(Oxo-)xanthene derivatives, their preparation and their use as immunomodulators

摘要

Xanthene derivatives 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 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 Y is an oxygen atom or two hydrogen atoms; 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 inhibit a binding of B7-1 to CD28, prevent the B7-1-dependent activation of T cells and inhibit IL-2 production from T cells, thus being used as an immunomodulator such as a graft rejection inhibitor or a pharmaceutical composition for therapeutic treatment of allergy, rheumatoid arthritis, autoimmune disease, nephritis, diabetes mellitus and so on; and a microorgansim, Aspergillus terreus FL- 67283 strain, capable of producing some of the compounds according to formula (I); and a method for screening for a compound having an activity for inhibiting or enhancing a binding of CD28 to B7-1, or a salt thereof, which comprises comparing (1) an amount of binding between CD28 and B7-1-Ig obtained when CHO-cell containing CD28 or its cell membrane fraction is contacted with soluble B7-1-Ig, with (2) an amount of binding between CD28 and B7-1-Ig obtained when CHO-cell containing CD28 or its cell membrane fraction is contacted with soluble B7-1-Ig and a test compound; and a CHO cell designated by CD28-CHO-11 (FERM BP-5431), a CHO cell represented by B7-1-CHO-22 (FERM BP-5430) or a CHO cell represented by sB7-1-Ig-CHO-20 (FERM BP-5432).