Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing heterocyclic carbon compound having only o – n – s,...
Reexamination Certificate
1997-03-04
2001-04-24
Weber, Jon P. (Department: 1651)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing heterocyclic carbon compound having only o, n, s,...
C435S130000, C435S256100, C514S183000, C514S687000, C568S308000
Reexamination Certificate
active
06221637
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to xanthene derivatives which are useful as pharmaceutical composition such as immunomodulator and so on.
2. Description of Related Art
An immune reaction is a cellular or humoral reaction in order to eliminate non-self under the basis of self
on-self discrimination. An immune system is a self-defense reaction which is conducted by the body when a foreign antigen invades into the body, including various infectious pathogens, and is an important system for defending oneself against a foreign enemy. The breakdown of this immune system and excess reaction makes it harmful to self, and causes various diseases, including autoimmune diseases and allergic diseases. Various diseases caused by the breakdown of this immune systems and excess reaction can be ameliorated by regulating the immune reaction.
The recent progress of the medical technique made it possible to manage organ transplantation. The immune reaction of the body interferes with this organ transplantation, and the suppression of the immune reaction is required for graft survival. Immunocompetent cells participate in the inflammatory reaction, and the excess immune reaction directly exacerbate the inflammatory reaction. Accordingly, various chronic inflammatory diseases such as rheumatoid arthritis and nephritis, can be ameliorated by suppressing the immune reaction.
When activated through recognition of antigens, T cells start to produce cytokines such as interleukin-2 (hereinafter abbreviated to IL-2) and proliferate. It has recently become clear that full activation of T cells requires second signal, termed costimulatory signal, from antigen presenting cells, in addition to the antigen specific signal delivered by T-cell receptors, hereinafter abbreviated “TCR”, engagement. Antigen stimulation through TCR without eostimulatory signal not only results in the suppression of T cell activation but includes an antigen specific unresponsive state (anergy), in which T-cells can not be activated even when they receive both antigenic stimulation through TCR and constimulatory signal again.
It is a B7/CD28 ligand receptor, which is a molecule serving for this costimulatory signal, to which a special attention is paid. B7 is expressed on the surface of the antigen presenting cells or activated B cells, while CD28 is expressed on the surface of T-cells, and the signal is transmitted to T-cells by interaction between them (Annual Review of Immunology, 1993, 11: 191-212). It is known that B7 includes two kinds of molecules, e.g. B7-1 (CD80) and B7-2 (CD86). It is assumed that there is a difference in role between them because timing of their expression on the surface is quite different. A receptor, which binds to B7 ligand includes not only CD28 which transmits an activated signal, but also CTLA-4 which is considered to deliver a negative signal. It is considered that CTLA-4, expressed on the activated T-cells, induces to an apoptosis by binding with B7, thereby terminating the immune response. It is reported that a binding activity of CTLA-4 to B7 is stronger than that of CD28 by one order. These molecules are proteins which belong to the immunoglobulin superfamily.
A trial of inhibiting this costimulatory signal to induce unresponsiveness to a specific antigen has already begun, and antibody against B7 ligand and a solubilized protein of CD28 or CTLA-4 have been tried to use as an inhibitor, thereby obtaining expected results (Annual Review of Immunology, 1993, 11: 191-212).
Heretofore, low-molecular compounds such as antimetabolite inhibiting the proliferation of activated immune cells, and steroids which is considered to have an activity of inhibiting production of various cytokines, have widely been used for immunosuppression. These compounds have a strong side effect, and it is hard to say that they specifically act on the immune cells.
Cyclosporin A and FK506 have recently been found as a drug for inhibiting a signal for activation of T-cells by antigen stimulation, and have generally been used for immunosuppression on organ transplantation. Although these drugs have high specificity to the immune system, toxicity is considerably remarkable.
