AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER
Jul 172017
 
Image result for helen p kavitha
SRM University
Chennai, Tamil Nadu, India

3b R = NITRO

str1

Dr. S. Sathishkumar

Dr. S. Sathishkumar
Assistant Professor in Chemistry, Kongu Engineering College, Perundurai, Erode – 638052

DR. HELEN P. KAVITHA

Dr. Helen P. Kavitha
Dr. Helen P. Kavitha

Professor and Head of the Department
E-mail: helen.p@rmp.srmuniv.ac.in
Area: Chemistry
Affiliation: Department of Chemistry, Ramapuram Campus, SRM University

Education

Ph.D. Organic Synthesis Bharathidasan University, Tiruchirapalli, 2000
M.Sc. General Chemistry Bharathidasan University, Tiruchirapalli, 1994
B.Sc. General Chemistry Bharathidasan University, 1992

Other Details:

Course

  • Chemistry
  • Principles of Environmental Science

Research Interests

  • Organic Synthesis
  • Medicinal Chemistry
  • Crystal Growth
  • Molecular Docking
  • Nano Synthesis

Selected PublicationS

  • A. Santhoshkumar, Helen P. Kavitha*, R. Suresh, Hydrothermal Synthesis, Characterization and Antibacterial Activity of NiO Nanoparticles, Journal of Advanced Chemical Sciences-Article in press
  • R. Kavipriya, Helen P. Kavitha, B. Karthikeyan, and A. Nataraj,” Molecular structure, spectroscopic (FT-IR, FT-Raman), NBO analysis of N,N0-diphenyl-6-piperidin-1-yl-[1,3,5]-triazine-2,4-diamine, Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 150 (2015) 476–487.
  • S. Sathishkumar, Helen P. Kavitha and S. Arulmurugan, In-silico anti-inflammatory evaluation of some novel tetrazolo and triazolodiazepine derivatives against COX-2 protien,  International Journal of Advanced Chemical Science and Applications, 3(1), 2015
  • S. Arulmurugan and Helen P Kavitha, S. Sathishkumar and R. Arulmozhi.       Review on biologically active benzimidazole, Miniriveviews in organic chemistry, 12(1), 178-195, 2015.
  • S. Sathishkumar and Helen P. Kavitha, Synthesis, Characterization and Anti-inflammatory Activity of Novel Triazolodiazepine Derivatives, IOSR Journal of Applied Chemistry, 8(1),47-52, 2015.
  • A. Silambarasan, Helen P. Kavitha, S. Ponnusamy, M. Navaneethan, Y. Hayakawa, Investigation of photocatalytic behavior of l-aspartic acid stabilized Zn(1−x)MnxS solid solutions on methylene blue Applied Catalysis A: General, 476, 22,1-8, 2014.
  • S. Sathish Kumar and Helen P. Kavitha, Synthesis and Biological Applications of Triazole Derivatives-A Review      Mini-Reviews in Organic Chemistry, 10(1), 2013.
  • Helen P. Kavitha and S. Arulmurugan     Synthesis, characterization and cytotoxic activity of benzoxazole, benzimidazole, imidazole and tetrazole      Acta pharmaceutica  63(2), 253-264, 2013
  • Jasmine P. Vennila, Jhon Thiruvadigal,  Helen P Kavitha,  G. Chakkaravarthi and V. Manivannan, N-[2-(3,4-Dimeth-oxy¬phenyl)eth¬yl]-N-methyl-naphthalene-1-sulfonamide, Acta Crystallogr Sect E, 68(Pt 3): o890, 2012.
  • Jasmine P. Vennila, D. Jhon Thiruvadigal,  and Helen P. Kavitha           Antibacterial evaluation of some organic compounds as potential inhibitors for glucosamine-6-phospate synthase            Journal of Pharmacy Research, 5(4), 1963-1966, 2012.
  • Helen P. Kavitha and R. Arulmozhi , Synthesis, Characterization and Anti inflammatory Activity of Some New Tetrazoles Derived from Quinazoline-4-one , International Journal of Chemistry, 1-6, 2012.
  • S. Arulmurugan, Helen P. Kavitha and S. Sathish Kumar.          Synthesis, characterization and molecular docking studies of some new benzoxazole, benzimidazole, imidazole and tetrazole compounds as potential inhibitors for thymidylate synthase, International Journal of Science and Technology, 1, 1-11 2012.
  • Jasmine P. Vennila, Jhon Thiruvadigal, G. E. Theboral Sugi Kamala,  Helen P Kavitha, Chakkaravarthi and V. Manivannan          N-[2-(3,4-Dimeth-oxy¬phen¬yl)eth¬yl]-N-methyl¬benzene-sulfonamide” Acta Crystallogr Sect E Struct Rep Online. 68(Pt 3), o882, 2012.
  • Helen P Kavitha, A. Silambarasan, S. Ponnusamy, M. Navaneethan and Y, Hayakawa, Monodispersed synthesis of hierarchical wurtzite ZnS nanostructures and its functional properties” Materials Letters 81, 209-211, 2012.
  • Jasmine P. Vennila, Jhon Thiruvadigal, Helen P Kavitha, G. Chakkaravarthi and V. Manivannan, 2-(4-Bromophenyl)-3-(4-hydroxyphenyl)-1,3-thiazolidin-4-one”  Acta Cryst., E67, o1902, 2011.
  • Jasmine P. Vennila, D Jhon Thiruvadigal, Helen P Kavitha, G. Chakkaravarthi and V. Manivannan    2,4-Bis(morpholin-4-yl)-6-phenoxy-1,3,5-triazine”  Acta Cryst. E67, o2451, 2011.
  • Jasmine P. Vennila, Jhon Thiruvadigal, Helen P Kavitha, G. Chakkaravarthi and V. Manivannan, 2-Chloro-4,6-bis(piperidin-1-yl)-1,3,5-triazine”  Acta Cryst. E67, o312, 2011.
  • Helen P. Kavitha, Samiappan Sathish kumar and Ramachandran Balajee           Antimicrobial Activity and Molecular Docking Studies of Some Novel Tetrazolo Diazepine Derivatives, Journal of Pharmacy Research,4(9), 2946-2949, 2011
  • Helen P. Kavitha and R. Arulmozhi  Study of Antimicrobial and Analgesic Activities of Novel Tetrazoles Derived from Quinazolin-4-one, Journal of Pharmacy Research , 4(12), 4696-4698, 2011.
  • R.Thilagavathy, Helen.P.Kavitha, R.Amrutha and Bathey.R.Venkatraman       Structural parameters, charge distribution and vibrational frequency analysis using theoretical SCF methods, Elixir Comp. Chem. 40, 5514-5516, 2011.
  • S. Sathish Kumar, Helen P. Kavitha, S. Arulmurugan  and B. R. Venkatraman, Review on Synthesis of Biologically Active Diazepam Derivatives           Mini-Reviews in Organic Chemistry, 8, 1-17, 2011.
  • Jasmine P. Vennila, Jhon Thiruvadigal, Helen P Kavitha, B. Gunasekaran and V. Manivannan, (E)-4-{(4-Bromopenzylidene) amino} phenol, Acta Cryst, E66, O316, 2010.
  • Subramaniyan Arulmurugan and Helen P. Kavitha, 2-Methyl-3-{4-[-(1H-tetrazol-5-yl)ethylamino]phenyl}-3H-quinazolin-4-one”,     Molbank, M695,1-5, 2010.
  • S. Arulmurugan, Helen P. Kavitha and B. R. Venkatraman        Biological Activities of Schiff Base and its Complexes”: A Review,           Rasayan Journal of Chemistry, 3(3), 385-410, 2010.
  • R. Thilagavathy, Helen P Kavitha and B. R. venkatraman          Isolation, Characterization and Anti-Inflammatory Property of Thevetia Peruviana     E-journal of Chemistry,7(4), 1584-1590, 2010.
  • Subramaniyan  Arulmurugan, Helen P. Kavitha, B. R. Venkatraman, Synthesis, Characterization and Study of antibacterial activity of some novel tetrazole derivatives” ,  Orbital Elec. J. Chem,  2(3), 271-276, 2010.
  • With R. Thilagavathi “Synthesis of 3-{4-[4-(benzylideneamino) benzene sulfonyl]-phenyl}-2-phenylquinazoline-4(3H)-one” Molbank, M589, 2009.
  • With S.Sathish Kumar “Synthesis of 3-Methyl-1-Morpholin-4-ylmethyl-2,6-Diphenylpiperidin-4-One”, Molbank, M617, 2009.
  • With S. Sathish Kumar “6-Methyl-2,7-Diphenyl-1,4-Diazepan-5-One”, Acta Cryst., E65, (o3211), 2009.
  • With R. Thilagavathi “2-phenyl-4H-3,1-benzoxazian-4-one”, Acta., Cryst. (E), E65, (o127), 2009.
  • With Suneel Manohar Babu “4-Bromo-3-{N[2-(3,4-dimethoxy phenyl)ethyl]-N-methyl-sulfamoyl}-5-methyl benzoic acid mono hydrate”, Acta., Cryst. (E), E65, (o1568), 2009.
  • With Suneel Manohar Babu “2,4-Dichloro-N-phenethyl benzene Sulfonamide” , Acta., Cryst. (E), E65, (o921), 2009.
  • With Suneel Manohar Babu “N-(5-Bromo-2-Chlorobenzyl)-N-cyclopropylnaphthlene-2-sulfonamide”,  Acta. Cryst. (E), E65, (o1098), 2009.
  • With Jasmine P. Vennila “4-nitrophenyl napthalene-1-sulfonate”, Acta Cryst. (E), (o1848), E64, 2008.
  • With R. Arulmozhi,”1- Naphthyl-9-HCarbazole-4-Sulphonate”, Acta Cryst., E66, 010208, 2008.
  • With T. Nithya “Antibacterial activity of Solanum Trilobatum”, Journal of  Ecotoxicol.Environ. Monit., 14, (237-239), 2004.
  • “Synthesis and Antimicrobial activity of1-(9’Acridinyl)-5-substituted phenyl Tetrazoles”, Asian Journal of chemistry, 16, (1191-1192), 2004.
  • With S. V. Selva bala “Study of Hypoglysemic Activity of Solanum Xanthocarpum L. on Alloxanised Diabetic Rats”, Adv. Pharmacol Toxicol., 4, (19-24), 2003.
  • Helen P. Kavitha “Study of anajesic activity some novel 1-(9’Acridinyl)-5-substituted phenyl tetrazoles”, Indian Journal of Chemical Technology, 9, (361-362), 2002.
  • With S.Malliga, “Effect of Soaking the Wood of Emblica officinalis,on Some Water Parameters”, Journal of   Swamy Bot. 15, (89-90), 1998.

Working Papers

  • With S. Arulmurugan, “Review on Biologically Active Benzimidazole derivatives”: Mini reviews in organic Chemistry.

Academic Experiences

  • Assistant Professor(S. G), SRM University, Ramapuram from Sep 2007 to Jun 2012
  • Lecturer, SRM University, Ramapuram from Aug 2004 to Aug 2007
  • Senior Lecturer, VRS College, Villupuram from Aug 2002 to May 2004
  • Lecturer, VRS College, Villupuram, from Aug 2000 to May 2002
  • Lecturer, ADM College for Women, Nagapattinam from July 94 to April 95

Other Professional Experiences

  • 4 Scholars have been  awarded Ph.D Degree
  • Guiding 3 Ph.D candidates
  • Guided 8 M. Phil and 20 M. Sc projects
  • Principal Investigator for a pilot project funded by SRM University (completed)
  • Co-investigator for a UGC major project (completed)
  • Reviewer for  International Journals
  • Convenor for the National Conference on New Renaissance in Chemical Research, 2011 and 2015.
  • Member Board of Studies –Chemistry,SRM University.
  • Doctoral Committee member in Karunya University
  • Undertaking consultancy work in the department
  • Question paper setter for various universities
  • Convenor for many programmes conducted in the campus
  • Chief Superintendent for SRM University-Ramapuram campus
  • Member in various professional bodies such as MISTE, FICCE and CTA
  • Author of five books in chemistry
  • Executive council member in Association of Chemistry Teachers, Mumbai

Achievement and Award

  • Received Award and cash prize for Research from SRM University from the year 2006-15

Image result for helen p kavitha

///////////////

Share

Synthesis of 2-[4-(4-Chlorophenyl)piperazin-1-yl]-2-methylpropanoic Acid Ethyl Ester

 spectroscopy, SYNTHESIS, Uncategorized  Comments Off on Synthesis of 2-[4-(4-Chlorophenyl)piperazin-1-yl]-2-methylpropanoic Acid Ethyl Ester
Dec 202016
 
str1
2-[4-(4-Chlorophenyl)piperazin-1-yl]-2-methylpropanoic Acid Ethyl Ester
1-Piperazineacetic acid, 4-(4-chlorophenyl)-α,α-dimethyl-, ethyl ester
2-[4-(4-Chlorophényl)-1-pipérazinyl]-2-méthylpropanoate d‘éthyle
Ethyl 2-[4-(4-chlorophenyl)-1-piperazinyl]-2-methylpropanoate
Ethyl-2-[4-(4-chlorphenyl)-1-piperazinyl]-2-methylpropanoat
1206769-44-9
2-[4-(4-Chlorophenyl)piperazin-1-yl]-2-methylpropanoic Acid Ethyl Ester (en)
AGN-PC-0JIRMK
AKOS016034964
ethyl 2-[4-(4-chlorophenyl)piperazin-1-yl]-2-methylpropanoate
MWt310.819
MFC16H23ClN2O2
Image result for MOM CAN TEACH YOU NMRNMR IS EASY
1H NMR PREDICT
 str0
ACTUAL VALUES……..1H NMR (400 MHz, CDCl3): δ ppm 1.27 (t, 3H, J = 7.2 Hz, -CH2-CH3), 1.35 (s, 6H, 2 x CH3), 2.74-2.76 (m, 4H, J = 4.8 Hz, -CH2-N-CH2-), 3.14-3.17 (m, 4H, J = 4.8 Hz, -CH2-N-CH2-), 4.20 (q, 2H, J = 7.2 Hz, -CH2-CH3), 6.81-6.83 (d, 2H, J = 6.8 Hz, phenyl protons), 7.17-7.20 (d, 2H, J = 6.8 Hz, phenyl protons).
str1
13C NMR PREDICT
str2
ACTUAL VALUES……..13C NMR (100 MHz, CDCl3): δ ppm 14.3 (CH3), 22.7 ((CH3)2), 46.6 (-CH2-N-CH2-), 49.7 (-CH2-N-CH2-), 60.5 (O-CH2), 62.4 (N-C-), 117.0, 124.3, 128.8, 149.8 (aromatic carbons), 174.3 (C=O).
str3
Paper

To a solution of 4-(4-chlorophenyl)piperazine dihydrochloride 1 (5.0 g, 0.0185 mol) in DMSO (30 ml), anhydrous cesium carbonate (30.0 g, 0.0925 mol), sodium iodide (1.39 g, 0.0093 mol) and ethyl 2-bromo-2-methylpropanoate 2 (3.97 g, 0.02 mol) were added. The resulting mixture was stirred at 25-30oC for 12 hours. The reaction mass was diluted with water (200 ml) and extracted with ethyl acetate (2 x 200 ml). The ethyl acetate layer was washed with water (2 x 100 ml), dried over anhydrous sodium sulfate (10.0 g) and concentrated under vacuum. The crude product thus obtained was purified by column chromatography (stationary phase silica gel 60-120 mesh; mobile phase 10% ethyl acetate in hexane). The title compound 3 was obtained as a white solid (4.73 g, 82 %).

