AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Worlddrugtracker, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his PhD from ICT ,1991, Mumbai, India, in Organic chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA as ADVISOR earlier GLENMARK LS Research centre as consultant,Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Prior to joining Glenmark, he worked with major multinationals like Hoechst Marion Roussel, now sSanofi, Searle India ltd, now Rpg lifesciences, etc. he is now helping millions, has million hits on google on all organic chemistry websites. His New Drug Approvals, Green Chemistry International, Eurekamoments in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 year tenure, good knowledge of IPM, GMP, Regulatory aspects, he has several international drug patents published worldwide . He gas good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, polymorphism etc He suffered a paralytic stroke in dec 2007 and is bound to a wheelchair, this seems to have injected feul in him to help chemists around the world, he is more active than before and is pushing boundaries, he has one lakh connections on all networking sites, He makes himself available to all, contact him on +91 9323115463, amcrasto@gmail.com

ECA Task Force will publish Draft Data Integrity Guideline at Conference in October

 Uncategorized  Comments Off on ECA Task Force will publish Draft Data Integrity Guideline at Conference in October
Sep 022016
 

Image result for Data Integrity

Data Integrity has become one of the most frequently observed GMP deviations at FDA and EU Inspections. For that reason the ECA Foundation decided to set up a Task Force on Data Integrity in December 2015 – with the goal to provide Guidance for the implementation in practice. Read more about the ECA Guidance on Data Integrity.

http://www.gmp-compliance.org/eca_mitt_05545_15488_n.html

Data Integrity has become one of the most frequently observed GMP deviations at FDA and EU Inspections. This is why the topic is currently in the centre of attention of both regulators and industry. And for that reason the ECA Foundation decided to set up a Task Force on Data Integrity in December 2015 – with the goal to provide Guidance for the implementation in practice.

The ECA Task Force will be comprised of members from both the IT Compliance Group and the Analytical QC Group. Current Members are:

– Dr. Wolfgang Schumacher, Hoffmann-La Roche, Switzerland
– Dr. Chris Burgess, Qualified Person and Consultant, UK
– Dr. Bob McDowall, Consultant, UK
– Ms. Margarita Sabater, ALK-Abelló A/S, Denmark

The Task Force decided to develop a Guidance entitled: “Data Governance and Data Integrity for GMP Regulated Facilities“. The ECA Guidance Document will cover – among others – the Roles and Responsibilities of Corporate and Senior Management in Data Governance as well as the necessary Policies, Procedures and Processes. Further information is provided on establishing criteria for Data Integrity and security of records based on ALCOA+Principles and on Auditing for Data Integrity and security of records.

The Guide will contain a Glossary as well as some illustrative appendices for further information.

Margarita Sabater, Member of the ECA Task Force, will present the Draft Version of the ECA Data Integrity Guidance Document during the Lab Data Integrity Conference on 20-21 October 2016 in Vienna, Austria. Every participant will receive a copy of the Draft Document – and is also invited to provide feedback to the Guidance Document.

 

//////ECA Task Force, Draft Data Integrity Guideline,  Conference

Share

New aspects of developing a dry powder inhalation formulation applying the quality-by-design approach

 Formulation, regulatory  Comments Off on New aspects of developing a dry powder inhalation formulation applying the quality-by-design approach
Sep 022016
 

Image for unlabelled figure

The current work outlines the application of an up-to-date and regulatory-based pharmaceutical quality management method, applied as a new development concept in the process of formulating dry powder inhalation systems (DPIs). According to the Quality by Design (QbD) methodology and Risk Assessment (RA) thinking, a mannitol based co-spray dried formula was produced as a model dosage form with meloxicam as the model active agent.

The concept and the elements of the QbD approach (regarding its systemic, scientific, risk-based, holistic, and proactive nature with defined steps for pharmaceutical development), as well as the experimental drug formulation (including the technological parameters assessed and the methods and processes applied) are described in the current paper.

Findings of the QbD based theoretical prediction and the results of the experimental development are compared and presented. Characteristics of the developed end-product were in correlation with the predictions, and all data were confirmed by the relevant results of the in vitro investigations. These results support the importance of using the QbD approach in new drug formulation, and prove its good usability in the early development process of DPIs. This innovative formulation technology and product appear to have a great potential in pulmonary drug delivery.

Fig. 1

Fig. 1.

Steps and elements of the QbD methodology completed by the authors and applied in the early stage of pharmaceutical development.

“By identifying the critical process parameters, the practical development was more effective, with reduced development time and efforts.”

Edina Pallagi, our QbD evangelist from Hungary shares her team’s experience applying QbD to Dry Powder Inhalation Formulation.

The paper covers:

  • QbD methodology the researchers applied
  • Formulation of dry powder inhalation – API and excipients
  • QTPP, CQA and CPPs  identified for pulmonary use along with target, justification and explanation
  • Characterization test methods
  • Knowledge Space development
  • QbD software used

New aspects of developing a dry powder inhalation formulation applying the quality-by-design approach

  • a Institute of Drug Regulatory Affairs, University of Szeged, Faculty of Pharmacy, Szeged, Hungary
  • b Department of Pharmaceutical Technology, University of Szeged, Faculty of Pharmacy, Szeged, Hungary

///////

Share

Continuous Flow Doebner–Miller Reaction and Isolation Using Continuous Stirred Tank Reactors

 PROCESS, Uncategorized  Comments Off on Continuous Flow Doebner–Miller Reaction and Isolation Using Continuous Stirred Tank Reactors
Aug 312016
 

Abstract Image

 

Continuous flow Doebner–Miller synthesis of different quinaldines from respective anilines is demonstrated using sulfuric acid as a homogeneous catalyst. The extent of reaction was monitored for various parameters, namely, temperature, residence time, mole ratio of sulfuric acid to substrate, mole ratio of crotonaldehyde to substrate, and so forth. Continuous stirred reactors in series were used as a preferred configuration for this rection that generates byproduct in the form of sticky solid material. The approach has been extended for six different anilines, and the results are compared with batch reactions. Continuous stirred reactors in series with distributed dosing of crotonaldehyde facilitated a continuous flow reaction with lower byproduct formation, increased yields, and continuous workup and is a scalable approach.

 

Continuous Flow Doebner–Miller Reaction and Isolation Using Continuous Stirred Tank Reactors

Chem. Eng. & Process Dev. Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pashan, Pune 411 008, India
Organic Chemistry Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pashan, Pune 411 008, India
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.6b00179
Publication Date (Web): August 22, 2016
Copyright © 2016 American Chemical Society
*E-mail: aa.kulkarni@ncl.res.in. Fax: +91-20-25902621.
Image result for Maruti B. Yadav ncl
Mr. Maruti Yadav
Project Assistant
M.Sc. Organic Chemistry, Pune University, 2013
Process Development of API production in continuous flow
logo
STR1str2

Image result for amol kulkarni ncl
Dr. Amol A. Kulkarni

logo

Dr. Amol A. Kulkarni is a Scientist in the Chemical Engineering Division at the National Chemical Laboratory. He did his B. Chem. Eng. (1998), M. Chem. Eng (2000) and Ph.D. in chemical engineering (2003) all from the University Dept. of Chem. Technology (UDCT, Mumbai). In 2004 he worked at the Max Planck Institute-Magdeburg (Germany) as a Alexander von Humboldt Research Fellow. At NCL he is driving a research program on the design of microreactors and exploring their applications for continuous syntheses including of nanoparticles. He has been awarded with the Max-Planck-Visiting Fellowship from the Max-Planck-Society, Munich for 2008-2011. His research areas include: (i) design and applications of microreactors, (ii) design of multiphase reactors, (iii) experimental and computational fluid dynamics, and (iv) nonlinear dynamics of coupled systems. He is an active member of Initiative for Research and Innovation in Science (IRIS) supported by Intel’s Education Initiative to organize National Science Fair and popularize science in India.

Research areas

  • Multiphase reactors and Microreactors
  • Process Development and Scale-up
  • Process Intensification & MAGIC Processes
  • Industrial Flow Processes

Contact

  • Dr. Amol A. Kulkarni
    Scientist
    Office: 529, PP-1 Building, CEPD
    National Chemical Laboratory
    Dr. Homi Bhabha Road
    Pune 411008, India
    Phone  +91 20 2590 2153
    Fax +91 20 2590 2621
    E-mail aa.kulkarni@ncl.res.in

///////////Continuous Flow,  Doebner–Miller Reaction, Isolation, Continuous Stirred Tank Reactors, chemical engeineering, process, Amol A. Kulkarni, ncl, pune

Share

Multicomponent-Multicatalyst Reactions (MC)2R: Efficient Dibenzazepine Synthesis

 spectroscopy, SYNTHESIS  Comments Off on Multicomponent-Multicatalyst Reactions (MC)2R: Efficient Dibenzazepine Synthesis
Aug 302016
 

Multicomponent-Multicatalyst Reactions (MC)2R: Efficient Dibenzazepine Synthesis
Jennifer Tsoung, Jane Panteleev, Matthias Tesch, and Mark Lautens

Org. Lett. 2014, 16, 110-113. DOI:10.1021/ol4030925 .

http://pubs.acs.org/doi/abs/10.1021/ol4030925

A RhI/Pd0 catalyst system was applied to the multicomponent synthesis of aza-dibenzazepines from vinylpyridines, arylboronic acids, and amines in a domino process with no intermediate isolation or purification.