The drugs for inhibiting the costimulatory signal can be expected not only inhibitory action of the immune cells but also suppressive activity of antigen specific immune response, i.e. action for inducing an unresponsive state to a specific antigen. Such a state makes it possible to ameliorate diseases due to the excess immune reaction against the specific antigen without damaging wide immune reaction of the body. It is particularly advantageous for immunosuppression on organ transplantation and inhibition of an allergic reaction. A trial of inhibiting a signal with an antibody against costimulatory molecules, thereby obtaining expected results. Accordingly, the low-molecular weight compound having such an action is useful as an antigen specific immunosuppressive agents for development of new immunotherapy.
Under these circumstances, the present inventors intensively studied so as to obtain a drug inhibiting binding of B7-1 to CD28 from microorganism metabolites. As a result, the present inventors succeeded in isolating a novel compound referred to as TAN-2421 from a culture, and found that the present compound inhibits not only a binding of B7-1 to CD28 but also an B7-1-dependent activation of T cells. The present inventors made further investigations based on these findings, and accomplished the present invention.
SUMMARY OF THE INVENTION
(1) A compound represented by the general formula:
wherein R
1
is a carboxyl group which may be esterified or amidated; R
2
is a hydrogen atom, a hydroxyl group, or a hydrocarbon group which may be substituted; R
3
and R
4
are the same or different and are a hydroxyl group which may be substituted; R
5
and R
6
are the same or different and are a hydrogen atom or a halogen atom; R
7
is a hydrogen atom, a nitro group, a halogen atom, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, or an acyl group which may be substituted; n is an integer of 0 to 2; and R
99
is a carbonyl or —CH
2
—; and when n is 0, R
2
may be a group represented by the formula:
wherein the symbols have the same meanings as defined above, or a salt thereof,
(2) The compound according to (1), wherein R
7
is a hydrogen atom or a halogen atom, (3) The compound according to (1), wherein R
2
is a group represented by —CH
2
(CHOH)m—R
2
′, wherein m is 0 or 1, and R
2
′ is a carboxyl group which may be esterified or amidated or a hydroxylmethyl group which may be substituted; R
7
is a hydrogen atom; and,
(4) The compound according to (1), wherein R
2
is (i) a hydrogen atom, (ii) a hydroxyl group or (iii) a C
1-19
hydrocarbon group which may be substituted by a group selected from the group consisting of (a) C
1-8
alkoxycarbonylcarbonyl, (b) carboxyl which may be esterified or amidated, (c) hydroxyl which may be acylated, (d) amino which may be substituted by C
1-10
alkyl, C
1-6
alkanoyl, C
1-6
alkylsulfonyl or C
6-14
arylsulfonyl, (e) C
1-6
alkoxy, (f) cyano, (g) sulfo, (h) a 5- or 6-membered heterocyclic group which may be substituted by C
1-6
alkyl, C
1-6
alkoxy, nitro, cyano, amino, halogen, hydroxyl or oxo, (i) nitro, (j) halogen and (k) oxo;
R
3
and R
4
are the same or different and are a hydroxyl group which may be substituted by (a) a acyl group or (b) a C
1-10
alkyl group which may be substituted;
R
7
is (i) a hydrogen atom, (ii) a nitro group, (iii) a halogen atom, (iv) a C
1-19
hydrocarbon group which may be substituted by a group selected from the group consisting of (a) carboxyl which may be esterified or amidated, (b) hydroxyl which may be acylated, (c) amino which may be substituted by C
1-10
alkyl, C
1-6
alkanoyl, C
1-6
alkylsulfonyl or C
6-14
arylsulfonyl, (d) C
1-6
alkoxy, (e) cyano, (f) sulfo, (g) a 5- or 6-membered heterocyclic group which may be substituted by C
1-6
alkyl, C
1-6
alkoxy, nitro, cyano
Hattori Masahiko
Hida Tsuneaki
Kurokawa Tsutomu
Nakanishi Atsushi
Hanley Susan
Takeda Chemical Industries Ltd.
Weber Jon P.
Wenderoth , Lind & Ponack, L.L.P.
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