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ORGANIC SPECTROSCOPY

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

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

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Specific Stereoisomeric Conformations Determine the Drug Potency of Cladosporin Scaffold against Malarial Parasite


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Specific Stereoisomeric Conformations Determine the Drug Potency of Cladosporin Scaffold against Malarial Parasite

https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.8b00565

Pronay Das†ab, Palak Babbar†c, Nipun Malhotra†c, Manmohan Sharmac , Goraknath R. Jachakab , Rajesh G. Gonnadebd, Dhanasekaran Shanmugambe, Karl Harlosf , Manickam Yogavelc , Amit Sharmac *, and D. Srinivasa Reddyab* †All three have contributed equally to this work.
aOrganic Chemistry Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India
b Academy of Scientific and Innovative Research (AcSIR), New Delhi 110025, India
cMolecular Medicine Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi 110067, India dCenter for Material Characterization, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India
e Biochemical Sciences Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India
fDivision of Structural Biology, Welcome Trust Centre for Human Genetics, The Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK
J. Med. Chem., Just Accepted Manuscript
DOI: 10.1021/acs.jmedchem.8b00565
Publication Date (Web): May 21, 2018
Copyright © 2018 American Chemical Society
The dependence of drug potency on diastereomeric configurations is a key facet. Using a novel general divergent synthetic route for a three-chiral centre anti-malarial natural product cladosporin, we built its complete library of stereoisomers (cladologs) and assessed their inhibitory potential using parasite-, enzyme- and structure-based assays.
We show that potency is manifest via tetrahyropyran ring conformations that are housed in the ribose binding pocket of parasite lysyl tRNA synthetase (KRS). Strikingly, drug potency between top and worst enantiomers varied 500-fold, and structures of KRS-cladolog complexes reveal that alterations at C3 and C10 are detrimental to drug potency where changes at C3 are sensed by rotameric flipping of Glutamate332.
Given that scores of anti-malarial and anti-infective drugs contain chiral centers, this work provides a new foundation for focusing on inhibitor stereochemistry as a facet of anti-microbial drug development.
Cladosporin (12) displays exquisite selectivity for the parasite lysyl-tRNA synthetase over human enzyme. This species specific selectivity of cladosporin has been previously described through comprehensive sequence alignment, where the residues val329 and ser346 seem to be sterically crucial for accommodating the methyl moiety of THP ring10. The structural features of compound 12 clearly indicate the presence of three stereocenters, and therefore 2n (n=3) i.e., eight stereoisomers are possible (Fig.1). Till date, only one asymmetric total synthesis of cladosporin13 has been achieved which was followed by another report of formal syntheses14. Here, we have developed a general chemical synthesis route to synthetically access all the eight possible stereoisomers of compound 12.
cladosporin (compound 12) (0.052 g) as a white solid with a yield of 54 %. Melting point: 171-173 °C; [α]25 D = -15.75 (c = 0.6, EtOH); IR υmax(film): cm-1 3416, 3022, 1656, 1218; 1H NMR (400 MHz, CDCl3): δ 11.06 (s, 1H), 7.47 (br. s., 1H), 6.29 (s, 1H), 6.16 (s, 1H), 4.68 (t, J = 9.8 Hz, 1H), 4.12 (s, 1H), 4.01 (s, 1H), 2.89 – 2.75 (m, 2H), 2.00 – 1.94 (m, 1H), 1.87 – 1.81 (m, 1H), 1.70 – 1.63 (m, 4H), 1.35 (d, J = 6.1 Hz, 2H), 1.23 (d, J = 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 169.9, 164.3, 163.1, 141.8, 106.7, 102.0, 101.5, 76.3, 68.0, 66.6, 39.3, 33.6, 30.9, 18.9, 18.1; HRMS calculated for C16H21O5 [M + H]+ 293.1384, observed 293.1379.
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Dr. D. Srinivasa Reddy has been appointed as an editor of Bioorganic & Medicinl Chemistry Letters, Elsevier Publications. Congratulation Sir !

Click here for details. https://www.journals.elsevier.com/bioorganic-and-medicinal-chemistry-letters

The research interests of his group lie in issues related to application of oriented organic synthesis, in particular total synthesis of biologically active natural products, medicinal chemistry and crop protection. This team has been credited with having accomplished total synthesis of more than 25 natural products with impressive biological activities. “Some of our recent achievements include identification of potential leads, like antibiotic compound based on hunanamycin natural product for treating food infections, anti-diabetic molecule in collaboration with an industry partner and  anti-TB compound using a strategy called ‘re-purposing of a drug scaffold’,” said Reddy.

A total of two awardees out of four were from CSIR institutes. In addition to Reddy, Rajan Shankarnarayanan, CSIR – CCMB, Hyderabad (basic sciences), also was conferred with the award. Vikram Mathews, CMC, Vellore (medical research) and Prof Ashish Suri, AIIMS, New Delhi (clinical research), were the others to receive the awards.

With more than 80 scientific publications and 35 patents, Reddy is one of the most prominent scientists in the city and has already been honoured with the Shanti Swarup Bhatnagar prize in chemical sciences. Reddy is also a nominated member of the scientific body of Indian Pharmacopoeia, government of India and was  elected as a fellow of the Telangana and Maharashtra Academies of Sciences in addition to the National Academy of Sciences, India (NASI).

//////////CLADOSPORIN, NCL, CSIR, SRINIVASA REDDY, PUNE, MALARIA
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DDD 107498


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DDD 107498, DDD 498

PATENT WO 2013153357,  US2015045354

6-Fluoro-2-[4-(morpholinomethyl)phenyl]-N-(2-pyrrolidin-1-ylethyl)quinoline-4-carboxamide

6-Fluoro-2-[4-(4-morpholinylmethyl)phenyl]-N-[2-(1-pyrrolidinyl)ethyl]-4-quinolinecarboxamide

4-Quinolinecarboxamide, 6-fluoro-2-[4-(4-morpholinylmethyl)phenyl]-N-[2-(1-pyrrolidinyl)ethyl]-

CAS 1469439-69-7

CAS 1469439-71-1 SUCCINATE

MF C27H31FN4O2
MW 462.559043 g/mol
      6-fluoro-2-[4-(morpholin-4-ylmethyl)phenyl]-N-(2-pyrrolidin-1-ylethyl)quinoline-4-carboxamide
  • Originator Medicines for Malaria Venture; University of Dundee
  • Class Small molecules
  • Mechanism of Action Protein synthesis inhibitors

Highest Development Phases

  • No development reported Malaria

Most Recent Events

  • 16 Jul 2016 No recent reports of development identified for preclinical development in Malaria in United Kingdom
  • 01 Apr 2015 DDD 498 licensed to Merck Serono worldwide for the treatment of Malaria
Inventors Ian Hugh Gilbert, Neil Norcross, Beatriz Baragana Ruibal, Achim Porzelle
Original Assignee University Of Dundee

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Prof Ian Gilbert:

Head of Biological Chemistry and Drug Discovery

BCDD, College of Life Sciences, University of Dundee, DD1 5EH, UK
Tel: +44 (0) 1382-386240

 

University of Dundee

Image result for School of Life Sciences University of Dundee

 

Image result for School of Life Sciences University of Dundee

SCHEMBL15322600.pngDDD498

 

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Merck Serono and MMV sign agreement to develop potential antimalarial therapy

Agreement further diversifies MMV’s partner base, strengthening our antimalarial research and development portfolio

01 April 2015

Photo © Merck Serono

Merck Serono, the biopharmaceutical business of Merck, and MMV announced today that an agreement has been signed for Merck Serono to obtain the rights to the investigational antimalarial compound DDD107498 from MMV. This agreement underscores the commitment of Merck Serono to provide antimalarials for the most vulnerable populations in need.

“This agreement strengthens our Global Health research program and our ongoing collaboration with Medicines for Malaria Venture,” said Luciano Rossetti, Executive Vice President, Global Head of Research & Development at Merck Serono. “MMV is known worldwide for its major contribution to delivering innovative antimalarial treatments to the most vulnerable populations suffering from this disease, and at Merck Serono we share this goal.”

DDD107498 originated from a collaboration between MMV and the University of Dundee Drug Discovery Unit, led by Prof. Ian Gilbert and Dr. Kevin Read. The objective of the clinical program is to demonstrate whether the investigational compound exerts activity on a number of malaria parasite lifecycle stages, and remains active in the body long enough to offer potential as a single-dose treatment against the most severe strains of malaria.

While development and commercialization of the compound is under Merck Serono’s responsibility, MMV will provide expertise in the field of malaria drug development, including its clinical and delivery expertise, and provide access to its public and private sector networks in malaria-endemic countries.

Merck Serono has a dedicated Global Health R&D group working to address key unmet medical needs related to neglected diseases, such as schistosomiasis and malaria, with a focus on pediatric populations in developing countries. Its approach is based on public-private partnerships and collaborations with leading global health institutions and organizations in both developed and developing countries.

“Working with partners like Merck Serono is critical to the progress of potential antimalarial compounds, like DDD107498, through the malaria drug pipeline,” said Dr. Timothy Wells, Chief Scientific Officer at MMV. “Their Global Health Program is gaining momentum and we need more compounds to tackle malaria, a disease that places a huge burden on the world’s most vulnerable populations. DDD107498 holds great promise and we look forward to working with the Merck Serono team through the development phase.”

According to the World Health Organization, there were an estimated 198 million cases of malaria worldwide in 2013, and an estimated 584,000 deaths, primarily in young children from the developing world. The launch of the not-for-profit research foundation, MMV, in 1999 and a number of collaborations and partnerships, including those with Merck Serono, has contributed to reducing the major gap in malaria R&D investment and subsequent dearth of new medicines.

“It’s hugely encouraging to see the German pharmaceutical industry increasing their engagement in the development of novel antimalarials,” said global malaria expert Prof. Dr. Peter Kremsner, Director of the Institute for Tropical Medicine at the University of Tübingen, Germany. “The Merck Serono and MMV collaboration to develop DDD107498 is a great step. It’s a compound that offers lots of promise so I’m excited to see how it progresses.

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Scots scientists in ‘single dose’ malaria treatment breakthrough

An antimalarial drug that could treat patients was discovered by Dundee university scientists

Scientists have discovered an antimalarial compound that could treat malaria patients in a single dose and help prevent the spread of the disease from infected people.

The compound DDD107498 also has the potential to treat patients with malaria parasites resistant to current medications, researchers say.

Scientists hope it could lead to treatments and protection against the disease, which claimed almost 600,000 lives amid 200 million reported cases in 2013.

The compound was identified through a collaboration between the University of Dundee’s drug discovery unit (DDU) and the Medicines for Malaria Venture (MMV), a separate organisation.

The compound is now undergoing further safety testing with a view to entering human clinical trials within the next year.

Details of the discovery have been published in the journal Nature.

Professor Ian Gilbert, head of chemistry at the DDU, who led the team that discovered the compound, said: “The publication describes the discovery and profiling of this exciting new compound.

“It reveals that DDD107498 has the potential to treat malaria with a single dose, prevent the spread of malaria from infected people and protect a person from developing the disease in the first place.

“There is still some way to go before the compound can be given to patients. However, we are very excited by the progress that we have made.”

The World Health Organisation reports that there were 200 million clinical cases of malaria in 2013, with 584,000 people dying from the disease. Most of these deaths were children under the age of five and pregnant women.

MMV chief executive officer Dr David Reddy said: “Malaria continues to threaten almost half of the world’s population – the half that can least afford it.

“DDD107498 is an exciting compound since it holds the promise to not only treat but also protect these vulnerable populations.

“The collaboration to identify and progress the compound, led by the drug discovery unit at the University of Dundee, drew on MMV’s network of scientists from Melbourne to San Diego.”The publication of the research is an important step and a clear testament to the power of partnership.”

MMV selected DDD107498 to enter preclinical development in October 2013 following the recommendation of its expert scientific advisory committee.

Since then, with MMV’s leadership, large quantities of the compound have been produced and it is undergoing further safety testing with a view to entering human clinical trials within the next year.

Merck Serono has recently obtained the right to develop and, if successful, commercialise the compound, with the input of MMV’s expertise in the field of malaria drug development and access and delivery in malaria-endemic countries.

Dr Michael Chew from the Wellcome Trust, which provides funding for the DDU and MMV, said: “The need for new antimalarial drugs is more urgent than ever before, with emerging strains of the parasite now showing resistance against the best available drugs.

“These strains are already present at the Myanmar-Indian border and it’s a race against time to stop resistance spreading to the most vulnerable populations in Africa.

“The discovery of this new antimalarial agent, which has shown remarkable potency against multiple stages of the malaria lifecycle, is an exciting prospect in the hunt for viable new treatments.”

PAPER

 

Abstract Image

Figure

Discovery of a Quinoline-4-carboxamide Derivative with a Novel Mechanism of Action, Multistage Antimalarial Activity, and Potent in Vivo Efficacy

Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, U.K.
Cell and Molecular Biology, Department of Life Sciences, Imperial College, London, SW7 2AZ, U.K.
§ School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
Eskitis Institute, Griffith University, Brisbane Innovation Park, Nathan Campus, Brisbane, QLD 4111, Australia
Swiss Tropical and Public Health Institute, Swiss TPH, Socinstrasse 57, 4051 Basel, Switzerland
#University of Basel, CH-4003 Basel, Switzerland
Medicines for Malaria Venture, International Centre Cointrin, Entrance G, 3rd Floor, Route de Pré-Bois 20, P.O. Box 1826, CH-1215, Geneva 15, Switzerland
J. Med. Chem., Article ASAP
DOI: 10.1021/acs.jmedchem.6b00723
*K.D.R.: phone, +44 1382 388 688; e-mail, k.read@dundee.ac.uk., *I.H.G.: phone, +44 1382 386 240; e-mail,i.h.gilbert@dundee.ac.uk.
Figure
Conditions: (a) morpholine, Et3N, DCM, 16 h, 72% yield; (b) MeMgBr, toluene, reflux, 4 h and then a 10% aqueous HCl, reflux, 1 h, 70% yield; (c) NBS, benzoyl peroxide, dichlorobenzene, 140 °C, 16 h, 70% yield; (d) morpholine, K2CO3, acetonitrile, 40 °C, 16 h, 64% yield; (e) 5-fluoroisatin, KOH, EtOH, 120 °C, microwave, 20 min, 30–76% yield; (f) amine, CDMT, N-methylmorpholine, DCM, 20–61% yield.

// https://tpc.googlesyndication.com/pagead/js/r20160906/r20110914/abg.js//

 

A single-dose treatment against malaria worked in mice to cure them of the disease. The drug also worked to block infection in healthy mice and to stop transmission, according to a study published in Nature today. The fact that the drug can act against so many stages of malaria is pretty new, but what’s even more exciting is the compound’s mode of action: it kills malaria in a completely new way, researchers say. The feature would make it a welcome addition to our roster of antimalarials — a roster that’s threatened by drug resistance.

RESEARCHERS SIFTED THROUGH A LIBRARY OF ABOUT 4,700 COMPOUNDS TO FIND THIS ONE

Malaria is an infectious disease that’s transmitted through mosquito bites; it’s also a leading cause of death in a number of developing countries. Approximately 3.4 billion people live in areas where malaria poses a real threat. As a result, there were 207 million cases of malaria in 2012 — and 627,000 deaths. There are drugs that can be used to prevent malaria, and even treat it, but drug resistance is halting the use of certain treatments in some areas.

A long search

Searching for a new drug is all about trial and error. To find this particular compound, researchers sifted through a library of about 4,700 compounds, testing them to see if they were capable of killing the malaria parasite in a lab setting. When they found something that worked, they tweaked the drug candidate to see if it could perform more effectively. “We went through a lot of these cycles of testing and designing new compounds,” says Ian Gilbert, a medicinal chemist at the University of Dundee in the UK, and a co-author of the study. “Eventually we optimized to the compound which is the subject of the paper.” For now, that compound’s unwieldy name is DDD107498.

To make sure DDD107498 really had potential, the researchers tested it on mice that had already been infected with malaria. A single dose was enough to provoke a 90 percent reduction in the number of parasites in their blood. The scientists also gave the compound to healthy mice that were subsequently exposed to malaria. DDD107498 helped the mice evade infection with a single dose, but it’s unclear how long that effect would last in humans. Finally, the researchers looked at whether the compound could prevent the transmission from an infected mouse to a mosquito. A day after receiving the treatment, mice were put in contact with mosquitoes. The scientists noted a 91 percent reduction in infected mosquitoes.

“IT HAS THE ABILITY TO BE A ONE-DOSE [DRUG], IN COMBINATION WITH ANOTHER MOLECULE.”

“What’s exciting about this molecule is obviously the fact that it has the ability to be a one-dose [drug], in combination with another molecule to cure blood stage malaria,” says Kevin Read, a drug researcher also at the University of Dundee and a co-author of the study. The fact that the compound has the ability to block transmission and protect against infection is equally thrilling. But the way in which DDD107498 kills malaria might be its most interesting feature. It halts the production of proteins — which are necessary for the parasite’s survival. No other malaria drug does that right now, Read says. “So, in principle, there’s no resistance out there already to this mechanism.”

The drug hasn’t been tested in humans yet, so it may not be nearly as good in the field. But Read says DDD107498 looks promising. “From all the pre-clinical or non-clinical data we’ve generated, it is comparable or better than any of the current marketed anti-malarials in those studies.” And at $1 per treatment, the price of the drug should fall “within the range of what’s acceptable,” he says.

“It looks like an excellent study, and the results look very important,” says Philip Rosenthal, a malaria drug researcher at The University of California-San Francisco who didn’t participate in the study. This is a big shift for Rosenthal’s field. Five years ago, “we had very little going on in anti-malarial drug discovery,” he says. Now, there’s quite a bit going on for malaria researchers, and a number of promising compounds are moving along. DDD107498 “is another player, and it’s got a number of positive features,” he says.

OTHER TREATMENTS HAVE TO BE TAKEN FOR A FEW DAYS

One of the features is the drug’s potency. It’s very active against cultured malaria parasites, Rosenthal says. But what’s perhaps most intriguing about DDD107498 is that the drug works against the mechanism that enables protein synthesis the malaria parasite’s cells. No other malaria drug does that right now, Read says. “Considering challenges of treating malaria, which is often in rural areas and developing countries, a single dose would be a big plus,” he says. “In addition, because of it’s long half life, it may also work to prevent malaria with once a week dosing, which is also a benefit.”

Still, no drug is perfect. The data suggests that DDD107498 doesn’t kill malaria as quickly as some other drugs, Rosenthal says. And when the researchers tested it to see how long it might take for resistance to develop, the results weren’t as promising as he would like. The parasites figured out a way to become resistant to the compound “relatively easily,” he says. That shouldn’t be “deal-killer,” however. “Its slow onset of action probably means it should be combined with a faster-acting drug,” he says.

BUT IT’S SLOW-ACTING

The compound is going through safety testing now. If everything goes well, it should hit human trials within the next year, Read says. Chances are, it will have to be used in combination with other malaria drugs, Gilbert says. “All anti-malarials are given in combination because it slows down resistance.”

“When you’re treating infectious diseases, you know that drug resistance is always a potential problem, so having a number of choices to treat malaria is a good thing,” Rosenthal says. In this case, the drug’s new mode of action may hold lead to an entirely new weapon against malaria. “Obviously it’s got a long way to go,” Read says. But the compound is “very exciting,” nonetheless.