Molbank 2009 m607 i001
Melting Point: 56oC.
EI-MS m/z (rel. int. %): 311 (100) [M+1]+, 236(40), 197(60), 154(45).
IR ν max (KBr) cm-1: 2839-2996 (C-H aliphatic); 1728 (C=O), 1595, 1505 (C=C aromatic), 1205 (C-O bending), 758 (C-Cl bending).
1H NMR (400 MHz, CDCl3): δ ppm 1.27 (t, 3H, J = 7.2 Hz, -CH2-CH3), 1.35 (s, 6H, 2 x CH3), 2.74-2.76 (m, 4H, J = 4.8 Hz, -CH2-N-CH2-), 3.14-3.17 (m, 4H, J = 4.8 Hz, -CH2-N-CH2-), 4.20 (q, 2H, J = 7.2 Hz, -CH2-CH3), 6.81-6.83 (d, 2H, J = 6.8 Hz, phenyl protons), 7.17-7.20 (d, 2H, J = 6.8 Hz, phenyl protons).
13C NMR (100 MHz, CDCl3): δ ppm 14.3 (CH3), 22.7 ((CH3)2), 46.6 (-CH2-N-CH2-), 49.7 (-CH2-N-CH2-), 60.5 (O-CH2), 62.4 (N-C-), 117.0, 124.3, 128.8, 149.8 (aromatic carbons), 174.3 (C=O).
Elemental analysis: Calculated for C16H23ClN2O2: C, 61.83%, H, 7.46%, N, 9.01%; Found: C, 61.90%, H, 7.44%, N, 8.98%.
Molbank 2009, 2009(3), M607; doi:10.3390/M607

Synthesis of 2-[4-(4-Chlorophenyl)piperazin-1-yl]-2-methylpropanoic Acid Ethyl Ester

1Department of Chemistry, Sambalpur University, JyotiVihar-768019, Orissa, India
2Institute of Chemical Technology (ICT), Matunga, Mumbai-400019, Maharashtra, India
*Author to whom correspondence should be addressed.
Received: 17 May 2009 / Accepted: 30 June 2009 / Published: 27 July 2009
Bijay K Mishra

Professor at Sambalpur University, Chemistry Department

Abstract

The title compound was synthesized by N-alkylation of 4-(4-chlorophenyl)piperazine with ethyl 2-bromo-2-methylpropanoate and its IR, 1H NMR, 13C NMR and Mass spectroscopic data are reported.

 

/////////

CCOC(=O)C(N1CCN(CC1)c1ccc(cc1)Cl)(C)C

Share

Women in Organic Chemistry

 Uncategorized  Comments Off on Women in Organic Chemistry
Jun 012015
 

 

List of female scientists before the 21st century – Wikipedia, the …

New

Women in Chemistry Win Student Service Award – News

cns.utexas.edu1667 × 1111Search by image

When Women in Chemistry (WIC), which has been awarded this year’s College of Natural Sciences Student Service Award, set out to survey chemistry graduate …

New

Prof.Vandana Patravale Keynote Speaker at nanobio Australia 2014 …

www.udctalumni.org.in

Vandana Patravale met their VC and Deans along with business tycoons in a special dinner party hosted by AIBC and they were very keen to work with Institute …

New

Prajakta Dandekar | LinkedIn

in.linkedin.com

 Prajakta Dandekar, UGC Assistant Professor in Engineering Sciences & Ramanujan Fellow, Institute Of Chemical Technology

New

New

Women in science | News Center | Wake Forest University

news.wfu.edu495 × 265Search by image

Professor Rebecca Alexander with Ph.D. student Veronica Casina: Still dealing with the

New

Dr Hina Siddiqui, Pakistani scientists, Eurasia Chemistry award
Dr. Hina Siddiqui, a research officer at ICCBS urged women to come towards Science and research.

New

Preshita Desai has received Best Oral Presentation Award …

www.udctalumni.org.in

Preshita Desai has received Best Oral Presentation Award – Newsroom – UDCT Alumni Network. «

New

Dr Deanna D’Alessandro wins L’Oreal Australia For Women in Science …

… from the School of Chemistry, has won a L’Oréal Australia For Women in Science Fellowship worth $20 000 for her work on metal-organic frameworks that …

New

LSU Tops in the Nation at Awarding Chemistry Ph.D. Degrees to …

www.lsu.edu300 × 200Search by image

BATON ROUGE – LSU is the top university in the nation in granting Ph.D. degrees in chemistry to women and underrepresented minority students, according to a …

New

Roxanne Bales vividly remembers the months she spent at a graduate program in organic chemistry in New England.

New

 

Ji Qi (GRS’06,’11), a graduate student pursuing a Ph.D. in chemistry, has been awarded a 2006-2007 Novartis Fellowship in Organic Chemistry for Women and …

New

 

LiveDNA: Publications of Suneela Sunil Dhaneshwar

livedna.org

Suneela Sunil Dhaneshwar,

Suneela Dhaneshwar – YouTube

www.youtube.com

Design and Development of Novel Azo Prodrugs using Various Permutations by Dr.Suneela

New

 

 

Chemistry professor Julia Kubanek

New

 

http://chemists.princeton.edu/knowles/

New

 

The 2014 winners of the The Elsevier Foundation Awards for Early Career Women Scientists in the Developing World accept their prizes at the annual AAAS …

One Organic Chemist One Day: Five Female Chemists Win TWAS Awardsoneorganichemistoneday.blogspot.com

Five Female Chemists Win TWAS Awards

New

 

 

Charusita Chakravarty

Women in Science

www.ias.ac.in1758 × 1995Search by image

Ph.D. (1990, Cambridge), FASc, is a recipient of S S Bhatnagar Award, Swarnajayanti Fellowship of the DST, the Bronze Medal of the Chemical Research Society …

New

 

.

One Organic Chemist One Day: Dr. Shamsun Nahar Khan

oneorganichemistoneday.blogspot.com

Dr. Shamsun Nahar Khan

New

 

 

One Organic Chemist One Day

 

One Organic Chemist One Day: Vinita Gupta, Group President and CEO …

oneorganichemistoneday.blogspot.com

Vinita Gupta, Group President and CEO at Lupin Pharmaceuticals

New

 

Annaliese K. Franz | UC Davis Department of Chemistry

 

 

One Organic Chemist One Day: Dr. Shamsun Nahar Khan

One Organic Chemist One Day: Prof Zuriati Zakaria…….Organic …

Women in Chemistry — Interview with Yamuna Krishnan :: ChemViews …

Women in Chemistry — Interview with Supawan Tantayanon …

Women in Chemistry — Interview with Zeinab Shaaban Abd El-Ati Abou …

Emma Carr, pioneering Physical Organic Chemist | Mount Holyoke College

Stanford Women in STEM Symposium

wiss.stanford.edu

Megan McClory is a lecturer in the Department of Chemistry. She is currently developing

New

Dr. Donna Nelson: Organic Chemist Synthesizing Research …

10 Indian women scientists you should be proud of

www.thealternative.in

She was an organic chemist from India who was known for her work in bio-organic chemistry, including “pioneering work in protein folding” and “ ..

New

Zakya H. Kafafi – 2007 SPIE Women in Optics Planner

spie.org

Head, Organic Optoelectronics Section, Optical Sciences Division, Naval Research Laboratory Washington, DC, USA

New

Blog Archive » Ms. Akiko Yagi has received the L’Oréal-UNESCO For …

synth.chem.nagoya-u.ac.jp

Ms. Akiko Yagi, Doctoral student in the Group of Prof. Itami has received the L’Oréal-UNESCO For Women in Science Award 2014!

New

Women in Nanoscience Blog

New

cl
June | 2007 | News @ Wesleyan

newsletter.blogs.wesleyan.edu

Andrea Roberts, visiting instructor of chemistry, has introduced “green” techniques into her organic chemistry laboratory sections.

New

Women in Chemistry—A European Journal :: ChemViews Magazine …

www.chemistryviews.org

From left to right: Jessica Nilsson, Francesca Novara, Karen Hindson, Katja Glatz, Rachel McGlue, Anne Deveson, Elisabeth von Roedern, Susan Wilkinson, …

New

One Organic Chemist One Day: Ranjala Ratnayake

oneorganichemistoneday.blogspot.com

Ranjala Ratnayake, Ph.D. (Natural Products Chemistry)

New

Sadhana Sathaye

Sadhana Sathaye

Associate professor of Pharmacy(Pharmacology) at Institute Of Chemical Technology

Lo Schiavo Science | University of San Francisco

blogs.usfca.edu

Tami Spector (on the left), professor of organic chemistry, in a chemistry lab with one of her current students: Amera Al-Faleh, a senior majoring in …

New

Kiran Mazumdar Shaw: (born 23 March 1953) She is the Chairman & Managing Director, Biocon Limited a biotechnology company based at Bangalore. She is on the Forbes list of the world’s 100 most powerful women and in business list on top 50 women released by the Financial Times’. In the year 1978, she started Biocon in the garage of her rented house in Bangalore with a seed capital of Rs. 10,000. Now the net worth of the company is more than $ 900 million. Now Biocon produces drugs for cancer, diabetes and auto-immune diseases. Product pipeline includes world’s first oral insulin, currently undergoing Phase III clinical trials.

Winners of the 2014 Elsevier Foundation Awards for Early Career Women Scientists in Developing Countries: (left to right) Dr. Eqbal Mohammed Abdu Dauqan (Biochemistry - Yemen), Dr. Simone Ann Marie Badal McCreath (Biochemistry - Jamaica), Dr. Taiwo Olayemi Elufioye (Pharmacology - Nigeria), Dr. Leni Ritmaleni (Medicinal Chemistry - Indonesia) and Dr. Nilufar Mamadalieva (Biochemistry - Uzbekistan). Photos by Alison BertWinners of the 2014 Elsevier Foundation Awards for Early Career Women Scientists in Developing Countries: (left to right) Dr. Eqbal Mohammed Abdu Dauqan (Biochemistry – Yemen), Dr. Simone Ann Marie Badal McCreath (Biochemistry – Jamaica), Dr. Taiwo Olayemi Elufioye (Pharmacology – Nigeria), Dr. Leni Ritmaleni (Medicinal Chemistry – Indonesia) and Dr. Nilufar Mamadalieva (Biochemistry – Uzbekistan). Photos by Alison Bert

Chicago — Five chemists were presented with the Elsevier Foundation Award for Early Career Women Scientists in the Developing World for research that looks to nature for ways to address cancer, malaria and other medical problems.The winning researchers, representing five regions of the developing world, are from Indonesia, Jamaica, Nigeria, Uzbekistan and Yemen. The prizes are awarded by The Elsevier Foundation, the Organization for Women in Science for the Developing World (OWSD) and The World Academy of Sciences for the advancement of science in developing countries (TWAS) with the aim of building scientific strength and advancing scientific knowledge in developing countries.

The 2014 winners

Central & South Asia

Nilufar Mamadalieva, PhD
Nilufar Mamadalieva, PhD

Dr. Nilufar Mamadalieva, Senior Scientific Researcher at the Institute of the Chemistry of Plant Substances in Tashkent, Uzbekistan, was honored for her work on the phytochemical and biological investigation of active compounds derived from medicinal plants growing in Central Asia, in particular the development of efficient nutraceuticals and the discovery of new lead compounds for the pharmaceutical industry.The field of natural substances, a tradition at the Tashkent Institute, is gaining more interest in western countries for the development of efficient nutraceuticals and the discovery of new lead compounds for the pharmaceutical industry.

Dr. Mamadalieva is the recipient of a number of international fellowships, which have allowed her to travel extensively and develop a network of international collaborators.

“This award gives me confidence and confirms that I’m going for the right goal,” she said.

East and South-East Asia & the Pacific

Leni Ritmaleni, PhD
Leni Ritmaleni, PhD

Dr. Leni Ritmaleni of the Faculty of Pharmacy at Gadjah Mada University in Yogyakarta, Indonesia, was honored for her work in the field of organic synthesis, focusing on the development of tropical medicines, in particular improved methods for the synthesis of sulfoxides and their application in the preparation of biologically active targets.She hopes her work will “encourage young women in Indonesia to love science, especially synthetic organic chemistry.”

“Women need science, science needs women and they need to work together,” she said.

Dr. Ritmaleni received her PhD from the School of Chemistry at Bristol University, UK after receiving a scholarship from the Indonesian government. She has won several awards in Indonesia and has published over 40 papers.

Dr. RItmaleni said researchers face various challenges at her institution, including a lack of access to scientific equipment and supplies and a scarcity of grants for basic science.

As a mother, she also strives to balance work and family, making “time management” an important priority.

She values the recognition provided by this award along with “the opportunity to connect with other scientists around the globe.”

Latin America & the Caribbean

Simone Ann Marie Badal McCreath, PhD
Simone Ann Marie Badal McCreath, PhD

Dr. Simone Ann Marie Badal McCreath manages the biochemistry lab at the Natural Products Institute at the University of the West Indies in Jamaica, and is designing a new cell culture lab at the same Institute. She was recognized for her work in designing a new cell culture lab to investigate the cancer-fighting properties of Jamaican natural compounds.Her interest is in screening Jamaican plant isolates for their potential properties slow down block or prevent the carcinogenic process. “Our findings have so far identified several isolates that are more potent in reducing cancer cell viability as well as potentially safer than anti-cancer drugs now on the market,” she said. “This research will pave the way for future research necessary for drug development and also the propagation and culture of novel Jamaican cancer and normal cells lines.

“Since cancer is the leading cause of death in Jamaica, such findings will prove useful in cancer treatment and prevention as well as earlier diagnosis in addition to identifying molecular targets that can improve selectivity of the isolates to cancer cells only.”

Dr. Badal McCreath has received numerous awards and has published extensively.

She said the challenges she faces in her career are less gender-based and more about the long delays in getting equipment and supplies to their lab as well as a lack of funding.

“Such challenges can cost us months even years of research,” she said. “Nonetheless, women in science do face challenges, and these become more apparent the higher the ladder you climb, the top of which is male dominated.”

Winning this award, she said, means attracting funding for cancer research in Jamaica and “the motivation of young and older women in science and other areas … to never give up but to persevere through gender-based and other issues that we daily face.”

Arab region

Eqbal Mohammed Abdu Dauqan, PhD PhD
Eqbal Mohammed Abdu Dauqan, PhD PhD

Dr. Eqbal Mohammed Abdu Dauqan is Head of the Department of Medical Laboratories Sciences at Al-Saeed University in Taizz, Yemen. She was honored for her research on the antioxidant properties of vegetable oils and specialized research in sensory evaluation and organic chemistry.She received her PhD from the National University of Malaysia. Her interests are in biochemistry and biotechnology, and she has conducted specialist research in food science, natural antioxidents and organic chemistry. She is also a dedicated teacher.

“Not all the people around us understand what natural antioxidents are,” she said. She and her colleagues do workshops for the public, pointing out the antioxident properties in vitamins such as C and E and how to find them in the foods they eat.

Sub-Saharan Africa

Taiwo Olayemi Elufioye, PhD
Taiwo Olayemi Elufioye, PhD

Dr. Taiwo Olayemi Elufioye is acting head of the Department of Pharmacognosy at the University of Ibadan, Nigeria. She was honored for her research on the medicinal properties of native Nigerian plants, in particular the effectiveness of different species in treating malaria, wounds, memory loss, leprosy and cancer.She said she has been able to identify a compound with good activity against a chloroquine-resistant strain of malaria parasites. Also, she and her research colleagues are creating an herb tea that that may be useful for dementia.

“My main challenge has been funding, typical for most developing world,” she said. “Also been a woman can be challenging considering the fact that prevailing conditions and policies are not necessarily woman-friendly.

“It’s just so great to know that despite these challenges, my contribution to science is being recognized. I feel so proud and definitely energized to do more.”

“The winners of the 2014 Elsevier Foundation prizes are impressive not just for their research, but also for their potential,” said TWAS Executive Director Romain Murenzi. “Certainly these awards could bring them exciting new opportunities for research. We also believe that, over time, these researchers also will fulfill their potential as teachers and mentors, as partners in international projects and as advisers to governments. Such leadership can make a long-lasting contribution to global science.”

David Ruth and Samira Omar Asam present the award to Dr. Nilufar Mamadalieva, Senior Scientific Researcher at the Institute of the Chemistry of Plant Substances in Uzbekistan.
David Ruth and Samira Omar Asam present the award to Dr. Nilufar Mamadalieva, Senior Scientific Researcher at the Institute of the Chemistry of Plant Substances in Uzbekistan.

Fang Xin, president of OWSD, said: “These five women, like all women undertaking scientific research in developing countries, will certainly have faced challenges on the road to this award. But their determination, commitment and enthusiasm have paid off. The award is recognition that they are excellent scientists and that their research has made an impact both regionally and internationally. They are an inspiration to all young women considering careers in science.”At the ceremony, Samira Omar Asem, VP for the OWSD Arab Region, said OWSD and TWAS see this award as “vital for encouraging women in developing countries to be more involved in science and technology and to make a more significant contribution to social and economic developments.”

