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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

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 29 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 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 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 29 year tenure till date Aug 2016, Around 30 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, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , 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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An insight into the therapeutic potential of quinazoline derivatives as anticancer agents


The Food and Drug Administration (FDA) has approved several quinazoline derivatives for clinical use as anticancer drugs. These include gefitinib, erlotinib, lapatinib, afatinib, and vandetanib (Fig.1) [43]. Gefitinib (Iressa®) was approved by the FDA in 2003 for the treatment of locally advanced or metastatic non-small-cell lung cancer (NSCLC) in patients after failure of both platinum-based and/or docetaxel chemotherapies. In 2004, erlotinib (Tarceva®) was approved by the FDA for treating NSCLC. Furthermore, in 2005, the FDA approved erlotinib in combination with gemcitabine for treatment of locally advanced, unrespectable, or metastatic pancreatic cancer. Erlotinib acts as a reversible tyrosine kinase inhibitor. Lapatinib (Tykreb®) was approved by the FDA in 2012 for breast cancer treatment. It inhibits the activity of both human epidermal growth factor receptor-2 (HER2/neu) and epidermal growth factor receptor (EGFR) pathways. Vandetanib (Caprelsa®) was approved by the FDA in 2011 for the treatment of metastatic medullary thyroid cancer. It acts as a kinase inhibitor of a number of cell receptors, mainly the vascular endothelial growth factor receptor (VEGFR), EGFR, and rearranged during transfection (RET)-tyrosine kinase (TK). Afatinib (Gilotrif®) was approved by the FDA in 2013 for NSCLC treatment. It acts as an irreversible covalent inhibitor of the receptor tyrosine kinases (RTK) for EGFR and erbB-2 (HER2).

An insight into the therapeutic potential of quinazoline derivatives as anticancer agents

*Corresponding authors

Abstract

Cancer is one of the major causes of worldwide human mortality. A wide range of cytotoxic drugs are available on the market, and several compounds are in different phases of clinical trials. Many studies suggest that these cytotoxic molecules are also associated with different types of adverse side effects; therefore researchers around the globe are involved in the development of more efficient and safer anticancer drugs. In recent years, quinazoline and its derivatives have been considered as a novel class of cancer chemotherapeutic agents that show promising activity against different tumors. The aim of this article is to comprehensively review and highlight the recent developments concerning the anticancer activity of quinazoline derivatives as well as offer perspectives on the development of novel quinazoline derivatives as anticancer agents in the near future.

http://pubs.rsc.org/en/Content/ArticleLanding/2017/MD/C7MD00097A?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FMD+%28RSC+-+Med.+Chem.+Commun.+latest+articles%29#!divAbstract

An insight into the therapeutic potential of quinazoline derivatives as anticancer agents

Med. Chem. Commun., 2017, Advance Article
DOI: 10.1039/C7MD00097A, Review Article
Shagufta, Irshad Ahmad
This article reviews the recent advances in the development of quinazoline derivatives as anticancer agents.
American University of Ras Al Khaimah UAE

Dr. Shagufta Waseem

ASSISTANT PROFESSOR – CHEMISTRY

Office No.: C42
Phone: Tel. Ext. 1331
str1
Biography

Dr. Shagufta joined the American University of Ras Al Khaimah as an Assistant Professor of Chemistry in the School of Arts and Sciences in August 2014. Prior to joining AURAK, Dr. Shagufta worked as an Adjunct Assistant Professor of Chemistry at the University of Modern Sciences, Dubai and American University of Ras Al Khaimah, UAE.

Dr. Shagufta also worked as a Postdoctoral Researcher Associate at the Department of Chemistry and Biochemistry, Oklahoma University, USA. She developed the noble drug delivery system for breast cancer drugs using carbon nanotubes and acquired the significant experience in nanotechnology and synthetic organic chemistry. She was appointed as a Postdoctoral Research Fellow and Visiting Scientist at Leiden/Amsterdam Centre for Drug Research (LACDR), Leiden, The Netherlands. Her research interest was In silico prediction and clinical evaluation of the cardiotoxicity of drug candidates. She was focused to identify chemical substructures as ‘chemical alerts’ that interact with this hERG channel.  Dr. Shagufta received a Ph.D. under the prestigious CSIR-JRF and SRF research fellowship in Chemistry from Central Drug Research Institute (CDRI)/Lucknow University, India in 2008, her PhD research work was in the field of estrogens and antiestrogens, design and synthesis of steroidal and non-steroidal tissue selective estrogen receptor modulators (SERMs) for breast cancer, 3D-QSAR CoMFA and CoMSIA studies and analysis of pharmaceutical important molecules.

Dr. Shagufta has published 20 articles in peer-reviewed International journals of Royal Society of Chemistry, Elsevier, Wiley and Springer. Dr. Shagufta teaches courses such as General chemistry, Organic Chemistry, Chemistry in Everyday Life, and Spectroscopy along with laboratory courses.

Research and Publication

Research Interest-Dr. Shagufta 

Organic Chemistry, Medicinal Chemistry focused on Breast Cancer and Osteoporosis, Heterogeneous catalysis and Nanotechnology.

Publications- Dr. Shagufta 

  1. Irshad Ahmad and Shagufta. 2015. Recent developments in steroidal and nonsteroidal aromatase inhibitors for the chemoprevention of estrogen-dependent breast cancer. European Journal of Medicinal Chemistry, 102, 375-386.
  1. Irshad Ahmad and Shagufta. 2015. Sulfones: An important class of organic compounds with diverse biological activities. International Journal of Pharmacy and Pharmaceutical Sciences, 7 (3), 19-27.
  1. Priyanka Singh, Subal Kumar Dinda, Shagufta, Gautam Panda. 2013. Synthetic approach towards trisubstituted methanes and a chiral tertiary α-hydroxyaldehyde, possible intermediate for tetrasubstituted methanes. RSC Adv.(Royal Society of Chemistry) 3, 12100-12103. [ISSN: 2046-2069] 
  1. Donna J. Nelson, Shagufta, Ravi Kumar. 2012. Characterization of a tamoxifen-tethered single-walled carbon nanotube conjugate by using NMR spectroscopy. Anal. Bioanal. Chem.[Springer] 404:771–776. [ISSN: 1618-2642]
  1. Donna J. Nelson, Ravi Kumar, Shagufta. 2012. Regiochemical reversals in nitrosobenzene reactions with carbonyl compounds – α-aminooxy ketone versus α-hydroxyamino ketone products. Eur. J. Org. Chem.(Wiley-VCH) 6013-6020. [ISSN: 1099-0690]
  1. Munikumar R. Reddy, Elisabeth Klaasse, Shagufta, Adriaan P. IJzerman, Andreas Bender. 2010. Validation of an in silico hERG model and its applications to the virtual screening of commercial compound databases. Chem. Med. Chem. (Wiley-VCH)5: 716-729. [ISSN: 1860-7187] 
  1. Shagufta, Dong Guo, Elisabeth Klaasse, Henk de Vries, Johannes Brussee, Lukas Nalos, Martin B Rook, Marc A Vos, Marcel AG van der Heyden and Adriaan P. IJzerman. 2009. Exploring the chemical substructures essential for hERG K+ channel blockade by synthesis and biological evaluation of dofetilide analogues. Chem. Med. Chem.(Wiley-VCH) 4:1722-1732. [ISSN: 1860-7187]
  1. Shagufta, Ritesh Singh and Gautam Panda. 2009, Synthetic studies towards steroid-amino acid hybrids. Indian Journal of Chemistry.(Indian Science) 48B: 989-995. [ISSN: 0975-0983]
  1. Maloy K. Parai, Shagufta, Ajay K. Srivastava, Matthias Kassack, Gautam Panda. 2008. An unexpected reaction of phosphorous tribromide on chromanone, thiochromanone, 3,4-dihydro-2H-benzo[b]thiepin-5-one, 3,4-dihydro-2H-benzo[b]oxepin-5-one and tetralone derived allylic alcohols: a case study. Tetrahedron (Elsevier)64: 9962-9976. [ISSN: 0040-4020]
  1. Gautam Panda, Maloy Kumar Parai, Sajal Kumar Das, Shagufta, Manish Sinha, Vinita Chaturvedi, Anil K. Srivastava, Anil N. Gaikwad, Sudhir Sinha. 2007. Effect of substituents on diarymethanes for antitubercular activity. European Journal of Medicinal Chemistry (Elsevier) 42: 410-419. [ISSN: 0223-5234]
  1. Shagufta and Gautam Panda. 2007. A new example of a steroid-amino acid hybrid: Construction of constrained nine membered D-ring steroids. Organic and Biomolecular Chemistry (Royal Society of Chemistry) 5 : 360- 366. [ISSN 1477-0539]
  1. Shagufta, Ashutosh Kumar, Gautam Panda and Mohammad Imran Siddiqi. 2007. CoMFA and CoMSIA 3D-QSAR analysis of diaryloxy methano phenanthrene derivatives as anti- tubercular agents. Journal of Molecular Modeling (Springer) 13: 99-107. [ISSN:0948-5023]
  1. Shagufta, Ajay Kumar Srivastava, Ramesh Sharma, Rajeev Mishra, Anil K. Balapure, Puvvada S. R. Murthy and Gautam Panda. 2006. Substituted phenanthrenes with basic amino side chains: A new series of anti-breast cancer agents. Bioorganic and Medicinal Chemistry (Elsevier) 14: 1497-1505. [ISSN: 0968-0896]
  1. Shagufta, Ajay Kumar Srivastava and Gautam Panda. 2006. Isomerization of allylic alcohols into saturated carbonyls using phosphorus tribromide. Tetrahedron Letters (Elsevier) 47: 1065-1070. [ISSN: 0040-4039]
  1. Gautam Panda, Jitendra K. Mishra, Shagufta, T. C. Dinadayalane and G. Narahari Sastry & Devendra S Negi. 2006. Hard-soft acid-base (HSAB) principle and difference in d-orbital configurations of metals explain the regioselectivity of nucleophilic attack to a carbinol in Friedel-Crafts reaction catalyzed by Lewis and protonic acids. Indian Journal of Chemistry (Indian Science)45B: 276-287. [ISSN: 0975-0983]
  1. Shagufta, Maloy Kumar Parai and Gautam Panda. 2005. A new strategy for the synthesis of aryl- and heteroaryl-substituted exocyclic olefins from allyl alcohols using PBr3. Terahedron Letters (Elsevier) 46: 8849-8852. [ISSN: 0040-4039]
  1. Shagufta, Resmi Raghunandan, Prakash R. Maulik and Gautam Panda. 2005. Convenient phosphorus tribromide induced syntheses of substituted 1-arylmethylnaphthalenes from 1-tetralone derivatives. Tetrahedron Letters (Elsevier) 46: 5337-5341. [ISSN: 0040-4039]
  1. Gautam Panda, Shagufta, Anil K. Srivastava and Sudhir Sinha. 2005. Synthesis and antitubercular activity of 2-hydroxy-aminoalkyl derivatives of diaryloxy methano phenanthrenes. Bioorganic and Medicinal Chemistry Letters (Elsevier) 15: 5222-5225. [ISSN: 0960-894X]
  1. Sajal Kumar Das, Shagufta, and Gautam Panda. 2005. An easy access to unsymmetric trisubstituted methane derivatives (TRSMs). Tetrahedron Letters (Elsevier) 46: 3097-3102. [ISSN: 0040-4039]
  1. Shagufta, Jitendra Kumar Mishra, Vinita Chaturvedi, Anil K. Srivastava, Ranjana Srivastava and Brahm S. Srivastava. 2004. Diaryloxy methano phenanthrenes: a new class of antituberculosis agents. Bioorganic and Medicinal Chemistry (Elsevier) 12: 5269-5276. [ISSN: 0968-0896]

Dr. Irshad Ahmad

ASSOCIATE PROFESSOR – CHEMISTRY

Office No.: C21
Phone: Tel. Ext. 1270
Biography

Dr. Irshad Ahmad joined the American University of Ras Al Khaimah in spring 2011 as an Assistant Professor of Chemistry. He received the master’s degree in chemistry from Jiwaji University in 1999. Subsequently acquired significant pharmaceutical industrial experience and developed cardio-selective beta-blocker drug molecule. He joined Central Salt and Marine Chemical Research Institute and Bhavnagar University under the sponsored project of DST and CSIR as a senior research fellow and received his PhD degree in chemistry in 2006. Subsequently, he accepted an invited scientist position in Korea Research Institute of Chemical Technology, South Korea and contributed his expertise in the field of Nanotechnology. Dr. Irshad is a recipient of prestigious European fellowships (NWO-Rubicon & FCT) and he joined Van’t Hoff Institute for Molecular Sciences, University of Amsterdam, The Netherlands as a NWO Rubicon fellow (Netherlands Organization for Scientific Research, the Dutch Science Foundation), he acquired expertise in the field of supramolecular chemistry.

Afterward, he moved to the Leibniz Institute for Surface Modification, Leipzig, Germany under the Deutsche Forschungsgemeinschaft Grant. Dr. Irshad developed “Novel ultra-fast metathesis catalyst” for the production of high quality alternating copolymers. Subsequently Dr. Irshad, joined Department of Chemistry and Biochemistry, Stephenson Life Science Research Center, University of Oklahoma, USA as a postdoctoral research associate.  He developed strategies for the novel environmentally friendly reactions for the production of value added chemicals from biomass.

Dr. Irshad specialized in the area of chemistry, bridging the traditional disciplines of inorganic, organic and bio-organic chemistry. He contributed US and European patent for green and clean technology development. He has published peer-reviewed international research articles in the American Chemical Society (ACS), Royal Society of Chemistry (RSC) Cambridge, Elsevier Science, Wiley, and Springer journals. He has presented his research at several scientific conferences worldwide and received awards.

Research and Publication

Research Interest:

Asymmetric catalysis, Biotechnology, Metathesis, Material science, Nanotechnology, Pharmaceutical, Renewable energy and Supramolecular chemistry

Book:

Asymmetric Homogeneous and Heterogeneous Catalysts: An Approach to the Synthesis of Chiral Drug Intermediates by Scholars Press, Germany. 2013, ISBN: 978-3-639-51138-3

Membership:   

  • American Chemical Society (ACS), USA
  • The Royal Society of Chemistry, Cambridge, UK

Patents:

  • United States Patent 7,235,676, H. Khan, S. H. R. Abdi, R. I. Kureshy, S. Singh, I. Ahmad, R. V. Jasra, P. K. Ghosh, ‘Catalytic process for the preparation of epoxides from alkenes.
  • Patent Cooperation Treaty (PCT) WO/2005/095370, N. H. Khan, S. H. R. Abdi, R. I. Kureshy, S. Singh, I. Ahmad, R. V. Jasra, P. K. Ghosh. An improved catalytic process for the preparation of epoxides from alkenes.
  • European Patent EP 1732910 A1, N. H. Khan, S. H. R. Abdi, R. I. Kureshy, S. SinghA, I. Ahmad, R. V. Jasra, P. K. Ghosh, An improved catalytic process for the preparation of epoxides from alkenes. 