5-(p-tolyl)-3-(trifluoromethyl)-10,11-dihydro-5H-benzo[b]pyrido[2,3-f]azepine (4a)

STR1

1H NMR
(400 MHz, CDCl3) δ 8.66 (d, J = 1.1 Hz, 1H), 7.97 (d, J = 1.8 Hz, 1H), 7.43 – 7.38 (m, 1H), 7.38 – 7.29
(m, 3H), 6.98 (d, J = 8.4 Hz, 2H), 6.57 – 6.51 (m, 2H), 3.33 – 3.21 (m, 2H), 3.09 – 2.99 (m, 2H), 2.26 (s,
3H);

13C NMR (101 MHz, CDCl3) δ 161.7 (q, J = 1.3 Hz), 145.8, 143.6, 143.4 (q, J = 4.0 Hz), 139.7,
139.5, 134.9 (q, J = 3.5 Hz), 130.3, 130.0, 129.9, 128.9, 128.2, 127.7, 125.3 (q, J = 33.1 Hz), 123.4 (q, J =
272.5 Hz), 114.0 (2), 35.9, 29.0, 20.4;

19F NMR (377 MHz, CDCl3) δ -62.0;

IR (NaCl, neat): 3063, 3028,
2926, 2862, 1616, 1506, 1489, 1456, 1435, 1429, 1410, 1339, 1319, 1296, 1267, 1240, 1207, 1165, 1128,
1086, 1036, 978, 947, 930, 910, 895, 808, 772, 756, 737, 721, 704, 687, 664, 646, 627 cm-1;

HRMS (ESI):
calcd for C21H18F3N2 (M+H)+: 355.1422; found. 355.1419.

STR1

Jennifer Tsoung

Jennifer Tsoung

Jennifer Tsoung

PhD graduate, organic chemistry

Department of Chemistry, University of Toronto

Experience

PhD

University of Toronto

(5 years 2 months)

Research Intern

Kyoto University

(3 months)Kyoto, Japan

Methodology project in asymmetric phase-transfer catalyzed alkylations.

Co-op student

Angiotech

(4 months)Vancouver, Canada Area

Formulation chemistry

Co-op student

Boehringer Ingelheim

(8 months)Montreal, Canada Area

On two hit-to-lead teams working to synthesize analogues of hit compounds for HIV research.

Publications

Diastereoselective Friedel−Crafts Alkylation of Hydronaphthalenes(Link)

The Journal of Organic Chemistry

September 27, 2011

An efficient and versatile synthesis of chiral tetralins has been developed using both inter- and intramolecular Friedel-Crafts alkylation as a key step. The readily available hydronaphthalene substrates were prepared via a highly enantioselective metal-catalyzed ring opening of meso-oxabicyclic alkenes followed by hydrogenation. A wide variety of complex tetracyclic compounds have been isolated…more

One-Pot Synthesis of Chiral Dihydrobenzofuran Framework via Rh/Pd Catlaysis

Organic Letters

October 12, 2012

A one-pot synthesis of the chiral dihydrobenzofuran framework is described. The method utilizes Rh-catalyzed asymmetric ring opening (ARO) and Pd-catalyzed C-O coupling to furnish the product in excellent enantioselectivity without isolation of intermediates. Systematic metal-ligand studies were carried out to investigate the compatibility of each catalytic system using product enantiopurity as an…more

Rh/Pd Catalysis with Chiral and Achiral Ligands: Domino Synthesis of Aza-Dihydrodibenzoxepines(Link)

Angew. Chem. Int. Ed

July 19, 2013

A game of dominoes: A synthetic route to aza-dihydrodibenzoxepines is described, through the combination of a Rh-catalyzed arylation and a Pd-catalyzed C-O coupling in a single pot. For the first time, the ability to incorporate a chiral and an achiral ligand in a two-component, two-metal transformation is achieved, giving the products in moderate to good yields, with excellent enantioselectivities.

Multicomponent-multicatalyst reactions (MC)(2)R: efficient dibenzazepine synthesis.

Organic Letters

January 13, 2014

A Rh(I)/Pd(0) catalyst system was applied to the multicomponent synthesis of aza-dibenzazepines from vinylpyridines, arylboronic acids, and amines in a domino process with no intermediate isolation or purification.

Formation of substituted oxa- and azarhodacyclobutanes.

Chemistry – A European Journal

December 6, 2013

The preparation of substituted oxa- and azarhodacyclobutanes is reported. After exchange of ethylene with a variety of unsymmetrically and symmetrically substituted alkenes, the corresponding rhodium-olefin complexes were oxidized with H2O2 and PhINTs (Ts=p-toluenesulfonyl) to yield the substituted oxa- and azarhodacyclobutanes, respectively. Oxarhodacyclobutanes could be prepared with excellent…more

Women in Chemistry group, 2015

Lautens Research Group :: Group Pictures

 

 

 

Mark Lautens , O.C.

University Professor
J. Bryan Jones Distinguished Professor
AstraZeneca Professor of Organic Chemistry
NSERC/Merck-Frosst Industrial Research Chair



Department of Chemistry
Davenport Chemical Laboratories
80 St. George St.
University of Toronto
Toronto, Ontario
M5S 3H6

Tel: (416) 978-6083
Fax: (416) 946-8185
E-Mail: mlautens@chem.utoronto.ca

Curriculum Vitae

Personal

Place and Date of Birth Hamilton, Ontario, Canada July 9, 1959

Education

Harvard University NSERC PDF with D. A. Evans 1985 – 1987
University of Wisconsin-Madison Ph.D. with B. M. Trost 1985
University of Guelph B.Sc. – Distinction 1981

Academic Positions

J. Bryan Jones Distinguished Professor University of Toronto 2013 – 2018
University Professor University of Toronto 2012 – present
NSERC/Merck Frosst Industrial Research Chair NSERC/Merck Frosst 2003 – 2013
AstraZeneca Professor of Organic Synthesis University of Toronto 1998 – present
Professor University of Toronto 1995 – 1998
Associate Professor University of Toronto 1992 – 1995
Assistant Professor University of Toronto 1987 – 1992

Awards & Honors

University of Toronto Alumni Faculty Award University of Toronto 2016
CIC Catalysis Award CSC 2016
Officer of the Order of Canada Governor General 2014
Killam Research Fellowship Canada Council for the Arts 2013-2015
CIC Medal Chemical Institute of Canada 2013
Fellow of the Royal Society of UK Royal Society of Chemistry 2011
Pedler Award Royal Society of Chemistry 2011
Senior Scientist Award Alexander von Humboldt Foundation
Berlin, Aachen and Gottingen
2009-2014
Visiting Professor University of Berlin 2009
Visiting Professor Université de Marseilles 2008
ICIQ Summer School ICIQ Tarragona, Spain 2008
Attilio Corbella Summer School Professor Italian Chemical Society 2007
Arthur C. Cope Scholar Award American Chemical Society 2006
Alfred Bader Award Canadian Society for Chemistry 2006
R. U. Lemieux Award Canadian Society for Chemistry 2004
Solvias Prize Solvias AG 2002
Fellow of the Royal Society of Canada Royal Society of Canada 2001

Areas of Research Interest and Expertise

  • new synthetic methods
  • metal catalyzed cycloaddition and annulation reactions
  • asymmetric catalysis with focus on rhodium, nickel and palladium catalysts
  • cyclopropane synthesis and reactions
  • hydrometallation reactions
  • reactions of organosilicon and organotin compounds
  • fragmentation reactions
  • new routes to medicinally/biologically interesting compounds
  • heterocycle synthesis using metal catalysts

 

///////Multicomponent, Multicatalyst Reactions,  (MC)2R,  Dibenzazepine Synthesis, Mark Lautens, University of Toronto ,
Toronto, Ontario, Jennifer Tsoung

Share

Continuous Processing and Efficient in Situ Reaction Monitoring of a Hypervalent Iodine(III) Mediated Cyclopropanation Using Benchtop NMR Spectroscopy

 spectroscopy, SYNTHESIS  Comments Off on Continuous Processing and Efficient in Situ Reaction Monitoring of a Hypervalent Iodine(III) Mediated Cyclopropanation Using Benchtop NMR Spectroscopy
Aug 292016
 

 

Abstract Image

Real-time NMR spectroscopy has proven to be a rapid and an effective monitoring tool to study the hypervalent iodine(III) mediated cyclopropanation. With the ever increasing number of new synthetic methods for carbon–carbon bond formation, the NMR in situ monitoring of reactions is becoming a highly desirable enabling method. In this study, we have demonstrated the versatility of benchtop NMR using inline and online real-time monitoring methods to access mutually complementary information for process understanding, and we developed new approaches for real-time monitoring addressing challenges associated with better integration into continuous processes.