David Ruth, Executive Director of the Elsevier Foundation, said professional visibility is crucial to developing high-profile international scientific careers, especially for women. He explained that the Elsevier Foundation provides support to early-career women scholars through its New Scholars grant programs as well as mentoring, research retreats, professional visibility, childcare, work-life integration and recognition programs.

“The awards for these impressive women scientists represent a cooperative effort supported by Elsevier, OWSD, AAAS and TWAS to build research capacity and advance scientific knowledge throughout the developing world,” he said, “and what better place than the annual AAAS conference to raise awareness among scientists, policymakers, journalists and the public about the need to retain and celebrate women scientists.”

chemistry at the Indian Institute of Science, Bangalore
MARGARET THATCHER AT OXFORD
alice

Dr. Alice Mohan Varghese

Assistant Professor

Specialization: Pharmaceutical Chemistry

M.Pharm., Ph. D.

Share

Market Opportunities Report on Poorly Soluble and Poorly Permeable Drugs

 Uncategorized  Comments Off on Market Opportunities Report on Poorly Soluble and Poorly Permeable Drugs
Jul 162014
 
AZoNano - The A to Z of Nanotechnology
Published on July 14, 2014 at 6:04 AM IN AZANO

Poor bioavailability is a major reason for compounds to fail in preclinical development. Technology Catalysts International (TCI), a leading global pharmaceutical consulting firm, has compiled and analyzed technical and market information pertaining to the delivery of poorly water soluble or poorly permeable pharmaceutical compounds.

http://www.azonano.com/news.aspx?newsID=30615

To download a complimentary excerpt of this report, go to:

http://www.technology-catalysts.com/pdf/psd7_bro.pdf

Source: http://www.technology-catalysts.com/

Share

Amidation of phenol derivatives: a direct synthesis of paracetamol (acetaminophen) from hydroquinone

 Uncategorized  Comments Off on Amidation of phenol derivatives: a direct synthesis of paracetamol (acetaminophen) from hydroquinone
May 302014
 

Green Chem., 2014, 16,2997-3002
DOI: 10.1039/C4GC00166D, Communication
Roxan Joncour, Nicolas Duguet, Estelle Metay, Amadeo Ferreira, Marc Lemaire
Paracetamol (acetaminophen) was prepared from hydroquinone and ammonium acetate in acetic acid with 88% yield and >99% purity.
A direct synthesis of paracetamol (acetaminophen) from hydroquinone has been developed using ammonium acetate as an amidating agent. The reaction proceeds in acetic acid at elevated temperatures without any metallic catalyst. Under these conditions, paracetamol was obtained with high yield and selectivity (>95%). The reaction has also been carried out on the multi-gram scale (44 g of hydroquinone) and a potential process has been proposed based on the recycling of the solvent and by-products. This amidation protocol has also been extended to other phenol derivatives.
ANTHONY MELVIN CRASTO

THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D

amcrasto@gmail.com

MOBILE-+91 9323115463
GLENMARK SCIENTIST ,  INDIA
web link
http://anthonycrasto.jimdo.com/

Congratulations! Your presentation titled “Anthony Crasto Glenmark scientist, helping millions with websites” has just crossed MILLION views.
アンソニー     安东尼   Энтони    안토니     أنتوني
join my process development group on google
you can post articles and will be administered by me on the google group which is very popular across the world
LinkedIn group
 
blogs are
 
shark

 

Share

Iloprost (ciloprost) used to treat a serious heart and lung disorder called pulmonary arterial hypertension

 orphan status  Comments Off on Iloprost (ciloprost) used to treat a serious heart and lung disorder called pulmonary arterial hypertension
Jan 132014
 

http://chem.sis.nlm.nih.gov/chemidplus/RenderImage?maxscale=30&width=300&height=300&superlistid=0078919138

Iloprost (ciloprost)

MF C22H32O4
Formula Wgt 360.5

6,9ALPHA-METHYLENE-11ALPHA,15S-DIHYDROXY-16-METHYL-PROSTA-5E,13E-DIEN-18-YN-1-OIC ACID

6,​9α-​methylene-​11α,​15S-​dihydroxy-​16-​methyl-​prosta-​5E,​13E-​dien-​18-​yn-​1-​oic acid

 

Iloprost Molecule

ILOPROST (Ventavis®) is used to treat a serious heart and lung disorder called pulmonary arterial hypertension. While iloprost inhalation solution will not cure this disorder, it is designed to improve symptoms and the quality of life. Generic iloprost inhalation solution is not yet available.

Iloprost is a second generation structural analog of prostacyclin (PGI) with about ten-fold greater potency than the first generation stable analogs, typified by carbaprostacyclin.1 Iloprost binds with equal affinity to the human recombinant IP and EP1 receptors with a Ki of 11 nM.2Iloprost constricts the isolated guinea pig ilium and fundus circular smooth muscle (an EP1 receptor preparation) as strongly as prostaglandin E2 (PGE2) itself.3 Iloprost inhibits the ADP, thrombin, and collagen-induced aggregation of human platelets with an ED50 of about 13 nM.1 In whole animals, iloprost acts as a vasodilator, hypotensive, antidiuretic, and prolongs bleeding time.4 It has been evaluated in several human clinical studies as a treatment for idiopathic pulmonary hypertension.5,6 In these studies, an aerosolized dose of 30 µg/day was effective, and doses as high as 150 µg/day for up to a year were well tolerated.

73873-87-7 CAS NO

78919-13-8 PHENACYL ESTER

Launched – 1992 bayer

Ilomedin®, Ventavis™

Iloprost.pngiloprost

An eicosanoid, derived from the cyclooxygenase pathway of arachidonic acid metabolism. It is a stable and synthetic analog of EPOPROSTENOL, but with a longer half-life than the parent compound. Its actions are similar to prostacyclin. Iloprost produces vasodilation and inhibits platelet aggregation.

BAY-q-6256 E-1030 SH-401 ZK-36374

  • BAY Q6256
  • Ciloprost
  • Iloprost
  • Iloprostum
  • Iloprostum [Latin]
  • UNII-AHG2128QW6
  • UNII-JED5K35YGL
  • Ventavis
  • ZK 00036374
  • ZK 36374

Endoprost Ilomedin Ilomédine Ventavis Iloprost is a synthetic prostacyclin analog discovered and developed by Schering AG and Berlex which has been available for more than ten years as therapy for peripheral arterial occlusive disease (PAOD), including Raynaud’s phenomenon and Buerger’s disease.

Iloprost improves blood flow, relieves the pain associated with circulatory disturbances and improves the healing of ulcers, which can develop as a result of poor arterial blood flow. Iloprost also produces vasodilatation of the pulmonary arterial bed, with subsequent significant improvement in pulmonary artery pressure, pulmonary vascular resistance and cardiac output, as well as mixed venous oxygen saturation. In 2003, Schering AG received approval in the E.U. for an inhaled formulation of iloprost (Ventavis[R]) for the treatment of primary pulmonary hypertension and the following year, the product was launched in Germany and the U.K.

Introduction on the U.S. market took place in March 2005 by CoTherix for the same indication in patients with NYHA Class III or IV symptoms. Iloprost is also available for the treatment of pulmonary hypertension and peripheral vascular disease. CoTherix had been developing a dry powder for potential use in the treatment of pulmonary hypertension; however, no recent development has been reported for this research. In Japan, phase III clinical trials are ongoing for the treatment of pulmonary arterial hypertension. In 2003, CoTherix licensed exclusive rights from Schering AG to market iloprost in the U.S. for primary pulmonary hypertension while Schering AG retained rights to the product outside the U.S. In April 2005, CoTherix established a collaborative research and development agreement with Quadrant to develop an extended-release formulation of iloprost inhalation solution. Iloprost was designated as an orphan medicinal product for the treatment of pulmonary hypertension in December 2000 by the EMEA and will fall under orphan drug protection until 2013.

The FDA has assigned to iloprost several orphan drug designations. In 1989, iloprost solution for infusion was granted orphan drug designation for the treatment of Raynaud’s phenomenon secondary to systemic sclerosis followed by another orphan drug designation in 1990 for iloprost solution for injection for the treatment of heparin-associated thrombocytopenia. In 2004, an additional orphan drug designation for iloprost inhalation solution for the treatment of pulmonary arterial hypertension was assigned.

The status has also been assigned in the E.U. for this indication. In 2012, orphan drug designation was assigned in the U.S. for the treatment of purpura fulminans in combination with eptifibatide and for the treatment of pulmonary arterial hypertension. In 2007, Cotherix was acquired by Actelion.

ILOPROST

 

 

iloprost phenacyl ester

Ventavis (TN), Iloprost phenacyl ester, Iloprost-PE, Iloprost (INN), CHEMBL138694, CHEMBL236025, AC1O6009, DAP000273, CID5311181

Molecular Formula: C30H38O5   Molecular Weight: 478.61972

2-oxo-2-phenylethyl 5-[(2Z)-5-hydroxy-4-[(1E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl]-octahydropentalen-2-ylidene]pentanoate

IMPORTANT PUBLICATIONS

Ciloprost Drugs Fut 1981, 6(11): 676

A carbohydrate approach for the formal total synthesis of the prostacyclin analogue (16S)-iloprost Tetrahedron Asymmetry 2012, 23(5): 388

Angewandte Chemie, 1981 ,  vol. 93,   12  pg. 1080 – 1081

Tetrahedron Letters, 1992 ,  vol. 33,   52  pg. 8055 – 8056

Helvetica Chimica Acta, 1986 ,  vol. 69,  7  pg. 1718 – 1727

Journal of Medicinal Chemistry, 1986 ,  vol. 29,  3  pg. 313 – 315

US5286494 A1

US 4474802

 US 2013253049

uS 2013184295

WO 1992014438

WO 1993007876

WO 1993015739

WO 1994008584

WO 2013040068

WO 2012174407

WO 2011047048

EP0011591A1 * Oct 18, 1979 May 28, 1980 Schering Aktiengesellschaft Prostane derivatives, their production and pharmaceutical compositions containing them
EP0084856A1 * Jan 19, 1983 Aug 3, 1983 Toray Industries, Inc. 5,6,7-Trinor-4, 8-inter-m-phenylene prostaglandin I2 derivatives
EP0099538A1 * Jul 11, 1983 Feb 1, 1984 Schering Aktiengesellschaft Carbacyclines, process for their preparation and their use as medicines

……………………………………

  •  5,6,7-trinor-4,8-inter-m-phenylene prostaglandin 12derivatives.
  • Prostaglandin I2, hereinafter referred to as PGI2, of

    Figure imgb0001

    was first found by J.R. Vane et.al. in 1976 and is biosynthe- sized from arachidonic acid via endoperoxide(PGH2 or PGG2) in the vascular wall. PGI2 is well known to show potent activity to inhibit platelet aggregation and to dilate peripheral blood vessels(C & EN, Dec. 20, 1976, page 17 and S. Moncade et al., Nature, 263,633(1976)).

  • [0003]
    Because of the unstable exo-enolether structure thereof, PGI2 is extremely unstable even in a neutral aqueous solution and is readily converted to 6-oxo-PGF which is almost physiologically inactive. Such instability of PGI2 is a big obstacle to its use as a drug. Furthermore, PGI2 is unstable in vivo as well and shows only short duration of action.
  • The compounds of the present invention are novel PGI2 derivatives in which the exo-enolether moiety characteristic of PGI2 is transformed into “inter-m-phenylene” moiety. In this sense the compounds may be regarded as analogs of PGI2.
  • The compounds of the present invention feature much improved stability in vitro as well as in vivo in comparison with PGI2. The compounds are highly stable even in an aqueous solution and show long duration of action in vivo. Further, the compounds have advantages over PGI2 for pharmaceutical application because they exhibit more selective physiological actions than PGI2, which has multifarious, inseperable biological activities.
  • Some prostaglandin I2 derivatives which have 5,6,7-tri- nor-4,8-inter-m-phenylene structure have already been described in publication by some of the present authors. (Kiyotaka Ohno, Hisao Nishiyama and Shintaro Nishio, U.S.P. 4,301,164 (1981)). But, the compounds of the present invention, which feature the presence of alkynyl side chain, have more potent physiological activities as well as decreased side effects than the already disclosed compounds analogous to those of the present invention.
  • It is an object of this invention to provide novel prostaglandin I2derivatives which are stable and possess platelet aggregation-inhibiting, hypotensive, anti-ulcer and other activities.

 

  • Figure imgb0004

    is named as 16-methyl-18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2.

  • Alternatively, the compound of the formula (II) may be named as a derivative of butyric acid by the more formal nomenclature. In such a case, the condensed ring moiety is named after the basical structure of 1H-cyclopenta[b]benzofuran of the following formula:

    Figure imgb0005

    The term “synthetic prostacyclins” as used herein can refer to any prostacyclin that can be prepared via synthetic organic chemistry, including those prostacyclins that are also naturally occurring, such as Prostacyclin (PGI2):

     

    Figure imgf000025_0001

    which is also known as Epopreostenol.

    Thus, examples of synthetic prostacyclins include, but are not limited to: Prosta

     

    Figure imgf000025_0002

    lloprost, which has the structure:

     

    Figure imgf000025_0003

    Trepro inil (also known as Rumodolin), which has the structure:

     

    Figure imgf000025_0004

    Beraprost, which has the structure:

     

    Figure imgf000026_0001

    as well as the esters, stereoisomers, and salts thereof, or other analogues or derivatives of the recited synthetic prostacyclins, such as compounds comprising other aliphatic linker groups linking the carboxylic acid group to the cyclic components of the synthetic prostacyclins, compounds containing additional alkene and/or alkyne bonds, and/or compounds containing additional substituents on the cyclic components of the synthetic prostacyclins.

    Figure imgf000031_0001

     iloprost, in contrast to PGI.sub.2 a stable prostacyclin derivative, has been known since 1980 by European patent application EP 11591, no other prostacyclin derivative has previously been tested in this indication. It is therefore reasonable to assume that a spontaneous healing is involved in the published case.

    It has now been found, surprisingly, that iloprost is effective in the case of cerebral malaria.

    For salt formation of iloprost, inorganic and organic bases are suitable, as they are known to one skilled in the art for the formation of physiologically compatible salts. For example, there can be mentioned: alkali hydroxides, such as sodium and potassium hydroxide, alkaline-earth hydroxides, such as calcium hydroxide, ammonia, amines, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, tris-(hydroxymethyl)-methylamine, etc.

    The β-cyclodextrin clathrate formation takes place according to EP 259468.

    The production of iloprost is described in detail in EP 11591.

    • Nileprost iloprost, and a process for preparing these compositions.
    • From EP 11 591 already carbacyclin derivatives of the cytoprotective effect on the gastric and intestinal mucosa, and the myocardial cytoprotection using carbacyclin derivatives is known.
    • It has now been found that iloprost (I) and Nileprost (II)

      Figure imgb0001

      and their salts with physiologically acceptable bases and cytoprotective effect in the kidney.

    • Forming salts of iloprost and Nileprost inorganic and organic bases are suitable, as are known to those skilled in the formation of physiologically compatible salts known. Examples which may be mentioned are: alkali metal hydroxides, such as sodium and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, ammonia, amines, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, tris (hydroxymethyl) methylamine, etc.
    • The production of iloprost and is described in detail in EP Nileprost 2234 and EP 11591.
    ………………..
    J. Med. Chem., 1986, 29 (3), pp 313–315
    DOI: 10.1021/jm00153a001

see paper

………………………………..
The formal total synthesis of the synthetic and stable analogue of prostacyclin, (16S) iloprost is described via a convergent synthesis starting from readily available d-glucose. Julia olefination and the aldol reaction are the key steps involved in the synthesis.
Full-size image (18 K)
……………………………………
  • Used as the starting material for the method described above ketone of general formula II can be prepared by reacting an alcohol of the formula IV

    Figure imgb0006

    (EJCorey et al., J. Amer. Chem. 93, 1490 (1971)) transformed with dihydropyran in the presence of catalytic amounts of p-toluenesulfonic acid in the tetrahydropyranyl ether V.

