with acid halide (oxazolyl chloride, thionyl chloride etc.) in an inert organic solvent (chloroform, methyhlene chloride, diethyl ether, tetrahydrofuran etc.) or without solvent, at −20° C. refluxing temperature to obtain sulfonylhalide and then by reacting the obtained sulfonylhalide with an amine in an inert organic solvent (chloroform, methyhlene chloride, diethyl ether, tetrahydrofuran etc.) in the presence of tertiary amine (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine etc.) at 0˜40° C. [0637]
  • (b) The compounds of the present invention of the formula (I-1-6) may be prepared by sulfonamidation of the compounds of the formula (1-1) in which at least one of R[0638] 1(s) is an amino or a group containing amino, i.e., the compounds of the formula (I-1-6b)
    Figure US20030073706A1-20030417-C01530
  • (wherein, R[0639] 1-1-6b is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-6b(s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) with the corresponding compounds containing sulfo.
  • The sulfonamidation may be carried out the same procedure for preparation of the said compounds of the formula (I-1-6a). [0640]
  • [7] The compounds of the present invention of the formula (I-1) in which at least one of R[0641] 1(s) is a substituted aminocarbonyloxy or a group containing a substituted aminocarbonyloxy, i.e., the compounds of the present invention of the formula (I-1-7)
    Figure US20030073706A1-20030417-C01531
  • (wherein, R R[0642] 1-1-7 is the same meanings as hereinbefore described for R1, provided that at least one of R R1-1-7(s) is a substituted aminocarbonyloxy or a group containing a substituted aminocarbonyloxy and the other symbols are the same meaning as hereinbefore described.) may be prepared by reacting the compounds of the formula (I-1) in which at least one of R1(s) is a hydroxy or a group containing hydroxy, i.e., the compounds of the formula (I-1-7a)
    Figure US20030073706A1-20030417-C01532
  • (wherein, R[0643] 1-1-7a is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-7a(s) is a hydroxy or a group containing hydroxy and the other symbols are the same meaning as hereinbefore described.) with the corresponding compounds containing isocyanate.
  • This reaction is well known. For example, it may be carried out in an organic solvent (tetrahydrofuran, methyhlene chloride, diethyl ether etc.) in the presence of base (1,8-diazabicyclo[5.4.0]undec-7-en (DBU), triethylamine, sodium hydride etc.) at 0˜100° C. [0644]
  • [8] The compounds of the present invention of the formula (I-1) in which at least one of R[0645] 1(s) is a substituted aminocarbonylamino or a group containing a substituted aminocarbonylamino, i.e., the compounds of the present invention of the formula (I-1-8)
    Figure US20030073706A1-20030417-C01533
  • (wherein, R[0646] 1-1-8 is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-8(s) is a substituted aminocarbonyl or a group containing a substituted aminocarbonyl and the other symbols are the same meaning as hereinbefore described.) may be prepared by reacting the compounds of the formula (I-1) in which at least one of R1(s) is an amino or a group containing amino, i.e., the compounds of the formula (I-1-8a)
    Figure US20030073706A1-20030417-C01534
  • (wherein, R R[0647] 1-1-8 is the same meanings as hereinbefore described for R1, provided that at least one of R R1-1-8a(s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) with the corresponding compounds containing isocyanate.
  • This reaction may be carried out by the same procedure for preparation of the said compounds of the formula (I-1-7). [0648]
  • [9] The compounds of the present invention of the formula (I-1) in which at least one of R[0649] 1(s) is a substituted oxycarbonylamino or a group containing a substituted oxyocarbonylamino, i.e., the compounds of the present invention of the formula (I-1-9)
    Figure US20030073706A1-20030417-C01535
  • (wherein, R R[0650] 1-1-9 is the same meanings as hereinbefore described for R1, provided that at least one of R R1-1-9(s) is a substituted oxycarbonylamino or a group containing a substituted oxyocarbonylamino and the other symbols are the same meaning as hereinbefore described.) may be prepared by esterification of the compounds of the formula (I-1) in which at least one of R1(s) is an amino or a group containing amino, i.e., the compounds of the formula (I-1-9a)
    Figure US20030073706A1-20030417-C01536
  • (wherein, R R[0651] 1-1-9a is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-9a(s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) with the corresponding halo formic acid ester.
  • This reaction is well known. For example, it may be carried out in an organic solvent (tetrahydrofuran, methyhlene chloride, diethyl ether etc.) in the presence of base (triethylamine, pyridine etc.) at −78˜40° C. [0652]
  • [10] The compounds of the present invention of the formula (I-1) in which at least one of R[0653] 1(s) is a substituted oxycarbonyloxy or a group containing a substituted oxycarbonyloxy, i.e., the compounds of the present invention of the formula (I-1-10)
    Figure US20030073706A1-20030417-C01537
  • (wherein, R[0654] 1-1-10 is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-10(s) is a substituted oxycarbonyloxy or a group containing a substituted oxycarbonyloxy and the other symbols are the same meaning as hereinbefore described.) may be prepared by esterification of the compounds of the formula (I-1) in which at least one of R1(s) is a hydroxy or a group containing hydroxy, i.e., the compounds of the formula (I-1-10a)
    Figure US20030073706A1-20030417-C01538
  • (wherein, R[0655] 1-1-10a is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-10a(s) is a hydroxy or a group containing hydroxy and the other symbols are the same meaning as hereinbefore described.) with the corresponding halo formic acid ester.
  • This reaction may be carried out by the same procedure for preparation of the said compounds of the formula (I-1-9). [0656]
  • [11] The compounds of the present invention of the formula (I-1) in which at least one of R[0657] 1(s) is a substituted (hydroxy)methyl or a group containing a substituted (hydroxy)methyl, i.e., the compounds of the present invention of the formula (I-1-11)
    Figure US20030073706A1-20030417-C01539
  • (wherein, R[0658] 1-1-11 is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-11(s) is a substituted (hydroxy)methyl or a group containing a substituted (hydroxy)methyl and the other symbols are the same meaning as hereinbefore described.) may be prepared by the following methods (a)˜(b).
  • (a) The compounds of the present invention of the formula (I-1-11) in which n is 0, i.e., the compounds of the present invention of the formula (I-[0659] 1-11a)
    Figure US20030073706A1-20030417-C01540
  • (wherein all the symbols are the same meanings as hereinbefore described.) may be prepared by reacting the compounds of the formula (I-1) in which at least one of R[0660] 1(s) is a formyl i.e., the compounds of the formula (1-1-11 aa)
    Figure US20030073706A1-20030417-C01541
  • (wherein, R[0661] 1-1-11aa is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-11a(s) is a formyl and the other symbols are the same meaning as hereinbefore described.)
  • with the corresponding Grignard's reagents or corresponding derivatives containing lithium. [0662]
  • This reaction is well known. For example, it may be carried out in an organic solvent (tetrahydrofuran, diethyl ether etc.) at −78˜0° C.[0663]
  • (b) The compounds of the present invention of the formula (I-1-11) in which n is 1 or 2, i.e., the compounds of the present invention of the formula (I-1-11b) [0664]
    Figure US20030073706A1-20030417-C01542
  • (wherein, n-1-11b is an integer of 1˜2 and the other symbols are the same meaning as hereinbefore described.) [0665]
  • may be prepared by oxidizing the said compounds of the formula (I-1-11a) as described in [1]. [0666]
  • [12] The compounds of the present invention of the formula (I-1) in which at least one of R[0667] 1(s) is a substituted carbonyl or a group containing substituted carbonyformyl, i.e., the compounds of the present invention of the formula (I-1-12)
    Figure US20030073706A1-20030417-C01543
  • (wherein, R[0668] 1-1-12 is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-12(s) is an substituted carbonyl or a group containing substituted carbonyl and the other symbols are the same meaning as hereinbefore described.)
  • may be prepared by oxidizing the said compounds of the formula (I-1-11). [0669]
  • This oxidation is well known. For example, it may be carried out in an organic solvent (methyhlene chloride, chloroform etc.) using oxidant (manganese dioxide, oxazolyl chloride, pyridinium dichromate etc.) at −78˜40° C. [0670]
  • [13] The compounds of the present invention of the formula (I-1) in which at least one of R[0671] 1(s) is an amino or a group containing amino, i.e., the compounds of the present invention of the formula (I-1 -13)
    Figure US20030073706A1-20030417-C01544
  • (wherein, R[0672] 1-1-13 is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-13(s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) may be prepared by reducing nitro in the compounds of the formula of (I-1) in which at least one of R1(s) is a nitro or a group containing nitro, i.e., the compounds of the formula (I-1-13a)
    Figure US20030073706A1-20030417-C01545
  • (wherein, R R[0673] 1-1-13a is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-13a(s) is a nitro or a group containing nitro and the other symbols are the same meaning as hereinbefore described.).
  • The reduction of nitro is well known. For example, it may be carried out by hydrogenolysis and reduction using organic metal. [0674]
  • This hydrogenolysis is well known. For example, it may be carried out in inert solvent [ethers (e.g., tetrahydrofuran, dioxane, dimethoxy ethane, diethyl ether etc.), alcohols (e.g., methanol , ethanol etc.), benzenes (e.g., benzene, toluene etc.), ketones (e.g., acetone, methyl ethyl ketone etc.), nitriles (e.g., acetonitrile etc.), amides (e.g., dimethylformamide etc.), water, ethyl acetate, acetic acid or mixture of the said two or more solvents etc.], in the presence of catalyst to hydrogenate (e.g., Pd-C, palladium black, Pd, palladium hydroxide, platinum oxide, Ni, Raney nickel, ruthenium chloride etc.), in the presence or absence of an inorganic acid (e.g., hydrochloric acid, sulfuric acid, hypochlorous acid, boric acid, tetrafluoroboric acid etc.) or an organic acid (e.g., acetic acid, p-toluenesulfonic acid, bromic acid, trifluoroacetic acid, formic acid etc.), at an ordinary or increased pressure under an atmosphere of hydrogen gas or in the presence of ammonium formate at 0˜200° C. When an acid is used, its salt may be used. [0675]
  • The reduction using an organic metal is well known. For example, it may be carried out in a water-admissible solvent (ethanol , methanol etc.) in the presence or absence of an aqueous hydrochloric acid solution, using an organic metal (Zn, Fe, Sn, SnCl[0676] 2, FeCl2 etc.) at 50˜150° C.
  • [14] The compounds of the present invention of the formula (I-1) in which at least one of R[0677] 1(s) is a —COOH, hydroxy or amino or a group containing —COOH, hydroxy or amino, i.e., the compounds of the present invention of the formula (I-1-14)
    Figure US20030073706A1-20030417-C01546
  • (wherein, R[0678] 1-1-14 is the same meanings as hereinbefore described for R1, provided that at least one of R R1-1-14(s) is a —COOH, hydroxy or amino or a group containing —COOH, hydroxy or amino and the other symbols are the same meaning as hereinbefore described.) may be prepared by removal of protecting group in the compounds of the formula (I-1) containing a protected COOH, hydroxy or amino, i.e., the compounds of the formula (I-1-14a)
    Figure US20030073706A1-20030417-C01547
  • (wherein, R[0679] 1-1-14a is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-14a(s) is a protected COOH (e.g., it is protected by methyl, ethyl, t-butyl and benzyl etc.), protected hydroxy (e.g., it is protected by methoxymethyl, tetrahydropyranyl, t-butyldimethylsilyl, acetyl, benzyl etc.) or protected amino (e.g., it is protected by benzyloxycarbonyl, t-butoxycarbonyloxy, trifluoroacetyl etc.) or a group containing such a group, and the other symbols are the same meaning as hereinbefore described.) according to alkaline hydrolysis, removal of protecting group in an acidic condition, removal of silyl or hydrogenolysis.
  • The removal of a protecting group according to alkaline hydrolysis is well known. For example, it may be carried out in an organic solvent (methanol, tetrahydrofuran, dioxane etc.), using hydroxide of an alkaline metal (sodium hydroxide, potassium hydroxide , lithium hydroxide etc.), hydroxide of an alkaline earth metal (barium hydroxide, calcium hydroxide etc.) or carbonate (sodium carbonate , potassium carbonate etc.) or an aqueous solution thereof or a mixture thereof at 0˜40° C. [0680]
  • The removal of a protecting group in an acidic condition is well known. For example, it may be carried out in an organic solvent (methyhlene chloride, chloroform, dioxane, ethyl acetate, anisole etc.), organic acid (acetic acid, trifluoroacetic acid, methanesulfonic acid, trimethylsilyliodide etc.) or inorganic acid (hydrochloric acid, sulfuric acid etc.) or a mixture thereof (bromohydroacetic acid etc.) at 0˜100° C. [0681]
  • The removal of silyl is well known. For example, it may be carried out in a water-admissible organic solvent (tetrahydrofuran, acetonitrile etc.), using tetrabutylammonium fluoride at 0˜40° C. [0682]
  • The removal of protecting group according to hydrogenolysis may be carried out by the same procedure of hydrogenolysis described in [13]. [0683]
  • Among the compounds of the formula (I), the compounds of the formula (I-2) [0684]
    Figure US20030073706A1-20030417-C01548
  • may be prepared by the following methods [15]˜[[0685] 17].
  • [15] The compounds of the present invention of the formula (I-2) in which m is 0, i.e., the compounds of the present invention of the formula (I-2-15) [0686]
    Figure US20030073706A1-20030417-C01549
  • (wherein all the symbols are the same meanings as hereinbefore described.) may be prepared by the following methods (a)˜(b). [0687]
  • (a) The compounds of the present invention of the formula (I-2-15) in which n is 1 or 2, i.e., the compounds of the present invention of the formula (I-2-15a) [0688]
    Figure US20030073706A1-20030417-C01550
  • (wherein, n-2-15a is an integer of 1˜2 and the other symbols are the same meanings as hereinbefore described.) may be prepared by reacting the said compounds of the formula (I-1-1a) or the compounds of the formula (I-1-1b) and the compounds of the formula (III) [0689]
    Figure US20030073706A1-20030417-C01551
  • (wherein all the symbols are the same meanings as hereinbefore described.). [0690]
  • This reaction is known one (to see J. Am. Chem. Soc., 72, 1985 (1950), J. Org. Chem., 54, 4232 (1989). For example, it may be carried out in an inert organic solvent (tetrahydrofuran, diethyl ether, methylene chloride, chloroform, benzene, toluene, dimethylformamide, dimethylsulfoxide, acetonitrile etc.) using hydride of an alkaline metal, hydroxide of an alkaline metal (sodium hydroxide, potassium hydroxide, lithium hydroxide etc.), hydroxide of an alkaline earth metal (barium hydroxide, calcium hydroxide etc.) or tertiary amine (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine etc.) or an aqueous solution thereof, or a mixture thereof at 0˜40° C. [0691]
  • (b) The compounds of the present invention of the formula (I-2-15) in which n is 0, i.e., the compounds of the present invention of the formula (I-2-15b) [0692]
    Figure US20030073706A1-20030417-C01552
  • (wherein all the symbols are the same meanings as hereinbefore described.) may be prepared by reduction of the compounds obtained by the. above mentioned method in which m is 0, n is 1, i.e., the compounds of the formula (I-2-15ab) [0693]
    Figure US20030073706A1-20030417-C01553
  • (wherein all the symbols are the same meanings as hereinbefore described.). [0694]
  • This reduction reaction is well known. For example, this reaction may be carried out in an organic solvent (diethyl ether, tetrahydrofuran etc.) using reductant (lithium aluminum hydride, aluminum diisobutylhydride etc.) at 0˜80° C. [0695]
  • [16] The compounds of the present invention of the formula (I-2) in which m is 1, i.e., the compounds of the present invention of the formula (I-2-16) [0696]
    Figure US20030073706A1-20030417-C01554
  • (wherein all the symbols are the same meanings as hereinbefore described.) may be prepared by oxidizing the said compounds of the formula (I-2-15). [0697]
  • This oxidation may be carried out by the same procedure for preparation of the compounds of the formula (I-1-1a) in [1]. [0698]
  • [17] The compounds of the present invention of the formula (I-2) in which m is 2, i.e., the compounds of the present invention of the formula (I-2-17) [0699]
    Figure US20030073706A1-20030417-C01555
  • (wherein all the symbols are the same meanings as hereinbefore described.) may be prepared by the following methods (a)˜(c). [0700]
  • (a) The compounds of the present invention of the formula (I-2-17) in which n is 1 or 2, i.e., the compounds of the present invention of the formula (I-2-17a) [0701]
    Figure US20030073706A1-20030417-C01556
  • (wherein, n-2-17a is an integer of 1˜2 and the other symbols are the same meaning as hereinbefore described.) [0702]
  • may be prepared by reacting the said compounds of the formula (I-11-a) or the compounds of the formula (I-1-1b) and the compounds of the formula (IV) [0703]
    Figure US20030073706A1-20030417-C01557
  • (wherein all the symbols are the same meanings as hereinbefore described.). [0704]
  • This reaction may be carried out by the same procedure described in the reaction of the compounds of the formula (I-2-15a) and the compounds of the formula (III) in [15]. [0705]
  • (b) The compounds of the present invention of the formula (I-2-17) in which n is 0, i.e., the compounds of the formula (I-2-17b) [0706]
    Figure US20030073706A1-20030417-C01558
  • (wherein all the symbols are the same meanings as hereinbefore described.) may be prepared by reduction of the compounds of the formula (V) [0707]
    Figure US20030073706A1-20030417-C01559
  • (wherein all the symbols are the same meanings as hereinbefore described.). [0708]
  • This reduction is known one. For example, it may be carried out by hydrogenation or by the method using triethylsilane. [0709]
  • This hydrogenation is known reaction. For example, it may be carried out in inert solvent [ethers (e.g., tetrahydrofuran, dioxane, dimethoxy ethane, diethyl ether etc.), alcohols (e.g., methanol, ethanol etc.), benzenes (e.g., benzene, toluene etc.), ketones (e.g., acetone, methyl ethyl ketone etc.), nitrites (e.g., acetonitrile etc.), amides (e.g., dimethylformamide etc.), water, ethyl acetate, acetic acid or mixture of the said two or more solvents etc.], in the presence of catalyst to hydrogenate (e.g., Pd-C, palladium black, Pd, palladium hydroxide, platinum oxide, Ni, Raney nickel, ruthenium chloride etc.), in the presence or absence of an inorganic acid (e.g., hydrochloric acid, sulfuric acid, hypochlorous acid, boric acid, tetrafluoroboric acid etc.) or an organic acid (e.g., acetic acid, p-toluenesulfonici acid, bromic acid, trifluoroacetic acid, formic acid etc.), at an ordinary or increased pressure under an atmosphere of hydrogen gas, or in the presence of ammonium formate at 0˜200° C. When an acid is used, its salt may be used. [0710]
  • This reduction using triethylsilane is well known. For example, it may be carried out in trifluoroacetic acid, in the presence of triethylsilane at 0˜100° C. [0711]
  • (c) The compounds of the present invention of the formula (I-2-17) in which n is 2, i.e., the compounds of the present invention of the formula (I-2-17c) [0712]
    Figure US20030073706A1-20030417-C01560
  • (wherein all the symbols are the same meanings as hereinbefore described.) may be prepared by oxidizing the compounds obtained by the above mentioned method in which m is 0 and n is 2, i.e., the compounds of the formula (I-2-15ac) [0713]
    Figure US20030073706A1-20030417-C01561
  • (wherein all the symbols are the same meanings as hereinbefore described.). [0714]
  • This reaction may be carried out by the same procedure for preparation of the compounds of the formula (I-1-1b) in [1]. [0715]
  • The compounds of the present invention of the formula (I-2) may be also prepared by not only the methods described in [15]˜[17] but also the following methods [18]˜[30]. [0716]
  • [18] The compounds of the present invention of the formula (I-2) in which at least one of R[0717] 1(s) or R2(s) is a substituted oxy or a group containing substituted oxy, i.e., the compounds of the present invention of the formula (I-2-18)
    Figure US20030073706A1-20030417-C01562
  • (wherein, R[0718] 1-2-18 and R2-2-18 are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-18(s) and R2-2-18(s) is a substituted oxy or a group containing substituted oxy and the other symbols are the same meaning as hereinbefore described.) may be prepared by the following methods (a)˜(b).
  • (a) The compounds of the present invention of the formula (I-2-18) may be prepared by eterification of the compounds of the formula (I-2) in which at least one of R[0719] 1(s) or R2(s) is hydroxy or a group containing hydroxy, i.e., the compounds of the formula (I-2-18a)
    Figure US20030073706A1-20030417-C01563
  • (wherein, R[0720] 1-2-18a and R2-2-18a are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-18a(s) and R2-2-18a(s) is a hydroxy or a group containing hydroxy and the other symbols are the same meaning as hereinbefore described.)
  • and the corresponding compounds containing a group which is removal (chloride, bromide, iodide, mesyl or tosyl etc.). [0721]
  • This eterification may be carried out by the same procedure for preparation of the compounds of the formula (I-1-2a) in [2]. [0722]
  • (b) The compounds of the present invention of the formula (I-2-18) may be prepared by eterification of the compounds of the formula (I-2) in which at least one of R[0723] 1(s) is a hydroxy or a group containing hydroxy, i.e., the compounds of the formula (I-2-18b)
    Figure US20030073706A1-20030417-C01564
  • (wherein, R[0724] 1-2-18b and R2-2-18b are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-18b(s) and R2-2-18b(s) is a hydroxy or a group containing hydroxy and the other symbols are the same meaning as hereinbefore described.)
  • with corresponding compounds containing hydroxy. [0725]
  • This eterification may be carried out by the procedure for preparation of the compounds of the formula (I-1-2b) in [2]. [0726]
  • [19] The compounds of the present invention of the formula (I-2) in which at least one of R[0727] 1(s) or R2(s) is a substituted amino or a group containing substituted amino, i.e., the compounds of the present invention of the formula (I-2-19)
    Figure US20030073706A1-20030417-C01565
  • (wherein, R[0728] 1-2-19 and R2-2-19 are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-19(s) and R2-2-19(s) is a substituted amino or a group containing substituted amino and the other symbols are the same meaning as hereinbefore described.) may be prepared by the following methods (a)˜(d).
  • (a) The compounds of the present invention of the formula (I-2-19) may be prepared by reacting the compounds of the formula (I-2) in which at least one of R[0729] 1(s) or R2(s) is a halogen (chloride, bromide, iodide) or a group containing halogen, i.e., the compounds of the formula (I-2-19a)
    Figure US20030073706A1-20030417-C01566
  • (wherein, R[0730] 1-2-19a and R2-2-19a are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-19a(s) and R2-2-19a(s) is a halogen (chloride, bromide, iodide) or a group containing halogen and the other symbols are the same meaning as hereinbefore described.)
  • and the compounds containing amino. [0731]
  • This reaction may be carried out by the same procedure for preparation of the compounds of the formula (I-1-3a) in [3]. [0732]
  • (b) The compounds of the present invention of the formula (I-2-19) may be prepared by reacting the compounds of the formula (I-2) in which at least one of R[0733] 1(s) or R2(s) is an amino or a group containing amino, i.e., the compounds of the formula (I-2-19b)
    Figure US20030073706A1-20030417-C01567
  • (wherein, R[0734] 1-2-19b and R2-2-19b are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-19b(s) and R2-2-19b(s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing halogen (chloride, bromide, and iodide).
  • This reaction may be carried out by the same procedure for preparation of the compounds of the formula (I-1-3a) in [3]. [0735]
  • (c) The compounds of the present invention of the formula (I-2-19) may be prepared by reacting the compounds of the formula (I-2) in which at least one of R[0736] 1(s) or R2(s) is an amino or a group containing amino, i.e., the compounds of the formula (I-2-19c)
    Figure US20030073706A1-20030417-C01568
  • (wherein, R[0737] 1-2-19c and R2-2-19c are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-19c(s) and R2-2-19c(s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing carbonyl.
  • This reaction may be carried out by the same procedure for preparation of the compounds of the formula (I-1-3c) in (3]. [0738]
  • (d) The compounds of the present invention of the formula (I-2-19) may be prepared by reductive amidation of the compounds of the formula (I-2) in which at least one of R[0739] 1(s) or R2(s) is a carbonyl or a group containing carbonyl, i.e., the compounds of the formula (I-2-19d)
    Figure US20030073706A1-20030417-C01569
  • (wherein, R[0740] 1-2-19d and R2-2-19d are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-19d(s) and R2-2-19d(s) is a carbonyl or a group containing carbonyl and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing amino.
  • This reductive amidation may be carried out by the same procedure for preparation of the compounds of the formula (I-1-3c) in [3]. [0741]
  • [20] The compounds of the present invention of the formula (I-2) in which at least one of R[0742] 1(s) or R2(s) is an amide or a group containing amide, i.e., the compounds of the present invention of the formula (I-2-20)
    Figure US20030073706A1-20030417-C01570
  • (wherein, R[0743] 1-2-20 and R2-2-20 are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-20(s) and R2-2-20(s) is an amide or a group containing amide and the other symbols are the same meaning as hereinbefore described.) may be prepared by the following methods (a)˜(b).
  • (a) The compounds of the present invention of the formula (I-2-20) may be prepared by amidation of the compounds of the formula (I-2) in which at least one of at least one of R[0744] 1(s) or R2(s) is a —COOH or a group containing —COOH, i.e., the compounds of the formula (I-2-20a)
    Figure US20030073706A1-20030417-C01571
  • (wherein, R[0745] 1-2-20a and R2-2-20a are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-1-20a(s) and R2-2-20a(s) is a —COOH or a group containing —COOH and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing amino.
  • The amidation may be carried out by the same procedure for preparation of the compounds of the formula (I-1-4) in [4]. [0746]
  • (b) The compounds of the present invention of the formula (I-2-20) may be prepared by amidation of the compounds of the formula (I-2) in which at least one of R[0747] 1(s) or R2(s) is an amino or a group containing amino, i.e., the compounds of the formula (I-2-20b)
    Figure US20030073706A1-20030417-C01572
  • (wherein, R[0748] 1-2-20b and R2-2-20b are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-20b(s) and R2-2-20b(s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing carboxy.
  • The amidation may be carried out by the same procedure for preparation of the compounds of the formula (I-1-4) in [4]. [0749]
  • [21] The compounds of the present invention of the formula (I-2) in which at least one of R[0750] 1(s) or R2(s) is an ester or a group containing ester, i.e., the compounds of the present invention of the formula (I-2-21)
    Figure US20030073706A1-20030417-C01573
  • (wherein, R[0751] 1-2-21 and R2-2-1 are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-2(s) and R2-2-21(s) is an ester or a group containing ester and the other symbols are the same meaning as hereinbefore described.) may be prepared by the following methods (a)˜(b).
  • (a) The compounds of the present invention of the formula (I-2-21) may be prepared by esterification of the compounds of the formula (I-2) in which at least one of R[0752] 1(s) or R2(s) is a —COOH or a group containing —COOH, i.e., the compounds of the formula (I-2-21a)
    Figure US20030073706A1-20030417-C01574
  • (wherein, R[0753] 1-2-21a and R2-2-21a are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-21a(s) and R2-2-21a(s) is a —COOH or a group containing —COOH and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing hydroxy.
  • This esterification may be carried out by the same procedure for preparation of the compounds of the formula (I-1-5) in [5]. [0754]
  • (b) The compounds of the present invention of the formula (I-2-21) may be prepared by esterification of the compounds of the formula (I-2) in which R[0755] 1(s) or R2(s) is a hydroxy or a group containing hydroxy, i e., the compounds of the formula (I-2-21b)
    Figure US20030073706A1-20030417-C01575
  • (wherein, R[0756] 1-2-21 and R2-2-21b are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-21b(s) and R2-2-21b(s) is a hydroxy or a group containing hydroxy and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing carboxy.
  • This esterification may be carried out by the same procedure for preparation of the compounds of the formula (I-1-5) in [5]. [0757]
  • [22] The compounds of the present invention of the formula (I-2) in which at least one of R[0758] 1(s) or R2(s) is a sulfonamide or a group containing sulfonamide, i.e., the compounds of the present invention of the formula (I-2-22)
    Figure US20030073706A1-20030417-C01576
  • (wherein, R[0759] 1-2-22 and R2-2-22 are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-22(s) and R2-2-22(s) is a sulfonamide or a group containing sulfonamide and the other symbols are the same meaning as hereinbefore described.) may be prepared by the following methods (a)˜(b).
  • (a) The compounds of the present invention of the formula (I-2-22) may be prepared by sulfonamidation of the compounds of the formula (I-2) in which at least one of R[0760] 1(s) or R2(s) is a —SO3H or a group containing —SO3H, i.e., the compounds of the formula (VI)
    Figure US20030073706A1-20030417-C01577
  • (wherein, R[0761] 1-2-22a and R2-2-22a are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-22a(s) and R2-2-22a(s) is a —SO3H or a group containing —SO3H and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing amino.
  • The sulfonamidation may be carried out by the same procedure for preparation of the compounds of the formula (I-1-6a) in [6]. [0762]
  • (b) The compounds of the present invention of the formula (I-2-22) may be prepared by sulfonamidation of the compounds of the formula (I-2) in which at least one of R[0763] 1(s) or R2(s) is an amino or a group containing amino, i.e., the compounds of the formula (I-2-22b)
    Figure US20030073706A1-20030417-C01578
  • (wherein, R[0764] 1-2-22b and R2-2-22b are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-22b(s) and R2-2-22b(s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing sulfo.
  • The sulfonamidation may be carried out by the same procedure for preparation of the compounds of the formula (I-1-6a) in [6]. [0765]
  • [23] The compounds of the present invention of the formula (I-2) in which at least one of R[0766] 1(s) or R2(s) is a substituted aminocarbonyloxy or a group containing a substituted aminocarbonyloxy, i.e., the compounds of the present invention of the formula (I-2-23)
    Figure US20030073706A1-20030417-C01579
  • (wherein, R[0767] 1-2-23 and R2-2-23 are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-23(s) and R2-2-23(s) is a substituted aminocarbonyloxy or a group containing a substituted aminocarbonyloxy and the other symbols are the same meaning as hereinbefore described,) may be prepared by reacting the compounds of the formula (I-2) in which at least one of R1(s) or R2(s) is a hydroxy or a group containing hydroxy, i.e., the compounds of the formula (I-2-23a)
    Figure US20030073706A1-20030417-C01580
  • (wherein, R[0768] 1-2-23a and R2-2-23a are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-23a(s) and R2-2-23a(s) is a hydroxy or a group containing hydroxy and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing isocyanate.
  • This reaction may be carried out by the same procedure for preparation of the compounds of the formula (I-1-7) in [7]. [0769]
  • [24] The compounds of the present invention of the formula (I-2) in which at least one of R[0770] 1(s) or R2(s) is a substituted aminocarbonylamino or a group containing a substituted aminocarbonylamino, i.e., the compounds of the present invention of the formula (I-2-24)
    Figure US20030073706A1-20030417-C01581
  • (wherein, R[0771] 1-2-24 and R2-2-24 are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-24(s) and R2-2-24(s) is a substituted aminocarbonylamino or a group containing a substituted aminocarbonylamino and the other symbols are the same meaning as hereinbefore described.) may be prepared by reacting the compounds of the formula (I-2) in which at least one of R1(s) or R2(s) is an amino or a group containing amino, i.e., the compounds of the formula (I-2-24a)
    Figure US20030073706A1-20030417-C01582
  • (wherein, R[0772] 1-2-24a and R2-2-24a are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-24a(s) and R2-2-24a(s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing isocyanate.
  • This reaction may be carried out by the same procedure for preparation of the compounds of the formula (I-1-7) in [7]. [0773]
  • [25] The compounds of the present invention of the formula (I-2) in which at least one of R[0774] 1(s) or R2(s) is a substituted oxycarbonylamino or a group containing a substituted oxyocarbonylamino, i.e., the compounds of the present invention of the formula (I-2-25)
    Figure US20030073706A1-20030417-C01583
  • (wherein, R[0775] 1-2-25 and R2-2-25 are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-25(s) and R2-2-25 (s) is a substituted oxycarbonylamino or a group containing a substituted oxyocarbonylamino and the other symbols are the same meaning as hereinbefore described.) may be prepared by reacting the compounds of the formula (I-2) in which at least one of R1(s) or R2(s) is an amino or a group containing amino, i.e., the compounds of the formula (I-2-25a)
    Figure US20030073706A1-20030417-C01584
  • (wherein, R[0776] 1-2-25a and R1-2-25a are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-25a(s) and R2-2-25a(s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing haloformic acid ester.
  • This reaction may be carried out by the same procedure for preparation of the compounds of the formula (I-1-9) in [9]. [0777]
  • [26] The compounds of the present invention of the formula (I-1) in which at least one of R[0778] 1(s) or R2(s) is a substituted oxycarbonyloxy or a group containing a substituted oxycarbonyloxy, i.e., the compounds of the present invention of the formula (I-2-26)
    Figure US20030073706A1-20030417-C01585
  • (wherein, R[0779] 1-2-26 and R2-2-26 are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-26(s) and R2-2-26(s) is a substituted oxycarbonyloxy or a group containing a substituted oxycarbonyloxy and the other symbols are the same meaning as hereinbefore described.) may be prepared by reacting the compounds of the formula (I-2) in which at least one of R1(s) or R2(s) is a hydroxy or a group containing hydroxy, i.e., the compounds of the formula (I-2-26a)
    Figure US20030073706A1-20030417-C01586
  • (wherein, R[0780] 1-2-26a and R2-2-26a are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-26a(s) and R2-22-6a(s) is a hydroxy or a group containing hydroxy and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing haloformic acid ester.
  • This reaction may be carried out by the same procedure for preparation of the compounds of the formula (I-1-9) in [9]. [0781]
  • [27] The compounds of the present invention of the formula (I-2) in which at least one of R[0782] 1(s) or R2(s) is a substituted (hydroxy)methyl or a group containing substituted (hydroxy)methyl, i.e., the compounds of the present invention of the formula (I-2-27)
    Figure US20030073706A1-20030417-C01587
  • (wherein, R[0783] 1-2-27 and R2-2-27 are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-27(s) and R2-2-27(s) is a substituted (hydroxy)methyl or a group containing a substituted (hydroxy)methyl and the other symbols are the same meaning as hereinbefore described.) may be prepared by reacting the compounds of the formula (I-2) in which at least one of R1(s) or R2(s) is a formyl, i.e., the compounds of the formula (I-2-27a)
    Figure US20030073706A1-20030417-C01588
  • (wherein, R[0784] 1-2-27a and R2-2-27a are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-27a(s) and R2-2-27a(s) is a formyl and the other symbols are the same meaning as hereinbefore described.) and Grignard's reagents or corresponding derivatives containing lithium.
  • This reaction may be carried out by the same procedure for preparation of the compounds of the formula (I-1-11a) in (11]. [0785]
  • [28] The compounds of the present invention of the formula (I-2) in which at least one of R[0786] 1(s) or R2(s) is a substituted carbonyl or a group containing a substituted carbonyl, i.e., the compounds of the present invention of the formula (I-2-28)
    Figure US20030073706A1-20030417-C01589
  • (wherein, R[0787] 1-2-28 and R2-2-28 are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-28(s) and R2-2-28(s) is a substituted carbonyl or a group containing a substituted carbonyl and the other symbols are the same meaning as hereinbefore described.) may be prepared by oxidizing the said compounds of the formula (I-2-27).
  • This reaction may be carried out by the same procedure for preparation of the compounds of the formula (I-1-12) in [12]. [0788]
  • [29] The compounds of the present invention of the formula (I-2) in which at least one of R[0789] 1(s) or R2(s) is an amino or a group containing amino, i.e., the compounds of the present invention of the formula (I-2-29)
    Figure US20030073706A1-20030417-C01590
  • (wherein, R[0790] 1-2-29 and R2-22-29 are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-29(s) and R2-2-29(s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) may be prepared by reduce of nitro in the compounds of the formula (I-2) in which at least one of R1(s) or R2(s) is a nitro or a group containing nitro, i.e., the compounds of the formula (I-2-29a)
    Figure US20030073706A1-20030417-C01591
  • (wherein, R[0791] 2-2-29a and R2-2-29a are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-29a(s) and R2-2-29a(s) is a nitro or a group containing nitro and the other symbols are the same meaning as hereinbefore described.).
  • The reduction of nitro may be carried out by the same procedure for preparation of the compounds of the formula (I-1-13) in [13]. [0792]
  • [30] The compounds of the present invention of the formula (I-2) in which at least one of R[0793] 1(s) or R2(s) is a —COOH, hydroxy or amino or a group containing —COOH, hydroxy or amino, i.e., the compounds of the present invention of the formula (I-2-30)
    Figure US20030073706A1-20030417-C01592
  • (wherein, R[0794] 1-2-30 and R2-2-30 are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-30(s) and R2-2-30(s) is a —COOH, hydroxy or amino or a group containing —COOH, hydroxy or amino and the other symbols are the same meaning as hereinbefore described.) may be prepared by removal of protecting group in the compounds of the formula (I-2) in which —COOH, hydroxy or amino which is protected by a protecting group or a group containing —COOH, hydroxy or amino which is protected by a protecting group, i.e., the compounds of the formula (I-2-30a)
    Figure US20030073706A1-20030417-C01593
  • (wherein, R[0795] 1-2-30a and R2-2-30a are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-30a(s) and R2-2-30a(s) is a protected —COOH (e.g., it is protected by methyl, ethyl, t-butyl and benzyl etc.), protected hydroxy (e.g., it is protected by methoxymethyl, tetrahydropyranyl, t-butyldimethylsilyl, acetyl, benzyl etc.) or protected amino (e.g., it is protected by benzyloxycarbonyl, t-butoxycarbonyloxy, trifluoroacetyl etc.) or a group containing such a group and the other symbols are the same meaning as hereinbefore described.) by an alkaline hydrolysis, by removal of protecting group in an acidic condition, by removal of silyl or by removal of protecting group based on hydrogenelysis. An alkaline hydrolysis, by removal of protecting group in an acidic condition, by removal of silyl or by hydrogenolysis may be carried out by same procedure for preparation of the compounds of the formula (I-1-14) in [14].
  • Reaction for removal of protecting group in the present invention means an ordinal one which is well known to the person in the art, for example, alkaline hydrolysis, removal of protecting group in an acidic condition and hydrogenolysis. The aimed compounds of the present invention may be prepared easily by choice of these reactions. [0796]
  • As well known to the person in the art, a protecting group of carboxy includes, for example, methyl, ethyl, t-butyl and benzyl. In addition, such a group includes the other protecting group which is removable selectively and easily, for example, one described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1991. [0797]
  • A protecting group of hydroxy includes, for example, methoxymethyl, tetrahydropyranyl, t-butyidimethylsilyl, acetyl, and benzyl. In addition, such a group includes the other protecting group which is removable selectively and easily, for example, one described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1991. [0798]
  • A protecting group of amino includes, for example, benzyloxycarbonyl, t-butoxycarbonyl, trifluoroacetyl. In addition, such a group includes the other protecting group which is removable selectively and easily, for example, one described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1991. [0799]
  • The compounds of the formula (V) are known per se or may be prepared according to the following Reaction Scheme or by known methods easily. [0800]
  • In Reaction Scheme, X is halogen. [0801]
    Figure US20030073706A1-20030417-C01594
  • The compounds of the formulae (III), (IV), (VI), (VII) or (VIII) used as starting materials have been known per se or may be prepared by known methods easily. [0802]
  • Further, the compounds of the formula (I-1-1 c) in which A is benzene, R[0803] 1 is carboxy, p is 1 and R1 is bonded at 4-position, i.e., the compounds of the formula (XI) are important intermediates of the compounds of the formula (I) of the present invention. The methods for preparation of the compounds of the formula (XI) are shown in the mentioned Reaction Scheme 5. Next, each step is explained in detail.
  • The reaction to synthesis of the compounds of the formula (XIII) from the compounds of the formula (XII) is well known. For example, it may be carried out in an inert organic solvent (acetonitrile, benzene, toluene, xylene, methyhlene chloride, chloroform, dimethoxy ethane, tetrahydrofuran, tetrahydropyran, dioxane, diethyl ether, acetone etc.) or mixture thereof, in the presence of Lewis acid (Znl[0804] 2, ZnCl2, aluminum chloride, TiCl2, lithium hypochloric acid, lithium borotetrafluoride, lithium hexafluoride etc.) and cyanide derivatives (trimethylsilylcyanide, diethyl aluminum cyanide, or diethyl cyanophosphonate etc.) at 0˜40°C.
  • The reaction to synthesis of the compounds of the formula (XIV) from the compounds of the formula (XIII) is well known. For example, it may be carried out in an inert organic solvent (benzene, toluene, ethyl acetate, dioxane, dimethoxy ethane, diethyl ether, tetrahydrofuran, tetrahydropyran, the mixture thereof etc.) in the presence of oxidant (2,3-dichloro-5,6-dicyano-1,4-benzoquinon, chloranil (2,3,5,6-tetrachloro-1,4-benzoquinon) etc.) at room temperature to refluxing temperature. Or it may be carried out, for example, in an organic solvent (ethylene glycol, oleic acid, diethylene glycol, dimethyl ether, toluene, benzene, xylene etc.) in the presence of hydrogen acceptor (nitrobenzene, maleic acid, cyclohexen, oleic acid, 1,5-cycloctadien, phenylacetylene, 2-butylic acid etc.) and in the presence of metal catalyst (Pd—C, palladium hydroxide, palladium black, Pd, platinum oxide, Ni, Raney nickel, ruthenium chloride etc.) at 60° C.˜refluxing temperature. [0805]
  • The reaction to synthesis of the compounds of the formula (XI) from the compounds of the formula (XIV) is well known. For example, it may be carried out in alcohol solvent (ethylene glycol, t-butanol, benzyl alcohol, methanol ethanol , propanol, isopropanol etc.) in the presence of alkali (sodium hydroxide, potassium hydroxide, lithium hydroxide etc.) at 60° C.˜refluxing temperature. [0806]
  • In each reaction in the present specification, obtained products may be purified by conventional techniques. For example, purification may be carried out by distillation at atmospheric or reduced pressure, by high performance liquid chromatography, by thin layer chromatography or by column chromatography using silica gel or magnesium silicate, by washing or by recrystallization. Purification may be carried out after each reaction, or after a series of reactions. [0807]
  • In addition, the optical isomers of the compounds of the present invention of the formula (I) may be obtained by an ordinal optical separation (e.g., separation by gas chromatography or by high performance liquid chromatography, separation by crystallization to diastermeric salt or clathrate compounds or separation by preferential crystallization etc.) or by ordinal method for preparation of racemic compound. [0808]
  • [Pharmacological Activities][0809]
  • According to the following experiments, it has been proved that the compounds of the present invention of the formula (I) possess inhibitory activities of producing IL-6 and/or IL-12. [0810]
  • (1) Assaying Inhibitory Activity on IL-6 production and cellular toxicity [0811]
  • [Experimental Method][0812]
  • 1.5×10[0813] 4 of A549 cells (human lung epithelial cell line) were suspended in dalbeco-modified eagle medium (DMEM) containing 0.5% fetus bovine serum (abbreviated as FBS) (100 μl) and incubated in 96 well-microplate over day and night. The test compound dissolved in various kinds of solvents at various concentrations (20 μl) and Tumor Necrosis Factor-α (TNF-α (Genzyme Co, Cat. No. TNF-H)) dissolved in DMEM at the concentration of 12.5 ng/ml (80 μl) were added thereto. After incubation for 24 hours, the supernatant (200 μl) was recovered to assay the quantity of IL-6 using Enzyme Linked Immuno Solvent Assay (ELISA) Method (R&D Systems Co., Cat. No. D6050), to calculate inhibitory activity of the test compound and determine 50 % inhibitory concentration (IC50). To the cells from which the supernatant was removed, a solution of brom 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolinium (abbreviated as MTT (Dojin Chemical Laboratory, Cat. No. 345-01821)) dissolved in DMEM containing 1 0% FBS at the concentration of 0.5mg/ml (100 μl) was added and incubated for 3 hours. After removing MTT solution, methanol (100 μl) was added thereto. After lyse the cells, the intensity of absorbance on 570 nm as a control of 690 nm was determined to assay cellular toxicity of the test compound. As a result, it has been proved that the compounds of the present invention possess an inhibitory activity on IL-6 production with an IC50 value of 20 μM or less. For example, free compound of the compound of
    • EXAMPLE 20(4) possessed an inhibitory activity on IL-6 production with an IC50 value of 4.4 μM and showed no cellular toxicity at 10 μM.
  • (2) Assaying Inhibitory Activity on IL-12 Production and Cellular Toxicity [0814]
  • [Experimental Method][0815]
  • 2.0×10[0816] 5 of peripheral monocyte prepared from healthy human blood by Ficole gravity centrifugation method (Pharmacia Biotech Co, Cat. No. 17-1440-02) were suspended in RPMI1640 medium containing 10% FBS (170 μl). The test compound dissolved in various kinds of solvents at the various concentrations (10 μl) and 6000 units/ml of Interferon-γ (IFN-γ (Serotec Co, Cat. No. PHP050)) (10 μl) dissolved in RPMI1640 medium containing 10% FBS. After incubation for 24 hours in 96 well-microplate, lipopolysaccharide (6 μg/ml) dissolved in RPMI1640 medium containing 10% FBS (LPS (Difco Co., Cat. No. 3120-25-0)) (10 μl) was added thereto. After incubation for 20 hours, the supernatant (150 μl) was recovered to assay the quantity of IL-12 using ELISA Method (R&D Systems Co, Cat. No. D1200), calculate for inhibitory activity of the test compound and determine 50% inhibitory concentration (IC50) (see J. Exp. Med., 183, 147 (1996)). To the cells from which the supernatant (150 μl) was removed, a solution of MTT dissolved in RPMI1640 medium containing 10% FBS at 1 mg/ml (50 μl) was added and incubated for 3 hours. 2-Propanol containing 0.04N HCl (100 μl) was added thereto. After lyse the cells, the intensity of absorbance on 570 nm as a control of 690 nm was determined to assay cellular toxicity of the test compound. As a results, it has been proved that the compounds of the present invention possess an inhibitory activity on IL-12 production with an IC50 value of 10 μM or less. For example, hydrochloride of the compound of Example 20(4) possessed an inhibitory activity on IL-12 production with an IC50 of 0.11 μM and showed no cellular toxicity at 1 μM.
  • [Toxicity][0817]
  • The toxicity of the compounds of the present invention is very low and therefore, it is confirmed that these compounds are safe for use as medicine. [0818]
  • [Application for Pharmaceuticals][0819]
  • The compounds of the present invention possess an inhibitory activity of producing IL-6 and/or IL-12 in animal, especially human, so they are useful for prevention and/or treatment of, for example, 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. [0820]
  • For the purpose above described, the compounds of the general formula (I) of the present invention, non-toxic salts, acid addition salts, or hydrates thereof may be normally administered systematically or locally, usually by oral or parenteral administration. [0821]
  • The doses to be administered are determined depending upon age, body weight, symptom, the desired therapeutic effect, the route of administration, and the duration of the treatment etc. In the human adult, the doses per person per dose are generally between 1 mg and 1000 mg, by oral administration, up to several times per day, and between 0.1 mg and 100 mg, by parenteral administration (preferred into vein) up to several times per day, or continuous administration between 1 and 24 hrs. per day into vein. [0822]
  • As mentioned above, the doses to be used depend upon various conditions. Therefore, there are cases in which doses lower than or greater than the ranges specified above may be used. [0823]
  • The compounds of the present invention may be administered as inner solid composition's or inner liquid compositions for oral administration, or as injections, liniments or suppositories etc. for parenteral administration. [0824]
  • Inner solid compositions for oral administration include compressed tablets, pills, capsules, dispersible powders, and granules. Capsules contain hard capsules and soft capsules. [0825]
  • In such inner solid compositions, one or more of the active compound(s) is or are, admixed with at least one inert diluent (lactose, mannitol, glucose, microcrystalline cellulose, starch etc.), connecting agents (hydroxypropyl cellulose, polyvinylpyrrolidone, magnesium metasilicate aluminate etc.), disintegrating agents (cellulose calcium glycolate etc.), lubricating agents (magnesium stearate), stabilizing agents, assisting agents for dissolving (glutamic acid, asparaginic acid etc.) etc. to prepare pharmaceuticals by known methods. The pharmaceuticals may, if desired, be coated with material such as sugar, gelatin, hydroxypropyl cellulose or hydroxypropyl cellulose phthalate etc., or be coated with two or more films. And further, coating may include containment within capsules of absorbable materials such as gelatin. [0826]
  • Inner liquid compositions for oral administration include pharmaceutically-acceptable water-agents, emulsions, syrups and elixirs etc. In such liquid compositions, one or more of the active compound(s) is or are comprised in inert diluent(s) commonly used in the art (purified water, ethanol or mixture thereof etc.). Besides inert diluents, such compositions may also comprise adjuvants such as wetting agents, suspending agents, sweetening agents, flavouring agents, perfuming agents and preserving agents. [0827]
  • Injections for parenteral administration include solutions, suspensions and emulsions, and solid injections. Aqueous solutions or suspensions include distilled water for injection and physiological salt solution. Non-aqueous solutions or suspensions include propylene glycol, polyethylene glycol, plant oil such as olive oil, alcohol such as ethanol, POLYSOLBATE80 (registered trade mark) etc. Such compositions may comprise additional diluents: e.g. preserving agents, wetting agents, emulsifying agents, dispersing agents, stabilizing agent, assisting agents such as assisting agents for dissolving (for example, glutamic acid, asparaginic acid). They may be sterilized for example, by filtration through a bacteria-retaining filter, by incorporation of sterilizing agents in the compositions or by irradiation. They may also be manufactured in the form of sterile solid compositions and which can be dissolved in sterile water or some other sterile diluent for injection immediately before use. [0828]
  • Other compositions for parenteral administration include liquids for external use, and endermic liniments, ointments, spray, suppositories and pessaries which comprise one or more of the active compound(s) and may be prepared by known methods. [0829]
  • Spray compositions may comprise additional substances other than inert diluents: e.g. stabilizing agents such as sodium hydrogen sulfate, stabilizing agents to give isotonicity, isotonic buffer such as sodium chloride, sodium citrate, citric acid. For preparation of such spray compositions, for example, the method described in the U.S. Pat. Nos. 2,868,691 or 3,095,355 may be used. [0830]
    • BEST MODE FOR CARRYING OUT THE INVENTION
  • The following reference Examples and Examples are intended to illustrate, but do not limit the present invention. [0831]
  • The solvents in parenthesis show the developing or eluting solvents and the ratios of the solvents used are by volume in chromatographic separations. The solvents in parentheses in NMR show the solvents used for measurement.[0832]
    • EXAMPLE 1 3-Phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0833]
    Figure US20030073706A1-20030417-C01595
  • To asolution of benzothiophene-1,1-dioxide (1 g) in tetrahydrofuran (10 ml) were added triethylamine (1.55 ml) and thiophenol (798 mg). The reaction mixture was stirred for 4 hours at room temperature. To the reaction mixture was water added. The mixture was extracted with ethyl acetate. The extract was washed by water, a saturated aqueous solution of sodium chloride successively, dried over anhydrous sodium sulfate, and concentrated. The residue was purified with chromatography on silica gel (hexane:ethyl acetate=1:1). The obtained compound was then recrystallized from ethanol to give the title compound (1.18 g) having the following physical data. [0834]
  • TLC: Rf 0.46 (hexane:ethyl acetate=2:1); [0835]
  • NMR (CDCl[0836] 3): δ 7.85-7.18 (9H, m), 4.98 (1H, t, J=7 Hz), 3.80 (1H, dd, J=14, 7 Hz), 3.51 (1H, dd, J=14, 7 Hz).
    • EXAMPLES 1(1)˜1(18)
  • By the same procedure as described in Example 1 using a corresponding thiol instead of thiophenol, the following compounds of the present invention were obtained. [0837]
    • EXAMPLE 1 (1) 3-(Thiophen-2-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0838]
    Figure US20030073706A1-20030417-C01596
  • TLC: Rf 0.53 (hexane:ethyl acetate=1:1); [0839]
  • NMR (CDCl[0840] 3):δ 7.81-7.66 (m, 3H), 7.58-7.51 (m, 1H), 7.42 (dd, J=5.4, 1.4 Hz, 1H), 7.14 (dd, J=3.6, 1.4 Hz, 1H), 7.00 (dd, J=5.4, 3.6 Hz, 1H), 4.78 (t-like, J=6.9 Hz, 1H), 3.80 (dd, J=14.0, 7.2 Hz, 1H), 3.51 (dd, J=14.0, 6.6 Hz, 1H).
    • EXAMPLE 1 (2) 3-(4-Methylphenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0841]
    Figure US20030073706A1-20030417-C01597
  • TLC: Rf 0.40 (hexane:ethyl acetate=2:1); [0842]
  • NMR (CDCl[0843] 3): δ 7.85-7.57 (m, 4H), 7.42 (d, J=8.0 Hz, 2H), 7.21 (d, J=8.0 Hz, 2H), 4.80 (t-like, J=6.5 Hz, 1H), 3.85 (dd, J=14.0, 7.5 Hz, 1H), 3.38 (dd, J=14.0, 6.0 Hz, 1H).
    • EXAMPLE 1 (3) 3-(4-Methoxyphenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0844]
    Figure US20030073706A1-20030417-C01598
  • TLC: Rf 0.38 (hexane:ethyl acetate=2:1); [0845]
  • NMR (CDC[0846] 3): δ 7.82-7.45 (4H, m), 7.36 (2H, d, J=7 Hz), 6.85 (2H, d, J=7 Hz), 4.83 (1 H, t, J=7 Hz), 3.83 (3H, s), 3.74 (1 H, dd, J=13, 7 Hz), 3.46 (1 H, dd, J=13, 7 Hz).
    • EXAMPLE 1 (4) 3-(4-Chlorophenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0847]
    Figure US20030073706A1-20030417-C01599
  • TLC: Rf 0.37 (hexane ethyl acetate=2:1); [0848]
  • NMR (CDCl[0849] 3): δ 7.88-7.67 (m, 4H), 7.32 (d, J=8.0 Hz, 2H), 7.25 (d, J=8.0 Hz, 2H), 4.83 (t-like, J=7.0 Hz, 1H), 3.83 (dd, J=14.5, 6.5 Hz, 1H), 3.52 (dd, J=14.5, 7.8 Hz, 1H).
    • EXAMPLE 1 (5) 3-(4-Fluorophenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0850]
    Figure US20030073706A1-20030417-C01600
  • TLC Rf 0.36 (hexane:ethyl acetate=2:1); [0851]
  • NMR (CDCl[0852] 3): δ 7.80-7.32 (m, 6H), 7.04 (t-like, J=8.8 Hz, 2H), 4.90 (t-like, J=6.6 Hz, 1H), 3.78 (dd, J=13.6, 7.6 Hz, 1H), 3.50 (dd, J=13.6, 6.4 Hz, 1H).
    • EXAMPLE 1 (6) 3-(4-Hydroxyphenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0853]
    Figure US20030073706A1-20030417-C01601
  • TLC: Rf 0.33 (hexane:ethyl acetate=1:1); [0854]
  • NMR (CDCl[0855] 3): δ 3.45 (dd, J=15, 7.5Hz, 1H), 3.75 (dd, J15, 7.5Hz, 1H), 4.80 (t, J=7.5 Hz, 1H), 5.60 (s, 1H), 6.75 (d, J=7.5 Hz, 2H), 7.30 (d, J=7.5 Hz, 2H), 7.45-7.80 (m, 4H).
    • EXAMPLE 1 (7) 3-(3-Hydroxyphenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0856]
    Figure US20030073706A1-20030417-C01602
  • TLC: Rf 0.36 (hexane:ethyl acetate=1:1); [0857]
  • NMR (CDCl[0858] 3): δ 3.50 (dd, J=15, 7.5 Hz, 1H), 3.85 (dd, J=15, 7.5 Hz, 1H), 5.00 (t, J=7.5 Hz, 1H), 5.65 (s, 1H), 6.75-7.00 (m, 3H), 7.10-7.30 (m, 1H), 7.50-7.80 (m, 4H).
    • EXAMPLE 1 (8) 3-(2-Hydroxyphenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0859]
    Figure US20030073706A1-20030417-C01603
  • TLC: Rf 0.33 (hexane ethyl acetate=1:1); [0860]
  • NMR (CDCl[0861] 3): δ 3.45 (dd, J=12.5, 5.0 Hz, 1H), 3.70 (dd, J=12.5, 7.5 Hz, 1H), 4.80 (dd, J=7.5, 5.0 Hz, 1H), 6.65 (s, 1H), 6.90 (t, J=7.5 Hz, 1H), 7.00 (d, J=7.5 Hz, 1H), 7.30 -7.80 (m, 6H).
    • EXAMPLE 1 (9) 3-(Pyridin-4-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0862]
    Figure US20030073706A1-20030417-C01604
  • TLC: Rf 0.45 (ethyl acetate) [0863]
  • NMR (CDCl[0864] 3): δ 3.58 (dd, J=13, 6 Hz, 1H), 4.00 (dd, J=13, 6 Hz, 1H), 5.22 (t, J=6 Hz, 1H), 7.20 (m, 2H), 7.69 (m, 4H), 8.51 (m, 2H)
    • EXAMPLE 1 (10) 3-(Pyrimidin-2-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0865]
    Figure US20030073706A1-20030417-C01605
  • TLC: Rf 0.55 (hexane:ethyl acetate=1:2); [0866]
  • NMR (CDCl[0867] 3): δ 3.71 (dd, J=14, 7 Hz, 1H), 4.24 (dd, J=14, 7 Hz, 1H), 5.70 (t, J=7 Hz, 1H), 7.10 (t, J=5 Hz, 1H), 7.52-7.85 (m, 4H), 8.58 (d, J=5 Hz, 2H).
    • EXAMPLE 1 (11) 3-(Thiazol-2-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0868]
    Figure US20030073706A1-20030417-C01606
  • TLC: Rf 0.52 (hexane:ethyl acetate=1:1); [0869]
  • NMR (CDCl[0870] 3): δ 3.55 (dd, J=13.4 Hz, 1H), 3.81 (dd, J=13, 7 Hz, 1H), 5.60 (dd, J=7, 4 Hz, 1H), 7.57-7.80 (m, 6H).
    • EXAMPLE 1 (12) 3-(3-Methylfuran-2-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0871]
    Figure US20030073706A1-20030417-C01607
  • TLC: Rf 0.45 (hexane ethyl acetate=4:1); [0872]
  • NMR (CDCl[0873] 3): δ 2.27 (s, 3H), 3.39 (dd, J=14.0 Hz, 6.0 Hz, 1H), 3.75 (dd, J=14.0 Hz, 6.0 Hz, 1H), 4.69 (t, J=6.0 Hz, 1H), 6.07 (d, J=2.0 Hz, 1H), 7.25 (d, J=2.0 Hz, 1H), 7.48-7.77 (m, 4H).
    • EXAMPLE 1 (13) 3-(3-Methoxyphenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0874]
    Figure US20030073706A1-20030417-C01608
  • TLC: Rf 0.44 (hexane:ethyl acetate=1:1); [0875]
  • NMR (CDCl[0876] 3): δ 3.50 (dd, J=12.5, 7.5 Hz, 1H), 3.75 (s, 3H), 3.80 (dd, J=12.5, 7.5 Hz, 1H), 5.00 (t, J=7.5 Hz, 1H), 6.85-7.05 (m, 3H), 7.20-7.30 (m, 1H), 7.50-7.80 (m, 4H).
    • EXAMPLE 1 (14) 3-(2-Methoxycarbonylphenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0877]
    Figure US20030073706A1-20030417-C01609
  • TLC: Rf 0.40 (hexane ethyl acetate=1:1); [0878]
  • NMR (CDCl[0879] 3): δ 3.60 (dd, J=15, 7.5 Hz, 1H), 3.90 (s, 3H), 3.95 (dd, J=15, 7.5 Hz, 1H), 5.25 (t, J=7.5 Hz, 1H), 7.30-7.80 (m, 7H), 7.95-8.05 (m, 1H).
    • EXAMPLE 1 (15) 3-Cyclohexylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0880]
    Figure US20030073706A1-20030417-C01610
  • TLC: Rf 0.32 (hexane:ethyl acetate=3:1); [0881]
  • NMR (CDCl[0882] 3): δ 1.26-2.10 (m, 10H), 2.80-2.93 (m, 1H), 3.52 (dd, J=13.4, 7.4 Hz, 1H), 3.92 (dd, J=13.4, 7.4 Hz, 1H), 4.68 (t, J=7.4 Hz, 1H), 7.47-7.54 (m, 1H), 7.59-7.67 (m, 1H), 7.70-7.75 (m, 2H).
    • EXAMPLE 1 (16) 3-(Naphthalen-1-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0883]
    Figure US20030073706A1-20030417-C01611
  • TLC: Rf 0.36 (hexane:ethyl acetate=2:1); [0884]
  • NMR (CDCl[0885] 3): δ 3.51 (dd, J=13.6, 5.8 Hz, 1H), 3.64 (dd, J=13.6 Hz, 7.3 Hz, 1H), 5.01 (t-like, J=6.4 Hz, 1H), 7.40-7.79 (m, 8H), 7.90-7.94 (m, 2H), 8.52-8.56 (m, 1H).
    • EXAMPLE 1 (17) 3-(2-Methoxyphenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0886]
    Figure US20030073706A1-20030417-C01612
  • TLC: Rf 0.49 (hexane:ethyl acetate=1:1); [0887]
  • NMR (CDCl[0888] 3): δ 3.55 (dd, J=12.5, 7.5 Hz, 1H), 3.75 (dd, J=12.5, 7.5 Hz, 1H), 3.90 (s, 3H), 5.10 (t, J=7.5 Hz, 1H), 6.90-7.00 (m, 2H), 7.30-7.80 (m, 6H).
    • EXAMPLE 1 (18) 3-(1-Methylimidazol-2-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0889]
    Figure US20030073706A1-20030417-C01613
  • TLC: Rf 0.50 (hexane:ethyl acetate=1:2); NMR (CDCl[0890] 3):5 3.54 (dd, J=14, 3 Hz, 1H), 3.65 (s, 3H), 4.04 (dd, J=14, 9 Hz, 1H), 6.58 (d, J=2.7 Hz, 1H), 6.65 (d, J=2.7 Hz, 1H), 6.95 (dd, J=9,3 Hz, 1H), 7.56 (m, 1H), 7.67 (m, 2H), 7.85 (m, 1H).
    • EXAMPLE 2 3-Phenylsulfinyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0891]
    Figure US20030073706A1-20030417-C01614
  • To potassium peroxymonosulfate (“OXONE” (trade name) marketed from Aldrich Co., abbreviated as OXONE®; 2.14 g), water (10 ml) was added. To a solution of a compound prepared in Example 1 (0.961 g) in methanol (50 ml), thus obtained aqueous solution of OXONE® (5.5 ml) was added at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes. To the reaction mixture, water was added. The mixture was extracted by ethyl acetate. The extract was washed by water (twice) and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from ethanol to give the title compound (361 mg) having the following physical data. [0892]
  • TLC: Rf 0.13 (hexane:ethyl acetate=1:1); [0893]
  • NMR (CDCl[0894] 3): δ 7.85-7.45 (9H, m), 4.57 (1H, t, J=7 Hz), 3.98 (1H, dd, J=14, 7 Hz), 3.19 (1H, dd, J=14, 7 Hz).
    • EXAMPLES 2 (1)˜2 (2)
  • By the same procedure as described in Example 2 using the compounds prepared in Example 1 (1) and Example 1 (14) instead of the compound prepared in Example 1, the following compounds of the present invention were obtained. [0895]
    • EXAMPLE 2 (1) 3-(Thiophen-2-yl)sulfinyl-2,3-dihydro-1,1 -dioxidebenzo[b]thiophene
  • [0896]
    Figure US20030073706A1-20030417-C01615
  • TLC: Rf 0.01 (hexane:ethyl acetate=1:1); [0897]
  • NMR (CDCl[0898] 3): δ 7.95-7.50 (4.5H m), 7.50-7.25 (1.5H, m), 7.25-7.10 (1H, m), 4.99 (0.5H, dd, J=8.4, 4 Hz), 4.81(0.5H, dd, J=8.4, 4 Hz), 4.02 (0.5H, dd, J=14.2, 4.4 Hz), 3.72-3.40 (1.5H, m).
    • EXAMPLE 2 (2) 3-(2-Methoxycarbonylphenyl)sulfinyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0899]
    Figure US20030073706A1-20030417-C01616
  • TLC: Rf 0.33 (hexane:ethyl acetate=1:1); [0900]
  • NMR (CDCl[0901] 3): δ 2.90 (dd, J=12.5, 7.5 Hz, 1H), 4.00 (s, 3H), 4.00(dd, J=12.5, 7.5 Hz, 1H), 5.05 (t, J=7.5 Hz, 1H), 7.55-7.90 (m, 5H), 8.10-8.25 (m, 3H).
    • EXAMPLE 3 3-Phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0902]
    Figure US20030073706A1-20030417-C01617
  • To OXONE® (2.14 9), water (10 ml) was added. To a solution of the compound prepared in Example 1 (0.961 g) in methanol (50 ml),was added thus obtained aqueous solution of OXONE® at room temperature. The reaction mixture was stirred for 2 hours at room temperature. To the reaction mixture, water was added. The mixture was extracted by ethyl acetate. The extract was washed by water (twice) and a saturated aqueous solution of sodium chloride successively, dried over anhydrous sodium sulfate, and concentrated. The residue was recrystallized from ethanol to give the compound of the present invention (1.54 g) having the following physical data. [0903]
  • TLC: Rf 0.45 (hexane:ethyl acetate=1:1); [0904]
  • NMR (CDCl[0905] 3): δ 3.65-3.85 (m, 2H), 5.10 (dd, J=10, 5.0 Hz, 1H), 7.40-7.80 (m, 8H), 8.05 (d, J=10 Hz, 1H).
    • EXAMPLES 3 (1)˜3 (17)
  • By the same procedure as described in Example 3 using the compounds prepared in Examples 1 (1)˜1 (17) instead of the compound prepared in Example 1, or using 3-chloroperbenzoic acid instead of OXONE® as an oxidant, the following compounds of the present invention were obtained. [0906]
    • EXAMPLE 3 (1) 3-(Thiophen-2-yl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0907]
    Figure US20030073706A1-20030417-C01618
  • TLC: Rf 0.18 (hexane:ethyl acetate=2:1); [0908]
  • NMR (CDCl[0909] 3): δ 8.08 (d, J=5.0 Hz, 1H), 7.82-7.66 (m, 5H), 7.20 (dd, J=5.0, 3.8Hz, 1H), 5.82 (dd, J=9.4, 3.1 Hz, 1H), 4.07 (dd, J=15.4, 9.4 Hz, 1H), 3.83 (dd, J=15.4, 3.1 Hz, 1H).
    • EXAMPLE 3 (2) 3-(4-Methylphenyl)sulfonyl-2,3-dihidro-1,1 -dioxidebenzo[b]thiophene
  • [0910]
    Figure US20030073706A1-20030417-C01619
  • TLC. Rf 0.11 (hexane:ethyl acetate=2:1); [0911]
  • NMR (CDCl[0912] 3): δ 8.04 (1H, d, J=8 Hz), 7.82-7.58 (3H, m), 7.53 (2H, d, J=9 Hz), 7.28 (2H, d, J=9 Hz), 5.08 (1 H, dd, J=1H, 8 Hz), 3.86-3.55 (2H, m), 2.42 (3H, s).
    • EXAMPLE 3 (3) 3-(4-Methoxyphenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0913]
    Figure US20030073706A1-20030417-C01620
  • TLC: Rf 0.23 (hexane:ethyl acetate=1:1); [0914]
  • NMR (CDCl[0915] 3): δ 8.04 (1H, d, J=8 Hz), 7.88-7.60 (3H, m), 7.54 (2H, d, J=7 Hz), 6.91 (2H, d, J=7 Hz), 5.06 (1 H, t, J=7 Hz), 3.85 (3H, s), 3.80-3.60 (2H, m).
    • EXAMPLE 3 (4) 3-(4-Chlorophenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0916]
    Figure US20030073706A1-20030417-C01621
  • TLC: Rf 0.26 (hexane:ethyl acetate=2:1); [0917]
  • NMR (CDCl[0918] 3): δ 8.02 (1H, d, J=8 Hz), 7.85-7.58 (3H, m), 7.58-7.32 (4H, m), 5.09 (1 H, t, J=7 Hz), 3.90-3.65 (2H, m).
    • EXAMPLE 3 (5) 3-(4-Fluorophenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0919]
    Figure US20030073706A1-20030417-C01622
  • TLC: Rf 0.41 (hexane:ethyl acetate=1:1) [0920]
  • NMR (CDCl[0921] 3): δ 8.03 (1H, d, J=8 Hz), 7.90-7.45 (5H, m), 7.20-7.00 (2H, m), 5.08 (1H, t, J=7 Hz), 3.80-3.75 (2H, m).
    • EXAMPLE 3 (6) 3-(4-Hydroxyphenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0922]
    Figure US20030073706A1-20030417-C01623
  • TLC: Rf 0.27 (hexane:ethyl acetate=1:1); [0923]
  • NMR (CD[0924] 3OD+CDCl3): δ 7.97 (1 H, d, J=7 Hz), 7.85-7.55 (3H, m), 7.46 (2H, d, J=9 Hz), 6.84 (2H, d, J=9 Hz), 5.09 (1H, t, J=7 Hz), 3.90-3.60 (2H, m).
    • EXAMPLE 3(7) 3-(3-Hydroxyphenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0925]
    Figure US20030073706A1-20030417-C01624
  • TLC: Rf 0.22 (hexane:ethyl acetate=1:1); [0926]
  • NMR (CDCl[0927] 3+DMSO-d6): δ 9.83 (1H, brs), 7.90-7.78 (1 H, m), 7.78-7.50 (3H, m), 7.42-7.08 (4H, m), 5.28-5.10 (1H, m), 3.90-3.58 (2H, m).
    • EXAMPLE 3 (8) 3-(2-Hydroxyphenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0928]
    Figure US20030073706A1-20030417-C01625
  • TLC: Rf 0.15 (hexane:ethyl acetate=1:1); [0929]
  • NMR (CDCl[0930] 3+DMSO-d6): δ 7.90-7.42 (6H, m), 7.13 (1H, d, J=8 Hz), 6.98 (1H, t, J=7 Hz), 5.71 (1H, dd, J=9, 5 Hz), 3.86 (1H, dd, J=14, 5 Hz), 3.65 (1H, dd, J=14, 9 Hz).
    • EXAMPLE 3 (9) 3-(Pyridin-4-yl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0931]
    Figure US20030073706A1-20030417-C01626
  • TLC: Rf 0.25 (hexane:ethyl acetate=1:2); [0932]
  • NMR (DMSO-d[0933] 6): δ 3.87 (dd, J=15, 3 Hz, 1H), 4.03 (dd, J=15, 9Hz, 1H), 5.94 (dd, J=9, 3 Hz, 1H), 7.70 (dd, J=4, 2 Hz, 2H), 7.81 (m, 4H), 8.88 (dd, J=4, 2 Hz, 2H).
    • EXAMPLE 3 (10) 3-(Pyrimidin-2-yl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0934]
    Figure US20030073706A1-20030417-C01627
  • TLC: Rf 0.15 (methylene chloride); [0935]
  • NMR (DMSO-d[0936] 6): δ 4.00 (dd, J=16, 4 Hz, 1H), 4.12 (dd, J=16, 9 Hz, 1H), 6.17 (dd, J=9, 4 Hz, 1H), 7.78 (m, 3H), 7.90 (m, 2H), 9.09 (dd, J=5, 1 Hz, 2H).
    • EXAMPLE 3 (11) 3-(Thiazol-2-yl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0937]
    Figure US20030073706A1-20030417-C01628
  • TLC: Rf 0.40 (hexane:ethyl acetate=1:1); [0938]
  • NMR (CDCl[0939] 3): δ 3.87 (dd, J=15, 9 Hz, 1H), 4.20 (dd, J=15, 5 Hz, 1H), 5.39 (dd, J=9, 5 Hz, 1H), 7.61-7.81 (m, 4H), 7.99-8.08 (m, 2H).
    • EXAMPLE 3 (12) 3-(3-Methylfuran-2-yl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]furan
  • [0940]
    Figure US20030073706A1-20030417-C01629
  • TLC: Rf 0.50 (hexane:ethyl acetate=3:2); [0941]
  • NMR (CDCl[0942] 3): δ 2.39 (s, 3H), 3.78 (dd, J=15, 4 Hz, 1H), 3.88 (dd, J=15, 8 Hz, 1H), 5.00 (dd, J=8, 4 Hz, 1H), 5.98 (d, J=2 Hz, 1H), 7.18 (d, J=2 Hz, 1H), 7.60-7.80 (m, 3H), 8.02 (m, 1H).
    • EXAMPLE 3 (13) 3-(3-Methyoxyphenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0943]
    Figure US20030073706A1-20030417-C01630
  • TLC: Rf 0.33 (hexane:ethyl acetate=1:1); [0944]
  • NMR (CDCl[0945] 3): δ 3.65-3.90 (m, 2H), 3.75 (s, 3H), 5.10 (dd, J=10, 5.0Hz, 1H), 7.10-7.50 (m, 4H), 7.60-7.80 (m, 3H), 8.00 (d, J=7.5 Hz, 1H).
    • EXAMPLE 3 (14) 3-(2-Methoxycarbonylphenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0946]
    Figure US20030073706A1-20030417-C01631
  • TLC: Rf 0.59 (methylene chloride:ethyl acetate=9:1); [0947]
  • NMR (CDCl3): δ 8.01-7.97 (m, 1H), 7.84-7.63 (m, 7H), 6.06 (dd, J=9.0, 4.5 Hz, 1H), 4.04 (s, 3H), 3.92 (dd, J=14.0, 4.5 Hz, 1H), 3.63 (dd, J=14.0, 9.0 Hz, 1H). [0948]
    • EXAMPLE 3 (15) 3-Cyclohexylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0949]
    Figure US20030073706A1-20030417-C01632
  • TLC: Rf 0.37 (hexane:ethyl acetate=1:1); [0950]
  • NMR (CDCl[0951] 3): δ 1.13-1.68 (m, 8H), 1.90-1.96 (m, 1H), 2.15-2.19 (m, 1H), 3.07-3.23 (m, 1H), 3.87 (dd, J=14.5, 8.2 Hz, 1H), 3.95 (dd, J=14.5, 5.2 Hz, 1H), 4.96 (dd, J=8.2, 5.2 Hz, 1H), 7.63-7.83 (m, 3H), 7.96-8.00 (m, 1H).
    • EXAMPLE 3 (16 ) 3-(Naphthalen-1-yl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0952]
    Figure US20030073706A1-20030417-C01633
  • TLC: Rf 0.40 (hexane:ethyl acetate=1:1); [0953]
  • NMR (CDCl[0954] 3): δ 3.38 (dd, J=14.4, 8.8 Hz, 1H), 3.77 (dd, J=14.4, 5.0 Hz, 1H), 5.31 (dd, J=8.8, 5.0 Hz, 1H), 7.60-7.81 (m, 7H), 8.00-8.05 (m, 1H), 8.22-8.28 (m, 2H), 8.72-8.77 (m, 1H).
    • EXAMPLE 3 (17) 3-(2-Methoxyphenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0955]
    Figure US20030073706A1-20030417-C01634
  • TLC: Rf 0.20 (hexane:ethyl acetate=1:1); [0956]
  • NMR (CDCl[0957] 3+DMSO-d6): δ 3.65 (dd, J=15, 10 Hz, 1H), 3.80 (dd, J=15, 5.0 Hz, 1H), 4.00 (s, 3H), 5.55 (dd, J=10, 5.0 Hz, 1H), 7.05-7.20 (m, 2H), 7.60-7.95 (m, 6H).
    • EXAMPLE 4 3-(4-(2-(Piperidin-1-yl)ethoxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0958]
    Figure US20030073706A1-20030417-C01635
  • To a solution of the compound prepared in Example 3 (6) (283 mg) in dimetyhylformamide (5 ml) were added N-chloroethylpiperidine (193 mg) and cesium carbonate (1.0 g). The reaction mixture was stirred at room temperature overnight. To the reaction mixture, water was added. The mixture was extracted by ethyl acetate. The extract was washed by water (three times), a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The residue was purified with column chromatography on silica gel (hexane:ethyl acetate=1:1) to give the compound of the present invention (186 mg) having the following physical data. [0959]
  • TLC: Rf 0.54 (ethyl acetate:methanol:28% ammonia water=100:10:1); [0960]
  • NMR (CDCl[0961] 3):δ 8.03 (1H, d, J=7 Hz), 7.85-7.55 (3H, m), 7.53 (2H, d, J=9 Hz), 6.92 (2H, d, J=9 Hz), 5.05 (1H, t, J=7 Hz), 4.13 (2H, t, J=6 Hz), 3.85-3.60 (2H, m), 2.76 (2H, t, J=6 Hz), 2.49 (4H, brt, J=6 Hz), 1.68-1.45 (6H, m).
    • EXAMPLES 4 (1)˜4 (4)
  • By the same procedure as described in Example 4 by using the compounds prepared in Examples 3 (6)˜3 (8) and corresponding halogenated compounds, the following compounds of the present invention were obtained. [0962]
    • EXAMPLE 4 (1) 3-(4- (2-(pyrrolidin-1-yl)ethoxy) phenyl)sulfonyl)-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0963]
    Figure US20030073706A1-20030417-C01636
  • TLC: Rf 0.35 (ethyl acetate:methanol:28% ammonia water=100:10:1); [0964]
  • NMR (CDCl[0965] 3): δ 8.03 (1H, d, J=7 Hz), 7.90-7.40 (5H, m), 6.93 (2H, d, J=7 Hz), 5.18-4.95 (1H, m), 4.14 (2H, t, J=6 Hz), 3.90-3.60 (2H, m), 2.91 (2H, t, J=6 Hz), 2.75-2.40 (4H, m), 1.84-1.74 (4H, m).
    • EXAMPLE 4 (2) 3-(4-(2-(Morpholine-1-yl)ethoxy) phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0966]
    Figure US20030073706A1-20030417-C01637
  • TLC: Rf 0.44 (ethyl acetate:methanol:28% ammonia water=100:10:1); [0967]
  • NMR (CDCl[0968] 3): δ 8.05 (1H, d, J=7 Hz), 7.85-7.40 (5H, m), 6.91 (2H, d, J=7 Hz), 5.06 (1H, t, J=7 Hz), 4.13 (2H, t, J=6 Hz), 3.95-3.50 (6H, m), 2.80 (2H, t, J=6 Hz), 2.70-2.40 (4H, m).
    • EXAMPLE 4 (3) 3-(3-Benzyloxyphenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0969]
    Figure US20030073706A1-20030417-C01638
  • TLC: Rf 0.55 (hexane:ethyl acetate=1:1); [0970]
  • NMR (CDCl[0971] 3): δ 8.02 (1H, d, J=7 Hz), 7.85-7.52 (3H, m), 7.52-7.10 (9H, m), 5.15-4.85 (3H, m), 3.80-3.45 (2H, m).
    • EXAMPLE 4 (4) 3-(2-Benzyloxyohenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0972]
    Figure US20030073706A1-20030417-C01639
  • TLC: Rf 0.37 (hexane ethyl acetate=1:1); [0973]
  • NMR (CDCl[0974] 3): δ 7.93 (1H, dd, J=8, 2 Hz), 7.85-7.30 (10 H, m), 7.25-7.08 (2H, m), 5.52 (1H, dd, J=9, 5 Hz), 5.28 (2H, s), 3.79 (1H, dd, J=14, 5 Hz), 3.48 (1H, dd, J=14, 9 Hz).
    • EXAMPLE 5 3-(4-(Pyridin-2-ylmethyloxy)phenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0975]
    Figure US20030073706A1-20030417-C01640
  • By the same procedure as described in Example 4 using the compound prepared in Example 1 (6) instead of the compound prepared in Example 3 (6), and using a corresponding halogenated compound instead of N-chloroethylpiperidine, the compound of the present invention having the following physical data was obtained. [0976]
  • TLC: Rf 0.58 (ethyl acetate) [0977]
  • NMR (CDCl[0978] 3): δ 8.65-8.55 (1H, m), 7.80-7.20 (9H, m), 7.00-6.90 (2H, m), 5.20 (2H, s), 4.85 (1H, t, J=7.5 Hz), 3.75 (1H, dd, J=12.5, 7.5 Hz), 3.45 (1H, dd, J=12.5, 7.5 Hz).
    • EXAMPLES 5 (1)˜5 (9)
  • By the same procedure as described in Example 5 using the compounds prepared in Examples 1 (6)˜1 (8), the following compounds of the present invention were obtained. [0979]
    • EXAMPLE 5 (1) 3-(4-Pyridin-3-ylmethyloxy)phenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0980]
    Figure US20030073706A1-20030417-C01641
  • TLC: Rf 0.42 (ethyl acetate); [0981]
  • NMR (CDCl[0982] 3): δ 8.70-8.60 (2H, m), 7.80-7.30 (8H, m), 7.00-6.90 (2H, m), 5.05 (2H, s), 4.85 (1H, t, J=5 Hz), 3.75 (1H, dd, J=15, 5 Hz), 3.45 (1H, dd, J=15, 5 Hz).
    • EXAMPLE 5 (2) 3-(4-(Pyridin-4-ylmethyloxy)phenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0983]
    Figure US20030073706A1-20030417-C01642
  • TLC: Rf 0.33 (ethyl acetate); [0984]
  • NMR (CDCl[0985] 3): δ 8.65-8.60 (2H, m), 7.80-7.30 (8H, m), 7.00-6.90 (2H, m), 5.10 (2H, s), 4.85 (1H, t, J=5 Hz), 3.75 (1H, dd, J=15, 5 Hz), 3.45 (1H; dd, J=15, 5 Hz)
    • EXAMPLE 5 (3) 3-(4-(3-Hydroxypropyloxy)phenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0986]
    Figure US20030073706A1-20030417-C01643
  • TLC: Rf 0.14 (hexane:ethyl acetate=1:1); [0987]
  • NMR (CD[0988] 3OD): δ 1.90-2.10 (m, 2H), 3.30-3.50 (m, 1H), 3.50-4.00 (m, 3H), 4.00-4.20 (m, 2H), 4.90-5.10 (m, 1H), 6.80-7.00 (m, 2H), 7.30-7.50 (m, 2H), 7.50-7.80 (m, 4H).
    • EXAMPLE 5(4) 3-(3-(Pyridin-3-ylmethyloxy)phenyl)thio-2,3-dihydro-1,1-dioxidebenzo [b] thiophene
  • [0989]
    Figure US20030073706A1-20030417-C01644
  • TLC: Rf 0.44 (ethyl acetate); [0990]
  • NMR (CDCl[0991] 3): δ 3.50 (dd, J=12.5, 7.5 Hz, 1H), 3.80 (dd, J=12.5, 7.5 Hz, 1H), 4.95-5.10 (m, 1H), 5.00 (s, 2H), 6.90-7.10 (m, 3H), 7.20-7.40 (m, 2H), 7.50-7.80 (m, 5H), 8.50-8.70 (m, 2H).
    • EXAMPLE 5(5) 3-(3-(3-Hydroxypropyloxy)phenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0992]
    Figure US20030073706A1-20030417-C01645
  • TLC: Rf 0.17 (hexane:ethyl acetate=1:1); [0993]
  • NMR (CDCl[0994] 3): δ 1.95-2.05 (m, 2H), 3.50 (dd, J=12.5, 7.5 Hz, 1H), 3.80 (dd, J=12.5,7.5 Hz, 1H), 3.85 (t, J=7.5 Hz, 2H), 4.05 (t, J=7.5 Hz, 2H), 5.00 (t, J=7.5 Hz, 1H), 6.80-7.05 (m, 3H), 7.20-7.30 (m, 1H), 7.50-7.80 (m, 4H)).
    • EXAMPLES 5 (6) 3-(2-(Pyridin-3-ylmethyloxy)phenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0995]
    Figure US20030073706A1-20030417-C01646
  • TLC: Rf 0.16 (hexane:ethyl acetate=1:1); [0996]
  • NMR (CD[0997] 3OD): δ 3.50 (dd, J=15, 5.0 Hz, 1H), 3.85 (dd, J=15, 7.5 Hz, 1H), 5.20 (dd, J=7.5, 5.0 Hz, 1H), 5.25 (s, 2H), 7.00 (t, J=7.5 Hz, 1H), 7.20 (d, J=7.5 Hz, 1H), 7.35-7.70 (m, 7H), 8.00 (d, J=7.5 Hz, 1H), 8.50 (dd, J=5.0, 2.5 Hz, 1H), 8.70 (d, J=2.5 Hz, 1H).
    • EXAMPLES 5 (7) 3-(2-(3-Hydroxypropyloxy)phenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [0998]
    Figure US20030073706A1-20030417-C01647
  • TLC: Rf 0.30 (hexane:ethyl acetate=1:2); [0999]
  • NMR (CDCl[1000] 3): δ 2.05-2.10 (m, 2H), 2.30-2.60 (m, 1H), 3.50 (dd, J=15, 5.0 Hz, 1H), 3.70 (dd, J=5, 7.5 Hz, 1H), 3.90 (t, J=5.0 Hz, 2H), 4.20-4.40 (m, 2H), 5.10 (dd, J=7.5, 5.0 Hz, 1H), 6.90-7.00 (m, 2H), 7.30 -7.80 (m, 6H).
    • EXAMPLE 5 (8) 3-(4-(2-(t-Butoxycarbonylamino)ethyloxy)phenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1001]
    Figure US20030073706A1-20030417-C01648
  • TLC: Rf 0.30 (toluene:ethyl acetate=4:1); [1002]
  • NMR (CDCl[1003] 3): δ 7.80-7.10 (6H, m), 6.80 (2H, d, J=10 Hz), 5.10-4.70 (2H, m), 4.00 (2H, t, J=5 Hz), 3.75 (1H, dd, J=15, 7.5 Hz), 3.60-3.40 (3H, m), 1.45 (9H, s).
    • EXAMPLE 5 (9) 3-(3-(2-(t-Butoxycarbonylamino)ethyloxy)phenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1004]
    Figure US20030073706A1-20030417-C01649
  • TLC: Rf 0.40 (hexane ethyl:acetate=1:1); [1005]
  • NMR (CDCl[1006] 3): δ 7.80-7.50 (4H, m), 7.40-7.20 (1H, m), 7.05-6.70 (3H, m), 5.05-4.90 (2H, m), 3.95 (2H, t, J=5 Hz), 3.80 (1H, dd, J=15, 5 Hz), 3.60-3.40 (3H, m), 1.45 (9H, s).
    • EXAMPLE 6 3-(4-(Pyridin-2-ylmethyloxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1007]
    Figure US20030073706A1-20030417-C01650
  • By the same procedure as described in Example 3 using the compound prepared in Example 5 instead of the compound prepared in Example 1, and then by converting into the corresponding hydrochloride by a known method, the compound of the present invention having the following physical data was obtained. [1008]
  • Free Compound: [1009]
  • TLC: Rf 0.44 (ethyl acetate); [1010]
  • NMR (DMSO-d[1011] 6): δ 8.60-8.55 (1H, m), 7.90-7.60 (7H, m), 7.50 (1H, d, J=7.5 Hz), 7.40-7.30 (1H, m), 7.20 (2H, d, J=7.5 Hz), 5.70 (1H, dd, J=10, 2.5 Hz), 5.30 (2H, s), 4.00 (1H, dd, J=15, 10 Hz), 3.75 (1H, dd, J=15, 2.5 Hz).
  • Hydrochloride: [1012]
  • TLC: Rf 0.49 (ethyl acetate:triethylamine=19:1); [1013]
  • NMR (CD[1014] 3OD): δ 3.80 (dd, J=15, 25 Hz, 1H), 3.95 (dd J-15, 10 Hz, 1H), 5.50 (dd, J=10, 2.5 Hz, 1H), 5.60 (s, 2H), 7.20 (d, J=7.5 Hz, 2H), 7.55-8 00 (m, 4H), 7.70 (d, J=7.5 Hz, 2H), 8.05-8.25 (m, 2H), 8.60-8.95 (m, 2H).
    • EXAMPLES 6 (1)˜6 (9)
  • Using the compounds prepared in Examples 5 (1)˜5 (9) instead of the compound prepared in Example 5, by the same procedure as described in Example 5, or by the same reaction using 3-chloroperbenzoic acid instead of OXONE® as an oxidant, and if necessary, by converting into corresponding salts, the following compounds of the present invention were obtained. [1015]
    • EXAMPLE 6 (1) 3-(4-(Pyridin-3-ylmethyloxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1016]
    Figure US20030073706A1-20030417-C01651
  • Free Compound: [1017]
  • TLC: Rf 0.27 (ethyl acetate); [1018]
  • NMR (CDCl[1019] 3): δ 8.70-8.55 (2H, m), 8.10-8.00 (1H, m), 7.80-7.50 (6H, m), 7.40-7.30 (1H, m), 7.10-6.90 (2H, m), 5.15 (2H, s), 5.20-5.00 (1H, m), 3.90-3.70 (2H, m).
  • Hydrochloride: [1020]
  • TLC: Rf 0.38 (ethyl acetate:triethylamine=19:1); [1021]
  • NMR (CD[1022] 3OD): δ 3.80 (dd,J=15,2.5 Hz, 1H), 3.95 (dd, J=15, 10 Hz, 1H), 5.45 (s, 2H), 5.45-5.55 (m, 1H), 7.20 (d, J=10 Hz, 2H), 7.60-8.00 (m, 4H), 7.60(d, J=10 Hz, 2H), 8.10-8.20 (m, 1H), 8.70-9.00 (m, 3H).
    • EXAMPLE 6 (2) 3-(4-(Pyridin-4-ylmethyloxy)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1023]
    Figure US20030073706A1-20030417-C01652
  • Free Compound: [1024]
  • TLC: Rf 0.22 (ethyl acetate); [1025]
  • NMR (DMSO-d[1026] 6): δ 8.60 (2H, d, J=5 Hz), 7.90-7.65 (6H, m), 7.45 (2H, d, J=5 Hz), 7.20 (2H, d, J=7.5 Hz), 5.75 (1 H, dd, J=7.5, 2.5 Hz), 5.30 (2H, s), 4.00 (1 H, dd, J=15, 7.5 Hz), 3.80 (1 H, dd, J=15, 2.5 Hz).
  • Hydrochloride: [1027]
  • TLC: Rf 0.35 (ethyl acetate:triethylamine=19:1); [1028]
  • NMR (DMSO-d[1029] 6): δ 3.80 (dd, J=15, 2.5 Hz, 1H), 4.00 (dd, J=15, 10 Hz, 1H), 5.55 (s, 2H), 5.75 (dd, J=10, 2.5 Hz, 1H), 7.25 (d, J=10 Hz, 2H), 7.65-7.90 (m, 4H), 7.70 (d, J=10 Hz, 2H), 7.95 (d, J=7.5 Hz, 2H), 8.90 (d, J=7.5 Hz, 2H).
    • EXAMPLE 6 (3) 3-(4-(3-Hydroxypropylpxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1030]
    Figure US20030073706A1-20030417-C01653
  • TLC: Rf 0.33 (ethyl acetate ); [1031]
  • NMR (CDCl[1032] 3): δ 2.05 (quint., J=5.0 Hz, 2H), 3.70-3.90 (m, 2H), 3.85 (t, J=5.0 Hz, 2H), 4.15 (t, J=5.0 Hz, 2H), 5.05 (t, J=7.5 Hz, 1H), 6.90 (d, J=10 Hz, 2H), 7.50 (d, J=10 Hz, 2H), 7.60-7.80 (m, 3H), 8.05 (d, J=7.5 Hz, 1H).
