Substituted thiophene pentamers

#This application is a national stage application of International Application Serial No. PCT/SE2009/051187, filed on Oct. 19, 2009, which claims the benefit of priority of Swedish Application No. 0850043-1 filed on Oct. 17, 2008 and Swedish Application No. 0850050-6, filed on Oct. 23, 2008, the contents of which are hereby incorporated by reference in their entireties.

#The present invention relates to novel substituted thiophene derivatives useful in therapy, especially therapy of a mammal suffering from a disease involving misfolded or aggregated forms of proteins.

#Natural biopolymers, such as proteins, frequently have ordered conformations, such as alpha-helix and beta-sheets, which contribute to the three-dimensional ordered structure and the specific function of the biopolymer. The structure of a protein is essential for the protein's function; it has been shown by many scientists that an unfolded protein may not be functional. More important, in the last few years there is increasing awareness of the danger of protein misfolding and misassembly into for example amyloid and other pathological forms. Misfolding can change a protein from something that is useful into nonfunctional, harmful or even toxic. Human health relies on properly folded protein, and in vivo deposition of amyloid fibrils is associated with many diseases related to protein conformation, including Alzheimer's disease, Huntington's disease, systemic amyloidoses, and the prion diseases. The prion diseases, i.e. transmissible spongiform encephalopathy (TSE), in animals [e.g. bovine spongiform encephalopathy (BSE), Scrapie and chronic wasting disease (CWD)] and in humans [Creutzfeldt Jakob disease (CJD), Gerstmann-Sträussler-Scheinker disease (GSS), Kuru] are associated with the conformational conversion of the normal cellular prion protein, (PrPC), to an infectious pathogenic disease-associated isoform denoted PrPSc. Proteins frequently alter their conformation due to different external stimuli and the importance of conformational changes of proteins leading to pathogenic states has been well documented. Especially under conditions that destabilize the native state, proteins can aggregate into characteristic fibrillar assemblies, known as amyloid fibrils. These beta-sheet rich protein assemblies have distinctively different conformations compared to that of the native state. The misfolded prion protein is even self-propagating (infectious), a property which is entirely encoded within the misfolded conformation.

#FIG. 1. Reference sample incubated 20 h, both scale bars represent 0.2 μm. Separated fibrils in sheet like aggregates marked by white arrows.

#FIG. 2. Reference sample incubated 20 h, scale bar represent 0.2 μm. Separated fibrils in sheet like aggregates are seen in front of the white arrows.

#FIG. 3. Reference sample incubated 66 h, both scale bars represent 0.2 μm. White arrows are directed towards visible fibrils that are separated from the fibrillar sheets.

#All words and abbreviations used in the present application shall be construed as having the meaning usually given to them in the relevant art, unless otherwise indicated. For clarity, some terms are however specifically defined below.

#The term alkyl or alkylene moiety, as used herein, is a C1-C6 alkyl or alkylene moiety, e.g. a C1-C4 alkyl or alkylene moiety and is intended to encompass also the alkyl or alkylene portion of any functional group, e.g. an alkoxy, alkylamino or carboxypolyoxyalkylene group. Thus, for example, any alkyl in an alkoxy or alkylamino group according to the invention is a C1-C6 alkyl group, e.g. a C1-C4 alkyl group.

#Also, any alkyl or alkylene group according to the invention may be branched or unbranched.