    Figure imgb0007
  • [0026]
    Lactone V with Diisobatylauminiumnydrid reduced at -70 ° C to the lactol VI, which is converted by Wittiereaktion Triphenylphosphoniummethylen with the olefin VII. After conversion to the tosylate with p-toluenesulfonyl chloride in the presence of pyridine is obtained by reaction with potassium nitrite in the dimethylsulfoxide 9SS-configured alcohol IX, which is converted with p-toluenesulfonyl chloride in the presence of pyridine in the tosylate X. Reaction with Malonsäurediäthylester in presence of potassium tert-butoxide gives the diester XI, which is converted by decarbalkoxylation with sodium cyanide in dimethyl sulfoxide in the ester XII.

    Figure imgb0008
  • [0027]
    Oxidative cleavage of the double bond in the compound XII with Hatrium p j o dat it out in the presence of catalytic amounts of osmium tetroxide to give the aldehyde XIII, which is oxidized with Jones reagent to the acid XIV which is then esterified with diazomethane to the compound XV. By Dieckmann condensation of XV with potassium tert-butoxide in tetrahydrofuran is obtained a mixture of isomers of the ketocarboxylic acid ester XVI and XVII, which by means of a decarbalkoxylation with 1,4-diazabicyclo [2,2,2] octane in xylene converted into ketone XVIII as the only reaction product is.

    Figure imgb0009
  • [0028]
    The removal of the Tetrahydropyranylätherschutzgruppe delivers the alcohol XIX, which is esterified with benzoyl chloride in the presence of pyridine to give the ester XX.

    Figure imgb0010
  • [0029]
    Benzyläthers hydrogenolytic cleavage of a catalytic amount of acid gives the alcohol XXI, which is according to ketalization compound XXII oxidized with Collins reagent to aldehyde XXIII.
  • [0030]
    This aldehyde XXIV with a phosphonate of the general formula

    Figure imgb0011

    wherein D, E and R 2 have the meanings given above is reacted in a Olefinicrungsreaktion to a ketone of the formula XXV.

    Figure imgb0012
  • [0031]
    After reduction of the 15-keto group with zinc borohydride or sodium borohydride or reaction with alkylmagnesium bromide or alkyllithium and. Epimerentrennung obtain the 15α-alcohols XXVI (PG numbering).

    Figure imgb0013
  • [0032]
    After hydrolysis of the ester group, for example with potassium carbonate in methanol and ketal cleavage with aqueous acetic acid yields the ketone of the formula XXVII,

    Figure imgb0014
……………………………………
ANTHONY MELVIN CRASTO

THANKS AND REGARD’S

DR ANTHONY MELVIN CRASTO Ph.D GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

did you feel happy, a head to toe paralysed man’s soul in action for you round the clock need help, email or call me

MOBILE-+91 9323115463
web link

I was  paralysed in dec2007, Posts dedicated to my family, my organisation Glenmark, Your readership keeps me going and brings smiles to my family

Share
Jan 092014
 

 

FAVIPIRAVIR

Toyama (Originator)

RNA-Directed RNA Polymerase (NS5B) Inhibitors

Chemical Formula: C5H4FN3O2
CAS #: 259793-96-9
Molecular Weight: 157.1

Anti-influenza compound

clinical trials  http://clinicaltrials.gov/search/intervention=Favipiravir
Chemical Name: 6-fluoro-3-hydroxy-2-pyrazinecarboxamide
Synonyms: T-705, T705, Favipiravir

T-705 is an RNA-directed RNA polymerase (NS5B) inhibitor which has been filed for approval in Japan for the oral treatment of influenza A (including avian and H1N1 infections) and for the treatment of influenza B infection.

The compound is a unique viral RNA polymerase inhibitor, acting on viral genetic copying to prevent its reproduction, discovered by Toyama Chemical. In 2005, Utah State University carried out various studies under its contract with the National Institute of Allergy and Infectious Diseases (NIAID) and demonstrated that T-705 has exceptionally potent activity in mouse infection models of H5N1 avian influenza.

T-705 (Favipiravir) is an antiviral pyrazinecarboxamide-based, inhibitor of of the influenza virus with an EC90 of 1.3 to 7.7 uM (influenza A, H5N1). EC90 ranges for other influenza A subtypes are 0.19-1.3 uM, 0.063-1.9 uM, and 0.5-3.1 uM for H1N1, H2N2, and H3N2, respectively. T-705 also exhibits activity against type B and C viruses, with EC90s of 0.25-0.57 uM and 0.19-0.36 uM, respectively. (1) Additionally, T-705 has broad activity against arenavirus, bunyavirus, foot-and-mouth disease virus, and West Nile virus with EC50s ranging from 5 to 300 uM.

Studies show that T-705 ribofuranosyl triphosphate is the active form of T-705 and acts like purines or purine nucleosides in cells and does not inhibit DNA synthesis

In 2012, MediVector was awarded a contract from the U.S. Department of Defense’s (DOD) Joint Project Manager Transformational Medical Technologies (JPM-TMT) to further develop T-705 (favipiravir), a broad-spectrum therapeutic against multiple influenza viruses.

Several novel anti-influenza compounds are in various phases of clinical development. One of these, T-705 (favipiravir), has a mechanism of action that is not fully understood but is suggested to target influenza virus RNA-dependent RNA polymerase. We investigated the mechanism of T-705 activity against influenza A (H1N1) viruses by applying selective drug pressure over multiple sequential passages in MDCK cells. We found that T-705 treatment did not select specific mutations in potential target proteins, including PB1, PB2, PA, and NP. Phenotypic assays based on cell viability confirmed that no T-705-resistant variants were selected. In the presence of T-705, titers of infectious virus decreased significantly (P < 0.0001) during serial passage in MDCK cells inoculated with seasonal influenza A (H1N1) viruses at a low multiplicity of infection (MOI; 0.0001 PFU/cell) or with 2009 pandemic H1N1 viruses at a high MOI (10 PFU/cell). There was no corresponding decrease in the number of viral RNA copies; therefore, specific virus infectivity (the ratio of infectious virus yield to viral RNA copy number) was reduced. Sequence analysis showed enrichment of G→A and C→T transversion mutations, increased mutation frequency, and a shift of the nucleotide profiles of individual NP gene clones under drug selection pressure. Our results demonstrate that T-705 induces a high rate of mutation that generates a nonviable viral phenotype and that lethal mutagenesis is a key antiviral mechanism of T-705. Our findings also explain the broad spectrum of activity of T-705 against viruses of multiple families.

favipiravir

Favipiravir also known as T-705 is an experimental anti-viral drug with activity against many RNA viruses. It, like some other experimental antiviraldrugs—T-1105 and T-1106, is apyrazinecarboxamide derivative. Favipiravir is active against influenza virusesWest Nile virusyellow fever virusfoot-and-mouth disease virus as well as other flavivirusesarenavirusesbunyavirusesand alphaviruses.[1]

The mechanism of its actions is thought to be related to the selective inhibition of viral RNA-dependent RNA polymerase. Favipiravir does not inhibit RNA of DNA synthesis in mammalian cells and is not toxic to them.[1]

  1.  Furuta, Y.; Takahashi, K.; Shiraki, K.; Sakamoto, K.; Smee, D. F.; Barnard, D. L.; Gowen, B. B.; Julander, J. G.; Morrey, J. D. (2009). “T-705 (favipiravir) and related compounds: Novel broad-spectrum inhibitors of RNA viral infections”. Antiviral Research 82 (3): 95–102. doi:10.1016/j.antiviral.2009.02.198PMID 19428599edit
  2. WO 2000010569
  3. WO 2008099874
  4. WO 201009504
  5. WO 2010104170
  6. WO 2012063931

 

Process route

OH

OH

hydrolysis

……………………………………………………………………………………

Influenza virus is a central virus of the cold syndrome, which has attacked human being periodically to cause many deaths amounting to tens millions. Although the number of deaths shows a tendency of decrease in the recent years owing to the improvement in hygienic and nutritive conditions, the prevalence of influenza is repeated every year, and it is apprehended that a new virus may appear to cause a wider prevalence.

For prevention of influenza virus, vaccine is used widely, in addition to which low molecular weight substances such as Amantadine and Ribavirin are also used

 

……………………………….

Synthesis of Favipiravir

ZHANG Tao1, KONG Lingjin1, LI Zongtao1,YUAN Hongyu1, XU Wenfang2*

(1. Shandong Qidu PharmaceuticalCo., Ltd., Linzi 255400; 2. School of Pharmacy, Shandong University, Jinan250012)

ABSTRACT: Favipiravir was synthesized from3-amino-2-pyrazinecarboxylic acid by esterification, bromination with NBS,diazotization and amination to give 6-bromo-3-hydroxypyrazine-2-carboxamide,which was subjected to chlorination with POCl3, fluorination with KF, andhydrolysis with an overall yield of about 22%.

………………………………..

US6787544

 

 

Figure US06787544-20040907-C00005

 

subs            G1 G2 G3 G4 R2
    compd 32 N CH C—CF3 N H

…………………

EP2192117

Figure US20100286394A1-20101111-C00001

Example 1-1

 

Figure US20100286394A1-20101111-C00002

 

To a 17.5 ml N,N-dimethylformamide solution of 5.0 g of 3,6-difluoro-2-pyrazinecarbonitrile, a 3.8 ml water solution of 7.83 g of potassium acetate was added dropwise at 25 to 35° C., and the solution was stirred at the same temperature for 2 hours. 0.38 ml of ammonia water was added to the reaction mixture, and then 15 ml of water and 0.38 g of active carbon were added. The insolubles were filtered off and the filter cake was washed with 11 ml of water. The filtrate and the washing were joined, the pH of this solution was adjusted to 9.4 with ammonia water, and 15 ml of acetone and 7.5 ml of toluene were added. Then 7.71 g of dicyclohexylamine was added dropwise and the solution was stirred at 20 to 30° C. for 45 minutes. Then 15 ml of water was added dropwise, the solution was cooled to 10° C., and the precipitate was filtered and collected to give 9.44 g of dicyclohexylamine salt of 6-fluoro-3-hydroxy-2-pyradinecarbonitrile as a lightly yellowish white solid product.

1H-NMR (DMSO-d6) δ values: 1.00-1.36 (10H, m), 1.56-1.67 (2H, m), 1.67-1.81 (4H, m), 1.91-2.07 (4H, m), 3.01-3.18 (2H, m), 8.03-8.06 (1H, m), 8.18-8.89 (1H, broad)

Example 1-2

4.11 ml of acetic acid was added at 5 to 15° C. to a 17.5 ml N,N-dimethylformamide solution of 5.0 g of 3,6-difluoro-2-pyrazinecarbonitrile. Then 7.27 g of triethylamine was added dropwise and the solution was stirred for 2 hours. 3.8 ml of water and 0.38 ml of ammonia water were added to the reaction mixture, and then 15 ml of water and 0.38 g of active carbon were added. The insolubles were filtered off and the filter cake was washed with 11 ml of water. The filtrate and the washing were joined, the pH of the joined solution was adjusted to 9.2 with ammonia water, and 15 ml of acetone and 7.5 ml of toluene were added to the solution, followed by dropwise addition of 7.71 g of dicyclohexylamine. Then 15 ml of water was added dropwise, the solution was cooled to 5° C., and the precipitate was filtered and collected to give 9.68 g of dicyclohexylamine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile as a slightly yellowish white solid product.

Examples 2 to 5

The compounds shown in Table 1 were obtained in the same way as in Example 1-1.

 

TABLE 1
Figure US20100286394A1-20101111-C00003
Example No. Organic amine Example No. Organic amine
2 Dipropylamine 4 Dibenzylamine
3 Dibutylamine 5 N-benzylmethylamine

 

Dipropylamine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile

1H-NMR (DMSO-d6) 6 values: 0.39 (6H, t, J=7.5 Hz), 1.10 (4H, sex, J=7.5 Hz), 2.30-2.38 (4H, m), 7.54 (1H, d, J=8.3 Hz)

Dibutylamine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile

1H-NMR (DMSO-d6) 6 values: 0.36 (6H, t, J=7.3 Hz), 0.81 (4H, sex, J=7.3 Hz), 0.99-1.10 (4H, m), 2.32-2.41 (4H, m), 7.53 (1H, d, J=8.3 Hz)

Dibenzylamine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile

1H-NMR (DMSO-d6) δ values: 4.17 (4H, s), 7.34-7.56 (10H, m), 8.07 (1H, d, J=8.3 Hz)

N-benzylmethylamine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile

1H-NMR (DMSO-d6) δ values: 2.57 (3H, s), 4.14 (2H, s), 7.37-7.53 (5H, m), 8.02-8.08 (1H, m)

Preparation Example 1

 

Figure US20100286394A1-20101111-C00004

 

300 ml of toluene was added to a 600 ml water solution of 37.5 g of sodium hydroxide. Then 150 g of dicyclohexylamine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile was added at 15 to 25° C. and the solution was stirred at the same temperature for 30 minutes. The water layer was separated and washed with toluene, and then 150 ml of water was added, followed by dropwise addition of 106 g of a 30% hydrogen peroxide solution at 15 to 30° C. and one-hour stirring at 20 to 30° C. Then 39 ml of hydrochloric acid was added, the seed crystals were added at 40 to 50° C., and 39 ml of hydrochloric acid was further added dropwise at the same temperature. The solution was cooled to 10° C. the precipitate was filtered and collected to give 65.6 g of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide as a slightly yellowish white solid.

1H-NMR (DMSO-d6) δ values: 8.50 (1H, s), 8.51 (1H, d, J=7.8 Hz), 8.75 (1H, s), 13.41 (1H, s)

 

………………….

jan 2014

Investigational flu treatment drug has broad-spectrum potential to fight multiple viruses
First patient enrolled in the North American Phase 3 clinical trials for investigational flu treatment drug

BioDefense Therapeutics (BD Tx)—a Joint Product Management office within the U.S. Department of Defense (DoD)—announced the first patient enrolled in the North American Phase 3 clinical trials for favipiravir (T-705a). The drug is an investigational flu treatment candidate with broad-spectrum potential being developed by BD Tx through a contract with Boston-based MediVector, Inc.

Favipiravir is a novel, antiviral compound that works differently than anti-flu drugs currently on the market. The novelty lies in the drug’s selective disruption of the viralRNA replication and transcription process within the infected cell to stop the infection cycle.

“Favipiravir has proven safe and well tolerated in previous studies,” said LTC Eric G. Midboe, Joint Product Manager for BD Tx. “This first patient signifies the start of an important phase in favipiravir’s path to U.S. Food and Drug Administration (FDA) approval for flu and lays the groundwork for future testing against other viruses of interest to the DoD.”

In providing therapeutic solutions to counter traditional, emerging, and engineered biological threats, BD Tx chose favipiravir not only because of its potential effectiveness against flu viruses, but also because of its demonstrated broad-spectrum potential against multiple viruses.  In addition to testing favipiravir in the ongoing influenzaprogram, BD Tx is testing the drug’s efficacy against the Ebola virus and other viruses considered threats to service members. In laboratory testing, favipiravir was found to be effective against a wide variety of RNA viruses in infected cells and animals.

“FDA-approved, broad-spectrum therapeutics offer the fastest way to respond to dangerous and potentially lethal viruses,” said Dr. Tyler Bennett, Assistant Product Manager for BD Tx.

MediVector is overseeing the clinical trials required by the  FDA  to obtain drug licensure. The process requires safety data from at least 1,500 patients treated for flu at the dose and duration proposed for marketing of the drug. Currently, 150 trial sites are planned throughout the U.S.

SOURCE BioDefense Therapeutics

 

Efficient synthesis of 3H,3’H-spiro[benzofuran-2,1′-isobenzofuran]-3,3′-dione as novel skeletons specifically for influenza virus type B inhibition.

Malpani Y, Achary R, Kim SY, Jeong HC, Kim P, Han SB, Kim M, Lee CK, Kim JN, Jung YS.

Eur J Med Chem. 2013 Apr;62:534-44. doi: 10.1016/j.ejmech.2013.01.015. Epub 2013 Jan 29.