    • EXAMPLE 6 (4) 3-(3-(Pyridin-3-ylmethyloxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride
  • [1033]
    Figure US20030073706A1-20030417-C01654
  • TLC: Rf 0.60 (ethyl acetate methanol:triethylamine=16:2:1); [1034]
  • NMR (CD[1035] 3OD): δ 3.85 (dd, J=15, 5.0 Hz, 1H), 3.95 (dd, J=15, 10 Hz, 1H), 5.35 (d, J=12.5 Hz, 1H), 5.45 (d, J=12.5 Hz, 1H), 5.55 (dd, J=10, 5.0 Hz, 1H), 7.20-7.85 (m, 7H), 7.95 (d, J=7.5 Hz, 1H), 8.15 (dd, J=10, 7.5 Hz, 1H), 8.75 (d, J=7.5 Hz, 1H), 8.85 (d, J=5.0 Hz, 1H), 9.00 (s, 1H).
    • EXAMPLE 6 (5) 3-(3-(3-Hydroxypropyloxy) phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1036]
    Figure US20030073706A1-20030417-C01655
  • TLC: Rf 0.33 (ethyl acetate ); [1037]
  • NMR (CDCl[1038] 3): δ 1.90-2.20 (m, 2H), 3.65-3.90 (m, 4H), 3.95-4.20 (m, 2H), 5.10 (dd, J=10, 5.0 Hz, 1H), 7.10-7.30 (m, 3H), 7.30-7.45 (m, 1H), 7.60-7.80 (m, 3H), 8.00 (d, J=5.0 Hz, 1H).
    • EXAMPLE 6 (6) 3-(2-(Pyridin-3-ylmethyloxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride
  • [1039]
    Figure US20030073706A1-20030417-C01656
  • TLC: Rf 0.51 (ethyl acetate:methanol triethylamine=16:2:1); [1040]
  • NMR (DMSO-d[1041] 6): δ 3.70 (dd, J=15, 2.5 Hz, 1H), 3.95 (dd, J=15, 10 Hz, 1H), 5.60 (s, 2H) 5.75 (dd, J=10, 2.5 Hz, 1H), 7.20-7.35 (m, 1H), 7.40-7.60 (m, 2H), 7.60-7.90 (m, 5H), 7.95-8.10 (m, 1H), 8.60 (d, J=7.5 Hz, 1H), 8.90 (d, J=5.0 Hz, 1H), 9.05 (s, 1H).
    • EXAMPLE 6 (7) 3-(2-(3-Hydroxypropylpxy)phenyl)sulfonyl-2,3-dyhydro-1,1-dioxidebenzo[b]thiophene
  • [1042]
    Figure US20030073706A1-20030417-C01657
  • TLC: Rf 0.37 (ethyl acetate); [1043]
  • NMR (CDCl[1044] 3): δ 5 2.00-2.30 (m, 2H), 2.50-2.80 (m, 1H), 3.55 (dd, J=15, 10 Hz, 1H), 3.80 (dd, J=15, 5.0 Hz, 1H), 3.95 (t, J=5.0 Hz, 2H), 4.25-4.50 (m, 2H), 5.65 (dd, J=10, 5.0 Hz, 1H), 7.10-7.20 (m, 2H), 7.60-7.80 (m, 4H), 7.80-7.95 (m, 2H).
    • EXAMPLE 6 (8) 3-(4-(2-(t-Butoxycarbonylamino)ethyloxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1045]
    Figure US20030073706A1-20030417-C01658
  • TLC: Rf 0.40 (hexane ethyl:acetate=1:2); [1046]
  • NMR (DMSO-d[1047] 6): δ 1.40 (s, 9H), 3.80 (dd, J=15, 2.5 Hz, 1H), 3.90-4.15 (m, 5H), 5.75 (dd, J=10, 2.5 Hz, 1H), 6.90-7.10 (m, 1H), 7.10 (d, J=7.5 Hz, 2H), 7.60-7.85 (m, 4H), 7.65 (d, J=7.5 Hz, 2H).
    • EXAMPLE 6 (9) 3-(3-(2-(t-Butoxycarbonylamino)ethyloxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1048]
    Figure US20030073706A1-20030417-C01659
  • TLC: Rf 0.13 (hexane:ethyl acetate=1:1); NMR (CDCl[1049] 3): δ 1.45 (s, 9H), 3.45-3.55 (m, 2H), 3.70-4.00 (m, 4H), 4.85-5.00 (m, 1H), 5.10 (dd, J=10, 5.0 Hz, 1H), 7.00-7.50 (m, 4H), 7.60-7.80 (m, 3H), 8.05 (d, J=7.5 Hz, 1H).
    • EXAMPLE 7 3-(4-(2-Aminoethyloxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride
  • [1050]
    Figure US20030073706A1-20030417-C01660
  • To a solution of the compound prepared in Example 6 (8) (200 mg) in dioxane (25 ml) and methanol (5 ml), was added a solution of 4N hydrochloric acid in dioxane (10 ml) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated to give the compound of the present invention (160 mg) having the following physical data. [1051]
  • TLC: Rf 0.16 (ethyl acetate:methanol:triethylamine=16:3:1); [1052]
  • NMR (CD[1053] 3OD): δ 3.35 (t, J=5.0 Hz, 2H), 3.80 (dd, J=15, 5.0 Hz, 1H), 3.95 (dd, J=15, 10 Hz, 1H), 4.30 (t, J=5.0 Hz, 2H), 5.45 (dd, J=10, 5.0 Hz, 1H), 7.10 (d, J=7.5 Hz, 2H), 7.60 (d, J=7.5 Hz, 2H), 7.60-8.00 (m, 4H).
    • EXAMPLE 7 (1) 3-(3-(2-Aminoethyloxy) phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride
  • [1054]
    Figure US20030073706A1-20030417-C01661
  • By the same procedure as described in Example 7 using the compound prepared in Example 6 (9) instead of the compound prepared in Example 6 (8), the compound of the present invention having the following physical data was obtained. [1055]
  • TLC: Rf 0.60 (ethyl acetate:methanol triethylamine=14:3:1); [1056]
  • NMR (CD[1057] 3OD): δ 3.25-3.45 (m, 2H), 3.80-4.00 (m, 2H), 4.15-4.35 (m, 2H), 5.55 (dd, J=7.5, 2.5 Hz, 1H), 7.20-7.50 (m, 4H), 7.60-8.00 (m, 4H).
    • EXAMPLE 8 3-(4-(2-(N,N-Dimethylamino)ethyloxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride
  • [1058]
    Figure US20030073706A1-20030417-C01662
  • To a solution of the compound prepared in Example 7 (105 mg) and 90% paraformaldehyde (87 mg) in a mixture of acetic acid (3 ml) and methanol (3 ml), was added sodium cyanoborohydride (86 mg) at 0° C. The reaction mixture was stirred at room temperature overnight. To the reaction mixture, a saturated aqueous solution of sodium bicarbonate was added. The mixture was extracted by ethyl acetate. The extract was washed by water, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified with column chromatography on silica gel (ethyl acetate:methanol:triethylamine=16:3:1). Then to a solution of the obtained compound in dioxane (25 ml) and methanol (5 ml), was added a solution of 4N hydrochloric acid-dioxane (10 ml) at room temperature. The reaction mixture was stirred for 30 minutes and concentrated to give the compound of the present invention (35 mg) having the following physical data. [1059]
  • TLC: Rf 0.40 (ethyl acetate:methanol:triethylamine=16:3:1); NMR (CD[1060] 3OD): δ 3.10(s, 6H), 3.60 (t, J=5.0 Hz, 2H), 3.80 (dd, J=15, 2.5 Hz, 1H), 3.95 (dd, J=15, 10 Hz, 1H), 4.45 (t, J=5.0 Hz, 2H), 5.50 (dd, J=10, 2.5 Hz, 1H), 7.10 (d, J=7.5 Hz; 2H), 7-60 (d, J=7.5 Hz, 2H), 7.60-8.00 (m, 4H).
    • EXAMPLE 8 (1) 3-(3-(2-(N,N-Dimethylamino)ethyloxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride
  • [1061]
    Figure US20030073706A1-20030417-C01663
  • By the same procedure as described in Example 8 using the compound prepared in Example 7 (1) instead of the compound prepared in Example 7, the compound of the present invention having the following physical data was obtained. [1062]
  • TLC: Rf 0.44 (ethyl acetate:methanol:triethylamine=16:2:1); [1063]
  • NMR (DMSO-d[1064] 6): δ 2.80 (s, 6H), 3.50 (t, J=5.0 Hz, 2H), 3.85 (dd, J=15, 2.5 Hz, 1H), 4.00 (dd, J=15, 10 Hz, 1H), 4.30-4.55 (m, 2H), 5.90 (dd, J=10, 2.5 Hz, 1H), 7.30-7.60 (m, 4H), 7.70-7.90 (m, 4H).
    • EXAMPLE 9 5-Nitro-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1065]
    Figure US20030073706A1-20030417-C01664
  • By the same procedure as described in Example 1 using 5-nitrobenzothiophene-1,1-dioxide instead of benzothiophene-1,1-dioxide, the compound of the present invention having the following physical data was obtained. [1066]
  • TLC: Rf 0.35 (hexane:ethyl acetate=2:1); [1067]
  • NMR (CDCl[1068] 3): δ 8.52 (1 H, d, J=2 Hz), 8.38 (1 H, dd. J=8.4, 2.0 Hz), 7.89 (1 H, d, J=8.4 Hz), 7.48-7.36 (5H, m), 4.97 (1H, dd, J=7.2, 6.8 Hz), 3.92 (1H, dd, J=13.6, 7.2 Hz), 3.60 (1H, dd, J=13.6, 6.8 Hz).
    • EXAMPLES 9 (1)˜9 (17)
  • By the same procedure as described in Example 9 using a corresponding benzothiophene-1,1-dioxide instead of 5-nitrobenzothiophene-1,1-dioxide, the following compounds were obtained. [1069]
    • EXAMPLE 9 (1)
  • 6-Methoxy-3-phenylthio-2,3-dihydro-1,1-di oxidebenzo[b]thiophene [1070]
    Figure US20030073706A1-20030417-C01665
  • TLC: Rf 0.60 (hexane:ethyl acetate=1:1); [1071]
  • NMR (CDCl[1072] 3): δ 3.52 (dd, J=13.6 Hz, 6.8 Hz, 1H), 3.81 (dd, J=13.6 Hz, 6.8 Hz, 1H), 3.86 (s, 3H), 4.92 (t, J=6.8 Hz, 1H), 7.14-7.21 (m, 2H), 7.32-7.40 (m, 3H), 7.40-7.43 (m, 2H), 7.57-7.61 (m, 1H).
    • EXAMPLE 9 (2) 4-Methoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo [b]thiophene
  • [1073]
    Figure US20030073706A1-20030417-C01666
  • TLC: Rf 0.21 (hexane:methylene chloride=1:4); [1074]
  • NMR (CDCl[1075] 3): δ 3.60 (dd, J=14.0 Hz, 1.8 Hz, 1H), 3.71 (dd, J=14.0 Hz, 6.9 Hz, 1H), 3.91 (s, 3H), 5.05 (dd, J=6.9 Hz, 1.8 Hz, 1H), 7.07 (dd, J=8.1 Hz, 0.7 Hz, 1H), 7.29-7.37 (m, 4H), 7.48-7.56 (m, 3H).
    • EXAMPLE 9 (3) 5-Methoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1076]
    Figure US20030073706A1-20030417-C01667
  • TLC: Rf 0.62 (hexane:ethyl acetate=1:1); [1077]
  • NMR (CDCl[1078] 3): δ 3.51 (dd, 1H, J=14, 5 Hz), 3.79 (dd, 1H, J=14, 5 Hz), 3.88 (s, 3H), 4.92 (t, 1H, J=5 Hz), 7.04 (dd, 1H, J=5 Hz, 2 Hz), 7.13 (d, 1H, J=2 Hz), 7.35 (m, 3H), 7.44 (m, 2H), 7.63 (d, 1 H, J=5 Hz).
    • EXAMPLE 9 (4) 7-Methoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1079]
    Figure US20030073706A1-20030417-C01668
  • TLC: Rf 0.42 (hexane:ethyl acetate=1:1); [1080]
  • NMR (CDCl[1081] 3): δ 7.62-7.38 (1H, m), 7.58-7.28 (6H, m), 6.79 (1H, d, J=8.4 Hz), 4.89 (1H, t, J=7.6 Hz), 3.97 (3H, s), 3.78 (1H, dd, J=13.5, 7.6 Hz), 3.52 (1H, dd, J=13.5, 7.6 Hz).
    • EXAMPLE 9 (5) 4-Chloro-3-phenylthin-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1082]
    Figure US20030073706A1-20030417-C01669
  • TLC: Rf 0.31 (hexane:ethyl acetate=2:1); [1083]
  • NMR (CDCl[1084] 3): δ 3.68 (dd, J=14.2, 3.0 Hz, 1H), 3.75 (dd, J=14.2, 5.6 Hz, 1H), 5.00 (dd, J=5.6, 3.0 Hz, 1H), 7.35-7.40 (m, 3H), 7.49-7.59 (m, 3H), 7.64-7.69 (m, 2H).
    • EXAMPLE 9 (6) 5-(t-Butoxycarbonylamino)methyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1085]
    Figure US20030073706A1-20030417-C01670
  • TLC: Rf 0.44 (hexane:ethyl acetate=1:1); [1086]
  • NMR (CDCl[1087] 3): δ 1.45 (s, 9H), 3.60 (dd, J=12.5, 2.5 Hz, 1H), 3.75 (dd, J=12.5 Hz, 7.5 Hz, 1H), 4.50 (dd, J=15, 5.0 Hz, 1H), 4.85 (dd, J=15, 7.5 Hz, 1H), 5.00-5.20 (m, 2H) 7.30-7.45 (m, 3H), 7.50-7.75 (m, 5H).
    • EXAMPLE 9 (7) 4,7-Dimethyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1088]
    Figure US20030073706A1-20030417-C01671
  • TLC: Rf 0.45 (hexane:ethyl acetate=2:1); [1089]
  • NMR (CDCl[1090] 3): δ 7.50-7.30 (5H, m), 7.20 (1H, d, J=7.8 Hz), 4.89 (1H, dd, J=5.8, 2.2Hz), 3.75-3.55 (2H, m), 2.60 (3H, s), 2.54 (3H, s).
    • EXAMPLE 9 (8) 4,6-Dimethyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1091]
    Figure US20030073706A1-20030417-C01672
  • TLC: Rf 0.50 (hexane:ethyl acetate=2:1); [1092]
  • NMR (CDCl[1093] 3): δ 5 7.56-7.24 (7H, m), 4.90 (1H, dd, J=6.0, 1.8 Hz), 3.80-3.66 (2H, m 2.56 (3H, s), 2.42 (3H, s).
    • EXAMPLE 9 (9) 4-Ethyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1094]
    Figure US20030073706A1-20030417-C01673
  • TLC: Rf 0.44 (hexane:ethyl acetate=2:1); [1095]
  • NMR (CDCl[1096] 3): δ 5 7.65-7.30 (8H, m), 4.99 (1H, dd, J=5.9, 2.4 Hz), 3.75-3.57 (2H, m 2.98 (2H, q, J=7.6 Hz), 1.37 (3H, t, J=7.6 Hz).
    • EXAMPLE 9 (10) 4-Methoxy-5-ethoxycarbonyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1097]
    Figure US20030073706A1-20030417-C01674
  • TLC: Rf 0.44 (hexane:ethyl acetate=2:1); [1098]
  • NMR (CDCl[1099] 3): δ 7.99 (1H, d, J=8.0 Hz), 7.60-7.50 (3H, m), 7.45-7.35 (3H, m), 5.11 (1H, dd, J=5.9, 2.8 Hz), 4.45 (2H, q, J=7.0 Hz), 4.09 (3H, s), 3.75-3.60 (2H, m), 1.44 (3H, t, J=7.0 Hz).
    • EXAMPLE 9 (11) 4-Bromo-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1100]
    Figure US20030073706A1-20030417-C01675
  • TLC: Rf 0.20 (hexane:ethyl acetate=3:1); [1101]
  • NMR (CDCl[1102] 3): δ 3.69 (dd, J=13.9, 2.8Hz, 1H), 3.74 (dd, J=13.9, 5.3Hz, 1H), 4.94 (dd, J=5.3, 2.8 Hz, 1H), 7.37-7.39 (m, 3H), 7.45 (t, J=7.8 Hz, 1H), 7.57-7.60 (m, 2H), 7.71 (d, J=7.8 Hz, 1H), 7.84 (dd, J=7.8, 0.9 Hz, 1H).
    • EXAMPLE 9 (12) 4-Hydroxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1103]
    Figure US20030073706A1-20030417-C01676
  • TLC: Rf 0.21 (hexane:ethyl acetate=1:1); [1104]
  • NMR (CDCl[1105] 3): δ 3.49 (dd, J=13.9, 5.9 Hz, 1H), 3.81 (dd, J=13.9, 7.5 Hz, 1H), 4.93 (dd, J=7.5, 5.9 Hz, 1H), 7.17 (dd, J=8.0, 0.5 Hz, 1H), 7.25-7.51 (m, 7H).
    • EXAMPLE 9 (13) 5-Hydroxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1106]
    Figure US20030073706A1-20030417-C01677
  • TLC: Rf 0.50 (hexane:ethyl acetate=1:1); [1107]
  • NMR (CDCl[1108] 3): δ 3.51 (dd, J=14.0, 7.0 Hz, 1H), 3.78 (dd, J=14.0, 7.0 Hz, 1H), 4.89 (t, J=7.0 Hz, 1H), 6.32 (s, 1H), 6.94 (dd, J=5.0 Hz, 2.0 Hz, 1H), 7.12 (d, J=2.0 Hz, 1H), 7.35 (m, 3H), 7.43 (m, 2H), 7.58 (d, J=5.0 Hz, 1H).
    • EXAMPLE 9 (14) 6-Hydroxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1109]
    Figure US20030073706A1-20030417-C01678
  • TLC: Rf 0.28 (hexane:ethyl acetate=1:1); [1110]
  • NMR (CDCl[1111] 3): δ 3.54 (dd, J=13.8, 5.9 Hz, 1H), 3.83 (dd, J=13.8, 7.4 Hz, 1H), 4.91 (t-like, J=6.6 Hz, 1H), 7.10-7.15 (m, 2H), 7.31-7.42 (m, 5H), 7.51-7.56 (m, 1H).
    • EXAMPLE 9 (15) 7-Hydroxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1112]
    Figure US20030073706A1-20030417-C01679
  • TLC: Rf 0.52 (hexane:ethyl acetate=2:1); [1113]
  • NMR (CDCl[1114] 3): δ 7.50-7.20 (5H, m), 7.11 (1 H, d, J=8.0 Hz), 6.85 (1 H, d, J=8.0 Hz), 6.68 (1H, dd, J=32.6, 6.6 Hz), 4.91 (1H, t, J=7.5 Hz), 3.79 (1H, dd, 14, 7.5 Hz), 3.50 (1H, dd, J=14, 7.5 Hz).
    • EXAMPLE 9 (16) 3-Phenylthio-2,3-dihydro-1,1-dioxidethieno[2,3-b]pyridine
  • [1115]
    Figure US20030073706A1-20030417-C01680
  • TLC: Rf 0.50 (hexane: ethyl acetate=1:1); [1116]
  • NMR (CDCl[1117] 3): δ 3.49 (dd, J=14.0, 7.0 Hz, 1H), 3.85 (dd, J=14.0, 8.0 Hz, 1H), 4.91 (dd, J=8.0, 7.0 Hz, 1H), 7.40 (m, 5H), 7.58 (dd, J=8.0, 5.0 Hz, 1H), 8.08 (m, 1H), 8.76 (m, 1H).
    • EXAMPLE 9 (17) 4,7-dihydroxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1118]
    Figure US20030073706A1-20030417-C01681
  • TLC: Rf 0.33 (methylene chloride:ethyl acetate=1:1); [1119]
  • NMR (CDCl[1120] 3): δ 9.25 (2H, brs), 7.55-7.45 (2H, m), 7.40-7.30 (3H, m), 6.96 (1H, d, J=8.8 Hz), 6.85 (1H, d, J=8.8 Hz), 5.09 (1 H, dd, J=7.4, 1.6 Hz), 3.71 (1H, dd, 13.9, 7.4 Hz), 3.50 (1H, dd, J=13.9, 1.6 Hz).
    • EXAMPLE 10 5-Nitro-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1121]
    Figure US20030073706A1-20030417-C01682
  • To a solution of the compound prepared in Example 9 (790 mg) in chloroform (45 ml) was added 3-chloroperbenzoic acid (70 % purity, 1.21 g). The reaction mixture was stirred at room temperature for 2 hours. To the reaction mixture, water was added. The mixture was extracted by ethyl acetate. The extract was washed by 2N aqueous solution of sodium hydroxide, water, a saturated aqueous solution of sodium chloride successively, dried over anhydrous magnesium sulfate and concentrated. The residue was purified with column chromatography on silica gel (hexane:ethyl acetate=3:2) to give the compound of the present invention (497 mg) having the following physical data. [1122]
  • TLC: Rf 0.39 (hexane:ethyl acetate=1:1); [1123]
  • NMR (CDCl[1124] 3): δ 3.98 (dd, J=15.5, 3.0 Hz, 1H), 4.19 (dd, J=15.5, 9.3 Hz, 1H), 5.95 (dd, J=9.3, 3.0 Hz, 1H), 7.59-7.67 (m 2H), 7.78-7.84 (m, 3H), 8.11 (d, J=8.6 Hz, 1H), 8.41 (d, J=2.0 Hz, 1H), 8.51 (dd, J=8.6, 2.0 Hz, 1H).
    • EXAMPLES 10 (1)˜10 (16)
  • Using the compounds prepared in Examples 9 (1)˜9 (16) instead of the compound prepared in Example 9, by the same procedure as described in Example 10, or by the same reaction using 3-chloroperbenzoic acid instead of OXONE@, the following compounds of the present invention were obtained. [1125]
    • EXAMPLE 10 (1) 6-Methoxy-3-phenylsulfonyl-2,3-dihydro-1,1 -dioxidebenzo[b]thiophene
  • [1126]
    Figure US20030073706A1-20030417-C01683
  • TLC: Rf 0.34 (hexane:ethyl acetate=1:1); [1127]
  • NMR (CDCl[1128] 3): δ 3.66-3.82 (m, 2H), 3.87 (s, 3H), 5.00 (dd, J=7.5, 5.5 Hz, 1H), 7.06 (d, J=2.4 Hz, 1H), 7.24 (dd, J=8.8, 2.4 Hz, 1H), 7.46-7.54 (m, 2H), 7.63-7.71 (m, 3H), 7.86 (d, J=8.8 Hz, 1H).
    • EXAMPLE 10 (2) 4-Methoxy-3-phenylsulfonyl-2,3-dihydro-1,1 -dioxidebenzo[b]thiophene
  • [1129]
    Figure US20030073706A1-20030417-C01684
  • TLC: Rf 0.17 (hexane:ethyl acetate=1:1); [1130]
  • NMR (CDCl[1131] 3): δ 3.49 (s, 3H), 3.76 (dd, J=14.9, 9.2 Hz, 1H), 4.31 (dd, J=14.9, 1.3 Hz, 1H), 5.23 (dd, J=9.2, 1.3 Hz, 1H), 6.90 (d, J=8.0 Hz, 1H), 7.31 (d, J=7.8 Hz; 1H) 745-7.54 (m, 3H), 7.58-7.68 (m, 1H), 7.72-7.77 (m, 2H).
    • EXAMPLE 10 (3) 5-Methoxy-3-phenylsulfonyl-2,3-dihydro-1, 1 -dioxidebenzo[b]thiophene
  • [1132]
    Figure US20030073706A1-20030417-C01685
  • TLC: Rf 0.50 (hexane:ethyl acetate=1:1); [1133]
  • NMR (CDCl[1134] 3): δ 3.70(dd, J=12, 8 Hz, 1H), 3.77(dd, J=12, 4 Hz, 1H), 3.94(s, 3H), 5.01 (dd, J=8, 4 Hz, 1H), 7.12(d, J=8 Hz, 1H), 7.44(s, 1H), 7.53(m, 3H), 7.68(m, 3H).
    • EXAMPLE 10 (4) 7-Methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1135]
    Figure US20030073706A1-20030417-C01686
  • TLC: Rf 0.40 (hexane:ethyl acetate=1:2); [1136]
  • NMR (DMSO-d[1137] 6): δ 7.80-7.55 (6H, m), 7.27 (1H, d, J=8.2 Hz), 7.15 (1H, d, J=8.2 Hz), 5.73(1H, dd, J=9.5, 3.4 Hz), 3.91 (1H, dd, J=15, 9.5 Hz), 3.87 (3H, s), 3.69 (1H, dd, J=15, 3.4 Hz).
    • EXAMPLE 10 (5) 4-Chioro-3-phenylsufonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1138]
    Figure US20030073706A1-20030417-C01687
  • TLC: Rf 0.43 (methylene chloride:ethyl acetate=15:1); [1139]
  • NMR (CDCl[1140] 3): δ 3.79 (dd, J=15.0, 9.2 Hz, 1H), 4.24 (dd, J=15.0, 1.0 Hz, 1H), 5.26 (dd, J=9.2, 1.0 Hz, 1H), 7.46-7.66 (m, 6H), 7.77-7.81 (m, 2H).
    • EXAMPLE 10 (6) 4-(t-Butoxycarbonylamino)methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1141]
    Figure US20030073706A1-20030417-C01688
  • TLC: Rf 0.26 (hexane:ethyl acetate=1:1); [1142]
  • NMR (CDCl[1143] 3): δ 1.45 (s, 9H), 3.75 (dd, J=15, 10 Hz, 1H), 3.85 (dd, J=15, 2.5 Hz, 1H), 4.40 (dd, J=5, 5.0 Hz, 1H), 4.95 (dd, J=15, 7.5 Hz, 1H), 5.35 (m, 2H), 7.45-7.90 (m, 8H).
    • EXAMPLE 10 (7) 4,7-Dimethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1144]
    Figure US20030073706A1-20030417-C01689
  • TLC: Rf 0.18 (hexane:ethyl acetate=2:1); [1145]
  • NMR (DMSO-d[1146] 6): δ 7.81-7.70 (3H, m), 7.70-7.55 (2H, m), 7.48 (1 H, d, J=7.8 Hz), 7.38 (1H, d, J=7.8 Hz), 5.73 (1H, t, J=5.2 Hz), 3.84 (2H, d-like, J=5.2 Hz), 2.40 (3H, s), 2.36 (3H, s).
    • EXAMPLE 10 (8) 4,6-Dimethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1147]
    Figure US20030073706A1-20030417-C01690
  • TLC: Rf 0.18 (hexane:ethyl acetate=2:1); [1148]
  • NMR (DMSO-d[1149] 6): δ 7.82-7.70 (3H, m), 7.70-7.55 (2H, m), 7.42 (2H, d, J=5.4 Hz), 5.73 (1 H, t, J=4.8 Hz), 3.86-3.80 (2H, m), 2.38 (6H, s).
    • EXAMPLE 10 (9) 4-Ethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1150]
    Figure US20030073706A1-20030417-C01691
  • TLC: Rf 0.22 (hexane:ethyl acetate=2:1); [1151]
  • NMR (CDCl[1152] 3): δ 7.68-7.40 (8H, m), 5.22 (1H, d, J=9.2 Hz), 3.99 (1H, d, J=15.2 Hz), 3.76 (1 H, dd, J=15.2, 9.2 Hz), 3.07 (2H, dd, J=7.6, 2.2 Hz), 1.33 (3H, t, J=7.6 Hz).
    • EXAMPLE 10 (10) 4-Methoxy-5-ethoxycarbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1153]
    Figure US20030073706A1-20030417-C01692
  • TLC: Rf 0.38 (hexane:ethyl acetate=1:1); [1154]
  • NMR (CDCl[1155] 3): δ 7.91 (1H, d, J=8.0 Hz), 7.83-7.45 (5H, m), 7.41 (1H, d, J=8.0 Hz), 5.28 (1H, d-like, J=8.0 Hz), 4.42 (2H, q, J=7.0 Hz), 4.17 (1H, dd, J=15, 1.6 Hz), 3.86 (3H, s), 3.75 (1H, dd, J=15, 8.0 Hz), 1.43 (3H, t, J=7.0 Hz).
    • EXAMPLE 10 (11) 4-Bromo-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1156]
    Figure US20030073706A1-20030417-C01693
  • TLC: Rf 0.35 (hexane:ethyl acetate=1:1); [1157]
  • NMR (CDCl[1158] 3): δ 3.79 (dd, J=15.0, 9.2 Hz, 1H), 4.23 (dd, J=15.0, 1.1 Hz, 1H), 5.23 (d-like, J=8.8 Hz, 1H), 7.44-7.54 (m, 3H), 7.62-7.70 (m, 2H), 7.78-7.83 (m, 3H).
    • EXAMPLE 10 (12) 4-Hydroxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1159]
    Figure US20030073706A1-20030417-C01694
  • TLC: Rf 0.22 (hexane:ethyl acetate=1:2); [1160]
  • NMR (DMSO-d[1161] 6): δ 3.96 (dd, J=15.0, 8.4 Hz, 1H), 4.08 (dd, J=15.0, 1.8 Hz, 1H), 5.51 (dd, J=8.4, 1.8 Hz, 1H), 7.00 (d-like, J=8.0 Hz, 1H), 7.16 (d, J=7.0 Hz, 1H), 7.47 (t, J=8.0 Hz, 1H), 7.56-7.63 (m, 2H), 7.71-7.81 (m, 3H).
    • EXAMPLE 10 (13) 5-Hydroxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1162]
    Figure US20030073706A1-20030417-C01695
  • TLC: Rf 0.30 (hexane:ethyl acetate=1:1); [1163]
  • NMR (DMSO-d[1164] 6): δ 3.66 (dd, J=14, 4 Hz, 1H), 3.90 (dd, J=14, 9 Hz, 1H), 5.71 (dd, J=9, 4 Hz, 1H), 7.07 (m, 2H), 7.55-7.82 (m, 6H), 10.80 (brs, 1H).
    • EXAMPLE 10 (14) 6-Hydroxy-3-phenylsulfonyl-2,3-dyhydro-1,1-dioxidebenzo[b]thiophene
  • [1165]
    Figure US20030073706A1-20030417-C01696
  • TLC: Rf 0.37 (hexane:ethyl acetate=1:2); [1166]
  • NMR (DMSO-d[1167] 6): δ 3.73 (dd, J=15.2, 3.2 Hz, 1H), 3.96 (dd, J=15.2, 9.2 Hz, 1H), 5.60 (dd, J=9.2, 3.2 Hz, 1H), 6.94 (s-like, 1H), 7.16 (d-like, J=8.4 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.57-7.64 (m, 2H), 7.71-7.76 (m, 3H).
    • EXAMPLE 10 (15) 7-Hydroxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1168]
    Figure US20030073706A1-20030417-C01697
  • TLC: Rf 0.31 (hexane:ethyl acetate 1:2); [1169]
  • NMR (DMSO-d[1170] 6): δ 7.80-7.45 (6H, m), 6.98 (2H, d, J=8.4 Hz), 5.66 (1H, dd, J=9.6, 3.2 Hz), 3.85 (1H, dd, J=15, 9.6 Hz), 3.68-3.58 (1H, m).
    • EXAMPLE 10 (16) 3-Phenylsulfonyl-2,3-dihydro-1,1-dioxidethieno[2,3-b]pyridine
  • [1171]
    Figure US20030073706A1-20030417-C01698
  • TLC: Rf 0.20 (hexane:ethyl acetate=1:1); [1172]
  • NMR (CDCl[1173] 3): δ 3.65 (dd, J=15, 8 Hz, 1H), 3.74 (dd, J=15, 6 Hz, 1H), 5.04 (dd, J=8, 6 Hz, 1H), 7.58 (m, 2H), 7.69 (m, 4H), 8.48 (m, 1H), 8.86 (m, 1H).
    • EXAMPLE 11 5-Amino-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1174]
    Figure US20030073706A1-20030417-C01699
  • Under an atmosphere of argon, to a solution of the compound prepared in Example 10 (110 mg) in ethanol (7.5 ml) and ethyl acetate (7.5 ml), was added 5% palladium-carbon (20 mg). The reaction mixture was stirred at room temperature for 2 hours under an atmosphere of hydrogen. The reaction mixture was filtrated through celite (trade name). The filtrate was concentrated. The residue was purified with column chromatography on silica gel (methylene chloride:ethyl acetate=2:1) to give the compound of the present invention (94 mg) having the following physical data. Then, it was converted into a corresponding salt by a known method to give the compound of the present invention having the following physical data. [1175]
  • Free Compound: [1176]
  • TLC: Rf 0.29 (hexane:ethyl acetate=1:2); [1177]
  • NMR (CDCl[1178] 3): δ 3.61 (dd, J=14.6, 8.3 Hz, 1H), 3.70 (dd, J=14.6, 5.6 Hz, 1H), 4.34 (brs, 2H), 4.94 (dd, J=8.3, 5.6 Hz, 1H), 6.79 (dd, J=8.0, 2.0 Hz, 1H), 7.21 (d, J=2.0 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.49-7.55 (m, 2H), 7.63-7.74 (m, 3H).
  • Hydrochloride: [1179]
  • TLC: Rf 0.47 (methylene chloride:methanol=18:1); [1180]
  • NMR (DMSO-d[1181] 6): δ 3.53 (dd, J=14.9, 3.8 Hz, 1H), 3.75 (dd, J=14.9, 9.4 Hz, 1H), 5.58 (dd, J=9.4, 3.8 Hz, 1H), 6.76 (dd, J=8.6, 2.1 Hz, 1H), 6.90 (d, J=2.1 Hz, 1H), 7.31 (d, J=8.6 Hz, 1H), 7.57-7.65 (m, 2H), 7.72-7.79 (m, 3H).
    • EXAMPLE 12 5-Acetylamino-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1182]
    Figure US20030073706A1-20030417-C01700
  • To a solution of the compound prepared in Example 11 (91 mg) in pyridine (2 ml), was added acetic anhydride (1 ml). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated. The residue was purified with column chromatography on silica gel (hexane:ethyl acetate=1:1) to give the compound of the present invention (86 mg) having the following physical data. [1183]
  • TLC: Rf 0.20 (hexane:ethyl acetate=1:2); [1184]
  • NMR (CDCl[1185] 3): δ 2.24 (s, 3H), 3.66 (dd, J=14.8, 8.3 Hz, 1H), 3.75 (dd, J=14.8, 5.2 Hz, 1H), 5.04 (dd, J=8.3, 5.2 Hz, 1H), 7.49-7.59 (m, 3H), 7.66-7.75 (m, 3H), 7.87-7.94 (m, 2H), 8.04 (s-like, 1H).
    • EXAMPLE 13 5-Aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride
  • [1186]
    Figure US20030073706A1-20030417-C01701
  • By the same procedure as described in Example 7 using the compound prepared in Example 10 (6) instead of the compound prepared in Example 6 (8), the compound of the present invention having the following physical data was obtained. [1187]
  • TLC: Rf 0.16 (ethyl acetate:methanol:triethylamine=16:2:1); [1188]
  • NMR (DMSO-d[1189] 6): δ 3.80-4.00 (m, 2H), 4.35 (d, J=15 Hz, 1H), 4.55 (d, J=15 Hz, 1H), 6.30-6.40 (m, 1H), 7.60-7.70 (m, 2H), 7.75-7.95 (m, 5H), 8.00-8.15 (m, 1H), 8.30-8.65 (m, 2H).
    • EXAMPLE 14 4-(N,N-dimethylamino)methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride
  • [1190]
    Figure US20030073706A1-20030417-C01702
  • By the same procedure as described in Example 8 using the compound prepared in Example 13 instead of the compound prepared in Example 7, the compound of the present invention having the following physical data was obtained. [1191]
  • TLC: Rf 0.50 (ethyl acetate:methanol:triethylamine=16:2:1); [1192]
  • NMR (DMSO-d6): δ 2.65 and 2.70 (both s, total 3H), 2.85 and 2.90 (both s, total 3H), 3.80 (d, J=12.5 Hz, 1H), 4.05 (dd, J=12.5, 7.5 Hz, 1H), 4.50-4.70 (m, 1H), 4.70-4.90 (m, 1H), 6.35 (d, J=7.5 Hz, 1H), 7.60-8.00 (m, 7H), 8.20-8.35 (m, 1H), 10.85 (brs, 1H). [1193]
    • EXAMPLE 15 4-Methoxy-5-formyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1194]
    Figure US20030073706A1-20030417-C01703
  • To a suspension of lithium aluminum hydride (54 mg) in tetrahydrofuran (10 ml), was added a solution of the compound prepared in Example 10 (10) (300 mg) in tetrahydrofuran (10 ml) at −78° C. dropwise. The reaction mixture was stirred at −78° C. for 1 hour. The reaction mixture was poured into ice-water. The mixture was extracted by ethyl acetate. The extract was washed by water, a saturated aqueous solution of sodium chloride, successively, dried over anhydrous sodium sulfate, and concentrated. The residue was purified with column chromatography on silica gel (hexane:ethyl acetate=1:1) to give the compound of the present invention (51 mg) having the following physical data. [1195]
  • TLC: Rf 0.27 (hexane:ethyl acetate=1:2); [1196]
  • NMR (CDCl[1197] 3): δ 3.80 (dd, J=15.2, 9.3 Hz, 1H), 4.05 (s, 3H), 4.14 (dd, J=15.2, 1.4 Hz, 1H), 5.28 (dd, J=9.3, 1.4 Hz, 1H), 7.46-7.54 (m, 3H), 7.63-7.78 (m, 3H), 8.05 (d, J=8.0 Hz, 1H), 10.33 (d, J=0.6 Hz, 1H).
    • EXAMPLE 16 4-Methoxy-3-(thiophen-2-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1198]
    Figure US20030073706A1-20030417-C01704
  • By the same procedure as described in Example 1 using 2-thiophenthiol and 4-methoxybenzothiophen-1,1-diol, the compound of the present invention having the following physical data was obtained. [1199]
  • TLC: Rf 0.27 (methylene chloride:hexane=4:1); [1200]
  • NMR (CDCl[1201] 3): δ 3.66 (d, J=5.5, 5.4 Hz, 1H), 3.73 (dd, J=15.5, 4.2 Hz, 1H), 3.95 (s, 3H), 4.88 (dd, J=5.4, 4.2 Hz, 1H), 7.01 (dd, J=5.4, 3.6 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 7.19 (dd, J=3.6, 1.2 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.44 (dd, J=5.4, 1.2 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H).
    • EXAMPLE 17 4-Methoxy-3-(thioiphen-2-yl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1202]
    Figure US20030073706A1-20030417-C01705
  • By the same procedure using the compound prepared in Example 16 instead of the compound prepared in Example 9, the compound of the present invention having the following physical data was obtained. [1203]
  • TLC: Rf 0.46 (methylene chloride:ethyl acetate=10:1); [1204]
  • NMR (CDCl[1205] 3): δ 3.73 (s, 3H), 3.79 (dd, J=15.0, 9.2 Hz, 1H), 4.23 (dd, J=15.0, 1.2 Hz, 1H), 5.32 (dd, J=9.2, 1.2 Hz, 1H), 7.04 (d, J=8.0 Hz, 1H), 7.11 (dd, J=4.9, 3.8 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.53 (dd, J=3.8, 1.4 Hz, 1H), 7.59 (t, J=8.0 Hz, 1H), 7.73 (dd, J=4.9, 1.4 Hz, 1H).
    • EXAMPLE 18 4-(4-Nitrophenylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1206]
    Figure US20030073706A1-20030417-C01706
  • To a solution of a compound prepared in Example 9 (12) (1.0 g) in dimethylformamide (30 ml), were added 4-nitrobenzylbromide (947 mg) and potassium carbonate (1.0 g). The reaction mixture was stirred at room temperature overnight. To the reaction mixture, water was added. The mixture was extracted by ethyl acetate. The extract was washed by water (three times), a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The residue was purified with column chromatography on silica gel (hexane:ethyl acetate=1:1) to give the compound of the present invention (1.1 g) having the following physical data. [1207]
  • TLC: Rf 0.29 (hexane:ethyl acetate=1:1); [1208]
  • NMR (CDCl[1209] 3): δ 8.25 (2H, d, J=8.5 Hz), 7.71 (2H, d, J=8.5 Hz), 7.60-7.20 (7H, m), 7.10 (1H, d, J=8 Hz), 5.32 (2H, s), 5.11 (1H, dd, J=7, 2 Hz), 3.85-3.55 (2H, m).
    • EXAMPLES 18 (1)˜18 (40)
  • By the sane procedure as described in Example 18 using compounds prepared in Examples 9 (12)˜9 (15) or Example 9 (17) and a corresponding halogenated compound, the following compounds of the present invention were obtained. [1210]
    • EXAMPLE 18 (1) 4-(3-Phenyloxypropyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1211]
    Figure US20030073706A1-20030417-C01707
  • TLC: Rf 0.27 (hexane ethyl acetate 2:1); [1212]
  • NMR (CDCl[1213] 3): δ 7.54-7.42 (3H, m), 7.32-7.19 (6H, m), 7.10 (1H, d, J=8.0 Hz), 6.95-6.84 (3H, m), 5.01 (1H, dd, J=6.6, 2.2 Hz), 4.31 (2H, t, J=6.0 Hz), 4.20 (2H, t, J=6.0 Hz), 3.69 (1H, dd, J=13.9, 6.6 Hz), 3.59 (1H, dd, J=13.9, 2.2 Hz), 2.31 (2H, quint, J=6.0 Hz).
    • EXAMPLE 18 (2) 4-Benzyloxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1214]
    Figure US20030073706A1-20030417-C01708
  • TLC: Rf 0.45 (hexane:ethyl acetate=2:1); [1215]
  • NMR (CDCl[1216] 3): δ 7.54-7.26 (12H, m), 7.13 (1H, d, J=9.0 Hz), 5.22 (2H, s), 5.03 (1H, dd, J=6.0, 2.6 Hz), 3.71 (1H, dd, J=13.8, 6.0 Hz), 3.63 (1H, dd, J=13.8, 2.6 Hz).
    • EXAMPLE 18 (3) 4-(3-Benzyloxypropyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1217]
    Figure US20030073706A1-20030417-C01709
  • TLC: Rf 0.47 (hexane:ethyl acetate=1:1); [1218]
  • NMR (CDCl[1219] 3): δ 2.13 (quint, J=6.0 Hz, 2H), 3.58 (dd, J=14.0, 2.4 Hz, 1H), 3.67 (dd, J=14.0, 6.6 Hz, 1H), 3.69 (t, J=6.0 Hz, 2H), 4.22 (t, J=6.0 Hz, 2H), 4.44 (d, J=12.0 Hz, 1H), 4.52 (d, J=12.0 Hz, 1H), 4.92 (dd, J=6.6, 2.4 Hz, 1H), 7.08 (d-like, J=7.4 Hz, 1H), 7.26 (s, 5H), 7.30-7.35 (m, 4H), 7.43-7.54 (m, 3H).
    • EXAMPLE 18 (4) 4-(Pyridin-3-ylmethyl) oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1220]
    Figure US20030073706A1-20030417-C01710
  • TLC: Rf 0.46 (ethyl acetate); [1221]
  • NMR (CDCl[1222] 3): δ 3.62 (dd, J=14.0, 2.2Hz, 1H), 3.72 (dd, J=14.0, 6.2Hz, 1H), 5.04 (dd, J=6.2, 2.2 Hz, 1H), 5.23 (s, 2H), 7.15 (dd, J=8.0, 1.0 Hz, 1H), 7.26-7.45 (m, 7H), 7.54 (t, J=8.0 Hz, 1H), 7.85-7.92 (m, 1H), 8.63 (dd, J=4.7, 2.0 Hz, 1H), 8.76 (dd, J=2.0, 0.6 Hz, 1H).
    • EXAMPLE 18 (5) 4-(Quinolin-2-ylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1223]
    Figure US20030073706A1-20030417-C01711
  • TLC: Rf 0.25 (hexane:ethyl acetate=1:1); [1224]
  • NMR (CDCl[1225] 3): δ 8.18 (1H, d, J=8 Hz), 8.10 (1H, d, J=8 Hz), 7.92-7.68 (3H, m), 7.68-7.40 (4H, m), 7.40-7.22 (4H, m), 7.16 (1H, d, J=8 Hz), 5.53 (2H, s), 5.18 (1H, dd, J=7, 2 Hz), 3.76 (1H, dd, J=14, 7 Hz), 3.66 (1H, dd, J=14, 2 Hz).
    • EXAMPLE 18 (6) 4-(Pyridin-2-ylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1226]
    Figure US20030073706A1-20030417-C01712
  • TLC: Rf 0.33 (ethyl acetate); [1227]
  • NMR (CDCl[1228] 3): δ 8.62 (1H, d, J=5 Hz), 7.80-7.58 (2H, m), 7.58-7.38 (3H, m), 7.38-7.18 (5H, m), 7.11 (1H, d, J=8 Hz), 5.35 (2H, s), 5.15 (1H, dd, J=7, 2 Hz), 3.85-3.58 (2H, m).
    • EXAMPLE 18 (7) 4-(Pyridin-4-ylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1229]
    Figure US20030073706A1-20030417-C01713
  • TLC: Rf 0.15 (ethyl acetate); [1230]
  • NMR (CDCl[1231] 3): δ 8.78-8.55 (2H, m), 7.65-7.18 (9H, m), 7.07 (1H, d, J=8 Hz), 5.23 (2H, s), 5.11 (1H, dd, J=7, 2 Hz), 3.82-3.53 (2H, m).
    • EXAMPLE 18 (8) 4-(3-(Pyridin-3-yl)propyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1232]
    Figure US20030073706A1-20030417-C01714
  • TLC: Rf 0.18 (ethyl acetate); [1233]
  • NMR (CDCl[1234] 3): δ 8.48-8.35 (m, 2H), 7.67-7.33 (m, 9H), 6.95 (d, J=8.0 Hz, 1H), 5.01 (d-like, J=8.5 Hz, 1H), 4.15-3.86 (m, 4H), 2.81 (t, J=7.0 Hz, 2H), 2.21-2.01 (m, 2H).
    • EXAMPLE 18 (9) 4-(3-Hydroxypropyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1235]
    Figure US20030073706A1-20030417-C01715
  • TLC: Rf 0.24 (hexane:ethyl acetate=1:2); [1236]
  • NMR (CDCl[1237] 3): δ 2.06-2.17 (m, 2H), 3.57 (dd, J=14.0, 2.2 Hz, 1H), 3.67 (dd, J=14.0, 6.6 Hz, 1H), 3.91 (br, 2H), 4.27 (t, J=5.8 Hz, 2H), 5.05 (dd, J=6.6, 2.2 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 7.30-7.38 (m, 4H), 7.49-7.56 (m, 3H).
    • EXAMPLE 18 (10) 5-Pentoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1238]
    Figure US20030073706A1-20030417-C01716
  • TLC: Rf 0.70 (hexane:ethyl acetate=2:1); [1239]
  • NMR (CDCl[1240] 3): δ 0.95 (t, J=7.0 Hz, 3H), 1.38-1.47 (m, 4H), 1.82 (quint, J=6.8 Hz, 2H), 3.51 (dd, J=15, 7 Hz, 1H), 3.79 (dd, J=15, 7 Hz, 1H), 4.00 (t, J=6.8 Hz, 2H), 4.89 (t, J=7.0 Hz, 1H), 7.01 (dd, J=8, 2 Hz, 1H), 7.12 (d, J=2 Hz, 1H), 7.36-7.38 (m, 3H), 7.41-7.43 (m, 2H), 7.61 (d, J=8 Hz, 1H).
    • EXAMPLE 18 (11) 5-(2-Phenyloxyethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1241]
    Figure US20030073706A1-20030417-C01717
  • TLC: Rf 0.75 (hexane:ethyl acetate=1:1); [1242]
  • NMR (CDCl[1243] 3): δ 7.65 (1H, d, J=8.5 Hz), 7.45-7.42 (2H, m), 7.34-7.29 (5H, m), 7.21 (1H, d, J=2.2 Hz), 7.09 (1 H, dd, J=8.5, 2.2 Hz), 7.00 (1 H, t, J=7.0 Hz), 6.95 (1 H, d, J=8.5 Hz), 4.93 (1H, t, J=7.0 Hz), 4.38 (4H, m), 3.78 (1H, dd, J=14.0, 7.0 Hz), 3.52 (1H, dd, J=14.0, 7.0 Hz).
    • EXAMPLE 18 (12) 5-(3-Hydroxypropyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1244]
    Figure US20030073706A1-20030417-C01718
  • TLC: Rf 0.25 (hexane:ethyl acetate=1:1); [1245]
  • NMR (CDCl[1246] 3): δ 2.10 (quint, J=6.5 Hz, 2H), 3.60 (dd, J=14, 6.7Hz, 1H), 3.82 (dd, J=14, 6.7 Hz, 1H), 3.89 (t, J=6.5 Hz, 2H), 4.20 (t, J=6.5 Hz, 2H), 4.98 (t, J=6.7 Hz, 1H), 7.20 (dd, J=8.5, 2.2 Hz, 1H), 7.35-7.47 (m, 6H), 7.61 (d, J=8.5 Hz, 1H).
    • EXAMPLE 18 (13) 5-(Pyridin-3-ylmethyl) oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1247]
    Figure US20030073706A1-20030417-C01719
  • TLC: Rf 0.40 (ethyl acetate); [1248]
  • NMR (CDCl[1249] 3): δ 3.51 (dd, J=9.0, 4.5 Hz, 1H), 3.79 (dd, J=9.0, 5.0 Hz, 1H), 4.91 (t-like, J=4.7 Hz, 1H), 5.14 (s, 2H), 7.11 (dd, J=5.6, 1.6 Hz, 1H), 7.21 (d, J=1.6 Hz, 1H), 7.33-7.42 (m, 6H), 7.65 (d, J=5.6 Hz, 1H), 7.77 (dt, J=5.4, 1.3 Hz, 1H), 8.63 (dd, J=3.2, 1.3 Hz, 1H), 8.70 (d, J=1.3 Hz, 1H).
    • EXAMPLE 18 (14) 5-(3-(Pyridin-3-yl)propyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1250]
    Figure US20030073706A1-20030417-C01720
  • TLC: Rf 0.16 (ethyl acetate); [1251]
  • NMR (CDCl[1252] 3): δ 8.36-8.28 (m, 2H), 7.78-7.55 (m, 4H), 7.42-7.36 (m, 5H), 7.01 (d, J=8.0 Hz, 1H), 5.11 (d-like, J=9.0 Hz, 1H), 4.12 (t, J=7.0 Hz, 2H), 3.88-3.64 (m, 2H), 3.05 (t, J=7.0 Hz, 2H), 2.35-2.26 (m, 2H).
    • EXAMPLE 18 (15) 6-(3-Phenyloxypropyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1253]
    Figure US20030073706A1-20030417-C01721
  • TLC: Rf 0.42 (hexane:ethyl acetate=2:1); [1254]
  • NMR (CDCl[1255] 3): δ 7.61-7.56 (1H, m), 7.43-7.25 (7H, m), 7.19-7.15 (2H, m), 6.95-6.89 (3H, m), 4.91 (1H, t-like, J=6.6 Hz), 4.22 (2H, t, J=6.0 Hz), 4.15 (2H, t, J=6.0 Hz), 3.80 (1H, dd, J=13.8, 7.3 Hz), 3.51 (1H, dd, J=13.8, 7.3 Hz), 2.28 (2H, quint, J=6.0 Hz).
    • EXAMPLE 18 (16) 6-Benzyloxy-3-phenylthio-2,3-dihydro-1,1-di oxidebenzo[b]thiophene
  • [1256]
    Figure US20030073706A1-20030417-C01722
  • TLC: Rf 0.58 (hexane:ethyl acetate=2:1); [1257]
  • NMR (CDCl[1258] 3): δ 7.63-7.58 (1 H, m), 7.45-7.31 (10H, m), 7.27-7.23 (2H, m), 5.10 (2H, s), 4.92 (1H, t-like, J=6.7 Hz), 3.81 (1H, dd, J=13.7, 7.5 Hz), 3.52 (1H, dd, J=13.7, 6.1 Hz).
    • EXAMPLE 18 (17) 6-pentoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1259]
    Figure US20030073706A1-20030417-C01723
  • TLC: Rf 0.51 (hexane:ethyl acetate=2:1); [1260]
  • NMR (CDCl[1261] 3): 7.60-7.55 (1H, m), 7.43-7.31 (5H, m), 7.19-7.12 (2H, m), 4.91 (1H, t, J=6.8 Hz), 3.99 (2H, t, J=6.6 Hz), 3.80 (1H, dd, J=13.8, 7.3 Hz), 3.51 (1H, dd, J=13.8, 6.2 Hz), 1.80 (2H, quint, J=7.0 Hz), 1.50-1.30 (4H, m), 0.92 (3H, t, J=7.0 Hz).
    • EXAMPLE 18 (18) 6-(2-(Morpholin-4-yl)ethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1262]
    Figure US20030073706A1-20030417-C01724
  • TLC: Rf 0.41 (hexane:ethyl acetate: triethylamine=2:4:1); [1263]
  • NMR (CDCl[1264] 3): δ 7.60 (1H, d, J=8.4 Hz), 7.42-7.32 (5H, m), 7.22-7.16 (2H, m), 4.92 (1H, t-like, J=6.8 Hz), 4.15 (2H, t, J=5.8 Hz), 3.81 (1H, dd, J=13.8, 7.2 Hz), 3.73 (4H, t-like, J=4.6 Hz), 3.52 (1H, dd, J=13.8, 6.1 Hz), 2.82 (2H, t, J=5.8 Hz), 2.57 (4H, t-like, J=4.6 Hz).
    • EXAMPLE 18 (19) 6-(3-Hydroxypropyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1265]
    Figure US20030073706A1-20030417-C01725
  • TLC: Rf 0.33 (hexane:ethyl acetate 1:2); [1266]
  • NMR (CDCl[1267] 3): δ 2.06 (quint, J=6.1 Hz, 2H), 3.51 (dd, J=13.6, 6.2 Hz, 1H), 3.80 (dd, J=13.6, 7.4 Hz, 1H), 3.85 (t, J=6.1 Hz, 2H), 4.17 (t, J=6.1 Hz, 2H), 4.92 (t-like, J=6.8 Hz, 1H), 7.16-7.21 (m, 2H), 7.32-7.45 (m, 5H), 7.57-7.61 (m, 1H).
    • EXAMPLE 18 (20) 6-(Pyridin-3-ylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1268]
    Figure US20030073706A1-20030417-C01726
  • TLC: Rf 0.31 (methylene chloride: ethyl acetate=2:1); [1269]
  • NMR (CDCl[1270] 3): “ 3.53 (dd, J=13.6, 6.2 Hz, 1H), 3.82 (dd, J=13.6, 7.2 Hz, 1H), 4.93 (t-like, J=6.6 Hz, 1H), 5.12 (s, 2H), 7.23-7.28 (m, 2H), 7.33-7.46 (m, 6H), 7.61-7.65 (m, 1H), 7.75-7.79 (m, 1H), 8.63 (dd, J=5.0, 1.6 Hz, 1H), 8.70 (d, J=1.6 Hz, 1H).
    • EXAMPLE 18 (21) 6-(3-Nitrophenylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1271]
    Figure US20030073706A1-20030417-C01727
  • TLC: Rf 0.49 (hexane:ethyl acetate=1:1), [1272]
  • NMR (CDCl[1273] 3): δ 8.33 (1H, brs), 8.22 (1H, dd, J=8, 2 Hz), 7.76 (1H, d, J=7.8 Hz), 7.70-7.48 (2H, m), 7.48-7.16 (7H, m), 5.21 (2H, s), 4.93 (1H, t-like, J=6.8 Hz), 3.83 (1H, dd, J=13.6, 7.6 Hz), 3.54 (1H, dd, J=13.6, 6.2 Hz).
    • EXAMPLE 18 (22) 6-(3-Bromopropyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1274]
    Figure US20030073706A1-20030417-C01728
  • TLC: Rf 0.48 (hexane:ethyl acetate=3:1); [1275]
  • NMR (CDCl[1276] 3). δ 2.35 (quint, J=7.5 Hz, 2H), 3.55 (t, J=7.5 Hz, 2H), 3.59 (dd, J=15, 7 Hz, 1H), 3.80 (dd, J=15, 7 Hz, 1H), 4.18 (t, J=7.5 Hz, 2H), 4.92 (t, J=7 Hz, 1H), 7.20 (dd, J=9, 2 Hz, 1H), 7.34-7.43 (m, 6H), 7.60 (d, J=9 Hz, 1H).
    • EXAMPLE 18 (23) 7-Pentoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1277]
    Figure US20030073706A1-20030417-C01729
  • TLC: Rf 0.80 (hexane:ethyl acetate=1:1); [1278]
  • NMR (CDCl[1279] 3): δ 5 7.54 (1H, t, J=7.8 Hz), 7.45-7.21 (6H, m), 6.91 (1H, d, J=8.6 Hz), 4.88 (1H, t, J=7.6 Hz), 4.11 (2H, t, J=7.0 Hz), 3.77 (1H, dd, J=13.6, 7.6 Hz), 3.50 (1H, dd, J=13.6, 7.6 Hz), 1.87 (2H, quint, J=7.0 Hz), 1.50-1.30 (4H, m), 0.92 (3H, t, J=7.2 Hz).
    • EXAMPLE 18 (24) 7-(2-Phenyloxyethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1280]
    Figure US20030073706A1-20030417-C01730
  • TLC: Rf 0.55 (hexane:ethyl acetate=1:1); [1281]
  • NMR (CDCl[1282] 3): δ 7.58 (1H, t, J=7.8 Hz), 7.45-7.25 (8H, m), 7.06 (1H, d, J=8.4 Hz), 7.05-6.90 (3H, m), 4.89 (1 H, t, J=7.6 Hz), 4.58 -4.45 (2H, m), 4.45-4.35 (2H, m), 3.78 (1 H, dd, J=13.6, 7.6 Hz), 3.52 (1H, dd, J=13.6, 7.6 Hz).
    • EXAMPLE 18 (25) 7-(3-Hydroxypropyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1283]
    Figure US20030073706A1-20030417-C01731
  • TLC: Rf 0.25 (hexane:ethyl acetate=1:2); [1284]
  • NMR (CDCl[1285] 3): δ 7.60-6.60 (8H, m), 4.90 (1 H, t, J=6.8 Hz), 4.36-4.26 (2H, m), 3.90 (2H, br) 3.79 (1H, d, J=13.8, 6.8 Hz), 3.52 (1H, dd, J=13.8, 6.8 Hz), 2.50-2.05 (2H, m).
    • EXAMPLE 18 (26) 7-(Pyridin-3-ylmethyl) oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1286]
    Figure US20030073706A1-20030417-C01732
  • TLC: Rf 0.12 (hexane:ethyl acetate=1:2); [1287]
  • NMR (CDCl[1288] 3): δ 8.66 (1H, d, J=2.2 Hz), 8.57 (1H, dd, J=4.8, 1.8 Hz), 7.93 (1H, d, J=8.2 Hz), 7.56 (1H, t, J=8.2 Hz), 7.45-7.30 (4H, m), 6.97 (1H, d, J=8.2 Hz), 5.30 (2H, s), 4.92 (1H, t, J=7.0 Hz), 3.82 (1H, dd, J=13.8, 7.8 Hz), 3.54 (1H, dd, J=13.8, 7.8 Hz).
    • EXAMPLE 18 (27) 4-(t-Butoxycarbonylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1289]
    Figure US20030073706A1-20030417-C01733
  • TLC: Rf 0.33 (hexane:ethyl acetate=2:1); [1290]
  • NMR (CDCl[1291] 3): δ 7.57-7.46 (3H, m), 7.37-7.32 (4H, m), 6.93 (1H, d-like, J=8.0 Hz), 5.16 (1H, dd, J=6.6, 2.0 Hz), 4.61 (2H, s), 3.72 (1H, dd, J=13.9, 6.6 Hz), 3.61 (1H, dd, J=13.9, 2.0 Hz), 1.49 (9H, s).
    • EXAMPLE 18 (28) 5-(t-Butoxycarbonylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1292]
    Figure US20030073706A1-20030417-C01734
  • TLC: Rf 0.52 (hexane:ethyl acetate=2:1); [1293]
  • NMR (CDCl[1294] 3): δ 1.50 (s, 9H), 3.48 (dd, J=14, 6.7 Hz, 1H), 3.82 (dd, J=14, 6.7 Hz, 1H), 4.66 (s, 2H), 4.95 (t, J=6.7 Hz, 1H), 7.18 (dd, J=9, 2.3 Hz, 1H) 7.40-7.53 (m, 6H), 7.62 (d, J=9 Hz, 1H).
    • EXAMPLE 18 (29) 6-(t-Butoxycarbonylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1295]
    Figure US20030073706A1-20030417-C01735
  • TLC: Rf 0.44 (hexane:ethyl acetate 2:1); [1296]
  • NMR (CDCl[1297] 3): δ 7.61 (1H, d, J=8.7 Hz), 7.44-7.32 (5H, m), 7.24 (1H, dd, J=8.7, 2.6 Hz), 7.08 (1H, d, J=2.6 Hz), 4.91 (1H, t-like, J=6.7 Hz), 4.56 (2H, s), 3.80 (1H, dd, J=13.7, 7.3 Hz), 3.51 (1H, dd, J=13.7, 6.1 Hz), 1.49 (9H, s).
    • EXAMPLE 18 (30) 7-(t-Butoxycatbonylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1298]
    Figure US20030073706A1-20030417-C01736
  • TLC: Rf 0.55 (hexane:ethyl acetate=1:1); [1299]
  • NMR (CDCl[1300] 3): δ 7.54 (1H, t, J=7.6 Hz), 7.45-7.27 (6H, m), 6.80 (1H, d, J=8.0 Hz), 4.90 (1H, t, J=7.6 Hz), 4.69 (2H, s), 3.79 (1H, dd, J=13.6, 7.6 Hz), 3.52 (1H, dd, J=13.6, 7.6 Hz), 1.46 (9H, s).
    • EXAMPLE 18 (31) 4-(2-(t-Butoxycarbonylamino)ethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1301]
    Figure US20030073706A1-20030417-C01737
  • TLC: Rf 0.35 (hexane:ethyl acetate=1:2); [1302]
  • NMR (CDCl[1303] 3): δ 1.35 (s, 9H), 3.46-3.66 (m, 2H), 3.62 (dd, J=14.2, 2.2 Hz, 1H), 3.73 (dd, J=14.2, 6.8 Hz, 1H), 4.11-4.25 (m, 2H), 5.06 (dd, J=6.8, 2.2 Hz, 1H), 5.39 (br, 1H), 7.08 (d, J=7.6 Hz, 1H), 7.31-7.39 (m, 4H), 7.44-7.57 (m, 3H).
    • EXAMPLE 18 (32) 4-(3-(t-Butoxycarbonylamino)propyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1304]
    Figure US20030073706A1-20030417-C01738
  • TLC: Rf 0.28 (hexane:ethyl acetate=1:1); [1305]
  • NMR (CDCl[1306] 3): δ 1.38 (s, 9H), 2.00-2.11 (m, 2H), 3.33-3.44 (m, 2H), 3.59 (dd, J=14.0, 2.2 Hz, 1H), 3.69 (dd, J=14.0, 6.6 Hz, 1H), 4.17 (t, J=5.9 Hz, 2H), 4.90 (br, 1H), 5.08 (dd, J=6.6, 2.2 Hz, 1H), 7.08 (dd, J=8.1, 0.7 Hz, 1H), 7.29-7.38 (m, 4H), 7.48-7.56 (m, 3H).
    • EXAMPLE 18 (33) 5-(2-(t-Butoxycarbonylamino)ethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1307]
    Figure US20030073706A1-20030417-C01739
  • TLC: Rf 0.40 (hexane:ethyl acetate=2:1); [1308]
  • NMR (CDCl[1309] 3): δ 1.46 (s, 9H), 3.52 (dd, J=15, 6 Hz, 1H), 3.56 (t, J=7.5 Hz, 2H), 3.80 (dd, J=15, 6 Hz, 1H), 4.10 (t, J=7.5 Hz, 2H), 4.88 (t, J=6 Hz, 1H), 4.99 (br, 1H), 7.03 (dd, J=9, 2 Hz, 1H), 7.12 (d, J=2 Hz, 1H), 7.35-7.47 (m, 5H), 7.64 (d, J=9 Hz, 1H).
    • EXAMPLE 18(34) 6-(3-(t-Butoxycarbonylamino)propyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1310]
    Figure US20030073706A1-20030417-C01740
  • TLC: Rf 0.43 (hexane:ethyl acetate=1:1); [1311]
  • NMR (CDCl[1312] 3): δ 5 1.44 (s, 9H), 2.01 (quint, J=6.2 Hz, 2H), 3.32 (q, J=6.2 Hz, 2H), 3.51 (dd, J=13.6, 6.0 Hz, 1H), 3.80 (dd, J=13.6, 7.4 Hz, 1H), 4.06 (t, J=6.2 Hz, 2H), 4.69 (br, 1H), 4.91 (t-like, J=6.8 Hz, 1H), 7.14-7.21 (m, 2H), 7.32-7.45 (m, 5H), 7.59 (d, J=8.4 Hz, 1H).
    • EXAMPLE 18(35) 6-(2-(t-Butoxycarbonylamino)ethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1313]
    Figure US20030073706A1-20030417-C01741
  • TLC: Rf 0.47 (hexane:ethyl acetate=1:1); [1314]
  • NMR (CDCl[1315] 3): δ 1.46 (s, 9H), 3.51 (dd, J=13.8, 6.2 Hz, 1H), 3.55 (q, J=5.2 Hz, 2H), 3.81 (dd, J=13.8, 7.4 Hz, 1H), 4.06 (t, J=5.2 Hz, 2H), 4.92 (t-like, J=6.4 Hz, 1H), 4.96 (br, 1H), 7.13 (d, J=2.4 Hz, 1H), 7.18 (dd, J=8.5, 2.4 Hz, 1H), 7.32-7.45 (m, 5H), 7.60 (d, J=8.5 Hz, 1H).
    • EXAMPLE 18(36) 7-(2-(t-Butoxycarbonylamino)ethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1316]
    Figure US20030073706A1-20030417-C01742
  • TLC: Rf 0.60 (hexane ethyl acetate=1:2); [1317]
  • NMR (CDCl[1318] 3): “ 7.60-7.24 (7H, m), 6.94 (1H, d, J=8.4 Hz), 5.38 (1H, bs), 4.90 (1H, t, J=7.4 Hz), 4.30-4.05 (2H, m), 3.79 (1H, dd, J=13.7, 7.4 Hz), 3.60-3.40 (3H, m), 1.42 (9H, s).
    • EXAMPLE 18(37) 4-(N-(t-Butoxycarbonyl)piperidin-4-yl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1319]
    Figure US20030073706A1-20030417-C01743
  • TLC: Rf 0.41 (hexane:ethyl acetate=1:1); [1320]
  • NMR (CDCl[1321] 3): δ 7.60-7.42 (3H, m), 7.42-7.25 (4H, m), 7.04 (1 H, d, J=8.2 Hz), 5.05 (1 H, dd, J=6.6, 2.2 Hz), 4.80-4.60 (1H, m), 3.85-3.32 (6H, m), 2.15-1.65 (4H, m), 1.48 (9H, s).
    • EXAMPLE 18(38) 4,7-B is [(2-(t-butoxycarbonylamino)ethyl) oxy]-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1322]
    Figure US20030073706A1-20030417-C01744
  • TLC: Rf 0.35 (hexane:ethyl acetate=1:2); [1323]
  • NMR (CDCl[1324] 3): δ 7.53-7.30 (5H, m), 7.20-6.85 (2H, m), 5.40 (2H, brs), 5.03-4.85 (1H, m), 4.25-4.00 (4H, m), 3.90-3.40 (6H, m), 1.43 (18H, s).
    • EXAMPLE 18(39) 4-(3-Nitrophenylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1325]
    Figure US20030073706A1-20030417-C01745
  • TLC: Rf 0.29 (hexane:ethyl acetate=1:1); [1326]
  • NMR (CDCl[1327] 3): δ 8.44 (1H, s), 8.24 (1 H, d, J=8.4 Hz), 7.86 (1H, d, J=8.0 Hz), 7.65-7.20, (8H, m), 7.14 (1H, d, J=7.2 Hz), 5.31 (2H, s), 5.13 (1H, dd, J=2.6 Hz, 6.6 Hz), 3.80-3.56 (2H, m).
    • EXAMPLE 18(40) 4,7-Bis(pyridin-3-ylmethyloxy)-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1328]
    Figure US20030073706A1-20030417-C01746
  • TLC: Rf 0.20 (ethyl acetate:methanol=10:1); [1329]
  • NMR (CDCl[1330] 3): δ 8.75-8.72 (1H, m), 8.70-8.50 (4H, m), 7.96-7.82 (2H, m), 7.46-7.24 (6H, m), 7.05 (1H, d, J=9.0 Hz), 6.93 (1H, d, J=9.0 Hz), 5.25 (2H, s), 5.15 (2H, s), 5.01-4.95 (1H, m), 3.81-3.59 (2H, m).
    • EXAMPLE 19 4-(3-Hydroxypropyl)oxy-3-phenylsulfynyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1331]
    Figure US20030073706A1-20030417-C01747
  • By the same procedure as described in Example 2 using the compound prepared in Example 18 (9) instead of the compound prepared in Example 1, the compound of the present invention having the following physical data was obtained. [1332]
  • TLC: Rf 0.18 (hexane:ethyl acetate=1:1); [1333]
  • NMR (CDCl[1334] 3): δ 2.17 (quint, J=6.0 Hz, 2H), 3.08 (dd, J=14.0, 8.6 Hz, 1H), 3.94 (t, J=6.0 Hz, 2H), 3.98 (dd, J=14.0, 4.8 Hz, 1H), 4.32 (t, J=6.0 Hz, 2H), 4.15 (dd, J=8.6, 4.8 Hz, 1H), 7.18 (d, J=7.9 Hz, 1H), 7.35 (d, J=7.9 Hz, 1H), 7.55-7.66 (m, 6H).
    • EXAMPLE 20 4-(4-Nitrophenylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1335]
    Figure US20030073706A1-20030417-C01748
  • By the same procedure as described in Example 10 using the compound prepared in Example 18 instead of the compound prepared in Example 9, the compound of the present invention having the following physical data was obtained. [1336]
  • TLC: Rf 0.67 (ethyl acetate:methanol:28% ammonia water=100:10:1); [1337]
  • NMR (DMSO-d[1338] 6): δ 8.25 (2H, d, J=9 Hz), 7.78-7.52 (6H, m), 7.52-7.20 (4H, m), 5.74 (1H, d, J=9 Hz), 5.26 (1H, d, J=14 Hz), 4.99 (1H, d, J=14 Hz), 4.19 (1H, d, J=15 Hz), 4.00 (1H, dd, J=15, 9 Hz).
    • EXAMPLES 20 (1)˜20 (39)
  • Using the compounds prepared in Examples 18 (1)˜18 (39) instead of the compound prepared in Example 18 by the same procedure as described in Example 20, or by the same reaction using 3-chloroperbenzoic acid instead of OXONEO as an oxidizer, and, if necessary, by converting into the corresponding salts by known methods, the following compounds of the present invention were obtained. [1339]
    • EXAMPLE 20 (1) 4-(3-Phenyloxypropyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1340]
    Figure US20030073706A1-20030417-C01749
  • TLC: Rf 0.33 (hexane:ethyl acetate=1:1); [1341]
  • NMR (CDCl[1342] 3): δ 2.20 (quint, J=6.0 Hz, 2H), 3.70 (dd, J=14.8, 9.3 Hz, 1H), 3.99-4.28 (m, 4H), 4.20 (dd, J=14.8, 1.2 Hz, 1H), 5.19 (dd, J=9.3, 1.2 Hz, 1H), 6.89-7.01 (m, 4H), 7.21-7.50 (m, 6H), 7.52-7.60 (m, 1H), 7.65-7.70 (m, 2H).
    • EXAMPLE 20 (2) 4-Benzyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1343]
    Figure US20030073706A1-20030417-C01750
  • TLC: Rf 0.39 (hexane:ethyl=11); [1344]
  • NMR (CDCl[1345] 6): δ 3.73 (dd, J=15.0, 9.0 Hz, 1H), 4.22 (d, J=15.0 Hz, 1H), 4.88 (d, J=11.7 Hz, 1H), 4.99 (d, J=11.7 Hz, 1H), 5.28 (d, J=9.0 Hz, 1H), 7.04 (d, J=7.8 Hz, 1H), 7.26-7.40 (m, 8H), 7.49-7.58 (m, 2H), 7.64-7.69 (m, 2H).
    • EXAMPLE 20 (3) 4-(3-Benzyloxypropyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1346]
    Figure US20030073706A1-20030417-C01751
  • TLC: Rf 0.26 (hexane:ethyl acetate=1:1); [1347]
  • NMR (CDCl[1348] 3): δ 1.96 (quint, J=6.1 Hz, 2H), 3.57-3.67 (m, 2H), 3.67 (dd, J=14.9, 9.2 Hz, 1H), 3.82-3.92 (m, 1H), 3.98-4.09 (m, 1H), 4.21 (dd, J=14.9, 0.5 Hz, 1H), 4.46 (d, J=12.1 Hz, 1H), 4.56 (d, J=12.1 Hz, 1H). 5.05 (dd, J=9.2, 0.5 Hz, 1H), 6.94 (d, J=8.4 Hz, 1H), 7.22-7.27 (m, 6H), 7.35-7.60 (m, 4H), 7.65-7.69 (m, 2H).
    • EXAMPLE 20 (4) 4-(Pyridin-3-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1349]
    Figure US20030073706A1-20030417-C01752
  • free compound: [1350]
  • TLC: Rf 0.17 (ethyl acetate); [1351]
  • NMR (DMSO-d[1352] 6): δ 3.95 (dd, J=15.0, 8.8 Hz, 1H), 4.16 (dd, J=15.0, 1.2 Hz, 1H), 4.93 (d, J=12.5 Hz, 1H), 5.15 (d, J=12.5 Hz, 1H), 5.66 (d-like, J=8.0 Hz, 1H), 7.35-7.45 (m, 5H), 7.55-7.72 (m, 4H), 7.80 (dt, J=8.0, 1.4 Hz, 1H), 8.56 (dd, J=5.0, 1.4 Hz, 1H), 8.61 (d, J=1.4 Hz, 1H).
  • Hydrochloride: [1353]
  • TLC: Rf 0.17 (ethyl acetate); [1354]
  • NMR (DMSO-d[1355] 6): δ 3.98 (dd, J=15.2, 8.6 Hz, 1H), 4.16 (d, J=15.2 Hz, 1H), 5.10 (d, J=12.8 Hz, 1H), 5.29 (d, J=12.8 Hz, 1H), 5.85 (d, J=8.6 Hz, 1H), 7.38-7.59 (m, 5H), 7.66-7.75 (m, 3H), 7.94 (dd, J=8.0, 5.4 Hz, 1H), 8.38 (d, J=8.0 Hz, 1H), 8.84 (d, J=5.4 Hz, 1H), 8.88 (s, 1H).
  • Methanesulfonic Acid Salt: [1356]
  • TLC: Rf 0.31 (ethyl acetate:methanol=9:1); [1357]
  • NMR (DMSO-d[1358] 6): δ 2.37 (3H, s), 4.00 (dd, J=15.0, 8.8 Hz, 1H), 4.17 (d-like, J=15.4 Hz, 1H), 5.13 (d, J=13.0 Hz, 1H), 5.32 (d, J=13.0 Hz, 1H), 5.85 (d-like, J=8.0 Hz, 1H), 7.39-7.45 (m, 4H), 7.52-7.59 (m, 1H), 7.66-7.77 (m, 3H), 8.05 (dd, J=8.2, 5.8 Hz, 1H), 8.49 (d, J=8.2 Hz, 1H), 8.89-8.92 (m, 2H).
    • EXAMPLE 20 (5) 4-(N-Oxidequinolin-2-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1359]
    Figure US20030073706A1-20030417-C01753
  • TLC: Rf 0.38 (ethyl acetate:methanol: 28% ammonia water=100:10:1); [1360]
  • NMR (CDCl[1361] 3): “ 8.77 (1H, d, J=8 Hz), 8.00-7.75 (4H, m), 7.75-7.63 (3H, m), 7.63-7.45 (2H, m), 7.45-7.22 (3H, m), 7.17 (1H, d, J=8 Hz), 5.72-5.25 (3H, m), 4.28 (1H, d, 15 Hz), 3.84 (1H, dd, J=15, 9 Hz).
    • EXAMPLE 20 (6a) 4-(Pyridin-2-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1362]
    Figure US20030073706A1-20030417-C01754
  • TLC: Rf 0.43 (ethyl acetate:methanol:28% ammonia water=100:10:1); [1363]
  • NMR (CDCl[1364] 3): “ 8.61 (1H, d, J=4 Hz), 7.88-7.18 (10H, m), 7.04 (1H, d, J=8 Hz), 5.37 (1H, d, J=9 Hz), 5.11 (1 H, d, J=14 Hz), 4.98 (1 H, d, J=14 Hz), 4.24 (1 H, d, J=15 Hz), 3.78 (1H, dd, J=15, 9 Hz).
    • EXAMPLE 20 (6b) 4-(N-Oxidepyridin-2-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1365]
    Figure US20030073706A1-20030417-C01755
  • TLC: Rf 0.09 (ethyl acetate:methanol:28% ammonia water=100:10:1); [1366]
  • NMR (CDCl[1367] 3+DMSO-d6): δ 8.42-8.22 (1H, m), 7.90-7.20 (11H, m), 5.83 (1H, d, J=8.5 Hz), 5.18 (1H, d, J=15 Hz), 4.93 (1H, d, J=15 Hz), 4.21 (1H, d, J=15 Hz), 4.03 (1H, dd, J=15, 8.5 Hz).
    • EXAMPLE 20 (7) 4-(Pyridin-4-ylmethyl)oxy-3-phenylsulfonyl-2,3-di hydro-1,1-dioxidebenzo[b]thiophene
  • [1368]
    Figure US20030073706A1-20030417-C01756
  • Free Compound: [1369]
  • TLC: Rf 0.26 (ethyl acetate:methanol:28% ammonia water=100:10:1); [1370]
  • NMR (CDCl[1371] 3+DMSO-d6): δ 8.57 (2H, d, J=6 Hz), 7.80-7.15 (10H, m), 5.75 (1H, d, J=9 Hz), 5.15 (1H, d, J=14 Hz), 4.90 (1H, d, J=14 Hz), 4.19 (1H, d, J=15 Hz), 4.00 (1H, dd, J=15, 9 Hz).
  • Hydrochloride: [1372]
  • TLC: Rf 0.31 (ethyl acetate:methanol=9:1); [1373]
  • NMR (DMSO-d[1374] 6): δ 8.93 (d, J=6.5 Hz, 2H), 8.00 (d, J=6.5 Hz, 2H), 7.74-7.68 (m, 3H), 7.60-7.54 (m, 1H), 7.47-7.42 (m, 3H), 7.33 (d, J=8.0 Hz, 1H), 5.93 (d, J=9.0 Hz, 1H), 5.46 (d, J=16.0 Hz, 1H), 5.18 (d, J=16.0 Hz, 1H), 4.19 (d, J=15.0 Hz, 1H), 4.03 (dd, J=15.0, 9.0 Hz, 1H).
  • Methanesulfonic Acid Salt: [1375]
  • TLC: Rf 0.31 (ethyl acetate:methanol=9:1); [1376]
  • NMR (DMSO-d[1377] 6): δ 8.94 (d, J=6.3 Hz, 2H), 8.03 (d, J=6.3 Hz, 2H), 7.74-7.68 (m, 3H), 7.60-7.55 (m, 1H), 7.47-7.42 (m, 3H), 7.34 (d, J=8.0 Hz, 1H), 5.92 (d, J=9.0 Hz, 1H), 5.46 (d, J=16.0 Hz, 1H), 5.19 (d, J=16.0 Hz, 1H), 4.19 (d, J=15.0 Hz, 1H), 4.03 (dd, J=15.0, 9.0 Hz, 1H), 2.38 (s, 3H).
    • EXAMPLE 20 (8) 4-(3-(Pyridin-3-yl)propyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-di oxidebenzo[b]thiophene
  • [1378]
    Figure US20030073706A1-20030417-C01757
  • TLC: Rf 0.41 (ethyl acetate:methanol:28% ammonia water=100:10:1); [1379]
  • NMR (CDCl[1380] 3+CD3OD): δ 8.50-8.36 (2H. m), 7.80-7.23 (9H, m), 7.00 (1H, d, J=8 Hz), 5.27 (1H, d, J=9 Hz), 4.26-3.68 (4H, m), 2.88 (2H, t, J=7 Hz), 2.20-1.90 (2H, m).
    • EXAMPLE 20 (9) 4-(3-Hydroxypropyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1381]
    Figure US20030073706A1-20030417-C01758
  • TLC: Rf 0.26 (hexane:ethyl acetate=1:1); [1382]
  • NMR (CDCl[1383] 3): δ 2.02 (quint, J=5.6 Hz, 2H), 2.28 (t, J=5.6 Hz, 1H), 3.71 (dd, J=14.8, 9.2 Hz, 1H), 3.91 (m, J=5.6 Hz, 2H), 4.05 (dd, J=14.8, 1.0 Hz, 1H), 4.10-4.17 (m, 2H), 5.28 (d-like, J=8.8 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 7.23 (d, J=7.8 Hz, 1H), 7.42-7.62 (m, 4H), 7.66-7.73 (m, 2H).
    • EXAMPLE 20 (10) 5-Pentoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1384]
    Figure US20030073706A1-20030417-C01759
  • TLC: Rf 0.40 (hexane:ethyl acetate=2:1); [1385]
  • NMR (CDCl[1386] 3): δ 0.96 (t, J=8 Hz, 3H), 1.42 (m, 4H), 1.86 (m, 2H), 3.70 (dd, J=14, 8 Hz, 1H), 3.80 (dd, J=14,6 Hz, 1H), 4.07 (m, 2H), 5.00 (dd, J=8,6 Hz, 1H), 7.10 (dd, J=8,2 Hz, 1H), 7.44 (d, J=2 Hz, 1H), 7.46-7.77 (m, 6H).
    • EXAMPLE 20 (11) 5-(2-Phenyloxyethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1387]
    Figure US20030073706A1-20030417-C01760
  • TLC: Rf 0.25 (hexane:ethyl acetate=1:1); [1388]
  • NMR (CDCl[1389] 3): (3.70 (dd, J=14, 8 Hz, 1H), 3.77 (dd, J=14, 6 Hz, 1H), 4.41 (m, 4H), 5.02 (dd, J=8, 6 Hz, 1H), 7.00 (m, 3H), 7.19 (dd, J=8, 2 Hz, 1H), 7.30-7.77 (m, 9H).
    • EXAMPLE 20 (12) 5-(3-Hydroxypropyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1390]
    Figure US20030073706A1-20030417-C01761
  • TLC: Rf 0.15 (hexane:ethyl acetate=1:1); [1391]
  • NMR (CDClo[1392] 3): δ 2.11 (m, 2H), 3.65 (dd, J=14, 8 Hz, 1H), 3.78 (dd, J=14, 5 Hz, 1H), 3.89 (m, 2H), 4.25 (m, 2H), 5.01 (dd, J=8, 5 Hz, 1H), 7.12 (dd, J=9, 2 Hz, 1H), 7.45-7.77 (m, 7H).
    • EXAMPLE 20 (13) 5-(Pyridin-3-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1393]
    Figure US20030073706A1-20030417-C01762
  • Free Compound: [1394]
  • TLC: Rf 0.30 (ethyl acetate); [1395]
  • NMR (DMSC-d[1396] 6): δ 3.79 (dd, J=15.1, 3.2 Hz, 1H), 4.00 (dd, J=15.1, 9.4 Hz, 1H), 5.27 (s, 2H), 5.74 (dd, J=9.4, 3.2 Hz, 1H), 7.20 (d, J=2.2 Hz, 1H), 7.36 (dd, J=8.7, 2.2 Hz, 1H), 7.47 (dd, J=7.8, 4.9 Hz, 1H), 7.57-7.65 (m, 2H), 7.71-7.82 (m, 4H), 7.91 (dt, J=7.8, 2.0 Hz, 1H), 8.58 (dd, J=4.9, 2.0 Hz, 1H), 8.71 (d, J=2.0 Hz, 1H).
  • Hydrochloride: [1397]
  • TLC: Rf 0.65 (ethyl acetate:triethylamine=10:1); [1398]
  • NMR (DMSO-d[1399] 6): δ 3.77 (dd, J=15.0, 3.4 Hz, 1H), 3.99 (dd, J=15.0, 9.6 Hz, 1H), 5.43 (s, 2H), 5.77 (dd, J=9.6, 3.4 Hz, 1H), 7.30 (d, J=2.0 Hz, 1H), 7.41 (dd, J=8.8, 2.2 Hz, 1H), 7.59-7.66 (m, 2H), 7.74-7.82 (m, 4H), 8.02 (dd, J=8.4, 5.6 Hz, 1H), 8.57 (d-like, J=8.4 Hz, 1H), 8.88 (d-like, J=5.6 Hz, 1H), 9.04 (s-like, 1H).
  • Methanesulfonic Acid Salt: [1400]
  • TLC: Rf 0.30 (ethyl acetate); [1401]
  • NMR (DMSO-d[1402] 6): δ 2.37 (3H, s), 3.77 (dd, J=15.0, 3.3 Hz, 1H), 4.00 (dd, J=15.0, 9.3 Hz, 1H), 5.77 (dd, J=9.3, 3.3 Hz, 1H), 7.31 (d, J=2.2 Hz, 1H), 7.41 (dd, J=8.7, 2.2 Hz, 1H), 7.59-7.66 (m, 2H), 7.74-7.83 (m, 4H), 8.06 (dd, J=8.0, 5.6 Hz, 1H), 8.61 (d-like, J=8.0 Hz, 1H), 8.91 (dd, J=5.6, 1.0 Hz, 1H), 9.07 (d, J=1.6 Hz, 1H).
    • EXAMPLE 20 (14) 5-(3-(Pyridin-3-yl)propyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride
  • [1403]
    Figure US20030073706A1-20030417-C01763
  • TLC: Rf 0.32 (ethyl acetate:methanol=10:1); [1404]
  • NMR (CD[1405] 3OD): δ 8.80 (1H, s), 8.71 (1H, d, J=6 Hz), 8.56 (1H, d, J=8 Hz), 8.02 (1H, t, J=7 Hz), 7.85-7.42 (6H, m), 7.27 (1H, d, J=10 Hz), 7.14 (1H, s), 5.50-5.32 (1H, m), 4.16 (2H, t, J=6 Hz), 3.98-3.65 (2H, m), 3.10 (2H, t, J=7 Hz), 2.40-2.10 (2H, m).
    • EXAMPLE 20 (15) 6-(3-Phenyloxypropyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1406]
    Figure US20030073706A1-20030417-C01764
  • TLC: Rf 0.43 (hexane:ethyl acetate=1:1); [1407]
  • NMR (CDCl[1408] 3): δ 2.29 (quint, J=6.0 Hz, 2H), 3.65-3.81 (m, 2H), 4.15 (t, J=6.0 Hz, 2H), 4.21 (t, J=6.0 Hz, 2H), 4.99 (dd, J=7.3, 5.9 Hz, 1H), 6.89-6.99 (m, 3H), 7.08 (d, J=2.2 Hz, 1H), 7.23 (dd, J=8.8, 2.2 Hz, 1H), 7.25-7.33 (m, 2H), 7.45-7.52 (m, 2H), 7.62-7.70 (m, 3H), 7.85 (d, J=8.8 Hz, 1H).
    • EXAMPLE 20 (16) 6-Benzyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1409]
    Figure US20030073706A1-20030417-C01765
  • TLC: Rf 0.50 (hexane:ethyl acetate=1:1); [1410]
  • NMR (CDCl[1411] 3): δ 3.71 (dd, J=14.7, 7.7 Hz, 1H), 3.80 (dd, J=14.7, 5.5 Hz, 1H), 5.00 (dd, J=7.7, 5.5 Hz, 1H), 5.10 (s, 2H), 7.15 (d, J=2.5 Hz, 1H), 7.30 (dd, J=8.5, 2.5 Hz, 1H), 7.40-7.53 (m, 7H), 7.63-7.71 (m, 3H), 7.87 (d, J=8.5 Hz, 1H).
    • EXAMPLE 20 (17) 6-Pentoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1412]
    Figure US20030073706A1-20030417-C01766
  • TLC: Rf 0.26 (hexane:ethyl acetate 2:1); [1413]
  • NMR (CDCl[1414] 3): δ 0.94 (t, J=6.4 Hz, 3H), 1.42 (m, 4H), 1.81 (m, 2H), 3.70 (dd, J=14.9, 7.6 Hz, 1H), 3.79 (dd, J=14.9, 5.7 Hz, 1H), 3.99 (t, J=6.4 Hz, 2H), 5.00 (dd, J=7.6, 5.7 Hz, 1H), 7.04 (d, J=2.4 Hz, 1H), 7.23 (dd, J=8.8, 2.4 Hz, 1H), 7.46-7.54 (m, 2H), 7.64-7.72 (m, 3H), 7.84 (d, J=8.8 Hz, 1H).
    • EXAMPLE 20 (18) 6-(2-(Morpholin-4-yl)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1415]
    Figure US20030073706A1-20030417-C01767
  • Free Compound: [1416]
  • TLC: Rf 0.27 (hexane:ethyl acetate: triethylamine=2:4:1); [1417]
  • NMR (CDCl[1418] 3): δ 2.56 (t, J=4.5 Hz, 4H), 2.81 (t, J=5.6 Hz, 2H), 3.70-3.77 (m, 6H), 4.14 (t, J=5.6 Hz, 2H), 5.01 (dd, J=7.5, 5.7 Hz, 1H), 7.08 (d, J=2.3 Hz, 1H), 7.25 (dd, J=8.7, 2.3 Hz, 1H), 7.47-7.54 (m, 2H), 7.64-7.72 (m, 3H), 7.83 (d, J=8.7 Hz, 1H).
  • Hydrochloride: [1419]
  • TLC: Rf 0.27 (hexane ethyl acetate:triethylamine=4:8:1); [1420]
  • NMR (CD[1421] 3OD): δ 3.43-3.53 (m, 4H), 3.68 (t, J=4.8 Hz, 2H), 3.80 (dd, J=15.4, 8.4 Hz, 1H), 3.95 (dd, J=15.4, 4.0 Hz, 1H), 3.92-4.02 (m, 4H), 4.51 (t, J=4.8 Hz, 2H), 5.45 (dd, J=8.4, 4.0 Hz, 1H), 7.33 (d, J=2.6 Hz, 1H), 7.42 (dd, J=8.8, 2.6 Hz, 1H), 7.55-7.63 (m, 2H), 7.71-7.81 (m, 4H).