// https://tpc.googlesyndication.com/pagead/js/r20160906/r20110914/abg.js//

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PATENT
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Example 16-Fluoro-2-[4-(morpholinomethyl)phenyl]-N-(2-pyrrolidin-1-ylethyl)quinoline-4-carboxamide, Example compound 1 in Scheme 2
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In a sealed microwave tube, a suspension of 2-chloro-6-fluoro-N-(2-pyrrolidin-1-ylethyl)quinoline-4-carboxamide (preparation 4) (2.00 g, 6 mmol), [4-(morpholinomethyl)phenyl]boronic acid, hydrochloride, available from UORSY, (3.20 g, 12 mmol), potassium phosphate (2.63 g, 12 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.21 g, 0.19 mmol) in DMF/Water 3/1 (40 ml) was heated at 130° C. under microwave irradiation for 30 min. The reaction was filtered through Celite™ and solvents were removed under reduced pressure. The resulting residue was taken up in DCM (150 ml) and washed twice with NaHCO3 saturated aqueous solution (2×100 ml). The organic layer was separated, dried over MgSO4 and concentrate to dryness under reduced pressure. The reaction crude was purified by flash column chromatography using an 80 g silica gel cartridge and eluting with DCM (Solvent A) and MeOH (Solvent B) and the following gradient: 1 min hold 100% A, followed by a 30 min ramp to 10% B, and then 15 min hold at 10% B. The fractions containing product were pooled together and concentrated to dryness under vacuum to obtain the desired product as an off-white solid (1 g). The product was dissolved in methanol (100 ml) and 3-mercaptopropyl ethyl sulfide Silica (Phosphonics, SPM-32, 60-200 uM) was added. The suspension was stirred at room temperature over for 2 days and then at 50° C. for 1 h. After cooling to room temperature, the scavenger was filtered off and washed with methanol (30 ml). The solvent was removed under reduced pressure and the product was further purified by preparative HPLC. The fractions containing product were pooled together and freeze dried to obtain the desired product as a white solid (0.6 g, 1.3 mmol, Yield 20%).
1H NMR (500 MHz; CDCl3) δ 1.81-1.84 (m, 4H), 2.50-2.52 (m, 4H), 2.63 (brs, 4H), 2.82 (t, 2H, J=5.9 Hz), 3.61 (s, 2H), 3.71 (dd, 2H, J=5.4 Hz, J=11.4 Hz), 3.74-3.76 (m, 4H), 6.84 (brs, 1H), 7.52-7.57 (m, 3H), 7.97-8.00 (m, 2H), 8.13 (d, 2H, J=8.2 Hz), 8.21 (dd, 1H, J=5.5 Hz, J=9.2 Hz) ppm. 19F NMR (407.5 MHz; CDCl3) δ−111.47 ppm.
Purity by LCMS (UV Chromatogram, 190-450 nm) 99%, rt=5.7 min, m/z 463 (M+H)+ HRMS (ES+) found 463.2501 [M+H]+, C27H32F1N4O2 requires 463.2504.
Example 26-Fluoro-2-[4-(morpholinomethyl)phenyl]-N-(2-pyrrolidin-1-ylethyl)quinoline-4-carboxamide; fumaric acid salt, compound (IB) in Scheme 2
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The starting free base (example 1) (0.58 g, 1 mmol) was dissolved in dry ethanol (10 ml) and added dropwise to a stirred solution of fumaric acid (0.15 g, 1 mmol) in dry ethanol (9 ml). The mixture was stirred at room temperature for 1 h. The white precipitate was filtered, washed with ethanol (20 ml) and then dissolved in 10 ml of water and freeze dried to obtain the desired salt as a white solid (0.601 g, 1 mmol, Yield 82%).
1H NMR (500 MHz; d6-DMSO) δ 1.83-1.86 (m, 4H), 2.41 (brs, 4H), 2.94 (brs, 4H), 3.03 (t, 2H, J=6.2 Hz), 3.57 (s, 2H), 3.60-3.65 (m, 6H), 6.47 (s, 2H), 7.51 (d, 2H, J=8.25), 7.74-7.78 (m, 1H), 8.06 (dd, 1H, J=2.9 Hz, J=10.4 Hz), 8.17 (dd, 1H, J=5.7 Hz, J=9.3 Hz), 8.24-8.26 (m, 3H), 9.24 (t, 1H, J=5.5 Hz) ppm. 19F NMR (407.5 MHz; d6-DMSO) δ-112.30 ppm.
Purity by LCMS (UV Chromatogram, 190-450 nm) 99%, rt=5.3 min, m/z 463 (M+H)+
Example 1AAlternative synthesis of 6-fluoro-2-[4-(morpholinomethyl)phenyl]-N-(2-pyrrolidin-1-ylethyl)quinoline-4-carboxamide, Example compound 1A in Scheme 4
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To a stirred suspension of 6-fluoro-2-[4-(morpholinomethyl)phenyl]quinoline-4-carboxylic acid (preparation 7) (2.20 g, 6 mmol) in DCM (100 ml) at room temperature, 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (1.26 g, 7 mmol) and 4-methylmorpholine (NMO) (1.33 ml, 12 mmol) were added. The reaction mixture was stirred at room temperature for 1 h and then 2-pyrrolidin-1-ylethanamine (0.77 ml, 6 mmol) was added and stirred at room temperature for further 3 h. The reaction mixture was washed with NaHCO3 saturated aqueous solution (2×100 ml) and the organic phase was separated, dried over MgSO4 and concentrated under reduced pressure. The resulting residue was absorbed on silica gel and purified by flash column chromatography using an 80 g silica gel cartridge and eluting with DCM (Solvent A) and MeOH (Solvent B) and the following gradient: 2 min hold 100% A followed by a 30 min ramp to 10% B and then 15 min hold at 10% B. The desired fractions were concentrated to dryness under vacuum to obtain the crude product as a yellow solid (95% purity by LCMS). The sample was further purified by a second column chromatography using a 40 g silica gel cartridge, eluting with DCM (Solvent A) and 10% NH3-MeOH in DCM (Solvent B) and the following gradient: 2 min hold 100% A, followed by a 10 min ramp to 23% B and then 15 min hold at 23% B. The desired fractions were concentrated to dryness under vacuum to obtain product as a white solid (1 g). Re-crystallisation form acetonitrile (18 ml) yielded the title compound as a white solid (625 mg, 1.24 mmol, 20%).
1H NMR (500 MHz; CDCl3) δ 1.81-1.84 (m, 4H), 2.50-2.52 (m, 4H), 2.63 (brs, 4H), 2.82 (t, 2H, J=5.9 Hz), 3.61 (s, 2H), 3.71 (dd, 2H, J=5.4 Hz, J=11.4 Hz), 3.74-3.76 (m, 4H), 6.84 (brs, 1H), 7.52-7.57 (m, 3H), 7.97-8.00 (m, 2H), 8.13 (d, 2H, J=8.2 Hz), 8.21 (dd, 1H, J=5.5 Hz, J=9.2 Hz) ppm.
1H NMR (500 MHz; d6-DMSO) δ 1.72-1.75 (m, 4H), 2.41 (brs, 4H), 2.56 (brs, 4H), 2.67 (t, 2H, J=6.6 Hz), 3.49-3.52 (m, 2H), 3.56 (s, 2H), 3.60-3.61 (m, 4H), 7.52 (d, 2H, J=8.3 Hz), 7.73-7.77 (m, 1H), 8.07 (dd, 1H, J=2.9 Hz, J=10.4 Hz), 8.18-8.21 (m, 2H), 8.26 (d, 2H, J=8.3 Hz), 8.85 (t, 1H, J=6.6 Hz) ppm.
13C NMR (125 MHz; d6-DMSO3) δ 23.2, 38.4, 53.2, 53.5, 54.5, 62.1, 66.2, 109.0, 109.1, 117.3, 120.1, 120.3, 124.1, 124.2, 127.1, 129.4, 132.2, 132.3, 136.8, 139.9, 142.8, 145.2, 155.3, 159.0, 161.0, 166.1 ppm.
19F NMR (500 MHz; d6-DMSO) δ-112.47 ppm.
Purity by LCMS (UV Chromatogram, 190-450 nm) 99%, rt=5.0 min, m/z 463 (M+H)+
PATENT
WO 2016033635
Patent
WO 2013153357

SCHEME 1

Figure imgf000018_0001

SCHEME 2

Figure imgf000019_0001

Preparation 4Yield: 54% Preparation 3

Yield: 27%

Figure imgf000019_0002

SCHEME 4 B

Figure imgf000021_0001

Yield: 72% Yield: 70% Preparation 6

Figure imgf000021_0002

Example 1 : 6-Fluoro-2-r4-(morpholinomethyl)phenyll-N-(2-pyrrolidin-1-ylethyl)quinoline- 4-carboxamide, Example compound 1 in Scheme 2

Figure imgf000050_0002

In a sealed microwave tube, a suspension of 2-chloro-6-fluoro-N-(2-pyrrolidin-1- ylethyl)quinoline-4-carboxamide (preparation 4) (2.00 g, 6 mmol), [4- (morpholinomethyl)phenyl]boronic acid, hydrochloride, available from UORSY, (3.20 g, 12 mmol), potassium phosphate (2.63 g, 12 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.21 g, 0.19 mmol) in DMF/Water 3/1 (40 ml) was heated at 130°C under microwave irradiation for 30 min. The reaction was filtered through Celite™ and solvents were removed under reduced pressure. The resulting residue was taken up in DCM (150 ml) and washed twice with NaHC03 saturated aqueous solution (2 x 100 ml). The organic layer was separated, dried over MgS04and concentrate to dryness under reduced pressure. The reaction crude was purified by flash column chromatography using an 80 g silica gel cartridge and eluting with DCM (Solvent A) and MeOH (Solvent B) and the following gradient: 1 min hold 100% A, followed by a 30 min ramp to 10 % B, and then 15 min hold at 10% B. The fractions containing product were pooled together and concentrated to dryness under vacuum to obtain the desired product as an off-white solid (1 g). The product was dissolved in methanol (100 ml) and 3-mercaptopropyl ethyl sulfide Silica (Phosphonics, SPM-32, 60- 200 uM) was added. The suspension was stirred at room temperature over for 2 days and then at 50°C for 1 h. After cooling to room temperature, the scavenger was filtered off and washed with methanol (30 ml). The solvent was removed under reduced pressure and the product was further purified by preparative HPLC. The fractions containing product were pooled together and freeze dried to obtain the desired product as a white solid (0.6 g, 1.3 mmol, Yield 20%).

1 H NMR (500 MHz; CDCI3) δ 1.81-1.84 (m, 4H), 2.50-2.52 (m, 4H), 2.63 (brs, 4H), 2.82 (t, 2H, J = 5.9 Hz), 3.61 (s, 2H), 3.71 (dd, 2H, J = 5.4 Hz, J = 1 1.4 Hz), 3.74-3.76 (m, 4H), 6.84 (brs, 1 H), 7.52-7.57 (m, 3H), 7.97-8.00 (m, 2H), 8.13 (d, 2H, J = 8.2 Hz), 8.21 (dd, 1 H, J = 5.5 Hz, J = 9.2 Hz) ppm . 19 F NMR (407.5 MHz; CDCI3) δ -11 1.47 ppm. Purity by LCMS (UV Chromatogram, 190-450nm) 99 %, rt = 5.7 min, m/z 463 (M+H)+ HRMS (ES+) found 463.2501 [M+H]+, C27H32F1 N402 requires 463.2504.

Example 2: 6-Fluoro-2-[4-(morpholinomethyl)phenyl1-N-(2-pyrrolidin-1-ylethyl)quinoline- 4-carboxamide; fumaric acid salt, compound (IB) in Scheme 2

Figure imgf000051_0001

The starting free base (example 1) (0.58 g, 1 mmol) was dissolved in dry ethanol (10 ml) and added dropwise to a stirred solution of fumaric acid (0.15 g, 1 mmol) in dry ethanol (9 ml). The mixture was stirred at room temperature for 1 h. The white precipitate was filtered, washed with ethanol (20 ml) and then dissolved in 10 ml of water and freeze dried to obtain the desired salt as a white solid (0.601 g, 1 mmol, Yield 82%).

1 H NMR (500 MHz; d6-DMSO) δ 1.83-1.86 (m, 4H), 2.41 (brs, 4H), 2.94 (brs, 4H), 3.03 (t, 2H, J = 6.2 Hz), 3.57 (s, 2H), 3.60-3.65 (m, 6H), 6.47 (s, 2H), 7.51 (d, 2H, J = 8.25), 7.74-7.78 (m, 1 H), 8.06 (dd, 1 H, J = 2.9 Hz, J = 10.4 Hz), 8.17 (dd, 1 H, J = 5.7 Hz, J = 9.3 Hz), 8.24-8.26 (m, 3H), 9.24 (t, 1 H, J = 5.5 Hz) ppm. 19 F NMR (407.5 MHz; d6- DMSO) δ -112.30 ppm.

Purity by LCMS (UV Chromatogram, 190-450nm) 99 %, rt = 5.3 min, m/z 463 (M+H)+

Example 1A: Alternative synthesis of 6-fluoro-2-[4-(morpholinomethyl)phenyl1-N-(2- pyrrolidin-1-ylethyl)quinoline-4-carboxamide, Example compound 1A in Scheme 4

Figure imgf000052_0001

To a stirred suspension of 6-fluoro-2-[4-(morpholinomethyl)phenyl]quinoline-4-carboxylic acid (preparation 7) (2.20 g, 6 mmol) in DCM (100 ml) at room temperature, 2-chloro- 4,6-dimethoxy-1 ,3,5-triazine (CDMT) (1.26 g, 7 mmol) and 4-methylmorpholine (NMO) (1.33 ml, 12 mmol) were added. The reaction mixture was stirred at room temperature for 1 h and then 2-pyrrolidin-1-ylethanamine (0.77 ml, 6 mmol) was added and stirred at room temperature for further 3 h. The reaction mixture was washed with NaHC03 saturated aqueous solution (2x 100 ml) and the organic phase was separated, dried over MgS04 and concentrated under reduced pressure. The resulting residue was absorbed on silica gel and purified by flash column chromatography using an 80 g silica gel cartridge and eluting with DCM (Solvent A) and MeOH (Solvent B) and the following gradient: 2 min hold 100% A followed by a 30 min ramp to 10 %B and then 15 min hold at 10%B. The desired fractions were concentrated to dryness under vacuum to obtain the crude product as a yellow solid (95% purity by LCMS). The sample was further purified by a second column chromatography using a 40 g silica gel cartridge, eluting with DCM (Solvent A) and 10% NH3-MeOH in DCM (Solvent B) and the following gradient: 2 min hold 100% A, followed by a 10 min ramp to 23 % B and then 15 min hold at 23% B. The desired fractions were concentrated to dryness under vacuum to obtain product as a white solid (1 g). Re-crystallisation form acetonitrile (18 ml) yielded the title compound as a white solid (625 mg, 1.24 mmol, 20%).

1 H NMR (500 MHz; CDCI3) δ 1.81-1.84 (m, 4H), 2.50-2.52 (m, 4H), 2.63 (brs, 4H), 2.82 (t, 2H, J = 5.9 Hz), 3.61 (s, 2H), 3.71 (dd, 2H, J = 5.4 Hz, J = 1 1.4 Hz), 3.74-3.76 (m, 4H), 6.84 (brs, 1 H), 7.52-7.57 (m, 3H), 7.97-8.00 (m, 2H), 8.13 (d, 2H, J = 8.2 Hz), 8.21 (dd, 1 H, J = 5.5 Hz, J = 9.2 Hz) ppm .

1 H NMR (500 MHz; d6-DMSO) δ 1.72-1.75 (m, 4H), 2.41 (brs, 4H), 2.56 (brs, 4H), 2.67 (t, 2H, J = 6.6 Hz), 3.49-3.52 (m, 2H), 3.56 (s, 2H), 3.60-3.61 (m, 4H), 7.52 (d, 2H, J = 8.3 Hz), 7.73-7.77 (m, 1 H), 8.07 (dd, 1 H, J = 2.9 Hz, J = 10.4 Hz), 8.18-8.21 (m, 2H), 8.26 (d, 2H , J = 8.3 Hz), 8.85 (t, 1 H, J = 6.6 Hz) ppm.

13C NMR (125 MHz; d6-DMS03) 5 23.2, 38.4, 53.2, 53.5, 54.5, 62.1 , 66.2, 109.0, 109.1 , 1 17.3, 120.1 , 120.3, 124.1 , 124.2, 127.1 , 129.4, 132.2, 132.3, 136.8, 139.9, 142.8, 145.2, 155.3, 159.0, 161 .0, 166.1 ppm.

19 F NM R (500 MHz; d6-DMSO) δ -1 12.47 ppm.

Purity by LCMS (UV Chromatogram, 190-450nm) 99 %, rt = 5.0 min, m/z 463 (M+H)+

PAPER
A Quinoline Carboxamide Antimalarial Drug Candidate Uniquely Targets Plasmodia at Three Stages of the Parasite Life Cycle
Angewandte Chemie, International Edition (2015), 54, (46), 13504-13506
original image

Putting a stop to malaria: Phenotypic screening against malaria parasites, hit identification, and efficient lead optimization have delivered the preclinical candidate antimalarial DDD107498. This molecule is distinctive in that it has potential for use as a single-dose cure for malaria and shows a unique broad spectrum of activity against the liver, blood, and mosquito stages of the parasite life cycle.

 Prof. P. M. O’Neill Department of Chemistry, University of Liverpool Liverpool, L69 7ZD (UK) E-mail: pmoneill@liverpool.ac.uk Prof. S. A. Ward Liverpool School of Tropical Medicine, Pembroke Place Liverpool, L3 5QA (UK)
 str1

Professor Ian Gilbert FRSC

Design and synthesis of potential therapeutic agents
Position:
Professor of Medicinal Chemistry and Head of the Division of Biological Chemistry and Drug Discovery
Address:
College of Life Sciences, University of Dundee, Dundee
Full Telephone:
+44 (0) 1382 386240, int ext 86240

Dr Neil Norcross

Position:
Medicinal Chemist
Address:
College of Life Sciences, University of Dundee, Dundee
Full Telephone:
(0) , int ext
Image result for Beatriz Baragana Ruibal
La investigadora asturiana Beatriz Baragaña, en La Pola. / PABLO NOSTI
Image result for Achim Porzelle

Achim Porzelle

REFERENCES

///////////DDD107498, DDD 107498, PRECLINICAL, DUNDEE, MALARIA, DDD 498, Achim Porzelle, Ian Gilbert, MERCK SERENO, Beatriz Baragaña, Medicines for Malaria Venture,  University of Dundee, Neil Norcross, 1469439-69-7, 1469439-71-1 , SUCCINATE

Fc1ccc2nc(cc(c2c1)C(=O)NCCN1CCCC1)-c1ccc(cc1)CN1CCOCC1

New Patent, WO 2016110874, Artemisinin , IPCA Laboratories Ltd


 

 

New Patent, WO 2016110874, Artemisinin , IPCA Laboratories Ltd

FOR Cancer; Parasitic infection; Plasmodium falciparum infection; Viral infection

WO-2016110874

KUMAR, Ashok; (IN).
SINGH, Dharmendra; (IN).
MAURYA, Ghanshyam; (IN).
WAKCHAURE, Yogesh; (IN)

Dr. Ashok Kumar, President – Research and Development (Chemical) at IPCA LABORATORIES LTD

IPCA LABORATORIES LIMITED [IN/IN]; 48, Kandivli Industrial Estate, Charkop, Kandivali (West), Mumbai 400067 (IN)

Novel process for preparing artemisinin or its derivatives such as dihydroartemisinin, artemether, arteether and artesunate. Also claims novel intermediates of artemesinin such as artemisinic acid or dihydroartemisinic acid. Discloses the use of artemisinin or its derivatives, for treating malaria, cancer, viral and parasitic infections.

In July 2016, Newport Premium™ reported that IPCA was capable of producing commercial quantities of artemether, arteether and artesunate; and holds an inactive US DMF for artemether since February 2009. In July 2016, IPCA’s website lists artemether, arteether and artesunate under its products and also lists artemether and artesunate as having EDMF and WHO certificates. The assignee also has Canada HPFB certificate for artemether.

The Central Drug Research Institute (CDRI) in collaboration with IPCA is developing CDRI-97/78 (1,2,4 trioxane derivative), a synthetic artemisinin substitute for treating drug resistant Plasmodium falciparum infection. In July 2016, CDRI-97/78 was reported to be in phase 1 clinical development. IPCA in collaboration with CDRI was also investigating CDRI-99/411, a synthetic artemisinin substitute for treating malaria; but its development had been presumed to have been discontinued; however, this application’s publication would suggest otherwise.

Writeup

Artemisinin is an active phytoconstituent of Chinese medicinal herb Artemisia annua, useful for the treatment of malaria. Generally, artemisinin/artemisinic acid is obtained by extraction of the plant, Artemisia annua. The plant Artemisia annua was first mentioned in an ancient Chinese medicine book written on silk in the West Han Dynasty at around 200 B.C. The plant’s anti-malarial application was first described in a Chinese pharmacopeia, titled “Chinese Handbook of Prescriptions for Emergency Treatments,” written at around 340 A.D.

Artemisinin being poorly bioavailable limits its effectiveness. Therefore semisynthetic derivatives of artemisinin such as artesunate, dihydroartemisinin, artelinate, artemether, arteether have been developed to improve the bioavailability of Artemisinin.

Artemisinin and its derivatives – dihydroartemisinin, artemether, arteether, and artesunate being a class of antimalarials compounds used for the treatment of uncomplicated, severe complicated/cerebral and multi drug resistant malaria. Additionally, there are research findings that artemisinin and its derivatives show anti-parasite, anti-cancer, and anti-viral activities.

Dihydroartemisinin Artesunate

The content of Artemisinin in the plant Artemisia annua varies significantly according to the climate and region/geographical area where it is cultivated. Further, the extraction methods provide artemisinin or artemisinic acid from the plant in very poor yields and therefore not sufficient to accommodate the ever-growing need for this important drug. Consequently, widespread use of these valuable drugs has been hampered due to the low availability of this natural product. Therefore, research has focused on the syntheses of this valuable drug in a larger scale to meet the increasing global demand and accordingly ample literature is available on the synthesis of artemisinin or its derivatives, but no commercial success being reported / known till date.

Artemisinin can be prepared synthetically from its precursors such as artemisinic acid or dihydroartemisinic acid according to literature methods known to skilled artisans. For example, dihydroartemisinic acid can be converted to artemisinin by a combination of photooxidation and air-oxidation processes as described in U.S. Patent No. 4,992,561.

Amorphadiene is an early starting material for synthesis of Artemisinic acid or dihydroartemisinic acid, which is an important intermediate for producing Artemisinin commercially, and WO2006128126 reported a preparation method as mentioned in scheme- 1.


acid

In accordance with the scheme 1, the amorphadiene is treated with di(cyclohexyl)borane ( δΗι ΒΗ followed by reaction with H2O2 in presence of NaOH to obtain the amorph-4-ene 12-ol which is further oxidized to dihydroartemisinic acid using CrCb/ifcSC^. The formation of amorph-4-ene 12-ol is taking place via epoxidation of the exocyclic double bond. However, the reported yields of this synthesis are very low, making it unviable to produce artemisinic acid at a cheaper cost than natural extraction, for commercial use.