Continuous Processing and Efficient in Situ Reaction Monitoring of a Hypervalent Iodine(III) Mediated Cyclopropanation Using Benchtop NMR Spectroscopy

Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K.
Magritek GmbH, Gebäude VO (Building VO), Triwo Technopark Aachen, Philipsstrasse 8, 52068 Aachen, Germany
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.6b00177
Steven V. Ley received his PhD from Loughborough University in 1972, after which he carried out post-doctoral research with Professor Leo Paquette at Ohio State University, followed by Professor Derek Barton at Imperial College London. In 1975, he joined that Department as a lecturer and became Head of Department in 1989. In 1992, he moved to the 1702 BP Chair of Organic Chemistry at the University of Cambridge and became a Fellow of Trinity College. He was elected to the Royal Society in 1990 and was President of the Royal Society of Chemistry (RSC) 2000-02. Steve has been the recipient of many prizes and awards including the Yamada-Koga Prize, Nagoya Gold Medal, ACS Award for Creative Work in Synthetic Organic Chemistry and the Paul Karrer Medal.
 

STR1 str2 STR3

Ethyl 2-(4-tert-butylphenyl)-1-nitrocyclopropanecarboxylate (5):

[E]-isomer: 1H NMR (600 MHz, CDCl3): δ 0.80-0.85 (t, J = 7.1 Hz, 3H), 1.29 (s, 9H), 2.16-2.21 (dd, J = 10.7, 6.6 Hz, 1H), 2.41-2.46 (dd, J = 9.1, 6.6 Hz, 1H), 3.72-3.77 (m, 1H), 3.88-4.04 (m, 2H), 7.12-7.15 (d, J = 8.3 Hz, 2H), 7.30-7.37 (d, J = 8.4 Hz, 2H).

13C NMR (150 MHz, CDCl3) δ 161.96, 151.38, 128.96, 128.15, 125.37, 71.71, 62.37, 34.54, 33.91, 31.21, 20.73, 13.35.

HRMS (ESI) Calcd. for C16H21NO4 ([M+H]+): 292.15, Found 292.15:

 

[Z]-isomer: 1H NMR (600 MHz, CDCl3): δ 1.30 (s, 9H), 1.34-1.37 (t, J = 7.1 Hz, 3H), 2.00-2.04 (dd, J = 9.9, 6.9 Hz, 1H), 2.64-2.68 (dd, J = 9.2, 6.9 Hz, 1H), 3.43-3.48 (t, J = 9.6 Hz, 1H), 4.31-4.41 (m, 2H), 7.14-7.17 (d, J = 8.3 Hz, 2H), 7.32-7.36 (d, J = 8.4 Hz, 2H).

13C NMR (150 MHz, CDCl3) δ 165.40, 151.56, 128.33, 127.99, 125.63, 72.63, 63.14, 34.55, 33.48, 31.22, 20.08, 13.98.

Zhu, S.; Perman, J. A.; Zhang, X. P. Angew. Chem. Int. Ed. 2008, 47, 8460-8463.

ORGANIC CHEMISTRY RESEARCH GROUP

Steve Ley

/////////

Share

Training Course – IN SILICO DRUG DISCOVERY & DESIGNING: INSIGHTS OF PROTEIN-LIGAND INTERACTIONS. Oct 01, 2016 at Le Méridien Bangalore Hotel in Bengaluru, India.

 CONFERENCE  Comments Off on Training Course – IN SILICO DRUG DISCOVERY & DESIGNING: INSIGHTS OF PROTEIN-LIGAND INTERACTIONS. Oct 01, 2016 at Le Méridien Bangalore Hotel in Bengaluru, India.
Aug 222016
 

 

Training Course – IN SILICO DRUG DISCOVERY & DESIGNING: INSIGHTS OF PROTEIN-LIGAND INTERACTIONS. Oct 01, 2016  at Le Méridien Bangalore Hotel in Bengaluru, India.

https://selectbiosciences.com/trainingCoursesID.aspx?tc=DDD16&pid=4820&conf=DDI16&se=india

http://selectbiosciences.com/conferences/index.aspx?conf=DDI16&se=india

http://selectbiosciences.com/conferences/venue.aspx?pid=4817&conf=DDI16&se=india

Dear Colleague,

SELECTBIO would like to remind you about its Training Course – IN SILICO DRUG DISCOVERY & DESIGNING: INSIGHTS OF PROTEIN-LIGAND INTERACTIONS. This is scheduled to be held on October 01, 2016 from 9:00am to 5:00pm at Le Méridien Bangalore Hotel in Bengaluru, India. This course will be held in conjunction with our 4th International Conference “Drug Discovery India 2016“. Attend the Training Course and the Conference andSave 10% against the regular registration charges.

PROFILE OF ATTENDEES
With basic knowledge in Life Science and Drug Design that would like to receive a comprehensive overview or refresher on the Drug Discovery Technology the target audience comprises:
• Student & Faculty: Bachelor, Masters, PhD, students as well as Faculty and Professors from Microbiology, Biochemistry, Biotechnology, Immunology, Pharmacy, Pharmaceutical Chemistry, Biomedical Technology, Genetics, Bioinformatics, Plant Science and Life Sciences.
• Professionals: Biotechnology, Bioinformatics and Pharmaceutical scientists from industry, academia and regulatory agencies.
Hands-on exercises will be performed individually using Software tools (no prior experience required).

COURSE CONTENTS

• Introduction of Drug Designing
• Science involved in Disease Target Identification
• Virtual Screening
Practical application will be done on 5 molecules and the software on which DEMONSTRATION & TRAINING will be given
• In-Silico Generation of Ligands by ChemSketch
• Conversion of mol files to pdf files by Open Babel
• Protein Optimization & Energy Minimization by SPDBV
• Molecular Docking by MGL Tools | Creation of Grid Parameter & Dock Parameter Files by AutoDock Software
• Running the Algorithm by Cygwin
• Selection of Potent Inhibitors on the basis of Binding Energies and Lipinski’s Rule of 5
• Structure Analysis – Protein & Ligand complex H-bond interaction by UCSF Chimera
• Prediction of Molecular Properties- Molinspiration
• Prediction of Bioactivity- Molinspiration & ACD iLabs
• Drug Likeness – Mol Soft
• Bioavailability & ADME- ACD iLabs
• Toxicity- OSIRIS Property Explorer & ACD iLabs

For more information, or to discuss registration options, please contact me on the details given below.

Thanks and Best Regards

Sakshi Modgil
Customer Services Manager
SELECTBIO INDIA
O: +91 172 5025050
M: +91 7696125050
s.modgil@selectbio.com

Copyright © 2016 SELECTBIO, All rights reserved.

 

///////////////Training Course,  IN SILICO DRUG DISCOVERY & DESIGNING, INSIGHTS OF PROTEIN-LIGAND INTERACTIONSOct 01, 2016  at Le Méridien Bangalore Hotel,  Bengaluru, India, selectbio

 

Share

Flow Chemistry Symposium + Workshop on 27-28th Aug’ 2016 at IISER – PUNE, Pune, India

 SYNTHESIS  Comments Off on Flow Chemistry Symposium + Workshop on 27-28th Aug’ 2016 at IISER – PUNE, Pune, India
Aug 192016
 

FC 1

Flow Chemistry Society – India Chapter is assisting the proliferation of Process Intensification and Flow Chemistry across the country

After  an  enthusiastic  response  at the  2nd FCS-India Symposium & Workshop held at IICT-Hyderabad  in June’16  with  27companies and 115 delegates attending,  we are happy to announce :

The 3rd   2-day FLOW CHEMISTRY Symposium + DEMO Workshop is organized on 27th – 28th August 2016 at  IISER – PUNE  by Flow Chemistry Society – India Chapter (in collaboration with IISER-Pune,  NCL  & IIT-B) ,  with speakers & demonstrators from India, UK, Netherlands and Hungary.

Prof. Ashwini Kumar Nangia,  Director – CSIR-NCL has kindly consented to be the Hon. Chief Guest and inaugurate the Symposium & Workshop.

Both days have intensive interactive sessions on the theory and industrial applications of Flow Chemistry followed by  livedemonstrations  using              5 to 6 different Flow Reactor platforms –each day  from microliters to 10,000 L/day  industrial scale.

