Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-05-30
2003-05-20
Trinh, Ba K. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S546000, C514S563000, C549S546000, C560S142000, C560S143000, C564S169000, C564S176000, C564S177000
Reexamination Certificate
active
06566394
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel salicylamide derivatives, to a process for producing the same and to drugs containing the same as the active ingredient. More particularly, the present invention relates to novel salicylamide derivatives exerting an effect of inhibiting the activation of NF-&kgr;B and useful as anti-inflammatory agents and immunosuppressive agents, to intermediates in the production thereof, to a process for producing the same, and to drugs containing the salicylamide derivatives or salts thereof as the active ingredient.
BACKGROUND ART
Anti-inflammatory agents conventionally used include steroid agents, prostaglandin synthesis inhibitors and so forth. Also, cyclosporin, FK506 (tacrolimus) and so forth have been used as immunosuppressive agents. However, it has been pointed out that these drugs have problems in effects and side effects.
In particular, generally many of them have strong side effects, which is a severe limit upon their use as anti-inflammatory agents and immunosuppressive agents.
Accordingly, it has been desired to discover or create novel drugs exerting little side effects and having novel chemical structures and operating mechanisms, so that there have been made studies for discovering or creating novel compounds that have different chemical structures and operating mechanisms from those of conventionally used drugs and exhibiting excellent anti-inflammatory activity or immunosuppressing activity.
NF-&kgr;B was identified as a nucleoprotein bonded to the enhancer of immunoglobulin &kgr;-chain gene (Cell 46, 705-716, 1986) and at first it was considered to be a transcription factor specific to B cells but afterwards it revealed that it exists in various types of cells. NF-&kgr;B is a hetero dimer consisting of two subunits and is constituted by various combinations of p50 or p52 having Rel homology domain (RHD) of about 300 amino acids with RelA, c-Rel or RelB (Annu. Rev. Immunol., 14, 649-681, 1996).
NF-&kgr;B is a dominant transcription factor in biophylaxis reaction and genes induced by NF-&kgr;B includes besides immunoglobulin, cytokines (IL-1, IL-2, IL-6, IL-8, TNF, etc.), cell adhesion factors (E-selectin, ICAM-1, VCAM-1, etc.), nitrogen oxide (NO) synthetase, Fas ligand, etc., most of which are deeply concerned in immune response or inflammatory reaction (Cell, 87, 13-20, 1996).
Factors known to cause activation of NF-&kgr;B include besides TNF-&agr;, IL-1, antigen stimulation, TPA, UV, activated oxygen (Annu. Rev. Immunol., 12, 141-179, 1994). Therefore, it is conceived that stimulation of cells with TNF-&agr; or the like and discovery of a low molecular weight substance induced by the stimulation that inhibits activation of NF-&kgr;B will undergo further development of anti-inflammatory agents and immunosuppressive agents.
DISCLOSURE OF INVENTION
In consideration of the above problems, the present inventors have repeated screening extensively and as a result they have found that novel salicylamide derivatives having specified chemical structures, i.e., compounds represented by the formula (1a) (DHM2EQ) and the compounds represented by the formula (1b) (DHM3EQ) described hereinbelow exert an effect of inhibiting the activation of NF-&kgr;B, thereby achieving the present invention.
That is, the present invention provides the following novel salicylamide derivatives, a process for producing the same, and drugs containing the same as the active ingredient.
[1] Salicylamide derivatives represented by formula (1)
wherein R
1
represents a hydrogen atom or a C2-4 alkanoyl group, R
2
represents a group represented by the following formulae (A), (B), (C), (D), (E), (F) or (G):
Wherein R
3
represents a C1-4 alkyl group.
[2] Salicylamide derivatives as described in [1] above represented by formulae (1a) or (1b)
[3] Salicylamide derivatives as described in [1] above, represented by formula (2)
wherein the symbol in the formula has the same meaning as described in [1] above.
[4] Salicylamide derivatives as described in [1] above, represented by formula (3)
wherein the symbols in the formula have the same meanings as described in [1] above.
[5] Salicylamide derivatives as described in [1] above, represented by formula (4)
wherein the symbol in the formula has the same meaning as described in [1] above.
[6] A salicylamide derivative as described in [1] above, represented by formula (5)
[7] Salicylamide derivatives as described in [1] above, represented by formula (6)
wherein the symbol in the formula has the same meaning as described in [1] above.
[8] A process for producing salicylamide derivatives represented by formula (2)
wherein the symbol in the formula has the same meaning as in described above, comprising reacting 2,5-dimethoxyaniline with O-alkanoylsalicyloyl halide represented by formula (7)
wherein R
1
has the same meaning as described in [1] above, and X represents a halogen atom.
[9] A process for producing salicylamide derivatives represented by formula (3)
wherein the symbols in the formula have the same meanings as described above, comprising reacting a salicylamide derivative represented by formula (2)
wherein the symbol in the formula has the same meaning as in [1] above, with an alkanol represented by formula R
3
OH wherein R
3
is a C1-4 alkyl group, in the presence of a compound represented by a formula C
6
H
3
I(OAc)
2
wherein Ac is an acetyl group.
[10] A process for producing salicylamide derivatives represented by formula (4)
wherein the symbol in the formula has the same meaning as described above, comprising subjecting a salicylamide derivative represented by formula (3)
wherein the symbols in the formula have the same meanings as in [1] above, to epoxidation.
[11] A process for producing a salicylamide derivative represented by formula (5)
comprising subjecting a salicylamide derivative represented by formula (4)
wherein the symbols in the formula have the same meanings as described in [1] above, to dedialkylketalation.
[12] A process for producing salicylamide derivatives represented by formula (6)
wherein the symbol in the formula has the same meaning as described above, comprising subjecting a salicylamide derivatives represented by formula (4)
wherein the symbols in the formula have the same meanings as in [1] above, to reduction.
[13] A process for producing a salicylamide derivative represented by formula (1a)
comprising subjecting a salicylamide derivative represented by formula (5)
to reduction.
[14] A process for producing a salicylamide derivative represented by formula (1b)
comprising subjecting a salicylamide derivative represented by formula (6)
wherein the symbol in the formula has the same meaning as described in [1] above, to dedialkylketalation.
[15] A drug comprising a salicylamide derivative represented by formulae (1a) or (1b) as described in [2] above or a salt thereof as the active ingredient.
[16] An agent for inhibiting the activation of NF-&kgr;B comprising a salicylamide derivative represented by formulae (1a) or (1b) as described in [2] above or a salt thereof as the active ingredient.
[17] Anti-inflammatory agent or immunosuppressive agent, comprising a salicylamide derivative represented by formulae (1a) or (1b) as described in [2] above or a salt thereof as the active ingredient.
REFERENCES:
Matsumoto et al., Bioorg. Med. Chem. Lett. , 2000, vol. 10, No. 9, pp. 865-869.*
Taylor et al., Synthesis, May 1998, pp. 775-790.
Agata Naoki
Hirano Shin-ichi
Isshiki Kunio
Matsumoto Naoki
Sawa Tsutomu
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Mercian Corporation
Trinh Ba K.
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