Amorpha -4, 11-diene

A similar method is published in, WO2009088404, for synthesis of dihydroartemisinic acid through preparation of amorph-4-ene-12-ol via epoxide formation, albeit, predominantly at exo position by reacting the amorpha-4,11-diene with H2O2 in presence of porphyrin catalyst (TDCPPMnCl). During reaction, epoxidation also occurred at endo position leading to formation of Amorphadiene- 4,5- epoxide that remain as impurity. The formed exo epoxide (amorphadiene – 11, 12 – epoxide) is further reduced to get amorph- 4-ene 12-ol and then converted to dihydroartemisinic acid and finally converted into artemisinin.

Amorphadiene-11,12-epoxide

This process involves expensive & industry unfriendly reagents. Moreover, desired stereo isomers were obtained only in poor yields, because several purification steps were needed to get desired stereo isomers leading to escalated production/operational costs.

Therefore there remains a need in the art to improve the yield of Dihydroartemisinic acid, which could potentially reduce the cost of production of Artemisinin and/or its derivatives. Consequently it is the need of the hour to provide a synthetic and economically viable process to meet the growing worldwide demand by improving the process for Artemisinin and/or its derivatives to obtain them in substantially higher yields with good purity by plant friendly operations like crystallization/extractions rather than column chromatography/other cost constraint procedures.

Therefore, the object of the invention is to prepare Artemisinic acid of formula-II, Dihydroartemisinic acid of formula-IIa, Artemisinin and its derivatives through Amorphadiene- 4,5- epoxide.

DHAA methyl ester

Scheme 2

Method 4 (From compound of formula IV (R = CI)):

In the 4-neck round bottom flask was charged Diphenyl sulfoxide (23.8 g), NaHC03 (32.96 g) and DMSO (80 ml) at 30°C. Further a solution of compound of formula IV (R = CI) (10 g) in DMSO (20 ml) was charged to the reaction mass at 30°C followed by heating and maintaining the temperature for 40 hours at 80°C till completion. DMSO was distilled out under vacuum. The reaction mass was cooled followed by charging water

(100 ml) and toluene (100 ml) to the reaction mass with stirring for 30 minutes at 28°C. The layers were separated out and aqueous layer was back extracted with toluene (2 X 100 ml). The organic layer was washed with water (100 ml) and saturated brine solution (100 ml). Solvent was distilled out under vacuum at 50°C, and the crude mass degassed under vacuum at 50-55°C. IPA (40 ml) was charged to the mass. Simultaneous addition of hydrazine hydrate (65% in aqueous solution) (3.8 g) and hydrogen peroxide (50% in aqueous solution) (2.5 ml) was done at 30-32°C over a period of 3.25 hours. After completion, reaction mass was cooled up to 5-10°C and water (100ml) was added to the reaction mass. The pH of the reaction mass was adjusted to 3.8 with dilute 8% aqueous HC1 (24 ml) at 10°C. Ethyl acetate (60 ml) was added to the reaction mass at 10°C and stirred for 15 minutes at 15-20°C. The layers were separated. Aqueous layer was back extracted with ethyl acetate (2 X 20 ml). The combined organic layer was washed with 10%) sodium metabisulfite solution (50 ml), water (50 ml) and saturated brine solution (50 ml). The organic layer was distilled out under vacuum at 45°C and the obtained crude mass was degassed at 50-55°C. To this was added DME (40 ml), Biphenyl (0.9 g) and Li-metal (1.63 g) and the reaction mass was maintained for 10 hours at 80-85°C till reaction completion. The reaction mass was cooled up to 0-5°C followed by drop wise addition of water within one hour, and the reaction stirred for two hours at 20-25°C. Toluene (35 ml) was charged with stirring and layers were separated. The aqueous layer was washed with toluene (35 ml) and the combined toluene layer was washed with water (20 ml). The combined aqueous layer was again washed with toluene (20 ml). The aqueous layer was cooled to 10-15°C and pH adjusted to 3.5-4 with dilute 16% aqueous HC1. MDC (50 ml) was charged and stirred 30 minutes at 20-25°C followed by separation of layers. The aqueous layer extracted with MDC (25 ml) and the combined MDC layer was washed with water (50 ml), then with saturated NaCl solution (25 ml). The solvent was distilled out under vacuum at 40-45°C and the crude mass (Purity: 70-80%>) was degassed at 65-70°C. The crude product (10 g) was dissolved in ethyl acetate (200 ml). 10%> aqueous NaOH (100 ml) was charged to the reaction mass and stirred one hour at 20°C followed by layer separation. Again 10%> aqueous NaOH (100ml) was added to the organic layer, stirred for 30 minutes and layers were separated out. The pH of the combined NaOH solution wash was adjusted to 4.0 with dilute 16%> aqueous HC1 at 5-10°C under stirring. Ethyl acetate (850 ml) was charged to aqueous acidic mass, stirred 30 minutes and layers were separated out. The aqueous layer was back extracted with ethyl acetate (2 X 30 ml) and the combined organic layer was washed with water (100 ml) and saturated brine (50 ml). The organic layer was dried over sodium chloride, solvent was distilled out under vacuum and the purified mass was degassed under vacuum at 50-55°C to obtain Dihydroartemisinic acid (Purity: 90-95%).

b) Methyl ester of Dihydroartemisinic acid:

To a clear solution of Dihydroartemisinic acid (40 g) dissolved in MDC (120 ml) was added thionyl chloride (SOCh) (14.85 ml) at 10±2°C and reaction mass was heated to reflux temperature 40±2°C. After the completion of reaction, solvent was distilled out and excess SOCh was removed under reduced pressure. The resulting concentrated mass of acid chloride was dissolved in MDC (200 ml). In another RBF was taken triethylamine (30.6 ml) and methanol (120 ml). To this solution was added above acid chloride solution at 30±2°C and maintained till completion of reaction. To the reaction mass was added water (400 ml) and organic layer was separated. The aqueous layer was washed with MDC and mixed with main organic layer and the combined organic layer was back washed with water till neutral pH. Then organic layer was concentrated to give methyl ester of Dihydroartemisinic acid as a brown color oily mass.

Weight: 41.88 gm

Yield = 98%

c) Artemisinin:

Methyl ester of dihydroartemisinic acid (67.7 g) was dissolved in methanol (338 ml). To this solution was added Sodium molybdate (29.5 g), 50% hydrogen peroxide (147.3 g) was added at 30±2°C and reaction was maintained for 3-4 hours. After completion of reaction was added water (300 ml) and MDC (300 ml) to the reaction mass. The organic layer was separated and aqueous layer washed with MDC (100 ml). The combined organic layer was concentrated to 475 ml containing hydroperoxide intermediate and directly used for next stage reaction. In another RBF containing MDC (475 ml) was added benzene sulfonic acid (1.27 g) and Indion resin (6.7 g). This heterogeneous solution was saturated with oxygen by passing O2 gas for 10 min at 0±2°C. To this was added previous stage hydroperoxide solution at same temperature with continuous 02 gas purging within 30-40 minutes. The oxygen gas was passed at same temp for 4 hours and temperature raised to 15±2°C with continued passing of oxygen for 5 hours. The

mixture was stirred at 25-30°C for 8-10 hours followed by filtration of resin. The filtrate was washed with water (200 ml X 3) and the combined aqueous layer back washed with MDC (50 ml). The combined organic layer was concentrated to give crude Artemisinin. Weight: 54 gm

Yield= 70.7%

Purification of Artemisinin:

Crude Artemisinin (10 g) was dissolved in ethyl acetate (25 ml) at 45-50°C. The solution was cooled to 30-35°C followed by addition of n-Hexane (100 ml). The material was isolated, stirred for 2 hours, filtered and vacuum dried at 45°C.

Weight: 4 gm

Yield: 40%

THE VIEWS EXPRESSED ARE MY PERSONAL AND IN NO-WAY SUGGEST THE VIEWS OF THE PROFESSIONAL BODY OR THE COMPANY THAT I REPRESENT, amcrasto@gmail.com, +91 9323115463 India

////////New Patent, WO 2016110874, Artemisinin , IPCA Laboratories Ltd, malaria, Cancer,  Parasitic infection,  Plasmodium falciparum infection,  Viral infection, artemether artemisinin,  artemotil,  artenimol,  artesunate,

Ivermectin


Ivermectin skeletal.svg

IVERMECTIN

MK933

22,23-dihydroavermectin B1a + 22,23-dihydroavermectin B1b

70288-86-7 Yes 71827-03-7

 

C95H146O28
Molecular Weight: 1736.15894 g/mol

UNII-8883YP2R6D.png

 

Ivermectin Chemical StructureC48H74O14, 875.09

Ivermectin is a macrocyclic lactone derived from Streptomyces avermitilis with antiparasitic activity. Ivermectin exerts its anthelmintic effect via activating glutamate-gated chloridechannels expressed on nematode neurons and pharyngeal muscle cells. Distinct from the channel opening induced by endogenous glutamate transmitter, ivermectin-activated channels open very slowly but essentially irreversibly. As a result, neurons or muscle cells remain at either hyperpolarisation or depolarization state, thereby resulting in paralysis and death of the parasites. Ivermectin does not readily pass the mammal blood-brain barrier to the central nervous system where glutamate-gated chloride channels locate, hence the hosts are relatively resistant to the effects of this agent.

This drug, ivermectin, was developed by William C. Campbell of Drew University and Satoshi Ōmura of Japan’s Kitasato University. They were awarded the Nobel Prize in Physiology or Medicine. Originally, the drug was used to treat parasites in livestock and pets before becoming the mainstay of the global campaigns to combat lymphatic filariasis and onchocerciasis.

A workhorse of a drug that a few weeks ago earned its developers a Nobel prize for its success in treating multiple tropical diseases is showing early promise as a novel and desperately needed tool for interrupting malaria transmission, according to new findings presented today at the American Society of Tropical Medicine and Hygiene (ASTMH) Annual Meeting.

At ASTMH annual meeting, new studies explore advances in using ivermectin in ‘mass drug administration’ campaigns to reduce infections in Africa and slow spread of drug resistance in Asia…http://www.pharmpro.com/news/2015/10/nobel-prize-winning-drug-could-also-fight-malaria?et_cid=4908183&et_rid=577220619&type=cta

http://www.forbes.com/sites/zackomalleygreenburg/2015/10/27/the-13-top-earning-dead-celebrities-of-2015/

This new finding was presented today at the American Society of Tropical Medicine and Hygiene (ASTMH) Annual Meeting by researchers from Colorado State University.

Ivermectin has been used for decades, given once per year as a part of Mass Drug Administration (MDA) programs, to reduce the disabling worm infections onchocerciasis, which causes river blindness, and filariasis, the cause of the hugely swollen legs (elephantiasis). Merck has generously donated the entire supply of drug; other companies have followed suit with different drugs for other neglected tropical diseases.

Ivermectin (22,23-dihydroavermectin B1a + 22,23-dihydroavermectin B1b) is a broad-spectrum antiparasitic drug in theavermectin family. It is sold under brand names Heartgard, Sklice[1] and Stromectol[2] in the United States, Ivomecworldwide by Merial Animal Health, Mectizan in Canada by Merck, Iver-DT[3] in Nepal by Alive Pharmaceutical and Ivextermin Mexico by Valeant Pharmaceuticals International. In Southeast Asian countries, it is marketed by Delta Pharma Ltd. under the trade name Scabo 6. While in development, it was assigned the code MK-933 by Merck.[4]

It is taken internally or used topically, depending on the treated condition.

It is on the World Health Organization’s List of Essential Medicines, a list of the most important medication needed in a basichealth system.[5]

It is a drug for the treatment of Onchocerciasis.

The disease is also known as river blindness. It is sometimes called Robles’ disease, after the Guatemalan doctor Rodolfo Robles, who first linked the blindness with an insect a century ago (1915).

Medical uses

Ivermectin is a broad-spectrum antiparasitic agent, traditionally against parasitic worms. It is mainly used in humans in the treatment of onchocerciasis (river blindness), but is also effective against other worm infestations (such as strongyloidiasis,ascariasis, trichuriasis, filariasis and enterobiasis), and some epidermal parasitic skin diseases, including scabies.

Ivermectin is currently being used to help eliminate river blindness (onchocerciasis) in the Americas, and to stop transmissionof lymphatic filariasis and onchocerciasis around the world in programs sponsored by the Carter Center using ivermectin donated by Merck.[6][7][8] The disease is endemic in 30 African countries, six Latin American countries, and Yemen, according to studies conducted by the World Health Organization.[9] The drug rapidly kills microfilariae, but not the adult worms. A single oral dose of ivermectin, taken annually for the 10- to 15-year lifespan of the adult worms, is all that is needed to protect the individual from onchocerciasis.[10]

An Ivermectin cream called Soolantra has been approved by the FDA for treatment of rosacea.[11][12]

SOOLANTRA (ivermectin) cream, 1% is a white to pale yellow hydrophilic cream. Each gram of SOOLANTRA cream contains 10 mg of ivermectin. It is intended for topical use.

Ivermectin is a semi-synthetic derivative isolated from the fermentation of Streptomyces avermitilis that belongs to the avermectin family of macrocyclic lactones.

Ivermectin is a mixture containing not less than 95.0 % and not more than 102.0 % of 5-O-demethyl-22,23-dihydroavermectin A1a plus 5-O-demethyl-25-de(1-methylpropyl)-25-(1-methylethyl)-22,23-dihydroavermectin A1a, generally referred to as 22,23-dihydroavermectin B1a and B1b or H2B1a and H2B1b, respectively; and the ratio (calculated by area percentage) of component H2B1a/(H2B1a + H2B1b)) is not less than 90.0 %.

The respective empirical formulas of H2B1a and H2B1b are C48H74O14and C47H72O14 with molecular weights of 875.10 and 861.07 respectively.

The structural formulas are:

SOOLANTRA™ (ivermectin) Structural Formula Illustration

Component H2B1a: R = C2H5, Component H2B1b: R = CH3.SOOLANTRA cream contains the following inactive ingredients: carbomer copolymer type B, cetyl alcohol, citric acid monohydrate, dimethicone, edetate disodium, glycerin, isopropyl palmitate, methylparaben, oleyl alcohol, phenoxyethanol, polyoxyl 20 cetostearyl ether, propylene glycol, propylparaben, purified water, sodium hydroxide, sorbitan monostearate, and stearyl alcohol.

River blindness?

The disease is also known as river blindness. It is sometimes called Robles’ disease, after the Guatemalan doctor Rodolfo Robles, who first linked the blindness with an insect a century ago (1915).

A sufferer of river blindness

The infection is associated with a nematode worm Onchocerca volvulus, which are transmitted by Simulium blackflies which live and breed near fast-flowing streams and rivers. The worms carry parasitic Wolbachia bacteria. The bite of the flies enables the worm larvae to enter the human’s body; after maturing into adults, followed by breeding, the larvae (microfilariae) formed move towards the skin, and release the bacteria when they die. The bacteria trigger an immune response which leads to lesions on the eye and possible blindness (the “river blindness”).

Simulium flyLifecycle of Onchocerciasis volvulus
Left: the Simulium fly (from http://flipper.diff.org/app/items/6730). Right: Simplified life cycle of Onchocerciasis volvulus, modified from the original at: http://emedicine.medscape.com/article/224309-overview#a0104.

Arthropod

More recent evidence supports its use against parasitic arthropods and insects:

  • Lice:[16][17] Ivermectin lotion (0.5%) is FDA-approved for patients six months of age and older.[18] After a single, 10-minute application of this formulation on dry hair, 78% of subjects were found to be free of lice after two weeks.[19] This level of effectiveness is equivalent to other pediculicide treatments requiring two applications.[20]
  • Bed bugs:[21] Early research shows that the drug kills bed bugs when taken by humans at normal doses. The drug enters the human bloodstream and if the bedbugs bite during that time, they will die in a few days.

Contraindications

Ivermectin is contraindicated in children under the age of five, or those who weigh less than 15 kg (33 lb);[22] and those who are breastfeeding, and have a hepatic or renal disease.[23]

Side effects

The main concern is neurotoxicity, which in most mammalian species may manifest as central nervous system depression, and consequent ataxia, as might be expected from potentiation of inhibitory GABA-ergic synapses.

Dogs with defects in the P-glycoprotein gene (MDR1), often collie-like herding dogs, can be severely poisoned by ivermectin.

Since drugs that inhibit CYP3A4 enzymes often also inhibit P-glycoprotein transport, the risk of increased absorption past the blood-brain barrier exists when ivermectin is administered along with other CYP3A4 inhibitors. These drugs include statins, HIV protease inhibitors, many calcium channel blockers, and glucocorticoids such as dexamethasone, lidocaine, and the benzodiazepines.[24]

For dogs, the insecticide spinosad may have the effect of increasing the potency of ivermectin.[25]

Pharmacology

Pharmacodynamics

Ivermectin and other avermectins (insecticides most frequently used in home-use ant baits) are macrocyclic lactones derived from the bacterium Streptomyces avermitilis. Ivermectin kills by interfering with nervous system and muscle function, in particular by enhancing inhibitory neurotransmission.

The drug binds and activates glutamate-gated chloride channels (GluCls).[26] GluCls are invertebrate-specific members of the Cys-loop family of ligand-gated ion channelspresent in neurons and myocytes.

Pharmacokinetics

Ivermectin can be given either by mouth or injection. It does not readily cross the blood–brain barrier of mammals due to the presence of P-glycoprotein,[27] (the MDR1 gene mutation affects function of this protein). Crossing may still become significant if ivermectin is given at high doses (in which case, brain levels peak 2–5 hr after administration). In contrast to mammals, ivermectin can cross the blood–brain barrier in tortoises, often with fatal consequences.

Ecotoxicity

Field studies have demonstrated the dung of animals treated with ivermectin supports a significantly reduced diversity of invertebrates, and the dung persists longer.[28]

History

The discovery of the avermectin family of compounds, from which ivermectin is chemically derived, was made by Satoshi Ōmura of Kitasato University, Tokyo and William C. Campbell of the Merck Institute for Therapeutic research. Ōmura identified avermectin from the bacterium Streptomyces avermitilis. Campbell purified avermectin from cultures obtained from Ōmura and led efforts leading to the discovery of ivermectin, a derivative of greater potency and lower toxicity.[29] Ivermectin was introduced in 1981.[30] Half of the 2015 Nobel Prize in Physiology or Medicine was awarded jointly to Campbell and Ōmura for discovering avermectin, “the derivatives of which have radically lowered the incidence of river blindness and lymphatic filariasis, as well as showing efficacy against an expanding number of other parasitic diseases”.[31]

It started with the avermectins. In 1974, a group of researchers headed by Professor Satoshi Ōmura of the Kitasato Institute, isolated an organism with promising antimicrobial properties in a soil sample (sample OS-3153) picked up near a golf course at Kawana, Ito City, Shizuoka Prefecture, Japan. This was passed on to researchers at the Merck, Sharpe and Dohme (MSD) research laboratories in the USA, who isolated a small family of natural products that became known as avermectins. For many years, scientists have looked in soil samples for the source of potential medicines, like the tetracyclines or streptomycin . There are 8 avermectins, molecules with closely related structures. They are made by fermentation from the bacterium Streptomyces avermitilis.

OmuraProfessor Satoshi Ōmura

the avermectins
The 8 different avermectins, with the differences between them shown in the table below.

Name R1 R2 X-Y
Avermectin A1a Me Et CH=CH
Avermectin A1b Me Me CH=CH
Avermectin A2a Me Et CH2CH(OH)
Avermectin A2b Me Me CH2CH(OH)
Avermectin B1a H Et CH=CH
Avermectin B1b H Me CH=CH
Avermectin B2a H Et CH2CH(OH)
Avermectin B2b H Me CH2CH(OH)

The avermectins proved to be have biocidal activity against a wide range of parasites – such as roundworms, lungworms, mites, lice and arachnids; one of these parasites is the tick Rhipicephalus (Boophilus) microplus, one of the most important cattle parasites in tropical regions. Those with the -CH=CH- function are the more active; the most potent was Avermectin B1, occurring as an 80:20 mixture of the similar molecules B1a and B1b, particularly the B1a component. Commercially it is known as Abamectin.

Veterinary use

In veterinary medicine ivermectin is used against many intestinal worms (but not tapeworms), most mites, and some lice. Despite this, it is not effective for eliminating ticks, flies, flukes, or fleas. It is effective against larval heartworms, but not against adult heartworms, though it may shorten their lives. The dose of the medicine must be very accurately measured as it is very toxic in over-dosage. It is sometimes administered in combination with other medications to treat a broad spectrum of animal parasites. Some dog breeds (especially the Rough Collie, the Smooth Collie, the Shetland Sheepdog, and the Australian Shepherd), though, have a high incidence of a certain mutation within the MDR1 gene (coding for P-glycoprotein); affected animals are particularly sensitive to the toxic effects of ivermectin.[32][33] Clinical evidence suggests kittens are susceptible to ivermectin toxicity.[34] A 0.01% ivermectin topical preparation for treating ear mites in cats (Acarexx) is available.

Ivermectin is sometimes used as an acaricide in reptiles, both by injection and as a diluted spray. While this works well in some cases, care must be taken, as several species of reptiles are very sensitive to ivermectin. Use in turtles is particularly contraindicated.

ivermectinIVERMECTIN

Chlorotris(triphenylphosphine)rhodium(I), [RhCl(PPh3)3]

http://www.chm.bris.ac.uk/motm/wilcat/wilcath.htm

Such selectivity found an important application in the synthesis of Ivermectin (MectizanTM). Avermectin is a naturally-occurring molecule with anthelmintic and insecticidal properties; selectively reducing one double bond using Wilkinson’s catalyst afforded Ivermectin. The resultant small change in molecular shape makes Ivermectin a much more effective drug to combat onchocerciasis (river blindness), a disease which affects many millions of people, mainly in poor African communities.