The Fees are Rs. 7,000 for Industry Delegates and Rs. 3,000 for Academic Delegates

The registration form  is BELOW

CLICK FOR REGISTRATION FORM 1-REGISTRATION FORM

contact : vk@pi-inc.co   or   msingh@cipla.com   or    rentala@inkarp.co.in 

Accomodation (optional)  : for Bookings please contact IISER-Pune Guest House directly

Mr. Charu Gurav; Mgr Guest Hse, managergh@iiserpune.ac.in   020-25908130    OR

Mr. Sreejit, Mgr-Catering, etc.    sreejit@iiserpune.ac.in    020-25908247

Tariff  per room night :  Rs. 1,500 (single occupancy) //  Rs. 2,000 (Double Occupancy)

best regards

 Vijay

                             Flow Chemistry Society – India Chapter

Vijay Kirpalani                                                                                      Manjinder Singh
President                                                                                Vice-President
email : vk@pi-inc.co                                                                         email : msingh@cipla.com

Tel: +91-9321342022                                                          Tel: +91-9321342022

CLICK FOR REGISTRATION FORM 1-REGISTRATION FORM

/////////

Day 16 of the 2016 Doodle Fruit Games! Find out more at g.co/fruit

P V SINDHU OF INDIA WINS SILVER AT RIO 2016 OLYMPICS IN BADMINTON

Share

Innogen summit India 2016, 18-19 Aug, Mumbai, India

 CONFERENCE  Comments Off on Innogen summit India 2016, 18-19 Aug, Mumbai, India
Aug 192016
 

 

i1Innogen summit India 2016, 18-19 Aug, Mumbai, India, HOTEL HOLIDAY INN, Mumbai International Airport,Organised by Inventicon Business Intelligence Pvt. Ltd………topic is Supergenerics, Innovation in Generics, commercialization, regulatory, other insights,

 

A0 a1

Dr. Ashok Kumar, President – Centre for Research & Development, Ipca Laboratories Ltd, at Innogen summit India 2016, 18-19 Aug, Mumbai, India,, HOTEL HOLIDAY INN, Mumbai International Airport,Organised by Inventicon Business Intelligence Pvt. Ltd — with DR ASHOK KUMAR OF IPCA at Holiday Inn-Mumbai Intl Airport.

 

A2

PANEL DISCUSSION, Dr. Ashok Kumar, President – Centre for Research & Development, Ipca Laboratories Ltd , Dr. Nilima A. Kshirsagar, National Chair Clinical Pharmacology, ICMR Government of India, Yugal Sikri, Chairman – Pharmaceutical Management, School of Business Management, SVKM’s Narsee Monjee Institute of Management Studies — with Yugal Sikri,, Nilima A. Kshirsagarand ASHOK KUMAR OF IPCA at Holiday Inn-Mumbai Intl Airport.

ashit

Ashit sikka, Koji nakamura, Uttam kumar, allfdron TERUMO, AT Innogen summit India 2016, 18-19 Aug, Mumbai, India,, HOTEL HOLIDAY INN, Mumbai International Airport,Organised by Inventicon Business Intelligence Pvt. Ltd — with Koji nakamura of terumo, Ashit Sikka and UTTAM KUMAR OF TERUMO at Holiday Inn-Mumbai Intl Airport.

 

INNO1 INNO3

ROHAN, RIDDHI AND PALLAVI OF INVENTICON

INNO4 S2

DR NIDHI SAPKAL OF ZIMLABS

S3

ALKA LUTHRA OF LUBRIZOL

 

SEEMA1

 

DR SEEMA SINGH, VP AND HEAD,-LEGAL AND IPM, MACLOEDS PHARMA, Innogen summit India 2016, 18-19 Aug, Mumbai, India,, HOTEL HOLIDAY INN, Mumbai International Airport,Organised by Inventicon Business Intelligence Pvt. Ltd — withSeema Singh.

 

lupin cadila

standing Mr Rajeev patil, Sr VP reg affairs Lupin and Mr Sushrut kulkarni Sr VP Zydus cadila, Head, Pharma tech cemtre — with sushrut kulkarni andrajeev patil.

Thanks to

STR1

Rohan Jagtap

Program Manager – Pharma & Lifesciences

 https://ci4.googleusercontent.com/proxy/XM6zLJNVF-KyjTdLe4_K-jsjBvWCfPVibLEfkfFi-qr6U362NxG0XVUkvsdpOUKmwJgUMkzmSETrv9F_bY4Pv0rEVxiUozAcfOcwUjawrQs2stF7iWDvdLcVkMJYElp6G8kNSGlsGwZJsFOoqQTnShF3BCHD=s0-d-e1-ft#https://docs.google.com/a/inventiconasia.com/uc?id=0BxGiCo9okSEbVlRmN0xxM1dpc1E&export=download

Inventicon Business Intelligence Pvt. Ltd.

Phone: +91 22 6511 3334 I Mob: +91 9011052025 Email: rohan.jagtap@inventiconasia.com

Times Square, Unit 1, Level 2, B Wing, Andheri Kurla Road, Andheri (E), Mumbai – 400059, MS – India.

http://inventiconasia.com/About-Us.aspxgards,

AGGENDA

////////

Share

Osanetant

 Uncategorized  Comments Off on Osanetant
Aug 172016
 

Osanetant.png

Osanetant (SR-142,801)

160492-56-8 CAS

: MW 605.257582985
Chemical Formula C35H41Cl2N3O2

(R)-(+)-N-[[3-[1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl]prop-1-yl]-4-phenylpiperidin-4-yl]-N-methylacetamide

Osanetant (SR-142,801) was a neurokinin 3 receptor antagonist developed by Sanofi-Synthélabo, which was being researched for the treatment of schizophrenia, but was discontinued.[1][2] It was the first non-peptide NK3 antagonist developed in the mid-1990s,[3][4] Other potential applications for osanetant is in the treatment of drug addiction, as it has been found to block the effects ofcocaine in animal models.[5][6]

Developed by Sanofi-Aventis (formerly Sanofi-Synthelabo), osanetant (SR-142801) is an NK3 receptor antagonist which was under development for the treatment of schizophrenia and other Central Nervous System (CNS) disorders. In a review of its R&D portfolio, the company announced in August 2005 that it would cease any further development ofosanetant. This follows an earlier decision to discontinue development of eplivanserin for schizophrenia

(R)-(+)-N-[[3-[1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl]prop-1-yl]-4-phenylpiperidin-4-yl]-N-methylacetamide and to a process for their preparation. (R)-(+)-N-[[3-[1-Benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl]prop-1-yl]-4-phenylpiperidin-4-yl]-N-methylacetamide, hereinafter denoted by its International Non-proprietary Name “osanetant”, is the first antagonist of the NK-3 receptor described in the literature, the preparation of which, in particular in the hydrochloride form, is illustrated in EP-A-673 928.
Osanetant.png
According to this document, osanetant is prepared by reacting N-methyl-N-(4-phenylpiperidin-4-yl)acetamide with 1-benzoyl-3-(3,4-dichlorophenyl)-3-(methanesulfonyloxyprop-1-yl)piperidine and by converting the osanetant thus obtained to its hydrochloride. It has been found that osanetant hydrochloride is isolated in the form of an amorphous solid which is difficult to purify. This product comprises impurities originating from the preceding synthetic stages.
Preparative chromatography starting from osanetant base can be used to obtain osenetant in the pure form.
Osanetant is a neurokinin (NK3) receptor antagonist under development by Sanofi-Synthélabo (formerly Sanofi) as a potential treatment for schizophrenia . Sanofi was originally investigating its potential use as a treatment for psychosis and anxiety . Following phase IIa clinical trials , osanetant entered phase IIb development in February 2001 . Osanetant was the first potent and selective non-peptide antagonist described for the NK3 tachykinin receptor . It has a higher affinity for human and guinea pig NK3 receptors than for rat NK3 receptors . In October 1999, Lehman Brothers predicted that the probability of the product reaching the market was 10%, with a possible launch in 2003 and potential peak sales of US $200 million in 2011 .
 
