CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application is the National Stage entry under 35 U.S.C. § 371 of International Application Number PCT/IB2019/056114 filed on Jul. 17, 2019, published on Jan. 23, 2020 under publication number WO 2020/016801 A1, which claims the benefit of priority under 35 U.S.C. § 119 of Italian patent application no. 102018000007265 filed on Jul. 17, 2018, the entire disclosure of which is incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to isoxazole derivatives and their uses, in particular in the treatment and/or prevention of FXR mediated diseases.

BACKGROUND OF THE INVENTION

Farnesoid X receptor (FXR, also known as BAR, NR1H4) is a ligand-dependent transcription factor and belongs to the super-family of nuclear hormone receptors.

Highly expressed in entero-hepatic tissues (liver and intestine), FXR regulates bile acid homeostasis, lipoprotein, glucose metabolism, liver regeneration and cardiovascular disorders (Mangelsdorf, D. J. et al. Cell 1995, 83; 835; Forman, B. M. et al. Cell 1995, 81, 687; Makishima, M. et al. Science 1999, 284, 1362; Parks, D. J. et al. Science 1999, 284, 1365; Wang, H. et al. Mol. Cell 1999, 3, 543; Kuipers, F. et al. Rev. Endocr. Metab. Disord. 2004, 5,319; Zhang et al. Proc. Natl. Acad. Sci. USA 2006, 103, 1006; Matsubara, T. et al. Mol. Cell. Endocrinol. 2013, 368, 17; Claudel, T. et al. Arterioscler. Thromb. Vasc. Biol. 2005, 25, 2020). Specific bile acids bind and activate FXR, the most potent being chenodeoxycholic acid (CDCA), which is an endogenous ligand of FXR and the primary bile acid found in human bile.

In recent years, various potent and selective FXR agonists have been reported, belonging to steroidal and non-steroidal chemical classes, such as 6-ECDCA, GW4064 and Fexaramine. However, several side effects result from advanced clinical trials with dis-regulation in serum lipids observed in patients with diabetes and liver steatosis (Fiorucci S. et al. Expert Opin. Ther. Targets 2014, 18, 1449-59).

In the context of non-steroidal ligand, GW4064 represents a milestone in the field of isoxazole-type FXR agonists.

Indeed, GW4064 showed limited intestinal absorption (<10%) in rats after oral administration, exhibiting a short terminal half-life. Furthermore, the widely delocalized n-electron system in the stilbene moiety is responsible for its UV light instability therefore GW4064 has a potential cell toxicity.

DISCLOSURE OF INVENTION

The object of the present invention is the identification of novel compounds that act as FXR agonists with improved pharmacokinetic properties compared to GW4064.

Said object is achieved by the present invention, relative to selective FXR agonists containing the isoxazole chemical scaffold of claim1, to a pharmaceutical composition of claim5, to the uses of claims6and7. Preferred embodiments are set out within the dependent claims.