Publications:

  • Pramoda, U. Gupta, I. Ahmad, R. Kumar, C.N.R. Rao, Assemblies of Covalently Cross-linked Nanosheets of MoS2 and of MoS2-RGO: Synthesis and Novel Properties, Journal of Materials Chemistry A, 4, 2016, 8989.
  • Shagufta, I. Ahmad, Recent insight into the biological activities of synthetic xanthone derivatives, European Journal of Medicinal Chemistry, 116, 2016, 267.
  • Ahmad, Shagufta, Recent Development in Steroidal and Non-steroidal Aromatase Inhibitors for the Chemoprevention of Estrogen dependent Breast Cancer, European Journal of Medicinal Chemistry, 102, 2015, 375.
  • Ahmad, Shagufta, Sulfones: An important class of organic compounds with diverse biological activities, International Journal of Pharmacy and Pharmaceutical Sciences, 7, 3, 2015, 19.
  • Kumar, K. Gopalakrishnan, I. Ahmad, and C. N. R. Rao, BN-Graphene Composites Generated by Covalent Cross-Linking with Organic Linkers, Advanced Functional Materials, 25, 37, 2015, 5910.
  • Kumar, D. Raut, I. Ahmad,   U. Ramamurty,   T. K. Maji and   C. N. R. Rao. Functionality preservation with enhanced mechanical integrity in the nanocomposites of the metal–organic framework, ZIF-8, with BN nanosheets, Materials Horizons, 1, 2014, 513.
  • R. Buchmeiser, I. Ahmad, V. Gurram and P. S. Kumar, Pseudo-Halide and Nitrate Derivatives of Grubbs and Grubbs_Hoveyda Initiators: Some Structural Features Related to the Alternating Ring-Opening Metathesis Copolymerization of Norborn-2-ene with Cyclic Olefins, Macromolecule, 44 (11), 2011, 4098.
  • Ahmad, G. Chapman and K. M. Nicholas, Sulfite-Driven, Oxorhenium-Catalyzed Deoxydehydration of Glycols, Organometallics, 30 (10), 2011, 2810.
  • Vkuturi, G. Chapman, I. Ahmad, K. M. Nicholas, Rhenium-Catalyzed Deoxydehydration of Glycols by Sulfite, Inorganic Chemistry, 49, 2010, 4744.
  • I. Kureshy, I. Ahmad, K. Pathak, N. H. Khan, S. H. R. Abdi, H. C. Bajaj, Solvent- free microwave synthesis of aryloxypropanolamines by ring opening of aryloxy epoxides, Research Letters in Organic Chemistry, 2009, Article ID 109717, doi:10.1155/2009/109717.
  • I. Kureshy, I. Ahmad, K. Pathak, N. H. Khan, S. H. R. Abdi, R. V. Jasra, Sulfonic acid functionalized mesoporous SBA-15 as an efficient and recyclable catalyst for the synthesis of chromenes from chromanols, Catalysis Communications 10, 2009, 572.
  • Pathak, I. Ahmad, S. H. R. Abdi, R. I. Kureshy, N. H. Khan, R. V. Jasra, The synthesis of silica-supported chiral BINOL: Application in Ti-catalyzed asymmetric addition of diethylzinc to aldehydes, Journal of Molecular Catalysis A-Chemical 280, 2008, 106.
  • Kluwer, I. Ahmad, J. N. H. Reek, Improved synthesis of monodentate and bidentate 2- and 3-pyridylphosphines, Tetrahedron Letter 48, 2007, 2999.
  • Pathak, I. Ahmad, S. H. R. Abdi, R. I. Kureshy, N. H. Khan, R. V. Jasra, Oxidative Kinetic Resolution of racemic Secondary Alcohols catalyzed by recyclable Dimeric Mn(III) salen catalysts, Journal of Molecular Catalysis A-Chemical 274, 2007, 120.
  • I. Kureshy, I. Ahmad, N. H. Khan, S. H. R. Abdi, K. Pathak, R. V. Jasra, Easily Recyclable Chiral Polymeric Mn (salen) Complex for Oxidative Kinetic resolution of Racemic Secondary Alcohols, Chirality, 19, 2007, 352.
  • Pathak, A. P. Bhatt, S. H. R. Abdi, R. I. Kureshy, N. H. Khan, I. Ahmad, R. V. Jasra, Enantioselective phenylacetylene addition to aromatic aldehydes and ketones catalyzed by recyclable polymeric Zn(II) salen complex, Chirality, 19, 2007, 1.
  • I. Kureshy, I. Ahmad, N. H. Khan, S. H. R. Abdi, K. Pathak, R. V. Jasra, Chiral Mn (III) salen complexes covalently bonded on modified MCM-41 and SBA-15 as efficient catalysts for enantioselective epoxidation of non- functionalized alkenes, Journal of Catalysis A-Chemical, 238, 2006, 134.
  • Pathak, A. P. Bhatt, S. H. R. Abdi, R. I. Kureshy, N. H. Khan, I. Ahmad, R. V. Jasra Enantioselective addition of diethylzinc to aldehydes using immobilized chiral BINOL-Ti complex on ordered mesoporous silicas, Tetrahedron: Asymmetry,17, 2006, 1506.
  • I. Kureshy, I. Ahmad, N. H. Khan, S. H. R. Abdi, K. Pathak, R. V. Jasra, Encapsulation of chiral MnIII (salen) complex in ordered mesoporous silicas: An approach Towards heterogenizing asymmetric Epoxidation catalysts for non-Functionalized alkenes, Tetrahedron: Asymmetry 16, 2005, 3562.
  • I. Kureshy, I. Ahmad, N. H. Khan, S. H. R. Abdi, S. Singh, P. H. Pandia, R. V. Jasra, New immobilized chiral Mn(III) salen complexes on pyridine N-Oxide Modified MCM-41as effective catalysts for epoxidation of nonfunctionalized Alkenes, Journal of Catalysis A- Chemical 235 , 2005, 28.
  • Pathak, A. P. Bhatt, S. H. R. Abdi, R. I. Kureshy, N. H. Khan, I. Ahmad, R. V. Jasra Enantioselective addition of diethylzinc to aldehydes using immobilized chiral BINOL-Ti complex on ordered mesoporous silicas, Tetrahedron: Asymmetry,17, 2006, 1506.
  • I. Kureshy, S. Singh, N. H. Khan, S. H. R. Abdi, I. Ahmad, A. Bhatt, R. V. Jasra, Improved catalytic activity of homochiral dimeric cobalt salen hydrolytic kinetic resolution of terminal racemic epoxides, Chirality, 17, 2005, 1.
  • I. Kureshy, S. Singh, N. H. Khan, S. H. R. Abdi , I. Ahmad, .Bhatt, R. V. Jasra, Environment friendly protocol for enantioselective epoxidation of non-functionalized Alkenes catalyzed by recyclable homochiral dimeric Mn(III)salen complexes with hydrogen peroxide and UHP adduct as Oxidants, Catalysis Letters, 107, 2005, 127.
  • I. Kureshy, N. H. Khan, S. H. R. Abdi, I. Ahmad, S. Singh, and R. V. Jasra, Dicationic chiral Mn (III) Salen complex exchange in the interlayers of Montmorillonite clay: a heterogeneous enantioselective catalyst for epoxidation of non-functionalised alkenes, Journal of Catalysis, 221, 2004, 234.
  • I. Kureshy, N. H. Khan, S. H. R. Abdi, S. Singh, I. Ahmad, R. V. Jasra, Catalytic asymmetric epoxidation of non-functionalised alkenes using polymeric Mn(III)Salen as catalysts and NaOCl as oxidant, Journal of Molecular Catalysis A-Chemical, 218, 2004, 141.
  • I. Kureshy, N.H. Khan, S.H. R. Abdi, A. P. Vyas, I. Ahmad, S. Singh, R. V. Jasra, Enantioselective Epoxidation of Non-Functionalised Alkenes catalysed by recyclable new Homo Chiral Dimeric Mn(III) Salen complexes, Journal of Catalysis, 224, 2004, 229.
  • I. Kureshy, N. H. Khan, S. H. R. Abdi, I. Ahmad, S. Singh, and R. V. Jasra, Immobilization of dicationic Mn(III) salen in the interlayers of montmorrillonite Clay for enantioselective epoxidation of non-functionalised alkenes, Catalysis Letters, 91, 2003, 207.

Selected International Events:

  • Applied Nanotechnology and Nanoscience International Conference (ANNIC), November 9-11, 2016, Barcelona, SPAIN.
  • 2nd International Conference on Smart Material Research (ICSMR), September 22-24, 2016, Istanbul, TURKEY.
  • Emirates Foundation’s Think Science Competition, April 17-19, 2016, World Trade Center, Dubai, UAE.
  • SSL Visiting Fellow 2013-15 at the International Centre for Materials Science, JNCASR, SSL, Bangalore, INDIA.
  • Global Conference on Materials Sciences (GC-MAS-2014), November 13-15, 2014, Antalya, TURKEY.
  • 5th Annual International Workshop on Advanced Material (IWAM 2013), organized by Ras Al Khaimah Center for Advance Materials (RAK CAM), Feb. 24-26, 2013 at Al Hamra Fort Hotel, Ras Al Khaimah, UAE.
  • Internal Quality Assurance in Higher Education Institutions workshop organized by the Commission for Academic Accreditation (CAA)- 2nd May 2011, Alghurair University campus, Dubai, UAE.
  • 45th American Chemical Society (ACS) Midwest Regional meeting, Oct. 27-30, 2010, Wichita, Kansas, USA.
  • 55th Annual American Chemical Society (ACS) PentaSectional Meeting- Biofuel, April 10, 2010, organized by American Chemical Society (ACS), Norman, Oklahoma, USA.
  • 18th International Symposium on Olefin Metathesis and Related Chemistry (ISOM XVIII), Organized by the Leibniz-Institute for Surface modification (IOM), August 2-7, 2009, Leipzig, GERMANY.
  • 16th International Symposium on Homogeneous Catalysis (ISHC-XVI), July 6-11, 2008, Organized by the Institute of Chemistry of Organometallic Compounds (ICCOM) of the Italian Research Council (CNR) held in Florence, ITALY.
  • European IDECAT Summer School on Computational Methods for Catalysis and Materials Science, 15-22 September 2007, Porquerolles, FRANCE.
  • 8th Netherland’s Catalysis and Chemistry Conference (NCCC), March 5-7, 2007, Noordwijkerhout, The NETHERLANDS.
  • 7th International Symposium on Catalysis Applied to Fine Chemicals organized by German Catalysis Society and Dechema. Oct 23-27, 2005, Bingen -Mainz, GERMANY.
  • 1st Indo- German Conference on Catalysis-A Cross Disciplinary Vision, February 6-8, 2003, Indian Institute of Chemical Technology (IICT), Hyderabad, INDIA.
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Novartis Kisqali® (ribociclib, LEE011) receives FDA approval as first-line treatment for HR+/HER2- metastatic breast cancer in combination with any aromatase inhibitor


Novartis logo: a global healthcare company

  • Approved based on a first-line Phase III trial that met its primary endpoint of progression-free survival (PFS) at interim analysis due to superior efficacy compared to letrozole alone[1]
  • At this interim analysis, Kisqali plus letrozole reduced risk of disease progression or death by 44% over letrozole alone, and demonstrated tumor burden reduction with a 53% overall response rate[1]
  • Kisqali plus letrozole showed treatment benefit across all patient subgroups regardless of disease burden or tumor location[1]
  • At a subsequent analysis with additional follow-up and progression events, a median PFS of 25.3 months for Kisqali plus letrozole and 16.0 months for letrozole alone was observed[2]

Basel, March 13, 2017 The US Food and Drug Administration (FDA) has approved Kisqali®(ribociclib, formerly known as LEE011) in combination with an aromatase inhibitor as initial endocrine-based therapy for treatment of postmenopausal women with hormone receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced or metastatic breast cancer.

Kisqali is a CDK4/6 inhibitor approved based on a first-line Phase III trial that met its primary endpoint early, demonstrating statistically significant improvement in progression-free survival (PFS) compared to letrozole alone at the first pre-planned interim analysis[1]. Kisqali was reviewed and approved under the FDA Breakthrough Therapy designation and Priority Review programs.

“Kisqali is emblematic of the innovation that Novartis continues to bring forward for people with HR+/HER2- metastatic breast cancer,” said Bruno Strigini, CEO, Novartis Oncology. “We at Novartis are proud of the comprehensive clinical program for Kisqali that has led to today’s approval and the new hope this medicine represents for patients and their families.”

The FDA approval is based on the superior efficacy and demonstrated safety of Kisqali plus letrozole versus letrozole alone in the pivotal Phase III MONALEESA-2 trial. The trial, which enrolled 668 postmenopausal women with HR+/HER2- advanced or metastatic breast cancer who received no prior systemic therapy for their advanced breast cancer, showed that Kisqali plus an aromatase inhibitor, letrozole, reduced the risk of progression or death by 44 percent over letrozole alone (median PFS not reached (95% CI: 19.3 months-not reached) vs. 14.7 months (95% CI: 13.0-16.5 months); HR=0.556 (95% CI: 0.429-0.720); p<0.0001)[1].

More than half of patients taking Kisqali plus letrozole remained alive and progression free at the time of interim analysis, therefore median PFS could not be determined[1]. At a subsequent analysis with additional 11-month follow-up and progression events, a median PFS of 25.3 months for Kisqali plus letrozole and 16.0 months for letrozole alone was observed[2]. Overall survival data is not yet mature and will be available at a later date.

“In the MONALEESA-2 trial, ribociclib plus letrozole reduced the risk of disease progression or death by 44 percent over letrozole alone, and more than half of patients (53%) with measurable disease taking ribociclib plus letrozole experienced a tumor burden reduction of at least 30 percent. This is a significant result for women with this serious form of breast cancer,” said Gabriel N. Hortobagyi, MD, Professor of Medicine, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center and MONALEESA-2 Principal Investigator. “These results affirm that combination therapy with a CDK4/6 inhibitor like ribociclib and an aromatase inhibitor should be a new standard of care for initial treatment of HR+ advanced breast cancer.”

Kisqali is taken with or without food as a once-daily oral dose of 600 mg (three 200 mg tablets) for three weeks, followed by one week off treatment. Kisqali is taken in combination with four weeks of any aromatase inhibitor[1].

Breast cancer is the second most common cancer in American women[3]. The American Cancer Society estimates more than 250,000 women will be diagnosed with invasive breast cancer in 2017[3]. Up to one-third of patients with early-stage breast cancer will subsequently develop metastatic disease[4].

Novartis is committed to providing patients with access to medicines, as well as resources and support to address a range of needs. The Kisqali patient support program is available to help guide eligible patients through the various aspects of getting started on treatment, from providing educational information to helping them understand their insurance coverage and identify potential financial assistance options. For more information, patients and healthcare professionals can call 1-800-282-7630.

The full prescribing information for Kisqali can be found at https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/kisqali.pdf(link is external).

About Kisqali® (ribociclib)
Kisqali (ribociclib) is a selective cyclin-dependent kinase inhibitor, a class of drugs that help slow the progression of cancer by inhibiting two proteins called cyclin-dependent kinase 4 and 6 (CDK4/6). These proteins, when over-activated, can enable cancer cells to grow and divide too quickly. Targeting CDK4/6 with enhanced precision may play a role in ensuring that cancer cells do not continue to replicate uncontrollably.

Kisqali was developed by the Novartis Institutes for BioMedical Research (NIBR) under a research collaboration with Astex Pharmaceuticals.

About the MONALEESA Clinical Trial Program
Novartis is continuing to assess Kisqali through the robust MONALEESA clinical trial program, which includes two additional Phase III trials, MONALEESA-3 and MONALEESA-7, that are evaluating Kisqali in multiple endocrine therapy combinations across a broad range of patients, including premenopausal women. MONALEESA-3 is evaluating Kisqali in combination with fulvestrant compared to fulvestrant alone in postmenopausal women with HR+/HER2- advanced breast cancer who have received no or a maximum of one prior endocrine therapy. MONALEESA-7 is investigating Kisqali in combination with endocrine therapy and goserelin compared to endocrine therapy and goserelin alone in premenopausal women with HR+/HER2- advanced breast cancer who have not previously received endocrine therapy.

About Novartis in Advanced Breast Cancer
For more than 25 years, Novartis has been at the forefront of driving scientific advancements for breast cancer patients and improving clinical practice in collaboration with the global community. With one of the most diverse breast cancer pipelines and the largest number of breast cancer compounds in development, Novartis leads the industry in discovery of new therapies and combinations, especially in HR+ advanced breast cancer, the most common form of the disease.

Kisqali® (ribociclib) Important Safety Information
Kisqali® (ribociclib) can cause a heart problem known as QT prolongation. This condition can cause an abnormal heartbeat and may lead to death. Patients should tell their healthcare provider right away if they have a change in their heartbeat (a fast or irregular heartbeat), or if they feel dizzy or faint. Kisqali can cause serious liver problems. Patients should tell their healthcare provider right away if they get any of the following signs and symptoms of liver problems: yellowing of the skin or the whites of the eyes (jaundice), dark or brown (tea-colored) urine, feeling very tired, loss of appetite, pain on the upper right side of the stomach area (abdomen), and bleeding or bruising more easily than normal. Low white blood cell counts are very common when taking Kisqali and may result in infections that may be severe. Patients should tell their healthcare provider right away if they have signs and symptoms of low white blood cell counts or infections such as fever and chills. Before taking Kisqali, patients should tell their healthcare provider if they are pregnant, or plan to become pregnant as Kisqali can harm an unborn baby. Females who are able to become pregnant and who take Kisqali should use effective birth control during treatment and for at least 3 weeks after the last dose of Kisqali. Do not breastfeed during treatment with Kisqali and for at least 3 weeks after the last dose of Kisqali. Patients should tell their healthcare provider about all of the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements since they may interact with Kisqali. Patients should avoid pomegranate or pomegranate juice, and grapefruit or grapefruit juice while taking Kisqali. The most common side effects (incidence >=20%) of Kisqali when used with letrozole include white blood cell count decreases, nausea, tiredness, diarrhea, hair thinning or hair loss, vomiting, constipation, headache, and back pain. The most common grade 3/4 side effects in the Kisqali + letrozole arm (incidence >2%) were low neutrophils, low leukocytes, abnormal liver function tests, low lymphocytes, and vomiting. Abnormalities were observed in hematology and clinical chemistry laboratory tests.

Please see the Full Prescribing Information for Kisqali, available at https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/kisqali.pdf(link is external).

