The present invention relates to compounds, processes for their preparation, compositions containing them, and their therapeutic use as vaccine adjuvants and in the treatment of various disorders.
The innate immune system recognises microbes via a limited number of germline-encoded Pattern-Recognition Receptors (PRRs) which have a number of important characteristics.
Toll-like receptors (TLR) are a family of structurally related PRRs that detect highly conserved microbial components common to large classes of pathogens. TLRs are expressed on immune cells and upon activation mobilize defense mechanisms aimed at eliminating the invading pathogens. Of the more than ten known TLRs that have been identified in humans, some appear to be restricted to cytoplasmic compartments and involved in the detection of non-self nucleic acids (TLRs 3, 7, 8, and 9). See, e.g., Akira et al., Nat Rev Immunol 2004, 4, 499-511; O'Neill, et al., Nat Rev Immunol 2013, 13, 453-460.
Activation of TLRs regulates intracellular signaling pathways leading to the expression of inflammatory cytokines/chemokines and type I interferons (IFNα/β), which can lead to the preferential enhancement of antigen-specific humoral and cell-mediated immune responses.
TLR7 and TLR8 are members of the subgroup of TLRs (TLRs 3, 7, 8, and 9) localised in the endosomal compartment of cells. TLR7 plays a key rôle in anti-viral defence via the recognition of ssRNA (Diebold S.S. et al, Science, 2004: 303, 1529-1531; and Lund J. M. et al, PNAS, 2004: 101, 5598-5603). TLR7 has a restricted expression-profile in human and is expressed predominantly by B cells and plasmacytoid dendritic cells (pDC), and to a lesser extent by monocytes. Plasmacytoid DCs are a unique population of lymphoid-derived dendritic cells (typically 0.2-0.8% of Peripheral Blood Mononuclear Cells (PBMCs)) and are the primary type I interferon-producing cells secreting high levels of interferon-alpha (IFNα) and interferon-beta (IFNβ) in response to viral infections (Liu Y-J, Annu. Rev. Immunol., 2005: 23, 275-306).
Small-molecule agonists of TLR7 have been described which can induce cytokines in animals and in man (Takeda K. et al, Annu. Rev. Immunol., 2003: 21, 335-76). TLR7 agonists include imidazoquinoline compounds such as imiquimod and resiquimod, oxoadenine analogues and also nucleoside analogues such as loxoribine and 7-thia-8-oxoguanosine, which are known to induce interferon alpha. International Patent Application publication number WO 2007/034882 (PCT/JP2006/318758; Dainippon Sumitomo Pharma Co. Ltd./AstraZeneca Aktiebolag) discloses certain adenine compounds identified as useful as medicine.
Certain adenine derivative compounds have been shown to be inducers of human interferon. Compounds which induce human interferon may be useful as vaccine adjuvants, as well as in the treatment of various disorders, including infectious diseases, asthma, cancer, inflammatory conditions, and allergic diseases. It is thus desirable to provide compounds having selectivity and/or potency for TLR7/8 and high relative cytokine induction.