    • EXAMPLE 20 (19) 6-(3-Hydroxypropyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1422]
    Figure US20030073706A1-20030417-C01768
  • TLC: Rf 0.22 (hexane:ethyl acetate=1:2); [1423]
  • NMR (CDCl[1424] 3): δ 2.06 (quint, J=6.0 Hz, 2H), 3.71 (dd, J=14.6, 7.5 Hz, 1H), 3.79 (dd, J=14.6, 5.6 Hz, 1H), 3.85 (t, J=6.0 Hz, 2H), 4.16 (t, J=6.0 Hz, 2H), 5.00 (dd, J=7.5, 5.6 Hz, 1H), 7.08 (d, J=2.4 Hz, 1H), 7.24 (dd, J=8.8, 2.4 Hz, 1H), 7.47-7.55 (m, 2H), 7.64-7.71 (m, 3H), 7.84 (d, J=8.8 Hz, 1H).
    • EXAMPLE 20 (20) 6-(Pyridin-3-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1425]
    Figure US20030073706A1-20030417-C01769
  • Free Compound: [1426]
  • TLC: Rf 0.39 (ethyl acetate); [1427]
  • NMR (DMSO-d6): δ 3.78 (dd, J=15.2, 3.1 Hz, 1H), 4.01 (dd, J=15.2, 9.2 Hz, 1H), 5.29 (s, 2H), 5.69 (dd, J=9.2, 3.1 Hz, 1H), 7.42-7.47 (m, 3H), 7.58-7.66 (m, 3H), 7.74-7.82 (m, 3H), 7.89 (dt, J=8.0, 1.0 Hz, 1H), 8.57 (dd, J=4.8, 1.6 Hz, 1H), 8.69 (d, J=1.6 Hz, 1H). [1428]
  • Hydrochloride: [1429]
  • TLC: Rf 0.39 (ethyl acetate); [1430]
  • NMR (DMSO-d[1431] 6): δ 3.78 (dd, J=15.2, 3.0 Hz, 1H), 4.01 (dd, J=15.2, 9.4 Hz, 1H), 5.72 (dd, J=9.4, 3.0 Hz, 1H), 7.46-7.51 (m, 2H), 7.59-7.66 (m, 3H), 7.75-7.83 (m, 3H), 7.99 (dd, J=8.0, 5.4 Hz, 1H), 8.52 (d, J=8.0 Hz, 1H), 8.87 (dd, J=5.4, 1.2 Hz, 1H), 8.99 (d, J=1.2 Hz, 1H).
    • EXAMPLE 20 (21) 6-(3-Nitrophenylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1432]
    Figure US20030073706A1-20030417-C01770
  • TLC: Rf 0.55 (hexane:ethyl acetate=1:2); [1433]
  • NMR (DMSO-d[1434] 6): δ 8.36-8.34 (m, 1H), 8.25-8.20 (m, 1H), 7.93 (d-like, J=7.6 Hz, 1H), 7.82-7.72 (m, 4H), 7.68-7.58 (m, 3H), 7.50-7.43 (m, 2H), 5.70 (dd, J=9.4, 3.0 Hz, 1H), 5.40 (s, 2H), 4.02 (dd, J=15.2, 9.4 Hz, 1H), 3.79 (dd, J=15.2, 3.0 Hz, 1H).
    • EXAMPLE 20 (22) 6-(3-Bromopropyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1435]
    Figure US20030073706A1-20030417-C01771
  • TLC: Rf 0.60 (hexane:ethyl acetate=1:1); [1436]
  • NMR (CDCl[1437] 3): δ 2.35 (m, 2H), 3.60 (t, J=6.0 Hz, 2H), 3.70-3.91 (m, 2H), 4.17 (t, J=6.0 Hz, 2H), 5.01 (dd, J=14, 7 Hz, 1H), 7.09 (d, J=3.0 Hz, 1H), 7.25 (m, 1H), 7.53 (m, 2H), 7.67 (m, 3H), 7.89 (m, 1H).
    • EXAMPLE 20 (23) 7-Pentoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1438]
    Figure US20030073706A1-20030417-C01772
  • TLC: Rf 0.48 (hexane:ethyl acetate=1:1); [1439]
  • NMR (CDCl[1440] 3): δ 7.70-7.43 (7H, m), 6.99 (1H, d, J=8.2 Hz), 5.01 (1H, dd, J=8.6, 5.4 Hz), 4.07 (2H, t, J=6.8 Hz), 3.73-3.68 (2H, m), 1.80 (2H, quint., J=6.8 Hz), 1.50-1.20 (4H, m), 0.89 (3H, t, J=6.8 Hz).
    • EXAMPLE 20 (24) 7-(2-Phenyloxyethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1441]
    Figure US20030073706A1-20030417-C01773
  • TLC: Rf 0.27 (hexane:ethyl acetate=1:1) [1442]
  • NMR (CDCl[1443] 3): δ7.70-6.88 (13H, m), 5.01 (1H, dd, J=8.1, 5.4 Hz), 4.50-4.40 (2H, m), 4.40-4.31 (2H, m), 3.76-3.70 (2H, m).
    • EXAMPLE 20 (25) 7-(3-Hydroxypropyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1444]
    Figure US20030073706A1-20030417-C01774
  • TLC: Rf 0.46 (ethyl acetate); [1445]
  • NMR (CDCl[1446] 3): δ 7.75-7.40 (7H, m), 7.07 (1H, d, J=8.0 Hz), 5.05 (1H, dd, J=8.4,5.4 Hz), 4.26 (2H, t, J=5.8 Hz), 3.85-3.65 (4H, m), 2.03 (2H, quint, J=5.8 Hz).
    • EXAMPLE 20 (26a) 7-(Pyridin-3-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride
  • [1447]
    Figure US20030073706A1-20030417-C01775
  • TLC: Rf 0.30 (ethyl acetate:triethylamine=20:1); [1448]
  • NMR (DMSO-d[1449] 6): δ 8.85-8.75 (2H, m), 8.27 (1H, d, J=7.6 Hz), 7.92-7.55 (7H, m), 7.43 (1H, d, J=8.2 Hz), 7.26 (1H, d, J=7.6 Hz), 5.80 (1H, dd, J=9.4, 3.2 Hz), 5.51 (2H, s), 3.99 (1H, dd, J=15.3, 9.4 Hz), 3.77 (1H, dd, J=15.3, 3.2 Hz).
    • EXAMPLE 20 (26b) 7-(N-Oxidepyridin-3-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1450]
    Figure US20030073706A1-20030417-C01776
  • TLC: Rf 0.26 (ethyl acetate: methanol triethylamine 16 3 1); [1451]
  • NMR (DMSO-d[1452] 6): δ 5.38 (1H, s), 8.30 (1H, d, J=5.4 Hz), 7.90-7.42 (8H, m), 7.39 (1H, d, J=7.8 Hz), 7.23 (1H, d, J=7.8 Hz), 5.78 (1H, dd, J=9.7, 3.4 Hz), 5.39 (2H, s), 3.99 (1 H, dd, J=15, 9.7 Hz), 3.78 (1H, dd, J=15, 3.4 Hz).
    • EXAMPLE 20 (27) 4-(t-Butoxycarbonylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1453]
    Figure US20030073706A1-20030417-C01777
  • TLC: Rf 0.28 (hexane:ethyl acetate=1:1); [1454]
  • NMR (CDCl[1455] 3): δ 1.48 (s, 9H), 3.76 (dd, J-14.9, 9.2 Hz, 1H), 4.16 (d, J=16.0 Hz, 1H), 4.25 (dd, J=1.9, 1.2 Hz, 1H), 4.31 (d, J=16.0 Hz, 1H), 5.36 (dd, J=9.2, 1.2 Hz, 1H), 6.82 (dd, J=8.1, 0.7 Hz, 1H), 7.35 (d, J=7.4 Hz, 1H), 7.44-7.57 (m, 3H), 7.59-7.67 (m, 1H), 7.78-7.83 (m, 2H).
    • EXAMPLE 20 (28) 5-(t-Butoxycarbonylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1456]
    Figure US20030073706A1-20030417-C01778
  • TLC: Rf 0.50 (hexane:ethyl acetate=1:1); [1457]
  • NMR (CDCl[1458] 3): δ 1.53 (s, 9H), 3.74 (d-like, J=6 Hz, 2H), 4.67 (m, 2H), 5.00 (t, J=6 Hz, 1H), 7.17 (dd, J=8, 2Hz, 1H), 7.45 (d, J=2 Hz, 1H), 7.50 (m, 2H), 7.55 (d, J=8 Hz, 1H), 7.66 (m, 3H).
    • EXAMPLE 20 (31) 6-(t-Butoxycarbonylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1459]
    Figure US20030073706A1-20030417-C01779
  • TLC: Rf 0.42 (hexane:ethyl acetate=1:1); [1460]
  • NMR (CDCl[1461] 3): δ 1.48 (s, 3H), 3.67-3.83 (m, 2H), 4.56 (s, 2H), 5.00 (dd, J=7.4, 5.6 Hz, 1H), 6.99 (d, J=2.6 Hz, 1H), 7.29 (dd, J=8.8, 2.6 Hz, 1H), 7.46-7.53 (m, 2H), 7.61-7.70 (m 2H), 7.89 (d, J=8.8 Hz, 1H).
    • EXAMPLE 20 (30) 7-(t-Butoxycarbonylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1462]
    Figure US20030073706A1-20030417-C01780
  • TLC: Rf 0.28 (hexane:ethyl acetate=1:1); [1463]
  • NMR (CDCl[1464] 3): δ 7.70-7.47 (7H, m), 6.91-6.86 (lH, m), 5.02 (1H, dd, J=8.3, 5.6 Hz), 4.64 (2H, s), 3.76-3.72 (2H, m), 1.44 (9H, s).
    • EXAMPLE 20 (31) 4-(2-(t-Butoxycarbonylamino)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1465]
    Figure US20030073706A1-20030417-C01781
  • TLC: Rf 0.35 (hexane:ethyl acetate=1:2); [1466]
  • NMR (CDCl[1467] 3): 3.42-3.56 (m, 1H), 3.63-3.76 (m, 1H), 3.73 (dd, J=15.2, 9.6 Hz, 1H), 4.02-4.34 (m, 2H), 4.10 (dd, J=15.2, 1.2 Hz, 1H), 5.29 (dd, J=9.6, 1.2 Hz, 1H), 5.78 (br, 1H), 7.02 (d-like, J=7.5 Hz, 1H), 7.22 (d, J=7.5 Hz, 1H), 7.40-7.64 (m, 4H), 7.21-7.76 (m, 2H).
    • EXAMPLE 20 (32) 4-(3-(t-Butoxycarbonylamino)propyl) oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1468]
    Figure US20030073706A1-20030417-C01782
  • TLC: Rf 0.30 (hexane:ethyl acetate 1:2); [1469]
  • NMR (CDCl[1470] 3): δ 1.41 (s, 9H), 1.93 (m, 2H), 3.35 (m, 2H), 3.72 (dd, J=15.0, 9.0 Hz, 1H), 3.99 (t, J=6.1 Hz, 2H), 4.09 (d, J=15.0 Hz, 2H), 4.95 (br, 1H), 5.35 (d, J=9.0 Hz, 1H), 7.02 (d, J=7.5 Hz, 1H), 7.25 (d, J=7.5 Hz, 1H), 7.43-7.67 (m, 4H), 7.70-7.75 (m, 2H).
    • EXAMPLE 20 (33) 5-(2-(t-Butoxycarbonylamino)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1471]
    Figure US20030073706A1-20030417-C01783
  • TLC: Rf 0.40 (hexane:ethyl acetate=1:1); [1472]
  • NMR (CDCl[1473] 3): δ 1.47 (s, 9H), 3.54 (m, 2H), 3.66 (dd, J=15, 8Hz, 1H), 3.80 (dd, J=15,5 Hz, 1H), 4.13 (t, J=5 Hz, 2H), 5.00 (dd, J=8, 5 Hz, 1H), 5.00 (br, 1H), 7.12 (dd, J=8, 2 Hz, 1H), 7.44 (d, J-2 Hz, 1H), 7.55 (m, 3H), 7.72 (m, 3H).
    • EXAMPLE 20 (34) 6-(3-(t-Butoxycarbonylamino)propyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1474]
    Figure US20030073706A1-20030417-C01784
  • TLC: Rf 0.41 (hexane:ethyl acetate=1:2); [1475]
  • NMR (CDCl[1476] 3): δ 1.44 (s, 9H), 2.01 (quint, J=6.2 Hz, 2H), 3.32 (q, J=6.2 Hz, 2H), 3.71 (dd, J=14.6, 7.7 Hz, 1H), 3.79 (dd, J=14.6, 5.5 Hz, 1H), 4.06 (t, J=6.2 Hz, 2H), 4.68 (br, 1H), 5.00 (dd, J=7.7, 5.5 Hz, 1H), 7.05 (d, J=2.4 Hz, 1H), 7.23 (dd, J=8.8, 2.4 Hz, 1H), 7.47-7.54 (m, 2H), 7.64-7.72 (m, 3H), 7.85 (d, J=8.8 Hz, 1H).
    • EXAMPLE 20 (35) 6-(2-(t-Butoxycarbonylamino)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1477]
    Figure US20030073706A1-20030417-C01785
  • TLC: Rf 0.24 (hexane ethyl acetate=1:1); [1478]
  • NMR (CDCl[1479] 3): δ 1.46 (s, 9H), 3.56 (q, J=5.4 Hz, 2H), 3.71 (dd, J=14.8, 7.7 Hz, 1H), 3.79 (dd, J=14.8, 5.6 Hz, 1H), 4.06 (t, J=5.4 Hz, 2H), 4.97 (br, 1H), 5.00 (dd, J=7.7, 5.6 Hz, 1H), 7.05 (d, J=2.6 Hz, 1H), 7.24 (dd, J=8.8, 2.6 Hz, 1H), 7.47-7.55 (m, 2H), 7.65-7.72 (m, 3H), 7.88 (d, J=8.8 Hz, 1H).
    • EXAMPLE 20 (36) 7-(2-(t-Butoxycarbonylamino)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1480]
    Figure US20030073706A1-20030417-C01786
  • TLC: Rf 0.36 (hexane:ethyl acetate=2:1); [1481]
  • NMR (CDCl[1482] 3): δ 7.72-7.40 (7H, m), 7.04 (1H, d, J=8.2 Hz), 5.22 (1H, bs), 5.02 (1H, dd, J=8.7, 5.0 Hz), 4.25-4.10 (2H, m), 3.85-3.65 (2H, m), 3.60-3.46 (2H, m), 1.42 (9H, s).
    • EXAMPLE 20 (37) 4-(N-(t-Butoxycarbonyl)piperidin-4-yl) oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1483]
    Figure US20030073706A1-20030417-C01787
  • TLC: Rf 0.19 (hexane:ethyl acetate=1:1); [1484]
  • NMR (CDCl[1485] 3): δ 7.80-7.38 (6H, m), 7.23 (1H, d, J=8 Hz), 7.05 (1H, d, J=8 Hz), 5.23 (1H, d, J=9 Hz), 4.70 -4.45 (1H, m), 4.08 (1H, d, J=15 Hz), 3.95-3.60 (2H, m), 3.72 (1H, dd, J=15, 9 Hz), 3.50-3.22 (2H, m), 2.15-1.58 (4H, m), 1.48 (9H, s).
    • EXAMPLE 20 (38) 4,7-Bis[(2-(t-butoxycarbonylamino)ethyl)oxy]-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1486]
    Figure US20030073706A1-20030417-C01788
  • TLC: Rf 0.25 (hexane:ethyl acetate=1:3); [1487]
  • NMR (CDCl[1488] 3): δ 7.77 (2H, d, J=8.2 Hz), 7.70-7.55 (1H, m), 7.55-7.40 (2H, m), 6.95 (2H, s), 5.71 (1H, brs), 5.40-5.15 (2H, m), 4.20-3.30 (10H, m), 1.43 (18H, s).
    • EXAMPLE 20 (39) 4-(3-Nitrophenylmethyl) oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1489]
    Figure US20030073706A1-20030417-C01789
  • TLC: Rf 0.13 (hexane ethyl acetate=1:1); [1490]
  • NMR (CDCl[1491] 3+CD30D): δ 8.35 (1H, s), 8.27 (1H, d, J=8 Hz), 7.87 (1H, d, J=8 Hz), 7.80-7.50 (5H, m), 7.50-7.25 (3H, m), 7.13 (1H, d, J=8 Hz), 5.36 (1H, d-like, J=9 Hz), 5.25-4.98 (2H, m), 4.11 (1H, dd, J=15, 1 Hz), 3.76 (1H, dd, J=15, 9 Hz).
    • EXAMPLE 21 4-Carboxymethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1492]
    Figure US20030073706A1-20030417-C01790
  • To a solution of the compound prepared in Example 20 (27) (105 mg) in methylene chloride (5 ml), was added trifluoroacetic acid (5 ml) at 0° C. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated. The residue was recrystallized from diethyl ether to give the compound of the present invention (63 mg) having the following physical data. [1493]
  • TLC: Rf 0.20 (chloroform:methanol=4:1); [1494]
  • NMR (CDCl[1495] 3+CD3OD): δ 3.79 (dd, J=14.9, 9.0 Hz, 1H), 4.23 (dd, J=14.9, 1.0 Hz, 1H), 4.26 (d, J=16.1 Hz, 1H), 4.43 (d, J=16.1 Hz, 1H), 5.45 (dd, J=9.0, 1.0 Hz, 1H), 6.91 (d, J=8.0 Hz, 1H), 7.36 (d, J=7.6 Hz, 1H), 7.45-7.59 (m, 3H), 7.62-7.70 (m, 1H), 7.77-7.81 (m, 2H).
    • EXAMPLES 21 (1)˜21 (3)
  • By the same procedure as described in Example 21 using the compounds prepared in Examples 20 (28)˜20 (30) instead of the compound prepared in Example 20 (27), the following compounds of the present invention were obtained. [1496]
    • EXAMPLE 21 (1) 5-Carboxymethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1497]
    Figure US20030073706A1-20030417-C01791
  • TLC: Rf 0.30 (chloroform:methanol=4:1); [1498]
  • NMR (CDCl[1499] 3+CD3OD): δ 3.79 (d-like, J=6 Hz, 2H), 4.76 (s, 2H), 5.10 (t, J=6 Hz, 1H), 7.20 (dd, J=8, 2 Hz, 1H), 7.39 (d, J=2 Hz, 1H), 7.51 (d, J=8 Hz, 1H), 7.55 (m, 2H), 7.69 (m, 3H).
    • EXAMPLE 21 (2) 6-Carboxymethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1500]
    Figure US20030073706A1-20030417-C01792
  • TLC: Rf 0.25 (chloroform:methanol=4:1); [1501]
  • NMR (CDCl[1502] 3+CD3OD): δ 3.70-3.85 (m, 2H), 4.68 (s, 2H), 5.07 (t-like, J=6.6 Hz, 1H), 7.07 (d, J=2.5 Hz, 1H), 7.32 (dd, J=8.8, 2.5 Hz, 1H), 7.47-7.55 (m, 2H), 7.63-7.73 (m, 3H), 7.83 (d, J=8.8 Hz, 1H).
    • EXAMPLE 21 (3) 7-Carboxymethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1503]
    Figure US20030073706A1-20030417-C01793
  • TLC: Rf 0.29 (ethyl acetate:acetic acid=10:1); [1504]
  • NMR (CDCl[1505] 3+DMSO-d6): δ 7.52-7.26 (6H, m), 7.20 (1H, d, J=7.8 Hz), 6.77 (1H, d, J=8.2 Hz), 4.98 (1H, dd, J=7.8, 5.6 Hz), 4.52 (2H, s), 3.58-3.54 (2H, m).
    • EXAMPLE 22 4-(N-Pyridin-3-ylmethyl)carbamoylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1506]
    Figure US20030073706A1-20030417-C01794
  • A suspension of the compound prepared in Example 21 (480 mg) in thionyl chloride (10 ml) was refluxed for 15 minutes. After removing thionylchloride, the residue was dissolved in methylene chloride (5 ml). Thereto was added dropwise a solution of 3-(aminomethyl)pyridine (0.15 ml) and triethylamine (1 ml) in methylene chloride (10 ml) under cooling with ice. The reaction mixture was stirred at room temperature for 2 hours. To the reaction mixture was added water. The mixture was extracted by ethyl acetate. The extract was washed by water, a saturated aqueous solution of sodium chloride successively, dried over anhydrous sodium sulfate and concentrated. The residue was purified with column chromatography on silica gel (ethyl acetate:triethylamine=100:1) to give the compound of the present invention (421 mg) having the following physical data. [1507]
  • Free Compound: [1508]
  • TLC: Rf 0.49 (ethyl acetate:methanol:triethylamine=8:1:1); [1509]
  • NMR (DMSO-d[1510] 6): δ 4.03 (dd, J=14.9, 8.4 Hz, 1H), 4.11 (d, J=14.5 Hz, 1H), 4.12 (dd, J=14.9, 1.6 Hz, 1H), 4.33 (dd, J=15.3, 6.0 Hz, 1H), 4.44 (dd, J=15.3, 6.0 Hz, 1H), 4.57 (d, J=14.5 Hz, 1H), 6.00 (dd, J=8.4, 1.6 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.34 (dd, J=8.0, 4.7 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.49-7.54 (m, 2H), 7.63-7.73 (m, 5H), 8.39 (t, J=6.0 Hz, 1H), 8.46 (dd, J=4.7, 1.7 Hz, 1H), 8.51 (d, J=1.7 Hz, 1H).
  • Hydrochloride: [1511]
  • TLC: Rf 0.49 (ethyl acetate:methanol:triethylamine=8:1:1); [1512]
  • NMR (DMSO-d[1513] 6): δ 4.04 (dd, J=15.0, 8.7 Hz, 1H), 4.12 (d, J=14.7 Hz, 1H), 4.13 (dd, J=1 5.0, 1.5 Hz, 1H), 4.49 (dd, J=1 5.8, 6.2 Hz, 1H), 4.57 (dd, J=15.8, 6.2 Hz, 1H), 4.60 (d, J=14.7 Hz, 1H), 6.15 (dd, J=8.7, 1.5 Hz, 1H), 7.25 (d, J=8.2 Hz, 1H), 7.40 (d, J=7.6 Hz, 1H), 7.52-7.57 (m, 2H), 7.64 (d, J=8.2 Hz, 1H), 7.68-7.74 (m, 3H), 7.93 (dd, J=8.0, 5.5 Hz, 1H), 8.37 (d, J=8.0 Hz, 1H), 8.68 (t, J=6.2 Hz, 1H), 8.78 (d, J=5.4 Hz, 1H), 8.81 (s 1H).
    • EXAMPLES 22 (1) And 22 (2)
  • By the same procedure as described in Example 22 using a corresponding amine compound instead of 3-(aminomethyl)pyridine, and if necessary, by converting into the corresponding salt by a known method, the following compounds of the present invention were obtained. [1514]
    • EXAMPLE 22 (1) 4-((2-(N,N-Dimethylamino)ethylamino)carbonylmethyl)oxy-3-phenylsuifonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1515]
    Figure US20030073706A1-20030417-C01795
  • Free Compound: [1516]
  • TLC: Rf 0.29 (ethyl acetate:methanol: triethylamine=8:1:1); [1517]
  • NMR (CDCl[1518] 3): δ 2.24 (s, 6H), 2.51 (t-like, J=6.0 Hz, 2H), 3.49 (m, J=6.0 Hz, 2H), 3.77 (dd, J=15.3, 9.6 Hz, 1H), 4.05 (dd, J=15.3, 1.3 Hz, 1H), 4.53 (d, J=14.2 Hz, 1H), 4.64 (d, J=14.2 Hz, 1H), 5.39 (d-like, J=9.0 Hz, 1H); 7.04 (d, J=8.0 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.42-7.48 (m, 2H), 7.57 (t, J=8.0 Hz, 1H), 7.59-7.65 (m, 1H), 7.70-7.74 (m, 2H), 7.94 (br, 1H).
  • hydrochloride: [1519]
  • TLC: Rf 0.29 (ethyl acetate:methanol:triethylamine=8:1:1); [1520]
  • NMR (DMSO-d[1521] 6): δ 2.76 (s, 6H), 3.14-3.18 (m, 2H), 3.44-3.56 (m, 2H), 4.00 (dd, J=15.0, 9.3 Hz, 1H), 4.03 (d, J=14.4 Hz, 1H), 4.17 (d, J=15.0 Hz, 1H), 4.50 (d, J=14.4 Hz, 1H), 6.24 (d-like, J=8.7 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.56-7.62 (m, 2H), 7.64 (t, J=8.0 Hz, 1H), 7.70-7.77 (m, 3H), 8.23 (t, J=5.5 Hz, 1H).
    • EXAMPLE 22 (2) 4-((N-Benzyl-2-(N′,N′-dimethylamino)ethylamino)carbonylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1522]
    Figure US20030073706A1-20030417-C01796
  • TLC: Rf 0.52 (ethyl acetate:methanol:triethylamine=9:1:1); [1523]
  • NMR (CDCl[1524] 3): δ 2.22 (s, 3H), 2.29 (s, 3H), 2.44-2.55 (m, 2H), 3.29-3.35 (m, 1H), 3.56-3.60 (m, 1H), 3.73-3.75 (m, 2H), 4.60 (d, J=15.0 Hz, 0.5H), 4.67 (s-like, 1H), 4.76 (d, J=15.0 Hz, 0.5H), 4.88 (s, 1H), 4.94-5.00 (m, 1H), 5.05 (d, J=15.0 Hz, 0.5H), 5.18 (d, J=15.0 Hz, 0.5H), 7.10-7.36 (m, 6H), 7.41-7.53 (m, 4H), 7.61-7.68 (m, 3H).
    • EXAMPLE 23 4-(2-Aminoethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene hydrochloride
  • [1525]
    Figure US20030073706A1-20030417-C01797
  • By the same procedure as described in Example 7 using the compound prepared in Example 20 (31) instead of the compound prepared in Example 6 (8), the compound of the present invention having the following physical data was obtained. [1526]
  • TLC: Rf 0.21 (ethyl acetate: methanol: triethylamine=8:2:1); [1527]
  • NMR (DMSO-d[1528] 6): δ 2.66-2.78 (m, 1H), 3.02-3.12 (m, 1H), 3.83-4.18 (m, 4H), 6.23 (d-like, J=6.6 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.39 (d, J=7.6 Hz, 1H), 7.58-7.68 (m, 3H), 7.72-7.79 (m, 3H), 8.02 (br, 2H).
    • EXAMPLES 23 (1)˜23 (7)
  • By the same procedure as described in Example 23 using the compounds prepared in Examples 20 (32)˜20 (38) instead of the compound prepared in Example 20 (31), the following compounds of the present invention were obtained. [1529]
    • EXAMPLE 23 (1) 4-(3-Aminopropyl) oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride
  • [1530]
    Figure US20030073706A1-20030417-C01798
  • TLC: Rf 0.12 (ethyl acetate:methanol: triethylamine=8:4:1); [1531]
  • NMR (DMSO-d[1532] 6): δ 1.85-1.93 (m, 2H), 2.93 (q, J=6.4 Hz, 2H), 3.87-4.08 (m, 2H), 3.97 (dd, J=15.0, 8.4 Hz, 1H), 4.11 (dd, J=15.0, 1.4 Hz, 1H), 5.65 (dd, J=8.4, 1.4 Hz, 1H), 7.26 (d, J=7.8 Hz, 1H), 7.33 (d, J=7.8 Hz, 1H), 7.59-7.78 (m, 6H), 8.15 (br, 3H).
    • EXAMPLE 23 (2) 5-(2-Aminoethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride
  • [1533]
    Figure US20030073706A1-20030417-C01799
  • TLC: Rf 0.25 (ethyl acetate methanol triethylamine 8:2:1); [1534]
  • NMR (DMSO-d[1535] 6): δ 7.81-7.72 (m, 4H), 7.66-7.59 (m, 2H), 7.32-7.27 (m, 2H), 5.77 (dd, J=9, 3.5 Hz, 1H), 4.27 (m, 2H), 3.94 (dd, J=15, 9 Hz, 1H), 3.71 (dd, J=15, 3.5 Hz, 1H), 3.38-3.32 (m, 2H).
    • EXAMPLE 23 (3) 6-(3-Aminopropyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride
  • [1536]
    Figure US20030073706A1-20030417-C01800
  • TLC: Rf 0.40 (ethyl acetate:methanol:triethylamine=8:2 :1); [1537]
  • NMR (DMSO-d[1538] 6): 5 2.05 (quint, J=6.8 Hz, 2H), 2.95 (t, J=6.8 Hz, 2H), 3.76 (dd, J=15.2, 3.0 Hz, 1H), 4.00 (dd, J=15.2, 9.4 Hz, 1H), 4.18 (t, J=6.8 Hz, 2H), 5.70 (dd, J=9.4, 3.0 Hz, 1H), 7.29-7.38 (m, 2H), 7.56-7.67 (m, 3H), 7.76-7.79 (m, 3H), 8.08 (br, 2H).
    • EXAMPLE 23 (4) 6-(2-Aminoethyl)oxy-3-phenylsulfonyl-1,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride
  • [1539]
    Figure US20030073706A1-20030417-C01801
  • TLC: Rf 0.16 (ethyl acetate:methanol:triethylamine=9:1:1); [1540]
  • NMR (DMSO-d[1541] 6): δ 3.22 (t, J=4.9 Hz, 2H), 3.79 (dd, J=15.1, 3.0 Hz, 1H), 4.01 (dd, J=15.1, 9.4 Hz, 1H), 4.32 (t, J=4.9 Hz, 2H), 5.73 (dd, J=9.4, 3.0 Hz, 1H), 7.35 (d, J=2.4 Hz, 1H), 7.40 (dd, J=8.8, 2.4 Hz, 1H), 7.62 (d, J=8.8 Hz, 1H), 7.64-7.66 (m, 2H), 7.76-7.81 (m, 3H), 8.35 (br, 3H).
    • EXAMPLE 23 (5) 7-(2-Aminoethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride
  • [1542]
    Figure US20030073706A1-20030417-C01802
  • TLC: Rf 0.38 (ethyl acetate:acetic acid:water=3:1:1); [1543]
  • NMR (DMSO-d[1544] 6): δ 8.18 (3H, brs), 7.83-7.60 (6H, m), 7.40 (1H, d, J=8 Hz), 7.22 (1H, d, J=8 Hz), 5.81 (1 H, dd, J=9.6, 3.2 Hz), 4.44-3.30 (2H, m), 3.96 (1 H, dd, J=15, 9.6 Hz), 3.76 (1H, dd, J=15, 3.2 Hz), 3.18 (2H, t, J=6 Hz).
    • EXAMPLE 23 (6) 4-(Piperidin-4-yl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene hydrochloride
  • [1545]
    Figure US20030073706A1-20030417-C01803
  • TLC: Rf 0.47 (ethyl acetate:acetic acid:water=3:1:1); [1546]
  • NMR (DMSO-d[1547] 6): δ 8.91 (2H, brs), 7.90-7.52 (6H, m), 7.41 (1H, d, J=8 Hz), 7.33 (1H, d, J=8 Hz), 5.71 (1H, d, J=7 Hz), 4.95-4.70 (1H, m), 4.20-3.80 (2H, m), 3.50-2.95 (4H, m), 2.30-1.60 (4H, m).
    • EXAMPLE 23 (7) 4,7-Bis[(2-aminoethyl)oxy]-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.2hydrochloride
  • [1548]
    Figure US20030073706A1-20030417-C01804
  • TLC: Rf 0.22 (ethyl acetate:methanol:triethylamine=4:1:1); [1549]
  • NMR (DMSO-d[1550] 6): δ 8.10 (6H, brs), 7.85-7.70 (3H, m), 7.70-7.50 (2H, m), 7.37 (1H, d, J=8.6 Hz), 7.23 (1H, d, J=8.6 Hz), 6.14 (1H, d, J=6.0 Hz), 4.50-4.15 (2H, m), 4.15-3.90 (4H, m), 3.85-3.65 (1H, m), 3.25-3.15 (2H, m), 3.15-2.90 (1H, m).
    • EXAMPLE 24 4-(2-(N,N-Dimethylamino)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1551]
    Figure US20030073706A1-20030417-C01805
  • By the same procedure as described in Example 8 using the compound prepared in Example 23 instead of the compound prepared in Example 7, the compounds of the present invention having the following physical data were obtained. [1552]
  • Free Compound: [1553]
  • TLC: Rf 0.47 (ethyl acetate:methanol:triethylamine=8:2:1); [1554]
  • NMR (CDCl[1555] 3): δ 2.33 (s, 6H), 2.52-2.77 (m, 2H), 3.72 (dd, J=15.0, 9.4 Hz, 1H), 3.79-3.89 (m, 1H), 4.00-4.12 (m, 1H), 4.18 (dd, J=15.0, 1.1 Hz, 1H), 5.35 (d-like, J=8.8 Hz, 1H), 6.99 (d, J=8.2 Hz, 1H), 7.28 (d, J=7.2 Hz, 1H), 7.43-7.66 (m, 4H), 7.72-7.77 (m, 2H).
  • Hydrochloride: [1556]
  • TLC: Rf 0.47 (ethyl acetate:methanol:triethylamine=8:2:1); [1557]
  • NMR (CD[1558] 3OD): δ 3.05 (s, 6H), 3.52-3.76 (m, 2H), 3.83-3.99 (m, 2H), 4.38-4.63 (m, 2H), 5.89 (t, J=5.4 Hz, 1H), 7.30 (d, J=7.7 Hz, 1H), 7.39 (d, J=7.7 Hz, 1H), 7.51-7.59 (m, 2H), 7.66-7.78 (m, 4H).
    • EXAMPLES 24 (1)˜24 (5)
  • By the same procedure as described in Example 14 using the compounds prepared in Examples 23 (1)˜23 (5) instead of the compound prepared in Example 23, and if necessary, by converting into the corresponding salts by known methods, the following compounds of the present invention were obtained, with the proviso that when compounds of Example 23 (1) and Example 23 (3) were used, compounds of Example 24 (1b) and Example 24 (3b) were also generated respectively. [1559]
    • EXAMPLE 24 (1a) 4-(3-(N,N-Dimethylamino)propyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1560]
    Figure US20030073706A1-20030417-C01806
  • Free Compound: [1561]
  • TLC: Rf 0.35 (ethyl acetate:methanol:triethylamine=8:2:1); [1562]
  • NMR (CDCl[1563] 3): δ 1.86 (quint, J=7.0 Hz, 2H), 2.26 (s, 6H), 2.47 (t, J=7.0 Hz, 2H), 3.74 (dd, J=5.0, 9.2 Hz, 1H), 3.83-4.03 (m, 2H), 4.21 (dd, J=15.0, 1.2 Hz, 1H), 5.25 (d-like, J=8.8 Hz, 1H), 6.99 (d, J=7.8 Hz, 1H), 7.24 (d, J=7.8 Hz, 1H), 7.48-7.74 (m, 6H).
  • Hydrochloride: [1564]
  • TLC: Rf 0.35 (ethyl acetate:methanol:triethylamine=8:2:1); [1565]
  • NMR (DMSO-d[1566] 6): δ 2.15 (m, 2H), 2.80 (s, 6H), 3.31 (t, J=7.5 Hz, 2H), 3.75 (dd, J=15.2, 9.2 Hz, 1H), 4.15 (t, J=6.2 Hz, 2H), 4.31 (dd, J=15.2, 1.1 Hz, 1H), 5.69 (dd, J=9.2, 1.1 Hz, 1H), 7.32-7.39 (m, 2H), 7.55-7.72 (m, 3H), 7.80-7.85 (m, 3H).
    • EXAMPLE 24 (1b) 4-(3-(N-Cyanomethyl-N-methylamino)propyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1567]
    Figure US20030073706A1-20030417-C01807
  • TLC: Rf 0.36 (ethyl acetate:triethylamine=9:1); [1568]
  • NMR (CDCl[1569] 3): δ 1.88 (quint, J=6.6 Hz, 2H), 2.38 (s, 3H), 2.69 (m, 2H), 3.51 (d, J=17.0 Hz, 1H), 3.61 (d, J=17.0 Hz, 1H), 3.73 (dd, J=15.0, 9.4 Hz, 1H), 3.96 (m, 2H), 4.13 (dd, J=15.0, 1.0 Hz, 1H), 5.28 (d-like, J=8.4 Hz, 1H), 7.00 (d, J=7.8 Hz, 1H), 7.24 (d, J=7.8 Hz, 1H), 7.42-7.74 (m, 6H).
    • EXAMPLE 24 (2) 5-(2-(N,N-Dimethylamino)ethyl)oxy-3-phenylsulfonyl-2,3-dihydeo-1,1-dioxidebenzo[b]thiophene
  • [1570]
    Figure US20030073706A1-20030417-C01808
  • Free Compound: [1571]
  • TLC: Rf 0.55 (ethyl acetate: methanol: triethylamine 8:2:1); [1572]
  • NMR (DMSO-d[1573] 6): δ 2.23 (s, 6H), 2.66 (t, J=6 Hz, 2H), 3.77 (dd, J=15, 3 Hz, 1H), 3.98 (dd, J=15, 10 Hz, 1H), 4.10 (m, 2H), 5.71 (dd, J=10, 3 Hz, 1H), 7.05 (d, J=2 Hz, 1H), 7.25 (dd, J=9, 2 Hz, 1H), 7.58-7.84 (m, 6H).
  • Hydrochloride: [1574]
  • TLC: Rf 0.55 (ethyl acetate:methanol:triethylamine=8:2:1); [1575]
  • NMR (DMSO-d[1576] 6): δ 2.84 (s, 6H), 3.56 (m, 2H), 3.75 (dd, J=15, 4 Hz, 1H), 3.97 (dd, J=15, 9 Hz, 1H), 4.45 (m, 2H), 5.76 (dd, J=9, 4 Hz, 1H), 7.22 (d, J=2 Hz, 1H), 7.33 (dd, J=9, 2 Hz, 1H), 7.64 (m, 2H), 7.79 (m, 4H).
    • EXAMPLE 24 (3a) 6-(3-(N,N-Dimethylamino) propyl) oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1577]
    Figure US20030073706A1-20030417-C01809
  • Free Compound: [1578]
  • TLC: Rf 0.53 (ethyl acetate:methanol:triethylamine=8:2:1); [1579]
  • NMR (CDCl[1580] 3): δ 1.97 (quint, J=6.6 Hz, 2H), 2.25 (s, 6H), 2.44 (t, J=6.6 Hz, 2H), 3.71 (dd, J=14.6, 7.6 Hz; 1H), 3.79 (dd, J=14.6, 5.6 Hz, 1H), 4.07 (t, J=6.6 Hz, 2H), 5.00 (dd, J=7.6, 5.6 Hz, 1H), 7.08 (d, J=2.6 Hz, 1H), 7.23 (dd, J=8.8, 2.6 Hz, 1H), 7.46-7.54 (m, 2H), 7.63-7.72 (m, 3H), 7.85 (d, J=8.8 Hz, 1H).
  • Hydrochloride: [1581]
  • TLC: Rf 0.53 (ethyl acetate:methanol:triethylamine=8:2:1); [1582]
  • NMR (DMSO-d[1583] 6): δ 2.17 (m, 2H), 2.78 (s, 6H), 3.20 (t, J=7.9 Hz, 2H), 3.77 (dd, J=15.4, 3.2 Hz, 1H), 4.00 (dd, J=15.4, 9.4 Hz, 1H), 4.18 (t, J=6.0 Hz, 2H), 5.71 (dd, J=9.4, 3.2 Hz, 1H), 7.30-7.38 (m, 2H), 7.58-7.67 (m, 3H), 7.75-7.79 (m, 3H).
    • EXAMPLE 24 (3b) 6-(3- (N-Cyanomethyl-N-methylamino)propyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1584]
    Figure US20030073706A1-20030417-C01810
  • TLC: Rf 0.33 (ethyl acetate:hexane:triethylamine=6:3:1); [1585]
  • NMR (CDCl[1586] 3): δ 1.97 (quint, J=6.5 Hz, 2H), 2.38 (s, 3H), 2.65 (t, J=6.5 Hz, 2H), 3.54 (s, 2H), 3.71 (dd, J=14.8, 7.8 Hz, 1H), 3.79 (dd, J=14.8, 5.2 Hz, 1H), 4.06 (t, J=6.5 Hz, 2H), 5.00 (dd, J=7.8, 5.2 Hz, 1H), 7.07 (d, J=2.6 Hz, 1H), 7.23 (dd, J=9.0, 2.6 Hz, 1H), 7.47-7.55 (m, 2H), 7.65-7.72 (m, 3H), 7.84 (d, J=9.0 Hz, 1H).
    • EXAMPLE 24 (4) 6-(2-(N,N-Dimethylamino)ethyl) oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1587]
    Figure US20030073706A1-20030417-C01811
  • Free Compound: [1588]
  • TLC: Rf 0.47 (ethyl acetate:methanol:triethylamine 9:1:1); [1589]
  • NMR (CDCl[1590] 3): δ 2.34 (s, 6H), 2.75 (t, J=5.4 Hz, 2H), 3.74 (dd, J=14.8, 7.8 Hz, 1H), 3.79 (dd, J=14.8, 5.4Hz, 1H), 4.09 (t, J=5.4 Hz, 2H), 5.00 (dd, J=7.8, 5.4Hz, 1H), 7.06 (d, J=2.4 Hz, 1H), 7.28 (dd, J=8.8, 2.4 Hz, 1H), 7.47-7.52 (m, 2H), 7.62-7.69 (m, 3H), 7.84 (d, J=8.8 Hz, 1H).
  • Hydrochloride: [1591]
  • TLC: Rf 0.47 (ethyl acetate:methanol:triethylamine=9:1:1); [1592]
  • NMR (DMSO-d[1593] 6): δ 2.83 (d, J=4.5 Hz, 6H), 3.50-3.54 (m, 2H), 3.78 (dd, J=15.0, 3.0 Hz, 1H), 4.01 (dd, J=15.0, 9.4 Hz, 1H), 4.49 (t, J=5.1 Hz, 2H), 5.73 (dd, J=9.4, 3.0 Hz, 1H), 7.41-7.44 (m, 2H), 7.60-7.67 (m, 3H), 7.77-7.80 (m, 3H), 10.83 (br, 1H).
    • EXAMPLE 24 (5) 7-(2-(N,N-Dimethylamino)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzp[b]thiophene hydrochloride
  • [1594]
    Figure US20030073706A1-20030417-C01812
  • TLC: Rf 0.32 (ethyl acetate:methanol:triethylamine=16:3:1); [1595]
  • NMR (DMSO-d[1596] 6): δ 7.85-7.60 (6H, m), 7.37 (1H, d, J=8.2 Hz), 7.22 (1H, d, J=8.2 Hz), 5.81 (1 H, dd, J=9.4, 3.2 Hz), 4.65-4.56 (2H, m), 3.97 (1H, dd, J=15, 9.4 Hz), 3.75 (1 H, dd, J=15, 3.2 Hz), 3.56-3. 45 (2H, m), 2.82 (6H, s).
    • EXAMPLE 25 4-(3-Aminophenylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1597]
    Figure US20030073706A1-20030417-C01813
  • By the same procedure as described in Example 11 using the compound prepared in Example 20 (39) instead of the compound prepared in Example 10, the compound of the present invention having the following physical data was obtained. [1598]
  • TLC: Rf 0.34 (chloroform:tetrahydrofuran:28% ammonia water=100:50:1); [1599]
  • NMR (DMSO-d[1600] 6): δ 7.80-7.55 (4H, m), 7.49 (2H, t, J=8 Hz), 7.31 (2H, dd, J=12, 8 Hz), 7.02 (1H, t, J=8 Hz), 6.60-6.45 (2H, m), 5.54 (1H, d, J=9 Hz), 5.10 (2H, bs), 4.91 (1H, d, J=12 Hz), 4.69 (1H, d, J=12 Hz), 4.20 (1H, d, J=15 Hz), 3.98 (1H, dd, J=15, 9 Hz).
    • EXAMPLE 26 4-(3-(Pyridin-3-ylcarbonylamino)phenylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1601]
    Figure US20030073706A1-20030417-C01814
  • To a solution of the compound prepared in Example 25 (143 mg) in pyridine (6 ml) was added nicotinyl chloride-hydrochloride (77 mg). The mixture was stirred at room temperature for 1.5 hours. To the reaction mixture, water was added. The mixture was extracted by ethyl acetate. The extract was washed by water, a saturated aqueous solution of sodium chloride successively, dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from ethanol to give the compound of the present invention (127 mg) having the following physical data. [1602]
  • TLC: Rf 0.34 (ethyl acetate:methanol:28% ammonia water=100:10:1); [1603]
  • NMR (DMSO-d[1604] 6): δ 9.12 (1H, d, J=2 Hz), 8.77 (1H, dd, J=5,2 Hz), 8.31 (1H, d, J=8 Hz), 7.82 (1H, s), 7.78-7.52 (7H, m), 7.52-7.25 (5H, m), 7.19 (1H, d, J=7 Hz), 5.59 (1H, d, J=8.5 Hz), 5.11 (1H, d, J=12 Hz), 4.86 (1H, d, J=12 Hz), 4.20 (1H, d, J=15 Hz), 4.01 (1H, dd, J=15, 8.5 Hz).
    • EXAMPLE 26 (1) 4-(2-(Pyridin-3-ylcarbonylamino)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1605]
    Figure US20030073706A1-20030417-C01815
  • By the same procedure as described in Example 26 using the compound prepared in Example 23 instead of the compound prepared in Example 25, and if necessary, by converting into the corresponding salt by known methods, the compounds of the present invention having the following physical data were obtained. [1606]
  • Free Compound: [1607]
  • TLC: Rf 0.43 (ethyl acetate:methanol:triethylamine=8:1:1); [1608]
  • NMR (DMSO-d[1609] 6): δ 3.36-3.55 (m, 2H), 3.81-3.88 (m, 1H), 4.02 (dd, J=15.0, 8.7 Hz, 1H), 4.04-4.10 (m, 1H), 4.13 (dd, J=15.0, 1.3 Hz, 1H), 5.61 (d-like, J=7.5 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.35 (d, J=7.2 Hz, 1H), 7.48 (dd, J=8.1, 4.8 Hz, 1H), 7.56-7.68 (m, 3H), 7.71-7.77 (m, 3H), 8.15 (dt, J=8.1, 1.8 Hz, 1H), 8.65-8.68 (m, 1H), 8.68 (dd, J=4.8, 1.8 Hz, 1H), 8.98 (d, J=1.8 Hz, 1H).
  • Hydrochloride: [1610]
  • TLC: Rf 0.43 (ethyl acetate:methanol:triethylamine=8:1:1); [1611]
  • NMR (DMSO-d[1612] 6): δ 3.41-3.56 (m, 2H), 3.83-3.89 (m, 1H), 4.01 (dd, J=15.0, 8.7 Hz, 1H), 4.07-4.12 (m, 1H), 4.12 (dd, J=15.0, 1.2 Hz, 1H), 5.67 (d-like, J=7.5 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.56-7.61 (m, 2H), 7.65 (t, J=8.0 Hz, 1H), 7.71-7.76 (m, 3H), 7.83 (dd, J=8.1, 5.4 Hz, 1H), 8.59 (dt, J=8.1, 1.6 Hz, 1H), 8.87 (dd, J=5.4, 1.6 Hz, 1H), 9.10 (t, J=5.4 Hz, 1H), 9.19 (d, J=1.6 Hz, 1H).
    • EXAMPLE 27 5-Methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1613]
    Figure US20030073706A1-20030417-C01816
  • To a solution of 5-methyl-1,1-dioxidebenzo[b]thiophene (353 mg) in ethanol (19.5 ml), were added water (0.5 ml), acetic acid (0.4 ml) and benzenesulfonic acid sodium salt (940 mg) successively. The reaction mixture was refluxed for 7 hours. The reaction mixture was cooled to room temperature. The crystals that appeared were separated by filtration. The crystals were washed by water, ethanol and hexane, sucessively, to give the compound of the present invention (381 mg) having the following physical data. [1614]
  • TLC: Rf 0.32 (hexane:ethyl acetate=1:1); [1615]
  • NMR (CDCl[1616] 3): δ 2.52 (s, 3H), 3.66 (dd, J=14.6, 8.7 Hz, 1H), 3.77 (dd, J=14.6, 4.9 Hz, 1H), 5.02 (dd, J=8.7, 4.9 Hz, 1H), 7.41-7.57 (m, 4H), 7.64-7.69 (m, 3H), 7.80 (s-like, 1H).
    • EXAMPLES 27 (1)˜27 (5)
  • By the same procedure as described in Example 27 using corresponding benzo[b]thiophene compounds instead of 5-methyl-1,1-dioxidebenzo[b]thiophene, the following compounds of the present invention were obtained. [1617]
    • EXAMPLE 27 (1) 5-(4-Chlorophenylcarbonyl)amino-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1618]
    Figure US20030073706A1-20030417-C01817
  • TLC: Rf 0.27 (methylene chloride ethyl acetate 8:1); [1619]
  • NMR (DMSO-d[1620] 6): δ 3.74 (dd, J=15.1, 3.7 Hz, 1H), 3.95 (dd, J=15.1, 9.3 Hz, 1H), 5.83 (dd, J=9.3, 3.7 Hz, 1H), 7.58-7.65 (m, 2H), 7.66 (d, J=8.7 Hz, 2H), 7.73-7.83 (m, 4H), 8.04 (d, J=8.7 Hz, 2H), 8.10 (dd, J=8.8, 2.0 Hz, 1H), 8.40 (d, J=2.0 Hz, 1H), 10.86 (s, 1H).
    • EXAMPLE 27 (2) 4-Cyano-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b][thiophene
  • [1621]
    Figure US20030073706A1-20030417-C01818
  • TLC: Rf 0.60 (methylene chloride:ethyl acetate=8:1); [1622]
  • NMR (DMSO-d[1623] 6): δ 3.95 (dd, J=15, 10 Hz, 1H), 4.15 (d, J=15 Hz, 1H), 5.80 (d, J=10 Hz, 1H), 7.60-7.80 (m, 2H), 7.80-7.90 (m, 3H), 7.95 (t, J=7.5 Hz, 1H), 8.20 (d, J=7.5 Hz, 1H), 8.35 (d, J=7.5 Hz, 1H).
    • EXAMPLE 27 (3) 6-Nitro-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1624]
    Figure US20030073706A1-20030417-C01819
  • TLC: Rf 0.44 (hexane ethyl acetate=1:1); [1625]
  • NMR (DMSO-d[1626] 6): δ 3.97 (dd, J=15.3, 3.0 Hz, 1H), 4.16 (dd, J=15.3, 9.3 Hz, 1H), 6.00 (dd, J=9.3, 3.0 Hz, 1H), 7.62-7.67 (m, 2H), 7.79-7.83 (m, 3H), 8.02 (d, J=8.4 Hz, 1H), 8.61 (s-like, 1H), 8.62 (dd, J=8.4, 2.1 Hz, 1H).
    • EXAMPLE 27 (4) 4,7-Dimethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1627]
    Figure US20030073706A1-20030417-C01820
  • TLC: Rf 0.48 (ethyl acetate ); [1628]
  • NMR (DMSO-d[1629] 6): δ 3.27 (s, 3H), 3.85 (s, 3H), 3.96 (dd, J=15.2, 8.8 Hz, 1H), 4.12 (dd, J=15.2, 1.5 Hz, 1H), 5.49 (dd, J=8.8, 1.5 Hz, 1H), 7.12 (d, J=9.0 Hz, 1H), 7.21 (d, J=9.0 Hz, 1H), 7.60-7.78 (m, 5H).
    • EXAMPLE 27 (5) 4,7-Bis(3-hydroxypropyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1630]
    Figure US20030073706A1-20030417-C01821
  • TLC: Rf 0.34 (ethyl acetate:methanol=9:19; [1631]
  • NMR (DMSO-d[1632] 6): 5 1.52-1.57 (m, 2H), 1.83 (quint, J_6.3 Hz, 2H), 3.43 (q, J=6.3 Hz, 2H), 3.55 (q, J=5.8 Hz, 2H), 3.60-3.67 (m, 1H), 3.80-3.87 (m, 1H), 3.96 (dd, J=14.8, 9.0 Hz, 1H), 4.09 (d-like, J=14.8 Hz, 1H), 4.08-4.21 (m, 2H), 4.46 (t, J=5.1 Hz, 1H), 4.52 (t, J=5.1 Hz, 1H), 5.45 (d-like, J=7.8 Hz, 1H), 7.14 (d, J=9.0 Hz, 1H), 7.20 (d, J=9.0 Hz, 1H), 7.58-7.63 (m, 2H), 7.72-7.77 (m, 3H).
    • EXAMPLE 28 4-(Pyridin-3-ylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene
  • [1633]
    Figure US20030073706A1-20030417-C01822
  • To 4-carboxy-1,1-dioxidebenzo[b]thiophene (prepared by the method described in Example 107 hereafter) (270 mg), was added thionyl chloride (2.0 ml). The mixture was refluxed for 2 hours, and concentrated. To a solution of (pyridin-3-ylmethyl)amine (154 mg) dissolved in methylene chloride (6.0 ml) and triethylamine (260 mg), a solution of the said chloride in methylene chloride (4.0 ml) were added dropwise. The mixture was stirred for 2 hours at room temperature. To the reaction mixture, ice-water and a 1N aqueous solution of sodium hydroxide (1.5 ml) were added dropwise. The mixture was extracted by ethyl acetate (40 ml). The extract was washed by a saturated sodium chloride, dried over anhydrous magnesium sulfate, and concentrated. The residue was recrystallized from a mixed solvent of ethyl acetate and hexane to give the compound of the present invention (330 mg) having the following physical data. [1634]
  • TLC: Rf 0.48 (methylene chloride: methanol=10:1); [1635]
  • NMR (CDCl[1636] 3): δ 8.56 (d, J=2.1 Hz, 1H), 8.53 (dd, J=4.5, 2.1 Hz, 1H), 7.93 (dd, J=7.2, 0.6 Hz, 1H), 7.79-7.72 (m, 2H), 7.70 (dd, J=7.5, 0.6 Hz, 1H), 7.55 (t, J=7.8 Hz, 1H), 7.31 (dd, J=7.8, 4.5 Hz, 1H), 6.86 (t, J=6.3 Hz, 1H), 6.77 (d, J=7.2 Hz, 1H), 4.65 (d, J=6.3 Hz, 2Hz.
    • EXAMPLES 28 (1)˜28 (33)
  • By the same procedure as described in Example 28 using carboxylic acid corresponding to 4-carboxy-1,1-dioxidebenzo[b]thiophene and amine derivative corresponding to (pyridin-3-ylmethyl)amine, and if necessary, by converting into the corresponding salt by a known method, the compounds of the present invention were obtained. [1637]
  • In the preparation of a compound of Example 28 (33), 4-aminomethyl-1,1-dioxidebenzo[b]thiophene and pyridin-3-ylcarboxylic acid were subjected to reaction. [1638]
    • EXAMPLE 28 (1) 4-(4-Benzylpiperazin-1-yl) carbonyl-1,1-dioxidebenzo[b]thiophene
  • [1639]
    Figure US20030073706A1-20030417-C01823
  • TLC: Rf 0.30 (ethyl acetate:methanol=50:1); [1640]
  • NMR (CDCl[1641] 3): δ 7.75 (d, J=7.4 Hz, 1H), 7.56 (t, J=7.4 Hz, 1H), 7.47 (d, J=7.4 Hz, 1H), 7.40-7.20 (m, 6H), 6.78 (d, J=7.0 Hz, 1H), 3.83 (m, 2H), 3.55 (s, 2H), 3.34 (m, 2H), 2.55 (m, 2H), 2.37 (m, 2H).
    • EXAMPLE 28 (2) 4-(N-(2-(Pyridin-3-yl)ethyl)-N-methylcarbamoyl)-1,1-dioxidebenzo[b]thiophene
  • [1642]
    Figure US20030073706A1-20030417-C01824
  • MS (APCI, Pos.): m/z 361 (M+MeOH+H)[1643] +, 329 (M+H)+.
    • EXAMPLE 28 (3) 4-(2-(2-Hydroxyethoxy)ethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene
  • [1644]
    Figure US20030073706A1-20030417-C01825
  • MS (APCI, Pos.): m/z 330 (M+MeOH+H)[1645] +, 298 (M+H)+.
    • EXAMPLE 28 (4) 4-(2,4-Dimethoxyphenylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene
  • [1646]
    Figure US20030073706A1-20030417-C01826
  • TLC: Rf 0.68 (ethyl acetate); [1647]
  • NMR (CDCl[1648] 3): δ 7.90 (d, J=7.5 Hz, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.60 (d, J=7.5 Hz, 1H), 7.55 (t, J=7.5 Hz, 1H), 7.25 (d, J=10 Hz, 1H), 6.75 (d, J=7.5 Hz, 1H), 6.60-6.40 (m, 3H), 4.55 (d, J=7.5 Hz, 2H), 3.85 (s, 3H), 3.80 (s, 3H).
    • EXAMPLE 28 (5) 4-(1-Benzylpiperidin-4-yl)carbamoyl-1,1-dioxidebenzo[b]thiophene
  • [1649]
    Figure US20030073706A1-20030417-C01827
  • Free Aicd: [1650]
  • TLC: Rf 0.50 (ethyl acetate:methanol=8:1.5); [1651]
  • NMR (CDCl[1652] 3): δ 7.90 (d, J=7.5 Hz, 1H), 7.80 (d, J=7.5 Hz, 1H), 7.60 (d, J=7.5 Hz, 1H), 7.55 (t, J=7.5 Hz, 1H), 7.50-7.20 (m, 5H), 6.75 (d, J=7.5 Hz, 1H), 6.05-5.95 (m, 1H), 4.10-3.90 (m, 1H), 3.55 (s, 2H), 3.00-2.90 (m, 2H), 2.30-2.10 (m, 2H), 2.10-1.90 (m, 2H), 1.70-1.50 (m, 2H).
  • Hydrochloride: [1653]
  • TLC: Rf 0.44 (methanol:ethyl acetate=1:10); [1654]
  • NMR (CD[1655] 3OD): δ 7.90-7.75 (m, 3H), 7.75-7.45 (m, 6H), 7.08 (d, J=7.0 Hz, 1H), 4.34 (s, 2H), 4.27-4.05 (m, 1H), 3.61-3.42 (m, 2H), 3.33-3.10 (m, 2H), 2.34-2.15 (m, 2H), 2.12-1.81 (m, 2H).
  • Methanesulfonic Acid Salt: [1656]
  • TLC: Rf 0.44 (methanol:ethyl acetate=1:10); [1657]
  • NMR (CD[1658] 3OD): δ 7.89-7.74 (m, 3H), 7.73-7.60 (m, 1H), 7.60-7.45 (m, 5H), 7.08 (d, J=7.0 Hz, 1H), 4.34 (s, 2H), 4.27-4.03 (m, 1H), 3.68-3.38 (m, 2H), 3.38-3.06 (m, 2H), 2.67 (s, 3H), 2.38-1.72 (m, 4H).
    • EXAMPLE 28 (6) 4-(Pyridin-4-ylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene
  • [1659]
    Figure US20030073706A1-20030417-C01828
  • TLC: Rf 0.29 (ethyl acetate:methanol=19:1); [1660]
  • NMR (CDCl[1661] 3+CD3OD): δ 8.50 (d, J=7 Hz, 2H), 8.25 (broad-t, J=7 Hz, 1H), 7.95 (d, J=7 Hz, 1H), 7.80 (d, J=8 Hz, 2H), 7.60 (t, J=8 Hz, 1H), 7.30 (d, J=7Hz, 2H), 6.80 (d, J=7 Hz, 1H), 4.60 (d, J=7 Hz, 2H).
    • EXAMPLE 28 (7) 4-(2-t-Butoxycarbonylethyl) carbamoyl-1,1-dioxidebenzo[b]thiophene
  • [1662]
    Figure US20030073706A1-20030417-C01829
  • TLC: Rf 0.40 (ethyl acetate:hexane=3:2); [1663]
  • NMR (CDCl[1664] 3): δ 8.00 (d, J=7 Hz, 1H), 7.80 (d, J=8 Hz, 1H), 7.70 (d, J=8 Hz, 1H), 7.60 (t, J=8 Hz, 1H), 6.95 (broad-s, 1H), 6.80 (d, J=7 Hz, 1H), 3 70 (q, J=7 Hz, 7H), 2.60 (t, J=7 Hz, 2H), 1.45 (s, 9H).
    • EXAMPLE 28 (8) 4-(Thiophen-2-ylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene
  • [1665]
    Figure US20030073706A1-20030417-C01830
  • TLC: Rf 0.48 (chloroform:methanol=9:1); [1666]
  • NMR (CDCl[1667] 3+DMSO-d6): δ 8.50 (t, J=7 Hz, 1H), 7.95 (d, J=6 Hz, 1H), 7.85 (d, J=8 Hz, 1H), 7.75 (d, J=8 Hz, 1H), 7.55 (t, J=8 Hz, 1H), 7.25 (d, J=6 Hz, 1H), 7.05 (d, J=3 Hz, 1H), 6.95 (dd, J=3 Hz and 6 Hz, 1H), 6.80 (d, J=6 Hz, 1H), 4.75 (d, J=7 Hz, 2H).
    • EXAMPLE 28 (9) 4-Benzylcarbamoyl-1,1-dioxidebenzo[b]thiophene
  • [1668]
    Figure US20030073706A1-20030417-C01831
  • TLC: Rf 040 (ethyl acetate hexane=1:1); [1669]
  • NMR (CDCl[1670] 3+DMSO-d6): δ 7.99 (d, J=7.2 Hz, 1H), 7.81-7.75 (m, 2H), 7.56 (t, J=7.5 Hz, 1H), 7.43 (t, J=5.7 Hz, 1H), 7.40-7.27 (m, 5H), 6.78 (d, J=7.2 Hz, 1H), 4.63 (d, J=5.7 Hz, 2H).
    • EXAMPLE 28 (10) 4-(Pyridin-2-ylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene
  • [1671]
    Figure US20030073706A1-20030417-C01832
  • TLC: Rf 0.30 (ethyl acetate:hexane=1:1); [1672]
  • NMR (CDCl[1673] 3): δ 8.56 (d, J=5.1 Hz, 1H), 8.05 (dd, J=7.2, 0.9 Hz, 1H), 7.84 (t, J=7.2 Hz, 1H), 7.73 (dt, J=0.9, 7.8 Hz, 1H), 7.68 (t, J=5.1 Hz, 1H), 7.61 (t, J=7.8 Hz, 1H), 7.33 (d, J=7.8 Hz, 1H), 7.59-7.23 (m, 2H), 6.78 (d, J=6.9 Hz, 1H), 4.76 (d, J=5.1 Hz, 2H).
    • EXAMPLE 28 (11) 4-(2-(Piperidin-1-yl)ethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene
  • [1674]
    Figure US20030073706A1-20030417-C01833
  • Free Aicd: [1675]
  • TLC: Rf 0.35 (methylene chloride:methanol=10:1); [1676]
  • NMR (CDCl[1677] 3): δ 8.04 (dd, J=7.2, 0.9 Hz, 1H), 7.80 (dt, J=7.8. 0.9 Hz, 1H), 7.72 (dd. J=7.8, 0.9 Hz, 1H), 7.59 (t, J=7.8 Hz, 1H), 7.02 (bs, 1H), 6.77 (d, J=7.2 Hz, 1H), 3.54 (q, J=5.7 Hz, 2H), 2.58 (t, J=5.7 Hz, 2H), 2.50-2.40 (m, 4H), 1.76-1.43 (m, 6H).
  • Hydrochloride: [1678]
  • TLC: Rf 0.60 (methylene chloride:methanol:triethylamine=8:1.5:0.5); [1679]
  • NMR (DMSO-d[1680] 6): δ 10.20 (br. s, 1H), 9.25-9.10 (m, 1H), 8.01 (d, J=7.0 Hz, 1H), 7.99 (d, J=7.0 Hz, 1H), 7.93 (d, J=6.9 Hz, 1H), 7.73 (t, J=7.0 Hz, 1H), 7.47 (d, J=6.9 Hz, 1H), 3.80-3.60 (m, 2H), 3.60-3.50 (m, 2H), 3.45-3.15 (m, 2H), 3.10-2.80 (m, 2H), 2.00-1.70 (m, 5H), 1.55-1.30 (m, 1H).
    • EXAMPLE 28 (12) 4-((1S)-1-t-Butoxycarbonyl-2-methylpropyl)carbamoyl-1,1-dioxidebenzo[b]thiophene
  • [1681]
    Figure US20030073706A1-20030417-C01834
  • TLC: Rf 0.48 (hexane:ethyl acetate=1:1); [1682]
  • NMR (CDCl[1683] 3): δ 7.95 (d, J=7.2 Hz, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.77 (d, J=7.8 Hz, 1H), 7.59 (t, J=7.8 Hz, 1H), 6.78 (d, J=7.2 Hz, 1H), 6.56 (d, J=8.4 Hz, 1H), 4.64 (dd, J=8.4, 4.2 Hz, 1H), 2.36-2.27 (m, 1H), 1.51 (s, 9H), 1.02 (d, J=6.9 Hz, 3H), 0.98 (d, J=6.9 Hz, 3H).
    • EXAMPLE 28 (13) 4-(2-Fluorophenylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene
  • [1684]
    Figure US20030073706A1-20030417-C01835
  • TLC: Rf 0.60 (chloroform:methanol=9:1); [1685]
  • NMR (CDCl[1686] 3+DMSO-d6): δ 7.95 (broad peak, 1H), 7.95 (d, J=7 Hz, 1H), 7.80 (d, J=8 Hz, 1H), 7.78 (d, J=8 Hz, 1H), 7.55 (t, J=8 Hz, 1H), 7.50-7.20 (m, 2H), 7.20-7.00 (m, 2H), 6.77 (d, J=7 Hz, 1H), 4.62 (d, J=7 Hz, 2H).
    • EXAMPLE 28 (14) 4-(3-Fluorophenylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene
  • [1687]
    Figure US20030073706A1-20030417-C01836
  • TLC: Rf 0.50 (chloroform:methanol=9:1); [1688]
  • NMR (CDCl[1689] 3+DMSO-d6): δ 8.40 (broad peak, 1H), 7.98 (d, J=7 Hz, 1H), 7.85 (d, J=8 Hz, 1H), 7.80 (d, J=8 Hz, 1H), 7.55 (t, J=8 Hz, 1H), 7.40-7.25 (m, 1H), 7.20-6.90 (m, 3H), 6.80 (d, J=7 Hz, 1H), 4.60 (d, J=7 Hz, 2H).
    • EXAMPLE 28 (15) 4-(3-Methylphenylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene
  • [1690]
    Figure US20030073706A1-20030417-C01837
  • TLC: Rf 0.60 (chloroform: methanol=9:1); NMR (CDCl[1691] 3): δ 7.95 (d, J=7 Hz, 1H), 7.75 (d, J=8 Hz, 1H), 7.65 (d, J=8 Hz, 1H), 7.52 (t, J=8 Hz, 1H), 7.30-7.20 (m, 1H), 7.20-7.10 (m, 3H), 6.75 (d, J=7 Hz, 1H), 6.40 (broad peak, 1H), 4.60 (d, J=7 Hz, 2H), 2.40 (s, 3H).
    • EXAMPLE 28 (16) 4-(2-Methoxyphenylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene
  • [1692]
    Figure US20030073706A1-20030417-C01838
  • TLC: Rf 0.64 (chloroform:methanol=9:1); [1693]
  • NMR (CDCl[1694] 3+DMSO-d6): δ 7.93 (d, J=7 Hz, 1H), 7.85-7.70 (m, 3H), 7.55 (t, J=8 Hz, 1H), 7.30 (m, 2H), 6.92 (m, 2H), 6.78 (d, J=7 Hz, 1H), 4.60 (d, J=7 Hz, 2H), 3.90 (s, 3H).
    • EXAMPLE 28 (17) 4-(2,3-dimethoxyphenylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene
  • [1695]
    Figure US20030073706A1-20030417-C01839
  • TLC: Rf 0.63 (chloroform:methanol=9:1); [1696]
  • NMR (CDCl[1697] 3+DMSO-d6): δ 7.97 (d, J=7.2 Hz, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.73 (broad peak, 1H), 7.54 (t, J=7.6 Hz, 1H), 7.06 (t, J=7.8 Hz, 1H), 7.00-6.85 (m, 2H), 6.77 (d, J=7.2 Hz, 1H), 4.63 (d, J=5.6 Hz, 2H), 3.90 (s, 3H), 3.88 (s, 3H).
    • EXAMPLE 28 (18) 4-(3,4-Dimethoxyphenylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene
  • [1698]
    Figure US20030073706A1-20030417-C01840
  • TLC: Rf 0.53 (chloroform:methanol=9:1); [1699]
  • NMR (CDCl[1700] 3+DMSO-d6): δ 8.57 (t-like, J=5.8 Hz, 1H), 7.97 (d, J=7.2 Hz, 1H), 7.86 (d, J=7.8 Hz, 1H), 7.77 (d, J=7.8 Hz,1H), 7.57 (t, J=7.8 Hz,1H), 7.00-6.80 (m, 4H), 4.53 (d, J=5.8 Hz, 2H), 3.88 (s, 3H), 3.87 (s, 3H).
    • EXAMPLE 28 (19) 4-(2,5-Difluorophenylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene
  • [1701]
    Figure US20030073706A1-20030417-C01841
  • TLC: Rf 0.45 (chloroform:methanol 9:1); [1702]
  • NMR (CDCl[1703] 3+DMSO-d6): δ 8.78 (t, J=6.0 Hz, 1H), 7.97 (dd, J=7.0 Hz and 1.0 Hz, 1H), 7.89 (dd, J=7.6 Hz and 1.0 Hz, 1H), 7.79 (d, J=7.6 Hz, 1H), 7.59 (t, J=7.6 Hz, 1H), 7.20-6.90 (m, 3H), 6.82 (d, J=7.0 Hz, 1H), 4.60 (d, J=6.0 Hz, 1H).
    • EXAMPLE 28 (20) 4-(3,4,5-Trimethoxyphenylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene
  • [1704]
    Figure US20030073706A1-20030417-C01842
  • TLC: Rf 0.33 (chloroform:methanol=9:1); [1705]
  • NMR (CDCl[1706] 3, DMSO-d6): δ 8.00 (broad peak, 1H), 7.98 (dd, J=7.2 Hz and 1.0 Hz, 1H), 7.82 (dd, J=7.6 Hz and 1.0 Hz, 1H), 7.78 (d, J=7.6 Hz, 1H), 7.56 (t, J=7.6 Hz, 1H), 6.79 (d, J=7.2 Hz, 1H), 6.61 (s, 2H), 4.54 (d, J=5.8 Hz, 2H), 3.86 (s, 6H), 3.83 (s, 3H).
    • EXAMPLE 28 (21) 4-(Benzimidazol-2-ylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene
  • [1707]
    Figure US20030073706A1-20030417-C01843
  • TLC: Rf 0.28 (chloroform:methanol=9:1); [1708]
  • NMR (CDCl[1709] 3+DMSO-d6): δ 8.97 (t, J=5.6 Hz, 1H), 8.08 (d, J=7.2 Hz, 1H), 7.94 (dd, J=7.8 Hz and 1.0 Hz, 1H), 7.79 (dd, J=7.8 Hz and 1.0 Hz, 1H), 7.62-7.50 (m, 3H), 7.30-7.15 (m, 2H), 6.81 (d, J=7.2 Hz, 1H), 4.85 (d, J=5.6 Hz, 2H).
    • EXAMPLE 28 (22) 4-(3,5-Difluorophenylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene
  • [1710]
    Figure US20030073706A1-20030417-C01844
  • TLC: Rf 0.57 (chloroform:methanol=9:1); [1711]
  • NMR (CDCl[1712] 3+DMSO-d6): δ 9.11 (t, J=5.8 Hz, 1H), 7.98 (dd, J=7.2 Hz and 1.0 Hz, 1H), 7.93 (dd, J=7.6 Hz and 1.0 Hz, 1H), 7.81 (d, J=7.6 Hz, 1H), 7.62 (t, J=7.6 Hz, 1H), 7.00-6.90 (m, 2H), 6.90 (d, J=7.2 Hz, 1H), 6.80-6.68 (m, 1H), 4.55 (d, J=5.8 Hz, 2H).
    • EXAMPLE 28 (23) 4-(N-Benzyl-N-methylcarbamoyl)-1,1-dioxidebenzo[b]thiophene
  • [1713]
    Figure US20030073706A1-20030417-C01845
  • TLC: Rf 0.69 (chloroform:methanol=9:1); [1714]
  • NMR (CDCl[1715] 3): δ 7.80-7.70 (m, 1H), 7.65-7.47 (m, 2H), 7.47-7.25 (m, 5H), 7.15-7.00 (m, 1H), 6.80-6.72 (m, 1H), 4.78 and 4.44 (each s, total 2H), 3.12 and 2.84 (each s, total 3H).
    • EXAMPLE 28 (24) 4-(4-Nitrophenylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene
  • [1716]
    Figure US20030073706A1-20030417-C01846
  • TLC: Rf 0.44 (chloroform:methanol 9:1); [1717]
  • NMR (CDCl[1718] 3+DMSO-d6): δ 9.20 (t, J=5.8 Hz, 1H), 8.20 (d, J=8 Hz, 2H), 7.98 (d, J=7 Hz, 1H), 7.93 (d, J=7.5 Hz, 1H), 7.81 (d, J=7.5 Hz, 1H), 7.62 (t, J=7.5 Hz, 1H), 7.57 (d, J=8 Hz, 2H), 6.89 (d, J=7 Hz, 1H), 4.67 (d, J=5.8 Hz, 2H).
    • EXAMPLE 28 (25) 5-(2-Hydroxyethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene
  • [1719]
    Figure US20030073706A1-20030417-C01847
  • TLC: Rf 0.38 (ethyl acetate); [1720]
  • NMR (CDCl[1721] 3+CD3OD): δ 7.98 (dd, J=8.0 Hz, 1.2 Hz, 1H), 7.88 (d, J=1.2 Hz, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.31 (d, J=6.8 Hz, 1H), 6.81 (d, J=6.8 Hz, 1H), 3.78 (t, J=4.8 Hz, 2H), 3.57 (t, J=4.8 Hz, 2H).
    • EXAMPLE 28 (26) 5-(Pyridin-3-ylmethyl)carbamoyl-4-methoxy-1,1-dioxidebenzo[b]thiophene
  • [1722]
    Figure US20030073706A1-20030417-C01848
  • MS (APCI, Pos.): m/z 363 (M+MeOH+H)[1723] +, 331 (M+H)+.
    • EXAMPLE 28 (27) 5-(2-Dimethylaminoethyl)carbamoyl-4-methoxy-1,1-dioxidebenzo[b]thiophene
  • [1724]
    Figure US20030073706A1-20030417-C01849
  • TLC: Rf 0.27 (methylene chloride:methanol=10:1); [1725]
  • NMR (CDCl[1726] 3): δ 8.23 (d, J=8.1 Hz,1H), 8.03 (t, J=5.7 Hz, 1H), 7.55 (d, J=8.1 Hz, 1H), 7.41 (d, J=6.9 Hz, 1H), 6.76 (d, J=6.9 Hz, 1H), 3.94 (s, 3H), 3.57 (q, J=5.7 Hz, 2H), 2.53 (t, J=5.7 Hz, 2H), 2.30 (s, 6H).
    • EXAMPLE 28 (28) 5-Dimethylcarbamoyl-4-methoxy-1,1-dioxidebenzo[b]thiophene
  • [1727]
    Figure US20030073706A1-20030417-C01850
  • TLC: Rf 0.35 (methanol:ethyl acetate=5:95); [1728]
  • NMR (CDCl[1729] 3): δ 7.52-7.38 (m, 3H), 6.75 (d, J=7.4 Hz, 1H), 3.93 (s, 3H), 3.15 (s, 3H), 2.88 (s, 3H).
    • EXAMPLE 28 (29) 5-(2,3,4,5,6,7-Hexahydro-1H-azepin-1-yl)carbonyl-4-methoxy-1,1-dioxidebenzo[b]thiophene
  • [1730]
    Figure US20030073706A1-20030417-C01851
  • TLC: Rf 0.60 (methylene chloride:methanol=10:1); [1731]
  • NMR (CDCl[1732] 3): δ 7.48 (dd, J=7.5,0.9Hz, 1H), 7.42 (dd, J=6.9, 0.9 Hz, 1H), 7.38 (d, J=7.5 Hz, 1H), 6.74 (d, J=6.9 Hz, 1H), 3.95 (s, 3H), 3.80-3.56 (m, 2H), 3.30-3.20 (m, 2H), 1.90-1.75 (m, 2H), 1.75-1.40 (m, 6H).
    • EXAMPLE 28 (30) 5-(2,3-Dihydroindol-1-yl)carbonyl-4-methoxy-1,1-dioxidebenzo[b]thiophene
  • [1733]
    Figure US20030073706A1-20030417-C01852
  • TLC: Rf 0.82 (methylene chloride:methanol=10:1); [1734]
  • NMR (CDCl[1735] 3): δ 8.31 (d, J=7.8 Hz, 1H), 7.54 (s, 2H), 7.45 (d, J=6.9 Hz, 1H), 7.33-7.20 (m, 2H), 7.20-7.07 (m, 1H), 6.77 (d, J=6.9 Hz, 1H), 3.97 (s, 3H), 3.90-3.66 (m, 2H), 3.25-3.10 (m, 2H).
    • EXAMPLE 28 (31) 5-(4-(2-Chlorophenyl)piperazin-1-yl)carbonyl-4-methoxy-1,1-dioxidebenzo[b]thiophene
  • [1736]
    Figure US20030073706A1-20030417-C01853
  • TLC: Rf 0.30 (ethyl acetate:hexane=1:1); [1737]
  • NMR (CDCl[1738] 3): δ 7.51 (d, J=7.8 Hz, 1H), 7.46 (d, J=7.8 Hz, 1H), 7.43-7.35 (m, 2H), 7.30-7.20 (m, 1H), 7.06-6.99 (m, 2H), 6.76 (d, J=6.9 Hz, 1H), 4.10-3.90 (m, 2H), 3.98 (s, 3H), 3.54-3.37 (m, 2H),3.20-2.90 (m, 4H).
    • EXAMPLE 28 (32) 5-(4-(2-(2-Trifluoromethylphenyl)ethyl)piperazin-1-yl)carbonyl-4-methoxy-1,1-dioxidebenzo[b]thiophene
  • [1739]
    Figure US20030073706A1-20030417-C01854
  • TLC: Rf 0.33 (ethyl acetate); [1740]
  • NMR (CDCl[1741] 3): δ 7.63 (d, J=7.8 Hz, 1H), 7.49 (d, J=7.5 Hz, 2H), 7.46-7.40 (m, 2H), 7.40-7.27 (m, 2H), 6.75 (d, J=7.5 Hz, 1H), 3.94 (s, 3H), 3.90-3.80 (m, 2H), 3.35-3.20 (m, 2H), 3.04-2.94 (m, 2H), 2.68-2.60 (m, 4H), 2.58-2.40 (m, 2H).
    • EXAMPLE 28 (33) 4-(Pyridin-3-ylcarbonyl)aminomethyl-1,1-dioxidebenzo[b]thiophene
  • [1742]
    Figure US20030073706A1-20030417-C01855
  • MS (APCI, Pos.): m/z 333 (M+MeOH+H)[1743] +, 301 (M+H)+.
    • EXAMPLE 29 4-(3-(Pyrrol-1-yl)-propyl) oxy-1,1-dioxidebenzo[b]thiophene
  • [1744]
    Figure US20030073706A1-20030417-C01856
  • 4-Hydroxy-1,1-dioxidebenzo[b]thiophene (370 mg), triphenylphosphine (630 mg) and 1-(3-hydroxypropyl)pyrrole (300 mg) were dissolved in anhydrous tetrahydrofuran (15 ml). Under an atmosphere of argon to the mixture, was added a solution of diethylazodicarboxylate (323 mg) in anhydrous tetrahydrofuran (4 ml) dropwise. The mixture was stirred at room temperature for 2 hours. To the reaction mixture methanol was added. The mixture was stirred for 10 minutes. The reaction mixture was concentrated. The residue was purified with column chromatography on silica gel (hexane:ethyl acetate=2:1) to give the compound of the present invention (473 mg) having the following physical data. [1745]
  • TLC: Rf 0.47 (hexane:ethyl acetate=1:1); [1746]
  • NMR (CDCl[1747] 3): δ 7.55-7.35 (m, 2H), 7.30 (d, J=8 Hz, 1H), 6.97 (d, J=8 Hz, 1H), 6.75-6.54 (m, 3H), 6.16 (t, J=2 Hz, 2H), 4.12 (t, J=6 Hz, 2H), 4.00 (t, J=6 Hz, 2H), 2.27 (q, J=6 Hz, 2H).
    • EXAMPLES 30˜30 (13)
  • By the same procedure as described in Example 18 using alcohol derivative corresponding to the compound prepared in Example 9 (12) and halogenated compound corresponding to 4-nitrobenzylbromide, or by the same procedure as described in Example 29 using alcohol derivative corresponding to 4-hydroxy-1,1-dioxidebenzo[b]thiophene and alcohol derivative corresponding to 1-(3-hydroxypropyl)pyrrole, the following compounds of the present invention were obtained. [1748]
    • EXAMPLE 30 4-(Quinolin-2-ylmethyl)oxy-1,1-dioxidebenzo[b]thiophene
  • [1749]
    Figure US20030073706A1-20030417-C01857
  • TLC: Rf 0.27 (hexane:ethyl acetate=1:1); [1750]
  • NMR (CDCl[1751] 3): δ 8.23 (d, J=8 Hz, 1H), 8.09 (d, J=8Hz, 1H), 7.95-7.68 (m, 2H), 7.68-7.50 (m, 3H), 7.50-7.22 (m, 2H), 7.14 (d, J=8 Hz, 1H), 6.66 (d, J=7 Hz, 1H), 5.49 (s, 2H).
    • EXAMPLE 30 (1) 4-(2-(Pyrrol-1-yl)ethyl)oxy-1,1-dioxidebenzo[b]thiophene
  • [1752]
    Figure US20030073706A1-20030417-C01858
  • TLC: Rf 0.50 (ethyl acetate:hexane=2:1); [1753]
  • NMR (CDCl[1754] 3): δ 7.55-7.22 (m, 3H), 6.94 (d, J=8 Hz, 1H), 6.73 (t, J=2 Hz, 2H), 6.62 (d, J=7 Hz, 1H), 6.19 (t, J=2 Hz, 2H), 4.32 (s, 4H).
    • EXAMPLE 30 (2) 4-(2-(4-Methylazol-5-yl)ethyl)oxy-1,1-dioxidebenzo[b]thiophene
  • [1755]
    Figure US20030073706A1-20030417-C01859
  • TLC: Rf 0.15 (ethyl acetate:hexane=2:1); [1756]
  • NMR (CDCl[1757] 3): δ 8.63 (s, 1H), 7.58-7.37 (m, 2H), 7.31 (d, J=8 Hz, 1H), 7.03 (d, J=8 Hz,1H), 6.64 (d, J=8 Hz, 1H), 4.26 (t, J=6 Hz, 2H), 3.31 (t, J=6 Hz, 2H), 2.46 (s, 3H).
    • EXAMPLE 30 (3) 4-(3-(Pyridin-4-yl)propyl)oxy-1,1-dioxidebenzo[b]thiophene
  • [1758]
    Figure US20030073706A1-20030417-C01860
  • TLC: Rf 0.36 (ethyl acetate:methanol=10:1); [1759]
  • NMR (CDCl[1760] 3): δ 8.53 (dd, J=1.6, 4.5 Hz, 2H), 7.60-7.22 (m, 3H), 7.14 (d, J=5.8 Hz, 2H), 7.00 (d, J=8.0 Hz, 1H), 6.62 (d, J=7.4 Hz, 1H), 4.09 (t, J=6.2 Hz, 2H), 2.84 (t, J=7.4 Hz, 2H), 2.19 (quint, J=6.2 Hz, 2H).
    • EXAMPLE 30 (4) 4-(1-t-Butoxycarbonylpiperidin-3-ylmethyl)oxy-1,1-dioxidebenzo[b]thiophene
  • [1761]
    Figure US20030073706A1-20030417-C01861
  • TLC: Rf 0.46 (hexane:ethyl acetate=1:1); [1762]
  • NMR (CDCl[1763] 3): δ 7.58-7.38 (m, 2H), 7.30 (d, J=7.6 Hz, 1H), 7.04 (d, J=8.2 Hz, 1H), 6.61 (d, J=7.0 Hz, 3.15-2.50 (m, 4H), 1.45 (s, 9H).
    • EXAMPLE 30 (5) 4-(2-(Pyrrolidin-1-yl)ethyl)oxy-1,1-dioxidebenzo[b]thiophene
  • [1764]
    Figure US20030073706A1-20030417-C01862
  • TLC: Rf 0.36 (ethyl acetate:acetic acid:water=3:1:1); [1765]
  • NMR (CDCl[1766] 3): δ 7.55-7.35 (m, 2H), 7.29 (d, J=7 Hz, 1H), 7.06 (d, J=8 Hz, 1H), 6.61 (d, J=7 Hz, 1H), 4.22 (t, J=6 Hz, 2H), 2.94 (t, J=6 Hz, 2H), 2.64 (t, J=6 Hz, 4H), 2.20-1.65 (m, 4H).
    • EXAMPLE 30 (6) 4-(2-(Piperidin-1-yl)ethyl)oxy-1,1-dioxidebenzo[b]thiophene
  • [1767]
    Figure US20030073706A1-20030417-C01863
  • TLC: Rf 0.44 (ethyl acetate:acetic acid:water=3:1:1); [1768]
  • NMR (CDCl[1769] 3): δ 7.60-7.58 (m, 2H), 7.29 (d, J=8 Hz, 1H), 7.07 (d, J=8 Hz, 1H), 6.61 (d, J=7 Hz, 1H), 4.21 (t, J=6 Hz, 2H), 2.80 (t, J=6 Hz, 2H), 2.51 (t, J=6 Hz, 4H), 1.90-1.35 (m 6H).
    • EXAMPLE 30 (7) 4-(2-(2-Acetyloxyethoxy)ethyl)oxy-1,1-dioxidebenzo[b]thiophene
  • [1770]
    Figure US20030073706A1-20030417-C01864
  • TLC: Rf 0.46 (ethyl acetate:hexane=2:1); [1771]
  • NMR (CDCl[1772] 3): δ 5 7.58-7.38 (m, 2H), 7.31 (d, J=7 Hz, 1H), 7.08 (d, J=9 Hz, 1H), 6.62 (d, J=7 Hz, 1H), 4.25 (t, J=5 Hz, 4H), 3.88 (t, J=5 Hz, 2H), 3.76 (t, J=5 Hz, 2H), 2.07 (s, 3H).
    • EXAMPLE 30 (8) 4-(2-(4-Benzylpiperazin-1-yl)ethyl)oxy-1,1-dioxidebenzo[b]thiophene
  • [1773]
    Figure US20030073706A1-20030417-C01865
  • TLC: Rf 0.57 (chloroform:methanol 5:1); [1774]
  • NMR (CDCl[1775] 3): δ 7.58-7.38 (m, 2H), 7.38-7.18 (m, 6H), 7.05 (d, J=8 Hz, 1H), 6.60 (d, J=7 Hz,1H), 4.35-4.05 (m, 2H), 3.52 (s, 2H), 2.85 (t, J=6 Hz, 2H), 2.78-2.35 (m, 8H).
    • EXAMPLE 30 (9) 4-Diethylcarbamoylmethyloxy-1,1-dioxidebenzo[b]thiophene
  • [1776]
    Figure US20030073706A1-20030417-C01866
  • TLC: Rf 0.25 (hexane:ethyl acetate=1:2); [1777]
  • NMR (CDCl[1778] 3): δ 7.52 (d, J=7.0 Hz,1H), 7.46 (t, J=8.0 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.05 (d, J=8.0 Hz, 1H), 6.63 (d, J=7.0 Hz, 1H), 4.80 (s, 2H), 3.41 (q, J=7.2 Hz, 2H), 3.36 (q, J=7.2 Hz, 2H), 1.23 (t, J=7.2 Hz, 3H), 1.15 (t, J=7.2 Hz, 3H).
    • EXAMPLE 30 (10) 4-Cyanomethyloxy-1,1-dioxidebenzo[b]thiophene
  • [1779]
    Figure US20030073706A1-20030417-C01867
  • TLC: Rf 0.30 (hexane:ethyl acetate=1:1); [1780]
  • NMR (CDCl[1781] 3): δ 7.65-7.35 (m, 3H), 7.15 (d, J=7.5 Hz, 1H), 6.70 (d, J=7.5 Hz, 1H), 4.90 (s, 2H).
    • EXAMPLE 30 (11) 5-(Pyridin-3-yloxy)methyl-4-methoxy-1,1-dioxidebenzo[b]thiophene
  • [1782]
    Figure US20030073706A1-20030417-C01868
  • MS (APCI, Pos.): m/z 336 (M+MeOH+H)[1783] +, 304 (M+H)+.
    • EXAMPLE 30 (12) 5-(2-t-Butoxycarbonylaminoethyl)oxy-4-nitro-1,1-dioxidebenzo[b]thiophene
  • [1784]
    Figure US20030073706A1-20030417-C01869
  • TLC: Rf 0.32 (hexane:ethyl acetate=1:1); [1785]
  • NMR (CDCl[1786] 3) δ 7.80 (d, J=8.6 Hz, 1H), 7.33 (d, J=7.0 Hz, 1H), 7.18 (d, J=8.6 Hz, 1H), 6.93 (d, J=7.0 Hz, 1H), 5.00 (br, 1H), 4.24 (t, J=5.2 Hz, 2H), 3.57 (q, J=5.2 Hz, 2H), 1.45 (s, 9H).
    • EXAMPLE 30 (13) 5-((2E)-3-Ethoxycarbonyl-2-propenyl) oxy-1,1-dioxidebenzo[b]thiophene
  • [1787]
    Figure US20030073706A1-20030417-C01870
  • TLC: Rf 0.51 (hexane:ethyl acetate=1:1); [1788]
  • NMR (CDCl[1789] 3): δ 7.65 (d, J=8.8 Hz, 1H), 7.14 (d, J=6.8 Hz, 1H), 7.12-6.85 (m, 4H), 6.74 (d, J=6.8 Hz, 1H), 6.23-6.10 (m, 1H), 4.82-4.73 (m, 2H), 4.23 (q, J=7.0 Hz, 2H), 1.31 (t, J=7.0 Hz, 3H).
    • EXAMPLE 31 4-(2,4-Dimethoxyphenylmethyl)aminomethyl-1,1-dioxidebenzo[b]thiophene
  • [1790]
    Figure US20030073706A1-20030417-C01871
  • 4-Bromomethyl-1,1-dioxidebenzo[b]thiophene (198 mg) was dissolved in acetonitrile (10 ml). Thereto was added a solution of 2,4-dimethoxybenzylamine, hydrochloride (188 mg) and triethylamine (0.26 ml) in acetonitrile (6 ml). The mixture was stirred at room temperature for 1 hour. To the reaction mixture a saturated aqueous solution of sodium bicarbonate was added. The mixture was extracted by ethyl acetate. The extract was washed by a saturated solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated. The residue was purified with column chromatography on silica gel (ethyl acetate:hexane 1:1→2:1) to give the compound of the present invention (113 mg) having the following physical data. [1791]
  • TLC: Rf 0.29 (ethyl acetate); [1792]
  • NMR (CDCl[1793] 3): δ 7.63-7.39 (m, 4H), 7.07 (d, J=8.0 Hz,1H), 6.66 (d, J=7.0 Hz,1H), 6.49-6.39 (m, 2H), 3.83 (s, 2H), 3.81 (s, 3H), 3.79 (s, 3H), 3.72 (s, 2H), 1.98 (s, 1H).