About Novartis
Novartis provides innovative healthcare solutions that address the evolving needs of patients and societies. Headquartered in Basel, Switzerland, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, cost-saving generic and biosimilar pharmaceuticals and eye care. Novartis has leading positions globally in each of these areas. In 2016, the Group achieved net sales of USD 48.5 billion, while R&D throughout the Group amounted to approximately USD 9.0 billion. Novartis Group companies employ approximately 118,000 full-time-equivalent associates. Novartis products are sold in approximately 155 countries around the world. For more information, please visit http://www.novartis.com.

Novartis is on Twitter. Sign up to follow @Novartis and @NovartisCancer at http://twitter.com/novartis(link is external) and http://twitter.com/novartiscancer (link is external)
For Novartis multimedia content, please visit www.novartis.com/news/media-library
For questions about the site or required registration, please contact media.relations@novartis.com

References
[1] Kisqali (ribociclib) Prescribing information. East Hanover, New Jersey, USA: Novartis Pharmaceuticals Corporation; March 2016.
[2] Novartis Data on File
[3] American Cancer Society. How Common Is Breast Cancer? Available at https://www.cancer.org/cancer/breast-cancer/about/how-common-is-breast-cancer.html(link is external). Accessed January 23, 2017.
[4] O’Shaughnessy J. Extending survival with chemotherapy in metastatic breast cancer. The Oncologist. 2005;10(Suppl 3):20-29.

Ribociclib skeletal.svg

рибоциклиб ريبوسيكليب 瑞波西利

Ribociclib « New Drug Approvals

////////////////Novartis,  Kisqali®, ribociclib, LEE011,  FDA 2017, HR+/HER2- metastatic breast cancer, рибоциклиб ريبوسيكليب 瑞波西利

FDA grants accelerated approval to new treatment for advanced ovarian cancer , Rubraca(rucaparib)


 

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The U.S. Food and Drug Administration today granted accelerated approval to Rubraca (rucaparib) to treat women with a certain type of ovarian cancer. Rubraca is approved for women with advanced ovarian cancer who have been treated with two or more chemotherapies and whose tumors have a specific gene mutation (deleterious BRCA) as identified by an FDA-approved companion diagnostic test.

Read more.

For Immediate Release

December 19, 2016

The U.S. Food and Drug Administration today granted accelerated approval to Rubraca (rucaparib) to treat women with a certain type of ovarian cancer. Rubraca is approved for women with advanced ovarian cancer who have been treated with two or more chemotherapies and whose tumors have a specific gene mutation (deleterious BRCA) as identified by an FDA-approved companion diagnostic test.

“Today’s approval is another example of the trend we are seeing in developing targeted agents to treat cancers caused by specific mutations in a patient’s genes,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research and acting director of the FDA’s Oncology Center of Excellence. “Women with these gene abnormalities who have tried at least two chemotherapy treatments for their ovarian cancer now have an additional treatment option.”

The National Cancer Institute estimates that 22,280 women will be diagnosed with ovarian cancer in 2016 and an estimated 14,240 will die of this disease. Approximately 15 to 20 percent of patients with ovarian cancer have a BRCA gene mutation.

BRCA genes are involved with repairing damaged DNA and normally work to prevent tumor development. However, mutations of these genes may lead to certain cancers, including ovarian cancers. Rubraca is a poly ADP-ribose polymerase (PARP) inhibitor that blocks an enzyme involved in repairing damaged DNA. By blocking this enzyme, DNA inside the cancerous cells with damaged BRCA genes may be less likely to be repaired, leading to cell death and possibly a slow-down or stoppage of tumor growth.

Today, the FDA also approved the FoundationFocus CDxBRCA companion diagnostic for use with Rubraca, which is the first next-generation-sequencing (NGS)-based companion diagnostic approved by the agency. The NGS test detects the presence of deleterious BRCA gene mutations in the tumor tissue of ovarian cancer patients. If one or more of the mutations are detected, the patient may be eligible for treatment with Rubraca.

The safety and efficacy of Rubraca were studied in two, single-arm clinical trials involving 106 participants with BRCA-mutated advanced ovarian cancer who had been treated with two or more chemotherapy regimens. BRCA gene mutations were confirmed in 96 percent of tested trial participants with available tumor tissue using the FoundationFocus CDxBRCA companion diagnostic. The trials measured the percentage of participants who experienced complete or partial shrinkage of their tumors (overall response rate). Fifty-four percent of the participants who received Rubraca in the trials experienced complete or partial shrinkage of their tumors lasting a median of 9.2 months.

Common side effects of Rubraca include nausea, fatigue, vomiting, low levels of red blood cells (anemia), abdominal pain, unusual taste sensation (dysgeusia), constipation, decreased appetite, diarrhea, low levels of blood platelets (thrombocytopenia) and trouble breathing (dyspnea).  Rubraca is associated with serious risks, such as bone marrow problems (myelodysplastic syndrome), a type of cancer of the blood called acute myeloid leukemia and fetal harm.

The agency approved Rubraca under its accelerated approval program, which allows approval of a drug to treat a serious or life-threatening disease or condition based on clinical data showing the drug has an effect on a surrogate (substitute) endpoint that is reasonably likely to predict clinical benefit. The sponsor is continuing to study this drug in patients with advanced ovarian cancer who have BRCA gene mutations and in patients with other types of ovarian cancer. The FDA also granted the Rubraca application breakthrough therapy designation and priority review status. Rubraca also received orphan drug designation, which provides incentives such as tax credits, user fee waivers and eligibility for exclusivity to assist and encourage the development of drugs intended to treat rare diseases.

Rubraca is marketed by Clovis Oncology, Inc. based in Boulder, Colorado. The FoundationFocus CDxBRCA companion diagnostic is marketed by Foundation Medicine, Inc. of Cambridge, Massachusetts.

////////////Rubraca, rucaparib, Clovis Oncology, Boulder, Colorado, fda 2016, cancer, ovarian

Consumption of a bioactive compound from Neem plant could significantly suppress development of prostate cancer


(From left to right) Principal Investigator Associate Professor Gautam Sethi and NUS PhD candidate Ms Zhang Jingwen from the Department of Pharmacology at the NUS Yong Loo Lin School of Medicine led a research which found that a bioactive compound from the neem plant could significantly suppress development of prostate cancer.

Credit: National University of Singapore

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Image result for nimbolideImage result for nimbolide

Date:September 29, 2016Source:National University of SingaporeSummary:Oral administration of nimbolide, over 12 weeks shows reduction of prostate tumor size by up to 70 per cent and decrease in tumor metastasis by up to 50 per cent, report investigators.

Nimbolide.png

Nimbolide; NSC309909; NSC 309909; Methyl[8-(furan-3-yl)-2a,5a,6a,7-tetramethyl-2,5-dioxo-2a,5a,6,6a,8,9,9a,10a,10b,10c-decahydro-2h,5h-cyclopenta[d]naphtho[2,3-b:1,8-b’c’]difuran-6-yl]acetate; CCRIS 5723;

CAS 25990-37-8;
Molecular Formula: C27H30O7
Molecular Weight: 466.5229 g/mol

Oral administration of nimbolide, over 12 weeks shows reduction of prostate tumor size by up to 70 per cent and decrease in tumor metastasis by up to 50 per cent

A team of international researchers led by Associate Professor Gautam Sethi from the Department of Pharmacology at the Yong Loo Lin School of Medicine at the National University of Singapore (NUS) has found that nimbolide, a bioactive terpenoid compound derived from Azadirachta indica or more commonly known as the neem plant, could reduce the size of prostate tumor by up to 70 per cent and suppress its spread or metastasis by half.

Prostate cancer is one of the most commonly diagnosed cancers worldwide. However, currently available therapies for metastatic prostate cancer are only marginally effective. Hence, there is a need for more novel treatment alternatives and options.

“Although the diverse anti-cancer effects of nimbolide have been reported in different cancer types, its potential effects on prostate cancer initiation and progression have not been demonstrated in scientific studies. In this research, we have demonstrated that nimbolide can inhibit tumor cell viability — a cellular process that directly affects the ability of a cell to proliferate, grow, divide, or repair damaged cell components — and induce programmed cell death in prostate cancer cells,” said Assoc Prof Sethi.

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Nimbolide: promising effects on prostate cancer

Cell invasion and migration are key steps during tumor metastasis. The NUS-led study revealed that nimbolide can significantly suppress cell invasion and migration of prostate cancer cells, suggesting its ability to reduce tumor metastasis.

The researchers observed that upon the 12 weeks of administering nimbolide, the size of prostate cancer tumor was reduced by as much as 70 per cent and its metastasis decreased by about 50 per cent, without exhibiting any significant adverse effects.

“This is possible because a direct target of nimbolide in prostate cancer is glutathione reductase, an enzyme which is responsible for maintaining the antioxidant system that regulates the STAT3 gene in the body. The activation of the STAT3 gene has been reported to contribute to prostate tumor growth and metastasis,” explained Assoc Prof Sethi. “We have found that nimbolide can substantially inhibit STAT3 activation and thereby abrogating the growth and metastasis of prostate tumor,” he added.

The findings of the study were published in the April 2016 issue of the scientific journal Antioxidants & Redox Signaling. This work was carried out in collaboration with Professor Goh Boon Cher of Cancer Science Institute of Singapore at NUS, Professor Hui Kam Man of National Cancer Centre Singapore and Professor Ahn Kwang Seok of Kyung Hee University.

Neem — The medicinal plant

The neem plant belongs to the mahogany tree family that is originally native to India and the Indian sub-continent. It has been part of traditional Asian medicine for centuries and is typically used in Indian Ayurvedic medicine. Today, neem leaves and bark have been incorporated into many personal care products such as soaps, toothpaste, skincare and even dietary supplements.

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Future Research

The team is looking to embark on a genome-wide screening or to perform a large-scale study of proteins to analyse the side-effects and determine other potential molecular targets of nimbolide. They are also keen to investigate the efficacy of combinatory regimen of nimbolide and approved drugs such as docetaxel and enzalutamide for future prostate cancer therapy.



Journal Reference:

  1. Jingwen Zhang, Kwang Seok Ahn, Chulwon Kim, Muthu K. Shanmugam, Kodappully Sivaraman Siveen, Frank Arfuso, Ramar Perumal Samym, Amudha Deivasigamanim, Lina Hsiu Kim Lim, Lingzhi Wang, Boon Cher Goh, Alan Prem Kumar, Kam Man Hui, Gautam Sethi. Nimbolide-Induced Oxidative Stress Abrogates STAT3 Signaling Cascade and Inhibits Tumor Growth in Transgenic Adenocarcinoma of Mouse Prostate Model. Antioxidants & Redox Signaling, 2016; 24 (11): 575 DOI:10.1089/ars.2015.6418

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A PAPER

Image result for nimbolide

NIMBOLIDE 1

http://pubs.rsc.org/en/content/articlelanding/2015/ra/c5ra16071e#!divAbstract

Nimbolide (1): Pale yellow crystals; C27H30O7;

FT-IR (KBr, υmax, cm -1): 2978, 1778, 1730, 1672, 1433, 1296, 1238, 1192, 1153, 1069, 951, 827, 750;

1H NMR (500 MHz, CDCl3) δH: 7.32 (t, J = 1.5 Hz, 1H), 7.28 (d, J = 9.5 Hz, 1H), 7.22 (s, 1H), 6.25 (m, 1H), 5.93 (d, J = 10.0 Hz, 1H), 5.53 (m, 1H), 4.62 (dd, J = 3.67 Hz, 12 .5 Hz, 1H), 4.27 (d, J = 3.5 Hz, 1H), 3.67 (d, J = 9.0 Hz, 1H), 3.54 (s, 3H), 3.25 (dd, J = 5.0 Hz, 16.25 Hz, 1H), 3.19 (d, J = 12.5 Hz, 1H), 2.73 (t, J = 5.5 Hz, 1H), 2.38 (dd, J = 5.5 Hz, 16.25 Hz, 1H), 2.22 (dd, J = 6.5 Hz, 12.0 Hz, 1H), 2.10 (m, 1H), 1.70 (s, 3H), 1.47 (s, 3H), 1.37 (s, 3H), 1.22 (s, 3H);

13C NMR (125 MHz, CDCl3) δC: 200.8 (CO), 175.0 (COO), 173.0 (COO), 149.6 (CH), 144.8 (C), 143.2 (CH), 138.9 (CH), 136.4 (C), 131.0 (CH), 126.5 (C), 110.3 (CH), 88.5 (CH), 82.9 (CH), 73.4 (CH), 51.8 (OCH3), 50.3 (C), 49.5 (CH), 47.7 (CH), 45.3 (C), 43.7 (C), 41.2 (CH2), 41.1 (CH), 32.1 (CH2), 18.5 (CH3), 17.2 (CH3), 15.2 (CH3), 12.9 (CH3);

HR-MS (m/z): 467.20795 [(M+H)+ ].

Content Page No 1 1H NMR spectrum of nimbolide S1 2 13C NMR spectrum of nimbolide S2 3 Mass spectrum of nimbolide

Dr Gautam Sethi

phcgs@nus.edu.sg
Tel.: (65)6516 3267
Fax: (65)6873 7690

Academic Qualifications
BSc. Chem. (Hons) 1998 Banaras Hindu University, Varanasi, India.
MSc. Biochemistry 2000 Banaras Hindu University, Varanasi, India.
Ph.D. Biotechnology 2004 Banaras Hindu University, Varanasi, India.
Appointments to Date
Assistant
Professor
2008-date Department of Pharmacology, National University of Singapore, Singapore
Postdoctoral Fellow 2004-2007 Department of Experimental Therapeutics,
The University of Texas.
MD Anderson Cancer Center, Houston TX USA.
Senior Research Fellow 2002-2004 (CSIR-NET) at School of Biotechnology,
Banaras Hindu University, Varanasi, India.
Junior Research Fellow 2000-2002 (CSIR-NET) at School of Biotechnology, Banaras Hindu University, Varanasi, India.
Honours and Awards
2007 Ramalingaswamy fellowship from Department of Biotechnology, Government of India for outstanding research contributions in the field of Cancer Biology.
2002 Senior Research Fellowship award, Council of Scientific and Industrial Research, New Delhi, India.
2000 Junior Research Fellowship award, Council of Scientific and Industrial Research, New Delhi, India.
Research Interests
Selected Publications
Reviews and Book Chapters

 

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/////////NIMBOLIDE, CANCER, NEEM, PROSTRATE, National University of Singapore, Gautam Sethi

CC1=C2C(CC1C3=COC=C3)OC4C2(C(C5(C6C4OC(=O)C6(C=CC5=O)C)C)CC(=O)OC)C

RO-5126766


RO5126766(CH5126766)

CHEBI:78825.png

RO-5126766

946128-88-7
MW 471.46
MF C21H18FN5O5S

Phase I

3- [[2-[(Methylaminosulfonyl)amino]-3- fluoropyridin-4-yl]methyl]-4-methyl-7-[(pyrimidin-2-yl)oxy]- 2H-1-benzopyran-2-one

3-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-4-methyl-7-pyrimidin-2-yloxychromen-2-one
Chugai Seiyaku Kabushiki Kaisha

Chugai Seiyaku Kabushiki Kaisha, Sakai, Toshiyuki

Hoffmann-La Roche
Collaborators:
Institute of Cancer Research, United Kingdom
Chugai Pharmaceutical

A MEK1/Raf inhibitor potentially for the treatment of solid tumors and multiple myeloma.

RO-5126766; RG-7304; CH-5126766; CKI-27; R-7304

CAS No. 946128-88-7

Although melanoma is the most aggressive skin cancer, recent advances in BRAF and/or MEK inhibitors against BRAF-mutated melanoma have improved survival rates. Despite these advances, a treatment strategy targeting NRAS-mutated melanoma has not yet been elucidated. We discovered CH5126766/RO5126766 as a potent and selective dual RAF/MEK inhibitor currently under early clinical trials. We examined the activity of CH5126766/RO5126766 in a panel of malignant tumor cell lines including melanoma with a BRAF or NRAS mutation. Eight cell lines including melanoma were assessed for their sensitivity to the BRAF, MEK, or RAF/MEK inhibitor using in vitro growth assays. CH5126766/RO5126766 induced G1 cell cycle arrest in two melanoma cell lines with the BRAF V600E or NRAS mutation. In these cells, the G1 cell cycle arrest was accompanied by up-regulation of the cyclin-dependent kinase inhibitor p27 and down-regulation of cyclinD1. CH5126766/RO5126766 was more effective at reducing colony formation than a MEK inhibitor in NRAS- or KRAS-mutated cells. In the RAS-mutated cells, CH5126766/RO5126766 suppressed the MEK reactivation caused by a MEK inhibitor. In addition, CH5126766/RO5126766 suppressed the tumor growth in SK-MEL-2 xenograft model

A method for producing a coumarin derivative of general formula (VII) is disclosed in Patent document 1 or 2. Patent document 1 or 2 discloses a method represented by the scheme below [In the scheme, DMF represents N,N-dimethylformamide, TBS represents a tert-butyldimethylsilyl group, dba represents dibenzylideneacetone, and BINAP represents 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl. Also, the numerical values (%) and “quant.” given below some structural formulas indicate the yields of the respective compounds], for example (see the manufacturing example for “compound 1j-2-16-2K” in Patent document 1 or 2).

