Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-04-23
2003-04-29
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S422000, C514S443000
Reexamination Certificate
active
06555555
ABSTRACT:
TECHNICAL FIELD
The present invention relates to fused thiophene derivatives and inhibitors of producing lnterleukin-6 (abbreviated as IL-6 hereafter) and/or Interleukin-12 (abbreviated as IL-12 hereafter) containing fused thiophene derivatives as an active ingredient.
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)
(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.
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).
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.
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)).
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-&ggr; (abbreviated as IFN-&ggr; 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-&ggr; 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)).
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.
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., 13, 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, 1281 (1995), Ann, NY Acad. Sci., 795, 371 (1996), Int. Immunol., 8, 569 (1996), Proc. Natl. Acad. Sci. USA, 92, 4823 (1996)).
Further, a compound of the formula (XI) is an important intermediate of pharmaceutical agents and an efficient method for preparation thereof has been desired.
For example,
(1) In the specifications of U.S. Pat. Nos. 3,629,438 and 3,686,216, it is disclosed that a benzothiophene-1,1-dioxide derivative of the formula (X)
(wherein X
x
is halogen, nitro, alkyl alkoxy, haloalkyl, carboxy or sulfonylhalide,
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.)
has an anti-fungal and anti-vital activities.
(2) In the specification of FR1585930, a compound of the formula (Y)
(wherein 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.
(3) In the specification of SU591474, it is described that a compound of the formula (Z)
(wherein R
Z
, R
1Z
, R
2Z
and R
3Z
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)
(wherein 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) 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)
(wherein 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
3V
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)
(wherein A
Z
is
(wherein 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
(wherein G
W
is —CONH—, —C(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 bicycloalky), (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
)
nW
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.
(7) In the specification of Japanese Patent Application Kokai Hei 1
Katsube Nobuo
Kishimoto Tadamitsu
Konishi Mikio
Konno Mitoshi
Lambkin Deborah C.
Ono Pharmaceutical Co. Ltd.
Sughrue & Mion, PLLC
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