 

 

US3631036 * Nov 4, 1969 Dec 28, 1971 American Home Prod 5-amino-2 6-substituted-7h-pyrrolo(2 3-d) pyrimidines and related compounds
US3745161 * Apr 20, 1970 Jul 10, 1973 Merck & Co Inc Phenyl-hydroxy-pyrazine carboxylic acids and derivatives
US4404203 * May 14, 1981 Sep 13, 1983 Warner-Lambert Company Substituted 6-phenyl-3(2H)-pyridazinones useful as cardiotonic agents
US4545810 * Mar 25, 1983 Oct 8, 1985 Sds Biotech Corporation Herbicidal and plant growth regulant diphenylpyridazinones
US4565814 * Jan 18, 1984 Jan 21, 1986 Sanofi Pyridazine derivatives having a psychotropic action and compositions
US4661145 * Sep 20, 1984 Apr 28, 1987 Rohm And Haas Company Plant growth regulating 1-aryl-1,4-dihydro-4-oxo(thio)-pyridazines
US5420130 May 16, 1994 May 30, 1995 Synthelabo 2-aminopyrazine-5-carboxamide derivatives, their preparation and their application in therapeutics
US5459142 * Aug 23, 1993 Oct 17, 1995 Otsuka Pharmaceutical Co., Ltd. Pyrazinyl and piperazinyl substituted pyrazine compounds
US5597823 Jun 5, 1995 Jan 28, 1997 Abbott Laboratories Tricyclic substituted hexahydrobenz [e]isoindole alpha-1 adrenergic antagonists
US6159980 * Sep 15, 1997 Dec 12, 2000 Dupont Pharmaceuticals Company Pyrazinones and triazinones and their derivatives thereof
EP0023358A1 * Jul 28, 1980 Feb 4, 1981 Rohm And Haas Company Process for the preparation of pyridazine derivatives
GB1198688A Title not available
HU9401512A Title not available
JPH09216883A * Title not available
JPS5620576A Title not available

 

ANTHONY MELVIN CRASTO

THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D

GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

did you feel happy, a head to toe paralysed man’s soul in action for you round the clock

need help, email or call me

MOBILE-+91 9323115463
web link

I was  paralysed in dec2007, Posts dedicated to my family, my organisation Glenmark, Your readership keeps me going and brings smiles to my family

Share

SURAMIN HEXASODIUM

 Uncategorized  Comments Off on SURAMIN HEXASODIUM
Jan 082014
 

 

suramin

A polyanionic compound with an unknown mechanism of action. It is used parenterally in the treatment of African trypanosomiasis and it has been used clinically with diethylcarbamazine to kill the adult Onchocerca. (From AMA Drug Evaluations Annual, 1992, p1643) It has also been shown to have potent antineoplastic properties.

A polyanionic compound with an unknown mechanism of action. It is used parenterally in the treatment of African trypanosomiasis and it has been used clinically with diethylcarbamazine to kill the adult Onchocerca. (From AMA Drug Evaluations Annual, 1992, p1643) It has also been shown to have potent antineoplastic properties. Suramin is manufactured by Bayer in Germany as Germanin®.

Also known as: Naphuride, Germanin, Naganol, Belganyl, Fourneau, Farma, Antrypol, Suramine, Naganin

8,8′-{Carbonylbis[imino-3,1-phenylenecarbonylimino(4-methyl-3,1-phenylene)carbonylimino]}di(1,3,5-naphthalenetrisulfonic acid) …FREE FORM

8,8′-[Ureylenebis[m-phenylenecarbonylimino(4-methyl-m-phenylene)carbonylimino]]di(1,3,5-naphthalenetrisulfonic acid) hexasodium salt

CAS  145-63-1 FREE FORM

129-46-4 of hexa sodium

LAUNCHED 1940 BAYER

Formula C51H40N6O23S6 
Mol. mass 1297.29

The molecular formula of suramin is C51H34N6O23S6. It is a symmetric molecule in the center of which lies ureaNH-CO-NH. Suramin contains eightbenzene rings, four of which are fused in pairs (naphthalene), four amide groups in addition to the one of urea and six sulfonate groups. When given as drug it usually contains six sodium ions that form a salt with the six sulfonate groups.

Suramin is a drug developed by Oskar Dressel and Richard Kothe of BayerGermany in 1916, and is still sold by Bayer under the brand nameGermanin.

Suramin sodium is a heparanase inhibitor that was first launched in 1940 by Bayer under the brand name Antrypol for the treatment of helminthic infection. It was later launched by Bayer for the treatment of trypanosomiasis (African sleeping sickness).

More recently, the product has entered early clinical development at Ohio State University for the treatment of platinum-pretreated patients with stage IIIB/IV non-small cell lung cancer, in combination with docetaxel or gemcitabine.

The National Cancer Institute (NCI) is conducting phase II clinical studies for the treatment of glioblastoma multiforme and for the treatment of adrenocortical carcinoma.

According to the National Cancer Institute there are no active clinical trials (as of April 1, 2008). Completed and closed clinical trials are listed here:[1]

In addition to Germanin, the National Cancer Institute also lists the following “Foreign brand names”: 309 F or 309 Fourneau,[1] Bayer 205, Moranyl, Naganin, Naganine.

It is used for treatment of human sleeping sickness caused by trypanosomes.[2]

It has been used in the treatment of onchocerciasis.[3]

It has been investigated as treatment for prostate cancer.[4]

Also, suramin as treatment for autism is being evaluated. [5]

Suramin is administered by a single weekly intravenous injection for six weeks. The dose per injection is 1 g.

The most frequent adverse reactions are nausea and vomiting. About 90% of patients will get an urticarial rash that disappears in a few days without needing to stop treatment. There is a greater than 50% chance of adrenal cortical damage, but only a smaller proportion will require lifelongcorticosteroid replacement. It is common for patients to get a tingling or crawling sensation of the skin with suramin. Suramin will cause clouding of the urine which is harmless: patients should be warned of this to avoid them becoming alarmed.

Kidney damage and exfoliative dermatitis occur less commonly.

Suramin has been applied clinically to HIV/AIDS patients resulting in a significant number of fatal occurrences and as a result the application of this molecule was abandoned for this condition. http://www.ncbi.nlm.nih.gov/pubmed/3548350

Suramin is also used in research as a broad-spectrum antagonist of P2 receptors[6][7] and agonist of Ryanodine receptors.[8]

ChemSpider 2D Image | 8,8'-{Carbonylbis[imino-3,1-phenylenecarbonylimino(4-methyl-3,1-phenylene)carbonylimino]}di(1,3,5-naphthalenetrisulfonic acid) | C51H40N6O23S6suramin

Its effect on telomerase has been investigated.[9]

It may have some activity against RNA viruses.[10]

In addition to antagonism of P2 receptors, Suramin inhibits the acitivation of heterotrimeric G proteins in a variety of other GPCRs with varying potency. It prevents the association of heteromeric G proteins and therefore the receptors Guanine exchange functionality (GEF). With this blockade the GDP will not release from the Gα subunit so it can not be replaced by a GTP and become activated. This has the effect of blocking downstream G protein mediated signaling of various GPCR proteins including Rhodopsin, the A1 Adenosine receptor, and the D2 dopamine receptor.[11]

A polyanionic compound with an unknown mechanism of action. It is used parenterally in the treatment of African trypanosomiasis and it has been used clinically with diethylcarbamazine to kill the adult Onchocerca. (From AMA Drug Evaluations Annual, 1992, p1643) It has also been shown to have potent antineoplastic properties. Suramin is manufactured by Bayer in Germany as Germanin®.

8-1-2012
InCl3-catalysed synthesis of 2-aryl quinazolin-4(3H)-ones and 5-aryl pyrazolo[4,3-d]pyrimidin-7(6H)-ones and their evaluation as potential anticancer agents.
Bioorganic & medicinal chemistry letters
9-1-2012
Identification of a sirtuin 3 inhibitor that displays selectivity over sirtuin 1 and 2.
European journal of medicinal chemistry
1-1-2013
Inhibition of the human deacylase Sirtuin 5 by the indole GW5074.
Bioorganic & medicinal chemistry letters
5-9-2013
Discovery of thieno[3,2-d]pyrimidine-6-carboxamides as potent inhibitors of SIRT1, SIRT2, and SIRT3.
Journal of medicinal chemistry
  1.  The formula of suramin was kept secret by Bayer for commercial reasons. But it was elucidated and published in 1924 by Fourneau and his team of the Pasteur Institute, and it is only on this date that its exact chemical composition was known. (E. Fourneau, J. and Th. Tréfouël and J. Vallée (1924). “Sur une nouvelle série de médicaments trypanocides”, C. R. Séances Acad. Sci. 178: 675.)
  2. Darsaud A, Chevrier C, Bourdon L, Dumas M, Buguet A, Bouteille B (January 2004). “Megazol combined with suramin improves a new diagnosis index of the early meningo-encephalitic phase of experimental African trypanosomiasis”Trop. Med. Int. Health 9 (1): 83–91.doi:10.1046/j.1365-3156.2003.01154.xPMID 14728611.
  3.  Anderson J, Fuglsang H (July 1978). “Further studies on the treatment of ocular onchocerciasis with diethylcarbamazine and suramin”Br J Ophthalmol 62 (7): 450–7.doi:10.1136/bjo.62.7.450PMC 1043255PMID 678497.
  4.  Ahles TA, Herndon JE, Small EJ, et al. (November 2004). “Quality of life impact of three different doses of suramin in patients with metastatic hormone-refractory prostate carcinoma: results of Intergroup O159/Cancer and Leukemia Group B 9480”. Cancer 101 (10): 2202–8.doi:10.1002/cncr.20655PMID 15484217.
  5.  http://medicalxpress.com/news/2013-03-drug-treatment-autism-symptoms-mouse.html
  6.  Abbracchio MP, Burnstock G, Boeynaems JM, Barnard EA, Boyer JL, Kennedy C, Knight GE, Fumagalli M, Gachet C, Jacobson KA, Weisman GA. (september 2006). “International Union of Pharmacology LVIII: update on the P2Y G protein-coupled nucleotide receptors: from molecular mechanisms and pathophysiology to therapy”. Pharmacol Rev. 58 (3): 281–341.doi:10.1124/pr.58.3.3PMID 16968944.
  7.  Khakh BS, Burnstock G, Kennedy C, King BF, North RA, Séguéla P, Voigt M, Humphrey PP. (march 2001). “International union of pharmacology. XXIV. Current status of the nomenclature and properties of P2X receptors and their subunits”. Pharmacol Rev. 53 (1): 107–118.PMID 11171941.
  8.  Wolner I, Kassack MU, Ullmann H, Karel A, Hohenegger M (October 2005). “Use-dependent inhibition of the skeletal muscle ryanodine receptor by the suramin analogue NF676”Br. J. Pharmacol. 146 (4): 525–33. doi:10.1038/sj.bjp.0706359PMC 1751178.PMID 16056233.
  9.  Erguven M, Akev N, Ozdemir A, Karabulut E, Bilir A (August 2008). “The inhibitory effect of suramin on telomerase activity and spheroid growth of C6 glioma cells”Med. Sci. Monit. 14(8): BR165–73. PMID 18667993.
  10.  Mastrangelo E, Pezzullo M, Tarantino D, Petazzi R, Germani F, Kramer D, Robel I, Rohayem J, Bolognesi M, Milani M (2012) Structure-based inhibition of norovirus RNA-dependent RNA-polymerases. J Mol Biol
  11.  Beindl W, Mitterauer T, Hohenegger M, Ijzerman AP, Nanoff C, Freissmuth M. (August 1996).“Inhibition of receptor/G protein coupling by suramin analogues”ol. Pharmacology. 50 (2): 415–23. PMID 8700151.
  12. Drugs Fut 1986, 11(10): 860
  13. WO 2012159107
  14. WO 2012087336
  15. US 2011257109
  16. WO 2009022897
  17. WO 2009020613
  18. WO 2008094027
  19.   EP 0486809
  20. US 5158940
  21. US 5173509
  22. WO 1993007864
  23. WO 1994008574

 

SURAMIN

Enterovirus-71 (EV71) is one of the major causative reagents for hand-foot-and-mouth disease. In particular, EV71 causes severe central nervous system infections and leads to numerous dead cases. Although several inactivated whole-virus vaccines have entered in clinical trials, no antiviral agent has been provided for clinical therapy. In the present work, we screened our compound library and identified that suramin, which has been clinically used to treat variable diseases, could inhibit EV71 proliferation with an IC50 value of 40μM. We further revealed that suramin could block the attachment of EV71 to host cells to regulate the early stage of EV71 infection, as well as affected other steps of EV71 life cycle. Our results are helpful to understand the mechanism for EV71 life cycle and provide a potential for the usage of an approved drug, suramin, as the antiviral against EV71 infection.

 

  • Suramin Hexasodium
  • 129-46-4

Synonyms

  • 309 F
  • Antrypol
  • BAY 205
  • Bayer 205
  • CI-1003
  • EINECS 204-949-3
  • Fourneau 309
  • Germanin
  • Moranyl
  • Naganin
  • Naganine
  • Naganinum
  • Naganol
  • Naphuride sodium
  • NF060
  • NSC 34936
  • SK 24728
  • Sodium suramin
  • Suramin Hexasodium
  • Suramin sodium
  • Suramina sodica
  • Suramina sodica [INN-Spanish]
  • Suramine sodique
  • Suramine sodique [INN-French]
  • Suramine sodium
  • Suraminum natricum
  • Suraminum natricum [INN-Latin]
  • UNII-89521262IH

 

Suramin Sodium, is an anticancer agent with a wide variety of activities.

Recently suramin was shown to inhibit FSH binding to its receptor (Daugherty, R. L.; Cockett, A. T. K.; Schoen, S. R. and Sluss, P. M. “Suramin inhibits gonadotropon action in rat testis: implications for treatment of advanced prostate cancer” J. Urol. 1992, 147, 727-732).

This activity causes, at least in part, the decrease in testosterone production seen in rats and humans that were administered suramin(Danesi, R.; La Rocca, R. V.; Cooper, M. R.; Ricciardi, M. P.; Pellegrini, A.; Soldani, P.; Kragel, P. J.; Paparelli, A.; Del Tacca, M.; Myers, C. E, “Clinical and experimental evidence of inhibition of testosterone production by suramin.” J. Clin. Endocrinol. Metab. 1996, 81, 2238-2246).

Suramin is the only non-peptidic small molecule that has been reported to be an FSH receptor binding antagonist.

Figure US06200963-20010313-C00003

Suramin is 8,8′ – (carbonylbis(imino-3,1-phenylenecarbonylimino (4-methyl-3,1-phenylene) carbonylimino)) bis-1,3 ,5-naphthalenetrisulfonic acid (GB Patent No. 224849). This polyanionic compound has been used for many decades as a prophylactic and therapeutic agent for try- panosomiasis. It was subsequently shown that suramin is able to block the activity of a variety of proteins like cellular and viral enzymes and growth factors (Mitsuya, M. et al. Science 226 : 172 (1984), Hosang, M. J. Cell. Biochem. 29 : 265 (1985), De Clercq, E. Cancer Lett. 8 : 9 (1979)).