Sanofi-Aventis CEO, Chris Vihebacher,
PATENT
EP 0673928; FR 2717477; FR 2717478; FR 2719311; JP 1996048669; US 5741910; US 5942523; US 6124316
N-Benzyl-4-hydroxy-4-phenylpiperidine (II) was prepared by addition of phenyllithium to N-benzyl-4-piperidone (I). Carbinol (II) was then converted to acetamide (III) by acid-catalyzed Ritter reaction with acetonitrile. Replacement of the acetamido for an N-Boc group in (III) was effected by acidic hydrolysis of amide (III) to give (IV), followed by treatment with di-tert-butyl dicarbonate. The resultant 1-benzyl-4-(Boc-amino)-4-phenylpiperidine (V) was subjected to catalytic hydrogenolysis in the presence of Pd/C, and the N-debenzylated piperidine (VI) was reprotected as the N-trityl derivative (VII) by treatment with triphenylmethyl chloride and triethylamine. Reduction of the N-Boc group of (VII) by LiAlH4, yielded the N-methyl amine (VIII). After acylation of (VIII) with acetyl chloride to acetamide (IX), its N-trityl group was cleaved by treatment with hot aqueous formic acid to produce the intermediate piperidine (X).
Michael addition of methyl acrylate (XII) to (3,4-dichlorophenyl)acetonitrile (XI) produced the cyano diester adduct (XIII). Catalytic hydrogenation of the cyano group of (XIII) over Raney nickel with concomitant intramolecular cyclization gave rise to the piperidinone (XIV). After basic hydrolysis of the methyl ester function of (XIV), the resultant piperidone propionic acid (XV) was reduced to piperidino alcohol (XVI) by means of borane in THF. Resolution of the racemic piperidine (XVI) employing (+)-camphorsulfonic acid provided the dextro enantiomer (XVII). After N-protection of (XVII) as the Boc derivative (XVIII), its primary alcohol was activated as the corresponding mesylate (XIX) with methanesulfonyl chloride and Et3N. Condensation between mesylate (XIX) and intermediate piperidine (X) in acetonitrile at 60 C, produced (XX). The title benzamido derivative was then obtained by acid-promoted Boc group cleavage in (XX), followed by acylation with benzoyl chloride.
WO 9805640
Bioorg Med Chem Lett 1996,6(19),2307
In a related synthesis, (3,4-dichlorophenyl)acetonitrile (XI) was alkylated with bromide (XXII) –prepared by protection of 3-bromopropanol (XXI) with dihydropyran– to afford (XXIII). Subsequent Michael addition of methyl acrylate (XII) to (XXIII) in the presence of Triton B?gave the cyanoacid (XXIV). This was cyclized to the glutarimide (XXV) by refluxing in HOAc in the presence of H2SO4. Reduction of (XXV) using borane-dimethylsulfide complex produced the already reported racemic piperidinoalcohol (XVI). After acylation of the amine group of (XVI) with benzoyl chloride to yield (XXVI), its hydroxyl group was converted into the target mesylate precursor (XXVII) with methanesulfonyl chloride and Et3N.
An alternative preparation of the precursor 4-(N-methyl-N-acetyl)amino-4-phenylpiperidine (XXXIX) has been reported. The N-benzyl protecting group of piperidine (III) was replaced with an N-Boc group by catalytic hydrogenolysis to (XXXVI), followed by treatment with Boc2O to yield (XXXVII). Amide (XXXVII) alkylation with iodomethane under phase-transfer conditions gave the N-methyl derivative (XXXVIII). Subsequent N-Boc group cleavage in (XXXVIII) was accomplished by using zinc chloride in CH2Cl2 to afford the piperidine-ZnCl2 complex (XXXIX). This was then alkylated with mesylate (XXVII), and the title compound was finally isolated from the racemic mixture by means of preparative chiral HPLC.
In a further method, aminopiperidine (IV) was converted to the formamide (XL) by heating in ethyl formate. Formyl group reduction in (XL) with LiAlH4 provided the N-metyl amine (XLI). The N-benzyl group of (XLI) was then removed by catalytic hydrogenation over Pd/C. Alkylation of the resultant piperidine (XLII) with mesylate (XXVII) gave adduct (XLIII). After acetylation of (XLIII) in neat Ac2O, the racemic mixture was separated by chiral HPLC.
In a further procedure, nitrile (XXIII) was alkylated with ethyl 3-bromopropionate (XXVIII) to give cyano ester (XXIX). Catalytic hydrogenation of the cyano group of (XXIX) gave rise to the piperidinone (XXX), which was further reduced to piperidine (XXXI) with LiAlH4 in THF. Acid deprotection of the tetrahydropyranyl group of (XXXI), followed by resolution with (+)-camphorsulfonic acid, furnished the desired (S)-piperidinoalcohol camphorsulfonate salt (XXXII). Treatment of piperidine (XXXII) with benzoyl chloride in the presence of DIEA yielded benzamide (XXXIII). Conversion of the primary alcohol of (XXXIII) into the desired alkyl iodide (XXXV) was achieved via formation of the mesylate ester (XXXIV), followed by displacement of the mesylate group with KI in refluxing acetone.
Bioorg Med Chem Lett 1997,7(5),555
A new method has been reported. Formamide (XL) was prepared form carbinol (II) by a modified Ritter reaction with cyanotrimethylsilane. Subsequent reduction of (XL) with LiAlH4 gave the N-methyl amine (XLI), which was converted to acetamide (XLIV) by treatment with acetyl chloride. Benzyl group hydrogenolysis in (XLIV) afforded the piperidine (X). Finally, alkylation of piperidine (X) with the chiral alkyl iodide (XXXV) provided the title compound.
Cited Patent Filing date Publication date Applicant Title
US5741910 * Feb 29, 1996 Apr 21, 1998 Sanofi Compounds which are selective antagonists of the human NK3 receptor and their use as medicinal products and diagnostic tools
US5942523 * Feb 29, 1996 Aug 24, 1999 Sanofi Compounds which are selective antagonists of the human NK3 receptor and their use as medicinal products and diagnostic tools
US6040316 * Sep 2, 1997 Mar 21, 2000 Warner-Lambert Company 3-alkyl-3-phenyl-piperidines
US6124316 * May 7, 1999 Sep 26, 2000 Sanofi Compounds which are specific antagonists of the human NK3 receptor and their use as medicinal products and diagnostic tools
Citing Patent Filing date Publication date Applicant Title
US7648992 Jul 4, 2005 Jan 19, 2010 Astrazeneca Ab Hydantoin derivatives for the treatment of obstructive airway diseases
US7655664 Dec 14, 2005 Feb 2, 2010 Astrazeneca Ab Hydantoin derivatives as metalloproteinase inhibitors
US7662845 Aug 7, 2006 Feb 16, 2010 Astrazeneca Ab 2,5-Dioxoimidazolidin-4-yl acetamides and analogues as inhibitors of metalloproteinase MMP12
US7666892 May 5, 2008 Feb 23, 2010 Astrazeneca Ab Metalloproteinase inhibitors
US7700604 Dec 14, 2005 Apr 20, 2010 Astrazeneca Ab Hydantoin derivatives as metalloproteinase inhibitors
US7754750 Jul 13, 2010 Astrazeneca Ab Metalloproteinase inhibitors
US7989620 Aug 2, 2011 Astrazeneca Ab Hydantoin derivatives for the treatment of obstructive airway diseases
US8153673 Jan 26, 2010 Apr 10, 2012 Astrazeneca Ab Metalloproteinase inhibitors
US8183251 Nov 28, 2007 May 22, 2012 Astrazeneca Ab Hydantoin compounds and pharmaceutical compositions thereof
US20080032997 * Dec 14, 2005 Feb 7, 2008 Astrazeneca Ab Novel Hydantoin Derivatives as Metalloproteinase Inhibitors
US20080064710 * Jul 4, 2005 Mar 13, 2008 Astrazeneca Ab Novel Hydantoin Derivatives for the Treatment of Obstructive Airway Diseases
US20080221139 * Nov 28, 2007 Sep 11, 2008 David Chapman Novel Compounds
US20080262045 * May 5, 2008 Oct 23, 2008 Anders Eriksson Metalloproteinase Inhibitors
US20080293743 * Dec 14, 2005 Nov 27, 2008 Astrazeneca Ab Novel Hydantoin Derivatives as Metalloproteinase Inhibitors
US20080306065 * May 6, 2008 Dec 11, 2008 Anders Eriksson Metalloproteinase Inhibitors
US20100144771 * Dec 2, 2009 Jun 10, 2010 Balint Gabos Novel Hydantoin Derivatives for the Treatment of Obstructive Airway Diseases
WO2007106022A2 * Mar 15, 2007 Sep 20, 2007 Astrazeneca Ab A new crystalline form g of (5s) -5- [4- (5-chloro-pyridin-2- yloxy) -piperidine-1-sulfonylmethyl] – 5 -methyl -imidazolidine – 2,4-dione (i) and intermediates thereof.
WO2007106022A3 * Mar 15, 2007 Nov 1, 2007 Astrazeneca Ab A new crystalline form g of (5s) -5- [4- (5-chloro-pyridin-2- yloxy) -piperidine-1-sulfonylmethyl] – 5 -methyl -imidazolidine – 2,4-dione (i) and intermediates thereof.

