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Name N-(3,4-Methylenedioxiphenylmethyl) -4 – (benzofuro [3,2-d] pyrimidin-4-yl) piperazine-1-carbothioamide.
CAS 850879-09-3
Formula 23 H 21 N 5 O 3 S
MW 447.51
Synonim MN-470, SGI-0470-03

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.

Scheme 1

Figure imgf000034_0001

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:


Figure imgf000104_0001

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

Figure imgf000106_0001


Figure imgf000107_0001

Scheme 1

Figure imgf000108_0001

Scheme 2 Scheme 3

,-NH2 /N Cl S

Figure imgf000108_0002

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.


Figure imgf000109_0001

(Ill- 1-3)

Information about this agent

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 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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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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