Figure US20140213786A1-20140731-C00003

Figure US20140213786A1-20140731-C00004

CITATION LIST Patent Literature

Patent document 1: WO 2007/091736

Patent document 2: WO 2009/014100

PATENT

http://www.google.co.in/patents/EP1982982A1?cl=en

      Compound 1j-2-16-2:

3-{2-(Methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyranFigure imgb0341

Methylamine (158 µL, 317 µmol) and DMAP (38.7 mg, 317 µmol) were added at -78 °C to a solution of sulfuryl chloride (28 µL, 340 µmol) in dichloromethane (2 mL), and the mixture was then stirred at room temperature for 2 hours to yield the corresponding sulfamoyl chloride. 3-(2-Amino-3-fluoropyridin-4-ylmethyl)-7-(pyrimidin-2-yloxy)-4-methyl-2-oxo-2H-1-benzopyran (compound 1h-2-16) (60 mg, 159 µmol), pyridine (65 µL, 795 µmol) and dichloromethane (2 mL) were added to the reaction solution, and the mixture was stirred at room temperature for 4 hours. After addition of water, the organic layer was extracted with dichloromethane. After washing with sodium hydrogen carbonate solution and saturated saline, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. The resultant residue was purified by silica gel column chromatography to yield the title compound (32 mg, 43%).

1H NMR (CD3OD, 270 MHz) δ (ppm): 2.54 (3H, s), 2.62 (3H, s), 4.22 (2H, s), 6.84 (1H, dd, J = 5.4 Hz), 7.20-7.30 (3H, m), 7.80-7.95 (2H, m), 8.63 (2H, d, J = 4.9 Hz)

ESI (LC/MS positive mode) m/z: 472 (M + H).

      Compound 1j-2-16-2Na:

3-(2-(N-Methylsulfamoyl)amino-3-fluoropyridin-4-ylmethyl)-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran sodium saltFigure imgb0342

The title compound was synthesized under the same conditions as in the manufacturing example for compound 1j-1-5-1Na, except that compound 1j-2-16-2 was used instead of compound 1j-1-5-1.

1H NMR (DMSO-d6, 270 MHz) δ (ppm): 2.30 (3H, s), 2.46 (3H, s), 3.89 (2H, s), 5.68 (1H, brs), 6.09-6.23 (1H, m), 7.20 (1H, dd, J = 2.4, 8.7 Hz), 7.34 (1H, t, J = 4.8 Hz), 7.38 (1H, d, J = 2.4 Hz), 7.55 (1H, d, J = 5.3 Hz), 7.90 (1H, d, J = 8.7 Hz), 8.69 (1H, d, J = 4.8 Hz).

ESI (LC/MS positive mode) m/z: 472 (M + 2H – Na).

      Compound 1j-2-16-2K:

3-(2-(N-Methylsulfamoyl)amino-3-fluoropyridin-4-ylmethyl)-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran potassium saltFigure imgb0343

The title compound was synthesized under the same conditions as in the manufacturing example for compound 1j-1-5-1Na, except that compound 1j-2-16-2 was used instead of compound 1j-1-5-1, and that KOH was used instead of NaOH.

1H NMR (DMSO-d6, 270 MHz) δ (ppm): 2.36 (3H, s), 2.47 (3H, s), 3.93 (2H, s), 6.26-6.40 (1H, m), 7.27 (1H, dd, J = 2.3, 8.6 Hz), 7.34 (1H, t, J = 4.8 Hz), 7.39 (1H, d, J = 2.3 Hz), 7.64 (1H, d, J = 4.8 Hz), 7.91 (1H, d, J = 8.6 Hz), 8.69 (1H, d, J = 4.8 Hz).

ESI (LC/MS positive mode) m/z: 472 (M + 2H – K).

PAPER

ACS Medicinal Chemistry Letters (2014), 5(4), 309-314.

Optimizing the Physicochemical Properties of Raf/MEK Inhibitors by Nitrogen Scanning

Research Division, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan
Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan
ACS Med. Chem. Lett., 2014, 5 (4), pp 309–314
DOI: 10.1021/ml400379x
Publication Date (Web): January 22, 2014
Abstract Image

Substituting a carbon atom with a nitrogen atom (nitrogen substitution) on an aromatic ring in our leads 11a and 13g by applying nitrogen scanning afforded a set of compounds that improved not only the solubility but also the metabolic stability. The impact after nitrogen substitution on interactions between a derivative and its on- and off-target proteins (Raf/MEK, CYPs, and hERG channel) was also detected, most of them contributing to weaker interactions. After identifying the positions that kept inhibitory activity on HCT116 cell growth and Raf/MEK, compound 1(CH5126766/RO5126766) was selected as a clinical compound. A phase I clinical trial is ongoing for solid cancers.

STR1

STR1

PATENT

https://www.google.com/patents/US20140213786

Step 5 Synthesis of 4-methyl-3-(3-fluoro-2-aminopyridin-4-ylmethyl)-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyranFigure US20140213786A1-20140731-C00047

Under a nitrogen atmosphere, potassium carbonate (2.3 g, 17 mmol) was added to a solution of the solid product of step 4 (3.0 g) and 2-bromopyrimidine (1.6 g, 9.8 mmol) in DMF (48 mL), and the mixture was stirred at 115° C. for 2.5 hours. The reaction mixture was cooled to 28° C., water (48 mL) was added dropwise over a period of 5 minutes at that temperature, and after cooling to 0° C., the mixture was stirred for 2 hours. The precipitated crystals were collected by filtration, washed with water (24 mL) and acetonitrile (24 mL) in that order, and dried under reduced pressure to obtain crude crystals (2.3 g). DMF (65 mL) was added to the crude crystals (2.3 g), and after heating to 60° C. and confirming the dissolution, the mixture was cooled to 25° C. Water (65 mL) was added at 25° C., and the mixture was further cooled to 0° C. and stirred for 4 hours. The precipitated crystals were collected by filtration, washed with water (22 mL) and acetonitrile (22 mL) in that order, and dried under reduced pressure to obtain the title compound (2.1 g). The title compound is a compound disclosed in WO 2007/091736.

Yield (overall yield from the 2-acetylamino-5-chloro-3-fluoropyridine used in step 2): 27%

Patent

https://www.google.com/patents/US20100004233

Compound 1h-2-16:

3-(3-Fluoro-2-aminopyridin-4-ylmethyl)-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyranFigure US20100004233A1-20100107-C00146

The title compound was synthesized under the same conditions as in the manufacturing example for compound 1h-2-4 (synthesis scheme 2), except that compound 5d-0-16 was used instead of compound 4a-0-4.

1H NMR (DMSO-d6, 270 MHz) δ (ppm): 2.45-2.55 (3H, m), 3.94 (2H, s), 6.12 (2H, brs), 6.28 (1H, dd, J=4.7 Hz), 7.27 (1H, dd, J=8.6 Hz, J=2.1 Hz), 7.34 (1H, dd, J=4.9 Hz), 7.38 (1H, d, J=2.1 Hz), 7.58 (1H, d, J=4.7 Hz), 7.91 (1H, d, J=8.6 Hz), 8.68 (2H, d, J=4.7 Hz).

ESI (LC/MS positive mode) m/z: 479 (M+H).

 Compound 1j-2-4-2:

3-{2-Fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyranFigure US20100004233A1-20100107-C00274

The title compound was synthesized under the same conditions as in the manufacturing example for compound 1j-1-5-2, except that compound 1h-2-4 was used instead of compound 1h-1-5.

1H NMR (270 MHz, DMSO-d6) δ (ppm): 2.45 (3H, s), 3.99 (2H, s), 6.83-6.92 (1H, m), 6.97-7.06 (1H, m), 7.17 (1H, brs), 7.34-7.40 (4H, m), 7.91 (1H, d, J=8.4 Hz), 8.69 (2H, dd, J=4.8, 1.2 Hz), 9.38 (1H, br.s).

One of the CH3 peaks was overlapped with the DMSO peak.

ESI (LC/MS positive mode) m/z: 471 (M+H).

Compound 1j-2-4-2Na:

3-{2-Fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran sodium saltFigure US20100004233A1-20100107-C00275

The title compound was synthesized under the same conditions as in the manufacturing example for compound 1j-1-5-1Na, except that compound 1j-2-4-2 was used instead of compound 1j-1-5-1.

1H NMR (270 MHz, DMSO-d6) δ (ppm): 2.33 (3H, d, J=3.3 Hz), 2.43 (3H, s), 3.89 (2H, s), 6.10-6.19 (1H, m), 6.58-6.66 (1H, m), 7.17 (1H, ddd, J=8.3, 1.5 Hz, JHF=8.3 Hz), 7.25 (1H, dd, J=8.7, 2.3 Hz), 7.33 (1H, t, J=4.8 Hz), 7.37 (1H, d, J=2.3 Hz), 7.88 (1H, d, J=8.7 Hz), 8.69 (2H, d, J=4.8 Hz)

ESI (LC/MS positive mode) m/z: 471 (M+2H—Na).

Compound 1j-2-4-2K:

3-{2-Fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(pyrimidin-2-yl-oxy)-2-oxo-2H-1-benzopyran potassium saltFigure US20100004233A1-20100107-C00276

The title compound was synthesized under the same conditions as in the manufacturing example for compound 1j-1-5-1Na, except that compound 1j-2-4-2 was used instead of compound 1j-1-5-1, and that KOH was used instead of NaOH.

1H NMR (270 MHz, DMSO-d6) δ (ppm): 8.69 (d, 2H, J=4.8 Hz), 7.88 (d, 1H, J=8.7 Hz), 7.36 (d, 1H, J=2.3 Hz), 7.33 (t, 1H, J=4.8 Hz), 7.25 (dd, 1H, J=8.7, 2.3 Hz), 7.16 (td, 1H, J=8.5, 1.4 Hz), 6.59 (t, 1H, J=7.8 Hz), 6.10 (t, 1H, J=6.3 Hz), 4.76 (q, 1H, J=5.8 Hz), 3.88 (s, 2H), 2.43 (s, 3H), 2.32 (d, 3H, J=5.6 Hz).

ESI (LC-MS positive mode) m/z: 471 (M+2H—K).

PATENT

 WO 2013035754 

Method for producing a coumarin derivative of formula (VII) are described in Patent Documents 1 and 2. Patent Documents 1 and 2, for example, in the following scheme [scheme, DMF is N, represents a N- dimethylformamide, TBS represents a tert- butyldimethylsilyl group, dba represents dibenzylideneacetone, BINAP is 2, I represents a 2′-bis (diphenylphosphino) -1,1′-binaphthyl. Further, numerical values given under the formula (%) or “quant.” Indicates the yield of the compound. Methods have been described that are shown in (see Preparation of “Compound 1j-2-16-2K” in Patent Documents 1 and 2).

Figure JPOXMLDOC01-appb-C000018

WO2007 / 091736 WO2009 / 014100

While coumarin derivatives of the general formula (VII) can be prepared by the methods described in Patent Documents 1 and 2, in the method described in Patent Documents 1 and 2, after the formylation reaction and a reduction reaction, and unintended Reaction To suppress, it is necessary to perform the introduction and removal steps of the protecting group for hydroxy group. Also, during the formylation reaction, from the viewpoint of cryogenic conditions of the reaction control (eg, -95 ℃ ~ -65 ℃) is required. Furthermore, the alkylation reaction (the seventh step in the above scheme), it is preferred that an excess amount of use of ethyl acetoacetate in terms of efficient synthesis, in which case, requires complicated operation of removing residual reagents become.

[Example 1]
Step 1:
Synthesis of 2-acetylamino-5-chloro-3-fluoropyridine:

Figure JPOXMLDOC01-appb-C000050

Under a nitrogen atmosphere, acetamide (94.8g, 1.61mol) in DMF with (200mL) and THF (830mL) was added and heated to 50 ℃. The resulting solution was a THF solution of 40wt% sodium hexamethyldisilazide (629g, 1.37mol) was added dropwise and stirred at the same temperature for 2 hours. 5-chloro-2,3-difluoro pyridine (100.0g, 0.67mol) After adding, THF and (20mL), and the mixture was stirred at the same temperature for 3 hours. After cooling to 0 ℃, it is added to 2.8M HCl (500mL) to the reaction mixture, and the organic layer was separated and the temperature was raised to room temperature.The organic layer was washed with 20wt% sodium chloride solution (500mL), and evaporated under reduced pressure. The residue in THF (500mL) was added, and the residue was dissolved by heating at 70 ℃. After confirming the solid precipitated by cooling to room temperature, n- heptane (1500mL) was added and further cooled to 0 ℃, followed by stirring at the same temperature for 3 hours. The The precipitated crystals were collected by filtration, to give after washing with a mixed solvent of THF (100mL) and n- heptane (500mL), and dried under reduced pressure to give the title compound (91.2g).
Yield: 72%
1 H-NMR (CDCl 3) δ (ppm): 2.36 (3H, s), 7.49 (1H, dd, J = 2.0,9.5Hz), 7.78 (1H, br), 8.17 (1H, d, J = 2.0Hz).
MS (ESI +): 189 [M + 1] +

Step 2:
Synthesis of 2-acetylamino-5-chloro-3-fluoro-4-formyl pyridine:

Figure JPOXMLDOC01-appb-C000051

Under a nitrogen atmosphere, and dissolved at room temperature 2-acetylamino-5-chloro-3-fluoropyridine (70.0g, 0.37mol) and 4-formyl-morpholine (128.2g, 1.11mol) to THF (840mL) It was. The solution was cooled to -20 ℃ and was added dropwise a THF solution of 24wt% of lithium hexamethyldisilazide (595g, 0.85mol), and stirred 5.5 hours at the same temperature. The reaction mixture, citric acid monohydrate (257g) and sodium chloride (70g) in an aqueous solution dissolved in water (420mL), and I was added at stirring at 0 ℃. The organic layer was separated and the resulting organic layer was successively washed with 50wt% phosphoric acid aqueous solution of potassium dihydrogen (350mL) and 20wt% sodium chloride solution (350mL) to (1458g). The portion of the organic layer was taken for analysis (292g), and evaporated remainder (1166g) at reduced pressure. The residue in THF (350mL) was added, and the solvent was distilled off under reduced pressure. Again, the residue in THF (350mL) was added to and evaporated under reduced pressure to give a solid (81.4g) containing the title compound. The product was used in the next step without further purification.
Some of the organic layer which had been collected (292g) to (29g), and evaporated under reduced pressure. The residue was purified by silica gel column chromatography: subjected to [eluent AcOEt / hexane (1 / 4-9 / 1)], I give the title compound (1.05g, 4.85mmol) as a white powdery solid.
Yield: 66%
1 H-NMR (CDCl 3) δ (ppm): 2.40 (3H, s), 7,59 (1H, br), 8.34 (1H, br), 10.42 (1H, s).
MS (ESI +): 217 (M + 1)

Step 3:
2 – [(4-2-acetylamino-3-fluoro-pyridin-yl) methyl] -3-oxobutanoic acid ethyl ester:

Figure JPOXMLDOC01-appb-C000052

Under a nitrogen atmosphere to dissolve the solid product of Step 2 (81.4g) in 2,2,2-trifluoroethanol (448mL), piperidine (4.4g, 51.7mmol), acetic acid (3.1g, 51 .7mmol) and 3-oxobutanoic acid ethyl (37.0g, 0.28mol) was added and stirred for 3 hours after raising the temperature to 50 ℃. After cooling the reaction mixture to room temperature, triethylamine (758mL, 5.5mol) and formic acid (172mL, 4.6mol) of 2-propanol (1248mL) solution and 20% Pd (OH) 2 carbon (21.2g, moisture content 46.2%) were added, followed by stirring for 4 hours the temperature was raised to 50 ℃. The reaction mixture was filtered through Celite, and the residue was washed with 2-propanol (679mL). Combined filtrate and washings (2795g), and evaporated under reduced pressure a part of the (399g) (remaining (2396g) I was saved). Ethyl acetate (24.2mL) was added to the residue obtained by evaporation of the solvent, and evaporated under reduced pressure. Again, the residue ethyl acetate (182mL) was added to the washed successively with an organic layer 20wt% brine (61mL), 10wt% of potassium dihydrogen phosphate solution (61mL) and 20wt% sodium chloride solution (61mL), under a reduced pressure The solvent was evaporated. Furthermore, in addition to the residue of 2,2,2-trifluoroethanol (24mL), and the solvent evaporated under reduced pressure to obtain oil containing the title compound (15.0g). The product was used in the next step without further purification.
1 H-NMR (CDCl 3) δ (ppm): 1.24 (3H, t, J = 7.0Hz), 2.27 (3H, s), 2.37 (3H, s), 3.16- 3.26 (2H, m), 3.86 (1H, t, J = 7.5Hz), 4.15-4.22 (2H, m), 6.98 (1H, t, J = 5.0Hz ), 7.68 (1H, br), 8.05 (1H, d, J = 5.0Hz).
MS (ESI +): 297 (M + 1)

