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EP-3710462-B1 - BRARTEMICIN ANALOGUES

EP3710462B1EP 3710462 B1EP3710462 B1EP 3710462B1EP-3710462-B1

Inventors

  • FOSTER, Amy Jane
  • STOCKER, Bridget Louise
  • TIMMER, Mattheus Simon Maria
  • YAMASAKI, SHO

Dates

Publication Date
20260513
Application Date
20181102

Claims (14)

  1. A compound of Formula IVb characterised in that X a and X b are independently selected from O or NH; each Y a and Y b is independently selected from the group comprising -I, -Br, -Cl, -F, -OH, -R 1 and -OR 1 where R 1 is selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl and (C 2 -C 6 )alkynyl, characterised in that (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl and (C 2 -C 6 )alkynyl are each optionally substituted with -OH or (C 1 -C 6 )alkoxy; n and m are independently 0 to 4; each Z a and Z b is independently selected from R 2 , -OR 2 , -NHR 2 , -NHC(O)-R 2 and -S-R 2 , where R 2 is selected from (C 5 -C 26 )alkyl, (C 5 -C 26 )alkenyl and (C 5 -C 26 )alkynyl, characterised in that (C 5 -C 26 )alkyl, (C 5 -C 26 )alkenyl and (C 5 -C 26 )alkynyl are each optionally substituted with -OH or (C 1 -C 6 )alkoxy; r and s are independently 1 to 3; alk a and alk b are absent such that the aryl ring connects directly to the C(O) carbon; characterised in that n + r = 1 to 5; and m + s = 1 to 5.
  2. A compound of claim 1 characterised in that X a and X b are both O, or X a and X b are both NH.
  3. A compound of any one of claims 1 to 2 characterised in that n and m are 0 to 3 and each of Y a and Y b are independently selected from -OH, -R 1 and -OR 1 where R 1 is selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl and (C 2 -C 6 )alkynyl, characterised in that (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl and (C 2 -C 6 )alkynyl are each optionally substituted with -OH or (C 1 -C 6 )alkoxy.
  4. A compound of claim 3 characterised in that each of Y a and Y b are independently selected from -OH and -(C 1 -C 6 )alkyl.
  5. A compound of claim 3 characterised in that n and m are both 1.
  6. A compound of any one of claims 1 to 5 characterised in that n and m are both 1 and Y a and Y b are independently selected from -OH and methyl.
  7. A compound of any one of claims 1 to 6 characterised in that each of Z a and Z b are independently selected from R 2 and -OR 2 , where R 2 is selected from (C 5 -C 26 )alkyl, (C 5 -C 26 )alkenyl and (C 5 -C 26 )alkynyl, characterised in that (C 5 -C 26 )alkyl, (C 5 -C 26 )alkenyl and (C 5 -C 26 )alkynyl are each optionally substituted with -OH or (C 1 -C 6 )alkoxy.
  8. A compound of any one of claims 1 to 7 characterised in that r and s are both 1.
  9. A pharmaceutical composition comprising a compound of any one of claims 1 to 8 and one or more pharmaceutical acceptable excipients.
  10. A therapeutically effective amount of a compound of any one of claims 1 to 8 for use in enhancing an immune response in a subject.
  11. A therapeutically effective amount of a compound of any one of claims 1 to 8, together with an antigen, for use in enhancing an immune response to an antigen in a subject.
  12. A therapeutically effective amount of a compound of any one of claims 1 to 8 for use in preventing or treating a disease or condition in a subject caused by an intracellular pathogen.
  13. A therapeutically effective amount of a compound for use according claim 12 characterised in that the intracellular pathogen is selected from the group consisting of human immunodeficiency virus (HIV), tuberculosis, hepatitis A virus, hepatitis B virus, hepatitis C virus, herpes simplex virus (HSV), influenza, pneumonia, meningitis, rotavirus, tetanus, Leishmaniasis, anthrax, human papillomavirus (HPV), measles, rubella, chicken pox, mumps, shingles, polio, pertussis, yellow fever, rabies, tetanus, dengue, typhoid, and Japanese encephalitis.
  14. A therapeutically effective amount of a compound of any one of claims 1 to 8 for use in preventing or treating cancer in a subject.