 

5-32-1977
Complement inhibitors
5-25-1977
Aromatic amidines as antiviral agents in animals
5-4-1977
Complement inhibitors
5-4-1977
Complement inhibitors
4-27-1977
Cyclodextrin sulfate salts as complement inhibitors
4-20-1977
Ureylenebis methyl-phenylene-carbonyl-bis-dihydro-2-oxo-naphthoxazine disultonic acids
3-30-1977
Water treatment for controlling the growth of algae employing biguanides
3-2-1977
Isoxazole substituted nitroimidazoles
2-16-1977
Amidophenyl-azo-naphthalenesulfonic complement inhibitors and method of use thereof
2-9-1977
Complement inhibitors
2-10-2011
MODULATION OF HUMAN MAST CELL ACTIVATION MODULATION OF HUMAN MAST CELL ACTIVATION
11-18-2010
Admixtures for inorganic binders based on a hydrogenated disaccharide, inorganic binders containing these admixtures and process for their preparation Admixtures for inorganic binders based on a hydrogenated disaccharide, inorganic binders containing these admixtures and process for their preparation
10-28-2010
THERAPEUTIC INHIBITORS OF VASCULAR SMOOTH MUSCLE CELLS
9-9-2010
APPARATUS FOR USING ELECTROPORATION MEDIATED DELIVERY OF DRUGS AND GENES
4-8-2010
PREPARATION AND USE OF SULFATED OLIGOSACCHARIDES
10-29-2009
THERAPEUTIC INHIBITOR OF VASCULAR SMOOTH MUSCLE CELLS THERAPEUTIC INHIBITOR OF VASCULAR SMOOTH MUSCLE CELLS
8-20-2009
METHOD OF MAKING MINERAL FIBRES METHOD OF MAKING MINERAL FIBRES
6-25-2009
OXYGEN-FUEL BOOST REFORMER PROCESS AND APPARATUS
4-23-2009
METHODS OF TREATING VASCULAR DISEASE WITH TNF ANTAGONISTS METHODS OF TREATING VASCULAR DISEASE WITH TNF ANTAGONISTS
3-26-2009
COPOLYMER COMPOSITIONS FOR ORAL DELIVERY
5-3-1978
1,3,5- Or 1,3,6-naphthalenetriyltris(sulfonylimino)aryl acids and salts
3-22-1978
Nitroimidazoles
2-15-1978
Treatment of rheumatoid arthritis and related diseases
1-4-1978
AROMATIC AMIDINES AS ANTIVIRAL AGENTS IN ANIMALS
1-4-1978
Malto-dextrin poly(H-)sulfates
12-14-1977
Disazo compounds useful as complement inhibitors
12-7-1977
Bis-substituted naphthalene-azo phenyleneazo-stilbene-disulfonic and naphthalene-sulfonic acid
9-28-1977
UREIDOPHENYLENEBIS(CARBONYLIMINO)DINAPHTHALENETRISULFONIC ACID COMPOUNDS
9-21-1977
Substituted bisnaphthylazo diphenyl ureido complement inhibitors
9-7-1977
Substituted-hydroxy-naphthalenedisulfonic acid compounds

 

1-12-1977
Complement inhibitors
12-22-1976
Complement inhibitors
10-13-1976
Complement inhibitors

 

EP0183352A2 * Sep 27, 1985 Jun 4, 1986 THE UNITED STATES OF AMERICA as represented by the Secretary United States Department of Commerce Use of suramin for clinical treatment of infection with any of the members of the family of human-t-cell leukemia (htvl) viruses including lymphadenopathy virus (lav)
EP0205077A2 * Jun 3, 1986 Dec 17, 1986 Bayer Ag Suramin sodium for use as an immunostimulant

 

EP0515523A1 * Feb 13, 1991 Dec 2, 1992 THE UNITED STATES OF AMERICA as represented by the Secretary United States Department of Commerce Use of suramin to treat rheumatologic diseases
EP0755254A1 * Mar 24, 1995 Jan 29, 1997 The Trustees Of The University Of Pennsylvania Prevention and treatment of ischemia-reperfusion and endotoxin-related injury using adenosine and purino receptor antagonists
EP1460087A1 * Feb 17, 1997 Sep 22, 2004 The Kennedy Institute Of Rheumatology Methods of treating vascular disease with TNF antagonists
EP1940376A2 * Oct 3, 2006 Jul 9, 2008 Rottapharm S.P.A. Use of neboglamine in the treatment of toxicodependency
EP1945204A2 * Oct 27, 2006 Jul 23, 2008 Brane Discovery S.R.L. V-atpase inhibitors for use in the treatment of septic shock
US5453444 * Oct 6, 1994 Sep 26, 1995 Otsuka Pharmaceutical Co., Ltd. Method to mitigate or eliminate weight loss
US5534539 * Jun 12, 1995 Jul 9, 1996 Farmitalia Carlo Erba S.R.L. Biologically active ureido derivatives useful as anit-metastic agenst
US5596105 * Jan 13, 1995 Jan 21, 1997 Farmitalia Carlo Erba S.R.L. Therapeutically active naphthalenesulfonic pyrrolecarboxamido derivatives
US7476693 Mar 26, 2003 Jan 13, 2009 Eastern Virginia Medical School Suramin and derivatives thereof as topical microbicide and contraceptive
US7608262 Feb 16, 1996 Oct 27, 2009 The Kennedy Institute Of Rheumatology Methods of preventing or treating thrombosis with tumor necrosis factor antagonists
US8552064 Dec 19, 2008 Oct 8, 2013 Eastern Virginia Medical School Suramin and derivatives thereof as topical microbicide and contraceptive
WO1994008574A1 * Oct 12, 1993 Apr 28, 1994 Otsuka America Pharmaceutical Treatment of cachexia and inhibition of il-6 activity
WO1994010990A1 * Nov 12, 1993 May 26, 1994 British Bio Technology Inhibition of tnf production
WO1997030088A2 * Feb 17, 1997 Aug 21, 1997 Kennedy Inst Of Rheumatology Methods of treating vascular disease with tnf antagonists
WO2004113920A1 * Jun 18, 2004 Dec 29, 2004 Babon Jeff James Screening method for substances binding to merozoite surface protein-1/42
WO2008138943A2 * May 14, 2008 Nov 20, 2008 Mara Galli Prophylactic and therapeutic use of sirtuin inhibitors in tnf-alpha mediated pathologies
WO2009137471A2 * May 5, 2009 Nov 12, 2009 University Of Miami Azo dye related small molecule modulators of protein-protein interactions
WO2010016628A1 * Jul 10, 2009 Feb 11, 2010 Sammy Opiyo Conjugated suramin amino compounds for medical conditions
WO2012159107A1 * May 21, 2012 Nov 22, 2012 Rhode Island Hospital Inhibition of renal fibrosis

 

 

 

ANTHONY MELVIN CRASTO

THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D

GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

did you feel happy, a head to toe paralysed man’s soul in action for you round the clock

need help, email or call me

MOBILE-+91 9323115463
web link

I was  paralysed in dec2007, Posts dedicated to my family, my organisation Glenmark, Your readership keeps me going and brings smiles to my family

 

 

Share

CASOPITANT

 Uncategorized  Comments Off on CASOPITANT
Jan 072014
 

CASOPITANT

Tachykinin NK1 Antagonists

(2S,4S)-4-(4-Acetyl-1-piperazinyl)-N-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]-2-(4-fluoro-2-methylphenyl)-N-methyl-1-piperidinecarboxamide

4-(S)-(4-Acetyl-piperazin-1-yl)-2- (R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic acid, [1-(R)-(3,5-bis-trifluoromethyl- phenyl)-ethyl]-methylamide

414910-30-8  MESYLATE
414910-27-3 (free base)

679769
GW-679769
GW-679769B

MF C30H35F7N4O2.CH4O3S MESYLATE
 Molecular Weight 712.719

 

Casopitant (trade names Rezonic (US), Zunrisa (EU)) is an neurokinin 1 (NK1receptor antagonist undergoing research for the treatment of chemotherapy-induced nausea and vomiting (CINV).[1] It is currently under development by GlaxoSmithKline (GSK).

In July 2008, the company filed a marketing authorisation application with the European Medicines Agency. The application was withdrawn in September 2009 because GSK decided that further safety assessment was necessary.[2]    Casopitant mesylate, a tachykinin NK1 receptor antagonist, had been filed for approval in the U.S. and the E.U. by GlaxoSmithKline for the prophylaxis of chemotherapy-induced nausea/vomiting.

In 2009 the company discontinued the development of the drug candidate for this indication. An MAA had also been filed for the treatment of postoperative nausea and vomiting, and in 2009 the application was withdrawn by the company.

Additional phase II clinical trials were ongoing at GlaxoSmithKline for the treatment of depression, anxiety, sleep disorders, fibromyalgia and overactive bladder, however, no recent developments have been reported for these indications.

  1.  Lohr L (2008). “Chemotherapy-induced nausea and vomiting”. Cancer J 14 (2): 85–93.doi:10.1097/PPO.0b013e31816a0f07PMID 18391612.
  2.  “GlaxoSmithKline withdraws its marketing authorisation application for Zunrisa”. London: EMEA. 13 October 2009. Retrieved 21 December 2009
  3. Casopitant mesilate
    Drugs Fut 2008, 33(9): 737
  4. WO 2002032867
  5. WO 2008046882
  6. Development of a control strategy for a defluorinated analogue in the manufacturing process of casopitant mesylate
    Org Process Res Dev 2010, 14(4): 832 NMR FREE BASE, MESYLATE
  7. WO 2006061233
  8. WO 2004091616
  9. US20040014770 ENTRY 1B MP MESYLATE 243
  10. Tetrahedron, 2010 ,  vol. 66,  26  p. 4769 – 4774 NMR FREE BASE
  11. Journal of Medicinal Chemistry, 2011 ,  vol. 54,   4  p. 1071 – 1079 NMR MESYLATE
WO2006061233A1 * Dec 7, 2005 Jun 15, 2006 Glaxo Group Ltd The use of medicament 4-(s)-(4-acetyl-piperazin-1-yl)-2-(r)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic acid, [1-(r)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide

 

WO2001044200A2 * Dec 14, 2000 Jun 21, 2001 David J Blythin Selective neurokinin antagonists
WO2002010141A1 * Jul 25, 2001 Feb 7, 2002 Michael Kirk Ahlijanian Imidazole derivatives
WO2002032867A1 * Oct 12, 2001 Apr 25, 2002 Giuseppe Alvaro Chemical compounds
US20020123491 * Dec 14, 2000 Sep 5, 2002 Neng-Yang Shih Selective neurokinin antagonists
US20030064980 * Jun 6, 2002 Apr 3, 2003 Neng-Yang Shih Selective neurokinin antagonists
US20030144270 * Nov 12, 2002 Jul 31, 2003 Schering Corporation NK1 antagonists

 

Casopitant (Rezonic, Zunrisa, casopitant mesylate, GW-679769, 679769, CAS #414910-27-3), 4-(4-Acetyl-piperazin-1-yl)-2-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic acid [1-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide, is a NK-1 receptor antagonist.

Casopitant is under investigation for the treatment of emesis, nausea, drug-induced nausea, chemotherapy-induced nausea and vomiting, post-operative nausea and vomiting, sleep disorders, anxiety disorders, depressive disorders, overactive bladder, and myalgia (Drug Report for Casopitant, Thomson Investigational Drug Database (Sep. 15, 2008); Reddy et al., Supportive Cancer Therapy 2006, 3(3), 140-142; and WO 2006/061233).

Casopitant has also shown promise in treating disorders of the central nervous system, tinitis, and sexual dysfunction (WO 2006/061233).

compound may be of value in the treatment of Sexual dysfunctions including Sexual Desire Disorders such as Hypoactive Sexual Desire Disorder and Sexual Aversion Disorder sexual arousal disorders such as Female Sexual Arousal Disorder and Male Erectile Disorder orgasmic disorders such as Female Orgasmic Disorder, Male Orgasmic Disorder and Premature Ejaculation sexual pain disorder such as Dyspareunia and Vaginismus, Sexual Dysfunction Not Otherwise Specified; paraphilias such as Exhibitionism, Fetishism, Frotteurism, Pedophilia, Sexual Masochism, Sexual Sadism Transvestic Fetishism, Voyeurism and Paraphilia Not Otherwise Specified gender identity disorders such as Gender Identity Disorder in Children and Gender Identity Disorder in Adolescents or Adults and Sexual Disorder Not Otherwise Specified.

 

Figure US20100137332A1-20100603-C00002

 

Casopitant is subject to CYP3A4-mediated oxidative metabolism at the 3-carbon of the piperazine ring to form a hydroxylated metabolite which may be further oxidized to the corresponding 3-oxo metabolite (Minthorn et al, Drug Metab. Disp., 2008, 36(9), 1846-1852). Adverse effects associated with casopitantadministration include: neutropenia, nausea, hiccups, headache, constipation, dizziness, pruritis, alopecia, and fatigue.

Overactive bladder is a term for a syndrome that encompasses urinary frequency, with or without urge incontinence, generally but not necessarily combined with pollacisuria and nocturia. Overactive bladder is also characterised by involuntary detrusor contractions which are either triggered by provocation or occur spontaneously. If the detrusor hyperactivity observed is based on neurological causes (e. g. Parkinson’s disease, apoplexy, some forms of multiple sclerosis, spinal cord injury or the cross section of the bone marrow) it is known as neurogenic detrusor hyperactivity. If no clear cause can be detected this is known as idiopathic detrusor hyperactivity. In addition, detrusor hyperactivity may be associated with anatomical changes in the lower urinary tract, for example, in patients with bladder outlet obstruction (an enlargement of the prostate gland in males)

International patent application WO 02/32867 describes novel piperidine derivatives. A 0 particular preferred compound described therein is 4-(S)-(4-Acetyl-piperazin-1-yl)-2-(R)- (4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic acid

 

…………………………………………………………………

CASOPITANT MESYLATE

http://chem.sis.nlm.nih.gov/chemidplus/RenderImage?maxscale=30&width=300&height=300&superlistid=0414910308

US20040014770

EXAMPLE 4

[0330] 4-(S)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-Carboxylic Acid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide Methanesulphonate

[0331] A solution of intermediate 4a (7.7 g) in acetonitrile (177 mL) was added to a solution of 1-acetyl-piperazine (3.9 g) in acetonitrile (17.7 mL) followed by sodium triacetoxyborohydride (6.4 g) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 24 hours and then quenched with a saturated sodium hydrogen carbonate (23.1 mL) and water (61.6 mL). The resulting solution was concentrated in vacuo, then AcOEt (208 mL) was added; the layers were separated and the aqueous layer was back-extracted with further AcOEt (2×77 mL). The collected organic phases were washed with brine (2×118 mL), dried and concentrated in vacuo to give the crude mixture of syn and anti diastereomers (nearly 1:1) as a white foam (9.5 g).

[0332] A solution of this intermediate in THF (85.4 mL) was added to a solution of methansulfonic acid (0.890 mL) in THF (6.1 mL) at r.t. After seeding, the desired syn diastereomer started to precipitate. The resulting suspension was stirred for 3 hours at 0° C. and then filtered under a nitrogen atmosphere. The resulting cake was washed with cold THF (15.4 mL) and dried in vacuo at +20° C. for 48 hours to give the title compound as a white solid (4.44 g).

[0333] NMR (d6-DMSO): δ (ppm) 9.52 (bs, 1H); 7.99 (bs, 1H); 7.68 (bs, 2H); 7.23 (m, 1H); 6.95 (dd, 1H); 6.82 (m, 1H); 5.31 (q, 1H); 4.45 (bd, 1H); 4.20 (dd, 1H); 3.99 (bd, 1H); 3.65-3.25 (bm, 5H); 3.17 (m, 1H); 2.96 (m, 1H); 2.88-2.79 (m+m, 2H); 2.73 (s, 3H); 2.36 (s, 3H); 2.30 (s, 3H); 2.13-2.09 (bd+bd, 2H); 2.01 (s, 3H); 1.89-1.73 (m+m, 2H); 1.46 (d, 3H).

[0334] m.p 243.0° C.

[0335] The compound is isolated in a crystalline form.

 

intermediate 4a is needed  for above syn, ignore 4b

[0168] Intermediate 4

[0169] 2-(R)-(4-Fluoro-2-methyl-phenyl)-4-oxo-piperidine-1-Carboxylic Acid, [1-(R)-3,5-bis-trifluoromethyl-phenyl)ethyl]-Methylamide (4a) and 2-(S)-(4-Fluoro-2-methyl-phenyl)-4-oxo-piperidine-1-Carboxylic Acid, [1-(R)-3,5-bis-trifluoromethyl-phenyl)-ethyl]-Methylamide (4b) Method A

[0170] A solution of triphosgene (147 mg) dissolved in dry DCM (5 mL) was added drop-wise to a solution of intermediate 2 (250 mg) and DIPEA (860 μL) in dry DCM (15 mL) previously cooled to 0° C. under a nitrogen atmosphere. After 2 hours, [1-(R)-3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamine hydrochloride (503 mg) and DIPEA (320 μL) in dry acetonitrile (20 mL) were added and the mixture was heated to 70° C. for 16 hours. Further [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamine hydrochloride (170 mg) and DIPEA (100 μL) were added and the mixture was stirred at 70° C. for further 4 hours. Next, the mixture was allowed to cool to r.t., taken up with AcOEt (30 mL), washed with a 1N hydrochloric acid cold solution (3×15 mL) and brine (2×10 mL). The organic layer was dried and concentrated in vacuo to a residue, which was purified by flash chromatography (CH/AcOEt 8:2) to give:

[0171] 1. intermediate 4a (230 mg) as a white foam,

[0172] 2. intermediate 4b (231 mg) as a white foam. …………….ignore

[0173] Intermediate 4a

[0174] NMR (d6-DMSO): δ (ppm) 7.98 (bs, 1H); 7.77 (bs, 2H); 7.24 (dd, 1H); 6.97 (dd, 1H); 6.89 (m, 1H); 5.24 (t, 1H); 5.14 (q, 1H); 3.61 (m, 1H); 3.55 (m, 1H); 2.71 (m, 2H); 2.56 (s, 3H); 2.50 (m, 2H); 2.26 (s, 3H); 1.57 (d, 3H).