 

References

  1.  “osanetant Sanofi-Aventis discontinued, France.”. Highbeam.
  2. Kamali, F (July 2001). “Osanetant Sanofi-Synthélabo”. Current opinion in investigational drugs (London, England : 2000). 2 (7): 950–6.PMID 11757797.
  3.  Emonds-Alt, X; Bichon, D; Ducoux, JP; Heaulme, M; Miloux, B; Poncelet, M; Proietto, V; Van Broeck, D; et al. (1995). “SR 142801, the first potent non-peptide antagonist of the tachykinin NK3 receptor”. Life Sciences. 56 (1): PL27–32. doi:10.1016/0024-3205(94)00413-M.PMID 7830490.
  4.  Quartara L, Altamura M (August 2006). “Tachykinin receptors antagonists: from research to clinic”. Current Drug Targets. 7 (8): 975–92.doi:10.2174/138945006778019381. PMID 16918326. Retrieved 2011-04-14.
  5.  Desouzasilva, M; Mellojr, E; Muller, C; Jocham, G; Maior, R; Huston, J; Tomaz, C; Barros, M (May 2006). “The tachykinin NK3 receptor antagonist SR142801 blocks the behavioral effects of cocaine in marmoset monkeys”. European Journal of Pharmacology. 536 (3): 269–78.doi:10.1016/j.ejphar.2006.03.010. PMID 16603151.
  6.  Jocham, Gerhard; Lezoch, Katharina; Müller, Christian P.; Kart-Teke, Emriye; Huston, Joseph P.; De Souza Silva, M. AngéLica (September 2006). “Neurokinin receptor antagonism attenuates cocaine’s behavioural activating effects yet potentiates its dopamine-enhancing action in the nucleus accumbens core”. European Journal of Neuroscience. 24 (6): 1721–32. doi:10.1111/j.1460-9568.2006.05041.x.PMID 17004936.
X Emonds-Alt et al. SR 142801, the first potent non-peptide antagonist of the tachykinin NK3 receptor. Life Sci. 1995, 56(1), PL27-32.
F Kamali. Osanetant Sanofi-Synthélabo. Curr. Opin. Invest. Drugs. 2001, 2(7), 950-956.
L Quartara and M Altamura. Tachykinin receptors antagonists: from research to clinic. Curr. Drug Targets. 2006, 7(8), 975-992.
MA De Souza Silva et al. The tachykinin NK3 receptor antagonist SR142801 blocks the behavioral effects of cocaine in marmoset monkeys. Eur. J. Pharmacol. 2006, 536(3), 269-278.
G Jocham et al. Neurokinin receptor antagonism attenuates cocaine’s behavioural activating effects yet potentiates its dopamine-enhancing action in the nucleus accumbens core. Eur. J. Neurosci. 2006, 24(6), 1721-1732.
Osanetant
Osanetant.png
Systematic (IUPAC) name
N-(1-{3-[(3R)-1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl]propyl}-4-phenylpiperidin-4-yl]-N-methylacetamide
Identifiers
CAS Number 160492-56-8 Yes
ATC code none
PubChem CID 219077
IUPHAR/BPS 2110
ChemSpider 189901 
UNII K7G81N94DT Yes
ChEMBL CHEMBL346178 
Chemical data
Formula C35H41Cl2N3O2
Molar mass 606.625 g/mol

///////Osanetant , SR-142,801, 

CC(=O)N(C)C1(CCN(CC1)CCC[C@@]2(CCCN(C2)C(=O)C3=CC=CC=C3)C4=CC(=C(C=C4)Cl)Cl)C5=CC=CC=C5

Share

AZD-1236 Revisited

 Uncategorized  Comments Off on AZD-1236 Revisited
Aug 172016
 

Figure imgf000002_0001

AZD1236

CAS 459814-89-2,
MF C15 H19 Cl N4 O5 S.  MW402.85
2,​4-​Imidazolidinedione, 5-​[[[4-​[(5-​chloro-​2-​pyridinyl)​oxy]​-​1-​piperidinyl]​sulfonyl]​methyl]​-​5-​methyl-​, (5S)​-
(5S)-5-[4-(5-chloro-pyridin-2-yloxy)-piperidine-1-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dione
(S)-5-[4-(5-ChIoro-pyridin-2-yloxy)-piperidine-l-suIfonylmethyl]-5-methyl- imidazoIidine-2,4-dione
UNII-B4OQY51WZS; B4OQY51WZS; (S)-5-(((4-((5-Chloropyridin-2-yl)oxy)piperidin-1-yl)sulfonyl)methyl)-5-methylimidazolidine-2,4-dione; AZD1236; AZD-1236;
Piperidine, 4-[(5-chloro-2-pyridinyl)oxy]-1-[[[(4S)-4-methyl-2,5-dioxo-4-imidazolidinyl]methyl]sulfonyl]- (9CI)(5S)-5-[[[4-[(5-Chloro-2-pyridinyl)oxy]-1-piperidinyl]sulfonyl]methyl]-5-methyl-2,4-imidazolidinedione

Mechanism of Action: Matrix metalloproteinase 9 & 12 (MMP9,12) inhibitor MMP9 MMP12i

Anders Eriksson, Matti Lepistö, Michael Lundkvist, af Rosenschöld Magnus Munck,Pavol Zlatoidsky,

Astrazeneca Ab INNOVATOR

UNII-B4OQY51WZS.png

  • OriginatorAstraZeneca
  • Class
  • Mechanism of ActionMatrix metalloproteinase inhibitors
  • Highest Development Phases
  • DiscontinuedChronic obstructive pulmonary disease

Most Recent Events

  • 29 Jul 2010Discontinued – Phase-II for Chronic obstructive pulmonary disease in Europe (PO)
  • 29 Jul 2010Discontinued – Phase-I for Chronic obstructive pulmonary disease in Japan (PO)
  • 29 Jul 2010Discontinued – Phase-I for Chronic obstructive pulmonary disease in Japan (PO)

AZD1236 is a selective MMP-9 and MMP-12 inhibitor (IC50 4.5 and 6.1nM) from Astrazeneca that, since it failed biomarker endpoints for COPD is included in the AZ Open Innovation 2014 set for repurposing. Pending any published link the structure identification is tenatative but seems likely to be the structure crystalised in WO2007106022.

Matrix metallopeptidase 9 and 12 (MMP9|MMP12) inhibitor http://www.ncbi.nlm.nih.gov/gene/4318; http://www.ncbi.nlm.nih.gov/gene/4321 Preclinical Pharmacology AZD1236 is a potent and reversible inhibitor of human MMP9 and MMP12 (IC50’s = 4.5 and 6.1nM, respectively), with 10 – 15-fold selectivity to MMP2 and MMP13 and >350-fold selectivity to other members of the enzyme family. Its activity is approximately 20- to 50-fold lower at the rat, mouse, and guinea pig orthologues. In acute models of lung injury, AZD1236 inhibited the hemorrhage and inflammation induced by instillation of human MMP12 into rat lungs by ~80% at 0.81 mg/kg, and also abolished macrophage infiltration into BAL fluid induced by tobacco smoke inhalation in the mouse. Safety and Tolerability In healthy human volunteers, AZD1236 was well tolerated in single doses from 2 to 1500 mg and in multiple doses of 15, 75 and 500 mg for periods of up to 13 days. AZD1236 was also well tolerated in COPD patients with moderate to severe disease when given at 75 mg BID for 6 weeks. Pre-clinical toxicology studies of up to 12 month duration have been performed. Toxicologically important findings mainly relate to chronic treatment and included: diffuse eye lens opacities after 6 months administration to rats and fibrodysplasia in the subcutis after 12 months to dogs. Clinical Pharmacology Target coverage data to date have been mixed. In healthy subjects, single dose of 30 or 75 mg inhibited ex vivo zymosanstimmulated whole blood MMP activity (the 75 mg dose yielding plasma compound levels at Cmax steady state of ~120 x IC50). In contrast, 75 mg BID for 6 wks in COPD patients compared to placebo did not identify any significant change in whole blood MMP activity.

 

STR1

PATENT

WO 2002074750 

WO 02/074767 further discloses a specific metalloproteinase inhibitor compound identified therein as (5S)-5-[4-(5-chloro-pyridin-2-yloxy)-piperidine-l-sulfonylmethyl]-5- methyl-imidazolidine-2,4-dione (page 65, lines 15 to 27; and page 120, lines 23 to 29). This compound is designated herein as compound (I).

Figure imgf000002_0001

(I)

WO 02/074767 further discloses processes for the preparation of compound (I). Thus, in one embodiment, compound (I) is prepared by a route analogous to that shown in the following Scheme (WO 02/074767; pages 87, 113 and 120) but substituting the appropriate amine in step (d):

Scheme 1

Figure imgf000003_0001
Figure imgf000003_0002

Reagents and conditions for Scheme 1: a) KCN, (NHLj)2CO3, EtOHTH2O, +900C, 3h;. b) Chiral separation, CHIRALPAK AD, methanol as eluent;. c) Cl2 (g), AcOH/H2O, <+15 0C, 25min; d) Diisopropylethylamine, THF. -20 0C, 30 min.