    • EXAMPLES 31 (1)˜31 (12)
  • By the same procedure as described in Example 31 using 4-bromomethyl-1,1-dioxidebenzo[b]thiophene and an amine derivative corresponding to 2,4-dimethoxybenzylamine-hydrochloride, and if necessary, by converting into the corresponding salt by a known method, the following compounds of the present invention were obtained. [1794]
    • EXAMPLE 31 (1) 4-(Pyridin-3-ylmethyl)aminomethyl-1,1-dioxidebenzo[b]thiophene-2hydrochloride
  • [1795]
    Figure US20030073706A1-20030417-C01872
  • TLC: Rf 0.37 (ethyl acetate:methanol=5:1); [1796]
  • NMR (CD[1797] 3OD): δ 9.11 (d, J=1.7 Hz, 1H), 8.92 (dd, J=5.5, 1.7 Hz, 1H), 8.73 (dt, J=8.2, 1.7 Hz, 1H), 8.10 (dd, J=8.2, 5.5 Hz, 1H), 7.94-7.90 (m, 2H), 7.84 (d, J=7.4 Hz, 1H), 7.20 (t, J=7.4 Hz,. 1H), 7.18 (d, J=7.4 Hz, 1H), 4.68 (s, 2H), 4.63 (s, 2H).
    • EXAMPLE 31 (2) 4-(2-(Dimethylamino)ethyl)aminomethyl-1,1-dioxidebenzo[b]thiophene
  • [1798]
    Figure US20030073706A1-20030417-C01873
  • MS (APCI, Pos.): mlz 299 (M+MeOH+H)[1799] +, 267 (M+H)+.
    • EXAMPLE 31 (3) 4-(N,N-Bis(2-hydroxyethyl)amino)methyl-1,1-dioxidebenzo[b]thiophene
  • [1800]
    Figure US20030073706A1-20030417-C01874
  • MS (APCI, Pos.): m/z 316 (M+MeOH+H)[1801] +, 284 (M+H)+.
    • EXAMPLE 31 (4) 4-(2-(2-Hydroxyethoxy)ethyl)aminoethyl)aminomethyl-1,1-dioxidebenzo[b]thiophene
  • [1802]
    Figure US20030073706A1-20030417-C01875
  • MS (APCI, Pos.): m/z 599 (2M+MeOH+H)[1803] +, 567 (2M+H)+, 316 (M+MeOH+H)+, 284 (M+H)+.
    • EXAMPLE 31 (5) 4-(4-Benzylpiperazin-1-yl)methyl-1,1-dioxidebenzo[b]thiophene
  • [1804]
    Figure US20030073706A1-20030417-C01876
  • Free Compound: [1805]
  • TLC: Rf 0.27 (ethyl acetate:hexane=1:1); [1806]
  • NMR (CDCl[1807] 3): δ 7.71 (d, J=7.0 Hz, 1H), 7.62 (t, J=4.6 Hz, 1H), 7.44 (d, J=4.6 Hz, 2H), 7.35-7.25 (m, 5H), 6.68 (d, J=7.0 Hz, 1H), 3.60 (s, 2H), 3.51 (s, 2H), 2.46 (brs, 8H).
  • 2hydrochloride: [1808]
  • TLC: Rf 0.32 (ethyl acetate); [1809]
  • NMR (CD[1810] 3OD): δ 7.86 (d, J=7.2 Hz, 1H), 7.76-7.70 (m, 2H), 7.63 (d, J=7.8 Hz, 1H), 7.58-7.47 (m, 5H), 7.07 (d, J=7.2 Hz, 1H), 4.38 (s, 2H), 4.13 (s, 2H), 3.41 (br, 4H), 3.13 (br, 4H).
    • EXAMPLE 31 (6) 4-(4-(Pyridin-2-yl)piperazin-1-yl)methyl-1,1-dioxidebenzo[b]thiophene
  • [1811]
    Figure US20030073706A1-20030417-C01877
  • MS (APCI, Pos.): m/z 374 (M+MeOH+H)[1812] +, 342 (M+H)+.
    • EXAMPLE 31 (7) 4-(4-Ethoxycarbonylpiperazin-1-yl)methyl-1,1-dioxidebenzo[b]thiophene
  • [1813]
    Figure US20030073706A1-20030417-C01878
  • MS (APCI, Pos.): m/z 369 (M+MeOH+H)[1814] +, 337 (M+H)+.
    • EXAMPLE 31 (8) 4-(4-(2-Hydroxyethyl)piperazin-1-yl)methyl-1,1-dioxidebenzo[b]thiophene
  • [1815]
    Figure US20030073706A1-20030417-C01879
  • MS (APCI, Pos.): m/z 649 (2M+MeOH+H)[1816] +, 617 (2M+H)+, 341 (M+MeOH+H)+, 309 (M+H)+.
    • EXAMPLE 31 (9) 4-(4-(Pyridin-4-yl)piperazin-1-yl)methyl-1,1-dioxidebenzo[b]thiophene
  • [1817]
    Figure US20030073706A1-20030417-C01880
  • MS (APCI, Pos.): m/z 374 (M+MeOH+H)[1818] +, 342 (M+H)+.
    • EXAMPLE 31 (10) 4-Benzylaminomethyl-1,1-dioxidebenzo[b]thiophene
  • [1819]
    Figure US20030073706A1-20030417-C01881
  • Free Compound: [1820]
  • TLC: Rf 0.66 (ethyl acetate); [1821]
  • NMR (CDCl[1822] 3): δ 7.62 (d, J=7.2 Hz, 1H), 7.56 (d, J=7.5 Hz, 1H), 7.52 (d, J=7.5 Hz, 1H), 7.46 (t, J=7.5 Hz, 1H), 7.39-7.24 (m, 5H), 6.69 (d, J=7.2 Hz, 1H), 3.89 (s, 2H), 3.81 (s, 2H), 1.59 (s, 1H).
  • Hydrochloride: [1823]
  • TLC: Rf 0.47 (ethyl acetate:hexane 2:1); [1824]
  • NMR (CD[1825] 3OD): δ 7.95-7.18 (m, 8H), 7.15 (d, J=7 Hz, 1H), 6.98 (d, J=7 Hz, 1H), 4.48 (s, 2H), 4.36 (s, 2H).
    • EXAMPLE 31 (11) 4-(1-Benzylpiperidin-4-yl)aminomethyl-1,1-dioxidebenzo[b]thiophene
  • [1826]
    Figure US20030073706A1-20030417-C01882
  • Free Compound: [1827]
  • TLC: Rf 0.27 (ethyl acetate:methanol=4:1); [1828]
  • NMR (CDCl[1829] 3): δ 7.65 (d, J=7.0 Hz, 1H), 7.61 (d, J=6.8 Hz, 1H), 7.56-7.40 (m, 2H), 7.34-7.22 (m, 5H), 6.68 (d, J=7.0 Hz, 1H), 3.91 (s, 2H), 3.50 (s, 2H), 2.91-2.77 (m, 2H), 2.60-2.43 (m, 1H), 2.12-1.95 (m, 2H), 1.95-1.80 (m, 2H), 1.60-1.32 (m, 3H).
  • 2hydrochloride: [1830]
  • TLC: Rf 0.30 (ethyl acetate:methanol:triethylamine=8:1.5:0.5); [1831]
  • NMR (DMSO-d[1832] 6+CD3OD): δ 7.97 (d, J=7.2 Hz, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.88 (d, J=7.5 Hz,1H),7.65-7.55 (m, 3H), 7.50-7.40 (m, 4H), 4.42 (s, 2H), 4.33 (s, 2H), 3.80-3.40 (m, 3H), 3.10-2.95 (m, 2H), 2.50-2.35 (m, 2H), 2.35-2.05 (m, 2H).
    • EXAMPLE 31 (12) 4-(Morpholin-4-yl)methyl-1,1-dioxidebenzo[b]thiophene
  • [1833]
    Figure US20030073706A1-20030417-C01883
  • TLC: Rf 0.31 (ethyl acetate:methylene chloride=1:1); [1834]
  • NMR (CDCl[1835] 3): δ 7.69 (d, J=7.2 Hz, 1H), 7.64 (t, J=4.8 Hz, 1H), 7.46 (d, J=4.8 Hz, 2H), 6.71 (d, J=7.2 Hz, 1H), 3.68 (t, J=4.5 Hz, 4H), 3.60 (s, 2H), 2.44 (t, J=4.5 Hz, 4H).
    • EXAMPLE 32 4-Ethoxycarbonyl-1,1-dioxidebenzo[b]thiophene
  • [1836]
    Figure US20030073706A1-20030417-C01884
  • To a solution of 4-Carboxy-1,1-dioxidebenzo[b]thiophene (2.42 g) in dimethylformamide (50 ml), were added potassium carbonate (3.10 g) and bromoethane (44.3 g). The mixture was stirred at room temperature overnight. To a reaction mixture, water was added. The mixture was extracted by ethyl acetate. The extract was washed by water and a saturated aqueous solution of sodium chloride sucessively, dried over anhydrous sodium sulfate and concentrated to give the compound of the present invention (2.08 g) having the following physical data. [1837]
  • TLC: Rf 0.24 (ethyl acetate:hexane=1:4); [1838]
  • NMR (CDCl[1839] 3). δ 8.25 (d, J=7.4 Hz, 1H), 8.20 (d, J=7.8 Hz, 1H), 7.88 (d, J=7.8 Hz, 1H), 7.61 (t, J=7.8 Hz, 1H), 6.84 (d, J=7.4 Hz, 1H), 4.44 (q, J=7.2 Hz, 2H), 1.44 (t, J=7.2 Hz, 3H).
    • EXAMPLE 32 (1) 4-Benzyloxycarbonyl-1,1-dioxidebenzo[b]thiophene
  • [1840]
    Figure US20030073706A1-20030417-C01885
  • By the same procedure as described in Example 32 using 4-carboxy-1,1-dioxidebenzo[b]thiophene and benzylbromide instead of bromoethane, the compound of the present invention having the following physical data was obtained. [1841]
  • MS (APCI, Pos.): m/z 301 (M+H)[1842] +.
    • EXAMPLE 33 4-(Pyridin-3-yl)-1,1-dioxidebenzo[b]thiophene
  • [1843]
    Figure US20030073706A1-20030417-C01886
  • To a solution of 4-bromo-1,1-dioxidebenzo[b]thiophene (492 mg) in dimethylformamide (5.0 ml), were added diethyl(3-pyridyl)boran (440 mg) and trispotassium phosphate (637 mg) and tetrakis(triphenylphosphine)palladium (0) (116 mg). The mixture was stirred at 80° C. for 2 hours. The reaction mixture was poured into water. The mixture was extracted by ethyl acetate. The extract was washed by a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The residue was purified with column chromatography on silica gel (chloroform:methanol=50:1) to give the compound of the present invention (490 mg) having the following physical data. [1844]
  • TLC: Rf 0.59 (chloroform:methanol=9:1); [1845]
  • MS (APCI, Pos.): m/z 276 (M+MeOH+H)[1846] +, 244 (M+H)+.
    • EXAMPLE 33 (1) 6-(Pyridin-3-yl)-1,1-dioxidebenzo[b]thiophene
  • [1847]
    Figure US20030073706A1-20030417-C01887
  • By the same procedure as described in Example 33, using 6-bromo-1,1-dioxidebenzo[b]thiophene instead of 4-bromo-1,1-dioxidebenzo[b]thiophene, and diethyl(3-pyridyl)borane, the compound of the present invention having the following physical data was obtained. [1848]
  • MS (APCI, Pos.): m/z 276 (M+MeOH+H)[1849] +, 244 (M+H)+.
    • EXAMPLE 34 4-(4,4-Dimethyl-4,5-dihydroxazol-2-yl)-1,1-dioxidebenzo[b]thiophene
  • [1850]
    Figure US20030073706A1-20030417-C01888
  • To the compound prepared in the following Example 72 (519 mg), was added thionyl chloride (2.1 ml). The mixture was stirred at room temperature for 1 hour. To the reaction mixture was added ethyl acetate. The extract was washed by a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, concentrated to give the compound of the present invention (392 mg) having the following physical data. [1851]
  • TLC: Rf 0.42 (ethyl acetate:hexane=1:1); [1852]
  • NMR (CDCl[1853] 3): δ 8.43 (d, J=7.0 Hz, 1H), 8.08 (d, J=7.8 Hz, 1H), 7.78 (d, J=7.8 Hz, 1H), 7.56 (t, J=7.8 Hz, 1H), 6.76 (d, J=7.0 Hz, 1H), 4.13 (s, 2H), 1.40 (s, 6H).
    • EXAMPLES 35˜35 (68)
  • By the same procedure as described in Example 27, using the compounds prepared in Examples 28˜28 (33), 29, 30˜30 (13), 31˜31 (12), 32˜32 (1), 33˜33 (1), 34 or corresponding compounds instead of 5-methyl-1,1-dioxidebenzo[b]thiophene, and if necessary, by converting into the corresponding salt by a known method, the compounds of the present invention having the following physical data were obtained. [1854]
    • EXAMPLE 35 4-(Pyridin-3-ylmethyl) carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1855]
    Figure US20030073706A1-20030417-C01889
  • Free Acid: [1856]
  • TLC: Rf 0.44 (methylene chloride:methanol=10:1); [1857]
  • NMR (DMSO-d[1858] 6): δ 9.41 (t, J=5.7 Hz, 1H), 8.67 (d, J=1.8 Hz, 1H), 8.46 (dd. J=4.8, 1.8 Hz,1H), 8.06 (d, J=6.3 Hz,1H), 7.96 (d, J=6.9 Hz, 1H), 7.90-7.67 (m, 5H), 7.66-7.58 (m, 2H), 7.36 (dd, J=8.1, 5.1 Hz, 1H), 6.27 (d, J=6.9 Hz, 1H), 4.54 (d, J=5.7 Hz, 2H), 4.10 (dd, J=15.6, 9.3 Hz, 1H), 3.98 (dd, J=15.6,1.5 Hz, 1H). hydrochloride:
  • TLC: Rf 0.45 (chloroform:methanol 9:1); [1859]
  • NMR (DMSO-d[1860] 6): δ 9.70-9.62 (br, 1H), 8.95 (s, 1H), 8.75 (d, J=5.4 Hz, 1H), 8.55 (d, J=7.5 Hz, 1H), 8.13 (d, J=7.5 Hz, 1H), 7.98 (d, J=6.9 Hz, 1H), 7.94 (d, J=7.5 Hz, 1H), 7.91-7.85 (m, 1H), 7.81-7.72 (m, 1H), 7.67-7.58 (m, 4H), 6.21 (d, J=9.0 Hz, 1H), 4.76 (dd, J=15.6, 6.0 Hz, 1H), 4.62 (dd, J=15.6, 5.1 Hz, 1H), 4.07 (dd, J=15.0, 9.0 Hz, 1H), 3.93 (d, J=15.0Hz, 1H).
    • EXAMPLE 35 (1) 4-(4-Benzylpiperazin-1-yl)carbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene hydrochloride
  • [1861]
    Figure US20030073706A1-20030417-C01890
  • TLC: Rf 0.46 (chloroform:methanol=19:1); [1862]
  • NMR (DMSO-d[1863] 6): δ 11.60-11.40 and 11.40-11.20 (each br, total 1H), 8.05-7.52 (m, 10H), 7.51-7.23 (m, 3H), 5.88 and 5.81 (each d, J=9.3 Hz, total 1H), 4.80-3.85 (m, 6H), 3.70-2.78 (m, 6H).
    • EXAMPLE 35 (2) 4-(N-(2-(Pyridin-3-yl)ethyl)-N-methylcarbamoyl)-3-phenylsulfonyl-2,3-dihydro-2,2-dioxidebenzo[b]thiophene.hydrochloride
  • [1864]
    Figure US20030073706A1-20030417-C01891
  • TLC: Rf 0.27 (chloroform: methanol=19:1); [1865]
  • NMR (DMSO-d[1866] 6): δ 8.96 and 8.81 (each s, total 1H), 8.75 and 8.73 (each d, J=5.4 Hz, total 1H), 8.55 and 8.32 (each d, J=7.5 Hz, total 1H), 7.95-7.62 (m, 9H), 5.81 and 5.79 (each d, J=8.4 Hz, total 1H), 4.15-3.84 and 3.73-3.62 (each m, total 4H), 3.50-3.05 (m, 2H), 3.16 and 3.13 (each s, total 3H).
    • EXAMPLE 35 (3) 4-(2-(2-Hydroxyethoxy)ethyl)carbamoyl-3-phenylSulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1867]
    Figure US20030073706A1-20030417-C01892
  • TLC: Rf 0.55 (methylene chloride:methanol=9:1); [1868]
  • NMR (DMSO-d[1869] 6): δ 8.84 (t, J=5.4 Hz, 1H), 7.98-7.90 (m, 2H), 7.84 (d, J=7.5 Hz, 1H), 7.81-7.73 (m, 3H), 7.69-7.60 (m, 2H), 6.36 (d, J=8.9 Hz, 1H), 4.58 t, J=5.1 Hz, 1H), 4.09 (dd, J=15.3, 8.9 Hz, 1H), 3.9 6 (d, J=15.3 Hz, 1H), 3.67-3.53 (m, 2H), 3.53-3.35 (m, 6H).
    • EXAMPLE 35 (4) 4-(2,4-Dimethoxyphenylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1870]
    Figure US20030073706A1-20030417-C01893
  • TLC: Rf 0.48 (methylene chloride:methanol=95:5); [1871]
  • NMR (DMSO-d[1872] 6): δ 5 9.04 (t, J=5 Hz, 1H), 8.03 (d, J=7.2 Hz, 1H), 7.92 (d, J=7.2 Hz, 1H), 7.90-7.70 (m, 5H), 7.62 (t, J=7.2 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 6.57 (d, J=2.4 Hz, 1H), 6.47 (dd , J=8.4, 2.4 Hz, 1H), 6.27 (d, J=8.5 Hz, 1H), 4.47 (dd, J=15, 5 Hz, 1H), 4.29 (dd, J=15, 5Hz, 1H), 4.08 (dd, J=15, 8.5 Hz, 1H), 3.97 (d, J=15 Hz, 1H), 3.83 (s, 3H), 3.74 (s, 3H).
    • EXAMPLE 35 (5) 4-(1-Benzylpiperidin-4-yl) carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1873]
    Figure US20030073706A1-20030417-C01894
  • Free Compound: [1874]
  • TLC: Rf 0.30 (methylene chloride:methanol=9:1); [1875]
  • NMR (CDCl[1876] 3+CD3OD). δ 8.00-7.50 (m, 8H), 7.45-7.20 (m, 1H), 6.25 (dd, J=7.5, 2.5 Hz, 1H), 4.10-3.90 (m, 1H), 3.8 0 (dd, J=15, 2.5 Hz, H), 3.70-3.60 (m, H), 3.55 (s, 2H), 3.10-2.90 (m H, ), 2.30-1.95 (m, 4H), 1.90-1.70 (m, 2H).
  • Hydrochloride: [1877]
  • TLC: Rf 0.40 (methanol:ethyl acetate=1:10); [1878]
  • NMR (CD[1879] 3OD): δ 8.04-7.43 (m, 13H), 6.15 (dd, J=8.2 Hz, 2.6 Hz, 1H), 4.35 (s, 2H), 4.34-4.06 (m,1H), 3.94 (dd, J=15.2 Hz, 8.2 Hz,1H), 3.83 (dd, J=15.2 Hz, 2.6 Hz,1H), 3.74-3.08 (m, 4H), 2.56-1.56 (m, 4H).
  • Methanesulfonic Acid Salt: [1880]
  • TLC: Rf 0.40 (methanol:ethyl acetate=1:10); [1881]
  • NMR (CD[1882] 3OD): δ 8.06-7.44 (m, 13H), 6.14 (dd, J=8.2 Hz, 2.6 Hz, 1H), 4.34 (s, 2H), 4.32-4.12 (m,1H), 4.01-3.77 (m, 2H), 3.68-3.08 (m, 4H), 2.69 (s, 3H), 2.54-1.74 (m, 4H).
    • EXAMPLE 35 (6) 4-(Pyridin-4-ylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1883]
    Figure US20030073706A1-20030417-C01895
  • TLC: Rf 0.35 (chloroform:methanol=9:1); [1884]
  • NMR (DMSO-d[1885] 6). δ 9.45 (t. J=7 Hz, 1H), 8.50 (d, J=8 Hz, 2H), 8.10 (d, J=8 Hz, 1H), 8.00 (d, J=8 Hz, 1H), 7.90 (t, J=8 Hz,1H), 7.80-7.55 (m, 5H), 7.45 (d, J=8 Hz, 2H), 6.30 (dd, J=1 Hz and 7 Hz, 1H), 4.55 (m, 2H), 4.10 (dd, J=7 Hz and 15 Hz, 1H), 4.00 (dd, J=1 Hz and 15 Hz, 1H).
    • EXAMPLE 35 (7) 4-(2-t-Butoxycarbonylethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1886]
    Figure US20030073706A1-20030417-C01896
  • TLC: Rf 0.37 (ethyl acetate:hexane=3:2); [1887]
  • NMR (DMSO-d[1888] 6): δ 8.90 (t, J=7 Hz, 1H), 8.00-7.55 (m, 8H), 6.25 (dd, J=1 Hz and 7Hz, 1H), 4.10 (dd, J=7Hz and 15Hz, 1H), 3.95 (dd, J=1 Hz and 15 Hz, 1H), 3.45 (m, 2H), 2.60 (t, J=7 Hz, 2H).
    • EXAMPLE 35 (8) 4-(Thiophen-2-ylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1889]
    Figure US20030073706A1-20030417-C01897
  • TLC: Rf 0.67 (chloroform:methanol=4:1); [1890]
  • NMR (DMSO-d[1891] 6): δ 9.40 (t, J=7 Hz, 1H), 8.00-7.60 (m, 8H), 7.40 (d, J=6 Hz, 1H), 7.10 (d, J=4 Hz, 1H), 7.00 (dd, J=4 Hz and6 Hz, 1H), 6.30 (dd, J=1 Hz and7 Hz, 1H), 4.75 (dd, J=7 Hz and 16 Hz, 1H), 4.55 (dd, J=7 Hz and 16 Hz, 1H),4.10 (dd, J=7 Hz and 12 Hz, 1H), 4.00 (dd, J=1 Hz and 12 Hz, 1H).
    • EXAMPLE 35 (9) 4-Benzylcarbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1892]
    Figure US20030073706A1-20030417-C01898
  • TLC: Rf 0.58 (methylene chloride:methanol=10:1); [1893]
  • NMR (CDCl[1894] 3+DMSO-d6): δ 8.74 (t, J=5.7 Hz,1H), 8.03 (dd, J=7.8, 0.9 Hz, 1H), 7.93-7.80 (m, 3H), 7.78-7.68 (m, 2H), 7.59 (t, J=7.8 Hz, 2H), 7.50 (d, J=6.9 Hz, 2H), 7.39-7.20 (m, 3H), 6.36 (d, J=7.8 Hz, 1H), 4.71 (dd, J=14.9, 5.7 Hz, 1H), 4.62 (dd, J 14.9, 5.7 Hz, 1H), 3.86 (d, J=15.0 Hz, 1H), 3.69 (dd, J=15.0, 7.8 Hz, 1H).
    • EXAMPLE 35 (10) 4-(Pyridin-2-ylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1895]
    Figure US20030073706A1-20030417-C01899
  • TLC: Rf 0.56 (methylene chloride:methanol=10:1); [1896]
  • NMR (DMSO-d[1897] 6): δ 9.42 (t, J=6.3 Hz, 1H), 8.54 (d, J=5.1 Hz, 1H), 8.11 (d, J=7.5 Hz, 1H), 7.97 (d, J=8.1 Hz, 1H), 7.95-7.82 (m, 1H), 7.80-7.70 (m, 4H). 7.62 (t, J=8.1 Hz, 2H), 7.55 (d, J=8.1 Hz, 1H), 7.30-7.24 (m, 1H), 6.30 (d, J=8.7 Hz, 1H), 4.65 (dd, J=16.0,4.8 Hz, 1H), 4.54 (dd, J=16.0, 4.8 Hz, 1H), 4.10 (dd, J=15.6,4.8 Hz, 1H), 4.00 (d, J=15.6, 9.3 Hz, 1H).
    • EXAMPLE 35 (11) 4-(2-(Piperidin-1-yl) ethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1898]
    Figure US20030073706A1-20030417-C01900
  • Free Compound: [1899]
  • TLC: Rf 0.10 (methylene chloride:methanol=10:1); [1900]
  • NMR (CDCl[1901] 3): δ 7.90-7.78 (m, 4H), 7.75-7.64 (m, 2H), 7.62-7.51 (m, 2H), 7.42 (bs, 1H), 6.29 (d, J=8.1 Hz, 1H), 3.84 (dd, J=15.0, 1.5 Hz, 1H), 3.75-3.60 (m, 2H), 3.58-3.45 (m, 1H), 2.77-2.60 (m , 2H), 2.55-2.40 (m, 4H), 1.80-1.40 (m, 6H).
  • Hydrochloride: [1902]
  • TLC: Rf 0.30 (ethyl acetate:methanol:triethylamine=8:1.5:0.5); [1903]
  • NMR (DMSO-d[1904] 6): δ 10.25 (br. s, 1H), 9.32 (t, J=5.4 Hz, 1H),8.10 (dd, J=7, 1.4 Hz, 1H), 8.00-7.80 (m, 2H),7.80-7.70 (m, 3H), 7.70-7.55 (m, 2H),6.30 (d, J=8 Hz, 1H), 4.14 (dd, J=15, 8 Hz, 1H ), 3.97 (d, J=15 Hz, 1H), 3.90-3.70 (m, 2H),3.70-3.50 (m, 2H), 3.50-3.10 (m, 3H), 3.10-2.80(m, 2H), 2.00-1.60 (m, 4H), 1.60-1.20 (m, 1H).
  • Methanesulfonic Acid Salt: [1905]
  • TLC: Rf 0.30 (ethyl acetate:methanol:triethylamine=8:1.5:0.5); [1906]
  • NMR (DMSO-d[1907] 6): δ 9.13 (t, J=5 Hz, 1H), 9.00 (br. s, 1H), 8.05 (dd, J=7, 1.4 Hz, 1H), 8.00-7.80 (m, 2H), 7.80-7.70 (m, 3H), 7.70-7.55 (m, 2H), 6.28 (d, J=8.2 Hz, 1H), 4.12 (dd, J=16, 8.2 Hz, 1H), 3.94 (d, J=16 Hz, 1H), 3.90-3.50 (m, 5H), 3.50-3.20 (m, 2H), 3.15-2.90 (m, 2H), 2.00-1.60 (m, 4H), 1.60-1.30 (m, 1H).
    • EXAMPLE 35 (12a) 4-((1S)-1-t-Butoxycarbonyl-2-methylpropyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1908]
    Figure US20030073706A1-20030417-C01901
  • TLC: Rf 0.34 (hexane:ethyl acetate=1:1); [1909]
  • NMR (CDCl[1910] 3): δ 7.99 (dd, J=7.5, 0.9 Hz, 1H), 7.87-7.84 (m, 3H), 7.75 (t, J=7.5 Hz, 1H), 7.72-7.67 (m, 1H), 7.60-7.55 (m, 2H), 6.80 (d, J=8.8 Hz, 1H), 6.25 (d, J=8.7 Hz, 1H), 4.67 (dd, J=8.8, 3.9 Hz, 1H), 3.80 (d-like, J=15.0 Hz, 1H), 3.65 (dd, J=15.0, 8.7 Hz, 1H), 2.47-2.41 (m, 1H), 1.54 (s, 9H), 1.12 (d, J=7.0 Hz, 3H), 1.06 (d, J=7.0 Hz, 3H).
  • (The determination of the absolute configuration of the carbon atom to which phenylsulfonyl is bonded is not performed, but this compound is a single isolated one.) [1911]
    • EXAMPLE 35 (12b) 4-((1S)-1-t-Butoxycarbonyl-2-methypropyl) carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1912]
    Figure US20030073706A1-20030417-C01902
  • TLC: Rf 0.34 (hexane:ethyl acetate=1:1); [1913]
  • NMR (CDCl[1914] 3): δ 7.98 (d, J=7.8 Hz, 0.5H), 7.91-7.80 (m, 3.5H), 7.76-7.67 (m, 2H), 7.60-7.55 (m, 2H), 6.92 (d, J=8.1 Hz, 0.5H), 6.84 (d, J=8.7 Hz, 0.5H), 6.25 (dd, J=9.3, 1.5 Hz, 0.5H), 6.18 (dd, J=9.3, 1.5 Hz, 0.5H), 4.66 (dd, J=8.7, 3.9 Hz, 0.5H), 4.62 (dd, J=8.1, 5.3 Hz, 0.5H), 3.87 (dd, J=15.0, 1.5 Hz, 0.5H), 3.80 (dd, J=15.0, 1.5 Hz, 0.5H), 3.67 (dd, J=15.0, 9.3 Hz, O.SH), 2.41-2.36 (m, 0.5H), 2.33-2.24 (m, 0.5H), 1.54 (s, 4.5H), 1.46 (s, 4.5H), 1.11 (d, J=6.9 Hz, 1.5H), 1.07 (d, J=6.9 Hz, 1.5H), 1.06 (d, J=6.9 Hz, 1.5H), 1.05 (d, J=6.9 Hz, 1.5H).
    • EXAMPLE 35 (13) 4-(2-Fluorophenylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1915]
    Figure US20030073706A1-20030417-C01903
  • TLC: Rf 0.60 (chloroform:methanol=9:1); [1916]
  • NMR (DMSO-d[1917] 6): δ 9.35 (t, J=7Hz, 1H), 8.05 (d, J=8Hz, 1H), 7.95 (d, J=8Hz, 1H), 7.85 (t, J=8 Hz, 1H), 7.80-7.50 (m, 6H), 7.40-7.10 (m, 3H), 6.25 (d, J=10 Hz, 1H), 4.60 (dd, J=16 Hz and 7Hz, 1H),4.45 (dd, J=16 Hz and 7Hz, 1H),4.10 (dd, J=16Hz and 10 Hz, 1H), 4.00 (d, J=16 Hz, 1H).
    • EXAMPLE 35 (14) 4-(3-Fluorophenylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1918]
    Figure US20030073706A1-20030417-C01904
  • TLC: Rf 0.60 (chloroform:methanol=9:1); [1919]
  • NMR (DMSO-d[1920] 6): δ 9.40 (t, J=7 Hz, 1H), 8.05 (d, J=8 Hz, 1H), 7.95 (d, J=8 Hz, 1H), 7.85 (t, J=8 Hz, 1H), 7.80-7.70 (m, 3H), 7.70-7.55 (m, 2H), 7.45-7.20 (m, 3H), 7.05 (m, 1H), 6.25 (d, J=10 Hz, 1H), 4.55 (d, J=7 Hz, 2H), 4.10 (dd, J=16 Hz and 10 Hz, 1H), 3.97 (dd, J=16 Hz, 1H).
    • EXAMPLE 35 (15) 4-(3-Methylphenylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1921]
    Figure US20030073706A1-20030417-C01905
  • TLC: Rf 0.69 (chloroform:methanol=9:1); [1922]
  • NMR (DMSO-d[1923] 6): δ 9.31 (t, J=6.0 Hz, 1H), 8.06 (d, J=7.6 Hz, 1H), 7.96 (d, J=7.6 Hz, 1H), 7.85 (t, J=7.6 Hz, 1H), 7.80-7.70 (m, 3H), 7.70-7.55 (m, 2H), 7.30-7.15 (m, 3H), 7.15-7.00 (m, 1H), 6.31 (dd, J=8.6 Hz and 2.0 Hz, 1H), 4.48 (m, 2H), 4.10 (dd, J=15 Hz and 8.6 Hz, 1H), 3.98 (dd, J=15 Hz and 2.0 Hz, 1H), 2.27 (s, 3H).
    • EXAMPLE 35 (16) 4-(2-Methoxyphenylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1924]
    Figure US20030073706A1-20030417-C01906
  • TLC: Rf 0.70 (chloroform:methanol=9:1); [1925]
  • NMR (DMSO-d[1926] 6): δ 9.15 (t-like, J=6 Hz, 1H), 8.08 (d, J=7.5 Hz, 1H), 7.95 (d, J 7.5 Hz,1H), 7.85 (t, J=7.5 Hz,1H), 7.80-7.70 (m, 3H), 7.70-7.55 (m, 2H), 7.50-7-35 (m, 1H), 7.35-7.20 (m, 1H), 7.10-6.80 (m, 2H), 6.28 (d, J=8 Hz, 1H), 4.57 (dd, J=16 Hz and 6 Hz, 1H), 4.35 (dd, J=16 Hz and 6 Hz, 1H), 4.10 (dd, J=15.5 Hz and 8 Hz, 1H), 4.00 (d, J=15.5 Hz, 1H), 3.85 (s, 3H).
    • EXAMPLE 35 (17) 4-(2,3-Dimethoxyphenylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1927]
    Figure US20030073706A1-20030417-C01907
  • TLC: Rf 0.52 (chloroform:methanol=9:1); [1928]
  • NMR (DMSO-d[1929] 6): δ 9.22 (t, J=5.5 Hz, 1H), 8.05 (d, J=7.0 Hz, 1H), 7.95 (d, J=7.0 Hz, 1H), 7.85 (t, J=7.0 Hz, 1H), 7.80-7.70 (m, 3H), 7.70-7.57 (m, 2H), 7.15-6.90 (m, 3H), 6.29 (dd, J=8.5 Hz and 2.0 Hz, 1H), 4.62 (dd, J=15.0 Hz and 5.5 Hz, 1H), 4.38 (dd, J=15.0 Hz and 5.5 Hz, 1H), 4.11 (dd, J=15.5 Hz and 8.5 Hz, 1H), 3.99 (dd, J=15.5 Hz and 2.0 Hz, 1H), 3.82 (s, 6H).
    • EXAMPLE 35 (18) 4-(3,4-Dimethoxyphenylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1930]
    Figure US20030073706A1-20030417-C01908
  • TLC: Rf 0.48 (chloroform:methanol=9:1); [1931]
  • NMR (DMSO-d[1932] 6): δ 9.27 (t, J=6.0 Hz, 1H), 8.04 (d, J=7.5 Hz, 1H), 7.95 (d, J=7.5 Hz, 1H), 7.85 (t, J=7.5 Hz, 1H), 7.80-7.70 (m, 3H), 7.70-7.57 (m, 2H), 7.44 (s, 1H), 7.00-6.85 (m, 2H), 6.31 (dd, J=8.6 Hz and 1.4 Hz, 1H), 4.45 (m, 2H), 4.11 (dd, J=15.0 Hz and 8.6 Hz, 1H), 3.99 (dd, J=15.0 Hz and 1.4 Hz, 1H), 3.73 (s, 3H), 3.72 (s, 3H).
    • EXAMPLE 35(19) 4-(2,5-Difluorophenylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1933]
    Figure US20030073706A1-20030417-C01909
  • TLC: Rf 0.59 (chloroform:methanol=9:1); [1934]
  • NMR (DMSO-d[1935] 6): δ 9.41 (t, J=5.8Hz, 1H), 8.09 (dd, J=7.6Hz and 1.5 Hz, 1H), 7.98 (dd, J=7.6 Hz and 1.5 Hz, 1H), 7.87 (t, J=7.6 Hz,1H), 7.80-7.70 (m, 3H), 7.70-7.57 (m, 2H), 7.50-7.35 (m, 1H), 7.35-7.07 (m, 2H), 6.26 (dd, J=15 Hz and 8.4 Hz,1H), 4.54 (d, J=5.8 Hz, 2H), 4.10 (dd, J=15 Hz and 8.4 Hz, 1H), 3.97 (dd, J=15 Hz and 2.0 Hz,1H).
    • EXAMPLE 35 (20) 4-(3,4,5-Trimethoxyphenylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1—dioxidebenzo[b]thiophene
  • [1936]
    Figure US20030073706A1-20030417-C01910
  • TLC: Rf 0.58 (chloroform:methanol=9:1); [1937]
  • NMR (DMSO-d[1938] 6): δ 9.31 (m, 1H), 8.06 (d, J=7.6 Hz, 1H), 7.95 (d, J=7.6 Hz, 1H), 7.85 (t, J=7.6 Hz, 1H),7.80-7.70 (m, 3H), 7.70-7.55 (m, 2H), 6.79 (s, 2H), 6.32 (d, J=8.4 Hz, 1H), 4.61 (dd, J=15.2 Hz and 6.6 Hz, 1H), 4.37 (dd, J=15.2 Hz and 4.6 Hz, 1H), 4.12 (dd, J=15 Hz and 8.4 Hz, 1H), 3.99(d, J=15 Hz, 1H), 3.73 (s, 6H), 3.61 (s, 3H).
    • EXAMPLE 35 (21) 4-(Benzimidazol-2-ylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1939]
    Figure US20030073706A1-20030417-C01911
  • TLC: Rf 0.27 (chloroform:methanol=9:1); [1940]
  • NMR (DMSO-d[1941] 6): δ 12.23 (broad-s, 1H), 9.48 (m, 1H), 8.17 (d, J=7 Hz, 1H), 8.00-7.80 (m, 2H), 7.80-7.70 (m, 3H), 7.70-7.45 (m, 4H), 7.20-7.10 (m, 2H), 6.29 (d, J=8 Hz, 1H), 4.89 (dd, J=16 Hz and 6 Hz, 1H), 4.51 (dd, J=16 Hz and 5 Hz, 1H), 4.13 (dd, J=15 Hz and 8 Hz, 1H), 3.99 (d, J=15 Hz, 1H).
    • EXAMPLE 35 (22) 4-(3,5-Difluorophenylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1942]
    Figure US20030073706A1-20030417-C01912
  • TLC: Rf 0.63 (chloroform:methanol=9:1); [1943]
  • NMR (DMSO-d[1944] 6): δ 9.44 (t, J=5.6 Hz, 1H), 8.11 (d, J=7.4 Hz, 1H), 7.98 (d, J=7.4 Hz,1H), 7.88 (t, J=7.4 Hz,1H), 7.80-7.70 (m, 3H), 7.70-7.55 (m, 2H), 7.30-7.00 (m, 3H), 6.29 (dd, J=8.5 Hz and 2 Hz, 1H), 4.55 (m, 2H), 4.11 (dd, J=15 Hz and 8.5 Hz, 1H), 3.98 (dd, J=15 Hz and 2 Hz,1H).
    • EXAMPLE 35 (23) 4-(N-Benzyl-N-methylcarbamoyl)-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1945]
    Figure US20030073706A1-20030417-C01913
  • NMR (CDCl[1946] 3): δ 8.00-7.25 (m, 13H), 6.00-5.90 (m, 1H), 5.19 (d, J=15 Hz) and 5.03 (d, J=18 Hz, total 1H), 4.49 (d, J=15 Hz) and 4.40 (d, J=18 Hz, total 1H), 3.75 (dd, J=2 Hz and 15 Hz, 1H), 3.63 (dd, J=8.5 Hz and 15 Hz, 1H), 3.18 and 3.12 (each s, total 3H).
    • EXAMPLE 35 (24) 4-(4-Nitrophenylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1947]
    Figure US20030073706A1-20030417-C01914
  • TLC: Rf 0.50 (chloroform:methanol=9:1); [1948]
  • NMR (DMSO-d[1949] 6): δ 9.52 (m, 1H), 8.30-7.55 (m, 13H), 6.27 (d, J=6.4 Hz, 1H), 4.65 (m, 2H), 4.10 (dd, J=15.5 Hz and 6.4 Hz, 1H), 3.97 (d, J=15.5 Hz, 1H).
    • EXAMPLE 35 (25) 5-(2-Hydroxyethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1950]
    Figure US20030073706A1-20030417-C01915
  • TLC: Rf 0.39 (ethyl acetate:methanol=95:5); [1951]
  • NMR (DMSO-d[1952] 6): δ 8.79 (t, J=5.7 Hz, 1H), 8.18 (brs,1H), 8.14 (d, J=8.1 Hz,1H), 7.91 (d, J=8.1 Hz,1H), 7.82-7.75 (m, 3H), 7.68-7.58 (m, 2H), 5.83 (dd, J=9.4 Hz, 8.0 Hz, 1H), 4.77 (t, J=5.7 Hz, 1H), 4.03 (dd, J=15.0 Hz, 9.6 Hz, 1H), 3.84 (dd, J=15.0 Hz, 3.0 Hz, 1H), 3.54 (q, J=5.7 Hz, 2H), 3.36 (q, J=5.7 Hz, 2H).
    • EXAMPLE 35 (26) 5-(Pyridin-3-ylmethyl)carbamoyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1953]
    Figure US20030073706A1-20030417-C01916
  • Free Compound: [1954]
  • TLC: Rf 0.32 (ethyl acetate:methanol=9:1); [1955]
  • NMR (CDCl[1956] 3): δ 8.59-8.56 (m, 2H), 8.04 (d, J=8.5 Hz, 1H), 7.74-7.68 (m, 3H), 7.58-7.53 (m, 1H), 7.47-7.31 (m, 5H), 5.16 (d, J=8.5 Hz, 1H), 4.68 (dd, J=15.0, 6.0 Hz, 1H), 4.59 (dd, J=15.0, 6.0 Hz, 1H), 4.11 (d, J=15.0 Hz, 1H), 3.77 (dd, J=15.0, 8.5 Hz, 1H), 3.67 (s, 3H).
  • Hydrochloride: [1957]
  • TLC: Rf 0.32 (ethyl acetate:methanol=9:1); [1958]
  • NMR (DMSO-d[1959] 6): δ 9.37 (t, J=5.5 Hz, 1H), 8.90 (s, 1H), 8.84 (d, J=5.5 Hz, 1H), 8.49 (d, J=8.0 Hz, 1H), 8.02 (dd, J=8.0, 5.5 Hz, 1H), 7.85-7.75 (m, 4H), 7.67-7.56 (m, 3H), 5.70 (d, J=9.0 Hz, 1H), 4.72-4.60 (m, 2H), 4.15 (d, J=15.0 Hz, 1H), 4.02 (dd, J=15.0, 9.0 Hz, 1H), 3.56 (s, 3H).
    • EXAMPLE 35 (27) 5-(2-Dimethylaminoethyl)carbamoyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1960]
    Figure US20030073706A1-20030417-C01917
  • Free Compound: [1961]
  • TLC: Rf 0.24 (ethyl acetate:methanol:triethylamine=8:1:1); [1962]
  • NMR (CDCl[1963] 3): δ 8.00 (d, J=8.0 Hz, 1H), 7.76-7.73 (m, 2H), 7.67-7.61 (m, 1H), 7.51-7.41 (m, 3H), 7.32 (bt, J=5.0 Hz, 1H), 5.23 (t, J=9.0 Hz, 1H), 4.19 (d, J=15.0 Hz, 1H), 3.81 (dd, J=15.0, 9.0 Hz, 1H), 3.77 (s, 3H), 3.64-3.42 (m, 2H), 2.51 (t, J=6.0 Hz, 1H), 2.28 (s, 6H).
  • Hydrochloride: [1964]
  • TLC: Rf 0.24 (ethyl acetate:methanol:triethylamine=8:1:1); [1965]
  • NMR (DMSO-d[1966] 6): δ 10.47 (br, 1H), 8.90 (t, J=5.5 Hz, 1H), 7.86-7.76 (m, 4H), 7.69-7.64 (m, 2H), 7.56 (d, J=8.0 Hz, 1H), 5.69 (d, J=8.5 Hz, 1H), 4.13 (d, J=15.0 Hz, 1H), 4.00 (d, J=15.0, 8.5 Hz, 1H), 3.65-3.60 (m, 2H), 3.63 (s, 3H), 3.25 (t, J=6.0 Hz, 2H), 2.82 (s, 6H).
    • EXAMPLE 35 (28) 5-Dimethylcarbamoyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1967]
    Figure US20030073706A1-20030417-C01918
  • TLC: Rf 0.35 (ethyl acetate); [1968]
  • NMR (DMSO-d[1969] 6): δ 7.83 (d, J=8.0 Hz, 2H), 7.44 (t, J=7.5 Hz, 1H), 7.63 (dd, J=8.0 Hz, 7.5 Hz, 2H), 7.49 (d, J=8.0 Hz,1H), 7.46 (d, J=7.5 Hz,1H), 5.63 (d, J=8.5 Hz, 1H), 4.13 (d, J=14.5 Hz, 1H), 4.02 (dd, J=14.5 Hz, 8.5 Hz, 1H), 3.59 (s, 3H), 3.01 (s, 3H), 2.78 (s, 3H).
    • EXAMPLE 35 (29) 5-(2,3,4,5,6,7-Hexahydro-1H-azepin-1-yl)carbonyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1970]
    Figure US20030073706A1-20030417-C01919
  • TLC: Rf 0.21 (ethyl acetate:hexane=2:1); [1971]
  • NMR (DMSO-d[1972] 6): δ 7.87-7.70 (m, 3H), 7.70-7.60 (m, 2H), 7.60-7.53 (m, 2H),5.67 (d, J=8.7 Hz, 1H), 4.26 (d, J=15.0 Hz, 1H), 4.05 (dd, J=15.0, 8.7 Hz, 1H), 3.70-3.54 (m, 2H), 3.48 (s, 3H), 3.20-3.15 (m, 2H),1.85-1.40 (m, 8H).
    • EXAMPLE 35 (30) 5-(2,3-Dihydroindol-1-yl)carbonyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1973]
    Figure US20030073706A1-20030417-C01920
  • TLC: Rf 0.54 (ethyl acetate:hexane=2:1); [1974]
  • NMR (DMSO-d[1975] 6): δ 8.13 (d, J=7.8 Hz, 1H), 7.87 (d, J=7.5 Hz, 1H), 7.83-7.70 (m, 2H), 7.70-7.56 (m, 2H), 7.66 (t, J=7.8 Hz, 2H), 7.31 (d, J=7.5 Hz,1H), 7.25 (t, J=7.5 Hz, 1H), 7.12 (t, J=7.5 Hz, 1H), 5.72 (d, J=8.7 Hz, 1H), 4.39-3.97 (m, 2H), 3.76 (dd, J=18.6, 8.7 Hz, 1H), 3.70-3.50 (m, 1H), 3.57 (s, 3H), 3.21-3.08 (m, 2H).
    • EXAMPLE 35 (31) 5-(4-(2-Chlorophenyl)piperazin-1-yl)carbonyl-4-methoxy-3-phenyisulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1976]
    Figure US20030073706A1-20030417-C01921
  • TLC: Rf 0.78 (methylene chloride:methanol=10:1); [1977]
  • NMR (CDCl[1978] 3+DMSO-d6): δ 7.94-7.86 (m, 1H), 7.77-7.66 (m, 2H), 7.64-7.50 (m, 4H), 7.44-7.16 (m, 2H), 7.10699 (m, 2H),5.38-5.27 (m, 1H), 4.26-4.00 (m, 2H), 3.95 and 3.78 (each s, total 3H), 3.90-3.65 (m, 2H),3.50-2.80 (m, 6H).
    • EXAMPLE 35 (32) 5-(4-(2-(2-Trifluoromethylphenyl)ethyl)piperazin-1-yl)carbonyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1979]
    Figure US20030073706A1-20030417-C01922
  • TLC: Rf 0.51 (methylene chloride:methanol=10:1); [1980]
  • NMR (CDCl[1981] 3): δ 7.93-7.86 (m, 1H), 7.74-7.43 (m, 7H), 7.40-7.30 (m, 3H), 5.31-5.20 (m, 1H), 4.24-3.64 (m, 7H), 3.34-3.10 (m, 2H), 3.06-2.90 (m, 2H), 2.70-2.30 (m, 6H).
    • EXAMPLE 35 (33) 4-(Pyridin-3-ylcarbonyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1982]
    Figure US20030073706A1-20030417-C01923
  • Free Compound: [1983]
  • TLC: Rf 0.38 (ethyl acetate:methanol=9:1); [1984]
  • NMR (DMSO-d[1985] 6): δ 9.31 (t, J=6.0 Hz, 1H), 9.05 (d, J=1.5 Hz, 1H), 8.72 (dd, J 5.0, 1.5 Hz, 1H), 8.23 (dt, J=8.0, 1.5 Hz. 1H); 7.87-7.63 (m, 8H), 7.52 (dd, J=8.0, 5.0 Hz, 1H), 6.05 (d, J=8.5 Hz, 1H), 5.01 (dd, J=16.0, 6.0 Hz, 1H), 4.78 (dd, J=16.0, 6.0 Hz, 1H), 4.02 (dd, J=15.3, 8.5 Hz, 1H), 3.86 (d, J=15.3 Hz, 1H).
  • Hydrochloride: [1986]
  • TLC: Rf 0.38 (ethyl acetate:methanol=9:1); [1987]
  • NMR (DMSO-d[1988] 6): δ 9.63-9.59 (m, 1H), 9.20 (s, 1H), 8.86 (d, J=5.0 Hz, 1H), 8.57-8.54 (m, 1H), 7.87-7.63 (m, 9H), 6.11 (d, J=8.5 Hz, 1H), 5.02 (dd, J=15.8, 5.7 Hz, 1H), -4.80 (dd, J=15.8, 5.7 Hz, 1H), 4.00 (dd, J=15.5, 8.5 Hz, 1H), 3.86 (d, J=15.5 Hz, 1H).
    • EXAMPLE 35 (34) 4-(3-Pyrrol-1-yl)propyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1989]
    Figure US20030073706A1-20030417-C01924
  • TLC: Rf 0.20 (ethyl acetate:hexane=1:1); [1990]
  • NMR (CDCl[1991] 3): δ 7.75-7.35 (m, 6H), 7.24 (d, J=8 Hz, 1H), 6.93 (d, J=8 Hz, 1H), 6.68 (t, J=2 Hz, 2H), 6.15 (t, J=2 Hz, 2H), 5.21 (d, J=9 Hz, 1H), 4.53-4.00 (m, 2H), 4.10 (d, J=15 Hz, 1H), 4.00-3.65 (m, 2H), 3.73 (dd, J=9, 15 Hz, 1H), 2.19 (quint, J=5 Hz, 2H).
    • EXAMPLE 35 (35) 4-(Quinolin-2-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1992]
    Figure US20030073706A1-20030417-C01925
  • Free Compound: [1993]
  • TLC: Rf 0.21 (benzene:ethyl acetate=2:1); [1994]
  • NMR (CDCl[1995] 3): δ 8.42 (d, J=9 Hz, 1H), 8.03 (d, J=8 Hz, 2H), 7.90-7.20 (m, 11H), 5.80 (d, J=8 Hz, 1H), 5.31 (d, J=13 Hz, 1H), 5.09 (d, J=13 Hz, 1H), 4.24 (d, J=15 Hz, 1H), 4.02 (dd, J=8, 15 Hz, 1H). hydrochloride:
  • TLC: Rf 0.30 (hexane:ethyl acetate=1:2); [1996]
  • NMR (DMSO-d[1997] 6): δ 8.64 (d, J=8.5 Hz, 1H), 8.20 (d, J=8.5 Hz, 1H), 8.13 (d, J=8.5 Hz, 1H), 7.92 (t-like, J=8.5 Hz, 1H), 7.81-7.65 (m, 5H), 7.48-7.31 (m, 5H), 5.91 (d, J=9.0 Hz, 1H), 5.42 (d, J=13.5 Hz, 1H), 5.21 (d, J=13.5 Hz, 1H), 4.22 (d, J=15.0 Hz, 1H), 4.02 (dd, J=9.0 Hz, 1H).
    • EXAMPLE 35 (36) 4-(2-(Pyrrol-1-yl)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [1998]
    Figure US20030073706A1-20030417-C01926
  • TLC: Rf 0.36 (hexane:ethyl acetate=1:2); [1999]
  • NMR (CDCl[2000] 3+CD3OD): δ 7.85-7.58 (m, 3H), 7.58-7.42 (m, 3H), 7.28 (d, J=8 Hz, 1H), 6.92 (d, J=8 Hz, 1H), 6.74 (t, J=2 Hz, 2H), 6.18 (t, J=2 Hz, 2H), 5.16 (d, J=9 Hz, 1H), 4.30-4.05 (m, 5H), 3.73 (dd, J=9,15 Hz, 1H).
    • EXAMPLE 35 (37) 4-(2-(4-Methylthiazol-5-yl)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride
  • [2001]
    Figure US20030073706A1-20030417-C01927
  • TLC: Rf 0.25 (ethyl acetate); [2002]
  • NMR (CD[2003] 3OD): δ 9.88 (s, 1H), 7.80-7.40 (m, 6H), 7.26 (d, J=8 Hz, 1H), 7.25 (d, J=8Hz, 1H), 5.48 (d, J=9 Hz, 1H), 4.42-4.18 (m, 2H), 4.08 (d, J=15 Hz, 1H), 3.92 (dd, J=9,15 Hz, 1H), 3. 55-3.15 (m, 2H), 2.60 (s, 3H).
    • EXAMPLE 35 (38) 4-(3-(Pyridin-4-yl)propyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2004]
    Figure US20030073706A1-20030417-C01928
    • Free Compound:
  • TLC: Rf 0.26 (ethyl acetate:methanol=10:1); [2005]
  • NMR (CDCl[2006] 3): δ 8.53 (dd, J=1, 5 Hz, 2H), 7.78-7.35 (m. 6H), 7.25 (d, J=7 Hz, 1H), 7.17 (d, J=6 Hz, 2H), 6.95 (d, J=8 Hz, 1H), 5.17 (d, J=9 Hz, 1H), 4.14 (d, J=15 Hz, IH), 4.05-3.82 (m , 2H), 3.74 (dd, J=9, 15 Hz, 1H), 2.87 (t, J=6 Hz, 2H), 2.10 (quint, J=6 Hz, 2H).
  • Hydrochloride: [2007]
  • TLC: Rf 0.39 (ethyl acetate:methanol:ammonia water=100:10:1); [2008]
  • NMR (DMSO-d[2009] 6): δ 8.83 (d, J=6 Hz, 2H), 7.90 (d, J=5 Hz, 2H), 7.85-7.52 (m, 6H), 7.34 (d, J=8 Hz, 1H), 7.24 (d, J=8 Hz, 1H), 5.64 (d, J=9 Hz, 1H), 4.18 (d, J=15 Hz, 1H), 4.00 (dd, J=9,15 Hz, 1H), 3.10-2.80 (m, 2H), 2.10-1.60 (m, 2H).
    • EXAMPLE 35 (39) 4-(1-t-Butoxycarbonylpiperidin-3-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2010]
    Figure US20030073706A1-20030417-C01929
  • TLC: Rf 0.23 (hexane:ethyl acetate=1:1); [2011]
  • NMR (CD[2012] 3OD): δ 7.95-7.45 (m, 6H), 7.40-7.05 (m, 2H), 5.53 (d, J=9 Hz, 1H), 4.15 (d, J=15 Hz, 1H), 3.92 (dd, J=9,15 Hz, 1H), 4.05-3.55 (m, 4H), 3.20-2.40 (m, 2H), 2.00-1.20 (m, 5H), 1.47 and 1.44 (each s, 9H).
    • EXAMPLE 35 (40) 4-(2-(Pyrrolidin-1-yl)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2013]
    Figure US20030073706A1-20030417-C01930
    • Free Compound:
  • TLC: Rf 0.17 (chloroform:methanol=10:1); [2014]
  • NMR (CDCl[2015] 3): δ 7.85-7.68 (m, 2H), 7.68-7.35 (m, 4H), 7.28 (d, J=8 Hz, 1H), 6.97 (d, J=8 Hz, 1H), 5.30 (d, J=9 Hz, 1H), 4.23 (d, J=15 Hz, 1H), 4.15-3.95 (m, 1H), 3.95-3.70 (m, 1H), 3.74 (dd, J=9, 15 Hz,1H), 2.78 (t, J=6 Hz, 2H), 2.70-2.45 (m, 4H), 1.95-1.60 (m, 4H).
  • Hydrochloride: [2016]
  • TLC: Rf 0.36 (ethyl acetate:acetic acid:water=3:1:1); [2017]
  • NMR (CDCl[2018] 3+CD3OD): δ 7.98-7.82 (m,2H), 7.80-7.45 (m, 4H), 7.34 (d, J=8 Hz, 1H), 7.26 (d, J=8 Hz, 1H), 6.20-6.05 (m, 1H), 4.75-4.50 (m, 1H), 4.50-4.25 (m, 1H), 4.10-3.85 (m, 2H), 3.85-3.45 (m, 4H), 3.30-2.90 (m, 2H), 2.40-2.00 (m, 4H).
    • EXAMPLE 35 (41) 4-(2-(Piperidin-1-yl) ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2019]
    Figure US20030073706A1-20030417-C01931
  • Free Compound: [2020]
  • TLC: Rf 0.24 (chloroform:methanol=10:1); [2021]
  • NMR (CDCl[2022] 3): δ 7.85-7.67 (m, 2H), 7.67-7.36 (m, 4H), 7.27 (d, J=8 Hz, 1H), 6.97 (d, J=8 Hz, 1H), 5.29 (d, J=9 Hz, 1H), 4.25 (d, J=15 Hz, 1H), 4.18-3.92 (m, 1H), 3.92-3.65 (m, 1H), 3.74 (dd, J=9, 15 Hz, 1H), 2.62 (t, J=6 Hz, 2H), 2.46 (t, J=6 Hz, 4H), 1.90-1.35 (m, 6H).
  • Hydrochloride: [2023]
  • TLC: Rf 0.40 (ethyl acetate:acetic acid:water=3:1:1); [2024]
  • NMR (CDCl[2025] 3+CD3OD): δ 7.95-7.75 (m, 2H), 7.75-7.45 (m, 4H), 7.32 (d, J=8 Hz, 1H), 7.30 (d, J=8 Hz, 1H), 6.05-5.85 (m, 1H), 4.75-4.38 (m,2H), 3.95-3.42 (m, 6H), 3.15-2.85 (m, 2H), 2.35-1.35 (m, 6H).
    • EXAMPLE 35 (42) 4-(2-(2-Acetyloxyethoxy)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2026]
    Figure US20030073706A1-20030417-C01932
  • TLC: Rf 0.17 (ethyl acetate:hexane=2:1); [2027]
  • NMR (CDCl[2028] 3): δ 7.82-7.70 (m, 2H), 7.65-7.35 (m, 4H), 7.27 (d, J=8 Hz, 1H), 7.00 (d, J=8 Hz, 1H), 5.30 (d, J=9 Hz, 1H), 4.32-4.05 (m, 4H), 4.05-3.88 (m, 1H), 3.84-3.75 (m, 5H), 2.05 (s, 3H).
    • EXAMPLE 35 (43) 4-(2-(4-Benzylpiperazin-1-yl)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2029]
    Figure US20030073706A1-20030417-C01933
  • Free Compound: [2030]
  • TLC: Rf 0.42 (chloroform:methanol=5:1); [2031]
  • NMR (CDCl[2032] 3): δ 7.80-7.68 (m, 2H), 7.68-7.37 (m, 4H), 7.37-7.18 (m, 6H), 6.96 (d, J=8 Hz, 1H), 5.27 (d, J=9 Hz, 1H), 4.22 (d, J=15 Hz, 1H), 4.15-3.94 (m, 1H), 3.94-3.70 (m, 1H), 3.72 (dd , J=9, 15 Hz, 1H), 3.52 (s, 2H), 2.68 (t, J=6 Hz, 2H), 2.63-2.35 (m, 8H).
  • 2hydrochloride: [2033]
  • TLC: Rf 0.28 (ethyl acetate:acetic acid:water=3:1:1); [2034]
  • NMR (CD[2035] 3OD): δ 7.907-7.22 (m, 13H), 6.13-6.00 (m, 1H), 4.68-4.35 (m, 2H), 4.46 (S, 2H), 4.10-3.40 (m, 12H).
    • EXAMPLE 35 (44) 4-Diethylcarbamoylmethyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2036]
    Figure US20030073706A1-20030417-C01934
  • TLC: Rf 0.40 (ethyl acetate); [2037]
  • NMR (CDCl[2038] 3): δ 7.83-7.77 (m, 2H), 7.68-7.59 (m, 1H), 7.56-7.45 (m, 3H), 7.32 (d, J=7.6 Hz, 1H), 7.01 (d, J=7.6 Hz, 1H), 5.44 (d, J=8.8Hz, 1H), 4.59 (d, J=14.5 Hz, 1H), 4.51 (d, J=14.5 Hz, 1H), 4.15 (d, J=15.0 Hz, 1H), 3.74 (dd, J=15.0, 8.8 Hz, 1H), 3.39 (q, J=7.0 Hz, 2H), 3.30 (q, J=7.0 Hz, 2H), 1.22 (t, J=7.0 Hz, 3H), 1.14 (t, J=7.0 Hz, 3H).
    • EXAMPLE 35 (45) 4-Cyanomethyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2039]
    Figure US20030073706A1-20030417-C01935
  • TLC: Rf 0.27 (hexane:ethyl acetate=1:2); [2040]
  • NMR (DMSO-d[2041] 6): δ 7.82-7.72 (m, 4H), 7.68-7.60 (m, 2H), 7.50 (d, J=8.0 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 5.60 (dd, J=9.0, 1.2 Hz, 1H), 5.04 (d, J=16.0 Hz, 1H), 4.90 (d, J=16.0 Hz, 1H), 4.20 (dd, J=15.2, 1.2 Hz, 1H), 4.00 (dd, J=15.2, 9.0 Hz, 1H).
    • EXAMPLE 35 (46) 5-(Pyridin-3-yloxy) methyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2042]
    Figure US20030073706A1-20030417-C01936
  • Free Compound: [2043]
  • TLC: Rf 0.27 (ethyl acetate); [2044]
  • NMR (CDCl[2045] 3): δ 8.37-8.36 (m, 1H), 8.31-8.29 (m, 1H), 7.76-7.71 (m, 3H), 7.66-7.61 (m, 1H), 7.49-7.43 (m, 3H), 7.27-7.25 (m, 2H), 5.25 (dd, J=9.5,1.0 Hz, 1H), 5.16 (d, J=12.5 Hz, 1H), 5.12 (d, J=12.5 Hz, 1H), 4.15 (dd, J=15.0,1.0 Hz, 1H), 3.90 (s, 3H), 3.81 (dd, J=15.0, 9.5 Hz, 1H)
  • Hydrochloride: [2046]
  • TLC: Rf 0.27 (ethyl acetate); [2047]
  • NMR (DMSO-d[2048] 6): δ 8.76 (d, J=2.5 Hz, 1H), 8.52 (d, J=5.0 Hz, 1H), 8.15 (dd, J=8.5, 2.5 Hz, 1H), 7.93-7.74 (m, 5H), 7.65-7.60 (m, 3H), 5.78 (d, J=8.5 Hz, 1H), 5.35 (s, 2H), 4.17 (d, J=15.0 Hz, 1H), 4.06 (dd, J=15.0, 8.5 Hz, 1H), 3.69 (s, 3H).
    • EXAMPLE 35 (47) 5-(2-(t-Butoxycarbonyl amino)ethyl)oxy-4-nitro-3-phenylsufonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2049]
    Figure US20030073706A1-20030417-C01937
  • TLC: Rf 0.34 (hexane:ethyl acetate=1:2); [2050]
  • NMR (CDCl[2051] 3): δ 7.86-7.70 (m, 4H), 7.63-7.54 (m, 2H), 7.41 (d, J=8.8 Hz, 1H), 5.69 (dd, J=9.0, 1.8 Hz, 1H), 5.07 (br, 1H), 4.38-4.22 (m, 2H), 3.90 (dd, J=15.0, 1.8 Hz, 1H), 3.75 (dd, J=15.0, 9.0 Hz, 1H), 3.68-3.52 (m, 2H), 1.46 (s, 9H).
    • EXAMPLE 35 (48) 5-((2E)-3-Ethoxycarbonyl-2-propenyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2052]
    Figure US20030073706A1-20030417-C01938
  • TLC: Rf 0.41 (hexane:ethyl acetate=1:1); [2053]
  • NMR (CDCl[2054] 3): δ 5 7.72-7.65 (m, 3H), 7.62-7.46 (m, 4H), 7.15 (dd, J=8.7,2.1 Hz,1H), 7.08 (dt, J=15.6, 4.2 Hz, 1H), 6.20 (dt, J=15.6, 2.1 Hz, 1H), 5.01 (dd, J=8.7, 4.8 Hz, 1H), 4.87-4.81 (m, 2H), 4.24 (q, J=7.2 Hz, 2H), 3.77 (dd, J=14.7,4.8 Hz, 1H), 3.70 (dd, J=14.7, 8.7 Hz, 1H), 1.31 (t, J=7.2 Hz, 3H).
    • EXAMPLE 35 (49) 4-(2,4-Dimethoxyphenylmethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2055]
    Figure US20030073706A1-20030417-C01939
  • Free Compound: [2056]
  • TLC: Rf 0.35 (ethyl acetate); [2057]
  • NMR (CDCl[2058] 3): δ 7.69 (dd, J=6.9, 1.5 Hz, 1H), 7.64-7.50 (m, 5H), 7.46-7.41 (m, 2H), 7.01 (d, J=8.0 Hz, 1H), 6.45 (d, J=2.5 Hz,1H), 6.43 (dd, J=8.0,2.5 Hz,1H), 6.05 (dd, J=9.3, 1.2 Hz, 1H), 4.51 (d, J=14.1 Hz, 1H), 3.91 (d, J=14.1 Hz, 1H), 3.85 (dd, J=15.0, 1.2 Hz, 1H), 3.81 (s, 3H), 3.78 (s, 3H), 3.73 (d, J=13.0 Hz, 1H), 3.66 (d, J=13.0 Hz, 1H), 3.65 (dd, J=15.0, 9.3 Hz, 1H).
  • Hydrochloride: [2059]
  • TLC: Rf 0.35 (ethyl acetate); [2060]
  • NMR (DMSO-d[2061] 6): δ 9.40 (br, 2H), 8.20-8.11 (m, 1H), 7.86-7.59 (m, 7H), 7.42 (d, J 8.4 Hz, 1H), 6.61-6.56 (m, 2H), 6.09 (dd, J=6.8, 3.0 Hz, 1H), 4.65 (d, J=13.8 Hz, 1H), 4.38 (d, J=13.8 Hz, 1H), 4.22-4.06 (m, 2H), 3.88-3.85 (m, 2H), 3.80 (s, 3H), 3.79 (s, 3H).
    • EXAMPLE 35 (50) 4-(Pyridin-3-ylmethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene 2hydrochloride
  • [2062]
    Figure US20030073706A1-20030417-C01940
  • TLC: Rf 0.44 (chloroform:methanol=9:1); [2063]
  • NMR (CD[2064] 3OD): δ 9.21 (s, 1H), 8.95 (d, J=5.6 Hz, 1H), 8.92-8.84 (m, 1H), 8.22 (dd, J=6.6, 2.2 Hz, 1H), 8.16 (dd, J=8.0, 5.6 Hz, 1H), 7.93-7.74 (m, 5H), 7.68-7.58 (m, 2H), 6.20 (dd, J=8.6, 1.6 Hz, 1H), 4.96 (d, J=13.2 Hz, 1H), 4.83-4.70 (m, 3H), 3.92 (dd, J=15.4, 8.6 Hz, 1H), 3.77 (dd, J=15.4, 1.6 Hz, 1H).
    • EXAMPLE 35 (51) 4-(2-Dimethylaminoethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene-2hydrochloride
  • [2065]
    Figure US20030073706A1-20030417-C01941
  • TLC: Rf 0.51 (chloroform:methanol:triethylamine=9:1:1); [2066]
  • NMR (DMSO-d[2067] 6): δ 10.85-10.50 (br, 1H), 10.10-9.75 (br, 1H), 9.72-9.40 (br, 1H), 8.22 (dd, J=5.4, 3.0 Hz, 1H), 7.90-7.85 (m, 2H), 7.82-7.75 (m, 3H), 7.67-7.59 (m, 2H), 6.47 (t like, J=1.5 Hz, 1H), 4.72 (brd, J=12.0 Hz, 1H), 4.51 (brd, J=12.0 Hz, 1H), 3.91-3.84 (m, 2H), 3.70-3.30 (m, 4H), 2.85 (s, 6H).
    • EXAMPLE 35 (52) 4-(N,N-Bis(2-hydroxyethyl)amino)methyl-3-phenylsulfonyl-2,3-dlhydro-1,1-dioxidebenzo[b]thiophene.hydrochloride
  • [2068]
    Figure US20030073706A1-20030417-C01942
  • TLC: Rf 0.53 (chloroform:methanol=9:1); [2069]
  • NMR (DMSO-d[2070] 6): δ 10.15-9.90 (br, 1H), 8.24 (d, J=6.6 Hz, 1H), 7.95-7.72 (m, 5H), 7.69-7.58 (m, 2H), 6.16 (d, J=8.7 Hz, 1H), 5.80-5.10 (br, 2H), 5.11 (brd, J=13.8 Hz, 1H), 4.70 (brd, J=13.8 Hz, 1H), 4.02 (dd, J=15.0, 8.7 Hz, 1H), 3.94-3.70 (m, 4H), 3.82 (d, J=15.0 Hz, 1H), 3.47-3.18 (m, 3H), 3.12-2.92 (m, 1H).
    • EXAMPLE 35 (53) 4-(2-(2-Hydroxyethoxy)ethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride
  • [2071]
    Figure US20030073706A1-20030417-C01943
  • TLC: Rf 0.46 (methylene chloride:methanol=9:1); [2072]
  • NMR (DMSO-d[2073] 6): δ 9.40-9.10 (br, 2H), 8.16 (dd, J=6.3, 2.4 Hz, 1H), 7.91-7.75 (m, 5H), 7.68-7.59 (m, 2H), 6.29 (dd, J=7.5, 2.4 Hz, 1H), 4.90-4.30 (br, 1H), 4.75-4.63 (m, 1H), 4.50-4.35 (m, 1H), 3.90 (dd, J=15 .6, 7.5 Hz, 1H), 3.84 (dd, J=15.6, 2.4 Hz, 1H), 3.74 (t, J=5.1 Hz, 2H), 3.58-3.47 (m, 4H), 3.28-3 15 (m, 2H).
    • EXAMPLE 35 (54) 4-(4-Benzylpiperazin-1-yl)methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2074]
    Figure US20030073706A1-20030417-C01944
  • Free Compound: [2075]
  • TLC: Rf 0.29 (chloroform:methanol=19:1); [2076]
  • NMR (CDCl[2077] 3): δ 7.68-7.57 (m, 4H), 7.56-7.50 (m, 2H), 7.50-7.42 (m, 2H), 7.36-7.20 (m, 5H), 6.33 (d, J=9.0 Hz, 1H), 4.69 (d, J=14.1 Hz, 1H), 3.90 (d, J=15.0 Hz, 1H), 3.72 (dd, J=15.0, 9.0 Hz, 1H), 3.51 (s, 2H), 3.41 (d, J=14.1 Hz,1H), 2.70-2.25 (m, 8H).
  • 2hydrochloride: [2078]
  • TLC: Rf 0.29 (chloroform:methanol=19:1); NMR (DMSO-d[2079] 6): δ 8.30-7.95 (br, 1H), 7.93-7.72 (m, 5H), 7.70-7.55 (m, 4H), 7.50-7.40 (m, 3H), 6.65-6.20 (br, 1H), 5.40-4.20 (br, 4H), 4.50-4.10 (br, 2H), 3.98 (dd, J=15.6, 9.0 Hz, 1H), 3.84 (d, J=15.6 Hz, 1H), 3.70-2.80 (m, 6H).
    • EXAMPLE 35 (55) 4-(4-(Pyridin-2-yl)piperazi n-1-yl)methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2080]
    Figure US20030073706A1-20030417-C01945
  • Free Compound: [2081]
  • TLC: Rf 0.43 (chloroform:methanol 19:1); [2082]
  • NMR (CDCl[2083] 3): δ 8.23-8.16 (m, 1H), 7.71-7.52 (m, 6H), 7.52-7.42 (m, 3H), 6.68-6.62 (m, 2H), 6.30 (d, J=9.0 Hz, 1H), 4.76 (d, J=14.1 Hz, 1H), 3.89 (d, J=15.0 Hz, 1H), 3.73 (dd, J=15.0, 9.0 Hz, 1H), 3.62-3. 45 (m, 4H), 3.49 (d, J=14.1 Hz, 1H), 2.73-2.61 (m, 2H), 2.58-2.44 (m, 2H). 3hydrochloride:
  • TLC: Rf 0.43 (chloroform:methanol=19:1); [2084]
  • NMR (DMSO-d[2085] 6): δ 12.05-11.70 (br, 1H), 8.35 (d, J=6.3 Hz, 1H), 8.15-8.09 (m, 1H), 7.96-7.84 (m, 3H), 7.83-7.75 (m, 3H), 7.68-7.58 (m, 2H), 7.24 (d, J=8.7 Hz,1H), 6.93 (t, J=6.3 Hz, 1H), 6.46 (d, J=8.7 Hz,1H), 4.87 (d, J=13.8 Hz, 1H), 4.62 (d, J=13.8 Hz, 1H), 4.55-4.30 (m, 2H), 4.00 (dd, J=15.0, 8.7 Hz, 1H), 3.83 (d, J=15.0 Hz, 1H), 3.72-3.50 (m, 2H), 3.50-3.15 (m, 4H).
    • EXAMPLE 35 (56) 4-(4-Ethoxycarbonylpiperazin-1-yl) methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2086]
    Figure US20030073706A1-20030417-C01946
  • Free Compound: [2087]
  • TLC: Rf 0.45 (chloroform:methanol 19:1); [2088]
  • NMR (CDCl[2089] 3): δ 7.69-7.52 (m, 6H), 7.51-7.41 (m, 2H), 6.16 (d, J=9.0 Hz, 1H), 4.71 (d, J=14.4 Hz, 1H), 4.15 (q, J=7.2 Hz, 2H), 3.91 (d, J=15.0 Hz, 1H), 3.74 (dd, J=15.0, 9.0 Hz, 1H), 3.54-3.39 (m, 5H), 2.55-2.46 (m, 2H), 2.41-2.29 (m, 2H), 1.27 (t, J=7.2 Hz, 3H).
  • Hydrochloride: [2090]
  • TLC: Rf 0.45 (chloroform:methanol=19:1); [2091]
  • NMR (DMSO-d[2092] 6): δ 11.60-11.30 (br, 1H), 8.40-8.20 (br, 1H), 8.00-7.74 (m, 5H), 7.68-7.58 (m, 2H), 6.31 (brd, J=8.1 Hz, 1H), 4.98-4.70 (m, 1H), 4.70-4.52 (m, 1H), 4.20-3.89 (m, 2H), 4.07 (q, J=7.2 Hz, 2H), 3.82 (d, J=15.3 Hz, 1H), 3.77-3.60 (m, 1H), 3.52-2.90 (m, 6H), 1.18 (t, J=7.2 Hz, 3H).
    • EXAMPLE 35 (57) 4-(4-(2-Hydroxyethyl)piperazin-1-yl)methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2093]
    Figure US20030073706A1-20030417-C01947
  • Free Compound: [2094]
  • TLC: Rf 0.31 (chloroform:methanol=9:1); [2095]
  • NMR (CDCl[2096] 3): δ 7.70-7.50 (m, 6H), 7.50-7.41 (m, 2H), 6.29 (d, J=9.0 Hz, 1H), 4.72 (d, J=14.1 Hz, 1H), 3.91 (d, J=15.0 Hz, 1H), 3.73 (dd, J=15.0, 9.0 Hz, 1H), 3.63 (t, J=5.1 Hz, 2H), 3.43 (d, J=14.1 Hz, 1H), 2.80-2.30 (m, 10H).
  • 2hydrochloride: [2097]
  • TLC. Rf 0.31 (chloroform:methanol=9:1); [2098]
  • NMR (DMSO-d[2099] 6): δ 11.50-10.60 (br, 1H), 8.30-8.00 (br, 1H), 7.88-7.73 (m, 5H), 7.67-7.58 (m, 2H), 6.60-6.30 (br, 1H), 5.80-4.92 (br, 2H), 4.92-4.10 (br, 1H), 3.99 (dd, J=15.0, 8.7 Hz, 1H), 3.86 (d, J=15.0 Hz, 1H), 3.81-3.74 (m, 2H), 3.73-2.80 (m, 10H).
    • EXAMPLE 35 (58) 4-(4-(Pyridin-4-yl)piperazin-1-yl)methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2100]
    Figure US20030073706A1-20030417-C01948
  • free compound: [2101]
  • TLC: Rf 0.36 (chloroform:methanol=9:1); [2102]
  • NMR (DMSO-d[2103] 6): δ 8.14 (d, J=6.6 Hz, 2H), 7.88-7.81 (m, 1H), 7.81-7.74 (m, 3H), 7.74-7.68 (m, 2H), 7.67-7.59 (m, 2H), 6.78 (d, J=6.6 Hz, 2H), 6.21 (d, J=9.0 Hz, 1H), 4.16 (d, J=14.4 Hz, 1H), 4.05 (dd, J=15.0, 9.0 Hz, 1H), 3.86 (d, J=15.0 Hz, 1H), 3.57 (d, J=14.4 Hz, 1H), 3.42-3.18 (m, 4H), 2.43 (t, J=4.8 Hz, 4H). 3hydrochloride:
  • TLC: Rf 0.36 (chloroform:methanol=9:1); [2104]
  • NMR (DMSO-d[2105] 6): δ 14.20-13.80 (br, 1H), 12.30-11.90 (br, 1H), 8.46-8.20 (br, 1H), 8.35 (d, J=6.9 Hz, 2H), 7.98-7.82 (m, 2H), 7.82-7.74 (m, 3H), 7.67-7.57 (m, 2H), 7.25 (d, J=6.9 Hz, 2H), 6.48 (brd, J=8.7 Hz,1H), 5.05-4.75 (m, 1H), 4.75-4.52 (m,1H), 4.52-4.15 (m, 2H), 3.98 (dd, J=15.3, 8.7 Hz, 1H), 3.95-3.55 (m, 6H), 3.84 (d, J=15.3 Hz, 1H).
    • EXAMPLE 35 (59) 4-Benzylaminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2106]
    Figure US20030073706A1-20030417-C01949
  • Free Compound: [2107]
  • TLC: Rf 0.46 (ethyl acetate); [2108]
  • NMR (CDCl[2109] 3): δ 7.74 (dd, J=7.2, 1.5 Hz, 1H), 7.65-7.51 (m, 5H), 7.45-7.40 (m, 2H), 7.36-7.25 (m, 5H), 5.84 (dd, J=9.3, 1.0 Hz, 1H), 4.49 (d, J=14.1 Hz, 1H), 3.98 (d, J 14.1 Hz, 1H), 3.85 (d, J=12.7 Hz, 1H), 3.84 (dd, J=15.0, 1.0 Hz, 1H), 3.77 (d, J=12.7, 1H), 3.65 (dd, J=15.0, 9.3 Hz, 1H).
  • Hydrochloride: [2110]
  • TLC: Rf 0.49 (ethyl acetate:triethylamine=6:0.5); [2111]
  • NMR (DMSO-d[2112] 6): δ 9.87 (brs, 1H), 9.57 (brs, 1H), 8.16 (d, J=6.6 Hz, 1H), 7.90-7.75 (m, 3H), 7.75-7.57 (m, 6H), 7.50-7.41 (m, 3H), 6.33-6.25 (m, 1H), 4.67 (d, J=13.5 Hz, 1H), 4.40 (d, J=13.5 Hz, 1H), 4.30 (s, 2H), 3.93-3.80 (m, 2H).
    • EXAMPLE 35 (60) 4-(1-benzylpiperidin-4-yl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2113]
    Figure US20030073706A1-20030417-C01950
  • Free Compound: [2114]
  • TLC: Rf 0.30 (ethyl acetate:methanol=2:1); [2115]
  • NMR (CDCl[2116] 3): δ 7.70 (dd, J=7.3, 1.3 Hz, 1H), 7.65-7.41 (m, 7H), 7.32-7.24 (m, 5H), 6.09 (dd, J=9.3, 1.0 Hz, 1H), 4.61 (d, J=14.0 Hz, 1H), 3.98 (d, J=14.0 Hz, 1H), 3.87 (dd, J=15.0, 1.0 Hz, 1H), 3.72 (dd, J=15.0, 9.3 Hz, 1H), 3.50 (s, 2H), 2.90-2.81 (m, 2H), 2.58-2.51 (m, 1H), 2.09-1.96 (m, 3H), 1.83-1.79 (m, 1H), 1.52-1.38 (m, 2H).
  • 2hydrochloride: [2117]
  • TLC: Rf 0.30 (ethyl acetate:methanol=2:1); [2118]
  • NMR (CD[2119] 3OD): δ 8.16-8.12 (m, 1H), 7.91-7.74 (m, 5H), 7.65-7.49 (m, 7H), 6.06 (dd, J=8.4, 1.8 Hz, 1H), 4.84-4.68 (m, 2H), 4.36 (br, 2H), 3.90 (dd, J=15.4, 8.4 Hz, 1H), 3.77 (dd, J=15.4, 1.8 Hz, 1H), 3.80-3.60 (m, 3H), 3.30-3.15 (m, 2H), 2.58-2.43 (m, 2H), 2.35-2.13 (m, 2H).
    • EXAMPLE 35 (61) 4-(Morpholin-4-yl)methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2120]
    Figure US20030073706A1-20030417-C01951
  • Free Compound: [2121]
  • TLC: Rf 0.34 (hexane:ethyl acetate=1:2); [2122]
  • NMR (CDCl[2123] 3): δ 7.68-7.51 (m, 6H), 7.48-7.42 (m, 2H), 6.21 (dd, J=9.3, 0.9 Hz, 1H), 4.68 (d, J=14.3 Hz, 1H), 3.91 (dd, J=15.0, 0.9 Hz, 1H), 3.74 (dd, J=15.0, 9.3 Hz, 1H), 3.74-3.64 (m, 4H), 3.45 (d, J=14.3 Hz, 1H), 2.58-2.52 (m, 2H), 2.40-2.33 (m, 2H).
  • Hydrochloride: [2124]
  • TLC: Rf 0.34 (hexane:ethyl acetate=1:2); [2125]
  • NMR (DMSO-d[2126] 6): δ 11.48 (br, 1H), 8.31 (d, J=7.2 Hz, 1H), 7.94-7.79 (m, 5H), 7.68-7.62 (m, 2H), 6.44 (d, J=8.1 Hz, 1H), 4.85-4.79 (m, 1H), 4.62-4.57 (m, 1H), 4.05-3.81 (m, 6H), 3.50-3.13 (m, 4H).
    • EXAMPLE 35 (62) 4-Ethoxycarbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2127]
    Figure US20030073706A1-20030417-C01952
  • TLC: Rf 0.18 (methylene chloride); [2128]
  • NMR (CDCl[2129] 3): δ 8.24 (dd, J=7.8 Hz, 1.5 Hz, 1H), 7.86 (dd, J=7.8 Hz, 1.5 Hz, 1H), 7.75 (t, J=7.8 Hz, 1H), 7.71-7.64 (m, 3H), 7.56-7.47 (m, 2H), 6.19 (dd, J=9.3 Hz, 1.5 Hz, 1H), 4.53-4.40 (m, 2H), 3.94 (dd, J=15.0 Hz, 1.5 Hz, 1H), 3.77 (dd, J=15.0 Hz, 9.3 Hz, 1H), 1.47 (t, J=7.2 Hz, 3H).
    • EXAMPLE 35 (63) 4-Benzyloxycarbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2130]
    Figure US20030073706A1-20030417-C01953
  • TLC: Rf 0.37 (chloroform:ethyl acetate=19:1); [2131]
  • NMR (CDCl[2132] 3): δ 8.26 (dd, J=7.5, 1.2 Hz, 1H), 7.85 (dd, J=7.8, 1.2 Hz, 1H), 7.78-7.70 (m, 1H), 7.69-7.60 (m, 3H), 7.55-7.47 (m, 4H), 7.47-7.35 (m, 3H), 6.13 (dd, J=9.3, 1.2 Hz, 1H), 5.45 (d, J=12.3 Hz, 1H), 5.40 (d, J=12.3 Hz, 1H), 3.91 (dd, J=15.0, 1.2 Hz, 1H), 3.73 (dd, J=15.0, 9.3 Hz, 1H).
    • EXAMPLE 35 (64) 4-(Pyridin-3-yl)-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride
  • [2133]
    Figure US20030073706A1-20030417-C01954
  • TLC: Rf 0.55 (chloroform:methanol=9:1); [2134]
  • NMR (DMSO-d[2135] 6): δ 9.11 (s, 1H), 8.86 (d, J=5.4 Hz, 1H), 8.57 (d, J=5.4 Hz, 1H), 7.99-7.84 (m, 4H), 7.73-7.64 (m, 1H), 7.53-7.43 (m, 2H), 7.42-7.35 (m, 2H), 5.99 (dd, J=7.2, 3.0 Hz, 1H), 4.07 (dd, J=15.3, 7.2 Hz, 1H), 4.01 (dd, J=15.3, 3.0 Hz, 1H).
    • EXAMPLE 35 (65) 6-(Pyridin-3-yl)-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride
  • [2136]
    Figure US20030073706A1-20030417-C01955
  • TLC: Rf 0 60 (chloroform:methanol 9:1); [2137]
  • NMR (DMSO-d[2138] 6): δ 9.29 (d, J=2.1 Hz, 1H), 8.85 (d, J=5.1 Hz, 1H), 8.76 (d, J=7.8 Hz, 1H), 8.37 (s, 1H), 8.29 (dd, J=8.4, 2.1 Hz, 1H), 7.96 (dd, J=8.4, 5.1 Hz, 1H), 7.89-7.75 (m, 4H), 7.71-7.60 (m, 2H), 5.93 (dd, J=9.3, 3.0 Hz, 1H), 4.06 (dd, J=15.0, 9.3 Hz, 1H), 3.85 (dd, J=15.0, 3.0 Hz, 1H).
    • EXAMPLE 35 (66) 4-(4,4-Dimethyl-4,5-dihydroxazol-2-yl)-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2139]
    Figure US20030073706A1-20030417-C01956
  • TLC: Rf 0.22 (ethyl acetate:hexane=1:1); [2140]
  • NMR (CDCl[2141] 3): δ 8.23 (d, J=6.0 Hz, 1H), 7.73-7.67 (m, 2H), 7.67-7.54 (m, 3H), 7.48-7.40 (m, 2H), 6.36 (dd, J=9.0 Hz, 1.8 Hz, 1H), 4.26 (d, J=7.5 Hz, 1H), 4.22 (d, J=7.5 Hz, 1H), 3.89 (dd, J=15.0 Hz, 1.8 Hz, 1H), 3.78 (dd, J=15.0 Hz, 9.0 Hz, 1H), 1.50 (s, 3H), 1.45 (s, 3H).
    • EXAMPLE 35 (67) 6-Bromo-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2142]
    Figure US20030073706A1-20030417-C01957
  • TLC: Rf 0.24 (methylene chloride); [2143]
  • NMR (DMSO-d[2144] 6): δ 8.13 (d, J=2.0 Hz, 1H), 8.02 (dd, J=8.5, 2.0 Hz, 1H), 7.83-7.76 (m, 3H), 7.67-7.60 (m, 3H), 5.79 (dd, J=9.5, 3.0 Hz, 1H), 4.05 (dd, J=15.5, 9.5 Hz, 1H), 3.85 (dd, J=15.5, 3.0 Hz, 1H).
    • EXAMPLE 35 (68) 6-Amino-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2145]
    Figure US20030073706A1-20030417-C01958
  • TLC: Rf 0.34 (hexane:ethyl acetate=1:2); [2146]
  • NMR (DMSO-d[2147] 6): δ 7.79-7.71 (m, 3H), 7.64-7.56 (m, 2H), 7.28 (d, J=8.5 Hz, 1H), 6.89 (dd, J=8.5, 2.2 Hz, 1H), 6.68 (d, J=2.2 Hz, 1H), 6.00 (s, 2H), 5.47 (dd, J=9.2,3.0 Hz, 1H), 3.89 (dd, J=15.2, 9.2 Hz, 1H), 3.64 (dd, J=15.2, 3.0 Hz, 1H).
    • EXAMPLES 36˜36 (3)
  • By the same procedure as described in Example 28 using carboxylic acid corresponding to 4-carboxy-1,1-dioxidebenzo[b]thiophene and amine corresponding to (pyridin-3-ylmethyl)amine, the following compounds of the present invention were obtained. [2148]
    • EXAMPLE 36 5-Methylcarbamoyl-4-methoxy-1,1-dioxidebenzo[b]thiophene
  • [2149]
    Figure US20030073706A1-20030417-C01959
  • TLC: Rf 0.38 (methanol:ethyl acetate=5:95); [2150]
  • NMR(DMSO-d[2151] 6): δ 8.40 (d, J=4.8 Hz, 1H), 7.75 (d, J=7.0 Hz, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.44 (d, J=7.0 Hz, 1H), 3.89 (s, 3H), 2.78 (d, J=4.8 Hz, 3H).
    • EXAMPLE 36 (1) 4-Dimethylcarbamoyl-1,1-dioxidebenzo[b]thiophene
  • [2152]
    Figure US20030073706A1-20030417-C01960
  • TLC: Rf 0.34 (methanol:ethyl acetate=5:95); [2153]
  • NMR(CDCl[2154] 3): δ 7.76 (dd, J=7.0 Hz, 1.4 Hz, 1H), 7.58 (t, J=7.0 Hz, 1H), 7.51 (dd, J=7.0 Hz, 1.4 Hz, 1H), 7.33 (d, J=6.8 Hz, 1H), 6.78 (d, J=6.8 Hz, 1H), 3.17 (s, 3H), 3.00 (s, 3H).
    • EXAMPLE 36 (2) 4-Carbamoyl-1,1-dioxidebenzo[b]thiophene
  • [2155]
    Figure US20030073706A1-20030417-C01961
  • TLC: Rf 0.50 (methanol:ethyl acetate=5:95); [2156]
  • NMR(DMSO-d[2157] 6): δ 8.22 (brs, 1H), 7.96 (d, J=7.2 Hz, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.78 (brs, 1H), 7.67 (t, J=8.0 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.43 (d, J=7.2 Hz, 1H).
    • EXAMPLE 36 (3) 4-(Furan-2-ylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene
  • [2158]
    Figure US20030073706A1-20030417-C01962
  • TLC: Rf 0.36 (ethyl acetate:hexane 1;1); NMR (CDCl[2159] 3+DMSO-d6): δ 7.96 (dd, J=7.2, 0.9 Hz, 1H), 7.81-7.76 (m, 2H), 7.56 (t, J=7.8 Hz, 1H), 7.51 (t, J=5.7 Hz, 1H), 7.40-7.38 (m, 1H), 6.78 (d, J=7.2 Hz, 1H), 6.37-6.30 (m, 2H), 4.62 (d, J=5.7 Hz, 2H).