[0175] Intermediate 4b

[0176] NMR (d6-DMSO): δ (ppm) 7.96 (bs, 1H); 7.75 (bs, 2H); 7.24 (dd, 1H); 6.98 (dd, 1H); 6.93 (dt, 1H); 5.29 (q, 1H); 5.24 (t, 1H); 3.56 (m, 1H); 3.48 (m, 1H); 2.70 (s, 3H); 2.50 (m, 4H); 2.26 (s, 3H); 1.54 (d, 3H). …….. ignore

[0177] Intermediate 4a

[0178] Method B

[0179] A saturated sodium hydrogen carbonate solution (324 mL) was added to a solution of intermediate 9 (21.6 g) in AcOEt (324 mL) and the resulting mixture was vigorously stirred for 15 minutes. The aqueous layer was back-extracted with further AcOEt (216 mL) and the combined organic extracts were dried and concentrated in vacuo to give intermediate 8 as a yellow oil, which was treated with TEA (19 mL) and AcOEt (114 mL). The solution obtained was added drop-wise over 40 minutes to a solution of triphosgene (8 g) in AcOEt (64 mL) previously cooled to 0° C. under a nitrogen atmosphere, maintaining the temperature between 0° C. and 8° C.

[0180] After stirring for 1 hours at 0° C. and for 3 hours at 20° C., [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamine hydrochloride (29.7 g), AcOEt (190 mL) and TEA (38 mL) were added to the reaction mixture which was then heated to reflux for 16 hours.

[0181] The solution was washed with 10% sodium hydroxide solution (180 mL), 1% hydrochloric acid solution (4×150 mL), water (3×180 mL) and brine (180 mL). The organic layer was dried and concentrated in vacuo to a residue, which was purified through a silica pad (CH/AcOEt 9:1) to give the title compound (21.5 g) as a brown thick oil.

[0182] NMR (d6-DMSO): 6 (ppm) 7.97-7.77 (bs+bs, 3H); 7.24 (dd, 1H); 6.97 (dd, 1H); 6.88 (td, 1H); 5.24 (m, 1H); 5.14 (q, 1H); 3.58 (m, 2H); 2.7 (m, 2H); 2.56 (s, 3H); 2.49 (m, 2H); 2.26 (s, 3H); 1.57 (d, 3H).

intermediate 2

[0152] Intermediate 2

[0153] 2-(4-Fluoro-2-methyl-phenyl)-piperidine-4-one

[0154] Method A

[0155] 2-Methyl-4-fluoro-benzaldehyde (4 g) was added to a solution of 4-aminobutan-2-one ethylene acetal (3.8 g) in dry benzene (50 mL) and the solution was stirred at r.t. under a nitrogen atmosphere. After 1 hour the mixture was heated at reflux for 16 hours and then allowed to cool to r.t. This solution was slowly added to a refluxing solution of p-toluensulphonic acid (10.6 g) in dry benzene (50 mL) previously refluxed for 1 hour with a Dean-Stark apparatus. After 3.5 hours the crude solution was cooled and made basic with a saturated potassium carbonate solution and taken up with AcOEt (50 mL). The aqueous phase was extracted with AcOEt (3×50 mL) and Et2O (2×50 mL). The organic layer was dried and concentrated in vacuo to a yellow thick oil as residue (7.23 g). A portion of the crude mixture (3 g) was dissolved in a 6N hydrochloric acid solution (20 mL) and stirred at 60° C. for 16 hours. The solution was basified with solid potassium carbonate and extracted with DCM (5×50 mL). The combined organic phases were washed with brine (50 mL), dried and concentrated in vacuo to give the title compound (2.5 g) as a thick yellow oil.

[0156] Method B

[0157] L-selectride (1M solution in dry THF, 210 mL) was added drop-wise, over 80 minutes, to a solution of intermediate 1 (50 g) in dry THF (1065 mL) previously cooled to −72° C. under a nitrogen atmosphere. After 45 minutes, 2% sodium hydrogen carbonate solution (994 mL) was added drop-wise and the solution was extracted with AcOEt (3×994 mL). The combined organic phases were washed with water (284 mL) and brine (568 mL). The organic phase was dried and concentrated in vacuo to get 1-benzyloxycarbonyl-2-(4-fluoro-2-methyl-phenyl)-piperidine-4-one as a pale yellow thick oil (94 g) which was used as a crude.

[0158] This material (94 g) was dissolved in AcOEt (710 mL), then 10% Pd/C (30.5 g) was added under a nitrogen atmosphere. The slurry was hydrogenated at 1 atmosphere for 30 minutes. The mixture was filtered through Celite and the organic phase was concentrated in vacuo to give the crude 2-(4-fluoro-2-methyl-phenyl)-piperidine-4-one as a yellow oil. This material was dissolved in AcOEt (518 mL) at r.t. and racemic camphorsulphonic acid (48.3 g) was added. The mixture was stirred at r.t for 18 hours, then the solid was filtered off, washed with AcOEt (2×50 mL) and dried in vacuo for 18 hours to give 2-(4-fluoro-2-methyl-phenyl)-piperidine-4-one, 10-camphorsulfonic acid salt as a pale yellow solid (68.5 g). (M.p.: 167-169° C.-NMR (d6-DMSO): 6 (ppm) 9.43 (bs, 1H); 9.23 (bs, 1H); 7.66 (dd, 1H); 7.19 (m, 2H); 4.97 (bd, 1H); 3.6 (m, 2H); 2.87 (m, 3H); 2.66 (m, 1H); 2.53 (m, 2H); 2.37 (s+d, 4H); 2.22 (m, 1H); 1.93 (t, 1H); 1.8 (m, 2H); 1.26 (m, 2H); 1.03 (s, 3H); 0.73 (s, 3H).

[0159] This material (68.5 g) was suspended in AcOEt (480 mL) and stirred with a saturated sodium hydrogen carbonate (274 mL). The organic layer was separated and washed with further water (274 mL). The organic phase was dried and concentrated in vacuo to give the title compound (31 g) as a yellow-orange oil.

[0160] NMR (d6-DMSO): 6 (ppm) 7.49 (dd, 1H); 7.00 (m, 2H); 3.97 (dd, 1H); 3.27 (m, 1H); 2.82 (dt, 1H); 2.72 (bm, 1H); 2.47 (m, 1H); 2.40 (m, 1H); 2.29 (s, 3H); 2.25 (dt, 1H); 2.18 (m, 1H).

[0161] MS (ES/+): m/z=208 [MH]+.

 

intermediate 9

[0220] Intermediate 9

[0221] 2-(R)-(4-Fluoro-2-methyl-phenyl)-piperidin-4-one Mandelic Acid.

[0222] A solution of L-(+)-mandelic acid (22.6 g) in AcOEt (308 mL) was added to a solution of intermediate 2 (31 g) in AcOEt (308 mL). Then isopropanol (616 mL) was added and the solution was concentrated in vacuo to 274 mL. The solution was then cooled to 0° C. and further cold isopropanol (96 mL) was added. The thick precipitate was stirred under nitrogen for 5 hours at 0° C., then filtered and washed with cold Et2O (250 mL) to give the title compound as a pale yellow solid (20.3 g).

[0223] M.p.: 82-85° C.

[0224] NMR (d6-DMSO): δ (ppm) 7.51 (dd, 1H); 7.40 (m, 2H); 7.32 (m, 2H); 7.26 (m, 1H); 7.0 (m, 2H); 4.95 (s, 1H); 4.04 (dd, 1H); 3.31 (m, 1H); 2.88 (m, 1H); 2.49-2.2 (m, 4H); 2.29 (s, 3H).

[0225] Chiral HPLC: HP 1100 HPLC system; column Chiralcel OD-H, 25 cm×4.6 mm; mobile phase: n-hexane/isopropanol 95:5+1% diethylamine; flow: 1.3 ml/min; detection: 240/215 nm; retention time 12.07 minutes.

 

 

………………….

NMR

mesylate

Org. Process Res. Dev., 2010, 14 (6), pp 1337–1346
DOI: 10.1021/op100150b

http://pubs.acs.org/doi/abs/10.1021/op100150b

Abstract Image

1H NMR (600 MHz, DMSO-d6): 9.57 (br s, 1H), 7.99 (br s, 1H), 7.68 (br s, 2H), 7.23 (m, 1H), 6.95 (dd, 1H), 6.82 (m, 1H), 5.31 (q, 1H), 4.45 (m, 1H), 4.20 (dd, 1H), 3.99 (m, 1H), 3.56 (m, 1H), 3.47 (m, 3H), 3.37 (m, 1H), 3.15 (m, 1H), 2.96 (m, 1H), 2.87 (m, 1H), 2.80 (t, 1H), 2.74 (s, 3H), 2.36 (s, 3H), 2.30 (s, 3H), 2.13 (m, 1H), 2.08 (m, 1H), 2.10 (s, 3H), 1.87 (m, 1H), 1.73 (m, 1H), 1.46 (d, 3H), MS: m/z 617 [MH]+, as free base.

 

 

……………

http://pubs.acs.org/doi/full/10.1021/op100209c

Org. Process Res. Dev., 2010, 14 (6), pp 1407–1419
DOI: 10.1021/op100209c

(2R,4S)-4-(4-Acetyl-1-piperazinyl)-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-N-methyl-1-piperidinecarboxamide Methanesulfonate Salt (Casopitant Mesylate 1)

A solution of casopitant 2 (0.86 wt) was diluted with EtOAc (overall solution of 2 in EtOAc was 4 L) and acetone (4.5 L) and was heated to the required temperature (from 39 °C). Thereafter, neat methanesulfonic acid (0.12 L, 1.64 mol) was charged, followed by a slurry of 2 (0.005 kg) in EtOAc (0.05 L) as seed. The obtained suspension was stirred for 1 h followed by the addition of 3 L of isooctane in the required time (1 h). The slurry was cooled to 20 °C in 2 h and aged 3 h. The suspension was filtered and the solid washed with EtOAc (3 × 4 L). The white solid was dried overnight under vacuum at 40 °C to give the desired casopitant mesylate 1 (0.94 kg).
1H NMR (600 MHz, DMSO-d6) δ 9.57 (br s, 1H), 7.99 (br s, 1H), 7.68 (br s, 2H), 7.23 (m, 1H), 6.95 (dd, 1H), 6.82 (m, 1H), 5.31 (q, 1H), 4.45 (m, 1H), 4.20 (dd, 1H), 3.99 (m, 1H), 3.56 (m, 1H), 3.47 (m, 3H), 3.37 (m, 1H), 3.15 (m, 1H), 2.96 (m, 1H), 2.87 (m, 1H), 2.80 (t, 1H), 2.74 (s, 3H), 2.36 (s, 3H), 2.30 (s, 3H), 2.13 (m, 1H), 2.08 (m, 1H), 2.10 (s, 3H), 1.87 (m, 1H), 1.73 (m, 1H), 1.46 (d, 3H). MS: m/z 617 [MH]+, as free base.
………….
Org. Process Res. Dev., 2010, 14 (4), pp 805–814
DOI: 10.1021/op1000622
NMR CASOPITANT FREE BASE
(2R,4S)-4-(4-Acetyl-1-piperazinyl)-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-N-methyl-1-piperidinecarboxamide (Casopitant 2)

HCOOH (0.49 L, 13 mol) was added to a cooled suspension of NaBH(OAc)3 (0.82 kg, 3.87 mol) in CH3CN (4 L), keeping the internal temperature between 10−15 °C; then the lines were washed with more CH3CN (1 L), and the mixture was stirred for 40 min.
1-Acetylpiperazine (0.7 kg, 5.46 mol) was added neat over the solution of piperidone-urea 3, and the mixture was diluted with CH3CN (3 L). The resulting mixture was added over the previous suspension; fresh CH3CN (4 L) was used to wash the line. The reaction mixture was stirred at 15 °C for 12 h. The solvent was evaporated under reduced pressure to 4 L.
The resulting suspension was diluted with fresh EtOAc (4 L), and then washed with ammonia [21% w/w solution (4 L, 11.25 M in NH3)], Na2CO3 [15% w/w solution (4 L)]. More EtOAc (4 L) was added, and the organic layer was washed with water (4 L). The organic phase was then concentrated to 2.5 L; again fresh EtOAc (4 L) was added, and the solution was concentrated to 2.5 L to give a solution of casopitant 2.
1H NMR (600 MHz, DMSO-d6): δ 7.99 (s, 1H), 7.68 (s, 2H), 7.18 (dd, 1H), 6.90 (dd, 1H), 6.76 (td, 1H), 5.33 (q, 1H), 4.14 (dd, 1H), 3.38 (m, 5H), 2.71 (s, 3H), 2.72 (m, 1H), 2.54 (m, 1H), 2.47 (m, 2H), 2.41 (m, 2H), 2.34 (s, 3H), 1.95 (s, 3H), 1.85 (m, 1H), 1.77 (m, 1H), 1.62 (dq, 1H), 1.47 (d, 3H), 1.40 (q, 1H).
Abstract Image

 picture    animation

 

……………………………….

J. Med. Chem., 2011, 54 (4), pp 1071–1079
DOI: 10.1021/jm1013264

http://pubs.acs.org/doi/full/10.1021/jm1013264?prevSearch=casopitant&searchHistoryKey=

(2R,4S)-1′-acetyl-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-N-methyl-4,4′-bipiperidine-1-carboxamide methanesulfonate salt 16a (casopitant)

nmr mesylate

1H NMR (600 MHz, DMSO-d6): 9.57 (bs, 1H), 7.99 (bs, 1H), 7.68 (bs, 2H), 7.23 (m, 1H), 6.95 (dd, 1H), 6.82 (m, 1H), 5.31 (q, 1H), 4.45 (m, 1H), 4.20 (dd, 1H), 3.99 (m, 1H), 3.56 (m, 1H), 3.47 (m, 3H), 3.37 (m, 1H), 3.15 (m, 1H), 2.96 (m, 1H), 2.87 (m, 1H), 2.80 (t, 1H), 2.74 (s, 3H), 2.36 (s, 3H), 2.30 (s, 3H), 2.13 (m, 1H), 2.08 (m, 1H), 2.10 (s, 3H), 1.87 (m, 1H), 1.73 (m, 1H), 1.46 (d, 3H). MS: m/z 617 [MH]+, as free base.

syn of intermediates

Figure

a(a) (i) 2-Bromo-5-fluorotoluene, Mg, THF, 60−70 °C; (ii) 4-methoxypyridine, benzyl chloroformate, THF, −20 °C, then Grignard’s reagent, −20 °C, 1 h; (b) (i) tris(triphenylphosphine)rhodium(I) chloride, 2-propanol, H2 (p = 5 atm), 60 °C, 5 h; (ii) Pd/C 5%, H2 (p = 4 atm), 20 °C, 5 h; (iii) (R,S)-10-camphorsulfonic acid, toluene; (c) CH2Cl2, H2O, 8% NaHCO3 (aq); l-(+)-mandelic acid, 2-propanol, heptanes; (d) MeNH2, EtOH, NaBH4, 25 °C, 1.5 h; (e) (i) ethyl acetate, NaHCO3 (aq. sat. soln), 5; (ii) triphosgene, triethylamine, ethyl acetate, then 5, 20 °C, 2 h; (f) R′RNH, CH3CN, NaBH(OAc)3, room temp, 24 h.

