Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-11-08
2002-05-07
Aulakh, Charanjit S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S247000, C546S168000, C546S269700, C544S336000, C514S255030, C514S314000, C514S342000
Reexamination Certificate
active
06384065
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel spiro compounds or salts thereof that inhibit the activity of a transcription factor AP-1 and are useful as agents for treating autoimmune diseases, agents for preventing and/or treating autoimmune diseases and an AP-1 inhibitor containing the same.
BACKGROUND ART
Up to today, therapeutic drugs for many diseases have been developed to control the functions of proteins such as enzymes and receptors. For example, for treating inflammatory diseases such as rheumatoid arthritis, etc., cycloxygenase synthesizing prostaglandins from arachidonic acid or 5-lipoxygenase synthesizing leucotrienes have been taken as a target, and a number of non-steroidal antiinflammatory drugs such as indomethacin have been developed and put to therapeutic uses (J. Pharm. Sci., Vol. 73, Pages 579-589, 1984). Inflammatory cytokines such as interleukins (IL)-1 and IL-6 and tumor necrotic factor (TNF) have attracted intention as amplifying or aggravating factors in inflammatory reaction. As agents for regulating the functions of these proteins, monoclonal antibodies for respective proteins (Arthritis Rheum., Vol. 36, Pages 1681-1690, 1993), low molecular weight cytokine production inhibitors (Ann. Rep. Med. Chem., Vol. 27, Pages 209-218, 1992), etc. are being developed. Further, the use of antibodies for those cytokine receptors is also being attempted clinically (Rheumatism, Vol. 37, No. 2, Page 174, 1997).
In the diseases caused by a quantitative abnormality of functional proteins existing in cells or on cell membranes or of functional molecules secreted from cells, however, it is considered that a therapy in the true sense is to regulate the quantity of transcription of functional molecule gene and thereby normalize the quantity of expression rather than to inhibit the activity of the functional molecules. It is known that not only the quantitative abnormalities of the above-mentioned inflammatory cytokines and lipid mediators synthesized from arachidonic acid but also the quantitative abnormalities of many functional proteins such as adhesion molecules and matrix metallo proteinases take part in the cause of autoimmune diseases such as rheumatoid arthritis and chronic inflammatory diseases (N. Engl. J. Med., Vol. 322, Pages 1277-1289, 1990). Although gene expression and production of these functional proteins are regulated by a plurality of transcription factors, it is known that the promoter region of a majority of such genes commonly involves a consensus sequences of transcription factor AP-1 (TRE sequence). Further, it has been reported that expression of some of these functional proteins is regulated by binding of AP-1 to the promoter region (Nature, Vol. 337, Pages 661-663, 1989).
A living body exhibits various defensive reactions against outer stimulation and attack, and shows immune responses and inflammatory reactions.
Cellular and molecular analyses of such reactions have made a surprising progress in the recent years, due to which it has become apparent that gene expression and production of proteins to make sure the physiological functions was induced the stimulation in all the cells constituting a living body.
The immune responses and inflammatory reactions are amplified and regulated by the interaction of these genes including inflammatory cytokines such as IL-1 and TNF&agr;, cell surface molecules such as cell-adhesion molecules and various cytokine receptors and enzymes such as matrix metallo-proteinases. On the other hand, autoimmune diseases typified by rheumatoid arthritis and other intractable chronic inflammatory diseases are considered caused by an excessive immunity and inflammatory reactions. That is, it is prospected that, in these inflammatory diseases, such a wide variety of genes directly relating to the etiology of disease are expressed in an excessive quantity, so that a mere inhibition or control of only one genetic product (protein) is incapable of realizing a sufficient therapy (radical therapy).
At the present time, non-steroidal anti-inflammatory agents and steroidal agents are used for the pharmaceutical treatment of chronic inflammatory diseases such as rheumatoid arthritis. Non-steroidal anti-inflammatory agents such as indomethacin and the like inhibit cycloxygenase and thereby suppress the production of lipid mediators such as prostaglandin E
2
and the like. However, such a treatment is not sufficient as a radical therapy because the use of these drugs is to suppress only one inflammatory mediator, cycloxygenase, and the effect thereof is nothing but an expectation of a conservative treatment. On the other hand, steroidal agents are known to exhibit regulating effect at the stage of expression of gene through intermediation of a glucocorticoid receptor, and it has actually been reported that these agents inhibit the activity of transcription factor AP-1 and thereby suppress the production of cytokines and other proteins (Cell, Vol. 62, Pages 1189-1204, 1990). Although effectiveness of such steroidal agents are sufficiently recognized, the use of such steroidal agents is restricted by the hormonal and side effects thereof, and they cannot be administered over a long period of time. Especially, the inflammatory diseases such as autoimmune diseases are generally chronic and require a long-term therapy, so that drugs having intense side effects cannot be used at least at the present time.
Thus, it has been desired to develop an agent for treating and/or preventing autoimmune diseases which inhibits AP-1 activity and can suppress the expression of a wide variety of genes through inhibiting AP-1 activity thereof, with lessened side reactions.
DISCLOSURE OF THE INVENTION
The present inventors have conducted extensive studies with the aim of developing an agent for treating and/or preventing autoimmune diseases which inhibits AP-1 activity and can suppress the expression of a wide variety of genes through inhibiting AP-1 activity thereof, with lessened side reactions. As a result, it has been found-that spiro compounds having a spiro ring skeleton represented by the following general formula [1]:
wherein A is a group of the following general formula:
wherein R
1a
represents hydrogen atom, halogen atom, cyano group, nitro group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, amino or heterocyclic group; and Y
0
represents oxygen atom, sulfur atom, an unsubstituted or substituted imino group, carbonyl group, methylene group, vinylene group, sulfinyl group, sulfonyl group or group —CH(OH)—; or a group of the following general formula:
wherein R
1c
and R
1d
, same or different, each represents hydrogen atom, halogen atom, cyano group, nitro group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, mercapto group, or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, amino or heterocyclic group;
or a group of the following general formula:
wherein R
1e
and R
1f
, same or different, each represents halogen atom, cyano group, nitro group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, amino or heterocyclic group; or a group of the following general formula:
wherein R
1g
represents an unsubstituted or substituted heterocyclic group;
R
2
represents hydrogen atom or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, acyl, aryl, aralkyl, alkylsulfonyl, arylsulfonyl or heterocyclic group; R
3
and R
4
, same or different, each represents hydrogen atom, halogen atom, cyano group, an unprotected or protected carboxyl group, an un
Aikawa Yukihiko
Chaki Hisaaki
Hirono Shuichi
Kuroda Hiroshi
Miyajima Mikako
Aulakh Charanjit S.
Toyama Chemical Co., Ltd.
LandOfFree
Spiro compounds or salts thereof and preventives/remedies... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Spiro compounds or salts thereof and preventives/remedies..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Spiro compounds or salts thereof and preventives/remedies... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2821482