Avermectin

You need to add just two hydrogen atoms to reduce a C=C bond in avermectin.

Notes and references

  1.  “SKLICE- ivermectin lotion (NDC Code(s): 49281-183-71)”. DailyMed. February 2012. Retrieved 2015-09-09.
  2.  “STROMECTOL- ivermectin tablet (NDC Code(s): 0006-0032-20)”. DailyMed. May 2010. Retrieved 2015-09-09.
  3.  Adhikari, Santosh (2014-05-27). “ALIVE PHARMACEUTICAL (P) LTD.: Iver-DT”. ALIVE PHARMACEUTICAL (P) LTD. Retrieved 2015-10-07.
  4.  Pampiglione S, Majori G, Petrangeli G, Romi R (1985). “Avermectins, MK-933 and MK-936, for mosquito control”. Trans R Soc Trop Med Hyg 79 (6): 797–9. doi:10.1016/0035-9203(85)90121-X. PMID 3832491.
  5.  “WHO Model List of Essential Medicines” (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
  6.  The Carter Center. “River Blindness (Onchocerciasis) Program”. Retrieved2008-07-17..
  7.  The Carter Center. “Lymphatic Filariasis Elimination Program”. Retrieved 2008-07-17..
  8.  WHO. “African Programme for Onchocerciasis Control”. Retrieved 2009-11-12..
  9.  United Front Against Riverblindness. “Onchocerciasis or Riverblindness”..
  10.  United Front Against Riverblindness. “Control of Riverblindness”..
  11.  Galderma Receives FDA Approval of Soolantra (Ivermectin) Cream for Rosacea
  12.  “SOOLANTRA- ivermectin cream (NDC Code(s): 0299-3823-30, 0299-3823-45, 0299-3823-60)”. DailyMed. December 2014. Retrieved 2015-09-09.
  13.  Brooks PA, Grace RF (August 2002). “Ivermectin is better than benzyl benzoate for childhood scabies in developing countries”. J Paediatr Child Health 38 (4): 401–4.doi:10.1046/j.1440-1754.2002.00015.x. PMID 12174005.
  14.  Victoria J, Trujillo R (2001). “Topical ivermectin: a new successful treatment for scabies”. Pediatr Dermatol 18 (1): 63–5. doi:10.1046/j.1525-1470.2001.018001063.x.PMID 11207977.
  15. ^ Jump up to:a b Strong M, Johnstone PW (2007). Strong, Mark, ed. “Interventions for treating scabies”. Cochrane Database of Systematic Reviews (Online) (3): CD000320.doi:10.1002/14651858.CD000320.pub2. PMID 17636630.
  16.  Dourmishev AL, Dourmishev LA, Schwartz RA (December 2005). “Ivermectin: pharmacology and application in dermatology”. International Journal of Dermatology 44(12): 981–8. doi:10.1111/j.1365-4632.2004.02253.x. PMID 16409259.
  17.  Strycharz JP, Yoon KS, Clark JM (January 2008). “A new ivermectin formulation topically kills permethrin-resistant human head lice (Anoplura: Pediculidae)”. Journal of Medical Entomology 45 (1): 75–81. doi:10.1603/0022-2585(2008)45[75:ANIFTK]2.0.CO;2.ISSN 0022-2585. PMID 18283945.
  18.  “Sklice lotion”.
  19.  David M. Pariser, M.D., Terri Lynn Meinking, Ph.D., Margie Bell, M.S., and William G. Ryan, B.V.Sc. (November 1, 2012). “Topical 0.5% Ivermectin Lotion for Treatment of Head Lice”. New England Journal of Medicine 367: 1687–1693.doi:10.1056/NEJMoa1200107.
  20.  Study shows ivermectin ending lice problem in one treatment, Los Angeles Times, Nov 5, 2012
  21.  DONALD G. MCNEIL JR. (2012-12-31). “Pill Could Join Arsenal Against Bedbugs”. The New York Times. Retrieved 2013-04-05.
  22. Jump up^ Dourmishev AL, Dourmishev LA, Schwartz RA (December 2005). “Ivermectin: pharmacology and application in dermatology”. International Journal of Dermatology 44(12): 981–988. doi:10.1111/j.1365-4632.2004.02253.x. PMID 16409259.
  23.  Huukelbach J, Winter B, Wilcke T, et al. (August 2004). “Tratmient masivo selectivo con ivermectina contra las helmintiasis intestinales y parasitos cutáneas en una población gravemente afectada”. Bull World Health Organ 82 (7): 563–571. doi:10.1590/S0042-96862004000800005.
  24.  Goodman and Gilman’s Pharmacological Basis of Therapeutics, 11th edition, pages 122, 1084-1087.
  25. Jump up^ “COMFORTIS® and ivermectin interaction Safety Warning Notification”. U.S. Food and Drug Administration (FDA) Center for Veterinary Medicine (CVM).
  26.  Yates DM, Wolstenholme AJ (August 2004). “An ivermectin-sensitive glutamate-gated chloride channel subunit from Dirofilaria immitis”. Int. J. Parasitol. 34 (9): 1075–81.doi:10.1016/j.ijpara.2004.04.010. PMID 15313134.
  27.  Borst P, Schinkel AH (June 1996). “What have we learnt thus far from mice with disrupted P-glycoprotein genes?”. European Journal of Cancer 32 (6): 985–990.doi:10.1016/0959-8049(96)00063-9.
  28.  Iglesias LE, Saumell CA, Fernández AS, et al. (December 2006). “Environmental impact of ivermectin excreted by cattle treated in autumn on dung fauna and degradation of faeces on pasture”. Parasitology Research 100 (1): 93–102. doi:10.1007/s00436-006-0240-x. PMID 16821034.
  29.  Fisher MH, Mrozik H (1992). “The chemistry and pharmacology of avermectins”. Annu. Rev. Pharmacol. Toxicol. 32: 537–53. doi:10.1146/annurev.pa.32.040192.002541.PMID 1605577.
  30.  W. C. CAMPBELL; R. W. BURG, , M. H. FISHER, and , R. A. DYBAS (June 26, 1984).“The Discovery of Ivermectin and Other Avermectins”. American Chemical Society. pp. 5–20. ISBN 9780841210837. |chapter= ignored (help)
  31.  “The Nobel Prize in Physiology or Medicine 2015” (PDF). Nobel Foundation. Retrieved7 October 2015.
  32.  “MDR1 FAQs”, Australian Shepherd Health & Genetics Institute, Inc.
  33.  “Multidrug Sensitivity in Dogs”, Washington State University’s College of Veterinary Medicine
  34.  Frischke H, Hunt L (April 1991). “Suspected ivermectin toxicity”. Canadian Veterinary Journal 32 (4): 245. PMC 1481314. PMID 17423775.

External links

Bibliography

Avermectin

  • R. W. Burg, B. M. Miller, E. E. Baker, J. Birnbaum, S. A. Currie, R. Hartman, Y.-L. Kong, R. L. Monaghan, G. Olson, I. Putter, J. B. Tunac, H. Wallick, E. O. Stapley, R. Oiwa, and S. Ōmura, Antimicrob. Agents Chemother., 1979, 15, 361-367 (production of avermectins)
  • T. W. Miller, L. Chaiet, D. J. Cole, L. J. Cole, J. E. Flor, R. T. Goegelman, V. P. Gullo, H. Joshua, A. J. Kempf, W. R. Krellwitz, R. L. Monaghan, R. E. Ormond, K. E. Wilson, G. Albers-Schönberg and I. Putter., Antimicrob. Agents Chemother., 1979, 15, 368-371 (isolation of avermectins)
  • J. R. Egerton, D. A. Ostlind, L. S. Blair, C. H. Eary, D. Suhayda, S. Cifelli, R. F. Riek and W. C. Campbell, Antimicrob. Agents Chemother., 1979, 15, 372-378 (efficacy of avermectins)
  • M. H. Fisher, Pure Appl. Chem., 1990, 62, 1231-1240 (avermectin review)
  • Y. J. Yoon, E.-S. Kim, Y.-S. Hwang and C.-Y. Choi, Appl. Microbiol. Biotechnol., 2004, 63, 626–634 (biosynthesis)

Ivermectin

  • J. C. Chabala, H. Mrozik, R. L. Tolman, P. Eskola, A. Lusi, L. H. Peterson, M. F. Woods, M. H. Fisher and W. C. Campbell, J. Med. Chem., 1980, 23, 1134-1136 (synth)
  • W. C. Campbell, M. H. Fisher, E. O. Stapley, G. Albers-Schönberg and T. A. Jacob, Science, 1983, 221, 823–828 (ivermectin as a new antiparasitic agent)
  • S. Ōmura and A. Crump, Nat. Rev. Microbiol., 2004, 2, 984-989. (“The life and times of ivermectin – a success story”).
  • K. Collins, Perspect. Biol. Med., 2004, 47, 100-109. (History of the Merck Mectizan donation program)
  • A. D. Hopkins, Eye, 2005, 19, 1057–1066 (improvements upon ivermectin treatment)
  • T. G. Geary, Trends in Parasitology, 2005, 21, 530–532 (20 years of ivermectin)
  • S. Ōmura, Int. J. Antimicrob. Ag., 2008, 31, 91–98 (25 years of Ivermectin)
  • A. G. Canga, A. M. S. Prieto, M. J. D. Liébana, N. F. Martínez, M. S.Vega and J. J. G. Vieitez, Vet. J., 2009, 179, 25–37 (pharmacokinetics and metabolism of ivermectin in domestic animal species)
  • A. Crump and S. Ōmura, Proc. Jpn. Acad., Ser. B., 2011, 87, 13-28 (ivermectin review)
  • I. Farrell, Education in Chemistry, November 2013. (“One in the eye for river blindness”), online.
  • The Mectizan donation program
  • Colombia eliminates river blindness

Doramectin

  • K. Stutzman-Engwall, S. Conlon, R. Fedechko, H. McArthur, K. Pekrun, Y. Chen, S. Jenne, C. La, N. Trinh, S. Kim, Y.-X. Zhang, R. Fox, C. Gustafsson and A. Krebber, Metabolic Engineering, 2005, 7, 27–37 (synth.)
  • J.-B. Wang, H.-X. Pan and G.-L. Tang, Bioorg. Med. Chem. Lett., 2011, 21, 3320–3323 (synth.)

 

 

 

Ivermectin
Ivermectin skeletal.svg
Systematic (IUPAC) name
22,23-dihydroavermectin B1a + 22,23-dihydroavermectin B1b
Clinical data
Trade names Stromectol
AHFS/Drugs.com monograph
MedlinePlus a607069
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Legal status
Routes of
administration
Oral, topical
Pharmacokinetic data
Protein binding 93%
Metabolism Liver (CYP450)
Biological half-life 18 hours
Excretion Feces; <1% urine
Identifiers
CAS Registry Number 70288-86-7 Yes 71827-03-7
ATC code D11AX22 P02CF01 QP54AA01QS02QA03
PubChem CID: 9812710
DrugBank DB00602 Yes
ChemSpider 7988461 Yes
UNII 8883YP2R6D Yes
KEGG D00804 Yes
ChEMBL CHEMBL341047 
PDB ligand ID IVM (PDBe, RCSB PDB)
Chemical data
Formula C
48H
74O
14
(22,23-dihydroavermectin B1a)
C
47H
72O
14
(22,23-dihydroavermectin B1b)
Molecular mass 875.10 g/mol

SIMILAR

Doramectin is a similar molecule, used to treat parasites in animals, such as cattle, horses, sheep and pigs.

doramectin

 

 

/////////////////ivermectin, MALARIA

KAE 609, NITD 609, Cipargamin for Malaria


 

NITD609.svg
Cipargamin, NITD 609
IUPAC Name: (3R,3’S)-5,7′-dichloro-6′-fluoro-3′-methylspiro[1H-indole-3,1′-2,3,4,9-tetrahydropyrido[3,4-b]indole]-2-one |
CAS Registry Number: 1193314-23-6
Synonyms: NITD609, NITD 609, NITD-609, GNF-609
KAE-609
NITD-609  
 390.238, C19 H14 Cl2 F N3 O
(1’R,3’S)-5,7′-Dichloro-6′-fluoro-3′-methyl-1,2,2′,3′,4′,9′-hexahydrospiro[indole-3,1′-pyrido[3,4-b]indole]-2-one
(1R,3S)-5′,7-Dichloro-6-fluoro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one
CURRENTLY IN -PHASE2
NITD609 is an experimental synthetic antimalarial molecule belonging to the spiroindolone class.[1][2] The compound was developed at the Novartis Institute for Tropical Diseases in Singapore, through a collaboration with the Genomics Institute of the Novartis Research Foundation (GNF), the Biomedical Primate Research Centre and the Swiss Tropical Institute. NITD609 is a novel, synthetic antimalarial molecule belonging to the spiroindolone class, awarded MMV Project of the Year 2009.
It is structurally related to GNF 493, a compound first identified as a potent inhibitor of Plasmodium falciparum growth in a high throughput phenotypic screen of natural products conducted at the Genomics Institute of the Novartis Research Foundation in San Diego, California in 2006. NITD609 was discovered by screening the Novartis library of 12,000 natural products and synthetic compounds to find compounds active against Plasmodium falciparum. The first screen turned up 275 compounds and the list was narrowed to 17 potential candidates.
KAE609 (cipargamin; formerly NITD609, Novartis Institute for Tropical Diseases) is a new synthetic antimalarial spiroindolone analogue with potent, dose-dependent antimalarial activity against asexual and sexual stages of Plasmodium falciparum.http://www.nejm.org/doi/full/10.1056/NEJMoa1315860
ChemSpider 2D Image | cipargamin | C19H14Cl2FN3O

KAE609 shows promise as next generation treatment for malaria

http://www.novartis.com/newsroom/media-releases/en/2014/1843976.shtml

  • KAE609 is the first antimalarial drug candidate with a novel mechanism of action to achieve positive clinical proof-of-concept in over 20 years
  • KAE609 was tested in adult patients with uncomplicated malaria and showed a median parasite clearance time of 12 hours, including in patients with resistant infections[1]
  • For more than a decade, Novartis has been a leader in the fight against malaria, setting the current gold standard for treatment and building one of the strongest malaria pipelines in the industry

KAE609 shows promise as next generation treatment for malaria

  • KAE609 is the first antimalarial drug candidate with a novel mechanism of action to achieve positive clinical proof-of-concept in over 20 years
  • KAE609 was tested in adult patients with uncomplicated malaria and showed a median parasite clearance time of 12 hours, including in patients with resistant infections[1]
  • For more than a decade, Novartis has been a leader in the fight against malaria, setting the current gold standard for treatment and building one of the strongest malaria pipelines in the industry

The digital press release with multimedia content can be accessed here:

Basel, Switzerland, July 30, 2014 Today, Novartis published clinical trial results in the New England Journal of Medicine showing that KAE609 (cipargamin), a novel and potent antimalarial drug candidate, cleared the parasite rapidly in Plasmodium falciparum (P. falciparum) and Plasmodium vivax (P. vivax) uncomplicated malaria patients[1]. Novartis currently has two drug candidates in development. Both KAE609 and KAF156 are new classes of anti-malarial compounds that treat malaria in different ways from current therapies, important to combat emerging drug resistance. Novartis has also identified PI4K as a new drug target with potential to prevent, block and treat malaria.

“Novartis is in the fight against malaria for the long term and we are committed to the continued research and development of new therapies to eventually eliminate the disease,” said Joseph Jimenez, CEO of Novartis. “With two compounds and a new drug target currently under investigation, Novartis has one of the strongest malaria pipelines in the industry.”

Malaria is a life-threatening disease primarily caused by parasites (P. falciparum and P. vivax) transmitted to people through the bites of infected Anopheles mosquitoes. Each year it kills more than 600,000 people, most of them African children[2].

“KAE609 is a potential game-changing therapy in the fight against malaria,” said Thierry Diagana, Head of the Novartis Institute for Tropical Diseases (NITD), which aims to discover novel treatments and prevention methods for major tropical diseases. “Novartis has given KAE609 priority project status because of its unique potential of administering it as a single-dose combination therapy.”

In June 2012, 21 patients infected by one of the two main malaria-causing parasite types took part in a proof-of-concept clinical study conducted in Bangkok and Mae Sot near the Thailand/Burma border where resistance to current therapies had been reported. Researchers saw rapid parasite clearance in adult patients (median of 12 hours)[2] with uncomplicated P. vivax or P. falciparum malaria infection including those with resistant parasites. No safety concerns were identified, however the study was too small for any safety conclusions.

“The growing menace of artemisinin resistance threatens our current antimalarial treatments, and therefore our attempts to control and eliminate falciparum malaria,” said Nick White, Professor of Tropical Medicine at Mahidol University in Thailand and lead author of the NEJM article. “This is why we are so enthusiastic about KAE609; it is the first new antimalarial drug candidate with a completely novel mechanism of action to reach Phase 2 clinical development in over 20 years.”

KAE609, the first compound in the spiroindolone class of treatment, works through a novel mechanism of action that involves inhibition of a P-type cation-transporter ATPase4 (PfATP4), which regulates sodium concentration in the parasite. Because KAE609 also appears to be effective against the sexual forms of the parasite, it could potentially help prevent disease transmission. The clinical trial was done in collaboration with the Wellcome Trust-Mahidol University – Oxford Tropical Medicine Research Programme. Research was supported by the Wellcome Trust, Singapore Economic Development Board, and Medicines for Malaria Venture.

KAE609 represents one of two new classes of antimalarial compounds that Novartis has discovered and published in the last four years.[3],[4] This drug candidate has shown potent in vitro activity against a broad range of parasites that have developed drug resistance against current therapies. KAE609 is currently being planned for Phase 2b trials.

References
[1] http://www.nejm.org/doi/full/10.1056/NEJMoa1315860
[2] World Health Organization, http://www.who.int/mediacentre/factsheets/fs094/en/
[3] Spiroindolones, a Potent Compound Class for the Treatment of Malaria, KAE609, Science, Sept. 2010
[4] Imaging of Plasmodium liver stages to drive next generation antimalarial drug discovery. Science Express, Nov. 17, 2011

http://www.ukmi.nhs.uk/applications/ndo/record_view_open.asp?newDrugID=6368

The current spiroindolone was optimized to address its metabolic liabilities leading to improved stability and exposure levels in animals. As a result, NITD609 is one of only a handful of molecules capable of completely curing mice infected withPlasmodium berghei (a model of blood-stage malaria).
Given its good physicochemical properties, promising pharmacokinetic and efficacy profile, the molecule was recently approved as a preclinical candidate and is now entering GLP toxicology studies with the aim of entering Phase I studies in humans in late 2010. If its safety and tolerability are acceptable, NITD609 would be the first antimalarial not belonging to either the artemisinin or peroxide class to go into a proof-of-concept study in malaria.
If NITD609 behaves similarly in people to the way it works in mice, it may be possible to develop it into a drug that could be taken just once – far easier than current standard treatments in which malaria drugs are taken between one and four times a day for up to seven days. NITD609 also has properties which could enable it to be manufactured in pill form and in large quantities. Further animal studies have been performed and researchers have begun human-stage trials.
NITD609
NITD609.svg
Identifiers
ChemSpider 24662493
Jmol-3D images Image 1
Properties
Molecular formula C19H14Cl2FN3O
Molar mass 390.24 g mol−1

Malaria is an old infectious disease caused by four protozoan parasites, Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae and Plasmodium ovale. These four parasites are typically transmitted by the bite of an infected female Anopheles mosquito. Malaria is a problem in many parts of the world, and over the last few decades the malaria burden has steadily increased. An estimated 1 to 3 million people die every year from malaria – mostly children under the age of 5. This increase in malaria mortality is due in part to the fact that Plasmodium falciparum, the deadliest malaria parasite, has acquired resistance against nearly all available antimalarial drugs, with the exception of the artemisinin derivatives.

Leishmaniasis is caused by one of more than twenty (20) varieties of parasitic protozoa that belong to the genus Leishmania, and is transmitted by the bite of female sandflies. Leishmaniasis is endemic in some 90 countries, including many tropical and sub-tropical areas.

There are four main forms of leishmaniasis. Visceral leishmaniasis, also called kala-azar, is the most serious form and is caused by the parasite Leishmania donovani. Patients who develop visceral leishmaniasis can die within months unless they receive treatment. The two main therapies for visceral leishmaniasis are the antimony derivatives sodium stibogluconate (Pentostam®) and meglumine antimoniate (Glucantim®). Sodium stibogluconate has been used for about 70 years and resistance to this drug is a growing problem. In addition, the treatment is relatively long and painful, and can cause undesirable side effects. Human African Trypanosomiasis, also known as sleeping sickness, is a vector-bome parasitic disease. The parasites concerned are protozoa belonging to the Trypanosoma Genus. They are transmitted to humans by tsetse fly {Glossina Genus) bites which have acquired their infection from human beings or from animals harbouring the human pathogenic parasites.