Step 4:
Synthesis of 3- (3-fluoro-2-amino-pyridin-4-ylmethyl) -7-hydroxy-4-methyl-2-oxo -2H-1- benzopyran methanesulphonate:

Figure JPOXMLDOC01-appb-C000053

Under a nitrogen atmosphere, oily product of Step 3 (15.0g) and I were dissolved in 2,2,2-trifluoroethanol (33mL). The solution of resorcinol (5.3g, 47.9mmol) and methane sulfonic acid (11.7mL, 181mmol) was added at 24 ℃, and stirred for 4 hours at 90 ℃. And allowed to stand for 13 hours and cooled to room temperature and ethanol (33mL) and water (11mL), and the mixture was stirred for 4.5 hours at 90 ℃. After adding 2-propanol (105mL) was cooled to 55 ℃, and allowed to stand for 14 hours then cooled to room temperature. The The precipitated crystals were collected by filtration to give 2-propanol was washed twice with (33mL), and dried under reduced pressure to give the title compound (8.2g).
(Total from 2-acetylamino-5-chloro-3-fluoropyridine was used in step 2 Yield) Yield: 49%
MS (ESI +): 301 [M + 1-MsOH] +

Step 5:
4-methyl-3- (3-fluoro-2-amino-pyridin-4-ylmethyl) -7- (pyrimidin-2-yloxy) -2-oxo -2H-1- benzopyran Synthesis:

Figure JPOXMLDOC01-appb-C000054

Under a nitrogen atmosphere, 3- (3-fluoro-2-amino-pyridin-4-ylmethyl) -7-hydroxy-4-methyl-2-oxo -2H-1- benzopyran methanesulphonate (7.6g, 19.2mmol) and 2-bromo-pyrimidine (4.0g, 24.9mmol) was dissolved in DMF (122mL), potassium carbonate (5.8g, 42.2mmol) was added, and the mixture was stirred for 3.5 hours at 115 ℃. After cooling the reaction mixture to 28 ℃, water (122mL) was added dropwise over the same temperature for 0.5 hours, and stirred for 2 minutes. In addition, after cooling to 0 ℃, and the mixture was stirred for 1 hour, and the precipitated crystals were collected by filtration. The obtained crystals were washed successively with water (61mL) and acetonitrile (61mL), to give the title compound was dried under reduced pressure and crystals (6.5g).
The resultant was taken for analysis a portion of the crystals (0.1g), it was suspended remainder (6.4g) in DMF (70mL). The resulting suspension was stirred 60 ℃ and heated for 5 minutes and stirred for 80 minutes by the addition of acetonitrile (185mL) at the same temperature. Then, it was stirred for 0.5 hours and then cooled to 40 ℃, and the mixture was stirred for 0.5 hours and further cooled to 25 ℃. After a further 1.5 hours with stirring and cooled to 0 ℃, the precipitated crystals were collected by filtration. After washing the resulting crystals in acetonitrile (46mL), was obtained by drying under reduced pressure to the title compound (5.5g). Incidentally, the title compound is a compound described in WO2007 / 091736.
Yield: 76%

Step 6:
3- {2- (methyl-aminosulfonyl) amino-3-fluoro-pyridin-4-ylmethyl} -4-methyl-7- (pyridin-2-yloxy) -2-oxo -2H-1- benzopyran Synthesis:

Figure JPOXMLDOC01-appb-C000055

Under a nitrogen atmosphere, 4-methyl-3- (3-fluoro-2-amino-pyridin-4-ylmethyl) -7- (pyrimidin-2-yloxy) -2-oxo -2H-1- benzopyran (1.7g, 4 the .5mmol) it was suspended in DMF (18mL). To this solution pyridine (0.8mL, 9.9mmol) was cooled to In 10 ℃ added, N- methyl-sulfamoyl chloride (1.05g, 8.1mmol) in acetonitrile (18mL) solution of the internal temperature of 15 ℃ it was dropped so as to maintain below. After stirring for 90 minutes at the same temperature, acetonitrile (3.4mL) was added and further water (50mL), was added dropwise the inner temperature so as to maintain the 20 ℃ below. It was cooled to an external temperature of 0 ℃, and the mixture was stirred for an internal temperature of 5 ℃ 2 hours after arrival. The precipitated crystals were collected by filtration, washed with water (8.5mL), and dried to give the title compound (1.9g, 4.0mmol) was obtained.
Yield: 88%
MS (ESI +): 472 [M + 1] +

Step 7:
Synthesis of 3- {2- (methyl-aminosulfonyl) amino-3-fluoro-pyridin-4-ylmethyl} -4-methyl-7- (pyridin-2-yloxy) -2-oxo -2H-1- benzopyran potassium salt:

Figure JPOXMLDOC01-appb-C000056

Under a nitrogen atmosphere, 3- {2- (methyl-aminosulfonyl) amino-3-fluoro-pyridin-4-ylmethyl} -4-methyl-7- (pyridin-2-yloxy) -2-oxo -2H-1- benzopyran ( 1.6g, was suspended 3.4mmol) in THF (10mL), water (3mL) was added. The suspension in 2.0M aqueous potassium hydroxide (1.8mL, 3.6mmol) was added dropwise over 10 min at 25 ℃, after raising the temperature to 60 ℃, and the mixture was stirred for 2 hours at the same temperature. After cooling the reaction mixture to 20 ℃, it was added dropwise over a period of THF (8mL) 30 min. After completion of the dropwise addition, the mixture was cooled to an external temperature of -5 ℃, and the mixture was stirred for an internal temperature of 0 ℃ reached after 160 minutes. The precipitated crystals were collected by filtration, then washed with a mixture of THF (14mL) and water (1.6mL) (pre-cooled to 5 ℃), further washed with THF (8mL), and dried to give the title compound (0 .72g, we got 1.4mmol).
Yield: 42%
MS (ESI +): 472 [M + 2H-K] +

CLIP

RO5126766 (CH5126766) is a first-in-class dual inhibitor of Raf/MEK [1].

The RAS/RAF/MEK/ERK signaling pathway is an important signal transduction system and participates in cell differentiation, movement, division and death. Activated Ras activates RAF kinase, which then phosphorylates and activates MEK (MEK1 and MEK2) [1]. The mutations in BRAF, RAS, and NF1 are associated with many human tumors [2].

RO5126766 (CH5126766) is a first-in-class dual Raf/MEK inhibitor. In cell-free kinase assays, CH5126766 effectively inhibited the phosphorylation of MEK1 protein by RAF and the activation of ERK2 protein by MEK1 with IC50 values of 0.0082-0.056 and 0.16 μM, respectively. In NCI-H460 (KRAS Q61H) human lung large cell carcinoma cell line, RO5126766 induced cell-cycle inhibitor p27Kip1 protein expression and caused G1 arrest. In HCT116 KRAS-mutant colorectal cancer cells, RO5126766 CH5126766 completely inhibited the phosphorylation of MEK and ERK [2].

In Japanese patients with advanced solid tumors, RO5126766 exhibited the maximum tolerable dose (MTD) of 2.25 mg/day once daily [1]. In a HCT116 (G13D KRAS) mouse xenograft model, RO5126766 (1.5 mg/kg) inhibited pERK and ERK signaling and exhibited ED50 value of 0.056 mg/kg [2].

References:
[1].  Honda K, Yamamoto N, Nokihara H, et al. Phase I and pharmacokinetic/pharmacodynamic study of RO5126766, a first-in-class dual Raf/MEK inhibitor, in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol, 2013, 72(3): 577-584.
[2].  Ishii N, Harada N, Joseph EW, et al. Enhanced inhibition of ERK signaling by a novel allosteric MEK inhibitor, CH5126766, that suppresses feedback reactivation of RAF activity. Cancer Res, 2013, 73(13): 4050-4060.

WO2007091736A1 9 Feb 2007 16 Aug 2007 Chugai Seiyaku Kabushiki Kaisha Novel coumarin derivative having antitumor activity
WO2009014100A1 18 Jul 2008 29 Jan 2009 Chugai Seiyaku Kabushiki Kaisha p27 PROTEIN INDUCER
JPH0236145A * Title not available
Reference
1 BIOORGANIC MEDICINAL CHEMISTRY, vol. 13, 2005, pages 1393 – 1402
2 JOURNAL OF MEDICINAL CHEMISTRY, vol. 47, 2004, pages 6447 – 6450
3 ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL, vol. 36, 2004, pages 347 – 351
4 * See also references of EP2754654A1
5 * STANCHO STANCHEV, ET AL.: “Synthesis and Inhibiting Activity of Some 4-Hydroxycoumarin Derivatives on HIV-1 Protease. Art 137637“, ISRN PHARMACEUTICS, vol. 63, no. 10, 2011, pages 1 – 9, XP055145297
6 * STANCHO STANCHEV, ET AL.: “Synthesis, computational study and cytotoxic activity of new 4-hydroxycoumarin derivatives“, EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 43, no. 4, 2008, pages 694 – 706, XP022576473
7 SYNTHETIC COMMUNICATIONS, vol. 34, 2004, pages 4301 – 4311
Patent ID Date Patent Title
US7897792 2011-03-01 Coumarin derivative having antitumor activity
US2011009398 2011-01-13 p27 Protein Inducer
Patent ID Date Patent Title
US2016024051 2016-01-28 SALTS AND SOLID FORMS OF ISOQUINOLINONES AND COMPOSITION COMPRISING AND METHODS OF USING THE SAME
US2015290207 2015-10-15 HETEROCYCLIC COMPOUNDS AND USES THEREOF
US2015283142 2015-10-08 TREATMENT OF CANCERS USING PI3 KINASE ISOFORM MODULATORS
US2015225410 2015-08-13 HETEROCYCLIC COMPOUNDS AND USES THEREOF
US2015111874 2015-04-23 HETEROCYCLIC COMPOUNDS AND USES THEREOF
US2014377258 2014-12-25 Treatment Of Cancers Using PI3 Kinase Isoform Modulators
US2014213786 2014-07-31 Method for Producing Coumarin Derivative
US2014038920 2014-02-06 TFEB PHOSPHORYLATION INHIBITORS AND USES THEREOF
US2011092700 2011-04-21 Novel Coumarin Derivative Having Antitumor Activity
US7897792 2011-03-01 Coumarin derivative having antitumor activity

//////////////RO-512676, RG-7304,  CH-5126766,  CKI-27,  R-730, 946128-88-7, PHASE 1, MEK1/Raf inhibitor,  treatment of solid tumors and multiple myeloma, CANCER

CC(C1=C(O2)C=C(OC3=NC=CC=N3)C=C1)=C(C2=O)CC4=C(F)C(NS(NC)(=O)=O)=NC=C4

Chidamide (Epidaza), A New Cancer Drug, Made in China


STR1

Figure CN103833626AD00031

Chidamide (Epidaza)

CS055; HBI-8000

CAS   743438-44-0  CORRECT

C22 H19 F N4 O2, Benzamide, N-(2-amino-4-fluorophenyl)-4-[[[1-oxo-3-(3-pyridinyl)-2-propen-1-yl]amino]methyl]-
Molecular Weight, 390.41
  • Benzamide, N-(2-amino-4-fluorophenyl)-4-[[[1-oxo-3-(3-pyridinyl)-2-propenyl]amino]methyl]-
  • N-(2-Amino-4-fluorophenyl)-4-[[[1-oxo-3-(3-pyridinyl)-2-propen-1-yl]amino]methyl]benzamide
  • CS 055
  • Chidamide
  • Epidaza
Activity: HDAC Inhibitor; Cancer Drug; Histone Deacetylase Inhibitor; HDAC-1, 2,3,10 Inhibitor; Treatment for Peripheral T-cell Lymphomas; Treatment for PTCL
Status: Launched 2014 (China)
Originator: Shenzhen Chipscreen Biosciences Ltd
SHENZHEN CHIPSCREEN BIOSCIENCES LTD. [CN/CN]; Research Institute of Tsinghua University, Suite C301, P.O. Box 28, High-Tech Industrial Park Nanshan District, Shenzhen, Guangdong 518057
 
 

ERROR IN STRUCTURE

FLUORO IN WRONG POSITION

Chidamide.svg

CAS Registry Number: 743420-02-2

As described for Example 2 according to the patent ZL03139760.3 obtained chidamide poor purity (about 95%). LC / MS analysis results shown in Figure 1, show that the product contains N- (2- amino-5-fluorophenyl) -4- (N- (3- pyridin-acryloyl group of 4.7% of the structure shown in formula II) aminomethyl) benzamide. 1H NMR analysis of the results shown in Figure 2, show that the product contains 1.80% of tetrahydrofuran, far beyond the technical requirements for people with drug registration International Conference on Harmonization (ICH, International Conference of Harmonizition) provided 0.072% residual solvent limits. Therefore, the solid

Body not for pharmaceutical manufacturing.

Figure CN103833626AD00041

Chidamide (Epidaza) is an HDAC inhibitor (HDI) developed wholly in China.[1] It was originally known as HBI-8000.[2]

It is a benzamide HDI) and inhibits Class I HDAC1, HDAC2, HDAC3, as well as Class IIb HDAC10.[3]

It is approved by the Chinese FDA for relapsed or refractory peripheral T-cell lymphoma (PTCL), and having orphan drug status in Japan.[2]

As of April 2015 it is only approved in China.[1]

It shows potential in treating pancreatic cancer.[4][5][6]

Is NOT approved for the treatment of pancreatic cancer.

Chidamide drug administration and clinical milestone

November 2005: China declared IND

November 2006: eligible for Phase I clinical documents of approval

November 2006: completion of the International Patent Licensing, China entered the international fray original new drug development

May 2008: completed Phase I clinical, showing international mechanism similar drugs have the potential to become the best

February 2009: eligible lymphoma indications II / III of this document

March 2009: Start of the Phase II clinical trial for the NDA to ①CTCL goal of clinical trials and ②PTCL

March 2009: IND by the FDA application is eligible to start Phase I clinical in the United States

July 2009: eligible for non-small cell lung cancer, breast cancer and prostate cancer clinical documents of approval

December 2010: of PTCL by a conventional phase II directly into Phase II clinical trial registered drug trial center and by recognition

March 2011: combination chemotherapy for non-small cell lung cancer clinical trials enter phase Ib

September 2012: of PTCL indication test deadline

December 2012: of PTCL clinical summary will be held

January 2013: Chidamide declare China NDA

December 2014: the State Food and Drug Administration (CFDA) approved the listing

STR1

Chidamide overview, location and clinical significance

Chidamide (Chidamide, love spectrum sand ® / Epidaza®) Shenzhen microchip biotechnology limited liability company developed a new subtype selective histone having a chemical structure and is eligible for a global patent licensing deacetylase inhibitor, belong to the new mechanisms of epigenetic regulation new class of targeted anticancer drugs, has now completed with relapsed or refractory peripheral T-cell lymphoma clinical trial study registered indications, was in March 2013 to the SFDA reporting new drug certificate (NDA) and the marketing authorization (MAA). While a number of Chinese Cancer clinical trials undertaken Chidamide is also China’s first approved by the US FDA clinical studies in the United States of Chinese chemical original new drug trials in the United States Phase I has been completed. Chidamide has won the national “Eleventh Five-Year” 863 major projects (project number: 2006AA020603) and the national “Eleventh Five-Year”, “significant Drug Discovery” science and technology and other major projects funded project (project number: 2009ZX09401-003), was chosen the Ministry of Science and one of the “Eleventh five-Year” major national scientific and technological achievements.

Relapsed or refractory peripheral T-cell lymphoma (PTCL) is Chidamide first approvedclinical indications, PTCL belongs to the category of rare diseases, the lack of standard drug currently recommended clinical treatment, conventional chemotherapy response rate is low, recur, 5-year overall survival rate was about 25%. The world’s first PTCL treatment Folotyn (intravenous drug use) is eligible for FDA clearance to market in 2009, the second drugs Istodax (intravenous drug use) approved by the FDA in 2011. Add a new drug information for these drugs is very expensive, and were listed in China. Chidamide album clinical trial results showed that the primary endpoint of objective response rate was 28%, reaching the intended target research and development; sustained remission rate of 24% three months; drug safety was significantly better than the international similar drugs, and oral medication.
Chidamide is a completely independent intellectual property rights China originator of innovative medicines, has been multi-national patent. In China, for patients with relapsed or refractory PTCL to carry out effective drug treatment is urgent clinical need, Chidamide expected to bring new treatment options for patients with PTCL, prolong survival and improve quality of life of patients.