    • EXAMPLES 37˜37 (6)
  • By the same procedure as described in Example 18 using an alcohol derivative corresponding to the compound prepared in Example 9 (12) and a halogenated compound corresponding to 4-nitrobenzylbromide, or by the same procedure as described in Example 29 using an alcohol derivative corresponding to 4-hydroxy-1,1-dioxidebenzo[b]thiophene and an alcohol derivative corresponding to 1-(3-hydroxypropyl)pyrrole, the following compounds of the present invention were obtained. [2160]
    • EXAMPLE 37 4-(2-(Pyridin-4-yl)ethyl) oxy-1,1-dioxidebenzo[b]thiophene
  • [2161]
    Figure US20030073706A1-20030417-C01963
  • TLC: Rf 0.23 (hexane:ethyl acetate=1:3); [2162]
  • NMR (CDCl[2163] 3): δ 8.56 (d, J=6.0 Hz, 2H), 7.46 (t, J=8.0 Hz, 1H), 7.31 (d, J=7.2 Hz, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.21 (d, J=6.0 Hz, 2H), 7.04 (d, J=8.0 Hz, 1H), 6.60 (d, J=7.2 Hz, 1H), 4.33 (t, J=6.5 Hz, 2H), 3.14 (t, J=6.5 Hz, 2H).
    • EXAMPLE 37 (1) 4-(2-(Pyridin-3-yl)ethyl)oxy-1,1-dioxidebenzo[b]thiophene
  • [2164]
    Figure US20030073706A1-20030417-C01964
  • TLC: Rf 0.38 (ethyl acetate); [2165]
  • NMR(CDCl[2166] 3): δ 8.56 (d, J=1.8 Hz, 1H), 8.52 (dd, J=4.8, 1.8 Hz, 1H), 7.60 (d, J=8.2 Hz, 1H), 7.45 (t, J=7.6 Hz, 1H), 7.35 (d, J=7.6 Hz, 1H), 7.28 (dd, J=7.0 Hz, 1H), 7.26 (d, J=7.6 Hz, 1H), 7.03 (d, J=8.2 Hz, 1H), 6.60 (d, J=7.0 Hz, 1H), 4.30 (t, J=6.4 Hz, 2H), 3.15 (t, J=6.4 Hz, 2H).
    • EXAMPLE 37(2) 4-Ethoxycarbonylmethyloxy-1,1-dioxidebenzo[b]thiophene
  • [2167]
    Figure US20030073706A1-20030417-C01965
  • TLC: Rf 0.38 (hexane:ethyl acetate=1:1); [2168]
  • NMR (CDCl[2169] 3): δ 7.53 (d, J=7.2 Hz, 1H), 7.47 (t, J=8.0 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 6.94 (d, J=8.0 Hz, 1H), 6.65 (d, J=7.2 Hz, 1H), 4.72 (s, 2H), 4.27 (q, J=7.0 Hz, 2H), 1.30 (t, J=7.0 Hz, 3H).
    • EXAMPLE 37 (3) 6-Ethoxycarbonylmethyloxy-1,1-dioxidebenzo[b]thiophene
  • [2170]
    Figure US20030073706A1-20030417-C01966
  • TLC: Rf 0.30 (hexane:ethyl acetate=1:1); [2171]
  • NMR (CDCl[2172] 3): “ 7.28 (d, J=8.4 Hz, 1H), 7.24 (d, J=2.6 Hz,1H), 7.17 (d, J=7.0 Hz, 1H), 7.05 (dd, J=8.4,2.6 Hz, 1H), 6.63 (d, J=7.0 Hz, 1H), 4.68 (s, 2H), 4.29 (q, J=7.0 Hz, 2H), 1.31 (t, J=7.0 Hz, 3H).
    • EXAMPLE 37 (4) 6-Cyanomethyloxy-1,1-dioxidebenzo[b]thiophene
  • [2173]
    Figure US20030073706A1-20030417-C01967
  • TLC: Rf 0.30 (hexane:ethyl acetate=1:1); [2174]
  • NMR (CDCl[2175] 3): δ 7.36 (d, J=8.4Hz,1H), 7.34 (dd, J=2.6,0.8Hz, 1H), 7.20 (dd, J=7.0, 0.8 Hz, 1H), 7.14 (dd, J=8.4, 2.6 Hz, 1H), 6.69 (d, J=7.0 Hz,1H), 4.84 (s, 2H).
    • EXAMPLE 37 (5) 5-Ethoxycarbonylmethyloxy-1,1-dioxidebenzo[b]thiophene
  • [2176]
    Figure US20030073706A1-20030417-C01968
  • TLC: Rf 0.31 (ethyl acetate:hexane=1:1); [2177]
  • NMR (CDCl[2178] 3): δ 7.64 (d, J=8.2 Hz, 1H), 7.15 (d, J=6.8 Hz, 1H), 6.98-6.86 (m,2H), 6.74 (d, J=6.8 Hz, 1H), 4.69 (s, 2H), 4.29 (q, J=7.2 Hz, 2H), 1.31 (t, J=7.2 Hz, 3H).
    • EXAMPLE 37 (6) 7-Ethoxycarbonylmethyloxy-1,1-dioxidebenzo[b]thiophene
  • [2179]
    Figure US20030073706A1-20030417-C01969
  • TLC: Rf 0.28 (ethyl acetate:hexane=1:1); [2180]
  • NMR (CDCl[2181] 3): δ 7.46 (dd, J=8.6 Hz, 7.0 Hz, 1H), 7.14 (d, J=7.0 Hz, 1H), 6.96 (d, J=7.0 Hz,1H), 6.89 (d, J=8.6 Hz,1H), 6.68 (d, J=7.0 Hz,1H), 4.84 (s, 2H), 4.28 (q, J=7.0 Hz, 2H), 1.29 (t, J=7.0 Hz, 3H).
    • EXAMPLES 38˜38 (3)
  • By the same procedure as described in Example 32 using a carboxylic acid derivative corresponding to 4-carboxy-1,1-dioxidebenzo[b]thiophene and a halogenated compound corresponding to bromoethane, the following compounds of the present invention having the following physical data were obtained. [2182]
    • EXAMPLE 38 5-Benzyloxycarbonyl-4-methoxy-1,1-dioxidebenzo[b]thiophene
  • [2183]
    Figure US20030073706A1-20030417-C01970
  • TLC: Rf 0.28 (hexane:ethyl acetate=1:1); [2184]
  • NMR (CDCl[2185] 3): δ 7.98 (d, J=8.0 Hz, 1H), 7.51-7.36 (m, 7H), 6.73 (d, J=7.0 Hz, 1H), 5.38 (s, 2H), 3.87 (s, 3H).
    • EXAMPLE 38 (1) 5-Ethoxycarbonyl-1,1-dioxidebenzo[b]thiophene
  • [2186]
    Figure US20030073706A1-20030417-C01971
  • TLC: Rf 0.43 (hexane:ethyl acetate=1:1); [2187]
  • NMR (CDCl[2188] 3): δ 8.22 (dd, J=8.0, 1.0 Hz, 1H), 8.03 (d, J=1.0 Hz, 1H),7.79 (d, J=8.0 Hz, 1H), 7.15 (d, J=7.0 Hz, 1H), 6.80 (d, J=7.0 Hz, 1H), 4.43 (q , J=7.0 Hz,1H), 1.42 (t, J=7.0 Hz,, 3H).
    • EXAMPLE 38 (2) 7-Methoxycarbonyl-1,1-dioxidebenzo[b]thiophene
  • [2189]
    Figure US20030073706A1-20030417-C01972
  • TLC: Rf 0.15 (hexane:ethyl acetate=2:1); [2190]
  • NMR (CDCl[2191] 3): δ 8.11 (d, J=8 Hz, 1H), 7.66 (t, J=8 Hz, 1H), 7.55 (d, J=8 Hz, 1H), 7.20 (d, J=7 Hz, 1H), 6.77 (d, J=7 Hz, 1H), 4.05 (s, 3H).
    • EXAMPLE 38 (3) 7-Ethoxycarbonyl-1,1-dioxidebenzo[b]thiophene
  • [2192]
    Figure US20030073706A1-20030417-C01973
  • TLC: Rf 0.39 (ethyl acetate:hexane=1:1); [2193]
  • NMR (CDCl[2194] 3): δ 8.13 (dd, J=7.6 Hz, 1.2 Hz, 1H), 7.65 (t, J=7.6 Hz, 1H), 7.52 (dd, J=7.6 Hz, 1.2 Hz, 1H), 7.18 (d, J=6.8 Hz, 1H), 6.76 (d, J=6.8 Hz, 1H), 4.53 (q, J=7.2 Hz, 2H), 1.48 (t, J=7.2 Hz, 1H).
    • EXAMPLE 39 5-t-Butoxycarbonyl-4-methoxy-1,1-dioxidebenzo[b]thiophene
  • [2195]
    Figure US20030073706A1-20030417-C01974
  • A suspension of 5-carboxy-4-methoxy-1,1-dioxidebenzo[b]thiophene (934 mg) in benzene (15 ml) was refluxed. Thereto was added dimethylformamidedi-t-butylacetal (4.02 g) dropwise. The mixture was refluxed for 1 hour. To the reaction mixture water was added. The mixture was extracted by benzene. The extract was washed by a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride sucessively, dried over anhydrous sodium sulfate and concentrated. The residue was purified with column chromatography on silica gel (ethyl acetate:hexane=1:0) to give the compound of the present invention (942 mg) having the following physical data. [2196]
  • TLC: Rf 0.25 (ethyl acetate:hexane=1:4); [2197]
  • NMR (CDCl[2198] 3): δ 7.87 (d, J=7.8 Hz, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.45 (d, J=7.0 Hz, 1H), 6.73 (d, J=7.0 Hz, 1H), 3.95 (s, 3H), 1.62 (s, 9H).
    • EXAMPLE 40 5-((E)-2-(Ethoxycarbonyl)ethenyl)-4-methoxybenzo[b]thiophene
  • [2199]
    Figure US20030073706A1-20030417-C01975
  • To a suspension of 62.5% sodium hydride (920 mg) in anhydrous tetrahydrofuran (40 ml), was added a solution of triethylphosphonoacetate (5.83 g) in anhydrous tetrahydrofuran (20 ml) dropwise. The mixture was stirred for 15 minutes. To the reaction mixture, was added a solution of 5-formyl-4-methoxybenzo[b]thiophene (3.84 g) in anhydrous tetrahydrofuran (20 ml) dropwise. The mixture was stirred at room temperature for 1 hour. To the reaction mixture, was added acetic acid (1.5 ml). The mixture was concentrated. The residue was purified with column chromatography on silica gel (hexane:ethyl acetate=9:1) to give the compound of the present invention (5.17 g) having the following physical data. [2200]
  • TLC: Rf 0.37 (hexane:ethyl acetate=5:1); [2201]
  • NMR (CDCl[2202] 3): δ 8.13 (d, J=16.2 Hz, 1H), 7.62-7.41 (m, 4H), 6.53 (d, J=16.2 Hz, 1H), 4.29 (q, J=7.2 Hz, 2H), 4.00 (s, 3H), 1.36 (t, J=7.2 Hz, 3H).
    • EXAMPLE 41 5-(2-(Ethoxycarbonyl)ethyl)-4-methoxybenzo[b]thiophene
  • [2203]
    Figure US20030073706A1-20030417-C01976
  • To a solution of the compound prepared in Example 40 (5.16 g) in ethanol (100 ml), 10% palladium carbon (200 mg) was added. Under an atmosphere of hydrogen the mixture was stirred at room temperature. The reaction mixture was filtrated through celite, and the filtrate was concentrated. The residue was purified with column chromatography on silica gel (hexane:ethyl acetate=9:1) to give the compound of the present invention (3.23 g) having the following physical data. [2204]
  • TLC: Rf 0.40 (hexane:ethyl acetate=5:1); [2205]
  • NMR (CDCl[2206] 3): δ 6 7.56 (d, J=8.1 Hz, 1H), 7.41 (q, J=5.4 Hz, 2H), 7.20 (d, J=8.1 Hz, 1H), 4.14 (q, J=7.2 Hz, 2H), 3.97 (s, 3H), 3.07 (t, J=8.0 Hz, 2H), 2.66 (t, J=8.0 Hz, 2H), 1.24 (t, J=7.2 Hz, 3H).
    • EXAMPLE 42 5-(2-(Ethoxycarbonyl)ethyl)-4-methoxy-1,1-dioxidebenzo[b]thiophene
  • [2207]
    Figure US20030073706A1-20030417-C01977
  • By the same procedure as described in 3 using the compound prepared in Example 41 instead of the compound prepared in Example 1, the compound of the present invention having the following physical data was obtained (with the proviso that 3-chloroperbenzoic acid was used instead of OXONE® as an oxidizer). [2208]
  • TLC: Rf 0.25 (hexane:ethyl acetate=2:1); [2209]
  • NMR (CDCl[2210] 3): δ 7.45-7.36 (m, 3H), 6.70 (d, J=6.8 Hz, 1H), 4.15 (q, J=7.4 Hz, 2H), 3.92 (s, 3H), 3.01 (t, J=7.6 Hz, 2H), 2.62 (t, J=7.6 Hz, 2H), 1.24 (t, J=7.4 Hz, 3H).
    • EXAMPLE 43 5-(4.4-Dimethyl-4,5-dihydroxazol-2-yl)-1,1-dioxidebenzo[b]thiophene
  • [2211]
    Figure US20030073706A1-20030417-C01978
  • Using the compound which was obtained with using 5-carboxy-1,1-dioxidebenzo[b]thiophene and (2-hydroxy-1,1-dimethylethyl)amine instead of 4-carboxy-1,1-dioxidebenzo[b]thiophene and (pyridin-3-ylmethyl)amine respectively, by the same procedure as described in Example 28, by the same procedure as described in Example 34, the compound of the present invention having the following physical data was obtained. [2212]
  • TLC: Rf 0.39 (ethyl acetate:hexane=1:1); [2213]
  • NMR (CDCl[2214] 3): δ 8.08 (dd, J=8.0 Hz, 1.2 Hz, 1H), 7.98 (d, J=1.2 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.23 (d, J=7.0 Hz, 1H), 6.77 (d, J=7.0 Hz, 1H), 4.16 (s, 2H), 1.40 (s, 6H).
    • EXAMPLES 44˜44 (24)
  • By the same procedure as described in Example 1 using the compounds prepared in Examples 36˜36 (2), Examples 37˜37 (6), Examples 38˜38 (3), Example 39, Example 42, Example 36 (3), Example 43 instead of 1,1-dioxidebenzo[b]thiophene or a corresponding derivative and thiol derivatives corresponding to thiophenol, the following compounds of the present invention were obtained. [2215]
    • EXAMPLE 44 5-Methylcarbamoyl-4-methoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2216]
    Figure US20030073706A1-20030417-C01979
  • TLC: Rf 0.58 (methanol:ethyl acetate 5:95); [2217]
  • NMR (CDCl[2218] 3): δ 8.10 (d, J=5.6 Hz, 1H), 7.56 (d, J=5.6 Hz, 1H), 7.54-7.48 (m, 2H), 7.43-7.35 (m, 3H), 7.17 (brs, 1H), 5.07 (dd, J=4.6 Hz, 1.4 Hz, 1H), 4.04 (s, 3H), 3.72 (dd, J=9.4 Hz, 4.6 Hz, 1H), 3.63 (dd, J=9.4 Hz, 1.4 Hz, 1H), 3.07 (d, J=4.8 Hz, 3H).
    • EXAMPLE 44 (1) 4-Dimethylcarbamoyl-3-phenylthio-2,3-di hydro-1,1-dioxidebenzo[b]thiophene
  • [2219]
    Figure US20030073706A1-20030417-C01980
  • TLC: Rf 0.52 (methanol:ethyl acetate=5:95); [2220]
  • NMR (CDCl[2221] 3): δ 7.78 (dd, J=7.5 Hz, 1.8 Hz, 1H), 7.63-7.51 (m, 4H), 7.43-7.34 (m, 3H), 5.41 (dd, J=7.8 Hz, 1.8 Hz, 1H), 3.74 (dd, J=14.1 Hz, 7.8 Hz, 1H), 3.61 (dd, J=14.1 Hz, 1.8 Hz, 1H), 3.17 (s, 3H), 3.00 (s, 3H).
    • EXAMPLE 44 (2) 4-Carbamoyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2222]
    Figure US20030073706A1-20030417-C01981
  • TLC: Rf 0.49 (methanol:ethyl acetate=5:95); [2223]
  • NMR (DMSO-d[2224] 6): δ 8.19 (brs, 1H), 7.96-7.64 (m, 4H), 7.52-7.30 (m, 5H), 5.87 (d, J=7.4 Hz, 1H), 4.10 (dd, J=14.6 Hz, 7.4 Hz, 1H), 3.61 (d, J=14.6 Hz, 1H).
    • EXAMPLE 44 (3) 4-(2-(Pyridin-4-yl)ethyl)oxy-3-phenylthio-2,3-dihydro-11-dioxidebenzo[b]thiophene
  • [2225]
    Figure US20030073706A1-20030417-C01982
  • TLC: Rf 0.44 (ethyl acetate:methanol=10:1); [2226]
  • NMR (CDCl[2227] 3): δ 8.50 (d, J=6 Hz, 2H), 7.60-7.13 (m, 9H), 7.07 (d, J=8 Hz, 1H), 4.93 (dd, J=2, 7 Hz, 1H), 4.50-4.15 (m, 2H), 3.80-3.50 (m, 2H), 3.15 (t, J=7 Hz, 2H).
    • EXAMPLE 44 (4) 4-(2-(Pyridin-3-yl)ethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2228]
    Figure US20030073706A1-20030417-C01983
  • TLC: Rf 0.38 (ethyl acetate); [2229]
  • NMR (CDCl[2230] 3): δ 8.57 (d, J=1.8 Hz, 1H), 8.48 (dd, J=5.0 Hz, 1.8 Hz, 1H), 7.63 (m, 1H), 7.54-7.32 (m, 7H), 7.19 (dd, J=7.8 Hz, 4.0 Hz, 1H), 7.05 (d, J=8.0 Hz, 1H), 4.97 (dd, J=6.2 Hz, 1.8 Hz, 1H), 4.32 (m, 2H), 3.67 (dd, J=14.2 Hz, 6.2 Hz, 1H), 3.58 (dd, J=14.2 Hz, 1.8 Hz, 1H), 3.16 (t, J=7.2 Hz, 2H).
    • EXAMPLE 44 (5) 4-Ethoxycarbonylmethyloxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2231]
    Figure US20030073706A1-20030417-C01984
  • TLC: Rf 0.45 (hexane:ethyl acetate=1:1); [2232]
  • NMR (CDCl[2233] 3): δ 7.57-7.53 (m, 2H), 7.49 (d, J=8.1 Hz, 1H), 7.38-7.33 (m, 4H), 6.96 (d, J=8.1 Hz, 1H), 5.16 (dd, J=7.0, 1.8 Hz, 1H), 4.71 (s, 2H), 4.28 (q, J=7.2 Hz, 2H), 3.72 (dd, J=14.0, 7.0 Hz, 1H), 3.62 (dd, J=14.0, 1.8 Hz, 1H), 1.30 (t, J=7.2 Hz, 3H).
    • EXAMPLE 44 (6) 6-Ethoxycarbonylmethyloxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2234]
    Figure US20030073706A1-20030417-C01985
  • TLC: Rf 0.54 (hexane:ethyl acetate=1:1); [2235]
  • NMR (CDCl[2236] 3): δ 7.62 (d, J=8.7 Hz, 1H), 7.43-7.40 (m, 2H), 7.35-7.33 (m, 3H), 7.25 (dd, J=8.7, 2.4 Hz, 1H), 7.10 (d, J=2.4 Hz, 1H), 4.91 (t, J=6.8 Hz, 1H), 4.66 (s, 2K), 4.28 (q, J=7.2 Hz, 2H), 3.81 (dd, J=13.7, 6.8 Hz, 1H), 3.52 (dd, J=13.7, 6.8 Hz, 1H), 1.31 (t, J=7.2 Hz, 3H).
    • EXAMPLE 44 (7) 6-Cyanomethyloxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2237]
    Figure US20030073706A1-20030417-C01986
  • TLC: Rf 0.54 (hexane:ethyl acetate=2:1); [2238]
  • NMR (CDCl[2239] 3): δ 7.69 (d, J=8.4 Hz, 1H), 7.44-7.41 (m, 2H), 7.38-7.34 (m, 3H), 7.28 (dd, J=8.4, 2.4 Hz, 1H), 7.24 (d, J=2.4 Hz, 1H), 4.93 (t, J=6.9 Hz, 1H), 4.83 (s, 2H), 3.83 (dd, J=13.7, 6.9 Hz 1H) 3.54 (dd, J=13.7, 6.9 Hz, 1H).
    • EXAMPLE 44 (8) 5-Ethoxycarbonylmethyloxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2240]
    Figure US20030073706A1-20030417-C01987
  • TLC: Rf 0.45 (ethyl acetate:hexane=1:1); [2241]
  • NMR (CDCl[2242] 3): δ 7.64 (d, J=8.6 Hz, 1H), 7.48-7.30 (m, 5H), 7.15 (d, J=2.2 Hz, 1H), 7.06 (dd, J=8.6 Hz, 2.2 Hz, 1H), 4.90 (t, J=7.0Hz, 1H), 4.69 (s, 2H), 4.29 (q, J=7.4Hz, 2H), 3.79 (dd, J=13.6 Hz, 7.0 Hz, 1H), 3.50 (dd, J=13.6 Hz, 7.0 Hz, 1H), 1.32 (t, J=7.4 Hz, 3H).
    • EXAMPLE 44 (9) 7-Ethoxycarbonylmethyloxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2243]
    Figure US20030073706A1-20030417-C01988
  • TLC: Rf 0.43 (ethyl acetate:hexane=1:1); [2244]
  • NMR (CDCl[2245] 3): δ 7.55 (t, J=8.4 Hz, 1H), 7.46-7.27 (m, 6H), 6.82 (d, J=8.4 Hz, 1H), 4.91 (dd, J=7.6 Hz, 6.6 Hz, 1H), 4.80 (s, 2H), 4.26 (q, J=7.2 Hz, 2H), 3.80 (dd, J=13.6 Hz, 7.6 Hz, 1H) 3.54 (dd, J=13.6 Hz, 6.6 Hz, 1H), 1.28 (t, J=7.2 Hz, 3H).
    • EXAMPLE 44 (10) 5-Benzyloxycarbonyl-4-methoxy-3-phenylethio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2246]
    Figure US20030073706A1-20030417-C01989
  • TLC: Rf 0.55 (hexane:ethyl acetate=1:1); [2247]
  • NMR (CDCl[2248] 3): δ 7.99 (d, J=8.0 Hz, 1H), 7.54-7.34 (m, 1H), 5.40 (s, 2H), 5.08 (dd, J=6.0, 2.5 Hz, 1H), 3.97 (s, 3H), 3.69 (dd, J=14.0, 6.0 Hz, 1H), 3.60 (dd, J=14.0, 2.5 Hz, 1H).
    • EXAMPLE 44 (1 1) 5-Ethoxycarbonyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2249]
    Figure US20030073706A1-20030417-C01990
  • TLC: Rf 0.55 (hexane:ethyl acetate=1:1); [2250]
  • NMR (CDCl[2251] 3): δ 8.36 (s, 1H), 8.20 (d, J=8.2 Hz, 1H), 7.78 (d, J=8.2 Hz, 1H), 7.47-7.33 (m, 5H), 4.97 (t, J=7.0 Hz, 1H), 4.44 (q, J=7.0 Hz, 2H), 3.84 (dd, J=13.7, 7.0 Hz, 1H), 3.54 (dd, J=13.7, 7.0 Hz, 1H), 1.43 (t, J=7.0 Hz, 3H).
    • EXAMPLE 44 (12) 7-Methoxycarbonyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2252]
    Figure US20030073706A1-20030417-C01991
  • TLC: Rf 0.39 (ethyl acetate:hexane=1:1); [2253]
  • NMR (CDCl[2254] 3): δ 8.12 (d, J=7.8 Hz, 1H), 7.93 (d, J=7.8 Hz, 1H), 7.72 (t, J=7.8 Hz, 1H), 7.48-7.33 (m, 5H), 4.92 (dd, J=7.6 Hz, 6.8 Hz, 1H), 4.01 (s, 3H), 3.86 (dd, J=13.6 Hz, 7.6 Hz, 1H), 3.56 (dd, J=1 3.6 Hz, 6.8 Hz, 1H).
    • EXAMPLE 44 (13) 7-Ethoxycarbonyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2255]
    Figure US20030073706A1-20030417-C01992
  • TLC: Rf 0.60 (ethyl acetate:hexane=1:1); [2256]
  • NMR (CDCl[2257] 3): δ 8.13 (d, J=7.8 Hz, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.72 (t, J=7.8 Hz, 1H), 7.46-7.38 (m, 2H), 7.38-7.30 (m, 3H), 4.92 (dd, J=7.8 Hz, 6.9 Hz, 1H), 4.48 (q, J=7.2 Hz, 2H), 3.84 (dd, J=13.5 Hz, 7.8 Hz, 1H), 3.55 (dd, J=13.5 Hz, 6.9 Hz, 1H), 1.44 (t, J=7.2 Hz, 3H).
    • EXAMPLE 44 (14) 5-t-Butoxycarbonyl-4-methoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2258]
    Figure US20030073706A1-20030417-C01993
  • TLC: Rf 0.22 (ethyl acetate:hexane 1:4); [2259]
  • NMR (CDCl[2260] 3): δ 7.88 (d, J=8.0 Hz,1H), 7.58-7.49 (m, 2H), 7.46 (d, J=8.0 Hz,1H), 7.43-7.34 (m, 3H), 5.10 (dd, J=6.0 Hz, 2.8 Hz, 1H), 4.08 (s, 3H), 3.70 (dd, J=13.8 Hz, 6.0 Hz, 1H), 3.61 (dd, J=13.8 Hz, 2.8 Hz, 1H), 1.63 (s, 9H).
    • EXAMPLE 44 (15) 5-(2-(Ethoxycarbonyl)ethyl)4-methoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2261]
    Figure US20030073706A1-20030417-C01994
  • TLC: Rf 0.25 (hexane:ethyl acetate=2:1); [2262]
  • NMR (CDCl[2263] 3): δ 7.55-7.50 (m, 2H), 7.44 (s, 2H), 7.43-7.30 (m, 3H), 5.08 (dd, J=6.9, 2.1 Hz, 1H), 4.15 (q, J=7.2 Hz, 2H), 4.05 (s, 3H), 3.68 (dd, J=15.2, 7.2 Hz, 1H), 3.60 (dd, J=15.2, 2.1 Hz, 1H), 3.18-3.00 (m, 2H), 2.66 (t, J=7.8 Hz, 2H), 1.25 (t, J=7.2 Hz, 3H).
    • EXAMPLE 44 (16) 4-(Furan-2-ylmethyl)carbamoyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2264]
    Figure US20030073706A1-20030417-C01995
  • TLC: Rf 0.37 (ethyl acetate:benzene=1:2); [2265]
  • NMR (DMSO-d[2266] 6): δ 9.24 (t, J=5.6 Hz, 1H), 7.93-7.82 (m, 2H), 7.77-7.66 (m, 1H), 7.55-7.51 (m, 1H), 7.47-7.31 (m, 5H), 6.37-6.29 (m, 2H), 5.75 (d, J=7.6 Hz, 1H), 4.46 (d, J=5.6 Hz, 2H), 4.12 (dd, J=14.2 Hz, 7.6 Hz, 1H), 3.62 (d, J=14.2 Hz, 1H).
    • EXAMPLE 44 (17) 5-(4,4-Dimethyl-4,5-dihydroxazol-2-yl)-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2267]
    Figure US20030073706A1-20030417-C01996
  • TLC: Rf 0.50 (ethyl acetate:hexane=1:1); [2268]
  • NMR (CDCl[2269] 3): δ 8.32 (brs, 1H), 8.12 (d, J=8.2 Hz, 1H), 7.75 (d, J=8.2 Hz, 1H), 7.50-7.30 (m, 5H), 4.96 (dd, J=7.2 Hz, 6.6 Hz, 1H), 4.18 (s, 2H), 3.82 (dd, J=13.8 Hz, 7.2 Hz, 1H), 3.54 (dd, J=13.8 Hz, 6.6 Hz, 1H), 1.42 (s, 6H).
    • EXAMPLE 44 (18) 3-Benzylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2270]
    Figure US20030073706A1-20030417-C01997
  • TLC: Rf 0.52 (hexane:ethyl acetate 1:1); [2271]
  • NMR (CDCl[2272] 3): δ 3.42 (dd, J=13.8Hz, 6.3Hz, 1H), 3.69 (dd, J=13.8Hz, 7.8Hz, 1H), 3.78 (d, J=13.7Hz, 1H), 3.86 (d, J=13.7Hz, 1H), 4.53 (t-like, J=7.1Hz, 1H), 7.27-7.33 (m, 5H), 7.46-7.56 (m,1H), 7.59-7.62 (m, 2H), 7.71 (d, J=7.6Hz, 1H).
    • EXAMPLE 44 (19) 3-(3,4-Dichlorophenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2273]
    Figure US20030073706A1-20030417-C01998
  • TLC: Rf 0.57 (hexane:ethyl acetate=1:1); [2274]
  • NMR (CDCl[2275] 3): δ 3.48 (dd, J=13.6Hz, 5.8Hz, 1H), 3.83 (dd, J=13.6Hz, 7.6Hz, 1H), 4.97 (t-like, J=6.8Hz, 1H), 7.23 (dd, J=8.3Hz, 2.2Hz, 1H), 7.41 (d, J=8.3Hz, 1H), 7.51 (d, J=2.2Hz, 1H), 7.54-7.62 (m, 1H), 7.66-7.69 (m, 2H), 7.74 (d, J=76Hz, 1H).
    • EXAMPLE 44 (20) 3-(4-Nitrophenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2276]
    Figure US20030073706A1-20030417-C01999
  • TLC: Rf 0.15 (methylene chloride); NMR (CDCl[2277] 3): δ 3.55 (dd, J=13.8Hz, 6.0Hz, 1H), 3.97 (dd, J=13.8Hz, 7.5Hz, 1H), 5.20 (t-like, J=6.8Hz, 1H), 7.47 (d, J=8.7Hz, 2H), 7.55-7.64 (m, 1H), 7.68-7.70 (m, 2H), 7.79 (d, J=7.6Hz,1H), 8.19 (d, J=8.7Hz, 2H).
    • EXAMPLE 44 (21) 5-Hydroxymethyl-4-methoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2278]
    Figure US20030073706A1-20030417-C02000
  • TLC: Rf 0.64 (ethyl acetate); [2279]
  • NMR (CDCl[2280] 3): δ 7.68 (d, J=7.8 Hz, 1H), 7.55-7.47 (m, 3H), 7.39-7.35 (m, 3H), 5.08 (dd, J=6.6, 2.5 Hz, 1H), 4.84 (d, J=6.0 Hz, 2H), 4.06 (s, 3H), 3.69 (dd, J=13.9, 6.6 Hz, 1H), 3.58 (dd, J=13.9, 2.5 Hz, 1H), 2.15 (t, J=6.0 Hz, 1H).
    • EXAMPLE 44 (22) 4-Hydroxymethyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2281]
    Figure US20030073706A1-20030417-C02001
  • TLC: Rf 0.22 (chloroform:ethyl acetate=4:1); [2282]
  • NMR (CDCl[2283] 3): δ 7.77-7.66 (m, 2H), 7.61 (d, J=7.4 Hz, 1H), 7.57-7.44 (m, 2H), 7.43-7.32 (m, 3H), 5.20 (dd, J=6.8, 2.0 Hz, 1H), 5.03 (s, 2H), 3.72 (dd, J=14.0, 6.8 Hz, 1H), 3.62 (dd, J=14.0, 2.0 Hz, 1H), 2.45-2.15 (br,1H).
    • EXAMPLE 44 (23) 6-Fluoro-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2284]
    Figure US20030073706A1-20030417-C02002
  • TLC: Rf 0.62 (ethyl acetate:hexane=1:4); [2285]
  • NMR (CDCl[2286] 3): δ 7.70 (ddd, J=7.6Hz, 4.4Hz, 0.4Hz,1H), 7.47-7.29 (m, 7H),4.93 (t, J=7.0 Hz, 1H), 3.84 (dd, J=13.8 Hz, 7.0 Hz, 1H), 3.55 (dd, J=13.8 Hz, 7.0 Hz, 1H).
    • EXAMPLE 44 (24) 4-Fluoro-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2287]
    Figure US20030073706A1-20030417-C02003
  • TLC: Rf 0.55 (ethyl acetate:hexane=1:4); [2288]
  • NMR (CDCl[2289] 3): δ 7.64-7.45 (m, 4H), 7.42-7.27 (m, 4H), 5.06 (dd, J=7.4 Hz, 2.8 Hz, 1H), 3.77 (dd, J=14.2 Hz, 7.4 Hz, 1H), 3.63 (dd, J=14.2 Hz, 2.8 Hz, 1H).
    • EXAMPLES 45˜45 (22)
  • Using the compounds prepared in Examples 44˜44 (15) and Examples 44 (18)˜44 (24) instead of the compound prepared in Example 1 by the same procedure as described in Example 3, or by the same reaction using 3-chloroperbenzoic acid instead of OXONE@ as an oxidizer, and if necessary, by converting into a corresponding salt by known methods, the following compounds of the present invention were obtained. [2290]
    • EXAMPLE 45 5-Methylcarbamoyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2291]
    Figure US20030073706A1-20030417-C02004
  • TLC: Rf 0.33 (methanol:ethyl acetate=5:95); NMR (DMSO-d[2292] 6): δ 8.47 (q-like, J=3.4 Hz, 1H), 7.87-7.73 (m, 3H), 7.69-7.60 (m, 3H), 7.50 (d, J=5.4 Hz, 1H), 5.65 (d, J=6.0 Hz, 1H), 4.13 (d, J=10.2 Hz, 1H), 3.98 (dd, J=10.2 Hz, 6.0 Hz, 1H), 3.59 (s, 3H), 2.77 (d, J=3.4 Hz, 3H).
    • EXAMPLE 45 (1) 4-Dimethylcarbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2293]
    Figure US20030073706A1-20030417-C02005
  • TLC: Rf 0.55 (methanol:ethyl acetate=5:95); [2294]
  • NMR (DMSO-d[2295] 6): δ 7.93-7.73 (m, 6H), 7.70-7.62 (m, 2H), 5.86 (d, J=9.3 Hz, 1H), 4.12 (dd, J=15.3 Hz, 9.3 Hz, 1H), 3.91 (d, J=15.3 Hz, 1H), 3.07 (s, 3H), 3.03 (s, 3H).
    • EXAMPLE 45 (2) 4-Carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2296]
    Figure US20030073706A1-20030417-C02006
  • TLC: Rf 0.43 (methanol:ethyl acetate=5:95); [2297]
  • NMR (DMSO-d[2298] 6): δ 8.30 (brs, 1H), 8.03 (d, J=7.8 Hz, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.86-7.72 (m, 5H), 7.68 (brs, 1H), 7.63 (t, J=7.8 Hz, 1H), 6.37 (d, J=9.3 Hz, 1H), 4.08 (dd, J=15.3 Hz, 9.3 Hz, 1H), 3.95 (d, J=15.3 Hz, 1H).
    • EXAMPLE 45 (3) 4-(2-Pyridin-4-yl)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2299]
    Figure US20030073706A1-20030417-C02007
  • Free Compound: [2300]
  • TLC: Rf 0.25 (ethyl acetate:methanol=10:1); [2301]
  • NMR (CDCl[2302] 3): δ 8.58 (d, J=6 Hz, 2H), 7.80-7.35 (m, 6H), 7.35-7.14 (m, 3H), 6.98 (d, J=8 Hz, 1H), 5.12 (d, J=9 Hz, 1H), 4.30-4.05 (m, 3H), 3.70 (dd, J=9, 15 Hz, 1H), 3.25-2.90 (m, 2H).
  • Hydrochloride: [2303]
  • TLC: Rf 0.25 (ethyl acetate:methanol=10:1); [2304]
  • NMR (DMSO-d[2305] 6): δ 8.83 (d, J=6.6 Hz, 2H), 7.96 (d, J=6.6 Hz, 2H), 7.78-7.58 (m, 6H), 7.35-7.30 (m, 2H), 5.40 (d, J=8.5 Hz, 1H), 4.36-4.28 (m, 1H), 4.19-4.12 (m, 1H), 4.11 (d, J=15.0 Hz, 1H),3.98 (dd, J=15.0, 8.5 Hz, 1H), 3.24-3.15 (m, 1H), 3.11-3.01 (m, 1H).
  • Methanesulfonic Acid Salt: [2306]
  • TLC: Rf 0.25 (ethyl acetate:methanol=10:1); [2307]
  • NMR (DMSO-d[2308] 6): δ 8.85 (d, J=6.6 Hz, 2H), 7.98 (d, J=6.6 Hz, 2H), 7.78-7.58 (m, 6H), 7.35-7.30 (m, 2H), 5.39 (d, J=8.5 Hz, 1H), 4.36-4.29 (m, 1H), 4.19-4.13 (m, 1H), 4.11 (d, J=15.0 Hz, 1H), 3.97 (dd, J=15.0, 8.5 Hz,1H), 3.25-3.17 (m, 1H), 3.11-3.02 (m, 1H).
    • EXAMPLE 45 (4) 4-(2-(Pyridin-3-yl)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1,-dioxidebenzo[b]thiophene.
  • [2309]
    Figure US20030073706A1-20030417-C02008
  • Free Compound: [2310]
  • TLC: Rf 013 (ethyl acetate); [2311]
  • NMR (DMSO-d[2312] 6): δ 8.46 (d, J=1.8 Hz, 1H), 8.43 (dd, J=4.8 Hz, 1.8 Hz, 1H), 7.86-7.54 (m, 6H), 7.42-7.30 (m, 4H), 5.43 (d, J=7.4Hz, 1H), 4.26-3.82, (m, 4H), 2.75 (t, J=6.6 Hz, 2H).
  • Hydrochloride: [2313]
  • TLC: Rf 0.13 (ethyl acetate); [2314]
  • NMR (DMSO-d[2315] 6): δ 8.88 (s, 1H), 8.80 (d, J=5.7 Hz, 1H), 8.49 (d, J=7.8 Hz, 1H), 8.04-7.92 (m, 1H), 7.78-7.54 (m, 6H), 7.30 (d, J=7.8 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 5.47 (d, J=7.8 Hz, 1H), 4.34-4.20 (m, 1H), 4.16-3.91 (m, 3H), 3.19-2.94 (m, 2H).
    • EXAMPLE 45 (5) 4-Ethoxycarbonylmethyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2316]
    Figure US20030073706A1-20030417-C02009
  • TLC: Rf 0.17 (hexane:ethyl acetate=1:1); [2317]
  • NMR (CDCl[2318] 3): δ 7.82-7.78 (m, 2H), 7.68-7.60 (m, 1H), 7.58-7.44 (m, 3H), 7.36 (d, J=8.0 Hz, 1H), 6.86 (d, J=8.0 Hz, 1H), 5.38 (d, J=8.5 Hz, 1H), 4.45 (d, J=16.2 Hz, 1H), 4.30 (d, J=16.2 Hz, 1H), 4.25 (q, J=7.0 Hz, 2H), 4.24 (d, J=15.0 Hz, 1H), 3.76 (dd, J=15.0, 8.5 Hz, 1H), 1.30 (t, J=7.0 Hz, 3H).
    • EXAMPLE 45 (6) 6-Ethoxycarbonylmethyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2319]
    Figure US20030073706A1-20030417-C02010
  • TLC: Rf 0.31 (hexane:ethyl acetate=1:1); [2320]
  • NMR (CDCl[2321] 3): δ 7.90 (d, J=8.8 Hz, 1H), 7.71-7.62 (m, 3H), 7.55-7.46 (m, 2H), 7.30 (dd, J=8.8, 2.4 Hz, 1H), 7.02 (d, J=2.4 Hz, 1H), 5.00 (dd, J=7.8, 5.4 Hz, 1H), 4.67 (s, 2H), 4.28 (q, J=7.2 Hz, 2H), 3.80 (dd, J=15.0, 5.4 Hz, 1H), 3.72 (dd, J=15.0, 7.8 Hz, 1H), 1.30 (t, J=7.2 Hz, 3H).
    • EXAMPLE 45 (7) 6-Cyanomethyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2322]
    Figure US20030073706A1-20030417-C02011
  • TLC: Rf 0.32 (hexane:ethyl acetate=2:1); [2323]
  • NMR (DMSO-d[2324] 6): δ 7.81-7.75 (m, 3H), 7.68-7.60 (m, 3H), 7.53 (d, J=2.5 Hz, 1H), 7.48 (dd, J=8.5, 2.5 Hz, 1H), 5.73 (dd, J=9.5, 3.0 Hz, 1H), 5.33 (s, 2H), 4.03 (dd, J=15.0, 9.5 Hz, 1H), 3.81 (dd, J=15.0, 3.0 Hz, 1H).
    • EXAMPLE 45 (8) 5-Ethoxycarbonylmethyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2325]
    Figure US20030073706A1-20030417-C02012
  • TLC: Rf 0.35 (ethyl acetate:hexane=1:1); [2326]
  • NMR (CDCl[2327] 3): δ 7.73-7.61 (m, 3H), 7.58-7.45 (m,3H), 7.44 (d, J=2.2 Hz, 1H), 7.18 (dd, J=8.8 Hz, 2.2 Hz, 1H), 5.00 (t, J=7.0 Hz, 1H), 4.78 (s, 2H), 4.33 (q, J=7.2 Hz, 2H), 3.81-3.65 (m, 2H), 1.35 (t, J=7.2 Hz, 3H).
    • EXAMPLE 45 (9) 7-Ethoxycarbonylmethyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2328]
    Figure US20030073706A1-20030417-C02013
  • TLC: Rf 0.17 (ethyl acetate:hexane=1:1); [2329]
  • NMR (CDCl[2330] 3): δ 7.72-7.47 (m, 7H), 6.91 (d, J=6.9 Hz, 1H), 5.03 (dd, J=8.7 Hz, 5.4 Hz, 1H), 4.76 (s, 2H), 4.24 (q, J=7.2 Hz, 2H), 3.79 (dd, J=14.7 Hz, 5.4 Hz, 1H), 3.73 (dd, J=14.7 Hz, 8 .7 Hz, 1H), 1.27 (t, J=7.2 Hz, 3H).
    • EXAMPLE 45 (10) 5-Benzyloxycarbonyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2331]
    Figure US20030073706A1-20030417-C02014
  • TLC: Rf 0.30 (hexane:ethyl acetate=1:1); [2332]
  • NMR (CDCl[2333] 3): δ 7.90 (d, J=8.0 Hz, 1H), 7.76-7.71 (m, 2H), 7.63-7.55 (m, 1H), 7.47-7.36 (m, 8H), 5.37 (s, 2H), 5.24 (dd, J=9.0, 1.0Hz, 1H), 4.16 (dd, J=15.0, 1.0 Hz, 1H), 3.74 (s, 3H), 3.73 (dd, J=15.0, 9.0 Hz, 1H).
    • EXAMPLE 45 (11) 5-Ethoxycarbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2334]
    Figure US20030073706A1-20030417-C02015
  • TLC: Rf 0.34 (hexane:ethyl acetate=1:1); [2335]
  • NMR (DMSO-d[2336] 6): δ 8.23 (d-like, J=8.0 Hz, 1H), 8.12 (s, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.85-7.78 (m, 3H), 7.69-7.61 (m, 2H), 5.91 (dd, J=9.3, 3.2 Hz, 1H), 4.38 (q, J=7.0 Hz, 2H), 4.10 (dd, J=15.3, 9.3 Hz, 1H), 3.91 (dd, J=15.3, 3.2 Hz; 1H); 1.35 (t, J=7.0 Hz, 3H).
    • EXAMPLE 45 (12) 7-Methoxycarbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2337]
    Figure US20030073706A1-20030417-C02016
  • TLC: Rf 0.16 (ethyl acetate:hexane=1:1); [2338]
  • NMR (CDCl[2339] 3): δ 8.23 (d, J=8.1 Hz, 2H), 7.81 (t, J=8.1 Hz, 1H), 7.72-7.64 (m, 3H), 7.55-7.47 (m, 2H), 5.07 (dd, J=9.3 Hz, 4.8 Hz, 1H), 3.97 (s, 3H), 3.84 (dd, J=14.7 (t, 4.8 Hz, 1H), 3.75 (dd, J=14.7 Hz, 9.3 Hz, 1H).
    • EXAMPLE 45 (13) 7-Ethoxycarbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2340]
    Figure US20030073706A1-20030417-C02017
  • TLC: Rf 0.22 (ethyl acetate:hexane=1:1); [2341]
  • NMR (CDCl[2342] 3): δ 8.25 (d, J=7.8 Hz, 1H), 8.23 (d, J=7.8 Hz, 1H), 7.80 (t, J=7.8 Hz, 1H), 7.73-7.65 (m, 3H), 7.56-7.48 (m, 2H), 5.06 (dd, J=9.3 Hz, 4.8 Hz, 1H), 4.44 (q, J=7.2 Hz, 2H), 3.83 (dd, J=14.7 Hz, 4.8 Hz, 1H), 3.73 (dd, J=14.7 Hz, 9.3 Hz, 1H), 1.40 (t, J=7.2 Hz, 3H).
    • EXAMPLE 45 (14) 5-t-Butoxycarbonyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2343]
    Figure US20030073706A1-20030417-C02018
  • TLC: Rf 0.37 (ethyl acetate:hexane 1:1); [2344]
  • NMR (CDCl[2345] 3): δ 7.80 (d, J=8.1 Hz, 1H), 7.78 (d, J=7.8 Hz, 2H), 7.66 (t, J=7.8 Hz, 1H), 7.51 (t, J=7.8 Hz, 2H), 7.37 (d, J=8.1 Hz, 1H), 5.27 (dd, J=9.3 Hz, 1.2 Hz, 1H), 4.14 (dd, J=15.0 Hz, 1.2 Hz, 1H), 3.86 (s, 3H), 3.74 (dd, J=15.0 Hz, 9.3 Hz, 1H), 1.61 (s, 9H).
    • EXAMPLE 45 (15) 5-(2-Ethoxycarbonylethyl)-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2346]
    Figure US20030073706A1-20030417-C02019
  • TLC: Rf 0.28 (ethyl acetate:hexane=1:1); [2347]
  • NMR (CDCl[2348] 3): δ 7.77-7.70 (m, 2H), 7.61 (t, J=7.5 Hz, 1H), 7.50-7.35 (m, 4H), 5.19 (dd, J=9.3, 1.8 Hz, 1H), 4.23 (dd, J=15.0, 1.8 Hz, 1H), 4.16 (q, J=7.2 Hz, 2H), 3.81 (dd, J=15.0, 9.3 Hz, 1H), 3.80 (s, 3H), 3.00-2.87 (m, 2H), 2.65-2.40 (m, 2H), 1.27 (t, J=7.2 Hz, 3H).
    • EXAMPLE 45 (16) 3-Benzylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2349]
    Figure US20030073706A1-20030417-C02020
  • TLC: Rf 0.39 (hexane:ethyl acetate=1:1); [2350]
  • NMR (CDCl[2351] 3): δ 3.89 (dd, J=15.0 Hz, 9.3 Hz, 1H), 3.98 (d, J=14.0 Hz, 1H), 4.03 (dd, J=15.0 Hz, 3.6 Hz, 1H), 4.31 (d, J=14.0 Hz, 1H), 4.91 (dd, J=9.3, Hz, 3.6 Hz, 1H), 7.21-7.35 (m, 5H), 7.62-7.71 (m, 2H), 7.80-7.90 (m, 2H).
    • EXAMPLE 45 (17) 3-(3,4-Dichlorophenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2352]
    Figure US20030073706A1-20030417-C02021
  • TLC: Rf 0.43 (hexane:ethyl acetate=1:1); [2353]
  • NMR (DMSO-d[2354] 6): δ 7.98 (d, J=2.1 Hz, 1H), 7.75-7.89 (m, 5H), 7.63 (dd, J=8.4, 2.1 Hz, 1H), 5.91 (dd, J=8.0, 4.4 Hz, 1H), 4.04 (dd, J=15.4, 8.0 Hz, 1H), 3.95 (dd, J=15.4, 4.4 Hz,1H).
    • EXAMPLE 45 (18) 3-(4-Nitrophenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2355]
    Figure US20030073706A1-20030417-C02022
  • TLC: Rf 0.33 (hexane:ethyl acetate=1:1); [2356]
  • NMR (DMSO-d[2357] 6): δ 8.41 (d, J=8.8 Hz, 2H), 8.04 (d, J=8.8 Hz, 2H), 7.76-7.85 (m, 4H), 5.97 (dd, J=9.0, 3.2 Hz, 1H), 4.04 (dd, J=15.4, 9.0 Hz, 1H), 3.90 (dd, J=15.4, 3.2 Hz,1H).
    • EXAMPLE 45 (19) 5-Hydroxymethyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2358]
    Figure US20030073706A1-20030417-C02023
  • TLC: Rf 0.51 (ethyl acetate); [2359]
  • NMR (DMSO-d[2360] 6): δ 7.80-7.72 (m, 4H), 7.64-7.51 (m, 3H), 5.66 (dd, J=8.5, 1.5 Hz, 1H), 5.43 (t, J=5.5 Hz, 1H), 4.52 (d, J=5.5 Hz, 1H), 4.13 (dd, J=15.0,8.5Hz, 1H), 4.00 (dd, J=15.0, 1.5 Hz, 1H), 3.58 (s, 3H).
    • EXAMPLE 45 (20) 4-Hydroxymethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2361]
    Figure US20030073706A1-20030417-C02024
  • TLC: Rf 0.54 (chloroform:methanol=9:1); [2362]
  • NMR (CDCl[2363] 3): δ 7.84 (d, J=7.5 Hz, 1H), 7.72-7.63 (m, 2H), 7.62-7.53 (m, 3H), 7.51-7.44 (m, 2H), 5.53 (d, J=9.3 Hz, 1H), 5.08 (d, J=13.5 Hz, 1H), 5.01 (d, J=13.5 Hz, 1H), 3.87 (d, J=15.0 Hz, 1H), 3.75 (dd, J=15.0, 9.3 Hz, 1H), 3.00-1.80 (br, 1H).
    • EXAMPLE 45 (21) 6-Fluoro-3-phenylsuifonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2364]
    Figure US20030073706A1-20030417-C02025
  • TLC: Rf 0.40 (ethyl acetate:hexane=1:1); [2365]
  • NMR (DMSO-d[2366] 6): δ 7.85-7.58 (m, 8H), 5.77 (dd, J=9.6 Hz, 2.7 Hz,1H), 4.07 (dd, J=15.6 Hz, 9.6 Hz, 1H), 3.87 (dd, J=15.6 Hz, 2.7 Hz, 1H).
    • EXAMPLE 45 (22) 4-Fluoro-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2367]
    Figure US20030073706A1-20030417-C02026
  • TLC: Rf 0.29 (ethyl acetate:hexane=1:1); [2368]
  • NMR (DMSO-d[2369] 6): δ 7.83-7.57 (m, 8H), 5.81 (dd, J=9.0 Hz, 1.5 Hz, 1H), 4.09 (dd, J=15.6 Hz, 1.5 Hz, 1H), 3.99 (dd, J=15.6 Hz, 9.0 Hz, 1H).
    • EXAMPLE 46 5-Methoxycarbonyl-4-ethoxybenzo[b]thiophene
  • [2370]
    Figure US20030073706A1-20030417-C02027
  • By the same procedure as described in Example 18 using 5-methoxycarbonyl-4-hydroxybenzo[b]thiophene instead of the compound prepared in Example 9 (12) and ethyl iodide instead of 4-nitrobenzylbromide, the compound of the present invention having the following physical data was obtained. [2371]
  • TLC: Rf 0.44 (hexane:ethyl acetate=4:1); NMR (CDCl[2372] 3): δ 7.82 (d, J=8 Hz, 1H), 7.63 (d, J=8 Hz, 1H), 7.54 (d, J=6 Hz, 1H), 7.43 (d, J=6 Hz, 1H), 4.21 (q, J=7 Hz, 2H), 3.95 (s, 3H), 1.49 (t, J=7 Hz, 3H).
    • EXAMPLE 47 5-Carboxy-4-ethoxybenzo[b]thiophene
  • [2373]
    Figure US20030073706A1-20030417-C02028
  • To the compound prepared in Example 46 (1.11 g), were added methanol (10 ml) and a 2N aqueous solution of sodium hydroxide (5.0 ml). The mixture was refluxed for 30 minutes. The reaction mixture was concentrated. The residue was acidified by addition of 1 N hydrochloric acid. The mixture was extracted by ethyl acetate. The extract was washed by water and a saturated aqueous solution of sodium chloride successively, dried over anhydrous sodium sulfate and concentrated to give the compound of the present invention (1.02 g) having the following physical data. [2374]
  • TLC: Rf 0.06 (hexane:ethyl acetate 4:1); [2375]
  • NMR (CDCl[2376] 3): δ 8.09 (d, J=8 Hz, 1H), 7.75 (d, J=8 Hz, 1H), 7.52 (d, J=6 Hz, 1H), 7.49 (d, J=6 Hz, 1H), 4.44 (q, J=7 Hz, 2H), 1.58 (t, J=7 Hz, 3H).
    • EXAMPLE 48 5-Benzyloxycarbonyl-4-ethoxybenzo[b]thiophene
  • [2377]
    Figure US20030073706A1-20030417-C02029
  • By the same procedure as described in Example 32 using the compound prepared in Example 47 instead of 4-carboxy-1,1-dioxidebenzo[b]thiophene, and benzyl bromide, the compound having the following physical data was obtained. [2378]
  • TLC: Rf 0.46 (hexane:ethyl acetate=4:1); [2379]
  • NMR (CDCl[2380] 3): δ 7.85 (d, J=8 Hz, 1H), 7.62 (d, J=8 Hz, 1H), 7.56-7.26 (m, 7H), 5.40 (s, 2H), 4.15 (q, J=7 Hz, 2H), 1.37 (t, J=7 Hz, 3H).
    • EXAMPLE 49 5-Benzyloxycarbonyl-4-ethoxy-1,1-dioxidebenzo[b]thiophene
  • [2381]
    Figure US20030073706A1-20030417-C02030
  • By the same procedure as described in 3 using the compound prepared in Example 48 instead of the compound prepared in Example 1, the compound having the following physical data was obtained (with the proviso that 3-chloroperbenzoic acid was used instead of OXONE™ as an oxidizer). [2382]
  • TLC: Rf 0.10 (hexane:ethyl acetate=4:1); [2383]
  • NMR (CDCl[2384] 3): δ 7.99 (d, J=8 Hz, 1H), 7.60-7.30 (m, 7H), 6.72 (d, J=7 Hz, 1H), 5.38 (s, 2H) 4.03 (q, J=7 Hz, 2H), 131 (t, J=7 Hz, 3H.
    • EXAMPLES 50˜50 (2)
  • By the same procedure as described in Example 46→Example 47→Example 48→Example 49 using a corresponding halide compound instead of ethyl iodide, the following compounds of the present invention were obtained. [2385]
    • EXAMPLE 50 5-Benzyloxycarbonyl-4-hexyloxy-1,1-dioxidebenzo[b]thiophene
  • [2386]
    Figure US20030073706A1-20030417-C02031
  • TLC: Rf 0.22 (hexane:ethyl acetate=4:1); (s, 2H), 3.93 (t, J=7 Hz, 2H), 7.55-7.30 (m, 7H), 6.72 (d, J=7 Hz, 1H), 5.38 (s, [2387] 2H), 3.93 (t, J=7 Hz, 2H), 1.80-1.45 (m, 2H), 1.45-1.10 (m, 6H), 0.90 (t, J=7 Hz, 3H).
    • EXAMPLE 50 (1) 5-Benzyloxycarbonyl-4-butoxy-1,1-dioxidebenzo[b]thiophene
  • [2388]
    Figure US20030073706A1-20030417-C02032
  • TLC: Rf 0.24 (hexane:ethyl acetate=4:1); [2389]
  • NMR (CDCl[2390] 3): δ 7.98 (d, J=8 Hz, 1H), 7.58-7.38 (m, 7H), 6.72 (d, J=7 Hz, 1H), 5.33 (s, 2H), 3.94 (t, J=7 Hz, 2H), 1.78-1.50 (m, 2H), 1.50-1.20 (m, 2H), 0.92 (t, J=7 Hz, 3H).
    • EXAMPLE 50 (2) 5-Benzyloxycarbonyl-4-octyloxy-1,1-dioxidebenzo[b]thiophene
  • [2391]
    Figure US20030073706A1-20030417-C02033
  • TLC: Rf 0.33 (hexane:ethyl acetate=4:1); [2392]
  • NMR (CDCl[2393] 3): δ 7.97 (d, J=8 Hz, 1H), 7.60-7.25 (m, 7H), 6.72 (d, J=7 Hz, 1H), 5.38 (s, 2H), 3.92 (t, J=7 Hz, 2H), 1.82-1.45 (m, 2H), 1.45-1.05 (m, 10H), 0.89 (t, J=7 Hz, 3H).
    • EXAMPLES 51˜51 (3)
  • By the same procedure as described in Example 27 using the compounds prepared in Example 49 and Examples 50˜50 (2) instead of 5-methyl-1,1-dioxidebenzo[b]thiophene, the following compounds of the present invention were obtained. [2394]
    • EXAMPLE 51 5-Benzyloxycarbonyl-4-ethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2395]
    Figure US20030073706A1-20030417-C02034
  • TLC: Rf 0.41 (chloroform hexane:methanol=5:5:1); [2396]
  • NMR (CDCl[2397] 3): δ 7.90 (d, J=8 Hz, 1H), 7.78-7.66 (m, 2H), 7.64-7.30 (m, 9H), 5.34 (s, 2H), 5.17 (d, J=9 Hz, 1H), 4.30 (dd, J=1, 15 Hz, 1H), 4.10-3.60 (m, 3H), 1.13 (t, J=7 Hz, 3H).
    • EXAMPLE 51 (1) 5-benzyloxycarbonyl-4-hexyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2398]
    Figure US20030073706A1-20030417-C02035
  • TLC: Rf 0.45 (chloroform:hexane:methanol=5:5:1); [2399]
  • NMR (CDCl[2400] 3): δ 7.88 (d, J=8 Hz, 1H), 7.78-7.64 (m, 2H), 7.60-7.28 (m, 9H), 5.34 (s, 2H), 5.15 (d, J=9 Hz, 1H), 4.32 (dd, J=1, 15 Hz, 1H), 4.00-3.46 (m, 3H), 1.75-1.05 (m, 8H), 0.91 (t, J=7 Hz, 3H).
    • EXAMPLE 51 (2) 5-Benzyloxycarbonyl-4-butoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2401]
    Figure US20030073706A1-20030417-C02036
  • TLC: Rf 0.43 (chloroform:hexane:methanol=5:5:1); [2402]
  • NMR (CDCl[2403] 3): δ 7.88 (d, J=8 Hz, 1H), 7.78-7.64 (m, 2H), 7.60-7.28 (m, 9H), 5.34 (s, 2H), 5.15 (d, J=9 Hz, 1H), 4.32 (dd, J=1, 15 Hz, 1H), 4.02-3.48 (m, 3H), 1.70-1.10 (m, 4H), 0.87 (t, J=7 Hz, 3H).
    • EXAMPLE 51 (3) 5-Benzyloxycarbonyl-4-octyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2404]
    Figure US20030073706A1-20030417-C02037
  • TLC: Rf 0.47 (chloroform:hexane:methanol=5:5:1); [2405]
  • NMR (CDCl[2406] 3): δ 7.88 (d, J=8 Hz, 1H), 7.76-7.64 (m, 2H), 7.60-7.26 (m, 9H), 5.34 (s, 2H), 5.15 (d, J=9 Hz, 1H), 4.32 (dd, J=1, 15 Hz, 1H), 4.00-3.46 (m, 3H), 1.75-1.05 (m, 12H), 0.90 (t, J=7 Hz, 3H).
    • EXAMPLE 52 5-Carboxy-4-ethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2407]
    Figure US20030073706A1-20030417-C02038
  • To a solution of the compound prepared in Example 51 (670 mg) in ethyl acetate (50 ml). Thereto was added 10% palladium carbon (220 mg). Under an atmosphere of hydrogen the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through celite. The filtrate was washed by ethyl acetate and concentrated. The residue was dissolved in ethyl acetate under heating and was recrystallized by addition of hexane (5 ml). The crystal was separated by filtration and dried to give the compound of the present invention (471 mg) having the following physical data. [2408]
  • TLC: Rf 0.21 (chloroform:acetic acid=10:1); [2409]
  • NMR (CDCl[2410] 3+acetone-d6): δ 8.02 (d, J=8 Hz, 1H), 7.86-7.72 (m, 2H), 7.72-7.58 (m, 1H), 7.58-7.32 (m, 3H), 5.33 (d, J=9 Hz, 1H), 4.30 (d, J=15 Hz, 1H), 4.24-4.06 (m, 1H), 4.20 (bs, 1H), 4.02-3. 74 (m, 2H), 1.25 (t, J=7 Hz, 3H).
    • EXAMPLES 52 (1)˜52 (3)
  • By the same procedure as described in Example 52 using the compounds prepared in Examples 51 (1)˜51 (3) instead of Example 51, the following compounds were obtained. [2411]
    • EXAMPLE 52 (1) 5-Carboxy-4-hexyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2412]
    Figure US20030073706A1-20030417-C02039
  • TLC: Rf 0.38 (chloroform:acetic acid=10:1); [2413]
  • NMR (CDCl[2414] 3+acetone-d6): δ 8.00 (d, J=8 Hz, 1H), 7.88-7.72 (m, 2H), 7.72-7.56 (m, 1H), 7.56-7.34 (m, 3H), 5.32 (d, J=9 Hz,1H), 4.31 (dd, J=1, 15 Hz, 1H), 4.20 (brs, H), 4.14 (dt, J=7, 9 Hz, 1H), 4.02-3.66 (m, 2H), 1.80-1.45 (m, 2H), 1.45-1.12 (m, 6H), 0.91 (t, J=7 Hz, 3H).
    • EXAMPLE 52 (2) 5-Carboxy-4-butoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2415]
    Figure US20030073706A1-20030417-C02040
  • TLC: Rf 0.34 (chloroform:acetic acid=10:1); [2416]
  • NMR (CDCl[2417] 3+acetone-d6): δ 8.00 (d, J=8 Hz, 1H), 7.86-7.72 (m, 2H), 7.72-7.56 (m, 1H), 7.56-7.34 (m, 3H), 5.32 (d, J=9 Hz,1H), 4.31 (dd, J=1, 15 Hz, 1H), 4.20 (brs, 1H), 4.15 (dt, J=7,9 Hz, 1H), 4.00-3.66 (m, 2H), 1.74-1.48 (m, 2H), 1.48-1.20 (m, 2H), 0.92 (t, J=7 Hz, 3H).
    • EXAMPLE 52 (3) 5-Carboxy-4-octyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2418]
    Figure US20030073706A1-20030417-C02041
  • TLC: Rf 0.40 (chloroform:acetic acid 10:1); [2419]
  • NMR (CDCl[2420] 3+acetone-d6): δ 8.00 (d, J=8 Hz, 1H), 7.84-7.72 (m, 2H), 7.72-7.57 (m, 1H), 7.57-7.34 (m, 3H), 5.33 (d, J=9 Hz, 1H), 4.31 (dd, J=1, 15 Hz, 1H), 4.13 (dt, J=7, 9 Hz, 1H), 4.10 (brs,1 H ), 4.00-3.66 (m, 2H), 1.74-1.43 (m, 2H), 1.43-1.05 (m, 10H), 0.90 (t, J=7 Hz, 3H).
    • EXAMPLES 53˜53 (3)
  • By the same procedure as described in Example 32 using the compounds prepared in Examples 52˜52 (3) instead of 4-hydroxy 1,1-dioxidebenzo[b]thiophene and corresponding alcohol derivatives instead of 1-(3-hydroxypropyl)pyrrole, the following compounds of the present invention were obtained. [2421]
    • EXAMPLE 53 5-Methoxycarbonyl-4-ethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2422]
    Figure US20030073706A1-20030417-C02042
  • TLC: Rf 0.35 (chloroform:hexane:methanol=5:5:1); [2423]
  • NMR (CDCl[2424] 3): δ 6 7.91 (d, J=8 Hz, 1H), 7.84-7.72 (m, 2H), 7.72-7.57 (m, 1H), 7.57-7.32 (m, 3H), 5.21 (d, J=9 Hz,1H), 4.28 (dd, J=1,15 Hz,1H), 4.20-4.00 (m, 1H), 3.93 (s, 3H), 3.95-3.68 (m, 2H), 1.26 (t, J=7 Hz, 3H).
    • EXAMPLE 53 (1) 5-Methoxycarbonyl-4-hexyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2425]
    Figure US20030073706A1-20030417-C02043
  • TLC: Rf 0.42 (chloroform:hexane:methanol=5:5:1); [2426]
  • NMR (CDCl[2427] 3): δ 7.89 (d, J=8 Hz, 1H), 7.82-7.69 (m, 2H), 7.69-7.55 (m, 1H), 7.55-7.30 (m, 3H), 5.19 (d, J=9 Hz, 1H), 4.30 (d, J=15 Hz, 1H), 4.08 (dt, J=7, 9 Hz, 1H), 3.93 (s, 3H), 3.95-3.55 (m, 2H), 1.80-1.46 (m, 2H), 1.46-1.15 (m, 6H), 0.92 (t, J=7 Hz, 3H).
    • EXAMPLE 53 (2) 5-Methoxycarbonyl-4-butoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2428]
    Figure US20030073706A1-20030417-C02044
  • TLC: Rf 0.37 (chloroform:hexane:methanol=5:5:1); [2429]
  • NMR (CDCl[2430] 3): δ 7.89 (d, J=8 Hz, 1H), 7.82-7.68 (m, 2H), 7.68-7.55 (m, 1H), 7.55-7.34 (m, 3H), 5.19 (d, J=9 Hz, 1H), 4.31 (dd, J=1, 15 Hz, 1H), 4.05 (dt, J=7, 9 Hz, 1H), 3.93 (s, 3H), 3.88-3.60 (m, 2H), 1.80-1.50 (m, 2H), 1.50-1.18 (m, 2H), 0.94 (t, J=7 Hz, 3H).
    • EXAMPLE 53 (3) 5-Methoxycarbonyl-4-octyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2431]
    Figure US20030073706A1-20030417-C02045
  • TLC: Rf 0.44 (chloroform:hexane:methanol=5:5:1); [2432]
  • NMR (CDCl[2433] 3): δ 7.89 (d, J=8 Hz, 1H), 7.80-7.69 (m, 2H), 7.69-7.55 (m, 1H), 7.55-7.34 (m, 3H), 5.19 (d, J=9 Hz, 1H), 4.30 (dd, J=1,15 Hz, 1H), 4.06 (dt, J=7, 9 Hz, 1H), 3.93 (s, 3H), 3.90-3.58 (m, 2H), 1.80-1.45 (m, 2H), 1.45-1.10 (m, 10H), 0.90 (t, J=7 Hz, 3H).
    • EXAMPLES 54˜54 (19)
  • By the same procedure as described in Example 28 using the compounds prepared in Examples 52˜52 (3) instead of 4-carboxy-1,1-dioxidebenzo[b]thiophene and amine derivatives corresponding to (pyridin-3-ylmethyl)amine, the following compounds of the present invention were obtained. [2434]
    • EXAMPLE 54 5-(4-(2-(2-Trifluoromethylphenyl)ethyl)piperazin-1-yl) carbonyl-4-ethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2435]
    Figure US20030073706A1-20030417-C02046
  • TLC: Rf 0.73 (chloroform:methanol=5:1); [2436]
  • NMR (CDCl[2437] 3): δ 7.90 (d, J=8 Hz, 1H), 7.78-7.15 (m, 10H), 5.33 and 5.19 (each d, J=9 Hz, total 1H), 4.40-3.50 (m, 6H), 3.40-2.25 (m, 10H), 1.30-1.10 (m, 3H).
    • EXAMPLE 54 (1) 5-(4-(2-Chlorophenyl)piperazin-1-yl)carbonyl-4-ethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2438]
    Figure US20030073706A1-20030417-C02047
  • TLC: Rf 0.75 (chloroform:methanol=5:1); [2439]
  • NMR (CDCl[2440] 3): δ 7.90 (d, J=8 Hz, 1H), 7.80-6.85 (m, 10H), 5.33 and 5.21 (each d, J=9 Hz, total 1H), 4.45-3.55 (m, 6H), 3.50-2.80 (m, 6H), 1.25 (t, J=7 Hz, 3H).
    • EXAMPLE 54 (2) 5-(2-Dimethylaminoethyl)carbamoyl-4-ethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2441]
    Figure US20030073706A1-20030417-C02048
  • TLC: Rf 0.34 (chloroform:methanol 5:1); [2442]
  • NMR (CDCl[2443] 3): δ 8.24 and 8.11 (each d, J=8 Hz, total 1H), 8.00-7.15 (m, 7H), 5.15 (d, J=9 Hz, 1H), 4.50-3.30 (m, 6H), 2.54 (t, J=7 Hz, 2H), 2.32 (s, 6H), 1.45-1.20 (m, 3H).
    • EXAMPLE 54 (3) 5-(2,3,4,5,6,7-Hexahydro-1H-azepin-1-yl)carbonyl-4-ethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2444]
    Figure US20030073706A1-20030417-C02049
  • TLC: Rf 0.19 (ethyl acetate:hexane=2:1); [2445]
  • NMR (CDCl[2446] 3): δ 7.87 (d, J=8 Hz, 1H), 7.80-7.20 (m, 6H), 5.32 and 5.20 (each d, J=9 Hz, total 1H), 4.40-2.90 (m, 8H), 2.10-1.00 (m, 11H).
    • EXAMPLE 54 (4) 5-(2,3-Dihydroindol-1-yl)carbonyl-4-ethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2447]
    Figure US20030073706A1-20030417-C02050
  • TLC: Rf 0.40 (ethyl acetate:hexane=2:1); [2448]
  • NMR (CDCl[2449] 3): δ 8.29 (d, J=8 Hz, 1H), 8.05-6.90 (m, 10H), 5.38-5.10 (m, 1H), 4.50-3.40 (m, 6H), 3.16 (t, J=8 Hz, 2H), 1.40-1.00 (m, 3H).
    • EXAMPLE 54 (5) 5-(4-(2-(2-Trifluoromethylphenyl)ethyl)piperazin-1-yl)carbonyl-4-hexyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2450]
    Figure US20030073706A1-20030417-C02051
  • TLC: Rf 0.57 (chloroform:methanol=10:1); [2451]
  • NMR (CDCl[2452] 3): δ 7.89 (d, J=8 Hz, 1H), 7.76-7.20 (m, 10H), 5.30 and 5.17 (each d, J=9 Hz, total 1H), 4.25 (d, J=15 Hz, 1H), 4.20-3.50 (m, 5H), 3.50-2.80 (m, 4H), 280-2.20 (m, 6H), 1.90-1.05 (m, 8H), 0.90 (t, J=7 Hz, 3H).
    • EXAMPLE 54 (6) 5-(4-(2-Chlorophenyl)piperazin-1-yl)carbonyl-4-hexyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-di oxidebenzo[b]thiophene
  • [2453]
    Figure US20030073706A1-20030417-C02052
  • TLC: Rf 0.66 (chloroform:methanol 10:1); [2454]
  • NMR (DMSO-d[2455] 6): δ 8.31 (s, 1H), 8.00-6.95 (m, 10H), 5.66 (d, J=9 Hz, 1H), 4.32 (d, J=15 Hz, 1H), 4.22-2.70 (m, 11H), 1.60-1.02 (m, 8H), 0.87 (t, J=7 Hz, 3H).
    • EXAMPLE 54 (7) 5-(2-Dimethylaminoethyl)carbamoyl-4-hexyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2456]
    Figure US20030073706A1-20030417-C02053
  • TLC: Rf 0.23 (chloroform:methanol=10:1); [2457]
  • NMR (CDCl[2458] 3): δ 8.21 and 8.07 (each d, J=8 Hz, total 1H), 7.90-7.10 (m, 7H), 5.13 (d, J=9 Hz,1H), 4.32 (d, J=15 Hz, 1H), 4.25-3.35 (m, 5H), 2.56 and 2.57 (each t, J=6 Hz, total 2H), 2.33 (s, 6H), 2.05-1.10 (m, 8H), 0.92 (t, J=7 Hz, 3H).
    • EXAMPLE 54 (8) 5-(2,3,4,5,6,7-Hexahydro-1H-azepin-1-yl)carbonyl-4-hexyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2459]
    Figure US20030073706A1-20030417-C02054
  • TLC: Rf 0.23 (hexane:ethyl acetate 1:1); [2460]
  • NMR (CDCl[2461] 3): δ 7.86 (d, J=8 Hz, 1lH), 7.78-7.20 (m, 6H), 5.30 and 5.18 (each d, J=9 Hz, total 1H), 4.25 (d, J=15 Hz, 1H), 4.35-3.00 (m, 7H), 2.10-1.10 (m, 16H), 0.91 (t, J=7 Hz, 3H).
    • EXAMPLE 54 (9) 5-(2,3-Dihydroindol-1-yl)carbonyl-4-hexyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2462]
    Figure US20030073706A1-20030417-C02055
  • TLC: Rf 0.39 (hexane:ethyl acetate=1:1); [2463]
  • NMR (CDCl[2464] 3) δ 8.29 (d, J=8 Hz, 1H), 8.10-6.80 (m, lIOH), 5.40-5.05 (m, 1H), 4.50-3.35 (m, 6H), 3.16 (t, J=8 Hz, 2H), 1.90-0.95 (m, 8H), 0.95-0.75 (m, 3H).
    • EXAMPLE 54 (10) 5-(4-(2-(2-Trifluoromethylphenyl)ethyl)piperazin-1-yl)carbonyl-4-butoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2465]
    Figure US20030073706A1-20030417-C02056
  • TLC: Rf 0.56 (chloroform:methanol=10:1); [2466]
  • NMR (CDCl[2467] 3): δ7.88 (d, J=8 Hz, 1H), 7.80-7.00 (m, 10H), 5.30 and 5.18 (each d, J=9 Hz, total 1H), 4.40-3.45 (m, 6H), 3.45-2.80 (m, 4H), 2.80-2.15 (m, 6H), 2.00-1.10 (m, 4H), 0.97 and 0.91 (each t, J=7 Hz, total 3H).
    • EXAMPLE 54 (11) 5-(4-(2-Chlorophenyl)piperazin-1-yl)carbonyl-4-butoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2468]
    Figure US20030073706A1-20030417-C02057
  • TLC: Rf 0.65 (chloroform:methanol=10:1); [2469]
  • NMR (CDCl[2470] 3): δ 7.89 (d, J=8 Hz, 1H), 7.80-7.17 (m, 8H), 7.17-6.85 (m, 2H), 5.31 and 5.19 (each d, J=9 Hz, total 1H), 4.40-3.55 (m, 6H), 3.55-2.70 (m, 6H), 2.00-1.15 (m, 4H), 0.99 and 0.94 (each t, J=7 Hz, total 3H).
    • EXAMPLE 54 (12) 5-(2-Dimethylamino ethyl)carbamoyl-4-butoxy-3-phenyl sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2471]
    Figure US20030073706A1-20030417-C02058
  • TLC: Rf 0.21 (chloroform:methanol=10:1); [2472]
  • NMR (CDCl[2473] 3): δ 8.08 (d, J=8 Hz, 1H), 7.85-7.35 (m, 6H), 7.25 (broad peak, 1H), 5.13 (d, J=9 Hz, 1H), 4.32 (d, J=15 Hz, 1H), 4.05-3.66 (m, 3H), 3.66-3.35 (m, 2H), 2.52 (t, J=7 Hz, 2H), 2.3 1 (s, 6H), 1.90-1.15 (m, 4H), 0.96 (t, J=7 Hz, 3H).
    • EXAMPLE 54 (13) 5-(2,3,4,5,6,7-Hexahydro-1H-azepin-1-yl)carbonyl-4-butoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2474]
    Figure US20030073706A1-20030417-C02059
  • TLC: Rf 0.19 (ethyl acetate:hexane=1:1); [2475]
  • NMR (CDCl[2476] 3). δ 7.85 (d, J=8 Hz, 1H), 7.76-7.20 (m, 6H), 5.29 and 5.18 (each d, J=9 Hz, total 1H), 4.25 (d, J=15 Hz, 1H), 4.25-3.60 (m, 4H), 3.60-3.00 (m, 3H), 2.10-1.10 (m, 12H), 0.96 and 0.92 (each t, J=7 Hz, total 3H).
    • EXAMPLE 54 (14) 5-(2,3-Dihydroindol-1-yl)carbonyl-4-butoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2477]
    Figure US20030073706A1-20030417-C02060
  • TLC: Rf 0.31 (ethyl acetate:hexane=1:1); [2478]
  • NMR (CDCl[2479] 3): δ 8.29 (d, J=8 Hz, 1H), 8.05-7.42 (m, 6H), 7.42-6.95 (m, 4H), 5.36-5.06 (m, 1H), 4.50-3.40 (m, 6H), 3.16 (t, J=7 Hz), 1.90-1.05 (m, 4H), 0.81 (t, J=7 Hz, 3H).
    • EXAMPLE 54 (15) 5-(4-(2-(2-Trifluoromethylphenyl)ethyl)piperazin-1-yl)carbonyl-4octyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2480]
    Figure US20030073706A1-20030417-C02061
  • TLC: Rf 0.66 (chloroform:methanol=10:1); [2481]
  • NMR (CDCl[2482] 3): δ 7.89 (d, J=8 Hz, 1H), 7.80-7.20 (m, 10H), 5.30 and 5.17 (each d, J=9 Hz, total 1H), 4.25 (d, J=15 Hz, 1H), 4.30-3.55 (m, 5H), 3.55-2.80 (m, 4H), 2.80-2.25 (m, 6H), 1.90-1.05 (m, 12H), 0.88 (t, J=7 Hz, 3H).
    • EXAMPLE 54 (16)
  • 5-(4-(2-Chlorophenyl)piperazin-1-yl)carbonyl-4-octyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene [2483]
    Figure US20030073706A1-20030417-C02062
  • TLC: Rf 0.74 (chloroform:methanol 10:1); [2484]
  • NMR (CDCl[2485] 3): δ 7.89 (d, J=8 Hz, 1H), 7.82-6.85 (m, 10H), 5.31 and 5.19 (each d, J=9 Hz, total 1H), 4.38-2.70 (m, 12H), 1.90-1.05 (m, 12H), 0.89 (t, J=7 Hz, 3H).
    • EXAMPLE 54 (17) 5-(2-Dimethylaminoethyl)carbamoyl-4-octyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2486]
    Figure US20030073706A1-20030417-C02063
  • TLC: Rf 0.34 (chloroform:methanol=10:1); [2487]
  • NMR (CDCl[2488] 3): δ 7.99 (d, J=8 Hz, 1H), 7.92-7.10 (m, 7H), 5.30-5.00 (m, 1H), 4.40-3.45 (m, 6H), 2.70 (t, J=6 Hz, 2H), 2.46 (s, 6H), 1.95-1.05 (m, 12H), 0.90 (t, J=7 Hz, 3H).
    • EXAMPLE 54 (18) 5-(2,3,4,5,6,7-Hexahydro-1H-azepin-1-yl)carbonyl-4-octyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2489]
    Figure US20030073706A1-20030417-C02064
  • TLC: Rf 0.26 (hexane:ethyl acetate 1:1); [2490]
  • NMR (CDCl[2491] 3): δ 7.85 (d, J=8 Hz, 1H), 7.88-7.15 (m, 6H), 5.29 and 5.18 (each d, J=9 Hz, total 1H), 4.40-3.00 (m, 8H), 2.10-1.05 (m, 20H), 0.90 (t, J=7 Hz, 3H).
    • EXAMPLE 54 (19) 5-(2,3-Dihydroindol-1-yl)carbonyl-4-octyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2492]
    Figure US20030073706A1-20030417-C02065
  • TLC: Rf 0.43 (hexane:ethyl acetate=1:1); [2493]
  • NMR (CDCl[2494] 3): δ 8.29 (d, J=8 Hz, 1H), 8.10-6.80 (m, 10H), 5.40-5.05 (m, 1H), 4.60-3.40 (m, 6H), 3.16 (t, J=8 Hz, 2H), 1.90-1.00 (m, 12H), 0.85 (t, J=7 Hz, 3H).
    • EXAMPLE 55 5-Hydroxy-4-formylbenzo[b]thiophene
  • [2495]
    Figure US20030073706A1-20030417-C02066
  • To a solution of 5-hydroxybenzo[b]thiophene (3.0 g) in methylene chloride (60 ml), were added at 0° C. dichloromethyl methyl ether (4.52 ml) and titanium tetrachloride (5.48 ml) dropwise. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured onto ice-water. The mixture was extracted by ethyl acetate. The extract was washed by a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The residue was purified with column chromatography on silica gel (methylene chloride) to give the compound of the present invention (1.50 g) having the following physical data. [2496]
  • TLC: Rf 0.69 (hexane:ethyl acetate=2:1); [2497]
  • NMR (CDCl[2498] 3): δ 11.97 (s, 1H), 10.55 (s, 1H), 7.96 (d, J=8.8 Hz, 1H), 7.77 (d, J=5.6 Hz, 1H), 7.72 (d, J=5.6 Hz, 1H), 7.02 (d, J=8.8 Hz, 1H).
    • EXAMPLE 56 5-Benzyloxy-4-formylbenzo[b]thiophene
  • [2499]
    Figure US20030073706A1-20030417-C02067
  • By the same procedure as described in Example 18 using the compound prepared in Example 55 instead of the compound prepared in Example 9 (12) and benzylbromide instead of 4-nitrobenzylbromide, the compound of the present invention having the following physical data was obtained. [2500]
  • TLC: Rf 0.65 (hexane:ethyl acetate=2:1); [2501]
  • NMR (CDCl[2502] 3): δ 10.81 (s, 1H), 8.43 (d, J=5.6 Hz, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.68 (d, J=5.6 Hz, 1H), 7.55-7.30 (m, 5H), 7.15 (d, J=8.8 Hz, 1H), 5.28 (s, 2H).
    • EXAMPLE 57 5-Benzyloxy-4-hydroxymethylbenzo[b]thiophene
  • [2503]
    Figure US20030073706A1-20030417-C02068
  • To a solution of the compound prepared in Example 56 (1.24 g) in methylene chloride (9.0 ml), were added sodium borohydride (246 mg) and methanol, (3.0 ml). The mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured onto 1 N hydrochloric acid and was extracted by ethyl acetate. The extract was washed by a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The residue was purified with chromatography on silica gel (hexane:ethyl acetate=4:1) to give the compound of the present invention (1.25 g) having the following physical data. [2504]
  • TLC: Rf 0.40 (hexane:ethyl acetate=2:1); [2505]
  • NMR (CDCl[2506] 3): δ 7.76 (d, J=8.8 Hz, 1H), 7.54-7.28 (m, 7H), 7.12 (d, J=8.8 Hz, 1H), 5.20 (s, 2H), 5.04 (br-s, 2H), 2.30-2.12 (br, 1H).
    • EXAMPLE 58 5-Benzyloxy-4-hydroxymethyl-1,1-dioxidebenzo[b]thiophene
  • [2507]
    Figure US20030073706A1-20030417-C02069
  • By the same procedure as described in Example 3 using the compound prepared in Example 57 instead of the compound prepared in Example 1, the compound having the following physical data was obtained (with the proviso that 3-chloroperbenzoic acid was used instead of OXONE@ as an oxidizer.). [2508]
  • TLC: Rf 0.43 (hexane:ethyl acetate=1:1); [2509]
  • NMR (CDCl[2510] 3): δ 7.61 (d, J=7.0 Hz,1H), 7.56 (d, J=7.0 Hz, 1H), 7.48-7.34 (m, 5H), 7.02 (d, J=8.4 Hz, 1H), 6.75 (d, J=7.0 Hz, 1H), 5.18 (s, 2H), 4.84 (brs, 2H), 2.26-2.10 (br, 1H).
    • EXAMPLE 59 5-Benzyloxy-4-hydroxymethyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2511]
    Figure US20030073706A1-20030417-C02070
  • By the same procedure as described in Example 1 using the compound prepared in Example 58 instead of 1,1-dioxidebenzo[b]thiophene, and thiophenol, the compound of the present invention having the following physical data was obtained. [2512]
  • TLC: Rf 0.60 (chloroform:ethyl acetate=19:1); [2513]
  • NMR (CDCl[2514] 3): δ 7.67 (d, J=8.4 Hz, 1H), 7.57-7.48 (m, 2H), 7.46-7.32 (m, 8H), 7.15, (d, J=8.4 Hz, 1H), 5.24 (s, 2H), 5.19 (dd, J=6.6, 1.8 Hz, 1H), 4.99 (d, J=6.0 Hz, 2H), 3.71 (dd, J=14.0, 6.6 Hz, 1H), 3.59 (dd, J=14.0, 1.8 Hz, 1H), 2.59 (t, J=6.0 Hz,1H).
    • EXAMPLE 60 5-Benzyloxy-4-bromomethyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenz[b]thiophene
  • [2515]
    Figure US20030073706A1-20030417-C02071
  • To a solution of the compound prepared in Example 59 (1.45 g) in methylene chloride (15 ml), was added triphenylphosphine (1.38 g) and carbon tetrabromide (1.74 g). The mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated. The residue was purified with column chromatography on silica gel (hexane:ethyl acetate=2:1) to give the compound of the present invention having the following physical data. [2516]
  • TLC: Rf 0.76 (hexane:ethyl acetate=1:1); NMR (CDCl[2517] 3): δ 7.66 (d, J=8.8 Hz, 1H), 7.60-7.51 (m, 2H), 7.50-7.30 (m, 8H), 7.12 (d, J=8.8 Hz, 1H), 5.27 (s, 2H), 5.15 (dd, J=6.8, 1.6 Hz, 1H), 5.02 (d, J=10 Hz, 1H), 4.94 (d, J=10 Hz, 1H), 3.74 (dd, J=13.8, 6.8 Hz, 1H), 3.60 (dd, J=13.8,1.6 Hz, 1H).
    • EXAMPLE 61 5-Benzyloxy-4-aminomethyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2518]
    Figure US20030073706A1-20030417-C02072
  • To a solution of 28% aqueous ammonia solution (6.75 ml) in tetrahydrofuran (30 ml), were added a solution of the compound prepared in Example 60 (1.60 g) in tetrahydrofuran (30 ml) and potassium carbonate (700 mg) successively. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated. The residue was purified with column chromatography on silica gel (chloroform:methanol=20:1) to give the compound of the present invention (747 mg) having the following physical data. [2519]
  • TLC: Rf 0.05 (hexane:ethyl acetate=1:1); [2520]
  • NMR (CDCl[2521] 3): δ 7.63 (d, J=8.5 Hz, 1H), 7.58-7.48 (m, 2H), 7.46-7.28 (m, 8H), 7.14 (d, J=8.5 Hz, 1H), 5.23 (s, 2H), 5.13 (dd, J=6.4, 1.6 Hz, 1H), 4.12 (d, J=13.6 Hz, 1H), 4.02 (d, J=13.6 Hz, 1H), 3.70 (dd, J=14.0, 6.0 Hz, 1H), 3.59 (dd, J=14.0, 1.6 Hz, 1H).
    • EXAMPLE 62 5-Benzyloxy-4-t-butoxycarbonylaminomethyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2522]
    Figure US20030073706A1-20030417-C02073
  • To the solution of the compound prepared in Example 61 (735 mg) in tetrahydrofuran (12 ml) and water (3.0 ml), were added sodium bicarbonate (165 mg) and di-t-butyldicarbonate (430 mg) at 0° C. The mixture was stirred at room temperature for 1 hour. The reaction mixture was poured onto water and was extracted by ethyl acetate. The extract was washed by a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The residue was purified with column chromatography on silica gel (hexane:ethyl acetate=2:1) to give the compound of the present invention (867 mg) having the following physical data. [2523]
  • TLC: Rf 0.73 (hexane:ethyl acetate=1:1); [2524]
  • NMR (CDCl[2525] 3): δ 7.70-7.56 (m, 3H), 7.48-7.30 (m, 8H), 7.12 (d, J=8.8 Hz, 1H), 5.66 (br-d, J=5.8 Hz, 1H), 5.22 (s, 2H), 5.20-4.88 (m, 2H), 4.25-4.10 (m, 1H), 3.71 (dd, J=14.0, 6.8 Hz, 1H), 3.56 (d, J=14.0 Hz, 1H), 1.41 (s, 9H).
    • EXAMPLE 63 5-Benzyloxy-4-t-butoxycarbonylaminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2526]
    Figure US20030073706A1-20030417-C02074
  • By the same procedure as described in Example 3 using the compound prepared in Example 62 instead of the compound prepared in Example 1, the compound of the present invention having the following physical data (with the proviso that 3-chloroperbenzoic acid was used instead of OXONE@ as an oxidizer.). [2527]
  • TLC: Rf 0.31 (hexane:ethyl acetate=2:1); [2528]
  • NMR (CDCl[2529] 3): δ 7.83-7.76 (m, 2H), 7.71-7.64 (m, 1H), 7.60 (d, J=8.7 Hz, 1H), 7.56-7.38 (m, 7H), 7.19 (d, J=8.7 Hz, 1H), 6.05 (brd, J=6.9 Hz, 1H), 5.27-5.15 (m, 1H), 5.25 (s, 2H), 5.10-4.95 (m, 1H), 4.27-4.16 (m, 1H), 3.81 (dd, J=15.3, 2.1 Hz, 1H), 3.74 (dd, J=15.3, 8.1, 1H), 1.37 (s, 9H).
    • EXAMPLE 64 5-Benzyloxy-4-aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene hydrochloride
  • [2530]
    Figure US20030073706A1-20030417-C02075
  • By the same procedure as described in Example 7 using the compound prepared in Example 63 instead of the compound prepared in Example 6 (8), the compound of the present invention having the following physical data was obtained. [2531]
  • TLC: Rf 0.43 (chloroform:methanol=9:1); [2532]
  • NMR (DMSO-d[2533] 6): δ 8.18 (brs, 3H), 7.86 (d, J=9.0 Hz, 1H), 7.83-7.75 (m, 3H), 7.67-7.48 (m, 5H), 7.47-7.33 (m, 3H), 6.37 (dd, J=6.0, 3.9 Hz, 1H), 5.41 (d, J=12.3 Hz, 1H), 5.33 (d, J=12.3 Hz, 1H), 4.44 (d, J=13.8 Hz, 1H), 4.24 (d, J=13.8 Hz, 1H), 3.90-3.76 (m, 2H).
    • EXAMPLE 65 5- Hydroxy-4-t-butoxycarbonylaminoethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2534]
    Figure US20030073706A1-20030417-C02076
  • By the same procedure as described in Example 52 using the compound prepared in Example 63 instead of the compound prepared in Example 51, the compound of the present invention having the following physical data was obtained. [2535]
  • TLC: Rf 0.22 (hexane:ethyl acetate=1:1); [2536]
  • NMR (CDCl[2537] 3): δ 10.75 (s, 1H), 7.75-7.58 (m, 3H), 7.56-7.41 (m, 3H), 7.18 (d, J=8.6 Hz, 1H), 6.35-6.50 (m, 1H), 5.24-5.15 (m, 1H), 4.76-4.60 (m, 1H), 4.34 (dd, J=16.0, 5.4 Hz,1H), 3.86-3.66 (m, 2H), 1.37 (s, 9H).