The obtained compound (I) is then purified either by precipitation and washing with ethanol/water or by preparative HPLC. In a second embodiment, the racemate of compound (I), (5RS)-5-[4-(5-chloro-pyridin-2- yloxy)-piperidine-l-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dione, was prepared by reacting l-[4-(5-chloro-pyridin-2-yloxy)-piperidine-l-sulfonyl]-propan-2-one with an excess of potassium cyanide and ammonium carbonate in ethanol, and isolating the product by precipitation. Compound (I), the (5S)-enantiomer, was then obtained by chiral HPLC (WO 02/074767; pages 55 and 65).

No crystalline forms of compound (I) are disclosed in WO 02/074767.

Compound (I) is a potent metalloproteinase inhibitor, particularly a potent inhibitor of

MMP 12, and as such is useful in therapy. However, when made according to the processes described in WO 02/074767, compound (I) exhibits unpredictable solid state properties with respect to thermodynamic stability. To prepare pharmaceutical formulations containing compound (I) for administration to humans in accordance with the requirements of U.S. and other international health registration authorities, there is a need to produce compound (I) in a stable form, such as a stable crystalline form, having constant physical properties.

str2

PATENT

WO  2007106022

WO 02/074767 further discloses a specific metalloproteinase inhibitor compound identified therein as (5S)-5-[4-(5-chloro-pyridin-2-yloxy)-piperidine-l-sulfonylmethyl]-5- methyl-imidazolidine-2,4-dione (page 65, lines 15 to 27; and page 120, lines 23 to 29). This compound is designated herein as compound (I).

Figure imgf000002_0001

(I)

WO 02/074767 further discloses processes for the preparation of compound (I). Thus, in one embodiment, compound (I) is prepared by a route analogous to that shown in the following Scheme (WO 02/074767; pages 87, 113 and 120) but substituting the appropriate amine in step (d):

Scheme 1

Figure imgf000003_0001
Figure imgf000003_0002

Reagents and conditions for Scheme 1: a) KCN, (NHLj)2CO3, EtOHTH2O, +900C, 3h;. b) Chiral separation, CHIRALPAK AD, methanol as eluent;. c) Cl2 (g), AcOH/H2O, <+15 0C, 25min; d) Diisopropylethylamine, THF. -20 0C, 30 min.

The obtained compound (I) is then purified either by precipitation and washing with ethanol/water or by preparative HPLC. In a second embodiment, the racemate of compound (I), (5RS)-5-[4-(5-chloro-pyridin-2- yloxy)-piperidine-l-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dione, was prepared by reacting l-[4-(5-chloro-pyridin-2-yloxy)-piperidine-l-sulfonyl]-propan-2-one with an excess of potassium cyanide and ammonium carbonate in ethanol, and isolating the product by precipitation. Compound (I), the (5S)-enantiomer, was then obtained by chiral HPLC (WO 02/074767; pages 55 and 65).

No crystalline forms of compound (I) are disclosed in WO 02/074767.

Compound (I) is a potent metalloproteinase inhibitor, particularly a potent inhibitor of

MMP 12, and as such is useful in therapy. However, when made according to the processes described in WO 02/074767, compound (I) exhibits unpredictable solid state properties with respect to thermodynamic stability. To prepare pharmaceutical formulations containing compound (I) for administration to humans in accordance with the requirements of U.S. and other international health registration authorities, there is a need to produce compound (I) in a stable form, such as a stable crystalline form, having constant physical properties.

A preferred process for the synthesis of compound (I) is shown in Scheme 2.

Figure imgf000022_0001

Scheme 2

KCN, (NH4)2CO3

(H) 2-propanol

Figure imgf000022_0002

Chromatography KOBu’

Figure imgf000022_0003

Cl2

AcOH AcOH, H2O

Figure imgf000022_0004

Compound (I)

Figure imgf000022_0005

Recrystallisation EtOH, H2O

Compound (I) Form G

Figure imgf000022_0006

Example 5

(S)-5-[4-(5-ChIoro-pyridin-2-yloxy)-piperidine-l-suIfonylmethyl]-5-methyl- imidazoIidine-2,4-dione Process 1

I5 a) 5-Chloro-2-(piperidin-4-yloxy)-pyridine

5-Chloro-2-(piperidin-4-yloxy)-pyridine acetate (40 g, 0.146 mol) was slurried in iso- PrOAc (664 mL) at 300C. To this slurry was added Na2CO3 (1.5 mol per litre; 196 mL, 2 mol eq.). The slurry was then rapidly stirred at 30 0C for 15 minutes. The biphasic mixture was allowed to settle, and the bottom aqueous phase was separated and discarded.

20 The above base washing procedure was repeated twice more. The organic phase was then washed once with water (200 mL). The resulting iso-VxOAc solution was reduced in volume to approximately 300 mL by distillation under reduced pressure. The solution was then diluted with zsø-PrOAc (400 mL) and again distilled down to approximately 300 mL. This procedure was repeated once more. A sample was removed for analysis of 5-chloro-

25 2-(piperidm-4-yloxy)-pyridine content and water content. The weight or the volume of the solution was measured in order to calculate the concentration of 5-chloro-2-(piperidin-4- yloxy)-pyridme in the Z-PrOAc solution.

fr) rSV5-r4-(5-Chloro-pyridin-2-yloxyVpiperidine-l-sulfonylmethvn-5-methyl- 30 imidazolidine-2 ,4-dione Diisopropylethylamine (24.3 mL, 0.139 mol, 1 mol eq.) was added to the iso-PrOAc solution prepared in part (a) [ca. 300 mL; equivalent to 31.2 g, 0.146 mol, 1.05 mol eq. of 5-chloro-2-(piperidin-4-yloxy)-pyridine] in one portion at RT. The solution was then cooled to -15 °C.

((S)-4-Methyl-2,5-dioxo-imidazolidin-4-yl)-methanesulfonyl chloride (31.65 g, 0.139 mol, 1 mol eq.) was dissolved in dry THF (285 mL) at RT with stirring. The resulting solution was then added to the iso-PrOAc solution of 5-chloro-2-(piperidin-4-yloxy)- pyridine dropwise at -15 0C over about 1.5 h. A precipitate was seen on addition of the ((S)-4-methyl-2,5-dioxo-imidazolidin-4-yl)-methanesulfonyl chloride. At the end of the addition, dry THF (32 mL) was added to the reaction mixture to wash the line and the mixture was stirred for 1 h at — 15 0C. It was then warmed to 20 °C over 1 h and stirred at 20 °C for 1 h further. The reaction was quenched with 10 wt% NaHSO4 (157 mL) with rapid stirring. After about 15 minutes, the biphasic mixture was allowed to settle, and the bottom aqueous phase was separated and discarded. This acid wash procedure was repeated once more. The organic phase was then washed with water (157 mL) using rapid stirring and allowing complete phase separation before partitioning. The reaction solution was then warmed to 40 °C and washed again with water (157 mL). THF (95 mL) was added to the organic layer that was then warmed to 40 0C and filtered at 400C to remove any particulate matter. The solvent volume was then reduced to about 157 mL by reduced pressure distillation with the jacket temperature at 55 °C. zso-PrOAc (317 mL) was then added and the volume was again reduced to about 157 mL. Two more put-and-takes of zsø-PrOAc (317 mL) were carried out. Solids began to precipitate out during the distillations and a suspension resulted. The volume was reduced to about 157 mL each time and after the final distillation a small sample of solvent was then removed from the reaction mixture for residual THF analysis. The 1H NMR showed no THF peaks. The contents of the reaction were then cooled to 0 °C and the product was collected by filtration. The reaction vessel was washed with zsø-PrOAc (63 mL) and this rinse was used to wash the product on the filter. The product was dried overnight in a vacuum oven at 40 °C. The required (S)-5-[4- (5-chloro-pyridin-2-yloxy)-piperidine-l-sulfonyhnethyl]-5-methyl-imidazolidine-2,4-dione was isolated as a white solid in 71% yield (41.8 g).

1H NMR (300MHz, d6-DMSO) δ 10.74 (IH, s), 8.20 (IH, d), 8.01 (IH, s), 7.81 (IH, dd), 6.87 (IH, d), 5.09 (IH, m), 3.52-3.35 (4H, m), 3.13 (2H, m), 2.02 (2H, m), 1.72 (2H, m), 1.33 (3H, s).