In China, for the effective treatment of patients with relapsed or refractory PTCL has undertaken urgent clinical need

Chidamide is a completely independent intellectual property rights China originator of innovative medicines

Chidamide (Chidamide) has been multi-national invention patents

In October 2006, the US HUYA biological microchip company formally signed the International Patent Chidamide licensing and international clinical cooperative development agreement; the United States in the ongoing Phase I clinical

Chidamide (Epidaza), a class I HDAC inhibitor, was discovered and developed by ChipScreen and approved by the CFDA in December 2014 for the treatment of recurrent of refractory peripheral T-cell lymphoma. Chidamide, also known as CS055 and HBI- 8000, is an orally bioavailable benzamide type inhibitor of HDAC isoenzymes class I , as well as class IIb 10, with potential antineoplastic activity. It selectively binds to and inhibits HDAC, leading to an increase in acetylation levels of histone protein H3.

Chidamide, the English called Chidamide, by the Shenzhen-core biotechnology limited liability company independent design and synthesis of a novel anti-cancer drugs with new chemical structures and global intellectual property, and its chemical name N- (2-amino-_4_ fluorophenyl) -4_ (N- (3- topiramate Li acryloyl) aminomethyl) benzamide, its chemical structure of the structural formula I

Figure CN103833626AD00031

The patent ZL03139760.3 and said US7,244,751, Chidamide have histone deacetylase inhibitory activity can be used to treat the differentiation and proliferation-related diseases such as cancer and psoriasis, especially for leukemia and solid tumors with excellent results.

 Patent No. ZL03139760.3 and US7,244,751 discloses a method for preparing chidamide, but did not specify whether the resulting product is a crystalline material, nor did the presence or absence of the compound polymorphism. In the above patent, the activity of the compound for evaluation is not conducted in a solid state and, therefore, does not disclose any description about characteristics of the crystal.

Chipscreen grabs CFDA approval for chidamide

Chipscreen BioSciences announced that the CFDA had approved chidamide for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL) in December 2014. The drug and Hengrui’s apatinib were the only two NCEs launched by domestic drug makers last year.

Chidamide (CS055/HBI-8000) is a HDAC1/2/3/10 inhibitor derived from entinostat (MS-27-275)[1] which was first discoved by Mitsui Pharmaceuticals in 1999. Chipscreen holds worldwide IP rights to chidamide (patents: WO2004071400, WO2014082354).

Syndax Pharmaceuticals (NASDAQ: SNDX) is testing entinostat in breast cancer and NSCLC in pivotal trials. The FDA granted Breakthrough Therapy Designation to entinostat for advanced breast cancer in 2013. Eddingpharm in-licensed China rights to entinostat from Syndax in September 2013.

Chipscreen disclosed positive results from Phase II study of chidamide in relapsed or refractory PTCL at 2013 ASCO Annual Meeting[2]. Out of 79 evaluable patients in the trial, 23 patients (29.1%) had confirmed responses (8 CR, 3 CRu, and 12 PR). The most common grade 3/4 AEs were thrombocytopenia (24%), leucocytopenia (13%), neutropenia(10%).

The FDA has approved three HDAC inhibitors, known as Zolinza (vorinostat), Istodax (romidepsin) and Beleodaq (belinostat), for the treatment of PTCL. Celgene priced Istodax at $12000-18000/month and reported annual sales of $54 million in 2013. The efficacy and safety profile of chidamide compares favorably with romidepsin.

Although a dozen of companies are developing generic vorinostat and romidepsin, no chemical 3.1 NDA has been submitted to the CFDA so far. Chipscreen will be the only domestic maker of HDAC inhibitor in the coming two years. Moreover, the company is testing chidamide in NSCLC and breast cancer in early clinical studies.

CLIP

Chiamide synthesis: US7244751B2

Procedure:

Step a: To a suspension of 0.33 g (2.01 mmol) of N,N’-carbonyldiimidazole in tetrahydrofunan (10 ml) is added drop-wise a solution of 0.30 g (2.01 mmol) of 3-pyridineacrylic acid at 0 °C. Then, the mixture is stirred at room temperature for 3 hours and added drop-wise to a separately prepared 2.0 ml (2.00 mmol) of 1N aqueous sodium hydroxide solution including 0.30 g (2.00 mmol) of 4-aminomethylbenzoic acid, followed by stirring at room temperature for 8 hours. The reaction mixture is evaporated under vacuum. To the residue is added a saturated solution of sodium chloride (2 ml), then the mixture is neutralized with concentrated hydrochloric acid to pH 5. The deposited white solid is collected by filtration, washed with ice-water, and then dried to give 4-[N-(Pyridin-3-ylacryloyl)aminomethyl]benzoic acid (0.46 g, 82%). HRMS calcd for C16H14N2O3: 282.2988. Found: 282.2990. MA calcd for: C16H14N2O3: C, 68.07%; H, 5.00%; N, 9.92%. Found: C, 68.21%; H, 5.03%; N, 9.90%.

Step b: To a suspension of 0.29 g (1.78 mmol) of N,N’-carbonyldiimidazole in tetrahydrofunan (15 ml) is added 0.50 g (1.78 mmol) of 4-[N-(Pyridin-3-ylacryloyl)aminomethyl]benzoic acid, followed by stirring at 45 °C. for 1 hour. After cooling, the reaction mixture is added to a separately prepared tetrahydrofiman (10 ml) solution including 0.28 g (2.22 mmol) of 4-fluoro-1,2-phenylenediamine and 0.20 g (1.78 mmol) of trifluoroacetic acid at room temperature. After reaction at room temperature for 24 hours, the deposited white solid is collected by filtration, washed with tetrahydrofunan, and then dried to give N-(2-amino-4-fluorophenyl)-4-[N-(Pyridin-3-ylacryloyl)aminomethyl]benzamide (0.40 g, 57%). 1H NMR (300 MHz, DMSO-d6): dppm: 4.49 (2H, d), 4.84 (2H, br.s), 6.60 (1H, t), 6.80 (2H, m),696 (1H, t), 7.18 (1H, d), 7.42 (2H, d), 7.52 (1H, d), 7.95 (2H, d), 8.02 (1H, d), 8.56 (1H, d), 8.72 (1H, br. t), 8.78 (1H, s), 9.60 (1H, br.s). IR (KBr) cm1: 3310, 1655, 1631, 1524, 1305, 750. HRMS calcd for C22H19N4O2F: 390.4170. Found: 390.4172. MA calcd for C22H19N4O2F: C, 67.68%; H, 4.40%; N, 14.35%. Found: C, 67.52%; H, 4.38%; N, 14.42%.

http://www.google.co.in/patents/US7244751

EXAMPLE 1

Preparation of 4-[N-(Pyridin-3-ylacryloyl)aminomethyl]benzoic acid

Figure US07244751-20070717-C00005

To a suspension of 0.33 g (2.01 mmol) of N,N′-carbonyldiimidazole in tetrahydrofunan (10 ml) is added drop-wise a solution of 0.30 g (2.01 mmol) of 3-pyridineacrylic acid at 0° C. Then, the mixture is stirred at room temperature for 3 hours and added drop-wise to a separately prepared 2.0 ml (2.00 mmol) of 1N aqueous sodium hydroxide solution including 0.30 g (2.00 mmol) of 4-aminomethylbenzoic acid, followed by stirring at room temperature for 8 hours. The reaction mixture is evaporated under vacuum. To the residue is added a saturated solution of sodium chloride (2 ml), then the mixture is neutralized with concentrated hydrochloric acid to pH 5. The deposited white solid is collected by filtration, washed with ice-water, and then dried to give the title compound (0.46 g, 82%). HRMS calcd for C16H14N2O3: 282.2988. Found: 282.2990. MA calcd for: C16H14N2O3: C, 68.07%; H, 5.00%; N, 9.92%. Found: C, 68.21%; H, 5.03%; N, 9.90%.EXAMPLE 2

Preparation of N-(2-amino-4-fluorophenyl)-4-[N-(Pyridn-3-ylacryloyl)aminomethyl]benzamide

Figure US07244751-20070717-C00006

To a suspension of 0.29 g (1.78 mmol) of N,N′-carbonyldiimidazole in tetrahydrofunan (15 ml) is added 0.50 g (1.78 mmol) of 4-[N-(Pyridn-3-ylacryloyl)aminomethyl]benzoic acid, followed by stirring at 45° C. for 1 hour. After cooling, the reaction mixture is added to a separately prepared tetrahydrofiman (10 ml) solution including 0.28 g (2.22 mmol) of 4-fluoro-1,2-phenylenediamine and 0.20 g (1.78 mmol) of trifluoroacetic acid at room temperature. After reaction at room temperature for 24 hours, the deposited white solid is collected by filtration, washed with tetrahydrofunan, and then dried to give the title compound (0.40 g, 57%). 1H NMR (300 MHz, DMSO-d6): δppm: 4.49 (2H, d), 4.84 (2H, br.s), 6.60 (1H, t), 6.80 (2H, m),696 (1H, t), 7.18 (1H, d), 7.42 (2H, d), 7.52 (1H, d), 7.95 (2H, d), 8.02 (1H, d), 8.56 (1H, d), 8.72 (1H, br. t), 8.78 (1H, s), 9.60 (1H, br.s). IR (KBr) cm1: 3310, 1655, 1631, 1524, 1305, 750. HRMS calcd for C22H19N4O2F: 390.4170. Found: 390.4172. MA calcd for C22H19N4O2F: C, 67.68%; H, 4.40%; N, 14.35%. Found: C, 67.52%; H, 4.38%; N, 14.42%.EXAMPLE 3

Preparation of 4-[N-cinnamoylaminomethyl]benzoic acid

Figure US07244751-20070717-C00007

To a suspension of 0.33 g (2.01 mmol) of N,N′-carbonyldiimidazole in tetrahydrofunan (10 ml) is added drop-wise a solution of 0.30 g (2.01 mmol) of cinnamic acid at 0° C. Then, the mixture is stirred at room temperature for 3 hours and added drop-wise to a separately prepared 2.0 ml (2.00 mmol) of 1N aqueous sodium hydroxide solution including 0.30 g (2.00 mmol) of 4-aminomethylbenzoic acid, followed by stirring at room temperature for 8 hours. The reaction mixture is evaporated under vacuum. To the residue is added a saturated solution of sodium chloride (2 ml), then the mixture is neutralized with concentrated hydrochloric acid to pH 7. The deposited white solid is collected by filtration, washed with ice-water, and then dried to give the title compound (0.51 g, 91%). HRMS calcd for C17H15NO3: 281.3242. Found: 281.3240. MA calcd for C17H15NO3: C, 72.58%; H, 5.38%; N, 4.98. Found: C, 72.42%; H, 5.37%; N, 4.98%.

EXAMPLE 4

Preparation of N-(2-amino-4-fluorophenyl)-4-[N-cinnamoylaminomethyl]benzamide

Figure US07244751-20070717-C00008

To a suspension of 0.29 g (1.78 mmol) of N,N′-carbonyldiimidazole in tetrahydrofunan (15 ml) is added 0.50 g (1.78 mmol) of 4-[N-cinnamoylaminomethyl]benzoic acid, followed by stirring at 45° C. for 1 hour. After cooling, the reaction mixture is added to a separately prepared tetrahydrofunan (10 ml) solution including 0.28 g (2.22 mmol) of 4-fluoro-1,2-phenylenediamine and 0.20 g (1.78 mmol) of trifluoroacetic acid at room temperature. After reaction at room temperature for 16 hours, the deposited white solid is collected by filtration, washed with tetrahydrofunan, and then dried to give the title compound (0.45 g, 64%). 1H NMR (300 MHz, DMSO-d6): δppm: 4.42 (2H, d), 4.92 (2H, br.s), 6.62 (1H, t), 6.78 (2H, m), 7.01 (1H, t), 7.32 (5H, m), 7.54 (5H, m), 8.76 (1H, br.t), 9.58 (1H, br.s). IR (KBr) cm−1: 3306, 1618, 1517, 1308, 745. HRMS calcd for C23H20N3O2F: 389.4292. Found: 389.4294. MA calcd for C23H20N3O2F: C, 70.94%; H, 5.18%; N, 10.79%. Found: C, 70.72%; H, 5.18%; N, 10.88%.

PATENT

https://www.google.com/patents/US20150299126

STR1

  • FIG. 2 is the 1H NMR spectrum of the solid prepared according to Example 2 of patent ZL 03139760.3;

NMR, MS ETC CLICK TO VIEW

C-NMR

CLIP

Chidamide (Epidaza), a class I HDAC inhibitor, was discovered and developed by ChipScreen and approved by the CFDA in December 2014 for the treatment of recurrent of refractory peripheral T-cell lymphoma. Chidamide, also known as CS055 and HBI- 8000, is an orally bioavailable benzamide type inhibitor of HDAC isoenzymes class I 1–3, as well as class IIb 10, with potential antineoplastic activity. It selectively binds to and inhibits HDAC, leading to an increase in acetylation levels of histone protein H3.74

This agent also inhibits the expression of signaling kinases in the PI3K/ Akt and MAPK/Ras pathways and may result in cell cycle arrest and the induction of tumor cell apoptosis.75

Currently, phases I and II clinical trials are underway for the treatment of non-small cell lung cancer and for the treatment of breast cancer, respectively.76 The scalable synthetic approach to chidamide very closely follows the discovery route,77–79 and is described in Scheme 10. The sequence began with the condensation of commercial nicotinaldehyde (52) and malonic acid (53) in a mixture of pyridine and piperidine. Next, activation of acid 54 with N,N0-carbonyldiimidazole (CDI) and subsequent reaction with 4-aminomethyl benzoic acid (55) under basic conditions afforded amide 56 in 82% yield.

Finally, activation of 56 with CDI prior to treatment with 4-fluorobenzene- 1,2-diamine (57) and subsequent treatment with TFA and THF yielded chidamide (VIII) in 38% overall yield from 52. However, no publication reported that mono-N-Boc-protected bis-aniline was used to approach Chidamide.

STR1

74. Ning, Z. Q.; Li, Z. B.; Newman, M. J.; Shan, S.; Wang, X. H.; Pan, D. S.; Zhang, J.;
Dong, M.; Du, X.; Lu, X. P. Cancer Chemother. Pharmacol. 2012, 69, 901.
75. Liu, L.; Chen, B.; Qin, S.; Li, S.; He, X.; Qiu, S.; Zhao, W.; Zhao, H. Biochem.
Biophys. Res. Commun. 2010, 392, 190.
76. Gong, K.; Xie, J.; Yi, H.; Li, W. Bio. Chem. J. 2012, 443, 735.
77. Lu, X. P.; Li, Z. B.; Xie, A. H.; Shi, L. M.; Li, B. Y.; Ning, Z. Q.; Shan, S.; Deng, T.;
Hu, W. M. US Patent 2004224991A1, 2004.
78. Lu, X. P.; Li, Z. B.; Xie, A. H.; Shi, L. M.; Li, B. Y.; Ning, Z. Q.; Shan, S.; Deng, T.;
Hu, W. M. CN Patent 1513839A, 2003.
79. Yin, Z. H.; Wu, Z. W.; Lan, Y. K.; Liao, C. Z.; Shan, S.; Li, Z. L.; Ning, Z. Q.; Lu, X.
P.; Li, Z. B. Chin. J. New Drugs 2004, 13, 536.

see  CN 105457038

CN 1513839

WRONG COMPD

WO2004071400

Example 2. Preparation of
N-(2-amino-5-fluorophenyl)-4-[N-(Pyridn-3-ylacryloyl)aminomethyl]benzamide

To a suspension of 0.29 g (1.78 mmol) of N, N’-carbonyldiimidazole in tetrahydrofunan (15 ml) is added 0.50 g (1.78 mmol) of 4-[N-(Pyridn-3-ylacryloyl)aminomethyl]benzoic acid, followed by stirring at 45°C for 1 hour. After cooling, the reaction mixture is added to a separately prepared tetrahydrofunan (10 ml) solution including 0.28 g (2.22 mmol) of 4-fluoro-1,2-phenylenediamine and 0.20 g (1.78 mmol) of trifluoroacetic acid at room temperature. After reaction at room temperature for 24 hours, the deposited white solid is collected by filtration, washed with tetrahydrofunan, and then dried to give the title compound (0.40 g, 57%). 1H NMR (300 MHz, DMSO-d6): δppm: 4.49 (2H, d), 4.84 (2H, br.s), 6.60 (IH, t), 6.80 (2H, m), 6.96 (IH, t), 7.18 (IH, d), 7.42 (2H, d), 7.52 (IH, d), 7.95 (2H, d), 8.02 (IH, d), 8.56 (IH, d), 8.72 (IH, br. t), 8.78 (IH, s), 9.60 (IH, br.s). IR (KBr) cm“1: 3310, 1655, 1631, 1524, 1305, 750. HRMS calcd for C229N4O2F: 390.4170. Found: 390.4172. MA calcd for C229N4O2F: C, 67.68%; H, 4.40%; N, 14.35. Found: C, 67.52%; H, 4.38%; N, 14.42%.

Photo taken on May 22, 2015 shows a box of Chidamide in Shenzhen, south China’s Guangdong Province. Chidamide is the world’s first oral HDAC inhibitor …

A New Cancer Drug, Made in China

After 14 years, Shenzhen biotech’s medicine is one of the few locally developed from start to finish

Xian-Ping Lu left his research job at a drug maker in the U.S. to co-found a biotech company in his native China.
Xian-Ping Lu left his research job at a drug maker in the U.S. to co-found a biotech company in his native China. PHOTO: SHENZHEN CHIPSCREEN BIOSCIENCES

HONG KONG— Xian-Ping Lu left his job as director of research at drug maker Galderma R&D in Princeton, N.J., to co-found a biotech company to develop new medicines in his native China.

It took more than 14 years but the bet could be paying off. In February, Shenzhen Chipscreen Biosciences’ first therapy, a medication for a rare type of lymph-node cancer, hit the market in China.

The willingness of veterans like Dr. Lu and others to leave multinational drug companies for Chinese startups reflects a growing optimism in the industry here. The goal, encouraged by the government, is to move the Chinese drug industry beyond generic medicines and drugs based on ones developed in the West.

Chipscreen’s drug, called chidamide, or Epidaza, was developed from start to finish in China. The medicine is the first of its kind approved for sale in China, and just the fourth in a new class globally. Dr. Lu estimates the research cost of chidamide was about $70 million, or about one-tenth what it would have cost to develop in the U.S.

“They are a good example of the potential for innovation in China,” said Angus Cole, director at Monitor Deloitte and pharmaceuticals and biotechnology lead in China.

China’s spending on pharmaceuticals is expected to top $107 billion in 2015, up from $26 billion in 2007, according to Deloitte China. It will become the world’s second-largest drug market, after the U.S., by 2020, according to an analysis published last year in the Journal of Pharmaceutical Policy and Practice.

China has on-the-ground infrastructure labs, a critical mass of leading scientists and interested investors, according to Franck Le Deu, head of consultancy McKinsey & Co.’s pharmaceuticals and medical-products practice in China. “There’re all the elements for the recipe for potential in China,” he said.

But there are obstacles to an industry where companies want big payoffs for a decade or more of work and tremendous costs it takes to develop a drug.

While the protection of intellectual property has improved, China’s cumbersome rules for drug approval and a government effort to cut health-care costs, particularly spending on drugs, could hurt the Chinese drug companies’ efforts, said Mr. Cole of Deloitte.

“Will you start to see success? Of course you will,” said Mr. Cole. However, “I’ve yet to see convincing or compelling evidence that it’s imminent.”

To date, many of the Chinese companies that are flourishing in the life sciences are contract research organizations that help carry out clinical trials, as well as providers of related services.

Some companies, like Shanghai-based Hua Medicine, are buying the rights to develop new compounds in China from multinational drug companies, what some experts consider more akin to an intermediate step to innovation.

Late last year, Hua Medicine completed an early-stage human clinical trial of a diabetes drug in China and in March filed an application to the Food and Drug Administration to develop it in the U.S. as well. The company has raised $45 million in venture funding to date.

Li Chen, who left an 18-year career at Roche Holding AG as head of research and development in China to help start Hua Medicine, said the company’s goal is to “create a game-changer of drug discovery.”

At Chipscreen Biosciences, Dr. Lu and his co-founders set up the company in 2001 in Shenzhen, a city that was quickly growing into a technology and research hub, just over the border from Hong Kong. They created a lab of 10 scientists to use a new analytic technique known as “chemical genomics” to examine the relationships between molecular structures of the existing and failed drugs, how they act on different targets in the body and what genes were being activated or repressed. Now they have more than 60 scientists.

By better predicting how chemicals would act on the body before entering human testing, they hoped they would be more likely get a drug to market.

“How can a small company compete with a multinational?” said Dr. Lu. “The only thing we can compete with is the scientific brain.”

The biggest challenges for the company have been financing and the Chinese regulatory system, said Dr. Lu. The company has raised a total of 300 million yuan ($48 million) over five rounds of venture funding, said Dr. Lu. Chipscreen also receives grant money from the Chinese government.

The company filed its application for approval of chidamide to the Chinese Food and Drug Administration, or CFDA, in early 2013. It had to wait nearly two years for approval, receiving the OK only in December.

Chidamide now is on the market in China for 26,500 yuan ($4,275) a month, a price far lower than patients in the U.S. pay for some of the newest cancer medicines but much more than the typical Chinese patient pays for drugs. Dr. Lu said the price reflects a balance between affordability for patients and return for shareholders. Some investors wanted to price the drug higher.

PAPER

Discovery of an orally active subtype-selective HDAC inhibitor, chidamide, as an epigenetic modulator for cancer treatment

Corresponding authors
aShenzhen Chipscreen Biosciences Ltd., BIO-Incubator, Suit 2-601, Shenzhen Hi-Tech Industrial Park, Shenzhen, P. R. China
E-mail: xplu@chipscreen.com
Med. Chem. Commun., 2014,5, 1789-1796

DOI: 10.1039/C4MD00350K, http://pubs.rsc.org/en/content/articlelanding/2014/md/c4md00350k#!divAbstract

Tumorigenesis is maintained through a complex interplay of multiple cellular biological processes and is regulated to some extent by epigenetic control of gene expression. Targeting one signaling pathway or biological function in cancer treatment often results in compensatory modulation of others, such as off-target drivers of cell survival. As a result, overall survival of cancer patients is still far from satisfactory. Epigenetic-modulating agents can concurrently target multiple aberrant or compensatory signaling pathways found in cancer cells. However, existing epigenetic-modulating agents in cancer treatment have not yet fully translated into survival benefits beyond hematological tumors. In this article, we present a historical rationale for use of chidamide (CS055/Epidaza), an orally active and subtype-selective histone deacetylase (HDAC) inhibitor of the benzamide chemical class. This compound was discovered and successfully developed as mono-therapy for relapsed and refractory peripheral T cell lymphoma (PTCL) in China. We discuss the evidence supporting chidamide as a durable epigenetic modulator that allows cellular reprogramming with little cytotoxicity in cancer treatments.

Graphical abstract: Discovery of an orally active subtype-selective HDAC inhibitor, chidamide, as an epigenetic modulator for cancer treatment
CLIPS
Chinese scientists develop world’s 1st oral HDAC inhibitor

Lu Xianping works in a lab at Shenzhen Chipscreen Biosciences Ltd. in Shenzhen, south China’s Guangdong Province, May 20, 2015. Lu Xianping, together with other four returned overseas scientists, spent 14 years to develop Chidamide, the world’s first oral HDAC inhibitor, which was given regulatory approval in January. (Xinhua/Mao Siqian)

GNT Biotech and Medicals Corporation Licenses Novel Cancer Molecule from Shenzhen Chipscreen Biosciences Ltd.

PR Newswire

SHENZHEN, China, Oct. 10, 2013 /PRNewswire/ — GNT Biotech and Medicals Corporation announces the grant of an exclusive license from Shenzhen Chipscreen Biosciences Ltd.for the development and commercialization of Chidamide in Taiwan. Chidamide, an oral, selective histone deacetylase (HDAC) inhibitor, is currently being evaluated in Phase II trials by Chipscreen Biosciences in Peripheral T-Cell Lymphoma (PTCL), Cutaneous T-Cell Lymphoma (CTCL) and Non-Small Cell Lung Cancer patients (NSCLC). GNTbm will develop and commercialize Chidamide primarily in PTCL, NSCLC and will also retain the rights to develop and commercialize Chidamide in other oncology indications in Taiwan.

About Chidamide

Chidamide is a selective HDAC inhibitor against subtype 1, 2, 3 and 10, and being studied in multiple clinical trials as a single agent or in combination with chemotherapeutic agents for the treatment of various hematological and solid cancers. Its anticancer effects are thought to be mediated through epigenetic modulation via multiple mechanisms of action, including the inhibition of cell proliferation and induction of apoptosis in blood derived cells, inhibition of epithelial to mesenchymal transition (EMT, a process that is highly relevant to tumor cell metastasis and drug resistance), induction of tumor specific antigen and antigen-specific T cell cytotoxicity, enhancement of NK cell anti-tumor activity, induction of cancer stem cell differentiation, and resensitization of tumor cells that have become resistant to anticancer agents such as platinums, taxanes and topoisomerase II inhibitors. Chidamide has demonstrated clinical efficacy in pivotal phase II trials on Cutaneous T-Cell Lymphoma (CTCL) and Peripheral T-Cell Lymphoma (PTCL) conducted in China, and is currently undergoing phase II trial in NSCLC together with first line PC therapeutic treatment. Due to its superior pharmacokinetic properties and selectivity, Chidamide may offer better clinical profile over the other HDAC inhibitors currently under development or being marketed.

About GNTbm

GNTbm is a subsidiary of GNT Inc, a Taiwanese company focused on the manufacture of nano-scale metallic particles for food and medical purposes. Founded in 1992 by a team of electronic professionals, GNT has successfully developed the innovative technology of physical metal miniaturization based on the patent of MBE (Molecular Beam Epitaxy). Further information about GNT Inc is available at www.gnt.com.tw.

GNTbm was established in August 2013, and housed in the Nankang Biotech Incubation Center, (NBIC), in Nankang, Taipei. Lead by Dr. Chia-Nan Chenalong with an experienced team of scientists, GNTbm will explore development and commercialization of novel drug delivery systems, Innovative biomedical and diagnostic tools based on gold nanoparticles.

About Shenzhen Chipscreen Biosciences Ltd.

Chipscreen is a leading integrated biotech company in China specialized in discovery and development of novel small molecule pharmaceuticals. The company has utilized its proprietary chemical genomics-based discovery platform to successfully develop a portfolio of clinical and preclinical stage programs in a number of therapeutic areas. Chipscreen’s business strategy is to generate differentiated drug candidates across multiple therapeutic areas. Drug candidates are either developed by Chipscreen or co-developed and commercialized in a partnership at the research, preclinical and clinical stages. The company was established as Sino-foreign joint venture in 2001. Further details about Chipscreen Bioscience is available atwww.chipscreen.com.

GNT Biotech and Medicals Corporation

Ekambaranellore Prakash, PhD

Director of International Department

GNT Biotech and Medicals Corporation

TEL: +886-2-7722-0388 #303

E-mail: prakash@gntbm.com.tw

Web site: www.gnt.com.tw

Shenzhen Chipscreen Biosciences Ltd.

Rebecca Hai

Investor Relations

Shenzhen Chipscreen Biosciences Ltd.

TEL: +86-755-26957317

E-mail: rebeccai_hai@chipscreen.com

Web site: www.chipscreen.com

SOURCE GNT Biotech and Medicals Corporation

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Chidamide
Chidamide.svg
Systematic (IUPAC) name
N-(2-Amino-5-fluorophenyl)-4-[[[1-oxo-3-(3-pyridinyl)-2-propen-1-yl]amino]methyl]-benzamide
Clinical data
Trade names Epidaza
Identifiers
CAS Number 743420-02-2
PubChem CID 9800555
ChemSpider 7976319
UNII 87CIC980Y0 Yes
Chemical data
Formula C22H19FN4O2
Molar mass 390.4 g/mol
Patent ID Date Patent Title
US2015299126 2015-10-22 CRYSTAL FORM OF CHIDAMIDE, PREPARATION METHOD AND USE THEREOF
US2010222379 2010-09-02 NOVEL HISTONE DEACETYLASE INHIBITORS
US7244751 2007-07-17 Histone deacetylase inhibitors of novel benzamide derivatives with potent differentiation and anti-proliferation activity

References

  1.  “China’s First Homegrown Pharma.”. April 2015.
  2. ^ Jump up to:a b [1]
  3.  HUYA Bioscience International Grants An Exclusive License For HBI-8000 In Japan And Other Asian Countries To Eisai. Feb 2016
  4.  Qiao, Z (2013-04-26). “Chidamide, a novel histone deacetylase inhibitor, synergistically enhances gemcitabine cytotoxicity in pancreatic cancer cells.”. Biochem Biophys Res Commun. 434 (1): 95–101. doi:10.1016/j.bbrc.2013.03.059. PMID 23541946.
  5.  Guha, Malini (2015-04-01). “HDAC inhibitors still need a home run, despite recent approval”. Nature Reviews Drug Discovery 14: 225–226. doi:10.1038/nrd4583.
  6.  Wang, Shirley S. (2015-04-02). “A New Cancer Drug, Made in China”. The Wall Street Journal. Retrieved 13 April 2015.
  7. References:
    1. Ning, Z. Q.; et. al. Chidamide (CS055/HBI-8000): a new histone deacetylase inhibitor of the benzamide class with antitumor activity and the ability to enhance immune cell-mediated tumor cell cytotoxicity. Cancer Chemother Pharmacol2012, 69(4), 901-909. (activity)
    2. Gong, K.; et. al. CS055 (Chidamide/HBI-8000), a novel histone deacetylase inhibitor, induces G1 arrest, ROS-dependent apoptosis and differentiation in human leukaemia cells. Biochem J 2012, 443(3), 735-746. (activity)

    3. Hu, W.; et. al. N-(2-amino-5-fluorophenyl)-4-[N-(Pyridin-3-ylacryloyl) aminomethyl ]benzamide or other derivatives for treating cancer and psoriasis. US7244751B2
    4. Lu, X.; et. al. Crystal form of chidamide, preparation method and use thereof. WO2014082354A1
    5. Yin, Z.-H.; et. al. Synthesis of chidamide,a new histone deacetylase (HDAC) inhibitor. Chin J New Drugs 2004, 13(6), 536-538. (starts with basic raw materials)
  8. Zhongguo Xinyao Zazhi (2004), 13(6), 536-538.

/////////Chidamide, Epidaza, CS055,  HBI-8000, orally active subtype-selective HDAC inhibitor, epigenetic modulator,  cancer treatment, CFDA, CHINA, CANCER

Fc3ccc(NC(=O)c1ccc(cc1)CNC(=O)/C=C/c2cccnc2)c(N)c3

(±)-Integrifolin, Compound from plants keeps human cancer cells from multipying


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CAS 89647-87-0

MFC15 H18 O4, MW 262.30
Azuleno[4,5-b]furan-2(3H)-one, decahydro-4,8-dihydroxy-3,6,9-tris(methylene)-, (3aR,4R,6aR,8S,9aR,9bR)-
  • Azuleno[4,5-b]furan-2(3H)-one, decahydro-4,8-dihydroxy-3,6,9-tris(methylene)-, [3aR-(3aα,4β,6aα,8β,9aα,9bβ)]-
  • (3aR,4R,6aR,8S,9aR,9bR)-Decahydro-4,8-dihydroxy-3,6,9-tris(methylene)azuleno[4,5-b]furan-2(3H)-one
  • 8-epi-Deacylcynaropicrin
  • 8β-Hydroxyzaluzanin C
  • Integrifolin (guaianolide)

STR1Integrifolin

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PATENT

WO 2011085979

Paper

Two New Amino Acid-Sesquiterpene Lactone Conjugates from Ixeris dentata

BLOG POST FROM CHEMISTRY VIEWS, WILEY

thumbnail image: Total Synthesis of (±)-IntegrifolinSTR1STR1STR1

(±)-Integrifolin

Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Total Synthesis of (±)-Integrifolin

Compound from plants keeps human cancer cells from multipying

Read more at Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Weight control is an important concern of human beings, both for medical (pharmaceutical and/or nutraceutical) as well as non-therapeutic, e.g. cosmetic, reasons. More importantly, excessive accumulation of body fat (i.e. obesity (= adiposity), especially with excessive fat in the ventral region and surrounding the viscera) can be dangerous and has been linked to health problems such as type II diabetes, hypertension, heart disease, atherosclerosis (where more than two of the preceding disorders are present, the condition is often called “Metabolic Syndrome” or “syndrome X”), hyperlipidemia, coronary heart disease, stroke, breast and colon cancer, sleep apnoea, gallbladder disease, reproductive disorders such as polycystic ovarian syndrome, gastroesophageal reflux disease, increased incidence of complications of general anesthesia, fatty liver, gout or thromboembolism (see, e.g., Kopelman, Nature 404: 635-43 (2000)). Obesity reduces life-span and carries a serious risk of the co-morbidities listed above, as well disorders such as infections, varicose veins,

acanthosis nigricans, eczema, exercise intolerance, insulin resistance, hypertension hypercholesterolemia, cholelithiasis, orthopedic injury, and thromboembolic disease (Rissanen et al, Br. Med. J. 301 : 835-7 (1990)). Obesity is one of the main factors in the development of cardiovascular diseases. As a side effect the levels of cholesterol, blood pressure, blood sugar and uric acid in obese people are usually higher than those of persons of normal weight. The morbidity from coronary heart disease among the overweight people is increased as well. Among the people aged 40-50, mortality will rise about 1% when body weight increases by 0.5 kg and the death rate will increase 74% when body weight exceeds 25% of the standard. The prevalence of obesity in the United States has more than doubled since the turn of the last century (whole population) and more than tripled within the last 30 years among children aged from 6 to 11. This problem more and more becomes a disease risk also in Europe. In Germany, particularly many people have been found to suffer from overweight recently, already 25% of the young people, children and adolescents there are affected by obesity and related disorders. Furthermore, being overweight is considered by the majority of the Western population as unattractive.