Chagas disease (also called American trypanosomiasis) is another human parasitic disease that is endemic amongst poor populations on the American continent. The disease is caused by the protozoan parasite Trypanosoma cruzi, which is transmitted to humans by blood-sucking insects. The human disease occurs in two stages: the acute stage, which occurs shortly after the infection, and the chronic stage, which can develop over many years. Chronic infections result in various neurological disorders, including dementia, damage to the heart muscle and sometimes dilation of the digestive tract, as well as weight loss. Untreated, the chronic disease is often fatal.

The drugs currently available for treating Chagas disease are nifurtimox and benznidazole. However, problems with these current therapies include their adverse side effects, the length of treatment, and the requirement for medical supervision during treatment. Furthermore, treatment is really only effective when given during the acute stage of the disease. Resistance to the two frontline drugs has already arisen. The antifungal agent amphotericin b has been proposed as a second-line drug, but this drug is costly and relatively toxic.

PAPER

Stereoselective Total Synthesis of KAE609 via Direct Catalytic Asymmetric Alkynylation to Ketimine

Institute of Microbial Chemistry (BIKAKEN), Tokyo, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan
JST, ACT-C, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan
Org. Lett., 2015, 17 (19), pp 4762–4765
DOI: 10.1021/acs.orglett.5b02300
Publication Date (Web): September 14, 2015
Copyright © 2015 American Chemical Society

Abstract

Abstract Image

A direct catalytic asymmetric alkynylation protocol is applied to provide the requisite enantioenriched propargylic α-tertiary amine, allowing for the stereoselective total synthesis of KAE609 (formerly NITD609 or cipargamin).

STR1

STR1

CLICK ON IMAGE TO VIEW

http://pubs.acs.org/doi/abs/10.1021/acs.orglett.5b02300?journalCode=orlef7

http://pubs.acs.org/doi/suppl/10.1021/acs.orglett.5b02300/suppl_file/ol5b02300_si_001.pdf

 

 STR1.jpg
STR1.jpg

PATENT

WO 2009/132921

Figure

In this process, the chiral amine is installed via an enzymatic resolution via deacylation of the acetamide 2. In addition to the wasteful resolution, other inefficiencies of this route include protection/deprotection (Ac/Boc, 2 to 4, and 5 to 6) and a three-step sequence to reduce the carboxylic acid to a methyl group (3 to 6).

Patent

US 2015/0045562

Figure

Improved Route to Cipargamin Employing Transaminase Reaction

For the transamination step, the enzyme ATA-256 was engineered by Codexis to accommodate the non-natural indole substrate 12. Since the substrate is not water-soluble, PEG 200 (approximately 20 vol %) is used as a cosolvent, an interesting selection given that DMSO or methanol are the most common cosolvents for enzymatic reactions. Isopropylamine is employed as the amine donor, a strategy that was adopted from the work of Merck and Codexis for the transamination of sitagliptin ketone.(2) During the transamination, which is a reversible reaction,i-PrNH2 is converted to acetone, which can be readily removed by evaporation to drive the reaction to completion. The workup involves filtration to remove enzyme residues followed by pH swings in which the product is extracted into the aqueous layer under acidic conditions, then basified for extraction into the organic layer. Addition of (+)-camphorsulfonic acid (CSA) provides the amine 14 as the crystalline CSA salt. No details are provided on enantioselectivity for the transamination, and it is not clear if the (+)-CSA is required to upgrade the ee or whether this salt was selected based on physical properties and the ability to develop a scalable crystallization process.
The final step to generate the spiroindole involves a diastereoselective condensation of the chiral amine with 5-chloroisatin (7) under acidic conditions. The diastereoselectivity of this reaction is not provided, nor any ee or de data for the final product. The spiroindole is also isolated as a (+)-CSA salt, which is then converted to the crystalline free base hemihydrate as the final form of cipargamin.

Example 12: Process for Preparing a Compound of formula (IVA) 1/z Hydrate

622.54 399.25

In a 750ml reactor with impeller stirrer 50g of compound (IVB) salt were dissolved in 300ml Ethanol (ALABD) and 100 ml deionised Water (WEM). The clear, yellowish sollution was heated to 58°C internal temperature. To the solution 85 g of a 10% aqueous sodium carbonate solution was added within 10 minutes. The clear solution was particle filtered into a second reaction vessel. Vessel and particle filter were each rinsed with 25 ml of a mixture of ethanohwater (3:1 v/v) in the second reaction vessel. The combined particle filtered solution is heated to 58°C internal temperature and 200ml water (WEM) were added dropwise within 15 minutes. Towards the end of the addition the solution gets turbid. The mixture is stirred for 10 minutes at 58°C internal temperature and is then cooled slowely to room temperature within 4hours 30 minutes forming a thick, well stirable white suspension. To the suspension 200 ml water are added and the mixture is stirred for additional 15hours 20 minutes at room temperature. The suspension is filtered and the filter cake is washed twice with 25 ml portions of a mixture of ethanohwater 9: 1 (v/v). The colourless crystals are dried at 60°C in vacuum yielding 26.23g (=91.2% yield). H NMR (400 MHz, DMSO-d6)

0.70 (s, 1H), 10.52 (s, 1H), 7.44 (d, J = 10.0 Hz, 1H), 7.33 (dd, J = 8.4, 2.1 Hz, 1H),.26 (d, J = 6.5 Hz, 1H), 7.05 (d, J = 2.3 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 3.83 – 4.00 (m,H), 3.13 (d, J = 6.0 Hz, 1H), 2.77 (dd, J = 15.1, 3.8 Hz, 1H), 2.38 (dd, J = 15.1, 10.5 Hz,H), 1.17 (d, J = 6.3 Hz, 3H).

 

 

Patent

http://www.google.com/patents/WO2009132921A1?cl=en

 

SCHEME G: Preparation of (lR,3S)-5′,7-dichloro-6-fluoro-3-methyl-2,3,4,9- tetrahydrospiro[β-carboline-l,3′-indol-2′(l’iϊ)-one (35) and (lR,3S)-5′-chloro-6-fluoro-3- methyl-2,3,4,9-tetrahydrospiro[β-carboline-l,3′-indoI-2′(l’H0-one (36)

Step 1 : POCl3 (2.43 mL, 26.53 mmol) was added dropwise to N, N-dimethylformamide (15.0 mL) at -20 °C and stirred below -5 0C for one hour. A solution of 6-chloro-5-fluoroindole (3.0 g, 17.69 mmol) in dimethylformamide (5.0 mL) was added dropwise to the above reaction mixture at -20 °C. The salt-ice bath was removed and the reaction mixture was warmed to 35 0C, After one hour, the reaction was poured onto ice and basified by solid sodium bicarbonate and extracted with ethyl acetate. The combined organic layer was washed with water and then concentrated to give 6-chloro-5-fluoro-1H-indole-3-carbaldehyde (3.4 g, 97 %) as a light brown solid. 1H ΝMR (500 MHz, CDCl3): δ 10.02 (s, 1 H), 8.10 (d, IH, J = 9.5 Hz), 7.87 (s, 1 H), 7.49 (d, IH, J= 5.5 Hz).

Step 2: The solution (0.2 M) of 6-chloro-5-fluoro-1H-indole-3-carbaldehyde (4.0 g, 20.24 mmol) in nitroethane (100 mL) was refluxed with ammonium acetate (1.32 g, 0.85 mmol) for 4 hours. The reaction mixture was concentrated under vacuum to remove nitroethane, diluted with ethylacetate and washed with brine. The organic layer was concentrated to give 6-chloro-5- fluoro-3-(2-nitro-propenyl)-1H-indole (5.0 g, 97 %) as a reddish orange solid. 1H ΝMR (500 MHz, CDCl3): δ 8.77 (s, IH), 8.32 (s, IH), 7.58 (d, IH, J= 2.5 Hz), 7.54 (d, IH, J = 9 Hz), 7.50 (d, IH, J= 5.9 Hz), 2.52 (s, 3H). Step 3: A solution of 6-chloro-5-fluoro-3-(2-nitro-propenyl)-1H-indole (5.0 g, 19.63 mmol) in tetrahydrofuran (10 mL) was added to the suspension of lithium aluminium hydride (2.92 g, 78.54 mmol) in tetrahydrofuran (20 mL) at 0 0C and then refluxed for 3 hours. The reaction mixture was cooled to 0 °C, and quenched according to the Fischer method. The reaction mixture was filtered through celite and the filtrate concentrated to give 2-(6-chloro-5-fluoro-1H-indol-3- yl-1-methyl-ethylamine (4.7 g crude) as a viscous brown liquid. The residue was used without further purification. 1H NMR (500 MHz, CDCl3): δ 8.13 (s, IH), 7.37 (d, IH, 6.Hz), 7.32 (d, IH, J = 10 Hz), 7.08 (s, IH), 3.23-3.26 (m, IH), 2.77-2.81 (m, IH), 2.58-2.63 (m, IH), 1.15 (d, 3H, J= 6.5 Hz).

Step 4: A mixture of 2-(6-chloro-5-fluoro-1H-indol-3-yl-l-methyl-ethylamine (4.7 g, 20.73 mmol), 5-chloroisatin (3.76 g, 20.73 mmol) and p-toluenesulphonic acid (394 mg, 2.07 mmol) in ethanol (75 mL) was refluxed overnight. The reaction mixture was concentrated to remove ethanol, diluted with ethyl acetate and washed with saturated aqueous NaHCO3. The organic layer was concentrated to give a brown residue, which was purified by silica gel chromatography (20 % ethyl acetate in hexane) to provide the corresponding racemate (4.5 g, 56 %) as a light yellow solid. The racemate was separated into its enantiomers by chiral chromatography to provide 35.

Compound 36 can be obtained in a similar fashion from 5-fluoroindole.

Alternatively 35 and 36 were be prepared in enantiomerically pure form by the following scheme.

SCHEME H: Alternative preparation of (lR,3S)-5′,7-dichloro-6-fluoro-3-methyl-2,3,4,9- tetrahydrospiro[β-carboline-l,3′-indol-2′(1’H)-one (35)

Step 1 : To a solution of 6-chloro-5-fluoroindole (1.8 g, 10.8 mmol) and Ac2O (10 niL) in AcOH (3OmL) was added L-serine (2.2 g, 20.9 mmol), the mixture was heated to 80 °C. After TLC indicated the reaction was complete, the mixture was cooled to 0 °C, neutralized to pH 11 , and washed with MTBE. The aqueous phase was acidified to pH 2 and extracted with EtOAc. The combined organic layers were washed with water and bπne, dπed with Na2SO4, filtered, and concentrated. The residue was purified with chromatography (Petroleum ether /EtOAc 1:1) to give 2-acetylamino-3-(6-chloro-5-fluoro-1H-mdol-3-yl)-propπonic acid as a light yellow solid (1.2 g, 37% yield).

Step 2: 2-Acetylamino-3-(6-chloro-5-fluoro-1H-indol-3-yl)-proprionic acid (2.5g, 8.4mmol) was dissolved in aqueous NaOH (IN, 10 niL) and water added (70 mL). The mixture was heated to 37-380C and neutralized with HCl (IN) to pΗ 7.3-7.8. L-Aminoacylase (0.5 g) was added to the mixture and allowed to stir for 2 days, maintaining 37-380C and pΗ 7.3-7.8. The mixture was heated to 60 °C for another hour, concentrated to remove part of water, cooled and filtered. The filtrate was adjusted to pΗ 5.89 and filtered again. The filtrate was adjusted to pΗ 2.0 and extracted with EtOAc. The combined organic layer was dried over Na2SO4, filtered, concentrated and the residue was purified with chromatography (petroleum ether /EtOAc 1 : IEtOAc) to give R- 2-acetylamino-3-(6-chloro-5-fluoro-1H-mdol-3-yl)-propπonic acid as a light yellow solid (1.2 g, 48% yield). Step 3: R-2-acetylamino-3-(6-chloro-5-fluoro-1H-indol-3-yl)-proprionic acid (1.2 g, 4.0 mmol) was dissolved in HCl (6N, 10 mL) and the mixture heated to reflux for 4 hours, and then concentrated to dryness. Toluene (50 mL) was added to the residue and concentrated to dryness to remove water and HCl. The residue was dried under vacuum and then dissolved in MeOH (20 mL). To the solution was added dropwise SOCl2 (0.5 mL, 6.8 mmol) at 0 °C, and the mixture was stirred overnight. After removal of solvent, the residue was dissolved in THF/water (40/10 mL) and NaHCO3 (1.0 g, 11.9 mmol) was added portionwise. Upon basifϊcation, BoC2O (1.2 g, 5.5 mmol) added at 0 °C and allowed to stir at room temperature. After TLC indicated the reaction was finished, EtOAc was added and separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried with Na2SO4, filtered, concentrated and the residue was purified with chromatography (petroleum ether /EtOAc: 5/1) to give R-2-tert-butoxycarbonylamino-3-(6-chloro-5-fluoro-l/-/-indol-3-yl)-proprionic acid methyl ester 460 g, 31% yield for 3 steps).

Step 4: To a solution of R-2-tert-butoxycarbonylamino-3-(6-chloro-5-fluoro-l//-indol-3-yl)- proprionic acid methyl ester (460mg, 1.2mmol) in dry ether (20 mL) was added portionwise LiAlH4 (92 mg, 2.4 mmol) at 0 °C. The mixture was heated to reflux for 2 hours. After TLC indicated the reaction was finished, the mixture was cooled and carefully quenched with Na2SO4. The mixture was filtered and the filtrate was washed with saturated aqueous NH4Cl and water, dried with Na2SO4, filtered, concentrated to give a crude product (400 mg), which was used without further purification.

Step 5: To a solution of the crude product (400 mg, 1.2mmol) and Et3N (0.3 mL, 2.2 mmol) in CH2Cl2 (5 mL) was added MsCl (160 mg, 1.4 mmol) dropwise at 0 °C. The mixture was stirred for 2 hours at room temperature. After TLC indicated the reaction was completed, the mixture was washed with water and brine, dried with Na2SO4, filtered, concentrated and the residue was purified with chromatography (petroleum ether/EtOAc 5:1) to give methansulfonic acid (R)-2- ?ert-butoxycarbonylamino-3-(6-chloro-5-fluoro-1H-indol-3-yl)-propyl ester as a light yellow solid (300 mg, 57% yield, 2 steps)

Step 6: To a solution of mesylate (300 mg, 0.7mmol) in dry ether (20 mL) was added portionwise LiAlH4 (55 mg, 1.4 mmol) at 0 °C. The mixture was stirred at room temperature overnight. After TLC indicated the reaction was finished, the mixture was cooled and carefully quenched with Na2SO4. The mixture was filtered and the filtrate was washed with saturated aqueous NH4Cl and water, dried with Na2SO4, filtered, concentrated and the residue was purified with chromatography (petroleum ether/EtOAc 10: 1) to give [(5)-2-(6-chloro-5-fluoro-1H-indol-3-yl)- 1 -methyl-ethyl] -carbamic acid tert-butyl ester as a light yellow solid (200 mg, 87% yield).

Step 7: A solution of [(S)-2-(6-chloro-5-fluoro-1H-indol-3-yl)-l-methyl-ethyl]-carbamic acid tert-butyl ester (200 mg, 0.6 mmol) in HCl/MeOH (10 mL) was stirred at room temperature. After TLC indicated the reaction was finished, the mixture was concentrated to remove the solvent. To the residue was added EtOAc (5OmL), and the mixture was neutralized with saturated NaHCO3 to pH 8~9, and then extracted with EtOAc. The combined organic phases were dried with Na2SO4, filtered, concentrated to give a crude (S)-2-(6-chloro-5-fluoro-1H-indol-3-yl)-l- methyl-ethylamine which was used without further purification.

Step 8: To a solution of (5)-2-(6-chloro-5-fluoro-1H-indol-3-yl)-l-methyl-ethylamine (120 mg, 0.5 mmol) in EtOH (1OmL) was added 5-chloroisatin (90 mg, 0.5 mmol) and p-TsOΗ (8 mg, 0.04 mmol). The mixture was heated in a sealed tube at 1100C for 16 hours. After TLC indicated the reaction was finished, the mixture was cooled and concentrated. The residue was dissolved in EtOAc (2OmL) and washed with NaOH (IN) and brine, dried with Na2SO4, filtered, concentrated and the residue was purified with chromatography (petroleum ether/EtOAc 5:1) to give 36 (150mg, 64% yield over two steps).

 

Example 48 (15,3R)-5′-Chloro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-l,3′-indol]-2′(l’JH)-one

(35)

35

Compound 35 may be prepared according to Scheme F using the same or analogous synthetic techniques and/or substituting with alternative reagents.

(lS^RVS’-Chloro-S-methyl-l^^^-tetrahydrospirotβ-carboline-l.S’-indoll-l^l’ZO-one: 1H NMR (300 MHz, DMSO-^6): δ 10.45 (s, IH), 10.42 (s, IH), 7.43 (d, J= 7.5 Hz, IH), 7.31 (dd, J = 2.1, 8.4 Hz, IH), 7.16 (d, J = 7.2 Hz, IH), 7.05-7.02 (m, 2H), 7.00-6.96 (m, IH), 6.92 (d, J = 8.1 Hz, IH), 3.98-3.86 (m, IH), 2.78 (dd, J= 3.6, 14.9 Hz, IH), 2.41 (dd, J= 4.5, 25.5 Hz, IH), 1.18 (d, J= 6.3 Hz, 3H); MS (ESI) m/z 338.0 (M+H)+.

Chiral compounds such as 36 and 37 can be prepared according to Scheme G or H using the same or analogous synthetic techniques and/or substituting with alternative reagents. Example 49

(IR^^-S’.T-Dichloro-ό-fluoro-S-methyl-l^^^-tetrahydrospiroIβ-carboline-l^’-indol]- 2\VH)-one (36)

36

35: 1H NMR (500 MHz, DMSO-Jd) δ 10.69 (s, IH), 10.51 (s, IH), 7.43 (d, J = 10.0 Hz, IH), 7.33 (dd, J= 8.4, 2.2 Hz, IH), 7.27 (d, J= 6.5 Hz, IH), 7.05 (d, J= 2.3, IH), 6.93 (d, J= 8.5 Hz, IH), 3.91 (m, IH), 3.13 (bd, J= 6.2 Hz, IH), 2.74 (dd, J= 15.0 , 3.0 Hz, IH), 2.35 (dd, J= 15.0, 10.3, IH), 1.15 (d, J= 6.0, 3H);

MS (ESI) m/z 392.0 (M+2H)+;

[α]25 D = + 255.4°

Example 50

(lS,3R)-5′,7-Dichloro-6-fluoro-3-methyI-2,3,4,9-tetrahydrospiro[β-carboline-l,3′-indol]- 2′(l’H)-one (37)

37

(lS^^-S’^-Dichloro-o-fluoro-S-methyl^jS^^-tetrahydrospirojP-carboline-l-S’-indol]- 2′(l’H)-one: 1H NMR (500 MHz, CDCl3) δ 8.49 (s, IH), 7.54 (s, IH), 7.24 (d, J= 9.7 Hz, IH), 7.21 (dd, J = 8.6, 2.0 Hz, IH), 7.14 (d, J= 6.0 Hz, IH), 7.11 (d, J= 1.8, IH), 6.77 (d, J= 8.3 Hz, IH), 4.14 (m, IH), 2.89 (dd, J = 15.4, 3.7 Hz, IH), 2.49 (dd, J = 15.3, 10.5, IH), 1.68 (bs, IH), 1.29 (d, J= 6.4 Hz, 3H); MS (ESI) m/z 392.0 (M+2H)+; [α]25D -223.3°

PATENT

US 2011275613

http://www.google.com/patents/WO2013139987A1?cl=en

 

Prior art:

(1 ‘R, 3’S)-5, 7′-dichloro-6′-fIuoro-3′-methyl-2′, 3′,4′, 9’-tetrahydrospiro[indoline-3, 1 – pyrido[3,4-b]indol]-2-one (eg. a compound of formula (IV), which comprises a spiroindolone moiety) and a 6-steps synthetic method for preparing, including known chiral amine intermediate compound (MA) are known (WO 2009/132921 ):

he present invention relates to processes for the preparation of spiroindolone compounds, such as (1’R,3’S)-5, 7′-dichloro-6′-fIuoro-3′-methyl-2′,3′,4′,9′- tetrahydrospiro[indoline-3, 1 ‘-pyhdo[3.4-b]indol]-2-one.

(1 ‘R, 3’S)-5, 7′-dichloro-6′-fluoro-3′-methyl-2′, 3′,4 9’-tetrahydrospiro[indoline-3, 1 ‘- pyrido[3, 4-b]indol]-2-one is useful in the treatment and/or prevention of infections such as those caused by Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale, Trypanosoma cruzi and parasites of the Leishmania genus such as, for example, Leishmania donovani., and it has the following structure:

(IVA)

(1 ‘R, 3’S)-5, 7′-dichloro-6′-fluoro-3′-methyl-2 3′, 4′, 9’-tetrahydrospiro[indoline-3, 1 – pyhdo[3, 4-b]indol]-2-one and a synthesis thereof are described in WO 2009/132921 Al in particular in Example 49 therein.

