Sepsis is a systemic inflammatory response syndrome (SIRS) which occurs due to an excess inflammatory response of a biological body against bacterial infection, and is a disease which may result in death when it is accompanied by shock or organ failure. Since there are only a few agents that are effective against sepsis until now, it is considered to be a disease that is difficult to prevent and treat. However, since its fatality is high and the number of patients is large, development of therapeutic agents for it is particularly important (for example, refer to Non-patent document 1).
Endotoxin (lipopolysaccharide, LPS), which is a membrane component of bacteria, acts against cells such as monocytes, macrophages and vascular endothelial cells, induces an excess generation of various inflammatory mediators such as TNF-α and the like, causes sudden blood pressure reduction, blood coagulation disorders, cardiovascular disturbances and the like in addition to systemic inflammatory responses, and thus exhibits sepsis (for example, refer to Non-patent document 2). Lipid A, which corresponds to lipopolysaccharide and its partial structure, activates intracellular signal transduction via TLR4 (Toll-like receptor 4), which is a functional cell surface receptor, after binding with CD14 (for example, refer to Non-patent document 3). Accordingly, lipid A initiates various cell responses represented by the generation of inflammatory mediators. Therefore, it is considered that a substance which suppresses the intracellular signal transduction or cell activation induced by endotoxin, and various cell responses induced by intracellular signal transduction and cell activation, the various cell responses being represented by an excess generation of inflammatory mediators such as TNF-α, can be an effective prophylactic and therapeutic agent for sepsis (for example, refer to Non-patent document 3, Non-patent document 4, Patent document 1 and Patent document 2).
Intracellular signal transduction or cell activation induced by endotoxin, and various cell responses induced by the intracellular signal transduction and cell activation, the various cell responses being represented by an excess generation of inflammatory mediators such as TNF-α, lead to development and progress of various diseases such as ischemic brain disorder, arteriosclerosis, poor prognosis after coronary angioplasty, heart failure, diabetes, diabetic complication, joint inflammation, osteoporosis, osteopenia, autoimmune disease, tissue disorder and rejection after organ transplantation, bacterial infection, virus infection, gastritis, pancreatitis, nephritis, pneumonia, hepatitis and leukemia, in addition to the aforementioned sepsis (for example, Non-patent document 5 and Patent document 3).
Therefore, a substance which suppresses intracellular signal transduction or cell activation induced by endotoxin, and various cell responses induced by the intracellular signal transduction and cell activation such as an excess generation of inflammatory mediators such as TNF-α, is considered to be effective as a prophylactic and/or therapeutic agent for these various diseases, and thus the development of an excellent therapeutic agent has been desired.    [Non-patent Document 1] Iqbal et al., Expert Opin. Emerging Drugs, Vol. 7, page 111, 2002    [Non-patent Document 2] Hawkins et al., Current Topics in Medicinal Chemistry, Vol. 4, page 1147, 2004    [Non-patent Document 3] Beutler, Nature, Vol. 430, pages 257-263, 2004    [Non-patent Document 4] Kakutani et al., Inflammation Research, Vol. 48, page 461, 1999    [Non-patent Document 5] Donald N. Cook et al., Nature Immunology, Vol. 5, pages 975-979, 2004    [Patent Document 1] Japanese Patent Application (Kokai) No. 2000-178246    [Patent Document 2] Japanese Patent Application (Kokai) No. 2004-2370    [Patent Document 3] International Publication WO 00/41698 Pamphlet