Overweight and obesity result from an imbalance between the calories consumed and the calories used by the body. When the calories consumed exceed the calories burned, the body is in positive energy balance and over time weight gain will occur. The excess calories are stored in the fat cells. When the calories burned exceed the calories consumed, the body is in negative energy balance and over time weight loss will occur.

Determinants of obesity include social factors, psychological factors, genetic factors, developmental factors and decreased physical activity. Some components of a comprehensive weight loss programs include medical assessment, behavioural and dietary modification, nutrition education, mental and cognitive restructuring, increased physical activity, and long term follow-up.

An increasing interest by consumers in the maintenance or reduction of their body weight can be found. This leads to a demand for products useful for these purposes. Preferred are such food products which can conveniently be consumed as part of the daily diet, for example meal replacer products, such as meal replacer bars and beverages. These are usually designed for use as a single-serving food product to replace one or two meals a day.

An issue is that often a saturating effect is missed when such products are consumed, resulting in hunger feelings only a relatively short time after consummation or even in the lack of a saturation feeling already directly after consummation.

Summing up, there remains a need for new safe and effective compositions for promoting weight loss and/or loss of body fat in subjects such as humans. The problem to be solved by the present invention is therefore to find compositions or compounds useful in the treatment of obesity; and/or for improving the total cholesterol HDIJLDL ratio.

Phytochemistry provides a large pool of compounds and compositions to be looked at whether they are able to solve this problem.

The present invention provides methods and compositions useful in the control, treatment and prevention of obesity and obesity-related conditions, disorders, and diseases; and/or and/or for improving the total cholesterol HDL/LDL ratio.

Rosinski, G., et al., Endocrinological Frontiers in Phyiological Insect Ecology, Wroclow Technical University Press, Wroclow 1989, describe that certain tricyclic sequiterpene lactones, such as grossheimin and repin, showed inhibition of larval growth and antifeeding activity in Mealworm (Tenebrio σιοΐϊίοή. Grossheimin shows no anti-feeding but little decrease of absorption of digested food constituents and a little decrease in efficiency in digesting. Repin exhibit low effects at all. Both compounds show no effect on lipid levels in blood.

Shimoda, H., et al, Bioinorganic & Medicinal Chemistry Letters 13 (2003), 223-228, describe that methanolic extracts from Artichoke (Cynara sclolymus L.) with cynaropicrin, aguerin B and grossheimin as components and certain sesquiterpene glycosides suppress serum triglyceride elevation in olive oil-loaded mice. Some of these compounds exhibit a moderate short term (2 hours after olive oil administration) anti-hyperlipidemic activity presented as a lowering of the serum triglyceride (serum TG) concentrations, the long term (6 hours) show in the case of cynaropicrin and aguerine B an increase of the serum TG. Furthermore the authors present data of the gastric emptying (GE) of a methanolic ectract of artichoke. They determine a significantly inhibited GE. However, as shown below, this mechanism is not an explanation for the anti obesity effect shown in the present invention (see Example 1 ).

Fritzsche, J., et al., Eur. Food Res. Technol. 215, 149-157 (2002) describe the effect of certain isolated artichoke leaflet extract components with cholesterol lowering potential. Ahn, E.M-., et al, Arch Pharm. res. 29(1 1 ), 937-941 , 2006, shows ACAT inhibitory activity for two sesquiterpene lactones. KR 20040070985 also shows an effect of certain sesquiterpene lactone derivatives on cholesterol biosynthesis involved enzymes. Gebhard, R., Phytother. Res. 16, 368-372 (2002) and J. Pharmacol. Exp. Ther. 286(3), 1 122-1 128 (1998), shows

enforcement of cholesterol biosynthesis inhibition in HepG2 cells by artichoke extracts. WO 2007/006391 also claims reduction in cholesterol by certain Cynara scolymus variety extracts.

Other reported activities of tricyclic sesquiterpene lactones are antioxidant activity (European Food Research & Technology (2002), 215(2): 149-157), inhibitors of NF kb (Food Style 21 (2007), 1 1 (6): 54-56; JP 2006-206532), serum triglyceride increase-inhibitory effect (Kagaku Kogyo (2006), 57(10): 740-745), hypoglycaemic effect (J. Trad. Med. (2003), 20(2): 57-61), bitter taste (DE 2654184). Any beneficial effects are included in this invention by reference.

None of the documents suggest that a control and treatment of obesity and body fat in warmblooded animals might be possible.

http://www.chemistryviews.org/details/ezine/9412451/Total_Synthesis_of_-Integrifolin.html?elq_mid=10181&elq_cid=1558306

Cynaropicrin, a tricyclic sesquiterpene lactone causes in vivo a strong weight loss. More surprisingly it was found that this effect is not correlated to a decrease in food intake. The weight balance is not affected by reduction of assimilation efficiency; the decrease of body fat and body weight is presumably caused by effects on energy metabolism. Surprisingly, it was found in addition that cynaropicrin also allows for improving the total cholesterol HDL7LDL ratio

Tricyclic sequiterpene lactones or known ingredients of plants of the subclass Asterides, especially from the family of Asteraceae, more specifically from species of the genera of the list consisting of Achilea, Acroptilon, Agranthus, Ainsliaea, Ajania, Amberboa, Andryala, Artemisia, Aster, Bisphopanthus, Brachylaena, Calea, Calycocorsus, Cartolepsis, Centaurea, Cheirolophus, Chrysanthemum, Cousinia, Crepis, Cynara, Eupatorium, Greenmaniella, Grossheimia, Hemistaptia, Ixeris, Jurinea, Lapsana, Lasiolaena, Liatris, Lychnophora, Macroclinidium, Mikania, Otanthus, Pleiotaxis, Prenanthes, Pseudostifftia, Ptilostemon,

Rhaponticum, Santolina, Saussurea, Serratula, Sonchus, Stevia, Taeckholmia, Tanacetum, Tricholepis, Vernonia, Volutarella, Zaluzania; even more specifically from species of the list consisting of Achillea clypeolata, Achillea collina, Acroptilon repens, Agrianthus pungens, Ainsliaea fragrans, Ajania fastigiata, Ajania fruticulosa, Amberboa lippi, Amberboa muricata, Amberboa ramose**, Amberboa tubuliflora and other Amberboa spp.*, Andryala integrifolia, Andryala pinnatifida, Artemisia absinthium, Artemisia cana, Artemisia douglasiana, Artemisia fastigiata, Artemisia franserioides, Artemisia montana, Artemisia sylvatica, Artemisia

tripartita, Aster auriculatus, Bishopanthus soliceps, Brachylaena nereifolia, Brachylaena perrieri, Calea jamaicensis, Calea solidaginea, Calycocorsus stipitatus, Cartolepsis intermedia, Centaurea babylonica, Centaurea bella, Centaurea canariensis*, Centaurea clementei, Centaurea conicum, Centaurea dealbata, Centaurea declinata, Centaurea glastifolia, Centaurea hermanii, Centaurea hyrcanica, Centaurea intermedia, Centaurea janeri, Centaurea kalscyi, Centaurea kandavanensis, Centaurea kotschyi, Centaurea linifolia, Centaurea macrocephala, Centaurea musimomum, Centaurea nicolai, Centaurea pabotii, Centaurea pseudosinaica, Centaurea repens, Centaurea salonitana, Centaurea scoparia, Centaurea sinaica, Centaurea solstitialis, Centaurea tweediei and other Centaurea spp. *, Cheirolophus uliginosus, Chrysanthemum boreale, Cousin ia canescens, Cousinia conifera, Cousinia picheriana, Cousinia piptocephala, Crepis capillaris, Crepis conyzifolia, Crepis crocea, Crepis japonica, Crepis pyrenaica, Crepis tectorum, Crepis virens, Crepis zacintha, Cynara alba, Cynara algarbiensis, Cynara auranitica, Cynara baetica, Cynara cardunculus, Cynara cornigera, Cynara cyrenaica, Cynara humilis, Cynara hystrix, Cynara syriaca, Cynara scolymus**, Cynara sibthorpiana and other Cynara spp.*, Eupatorium anomalum,

Eupatorium chinense, Eupatorium lindleyanum, Eupatorium mohrii, Eupatorium

rotundifolium, Eupatorium semialatum, Greenmaniella resinosa, Grossheimia

macrocephala** and other Grossheimia spp. *, Hemisteptia lyrata, Ixeris chinensis, Ixeris debilis, Ixeris dentata, Ixeris repens, Ixeris stolonifera, Jurinea carduiformis, Jurinea derderioides, Jurinea maxima, Lapsana capillaris, Lapsana communis, Lasiolaena morii, Lasiolaena santosii, Liatris chapmanii, Liatris gracilis, Liatris pycnostachya, Lychnophora blanchetii, Macroclinidium trilobum, Mikania hoehnei, Otanthus maritimus, Pleiotaxis rugosa, Prenanthes acerifolia, Pseudostifftia kingii, Ptilostemon diacanthus, Ptilostemon

gnaphaloides, Rhaponticum serratuloides, Santolina jamaicensis, Saussurea affinis,

Saussurea elegans, Saussurea involucrata, Saussurea laniceps, Saussurea neopulchella** and other Sauusurea spp. *, Serratula strangulata, Sonchus arborea, Stevia sanguinea, Taeckholmia arborea, Taeckholmia pinnata, Tanacetum fruticulosum, Tanacetum

parthenium, Tricholepis glaberrima** and other Tricholepsis spp. *, Vernonia arkansana, Vernonia nitidula, Vernonia noveboracensis, Vernonia profuga, Vernonia sublutea,

Volutarella divaricata, Zaiuzania resinosa; and can potentially be isolated from any part of the plants. Those genera and/or species marked with an asterisk (*) and especially those species marked with two asterisks (**) are especially preferred.

Appropriate plant material can be obtained from various sources, e.g. from:

Alfred Galke GmbH, Gittelde/Harz, Germany; Miiggenburg Pflanzliche Rohstoffe, Bad Bramstedt, Germany; Friedrich Nature Discovery, Euskirchen, Germany; VitaPlant AG, Uttwil, Switzerland; Amoros Nature SL, Hostalric, Spain.

(±)-Integrifolin

Banksia integrifolia

Coast Banksia

Family: Proteaceae

Banksia integrifolia is a tall shrub or small tree 6 – 16m tall. It is common in sandy coastal areas, but also grows in the forests of tablelands. The light grey bark is hard and rough.

Mature leaves 5 -10 cm long, are stiff, entire (untoothed), dull dark green above and hairy-white underneath. They are generally lanceolate. Younger leaves are irregularly toothed and shorter than the mature leaves. The species name ‘integrifolia’ means whole-leaved.

The pale yellow flower spikes of Banksia integrifolia range from 7-14cm long and 7cm wide. The bent styles emerge from individual flowers on the spike, straightening and spreading.

A short time after flowering, the seed pods protrude cleanly from the woody cone and open to shed black, papery, winged seeds.

Banksia integrifolia flowers from January to June.

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https://www.jstage.jst.go.jp/article/cpb1958/33/8/33_8_3361/_pdf

PAPER

http://onlinelibrary.wiley.com/doi/10.1002/chem.201601275/abstract

Total Synthesis of (±)-Integrifolin

  • DOI: 10.1002/chem.201601275

///////(±)-Integrifolin,  human cancer cells,  multipying

C=C1C(=O)O[C@@H]2[C@H]3C(=C)[C@@H](O)C[C@H]3C(=C)C[C@@H](O)[C@@H]12

GSK 1070916 For Advanced solid tumor


GSK 1070916

NMI-900 , GSK-1070916, GSK-1070916A

4-[3-(4-N,N-Dimethylcarbamylaminophenyl)-1-ethyl-1H-pyrazol-4-yl]-2-[3-(dimethylaminomethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine

N’-[4-[4-[2-[3-[(Dimethylamino)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-1-ethyl-1H-pyrazol-3-yl]phenyl]-N,N-dimethylurea

CAS 942918-07-2,

MFC30H33N7O,

MW507.63

PHASE 1/II , Advanced solid tumor, Cancer Research Technology,

off-white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm 12.14 (d, J = 1.8 Hz, 1H), 8.31 (s, 1H), 8.27 (s, 1 H), 8.07 (d, J = 4.8 Hz, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.77 (s, 1H), 7.43 (d, J = 8.6 Hz, 2H), 7.39 (d, J = 8.1 Hz, 1H), 7.27 (d, J = 8.6 Hz, 2H), 7.27 (dd, 1H), 6.79 (d, J = 5.1 Hz, 1H), 6.76 (d, J = 2.0 Hz, 1H), 4.27 (q, J = 7.3 Hz, 2H), 3.43 (s, 2H), 2.91 (s, 6H), 2.18 (s, 6H), 1.51 (t, J = 7.2 Hz, 3H).

MS m/z 508.4 [M + H]+. Anal. (C30H33N7O·1.0H2O) C, H, N.

GSK1070916 is a reversible and ATP-competitive inhibitor of Aurora B/C with IC50 of 3.5 nM/6.5 nM; displays >100-fold selectivity against the closely related Aurora A-TPX2 complex(IC50=490 nM).

NMI-900, an Aurora B/C kinase inhibitor, is under development at Cancer Research Technology in phase I/II clinical studies for the treatment of advanced and/or metastatic solid tumors. Other phase I clinical trials for the treatment of solid tumors had been previously completed, in a collaboration between GlaxoSmithKline and Cancer Research Technology, under the Cancer Research UK’s Clinical Development Partnerships (CDP) program.

The drug was originated by GlaxoSmithKline. The rights of the product were acquired by Cancer Research Technology from GlaxoSmithKline after the company elected not to take the program forward. In December 2015, the product was licensed by Cancer Research Technology to Nemucore Medical Innovations for the exclusive worldwide development and commercialization for the treatment of difficult-to-treat cancers.

GSK-1070916

PATENT

US 20070149561

https://www.google.com/patents/US20070149561

PAPER

Journal of Medicinal Chemistry (2010), 53 (10), 3973-4001

http://pubs.acs.org/doi/abs/10.1021/jm901870q

Discovery of GSK1070916, a Potent and Selective Inhibitor of Aurora B/C Kinase

Cancer Research, Oncology R&D
Molecular Discovery Research
GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426
§ Tsukuba Research Laboratories, Japan
J. Med. Chem., 2010, 53 (10), pp 3973–4001
DOI: 10.1021/jm901870q
Abstract Image

The Aurora kinases play critical roles in the regulation of mitosis and are frequently overexpressed or amplified in human tumors. Selective inhibitors may provide a new therapy for the treatment of tumors with Aurora kinase amplification. Herein we describe our lead optimization efforts within a 7-azaindole-based series culminating in the identification of GSK1070916 (17k). Key to the advancement of the series was the introduction of a 2-aryl group containing a basic amine onto the azaindole leading to significantly improved cellular activity. Compound 17k is a potent and selective ATP-competitive inhibitor of Aurora B and C with Ki* values of 0.38 ± 0.29 and 1.5 ± 0.4 nM, respectively, and is >250-fold selective over Aurora A. Biochemical characterization revealed that compound 17k has an extremely slow dissociation half-life from Aurora B (>480 min), distinguishing it from clinical compounds 1 and 2. In vitro treatment of A549 human lung cancer cells with compound 17k results in a potent antiproliferative effect (EC50 = 7 nM). Intraperitoneal administration of 17k in mice bearing human tumor xenografts leads to inhibition of histone H3 phosphorylation at serine 10 in human colon cancer (Colo205) and tumor regression in human leukemia (HL-60). Compound 17k is being progressed to human clinical trials.

http://pubs.acs.org/doi/pdf/10.1021/jm901870q………..PDF FILE