    • EXAMPLES 66˜66 (1)
  • By the same procedure as described in Example 29 using the compound prepared in Example 65 instead of 4-hydroxy-1,1-dioxidebenzo[b)thiophene and alcohol derivatives corresponding to 1-(3-hydroxypropyl)pyrrole, the following compounds of the present invention were obtained. [2538]
    • EXAMPLE 66 5-Methoxy-4-t-butoxycarbonylaminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2539]
    Figure US20030073706A1-20030417-C02077
  • TLC: Rf 0.28 (hexane:ethyl acetate=1:1); [2540]
  • NMR (CDCl[2541] 3): δ 7.86-7.75 (m, 2H), 7.74-7.47 (m, 4H), 7.14 (d, J=8.8 Hz, 1H), 6.10-6.00 (m, 1H), 5.32-5.18 (m, 1H), 5.10-4.92 (m, 1H), 4.25-4.10 (m, 1H), 4.00 (s, 3H), 3.85-3.65 (m, 2H), 1.38 (s, 9H).
    • EXAMPLE 66 (1) 5-(3-Phenylpropyl) oxy-4-t-butoxycarbonylaminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2542]
    Figure US20030073706A1-20030417-C02078
  • TLC: Rf 0.51 (hexane:ethyl acetate=1:1); [2543]
  • NMR (CDCl[2544] 3): δ 7.87-7.73 (m, 2H), 7.73-7.40 (m, 6H), 7.40-7.16 (m, 3H), 7.07 (d, J=8.8 Hz, 1H), 6.55-6.30 (br, 1H), 6.07-5.95 (m, 1H), 5.26-5.12 (m, 1H), 5.10-4.90 (m, 1H), 4.20-4.05 (m, 2H), 3.86-3.64 (m, 2H), 2.86 (t, J=7.0 Hz, 2H), 2.33-2.15 (m, 2H), 1.38 (s, 9H).
    • EXAMPLES 67˜67(1)
  • By the same procedure as described in Example 7 using the compounds prepared in Examples 66˜66 (1) instead of the compound prepared in Example 6 (8), the following compounds of the present invention were obtained. [2545]
    • EXAMPLE 67 5-Methoxy-4-aminomethyl-3-phenyisulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride
  • [2546]
    Figure US20030073706A1-20030417-C02079
  • TLC: Rf 0.19 (chloroform:methanol=4:1); [2547]
  • NMR (DMSO-d[2548] 6): δ 8.19 (brs, 3H), 7.89-7.76 (m, 4H), 7.68-7.60 (m, 2H), 7.47 (d, J=8.7 Hz, 1H), 6.39 (t, J=5.4 Hz, 1H), 4.47-4.28 (br, 1H), 4.25-4.08 (br, 1H), 3.98 (s, 3H), 3.82 (d, J=5.4 Hz, 2H).
    • EXAMPLE 67 (1) 5-(3-Phenylpropyl)oxy-4-aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thibphene.hydrochloride
  • [2549]
    Figure US20030073706A1-20030417-C02080
  • TLC: Rf 0.43 (chloroform:methanol=9:1); [2550]
  • NMR (DMSO-d[2551] 6): δ 8.14 (brs, 3H), 7.86-7.76 (m, 4H), 7.68-7.61 (m, 2H), 7.45 (d, J=8.7 Hz, 1H), 7.34-7.27 (m, 4H), 7.25-7.15 (m, 1H), 6.45-6.34 (m, 1H), 4.47-4.13 (m, 4H), 3.89-3.75 (m, 2H), 2.86-2.73 (m, 2H), 2.22-2.08 (m, 2H).
    • EXAMPLE 68 5-Benzyloxy-4-hydroxymethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2552]
    Figure US20030073706A1-20030417-C02081
  • By the same procedure as described in Example 3 using the compound prepared in Example 59 instead of the compound prepared in Example 1 the compound of the present invention having the following physical data was obtained (with the proviso that 3-chloroperbenzoic acid was used instead of OXONE@ as an oxidizer). [2553]
  • TLC: Rf 0.25 (hexane:ethyl acetate=1:1); NMR (CDCl[2554] 3): δ 7.72-7.58 (m, 3H), 7.56-7.30 (m, 8H), 7.20 (d, J=8.8 Hz, 1H), 5.53 (dd, J=8.4,1.8Hz, 1H), 5.33 (d, J=11.8 Hz, 1H), 5.25 (d, J=11.8 Hz, 1H), 5.10-5.01 (m, 2H), 3.87 (dd, J=15.4,1.8 Hz, 1H), 3.75 (dd, J=15.4,1.8 Hz, 1H), 3.40-3.28 (m, 1H).
    • EXAMPLE 69 5-Benzyoxy-4-carboxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2555]
    Figure US20030073706A1-20030417-C02082
  • To a solution of the compound prepared in Example 68 (444 mg) in methylene chloride (10 ml) were added pyridinium dichromate (564 mg) and magnesium sulfate (500 mg). The mixture was stirred at room temperature for 6 hours. The undissolved ingredients were filtered off. The filtrate was poured onto 1 N hydrochloric acid and was extracted by methylene chloride. The extract was washed by a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The residue was washed by methanol and was dried. The obtained solid was dissolved in dimethylformamide (16 ml) and water (4.0 ml). Thereto, were added 2-methyl-2-butene (0.48 ml), sodium phosphate bishydrate (120 mg) and sodium hypochloric acid (358 mg). The mixture was stirred at room temperature for 1 hour. The reaction mixture was poured onto 0.5 N hydrochloric acid and was extracted by ethyl acetate. The extract was concentrated. The residue was washed by ether to give the compound of the present invention (305 mg) having the following physical data. [2556]
  • TLC: Rf 0.17 (chloroform:methanol=9:1); [2557]
  • NMR (DMSO-d[2558] 6): δ 13.52 (s, 1H), 7.92-7.68 (m, 4H), 7.67-7.30 (m, 8H), 5.88 (d, J 9.0 Hz, 1H), 5.37 (s, 2H), 4.09 (dd, J=15.0, 9.0 Hz, 1H), 3.88 (d, J=15.0 Hz, 1H).
    • EXAMPLE 70 5-Benzyloxy-4-(pyridin-3-ylmethyl) carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2559]
    Figure US20030073706A1-20030417-C02083
  • By the same procedure as described in Example 28 using the compound prepared in Example 69 instead of 4-carboxy-1,1-dioxidebenzo[b]thiophene, and (pyridin-3-ylmethyl)amine, the compound of the present invention having the following physical data was obtained. [2560]
  • TLC: Rf 0.53 (chloroform:methanol=9:1); [2561]
  • NMR (DMSO-d6): δ 9.05 (t, J=6.0 Hz, 1H), 8.59 (d, J=1.5 Hz, 1H), 8.41 (dd, J=4.8, 1.5 Hz,1H), 7.85 (d, J=8.7 Hz, 1H), 7.80-7.72 (m, 3H), 7.65-7.55 (m, 4H), 7.48-7.41 (m, 2H), 7.38-7.30 (m, 3H), 7.15 (dd, J=8.1, 4.8 Hz, 1H), 5.96 (d, J=9.0 Hz, 1H), 5.29 (s, 2H), 4.63 (dd, J=15.0, 6.0 Hz,1H), 4.35 (dd, J=15.0, 6.0 Hz, 1H), 4.06 (dd, J=15.0,9.0 Hz, 1H), 3.87 (d, J=15.0 Hz, 1H). [2562]
    • EXAMPLE 71 5-Hydroxy-4-(pyridin-3-ylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2563]
    Figure US20030073706A1-20030417-C02084
  • By the same procedure as described in Example 52 using the compound prepared in Example 70 instead of the compound prepared in Example 51, the compound of the present invention having the following physical data was obtained. [2564]
  • TLC: Rf 0.29 (chloroform:methanol=9:1); [2565]
  • NMR (DMSO-d[2566] 6): δ 11.70 (br, 1H), 9.10-8.90 (br, 1H), 8.66 (d, 1H), 8.44 (dd, 1H), 7.88-7.81 (m, 1H), 7.78-7.68 (m, 3H), 7.67-7.54 (m, 3H), 7.34 (dd, J=7.5, 4.8 Hz, 1H), 7.23 (d, J=8.7 Hz,1H), 6.14 (d, J=9.0 Hz, 1H), 4.67 (dd, J=15.3, 6.3 Hz, 1H), 4.39 (dd, J=15.3, 5.4 Hz, 1H), 4.02 (dd, J=15.0, 9.0 Hz, 1H), 3.84 (d, J=15.0 Hz, 1H).
    • EXAMPLES 72˜72 (31)
  • By the same procedure as described in Example 28 using carboxylic acids corresponding to 4-carboxy-1,1-dioxidebenzo[b]thiophene and amine derivatives corresponding to (pyridin-3-ylmethyl)amine, and if necessary, by converting into the corresponding salts by known methods, the following compounds of the present invention were obtained. [2567]
    • EXAMPLE 72 4-(1,1-Dimethyl-2-hydroxyethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene
  • [2568]
    Figure US20030073706A1-20030417-C02085
  • TLC: Rf 0.64 (ethyl acetate); [2569]
  • NMR (DMSO-d[2570] 6): δ 8.05 (brs, 1H), 7.91 (d, J=7.4 Hz, 1H), 7.76 (d, J=7.0 Hz, 1H), 7.75 (d, J=7.4 Hz, 1H), 7.63 (t, J=7.4 Hz, 1H), 7.43 (d, J=7.0 Hz, 1H), 4.87 (t, J=5.8 Hz, 1H), 3.54 (d, J=5.8 Hz, 2H), 1.29 (s, 6H).
    • EXAMPLE 72 (1) 4-(2-Hydroxyethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene
  • [2571]
    Figure US20030073706A1-20030417-C02086
  • TLC: Rf 0.30 (ethyl acetate); [2572]
  • NMR (DMSO-d[2573] 6): δ 8.72 (t, J=5.6 Hz, 1H), 7.95 (d, J=7.4 Hz, 1H), 7.88-7.80 (m, 2H), 7.66 (t, J=7.4 Hz, 1H), 7.45 (d, J=7.0 Hz, 1H), 4.77 (t, J=5.6 Hz, 1H), 3.53 (q, J=5.6 Hz, 2H), 3.33 (q, J=5.6 Hz, 2H).
    • EXAMPLE 72 (2) 4-(4-(2-Hydroxyethyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene
  • [2574]
    Figure US20030073706A1-20030417-C02087
  • TLC: Rf 0.45 (ethyl acetate:methanol=9:1); [2575]
  • NMR (CDCl[2576] 3): δ 7.76 (d, J=7.5 Hz, 1H), 7.57 (t, J=7.5 Hz, 1H), 7.47 (dd, J=7.5, 1.2 Hz, 1H), 7.32 (dd, J=7.2, 1.2 Hz, 1H), 6.79 (d, J=7.2 Hz, 1H), 4.26-4.19 (m, 1H), 4.03-3.96 (m,1H), 3.88-3.78 (m, 2H), 3.35 (br, 2H), 2.72-2.67 (m, 2H), 2.67-2.60 (m, 2H), 2.50-2.42 (m, 2H).
    • EXAMPLE 72 (3) 4-(N-Methyl-N-methoxycarbamoyl)-1,1-dioxidebenzo[b]thiophene
  • [2577]
    Figure US20030073706A1-20030417-C02088
  • TLC: Rf 0.22 (hexane:ethyl acetate=1:1); [2578]
  • NMR (CDCl[2579] 3) δ 7.78 (dt, J=7.8, 1.0 Hz, 1H), 7.72 (dd, J=7.8, 1.0 Hz, 1H), 7.57 (t, J=7.8 Hz, 1H), 7.41 (dd, J=7.0, 1.0 Hz, 1H), 6.76 (d, J=7.0 Hz, 1H), 3.49 (s, 3H), 3.40 (s, 3H).
    • EXAMPLE 72 (4) 4-(4-(Thiazol-2-ylsulfamoyl)phenyl)carbamoyl-1,1-dioxidebenzo[b]thiophene
  • [2580]
    Figure US20030073706A1-20030417-C02089
  • TLC: Rf 0.20 (chloroform:methanol 9:1); [2581]
  • NMR (CDCl[2582] 3+DMSO-d6): δ 10.71 (s, 1H), 7.98 (d, J=7.5 Hz, 1H), 7.90-7.67 (m, 6H), 7.67 (t, J=7.8 Hz, 1H), 6.97 (d, J=7.5 Hz, 1H), 6.94 (d, J=5 Hz, 1H), 6.52 (d, J=5 Hz, 1H), 5.30 (broad peak, 1H).
    • EXAMPLE 72 (5) 4-((1 R)-1-t-Butoxycarbonyl-2-methylpropyl)carbamoyl-1,1-dioxidebenzo[b]thiophene
  • [2583]
    Figure US20030073706A1-20030417-C02090
  • TLC: Rf 0.48 (hexane:ethyl acetate=1:1); [2584]
  • NMR (CDCl[2585] 3): δ 7.95 (dd, J=7.2, 1.0 Hz, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.76 (dd, J=7.8, 1.0 Hz, 1H), 7.59 (t, J=7.8 Hz, 1H), 6.78 (d, J=7.2 Hz, 1H), 6.55 (d, J=8.4 Hz, 1H), 4.64 (dd, J=8.4, 4.5 Hz, 1H), 2.36-2.25 (m, 1H), 1.51 (s, 9H), 1.02 (d, J=6.9 Hz, 3H), 0.98 (d, J=6.9 Hz, 3H).
    • EXAMPLE 72 (6) 6-(1-Benzylpiperidin-4-yl)carbamoyl-4-methoxy-1,1-dioxidebenzo[b]thiophene
  • [2586]
    Figure US20030073706A1-20030417-C02091
  • TLC: Rf 0.44 (ethyl acetate:methanol 4:1); [2587]
  • NMR (CDCl[2588] 3): δ 7.66 (s, 1H), 7.54 (s, 1H), 7.45 (d, J=7.0 Hz, 1H), 7.40-7.20 (m, 5H), 6.73 (d, J=7.0 Hz, 1H), 6.40-6.20 (m, 1H), 4.10-3.90 (m, 1H), 3.97 (s, 3H), 3.53 (s, 2H), 3.00-2.80 (m, 2H), 2.30-2.10 (m, 2H), 2.10-1.90 (m, 2H), 1.70-1.50 (m, 2H).
    • EXAMPLE 72 (7) 6-(2-Diethylaminoethyl)carbamoyl-4-methoxy-1,1-dioxidebenzo[b]thiophene
  • [2589]
    Figure US20030073706A1-20030417-C02092
  • TLC: Rf 0.33 (ethyl acetate:methanol:triethylamine=14:4:1); [2590]
  • NMR (CDCl[2591] 3): δ 7.71 (s, 1H), 7.57 (s, 1H), 7.46 (d, J=6.9 Hz, 1H), 7.10-7.00 (m,1H), 6.71 (d, J=6.9 Hz, 1H), 3.98 (s, 3H), 3.52 (q, J=5.5 Hz, 2H), 2.53 (t, J=5.5 Hz, 2H), 2.28 (s, 6H).
    • EXAMPLE 72 (8) 6-(Pyridin-3-ylmethyl)carbamoyl-4-methoxy-1,1-dioxidebenzo[b]thiophene
  • [2592]
    Figure US20030073706A1-20030417-C02093
  • TLC: Rf 0.49 (ethyl acetate:methanol=4:1); [2593]
  • NMR (DMSO-d[2594] 6): δ 9.36 (t, J=6.0 Hz, 1H), 8.58 (s, 1H), 8.48 (d, J=4.5 Hz, 1H), 7.88 (s, 1H), 7.81 (s, 1H), 7.75 (d, J=7.8Hz, 1H), 7.64 (d, J=7.0Hz, 1H), 7.42 (d, J=7.0 Hz, 1H), 7.36 (dd, J=7.8, 4.5 Hz, 1H), 4.53 (d, J=6.0 Hz, 2H), 3.99 (s, 3H).
    • EXAMPLE 72 (9) 5-(6-Dimethylaminohexyl)oxycarbonyl-1,1-dioxidebenzo[b]thiophene -hydrochloride
  • [2595]
    Figure US20030073706A1-20030417-C02094
  • TLC: Rf 0.16 (chloroform:methanol=9:1); [2596]
  • NMR (CDCl[2597] 3): δ 12.60-12.30 (br, 1H), 7.96 (d, J=7.4 Hz, 1H), 7.54-7.43 (m, 2H), 6.76 (d, J=7.2 Hz, 1H), 4.35 (t, J=6.6 Hz, 2H), 3.97 (s, 3H), 3.06-2.90 (m, 2H), 2.81 (s, 3H), 2.79 (s, 3H), 2.03-1.73 (m, 4H ), 1.57-1.35 (m, 4H).
    • EXAMPLE 72 (11) 4-(4-t-Butoxycarbonylpiperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene
  • [2598]
    Figure US20030073706A1-20030417-C02095
  • TLC: Rf 0.65 (methylene chloride:methanol 10:1); [2599]
  • NMR (CDCl[2600] 3): δ 7.78 (dd, J=7.2, 1.2 Hz, 1H), 7.59 (t, J=7.2 Hz, 1H), 7.48 (dd, J=7.2, 1.2 Hz, 1H), 7.32 (d, J=6.9 Hz, 1H), 6.80 (d, J=6.9 Hz, 1H), 3.85-3.70 (m, 2H), 3.65-3.45 (m, 2H), 3.45-3.24 (m, 4H), 1.47 (s, 9H).
    • EXAMPLE 72 (11) 4-(Piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene hydrochloride
  • [2601]
    Figure US20030073706A1-20030417-C02096
  • TLC: Rf 0.13 (methylene chloride:methanol=10:1); [2602]
  • NMR (DMSO-d[2603] 6): δ 9.35 (bs, 2H), 7.96 (d, J=6.9 Hz, 1H), 7.80-7.73 (m, 2H), 7.60 (d, J=7.2 Hz, 1H), 7.51 (d, J=7.2 Hz, 1H), 4.00-3.80 (m, 2H), 3.60-3.40 (m, 2H), 3.30-3.15 (m, 2H), 3.15-3.00 (m, 2H).
    • EXAMPLE 72 (12) 4-(4-(4-Methoxyphenylmethyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene.hydrochloride
  • [2604]
    Figure US20030073706A1-20030417-C02097
  • TLC: Rf 0.50 (methylene chloride:methanol=10:1); [2605]
  • NMR (DMSO-d[2606] 6): δ 7.97 (t, J=4.2 Hz, 1H), 7.71 (d, J=4.2 Hz, 2H), 7.58-7.43 (m, 2H), 7.54 (d, J=4.2 Hz, 2H), 7.01 (d, J=8.4 Hz, 2H), 4.65-4.50 (m, 1H), 4.30-4.20 (m, 2H), 3.78 (s, 3H), 3.70-3.00 (m, 8H).
    • EXAMPLE 72 (13) 4-(4-(4-Phenylphenylmethyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene.hydrochloride
  • [2607]
    Figure US20030073706A1-20030417-C02098
  • TLC: Rf 0.33 (ethyl acetate); [2608]
  • NMR (DMSO-d[2609] 6): δ 8.00-7.92 (m, 1H), 7.80-7.64 (m, 8H), 7.60-7.35 (m, 5H), 4.65-4.50 (m, 1H), 4.48-4.30 (m, 2H), 3.70-3.00 (m, 8H).
    • EXAMPLE 72 (14) 4-(4-(Naphthalen-1-ylmethyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene.hydrochloride
  • [2610]
    Figure US20030073706A1-20030417-C02099
  • TLC: Rf 0.70 (ethyl acetate); [2611]
  • NMR (DMSO-d[2612] 6): δ 8.42-7.30 (m, 1H), 8.13-7.77 (m, 4H), 7.76-7.40 (m, 7H), 4.93-4.76 (m, 2H), 4.66-4.53 (m, 1H), 3.64-3.00 (m, 8H).
    • EXAMPLE 72 (15) 4-(4-(4-Ethylphenylmethyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene.hydrochloride
  • [2613]
    Figure US20030073706A1-20030417-C02100
  • TLC: Rf 0.40 (ethyl acetate); [2614]
  • NMR (DMSO-d[2615] 6): δ 7.98 (t, J=4.2 Hz, 1H), 7.71 (d, J=4.2 Hz, 2H), 7.56 (d, J=7.2 Hz, 1H), 7.52 (d, J=7.2 Hz, 1H), 7.47 (d, J=7.8 Hz, 2H), 7.31 (d, J=7.8 Hz, 2H), 4.66-4.45 (m, 1H), 4.33-4.20 (m, 2H), 3.66-3.00 (m, 8H), 2.63 (q, J=7.5 Hz, 2H), 1.19 (t, J=7.5 Hz, 3H).
    • EXAMPLE 72 (16) 4-(4-(Naphthalen-2-ylcarbonylmethyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene hydrochloride
  • [2616]
    Figure US20030073706A1-20030417-C02101
  • TLC: Rf 0.40 (ethyl acetate); [2617]
  • NMR (DMSO-d[2618] 6): δ 8.72 (s, 1H), 8.20-7.93 (m, 5H), 7.80-7.64 (m, 4H), 7.60 (d, J=7.2 Hz, 1H), 7.55 (d, J=7.2 Hz, 1H), 5.30-5.10 (m, 2H), 4.60-4.40 (m, 1H), 3.80-3.10 (m, 8H).
    • EXAMPLE 72 (17)
  • 4-(4-(Pyridin-2-ylmethyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene.2hydrochloride [2619]
    Figure US20030073706A1-20030417-C02102
  • TLC: Rf 0.46 (methylene chloride:methanol=10:1); [2620]
  • NMR (DMSO-d[2621] 6): δ 8.69 (d, J=5.1 Hz, 1H), 8.00-7.90 (m, 2H), 7.75-7.64 (m, 3H), 7.60-7.46 (m, 3H), 4.50 (s, 2H), 4.09-3.90 (m, 2H),3.67-3.59 (m, 2H), 3.48-3.35 (m, 2H), 3.33-3.20 (m, 2H).
    • EXAMPLE 72 (18) 4-(4-(Pyridin-3-ylmethyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene.2hydrochloride
  • [2622]
    Figure US20030073706A1-20030417-C02103
  • TLC: Rf 0.46 (methylene chloride:methanol=10:1); [2623]
  • NMR (DMSO-d[2624] 6): δ 8.90 (s, 1H), 8.80-8.73 (m, 1H), 8.36-8.30 (m, 1H), 7.98-7.92 (m, 1H), 7.80-7.66 (m, 3H), 7.57 (d, J=7.2 Hz, 1H), 7.52 (d, J=7.2 Hz, 1H), 4.50-3.00 (m, 10H).
    • EXAMPLE 72 (19) 4-(4-benzoylpiperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene
  • [2625]
    Figure US20030073706A1-20030417-C02104
  • TLC: Rf 0.52 (methylene chloride:methanol=10:1); [2626]
  • NMR (CDCl[2627] 3): δ 7.79 (d, J=7.5 Hz, 1H), 7.59 (t, J=7.5 Hz, 1H), 7.53-7.36 (m, 6H), 7.34 (d, J=6.0 Hz, 1H), 6.81 (d, J=7.5 Hz, 1H), 4.00-3.25 (m, 8H).
    • EXAMPLE 72 (20) 4-(4-(Furan-2-ylcarbonyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene
  • [2628]
    Figure US20030073706A1-20030417-C02105
  • TLC: Rf 0.46 (methylene chloride:methanol=10:1); [2629]
  • NMR (CDCl[2630] 3): δ 7.80 (d, J=6.9 Hz, 1H), 7.61 (t, J=7.8 Hz, 1H), 7.51 (d, J=7.8 Hz, 2H), 7.35 (d, J=6.9 Hz, 1H), 7.11 (d, J=3.6 Hz, 1H), 6.81 (d, J=6.9 Hz, 1H), 6.52 (d, J=3.6 Hz, 1H), 4.06-3.36 (m, 8H).
    • EXAMPLE 72 (21) 4-(4-Benzylcarbonylpiperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene
  • [2631]
    Figure US20030073706A1-20030417-C02106
  • TLC: Rf 0.47 (methylene chloride:methanol=10:1); [2632]
  • NMR (CDCl[2633] 3): δ 7.77 (d, J=7.5 Hz, 1H), 7.57 (t, J=7.5 Hz, 1H), 7.48-7.14 (m, 6H), 7.28 (d, J=7.2 Hz, 1H), 6.78 (d, J=7.2 Hz, 1H), 3.86-3.00 (m, 10H).
    • EXAMPLE 72 (22) 4-(2-(pyrrolidin-1-yl)ethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene
  • [2634]
    Figure US20030073706A1-20030417-C02107
  • TLC: Rf 0.26 (ethyl acetate:acetic acid:water=3:1:1); [2635]
  • NMR (CDCl[2636] 3): δ 8.00 (dd, J=7.5 Hz and 1 Hz, 1H), 7.79 (dt, J=7.5 Hz and 1 Hz, 1H), 7.72 (dd, J=7.5 Hz and 1 Hz, 1H), 7.57 (t, J=7.5 Hz, 1H), 6.90 (broad s, 1H), 6.76 (d, J=7.5 Hz, 1H), 3.55 (m, 2H ), 2.73 (t, J=6 Hz, 2H), 2.57 (m, 4H), 1.80 (m, 4H).
    • EXAMPLE 72 (23) 4-(3-(Pyrrolidin-1-yl)propyl)carbamoyl-1,1-dioxidebenzo[b]thiophene
  • [2637]
    Figure US20030073706A1-20030417-C02108
  • TLC: Rf 0.19 (ethyl acetate acetic acid:water 3:1:1); [2638]
  • NMR (CDCl[2639] 3): δ 9.30 (broad s, 1H), 8.17 (d, J=7.5 Hz, 1H), 7.78 (d, J=7.5 Hz, 1H), 7.64 (d, J=7.5 Hz, 1H), 7.52 (t, J=7.5 Hz, 1H), 6.76 (d, J=7.5 Hz, 1H), 3.58 (m, 2H), 2.76 (t, J=6 Hz, 2H), 2.5 9 (m, 4H), 2.00-1.70 (m, 6H).
    • EXAMPLE 72 (24) 4-(4-(2-Methylphenyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene.hydrochloride
  • [2640]
    Figure US20030073706A1-20030417-C02109
  • TLC: Rf 0.64 (ethyl acetate:hexane=2:1); [2641]
  • NMR (DMSO-d[2642] 6): δ 7.97-7.90 (m, 1H), 7.74-7.65 (m, 2H), 7.57 (d, J=7.2 Hz, 1H), 7.51 (d, J=7.2 Hz, 1H), 7.20-7.10 (m, 2H), 7.06-6.93 (m, 2H), 3.90-3.78 (m, 2H), 3.45-3.34 (m, 2H), 3.00-2.90 (m, 2H), 2.85-2.74 (m, 2H), 2.27 (s, 3H).
    • EXAMPLE 72 (25) 4-(4-(3-Methylphenyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene.hydrochloride
  • [2643]
    Figure US20030073706A1-20030417-C02110
  • TLC: Rf 0.48 (ethyl acetate:hexane=2:1); [2644]
  • NMR (DMSO-d[2645] 6): δ 8.00-7.92 (m, 1H), 7.74-7.66 (m, 2H), 7.56 (d, J=7.2 Hz, 1H), 7.49 (d, J=7.2 Hz, 1H), 7.14 (t, J=7.8 Hz, 1H), 6.90-6.80 (m, 2H), 6.71 (d, J=7.8 Hz, 1H), 3.90-3.80(m, 2H), 3. 46-3.36 (m, 2H), 3.36-3.24 (m, 2H), 3.18-3.08 (m, 2H), 2.56 (s, 3H).
    • EXAMPLE 72 (26) 4-(4-(2-Fluorophenyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene.hydrochloride
  • [2646]
    Figure US20030073706A1-20030417-C02111
  • TLC: Rf 0.59 (ethyl acetate:hexane=2:1); [2647]
  • NMR (DMSO-d[2648] 6): δ 8.00-7.90 (m, 1H), 7.74-7.66 (m, 2H), 7.56 (d, J=7.2 Hz, 1H), 7.50 (d, J=7.2 Hz, 1H), 7.20-6.96 (m, 4H), 3.90-3.80 (m, 2H), 3.46-3.36 (m, 2H), 3.18-3.06 (m, 2H), 3.02-2.90 (m, 2H).
    • EXAMPLE 72 (27) 4-(4-(4-Fluorophenyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene.hydrochloride
  • [2649]
    Figure US20030073706A1-20030417-C02112
  • TLC: Rf 0.40 (ethyl acetate:hexane=2:1); [2650]
  • NMR (DMSO-d[2651] 6): δ 8.00-7.90 (m, 1H), 7.74-7.65 (m, 2H), 7.54 (d, J=6.9 Hz, 1H), 7.49 (d, J=6.9 Hz, 1H), 7.14-6.97 (m, 4H), 3.89-3.78 (m, 2H), 3.45-3.34 (m, 2H), 3.30-3.19 (m, 2H), 3.13-3.00 (m, 2H).
    • EXAMPLE 72 (28) 4-(4-(4-Methoxyphenyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene.hydrochloride
  • [2652]
    Figure US20030073706A1-20030417-C02113
  • TLC: Rf 0.22 (ethyl acetate:hexane=2:1); [2653]
  • NMR (DMSO-d[2654] 6): δ 8.00-7.92 (m, 1H), 7.77-7.66 (m, 2H), 7.58 (d, J=6.9 Hz, 1H), 7.50 (d, J=6.9 Hz, 1H), 7.13-7.08 (m, 2H), 6.96-6.86 (m, 2H), 4.10-3.70 (m, 2H), 3.72 (s, 3H), 3.54-3.40 (m, 2H), 3.38-3.22 (m, 2H), 3.20-3.06 (m, 2H).
    • EXAMPLE 72 (29) 4-(4-(3-Trifluoromethylphenyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene.hydrochloride
  • [2655]
    Figure US20030073706A1-20030417-C02114
  • TLC: Rf 0.47 (ethyl acetate:hexane=2:1); [2656]
  • NMR (DMSO-d[2657] 6): δ 7.98-7.93 (m, 1H), 7.74-7.67 (m, 2H), 7.56 (d, J=6.9 Hz, 1H), 7.49 (d, J=6.9 Hz, 1H), 7.48-7.40 (m, 1H), 7.27-7.16 (m, 2H), 7.14-7.07 (m, 1H), 3.88-3.67 (m, 2H), 3.46-3.34 (m, 4H), 3.27-3.18 (m, 2H).
    • EXAMPLE 72 (30) 4-((3R)-1-Benzylpyrrolidin-3-yl)carbamoyl-1,1-dioxidebenzo[b]thiophene
  • [2658]
    Figure US20030073706A1-20030417-C02115
  • TLC: Rf 0.45 (chloroform:methanol=9:1); [2659]
  • NMR (CDCl[2660] 3): δ 7.92 (dd, J=1.0 Hz and 7.0 Hz, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.68 (dd, J=1.0 Hz and 7.5 Hz, 1H), 7.54 (t, J=7.5 Hz, 1H), 7.40-7.20 (m, 5H), 6.75 (d, J=7.0 Hz, 1H), 6.70 (m, 1H), 4.65 (m, 1H), 3.66 (s, 2H), 3.05-2.95 (m, 1H), 2.78 (dd, J=1.0 Hz and 10 Hz, 1H), 2.60 (dd, J=6.0 Hz and 10 Hz, 1H), 2.50-2.20 (m, 2H), 1.85-1.70 (m, 1H).
    • EXAMPLE 72 (31) 4-((3S)-1-Benzylpyrrolidin-3-yl)carbamoyl-1,1-dioxidebenzo[b]thiophene
  • [2661]
    Figure US20030073706A1-20030417-C02116
  • TLC: Rf 0.45 (chloroform:methanol=9:1); [2662]
  • NMR (CDCl[2663] 3): δ 7.92 (dd, J=1.0 Hz and 7.0 Hz, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.68 (dd, J=1.0 Hz and 7.5 Hz, 1H), 7.54 (t, J=7.5 Hz, 1H), 7.40-7.20 (m, 5H), 6.75 (d, J=7.0 Hz, 1H), 6.70 (m, 1H), 4.65 (m, 1H), 3.66 (s, 2H), 3.05-2.95 (m, 1H), 2.78 (dd, J=1.0 Hz and 10 Hz, 1H), 2.60 (dd, J=6.0 Hz and 10 Hz, 1H), 2.50-2.20 (m, 2H), 1.85-1.70 (m, 1H).
    • EXAMPLES 73˜73 (29)
  • By the same procedure as described in Example 18 using an alcohol derivative corresponding to the compound prepared in Example 9 (12) and a halogenated compound corresponding to 4-nitrobenzylbromide, or by the same procedure as described in Example 29 using an alcohol derivative corresponding to 4-hydroxy-1,1-dioxidebenzo[b]thiophene and an alcohol derivative corresponding to 1-(3-hydroxypropyl)pyrrole, the following compounds of the present invention were obtained, with the proviso that when the compounds of the following Examples 73 (26)˜73 (29) were prepared by the same procedure as described in Example 18, an aqueous solution of sodium hydroxide was used instead of potassium carbonate. [2664]
    • EXAMPLE 73 5-Acetylmethyloxy-1,1-dioxidebenzo[b]thiophene
  • [2665]
    Figure US20030073706A1-20030417-C02117
  • TLC: Rf 0.25 (ethyl acetate:hexane:methylene chloride=1:1:1); [2666]
  • NMR (CDCl[2667] 3): δ 7.65 (d, J=8.2Hz, 1H), 7.15 (d, J=6.8Hz, 1H),6.92 (dd, J=8.2Hz, 2.2 Hz, 1H), 6.87 (d, J=2.2 Hz, 1H), 6.75 (d, J=6.8 Hz, 1H), 4.64 (s, 2H), 2.30 (s, 3H).
    • EXAMPLE 73 (1) 5-Cyanomethyloxy-1,1-dioxidebenzo[b]thiophene
  • [2668]
    Figure US20030073706A1-20030417-C02118
  • TLC: Rf 0.36 (hexane:ethyl acetate=1:1); [2669]
  • NMR (CDCl[2670] 3): δ 7.72 (d, J=8.4 Hz, 1H), 7.18 (d, J=7.2 Hz, 1H), 7.07 (dd, J=8.4, 2.4 Hz, 1H), 6.98 (d, J=2.4 Hz, 1H), 6.79 (d, J=7.2 Hz, 1H), 4.86 (s, 2H).
    • EXAMPLE 73 (2) 5-t-Butoxycarbonylmethyloxy-1,1-dioxidebenzo[b]thiophene
  • [2671]
    Figure US20030073706A1-20030417-C02119
  • TLC: Rf 0.54 (hexane:ethyl acetate=1:1); [2672]
  • NMR (CDCl[2673] 3): δ 7.63, (d, J=8.4 Hz, 1H), 7.13 (d, J=6.9 Hz, 1H), 6.91 (dd, J=8.4, 2.4 Hz, 1H), 6.88 (d, J=2.4 Hz, 1H), 6.73 (d, J=6.9 Hz, 1H), 4.58 (s, 2H), 1.49 (s, 9H).
    • EXAMPLE 73 (3) 5-(3-(Ethoxycarbonyl)propyloxy-1,1-dioxidebenzo[b]thiophene
  • [2674]
    Figure US20030073706A1-20030417-C02120
  • TLC: Rf 0.50 (hexane:ethyl acetate=1:1); [2675]
  • NMR (CDCl[2676] 3): δ 7.61 (d, J=8.7 Hz, 1H), 7.12 (d, J=6.9 Hz, 1H), 6.94 (dd, J=8.7, 2. 0 Hz, 1H), 6.84 (d, J=2.0 Hz, 1H), 6.71 (d, J=6.9 Hz, 1H), 4.15 (q, J=7.2 Hz, 2H), 4.08 (t, J=6.6 Hz, 1H), 2.51 (t, J=6.6 Hz, 1H), 2.13 (quint, J=6.6 Hz, 1H), 1.26 (t, J 7.2 Hz, 3H).
    • EXAMPLE 73 (4) 5-(4-(Ethoxycarbonyl)butyl)oxy-1,1-dioxidebenzo[b]thiophene
  • [2677]
    Figure US20030073706A1-20030417-C02121
  • TLC: Rf 0.48 (hexane:ethyl acetate=1:1); [2678]
  • NMR (CDCl[2679] 3): δ 7.61 (dd, J=8.4, 0.9 Hz, 1H), 7.12 (dd, J=6.9, 0.9 Hz, 1H), 6.93 (dd, J=8.4,2.4Hz, 1H), 6.84 (d, J=2.4Hz, 1H), 6.71 (d, J=6.9Hz, 1H), 4.13 (q, J=7.0Hz, 2H), 4.03 (t, J=6.0 Hz, 2H), 2.39 (t, J=7.0 Hz, 2H), 1.88-1.80 (m, 4H), 1.26 (t, J=7.0 Hz, 3H).
    • EXAMPLE 73 (5) 4-(Pyridin-3-ylmethyl)oxy-1,1-dioxidebenzo[b]thiophene
  • [2680]
    Figure US20030073706A1-20030417-C02122
  • TLC: Rf 0.42 (ethyl acetate:methanol=9:1); [2681]
  • NMR (CDCl[2682] 3): δ 5.19 (s, 2H), 6.63 (d, J=7.0 Hz, 1H), 7.13 (d, J=8.0 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.37 (dd, J=8.0 Hz, 5.0 Hz, 1H), 7.45 (dd, J=7.0 Hz, 1.0 Hz, 1H), 7.49 (t, J=8.0 Hz, 1H), 7.75 (dt, J=8.0 Hz, 2.0 Hz, 1H), 8.64 (dd, J=5.0 Hz, 2.0 Hz, 1H), 8.70 (d, J=2.0 Hz, 1H).
    • EXAMPLE 73 (6) 4-(Pyridin-4-ylmethyl)oxy-1,1-dioxidebenzo[b]thiophene
  • [2683]
    Figure US20030073706A1-20030417-C02123
  • TLC: Rf 0.16 (methylene chloride:ethyl acetate=1:1); [2684]
  • NMR (CDCl[2685] 3): δ 8.66 (d, J=6.0 Hz, 2H), 7.51 (dd, J=7.0, 1.0 Hz, 1H), 7.47 (t, J=8.0 Hz, 1H), 7.36-7.31 (m, 3H), 7.03 (d, J=8.0 Hz, 1H), 6.67 (d, J=7.0 Hz, 1H), 5.21 (s, 2H).
    • EXAMPLE 73 (7) 4-(4-Trifluoromethylphenylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2686]
    Figure US20030073706A1-20030417-C02124
  • TLC: Rf 0.67 (hexane:ethyl acetate=1:2); [2687]
  • NMR (CDCl[2688] 3): δ 7.70 (d, J=7.5 Hz, 2H), 7.60-7.30 (m, 5H), 7.10 (d, J=10 Hz, 1H), 6.65 (d, J=7.5 Hz, 1H), 5.25 (s, 2H).
    • EXAMPLE 73 (8) 4-(3,5-Dimethylisoxazol-4-ylmethyl) oxy-1,1-dioxidebenzo[b]thiophene
  • [2689]
    Figure US20030073706A1-20030417-C02125
  • TLC: Rf 0.53 (hexane:ethyl acetate=1:2); [2690]
  • NMR (CDCl[2691] 3): δ 7.60-7.40 (m, 1H), 7.40-7.30 (m, 2H), 7.10 (d, J=7.5 Hz, 1H), 6.60 (d, J=7.5 Hz,1H), 4.90 (s, 2H), 2.40 (s, 3H), 2.30 (s, 3H).
    • EXAMPLE 73 (9) 4-(4-Methoxycarbonylphenylmethyl)oxy-1, -dioxidebenzo[b]thiophene
  • [2692]
    Figure US20030073706A1-20030417-C02126
  • TLC: Rf 0.58 (hexane:ethyl acetate=1:2); [2693]
  • NMR (CDCl[2694] 3): δ 8.10 (d, J=7.5 Hz, 2H), 7.55-7.30 (m, 5H), 7.10 (d, J=10 Hz, 1H), 6.65 (d, J=7.5 Hz,1H), 5.25 (s, 2H), 3.95 (s, 3H).
    • EXAMPLE 73 (10) 4-(Benzotriazol-1-ylmethyl)oxy-1,1-dioxidebenzo[b]thiophene
  • [2695]
    Figure US20030073706A1-20030417-C02127
  • TLC: Rf 0.62 (hexane:ethyl acetate 1:2); [2696]
  • NMR (CDCl[2697] 3): δ 8.20-8.10 (m, 1H), 7.70-7.30 (m, 7H), 6.65 (s, 2H), 6.60 (d, J=7.5 Hz, 1H).
    • EXAMPLE 73 (11) 4-(2,6-Dimethylphenyl)carbamoylmethyloxy-1,1-dioxidebenzo[b]thiophene
  • [2698]
    Figure US20030073706A1-20030417-C02128
  • TLC: Rf 0.50 (hexane:ethyl acetate=1:2); [2699]
  • NMR (CDCl[2700] 3): δ 7.65-7.40 (m, 4H), 7.20-7.00 (m, 4H), 6.75 (d, J=7.5 Hz, 1H), 4.80 (s, 2H), 2.20 (s, 6H).
    • EXAMPLE 73 (12) 4-Trimethylsilylmethyloxy-1,1-dioxi debenzo[b]thiophene
  • [2701]
    Figure US20030073706A1-20030417-C02129
  • TLC: Rf 0.60 (hexane:ethyl acetate=1:1); [2702]
  • NMR (CDCl[2703] 3): δ 7.50-7.35 (m, 2H), 7.30-7.10 (m, 2H), 6.60 (d, J=7.5 Hz, 1H), 3.70 (s, 2H), 0.20 (s, 9H).
    • EXAMPLE 73 (13) 4-(Pyridin-2-ylmethyl)oxy-1,1-dioxidebenzo[b]thiophene
  • [2704]
    Figure US20030073706A1-20030417-C02130
  • TLC: Rf 0.31 (hexane:ethyl acetate=1:2); [2705]
  • NMR (CDCl[2706] 3): δ 8.70-8.55 (m, 1H), 7.85-7.70 (m, 1H), 7.60-7.20 (m, 5H), 7.10 (d, J=7.5 Hz, 1H), 6.65 (d, J=7.5 Hz, 1H), 5.35 (s, 2H).
    • EXAMPLE 73 (14) 4-(2-(Pyridin-3-ylcarbonyl)aminoethyl) oxy-1,1-dioxidebenzo[b]thiophene
  • [2707]
    Figure US20030073706A1-20030417-C02131
  • TLC: Rf 0.33 (ethyl acetate:methanol=9:1); [2708]
  • NMR (CDCl[2709] 3): δ 8.98 (dd, J=1.8, 0.9 Hz, 1H), 8.72 (dd, J=4.5, 1.8 Hz, 1H), 8.12 (d, J=8.0, 1.8 Hz, 1H), 7.49-7.42 (m, 2H), 7.28 (d, J=7.0 Hz, 1H), 7.08 (d, J=8.0 Hz, 1H), 6.83 (br, 1H), 6.58 (d, J=7.0 Hz, 1H), 4.30 (t, J=5.4 Hz, 2H), 3.93 (q, J=5.4 Hz, 2H).
    • EXAMPLE 73 (15) 4-(3-(Pyridin-3-yl)propyl)oxy-1,1-dioxidebenzo[b]thiophene
  • [2710]
    Figure US20030073706A1-20030417-C02132
  • TLC: Rf 0.32 (ethyl acetate:methanol 10:1); [2711]
  • NMR (CDCl[2712] 3+CD3OD): δ 8.52-8.25 (m, 2H), 7.80-7.18 (m, 5H), 7.07 (d, J=8 Hz, 1H), 6.68 (d, J=7 Hz, 1H), 4.14 (t, J=7 Hz, 2H), 2.87 (t, J=7 Hz, 2H), 2.35-2.10 (m, 2H).
    • EXAMPLE 73 (16) 4-(2-(Pyridin-2-yl)ethyl)oxy-1,1-dioxidebenzo[b]thiophene
  • [2713]
    Figure US20030073706A1-20030417-C02133
  • TLC: Rf 0.39 (ethyl acetate:methanol=10:1); [2714]
  • NMR (CDCl[2715] 3): δ 8.57 (d, J=5 Hz, 1H), 7.64 (dt, J=2, 7 Hz, 1H), 7.45 (t, J=8 Hz, 1H), 7.35-6.98 (m, 5H), 6.56 (d, J=7 Hz. 1H), 4.50 (t, J=7 Hz, 2H), 3.29 (t, J=7 Hz, 2H).
    • EXAMPLE 73 (17) 4-(1-t-Butoxycarbonylpiperidin-4-yl)oxy-1,1-dioxidebenzo[b]thiophene
  • [2716]
    Figure US20030073706A1-20030417-C02134
  • TLC: Rf 0.63 (ethyl acetate hexane=1:1); [2717]
  • NMR (CDCl[2718] 3): δ 7.55-7.38 (m, 2H), 7.30 (d, J=8 Hz, 1H), 7.07 (d, J=8 Hz, 1H), 6.23 (d, J=7 Hz, 1H), 4.70-4.50 (m, 1H), 3.85-3.58 (m, 2H), 3.50-3.28 (m, 2H), 2.15-1.88 (m, 2H), 1.88-1.66 (m, 2H), 1.47 (s, 9H).
    • EXAMPLE 73 (18) 4-(5-Methyl-1-tritylimidazol-4-ylmethyl) oxy-1,1-dioxidebenzo[b]thiophene
  • [2719]
    Figure US20030073706A1-20030417-C02135
  • TLC: Rf 0.11 (hexane:ethyl acetate=1:1); [2720]
  • NMR (CDCl[2721] 3): δ 7.55-7.23 (m, 14H), 7.23-7.00 (m, 6H), 6.56 (d, J=7 Hz, 1H), 5.13 (s, 2H), 1.45 (s, 3H).
    • EXAMPLE 73(19) 4-(1,2,4-oxadiazol-3-ylmethyl)oxy-1,1-dioxidebenzo[b]thiophene
  • [2722]
    Figure US20030073706A1-20030417-C02136
  • TLC: Rf 0.45 (hexane:ethyl acetate=1:2); [2723]
  • NMR (DMSO-d[2724] 6): δ 9.70 (s, 1H), 7.62 (t, J=8.0 Hz, 1H), 7.57 (d, J=6.9 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.31 (d, J=6.9 Hz, 1H), 5.58 (s, 2H).
    • EXAMPLE 73 (20) 6-(Pyridin-3-ylmethyl)oxy-1,1-dioxidebenzo[b]thiophene
  • [2725]
    Figure US20030073706A1-20030417-C02137
  • TLC: Rf 0.40 (ethyl acetate); [2726]
  • NMR (CDCl[2727] 3): δ 8.69 (d, J=1.7 Hz, 1H), 8.62 (dd, J=5.0, 1.7 Hz, 1H), 7.77 (d, J=7.8 Hz, 1i H), 7.39-7.27 (m, 3H), 7.18 (d, J=7.0 Hz, 1H), 7.09 (dd, J=8.2, 2.2 Hz, 1H), 6.58 (d, J=7.0 Hz, 1H), 5.14 (s, 2H).
    • EXAMPLE 73 (21) 6-(3-Nitrophenylmethyl)oxy-1,1-dioxidebenzo[b]thiophene
  • [2728]
    Figure US20030073706A1-20030417-C02138
  • MS (APCI, Pos.): m/z 318 (M+H)[2729] +.
    • EXAMPLE 73 (22) 6-(3-(t-Butoxycarbonylamino)propyl)oxy-1,1-dioxidebenzo[b]thiophene
  • [2730]
    Figure US20030073706A1-20030417-C02139
  • TLC: Rf 0.14 (hexane:ethyl acetate=2:1); [2731]
  • NMR (CDCl[2732] 3): δ 7.27-7.23 (m, 2H), 7.16 (d, J=6.9 Hz, 1H), 7.01 (dd, J=8.3,-2.3 Hz, 1H), 6.60 (d, J=6.9 Hz, 1H), 4.69 (br, 1H), 4.08 (t, J=6.6 Hz, 2H), 3.32 (q, J=6.6 Hz, 2H), 2.01 (quint, J=6.6 Hz, 2H), 1.44 (s, 9H).
    • EXAMPLE 73 (23) 7-t-Butoxycarbonylmethyloxy-1,1-dioxidebenzo[b]thiophene
  • [2733]
    Figure US20030073706A1-20030417-C02140
  • TLC: Rf 0.41 (hexane:ethyl acetate=1:1); [2734]
  • NMR (CDCl[2735] 3): δ 7.45 (dd, J=8.5, 7.5 Hz, 1H), 7.12 (d, J=6.9 Hz, 1H), 6.94 (d, J=7.5 Hz, 1H), 6.86 (d, J=8.5 Hz, 1H), 6.66 (d, J=6.9 Hz, 1H); 4.72 (s, 2H), 1.46 (s, 9H).
    • EXAMPLE 73 (24) 6-(Pyridin-3-yloxy)methyl-4-methoxy-1,1-dioxidebenzo[b]thiophene
  • [2736]
    Figure US20030073706A1-20030417-C02141
  • TLC: Rf 0.36 (ethyl acetate); [2737]
  • NMR (CD[2738] 3OD): δ 8.35 (d, J=3.0 Hz, 1H), 8.17 (d, J=4.0 Hz, 1H), 7.60-7.50 (m, 1H), 7.53 (d, J=7.2 Hz, 1H), 7.45-7.35 (m, 3H), 6.87 (d, J=7.2 Hz, 1H), 5.27 (s, 2H), 3.98 (s, 3H).
    • EXAMPLE 73 (25) 4,7-Bis(3-hydroxypropyl)-1,1-dioxidebenzo[b]thiophene
  • [2739]
    Figure US20030073706A1-20030417-C02142
  • TLC: Rf 0.44 (ethyl acetate:methanol=9:1); [2740]
  • NMR (CDCl[2741] 3): δ 7.34 (d, J=7.0 Hz, 1H), 7.04 (d, J=9.2 Hz,1H), 6.97 (d, J=9.2 Hz, 1H), 6.54 (d, J=7.0 Hz, 1H), 4.24 (t, J=5.8 Hz, 2H), 4.14 (t, J=5.8 Hz, 2H), 3.89 (t, J=5.8 Hz, 2H), 3.83 (t, J=5.8 Hz, 2H), 2.00-2.08 (m, 4H).
    • EXAMPLE 73 (26) 5-Carboxy-4-ethoxy-1,1-dioxidebenzo[b]thiophene
  • [2742]
    Figure US20030073706A1-20030417-C02143
  • TLC: Rf 0.38 (chloroform:methanol=10:1); [2743]
  • NMR (CD[2744] 3OD): δ 8.00 (d, J=7 Hz, 1H), 7.61 (dd, J=1, 7 Hz, 1H), 7.52 (dd, J=1, 7 Hz, 1H), 7.03 (d, J=7 Hz, 1H), 4.16 (q, J=7 Hz, 2H), 1.42 (t, J=7 Hz, 3H).
    • EXAMPLE 73 (27) 5-Carboxy-4-butoxy-1,1-dioxidebenzo[b]thiophene
  • [2745]
    Figure US20030073706A1-20030417-C02144
  • TLC: Rf 0.48 (chloroform:methanol=10:1); [2746]
  • NMR (CD[2747] 3OD): δ 7.98 (d, J=7 Hz, 1H), 7.58 (dd, J=1, 7 Hz,1H), 7.51 (dd, J=1, 7 Hz, 1H), 7.03 (d, J=7 Hz, 1H), 4.01 (t, J=7 Hz, 2H), 1.95-1.66 (m, 2H), 1.66-1.36 (m, 2H), 0.99 (t, J=7 Hz, 3H).
    • EXAMPLE 73 (28) 5-Carboxy-4-hexyioxy-1,1-dioxidebenzo[b]thiophene
  • [2748]
    Figure US20030073706A1-20030417-C02145
  • TLC: Rf 0.50 (chloroform:methanol=10:1); [2749]
  • NMR (CD[2750] 3OD): δ 7.98 (d, J=7 Hz, 1H), 7.58 (dd, J=1, 7 Hz, 1H), 7.51 (dd, J=1, 7 Hz, 1H), 7.03 (d, J=7 Hz, 1H), 4.10 (t, J=7 Hz, 2H), 1.95-1.65 (m, 2H), 1.65-1.05 (m, 6H), 0.92 (t, J=7 Hz, 3H).
    • EXAMPLE 73 (29) 5-Carboxy-4-octyloxy-1-dioxidebenzo[b]thiophene
  • [2751]
    Figure US20030073706A1-20030417-C02146
  • TLC: Rf 0.50 (chloroform:methanol=10:1); [2752]
  • NMR (CD[2753] 3OD): δ 7.98 (d, J=7 Hz, 1H), 7.57 (dd, J=1, 7 Hz, 1H), 7.51 (dd, J=1, 7 Hz, 1H), 7.03 (d, J=7 Hz, 1H), 4.10 (t, J=7 Hz, 2H), 1.95-1.65 (m, 2H), 1.65-1.05 (m, 10H), 0.90 (t, J=7 Hz, 3H).
    • EXAMPLES 74˜74 (5)
  • By the same procedure as described in Example 32 using carboxylic acid derivative corresponding to 4-carboxy-1,1-dioxidebenzo[b]thiophene and a halogenated compound corresponding to bromoethane, the compounds of the present invention having the following physical data were obtained, with the proviso that in the preparation of the compound of Example 74, 1 mol equivalent of bromoethane was used. [2754]
    • EXAMPLE 74 5-Ethoxycarbonyl-4-hydroxy-1,1-dioxidebenzo[b]thiophene
  • [2755]
    Figure US20030073706A1-20030417-C02147
  • TLC: Rf 0.32 (hexane:ethyl acetate=2:1); [2756]
  • NMR (CDCl[2757] 3): δπ11.37 (s, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.52 (dd, J=7.0, 0.8 Hz, 1H), 7.24 (dd, J=8.0, 0.8 Hz, 1H), 6.66 (d, J=7.0 Hz, 1H), 4.47 (q, J=7.0 Hz, 2H), 1.45 (t, J=7.0 Hz, 3H).
    • EXAMPLE 74 (1) 5-Ethoxycarbonyl-4-methoxy-1,1-dioxidebenzo[b]thiophene
  • [2758]
    Figure US20030073706A1-20030417-C02148
  • TLC: Rf 0.31 (hexane:ethyl acetate=2:1); [2759]
  • NMR (CDCl[2760] 3): δ 7.98 (d, J=7.4 Hz, 1H), 7.49 (t, J=7.4 Hz, 2H), 6.75 (d, J=7.4 Hz, 1H), 4.43 (q, J=7.0 Hz, 2H), 3.97 (s, 3H), 1.43 (t, J=7.0 Hz, 3H).
    • EXAMPLE 74 (2) 5-lsopropyloxycarbonyl-4-methoxy-1,1-dinxidebenzo[b]thiophene
  • [2761]
    Figure US20030073706A1-20030417-C02149
  • TLC: Rf 0.36 (hexane:ethyl acetate=2:1); [2762]
  • NMR (CDCl[2763] 3): δ 7.94 (d, J=7.8 Hz, 1H), 7.52-7.42 (m, 2H), 6.74 (d, J=7.2 Hz, 1H), 5.38-5.19 (m, 1H), 3.96 (s, 3H), 1.40 (d, J=6.2 Hz, 6H).
    • EXAMPLE 74 (3) 5-(2-Methylpropyl)oxycarbonyl-4-methoxy-1,1-dioxidebenzo[b]thiophene
  • [2764]
    Figure US20030073706A1-20030417-C02150
  • TLC: Rf 0.42 (hexane:ethyl acetate=2:1); [2765]
  • NMR (CDCl[2766] 3): δ 7.97 (d, J=7.8 Hz, 1H), 7.53-7.43 (m, 2H), 6.75 (d, J=7.2 Hz, 1H), 4.15 (d, J=6.8 Hz, 2H), 3.97 (s, 3H), 2.20-1.98 (m, 1H), 1.03 (d, J=6.6 Hz, 6H).
    • EXAMPLE 74(4) 6-Methoxycarbonyl-4-methoxy-1,1-dioxidebenzo[b]thiophene
  • [2767]
    Figure US20030073706A1-20030417-C02151
  • TLC: Rf 0.41 (hexane:ethyl acetate=1:1); [2768]
  • NMR (CDCl[2769] 3): δ 7.95 (t, J=1.0 Hz, 1H), 7.75 (d, J=1.0 Hz, 1H), 7.46 (dd, J=7.0, 1.0 Hz, 1H), 6.74 (d, J=7.0 Hz, 1H), 3.98 (s, 3H), 3.96 (s, 3H).
    • EXAMPLE 74 (5) 6-Methoxymethoxycarbonyl-4-methoxy-1,1-dioxidebenzo[b]thiophene
  • [2770]
    Figure US20030073706A1-20030417-C02152
  • TLC: Rf 0.38 (hexane:ethyl acetate=1:1); [2771]
  • NMR (CDCl[2772] 3): δ 7.99 (s, 1H), 7.79 (s, 1H), 7.47 (d, J=7.0 Hz, 1H), 6.76 (d, J=7.0 Hz, 1H), 5.52 (s, 2H), 4.00 (s, 3H), 3.58 (s, 3H).
    • EXAMPLES 75˜75(2)
  • By the same procedure as described in Example 31 using 4-bromomethyl-1,1-dioxidebenzo[b]thiophene and amine derivative corresponding to 2,4-dimethoxybenzylamine hydrochloride, the following compounds of the present invention were obtained. [2773]
  • With the proviso that in the preparation of the compounds of Example 75 and Example 75 (2), more than 2 mol equivalent of 4-bromomethyl-1,1-dioxidebenzo[b]thiophene versus amine derivative. [2774]
    • EXAMPLE 75 4-(N-(Pyridin-2-ylmethyl)-N-(1,1-dioxidebenzo[b]thiophen-4-ylmethyl)amino)methyl-1,1-dioxidebenzo[b]thiophene
  • [2775]
    Figure US20030073706A1-20030417-C02153
  • TLC: Rf 0.48 (methanol:methylene chloride=1:10); [2776]
  • NMR (CDCl[2777] 3): δ 8.59 (d, J=4.6 Hz, 1H), 7.72-7.55 (m, 3H), 7.55-7.38 (m, 4H), 7.35-7.16 (m, 3H), 7.10 (d, J=7.8 Hz, 1H), 6.68 (d, J=7.0 Hz, 2H), 3.76 (s, 4H), 3.73 (s, 2H).
    • EXAMPLE 75 (1) 4-(Pyridin-2-ylmethyl)aminomethyl-1,1-dioxidebenzo[b]thiophene
  • [2778]
    Figure US20030073706A1-20030417-C02154
  • TLC: Rf 0.31 (methylene chloride:methanol=10:1); [2779]
  • NMR (CD[2780] 3OD+CDCl3): δ 8.75-8.52 (m, 1H), 7.96-7.72 (m, 4H), 7.64 (t, J=8 Hz, 1H), 7.55-7.25 (m, 2H), 6.93 (d, J=7 Hz, 1H), 4.43 (s, 2H), 4.38 (s, 2H).
    • EXAMPLE 75 (2) 4-(N-(2,4-Dimethoxyphenylmethyl)-N-(1,1-dioxidebenzo[b]thiophene-4-ylmethyl) amino) methyl-1,1-dioxidebenzo[b]thiophene
  • [2781]
    Figure US20030073706A1-20030417-C02155
  • TLC: Rf 0.57 (ethyl acetate:benzene=1:1); [2782]
  • NMR (CDCl[2783] 3): δ 7.65-7.55 (m, 2H), 7.50-7.38 (m, 4H), 7.07-6.99 (m, 1H), 6.87 (d, J=7.0 Hz, 2H), 6.57 (d, J=7.0 Hz, 2H), 6.48-6.40 (m, 2H), 3.81 (s, 3H), 3.63 (s, 3H), 3.60 (s, 4H), 3.45 (s, 2H).
    • EXAMPLES 76˜76 (1)
  • By the same procedure as described in Example 1 using a derivative corresponding to 1,1-dioxidebenzo[b]thiophene and thiophenol, the following compounds of the present invention were obtained. [2784]
    • EXAMPLE 76 4,7-Dimethoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2785]
    Figure US20030073706A1-20030417-C02156
  • TLC: Rf 0.27 (hexane:methylene chloride 1:10); [2786]
  • NMR (CDCl[2787] 3): δ 7.52-7.47 (m, 2H), 7.35-7.32 (m, 3H), 7.02 (d, J=8.9 Hz, 1H), 6.91 (d, J=8.9 Hz,1H), 5.00 (dd, J=7.0,1.6 Hz, 1H), 3.92 (s, 3H), 3.85 (s, 3H), 3.73 (dd, J=13.9, 7.0 Hz, 1H), 3.59 (dd, J=13.9,1.6 Hz, 1H).
    • EXAMPLE 76 (1) 6-Bromo-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2788]
    Figure US20030073706A1-20030417-C02157
  • TLC: Rf 0.45 (hexane:ethyl acetate=2:1); [2789]
  • NMR (CDCl[2790] 3): δ 7.83 (d, J=1.8 Hz, 1H), 7.75 (dd, J=8.3, 1.8 Hz, 1H), 7.58 (d, J=8.3 Hz, 1H), 7.43-7.40 (m, 2H), 7.37-7.34 (m, 3H), 4.88 (t, J=6.9 Hz, 1H), 3.80 (dd, J=13.8, 6.9 Hz, 1H), 3.50 (dd, J=13.8, 6.9 Hz, 1H).
    • EXAMPLE 77 5-Acetyloxy-4-nitro-1,1-dioxidebenzo[b]thiophene
  • [2791]
    Figure US20030073706A1-20030417-C02158
  • By the same procedure as described in Example 12 using 5-hydroxy-4-nitro-1,1-dioxidebenzo[b]thiophene instead of the compound prepared in Example 11, the compound of the present invention having the following physical data was obtained. [2792]
  • TLC: Rf 0.49 (hexane:ethyl acetate=1:1); [2793]
  • NMR (DMSO-d[2794] 6): δ 8.32 (dd, J=8.0,1.0 Hz,1H),7.78 (d, J=7.0 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.69 (dd, J=7.0, 1.0 Hz, 1H), 2.35 (s, 3H).
    • EXAMPLES 78˜78 (1)
  • By the same procedure as described in Example 7 using the compounds prepared in Example 35 (39) and Example 35 (47) instead of the compound prepared in example 6 (8), the following compounds of the present invention were obtained. [2795]
    • EXAMPLE 78 4-(Piperidin-3-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride
  • [2796]
    Figure US20030073706A1-20030417-C02159
  • TLC: Rf 0.41 and 0.50 (ethyl acetate:acetic acid:water=3:1:1); [2797]
  • NMR (CD[2798] 3OD): δ 7.85-7.42 (m, 6H), 7.35-7.18 (m 2H), 5.68-5.50 (m, 1H), 4.15-3.90 (m, 3H), 3.90-3.50 (m, 2H), 3.50-3.30 (m, 1H), 3.20-2.90 (m, 2H), 2.45-2.15 (m, 1H), 2.15-1.40 (m, 4H).
    • EXAMPLE 78 (1) 5-(2-Aminoethyl)oxy-4-nitro-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride
  • [2799]
    Figure US20030073706A1-20030417-C02160
  • TLC: Rf 0.17 (ethyl acetate:methanol=2:1); [2800]
  • NMR (DMSO-d[2801] 6): δ 8.25 (br, 3H), 8.16 (d, J=8.7 Hz, 1H), 7.86-7.65 (m, 6H), 5.99 (d, J=7.2 Hz, 1H), 4.63-4.50 (m, 2H), 4.15-4.00 (m, 2H), 3.30-3.26 (m, 2H).
    • EXAMPLE 79 4-(2-(2-Hydroxyethoxy)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2802]
    Figure US20030073706A1-20030417-C02161
  • To a solution of the compound prepared in Example 35 (42) (258 mg) in ethanol, was added 47% aqueous solution of hydrobromic acid (1.0 ml). The mixture was refluxed for 1 hour. The reaction mixture was concentrated. The residue was dissolved in ethyl acetate. The mixture was washed by a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride successively, dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from ethyl acetate to give the compound of the present invention (174 mg) having the following physical data. [2803]
  • TLC: Rf 0.22 (ethyl acetate); [2804]
  • NMR (CDCl[2805] 3): δ 7.85-7.72 (m, 2H), 7.66-7.34 (m, 4H), 7.25 (d, J=8 Hz, 1H), 6.99 (d, J=8 Hz, 1H), 5.34 (d, J=9 Hz, 1H), 4.19 (d, J=15 Hz, 1H), 4.25-3.95 (m, 3H), 3.95-3.55 (m, 7H), 2.50 (brs, 1H).
    • EXAMPLE 80 4-(4,5-Dihydroxazol-2-yl)-1,1-dioxidebenzo[b]thiophene
  • [2806]
    Figure US20030073706A1-20030417-C02162
  • The compound prepared in Example 72 (1) (369 mg) was dissolved in diisopropylethylamine (0.55 ml) and methylene chloride (40 ml). The mixture was cooled to −78° C. Thereto was added trifluoromethanesulfonate anhydride (0.30 ml). The mixture was stirred at O° C. for 2.5 hours and thereto was added trifluoromethanesulfonate anhydride (0.15 ml). The mixture was stirred at room temperature for 1 hour. To the reaction mixture, were added ethyl acetate and 1N hydrochloric acid. The mixture was extracted by ethyl acetate. The extract was washed by 1N sodium hydroxide and a saturated aqueous solution of sodium chloride successively, dried over anhydrous sodium sulfate and concentrated. The residue was purified with column chromatography on silica gel (ethyl acetate:hexane=1:1) to give the compound of the present invention (97 mg) having the following physical data. [2807]
  • TLC: Rf 0.53 (ethyl acetate); [2808]
  • NMR (CDCl[2809] 3): δ 8.42 (d, J=7.0 Hz, 1H), 8.10 (d, J=7.8 Hz, 1H), 7.80 (d, J=7.8 Hz, 1H), 7.57 (t, J=7.8 Hz, 1H), 6.77 (d, J=7.0 Hz, 1H), 4.46 (t, J=9.4 Hz, 2H), 4.13 (t, J=9.4 Hz, 2H).
    • EXAMPLE 80 (1) 5-(4,5-Dihydroxazol-2-yl)-1,1-dioxidebenzo[b]thiophene
  • [2810]
    Figure US20030073706A1-20030417-C02163
  • By the same procedure as described in Example 80 using the compound prepared in Example 28 (25) instead of the compound prepared in Example 72 (1), the compound of the present invention having the following physical data was obtained. [2811]
  • TLC: Rf 0.39 (ethyl acetate); [2812]
  • NMR (CDCl[2813] 3): δ 8.10 (dd, J=7.8 Hz, 1.2 Hz, 1H), 7.97 (d, J=1.2 Hz, 1H), 7.76 (d, J=7.8 Hz, 1H), 7.25 (d, J=6.8 Hz, 1H), 6.78 (d, J=6.8 Hz, 1H), 4.50 (t, J=9.6 Hz, 2H), 4.11 (t, J=9.6 Hz, 2H).
    • EXAMPLES 81˜81 (1)
  • By the same procedure as described in Example 52 using the compounds prepared in Example 45 (10) and Example 35 (63) instead of the compound prepared in example 51, the following compounds of the present invention were obtained. [2814]
    • EXAMPLE 81 5-Carboxy-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2815]
    Figure US20030073706A1-20030417-C02164
  • TLC: Rf 0.22 (ethyl acetate:methanol=2:1); [2816]
  • NMR (DMSO-d[2817] 6): δ 7.91 (d, J=8.0 Hz, 1H), 7.86-7.74 (m, 3H), 7.68-7.61 (m, 2H), 7.56 (d, J=8.0 Hz, 1H), 5.68 (d, J=8.5 Hz, 1H), 4.19 (d, J=15.5 Hz, 1H), 4.01 (dd, J=15.5, 8.5 Hz, 1H), 3.66 (s, 3H). 3.35 (br, 1H).
    • EXAMPLE 81 (1)
  • 4-Carboxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene [2818]
    Figure US20030073706A1-20030417-C02165
  • Free Compound: [2819]
  • TLC: Rf 0.11 (chloroform:methanol 9:1); [2820]
  • NMR (DMSO-d[2821] 6): δ 13.78 (s, 1H), 8.24 (d, J=7.5 Hz, 1H), 8.05 (d, J=7.8 Hz, 1H), 7.91-7.84 (m, 1H), 7.82-7.74 (m, 3H), 7.69-7.61 (m, 2H), 6.27 (dd, J=7.8, 2.1 Hz, 1H), 4.20-3.95 (m, 2H).
  • Sodium Salt: [2822]
  • TLC: Rf 0.11 (chloroform:methanol=9:1); [2823]
  • NMR (DMSO-d[2824] 6): δ 8.22 (dd, J=7.4 Hz and 1.4 Hz, 1H), 7.95-7.85 (m, 3H), 7.85-7.70 (m, 2H), 7.70-7.55 (m, 2H), 6.62 (dd, J=8.0 Hz and 2.0 Hz, 1H), 4.10 (dd, J=15 Hz and 8.0 Hz, 1H), 3.95 (dd, J=15 Hz and 2.0 Hz, 1H).
    • EXAMPLE 82 4-Formyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2825]
    Figure US20030073706A1-20030417-C02166
  • To a solution of the compound prepared in Example 45 (20) (1.46 g) in methylene chloride (40 ml), were added pyridinium dichromate (2.44 g) and magnesium sulfate (1.0 g). The mixture was stirred at room temperature for 6 hours. The undissolved ingredients were filtered off. The filtrate was poured onto 1N hydrochloric acid. The mixture was extracted by ethyl acetate. The extract was washed by a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated. The residue was washed by methanol to give the compound of the present invention (1.03 g) having the following physical data. [2826]
  • TLC: Rf 0.65 (chloroform:methanol=9:1); [2827]
  • NMR (DMSO-d[2828] 6): δ 10.29 (s, 1H), 8.29 (dd, J=7.4, 1.2 Hz, 1H), 8.16 (dd, J=7.6,1.2 Hz, 1H), 8.03-7.92 (m, 1H), 7.86-7.72 (m, 3H), 7.71-7.57 (m, 2H), 6.41 (dd, J=8.0, 2.2 Hz, 1H), 4.08 (dd, J=15.2, 8.0 Hz, 1H), 3.97 (dd, J=15.2, 2.2 Hz, 1H).
    • EXAMPLES 83˜83 (3)
  • By the same procedure as described in Example 21 using the compounds prepared in Example 73 (2), Example 73 (23), Example 28 (12) and Example 72 (5) instead of the compound prepared in Example 20 (27), the following compounds of the present invention were obtained. [2829]
    • EXAMPLE 83 5-Carboxymethyloxy-1,1-dioxidebenzo[b]thiophene
  • [2830]
    Figure US20030073706A1-20030417-C02167
  • TLC: Rf 0.18 (ethyl acetate:methanol=5:1); [2831]
  • NMR (DMSO-d[2832] 6): δ 7.75 (dd, J=8.3, 0.9 Hz, 1H), 7.53 (dd, J=6.9, 0.9 Hz, 1H), 7.34 (d, J=6.9 Hz, 1H), 7.16 (d, J=2.7 Hz, 1H), 7.07 (dd, J=8.3, 2.7 Hz, 1H), 4.83 (s, 2H).
    • EXAMPLE 83 (1) 7-Carboxymethyloxy-1,1-dioxidebenzo[b]thiophene
  • [2833]
    Figure US20030073706A1-20030417-C02168
  • TLC: Rf 0.21 (ethyl acetate:methanol=4:1); [2834]
  • NMR (DMSO-d[2835] 6): δ 7.57 (t, J=7.8 Hz, 1H), 7.51 (d, J=6.9 Hz, 1H), 7.25 (d, J=6.9 Hz, 1H), 7.11 (d, J=7.8 Hz, 2H), 4.92 (s, 2H).
    • EXAMPLE 83 (2) 4-((1S)-1-Carboxy-2-methylpropyl)carbamoyl-1,1-dioxidebenzo[b]thiophene
  • [2836]
    Figure US20030073706A1-20030417-C02169
  • TLC: Rf 0.16 (ethyl acetate:methanol=4:1); [2837]
  • NMR (DMSO-d[2838] 6): δ 8.89 (d, J=7.8 Hz, 1H), 7.97 (d, J=7.3 Hz, 1H), 7.81 (d, J=7.3 Hz, 1H), 7.77 (d, J=7.3 Hz, 1H), 7.69 (t, J=7.3 Hz, 1H), 7.48 (d, J=7.3 Hz, 1H), 4.33 (dd, J=7.8, 6.0 Hz, 1H), 2.23-2.12 (m, 1H), 0.97 (d, J=6.6 Hz, 3H), 0.96 (d, J=6.6 Hz, 3H).
    • EXAMPLE 83 (3) 4-((1R)-1-Carboxy-2-methylpropyl)carbamoyl-1,1-dioxidebenzo[b]thiophene
  • [2839]
    Figure US20030073706A1-20030417-C02170
  • TLC: Rf 0.16 (ethyl acetate:methanol=4:1); [2840]
  • NMR (DMSO-d[2841] 6): δ 8.89 (d, J=7.8 Hz, 1H), 7.97 (d, J=7.3 Hz, 1H), 7.81 (d, J=7.3 Hz, 1H), 7.77 (d, J=7.3 Hz, 1H), 7.69 (t, J=7.3 Hz, 1H), 7.47 (d, J=7.3 Hz, 1H), 4.33 (dd, J=7.8, 6.0 Hz, 1H), 2.25-2.13 (m, 1H), 0.97 (d, J=6.6 Hz, 3H), 0.96 (d, J=6.6 Hz, 3H).
    • EXAMPLE 84 5-(3-Carboxypropyl) oxy-1,1-dioxidebenzo[b]thiophene
  • [2842]
    Figure US20030073706A1-20030417-C02171
  • To a solution of the compound prepared in Example 73 (3) (98 mg) in dimethylsulfoxide (5.0 ml) were added phosphate buffer (pH 7.4, 25 ml) and porcine liver esterase (100 μl). The mixture was stirred at room temperature for 18 hours. The reaction mixture was poured onto 1 N hydrochloric acid. The mixture was extracted by ethyl acetate. The extract was washed by a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated to give the compound of the present invention (90 mg) having the following physical data. [2843]
  • TLC: Rf 0.26 (chloroform:methanol=9:1); [2844]
  • NMR (CDCl[2845] 3): δ 7.62 (d, J=8.4 Hz, 1H), 7.13 (d, J=6.8 Hz, 1H), 6.95 (dd, J=8.4, 2.2 Hz, 1H), 6.85 (d, J=2.2 Hz, 1H), 6.73 (d, J=6.8 Hz, 1H), 4.10 (t, J=6.2 Hz, 2H), 2.58 (t, J=7.0 Hz, 2H), 2.24-2.07 (m, 2H).
    • EXAMPLE 84 (1) 5-((2E)-3-Carboxy-2-propenyl) oxy-1,1-dioxidebenzo[b]thiophene
  • [2846]
    Figure US20030073706A1-20030417-C02172
  • By the same procedure as described in Example 84 using the compound prepared in Example 30 (13) instead of the compound prepared in Example 73 (3), the compound of the present invention having the following physical data was obtained. [2847]
  • TLC: Rf 0.14 (chloroform:methanol=9:1); [2848]
  • NMR (CD[2849] 3OD): δ 7.64 (d, J=8.8 Hz, 1H), 7.38 (d, J=7.0 Hz, 1H), 7.16-7.00 (m, 3H), 6.95 (d, J=7.0 Hz, 1H), 6.13 (dt, J=15.8, 2.0 Hz, 1H), 4.89-4.80 (m, 2H).
    • EXAMPLE 85 5-(4-Phenylbutyl)aminomethyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2850]
    Figure US20030073706A1-20030417-C02173
  • To a solution of 4-Phenylbutylamine (164 mg) and the compound prepared in example 15 (366 mg) in methylene chloride (3.0 ml), was added sodium sulfate (1.0 g) at room temperature. The mixture was stirred for 1 hour. To the reaction mixture were added sodium borocyanohydride (63 mg), methanol (3.0 ml) and 4N solution of hydrogen chloride in dioxane (0.3 ml). The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated. To the residue was added chloroform. The undissolved ingredients were filtered off. The filtrate was concentrated. The residue was purified with column chromatography on silica gel (chloroform:methanol=100:5) to give the compound of the present invention (340 mg) having the following physical data, and then converted into hydrochloride by a known method to give the compound of the present invention having the following physical data. [2851]
  • Free Compound: [2852]
  • TLC: Rf 0.42 (chloroform:methanol=10:1); [2853]
  • NMR (CDCl[2854] 3): δ 7.80-7.50 (m, 6H), 7.33-7.12 (m, 6H), 5.34 (d, J=4.8 Hz, 1H), 4.15-3.90 (m, 4H), 3.75 (s, 3H), 2.98 (t, J=7.8 Hz, 2H), 2.63 (t, J=7.8 Hz, 2H), 1.88-1.60 (m, 4H).
  • Hydrochloride: [2855]
  • TLC: Rf 0.42 (chloroform:methanol=10:1); [2856]
  • NMR (CDCl[2857] 3): δ 9.49 (bs, 2H), 7.93 (d, J=8.1 Hz, 1H), 7.77-7.70 (m, 2H), 7.65 (t, J=8.1 Hz, 1H), 7.50 (t, J=8.1 Hz, 2H), 7.35-7.12 (m, 6H), 5.27 (d, J=8.1 Hz, 1H), 4.18-4.02 (m, 2H), 3.98 (d, J=15.0 Hz, 1H), 3.88 (s, 3H), 3.85 (dd, J=15.0, 8.1 Hz, 1H), 3.00-2.85 (m, 2H), 2.63 (t, J=7.5 Hz, 2H), 2.00-1.60 (m, 4H).
    • EXAMPLE 85 (1) 5-(Pyridin-3-ylmethyl)aminomethyl-4-methoxy-3-phenysulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2858]
    Figure US20030073706A1-20030417-C02174
  • By the same procedure as described in Example 85 using the compound prepared in Example 15, and (pyridin-3-ylmethyl)amine instead of 4-phenylbutylamine, the compound of the present invention having the following physical data was obtained. And then, by converting into hydrochloride using the obtained compound by a known method, the compound of the present invention having the following physical data was obtained. [2859]
  • Free Compound: [2860]
  • TLC: Rf 0.35 (chloroform:methanol=10:1); [2861]
  • NMR (CDCl[2862] 3): δ 8.59 (d, J=2.0 Hz, 1H), 8.55 (dd, J=4.8, 2.0 Hz, 1H), 7.80-7.65 (m, 4H), 7.58 (d, J=6.0 Hz, 1H), 7.43 (dd, J=7.6, 2.0 Hz, 3H), 7.30 (dd, J=7.6, 4.8 Hz, 1H), 5.20 (d, J=8 .2 Hz, 1H), 4.17 (d, J=13.4 Hz, 1H), 3.95-3.70 (m, 5H), 3.80 (s, 3H).
  • 2hydrochloride: [2863]
  • TLC: Rf 0.35 (chloroform:methanol=10:1); [2864]
  • NMR (DMSO-d[2865] 6): δ 10.35 (brs, 1H), 10.15 (bs, 1H), 9.03 (s, 1H), 8.85 (d, J=5.2 Hz, 1H), 8.55 (d, J=8.4 Hz, 1H), 8.06 (d, J=8.4 Hz, 1H), 7.95-7.72 (m, 4H), 7.70-7.55 (m, 3H), 5.85-5.77 (m, 1H), 4.40-4.00 (m, 6H), 3.69 (s, 3H).
    • EXAMPLE 86 6-Dimethylamino-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2866]
    Figure US20030073706A1-20030417-C02175
  • By the same procedure as described in Example 8 using the compound prepared in Example 35 (68) instead of the compound prepared in Example 7, the compound of the present invention having the following physical data was obtained. [2867]
  • TLC: Rf 0.48 (hexane:ethyl acetate=1:2); [2868]
  • NMR (DMSO-d[2869] 6): δ 7.81-7.74 (m, 3H), 7.66-7.58 (m, 2H), 7.40 (d, J=9.0 Hz, 1H), 7.09 (dd, J=9.0, 2.5 Hz, 1H), 6.80 (d, J=2.5 Hz, 1H), 5.56 (dd, J=9.5, 3.0 Hz,1H), 3.91 (dd, J=15.0, 9.5 Hz, 1H), 3.67 (dd, J=15.0, 3.0 Hz, 1H), 2.99 (s, 6H).
    • EXAMPLE 87 4-(2-Dimethylaminoethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride
  • [2870]
    Figure US20030073706A1-20030417-C02176
  • By the same procedure as described in Example 28 using the compound prepared in Example 81 (1) instead of 4-carboxy-1,1-dioxidebenzo[b]thiophene, and (2-dimethylaminoethyl)amine instead of (pyridin-3-ylmethyl)amine, and then by converting into hydrochloride by known methods, the following compound of the present invention was obtained. [2871]
  • TLC: Rf 0.62 (chloroform:methanol:triethylamine=8:2:1); [2872]
  • NMR (DMSO-d[2873] 6): δ 10.40-10.20 (br, 1H), 9.19 (t, J=5.4Hz, 1H), 8.13 (d, J=6.9 Hz, 1H), 7.94 (d, J=7.5 Hz, 1H), 7.87 (d, J=7.8 Hz, 1H), 7.84-7.72 (m, 3H), 7.67-7.58 (m, 2H), 6.27 (d, J=9.0 Hz, 1H), 4.13 (dd, J=9.0,15.0 Hz, 1H), 3.96 (d, J=15.0 Hz, 1H), 3.77-3.55 (m, 2H), 3.40-3.22 (m, 2H), 2.87-2.74 (m, 6H).
    • EXAMPLES 88˜88 (2)
  • Using the compounds prepared in Example 18 (40), Example 20 (4) and Example 45 (3) instead of the compound prepared in Example 1 by the same procedure as described in Example 3 or by the same reaction using 3-chloroperbenzoic acid instead of OXONE@ as an oxidizer, the following compounds of the present invention were prepared. [2874]
    • EXAMPLE 88 4,7-Bis(pyridin-3-ylmethyloxy)-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2875]
    Figure US20030073706A1-20030417-C02177
  • TLC: Rf 0.36 (ethyl acetate:methanol=2:1); [2876]
  • NMR (CDCl[2877] 3): δ 8.65-8.60 (m, 3H), 8.57 (dd, J=5.0,1.5 Hz, 1H), 7.90-7.80 (m, 2H), 7.68-7.65 (m, 2H), 7.60-7.55 (m, 1H), 7.41-7.31 (m, 4H), 7.01 (d, J=9.0 Hz,1H), 6.98 (d, J=9.0 Hz, 1H), 5.25 (d, J=13.0 Hz, 1H), 5.21 (dd, J=9.5, 1.0 Hz, 1H), 5.20 (d, J=13.0 Hz,1H), 4.96 (d, J=12.0 Hz, 1H), 4.87 (d, J=12.0 Hz, 1H), 4.12 (dd, J=15.0, 1.0 Hz, 1H), 3.75 (dd, J=15.0, 9.5 Hz, 1H).
    • EXAMPLE 88 (1) 4-(N-Oxidepyridin-3-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2878]
    Figure US20030073706A1-20030417-C02178
  • TLC: Rf 0.30 (ethyl acetate:methanol=2:1); [2879]
  • NMR (DMSO-d[2880] 6): δ 8.29 (s, 1H), 8.20 (d, J=6.2 Hz, 1H), 7.73-7.57 (m, 4H), 7.51-7.31 (m, 6H), 5.77 (d, J=8.8 Hz, 1H), 5.10 (d, J=12.8 Hz, 1H), 4.90 (d, J=12.8 Hz, 1H), 4.18 (d, J=15.0 Hz, 1H), 3.95 (dd, J=15.0, 8.8 Hz, 1H).
    • EXAMPLE 88 (2) 4-(2-(N-Oxidepyridin-4-yl)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2881]
    Figure US20030073706A1-20030417-C02179
  • TLC: Rf 0.23 (ethyl acetate:methanol=9:1); [2882]
  • NMR (DMSO-d[2883] 6): δ 8.11 (d, J=6.9 Hz, 2H), 7.79-7.72 (m, 3H), 7.65-7.60 (m, 3H), 7.34 (d, J=7.5 Hz, 1H), 7.28-7.25 (m, 3H), 5.41 (d, J=8.5 Hz, 1H), 4.16 (d, J=15.0 Hz, 1H), 4.15-3.90 (m, 2H), 4.02 (dd, J=15.0, 8.5 Hz, 1H), 2.88-2.66 (m, 2H).
    • EXAMPLE 89 4-methoxy-3-(4-hydroxyphenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2884]
    Figure US20030073706A1-20030417-C02180
  • By the same procedure as describe in 1 using the compound prepared in example 28 (27) instead of 1,1-dioxidebenzo[b]thiophene and 4-mercaptphenol instead of thiophenol, the compound of the present invention having the following physical data was obtained. [2885]
  • TLC: Rf 0.27 (hexane:ethyl acetate=1:1); [2886]
  • NMR (CDCl[2887] 3): δ 7.60-7.00 (m, 3H), 7.35 (d, J=7.5 Hz, 2H), 6.80 (d, J=7.5 Hz, 2H), 6.00 (s, 1H), 4.90 (dd, J=5.0, 1.2 Hz, 1H), 3.90 (s, 3H), 3.75-3.50 (m, 2H)
    • EXAMPLE 90 4-Methoxy-3-(4-(pyridin-3-ylmethyloxy) phenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2888]
    Figure US20030073706A1-20030417-C02181
  • By the same procedure as described in Example 18 using the compound prepared in Example 89 instead of the compound prepared in Example 9 (12) and a halogenated compound corresponding to 4-nitrobenzylbromide, the compound of the present invention having the following physical data was obtained. [2889]
  • TLC: Rf 0.22 (ethyl acetate). [2890]
    • EXAMPLE 91 4-Methoxy-3-(4-(pyridin-3-ylmethyloxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride
  • [2891]
    Figure US20030073706A1-20030417-C02182
  • By the same procedure as described in Example 3 using the compound prepared in Example 90 instead of the compound prepared in Example 1, the compound of the present invention having the following physical data was obtained. [2892]
  • TLC: Rf 0.39 (ethyl acetate:triethylamine=95:5); [2893]
  • NMR (DMSO-d[2894] 6): δ 9.05 (br.s, 1H), 8.90 (d, J=5.0 Hz, 1H), 8.55 (d, J=7.5 Hz, 1H), 8.00 (dd, J=7.5, 5.0 Hz, 1H), 7.80-8.60 (m, 3H), 7.50-7.15 (m, 4H), 5.60-5.40 (m, 3H), 4.20 (d, J=15 Hz, 1H), 4.00 (dd, J=15, 7.5 Hz, 1H), 3.45 (s, 3H).
    • Examples 92˜92 (1)
  • By the same procedure as described in Example 1 using the compounds prepared in Example 28 (27) and Example 28 (26) instead of 1,1-dioxidebenzo[b]thiophene, and thiophenol, the following compounds of the present invention were obtained. [2895]
    • EXAMPLE 92 5-(2-Dimethylaminoethyl)carbamoyl-4-methoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2896]
    Figure US20030073706A1-20030417-C02183
  • TLC: Rf 0.40 (ethyl acetate:methanol:triethylamine=8:1:1); [2897]
  • NMR (CDCl[2898] 3): δ 8.10 (d, J=8.0 Hz, 1H), 7.67 (br, 1H), 7.55-7.48 (m, 3H), 7.39-7.36 (m, 3H), 5.10 (dd, J=6.5, 2.0 Hz, 1H), 4.06 (s, 3H), 3.71 (dd, J=14.0, 6.5 Hz, 1H), 3.61 (dd, J=14.0, 2.0 Hz, 1H), 3.57 (q, J=6.0 Hz, 2H), 2.53 (t, J=6.0 Hz, 2H), 2.29 (s, 6H).
    • EXAMPLE 92 (1) 5-(Pyridin-3-ylmethyl)carbamoyl-4-methoxy-3-phenylthio-2,3-dihydro 1,1-dioxidebenzo[b]thiophene
  • [2899]
    Figure US20030073706A1-20030417-C02184
  • TLC: Rf 0.46 (ethyl acetate:methanol=9:1); [2900]
  • NMR (CDCl[2901] 3): δ 8.60-8.52 (m, 2H), 8.06 (d, J=8.0 Hz, 1H), 7.77-7.74 (m, 2H), 7.53-7.45 (m, 3H), 7.37-7.30 (m, 4H), 5.03 (dd, J=6.5, 2.0 Hz, 1H), 4.67 (d, J=6.0 Hz, 2H), 3.92 (s, 3H), 3.70 (dd, J=14.0, 6.5 Hz, 1H), 3.58 (dd, J=14.0, 2.0 Hz, 1H).
    • EXAMPLE 93 4-(2-(Piperidin-1-yl)ethyl)aminomethyl-1,1-dioxidebenzo[b]thiophene
  • [2902]
    Figure US20030073706A1-20030417-C02185
  • By the same procedure as described in Example 31 using 4-bromomethyl-1,1-dioxidebenzo[b]thiophene, and 1-(2-aminoethyl)piperidine instead of 2,4-dimethoxybenzylamine -hydrochloride, the compound of the present invention having the following physical data was obtained. And then, the obtained compound was converted into hydrochloride by a known method to give the compound of the present invention having the following physical data. [2903]
  • Free Compound: [2904]
  • TLC: Rf 0.16 (ethyl acetate:methanol:triethylamine=90:5:5); [2905]
  • NMR (CDCl[2906] 3): δ 7.75-7.60 (m, 2H), 7.60-7.40 (m, 2H), 6.70 (d, J=7.5 Hz, 1H), 3.90 (s, 2H), 2.70 (t, J=7.5 Hz, 2H), 2.50-2.20 (m, 4H), 2.40 (t, J=7.5 Hz, 2H), 1.65-1.35 (m, 6H).
  • 2hydrochloride: [2907]
  • TLC: Rf 0.28 (ethyl acetate:methanol:triethylamine=8:1:0.5); [2908]
  • NMR (DMSO-d[2909] 6+pyridine-d5): δ 8.15 (d, J=7.5 Hz, 1H), 8.00 (d, J=7.5 Hz, 1H), 7.90 (d, J=7.5 Hz, 1H), 7.70 (t, J=7.5 Hz, 1H), 7.50 (d, J=7.5 Hz, 1H), 4.40 (s, 2H), 3.55-3.30 (m, 4H), 3.30-3.10 (m, 4H), 1.90-1.70 (m, 4H), 1.65-1.50 (m, 2H).