 

Example 10: Process for Conversion of Compound (IA) to Compound (IIA) in 30g Scale

458.97

152.48g /so-propylamine hydrochloride and 0.204g pyridoxalphosphate monohydrate were dissolved in 495ml water while stirring. To this yellow clear solution a solution of 30. Og ketone in 85ml poly ethylene glycol (average mol weight 200) within 15 minutes. Upon addition the ketone precipitates as fine particles which are evenly distributed in the reaction media. To the suspension 180ml triethanolamine buffer (0.1 mol/l, pH 7) were added and the pH was adjusted to 7 by additon of aqueous sodium hydroxide solution (1 mol/l). The reaction mixture is heated to 50°C and a solution of 1.62g transaminase SEQ ID NO: 134 dissolved in 162ml triethanolamine buffer (0 1 mol/l, pH 7) is added. The reaction mixture is continiously kept at pH 7 by addition of 1 mol/l aqueous sodium hydroxide solution. The reaction mixture is stirred 24h at 50°C and a stream of Nitrogen is blown over the surface of the reaction mixture to strip off formed acetone. The reaction mixture is then cooled to 25°C and filtered over a bed of cellulose flock. The pH of the filtrate is adjusted to «1 by addition of concentrated sulfuric acid. The acidified filtrated is extracted with 250 ml /so-Propyl acetate. The layers are separated and the pH of the aqueous phase is adjusted to ¾10 by additon of concentrated aqueous sodium hydroxide solution. The basified aqueous phase is extracted with /so-propyl acetate. The layers are seperated and the organic phase is washed with 100 ml water. The organic phase is concentrated by distillation to 2/3 of its origin volume. In a second reactor 33.98g (+)- camphor sulfonic acid is dissolved in 225 ml /so-propyl acetate upon refluxing and the concentrated organic phase is added within 10 minutes. After complete addition the formed thin suspension is cooled to 0°C within 2 hours and kept at 0°C for 15 hours. The precipitated amine-(+)-camphor sulfonate salt is filtered, washed with 70 ml /so-propyl acetate and dried at 40°C in vaccuum yielding 51.57g of colourless crystals (84.5% yield t.q.)

Analytical Data

IR:

v (crn 1)=3296, 3061 , 2962, 2635, 2531 , 2078, 1741 , 1625, 1577, 1518, 1461 , 1415, 1392, 1375, 1324, 1302, 1280, 1256, 1226, 1 170, 1 126, 1096, 1041 , 988, 966, 937, 868, 834, 814, 790, 766, 746, 719, 669, 615.

LC-MS (ESI +):

Ammonium ion: m/z =227 ([M+H]), 268 ([M+H+CH3CN]), 453 ([2M+H]).

Camphorsulfonate ion: m/z =250 ([M+NH4]), 482 ([2M+NH4]).

LC-MS (ESI -):

Camphorsulfonate ion: m/z=231 ([M-H]), 463 ([2M-H]).

1H-NMR (DMSO-d6, 400 MHz):

1 1.22 (br. s., 1 H), 7.75 (br. s., 3H), 7.59 (d, J = 10.3 Hz, 1 H), 7.54 (d, J = 6.5 Hz, 1 H), 7.36 (d, J = 2.3 Hz, 1 H), 3.37 – 3.50 (m, 1 H), 2.98 (dd, J = 14.3, 5.8 Hz, 1 H), 2.91 (d, J = 14.8 Hz, 1 H), 2,81 (dd, J = 14.3, 8.0 Hz, 1 H), 2.63 – 2.74 (m, 1 H), 2.41 (d, J = 14.6 Hz, 1 H), 2.24 (dt, J = 18.3, 3.8 Hz, 1 H), 1 .94 (t, J = 4.4 Hz, 1 H), 1.86 (dt, J = 7.4, 3 6 Hz, 1 H), 1.80 (d, J = 18.1 Hz, H), 1.23 – 1 .35 (m, 2H), 1.15 (d, J = 6.3 Hz, 3H), 1.05 (s, 3H), 0.74 (s, 3H)

Free Amine (obtained by evaporatig the iso-Propylacetate layer after extraction of the basified aqueous layer):

1H NMR (400MHz, DMSO-d6): 11 .04 (br. s., 1 H), 7.50 (d, J = 10.5 Hz, 1 H), 7.48 (d, J = 6.5 Hz, 1 H), 7.25 (s, 1 H), 3.03 (sxt, J = 6.3 Hz, 1 H), 2.61 (dd, J – 14.3, 6.5 Hz, 1 H), 2.57 (dd, J = 14.1 , 6.5 Hz, 1 H), 1.36 (br. s., 2H), 0.96 (d, J = 6.3 Hz, 3H)

Example 11: Process for Conversion of Compound (HA) to Compound (IVB)

3. solvent exchange to TP

13.62 g 5-chloroisatin is suspended in 35 ml /so-propanol and 2.3 g triethyl amine is added. The suspension is heated to reflux and a solution of 34.42g amine-(+)-camphor sulfonate salt dissolved in 300 ml /so-propanol is added within 50 minutes. The reaction mixture is stirred at reflux for 17 hours. The reaction mixture is cooled to 75°C and 17.4g (+)-camphorsulfonic acid are added to the reaction mixture. Approximately 300 ml /so- propanol are removed by vacuum distillation. Distilled off /so-propanol is replaced by iso- propyl acetate and vacuum distillation is continued. This is distillation is repeated a second time. To the distillation residue 19 ml ethanol and 265 ml ethyl acetate is added and the mixture is heated to reflux. The mixture is cooled in ramps to 0°C and kept at 0°C for 24 hours. The beige to off white crystals are filtered off, washed with 3 portions (each 25 ml) precooled (0°C) ethylacetate and dried in vacuum yielding 40.3 g beige to off white crystals. (86.3% yield t.q.)

IR:

v (crrr)= 3229, 3115, 3078, 3052, 2971 , 2890, 2841. 2772. 2722, 2675, 2605, 2434. 1741 , 1718, 1621 , 1606, 1483, 1460, 1408, 1391 , 1372, 1336, 1307, 1277, 1267, 1238, 1202, 1 184, 1 162, 1 149, 1 128, 1067, 1036, 987, 973, 939, 919, 896, 871 , 857, 843, 785, 771 , 756, 717, 690, 678, 613.

LC-MS (ESI +):

Ammonium ion: m/z =390 ([M+H]), 431 ([M+H+CH3CN]) Camphorsulfonate ion: m/z =250 ([M+NH4]), 482 ([2M+NH4])

LC-MS (ESI -):

Camphorsulfonate ion: m/z=231 ([M-H]), 463 ([2M-H])

1H NMR (DMSO-d6, 600 MHz):

11.49 (s, 1 H), 1 1.23 (s, 1 H), 10.29 – 10.83 (m, 1 H), 9.78 – 10.31 (m, 1 H), 7.55 – 7.60 (m, 2H), 7.52 (s, 1 H), 7.40 (d, J = 6.2 Hz, H), 7.16 (d, J = 8.8 Hz, 1 H), 4.52 – 4.63 (m, 1 H). 3.20 (dd, J = 16.3, 4.2 Hz, 1 H), 2.96 (dd, J = 16.1 , 11.3 Hz, 1 H), 2.90 (d, J = 15.0 Hz, 1 H), 2.56 – 2.63 (m, 1 H), 2.39 (d, J = 14.6 Hz, 1 H), 2.21 (dt, J = 18.0, 3.8 Hz, 1 H), 1.89 – 1.93 (m, 1 H), 1.81 (ddd, J = 15.3, 7.8, 3.7 Hz, 1 H), 1.76 (d, J = 18.3 Hz, 1 H), 1 .53 (d, J = 6.6 Hz, 3H), 1.20 – 1.33 (m, 2H), 0.98 (s, 3H), 0.70 (s, 3H)

Example 12: Process for Preparing a Compound of formula (IVA) 1/z Hydrate

mw622.54 …………………………………………………………………..mw399.25

In a 750ml reactor with impeller stirrer 50g of compound (IVB) salt were dissolved in 300ml Ethanol (ALABD) and 100 ml deionised Water (WEM). The clear, yellowish sollution was heated to 58°C internal temperature. To the solution 85 g of a 10% aqueous sodium carbonate solution was added within 10 minutes. The clear solution was particle filtered into a second reaction vessel. Vessel and particle filter were each rinsed with 25 ml of a mixture of ethanohwater (3:1 v/v) in the second reaction vessel. The combined particle filtered solution is heated to 58°C internal temperature and 200ml water (WEM) were added dropwise within 15 minutes. Towards the end of the addition the solution gets turbid.

The mixture is stirred for 10 minutes at 58°C internal temperature and is then cooled slowely to room temperature within 4hours 30 minutes forming a thick, well stirable white suspension. To the suspension 200 ml water are added and the mixture is stirred for additional 15hours 20 minutes at room temperature. The suspension is filtered and the filter cake is washed twice with 25 ml portions of a mixture of ethanohwater 9: 1 (v/v). The colourless crystals are dried at 60°C in vacuum yielding 26.23g (=91.2% yield). H NMR (400 MHz, DMSO-d6)

0.70 (s, 1H), 10.52 (s, 1H), 7.44 (d, J = 10.0 Hz, 1H), 7.33 (dd, J = 8.4, 2.1 Hz, 1H),.26 (d, J = 6.5 Hz, 1H), 7.05 (d, J = 2.3 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 3.83 – 4.00 (m,H), 3.13 (d, J = 6.0 Hz, 1H), 2.77 (dd, J = 15.1, 3.8 Hz, 1H), 2.38 (dd, J = 15.1, 10.5 Hz,H), 1.17 (d, J = 6.3 Hz, 3H).

 

PAPER
 Journal of Medicinal Chemistry, 2010 ,  vol. 53,   14  p. 5155 – 5164

(1R,3S)-5′,7-Dichloro-6-fluoro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one (19a)

1H NMR (500 MHz, DMSO-d6): δ 10.69 (s, 1H), 10.51 (s, 1H), 7.43 (d, J = 10.0 Hz, 1H), 7.33 (dd, J = 8.0, 2.2 Hz, 1H), 7.27 (d, J = 6.5 Hz, 1H), 7.05 (d, J = 2.3 Hz, 1H), 6.93 (d, J = 8.5 Hz, 1H), 3.91 (m, 1H), 3.13 (bd, J = 6.2 Hz, 1H), 2.74 (dd, J = 15.0, 3.0 Hz, 1H), 2.35 (dd, J = 15.0, 10.3 Hz, 1H), 1.15 (d, J = 6.0 Hz, 3H). MS (ESI) m/z 392.0 (M + 2H)+; [α]D25 = +255.4° (c = 0.102 g/L, methanol).
CLIPS

Z.Zhang, WO 2007 / 104714,2007).

 

Figure CN102432526AD00051

[0008] (2) year 2008 Roche pharmaceutical company disclosed a spiro [oxindole – cyclohexenone] skeleton biomedicine, PCT International Application No. W02008 / 055812. It also announced the preparation of anti-cancer agents and antagonists of the application of the compound is used as the interaction with MDM2 (reference:. Liu, J.-J; Zhang, Z; (Hoffmann-LaRoche AG), PCT Int App 1. . W02008 / 055812, 2008), its structural formula is as follows:

[0009]

Figure CN102432526AD00052

(3) Melchiorre research group abroad chiral amines and o-fluoro-3-benzyl benzoate as catalyst methylene-indole-2-one (3-benzylideneindolin-2-one, CAS Number: 3359-49- 7) with α, β – unsaturated ketone synthesis of chiral spiro [cyclohexane _1,3′- indole] _2,4 ‘- dione [s pir0 [cycl0hexane-l, 3’ -indoline] – 2 ‘, 4-diones] compounds (see:.. Bencivenni, G; ffu, LY; Mazzanti, A .; Giannichi, B.; Pesciaioli, F; Song, Μ P.; Bartoli, G.; Melchiorre, P …. .Angew Chem Int Ed 2009,48,7200), the structure of the total formula is as follows:

 

Figure CN102432526AD00061

(4) Gong Flow column team found to cyclohexanediamine derived Bronsted acid – a bifunctional catalyst Lewis base catalysis of 3-benzyl-methylene-indole-2-one and α, β- unsaturated 1,3 tandem reaction dicarbonyl compound (Nazarov reagent) can be obtained with high stereoselectivity chiral spiro [cyclohexane _1,3′- indol] -2 ‘, 4-dione [spiro [cyclohexane-l, 3 ‘-indoline] -2’, 4-diones] compounds; and by this method successfully synthesized 7 Roche pharmaceutical companies to develop chiral anti-tumor agents (see: Q Wei, L -Z Gong, Org Lett 2010….. , 12, 1008.).

(5) Wang Lixin research group recently reported that primary amines derived from cinchona alkaloids and Bronsted acid as catalyst N- protected indolone compounds and double Michael addition reaction of diketene generate hand spiro [cyclohexane-1, 3′-indol] -2 ‘, 4-dione [spiro [cyclohexane-l, 3’ -indoline] -2 ‘, 4-diones] type of tx ^ (: L. -L. Wang, L. Peng, J. -F. Bai, L. -N. Jia, X. -Y. Luo, QC Huang, L. -X. Wang, Chem. Commum. 2011,47, 5593.).

WO2009132921A1 * Apr 1, 2009 Nov 5, 2009 Novartis Ag Spiro-indole derivatives for the treatment of parasitic diseases
WO2010081053A2 * Jan 8, 2010 Jul 15, 2010 Codexis, Inc. Transaminase polypeptides
WO2012007548A1 * Jul 14, 2011 Jan 19, 2012 Dsm Ip Assets B.V. (r)-selective amination
AT507050A1 * Title not available
EP0036741A2 * Mar 17, 1981 Sep 30, 1981 THE PROCTER &amp; GAMBLE COMPANY Phosphine compounds, transition metal complexes thereof and use thereof as chiral hydrogenation catalysts
EP0120208A2 * Jan 24, 1984 Oct 3, 1984 Degussa Aktiengesellschaft Microbiologically produced L-phenylalanin-dehydrogenase, process for obtaining it and its use
EP0135846A2 * Aug 31, 1984 Apr 3, 1985 Genetics Institute, Inc. Production of L-amino acids by transamination
GB974895A * Title not available
US3282959 * Mar 21, 1962 Nov 1, 1966 Parke Davis & Co 7-chloro-alpha-methyltryptamine derivatives
US4073795 * Jun 22, 1976 Feb 14, 1978 Hoffmann-La Roche Inc. Synthesis of tryptophans
WO2005009370A2 * Jul 22, 2004 Feb 3, 2005 Pharmacia Corp Beta-carboline compounds and analogues thereof and their use as mitogen-activated protein kinase-activated protein kinase-2 inhibitors
EP0466548A1 * Jun 27, 1991 Jan 15, 1992 Adir Et Compagnie 1,2,3,4,5,6-Hexahydroazepino[4,5-b]indole and 1,2,3,4-tetrahydro-beta-carbolines, processes for their preparation, and pharmaceutical compositions containing them

Рисунок из Science 2010, 329, 1175

Исследовательская группа Элизабет Винцелер (Elizabeth A. Winzeler) разработала новый препарат, первоначально проведя скрининг библиотеки, состоящей из 12000 соединений, а затем получив производные наиболее перспективных кандидатов. В результате долгой работы исследователи отобрали единственное соединение спироиндолоновой структуры, получившее регистрационный номер NITD609. В случае успешного прохождения экспертизы фармакологических и токсикологических свойств нового соединения исследователи надеются приступить к первой фазе его клинических испытаний уже в конце этого года.

Было обнаружено, что NITD609 быстро останавливает белковый синтез в организме возбудителя малярии, ингибируя ген аденозинтрифосфатазы, ответственной за транспорт катионов через мембрану клетки возбудителя. То, что механизм действия нового соединения отличается от механизма, характерного для других средств лечения малярии, объясняет причины успешного действия нового препарата в том числе и против штаммов малярии, выработавших резистентность.

 HPLC
Analyte quantization was performed byLC/MS/MS. Liquid chromatography was performed using an Agilent
1100 HPLC system(Santa Clara, CA), with the Agilent Zorbax XDB Phenyl (3.5μ, 4.6 x75 mm) column at
an oven temperature of 35 °C, coupled with a QTRAP4000 triple quadruple mass
spectrometer (Applied Biosystems, Foster City, CA). Instrumentcontrol and dataacquisition were performed using Applied Biosystems software Analyst 1.4.2. Themobile phases used were A: water:acetic acid (99.8:0.2, v/v) and B: acetonitrile:aceticacid (99.8:0.2, v/v), using a gradient, with flow rate of 1.0 mL/min, and run time of 5minutes. Under these conditions the retention time of9a
was 3.2 minutes. Compounddetection on the mass spectrometer was performed in electrospraypositive ionizationmode and utilized multiple reaction monitoring (MRM) for specificity (9atransitions338.3/295.1, 338.3/259.2) together with their optimized MS parameters. The lower limitof quantification for9awas 70 ng/mL.
Extraction and LCMS analysis of 20a.Plasma samples were extracted withacetonitrile:methanol-acetic acid (90:9.8:0.2 v/v) for the analyte and internal standard(17a) using a 3.6 to 1 extractant to plasma ratio. Analyte quantitation was performed by
LC/MS/MS. Liquid chromatography was performed using an Agilent1100 HPLC systemS7(Santa Clara, CA), with the Agilent Zorbax XDB-Phenyl (3.5μ, 4.6x75mm) column atan oven temperature of 45 °C coupled with a QTRAP 4000 triple quadruple massSpectrometer (Applied Biosystems, Foster City, CA). Instrumentcontrol and dataacquisition were performed using Applied Biosystems software Analyst 1.4.2. Themobile phases used were A: water:acetic acid (99.8:0.2, v/v) and B: methanol:acetic acid
(99.8:0.2, v/v), using gradient elution conditions with a flow rate of 1.0 mL/min and a runtime of 6 minutes
++++++++++++++++++++++==
+++++++++++++++++++++++++++=

References

  1.  “NITD 609”. Medicines for Malaria Venture.
  2.  Rottmann M, McNamara C, Yeung BK, Lee MC, Zou B, Russell B, Seitz P, Plouffe DM, Dharia NV, Tan J, Cohen SB, Spencer KR, González-Páez GE, Lakshminarayana SB, Goh A, Suwanarusk R, Jegla T, Schmitt EK, Beck HP, Brun R, Nosten F, Renia L, Dartois V, Keller TH, Fidock DA, Winzeler EA, Diagana TT (2010). “Spiroindolones, a potent compound class for the treatment of malaria”. Science329 (5996): 1175–80. doi:10.1126/science.1193225. PMC 3050001. PMID 20813948.

Ang, S. H., Krastel, P., Leong, S. Y., Tan, L. J., Wong, W. L. J., Yeung, B. K., and Zou, B. Spiro-indole derivatives for the treatment of parasitic diseases. WO2009132921 A1, November 5, 2009.

Cipargamin
NITD609.svg
Names
IUPAC name

(1R,3S)-5’,7-Dichloro-6-fluoro-3-methyl-spiro[2,3,4,9-tetrahydropyrido[3,4-b]indole-1,3’-indoline]-2’-one
Identifiers
1193314-23-6
ChemSpider 24662493
Jmol interactive 3D Image
PubChem 44469321
Properties
C19H14Cl2FN3O
Molar mass 390.24 g·mol−1

SEE……….http://apisynthesisint.blogspot.in/2016/02/kae-609-nitd-609-cipargamin-for-malaria.html

////

C[C@H]1Cc2c3cc(c(cc3[nH]c2[C@]4(N1)c5cc(ccc5NC4=O)Cl)Cl)F

Ranbaxy to introduce malarial treatment Synriam in African nations


 

 

Ranbaxy to introduce malarial treatment Synriam in African nations
Ranbaxy Laboratories has obtained regulatory approval to introduce India’s first new chemical entity (NCE) Synriam (arterolane maleate 150mg and piperaquine phosphate 750mg drug) in seven African countries.

read at

http://www.pharmaceutical-technology.com/news/newsmalarial-treatment-synriam-4471331?WT.mc_id=DN_News

Synriam is a new age therapy recommended to treat uncomplicated Plasmodium falciparum malaria in adults. It was launched in India in April 2012.

The product was also launched in Uganda and is set to be introduced in Nigeria, Senegal, Cameroon, Guinea, Kenya and Ivory Coast by the end of January 2015.

 

Arterolane.png

 

Arterolane

cas 664338-39-0, UNII-3N1TN351VB, OZ277, RBX-11160, NCGC00274173-01
Molecular Formula: C22H36N2O4
 Molecular Weight: 392.53224
Ranbaxy Lab Ltd innovator
 cis-adamantane-2-spiro-3’-8’-[[[(2’-amino-2’ methylpropyl) amino] carbonyl] methyl] 1’,2’,4’-trioxaspiro [4.5] decane
cis-adamantane-2-spiro-3′-8′-[[[(2′- amino-2′-methylpropyl)amino]carbonyl]-methyl]- 1 ‘,2′,4′-trioxaspiro[4.5]decane

Arterolane, also known as OZ277 or RBx 11160,is a substance being tested for antimalarial activity[1] by Ranbaxy Laboratories.[2] It was discovered by US and European scientists who were coordinated by the Medicines for Malaria Venture (MMV).[3] Its molecular structure is uncommon for pharmacological compounds in that it has both an ozonide group and an adamantane substituent.[4]

Phase III clinical trials of arterolane, in combination with piperaquine, began in India in 2009.[5] When clinical trial results were disappointing, the MMV withdrew support[2] and Ranbaxy continued developing the drug combination on its own.

Ranbaxy launched India’s first new drug, SynriamTM, treating Plasmodium falciparummalaria in adults. The drug provides quick relief from most malaria-related symptoms, including fever, and has a high cure rate of over 95 %.