Example 6

(S)-5-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-l-sulfonylmethyl]-5-methyl- imidazolidine-2,4-dione Process 2 a) 5-Chloro-2-(piperidm-4-yloxy)-pyridine

5-Chloro-2-(piperidm-4-yloxy)-pyridine acetate (70 g, 257 mmol) was slurried in toluene

(560 mL) at RT. IM NaOH (420 mL) was added and the slurry was then rapidly stirred at RT for 15 min. The biphasic mixture was allowed to settle, and the bottom aqueous phase was separated and discarded. The organic phase was then washed with water (2 x 420 mL). A sample was removed from the organic phase and assayed for 5-chloro-2-(piperidin-

4-yloxy)-pyridine.

The resulting toluene solution was then reduced in volume by distillation at reduced pressure, down to approximately 168 mL (2.4 vol eq. with respect to 5-chloro-2-(piperidin-

4-yloxy)-pyridine acetate charge). The solution was then diluted with toluene (420 mL) and again distilled down to approx 168 mL (2.4 vol eq.). A sample was removed for analysis of water content.

b*) (S)-5-r4-r5-Chloro-pyridm-2-yloxy)-piperidine-l-sulfonylmethvH-5-methyl- imidazolidine-2 ,4-dione

Diisopropylethylamine (38.4 mL, 220 mmol) was added to the toluene solution of 5-chloro-2-(piperidin-4-yloxy)-pyridine obtained in step (a) (containing 236 mmol) in one portion followed by dry THF (151 mL) as a line wash. ((S)-4-Methyl-2,5-dioxo- imidazolidin-4-yl)-methanesulfonyl chloride (48.7 g, 215 mmol) was dissolved in dry THF (352 mL) at RT with stirring. The resulting solution of the sulfonyl chloride was then added dropwise to the toluene/THF solution of 5-chloro-2-(piperidin-4-yloxy)-pyridine and diisopropylethylamine at RT over 1 to 2 h. A precipitate was seen on addition of the sulfonyl chloride. At the end of the addition, dry THF (50 mL) was added to the reaction 5 mixture as a line wash. After the addition was complete, the reaction was stirred for about 30 min at RT.

The reaction was quenched with 10 wt% NaHSO4 (251 mL) with rapid stirring for approx 15 min. The biphasic mixture was allowed to settle, when the bottom aqueous phase was io separated and discarded. This acid wash procedure was repeated once more. The solvent volume was then reduced to about 220 mL by reduced pressure distillation. Toluene (300 mL) was then added and the volume was reduced to about 245 mL Solids begin to precipitate during the distillations and a suspension resulted. After the final distillation, a small sample of solvent was then removed from the reaction mixture for residual THF i5 analysis.

The contents of the reaction mixture were then cooled to 0 °C, stirred for about 30 minutes at this temperature and the product was collected by filtration. The reaction vessel was washed with toluene (100 mL) and this rinse was used to wash the product on the filter. 20 The product was dried in a vacuum oven at 40 0C to constant weight. (S)-5-[4-(5-Chloro- pyridin-2-yloxy)-piperidine-l-sulfonylmethyl]-5-methyl-imidazolidine-2,4-dione was isolated as a white solid in typically 85 to 88% yield over the two steps.

Aerial view of Mölndal

Patent

WO 2003106689

Paul Hudson, President, AstraZeneca U.S. and Executive Vice President, North America, joined by AstraZeneca volunteers to celebrate the AstraZeneca Hope Lodge’s fifth birthday.

Paul Hudson, President, AstraZeneca U.S. and Executive Vice President, North America, joined by AstraZeneca volunteers to celebrate the AstraZeneca Hope Lodge’s fifth birthday.

CLIPS

 

STR3

 

STR4

 

Astra boss Pascal Soriot

STR1

 

 

 

STR3

Massachusetts Economic Development Secretary Jay Ash (left) congratulates Kumar Srinivasan, Head of AstraZeneca R&D Boston (right), at a ceremony to launch AstraZeneca’s Gatehouse Park BioHub.

Massachusetts Economic Development Secretary Jay Ash (left) congratulates Kumar Srinivasan, Head of AstraZeneca R&D Boston (right), at a ceremony to launch AstraZeneca’s Gatehouse Park BioHub.

 

 

STR1

 

str2

 

 

STR1

 

str2

 

References
1. AstraZeneca. 
AZD1236.
Accessed on 31/10/2014. Modified on 31/10/2014. Open Innovation, http://openinnovation.astrazeneca.com/what-we-offer/compound/azd1236/
2. Dahl R, Titlestad I, Lindqvist A, Wielders P, Wray H, Wang M, Samuelsson V, Mo J, Holt A. (2012)
Effects of an oral MMP-9 and -12 inhibitor, AZD1236, on biomarkers in moderate/severe COPD: a randomised controlled trial.
Pulm Pharmacol Ther25 (2): 169-77. [PMID:22306193]

https://ncats.nih.gov/files/AZD1236.pdf

AZD1236

WO1992001062A1 * Jul 4, 1991 Jan 23, 1992 Novo Nordisk A/S Process for producing enantiomers of 2-aryl-alkanoic acids
WO1996021640A1 * Jan 16, 1996 Jul 18, 1996 Teva Pharmaceutical Industries, Ltd. Optically active aminoindane derivatives and preparation thereof
WO2002074767A1 * Mar 13, 2002 Sep 26, 2002 Astrazeneca Ab Metalloproteinase inhibitors
WO2003093260A1 * Apr 29, 2003 Nov 13, 2003 Biogal Gyogyszergyar Rt. Novel crystal forms of ondansetron, processes for their preparation, pharmaceutical compositions containing the novel forms and methods for treating nausea using them
WO2003094919A2 * May 12, 2003 Nov 20, 2003 Teva Pharmaceutical Industries Ltd. Novel crystalline forms of gatifloxacin
EP0175312A2 * Sep 14, 1985 Mar 26, 1986 Kanegafuchi Kagaku Kogyo Kabushiki Kaisha Process for preparing optically active hydantoins
EP0255390A2 * Jul 30, 1987 Feb 3, 1988 MediSense, Inc. Rhodococcus bacterium for the production of aryl acylamidase
EP0442584A1 * Feb 14, 1991 Aug 21, 1991 Dsm N.V. Process for the preparation of an optically active amino acid amide
EP0580210A1 * Jul 6, 1993 Jan 26, 1994 Dsm N.V. Process for the preparation of optically active methionine amide
EP0909754A1 * Oct 13, 1998 Apr 21, 1999 Eli Lilly And Company Process to make chiral compounds
EP1550725A1 * Jun 5, 2003 Jul 6, 2005 Kaneka Corporation PROCESS FOR PRODUCING OPTICALLY ACTIVE alpha-METHYLCYSTEINE DERIVATIVE
US4983771 * Sep 18, 1989 Jan 8, 1991 Hexcel Corporation Method for resolution of D,L-alpha-phenethylamine with D(-)mandelic acid
US20040044215 * Aug 28, 2003 Mar 4, 2004 Alain Alcade Crystalline forms of osanetant
US20040266832 * Jun 24, 2004 Dec 30, 2004 Li Zheng J. Crystal forms of 2-(3-difluoromethyl-5-phenyl-pyrazol-1-yl)-5-methanesulfonyl pyridine
Reference
1 * HIRRLINGER B. ET AL.: ‘Purification and properties of an amidase from Rhodococcus erythropolis MP50 which enantioselectively hydrolyzes 2-arylpropionamides‘ JOURNAL OF BACTERIOLOGY vol. 178, no. 12, June 1996, pages 3501 – 3507, XP001174103
2 * See also references of EP2064202A2
Citing Patent Filing date Publication date Applicant Title
US7625934 Dec 1, 2009 Astrazeneca Ab Metalloproteinase inhibitors
US7772403 Mar 15, 2007 Aug 10, 2010 Astrazeneca Ab Process to prepare sulfonyl chloride derivatives
Patent ID Date Patent Title
US2011003853 2011-01-06 Metalloproteinase Inhibitors
US7754750 2010-07-13 Metalloproteinase Inhibitors
US7625934 2009-12-01 Metalloproteinase Inhibitors
US7427631 2008-09-23 Metalloproteinase inhibitors
US2004147573 2004-07-29 Metalloproteinase inhibitors

US20110038532011-01-06Metalloproteinase InhibitorsUS77547502010-07-13Metalloproteinase InhibitorsUS76259342009-12-01Metalloproteinase InhibitorsUS20092216402009-09-03Novel Crystal ModificationsUS74276312008-09-23Metalloproteinase inhibitorsUS20041475732004-07-29Metalloproteinase inhibitors

///////AZD1236,  AZD-1236, AZD 1236,

O=S(=O)(C[C@@]1(C)NC(=O)NC1=O)N3CCC(Oc2ccc(Cl)cn2)CC3

Day 13 of the 2016 Doodle Fruit Games! Find out more at g.co/fruit

Share
Follow

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

Join other followers: