The incidence of gram negative bacteria in the United States has been estimated to be approximately 100,000 to 300,000 cases per year, with a mortality rate of 30-60%. Antibiotics are commonly used as the primary chemotherapy for this disease; however, their bactericidal action can result in disruption of the bacterium and concomitant release of endotoxin, i.e., the lipopolysaccharide (LPS) moiety of the bacterial outer membrane. The liberated LPS induces a number of pathophysiological events in mammals (collectively referred to as gram-negative endotoxemia or sepsis syndrome). These include fever, generalized inflammation, disseminated intravascular coagulation (DIC), hypotension, acute renal failure, acute respiratory distress syndrome (ARDS), hepatocellular destruction and cardiac failure.
It has previously been established that, for infections caused by gram-negative bacteria, sepsis is related to the toxic components of the bacteria. Specifically, among the well-described bacterial toxins are the endotoxins or lipopolysaccharides (LPS), a cell-wall structure of the gram-negative bacteria. These molecules are glycolipids that are ubiquitous in the outer membrane of all gram-negative bacteria. While the chemical structure of most of the LPS molecule is complex and diverse, a common feature is the lipid A region of LPS (Rietschel, et al., in the Handbook of Endotoxins, 1: 187-214 eds. R. A. Proctor and E. Th. Rietschel, Elsevier, Amsterdam (1984)); recognition of lipid A in biologic systems initiates many, if not all, of the pathophysiologic changes of sepsis. Because lipid A structure is highly conserved among all types of gram-negative organisms, common pathophysiologic changes characterize gram-negative sepsis. It is also generally thought that the distinct cell wall substances of gram-positive bacteria and fungi trigger a similar cascade of events, although the structures involved are not as well studied as gram-negative endotoxin.
Although endotoxin initiates septic shock, it has little or no direct toxic effect on tissues; instead, it triggers an immunobiological response leading to a cascade of release of cytokines such as tumor-necrosis factor (TNF), interleukin-1, interleukin-6 and interleukin-8, and other biological mediators such as nitric oxide, as well as an array of secondary mediators (e.g., prostaglandins, leukotrienes, interferons, platelet-activating factor, endorphins and colony-stimulating factors).
Therapies for endotoxin-related diseases have generally been directed towards controlling the inflammatory response. Such therapies include corticosteriod treatment, suggested to ameliorate endotoxin-mediated cell membrane injury and to reduce production of certain biological mediators; administration of antibodies designed to neutralize bacterial LPS; treatment with agents to suppress hypotension or with naloxone which apparently blocks the hypotensive effects associated with sepsis syndrome; and treatment with nonsteroidal anti-inflammatory drugs, purported to block cyclooxygenases and thereby decrease the production of certain secondary mediators such as prostaglandins and thromboxane.
However, none of these therapies to date has resulted in significant reduction in the morbidity and mortality resulting from sepsis and septic shock syndrome. Thus there is a long felt need for agents to affirmatively treat this disorder.
Certain lipodisaccharides are disclosed in Macher et al., Great Britain patent 2,179,945, Meyers et al., Great Britain patent 2,220,211, Shiba et al., European patent 172,581, Anderson et al., U.S. Pat. No. 4,495,346 and Shiba et al., U.S. Pat. No. 5,066,794.
Christ, et al., “Anti-Endotoxin Compounds,” U.S. Pat. No. 5,530,113, filed Aug. 25, 1992, the contents of which are included by reference, also disclose certain disaccharide compounds, such as B531 shown below, useful for the treatment of endotoxemia.

Lipodisaccharides with enhanced pharmacological selectivity, efficacy and increased persistence in action were disclosed in U.S. Pat. No. 5,935,938, the entire contents of which are incorporated herein by reference. Specifically, lipodisaccharide B1287 was identified as having a better pharmacological profile than some of its congeners, and thus shows great promise for the treatment of LPS-mediated disorders.

However, existing methods for its preparation typically involve >36 synthetic steps, and are thus not well suited for industrial applicability. Specifically, the synthetic approaches for preparing B1287 that are disclosed in U.S. Pat. No. 5,935,938 are lengthy, hazardous (e.g., involve azide chemistry) and thus inadequate for large-scale syntheses.
Clearly, there remains a need to develop efficient and high yielding synthetic methodologies to access a variety of analogues of Lipid A, particularly B1287 and stereosiomers thereof, which compounds are useful as in the prophylactic and affirmative treatment of endotoxin exposure including sepsis, septicemia, endotoxemia, various forms of septic shock and related disorders using novel liposaccharide analogs.