Just one tablet per day is required, for three days, instead of two to four tablets, twice daily, for three or more days with other medicines. The drug is independent of dietary restrictions for fatty foods or milk.

Ranbaxy developed Synriam as a fixed-dose combination of arterolane maleate and piperaquine phosphate, where arterolane is the new chemical entity (NCE) that was developed as an alternative to artemisinin. It is the first recently developed antimalarial not based on artemisinin, one of the most effective treatments for malaria, which has shown problems with resistance in recent years. Arterolane was discovered by a collaborative drug discovery project funded by the Medicines for Malaria Venture. Since SynriamTM has a synthetic source, unlike artemisinin-based drugs, production can be scaled up whenever required and a consistent supply can be maintained at a low cost.

The new drug, has been approved by the Drug Controller General of India (DCGI) for marketing in India and conforms to the recommendations of the World Health Organization (WHO) for using combination therapy in malaria. Ranbaxy is also working to make it available in African, Asian and South American markets where Malaria is rampant. SynriamTM trials are ongoing for Plasmodium vivax malaria and a paediatric formulation.

Derek Lowe of the famous In the Pipeline blog had written about arterolane in 2009. At the time it was in Phase III trial, which I assumed were the trials that Ranbaxy was conducting. But it turned out that arterolane was developed by a collaboration between researchers in the US, the UK, Switzerland and Australia who were funded by the World Health Organization and Medicines for Malaria Venture (a Swiss non-profit).

They published this work in Nature in 2004 and further SAR (Structure Activity Relationship) studies in J Med Chem in 2010. So Ranbaxy did not develop the drug from scratch? But the press release quotes Arun Sawhney, CEO and Managing Director of Ranbaxy which misleads people to think so: “It is indeed gratifying to see that Ranbaxy’s scientists have been able to gift our great nation its first new drug, to treat malaria, a disease endemic to our part of the world.

This is a historic day for science and technology in India as well as for the pharmaceutical industry in the country. Today, India joins the elite and exclusive club of nations of the world that have demonstrated the capability of developing a new drug”. So Ranbaxy mixes a known active compound (piperaquine) with a new compound that someone else found to be active (arterolane) and claims that they developed a new drug?

In an interview in LiveMint, Sawhney says, “Ranbaxy spent around $30 million on Synriam and the contribution from DST [India’s Department of Science & Technology] was Rs.5 crore.

The drug went through several phases of development since the project began in 2003. We did not look at this as a commercial development. Instead, this is a CSR [Corporate Social Responsibility] venture for us.” That’s a give away because developing a new drug from scratch has to cost more than $30 million + Rs.50 million.


Ranbaxy  now taken over by sun

SynriamTM

Generic Name
Arterolane Maleate and Piperaquine Phosphate Tablets
Composition
Each film coated tablet contains: Arterolane maleate equivalent to Arterolane ……………………………150 mg Piperaquinephosphate……………750 mg
Dosage Form
Tablets
Inactive ingredients:
Microcrystalline cellulose, Crospovidone, Magnesium stearate, Hydroxypropyl methyl cellulose/Hypromellose, Titanium dioxide, Macrogol/ Polyethylene glycol, Talc, Ferric Oxide (Yellow), Ferric Oxide (Red)

Description SynriamTM is a fixed dose combination of two antimalarial active ingredients arterolane maleate and piperaquine phosphate.

Arterolane maleate is a synthetic trioxolane compound. The chemical name of arterolane maleate is cis-adamantane-2-spiro-3’-8’-[[[(2’-amino-2’ methylpropyl) amino] carbonyl] methyl] 1’,2’,4’-trioxaspiro [4.5] decane hydrogen maleate. The molecular formula is C26H40N2O8 and molecular weight is 508.61. The structural formula is as follows:

MALARIA
Malaria is one of the most prevalent and deadly parasitic diseases in the world. Up to 289 million cases of malaria may have occurred in 2010, causing between 660,000 and 1.25 million deaths, mainly in Africa and mostly of children younger than 5 years.
(WHO: http://www.who.int/malaria/publications/world_malaria_report_2012/en/index.html; Fidock, D. A. Eliminating Malaria. Science 2013, 340, 1531-1533.)

The most serious problem in malaria treatment is that the parasites causing the disease, particularly the deadly Plasmodium falciparum, have developed resistance to widely used drugs, particularly chloroquine (CQ). Currently, the most efficacious therapies are combinations of an artemisinin-type compound with a long-lasting partner drug like lumefantrine, amodiaquine or mefloquine.

Malaria, the most common parasitic disease of humans, remains a major health and economic burden in most tropical countries. Large areas of Central and South America, Hispaniola (Haiti and the Dominican Republic), Africa, the Middle East, the Indian subcontinent, Southeast Asia, and Oceania are considered as malaria-risk areas. It leads to a heavy toll of illness and death, especially amongst children and pregnant women.

According to the World Health Organization, it is estimated that the disease infects about 400 million people each year, and around two to three million people die from malaria every year. There are four kinds of malaria parasites that infect human: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale and Plasmodium malariae.

Malaria spreads from one person to another by the bite of mosquito, Anopheles gambiae, which serves as vector. When a mosquito sucks the blood of human, sporozoites are transfused into the human body together with saliva of the mosquito. The sporozoites enter into the hepatocytes, reproduce asexually and finally enter into the blood stream. The parasites continue to multiply inside the red blood cells, until they burst and release large number of merozoites.

This process continues, destroying a significant number of blood cells and causing the characteristic paroxysm (“chills and fever”) associated with the disease. In the red blood cells, some of the merozoites become male or female gametocytes. These gametocytes are ingested by the mosquito when it feeds on blood. The gametocytes fuse in the vector’s gut; sporozoites are produced and are migrated to the vector’s salivary glands.

The clinical symptoms of malaria are generally associated with the bursting of red blood cells causing an intense fever associated with chills that can leave the infected individual exhausted and bedridden. More severe symptoms associated with repeat infections and/or infection by Plasmodium falciparum include anaemia, severe headaches, convulsions, delirium and, in some instances, death.

Quinine, an antimalarial compound that is extracted from the bark of cinchona tree, is one of the oldest and most effective drugs in existence. Chloroquine and mefloquine are the synthetic analogs of quinine developed in 1940’s, which due to their effectiveness, ease of manufacture, and general lack of side effects, became the drugs of choice. The downside to quinine and its derivatives is that they are short-acting and have bitter taste.

Further, they fail to prevent disease relapses and are also associated with side effects commonly known as “Chinchonism syndrome” characterized by nausea, vomiting, dizziness, vertigo and deafness. However, in recent years, with the emergence of drug- resistant strains of parasite and insecticide-resistant strains of vector, the treatment and/or control of malaria is becoming difficult with these conventional drugs.

Malarial treatment further progressed with the discovery of Artemisinin

(qinghaosu), a naturally occurring endoperoxide sesquiterpene lactone isolated from the plant Artemisia annua (Meshnick et al., Microbiol. Rev. 1996, 60, p. 301-315; Vroman et al., Curr. Pharm. Design, 1999, 5, p. 101-138; Dhingra et al., 2000, 66, p. 279-300), and a number of its precursors, metabolites and semi-synthetic derivatives which have shown to possess antimalarial properties. The antimalarial action of artemisinin is due to its reaction with iron in free heme molecules of the malaria parasite, with the generation of free radicals leading to cellular destruction. This initiated a substantial effort to elucidate its molecular mechanism of action (Jefford, dv. Drug Res. 1997, 29, p. 271-325; Cumming et al., Adv. Pharmacol. 1997, 37, p. 254-297) and to identify novel antimalarial peroxides (Dong and Vennerstrom, Expert Opin. Ther. Patents 2001, 1 1, p. 1753-1760).

Although the clinically useful artemisinin derivatives are rapid acting and potent antimalarial drugs, they have several disadvantages including recrudescence,

neurotoxicity, (Wesche et al., Antimicrob. Agents. Chemother. 1994, 38, p. 1813-1819) and metabolic instability (White, Trans. R. Soc. Trop. Med. Hyg., 1994, 88, p. 41-43). A fair number of these compounds are quite active in vitro, but most suffer from low oral activity (White, Trans. R. Soc. Trop. Med. Hyg., 1994, 88, p. 41-43 and van Agtmael et al., Trends Pharmacol. Sci., 1999, 20, p. 199-205). Further all these artemisinin derivatives are conventionally obtained from plant source and are therefore expensive.

As the cultivation of the plant material is dependent on many factors including the weather conditions, the supply source thus becomes finite and there are chances of varying yield and potency. This leads to quality inconsistencies and supply constraints. As malaria is more prevalent in developing countries, a switch to cheaper and effective medicine is highly desirable.

Thus there exists a need in the art to identify new peroxide antimalarial agents, especially those which are not dependent on plant source and can be easily synthesized, are devoid of neurotoxicity, and which possess improved solubility, stability and pharmacokinetic properties.

Following that, many synthetic antimalarial 1 ,2,4-trioxanes (Jefford, Adv. Drug Res. 1997, 29, p. 271-325; Cumming et al., Adv. Pharmacol. 1997, 37, p. 254-297), 1,2,4,5-tetraoxanes (Vennerstrom et al., J. Med. Chem., 2000, 43, p. 2753-2758), and other endoperoxides have been prepared. Various patents/applications disclose means and method for treating malaria using Spiro or dispiro 1,2,4-trioxolanes for example, U.S.

Patent Application No. 2004/0186168 and U.S. Patent Nos. 6,486, 199 and 6,825,230. The present invention relates to solid dosage forms of the various spiro or dispiro 1 ,2,4- trioxolanes antimalarial compounds disclosed in these patents/applications and are incorporated herein by reference.

Active compounds representing various Spiro and dispiro 1 ,2,4-trioxolane derivatives possess excellent potency, efficacy against Plasmodium parasites, and a lower degree of neurotoxicity, in addition to their structural simplicity and ease of synthesis. Furthermore, these compounds have half-lives which are believed to permit short-term treatment regimens comparing favorably to other artemisinin-like drugs. In general, the therapeutic dose of trioxolane derivative may range between about 0.1-1000 mg/kg/day, in particular between about 1-100 mg/kg/day. The foregoing dose may be administered as a single dose or may be divided into multiple doses. For malaria prevention, a typical dosing schedule could be, for example, 2.0-1000 mg/kg weekly beginning 1-2 weeks prior to malaria exposure, continued up to 1-2 weeks post-exposure.

Monotherapy with artemisinin (natural or synthetic) class of drugs might cure the patients within 3 days, however perceiving the potential threat of the malarial parasite developing resistance towards otherwise very potent artemisinin class of drugs, WHO had strictly called for an immediate halt to the provision of single-drug artemisinin malaria pills. Combination therapy in case of malaria retards the development of resistance, improve efficacy by lowering recrudescence rate, provides synergistic effect, and increase exposure of the parasite to the drugs.

Artemsinin based combinations are available in the market for a long time.

Artemether-lumafentrine (Co-artem®) was the first fixed dose antimalarial combination containing an artemisinin derivative and has been known since 1999. This combination has passed extensive safety and efficacy trials and has been approved by more than 70 regulatory agencies. Co-artem® is recommended by WHO as the first line treatment for uncomplicated malaria.

Other artemisinin based combinations include artesunate and amodiaquine (Coarsucam®), and dihydroartemisin and piperaquine (Eurartesim®). Unfortunately, all the available artemisinin based combinations have complicated dosage regimens making it difficult and inconvenient for a patient to comply completely with the total prescribed duration. For example, the dosage regimen of Co-artem®for an adult having body weight of more than 35 kg includes 6 doses over three days.

The first dose comprises four tablets initially, the second dose comprises four tablets after eight hours, the third to sixth doses comprise four tablets twice for another two days; making it a total of 24 tablets. The dosage regimen of Coarsucam® for an adult having body weight of more than 36 kg or age above 14 years includes three doses over three days; each dose comprises two tablets; making it a total of six tablets. The dosage regimen of Eurartesim® for an adult having body weight between 36 kg – 75 kg includes 3 doses over three days, each dose comprises of three tablets, making it a total of nine tablets.

It is evident that the available artemisinin-based combinations have a high pill burden on patients as they need to consume too many tablets. As noted above, this may increase the possibility of missing a few doses, and, consequently, could result in reduced efficacy due to non-compliance and may even lead to development of resistance for the drug. Therefore, there is an urgent and unmet need for anti-malarial combinations with a simplified daily dosing regimen that reduces the pill burden and would increase patient compliance.

Apart from simplifying the regimen, there are certain limitations for formulators developing formulations with trioxolones, the first being their susceptibility to degradation in presence of moisture that results in reduced shelf lives. Another is their bitter taste, which can result in poor compliance of the regimen or selection of another, possibly less effective, therapeutic agent.

……………………..

PATENT

http://www.google.st/patents/US6906205

Figure US06906205-20050614-C00051

……………………

PATENT

http://www.google.st/patents/WO2013008218A1?cl=en

structural Formula II.

 

Figure imgf000013_0001

Formula II

Active compound includes one or more of the various spiro and dispiro trioxolane derivatives disclosed in U.S. Application No. 2004/0186168 and U.S. Patent Nos.

6,486,199 and 6,825,230, which are incorporated herein by reference. These trioxolanes are relatively sterically hindered on at least one side of the trioxolane heterocycle which provides better in vivo activity, especially with respect to oral administration. Particularly, spiro and dispiro 1,2,4-trioxolanes derivatives possess excellent potency and efficacy against Plasmodium parasites, and a lower degree of neurotoxicity.

The term “Active compound I” herein means cis-adamantane-2-spiro-3′-8′-[[[(2′- amino-2′-methylpropyl)amino]carbonyl]-methyl]- 1 ‘,2′,4′-trioxaspiro[4.5]decane hydrogen maleate. The Active compound I may be present in an amount of from about 5% to about 25%, w/w based on the total dosage form.

 

………………

PATENT

http://www.google.st/patents/WO2007138435A2?cl=en

A synthetic procedure for preparing compounds of Formula I, salts of the free base c«-adamantane-2-spiro-3′-8′-[[[(2′-amino-2′-methyl propyl) amino] carbonyl] methyl]- 1 ‘, 2′, 4′-trioxaspiro [4.5] decane has been disclosed in U.S. 6,906,205.

Figure imgf000002_0001

 

The process for the preparation of compounds of Formula I wherein a compound of Formula II (wherein R is lower alkyl) is reacted with a compound of Formula III (wherein R is lower alkyl) to obtain compound of Formula IV;

Figure imgf000005_0001
Figure imgf000005_0002

Formula Formula IV

followed by hydrolysis of the compounds of Formula IV to give a compound of Formula V;

Figure imgf000005_0003

Formula V followed by the reaction of the compound of Formula V with an activating agent, for example, methyl chloroformate, ethyl chloroformate, propyl chloro formate, n-butyl chloro formate, isobutyl chloroformate or pivaloyl chloride leads to the formation of mixed anhydride, which is reacted in situ reaction with 1 ,2-diamino-2-methyl propane to give a compound of Formula VI; and

Figure imgf000005_0004

Formula Vl reacting the compound of Formula VI with an acid of Formula HX (wherein X can be the same as defined earlier) to give compounds of Formula I.

Example 1 : Preparation of O-methyl-2-adamantanone oxime

To a solution of 2-adamantanone (50 g, 0.3328 mol, 1 equiv.) in methanol (0.25 lit), sodium hydroxide solution (15 g, 0.3761mol, 1.13 equiv, in 50 mL water) was added followed by methoxylamine hydrochloride (37.5 g x 81.59% Purity= 30.596 g, 0.366 mol, 1.1 equiv) at room temperature under stirring. The reaction mixture was stirred at room temperature for 1 to 2 h. The reaction was monitored by HPLC. The reaction mixture was concentrated at 40- 45°C under vacuum to get a thick residue. Water (250 mL) was added at room temperature and the reaction mixture was stirred for half an hour. The white solid was filtered, washed with water (50 mL), and dried at 40 to 45°C under reduced pressure. O-methyl 2- adamantanone oxime (57 g, 95 % yield) was obtained as a white solid.

(M++l) 180, 1HNMR (400 MHz, CDCl3 ): δ 1.98 – 1.79 (m, 12H), 2.53 (s, IH), 3.46 ( s, IH), 3.81 (s, 3H).

Example 2: Preparation of 4-(methoxycarbonvmethvPcvclohexanone A high pressure autoclave was charged with a mixture of methyl (4- hydroxyphenyl)acetate (50 g, 0.30 mol), palladium ( 5g) (10 %) on carbon (50 % wet) and O- xylene (250 mL). The reaction mixture was stirred under 110 to 115 psi of hydrogen pressure for 7 to 8 h at 1400C. The reaction was monitored by HPLC. The reaction mixture was then cooled to room temperature, and the catalyst was filtered off. Filtrate was concentrated under reduced pressure to get 4-(methoxycarbonylmethyl)cyclohexanone as light yellow to colorless oily liquid (48.7 g, 97.4 %).

(M++!) 171, ‘ HNMR (400 MHz, CDCl 3): δ 1.48 – 1.51 ( m, 2H), 2.1 1-2.07 (m, 2H), 2.4- 2.23 (m, 7H), 3.7 (s, 3H).

Example 3: Preparation of methyl (Is, 4s)-dispiro [cyclohexane-l, 3′-f 1,2,4] trioxolane-5′, 2″-tricvclor3.3.1.1371decan1-4-ylacetate

A solution of O-methyl-2-adamantanone oxime (example 1) (11.06 g, 61.7 mmol, 1.5 equiv.) and 4-(methoxycarbonymethyl)cyclohexanone (example 2) (7.0 g, 41.1 mmol, 1 equiv.) in cyclohexane ( 200ml) and dichloromethane (40 mL) was treated with ozone (ozone was produced with an OREC ozone generator [0.6 L/min. O2, 60 V] passed through an empty gas washing bottle that was cooled to -780C). The solvent was removed after the reaction was complete. After removal of solvents, the crude product was purified by crystallization from 80% aqueous ethanol (200 mL) to afford the title compound as a colorless solid. Yield: 10.83 g, 78%, mp: 96-980C; 1HNMR (500 Hz3CDCl3): δ 1.20-1.33 (m, 2H), 1.61-2.09 (m, 5 21H), 2.22 (d, J = 6.8Hz, 2H), 3.67(s,3H).

Example 4: Preparation of (Is, 4s)-dispiro [cyclohexane-1, 3′-[l,2,4] trioxolane-5′, 2″- tricvclo [3.3.1.137] decanl-4-ylacetic acid

Sodium hydroxide (3.86 g, 96.57 mmol, 3 equiv.) in water (80 mL) was added to a solution of methyl (\s, 4s)-dispiro [cyclohexane-1, 3′-[l,2,4] trioxolane-5′, 2″-tricyclo

10 [3.3.1.I37] decan]-4-ylacetate (example 3) (10.83 g, 32.19 mmol, 1 equiv.) in 95% ethanol (150 mL). The mixture was stirred at 500C for about 4 h, cooled to O0C, and treated with IM hydrochloric acid (129ml, 4 equiv). The precipitate was collected by filtration, washed with 50 % aqueous ethanol (150 mL) and dried in vacuum at 40 0C to give the title compound as colorless solid. Yield: 9.952 g, 96%, mp: 146-1480C ( 95% ethanol), 1HNMR (500 Hz,

15 CDCl3): δ 1.19-1.41 (m,2H), 1.60-2.05 (m,21H), 2.27 (d, J=6.8 Hz,2H).

Example 5: Preparation of c?s-adamantane-2-spiro-3′-8′-[[[(2′-amino-2′-methyl propyl) amino] carbonyl] methyl]-! ‘, T , 4′-trioxaspiro [4.5] decane

Method A:

(Is, 4s)-dispiro[cyclohexane- 1 ,3 ‘-[ 1 ,2,4]trioxolane-5 ‘,2 ‘ ‘-tricyclo[3.3.1.137]decan]-4-

.0 ylacetic acid (example 4) (5 g ,15.5mmol, 1 equiv) was mixed with triethylamine (2.5 g , 24.8 mmol, 1.6 equiv) in 100ml of dichloromethane. The reaction mixture was cooled to – 1O0C to 00C. Ethyl chloro formate (1.68 g, 17 mmol, 1.0 equiv) in 15 mL dichloromethane was charged to the above reaction mixture at – 100C to 00C. The reaction mixture was stirred at the same temperature for 10 to 30 minutes. The resulting mixed anhydride reaction mixture

15 was added dropwise to a previously prepared solution of l,2-diamino-2-methylpropane (1.64 g, 18.6 mmol, 1.2 equiv), in 100 mL dichloromethane at -100C to O0C. The temperature of reaction mixture was raised to room temperature. The reaction mixture was stirred at the same temperature till the reaction was complete. Reaction monitoring was done by thin layer chromatography using 5 to 10% methanol in dichloromethane. The reaction was complete

>0 within 2 h. Nitrogen atmosphere was maintained throughout the reaction. Water (50 mL) was charged, organic layer was separated and washed with 10% sodium bicarbonate solution (50 mL) and water (50 mL) at room temperature. The organic layer was dried over sodium sulphate and the solvent was removed at 25 to 4O0C under reduced pressure. Hexane (50ml) was added to obtain residue under stirring at room temperature. The mixture was filtered and washed with 5 mL of chilled hexane. The solid was dried under reduced pressure at room 5 temperature.