Description

1. FIELD OF THE INVENTION This invention relates generally to brartemicin analogues, pharmaceutical compositions comprising these and their uses. 2. BACKGROUND TO THE INVENTION Adjuvants have traditionally been used to enhance the adaptive immune response to a vaccine, with most current vaccines providing protection primarily through humoral immunity. However, humoral immunity is insufficient to confer protection against some pathogens, thus necessitating the need for adjuvants that enhance acquired cellular (Th1) immunity. Th1 cells secrete cytokines which activate macrophages, inducing production of opsonizing antibodies by B cells. The Th1 response protects against invasive pathogens such as bacteria, protozoa, fungi and viruses. The Th1 response also activates cytotoxic T-lymphocytes (CTL), a sub-group of T cells that induce death of pathogen-infected cells. Natural killer (NK) cells are also activated by the Th1 response and play a major role in apoptosis in tumours and virus-infected cells. Effective Th1-stimulating adjuvants often engage the innate immune system by activating pattern recognition receptors (PRRs) on professional antigen presenting cells (APCs). Previously, there has been much interest in the Toll-like receptors (TLRs) as targets for vaccine adjuvants. However more recently, Macrophage inducible C-type lectin (Mincle) has been identified as a PRR on the surface of macrophages and dendritic cells (DCs) and so is a promising new target for vaccine development. Pathogen associated molecular patterns (PAMPs) are molecules associated with groups of pathogens that are recognised by cells of the innate immune system. A large number of molecules can act as PAMPs, including glycans and glycoconjugates. PAMPs bind to PRRs, with the specificity of the ensuing immune response being directed by the type of PRR activated and the structure of each specific PAMP. Mincle is activated by a number of PAMPs including the Mycobacterium tuberculosis cell wall glycolipid trehalose dimycolate (TDM) with Mincle activation leading to the induction of the FcRy-Syk-Card9-Bcl10-Malt1 signalling axis and a Th1-polarised immune response. A number of synthetically derived ligands also bind and activate Mincle, for example, trehalose dibehenate (TDB). However, TDM is highly toxic so cannot be used as a therapeutic agent. It also comprises a complex mixture of compounds and is difficult to synthesise. Accordingly, alternative Mincle agonists are needed, preferably compounds with high activity and low toxicity that are simple to prepare. It is an object of the invention to go at least some way towards providing an alternative Mincle agonist and/or a method of enhancing an immune response in a subject using such an alternative Mincle agonist and/or to provide at least one Th1-stimulating vaccine adjuvant and/or to at least provide the public with a useful choice. In this specification where reference has been made to patent specifications, other external documents, or other sources of information, this is generally for the purpose of providing a context for discussing the features of the invention. Unless specifically stated otherwise, reference to such external documents is not to be construed as an admission that such documents, or such sources of information, in any jurisdiction, are prior art, or form part of the common general knowledge in the art. US2013331346 discloses an invention relating to trehalose derivatives with general formula (I) defined therein, a preparation method and uses thereof, wherein 6,6'-bis(2,3-dimethoxybenzoyl)-alpha,alpha-D-trehalose has anti-colon cancer 26-L5 cell invasion activity which is better than that of a natural product Brartemicin, IC50 is 0.10 mug/mL (0.15 muM), and when the IC50 is 10 mug/mL, 6,6'-bis(2,3-dimethoxybenzoyl)-alpha,alpha-D-trehalose has no cytotoxicity, shows high-selectivity anti-tumor invasion activity and can be used for preparing medicaments for preventing and treating invasion and metastasis of colon cancer and the like. CN102260297 discloses an invention relating to a trehalose amide derivative as well as a preparation method thereof and an application thereof, wherein 6,6'-di(2-hydroxy benzamido)-6,6'-didesoxy-alpha, alpha-D-trehalose shows more superior activity against invasion of colon cancer 26-L5 cells than a natural product Brartemicin; IC50 is 0.20 micrograms per milliliter (0.33 microns); and the 6,6'-di(2-hydroxy benzamido)-6,6'-didesoxy-alpha, alpha-D-trehalose shows no cytotoxicity while the IC 50 is 10 micrograms per milliliter, shows antitumor invasion activity with high selectivity and is used for preparing drugs for preventing and treating invasion and transfer of colon cancers and the like. The article entitled "Synthesis and structure-activity relationships studies of brartemicin analogs as anti-invasive agents", by JIANG YONG-LI ET AL, published in THE JOURNAL OF ANTIBIOTICS, GB, vol. 66, no. 9, doi:10.1038/ja.2013.37, ISSN 0021-8820, pages