    • EXAMPLE 94 4-(2-(Piperidin-1-yl)ethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2910]
    Figure US20030073706A1-20030417-C02186
  • By the same procedure as described in Example 27 using the compound prepared in Example 93 instead of 5-methyl-1,1-dioxidebenzo[b]thiophene, the compound of the present invention having the following physical data was obtained. And then, the obtained compound was converted into hydrochloride by a known method to give the compound of the present invention having the following physical data. [2911]
  • Free Compound: [2912]
  • TLC: Rf 0.18 (ethyl acetate:methanol:triethylamine=90:5:5); [2913]
  • NMR (CDCl[2914] 3): δ 7.80-7.40 (m, 8H), 6.10 (d, J=10 Hz, 1H), 4.60 (d, J=15 Hz, 1H), 3.95 (d, J=15 Hz, 1H), 3.90 (d, J=15 Hz, 1H), 3.75 (dd, J=15, 10 Hz, 1H), 2.80-2.60 (m, 2H), 2.60-2.20 (m, 6H), 1.60-1.30 (m, 6H).
  • 2hydrochloride: [2915]
  • TLC: Rf 0.30 (ethyl acetate:methanol:triethylamine=8:1:0.5); [2916]
  • NMR (DMSO-d[2917] 6+pyridine-d5): δ 8.35 (d, J=7.5 Hz, 1H), 8.00-7.75 (m, 5H), 7.65 (t, J=7.5 Hz, 2H), 6.70 (d, J=7.5 Hz, 1H), 4.80 (d, J=15 Hz, 1H), 4.50 (d, J=15 Hz, 1H), 4.20-3.95 (m, 2H), 3.65-3.35 (m, 4H), 3.30-3.00 (m, 4H), 2.00-1.70 (m, 4H), 1.70-1.40 (m, 2H).
    • EXAMPLE 95 4-t-Butoxycarbonylaminobenzo[b]thiophene
  • [2918]
    Figure US20030073706A1-20030417-C02187
  • To a suspension of 4-carboxybenzo[b]thiophene (3.2 g) in t-butanol (170 ml), were added triethylamine (7.5 ml) and diphenylphosphorylamide (4.2 ml). The mixture was stirred at 95° C. for 2 hours. The precipitate was filtered off and the filtrate was concentrated. The residue was extracted with ethyl acetate. The extract was washed by water, dried over anhydrous magnesium sulfate and concentrated. The residue was purified with column chromatopgaphy on silica gel (hexane:ethyl acetate=5:1) to give the compound of the present invention (3.0 g) having the following physical data. [2919]
  • TLC: Rf 0.41 (hexane:ethyl acetate=3:1); NMR (CDCl[2920] 3): δ 7.81-7.78 (m, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.44-7.24 (m, 3H), 6.74 (br, 1H), 1.55 (s, 9H).
    • EXAMPLE 96 4-t-Butoxycarbonylamino-1,1-dioxidebenzo[b]thiophene
  • [2921]
    Figure US20030073706A1-20030417-C02188
  • To a solution of the compound prepared in Example 95 (3.0 g) in chloroform (100 ml) was added m-chloroperbenzoic acid (8.2 g) at 0° C. The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated. The residue was extracted with ethyl acetate. The extract was washed by an aqueous solution of sodium hydroxide, water and a saturated solution of sodium chloride successively, dried over anhydrous magnesium sulfate and concentrated. The residue was dissolved in methylene chloride and was allowed to stand overnight. The crystals that appeared were filtered. The filtrate was concentrated. The residue was purified with column chromatography on silica gel (methylene chloride), combined with the said crystals, to give the compound of the present invention (3.0 g) having the following physical data. [2922]
  • TLC: Rf 0.41 (hexane:ethyl acetate=1:1); NMR (CDCl[2923] 3): δ 7.83-7.80 (m, 1H), 7.49 (t, J=7.5 Hz, 1H), 7.46-7.43 (m, 1H), 7.31 (dd, J=7.2, 1.0 Hz,1H), 6.70 (d, J=7.2 Hz,1H), 6.54 (br,1H), 1.53 (s, 9H).
    • EXAMPLE 97 4-Amino-1,1-dioxidebenzo[b]thiophene hydrochloride
  • [2924]
    Figure US20030073706A1-20030417-C02189
  • To a solution of the compound prepared in Example 96 (2.5 g) in ethyl acetate (30 ml) was added 4N solution of hydrogen chloride in ethyl acetate (10 ml). The mixture was stirred at room temperature for 3 hours. After removing the solvent, the residue was washed by ethyl acetate to give the compound of the present invention (1.8 g) having the following physical data. [2925]
  • TLC: Rf 0.29 (hexane:ethyl acetate=1:2); [2926]
  • NMR (CD[2927] 3OD): δ 7.63 (dd, J=7.0, 1.0 Hz, 1H), 7.61 (t, J=7.5 Hz, 1H), 7.54 (dt, J=7.5,1.0 Hz, 1H), 7.42 (dd, J=7.5, 1.0 Hz, 1H), 7.08 (d, J=7.0 Hz, 1H).
    • EXAMPLE 98 4-(4-Fluorobenzylcarbonylamino)-1,1-dioxidebenzo[b]thiophene
  • [2928]
    Figure US20030073706A1-20030417-C02190
  • To a solution of the compound prepared in Example 97 (100 mg), 4-fluorophenylacetic acid (192 mg) and triethylamine (1 ml) in dimethylformamide (3 ml) was added propanephosphonic acid cyclic anhydride (50 % solution in dimethylformamide; 3 ml). The mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added ethyl acetate. The mixture was washed by water, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, and concentrated. The residue was purified with column chromatography on silica gel (hexane:ethyl acetate=1:1), followed by recrystallization from ethyl acetate-hexane to give the compound of the present invention having the following physical data. [2929]
  • TLC: Rf 0.63 (ethyl acetate); [2930]
  • NMR (DMSO-d[2931] 6): δ 10.27 (s, 1H), 7.88-7.82 (m, -1H), 7.64 (d, J=7.0 Hz, 1H), 7.61-7.55 (m, 2H), 7.41-7.34 (m, 3H), 7.16 (t, J=9.0 Hz, 2H), 3.75 (s, 2H).
    • EXAMPLES 98 (1)˜98 (5)
  • By the same procedure as described in Example 98 using the compound prepared in Example 97 and a carboxylic acid derivative corresponding to 4-fluorophenylacetic acid, the compounds of the present invention having the following physical data. [2932]
    • EXAMPLE 98 (1) 4-(Pyridin-3-ylcarbonyl)amino-1,1-dioxidebenz[b]thiophene
  • [2933]
    Figure US20030073706A1-20030417-C02191
  • TLC: Rf 0.18 (ethyl acetate); [2934]
  • NMR (DMSO-d[2935] 6): δ 10.69 (s, 1H), 9.17 (d, J=2.0 Hz, 1H), 8.80 (dd, J=5.0, 2.0 Hz,1H), 8.34 (dt, J=7.8, 2.0 Hz, 1H), 7.82 (dd, J=7.5, 1.5 Hz, 1H), 7.72-7.63 (m, 3H), 7.60 (dd, J=7.8, 5.0 Hz, 1H), 7.36 (d, J=7.2 Hz, 1H).
    • EXAMPLE 98 (2) 4-(3-Chlorobenzoyl) amino-1,1-dioxidebenzo[b]thiophene
  • [2936]
    Figure US20030073706A1-20030417-C02192
  • TLC: Rf 0.25 (hexane:ethyl acetate=1:1); [2937]
  • NMR (DMSO-d[2938] 6): δ 10.62 (s, 1H), 8.07 (t, J=1.5Hz, 1H), 7.96 (dt, J=7.7,1.5 Hz, 1H), 7.78 (dd, J=7.7, 1.5 Hz, 1H), 7.73-7.64 (m, 4H), 7.60 (t, J=7.7 Hz, 1H), 7.35 (d, J=6.6 Hz,1H).
    • EXAMPLE 98 (3) 4-Benzylcarbonylamino-1,1-dioxidebenzo[b]thiophene
  • [2939]
    Figure US20030073706A1-20030417-C02193
  • TLC: Rf 0.45 (hexane:ethyl acetate=1:2); [2940]
  • NMR (CDCl[2941] 3): δ 7.75-7.72 (m, 1H), 7.48-7.35 (m, 7H), 7.29 (br, 1H), 6.79 (d, J=7.2 Hz, 1H), 6.58 (d, J=7.2 Hz, 1H), 3.79 (s, 2H).
    • EXAMPLE 98 (4) 4-(Dimethylaminoacetyl)amino-1,1-dioxidebenzo[b]thiophene
  • [2942]
    Figure US20030073706A1-20030417-C02194
  • TLC: Rf 0.31 (ethyl acetate:methanol=4:1); [2943]
  • NMR (CDCl[2944] 3): δ 9.52 (br, 1H), 8.06 (m, 1H), 7.56-7.48 (m, 2H), 7.28-7.25 (m, 1H), 6.73 (d, J=7.0 Hz, 1H), 3.15 (s, 2H), 2.44 (s, 6H).
    • EXAMPLE 98 (5) 4-Acetylamino-1,1-dioxidebenzo[b]thiophene
  • [2945]
    Figure US20030073706A1-20030417-C02195
  • TLC: Rf 0.25 (ethyl acetate); [2946]
  • NMR (DMSO-d[2947] 6): δ 1 0.05 (s, 1H), 7.89-7.83 (m, 1H), 7.70 (d, J=7.0 Hz, 1H), 7.61-7.55 (m, 2H), 7.33 (d, J=7.0 Hz, 1H), 2.12 (s, 3H).
    • EXAMPLES 99˜99 (10)
  • By the same procedure as described in Example 28 using 4-carboxy-1,1-dioxidebenzo[b]thiophene (prepared in Example 107 hereinafter described) and a corresponding amine derivative instead of (pyridin-3-ylmethyl)amine, and if necessary, by converting into the corresponding salt by known methods by a known method, the compounds of the present invention having the following physical data were obtained. [2948]
    • EXAMPLE 99 4-(3-(2-Oxopyrrolidin-1-yl)propyl)carbamoyl-1,1-dioxidebenzo[b]thiophene
  • [2949]
    Figure US20030073706A1-20030417-C02196
  • TLC: Rf 0.36 (chloroform:methanol=9:1); [2950]
  • NMR (CDCl[2951] 3): δ 8.19 (dd, J=7.0 Hz and 1.0 Hz, 1H), 8.05 (broad s, 1H), 7.95 (dd, J=8.0 Hz and 1.0 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.60 (t, J=8.0 Hz, 1H), 6.75 (d, J=7.0 Hz, 1H), 3.50-3.35 (m, 6H), 2.46 (t, J=8.0 Hz, 2H), 2.20-2.00 (m, 2H), 1.90-1.70 (m, 2H).
    • EXAMPLE 99 (1) 4-(2-Dimethylaminoethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene
  • [2952]
    Figure US20030073706A1-20030417-C02197
  • TLC: Rf 0.20 (ethyl acetate:acetic acid:water=3:1:1); [2953]
  • NMR (CDCl[2954] 3): δ 8.03 (dd, J=7.2 Hz and 1.0 Hz, 1H), 7.79 (dt, J=7.8 Hz and 1.0 Hz, 1H), 7.69 (dd, J=7.8 Hz and 1.0 Hz, 1H), 7.57 (t, J=7.8 Hz, 1H), 6.77 (d, J=7.2 Hz, 1H), 3.49 (m, 2H), 2.67 (t, J=6.0 Hz, 2H), 2.58 (q, J=7.2 Hz, 4H), 1.04 (t, J=7.2 Hz, 6H).
    • EXAMPLE 99 (2) 4-(2-(N-Ethyl-N-(3-methylphenyl)amino)ethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene
  • [2955]
    Figure US20030073706A1-20030417-C02198
  • TLC: Rf 0.61 (chloroform:methanol 9:1); [2956]
  • NMR (CDCl[2957] 3): δ 7.91 (d, J=7.0 Hz, 1H), 7.74 (m, 1H), 7.55-7.40 (m, 2H), 7.13 (dd, J=9.0 Hz and 7.4 Hz, 1H), 6.73 (d, J=7.0 Hz, 1H), 6.70-6.55 (m, 3H), 6.35 (broad s, 1H), 3.75-3.50 (m, 4H), 3.19 (q, J=7.0 Hz, 2H), 2.29 (s, 3H), 1.16 (t, J=7.0 Hz, 3H).
    • EXAMPLE 99 (3) 4-(2,4,6-Trimethoxybenzyl) carbamoyl-1,1-dioxidebenzo[b]thiophene
  • [2958]
    Figure US20030073706A1-20030417-C02199
  • TLC: Rf 0.63 (chloroform:methanol=9:1); [2959]
  • NMR (CDCl[2960] 3+DMSO-d6): δ 7.89 (d, J=7.0 Hz, 1H), 7.80-7.65 (m, 3H), 7.55 (t, J=7.4 Hz, 1H), 6.88 (d, J=7.0 Hz, 1H), 6.17 (s, 2H), 4.56 (d, J=4.8 Hz, 2H), 3.84 (s, 6H), 3.82 (s, 3H).
    • EXAMPLE 99 (4) 4-(4-(2-Hydroxyethyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thioiphene.hydrochloride
  • [2961]
    Figure US20030073706A1-20030417-C02200
  • TLC: Rf 0.33 (methylene chloride:methanol=10:1); [2962]
  • NMR (DMSO-d[2963] 6): δ 8.00-7.93 (m, 1H), 7.76-7.66 (m, 2H), 7.58 (d, J=6.9 Hz, 1H), 7.52 (d, J=6.9 Hz, 1H), 5.40 (bs, 1H), 4.64-4.46 (m, 1H), 6.85-3.73 (m, 2H), 3.70-3.00 (m, 10H).
    • EXAMPLE 99 (5) 4-(4-Benzyloxycarbonylpiperazin-1-yl) carbonyl-1,1-dioxidebenzo[b]thiophene
  • [2964]
    Figure US20030073706A1-20030417-C02201
  • TLC: Rf 0.64 (methylene chloride:methanol=10:1); [2965]
  • NMR (CDCl[2966] 3): δ 7.78 (d, J=7.5 Hz, 1H), 7.59 (t, J=7.5 Hz, 1H), 7.47 (d, J=7.5 Hz, 1H), 7.36 (s, 5H), 7.32 (d, J=6.9 Hz, 1H), 6.79 (d, J=6.9 Hz, 1H), 5.16 (s, 2H), 3.88-3.72 (m, 2H), 3.70-3.56 (m, 2H), 3.54-3.40 (m, 2H), 3.40-3.25 (m, 2H).
    • EXAMPLE 99 (6) 4-(N-Ethyl-N-2-(piperidin-1-yl) ethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene
  • [2967]
    Figure US20030073706A1-20030417-C02202
  • TLC: Rf 0.25 (chloroform:methanol=9:1); NMR (CDCl[2968] 3): δ 7.80-7.20 (m, 4H), 6.75 (d, J=6.8 Hz, 1H), 3.80-3.50 (m, 2H), 3.35-3.10 (m, 2H), 2.70-2.10 (m, 6H), 1.70-1.20 (m, 6H), 1.26 and 1.06 (each t, J=7.0 Hz, total 3H).
    • EXAMPLE 99 (7) 4-(3-(Imidazol-1-yl)propyl)carbamoyl-1,1-dioxidebenzo[b]thiophene
  • [2969]
    Figure US20030073706A1-20030417-C02203
  • TLC: Rf 0.43 (chloroform:methanol=4:1); [2970]
  • NMR (CDCl[2971] 3): δ 7.95 (d, J=7.0 Hz, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.52 (t, J=7.6 Hz, 1H), 7.55 (broad s, 1H), 7.41 (s, 1H), 6.98 (s, 1H), 6.96 (s, 1H), 6.76 (d, J=7.0 Hz, 1H), 4.07 (t, J=6.6 Hz, 2H), 3.44 (q, J=6.6 Hz, 2H), 2.14 (m, 2H).
    • EXAMPLE 99 (8) 4-(N-2-(Piperidin-1-yl)ethyl-N-methyl)carbamoyl-1,1-dioxidebenzo[b]thiophene
  • [2972]
    Figure US20030073706A1-20030417-C02204
  • TLC: Rf 0.30 (methylene chloride:methanol=9:1); [2973]
  • NMR (CDCl[2974] 3): δ 7.85-7.30 (m, 4H), 6.76 (d, J=7.2 Hz, 1H), 3.74 and 3.30 (each t, J=6.0 Hz, total 2H), 3.14 and 2.88 (each s, total 3H), 2.70-2.10 (m, 6H), 1.70-1.30 (m, 6H).
    • EXAMPLE 99 (9) 4-(4-(1,3-Dioxaindan-5-ylmethyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene
  • [2975]
    Figure US20030073706A1-20030417-C02205
  • TLC: Rf 0.26 (ethyl acetate); [2976]
  • NMR (DMSO-d[2977] 6): δ 8.00-7.92 (m, 1H), 7.74-7.65 (m, 2H), 7.56 (d, J=6.9 Hz, 1H), 7.52 (d, J=6.9 Hz, 1H), 7.21 (s, 1H), 7.03-6.95 (m, 2H), 6.07 (s, 2H), 4.64-4.50 (m, 1H), 4.28-4.15 (m, 2H), 3.70-2.96 (m, 8H).
    • EXAMPLE 99 (10) 4-(4-((2E)-3-Phenyl-2-propenyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene hydrochloride
  • [2978]
    Figure US20030073706A1-20030417-C02206
  • TLC: Rf 0.10 (ethyl acetate); [2979]
  • NMR (DMSO-d[2980] 6): δ 8.00-7.92 (m, 1H), 7.76-7.65 (m, 2H),7.58 (d, J=6.9 Hz, 1H), 7.53-7.46 (m, 2H),7.51 (d, J=6.9 Hz, 1H), 7.45-7.28 (m, 3H), 6.84 (d, J=15.3 Hz, 1H), 6.47-6.33 (m, 1H), 4.60 (m,1H), 3.98-3.84 (m, 2H), 3.70-2.97 (m, 8H).
    • EXAMPLES 100˜100 (24)
  • By the same procedure as described in Example 28 using the compound prepared in Example 81 (1) instead of 4-carboxy-1,1-dioxidebenzo[b]thiophene, and an amine derivative instead of (pyridin-3-yl)ethylamine, and if necessary, by converting into the corresponding salt by a known method, the following compounds of the present invention having the following physical data were obtained. [2981]
    • EXAMPLE 100 4-(Furan-2-ylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2982]
    Figure US20030073706A1-20030417-C02207
  • TLC: Rf 0.43 (hexane:ethyl acetate=1:2); [2983]
  • NMR (DMSO-d[2984] 6): 8 9.29 (t, J=5.5 Hz, 1H), 7.99 (d, J=7.6 Hz, 1H), 7.95 (d, J=7.6 Hz, 1H), 7.83 (t, J=7.6 Hz, 1H), 7.79-7.76 (m, 3H), 7.67-7.60 (m, 3H), 6.48-6.35 (m, 2H), 6.25 (d, J=9.0 Hz, 1H), 4.55 (dd, J=15.5, 5.5 Hz, 1H), 4.40 (dd, J=15.5, 5.5 Hz, 1H), 4.10 (dd, J=15.3, 9.0 Hz, 1H), 4.00 (d, J=15.3 Hz, 1H).
    • EXAMPLE 100 (1) 4-(2,4,6-Trimethoxybenzyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2985]
    Figure US20030073706A1-20030417-C02208
  • TLC: Rf 0.55 (ethyl acetate); [2986]
  • NMR (DMSO-d[2987] 6): δ 8.40 (t, J=4.8 Hz, 1H), 7.89-7.86 (m, 2H), 7.86-7.69 (m, 4H), 7.67-7.58 (m, 2H), 6.25 (s, 2H), 6.18 (dd, J=8.1, 2.1 Hz, 1H), 4.46-4.30 (m, 2H), 4.11-3.94 (m, 2H), 3.77 (s, 9H).
    • EXAMPLE 100 (2) 4-(3-(2-Oxopyrrolidin-1-yl)propyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2988]
    Figure US20030073706A1-20030417-C02209
  • TLC: Rf 0.44 (ethyl acetate:methanol=2:1); [2989]
  • NMR (CDCl[2990] 3): δ 8.20-8.08 (m, 1H), 8.02 (d, J=7.5 Hz, 1H), 7.83-7.62 (m, 5H), 7.59-7.49 (m, 2H), 6.40 (dd, J=9.3, 1.2 Hz, 1H), 3.89-3.61 (m, 4H), 3.51-3.33 (m, 2H), 3.32-3.20 (m, 1H), 3.20-3.06 (m, 1H), 2.53-2.33 (m, 2H), 2.15-1.88 (m, 3H), 1.85-1.74 (m,1H).
    • EXAMPLE 100 (3) 4-((3S)-1-Benzylpyrrolidin-3-yl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2991]
    Figure US20030073706A1-20030417-C02210
  • More Polar Compound: [2992]
  • TLC: Rf 0.27 (methanol:ethyl acetate:triethylamine=1:8:0.05); [2993]
  • NMR (CDCl[2994] 3): δ 7.90-7.80 (m, 4H), 7.75-7.66 (m, 2H), 7.62-7.53 (m, 2H), 7.37-7.13 (m, 5H), 6.70 (d, J=8.7 Hz, 1H), 6.24-6.17 (m, 1H), 4.74-4.62 (m, 1H), 3.80 (dd, J=15.0,1.5 Hz, 1H), 3.68 (d, J=12.9 Hz, 1H), 3.63 (dd, J=15.0, 9.3 Hz, 1H), 3.57 (d, J=12.9 Hz, 1H), 3.00-2.86 (m, 2H), 2.72 (dd, J=9.9, 6.3 Hz, 1H), 2.51-2.31 (m, 2H), 1.89-1.77 (m, 1H).
  • Less Polar Compound: [2995]
  • TLC: Rf 0.35 (methanol:ethyl acetate:triethylamine=1:8:0.05); [2996]
  • NMR (CDCl[2997] 3): δ 7.94-7.87 (m, 2H), 7.87-7.78 (m, 2H), 7.75-7.66 (m, 2H), 7.64-7.56 (m, 2H), 7.41-7.23 (m, 5H), 6.73 (d, J=8.1 Hz, 1H), 6.28-6.21 (m, 1H), 4.71-4.59 (m, 1H), 3.80 (dd, J=14.7, 1.2 Hz, 1H), 3.64 (s, 2H), 3.62 (dd, J=14.7, 9.3 Hz, 1H), 2.95-2.84 (m, 1H), 2.80-2.67 (m, 2H), 2.46-2.30 (m, 2H), 2.12-1.95 (m, 1H).
  • The determination of the absolute configuration of * is not performed, but the said more polar and less polar isomers are each single optically active compounds. [2998]
    • EXAMPLE 100 (4) 4-(2-(Pyrrolidin-1-yl)ethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [2999]
    Figure US20030073706A1-20030417-C02211
  • Free Compound: [3000]
  • TLC: Rf 0.33 (ethyl acetate:methanol:triethylamine=4:2:0.5); [3001]
  • NMR (CDCl[3002] 3): δ 7.93-7.78 (m, 4H), 7.75-7.66 (m, 2H), 7.63-7.53 (m, 2H), 7.10 (brs, 1H), 6.31-6.24 (m, 1H), 3.83 (dd, J=15.0, 1.5 Hz, 1H), 3.73-3.49 (m, 3H), 2.80 (t, J=5.7 Hz, 2H), 2.69-2.53 (m, 4H), 1.86-1.73 (m, 4H).
  • Hydrochloride: [3003]
  • TLC: Rf 0.37 (ethyl acetate:methanol:triethylamine=4:2:0.5); [3004]
  • NMR (DMSO-d[3005] 6): δ 9.18 (t, J=5.4 Hz, 1H), 8.14 (d, J=7.5 Hz, 1H), 7.96-7.90 (m, 1H), 7.85 (t, J=7.5 Hz, 1H), 7.81-7.72 (m, 3H), 7.67-7.58 (m, 2H), 6.27 (d, J=9.3 Hz, 1H), 4.13 (dd, J=15.6, 9.3 Hz, 1H), 3.96 (d, J=15.6 Hz, 1H), 3.78-3.50 (m, 4H), 3.48-3.28 (m, 2H), 3.06-2.94 (m, 2H), 2.09-1.78 (m, 4H).
    • EXAMPLE 100 (5) 4-(2-Diethylaminoethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [3006]
    Figure US20030073706A1-20030417-C02212
  • Free Compound: [3007]
  • TLC: Rf 0.47 (ethyl acetate:methanol:triethylamine=4:2:0.5); [3008]
  • NMR (CDCl[3009] 3): δ 7.92-7.80 (m, 4H), 7.76-7.66 (m, 2H), 7.62-7.56 (m, 2H), 7.03 (brs, 1H), 6.29 (dd, J=9.0, 1.5 Hz, 1H), 3.84 (dd, J=14.4, 1.5 Hz, 1H), 3.72-3.44 (m, 3H), 2.73 (t, J=6.0 Hz, 2H), 2.60 (q, J=7.2 Hz, 4H), 1.04 (t, J=7.2 Hz, 6H).
  • Hydrochloride: [3010]
  • TLC: Rf 0.49 (ethyl acetate:methanol:triethylamine=4:2:0.5); [3011]
  • NMR (DMSO-d[3012] 6): δ 10.32 (brs, 1H), 9.30-9.20 (m, 1H), 8.08 (d, J=7.5 Hz, 1H), 7.94 (d, J=7.5 Hz, 1H), 7.86 (t, J=7.5 Hz, 1H), 7.82-7.72 (m, 3H), 7.68-7.58 (m, 2H), 6.29 (d, J=9.3 Hz, 1H), 4.12 (dd, J=15.6, 9.3 Hz, 1H), 3.96 (d, J=15.6 Hz, 1H), 3.80-3.57 (m, 2H), 3.40-3.08 (m, 6H), 1.24 (t, J=7.2 Hz, 6H).
    • EXAMPLE 100 (6) 4-(2-(N-Ethyl-N-(3-methylphenyl)amino)ethyl) carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [3013]
    Figure US20030073706A1-20030417-C02213
  • Free Compound: [3014]
  • TLC: Rf 0.49 (ethyl acetate:triethylamine=6:0.5); [3015]
  • NMR (CDCl[3016] 3): δ 7.94-7.87 (m, 2H), 7.82 (d, J=6.9 Hz, 1H), 7.75-7.67 (m, 1H), 7.67-7.54 (m, 4H), 7.17-7.11 (m, 1H), 6.72-6.64 (m, 2H), 6.56 (d, J=7.8 Hz, 1H), 6.49 (brs, 1H), 6.26 (dd, J=9.0, 1.2 Hz, 1H), 3.81 (dd, J=14.7, 1.2 Hz, 1H), 3.77-3.47 (m, 5H), 3.43 (q, J=7.2 Hz, 2H), 2.30 (s, 3H), 1.15 (t, J=7.2 Hz, 3H).
  • Hydrochloride: [3017]
  • TLC: Rf 0.47 (ethyl acetate:triethylamine=6:0.5); [3018]
  • NMR (CD[3019] 3OD): δ 7.98-7.60 (m, 6H), 7.59-7.26 (m, 6H), 6.36-6.15 (m, 1H), 4.09-3.89 (m, 4H), 3.88-3.40 (m, 4H), 2.44 (s, 3H), 1.17 (t, J=7.2 Hz, 3H).
    • EXAMPLE 100 (7) 4-(N-Ethyl-N-2-(piperidin-1-yl)ethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [3020]
    Figure US20030073706A1-20030417-C02214
  • Free Compound: [3021]
  • TLC: Rf 0.29 (methylene chloride:methanol=6:1); [3022]
  • NMR (CDCl[3023] 3): δ 8.00-7.55 (m, 8H), 5.85 (d, J=8 Hz, 1H), 3.85-3.30 (m, 6H), 2.85-2.50 (m, 2H), 2.55 (m, 2H), 2.40 (m, 2H), 1.80-1.40 (m, 6H), 1.34 and 1.36 (each t, J=7 Hz, total 3H).
  • Hydrochloride: [3024]
  • TLC: Rf 0.29 (methylene chloride:methanol=6:1); [3025]
  • NMR (CDCl[3026] 3+DMSO-d6): δ 11.30 (broad s, 1H), 7.95-7.60 (m, 8H), 5.89 (d, J=8 Hz, 1H), 4.20-3.80 (m, 3H), 3.80-3.20 (m, 7H), 3.00 (m, 2H), 2.11 (m, 2H), 2.00 (m, 3H), 1.50 (m, 1H), 1.41 (t, J=7 Hz, 3H).
    • EXAMPLE 100 (8) 4-(3-(Imidazol-1-yl)propyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [3027]
    Figure US20030073706A1-20030417-C02215
    • Free Compound:
  • TLC: Rf 0.50 (methylene chloride:methanol=4:1); [3028]
  • NMR (CDCl[3029] 3): δ 7.90-7.50 (m, 9H), 7.56 (s, 1H), 6.98 (s, 1H), 6.93 (s, 1H), 6.27 (dd, J=2 Hz and 7 Hz, 1H), 4.20-3.95 (m, 2H), 3.80-3.55 (m, 3H), 3.30 (m, 1H), 2.13 (m, 2H).
  • Hydrochloride: [3030]
  • TLC: Rf 0.50 (methylene chloride:methanol=4:1); [3031]
  • NMR (CDCl[3032] 3+DMSO-d6): δ 9.59 (s, 1H), 9.49 (t-like, 1H), 8.23 (t, J=4.4 Hz, 1H), 7.85-7.60 (m, 5H), 7.60-7.40 (m, 4H), 7.29 (s, 1H), 6.23 (dd, J=4.0 Hz and 6.8 Hz, 1H), 4.65-4.35 (m, 2H), 3.82 (m, 2H), 3.65 (m, 1H), 3.25 (m, 1H), 2.40 (m, 1H), 2.20 (m, 1H).
    • EXAMPLE 100 (9) 4-((3R)-1-Benzylpyrrolidin-3-yl)carbamoyl-3-phenylsuilfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [3033]
    Figure US20030073706A1-20030417-C02216
  • Less Polar Compound: [3034]
  • TLC: Rf 0.35 (methanol:ethyl acetate:triethylamine=1:8:0.05); [3035]
  • NMR (CDCl[3036] 3) δ 7.94-7.87 (m, 2H), 7.87-7.78 (m, 2H), 7.75-7.67 (m, 2H), 7.64-7.56 (m, 2H), 7.38-7.26 (m, 5H), 6.68 (d, J=8.1 Hz, 1H), 6.28-6.20 (m, 1H), 4.73-4.59 (m, 1H), 3.80 (dd, J=14.7, 1.5 Hz, 1H), 3.66 (s, 2H), 3.63 (dd, J=14.7, 9.3 Hz, 1H), 2.96-2.87 (m, 1H), 2.82-2.66 (m, 2H), 2.47-2.30 (m, 2H), 2.12-1.86 (m, 1H).
  • More Polar Compound: [3037]
  • TLC: Rf 0.27 (methanol:ethyl acetate:triethylamine=1:8:0.05); [3038]
  • NMR (CDCl[3039] 3): δ 7.90-7.78 (m, 4H), 7.74-7.65 (m, 2H), 7.62-7.52 (m, 2H), 7.36-7.13 (m, 5H), 6.79 (d, J=8.4 Hz, 1H), 6.25-6.18 (m, 1H), 4.72-4.60 (m, 1H), 3.80 (dd, J=15.0,1.5 Hz, 1H), 3.65 (d, J=12.9 Hz, 1H), 3.62 (dd, J=15.0, 9.0 Hz, 1H), 3.54 (d, J=12.9 Hz, 1H), 2.96-2.83 (m, 2H), 2.72 (dd, J=9.9, 6.3 Hz, 1H), 2.49-2.32 (m, 2H), 1.90-1.73 (m, 1H).
  • The determination of the absolute configuration of * is not performed, but the said more polar and less polar isomers are each single optically active compounds. [3040]
    • EXAMPLE 100 (10) 4-(3-(Pyrrolidin-1-yl)propyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [3041]
    Figure US20030073706A1-20030417-C02217
  • Free Compound: [3042]
  • TLC: Rf 0.25 (methanol:ethyl acetate:triethylamine=2:4:0.5); [3043]
  • NMR (CDCl[3044] 3): δ 9.16-9.06 (m, 1H), 7.91-7.84 (m, 2H), 7.84-7.77 (m, 2H), 7.75-7.62 (m, 2H), 7.61-7.53 (m, 2H), 6.44-6.37 (m, 1H), 3.85 (dd, J=14.7, 1.2 Hz, 1H), 3.80-3.61 (m, 2H), 3.59-3.44 (m, 1H), 2.91-2.72 (m, 2H), 2.71-2.59 (m, 4H), 2.00-1.63 (m, 6H).
  • Hydrochloride: [3045]
  • TLC: Rf 0.26 (methanol:ethyl acetate:triethylamine=2:4:0.5); [3046]
  • NMR (DMSO-d[3047] 6): δ 10.43 (brs, 1H), 9.00 (t, J=5.7 Hz, 1H), 8.02 (d, J=7.5 Hz, 1H), 7.94 (d, J=7.5 Hz, 1H), 7.90-7.74 (m, 4H), 7.71-7.61 (m, 2H), 6.30 (d, J=9.0 Hz, 1H), 4.11 (dd, J=15.0, 9.0 Hz, 1H), 3.94 (d, J=15.0 Hz, 1H), 3.60-3.10 (m, 6H), 3.10-2.78 (m, 2H), 2.11-1.73 (m, 6H).
    • EXAMPLE 100 (11) 4-(N-2-(Piperidin-1-yl)ethyl-N-methyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [3048]
    Figure US20030073706A1-20030417-C02218
  • Free Compound: [3049]
  • TLC: Rf 0.29 (methylene chloride:methanol=6:1); [3050]
  • NMR (CDCl[3051] 3): δ 8.05-7.55 (m, 8H), 5.88 (dd, J=8.8 Hz and 2.0 Hz, 1H), 4.00-3.55 and 3.30 (each m, total 4H), 3.20 and 3.17 (each s, total 3H), 2.80-2.35 (m, 6H), 1.70-1.40 (m, 6H)
  • Hydrochloride: [3052]
  • TLC: Rf 0.29 (methylene chloride:methanol=6:1); [3053]
  • NMR (DMSO-d[3054] 6): δ 10.49 (broad s, 1H), 8.15 (d, J=6.2 Hz, 1H), 8.00-7.60 (m, 7H), 5.87 (d, J=8.8 Hz, 1H), 4.25-3.70 (m, 4H), 3.70-2.80 (m, 6H), 3.33 and 3.16 (each s, total 3H), 2.00-1.60 (m, 5H), 1.44 (m, 1H).
    • EXAMPLE 100 (12) 4-(3,5-Dimethoxybenzyl) carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [3055]
    Figure US20030073706A1-20030417-C02219
  • TLC: Rf 0.45 (methylene chloride:ethyl acetate=4:1); [3056]
  • NMR (DMSO-d[3057] 6): δ 9.26 (t, J=5.8 Hz, 1H), 7.78 (d, J=7.6 Hz, 1H), 7.91 (dd, J=7.6, 1.0 Hz, 1H), 7.84 (dd, J=7.0, 1.0 Hz, 1H), 7.13 (t, J=7.6 Hz, 1H), 7.45 (d, J=7.0 Hz, 1H), 6.51 (d, J=2.2 Hz, 2H), 6.39 (t, J=2.2 Hz, 1H), 4.42 (d, J=5.8 Hz, 2H), 3.73 (s, 6H).
    • EXAMPLE 100 (13) 4-(3-(Piperidin-1-yl) propyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene hydrochloride
  • [3058]
    Figure US20030073706A1-20030417-C02220
  • TLC: Rf 0.30 (ethyl acetate:methanol:triethylamine=8:1.5:0.5); [3059]
  • NMR (DMSO-d[3060] 6): δ 10.40 (broad s, 1H), 9.08 (t, J=5.3 Hz, 1H), 8.10-7.60 (m, 8H), 6.33 (d, J=9.2 Hz, 1H), 4.13 (dd, J=15.0 Hz and 9.2 Hz, 1H), 3.94 (d, J=15.0 Hz, 1H), 3.60-3.00 (m, 6H), 2.80 (m, 2H),2.05 (t, J=6.5 Hz, 2H), 1.73 (m, 5H), 1.36 (m,1H).
    • EXAMPLE 100 (14) 4-(2-Diisopropylaminoethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride
  • [3061]
    Figure US20030073706A1-20030417-C02221
  • TLC: Rf 0.46 (ethyl acetate:methanol:triethylamine=8:1.5:0.5); [3062]
  • NMR (DMSO-d[3063] 6): δ 10.01 (s, 1H), 9.27 (t, J=5.7 Hz, 1H), 8.09 (d, J=7.0 Hz, 1H), 7.97 (d, J=7.0 Hz, 1H), 7.88 (t, J=7.0 Hz, 1H), 7.80-7.76 (m, 3H), 7.68-7.60 (m, 2H), 6.36 (d, J=9.0 Hz, 1H), 4.11 (dd, J=15.3 Hz and 9.0 Hz, 1H), 3.96 (d, J=15.3 Hz,1H), 3.90-3.60 (m, 4H), 3.33 (m, 1H), 3.18 (m, 1H), 1.42 (d, J=6.6 Hz, 3H), 1.38 (d, J=6.6 Hz, 3H), 1.34 (d, J=6.6 Hz, 3H), 1.32 (d, J=6.6 Hz, 3H).
    • EXAMPLE 100 (15) 4-(2-(Morpholin-4-yl)ethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzolb]thiophene.hydrochloride
  • [3064]
    Figure US20030073706A1-20030417-C02222
  • TLC: Rf 0.33 (ethyl acetate:methanol:triethylamine=8:1.5:0.5); [3065]
  • NMR (DMSO-d[3066] 6): δ 11.14 (broad s, 1H), 9.27 (broad t-like, 1H), 8.13 (d, J=7.5 Hz, 1H), 7.93 (d, J=7.5 Hz, 1H), 7.86 (t, J=7.5 Hz, 1H), 7.82-7.70 (m, 3H), 7.70-7.60 (m, 2H), 6.30 (d, J=8.4 Hz, 1H), 4.14 (dd, J=15.6 Hz and 8.4 Hz, 1H), 4.00-3.65 (m, 7H), 3.65-3.00 (m, 6H).
    • EXAMPLE 100 (16) 4-(N-2-(Piperidin-1-yl)ethyl-N-propyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene hydrochloride
  • [3067]
    Figure US20030073706A1-20030417-C02223
  • TLC: Rf 0.47 (ethyl acetate:methanol:triethylamine=8:1.5:0.5); [3068]
  • NMR (DMSO-d[3069] 6): δ 10.70 and 10.66 (each broad s, total 1H), 8.00-7.65 (m, 8H), 5.83 (d, J=8.7 Hz, 1H), 4.14 (dd, J=15.3 Hz and 8.7 Hz, 1H), 4.00-3.70 (m, 3H), 3.65-3.10 (m, 6H), 3.10-2.80 (m, 2H), 2.00-1.60 (m, 6H), 1.40 (m, 1H), 0.98 and 0.86 (each t, J=7.2 Hz, total 3H).
    • EXAMPLE 100 (17) 4-(N-2-(Piperidin-1-yl)ethyl-N-isopropyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride
  • [3070]
    Figure US20030073706A1-20030417-C02224
  • TLC;Rf 0.55 (ethyl acetate:methanol:triethylamine=8:1.5:0.5); [3071]
  • NMR (DMSO-d[3072] 6): δ 10.78 (broad s, 1H), 8.00-7.60 (m, 8H), 5.90 (d, J=9.2 Hz, 1H), 4.40-4.03 (m, 3H), 4.00-2.80 (m, 8H), 2.00-1.60 (m, 5H), 1.40 (m, 1H), 1.44 and 1.28 and 1.04 (each d, J=6.4 Hz, total 6H).
    • EXAMPLE 100 (18) 4-(4-Benzoylpiperazin-1-yl)carbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [3073]
    Figure US20030073706A1-20030417-C02225
  • TLC: Rf 0.48 (methylene chloride:methanol=10:1); [3074]
  • NMR (DMSO-d[3075] 6): δ 7.95-7.80 (m, 3H), 7.80-7.56 (m, 5H), 7.42 (s, 5H), 5.92 (dd, J=9.0, 1.5 Hz, 1H), 4.40-4.00 (m, 2H), 3.90-3.40 (m, 6H), 3.72 (dd, J=15.0, 1.5 Hz, 1H), 3.65 (dd, J=15.0, 9.0 H z, 1H).
    • EXAMPLE 100 (19) 4-(4-(4-Ethylbenzyl)piperazin-1-yl)carbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride
  • [3076]
    Figure US20030073706A1-20030417-C02226
  • TLC: Rf 0.55 (methylene chloride:methanol 10:1); [3077]
  • NMR (DMSO-d[3078] 6): δ 7.88-7.73 (m, 6H), 7.67-7.63 (m, 2H), 7.47 (d, J=7.0 Hz, 2H), 7.21 (d, J=7.0 Hz, 2H), 5.87 (dd, J=10.0, 1.5 Hz, 1H), 4.16 (bs, 2H), 4.05 (dd, J=15.0, 10.0 HZ, 1H), 3.79 (dd, J=15.0, 1.5 Hz, 1H), 3.30-2.90 (m, 8H), 2.58 (q, J=8.0 Hz, 2H), 1.17 (t, J=8.0 Hz, 3H).
    • EXAMPLE 100 (20) 4-(4-(4-Phenylbenzyl)piperazin-1-yl)carbonyl-3-phenylsulfonyl-2,3-dihydro-1,1dioxidebenzo[b]thiophene.hydrochloride
  • [3079]
    Figure US20030073706A1-20030417-C02227
  • TLC: Rf 0.55 (methylene chloride:methanol=10:1); [3080]
  • NMR (DMSO-d[3081] 6): δ 7.88-7.78 (m, 3H), 7.78-7.72 (m, 3H), 7.67-7.58 (m, 7H), 7.48-7.41 (m, 3H), 7.38-7.34 (m, 1H), 5.88 (d, J=9.5 Hz, 1H), 4.21 (bs, 2H), 4.10-3.70 (m, 8H), 4.06 (dd, J=15.5, 9.5 Hz, 1H), 3.79 (d, 15.5 Hz, 1H), 3.19 (s, 2H).
    • EXAMPLE 100 (21) 4-(4-(1,3-Dioxaindan-5-ylmethyl)piperazin-1-yl)carbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride
  • [3082]
    Figure US20030073706A1-20030417-C02228
  • TLC: Rf 0.54 (methylene chloride:methanol=10:1); [3083]
  • NMR (DMSO-d[3084] 6): δ 7.86-7.76 (m, 4H), 7.74 (d, J=8.0 Hz, 2H), 7.64 (t, J=8.0 Hz, 2H), 7.08 (bs, 1H), 6.98-6.92 (m, 1H), 6.83 (d, J=8.0 Hz, 1H), 5.96-5.92 (m, 2H), 5.86 (d, J=8.5 Hz, 1H), 4.15-3.70 (m, 2H), 4.04 (dd, J=15.0, 8.5 Hz, 1H), 3.78 (d, J=15.0 Hz, 1H), 3.15-2.80 (m, 8H).
    • EXAMPLE 100 (22) 4-(4-Benzyloxycarbonylpiperazin-1-yl)carbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [3085]
    Figure US20030073706A1-20030417-C02229
  • TLC: Rf 0.80 (methylene chloride:methanol=10:1); [3086]
  • NMR (DMSO-d[3087] 6): δ 7.96-7.80 (m, 4H), 7.76 (d, J=7.5 Hz, 2H), 7.66 (t, J=7.5 Hz, 2H), 7.45-7.36 (m, 5H), 5.89 (d, J=8.7 Hz, 1H), 5.11 (s, 2H), 4.13 (dd, J=14.7, 8.7 Hz, 1H), 3.93 (d, J=14.7 Hz, 1H), 3.80-3.40 (m, 8H).
    • EXAMPLE 100 (23) 4-(4-(2-Methylphenyl)piperazin-1-yl)carbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-diozidebenzo[b]thiophene hydrochloride
  • [3088]
    Figure US20030073706A1-20030417-C02230
  • TLC: Rf 0.80 (methylene chloride:methanol=10:1); [3089]
  • NMR (DMSO-d[3090] 6): δ 7.97-7.90 (m, 2H), 7.90-7.74 (m, 4H), 7.74-7.63 (m, 2H), 7.23-7.10 (m, 2H), 7.10-6.83 (m, 2H), 5.92 (d, J=9.6 Hz, 1H), 4.15 (dd, J=15.3, 9.6 Hz, 1H), 3.93 (d, J=15.3 Hz, 1H), 3.92-3.80 (m, 2H), 3.08-2.90 (m, 6H), 2.30 (s, 3H).
    • EXAMPLE 100 (24) 4-(4-(4-Methoxyphenyl) piperazin-1-yl)carbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene hydrochloride
  • [3091]
    Figure US20030073706A1-20030417-C02231
  • TLC: Rf 0.75 (methylene chloride:methanol=10:1); NMR (DMSO-d[3092] 6): δ 8.02-7.92 (m, 2H), 7.92-7.73 (m, 4H), 7.72-7.64 (m, 2H), 7.36-7.14 (m, 2H), 7.00-6.90 (m, 2H), 5.91 (d, J=9.6 Hz, 1H), 4.20-3.76 (m, 4H), 4.14 (dd, J=15.3, 9.6 Hz, 1H), 3.93 (d, J=15.3 Hz, 1H), 3.72 (s, 3H), 3.45-3.26 (m, 4H).
    • EXAMPLES 101˜101 (1)
  • By the same procedure as described in Example 1 using the compounds prepared in Examples 28 (11) and 73 (16) instead of 1,1-dioxidebenzo[b]thiophene, the following compounds of the present invention were obtained. [3093]
    • EXAMPLE 101 4-2-(Piperidin-1-yl)ethyl)carbamoyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [3094]
    Figure US20030073706A1-20030417-C02232
  • TLC: Rf 0.40 (methanol:water:acetic acid=1:1:0.1); [3095]
  • NMR (CDCl[3096] 3): δ 7.81 (dd, J=7.6, 1.1 Hz, 1H), 7.75 (dd, J=7.6, 1.1 Hz, 1H), 7.61 (t, J=7.6 Hz, 1H), 7.56-7.53 (m, 2H), 7.38-7.35 (m, 3H), 6.91 (br, 1H), 5.74 (dd, J=7.3, 1.3 Hz, 1H), 3.72 (dd, J=13.9, 7.3 Hz, 1H), 3.68-3.58 (m, 1H), 3.60 (dd, J=13.9, 1.3 Hz, 1H), 3.55-3.45 (m, 1H), 2.55 (t, J=5.8 Hz, 2H), 2.38 (br, 4H), 1.56-1.48 (m, 4H), 1.44-1.39 (m, 2H).
    • EXAMPLE 101 (1) 4-(2-(Pyridin-2-yl)ethyl)oxy-3-phenylthio-1,1-dioxidebenzo[b]thiophene
  • [3097]
    Figure US20030073706A1-20030417-C02233
  • TLC: Rf 0.30 (hexane:ethyl acetate=1:1); [3098]
  • NMR (CDCl[3099] 3): δ 8.54 (ddd, J=4.8, 1.7, 1.0 Hz, 1H), 7.54 (dt, J=7.7, 1.7 Hz, 1H), 7.49 (t, J=8.0 Hz, 1H), 7.43-7.40 (m, 2H), 7.34-7.22 (m, 5H), 7.15-7.10 (m, 2H), 4.91 (dd, J=6.9, 1.8 Hz, 1H), 4.52 (t, J=6.6 Hz, 2H), 3.66 (dd, J=13.8, 6.9 Hz, 1H), 3.57 (dd, J=13.8, 1.8 Hz, 1H), 3.31 (t, J=6.6 Hz, 2H).
    • EXAMPLE 102 4-(2-(Piperidin-1-yl)ethyl)carbamoyl-3-(4-nitrophenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [3100]
    Figure US20030073706A1-20030417-C02234
  • By the same procedure as described in Example 27 using the compound prepared in Example 28 (11) instead of 5-methyl-1,1-dioxidebenzo[b]thiophene, and 4-nitrobenzenesulfonic acid sodium salt instead of benzenesulfonic acid sodium salt, and if necessary, by converting into hydrochloride by a known method, the compounds of the present invention having the following physical data were obtained. [3101]
  • Free Compound: [3102]
  • TLC: Rf 0.40(methanol:water:acetic acid=5:5:0.5); [3103]
  • NMR (CDCl[3104] 3): δ 8.35 (d, J=8.7 Hz, 2H), 8.01 (d, J=8.7 Hz, 2H), 7.91 (dd, J=7.5,1.7 Hz, 1H), 7.81 (dd, J=7.5, 1.7 Hz, 1H), 7.76 (t, J=7.5 Hz, 1H), 7.59 (br, 1H), 6.42 (dd, J=9.2, 1.5 Hz, 1H), 3.88 (dd, J=15.0,1.5 Hz, 1H), 3.75 (dd, J=15.0, 9.2 Hz, 1H), 3.75-3.64 (m, 1H), 3.57-3.48 (m, 1H), 2.77-2.65 (m, 2H), 2.53 (br, 4H), 1.66-1.57 (m, 4H), 1.52-1.45 (m, 2H).
  • Hydrochloride: [3105]
  • TLC: Rf 0.40 (methanol:water:acetic acid=5:5:0.5); [3106]
  • NMR (DMSO-d[3107] 6): δ 9.98 (br, 1H), 9.28 (br, 1H), 8.42 (d, J=8.7 Hz, 2H), 8.11 (d, J=7.5 Hz, 1H), 8.03 (d, J=8.7 Hz, 2H), 7.97 (d, J=7.5 Hz, 1H), 7.89 (t, J=7.5 Hz, 1H), 6.41 (dd, J=7.3, 3.2 Hz, 1H), 4.16 (dd, J=15.5, 7.3 Hz, 1H), 4.10 (dd, J=15.5, 3.2 Hz, 1H), 3.72-3.70 (m, 2H), 3.57-3.48 (m, 2H), 3.32-3.25 (m, 2H), 2.96 (br, 2H), 1.82-1.68 (m, 5H), 1.45-1.35 (m, 1H).
    • EXAMPLES 103˜103 (41)
  • By the same procedure as described in Example 31 using 4-methylsulfonyloxymethyl-3-phenyisulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene instead of 4-bromomethyl-1,1-dioxidebenzo[b]thiophene and an amine derivative corresponding to 2,4-dimethoxybenzylamine hydrochloride, and if necessary, by converting into the corresponding salt by a known method, the following compounds of the present invention were obtained. [3108]
    • EXAMPLE 103 4-(N-2-(Piperidin-1-yl)ethyl-N-methyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.2hydrochloride
  • [3109]
    Figure US20030073706A1-20030417-C02235
  • TLC: Rf 0.48 (methanol:ethyl acetate:triethylamine=2:8:0.5); [3110]
  • NMR (CD[3111] 3OD+D2O (4 drops)): δ 8.16 (d, J=7.5 Hz, 1H), 7.90 (t, J=7.5 Hz, 1H), 7.85-7.73 (m, 4H), 7.64-7.55 (m, 2H), 6.18-6.10 (m, 1H), 4.93 (d, J=14.4 Hz, 1H), 4.60 (d, J=14.4 Hz, 1H), 4.03 (dd, J=15.6, 9.0 Hz, 1H), 3.84 (dd, J=15.6, 0.9 Hz, 1H), 3.72-3.00 (m, 8H), 2.74 (s, 3H), 2.00-1.55 (m, 6H).
    • EXAMPLE 103 (1) 4-(2-(N-Ethyl-N-3-methylphenyl)aminoethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene 2hydrochloride
  • [3112]
    Figure US20030073706A1-20030417-C02236
  • TLC: Rf 0.45 (ethyl acetate:triethylamine=6:0.5); [3113]
  • NMR (DMSO-d[3114] 6): δ 9.64 (brs, 2H), 8.21 (d, J=6.3 Hz, 1H), 7.89-7.74 (m, 5H), 7.67-7.58 (m, 2H), 7.18-7.04 (m, 1H), 6.96-6.50 (m, 3H), 6.46 (dd, J=6.9, 3.0 Hz, 1H), 4.73-4.59 (m, 1H), 4.49-4.35 (m, 1H), 3.97-3.80 (m, 2H), 3.80-3.58 (m, 2H), 3.50-3.33 (m, 2H), 3.29-3.10 (m, 2H), 2.25 (s, 3H), 1.06 (t, J=6.9 Hz, 3H).
    • EXAMPLE 103 (2) 4-(N-Benzyl-N-ethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene hydrochloride
  • [3115]
    Figure US20030073706A1-20030417-C02237
  • TLC: Rf 0.67 (ethyl acetate:triethylamine=6:0.5); [3116]
  • NMR (CD[3117] 3OD+pyridine-d5) δ 7.92 (d, J=7.2 Hz, 1H), 7.71-7.58 (m, 4H), 7.57-7.45 (m, 3H), 7.32-7.15 (m, 5H), 5.84 (dd, J=8.4, 1.8 Hz, 1H), 4.33 (d, J=14.7Hz, 1H), 3.90-3.62 (m, 4H),3.60 (d, J=13.2 Hz, 1H), 2.65 .(q, J=7.2Hz, 2H), 1.14 (t, J=7.2 Hz, 3H).
    • EXAMPLE 103 (3) 4-(2-Diethylaminoethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene-2hydrochloride
  • [3118]
    Figure US20030073706A1-20030417-C02238
  • TLC: Rf 0.35 (methanol ethyl acetate triethylamine=2:8:0.5); [3119]
  • NMR (DMSO-d[3120] 6): δ 10.66 (brs, 1H), 9.96 (brs, 1H), 9.76 (brs, 1H), 8.26-8.26 (m, 1H), 7.91-7.74 (m, 5H), 7.67-7.57 (m, 2H), 6.54-6.45 (m, 1H), 4.83-4.65 (m, 1H), 4.60-4.42 (m, 1H), 3.96-3.82 (m, 2H), 3.70-3.37 (m, 4H), 3.28-3.10 (m, 4H), 1.26 (t, J=7.2 Hz, 6H).
    • EXAMPLE 103 (4) 4-(4-Methylbenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride
  • [3121]
    Figure US20030073706A1-20030417-C02239
  • TLC: Rf 0.47 (ethyl acetate:triethylamine=6:0.5); [3122]
  • NMR (DMSO-d[3123] 6): δ 9.83 (brs, 1H), 9.54 (brs, 1H), 8.16 (d, J=6.9 Hz, 1H), 7.89-7.75 (m, 3H), 7.75-7.68 (m, 2H), 7.68-7.59 (m, 2H), 7.50 (d, J=8.1 Hz, 2H), 7.25 (d, J=8.1 Hz, 2H), 6.29 (dd, J=4.8, 3.9 Hz, 1H), 4.72-4.58 (m, 1H), 4.44-4.32 (m, 1H), 4.25 (brs, 2H), 3.93-3.80 (m, 2H), 2.32 (s, 3H).
    • EXAMPLE 103 (5) 4-(N-Ethyl-N-2-(piperidin-1-yl)ethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.2hydrochloride
  • [3124]
    Figure US20030073706A1-20030417-C02240
  • TLC: Rf 0.47 (methanol ethyl:acetate triethylamine=2:8:0.5); [3125]
  • NMR (CD[3126] 3OD+D2O (1 drop)) δ 8.24 (d, J=7.5 Hz, 1H), 7.92-7.69 (m, 5H), 7.61-7.52 (m, 2H), 6.21-6.10 (m, 1H), 5.15 (d, J=14.4 Hz, 1H), 4.70 (d, J=14.4 Hz, 1H), 4.05 (dd, J=15.3, 9.0 Hz, 1H), 3.84 (dd, J=15.3, 0.9 Hz, 1H), 3.76-2.80 (m, 10H), 1 98-1.50 (m, 6H), 1.45 (t, J=7.2 Hz, 3H).
    • EXAMPLE 103 (6) 4-(2-Methoxybenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride
  • [3127]
    Figure US20030073706A1-20030417-C02241
  • TLC: Rf 0.49 (ethyl acetate:triethylamine=6:0.5); [3128]
  • NMR (DMSO-d[3129] 6): δ 9.51 (brs, 2H), 8.21-8.11 (m, 1H), 7.89-7.775 (m, 3H), 7.74-7.58 (m, 4H), 7.51 (d, J=7.5 Hz, 1H), 7.47-7.38 (m, 1H), 7.08 (d, J=8.1 Hz, 1H), 7.01 (t, J=7.5 Hz, 1H), 6.16-6.06 (m, 1H), 4.77-4.62 (m, 1H), 4.52-4.37 (m, 1H), 4.31-4.12 (m, 2H), 3.95-3.82 (m, 2H), 3.81 (s, 3H).
    • EXAMPLE 103 (7) 4-(3-Phenylpropyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride
  • [3130]
    Figure US20030073706A1-20030417-C02242
  • TLC: Rt 0.37 (ethyl acetate:triethylamine=6:0.5); [3131]
  • NMR (DMSO-d[3132] 6): δ 9.50 (brs, 1H), 8.16 (d, J=6.3 Hz, 1H), 7.90-7.73 (m, 5H), 7.68-7.58 (m, 2H), 7.35-7.16 (m, 5H), 6.44 (dd, J=6.9, 3.0 Hz, 1H), 4.69-4.54 (m, 1H), 4.45-4.31 (m , 1H), 3.95-3.79 (m, 2H), 3.14-2.95 (m, 2H), 2.68 (t, J=7.2 Hz, 2H), 2.09-1.91 (m, 2H).
    • EXAMPLE 103 (8) 4-(3,5-Dimethoxybenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride
  • [3133]
    Figure US20030073706A1-20030417-C02243
  • TLC: Rf 0.43(ethyl acetate:triethylamine=6:0.5); [3134]
  • NMR (DMSO-d[3135] 6): δ 9.94 (brs, 1H), 9.65 (brs, 1H), 8.17 (d, J=6.9 Hz, 1H), 7.90-7.75 (m, 3H), 7.75-7.67 (m, 2H), 7.67-7.58 (m, 2H), 6.87 (d, J=2.1 Hz, 2H), 6.55 (t, J=2.1 Hz, 1H), 6.30 (t, J=4.5 Hz, 1H), 4.72-4.57 (m, 1H), 4.43-4.28 (m, 1H), 4.23 (brs, 2H), 4.00-3.67 (m, 2H), 3.75 (s, 6H).
    • EXAMPLE 103 (9) 4-((3R)-1-Benzylpyrrolidin-3-yl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.2hydrochloride
  • [3136]
    Figure US20030073706A1-20030417-C02244
  • TLC: Rf 0.45(methanol:ethyl acetate:triethylamine=2:8:0.5); [3137]
  • NMR (CD[3138] 3OD): δ 8.20 (d, J=6.9 Hz, 1H), 7.91-7.70 (m, 5H), 7.66-7.54 (m, 4H), 7.53-7.43 (m, 3H), 6.18-6.05 (m, 1H), 4.77 (d, J=14.1 Hz, 1H), 4.67-4.32 (m, 4H), 4.02-3.66 (m, 5H), 3.62-3.38 (m, 1H), 2.88-2.40 (m, 2H).
    • EXAMPLE 103 (10) 4-((3S)-1-Benzylpyrrolidin-3-yl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene 2hydrochloride
  • [3139]
    Figure US20030073706A1-20030417-C02245
  • TLC: Rf 0.45(methanol:ethyl acetate:triethylamine=2:8:0.5); [3140]
  • NMR (CD[3141] 3OD): δ 8.20 (d, J=6.9 Hz, 1H), 7.91-7.70 (m, 5H), 7.66-7.54 (m, 4H), 7.53-7.43 (m, 3H), 6.18-6.04 (m, 1H), 4.78 (d, J=12.9 Hz, 1H), 4.68-4.32 (m, 4H), 4.02-3.66 (m, 5H), 3.62-3.38 (m, 1H), 2.88-2.40 (m, 2H).
    • EXAMPLE 103 (11) 4-(2-Phenylethyl)aminomethyl-3-phenylsulfonyl-2,3-dohydro-1,1-dioxidebenzo[b]thiophene
  • [3142]
    Figure US20030073706A1-20030417-C02246
  • Free Compound: [3143]
  • TLC: Rf 0.28 (ethyl acetate); [3144]
  • NMR (CDCl[3145] 3): δ 7.65-7.40 (m, 8H), 7.30-7.15 (m, 5H), 5.90 (dd, J=9.3, 0.9 Hz, 1H), 4.66 (d, J=14.2 Hz, 1H), 3.92 (d, J=14.2 Hz, 1H), 3.73 (dd, J=15.0, 0.9 Hz, 1H), 3.42 (dd, J=15.0, 9.3 Hz, 1H), 3.01-2.74 (m, 4H).
  • Hydrochloride: [3146]
  • TLC: Rf 0.28 (ethyl acetate); [3147]
  • NMR (DMSO-d[3148] 6): δ 9.55 (br, 1H), 9.35 (br, 1H), 8.18 (dd, J=6.2, 2.5 Hz, 1H), 7.94-7.87 (m, 2H), 7.82-7.78 (m, 3H), 7.67-7.62 (m, 2H), 7.38-7.33 (m, 2H), 7.29-7.25 (m, 3H), 6.41 (dd, J=7.5, 2.1 Hz, 1H), 4.69-4.6 5 (m, 1H), 4.45-4.41 (m, 1H), 3.92 (dd, J=15.3, 7.5 Hz, 1H), 3.84 (dd, J=15.3, 2.1 Hz, 1H), 3.32-3.25 (m, 2H), 3,08-2.98 (m, 2H).
    • EXAMPLE 103 (12) 4-(N-Benzyl-N-methyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [3149]
    Figure US20030073706A1-20030417-C02247
  • Free Compound: [3150]
  • TLC: Rf 0.42 (hexane:ethyl acetate=1:2); [3151]
  • NMR (CDCl[3152] 3): δ 7.71 (dd, J=7.2,1.2 Hz, 1H), 7.64-7.49 (m, 5H), 7.44-7.39 (m, 2H), 7.34-7.20 (m, 5H), 6.08 (dd, J=9.3, 1.0 Hz, 1H), 4.66 (d, J=14.1 Hz, 1H), 3.88 (dd, J=15.0, 1.0 Hz, 1H), 3.69 (dd, J=15.0, 9.3 Hz, 1H), 3.61 (d, J=12.9 Hz, 1H), 3.53 (d, J=14.1 Hz, 1H), 3.47 (d, J=12.9 Hz, 1H), 2.16 (s, 3H).
  • Hydrochloride: [3153]
  • TLC: Rf 0.42 (hexane:ethyl acetate=1:2); [3154]
  • NMR (CD[3155] 3OD+pyridine-d5): δ 7.92 (d, J=7.5 Hz, 1H), 7.73-7.63 (m, 5H), 7.56-7.50 (m, 2H), 7.37-7.31 (m, 5H), 5.99 (dd, J=7.0, 3.0 Hz, 1H), 4.52 (d, J=14.4 Hz, 1H), 3.94-3.85 (m, 3H), 3.83 (d, J=13.0 Hz, 1H), 3.76 (d, J=13.0 Hz, 1H), 2.32 (s, 3H).
    • EXAMPLE 103 (13) 4-(3-(2-Oxopyrrolidin-1-yl)propyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [3156]
    Figure US20030073706A1-20030417-C02248
  • Free Compound: [3157]
  • TLC: Rf 0.27 (ethyl acetate:methanol:triethylamine=8:1:1); [3158]
  • NMR (CDCl[3159] 3): δ 7.72 (dd, J=7.5, 1.5 Hz, 1H), 7.65-7.54 (m, 4H), 7.51 (dd, J=7.5, 1.5 Hz, 1H), 7.47-7.42 (m, 2H), 5.98 (t-like, J=5.1 Hz, 1H), 4.56 (d, J=13.8 Hz, 1H), 3.91-3.87 (m, 3H), 3.40-3.30 (m, 4H), 2.67-2.53 (m, 2H), 2.41-2.38 (m, 2H), 2.05-1.95 (m, 2H), 1.78-1.69 (m, 2H).
  • Hydrochloride: [3160]
  • TLC: Rf 0.27 (ethyl acetate:methanol:tiethylamine=8:1:1); [3161]
  • NMR (DMSO-d[3162] 6): δ 9.32 (m, 1H), 9.08 (m, 1H), 8.14 (dd, J=6.3, 2.1 Hz, 1H), 7.90-7.78 (m, 5H), 7.67-7.62 (m, 2H), 6.40 (dd, J=7.5, 2.0 Hz, 1H), 4.66-4.60 (m, 1H), 4.43-4.37 (m, 1H), 3.94-3.81 (m, 2H), 3.38-3.25 (m, 4H), 3.03-2.97 (m, 2H), 2.26 (t, J=8.0 Hz, 2H), 1.99-1.83 (m, 4H).
    • EXAMPLE 103 (14) 4-(4-Aminobenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [3163]
    Figure US20030073706A1-20030417-C02249
  • Free Compound: [3164]
  • TLC: Rf 0.47 (ethyl acetate:methanol:triethylamine=8:1:1); [3165]
  • NMR (DMSO-d[3166] 6): δ 7.90 (dd, J=7.0, 2.0 Hz, 1H), 7.80-7.61 (m, 7H), 6.97 (d, J 8.5 Hz, 2H), 6.52 (d, J=8.5 Hz, 2H), 5.81 (dd, J=8.0, 1.8 Hz, 1H), 4.93 (s, 2H), 4.01 (d, J=14.7 Hz, 1H), 3.91 (dd, J=15.0, 8.0 Hz, 1H), 3.84 (dd, J=15.0, 1.8 Hz, 1H), 3.77 (d, J=14.7 Hz, 1H), 3.48 (s, 2H).
  • Hydrochloride: [3167]
  • TLC: Rf 0.47 (ethyl acetate:methanol:triethylamine=8:1:1); [3168]
  • NMR (DMSO-d[3169] 6): δ 9.90 (br, 1H), 9.59 (br, 1H), 8.18 (dd, J=7.0, 1.5 Hz, 1H), 7.88-7.60 (m, 9H), 7.21 (d, J=7.8 Hz, 2H), 6.37-6.34 (m, 1H), 4.70-4.64 (m, 1H), 4.42-4.32 (m, 1H), 4.28 (s, 2H), 3.93-3.82 (m, 2H).
    • EXAMPLE 103 (15) 4-(4-((2E)-3-Phenyl-2-propenyl)piperazin-1-yl)methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [3170]
    Figure US20030073706A1-20030417-C02250
  • Free Compound: [3171]
  • TLC: Rf 0.48 (ethyl acetate:methanol=9:1); [3172]
  • NMR (CDCl[3173] 3): δ 7.65-7.20 (m, 13H), 6.52 (d, J=15.9 Hz, 1H), 6.30 (dd, J=9.3, 1.2 Hz, 1H), 6.26 (dt, J=15.9, 6.8 Hz, 1H), 4.70 (d, J=14.3 Hz, 1H), 3.91 (dd, J=15.0, 1.2 Hz, 1H), 3.73 (dd, J=15.0, 9.3 Hz, 1H), 3.42 (d, J=14.3 Hz, 1H), 3.16 (d, J=6.8 Hz, 2H), 2.60-2.40 (m, 8H).
  • Hydrochloride: [3174]
  • TLC: Rf 0.48 (ethyl acetate:methanol=9:1); [3175]
  • NMR (CD[3176] 3OD+D2O): 5 7.93 (d, J=7.0 Hz, 1H), 7.78-7.72 (m, 4H), 7.66 (d, J=7.0 Hz, 1H), 7.61-7.50 (m, 2H), 7.41-7.33 (m, 3H), 6.95 (d, J=15.6 Hz, 1H), 6.33 (dt, J=15.6, 7.7 Hz, 1H), 6.16 (d, J=9.0 Hz, 1H), 4.54 (d, J=14.5 Hz, 1H), 4.02 (dd, J=15.0,9.0Hz, 1H), 3.96 (d, J=7.7Hz, 2H), 3.89 (d, J=15.0Hz, 1H), 3.85 (d, J=14.5 Hz, 1H), 3.42 (br, 4H), 3.29 (br, 4H).
    • EXAMPLE 103 (16) 4-(2-Aminobenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [3177]
    Figure US20030073706A1-20030417-C02251
  • Free Compound: [3178]
  • TLC: Rf 0.30 (ethyl acetate); [3179]
  • NMR (CDCl[3180] 3): δ 7.74 (d, J=7.5 Hz, 1H), 7.65-7.55 (m, 2H), 7.51-7.39 (m, 5H), 7.09 (dt, J=7.5, 1.5 Hz, 1H), 6.97 (dd, J=7.5, 1.5 Hz, 1H), 6.67 (dt, J=7.5, 1.5 Hz, 1H), 6.63 (dd, J=7.5, 1.5 Hz, 1H), 5.43 (dd, J=9.5, 1.2 Hz, 1H), 4.29 (d, J=14.3 Hz, 1H), 4.02 (d, J=14.3 Hz, 1H), 3.88 (d, J=12.6 Hz, 1H), 3.82 (dd, J=15.0, 1.2 Hz, 1H), 3.81 (d, J=12.6 Hz, 1H), 3.66 (dd, J=15.0, 9.5 Hz, 1H).
  • Hydrochloride: [3181]
  • TLC: Rf 0.30 (ethyl acetate); NMR (DMSO-d[3182] 6): δ 8.17 (dd, J=6.3, 2.4 Hz, 1H), 7.87-7.71 (m, 5H), 7.66-7.61 (m, 2H), 7.50 (br, 2H), 7.29 (dd, J=7.5, 1.2 Hz, 1H), 7.13 (dt, J=7.5, 1.2 Hz, 1H), 6.75 (d, J=7.5 Hz, 1H), 6.63 (t, J=7.5 Hz, 1H), 6.21 (t-like, J=5.0 Hz, 1H), 4.72 (d, J=13.8 Hz, 1H), 4.46 (d, J=13.8 Hz, 1H), 4.26-4.17 (m, 2H), 3.93-3.82 (m, 2H).
    • EXAMPLE 103 (17) 4-(4-Benzylpiperidin-1-yl)methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [3183]
    Figure US20030073706A1-20030417-C02252
  • Free Compound: [3184]
  • TLC: Rf 0.50 (hexane:ethyl acetate=1:1); [3185]
  • NMR (CDCl[3186] 3) δ 7.66-7.56 (m, 4H), 7.53-7.51 (m, 2H), 7.48-7.43 (m, 2H), 7.30-7.25 (m, 2H), 7.21-7.11 (m, 3H), 6.36 (d, J=9.3 Hz, 1H), 4.62 (d, J=14.4 Hz, 1H), 3.89 (d, J=15.0 Hz, 1H), 3.71 (dd, J=15.0, 9.3 Hz, 1H), 3.35 (d, J=14.4 Hz, 1H), 3.04-3.00 (m, 1H), 2.53 (d, J=6.9 Hz, 2H), 2.55-2.50 (m, 1H), 2.05 (dt, J=11.5, 2.5 Hz, 1H), 1.85 (dt, J=11.5, 2.5 Hz, 1H), 1.74-1.68 (m, 1H), 1.62-1.15 (m, 2H), 1.35 (dt, J=12.0, 3.5 Hz, 1H), 1.16-1.02 (m, 1H).
  • Hydrochloride: [3187]
  • TLC: Rf 0.50 (hexane:ethyl acetate=1:1); [3188]
  • NMR (DMSO-d[3189] 6): δ 10.42 (br, 1H), 8.22 (d, J=7.0 Hz, 1H), 7.92-7.72 (m, 5H), 7.65-7.60 (m, 2H), 7.31-7.15 (m, 5H), 6.30 (d, J=9.0 Hz, 1H), 4.72 (dd, J=13.8, 5.3 Hz, 1H), 4.53 (dd, J=13.8,5.3 Hz, 1H), 4.02 (dd, J=15.3,9.0 Hz, 1H), 3.83 (d, J=15.3 Hz, 1H), 3.42-3.39 (m, 1H), 3.12-3.00 (m, 3H), 2.60-2.42 (m, 2H), 1.79-1.49 (m, 5H).
    • EXAMPLE 103 (18) 4-(4-Chlorobenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [3190]
    Figure US20030073706A1-20030417-C02253
  • Free Compound: [3191]
  • TLC: Rf 0.43(ethyl acetate); [3192]
  • NMR (CDCl[3193] 3): δ 7.75 (dd, J=7.0,1.2 Hz, 1H), 7.66-7.51 (m, 5H), 7.47-7.42 (m, 2H), 7.32 (d, J=8.4 Hz, 2H), 7.24 (d, J=8.4 Hz, 2H), 5.81 (dd, J=9.3,1.3 Hz, 1H), 4.48 (d, J=14.0 Hz, 1H), 3.99 (d, J=14.0 Hz, 1H), 3.86 (dd, J=15.0,1.3 Hz, 1H), 3.84 (d, J=13.3 Hz, 1H), 3.78 (d, J=13.3 Hz, 1H), 3.68 (dd, J=15.0, 9.3 Hz, 1H).
  • Hydrochloride: [3194]
  • TLC: Rf 0.43 (ethyl acetate); [3195]
  • NMR (DMSO-d[3196] 6): δ 9.86 (br, 1H), 9.55 (br, 1H), 8.16 (dd, J=6.6, 1.8 Hz, 1H), 7.88-7.72 (m, 5H), 7.67-7.62 (m, 4H), 7.53 (d, J=8.4 Hz, 2H), 6.31 (dd, J=6.2, 3.5 Hz, 1H), 4.70-4.66 (m, 1H), 4.43-4.39 (m, 1H), 4.32 (s, 2H), 3.90 (dd, J=15.5, 6.2 Hz, 1H), 3.84 (dd, J=15.5, 3.5 Hz, 1H).
    • EXAMPLE 103 (19) 4-(3-Chlorobenzyl) aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [3197]
    Figure US20030073706A1-20030417-C02254
  • Free Compound: [3198]
  • TLC: Rf 0.51 (ethyl acetate); [3199]
  • NMR (CDCl[3200] 3): δ 7.76 (dd, J=7.0, 1.2 Hz, 1H), 7.67-7.40 (m, 7H), 7.30-7.14 (m, 4H), 5.80 (dd, J=9.2,1.4 Hz, 1H), 4.48 (d, J=14.0 Hz, 1H), 3.99 (d, J=14.0 Hz, 1H), 3.87 (dd, J=15.4, 1.4 Hz, 1H), 3.86 (d, J=13.6 Hz, 1H), 3.77 (d, J=13.6 Hz, 1H), 3.69 (dd, J=15.4, 9.2 Hz, 1H).
  • Hydrochloride: [3201]
  • TLC: Rf 0.51 (ethyl acetate); [3202]
  • NMR (DMSO-d[3203] 6): δ 9.92 (br, 1H), 9.62 (br, 1H), 8.18 (dd, J=6.6, 1.8 Hz, 1H), 7.88-7.74 (m, 6H), 7.67-7.59 (m, 3H), 7.52-7.45 (m, 2H), 6.39 (dd, J=5.7, 4.2 Hz, 1H), 4.74-4.69 (m, 1H), 4.44-4.40 (m, 1H), 4.35 (s, 2H), 3.90 (dd, J=15.6, 5.7 Hz, 1H), 3.84 (dd, J=15.6, 4.2 Hz, 1H).
    • EXAMPLE 103 (20) 4-(3-Methoxybenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [3204]
    Figure US20030073706A1-20030417-C02255
  • Free Compound: [3205]
  • TLC: Rf 0.41 (ethyl acetate); [3206]
  • NMR (CDCl[3207] 3): δ 7.75 (dd, J=7.2, 1.2 Hz, 1H), 7.65-7.50 (m, 5H), 7.46-7.40 (m, 2H), 7.26-7.21 (m, 1H), 6.86-6.79 (m, 3H), 5.81 (dd, J=9.3, 1.2 Hz, 1H), 4.48 (d, J=14.1 Hz, 1H), 3.98 (d, J=14.1 Hz, 1H), 3.84 (d, J=13.5 Hz, 1H), 3.84 (dd, J=15.0, 1.2 Hz, 1H), 3.80 (s, 3H), 3.74 (d, J=13.5 Hz, 1H), 3.66 (dd, J=15.0, 9.3 Hz, 1H).
  • Hydrochloride: [3208]
  • TLC: Rf 0.41 (ethyl acetate); [3209]
  • NMR (DMSO-d[3210] 6): δ 9.83 (br, 1H), 9.55 (br, 1H), 8.16 (dd, J=6.6, 1.8 Hz, 1H), 7.89-7.78 (m, 3H), 7.73-7.61 (m, 4H), 7.36 (t, J=7.9 Hz, 1H), 7.30 (d, J=2.5 Hz, 1H), 7.15 (d, J=7.9Hz, 1H), 7.00 (dd, J=7.9,2.5Hz, 1H), 6.27 (dd, J=6.0,3.9Hz, 1H), 4.70-4.65 (m, 1H), 4.42-4.37 (m,1H), 4.29 (br, 2H), 3.89 (dd, J=15.5, 6.0 Hz, 1H), 3.84 (dd, J=15.5, 3.9 Hz, 1H), 3.78 (s, 3H).
    • EXAMPLE 103 (21) 4-(3,4-Dichlorobenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [3211]
    Figure US20030073706A1-20030417-C02256
  • Free Compound: [3212]
  • TLC: Rf 0.42(ethyl acetate); [3213]
  • NMR (CDCl[3214] 3): δ 7.77 (dd, J=7.2, 1.2 Hz, 1H), 7.67-7.52 (m, 5H), 7.47-7.39 (m, 4H), 7.15 (dd, J=8.3, 2.0 Hz, 1H), 5.76 (dd, J=9.5, 1.2 Hz, 1H), 4.45 (d, J=13.8 Hz, 1H), 4.00 (d, J=13.8 Hz, 1H), 3.86 (dd, J=15.0, 1.2 Hz, 1H), 3.84 (d, J=13.8 Hz, 1H), 3.78 (d, J=13.8 Hz, 1H), 3.70 (dd, J=15.0, 9.5 Hz, 1H).
  • Hydrochloride: [3215]
  • TLC: Rf 0.42 (ethyl acetate); [3216]
  • NMR (DMSO-d[3217] 6): δ 9.94 (br, 1H), 9.62 (br, 1H), 8.17 (dd, J=6.6, 2.1 Hz, 1H), 7.96 (d, J=1.8 Hz,1H), 7.89-7.73 (m, 6H), 7.67-7.60 (m, 3H), 6.40 (dd, J=5.5, 4.2 Hz, 1H), 4.75-4.68 (m, 1H), 4.45-4.40 (m, 1H), 4.35 (s, 2H), 3.95 (dd, J=15.5, 5.5 Hz, 1H), 3.85 (dd, J=15.5, 4.2 Hz, 1H).
    • EXAMPLE 103 (22) 4-(1,3-Dioxaindan-5-ylmethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [3218]
    Figure US20030073706A1-20030417-C02257
  • Free Compound: [3219]
  • TLC: Rf 0.43(ethyl acetate); [3220]
  • NMR (CDCl[3221] 3): δ 7.73 (dd, J=7.5, 1.2 Hz, 1H), 7.65-7.49 (m, 5H), 7.46-7.41 (m, 2H), 6.77 (d, J=1.5 Hz,1H), 6.74 (d, J=8.0 Hz, 1H), 6.69 (dd, J=8.0, 1.5 Hz, 1H), 5.95-5.94 (m, 2H), 5.88 (dd, J=9.5,1.0 Hz, 1H), 4.50 (d, J=14.0 Hz,1H), 3.96 (d, J=14.0 Hz, 1H), 3.86 (dd, J=15.0, 1.0 Hz, 1H), 3.77 (d, J=13.0 Hz, 1H), 3.68 (d, J=13.0 Hz, 1H), 3.68 (dd, J=15.0, 9.5 Hz, 1H).
  • Hydrochloride: [3222]
  • TLC: Rf 0.43 (ethyl acetate); [3223]
  • NMR (DMSO-d[3224] 6): δ 9.78 (br, 1H), 9.47 (br, 1H), 8.15 (dd, J=6.6, 1.8 Hz, 1H), 7.88-7.72 (m, 5H), 7.66-7.61 (m, 2H), 7.25 (d, J=1.5 Hz, 1H), 7.08 (dd, J=7.8, 1.5 Hz, 1H), 6.99 (d, J=7.8 Hz, 1H), 6.30 (t-like, J=4.5 Hz, 1H), 6.05 (s, 2H), 4.67-4.61 (m, 1H), 4.38-4.33 (m, 1H), 4.23 (s, 2H), 3.93-3.83 (m, 2H).
    • EXAMPLE 103 (23) 4-(2,3-Dimethoxybenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [3225]
    Figure US20030073706A1-20030417-C02258
  • Free Compound: [3226]
  • TLC: Rf 0.36(ethyl acetate); [3227]
  • NMR (CDCl[3228] 3): δ 7.71 (dd, J=7.0, 1.3 Hz, 1H), 7.63-7.48 (m, 5H), 7.45-7.39 (m, 2H), 7.00 (t, J=7.8 Hz, 1H), 6.84 (dd, J=7.8, 1.5 Hz, 1H), 6.78 (dd, J=7.8, 1.5 Hz, 1H), 6.06 (dd, J=9.3, 1.3 Hz, 1H), 4.52 (d, J=14.1 Hz, 1H), 3.92 (d, J=14.1 Hz, 1H), 3.86 (s, 3H), 3.85 (dd, J=15.0, 1.3 Hz, 1H), 3.80 (d, J=13.3 Hz, 1H), 3.76 (s, 3H), 3.73 (dd, J=15.0, 9.3 Hz, 1H), 3.69 (d, J=13.3 Hz, 1H).
  • Hydrochloride: [3229]
  • TLC: Rf 0.36 (ethyl acetate); [3230]
  • NMR (DMSO-d[3231] 6): δ 9.70-9.60 (br, 2H), 8.17 (dd, J=6.6, 2.1 Hz, 1H), 7.89-7.73 (m, 5H), 7.67-7.62 (m, 2H), 7.25-7.21 (m, 1H), 7.15-7.13 (m, 2H), 6.12 (dd, J=6.8, 2.5 Hz, 1H), 4.71-4.67 (m, 1H), 4.45-4.41 (m, 1H), 4.32-4.20 (m, 2H), 3.93-3.83 (m, 2H), 3.83 (s, 3H), 3.80 (s, 3H).
    • EXAMPLE 103 (24) 4-(3,4,5-Trimethoxybenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [3232]
    Figure US20030073706A1-20030417-C02259
  • Free Compound: [3233]
  • TLC: Rf 0.20(ethyl acetate); [3234]
  • NMR (CDCl[3235] 3): δ 7.79 (dd, J=7.2, 1.2 Hz, 1H), 7.66-7.52 (m, 5H), 7.47-7.42 (m, 2H), 6.54 (s, 2H), 5.72 (dd, J=9.3, 1.2 Hz, 1H), 4.45 (d, J=14.0 Hz, 1H), 4.03 (d, J=14.0 Hz, 1H), 3.86 (s, 6H), 3.84 (s, 3H), 3.84 (dd, J=15.0, 1.2 Hz, 1H), 3.82 (d, J=13.5 Hz, 1H), 3.74 (d, J=13.5 Hz, 1H), 3.66 (dd, J=15.0, 9.3 Hz, 1H).
  • Hydrochloride: [3236]
  • TLC: Rf 0.20 (ethyl acetate); [3237]
  • NMR (DMSO-d[3238] 6): δ 9.98 (br, 1H), 9.63 (br, 1H), 8.18 (dd, J=6.6, 1.5 Hz, 1H), 7.89-7.78 (m, 3H), 7.72-7.60 (m, 4H), 7.06 (s, 2H), 6.30 (dd, J=6.0, 3.5 Hz, 1H), 4.69-4.66 (m, 1H), 4.39-4.37 (m, 1H), 4.24 (s, 2H), 3.92-3.84 (m, 2H), 3.80 (s, 6H), 3.67 (s, 3H).
    • EXAMPLE 103 (25) 4-(4-(t-Butyloxycarbonyl)piperazin-1-yl)methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [3239]
    Figure US20030073706A1-20030417-C02260
  • Free Compound: [3240]
  • TLC: Rf 0.49 (hexane:ethyl acetate=1:2); [3241]
  • NMR (CDCl[3242] 3): δ 7.66-7.52 (m, 6H), 7.48-7.43 (m, 2H), 6.18 (dd, J=9.0, 1.0 Hz, 1H), 4.69 (d, J=14.3 Hz, 1H), 3.89 (dd, J=15.0, 1.0 Hz, 1H), 3.72 (dd, J=15.0, 9.0 Hz, 1H), 3.49-3.35 (m, 4H), 3.45 (d, J=14.3 Hz, 1H), 2.52-2.45 (m, 2H), 2.36-2.29 (m, 2H), 1.46 (s, 9H).
  • Hydrochloride: [3243]
  • TLC: Rf 0.49 (hexane:ethyl acetate=1:2); [3244]
  • NMR (CD[3245] 3OD): δ 8.11 (d, J=7.2 Hz, 1H), 7.92-7.83 (m, 2H), 7.77-7.73 (m, 3H), 7.60-7.55 (m, 2H), 6.03 (dd, J=8.7, 1.0 Hz, 1H), 5.01 (d, J=14.3 Hz, 1H), 4.71 (d, J=14.3 Hz, 1H), 4.22 (br, 2H), 3.99 (dd, J=15.3, 8.7 Hz, 1H), 3.84 (dd, J=15.3,1.0 Hz, 1H), 3.65-3.25 (br, 6H), 1.47 (s, 9H).
    • EXAMPLE 103 (26) 4-(2-Diisopropylaminoethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.2hydrochloride
  • [3246]
    Figure US20030073706A1-20030417-C02261
  • TLC: Rf 0.43(methanol:ethyl acetate:triethylamine=2:8:0.5); [3247]
  • NMR (CD[3248] 3OD+D2O): δ 8.18 (d, J=7.5 Hz, 1H), 7.97-7.76 (m, 5H), 7.70-7.60 (m, 2H), 6.20-6.12 (m, 1H), 4.85 (d, J=13.8 Hz, 1H); 4.67 (d, J=13.8 Hz, 1H), 4.01-3.50 (m, 8H), 1.44(d, J=6.3 Hz, 12H).
    • EXAMPLE 103 (27) 4-(2-(Morpholin-4-yl)ethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene 2hydrochloride
  • [3249]
    Figure US20030073706A1-20030417-C02262
  • TLC: Rf 0.37(methanol:ethyl acetate:triethylamine=2:8:0.5); [3250]
  • NMR (CD[3251] 3OD+D2O): δ 8.18 (d, J=7.5 Hz, 1H), 7.97-7.76 (m, 5H), 7.69-7.60 (m, 2H), 6.17-6.10 (m, 1H), 4.86 (d, J=13.8 Hz, 1H), 4.69 (d, J=13.8 Hz, 1H), 4.05-3.90 (m, 5H), 3.89-3.71 (m, 3H), 3.67-3.53 (m, 2H), 3.5 1-3.33 (m, 4H).
    • EXAMPLE 103 (28) 4-(N-2-(Piperidin-1-yl)ethyl-N-propyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [3252]
    Figure US20030073706A1-20030417-C02263
  • Free Compound: [3253]
  • TLC: Rf 0.51 (ethyl acetate:triethylamine 9:1); [3254]
  • NMR (CDCl[3255] 3): δ 7.68 (d, J=7.2 Hz, 1H), 7.64-7.46 (m, 5H), 7.44-7.39 (m, 2H), 6.29 (dd, J=9.3, 1.2 Hz, 1H), 4.69 (d, J=14.4 Hz, 1H), 3.90 (dd, J=15.0, 1.2 Hz, 1H), 3.72 (dd, J=15.0, 9.3 Hz, 1H), 3.58 (d, J=14.4 Hz, 1H), 2.70-2.30 (m, 10H), 1.57-1.38 (m, 8H), 0.79 (t, J=7.2 Hz, 3H).
    • Hydrochloride:
  • TLC: Rf 0.51 (ethyl acetate:triethylamine=9:1); [3256]
  • NMR (CD[3257] 3OD+pyridine-d5): δ 7.93 (d, J=7.2 Hz, 1H), 7.74-7.68 (m, 4H), 7.61-7.52 (m, 3H), 6.01 (dd, J=8.7,1.2 Hz, 1H), 4.38 (d, J=14.7 Hz, 1H), 3.99 (dd, J=15.3, 8.7 Hz, 1H), 3.89 (dd, J=15.3, 1.2 Hz, 1H), 3.85 (d, J=14.7 Hz, 1H), 3.27-3.22 (m, 2H), 3.14 (br, 4H), 2.97-2.81 (m, 2H), 2.61-2.45 (m, 2H), 1.85-1.77 (m, 4H), 1.65-1.53 (m, 4H), 0.89 (t, J=7.3 Hz, 3H).
    • EXAMPLE 103 (29) 4-(N-2-(Piperidin-1-yl)ethyl-N-isopropyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [3258]
    Figure US20030073706A1-20030417-C02264
  • Free Compound: [3259]
  • TLC: Rf 0.48 (ethyl acetate:triethylamine=9:1); [3260]
  • NMR (CDCl[3261] 3): δ 7.77 (d, J=7.2 Hz, 1H), 7.65-7.47 (m, 5H), 7.45-7.40 (m, 2H), 6.09 (d, J=9.0, 1.0 Hz, 1H), 4.54 (d, J=15.0 Hz, 1H), 3.88 (dd, J=15.0, 1.0 Hz, 1H), 3.74 (d, J=15.0 Hz, 1H), 3.73 (dd, J=15.0, 9.0 Hz, 1H), 2.84 (sept, J=6.6 Hz, 1H), 2.57-2.51 (m, 2H), 2.38-2.17 (m, 6H), 1.55-1.48 (m, 4H), 1.42-1.35 (m, 2H), 1.06 (d, J=6.6 Hz, 3H), 1.03 (d, J=6.6 Hz, 3H).
  • Hydrochloride: [3262]
  • TLC: Rf 0.48 (ethyl acetate:triethylamine=9:1); [3263]
  • NMR (CD[3264] 3OD+pyridine-d5): δ 7.99 (d, J=7.5 Hz, 1H), 7.75-7.70 (m, 4H), 7.61-7.54 (m, 3H), 5.93 (dd, J=8.7, 1.5 Hz, 1H), 4.27 (d, J=15.6 Hz, 1H), 3.99 (dd, J=15.3, 8.7 Hz, 1H), 3.96 (d, J=15.6 Hz, 1H), 3.88 (dd, J=15.3, 1.5 Hz, 1H), 3.20-2.80 (m, 9H), 1.82-1.75 (m, 4H), 1.63-1.58 (m, 2H), 1.17-1.14 (m, 6H).
    • EXAMPLE 103 (30) 4-(3,4-Dimethoxybenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [3265]
    Figure US20030073706A1-20030417-C02265
  • Free Compound: [3266]
  • TLC: Rf 0.19 (ethyl acetate); [3267]
  • NMR (CDCl[3268] 3): δ 7.76 (dd, J=7.2, 1.0 Hz, 1H), 7.65-7.51 (m, 5H), 7.46-7.41 (m, 2H), 6.84-6.82 (m, 3H), 5.79 (d, J=9.3 Hz, 1H), 4.47 (d, J=14.0 Hz, 1H), 4.00 (d, J=14.0 Hz, 1H), 3.87 (s, 6H), 3.85 (d, J=15.0 Hz, 1H), 3.82 (d, J=13.2 Hz, 1H), 3.73 (d, J=13.2 Hz, 1H), 3.66 (dd, J=15.0, 9.3 Hz, 1H).