Yield: 5.2 g (85.4 %), (M++l) 393, 1HNMR (400 MHz, DMSO-J6 ): δ 0.929 ( s, 6H), 1.105 – 1.079 (m, 2H), 1.887-1.641 (m, 21H), 2.030-2.017 (d, 2H), 2.928 (d, 2H).

Method B:

(Is, 4s)-dispiro [cyclohexane-1, 3′-[l,2,4] trioxolane-5′, 2″-tricyclo [3.3.1.I37]

10 decan]-4-ylacetic acid (example 4) (10 g, 31mmol, 1 equiv) was treated with isobutyl chloroformate (4.5 g, 33mmol, 1.1 equiv) in presence of organic base like triethyl amine (5 g, 49.6mmol, 1.6 equiv) at 00C to 7°C in 250ml of dichloromethane. The solution was stirred at O0C to 7°C for aboutlO to 30 minutes. To the above reaction mixture, previously prepared solution of l,2-diamino-2-methylpropane (3.27 g, 37 mmol, 1.2 equiv), in 50 mL of

15 dichloromethane was added at O0C to 7°C in one lot. The temperature of reaction mixture was raised to room temperature. The reaction mixture was stirred at the room temperature till reaction was over. Reaction monitoring was done by thin layer chromatography using 5 to 10% methanol in dichloromethane. Reaction was complete within 2 h. The reaction nitrogen atmosphere was maintained throughout the reaction. Water (250 mL) was charged, organic

20 layer was separated and washed with 10% sodium bicarbonate solution (200 mL) and water (100 mL) at room temperature and the solvent was removed at 25 to 4O0C under reduced pressure. Hexane (100ml) was added to the residue, under stirring, at room temperature. The mixture was filtered and washed with chilled hexane (10 mL). The resultant solid was dried under reduced pressure at room temperature. Yield: 10.63 g (87%), (M++l) 393, 1HNMR

>5 (400 MHz, DMSO-J6 ) :δ 0.928 ( s, 6H), 1.102 – 1.074 (m, 2H), 1.859-1.616 (m, 21H), 2.031- 2.013 (d, 2H), 2.94-2.925 (d, 2H). Method C:

(\s, 4s)-dispiro[cyclohexane-l,3′-[l,2,4]trioxolane-5′,2″-tricyclo[3.3.1.13>7]decan]-4- ylacetic acid (example 4) (5 g, 15.5mmol, 1 equiv) was treated with pivaloyl chloride (1.87 g, 15.5 mmol, 1 equiv) and triethylamine (2.5gm, 24.8mmol, 1.6 equiv) at -15°C to -100C in dichloromethane (125 mL). The solution was stirred at -150C to -100C for aboutlO to 30 minutes. It resulted in the formation of mixed anydride. To the above reaction mixture, previously prepared solution of 1 ,2-diamino-2-methylpropane (1.64 g, 18.6 mmol, 1.2 equiv) in 25 mL dichloromethane was added at -15°C to -100C. The temperature of reaction mixture was raised to room temperature. The reaction mixture was stirred at the room temperature till reaction was over. Reaction monitoring was done by thin layer chromatography using 5 to 10% methanol in dichloromethane. The reaction was complete within 2 h. Nitrogen atmosphere was maintained throughout the reaction. Water (125 mL) was charged, organic layer was separated and washed with 50 mL of 10% sodium bicarbonate solution and 125 mL of water, respectively at room temperature. Finally solvent was removed at 25 to 4O0C under reduced pressure. 50 mL of 5% Ethyl acetate – hexane solvent mixture was added to the residue under stirring at room temperature. The mixture was filtered and washed with 5 mL of chilled hexane. Solid was dried under reduced pressure at room temperature. Yield: 5.03 g (83 %), (M++l) 393, 1JINMR (400 MHz, OMSO-d6 ):δ 0.93 ( s, 6H), 1.113 – 1.069 (m, 2H), 1.861-1.644 (m, 21H), 2.033-2.015 (d, 2H), 2.948-2.933 (d, 2H).

Example 6: Preparation of c/s-adamantane-2-spiro-3′ -8 ‘-πT(2′-amino-2′ -methyl propyl) amino! carbonyl] methyli-l ‘, 2\ 4′-U-JoXaSpJrQ [4.51 decane maleate To a solution of c/s-adamantane-2-spiro-3′-8′-[[[(2′-amino-2′-methyl propyl) amino] carbonyl] methyl]-! ‘, 2′, 4′-trioxaspiro [4.5] decane (example 5) (60 g, 0.153 moles) in ethanol (150 mL) was added a solution of maleic acid (17.3 g, 0.15 moles, 0.98 equiv. in ethanol 90 mL) and the reaction mixture was stirred for about 1 h. To this clear solution, n- heptane (720 mL) was added at room temperature in 1 h and the reaction mixture was stirred for 3 h. It was then cooled to 0 to 100C and filtered. The cake was washed with n-heptane (60 mL) and dried under vacuum at 40-450C.

Yield: 67 g, 77.4%, mp: 1490C (decomp), (M++l) 393.5, 1HNMR (300 MHz, DMSO-^ ): δ 1.05-1.11 (2H,m), 1.18 (6H,s), 1.64-1.89 (21H,m), 2.07(2H,d), 3.21 (2H,d), 6.06 (2H,d), 7.797 (2H, bs), 8.07 (IH, t).

 

References

  1.  Dong, Yuxiang; Wittlin, Sergio; Sriraghavan, Kamaraj; Chollet, Jacques; Charman, Susan A.; Charman, William N.; Scheurer, Christian; Urwyler, Heinrich et al. (2010). “The Structure−Activity Relationship of the Antimalarial Ozonide Arterolane (OZ277)”. Journal of Medicinal Chemistry 53 (1): 481–91. doi:10.1021/jm901473sPMID 19924861.
  2.  Blow to Ranbaxy drug research plans at LiveMint.com, Sep 21 2007
  3.  Vennerstrom, Jonathan L.; Arbe-Barnes, Sarah; Brun, Reto; Charman, Susan A.; Chiu, Francis C. K.; Chollet, Jacques; Dong, Yuxiang; Dorn, Arnulf et al. (2004). “Identification of an antimalarial synthetic trioxolane drug development candidate”. Nature 430 (7002): 900–4.doi:10.1038/nature02779PMID 15318224.
  4.  In the Pipeline: “Ozonides As Drugs: What Will They Think Of Next?”, by Derek Lowe, November 23, 2009, at Corante.com
  5.  Indian company starts Phase III trials of synthetic artemisinin, May 4 2009, at the WorldWide Antimalarial Resistance Network
  6. http://www.nature.com/nature/journal/v430/n7002/full/nature02779.html
5-27-2011
PROCESS FOR THE PREPARATION OF DISPIRO 1,2,4-TRIOXOLANE ANTIMALARIALS (OZ277)
2-13-2009
STABLE DOSAGE FORMS OF SPIRO AND DISPIRO 1,2,4-TRIOXOLANE ANTIMALARIALS
6-15-2005
Spiro and dispiro 1,2,4-trioxolane antimalarials
11-31-2004
Spiro and dispiro 1,2,4-trixolane antimalarials

ANTIMALARIALS

 

 

http://www.rsc.org/chemistryworld/2013/03/new-antimalarial-drug-class-resistance-elq-300-quinolone

 

Antimalarial drugsSpeeding to a new lead

http://www.nature.com/nrd/journal/v9/n11/full/nrd3301.html
Structure of NITD609; the 1R,3Sconfiguration is fundamental for its antimalarial activity

Tafenoquine…..GSK Launches Phase 3 Malaria Drug Trials


Tafenoquine.svg

 

Tafenoquine

N-[2,6-dimethoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]quinolin-8-yl]pentane-1,4-diamine

WR-238605, WR 238605, cas no 106635-80-7,
N(4)-(2,6-Dimethoxy-4-methyl-5-((3-trifluoromethyl)phenoxy)-8-quinolinyl)-1,4-pentanediamine
Molecular Formula: C24H28F3N3O3
 Molecular Weight: 463.49263

Medicines for Malaria Venture  
Walter Reed Army Institute (Originator)  

April 28, 2014
GlaxoSmithKline (GSK) and Medicines for Malaria Venture (MMV) announced the start of a Phase 3 global program to evaluate the efficacy and safety of tafenoquine, an investigational medicine which is being developed for the treatment and relapse prevention (radical cure) of Plasmodium vivax (P. vivax) malaria.

P. vivax malaria, a form of the disease caused by one of several species of Plasmodium parasites known to infect humans, occurs primarily in South and South East Asia, Latin America and the horn of Africa. Severe anemia, malnutrition and respiratory distress are among the most serious consequences described to be caused by the infection.

The Phase 3 program includes two randomized, double-blind treatment studies to investigate tafenoquine in adult patients with P. vivax malaria. The DETECTIVE study (TAF112582) aims to evaluate the efficacy, safety and tolerability of tafenoquine as a radical cure for P. vivax malaria, co-administered with chloroquine, a blood stage anti-malarial treatment. The GATHER study (TAF116564) aims to assess the incidence of hemolysis and safety and efficacy of tafenoquine compared to primaquine, the only approved treatment currently available for the radical cure of P. vivax malaria.

Tafenoquine is not yet approved or licensed for use anywhere in the world.

“P. vivax malaria can affect people of all ages and is particularly insidious because it has the potential to remain dormant within the body in excess of a year, and causes some patients to experience repeated episodes of illness after the first mosquito bite,” said Nicholas Cammack, head, Tres Cantos Medicines Development Center for Diseases of the Developing World.  “Our investigation of tafenoquine for the treatment of P. vivax malaria is part of GSK’s efforts to tackle the global burden of malaria. Working with our partners, including MMV, we are determined to stop malaria in all its forms.”

“One of the big challenges we face in tackling malaria is to have new medicines to prevent relapse, caused by dormant forms of P. vivax,” said Dr. Timothy Wells, MMV’s chief scientific officer. “The Phase 3 program is designed to build upon the promising results of the Phase 2b study which showed that treatment with tafenoquine prevented relapses. If successful, tafenoquine has the potential to become a major contributor to malaria elimination. It’s a great privilege to be working with GSK on this project; they have a clear commitment to changing the face of public health in the countries in which we are working.”

 

 

Tafenoquine succinate, Etaquine, SB-252263, WR-238605

in phase 2

Medicines for Malaria Venture  
Walter Reed Army Institute (Originator)  

Tafenoquine is an 8-aminoquinoline drug manufactured by GlaxoSmithKline that is being investigated as a potential treatment for malaria, as well as for malaria prevention.[1][2]

The proposed indication for tafenoquine is for treatment of the hypnozoite stages of Plasmodium vivax (and also Plasmodium ovale) that are responsible for relapse of these malaria species even when the blood stages are successfully cleared. This is only now achieved by administration of daily primaquine for 14 days. The main advantage of tafenoquine is that it has a long half-life (2–3 weeks) and therefore a single treatment may be sufficient to clear hypnozoites. The shorter regimen has been described as an advantage.[3]

Like primaquine, tafenoquine causes haemolysis in people with G-6-P deficiency.[1] Indeed the long half-life of tafenoquine suggests that particular care should be taken to ensure that individuals with severe deficiency do not receive the drug.

The dose of tafenoquine has not been firmly established, but for the treatment of Plasmodium vivax malaria, a dose of 800 mg over three days has been used.[4]

Synonyms

  • Etaquine[5]
  • WR 238605 [5]
  • SB-252263

………………..

US 4431807

Nitration of 1,2-dimethoxybenzene (XXIX) with HNO3/AcOH gives 4,5-dimethoxy-1,2-dinitrobenzene (XXX), which is treated with ammonia in hot methanol to yield 4,5-dimethoxy-2-nitroaniline (XXXI). Cyclization of compound (XXXI) with buten-2-one (XXXII) by means of H3PO4 and H3AsO4 affords 5,6-dimethoxy-4-methyl-8-nitroquinoline (XXXIII), which is selectively mono-demethylated by means of HCl in ethanol to provide 5-hydroxy-6-methoxy-4-methyl-8-nitroquinoline (XXXIV). Reaction of quinoline (XXXIV) with POCl3 gives the corresponding 5-chloro derivative (XXXV), which is condensed with 3-(trifluoromethyl)phenol (IV) by means of KOH to yield the diaryl ether (XXXVI). Finally, the nitro group of (XXXVI) is reduced by means of H2 over PtO2 in THF or H2 over Raney nickel.

 

 

 

Nitration of 2-fluoroanisole (XXXVII) with HNO3/Ac2O gives 3-fluoro-4-methoxynitrobenzene (XXXVIII), which is reduced to the corresponding aniline (XXXIX) with SnCl2/HCl. Reaction of compound (XXXIX) with Ac2O yields the acetanilide (XL), which is nitrated with HNO3 to afford 5-fluoro-4-methoxy-2-nitroacetanilide (XLI). Hydrolysis of (XLI) with NaOH provides 5-fluoro-4-methoxy-2-nitroaniline (XLII), which is cyclized with buten-2-one (XXXII) by means of As2O5 and H3PO4 to furnish 5-fluoro-6-methoxy-4-methyl-8-nitroquinoline (XLIII). Condensation of quinoline (XLIII) with 3-(trifluoromethyl)phenol (IV) by means of K2CO3 gives the diaryl ether (XXXIV), which is finally reduced by means of H2 over PtO2 in THF.

………………..

US 4617394

Reaction of 8-amino-6-methoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]quinoline (XIV) with phthalic anhydride (XV) affords the phthalimido derivative (XVI), which is oxidized with MCPBA to yield the quinoline N-oxide (XVII). Treatment of compound (XVII) with neutral alumina gives the quinolone derivative (XVIII), which by reaction with POCl3 in refluxing CHCl3 provides the 2-chloroquinoline derivative (XIX). Alternatively, reaction of the quinoline N-oxide (XVII) with POCl3 as before also gives the 2-chloroquinoline derivative (XIX) The removal of the phthalimido group of compound (XIX) by means of hydrazine in refluxing ethanol gives the chlorinated aminoquinoline (XX), which is finally treated with MeONa in hot DMF.

……………….

US 6479660; WO 9713753

Chlorination of 6-methoxy-4-methylquinolin-2(1H)-one (I) with SO2Cl2 in hot acetic acid gives the 5-chloro derivative (II), which is nitrated with HNO3 in H2SO4 to yield the 8-nitroquinolinone (III). Condensation of compound (III) with 3-(trifluoromethyl)phenol (IV) by means of KOH in NMP provides the diaryl ether (V), which is treated with refluxing POCl3 to afford the 2-chloroquinoline (VI). Reaction of compound (VI) with MeONa in refluxing methanol results in the 2,6-dimethoxyquinoline derivative (VII), which is reduced with hydrazine over Pd/C to give the 8-aminoquinoline derivative (VIII). Condensation of aminoquinoline (VIII) with N-(4-iodopentyl)phthalimide (IX) by means of diisopropylamine in hot NMP yields the phthalimido precursor (X), which is finally cleaved with hydrazine in refluxing ethanol.

 

Reaction of 1,4-dibromopentane (XI) with potassium phthalimide (XII) gives N-(4-bromopentyl)phthalimide (XIII), which is then treated with NaI in refluxing acetone.

 

 

Reaction of 4-methoxyaniline (XXI) with ethyl acetoacetate (XXII) by means of triethanolamine in refluxing xylene gives the acetoacetanilide (XXIII), which is cyclized by means of hot triethanolamine and H2SO4 to yield 6-methoxy-4-methylquinolin-2(1H)-one (I), which is treated with refluxing POCl3 to provide 2-chloro-6-methoxy-4-methylquinoline (XXIV). Reaction of compound (XXIV) with SO2Cl2 in hot AcOH affords 2,5-dichloro-6-methoxy-4-methylquinoline (XXV), which is treated with MeONa in refluxing methanol to furnish 5-chloro-2,6-dimethoxy-4-methylquinoline (XXVI). Alternatively, the reaction of compound (XXIV) with MeONa as before gives 2,6-dimethoxy-4-methylquinoline (XXVII), which is treated with SO2Cl2 in hot AcOH to give the already described 5-chloro-2,6-dimethoxy-4-methylquinoline (XXVI). Nitration of compound (XXVI) with KNO3 and P2O5 gives the 8-nitroquinoline derivative (XXVIII), which is condensed with 3-(trifluoromethyl)phenol (IV) by means of KOH in hot NMP to yield the diaryl ether (VII). Finally, the nitro group of compound (VII) is reduced with hydrazine over Pd/C.

 

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J Med Chem 1989,32(8),1728-32

 

Synthesis of the intermediate diazepinone (IV) is accomplished by a one-pot synthesis. Condensation of 2-chloro-3-aminopyridine (I) with the anthranilic ester (II) is effected in the presence of potassium tert-butoxide as a catalyst. The resulting anthranilic amide (III) is cyclized under the influence of catalytic amounts of sulfuric acid. Treatment of (IV) with chloroacetylchloride in toluene yields the corresponding choroacetamide (V). The side chain of AQ-RA 741 is prepared starting from 4-picoline, which is alkylated by reaction with 3-(diethylamino)propylchloride in the presence of n-butyllithium. Hydrogenation of (VIII) using platinum dioxide as a catalyst furnishes the diamine (IX), which is coupled with (V) in the presence of catalytic amounts of sodium iodide in acetone leading to AQ-RA 741 as its free base.

  1.  Shanks GD, Oloo AJ, Aleman GM et al. (2001). “A New Primaquine Analogue, Tafenoquine (WR 238605), for prophylaxis against Plasmodium falciparum malaria”. Clin Infect Dis 33 (12): 1968–74. doi:10.1086/324081JSTOR 4482936.PMID 11700577.
  2. Lell B, Faucher JF, Missinou MA et al. (2000). “Malaria chemoprophylaxis with tafenoquine: a randomised study”.Lancet 355 (9220): 2041–5. doi:10.1016/S0140-6736(00)02352-7PMID 10885356.
  3.  Elmes NJ, Nasveld PE, Kitchener SJ, Kocisko DA, Edstein MD (November 2008). “The efficacy and tolerability of three different regimens of tafenoquine versus primaquine for post-exposure prophylaxis of Plasmodium vivax malaria in the Southwest Pacific”Transactions of the Royal Society of Tropical Medicine and Hygiene 102 (11): 1095–101.doi:10.1016/j.trstmh.2008.04.024PMID 18541280.
  4.  Nasvelda P, Kitchener S. (2005). “Treatment of acute vivax malaria with tafenoquine”. Trans R Soc Trop Med Hyg 99 (1): 2–5. doi:10.1016/j.trstmh.2004.01.013PMID 15550254.
  5.  Peters W (1999). “The evolution of tafenoquine–antimalarial for a new millennium?”. J R Soc Med 92 (7): 345–352.PMID 10615272.
  6. J Med Chem 1982,25(9),1094

 

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CDRI planning to launch Phase-1 trials on 2 candidate drugs to fight malaria, diabetes


 

 

CDRI LUCKNOW INDIA

http://www.cdriindia.org/home.asp

 

CDRI planning to launch Phase-1 trials on 2 candidate drugs to fight malaria, diabetes

pharmabiz.com

The Central Drug Research Institute (CDRI), the public sector premier institution for drug discovery, will soon start Phase 1 clinical trials of a candidate …

Joseph Alexander, New Delhi
Monday, April 14, 2014, 08:00 Hrs  [IST]

The Central Drug Research Institute (CDRI), the public sector premier institution for drug discovery, will soon start Phase 1 clinical trials of a candidate drug against malaria and another one to fight diabetes.

The institute has developed and licensed the anti-hyperglycemic candidate drug (CDR134F194) to TVC Sky Shop Ltd., Mumbai. The process of formulation of the drug in a GMP certified company is in progress. The single dose and multi-dose Phase- I clinical trial will be initiated soon at KEM Hospital & Seth GS Medical College in Mumbai. The permission for the trials was already given by the Drugs Controller General of India (DCGI), sources said.

Another candidate drug developed by the CDRI and waiting for the trials is in the therapeutic area of malaria. The single dose pharmacokinetic study in healthy volunteers as per revised protocol approved by DCGI was completed at PGIMER, Chandigarh for the CDRI compound 97/78 (Anti-malarial agent).  A total of 16 volunteers completed the trial. The blood samples were analysed inthe Pharmacokinetics & Metabolism division and the final report on single dose pharmacokinetic study submitted to IPCA, Mumbai.

http://www.pharmabiz.com/NewsDetails.aspx?aid=81386&sid=1

 

Glaxo Plans to File for Malaria Vaccine Approval Next Year


Malaria vaccine candidate reduces disease over 18 months of follow-up in late-stage study of more than 15,000 infants and young children

Malaria is a significant public health burden, claiming 660,000 lives a year – mostly children in sub-Saharan Africa
-Data support plan to submit regulatory application in 2014

Multilateral Initiative on Malaria Pan African Conference, Durban, South Africa — Results from a large-scale Phase III trial, presented today in Durban, show that the most clinically advanced malaria vaccine candidate, RTS,S, continued to protect young children and infants from clinical malaria up to 18 months after vaccination. Based on these data, GSK now intends to submit, in 2014, a regulatory application to the European Medicines Agency (EMA). The World Health Organization (WHO) has indicated that a policy recommendation for the RTS,S malaria vaccine candidate is possible as early as 2015 if it is granted a positive scientific opinion by EMA.

READ ALL AT

http://www.pharmalive.com/glaxo-plans-to-file-for-malaria-vaccine-approval-next-year

 

DRUG DISCOVERY PRESENTATION BY DR ANTHONY CRASTO


 

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