 

ANTHONY MELVIN CRASTO

THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D

GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

did you feel happy, a head to toe paralysed man’s soul in action for you round the clock

need help, email or call me

MOBILE-+91 9323115463
web link

I was  paralysed in dec2007, Posts dedicated to my family, my organisation Glenmark, Your readership keeps me going and brings smiles to my family

 

Share

SOVAPREVIR in phase II clinical trials at Achillion for the oral treatment of naive patients with chronic hepatitis C virus genotype 1

 phase 2, Uncategorized  Comments Off on SOVAPREVIR in phase II clinical trials at Achillion for the oral treatment of naive patients with chronic hepatitis C virus genotype 1
Jan 062014
 

SOVAPREVIR

(2S, 4R) -1 – [(2S)-2-tert-butyl-4-oxo-4-(piperidin-1-yl) butanoyl]-N-{(1R, 2S) -1 – [(cyclopropanesulfonyl) carbamoyl]-2-ethenylcyclopropyl} -4 – [(7-methoxy-2-phenylquinolin-4-yl) oxy] pyrrolidine-2-carboxamide

http://www.ama-assn.org/resources/doc/usan/sovaprevir.pdf

PATENT

US 2009048297 ENTRY 60

WO 2008008502

CN 103420991

 

THERAPEUTIC CLAIM ….Treatment of hepatitis C

CHEMICAL NAMES

1. 2-Pyrrolidinecarboxamide, N-[(1R,2S)-1-[[(cyclopropylsulfonyl)amino]carbonyl]-2-
ethenylcyclopropyl]-1-[(2S)-3,3-dimethyl-1-oxo-2-[2-oxo-2-(1-piperidinyl)ethyl]butyl]-4-
[(7-methoxy-2-phenyl-4-quinolinyl)oxy]-, (2S,4R)-

2. (2S,4R)-N-{(1R,2S)-1-[(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl}-1-{(2S)-
3,3-dimethyl-2-[2-oxo-2-(piperidin-1-yl)ethyl]butanoyl}-4-[(7-methoxy-2-phenylquinolin-
4-yl)oxy]pyrrolidine-2-carboxamide

MOLECULAR FORMULA C43H53N5O8S

MOLECULAR WEIGHT 800.0

SPONSOR Achillion Pharmaceuticals, Inc.

CODE DESIGNATION ACH-0141625

CAS REGISTRY NUMBER 1001667-23-7

  • ACH-0141625
  • Sovaprevir
  • UNII-2ND9V3MN6O

Sovaprevir (formerly ACH-0141625), an HCV NS3 protease inhibitor, is in phase II clinical trials at Achillion for the oral treatment of naive patients with chronic hepatitis C virus genotype 1.

In 2012, fast track designation was assigned by the FDA for the treatment of hepatitis C (HCV). In 2013, a clinical hold was placed for the treatment of hepatitis C (HCV) in combination with atazanavir after elevations in liver enzymes associated with the combination of both compounds.

Sovaprevir, previously referred to as ACH-1625, is an investigational, next-generation NS3/4A protease inhibitor discovered by Achillion that is currently on clinical hold. In 2012, Fast Track status was granted by the U.S. Food and Drug Administration (FDA) to sovaprevir for the treatment of chronic hepatitis C viral infection (HCV).

Achillion has initiated a Phase 2 clinical trial (007 Study) to evaluate the all-oral, interferon-free combination of sovaprevir and its second-generation NS5A inhibitor, ACH-3102, with ribavirin (RBV), for a 12 week treatment duration, in treatment naïve, genotype 1 (GT1) HCV patients. In July 2013, sovaprevir was placed on clinical hold after elevated liver enzymes were observed in a Phase 1 healthy subject drug-drug interaction study evaluating the effects of concomitant administration of sovaprevir with ritonavir-boosted atazanavir.

In accordance with the clinical hold, the FDA provided that no new clinical trials that included dosing with sovaprevir could be initiated, however, the FDA allowed continued enrollment and treatment of patients in the Phase 2 -007 clinical trial evaluating 12-weeks of sovaprevir in combination with ACH-3102 and RBV for patients with treatment-naive genotype 1 HCV. In September 2013, after reviewing Achillion’s response, the FDA stated that although all issues identified in the June 2013 letter had been addressed, it had concluded that the removal of the clinical hold was not warranted at this time.

The FDA requested, among other things, additional analysis to more fully characterize sovaprevir pharmacokinetics and the intrinsic and extrinsic factors that may lead to higher than anticipated exposures of sovaprevir or other potential toxicities in addition to the observed liver enzyme elevations.

The FDA also requested Achillion’s proposed plan for future clinical trials in combination with other directly-acting antivirals. At the request of the FDA, Achillion plans to submit a proposed plan for analyzing the additional clinical, non-clinical and pharmacokinetic data requested before the end of 2013, and if that analysis plan is approved by the FDA, submit a complete response during the first half of 2014. Achillion retains worldwide commercial rights to sovaprevir.

 

Sovaprevir has demonstrated activity against all HCV genotypes (GT), including equipotent activity against both GT 1a and 1b (IC50 ~ 1nM) in vitro.

 

With its rapid and extensive partitioning to the liver, as well as high liver/plasma ratios, sovaprevir has been clinically demonstrated to allow for once-daily, non-boosted dosing.

The current safety database for sovaprevir includes more than 560 subjects dosed to date and demonstrates that sovaprevir is well tolerated in these subjects.

Sovaprevir has demonstrated high rates of clinical cures in combination with pegylated-interferon and RBV in a challenging, real world, patient population of genotype 1 treatment-naive patients.

100% of GT1b subjects achieved a rapid virologic response (RVR) in the 007 Study evaluating the interferon-free combination of sovaprevir + ACH-3102 + RBV for 12 weeks. The Phase 2 study is ongoing.

 

Sovaprevir in vitro retains activity against mutations that confer resistance to 1st-generation protease inhibitors.

In clinical studies to date, sovaprevir has demonstrated a high pharmacologic barrier to resistance with no on-treatment viral breakthrough reported to date in GT1b patients.

 

Sovaprevir is believed to be synergistic when combined with other classes of DAAs, including the second-generation NS5A inhibitor, ACH-3102.

For more information about the next-generation NS3/4A protease inhibitor, sovaprevir, please see the Related Links on this page or visit Resources.

Sovaprevir is an investigational compound. Its safety and efficacy have not been established. (Updated December 2013)

SOVAPREVIR

 

An estimated 3% of the world’s population is infected with the hepatitis C virus. Of those exposed to HCV, 80% become chronically infected, at least 30% develop cirrhosis of the liver and 1-4% develop hepatocellular carcinoma. Hepatitis C Virus (HCV) is one of the most prevalent causes of chronic liver disease in the United States, reportedly accounting for about 15 percent of acute viral hepatitis, 60 to 70 percent of chronic hepatitis, and up to 50 percent of cirrhosis, end-stage liver disease, and liver cancer. Chronic HCV infection is the most common cause of liver transplantation in the U.S., Australia, and most of Europe. Hepatitis C causes an estimated 10,000 to 12,000 deaths annually in the United States. While the acute phase of HCV infection is usually associated with mild symptoms, some evidence suggests that only about 15% to 20% of infected people will clear HCV.

HCV is an enveloped, single-stranded RNA virus that contains a positive-stranded genome of about 9.6 kb. HCV is classified as a member of the Hepacivirus genus of the family Flaviviridae. At least 4 strains of HCV, GT-1-GT-4, have been characterized.

The HCV lifecycle includes entry into host cells; translation of the HCV genome, polyprotein processing, and replicase complex assembly; RNA replication, and virion assembly and release. Translation of the HCV RNA genome yields a more than 3000 amino acid long polyprotein that is processed by at least two cellular and two viral proteases. The HCV polyprotein is:

NH2-C-E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B-COOH.

The cellular signal peptidase and signal peptide peptidase have been reported to be responsible for cleavage of the N-terminal third of the polyprotein (C-E1-E2-p7) from the nonstructural proteins (NS2-NS3-NS4A-NS4B-NS5A-NS5B). The NS2-NS3 protease mediates a first cis cleavage at the NS2-NS3 site. The NS3-NS4A protease then mediates a second cis-cleavage at the NS3-NS4A junction. The NS3-NS4A complex then cleaves at three downstream sites to separate the remaining nonstructural proteins. Accurate processing of the polyprotein is asserted to be essential for forming an active HCV replicase complex.

Once the polyprotein has been cleaved, the replicase complex comprising at least the NS3-NS5B nonstructural proteins assembles. The replicase complex is cytoplasmic and membrane-associated. Major enzymatic activities in the replicase complex include serine protease activity and NTPase helicase activity in NS3, and RNA-dependent RNA polymerase activity of NS5B. In the RNA replication process, a complementary negative strand copy of the genomic RNA is produced. The negative strand copy is used as a template to synthesize additional positive strand genomic RNAs that may participate in translation, replication, packaging, or any combination thereof to produce progeny virus. Assembly of a functional replicase complex has been described as a component of the HCV replication mechanism. Provisional application 60/669,872 “Pharmaceutical Compositions and Methods of Inhibiting HCV Replication” filed Apr. 11, 2005, is hereby incorporated by reference in its entirety for its disclosure related to assembly of the replicase complex.

Current treatment of hepatitis C infection typically includes administration of an interferon, such as pegylated interferon (IFN), in combination with ribavirin. The success of current therapies as measured by sustained virologic response (SVR) depends on the strain of HCV with which the patient is infected and the patient’s adherence to the treatment regimen. Only 50% of patients infected with HCV strain GT-1 exhibit a sustained virological response. Direct acting antiviral agents such as ACH-806, VX-950 and NM 283 (prodrug of NM 107) are in clinical development for treatment of chronic HCV. Due to lack of effective therapies for treatment for certain HCV strains and the high mutation rate of HCV, new therapies are needed.

 

…………………………………………

https://www.google.co.in/patents/US20090048297

(2S,4R)-1-((S)-2-tert-butyl-4-oxo-4-(piperidin-1-yl)butanoyl)-N-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropyl)-4-(7-methoxy-2-phenylquinolin-4-yloxy)pyrrolidine-2-carboxamide

 

 

Figure US20090048297A1-20090219-C00105

 

SOVAPREVIR IS DESCRIBED AS 60 IN CLAIM

 

SYNTHESIS OF INTERMEDIATE 13 BELOW AND ALSO  COMPD 8 IE SOVAPREVIR IN STEP 4

 

Example 1

SYNTHESIS OF 1-((2S,4R)-1-((S)-2-TERT-BUTYL-4-OXO-4-(PIPERIDIN-1-YL)BUTANOYL)-4-(7-METHOXY-2-PHENYLQUINOLIN-4-YLOXY)PYRROLIDINE-2-CARBOXAMIDO)-2-VINYLCYCLOPROPANECARBOXYLIC ACID

Step 1. Preparation of N-(cyclopropylsulfonyl)-1-(BOC-amino)-2-vinylcyclopropanecarboxamide

 

Figure US20090048297A1-20090219-C00047

 

CDI (2.98 g, 18.4 mm, 1.1 eq) is dissolved in ethyl acetate. N-Boc-cyclopropylvinyl acid (3.8 g, 16.7 mm, 1.0 eq), prepared via the procedure given by Beaulieu, P. L. et al. (J. Org. Chem. 70: 5869-79 (2005)) is added to the CDI/ethyl acetate mixture and stirred at RT until the starting material is consumed. Cyclopropyl sulfonamine (2.2 g, 18.4 mm, 1.1 eq) is added to this mixture followed by DBU (2.1 ml, 20.5 mm, 1.23 eq) and the mixture is stirred at RT for 2 h. Workup and purification by silica gel chromatography provides 2g of compound 2.

Step 2. Preparation of (2S,4R)-tert-butyl 2-(1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)-4-(7-methoxy-2-phenylquinolin-4-yloxy)pyrrolidine-1-carboxylate and (2S,4R)—N-(1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropyl)-4-(7-methoxy-2-phenylquinolin-4-yloxy)pyrrolidine-2-carboxamide

 

Figure US20090048297A1-20090219-C00048

 

Compound 1 (4.3 g, 9.3 mmol, 1.1 eq), prepared according to the method given ins WO 02/060926, in DMF is stirred with O-(Benzotriazol-lyl)-N,N,N′,N′-Tetramethyluronium hexafluorophosphate (4.1 g, 10.5 mmol, 1.3 eq) for 30 minutes, followed by addition of cyclopropylamine 2 (1.92 g, 8.3 mmol, 1.0 eq) and N-methylmorpholine (2.52 g, 25.0 mmol, 3.0 eq). The mixture is stirred over night and the solvent removed under reduced pressure. The resulting residue is diluted with ethyl acetate and washed with saturated aqueous NaHCO3. The organic solvent is dried over MgSOand concentrated under reduced pressure to afford crude 3, which is used for next step without further purification.

Compound 3 in 10 ml dry CH2Clis treated with 5 mL TFA and stirred over night. The solvent is removed and the residue recrystallized from ethyl acetate to afford 4.12 g Compound 4 (61% yield two steps).

Step 3. Preparation of (3S)-3-((2S,4R)-2-(1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)-4-(7-methoxy-2-phenylquinolin-4-yloxy)pyrrolidine-1-carbonyl)-4,4-dimethylpentanoic acid

 

Figure US20090048297A1-20090219-C00049

 

The Acid 5 (58 mg, 0.25 mmol, 1.2 eq), prepared via the procedure given by Evans, D. A., et al. (J. Org. Chem. 64: 6411-6417 (1999)) in 1.2 mL DMF is stirred with 4 (138 mg, 0.21 mmol), HATU (160 mg, 0.42 mmol, 2.0 eq), and DIEA (0.63 mmol, 3.0 eq) overnight. The mixture is subjected to HPLC purification to afford 121 mg 6 (77% yield), which is further treated with 0.5 mL TFA in 1.0 mL DCM overnight. The solvent was removed to provide Compound 7 in 100% yield.

Step 4. Preparation of (2S,4R)-1-((S)-2-tert-butyl-4-oxo-4-(piperidin-1-yl)butanoyl)-N-(1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropyl)-4-(7-methoxy-2-phenylquinolin-4-yloxy)pyrrolidine-2-carboxamide

 

Figure US20090048297A1-20090219-C00050

PLEASE  NOTE 8 IS SOVAPREVIR

The Acid 7 (0.15 mmol) in 1.0 mL DMF is stirred with pepridine (excess, 0.6 mmol, 4 eq), HATU (115 mg, 0.3 mmol, 2.0 eq), and DIEA (0.45 mmol, 3.0 eq) for 4 hrs. The mixture is subjected to HPLC purification to afford 77.1 mg 8.

Step 5. Preparation of (3S)-3-((2S,4R)-2-(1-(ethoxycarbonyl)-2-vinylcyclopropylcarbamoyl)-4-(7-methoxy-2-phenylquinolin-4-yloxy)pyrrolidine-1-carbonyl)-4,4-dimethylpentanoic acid

 

Figure US20090048297A1-20090219-C00051

 

Step 5. Preparation of (3S)-3-((2S,4R)-2-(1-(ethoxycarbonyl)-2-vinylcyclopropylcarbamoyl)-4-(7-methoxy-2-phenylquinolin-4-yloxy)pyrrolidine-1-carbonyl)-4,4-dimethylpentanoic acid

The Acid 5 (105 mg, 0.46 mmol, 1.2 eq) in 1.2 mL DMF is stirred with 9 (202 mg, 0.38 mmol), HATU (290 mg, 0.76 mmol, 2.0 eq), and DIEA (1.2 mmol, 3.0 eq) overnight. The mixture is subjected to HPLC purification to afford 204.3 mg 10 (75% yield), which is further treated with 0.5 mL TFA in 1.0 mL DCM overnight. The solvent is removed to provide 11 in 100% yield.

 

Figure US20090048297A1-20090219-C00052

 

Step 6. Preparation of Final Product

The Acid 11 (30 mg, 0.045 mmol) in 1.0 mL DMF is stirred with pepridine (0.27 mmol, 6 eq), HATU (34 mg, 0.09 mmol, 2.0 eq), and DIEA (0.14 mmol, 3.0 eq) for 2 hrs. The mixture is subjected to HPLC purification to afford 21.2 mg 12 (65% yield), which is hydrolyzed in methanol with 2N NaOH for 6 hrs. The mixture is acidified with 6N HCl and subjected to HPLC purification to afford 7.6 mg 13.

………………………………

 

 picture    animation

ANTHONY MELVIN CRASTO

THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D

GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

did you feel happy, a head to toe paralysed man’s soul in action for you round the clock

need help, email or call me

MOBILE-+91 9323115463
web link

I was  paralysed in dec2007, Posts dedicated to my family, my organisation Glenmark, Your readership keeps me going and brings smiles to my family

Share
Follow

Get every new post on this blog delivered to your Inbox.

Join other followers: