AMUVATINIB

AMUVATINIB

Amuvatinib (MP-470) is an orally bioavailable synthetic carbothioamide with potential antineoplastic activity. Multitargeted receptor tyrosine kinase inhibitor MP470 binds to mutant forms of the stem cell factor receptor (c-Kit; SCFR), inhibiting clinically relevant mutants of this receptor tyrosine kinase that may be associated with resistance to therapy. In addition, MP470 inhibits activities of other receptor tyrosine kinases, such as c-Met, Ret oncoprotein, and mutant forms of Flt3 and PDGFR alpha, which are frequently dysregulated in variety of tumors. This agent also suppresses the induction of DNA repair protein Rad51, thereby potentiating the activities of DNA damage-inducing agents. Mutant forms of c-Kit are often associated with tumor chemoresistance.

http://www.google.co.in/patents/EP1678166A2?cl=en

Scheme 1

EXAMPLE 34 Synthesis and Analysis of Further Illustrative Compounds Compound (111-1-3), also referred to herein as HPK56/MP-470, is an illustrative compound of the present invention having the following structure:

 

Analogues of (111-1 -3) were designed and synthesized in order to evaluate and optimize kinase selectivity, aqueous solubility, and to improve pharmacokinetic and pharmacodynamic profiles. Illustrative synthesis approaches for generating (111-1 -3) analogues are depicted in the synthesis schemes below. Synthesis of R-i substituted benzofuranopyrimidines was undertaken. The methyl 3-guanidinobenzofuran-2-carboxylate is prepared from methyl 3-aminobenzofuran-2-carboxylate by reacting with cyanoacetamide in presence of dioxane and dry HCI gas. The obtained guanidine is cyclized in the presence of aqueous NaOH. Similar procedures were utilized for preparing 2- substituted (111-1-3) and its analogues as depicted in the Schemes 8-10 set forth below. Introduction of -NH₂ at the 2 position was utilized for various sulfonic, inorganic and hydroxyacid salts. Illustrative compounds are shown in Table 4 below.Table 4

 

Scheme 1 

Scheme 2 Scheme 3

,-NH_{2 /}N Cl S

EXAMPLE 35 Analysis of Compound Binding and Inhibitory Activity against c-kit Mutants

The published crystal structure of c-kit kinase (pdb code:1 PKG) and its mutated structure were used to study the mode of binding of compound (111-1-3) (HPK56/MP-470), a benzofuranopyrimidine compound, its 2-substituted analogs, and quinazoline derivatives.

 

(Ill- 1-3)

According to news published on 15 Apr 2008;  Research data build upon previous results showing that MP-470 exhibits anti-tumor activity in breast and http://www.medicalnewstoday.com/articles/150086.php”>prostate cancer cells. The fact that MP-470 in combination with erlotinib effectively suppressed the HER pathway suggests that concurrent administration of both compounds could represent a new treatment for prostate and breast cancers.

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