  • Hydrochloride: [3269]
  • TLC: Rf 0.19 (ethyl acetate); [3270]
  • NMR (DMSO-d[3271] 6): δ 10.00-9.70 (br, 2H), 8.38-8.28 (m, 1H), 8.06-7.94 (m, 3H), 7.88-7.76 (m, 4H), 7.56 (d, J=1.4 Hz, 1H), 7.27 (dd, J=8.4, 1.4 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 6.43-6.38 (m, 1H), 4.80 (d, J=12.8 Hz, 1H), 4.53 (d, J=12.8 Hz, 1H), 4.40 (s, 2H), 4.13-4.00 (m, 2H), 3.94 (s, 6H).
    • EXAMPLE 103 (31) 4-(3-(2-Methylpiperidin-1-yl)propyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.2hydrochloride
  • [3272]
    Figure US20030073706A1-20030417-C02266
  • TLC: Rf 0.33 (ethyl acetate:methanol:triethylamine=8:2:0.5); [3273]
  • NMR (CD[3274] 3OD): δ 8.18 (d, J=7.2 Hz, 1H), 7.92-7.73 (m, 5H), 7.67-7.57 (m, 2H), 6.22-6.23 (m, 1H), 4.80 (d, J=13.5 Hz, 1H), 4.62 (d, J=13.5 Hz, 1H), 3.98-3.91 (m, 1H), 3.83-3.74 (m, 1H), 3.64-2.98 (m, 7H), 2.37-2.17 (m, 2H), 2.07-1.52 (m, 6H), 1.41 (d, J=6.3 Hz, 3H).
    • EXAMPLE 103 (32) 4-(4-(Piperidin-1-yl)piperidin-1-yl)methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.2hydrochloride
  • [3275]
    Figure US20030073706A1-20030417-C02267
  • TLC: Rf 0.41 (ethyl acetate methanol:triethylamine=8:2:0.5); [3276]
  • NMR (D[3277] 2O): δ 8.17-8.08 (m, 1H), 8.03-7.94 (m, 2H), 7.91-7.82 (m, 1H), 7.79-7.73 (m, 2H), 7.72-7.62 (m, 2H), 4.71 (d, J=14.4 Hz, 1H), 4.65 (d, J=14.4 Hz, 1H), 4.21-4.05 (m, 2H), 3.87-3.75 (m, 1H), 3.69-3.48 (m, 4H), 3.38-2.98 (m, 4H), 2.52-2.32 (m, 2H), 2.19-1.93 (m, 4H), 1.91-1.65 (m, 3H), 1.59-1.40 (m, 1H).
    • EXAMPLE 103 (33) 4-(3-(Piperidin-1-yl)propyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.2hydrochloride
  • [3278]
    Figure US20030073706A1-20030417-C02268
  • TLC: Rf 0.25 (methanol:ethyl acetate:triethylamine=2:8:0.5); [3279]
  • NMR (CD[3280] 3OD+D2O) δ 8.16 (d, J=7.2 Hz, 1H), 7.95-7.74 (m, 5H), 7.69-7.59 (m, 2H), 6.17-6.08 (m, 1H), 4.78 (d, J=14.1 Hz, 1H), 4.62 (d, J=14.1 Hz, 1H), 4.02-3.88 (m, 1H), 3.85-3.73 (m, 1H), 3.73-2.76 (m, 8H), 2.3 8-2.21 (m, 2H), 2.14-1.44 (m, 6H).
    • EXAMPLE 103 (34) 4-(3-Bromobenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride
  • [3281]
    Figure US20030073706A1-20030417-C02269
  • TLC: Rf 0.50 (ethyl acetate:triethylamine 6:0.5); [3282]
  • NMR (DMSO-d[3283] 6): δ 9.83 (brs, 1H), 9.56 (brs, 1H), 8.16 (d, J=6.6 Hz, 1H), 7.90-7.70 (m, 6H), 7.68-7.58 (m, 4H), 7.41 (t, J=7.5 Hz, 1H), 6.41-6.28 (m, 1H), 4.80-4.60 (m, 1H), 4.52-4.22 (m, 3H), 3.96-3.80 (m, 2H).
    • EXAMPLE 103 (35) 4-(4-Nitrobenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene hydrochloride
  • [3284]
    Figure US20030073706A1-20030417-C02270
  • TLC: Rf 0.34 (ethyl acetate:triethylamine=6:0.5); [3285]
  • NMR (DMSO-d[3286] 6): δ 10.05 (brs, 1H), 9.79 (brs, 1H), 8.29 (d, J=8.1 Hz, 2H), 8.18 (d, J=6.6 Hz, 1H), 7.94-7.70 (m, 7H), 7.67-7.57 (m, 2H), 6.48-6.33 (m, 1H), 4.83-4.64 (m, 1H), 4.59-4.35 (m, 3H), 3.95-3.81 (m, 2H).
    • EXAMPLE 103 (36) 4-(4-Aminosulfonylbenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [3287]
    Figure US20030073706A1-20030417-C02271
  • Free Compound: [3288]
  • TLC: Rf 0.40 (ethyl acetate:methanol=9:1); [3289]
  • NMR (DMSO-d[3290] 6): δ 7.93 (dd, J=7.0, 1.5 Hz, 1H), 7.79-7.66 (m, 7H), 7.63-7.58 (m, 2H), 7.53 (d, J=8.0 Hz, 2H), 7.31 (s, 2H), 5.93 (dd, J=8.3, 1.5 Hz, 1H), 4.07 (d, J=14.1 Hz,1H), 3.95 (dd, J=15.0, 8.3 Hz, 1H), 3.87 (dd, J=15.0, 1.5 Hz, 1H), 3.82 (d, J=14.1 Hz, 1H), 3.75 (s, 2H), 2.86 (br, 1H).
  • Hydrochloride: [3291]
  • TLC: Rf 0.40 (ethyl acetate:methanol=9:1); [3292]
  • NMR (DMSO-d[3293] 6): δ 9.80 (br, 1H), 9.52 (br, 1H), 8.15 (d, J=7.0 Hz, 1H), 7.89-7.74 (m, 9H), 7.67-7.62 (m, 2H), 7.44 (s, 2H), 6.37-6.32 (m, 1H), 4.78-4.70 (m, 1H), 4.47-4.41 (m, 1H), 4.41 (s, 2H), 3.96-3.84 (m, 2H).
    • EXAMPLE 103 (37) 4-(Piperazin-1-yl) methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.2hydrochloride
  • [3294]
    Figure US20030073706A1-20030417-C02272
  • TLC: Rf 0.10 (ethyl acetate:methanol triethylamine=8:2:1); [3295]
  • NMR (CD[3296] 3OD+D2O): δ 7.96 (d, J=7.8 Hz, 1H), 7.80-7.67 (m, SH), 7.61-7.56 (m, 2H), 6.16 (dd, J=9.0, 1.3 Hz, 1H), 4.60 (d, J=14.5 Hz, 1H), 4.01 (dd, J=15.4, 9.0 Hz, 1H), 3.95 (d, J=14.5 Hz, 1H), 3.89 (dd, J=15.4, 1.3 Hz, 1H), 3.37-3.33 (m, 4H), 2.98-2.90 (m, 4H).
    • EXAMPLE 103 (38) 4-(2,4,6-Trimethoxybenzyl)methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [3297]
    Figure US20030073706A1-20030417-C02273
  • Free Compound: [3298]
  • TLC: Rf 0.38 (ethyl acetate:methanol=9:1); [3299]
  • NMR (CDCl[3300] 3): δ 7.69 (dd, J=7.0,1.5Hz, 1H), 7.64-7.49 (m, 5H), 7.45-7.40 (m, 2H), 6.19 (dd, J=9.0,1.0 Hz, 1H), 6.12 (s, 2H), 4.50 (d, J=14.3 Hz, 1H), 3.88 (d, J=14.3 Hz, 1H), 3.85 (dd, J=15.0,1.0 Hz, 1H), 3.81 (s, 3H), 3.75 (s, 6H), 3.73 (d, J=12.6 Hz, 1H), 3.65 (d, J=12.6 Hz, 1H), 3.64 (dd, J=15.0, 9.0 Hz, 1H).
  • Hydrochloride: [3301]
  • TLC: Rf 0.38 (ethyl acetate:methanol=9:1); [3302]
  • NMR (DMSO-d[3303] 6): δ 9.11 (br, 1H), 8.94 (br, 1H), 8.16-8.13 (m, 1H), 7.88-7.87 (m, 2H), 7.84-7.79 (m, 1H), 7.71-7.61 (m, 4H), 6.31 (s, 2H), 5.92 (dd, J=8.0,1.8 Hz, 1H), 4.66-4.62 (m, 1H), 4.39-4.34 (m, 1H), 4.18-4 .13 (m, 1H), 3.97-3.91 (m, 1H), 3.92 (dd, J=15.3, 8.0 Hz, 1H), 3.83 (dd, J=15.3, 1.8 Hz, 1H), 3.82 (s, 3H), 3.79 (s, 6H).
    • EXAMPLE 103 (39) 4-(Piperidin-1-yl)carbonylmethylaminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [3304]
    Figure US20030073706A1-20030417-C02274
    • Free Compound:
  • TLC: Rf 0.42 (ethyl acetate:methanol:triethylamine=8:1:1); [3305]
  • NMR (CDCl[3306] 3): δ 7.75.(dd, J=6.9, 2.1 Hz, 1H), 7.66-7.60 (m, 3H), 7.58-7.53 (m, 2H), 7.48-7.43 (m, 2H), 6.13 (dd, J=9.0, 1.2 Hz, 1H), 4.61 (d, J=13.8 Hz, 1H), 3.97 (d, J=13.8Hz, 1H), 3.87 (dd, J=15.0,1.2Hz, 1H), 3.75 (dd, J=15.0,9.0Hz, 1H), 3.58 (t, J=5.2 Hz, 2H), 3.50 (d, J=16.0 Hz, 1H), 3.41 (d, J=16.0 Hz, 1H), 3.30 (t, J=5.2 Hz, 2H), 1.69-1.55 (m, 6H).
  • Hydrochloride: [3307]
  • TLC: Rf 0.42 (ethyl acetate:methanol: triethylamine=8:1:1); [3308]
  • NMR (DMSO-d[3309] 6): δ 9.63 (br, 1H), 9.18 (br, 1H), 8.11 (d, J=7.2 Hz, 1H), 7.93-7.80 (m, 5H), 7.70-7.64 (m, 2H), 6.28 (dd, J=6.0, 4.0 Hz, 1H), 4.83 (d, J=13.2 Hz, 1H), 4.32 (d, J=13.2 Hz, 1H), 4.28-4.16 (m, 2H), 3.85 (dd, J=15.3, 6.0 Hz, 1H), 3.80 (dd, J=15.3, 4.0 Hz, 1H), 3.54-3.50 (m, 2H), 3.37-3.32 (m, 2H), 1.64-1.49 (m, 6H).
    • EXAMPLE 103 (40) 4-(Pyrrolidin-1-yl)ethylaminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene 2hydrochloride
  • [3310]
    Figure US20030073706A1-20030417-C02275
  • TLC: Rf 0.22(methanol:ethyl acetate:triethylamine=2:8:0.5); [3311]
  • NMR (CD[3312] 3OD+D2O): 8.16 (d, J=7.5 Hz, 1H), 7.94-7.75 (m, 5H), 7.68-7.58 (m, 2H), 6.15-6.08 (m, 1H), 4.81 (d, J=13.8 Hz, 1H), 4.63 (d, J=13.8 Hz, 1H), 4.01-3.88 (m, 1H), 3.86-3.76 (m, 1H), 3.75-3.62 (m, 4H), 3.6 2-3.38 (m, 4H), 2.20-2.06 (m, 4H).
    • EXAMPLE 103 (41) 4-(4-(1,3-Dioxaindan-5-ylmethyl)piperazin-1-yl)methyl-1,1-dioxidebenzo[b]thiophene-2hydrochloride
  • [3313]
    Figure US20030073706A1-20030417-C02276
  • TLC: Rf 0.51 (ethyl acetate:triethylamine=6:0.5); [3314]
  • NMR (CD[3315] 3OD+D2O): δ 7.90 (d, J=7.5 Hz, 1H), 7.79-7.52 (m, 7H), 7.04-6.96 (m, 2H), 6.95-6.87 (m, 1H), 6.15-6.07 (m, 1H), 6.01 (s, 2H), 4.45 (d, J=14.4 Hz, 1H), 4.25 (s, 2H), 4.01 (dd, J=15.6, 8.7 Hz,1H), 3.90 (dd, J=15.6, 1.2 Hz, 1H), 3.77 (d, J=14.4 Hz, 1H), 3.50-3.10 (br, 4H), 2.98-2.63 (br, 4H).
    • EXAMPLE 104 4-Cyano-6,7-dihydrobenzo[b]thiophene
  • [3316]
    Figure US20030073706A1-20030417-C02277
  • To a suspension of zinc iodide (6.2 g) in acetonitrile (200 ml) were added 4-keto-4,5,6,7-tetrahydrothianaphthene (20 g) and trimethylsilylcyanide (18 ml) successively. The mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated. The residue was dissolved in pyridine (65 ml), followed by adding phosphryl chloride (15 ml) dropwise at room temperature. The mixture was refluxed for 30 minutes. The reaction mixture was cooled with ice and thereto was added dropwise isopropanol. The reaction mixture was poured onto ice water and extracted with ethyl acetate. The extract was washed by hydrochloric acid, water and a saturated aqueous solution of sodium chloride successively, dried over anhydrous magnesium sulfate and concentrated to give the title compound (17 g) having the following physical data. [3317]
  • TLC: Rf 0.45 (hexane:ethyl acetate=3:1); [3318]
  • NMR (CDCl[3319] 3): δ 7.12 (d, J=5.4 Hz, 1H), 7.07 (d, J=5.4 Hz, 1H), 6.62 (t, J=4.8 Hz, 1H), 2.93 (t, J=9.0 Hz, 2H), 2.60 (t, J=9.0, 4.8 Hz, 2H).
    • EXAMPLE 105 4-Cyanobenzo[b]thiophene
  • [3320]
    Figure US20030073706A1-20030417-C02278
  • To a solution of the compound prepared in Example 104 (17 g) in benzene (200 ml), was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (30 g). The mixture was refluxed for 1.5 hours. The mixture was filtered. The filtrate was concentrated. The residue was extracted with a mixed solvent (hexane:ethyl acetate=1:1). The extract was washed by an aqueous solution of sodium hydroxide, water and a saturated aqueous solution of sodium chloride successively, dried over anhydrous magnesium sulfate and concentrated. The residue was purified with column chromatopgaphy on silica gel (hexane:ethyl acetate=100:1) to give the title compound (14.5 g) having the following physical data. [3321]
  • TLC: Rf 0.40 (hexane:ethyl acetate=4:1); [3322]
  • NMR (CDCl[3323] 3): δ 7.45 (t, J=7.5Hz, 1H), 7.60 (d, J=5.0 Hz, 1H), 7.70 (d, J=5.0 Hz, 1H), 7.75 (d, J=7.5Hz, 1H), 8.10 (d, J=7.5Hz, 1H).
    • EXAMPLE 106 4-Carboxybenzo[b]thiophene
  • [3324]
    Figure US20030073706A1-20030417-C02279
  • 1) To a suspension of the compound prepared in Example 105 (14.5 g) in ethyleneglycol (50 ml) was added 85% potassium hydroxide (19 g). The mixture was stirred at 1 80“C for 2 hours. The reaction mixture was poured into hydrochloric acid, and the acidic mixture was extracted with ethyl acetate. The extract was washed by water and a saturated aqueous solution of sodium chloride sucessively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate and hexane to give the title compound (12.2 g) having the following physical data. [3325]
  • The above title compound may be prepared by the following method. 2) A mixture of the compound prepared in Example 104 (1.61 g), nitrobenzene (2.46 g), ethyleneglycol (10 ml) and 10% palladium carbon (161 mg) was stirred at 200° C. for 3 hours and at 1 80“C for 17 hours. To the reaction mixture, sodium hydroxide was added at 150° C. The mixture was stirred at 180° C. for 1 hour. The reaction mixture was cooled to room temperature. Thereto were added water (10 ml) and activated charcoal. The mixture was filtrated. The filtrate was washed by ethyl acetate (20 ml). To aqueous layer was added concentrated hydrochloric acid (2.5 ml). The mixture was extracted with ethyl acetate, washed by water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from acetonitrile (25 ml) to give the title compound (1.46 g). [3326]
  • TLC: Rf 0.10 (hexane:ethyl acetate=4:1); [3327]
  • NMR (CDCl[3328] 3): δ 8.32 (dd, J=5.6, 1.0 Hz, 1H), 8.27 (dd, J=7.6, —1.0 Hz, 1H), 8.18-8.11 (m, 1H), 7.68 (d, J=5.6 Hz, 1H), 7.51-7.41 (m, 1H).
    • EXAMPLE 107 4-Carboxy-1,1-dioxidebenzo[b]thiophene
  • [3329]
    Figure US20030073706A1-20030417-C02280
  • To a suspension of the compound prepared in Example 106 (35 g) in methanol (720 ml), was added a suspension of OXONE@ (362 g) in pure water (720 ml) at room temperature. The mixture was stirred at 40° C. for 2 hours. The reaction mixture was filtered. The filtrate was concentrated. The residue was extracted with ethyl acetate. The organic layer was washed by a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from hexane, followed by drying to give the compound of the present invention (30 g) having the following physical data. [3330]
  • TLC: Rf 0.18 (ethyl acetate); [3331]
  • NMR (CDCl[3332] 3): δ 8.28 (d, J=7.5 Hz, 1H), 8.26 (d, J=7.5 Hz, 1H), 7.94 (d, J=7.5 Hz, 1H), 7.66 (t, J=7.5 Hz, 1H), 6.87 (d, J=7.5 Hz, 1H).
  • Examples relates to different method for preparation of the compounds of the present invention [3333]
  • The compounds prepared in Examples 35 (49)˜(61), Example 70, Example 94, Examples 103˜103 (29) may be prepared by the same procedure as described hereinafter in Example 108 or Example 109. [3334]
  • 1) For example, the compound described in Example 35 (50) may be prepared by the following procedure. [3335]
    • EXAMPLE 108 4-(Pyridin-3-ylmethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.2hydrochloride
  • [3336]
    Figure US20030073706A1-20030417-C02281
  • Under an atmosphere of argon, to a solution of the compound prepared in Example 82 in dimethylformamide (5 ml) was added a solution of 3-(aminomethyl)pyridine (73 μl) in dimethylformamide (1 ml), followed by adding 5% palladium-carbon (50 mg). Then, an atmosphere was replaced by hydrogen. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was filtered. The filtrate was concentrated. The obtained residue was purified with column chromatography on silica gel (chloroform methanol 25:1) followed by converting into hydrochloride by addition of 4N hydrochloride/ethyl acetate and recrystallization using ethanol to give the compound of the present invention (231 mg). [3337]
  • A free compound of the compound described in Example 35 (52) may be prepared by the following procedure. [3338]
    • EXAMPLE 109 4-(N,N-Bis(2-hydroxyethyl)amino)methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
  • [3339]
    Figure US20030073706A1-20030417-C02282
  • To a suspension of the compound prepared in Example 82 (168 mg) in methylene chloride (2 ml) were added diethanolamine (53 μl), sodium borocyanohydride (63 mg), concentrated hydrochloric acid (2 drops) and methanol (0.5 ml). The mixture was stirred at room temperature for 6 hours. The reaction mixture was poured into water, and extracted with a mixed solvent (methylene chloride and methanol). The organic layer was washed by a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The residue was purified with column chromatography on silica gel to give the compound of the present invention (50 mg). [3340]
  • 2) The compound prepared in Example 81 (1) may be prepared by the same procedure as described in Example 27 using the compound prepared in Example 107 instead of 5-methyl-1,1-dioxidebenzo[b]thiophene, and if necesary, by converting into a corresponding free compound by a known method. [3341]
  • 3) The compounds prepared in Examples 35˜35 (32), Examples 45 (1)˜45 (2), Example 70, Example 71 and Example 87 may be prepared by the same procedure as described in Example 100. [3342]
  • For example, the compound prepared in Example 35 (11) may be prepared by the same procedure as described in Example 100 using the compound (free compound or sodium salt) prepared in Example 81 (1), and 2-(piperidin-1-yl)ethylamine instead of furan-2-ylmethylamine. [3343]
    • FORMULATION EXAMPLE Formulation Example 1
  • The following components were admixed in a conventional method and punched out to obtain 100 tablets each containing 50 mg of active ingredient. [3344]
    4-(Pyridin-3-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1- 5.0 g
    dioxidebenzo[b]thiophene
    Carboxymethylcellulose calcium (disintegrating agent) 0.2 g
    Magnesium stearate (lubricating agent) 0.1 g
    Microcrystalline cellulose 4.7 g
    • Formulation Example 2
  • The following components were admixed in a conventional method, and the solution was sterilized in a conventional method, placed 5 ml portions into ampoules and freeze-dried in a conventional method to obtain 100 ampoules each containing 20 mg of active ingredient. [3345]
    4-(Pyridin-3-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-  2.0 g
    dioxidebenzo[b]thiophene
    Mannitol   20 g
    DIstilled water  500 ml

Claims (16)

1. An inhibitor of producing interleukin-6 and/or interieukin-12 comprising, as an active ingredient, a fused thiophene derivative of the formula (I)
Figure US20030073706A1-20030417-C02283
[wherein
Figure US20030073706A1-20030417-P00002
is a single or double bond,
Y is
Figure US20030073706A1-20030417-C02284
 or
(ii) hydrogen
 (with a proviso that when
Figure US20030073706A1-20030417-P00002
is a double bond, Y is hydrogen, and when
Figure US20030073706A1-20030417-P00002
is a single bond, Y is
Figure US20030073706A1-20030417-C02285
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,
Figure US20030073706A1-20030417-C02286
 is
(i) benzene ring or
(ii) 6-membered monocyclic hetero aryl containing 1-2 nitrogen atom(s),
Figure US20030073706A1-20030417-C02287
 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,
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, —OR14 (wherein R14 is hydrogen or C1-8 alkyl.) or cyano, 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;
plural R15s are each independently, hydroxy or C1-8 alkoxy,
plural R16s are each 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, R23 is hydrogen, C1-8 alkyl, Cyc1 or C1-8 alkyl substituted with Cyc1 or NR24R25 (R24 and R25 are each independently hydrogen, C1-8 alkyl, 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 Cyc1, Si(R2)3 (wherein plural R26s are each independently C1-8 alkyl.) or —OR27 (wherein R27 is hydrogen, C1-8 alkyl or C2-5 acyl.),
R9 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, 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,
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) —SO2NR45R44, (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 —OR , —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,
Cyc3is
(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,
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.
2. 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 containing a fused thiophene derivative of the formula (I) depicted in claim 1, an N-oxide derivative thereof or a non-toxic salt thereof as an active ingredient.
3. An inhibitor of producing interleukin-6 and/or interleukin-12 according to claim 1, comprising a compound which is
(1) 3-(thiophen-2-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(2) 6-nitro-3-(thiophen-2-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(3) 3-(thiophen-2-yl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(4) 4,5-dimethyl-1,1-dioxidebenzo[b]thiophene,
(5) 4,6-dimethyl-1,1-dioxidebenzo[b]thiophene,
(6) 4,7-dimethyl-1,1-dioxidebenzo[b]thiophene,
(7) 5,6-dimethyl-1,1-dioxidebenzo[b]thiophene,
(8) 5,7-dimethyl-1,1-dioxidebenzo[b]thiophene,
(9) 6,7-dimethyl-1,1-dioxidebenzo[b]thiophene,
(10) 4-carboxymethyl-1,1-dioxidebenzo[b]thiophene,
(11) 6-(2,2-bis(ethoxycarbonyl)ethenyl)amino-1,1-dioxidebenzo[b]thiophene,
(12) 4-methylaminocarbonyloxy-1,1-dioxidebenzo[b]thiophene,
(13) 5-(2-(N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-ylmethyl)-N-methylamino) ethyl)-1-dioxidebenzo[b]thiophene,
(14) 5-(2-hydroxyethyl)-1,1-dioxidebenzo[b]thiopherie,
(15) 5-bromo-7-methyl-1,1-dioxidebenzo[b]thiophene,
(16) 7-bromo-5-methyl -methyl-1,1-dioxidebenzo[b]thiophene,
(17) 5-bromo-6-methyl-1,1-dioxidebenzo[b]thiophene,
(18) 5-bromo-4-methyl-1,1-dioxidebenzo[b]thiophene,
(19) 6-bromo-5-methyl-1,1-dioxidebenzo[b]thiophene,
(20) 4-bromo-5-methyl- -methyl-1,1-dioxidebenzo[b]thiophene,
(21) 6-amino-1,1-dioxidebenzo[b]thiophene,
(22) 6-acetylamino-1,1-dioxidebenzo[b]thiophene,
(23) 6-(4-diethylaminophenyl)-1,1-dioxidebenzo[b]thiophene,
(24) 1,1-dioxidethieno[2,3-b]pyridine,
(25) 1,1-dioxidethieno[3,2-b]pyridine,
(26) 1,1-dioxidethieno[2,3-c]pyridine,
(27) 5-amino-1,1-dioxidebenzo[b]thiophene,
(28) 5-(3-methyl-5-oxo-4,5-dihydropyrazol-1-yl)-1,1-dioxidebenzo[b]thiophene,
(29) 4-(2-(1,1-dioxidebenzo[b]thiophen-3-yl)ethyl)-1,1-dioxidebenzo[b]thiophene,
(30) 7-methyl-1,1-dioxidethieno[2,3-c]pyridine,
(31) 1,1-dioxidebenzo[b]thiophene,
(32) 4-(4-methoxyphenyl)-1,1-dioxidethieno[3,2-c]pyridine,
(33) 5-((E)-2-(ethoxycarbonyl)ethenyl)-4-methoxybenzo[b]thiophene,
(34) 5-(2-(ethoxycarbonyl)ethyl-4-methoxybenzo[b]thiophene,
(35) 5-methoxycarbonyl-4-ethoxybenzo[b]thiophene,
(36) 5-carboxy-4-ethoxybenzo[b]thiophene,
(37) 5-benzyloxycarbonyl-4-ethoxybenzo[b]thiophene,
(38) 5-hydroxy-4-formylbenzo[b]thiophene,
(39) 5-benzyloxy-4-formylbenzo[b]thiophene,
(40) 5-benzyloxy-4-hydroxymethylbenzo[b]thiophene or
(41) 4-t-butoxycarbonylaminobenzo[b]thiophene,
or an N-oxide derivative thereof, or a non-toxic salt thereof as active ingredient.
4. A fused thiophene derivative of formula (IA)
Figure US20030073706A1-20030417-C02288
[wherein
Figure US20030073706A1-20030417-P00002
is a single or double bond,
Y is (i)
Figure US20030073706A1-20030417-C02289
 or
(ii) hydrogen
 (with a proviso that when
Figure US20030073706A1-20030417-P00002
is a double bond, Y is hydrogen, and when
Figure US20030073706A1-20030417-P00002
is a single bond, Y is
Figure US20030073706A1-20030417-C02290
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,
Figure US20030073706A1-20030417-C02291
is
(i) benzene ring or
(ii) 6-membered monocyclic hetero aryl containing 1-2 nitrogen atom(s),
Figure US20030073706A1-20030417-C02292
 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,
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, —OR4 (wherein R14 is hydrogen or C1-8 alkyl.) or cyano, 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;
plural R15s are each independently, hydroxy or C1-8 alkoxy,
plural R16s are each 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, R22 is hydrogen, C1-8 alkyl, Cyc1 or C1-8 alkyl substituted with Cyc1 or NR24R25 (R24 and R25 are each independently hydrogen, C1-8 alkyl, 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 Cyc1, Si(R26)3 (wherein plural R26s are each independently C1-8 alkyl.) or —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,
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) —OR3, (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, —OR3, —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,
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) —OR4 , (xi) —SR42, (xii) —NR4R44, (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),
R59 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 14 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom,
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) —NR62R6 , (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
(1) when A2 is (vi) —NR5C(O)—, (x) —NR7SO2—, (xiv) —NR13C(O)O— or (xv) —OC(O)O—, then A3 is not hydrogen,
(2) when
Figure US20030073706A1-20030417-P00002
is a double bond and Y is hydrogen, then n is 1 or 2,
(3) when
Figure US20030073706A1-20030417-P00002
is a single bond, Y is
Figure US20030073706A1-20030417-C02293
 n is 2, m is 0 or 2, p is 0 or an integer of 1-4, ring A and ring B are benzene ring, R1 is C1-8 alkyl, C1-8 alkoxy, halogen, carboxy, nitro or C1-8 alkyl substituted with halogen, then q is not 0,
(4) when
Figure US20030073706A1-20030417-P00002
is a single bond, Y is
Figure US20030073706A1-20030417-C02294
 n is 2, m is 0 or 2, p is 0 or an integer of 1-4, ring A and ring B are benzene ring, R1 is C1-8 alkyl, C1-8 alkoxy, halogen, carboxy, nitro or C1-8 alkyl substituted with halogen, and q is an integer of 1-5, then R2 is not C1-8 alkyl, C1-8 alkoxy, halogen, carboxy, nitro or C1-8 alkyl substituted with halogen,
(5) when
Figure US20030073706A1-20030417-P00002
is a double bond, Y is hydrogen, n is 2, p is 1 and ring A is benzene ring, then R1 is not halogen, C1-8 alkyl, phenylsulfonylamino, 2-methylphenylsulfonylamino, 3-methylphenylsulfonylamino, 4-methylphenylsulfonylamino, hydroxy, C1-8 alkoxy, nitro, or C1-8 alkoxy substituted with carboxy, hydroxy, C1-8 alkoxycarbonyl or hydroxyaminocarbonyl,
(6) when
Figure US20030073706A1-20030417-P00002
is a double bond, Y is hydrogen, n is 2, p is 2 and ring A is benzene ring and one R1 is phenylsulfonylamino, 2-methylphenylsulfonylamino, 3-methylphenylsulfonylamino or 4-methylphenylsulfonylamino, then the other R1 is not C1-8 alkyl,
(7) when
Figure US20030073706A1-20030417-P00002
is a double bond, Y is hydrogen, n is 2, p is 2-3, ring A is benzene ring, one R1 is hydroxy, C1-8 alkoxy, or C1-8 alkoxy substituted with carboxy, hydroxy, C1-8 alkoxycarbonyl or hydroxyaminocarbonyl, then the other R1 is neither halogen nor C1-8 alkyl,
(8) when
Figure US20030073706A1-20030417-P00002
is a double bond, Y is hydrogen, n is 2, p is 3-4 and ring A is benzene ring, then two or three R1 are not t-butyl at the same time, and
(9) the following compounds (1)-(32) are excluded:
(1) 3-(thiophen-2-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(2) 6-nitro-3-(thiophen-2-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(3) 3-(thiophen-2-yl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(4) 4,5-dimethyl-1,1-dioxidebenzo[b]thiophene,
(5) 4,6-dimethyl-1,1-dioxidebenzo[b]thiophene,
(6) 4,7-dimethyl-1,1-dioxidebenzo[b]thiophene,
(7) 5,6-dimethyl-1,1-dioxidebenzo[b]thiophene,
(8) 5,7-dimethyl-1,1-dioxidebenzo[b[thiophene,
(9) 6,7-dimethyl-1,1-dioxidebenzo[b]thiophene,
(10) 4-carboxymethyl-1,1-dioxidebenzo[b]thiophene,
(11) 6-(2,2-bis(ethoxycarbonyl)ethenyl)amino-1,1-ioxidebenzo[b]thiophene,
(12) 4-methylaminocarbonyloxy-1,1-dioxidebenzo[b]thiophene,
(13) 5-(2-(N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-ylmethyl)-N-methylamino)ethyl)-1,1-dioxidebenzo[bjthiophene,
(14) 5-(2-hydroxyethyl)-1,1-di oxidebenzo[b]thiophene,
(15) 5-bromo-7-methyl-1,1-dioxidebenzo[b]thiophene,
(16) 7-bromo-5-methyl-1,1-dioxidebenzo[b]thiophene,
(17) 5-bromo-6-methyl-1,1-dioxidebenzo[b]thiophene,
(18) 5-bromo-4-methyl-1,1-dioxidebenzo[b]thiophene,
(19) 6-bromo-5-methyl-1,1-dioxidebenzo[b]thiophene,
(20) 4-bromo-5-methyl-1,1-dioxidebenzo[b]thiophene,
(21) 6-amino-1,1-dioxidebenzo[b]thiophene,
(22) 6-acetylamino-1,1-dioxidebenzo[b]thiophene,
(23) 6-(4-diethylaminophenyl)-1,1-dioxidebenzo[b]thiophene,
(24) 1,1-dioxidethieno[2,3-b]pyridine,
(25) 1,1-dioxidethieno[3,2-b]pyridine,
(26) 1,1-dioxidethieno[2,3-c]pyridine,
(27) 5-amino-1,1-dioxidebenzo[b]thiophene,
(28) 5-(3-methyl-5-oxo-4,5-dihydropyrazol-1-yl)-1,1-dioxidebenzo[b]thiophene,
(29) 4-(2-(1,1-dioxidebenzo[b]thiophen-3-yl)ethyl)-1,1-dioxidebenzo[b]thiophene,
(30) 7-methyl-1,1-dioxidethieno[2,3-c]pyridine,
(31) 1,1-dioxidebenzo[b]thiophene or (32) 4-(4-methoxyphenyl)-1,1-dioxidethieno[3,2-c]pyridine.], an N-oxide derivative thereof or a non-toxic salt thereof.
5. A fused thiophene derivative of the formula (IA) depicted in claim 4, wherein
Figure US20030073706A1-20030417-P00002
is a double bond, an N-oxide derivative thereof, or a non-toxic salt thereof.
6. A fused thiophene derivative of the formula (IA) depicted in claim 4, wherein
Figure US20030073706A1-20030417-P00002
is a single bond, an N-oxide derivative thereof or a non-toxic salt thereof.
7. A fused thiophene derivative of the formula (IA) depicted in claim 4, wherein
Figure US20030073706A1-20030417-C02295
is benzene, an N-oxide derivative thereof or a non-toxic salt thereof.
8. A fused thiophene derivative of the formula (IA) depicted in claim 4, wherein
Figure US20030073706A1-20030417-C02296
is 6-membered monocyclic hetero aryl containing 1-2 nitrogen atom(s), an N-oxide derivative thereof or a non-toxic salt thereof.
9. A fused thiophene derivative of the formula (IA) depicted in claim 4, wherein
Figure US20030073706A1-20030417-C02297
is a C3-15 mono-, bi- or tricyclic carbo ring, an N-oxide derivative thereof, or a non-toxic salt thereof.
10. A fused thiophene derivative of the formula (IA) depicted in claim 4, wherein
Figure US20030073706A1-20030417-C02298
is a 4-membered mono-, bi- or tricyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom, an N-oxide derivative thereof, or a non-toxic salt thereof.
11. A fused thiophene derivative of the formula (IA) depicted in claim 4, wherein
Figure US20030073706A1-20030417-C02299
is 5-10 membered mono-, bi- or tricyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom, an N-oxide derivative thereof, or a non-toxic salt thereof.
12. A fused thiophene derivative of the formula (IA) depicted in claim 4, wherein
Figure US20030073706A1-20030417-C02300
is 11-18 membered mono-, bi- or tricyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom, an N-oxide derivative thereof, or a non-toxic salt thereof.
13. A compound according to claim 4, which is
(1) 3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(2) 3-(thiophen-2-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(3) 3-(4-methylphenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(4) 3-(4-methoxyphenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(5) 3-(4-chlorophenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(6) 3-(4-fluorophenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(7) 3-(4-hydroxyphenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(8) 3-(3-hydroxyphenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(9) 3-(2-hydroxyphenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(10) 3-(pyridin-4-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(11) 3-(pyrimidin-2-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(12) 3-(thiazol-2-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(13) 3-(3-methylfuran-2-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(14) 3-(3-methoxyphenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(15) 3-(2-methoxycarbonylphenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(16) 3-cyclohexylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(17) 3-(naphthalen-1-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(18) 3-(2-methoxyphenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(19) 3-(1-methylimidazol-2-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(20) 3-phenylsulfinyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(21) 3-(thiophen-2-yl)sulfinyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(22) 3-(2-methoxycarbonylphenyl)sulfinyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(23) 3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(24) 3-(thiophen-2-yl) sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(25) 3-(4-methylphenyl) sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(26) 3-(4-methoxyphenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(27) 3-(4-chlorophenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(28) 3-(4-fluorophenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(29) 3-(4-hydroxyphenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(30) 3-(3-hydroxyphenyl)sulfonyl-2,3-dihydro-1,1-dloxidebenZo[b]thiophene,
(31) 3-(2-hydroxyphenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(32) 3-(pyridin-4-yl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(33) 3-(pyrimidin-2-yl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(34) 3-(thiazol-2-yl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(35) 3-(3-methylfuran-2-yl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(36) 3-(3-methoxyphenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(37) 3-(2-methoxycarbonylphenyl) sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(38) 3-cyclohexylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
(39) 3-(naphthalen-1-yl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(40) 3-(2-methoxyphenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(41) 3-(4-(2-(piperidin-1-yl)ethoxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(42) 3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(43) 3-(4-(2-(morpholin-4-yl)ethoxy) phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(44) 3-(3-benzyloxyphenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(45) 3-(2-benzyloxyphenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(46) 3-(4-(pyridin-2-ylmethyloxy) phenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(47) 3-(4-(pyridin-3-ylmethyloxy) phenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(48) 3-(4-pyridin-4-ylmethyloxy)phenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(49) 3-(4-(3-hydroxypropyloxy) phenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(50) 3-(3-(pyridin-3-ylmethyloxy)phenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(51) 3-(3-(3-hydroxypropyloxy)phenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(52) 3-(2-(pyridin-3-ylmethyloxy)phenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(53) 3-(2-(3-hydroxypropyloxy)phenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(54) 3-(4-(2-(t-butoxycarbonylamino)ethyloxy)phenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(55) 3-(3-(2-(t-butoxycarbonylamino)ethyloxy)phenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(56) 3-(4-(pyridin-2-ylmethyloxy) phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(57) 3-(4-(pyridin-3-ylmethyloxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(58) 3-(4-(pyridin-4-ylmethyloxy) phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(59) 3-(4-(3-hydroxypropyloxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(60) 3-(3-(pyridin-3-ylmethyloxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(61) 3-(3-(3-hydroxypropyloxy) phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(62) 3-(2-(pyridin-3-ylmethyloxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(63) 3-(2-(3-hydroxypropyloxy) phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(64) 3-(4-(2-(t-butoxycarbonylamino)ethyloxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(65) 3-(3-(2-(t-butoxycarbonylamino)ethyloxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(66) 3-(4-(2-aminoethyloxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(67) 3-(3-(2-aminoethyloxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[bjthiophene,
(68) 3-(4-(2-(N,N-dimethylamino)ethyloxyphenyl)sulfonyl-2,3dihydro-1,1-dioxidebenzo[b]thiophene,
(69) 3-(3-(2-(N,N-dimethylamino)ethyloxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(70) 5-nitro-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(71) 6-methoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(72) 4-methoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene, (73) 5-methoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(74) 7-methoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(75) 4-chloro-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(76) 5-(t-butoxycarbonylamino) methyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(77) 4,7-dimethyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(78) 4,6-dimethyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(79) 4-ethyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(80) 4-methoxy-5-ethoxycarbonyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(81) 4-bromo-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(82) 4-hydroxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(83) 5-hydroxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(84) 6-hydroxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(85) 7-hydroxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(86) 3-phenylthio-2,3-dihydro-1,1-dioxidethieno[2,3-b]pyridine,
(87) 4,7-dihydroxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(88) 5-nitro-3-phenyisulfonyl-2,3-dihydro-1,1-di oxidebenzo[b]thiophene,
(89) 6-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(90) 4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(91) 5-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(92) 7-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(93) 4-chloro-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(94) 4-(t-butoxycarbonylamino) methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(95) 4,7-dimethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(96) 4,6-dimethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(97) 4-ethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(98) 4-methoxy-5-ethoxycarbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(99) 4-bromo-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(100) 4-hydroxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(101) 5-hydroxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
(102) 6-hydroxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(103) 7-hydroxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(104) 3-phenylsulfonyl-2,3-dihydro-1,1-dioxidethieno[2,3-b]pyridine,
(105) 5-amino-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(106) 5-acetylamino-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(107) 4-aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(108) 4-(N,N-dimethylamino) methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(109) 4-methoxy-5-formyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(110) 4-methoxy-3-(thiophen-2-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(111 ) 4-methoxy-3-(thiophen-2-yl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(112) 4-(4-nitrophenylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(113) 4-(3-phenyloxypropyl) oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(114) 4-benzyloxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(115) 4-(3-benzyloxypropyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(116) 4-(pyridin-3-ylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(117) 4-(quinolin-2-ylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(118) 4-(pyridin-2-ylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(119) 4-(pyridin-4-ylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(120) 4-(3-(pyridin-3-yl)propyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(121) 4-(3-hydroxypropyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(122) 5-pentoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(123) 5-(2-phenyloxyethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(124) 5-(3-hydroxypropyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(125) 5-(pyridin-3-ylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(126) 5-(3-(pyridin-3-yl) propyl) oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(127) 6-(3-phenyloxypropyl) oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(128) 6-benzyloxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(129) 6-pentoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(130) 6-(2-(morpholin-4-yl) ethyl) oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(131) 6-(3-hydroxypropyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(132) 6-(pyridin-3-ylmethyl) oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(133) 6-(3-nitrophenylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(134) 6-(3-bromopropyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(135) 7-pentoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(136) 7-(2-phenyloxyethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(137) 7-(3-hydroxypropyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(138) 7-(pyridin-3-ylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(139) 4-(t-butoxycarbonylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(140) 5-(t-butoxycarbonylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(141) 6-(t-butoxycarbonylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(142) 7-(t-butoxycarbonylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(143) 4-(2-(t-butoxycarbonylamino)ethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(144) 4-(3-(t-butoxycarbonylamino)propyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(145) 5-(2-(t-butoxycarbonylamino) ethyl) oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[bjthiophene,
(146) 6-(3-(t-butoxycarbonylamino)propyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(147) 6-(2-(t-butoxycarbonylamino)ethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(148) 7-(2-(t-butoxycarbonylamino) ethyl) oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(149) 4-(N-(t-butoxycarbonyl) piperidin-4-yl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(150) 4,7-bis[(2-(t-butoxycarbonylamino)ethyl)oxy]-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(151) 4-(3-nitrophenylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(152) 4,7-bis(pyridin-3-ylmethyloxy)-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(153) 4-(3-hydroxypropyl)oxy-3-phenylsulfinyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(154) 4-(4-nitrophenylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(155) 4-(3-phenyloxypropyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(156) 4-benzyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(157) 4-(3-benzyloxypropyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(158) 4-(pyridin-3-ylmethyl) oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(159) 4-(N-oxidequinolin-2-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(160) 4-(pyridin-2-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(161) 4-(N-oxidepyridin-2-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(162) 4-(pyridin-4-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(163) 4-(3-(pyridin-3-yl) propyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(164) 4-(3-hydroxypropyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(165) 5-pentoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(166) 5-(2-phenyloxyethyl) oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(167) 5-(3-hydroxypropyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(168) 5-(pyridin-3-ylmethyl) oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(169) 5-(3-(pyridin-3-yl)propyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(170) 6-(3-phenyloxypropyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(171) 6-benzyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(172) 6-pentoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(173) 6-(2-(morpholin-4-yl)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(174) 6-(3-hydroxypropyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(175) 6-(pyridin-3-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(176) 6-(3-nitrophenylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(177) 6-(3-bromopropyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(178) 7-pentoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(179) 7-(2-phenyloxyethyl)oxy-3-phenylsuffonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(180) 7-(3-hydroxypropyl) oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(181) 7-(pyridin-3-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(182) 7-(N-oxidepyridin-3-ylmethyl) oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(183) 4-(t-butoxycarbonylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(184) 5-(t-butoxycarbonylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(185) 6-(t-butoxycarbonylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(186) 7-(t-butoxycarbonylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(187) 4-(2-(t-butoxycarbonylamino)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(188) 4-(3-(t-butoxycarbonylamino) propyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(189) 5-(2-(t-butoxycarbonylamino)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(190) 6-(3-(t-butoxycarbonylamino) propyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(191) 6-(2-(t-butoxycarbonylamino)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(192) 7-(2-(t-butoxycarbonylamino)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(193) 4-(N-(t-butoxycarbonyl) piperidin-4-yl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(194) 4,7-bis[(2-(t-butoxycarbonylamino)ethyl)oxy]-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(195) 4-(3-nitrophenylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(196) 4-carboxymethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(197) 5-carboxymethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(198) 6-carboxymethoxy-3-phenylsutfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(199) 7-carboxymethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(200) 4-(N-(pyridin-3-ylmethyl) carbamoylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo [b]thiophene,
(201) 4-((2-(N,N-dimethylamino)ethylamino)carbonylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(202) 4-(N-benzyl-2-(N′,N′-dimethylamino)ethylamino)carbonymethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(203) 4-(2-aminoethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(204) 4-(3-aminopropyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(205) 5-(2-aminoethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(206) 6-(3-aminopropyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(207) 6-(2-aminoethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(208) 7-(2-aminoethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(209) 4-(piperidin-4-yl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(210) 4,7-bis[(2-aminoethyl)oxy] -3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(211) 4-(2-(N,N-dimethylamino)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(212) 4-(3-(N,N-dimethylamino)propyl) oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(213) 4-(3-(N-cyanomethyl-N-methylamino)propyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(214) 5-(2-(N,N-dimethylamino)ethyl)oxy-3-phenyisulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(215) 6-(3-(N,N-dimethylamino)propyl)oxy-3-phenyisulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(216) 6-(3-(N-cyanomethyl-N-methylamino)propyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(217) 6-(2-(N,N-dimethylamino)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(218) 7-(2-(N,N-dimethylaminoethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(219) 4-(3-aminophenylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(220) 4-(3-(pyridin-3-ylcarbonylamino)phenylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(221) 4-(2-(pyridin-3-ylcarbonylamino)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(222) 5-methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(223) 5-(4-chlorophenylcarbonyl)amino-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(224) 4-cyano-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(225) 6-nitro-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(226) 4,7-dimethoxy-3-phenylsulfonyl-2;3-dihydro-1,1-dioxidebenzo[b]thiophene,
(227) 4,7-bis(3-hydroxypropyl)oxy-3-phenyIsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(228) 4-(pyridin-3-ylmethyl) carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(229) 4-(4-benzylpiperazin-1-yl)carbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(230) 4-(N-(2-(pyridin-3-yl) ethyl)-N-methylcarbamoyl)-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(231) 4-(2-(2-hydroxyethoxy)ethyl) carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(232) 4-(2,4-dimethoxyphenylmethyl) carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(233) 4-(1-benzylpiperidin-4-yl) carbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(234) 4-(pyridin-4-ylmethyl) carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(235) 4-(2-t-butoxycarbonylethyl) carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(236) 4-(thiophen-2-ylmethyl)carbamoyl-3-phenylsufonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(237) 4-benzylcarbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(238) 4-(pyridin-2-ylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(239) 4-(2-(piperidin-1-yl)ethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(240) 4-((1S)-1-t-butoxycarbonyl-2-methylpropyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(241) 4-(2-fluorophenylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(242) 4-(3-fluorophenylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(243) 4-(3-methylphenylmethyl)carbamoyl-3-phenyisulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(244) 4-(2-methoxyphenylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(245) 4-(2,3-dimethoxyphenylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(246) 4-(3,4-dimethoxyphenylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(247) 4-(2,5-difluorophenylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(248) 4-(3,4,5-trimethoxyphenylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(249) 4-(benzimidazol-2-ylmethyl) carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(250) 4-(3,5-difluorophenylmethyl) carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(251) 4-(N-benzyl-N-methylcarbamoyl)-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(252) 4-(4-nitrophenymethyl)carbamoyl-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(253) 5-(2-hydroxyethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(254) 5-(pyridin-3-ylmethyl)carbamoyl-4-methoxy-3-phenylsufonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(255) 5-(2-dimethylaminoethyl)carbamoyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(256) 5-dimethylcarbamoyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(257) 5-(2,3,4,5,6,7-hexahydro-1H-azepin-1-yl)carbonyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(258) 5-(2,3-dihydroindol-1-yl)carbonyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(259) 5-(4-(2-chlorophenyl)piperazin-1-yl)carbonyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(260) 5-(4-(2-(2-trifluoromethylphenyl)ethyl)piperazin-1-yl) carbonyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(261) 4-(pyridin-3-ylcarbonyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(262) 4-(3-(pyrrol-1-yl) propyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(263) 4-(quinolin-2-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(264) 4-(2-(pyrrol-1-yl)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(265) 4-(2-(4-methylthiazol-5-yl)ethyl) oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(266) 4-(3-(pyridin-4-yl) propyl)oxy-3-phenylsuffonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(267) 4-(1-t-butoxycarbonylpiperidin-3-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(268) 4-(2-(pyrrolidin-1-yl)ethyl)oxy-3-phenyisulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(269) 4-(2-(piperidin-1-yl)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(270) 4-(2-(2-acetyloxyethoxy)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(271) 4-(2-(4-benzylpiperazin-1-yl)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(272) 4-diethylcarbamoylmethyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(273) 4-cyanomethyloxy-3-phenyl sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(274) 5-(pyridin-3-yloxy)methyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(275) 5-(2-(t-butoxycarbonylamino)ethyl)oxy-4-nitro-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(276) 5-((2E)-3-ethoxycarbonyl-2-propenyl) oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(277) 4-(2,4-dimethoxyphenylmethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo [b]thiophene,
(278) 4-(pyridin-3-ylmethyl) aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(279) 4-(2-dimethylaminoethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(280) 4-(N,N-bis(2-hydroxyethyl)amino)methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(281) 4-(2-(2-hydroxyethoky)ethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(282) 4-(4-benzylpiperazin-1-yl) methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(283) 4-(4-(pyridin-2-yl)piperazi n-1-yl)methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(284) 4-(4-ethoxycarbonylpiperazin-1-yl)methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(285) 4-(4-(2-hydroxyethyl)piperazin-1-yl) methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(286) 4-(4-(pyridin-4-yl)piperazin-1-yl)methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(287) 4-benzylaminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(288) 4-(1-benzylpiperidin-4-yl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(289) 4-(morpholin-4-yl)methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(290) 4-ethoxycarbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(291) 4-benzyloxycarbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(292) 4-(pyridin-3-yl)-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(293) 6-(pyridin-3-yl)-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(294) 4-(4,4-dimethyl-4,5-dihydroxazol-2-yl)-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(295) 6-bromo-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(296) 6-amino-3-phenylsufonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(297) 5-methyicarbamoyl-4-methoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(298) 4-dimethylxarbamoyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(299) 4-carbamoyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(300) 4-(2-(pyridin-4-yl)ethyloxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(301) 4-(2-(pyridin-3-yl)ethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(302) 4-ethoxycarbonylmethyloxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(303) 6-ethoxycarbonylmethyloxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(304) 6-cyanomethyloxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(305) 5-ethoxycarbonylmethyloxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(306) 7-ethoxycarbonylmethyloxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(307) 5-benzyloxycarbonyl-4-methoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(308) 5-ethoxycarbonyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(309) 7-methoxycarbonyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(310) 7-ethoxycarbonyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(311) 5-t-butoxycarbonyl-4-methoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(312) 5-(2-(ethoxycarbonyl)ethyl)-4-methoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(313) 4-(furan-2-ylmethyl)carbamoyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(314) 5-(4,4-dimethyl-4,5-dihydroxazol-2-yl) -3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(315) 3-benzylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(316) 3-(3,4-dichlorophenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(317) 3-(4-nitrophenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(318) 5-hydroxymethyl-4-methoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(319) 4-hydroxymethyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(320) 6-fl uoro-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(321) 4-fluoro-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(322) 5-methylcarbamoyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(323) 4-dimethylcarbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(324) 4-carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(325) 4-(2-(pyridin-4-yl)ethyl)oxy-3-phenylsufonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(326) 4-(2-(pyridin-3-yl)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(327) 4-ethoxycarbonylmethyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(328) 6-ethoxycarbonylmethyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(329) 6-cyanomethyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(330) 5-ethoxycarbonylmethyloxy-3-phenylsufonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(331) 7-ethoxycarbonylmethyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(332) 5-benzyloxycarbonyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(333) 5-ethoxycarbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(334) 7-methoxycarbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(335) 7-ethoxycarbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(336) 5-t-butoxycarbonyl-4-methoxy-3-phenyisulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(337) 5-(2-ethoxycarbonylethyl)-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(338) 3-benzylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(339) 3-(3,4-dichlorophenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(340) 3-(4-nitrophenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(341) 5-hydroxymethyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(342) 4-hydroxymethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(343) 6-fluoro-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(344) 4-fluoro-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(345) 5-benzylozycarbonyl-4-ethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(346) 5-benzyloxycarbonyl-4-hexyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(347) 5-benzyloxycarbonyl-4-butoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(348) 5-benzyloxycarbonyl-4-octyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(349) 5-carboxy-4-ethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(350) 5-carboxy-4-hexyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(351) 5-carboxy-4-butoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(352) 5-carboxy-4-octyloxy-3-phenylsuldonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(353) 5-methoxycarbonyl-4-ethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(354) 5-methoxycarbonyl-4-hexyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(355) 5-methoxycarbonyl-4butoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(356) 5-methoxycarbonyl-4-octyloxy-3-phenylsufonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(357) 5-(4-(2-(2-trifluoromethylphenyl)ethyl)piperazin-1-yl)carbonyl-4-ethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(358) 5-(4-(2-chlorophenyl)piperazin-1-yl)carbonyl-4-ethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(359) 5-(dimethylaminoethylcarbamoyl-4-ethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo [b]thiophene,
(360) 5-(2,3,4,5,6,7-hexahydro-1H-azepin-1-yl)carbonyl-4-ethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(361) 5-(2,3-dihydroindol-1-yl)carbonyl-4-ethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(362) 5-(4-(2-(2-trifluoromethylphenyl)ethyl)piperazin-1-yl)carbonyl-4-hexyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(363) 5-(4-(2-chlorophenyl)piperazin-1-yl)carbonyl-4-hexyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo [b]thiophene,
(364) 5-(2-dimethylaminoethyl)carbamoyl-4-hexyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo [b]thiophene,
(365) 5-(2,3,4,5,6,7-hexahydro-1H-azepin-1-yl)carbonyl-4-hexyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(366) 5-(2,3-dihydroindol-1-yl)carbonyl-4-hexyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo [b]thiophene,
(367) 5-(4-(2-(2-trifluoromethylphenyl)ethyl)piperazin-1-yl) carbonyl-4-butoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(368) 5-(4-(2-chlorophenyl) piperazin-1-yl)carbonyl-4-butoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(369) 5-(2-dimethylaminoethyl)carbamoyl-4-butoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(370) 5-(2,3,4,5,6,7-hexahydro-1H-azepin-1-yl)carbonyl-4-butoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(371) 5-(2,3-dihydroindol-1-yl) carbonyl-4-butoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(372) 5-(4-(2-(2-trifluoromethylphenyl)ethyl)piperazin-1-yl)carbonyl-4-octyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(373) 5-(4-(2-chlorophenyl) piperazin-1-yl)carbonyl-4-octyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(374) 5-(2-dimethylaminoethyl)carbamoyl-4-octyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(375) 5-(2,3,4,5,6,7-hexahydro-1H-azepin-1-yl)carbonyl-4-octyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(376) 5-(2,3-dihydroindol-1-yl)carbonyl-4-octyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-di oxidebenzo[b]thiophene,
(377) 5-benzyloxy-4-hydroxymethyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(378) 5-benzyloxy-4-bromomethyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(379) 5-benzyloxy-4-aminomethyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(380) 5-benzyloxy-4-t-butoxycarbonylaminomethyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(381) 5-benzyloxy-4-t-butoxycarbonylaminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(382) 5-benzyloxy-4-aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(383) 5-hydroxy-4-t-butoxycarbonylaminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(384) 5-methoxy-4-t-butoxycarbonylaminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(385) 5-(3-phenylpropyl) oxy-4-t-butoxycarbonylaminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(386) 5-methoxy-4-aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(387) 5-(3-phenylpropyl)oxy-4-aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(388) 5-benzyloxy-4-hydroxymethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(389) 5-benzyloxy-4-carboxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(390) 5-benzyloxy-4-(pyridin-3-ylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(391) 5-hydroxy-4-(pyridin-3-ylmethyl)carbamoyl-3-phenylsuifonyi-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(392) 4,7-dimethoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(393) 6-bromo-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(394) 4-(piperidin-3-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(395) 5-(2-aminoethyl)oxy-4-nitro-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(396) 4-(2-(2-hydroxyethoxy)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(397) 5-carboxy-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(398) 4-carboxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(399) 4-formyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(400) 5-(4-phenylbutyl)aminomethyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(401) 5-(pyridin-3-ylmethyl)aminomethyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(402) 6-dimethylamino-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(403) 4-(2-dimethylaminoethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(404) 4,7-bis(pyridin-3-ylmethyloxy)-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(405) 4-(N-oxidepyridin-3-ylmethyl) oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(406) 4-(2-(N-oxidepyridin-4-yl)ethyl)oxy-3-phenylsulfonyl-2,3-di hydro-1,1-dioxidebenzo[b]thiophene,
(407) 4-methoxy-3-(4-hydroxyphenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(408) 4-methoxy-3-(4-(pyridin-3-ylmethyloxy)phenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(409) 4-methoxy-3-(4-(pyridin-3-ylmethyloxy) phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(410) 5-(2-dimethylaminoethyl)carbamoyl-4-methoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(411) 5-(pyridin-3-ylmethyl)carbamoyl-4-methoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(412) 4-(2-(piperidin-1-yl)ethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(413) 4-(furan-2-ylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(414) 4-(2,4,6-trimethoxybenzyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(415) 4-(3-(2-oxopyrrolidin-1-yl)propyl)carbamoyl-3-phenylsuIfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(416) 4-((3S)-1-benzylpyrrolidin-3-yl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(417) 4-(2-(pyrrolidin-1-yl)ethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(418) 4-(2-diethylaminoethyl) carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(419) 4-(2-(N-ethyl-N-(3-methylphenyl)amino)ethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(420) 4-(N-ethyl-N-2-(piperidin-1-yl)ethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(421) 4-(3-(imidazol-1-yl) propyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(422) 4-((3R)-1-benzylpyrrolidin-3-yl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(423) 4-(3-(pyrrolidin-1-yl)propyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(424) 4-(N-2-(piperidin-1-yl)ethyl-N-methyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(425) 4-(3,5-dimethoxybenzyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(426) 4-(3-(piperidin-1-yl)propyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(427) 4-(2-diisopropylamino)ethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(428) 4-(2-(morpholin-4-yl)ethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(429) 4-(N-2-(piperidin-1-yl)ethyl-N-propyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(430) 4-(N-2-(piperidin-1-yl)ethyl-N-isopropyl) carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(431) 4-(4-benzoylpiperazin-1-yl)carbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(432) 4-(4-(4-ethylbenzyl)piperazin-1-yl)carbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(433) 4-(4-(4-phenylbenzyl)piperazin-1-yl)carbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(434) 4-(4-(1,3-dioxaindan-5-ylmethyl)piperazin-1-yl) carbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(435) 4-(4-benzyloxycarbonylpiperazin-1-yl) carbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(436) 4-(4-(2-methylphenyl) piperazin-1-yl)carbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(437) 4-(4-(4-methoxyphenyl) piperazin-1-yl) carbonyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(438) 4-(2-(pyridin-2-yl)ethyl) oxy-3-phenylthio-1,1-dioxidebenzo[b]thiophene,
(439) 4-(2-(piperidin-1-yl)ethyl)carbamoyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(440) 4-(2-(piperidin-1-yl)ethyl)carbamoyl-3-(4-nitrophenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(441) 4-(N-2-(piperidin-1-yl)ethyl-N-methyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(442) 4-(2-(N-ethyl-N-3-methylphenyl)aminoethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(443) 4-(N-benzyl-N-ethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(444) 4-(2-diethylaminoethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(445) 4-(4-methylbenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(446) 4-(N-ethyl-N-2-(piperidin-1-yl)ethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(447) 4-(2-methoxybenzyl) aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(448) 4-(3-phenylpropyi)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(449) 4-(3,5-dimethoxybenzyl)aminomethyl-3-phenyisulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(450) 4-((3R)-1-benzylpyrrolidin-3-yl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(451) 4-((3S)-1-benzylpyrrolidin-3-yl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(452) 4-(2-phenylethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(453) 4-(N-benzyl-N-methyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(454) 4-(3-(2-oxopyrrolidin-1-yl)propyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(455) 4-(4-aminobenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(456) 4-(4-((2E)-3-phenyl-2-propenyl) piperazin-1-yl) methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(457) 4-(2-aminobenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(458) 4-(4-benzylpiperidin-1-yl)methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(459) 4-(4-chlorobenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(460) 4-(3-chlorobenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(461) 4-(3-methoxybenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(462) 4-(3,4-dichlorobenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(463) 4-(1,3-dioxaindan-5-ylmethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(464) 4-(2,3-dimethoxybenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(465) 4-(3,4,5-trimethoxybenzyl)aminomethyl3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(466) 4-(4-(t-butyloxycarbonyl) piperazin-1-yl) methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(467) 4-(2-diisopropylamino) ethyl) aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(468) 4-(2-(morpholin-4-yl) ethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(469) 4-(N-2-(piperidin-1-yl) ethyl-N-propyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(470) 4-(N-2-(piperidin-1-yl)ethyl-N-isopropyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(471) 4-(3,4-dimethoxybenzyl) aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(472) 4-(3-(2-methylpiperidin-1-yl)propyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(473) 4-(4-(piperidin-1-yl)piperidin-1-yl) methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(474) 4-(3-(piperidin-1-yl)propyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(475) 4-(3-bromobenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(476) 4-(4-nitrobenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(477) 4-(4-aminosulfonylbenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(478) 4-(piperazin-1-yl)methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(479) 4-(2,4,6-trimethoxybenzyl) methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(480) 4-(piperidin-1-yl)carbonylmethylaminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(481) 4-(pyrrolidin-1-yl)ethylaminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(482) 4-(4-(1,3-dioxaindan-5-ylmethyl)piperazin-1-yl) methyl-1,1-dioxidebenzo[b]thiophene, or
an N-oxide derivative thereof or a non-toxic salt thereof.
14. A compound ccording to claim 4, which is
(1) 4-(pyridin-3-ylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
(2) 4-(4-benzyl piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene,
(3) 4-(N-(2-(pyridi n-3-yl)ethyl)-N-methylcarbamoyl) -1,1-dioxidebenzo[b]th iophene,
(4) 4-(2-(2-hydroxyethoxy)ethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
(5) 4-(2,4-dimethoxyphenylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
(6) 4-(1-benzylpiperidin-4-yl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
(7) 4-(pyridin-4-ylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
(8) 4-(2-t-butoxycarbonylethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
(9) 4-(thiophen-2-ylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
(10) 4-benzylcarbamoyl-1,1-dioxidebenzo[b]thiophene,
(11) 4-(pyridin-2-ylmethyl) carbamoyl-1,1-dioxidebenzo[b]thiophene,
(12) 4-(2-t(piperidin-1-yl)ethyl)carbamoyl-1,1-dioxidebenzo[b]thlophene,
(13) 4-((1 S)-1-t-butoxycarbonyl-2-methylpropyl) carbamoyl-1,1-dioxidebenzo[b]thiophene,
(14) 4-(2-fluorophenylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
(15) 4-(3-fluorophenylmethyl)carbamoyl-1,1-di oxidebenzo[b]thiophene,
(16) 4-(3-methylphenylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
(17) 4-(2-methoxyphenylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
(18) 4-(2,3-dimethoxyphenylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
(19) 4-(3,4-dimethoxyphenylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
(20) 4-(2,5-difluorophenylmethyl)carbamoyl-1,1-dioxidebenzo[bjthiophene,
(21) 4-(3,4,5-trimethoxyphenylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
(22) 4-(benzimidazol-2-ylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
(23) 4-(3,5-difluorophenylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
(24) 4-(N-benzyl-N-methylcarbamoyl)-1,1-dioxidebenzo[b]thiophene,
(25) 4-(4-nitrophenylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
(26) 5-(2-hydroxyethyl)carbamoyl-1,1-di oxidebenzo[b]thiophene,
(27) 5-(pyridin-3-ylmethyl) carbamoyl-4-methoxy-1,1-dioxidebenzo[b]thiophene,
(28) 5-(2-dimethylaminoethyl) carbamoyl-4-methoxy-1,1-dioxidebenzo[b]thiophene,
(29) 5-dimethylcarbamoyl-4-methoxy-1,1-dioxidebenzo[b]thiophene,
(30) 5-(2,3,4,5,6,7-hexahydro-1H-azepin-1-yl)carbonyl-4-methoxy-1,1-dioxidebenzo[b]thiophene,
(31) 5-(2,3-dihydroindol-1-yl) carbonyl-4-methoxy-1,1-dioxidebenzo[b]thiophene,
(32) 5-(4-(2-chlorophenyl)piperazin-1-yl) carbonyl-4-methoxy-1,1-dioxidebenzo[b]thiophene,
(33) 5-(4-(2-(2-trifluoromethylphenyl)ethyl)piperazin-1-yl)carbonyl-4-methoxy-1,1-dioxidebenzo[b]thiophene,
(34) 4-(pyridin-3-ylcarbonyl) aminomethyl-1,1-dioxidebenzo[b]thiophene,
(35) 4-(3-(pyrrol-1-yl)propyl)oxy-1,1-dioxidebenzo[b]thiophene,
(36) 4-(quinolin-2-ylmethyl)oxy-1,1-dioxidebenzo[b]thiophene,
(37) 4-(2-(pyrrol-1-yl)ethyl)oxy-1,1-dioxidebenzo[b]thiophene,
(38) 4-(2-(4-methylthiazol-5-yl)ethyl)oxy-1,1-dioxidebenzo[b]thiophene,
(39) 4-(3-(pyridin-4-yl) propyl)oxy-1,1-dioxidebenzo[b]thiophene,
(40) 4-(1-t-butoxycarbonylpiperidin-3-ylmethyl)ox-1,1-dioxidebenzo[b]thiophene,
(41) 4-(2-(pyrrolidin-1-yl)ethyl)oxy-1,1-dioxidebenzo[b]thiophene,
(42) 4-(2-(piperidin-1-yl)ethyl)oxy-1,1-dioxidebenzo[b]thiophene,
(43) 4-(2-(2-acetyloxyethoxy)ethyl)oxy-1,1-dioxidebenzo[b]thiophene,
(44) 4-(2-(4-ebnzylpiperazin-1-yl)ethyl)oxy-1,1-dioxidebenzo[b]thiophene,
(45) 4-diethylcarbamoylmethyloxy-1,1-dioxidebenzo[b]thiophene,
(46) 4-cyanomethyloxy-1,1-dioxidebenzo[b]thiophene,
(47) 5-(pyridin-3-yloxy)methyl-4-methoxy-1,1-dioxidebenzo[b]thiophene,
(48) 5-(2-t-butoxycarbonylaminoethyl)oxy-4-nitro-1,1-dioxidebenzo[b]thiophene,
(49) 5-((2E)-3-ethoxycarbonyl-2-propenyl)oxy-1,1-dioxidebenzo[b]thiophene,
(50) 4-(2,4-dimethoxyphenylmethyl)aminomethyl-1,1-dioxidebenzo[b]thiophene,
(51) 4-(pyridin-3-ylmethyl)aminomethyl-1,1-dioxidebenzo[b]thiophene,
(52) 4-(2-(dimethylamino)ethyl)aminomethyl-1,1-dioxidebenzo[b]thiophene,
(53) 4-(N,N-bis(2-hydroxyethyl) amino)methyl-1,1-dioxidebenzo[b]thiophene,
(54) 4-(2-(2-hydroxyethoxy)ethyl)aminomethyl-1,1-dioxidebenzo[b]thiophene,
(55) 4-(4-benzylpiperazin-1-yl)methyl-1,1-dioxidebenzo[b]thiophene,
(56) 4-(4-(pyridin-2-yl)piperazin-1-yl)methyl-1,1-dioxidebenzo[b]thiophene,
(57) 4-(4-ethoxycarbonylpiperazin-1-yl)methyl-1,1-dioxidebenzo[b]thiophene,
(58) 4-(4-(2-hydroxyethyl)piperazin-1-yl)methyl-1,1-dioxidebenzo[b]thiophene,
(59) 4-(4-(pyridin-4-yl)piperazin-1-yl)methyl-1,1-dioxidebenzo[b]thiophene,
(60) 4-benzylaminomethyl-1,1-dioxidebenzo[b]thiophene,
(61) 4-(1-benzylpiperidin-4-yl)aminomethyl-1,1-dioxidebenzo[b]thiophene,
(62) 4-(morpholin-4-yl)methyl-1,1-dioxidebenzo[b]thiophene,
(63) 4-ethoxycarbonyl-1,1-dioxidebenzo[b]thiophene,
(64) 4-benzyloxycarbonyl-1,1-dioxidebenzo[b]thiophene,
(65) 4-(pyridin-3-yl)-1,1-dioxidebenzo[b]thiophene,
(66) 6-(pyridin-3-yl)-1,1-dioxidebenzo[b]thiophene,
(67) 4-(4,4-dimethyl-4,5-dihydroxazol-2-yl)-1,1-dioxidebenzo[b]thiophene,
(68) 5-methylcarbamoyl-4-methoxy-1,1-dioxidebenzo[b]thiophene,
(69) 4-dimethylcarbamoyl-1,1-dioxidebenzo[b]thiophene,
(70) 4-carbamoyl-1,1-dioxidebenzo[b]thiophene,
(71) 4-(furan-2-ylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
(72) 4-(2-(pyridin-4-yl)ethyl) oxy-1,1-dioxidebenzo[b]thiophene,
(73) 4-(2-(pyridin-3-yl)ethyl)oxy-1,1-dioxidebenzo[b]thiophene,
(74) 4-ethoxycarbonylmethyloxy-1,1-dioxidebenzo[b]thiophene,
(75) 6-ethoxycarbonylmethyloxy-1,1-dioxidebenzo[b]thiophene,
(76) 6-cyanomethyloxy-1,1-dioxidebenzo[b]thiophene,
(77) 5-ethoxycarbonylmethyloxy-1,1-dioxidebenzo[b]thiophene,
(78) 7-ethoxycarbonylmethyloxy-1,1-dioxidebenzo[b]thiophene,
(79) 5-benzyloxycarbonyl-4-methoxy-1,1-dioxidebenzo[b]thiophene,
(80) 5-ethoxycarbonyl-1,1-dioxidebenzo[b]thiophene,
(81) 7-methoxycarbonyl-1,1-dioxidebenzo[b]thiophene,
(82) 7-ethoxycarbonyl-1,1-dioxidebenzo[b]thiophene,
(83) 5-t-butoxycarbonyl-4-methoxy-1,1-dioxidebenzo[b]thi ophene,
(84) 5-(2-(ethoxycarbonyl)ethyl)-4-methoxy-1,1-di oxidebenzo[b]thiophene,
(85) 5-(4,4-dimethyl-4,5-dihydroxazol-2-yl)-1,1-dioxidebenzo[b]thiophene,
(86) 5-benzyloxycarbonyl-4-ethoxy-1,1-dioxidebenzo[b]thiophene,
(87) 5-benzyloxycarbonyl-4-hexyloxy-1,1-dioxidebenzo[b]thiophene,
(88) 5-benzyloxycarbonyl-4-butoxy-11-dioxidebenzo[b]thiophene,
(89) 5-benzyloxycarbonyl-4-octyloxy-1,1-di oxidebenzo[b]thiophene,
(90) 5-benzyloxy-4-hydroxymethyl-1,1-dioxidebenzo[b]thiophene,
(91) 4-(1,1-dimethyl-2-hydroxyethyl) carbamoyl-1,1-dioxidebenzo[b]thiophene,
(92) 4-(2-hydroxyethyl) carbamoyl-1,1-dioxidebenzo[b]thiophene,
(93) 4-(4-(2-hydroxyethyl)piperazin-1-yl) carbonyl-1,1-dioxidebenzo[b]thiophene,
(94) 4-(N-methyl-N-methoxycarbamoyl)-1,1-dioxidebenzo[b]thiophene,
(95) 4-(4-(thiazol-2-ylsulfamoyl)phenyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
(96) 4-((1R) -1-t-butoxycarbonyl-2-methylpropyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
(97) 6-(1-benzylpiperidin-4-yl)carbamoyl-4-methoxy-1,1-dioxidebenzo[b]thiophene,
(98) 6-(2-diethylaminoethyl) carbamoyl-4-methoxy-1,1-dioxidebenzo[b]thiophene,
(99) 6-(pyridin-3-ylmethyl) carbamoyl-4-methoxy-1,1-dioxidebenzo[b]thiophene,
(100) 5-(6-dimethylaminohexyl)oxycarbonyl-1,1-dioxidebenzo[b]thiophene,
(101) 4-(4-t-butoxycarbonylpiperazin-1-yl)carbonyl-11-dioxidebenzo[b]thiophene,
(102) 4-(piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene,
(103) 4-(4-(4-methoxyphenylmethyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene,
(104) 4-(4-(4-phenylphenylmethyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene,
(105) 4-(4-(naphthalen-1-ylmethyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene,
(106) 4-(4-(4-ethylphenylmethyl) piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene,
(107) 4-(4-(naphthalen-2-ylcarbonylmethyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene,
(108) 4-(4-(pyridin-2-ylmethyl) piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene,
(109) 4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene,
(110) 4-(4-benzoylpiperazin-1-yl) carbonyl-1,1-dioxidebenzo[b]thiophene,
(111) 4-(4-(furan-2-ylcarbonyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene,
(112) 4-(4-benzylcarbonylpiperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene,
(113) 4-(2-(pyrrolidin-1-yl) ethyl) carbamoyl-1,1-dioxidebenzo[b]thiophene,
(114) 4-(3-(pyrrolidin-1-yl) propyl) carbamoyl-1,1-dioxidebenzo[b]thiophene,
(115) 4-(4-(2-methylphenyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene,
(116) 4-(4-(3-methylphenyl) piperazin-1-yl) carbonyl-1,1-dioxidebenzo[b]thiophene,
(117) 4-(4-(2-fluorophenyl) piperazin-1-yl) carbonyl-1,1-dioxidebenzo[b]thiophene,
(118) 4-(4-(4-fluorophenyl)piperazin-1-yl) carbonyl-1,1-dioxidebenzo[b]thiophene,
(119) 4-(4-(4-methoxyphenyl) piperazin-1-yl) carbonyl-1,1-dioxidebenzo[b]thiophene,
(120) 4-(4-(3-trifluoromethylphenyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene,
(121) 4-((3R)-1-benzylpyrrolidin-3-yl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
(122) 4-((3S)-1-benzylpyrrolidin-3-yl) carbamoyl-1,1-dioxidebenzo[b]thiophene,
(123) 5-acetylmethyloxy-1,1-dioxidebenzo[b]thiophene,
(124) 5-cyanomethyloxy-1,1-dioxidebenzo[b]thiophene,
(125) 5-t-butoxycarbonylmethyloxy-1,1-dioxidebenzo[b]thiophene,
(126) 5-(3-(ethoxycarbonyl)propyl)oxy-1,1-dioxidebenzo[b]thiophene,
(127) 5-(4-(ethoxycarbonyl)butyl) oxy-1,1-dioxidebenzo[b]thiophene,
(128) 4-(pyridin-3-ylmethyl)oxy-1,1-dioxidebenzo[b]thiophene,
(129) 4-(pyridin-4-ylmethyl)oxy-1,1-dioxidebenzo[b]thiophene,
(130) 4-(4-trifluoromethylphenylmethyl)oxy-3-phenylthio-1,1-dioxidebenzo[b]thiophene,
(131) 4-(3,5-dimethylisoxazol-4-ylmethyl)oxy-1,1-dioxidebenzo[b]thiophene,
(132) 4-(4-methoxycarbonylphenylmethyl)oxy-1,1-dioxidebenzo[b]thiophene,
(133) 4-(benzotriazol-1-ylmethyl)oxy-11-dioxidebenzo[b]thiophene,
(134) 4-(2,6-dimethylphenyl) carbamoylmethyloxy-1,1-dioxidebenzo[b]thiophene,
(135) 4-trimethylsilylmethyloxy-1,1-dioxidebenzo[b]thiophene,
(136) 4-(pyridin-2-ylmethyl)oxy-1,1-dioxidebenzo[b]thiophene,
(137) 4-(2-(pyridin-3-ylcarbonyl)aminoethyl)oxy-1,1-dioxidebenzo[b]thiophene,
(138) 4-(3-(pyridin-3-yl)propyl)oxy-1,1-dioxidebenzo[b]thiophene,
(139) 4-(2-(pyridin-2-yl) ethyl) oxy-1,1-dioxidebenzo[b]thiophene,
(140) 4-(1-t-butoxycarbonylpiperidin-4-yl)oxy-1,1-dioxidebenzo[b]thiophene,
(141) 4-(5-methyl-1-tritylimidazol-4-ylmethyl)oxy-1,1-dioxidebenzo[b]thiophene,
(142) 4-(1,2,4-oxadiazol-3-yl methyl)oxy-1,1-dioxidebenzo[b]thiophene,
(143) 6-(pyridin-3-ylmethyl)oxy-1,1-dioxidebenzo[b]thiophene,
(144) 6-(3-nitrophenylmethyl)oxy-1,1-dioxidebenzo[b]thiophene,
(145) 6-(3-(t-butoxycarbonylamino) propyl)oxy-1,1-dioxidebenzo[b]thiophene,
(146) 7-t-butoxycarbonylmethyloxy-1,1-dioxidebenzo[b]thiophene,
(147) 6-(pyridin-3-yloxy) methyl-4-methoxy-1,1-dioxidebenzo[b]thiophene,
(148) 4,7-bis(3-hydroxypropyl)-1,1-dioxidebenzo[b]thiophene,
(149) 5-carboxy-4-ethoxy-1,1-dioxidebenzo[b]thiophene,
(150) 5-carboxy-4-butoxy-1,1-dioxidebenzo[b]thiophene,
(151) 5-carboxy-4-hexyloxy-1,1-dioxidebenzo[b]thiophene,
(152) 5-carboxy-4-octyloxy-1,1-dioxidebenzo[b]thiophene,
(153) 5-ethoxycarbonyl-4-hydroxy-1,1-dioxidebenzo[b]thiophene,
(154) 5-ethoxycarbony-4-metoxy-1,1-dioxidebenzo[b]thiophene,
(155) 5-isopropyloxycarbonyl-4-methoxy-1,1-dioxidebenzo[b]thiophene,
(156) 5-(2-methylpropyl)oxycarbonyl-4-methoxy-1,1-dioxidebenzo[b]thiophene,
(157) 6-meth oxycarbonyl-4-methoxy-1,1-dioxidebenzo[b]thiophene,
(158) 6-methoxymethoxycarbonyl-4-methoxy-1,1-dioxidebenzo[b]thiophene,
(159) 4-(N-(pyridin-2-ylmethyl)-N-(1,1-dioxidebenzo[b]thiophen-4-ylmethyl)amino)methyl-1,1-dioxidebenzo[b]thiophene,
(160) 4-(pyridin-2-ylmethyl)aminomethyl-1,1-dioxidebenzo[b]thiophene,
(161) 4-(N-(2,4-dimethoxyphenylmethyl)-N-(1,1-dioxidebenzo[b]thiophen-4-ylmethyl)amino)methyl-1,1-dioxidebenzo[b]thiophene,
(162) 5-acetyloxy-4-nitro-1,1-dioxidebenzo[b]thiophene,
(163) 4-(4,5-dihydroxazol-2-yl) -1,1-dioxidebenzo[b]thiophene,
(164) 5-(4,5-dihydroxazol-2-yl) -1,1-dioxidebenzo[b]thiophene,
(165) 5-carboxymethyloxy-1,1-dioxidebenzo[b]thiophene,
(166) 7-carboxymethyloxy-1,1-dioxidebenzo[b]thiophene,
(167) 4-((1S)-1-carboxy-2-methylpropyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
(168) 4-((1R)-1-carboxy-2-methylpropyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
(169) 5-(3-carboxypropyl)oxy-1,1-dioxidebenzo[b]thiophene,
(170) 5-((2E)-3-carboxy-2-propenyl)oxy-1,1-dioxidebenzo[b]thiophene,
(171) 4-2-(piperidin-1-yl) ethyl)aminomethyl-1,1-dioxidebenzo[b]thiophene,
(172) 4-t-butoxycarbonylamino-1,1-dioxidebenzo[b]thiophene,
(173) 4-amino-1,1-dioxidebenzo[b]thiophene,
(174) 4-(4-fluorobenzylamino)-1,1-dioxidebenzo[b]thiophene,
(175) 4-(pyridin-3-ylcarbonyl)amino-1,1-dioxidebenzo[b]thiophene,
(176) 4-(3-chlorobenzoyl)amino-1,1-dioxidebenzo[b]thiophene,
(177) 4-benzylcarbonylamino-1,1-dioxidebenzo[b]thiophene,
(178) 4-(dimethylaminoacetyl)amino-1,1-dioxidebenzo[b]thiophene,
(179) 4-acetylamino-1,1-dioxidebenzo[b]thiophene,
(180) 4-(3-(2-oxopyrrolidin-1-yl)propyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
(181) 4-(2-diethylaminoethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
(182) 4-(2-(N-ethyl-N-(3-methylphenyl)amino)ethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
(183) 4-(2,4,6-trimethoxybenzyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
(184) 4-(4-(2-hydroxyethyl)piperazin-1-yl) carbonyl-1,1-dioxidebenzo[b]thiophene,
(185) 4-(4-benzyloxycarbonylpiperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene,
(186) 4-(N-ethyl-N-2-(piperidin-1-yl)ethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
(187) 4-(3-(imidazol-1-yl)propyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
(188) 4-(N-2-(piperidin-1-yl)ethyl-N-methyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
(189) 4-(4-(1,3-dioxaindan-5-ylmethyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene,
(190) 4-(4-((2E)-3-phenyl-2-propenyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene, or
an N-oxide derivative thereof or a non-toxic salt thereof.
15. A pharmaceutical composition comprising a fused thiophene derivative of the formula (IA) depicted in claim 4, an N-oxide derivative thereof or a non-toxic salt thereof as an active ingredient.
16. A method for preparation of a compound of the formula (XI)
Figure US20030073706A1-20030417-C02301
which is characterized by cyanization of a compound of the formula (XII)
Figure US20030073706A1-20030417-C02302
to obtain a compound of the formula (XIII)
Figure US20030073706A1-20030417-C02303
then by subjecting to dehydration of the said compound of the formula (XIII) to obtain a compound of the formula (XIV)
Figure US20030073706A1-20030417-C02304
and then followed by subjecting to hydrolysis of the said compound of the formula (XIV).
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3799870A1 (en) * 2010-04-05 2021-04-07 Fosun Orinove Pharmatech, Inc. Ire-1a inhibitors
WO2021088265A1 (en) * 2019-11-05 2021-05-14 中山大学 Imidazo pyridine compound, pharmaceutical composition containing the compound, preparation method therefor, and use thereof
US11452713B2 (en) 2016-02-29 2022-09-27 University Of Florida Research Foundation, Incorporated Chemotherapeutic methods for treating low-proliferative disseminated tumor cells

Families Citing this family (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6794397B2 (en) * 2000-01-27 2004-09-21 Cytovia, Inc. Substituted nicotinamides and analogs as activators of caspases and inducers of apoptosis and the use thereof
US6608053B2 (en) * 2000-04-27 2003-08-19 Yamanouchi Pharmaceutical Co., Ltd. Fused heteroaryl derivatives
HUP0302473A2 (en) * 2000-05-18 2003-11-28 Daiichi Pharmaceutical Co., Ltd. Novel benzothiophene derivatives
DE10133927A1 (en) * 2001-07-12 2003-01-23 Bayer Ag Benzodioxinothiophenes, their preparation and use
US7563810B2 (en) 2002-11-06 2009-07-21 Celgene Corporation Methods of using 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione for the treatment and management of myeloproliferative diseases
US8034831B2 (en) 2002-11-06 2011-10-11 Celgene Corporation Methods for the treatment and management of myeloproliferative diseases using 4-(amino)-2-(2,6-Dioxo(3-piperidyl)-isoindoline-1,3-dione in combination with other therapies
US7094790B2 (en) * 2003-05-07 2006-08-22 Abbott Laboratories Fused bicyclic-substituted amines as histamine-3 receptor ligands
CA2539227A1 (en) * 2003-08-08 2005-02-17 Vertex Pharmaceuticals Incorporated Heteroarylaminosulfonylphenyl derivatives for use as sodium or calcium channel blockers in the treatment of pain
US20050107350A1 (en) * 2003-08-22 2005-05-19 Pharmacia Corporation Method for the treatment or prevention of bone disorders with a cyclooxygenase-2 inhibitor alone and in combination with a bone disorder treatment agent and compositions therewith
US7781478B2 (en) * 2004-07-14 2010-08-24 Ptc Therapeutics, Inc. Methods for treating hepatitis C
US7772271B2 (en) * 2004-07-14 2010-08-10 Ptc Therapeutics, Inc. Methods for treating hepatitis C
EP1771169A1 (en) * 2004-07-14 2007-04-11 PTC Therapeutics, Inc. Methods for treating hepatitis c
US7868037B2 (en) * 2004-07-14 2011-01-11 Ptc Therapeutics, Inc. Methods for treating hepatitis C
NZ553329A (en) * 2004-07-22 2010-09-30 Ptc Therapeutics Inc Thienopyridines for treating hepatitis C
CN101076531A (en) * 2004-10-12 2007-11-21 解码遗传学公司 Carboxylic acid peri-substituted bicyclics for occlusive artery disease
JP2009013065A (en) * 2005-10-14 2009-01-22 Astellas Pharma Inc Condensed heterocyclic compound
PE20071321A1 (en) * 2006-01-20 2007-12-29 Schering Corp BENCENSULFONIL-CHROMANE, THIOCHROMANE, TETRAHYDRONAPHTHALENE AND RELATED GAMMA SECRETASE INHIBITORS
TW200900408A (en) * 2007-03-02 2009-01-01 Kyowa Hakko Kogyo Kk Fused pyridine derivative
US8318928B2 (en) * 2008-12-15 2012-11-27 Glenmark Pharmaceuticals, S.A. Fused imidazole carboxamides as TRPV3 modulators
EP3072891A1 (en) * 2015-03-24 2016-09-28 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. New Toll-Like Receptor 9 Antagonists

Family Cites Families (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2930800A (en) 1954-10-28 1960-03-29 Kloetzel 4-thianaphtheneacetic acids and preparation thereof
US3686216A (en) 1969-01-23 1972-08-22 Uniroyal Inc Benzothiophene 1,1-dioxide derivatives and method of preparing same
US3629438A (en) 1969-01-23 1971-12-21 Uniroyal Inc Benzothiophene-1 1-dioxide derivatives as fungicides and bactericides
SU591474A1 (en) 1976-05-24 1978-02-05 Институт Химии Ан Таджикской Сср Benzo-(b)-thiophene-1,1-dioxide n-arylsulfonylamines possessing spasmolytic and cholinolytic activity
US4436748A (en) 1980-10-20 1984-03-13 Hoechst-Roussel Pharmaceuticals Inc. Benzo[b]thiophenes
DE3484867D1 (en) 1983-12-14 1991-09-05 Upjohn Co SUBSTITUTED NAPHTHALENE, INDOLE, BENZOFURANE AND BENZOTHIOPHENE AS LYPOXYGENASE INHIBITORS.
US4737519A (en) 1983-12-14 1988-04-12 The Upjohn Company Substituted naphthalenes, indoles, benzofurans, and benzothiophenes as lipoxygenase inhibitors
US5093351A (en) 1989-01-05 1992-03-03 Du Pont Merck Pharmaceutical Company Substituted indole, benzofuran and benzothiophene derivatives as 5-lipoxygenase inhibitors
US5552415A (en) * 1993-12-21 1996-09-03 Eli Lilly And Company Method of inhibiting Alzheimer's Disease
ES2173182T3 (en) 1994-04-11 2002-10-16 Chugai Pharmaceutical Co Ltd DERIVED FROM 4,6-DL-BUTIL-2,3-DIHYDROBENZOTIOPHENES AS AN LDL ANTIOXIDANTS.
US5521213A (en) * 1994-08-29 1996-05-28 Merck Frosst Canada, Inc. Diaryl bicyclic heterocycles as inhibitors of cyclooxygenase-2
AU708374B2 (en) 1995-02-06 1999-08-05 Eli Lilly And Company Methods of inhibiting effects of IL-6
US5484808A (en) 1995-02-09 1996-01-16 Eli Lilly And Company Methods of inhibiting cell-cell adhesion
US6294537B1 (en) * 1995-03-17 2001-09-25 Sanofi-Synthelabo Compounds which are specific antagonists of the human NK3 receptor and their use as medicinal products and diagnostic tools
US5863936A (en) * 1995-04-18 1999-01-26 Geron Corporation Telomerase inhibitors
DE19534868A1 (en) * 1995-09-20 1997-03-27 Bayer Ag Benzothiophene-2-carboxamide-S, S-dioxide for use in antifouling
JPH09310078A (en) 1996-05-22 1997-12-02 Tonen Corp Biodegradation of benzothiophene
CA2214072C (en) * 1996-08-29 2006-11-14 Eli Lilly And Company Benzo [b] thiophene compounds, intermediates, processes, compositions, and methods
TNSN97092A1 (en) * 1996-09-18 1999-12-31 Agouron Pharma Metal protein enzyme inhibitors and pharmaceutical formulations containing these inhibitors and their pharmacological use and methods and intermediates useful for preparing the aforementioned formulations.
JP4166296B2 (en) 1997-04-25 2008-10-15 塩野義製薬株式会社 Compound having dopamine receptor antagonistic action
WO1998055454A2 (en) 1997-06-05 1998-12-10 Takeda Chemical Industries, Ltd. Benzofurans and benzothophenes as suppressors of neurodegeneration
GB9725953D0 (en) * 1997-12-08 1998-02-04 Pfizer Ltd Compounds useful in therapy
US6271642B1 (en) 1998-02-13 2001-08-07 Johnson Controls Technology Company Advanced battery controller with state of charge control
US6251936B1 (en) * 1998-05-12 2001-06-26 American Home Products Corporation Benzothiophenes, benzofurans, and indoles useful in the treatment of insulin resistance and hyperglycemia
DE60105195T2 (en) * 2000-12-05 2005-09-08 F. Hoffmann-La Roche Ag BENZOFURAN AND BENZOTHIOPHENE DERIVATIVES AS SELECTIVE COX-2 INHIBITORS

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3799870A1 (en) * 2010-04-05 2021-04-07 Fosun Orinove Pharmatech, Inc. Ire-1a inhibitors
US11337956B2 (en) 2010-04-05 2022-05-24 Fosun Orinove Pharmatech, Inc. IRE-1α inhibitors
US11452713B2 (en) 2016-02-29 2022-09-27 University Of Florida Research Foundation, Incorporated Chemotherapeutic methods for treating low-proliferative disseminated tumor cells
WO2021088265A1 (en) * 2019-11-05 2021-05-14 中山大学 Imidazo pyridine compound, pharmaceutical composition containing the compound, preparation method therefor, and use thereof

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